IE45882B1 - Hydantoin analogues - Google Patents

Description

This invention relates to heterocyclic compounds, their synthesis, compositions containing them, and their use in medicine.

Hydantoin derivatives, defined hereinbelow in formula ¢1), have been found to have pharmacological properties related to those of natural prostaglandins, as demonstrated by their ability to mimic or anatagonise the physiological effects of the natural prostaglandins in various biological preparations. In particular, certain compounds of formula (I) have been found to be potent mimmetics of the antiplatelet aggregatory properties of prosaglandin E^.

In formula (I) 12 Z is alkyl; one of Z and Z is represented by the group -CH2-X-X -X ; wherein X is phenylene, -CsC-, cis or trans, -CHCH- or -CH2~CQ2- in which each Q is dependently selected from hydrogen and alkyl or the two Q’s together form an alkylene radical having four, five or six carbon atoms; X4 is a covalent bond or a straight or branched alkylene chain having 1 to 6 carbon atoms optionally having one of its methylene groups replaced by oxa(-0-) provided that at least one carbon atom separates the oxa group from a -CsC-, -CHCH- or -C05 group; and X" is selected from 5-tetrazolyl, carboxyl, carbomoyl, hydroxymethylene and alkoxyearbonyl; 12 3 and the other of Z and Z is represented by the group -Y~Y »y -y · ~ ι » wherein Y is -CRj-CHj- in which each R is independently selected from hydrogen and methyl; Y3- is carbonyl, methylene, methylene substituted by hydroxy or methylene substituted by hydroxy and alkyl; Y is a covalent bond or straight or branched alkylene having 1 to 7 carbon atoms optionally substituted on the carbon adjacent Y1 by one or two groups, independently selected from alkyl, cyeloalkyl and bicycloalkyl; Y is hydrogen, hydroxy, alkoxy having 1 to 7 carbon atoms, cyeloalkyl, bicycloalkyl, phenyl, benzyl, phenoxy or benzyloxy, wherein each of phenyl, benzyl, phenoxy and benzyloxy may be substituted in the benzene ring by one or more groups selected from hydroxy, halo, nitro, amino, acylamino, alkenyl, alkoxy, phenyl and alkyl which may itself be substituted by one or more halo groups; ? ? or Y is a bond, -CH2_ or -CHj.CHj- and Υ , Y and Y taken together form a cyeloalkyl group substituted by hydroxy.

Unless otherwise stated, in formula (I) and other formulae in this specification, alkyl moieties are selected from methyl, ethyl, propyl, butyl, pentyl and hexyl, including all isomers thereof? 2 For example, in the definitions of Y and Y the alkyl groups are preferably methyl; and the alkyl moiety of alkoxycarbonyl is desirably methyl or ethyl. Similarly alkylene groups have 2 to 4 carbon atoms for example vinyl.

In formula (I) cyeloalkyl groups have 3 to 10 carbon atoms and bicycloalkyl groups have 4 to 10 carbon atoms for example adamantyl.

In a compound of formula (I) the bonding of the divalent phenylene group may be ortho, meta or para, and the oxa group is preferably adjacent the phenylene or when X is other than phenylene than X1 may be ~CH2-O-CH2-.

Included in the meaning of compounds of formula (I) are the salts 2 corresponding to the carboxylic acids and tetrazoles when X is carboxyl or tetrazolyl respectively, and the salts which may also be formed when Z is hydrogen. Particularly valuable salts for medical purposes are those having a pharmaceutically acceptable cation such as ammonium or that of an alkali metal eg. sodium and potassium, an alkaline earth metal eg. calcium and magnesium, or an organic base, particularly an amine such as ethanoImine. Salts having non-pharmaceutically acceptable cations are included within the ambit of this invention as useful intermediates to pharmaceutically acceptable salts, or the acids or esters of formula (I) · Except when there is clear indication to the contrary, formula (I) and other formulae in the specification embrace all stereoisomers represented therein. In particular such formulae include the enantiomeric forms, such mixtures as are designated racemates, and diastereoisomers.

It has been found that compounds of formula (I) wherein one of 12 Z and Z is represented by the group -CH2~X-X -X ; wherein X is -CH2CH2; X1 is a straight or branched alkylene chain having 1 to 6 carbon atoms; and X is carboxyl or alkoxyearbonyl, and the other of z3, and Z2 is represented by the group -Y-Y^-Y2-Y3; wherein Y is -CH2-CH2-; Y3, is methylene or methylene substituted 2 by hydroxy; Y is a covalent bond or a straight or branched alkylene chain; and Y is a hydrogen, have particularly interesting protaglandin-related properties. - 3 45882 The compounds of formula (I) may be synthesised by any method known in the art for the synthesis of compounds of analogous structure. For example, they may be prepared from the corresponding derivatives of hydantoic acid of formula (II) wherein G is carboxy or a derivative thereof such as amide or ester 1 2 in particular an alkyl ester, and each of Z, 2 and Z has the same meaning as in formula (I), by cyclisation under acidic conditions or by heating alone. The reaction may be effected in the absence of a solvent, but if desired an inert solvent may be used, for example a hydrocarbon such as petrol. Alternatively, where G is alkoxycarbonyl, cyclisation may be effected in the presence of a suitable base, for example an alkoxide such as sodium ethoxide.

Compounds of formula (II) are conveniently prepared from an amino acid derivative of formula (III) (HI) HN ^z2 2 whereinG, Z and Z are as defined in formula (I) provided that G may also be nitrile by reaction with an alkyl iso-cyanate. The - 4 4S882 reaction may proceed in the absence of a solvent but desirably an inert solvent is used which is preferably polar such as water or a mixture of water with acetone, dimethylformamide, dimethylsulphoxide or a lower alkanol such as ethanol or it may be a hydrocarbon, an ether or halogenated hydrocarbon such as chloroform. Where desired, for example if no solvent is used, the reaction may be promoted by heating the reactants.

Instead of using an isocyanate, a compound of formula (III) may be reacted with urea, nitrourea or an N-alkylurea as appropriate. A solvent is not essential but if desired an inert solvent such as one mentioned above may be used, and the reaction is preferably effected at an elevated temperature, for example from 100° to 125°C but temperatures up to 150°C may be employed.

In the above described synthesis, the intermediates of formula (II) need not be isolated from the reaction mixture and may be converted directly to compounds of formula (I) under the described reaction conditions.

An intermediate of formula (III) may be conveniently prepared by reaction of a compound of formula (IV) with a compound of formula (V) „ „1 Q (IV) q2-z2 (V) ~ 2 1 wherein G, Z and Z are as defined in formula (III), one of Q and 2 Q is amino and the other is halogeno, preferably bromo. The reaction may be carried out by heating in the absence of solvent or in the presence of an inert solvent such as ethanol. - 5 45882 12 3 The intermediates of formula (III) wherein Z is -Y-Y -Y -Y when Y1 is carbonyl may also be prepared by reaction of an amine of formula (IV) wherein is amino with an unsaturated ketone of formula (VI) CR2=CH.CO.Y2.Y3 (VI) 3 wherein Y and Y have the same meaning as in formula (III); the reaction being effected in the presence or absence of an inert solvent, and at room temperature, or optionally with heating.

Hydantoins of formula (I) may also be prepared by cyclisation of a compound of formula (VII) Z-N (VII) wherein Ζ, Z and Z are as defined in formula (I) and G is carboxyl or a reactive derivative thereof such as alkoxycarbonyl eg. ethoxycarbonyl. Compounds of formula (VII) may be cyclised under similar conditions as a compound of formula (II) and conveniently the method used to prepare a compound of formula (VII) is chosen such that the prevailing reaction conditions permit spontaneous cyclisation.

For example, the intermediates of formula (VII ) may be prepared by reactinga compound of formula (V) with a compound of formula (VIII). q2-Z2 (V) Z—N (VIII) θ wherein one of Q and Q is halogeno, preferably chloro or bromo and 12 1 the other is amino and each of Ζ,Ζ , Z and G have the same meaning as in formula (VII). The reaction may be effected by admixture of the reactants or optionally an inert solvent is used and the mixture is heated. Suitable solvents include alkanols, ethers, hydrocarbons and halogenated hydrocarbons.

The compounds of formula (VIII) may themselves be made by reacting an appropriate carbamic acid derivative, for example an alkyl ester, with a compound of formula (IV), using techniques known to those skilled in the art.

In a method related to those described hereinbefore, the hydantoins of formula (I) may be prepared by reacting a compound of formula (IX) 2 wherein each of Ζ, Z and Z has the same meaning as in formula (I) with a carbonic acid derivative. Any carbonic acid derivative known to those skilled in the art as appropriate may be used, for example phosgene, diphenylcarbonate or an alkyl haloformate such as ethyl ehloroformate. The reaction is desirably effected in the presence of a base, for example an amine such as triethylamine or di-iso-propyl ethylamine, and using an inert aprotic solvent such as toluene, dimethylformamide or an ether such as diethylether. The reaction may be carried out at room temperature but if desired the reaction mixture may be heated.

The intermediates of formula (IX) may be made using methods analogous to those described above for the preparation of compounds of formula (III).

The hydantoins of formula (I) may also be prepared by alkylation, - 7 45882 using an alkylating agent which may be designated as a reactive 3 ester derivative of an alcohol J .OH, of a compound of formula (X) (X) .ii u j.i, iiyux.uyeu ui. ciiaji, u ia nyuxuyexi υ£ ώ , J is hydrogen 3 12 12 or Z and J is alkyl, Z or Ζ , provided that one of J, J and J is 12 hydrogen and J does not have the same value as J, J or J ; in the 3 12 definition of J , J and J* each of Z and Z has the same meaning as in formula (I). Suitable reactive ester derivatives include chloride, bromide, iodide and sulphonates such as £>-toluenesulphonate, methanesulphonate and benzenesulphonate. The alkylation may be effected using reaction conditions which are known in the art to be suitable, for example in the presence of a base such as an alkalimetal hydride, alkali metal amide, or alkalimetal alkoxide, typically sodium hydride or a sodium alkoxide eg. sodium methoxide.

The reaction is conveniently carried out in an inert solvent which simply acts as a diluent for the reactants such as tolune, dioxan, ether, dimethylformamide, tetrahydrofuran, dimethyldulphoxide or acetonitrile or when the base is an alkali metal alkoxide then the corresponding alkanol may be used.

It will be appreciated that the intermediates of formula (X) wherein J is hydrogen are also compounds of formula (I) and may be prepared by one of the foregoing methods. The compounds of formula (X) may further be prepared by adaptation of methods already known in the 45883 art (see for example Chemical Reveiws (1950) 46, p. 403-325).

A further preparation of compounds of formula (I) is by reduction of a corresponding unsaturated compound of formula (XI) Z—N J (XI) wherein either J is ’CR-C^-yI-Y^Y2 and J Is -C^-X-X^-X2 or Z3 is =CH-X-X1-X2 and z4 is -Y-Y1-Y2-Y3 in which each of R, X to 2 3 X and Y to Y is as defined in formula (I), with a suitable reducing agent.

A suitable reducing agent is stannous chloride which may be used as 10 an aqueous solution optionally in the presence of dilute mineral acid or catalytic hydrogenation may be effected in the presence of for example Raney nickel, platinum, palladium, ruthenium or rhodium. The choice of reducing agent in a given situation will of course be dictated by the presence of other reactive groups in the molecule which may themselves be susceptible to reduction.

The intermediates of formula (XI) may be prepared by the following series of reactions: G CH(0G)2 \ X CH 4 G .2 G CH(OGJ), 2 CH NH, Ph3P= NH \z4 (xii) (XIV) J, + (xi) 4 In the above formulae Ζ, Ζ , Z and G have the same meaning as in 3 formulae (XI) and (III) respectively, G is alkyl for example n-butyl and G is halogeno such as bromo. The formation of (XIII) is analogous to the ring closure involving a compound of formula (II) and compounds of formula (XIV), are prepared using concentrated mineral acid such as hydrochloric acid.

Tetrazoles of formula (I) may be prepared from corresponding 2 compounds wherein the group -X is replaced by -C=N 14 I 3 x4 x 4 3 wherein X and X together form a bond (nitrile), X is hydrogen or alkyl and x is alkoxy (imidoester), alkylthio (imidothioester), 3 4 -NH-NH2 (amidrazone), or amino (amidine) or R is hydroxy and R is amino (amidoxime). The reaction is preferably carried out in a polar aprotic liquid medium such as dimethylformamide using a 2 salt of a hydrazoic acid eg. sodium azide. However, when X is 45383 replaced by an amidine or amidrazone, a suitable reagent is nitrous acid. If an amidine is reacted with nitrous acid then reduction of the intermediate nitrosation product, with or without prior isolation, using for example sodium amalgam is required to give the corresponding tetrazole. The tetrazole precursor may be obtained by well known methods, for example the nitrile may be obtained by dehydration of the corresponding amide.

The alcohols of formula (I) wherein X is hydroxymethylene may also be obtained by reduction with an appropriate reducing agent of the corresponding acid, ester, acid halide, acid anhydride or aldehyde. The appropriate reducing agent will depend on the particular substrate, but reactants which may be used are sodium in ethanol. In particular a carboxylic acid may for example be converted to a corresponding mixed anhydride with ethylchloroformate in the presence of a base such as triethylamine, and subsequently reduced to the alcohol using sodium borohydride. Similarly an ester may be reduced to the alcohol using di-iso-butyl aluminium hydride in an inert solvent such as ether or hydrocarbon such as hexane or benzene. Such alcohols may also be prepared by catalytic hydrogenation. ο Alternatively the alcohols of formula (I) wherein X is hydroxymethylene may be prepared by hydrolysis of a corresponding halide with an appropriate reagent. For this purpose a hydroxide may be used for example an aqueous alkali or a suspension of silver oxide in water.

In the synthesis of hydantoins of formula (I) having a hydroxyl 43883 group in a side chain it may be desirable to protect this during the course of the reaction. This may be readily effected in known manner using a protecting group such as acyl, aroyl, tetrahydropyran-2-yl, 1-ethoxyethyl or aralkyl, for example benzyl.

Removal of protecting groups may be carried out by appropriate methods known to those skilled in the art: for example an acyl group may be removed by acid or base hydrolysis, and a benzyl group by reductive cleavage.

Furthermore a ketone of formula (I) wherein Y3 is carbonyl may be converted to the corresponding secondary alcohol by reduction with a suitable reducing agent, such as sodium borohydride. Also, an 1 alcohol of formula (I) wherein Y is -CH.OH- may be oxidised to the corresponding ketone using Jones' reagent, acid dichromate or any other suitable reagent.

Similarly where the compounds of formula (I) have a C=C or CHCH bond these may be converted by conventional hydrogenation techniques, for example using a Lindlar type or Adams catalyst, to the corresponding ethylenic or unsaturated compounds as appropriate.

The hydantoins of formula (I) have an asymmetric 5-carbon atom, and a further asymmetric centre is present in those compounds wherein Y3- includes a hydroxyl group. Such alcohols therefore exist as four isomers which are separable by thin layer chromatography or high performance liquid chromotography into two diastereomers, each of which is a racemic mixture of two isomers.

On separation cf the diastereomers, one diastereomer may be converted to a mixture of the four isomers by treatment with a base, such as an alkali metal hydroxide, and subsequently re-separated to provide two diastereomers. Repeated use of this technique enables the effectual conversion of one diastereomer to the other? this may be desirable when one diastereomer has a biological activity preferred to the other.

The corresponding alcohols of formula (III) also exist in four isomeric forms. If desired, these may be separated into two epimers and subsequent cyclisation to a compound of formula (I) retains the stereochemical configuration.

In all of the foregoing chemical procedures it is of course evident that the choice of reactant will be dictated in part by the functional groups present in the substrate, and where necessary reactants having an appropriate selectivity of action must be used.

The hydantoins of formula (I) are of value in having pharmacological properties related to those of natural prostaglandins; that is, the hydantoins mimic or antagonise the biological effects of members of the prostaglandin (PG) Ά', 'B', 'C', 'D', Έ', and 'F' series. For example, hydantoins of formula (I) have been found to mimic the antiaggregatory effect of PGE^ on blood platelets, and to antagonise the contraction induced by PGE2 or PGF2on sm00tk muscle taken from therat stomach, rat colon, chick rectum and guinea pig trachea. In general, antagonistic properties, as opposed to mimetic, have been observed when using larger doses of the hydantoins. The pharmacological profile, by which is meant the relative activities, mimetic or antagonistic, compared with the natural prostaglandins, will of course vary depending on the specific hydantoin under consideration.

By reason of their prostaglandin-related properties, the hydantoins of formula (I) are useful in the pharmacological characterisation and differentiation of the bilogical activities of the natural prostaglandins and their 'receptors'. The further understanding of the physiological role of prostaglandins is of course valuable in the search for new and improved therapeutic substances.

The hydantoins of formula (I) are also of value as therapeutic agents. In particular hydantoins such as those described previously as having a potent anti-aggregatory effect on blood platelets are useful whenever it is desired to inhibit platelet aggregation or to reduce the adhesive character of platelets, and may be used to treat or prevent the formation of thrombi in mammals, including man. For example, the compounds are useful in the treatment and prevention of myocardial infarcts, to treat and prevent thrombosis, to promote patency of vascular grafts following surgery, and to treat complications of arteriosclerosis and conditions such as atherosclerosis, blood clotting defects due to lipermia, and other clinical conditions in which the underlying aetiology is associated with lipid imbalance or hyperlipidemia. A further use for such compounds is as an additive to blood and other fluids which are used in artificial extra-corporeal circulation and perfusion of isolated body portions.

It has also been found that hydantoins of formula (I) cause relaxation of vascular smooth muscle in a similar way as do members of the prostaglandin Ά' and Έ' series, compounds relaxing vascular smooth muscle are capable of inducing vasodilation and therefore have antihypertensive properties and are useful in lowering blood pressure in mammals, including man, and may be used alone or in combination with a 6-adrenoceptor blocking agent or another antihypertensive substance for the treatment of all grades of hypertension including essential, malignant and s econdary hypertens ion.

The compounds may also mimic the effect of PGE^ of antagonising histamine induced broncho-constriction. The hydantoins of formula (I) having this property may be used in the treatment or prophylaxis of bronchial asthma and bronchitis by alleviating the bronchoconstriction associated with this condition.

Hydantoins of formula (I) 5-(6-carboxyhexyl)-3-methyl-l-(3-oxooctyl)hydantoin, which inhibit pentagastrin-induced gastric acid secretion and reduce the formation cf aspirin-induced gastric lesions in rats are useful in reducing excessive gastric secretion, reducing and avoiding gastro-intestinal ulcer formation and accelerating the healing of such ulcers already present in the gastrointestinal tract whether such ulcers arise spontaneously or as a component of polyglandular adenoma syndromes.

Intravenous infusions of certain hydantoins of formula (I), to dogs has been found to increase urine volume indicating a potential utility for such compounds as diuretic agents, the uses of which include the treatment of oedema for example associated with heart failure, liver failure or kidney failure in man or other mammals.

A further use for hydantoins of formula (I) which mimic the uterine smooth muscle effects of PGE2 and PGFgOi is as anti- 15 fertility agents, in particular as abortifacients.

The amount of a compound of formula (I) required to achieve the desired biological effect will of course depend on a number of factors, for example, the specific compound chosen, the use for which it is intended, the mode of admi.iisirt.ciua, aad idle recipient. In general, a daily dose may be expected to lie in the range of from 1 ug to 20 mg per kilogram bodyweight. For example, an intravenous dose may lie in the range of from 5 ug to 1 mg/kg which may conveniently be administered as an infusion of from 0.01 to 50 ug per kilogram per minute. Infusion fluids suitable for this purpose may contain from 0.001 to 100, for example from 0.01 to 10 ug per millilitre. Unit doses may contain from 10 ug to 100 mg of a compound of iormula (I), for example ampoules for injection may contain from 0.01 to 1 mg, and orally administrable unit dose formulations such as tablets or capsules may contain from 0.1 to 50, for example 2 to 20 mg.

More specifically, when a compound of formula (I) is used to inhibit platelet aggregation it is generally desirable to achieve a concentration in the appropriate liquid, whether it be the blood of a patient or a perfusion fluid, of about lug t0 1° »5» for example from 10 ug to 1 mg, per liter.

The above mentioned doses refer to the acids, amides, esters, alcohols and tetrazoles of formula (I); where a salt is used, the dose should be taken as referring to the corresponding anion.

For use in the treatment or prophylaxis of the conditions referred to above, while the hydantoin compounds may be used as the raw 58 8 3 chemical they are preferably presented with an acceptable carrier therefor as a pharmaceutical formulation. The carrier must of course be 'acceptable' in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. The carrier may be a solid or a liquid, and is preferably formulated with a hydantoin compound as a unit-dose formulation, for example a tablet, which may contain from 0.05% to 95% by weight of the hydantoin compound. Other pharmacologically active substances may also be present in formulations of the present invention as indicated above. The hydantoin compounds may be incorporated in the formulations either in the form of the acid or the salt or ester thereof, and the formulations may be prepared by any of the well-known techniques of pharmacy consisting essentially of admixture of the components of the formulation.

The formulations include those suitable for oral, rectal, topical (buccal - eg. sub-lingual), the parenteral (that is subcutaneous, intramuscular and intravenous) administration, although the most suitable route in any given case will depend on the nature and severity the condition being treated, and on the nature of the hydantoin compound.

Formulations suitable for oral administration may be presented as discrete units such as capsules, cachets, lozenges or tablets each containing a predetermined amount of hydantoin compound; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; as an oil-in-water emulsion; or as 45883 a water-in-oil liquid emulsion. Such formulations may be prepared by any of the methods of pharmacy but all methods include the step of bringing into association the hydantoin compound with the carrier which constitutes one or more accessoiy ingredients. In general they are prepared by uniformly and intimately admixing the hydantoin compound with liquid or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation. For example a tablet may be prepared by compression or moulding a powder or granules of the hydantoin compound, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing, in a suitable machine, the hydantoin compounds in a free-flowing form such as a powder or granules optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent(s). Moulded tablets may be made by moulding in a suitable machine the powdered hydantoin compound moistened with an inert liquid diluent.

Formulations suitable for buccal (sub-lingual) administration include lozenges comprising a hydantoin compound in a flavoured basis, usually sucrose and acacia or tragacanth; and pastilles comprising a hydantoin compound in an inert basis such as gelatin and glycerin; or sucrose and acacia.

Formulations of the present invention suitable for parenteral administration conveniently comprise sterile aqueous preparations of a hydantoin compound, which preparations are preferably isotonic with the blood of the intended recipient.

These preparations are preferably administered intravenously, - 18 45882 although administration may also be effected by means of subcutaneous or intramuscular injection. Such preparations may be conveniently prepared by admixing the hydantoin compound with water and rendering the product sterile and isotonic with the blood.

Formulations suitable for rectal administration are preferably presented as unit-dose suppositories. These may be prepared by admixture of the hydantoin compound with one or more of the conventional solid carriers, for example cocoa butter, and shaping of the resulting mixture.

It will be appreciated from the foregoing that what we will claim may comprise any novel feature described herein, principally and not exclusively, for example:(a) The novel compounds of formula (I) as hereinabove defined. (b) A method for the preparation of the novel compounds of formula (I) as hereinabove described. (c) A pharmaceutical formulation comprising a compound of formula (I) in association with a pharmaceutically acceptable carrier therefor, and methods for the preparation of such formulations. (d) A method of inhibiting the aggregation of blood platelets, comprising the bringing Of said platelets into association with an effective platelet aggregatory inhibiting amount of a compound of formula (I).

EXAMPLE 1 - Preparation of 5-(6-Carboxyhexyl)-3-methyl-l-(3hydroxyoctyl)hydantoin (a) Diethyl 2-aminononanedioate Diethyl acetamidomalonate (16.7 g) and ethyl 7-bromoheptanoate (16.6 g) were dissolved in ethanolic ethoxide (prepared from sodium (1.51 g) and absolute ethanol (30 ml) and the mixture was refluxed for twenty seven hours. The cooled solution T>s poured into ice-water, the product was extracted into ether, and the dried extract was evaporated to give crude diethyl acetamido(6-ethoxycarbonylhexyl) malonate as a pale yellow oil, 2.2 (3H, singlet, -COCHg), 4.17 (6H, multiplet, 3 x -OCHg-CHg). This amide was refluxed with concentrated hydrochloric acid (111 ml) for 5¾ hours, the cooled solution was washed with ether, and the aqueous layer was decolourised with activated charcoal and evaporated to dryness in vacuo. The residual colourless glass was dissolved in the minimum quantity of absolute ethanol and added dropwise to a stirred, cooled (-10°C) mixture of absolute ethanol (125 ml) and thionyl chloride (15.7 g). The resulting solution was set aside at room temperature for 1 hour, refluxed for 1¾ hours, cooled and poured into ice-water adjusting the pH to 9 with aqueous sodium hydroxide. The mixture was extracted with ether, and the dried extract was concentrated and distilled, giving diethyl 2-aminononanedioate (55% yield) as a colourless oil, b.p. 114-115°/O.02-03 mm. (b) Diethyl 2-((4,4-dimethyl-3-oxo-phenylpentyl)amino)nonanedioate.

To diethyl 2-aminononanedioate (5.18 g) was added dropwise 4.4dimethyl-5-phenylpent-l-en-3-one (3.95 g) with cooling and stirring. The mixture was allowed to stand at room temperature for 21 hours to give diethyl 2-((4,4-dimethyl-3-oxo-phenylpentyl) amino)nonanedioate. (c) 5-(6-carboxyhexyl)-3-methyl-l-(3-hydroxyoctyl) hydantoin Diethyl 2-(3-oxooctylamino)nonanedioate (7.7 g), prepared by the method described in Example lb, was allowed to react with methyl Isocyanate as described in Example 2 below to give 5-(65 ethoxycarbonylhexyl)-3-methyl-l-(3-oxooctyl)hydantoin, which was hydrolysed to 5-(6-carboxyhexyl)-3-methyl-l-(3-oxo-octyl) hydantoin, a colourless oil.

This keto-acid (1.23 g) was dissolved in 0.25 N-sodium hydroxide solution (15 ml) and the solution was stirred in an ice bath during the addition of sodium borohydride (63 mg). After 3 hours' stirring at room temperature, the solution was acidified and extracted with ether. The washed and dried ether extract was evaporated to leave an oil which was purified by chromatography on a column Of silica using a mixture of chloroform and methanol (50:1) as eluant to give 5-(6-carboxyhexyl)-3-methyl-l-(3hydroxyoctyl)hydantoin as a colourless viscous oil.

EXAMPLE 2 - Preparation of 5-(6-Carboxyhexyl)-3-methyl-l-octylhydantoin (a) Diethyl 2-((5-phenylpentyl)amino)nonanedioate hydrobromide 2o A mixture of diethyl 2-aminononanedioate (25.9 g) and 5-phenylpentyl bromide (22.7 g) was heated in a bath at 100°C for 3 hours. After cooling, ether (100 ml) was added to the mixture, which was then'allowed to stand for 2 hours, at O°C. The colourless solid (21.95 g) which crystallised, was collected and dried.

This diethyl 2-((5-phenylpentyl)amino)nonanedioate hydrobromide melted at 7O-72°C. (b) 5-(6-carboxyhexyl)-1-(5-phenylpentyl)hydantoin A solution of the hydrobromide above (4.86 g) in ethanol (20 ml) and 2 N-hydrochloric acid (5 ml) was cooled in ice and stirred during the gradual addition of a solution of potassium cyanate (1.62 g) in water (5 ml), after which, the solution was allowed to stand at room temperature for 18 hours. The alcohol was evaporated, water was added, the insoluble oil was extracted with ether, and the ethereal extract was dried and evaporated to leave a pale yellow oil. This material was heated on thesteam bath for 6 hours to give 5-(6-ethoxycarbonylhexyl)-1-(5-phenylpentyl) hydantoin.

The foregoing ester (4.0 g) was hydrolysed by treatment with dilute sodium hydroxide solution, and the product was purified by chromatography on silica gel, to give 5-(6-carboxyhexyl)-1(5-phenylpentyl)hydantoin crystallising from ethyl acetate-light petroleum (b.p. 6O-8O°C) in colourless prismatic needles, m.p. 9O-92°C. (c) 5-(6-carboxyhexyl)-3-methyl-l-octyhydantoin.

Diethyl 2-octylaminonananedioate was prepared from the appropriate alkyl halide, using the method of Example 2a. A solution of diethyl 2-octylaminononanedioate (742 mg) and methyl isocyanate (120 mg) in dry ether (7.5 ml) was allowed to stand at room temperature for 48 hours, after which time the ether was evaporated to leave a pale yellow oil (800 mg). The oil was heated on the steam bath for 2 hours to give 5-(6-ethoxycarbonyl) -3-methyl-l-octylhydantoin as a yellow oil.

The ester (650 mg) was hydrolised by standing in solution in ethanol (2.4 ml) and 5N-sodium hydroxide solution (0.6 ml) for 3 hours at room temperature. After evaporation of the ethanol, the acidic product was isolated by extraction with ether, and purified by chromatography on a column of silica gel to give 5-(6-carboxyhexyl)-3-methyl-l-octylhydantoin as a colourless oil.

EXAMPLE 3 - Preparation of 1-(6-carboxyhexyl)-3-methyl-5-octylhydantoin. (a) Ethyl 2-(6-ethoxycarbonylhexylamino) decanoate 2-aminodecanoic acid (J.Am. Chem. Soc., 1946, 68, 450) (16.0 g) was added in portions to a cooled (-10°C) mixture of absolute ethanol (70 ml) and thionyl chloride (6 ml) with stirring. The resulting solution was set aside for 2 hours, at room temperature, refluxed for 1 hour, cooled, poured into ice-water, and the pH of the solution was adjusted to 9 with aqueous sodium hydroxide. The mixture was extracted with ether, the extract was dried, concentrated then distilled, giving ethyl 2-amino decanoate (75%) as a colourless oil, b.p. 82-4°C/0.2 mm.

A solution of the above aminoester (18 g) and ethyl 7-bromoheptanoate (20 g) in absolute ethanol (50 ml) was refluxed for 24 hours, and the ethanol was then evaporated. Addition of ether precipitated a hydrobromide salt, m.p. 98°C, which was dissolved in a little diehloromethane, treated with an equivalent amount of triethylamine, washed thoroughly with water, and dried; removal of the solvent gave ethyl 2-(6-ethoxycarbonylhexylamino)decanoate (52%) as a colourless viscous oil, b.p. 142-4°C/O.OO1 mm. (b) 1-(6-carboxylhexyl)-5-octylhydantoin.

The decanoate of part (a) above (7.4 g) was reacted with potassium 883 cyanate and hydrochloric acid to give 1-(6-ethoxycarbonylhexyl)5-octylhydantoin which formed colourless crystals, m.p. 68-7O°C, from light petroleum (b.p. 6O-8O°C).

This ester (4.0 g) was hydrolysed with sodium hydroxide solution to give 1-(6-carboxyhexyl)-5-octylhydar.toih which crystallised from a mixture of ethyl acetate and light petroleum (b.p. 6O-8O°C) as colourless needles, m.p. 65-66°C. (c) 1-(6-carboxyhexyl)-3-methyl-5-octylhydantoin By the method described in Example 2(c) , the decanoate of part (a) above, was converted into 1-(6-ethoxycarbonylhexyl)-3-methy15-octylhydantoin, and thence by hydrolysis into 1-(6-carboxyhexyl)3-methyl-5-octylhydantoin, isolated as a colourless oil.

EXAMPLE 4 -Preparation of 3-butyl-5-(6-carboxyhexyl)-1-octyl hydantoin To a solution of sodium (308 mg) in ethanol (40 ml) was added 5-(6-ethoxycarbonylhexyl)-1-octylhydantoin which was prepared by the method of Example 2(b) from diethyl-2-octylaminononanedioate Example 2(c). To the solution, was further added butyl bromide (1.8 g), and the solution was refluxed for 24 hours.

The solvent was evaporated, water was added and the insoluble oil was extracted with ether. The washed and dried extract was evaporated to give 3-butyl-5-(6-ethoxycarbobylhexyl)-1-octylhydantoin.

This ester (3.2 g) was dissolved in ethanol (15 ml) and 2 Nsodium hydroxide (15 ml) and left at room temperature for 1 hour.

The acidic product was isolated by extraction with ether and purified by chromatography on silica gel to give 3-butyl-5(6-carboxyhexyl)-1-octylhydantoin as a colourless oil.

EXAMPLE 5- Preparation of 3-butyl-l-(6-carboxyhexyl)-5-octyl5 hydantoin By the method of Example 4, 1-(6-ethoxycarbonylhexyl)-5-octylhydantoin (see Example 3(b)), was converted in 3-butyl-l-(6ethoxycarbonylhexyl)-5-octylhydantoin, which was hydrolised to give 3-butyl-l-(6-carboxyhexyl)-5-octylhydantoin as a colourless oil.

EXAMPLE A The compound 5-(6-Carboxyhexyl)-3-methyl-l-(3-oxooctyl)hydantoin was found to reduce aspirin-induced gastric ulceration in rats: an oral dose of Img/Kg gave 80% protection.

Claims (25)

1. CLAIMS :1. A compound of formula (I) 1 2 wherein Z is alkyl; one of Z and Z is represented by the 5 group wherein X is phenylene, -CsC-, cis or trans -CH=CH- or -CH2~CQ2 - in which each Q is independently selected from hydrogen and alkyl or the two Q's together form an alkylene radical having four, five or six carbon atoms; X 2 is a 10 covalent bond or a straight or branched alkylene chain having 1 to 6 carbon atoms optionally having one of its methylene groups replaced by oxa (-0-) provided that at least one carbon atom separates the oxa group from a -CsC-, -CH=CH- or -CO- group; and X is selected from 515 tetrazolyl, carboxyl, carbamoyl, hydroxymethylene and alkoxyearbonyl; 1 2 and the other of z and Z is represented by the group 12 3 -Y-Y-Y -Y J ; wherein Y is -CR 2 - CH 2 ~ in each R is independently 2. O selected from hydrogen and methyl; Y 1 is carbonyl, methylene, methylene substituted by hydroxy or methylene substituted by 2 hydroxy and alkyl; Y is a covalent bond or straight or branched alkylene having 1 to 7 carbon atoms optionally substituted on the carbon adjacent Y 3- by one or two groups, independently selected from alkyl, cyeloalkyl and bicycloalkyl; Y is hydrogen, hydroxy, alkoxy having 1 to 7 carbon atoms, cyeloalkyl, bicycloalkyl, phenyl, benzyl, phenoxy or benzyloxy, wherein each of phenyl, benzyl, phenoxy and benzyloxy may be substituted in the benzene ring by one or more groups selected from hydroxy, halo, nitro, amino, acylamino, alkenyl, alkoxy, phenyl and alkyl which may itself be substituted by one or more halo groups; or Y is a bond, -CHg- Or -CHg.CHg- and Y 1 , Y 2 and Y 3 taken together, form a cyeloalkyl group substituted by hydroxyl; and salts thereof. 1 2

2. The compound of claim 1 wherein one of 2 and Z is 1 2 represented by the group -CHg-X-X -X 1 wherein X is -CHg-CHg-;X is a straight or branched 2 alkylene chain having 1 to 6 carbon atoms; and X is carboxyl or alkoxycarbonyl; 1 2 and the other of Z and Z is represented by the group 12 3 -Y-Y -Y -Y -5 wherein Y is -CHg-CHg-; Y 3- is methylene or methylene 2 substituted by hydroxy; Y is a covalent bond or a straight or branched alkylene chain; and Y is hydrogen.

3. A compound selected from 5-(6-carboxyhexyl)-3-methyl-l-octylhydantoin; 5-(6-ethoxycarbonylhexyl)-3-methyl-l-octylhydantoin; 5-(6-carboxyhexyl)-3-methyl-l-(3-hydroxyoctyl)hydantoin; 5-(6-earboxyhexyl)-S-methyl-l-(3-oxooctyl) hydantoin; 5-(6-ethoxycarbonylhexyl)-3-methyl-l-(3-oxooctyl)hydantoin; 1-(6-carboxyhexyl)-3~methyl-5-octylhydantoin; 5 1-(6-ethoxycarbonylhexyl)-3-methyl-5-octylhydantoin; 3-butyl-5-(6-carboxyhexyl)-1-octylhydantoin; 3-butyl-5-(6-ethoxycarbonylhexyl)-1-octylhydantoin; 3-butyl-l-(6-carboxyhexyl)-5-octylhydantoin; and 3-butyl-l-(6-ethoxycarbonylhexyl)-5-octylhydantoin; 10 salts thereof, and where a compound contains a terminal carboxy group, esters thereof.

4. A composition comprising a compound of formula (I) as defined in any of claims 1 to 3 in association with a pharmaceutically acceptable carrier.

5. A composition as claimed in claim 4 wherein the carrier is a liquid.

6. A composition as claimed in claim 4 or 5 in the form of a sterile injectable solution.

7. A composition as olaimed in claim 5 or 6 comprising from 20 0.001 to 100 ug of a compound of formula (I) per millilitre.

8. A composition as claimed in claim 5, 6 or 7 in the form of a unit dose comprising from 0.01 to 1 mg of a compound of formula (I).

9. A composition as claimed in claim 4 wherein the carrier is a solid. 28 45882

10. A composition as claimed in claim 9 in the form of a unit dose.

11. A composition as claimed in claim 9 or 10 in form of a tablet, capsule, cachet or suppository.

12. A composition as claimed in claim 9, 10 or 11 comprising from 0.1 to 50 mg of a compound of formula (I) .

13. A method of preparing a compound of formula (I) as defined in any of claims 1 to 3 comprising cyclisation of a compound of formula (II) wherein G is carboxyl or a derivative thereof, and each of 1 2 Ζ, Z and Z has the same meaning as in formula (I).

14. A method of preparing a compound of formula (I) as defined in any of claims 1 to 3 comprising cyclisation of a compound of formula (VII) (VII) 29 45882 wherein G is carboxyl or a derivative thereof, and each of 1 2 Ζ, Z and Z has the same meaning as in formula (I). A method of preparing a compound of formula (I) as defined in any of claims 1 to 3 comprising reaction of a carbonic 5 acid derivative with a compound of formula (IX) (IX) 1 2 wherein each of Ζ, Z and Z has the same meaning as in formula (I). 16. A method of preparing in any of claims 1 to of formula (X) a compound of formula (I) as defined 3 comprising alkylation of a compound with a reactive ester derivative of an alcohol of formula 3 1 J .OH, wherein J is hydrogen or alkyl, J is hydrogen or 30 45882 12 2 Ζ , J is hydrogen or Z that one of J. J 1 and J 2 the same value as J, J 1 3 12 and J each of Z and Z 17. A method of preparing in any of claims 1 to of formula (XI) 3 12 and J is alkyl, Z or Z provided is hydrogen and J 3 does not have 2 12 or J ; in the definition of J , J has the same meaning as in formula a compound of formula (I) as defined 3 comprising reduction of a compound (XI) J ,.2 or Z 3 is =CH-X 1 -X 2 and Z 4 is -Y-Y 1 -Y 2 -Y 3 in which each of 2 3 R, X to X , Y to Y and Z is as defined in formula (I). 18. A method of preparing a compound of formula (I) as defined 2 in claim 1 wherein X is tetrazolyl comprising reaction of 2

15. The corresponding precursor, wherein in formula (I) X is 3 4 3 4 replaced by -C.X =N.X in which X and X together form a 3 4 bond, X is hydrogen or alkyl and X is alkoxy, alkylthio, amino or -NH-NH 2 , with nitrous acid or a salt of hydrazoic acid as appropriate. 2o 19. A method of preparing a compound of formula (I) as defined in 2 claim 1 wherein X is hydroxymethylene comprising reduction of a corresponding acid, ester, acid halide, acid anhydride or aldehyde. - 31 45882

16. 20. A method of preparing a compound of formula (X) as defined in claim 1 wherein X is hydroxymethylene comprising hydrolysis of a corresponding halide.

17. 21. A method of preparing a compound of formula (I) as defined 5 in claim 1, substantially as hereinbefore described with reference to Examples 1 to 5.

18. 22. A compound of formula (I) as defined in any of claims 1 to 3 when prepared by a process defined by any one of claims 13 to 20. 10

19. 23. A method of inhibiting the aggregation of blood platelets, comprising the bringing of said platelets into association with an effective platelet aggregatory inhibiting amount of a compound of formula (I) as defined in any of claims 1 to 3.

20. 24. A pharmaceutical composition comprising a compound of 15 formula (I) as defined in claim 1 in association with a pharmaceutically acceptable carrier substantially as hereinbefore described.

21. 25. A method of preparing a composition as claimed in claim 24 which comprises admixture of the compound of formula (I) and a 20 pharmaceutically acceptable carrier.

22. 26. A compound substantially as hereinbefore described with reference to the Examples.

23. 27. A composition substantially as hereinbefore described with particular reference to Example A.

24. 28. A method of preparing a compound substantially as hereinbefore described with reference to Examples 1 to 5,

25. 29. A method of inhibiting the aggregation of blood platelets substantially as hereinbefore described.