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

Claim 2

A compound having the formula I including all stereoisomers thereof, wherein m is 1, 2 or 3; n is 0, 1, 2, 3 or 4; Z is -(CH 2 ) 2 - or -CH = CH- with the proviso when Z is -CH = CH-, n is 1, 2, 3 or 4; R is C0 2 H, CO 2 alkali metal, CO 2 lower alkyl, CH 2 0H, CONHSO 2 R 3 , CONHR 3a or -CH 2 -5-tetrazolyl; X is 0, S or NH; R 1 is lower alkyl, lower alkenyl, lower alkynyl, 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; R 3 is lower alkyl, aryl or aralkyl; and R 3a is hydrogen, lower alkyl, aryl Q r aralkyl. -

Claim 3

The compound according to Claim 1 having the formula

Claim 4

The compound according to Claim 2 having the formula

Claim 5

The compound according to Claim 2 where m = 1 and n = 2.

Claim 6

The compound according to Claim 1 having the formula

Claim 7

The compound according to Claim 5 where m = and n =2.

Claim 8

The compound according to Claim 5 having the formula

Claim 9

The compound according to Claim 1 having the formula

Claim 10

The compound according to Claim 1 having the formula

Claim 11

The compound according to Claim 1 wherein R is CO 2 H, CONHSO 2 R 3 or -CH 2 -5-tetrazolyl.

Claim 12

The compound according to Claim 1 having the formula

Claim 13

The compound according to 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; [1 S-[1 α,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-[1a,2a(Z)-,3α,4α]]-6-[3-[4-[(1-pyrrolidinyl)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoic acid, or esters or salts thereof; [1 S-[1α,2α(Z),3α,4α]]-6-[3-[4-[(cyclohexylamino)carbonyl]-2-oxazolyl]-7-oxabicyelo[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]hept-2-yl]-4-hexenoic aicd, or esters or salts thereof; [1 S-[1 α,2α(Z),3α,4α]]-6-[3-[4-[[[2-(4-chlorophenyl)ethyl]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-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-[4a-[[(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]hept-2-yl]-4-hexenoic acid, or esters or salts thereof; [1 S-[1 α,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-oxabicyclo[2.2.1 ]hept-2-yl]-4-hexenoic acid, or esters or salts thereof; [1S-[1a,2a(Z),3a,4a]]-6[3-[4-{(2,3-dihydro-1H-indol-1-yl)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexerioic 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; [1S-[1α,2α(Z),3α,4α]]-6-[3-[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-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,3α,4α]-6-[3-[4-[[(7,7-dimethyloctyl)amino]carbonyl]-2-oxazolyi]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoic acid, or esters or salts thereof; [1 S-[1 α,2α(E),3α,4α]]-6-[3-[4-[[(4-cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]-hept-2-yl]-4-hexenoic acid; [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 14

The compound according to 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.

Claim 15

A compound of the general formula I according to any one of claims 1 to 13 for use in a method of inhibiting platelet aggregation and bronchoconstriction.

Claim 16

A compound of the general formula I according to any one of claims 1 to 13 for use in a method for improving post-ischemic myocardial function.

Claim 17

A compound of the general formula I according to any one of claims 1 to 13 for use in a method for treating toxemia during pregnancy.

Claim 18

A compound of the general formula I according to any one of claims 1 to 13 for use in a method for preventing or reducing venous thrombosis.

Claim 19

A compound of the general formula I according to any one of claims 1 to 13 for use in a method for preventing or reducing platelet loss during extracorporeal circulation.

Claim 20

A compound of the general formula I according to any one of claims 1 to 13 for use in a method for treating burn injuries and/or promoting wound healing.

Claim 21

A compound of the general formula I according to any one of claims 1 to 13 for use in a method for reducing post-ischemic myocardial injury together with an effective amount of a thrombolytic agent within 6 hours of a myocardial infarction.

Claim 22

A compound of the general formula I according to any one of claims 1 to 13 for use in a method according to claim 20 wherein said thrombolytic agent is t-PA, streptokinase, urokinase, prourokinase or anisoylated plasminogen-streptokinase activator complex.