AMINOCYCLOPENTANE ALKENOIC ACIDS AND ESTERS AND THEIR PREPARATION AND PHARMACEUTICAL FORMULATION

ACIDES AMINOCYCLOPENTANE-ALCENOIQUES ET LEURS ESTERS; PREPARATION ET COMPOSITIONS PHARMACEUTIQUES

English Abstract

ABSTRACT
Compounds are described of the formula
<IMG>
(1)
(and their salts and solvates) in which:
X is cis or trans -CH=CH-;
R1 is C1-7 alkyl terminated by -COOR3 where R3
is H, C1-6 alkyl or C7-10 aralkyl;
Y is a saturated heterocyclic amino group
having 5-8 ring members; and
R2 is C2-4 alkanoyl, C3-6 alkenyl (optionally
substituted), C1-12 alkyl, or substituted or
unsubstituted phenylalkyl, biphenylalkyl
or naphthylalkyl.
These compounds inhibit blood platelet aggregation
and bronchoconstriction and may be formulated for use
as antithrombotic and anti-asthmatic agents.

Claims

Claims:
1. A process for the preparation of a compound of the
general formula (1)
<IMG>
wherein
X is cis or trans -CH=CH-;
R1 is straight or branched C1-7 alkyl bearing as a
terminal substituent -COOR3 where R3 is a hydrogen atom,
C1-6 alkyl or C7-10 aralkyl;
Y represents a saturated heterocyclic amino group which
has 5 to 8 ring members selected from pyrrolidino, piperidino,
morpholino, piperazino, thiamorpholino, 1-dioxothiamorpholino,
homomorpholino, and hexamethyleneimino;
R2 is (i) C2-4 alkanoyl; (ii) C3-6 alkenyl, option-
ally substituted by phenyl (the phenyl being optionally
substituted by C1-4 alkyl, C1-4 alkoxy, halogen, C5-7
cycloalkyl or phenyl (C1-4 alkyl), biphenyl (optionally
substituted by C1-4 alkyl, C1-4 alkoxy or halogen), or
naphthyl; (iii) C1-12 alkyl; (iv) C1-5 alkyl substituted
by (a) phenyl [optionally substituted by halogen, hydroxy,
C1-6 alkyl, C1-6 alkoxy, C1-4 hydroxyalkoxy, trifluoro-
methyl, cyano, aryloxy, C5-7 cycloalkyl, aralkoxy, di-
methylaminomethyl, carboxamido (-CONH2), thiocarboxamido
(-CSNH2), C1-4 alkanoyl, -NR5R6 (where R5 and R6
are the same or different and are each a hydrogen atom or
C1-4 alkyl, or where -NR5R6 is a saturated heterocyclic
amino group as defined above for Y), C1-3 alkylthio, C1-3
alkylsulphinyl, C1-3 alkylsulphonyl, phenylalkyl having a
C1-3 alkyl portion, aminosulphonyl, C1-3 alkanoylamino-
sulphonyl, phenylsulphonyl (the phenyl portion being
optionally substituted by C1-3 alkyl or C1-3 alkoxy),
nitro, or thienyl], (b) biphenyl (optionally substituted
by phenyl or one or two C1-4 alkyl, C1-4 alkoxy, halogen
77

substituents), or (c) naphthyl (optionally substituted by
C1-4 alkyl, C1-4 alkoxy or halogen);
and the physiologically acceptable salts and the solvates
thereof; which process comprises:
(a) oxidising a compound of formula (2)
<IMG>
in which R1a is a straight or branched alkyl group
substituted by -COOR3, -CH2OH or -CHO, the -COOH
group in compounds in which R3 is a hydrogen atom
being optionally protected during the reaction;
(b) in the preparation of a compound in which R3 is
alkyl or aralkyl, esterifying the corresponding compound in
which R3 is a hydrogen atom;
(d) reducing a corresponding compound in which X is an
acetylene group; or
(e) in the preparation of a salt, treating a compound of
formula (1) with an acid or (where R3 is a hydrogen atom)
with a base, or converting one salt into another by exchange
of cation.
2. A process according to claim 1 for the preparation of
a compound of general formula (1) in which Y is morpholino,
dioxothiamorpholino, homomorpholino, thiamorpholino or
piperidino; or a physiologically acceptable salt or solvate
thereof; which process comprises carrying out any one of
reactions (a), (b), (d) or (e) defined in claim 1 employing
a starting material for each said reaction in which Y is
as defined above.
78

3. A process according to claim 1 for the preparation of
a compound of general formula (1) in which X is cis-CH=CH-;
or a physiologically acceptable salt or solvate thereof;
which process comprises carrying out any one of reactions
(a), (b) or (e) defined in claim 1 employing a starting
material for each said reaction in which X is as defined
above, or carrying out reaction (d) and, if necessary,
isolating the cis isomer from the reaction product.
4. A process according to claim 1 for the preparation of
a compound of general formula (1) in which R1 is
-(CH2)2COOR3 where R3 is a hydrogen atom or C1-3
alkyl; or a physiologically acceptable salt or solvate
thereof; which process comprises carrying out reaction (a)
defined in claim 1 employing a compound of formula (2) in
which R1a is the same as R1 defined above or
-(CH2)2CH2OH or -(CH2)2CHO; or carrying reaction (b)
employing said corresponding compound in which R1 is
-(CH2)2COOH and the esterifying compound is a C1-3 alkyl
compound; or carrying out reaction (d) in which the corres-
ponding compound has a group R1 as defined above; or
carrying out reaction (e) to form a salt of the compound of
formula (1) in which R1 is -(CH2)2COOH.
5. A process according to claim 1 for the preparation of
a compound of general formula (1) in which R2 is phenyl
(C1-3)alkyl in which the phenyl group is substituted by
C1-3 alkylthio, thienyl or phenyl (optionally substituted
by C1-3 alkyl, C1-3 alkoxy, halogen or phenyl); or
cinnamyl; or a physiologically acceptable salt or solvate
thereof; which process comprises carrying out any one
of reactions (a), (b), (d) or (e) as defined in claim 1
employing the starting material for each said reaction in
which R2 is as defined above.
6. A process according to claim 1 for the preparation of
a compound of general formula (1) in which R2 is phenyl
(C1-3) alkyl in which the phenyl group is substituted by
phenyl, C1-3 alkylthio, C1-3 alkoxyphenyl or halophenyl;
79

or cinnamyl; or a physiologically acceptable salt or
solvate thereof; which process comprises carrying out any
one of reactions (a), (b), (d) or (e) as defined in claim
1 employing the starting material for each said reaction
in which R2 is as defined above.
7. A process according to claim 1 for the preparation of
a compound of general formula (1) in which:
X is cis -CH=CH-;
R1 is -(CH2)2COOH;
Y is morpholino or piperidino;
R2 is phenyl (C1-3) alkyl in which the phenyl group
is substituted by phenyl, C1-3 alkylphenyl,
C1-3 alkoxyphenyl or halophenyl; or cinnamyl,
or a physiologically acceptable salt or solvate thereof;
which process comprises:
carrying out reaction (a) as defined in claim 1
employing said compound of formula (2) in which X, Y and
R2 are as defined above and R1a represents -(CH2)2COOH (in which the -COOH
is optionally protected), -(CH2)2CH2OH or -(CH2)2CHO;
carrying out reaction (d) employing said corresponding
compound in which R1, Y and R2 are as defined above,
followed if necessary by isolation of the cis isomer; or
carrying out reaction (e) on a compound of formula (1) in
which X, R1, Y and R2 are as defined above, or an
ester or salt theeof.
8. A process according to claim 1 for the preparation of
a compound of general formula (1) in which:
X is cis -CH=CH-;
R1 is -(CH2)2COOH;
Y is morpholino;
R2 is 1,1'-biphenylmethyl; 1,1'-biphenylmethyl
substituted in the 4'-position by methyl, methoxy
or chloro or in the 3'-position by methoxy;
1,1'-biphenylpropyl; or cinnamyl;
or a physiologically acceptable salt or solvate thereof;
which process comprises:

carrying out reaction (a) as defined in claim 1
employing said compound of formula (2) in which X, Y and
R2 are as defined above and R1a represents -(CH2)2COOH (in which the
-COOH is optionally protected),-(CH2)2CH2OH or -(CH2)2CHO;
carrying out reaction (d) employing said corresponding
compound in which R1, Y and R2 are as defined above,
followed if necessary by isolation of the cis isomer; or
carrying out reaction (e) on a compound of formula (1) in
which X, R1, Y and R2 are as defined above, or an
ester or salt thereof.
9. A process according to claim 1 for the preparation of
a compound of general formula (1) in which the carbon atom
carrying the -(CH2)2XR1 group is in the R-configuration;
or a physiologically acceptable salt or solvate thereof;
which process comprises carrying out any one of reactions
(a), (b), (d) or (e) either using the R-configuration
isomer of the starting material or separating the
R-configuration product from the reaction product if an
isomer mixture is formed.
10. A process for the preparation of [1.alpha.(Z),2.beta.,5a.alpha.]-(?)-7-
[5[[(1,1'-biphenyl)-4-yl]methoxy]-2-(4-morpholinyl)-3-
oxocyclopentyl]-4-heptenoic acid or a physiologically
acceptable salt or solvate thereof; which process
comprises:
(a) oxidising a compound of formula (2) (as defined in
claim 1) in which R2 is biphenylmethyl, X is cis-CH=CH-,
Y is morpholino and R1a is -(CH2)2CH2OH, -(CH2)2CHO or
-(CH2)2COOH (the latter -COOH group being optionally protected
during the reaction);
(d) reducing the corresponding 4-heptynoic acid, or
(e) in the preparation of a salt, treating the said
compound with an acid or a base, or converting one salt
into another by exchange of cation.
11. A process for the preparation of [1R[1.alpha.(Z),2.beta.,5.alpha.]]-(-)-
7-[5-[[(1,1'-biphenyl)-4-yl]methoxy]-2-(4-morpholinyl)-3-
oxocyclopentyl]-4-heptenoic acid and the physicologically
81

acceptable salts and solvates thereof; which process
comprises:
(a) oxidising a compound of formula (2) (as defined in
claim 1) in which R2 is biphenylmethyl, X is cis-CH=CH-,
Y is morpholino and R1a is -(CH2)2CH2OH, -(CH2)2CHO or
-(CH2)2COOH (the latter -COOH group being optionally protected
during the reaction);
(d) reducing the corresponding 4-heptynoic acid, or
(e) in the preparation of a salt, treating the said
compound with an acid or a base, or converting one salt
into another by exchange of cation,
wherein, in the above reactions, the starting material
employed has the carbon atom carrying the -(CH2)2XR1a
or -(CH2)2XR1 group in the R-configuration, or the
R-configuration isomer is isolated from the reaction
product.
12. A process according to claim 10 wherein the calcium
salt of the said compound is formed by treating the
compound with a basic calcium compound or ion in step (e).
13. A process according to claim 11 wherein the calcium
salt of the said compound is formed by treating the
compound with a basic calcium compound or ion in step (e).
14. A process according to claim 10 wherein the piperidine,
piperazine or N,N-dimethyl-piperazine salt of said compound
is formed by treating said compound with piperidine,
piperazine or N,N-dimethyl-piperazine.
15. A process according to claim 11 wherein the piperidine,
piperazine or N,N-dimethyl-piperazine salt of said compound
is formed by treating said compound with piperidine,
piperazine or N,N-dimethyl-piperazine.
16. Compounds of the general formula (1)
<IMG>
wherein
82

X is cis or trans -CH=CH-;
R1 is straight or branched C1-7 alkyl bearing as a
terminal substituent -COOR3 where R3 is a hydrogen atom,
C1-6 alkyl or C7-10 aralkyl;
Y represents a saturated heterocyclic amino group which
has 5 to 3 ring members selected from pyrrolidino, piperidino,
morpholino, piperazino, thiamorpholino, 1-dioxothiamorpholino,
homomorpholino, and hexamethyleneimino;
R2 is (i) C2-4 alkanoyl; (ii) C3-6 alkenyl, option-
ally substituted by phenyl (the phenyl being optionally
substituted by C1-4 alkyl, C1-4 alkoxy, halogen, C5-7
cycloalkyl or phenyl (C1-4 alkyl), biphenyl (optionally
substituted by C1-4 alkyl, C1-4 alkoxy or halogen), or
naphthyl; (iii) C1-12 alkyl; (iv) C1-5 alkyl substituted
by (a) phenyl [optionally substituted by halogen, hydroxy,
C1-6 alkyl, C1-6 alkoxy, C1-4 hydroxyalkoxy, trifluoro-
methyl, cyano, aryloxy, C5-7 cycloalkyl, aralkoxy, di-
methylaminomethyl, carboxamido (-CONH2), thiocarboxamido
(-CSNH2), C1-4 alkanoyl, -NR5R6 (where R5 and R6
are the same or different and are each a hydrogen atom or
C1-4 alkyl, or where -NR5R6 is a saturated heterocyclic
amino group as defined above for Y), C1-3 alkylthio, C1-3
alkylsulphinyl, C1-3 alkylsulphonyl, phenylalkyl having a
C1-3 alkyl portion, aminosulphonyl, C1-3 alkanoylamino-
sulphonyl, phenylsulphonyl (the phenyl portion being
optionally substituted by C1-3 alkyl or C1-3 alkoxy),
nitro, or thienyl], (b) biphenyl toptionally substituted
by phenyl or one or two C1-4 alkyl, C1-4 alkoxy, halogen
substituents), or (c) naphthyl (optionally substituted by
C1-4 alkyl, C1-4 alkoxy or halogen);
and the physiologically acceptable salts and the solvates
thereof; whenever prepared by the process of claim 1 or an
obvious chemical equivalent.
83

17. Compounds as claimed in claim 16 in which Y is morpho-
lino, dioxothiamorpholino, homomorpholino, thiamorpholino
or piperidino, whenever prepared according to the process
of claim 2, or an obvious chemical equivalent.
18. Compounds as claimed in claim 16 in which X is cis
-CH-CH-, whenever prepared according to the process of
claim 3, or an obvious chemical equivalent.
19. Compounds as claimed in claim 16 in which R1 is
-(CH2)2COOR3 where R3 is a hydrogen atom or C1-3
alkyl, whenever prepared according to the process of
claim 4, or an obvious chemical equivalent.
20. Compounds as claimed in claim 16 in which R2 is
phenyl (C1-3) alkyl in which the phenyl group is
substituted by C1-3 alkylthio, thienyl, or phenyl
(optionally substituted by C1-3 alkyl, C1-3 alkoxy,
halogen or phenyl); or cinnamyl, whenever prepared
according to the process of claim 5, or an obvious
chemical equivalent.
21. Compounds as claimed in claim 16 in which R2 is
phenyl (C1-3) alkyl in which the phenyl group is
substituted by phenyl, C1-3 alkylphenyl, C1-3 alkoxy-
phenyl or halophenyl; or cinnamyl, whenever prepared
according to the process of claim 6, or an obvious
chemical equivalent.
22. Compounds as claimed in claim 16 in which:
X is cis -CH=CH-;
R1 is -(CH2)2COOH;
Y is morpholino or piperidino;
R2 is phenyl (C1-3) alkyl in which the phenyl group
is substituted by phenyl, C1-3 alkylphenyl,
C1-3 alkoxyphenyl or halophenyl; or cinnamyl;
whenever prepared according to the process of claim 7, or
an obvious chemical equivalent.
23. Compounds as claimed in claim 16 in which:
X is cis -CH=CH-;
R1 is -(CH2)2COOH;
Y is morpholino;
84

R2 is 1,1'-biphenylmethyl; 1,1'-biphenylmethyl
substituted in the 4'-position by methyl, methoxy
or chloro or in the 3'-position by methoxy;
1,1'-biphenylpropyl; or cinnamyl;
or a physiologically acceptable salt or solvate thereof;
whenever prepared according to the process of claim 8, or
an obvious chemical equivalent.
24. Compounds as claimed in claim 16 in which the carbon
atom carrying the -(CH2)2XR1 group is in the
R-configuration, whenever prepared according to the
process of claim 9, or an obvious chemical equivalent.
25. [1.alpha.(Z),2.beta.,5.alpha.]-(?)-7-[5-[[(1,1'-biphenyl)-4-yl] methoxy]
-2-(4-morpholino)-3-oxocyclopentyl]-4-heptenoic acid and
the physiologically acceptable salts and solvates thereof,
whenever prepared according to the process of claim 10, or
an obvious chemical equivalent.
26. [1R[1.alpha.(Z),2.beta.,5.alpha.]]-(-)-7-[5-[[(1,1'-biphenyl)-4-yl]
methoxy]-2-(4-morpholinyl)-3-oxocyclopentyl]-4-heptenoic
acid and the physiologically acceptable salts and solvates
thereof, whenever prepared according to the process of
claim 11, or an obvious chemical equivalent.
27. The calcium salt of the compound claimed in claim 25;
whenever prepared according to the process of claim 12, or
an obvious chemical equivalent.
28. The calcium salt of the compound claimed in claim 26
whenever prepared according to the process of claim 13, or
an obvious chemical equivalent.
29. The piperidine, piperazine or N,N-dimethylpiperazine
salt of the compound claimed in claim 25; whenever
prepared according to the process of claim 14, or an
obvious chemical equivalent.
30. The piperidine, piperazine or N,N-dimethylpiperazine
salt of the compound claimed in claim 26; whenever
prepared according to the process of claim 15, or an
obvious chemical equivalent.

31. A process for the preparation of a compound of the
general formula (l)
<IMG>
wherein
X is cis or trans -CH=CH-;
R1 is straight or branched C1-7 alkyl bearing as a
terminal substituent -COOR3 where R3 is a hydrogen atom,
C1-6 alkyl or C7-10 aralkyl;
Y represents a saturated heterocyclic amino group which
has 5 to 8 ring members selected from pyrrolidino, piperidino,
morpholino, piperazino, thiamorpholino, 1-dioxothiamorpholino,
homomorpholino, and hexamethyleneimino;
R2 is (i) C2-4 alkanoyl; (ii) C3-6 alkenyl, option-
ally substituted by phenyl (the phenyl being optionally
substituted by C1-4 alkyl, C1-4 alkoxy, halogen, C5-7
cycloalkyl or phenyl (C1-4 alkyl), biphenyl (optionally
substituted by C1-4 alkyl, C1-4 alkoxy or halogen), or
naphthyl; (iii) C1-12 alkyl; (iv) C1-5 alkyl substituted
by (a) phenyl [optionally substituted by halogen, hydroxy,
C1-6 alkyl, C1-6 alkoxy, C1-4 hydroxyalkoxy, trifluoro-
methyl, cyano, aryloxy, C5-7 cycloalkyl, aralkoxy, di-
methylaminomethyl, carboxamido (-CONH2), thiocarboxamido
(-CSNH2), C1-4 alkanoyl, -NR5R6 (where R5 and R6
are the same or different and are each a hydrogen atom or
C1-4 alkyl, or where -NR5R6 is a saturated heterocyclic
amino group as defined above for Y), C1-3 alkylthio, C1-3
alkylsulphinyl, C1-3 alkylsulphonyl, phenylalkyl having a
C1-3 alkyl portion, aminosulphonyl, C1-3 alkanoylamino-
sulphonyl, phenylsulphonyl (the phenyl portion being
optionally substituted by C1-3 alkyl or C1-3 alkoxy),
nitro, or thienyl], (b) biphenyl (optionally substituted
by phenyl or one or two C1-4 alkyl, C1-4 alkoxy, halogen
86

substituents), or (c) naphthyl (optionally substituted by
C1-4 alkyl, C1-4 alkoxy or halogen);
and the physiologically acceptable salts and the solvates
thereof; which process comprises:
(a) oxidising a compound of formula (2)
<IMG>
in which R1a is a straight or branched alkyl group
substituted by -COOR3, -CH2OH or -CHO, the -COOH
group in compounds in which R3 is a hydrogen atom
being optionally protected during the reaction.
32.A process for the preparation of a compound of the
general formula (1)
<IMG>
wherein
X is cis or trans -CH=CH-;
R1 is straight or branched C1-7 alkyl bearing as a
terminal substituent -COOR3 where R3 is C1-6 alkyl or
C7-10 aralkyl;
Y represents a saturated heterocyclic amino group which
has 5 to 8 ring members selected from pyrrolidino, piperidino,
morpholino, piperazino, thiamorpholino, 1-dioxothiamorpholino,
homomorpholino, and hexamethyleneimino;
R2 is (i) C2-4 alkanoyl; (ii) C3-6 alkenyl, option-
ally substituted by phenyl (the phenyl being optionally
substituted by C1-4 alkyl, C1-4 alkoxy, halogen, C5-7
cycloalkyl or phenyl (C1-4 alkyl), biphenyl (optionally
substituted by C1-4 alkyl, C1-4 alkoxy or halogen), or
napthyl; (iii) C1-12 alkyl; (iv) C1-5 alkyl substituted
by (a) phenyl [optionally substituted by halogen, hydroxy,
87

C1-6 alkyl, C1-6 alkoxy, C1-4 hydroxyalkoxy, trifluoro-
methyl, cyano, aryloxy, C5-7 cycloalkyl, aralkoxy, di-
methylaminomethyl, carboxamido (-CONH2), thiocarboxamido
(-CSNH2), C1-4 alkanoyl, -NR5R6 (where R5 and R6
are the same or different and are each a hydrogen atom or
C1-4 alkyl, or where -NR5R6 is a saturated heterocyclic
amino group as defined above for Y), C1-3 alkylthio, C1-3
alkylsulphinyl, C1-3 alkylsulphonyl, phenylalkyl having a
C1-3 alkyl portion, aminosulphonyl, C1-3 alkanoylamino-
sulphonyl, phenylsulphonyl (the phenyl portion being
optionally substituted by C1-3 alkyl or C1-3 alkoxy),
nitro, or thienyl], (b) biphenyl (optionally substituted
by phenyl or one or two C1-4 alkyl, C1-4 alkoxy, halogen
substituents), or (c) naphthyl (optionally substituted by
C1-4 alkyl, C1-4 alkoxy or halogen);
and the physiologically acceptable salts and the solvates
thereof; which process comprises:
esterifying the corresponding compound in which R3
is a hydrogen atom.
33 A process for the preparation of a compound of the
general formula (1)
<IMG>
wherein
X is cis or trans -CH-CH-;
R1 is straight or branched C1-7 alkyl bearing as a
terminal substituent -COOR3 where R3 is a hydrogen atom,
C1-6 alkyl or C7-10 aralkyl;
Y represents a saturated heterocyclic amino group which
has 5 to 8 ring members selected from pyrrolidino, piperidino,
morpholino, piperazino, thiamorpholino, 1-dioxothiamorpholino,
homomorpholino, and hexamethyleneimino;
88

R2 is (i) C2-4 alkanoyl; (ii) C3-6 alkenyl, option-
ally substituted by phenyl (the phenyl being optionally
substituted by C1-4 alkyl, C1-4 alkoxy, halogen, C5-7
cycloalkyl or phenyl (C1-4 alkyl), biphenyl (optionally
substituted by C1-4 alkyl, C1-4 alkoxy or halogen), or
naphthyl; (iii) C1-12 alkyl; (iv) C1-5 alkyl substituted
by (a) phenyl [optionally substituted by halogen, hydroxy,
C1-6 alkyl, C1-6 alkoxy, C1-4 hydroxyalkoxy, trifluoro-
methyl, cyano, aryloxy, C5-7 cycloalkyl, aralkoxy, di-
methylaminomethyl, carboxamido (-CONH2), thiocarboxamido
(-CSNH2), C1-4 alkanoyl, -NR5R6 (where R5 and R6
are the same or different and are each a hydrogen atom or
C1-4 alkyl, or where -NR5R6 is a saturated heterocyclic
amino group as defined above for Y), C1-3 alkylthio, C1-3
alkylsulphinyl, C1-3 alkylsulphonyl, phenylalkyl having a
C1-3 alkyl portion, aminosulphonyl, C1-3 alkanoylamino-
sulphonyl, phenylsulphonyl (the phenyl portion being
optionally substituted by C1-3 alkyl or C1-3 alkoxy),
nitro, or thienyl], (b) biphenyl (optionally substituted
by phenyl or one or two C1-4 alkyl, C1-4 alkoxy, halogen
substituents), or (c) naphthyl (optionally substituted by
C1-4 alkyl, C1-4 alkoxy or halogen);
and the physiologically acceptable salts and the solvates
thereof; which process comprises:
in the preparation of a salt, treating a compound of
formula (1) with an acid or (where R3 is a hydrogen atom)
with a base, or converting one salt into another by exchange
of cation.
89

34. A process for the preparation of a compound of the
general formula (1)
<IMG>
wherein
X is cis or trans -CH=CH-;
R1 is straight or branched C1-7 alkyl bearing as a
terminal substituent -COOR3 where R3 is a hydrogen atom,
C1-6 alkyl or C7-10 aralkyl;
Y represents a saturated heterocyclic amino group which
has 5 to 8 ring members selected from pyrrolidino, piperidino,
morpholino, piperazino, thiamorpholino, 1-dioxothiamorpholino,
homomorpholino, and hexamethyleneimino;
R2 is (i) C2-4 alkanoyl; (ii) C3-6 alkenyl, option-
ally substituted by phenyl (the phenyl being optionally
substituted by C1-4 alkyl, C1-4 alkoxy, halogen, C5-7
cycloalkyl or phenyl (C1-4 alkyl), biphenyl (optionally
substituted by C1-4 alkyl, C1-4 alkoxy or halogen), or
naphthyl; (iii) C1-12 alkyl; (iv) C1-5 alkyl substituted
by (a) phenyl [optionally substituted by halogen, hydroxy,
C1-6 alkyl, C1-6 alkoxy, C1-4 hydroxyalkoxy, trifluoro-
methyl, cyano, aryloxy, C5-7 cycloalkyl, aralkoxy, di-
methylaminomethyl, carboxamido (-CONH2), thiocarboxamido
(-CSNH2), C1-4 alkanoyl, -NR5R6 (where R5 and R6
are the same or different and are each a hydrogen atom or
C1-4 alkyl, or where -NR5R6 is a saturated heterocyclic
amino group as defined above for Y), C1-3 alkylthio, C1-3
alkylsulphinyl, C1-3 alkylsulphonyl, phenylalkyl having a
C1-3 alkyl portion, aminosulphonyl, C1-3 alkanoylamino-
sulphonyl, phenylsulphonyl (the phenyl portion being
optionally substituted by C1-3 alkyl or C1-3 alkoxy),
nitro, or thienyl], (b) biphenyl (optionally substituted
by phenyl or one or two C1-4 alkyl, C1-4 alkoxy, halogen

substituents), or (c) naphthyl (optionally substituted by
Cl-4 alkyl, Cl-4 alkoxy or halogen);
and the physiologically acceptable salts and the solvates
thereof; which process comprises:
reducing a corresponding compound in which X is an
acetylene group
35. A process for the preparation of a compound of the
general formula (1)
<IMG>
wherein
X is cis or trans -CH=CH-;
Rl is straight or branched Cl-7 alkyl bearing as a
terminal substituent -COOR3 where R3 is a hydrogen atom,
C1-6 alkyl or C7-10 aralkyl;
Y represents a saturated heterocyclic amino group which
has 5 to 8 ring members selected from pyrrolidino, piperidino,
morpholino, piperazino, thiamorpholino, l-dioxothiamorpholino,
homomorpholino, and hexamethyleneimino;
R2 is (i) C2-4 alkanoyl; (ii) C3-6 alkenyl, option-
ally substituted by phenyl (the phenyl being optionally
substituted by C1-4 alkyl, C1-4 alkoxy, halogen, C5-7
cycloalkyl or phenyl (Cl-4 alkyl), biphenyl (optionally
substituted by Cl-4 alkyl, Cl-4 alkoxy or halogen), or
naphthyl; (iii) Cl-l2 alkyl; (iv) Cl-5 alkyl substituted
by (a) phenyl [optionally substituted by halogen, hydroxy,
C1-6 alkyl, Cl-6 alkoxy, Cl-4 hydroxyalkoxy, trifluoro-
methyl, cyano, aryloxy, C5-7 cycloalkyl, aralkoxy, di-
methylaminomethyl, carboxamido (-CONH2), thiocarboxamido
(-CSNH2), C1-4 alkanoyl, -NR5R6 (where R5 and R6
are the same or different and are each a hydrogen atom or
Cl-4 alkyl, or where -NR5R6 is a saturated heterocyclic
91

amino group as defined above for Y), Cl-3 alkylthio, Cl-3
alkylsulphinyl, Cl-3 alkylsulphonyl, phenylalkyl having a
Cl-3 alkyl portion, aminosulphonyl, Cl-3 alkanoylamino-
sulphonyl, phenylsulphonyl (the phenyl portion being
optionally substituted by Cl-3 alkyl or C1-3 alkoxy1),
nitro, or thienyl], (b) biphenyl (optionally substituted
by phenyl or one or two Cl-4 alkyl, Cl-4 alkoxy, halogen
substituents), or (c) naphthyl (optionally substituted by
Cl-4 alkyl, Cl-4 alkoxy or halogen);
and the physiologically acceptable salts and the solvates
thereof; which process comprises:
(a) oxidising a compound of formula (2)
<IMG>
in which Rla is a straight or branched alkyl group
substituted by -COOR3, -CH20H or -CHO;
(b) in the preparation of a compound in which R3 is
alkyl or aralkyl, esterifying the corresponding compound in
which R3 is a hydrogen atom;
(d) reducing a corresponding compound in which X is an
acetylene group; or
(e) in the preparation of a salt, treating a compound of
formula (1) with an acid or (where R3 is a hydrogen atom)
with a base, or converting one salt into another by exchange
of cation.
92

Description

~ 173830
Aminocyclopentane alkenoic acids and ester_ and their
prepara~ion and Pharmaceutical formulation
The endoperoxides prostaglandins G2 and H2, and
thromboxane A2 are naturally occurring, reactive meta-
bolites of arachidonic acid in human platelets. Theyare not only potent aggregatory agents but are also
constrictvrs of vascular and bronchial smooth muscle,
and therefore substances which antagonise their effects
are of considerable interest in human medicine.
We have now ~ound a new group of compounds which have
shown endoperoxide and thromboxane antagonist activity,
and are therefore o~ interest in the treatment of asthma
and cardiovascular diseases. These compounds can broadly
be described as cyclopentanealkenoic acids and esters in
which the double bond is in the 3,4-position in relation
to the cyclopentane ring and in which the ring is substi-
tuted by heterocyclic amino, oxo and alkanoyloxy or ether
(particularly aralkoxy) groups.
The invention thus provid2es compounds o~ ~he general
~ormula ~1) ~
~ "- (C~12 ) ~XR
~1 '
~ --~ Y
wherein X is cis or trans -C~=C~-;
~i
~i
:, . . ~.

~ ~73~3~V
Rl is straight or branched Cl 7 alkyl bearing as a
terminal substituent -CooR3 where R3 is a hydrogen
atom, Cl_6 alkyl or C7_l0 aralkyl; Y represents a
saturated heterocyclic amino group which has 5 to 8 ring
members selected from pyrrolidino, piperidino, morpholino,
piperazino, thiamorpholino, l-dioxothiamorpholino~ homo-
morpholino, and hexamethyleneimino; R2 is (i) C2 4
alkanoyl; (ii) C3 6 alkenyl, optionally substituted by
phenyl (the phenyl being optionally substituted by C
alkyl, Cl 4 alkoxy, halogen, C5~7 cycloalkyl or phenyl
(Cl 4 alkyl), biphenyl (optionally substituted by Cl 4
alkyl, Cl 4 alkoxy or halogen), or naphthyl; (iii)
Cl 12 alkyl; (iv) Cl 5 alkyl substituted by (a) phenyl
[optionally substituted by halogen, hydroxy, Cl_6 alkyl,
Cl 6 alkoxy, Cl 4 hydroxyalkoxy, trifluoromethyl,
cyano, aryloxy, C5 7 cycloalkyl, aralkoxy, dimethylamino-
methyl, carboxamido (~CON~2), thiocarboxamido (-CSNH2),
Cl 4 alkanoyl, -NR5R6 (where R5 and R6 are the
same or different and are each a hydrogen atom or Cl_~
alkyl, or where -NR5R6 is a saturated heterocyclic
amino group as defined above for Y), Cl 3 alkylthio,
Cl 3 alkylsulphinyl, Cl 3 alkylsulphonyl, phenylalkyl
having a Cl 3 alkyl portion, aminosulphonyl, Cl 3
alkanoylaminosulphonyl, phenylsulphonyl (the phenyl
portion being optionally substituted by Cl 3 alkyl or
Cl_3 alkoxy), nitro, or thienyll, (b) biphenyl (option-
ally substituted by phenyl or one or two Cl 4 alkyl,
Cl_4 alkoxy, halogen substituents), or (c)
f '~
.'j,~'.')~

~ :1738~
na~lthyl (optionally substituted by Cl 4 alkyl, Cl_4
alkoxy or halogen);
and the physiologically acceptable salts and the
solvates (e.g. hydrates) thereof.
The structural formulae herein are to ~e under-
stood to include the enantiomers of each of the compounds
concerned as well as mixtures of the enantlomers,
including racemates, even though the precise structure
as set out only relates to one enantiomer~
lU The alkyl groups referred to abo~e in the
definition of the compounds of formula (1) may be
straight or branched
~he alkyl portion of the group Rl may for
example contain 1-5 carbon atoms in a straight or branched
chain, and is preferably -CH2CH2-, Examples of s~itable
R groups are Cl_3 alkyl (e.g. methyl)~ but R is preferably
a hydrogen atom. R is thus prefera~ly -~C~2)2COOH.
When R3 is a hydrogen atom, the compounds are
capable of salt formation wi~h bases and the compounds
20 are preferably used in the form of such salts. Examples
of suitable salts are alkali metal (e.g. sodium and
potassium) r alkaline earth metal (e.g. calcium or
magnesium), ammonium, substituted ammonium (e.g.
tromethamine or dimethylaminoethanol), piperazine,
2S N,N-dimethylpiperazine, morpholine, piperidine and
tertiary amino (e.g. triethylamine) salt~. Inorganic
salts are preferred.
;~1 '
.
, :

~ ~383~
-- 4 --
X is preferably a cis -CH=CH- group.
The heterocyclic amino group Y is selected from pyrro-
lidino, piperidino, morpholino, piperazino, thiamorpholino,
l-dioxothiamorpholino, homomorpholino and hexamethylene-
imino. Y is preferably p;peridino, morpholino, homomor-
pholino, thiamorpholino or l-dioxothiamorpholino, and
compounds in which Y is a morpholino or piperidino group
are particulàrly preferred.
The amino group Y enables the compounds to form salts
with organic acids, e.g. maleates.
R2 may for example be C5_10 alkyl (e.g. pentyl or
decyl); C3_5 alkenyl (e.g. allyl, optionally substituted
by phenyl); or Cl_5 alkyl ~e.g. methyl or propyl) sub-
stituted by phenyl loptionally substituted by a Cl 4
alkyl (e.g. tert butyl), C5 7 cycloalkyl (e.g. cyclo-
hexyl), Cl 3 alkylthio ~e.g~ methylthio), phenyl (Cl 3)
alkyl ~e.g. benzyl) or thienyl],
r~

~ ~ l 3 8 3 ~
-- 5 --
biphenyl [optionally substituted by Cl 3 alkyl (e.g.
methyl), Cl 3 alkoxy ~e.g. methbxy), halogen ~e.g.
chlorine) or phenyl], or naphthyl.
R is preferably a phenylalkyl group in which the
alkyl portion contains Cl 3 carbon atoms and the phenyl
is substituted with one of the following groups:
Cl 3 alkylthio, thienyl or phenyl optionally substituted
by Cl 3 alkyl, Cl 3 alkoxy; halogen or phenyl; or cinnamyl.
Particularly preferred R2 groups are phenylalkyl groups
in which the alkyl portion is a Cl 3 alkylene chain and
the phenyl group carries a phenyl substituent,
preferably in the para-position (which phenyl
substituent is optionally substituted by a Cl 3 alkyl,
Cl 3 alkoxy or halogen, this additional substituent
preferably being in the meta or more particularly the
para-position); or cinnamyl.
A particularly preferred group of compounds has the
formula (1) in which:
X is cis -CH=CH-,
R is -CH2CH2COOH,
Y is morpholino or piperidino, and
R2 is phenyl (Cl 3) alkyl in which the
phenyl group is substituted by phenyl (which phenyl
substituent is optionally substituted by Cl 3 alkyl,
Cl 3 alkoxy or halogen); or cinnamyl.
and the physiologically acceptable salts and
solvates (e.g. hydrates) thereof.

1 ~3~3~
Particularly important compounds in this latter
group are those in which Y is morpholino and R2 is
l,l'-biphenylmethyl; l,l'-biphenylmethyl su~stituted
in the para-position by methyl, methoxy or chloro or
in the meta-position by methoxy; l,l'-biphenylpropyl;
or cinnamyl; and those in which
Y is piperidino and R2 is 1, l'-biphenylmethyl or
4'-methoxy-1,1'-biphenylmethyl. Especially important
are:
[la(Z), 2~,5a~ )-7-[5-~[(1,1'-biphenyl)-4-yl~
methoxy]-2-(4-morpholinyll-3-oxocyclopentyl]-4-heptenoic acid;
and
[lR-[la(Z),2~,5a]]-(-)-7-~5-[[(1,1'-biphenyl)-4-yl]
methoxy]-2-(4-morpholinyl)-3-oxocyclopentyl]-4-heptenoic acid;
and the hydrates and salts thereof, particularly the
calcïum, piperidine, piperazine and N,N-dimethylpiperazine
salts. The calcium salts are particularly important.
In general, compounds of formula (1) in which the
carbon atom carrying the -(CH2)2XRl group is in the
R-configuration (and mixtures containing this isomer) are
preferred.
Compounds of formula (1) inhibit blood platelet
aggregation and bronchoconstriction. The test for
inhibition of platelet aggregation is as described
by G.V. Born in ~ature 194, 927-929 (1962) except in that
collagen is used instead of ADP as the pro-aggregatory
agent. The test for potential inhibition o~ broncho-
constriction is as described by K.M. Lulich et al in
Briti~h Journal o Pharmacology 58, 71-79, ~1976)
~xcept ~uinea-pig lung is used instead o cat lung.
~!
: ,
.
~, ` "~ '

3 8 ~
-- 7 --
The compounds are thus of interest in the treatment
of asthma, and as inhibitors of platelet aggregation
and thrombosis for use i~ renal dialysis and thè
teeatment and prevention of occlusive vascular diseases
such as arteriosclerosis, a~herosclerosis, peripheral
vasculaE disease, cerebral vascular disease including
transient ischaemic attacks, stroke, pulmo~ary
embolism, diabetic retinopathy, post operative thrombosis,
angina and myocardial infarction; They may be formulated
in conventional manner for use, with one or more
pharmaceutical carriers.
For oral administration, the pharmaceutical
composition may take the orm of, for example, tablets,
capsules, powders, solutions, syrups, or suspensions
lS prepared by conventional means with acceptable excipients.
The compounds may be formulated for paren~eral
administration by bolus injections or continuous
infusion. Formulations ~or injections may be presented
in unit dosage form in ampoules, or in multi-dose
20 containers, with an added preservative. The compositions
may take such forms as suspensions, solutions or
emulsions in oily or aqueous vehicles, and may contain
formulatory agents such as suspending, stabilising
and/or dispersing agents. Alternatively, the active
ingredient may be in powder form for reconstitution
before use with a suitable vehicle, e.g. sterile
pyrogen free water.
For administration by inhalation the compounds
are conveniently delivered in the ~orm o~ an aerosol
30 spray presenta~ion from pressurised packs or a nebuliser,
or as a cartridge ~rom which the powdered composition
may be inhaled with the aid o~ a suitable device.
In the case of a pressurised aerosol the dosage unit
may be determined by providing a valve to deliver
35 a metered amount.
For use as antithrombotic agents, the compounds
are pre~erably administered orally, for example in
amounts o0.05 to 10 mq/kg body weight, 1 to 4 times
daily.
.~
.
,

~17~
-- 8 --
For use in the treatment of asthma, the compounds
may als~ be administered orally in amount~ of 0.~5 to
10 mg/kg body weight, 1 to 4 times daily; preferably
however they are administered by inhalation at
doses varying from 0.3 to 30 mg, 1 to 4 t~mes daily.
The compounds may be used in combination with o~her anti-
asthmatic agents.
The pxecise dose a~mini~tered will of course
,depend on the age and condition of th~ patent.
Suitable methods for preparing compounds of
formula (1) are describea below.
In the following discussion, the groups Rl,
R2, R3, X and Y are as defined above except where
otherwise indicated.
15 (2) Compounds of formula (1) may be prepe.red by
oxidising a corresponding hydroxy compound, e.g. a
compound of formula (2) oR2
~"ICH212XRla
~ ' .
~0 Y
l21
(,wherein Rla i~ Cl 7 alkyl substituted ~y -Coo,R3,
-CH2QH or -CHQ~.
Suitable methods o~ oxidatlon include using a
CrV~ oxidlsing reage~t in a suitabLe solvent, e.g.
chromic acld in aceton~ (e.g~ Jones reagent, pre~erably
used in the presence Q~ a diatomaceous sLlica such as
Celite~ or CrO3 in pyrLdine. The~e reagents are
.'.
,

~ 1~38.~0
g
for example used at temperatures o -20 to room
temperature.
Other important methods include using an
activated sulphur reagent, e.g. (i) N-chlorosuccin~mide-
dimethy}sulphide complex in a suitable solvent (e.g.toluene or dichloromethane) at temperatures of for
example -25 to 25, preferably at 0-5, (ii),a
dimethylsulphide (e.g. dimethylsulphoxide) activated by
a ~uitable electrophilic reagent (such as oxalyl chloride,
acetyl bromide or thionyl chloride) in a suitable sol~ent
~e.g. toluene or dichloromethane), e.g. at -70 to -20; di-
cyclohexylcarbodiimide can also be used as the electrophllIc
reagent (preferably in the presence of CF3COO~ or its
pyridinium salt) at for example -10 to room temperature,
I5 using the same solvent~, or (iii) pyridine -SO~
complex in dimethylsulphoxide, preferably at 0 to
room temperature.
When R3 is a hydrogen atomr better yields are
sometimes obtained by prior protection of the carboxyl
group, for example in the form of a trialkyl (e.g.
trimethyl, triethyl or dimethyl(l,l-dimethylethyl))silyl
ester.
CrV~ oxidising agents are generally preferred. Ihc
choice of oxidation method however will depend on the nature
of the starting material of formula t2). Thus when Rla is
-CH2OH or -CHO, a CrVl oxidising agent will generally be used.
When Y is in the a-configuration conditions should be
chosen to effect epimerisation, either at the same time or
after oxidation.
Any hydroxy or amino group present in the
s~ar~ing material and re~ulred in ~he end product should
be suitably protected in this reaction.
~bl Compounds o ~ormula (1) in which R ~s an
alkyl or aralkyl group can be prepared ~y esterification
o ~he corresponding carboxylic acid in which R is
a hydrogen atom, reaction with a diazoalkane being
preferred.
: ' .

~ 173~3~
-- 10 --
Alternatively, the acid may be con~erted into
an activ~ated derivative (e.g. a correspondlng mixed
anhydridel e.g. by reaction with an alkyl chl~ro-
formate (e.g. isobutyl chloroformate) ir~ the presence
of a suitable base, e.g. triethylamine or pyridine.
The activated derivative can then be reacted wlth an
appropriate alcohol, for example using a solvent such
as acetone and temperatures of -10 to room temperature.
(c~ Compounds of formula (l) in which ~ is Pb~X~
substituted by amino may be prepared by reduction of
the corresponding azide, for example using zinc and
sodium dihydrogen phosphate (~.g. in tetrahydrofuran~.
(d) Compounds of formula (1) may also be prepared
by selective reduction of a corresponding compound o~
formula (l! in whlch X is an acetylene group. These
intermediates are also novel compounds. Suitable methods
of reduction include using hydrogen in the presence of a
catalyst, e.g. palladium on a support (e.g. CaC03
or BaS04) and poisoned or example by lead or pyridine
Suitable solvents include ethyl acetate or methanol.
(e) Where salts o compounds of formula t1) are
desired such salts may be formed by conventional methods,
for example by treating acids o ormula (l) with
appropriate bases. Salts may also be formed with acids.
, The salts may be formed in conventional manner.
For example, amlne salts are conveniently prepared by
adding the amine to a solution o~ an acid o~ ~ormula
~l) in a solvent such as ether. Salts of inorganic
bases may be prepared by adding the base to a
3~ ~olutlon o the acid in an a~ueous organlc solvenb~
Certain salts may also be prepared by exchange o~ catlan;
~or example, calcium salts may be prepared by addition
o a aalcium salt (e.g. the chloride or acetate) to a
solution o~ a salt of a compound of ormula (l), e.g. an
amine or alkali metal salt.

~ i 73~
,_ Th~e principal intermediates required for the
reactions described above may be prepared by the-
following methods.
It will be appreciated that the following reactions
5 will frequently require the use of, or will conveniently
be applied to, starting materials having protected
functional groups. It is to be understood generally
that the reerences below to specific starting materials
are intended to include references to corresponding
1~ materials having protected functional groups.
It will also be appreciated that certain of
the reactions described below are capable of affecting
other groups in the starting material which are desired
in the end product, and account must be taksn of this
when performing multi-stage reactions.
~f) Compounds of formula (3)
' ' ' .
., oR2
,~ z.
HO 5~' ~3~
~where Rl L~ as de~ined abo~e for ~1 where R3 is a
hydroc~en atom) may be prepared by reacting a compound of
~ormula ~)
~1

~ ~383~
- 12 -
I~R
</~ VCH~
y ll,l
with an appropriate Wittig reagent, e.g. a phosporane
of formula R7P=CHRl (where R7 is Cl 6 alkyl or ary:L,
e.g. monocyclic aryl such as phenyl) or a salt thereof,
e.g. the potassium salt. Suitable reaction solvents
include hydrocarbons (e.g. benzene and toluene),
ethers (e.g. tetrahydrofuran), dialkylGulphoxides
(e.g. dimethylsulphoxida2, alcohols and halogenated
hydrocarbons. The reaction may be carried out at
any suitable temperature from -70 to 50C, preferably
at room temperature.
The reaction is particularly suitable for the
preparation of compounds in which Rl is terminally
substituted by -COOH (in salt form). Any hydroxy
group present is preferably in a protected state
prior to this reaction. Suitable hydroxyl protecting
groups are described below. Any -NH2 gro~p present
~hould also be protect~.d, e.g. by t-butoxycarbonyl.
I~ desired, th~ configuration o ~he group
2~ X and Rl and ~ may then be modified to provide other
compounds o Eormula (21 e.~. by m~thods (1) - ~o)
below or Cbl or ~c) above.

~ 1~ 3~3~
- 13 -
The starting materials of formula ~4) may be prepared
by the following sequence: 2
y OR
o/~u ~ \~ oR8
H ~ oR2 ~ (4)
(5) HO (6)
A lactol of formula (5) is treated with an appropriate
Wittig reagent (e.g. R7P=CHoR8, where R7 is as defined
above and R8 is Cl 4 alkyl) to give the vinyl ether
(6). The reactions may be performed as described for
process (f). ~he vinyl ether (6) is then hydrvlysed to
give the aldehyde (4), for example using a dilute acid0 such as hydrochloric acid. Acetone is a suitable solvent.
Lactols of the formula ~7)
~ (7)
HO oR2
may be prepared by the method described in Glaxo Group
Limited's British Patent Specification 2028805A published
on 12 March 1980, using starting materials containing the
appropriate R group.

~ ~73~3~
Lactols of formula (8)
~1 18~ :
HO oR2
reql}:i.red a~ starting materials may be prepared by
th~ followincJ sequence:
o R ~OH
l 9: 1 1101 \~
Y,~
~-- ~ RhOG~R2
oR2
112) 1~1

~ 173~3~)
- 15 -
(Rh above represen-ts a hydroxyl protecting group)
l'hus the n~rbornanone (9) is first redueed (e.g.
wi-th NaBH~) to the alcohol (10) into which the R2
group is then introcluced (e.CJ. by reaction with R L,
wllere ~ is a leaving group, e.g. halogen or tosyla-te)
-to give the compound (llj. The protectiny group (Rh)
is then removed and the hydroxy group oxidlsed (e.g. as
d~scribed ~or process (a~) to give the norbornanolle
(L2). The latter can then be converted into -the
lactol ~8) by Baeyer-Villiger oxidation followed by
reduction (e.g. with di-isobutyl aluminium hydride).
(cJ) Compounds of formula (2) in which the groups Y
and Oll are both in tlle B-position may be prepaxed by
reducing the corresponding compound of formula (1), e.g.
with lithium tri-see-butyl horohydride.
(h) Compounds oE formula (2) in which R a contains
-C112O~I may be prepared by redueing -the corresponding acid
or ester of formula (2) or (1), e.g. with LiA1114.
(j) Compounds of formula (2) in whieh Rl~ contains
-C~IO may be prepared in the same manner as generally
described Eor proeess (f) by reae-ting a eompound o~
~ormula (4) with a phosphorane of formula R7P=C~Rla
in whieh Rla is Cl 7 alkyl substituted by a proteeted
formyl group (e.g. acetal). Removal of the protecting
group then CJiVeS the`rec~uired formyl intermecliate.
(k) Compouncls o formula (2) in whieh Y is in the Cl-
eon~i~uration and the r:Lng hydroxy CJroup is ln the
~eon1cJuration may be prepared by epimeri~ing the
eorrqspondin~ eompound in whieh the ring hydroxy c3roup
;Ls in th~ ~-pos:Lt.ion. This may Eor example be e~eet~d
wlth ~riphenylphosuhine in -the prqs~nee o~ an aeicl

~173~ 3
, ~;
(e.c3. formic or benzoic acid) and ~C2115OOC.N)2 at
a low temperature. Tetrahydrofuran is a suitable solvent.
(k) The acetylenes required as startincJ ma-terials
for process (d) may be prepared by first reactinc;
a compound o formula (7) with a WitticJ reagent
(R7P=CBrRl), as descrihed above for process (f). q'he
product is then dehydrobrominated to form the side
chain acetylene group, and the ring hydroxy clroup then
o~.~iclised, as descrlbed for process (a).
(nl) Com~)o~lnds oE formula (2) in wllich X is trans
-CII=CII- may be prepared by isomerising the corresponding
cis compound. The isomerisation may for example be effected
by treatment with, for example, p-toluene sulphinic acid
in dioxan (e.g.` at reflux) or azobisisobutyronitrile and
thiophenol, using for example a hydrocarbon solvent (e.c3.
benzene) and any suitable temperature up to reflux.
(n) Compounds of formula (2) in which R2 is phenalkyl
substituted by -C~12N(C113)2 may be prepared by -treatmen-t
of the corresponding formyl compound with dimethylamine
in the presence of a reducing agent, e.q. sodium cyano
borohydride. The starting materials for this reaction
may be made by the general me-thod (f).
(o) Compounds of formula (2) in which R2 is phenalkyl
subs-tituted by -CON~12~ or -CSNE-12 and R3 is hydroyen may
be prep~recl roM the corresponclinq cyano compoulld by
hydroJ.ysls or hydrosulpllidation, ~.y. with sulphur in
the presence o~ a recluciny aCJent.
(p~ C'ompo-lrlcls oE Eormula (2) in which 1~2 i5 phenalkyl
substltuted by alkylsulphinyl or alkylsulphonyl may
be prep~red by oxidation oE the correspondincJ al]cylthio
compou!ld with a peracid, or example per~cetic acid
at room tcmperatllr3.
.

~ 1 ~J 3 ~3 ~3 ~
, - 17 -
(q) Compounds of formula (3) in which -OR is an
ether group and Y is in the ~-configuration may be
prepared by etherification of thc correspondinc~ hydroxy
compound in which R2 is a hydrogen atom. The reaction
may for example be performed with an appropriate rea~ent
E~ L (L is as defined above), for example by reaction
at room temperature in the presence of a sui-table base
te.cJ. sodium hydride) in a suitable solvent (e.g. dimethyl-
formamide).
(r) Compounds of formula (3) in which R2 is an
- alkanoyl group and Y is in the ~-configuration may be
prepared by acylation of the corresponding hydroxy
compound, for example with the appropriate alkanoic acid
or an anhydride or halide thereof.
Any other hydroxy group present in the startinc3
material-used in process (q) or ~r) should be protected
in this reaction, as should the -COOH group in compounds
in which R3 is a hydrogen atom.
Suitable starting materials of formula (16) for
processes (q) and (r) above may be prepared by the
followin~ sequellce:
~OH ~H
Rho~ Y 11~) R!lo"
,~Xv~ - Rl ¢~,~CHO,
Rho~ y Rh~ Y
1161 . ll5~
.

:~ ~ 7 ~
- 18 -
A lactol of formula (13~, in which -ORh is a
protect~d hydroxy group is first treated with a Wittig
reagent to give the vinyl ether ~14), which i~ then
converted into the aldehyde (15) by treatment with
5 mercuric acetate. These steps ar~ performed in t~e same
general way as for the preparation of compounds of formula (4).
The compound of formula (16) may then be formed from
the aldehyde (15) by the method of process (f).
The preparation of the lac~ols (133 is described
in British Patent Specification 2028805A.
As an alternative to the formation of the ether
group by process (q), it may be formed at an earlier stage,
by etherification of the compound of formula (14).
~s) Compounds of formula (2) may also be prepared by
modifying the corresponding compound in which Y is
N~2 '
This reaction may be performed by treating
the starting material with a compound of the formula
~R9Z, where 2 is a readily displaceable group (such
~0 as halo, e.g. iodo, or hydrocarbylsulphonyloxy, e.g.
p-toluenesulphonyloxy) and R9 is the appropriate
divalent group ~e.g. -(CH2)2S(C~2)2 )
may be carried out in a solvent such as acetonitrile
or methanol at reflux, in the presence of a suitable ~ase,
e.g. potassium carbonate or sodium bicarbonate.
~he amines required as starting ma~erial~ ~or
process (~) may be prepared by reduction o~ the corres-
ponding azide, ~or example as described ~or process
(c) .
The azide starting materials may be prepared
by methods analogous to those or preparing the compounds
o~ formula (3), using reagents in which ~ is an azido

~ 173~3~
-- 19 --
group. In particular, -the preparations of 1actols
of formula (7) in which Y is azido is described in
British Patent Specification 2028805~. '
If desired, modification of the group R1 or
the configura-tion of the double bond may be effected
before the formation of the group Y by process (s). The
amino yroup may need to be protected in such
transformations.
In the preparation of the intermedia-tes the
ring hydroxy group will often be protected and the
liberation of this (or~any other hydroxy group present)
will frequently be the last step in the preparation.
Conventional methods of protection may be used, protection
in the form of dimethyl~ dimethylethyl-silyloxy or
tetrahydropyranyloxy groups beiny preferred. These ~roups
may be removed by acid hydrolysis. Hydroxy groups
may also be protected in the form of alkanoyloxy groups
having up to 7 carbon atoms, e.g. acetoxy. These
groups may be removed by alkaline hydrolysis.
~hen a specific enantiomer of formula ~1) is
required, intermedia-tes having the required stereochemical
configuration should be used in the above processes.
For example, enantiomeric,bromohydrin (17)
.,. ~' .
/ 117)
~`~
~r 0~1

~ 173~
- 20 ~
can be prepared by the me-thod described by Newton et
al in J.C.S. Chem. Comm., 1979, 908. This can *hen
be converted into a compound of formula (I) in which
the carbon atom carrying the -(C112)2XRl group is in the
(R)-configuration, via the appropria-te enantiomer of
the lactol (7), using the methods described above.
The followiny examples illustrate the invention.
i'Jones reayen-t" is a solution of chromic acid and
sulphuric acid in water. A 2.67M solution contains
CrO3 (26.7g) arld concentrated il2SO4 (23ml) made up to
lOOml with water.
, ~ - . .
'. ' ' ~,., ',' . . , -
'
.

~ ~7~30
- 21 -
Temperatures are in C. The following abbreviations
are used:
TLC - thin layer chromatography using SiO2; PE -petroleum
ether (boiling at 40-60 unless otherwise stated);
DIBAL - diisobutylaluminium hydride; THF - tetrahydrofuran;
DMF - dimethylformamide; ER -ether; EA - ethyl acetate;
DMSO - dimethylsulphoxide. Chromatography was carried
out using silica gel unless otherwise stated. 'Dried'
refers to drying with MgS04. '~yflo' is a filtration aid.
Intermediate 1
(endo!anti)~ 5-Hydroxy-7-(4 morpholinyl)bicyclo~2 2.1]
heptan-2-one
A mixture of (endo,anti)-5-acetyl-7-(4-morpholinyl)-
bicyclo [2.2.1]heptan-2-one (1649) and 5N NaOH solution
(i50 ml) was stirred for 3h and then extracted with
- CH2C12 (4 x 500 ml). The dried organic layers were
evaporated in vacuo to give a semi-solid. Trituration
with ER (500 ml) gave the title compound (83g) as
prisms, m.p. 119-121.
Intermediate 2
a) (endo,anti)-(+)-5-[~(1,1'-Biphenyl-4-yl]meth~xy]-
7-(4-morpholinyl)bicyclo[2.2.1]heptan-2-one
To a solution of In~ermediate 1 (10.5g), 1-
(bromomethyl)-l,l'-biphenyl (13.6g) and benzyl-
triethyl ammonium chloride (1,14g) in CH2C12
~(200 ml) was added 17N NaOH (100 ml) and the
mixture stirred vigorously for 18h. The layers
were separated and the aqueous layer extracted
30- with CH2Cl~ (3xlOOml). The combined organ;c
layers were washed with water (200ml), dried
and ev'aporated ln vacuo. The residue was cry~tal-
lised from iso-propyl acetate to give the t'tle
_o ~ (lSg) as prisms, m.p. 1~9.5-151.5.
The following cornpounds were prepared by a
similar proced~re.
b) (endo,anti)~ 5-~4-Methoxy(phenylmethoxy)]-
7-(4-m~ olinyl)bicvclo~2.2.1]heptan-2-one,
_. _

~ ~7383~
- 22 -
m.p. 109-111, from Intermediate 1 and p~methoxy-
benzyl bromide. Purification by chromatography
using 3:1 ER-PE through to 5:1 ER-methanol as eluent.
c) (+)-4-[~endo,endo,anti)-2-[[~1,1'-Biphenyl)-
4-yl]methoxy]-5-[~tetrahydro-2H-pyran-2-yl)oxy]bicyclo-
[2.2.1] heptan-7-yl~morpholine, m.p. 109-110
from Intermediate 27. Purification by chromatography
using 7:3 ER-PE as eluent.
d) (endo,anti)-~+)-5-~[(1,1'-Biphenyl)-4-yl]methoxy]-7-
(1-piperidinyl)blcyclo[2.2.1]heptan-2-one,
m.p. 89-91 from Intermediate 57. Purification
by chromatography using 3:2 PE-ER as eluent.
Intermediate 3
a) (endo,anti)-(+)-6-[~(l,l'Biphenyl)-4-yl]methoxY]-
8-(4-morpholinyl)-2- oxabicyclo~3.2.1]octan-
3-one
38% Peracetic acid in acetic acid (20ml) ~as
added dropwise over 10 min. to a stirred solution
of Intermediate 2a (12.5g) in CH2C12 (60 ml)
maintained at 12-15. Stirring was continued
at 15-20 for 24h, the mixture then cooled
to 5 and treated with a solution of Na2SO3
(25.1g) in water (125ml) whilst maintaining
the temperature below 20. Isopropyl acetate
(90 ml) was added and the aqueous phase was
separated. The organic phase was extracted
with lN NaOH (60 ml) and water (2 x 60ml),
then dried and reduced in volume to about 35ml.
On eooling to 20 the ~ erystallised
and was eolleeted and dried ~6 25g), m.p. 137-
139.
~he ~ollowing eompounds were prepared by a
similar proeedure:
b) (endo,anti)-(~)-6-E4-Methoxy~henylmethoxy)]-
~ holinyl)-~-oxabieyeloE3.2.11O_tcln-
3-one, m.p. 158-1.60, from Intermediate 2b.
Purifieation from CH2C12-PE.
e) (endo, _t~ 6-[[~l,l'-Biphenyl)-4-yl]methoxy]-

~ 1~3~3~
-- 23 -
8-(1-piperidinyl)-2-oxabicyclo~3.2.1]octan-
3-one, m.p. 88-90 from Intermediate 2d.
d) (endo,anti)-(+)-6-Decyloxy-8-(4-morpholinyl)-
2-oxabicyclo~3~2.l]octan-3-one m.p. 59-61, fLom
intermedia~e 80. Purification from PE.
Intermediate 4
a) (la,2~,3a,5~)-t~)-5-[[(1,1'-Biphenyl)-4-yi]methOXy~-
3-hydroxy-2-(4-morpholinyl)cyclopenta-ne acetaldehyde
DIBAL in hexane (1.4M; 6.9 ml) was added dropwise
to a sol~tion of Intermediate 3a) (1.9g) in
dry CH2C12 (30 ml) under nitrogen at -70.
Stirring was continued for 2h at -70 when
methanol (50 ml) was cautiously added and the
' mixture then allowed to come to ambient temperature
and stirred for a further 3h. The mixture
was filtered through hyflo and the filtrate
evaporated in vacuo The residue was taken
up into CH2C12 (50 ml), dried, filtered a'nd concentrated
to give the title compound as a glass (1.8g~
I.R. (CHBr3) 3580, 1718 cm 1.
The following compounds were prepared by a
similar procedure:
b) (la,2~,3,5a)-(+)-3-Hydroxy-5-~4-methoxy(phenyl-
methoxy)]-2-(4-morpholinyl)cyclopentane acetaldehyde,
'25 from Intermediate 3b. Purification by chromatography
using 98:2 CHC13-methanol as eluent.
TLC 95:5 CHCl~-methanol Rf 0.8.
c) (la,2a,3a,5a)-(t)-5-[[(1,1'-Biphenyl)-4-yl]methoxy]-
3-hydroxy-2-(4-morpholinyl)cyclopentane acetaldehyde,
m.p~ 136-138 rom Intermecliate 30.
d) (3aa,4a,5~,6aa)-(~)-Hexahydro-5-~(tetrahydro-
2H-pyranl-2-yl)oxy~-4-(4-thiomorpholinyl)-2
cyclopenta~b)uran-2-ol, 'from Intermediate 55a~
TLC 9:1 Benæene-methanol Rf 0.25
e) ~la,2~,3a,5a)-(t)-5-~[~1,1'-Biphenyl)-4-yl]methox
3-hydroxy-2-(1-piperidinyl)cyclopentane acetal h~
~rom Intermediate 3c. TLC 85:15 ER-methanol
R~ 0.38.

~ ~3~^~0
- 24 -
f) ~3a~,4a,5B,6aa)-(+)-Hexahydro-4-(hexahydro-
1,4-oxazepin-4-yl)-5-[(tetrahydro-2H-pyran-
2-yl)oxy]-2H-cyclopenta(b)furan-2-ol, from
Intermediate 55b. TLC 9:1 ER-methanol Rf 0.31.
9) (la~2B~3a~5a)-(+)-5-Decyloxy-3-hydroxy-2-(4
morpholinyl)cyclopentane acetaldehyde from
Intermediate 3d TLC (SiO2) EA Rf 0~21.
Intermediate 5
a) (la~2B~3a~4a)-(+)-4-[[(~ -Biphenyl)-4-yl]-
methoxy~-3-(3-methoxy-2-propenyl)-2-(4-morpholinyl)-
cyclopentanol
To a cold (0) stirred solution of potass~um
t _ -butoxide (1.55g) in dry THF (40 ml) under
nitrogen, was added portionwise (methoxymethyl)-
trlphenyl phosphonium chloride (4.729). The
resulting suspension was stirred for 25 min.
whereupon a solution of Intermediate 4a) (1.829)
in dry THF (15 ml) was added dropwise. Stirring
was continued at room temperature for l.5h.
The reaction mixture was poured into brine,
the pH adjusted to 6.5, and the mixture extracted
with EA. The dried extracts were evaporated
to leave a viscous oil. This crude material
was flash chromatographed on silica. Eluting
with 95:5 EA-methanol and recycling of the
impure fractions gave the title compound as
an oil (1.29g). IR (CHBr3) 3950(br), 3540,
1668 cm~l.
The foll~wing compounds were prepared in a
similar manner.
b) ~ L~~3~4a ? - (+ ) -2-(3-Methoxy-2-propenyl L-
4-[(tetrahydro-2EI-pyran-2-yl)oxyl-3-(4-t i~ E~
o nyl)cyclopentanol, from Intermediate 4d.
Puri~ication by chromato~raphy U5 ing ether
as eluent. ~LC ~R Rf 0.28.
c) 1~,2~,3B,4a)-~)-?-(3-Methaxy-2 e_o ~ ~
~plperidinyl)-4 ~(tetrahydro-2H-pyran-2-yl)-
- oxy]cycl~E~_anol, frorn (3aa,4,5B,6a~3~

~ ~73~33~
- 25 -
hexahydro-4-(1-piperidinyl)-5-~(tetrahydro-
2H-pyran~2-yl)oxy]-2H-cyclopenta(b)furan-2-
ol. TLC 4:1 EA-methanol Rf 0.22.
Intermediate 6
(1~,2~,3a,5a)-(+)-5-[[(1,1'-Biphenyl)-4-yl]methoxy]-
3-hydroxy-2-(4-moryholinyl)-cyclopentane propanal,
hydrochloride
Intermediate 5a (1.8359) was dissolved in 1:1
acetone/0.5~ ~12SO~ (65 ml) and was left standing
overnight at room temperature. The acetone was evaporated
and the residue treated with 8~ NaHC03 solution and
extracted with EA. The dried extracts were evaporated
to give a foam ~1.73g) which was dissolved in ether
and treated with ethereal hydrogen chloride. The
title compound was filtered off and dried, m.p. 169-172.
Intermediate 7
a) (la,2a,3~,4~ )-2-(3-Methoxy-2-propenyl)-
3-(4-morpholinyl)-4-~(tetrahydro-2H-pyran-2-
yl)oxy]cyclopentanol, acetate (ester)
To a cold (0) stirred solution of potassium
tert-butoxide (2.15g) in dry THF (40 ml) under
nitrogen, was added portionwise (methoxymethyl~tri-
phenyl phosphonium chloride (6.57g). The suspension
was stirred for 15 min., whereupon a solution
of (3a~,4a,5~,6a~)-hexahydro-4-(4-morpholinyl)-
5-(tetrahydro-2H-pyran-2-yl)oxy-2H-cyclopenta(b)-
furan-2-ol (2g) in dry THF (30 ml) was added
~ dropwise. Stirring was continued at room temperature
for lh, when methanol (30 ml) was added followed
by evaporation of the mixture to dryness.
The residue was treated with acetic anhydride
~3 ml) and pyricline (10 ml) and left for 40h.
Evaporation ~n vacuo gave a residue which was
treated with 8% Na~lC03 solution (50 ml) and
extracted with CH2C12 (3 x 20 ml). I'he combined
extracts were washed with brine (2 x lS ml),
dried and concentrated. Purification of the

~ ~73~30
- 26 -
residue, initially by chromatography using
4:1 ER-methanol as eluent, and then by trituration
with PE gave the title compound as an oil (13.23g).
IR (Neat) 1735, 1655 cm 1
The following compounds were prepared in a
similar manner:
b) (la,2a,3~, 4a) - (~) -2-(3-Methoxy-2-propenyl)-
4-~(tetrahydro-2~I-pyran-2-yl)oxy]-3-(4-thiomorph-
olinyl)cyclopentanol, acetate (ester), S-dioxide,
m.p. 131-13~ from Intermediate 63. Purification
initially by chromatography using 1:1 EA-PE
as eluent, followed by crystallisation from
isopropanol-ER-isopentane.
c) (l~2a,3~4~)-(+)-3-(Hexahydro-l,4-oxazepin-
4-yl)-2~(3-methoxy-2-propenyl)-4-[(tetrahydro-
2H-pyran-2-yl)oxy]cyclopentanol, acetate (ester),
from Intermediate 4f. Purification by chromatography
using 95:5 ER-methanol as eluent. T~C 19:1
ER-methanol Rf 0O65.
Intermediate 8
(1,2~,3~,4a) - (+) -2-(3-Methoxy-2-propenyl)-3-(4-morpho-
linyl)-4-[~tetrahydro-2H-pyran-2-yl)oxy]cyclopentan
~ solution of Intermediate 7a (0.3g) in 0.5N
NaOH (10 ml) was left to stand for 10 min., then
extracted with ER (3 x 20 ml). The combined extracts
were dried, filtered and evaporated to given the
title compound as an oil (0.25g). IR (Neat) 3450,
1655 cm~l ~`
~ntermediate 9
2- ~ 5-~(tetrahydro-2H-
pyran-2-yl)oxy]cyclopentyl]morpholine
Na}l (0.48g, 80~ dispersion in oil) was added
to a solution of Intermediate 8 (2.2g) and
2-(bromomethyl)naphthalene t3.56g) in dry DMF
(8 ml) at 0~. After stirring for 7h, the suspension
was poured into saturated NH4Cl solution (75 ml)
and extracted into ER (3 x 50 ml). The combined

~7383~ ~
- 27 -
extracts were dried and concentrated, and 'the
residue chromatographed on silica using ER
as eluent to give the title com~_und as an
oil (2.lg). IR (Neat) 1716, 1655 cm 1
The following compounds were prepared by a
similar procedure:
b) (la,2~,3~,5~-t+)-4-~2-(3-Methoxy-~E~ropenyl)-
3-[4-(1,1-dimethylethyl)phenylmethoxy]-5-[(tetrahydro_
2H-pyran-2-yl]oxy]cyclopentyl]morpholine, from
Intermediate 8 and 4-(1,1-dimethylethyl')phenyl-
methyl' bromide. Purification by chromatography
using ER as eluent. IR (Neat) 1650, 1120 cm 1
c) (la,2~,3B,5~ )-4-[3-(4-Cyclohexylphenylmethoxy)-
2-(3-methoxy-2-propenyl)-5-[(tetrahydro-2H-
- 15 pyran-2-yl)oxy]cyclopenty~]morpholine, from
Intermediate 8 and 4-cyclohexylphenylmethyl
- iodide. Purification by chromatography using
ER as eluent.
d) (1~,2B,3~,5~)-(+)-4-[2-(3-Methoxy-2-propenyl)-
3-(pentyloxy)-5-[(tetrahydro-2H-pyran-2-yl)oxy]
pentyl]morpholine, from Intermediate 8'and
n-pentyl-tosylate. Purification by chromatography
using EA as eluent.
e) (la,2~,3~,5B)-(+)-4-[2-(3-Methoxy-2-propen~l)-
3-[4-(phenylmethyl)phenylmethoxy]-5-[(tetrahydro-
2H-pyran-2-yl~oxy]cyclopentyl]morpholine, from
Intermediate 8 and 1-(bromomethylj-4-(phenylmethyl)-
- benzene. Purification by chromatography using
~R as eluent.
fj (laL2~L~ R ~ o'ro(l,ll-biphenyl)-
thoxy~-2-(3-methoxy-2-propen ~ tetrahydro-
2 - ~ l]morpho]ine, from
Intermediates 8 and 68. IR (Neat) 1650, 1120 cm 1
y) (la,2~,3~,5~ )-4-~2-(3-Methoxy-2-propenyl)-
3-(2-proPenyloxy)-5-~(tetrahydro-2H-pyran-2-
yl)oxy]cyclope~]]morpholine, from Intermediate
. . .
8 and allyl bromide.
h) (la~2~3~5~)-(+)---[2-(3-Methoxy-2-propenyl)

1 17383t~
- 28 -
3-[4-methylthio(phenylmethoxy)]-5-[(tetrahydro-
y_an-2-yl)oxy]cyclopentyl]morpholiner from
Intermediate 8 and 1-(bromomethyl)-4-(methylthio)-
benzene. Purification by chromatography using
ER as eluent. IR (~eat) 1650, 1120 cm 1
i) (la,2~,3~,5~)-(-)-4-[2-(3-Methoxy-2-propenyl)-
5-[(tetrahydro-2H-pyran-2-yl~oxy~-3-[(4-thien-
2-yl)phenylmethoxy]cyclopentyl]morpholine,-
from Intermediates 8 and 24a. Purification
by chromatography using ER as eluent.
j) (la,2~,3~,5~)-(+)-4-[2-(3-Methoxy-2-propenyI)-
3-[~(1,1':4',1"-terphenyl)-4-yllmethoxy]-5-
[(tetrahydro-2H-pyran-2-yl)oxy]cyclopentyl]morpholine,
from Intermediates 8 and 24b. Purification
by chromatography using ER as eluent. TLC
ER Rf 0.18.
1) ~la,2~3~(E),5~]-(-)-4-~2-(3-Methoxy-2-propenyl)-
3-[(3-phenyl-2-propenyl)oxy]-5-l(tetrahydro-
2H-pyran-2-yl)oxY]cyclopentyl]morpholine, from
Intermediate 8 and cinnamyl bromide. Purification
by chromatography using ether as eluent.
m) (la,2R,3~,5~)-(-)-4-~3-[[(1,1'-Biphenyl)-4-
yl]methoxy]-2-(3-methoxy-2-propenyl~-5-[(tetrahydro-
2H-pyran-2-Yl)oxY]cyclopentyl~thiomorpholine,
from Intermediate 5b and l-(bromomethyl)-l,1'-
biphenyl. Purification by chromatography using
3:2 ER-PE. TLC ER Rf 0.42.
n) ~la,2~,3R,5~ )-4-[3-[[4'-Methoxy(l,1'-biphenyl)-
4-yl]methoxY]-2-~3-methoxy-2-propenyl)-5-~(tetrahy-dro-
2H-pyran-2-yl)oxy]cyclopentyl]thiomorpholine,
S-dloxide, rom Intermediat~ 5~a and 4~(bromomethyl)-
4~-methoxyt~ biphenyl)~ Purification by
chromato~raphY using CH2C12 ollowed by EEi
.
,
. .

- 29 -
as eluents. TLC ER Rf 0.41.
- o) (la,2B,3~,5B)-(~)-4-[2-_3-Methoxy-2-propenyl)-
3-[~4'-methyl(l,l'-biphenyl)-4-yl]methoxy~-
5-(tetrahydro-2H-pyran-2-yl)oxy]cyclopenty]]thi
morpholine, S-dioxide, from Intermediates 59a)
and 66. Purification by chromatography using
CH2C12 followed by 4:1 ER-PE as eluent.
p) (Ia,2~,3~,5B)-(-)-4-~2-(3-Methoxy-2-propenyl)-
3-[4-(phenylmethyl)phenylmethoxy]-5-~(tetrahydro-
2H-pyran-2-yl)oxy]cyclopentyl]thiomorpholine,
S-dioxide, from Intermediate 59a) and l-(bromomethyl)-
4-(phenylmethyl)benzene. Purification by chromato-
graphy using CH2C12 fo]lowéd by ER as eluents.
TLC EA Rf 0.5.
q) (la,2~,3B,5B)-(-)-4-[3-~[(1,1'-Biphenyl)-4-
yl~methoxy]-2-(3-methoxy-2-propenyl)-5-E(tetrahydr
2H-pyran-2-yl)oxy]cyclopentyl~thiomorpholine,
S-dioxide, from Intermediate 59a) and l-(bromomethyl)-
l,1'-biphenyl. TLC 95:5 ER-methanol Rf 0.7.
r) (1~,2B,3~,5B)-(~)-4-[3-[(l,li-Biphenyl)-4-yl]-
methoxY]-2-(3-methoxy-2-propenyl)-5-[(tetrahydro-
2H-pyran-2-yl)oxy]cyclopentylIhexahydro-l~4-
oxazepin, from Intermediate 59b. TLC 97:3
ER-methanol Rf 0.68.
s) (la,2~,3~,5B)-(-)-1-[3-[[4'-MethoxY(l~
bipherlyl)-~-yl]methoxy]-2-(3-methoxy-2-propenyl)-
5-[(tetrahydro-2H-pyran-2-yl)oxy]cyclopentyl]-
piperidine, from Intermediate 5c. Purification
by chromatography using 98:2 CH2C12-methanol
as eluen~
t) _a ~2 ~ ~) ~ -
ropoxy_-2-(3-methoxy-2-propenyl)-5-[(tetra-
hydro-2H-pyran-2-yl)oxy]cyclopentyl]morpholine,
~rom Intermediates 8 ancl 60. Puriication
by chromatography using EA as eluent.
u) ~ J3B,5B)-(~)-4-[3-[[3'-Methoxy(],1'-bipllenyl)-
~yl]methoxy]-2-(3-methoxy-2-propenyl)-5-[ttetra-
hydro-2H-pyran-2-yl)oxy]cyclopentyl]morpholine,

~ ~ 73~0
- 30 -
f.rom Intermediates 8 and 2~c. Purification
by chromatography using EA as eluent.
, v) (lcll2~,3~,5~)-(+)-4-[3-[~4'-Methoxy(l,l'-biphenyl)
3-yl]methoxy]-2-(3-meth~L-2-propenyl)-5-f(tetra-
hydro-2H-pyr~n-2-yl)oxy]cyclopentyl]morpholine,
from Intermediate 8 and 3-(bromomethyl)-4'-
methoxy(l,l'-biphenyl). Purification by chromato-
graphy ~sing EA as eluent~
Intermediate 10
10 a) (1 ,2~,3,5a)-(+)-3-Hydroxy-2-(4-morpholinyl)-
5-(2-naphthalenylmethoxy)cyclopentanepropanal
A solution of Intermediate 9a (2.19) in acetone
(10 ml) containing 2N hydrochloric acid (5 ml)
was allowed to stand at room temperature for
lh. After evaporation in vacuo the residue
was neutralised with 8~.NaHCO3 solution and
extracted with CH2C12 (3 x 30 ml). The combined
extracts were dried, filtered and concentrated
to afford the title compound as a viscous oil
. 20 (1.7g). IR (Neat) 3420, 1720 cm 1
The following compounds were prepared by a
similar procedure:
b) (la,2~,3a,5~)-(+)-3-Hydroxy-5-~4-(I,l-dimethy~
ethyl)-phenylmethoxy]-2-(4-morpholinyl)cyclopentane-
propanal, from Intermediate 9b. TLC 4:1 ER-
.~methanol-Rf 0.52.
c) (la,2~,3~,5a)-(+)-5-(4-Cyclohexylphenylmethoxyj-
. 3-hyd~oxy-2-(4-morpholinyl)cyclopentanepropanal,
from Intermediate 9c. TTJC 17:3 ER-methanol
Rf 0.2B.
d) ~la,2~,3a,5a)-(~)-3-~ydroxy-2-(4-morphollnyl)-
cyclopentanepropanal, from Intermediate
9d. TLC 95:S F,A-meth~nol Rf 0.08.
~) ~la,2~,3a,5a)~ 3-~ydiox~-2-(4-morpholi~yl)-
5-~4-(phenylmethyl)phenylmethoxy]cyclopent~E~opanal,
from Intermediat~ 9e. Puri~ication by chromatography
uslng 9:1 ER-methanol as eluent.
E~ 2~ L~ (+)-5-[14l-chloro(l~ bipt~
~ ' ,

` - 31 - ~3~t~
4-yl]methoxy]-3-hydroxy-2-(4-mor~holinyl)cyclo-
r ~ ~, from Intermediate 9f. Purification
by chromatography using CHC13 through to 98:2
CHC13-methanol as eluent.
g) (1,2~,3a~5a)-(+~-3-Hydroxy-2-(4-morpholinyl)
5-(2-propenyloxy)cyclopentanepropanal, from
Intermediate 9g. Purification by chromatography
using 4:1 ER-methanol as eluent.
h) (la,2~3a~5a)-~+)-3-Hydroxy-5-[4-methylthio(phen
methoxy)]-2-(4-morpholinyl)cycloperitanepropanal,
from Intermediate 9h. Purification by chromatography
using S5:15 ER-methanOl as eluent. TLC 85:15
ER-methanol Rf 0 28.
i) (la,2~,3,5a)-(+)-3-Hydroxy-2-(4-morpholinyl)--
5-[(4-thien-2-yl)phenylmethox~]cyclopentanepropanal~
from Intermediate 9i. Purification by chromatography
using CHC13 through to 98:2 CHC13-methanol as
eluent. TLC 95:5 CHC13-methanol Rf 0.3.
j) (la,2~,3a,5a)-~+)-3-Hydroxy-2-(4-morpholiny
- 4-~ 4',1"-terphenYl)-4-yl]methoxy]cYcl~o-
pentanepropanal, m.p. 151-153 from Intermediate
9j .
1) [la,2~,3a,5a(E)]-(-)-3-Hydroxy-2-(4-morpholinyl)-
5-~(3-phenyl-2-propen l)oxy]cyclopentanepropanal,
from Intermediate 91. IR (CHBr3) 3580, 3560,
1720 cm
m) (la,2~,3a,5a)-(+)-5-~[(1,1'-Biphenyl)-4-yl]rnethoxy]-
3-hydroxy-2-(4-thiomorpholinyl)cyclopentanepropanal,
m.p. 109-110 from Intermediate 9m.
Purification ~y chromatography using ER as
eluent.
n) ~ ~ ~ 1'-
biphenyl)- ~ olinyl)

1 173~3~
- 32 -
pentanepropanal, S-dioxide, from Intermediate 9n.
IR (CHBr3) 3580, 2720, 1720 cm 1
o) (la,2~,3~,5a)-(+)-3-Hydroxy-5-~4'-methyl(l,l'-
biphenyl)-4-yl]methox~]-2-t4-thiomorpholinyl)cyclopen-
tanepropanal, S-dioxide, from Intermediate 9O~
IR (CHBr3) 3580, 2725, 1720 cm
p) (la,2~,3a,Sa)-(~)-3-Hydroxy-5-~4-(phenylmethyl)-
~henylmethoxy~-2-(4-thiomorpholinyl)cyclopentane-
propanal, S-dioxide, from Intermediate 9p.
IR (CHBr3) 3580, 2720, 1720 c~ L
q) (la,2~,3,5a)-t~)-5-~[(1,1l-Biphenyl)-4-yl]methoxy]-
3-hydroxy-2-(4-thiomorpholinyl)cyclopentanepropanal,
S-dioxide, m.p. 152.5-154 (dec.) from Intermediate
9q .
r) (l~2~r3a~5aj-(+)-s-~[lll~-Biphenyl)-4-yl]methoxy]-
2-thexahydro-1,4 oxazepin-4-yl)-3-hydroxycyclopentane-
propanal, from Intermediate 9r. IR (CHBr3)
3580, 2730,-1720 cm
s) (1~,2~,3a,5a)-(+)-3-Hydroxy~5-~[4'-methoxy(l,l'-
biphenyl)-4-yl]methoxy]-2-(1-piperidinyl)cyclopentane-
propanal, from Intermediate 9s. IR ~CHBr3)
3520~ 2730, 1720 cm~
t) (la~2~,3a~5~)-(-)-5-[3-[~ Biphenyl)-4-yl3-
~ropoxy~-3-hydroxy-2-(4-morpholinyl)cyclopentane-
propanal, from Intermediate 9t. IR (CHBr
3580, 2?30, 1723 cm
u) (la,2~,3a,5a)-(+)-~3-Hydroxy-5-[~3'-methoxy(l,l'-
biphenyl)-4-yl]methoxy]-2-(4-morpholinyl)]cyclo-
pentanepropanal~ from Intermediate 9u. IR
,
(CHBr3) 3580, 2720, 1720 cm ~L
V )
enyl)-3-yl]methoxy~-2-(4-morpholin ~ yclo-
pentanepropanal, ~rom Intermediate 9v. IR
(C~IBr3) 3560, 2720, 1720 cm 1
Intermedlate 11
(1~,2R,3~,5~ 3-Hyclroxy-5-[4-methoxytph~ lme h~
2-(4-morpholinyl)cyclopentanepropanal
Prepared as an oil from Intermediate 4b according
to the methods described for Intermediates 5 and

- 33 -
6. IR (Neat) 3380(br.), 2720, 1720, 1118 cm 1
Intermediate 12
a~ ~la(Z),2~,3,5a~-t-)-7-[5-[(l~ Biphenyl)-,
4-yl~methoxy]-3-hydroxy-2-(4-morpholinyl)cyclopentyl]-
4-heptenoic acid
To an intimate mixture of potassium tert-butoxide
(1.29g) and (3-carboxypropyl)triphenylphosphonium
bromide (2041g) under nitrogen was added dry
THF (50 ml). The suspension formed was stirred
for 30 min whereupon a solution of the free
base of Intermediate 6 (1.18g) in dry TMF (50
ml) was added dropwise. Stirring was maintained
for 1.5h whereupon water was added and all
organic solvents were evaporated. The pH of
the remaining suspension was adjusted to 10
with 2N NaOH solution and the suspension was
then extracted with EA to remove phosphorus
contaminants. The pH-was then adjusted to
about 6.5 with phosphate buffer and the product
extracted from the suspension with EA. The
dried extracts were filtered and concentrated
to give the title compound as a foam (0.93g).
IR (CHBr3) 3460, 1710 cm 1
Hydrochloride salt
To a solution of Intermediate 12a (0.25g) in
EA (5 ml~ was added ethereal hydrogen chloride
until no more cloudiness was produced. The
solvents were decanted and the resulting oil
repeatedly washed with dry ER to give a powder
3b (0.13g), m.p. 125.5 - 126.5.
Methanesul~honate salt
To a sollltion oE Intermediate 12a (O.O~g)
in EA (2 ml) was added methanesulphonic acid
(Q.Olg) at 20 and the mixture stirred for
35 ' lh. The solid was filtered off, washed with '
EA and dried. Recrystallisation,,~rom ethanol
' gave material of m.p. 171-174.
The follow;ng compounds were prepared ~y a
.
:, :
.. , - ,
'

~ ~73~3V
- 34 -
similar procedure:
b) [la(7,),2~,3a,5a]~ 7-[3-Hydroxy-2-~4-morpho]inyl)-
5-(2-naphthalenylmethoxy)cyclopentyl]-4-heptenoic
acid, from Intermediate lOa. Purification
by chromatography using 85:15 ER-methanol as
eluent. IR (Neat) 3450-2300(br.), I715 cm 1
c) ~la(Z),2~,3a,5a]-(+)-7-[3-Hydroxy-5-~4-methoxy-
(phenylmethoxy)~-2-(4-morpholinyl)cyclopentyl]-
4-heptenoic acid, from Intermediate 11. Purifica~ion
by chromatography using 95:5 CHC13-methanol
as eluent. IR (CHBr3) 3580, 3500, 1720, 1710
cm 1
d) [la(Z),2~;3a,5a]-(+)-7-[3-Hydroxy-5-[4~(1,1-
dimethylethyl)phenylmethoxy]-2-(4-morpholinyl)-
cyclopentyl]-4-heptenoic acid, from Intermediat-e
lOb.
Purification by chromatography using 9:1 ER-
methanol as eluent. IR (CHBr3) 3500, 1740,
1710 cm~1
e) [la(Z),2~,3a,5a]-(-)-7-[5-(4-Cyclohexylphenyl-
methoxy)-3-hydroxy-2-(4-morpholinyl)cyclopentyl]-
4-heptenoic acid, from Intermediate lOc. IR
(CHBr3) 3500, 1720, 1708 cm
f) [la(Z),2~,3a,5a]-(~)-7-[3-Hydroxy-2-(4-morpholinyl)-
~ 5-(pentyloxy)cyclopen~y~-4-heptenoic acid,
from Intermediate lOd. Purification by chromato-
graphy using acetone as eluent.
g) [la(Z),2~,3a,5à]-t-)-7-E3-~Iydroxy-2-(4-morpholinyl)-
~ ~DY~ ~ lmethoxy]cyclopentyl]-
~-h~te ~ , rom Intermediate lOe. Puriei-
cation by chromatography using 4:1 ~R-methanol
as eluent.
h) _a(Z),2~,3a,5a~ ( ~ 1'-
hiphenyl)-~-yllmethoxyl-3 ~,"~ox _
cyclopentyl]-~-heptenoic ac;d, from Intermedia~e
10. Purific~tion by chromatography using
CHC13 through to 96:4 CHC13-methanol as eluent.
IR (CHBr3) 3500, 1710 cm
. - , . . .

~ 17383~
- 35 -
i) [la(z~,2~3a,5a]-(+)-7-[3-Hydroxy-2-(4-morpholinyl)
enyloxy)cyclopentyl]-4-heptenoic acid,
from Intermediate lOg. Purification by chromato-
graphy using 9:1 ER-methanol as eluent. IR
(CHBr3) 3500, 1740-1710(br.) cm 1
j) ~la(Z),2~,3a,5a]-(~)~7-~3~Hydroxy-5-[4~methylthio~
(phenylmethoxy)]~2-(4~morpholinyl)cyclopentyl~-
4-heptenoic acid/ from Intermediate lOh. Purifi-
cation by chromatography using 9:1 ER-methanol
as eluent. IR (CHBr3) 3600-3400(br.), 1730~sh.),
1710 cm~l
k) [l~(Z),2~,3~,5~]-(+)-7-[3-Hydroxy-2~(4~morpholinyl)~
5~~(4~thien~2-yl)phenylmethoxy]c~ pentyll-
4-heptenoic acid, from Intermediate lOi. Purifi-
cation by chromatography using CHC13 through
to 94:6 CHC13~methanol as eluent. IR (CHBr3)
3500, 1738, 1710~cm 1
1) ~la(z)~2~3a~5a]-(+)-7-~3-Hydroxy-2-(4~morpholinyl)-
5-[~(1,1':4,1"-terphenyl)-4-yl]methoxy]cyclopentyl~-
4-h~ptenoic acid, from Intermediate lOj. IR
(CHBr3) 3500, 1720 cm 1
m) ~l~(z)~2~3a~5a]-(+)-9~~5-~[(~ -Biphenyl)~
4~yl]methoxy]~3~hydroxy-2-(4-morpholinyl)cyclopentyl]-
6-nonenoic acid, from Intermediate 6 and (5-
carboxypentyl)triphenylphosphonium bromide.
IR (CHBr3), 3510, 1730 (Sh.), 1710 cm 1
o) [ 1~ (Z ), 2~, 3a, 5~ (E) ] - (+) -7-~3-Hydroxy-2~(4-
morpholinyl)-5-~(3~phenyl-2-propenyl)oxy]cyclopentyl]-
4-he_tenoic ac`id, from Intermediate 101. Purifi-
cation by chromatography using 9:1 ether-methanol
as eluent. IR ~cllBr3) 3500, 1720 cm~
p) ~lnlz~,2~3 ~ -7 [5-[[l, ~
vl]mg~b~K~1-3~ thiomorpholinyl)-
~ ~ 1-4-h~E~enoic aaid, from Intermediate
lOm. IR ~CHBr3) 3S00, 1730, 17:lO cm 1
.

- 36 ~
q) [la(Z),2~,3,5]~ )-7-[3-Hydroxy-5-~[4'-methoxy-
(l,l'-biphenyl)-4-yl]methox ~-2-(4-thio~orpholinyl)-
cyclopentyl]-4-heptenoic acid, S-dioxide, m.p.
113-115 from Intermediate lOn. Purification
by chromatography using 98:2 through to 96:4
ER-methanol as eluent.
r) ~la(~),2~,3a,5a]-(+)-7-~3-Hydroxy-5-[~4'-methyl-
(l,l'-biphenyl)-4-yl]methoxy]-2-(4-thiomorpholinyl)
cyclopentyl]-4 heptenoic acid, S-d1oxide, m.p.
119.5-121.5 from Intermediate lOo.
s) [l(Z),_~,3a,5a]-(-)-7-[3-Hydroxy-5-~4-(phenylmethyl)-
phenylmethoxy]-2-(4-thiomorpholinyl)cyclopentyl]-
4-heptenoic acid, S-dioxide, m.p. 127.5-128.5
from Intermediate lOp. Purification by chromato-
graphy using 96:4 RR-methanol as eluent
.~ t) [la(Z),2~,3a,5]-(-)-7-~5-[[(1,1'-Biphenyl)-
4-yl]methoxy]-3-hydroxy-2-(4-thiomorpholinyl)cyclo--
pentyl]-4-heptenoic acid, S-dioxicde, m.p. 109.5-111.5
from Intermediate lOq. Purification by chromato-
graphy using 9~:2 ER-methanol as eluent.
u) [la(Z),2~,3a,5a]-(+)-7-[5-[[(1,1'-Bipheny~)-
4-yl]methoxy}-2-!hexahYdro-1,4-oxazepin-4-yl)-
3-hydroxycyclopentyl]-4-heptenoic acid, from
Intermediate lOr. TLC (SiO2) 3:1 ER-methanol
Rf 0.29.
v) [la(Z),2~,3a,5a]-(+)-7-[3-Hydroxy-5-[[4'-methoxy-
(l,l'-biphenyl?-4-yl]-methoxy3-2-(1-piperidinyl)-
cyclopentyl]-4-heptenoic acid, compound with
~ zlne (2:1), m.p. 106-112 from Intermediate
lOs. The title ~ crystallised from
a solution o~ the acid and piperazine in 2-1
EA-ER.
w) [l l~ ~ a,5~ 7-[5-[3-[(1,1'-Biphenyl)-
~ rpholi ~ ~ 1-
4-heptenoic acid, ~rom Intermediate lOt.
Purification by chromatography using 5:1 EA-
methanol as eluent. TLC 5:1 EA-methanol Rf
0.3.

1 ~3~3~)
- 37 -
x) [la(Z),26,3~,5a]-(+)-7-~3-Hydroxy-5-[[3'-methQxy-
~ biphenyl)-4-yl~-mèthoxy]-2-(4-mo-rpholinyl)
cyclopentyl]-4-heptenoic acid, from Intermediate
lOu. IR (CHBr3) 3500, 1725(sh.), 1710 cm 1.
y) [la(Z),2~,3a,5~]-(+)-7-[3-HydroxY-5-[[4'-methoxy-
(l,l'-biphenyl)-3-yl]-methoxy~-2-~4-morpholinyl)-
cyclopentyl~-4-heptenoic ac}d, from Intermediate
lOv. IR (CHBr3) 3500, 1735 (sh.), 1710 cm 1.
z) [la(Z),2~,3~,5]-(+?-7-[5-Decyloxy-3-hydroxy-
2-(4-mor~ olinyl)cyclopentyl]-4-heptenoic acid,
from Intermediate 17d. IR (CHBr3) 3500, 1725(sh),
1710cm~l.
Intermediate 13
[1Q (Z) ,2~3a~5a]-(~)-8-[5-[[(~ -Biphenyl)-4-yl]methoxy]
3-hydroxY-2-(4-morpholinyl)cyclopentyl]-5-octenoic acid
Prepared from Intermediate 6 (19) and (4-carboxy-
butyl)triphenylphosphonium bromide (3.17 g) in an
analogous manner to that described for Intermediate
;~ 12a. The title compound was isolated as a foam ~0.92 9).
IR (CHBr3) 3500, 1740, 1705 cm
Intermediate 14
[la(Z),2~,3a,5a~ )-Methyl 7-[5-~[1,1'-Biphenyl)-
4-yl]methoxy]-3-hydroxy-2-(4-morpholinyl)cyclopentyl]-
4-heptenoate
A solution of Intermediate 12a (0.7g) in 9:1
methanol-H2S04 (20 ml) was stirred at room temperature
for 2h. Solid NaHCO3 was added until pH 7.5-8, followed
by water and extraction with ER. The combined extracts
were dried, filtered and evaporated to give the title
~E~nd as an oil (O.S~g). LR (C~lBr3) 3580-3510, 1730 cm~ .
IntermecliAte lS
___~ ~ lphenyl)~4-yl]-
methoxyl-3-(4 morpholillyl)-2-oxabicyclo[3.2.1~octan-
3-one
Zinc bromide (27g) in dry THF (lBOml) was stirred
under nitrogen at 15-20 during the addition oE p-
methylphenylmagnesium bromide ~prepared in ether
(160ml) from Mg ~3.24`y) and 4-bromotoluene t20.52g~].
The mixture was stirred at 20 for 2h.

~~ ~
3 ~ ~ ~
- 38 -
Nickel acetylacetonate (1.8g) and triphenylphosphine
(7.34g) were taken into THF (40ml) and stirred under
nitrogen during the addition of DIBAL (lM in hexane,
7ml). After 5 min. Intermediate 72 (~.75g) in THF
(65ml) was added followed, after a further 5 min.
by the organozinc reagent. The mixture was then
stirred at 22 for 30h, whereupon saturated NH4Cl
solution (500ml) and EA (300ml) were added. The
aqueous solution was adjusted to pH 5-6 with 2N hydro-
chloric acid and the layers separated. The aqueoussolution was extracted with EA and the combined extracts
dried and evaporated. The residue was chromatographed
- on silica using 7:3 through to 9:1 EA-PE (b.p. 60-80)
as eluent to give ~he title compound (3.19) as prisms,
m.~. 141-144.
Intermediate 16
(la,2R,3a,5a)-(+)-3-Hydroxy-5-~[4'-methyl(l,l'-biphenyl)
4-yl~methoxy]-2-(~-morpho~in~l)cyclopentane acetaldehyde
A stirred solution of Intermediate 15 (4.59)
in dry CH2C12 (75ml) at -75 under nitrogen was treated
with DIBAL (1.43M in hexane, 17.4ml). Stirr~ng was
continued for lh, whereupon methanol (75ml) was carefully
added and the temperature allowed to rise to ambient.
After 17h, the mixture was filtered and the ~iltrate
evaporated to give the title compound as a foam (4.63g).
TLC 9:1 E~-methanol Rf 0.35.
.. ..
Intermediate 17
(la,2~,3a,5a)-(+)-3-Hydroxy-5-[[4'-methyl(l,l'-
_iphenyl)-4~yllrnethoxy]~2-(4-morpholinyl)cyclo
pentanepropanal
To a stirred solution oE potassium t~butoxide
(3.899) in dry THF ~ ml) at ~5Q was added (methoxy~
methyl)triphenylphosphonium chloride tll.89g) portionwise
over 15 min. A~ter stir~ing ~or 30 rnin. at ~5 to
0 a solution o~ Intermediate 16 (4.039) in dry THF
(35ml) was added. The mixture was stirred at 5
for 15 min. and then at 20 for 1.75h, quenched with
water (,ml) and the solvents rernoved ln vacuo. The

~ 17383~
- 39 -
residue was then treated with 2N hydrochloric acid
(20ml) in acetone (50ml) at 20 for 3.5h. Aqueous
Na2C03 was added to give a solution of pH 8 which
was then diluted with water (lOOml) and extracted
with EA (3 x 75ml). The combined extracts were dried
and evaporated and the residue chromatographed ~n
silica (400g) using 97:3 through to 9:1 EA-methanol
as eluent to give the title compound as an oil (4.33g).
IR (Neat) 3400(br.), 1720 cm 1.
The following compounds were prepare~ by a
similar procedure:
b) (la,2a!3a,5a)-(+)-5-~[1,1'-Biphenyl)-4-yl]methoxy~-
- 3-hydroxy-2-(4-morpholinyl)cyclopentanepropanal,
m.p. 114-116 from Intermediate 4c.
c) (1~,2~,3a,5a)-(-)-5-[[1,1' Biphenyl~-4-yl]methoxy]-
3-hydroxy-2-(1-piperidinyl)cyclopentanepropanal,
from Intermediate 4e. IR (CHBr3~ 3500-3400(br.),
1718 cm 1.
d) (la,2~,3a,5~ )-5-Decyloxy-3-hydroxy-2-(4-
morpholinyl)cyclopentanepropanal~ from intermediate
- 49. Purification by chromatography us1ng EA
through to 95:5 EA-methanol as eluents IR (Neat)
3530, 1723 cm 1.
Intermediate 18
Ela (z) ,2~,3a,5a]-(+)-7-[3-Hydroxy-5-~[4'-methyl!l,l'-
phenyl)-4-yl]methoxy3-2-(4-morpholinyl)cyclopent
4-heptenoic acid
(3-Carboxypropyl)triphenylphosphonium bromide
(12.99) was added to a solution of potassium t-butoxide
~0 (6.739) in dry T~IF (170ml) and the res;lltant suspension
stirred at 20 ~or 35 min. A solution of Intermediate
17a ~4.23~) in THF (40ml) was added and stirring
continued a~ 20 ~or 2h. Water (5ml) was then added,
the solvent removed in vacuo and the residue taken
into water (300ml) and adjusted to pH 12 with 2N
NaOH Non-acidic material was extracted with EA
(2 x lOOml) and the aqueous solution then re-adjusted
to pH 6.5 with 2N hydrochloric acid. This solutio
was extracted with EA (3 x lOOml) and the combined
extracts dried and evaporated to give the tl e

~ 173830
- ~o - .
as an oil (3.97g). IR (CHBr3) 3580, 3500, 1720, 1710 cm 1
Intermediate 19
(1,2~3~,5~)-(+)-4-~3-~[4'-Methoxy(l,l'-biphenyl)-
4-yl]methoxy]-2--(3-methoxy-2-propenyl)-5-[(tetrahydr
2H-pyran~2-yl)oxy]cyclopentyl]morpholine
NaH (74% dispersion in oil, 316mg) was added
to a solution of Intermediate 8 (l.llg) and 4-(bromomethyl)-
4'-methoxy(l,l'-biphenyl) (2.86g) in dry DMF (15ml)
under nitrogen at 0. The mixture was stirred at
room temperature for 2h whereupon NaH (74~r 52mg)
was added and the stirring continued for lh. The
mixture was poured into aqueous NH4Cl (150ml) and
extracted with CHC13 (4 x 60ml). The dried organic
layers were evaporated and the residue chromatographed
on silica (400g) using 8:2 ER-PE (b.p. 60-80) through
to ER as eluent to give the title Gompound as an
oil (1.17g)~ IR (CHBr3) 1675, 1245 cm
Intermediate 20
(la,2~,3a,5a)-(+)-~3-Hy.droxy-5-r~4'-methoxy(l,l'-
biphenyl)-4-yl]methoxy]-2-(4-morpholinyl)cyclopentanepropana
A solution of Intermediate 19 (2.99gj in 2~
hydrochloric acid (25ml), acetone (50ml) and CH2C12
(7ml) was s~tirred for 30 min. The mixture was poured
into 8% NaHC03 solution (200ml) and extracted with
C~2C12 (3 x 85ml~. The dried organic layers were
evaporated and the residue chromatographed on silica
(lOOg) using ER through to 4:1 ER-methanol as eluent
to give the title compound as an oil (2.099). IR
(CHBr3) 3600-3500(br.~, 2725, 1720 cm
Intermediate 21
~ 2~ ~ _4 ~ 1,1'~
biphenyl)-4-yl~methoxy]-2-(4-morpholinYl)cyclopentyll~
~-heptenoic acid
(4-Carboxypropyl)triphenylphosphonium bromide
~3.99) and potassiumn t-butoxide (2.049) in dry THF
(9Oml) were stirred at room temperature for 15 min.
A solution of Intermediate 20 (29) in dry THF (40ml)
was added and the mixture stirred for 2h. Water
(30ml) was added and the solvent evaporated. The

~ 1738.~ .
residue was poured into 0.3N NaOH (150ml) and washed
with EA. The basic layer was neutralised by the
dropwise addition of 5N hydrochloric acid and then
extracted with CH2C12 (70ml). The pH was adjusted
to 6.5 and the aqueous layer re-extracted with CH2C12
(70ml). The combined CH2C12 layers were dried and
evaporated to give the title compound as a foam (1.669).
IR (CHBr3) 3590, 3500, 1720 cm 1.
Intermedi_te 22
10 a) _ethyl 4-(Thien-2-~l)benzoate
The Grignard reagent from 2-bromothiophene
(17.5g) and Mg (2.7g) in dry ER (200ml~ was
added to a stirred solution of anhydrous ZnBr2
(22.5g) in dry THF (200mll at 5.
Simultaneously a solution of bis(,triphenyl-
phosphine)palladium (II) dichloride (lg) in
THF (200ml) was treated with ~IBAL in hexane
(1.43M, 2ml) at room temperature un~er nitrogen.
After 5 min a solution of methyl p-bromobenzoate
(5g) in ER (50ml) was added followed after a further
' 5 min by the organozinc reagent descri~ed
above. The mixt,ure was stirred at room temperature
for 18h and then poured into NH4Cl solution
and extracted with EA. The combined extracts
were dried and evaporated, and the residue
chromatographed on silica using 1:20 through
to 1:1 EA-PE as eluent. The title compound
was further purified by crystallisation from
PE (b.p. 60-80) (2.8g), m.p. 1~1-142.
Th,e following compound was prepared in
a ~imilar manner:
b) Mcl~y~ MLtt:~y_l,lt bi~ _ nyl)-~-carboxylate,
m.p. 52-54 from 3-bromoanisole and methyl p-
bromobenzoate uslng the catalyst prepared
from DIBAL, nickel acetylacetonate and triphenyl-
phosphine. The product was purified by chroma~o-
graphy using 1:4 EA-PE (b.p. 60-80) as eluent.
Intermediate 23
a) 4-(Thi ~ enzene methanol

~ 1 7~3~
- 42 -
To a stirred suspension of LiAlH4 (2.28g)
in THF ~200ml) at room temperature was added
dropwise a solution of Intermediate 22a) (6.69)
in THF (SOml). The mixture was heated under
S reflux for 2h and then stirred at room temperature
for 16h. EA (lOml) was careflly added, followed
by 2N hydrochloric acid (lOOml). The THF was
removed in vacuo and the residue extracted
with ER. The combined extracts were dried,
filtered and concentrated. Crystallisation
of the residue from cyclohexane gave the title
compound (4.5g) as plates, m.p. 115.
The following compounds were prepared in
a similar manner:
b) 3-E(~ -Biphenyl)-4-yl]propanol~ m.p. 73-74
; from 3-~ biphellyl)-4-yl~propanoic acid.
c) [3'-Methoxy(l,l'-biphenyl)-4-yl]methanol~ from
Intermediate 22b. TLC EA Rf. 0.6.
Intermediate 24
a) 2-(4-Bromomethylphenyl)thiophene
A solution of Intermediate 23a (4.3g) in
dry CH2C12 (80ml) was treated with a solution
of PBr3 (2.15ml~ in CH2C12 (20ml) and the mixture
stirred for lh. 10% NaHC03 solution (lOOml)
was added, the organic phase separated, and
the a~ueous phase fur~her extracted with CM2C12.
The combined organic phase was driedr filtered
and concentratèd to give the title compound
(4.6g) as a solid, m.p. 80-100.
The ~ollowing compounds were prepared by
a similar procedure:
b) 4-Brornomethyl(1,1l:4',1")terphenyl, m.p. 213-215
from 4-[(l,~ ")terphenyllmethanol.
c) 4-Bromome~ l 3' ~ , from
Intermediate 23c. TLC ER Rf 0.58.
Inter.med;ate 25
a) [la(E),2~,3,5a]-(~)-7-~3-Hydroxy-5-[[4'-methyl(l,l'-
biphenyl)-4-yl]methoxv]-2-(4-mor~ho]i~ cyclopentyl]-
_ _ _

~ ~38~
- 43 -
4-heptenoic acid
A solution of Intermediate 18 (1.32g) and
p-toluene sulphinic acid ~0.639) in dry 1,4-
dioxan (60ml) was heated under refl~x in a
nitrogen atomosphere for 3.5h. The mixture
was diluted with EA (80ml), washed with pH 6
phosphate buffer (50ml~, dried and evaporated.
The residue was chromatographed on silica using
9:1 EA-methanol as eluent to give the title
compound as an oil, which on trituration with
ER crystallised (0.639), m.p. 108-111.
The following compounds was prepared in
a similar manner: -
b) ~la~E),2~,3a,5a]-(~)-7-~5-[[~1;1'-Biphenyl)-
4-yl]methoxy]-3-hydroxy-2-(4-rnorpholinyl)cyclopentyl]-
4-hepteno~c acidl from Intermediate 12a. Purifi-
; cation by chromatography using 9:1 EA-methanol
as eluent. TLC 85:15 ER-methanol Rf
0.24.
Intermediate 26
~la(Z),2~,3a,5a]-(~)-7-[5-[[1,1'-Biphenyl)-4-yl]methoxy]-
3-hydroxy-2-(4-morpholinyl)cyclopentyl]-4-hepten
A solution of Intermediate 12a (lg) in dry
THF (lOml) was added dropwise under nitrogen to a
stirred suspension of LiAlH4 (0.169) in dry T~F (lOml~
and the mixture heated under reflux for 2h. After
cooling 1:1 water in THF (lOml) was added followed
by 5N NaOH (lOml) and the mixture extracted with
EA (3 x 20ml)~ The combined extracts were dried,
concentrated and the residue chromatographed on silica
~lsing 95:5 ~R-methanol as eluent to give an oil which
slowl~ crystallised (0.71g). Recrystallisation from
~R~isopentane gave the title com ~ o~ m.p. 70-71.5.
Intermediate ?7
~anti,endo,endo)~ 7-(4-Mor
2H-pyran-2 yl)oxyl~ lo~2.2.1]heptan-2-ol
NaBH~ (2 29) was added in portions to a stirred
solution o IntermedLate 69 (17q) in dry methanol
,'
,
.
, .
.. . .

~ 1~38'3(~
- 44 -
t250ml) at 0. After 30 min the mixt~re was poured
into saturated NH4Cl solution (350ml) and extracted
with ER (3 x 200ml). The combined extracts were
dried, filtered and concentrated to give the title
compound as a foam (17.5g). IR (Neat) 3440(br.), 1120
Cm~l
Intermediate 28
(endo,syn,endo)-(+)-5-[[(l,l'-Biphenyl)-4-yl~methoxy]
7-(4-morpholinyl)bicyclo~2.2.1]heptan-2-ol
A solution of Intermediate 2c (20.1g) in 10%
concentrated H2SO~ in methanol (60ml) was stood at
room temperature for lh. The solution was neutralised
with solid NaHC03 and extracted with CH2C12 (3 x 2~0ml).
The combined extracts were dried, filtered and concentrated
lS to give the title compound as a solid (179), m.p.
138-140.
Intermediate 29
(endo,syn)-(+)~5-~ E (l~l~-Biphenyl)-4-yl]methoxy]
7-(4-morpholinyl)bicyclo~2.2.1]heptan-2-one
A mixture of dry dimethylsulphoxide (13.5ml)
and dry CH2C12 (50ml) was added under nitrogen to
a solution of oxalyl chloride (15.2ml) in dry CH2C12
(25ml) at -78 and the resultant activated cornplex
stirred for 15 min. A solution of Intermediate 28
(15g) in dry C~2C12 (50ml) was added dropwise and
stirring continued for 5h. Triethylamine (55.lml)
in dry CH2C12 (50ml) was added dropwise and the mixture
was then allowed to reach room temperature wi~h further
stirring for 1.5h. Water (350ml) was added and the
solution extracte~d with CH2C12 (3 x 200ml). The
combined extracts were dried, Eiltered and evaporated
and the resid-le chromatographed on sillca using ER
as eluent. The title ~ wa5 obtained as a
solid Which was further purified by crystallisation
from EA-PE (b~p. 60-80) to glve material (6.67g)
of m.p. 164-165.

.~! .l 738
- 45 -
Intermediate 30
(endo,syn)-(+ _6-[[(l,l'-Biphenyl)-4-yllmethoxy]-
8-(4-morpholinyl)-2-oxabicyclo[3.2.1]octan-3-one
Peracetic acid (4.33ml, 6.12 M) was added dropwise
to a mixture of Intermediate 29 (29), sodium acetate
(2.179~, acetic acid (20ml) and water (lOml) at 0.
After stirring for 6 days a further quantity of peracetic
acid (0.87ml) was added and stirring continued for
24h. Na2S03 was added to destroy excess oxidising
agent and the mixture was then evaporated to dryness.
The residue was neutralised with 8% NaHC03 solution
and extracted with EA (3 x 75ml). The combined extracts
were dried, filtered and evaporated and the residue
chromatographed on silica using 1:1 ER-CH2C12 as
eluent to give the title compound as a solid (1.59),
m.p. 244-246~.
Intermediate 31
~la(Z),2,3~,5a]-(-)-Methyl 7-~5-[~1,1'-Biphenylj-
4-yl]methoxv]-3-hydroxy-2-(4-morpholinyl)cyclopentyl]-
4-heptenoate
Prepared as an oil from Intermediate lia according
to the methods described for Intermediates 12a and
14. IR (Neat) 3440 (br), 1730 cm l
Intermediate 32
E la(Z),2~,3~,5a]-(+)-Methyl 7-~3-(Acetyloxy)-5-[[(l,l'-
biphenyl)-4-yl]methoxy]-2-(4-morpholinyl)cyclopentyl]-
-heptenoate
A solution of Intermediate 31 (1.2g) and acetic
anhydride (2ml) in pyridine (lOml) was heatecl at
~5 ~or 18h. The mixture was diluted with }~R (50ml)
and therl wa~he~ with ~ Na~lC03 solution (150ml).
The aqueous solution was re-e~tracted with F.R (lOOml) and
khe combined orqanic phase dried and concentrated. The
residue was chromato~raphed on ~ilica using ~R as
eluent to give the title compound as an oil (0.85q).
IR (CHBr3) 1742 cm l.

3~
- 46 - -
- Intermediaté 33
a) [l(Z~,2a,3N,5~]~ 7-[5-[[(1~ Biphenyl)-
4-yl]methoxy]-3-hydroxy-2-(4-morpholinyl)cyclopentyl]-
4-heptenoic acid
A solution of Intermediate 32 tO.83g) in
methanol (30ml) containing 2N ~aOH (5ml) was
allowed to stand at room ternperature for 2
days. pH 6.5 Buffer (made from 2:3 KH2P04:Na2HP04)
(30ml) was added and the solution extracted
with CH2C12 12 x 50ml). The combined extracts
were dried and concentrated and the residue
purified from CH2C12-PE (b.p. 60-80) to give
the title compound (0.61g), m.p. 163-165.
The following compound was prepared in
a similar manner:
b) [l~(Z) ,2~,3a,5a]-( - )-7-[5-[[(1,1'-Biphenyl)-
4-yl]methoxy]-3-hydroxy-2-(l-piperidinyl)c~clopent
4-heptenoic acid, from Intermediate 58. IR
(CHBr3) 3500, 1700, 1598 cm
Intermediate 34
[la(Z),2~,3~,5a]-(~)-7-[5-[[1,1'-Biphenyl~-4'yl]methoxy]-
3-hydroxy-2-(4-morpholinyl)cyclopentyl]-4-heptenoic
acid
A stirred solution of lithium tri-sec-butylboro-
hydride in THF (12ml, 1 M) under nitrogen at -28
was treated slowly dropwise with a solution of Example
la (0~6g) in dry THF (12ml). After 3h the mixture
' was poured into 2N ~2SO~ (20mll and pH 6.5 phosphate
bu~fer (SOml) and washed with ER (1 x lSOml, 1 x SOml).
The a~ueous layer was adjusted to pH 6.5 with ~N NaOH
and extracted with EA (2 x lOOml). The combine~
extracts were dried and evaporated, and the residue
chromatograph~d on silica using 4:1 ~A-methanol as
eluent to give the title ~ as a foarn (0.359).
3S TLC (SiO~ 20:79 Acetic acid methanol EA Rf 0.17.
Intermediates 3S"~and 36
_S,endo)~ Bicyclo[3.2.0]hept-2-en-6-ol (
(lR,exo)-(-)-Bicyclo~3.2.0~hept-2-en-6-ol (3~)
:: ; ~ ' '

~ 173~0
- 47 -
Bakers yeast (6kg) and glucose (2.5kg) in water
~24 1) was stirred at 25 for 2h. (+)-Bicyclo[3.2.0~hept-
2-en-6-one (120g) was added dropwise over 30 min.
Stirring was maintained for 2.5h whereupon a further
quantity of glucose (3.5kg) and water (4 1) was added.
This addition was repeated after 20h and 26h, glucose
(4.5kg) and water (5 1) being added on each occasion.
The reaction mixture was distilled at atmospheric
pressure to give about 11 1 of aqueous ethanol containing
10- starting material and some product-FRACTION A. Then
a steam distillation of the remaining reaction mixture
gave 36 1 of aqueous distillate which was salted
(7.25kg) and extracted with CH2C12(3 x 10 1). The
CH2C12 was distilled at atmospheric pressure through
a helix filled column (93 x 5cm) to leave a residue
(about 400ml)-E~RACTION B. FRACTION A was concen-trated
by distilling off most of the solvent through a helix
fille~ column (50 x 3cm). The residue was salted
and extracted into CH2C12-FRACTION C.
Fractions B and C were combined, dried and
the solvent was removed at atmospheric pressure to
Ieave a residue (55g) which was distilled at 120C
and 15 mm~g pressure to give an oil (39.8g). This
material was chromatographed on silica using 1:4
ether:isopentane as eluent to give the title compound
as ethereal solutions after removal of most the solvent.
Intermediate 3S (26.8g) 64.5% w/w in ether.
Intermediate 36 ~33.4g) 30.4% w/w in ether.
The bulk of the material was used as above
3n Eor the next stage. However 2ml portions oE the
fiolutions were taken and distilled at atmospheric
pressure in a micro distillation apparatus to give:
Intermediate 35
TLC ~:] PE'-ER Rf 0 3 [~D =-~6.1 (CHC1
Intermediate 36
TLC 4:1 PE-ER Rf 0.2 ~a~26__73.9~ (C~IC13).

~ ~ 7 3 ~
- 48 -
Intermediate 37
[lR-(exo,endo)]-(-)-2-Bromo-3-hydroxybicyclo[3.2.0~heptan-
6-one
To a stirred solution of Intermediate 35 (6.64g)
in acetone (220ml) and water (55ml) was added glacial
acetic acid (0.65ml) and N-bromosuccinimide (43.22g)
and stirring was maintained for 18h~ The mixture
was poured into sodium thiosulphate solution (250ml)
and extracted with ER (2 x 175ml). The organic
layer was washed with 8% NaHC03 solution (150ml),
dried and evaporated and the residue chromatographed
on silica using 1:1 ER-PE as eluent. The title compound
was obtained as a solid which crystallised from CC14
as needles (4.169), m.p. 90-92. [a]2=-60.8 (MeOH).
Intermediate 41
[lR-(endo,anti)]-(+)-5-Hydroxy-7-(4-morpholinyl)bicyclo-
~2.2.1]heptan-2-one
A solution of Intermediate 37 (8.82g) in CH2C12
(85ml) containing morpholine (15ml) was stirred at
room temperature for 20h. The precipitate was filtered
off and washed with CH2C12 (lOOml). The combined
filtrates were washed with NaHC03 solution and water
(75ml each) dried and evaporated to give a semi-solid
which was chromatographed on silica using EA as eluent.
The title compound was obtained as a solid which
crystalli~ed from 1:1 EA-PE (b.p. 60-80) to give
materiàl (6.1g) of m.p. 137-139. Ea]2=~55.73
= (MeOH).
Intermediate 430 [lR-(endo,a ~ ~ ~ [(l,l'-Bipheny`l)-~-yl]methoxy]-
b~y__o[ ~ llheptan-2-one
A mixture Oe Intermediate ~1 (10.459), benzyl
triethylammonium chloride (1.59) and biphenylmethyl
bromide (l5.3g) in C~l2c12 (50ml) was cooled to 0
whilst NaOH (12g) in water (20ml) was added. The
two phases were stirred vigorously ~or 24h at 20.
The mixture was diluted with water (120ml) and extracted
with CH~C12 (3 x lOOml). The combined extracts were

~ 173~30
- 49 -
washed with brine (2 x 50ml), dried'and evaporated,
and the residue triturated with ER (lOOml) to give
a solid (16g). The solid was crystallised from iso-
propyl acetate (120ml) to give the title compound
(9.6g) as platelets, m.p. 138-140. [a]21=+22.~2
(CHC13).
Intermediate 44
~l~-(endo,anti)]-(-)-6-~[(1,1'-Biphenyl)-4-yl]methoxy]-
8-(4-morpholinyl-2-oxabicyclo[3.2.l]octan-3-one
- 10 Peracetic acid (8.7ml, 6.12 M) was added dropwise
to a stirred solution of Intermediate 43 (5g) in
CH2C12 (25ml) at 0. The mixture was stirred for
24h while allowing the temperature to rise to ambient.
20% w/w Na2SO3 in water (60ml) was added dropwise
at 0 and the mixture was stirred at room temperature
for 0.75h. Iso-propyl acetate ~25ml) was added and
the layers were separated. The aqueous layer was
extracted with (1:1) isopropyl acetate-CH2C12
(2 x 25ml), and the combined organic layers were
washed with lN NaOH (2 x s0ml) and brine (50ml) then
dried and evaporated to give a solid (3.3g). The
solid was crystallised from 1:1 EA~PE (80ml) to give
the title compound as prisms (6.9g), m.p. 147-148.
[~]21 5=-26.44O (CHC13).
Intermediate 45
[lR-(lal2~l3~5~)]-5-E~ -Biphenyl)-4-yl]meth
3-hydroxy-2-(4-morpholinyl)cyclopentane acetaldehyde
-~' A solution of Intermediate 44 (3g) in dry CH2C12
(60ml) was cooled t-78) and stirred under nitrogen
whilst a solution of DIB~L in hexane ('10.7ml, 1.43 M)
was added dropwise, Methanol ~60ml) was added dropwise
at -73 and the cooling bath was removed. After
stirring at room temperature for 2h the precipitate
was filtered off and was washed well with methanol.
The combined filtrates were evaporated ln vacuo and '
the residue was d'issolved in CH2C12 (lOOml), dried,
filtered and evaporated to give the title co~pound
as a foam (2.95g). IR ~C~Br3) 3580~ 1718 cm.l.
.

~ ~73~33~3
,
Intermediate 46
~lR-~la~2~3~5~)]-5-~[~ -Biphenyl)-4-yl]methoxy]
3-hydroxy-2-(4-morpholinyl)cyclopentanepropanal
(Methoxymethyl)triphenylphosphonium chloride
(7.15g) was added to a stirred solution of potassium
tert.-butoxide (2.35g) in dry THF (40ml) under nitrogen.
After 15 min a solution of Intermediate 45 ~2.759)
in dry THF (20ml) was added dropwise and stirring
continued for 30 min.
The reaction mixture was poured into 2N hydrochloric
acid (50ml) at 0 and was stirred at 10-15 for 1.5h.
The mixture was adjusted to about pH 10 with saturated
K2C03 solution and extracted with CH2C12 (3 x lOOml).
The combined extracts were washed with brine (l~OOml),
dried and evaporated and the residue chromatographed
on silica using 9:1 EA-methanol as eluent to give
the title compound as a foam (2.47g). TLC 9:1 EA-
methanol Rf 0.3.
Intermediate 47
[lR-~la(Z),2~,3a,5a]]-(+)-7-[5-[ E (l,l'-Biphenyl)-
4-yl]methoxY]-3-hydroxy-2-(4-morpholinyl)cyclopentyl]
4-he tenoic acid hvdrochloride
P ~ ,
Dry THF (9Oml) was added to a stirred mixture
of potassium tert.-butoxide (2.469) and 3-(carboxypropyl)-
triphenylphosphonium bromide (4.6g) under nitrogen.After about'30 min Intermediate 46 (2.259) in dry
THF (50ml) was added dropwise and stirring continued
for 2.5h. Water (25m`1)'was added and most of the
T}IF was removed ln vacuo. The residue in water (50ml)
and 2~ NaO~I (20ml) was extracted with ~A (2 x 50ml).
The aqueous layer was adjustec3 to pT-I 6 with buffer
(lM KH2P0~ 3 parts, lM Na2HP04 1 part) and was extracted
with CH2C12 (3 x 50ml). The combined extracts were
washed with brine, dried and evaporated to give a
foam (2.7g). This material was dissolved in EA (lOOm~)
and treated with an excess of ethereal hydrogen chloride.
After cooling at 0 for 16h the salt was collected
and washed with 1:1 ER-E~ (25ml) followed by .ER (40ml).
Crystalllsation from 5:1 EA-methanol gave the title

1173f3~
.
- 51 -
compound (1.6g) as prisms, m.p. 152-153. [~]D =+54
(CHC13).
Intermediate 51
(endo,anti)-(+)-7-Azido-5-hydroxybicyclo~2.2.1]heptan-
2-one
A solution of (exo,endo)-~+)-3-acetoxy-2-bromobicyclo-
[3.2.0]heptan-6-one (50g? and potassium t-butoxide
(27.25g) in THF (1.5 1) was stirred at -75 for lh.
I'he solution was allowed to warm to 0 and a solution
of sodium azide (16.45g) in water (600 ml) was added
and stirring continued at 20 for 18h.
The t~o layers were separated ancl ether was added
to the organic layer which was washed with water (2x250 ml).
The combined aqueous layers were extracted with ER
(2x250 ml). The combined organic layers were dried
and evaporated to give a gum (28.1g). A solution
of the gum in methanol (225 ml) was stirred with K2CO3
(18.37g) for 3.5h at room temperature. The mixture
was filtered and the ~iltrate was evaporated in vacuo
to give a solid which was taken into ER (150 ml) and
washed with water (150 ml). The aqueous layer was
extracted with ER (3x125 ml) and the combined organic
layers were dried and evaporated to give an oil (24.5g)
which was chromatographed on silica. Elution with
2:1 ER-PE gave an oil (18.7g) which was triturated
with ER to give the title compound as a solid (14.6g),
m.p. 72-74.
Intermediate 52
( a,4~,5,6aa)-(+)-4-~zido-hexahydro-5-hy _ oxy-2H-
~ penta(b)furan-2-one
____
.

:~ ~73~33~
- 52 -
40~ Peracetic acid ~64.35 ml) was added to a
cooled (0) stirred solution of Intermediate 51 (12.9g)
and sodium acetate (31.2g) in acetic acid (155 ml)
and water (15.5 ml) and the resulting solution then
stirred at ambient temperature for 24h. Excess Na2SO3
solution was added to the cooled solution and stirring
continued for lh. After evaporation in vacuo the residue
was dissolved in 5N NaOH solution (400ml) with cooling
and the solution stirred for 0.5h. Concentrated hydrochloric
-acid (30 ml) was added with cooling and the solution
was continuously extracted with CH2C12 (600 mI) for
18h. The organic extracts were washed with 2N Na2CO3
solution (100 ml) and brine (100 ml), dried and evaporated
to give a solid (3.5g). A portion (lg) was recrystallised
15 ~ from ER-PE (b.p. 60-80) to qive the title co'mpound
~816mg), m.p.,73-74.
Intermediate 53
(3aa,4~,5a,6a~)-(+)-4-Azido-hexahydro-5-[(tetrahydro-
2H- ran-2-vl)oxv]-2H-cvclopenta(b)furan-2-one
PY
Dihydropyran (6.1 ml) was added to a cold (-20)
stirred solu'tion of p-toluenesulphonic acid (0.685g)
and I,ntermediate 52 (6.63g) in CH2C12 (35 ml). After
2h at -20 the mixture was poured into 8% NaHCO3 'solution
(300 ml). The organic layer was separated and the
aqueous layer extracted with CH2C12 (3x100 ml). The
combin~èd extracts were washed with brine ~200 ml),
dried and evaporated in vacuo to give an oil (1'3.23g)
which was puri~ied by chromatography on silica. Elution
w;ith 2:~ F~-PF. (b.p~ 60-80) gave the title com~ound
as an oil (5.39g), IR (Neat) 2100, 1780 cm 1.
~nte~mediat 54
-5-[(tet,rahydro-

1 ~7383~
2H-pyran-2-yl)oxy]~2H-cyclopenta(b)furan-2-one
A solution of Intermediate 53 (28.4g) in ethanol
(175 ml) was hydrogenated at atmospheric pressure over
pre-reduced 10~ palladium oxide on charcoal (5.3g)
at 20 for 24h. The mixture was filtered ('Hyflo')
and the filtcate evaporated to give an oil 524.lg).
IR (CHBr3) 3370, 3300, 1762 cm 1.
Intermediate 55
a) (3a~,4~,5~,6aa)-(+)-Hexahydro-5-[(tetrahy~ro-
2H-pyran-2-yl)oxy~-4-(4-thiomorpholinyl)--2H-
cyclopenta(b)furan-2-one
,
A mixture of Intermediate 54 (6g), anhydrous
NaHCO3 (5.2g), NaI (9.72g) and bis-(2-chloroethyl)-
sulphide (5.15g) in acetonitrile (250 ml) was
' 15 heated under reflux for 18h. The solvent was
removed in vacuo and the residue in water (200 ml)
was extracted with EA (4x200 ml~. The combined
extracts were washed with brine (200 ml), dried
and evaporated to give an oi~ (10.2g) which
was purified by chromatography on silica.
Elution with ER and then 3:97 methanol-~R gave
a solid (4.89). A~portion was crystallised
from ER-PE to give the title 'compound, m.p.
83-84.
The following compound was prepared in a sirnilar
manner:
b) (3aa,4a,5B,6aa)-(+)-4-(hexahydro-1,4-oxazepin-
4-yl)-5-[(tetr`ahydro-2H-pyran-2-yl)oxy]-2H-
cyclopenta(b)Euran-2-one, m.p. 68.5-72.5 from
Intermediate 5~. Puri~ication by chrormatography
using 35:15 E'R-methanol as eluent.
In ~
(anti enclo)-(~)-7-(1~ erld ~ (tet ~ dro-
Piperidine (6~.1 ml) was adcled c3ropwise to a
solution oE (exo,~endo)-(~)-2-bromo-3-[(tetrahydro-
2H-pyran-2-yl)oxy]bicyclo~3.2.0]heptan-6-one (759)
in high purity acetone (250 ml) at 0. The ~ixture was

~ ~J383l~
stirred in the dark for 24h and then filtered. The
filtrate was washed with water ~2x150 ml), and the
aqueous solution extracted with ER ~3 x 200 ml). The
combined organic layers were dried, filtered and~evaporated
to give the title compound as an oil (77.2g).
TLC 7:3 ER-PE Rf 0.18.
Intermediate 57
(endo,anti)-(+)-5-Hydroxy-7-(1-piperidinyl)bicyclo[2.2.1]-
heptan-2-one, hydrochloride
Ethereal hydrogen chloride (20 ml) was added
dropwise to a solution o~ Intermediate 56 ~77.2g) in
methanol (300 ml) at 0. After stirring for 1.5h at
room temperature the'solvent was removed in vacuo,
and the residue triturated with iso-propanol to give
the title compound as a solid (52g), m.p. 246-248.
Intermediate 58
[la(Z),2~,3a,5a]-(+)-Methyl 7-[5-~[(1,1'-Biphenyl)-
~4-yl]methoxy]-3-hydroxy-2-(1-piperidinyl)cyclopentyl]-
4-heptenoate
Prepared as an oil from Intermediate 17c according
to the methods described for Intermediates l~a and
14. Purification by chromatography using 9:1 EA-methanol
as eluent. IR (CHBr3) 3520, 1725 cm
Intermediate 5g
a) (la,2a,3~,4a)-( )-2-(3-Methoxy-2-propenyl)-
4-[(tetrahydro-2R-pyran-2-yl)oxy]-3-~4-thiomorpho-
linyl)-cyclopentanol~ S-dioxide
h solution of I~ntermediate 7b (12.lg) in methanol
(80 ml) containing lN NaOH (60 ml) was stirred
at room temperatur'e for Sh. The.mixture was
poured into brine (650 ml) and extracted with
CH2Cl~ (5xlS0 ~ he combined extracts were
dried, 'filtered and concentrated to give an
oil, which was chromatographed on silica using
13:7 ~A-PE (b.p. 60-80) through to EA as eluen~t
to give the title co_E~ound as an oil (8.389).
.
' IR (Neat) 3510 (br'~, 1650 cm 1.
The following cornpound was prepared by.a similar

3$~ 3 ~
- 55 -
proced~re:
b) (la,2a,3R,4~)-(+)-3-(HexahydrO-1,4-Oxazepin-
4-yl)-2-(3-methoxy-2-prope-nyl)-4-[~tetrahydro-
2H-pyran-2-yl)oxy]cyclopentanol~ from Intermediate
7c IR (CHBr3) 3500, 1655 cm 1.
Intermediate 60
3-[(1,1'-Biphenyl)-4-yl]propanol,4-methylbenzenesulphonate
A stirred solution of Intermediate 23b (4.28g)
in pyridine (40 ml) at 0 was treated portionwise
with p-toluene sulphonyl chloride (7.71g) over lh.
Stirring was continued at 0 for 7h when water (20 ml)
was added and the mixture allowed to warm to room temperature
with stirring for a further lh. The mixture was partitioned
between 2~.H2SO4 (250 ml) and ER (250 ml), the layers
separated and the organic phase washed with a further
quantity of 2N.H2SO4 (2x250 ml). The organic phase
was then washed with 2N.NaOH (3x100 ml), water (2x100 ml)
and dried. Evaporation of the solvent gave the title
compound as a solid (4.95g), m.p. 86-87.
Intermediate 61
(3aa,4a,5~,6a~)-(+)-Hexahydro-5-hydroxy-4-(4 thiomorpho-
linyl~-2H-cyclopenta(b)furan-2-one, S-dioxide, hydrochloride
A solution of (endo,anti?-(-)-6-(phenylmethoxy)-
8-~4-thiomorpholinyl)-2-oxabicyclo[3.2.1~octan-3-one,
S-dioxide (lOg) in ethanol (60 ml) and water (40 ml)
containing ooncentrated hydrochloric acid (40 ml) was
hydrogenated over pre-reduced 10% palladium oxide on
charcoal (5g, 50% dispersion in water) in ethanol (40 ml).
The mixture was ~iltered and the filtrate evaporated
in vacuo to give the title compound as a solid (B.55g),
m,p. ahove 230 (dec.) (~rom water~ethanol).
Intermediate 62
2-yl)oxyl-~ thiornorpholinyl)-2
2-one S-dioxide
~,
Dihydropyran (3.1 ml) was added to a stirred
solution o~ the free base o~ Intermediate 61 (1.56g)
and p-toluene sulphonic acid monohydrate (~.17g) in
'~ .

~ 3 ~ 3 ()
- 56 -
dry DMF (30 ml) at -10. The mixture was allowed to
reach ambient temperature and stirring continued for
18h, whereupon it was poured into satura~ed aqueous
NaHCO3 solution (50 ml), extracted with EA (4 x 100 ml),
washed with water, dried, filtered and concentrated.
The residue was chromatographed using 19:1 ER-methanol
as eluent to give the title compound as a viscous
oil (1.89g). IR tCHBr3~ 1762 cm 1.
Intermediate 63
(3aa,4~,5~,6aa)-(+)-Hexahydro-5-~(tetrahydro-
2H-pyran-2-yl)oxyJ-4-(4-thlomorpholiny].)-2H-
cyclopenta(b)furan-2-ol, S-dloxide
A solution of Intermediate 62 (lg) in CH2C12
(25 ml) at -70 under dry nitrogen was stirred during
the addition of DIBAL (1 M in hexane, 8.7 ml). After
1.5h at -70, methanol (25 ml) was carefully added
and the mixture was then allowed to rise to ambient
temperature whereupon stirring was continued for 18h.
The mixture was filtered through 'Hyflo' and the filtrate
-20 evaporated to give the title compound as an oil (0.959).
Analysis Found: C, 53.2; H, 7.6; N, 3.5.
C16H27NO6S requires: C, 53.2; H, 7.5; N, 3.9
Intermediate 66
[4'Methyl-~ b~hen~ 4-yl]methanol
4-Methyl-(l,l'~biphenyl)-4-carboxylic acid, methyl
ester ~(1.43g) -in ER (25 ml) and THF (25 ml) was added
over 5 min to LiAlH4~(420 mg) in ER (25 ml). The mixture
was stirred at room temperature for 1 h and then cooled
in ice. A~ueous NaOH (lM, 2.1 ml) was.added and after
stirring (15 min) ~xcess anhydro-ls Na~SO~ was addecl.
The mixture wa~ filtered and the filtrate evaporat~cl
to give a solid. Crystallisation from cyclohexane-
methanol gave the tltle compound (1.0~g) m.p. 128-31.
. .

3 8 3 ~
- 57 -
Intermediate 67
4-Bromomethyl-4'-methyl ~,1' biphenyl)
To a cold (0) solution of Intermediate 66
(0.917 g) in dry CH2C12 (14 ml) was added PBr3 (0.29 ml).
After stirring for 1 h at 0, 8% NaHCO3 solution
(30 ml) was added and the layers separated. The
aqueous layer was extracted with CH2C12 (2 x 30 ml),
dried and evaporated to give a solid (0~99g). Crystal-
lisation from PE (b.p. 60-80) afforded the title
_ompound (0.91 g) m.p. 100-102.
Intermediate 68
4-Bromomethyl-4'-chloro-1,1'-biphenyl
4'-Chloro(l,l'-biphenyl)-4-methanol (5.8g)
~ was converted into the title c_mpound (6.8g), m.p.
; 15 64-66 by the method for the preparation of Intermediate
67.
Intermediate 69
~+)-7-anti-(4-Morpholinyl)-5-endo-[tetrahYdrc-2~-
pyran-2-yl)oxy~bicyclo~2.2.1]heptan-2-one
Morpholine (76 ml) was added dropwise over
15 mins to a stirred solution of 2-exo-bromo-3-endo-
[~tetrahydro-2H-pyran-2-yl)oxy]bicyclo[3.2.0~heptan-
6-one (100.8g) in acetone (500 ml) at 0. A~ter
2h at 5 the mixture was stirred at 20 for 18h
and then filtered. Evaporation of the filtrate gave
an oil which was taken into ER (350 ml), filtered
and washed (water, 2 x 100 ml). The ethereal solution
was dried, filtered cand evaporated to give the title
c ~ as a solid. Puriication from PE gave material
(85.$g) o m,p. 86-88.
~0
~ ~ 4 a olinyl)bicYclo[2.2.
heptan-2-one, hydrochloride
To a stirred solution of Intermediate 69 (96.4~)
in methanol (600 ml) was added an ethereal solution
,

~ 1738~
- 5~ -
of HCl (240 ml) and the mixture stirred at 20 for
2.5h (pH 1.5-2). Filtration followed by evaporation
of the filtrate gave an oil which solidified on trituration
with EA (2 x 200 ml)~ Coloured impurities were removed
by extraction with boiling isopropanol to leave the
title compound as a solid (70.6g), m.p. 181-182.
Intermediat~ 71
(+)-5-endo-(4-Bromophenylmethoxy)-7-anti-~4-morpholinyl)-
bicyclo~2.2.1]heptan-2-one
Aqueous NaOH solution (10~j 200 ml) was aclded
to a solution of the free base of Intermediate 70
(21.19), benzyltriethylammonium chloride (49) and
4-bromobenzyl bromide (27.5g) in CH2C12 (400 ml)
and the mixture stirred vigorously for 4h. A further
portion of 4-bromobenzylbromide (99) was then added
and stirring continued for 68h. Water (~00 ml) was
added and the layers separated. The aqueous layer
was extracted with ~A (2 x 75 ml), washed with water,
dried and evaporated to give an oil (489) which solidified
on standing. Excess alkylating agent was removed
by triturition with PE (b.p. 60-80) ànd crystallisation
from EA-PE (b.p. 60-80) then gave the title compound
(34.1g) as a solid, m.p. 130-131.
Intermediate 72
(+)-6-endo-(4-Bromophenylmethoxy)-8-anti-(4-morpholinyl)-
2-oxa~bic clot3.2.1]octan-3-one
Y
Intermediate 71 (13.2g) in acetic acid (110 ml)
and water (55 ml) containing CH3COONa.3H20 (23.7g)
was cooled (ca. 5-10) and stirred cluring the dropwise
acldition o peracetic acid (6.1M; 28.5 ml). The
resulting solution was stirred at 20 or 48h when
10% Na~SO3 solution (200 ml), was added, maintaining
the temperature of the mixture at 10-15. A~ter
].5h solvents were removed in vacuo at 35, the res,idue
taken into water (150 ml) and basified to p~l 9 with
Na2CO3 solution. Extraction with EA (3 x 200 ml)
~ollowed by drying ancl evaporation gave a solid which
crystallised ~rom E'A to give the title compound (5.49g),
m.p. 154-156.
.~ .

~ 173P~
- 5~ -
Intermediate 77
~la(Z/E),2~,3a,5~]~(+)-7~[5~[[(1,1'-BiPhenyl)-4~
yl]methoxy]-3-hydroxy-2-(4-morpholinyl)cyclopentyl]-
4-bromo-4-heptenoic acid
To a stirred solution of potassium tert-butoxide
(6.06q) in dry THF (140 ml) at -70 was added (4-
carbethoxypropyl)triphenylphosphonium bromide (22.16g).
After 0.5h at ~70 a solution of bromine in CH2C12
!25~ v/v, 6.7 ml) was added dropwise and then stirring
maintained for 0.9h. A sol~tion of Intermediate
6 (4.099) in THF (30 ml) was then added and, after
0.5h, the temperature of the mixt~re allowed to rise
to 0 over lh. 2N NaOH (60 ml) and methanol t60 ml~
were added and stirring continued at 20 for 4h.
After evaporation in vacuo the residue was taken
into water (200 ml) and adjusted to pH 12 with 2N
NaOH. Non~acidic material was removed by extraction
with EA (1 x 100 ml, 2 x 50 ml), and the aqueo~s
phase then re~adjusted to pH 6 with 2N hydrochloric
acid. Extraction with EA (4 x 60 ml), drying and
concentration gave the title compounds as a foam
(5.23q)~ IR (CHBr3) 3500, 1725, 1710 cm 1.
Intermediate 78
(la,2~,3a,5a)-(+)~7~[5~[[(1,1'~Biphenyl)-4-y _methoxy]-
3~hydroxy~2-(4~morphollnyl)cyclopentyl]~4~heptynoic
acid, hydrochloride
To a stirred solution o~ Intermediate 77 (2q)
in TI~F (15 ml) at 0 was added potassium tert-b~toxide
(2.4g) in ~M50 (lS ml). The mixture was stirred
L

- 60 - 3 ~3~3~
at 0 for 0.5h and at 20 for 1.5h whereupon water
(200 ml) was added and the mixture extracted with
EA (1 x 50 ml). The aqueous solution was adjusted
to pH 6 with 2N hydrochloric acid and extracted with
EA (3 x 60 ml). The combined extracts were washed
with water (3 x 60 ml), dried and evaporated to give
an oil, which was purified by chromatography on silica
(130g) using 4:1 EA-methanol as eIuent to give a
foam (0.65g). A sample was treated with ethereal
hydrogen chloride to give the title compound. Crystal-
lisation from EA gave material of m.p. 162-163.5 .
Intermediate 79
(1~,2~,$~)-(+)-[5-~[(1,1'-Biphenyl)-4-yl]methoxy~-
2-(4-morpholinyl)-3-oxo-cYclopentyl]-4-heptynoic
acid
Prepared from the free base of Intermediate
78 according to the procedure described for Example
3a. Purification by chromatography using ER through
- to 98:2 ER-methanol as eluent. Crystallisation from
ER-PE (b.p. 60-80) gave material of m.p. 90-93.
Intermediate 80
(endo,anti)-(~)-5-Decyloxy-7-~4-morpholinyl)bicyclo-
[2.2.1]heptan-2-one
Sodium hydride (46% dispersion in oil, 0.522g)
was added portionwise over 10 min to a stirred soIution
of Intermediate 1 (1.06g) and decyl tosylate (2.34g)
in dry DMF (lOml) under dry nitrogen at room temperature.
The mixture was stirred for 5h, poured into water
(SOml) and extracted with ER (SOml, 2 x 25ml). The
combined extracts were washed with water (25ml),
dried and concentrated to give a solid. Crystallisation
from PE gave the t tle ompound (0.59g), m.p; 64--
65~.

7 ~73831~
- 61 -
EXAMPLE I
a) [la(2)r2B~5~]-(+)-7-[5-[[~ Biphenyl)-4-
yl]methoxy]-2-(4-morpholinyl)-3-oxocyclopentyl]-
4-heptenoic acid
Method I
To a cold (-11~ stirred solution of Intermediate
12a) (920 mg) and triethylamine (2.14 ml) in CH2C12
(10 ml) and DMSO (10 ml) was added pyridine-sulphur
trioxide complex (915 mg) in DMSO (10 ml). Stirring
was maintained at 25C for 3h whereupon water (10 ml)
was added and the CH2C12 evaporated. To the resulting
suspension a solution of citric acid (1.07g) in water
(10 ml) was added. The mixture was extracted with
EA, the combined extracts dried and concentrated.
i5 The residual oil was chromatographed on silica using
ER as eluent to give the title compound as an oil
which slowly crystallised (0.37g). Recrystallisation
of a sample from ER-iso-pentane at 0 gave material
of m~p. 77.5-80, IR (Nujol) 3350-2aoo (br), 1735,
1705cm 1; whereas recrystallisation above 5 gave
a different polymorphic form of m.p. 98-100.5, IR
(Nujol) 3400-2300 (br), 1735, 1702, 1250, 1005cm 1.
Analysis ~ound: C, 72.9; H, 7.4; N, 2.9.
C29H35NO5 requires; C, 72.9; H, 7 4; N, 2.9%.
2~ ~ethod 2
Jones reagent (0.54ml, 2.67M) was added to
a mix~ure of Intermediate 26 (0.259) and 'Hy~lo'
tlg) in acetone (10-ml) and stirred for lh. Isopropanol

3 ~ 3 1~
- 62 -
(lml) was added, the mixture filtered and the filtrate
washed with pH 5 buffer ~2 x lOml). After drying
and evaporation the residue was purified by chromatography
on silica using ER as eluent to give the title compound
~0.024g).
Method 3
From Intermediate 33a) by the procedure described
under Method 2.
Method 4
From Intermediate 34 by the procedure described
under Method 2
Method 5
A suspension of 5~ Pd on CaCO3 poisoned with
lead (70 mg) in EA (5 ml) containing triethylamine
(0.2 ml) was hydrogenated at 21 and atmospheric
pressure for 0.5h. A solution of Intermediate 79
(36 mg) in EA (4 ml) was added and the hydrogenation
continued for 2h. The mixture was- filtered, diluted
with ER (20 ml) and washed with pH 6 phosphate buffer
solution (30 ml). Evaporation of the dried ethereal
solution gave a solid (35 mg) which crystallised
: from ER-PE (b.p. 60-80) to give the title compound
(23 mg), m.p. 95-98.
- The following compounds were prepared by the
procedure described for Method 1.
b) [la(Z), 2~,5~]-(~j-8-[5-[[(1,1'-Biphenyl)-4-
yl~met/hoxy]-2-(4-morpholinyl)-3-oxocyclopentyl]-
5-octenoic acid, m.p. 118-120 from Intermediate
13.
Analysis found: C, 73.6; H, 7.7; N, 2.9.
C30H37NO5 requires; C, 73.3; H, 7-6; N~
2.9%.
c) ~ 5aJ~ 7-[21-Morpholinyl)-5-
~ - .
(2-naPhthalenylmethoxxl~3-oxocvclopentvlJ-4
heptenoic acid ~rom Intermediate 12h.
_
Purification by chromatography using ER as
eluent
IR (CHBr3) 3600 - 2300~br), 1735, 1702 cm 1

? 1 ~383
- 63 -
Analysis Found: C, 71.1; H, 7.5; Nr 3.2
C27H35NO5 requlres: C, 71.8; H, 7.4; N, 3.1~
d) [la(Z)~ 2~, 5~]~ 7-[5-[4-(1,1-Dimethylethyl)-
~henylmethoxy]-2-(4-morpholinyl)-3-oxocyclopentyl~-
4-heptenoic acid, from Intermediate 12d.
Purification by chromatography using ER as
el~ent.
IR (CHBr3) 3500, 1738, 1705 cm
TLC 95:5 ER-methanol Rf 0.53
e) [l~(Z), 2~, 5~]-(+) 7-~5-[4-Methylthio(phenyl-
methoxy)]-2-(4-morPholinyl)-3-oxocyclopentyl)
4-heptenoic acid, compound with piperazine
(2:1) r from Intermediate 12i.
The acid was p~rified by chromatography using
ER as eluént. The title compound (106mg) crystal-
lised from a solution Of the acid (168mg) and
piperazine (25mg) in ER (5ml) to give material
of m.p. 75-76.5.
- IR (CHBr3) 1735 r 1590 cm 1
f) [l(Z), 2~, 5a]~ -7-[5-[[(1,1'-Biphenyl)-
4-yl]methoxy]-3-oxo-2-(4-thiomorpholinyl) cyclo-
pentyl]-4-heptenoic acid, from Intermediate
12p. Purification by chromatography using
7:3 ER-isopentane as eluent.
IR (CHBr3) 3500, 1740, 1705 cm 1. TLC ER R
0.45
g) [l~Z), 2~, 5a]-(-)-7-[5-[~4'-Methoxy(l,l'-
biphenyl)-3-yl]methoxy]-2-(4-morpholinyl)-3-
oxocyclopentyl]-4~heptenoic acid, ~rom Intermediate
12y. Purification by chromatograp}ly u~ing
4:1 EA-PE (b.p. 60-80) as eluent.
IR (C~IBr3) 3500, 1740, 1710 cm 1 TLC 4:1
E~-PE ~b.p. 60-80) R 0.44
EX~MPLE 2
[l(Z),2~,5a~ )-Methyl 7-~5-~[(1,1'-Biphenyl)-4-
y~_~meth~x,~ ~ Eh 1inyl)-3-oxocycloE~n_
~o_
To a cold (-60), 5tirred solution of ~xalyl
;'
- . . .
,,

`` ~ 173~30
- 6~ -
chloride (0.144 ml) in dry C~2C12 (20ml) was added
DMSO (0.133ml). The solution was stirred for 15
min, when a solution of Intermediate 14 (0.37g) in
dry CH2Cl2 (20ml) was added. After stirring for
2h, triethylamine tl.04ml) in dry CH2Cl~ (5ml) was
added and the temperature then allowed to rise to
ambient over 0.75h. ER was then added and the mixture
washed with 8% NaHCO3 solution. The organic phase
was separated, dried and concentrated, and the residue
chromatographed on silica. Elution with 3:1 ER-isopentane
gave the title compound as an oil (0.23g). I.R.
(CHBr3) 1730 cm
Analysis Found: C, 73.1; H, 7.0; N, 2.8
C30H37NO5 requ-ires: C, 73.3; H, 7.6; N, 2.9%.
Example 3
a) [la(z)~2~5a~-(+)-7-[5-[4-Methoxy(phenylmethoxy)]
2-(4-morphoIinyl)-3-oxocyclopentYl]-4-heptenoic
acid, compound with chloroform (3:1)
To a solution of Intermediate 12c) (0.189)
in acetone (lO ml) at -5 was added 'hyflo' ~0.79)
followed by Jones reagent (2.67M, 0.36 ml). The
temperature was allowed to rise to 5 during 45 min
when isopropanol (1 ml) was added. After 5 min the
mixture was filtered and the solid washed thoroughly
with ER. The combined organic layers were washed
with pH 6.5 phosphate buffer (2x20 ml), dried and
concentrated.- Purification by chromatography using
98:2 CHCl3-methanol~as eluent gave the title compound
as an oil (0.06g).
IR ~CHBr3) 3500, 1740, 1710 cm
TLC 98:2 CHCl3-m~thanol Rf 0 4
The following compounds were prepared using
a similar procedure:
b) [la~Z),2~,5a~-(+)-7-E5-[[4'-ChlorO(l,l'-biphenyl)-
4-yl]methoxy}-2-(4-m~phQlinyl)-3-oxocyclopent~yl]
4-heptenolc acid, from Intermediate 12h
Purification by chromatography using 99:1 CHCl3-
meth~nol as eluent. TR (CH~r3) 3490~ 1740,

73~30
-- 65 r
1705 cm 1
Analysis found: C, 67.7; H, 6.6; N, 2.8.
C29H34ClNO5 requires: C, 68.0; H, 6.7; N,
c) [la~Z)~2~5a]-~-)-7-[2-~4-Morpholinyl)-3-Ox'O-
5-(2-propenYloxy)cyclopentyl}-4-heptenoic acid,
from Intermediate 12i. Puri'fication by chromato-
graphy using 4:1 ER-PE (b.p. 60-80) as eluent.
IR (CHBr3) 3500, 1735j 1705 cm 1. TLC 4:1
ER-PE (b.p. 60-80) Rf 0.28.
d) ~la(Z),2~,5a]-(+)-7-~2-(4-Morpholinyl)-3-oxo-
5-[(4-thien-2-yl)phenylmethoxy]cyclopentyl]-
4-heptenoic acid, comPound with piperazine
(2:1), from Intermediate 12k. The acid was
lS purifi~ed by chromatography uslng~1:99~methanol- '
CHC13 as eluent. The title compound -(140~mg)
;~ precipitated from a solution of the acid (200 mg)
and piperazine (100 mg) in ER. Crystallisa~tion
from EA gave material of m.p. 115 (dec1.
IR (CHBr3)~1740 cm 1. TLC~ER Rf 0.7.
ej [l(Z),2~,5a]-(+)-7-~2-(4-MorpholinYl)-3-oxo-
5-[[(1,1i:4',1"-terphenyl)-4-yl]methoxy]cyclopentyl]-
4 l~ , m.p. 105 (dec) from Intermediate
12 1). Purification initially by chromatography
using ether as eluent'and then by crystallisation
' from En-isopentane at 0. TLC 9:1 ER-methanol
Rf 0.23;
f) [la(E),2~,5a]-(-)-7-[5-[~4l-Methyl(l,l'biphenyl)-
' 4-Yl]methoxy]-2-(4-morpholinyl)-3-oxocyclopentyl]
_h ~ , m.p. 80-85 f~om Intermediate
25a. Puri~ication initially by chroma~ography
using ~R a5 eluent and then by crys~allisation
from ER-i~opentane at -20
~nalysis Found: C, 73.1; ~, 7.7; N, 2.8.
C30H37NO5 requires: C, 73.3; H, 7.6~ N, 2.9~.,
9) ~ a ~ ~
yl]methoxY]-2-(4-morpholinyl)-3-oxocyclopentyl]-
4=~ c ~, m.p. 103-105 from Intermediate
25b.~- Puriication initially'by chromatography
,
'' . ' ` ', ~ .
,
. i . - . -
.
~ : ' : ' `~'

-
3~30
66 ~
using ER as eluent and then by crystallisation
from ER at -20.
Analysis Found: C, 72.8; H, 7.7; N, 3Ø
C29H35NO5 requires: C, 72.9; H, 7.4; N, 2.9%.
h) [la(Z),2~,5a]~ 9-[5-[[(1,1'-Biphenyl)-4-
y~]methoxy]-2-(4-morpholinyl)-3-oxocyclopent
6-nonenoic acid, mOp. 83-84 from Intermediate
12 m. Purification initially by chromatography
using ER as eluent and then by crystallisation
from ER-isopentane.
Analysis Found: C, 73.3; H, 7.7; N, 2.8.
C31H39NO5 requires: C, 73.6; H, 7.8; N, 2.8%.
i) [la(Z),2~,5a(E)]-(+)-7-[2-(4-Morpholinyl)-3-
oxo-5-~(3-phenyl-2-propenyl)oxy]cyclopentyl]-
4-heptenoic acid, m.p. 74.5-76 from Intermediate
12O. Purification by chromatography using
- ER as eluent.
Analysis Found: C, 70.3; H, 7.9; N, 3.3.
C25H33NO5 requires: C, 70.2; H, 7.8; N, 3.3%.
j) [la(Z),2~,5a]-(+)-7-[5-[[4'-Methyl(l,l'-biphenyl)-
4-yl3methoxy3-3-oxo-2-(4-thiomorpholinyl)cyclopentYl]-
4-heptenoic acid, S-dioxide, from Intermediate
12r. Purification by chromatography using
98:2 ER-methanol as eluent. IR (CHBr3) 3500,
1740, 1710 cm~l.
Analysis Found: C, 66.5; H, 7.1; N, 2.2;
C30H37NO6S requlres: C, 66.8; H, 6.9; N, 2.6%.
k) [la~Z),2~,5]-(-)-7-[3-Oxo-5-~4-~phenylmethyl)-
phenylmet~y_-2-(4-thiomorpholinyl)cyclopentyl]-
~-heptenoi _acid, S-dioxide, m.~. 126.5-128
(flec) from Intermediate 12s. Puri~ication
by chromato~raphy using ~R as eluent. TLC 95:5
ER-methanol Rf 0.46.
1) [la~Z),2~,5a~ )-7-~5-[~(1,1'-Biphenyl)-4-
yl]methoxy]-3-oxo-2-(4-thiomorpholinYl)cyclopen
4-h_~e c acid, S-dioxideL from Intermediate
12t, Purificatic)n by chromatoyraphy using
g8:2 ER-methanol as eluent. IR (CHBr3) 3480,
1743, 1710 cm
Allalysis Foun~: C, 66.0; H, 6.7; N, 2.6;

3 (3
- 67 -
C29H35~06S requires: C, 66.3; H, 6.7; N, 2.7%-
m~ l~(Z),2~5a]-(-)-7-r5-~ Biphenyl)-4-
yl)methoxy]-2-(hexahydro-1,4-oxazepin-~-yl-
3-oxocyclopentyl]-4-heptenoic acid, from Inter-
mediate 12 u. Purification by chromatography
using ER as eluent. IR (Neat) 3500-2500 (br),
1740, 1710 cm 1. TLC ER Rf 0.47.
n) Ela(z),2~,5a]-(-)-7-[5-~3~ l'-Biphenyl)-
4-yl]propoxy]-2-(4-morpholinyl)-3-oxocyclopentyl]-
4-heptenoic acid, from Intermediate 12w. Purifi-
cation by chromatography using ER as eluent.
IR (Neat) 3700-2200 (br), 1740, 1712 cm 1.
TLC ER Rf 0.25.
) ~l~(z)r2~l5a]-l-)-7-[5-[[3~-Methoxy(l~l'-biphenyl)
4-yl]methoxy~-2-(4-morpholinyl)-3-oxocyclopentyl]
4-heptenoic acid, from Intermediate 12x. Purifi-
cation by chromatography using ER as eluent.
IR (CHBr3) 3500, 1740, 1710 cm 1. TLC ER Rf 0.2.
p) [la(Z!,2~,5~)-(-)-7-[5-Decyloxy-2-(4-morpholinyl)-
3-oxocyclopentyl]-4-heptenoic acid from Intermediate
12z. Purification by chromatography usi-ng 4:1
ER-PE as eluent. IR (CHBr3) 3500, 1740, 1710 cm 1.
TLC (SiO2) 4:1 ER-PE Rf 0.21.
Example 4
a) [la(Z),2~,5a]-(+)-7-[5-(4-Cyclohexylphenylmethoxy)-
2-(4~morpholinyl)-3-oxocyclopentyl]-4-heptenoic acid
-~A stirrecl solution of oxalyl chloride (0.612ml)
in dry toluene (5mll under nitrogen at -60 was treated
dropwise with a solution of dry DMSO (0.5ml) in dry
toluene (5ml) and the mixture stirred.for 10 min~
Simultaneously ch~orotrimethylæilane (0.24ml) was
added dropwise to a solution of Intermediate 12e,
(0.84g) and triethylamine (0.264ml) in dry toluene
(lOml) under nitrogen. This mixture was swirled
for S min before being added dropwise to the above ,
reaction mixture~ The resulting solution was stirred
at -60 for 15 min and then quenched with triethylamine
(2.8ml). The mixture was allowed to warm to O,
poured into aqueous KH2P04 (3.5g in 200ml water)
and extracted with EA (4 x 50ml). The combined organic
- . .

3 ~
- 68 -
extracts were washed with pH 6.5 phosphate buffer
(2 x 20ml), dried and concentrated. The residue
was purified by chromatography on silica using 3:1
ER-PE as eluent to give the title compound as a gum
t56m9)~ IR (CHBr3) 3500, 1740, 1710 cm 1. TLC 80:1
ER-acetic acid Rf 0.39.
The following compounds were prepared using
a similar procedure:
b) [la(Z),2~,5a]-(+)-7-[2-(4-Morpholinyl)-3-oxo-
5-~pentyloxy)cyclopentyl]-4-heptenolc acid,
compound with piperazine (2:1), from Intermediate
12f. Purification of the acid by chromatography
using ER as eluent. The title compound (212mg)
crystallised from a solution of the acid (271mg)
and piperazine (45mg) in ER (lOmI) to give
material of m.p. 99-102.5 (dec).
Analysis Found: C, 64.9; H, 9.5; N, 6.8.
C23H40N205 requires: C, 65.1; N, 9.5; N, 6.6~.
c) [la(Z),2~,5]-(+)-7-r2-(4-~orpho]inyl)-3-oxo-
5-[4-~phenylmethyl)phenylmethoxy]cyclopentyl}-
4-heptenoic acid, compound with piperazine
(2:1), m.p. 107-108 from Intermediate 12 g.
Analysis Found: C, 71.6; H, 7.9; N, 5.2
C32H42N205 requires: C, 71.9; H, 7.9; N, 5.2%.
e) [la(Z),2~,5a]-(-)-7-[5-[[(1,1'-Biphenyl)-4-
yl]methoxy]-3-oxo-2-(1-piperidinyl)cyclopentyl]-
4-heptenoic acid, compound with piperazine
(2:1), m.p. 91-94 (dec) from Intermediate
33b. IR ~CHar3) 1738 cm 1.
~) ~ 5a~ 7-[5-~[9'~325~ ~L~i Deh9cYl)-
methoxyl-3-oxo-2-(4-~thiomorpholinyl)cyclopentyl]-
~heptenoic aci~L S-dioxide, from Intermediate
..' ' . ~' ' ' . . '' ' ' ' '.
,

~ ~3~3~0
- 69 -
12q. Purification by chromatography using
98:2 ER-methanol as eluent. TLC 95:5 ER-methanol
Rf 0.46. IR (CHBr3) 3480~ 1740, 1710 cm -.
g~ [l(Z),2~,5a]-~)-7-~5-[[4'-Methoxy(l,l'-biphenyl~-
4-yl]methoxy)-3-oxo-2-(l-piperidinyl)cyclopentyl]
4-heptenoic acid, compound with piperazine
(2:11, m.p. 68-76 (dec) from Intermediate
12v. IR (CHBr3) 1740 cm
Example 5
[l(Z~,2~,5]-(~-7-[5-[~4'-Methyl~l,l'-biphenyl)-
4-yl]methoxy]-2~(4-morpholinyl)-3-oxocyclopen~yl]-
4-heptenoic aci_
A solution of Intermediate 18 ~928mg~ in acetone
(30ml) was stirred with Jones reagent (2.67 M; 1.5ml~
lS at -5 to -3 for 40 min. Isopropanol (1.5ml) was
added and after stirring for 5 min, the mixture was
poured into pH 6 phosphate buffer (lOOml) and extracted
with ER (3 x 50ml). The combined extracts were e~aporated
and the residue taken into ER and dried; evaporation
of this ethereal solution gave a foam (840mg) which
was purified by chromatography on acid-washed siIica
gel (85g~ using ER as eluent. Crystallisation from
ER-isopentane at 0 gave the title compound (0.269)
of m.p. 98 102. IR (CHBr3) 3500, 1740, 1710 cm
Analysis Found: C, 72.9; H, 7.6; N, 2.9.
C30H37N05 requires: C, 73.3; H, 7.6; N, 2.9%.
Exam~le 6
[la(Z),2R,5a]-(+~-7-~5-[~4'-Methoxy(l,l'-biphenyl)-
4-yl]methoxyl-2-(4-morpholinyl~-3-oxocyclopentyl]-
_-heptenoic acid, compound with piperazine ~
Jones reagent (0.883ml, 2.7 M) was added to
Intermediate 21 (600mg) in acetone (2Sml) at -10
and stirred ~or ~5 min At 10. The mixture was neutralised
by (~Sml) dropwise addition of 2N aqueous Na2co3
and then poured into Na2HP04/K~I~PO~ bu~er solution
(pH 6). ~he mixture was extracted with CH2C12 (3 x 50ml)
and the combined extracts dried, ~iltered and evaporated.
The residue was chromatographed on acid washed silica

~ 1 ~383~
- 70 -
using 1.1 through to 3:1 ER-PE (b.p. 60-80) as eluent
to give an oil, which was dissolved in ER and treated
with an excess of piperazine in ER to give the title
compound as a solid (0.129), m.p. 116-117 (decj.
Analysis Found: C, 69,7; H, 7.6; N, 5.2
~32H42N26 requires C, 69.8; H, 7.7; N, 5.1%.
Example 7
[la(Z),2~,5a]-(-)-7-~5-~[(l,l'-Biphenyl)-4-ylJmethoxyl-
2-(4-morpholinyl)-3-oxocyclopentyl]-4~h
compound with piperazine (2:1), hemihydrate
To a solution of Example la (0.379) in dry
ER (20ml) was added piperazine (0.037g) in dry ER
(4ml). The ER was decanted off and the resid~e crystal-
lised from CH2C12-isopentane to give the title compound
(0.29) m.p. 113-114.
Analysis found: C, 70.9; H, 7.7; N, 5.4.
C31H40N205.1/4 ~2 requires: C, 70.9; H, 7.7; N,
5.4%.
Example 8
[la (Z) ,2~,5a]-(+)-7-[5-[[(l,l'-BiPhenyl)-4-yl]meth
2-(4-morpholinyl)-3-oxocyclopentyl]-~-heptenoic acid,
calcium (2~) (2:1), monohydrate
Aqueous 0.2N.NaOH (2ml) was added dropwise
with stirring to a solution of Example la (0.259)
in aqueous acetone (1:1), lOml) at room temperature
until the pH reached 7.8. 7.2~ w/v CaC12 (lml) was
then added followed by water (lOml) and stirring
~ continued for 2h. The solid was filtered off, washed
with water (5ml) followed by ER (lOml) and dried
(35/O.OSmmHg/7h) to aford the title compound tO.163g),
m.p. 132-134.
Analysis Found:C, 69.1; El, 6.8; N, 2.6; Ca, 3.9.
C58H6~N2010Ca -H2
requires: C, 68.9; H, 7,0; N, 2.8; Ca, 4.0%.
35 ~xa~ 9
[la(Z)L2~,5a]~7-[5-[[(1,1' Biphenyl)-4-yl]methoxyl-
2-(4--morpholinyl)-3--oxocyclopentyl]-9~heptenoic a~
calcium (2-~) (2~ trihydrate
.

~ ~73~3(3
- 71 -
Aqueous calcium acetate solution (0.17g in
12ml) was added dropwise with stirring to a solution
of Example la) (0.6g) and NaHC03 (001059) in aqueous
ethanol (1:1, 24ml). The mixture was stirred for
30 min when the solid was filtered off, washed with
water (lOml) followed by ER (5ml) and dried (45/200mmHg/4h)
to afford the title _ mpound (0.569), m.p. 135 (dec).
Analysis Found: C, 66.2; H, 6.9; N, 2.6; Ca, 3.6.
C58H68N2010Ca 3H2
requires: C, 66.5; ~, 6.g; N, 2.7; Ca,
3.8~.
Example 10
[l~(Z),2~,5~]-(+)-7-~5-[~(1,1'-8iphenvl)-4-yl]methoxyl-
2-(4-morpholinyl)-3-oxocyclopenty~]-4-hePtenoic acid,
compound with N~N-dimethyl~iperazine (2:1)
A solution of Example la) ~0.359~ in ER (25ml)
was treated with a solution of N,N-dimethylpiperazine
tO.084g) in ER (5ml) and the mixture was allowed
to stand in the cold. ~he title compound was filtered
off and dried (0.339), m.p. 106-108.
Analsis Found C, 71.9; H, 7.9; N, 5;1.
C32H42N205 requires: C, 71~9; H, 7.9; N, 5.2%.
Example 11
a) [lR-[l~(Z),2~5a]l-(-)-7-[5-[[(l,l'-Biphenyl)-
4-yl]methoxy]-2-(4-morph~linyl)-3-oxocyclopentyl]-
4-heptenoic acid
. ~ _
Jones reagent (1.83ml, 2.67M~ was added to
a stirred mixture o 'hyflo' (4.8g) and the free
base o Intermediate 47a) (1.2g) in acetone (~Oml)
at 5 and stirring was continued for 40 min. Isopro-
panol (1.8ml) was added dropwise and a~ter 10 min
the hy~lo was removed by filtration and was washed
with acetone (30ml) and pH 5 bufer (50ml, KH2PO~
and Na2HP04 in water). The combined filtrates were,
evaporated in vac_o at 10-15 to remove most of the
acetone. The residue was diluted with pH 5 buffer
(25ml) and extracted with ER (4xSOml). The combined
extracts were washed with pH 5 buffer (20r~1) and

` ~ 173~30
- 72 -
brine (20ml), then dried and evaporated to give`an
oil. The oil was chromatographed on silica using
ER as eluent to give a solid (0.589) which was recrystal-
lised from 2:1 ER-iSopentane ~15ml) to give the title
compound (0.484g), m.p. 86 88. [a]21~5 = -13.66
(CHC13).
Analysis Found: C, 72.5; H, 7.5; N, 2.7.
C29H35NO5 requires: C, 72.9; H, 7.4; N, 2.9~.
The following compound was prepared starting
from Intermediate 35, in a similar manner to the
preparation of the lR compound:
b) [lS-~l~(Z),2~,5~]]-(+)-7-[5-~ f (~ BiphenYl)-
4-yl]methoxy]-2-(4-morpholinyl)-3-oxocyclopentyl]-
4-heptenoic acid, m.p. 81-84.
Analysis Found: C, 72.8; H, 7.3; N, 2.7.
C29H35NO5 re~uires: C, 72.9; H, 7.4; N, 2.9%.
Example 13
[lR-~l(Z),2~,5a]]-(-)-7-[5-[[1,1'-Biphenyl)-4-yl]methoxy]-
2-(4 morpholinyl)-3-oxocyclopentyl]-4-heptenoic acid,
calcium (2+) (2:1), dihydrate
Aqueous calcium acetate solution (0.0839 in
4.8ml) was added dropwise with stirring to a solution
of Example 11 (0.259) and NaHCO3 (40mg) in aqueous
ethanol (1:1, 9.6ml). The mixture was stirred at
room temperature for 2h when the solid was filtered
o~, washed with water and dried (20/Q.lmmHg/20hJ
to a~ord the title com~ound (0.23g), m.p. 129-131.
~aJ21 ~ -28.47 (CMC13).
Anal~sis Found: C, 67.~; Il, 6.8; N, 2.7; Ca, 3.5.
C58H68N2~l0ca~2~2o
req~ires: C, 67.7; H, 7.0; ~, 2.7; Ca, 3.9~.

~ ~738,30
' 73 -
Pharmaceutical Examples
Tablets
These may be prepared by direct compression
or wet granulation. The direct compression method
is preferred but may not be suitable in all cases
as it is dependent upon the dose level and physical
characteristics of the active ingredient.
A. Direct Compression mg/tablet
Active ingredient 100.00
Microcrystalline Cellulose B.P.C. 298.00
Magnesium Stearate 2.00
Compression Weight 400.00
The active ingredient is sieved through a 250 m 6
sieve, blended with the excipients and compressed
using lO.Omm punches. Ta~lets of other strengths
may be prepared by altering the compression weight
and using punches to suit.
B. Wet Granulation mg/tablet
Active ingredient 100.00
Lactose B.P. 238.0
Starch B.P. 40.00
Pregelatinised Maize Starch B.P. 20.00
Magnesium Stearate B.P. 2.00
Compressed Weight 400.00
The active ingredient is sieved through a 250 m 6
sieve and blended wikh the lactose, starch and pre-
gelatinised starch, The mixed powders are moistenecl
~V with puri~ied water, granules are made, dried, screened

~ :~73~330
- 74 -
and blended with the magnesium stearate. The lubricated
granules are compressed into tablets as described
for the direct compression formulae.
The tablets may be film coated with suitable
film forming materials, e.g. methyl cellulose or
hydroxylpropyl methyl cellulose using standard techniques.
Alternatively the tablets may be sugar coated.
- Capsules mg/capsule
Active ingredient 100.00
*STA-RX 1500 99.00
Magnesium Stearate B.P. 1.00
Fill Weight 200.00mg
~ * A form of directly compressible starch supplied
by Colorcorn ~td~, Orpington, Kent.
The active ingredient is sieved through a 250 m 6
sieve and blended with the other materials. The
mix is filled into No. 2 hard gelatin capsules using
a suitable filling machine. Other doses may be prepared
by altering the fill weight and if necessary changing
the capsule size to suit.
Inhalation Cartridqes /cartridge
Active ingredient (micronised) 3 mg
~actose B.P~ to 25 mg

~ :~73%3~
~ 75 -
The active ingredient is micronised so that
the majority of the particles are between l m 6 and
5 m 6 in longest dimensions and none are greater
than lO m 6, The active ingredient is then blended
with the lactose and the mix is filled into No. 3
hard gelatin capsules using a suitable filling machine.
Suspensions mg/5ml dose
Active ingredient lO0.0
Aluminium monostearate 75.0
Sucrose (powdered) 125.0
Flavour~ as
Colour ) required
Fractionated coconut oil to 5.00ml.
The aluminium monostearate is dispersed in
about 90% of the fractionated coconut oil. The resulting
suspension is heated to 115C while stirring and
then cooled. The flavour and colour are added and
the active ingredient and sucrose are suitably dispersed.
The suspension is made up to volume with the remaining
fractionated coconut oil and mixed.
In ection for Intravenous Administration
Active ingredient 50mg
Suitable vehicle to Sml.
~ A sterile presentation of the active ingredient
in an ampoule or vial together with an ampo-lle containin~
a suitable vehicle. The ~ormer may be prepared by
(a) 111ing sterile material into vials under aseptic
conditions ~b) reexe drying a sterile solution o~
the active ingredient under aseptic conditions.
The vehicle may be ~a) Water ~or Injections
B.P. ~b) Water ~or Injections B.P. containing~
Sodium chloride to adjust the tonicity of the solution
and/or ~2) buffer salts or di~ute acid or alkali
to facilitate solution of the active ingredient.

~ 173~3~
- 76 -
The vehicle is prepared, clarified and filled
into appropriate sized ampoules sealed by fusion
of the glass. The vehicle is sterilised by heating
in an autoclave using one of the acceptable cycles.
~ ' ,
- '~