Thiohydantoins having prostaglandin-like activities

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. 2724948 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, --CH.tbd.C--, cis- or trans --CH.dbd.CH-- or --CH.sub.2 --CO.sub.2 -- where each radical Q independently of the other is hydrogen and/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.tbd.CH-- or CO group, and X.sup.2 is tetrazolyl, carboxyl, carboxamide, hydroxymethylene and/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 and/or methyl, Y.sup.1 is carbonyl, methylene, methylene substituted by a hydroxy group or methylene substituted by a hydroxy and 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 group may be substituted in the benzene ring 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. 2724948.
Accordingly, the present invention provides compounds of the formula (I): ##STR3## wherein: Y is --CH.sub.2 CH.sub.2 --, --CH.tbd.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, C.sub.1-4 alkyl, trifluoromethyl, or phenyl;
R.sub.3 is hydroxy or protected hydroxy;
R.sub.5 is hydrogen, C.sub.1-6 alkyl, phenyl or phenyl C.sub.1-6 alkyl, any of which phenyl moieties may be substituted by one or more halogen, trifluoromethyl, C.sub.1-6 alkyl, C.sub.1-6 alkoxy or nitro groups; and
X is CH.sub.2 and
R.sub.4 is C.sub.1-9 alkyl, C.sub.3-8 cycloalkyl-C.sub.1-6 alkyl, phenyl-C.sub.1-6 alkyl or naphthyl-C.sub.1-6 alkyl, any of which groups may have one acyclic carbon-carbon bond interrupted by an oxygen atom; hydrogen, C.sub.3-8 cycloalkyl, phenyl or naphthyl, any of which phenyl or naphthyl moieties in R.sub.4 may be substituted by one or more halogen, trifluoromethyl, C.sub.1-6 alkyl, hydroxy, 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; or
X is CS and
R.sub.4 is C.sub.1-9 alkyl, C.sub.3-8 cycloalkyl-C.sub.1-6 alkyl, phenyl-C.sub.1-6 alkyl or naphthyl-C.sub.1-6 alkyl, having one acyclic carbon-carbon bond interrupted by an oxygen atom; and in which any phenyl or naphthyl moieties may be substituted by one or more halogen, trifluoromethyl, C.sub.1-6 alkyl, hydroxy, C.sub.1-6 alkoxy or nitro groups, and salts thereof.
Suitably Y is --CH.sub.2 --CH.sub.2 --.
Suitably n is 2, 3 or 4, preferably 3.
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. 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.
Suitably CO.sub.2 R.sub.1 can also represent an ester group which is readily hydrolysable in vivo to give the free acid. Examples of R.sub.1 in this case include phthalidyl, pivaloyloxymethyl, 1-(ethoxycarbonyloxy)-ethyl and acetoxymethyl, more suitably phthalidyl.
Suitable examples of R.sub.2 include hydrogen, methyl, ethyl and phenyl. More suitably R.sub.2 is hydrogen, methyl, or ethyl, preferably methyl. R.sub.2 may also be CF.sub.3.
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 hydroxyl groups esterified by readily removeable inert groups such as the benzyl group or like groups. Preferably R.sub.3 is hydroxyl.
Suitable groups R.sub.4 when R.sub.4 is a C.sub.1-9 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-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.7, CH(CH.sub.3)R.sub.7 or C(CH.sub.3).sub.2 R.sub.7, wherein R.sub.7 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.7 and C(CH.sub.3).sub.2 R.sub.7 wherein R.sub.7 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 for example be a cyclopropyl or 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 amyl.
When R.sub.4 is an aryl group as previously defined, suitable groups R.sub.4 include phenyl, phenylmethyl, phenylethyl, phenyl n-propyl, phenyl n-butyl, naphthyl, naphthyl-methyl, naphthyl-ethyl, naphthyl n-propyl and naphthyl n-butyl, and such groups branched in the alkyl moiety by one or two methyl groups (at the same or different carbon atoms). These groups may be substituted in the phenyl or naphthyl moiety by normally one, two or three groups selected from those substituent groups listed hereinbefore. Examples of suitable substituent groups include fluorine, chlorine and bromine atoms and CF.sub.3, methyl, ethyl, n- and iso-propyl, methoxy and ethoxy, n- and iso-propoxy and nitro groups. Other examples of such groups include hydroxy. Preferably the aryl moieties when substituted by such groups will be mono or di-substituted.
When R.sub.4 is a C.sub.1-9 alkyl group interrupted by an oxygen atom, it may be represented as a C.sub.1-8 alkoxy-C.sub.1-8 alkyl group containing of course no more than 9 carbon atoms. Suitable examples of the alkyl moieties therein are as described above for a C.sub.1-9 alkyl R.sub.4 group.
More suitably, R.sub.4 alkyl groups interrupted by an oxygen have the structure --CH.sub.2 --(CH.sub.2)j --O--(CH.sub.2).sub.k --CH.sub.3, optionally substituted by one or two methyl groups at the same or different carbon atoms, wherein j and k are each 0 to 3 and j+k is 3 to 5 and preferably 4. Preferably k is 0 or 1, so that a specific example of such a group is --(CH.sub.2).sub.5 --O--Me.
When R.sub.4 is C.sub.3-8 cycloalkyl-C.sub.1-6 alkyl, phenyl-C.sub.1-6 alkyl or naphthyl-C.sub.1-6 alkyl in which one acyclic carbon-carbon bond is interrupted by an oxygen atom, then it can suitably be a group of formula --CH.sub.2 --(CH.sub.2).sub.m --O--(CH.sub.2).sub.n --[cyclic moiety] optionally substituted by one or two methyl groups at the same or different acyclic carbon atoms, wherein m and n are 0 to 5 and m+n is no more than 5.
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.
Suitable examples of R.sub.5 include hydrogen, methyl, ethyl, n- and iso -propyl, n-, sec- and tert-butyl; phenyl; phenylmethyl, phenethyl, phenyl-n-propyl, phenyl-n-butyl; and such phenylalkyl groups branched in their alkyl moieties by one or two methyl groups (at the same or different carbon atoms).
More suitably R.sub.5 is C.sub.1-6 alkyl such as methyl and ethyl, e.g. methyl.
When R.sub.5 is or includes a phenyl moiety, it can optionally be substituted as described above for R.sub.4 aryl groups.
The compounds of the formula (I) may form conventional salts. Such salts include those with alkali and alkaline earth metals, such as sodium and potassium, and ammonium and substituted ammonium salts.
The compounds of the formula (I) may also form conventional acid addition salts. Such salts include salts with pharmaceutically acceptable acids such as hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric and methane-sulphonic acid.
A group of compounds within the compounds of the formula (I) as defined are those wherein X is CH.sub.2 and R.sub.4 is C.sub.1-9 alkyl, C.sub.3-8 cycloalkyl-C.sub.1-6 alkyl, phenyl-C.sub.1-6 alkyl or naphthyl-C.sub.1-6 alkyl, any of which groups may have one acyclic carbon-carbon bond interrupted by an oxygen atom; hydrogen C.sub.3-8 cycloalkyl, phenyl or naphthyl, any of which phenyl or naphthyl moieties in R.sub.4 may be substituted by one or more halogen, trifluoromethyl, C.sub.1-6 alkyl, hydroxy, 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; and other variables are as defined in formula (I); and salts thereof.
From the aforesaid it will be seen that one particular suitable sub-group of compounds within formula (I) is of the formula (II): ##STR4## wherein: Y, R.sub.1 and R.sub.5 are as defined in formula (I);
n.sup.1 is 2, 3 or 4.
R.sup.1.sub.2 is hydrogen, methyl, ethyl or phenyl;
R.sup.1.sub.4 is hydrogen or C.sub.1-9 alkyl; and salts thereof.
In formula (I) n.sup.1 is preferably 3. Also Y is preferably --CH.sub.2 CH.sub.2 --.
R.sup.1.sub.2 is more suitably hydrogen, methyl or ethyl, preferably methyl.
While R.sup.1.sub.4 may be hydrogen or 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.sup.1.sub.4 include those previously described as suitable and preferred for the group R.sub.4 when R.sub.4 is a C.sub.4-9 alkyl group. Such preferred groups R.sup.1.sub.4 include straight chain pentyl, hexyl and heptyl, and of these normally the most useful is straight chain hexyl. Other preferred groups R.sup.1.sub.4 include CH(CH.sub.3)R.sup.1.sub.7 and C(CH.sub.3).sub.2 R.sup.1.sub.7 wherein R.sup.1.sub.7 is straight chain butyl, pentyl or hexyl.
Suitably R.sub.5 is C.sub.1-6 alkyl such as methyl and ethyl, preferably methyl.
A second sub-group of compounds within formula (I) of particular interest are those of formula (III): ##STR5## wherein: Y, R.sub.1 and R.sub.5 are as defined in formula (I);
n.sup.1 is 2, 3 or 4.
R.sup.1.sub.2 is hydrogen, methyl, ethyl or phenyl;
R.sup.2.sub.4 is a group of formula (IV): ##STR6## 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 W, Y and Z are each hydrogen or fluorine, chlorine or bromine atoms, or CF.sub.3, methyl, ethyl, n- or iso-propyl, methoxy, ethoxy, n- or iso-propoxy or nitro groups; and salts thereof.
In formula (III) n.sup.1 is preferably 3. Also Y is preferably --CH.sub.2 CH.sub.2 --;
R.sup.1.sub.2 is more suitably hydrogen, methyl or ethyl, preferably methyl.
In formula (IV) often T will be a group --(CH.sub.2).sub.q -- wherein q is 0 to 4. Also, suitably W and Y are hydrogen.
Suitably R.sub.5 is C.sub.1-6 alkyl such as methyl and ethyl, preferably methyl.
A further sub-group of compounds within formula (I) of interest is of formula (V): ##STR7## wherein: Y, R.sub.1 and R.sub.5 are as defined in formula (I):
n.sup.1 is 2, 3 or 4;
R.sup.1.sub.2 is hydrogen, methyl, ethyl or phenyl;
R.sup.3.sub.4 is a group of formula (VI): ##STR8## wherein T is as defined in formula (IV) and r is 0 to 3; and salts thereof.
In formula (V) n.sup.1 is preferably 3. Also Y is preferably --CH.sub.2 CH.sub.2 --;
R.sup.1.sub.2 is more suitably hydrogen, methyl or ethyl, preferably methyl.
In formula (VI) often T will be a group --(CH.sub.2).sub.q -- wherein q is 0 to 4. Also suitably r is 1.
Suitably R.sub.5 is C.sub.1-6 alkyl such as methyl and ethyl, preferably methyl.
A further sub-group of compounds within formula (I) of interest is of formula (II) as defined, but wherein R.sup.1.sub.4 is a C.sub.1-9 alkyl, C.sub.3-8 cycloalkyl-C.sub.1-6 alkyl or phenyl-C.sub.1-6 alkyl group in which groups one acyclic carbon-carbon bond is interrupted by an oxygen atom and in which any phenyl moiety may be optionally substituted as hereinbefore described.
In this sub-group preferred R.sub.4 groups include an alkyl group interrupted by oxygen which may be represented as a C.sub.1-8 alkoxy-C.sub.1-8 alkyl group containing of course no more than 9 carbon atoms, as hereinbefore described.
Another sub-group of compounds within formula (I) is of formula (VII): ##STR9## wherein: R.sub.4.sup.4 is C.sub.1-9 alkyl, C.sub.3-8 cycloalkyl-C.sub.1-6 alkyl, phenyl-C.sub.1-6 alkyl or naphthyl-C.sub.1-6 alkyl, having one acyclic carbon-carbon bond interrupted by an oxygen atom; in which phenyl or napthyl moieties may be substituted by one or more halogen, trifluoromethyl, C.sub.1-6 alkyl, hydroxy, C.sub.1-6 alkoxy or nitro groups; and the remaining variables are as defined in formula (I).
Suitable and preferred variables other than R.sub.4.sup.4 are as so described below formula (I).
Suitable and preferred R.sub.4.sup.4 are as so described under formula (I) for R.sub.4 having one acyclic carbon-carbon bond interrupted by an oxygen atom.
In the sub-groups hereinbefore described, 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.
Preferably in the sub-groups R.sub.1 is hydrogen, or a C.sub.1-6 alkyl group.
However it is believed that in the sub-groups, compounds where CO.sub.2 R.sub.1 is an in vivo hydrolysable ester will also be of particular interest as ready sources of the corresponding free acid. Examples of R.sub.1 in each case include phthalidyl, pivaloyloxymethyl, 1-(ethoxycarbonyloxy)ethyl and acetoxymethyl, more suitably phthalidyl.
It will of course be realised that the compounds of the formula (I) have asymetric 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 usual methods.
The present invention further provides a process for the preparation of the compounds of the formula (I), wherein X is CH.sub.2, which process comprises reducing a compound of the formula (IX): ##STR10## wherein R.sub.4.sup.5 is as defined for R.sub.4 when X.dbd.CH.sub.2 in formula (I) and remaining groups are as hereinbefore defined; and thereafter if desired or necessary converting Y, R.sub.1, R.sub.3 or a R.sub.5 hydrogen in the compound thus formed into another Y, R.sub.1, R.sub.3 or R.sub.5.
The reductive desulphurisation may be carried out in the presence of a suitably conventional hydrogenation catalyst, such as Raney nickel, under conventional conditions for such reactions. For example a solution of the chosen compound of the formula (IX) in an organic solvent may be added to a refluxing suspension of the catalyst in a similar solvent. It will be appreciated by the skilled man that when Y is --CH.dbd.CH-- or --C.tbd.C--, the reaction conditions must be selected having regard to the reactivity of Y.
The present invention also provides a process for the preparation of the compounds of the formula (I) wherein X is CS, i.e. the compounds of the formula (VII), which process comprises the cyclisation of a compound of the formula (VIII): ##STR11## wherein the variable groups are as hereinbefore defined.
Preparation of Intermediates
The same process may be used for the preparation of the intermediates of the formula (IX) by the cyclisation of a compound of formula (X): ##STR12## wherein the variable groups are as hereinbefore defined in formula (IX).
Either cyclisation may suitably be carried out by warming the compound of the formula (VIII) or (X) alone, or by heating the compound of the formula (VIII) or (X) in an inert organic solvent such as benzene or the like, suitably under reflux. When R.sub.5 is hydrogen the solvent should be non-hydroxylic. In some cases the necessary cyclisation of the compound of the formula (VIII) or (X) under these conditions can only be achieved in the presence of a strong base, such as sodium hydride or sodium ethoxide, in a dry organic solvent. This may be necessary when R.sub.5 is a sterically hindered group.
When R.sub.5 is hydrogen, such compounds of the formula (VIII) or (X) can be prepared by reacting a salt M.sup.+ CNS.sup.-, wherein M.sup.+ is a metal ion, with a compound of the formula (XI) or (XII) respectively in the presence of an acid, e.g. by using a mineral acid such as aqueous hydrochloride acid, or a corresponding acid addition salt of the compound of the formula (XI) or (XII) respectively: ##STR13## wherein the variable groups are as hereinbefore defined. This reaction can conveniently be carried out at room temperature. Suitably M.sup.+ is a sodium or potassium ion.
When both R.sub.1 and R.sub.5 are other than hydrogen in the compound of the formula (VIII) or (X), the compound of the formula (VIII) or (X) is conveniently prepared by the reaction of a compound of the formula (XI) or (XII) respectively with R.sub.5 NCS wherein R.sub.5 is not hydrogen in an inert organic solvent such as benzene or the like, a preferred process of the invention.
In this case the compound of the formula (VIII) or (X) is conveniently cyclised in situ, suitably under reflux in the organic solvent used. The presence of a strong base may be necessary as noted above.
Intermediates of the formulae (VIII) and (XI) are believed to be novel and form an aspect of the present invention.
The conversion of a compound of the formula (I), wherein Y, R.sub.1, R.sub.3 or R.sub.5 (when R.sub.5 is hydrogen) is altered when desired or necessary, may be achieved in a conventional manner. The conversion of a compound of formula (I) wherein X.dbd.CS, i.e. a compound of formula (VIII), to a compound wherein X.dbd.CH.sub.2, may be achieved in the manner hereinbefore described for the conversion of a compound of the formula (IX) to a compound of the formula (I) wherein X.dbd.CH.sub.2.
By way of example of such conversions the group R.sub.1 in the compound of the formula (I) may be varied by conventional esterification and/or de-esterification.
Similarly, it will be realised that when a compound is desired wherein CO.sub.2 R.sub.1 is an ester group which is readily hydrolysable in vivo to the free acid it may be preferred to convert the group CO.sub.2 R.sub.1 to such an ester group as a final reaction step.
Similarly, 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.
Protected R.sub.3 hydroxyl moieties may be deprotected in conventional manner. For example when R.sub.3 is a benzyloxy group, the benzyl group may be removed by hydrogenolysis. 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 R.sub.5 is hydrogen, compounds of the formula (I) may be converted to corresponding compounds but with different R.sub.5 values by conventional substitution reactions with R.sub.5 X wherein X is a displaceable group such as a halide or other good leaving group. In such reactions it may be necessary to first convert the compound of the formula (I) to an alkali metal salt of the R.sub.5 hydrogen.
The skilled man will realise that in some cases substituting a R.sub.5 hydrogen will also substitute a R.sub.1 hydrogen. Thus if a compound is desired wherein R.sub.1 is hydrogen and R.sub.5 is substituted, in such cases it will be preferred to esterify the R.sub.1 hydrogen before the substitution reaction, and then de-esterify after the substitution reaction, to give the desired R.sub.1 hydrogen compound.
When a compound of the formula (I) contains an acidic hydrogen atom, salts thereof may be prepared in a conventional manner by for example reacting the compound of the formula (I) with the required base. For salts of compounds wherein R.sub.5 is hydrogen, the base should be a strong base such as for example sodium in an alcohol such as ethanol, or the like.
Compounds of the formula (I) contain a basic nitrogen atom when X is CH.sub.2, and acid addition salts thereof may be prepared in a conventional manner by for for example reacting the compound of the formula (I) with the required acid.
Compounds of formula (XI) or (XII) may conveniently be prepared by a process which comprises reacting a compound of formula (XIII): R.sub.1 O.sub.2 C--CH(Q.sub.1)--CH.sub.2 --Y--(CH.sub.2).sub.n CO.sub.2 R.sub.1 with a compound of the formula (XIV): Q.sub.2 (CH.sub.2).sub.2 CR.sub.2 R.sub.3 R.sub.4.sup.5 or (XV): Q.sub.2 (CH.sub.2).sub.2 CR.sub.2 R.sub.3 R.sub.4.sup.4 in which compounds one of Q.sub.1 and Q.sub.2 is amino and the other of Q.sub.1 and Q.sub.2 is a good leaving group, such as tosylate or a halide or like readily displaceable group. Preferred examples of such good leaving groups include bromide.
This displacement reaction is suitably carried out in an inert organic solvent, such as hexamethylphosphoramide or N,N-dimethylformamide, at non-extreme temperature, in the presence of a base, such as sodium carbonate or sodium hydride, and a source of alkali metal ions, such as an alkali metal halide. Suitable alkali halides include sodium iodide and lithium iodide.
Preparative procedures of this general nature for the synthesis of compounds of the formula (XI) or (XII) are described in Offenlegungsschriften Nos: 2552312, 2647969 and 2724948.
Compounds within the formula (I) have useful pharmacological activity. For example compounds within the formula (I) have anti-gastric secretion activity e.g. anti-ulcer activity, cardiovascular activity, platelet aggregation inhibition activity, affect the respiratory tract e.g. bronchodilator activity, and have anti-fertility, smooth muscle and anti-arrhythmic activity.
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) have particularly useful bronchodilator activity.
The invention therefore also provides a pharmaceutical composition comprising a compound of the formula (I) and a pharmaceutically acceptable carrier.
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 other factors such as a preference in a particular area of therapy for a particular mode of administration.
The compositions may be in the form of tablets, capsules, powders, granules, lozenges or liquid preparations, such as oral or sterile parenteral solutions of suspensions.
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 normal pharmaceutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oil suspensions, solutions, 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 utilizing the compounds 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 sterilized before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a 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 sterilization cannot be accomplished by filtration. The compound can be sterilized 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 accomplished 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 propylaxis of disorders in human beings and animals which comprises the administration to the sufferer of an effective amount of a compound of the formula (I).

The following Examples 2 and 3 illustrate the preparation of compounds of the formula (I) and their pharmacological properties.
EXAMPLE 1
Compound 1 ##STR14##
Dimethyl 2-[N-3'-hydroxy-3'-methyl-n-nonyl] aminoazelate (10 g) was refluxed with methyl isothiocyanate (1.89 g) in dry toluene (100 ml) for 3 hours. The toluene was evaporated in vacuo to give a yellow oil (11.1 g). The oil was chromatographed on kieselgel (330 g) using chloroform as eluant to give 1-(3'-hydroxy-3'-methyl-n-nonyl)-3-methyl-5-(6"-methoxycarbonyl-n-hexyl)-2-thiohydantoin (9.49 g) as a pale yellow oil.
The compounds shown in Table 1 were prepared in similar manner:
TABLE 1______________________________________ ##STR15##Compoundnumber R.sub.1 R.sub.2 R.sub.4 R.sub.5 d______________________________________2 CH.sub.3 CH.sub.3 Ph CH.sub.3 63 CH.sub.3 CH.sub.3 CH(CH.sub.3)C.sub.4 H.sub.9 CH.sub.3 64 CH.sub.3 ##STR16## CH.sub.3 65 CH.sub.3 CH.sub.3 C.sub.2 H.sub.5 CH.sub.3 611 CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3 612 CH.sub.3 H C.sub.2 H.sub.5 CH.sub.3 613 CH.sub.3 CH.sub.3 ##STR17## CH.sub.3 614 CH.sub.3 CH.sub.3 C.sub.5 H.sub.11 CH.sub.3 6______________________________________
EXAMPLE 2
Compound 6 ##STR18##
1-(3'-hydroxy-3'-methyl-n-nonyl)-3-methyl-5-(6"-methoxy-carbonyl-n-hexyl)-2-thiohydantoin (3.3 g) in methanol (10 ml) was added, over five minutes, to a stirred, refluxing, suspension of Raney nickel [NICAT 101]* (c. 20 g) in methanol (100 ml); reflux was continued for thirty minutes. The hot suspension was filtered through kieselguhr and the residue was well washed with methanol. The methanol solution was evaporated in vacuo and the residue was dissolved in ether.
*Raney nickel [NICAT 101] was supplied by Joseph Crosfield and Sons Limited, P.O. Box 26, Warrington, WA5 1AB, Cheshire. The ether solution was washed with water and dried and evaporated in vacuo to give a yellow gum (2.4 g) which was purified via column chromatography on silica gel using chloroform/1% methanol as eluant to give 1-(3'-hydroxy-3'-methyl-n-nonyl)-3-methyl-5-(6"-methoxycarbonyl-n-hexyl)-4-imidazolidone (2.3 g) as a clear gum.
The compounds shown in Table 2 were produced in a similar manner.
TABLE 2______________________________________ ##STR19##CompoundNumber R.sub.1 R.sub.2 R.sub.4 R.sub.5 d______________________________________7 CH.sub.3 CH.sub.3 Ph CH.sub.3 68 CH.sub.3 CH.sub.3 CH(CH.sub.3)C.sub.4 H.sub.9 CH.sub.3 69 CH.sub.3 ##STR20## CH.sub.3 610 CH.sub.3 CH.sub.3 C.sub.2 H.sub.5 CH.sub.3 615 CH.sub.3 H C.sub.2 H.sub.5 CH.sub.3 616 CH.sub.3 CH.sub.3 C.sub.5 H.sub.11 CH.sub.3 6______________________________________
EXAMPLE 3
The compounds shown in Table 3 may be prepared in similar manner to the compounds listed in Table 2 of Example 2, from the corresponding intermediate compounds 11 and 13.
TABLE 3______________________________________ ##STR21##Compound Number R.sub.1 R.sub.2 R.sub.4 R.sub.5 d______________________________________17 CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3 618 CH.sub.3 CH.sub.3 ##STR22## CH.sub.3 6______________________________________
______________________________________ CHARACTERISING DATA______________________________________8c Compound 1 (The compound of Example 1)144 -R23## I.R. (cm.sup.-1) : 3510, [OH]; ##STR24##NMR (.tau.) : 7.75, (m), [OH; CH.sub.2CO.sub.2 CH.sub.3 ]; 6.8, (s), [NCH.sub.3 ]; 7 to 6.2, (m), [NCH.sub.2 ]; 6.35, (s), [CO.sub.2 CH.sub.3 ]; 5.9, (m), [NCH].Analysis : C.sub.22 H.sub.40 N.sub.2 O.sub.4 Srequires : C, 61.64; H, 9.41; N, 6.53; S, 7.48%found : C, 61.71; H, 9.51; N, 6.54; S, 7.34%Mass Spec. : C.sub.22 H.sub.38 N.sub.2 O.sub.3 S [m*-H.sub.2 O]requires : 410.2603found : 410.2610Compound 3 ##STR25##I.R. (cm.sup.-1) : ##STR26##NMR (.tau.) : 7.95, (s), [OH]; 7.75, (t), [CH.sub.2 CO.sub.2 CH.sub.3 ]; ##STR27## ##STR28## 6.4, (s), [CO.sub.2 CH.sub.3 ]; ##STR29##Mass Spec. : C.sub.22 H.sub.38 N.sub.2 O.sub.3 S [m*-H.sub.2 O]requires : 410.2603found : 410.2645Analysis : C.sub.22 H.sub.40 N.sub.2 O.sub.4 Srequires : C, 61.64; H, 9.40; N, 6.53; S, 7.47found : C, 61.72; H, 9.25; N, 6.27; S, 7.6.Compound 4 ##STR30##I.R. (cm.sup.-1) : 3550, [OH]; ##STR31##NMR (.tau.) : 7.8, (t) [CH.sub.2 CO.sub.2 CH.sub.3 ]; 7.75, (s), [OH]; ##STR32## ##STR33## 6.4, (s), [CO.sub.2 CH.sub.3 ]; 5.95, (t), [NCH];Mass Spec. : C.sub.20 H.sub.32 N.sub.2 O.sub.3 S, (*m-H.sub.2 O)requires : 380.2133found : 380.2124Analysis : C.sub.20 H.sub.34 N.sub.2 O.sub.4 Srequires : C, 60.27; H, 8.59, N, 702; S, 8.04found : C, 60.15; H, 8.75; N, 7.01; S, 8.0Compound 5 ##STR34##I.R. (cm.sup.-1) : 3550, [OH]; 1750 (shoulder 1730) ##STR35##NMR (.tau.) : 7.75, (t), [CH.sub.2 CO.sub.2 CH.sub.3 ]; 7.55, (s), [OH]; ##STR36## ##STR37## 6.4, (s), [CO.sub.2 CH.sub.3 ]; 5.9, (m), [NCH];Compound 6 - (the compound of Example 2) ##STR38##I.R. (cm.sup.-1) : 3550, [OH]; 1740, (broad), ##STR39##NMR (.tau.) : 7.75, (t), [CH.sub.2 CO.sub.2 CH.sub.3 ]; ##STR40## ##STR41## 6.4, (s), [CO.sub.2 CH.sub.3 ]; ##STR42## ##STR43## 6.1 to 5.5 (hump) [OH];Mass Spec. : C.sub.22 H.sub.42 N.sub.2 O.sub.4, [m*],requires : 398.3145found : 398.3125Compound 7 ##STR44##I.R. (cm.sup.-1) : 3450, [OH]; 1735, [CO.sub.2 CH.sub.3 ] ; ##STR45##Compound 8 ##STR46##I.R. (cm.sup.-1) : 3500, [OH]; 1740, [cO.sub.2 CH.sub.3 ]; 1710, ##STR47##NMR (.tau.) : 7.75, (t), [CH.sub.2 CO.sub.2 CH.sub.3 ]; 7.5, to 6.8, (m), [NCH.sub.2 ]; 7.2, (s), [NCH.sub.3 ]; 6.4. (s), [CO.sub.2 CH.sub.3 ]; 6.3, [NCH]; ##STR48## 6.1, to 5.1, (hump), [OH];Compound 9 ##STR49##I.R. (cm.sup.-1) : 3500, [OH]; 1740, [CO.sub.2 CH.sub.3 ]; ##STR50##NMR (.tau.) : 7.65, (t), [CH.sub.2 CO.sub.2 CH.sub.3 ]; ##STR51## ##STR52## 6.3, (s), (CO.sub.2 CH.sub.3 ]; ##STR53## ##STR54## 6.1, to 5.6, (hump), [OH];Compound 10 ##STR55##IR (cm.sup.-1) : 33450, [OH]; 1740, [CO.sub.2 CH.sub.3 ]; ##STR56##N.M.R. : 7.75, (t), [CH.sub.2 CO.sub.2 CH.sub.3 ];(.tau.) ##STR57## ##STR58## 6.4, (s), [CO.sub.2 CH.sub.3 ]; ##STR59## ##STR60##Mass Spec. : C.sub.18 H.sub.34 N.sub.2 O.sub.4 [m*]requires : 342.2519found : 342.2555Compound 11 ##STR61##I.R. (cm.sup.-1) : ##STR62## CO.sub.2 CH.sub.3 ]NMR (.tau.) : 7.75, (brm), [CH.sub.2 CO.sub.2 CH.sub.3 ]; 7.45, (s), [OH]; ##STR63## ##STR64## 6.4, (s), [CO.sub.2 CH.sub.3 ]; ##STR65##Mass Spec. : C.sub.17 H.sub.30 N.sub.2 O.sub.4 S [m*]requires : 358.1926found : 358.1956Compound 12 ##STR66##I.R. (cm.sup.-1) : 3500, [OH]; 1740 (broad) ##STR67##NMR (.tau.) : 7.7, (t), (CH.sub.2 CO.sub.2 CH.sub.3 ]; ##STR68## ##STR69## 6.4, (s), [CO.sub.2 CH.sub.3 ]; ##STR70##Analysis : C.sub.17 H.sub.30 N.sub.2 O.sub.4 Srequires : C, 56.96; H, 8.43; N, 7.81; S, 8.94%.found : C, 57.07; H, 8.67; N, 7.66; S, 8.53%.Mass Spec. : C.sub.17 H.sub.30 N.sub.2 O.sub.4 S [m*].requires : 358.1926.found : 358.1894.Compound 13 ##STR71##I.R. (cm.sup.-1) : 3470, [OH]; 1740 (broad), ##STR72##NMR (.tau.) : 7.8, (t), [CH.sub.2 CO.sub.2 CH.sub.3 ]; 7.75, (bs), [OH]; ##STR73## ##STR74## 6.4, (s), [ CO.sub.2 CH.sub.3 ]; ##STR75##Mass Spec : C.sub.22 H.sub.36 N.sub.2 O.sub.3 S [M*-H.sub.2 O];requires : 408.2430found : 408.2437COMPOUND 14 ##STR76##I.R. (cm.sup.-1) : 3470, [OH]; 1740 (broad), ##STR77##NMR (.tau.) : 7.85, (t), [CH.sub.2 CO.sub.2 CH.sub.3 ]; 7.75, (s), [OH]; ##STR78## ##STR79## 6.4, (s), [CO.sub.2 CH.sub.3 ]; ##STR80##Analysis : C.sub.21 H.sub.38 N.sub.2 O.sub.4 Srequires : C, 60.85; H, 9.24; N, 6.76; S, 7.73%.found : C, 60.51; H, 9.31; N, 6.35; S, 7.92%.Mass Spec. : C.sub.21 H.sub.38 N.sub.2 O.sub.4 S [M*];requires : 414.2581found : 414.2565COMPOUND 15 ##STR81##I.R. (cm.sup.-1) : 3450, [OH]; 1740 [CO.sub.2 CH.sub.3 ]; ##STR82##NMR (.tau.) : 7.75, (t), [CH.sub.2 CO.sub.2 CH.sub.3 ]; ##STR83## ##STR84## ##STR85## 6.3, (s), [CO.sub.2 CH.sub.3 ]; ##STR86##Mass Spec. : C.sub.17 H.sub.32 N.sub.2 O.sub.4 [M*].requires : 328.2362found : 328.2354.COMPOUND 16 ##STR87##I.R (cm.sup.-1) : 3430, [OH]; 1735, [CO.sub.2 CH.sub.3 ]; ##STR88##NMR (.tau.) : 7.75, (t), [CH.sub.2 CO.sub.2 CH.sub.3 ]; ##STR89## ##STR90## ##STR91## ##STR92##______________________________________
Pharmacological Data
1. Bronchodilation Activity
The compounds were examined for their ability to inhibit 5-hydroxytryptamine or histamine induced bronchoconstristion in the anaesthetised, artificially respired guinea pig (Konzett-Rossler preparation). The compounds were administered intravenously. The results are shown in the Table.
______________________________________Compound ID50 against 5-hydroxytryptamineNumber induced constriction g/Kg, i.v.______________________________________6 30______________________________________
2. Anti-ulcer activity Method
Anti-ulcer activity was assessed by the inhibition of indomethacin induced gastric damage in the rat according to the method of Eleghe (1974) Israeli J. Med. Sci. 10. 1451. Rats were starved overnight and given 15 mg/kg indomethacin subcutaneously and sacrificed 4 hours later. Stomachs were reflated with n. saline, cut along the greater curvature pinned out and scored for gastric damage by the following system:
Score 1-3--according to degree of erythema and slight haemorrhage.
Score 4-6--according to degree of muscosal erosion.
Score 7-9--according to depth of gastric damage.
Groups of 7 rats were used for each treatment and the test compound or vehicle were administered 30 minutes prior to giving the indomethacin. Dose of test compound was 100 mg/kg orally and control groups receiving vehicle only were obtained using the above scoring system and the Mann Witney test applied for significance of difference between the values obtained with the treatments.
The results are shown in the Table:
______________________________________ Vehicle Control Rest CompoundCompound Mean Score .+-. S.E. Mean Score .+-.Number of Mean S.E. of Mean______________________________________6 3.71 .+-. 0.80 0.71 .+-. 0.42 (P < 0.01)______________________________________
3. Toxicity
No toxic effects were observed at the test dosage.

Number	Date	Country	Kind
12367/78	Mar 1978	GBX
40506/78	Oct 1978	GBX

Number	Name	Date
4147796	Wootton	Apr 1979
4152445	Wootton	May 1979
4204068	Galdwell	May 1980

Thiohydantoins having prostaglandin-like activities

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