This invention relates to novel compounds having pharmacological activity, 
to a process for their preparation, to intermediates useful in that 
process and to pharmaceutical compositions containing them. 
German Offenlegungsschrift No. 2,724,948 discloses that compounds of the 
general formula (A): 
##STR2## 
wherein Z is hydrogen or alkyl; one of Z.sup.1 and Z.sup.2 is a group 
--CH.sub.2 --X--X.sup.1 --X.sup.2 in which X is phenylene, --C.tbd.C--, 
cis-, or trans- --CH.dbd.CH-- or --CH.sub.2 --CQ.sub.2 --, where each 
radical Q independently of the other is hydrogen or alkyl or the two 
radicals Q together are C.sub.4-6 alkylene, X.sup.1 is a covalent bond or 
a straight or branched C.sub.1-6 alkylene chain, in which one methylene 
group is optionally substituted by an oxa (--O--) group, with the proviso 
that at least one carbon atom separates the oxa group from a --C.tbd.C, 
--CH.dbd.CH-- or CO group, and 
X.sup.2 is tetrazolyl, carboxyl, carboxamide, hydroxymethylene or 
alkoxycarbonyl; 
and the other one of Z.sup.1 and Z.sup.2 is a group --Y--Y.sup.1 --Y.sup.2 
--Y.sup.3 in which Y is --CR.sub.2 --CH.sub.2 --, where each radical R 
independently of the other is hydrogen or methyl, 
Y.sup.1 is carbonyl, methylene, methylene substituted by a hydroxy group or 
methylene substituted by a hydroxy and an alkyl group, 
Y.sup.2 is a covalent bond or straight-chain or branched C.sub.1-7 alkylene 
optionally substituted on the carbon atom adjacent to Y.sup.1 by one or 
two mutually independent alkyl, bicycloalkyl or cycloalkyl groups, 
Y.sup.3 is hydrogen, hydroxy, C.sub.1-7 (preferably C.sub.1-4) alkoxy, 
cycloalkyl, bicycloalkyl, phenyl, benzyl, phenoxy or benzyloxy, where each 
phenyl, benzyl, phenoxy or benzyloxy by one or more hydroxy, halogen, 
nitro, amino, acylamino, alkenyl, alkoxy, phenyl and/or alkyl groups, 
which themselves may be substituted by one or more halogens or Y is a 
bond, --CH.sub.2 -- or --CH.sub.2.CH.sub.2 --; and 
Y.sup.1, Y.sup.2 and Y.sup.3 together are cycloalkyl which is substituted 
by a hydroxy group which is preferably separated by 3 carbon atoms from 
the hydantoin ring, have similar pharmacological activity to natural 
prostaglandins. 
We have now discovered a class of compounds which have useful 
pharmacological activity and which are structurally distinct from the 
compounds disclosed in Offenlegungsschrift No. 2,724,948. 
This class of compounds of this invention is also structurally distinct 
from the compounds of formula (B): 
##STR3## 
wherein: X is O to S; 
n is 1 to 8; 
R.sub.1 is hydrogen, or CO.sub.2 R.sub.1 represents an ester group in which 
the R.sub.1 moiety contains from 1-12 carbon atoms; 
R.sub.2 is hydrogen, C.sub.1-4 alkyl, or phenyl; 
R.sub.3 is hydroxy or protected hydroxy; 
R.sub.4 is hydrogen, C.sub.1-9 alkyl, C.sub.3-8 cycloalkyl, C.sub.3-8 
cycloalkyl -C.sub.1-6 alkyl, phenyl, phenyl C.sub.1-6 alkyl, naphthyl, 
naphthyl-C.sub.1-6 -alkyl, any of which phenyl or naphthyl moieties may be 
substituted by one or more halogen, trifluoromethyl, C.sub.1-6 alkyl, 
hydroxy, C.sub.1-6 alkoxy, phenyl C.sub.1-6 alkoxy or nitro groups; or 
R.sub.2 and R.sub.4 taken with the carbon atom to which they are joined 
represent a C.sub.5-8 cycloalkyl group; 
R.sub.5 is hydrogen, C.sub.1-6 alkyl, C.sub.1-6 alkyl substituted by a 
nitro, hydroxy, C.sub.1-6 alkoxy, CO.sub.2 A, (CO.sub.2 A).sub.2, CN or 
halogen group, C.sub.5-8 cycloalkyl, phenyl, phenyl-C.sub.1-6 alkyl, 
phenyl-C.sub.3-6 cycloalkyl, any of which phenyl moieties may be 
substituted by one or more halogen, trifluorormethyl, C.sub.1-6 alkyl, 
C.sub.1-6 alkoxy or nitro groups; or a group CO.sub.2 A; in R.sub.5 when 
present A is hydrogen or CO.sub.2 A represents an ester group in which the 
A moiety contains from 1 to 12 carbon atoms; and salts thereof; which are 
disclosed in our West German Offenlegungsschrift No. 2,755,771 as having 
useful prostaglandin-like activity. It should be noted that West German 
Offenlegungsscrift No. 2,755,771 published after the date of filing of the 
priority application for this invention. 
Accordingly, the present invention provides a compound of formula (I): 
##STR4## 
wherein: X is O or S; 
Y is --CH.sub.2 --CH.sub.2 --, --CH.dbd.CH-- or --C.tbd.C--; 
n is 1 to 5; 
R.sub.1 is hydrogen or CO.sub.2 R.sub.1 represents an ester group in which 
the R.sub.1 moiety contains from 1 to 12 carbon atoms; 
R.sub.2 is hydrogen or C.sub.1-4 alkyl; 
R.sub.3 is hydroxy or protected hydroxy; 
R.sub.4 is C.sub.1-9 alkyl, C.sub.3-8 cycloalkyl or C.sub.3-8 
cycloalkyl-C.sub.1-6 alkyl; or 
R.sub.2 and R.sub.4 taken with the carbon atom to which they are joined 
represent a C.sub.5-8 cycloalkyl group; and 
R.sub.5 is (CH.sub.2).sub.a NR.sub.6 R.sub.7, wherein a is 0 to 3 and 
R.sub.6 and R.sub.7 are hydrogen, C.sub.1-4 alkyl or phenyl C.sub.1-4 
alkyl, or R.sub.6 and R.sub.7 taken with the nitrogen atom to which they 
are joined represent a 4 to 7 membered heterocyclic ring which may contain 
as sole further hetero atom one oxygen atom or one optionally C.sub.1-4 
alkyl substituted nitrogen atom; allyl or propargyl; (CH.sub.2).sub.b 
--CO--(CH.sub.2).sub.c --CH.sub.3 wherein b+c is 1 to 5 and b is not zero; 
or S-R.sub.8 wherein R.sub.8 is C.sub.1-6 alkyl, phenyl, or phenyl 
substituted by a halogen, trifluoromethyl, C.sub.1-6 alkyl, C.sub.1-6 
alkoxy or nitro group; and salts thereof. 
One group of such compounds is as defined but wherein R.sub.5 is 
(CH.sub.2).sub.a NR.sub.6 R.sub.7, wherein a is 0 to 3 and R.sub.6 and 
R.sub.7 are hydrogen or C.sub.1-4 alkyl, or R.sub.6 and R.sub.7 taken with 
the nitrogen atom to which they are joined represent a 4 to 7 membered 
heterocyclic ring containing one hetero atom; allyl or propargyl; 
(CH.sub.2).sub.b --CO--(CH.sub.2).sub.c --CH.sub.3 wherein b+c is 1 to 5 
and b is not zero; or S-R.sub.8 wherein R.sub.8 is C.sub.1-6 alkyl, 
phenyl, or phenyl substituted by a halogen, trifluoromethyl, C.sub.1-6 
alkyl, C.sub.1-6 alkoxy or nitro group; and salts thereof. 
More suitably X is O. Also, most suitably Y is --CH.sub.2 --CH.sub.2 --. 
Often n will be 2 to 4, for example 3. 
Suitable examples of R.sub.1 include hydrogen, methyl, ethyl, n- and iso- 
propyl, n-,sec- and tert butyl, phenyl, benzyl, tolyl and the like, while 
normally hydrogen or C.sub.1-6 alkyl groups are preferred. 
Suitable examples of R.sub.2 include hydrogen, methyl and ethyl. More 
suitably R.sub.2 is hydrogen or methyl, preferably methyl. 
Suitable protected hydroxyl groups R.sub.3 include readily hydrolysable 
groups such as acylated hydroxy groups in which the acyl moiety contains 1 
to 4 carbon atoms, for example the acetoxy group; and hydroxy groups 
etherified by readily removable inert groups such as the benzyl groups or 
like groups. Preferably R.sub.3 is hydroxyl. 
Suitable groups R.sub.4 when R.sub.4 is an alkyl group include C.sub.4-9 
alkyl groups. Such C.sub.4-9 alkyl groups may be straight chain alkyl 
groups, such as n-butyl, n-pentyl, n-hexyl and n-heptyl, or may be alkyl 
groups branched by one or two methyl groups (at the same or different 
carbon atoms). Thus for example, R.sub.4 may be a group CH.sub.2 R.sub.9, 
CH(CH.sub.3)R.sub.9 or C(CH.sub.3).sub.2 R.sub.9, wherein R.sub.9 is a 
straight chain alkyl group such that the carbon content of the resultant 
group R.sub.4 is 4 to 9. 
In general preferred groups R.sub.4 when R.sub.4 is an alkyl group include 
straight chain pentyl, hexyl and heptyl groups. Of these, straight chain 
hexyl is often the most useful. Other preferred groups R.sub.4 include 
groups CH(CH.sub.3)R.sub.9 and C(CH.sub.3).sub.2 R.sub.9 wherein R.sub.9 
is straight chain butyl, pentyl and hexyl. 
Other suitable examples of R.sub.4 when R.sub.4 is an alkyl group include 
the lower alkyl groups, that is when R.sub.4 is a C.sub.1-4 alkyl group. 
When R.sub.4 is or contains a C.sub.3-8 cycloalkyl moiety, the moiety may 
be cyclopropyl. The moiety may also be a C.sub.5-8 cycloalkyl moiety such 
as a cyclohexyl moiety. Examples of suitable C.sub.1-6 alkyl moieties when 
R.sub.4 is a C.sub.3-8 cycloalkyl -C.sub.1-6 alkyl group include methyl, 
ethyl, propyl, butyl and pentyl. 
Also, R.sub.2 and R.sub.4 taken with the carbon atom to which they are 
joined can represent a C.sub.5-8 cycloalkyl group, such as the cyclohexyl 
group. 
When R.sub.5 is a group (CH.sub.2).sub.a NR.sub.6 R.sub.7, it may with 
advantage be amino. However, other suitable examples of R.sub.5 include 
the group wherein R.sub.6 and R.sub.7 are methyl, ethyl and n- and iso- 
propyl, and the group wherein NR.sub.6 R.sub.7 represent the ring 
##STR5## 
a Is suitably 0 to 1, but when R.sub.6 and R.sub.7 represent a ring, then 
a is preferably 1. 
Other examples of uncyclised R.sub.6 and R.sub.7 in a group R.sub.5 of 
formula (CH.sub.2).sub.a NR.sub.6 R.sub.7 include benzyl and phenylethyl. 
Often in such groups R.sub.6 and R.sub.7 will be identical, for example 
dibenzyl. 
Other examples of cyclised R.sub.6 and R.sub.7 in a group R.sub.5 of 
formula (CH.sub.2).sub.a NR.sub.6 R.sub.7 include morpholino and 
##STR6## 
wherein R.sub.6.sup.I is hydrogen or C.sub.1-4 alkyl, such as methyl. In 
general it will be appreciated from the foregoing that when R.sub.6 and 
R.sub.7 are in cyclised form the corresponding ring preferably contains 6 
ring atoms. 
Thus it can be seen that suitable examples of R.sub.5 include when R.sub.5 
is (CH.sub.2).sub.a NR.sub.6 R.sub.7, wherein a is 0, 1 or 2, and R.sub.6 
and R.sub.7 are hydrogen, methyl or benzyl, or R.sub.6 and R.sub.7 taken 
with the nitrogen atom to which they are joined represent a 5 or 6 
membered hetrocyclic ring which may contain as sole further hetero atom 
one oxygen atom, or one optionally C.sub.1-4 alkyl substituted nitrogen 
atom. 
Preferred such examples include those wherein a is 0 or 1, R.sub.6 and 
R.sub.7 are hydrogen or methyl, or R.sub.6 and R.sub.7 taken with the 
nitrogen atom to which they are joined represent pyrrolidino, morpholino 
or piperidino. 
Most preferably such R.sub.5 groups are amino, or a is 1 and R.sub.6 and 
R.sub.7 are hydrogen or methyl. 
R.sub.5 may also be a group (CH.sub.2).sub.b --CO--(CH.sub.2).sub.c 
--CH.sub.3 as defined. Suitably b is 1 and c is 0 or 1, preferably b is 1 
and c is 0. 
When R.sub.5 is a group S-R.sub.8, then suitably examples of R.sub.8 
include methyl, ethyl, n- and iso- propyl; phenyl; or phenyl substituted 
by one or two of the substituents previously defined. 
The compounds of the formula (I) may form conventional salts. Such salts 
include those with alkali and alkaline earth metals, suitably sodium and 
potassium, and ammonium and substituted ammonium salts. 
From the aforesaid it will be seen that one particularly suitably group of 
compounds within formula (I) is of formula (II): 
##STR7## 
wherein X, Y, R.sub.1 and R.sub.4 are as defined; 
R.sup.1.sub.2 is hydrogen, methyl or ethyl; and 
R.sup.1.sub.5 is (CH.sub.2).sub.a NR.sub.6 R.sub.7 as defined; and salts 
thereof. 
In formula (II) suitably X is O. 
In formula (II) suitably X is O. 
R.sup.1.sub.5 is more suitably hydrogen or methyl, preferably methyl. 
When R.sub.4 is a C.sub.1-9 alkyl group, it is normally a C.sub.4-9 alkyl 
group. In such cases suitable and preferred straight chain and branched 
groups R.sub.4 include those previously described. Such preferred groups 
R.sub.4 include straight chain pentyl, hexyl, and heptyl and of these 
normally the most useful is straight chain hexyl. Other preferred groups 
R.sub.4 include CH(CH.sub.3)R.sub.9 and C(CH.sub.3).sub.2 R.sub.9 wherein 
R.sub.9 is straight chain butyl, pentyl or hexyl. 
In formula (II) R.sub.4 may also suitably be a group of formula (III): 
##STR8## 
wherein T is a bond, or a C.sub.1-6 alkylene group which may be straight 
chain or branched by one or two methyl groups at the same or different 
carbon atoms; and r is 0 to 3. In formula (III) often T will be a group 
--(CH.sub.2).sub.q -- wherein q is 0 to 4. Also suitably r is 1. 
Suitable and preferred examples of R.sup.1.sub.5 in formula (II) include 
those groups said to be suitable and preferred for such R.sub.5 groups 
hereinbefore. 
A second interesting group of compounds within formula (I) are of formula 
(IV): 
##STR9## 
wherein the variable groups, and suitable and preferred examples thereof, 
are as for formula (II); and R.sup.2.sub.5 is allyl or propargyl; and 
salts thereof. 
A third particularly useful group of compounds within formula (I) is of 
formula (V): 
##STR10## 
wherein the variable groups, and suitable and preferred examples thereof, 
are as formula (II); and R.sup.3.sub.5 is a group (CH.sub.2).sub.b 
--CO--(CH.sub.2).sub.c --CH.sub.3 as previously defined; and salts 
thereof. 
Suitable examples of R.sup.3.sub.5 include CH.sub.2 COCH.sub.3 and the 
other groups hereinbefore described as suitable for such R.sub.5 groups. 
A fourth group of compounds within formula (I) is of formula (VI): 
##STR11## 
wherein the variable groups, and suitable and preferred examples thereof, 
are as for formula (II); and R.sup.4.sub.5 is a group S-R.sub.8 as 
defined; and salts thereof. 
Suitable examples of R.sup.4.sub.5 include groups hereinbefore described as 
suitable for such R.sub.5 groups. 
It will of course be realised that the compounds of the formula (I) have 
asymmetric centres, and thus are capable of existing in a number of 
stereoisomeric forms. The invention extends to each of these 
stereoisomeric forms, and to mixtures thereof. The different 
stereoisomeric forms may be separated one from the other by the normal 
methods. 
The present invention further provides a process for the preparation of the 
compounds of the formula (I), wherein R.sub.5 is not (CH.sub.2).sub.a 
NR.sub.6 R.sub.7, which process comprises the cyclisation of a compound of 
formula (VII): 
##STR12## 
wherein the variable groups are as defined; and thereafter if desired or 
necessary converting Y, R.sub.1 or R.sub.3 in the thus formed compound 
into other variables Y, R.sub.1 or R.sub.3. 
The compound of the formula (VII) is conveniently prepared in situ during 
the reaction of a compound of the formula (VIII): 
##STR13## 
wherein n, R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are as defined, with 
R.sub.5 NCX, a preferred process of the invention for compounds of formula 
(I) wherein R.sub.5 is other than amino. 
This preferred process is suitably carried out under reflux in an inert 
solvent such as benzene or the like. It should be stated that when in this 
reaction R.sub.5 is a sterically hindered group then this reaction may 
proceed only as far as the uncyclised compound of formula (VII) in which 
case the necessary cyclisation of the compound (VII) can be achieved with 
a strong base, such as sodium hydride or sodium ethoxide, in a dry organic 
solvent. Sodium ethoxide in benzene, or potassium t-butoxide in toluene, 
benzene or hexamethylphosphoramide are suitable reagents. 
The present invention also provides a further process for the preparation 
of compounds of the formula(I) wherein R.sub.5 is not (CH.sub.2).sub.a 
NR.sub.6 R.sub.7 in which a is 0 or 1, which process comprises the 
reaction of a compound of the formula (IX): 
##STR14## 
wherein the variables are as defined in formula (I), with R.sub.5 L 
wherein R.sub.5 is as defined in formula (I) and L is a good leaving 
group. In such reactions it may be necessary to convert the compound of 
the formula (VII) first to an alkali metal salt at the 10-position 
(prostaglandin numbering). 
This reaction is carried out under conventional conditions for substitution 
reactions. L may suitably be a halide. 
It will be appreciated that in any such reaction including a free amino 
group in R.sub.5 then it may be necessary or advisable to protect this 
free amino group during the reaction. 
Compounds of the formula (IX) may be prepared by the reaction of a compound 
of formula (VIII) as defined with a salt M.sup.+ C.sup.- NX, wherein 
M.sup.+ is a metal ion, in the presence of acid. 
In this reaction the necessary acid may conveniently be provided by using 
an acid addition salt of the compound of formula (VIII), such as the 
hydrochloride, or by carrying out the reaction in aqueous acid. 
The subsequent conversion of a compound of the formula (I) to another 
compound of the formula (I) wherein Y, R.sub.1 or R.sub.3 are altered, 
when desired or necessary, may be achieved in conventional manner. 
For example, if desired, compounds wherein Y is --C.tbd.C-- may be reduced 
to compounds wherein Y is --CH.dbd.CH-- in known manner. Suitably this 
reaction is carried out using catalytic hydrogenation, such as Lindlar 
catalysis. 
When Y is --CH.dbd.CH--, it may be reduced to --CH.sub.2 --CH.sub.2 in 
known manner, suitably using catalytic hydrogenation such as transition 
metal catalysis. 
Also, if desired the group R.sub.1 in the compound may be varied by 
conventional esterification and/or de-esterification reactions. Similarly, 
protected R.sub.3 hydroxy moieties may be deprotected in conventional 
manner. For example when R.sub.3 is a benzyloxy group, the benzyl group 
may readily be removed by acidic hydrolysis. Thus it may be seen that 
`protected hydroxy` compounds of the formula (I) are useful intermediates 
in the preparation of the corresponding `free hydroxy` compounds of the 
formula (I). 
Also when a compound of the formula (I) contains an acidic hydrogen atom, a 
salt thereof may be prepared in conventional manner for example by 
reacting the compound of the formula (I) with the required base. 
Compounds of the formula (I) wherein R.sub.5 is NR.sub.6 R.sub.7 may be 
prepared by the N-amination of a compound of formula (IX) as hereinbefore 
defined. 
Suitably this reaction is carried out with reagents such as 
O-(2,4-dinitrophenyl) hydroxylamine. 
Compounds of the formula (I) wherein R.sub.5 is CH.sub.2 NR.sub.6 R.sub.7 
may be prepared by a coupling reaction between the amine HNR.sub.6 R.sub.7 
and a compound of the formula (IX). Suitably this reaction is carried out 
as for Mannich type reactions, for example by use of formaldehyde as the 
coupling reagent. 
After these reactions any desired or necessary interconversion of groups in 
the resultant compound of the formula (I) may be carried out as 
hereinbefore described. 
The compounds of formula (VIII) are known compounds or may be prepared in 
analogous manner to known compounds. 
Compounds within the formula (I) have particularly useful pharmacological 
activity. For example compounds within the formula (I) have anti-gastric 
secretion activity, anti-ulcer activity, cardiovascular activity e.g. 
anti-hypertensive activity, platelet aggregation inhibition activity, 
affect the respiratory tract, e.g. bronchodilator activity, and have 
anti-fertility, smooth muscle and anti-arrhythmic activity. 
Compounds of the formula (I) may accordingly be used in the treatment and 
prophylaxis of corresponding disorders in humans and animals. 
In general it may be said that compounds within the formula (I) have a 
range of pharmacological activities similar to those shown by the natural 
prostaglandins, but that these activities tend to be rather more 
selective. 
The compounds of the formula (I) are especially useful as bronchodilation 
agents. 
The invention therefore also provides a pharmaceutical composition 
comprising a compound of the formula (I) ans a pharmaceutically acceptable 
carrier. 
The compounds of the formula (I) also have good stability. 
Clearly the formulation of the said pharmaceutical composition will depend 
on the nature of the activity shown by the chosen compound of the formula 
(I), and on factors such as a preference in a particular area of therapy 
for a particular mode of administration. 
The composition may be in the form of tablets, capsules, powders, granules, 
lozenges or liquid preparations, such as oral or sterile parenteral 
solutions or suspension. 
Tablets and capsules for oral administration may be in unit dose 
presentation form, and may contain conventional excipients such as binding 
agents, fillers, tabletting lubricants, disintegrants, and acceptable 
wetting agents and the like. The tablets may be coated according to 
methods well known in pharmaceutical practice. Oral liquid preparations 
may be in the form of, for example, aqueous or oily suspensions, 
emulsions, syrups, or elixirs, or may be presented as a dry product for 
reconstitution with water or other suitable vehicle before use. Such 
liquid preparations may contain conventional additives such as suspending 
agents, emulsifying agents, non-aqueous vehicles (which may include edible 
oils), preservatives, and if desired conventional flavouring or colouring 
agents, and the like. 
For parenteral administration, fluid unit dosage forms are prepared 
utilising the compound of the formula (I) and a sterile vehicle. The 
compound, depending on the vehicle and concentration used, can be either 
suspended or dissolved in the vehicle. In preparing solutions the compound 
can be dissolved for injection and filter sterilised before filling into a 
suitable vial or ampoule and sealing. Advantageously, adjuvants such as 
local anaesthetic, preservatives and buffering agents can be dissolved in 
the vehicle. Parenteral suspensions are prepared in substantially the same 
manner except that the compound is suspended in the vehicle instead of 
being dissolved and sterilisation cannot be accomplished by filtration. 
The compound can be sterilised by exposure to ethylene oxide before 
suspending in the sterile vehicle. Advantageously, a surfactant or wetting 
agent is included in the composition to facilitate uniform distribution of 
the compound. 
When appropriate, the compositions of this invention may be presented as an 
aerosol for oral administration, or as a microfine powder for 
insufflation. 
As is common practice, the compositions will usually be accompanied by 
written or printed directions for use in the medical treatment concerned. 
It will of course be realised that the precise dosage used in the treatment 
of any of the hereinbefore described disorders will depend on the actual 
compound of the formula (I) used, and also on other factors such as the 
seriousness of the disorder being treated. 
The invention also provides a method of treatment and/or prophylaxis of 
disorders in human being or animals which comprises the administration to 
the sufferer of an effective amount of a compound of the formula (I). 
Normally however the compounds will be used in the therapy of human 
disorders.