CA1246594A - Prostaglandins - Google Patents

Abstract

ABSTRACT
PROSTAGLANDINS
A process for the preparation of a compound of formula (I) (I) wherein represents one of the divalent cyclic groups the letters a and b indicating in each case the points 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, napthyl, fluorenyl, dibenzocyclohexyl, dibenzo-cycloheptyl, pyridyl, benzthiazolyl, dihydrobenzthiazolyl, N-methyl-dihydrobenzthiazolyl, benzoxazolyl, dihydrobenzoxazolyl or N-methyl-dihydrobenzoxazolyl 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, -OR4, -A-R3 or -N=R5 in which A is -NH-, -NH.CO-, -NH.CO.CH2N(R6)-, -NH.SO2-, -NH.CO.NH- or -NH.CS.NH- and wherein R3 is a C1-10 aliphatic hydrocarbon group, an aromatic group Ar or an aliphatic hydrocarbon group substituted by one or more groups Ar directly or through an oxygen or sulphur atom, R4 is a C1-10 aliphatic hydrocarbon group which is substituted through an oxygen atom by a C1-10 aliphatic hydrocarbon group which is itself substituted directly by one or more aromatic groups Ar, R5 is a C1-10 aliphatic hydrocarbon group, an aromatic group Ar', where Ar' is a fluorenylidene, dibenzo-cyclohexylidene, dibenzocycloheptylidene, dihydrobenzthiazolylidene, N-methyldihydrobenzthiazolylidene, dihydrobenzoxazolylidene or N-methyldihydrobenzoxazolylidene group or such a group Ar' substituted on a benzene ring or rings thereof by one or more substituents selected from C1-10 alkoxy, halogen, C1-10 halogen-substituted alkyl, sulphamoyl, amino hydroxyl, nitro and C1-10 groups, or a C1-10 aliphatic hydrocarbon group substituted by one or more aromatic groups Ar directly or through an oxygen or sulphur atom, and R6 is hydrogen, 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; with the proviso that when R is a group -OR3, -NH.COR3 or -NH.CO.NHR3 then excludes the divalent cyclic groups and comprises reacting a compound of formula (II)

Description

P~OSTAGLANDINS
This invention 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 05 via prostaglandin H2 (PGH2), is implicated in several potentially noxious actions on various body systems, including platelet aggrega-tion, 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~ ~loreover, the constrictor actions of TXA2 on bronchiolar, pulmonary vascular and systemic vascular smooth muscle may be impor-tant in the development of several anaphylactic conditions includ:Lng bronch:Lal asthllia. There is also some evidence to implicate PGHz and TXA2 in the genesis of inflammation.
It is an objec-t of the present invention to provide compounds having activity at thromboxane receptor sit~s, 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.
AccordingLy the presen-t invention comprises a compound of formula (I) Rl ¦ (I) wherein IC(R )=NR
H

X ¦represents one of the divalent cyclic 1- groups H

.

b o </^"

~ C~ c~

0~ .

s~ ~

the letters a and b indicatlng in each case the points of attachment of the substituents Rl and C(R2)=NR, respectively; Rl 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 05 more of the followlng: (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 Cl lO aliphatic hydrocarbon group or a Cl_10 aliphatic hydrocarbon group substitu~ed dlrectly or through an oxygen or sulphur atom by an aromatic group Ar, where Ar is a phenyl, napthyl, fluorenyl, dibenzocyclohexyl, dibenzo-cycloheptyl, pyridyl, benzthiazolyl, dihydrobenzthiazolyl, ~-me~hyl-dihydrobenzthiazolyl, benzoxazolyl, dihydrobenzoxazolyl or N-methyl-dihydrobenzoxa701yl group or such a group substituted by one or more substituents selected Erom Cl 10 alkoxy, halogen, Cl_10 halogen-substituted alkyl, sulphamoyl, a~ino, hydroxyl, nitro and Cl 10 alkyl groups, and R is a group -oR3, -OR', -A-R3 or -N=R5 in which A is -N}l-, -~H-CO-~ -NH-CO-CH2~(R6)-, -NH.S02~ .CO.NH- or -~H.CS.NH- and wherein R3 is a Cl 10 aliphatic hydrocarbon group, an aromatic group Ar or an aliphatic hydrocarbon group substituted by one or more groups Ar directly or through an oxygen or sulphur atom, R4 is a Cl lO aliphatic hydrocarbon group which is substituted through an oxygen atom by a Cl_10 aliphatic hydrocarbon group which is itself substituted directly by one or more aromatic groups Ar, R5 is a Cl 10 aliphatic hydrocarbon group, an aromatic group Ar', where Ar' is a fluorenylidene, dibenzo-cyclohexylidene, dibenzocycloheptylidene, dihydroben~thia~olylidene, N-methyldihydroben~thiazolylidene, dihydrobenzoxazolylidene or N-methyldihydrobenzoxazolylidene group or such a group Ar' substituted on a benzene r~ng or rings thereof by one or more substituents selected from Cl_10 alkoxy, halogen, Cl 10 halogen-substituted alkyl, sulphamoyl, a~ino hydroxyl, nitro and Cl 10 groups, or a Cl_10 aliphatic y group substituted by one or more aromatic groups Ar dlrectly or ~hrough a~ oxygen or sulphur atom, and R6 is hydrogen, a Cl 10 sliphatic hydrocarbon group, an aromatic group Ar or a Cl 10 aliphatic hydrocarbon group substltuted by one or more groups Ar directly or . ~ , ~2~

- 3a -through an oxygen or sulphur ato~; with the proviso that when R is a group -oR3, -NH.50R or -NH.CO.NHR then C/
X ¦ excludes the divalent cyclic groups H

~ and ~ ¦

: ` ~2~94 The various bridged ring systems indicated above may alter-natively be represented in planar form, i.e. in the same order as ~ à / ~ ~

(the two free valencies in the centre of the last two formulae indicating methyl groups), but the more usual convention has 05 generally been followed throughout the specification of representing these systems in non-planar form. It will be appreciated, however, that the compounds (I) may exist in various stereoisomeric forms, which are included within the scope of the inven-tion, 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. Taking the vicinally disubstituted bicyclo [2,2,1]
heptane ring system as an example, such pairs of enantiomorphs may be shown as follows (the rings being numbered according to the system used herein).

9 ~

3~ D ~ ~ _ ~J3

2 6 ~ 2 For the sake of added clarity it 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 di.rectly above is 05 equivalent to 2 ~ Qnd Ql90 ~

It will be seen that the modifications of the 6-carboxyhex-2-enyl group which may be made in compounds according to the present invention : are of two types. Thus, the modifications either involve the hex-2-enyl group or the 6-carboxy group. Among modifications of the first form, which are listed under ~a) to (c) above, certain preferences may be indicated. Thus, where the double bond is reduced and a carbon atom replaced, the replacement is conveniently by an oxygen rather than a sulphur atom and also is conveniently at the 2 or 3 position. Moreover, where the position of the double bond is altered, this is conveniently to the 3,4 position and where the carbon chain is shortened or lengthened, this is conveniently at the end of the chain adjacent to the carboxy group.

' 9~

Among the second form of modification, listed under (d) above, examples of amide, ester and salt derivatives of particular interest are to be found in the prostaglandin art and include esters such as alkyl esters, amides such as those containing the group -CONHS02CH3 05 and variants -thereon, and salts with various physiologically acceptable cations. Specific examples of salts are 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-hydroxymethyl-propane-1,3-diol). It will be appreciated that certain of the compounds having such a second form of modification are bioprecursors for the corresponding compound containing a carboxy group to which they are converted in vivo.
Examples of specific groups R are -CH2-CH=CH-(CH2)3C02H, -(CH2)6C02H and -(CH2)20(CH2)3C02H, and functional derivatives formed at the carboxy groups thereof.
Compounds in which the group R2 is not hydrogen more usually contain al;phatic and araliphatic groups of` the type described hereinafter in relation to the group R , aliphatic hydrocarbon groups substituted directly by an aromatic group and particularly unsubstituted aliphatic hydrocarbon groups being of most interest.
The size of the group R can however influence the ease with which the compounds may be prepared and R is preferably either hydrogen or one of the smaller alkyl groups, for example of 1 to 3 carbon atoms, in substituted form, or particularly in unsubstituted form, 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 o~ the aliphatic group which is itself attached directly to the carbon atom of the group C(R2~=NR.
Thus, for example, a 2-phenylethyl group is preferred to a 1-phenylethyl or phenylmethyl (benzyl) group. Good levels of activity have been achieved with compounds in which ~2 is one of hydrogen, ethyl and especially methyl. The increase in activity resulting from the presence of a group R2 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 f~rm -NH.CO. NHR3 or -NH . CS . NHR3 .
Among the groups C(R2)=NR, those which terminate in a group R3 are of particular interest. As indicaked, the group R3 can be of various forms. Aliphatic hydrocarbon groups constituting R3 may cor~veniently be of one to five, six, seven, eight, nine, ten or even more carbon atoms, being, for example an alkyl group which may be branched or unbranched such as methyl, ethyl, propyl, butyl, amyl, and also a cycloalkyl group such as cyclopentyl, cyclohexyl, as well as combinations of alkyl and cycloalkyl groups such as cyclohexylmethyl.
Aromatic groups constituting R3 are of greater interest than the unsubstituted aliphatic hydrocarbon groups and may be hydro-carbon or heterocyclic groups which may be unsubstit-uted or substituted. Moreover r the term 'aromatic group' as used herein extends to groups derived from ring systems having aromatic - 7a - I 2~5~4 properties but in which the ~-electron system is not fullv delocalised over the entire ring system, such qroups including those derived from fluorene, dihydrobenzoxazole, dihydrobenz-thiazole, N-methyldihydrobenzthiazole, and 1,2,4,5-dibenzocyclo-heptane. The heterocyclic groups which conveniently contain one, two or more, similar or different nitrogen, oxygen or sulphur atoms, are more generally lin~ed 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 ,... .

~' ~2~

non-benzenoid rings, such as those derived from fluorene and its cyclohexyl and cycloheptyl analogues, and from benzthia~ole, dihydrobenz-thiazole & N-~ethyl~ihydrobenzthiazole and their benzoxazole analogues,linkage o~ the group 05 is more usually effected through a non-benzeno:Ld ring.
Amon~ the aro~atic groups constituting R3, aromatic hydrocarbon groups, for example nap~hyl and particularly phenyl are, however, generally of rather greater lnterest than heteroc~ci~c groups.
Both the aromatic hydrocarbon and the heterocyclic group~ may be 1~ substitu~ed, by one or more of various types of subs~ituent, particularly by alkoxy groups, for example those containing alkyl groups of 1,2,3 or more carbon atoms as described above and ~ especially methoxy, and by substituents being or contalnlng a halogen residue, for example chloro and especially fluoro, and also halogen substituted alkyl groups suc~ as CFj. Examples of other substituents are sulph~oyl groupJ which may optionally be N-substltuted, amino groups which may be free or substituted, for example dimethylamino, hydroxyl, nitro, and alkyl groups, for example of I to 3 carbon atoms or otherwise as described above, Substitutlon may be present at one or more of the ortho, meta and para positions of a phenyl rinK or at a combination o two or more such positlons (including two similar positions), for example at the 2 and 4 posltions. Substitutlon and th~ positlon of ~ubstltution, for example by alkoxy groups and 3roups being or containlng a halogen, may have a definlte effect upon the level of activlty of a compound.
Also of considerable interest, are groups R3 which are aliphatic hydrocarbon groups substitutet by one or more aromatic groups directly or through.a sulphur or particularly an oxygen atom. The allphatlc groupg may be of a slmllar slze to those described above but preferably comprise an acyclic group, convenlently of three carbon atoms, partlcularly of two carbon atoms and especially of one carbon atom, although this acyclic group may carry a cyclo-alkyl group as well as an aromatic group. Preferred acyclic groups thus J

, . .. . . ~ .

~2~ ~g~

_ g _ take the form of unbranched alkylene groups such as methylene, ethylene or propylene which link the group C(R2)=N- and the aromatic group, or corresponding trivalent groups of similar size. Similar aromatic hydrocarbon and heterocyclic residues are generally of 0~ interest for attachment to the aliphatic groups as have already been described above, the aromatic hydrocarbon groups again generally being of rather more interest than the heterocyclic groups. Heterocyclic 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. Substitution of an aliphatic hydrocarbon group, particularly terminally, by two or even three aromatic groups, for example phenyl, is of particular interest, whilst also of interest are acyclic groups carrying terminally both an aromatic group, for example phenyl, and a cyclo-alkyl group, for example cyclohexyl. ~ther substituted aliphatic hydrocarbon groups of especial note are those which are substituted by an aromat1c group through a sulphur or particularly an oxygen atom, although in this case the aliphatic hydrocarbon group is conveniently of at least two carbon atoms in the case of some forms of group C(R2)=NR in view of the relative instability of the linkages -0-CH2-S- and -0-CH2-0-When the group R3 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 o~p>m, when R3 is a substituted phenyloxyethyl group it is o>m>p, and when R3 is a substituted phenyl group it is m~p~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.
Among the various groups R which terminate in a group R3, those of particular interest are the groups in which R is d group -oR3 or a group -A-R3 in which A is -NH.C0-, -NH.S02-, -NH.CO.NH- or -NH.CS.NH-. Very good levels of activity have been obtained 9~

with compounds in which R is a group -OR or particularly a group -~H.Co.iNHR3 and especially a gro~p -NH.Cs.NHR3. Among various groups R terminating in a group R , .nose in which R is an aliphatic hydrocarbon group are perhaps of rather less interest than the 05 others, groups R which are aliphatic hydrocarbon groups substituted by oneor more aromatic groups directly or through an ox~en or sulphur atom 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 -A-R is ~ that consisting of an ethyl group substituted at the l-position by a napthyl group, for example a napth-l-yl group. The reagent H2N,~H.CO.NHCH(CH3)-napth-1-yl, which may be used to prepare compounds (I) containlng such a group, is of particular interest since it contains an asymmetric carbon atom and may be obtained in optically active ~orm. Examples of specific groups R3 are:

~CH2)n~ _(CH2)m--o~3 ~ H2) 2)n ~ ~ (CH2) ~ X
X

_~CH~ CU2)n ~ CH~

,~ 3L2~ 4 "

--(CH2)p -- CH t~ ) ( 2)p ~ ~X)~

~X r ) ~N

--(CHz)qCH3 \=/

6~4 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=l, 2, 3, 4 or 5 and X=OCH3, Cl, F, CF3 or CH3 (preferences between ortho, meta and para substitution in the cases where n is 0 or not being lndicated o5 hereinbefore).
- In addition to compounds containing 0-substituted oxime groups of the C(R )=NoR3 type which are discussed above, the invention also includes compounds containing O-substituted oxime groups of the type C(R2)=NoR4O The group R4, as indicated above, is an aliphatic hydrocarbon group which is substituted through an oxygen atom by an aliphatic hydrocarbon group which is itself substituted directly by one or more aromatic groups an~ preferences as regards both aliphatic hydrocarbon groups and the aromatic groupsare broadly as expressed above in the case of the group R . In particular, the aliphatic hydrocarbon group attached to the oxime oxygen atom is preferably of more than one carbon atom, for example being of three or parti-cularly two carbon atoms, whilst the aliphatic hydrocarbon group substituted by ~ne or more aromatic groups ispreferably of one to three carbon atoms, for e~ample one carbon atom, This latter aliphatic hydrocarbon group may conveniently be terminally substituted by one, two or even three aromatic groups although two or only one aromatic groups are preferred and these may conveniently be phenyl groups or substituted phenyl groups as described above in relation to R .
As well as compounds (I) containing a group C(R2)=NR ter-minating in a monovalent group R3 or R4 other compounds (I) of some interest contain a group C(R )=NR ln whlch R is -N=R5, R5 being a divalent organic group as defined above. Unsubstituted and substituted aliphatic hydrocarbon groups R5 most usually are groups slmilar to those described above in relation eo R3 but which contain two free valencies at the point of linkage. In the case of groups R5 which are aromatic groups it will be appreciated that there will not be such a close correspondence to the groups R described above as these aromatic groups, because ot their b ~2~.~59~

divalent nature, cannot derive from many of the aromatic systems described above in which the n-electrons are fully deloca-lised over the whole ring system, such as those comprising a single benzene or pyridine ring. Such aromatic groups constituting 05 R are therefore of the type described hereinbefore in which the n-electron system is not fully delocalised over the entire ring system and, indeed, this type of residue is one of those preferred in the case of R , specific preferences among such types of aromatic group being as discussed above in relation to R3. Another preferred type of group R5 is a methylene group in which both hydrogen atoms are substituted by an aromatic group, for example such as phenyl, so that the double bonds of the C~R )=N-N=C system ~re in conjugation with the aromatic system.
Examples of specific groups R5 are:
=~ /s~="~3 As regards the group R6 which consti3utes a part of groups -A-R of the specific type -NH.CO.CH2N ~RR6, the preferences among aliphatic, aromatic and araliphatic groups R6 generally correspond to those indicated above for R3 although aliphatic hydrocarbon groups are of rather more interest than is generally the case and, with the araliphatic groups, direct substitution by an aromatic group is preferred to substitution through an oxygen or sulphur atom.
Moreover, an important additional alternative is3 for R6 to be hydrogen. Conveniently the group -NH.CO.CH2.N'RR6 either contains ,, ~ ,i ~;~4l~59~L

a group R6 which is identical to the group R3, for example both being an unsubstituted aliphatic hydrocarbon group or one substituted directly by an aromatic group, or a group R6 which is hydrogen. Thus, specific examples of the larger group are 05 ~NH.CO.CH2.N(CH2C6Hs)2, -NH.CO.CH2N(C2Hs)2 and -NH.CO.CH2NH(CH2C6Hs).
As indicated above, compounds according to the present invention may contain, in the order shown previously, one of the following types of ring system: bicyclo [2,2,1] heptane, bicyclo [2,2,1] hept-2Z-ene, 7-oxa-bicyclo [2,2,1] heptane, 7-oxa-bicyclo [2,2,1] hept-2Z-ene, bicyclo [2,2,2] octane, bicyclo [2,2,2]
oct-2Z-ene, 6,6-dimethyl-bicyclo [3,1,1] heptane, cyclohexene, cyclohexane and hydroxycyclopentane. The 6,6-dimethyl-bicyclo [3,1,1] heptane ring system, unlike the others, may be substituted in either of two ways~ corresponding to reversal of the substituents shown at the a and b positions. It will be appreciated that the bridged ring systems present in compounds according -to the present invention show a range of degrees of asymmetry. Thus, the 6,6-dimethyl-bicyclo [3,1,1] heptane ring system is sufficiently asymmetric for reversal of the substituents at the a and b positions to result in a dlfferent structural isomer, and thus a different compound (I), both types of compound (I) containing the 6,6-dimethyl-bicyclo [3,1,1] heptane ring systern being covered by the present invention. In the case of the bicyclo [2,2,1] heptane and bicyclo [2,2,1] hept-2Z-ene ring systems and their 7-oxa analogues, however, reversal of these substituents would merely provide a structure which represents an alternative stereoisomer, the invention, as has previously been indicated, extending to the compounds (I) in their various stereoisomeric forms. The situation with the bicyclo [2,2,2~ oct-2Z-ene ring system is similar to that pertaining in the case of its 7-membered analogue but the bicyclo [2,2,2] octane ring system has a sufficient degree of symmetry for such reversa`l of the a and b substituents to give the same compound (I) of identical stereochemistry. Among 29~

these ring systems, the bridged ring systems are of particular interest and of these the bicyclo [2,2,~] octaneand the 6,6-dimethyl-bicyclo [3,1,1] heptane ring substituted at the 2-position by the group C(R )=NR rather than the group R may be mentioned parti-05 cularly. Among those bridged ring systems which may be saturatedor unsaturated, the former are usually preferred, particularly in the case of the compounds containing an oxygen bridging group, as unsaturation generally confers lower stability whilst the level of biological activity is generally substantially similar.
It wlll be appreciated that the structures of the compounds described above provide various opportunities for the occurrence of stereoisomerismO The substituent groups R and C(R2)=NR may be in the cis or trans relationship to each other, compounds of the latter configuration more generally being preferred. ~oreover, when the ring system is one which is bridged or contains a hydrogen substituent then, in most cases, different isomers will exist which vary according to the way ln which the substituent groups R1 and C(R2)=NR
are disposed in relation to the bridging groups or the substituent.
lsomers of particular interest are shown below in one of the two enantiomotphic forms which can exist in each case, the other enantiomorph having a structure which is the mirror image of that shown. The unsaturated ring system is illustrated where the ring system may be saturated or unsaturated and the symbol B represents -CH2- (position 7), -O- (position 7) or -CH2CH2-(positions 7 and 7~ 8). As indicated above, the bicyclo [2,2,2] octane system possesses a greater degree of symmetry than the other bridged ring systems, as the two bridging groups attached together at the bridge positions (1 and 4) are identical, both being -CH2CH2-. In this case ~herefore, although the trans isomer i9 preferred and can exist in two enantiomorphic forms, the endo, exo type isomerism which can occur with the other bridged ring systems cannot arise.
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. rt should be noted that ~he s.stem of numbering ~ 2 ~L~ 594 adopted for the bridged ring systems which can exist in both saturated and unsaturated form is chosen so that the double bond in the unsaturated ring syste~ receives the lowest number possible (2), the substituents Rl and C(R2)=NR then being at the S and 6 positions 05 respectively. For conformity, a similar system of numbering is followed for the analogous saturated ring systems, the substituents again being described as at the S and 6, rather than the 2 and 3, positions as in the 6,6-dimethyl ~3,1,1~ heptane system.

3~~ ~R~ R

~ C (R2) - NR 2 6 C (R2) ~ NR
5-exo, 6-endo 5-endo, 6-exo ~ ~ R or C(R2)= N R

CH3 C(R2)=NR or 2~, 3~, 6~

, R or C (R2)= NR

CH3 C(R )=NR or R
2~, 3 ~, 6~

( OH - o~
" R ~, R

C ( R2 ) e N ~ ~ C (R ) = N
~, æ~3~

Among the isomers illustrated above, of thetwo forms shown in each case one is usually preferred to a somewhat greater extent than the other. In the case of the 5-exo, 6-endo and 5-endo, 6-exo isomer5 the latter i3 most usually preferred but in the case where B is -0- the 5-e~o, 6-endo isomer is also of considerable interest.
In the case oE the 2p, 3~, 6~ and 2~, 30, 6a isomers the latter ls of most interest. ~The conventlon applled herein ~or naming the compoundq (I) containing a 6,6-dimethyl-bicyclo [3,1,11 heptane rin8 system i5 the use of~ and ~ to inticate the directlons in ~hich the substituents at the 2- and 3-positions are directed. In the designations used above the position of the ~rldging carbon atom at positlon 6 has for simplicity also been indicated bv an ~ or a ~ (the ?osition of the gem dimethvl ~ro~?s at the 1~ .

.. . . . . . . ..

- 18 _ ~2l.~

6-position is dictated by that of the carbon atom to which they are attached)]. In the case of the 1~, 2~, 3O~ and 1~, 2~, 3 isomers the latter is again of most interest.
Where the substituent R is a 6-carboxyhex-2-envl group or a 05 group modified therefrom but still containing the double bond, then the configuration about this bond is preferably cis (Z) rather than trans (E). In the other substituent C(R )=NR, syn and anti isomeris~ 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 compo-lnds of the present inveneion 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 enantiomers may be obtained either by the use of an optically active starting material or by resolution of a pair of enantiomorphs.
Specific compounds according to the present invention include the 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-carbo~yhexyl group and/or the group R2 is the other two of the groups hydrogen, methyl and eehyl than the one appearing in the specific compound in question, for example the ccmpoun~

CO~ H

~ --~ C(CH3 ) = N NHCSNH ~3 Compounds of formula (I) according to the present invention may be prepared by reacting a compound of formula (II) ,- , . j~
..

c ~ y I ~ C(R )=O
with a reagent ZNH2, Y being either R as defined above for compound (I~ or a precursor for R and Z being either R as defined above for compound (I) or a precursor or R, and the other symbols being as defined for compound (I) but with the letters a and b 05 relating instead to the substituents Y and C(R )=0, ~espectively, and where appropriate converting the group Y and/or the group Z in the resultant product into the groups R and R, respectivel~, of the compound (I). Preferably Z and conveniently also Y correspond to the corresponding groups R and R in the compound ~I). -A convenient fonm of intermediate for the preparation of all the various compounds (I) according to the present invention is a compound of formula (III) in which the symbols have the meaning lndicated for formula (II). When the desired compound tI) contains a substituent C(R2)=NR in which R2 is hydrogen then the compound of formula (LII) corresponds to that of formula (II) and is itself reacted with the reagent ZNH2 to give the compound (I) either directly or after modification of Y and/or Z. When the desired compound of formula (I) contains a substltuent C(R )=N~ in which R is not hydrogen, the compound of for~ula (III) may conveniently be reacted with a Grignard reagent of the form R2MgHalogen, followed by oxidatlon of the secondary alcohol of formula (IV) so formed, for example using ~ones reagent, and the resulting compound of formula (II) containing the deslred group R2 reacted with the reagent ZNH2 as lndicated prevlously H H

X / I (lll) ~ 2 I CHO I - CH(R )OH
H H
.. . .
k ~ ~ .

ig4 ~Various of the intermediates just described are the subject of a co-pending application). The preparation of such compounds of formula (III) is described in detail in the Examples for various 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. The 5-endo, 6-exo isomer is illustrated throughout the scheme in one enantiomeric form, although as explained hereinbefore the product obtained by this route i5 racemic and it is also possible that some minor contamination with other isomers may occur.
The corresponding bicyclo [2,2,2] octane compounds (III) are prepared by a similar route to that used for the bicyclo [2,2,1] heptane compounds (III). In this case, however, it is preferred to use an acetal prepared from ethylene ylycol rather than ethanol since the e~uilibrium of the reaction with ethanol does not lie sufficiently towards the ring closed form.
Preparation of compounds (III) in the case of many of the remaining ring systems is readily achieved by modification of the syntheses described herein. Thus the unsaturated bicyclic ring systems bicyclo [2,2,1] hept-2Z-ene and bicyclo [2,2,2] oct-2Z-ene may be prepared by omitting the reduction step which converts the unsaturated ring system which is pro-duced initially in each case to the corresponding saturated ring system, for example by omitting the catalytic reduction employing M2/Pd in the schematic route ~he synthesis of the bicyclo [2 2 1] hept-2Z-ene compound of formula (III) is described in de-tail ~:' 12~65~4 in U.~. Patent Application 8000279, published under the serial number G~ 2039909A, and also in the corresponding applications filed in other countries~] Compounds (III) containing the cyclohexane ring system may be obtained by the introduction of a H2/Pd-C reduction step, such as is illustrated in the schematic route, into the synthesis of the equivalent cyclohexene compound, reducing the cis~4,5-bis-hydroxymethylcyclohex-1-ene to give cis-4,5-bis-hydroxymethylcyclohexane before proceedlng with the formation of the monobenzyl ether. Alternatively, cyclohexane 1,2-dicarboxylic acid anhydride may be used as the starting material. The 7-oxa-bicyclo [2,2,1] heptane and hept-2Z-ene compo~mds oE formula (III) are obtainable, for example in the 5-endo, 6-exo form, by routes described in the literature which yield compounds containing a 6-carboxyhex-2'Z-enyl or 6-carboxy-hexyl substituent Rl, for example ~ggelte et al, J.C.S. Perkin I, 1978, 980 and Sprague et al, Advances in Prostaglandin and Thromboxane Research, 1980, 6, 493.
Other stereoisomers are obtainable by modified routes.
Thus, for example ~-pinene may be obtained in both optically active forms thus providing a route to (~)-nopol and (+~-myrt-enol as alternative starting materials for use in the routes described in Examples 6, 7 and 8. Also, in the case of the 7-oxa-bicyclo [2,2,1] heptane compounds and their ring unsatur-ated analoguesmodifications of the routes described in the literature may be used to produce other stereoisomers.

~. , ' i 5~4 , . .

When the group Rl 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 schematic route, contain a carboxy o5 group in protected form, for example as an ester and particularly as the methyl ester which may conveniently be :Eormed with diazo-methane~ Following reaction with the reactant Z.NH2 such a protecting group may then be removed, for example by de-esterifi-cation using KOH/CH30H/H20. Such protection will 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 a variety of forms of groups R , R~ and R~- in R. Thus, for example, the reagents H2N.~H,Co.R3 may conveniently be prepared by the reaction of hydrazine with the corresponding ester,for e~ample the e'thyl ester, R3.Co2C2H5. The reagents H2N.NH.CO.NHR
may be prepared by the reaction of hydrazine.with che corresponding N-substituted carbamate, for example the ethyl carbamate, R3NHCo2C2H5 (particularly for the preparation of phenyl semicarbazide) or more often as a ~eneral procedure with the corresponding isocyanate, R NC0.
Reagents H2N.NHCSNHR may be prepared very conveniently through the reaction of the corresponding primary amine R3NH2 with carbon disulphide in the presence of dicyclohe~ylcarbodiimide, followed by reaction of the resulting isothiocyanate, R3NCS. with hydrazine. Reaction between the compound of formula (II) and the reactant ZNH2 is often effected either with lts HCl salt in pyridine or with the free base in a neutral solvent, for e~ample tetrahydro-3o furan or dioxane, some degree of heating often being used as shownin the E~amples. Particular care may oEten be needed when using certain reactants H2N.NHR (o~ten obtainable by H2/Pd reduction of H2N.N=R ) to avoid o~idation with formation of a compound containing a group C(R )=N-N=R rather than one containing a group C(R )=N-~HR .

4e~. ' ~' -` ~L % ~ 3 4 This problem is particularly likely to be encountered where R is a methyl group substituted by two aromatic groups, for example where R is a diphenylmethyl or a fluoren-9-yl ~roup and groups not of this type are accordingly preferred in the case of groups R
05 of type -NHR3.
Modification of the 6-carboxyhex-2-enyl group may be effected through the initial introduction 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 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, where, as is the case in the schematic route a precursor of structure ~ C \~ C02H
~I
I ~CHO (in acetal form) i~ involved in the synthesis 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 exa~ple with H2tPd-C. The preparation of compounds containing a 6-carboxyhexyl-group in this manner is described in application G~ 2039909A. Where the synthetic route initia}ly involves compounds containing the corresponding unsaturated ring it may be possible, if desired, to reduce both the ring and chain double bonds at this stage in one step. In the case of other ring ~.~

~2i~ 4 .

systems, particularly 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 05 8-carboxy-1-formyl-oct-1-ene and cyclopentadiene (a separation of the two trans isomers obtained being required). Introduction of a 3-oxa-6-carboxyhexyl group is similarly best effected at an early stage of the synthesis. A convenient route for doing this involves the use of a compound of structure ~ CH
wherein the residue X is a saturated one, such as 6,6-dimethyl-2-(2'-hydroxyethyl)-bicyclo [3,1,1] hept-2-ene, as a starting material.
Reaction with acrylonitrile in the presence of Triton B (ben~yl-methylammonium hydroxide) in a Michael reaction is then used to modify the 2 substituent to form a 5'-cyano-3'-oxapentyl group which is then chain extended using, in turn9 lithium aluminium 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 ~ -(CH ) O(CH ) CH NH TsCl (CH ) O(CH ) NHT
(1)NaH -(CH2)20(C~2)3NTs2 CN-~ (CH2)2 ( 2 3 (2)TsCl Acid hydrolysis and es~erification 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 reaction at the double bond to yield a compound of the type (II) described hereinbefore having the structure ~ C ~ ~ Co~ ct~3 X
t ~ tlO
H

B
.

5~

It will be appreciated that ~he methods described above are not the only ones which may be used for the preparation of compounds according to the present invention and that various alternative procedures may be used as will be apparent to those skilled in the 05 art of prostaglandin chemistry.
It has been found that compounds according to the present invention inhibit the aggregatory activity of l5S-hydroxy-1la-9~
-(epoxymethano)-prosta-5Z, 13E-dienoic acid [ll,9-(epoxymethano) P~H2], which is a stable TXA2 mimic, on human platelets and on the 1~ rabbit aorta in vitro. Tests on compounds according to the present invention have also illustrated their ability to inhibit the aggrega~ory activity of both 11,9-(epoxymethano) PGH2 and collagen ~ in vivo in guinea pigs and of collagen ln vivo in rats. ~oreover, in the guinea pig tests the Konzett-Rossler test showed inhibition 1~ of the bronchoconstrictory effect of both ll,9-(epoxymethano) PGH2 and the collagen. It is believed that such inhibition is the result of the compounds being thromboxane antagonists and the activity of the compounds is for convenience hereinafter discussed in these terms. Preferred compounds according to the present invention e~hibit a pure antagonist activity. However antagonist and agonist activities have been found to be lin'~ed in some compounds and in consequence certain of the compounds have been Eound to show a partial agonist activity in certain tests, such as in the test based on the contractile activity of 11,9-(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 Lt has been found that structural features whlch 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 an oxime containing a phenoxyethyl group R ; (b) the absence of a halogen substituent at the meta position of an oxime containing a benzyl group R ; and (c) the presence of two benzene , ~, ., ~r ~

5~

rings in the oxime 3ubstituent, these rings bein~ located, for example, on a carbon atom joined directly to the oxygen atom of the oxime group.
Preferred compounds such as the c~mpounds of Examples 1 and 2 05 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 the aggregatory action of ADP which acts via non TXA2 - sensitive syste~s. MoreGver, they - -are pure antagonists in the rabbit aorta strip test but do not block the contractile action of noradrenaline which acts on a-adrenoceptors. Some activity has also been observed in compounds according to the present invention on guinea pig tracheal 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 e~ample as bronchodilators for the treatment of asthma and hypoxia, They additionally have potential as anti-lnflammatory agents. It will be appreciated that the spectru~ of activity shown by any particular compound will vary and that certain compounds may be of particular lnterest in one of these applications whilst other compounds are of particular interest in another of them. ~odifications 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 of modifications thereof of the type (a), ~b) and (c) can have advantages in relation to slow release depot preparation through conversion in vivo to the active compound contain~ng a free carboxy grou~, 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 ls in salt form, for example the sodium salt, can be of value due to the enhancement of water solubillty whlch generally results, It will be appreciated that compounts showing a partial enhancing action on thrombo~ane actlvlty are also of some interese in respect of this activity although to a much lesser extent ~han with inhibitorv activitv. rhus, certain compoun~s according to ~ ~ ~2~6~
(.

the present invention ~ay be of interest for laboratory or even for pharmaceutical purposes, for example iff the control of bleeding by toplcal administration which avoids any systemlc take-up, by virtue of the thromboxane enhancing facet of their activity which is shown under certain conditions.
The compounds may be formulated for use as pharmaceuticals for both animal and particularly human administration by a variety of methods, but usually together with a physiologically accepeable-diluent or carrier. The compounds may, for lnstance, be applied 13 as an aqueous or oily solution or as an emulsion for parenteral administration, the composition therefore preferably being sterile and pyrogen-free. The preparation of aqueous solutions of compounds ~ in which the group R terminates in a free carboxy group may be aided by salt formation. (The oxygen-bridged compounds do, however, have a higher water solubility than the corresponding carbon-bridged compounds). 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.
Alternative for~ulations 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.
In the case of systemic administration to produce a thromboxane antagonism the normal daily dosage which is proposed lies in the range from ~ 0,1 mg to 10 mg per kilogram (the average weight of a human being 70 kg) and particularly from 1 mg to 5 mg per kilogram. It will be appreciated, however that dosages outslde this range may be consldered, 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 illustraeed by the follo~ing Examples.
The compounds of the present invention are related to the compounds descrlbed and claimed in our ~'.K. patent applications of nu bers 8000~78 and 8000279, published as CB 2039480A and GB 2039909A, respectively, in which ;~

.. . .. . . . . .. .. . .. . . . .. . . . . . . . . . ... . .

5~4 bicyclo ~2,2,1] heptanes and hept-2~ enes are disclosed and claimed which are substituted at the 5-position by a 6-carboxy-hex~2-enyl group or a modification thereof, and at the 6-position by a group C(R2)-MR in which R represents a group -oR3, -NH.Co.R3 or -NH.CO.NTn-R3 and R3 includes the groups R3 described herein. Although such compounds are specifically excluded from the present invention the examples of Gs 2039480A
and GB 2039909A further illustrate the wide range of groups of the type C(R2)=NR which may be present in the compounds of thP

present invention.
In the Examples, where possible, the stereochemistry which the compounds are believed to possess has been indicated.
However, some contamination o a minor nature by other isomers may often be present, i.e. by the other of the pairs of preferred isomers illustrated hereinbefore or particularly by the corresponding cis isomer. It will be appreciated that the proportion of such contaminants does not necessarily depend upon the stereochemical nature of the intermediates in earlier sLages of the synthesis. Thus, certain compounds are capable of epimerisation under particular conditions, and the formyl compounds (III) in particular can undergo an epimerisation involving the formyl group, for example at the stage in the synthesis of many of these compounds where the formyl group is generated by the action of acid onan acetal.
In most cases the compounds are obtained in the form of a racemic mixture but in the case of the compounds of Examples ~, 7 and ~ an optically active starting material is .', h ~

- 28a -used and these compounds are therefore also optically active.
It should also be noted that the full stereochemistry has not been designated in the names of the compounds of Examples 6 and 7 in as far as no attempt has been made to indicate the orientation of the substituents Rl and C(R2)=NR relative to the two bridging groups CH2- and -C(CH3)2--, the full orient-ation being as shown in the structure designated 2~, 3~, 6~, illustrated hereinbefore. In the case of ~xample 8, this is also true for the stereochemistry of compounds of sections 5 and 6, although in admixture with another isomer.

~ j ~2~i65i~

2~ -~` The mass spectroscopy data given in these examples is generally obtained by direct inlet except for those cases where the compound has a substituent R which terminates in an ester grouping when the data .

~2~5~

- 29 - 23410-~35 is obtained by gas chromatography mass spectroscopy. In certain cases, which are indicated, the free carboxy group of the substituent Rl js converted to a methyl ester group before the mass spectrum is run (by gas chromatography mass spectroscopy). Such 05 conversion is readily achieved by solution in methanol, using warming and addition of NaHD03 as necessary7 followed by the addition of an excess of ethereal diazomethane to the methanolic solution, standing, and the removal of solvent.
EXAMPLES
Example l : 5-endo-(6'-Carboxyhex-2'Z-enyl)-6-exo-rN-(benzyl-thiocarbamoyl)-hydrazonomethyll-bicyclo r2.2,ll hePtane (l) Maleinaldehydic acid pseudo-ethYl ester 30g of redistilled furan-2-aldehyde is mixed with 600 ml dry ethanol and 300 mg of methylene blue is added. Dry air is blown gently through the solution and the material is irradiated with a 300 W tungsten lamp for about two days until t.l.c. in a silica gel/ether system shows essentially no remaining starting material.
The solution is then stirred with vanadium pentoxide for four hours, filtered, and the solvent removed under reduced pressure. The residual oil is distilled under high vacuum to give the title compound as an oil (23.69, 76%), b.p. 90 - 92O C/0.2 mm.
(2) Diels-Alder react_on between maleinaldehydic acid pseudo-eth~l ester and cvclopentadiene Freshly cracked cyclopentadiene (9.Og) is mixed with ll.Og of the pseudo ester (l). 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 without purification.
(3) 5-endo-Ethoxycarbonyl-6-exo-diethoxymethyl-bicyclo r?.2,l]
hept-2Z-ene The Diels-Alder adduct (2) (lOg) is heated in a mixture of triethyl orthoformate ~lO ml), dry ethanol (lO0 ml), and concentrated sulphuric acid (l ml). The mixture darkens and after 12 hours is cooled and treated with anhydrous potassium carbonate (5g) and ~ n ~2~i5~

ether (150 ml). Water is then slowly added with efficient mixing to neutralise the acid. The product is extracted with ether, washed with water and distilled to give the title compound as an oil (7.3g, 63%), b.p. 115 - 120C/0.3 mm.
05 (4) 5-endo-Ethoxycarbonyl-6-exo-diethoxymethyl-bicvclo r2,2,1 heptane 5-endo-Ethoxycarbonyl-6-exo-diethoxymethyl-bicyclo [2,2,1]
hept-2Z-ene (309) is dissolved in 200 ml of ethanol and 0.3g of 10%
palladium on charcoal is added. The mixture is vigorously stirred in 1 atmosphere of hydrogen gas at room 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~l) pad, followed by evaporation of the filtrate to give a quantitative yield of the title compound as an oil b.p. 105 -llOoC/1.5 mm.
(5) 5-endo-Hydroxymethvl-6-exo-diet~ox~_ethyl-bic~y~o r2,2,1 hePtane The ester (4) (27g) is added in ether to a 10% excess of lithium aluminium hydride (2.19) in ether with 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%
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 r2.2.11 he~tane The alcohol (5) (20g) in a minimum volume of dry pyridine is added slowly to 209 of p-toluenesulphonyl chloride in 130 ml dry pyridine with stirring at OoC. The mixture is kept at 5OC 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 in 85% yield as an off-white solid, m.p. 84 - 86OC (dec.).
The tosylate (149) in 15 ml dimethyl sulphoxide is added to Sg of dry potassium cyanide in 20 ml dimethyl sulphoxide.
The mixture is stirred under nitrogen and the temperature slowly (1) Celite is a registered trade mark .~

`~ 2~

raised over 1 hour to 110 C. 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/1.5 mm.
(7) 6-exo-Diethoxymethyl-5-endo-formylmethyl-bicyclo 12,2,1]
_eptane 05 The cyano compound (6) (20g) is stirred at -15 C in 200 ml dry toluene under nitrogen. Di-isobutylaluminium hydride (113 ml of a lM solution in hexane) is added to the substrate over 25 minutes and the mixture allowed to reach room temperature. After 1 hour, methanol (30 ml) is cautiously added, followed by 400 ml 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 (Mg S04) and the solvent removed to give a yellow oil. This ls chromatographed on Florisil(in benzene to give the pure title compound as a colour-less oil (17.2g, 85%), vmax (film): 1725 cm - (8) [2t2,1] heptane (4-Carboxy-n-butyl)-triphenylphosphonium bromide (23.3g) is dried at 75C under vacuum for 2.5 hours. The resulting white solid is then cooled, the vacuum released to dry nitrogen, and 30 ml of dimethyl sulphoxide is added. A 2M solution of dimesyl sodium in dimethyl sulphoxide (50 ml) is added slowly while the mixture is maintained at 25C with a water bath. After 15 minutes the 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 55-60C 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%).

( ) Florisil is a registered trade mark ,',, ,` - ' j~
,f ' .' (, _ 32 -(9) 5-endo-(6'-Carbox The acid/acetal (8) (1.8g) is dissolved in 200 ml chloroform and 50 ml 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 solutLon dried 05 and concentrated. The residual oil is purified by silicic acid chromatography, the oil being applied to the column (prepared by slurrying IOg 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 chroma-~ tography gives ~he title compound as a colourless oil (1.4g, 83%), ~(CDCl3)1.2 to 2,6 (18H,m), 5.4 (2H,m), 9.6 (IH,d).
~ote: Care should be taken to avoid contact of this compound with methanol since it very readily fonT~s a dimethyl acetal.(10) 5-endo-(~'~arboxyhex-2'Z-enYl)-6-e~o- [~-(benzylt_iocarbamovl) -hydrazonomethyl~ -bicvclo [2,2,1~ heptane The aldehyde/acid (9) (100 mg) is heated at 60 C with benzyl-thiosemicarbazide (110 mg) in tetrahydrofuran (THF) (~ ml) for 2 hours. The THF is removed in vacuo, and the resulting product is purified by silica gel chromatography (lOg charge), eluting with a linear gradient from IOX v/v ethyl acetate in benzene to pure ethyl acetate and monitoring the fractions by t.l.c. The chroma-tography gives the title compound as a yellow oil (85 mg), ~ a (CH30H) 270 nm, emaX 25~200~ ~(CDC13) 4.90 (d,2H), 5.30 (m, 2H), 7.20 (d), 7.35 (s, 5H), 7,60 (t, IH), 10,2 (br, 2H); M 413 ~very small, ~-2 prominent).
` The benzylthiosemicarbazide is prepared as ~ollows.
Dicyclohexylcarbodiimide ~10,3g) and carbon disulphide (20 ml) are stirred in a round-bottomed flask with 20 ml o~ diethyL
ether at -10 C. Benzylamine (5,~Sg, S.5 ml~ in 20 ml ether is ~ ~ ff~ale ~llf~

, .
~ 'Y
.' ~ ~ .

( added slo~ly when a white precipitate forms immediately, The reaction mixture is stirred overnight, fil~ered and ~he ether removed in vacuo. The residue is suspended in eth r, filtered and the ethe~ removed in vacuo. The remaining oil is dis~illed under oS vacuum (0.5 ~m, 100 C approx.) to give benzylisothiocyanate as an oil ~4.7g, 62~).
Benzylisothiocyanate (4.0g~ is slowly added to 1,8g of anhydrous hydrazine in 50 ml dioxane. The reaction mixture is stirred at room temperature, the dioxane is then removed in vacuo and the residue is recrystallised from ethanol eO give 4-benzylthiosemi-carbazide as a crystalllne solid (2.5g), m.p. 127.6C.
Example 2 : 5-endo-(6'Carboxyhex-2'Z-enyl~-6-exo-{1'- [~-~phenylthio-carbamoyl)-hydrazono]-ethy~ bicyclo [2,2,1] heptane (1) 5-endo-(6~Carboxyhex-2'Z enyl)-6-exo-(1'-hvdroxyethvl)-bi~clo [2,~ heptane 5-endo-(6'-Carboxyhe~-2'Z-enyl)-6-e~o-form~l-bicyclo ~2,2,1~
heptane is prepared as described in Example 1(9). ThLs aldehyde/
acid (250 mg) is dissolved in dry tetrahydrofuran (10 ml) at O C
and treated under nitrogen and with stirring over 30 minutes with a 1~ solution of methyl ~agnesiu~ iodide in ether (2 ml). Th~
mixture is stirred under nitrogen overnight whilst it is allowed to come to room temperature. The reaction ls then quenched by the addition of dilute aqueous hydrochloric acid and the product is extracted with ether (3x) ~ the ether solution is dried and evaporated to give the title compound as an oil (200 mg). 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 IBo2~ a ~ value of 352 and a base peak of 117~
Chromatography on a column of Sephadex LH 20 substituted wlth Uedox 111~ olefin o~lde to 20Z w/w (Lipide~ )of the bulk of the oily product using a mixeure of (all proporeions by volume) 100 parts of he~ne, 100 parts of 1,2-d$ch10roethane, 5 parts of eth~nol and 0.1% of the total of glacial ~cetic lcld, as eluant yie1ds the t~io iscmerLc secondarJ a1coho1; dift2ring in the (l) Sephadex, Nedox and Lipidex are Registered Trade Marks.
~ ,.

5~

configuration at -the newly in-troduced asymmetric carbon atom (-CMOH.CH3). N.m.r spectroscopy on these isomeric products in CDCl3 gives the following ~ values: First isomer eluted: 7.3 (s, broadg lH), 5,45 (m, 2H), 3.6 (m-qxd, lH), 2.5-1.0 (m, 21H), 102 05 (d). Second isomer eluted: 7.8 (s, broad, lH), 5.4 (m, 2H), 3.55 (m-qxd), 2.5-1.0 (m, 18H), 1.2 (d)~
(2) 5-endo-(6'-Carboxyhex-2'Z-enyl)-6--exo-acetyl-bicyclo [2,2,1]
heptane The procedure described under (1) is repeated with 600 mg of the aldehyde to give a mixture of the two isomeric alcohols (500 mg). This mixture is dissolved in pure acetone (15 ml) and the solution is cooled to 0C. Jones reagent (600 ~l of a solution prepared by dissolving 26.7g of chromic anhydride in 23 ml of concentrated suLphuric acid and diluting to 100 ml with water, folLowed by ~iltratLon) -ls added slowly to the coolecl soLutlon with vigorous stLrrLng over 15 minutes. AEter a further 10 minntes stirring at 0C the mixture is poured into water and the product extracted with ether. The ether solution is dried and evaporated to give the title compound as an oil (about 75% overall yield from formyl compound), ~(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 value of 17.15, a M value of 278 and a base peak of ~3/137.
(3) 5-endo-(6'-Carboxyhex-2'Z-enyl)-6-exo-~1'-[N-(phenyl-thiocarbamoyl)-hydrazono]-ethyl} -bicyclo [2,2,1] heptane The ketone (2) (100 mg) is heated at 60C with phenylthio-semicarbazide (110 mg; prepared by an analogous procedure to that described for ~-benzylthiosemicarbazide in Example 1 (10) and having m.p. 113.7C) in dioxane (5 ml) for 2 hours. The dioxane is removed in vacuo, and the resulting product is purified by silica gel chromatography (lOg charge), eluting with a linear gradient from 10% v/v ethyl acetate in benzene to pure ethyl acetate and monitoring the fractions by t.l.c. The chromatography gives the title compound as an oil (107 mg), ~ (CH30H) 277nm, iZ~;94 24, 780, ~ (CDCl3) 2.00 (s, 3H), S.35 (m,2H), 7.2-7.7 tm, SH), 8.95 (br, lH), 9.30 (br, lH), ~ 413 (very small, ~-2 prominent)~
Example 3_ 5-endo-(6'-Carboxvhex-2'7-enyl)-6-e~o~ L'-[N=(pheny~-thiocarbamoyl)-hydrazono~-propyl~-bicyclo [2,2,1]
heptane (1) ~ ~ ~ o~
bic~clo 12,2,1] heetane 5-endo-(6'-Carboxyhex-2'Z-enyl)-6-exo-formyl-bicyclo [2,2,1]
heptane is prepared as described in Example 1(9). This acid/
05 aldehyde (600 mg) is dissolved in dry te~rahydrofuran (25 ml) at 0C and treated under nitrogen and with stirring over 30 minutes with a 0.5M solution of ethyl magnesium bromide in ether tl0 ml~.
The solution is allowed to warm up to room temper~ture and is then treated with dilute aqueous hydrochloric acid and the product 0 extrac~ed with ether (3x). The ethereal extracts are dried and evaporated to give the title compound as an oil. ~ small sample ls treated to form the methyl ester trimethylsilvl ether and on gas chromatographv mass spectroscopy this shows prominent ions at m/e values of 366 (M ), 337 (~-29), ~76 (~-90) and 131 (C2H5.CH,OI~IS).
The bulk of the oil is subjected to gel partition chroma-tography on a column of Sephade~ ~H20 substituted with Nedox~
olefin oxide to 20% wtW (Lipidex~ usLng as eluant a mixture of t~ll proportions by volume) 100 parts hexane, 100 parts 1,2-dichloro-ethane, 5 parts ethanol and 0.1Z of the total of glacial acetic acid. The chromatography separates the product into two main zones corresponding to the two isomeric secondary alcohols differing ln configuration at the newly introduced asymmetric carbon atom (-CHOH.CH3). ~.m.r. spectroscopy on these isomeric products in CDC13 gives the foLlowing ~ values. First isomer eluted: 7.5 (broad, 2H), 5.~ ~m, 2H), 3.22 ~d x t, IH), 2.5-0.9 tm, 25H).
Second isomer eluted: 7.5 (br, 2H), 5.4 (m, 2H), 3.40 (m, IH), 2.5-1.0 (m, 25H~.
r~

~3 ~2~

(2) 5-endo-~6'-Carbox~hex-?'Z-envl)-6-exo-proPionyl-bicyclo r?y291 heptane The alcohol/acid (1) of the first zone (145 mg) is oxidized with Jones reagent at OoC in acetone in an exactly analogous manner to 05 that described in Example 2(2) to give the title compound as an oil (95 mg), ~ (CDC13) 9.0 ~br, lH). 5.35 (m, 2H), 2.7-0.9 (m, 23H), M~ 292 together with 235 (M-57) and 151 (M-141) ~as methyl ester -a single peak being obtained on gas chromatography).
The alcohol/acid (1) of the second zone is treated similarly to give the same product (105 mg).
(3) 5-endo-~6'-CarboxYhex-2'Z-envl)-6-exo-~1'-rN-~enyl-thiocarbamovl)-hydrazonol-Propyl~-bicyclo r2.2?11 hePtane The ketone/acid (2) (100 mg) and phenylthiosemicarbazide (110 mg) in dioxane (5 ml) are heated to 500C overnight. The dioxane is removed in vacuo, and the resulting product is purified by silica gel chromatography (lOg charge) eluting with a linear gradient from 10~ v/v ethyl acetate in benzene to pure ethyl acetate and monitoring the fractions by t.l.c. The chromatography gives the title compound as an oil (20 mg, 15%), ~max (CH30H) 277 nm, ~max 22,380, ~(CDC13) 9.7 (br, lH), 9.1 (br, lH), 7.8-7.0 (m, 5H), 5.4 (m, 2H), 2.5-1.0 (m, 23H). M+ 427.
Example 4 : trans-5-(6'-Carbox~hex-2'Z-enyl)-6-[N-~phenvl-carbamovl)-hydrazonomethyll-bic~clo r2.2 21 octane ~1) Diels-Alder reaction between maleinaldehYdic acid pseudo-ethyl ester and cYclohexadiene Cyclohexadiene (4.5g) and the maleinaldehyde acid pseudo-ethyl ester described in Example 1(1) (6.4g) are heated together in a thick walled glass tube at 1200C for 10 hours and the product is distilled to give the Diels-Alder adduct of these two compounds in over 90% yield, b.p. 95-970C/0.2 mm, M~ 208.
(2) 5-endo-Hydroxvmeth~1-6-exo-(1'.3'-dioxacvclopent-2'-yl)-bicyclo r2.2,21 oct-2Z-ene The Diels-Alder adduct (1) (lOg) is heated under a Dean and Stark apparatus with 12 ml of ethylene glycol in 100 ml toluene i5g~

- 37 _ 23410-235 containing a crystal of p-toluenesulphonic acid. After water has ceased to form, half of the solvent is distilled off and the resultant solution of S-endo-ethoxycarbonyl-6-exo-(1',3'-dioxacyclopent-2'-yl)-bicyclo [2,2,2] oct-2Z-ene is added to excess 05 lithium aluminium hydride (39) in 200 ml of dry ether. The addition is performed at a rate which maintains a gentle boiling of the ether (30 to 60 minutes). After a further 1 hour of heating the excess hydride is destroyed bv the careful addition of wet ether followed by water. The mixture is then treated with aqueous 10% w/v sodium hydroxide solution to precipitate aluminium salts. The mixture is dried over magnesium sulphate and then filtered. The organic solvent is evaporated to give the title compound as an oil which is used directlv in step (3).
(3) trans-5-H~y_roxymethyl-6-(1'.3'-dioxacyclopent-2'-yl)-bicYclo r2,2,?l_octane The crude alcohol/acetal obtained in (2) is dissolved in ethanol and hydrogenated at atmospheric pressure over 10% palladium on charcoal, one molecular equivalent of hydrogen being absorbed. The catalyst is filtered o~f and the solvent evaporated. Distillation of the residue gives the title compound as a colourless oil (6.1g, 60%), b.p. 110-112C/0.15 mm.
(~) trans-5-Cyano-6-(1',3'-dioxacycloPent-2'-yl)-bicvclo r2.2.2l octane The alcohol/acetal (3) ~7.0g) in lS ml dry pyridine is added to 7.5g of p-toluenesulphonyl chloride in 45 ml of pyridine at OoC
with stirring. After 20 hours the mixture is poured into ice/water and after 30 minutes stirring the mixture is extracted with ether to give the tosylate ester of the alcohol as a colourless o11 in good yield.
The tosylate ester (12.0g) in dimethyl sulphoxide (15 ml) is added to potassium cyanide (3.09) in dimethyl sulphoxide (20 ml].
The mixture is stirred and heated at lOOoC under nitrogen for 6 hours. The reaction mixture is then poured into water and the mixture is extracted with ether to give the title compound as an 5~

oil ~7.2g), VmaX2205 cm~l, which i5 purified by passage through a short Florisil* column with toluene as eluant.
(5) trans-5-Formylmethvl-6-(1',3'-dioxacycloPent-2l-yl)-bicyclo r 2.2~21 octane 05 The nitrile/acetal (4j (7.09) is stirred in 100 ml of dry toluene under nitrogen at -150C. Di-isobutylaluminium hydride, (42.5 ml of lM solution in toluene) is added slowly over 25 minutes and the mixture is allowed to warm slowly to room temperature.
After 1 hour, methanol (10 ml) is slowly added, followed by 200 ml of saturated aqueous sodium hydrogen tartrate. The mixture is stirred at 400C for 2 hours and the upper organic layer is then separated and the aqueous phase further extracted with ethyl acetate. The combined organic solutions are dried (MgS04) and evaporated. The yellow oil obtained is chromatographed on Florisil in toluene to give the title compound as an oil (5.~g, 83%), max vmaX (film) 1720 cm~l ~(CDC13) 9.75 (t, J=2H~, lH),

4.85 (d, J=8Hz, lH), 3.9 (m, 4~1), 2.8-2.4 (m, 2H), 2.1-1.2 (m, 12H).
(6) trans-5-(6'=CarboYhex-?'Z-enyl~-6-formvl-bicvclo r2.2.2]
octane (4-Carboxy-n-butyl)tripheny~phosphonium bromide (17.0g) is dried at 750C for 3 hours under vacuum. The solid is cooled and the vacuum released to argon. Dimethyl sulphoxide (50 ml) i5 added and butyllithium (270 ml of a 1.5 M solution in pentane) is added slowly over 1 hour. The deep red ylide thus formed is stirred at room temperature for 15 minutes and then the aldehyde/acetal (5) (4.6g) is added slowly over 15 minutes. The mixture is stirred overnight at room temperature, and then the solvent is removed at 50-600C
under vacuum. The residue is dissolved in water and the aqueous phase is extracted with ether to remove non-acidic material. The water layer is acidified (pH = 4) with 2N aqueous hydrochloric acid and then extracted with ether. The ethereal solution is dried and evaporated to give trans-5-(6'-carboxyhex-2'Z-enyl)-6-(1',3'-dioxacyclopent-2'-yl)-bicyclo [2,2,2] octane as an oil (3.59, 55%~.

* Trade Mark - ~,;f l ~16~

- 39 - 23~10-235 The acetal group is removed by stirring this material (39) with 200 ml of water/dioxane (1:1 v/v) containing O.lN aqueous hydrochloric acid at 400C. The mixture is extracted with ether and the ethereal extract is dried (MgS04) and evaporated to give a 05 residue which is purified by chromatography on silica ge1 in toluene/ethyl acetate (90:10 v/v) to give the title compound as an oil [2.3g, 48% from (5)~, vmax (film) 1725 and 1710 cm~l, ~(CDC13) 9.73 ~s, lH), 5.5-5.3 (m, 2H), and 2.2-1.45 lm, 20H).
(7) trans-5-(6~-Carboxyhex-2'Z-enyl)-6-rN-(phenYlcarbamoYl)-hydrazonomethyll-bicyclo r?.2,2l octane The acid/aldehyde ~6) (100 mg) is heated with phenyl semicarbazide (85 mg) in dioxane for 2 hours at 400C. The solvent is then evaporated and the residue purified by liquid-gel partition chromatography using a 400 x 15 mm 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. The chromatography gives the title compound as an oil (87 my), ~(CDC13) 9.60 (br, lH), 8.10 (br, lH) 7.7-7.1 ~m, 5H),

5.35 (m, 2H).
The phenyl semicarbazide is prepared as follows. Ethyl-N-phenyl carbamate (8.25g~ is refluxed with hydrazine hydrate (3.75g~
for 3 hours. The mixture is evaporated to dryness, the residue is treated with ether, and the solid phenyl semicarbazide (1.5g) is filtered off, washed with ether and dessicated, m.p. 122 - 1240C.
Note: In a variant of the procedure described in this Example the acid/aldehyde (6) (100 mg) is reacted with p-fluorobenzoic hydrazide (H2NNHC0 ~ F) (45 mg) in place of the phenyl semicarbazide (H2NNHCONH ~ ), the reaction being carried out in tetrahydrofuran for 1.5 hours at 400C to yield the alternative bicyclo [2,2,2] octane derivative, trans-5-(6'-carboxyhex-2'Z-enyl)-~-EN~(p-fluorobenzoyl)-hydrazono methyl]-bicyclo [2,2,2]
octane.
The p-fluorobenzoic acid hydrazide is prepared as follows.
Ethyl p-fluorobenzoate (8.49) is refluxed with hydrazine hydrate 1 ~ .

L ~ ~ g ~

(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.
05 Example 5 : trans~5-(6'-Carboxyhex-2'Z-enyl)-6- ~1'-[N-(phenyl-thiocarbamoyl)-hydrazono_J -ethyl~ -bicyclo f2,2,2 ~ octane (1) trans-5=(6'-Carboxyhex-2'Z-enyl)-6-acetyl--bi~clo [2,2 octane trans-5-(6'-Carboxyhex-2'Z-enyl)-6-formyl-bicyclo [2,2,2~
octane is prepared as described in Example 4. This acid/aldehyde (2g) is dissolved in dry tetrahydrofuran (20 ml) at O C and treated under nitrogen with lM solution of methyl magnesium bromide in ether (23 ml) during 2 hours. The reaction is quenched by the addition of dilute aqueous hydrochloric acid and the mixture is extracted with ether (3x). The ethereal solution is dried and evaporated to give a residue which is ehromatographed on silica gel using increasing proportions of ethyl acetate in toluene as eluant.
Traees of the starting material are eluted with 20% v/v ethyl acetate in toluene and 50% v/v ethyl aeetate in toluene elutes trans-5-(6'-carboxyhex-2'Z-eny ~ 6-(1'-hydroxyethyl)-bicyclo [2,2,2~
octane in the form of an epimeric mixture differing in configuration at the asymmetric carbon atom of the group -CHOHCH3.
The solution of the epimeric alcohols is evaporated and the residue (1.6g) in acetone (20 ml) is oxidized using Jones reagent [2.2 ml, prepared as described in Example 2(2)] at O C for 30 minutes. The reaction mixture is worked up as deseribed in Example 2(2) to give trans-5-(6'-earboxyhex-2'Z enyl)-6-acetyl bieyelo [2,2,2] octane as an oil (1.3g), 6(CDC13) 5.4 (m, 2H), 2.2 (s, 3H) 2.6-1.3 (m, 20H), M 292 and also 249 (M-43) and 151 (M-141) (as methyl ester).
(2) trans-5-(6'-Carboxyhex-2'Z-enyl)-6- ~1'-[N- enylthio-carbamoyl)-hydrazono] -ethyl~ -bicyelo [ 2,2,2] oetane The acid/ketone (l) (30 mg) is heated at 40C with phenyl-thiosemicarbazide [115 mg1 prepared as described in Example 2(3)]

5~9~

- 4~1 -in dioxane for 2 hours. The solvent ls removed in vacuo and the residue ls purified by gel partition chromatography on a column of Sephadex LH20 substituted ~th Nedox 1114 oleEin oxide to 20Z w/w (Lipidex) using as eluant a mixture of (all proportions by volume) oS 100 parts of hexane7 100 parts of 1,2-dichloroethane, 5 parts of ethanol and O.lX of the total of glacial acetic acid. The chroma-tography gives the title compound as an oil tl7 mg), ~tCDC13) 9.50 (br, lH), 8.75 (br, lH), 7.7-7.1 tm, 5H), S.35 (m, 2H~, 2.0 ~s) and 2.18 ~s, 3H together - may be due to syn/anti isomerism).

~,j .

~`
- 42 _ ExamDle_ 6 : 2 ~
carbamovl)-hydrazonomethyl]-6 6-dimethyl-bicYclo 13L~_13 heptane . . ., ~, (1) 2-(2'-Benzyloxyethyl)-6,6-dimethyl-bi 2-(2'-Hydroxyethyl)-6,6 dimethyl-bicyclo [3,3,1] hept-2-ene [(-)-nopol] (66g) is added slowly with stirring to 12.Sg of 80%
sodium hydride dispersion in oil in ~0 ml of dimethylformamide at room temperature. After addition (ca. 1 hour), stirring is continued 05 for 4-5 hours until all hydrogen evolution has ceased. Benzyl chloride (52g, 46 ml) i5 added over 1-2 hours at room temperature when an exothermic reaction is observed. After the addition, the - mixture is heated at 80 C for 4 hours. The material ls then cooled, poured into water and the product isolated by ether extraction followed by distillation under vacuum to give the title compound as an oil ~71g, 70Z), b.p. 128-131 C/0.2 mm.
(2) 2c~-t2'-Benzyloxyethyl)-3 ~ yl-6,6-dimethyl-bicyclo [3,1,1] hept ne The benzyl ether (1) (10.2g) is placed in a large flask (11.) with 30 ml THF (dry) under argon and 9-bora-bicyclo [3,3,1] nonane (9-BBN) in THF (90 ml of O.SM solution) is added over S-10 minutes at room temperature. The solution is refluxed for 30 hours main-taining the inert atmosphere, after which most of the conpound has reactPd at the double bond.
The hydroborated benzyl ether is cooled to 0C while the argon atmosphere is replaced by carbon monoxide. A solution of lithium trimetho~yaluminium hydride (62 ml of 0.7~) is prepared from lithium aluminium hydride and methanol in IHF and added over 30-60 minutes with vigorous stirring maintaining a positive pressure of carbon monoxide in the system~ A vigorous uptake of gas is ~ observed (ca. 1,000 ml) and after a further 1 hour of vigorous stirring the argon atmosphere is re-established and 82 ml of pH7 aqueous saturated phosphate buffer (buffer prepared from 9~.5~
~aH2P04O2H20 + L08.75g K2HP0, dlssolved in 2~0 ml water) is added with vigorous stirring. Finally 1~ ml of- ~0~ hvdrogen pero~ide is carefu11v added whi1e keeping the tempera~ure or the mi~ture be~ow ~ ~ .
~ - .

20 C. The mixture is stirred for a further 10 minutes and then poured into water, The title compound is isolated by ether extrac-tion and purified by chromatography on Florisil eluting with petrol/ether, being obtained as an oil (8.9g, 8170),~ (film) 05 1718 cm (3) ~ -(2'-Benzyloxyethyl)-3 ~ -(dimethoxymethyl)-6,6-dimethyl-bicyclo 13,1,1] heptane The benzyl ether/aldehyde (2) (10g) is dissolved in 100 ml of methanol containing 10 ml trimethyl orthoformate. A few crystals of p-toluene sulphonic acid are added and the mixture is kept overnight. The solution is treated with anhydrous sodium carbonate (0.5g) and water (20 ml) is slowly added with efficient mixing.
The mixture is added to excess water and the title compound isolated by ether extraction in impure form as an oil in 100% yield, M 342.
(4) 2G~-(2'-Hydroxvethyl)-3~ -(dimethoxymethyl)-6,6-dimethyl-bicyclo [3,1,1] heptane The benzyl ether/acetal (3) (lOg) is dissolved in 100 ml of methanol and 300 mg of 10% palladium on charcoal is added. The mixture is then hydrogentated at room temperature and atomospheric pressure. After take up of 1 molar equivalent of hydrogen the title compound is isolated in impure form as an oil in 100% yield by filtration of the mixture through Celite and evaporation of the methanol.
(5) 2~-(2'-Formvlmethvl)-3~ -(dimethoxymethyl)-6,6-dimethyl-bicvclo [3,1,1~ heptane The alcohol/acetal (4) (5.0g) is dissolved in dry methylene chloride (10 ml) and the solution is added with stirring over 10 minutes to pyridinium chlorochroma~e (6.0g) in 30 ml methylene * Some samples of catalyst may be found to encourage cyclisation of the debenzylate~ compound ~o give a cyclic acetal. In the event of this presenting difficulty, an alternative procedure is to use sodium in 1i~uid ammonia for this stage.-~3-~ ' _ 44 _ 23410-235 chloride containing 0.59 of dry finely divided sodium acetate.
After 2 hours, 200 ml of dry ether is added to the mixture and after a further 15 minutes, the mixture is poured into water. The ether layer is quickly washed with 3% aqueous sodium hydroxide 05 (2 x 200 ml~, followed by brine. The solution is dried over sodium sulphate, the ether evaporated and the residue chromatographed on Florisil with benzene/ether as eluant to give the title compound (2.19, 43%), vmaX (film) 1720 cm~l, M+ 240.

(6) 2~-(6'-Carboxyhex-2'Z-enyl)-3~-~dimethoxymethyl)-6.6-dimethyl-bicyclo_r3,1,11 heptane The aldehyde/acetal (5) (0.59) is reacted with 2.2 equivalentsof 4-carboxy-n-butyl-triphenyl-phosphonium bromide in the presence of dimesyl sodium in dimethyl sulphoxide as described for the bicyclo [2,2,1] acid/acetal in Example 1(8) to give the title compound in a high purity (0.519, 72%), M+ 338.

(7) 2~-(6'-Carbox~yhex-2'Z-en~ 3@-formyl-6,6-dimeth~l-bicyclo r31 ~_1 heptane The acid/acetal (6) (0.5g) is dissolved in 20 ml of dioxane-water mixture (1:1~ and the solution is heated at 40OC
for 2.5 hours with an excess of 0.2M aqueous hydrochloric acid. The title compound is isolated as an oil by extraction with ether followed by chromatography on silicic acid eluting with 5X ether in toluene (0.369, 72%), VmaX (~ilm) 1720 cm~l, ~(CDC13) 0.7 (d, lH), 1.2 (s, 3H), 1.5-2.8 (m, l5H), 5.4 (m, 2H), 8.5 ~s, very broad, lH), 9.6 (d, lH), M+ 292 (methyl ester.
t8) ?a~ 6l-carboxyhex-2lz-eny-ll-3~-rN-(phenylthiocarbamoyl) hydrazonomethyll-6,6-dimethyl-bicyclo r3.1,11 heptane The acid~aldehyde (7) (100 mg) is heated with 4-phenylthio-semicarbazide (100 mg) in 5 ml dioxane at 60OC for 2 hours. The solvent is removed 7n vacuo and the residue purified on Lipidex using the procedure described in Example 2(1) to give the title compound as an oil (126 mg), VmaX (CH30H) 274.5 nm, ~max 16,650, ~(CDC13) 1.10 (s, 3H), 1.25 (s, 3H), 5.40 (m, 2H), 7.2-7.7 (m, 5H), 9.05 (br, lH), 10.30 (br, lH), M+ 427 (very small, M-2 prominent).

iS~

- 45_ 23410-235 Example 7 : 2~-(6 -Carboxyhex-2'Z-enyl)-3n-{1'-~N-(Dhenvl-carbamoyl)-hvdrazonol-ethyl~-60~-dimethyl-bicyclo 13.1.11 heptane (1) 2~-(6'-CarboxYhex-2'Z-enyl)-3~-acetyl-6.6-dimethyl-bicyclo .r3~1 .11 heptane 05 2~-(6'-Carboxyhex-2'Z-enyl)-3~-formyl-6,6-dimethyl-bicyclo ~3,1,1] heptane is prepared as described in Example 6(7). This acid/aldehyde (l.lg) is dissolved in dry tetrahydrofuran (20 ml) and treated at OoC under nitrogen with a lM solution of methyl magnesium bromide in diethyl ether (12 ml). The mixture is stirred overn;ght and is then allowed to come to room temperature and is quenched by the addition of dilute aqueous hydrochloric acid. The mixture is extracted with ether (3x) and the ether solution is dried and evaporated to give, as an oil, 2~-(6'-carboxyhex-2'Z-enyl)-3~-(l'-hydroxyethyl)-6,6-dimethyl-bicyclo [3,1,1] heptane in the form of an epimeric mixture differing in configuration at the asymmetric carbon atom of the group -CHOHCH3.
The acid/alcohol mixture is treated with Jones reagent (1.25 ml) in acetone at OoC for 30 minutes in an analogous fashion to that described in Example 2(2). The reaction mixture is then quenched with water and the product immediately extracted with ether. The ether solution ;s dried and evaporated and the oily residue is chromatographed on silica gel using increasing concentrations of ethyl acetate in toluene as eluant. The bulk of the desired product is contained in the 20% vJv ethyl acetate/toluene fraction which is evaporated to give the title compound (0.625g), ~(CDC13) 5.35 (m, 2H), 2.18 (s, 3H), 3.0-1.6 (m, 17H), 1.07 (s, 3H), 1.22 (s, 3H), 0.87 (d, lH), M+ 306 and also 263 ~M-43), 165 (M-141) and 125 (on methyl ester). The methyl ester-butyl oxime derivative, unlike the methyl ester, shows twin peaks on gas chromatography (syn/anti isomers). The major compound on g.c.m.s shows prominent ions at m/e 377 (M+), 320 (M-57), 304 (M-73), 142 and 116.

(2) 2~-(6'-Carboxyhex-2'Z-enyl)-3~-~1'-rN-(phenvlcarbamoyl)-hvdrazonol-ethYl}-6,6-dimethyl-b1cyclo r3.1 ~l 1 heptane The acid/ketone (1) ~100 mg) is heated at 40OC with phenyl-semicarbazide [90 mg, prepared as described in Example 4 (7)~ in 05 dioxane for 2 hours. The solvent is removed in vacuo and the residue is purified by gel partition chromatography on a column of Sephadex LH20 substituted with Nedox 1114 olefin oxide to 20% w/w ~Lipidex) using as an eluant a mixture of ~all proportions by volume) 100 parts of hexane, 100 parts of 1,2-dichloroethane, 5 parts of ethanol and 0.1% of the total of glacial acetic acid.
The chromatography gives the title compound as an oil (75 mg), ~(CDC13), 9.20 (br, lH), 8.30 (br, lH) 5.40 (m, 2H) 1.98 (s, 3H), 1,24 (s, 3H), 1.12 (s, 3H).
Example 8 : 3R-(6l-CarboxYhex-2~Z-enYl)-2-rN-(Phenylcarb-amoyl) lS hydrazonometh~ll-6,6-dimethyl-bicyclo ~3.1,11 heptane (1) 2-(Vinyloxymeth~yl)-6,6-dimethyl-bicyclo r3.1,11 hePt-2-ene A mixture of 2-hydroxymethyl-6,6-dimethyl-bicyclo ~3,3,1]
hept-2-ene [~ myrtenol] (26g), mercuric acetate (2.6g) and ethyl vinyl ether (500 ml) is heated under reflux in an atmosphere of argon for 16 hours. On cooling, anhydrous potassium carbonate (4.59~ is added and the excess ethyl vinyl ether is removed by distillation. The residue is filtered, the solid washed with hexane (2 x 20 ml) and the combined filtrate and washings are distilled to give the title compound as an oil ~22g, 72%), b.p. 105-109C/17 mm, vmax (film) 2975, 2910, 2820 and 1605 cm~l.
(2) 3~-FormylmethYl-2-methylene-6.6-dimeth~l-bicyclo r3~l_Ll1 hePtane The vinyl ether (1) (2.Qg) is heated in a sealed tube at 200OC
for 7 hours. The resulting yellow oil is purified by chromatography on silica gel with toluene as eluant to give the title compound as an oil (1.4g, 70%), ~max(film) 1720 cm~l.
In an alternative procedure which may produce higher yields, the vinyl ether (1) is passed in a stream of argon or nitrogen through a tube (1 cm x 10 cm) packed with glass wool and heated at , 59~

190 C, the product being condensed in a cold trap and distilled to give the title compound as an oll, b.p, 7a-75C/l ~m.
(3) 3~-(6'-Carboxyhex-2'Z-enYl~-2-methylene ~ 5-d~ LE~
[3,1,1] heptane 4-(Carboxy-n-butyl)triphenylphosphonium bromide ~7,0g) is dried at 75C under vacuum for 90 minutes, cooled and the flask o5 released to dry nitrogen~ Dry dimethyl sulphoxide (DMS0) (25 ml) is added, followed by the slow addition of 18 ml of a 1.6 M solution of butyl-lithium in hexane. The eemperature ls held at 25 C and the aldehyde (2) (1-58) in DMS0 (5 ml) is added to ehe red ylid solution. The mixture is stlrred overnight under nitrogen9 then poured into lOZ w/v aqueous sodium chloride (200 ml3. The aqueou~
mixture is extracted with ether (3 x 75 ml), and the aqueous layer is then acidified to pH4 with 2N hydrochloric acid and re-extracted with ether (3 x 50 ml). The extracts of the acidlfied aqueous layer are dried over ma~nesium sulphate and evaporated to give the title compound as a yellow oil (2.0g, 86~), 6(CDC13) 0,75 (s, 3H), 1.25 t9, 3H), 4.73 (m, 2H), 5.45 (m, 2H).
(4) 3 ~-(6'-~ethoxycarbonylhex-2'Z-enyl?-2-methx~_ne-6,6-dimethyl-bicyclo ~3,t,l~ heptane The acid ~3) (2.0g) is treated with an ethereal solution of diazomethane (120 ml) and a few drops of methanol are added. The solution is stirred for 20 minutes and the solvent i~ then removed under vacuum to give ehe title compound as a yellow oil (2.2g, 100~) .
(5) 2~ -Hydroxymethyl-3~ -(6'-methoxycarbonvlhex-2'Z-enyl)-6,6-dimethyl-bicvclo ~3,1,1] heptane and 2 ~-Hydroxymethy}-3~ -(6'-~ethoxycarbonylhex-2'Z-enyl~-6,6-dimethyl-bicyclo 13,1,1]
heptane The ester (4) (0.92g) is placed in a dry 100 ml round-bottomed flask under nitrogen and is treated at 0C over 5 minute~ using magnetic stirring with 9-bora-bicyclo [3,3,11 nonane ~a-B8~) in tetrahydrofuran (~0 ml of O.SM solution). The reaction mixture is seirred at room tem?erature for 3 hours, and then 3N aqueous ,` , .

``- i 2 ~J.~

(., sodium hydroxide (3.3 ml, 10 mmol) is added, followed by 30~ v/v aqueous hydrogen peroxide (3.3 ml~ over a period of 10 minutes, cooling being required to control the resulting exothermic reaction.
The mixture is then stirred under air for 15 minutes, treated with 05 potassium carbonate (3g), and the organic upper layer separated off and dried over potassium carbonate. Evaporation of the solvent gives a cloudy yellow oil, which is stirred overnight ln a 10:1 v/v toluene:light pet.oleum mixture (30 ml~. The upper layer is decanted and evaporated to give a mixture of the title compounds as an oil (0.4g, 41~ (CDC13) C.92 (s) and 0098 (s, total of 3H), 1.23 (s, 3H), 3.6-3,9 (m, 2H), 3.67 (s, 3H), 5,42 (m, 2H~.
(6) 2cx-Fonmyl-3~-(6'-methoxycarbonlvl-hex-2~z-eny-l~-6~6-dimethyl-bicyclo ~3,1,l~ heptane and 2 ~ -fo_myl-3 ~-(6'-methoxy~arbonyl-hex-2'Z-enyl)-6,6-dimethyl-bicvclo [3tl.1~ heptane The mixture of epimeric alcohols (5) (0.294g) is dissolved in dry dichloromethane (l.S ml) and pyridinium dichromate ~0,6g) is added, The mixture is stirred for 22 hours at room temperature and then dry ether (3 ml) and hexane (3 ml) are added, Stirring is continued for IS minutes, and the mixture is then filtered.
The last traces of the chromium salt are removed by passing the filtrate through anhydrous magnesium sulphate (5g). Evaporation of the filtrate gives a mixture of the title compounds as an oil (0.07Sg, 2514%)~ ~(CDC13) 0,75 (s) and 0.96 (s, total of 3H), 1.21 (s, 3H), 3.67 (s, 3H), 5.42 (m, 2H), 9.70 (d) and 9,87 (d, total o~ lH).
(7) 3 ~-(6'-Carboxyh ~ ormyl-6,6-dime_hyl-bicyclo [3._L~ll heptane The aldehyde ester (6) (0,075g) is treated with 0.2N 5% v/v aqueous methanolic potassium hydroxide at ~0C for 2 hours. The solution is then neutralized with 2N aqueous hydrochlorlc acid and extracted with ether (3 x 20 ml). The extracts are dried over magnesium sulphate and the solvene evaporated to give the title compound as an oil (0.065g, 6;~ tCDC13) 0.75 (s, 3H), 1.22 (s, 3H), 5.4S (m, 2H). 906 (br, IH), 9.~I (s or rinely split d. IH).

~.-! '' ' 'i .

~L2~ 4 This aldehyde/acid (7) is ob-tained as a compound having a 2-formyl substituent with either the ~ or ~ configuration. The formation of a single com-pound from the aldehyde ester (6) which is a mixture of compounds having a 2-formyl substituent with either an exo or an endo configuration is due to the epimerization resulting from the use of -the base to eEfect de-esterification.
It has not been possible, however, to identify which of -the two configurations should be assigned to the 2-formyl substituent of the aldehyde acid.

(8) 3~-(6'-Carboxyhex-2'Z-enyl)-2- LM- (phenylcarbamoyl)-hydrazonomethyl]-6,6-dimethyl-bicyclo[3,1,1]hep-tane The acid/aldehyde (50 mg) is heated at 40 C with phenylsemicarbazide ~45 mg, prepared as described in Example 4(7)] in dioxane for 2 hours. The dioxane is removed in vacuo, a~d the resulting product is chromatographed on Sephadex 1,H20 substituted by Nedox 1114 oleEin oxide -to 20% w/w, eluting wi-th (all proportions by volume) 100 parts of hexane, 100 parts oE 1,2-dichloroethane and 5 parts oE ethanol wi-th 0.1~ oE the total of glacial acetic acid. The chromatography gives the title compound as an oil (27 mg), A (CH30H) 246.5 nm, 16,000, ~(CDCl ) 0.98 (s, 3H), 1.25 (s, 3H), 5.40 (m, 2H), 7.0-7.6 (m, 5H), max 3 8.05 (br, lH), g.60 (br, lH), M 411.
Example 9: trans-4 (6'-Carboxyhex-2'Z-enyl)-5-~0-p-fluorobenzyloxyiminomethyl)-cyclohex-l-ene (1) cis-4,5-bis-Hydroxymethylcyclohex-l-ene A solution of the anhydride of 3,4-dicarboxycyclohex-1-ene (25.8 g) in THF (150 ml) is added with cooling to a stirred suspension of LiAlH4 (9g) in THF (200 ml) under N2 at a rate such as to maintain the temperature at 0 C.
After stirring for 18 hours ~,~

~.2~594 _ 50 -at room temperature the micture is gently refluxed for one hour and cooled in ice, The excess lithium aluminium hydride is decomposed by the careful addition of 1:1 THF-H20 mixture (100 ml)O
~fter dilution with chlorofor~ (1;0 ml) the resulting micture is filtered and the solid is washed with chloroform (3 x 25 ml).
Concentration of the filtrate under reduced pressure yields an oily residue which is dissolved in benzene, dried over (~gS04) and reconcentrated in vacuo to give the title compound as an oil (22g, ca, 90~ ax (film) 3350cm (2) cis-4-Hydroxvme hyl-s-benzYlo~cymethylcyclohe~c-l-ene The diol (1) (16.2g) in dimethylformamide (50 ml) is added dropwise to sodium hydride (3,lg) in dimethylformamide (DMF) (50 ml). The micture is stirred for 20 minutes and then benzyl chloride (16g) is added and stirring is continued for a further 18 hours at 70 C. ~fter removing the D~F tn vacuo, water is added and the mixture is ectracted with ether. The combined extracts are dried (~gS04) and the solvent is evaporated to give a residue which is distilled under reduced pressure to give the title compound as an oil (160~g, ca. 60/,), b.p, liO~ ; C/0,03 mm, v a (fil~) 3440 and 1600 c~ .
(3) cis-4-D-ToluenesulohonvloxvmethYl-S-benzv10cYmethYl cYclo-. _ hex-1-e;ne Ihe alcohol/benzyl ether (2) (10g) in 20 rl of dry pyridine is added slowly at 0C to p-toluenesulphonyl chloride ~10.'1g) in pyridine (60 ml). The ricture is kept overnight at room temperature and is then quenched by pouring over crushed ice with vigorous shaking. The product is ectracted with ether, washed consecutively with water, 0.1 ~ sodium carbonate and brine, dried (~gS04), and concentrated in vacuo at room temperature. The crude product is purified on a silica gel colurn, eluting with benzene-ethyl acetate (~7~: 5X v/v) to give the title ccrpound (1~g, 90~). The i.r.
spectrum shows the abs2nce o~ a h-drocyl group.

~ ~J

~1 (4) cis-4-Cyanomethyl-5-benzyloxymethylcyclohex-l-ene The p-toluene sulphonyl ester/benzyl ether (3) (12g) in dimethylsulphoxide (DMS0) (15 ml) is added with stirring to potassium cyanide (3g) in DMS0 (20 ml). The mixture is heated at 100C
under nitrogen for 6 hours and is then cooled, poured into water 05 and the product extracted with ether. The solvent is removed and the residue purified on a Florisil column, eluting with petroleum ether-benzene (1:1) to give t~e title compound as an oil (6.5g, ca. 80%) v (film) 2220 and 1600 cm 1.
max (5) cis-4-Formylmethyl-5-benzyloxymethylcyclohex-1-ene Di-isobutyl aluminium hydride (25 ml of a lM solution in hexane) is added with stirring over a 15 minute period to the cyano/benzyl ether (4) (5.0g) in dry toluene (70 ml) at -10 C
under N2. After stirring for a further one hour at room temperature, the reaction is terminated by the cautious addi-tion of methanol (6 mL), followed by saturated aqueous sodium hydrogen tartra-te (95 ml). The mixture is then stirred and heated at 40 C Eor 2 hours. The organic phase is separated and the aqueous layer is further extracted with ethyl acetate, the combined organic solutions being dried and the solvent evaporated to give an oil~ Chromato-graphy of the oil on Florisil, eluting with benzene gives the pure title compound as an oil (3.0g 60%), vmax (film) 1715 cm (6) cis-4-(6'-Carboxyhex-2'Z-enyl)-5-benzyloxymethyl -cyclo-hex-l-ene (4-Carboxyl-n-butyl)-triphenylphosphonium bromide (7.0g) is dried at 75C under vacuum for 2 hours. The white solid is cooled, the vacuum is released to dry nitrogen and DMS0 (10 ml) is added followed by 9 ml of 2M solution of dimesyl sodium in DMS0. The .
temperature is maintained at 25 C and the aldehyde/benzyl ether (5) (1.5g) in DMS0 is added to the deep red ylide solution. After stirring overnight the solvent is removed at 55 - 60 C under reduced pressure. The residue is dissolved in water, extracted with ether, and the aqueous phase carefully acidified to pH 4 with 2N HCl. The mixture is extracted with ether and the ethereal `` .~2~

solution dried (MgS04) and concentrated in vacuo to give the title compound (109), vmaX (film) 1700 cm~l.
(7) cis-4-[6'-Carbox~hex-2'Z-envl)-5-hydroxymethvlcyclohex-1-ene To a stirred suspension of 1.59 of the acid/benzyl ether (6) 05 in 100 ml of liquid ammonia is added a total of lg of sodium in portions over 10 - 12 minutes at the end of which time the characteristic deep blue colour persists. The mixture is stirred for 30 minutes, the blue colour is then discharged by the careful addition of ammonium chloride and the reaction mixture is evaporated to dryness under a stream of nitrogen. The solid residue is triturated with 50 ml of benzene (to remove benzyl alcohol) and it is then dissolved in 40 ml of water. The aqueous solution is treated with Norit, then acidified with acetic acid and extracted with chloroform. Evaporation of the solvent gives the title compound as an oil (0.9g), vmax (film) 3350-3450 and 1700 cm~l.
(8) cis-4-(6'-Et o~arbonylhex-2'Z-enyl~-5-hydroxvmethylcvclo-hex-l-ene The acid/alcohol (7) (0.75g) is dissolved in ethanol, 0.3 ml of concentrated su1phuric acid is added and the mixture is heated under reflux for 18 hours. The mixture is then diluted with water and extracted with ether. The ethereal extracts are washed with water, saturated aqueous sodium bicarbonate and aqueous sodium chloride, and then dried (MgS04). Evaporation of the solvent gives the title compound as an oil (0.89), vmaX (film) 1725 cm~l.

(9) 4-(~'-Ethoxvcarbonylhex-2'Z-envl)-5-formylcvclohex-_-ene The ester/alcohol (8) (1.39)~ dicyclohexylcarbiimide (3.5g) DMS0 (5 ml) and dry benzene (10 ml) are placed in a 125 ml flask under nitrGgen. Pyridinium trifluoroacetate (0.89) is added in one portion and the mixture is stirred for 18 hours. ~thyl acetate (50 ml) is added and the reaction mixture is then filtered. The filtrate is washed with water, saturated aqueous sodium chloride, and dried (Na2S04). The solvent is evaporated to give a slurrv residue which is redissolved in benzene. Solid particles separate from the solution and the solvent is then evaporated to give the ~iol ,~ ~d ~
.`3 5hf~
title compound as an oiL (l.Og)9 ~ (film) 1715 cm ~ ~(CDC13) 1.61-2.06 (m) 2.15-2.28 (t, lH), 2040 (t, 2H), 5.40 (m, 2H)~ 5.70 (s, 2H), 9.79 (d, lH), M 250 (as me-thyl es-ter).

(10) trans-4-(6'-Carb~xyhex-2'Z-eny ~ e~fluorob~3n~yloxyimino~
met~ cyclohex-l-e_e The ester/aldehyde (9) (100 mg) is hea-ted with p~fluorobenzyl-05 oxyamine hydrochloride (120 mg) in 5 ml pyridine for two hours at 60 C. The pyridine is removed in vacuo and the residue is parti~
tioned between water of pH 4 and ether. The ethereal solution is dried (MgS04) and the solvent evaporated to give the title compound in the form of its ethyl ester as an oil. This ester is hydrolysed by heating in aqueous methanolic (2 1, CH30H/H20) O.lN potassium hydroxide for three hours at 40 C. The mix-ture is diluted with wa-ter and extracted once wi-th ether. The aqueous layer is then acidifled -to pH 4 and extracted with ether~ Evaporation oE the solvent gives the tltle compound as an oll, ~ x (C~1301l) 263 nm, c ax 480, ~CDC13) 5,01 (s, 2~1), 5,39 (m, 2H), 5~65 (m, 2tl)~ 6.75 (d, lH), 6~90-7.50 (m, 4H); M 387 (as methyl ester).
The p-fluorobenzyloxamine hydrochloride is prepared as follows.
N Hydroxyphthalimide (~2~0g) in 130 ml dime-thyl sulphoxide is treated with anhydrous finely divided potassium carbona-te (606g)S
when the dark red colour of the anion develops. The mixture is then -treated dropwise at room temperature with p-fluorobenzyl chloride (20g) and the mixture ls stirred overnight or un-til the red colour is discharged. The reaction mixture is poured into water, and the resultan-t crystaLline product is filtered off.
Recrystallisation from ethanol gives N~~p-fluorobenzyloxyphthalImide in pure form as white needles. (16.4g, 82~), m.p. L56-157 C.
The imide (13.5g) is boiled in 400 ml ethanol with 99~ hydrazine hydrate (2,5g) for two hours. The mix-ture is cooled 7 7 ml of conc. hydrochloric acid is added and the precipitate of phthal-hydrazide is removed by filtration. The solution is concentratedto dryness and the salt taken up in water, washed with ether and then basified. The free base is taken into ether to give an ethereal solution which is washed wlth brine and then dried ('IgS04~.
Dry hydrogen chloride gas is passed into the ethereal solution to d~posit pure p-fluorobenzyloxyamine hydrochloride which is recrystal-lised from ethanol as white plates (7t9g~ gO~), m.p. 298-300 C.
Exam le lO ~ -H droxv-2a-(6'-carboxy h e ~ -2'Z-enyl)~30-(0-di-P Y
phenylmethyloxviminomethyl)-cy~lo~ntane (1) 6-(1,3-Dioxacyclopent-2-yl)-2-oxabicvclo [3,3,0] octane-3-one 05 6-Formyl-2-oxabicyclo E3.3.0] octane-3-one (2.0g) is heated at 60 C in benzene (50 ml) with ethylene glycol (1 ml) and a trace of toluene-p-sulphonic acid under a Dean and Stark head. When reaction ceases, the reaction mixture is cooled and treated with water (20 ml) and lOZ w/v aqueous ~aHCO3 (20 ml). The organic . 10 phase is separated, ~ashed wlth water, dried and concentrated to give the title compound in ~;~ yield, ~ (film) 1750 cm 1.
The starting material ls prepared by the treatment of 1,3-eyclohexadiene with dichloroacetyL chlorlde, fol1Owed by dech1Orination wi~h zinc and acetic acid of the resulting atduct 15 to give bicyclo [~,2,0]-oct-2-en-7-one. This compound is subjected to Baeyer-VilLiger oxidation to give ~o~abicyclo ~4,3,0] non-2-en-8-one which ls treated with thallium (III) nierate under carefully controlled conditions to give 6-formyl-2-oxabicyclo [3~370] octane-3-one having properties ldentical with those reportet by Corey and 20 Ravindranathan, Tetrahedron Let~ers, 1971, 4753.
- (23 6-(1~3--Dioxacyclo~ent-2-~1)-3-hydroxy-2-oxabicy octane The lactone/acetal (1) (O.Sg) in dry toluene is cooled to -60 C and treated under N2 dropwise from a syrlnge wlth 2 ml of a . 257a w/v solution of diisobueylaluminium hydride in toluene. The reaction is quenched at -60 C after 2~5 hours by the careful addition of methanol (1 ml). The reaction mixture is then dlluted with ether (50 ml) and is warmed to room temperature. Water (0.~ ml) is added and stirring ls continued ~or 40 minutes Eollo~ed by drving over anhydrous ~18~4- Evaporation of the solvent in vacuo gives the title ccmpound as an oil (0.42g), v~a~ (fL1m) 30 3400 c~ .

~ ~3 , , ' ~ ' -` ~Lf~5g4 _ 55 _ 23410-235 (3) 1~-Hvdroxy-2~-(6~-carboxyhex-2'Z-enyl)-3~-(1'.3'-dioxa-cvclopent-2'-yl)-cyclopentane Dimesyl sodium in DMSO (2.05 ml) is added dropwise to a solution of (4-carboxy-n-butyl)-triphenylphosphonium bromide (2.3g) (dried 05 before use) in 3 ml of DMSO. To the resultant red solution of the ylide is added dropwise a solution of the hydroxy/acetal (2) (0.5g) in S ml of DMSO and the mixture is stirred overnight. The reaction mixture is then diluted with water (50 ml) and extracted with ethyl acetate. The cooled aqueous layer is acidified with dilute HCl to pH 4 and extracted with ethyl acetate. The organic extracts are washed with water, dried (MgS04) and concentrated. The resulting crude product is purified by chromatography on Unisil using toluene-ether (1:1 v/v) as eluant to yield the title compound as an oil (0.4g), VmaX (film) 3350-3420 cm~l.
~4) 1~-HydroxY-2-(6~-carboxyhex-2~z-enyl)-3~-formylc~clopentane The hydroxy/acid/acetal (3) (0.15 g) is hydrolysed by dissolving it in 20 ml of dioxane-water mixture (1:1 v/v) and heated at 40C
with U.OSM aqueous HCl for 3 hours~ 100 ml of water is added and the product extracted with ether. The solvent is evaporated and the residue purified by silica gel chromatography, eluting with a gradient from 10% v/v ethyl acetate in toluene to pure ethyl acetate, to give the title compound as an oil (95 mg), ~(CDC13) 4.30 (br, lH), 5.40 (m, 2H), 6.70 (br, lH), 9.60 (d, lH).
(S) l~-HYdroxy-2~-(6'-carboxyhex-2'Z-enyl)-3~-(0-diphenyl-methyloxyiminomethYl)-cvcloPentane The hydroxy/acid/aldehyde (4) (50 mg) is heated at 600C
for 2 hours in pyridine (5 ml) with diphenylmethyloxyamine hydrochloride (70 mg, prepared by an analogous route to that described in Example 9 for p-fluorobenzyloxyamine hydrochloride).
The pyridine is removed in vacuo and the residue partitioned between water (pH 4) and ether. The ethereal extract is dried and the solvent evaporated to give a residue which is purified by liquid-gel partition chromatography on a column of Sephadex LH20 substituted with Nedox 1114 olefinoxide to 20% w/w, eluting with hexane/

~ 56 dichloroethane/ethanol (100:100:5 v/v/v) containing 0.1% v/v of acetic acid, to give the title compound as an oil (32 mg), kmax(CH30H) 258 nm, ~ aX;90, ~(CDC13) 4.25 (br, lH), 5~40 (m, 2H), 5.80 (br, lH), 6.20 (s, lH), 6.65 (d) and 2.50(d, lH together), 05 7.30 (s, lGH): M not seen, M-167 and 167 [CH(C6Hs)2] prominent (as methyl ester).
Exam~le 11: 5-endo-56 -Carboxyhex-2'Z-enyl)-6-exo- 0-~2'-(diphenyl-. . .
methoxy~-eth~ -oxyiminomethyl]-bicyclo E2~2,1] heptane 5-endo-(6'-Carboxyhex-2 t Z-enyl)-6-exo-formyl-bicyclo [2,2,1]
heptane [100 mg, prepared as described in Example 1 (9)] is heated at 60C for 2 hours i~ dry pyridine (5 ml) with a 50%
excess of (2'-diphenylmethoxyethyl)-oxy~mine hydrochloride. The pyridine is evaporated off in vacuo and the residue is partitioned between water (pH 4) and ether. The ether layer is dried (~S04) and evaporated. The residue is chromatographed on Sephadex LH20 substituted by ~edox lll4 olefin oxide to 20% w/w, eluting with dichloroethane/hexanelethanol (100:100:5 v/v/v) containing 0.1%
v/v of acetic acid to give the title compound as an oil (101 mg~, ~(CDC13) 3.70 (t, 2H), 4.20 (t, 2H), 5.30 (rn, 2H), 5.40 (s, lH), 6.50 (d, lH), 7.~0 (s, lOH), M 47; and ~-167 (as methyl ester).
The (2'-diphenylmethoxyethyl)-oxyamine hydrochloride is prepared from l~chloro-2-(diphenylmethoxy)-ethane in an analogous fashion to that described in Example 9 for p-fluorobenzyloxyamine hydrochloride.
Exam~le 12: 5-endo-(6'- ~ 'Z-envl~-6-e~o-~-(dibenzvlaminoacetyl)-hydrazonomethyl ~ o [2,2,1] heptane 5-ento-(6'-Carboxyhex-2'Z-enyl)-6-exo-formyl-bicyclo [2,2,1]
- heptane (tO0 mg) is heated at 60 C for two hours in ethanol with a 50~ excess of (dibenzylaminoacetyl)-hydrazine. The solvent is evaporated off and the resldue is chromatographed using the system descrlbed in E~ample 12 to give the tltle compound as an oll ,~, .
. ..
",. ,~ -~2~
, .,, ...~

_ 57 _ 23410-235 (129 mg), ~max (CH30H) 232 nm (shoulder), ~max 10,270, and 215 nm (steep portion), max 21,540, ~(CDC13) 3.25 (s, 2H), 3.65 (s, 2H), 5.35 (m, 2H), 7.30 (s, lOH), M+ 499 (loss of 2H).
The (dibenzylaminoacetyl)-hydrazine used in this Example is OS prepared as follows. Ethyl bromoacetate (8.35g) ;n sodium dried benzene is added slowly to dibenzylamine (10.7g) and the mixture stirred for three hours. The mixture is then filtered and the solvent removed to give a residue which is a mixture of the hydrobromide of dibenzylamine and the ethyl ester of dibenzylamino-acetic acid. These compounds are separated by differential crystallisation from ethanol, the hydrobromide, m.p. 227OC, crystallising from hot ethanol and the ester, m.p. 54.90C from ethanol at -20OC after standing overnight. The ester (39) is added slowly to hydrazine (3g) in dioxane and the mixture is refluxed.
lS The (d~benzylaminoacetyl)-hydrazine crystallises from the mixture and is recrystallised from cold ether, m.p. 124.2C.
ExamPle 13 : S-endo-(6~-CarboxYhex-2~z-envl)-6-exo-~N-benzoxa 2-yl-hvdrazonomethyl)-bic~clo ~2,2,11 hePtane 5-endo-(6'-Carboxyhex-2'Z-enyl)-6-exo-formyl-bicyclo [2,2,1~
heptane (100 mg) is heated at 60OC for two hours in pyridine/dioxane with benzoxazol-2-yl hydrazine hydrochloride (150 mg). The solvent is then evaporated in vacuo and the residue is partitioned between water (pH 4) and ether. The ether layer is dried (MgS04) and evaporated. The redsidue is chromatographed using the system described 1n Example 2(1) to give the title compound as an oil (32.4 mg), ~max (CH30H) 255 nm, Emax 13,700. and 285 nm, ~max 18,400, ~(CDC13) 5.49 (m, 2H), 6.60 (d, lH), 7.0-7.5 (m, 4H), M+ 381 and also M-127.
The benzoxazol-2-yl-hydrazine hydrochloride used in this Example is prepared from 2-chlorobenzoxazole b.p. 80-2C/15 mm, which is in turn prepared from 2-mercaptobenzoxazole by the procedure described in the Journal of the Chemical Society, 1965, 4393. The 2-chlorobenzoxazole is heated in dioxane for two hours with an .

~2~ i9~

equimolar proportion of hydrazine and the benzoxazol-2-yl hydrazine hydrochloride is precipitated by the addition o~ ether to the reaction mixture.
~xample 14 : S-endo-(6'-Carboxyhex-2'Z-envl)-6-exo-(N-p-toluene-05 sulphonvlh~drazonometh~l)-bicyclo ~2.2,11 heptane 5-endo-(6'-Carboxyhex-2'Z-enyl)-6-exo-formyl-bicyclo [2,2,1]
heptane (100 mg) is heated at 60OC for two hours in tetrahydrofuran (S ml) with p-toluene sulphonyl hydrazide. The solvent is evaporated in vacuo and the residue is chromatographed on Unisil(l) (lOg) using as eluant a gradient from 10~ ethyl acetate in benzene to pure ethyl acetate to give the title compound as an oil (50 mg), ~max (CH30H) 227 nm, ~max 11,900, ~(CDC13) 2.40 (s, 3H), 5.25 (m, 3H), 6.55 (d) and 7.15 (d, lH together), 7.30 (m) and 7.80 ~m, 4H together).
The p-toluene sulphonyl hydrazide used in this Example is prepared by reacting p-toluene sulphonyl chloride with hydrazine hydrate.
Example 15 : 5-endo-(6'-Carboxvhex-2'Z-enylL~6-exo-(N-diphen~l-methvlenehydrazonomethYl)-bicyclo r2.2 11 hePtane 5-endo-(6'-Carboxyhex-2'Z-enyl)-6-exo-formyl-bicyclo [2,2,1]
heptane (100 mg) is heated at 40OC for two hours in ethanol (5 ml~
with benzophenone hydrazone (100 mg). The solvent is then evaporated in vacuo and the residue is chromatographed using the system described in Example 12 to give the title compound as an oil (106 mg), ~max (CH30H) 243 nm, ~max 11,240, and 270 nm, ~max 12,200, ~(CDC13) 5.30 (m, 2H), 7.2-7.80 (m, lOH).
The benzophenone hydrazone used in thls Example is prepared by reàcting refluxing benzophenone in ethanol with a 3-molar excess of hydrazine hydrate for three hours, then cooling the reaction mixture to -20OC to crystallise the hydrazone, m.p. 99.1oC.
Example 16_ Further compounds The additional compounds of formula (I) listed in Table 1 below are prepared by analogous procedures to those described in (1) Unisil is a Registered Trade Mark , ~9 previous examples; the semicarbazone and thiosemicarbazone derivatives, for example, being obtained through reaction with an approximately 50% molar excess of the appropriate reagent RNH2 for two hours at 40C. In Table 1 the melting point of the individual 05 reagents RNH2 is given together with the amount of aldehyde or ketone intermediate used and the amount of the compound (I) which is obtained. The solvent ùsed for the reaction is dioxane in the case of compounds 1, 6, 9 and 10; tetrahydrofuran in the case of compounds 2 and 3; ethanol in the case of compounds 4, 5, 7, 8;
and pyridine in the case of compound 11.
Each of the compounds contains an unmodified 6-carboxyhex-2 Z-enyl group. However, the free acids, in the case of these compounds and also those described in previous examples, are convertible to the methyl esters by solution in methanol, using warming and addition of NaHC03 as necessary, followed by the addition of an excess of ethereal diazomethane to the methanolic solution, stflnding, and the removal of solvent, PhysLcal data on the compounds are presented in Tables 2 and 3, U.V., M.S., and N.M.R. data being given for compounds 2, 3, 10 and 11 and analysed N.M.R. data for the remaining semicarbazone and thiosemicarbazone derivatives.
The U.V. data is for a methanolic solution and the N.M.R. data is given as ~ values relating to a CDC13 solution~ referred to (CH3)4Si.

~ 2~ 9L
` ., f Table 1 _ Compound Mp of Starting ¦
_ RNH Material/
No. ,- C/ R2 R oc2 product X I (mg/m9) _ ~\ .
1 - NHCSNHC6 ~5 133.7 `loo/92 ~ H - N ~ . 2(1 I00/8 3 _ _ - N~ l59.6 loo/87 4 - NHCS~H Q l58.7(2)loo/85 ~ ~ CH3 - NHCSNH Q 15807 80/87 6 - ~HCS~H ~OCH3 149.8 50h2 7 - NHCSNH ~ 114.1 80/94 _ C F3 8 ~ CH3 - NHCO N H ~ oc H3 210 3 100/102 9 - NHCSN~ ~ 158.5 loo/32 _ ~ H - NHCS~C6 H~ 133.7 50/56 ~1 ~ H --oCH2 e3 F A HCI 100/77 `~
Footnotes (Table 1) (1) This compound is available from Aldrich as the HCl.H20 salt;
before use it is partitioned between water (pH 10) and ether, the ether evaporated and the residue recrystallised from ethanol to give the free base having the m9p. shown. 5 (2) The corresponding p-fluoro intermediate E~H2, which may be used to prepare the corresponding p-fluoro substituted compound (I), has m.p. 121.4 C.
Table 2 I

Compound W Data MS Data NMR Data No. M+ (CDC13) _~max 6max 2 22625,070 411 3,50 (s, 3H), 5.40 ~m, 2H), 31117,830 6.8-7.4 (m, 4H), 7.70 (d, 1H) ¦

3 25954,500 426 5.40 (m, 2H), 7.2-8.0 (m, 8H) . 31015,300 274.5 25,800 (1) 5.35 (m, 2H), 5.70 (m, 2H), 7.2-7.7 (m, 5H), 9.05 (br, lH) 10.30 (br, lH)

11 263870 449(2) 4.25 (br, 1H), 5.0 (s, 2H), 5.30 (m, 2H), 6.60 (d, lH), 6.9-7.5 (m, 4H) Footnotes (Table 2) (1) M not seen, intense ion at m/e 135 arising from C6H5CNS.
(2) On methyl ester.

5~

lable 3 Compound I Olefinic protons R2 ~H ¦Aromatic¦ Protons of ¦
~o. of R proton(s) protons ¦protons aromatic . _ __. _ __ 1 5.40(m) 6~45(d) 9.05(br) 7.2-707 10.30(br) (~) 4 5.35(m) 2.0(9) 8.90(br) 6.8-7.8 9.35(br) (m) S 5.35(m) 1.98(s) 8.80(br) 6.7-7.6 3.83(s) 9.30(br) (~) 6 ;030(m) 1.95(5) 8.80(br)l6.8-7.5 3.80(s) 9,20(br)i (m) i 5,38(m) 2,0(s) 8.95(br)¦7.4-8.0 ¦ - l ¦ 9,45(br)1 (m) I ¦
8 5,!~0(m) l.90(s) ! 8.20(br)l6.8-7,5 1 3.80(s) 1 9.70(br)l (m) 9 S.SO(m) 1,90(s) ¦ 9.0(br) ¦7.3-8.8 ¦ -¦ 9.8(br) _ EcamDle 17: In vitro tests o~ biolo~ical activity . . ~ . .
Various of the compounds oE formula (I? described in the Examples were tested for biological activity in the rabbit aorta and human platelet systems. The compounds, and the results obtained ln each case, are shown in rable 4, all Oe the compounds tested oS containing an unmodified 6-carboxyhex-2~Z-enyl group.
Rabbi~ Aorta Svstem ~ Spiral strips of thoracic aorta are suspended in ~reb's-Henseleit solution and aerated with 957 2/5~ C2 at 37C. Tension changes are recorded wi~h a Grass FT03 Eorce transducer. Initially, cumulative dose response curJes to 11,9-(epocvmethano) PGH~
~o~ x ln 9, 1 x 10 3, 5 x 10 8 and 2,~ c 10 M) are obtained~ In a second experi-ent the individual compounds are added 30 minutes ~" '' .

- 63 ~
previous to the addition of the series of agonist doses. In tne case of each compound, ~he affinity constant, KB, for the compound is calculated according to the Gadd.um - Schild Equation (based on Law of ~lass .~ction).
DR-I = [B] x KB DR = dose ratio [B] = molar concentration of compound Human Platelet Svstem 05 Platelet-rich plasma is obtained from fresh; citrated human -blood. .~ddition of the ll,9-(epoxymethano) PGH2 (1 x 10 to 5 x 10 ~) causes immediate aggregation recorded as an increase in light transmission (600 nm). In a second e~periment the individual compounds are added five minutes previous to the addltion of the PGH2 analogue. Ihe dose of the PGH2 analogue added is then increased to a level which gives a similar response to that obtained in the absence of antagonist. The affinity constant, ~B~ for the compound is calculated according to the Gaddum - Schild Equation (based on Law of .'lass .~ction), DR-I = [a] ~ ~3 DR = dose ratio [B~ = molar concentration of compound ~ . _ , .

~ ' ~2~6~

Table !~
_.._ ' ~f f ini ty Co~atant, H/ Compound ¦ x10 ~_ I R R Rabbit Human H\ AortaPlatelet _ .. ~ ._ ~1 --NIICSNIl ~3 1,9 3.8 11 --NHCSNHCH ~3 1.9 o. 7a C L~3 --N H C â 1~1 H ~ 1 1 20 ~ c~3 --NHCSNHQ l4.2 22 G~ C~3 --NHCSNH ~ to.5 8.5 C~3 --N 't C S N rl ~3 O C ~13 4 . 7 9 . 8 - CH3 --NHCS~H~ 8.5 5.3 C2~5 ~ NHCSN11~ _ 3.9 ~ .... ..
. ~ --N HCO r~ ) I .

CH ~ _ NHCo~l~H ~tOCH

. CH3 --IYHCSM~ ~ 12 -CH3 --~H.S ~H ~ 3.~3 I, , ~ 'i I 1 ... ~ ~ - .

,~ ~

Table 4 continued C~ H ~ --NHCSNH ~) o.6 0035 C~13 CH3 - N H CO i'l H ~;3 2. 8 1~1 ~H3 ~ , _ ~

~H~ l~r H - NH CO 1~1 H ~ 3~0 o. 50 H --NHCSNI 1~3 0.9l 2iO
__ H --i~=< ~1 o~660.29 Ci~3 1~
i~ N~ (2) H ~ 1, 5( 2, 1-1 NH~N~ 2.0 0~18 H --Ni~lCOCH2 i~(ci~2 ~9)2 1.2 _ H --~IHS02 ~Ci~3 2.9 1,5 i~ --OCH2~:1 120CH (~3)2 o, lo_ 23 __ :~ _ __ ~2,~94 ~ 66 ~

Tabl~ 4 continued :

¢~ H_OCHZ ~3F z.6 0.~2 OH H--O C tl2 ~ F o. ~o . . H 2 . : (2) (1) A hyphen indicates that the particular test was not carried out on the compound in question.
(2) An accurate value could ~ot be obtained for these compounds as total inhibitlon occurred above a certain value; in 05 addition the action of ADP on human platelets is also blocked.
Example 19: In vivo T~sts of Biological Activity tl) Inhibition o~ Platelet Aggregation The technlque employed in this test was basically that Qf Smith and Freuler, Bibl. anat., 19?3, 12, 229-234, which utilises the Technicon Autocounter and provides a completely automated syste~ for counting platelets and cells. Blood is continuously sampled from a ~uitable artery and to avoid the use of ~n anticoagu-lant, a double cannula is used which enables 3.8Z wlv aqueous trisodium citrate to be pumped to the tlp of the cannula and the citrated blood then to be removed at O.lml/minute and diluted in the manifold where the red cells are lysed with 1X w/v ammonium oxalate/0.002~ w/v saponin solution. The platelets are then counted optically and the count continuously recorded on precali-brated chart paper.
(a) Tests in Rats Each of a group of six male Sprague-Dawley rats anàesthetised with pentabarbitone was injected intravenously with ~O~g/k~ of . .~ ~ , .

~'2~;9~
~ 67 colIagen followed, 15 "inutes later, by 30~g/kg of collag2n, which gives a dose-dependent and reproducible fall in platelet count.
Ten minutes after the second injection of collagen, the rats were treated intravenously with a dose of Img/kg of 5-endo-(6'-carbo~yhe~-o5 2'Z-enyl)-6-e~o-~1'-[~-(phenylthiocarbamoyl)-hydrazono]ethyl~ -bicyclo [2,2,1] heptane pre2ared as described in E~ample 2. At 5 and ~0 mlnutes after the administration of this ccmpound a further ~O~g/kg and 80~g/kg of collagen, respectively, were ad~ninisteredO The levels of platelet aggregation resulting from the administration of the collagen before and after the administration of the bicyclo [2,2,1] heptane were recorded continuously as indicated above.
The responses, calculated as the percentage fall in the platelet count, to the administration of the two doses of collagen before and after adninis~ration of the bicyclo ~2,2,1] heptane are l; shown in Table 5, the average response to ~0~ g collagen being significantly reduced ~one tailed paired t-test gives t n 2~25 (jDf), P~0.051, as is the average response to 80 g/';g colIagen (t = 2.86 (SDf), P~0.02).
/

t' ~2~{~
.

Table 5 Rat Percentage Fall in platelet count No. on administering collagen Before After ...._ Collagen ~g/kg Collagen ~g/kg _ 4~ 80 . __ 1 21.5 38.3 14.0 18.3 2 20.3 27.7 13.3 27.1 3 28.5 42.8 14.6 28.4 4 35.4 4~.5 25.0 34.4 16.7 35.9 1~.5 34.5 6 17.7 33.5 19.4 28.2 , ~ 23.35 37.78 17.47 28.5 SE~2.95 2.97 1.82 2.45 (b) Tests in Guinea Pi~s In three experirnents, each conducted on one male albino guinea pig (400-10,0009) anaesthetised with a mixture of allyl barbituric asid and urethane, the guinea pig was given intravenously 05 a dose of 50 ~g/kg of collagen, followed 15 minutes later by 0.35 ~g/kg of ll,9-(epoxymethane) PGH2 to give two reliable platelet aggregation responses for each material. After a further period of 10 minutes, the guinea pig was treated intravenously with a dose of 1 mg/kg of 5-endo-(6'-carboxyhex-2'Z-enyl)-6-exo{l'-~N- -(phenylthiocarbamoyl)-hydrazono]-ethyl}-bicyclo [2,2,1~ heptane prepared as described in Example 2. Commencing 5 minutes after the administration of the bicyclo ~2,2,1] heptane, the alternate treatments at 15 minute intervals with collagen and ll,9-(epoxymethano) PGH2 were repeated, the second treatment with the latter compound being followed after 15 minutes by a final treatment with collagen. (In the first experiment, only, the last administration of each compound was omitted).

;,~,i The level of platelet aggregation was recorded continuously throughout the experiment as described above, The administration of the bicyclo [2,2,1~ heptane caused an inhibition of the platelet aggregation produced by both the collagen anci the ll,9-(epoxymethano) 05 PGH2, the results being summarised in Table 6 which shows the percentage inhibition produced by the bicyclo [2,2,1] heptane in each of the responses to collagen and to the PGH2 derivative obtained after administration of the drug. In the Table each figure corres~onds to inhibition of either a collagen or PGH2 derivative initiated response, as shown, the former material being administered at 5, 35 and 65 minutes after administration of the drug and the latter at 20 and 50 minutes thereafter.
Table 6 _ _ _ _ Platelet Dose of Dose of Percentage Inhibition at Aggregator Aggregator Bicyclo various time intervals (~g/kg) [2,2,1] after administration of drug Heptane 5 20 35 50 65 (~g/kg) min min min min min _ . _ - - l Collagen 50 l 73.6 67~3 _ PGH2 deriv. 0.35 1 75.7 _ _ _ Collagen 50 1 64.5 64.4 56.1 PGH2 deriv. 0.35 1 85.2 65.5 , __ Collagen 50 1 68.3 56.i 51.5 P 2 deriv. 0.35 1 83.7 64.6 _ _ . ~, Average 68.8 81~5 62.6 65.1 53.8 l _ ! . _ . _ (2) Inhibition of ~ronchocc)nst}ictic)n The same three experiments on guinea pigs described under l(b) are used to give a measure in a modified ~onzett-Rossler test , ~3 .

5~
_ 70 -of the inhibition produced by 5-endo-(6'-carboxyhex-2'Z-enyl)-6-exo ~l'[~-(phenylthiocarbamoyl)-hydrazono]ethyl~-bicyclo [2,2,1]
heptane, prepared as described in Example 2, of the bronchocon-striction resulting from ad~inistration of the collagen and the 05 PGH2 derivative. This test involves artificially respiring the animals and measuring the amount of residual air with a pressure transducer. The collagen and PGH~ derivative given prior to the bicyclo [2,2,1] heptane were each found to cause bronchoconstriction as shown by an increase in insufflation pressure but when this pressure was again measured 5 minutes after the administration of the bicyclo [2,2,1] heptane it was found in each ins~ance that a complete inhibition of the bronchoconstricting effect i;ad been - produced by this compound.

.,, ~ .

~2~5~9L

~ ALDER ~

OEt OEt ~`CO2Et H2~Pd-C ~``C2 Et ', CH(OEt)2 CH(OEt)2 LiA~ H4 <~OH

CH~OEt)2 l.TsC~/pyr <~ BU2A~H <~ CHo 2.CN-/DMSO CH(OEt)2 tol~leAe CH~OEt)2 Ph3P (CH2)4COOH Br /~ =WcooH
Na+ CH3 SO2- ~
DMSO . . \ CH (OEt)2 \~

OOCH3 A>~ O2H

CHO 9/ CHO q

Claims (61)

1. A compound of formula (I) (I) wherein represents one of the divalent cyclic groups the letters a and b indicating in each case the points 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, benzthiazolyl, dihydrobenzthiazolyl, N-methyldihydro-benzthiazolyl, benzoxazolyl, dihydrobenzoxazolyl or N-methyl-dihydrobenzoxazolyl 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, -OR4, -A-R3 or -N=R5 in which A is -NH-, -NH.CO-, -NH.CO.CH2N(R6)-, -NH.SO2-, -NH.CO.NH- or -NH.CS.NH- and wherein R3 is a C1-10 aliphatic hydrocarbon group, an aromatic group Ar or an aliphatic hydrocarbon group substituted by one or more groups Ar directly or through an oxygen or sulphur atom, R4 is a C1-10 aliphatic hydrocarbon group which is substituted through an oxygen atom by a C1-10 aliphatic hydrocarbon group which is itself substituted directly by one or more aromatic groups Ar, R5 is a C1-10 aliphatic hydrocarbon group, an aromatic group Ar', where Ar' is a fluorenylidene, dibenzocyclohexylidene, dibenzocycloheptylidene, dihydrobenzthiazolylidene, N-methyl-dihydrobenzthiazolylidene, dihydrobenzoxazolylidene or N-methyl-dihydrobenzoxazolylidene group or such a group Ar' substituted on a benzene ring or rings thereof by one or more substituents selected from C1-10 alkoxy, halogen, C1-10 halogen-substituted alkyl, sulphamoyl, amino, hydroxyl, nitro and C1-10 groups, or a C1-10 aliphatic hydrocarbon group substituted by one or more aromatic groups Ar directly or through an oxygen or sulphur atom, and R6 is hydrogen, 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; with the proviso that when R is a group -OR3, -NH.COR3 or -NH.CO.NHR3 then excludes the divalent cyclic groups and

2. A compound according to Claim 1, in which the divalent cyclic group is other than a 6,6-dimethyl-bicyclo [3,1,1] heptane ring system having the group R1 at the 3-position.

3. A compound according to Claim 1, in which the divalent cyclic group is a bridged group.

4. A compound according to Claim 1, which contains a bicyclo [2,2,1] heptane, bicyclo [2,2,1] hept-2Z-ene, bicyclo [2,2,2]
octane or bicyclo [2,2,2] oct-2Z-ene ring system.

5. A compound according to Claim 1, which contains a 6,6-dimethyl-bicyclo [3,1,1] heptane ring system having the group R1 at the 3-position.

6. A compound 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.

7. A compound according to Claim 1, in which R1 is a 6-carboxyhex-2Z-enyl group or a derivative thereof formed at the carboxy group.

8. A compound according to Claim 1, in which R1 is a 6-carboxyhexyl group or a derivative thereof formed at the carboxy group.

9. A compound according to Claim 1, in which R1 is a group terminating in a free carboxy group.

10. A compound according to Claim 1, in which R1 is a group terminating in a salt derivative of the carboxy group.

11. A compound according to Claim 1, in which R1 is hydrogen or an aliphatic hydrocarbon group.

12. A compound according to Claim 1, in which R2 is hydrogen.

13. A compound according to Claim 1, in which R2 is an alkyl group of 1 to 3 carbon atoms.

14. A compound according to Claim 1, in which R2 is ethyl.

15. A compound according to Claim 1, in which R2 is methyl.

16. A compound according to Claim 1, in which R is a group -OR3 -NH.CO.NHR3 -NH.CS.NHR3, or -N=R5.

17. A compound according to Claim 1, in which R is a group -OR3.

18. A compound according to Claim 1, in which R is a group -NH.CO.NHR3 or -NH.CS.NHR3.

19. A compound according to Claim 1, in which R is a group -OR3 or -AR3 wherein R3 is an aromatic group Ar.

20. A compound according to Claim 1, in which R is a group -OR3 or -AR3 wherein R3 is a C1-10 aliphatic hydrocarbon group or a C1-10 aliphatic hydrocarbon group substituted by one or more aromatic groups Ar.

21. A compound according to Claim 1, in which R is a group -OR3 or -AR3 wherein R3 is a C1-10 alkyl group or a C1-10 alkyl group substituted by one or more aromatic groups Ar.

22. A compound according to Claim 1, in which R is a group -OR3 or -AR3 wherein R3 is a C1-10 alkyl group substituted by one or more aromatic groups Ar.

23. A compound according to Claim 1, in which R is a group -OR3 or -AR3 wherein R3 is a C1-3 acyclic alkyl group substituted by one or more aromatic groups Ar.

24. A compound according to Claim 1, in which R is a group -OR3 or -AR3 wherein R3 is a C1-3 acyclic alkyl group substituted by a cyclohexyl group and by one or more aromatic groups Ar.

25. A compound according to Claim 1, in which R is a group -OR3 or -AR3 wherein R3 is a terminally substituted acyclic alkyl group which is of 1 to 3 carbon atoms when substituted directly by the aromatic group or groups Ar and of 2 or 3 carbon atoms when substituted through an oxygen or sulphur atom by any aromatic group Ar.

26. A compound according to Claim 1, in which R is a group -OR3 or -AR3 wherein R3 is a C1-3 acyclic alkyl group substituted directly by one or two aromatic groups Ar or through an oxygen or sulphur atom by one aromatic group Ar.

27. A compound according to Claim 1, in which R is a group -OR3 or -AR3 wherein R3 is an aromatic group Ar selected from unsubstituted and substituted phenyl and pyridyl groups.

28. A compound according to Claim 1, in which R is a group -OR3 or -AR3 wherein R3 is a C1-10 alkyl group substituted by one or more aromatic groups Ar selected from unsubstituted and substituted phenyl and pyridyl groups.

29. A compound according to Claim 1, which contains a bicyclo [2,2,1] heptane, bicyclo [2,2,1] hept-2Z-ene, bicyclo [2,2,2]
octane, bicyclo [2,2,2] oct-2Z-ene or 6,6-dimethyl-bicyclo [3,1,1]
heptane ring system and in which R is a group -NH.CS.NHR3 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-1-yl group.

30. A compound according to Claim 1, which contains a bicyclo [2,2,2] octane, bicyclo [2,2,2] oct-2Z-ene or 6,6-dimethyl-bicyclo [3,1,1] heptane ring system and in which R is a group -NH.CO.NHR3 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-1-yl group.

31. A compound according to Claim 1, which contains a bicyclo [2,2,2] octane, bicyclo [2,2,2] oct-2Z-ene or 5,6-dimethyl-bicyclo [3,1,1] heptane ring system and in which R is a group -OR3 wherein R3 is selected from C1-3 acyclic alkyl groups directly substituted terminally by two groups Ar selected from unsubstituted and substituted phenyl, and an unsubstituted pyrid-l-yl group.

32. A compound according to Claim 1, in which R is a group -OR3 or -AR3 wherein R3 is an aromatic group Ar selected from unsubstituted and substituted phenyl groups.

33. A compound according to Claim 1, in which R is a group -OR3 or -AR3 wherein R3 is a C1-10 alkyl group substituted by one or more aromatic groups Ar selected from unsubstituted and substituted phenyl groups.

34. A compound according to Claim 1, in which the or each group Ar is a phenyl group.

35. A compound according to Claim 1, in which Ar is selected from an unsubstituted phenyl group and substituted phenyl groups having a single substituent at an ortho, meta or para position or two similar substituents at two of such positions.

36. A compound according to Claim 1, in which Ar is selected from an unsubstituted phenyl group and substituted phenyl groups having a single substituent at an ortho, meta or para position or two similar substituents at the 2 and 4 or the 3 and 4 positions.

37. A compound according to Claim 1, in which R is a group -OR3 or -AR3 wherein R3 is an aromatic group Ar or a C1-10 alkyl group substituted by one or more aromatic groups Ar, Ar being selected from an unsubstituted phenyl group and phenyl groups substituted by one or more groups which are selected from C1-3 alkoxy, halogen, C1-3 halogen-substituted alkyl groups and C1-3 alkyl groups.

38. A compound according to Claim 1, in which R is a group -OR3 or -AR3 wherein R3 is an aromatic group Ar or a C1-10 alkyl group substituted by one or more aromatic groups Ar selected from an unsubstituted phenyl group and phenyl groups substituted by one or more groups which are selected from methyl, methoxy, fluoro, chloro, bromo and trifluoromethyl.

39. A compound according to Claim 1, in which R is a group -OR3 or -AR3 wherein R3 is an aromatic group Ar or a C1-10 alkyl group substituted by one or more aromatic groups Ar selected from an unsubstituted phenyl group and phenyl groups substituted at the meta position by a methoxy, fluoro or trifluoromethyl group or at the para position by a methoxy group.

40. A compound according to Claim 1 in which R is a group -N=R5 wherein R5 is an aromatic group Ar' or a methylene group substituted directly by two unsubstituted or substituted phenyl groups.

41. A compound according to Claim 1, in which R is a group -N=R5 wherein R5 is a diphenylmethylene, fluoren-9-ylidene or 1,2,4,5-dibenzocyclohept-3-ylidene group.

42. A compound according to Claim 1, or in which R is a group -N=R5 wherein R5 is a dihydrobenzthiazol-2-ylidene, N-methyl-dihydrobenzthiazol-2-ylldene, dihydrobenzoxazol-2-ylidene or N-methyldihydrobenzoxazol-2-ylidene group.

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

44. A compound according to Claim 1, in which the substituents R1 and C(R2)=NR are in a trans relationship.

45. A compound according to Claim 1, in which the divalent cyclic group has the 5-endo, 6-exo configuration when it is a bicyclo [2.2.1] heptane, bicyclo [2,2,1] hept-2Z-ene, 7-oxa-bicyclo [2,2,1]
heptane, 7-oxa-bicyclo [2,2,1] hept-2Z-ene or bicyclo [2,2,2]
oct-2Z-ene, the 2.alpha., 3.beta., 6.alpha. configuration when it is a 6,6-dimethyl-bicyclo [3,1,1] heptane and the 1.alpha., 2.alpha., 3.beta.
configuration when it is a 1-hydroxycyclopentane.

46. A compound according to Claim 1, which is a bicyclo [2,2,1]
heptane or bicyclo [2,2,1] hept-2Z-ene having a 5-endo substituent which is a 6-carboxyhex-2Z-enyl or 6-carboxyhexyl group or an amide, ester or salt derivative thereof and a 6-exo substituent which is a hydrazonomethyl, 1-hydrazonoethyl or 1-hydrazonopropyl group that is itself N-substituted by a benzylthiocarbamoyl, phenylthiocarbamoyl, m-fluorophenylthiocarbamoyl, m-methoxyphenyl-thiocarbamoyl, p-methoxyphenylthiocarbamoyl, m-trifluoromethyl-phenylthiocarbamoyl or pyrid-3-ylthiocarbamoyl group.

47. A compound according to Claim 1, which is (a) a -trans-5,6-substituted bicyclo [2,2,2] octane or 5-endo,6-exo-substituted bicyclo [2,2,2] oct-2Z-ene, (b) a trans-4,5-substituted cyclohex-1-ene or trans-4,5-substituted cyclohexane, or (c) a 2.alpha., 3.beta.-substituted 1.alpha.-hydroxycyclopentane, in which the substituent group at the 5, 4 or 2 position, respectively, is a 6-carboxyhex-2Z-enyl or 6-carboxyhexyl group or an amide, ester or salt derivative thereof and the substituent at the 6, 5 or 3 position, respectively, is a hydrazonomethyl, 1-hydrazonoethyl or 1-hydrazonopropyl group that is itself N-substituted by a benzylthiocarbamoyl, phenylthiocarbamoyl, m-fluorophenylthio-carbamoyl, m-methoxyphenylthiocarbamoyl, p-methoxyphenylthio-carbamoyl, m-trifluoromethylphenylthiocarbamoyl, pyrid-3-ylthio-carbamoyl, phenylcarbamoyl, m-fluorophenylcarbamoyl, m-methoxy-phenylcarbamoyl, p-methoxyphenylcarbamoyl, m-trifluoromethylphenyl-carbamoyl or pyrid-3-yl-carbamoyl group.

4B. A compound according to Claim 1, which is a 6,6-dimethyl-bicyclo [3,1,1] heptane having a 2.alpha.-substituent or a 3.beta.-substituent which is a 6-carboxyhex-2Z-enyl or 6-carboxyhexyl group or an amide, ester or salt derivative thereof together with, respectively, a 3.beta.-substituent or a 2-substituent which is a hydrazonomethyl, 1-hydrazonoethyl or 1-hydrazonopropyl group that is itself N-substituted by a benzylthiocarbamoyl, phenylthio-carbamoyl, m-fluorophenylthiocarbamoyl, m-methoxyphenylthio-carbamoyl, pyrid-3-ylthiocarbamoyl, benzylcarbamoyl, phenyl-carbamoyl, m-fluorophenylcarbamoyl, m-methoxyphenylcarbamoyl, p-methoxyphenylcarbamoyl, m-trifluoromethylphenylcarbamoyl or pyrid-3-yl-carbamoyl group.

49. A compound according to Claim 1, which is (a) a trans-5,6-substituted bicyclo [2,2,2] octane or 5-endo, 6-exo-substituted bicyclo [2,2,2] oct-2Z-ene, (b) a trans-4,5-substituted cyclohex-1-ene or trans-4,5-substituted cyclohexane, or (c) a 2.alpha., 3.beta.-substituted 1.alpha.-hydroxycyclopentane, in which the substituent group at the 5, 4 or 2 position, respectively, is a carboxyhex-2Z-enyl or 6-carboxyhexyl group or an amide. ester or salt derivative thereof and the substituent at the 6, 5 or 3 position, respectively, is a hydroxyiminomethyl, 1-hydroxyiminoethyl or 1-hydroxyimino-propyl group that is itself 0-substituted by a p-fluorophenylmethyl or diphenylmethyl group.

50. A compound according to Claim 1, which is a 6,6-dimethyl-bicyclo [3,1,1] heptane having a 2.alpha.-substituent or a 3.beta.-substituent which is a 6-carboxyhex-2Z-enyl or 6-carboxyhexyl group or an amide, ester or salt derivative thereof together with, respectively, d 3.beta.-substituent or a 2-substituent which is a hydroxyiminomethyl, 1-hydroxyiminoethyl or 1-hydroxyiminopropyl group that is itself 0-substituted by a p-fluorophenylmethyl or diphenylmethyl group.

51. A compound according to Claim 1, which is a (a) a bicyclo [2,2.1] heptane, bicyclo [2,2,1] heptene, trans-5,6-substituted bicyclo [2,2,2] octane or 5-endo, 6-exo-substituted bicyclo [2,2,2]
oct-2Z-ene, (b) a trans-4,5-substituted cyclohex-1-ene or trans-4,5-substituted cyclohexane, or (c) a 2.alpha., 3.beta.-substituted 1.alpha.-hydroxycyclopentane, in which the substituent group at the 5, 4 or 2 position, respectively, is a 6-carboxyhex-2Z-enyl or 6-carboxyhexyl group or an amide, ester or salt derivative thereof and the substituent at the 6, 5 or 3 position, respectively, is a hydrazonomethyl, 1-hydrazonoethyl or 1-hydrazonopropyl group that is itself N-substituted by a N-methylbenzthiazol-2-ylidene, fluoren-9-ylidene, diphenylmethylene or benzoxazol-2-yl group.

52. 5-endo-(6'-Carboxyhex-2'Z-enyl)-6-exo-[N-(phenylthiocarbamoyl)-hydrazonomethyl]-bicyclo [2,2,1] heptane, 5-endo-(6'-carboxyhex-2'Z-enyl)-6-exo-[N-(benzylthiocarbamoyl)-hydrazonomethyl]-bicyclo [2,2,1] heptane or 5-endo-(6'-carboxyhex-2'Z-enyl)-6-exo-(1'-[N-phenylthiocarbamoyl)-hydrazono]-propyl)-bicyclo [2,2,1]
heptane, or a carboxylate salt thereof.

53. 5-endo-(6'-Carboxyhex-2'Z-enyl)-6-exo-(1'-[N-phenylthio-carbamoyl)-hydrazono]-ethyl)-bicyclo [2,2,1] heptane or a carboxylate salt thereof.

54. A substituted 5-endo-(6'-carboxyhex-2'Z-enyl)-6-exo-{1'-[N-(phenylthiocarbamoyl)-hydrazono]-ethyl)-bicyclo [2,2,1]
heptane in which the phenyl group has a m-fluoro, m-trifluoro-methyl, m-methoxy or p-methoxy substituent, or a carboxylate salt thereof.

55. trans-5-(6'-Carboxyhex-2'Z-enyl)-6-N-(phenylcarbamoyl)-hydrazonomethyl]-bicyclo [2,2,2] octane or trans-(6'-carboxyhex-2'Z- enyl)-6- (1'-[N-(pyrid-3-ylthiocarbamoyl)-hydrazono]-ethyl)-bicyclo [2,2,2] octane, or a carboxylate salt thereof.

56. trans-5-(6'-Carboxyhex-2'Z-enyl)-6-(1'-[N-(phenylcarbamoyl)-hydrazono]-ethyl]-bicyclo [2,2,2] octane or a carboxylate salt thereof.

57. trans-5-(6'-Carboxyhex-2'Z-enyl)-6-{1'-[N-(p-methoxyphenyl-thiocarbamoyl)-hydrazono]-ethyl}-bicyclo [2,2,2] octane or a carboxylate salt thereof.

58. A pharmaceutical composition comprising a compound according to Claim 1 as an active ingredient thereof together with a physiologically acceptable diluent or carrier.

59. A process for the preparation of a compound of formula (I) as defined in Claim 1 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), 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).

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

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