CA1214163A - Prostaglandins - Google Patents

Abstract

ABSTRACT
PROSTAGLANDINS
Novel compounds have a formula (I) (I) represents one of the divalent cyclic groups

Description

4~3 ~ 1 --This inventio~l relates to biologically active compounds and in particular to certain novel compounds exhibiting activity at thromboxane receptor sites.
Thromboxane A2 (TXA2), which is derived from arachidonic acid via pro-staglandin H2 (PGH2), is implicated in several potentially noxious actions on various body systems, including platelet aggregation, bronchoconstriction and pulmonary and systemic vasoconstriction. Thus TXA2 may be involved in the normal sealing of blood vessels following injury but in addition may contribute to pathological intravascular clotting or thrombosis. Moreover, the constrictor actions of TXA2 on bronchiolar, pulmonary vascular and systemic vascular smooth muscle may be important in the development of several anaphylactic conditions including bronchial asthma. There is also some evidence to implicate PGH2 and TXA2 in the genesis of inflammation.
It is an object of the present invention to provide compounds having activity at thromboxane receptor sites, and most especially to provide compounds which are inhibitors of thromboxane activity and are therefore of interest in one or more areas of medical treatment including the treatment of thrombotic disorders, the treatment of anaphylactic disease states, and treatments utilising anti-inflammatory agents.
According to the present invention a process for the preparation of a Ocompound of formula (I) H

(I) wherein ~ \ C
/ ¦ ~ C(R2)=NR
A /\ H

\ represents one of the divalent cyclic groups H

~ ~ and ~

the letters a and b in each case indicating the point of attachment of the substituents R and C(R ~-NR, respectively; R is a 6-carboxyhex-2-enyl group or a modification thereof in which the group is altered by one, or an appropriate combination of two or more, of the lollowing: (a~ reduction of the double bond optionally accompanied by replacement of a carbon atom at the 1, 2 or 3 position by a sulphur or oxygen atom, (b) alteration o~ the position of the double bond, ~c) shortening or lengthening o~ the carbon chain by one or t~o me~hylene groups, and (d) formation of an amide, ester or salt derivative of the carboxy group; R2 is hydrogen, a Cl 10 aliphatic hydrocarbon group or a Cl 10 aliphatic hydrocarbon group substituted directly or through an oxygen or sulphur atom by an aromatic group Ar, ~here Ar is a phenyl, naphthy~ fluorenyl, dibenzocyclohexyl, d~benzocycloheptyl, pyridyl, benzothiazolyl, dihydrobenzothIazolyl, N-methyldihydro~enzot~iazolyl, ~enæoxazolyl, dihydrobenzoxazolyl or N-methyldihydrobenzoxazolyl group or such a group substituted by one or more substituents selected from Cl 1O
alkoxy~, halo~en, Cl_}O halogen-substituted alkyl, sulphamoyl, ami~lo, hydroxyl, nitro and C~_lO alkyl groups; and R is a group -OR , -NH.COR or NH.CO.NHR t~herein R is a Cl 10 aliphatic hydrocarbon group, an aromatic group Ar or a Cl 1O aliphatic ~ydrocarbon group substituted by one or more groups Ar directly or through an oxygen or sulphur atom; comprises reacting a compound o~ formula (II) f C''' (II~
-C(R2)- 0 ~Q' :i;
'~,d ~ 2a -with a reagent ZNH2, Y being either R ~s defined aboYe for compound (I) or a precursor for Rl, Z being either R as defined above for compound (I) or a precursor for R, and the other symbols being as defined for compound (I) but with the letters a and b indicating the point of attachment of the substituents Y and C(R2?=0, respectively, and where appropriate converting the group Y and/or the group Z in the resultant product into the groups R and R, respectively, of the compound ~I).
The bicyclo r2,2,1~ heptane and bicyclo r2,2,13 hept-2Z-ene bridged ring systems indicated above may alternatively be represented in planar form, i.e. as ~ and ~

but the more usual convention has generally been followed throughout the specification of represent~ng the~e systmes ~n non-planar form.
It will be appreciated, however, that the compounds ~I3 may exist in various stereoisomeric forms, ~hich are included within the scope of the invention, and in particular that each geometric isomer of a bridged ring compound ~I? will exist in two enantiomorphic forms.
These two forms will have the structure illustrated hereinbefore and the mirror image of that structure. Such paîrs of enantiomorphs may be shown as follows (the rings being nu~bered ~ccording to the system used herein).

L~

3 ~ 2 For the sake of added clarity i~ might be mentioned that alternative, equivalent, modes of showing these non-planar structures may be used. Thus the right hand of the two formulae shown directly above is equivalent to

2 ~ and alro ~

05 Certain of the compounds containing a modified 6-carboxyhex-2-enyl group act through the conversion of the modified group back to the unmodified group _ vivo. In additon to such bioprecursors, the invention also extends in general to other pharmaceutically acceptahle bioprecursors for the compounds described above, such a bioprecursor being a compound having a structural formula differen~
from the active c~mpound but which upon administration is converted thereto in vivo.
Modifications of the 6-carboxyhex-2-enyl group which may be made in compounds according to the present invention are of two types. Firstly, there are modifications which involve alteration of the 6-carboxyhex-2-enyl group by one, or where appropriate by a comblnation, of the following: (a) reduction of thP double bond optionally accompanied by the replacemen~ of a carbon atam a~ the 2~4~3 2,3 or even 1 position by a sulphur or particularly an oxygen atom; (b) alteration of the positon of the double bond, for example to the 3,4 position; and (c) shortening or lengthening of the carbon cha-ln, particularly by two or especially one methylene o~ groups and conveniently at the end of the chain adjacent to the carboxy group.
The second form of modification, which may if desired be combined with a modification of the first type, involves conversion of ~he carboxy group to a functional derivative including salts thereof. Functional derivatives described in the prostaglandin art are of particular interest, including (a) esters, especially alkyl esters, for example those contain~ng a Cl-C10 alkyl group;
(b) amides, which may contain a group -CONH2 or such a group in which the nitrogen at~m is substituted, especially by one or two groups selected from substituted or unsubstituted phenyl groups, for example as described hereinafter, al~yl groups, for example Cl-C10 alkyl groups, and from more complex groups such as -S02CH3 or an analogue thereof containing a C2-C10 alkyl group, for example to provide a group of the fonm -CONHS02CH3; and (c) salts with various physiologically acceptable cations. Salt derivatives are of especial interest, specific examples of salts being those formed with an alkali metal such as sodium or with quaternary ammonium ions or amines such as tris (the symbol tris represents the compound 2-amino-2-hydroxymethylpropane 1,3-diol). As mentioned above, it will be appreciated that many of such compounds are in fact bioprecursors ~or the corresponding compound containing a carboxy group to which they are converted in vivo.
Examples of specific groups R are -CH2-CH=CH-(CH2)3C02~, -(CH2)6C02H and (CH2)20(CH2)3C02H, and functional derivatives formed at the carboxy groups thereof.
Compounds in which the group R is not hydrogen more usually contain aliphatic and araliphatic groups of the type described hereinaf~er in relation to ~he group R , aliphatic hydrocarbon g~oups substituted directly by an aromatic group and particularly unsubstituted sliphatic hydrocarbon groups being of most interesta ~2~

The size of the group R2 can however influence the ease with which the compounds may be prepared and R2 is preferably either hydrogen or one of the smaller alkyl groups, for example of 1 to 3 carbon atoms9 in substituted form, or particularly in unsubstituted form, 05 for example ethyl and especially methyl. When the group R contains an aliphatic hydrocarbon group directly substituted by an aromatic group, then it is preferred that the aromatic group is not attached to a carbon atom of the aliphatic group which is itself attached directly to the carbon atom of the group C(R )=NR. Thus, for example, a 2-phenylethyl group is preferred to a l-phenylethyl or phenylmethyl (benzyl) group. Good levels of activity have been achieved with compounds in which R2 is one of hydrogen, ethyl and especially methyl. An increase in activity resulting from the presence of a group R which is methyl rather than hydrogen has been found to be particularly marked in the case of compounds (I) containing a group R of the form -NH.CO.NHR .
As indicated, the group R3 can be of various forms. Aliphatic hydrocarbon groups constituting R may conveniently be of one to five, six, seven9 eight, nine, ten or even more carbon atoms, being, for example an alkyl group and including branched or unbranched acyclic alkyl groups such as methyl, ethyl, propyl, butyl, amyl, etc., cyclic alkyl groups such as cyclopentyl, cyclohexyl etc., and also combinations thereof such as cyclohexyll~ethyl etc.
Aromatic groups constituting R are o~ greater interest than the unsubstituted aliphatic hydrocarbon groups and ~ay be hydro-carbon or heterocyclic groups which may be unsubstituted or substituted. Moreover, the term 'aromatic group' as used herein extends to groups derived from ring systems having aromatic properties but in which the n-electron system is not fully delocalised over the entire ring system, such groups including those derived from fluorene, dihydrobenzoxazole, dihydrobenzo-thiazole, N-methyldihydrobenzothiazole, and 1,2,4,5-dibenzocyclo-heptane. The heterocyclic groups which conveniently contain one, two or more, similar or different nitrogen, oxygen or sulphur ~3 ` - 6 ~2~ 3 atoms, are more generally linked through a carbon atom so that, in the case of a pyridyl group, pyrid-2-yl, pyrid-3-yl and pyrid-4-yl are of particular interest.
Moreover, in the case of those groups containing one or more benzene rings together with one or more non-benzenoid rings, such as those derived from fluorene and its cyclohexyl and cycloheptyl analogues, and from benzothiazole, dihydrobenzothiazole and N-methyldihydrobenzothiazole and their benzooxazole analogues, linkage of the group is more usually effected through a non-benzenoid ring.
Among the aromatic groups constituting R , aromatic hydrocarbon groups, for example napthyl and particularly phenyl are, however, generally of rather greater interest than heterocyclic groups. Both the aromatic hydrocarbon and the heterocyclic groups may be substituted by one or more of various types of sub-stituent, particularly by alkoxy groups, for example those containing alkyl groups of 1 to 10 carbon atoms as described above, for example 1, 2 or 3 carbon atoms and especially a methoxy group, and by substituents being or containing a halogen residue, for example bromo, chloro and especially fluoro, and also halogen sub-stituted alkyl groups such as CF3. Examples of other substituents are sulphamoyl groups which may optionally be N-substituted, amino groups which may be free or substituted, for example dimethylamino, hydroxyl, nitro, and alkyl groups, for example of 1 to 3 carbon atoms or otherwise as described above, etc. Substitution may be present at one or more of the ortho, meta and para positions of a phenyl ring or at a combination of two or more such positions Sincluding two similar positions), for example at the 2 and 4 positions. Substitution and the position of substitution, for example by alkoxy groups and groups being or containing a halogen, may have a definite effect upon the level of activity of a compound.
Also of considerable interest, are groups R3 which are aliphatic hydro-carbon groups substituted directly or through a sulphur or particularly an oxygen atom by an aromatic group or groups. The aliphatic groups may be of a similar size to those described above but preferably comprise an acyclic group, conveniently of three carbon atoms, particularly of two carbon atoms and especially of one carbon atom, although th~s acyclic group may carry a cyclo-alkyl group as well as an aromatic group. Preferred a~yclic groups thus take the form of unbranched alkylene groups ~uch as methylene9 05 ethylene or propylene which link the group C(R )=N- and the aromatic group, or corresponding trivalent groups of similar size. Similar aromatic hydrocarbon and heterocyclic residues are generally of interest for attachment to the aliphatic groups as has already been described above, the aromatic hydrocarbon groups again generally being of rather more interest than the heterocyclic groups. ~eterocyclic groups, where used, are of most interest in this context when linked to the aliphatic hydrocarbon group through a hetero atom such as in pyrid-l-yl. Direct substitutlon of an aliphatic residue by an aromatic residue or residues, particularly terminally, for example substitution by two or even three aromatic groups, for exa~ple phenyl, and/or substitution by an aromatic residue through a sulphur or particularly an oxygen atom are all of some considerable interest. In the case of substitution through sulphur or oxygen, the aliphatic hydrocarbon residue is conveniently of at least two carbon atoms in the case of the oxime and semicar-bazone type of grouping referred to below, particularly in view of some relative lack of stability in compounds containing linkages of the type -0-CH~-S- and -O-CH2-0-. Also of interest are acyclic groups carrying terminally both an aromatic group, for example phenyl, and a c~clo-alkyl group, for example cyclohexyl.
When the group R is or contains a substituted aromatic group, some positions of substitution may be of more interest than others in particular cases. Thus, for example, when R3 is a substituted benzyl group the order of interest is often ovp>m, when R3 is a substituted phenyloxyethyl group ~t is o>m>p, and when R is a substituted phenyl group it is ~rp>o. It will be appreciated that, particularly when two positions are of similar interest, it may be of value to have a substituent at each position as when the group R3 is 3,4-dimethoxyphenyl.

Groups C(R )=NR in compounds according to the present invention are of the oxime, acylhydra~one or semicarbazone type according as to whether R is of the form OR , NHCOR or NHCONHR , respectively, the two latter forms being capable of representatlon as NHCOtNH) R
05 with a = O or l. Among the different types of groups R, very good levels of activity have been obtained with compounds in which R is a group ~oR3 or particularly a group -NH.CO.NHR . Among the various groups R, those in which R is an aliphatic hydrocarbon group are perhaps of rather less in~erest than the others, groups R which are aliphatic hydrocarbon groups substituted directly or through an oxygen or sulphur atom by an aromatic group being of somewhat greater interest when R is a group -OR and groups R
- which are aromatic groups being of somewhat greater interest when R is a group -A-R . It will be appreciated, however, that this is only a broad generalisation, so that, for example, one group R3 containing an aliphatic hydrocarbon group substituted by an aromatic group which is of some interest in groups -NH.CO.NHR is that consisting of an ethyl group subs~ituted at the l-position by a napthyl group, for example a napth-l-yl group. The reagent H2N.NH.CO.NHCH(CH3~-napth l-yl, which may be used to prepare compounds (I) containing such a group, is of particular interest since it contains an asymmetric carbon atom and may be obtained in op*ically active form. Examples of specific groups R are:

-(CH2)n~ (CH2)m-0 -~CH2) ~X (CH~)n_,, ~X

-2)n X -(CH2~

- ~CH2) n~--X --(CH2)--O ~) X X

2)p CN ~ --(CH2 )~ CH~3 r --(CU2) --CH~ (C~2)p CH~

-- (CH2) CH3 ~N~
\~

N--~ <N~

3 ~==( - 10 ~
wherein n=0, 1, 2 or 3, m=l, 2 or 3 (but particularly 2 or 3 in some cases as discussed above), p=0, 1 or 2, q=1, 2, 3, 4 or 5 and X= OC~3, Cl, F, CF3 or CH3 (preferences between ortho, meta and para substitution in the cases where n is 0 or not being indicated 05 hereinbefore).
Among the two bridged ring systems, the saturated bicyclo [2,2~1]
system is perhaps the more generally preferred as saturation usually confers the highest level of stability whilst the level of biological activity is generally substantially similar for both types of ring.
It will be appreciated that the structures of the compounds described above provide various opportunities for the occurrence of stereoisomerism. The substituent groups R and C(R j=NR may be in the cis or trans relationship to each other, compounds of the latter configuration being preferred. Moreover, different isomers will exist which vary according to the way in which the substituent groups R and C(R )=NR are disposed in relation to the bridging group. Isomers of particular interest are shown below for the unsaturated ring system in one of the two enantiomorphic forms which can exist, the other enantiomorph having a structure which is the mirror image of that shownO Of the two isomers, the 5-endo, 6-exo isomer is of more especial interest.
It will be seen that in the structures shown below the numbering applied herein to the various positions of the ring system has been indicated. It should be noted that the system o~ numbering adopted is chosen so that the double bond in the unsaturated ring system receives the lowest number possible (2), the substituents R and C(R )=NR then being at the 5 and 6 positions respectively, For conformity, a simllar system of numbering ls followed for the analogous saturated ring systems, the subs*ltuents again being described as at the 5 and 6, rather than the 2 and 3 positions.

3~ ~ ~l 3 ~ ~

2 6 ~ 2 6 . 2 C(R23=NR C(R )=NR
5-exo,6-endo 5-endo,6-exo . _ ~2~

Where the substituent R is a 6-carboxyhex-2-enyl group or a group modified therefrom but still containing the double bond, t'nen the configuration about this bond is preferably cis ~Z) rather than trans (E). In the other substituent C(R )=NR, syn and 05 anti isomerism is possible about the carbon-nitrogen double bond but the isomers may often be readily interconvertible at room temperature and thus difficult to separate, existing as a mixture which shows biological activity that may, however, derive pre-dominantly from one isomer. In addition to the foregoing isomerism, as indicated previously, the compounds of the present invention will in most cases additionally be resolvable into enantiomorphic forms and one among these may be preferred by virtue of biological activity or physical properties. Single enantinmers may be ob~ained either by the use of an optically actiYe starting material or by resolution of a pair of enantiomorphs.
Specific compounds according to the present invention include ~he various compounds described in the Examples as well as the analogues thereof in which a 6-carboxyhex-2Z-enyl group is replaced by a 6-carboxyhexyl group and/or the group R2 is the other two of the groups hydrogen, methyl and ethyl than the one appearing in the specific compound in question, for example the compounds N-0-(CH2~2-0- ~

~"~W C2H
N-0-CH(C6H5)2 ~ N_o_cH2_~F

~2~

-NHC-(N~a~(CH2)2--( )a ( 6 5)2 ~N-IIUCO- (NH) a~3 F

(a being O or l) as well as the chloro and trifluoromethyl analogues of the fluoro compounds, the ring saturated analogues of all these compounds and amide, ester and salt derivatives of each of these free acids.
05 Compounds of fonmula (I) according to the present invention may be prepared by reacting a compound of formula (II) ~ I Y

A` (II) \
I - C(R )=O

...

with a reagent ZNH2, Y being either R as defined above for compound (I) or a precursor for Rl and Z belng either R as defined above for compound (I) or a precursor for R, and the other symbols being as defined for compound (I), and where appropriate convertlng 05 the group Y and/or the group Z in the resultant product into the ~roups R and R, respectively, of the compound (I). Preferably Z
and conveniently also Y correspond to the corresponding groups R
and R in the compound (I).
A con~enient form of intermediate for the preparation of the various compounds (I) according to the present invention is a compound of formula (III) in which the symbols have the meaning indicated for formula (II). When the desired compound (I) contains a substituent C(R )=NR in which R is hydrogen, then the compound of formula (III) corresponds to that of formula ~II) and is itself reacted with the reagent ~NH2 to give the compound ~I) either directly or after modification of Y and~or Z. When the desired compound of formula (I) contains a substituent C(R )=NR in which R2 is not hydrogen, the compound of formula (III) may convenien~ly be reacted with a Grignard reagent of the form R2MgHalogen, followed by oxidation of the secondary alcohol of formula (IV) so formed, for example using Jones reagent, and the resulting compound of formula (II) containing the desired group R2 reacted with the reagent Z~H2 as indicated previously C ¦ (III) ' ¦ (IV) ¦ - CHO I CH(R )OH
It will be appreciated that various intermediates as just described are included by the present invention in view of their value in the preparstion of the compounds (I). The preparation of such compounds o~ formula ~III) is described in detail in the Examples for both of the ring systems and the synthesis of a compound (III) containing the bicyclo ~2,2,1] heptane ring system is shown schematically at the end of the Examples.

~z~

In this scheme, the numbering of the compounds corre~ponds to that used in Example 1 and which has also been followed ln Example for the ring saturated analogue. The following abbreviations are employed in the scheme: Ts, toluene sulphonyl; DMS0, dlmethyl 05 sulphoxide; Et, ethyl; Bu, butyl. The 5-endo-, 6-exo isomer is illustrated throughout the scheme in one enantiomeric form, although as explained hereinafter the product obtained by this route is racemic and it is also possible that some minor contamination with other isomers may occur, (It will be appreciated that the proportion - 10 of such contaminants does not necessarily depend upon the stereo-chemical nature of the intermediates in earlier stages of the synthesis. Thus certain compounds are capable of epimerisation under particular conditions and the compounds (III) in particular can undergo an epimerisation involving the formyl group at the time when these products are generated by the action of acid on the acetal.) It w1ll be seen that the scheme involves the use as a starting material of a compound containing the unsaturated ring system and having substituents on the ring system which are suitable precursors for those in the final compound. The formation of such an unsatu-rated bicyclic ring system is conveniently effected by means of a Diels-Alder reaction of the maleinaldehydic acid pseudo ester of formula OY' wherein Y' represents a hydrocarbon residue, preferably an aliphatic residue such as methyl or especially ethyl. Following reaction of this compound wlth cyclopentadlene in a Diels-Alder reaction to form a bicyclo 12,2,1] hept-2Z-ene ring system, modification of the substituents provided by the pseudo ester is effected, con-veniently to give initially a 6 carboxyhex-2-enyl group or a modification thereof and a formyl group, -C~10, which may readily be modified further as desired. The use of ethoxycarbonyl rather than methoxycarbonyl and of ethyl rather than methyl acetal groups has been found to be of value in the reaction scheme.
05 The unsaturated bicyclo [2,2,1] hept-2Z-ene ring system may be prepared by omitting or modifying the reduction step of the scheme which converts the unsaturated ring system which is produced initally to the corresponding saturated ring system, for example by simply omittlng the catalytic reduction employing H2/Pd in the route.
When the group R in the desired compound of formula (I) contains a free carboxy group then the group Y in the compound of formula (II) may similarly contain a free carboxy group or may, as illustrated in the scheme at the end of the Examples,contain a carboxy group in protected form, for example as an ester and particularly as the methyl ester which may conveniently be formed wlth diazomethane. Following reaction with the reac-tant Z.NH2 such a protecting group may then be removed, for example by de-esterificatlon using KOH/CH30H/H20. Such protection wlll ~0 generally lead to a slightly greater overall yield of the compound (I) from the compound (II).
The reactants ZNH2 are most usually of the form RNH2 and may be prepared by various procedures known in the art and illustrated in the Examples, the procedures illustrated generally being appli-cable to groups R containing a variety of forms of group R . Thus, for example, the reagents H2N.NH.Co.R3 may conveniently be prepared by the reaction of hydrazine with the corresponding ester, for example the ethyl ester, R .C02C2H5. The reagents H2N.NH.CO.NHR
may be prepared by the reaction of hydrazine with the corresponding N-substituted carbamate, for example the ethyl carbamate, R NHC02C2H5 (particularly for the preparation of phenyl se~icarbazide~ or more often in general with the corresponding isocyanate, R NCO. The reagents NH20R3 may be prepared by reaction of the corrPsponding halide R3cl with N-hydroxyphthalimide followed by reaction of the resulting imide with hydrazine hydrate.
' ~2~

Modification of the 6-carboxyhex-2-enyl group may be effected through the initial introductlon of a modified group or by modifi-cation of this group during or at the end of the synthesis, ester formation conveniently being effected, for example, at the stage 05 indicated hereinbefore and amides similarly being prepared by conventional procedures. Indeed, the procedures for effecting the various modifications indicated above will be apparent from the considerable literature existing on prostaglandin chemistry.
Thus, for example, in the case of a saturated ring system, w~ere, as is the case in ~he scheme shown at the end of the Examples, a precursor of structure ~f 1 ~/\/C02H

A
~ :
¦ \ CH0 ~in acetal form) is involved in the synthesls of compounds containing a 6 carboxy-hex-2-enyl group, then a convenient route to the analogues containing a 6-carboxyhexyl group involves the reduction of this precursor, for example with H2/Pd-C, It may be possible, if desired, to reduce both the ring and chain double bonds in one step. In the case of the unsaturated ring systems, a 6-carboxyhexyl group is best introduced at an earlier stage of the synthesis. Thus, a route to bicyclo ~2,2,1] hep-2Z-enes containing a 6-carboxyhexyl group involves an initial Diels-Alder reaction of 8-carboxy-1-formyl-oct-l-ene and cyclopentadiene (a separation of the two trans isomers obtained being required). In~roduction of a 3-oxa-6-carboxyhexyl group is similarly best effected at an early ~3 `
\~

.: ,.

stage of the synthesis. A convenient route for doing this involves the use of a compound of structure ~/ C --CH2CH2H

wherein the residue A is a saturated one, as a starting material.
Reaction with acryloni~rile in the presence of Triton B (ben~yl-05 methylammonium hydroxide) in a Michael reaction is then used tomodify the 2 subst~tuent to form a 5'-cyano-3'-oxapentyl group which is then chain extended using, in turn, lithium alu~inium hydride, toluene sulphonyl (Ts) chloride in pyridine, sodium hydride followed by Ts chloride, and cyanide ion to give a 6'-cyano-3'-oxahexyl group by the sequence of reactions -(CH2)20(CH2)2CN ~ -(CH2)20(CH2)2CH2NH2 ~ 2)20(CH2)3NHTs (l)NaH -(CH2)20(CH2)3NTs2 CN > ( 2)2 2 3 (2)TsCl Acid hydrolysis and esterification are then used to convert the cyano group to a methoxycarbonyl group and the reactant 9-borabi-cyclo [3,3,1] nonane is finally employed to effect reactlon at the double bond to yield a compound of the type (II) described hereinbefore having the structure / C /\~/ W C02CH3 ~1 It will be appreciated ~hat the methods described above are not the only ones which may be used for the preparatlon of compounds according to tlle present invention and that various alternative procedures may be used as will be apparent to those skilled in the art of prostaglandin chemistry~ .

' ~2~

It has been found that compounds according to the present invention inhlbit the aggregatory activity of 15S-hyd~oxy~
-(epoxymethano)-prosta-5Z, 13E-dienoic acid 111, 9-(epoxymethano) PGH2], which is a stable TXA2 mimic, on human platelets and on the 05 rabblt aorta _ vitro. Tests on compounds according to the present invention have also illustrated their ability to inhibit the aggregatory activity of both 11, 9-(epoxymethano) PGH2 and collagen in vivo in guineapigs and of collagen in vivo in rats. Moreover, in the guinea pig tests the Konzett-Rossler test showed inhibitlon of the bronchoconstrictory effect of both 11, 9-~epoxymethano) PGH2 and the collagen. It is believed that such inhibition is the resul~ of the compounds being thromboxane antagonists and the activit~ of the compounds is for convenience hereinafter discussed ln these terms. Preferred compounds according to the present invention exhibit a pure antagonist activity. However antagonlst and agonist activi~ies have been found to be linked in some compounds and in consequence certain of the compounds have been found to show a par~ial agonist activity in certaln tests, such as in the test based on the contractile activity of 11, ~-(epoxymethano) PGH2 on the rabbit aorta strip, although they are antagonists in a platelet test. Such partial agonist activity is most common in the oximes, which contain a substituent C(R2)=NoR3, and it has been found that structural features which tend to endow a compound of this type with a more pure antagonist form of activity are (a) the absence of a halogen substituent, particularly at the para position, in the benzene ring of a phenoxyethyl ~-substituted oxime; (b) the absence of a halogen substituent at the meta position of a benzyl 0-substituted oxime; and (c) the presence of two benzene rings in the oxime substituent, these rings being located, for example, on a carbon atom ~oined directly to the oxygen atom of the oxime group, Preferred compounds, including~ inter alia the compounds of Examples 1 ~o 6, are antagonists in the platelet test, block the aggregatory action of arachidonic acid which is converted to TXA2 by the platelet enzyme system and may or may not block ~ . ~ .

~L2~

the aggregatory action of ADP which acts via non-TXA2 - sensitive syste~s. Moreove~, they are pure antagonists in the rabblt aorta strip test but do not block the contractile action of noradrenaline which acts on a-adrenoceptors. Some activity has also been observed 05 in compounds according to the present invention on guineapig tr~cheal muscle.
Compositions according to the present invention are of interest for the treatment of thrombotic disorders and also for the treatment of anaphylactic disease states, for example as bronchodilators for the treatment of asthma, in hypoxia, etc. They additionally have potential as anti-inflammatory agents. It will be appreciated that the spectrum of activity shown by any particular compound will vary and that certain compounds may be of particular interest in one of these applications whilst other compounds are of particular interest in another of them. Modifications of a compound can have other advantages. Thus, for example, the use of esters and other derivatives of the 6-carboxyhex-2-enyl group or modifications thereo can have advantages in relation to slow release depot preparation through conversion in vivo to the active compound 2~ containing a free carboxy group, although the low water solubility of the esters must be taken account of. Alternatively, the use of a compound in which the 6-carboxy group is in salt form, for example the sodium salt, can be of value due to the enhancement of water solubility whlch generally results.
It will be appreciated that compounds showing a partial enhancing action on thromboxane activity are also of some interest in respec~ of this activity although to a much lesser extent than with inhibitory activity. Thus, cer~ain compounds according to the present invention may be of interest for labora~ory or even for pharmaceutical purposes, for example in the control of bleeding by topical administration which avoids any systemic take-up, by virtue of the thromboxane enhancing facet of their activity which is shown under certain conditions.
The c~mpounds may be formulated for use as pharmaceuticals for both animal and particularly human administration by a variety of methods, but usually ~ogether with a phys~ologically acceptable diluent or carrier~ The compounds may, for instance, be applied as an aqueous or oily solution or as an emulsion for parenteral administration, the composition therefore preferably being sterile 05 and pyrogen-free. The preparation of aqneous solutlons of compounds in which the group Rl terminates in a free carboxy group may be aided by salt formation. The compounds may also be compounded for oral administration in the presence of conventional solid carrier materials such as starch, lactose, dextrin and magnesium stearate.
0 Alternative formulations are as aerosols, suppositories, cachets, and, for localised treatment, as suitable creams or drops. Without commitment to a rigid definition of dosage, which is difficult in view of the different levels of activity, methods of formulation, and methods of administration, some general guidance may be given.
]5 In the case of systemic administration to produce a thromboxane antagoni~sm the normal daily dosage which is proposed lies in the range from about O.lmg to about lOmg per kilogram (the average weight of a human being about 70kg) and particularly from about lmg to about 5mg per kilogram. It will be appreciated, however, that dosages outside this range may be considered, for example in the case of topical application to produce a localised thromboxane agonism, and that the daily dosage may be divided into two or more portions.
The invention is illustrated by the following Examples.
The compo~mds of the present invention are related to the compounds descrlbed and claimed in our Canadian patent application of number 380907 in which related compounds are disclosed. Although such compounds are not encompassed by the present invention the Examples of that application further illustrate the wide range of groups of the ~ype C(R )=NR ~hich may be present in the compounds of the present invention.
In the Examples, where possible, the stereochemistry which the compounds are believed to possess has been indicated. However~
some con~amination of a mlnor nature by other isomers may often be present, i.e. by the 5-exo, 6-endo isomer or particularly by the corresponding cis isomer. The e~mpounds are generally obtained in the form o~ a racemic mixture.
The mass spectroscopy data given in these examples i8 usually obtained by direct inlet except for those cases where the compound 05 has a substituent Rl which terminates in an ester grouping when the data is obtained by gas chromatography mass spectroscopy. In certain cases, which are indicated, the compound is converted to a derivative before the mass spectrum is run, usually the methyl ester derivative of a carboxy group, and in those cases, also, gas chromatography mass spectroscopy is used. Such conversion to a methyl ester is readily acheived by solution in methanol, using warming and the addition of NaHC03 as necessary, followed by the addition of an excess of ethereal diazomethane to the methanalic solution, standing, and the removal of solvent. A similar procedure may be used for the preparation,of the methyl ester of varlous other compounds described in the Examples containing a group R
which terminates in a free carboxy group, The W data relate to the main peak(s) of the spectrum and the NMR data similarly generally identify only certain peaks, 2~ the values being referred ~o (CH3)4 Si as the standard.
The numbering used for the s~tb-sections of Example 1 is in accordance with that used in the reaction scheme which follows the Examples. In Example 4, sub-sections relating to the analogous ring unsaturated compounds have been similarly numbered.
EXAMPLES
Example 1: 5-endo-(6~-Carboxyhex-2'Z-enyl)-6-exo-tO-p-fluoro-benzyloxyimin~tethyl)-bicyclo [2,2,1] heptane (1) Maleinaldehydic acid pseudo-ethyl ester 30g of redistilled furan-2-aldehyde is mixed with 600ml dry ethanol and 300mg of methylene blue is added. Dry air is blown gently through the solution and the material is irradiated with a 300W tungsten lamp for about two days un~il t.l.c. in a silica gellether system shows essent~ally no remaining starting material.
The solution is then stirred with vanadium pentoxide for four hours, filtered, and the solvent removed under reduced pressure.

~, , ~2~ 3 The residual oil is distilled under high vacuum to give the title compound as an oil (23,6g, 76%), b.p. 90 - 92C/0.2m~.
(2) Diels-Alder reaction between maleinaldehydic acid psuedo-ethyl ester and cyclopentadiene 05 Freshly cracked cyclopentadiene (9.Og) is mixed with 11.9g of the pseudo ester (1). A gentle warming is observed and the mixture is allowed to stand overnight. The n.m.r. spectrum typically shows the formation of the adduct (2) to be complete and the material is taken to the next step wlthout purification.
(3) 5-endo-Ethoxycarbonyl-6-exo-diethoxymethyl-bicyclo [2,2,1]
hept-2Z-ene The Diels-Alder adduct (2) (lOg) is heated in a mixture of triethyl orthoformate (lOml), dry ethanol (lOOml), and concentrated sulphuric acid (lml). The mixture darkens and after 12 hours is cooled and treated wlth anhydrous potassium carbonate (5g) and ether (150ml). Water is then slowly added with efficient mixing to neutralise the acid. The product is extracted with ether, washed with water and d~stilled to give the title compound as an oil (7~3g, 63~), b.p. 115 - 120C/0.3mm.

(4) 5-endo-Ethoxycarbonyl-6-exo-diethoxymethyl-bicyclo ~2,2,1]
heptane

5-endo-Ethoxycarbonyl-6-exo-diethoxymethyl-bicyclo [2,2,1]
hept-2-ene (30g) is dissolved in 200ml of ethaaol and 0.3g of 10%
palladium on charcoal is added. The mixture is vigorously stirred in 1 atmosphere of hydrogen gas at roam temperature. 1 molar equivalent of hydrogen gas is absorbed and the product is then isolated by removal of the catalyst by filtration through a Celite pad, followed by evaporation of the fil~rate to give a quantitative yield of the title compound as an oil b.p. 105 - 110 C/1.5mm.
(5) 5-endo-Hydroxymethyl-6-exo-diethoxymethyl-bicyclo ~2,2?1]-heptane The es~er (4) (27g) is added in ether to a 10% excess of lithium aluminium hydride (2.1g3 in ether ~ith stirring at reflux temperature. The mixture is boiled for 1 hour after the addition and is then quenched by the addition of wet ether followed by 5%

~ . . .

~ 2~

aqueous sodium hydroxide to precipitate aluminium salts. The colourless organic phase is dried over magnesium sulphate, filtered and evaporated to give the title compound as an oil (20g, 91%).

(6) 5-endo-Cyanomethyl-6-exo-diethoxy-bicyclo [2,2,1] heptane 05 The alcohol (5) (20g~ in a minimun volume of dry pyridine is added slowly to 20g of p-toluenesulphonyl chloride in 130m1 dry pyridine with stirring ~t 0 C. The mixture is kept at 5 C overnight and then poured into a water-ice mixture. The resulting precipitate is filtered off and dried to give the tosylate ester of the alcohol 0 in 85% yield as an off-white solid, m.p. 83 - 86C (dec.).
The tosylate (14g~ in 15ml dimethyl sulphoxide is added to 5g of dry potassium cyanide in 20ml dimethyl sulphoxide. The mixture is stirred under nitrogen and the temperature slowly raised over 1 hour ~o 110C. After 5 hours the reaction mixture is cooled and poured into water. The product is isolated by ether extraction, and purified by distillation to give the title compound (7.8g, 90%), b.p. 115 - 126C/1.5mm.

(7) 6-exo-Diethoxymethyl-5-endo-formylmethyl-bicyclo [2,2,1]
~tane The cyano compound (6) (20g) is stirred at -15 C in 200m1 dry toluene under nitrogen. Di-isobutylaluminium hydride (113ml of a lM solution in hexane) is added to the substrat~ over 25 minutes and the mixture allowed to reach room temperature. After 1 hour, methanol (30ml) is cautiously added, followed by 400m1 of saturated aqueous sodium hydrogen tartrate. The mixture is stirred and heated at 40C for 2 hours. The upper organic layer is separated and the aqueous phase further extracted with ethyl acetate. The combined organic solutions are dried (MgS04) and the solvent removed to gi~e a yellow oil. This is chromatographed on ~lorisil in benzene to give the pure title compound as a colourless oil ~17-2g, 85%), v ax ~film): 1725cm

(8) 5-endo-(6~-Carboxyhex-2~Z-enyl)-6-exo-diethoxymethyl-bicyclo 12,2,1] heptane (4-Carboxy-n-butyl~-triphenylphosphonium bromide ~23.3g) is 5 dried at 75C under vacuum for 2.5 hours. The resulting white ~z~ 3 solid is then cooled, ~he vacuum released to dry nitrogen, and 30ml of dime~hyl sulphoxide is added. A 2M solution of dimesyl sodium in dime~hyl sulphoxide (50m1) is added slowly whlle the mixture is main-tained at 25C with a water bath. After 15 minutes 05 ~he aldehyde (7) (5.0g) is added to the deep red ylide thus produced.
The mixture is stirred overnight and then the solvent is removed at 55 ~ 60 C under vacuum. The residue is dissolved in water, and the aqueous phase is extracted with ether and then carefully acidified to pH4 with 2N HCl. The precipitate is extracted into ether and the ethereal solution is dried and concentrated to give the title compound as an oil (3~7g, 55%).

(9) 5-endo-(6'-Carboxyhex-2'Z-enyl)-6-exo-formyl-bicyclo [2,2,1]
heptane The acid/acetal (8) (1.8g) is dissolved in 200ml chloroform and 50ml of concentrated hydrochloric acid is added to form a two phase system. The mixture is vigorously stirred for 90 minutes and is then extracted with ether and the ethereal solution dried and concentrated. The residual oil is purified by silicic acid chromatography, the oil being applied to the column (prepared by slurrying lOg of Unisil silicic acid - Clarkson Chemical Co., USA - in hexane and pouring into a glass chromatography column) in hexane and elution being carried out with increasing proportions of diethyl ether in hexane up to pure diethyl ether. The chromato-graphy gives the title compound as a colourless oil (1.4g, 83%), ~ma (film) 795,1715 (broad), 270Qcm , ~(CDC13)1.2 to 2.6 (18H,m), 5.4 (2H,m), 9.6 (lH,d).
Note: Care should be taken to avoid contact of this compound ~ith methanol since it very readily forms a dime~hyl acetal.

(10) 5-endo-(6'-Carboxyhex-2'Z-enyl)-6-exo-(0-p-fluorobenzyl-oxyiminomethyl)-bicyclo [2,2,1] heptane The acid/aldehyde (75mg~ is heated with lOOmg of p-fluoro-benzyloxyamine hydrochloride in dry pyridine (5ml) for 1 hour at 60CO The pyridine is removed in vacuo, and the residue partitloned between water a~d diethyl etherO The ether phase is evaporated to dryness and the resulting product is purified by liquid-gel partition - ~ \
~29~

chroma~ography using a 400 x 15mm column o~ Sephadex LH 20 substi-tuted with Nedox 1l14 olefin oxide to 20% w/w and eluting with dichloroethane/hexane/ethanol (100:100:5 v/v/v) cont~ining 0.1% v/v of acetic acid at a flow rat~ of 12ml/hour. The chromatography 05 gives the title compound as a colourless oil (50mg), ~max (CH30H) 263nm, max 650; MS:M 373 (as methyl ester:~ 387), ~(CDC13) 5.00-5.05(s,2H), 5.35(m,3H), 6.5(d,lH), 6.9-7.4(m,4H).
The p-fluorobenzyloxamine hydrochloride is prepared as follows:
N-Hydroxyphthalimide (12.0g) in 130ml dimethyl sulphoxide is treated with anhydrous finely divided potassium carbonate (6.6g), when the dark red colour of the anion develops. The mixture is then treated dropwise at room temperature with p-fluorobenæyl chloride (20g~ and the mixture is stirred overnight or until the red colour is discharged. The reaction mixture is poured into water, and the resultant crystalline product is filtered off.
Recrystallisation from ethanol gives N -p-fluorobenzyloxyphthalimide in pure form as white needles. (16.4g, 8~%), m.p. 156 - 157C.
The imide (13.5g) is boiled in 40~ml ethanol with 99~ hydrazine hydrate (2.5g) for two hours. The mixture is cooled, 7ml of concentrated hydrochloric acid is added and the precipitate of phthalhydrazide is removed by filtration. The solution is concen-trâted to dryness and the salt taken up in water, washed wlth ether and then basified. The free base is taken into ether to give an ethereal solution which is washed with brine and then dried (MgS04).
Dry hydrogen chloride gas is passed into the ethereal solution to deposit pure p-fluorobenzyloxyamine hydrochloride which is recry-stallised from ethanol as white plates ~7.~g, 90%), m.p. 298 - 300C.
Example_2_ 5-endo-(6'-Carboxyhex-2'Z-enyl)-6-exo-~N-p-fluoro-benzoylhydrazonomethyl)-bicyclo [2,2,1] heptane 5-endo-(5~-Carboxyhex-2'Z-enyl)-6-exo-formyl-bicyclo [2,2,1]
heptane [lOOmg prepared as described in Example 1(9)3 is heated with p-fluorobenzoic acid hydrazide (40mg) in tetrahydrofuran (5ml) for 1.5 hours at 40C. The solvent is then evaporated and the residual oil is purified by silicic acid chromatography, the oil being applied to the column (~hich is prepared by slurrying .

;3 lOg of Unisil silicic acid - Clarkson Ch0nical Co " ~SA - in hexane and pouring into a glass chromatography column) in hexane and elution being car~ied out wlth ilcreasing proportions of diethyl ether in hexane up to pure diethyl ether. The chromato-05 graphy gives the title compound as an oil (27mg) which is notreadily soluble in ether, ~ma (CH30H3 254nm, ~max 12,350; MS:M 386 (the ~ethyl ester trimethylsilyl ether derivative runs as a single peak on gas chromatography mass spec~roscopy and has M 472);
~(CDC13) 5.35(m,2H); 7.1 and 7.9 (each m, together 4H), 7.6(br,1H).
The p-fluorobenzoic acid hydrazide is prepared as follows:
Ethyl p-fluorobenzoate (8.4g) is refluxed with hydrazine hydrate (3.75g) for 3 hours. The mixture is then cooled, ether is added and the precipitate of p-fluorobenzoic acid hydrazide (3.2g) is removed by filtration, washed with ether and desiccated, m.p.
149 - 151C.
Example 3: 5-endo-(6'-Carboxyhex-2'Z-enyl)-6-exo-[~-(phenylcarbamoyl)-hydrazonomethyl]-bicyclo r2,2,_] heptane 5-endo-(6'-Carboxyhex-2'Z-enyl)-6-exo-formyl-bicyclo [2 9 2,1]
heptane [lOOmg; prepared as described in E2ample 1(9)] is heated with phenyl semicarbazide (80mg) in tetrahydrofuran or 2 hours at 40 C. The solvent is then evaporated and the residue purifed by 6ilicic acid chromatography as described under Example ~ followed by liquid gel partition chromatography u~ing a 400 x 15mm column of Sephadex (trade na~ne) L~20 substituted with Nedox (trade name) 1114 olefin oxide to 20~ w/w and elutlng with dichloroethane/
hexane/ethanol tlOO:100:5 v/v/v) containing 0.1~ v/v of acetic acid at a flow rate of 12ml/hour. The chromatography gives the title compound as an oil (64mg), ~ (CH30H) 248.5nm, ~ 23,500;
MS:M 383; ~(CDC13) 5.35(m,2H), 7.0-7.6(m,5H), 3.05(br,1H), 9.7(br,lH).
The phenyl semicarbazide is prepared as follows: Ethyl-N-phenyl carbamate (8.25g) is refluxed with hydrazine hydrate t3.75g) for 3 hours. The mixture is evaporated to dryness and the residue is treated with ether~ and the solid phenyl semicarbazide (1.5g~
is filtered off, washed with ether and desiccated, m.p. 122 - 124 C.

2~

Example 4: 5-endo-(6'-Carboxyhex-2'Z-enyl)-6-exo-(0-p-fluoro-benzyloxyiminomethyl~-bicyclo [2,2,1] hept-2Z-ene (1), (2), (3) 5-endo-Ethoxycarbonyl 6-exo-diethoxymethyl~bicyclo ~2,2,1]-hept-2Z-ene Maleinaldehydic acid pseudo-ethyl ester is prepared as described 05 in Example 1(1) and reacted with cyclopentadiene in a Diels-Alder reaction as described in Example 1(2). The Diels-Alder adduct is treated with ethanol under acidic conditions as described in Example 1(3) to give 5-endo-ethoxycarbonyl-6-exo-diethoxymethyl-bicyclo [2,2,1] hept-2Z-ene (3).
(5) 5-endo-Hydroxymethyl-6-exo-diethoxymethyl-bicyclo [2,2,1] hept -2Z-ene The ester (3) is added in ether to lithium aluminium hydride (10% excess) in ether with stirring at reflux temperature. After the addition, the mixture is boiled for a further 1 hour. The reaction is quenched with wet ether and then 5% aqueous sodium hydroxide to precipitate aluminium. The colourless organic phase~
is filtered, dried over anhydrous potassium carbonate, and the resulting alcohol (85 ~ 90% yield) used directly in the next stage.
(6) 5-endo-Cyanomethyl-6-exo-diethoxymethyl-bic~clo [2~2,1] hept -2Z-ene The alcohol (5) (7g~ in 15ml dry pyridine is added slowly at 0C to p-toluenesulphonyl chloride (7.5g) in pyridlne (45ml). The mixture is kept overnight at 10C and then quenched by pouring over ice with vigorous shaking. The product is extracted with ether, washed consecutively with water, O.lM sodium earbonate and brine, and then dried (K2C03) and the solvent removed to give the tosylate ester of the alcohol as a colourless oll in high yield.
The tosylate ester (12g) in dimethyl sulphoxide (15ml) is added with stirring to potassium cyanide (3g) in dimethyl sulphoxide (20~1). The mixture is heated to 100C under nitrogen ~or 6 hours and is then cooled, poured into water and the product taken into ether. The solvent is removed and the residue distilled to glve title compound as an oil (6.6g, 88~), b.p. 112 - 124 C/1.8mm.

, . .

(7) 6-exo-Diethoxymethyl-5-endo-formylmethyl-bicyclo [2,2,1] hept -2Z-ene Di-isobutylaluminium hydride (25ml of lM solution in hexane) is added with stirrlng over a 10 minute period to the cyano 05 compound (6) (5.0g) in dry toluene (70ml) at -15C under nitrogenO
After a further 1 hour at roon temperature the reaction i8 terminated by the additon with caution of methanol (6ml), followed by saturated aqueous sodium hydrogen tartrate (95ml). The mixture is then stlrred and heated at 40C for 2 hours. The organic phase is separated and the aqueous layer is further extracted with ethyl acetate, the combinèd organic solutions being dried and stripped of solvent to give the product as a yellow oil. Chromatography on Florisil (trade name) in ben7.ene gives the pure tltle compound as a colourless oll (3.2g, 63~) Vmax(film): 1725cm (8) 5-endo-Carboxyhex-2tZ-enyl-6-exo-diethoxymethyl-bicyclo [2,2,1]
hept-2Z-ene (4-Carboxy-n-butyl)-triphenylphosphonium bromide (7.0g) is dried a~ 75C under vacuum for 90 minutes. The white solid is cooled, the ~acuum is released to dry nitrogen and lOml of dimethyl sulphoxide is added followed by 15ml of a 2M solution of dimesyl sodium in dimethyl sulphoxide. The temperature is maintained at 25C and the aldehyde (7) (1.5g) is added to the deep red yield solution. After stirring overnight the solvent is removed at 55 - 60C under vacuum. The residue is dissolved in water, extracted with e~her, and the aqueous phase carefully acidified to p~4 with 2N ~Cl. The mixture is extracted ~lth ether and the ethereal solution d~ied and concentrated to give the title compound as an oil ~1.34g, 66%)u (9') 5-endo-(6 t -Methoxycarbonylhex-2'Z-enyl)-6-exo-fonmyl-bicyclo [2,2,1] hept-2Z-ene The acid/acetal (8) (Sg) in ether is treated wlth excess ethereal diazomethane to fonm the methyl ester and then ~he ketal protecting group is removed by dissolving the compound in 215ml chloroform and adding concentrated hydrochloric acid (55ml) to fonm a two-phase system. The mixture ls ex~racted with ether and the ethereal solution dried and concentrated to give the title compound as an oil (3.38g9 90~).
Note: Care should be taken to avoid contact of this compound with methanol since it very readily forms the dimethyl acetal.
05 (10'~ 5-endo-(6'-Methoxycarbonyl-hex-2'Z-enyl)-6-exo-(0-p-fluoro-benzyloxyiminomethyl)-bicyclo [2,2,1] hept-2Z-ene The esterJaldehyde (9~ (lOOmg) is heated with p-fluorobenzyl-oxyamine hydrochloride (lOOmg) in dry pyridine (5ml) for 3 hours at 60 C. The pyridine ls removed in vacuo, the residue is partl-tioned between water and diethyl ether and the ether phase is evaporated to dryness. The product is purified by liquid-gel partition chromatography using a 400 x 15mm column of Sephadex LH20 (trade name - Pharmacia) substituted with Nedox 1114 olefin oxide (Ashland Chcmical Co. USA) to 50% w/w and eluting with hexanejdichlorethane (90:10 v/v) at a flow rate or 12ml/hour.
The chromatography gives the title compound as an oil.
(10) 5-endo-(6'-Carboxyhex-2'Z-enyl)-6-exo-(0-p-fluorobenzyloxyimino-methyl)-bicyclo [2,2,1] hept-2Z-ene Ester cleavage in compo~nd (10') is effected by heating in aqueous methanol with potassium hydroxide (OolN) for 3 hours at 40C. The product is again purified by liquld-gel chroma~ography but using a 400 x 15mm column of Sephadex LH20 substituted with Nedox 1114 olefin oxide to 20~ w/w and eluting with dichloroethane/
hexane/ethanol (100:100:5 v/v/v) containing 0.1~ v¦v of acetic acid at a flow rate of 12ml/hour. The chromatography gives the title compound as an oil in 50 - 60% overall yield from conpound (9), ~max (CH30H) 263nm, &ma 625; MS (methyl ester):M 371.
Example 5: 5-endo-(6'-Carboxyhex-2'Z-enyl)-6-exo-(N-p-fluoro-benzoylhydra onomethyl)-bicyclo ~2,2,1~ hep~-2Z-ene (1) 5-endo-(6l-Carboxyhex-2'Z-enyl~-6-exo-formyl-bicyclo [2,2,13 hept-2Z-ene 5-endo-(6'-Carboxyhex-2'Z-enyl)-6-exo-diethoxymethyl-bicyclo [2,2,1] hept-2Z-ene ~prepared as described in Example 4(8~] is reacted as descrlbed for the analogous heptane in Example 1(9) to ~2~

give the title co~pound,~ (CDCl3) 2.35(tl2H), 2,B8(m71H), 3.04(m,1H), 5.40(m,2H), 6.20(m,2H), 9.78(d,1H), 11.1(br,1H).
(2) 5-endo-(6'-Carboxyhex-2'Z-enyl)-6-exo-(N-p-fluorobenzoyl hydrazonomethyl)-bicyclo [2,2,1] hept-2Z-ene 05 The acid/aldehyde (75mg) prepared in (1) above is reacted with p-fluorobenzoic acid hydrazide by the procedure described in Example 2, bu~ using dioxane rather than tetrahydrofuran as the solvent, and the reaction mixture worked up as described therein to give the title compound as an oil (lOOmg),~ (CH30H) 256nm, 14,590, MS:M 384; ~(CDC13) 5.35 (m,2H), 6.15 (m,2H), 6.9-8.1 (m,5H).
In a variant of this procedure the reaction with p-fluorobenzoic acid hydrazide is carried out with 5-endo~(6'-methoxycarbonylhex-2'Z-enyl)-6-exo-formyl-blcyclo [2,2,1] hept-2Z-ene to give 5-endo-(6'-methoxycarbonylhex-2'Z-enyl)-6-exo-N-p-fluorobenzoylhydrazono-methyl)-bicyclo [2,2,1] hept-2Z-ene which is hydrolysed by the procedure of Example 4(10) to give 5-endo-(61-Carboxyhex-2'Z-enyl)-6-exo-(N-fluorobenzoylhydrazono~ethyl~-bicyclo 12,2,1] hept-2Z-ene.
Example 6: 5-endo-(6'-Carboxy-2'Z-enyl)-6-exo-[N-(phenylcarbamoyl)-hydrazonomethyl]-bicyclo 12,2,1] hept-2Z-ene 5-endo-6'-(Carboxyhex-2'Z-enyl)-6-exo-fonmyl-bicyclc 12,2,1]
hept-2Z-ene 150mg; prepared as described in Example 5(1)] ls reacted with phenyl semicarbazide according to the procedure described in Example 3, but using ethanol as the solvent in place of tetrahydrofuran, and the reaction mixture worked up as described therein to give the title compound as an oll (53mg), ~ (CH30H) 249.5, 22,670; MS:M 381; ~CDCl3) 2.9 (m,2H), 5.4 (m,2H), 6.2 (m,2H), 7.0-7.6 (m,5H), 8.I (br,lH), 9~75 (br,lH).
Example 7: 5-endo-(6'-Carboxyhex-2'Z-enyl)-6-exo-[l'-(p-fluoro-benzyloxyimino)-ethyl]-bicyclo 12,2,1] heptane and 5-endo-(6'-Carboxyhex-2'Z-enyl)-6-exo-[1'-(diphenylmethyloxylmino)-ethyl]-bicyclo 12,2~1] heptane ~1) 5-endo-(6'-Carboxyhex-2'~-enyl)-6-exo-(1'-hydroxyethyl)-bicyclo 12,2,1] he~
5-endo-(6'-Carboxyhex-2'Z-enyl)-6-exo-fonmyl-blcyclo 12,2,11 heptane [250mg; prepared as described in Example 1(93] is dissolved ~2~

in dry tetrahyd~ofuran (10ml) at 0C and treated under nitrogen and with stirring over 30 minutes with a lM solution of methyl magnesium iodide in ether (Zml). The mixture is stirred under nitrogen overnight whilst it is allowed to come to room temperature.
S The reaction is then quenched by the addition of dilute aqueous hydrochloric acid and the produc-t is extracted wi~h ether (3x), the e~her solution is dried and evaporated to give the title compound as an oil (200mg). A small sample is treated to form the methyl ester trimethylsilyl ether and on gas chromatography mass spectroscopy on a 3% OVI column this shows a carbon value of 18.2, a M value of 352 and a base peak of 117.
Chromatography on a column of Sephadex LH20 substituted with Nedox 1114 olefin oxide to 20% w/w (Lipidex) of the bulk af the oily product using a mixture of (all proportions by volume) 100 l5 parts of hexane, 100 parts of 1,2-dichloroethane, 5 parts of ethanol and 0.1% of the total of glacial acetic acid, as eluant yields the two isomeric secondary alcohols differing in the con-figuration ~t ~he newly introduced asymmetric carbon a~om ~-CHO~.CH3).
~.m.r. spectorscopy on these isomeric products in CDC13 gives the 20 following~ values: First isomer eluted: 7.3 (s, broad, lH), 5.45 (m,2H), 3.6 (m-qxd,iH~ 2.5-1.0 (m,2lH), 1.~ (d). Second isomer eluted: 7.8 ~s, broad, lH), 5.4 (m,2H), 3.55 (m-qxd), 2.5-1.0 (~,18H), 1.2 (d).
(2~ 5-endo-(6'-Carboxyhex-2'Z-enyl)-6-exo-acetyl-bicyclo l2,2,1 heptane The procedure described under (1) is repeated with 600mg of the acid/aldehyde to give a mixture of the two isomeric alcohols ~500mg).
This mixture is dissolved in pure acetone (15ml) and the solution is cooled to 0C. Jones reagent ~600~1 of a solution prepared by 30 dissolving 26.7g of chromic anhydride in 23ml of concentrated sulphuric acid and diluting to 100ml with water, followed by filtra~ion) is added slo~ly to the cooled solution with vigorous stirring over 15 minutes. After a further 10 minutes stirring a~
0C ~he mixture is poured into water and the product extracted ~L2~6~

with ether. The ether solution is dried and evaporated to give the tltle compound as an oil (about 75% overall yield from formyl compound), S(CDCl3) 10.0 (s-broad, lH), 5.4 (m,2H), 2.8-1.1 (m,21H), 2.2 (s). G.C.M.S. (3% OVI) on the methyl ester gives a carbon 05 value of 17.15, a M value of 278 and a base peak of 43/137.
(3) 5-endo-(6'-Carboxyhex-2'Z-enx~)-6-exo-~1'-(p-fluoro benzyloxyimino)-ethyl] bicyclo [2,2,1] heptane The acid/ketone (lOOmg) prepared as described in (2) is heated with p-fluorobenzyloxyamine hydrochloride (lOOmg) in dry pyridlne (5ml) at 60 C for 2 hours. The pyridine is removed ln vacuo and the residue is partitioned between water (pH 4) and diethyl ether. The ether is remo~ed in vacuo to give an oil which is purified by liquid-gel partition chromatography on a column of Sephadex LH20 substituted with Nedox 1114 olefin oxide to 20% w/w, eluting with dichloroethanelhexane/ethanol (100:100:5 v/v¦v) containing 0.1~ v/v of acetic acid. The chromatography gives 5-endo-(6'-carboxyhex-2tZ-enyl)-6-exo-[1'-(p-fluorobenzyloxyimino~-ethyl]-bicyclo [2,2,1] heptane as an almost colourless oil (9Omg), ~max ~CH30H) 263nm, ~ma 620; MS~methyl ester):M 401; ~(CDCl3) 1.85 (s, about 3H), 5.00 (s,2H), 5,30 (m,2H), 6.9-7.5 (m,4H~.
In a variant of the reaction described above the p-fluoro-benzyloxyamine hydrochloride is replaced by dipheylmethyloxyamine hydrochloride (prepared by an analogous procedure to that described for the former compo~nd in Example 1) tG give 5-endo-(6'-carboxyhex-2'Z-enyl-6-exo-[1'-(diphenylmethyloxyimino)-ethyl]-bicyclo [2,2,1]
heptane as an oil (109mg), ~ 258nm7 ~ax 590; MS:M absent, m/e 167 base peak; ~(CDCl3~ 1.9~ (s,3H) 5020 (m,2H), 6.~0 (s,1H), 7030 (~,10H~.
Example 8: 5-endo-(6'-Carboxyhex-21Z-enyl)-6-exo-[l'-(diphenyl-acetylhydrazono)-ethyl~-bicyclo 12,2,1] heptane and 5-endo-(6'-Carboxyhex-2'Z-enyl)-6-exo-[1'-(p-fluorobenzoylhydrazono)-ethyl]-bicyclo [2,2,1] heptane 5-endo-(6'-Carboxyhex-2'Z-enyl3-6-exo-ace~yl-bicyclo ~2,2,1]
hep~ane [lOOmg; prepared as described in Example 7~2)] is reac~ed wi~h diphenyl acet~c acid hydrazide (prepared analogously to ~L2~4~B3 p-fluorobenzoic acid hydrazide as described in Example 2~ by the procedure described in Example 2 but using ethanol as solvent in place of tetrahydrofuran. The reaction mix~ure ls worked up as descrihed in Example 2 to ~ive 5-endo-(6'-carboxyhex-2'Z-enyl)-6-exo-05 ~ (diphenylacetyl-hydrazono)-ethyl]-bicyclo [2,2,1] heptane as an oil (68mg), ~ma 235nm, ~ a 12,300; MS:M 472; ~(CDC13) 1.82 (s,3H), 5.30 (m,2H), 6.02 (s,lH), 7.30 (m,lOH), 9.6 (br,lH).
In a variant of the reaction described above the diphenyl acetic acid hydrazide is replaced by p-fluorobenzoic acid hydrazide, effecting the reaction in pyridine as solvent with a reaction temperature of 4 hours at 60C, ~o give 5-endo-(6'-Carboxyhex-2'~-enyl)-6-exo-[1'-(p-fluorobenzoylhydrazono)-ethyl]-bicyclo ~2,2,1]
heptane.
~xample ~: 5-endo-(6'-Carbox hex-2'Z-en 1)-6-exo-~1'-[N-( he 1-Y Y p ny carbamoyl)-hydrazono~-ethyl3-bicyclo [2,2~1~ heptane and 5-endo-t6'-Carboxyhex-2'Z-enyl)-6-exo-~ -(m-tol ~ drazono]-ethyl~-bicyclo [2 2,1] heptane 5-endo-(6'-Carboxyhex-2'Z-enyl)-6-exo-acetyl-bicyclo [2,2,1]
heptane ~lOOmg: prepared as described in Example 7(2)] is reacted wi~h phenyl semicarbazide by the procedure described in Example 3 but using e~hanol in place of tetrahydrofuran as solvent. The reaction mixture is worked up as described in Example ~ to give 5-endo-(6'-Carboxyhex-2'Z-enyl)-6-exo-~1'-[N-phenylcarbamoyl)-hydrazono~-ethyl~-bicyclo [2,2,1] heptane as an oil (11nmg) which crystallises rom ethanol at -20 C9 m.p. 141.7 C; ~ (CH30H) 248nm, max 21,000; MS:M 397; ~(CDC13) 1.98 (s,2H), 5.4 (m,2H), 7-0-7-6 ~m,5H), ~.2 (br~lH), 9~3 (br,lH~.
In a varian~ of the reaction described above the phenyl semicarbazide is replaced by m-tolyl semicarbazide (prepared with m.p. 109.8C by an analogous procedure to that described in Example 3 for the former compound) to give 5-endo-(6'-carboxyhex-2~Z-enyl)-6-exo-{1'-[N-(m-tolylcarbamoyl)-hydrazono]-ethyl~-bicyclo [2,2,1] heptane as an oil (92mg), MS:M 411, ~(CDC13) 1~93 (s,3H), 2.34 (s,1H), 5.38 ~m,2Hj, 6.8-7~4 ~m,4H), 8.2 (br,1H), 9.3 (br,1H~.

~2~

Example 10: 5-endo-(6'-Carboxyhex-2'Z-enyl)-6-exo~ [N-(phenyl-carbamoyl)-hydrazono]-ethyl}-bicyclo [2,2,1] bept-2Z-ene (1) 5-endo-(6'-Carboxyhex-2'Z-enyl)-6-exo-(l'~hydroxyethyl)-bicyclo [2,2,1] hept-2Z-Pne 05 5-endo-(6'-Carboxyhex-2'Z-enyl)-6-exo-formyl-bicyclo [2,2,1]
hept-2Z-ene [prepared as described in Example 5(1)] is reacted with methyl magnesium iodlde by the procedure of Example 7(1) and the reaction mxiture is worked up as described therein to give the ~itle compound as a mixture of the two isomeric alcohols, MS
(methyl ester trimethyl silyl ether):M 350 together with m¦e of 284 (M-66), 143 (M-66-141) and 117 (CH3.CH.OTMS), ~(CDC13), 2.80 (m,2H), 3.63 (m,lH), 5.42 (m,2~)~ 6.12 (m,2H), 6.23 (br,2H).
(2) 5-endo-(61-Carboxyhex-2'Z-enyl)-6-exo-acetyl-bicyclo [2,2,1]
hept-2Z-ene The acid/alcohol prepared in (1) above is oxidized by the procedure of Example 7(2) to give the title compound as an oil, MS
(methyl ester): M 276 together with m/e of 211 ~M-65) and 179 (M-65-32); ~(CDC13), 2.22 (s,3H), 2.86 (m,2H), 5.40 (m,2H), 6.20 (m,2H) and 9.5 (br,lH).
(3) 5-endo-(6'-Carboxyhex-2'Z-enyl)-6-exo- ~'-[N-(phenylcarbamoyl)-hydrazono)-ethyl~-bicyclo [2,2,1] hept-2Z-ene The acid/ketone (50mg) prepared as described in (2) is reacted with phenyl semicarba~ide by the procedure described in Example 3 but using ethanol ln place of tetrahydrofuran as solvent. The reaction ~ixture is worked up as described ln Example 3 to give the title compound as an oil (45mg), ~ (CH OH) 248nm, &
max 3 max 2i,630; ~(CDC13), 2.00 (s,3H), 2.9 (m,2H), 5.4 (m,2H), 6.22 (m,2H)~
7.0-7.6 (m,5H), 8.25 (br,lH), 9.20 (br,lH).
Example 11: 5-endo-t6'-Carboxyhex-2'Z-enyl)-6-exo~ N-(phenyl carbamoyl)-hydra~ono~-propyl}-bicyclo 12,2,1~ heptane (1) 5-endo-~6'-Carboxyhex-2'Z-enyl)-6-exo-(1'-hydroxypropyl?-bicyclo ~2,2?1~ heptane 5-endo-(6'-Carboxyhex-2'Z-enyl)-6-exo-formyl-bicyclo 12,2,1 heptane ~600mg; prepared as described in Example 1(9)~ is dis-solved in dry tetrahydrofuran (25ml) at O C and treated under nitrogen and with stirring over 30 minutes with a 0.5M solution of ethyl magnesium bromide in ether (lOml). The solution is allowed to warm up to room temperature and is then treated with dilute aqueous hydrochloric acid and -the product extracted with ether (3x). The ethereal extracts are dried and evaporated to give the title compound as an oil. A small sample is treated to form the methyl ester trimethylsilyl ether and on gas chromatography mass spectroscopy this shows M 366 together with m/e of 337 (M-29), 276 (M-90) and 131 (C2~5.CH.OTMS).
The bulk of the oil is subjected to gel partition chromato-graphy on a column of Sephadex LH20 substituted with Nedox 1114 olefin oxide ~o 20% w/~ (Lipidex) using as eluant a mixture of (all proportions by volume) 100 parts hexane, 100 parts 1,2-dichloroethane, 5 parts ethanol and 0.1% of the total of glacial acetic acid. The chromatography separates the prGduct into two main zones corresponding to the two isomeric secondary alcohols differing in configuration at the newly introduced asymmetric carbon atom (-C~OH.CH3). N.m.r. spectroscopy on these isomeric products in CDC13 gives the following S values. First isomer eluted: 7.5 (broad, 2H), 5.4 (m, 2~) 3.22 (d x t, lH), 2.5-0.9 (m, 25H~. Second isomer eluted: 7.5 (br, 2H), 5.4 (m, 2H), 3.40 (m, 1~), 2.5-1.0 (m, 25H).
(2) 5-endo-(6'-Carboxyhex-2'Z-enyl)-6-exo-propionyl-bicyclo ~ 2?2,}_ heptane The acid/alcohol (1) of the first zone (145mg) is oxidized with Jones reagent at 0C in acetone in an exactly analogous manner to that described in Example 2(2) to give the title compound as an oil (95mg), MS(methylester): M 292 together with m/e of 235 (M-57) and 151 (M-141) (a single peak being obtained on gas chromatography); ~(CDC13 9.0 (br, 1~) 7 5.35 (~, 2~), 2.7-0.9 (m, 23~).
The alcohollacid (1) of the second zone is treated similarly ~o give the same prod~c~ (lOSmg)~

~2~

(3) 5-endo-(6'-Carboxyhex-2'Z-enyl)-6-exo ~l'-[N-(phenyl c amoyl)-hydra~ono]-propyl~-bicyclo ~2,2,1~ heptane The acid/ketone prepared as described in (2) is reacted with phenyl semicarbazide in ethanol by the procedure described in 05 Example 9 and the reaction mixture worked up as described therein to give the title c~mpound as an oil, ~ (CH30H) 248nm, 23,200; M$:M 411.
Example 12: 5-endo-(6'-Carboxyhexyl)-6-exo-(0-p-fluorobenzyl-oxyiminomethyl)-bicyclo 12 t 2,1] heptane IO (1) 5-endo-(6'-Carboxyhexyl)-6-exo-formyl-bicyclo [2,2,1] heptane 5-endo-(6'-Carboxyhex-2'Z-enyl)-6-exo-diethoxymethyl-bicyclo [2,2,1] heptane [300mg; prepared as described in Example 1 (8)]
is stirred with 10% palladium charcoal (50mg) in absolute ethanol (lOml) for 30 minutes whilst continuously passing hydrogen gas through the suspension. The catalyst is removed by filtration through a Whatman No. 550 filter disc and ~he ethanol is then removed ln vacuo. The oily residue of 5-endo-(6'-carboxyhexyl)-6-exo-diethoxymethyl-bicyclo 12,2,1] heptane is dissolved in CHC13 (50ml), 2N aqueous hydrochloric acid (50ml) is added, and the two phase system is stirred for 6 hours at room temperature. Water (lOOml) is then added, followed by diethyl ether (150ml) and after vigorous shaking the organic phase is separated. The aqueous phase is extracted with a further 150ml of diethyl ether and the two ether extracts are combined. Evaporation of the diethyl ether from the dried solution gives 5-endo-(6'-carboxyhexyl)-6-exo-fon~yl-bicyclo [2,2,1] heptane as an oil (152mg), ~ (film) 1715cm 1 (broad); MS (methyl ester): M /M ~1 266/267 - single peak;
~ (CDC13) 1.1-2.6 (m, 22~1), 9.6 (d, lH), 10.0 tbr, lH).
(2~ 5-endo-~6'-Carboxyhexyl)-6-exo-(O-p-fluoroben7yloxyimino-methyl)-bicyclo ~2,2,1] heptane The acid/aldehyde (1) (50mg) is reacted in dry pyridlne with p-fluaroben7yloxyamine hydrochloride according to the procedure described in ~xanple 1(10~ and the reaction mixture is worked up as described therein to give the title compound as an oil (49mg), max ~C~30~) 263nm, e max 720; MS (methyl ester): M 389-Example 13: 5-endo-(67-Carboxyhexyl)-6-exo~(0-diphenylmethyloxy-iminomethyl)-bicyclo [2,2,1] heptane 5-endo-(6'-~arboxyhexyl)-6-exo-formyl-bicyclo ~2,2,1] heptane [50mg; prepared as described in Example 12(1)] is reacted in dry 05 pyridine with diphenylmethyloxyamine hydrochloride according to the procedure descrlbed in Example 1(10) and the reaction mixture is worked as described therein to give the title compound as an oil (50mg), ~max (C~30H) 248nm, ~max 415, MS (methyl ester):M not apparent, the spectrum being dominated by the m/e 167 ion;
~ (CDC13) 6.15 (s, lH), 6.55 (d, about 0.5H, wC = N, other isomer not detectable), 7.30 (m, lOH,).
Example 14: 5-endo-(6'-Carboxyhexyl)-6-exo-[N-(phenylcarbamoyl)-hydrazononethyl~-bicyclo 12.2,1] heptane 5-endo-(6'-Carboxyhexyl)-6-exo-formyl-bicyclo [2,2,1] heptane ]5 [50mg; prepared as described ln Example 12(1)] is reacted in tetrahydrofuran with phenyl semicarbazide according to the procedure described in Example 3 and the reaction mixture is worked up as described therein to give the title compound as an oil (48mg, )~ max (CH30~ 248nm,s max 15,750, MS M+385-Example 15: 5-endo-(6'-Carboxyhex-2'Z-enyl)-bicyclo[2,2,1] hept-2Z-enes and heptanes containing other 6-exo substituents (A) The additional compounds of fonmula A

X ~V C02H

Y , NoR3 r listed in Table 1 with UV and MS data are prepared as described in Example 1 (for ring saturated compounds) or as described in Example 4 (for ring unsaturated compounds) using the appropriate oximating a8ent. This agent may however either be reacted with a precursor in which the carboxy group is in the free state as in Example 1 or is protected as in Example 4.

- 3~ -COMPOUND U.V~ DATA (CH30H) M~S. DATA
XY R3 ax max (Methyl ester) . _ _ . _ __ __ = -CH2 ~ 257. 370 367 . ..
= -CH2 ~ Cl 267 270 401/3 _ .... _ =-CH ~ ) 258450 (1~
.
= -(CH2~3 ~ 261 270 295 __ =( 2)2 ~ 2711450 397 _ .
=-(CH2)2- ~ Cl 2811550 4311433 .. . _ = -(CH2)2- ~ F 279 ~ 1320 415 _ .
H,HCH2 ~ 267 350 403/405 H,H-CH2 ~ Cl 272 380 4371439/441 ~ _.. . ~
H,H-C~2 - ~ 263 . 605 437 _ ~ _ . ._ _ . . ~ _ _ H,H 2 258 405 (1) H,H ~~ 2~4 3 No. U.V. Chro~ophore 349 .

eontinued....

TABLE 1 continued COMPOUND U.V. DATA (CH30H) M.S. DATA
XY R ~:~ (Methyl ester) ~,~ 272 1790 t (1) M not apparent: ion at 167 (C6H5)2CH~
(2) Free acid by direct inlet.
N.m.r. data on the bicyclo [2,2,1] heptane compounds (XY is H,H) of Table 1 is presented in Table 2. All of the ~ values 05 relate to CDC13 solution.

... __ . _ ......... __ Proton of Protons of group R3 Ethylenic aldoxime _ _ _ COMPOUND protons of group R
Rgroup R (1) aliphatic (2) aromatlc _ . .. ____ ~ . __ -CH ~ 15.30 (m) 2H 6.60 (d) 6.20 (s) lH 7.35 (m) 10~
. . . . _ __ -(C~2)4CH35.35 (m) 2a 6.50 (d) 4 00/~.05 _ H2 ~5~30 (m) 2H 6.55 (d) 5.00/5.05 7.1 - 7.4 Cl . (s) 2H (m) 4H

-CH2 ~ Cl5.30 (m) 2H 6.55 (d) 5.10/5.15 7.1 ~ 7.5 Cl . _ ~s) 2U (m~ 3H

continued....
,:

:~2~ 3 TABLE 2 continued Proton of Protons of group R3 Ethylenic aldoxime COMPOUND protons of group R .. _ _ _ group R (1) aliphatic (2) aromatic -CH2 ~5.35 (m) 2H 6.80 (d) 5.10/5.15 7.4 - 7.7 CF3 (s) 2H (m) 3H

~ ~ ~5 ~ _ ~

(1) Only the signal corresponding to the proton of one of the isomers (syn and anti) is observed as the signal corresponding to the proton of the other isomer is obscured by the signal corres-ponding to the aromatic R protons; the strength of the signal is 05 therefore less than lH.
(2) The signals corresponding to these protons in the two isomers overlap and cannot be separately recorded.
(B~ The additional c~mpounds of for~ula ~ ' .
¦ ~ ~ 2 ~ N-NH-COR

listed in Table 3 below are prepared as dPscribed in Example 2 ~o uslng the appropriate hydraz~de in tetrahydrofuran, or in dioxane or ethanol if it is desired to improve the solubility of the hydrazide~

COMPOUND V.V. Data (C1~30H) M.S. Data , R3 ~ M
maxmax OCH3 267.522,400 398 ~ N(CH3)2 31723,200 -CH2 ~ 23314,300 382 -C~ 23613,~50 ~i~

/ \ 21922,650 -CHz-CH- ~ ~ 472 2 23515,400 _ _C~2-O ~ 22016,050 398 ~ 236.5 . 18,800 - -C ~ 25517,50~ 456 .
2~5.516,600 ~ 3014,560 .

( 2 3 3233 5 13,400 348 N.m.r. data on the majority of the compounds of Table 3 is presented in Table 4~ All of the ~ values relate to CDC13 solution. The term "carbimino proton" is used to identify that proton comprising the group R whilst the term "hydrazono proton" is used to identify the proton of the =N-NH group.
TABL~ 4 _ Ethylenic Carbimino Protons COMPOUND protons of proton of Hydrazono of group R3 group Rl group R proton ~1) R3 5.35 (m) 2H obscured 7.6 (br)lH 3.80(s)3H
OCH3 by aromatic 6-90(~))4H
H 7.90(m)) 5.35 (m) 2H 7.45(d)1H 6.2 (br)lH 3.05(s)6H
~ N (CH3) 2 7 B D ( ~ ~

-CH- ~ ~ 5.30 (m) 2H 7.20~d)lH not 6.00(s)lH
/2 detected 7.40(m)10H

5.35 (m) 2H 7.00(d)lH not 3.40(d)2H
-CH -CH ~ ) detected 4.70(t)lH
_ 7.25(m~10H

5~35 (m) 2H obscured not 4.60(s)2H
-CH2O ~ by aromatic detected 6.85-H 7.50(m)4H

_ 5.75(s)lH
- C~ l 5.30 (m) 2H not 10.7 (br~lH 7.20-7.80 ~ detected (m) 8H

-(CH2)3CH3 5.40 (m) 2H 7.15(d)1H 8.8 (br)lH 2.70(t)2H
O.g5(t)3x _ (1) The hydrazono proton is al~ays broad and in some cases the 05 broadening is such that the signal cannot be detected.

Example 16: Tests of siological Activity -Various of the compounds described in Examples 1 to 15 are tested for biological activity in the human platelet and rabbit aorta systems.
05 Human platelet system Platelet-rich plasma is obtained from fresh, citrated human blood. Addition of the 11,9-epoxymethano analogue of PGH2 (1 x 10 to 5 x 10 M~ causes immediate aggregation recorded as an increase in light transmission (600nm). In a second experiment the indivi-}O dual compounds are added 5 minutes previously to addition of thePGH2 analogue. The dose of the PG~2 analogue added is then increased to a level which gives a similar response to that obtained in the absence of antagonist. The affinity constant, KB, for the compound is calculated according to the Gaddu~ - Schild Equation (based on Law of Mass Action).
DR-1 = ~B] x KB DR = dose ratio [B] = molar concentration of compound Rabbit aorta system Spiral strips of thoracic aorta are suspended i~
Rreb~s-Henseleit solution and aerated with 95% 2/5~ C2 at 37 C.
Tension changes are recorded with a Grass FTO3 force transducer.
Initially, cumulative dose response curves to 11,~-(epoxymethano) PGH2 (2 x 10 9, 1 x 10 8, 5 x 10 and 2.5 x 10 M) are obtainedO
In a second experiment the individual compounds are added 30 ~inutes previous to the addition of the series of agonist doses, ~fflnity constants are calculated as above.
Results typical of those obtained for the various compounds are shown in Tables 5, 6 and 7 relating to oximes, in which R is a group OR , acyl hydrazones, in which R is a group NH.C~R I and semi carbazones, in which R is a group NH.CO.N~R , respectively. The sy~bols U and S used to indicate unsaturated (hept-2Z-ene~ and saturated (heptane) rings, respectively, and all o~ the compounds contain a 6-carboxyhex-2Z-enyl group at the 5-position unless otherwise indicated. As a standard of comparlson, the affinity constant of the potent ~uscarinic receptor antagonist atrophine is 1 x 109 litres/mole.

-~ ~z~

TABLE 5 (OXIMES) AFFINITY CONSTANTS x 10 COMPOUNDS litres/mole __ Ring ~2 R3 Human platelets Rabbit aorta U H -CH2 ~ 1.9 15 U H -CH2 ~ F 4.0 36 U H -CH2 ~ Cl 2.1 67 ... ___ . ...
U H -CH ~ ) 510(1) 5.9 U H -(CH2)2- ~ 0.5 25 U H -(CH2)2-~ ~ Cl 1.0 (2) U H -(CH2)2- ~ F 0 4 (2) .. _ .. __.
S ~-CH2 ~ F 5.8 23 S HCH2 ~ C (2) S H2 ~ Cl 5 9 (2) _ S H-CH2 ~ Cl 2.8 42 S ~~ ~ ) 2 __ _480(l) l.9 S H( 2)4 3 _ 1.5 continued....

\
6~

TABLE 5 (OXIMES) continued - AFFINITY CONSTANTS x 10 COMPOUNDS litres/mole Ring R Human platelets Rabbit aorta 5 (3) H -CH2 ~ F 0.83 _ S CH3 -CHz ~ F 6.0 27 _ . _ S C~3 -C~ ~ ) >500(l) 2.9 (1) significant antagonism of ADP and thrombin is shown by these three substances with a KB (ADP) of about 190 x 10 .
The other compounds do not block ADP, having KB(ADP) of < 0.25 x 10 .
05 (2) Partial agonist.
(3) Double bond in group Rl is also reduced in this compound.
TABLE 6 ~ACYL HYDRAZONES?

AEFINITY CONSTANTS x 10 5 COMPOUNDS litres/mole Ring R2 R Human platelets Rabbit aorta _ U R ~ F 3.6 6.9 S H ~ 2.1 7.8 S 3 ~ N(CH3~2 ~ 1.0 <L 5 A ~t ~ ~

continued....

~2~8~

- 46 -(NF262/0071C~
TABLE 6 (ACYL HYDRAZO~ES) continued . AFFINITY CONST~NTS x 10 5 COMPOUNDS lit~es/mole Ring R R3 Human platelets Rabbit aorta S H ~ ~2 7.2(1) 39 S H - CH2 -CH ~ ~ 20 6.6 S H -CH2- ~ 0.52 3.7 S CH3 ~ )2 4.4 9.4 (1) Slight antagonism of ADP; KB (ADP) = 1.2 x 10 . The other compounds do not block ADP, having KB (ADP) of ~ 0.25 x 10 .
TABLE 7 ~SEMICARBAZONES) _ _ 5 AFFINITY CONSTANTS x 10 COMPOUNDS litres/mole Ring R RHuman platelets Rabbit aorta U H . ~ 17 43 .._ .
S H ~ 7.0 13 _ ~__ _ .
S (1) ~ ~ 6.9 8.3 U CH3 ~ 78 52 S CH3 _ . 120 S CH3 ~ CH3 56 62 (I) Double b ~nd group Rl is also r ~duced in this c~ npound.

o ~H 6~o OEt OEt H /EtOH ~C02Et H2/pd-c <~CO2 Et CH(OEt)2 CH(OEt)2' LiA~ H4 <~/OH
CH(oEt)2 1 TsC~pyr <~/ .B~l2A~H <~/
2.CN-/DMSO GH(oEt)2 tol78nce CH(OEt)2 ._ Ph3P (CH2)4COOH Br /` >"~=WCOOH
N~ CH3 S2 DMSO ~ CH (oEt)2 COOCH3 ~ =WCO2H

CHO q/ C~O 9 . ,:,..... , --

Claims (84)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for the preparation of a compound of formula (I) (I) wherein represents one of the divalent cyclic groups and the letters a and b in each case indicating the point of attachment of the substituents R1 and C(R2)=NR, respectively; R1 is a 6-carboxyhex-2-enyl group or a modification thereof in which the group is altered by one, or an appropriate combination of two or more, of the following: (a) reduction of the double bond optionally accompanied by replacement of a carbon atom at the 1, 2 or 3 position by a sulphur or oxygen atom, (b) alteration of the position of the double bond, (c) shortening or lengthening of the carbon chain by one or two methylene groups, and (d) formation of an amide, ester or salt derivative of the carboxy group; R2 is hydrogen, a C1-10 aliphatic hydrocarbon group or a C1-10 aliphatic hydrocarbon group substituted directly or through an oxygen or sulphur atom by an aromatic group Ar, where Ar is a phenyl, naphthyl, fluorenyl, dibenzocyclohexyl, dibenzocycloheptyl, pyridyl, benzothiazolyl, dihydrobenzothiazolyl, N-methyldihydrobenzothiazolyl, benzoxazolyl, dihydrobenzoxazolyl or N-methyldlhydrobenzoxazolyl group or such a group substituted by one or more substituents selected from C1-10 alkoxy, halogen, C1-10 halogen-substituted alkyl, sulphamoyl, amino, hydroxyl, nitro and C1-10 alkyl groups; and R is a group -OR3, -NH.COR3 or NH.CO.NHR3 wherein R3 is a C1-10 aliphatic hydrocarbon group, an aromatic group Ar or a C1-10 aliphatic hydrocarbon group substituted by one or more groups Ar directly or through an oxygen or sulphur atom; which comprises reacting a compound of formula (II) (II) with a reagent ZNH2, Y being either R1 as defined above for compound (I) or a precursor for R1, Z being either R as defined above for compound (I) or a precursor for R, and the other symbols being as defined for compound (I) but with the letters a and b indicating the point of attachment of the substituents Y and C(R2)=0, respectively, and where appropriate converting the group Y and/or the group Z in the resultant product into the groups R1 and R, respectively, of the compound (I).

2. A process according to Claim 1, in which any modification of the 6-carboxyhex-2-enyl group of type (c) is a shortening or lengthening of the carbon chain by one methylene group.

3. A process according to Claim 1, in which R1 is a 6-carboxyhex-2-enyl group or an amide, ester or salt derivative thereof.

4. A process according to Claim 1, in which R1 is a 6-carboxyhexyl group or an amide, ester or salt derivative thereof.

5. A process according to Claim 1, in which R1 terminates in a free carboxy group.

6. A process according to Claim 1, in which R1 terminates in a carboxy group in the form of a salt.

7. A process according to Claim 1, in which R2 is hydrogen.

8. A process according to Claim 1, in which R2 is a C1-10 aliphatic hydrocarbon group or a C1-10 aliphatic hydrocarbon group substituted directly by an aromatic group.

9. A process according to Claim 1, in which R2 is a C1-3 alkyl group.

10. A process according to claim 1, in which R2 is ethyl.

11. A process according to claim 1, in which R2 is methyl.

12. A process according to claim 1, in which R is -OR3.

13. A process according to claim 1, in which R is -NHCOR3.

14. A process according to claim 1, in which R is -NHCONHR3.

15. A process according to claim 1, in which R3 is a C1-10 aliphatic hydrocarbon group.

16. A process according to claim 1, in which R3 is a C1-10 aliphatic hydrocarbon group substituted by an aromatic group or groups Ar or is an aromatic group Ar.

17. A process according to claim 16, in which R3 is a C1-10 aliphatic hydrocarbon group substituted either directly or through an oxygen or sulphur atom by one aromatic group or directly by two aromatic groups.

18. A process according to claim 16, in which R3 is a substituted C1-10 alkyl group.

19. A process according to claim 16, in which R3 is a substituted C1-3 acyclic alkyl group.

20. A process according to claim 16, in which R3 is an acyclic alkyl group terminally substituted by an aromatic group or groups Ar, the alkyl group being of 1 to 3 carbon atoms when substituted directly by the group or groups and being of 2 or 3 carbon atoms when substituted by the group or one of the groups through an oxygen or sulphur atom.

21. A process according to claim 16, in which R3 is an acyclic C1-3 alkyl group substituted by a cyclohexyl group and by one or more aromatic groups Ar.

22. A process according to claim 1, in which the aromatic group or groups Ar are selected from unsubstituted and substituted phenyl and pyridyl groups.

23. A process according to claim 1, in which R is a group -OR3 wherein R3 is selected from C1-3 acyclic alkyl groups directly substituted terminally by one or two groups Ar selected from unsubstituted and substituted phenyl groups and an unsub-stituted pyrid-l-yl group.

24. A process according to Claim 1, in which R is a group -NHCOR3 wherein R3 is either a group Ar selected from unsubstituted and substituted phenyl groups, and unsubstituted pyrid-2-yl, pyrid-3-yl and pyrid-4-yl groups, or is a group CH2Ar wherein Ar is selected from unsubstituted and substituted phenyl groups, and an unsubstituted pyrid-l-yl group.

25. A process according to Claim 1, in which R is a group -NHCONHR3 wherein R3 is either a group Ar selected from unsubstituted and substituted phenyl groups, and unsubstituted pyrid-2-yl, pyrid-3-yl and pyrid-4-yl groups, or is a group CH2Ar wherein Ar is selected from unsubstituted and substituted phenyl groups and an unsubstituted pyrid-l-yl group.

26. A process according to Claim 1, in which the aromatic group or groups Ar are selected from unsubstituted and substituted phenyl groups.

27. A process according to Claim 1, in which the aromatic group or groups Ar are selected from a phenyl group and substituted phenyl groups having a single substituent at an ortho, meta or para position or two identical substituents at any combination of ortho, meta and para positions.

28. A process according to Claim 16, in which R3 is a C1-10 aliphatic hydrocarbon group substituted by an aromatic group or groups Ar selected from unsubstituted and substituted phenyl groups.

29. A process according to Claim 16, in which R3 is an aromatic group Ar selected from unsubstituted and substituted phenyl groups.

30. A process according to Claim 1, in which the aromatic group or groups Ar are selected from an unsubstituted phenyl group and phenyl groups substituted by one or more substituent groups selected from C1-3 alkoxy, halogen, C1-3 halogen-substituted alkyl and C1-3 alkyl groups.

31. A process according to Claim 1, in which the aromatic group or groups are selected from an unsubstituted phenyl group and phenyl groups substituted by one or more substituent groups selected from methoxy, fluoro, chloro, bromo, trifluoromethyl and methyl.

32. A process according to Claim 1, in which the compound of formula (I) is a bicyclo [2,2,1] hept-2Z-ene.

33. A process according to Claim 1, in which the compound of formula (I) is a bicyclo [2,2,1] heptane.

34. A process according to Claim 1, in which the configuration about any double bond in the group R1 is cis.

35. A process according to Claim 1, in which the groups R1 and C(R2)=NR are in trans relationship.

36. A process according to Claim 1, in which the groups R1 and C(R2)=NR are in trans relationship and the group R1 is oppositely disposed to the bridging methylene group.

37. A process according to Claim 1, in which R1 is a 6-carboxyhex-2Z-enyl or 6-carboxyhexyl group an amide, ester or salt derivative thereof, R2 is hydrogen, methyl or ethyl, and R is -NHCOR3 with R3 being butyl, pentyl, phenyl, p-fluorophenyl, p-methoxyphenyl, p-dimethylaminophenyl, m-tolyl, fluorenyl, benzyl, p-fluorobenzyl, p-chlorobenzyl, m-chlorobenzyl, 2,4-dichlorobenzyl, m-trifluoromethyl-benzyl, diphenylmethyl, 2,2-diphenylethyl, 3-phenylpropyl, phenoxy-methyl, phenoxyethyl, p-chlorophenoxyethyl or p-fluorophenoxyethyl, or R is -OR3 or -NHCONHR3 with R3 being butyl, pentyl, phenyl, p-fluorophenyl, p-methoxyphenyl, p-dimethylaminophenyl, m-tolyl, fluorenyl, benzyl, p-fluorobenzyl, p-chlorobenzyl, m-chlorobenzyl, 2,4-dichlorobenzyl, m-trifluoromethylbenzyl, diphenylmethyl, 2,2-diphenylethyl, 3-phenylpropyl, phenoxyethyl, p-chlorophenoxyethyl or p-fluorophenoxyethyl, the group R1 having the endo configuration and the group C(R2)=NR having the exo configuration.

38. A process according to Claim 1, in which R1 is a 6-carboxyhex-2Z-enyl group, R2 is hydrogen or methyl, and R is -NHCOR3 with R3 being butyl, pentyl, phenyl, p-fluorophenyl, p-methoxyphenyl, p-dimethylaminophenyl, m-tolyl, fluorenyl, benzyl, p-fluorobenzyl, p-chlorobenzyl, m-chlorobenzyl, 2,4-dichlorobenzyl, m-trifluoromethyl-benzyl, diphenylmethyl, 2,2-diphenylethyl, 3-phenylpropyl, phenoxy-methyl, phenoxyethyl, p-chlorophenoxyethyl or p-fluorophenoxyethyl, or R is -OR3 or -NHCONHR3 with R3 being butyl, pentyl, phenyl, p-fluorophenyl, p-methoxyphenyl, p-dimethylaminophenyl, m-tolyl, fluorenyl, benzyl, p-fluorobenzyl, p-chlorobenzyl, m-chlorobenzyl, 2,4-dichlorobenzyl, m-trifluoromethylbenzyl, diphenylmethyl, 2,2-diphenylethyl, 3-phenylpropyl, phenoxyethyl, p-chlorophenoxyethyl or p-fluorophenoxyethyl, the group R1 having the endo configuration and the group C(R2)=NR having the exo configuration.

39. A process according to Claim 1, in which (I) is a 5-endo, 6-exo substituted bicyclo [2,2,1] heptane or bicyclo [2,2,1] hept-2Z-ene, the substituent at the 5-position being a 6'-carboxyhex-2'Z-enyl group and that at the 6-position being an O-diphenylmethyloxy-iminomethyl or a 1'-(diphenylmethyloxyimino)-ethyl group.

40. A process according to Claim 1, in which (I) is a 5-endo, 6-exo substituted bicyclo [2,2,1] hept-2Z-ene, the substituent at the 5-position being a 6'-carboxyhex-2'Z-enyl group and that at the 6-position being a N-(phenylcarbamoyl)-hydrazonomethyl, N-(m-methyl-phenylcarbamoyl)-hydrazonomethyl, 1'-[N-(phenylcarbamoyl)-hydrazono]-ethyl or 1'-[N-(m-methylphenylcarbamoyl)-hydrazono]-ethyl group.

41. A process according to Claim 1, in which (I) is a 5-endo, 6-exo substituted bicyclo [2,2,1] heptane, the substituent at the 5-position being a 6'-carboxyhex-2'Z-enyl or 6'-carboxyhexyl group and that at the 6-position being a N-(phenylcarbamoyl)-hydrazonomethyl, N-(m-methylphenylcarbamoyl)-hydrazonomethyl, 1'- [N-(phenylcarbamoyl)-hydrazono]-ethyl or 1'-[N-(m-methylphenylcarbamoyl)-hydrazono]-ethyl group.

42. A process according to Claim 1, in which the reagent ZNH2 has the form RNH2.

43. A process according to Claim 1, in which Y is R1.

44. A compound of formula (I) (I) wherein represents one of the divalent cyclic groups and the letters a and b in each case indicating the point of attachment of the substituents R1 and C(R2)=NR, respectively, and R1, R2 and R
are as defined in Claim 1, when prepared by the process of Claim 1 or an obvious chemical equivalent thereof.

45. A compound according to Claim 44, in which any modification of the 6-carboxyhex-2-enyl group of type (c) is a shortening or lengthening of the carbon chain by one methylene group when prepared by a process according to Claim 2 or an obvious chemical equivalent thereof.

46. A compound according to Claim 44, in which R1 is a 6-carboxyhex-2-enyl group or an amide, ester or salt derivative thereof when prepared by a process according to Claim 3 or an obvious chemical equivalent thereof.

47. A compound according to Claim 44, in which R1 is a 6-carboxyhexyl group or an amide, ester or salt derivative thereof when prepared by a process according to Claim 4 or an obvious chemical equivalent thereof.

48. A compound according to Claim 44, in which R1 terminates in a free carboxy group when prepared by a process according to Claim 5 or an obvious chemical equivalent thereof.

49. A compound according to Claim 44, in which R1 terminates in a carboxy group in the form of a salt when prepared by a process according to Claim 6 or an obvious chemical equivalent thereof.

50. A compound according to Claim 44, in which R2 is hydrogen when prepared by a process according to Claim 7 or an obvious chemical equivalent thereof.

51. A compound according to Claim 44, in which R2 is a C1-10 aliphatic hydrocarbon group or a C1-10 aliphatic hydrocarbon group substituted directly by an aromatic group when prepared by a process according to Claim 8 or an obvious chemical equivalent thereof.

52. A compound according to Claim 44, in which R2 is a C1-3 alkyl group when prepared by a process according to Claim 9 or an obvious chemical equivalent thereof.

53. A compound according to Claim 44, in which R2 is ethyl when prepared by a process according to Claim 10 or an obvious chemical equivalent thereof.

54. A compound according to Claim 44, in which R2 is methyl when prepared by a process according to Claim 11 or an obvious chemical equivalent thereof.

55. A compound according to Claim 44, in which R is -OR3 when prepared by a process according to Claim 12 or an obvious chemical equivalent thereof.

56. A compound according to Claim 44, in which R is -NHCOR3 when prepared by a process according to Claim 13 or an obvious chemical equivalent thereof.

57. A compound according to Claim 44, in which R is -NHCONHR3 when prepared by a process according to Claim 14 or an obvious chemical equivalent thereof.

58. A compound according to Claim 44, in which R3 is a C1-10 aliphatic hydrocarbon group when prepared by a process according to Claim 15 or an obvious chemical equivalent thereof.

59. A compound according to Claim 44, in which R3 is a C1-10 aliphatic hydrocarbon group substituted by an aromatic group or groups Ar or is an aromatic group Ar when prepared by a process according to Claim 16 or an obvious chemical equivalent thereof.

60. A compound according to Claim 44, in which R3 is a C1-10 aliphatic hydrocarbon group substituted either directly or through an oxygen or sulphur atom by one aromatic group or directly by two aromatic groups when prepared by a process according to Claim 17 or an obvious chemical equivalent thereof.

61. A compound according to claim 44, in which R3 is a substituted C1-10 alkyl group when prepared by a process according to claim 18 or an obvious chemical equivalent thereof.

62. A compound according to claim 44, in which R3 is a substituted C1-3 acyclic alkyl group when prepared by a process according to claim 19 or an obvious chemical equivalent thereof.

63. A compound according to claim 44, in which R3 is an acyclic alkyl group terminally substituted by an aromatic group or groups Ar, the alkyl group being of 1 to 3 carbon atoms when substituted directly by the group or groups and being of 2 or 3 carbon atoms when substituted by the group or one of the groups through an oxygen or sulphur atom when prepared according to claim 20 or an obvious chemical equivalent thereof.

64. A compound according to claim 44, in which R3 is an acyclic C1-3 alkyl group substituted by a cyclohexyl group and by one or more aromatic groups Ar when prepared by a process according to claim 21 or an obvious chemical equivalent thereof.

65. A compound according to claim 44, in which the aromatic group or groups Ar are selected from unsubstituted and substituted phenyl and pyridyl groups when prepared by a process according to claim 22 or an obvious chemical equivalent thereof.

66. A compound according to claim 44, in which R is a group -OR3 wherein R3 is selected from C1-3 acyclic alkyl groups directly substituted terminally by one or two groups Ar selected from unsubstituted and substituted phenyl groups and an unsub-stituted pyrid-l-yl group when prepared by a process according to claim 23 or an obvious chemical equivalent thereof.

67. A compound according to claim 44, in which R is a group -NHCOR3 wherein R3 is either a group Ar selected from unsubstituted and substituted phenyl groups, and unsubstituted pyrid-2-yl, pyrid-3-yl and pyrid-4-yl groups, or is a group CH2Ar wherein Ar is selected from unsubstituted and substituted phenyl groups, and an unsubstituted pyrid-l-yl group when prepared by a process according to claim 24 or an obvious chemical equivalent thereof.

68. A compound according to Claim 44, in which R is a group -NHCONHR3 wherein R3 is either a group Ar selected from unsubstituted and substituted phenyl groups, and unsubstituted pyrid-2-yl, pyrid-3-yl and pyrid-4-yl groups, or is a group CH2Ar wherein Ar is selected from unsubstituted and substituted phenyl groups and an unsubstituted pyrid-l-yl group when prepared by a process according to Claim 25 or an obvious chemical equivalent thereof.

69. A compound according to Claim 44, in which the aromatic group or groups Ar are selected from unsubstituted and substituted phenyl groups when prepared by a process according to Claim 26 or an obvious chemical equivalent thereof.

70. A compound according to Claim 44, in which the aromatic group or groups Ar are selected from a phenyl group and substituted phenyl groups having a single substituent at an ortho, meta or para position or two identical substituents at any combination of ortho, meta and para positions when prepared by a process according to Claim 27 or an obvious chemical equivalent thereof.

71. A compound according to Claim 44, in which R3 is a C1-10 aliphatic hydrocarbon group substituted by an aromatic group or groups Ar selected from unsubstituted and substituted phenyl groups when prepared by a process according to Claim 28 or an obvious chemical equivalent thereof.

72. A compound according to Claim 44, in which R3 is an aromatic group Ar selected from unsubstituted and substituted phenyl groups when prepared by a process according to Claim 29 or an obvious chemical equivalent thereof.

73. A compound according to Claim 44, in which the aromatic group or groups Ar are selected from an unsubtituted phenyl group and phenyl groups substituted by one or more substituent groups selected from C1-3 alkoxy, halogen, C1-3 halogen-substituted alkyl and C1-3 alkyl groups when prepared by a process according to Claim 30 or an obvious chemical equivalent thereof.

74. A compound according to Claim 44, in which the aromatic group or groups are selected from an unsubstituted phenyl group and phenyl groups substituted by one or more substituent groups selected from methoxy, fluoro, chloro, bromo, trifluoromethyl and methyl when prepared by a process according to Claim 31 or an obvious chemical equivalent thereof.

75. A compound according to Claim 44, in which the compound of formula (I) is a bicyclo [2,2,1] hept-2Z-ene when prepared by a process according to Claim 32 or an obvious chemical equivalent thereof.

76. A compound according to Claim 44, in which the compound of formula (I) is a bicyclo [2,2,1] heptane when prepared by a process according to Claim 33 or an obvious chemical equivalent thereof.

77. A compound according to Claim 44, in which the configuration about any double bond in the group R1 is cis when prepared by a process according to Claim 34 or an obvious chemical equivalent thereof.

78. A compound according to Claim 44, in which the groups R1 and C(R2)=NR are in trans relationship when prepared by a process according to Claim 35 or an obvious chemical equivalent thereof.

79. A compound according to Claim 44, in which the groups R1 and C(R2)=NR are in trans relationship and the group R1 is oppositely disposed to the bridging methylene group when prepared by a process according to Claim 36 or an obvious chemical equivalent thereof.

80. A compound according to Claim 44, in which R1 is a 6-carboxyhex-2Z-enyl or 6-carboxyhexyl group an amide, ester or salt derivative thereof, R2 is hydrogen, methyl or ethyl,and R is -NHCOR3 with R3 being butyl, pentyl, phenyl, p-fluorophenyl, p-methoxyphenyl, p-dimethylaminophenyl, m-tolyl, fluorenyl, benzyl, p-fluorobenzyl, p-chlorobenzyl, m-chlorobenzyl, 2,4-dichlorobenzyl, m-trifluoromethyl-benzyl diphenylmethyl, 2,2-diphenylethyl, 3-phenylpropyl, phenoxymethyl, phenoxyethyl, p-chlorophenoxyethyl or p-fluorophenoxyethyl, or R
is -OR3 or -NHCONHR3 with R3 being butyl, pentyl, phenyl, p-fluoro-phenyl, p-methoxyphenyl, p-dimethylaminophenyl, m-tolyl, fluorenyl, benzyl, p-fluorobenzyl, p-chlorobenzyl, m-chlorobenzyl, 2,4-dichloro-benzyl, m-trifluoromethylbenzyl, diphenylmethyl, 2,2-diphenylethyl, 3-phenylpropyl, phenoxyethyl, p-chlorophenoxyethyl or p-fluorophenoxy ethyl, the group R1 having the endo configuration and the group C(R2)=NR
having the exo configuration when prepared by a process according to Claim 37 or an obvious chemical equivalent thereof.

81. A compound according to Claim 44, in which R1 is a 6-carboxyhex-2Z-enyl group, R2 is hydrogen or methyl, and R is -NHCOR3 with R3 being butyl, pentyl, phenyl, p-fluorophenyl, p-methoxyphenyl, p-dimethylaminophenyl, m-tolyl, fluorenyl, benzyl, p-fluorobenzyl, p-chlorobenzyl, m-chlorobenzyl, 2,4-dichlorobenzyl, m-trifluoromethyl-benzyl, diphenylmethyl, 2,2-diphenylethyl, 3-phenylpropyl, phenoxy-methyl, phenoxyethyl, p-chlorophenoxyethyl or p-fluorophenoxyethyl, or R is -OR3 or -NHCONHR3 with R3 being butyl, pentyl, phenyl, p-fluorophenyl, p-methoxyphenyl, p-dimethylaminophenyl, m-tolyl, fluorenyl, benzyl, p-fluorobenzyl, p-chlorobenzyl, m-chlorobenzyl, 2,4-dichlorobenzyl, m-trifluoromethylbenzyl, diphenylmethyl, 2,2-diphenylethyl, 3-phenylpropyl, phenoxyethyl, p-chlorophenoxyethyl or p-fluorophenoxyethyl,the group R1 having the endo configuration and the group C(R2)=NR having the exo configuration when prepared by a process according to Claim 38 or an obvious chemical equivalent thereof.

82. A compound according to Claim 44, in which (I) is a 5-endo, 6-exo substituted bicyclo [2,2,1] heptane or bicyclo [2,2,1] hept-2Z-ene, the substituent at the 5-position being a 6'-carboxyhex-2'Z-enyl group and that at the 6-position being an O-diphenylmethyl-oxyiminomethyl or a 1'-(diphenylmethyloxyimino)-ethyl group when prepared by a process according to Claim 39 or an obvious chemical equivalent thereof.

83. A compound according to Claim 44, in which (I) is a 5-endo, 6-exo substituted bicyclo [2,2,1] hept-2Z-ene, the substituent at the 5-position being a 6'-carboxyhex-2'Z-enyl group and that at the 6-position being a N-(phenylcarbamoyl)-hydrazonomethyl, N-(m-methylphenylcarbamoyl)-hydrazonomethyl, 1'-[N-(phenylcarbamoyl)-hydrazono]-ethyl or 1'-[N-(m-methylphenylcarbamoyl)-hydrazono]-ethyl group when prepared by a process according to Claim 40 or an obvious chemical equivalent thereof.

84. A compound according to Claim 44, in which (I) is a 5-endo, 6-exo substituted bicyclo [2,2,1] heptane, the substituent at the 5-position being a 6'-carboxyhex-2'Z-enyl or 6'-carboxyhexyl group and that at the 6-position being a N-(phenylcarbamoyl)-hydrazono-methyl, N-(m-methylphenylcarbamoyl)-hydrazonomethyl, 1'-[N-(phenyl-carbamoyl)-hydrazono]-ethyl or 1'-[N-(m-methylphenylcarbamoyl)-hydrazono]-ethyl group when prepared by a process according to Claim 41 or an obvious chemical equivalent thereof.