the term &# 34 ; alkyl &# 34 ; includes both straight and branched chain radicals of up to 12 carbons , preferably 1 to 4 carbons , such as methyl , ethyl , propyl , isopropyl , butyl , t - butyl , isobutyl , pentyl , hexyl , isohexyl , heptyl , 4 , 4 - dimethylpentyl , octyl , 2 , 2 , 4 - trimethylpentyl , nonyl , decyl , undecyl , dodecyl , the various branched chain isomers thereof and the like , which may be substituted with one or two trifluoromethyl , halo or hydroxyl groups . the term &# 34 ; cycloalkyl &# 34 ; includes saturated cyclic hydrocarbon groups containing 3 to 12 carbons , preferably 3 to 8 carbons , which include cyclopropyl , cyclobutyl , cyclopentyl , cyclohexyl , cycloheptyl , cyclooctyl , cyclodecyl and cyclododecyl . the term &# 34 ; aryl &# 34 ; or &# 34 ; ar &# 34 ; refers to monocyclic or bicyclic aromatic groups containing from 6 to 10 carbons in the ring portion , such as phenyl and naphthyl , which may include 1 or 2 substituents on either the phenyl or naphthyl such as alkyl , trifluoromethyl , halogen ( cl , br , i or f ), alkoxy , arylalkoxy , hydroxy , alkylthio , alkylsulfinyl , alkylsulfonyl , phenylthio , phenylsulfinyl and / or phenylsulfonyl . the term &# 34 ; aralkyl &# 34 ; refers to alkyl groups as discussed above having an aryl substituent , such as benzyl . the terms &# 34 ; alkoxy &# 34 ; and &# 34 ; aralkoxy &# 34 ; refer to the above alkyl and aralkyl groups linked to an oxygen atom . the term &# 34 ; halogen &# 34 ; or &# 34 ; halo &# 34 ; refers to chlorine , bromine , fluorine or iodine , with chlorine being preferred . the term &# 34 ; alkenyl &# 34 ; as employed herein with respect to the r 1 substituent includes a carbon chain of up to 12 carbons , preferably 3 to 10 carbons , having at least one double bond , which will be separated from &# 34 ; n &# 34 ; by at least one saturated carbon moiety such as --( ch 2 ) q -- where q can be 1 to 14 , such as 2 - propenyl , 2 - butenyl , 3 - butenyl , 2 - pentenyl , 4 - pentenyl and the like , and may include a halogen substituent such as i , cl , or f . the term &# 34 ; alkynyl &# 34 ; as employed herein with respect to the r 1 substituent includes a carbon chain of up to 16 carbons , preferably 3 to 10 carbons , having at least one triple bond , which will be separated from &# 34 ; n &# 34 ; by at least one saturated carbon moiety such as --( ch 2 ) q -- wherein q can be 1 to 14 , such as 2 - propynyl , 2 - butynyl , 3 - butynyl and the like . the term &# 34 ; cycloheteroalkyl &# 34 ; as used herein as an r 1 substituent refers to 5 -, 6 - or 7 - membered saturated rings that include 1 or 2 heteroatoms such as nitrogen , oxygen and / or sulfur , and which are linked to the &# 34 ; n &# 34 ; of the ## str7 ## group through a carbon atom either beta or gamma to a heteroatom , such as ## str8 ## and the like . the term &# 34 ; heteroaryl &# 34 ; or &# 34 ; heteroaromatic &# 34 ; as an r 1 substituent refers to 5 - or 6 - membered aromatic rings that include 1 or 2 heteroatoms such as nitrogen , oxygen or sulfur , which are not directly linked through a heteroatom to the &# 34 ; n &# 34 ; of the ## str9 ## group , such as ## str10 ## and the like . the term &# 34 ; cycloheteroalkylalkyl &# 34 ; as used herein with respect to r 1 refers to 5 - , 6 - or 7 - membered saturated rings that include 1 to 2 heteroatoms such as nitrogen , oxygen or sulfur , and are linked to the &# 34 ; n &# 34 ; of the ## str11 ## group through a ( ch 2 ) x chain wherein x is 1 to 12 , preferably 1 to 8 , such as ## str12 ## and the like . the term &# 34 ; heteroarylalkyl &# 34 ; as used herein with respect to r 1 refers to 5 -, 6 - or 7 - membered aromatic rings that include 1 to 4 nitrogen and / or 1 or 2 oxygen or sulfur atoms , and is linked to the &# 34 ; n &# 34 ; of the ## str13 ## group through a --( ch 2 ) x -- chain where x is 1 to 12 , preferably 1 to 8 , such ## str14 ## and the like . compounds of the invention wherein y is a single bond and x is n are prepared starting with bromophenylalkyl alcohol a ## str15 ## wherein n is 1 , 2 , 3 or 4 . compound a is treated with a protecting compound ( e . g ., t - butylchlorodiphenylsilane ) in the presence of an amine base ( e . g ., triethylamine ) and an inert solvent , employing conventional procedures , to form the protected bromophenylalkyl compound b ## str16 ## wherein pro represents a protecting group . of protecting compounds suitable for use herein in reacting with bromophenalkyl alcohol a include but are not limited to ## str17 ## the protected compound b then undergoes a metal - halogen exchange reaction by treatment with , for example , t - c 4 h 9 li or n - c 4 h 9 li in the presence of diethyl ether or tetrahydrofuran ( thf ) at about - 100 ° to about 0 ° c ., or is preferably subjected to a grignard reaction by treatment with magnesium in the presence of an inert organic solvent ( e . g ., thf or diethyl ether ) and then is condensed with ( exo ) octahydro - 5 , 8 - epoxy - 1h - benzopyran - 3 - ol or ( exo ) octahydro - 4 , 7 - epoxyisobenzofuran - 1 - ol ( prepared as described in u . s . pat . no . 4 , 143 , 054 or in patel et al ., &# 34 ;( exo , exo )- 7 - oxabicyclo [ 2 . 2 . 1 ] heptane - 2 , 3 - dimethanol , monoacyl ester , diacyl ester and enzymatic hydrolysis thereof &# 34 ;, u . s . ser . no . 629 , 780 , filed dec . 18 , 1990 ) of the structure c ## str18 ## employing a molar ratio of c : b from about 1 : 2 to about 1 : 4 , in the presence of an inert organic solvent such as thf at about - 78 ° to about 25 ° c . to form the condensed 7 - oxabicycloheptane compound ## str19 ## the condensed compound ii is then subjected to hydrogenolysis by treatment with hydrogen in hydroxide on charcoal ) in acetic acid or an inert organic solvent ( e . g ., ethyl acetate ) to form the alcohol ## str20 ## when the protecting group ( pro ) in alcohol iii is thexyldimethylsilyl or t - butyldimethylsilyl , alcohol iii may be reacted with an acetylating agent ( e . g ., acetic anhydride ) in the presence of pyridine and dimethylamnopyridine ( dmap ) to form ## str21 ## acetylated compound iv is then reacted with jones reagent ( see fieser and fieser , reagents in organic synthesis , vol . 1 , p . 242 ) at about - 10 ° to 10 ° c . in acetone to form an acetate - acid ## str22 ## the acetate - acid v is reacted with an aqueous alkali metal hydroxide in tetrahydrofuran to form an alcohol - acid ## str23 ## alcohol - acid vi ( or acetate - acid v ) is then esterified with a solution of acid in alcohol ( e . g ., hcl / ch 3 oh ) at about - 10 ° to 10 ° c . to form an alcohol ester ## str24 ## alcohol - ester vii is oxided with jones reagent at about - 10 ° to 10 ° c . in acetone to form an acid - ester ## str25 ## acid - ester viii reacts with hydrazine or hydrazine hydrochloride in an organic solvent ( e . g ., dimethylformamide ) in the presence of a coupling reagent such as 1 -( 3 - dimethylaminopropyl )- 3 - ethylcarbodiimide hydrochloride ( wsc ) or dicyclohexylcarbodiimide ( dcc ) and the catalyst hydroxybenzotriazole ( hobt ) hydrate and an amine base ( e . g ., n - methylmorpholine ) at about 20 ° to 30 ° c . under an inert atmosphere ( e . g ., argon ) to form a hydrazide ## str26 ## hydrazide ix reacts with the thioamide ## str27 ## in an organic solvent ( e . g ., methanol ) under an inert atmosphere ( e . g ., argon ) in the presence of sodium methoxide to form a thioamide ## str28 ## thioamide d may be derived from 2 , 2 - aminothioethanoic acid , ethyl ester , which is prepared as described in boon , w . r ., j . chem . soc . ( 1945 ), 601 and oliver , j . e . and sonnet , p . e . j . org . chem . 38 ( 1973 ), 1437 . this ester is reacted with an amine reagent hnr 1 r 2 , ( e . g ., 4 - cyclohexylbutylamine ) to form thioamide d . analogous preparations are described in weddige , a ., j . pract . chem ., 9 ( 1874 ), 132 ; walter , w . and bode , k . d ., liebigs ann . chem ., 660 ( 1962 ), 74 . compound x undergoes cyclodehydration by heating to about 180 ° to 220 ° c . under high vacuum to form compound i wherein y is a single bond , x is nh , r is co 2 r &# 39 ; and r &# 39 ; is alkyl . these thioamide coupling and cyclodehydration steps are analogous to procedures described in t . vanek et al ., coll . czech . chem . comm ., 49 ( 1984 ), 2492 . alternatively , when x is o , compound viii is converted to its acid chloride at about 0 to 30 ° c . under an inert atmosphere ( e . g ., argon ) in an organic solvent ( e . g ., toluene ) in the presence of oxalyl chloride and optionally in the presence of dmf . the acid chloride is then reacted with a hydroxyamide ## str29 ## in the presence of a base ( e . g ., pyridine ) in an organic solvent ( e . g ., chloroform ) under an inert atmosphere ( e . g , argon ) at about 0 to 30 ° c . to form ## str30 ## compound xi undergoes cyclodehydration as described for compound x to form compound i wherein x is o , y is a single bond , r is co 2 r &# 39 ; and r &# 39 ; is alkyl . analogous preparations are found in hennen , w . j . and robins , r . k ., j . het . chem ., 22 ( 1985 ), 1747 ; european patent application 239 , 309 ; and ruccia , m . and vivona , n ., ann . chim . ( rome ), 58 ( 1968 ), 484 . hydroxyamide e is prepared by reacting thioamide d with hydroxyamine in methanol solution at about 20 ° to 30 ° c . under an inert atmosphere such as argon . compounds of the invention wherein y is o may be prepared as follows . bromophenol a 1 ## str31 ## is treated with bromomethyl methyl ether to form the compound ## str32 ## compound b 1 is metallated ( using a procedure similar to that set out above with respect to metal - halogen exchange of b using n - butyllithium in thf ) and condensed with hemiacetal c to form the condensed 7 - oxabicycloheptane compound ## str33 ## the condensed compound xii is then subjected to hydrogenolysis by treatment with hydrogen in the presence of a catalyst such as palladium on charcoal in acetic acid , to form the alcohol ## str34 ## compound xiii is deprotected by treatment with , for example , a solution of methanol and aqueous hydrochloric acid to form the deprotected alcohol ## str35 ## the alcohol xiv is then deprotonated by treating a solution of alcohol xiv in tetrahydrofuran with a molar equivalent of sodium hydride or one to four equivalents of a carbonate base such as potassium carbonate . the resulting phenoxide solution is alkylated by treating with a haloalkanoic acid ester employing a molar ratio of f : xiv of about 1 : 1 to 3 : 1 in the presence of an inert organic solvent ( e . g ., thf , dimethylformamide or dimethoxyethane ) to form ester ## str36 ## alcohol ester xv is treated as described above for compound vii to form compound i wherein y is -- o --. compounds of formula i wherein y is -- ch ═ ch -- may be prepared starting with alcohol a wherein n is 2 , which may be prepared by subjecting the aldehyde ## str37 ## a wittig reaction with ( c 6 h 5 ) 3 pchco 2 ch 3 to form ester ## str38 ## ester h undergoes a double bond reduction by treatment with hydrogen in the presence of rhodium on alumina catalyst in the presence of methanol to form ester ## str39 ## ester h 1 is then reduced by treatment with diisobutyl - aluminum hydride in the presence of toluene solvent to form alcohol a wherein n is 2 . alcohol a is used as described previously herein to form alcohol - ester vii wherein n is 2 , which is treated with a silane protecting compound as described hereinbefore in the presence of an amine base ( e . g ., triethylamine ) and an inert solvent ( e . g ., methylene chloride ) and n , n - dimethylaminopyridine ( dmap ) to form the protected alcohol ## str40 ## the protected alcohol xvi is then treated with lithium diisopropylamide in tetrahydrofuran solution at low temperature (- 78 ° to 0 ° c .) under an inert atmosphere ( e . g ., argon ). the resulting mixture is treated with diphenyl diselenide at about - 78 ° to 25 ° c ., to form the corresponding selenide ## str41 ## selenide xvii in an inert organic solvent ( e . g ., ethyl acetate and / or methanol ) is treated with an oxidizing agent ( e . g ., aqueous hydrogen peroxide ) to form the cinnamate ## str42 ## the protecting group is removed from cinnamate xviii by treatment with a solution of hydrogen chloride in methanol to form the alcohol ## str43 ## which may then be employed to form compounds of formula i wherein y is -- ch ═ ch -- employing procedures described for treatment of alcohol - ester vii . the compounds of formula i wherein z is -- ch ═ ch -- or --( ch 2 ) 2 -- may be prepared as follows . compounds of the invention where z is -- ch ═ ch -- and preferably in the cis form , and x is o are prepared starting with the hydroxymethyl compound ## str44 ## which is prepared as described in u . s . pat . no . 4 , 143 , 054 . compound xx is subjected to a jones oxidation with jones &# 39 ; reagent ( cro 3 dissolved or suspended in aqueous sulfuric acid , prepared as described in fieser & amp ; fieser , reagents for organic synthesis , vol i , p . 142 ( 1967 )) in the presence of acetone under an inert atmosphere ( e . g ., argon ) at about - 10 ° to 20 ° c . to form the corresponding carboxylic acid - ester ## str45 ## acid - ester xxi is then reacted as described above for compounds viii → ix → x → i ( or viii → xi → i ) to form compound i wherein z is -- ch ═ ch --. the trans double bond isomer wherein z is -- ch ═ ch -- in formula i may be prepared starting with hydroxymethyl compound xx , which includes a cis double bond . compound xx is treated with a protecting compound such as t - butyldimethylsilyl chloride or other silyl protecting group as described hereinbefore in the presence of imidazole or triethylamine and an inert organic solvent such as methylene chloride or tetrahydrofuran , to form the protected compound ## str46 ## a solution of the protected alcohol in an inert organic solvent such as methylene chloride or acetone is treated with excess ozone at reduced temperature ( about - 78 ° to - 60 ° c .) followed by treatment with dimethyl sulfide ( molar ratio of xxii :( ch 3 ) 2 s of about 0 . 01 : 1 to 0 . 2 : 1 ), to form the aldehyde ## str47 ## aldehyde xxiii is then treated with a mixture of lithium bromide or lithium chloride and trimethylphosphonoacetate and triethylamine in an inert organic solvent such as methylene chloride or chloroform to form the ester ## str48 ## a solution of ester xxiv in an inert organic solvent ( e . g ., tetrahydrofuran , diethyl ether or dimethyoxyethane ) is cooled to about - 78 ° to 0 ° c . and reacted with diisobutylaluminum hydride in an aromatic solvent such as toluene for about 0 . 5 to 4 hours to form alcohol ## str49 ## alcohol xxv is treated with bromotriphenylphosphonium bromide ( formed by adding bromine to triphenylphosphine in toluene or other aromatic solvent under argon at about - 10 ° to 10 ° c .) in the presence of pyridine and toluene , at about - 10 ° to 10 ° c . to form bromide ## str50 ## an acetic acid ester such as t - butyl acetate or ethyl acetate is treated with a solution of lda ( lithium diisopropylamide ) in an inert organic solvent such as tetrahydrofuran and at about - 78 ° to - 60 ° c . for about 0 . 5 to 2 hours , followed by addition of a solution of bromide xxvi in an inert solvent such as tetrahydrofuran to form ester ## str51 ## wherein n is 2 . for compounds of the invention wherein z is -- ch ═ ch -- in the trans form and n is 1 , 3 , or 4 , aldehyde xxiii is allowed to react with a phosphonium salt of formula ## str52 ## in the presence of a strong base such as potassium t - amylate in toluene or nah / dimethylsulfoxide to give ## str53 ## which is oxidized and esterified using procedures known in the art to form ester xxvii wherein n is 1 , 3 or 4 . ester xxvii is then deprotected by treatment in methanol under an inert atmosphere such as argon with hydrochloric acid in methanol ( prepared by adding acetyl chloride to methanol ) to form alcohol ## str54 ## alcohol xxix may then be used in place of compound xx as a starting material following the procedure hereinbefore described to form compound i wherein z is -- ch ═ ch -- in the trans double bond isomeric form . compounds of formula i wherein z is --( ch 2 ) 2 -- may be prepared from the corresponding acids wherein z is -- ch ═ ch -- by hydrogenation using , for example , a hydrogenation catalyst ( e . g ., palladium on carbon ) in an inert organic solvent ( e . g ., ethyl acetate or acetic acid ). compounds of the invention wherein n is 0 , z is phenylene , and y is a single bond may be prepared starting with a bromobenzyl alcohol ## str55 ## which is treated with a protecting compound ( e . g ., t - butylchlorodiphenylsilane ) in the presence of 4 - dimethylaminopyridine and an amine base ( e . g ., triethylamine ) in an inert solvent ( e . g ., methylene chloride ) to form the protected bromobenzyl compound ## str56 ## wherein pro represents a protecting group . examples of protecting compounds suitable for use herein are as set out hereinbefore in reacting with bromophenalkyl alcohol a , with the exclusion of benzyl bromide . the protected compound b 2 is metallated by treatment with t - c 4 h 9 li or n - c 4 h 9 li in the presence of diethyl ether or thf at about - 100 ° to 0 ° c . or is subjected to a grignard reaction by treatment with magnesium in the presence of an inert organic solvent such as thf or diethyl ether . the so - treated compound b 2 is then condensed with compound c in a c : b 2 molar ratio of about 1 : 2 to 1 : 4 in the presence of an inert organic solvent such as thf at about - 78 ° to 25 ° c . to form a condensed 7 - oxabicycloheptane compound ## str57 ## compound xxx is then protected by treatment with , for example , a solution of acetic anhydride and pyridine in the presence of 4 - dimethylaminopyridine to form compound ## str58 ## the protected alcohol xxxi is then deprotected using conventional procedures , and the resulting alcohol is subjected to a jones oxidation employing procedures described hereinbefore to form a crude acid . the crude acid is deacetylated by reaction with aqueous hydroxide in the presence of an inert organic solvent such as thf and then esterified , for example , by treatment with a diazoalkane ( e . g ., diazomethane ) or acidic alcohol , to form the alcohol ester ## str59 ## the alcohol ester xxxii is then subjected to hydrogenolysis as described above to provide the alcohol ester ## str60 ## next , the alcohol ester xxxiii is subjected to a jones oxidation to form the acid ester ## str61 ## acid ester xxxiv is treated as described above for compound viii to form compound i wherein z is phenylene , y is a single bond , and n is o . compounds of formula i wherein r is co 2 r &# 39 ; and r &# 39 ; is alkali metal can be prepared from the corresponding esters by treating the ester with bases such as lithium hydroxide or potassium hydroxide . the corresponding acids ( wherein r &# 39 ; is hydrogen ) are prepared by neutralizing the foregoing alkali metal salts with an acid ( e . g ., dilute hydrochloric acid or oxalic acid ). compounds of formula i wherein r is -- ch 2 oh may be prepared by treating the corresponding esters ( wherein r is co 2 r &# 39 ; and r &# 39 ; is alkyl ) with a reducing agent such as libh 4 in the presence of diethyl ether and thf . compounds of the invention wherein r is conhso 2 r 3 are prepared by treating the associated acids ( wherein r is co 2 h ) with a sulfonamide ## str62 ## in the presence of a coupling agent ( e . g ., dicyclohexylcarbonyldiimide or wsc ) in the presence of dimethylaminopyridine under an inert atmosphere ( e . g ., argon ). compounds wherein r is -- ch 2 - 5 - tetrazolyl are prepared by reacting the associated ester with , in sequence , ( 1 ) a hydride reducing reagent ( e . g ., lithium borohydride or sodium borohydride ), ( 2 ) triphenylphosphonium dibromide in an inert solvent such as toluene , ( 3 ) an alkali metal cyanide in a polar solvent such as methanol / water , and ( 4 ) sodium azide in the presence of ammonium chloride , dmf and lithium chloride at about 100 to 130 ° c . compounds of formula i wherein r is conhr 4 wherein r 4 is other than hydrogen may be prepared from the corresponding acid by treatment with wsc in the presence of dmf , hobt , an organic base ( e . g ., triethylamine ) and an amine where r 4 is hydrogen , ammonium chloride is used in place of the above amine . the compounds of this invention have four centers of asymmetry as indicated by the asterisks in formula i . however , it will be apparent that each of the formulae set out above which do not include asterisks still represent all of the possible stereoisomers thereof . all of the various stereoisomeric forms are within the scope of the invention . the various stereoisomeric forms of the compounds of the invention , namely , cis - exo , cis - endo and all trans forms and stereoisomeric pairs may be prepared with starting materials and procedures in u . s . pat . no . 4 , 143 , 054 . the nucleus in each of the compounds of the invention is depicted as ## str63 ## for convenience ; the nucleus may also be depicted as ## str64 ## the compounds of this invention are thromboxane receptor antagonists and as such are useful as inhibitors of thromboxane receptor mediated actions . the term &# 34 ; thromboxane receptor antagonist &# 34 ; includes compounds that are so - called thromboxane a 2 receptor antagonists , thromboxane a 2 antagonists , thromboxane a 2 / prostaglandin endoperoxide antagonists , tp - receptor antagonists , or thromboxane antagonists . the compounds of the invention are also thromboxane synthetase inhibitors and thus are useful as inhibitors of thromboxane production . the compounds of this invention are useful as inhibitors of platelet function , i . e ., for the prevention and treatment of thrombotic vascular occlusive disorders , whether complete or partial , for example , arterial thrombosis , including that of the coronary , cerebral , ophthalmic , hepatic , mesenteric , renal , peripheral arteries or vascular or organ grafts , unstable angina , transient ischemic attacks , or intermittent claudication . they may be useful to prevent thrombosis following vascular injury produced in the course of diagnostic or therapeutic procedures such as endarterectomy or angiography . the compounds may be useful in the treatment or prevention of disorders characterized by platelet consumption and / or activation , including , platelet activation , dysfunction , and / or loss during extracorporeal circulation , the use of radiographic contrast agents , thrombotic thrombocytopenia purpura , disseminated intravascular coagulation , purpura fulminans , hemolytic transfusion reaction , or hemolytic uremic syndrome , systemic lupus , cyclosporine - induced renal toxicity , pulmonary hypertension , side effects from dialysis , or abdominal aortic aneurism repair . the compounds may be used in the treatment of venous thrombosis or embolism , including pulmonary embolism , deep venous thrombosis , hepatic vein thrombosis , and renal vein thrombosis . the compounds of this invention are useful as inhibitors of arterial or venous vasoconstriction . accordingly , they may be useful to prevent vasoconstriction associated with unstable angina , chronic stable angina , and variant , or prinzmetal &# 39 ; s angina , raynaud &# 39 ; s syndrome , migraine headache , vasospasm of the coronary , cerebral , ophthalmic , hepatic , mesenteric , renal , peripheral arteries or vascular grafts , vascular injury such as that associated with surgery or trauma . hypertension of pregnancy , the hepato - renal syndrome , and pulmonary hypertension are additional examples of vasoconstrictive disorders treatable by the compounds of this invention . the compounds of this invention are useful as inhibitors of bronchoconstriction , i . e ., airway hyperresponsiveness , allergic bronchospasm , asthma , and bronchoconstrictive responses to environmental , infectious , noxious or mechanical stimuli . the compounds of this invention are useful as inhibitors of ischemic and reperfusion injury to various tissues , including , myocardium , skin , brain , bowel , or kidney , alone or in combination with other agents intended to restore blood flow . for example , these compounds may be useful for improving postischemic myocardial function and decreasing myocardial infarct size . ischemia caused by reduced blood flow during diagnostic or therapeutic procedures may benefit by treatment with these compounds , for example , they reduce the myocardial stunning observed after bypass surgery . in addition , they may be useful for reducing the tissue injury caused by a stroke . the compounds of this invention may be useful in the prevention or treatment of other conditions including burns , diabetic retinopathy , tumor metastases and tardive dyskinesia . the compounds may be useful in potentiating diuretic - induced diuresis . in addition , the thromboxane receptor antagonists of the invention may be used with a thrombolytic agent such as t - pa , streptokinase , urokinase , prourokinase or anisoylated plasminogenstreptokinase activator complex ( apsac ) within 6 hours of a myocardial infarction . in such case , the thrombolytic agent may be used in amounts conventionally employed , for example , as disclosed in the physicians &# 39 ; desk reference for reducing post - ischemic myocardial injury . the compounds of the invention can be administered orally or parenterally to various mammalian species known to be subject to such maladies , e . g ., humans , cats , dogs and the like in an effective amount within the dosage range of about 0 . 1 to about 100 mg / kg , preferably about 0 . 2 to about 50 mg / kg and more preferably about 0 . 5 to about 25 mg / kg ( or from about 1 to about 2500 mg , preferably from about 5 to about 2000 mg ) on a regimen in single or 2 to 4 divided daily doses . the active substance can be utilized in a composition such as tablet , capsule , solution or suspension containing about 5 to about 500 mg per unit of dosage of a compound or mixture of compounds of formula i or in topical form for wound healing ( 0 . 01 to 5 % by weight compound of formula i , 1 to 5 treatments per day ). they may be compounded in conventional matter with a physiologically acceptable vehicle or carrier , excipient , binder , preservative , stabilizer , flavor , etc ., or with a topical carrier such as plastibase ( mineral oil gelled with polyethylene ) as called for by accepted pharmaceutical practice . also as indicated in the discussion above , certain members additionally serve as intermediates for other members of the group . the compounds of the invention may also be administered topically to treat peripheral vascular diseases and as such may be formulated as a cream or ointment . the following examples represent preferred embodiments of the present invention . unless otherwise indicated , all temperatures are expressed in degrees celsius . to a stirred solution of 161 . 2 g ( 871 mmol ) of 2 - bromobenzaldehyde in 700 ml of dry thf ( distilled from potassium / benzophenone ) at room temperature under argon , was added 298 . 4 g ( 892 mmol , 1 . 024 equiv ) of methyl ( triphenylphosphoranylidene ) acetate ( aldrich ) over 1 hour in 20 g portions . reaction was mildly exothermic and the mixture became homogeneous . the resulting solution was stirred for 18 hours during which some precipitate formed . addition of 200 ml hexane caused further precipitation . filtration was followed by evaporation . the residue was slurried with a large volume of hexane ( more precipitation ) and refrigerated overnight . this was filtered , and the filtrate was passed through a plug of silica gel ( approximately 1 kg ), eluting with 10 % ethyl acetate ( etoac ) in hexane . the eluant was concentrated in vacuo to give 201 . 5 g of a colorless oil . this oil was pure title compound as a 4 : 1 mixture of double bond isomers ( trans predominating ). the yield of title compound was 96 %. a mixture of 201 . 5 g ( 836 mmol ) of the part a acrylate and 8 . 4 g of 5 % rhodium on alumina catalyst ( mcb ) in 1 . 0 l of methanol was stirred at room temperature under an atmosphere of hydrogen ( balloon ) for over 8 hours . 1 h nmr analysis of an aliquot showed about a 1 : 1 mixture of title compound and trans part a compound with no cis part a compound . the mixture was diluted with 500 ml additional methanol ( meoh ) and 12 . 6 g more catalyst was added . after hydrogenation overnight , the reaction was complete . the reaction mixture was passed through celite and a millipore / fluropore membrane filter ( 0 . 5 μm fh ) with a prefilter pad , and the filtrate was concentrated in vacuo to obtain two immiscible oils . one of the oils was water - soluble and gave a highly acid aqueous solution . solid nahco 3 and na 2 so 4 were carefully added ( gas was evolved ). the mixture was diluted with ch 2 cl 2 , filtered , and evaporated ( and re - evaporated with ch 2 cl 2 to drive off methanol ) to obtain 196 . 9 g of clear oil . this oil was 95 % pure title compound with 5 % of dibromo title compound . the corrected yield of the title compound was 92 % ( 187 . 1 g ). to a stirring solution of 196 . 9 g ( 95 % pure = 187 . 1 g , 770 mmol ) of compound b in 770 ml of toluene under argon cooled to 0 ° c . ( ice bath ), 830 ml of 1 . 0m diisobutylaluminum hydride ( dibal - h ) in toluene solution ( 830 mmol , aldrich ) was added over 45 minutes . the reaction was not very exothermic . after the mixture was stirred for 1 hour , tlc indicated approximately half of the starting material remained . next , 580 ml of 1 . 5m dibal - h in toluene solution ( 870 mmol , aldrich ) was added slowly . the ice bath was removed and stirring was continued for 2 hours . the mixture was then poured slowly into 1 . 2 l of 6m aqueous hcl stirring in an ice bath . this quench was exothermic and gas was evolved . after the mixture was recooled to 0 °, the layers were separated , and the organic layer was washed with 1m aqueous hcl and brine . it was then dried over na 2 so 4 and mgso 4 and evaporated ( and re - evaporated with ch 2 cl 2 to drive off toluene ) to obtain 173 . 0 g of clear , colorless oil . this oil was 95 % pure title compound with 5 % of dibromo title compound . the corrected yield of the title compound was 99 % ( 164 . 3 g ). to a solution of 29 . 0 g ( 135 mmol ) of the crude part c alcohol and 24 . 1 g ( 135 mmol , petrarch ) of thexyldimethylchlorosilane in 200 ml of dry methylene chloride ( distilled from phosphorous pentoxide ) was added at room temperature 20 ml ( 143 mmol , distilled from calcium hydride ) of triethylamine and then 200 mg ( 1 . 64 mmol , aldrich ) of 4 - dimethylaminopyridine . the reaction mixture was stirred at room temperature for 18 hours . the resulting slurry was diluted with 100 ml of hexane , cooled to 0 ° c . with stirring for 15 minutes , then filtered to remove solid triethylamine hydrochloride . the filtrate was concentrated in vacuo to give an oil . the crude oil was purified by flash chromatography ( merck silica , 15 × 10 cm , 1 : 9 ethyl acetate / petroleum ether ) to afford 45 . 5 g ( 127 mmol , 94 %) of the title compound as a colorless liquid . to a solution of 5 . 00 g ( 14 . 0 mmol ) of compound d in 30 ml of dry diethyl ether ( distilled from ketyl ) cooled to - 100 ° c . was added dropwise 15 ml ( 1 . 7m in pentane , 25 mmol , aldrich ) of t - butyllithium solution over 15 minutes . the reaction mixture was stirred at - 100 ° c . for 15 minutes then at 0 ° c . for 15 minutes . the resulting pale yellow anion solution was recooled to - 78 ° c ., 30 ml of dry thf ( distilled from ketyl ) was introduced , and a solution of 875 mg ( 5 . 61 mmol ) of [ 3ar -( 3aα , 4β , 7β )]- octahydro - 4 , 7 - epoxyisobenzofuran -( 1 - ol in 10 ml of thf was rapidly added . the reaction mixture was warmed to 0 ° c ., stirred for 1 hour , quenched with 5 ml of water , then partitioned between 100 ml of water and 25 ml of ethyl acetate . the organic layer was separated and the aqueous layer was extracted with an additional 25 ml of ethyl acetate . the organic extracts were combined , dried ( magnesium sulfate ), and concentrated in vacuo to give an oil . the crude oil was purified by flash chromatography ( merck silica , 12 × 5 . 0 cm , 1 : 4 ethyl acetate / petroleum ether then 4 : 1 ethyl acetate / petroleum ether ) to afford 2 . 35 g ( 5 . 41 mmol , 97 %) of the title diasteromeric alcohols as a colorless oil . a mixture of 1 . 90 g ( 4 . 38 mmol ) of the part e diastereomeric alcohols and 1 . 9 g of 20 % palladium hydroxide on carbon catalyst ( moist , less than 50 % water , aldrich ) in 60 ml of glacial acetic acid was stirred rapidly under an atmosphere of hydrogen ( balloon ) for 5 hours . the reaction mixture was filtered through a 4 μm polycarbonate membrane and the filtrate was concentrated in vacuo ( room temperature bath ). the residue was partitioned between 50 ml of water and 50 ml of ethyl acetate . the organic layer was separated , washed with 50 ml of 1m aqueous sodium hydroxide solution , dried ( magnesium sulfate ), and concentrated in vacuo to give an oil . the crude material was purified by flash chromatography ( merck silica , 12 × 5 . 0 cm , 1 : 2 ethyl acetate / petroleum ether ) to afford 1 . 03 g ( 2 . 39 mmol , 55 %) of the title compound as a colorless oil . in addition , 573 mg ( 1 . 37 mmol , 30 %) of the part e starting material ( as a single diastereomer ) was recovered . a solution of 1 . 00 g ( 2 . 39 mmol ) of compound f and 50 mg ( 0 . 41 mmol , aldrich ) of 4 - dimethylaminopyridine in 6 ml of 1 : 1 dry pyridine / acetic anhydride was stirred at room temperature for 2 hours . the reaction mixture was concentrated in vacuo and the residue partitioned between 25 ml of ethyl acetate and 20 ml of 1m aqueous hcl solution . the organic layer was separated , washed with 20 ml of 1m aqueous naoh and 20 ml of brine , dried ( magnesium sulfate ), and concentrated in vacuo to afford the crude acetate as an oil . to a solution of the crude acetate in 15 ml of reagent acetone cooled to 0 ° was added rapidly 3 . 3 ml of jones reagent ( 2 . 6m in cr + 6 , see fieser & amp ; fieser , reagents for organic synthesis , vol . 1 , p . 142 ). the reaction mixture was stirred for 2 hours , quenched by addition of 1 ml of isopropanol and stirred for an additional 30 minutes . the resulting green slurry was filtered through a pad of celite . the filtrate was concentrated in vacuo and the residue partitioned between 25 ml of diethyl ether and 25 ml of water . the organic layer was separated and concentrated in vacuo to give the crude acetate - acid as an oil . a solution of the crude acetate - acid in 15 ml of 2 : 1 1m aqueous naoh / thf was stirred at room temperature for 30 minutes . the reaction mixture was cooled in an ice - bath , quenched by 15 ml of 1m aqueous hcl solution , then extracted with two 25 - ml portions of diethyl ether . the ether extracts were combined , washed with 25 ml of brine and concentrated in vacuo to give the crude alcohol - acid as an oil . a solution of the crude alcohol - acid in 10 ml of acidic methanol ( prepared by addition of 0 . 5 ml of acetyl chloride to 10 ml of dry methanol at 0 ° c .) was stirred at 0 ° for 2 hours and then concentrated in vacuo . the resulting oil was purified by flash chromatography ( merck silica , 15 × 3 . 0 cm , ethyl acetate ) to afford 526 mg ( 1 . 76 mmol , 74 % from compound f ) of the title compound as a colorless oil . to a solution of 495 mg ( 1 . 63 mmol ) of compound g in 5 ml of reagent acetone cooled to 0 ° c . was added rapidly 2 . 0 ml ( 2 . 6m in cr + 6 ) of jones reagent . the reaction mixture was warmed to room temperature , stirred for 2 hours , then quenched by about 1 ml of isopropanol . after 15 minutes , the resulting green slurry was filtered through a pad of celite . the filtrate was partitioned between 20 ml of diethyl ether and 20 ml of water . the organic layer was separated , and the aqueous layer was extracted with an additional 20 ml of diethyl ether . the ether extracts were combined , dried ( magnesium sulfate ), and concentrated in vacuo to give 560 mg ( 1 . 59 mmol , 98 %) of crude title compound as a colorless oil . 2 , 2 - aminothioethanoic acid , ethyl ester was prepared as described in boon , w . r ., j . chem . soc . ( 1945 ), 601 ( see also oliver , j . e . and sonnet , p e ., j . org . chem . 38 ( 1973 ), 1437 note 6 ). a solution of pure 2 , 2 - aminothioethanoic acid , ethyl ester ( 7 . 06 g , 53 . 1 mmol ) in 10 ml of methanol was stirred at room temperature under argon as 7 . 35 g of 4 - cyclohexylbutylamine ( 47 . 4 mmol ) was added . a mildly exothermic reaction ensued , during which the reaction mixture warmed significantly . after about 30 minutes , a precipitate began to form . tlc indicated that both starting materials had been consumed completely and several products had formed . the precipitate was filtered . it was not the desired title compound ( h 2 ncsconhr ), but rather rnhcsconhr . the mother liquors were evaporated , and flash chromatography ( 10 % to 100 % etoac in hexane gradient , discarding mixed fractions ) was used to isolate four other products . aside from 2 . 24 g of the title compound ( h 2 ncsconhr ), the regioisomer rnhcsconh 2 , and two other compounds , h 2 ncsconh 2 and either h 3 cocsconhr or rnhcscooch 3 were isolated . the yield of the title compound , a yellow solid , was 20 %. for analogous preparations , see a ) a . weddige , j . pract . chem . 9 ( 1874 ), 132 . b ) w . walter and k .- d . bode , liebigs ann . chem ., 660 ( 1962 ), 74 . for spectroscopic data of related compounds , see r . a . dommisse , et al ., bull . soc . chim . belg ., 88 ( 1979 ), 261 . ______________________________________tlc : ( 25 % etoac in hexane - anisaldehyde ): 2 , 2 - aminothioethanoic acid , ethyl ester 0 . 294 - cyclohexylbutylamine 0 . 00title compound 0 . 40rnhcsconhr 0 . 71rnhcsconh . sub . 2 0 . 33h . sub . 2 ncsconh . sub . 2 0 . 10h . sub . 3 cocsconhr or rnhcscooch . sub . 3 0 . 50 . sup . 13 c nmr ( 67 . 8 mhz in cdcl . sub . 3 ): 191 . 3 , 158 . 0 , 40 . 8 , 37 . 4 , 36 . 9 , 33 . 3 , 29 . 3 , 26 . 6 , 26 . 3 , 24 . 1______________________________________ 14 . 1 ml of 25 % sodium methoxide in methanol solution ( 4 . 37m , 61 . 7 mmol ) was added to a solution of 4 . 29 g of h noh . hcl ( 61 . 7 mmol ) in 50 ml of methanol . the neutralization was mildly exothermic , and the mixture was allowed to cool to room temperature and fully precipitate nacl . the supernatant ( approximately 1m methanolic hydroxylamine solution ) was then drawn . a solution of 0 . 69 g of pure part i compound ( 2 . 85 mmol ) in 10 ml of methanol was stirred at room temperature under argon as 6 ml of the approximately 1m methanolic solution of hydroxylamine ( 6 mmol ) was added . after stirring for 5 hours , the mixture was diluted with ch 2 cl 2 and water was added . the mixture was extracted three times with ch 2 cl 2 , the extracts were dried over na 2 so 4 , and evaporation gave 0 . 71 g ( quantitative yield ) of pure title compound as a white solid . a solution of 0 . 75 g of pure compound h ( 2 . 36 mmol ) in 15 ml of toluene was stirred at room temperature under argon as 0 . 26 ml of oxalyl chloride ( 0 . 38 g , 3 . 0 mmol ) was added . the mixture bubbled . after 5 minutes , a small drop ( about 3 mg ) of dimethylformamide was added , and the bubbling accelerated . after about 1 hour the bubbling had stopped and the solvent was evaporated . the resulting acid chloride was dissolved in 4 ml of chcl 3 and transferred ( using two additional 4 ml portions of chcl 3 to transfer residual acid chloride ) to a solution of 0 . 68 g of pure amidoxime compound j ( 2 . 8 mmol , 1 . 2 equiv ) and 0 . 4 ml of pyridine ( 0 . 4 g , 5 mmol , 2 equiv ) in 25 ml of chcl 2 , stirring at room temperature under argon . after stirring overnight ( reaction was complete much sooner ), the mixture was evaporated . flash chromatography ( 30 % to 50 % etoac in hexane gradient ) gave 1 . 21 g of pure compound k as a white solid . the yield of compound k was 95 %. for analogous preparations , see a ) w . j . hennen and r . k . robins , j . het . chem ., 22 , ( 1985 ), 1747 . b ) european patent 0239309 c ) m . ruccia and n . vivona , ann . chim . ( rome ), 58 , ( 1968 ) 484 . 13 c nmr ( 67 . 8mhz in cdcl 3 ): 173 . 3 , 168 . 6 , 158 . 7 , 148 . 7 , 138 . 5 , 137 . 9 , 130 . 1 , 128 . 9 , 126 . 7 , 126 . 5 , 78 . 6 , 77 . 7 , 51 . 6 , 49 . 0 , 39 . 7 , 37 . 4 , 36 . 9 , 34 . 7 , 33 . 2 , 32 . 4 , 29 . 5 , 28 . 7 , 27 . 4 , 26 . 6 , 26 . 3 , 24 . 0 0 . 73 g of pure compound k ( 1 . 35 mmol ) was placed under high vacuum ( 4 torr ) and heated to 200 ° c . ( the material melted and began to bubble at about 185 °.) after 1 . 5 hours , tlc indicated nearly complete conversion to compound l with a small amount of compound j present . the material was cooled , and flash chromatography ( 25 % to 40 % etoac in hexane gradient ) gave 0 . 64 g of pure compound l as a white solid . the yield of compound l ( example 1 ) was 90 %. 13 c nmr ( 67 . 8mhz in cdcl 3 ): 180 . 1 , 173 . 0 , 163 . 3 , 156 . 1 , 138 . 5 , 137 . 1 , 129 . 6 , 128 . 9 , 126 . 8 , 126 . 5 , 79 . 6 , 78 . 5 , 51 . 5 , 49 . 6 , 45 . 7 , 39 . 7 , 37 . 4 , 36 . 9 , 34 . 8 , 33 . 2 , 32 . 2 , 29 . 8 , 29 . 5 , 28 . 7 , 27 . 5 , 26 . 6 , 26 . 3 , 24 . 1 . a solution of 340 mg of nearly pure example 1 ( 95 % pure = 323 mg , 0 . 62 mmol ) in 10 ml of thf , 4 ml of 1 . 0m aqueous naoh , and 10 ml of methanol was prepared and stirred at room temperature under argon . after 30 minutes , tlc ( using both 50 % etoac in hexane and the tlc solvent system below ) showed that all example 1 had been consumed and two carboxylic acid products had formed . furthermore , a trace of another compound , presumably example 3 methyl ester , which subsequently disappeared , was present . after 50 minutes addition of ch 2 cl 2 , water , and brine was followed by acidification to ph 1 with 1 . 0m aqueous hydrochloric acid . the mixture was extracted three times with ch 2 cl 2 . the combined extracts were dried over na 2 so 4 and evaporated . flash chromatography ( silica gel , 25 % to 60 % ( 5 % acetic acid in etoac ) in hexane ), followed by coevaporation with ch 2 cl 2 and toluene gave 41 mg of pure example 2 as an oil , yield 13 %. [ α ] d =+ 5 . 95 ° in chcl 3 at c = 2 . 05 g / 100 ml . also isolated was about 300 mg ( the balance of the mass ) of example 3 as an oil . [ α ] d =+ 48 . 7 ° in chcl 3 at c = 1 . 68 g / 100 ml tlc ( 50 % 5 % acetic acid ( acoh ) in etoac in hexane - anisaldehyde ): to a solution of 1 . 3 g of pure compound h from example 1 ( 4 . 1 mmol ) in 14 ml of n , n - dimethylformamide stirring at room temperature under argon , was added 0 . 56 g of hobt hydrate ( 4 . 1 mmol , 1 . 0 equiv ), 2 . 0 ml of n - methylmorpholine ( 1 . 8 g , 18 mmol , 4 . 4 equiv ), 0 . 35 of n 2 h 4 hcl ( 5 . 1 mmol , 1 . 2 equiv ), and lastly 0 . 86 g wsc ( 4 . 5 mmol , 1 . 1 equiv .). after 3 hours , 80 mg of n 2 h 4 ( free base , mmol ) and 0 . 10 g additional wsc were added to drive the reaction to completion . after 2 . 5 hours , the mixture was coevaporated three times with toluene to remove n , n - dimethylformamide . flash chromatography silica gel , 5 % ( 10 % concentrated aqueous nh 3 in methanol ) methylene chloride , discarding mixed fractions ] allowed isolation of mg of hydrazide a , a white solid . tlc ( 10 % ( 10 % concentrated aqueous nh 3 in methanol ) in ch 2 cl 2 -- anisaldehyde ): 13 c nmr ( 67 8mhz in cdcl 3 ): 173 . 0 , 172 2 , 138 . 5 , 138 . 0 , 129 . 5 , 128 . 8 , 126 . 4 , 126 . 4 , 78 . 8 , 78 . 4 , 53 . 5 , 51 . 5 , 47 . 9 , 34 . 8 , 31 . 8 , 29 . 4 , 28 . 7 , 27 . 4 to a solution of 0 . 31 g of hydrazide a ( 0 . 93 mmol ) and 0 . 29 g of thioamide i from example 1 ( 1 . 2 mmol , 1 . 3 equiv ) in 20 ml of methanol stirring at room temperature under argon , was added 2 . 0 ml of 25 % sodium methoxide in methanol solution ( 4 . 37m , 8 . 7 mmol , 9 . 4 equiv ). after stirring overnight , the mixture was diluted with ch 2 cl 2 , and water and brine were added . the mixture was extracted three times with ch 2 cl 2 , the extracts were dried over na 2 so 4 , and the solvent was evaporated . flash chromatography [ silica gel , 2 % to 5 % ( 10 % concentrated aqueous nh 3 in methanol ) in methylene chloride gradient ] gave 417 mg of pure compound b as a gum , yield 83 %. 1 h nmr showed what appeared to be two isomers ( 4 : 1 ). for an analogous preparation , see t . vanek , et al ., coll . czech ., chem . comm ., 49 ( 1984 ), 2492 . tlc ( 10 % [ 10 % concentrated aqueous nh 3 in methanol ] in ch 2 cl 2 -- anisaldehyde ): 100 mg of pure compound b ( 0 . 19 mmol ) was placed under high vacuum ( 4 torr ) and heated to 200 ° c . ( as the temperature was increased , the gum first solidified and then melted at about 185 ° c .) after 1 hour , 1 h - nmr indicated a ratio of b to c of about 4 : 1 . continued heating under vacuum for 7 hours more drove the reaction essentially to completion . the material was cooled , and flash chromatography ( 4 % 2 - propanol in toluene , discarding mixed fractions ) gave about 60 mg of nearly pure compound c as a white solid , 60 %. 13 c nmr ( 67 . 8mhz in cdcl 3 ) 173 . 4 , 158 . 7 , 138 . 5 , 138 . 3 , 129 . 7 , 128 . 9 , 126 . 4 , 126 . 4 , 80 , 7 , 78 . 8 , 51 . 6 , 49 . 6 , 46 . 2 , 39 . 5 , 37 . 5 , 37 . 1 , 35 . 0 , 33 . 3 , 32 . 7 , 29 . 8 , 29 . 6 , 29 . 3 , 27 . 7 , 26 . 6 , 26 . 3 , 24 . 2 a solution of about 60 mg of nearly pure example 4 ( about 0 . 11 mmol ) in 5 ml of tetrahydrofuran and 10 ml of methanol was prepared under argon with gentle warming and then cooled to room temperature . to this was added 4 ml of 1 . 0m aqueous naoh solution . after 3 hours , the addition of ch 2 cl 2 and brine was followed by acidification to ph 1 with 1 . 0m aqueous hydrochloric acid . the mixture was extracted three times with ch 2 cl 2 . the combined extracts were dried over na 2 so 4 and evaporated . flash chromatography [ silica gel , 10 % ( 50 % acoh in 2 - propanol ) in toluene ], followed by coevaporation with ch 2 cl 2 and toluene gave 49 mg of example 5 as a white solid ( melting point 210 ° to 213 ° c ., yield about 80 %). [ α ] d =+ 8 . 09 ° in 50 % methanol in chcl 3 at c = 1 . 31g / 100 ml . the starting material for the following examples is [ 1s -( 1α , 2β ( 5z ), 3β , 4α )]- 7 -[ 3 -( hydroxymethyl )- 7 - oxabicyclo [ 2 . 2 . 1 ] hept - 2 - yl ]- 5 - heptenoic acid , methyl ester , which is prepared as described in u . s . pat . no . 4 , 143 , 054 , column 9 , example 7 . this compound may be treated following the procedures of example 1 , parts h to l and examples to 5 to form the following examples :