Note: Descriptions are shown in the official language in which they were submitted.
CYCLOPENTYL ETHERS AND THEIR PREPARATION
AND PHARMACEUTICAL FORMULATION
Prostaglandin E2 is a naturally occurring substance which has
many physiological actions. For example, it inhibits gastric acid
secretion and provides gastrointestinal cytoprotection, lowers blood
pressure, stimulates and relaxes smooth muscle, inhibits platelet
aggregation and inhibits lipolysis.
Synthetic PGE2 analoques offer the possibility of different
potency, longer duration of activity and increased selectivity of
action and are therefore of considerable intzrest~
Many different PGE2 analogues have been suggested in the past for
use in medicine but in only one instance have 13-oxa compounds been
proposed in this respect. Thus, British Patent Specification 2082176A
describes a group of compounds which includes 2-(heptyloxy)-3-~hydroxy-
5-oxo-cyclopentaneheptanoic acid and a 15-hydroxy derivative thereof.
These compoun~s are stated to inhibit blood platelet agqregation and
have bronchodilatory activity, and are proposed for use as
antithrombotic or antiasthmatic agents.
We have now found a new group of cyclopentyl ethers that have
PGE2-type activity. Compounds in this class have a particularly useful
profile of biological action. In particular they have shown high
2~ potency and extended duration of action as regards the inhibition of
gastric acid secretion and gastrointestinal cytoprotection and are
therefore of interest in the treatment of ulcers.
The invention thus provides compounds of the qeneral formula (l)
1
cH 2 ) nx ( cH 2) mcû 2R
(1)
HO OY
wherein
n is l or 2;
m is 2-5 and X is cis or ~rans -CH=CI-I- or -C~l2-CH2 ; or m is 1-4
and X is -CH=C=CH-;
Rl is
(a) phenyl [optionally substituted by Cl_4 alkyl, Cl_4 alkoxy, Cl_4
alkanoyl, methylthio, methylsulphinyl~ methylsulphonyl, haloqen (e.g.
chlorine or bromine), -Cû2R2 [where R2 is a hydrogen atom or Cl_4
alkyl or phenyl~, -NHCOR2 [where R2 is as deFined above or is a phenyl
group optionally substituted by hydroxyl, CH3CONH- or ~ -CONH-,
-CoNR3R4 [where R3 and R4 may be the same or different and are each a
hydrogen atom or C~4 alkyl group], -NHCONH2, -CH2CH(CûNH2)NHCOCH3, or
-CH2CH(CONH2)NHCO~ ]
or
(b) 2-naphthyl;
\ /
Y is _ CH2 _ /C\ _ C - ûAr
R5 OH
where R5, R6 and R7 is each a hydrogen atom or a methyl group and at
least one is a hydrogen atom; and
Ar is a phenyl group (optionally substituted by one or two Cl_4
alkyl, Cl_4 alkoxy, Cl_4 alkylthio, Cl_4 alkylsulphinyl, Cl_4
alkylsulphonyl, halogen or trifluoromethyl groups); and the
physiologically acceptable salts thereof.
The structural formula herein are to be understood to include the
enantiomers of each of the compounds concerned as well as mixtures of
; 25 the enantiomers including racemates.
In general, the compounds of formula (l) in which the carbon atom
carrying the group -(CH2)nX(CH2)mC02Rl and/or the carbon atom in
the group Y carrying the -OH group (particularly the former) are in
the R-configuration and mixtures containing such isomers are
preferred.
The alkyl groups referred to above in the definition of the
compounds of formula (l) may be straiqht or branched.
When Rl in the compounds of formula (l) is phenyl substituted by
a group -C02H the compounds are capable of salt formation with bases.
Examples of suitable salts are alkali metal (e.g. sodium and
potassium) salts.
~ ~75~3~
In compounds where X is -CH-CH- or -CH2CH2-, m is preferably 3
when n is 1, and m is preferably 2 or ~ when n is 2. When X is
-CH_C=CH-, m is preFerably 2 and n is 1, and 1 or 3 ~hen n is 2.
When X is -CH=CH- it is preferably cis -CH=CH-.
When Rl is a substituted phenyl group it may be, for example,
phenyl substituted in the meta, ortho or, in particular, para
positions by a chlorine or bromine atom or a methyl, ethyl propyl,
n-butyl, t butyl, methoxy, ethoxy, propoxy, butoxy, acetyl) propionyl,
methylthio, methylsulphinyl, methylsulphonyl, -C02H, -Cû2CH3,
-C02CH2CH3, -C02- ~ , -NHCHO 9 -NHCOCH3, benzoylamino,
(acetylamino)benzoylamino, (hydroxy)benzoylamino, -CONH2, -CONHCH3
-CON(CH3)2, -CONHCH2CH3, -CONH(CH2CH3)2, -NHCONH2,
-CH2CH(CONH2)NHCOCH3 or -CH2CH(CONH2)NHCO- ~ group.
Particularly useful substituents which may be present on a
substituted phenyl group Rl include Cl 4 alkoxy, Cl_~ alkanoyl~
methylthio, methylsulphonyl, -C02R2, -NHCOR2, -CoNR3R4 [where R2, R3
and R4 are as defined for formula (I)], -NHCONH2 or
-CH2CH(CONH2)NHCOCH3 groups. Especially useful substituents of this
type include methoxy, acetyl, methylthio, methylsulphonyl, -C02CH3,
-NHCOCH3, benzoylamino, (p-acetylamino)benzoylamino, (p-hydroxy)-
benzoylamino, -CONH2, -CON(CH3)2, -NHCûNH2 or -CH2CH(CONH2)NHCOCH3.
The group Rl is preferably a substituted phenyl group where the
substituent may be in the meta~ ortho or, in particular7 para
positions, or is a 2-naphthyl group.
Compounds in which Rl is a phenyl group substituted (particularly
in the para-position) by a methoxy, acetyl, -C02CH3, -NHCOCH3,
benzoylamino, -CONH2, -CON(CH3)2 or -CH2CH~CONH2)NHCOCH3 group, or Rl
is a 2-naphthyl group, are particularly useful.
In the group Y, R6 and R7 are preferably hydrogen atoms.
Compounds in which R5 is H or -CH3 and R6 an~ R7 are hydrogen atoms
are also preferred.
When the Ar phenyl group is substituted, the substituent may be
in the meta, ortho or para positions and may be for example methyl,
ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, metylthio,
rnethylsulphinyl, methylsulphonyl, fluoro, chloro, bromo or
trifluoromethyl. Preferably, only fl single substituellt is present,
particularly at the para-position. In general, Ar is preferably phenyl
~75~
- 4
or phenyl substitued by halogen, particularly fluoro or chloro.
The preferences indicated above apply both separately and in
combination with one or more of the other stated preferences.
A preferred group of compo(Jnds of the invention thus has the
formula (l) in which:
X is -CH=CH- or -CH2CH2- and n is l and m is 3 or n is 2 and m is
2 or 4, or X is -CH=C=CH- and n is l and m is 2 or n is 2 and m is l
or 3;
Rl is a phenyl group substituted (preferably in the
para-position) by a methoxy, acetyl, -C02CH3 -NHCOCH3, benzoylamino,
-CONH2, -CON(CH3)2 or -CH2CH(CONH2)NHCOCH3 gro~p or Rl is a 2-naphthyl
group;
R5 is a hydrogen atom or a methyl group;
R6 and R7 are hydrogen atoms; and
Ar is phenyl or phenyl substituted by fluoro or chloro.
Compounds of this type in which the carbon atom carrying the
~(CH2)nX(CH2)mCû2Rl group is in the R- configuration are
particularly preferred. Especially preferred compounds of this type
are those in which Rl is a phenyl group substituted (preferably in the
parawposition) by benzoylamino or -CONH2, particularly the former.
A particularly useful group of compounds according to the
invention are the following :
[1R-[1~(Z),2~(R*),3a]]-(-)-4-Acetylphenyl 7-[3-hydroxy-
2-(2-hydroxy-3-phenoxypropoxy)-5-oxocyclopentyl]-5-heptenoate;
[1R-[1(Z),2~(R~),3a]]-(-)-4-(Acetylamino)phenyl 7-[3-hydroxy-
2-(2-hydroxy-3-phenoxypropoxy)-5-oxocyclopentyl]-5-heptenoate;
[1R-[1a(Z),2~(R*),3a]]-(-)-4-(Benzoylamino)phenyl 7-[3-hydroxy-
2-(2-hydroxy-3-phenoxypropoxy)-5-oxocyclopentyl]-5-heptenoate;
[1R-[1a(Z,S*),2~(R*),3a]]-(+)-4-[2-(Acetylamino)-3-amino-3-
oxopropyl]phenyl 7-[3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5-
oxocyclopentyl]-5-heptenoate,
[1R-[1a(Z),2~(R*),3a]]-(-)-4-(Aminocarbonyl)phenyl
7-[3-hydroxy-Z-(2-hydroxy-3-phenoxypropoxy)-5-oxocyclopentyl]
-5-heptenoate;
[1R-[1~(Z),2~(R~),3a]]-(-)-3-(Benzoylamino)phenyl 7-[3-hyclroxy
-2-(2-hydroxy-3-phenoxypropoxy)-5-oxocyclopentyl]-5-heptenoate;
~50~L
-- 5 --
[1R-[1a(Z),2~(R*),3a]]-(-)-4-(N,N-Dimethylaminocarbonyl)phenyl
7-[3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5-oxocyclopentyl]-5-
heptenoate;
[1R-[1a(Z),2~(R*),3a]~-(-) Methyl 4-[[7-t3- hydroxy-2-
(2-hydroxy-3-phenoxypropoxy)-5-oxocyclopentyl}-1-oxo-5-heptenyl]oxy~-
benzoate;
[1R-[1a(Z),2~(R*),3a]]-2-Naphthalenyl 7-[3-hydroxy-2-(2-
hydroxy-3-phenoxypropoxy)-5-oxocyclopentyl]-S--heptenoate;
[lR-[1(Z),2~,3a}]-(-)-4-(Benzoylamino)phenyl 7-[3-hydroxy-
2-(2-hydroxy-2-methyl-3-phenoxypropoxy)-5-oxocyclopentyl]-5-
heptenoate;
[1R-[1a(Z),2~,3a]]-4-Methoxyphenyl 7-[2-[3-(4-fluorophenoxy)-2-
hydroxypropoxy]-3-hydroxy-5-oxocyclopentyl]-5-heptenoate;
[1R-[1a(Z),2~(R*),3a]]-(-)-4-(Benzoylamino)phenyl 7-~3-hydroxy-
lS 2-(2-hydroxy-3-phenoxypropoxy)-5-oxocyclopentyl]-4-heptenoate;
[1R-[1a,2~(R*),3a]]-(-)-4-(Benzoylamino)phenyl 3-hydroxy-2-(2-
hydroxy-3-phenoxypropoxy)-5-oxocyclopentaneheptanoate; and
[1R-[1a(E),2~(R*),3a]]-(-)-4-(Aminocarbonyl)phenyl 7-
[3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5-oxocyclopentyl]-5-
heptenoate.
An especially useful group of compounds of this type are :
[1R-[1a(Z),2~(R*),3a~]-~-)-4-Acetylphenyl 7-[3-hydroxy-2-
(2-hydroxy-3-phenoxypropoxy)-5-oxocyclopentyl]-5-heptenoate;
[1R-[1a(Z),2~(R*),3a]]-(-)-4-(Acetylamino)phenyl
7-[3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5-oxocyclopentyl]
-5-heptenoate;
[1R-[1a(Z),2~(R*),3a]]-(-)-4-(Benzoylamino)phenyl
7-[3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5-oxocyclopentyl]
-5-heptenoate;
[1R-[1a(Z),2~(R*),3a]]-(-)-4-(Aminocarbonyl)phenyl
7-[3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5-oxocyclopentyl]
-5-heptenoate;
[1R-[1a(Z),2~(R*),3]]-(-)-3-(Benzoylamino)phenyl
7-[3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5-oxocyclopentyl]
-5-heptenoate;
[1R-[1a(Z),2~(R*),3a]]-(-)-4-(N,N-Dimethyl~minocarbonyl~phenyl
7-[3-hydroxy-2-(2-hydroxy-3-pherloxypropoxy)-5-oxocyclopentyl]-5-
heptenoate;
7~
[1R-[1(Z),2~(R*),3a~]-(-) Methyl 4~[[7-[3- hydroxy 2-
(2-hydroxy-3-phenoxypropoxy)-5-oxocyclopentyl]-1-oxo-5-heptenyl]oxy]-
benzoate;
[1R-[1a(Z),2~(R*),3a]]-2-Naphthalenyl 7--[3-hydroxy-2-(2-
hydroxy-3-phenoxypropoxy)-5-oxocyclopentyl]-5-heptenoate;
[1R-[la(Z),2~,3~]]-4-Methoxyphenyl 7-[2 [3-(4-~luorophenoxy) 2-
hydroxypropoxy]-3-hydroxy-5-oxocyclopentyl]-5~heptenoate;
[1R-[1a(Z),2~(R*),3a]} ( )-4-(Benzoylam:ino)phenyl 7-[3-hydroxy-
2-(2-hydroxy-3-phenoxypropoxy)-5-oxocyclopentyl]-4-heptenoate; and
[1R-[1a,2~(R~),3a]]-(-)-4-(Benzoylamino)phenyl 3-hydroxy-2-(2-
hydroxy-3-phenoxypropoxy)-5-oxocyclopentaneheptanoate.
A ~urther important group of compounds according to the invention
that have especially useful physico-chemical properties which make
them very suitable for pharmaceutical formulation are :
[1R-[1a(Z),2~(R*),3a]]-(-)-4-Acetylphenyl 7-[3-hydroxy-2-(2-
hydroxy-3-phenoxypropoxy)-5-oxocyclopentyl]-5-heptenoate;
[1R-[1a(Z),2~(R*),3a]]-(-)-4-(Acetylamino)phenyl 7-[3-hydroxy
-2-(2-hydroxy-3-phenoxypropoxy)-5-oxocyclopentyl]-5-heptenoate;
[1R-[1a(Z),2~(R*),3a]]-(-)-4-(Benzoylamino)phenyl 7-[3-hydroxy
_
-2-(2-hydroxy-3-phenoxypropoxy)-5-oxocyclopentyl]-5-heptenoate;
[1R-[1a(Z),2~(R*),3a]]-(-)-4-[4-(Acetylamino)benzoylamino]phenyl 7-~3-
hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5-oxocyclopentyl]-5-heptenoate;
[1R-[1a(Z),2~(R*)93a]]-(-)-4-(Aminocarbonyl)phenyl 7-[3-hydroxy
-2-(2-hydroxy-3-phenoxypropoxy)-5-oxocyclopentyl]-5-heptenoate;
[1R-[1a(Z,S*),2~(R*),3a]]-(+)-4-[2-(Acetylamino)-3-amino-3-oxo
_ _ _
propyl]phenyl 7-[3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5-oxocyclo-
pentyl]-5-heptenoate;
[1R-[1a(Z),2~(R*),3a]]-(-)-3-(~enzoylamino)phenyl 7-[3-hydroxy
-2-(2-hydroxy-3-phenoxypropoxy)-5-oxocyclopentyl]-5-heptenoate;
~5~
-- 7 --
[1R-[la(Z),2~(R*),3a]]-(-) Methyl 4-[[7-[3-hydroxy-2
(2-hydroxy-3-phenoxypropoxy)-5-oxocyclopentyl]-l-oxo-5-heptenyl]oxy]-
benzoate;
[1R-[1a(Z),2~(R*),3a]]-2-(Benzoylamino1phenyl 7-~3-hydroxy-2-
(2-hydroxy-3-phenoxypropoxy)-5-oxocyclopentyl¦-5-heptenoate~
[1R-[1a(Z),2~(R*),3a~]-2-Naphthalenyl 7-[3-hydroxy-2-(2-
hydroxy-3-phenoxypropoxy)-5-oxocyclopentyl]-5--heptenoate;
[1R-[1a(Z),2~,3a]]-4-(Methylsulphonyl)phenyl 7-[3-hydroxy-2-[2-
hydroxy-3-r4-(methylthio)phenoxyJpropoxy]-5-oxocyclopentyl]-5-
heptenoate;
t1R-~1a(Z),2~(R*),3]]-(-)-4-(Benzoylamino)phenyl 7-[3-hydroxy-
2-(2-hydroxy-3-phenoxypropoxy)-5-oxocyclopentyl]-4-heptenoate;
[1R-[1a(Z),2~(R*),3a]]-(-)-4-(Benzoylamino)phenyl 9-[3-
hydroxy-2-(2 hydroxy-3-phenoxypropoxy)-5-oxocyclopentyl]-7-nonenoate;
and
[1R-[1,2~(R*),3]]-(-)-4-(Benzoylamino)phenyl 3-hydroxy-2-(2-
hydroxy-3-phenoxypropoxy)-5-oxocyclopentaneheptanoate.
A particularly preferred compound according to the invention is :
[1R-[1a~Z),2~(R*),3]]-(-)-4-(Benzoylamino)phenyl 7-[3-hydroxy-2-
(2-hydroxy-3-phenoxypropoxy)-5-oxocyclopentyl]-5-heptenoate.
Compounds of formula (l) inhibit gastric acid secretion, as
determined for example by their ability to inhibit histamine-induced
secretory responses in the rat perfused stomach, following the method
of Ghosh M.N. and Schild in Br.J.Pharmacol., 1958, 13, 54 as modified
by Parsons M.E. 9 Ph.D Thesis, University of London, 1969.
The compounds also provide gastrointestinal cytoprotection, as
determined for example by their ability to inhibit ethanol-induced
lesions in the conscious rat, following the method of Robert et al in
Gastroenterology, 1979, 77, 433, modified by the use of 5mg/kg/s.c.
indomethacin prior to the administration of the test compound.
The compounds are thus of interest in the prevention and/or
treatment of ulcers. They may also be used in the treatment of other
conditions which arise from the hypersecretion of gastric acid. They
may be formulated in conventional manner with one or more
pharmaceutical carriers, for example for oral, buccal, parenteral or
rectal administration.
~7~0~3~
-- 8 --
The compounds may be Formulated for oral administration as, for
sxample, tablets, capsules, powders, solutions or syrups prepared by
conventional means with acceptable excipents.
The compounds may be formulated for parenteral administration by
bolus injections or continuous infusion. Formulations for injections
may be przsented in unit dosage form in ampoules, or in multi-dose
containers, with an added preservative.
For buccal administration9 the compounds may be formulated as
tablets or lozenges in conventional manner; and for rectal
administration compositions such as suppositories or retention enemas,
for example containing conventional suppository bases such as cocoa
butter or other glyceride9 can be used.
The compounds are preferably administered orally, for example in
amounts of 0~5 to 300 ~g/kg body weight, l to 4 times daily. For
parenteral administration, the compounds may be administèred in
amounts of 0.01 to 10~g/kg body weight, l to 4 times daily. The
precise dose will of course depend on the age and condition of the
patient.
Suitable methods for preparing the compounds of the invention are
described below, the various groups and symbols being as defined above
except where otherwise indicated.
(a) Compounds of formula (l) may be prepared by deprotection of a
corresponding compound in which the ring hydroxy group and the hydroxy
group in Y are protected.
The protected compounds are thus of formula (2)
(CH2)nx(cH2)mco2R
~50~
_ 9 _
in which R8 is a suitable hydroxyl protecting group [e.g.
tetrahydropyran-2 yl, tetrahydrofuran-2 yl, ethoxyethyl,
tri(hydrocarbyl)silyl or arylmethyl] and Y' is defined as a group
R6 R7
CH2 - /C\- C - OAr
RS oR8
The two R8 groups in the compounds of formula (2) are
conveniently the same, but they may be different if desired.
Where R8 is tri(hydrocarbyl)silyl the hydrocarbyl substituents
may bP the same or different e.g. Cl_6 alkyl, C2_6 alkenyl, C3_7
cycloalkyl, C7_20 aralkyl and C6-20 aryl groups. Such groups include
methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, allyl,
phenyl and ben~yl. Preferred hydrocarbyl groups are Cl-4 alkyl, e.g.
methyl and t-butyl. Trimethylsilyl and t-butyldimethylsilyl groups are
particularly preferred.
When R8 is an arylmethyl group it may contain up to 2û carbon
atoms, e.g. benzyl, diphenylmethyl or triphenylmethyl.
The method used to deprotect the protected hydroxyl group will
depend on the nature of R8 but in general acid hydrolysis or reduction
may be used.
Thus, for example when R8 is a tetrahydropyran-2-yl,
tetrahydrofuran-2-yl or ethoxyethyl group deprotection may be carried
out with an acid. Suitable acids include inorganic acids such as
hydrochloric acid and organic acids such as acetic acid or
trifluoroacetic acid. Suitable solvents include ethers (e.g. diethyl
ether, dioxan and tetrahydrofuran) halogenated hydrocarbons (e.g.
dichloromethane, hydrocarbons (e.g. toluene), dipolar aprotic solvents
(e.g. acetone, acetonitrile, dimethylsulphoxide and
dimethylformamide) and alcohols (e.g. methanol, ethanol and ethylene
gylcol). Where desired the solvents may be used in combination with
water. The reaction may be carried out at any suitable temperature,
such as from 0 to 50C, e.9. 40 to 50C.
A tri(hydrocarbyl)silyl group may for example be removed by acid
hydrolysis, e.g. with dilute mineral acid or trifluoroacetic ~cid or
by treatment with fluoride ions (e.g. from a quaternary 2mmonium
-- 10 --
fluoride such as tetra-n-butyl amm~nium fluoride), or by treatment
with aqueous hydrogen fluoride. Arylmethyl groups may be removed by
reduction9 e g. by hydrogenolysis9 e.g. ~ith a noble metal catalyst
such as platinum or palladi~m, or by treatment with a Lewis acid (e.g.
boron trifluoride-etherate) in the presence of a thiol (e.g.
ethanethiol) in a suitable solvent such as dichloromethane at e.g.
room temperature.
Compounds of formula (2) may be prepared by oxidation of a
compound of formula (3)
OH
/-\ (CH2)nx(cH2)mcû2Rl
I I (3)
15 R80 oy1
with for example pyridinium chlorochromate in the presence of a buffer
(e.g. sodium acetate) in a suitable solvent (e.g. dichloromethane) at
an appropriate temperature (e.g. -10C to room temperature).
Alternatively, the oxidation may be carried out with
dimethylsulphoxide, activated by N,N'-dicyclohexylcarbodiimide, in the
presence of pyridinium trifluoroacetate in a solvent such as
dichloromethane at e.g. -10C to room temperature. Other conventional
oxidative methods can also be used, for example Jones reagent.
Intermediate compounds of formula (3) may be prepared by the
methods generally described in European Patent Specification 160495.
It will be appreciated that the deprotection method (a) is
usually appliad in connection with the formation by oxidation of the
cyclopentyl ring oxo group. Thus, the compounds of formula (1) may
generally be prepared by oxidising a corresponding compound of formula
(3).
The formation of the ring oxo group may however be effected prior
to the introduction of the desired Rl group by esterification (e.g. by
method (b) below) and the protecting groups removed thereafter.
30~75~
(b) Compounds of formula (l) may also be prepared by esterifying the
corresponding carboxylic acids, i.e. the compounds in which Rl is a
hydrogen atom, by conventional methods.
Thus for example a compound of formula (l) may be prepared by
conversion of the corresponding carboxylic acid into an acti~ated
derivative (e.g. a corresponding mixed anhydride) formed for example
by reaction with an alkyl chloroformate (e.g. isobutyl chloroformate)
or an acid chloride (e.g. pivaloyl chloride) in the presence of a
suitable base (e.g. triethylamine or pyridine). The activated
derivative can then be reacted with an appropriate compound RlûH,
which are either known compounds or may be prepared by methods
analogous to those used for the preparation of known compounds.
Suitable solvents include dipolar aprotic solvents (e.g. acetone,
acetonitrile and dimethylformamide) and halogenated hydrocarbons (e.g.
lS dicloromethane). The reaction may be carried out at any suitable
temperature e.g. from ûC to room temperature.
The same group of compounds of formula (1) may also be prepared
by first reacting the corresponding carboxylic acid with
dicyclohexylcarbodiimide in the presence of 4-dimethylaminopyridine
and then treating the product with a phenol RlûH. This reaction is
conveniently performed at an appropriate temperature (e.q. 0C to room
temperature) in a solvent such as ether or dichloromethane.
The carboxylic acids required as starting materials for this
reaction may be prepared by the methods generally described in
European Patent Specification 160495.
(c) Compounds of formula (1) in which X is a -CH2-CH2- group may be
prepared by reduction of a corresonding compound in which X is a cis
or trans -CH=CH- group or an acetylene group. Suitable methods of
reduction include hydroqen in the presence of a catalyst, e.q.
palladium, on a support (e.g. carbon). Suitable solvents include
ethyl acetate, ethanol and methanol.
(d) Cornpounds of formula (1) in which X is a -CH=CH- group may be
prepared by selective reduction of a corresponding compound in which X
is an acetylene group. Suitable methods of reduction include hydrogen
in the presence of a catalyst, e.g. palladiwn on a support (e.g. CaC03
or BaS04) and poisoned for example by lead or quinoline. Suitable
solvents include ethyl acetate and methanol. This reaction is
particularly suitable for the preparation of compounds in which X is
cis -C~=C~
The acetylenes required as starting materials may be prepared
from the corresponding acetylenic acids by esterification using the
methods described above. The acetylenic acid intermediates may be
prepared by the methods generally described in European Patent
Specification 160495.
(e) Compounds of formula (l) in which X is a trans -CH=CH- group may
be prepared by isomerisation of a corresponding compound in which X is
a cis CH=CH- group.
The isomerisation may for example be effected by treating the
corresponding cis compound with toluene-p-sulphinic acid in dioxan
(e.g. at reflux), or azobisisobutyronitrile and thiophenol, using for
example a hydroarbon solvent (e.g. benzene) at any suitable
temperature up to reflux.
The processes in methods (b-e) may also be applied to compounds
of formula (2) and (3) and the products subsequently converted into
compounds of Formula (l) by the methods described above.
When a specific enantiomer of formula (l) is required, startinq
materials having the desired stereochemical configuration should be
used in the above processes. Such starting materials may be prepared
for example using the methods dscribed in European Patent
Specification 16C495 from an enantiomeric intermediate as described in
European Patent Specification 74856.
- 13 -
The following examples illustrate the invention.
Temperatures are in C.
'Dried' refers to drying with anhydrous Mg504. T.l.c. - Thin layer
Chromatography on silica. Chromatography was carried out on silica
gel.
The following abbreviations are used:
ER-ether; EA-ethyl acetate; PE-petroleum ether (b.p. 60-80 unless
otherwise stated); DIBAL-diisobutylaluminium hydride; THF-tetrahydro-
furan; CH2Cl2-dichloromethane; CHCl3-chloroform; CHBr3-bromoform; DMF
-dimethylformamide; DMSû-dimethylsulphoxide; EtOH-ethanol;
MeOH-methanol; CH3CN-acetonitrile; Et3N-triethylamine; N.T.P. - normal
temperature and pressure.
Intermediate 1
[(tetrahydro-2H pyran-2-yl)oxy]propoxy~-3-[(tetrahydro-2H-pyran-2
yl)oxy]cyclopentyl]-5-heptenoic acid
Intermediate 2
[15-[1a_Z),2~,3a~5]]-(~) Methyl 7-[5-hydroxy-2-[2-methyl-3-phen-oxy-=2
r(tetrahydro-2H-pyran-2-yl)oxy]propoxy]-3-t(tetrahydro-2H-PYran-2-
yl)oxy]cyclopentyl]-5-heptenoate
Intermediate 3
(a) [15-[la(Z),23,3a,5]]-(+?-Methyl 7-[2-[3-(4-fluorophenoxy)-2-
[(tetrahydro-2H-pyran-2-yl)oxy]propoxy]-5-hydroxy-3-[(tetrahydro-2H-
pyran-2-yl)oxy]cyclopentyl]-5-heptenoate
(b) [1S-[1a(Z),2~,3a,5a]]-(+)-Methyl 7-[2-[3-(3-chlorophenoxy)-2-
~=~
2H-pyran-2-yl)oxy]cyclopentyl]-5-heptenoate
(c) [1S-[1a( ~ 2~,3a,5a]]-(+)-Methyl 7-[5-Hydroxy-2-[3-t4-
(methylthio)phenoxy]-2-[(tetrahydro-2H-pyran-Z-yl)oxy]propoxy]-
~
~s~
- 14 -
Intermediate 4
~ : =
[3aR-[3a~,4a
2H~i~yra_-2 ~ oxy]propoxy]-5-[(tetrahydro-2H-pyran-2-yl)oxy]-2H-
cyclopenta[b]furan-2-ol
Intermediate 5
__
[1R-[1a,5a,6a,8R*
(phenylmethoxy)-2-oxabicyclo[3.2.1]octan-3-one
Intermediate 6
[15-[1a(Z),2~(25*)~3a,5a]]-(+)-Meth~l 9-[5-hydroxy-2-[3-phenoxy-2-
[(tetrahydro-2H-pyran-2-yl)oxy]_ropoxy3-3-[(tetrahydro-2 ~ -
oxy]cyclopentyl]-7-nonenoate
lS Intermediates 1-6 were prepared as described in European Patent
Specification No 160495.
Intermediate 7
Methyl 4-[(tetrahydro-2H-pyran-2-yl)oxy]benzoate
A solution of methyl 4-hydroxybenzoate (1ûg) in EA (6ûmQ) containing
saturated ethereal HCl (3.5 mQ) was treated with dihydropyran (12mQ)
and the solution was allowed to stand at room temperature for 24h. A
further quantity of dihydropyran (12mQ) and ethereal HCl (3.SmQ) was
added and the solution was left for 17h. The solvent was evaporated
and the residue was dissolved in ER (10ûmQ) and washed with 2N NaOH
solution (2x50mQ), brine (50mQ) and then dried. Evaporation gave a
residue which on purification by chromatography using 3:97 ER -
toluene as eluant gave the title compound as a white solid (1û.2g),
m.p. 58-62.
Intermediate 8
4-[(Tetrahydro-2H-pyran-2-yl)oxy]benzoic acid
A suspension of Intermediate 7 (10.09) in MeOH (20ûmQ) and 5N NaOH
solution (3ûmQ) was stirred at room temperature for 24h. The solution
was evaporated to about 5ûmQ and diluted with water (10ûmQ). The
mixture was filtered through hyflo and the filtrate was washed with ER
~50~
- 15 -
(2x30mQ) and acidified by the dropwise addition of 5N hydrochloric
acid. The resulting precipitate was filtered off to give the title
co pound as a white solid (8.259), m.p. 138-399.
Intermediate 9
.
N-(4-HydroxyphenYl)-4-~(tetrahydro-2H-Dvran-2-yl)oxy]benzamide
A solution of Intermediate 8 (~.19) in dry THF (200mQ) at 0 was
treated with Et3N (6.0m~) and then pivaloyl chloride (5.4mQ) and the
mixture was stirred at 0 for 30 min. A solution of 4-aminophenol
(3.09) in DMF ~30m~) was added and the mixture was stirred for 17h at
room temperature and for 1.5h at 80. The mixture was filtered, the
filtrate was evaporated and the residue dissolved in ER (200mQ).
Pouring into water (200mQ) gave a precipitate wi~ich was filtered off
and crystallised from EA-MeOH to give the title compourd as a white
solid (5.69)~ m.p. 173-174.
Intermediate 10
(a) [15-[1a(Z),2~(25*)J3aL5a]]-(~)-4-Acetylphenyl 7-[5-hydroxy-
2-[3-phenoxy-2-[(tetrahydro~2H-pyran-2-yl)oxy]propoxy]-3-[(tetra-
~ py-ran--2-yl)oxy]cyclopentyl]-5-heptenoate
A solution of Intermediate 1 (0.459) in dry CH3CN (15m~) at -10 was
treated with Et3N (0.2m~) followed by isobutyl chloroformate
(0.14mQ). After stirring for 45 min. p-hydroxyacetophenone (0.239)
was added. Stirring was continued for 2h at -10 to 0~ and then the
mixture was diluted with water and extracted with ER (3 x 5BmR). The
combined extracts were washed with 10o copper sulphate solution
(75m~), water (10m~) and then dried. Evaporation gave a residue which
on purification by chromatography usinq 2:1 ER-PE (40-60) as eluent
gave the title compound as a gum (0.439).
I.r. (CHBr3) 3550, 1753, 1678cm-l, [a]D ~ 19.6 (MeOH)
The following compounds were prepared in a similar manner from
Intermediate l and the appropriate phenol:-
~ ~75~
- 16 -
(b) [15-[1(Z),2~(25*),3a,5a]]-(+)-4-(Acetylamino)phenyl 7-[5-
hydroxy-2-[3-phenoxy-2-[(tetrahydro-2H-pyran-2- ~ xy]propoxy]-3-
[(tetrahydro-2H_cyran-2-yl)oxy]cycloDentyl]-5-heptenoate
I.r. (CHBr3) 3580, 3425, 1750, 1690cm~l, []D~ ~ 7 9 (MeOH)
(c) ~ nocarbonyl)amino]phenyl
2-[3-phenoxy-2-[(tetrahydro-2
[(tetrahydro-2H-pYran-2-yl)oxy]cyclopentyl]-5-heptenoate
I.r. (CHBr3) 3510, 3410, 1748, 1682cm-l, [a]22 + 15.4 (MeOH)
(d) [15-~1a(Z),2~(25*)~3a,5a]]-(+)-4-(Benzoylamino)phenyl 7-[5-
hydroxy-2-~3-phenoxy-2-[(tetrahydro-2H=pyran-2-yl)oxy]propo~y]-3-
Pivaloyl chloride (0.189) was added to a solution of Intermediate 1
(0.79) and Et3N (0.389) in dry DMF (5mQ) at 0. After 10 min a
solution of 4-(benzoylamino)phenol (0.539) in DMF (2mQ) was added and
stirring continued For 6h at 0 and 18h at room temperature. The
reaction mixture was diluted with EA (150mQ) and washed consecutively
with water (2 x 50mQ), 10o copper sulphate solution (2 x 50mQ), water
(50mQ) and brine (50mQ). The dried organic extract was evaporated to
give a residue which was purified by chromatography on
Et3N-deactivated silica using 1:1 cyclohexane-EA as eluent. The title
compound was obtained as a gum (0.559).
~n
I.r. (CHBr3) 3520, 3425, 1750, 1673cm-l, [a]D + 20 (CHCl3)
The following compounds were prepared in a similar manner to
Intermediate 10d from Intermediate l and the appropriate phenol:-
(e)
amino]phenyl 7-[5-hydroxv-2-[3-phenoxy-2-[(tetrah
yl)oxy]propoxy]-3-[(tetrahydro-2H-pyran-2-yl)oxy]cyclopentyl]-5-
~e~
I.r. (CHBr3) 3580, 3520, 3425, 1745, 1690, 1670cm-l, []DO * 20.6
(CHCl3)
~ ~7~19~
(f) [15-[1a(Z)~2~(2s*)93a25a]]-(+?-4-(-Ami--n-ocarbonyl)p-h-e-nyl 7-[5-
~droxy-2-[3-phenoxy-2-[(tetrahydro-2H-Pyran-2-yl)oxy]pr-op-oxy]-3
[(tetrahyd _ 2H_pyran-2-yl)oxy]cyciopentyl]-5-heptenoate
I.r. (CHBr3) 3520, 34D0, 1755, 1672cm~l, [a]D ~ 20 (CHCl3)
(9) _15-[1a(Z,R*),2~(25*),3a~5a]]-(+)-4-[2-(Acetylamino)-3-amino-
3-oxopropyl]pheny-l _-[ _ hydrox ~ -[(tetrahydro-2H-pyran-
2-yl?o~y]propoxy]-3-[(tetrahydro-2H-pyran-2-yl ~ lopentyl]-5-
I.r. (CHBr3) 3500, 3400, 1745, 1690, 1660cm-l, [a]D + 24 (CHCl3)
(h)
nydroxy-2-[3-phenoxy-2-[(tetrahydro-2H=pyran-2-yl)oxy]pro oxy]-3-
I.r. (CHBr3) 3700-3100, 1755, 1677cm-l, [a]D + 27 (CHCl3)
(i) ~
7-[5-hydroxy-2-[3-phenoxy-2-[(tetrahydro-2H-pyran-2-yl)oxy]
propoxy]-3
I.r. (CHBr3) 3530, 1750, 1740, 1626cm-l
(j) [15-[1a(Z),2~(25*) ,3a~5a]] Methyl 4-[[7-[5-hydroxy-2-[3-
phenoxy-2-[(tetrahydro-2H_pyran-2-yl)oxy]propoxy]-3-[-(tetrahydro-2H
pyran-2-yl)oxy]cyclopentyl]-1-oxo-5-heptenyl]oxy]benzoate
I.r. (CHBr3) 35~0, 3520, 1750, 1715cm~l
(k) [15-[1a(Z),2~(25*),3a,5a)-(+)-4-[[[4-[(tetrahydro-2H-PYran-2-
yl)oxy]phenyl]carbonyl]amino]phenyl 7-[5-hydroxy 2-[3 p_ noxy-2-
[(tetrahydro-2H-pyran-2-yl)oxy]propoxy]-3-[(tetra
oxy]cyclopentyl]-5-heptenoate, from Intermediates 1 and 9
I.r. (CHBr3) 3580, 3420, 1748, 1668cm-l, [a]D + 21 (CHC13)
~7~
- 18 -
(~) [15-[1a(Z),2~(25*),3,5a]]-2-(Benzoylamino)phenyl 7-[5-
[(tetrahydro-2H_pyran-2-yl)oxy]cyclopentyl]-5-heptenoate
I.r. (CHBr3) 3520, 3440, 1728, 1688, 1516cm~l
(m) [15-[1a(Z),2~(25*),3a?5a]]-2 Naphthale_yl 7-[5-hydroxy-2-[3-
phenoxy-2-[(tetrahydro-2H_pyran-2-~ )oxy]propoxy]-3-[(tetrahydro-2H-
yran-2-yl)oxy]cyclopentyl]-5-heptenoate
I.r. (CHBr3) 3530, 1750cm~
1~
(n) [15-[1a(Z)~ 3a~5a]]-4-(Benzoylamino)phenyl 7-[5-hydroxy-2-
[2-methyl-3-phenoxy-2-[(tetrahydro-2H-pyran-2-yl)oxy]propoxy]-3-
[(tetrahydro-2H-pyran-2-yl)oxy]cyclopentyl]-5-heptenoate~ from
Intermediate 12a.
lS I.r. (CH8r3) 3520, 3430, 1750, 1675cm~l
(o) [15-[1a(Z),2~,3,5]]-4-Methoxyphenyl 7-[2-[3-(4-fluoro
phenoxy)-2-[(tetrahydro-2H-pyran-2-yl)oxy]propoxy]-5-hydroxy-3
~ , from
ZO Intermediate 12b. I.r. (CHBr3) 3590, 3530, 1748cm~l
(p) ~ (Methylthio)phenyl 7-[2-[3-(3-
chlorophenoxy)-2-[(tetrahydr _ -pyran-2 yl)oxy]propoxy]-5-hydroxy-3-
[(tetrahydro-2H-pyran-2-yl)oxy]cyclopentyl]-5-heptenoate,
from Intermediate 12c. I.r. (CH8r3) 3580, 3520, 1750cm~l
(q) [15-[1a(Z),2~,3a,5a]]-4-(Methylsulphonyl)phenyl 7-[5-
hydroxy-2-[3-[4-(methylthio)phenoxy]-2-[(tetrahydro-2H_pyran-2-yl)
oxy]propoxy]-3-[(tetrahydro-2H-pyran-2-yl)oxy]cycl~entyl]-5
heptenoate, from Intermediate 12d. I.r. (CH8r3) 3520, 1758cm~
(r)
hydroxy-2-[3-phenoxy-2 [(tetrahydro-2H_pyran-2-yl)oxy]propoxy]-3
Lc _~'
from Intermediate 12e. I.r. (CHBr3) 3520, 3405, 3600-3200, 1960,
1758, 1675cm~l
-- 19 --
(s) t15-[1a(Z)L2~(25*),3~,5~]]-4-(8enzoylamino)phenyl 7-[5~ydroxy
-2-[3-Dhenoxv-2-[(tetrahvdro-2H-pyran-2-Yl)oxy]propoxy]-3
[(tetrahvdro-2H-ovran-2-vl)oxv]cvloDentvl]-4-hepten~ate,
from Intermediate 12f. I.r. (CH8r3) 3520, 3430, 1750, 1678cm~l
(t) [15-[1a(Z)~2~(25*)?3,5a3]-4-(Benzoylamino)phenyl 9-[5-
hydroxy-2-[3-phenox ~ 2-yl)oxy]propo_y]-3-
nonenoate,
from Intermediate 129. I.r. (CHBr3) 3520, 3420, 1748, 1672cm~
Intermediate 11
-
(a) ~ 2R*),3~]]-(-)-4 ~
phenoxy-2-[(tetrahydro-2H-pyran-2-yl)oxy]propoxy]-3-[(tetrahy~ro-2H-
pyran-2-yl ~ v]cyclopentyl]-5-heptenoate
A stirred solution of Intermediate 10a (0.399) in dry CH2Cl2 (4m~) and
dry DMSO (0.4m~) was treated with dicyclohexylcarbodiimide (0.59)
followed by pyridinium trifluoroacetate (0.179). After 5h at roorn
temperature the mixture was poured into water (50mQ) and extracted
with ER (3x75m~). Evaporation of the dried extracts gave a residue
which was purified by chromatography on acid-washed (pH3.8) silica.
The title_compound was obtained as a colourless gum (0.279).
I.r. (CHBr3) 1760, 1743, 16aOcm-l, []D2 2 -13.7 (MeOH)
The following compound was prepared in a similar manner:-
(b) [1R-[1(z)~2~(2R*)~3a]]-(+)-4-(Acetylamino)phenyl 7-[5=oxo-2-
[3-phenoxy-2-[(tetrahydro-2H-Pyran-2-yl)oxy]propoxy]-3-[(tetrahydro
_ -pyran-2-yl)oxy]cyclopentyl]-5-heptenoate, from Intermediate 10b
I.r. (CHBr3) 3420, 1740, 1685cm-l, []D + 16.7 (MeOH)
(c) ~
oxo-Z-[3-phenoxY-2-[(tetrahydro-2H-Dvran-2-vl)oxylDroDoxy]-3
[(tetrah dro-2H-Dvran-2-Yl)oxY]cYcloDentyl-5-heptenoate
A cold (0), stirred suspension of Intermediate 10c (0.159) and
anhydrous sodium acetate (0.059) in CH2Cl2 (2m~) was treated with
pyridinium chlorochromate (0.13q). The mixture was stirred at 0 for
- 20 -
30 min. and at room temperature for 1h and then purified by
chromatography on acid-washed (pH3.8) silica using EA as eluent. The
title compound was obtained as a gum (0.09g). T.l.c. EA Rf 0.3.
The following compounds were prepared in a similar manner:-
(d) [1R-[1a(z)~2~(2R*)~3a]~ )-4-(Benzoylamino)phenyl 7-[5-oxo-
2H_~yran-2 ~l)oxy]cyclopentyl~-5-heptenoate, from Intermediate 10d
I.r. (CHBr3) 3430, 1740~ 1675cm-l, [~D -11 (CHCl3)
(e) ~
phenyl 7-[5-oxo-2-[3-phenoxy-2-[(tetrahydro-2~l-pyran-2-yl)oxy]propoxy]
-3-[(tetrahydro-2~H-pyr-a-n-2-yl)oxy]cyclopentyl3-5-heptenoate~ from
Intermediate 10e
I.r. (CHBr3) 3420, 1740, 1690, 1670cm-l, [a]D -5 (CHCl3)
(f)
2-[3-phenoxy-2-[(tetrahydro-2H pyran-2-yl)oxy]propoxy]-3-[(tetrahydr
2~!-pyran-2-yl)oxy]cyclopentyl]- -heptenoate, from Intermediate 10f
I.r. (CHBr3) 3525, 3405, 1742, 1675, 1599cm-l, ~a]D -16.3 (CHCl3)
(9) [1R-[1a(Z,S* L2~(2R*)~3a]]-(-)-4-[2-(Acetylamino)-3-amino-3-
oxooroDvl~phenYl 7-[5-oxo-2-[3-PhenoxY-2-[(tetrahYdro-2H- ran-2-vl)-
oxy]propoxy-3-[(tetrahydro--2H-pyran-2-yl)oxy]cyclopentyl]-5
heptenoate, from Intermediate 109.
I.r. (CHBr3) 3505, 3400, 1740, 1690, 1665cm-l, [a]D -3.4 (CHCl3)
(h)
oxo-2-[3-phenoxy-2-[(tetrahydro-2H pyran-2-yl)oxy]proeoxy]-3-
~
from Intermediate 1Oh. I.r. (CHBr3) 3430, 1742, 1680, 1526cm-l, ~a]D
-7 (CHC13)
9~
- 21 -
7-[5-oxo-2-[3-phenoxy-2-[(tetrahydro-2H-pyran-2-yl)oxy]propoxy]-3-
[(tetrahydro-2H-pyran-~ )oxy]cyclopentyl]-5--heptenoate~ from
Intermediate 10i. I.r. (CHBr3) 1740, 1622cm-1
(j) [1R-[1a(Z),2~(2R*),3a]] Methyl 4-[[7-[5-oxo-2-[3-phenoxy-2=
[(tetrahydro-2H pyran-2-yl)oxy]propoxy]-3-r(tetrahydro-2H~pyran-2-
yl)oxy]cyclopentyl]-1-oxo-5- eptenyl]oxy]benzoate, from Intermediate
10j. I.r. (CHBr3) 1745, 1720cm~
(k) [1R-[1(Z),2~(2R*),3a]~-(-)4-[[[4-[(Tet
yl_oxy]ph_nyl~carbonyl]amino]phenyl 7-[5-oxo-2-[3-phenoxy-2-
[(tetrahydro-2H-pyran-2-yl)oxy]propoxy-3-[(tetrahydro-2H-pyran-2-yl)
oxy]cyclopentyl]-5-heptenoate, from Intermediate 10k
I.r. (CHBr3) 3435, 1745, 1720, 1672cm~
[a]D -8.9 (CHCl3)
11Q) [1R-[1a(Z),2~(2R*)3a]]-2-(8enznylamino)phenyl 7-[5-oxo-2-[3-
phenoxy-2-[(tetrahydro-2H_pyran-2-yl)oxy]propoxy]-3-[(tetrahydro-2H-
pyran-2-yl)oxy]cyclopentyl]-5-heptenoate, from Intermediate 10Q
I.r. (CHBr3) 3440, 1760, 1740, 1678cm~l
11m) [1R-[1a(Z)72~(2R*),3a]]-2-Naphthalenyl 7-[5-oxo-2-[3-phenoxy-2-
[(tetrahydro-2H_pyran-2-yl)oxy]propoxy]-3-r(tetrahydro-2H-pyran-2-yl)
oxy]cyc~opentyl]-5-heptenoate, from Intermediate 10m
I.r. (CHBr3) 1745cm~l
11n) [1R-[1a(z)~2~3a]]-4-(Benzoylamino)phenyl 7-[2-[2-methyl-3-
phenoxy-2-[(tetrahydro 2H-pyran-2-yl)oxy~propoxy]-5-oxo-3-[(tetrahydro
_2H-pyran-2-yl)oxy]cyclopentyl]-5-heptenoate, from Intermediate 10n
I.r. (CHBr3) 3430, 1740, 1672cm~l
110) ~ Metho_yphenyl 7-[2-[3-(4-fluorophenoxy)
~y~ y_)oxy]cyclope tyl]-5-heetenoate, from Intermediate 10O.
- 22 -
I.r. (CHBr3) 1744cm~l
The following compounds wsre prepared in a similar manner to
Intermediate 11a:-
11p) [1R-[1a(Z)~2~,3a]]-4-(Methylth_)phenyl 7-[2-[3-
~3-chlorop~henoxy)-2-[(tetrahydr
[(tetrahydro-2 ~ _ ~ nt~V.)~]~ heptenoate, from
Intermediate 10p. I.r. (CHBr3) 1742cm~l
(q) [1R-[1a(Z)~2~3a]]-4-(Methylsulphony-l)phenyl 7-[2-[3 [4-
(methylthio)phenoxy]-2-[(tetrahydro-2 ~ _5_
oxo-3-C(tetrahydro-2H-pyran-2-yl)oxy]cy_lopentyl]-5-heptenoate,
from Intermediate 10q. I.r. (CHBr3) 1740cm~l
The following compounds were prepared in a similar manner to
Intermediate 11c:-
(r) ~phenox_-2-[(tetrahydro-2H_nvran_2_yl)oxy]propoxy]-3-[(tetrahydro-2H-
pyran-2-yl)oxy]cyclopentyl]-4,5-heptadienoate, from Intermediate 10r
I.r. (CHBr3) 3520, 3410, 1962, 1742, 1676cm~l
'~ (s) ~, ~ ~
2-[3-phenoxy-2-[(tetrahydro-2H pyran-2-yl)oxy]propoxy]-3-[(tetrahydro-
~ , from Intermediate 10s
I.r. (CHBr3) 3430, 1742, 1675cm~
(t)
~3-phenoxy-2-[(tetrahydro-2H-pyran-2-yl)oxy]propoxy]-3-
~ , from
Intermediate 10t. I.r. (CHBr3) 3430, 1742, 1678cm~l.
Intermediate 12
(a) [15_[1(z),2~,3a,5a]l-7-[5-Hydroxy-2-[2-methyl-3-phen
2-[(tetrahydro-2H-pyran-2-yl)oxy]prop-oxy]-3-[(tetrahydro-2H-~-yr-n
yl)oxy]cyclopentyl]-5-heptenoic acid
A solution of Intermediate 2 (0.98~) in MeOH (15m~) was treated with
5N NaOH solution (6mQ). After 30 min the mixture was poured into
water (100mQ) and extracted with ER (150mQ). The aqueous solution was
- 23 -
acidified with a saturated NH4Cl solution (150mQ) and then extracted
with EA (4x50mQ). The combined extracts were dried and evaporated to
give the title com~ound as a gum (0.889). I.r. (CHBr3) 3510,
3400-2500, 1730, 1708cm~l
The following compounds were prepared in a similar manner:-
(b) [15[1a(Z),2~,3a,5a]]-7-[2-[3-(4-Fluorophenoxy)-2-[(tetrahydro-
2H-pyran-2-yl?oxy]propoxy]-5-hydroxy ~ tr~lhydro-2H-pyran-2-yl?
~]cyclopenty -5-he~ enoic acid, from Intermediate 3a. I.r. (CHBr3)
3510, 3400-24ûO, 1730, 1708cm~l
(c) [1S[1a( ~ 2~,3a,5a]]-7-[2-[3-(3-Chlorophenoxy)-2-
[(tetrahydro-2H_pyran-2=yl)oxy]propoxy]-5-hydroxy-3-[(tetrahydro-2H
yran-2-yl)oxy]cyclopentyl]=5-heptenoic acid, from Intermediate 3b
I.r. (CHBr3) 3590, 3510, 3700-2400, 1730, 1705cm-l
(d) [15-[1~(Z)~2~L_a~5a]]-7-[5-Hydroxy-2-[3-[4-(methylthio)
phenoxy]-2- ~ -
-
pyran-2-yl)oxy]cyclopentyl]-5-heptenoic acid, from Intermediate 3c.
I.r. (CHBr3) 3520, 3600-2500, 1730, 1708cm~l
(e) [15-[1a,2~(2S*),3a,5a]]-7-[5-Hydroxy-2-[3-phenoxy-2-
[(tetrahydro-2H_pyran-2-yl)oxy]propoxy]-3-[(tetrahydro-2H-pyran-2
yl)oxy]cyclopentyl]-4~5-heptadienoic acid, from Intermediate 15
I.r. (CHBr3) 3500, 1920, 1730cm-
(f)
[(tetrahydro-2H_pyran-2-yl)oxy]propoxy]-3-[(tetrahydro-2H-pyran-2
yl)oxy]cyclopent~ ]-4-heptenoic acid
(3-Carboxypropyl)triphenylphosphonium bromide (1.119) and potassium
tert-butoxide (0.589) in dry THF (10mR) were stirred at ambient
temperature for 45 min. A solution of the Intermediate 19 (0.58q) in
dry THF ~10m~) was added and stirring at ambient temperature was
continued for 1h. A further identical quantity of preformed ylide was
added to the reaction mixture and stirring was continued for 1.5h.
Water (20mQ) was added and the mixture was washed with E~ (3x50m~).
~7~
- 24 -
The organic washings were back extracted with 8o NaHC03 solution
(2x20mQ) The combined aqueous extracts were treated with saturated
NH~Cl (30mQ) and the product was extracted with ER (3x50mQ). The
extracts were washed with brine (15mQ), dried and concentrated in
vacuo to yield the title compound as an oil (0.559).
I.r. (CHBr3) 3500, }600-2300, 172B, 1710cm~l
The following compound was prepared in a similar manner to
Intermediate 12a:-
(9) [1S-[1a(Z),2~(2 ~ y-2-[3-phenoxy~2-
[(tetrahydro-2H--pyran-2-yl)oxy]propoxy]-3-[(tetrahydro-2H-pyran
, from Intermediate 6
I.r. (CHBr3) 3510, 3000-2500, 1730, 1710cm~
Intermediate 13
~1s-[1a22-~(2s*)~3a~5a]]-Me-thy--l 6-hydroxy-7-[5-hydroxy-2-[3-phenoxy-2-
-
[(tetrahydro-2H-pyran-2-yl)oxy~propoxy]-3-[(tetrahydro-2H
pyran-2-yl)oxy]cyclopentyl]--4-heptynoate
n-Butyl lithium (1.6M in hexane, 61.5mQ) was added to a solution of
diisopropylamine (13.8mQ) and hexamethylphosphoramide (17.5mQ) in ER
(140mQ) at 0 under nitrogen. The solution was cooled to -70 and a
solution of 4-pentynoic acid (4.879) in THF (50mQ) added. The mixture
was then allowed to warm to room temperature, and after 1h, a solution
of Intermediate 4 (3.59) in ER (60mQ) was added. After 18h, a
solution of oxalic acid dihydrate (149) in water (200mQ) was added and
the organic phase separated. The aqueous phase was extracted with EA
(200mQ) and the combined organic phases dried and evaporated. The
residue was dissolved in DMF (30mQ) and treated with methyl iodide
(12mQ) and potassium fluoride (89). After 3h the solution was diluted
with EA (20nmQ) and washed with water (3x200mQ) and brine (200mQ).
The aqueous washings were back-extracted with EA (200mQ) and the
combined organic phases dried and evaporated. The residue was
purified by chromatography using 4:1 increasing to 2:1 ER-EA as eluent
to give the title compound as an oil (2.99).
I.r. (CHBr3) 3580, 3500, 1728cm~l
~X75~
- 25 -
Intermediate 14
[1R-[1a~2~(2R*)93a95a~]-Methyl 6-acetyloxy-7-[5-acetylox~ 2-[3-
phenoxy-2-[(tetrahydro-2H-pyran-2-yl)oxy]propoxy]-3-[(tetrahydro-2H-
pyran-2-y ~ cyclopentyl]-4-heptynoate
Triethylamine (8.2m~), acetic anhydride (6.7m~) and 4-dimethylamino
pyridine (70mg) were added to a stirred solution of Intermediate 13
(2.89) in CH2Cl2 (60mQ). After 2h the solvent was removed and
chromatography of the residue using 4:1 ER-PE (40-60) as eluent gave
the title compound as an oil (3.19). I.r. (CHBr3) 1728cm~
Intermediate 15
2R*)~3a~5a]]-Methyl 7-[5-acetyloxy-2-[3-phenoxy-2-
[(tetrahydro-2H_pyran-2-yl)oxy]oroDoxy]-3-[(tetrahydro-2H-pyran-2
yl)oxy]cyclopentyl~-4-S-heptadienoate
Methyl lithium (1.6M in ER, 44.5mQ) was added to a stirred suspension
of cuprous iadide (6.89) in ER (120mQ) at -1û under nitrogen. When
the addition was complete, a clear solution was obtained which was
then cooled to -78 and a solution of the Intermediate 14 (0.859) in
ER (50m~) at -78 was added. After 1.5h, saturated NH4Cl solution
(2ûOmR) was added and the mixture stirred at room temperature for 1h.
The organic phases was washed with saturated brine (2ûOmQ) and the
aqueous phase extracted with ER (2ûûmQ). The dried organic extracts
were evaporated and the residue purified by chromatography
using 3:1 ER - PE (40-60) as eluent to give the title compound as an
oil (1.2q). I.r. (CHBr3) 1960, 1728cm~
Intermediate 16
[1R-[1a75a~6a~8R*(R*)]]-8-(2-Hydroxy-3-phenoxypropoxy)-6-(phen
methoxy)-2-oxabicyclo[3.2.1]octan-3-ol
DIBAL (1M in hexane, 10mQ) was added to a cold (-78), stirred
solution of Intermediate 5 (2.79) in CH2Cl2 (50m~). After 2h a
further quantity of DIBAL (6.7m~) was added and stirring continued for
2.5h. MeOH (20mQ) was added dropwise and after 15 min at room
temperature ether (60m~)was added. The resultant mixture was filtered
through hyflo and ti1e filtrate evaporated to qive the title compound
as a qum (2.69). I.r. (CHBr~) 3580, 2720, 1718cm~l
S~9~
- 26 -
Intermediate 17
,
[1S-[1 ~ 3-phenoxypro~poxy)-S-
._.
To a cold (0) salution of potassium tert-butoxide (2.99) in THF
(40mQ), under N2, was added (methoxymethyl)triphenylphosphonium
chloride (S.849). After 5 min a solution of Intermediate 16 (2.69) in
THF (25mQ) was added and the mixture stirred at 0 for 30 min. A
saturated solution of NH4Cl (50mQ) was added and the mixture was
extracted with ER (3x60mQ). The combined extracts were dried and
evaporated to yield an oil (9.19).
The crude product was stirred in 1:1 0.25N sulphuric acid - acetone
(80mQ) for 48h at ambient temperature. The organic solvent was then
removed in vacuo and the aqueous residue extracted with EA (3x50mQ).
The combined organic phases were washed with saturated brine (}OmQ),
dried and evaporated. The residue was purified by chromatography
using ER as eluent to give the title com~ound as an oil ~1.5q).
I.r. (CHBr3) 3580, 3460, 2720, 1718cm-l.
Intermediate 18
[1S-[1a92~(25*),3a,5a]]-2-[3- Phenoxy-2-[(tetrahydro-2H-~yran-2-
yl)oxy]propoxy]-5-(phenylmethoxy)-3-[(tetrahydro-2H-pyran-2-yl)oxy]
cyclopentanepropanal
Dihydropyran (0.95mQ) and pyridinium toluene-p-sulphonate (0.19) were
added to a stirred solution of Intermediate 17 (1.449) in CH2Cl2
(40mQ) at 0. After stirring for 20h at room temperature the mixture
was washed with water (2x10mQ)9 8o NaHC03 (2x10mQ) and brine (2x10mQ).
The solvent was evaporated and the residue purified by chromatography
using 1:1 ER-PE (40-60) as eluent to yield the title compound as a
gum (1.99). I.r. (CHBr3) 2720, 1720cm-l.
Intermediate 19
[4aR-[4aa 5a(2R*) 6!3 7aa]]-octahydro-5-[3-p-enoxy-z-~(tetrahydr
cyclopenta[b]pyran-2-ol
A solution of Intermediate 18 (0.94q) in EA (50mR) was hydrogenated
over pre-reduced 10o palladiurn on charcoal (0.979) at N.T.P. for 22h.
-- - 27 -
The catalyst and solvent were removed and the residual oil (0.759)
purified by chromatography using 3:1 ER-PE (40-60) as eluent to give
the title compound as an oil (0.499).
I.r. (CHBr3) 3570cm~l
In the following examples, where the experimental details are not
given, the compounds were prepared in a similar manner to the compound
of Example 1
Example 1
[ ~ Z ~2~(R*)~3a]]-(-)-4-Acetylphenyl 7-[3-hydro~y~-2-(2-hydroxy
3-phenoxvDropoxv)-5-oxocvcloDentyl]-5-heptenoate
A solution of Intermediate 11a (0.249) in 20:10:3 acetic acid-water-
THF (2.5mQ) was heated at 40 for 4h. The solvent was removed in
vacuo and the residue purified by chromatography on acid-washed
(pH3.8) silica using 75:1 ER-MeOH as eluent to qive the title compound
as a white solid (0.149), m.p. 55-56.5. Crystallisation from methyl
acetate-PE gave a white solid, m.p. 64-65, L~]D -18.1 (MeûH)
Analysis Found: C,68.02; H,6.63.
C29H340,3 requires C,68.22; H~6.71nn.
Example 2
[1R-[1a(z)t2~(R*)L~a]]-(-)-4=(Acetylamino)phenyl 7~[3-hydroxy-2-
(2-hydroxy-3-phenoxypr poxy)-5-oxocyclopentyl]-5-heptenoate
A solution of Intermediate 11b (0.39) in 20:10:3 acetic acid-water-THF
(3mQ) was heated at 40-43 for 4h. The solvent was removed in vacuo
and the residue purified by chromatography on acid-washed (pH 3.8)
silica using EA as eluent to give the title compound as a white solid
(0.129), m.p. 60-63. Crystallisation from t-butylmethylether gave a
white solid, m.p. 74 5~75 [a]D -19.4 (MeOH)
Analysis Found: C,65.86, H,6.71; N,2.66.
C29H35N08 requires C~66.27; H,6.71; N,2.57nD.
~%~
- 28 -
Example 3
[1R-[1a(Z) 2~(R*) 3]]-4-[(Aminocarbonyl)amino]phenyl 7-[3-hydroxy-
2-(2-hydroxy-3-phenoxypropoxy)-5-oxocyclopentyl]-5-heptenoate~ (0.04g)
from Intermediate 11c (0.099) puriFied using 20:1 EA MeOH as eluent.
T.l.c. 20:1 EA-MeOH Rf 0.25. I.r. (CHBr3) 3570, 3500, 3400, 1740,
1680cm~l
Exarnple 4
[1R-[1a(z?,2~(R*),3]]-(-)-4-(Benzoylamino)phenyl 7-[3-hydroxy-2-(2-
hvdroxv-~-ohenoxvDroooxv)-5-oxocyclopentyl3-5-heptenoate
A solution of Intermediate 11d (00249) in 20:10:3 acetic acid-water-
THF (3mQ) was heated at 40-42 for 3h. The solvent was removed in
vacuo and the residue purified by chromatography on acid-washed (pH
3.8) silica using 7:3 EA-cyclohexane as eluent to give after
trituration with ER the title compound as a white powder (0.07g), m.p.
125-127. []DO -29.3 (CHCl3)
Analysis Found: C,69.4; H,6.4; N,2.3.
C34H37N8 C,69.5; H,6.4; N,2.4o.
Example 5
[1R-[1(z)~2~(R*)~3a]]-(-)-4-[4-(Acetylamino)benzoylamino]phenyl 7-~3-
hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5-oxocyclopentyl]-5-heptenoate
A solution of Intermediate 11e (0.249) in 20:10:3 acetic acid-water-
THF (3mQ) was heated at 40-42 for 4h. The solvent was removed in
vacuo to give a solid residue which was purified by chromatography on
~
acid-washed (pH3.8) silica using FA as eluent to give after
trituration with ER the title compound as a white powder (0.069), m.p.
150-154, []D -10 (MeOH)
Analysis Found: C,66.7; H,6.3; N,4.5.
C36H40N209 requires C,67.1; H,6.3; N,4.40.
~e~
[1R-[1a(Z) 2~(R*) 3a3]-(-)-4-(Aminncarbonyl) hen l 7-[3-hyclroxy-2-(2-
~ . , P y
hvdroxv-3-DhenoxYDropoxv)-5-oxocyclopentyl]-5-heptenoate
A solution of Intermediate 11f (0.449) in 20:10:3 acetic acid-water-
THF (5rn~) was heated at 40 for 3h. The solvent was removed in vacuo
-- 29 --
and the residue purified by chromatography on acid-washed (pH3.8)
silica using 95:5 EA-EtOH as eluent. Tritoration with ER followed by
crystallisation from EA-PE gave the title ccmpound as a white solid
(0.149), m.p. 1û4-105, [a]DU -13.2 (EtûH)
Analysis Found: C,65.65; H,6.7; N,2.7.
C28H33NO8 requires C,65.7; H,6.5; N,2.7~.
Example 7
[1R-[1a(z 5*) 2~(R*1 3a]]-(+)-4-[2-(AcetYlamin ~ -
hen l 7 [3-hvdroxv-2-(2-hvdroxY-3-ohenoxYpropoxy)-5-oxocyclopentyl]
5-heptenoate
A solution of Intermediate 119 (0.379) in 20:1û:3 acetic acid-water-
THF (6m~) was heated at 40 for 3h. The solvent was removed in vacuo
and a portion of the residue (0.199) was purified by chromatography on
acid-washed (pH3.8) silica gel using 9:1 CH2Cl2-EtOH as eluent.
Trituration with ER followed by crystallisation from EA-PE gave the
title compound as a white solid ~0.049), m.p. 105
[a]D + 3-5 (EtOH), I.r. (Nujol) 1740, 1720, 1660, 1645cm-1.
Example 8
hydroxy-3-phenoxypropoxy)-~5-oxoc clopentyl]-5-heptenoate
A solution of Intermediate 11h (0.359) in 2û:1û:3 acetic acid-water-
THF (5mQ) was heated at 40-42 for 2.5h. The solvent was removed in
vacuo and the residue purified by chromatography on acid-washed (pH
3.8) silica using 3:1 EA-cyclohexane as eluent to give after
trituration with ER the title compound as a ~hite powder (0.169),
m.p. 89-91, [a]D -25.7 (CHCl3)
Analysis Found: C969.3; H,6.4; N,2.2.
C34H37NOs C,69.5; H,6.4; N,2.4~.
Example 9
~1R-[1(z)~2~(R*)~3a]]-(-)-4-(N~N-Dimethylaminocarbonyl)phen
7-[3-h~dr_x ~ ~droxy=3-ehenoxy~ropoxy)-5-oxocyclopentyl]
-5-hepte_oate, (0.089) from Intermediate 11i (0.249) purified using EA
- 30 -
as eluent. I.r. (CHBr3) 3580, 3420~ 1745, 1624cm~l, ta]D -29
(CHCl3)
Analysis Found: C,66.53; H,7.04; N~2.53.
C30H37N08 requires C,66.77; H,6091; N~2.60o.
Example 10
t1R-[1(Z),2~(R*)~3J]-(-) Methyl 4-[[7-[3- hy ~
(2-h drox -3- henox ro QX )-5-oxoc clopentYl]-1-oxo-5-heptenyl]oxy]=
Y Y _P YP P Y . Y
benzoate
A solution of Intermediate 11i (0.199) in 20:1U:3 acetic acid-water-
THF (10mQ) was heated at 40 for 3h. The solvent was removed in vacuo
and the residue purified by chromatography on acid-washed (pH 3.8)
silica using ER as eluent to give the title compound as a white solid
(0.19), m.p. 45-47, [a]D -33 (CHCl3)
Analysis Found: C,66.25; H,6.63.
C29H3409 requires C,66.15; H,6.51o
[1R-[1(Z)t2~(R*),3a]]-(-)-4-[4-(Hydroxy)benzoylamino]phenyl 7-[3-
h drox -2-(2-h drox -3- henox ropox )-5-oxocYcloDentyl]-5-heptenoate
Y =. Y = _ Y Y P _Y~ _ _Y , . . . .
A solution of Intermediate 11k (0.579) in 20:10:3 acetic
acid-water-THF (10mR) was heated at 40 for 3.5h. The solvent was
removed in vacuo and the residue was purified by chromatography on
acid-washed (pH3.8) silica using 4:1 EA-PE as eluent to give after
trituration with ER a white powder (0.229). Crystallisation ~rom
EA-PE gave the title compound as a white solid (0.189), m.p. 108-110
[a]D - 13.9 (EtOH)
Analysis Found: C,67.35; H,6.1; N,2.2.
C34H37NOg requires C,67.65; H,6.2; N,2.3~.
Example 12
[1R-[1a(z) 2~(R*) 3a]]-2-(Ben~ovlamino)phenyl 7-[3~hydroxy-2-(2-
~ 9 , ~
h drox -3- henox ro ox )-5-oxoc clopentvl]-5-heotenoate, (0.0299)
_Y_ Y P YP P Y . Y_~
from Intermediate 11~ (0.0509) purified using 2:1 EA-cyclohexane as
- 31 -
eluent. T.l.c. 2:1 EA-cyclohexane Rf û.2, I.r. (CHBr3) 3580, 3440,
1742, 1675cm-
Example 13
[1R-[1~(Z) 2~(R*) 3a]]-2-Na hthalen l 7-[3-hydroxy-2-(2-hydroxy-3-
~ ? p_ y
nhenoxvoroooxv)-5-oxocvclopentyl~-5-heptenoate
A solution of Intermedia~e 11m (0.449) in 2n:10:3 acetic acid-water-
THF (12m~) was heated at 40-42 for 3h. The solvent was removed in
vacuo and the residue was purified by chromatography on acid-washed
(pH3.8) silica using 3:1 ER-EA as eluent to qive aFter trituration
with ER the ~ as a white powder (0.159), m.p. 71-73.
[a]D -35 (CHCl3)
Analysis Found: C,71.79; H,6.60~
C3lH34û7 requires C,71.79; H,6.61o.
Example 14
[1R-[1a(Z)~ ~,3a]]-(-)--4-(Benzoylamino)phenyl 7-[3-hydroxy-2-(2-
hydroxy-2-methyl-3-phenoxypropoxy)-5-oxocyclopentyl]-5-heptenoate,
(0.069) from Intermediate 11n (0.11q) puriFied using ER as eluent.
I.r. (CHBr3) 3580, 3420, 1742, 1672cm-l, [a]D -7 (MeOH)
Analysis Found: C,69.42; H,6.85; N,2.21.
C35H39N08 requires C,69.87; H,6.53; N,2.3o.
Example 15
[1R-[1a(Z) 2~ 3]]-4-Methox hen l 7-[2-[3-(4-Fluoro henox )-2-
~ Y P Y P . Y
hydroxypropoxy]-3-hydroxy-5-oxocyclopentyl]-5-heptenoate,
(0.069) from Intermediate 110 (0.09q) purified using 97:3 ER-MeOH as
eluent. I.r. (CHBr3) 3580, 3450, 1745cm~
Analysis Found: C,64.75; H,6.59.
C28H33F08 requires C,65.10; H,6.44o.
[1R-[1a(z)~2~3-]]-4-(Methylthio)phenyl 7-[2-[3-(4-chlorophenoxy)-2-
hydroxypr_poxy]-3-hydroxy-5-oxocyclopent ~ -h_ptenoate,
~509~L
- 32 -
0.19) from Intermediate 11p (0.169) purified using 98:2 ER-~enH as
eluent. I.r. (CHBr3) 3580, 3440, 1742cm~l, T.l.c. 98:2 ER-MeOH Rf
0.25
Exam~le 17
[1R-~1(z)~2~3a]]-4-(Methylsulphonyl?phenyl 7-[_-hydroxy-2-[2-
hydroxy-3-[4-(methylthio)phenoxy]propoxy]-5-o_ocyclopentyl~-5-
heptenoate
A solution of Intermediate 11q (0.149) in 20:10:3 acetic acid-water-
THF (3mQ) was heated at 40-42 for 3h. The solvent was removed in
va and the residue was purified by chromatography on acid-washed
(pH3.8) silica using 75:25 increasing to 90:10 EA-ER as eluent to qive
the title compound as a white solid (0.099), m.p. 73-76
I.r. (CHBr3) 3580, 3440, 1742cm~
Ex mple 18
[1R-(1~2~(R*),3a)]-(-)-4-(Aminocarbonyl)phenyl 7-[3-hydroxy-2-
(2-hydroxy-3-phenoxypropoxy)-5-oxocyclopentyl]-4,5-hepta _enoate,
(0.199) from Intermediate 11r (0.359) purified using 3:2 EA-CH3CN as
eluent. T.l.c. 3:2 EA-CH3CN Rf 0.3, I.r. (CHBr3) 3580, 3520, 3400,
1960, 1740, 1672cm~l, [a]D -21.0 (CHCl3)
Example 19
2~(R*)~3a]]-(-)-4-(Be-~oylamino)phenyl 7-[3-hydroxy-2-
(2-hydroxy-3-phenoxypropoxy?-5-oxocyclopentyl]-4-heptenoate
A solution of Intermediate 11s (0.179) in 20:10:3 acetic acid-water-
TIIF (10mQ) was heated at 40 for 2h. The solvent was removed in vacuo
and the residue purified by chromatography on acid-washed (pll 3.8)
silica using 2:1 EA-cyclohexane as eluent to qive the title compound
as a solid (0.119), m.p. 85-B8
I.r. (CIIBr3) 3580, 3430, 1745, 1675, []D ~ 27 (CHCl3)
33 -
Example 20
,
[1R-[1a(Z),2~(R*),3a]]-(-?-4-(Benzoylamino)phe~_ 9 -
hvdroxv-3-PhenoxyproDoxv)-5-oxocvclo~entvl]-7-nonenoate
A solotion of Intermediate 11t (0.55q) in 20:10:3 acetic acid-water-
THF (15mQ) was heated at 40 for 4h. The solvent was removed in vacuo
and the residue purified by chromatography on acid-washed (pH 3.8)
silica using 7:3 EA:cyclohexane as eluent to give after trituration
with ER the ~ as a white solid (0.249), mOp. 121-122
[a]D ~34 (CHCl3)
Analysis Found: C,7û.23; H,6.66; N,2.17.
C36H4lN08 requires C,70.22; H,6.71; N,2.27o.
_ ample 21
[1R-[1a,2~(R*),3a]]-(-)-4-(Benzoylamino)~_enyl 3-hydroxy-2-(2-
hydroxy-3-phenoxypropoxy)-5-oxocyclopentaneheptanoate
A solution of the compound of Example 4 (0.1q) in EA (35mR) was
hydrogenated over pre-reduced 10~ palladium on charcoal (0.03~) at
N.T.P. for 40 min and then the solvent and catalyst were removed. The
title compound was obtained as a white solid (0.079), m.p. 127-130,
[a]D -29.3 (CHCl3)
Analysis Found: C,69.38; H,6.69; N,2.15.
C34H39N08 requires C,69.25; H,6.67; N~2.38o.
Example 22
[1R-[1(E)~2~(R*)~3-a]]-(-)-4-(Aminocarbonyl)pheny -[3-hydroxy-2-(2-
hydroxy-3-phenoxypropoxy)-5-oxocy~clopentyl]-5-heptenoate
A solution of the compound of Example 6 (0.159), thiophenol (0.46mQ)
and azobisisobutyronitrile (0.19) in CH2CN (3m~) and benzene (3mQ) was
stirred at reflux for 6.5h. Purification by chromatography (x2) on
acid-washed (pH3.8) silica using 9:1 EA-CH3CN as eluent gave the title
compound as a gum (0.13q).
I.r. (CHBr3) 3580~ 3515, 3400, 1742, 1672cm-l, [a]D -30 (CHCl3)
Analysis Found: C,66.12; H,6.8; N,2.52.
~5~ ~
- 34 -
C28H33N08 requires C~65.74; H,6.5; ~2.74~o.
Example 23
[1R-[1(
h drox -3- henox ro ox )-5-oxocvclop~nt 1]-5-heptenoate
- Y Y P _ Yp~ ~P Y y _
Pivaloyl chloride (O.OlmR) was added to a solution of Intermediate 1
(0.039) and Et3N (0.01m~) in dry DMF (1mQ) at 0. After 10 min a
solution of 4-(benzoylamino)phenol (0.17q) and Et3N (0.01m~) in DMF
(1m~) was added and stirring continued for 2h at 0 and 3.5h at room
temperature. The reaction mixtu~e was diluted with EA (30m~) and
washed consecutively with water (10mQ), 10~o copp0r sulphate solution
(15m~), water (10rnQ) and brine (15mQ). The dried organic extract was
evaporated to give a residue which was purified by chromatogra~hy on
acid-washed (pH3.~3) silica using 1:1 cyclohexane-EA as eluent. The
title compound was obtained as a white solid (0.059).
I.r. (CHBr~) 3580, 3430, 1745, 1675cm l, T.l.c. 1:1 Cyclohexane-EA Rf
0.15
The following are examples of pharmaceutical formulations using
compounds of the invention. In the examples, the term "active
ingredient" is used to denote a compound of the invention, such as a
compound described in the preceding examples, for example the compound
of Example 4.
1. Tablets
-
These may be prepared by direct compression
mq/tablet
Active Ingredient 0.015 to n.2
Magnesium stearate, BP 1.5
Microcrystalline cellulose, USP 150.0
to compression weight
The active ingredient is blended with about 10~n of the
microcrystalline cellulose then blended with the remaining
microcrystalline cellulose and magnesium stearate. The blend is then
compressed using 6mm diameter punches into tablets on a suitable
machine.
- 35
The tablets may be film coated with suitable film forming materials
e.g. methyl cellulose or hydroxypropyl methylcellulose usinq standard
techniques.
2. Capsules
mg/tablet
Active ingredient O.û15 to 0.2
Magnesium stearate, BP 1.0
; *Starch 1500 100.0
to fill weight
*A form of directly compressible starch.
The active ingredient is p~eblended with some of the Starch 1500 then
this preblend is mixed with the remaining Starch 1500 and magnesium
stearate. The mix is then filled into size No 2 hard qelatin capsule
shells using suitable machinery.
