GB2032419A - Hydantoin Prostaglandin Analogues - Google Patents

Abstract

Compounds of formula <IMAGE> wherein Z is hydrogen or alkyl, Z<1> and Z<2> being prostaglandin side chains, with the group Z<1> containing one oxa or thia group. The compounds are for use in human medical and veterinary practice as, for example, anti-platelet aggregatory agents, vasodilators, bronchodilators, abortifacients, contraceptives, and anti-allergic agents.

Description

SPECIFICATION Biologically Active Nitrogen Heterocycles, their Synthesis and use in Medicine This invention relates to heterocyclic compounds, their synthesis, compositions containing them, and their use in medicine.

Hydantoin derivatives, defined hereinbelow in formula (I), have been found to have pharmacological properties related to those of natural prostaglandins, as demonstrated by their ability to mimic or antagonise the physiological effects of the natural prostaglandins in various biological preparations. In particular, certain compounds of formula (I) have been found to be potent mimetics of the antipiatelet aggregatory properties of prostaglandin E1.

In formula (I):

Z is hydrogen or alkyl; one of Z1 and Z2 is represented by the group -X-X1-X2-X3, wherein X methylene, oxa (-0-) or thia (-S-), X1 is phenylene, or H2Q- in which each Q is independently selected from hydrogen and alkyl, such as ethyl, or the two Q's together form an aikylene radical having four, five or six carbon atoms, one of any methylene groups of X being replaceable by oxa or thia; X2 is a covalent bond or a straight or branched alkylene chain having 1 to 6 carbon atoms;X3 is selected from 5-tetrazolyl, carboxyl, carboxamide, hydroxymethyl and alkoxycarbonyl- with the provisos that X and Xr together contain only one oxa or thia group and that at least one carbon atom separates the oxa or thia group from a --COO- or 5-tetrazolyl group and from the nitrogen of the hydantoin ring; and the other of Z1 and Z2 is represented by the group -Y-Y1-Y2-Y3, wherein Y is -0R2-0H2- in which each R is independently selected from hydrogen and methyl; Y1 is carbonyl, methylene, methylene substituted by hydroxyl or methylene substituted by hydroxyl and alkyl;; y2 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 each of which may be alkyl or a cyclic radical; Y3 iS hydrogen, hydroxy, alkoxy having 1 to 7, preferably 1 to 4, carbon atoms, a cyclic radical, 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, halogeno, nitro, amino, acylamino, alkenyl, alkoxy, phenyl, benzyloxy and alkyl which may itself be substituted by one or more halogeno groups; or y2 and Y3 together form an alkyl group having 1 to 7 carbon atoms of which at least one hydrogen is replaced by fluoro; or Y is a bond, -CH2-, or CH2.CH2- and Y1, Y2 and Y3 taken together form a cycloalkyl or bicycloalkyl group substituted by a hydroxyl group which preferably has three carbon atoms separating it from the hydantoin ring.

In formula (I), the term cyclic radical means a monovalent radical derived by loss of a ring hydrogen atom from a monocyclic or polycylic compound having from 3 to 12 ring atoms selected from carbon, nitrogen, oxygen and sulphur, which compound may be saturated or unsaturated and may be further substituted by one or more alkyl groups, but excluding phenyl Such cyclic radicals include cycloalkyl having 3 to 10 carbon atoms such as cyclopropyl, cyclopentyl, cyclohexyl and cyclooctyl, bicycloalkyl having 4 to 10 carbon atoms such as norbornanyl (bicyclo[2,2, 1 ]heytyl), or adamantyl, spiroalkanyl having 5 to 12 carbon atoms such as 2-spiro[3,3]-heptyl, 1 -spiro[4,4]nonyl and 8-spiro [4,5]decyl, cycloalkenyl having 4 to 10 carbon atoms such as 4-cyclopentenyl, heterocyclic radicals such as tetrahydrofuranyl and tetrahydropyranyl and heteroaryl radicals such as thienyl, furyl, pyridyl, pyrimidyl, thiazolyl, imidazolyl and diazepinyl. Included in the term cyclic radical are those wherein one or more hydrogen atoms are replaced byfluoro.

Unless otherwise stated, in formula (I) and other formulae in this specification, alkyl moieties are selected from methyl, ethyl, propyl, butyl, pentyl and hexyi, including all isomers thereof; for example, in the definitions of Y1 andY2 the alkyl groups are preferably methyl; and the alkyl moiety of alkoxycarbonyl is desirably methyl or ethyl.

Similarly alkenyl groups have 2 to 4 carbon atoms for example vinyl.

In a compound of formula (I) the bonding of the diva lent phenylene group may be ortho, meta or para.

Included in the meaning of compounds of formula (I) are the salts corresponding to the carboxylic acids and tetrazoles when X3 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 e.g. sodium and potassium, and alkaline earth metal e.g. calcium and magnesium, or an organic base, particularly an amine such as ethanolamine. 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.

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 (all):

wherein G is carboxyl or a derivative thereof such as amide or ester in particular an alkyl ester, and each of Z, Z1 and Z2 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 (111):

wherein G, Z1 and Z2 are as defined in formula (I) provided tha G may also be nitrile, by reaction with cyanic acid or an alkyl iso-cyanate depending respectively on whether Z is hydrogen or alkyl.

When cyanic acid is used, the cyanic acid is conveniently produced in situ by the use of an alkali metal cyanate, e.g. potassium cyanate, and an acid which may be present as an acid addition salt of the compound of formula (ill) or a free acid of formula (Ill) wherein either or both of R and X3 is hydrogen. Alternatively an equivalent amount of mineral acid or an organic acid may be added to the reaction medium. The 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.

Similar reaction conditions may be used when an alkyl iso-cyanate is used except that it is unnecessary to provide an equivalent amount of acid, as an acid addition salt or otherwise, in the rectants.

Instead of using a cyanate or iso-cyanate, 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 1000C to 1250C but temperatures up to 1500C 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):

wherein G, Z1 and Z2 are as defined in formula (III), one of Q1 and Q2 jS amino and the other is halogeno, preferably bromo. The reaction may be carried out by heating in the absence of a solvent or in the presence of an inert solvent such as ethanol.

The intermediates of formula (III) wherein Z2 iS -Y-Y1-Y2-Y3 when Y1 is carbonyl, may also be prepared by reaction of an amine of formula (IV) wherein Q1 is amino with an unsaturated ketone of formula (VI): C(R)2=CH.CO.Y2.Y3 (Vl) wherein Y2 and Y3 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 bycyclisation of a compound of formula (VII):

wherein Z, Z' and Z2 are as defined in formula (I) and G' is carboxyl or a reactive derivative therof such as alkoxycarbonyl e.g. 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 reacting a compound of formula (V) with a compound of formula (VIII):

wherein one of Q1 and Q2 iS halogeno, preferably chloro or bromo and the other is amino and each of Z, Z1, Z2 and G1 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):

wherein each of Z, Za and Z2 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 chloroformate. 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 diethyl ether. 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) wherein Z is alkyl may also be prepared by alkylation, using an alkylating agent which may be designated as a reactive ester derivative of an alcohol J3. OH, of a compound of formula (X):

wherein J is hydrogen or alkyl, J' is hydrogen or Z1, J2 is hydrogen or z2 and J3 is alkyl, Z' or Z2, provided that one of J, JX and J2 is hydrogen and J3 does not have the same value as J, J' or J2; in the definition of J1 J2 and J3 each of Z1 and ZZ has the same meaning as in formula (I). Suitable reactive ester derivatives include chloride, bromide, iodide and sulphonates such asp- 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 usch as an alkali metal hydride, alkali metal amide, or alkali metal alkoxide, typicaily sodium hydride or a sodium alkoxide e.g. sodium methoxide.

The reaction is conveniently carried out in an inert solvent which simply acts as diluent for the reactants such as toluene, dioxan, ether, dimethylformamide, tetrahydrofuran, dimethylsulphoxide 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 aiready known in the art (see for example Chemical Reviews (1950) 46, p. 403425).

A further preparation of compounds of formula (I) is by reduction of a corresponding unsaturated compound of formula (XI):

wherein either Z3 is -CR-CH2-Y1-Y2-Y3 and Z4 is -X-X1-X2-X3 or Z3 is =CH-X1-X2- X3 and Z4 iS V~V1~YZ~Y3 in which each of R, X to X3 and Y to Y3 iS as defined in formula (I), with a suitable readucing agent.

A suitable reducing agent is stannous chloride which may be used as 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 (Xl) may be prepared by the following series of reactions:

In the above formulae Z, Z3, Z4 and G have the same meaning as in formula (Xl) and (III) respectively, G3 is alkyl for example n-butyl and G4 is halogeno such as bromo. The formation of (XIII) is analogous to the ring closure involving a compound of formula (all); and compounds of formula (XIV) are prepared using concentrated mineral acid such as hydrochloric acid.

Tetrazoles of formula (I) may be prepared from corresponding compounds wherein the group -X3 is replaced by

wherein X4 and X5 together form a bond (nitrile); X4 iS hydrogen or alkyl and X5 iS alkoxy (imidoester), alkylthio (imidothioester), -NH NH2 (amidrazone), or amino (amidine); or X4 iS hydroxy and X5 iS amino (amidoxime). The reaction is preferably carried out in a polar aprotic liquid medium such as dimethylformamide using a salt of hydrazoic acid e.g. sodium azide.

However, when X3 iS 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 X3 iS hydroxymethyl 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 ethyl chloroformate 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 catalvtic hvdrogenation Alternatively the alcohols of formula (I) wherein X3 is hydroxymethyl 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 syntheses of hydantoins of formula (I) having a hydroxyl 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 inthe 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 Y is carbonyl may be converted to the corresponding secondary alcohol by reduction with a suitable reducing agent, such as sodium borohydride. Also, an alcohol of formula (1) wherein Y' is --CH.OHH- 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 CH=CH bond these may be converted by conventional hydrogenation techniques, for example using a Lindlar type or Adams catalyst, to the corresponding ethylenic or saturated 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 Y' includes a hydroxyl group. Such alcohols therefore exist as four isomers which are separable by thin layer chromatography or high performance liquid chromatography into two diastereomers, each of which is a racemic mixture of two isomers. On separation of the diastereomers, one diastereomer may be converted to a mxiture 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 should 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) 'A', 'B', 'C', 'D', 'E' and 'F' series. For example, hydantoins of formula (I) have been found to mimic the anti-aggregator effect of PGE, on blood platelets, and to antagonise the contraction induced by PGE2 or PGF2 on smooth muscle taken from the rat stomach, rat colon, chick rectum and guinea pig trachea. In general, antagonistic properties, as opposed to mimetic, hate 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 pharmacologicl characterisation and differentiation of the biological 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 lipemia, 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 extracorporeal circulation and perfusion of isolated body portions.

A group of compounds which are particularly valuable as inhibitors of platelet aggregation are those of formula (I) wherein Z is hydrogen; Za is carboxyalkyl wherein the alkylene moiety has 3 to 9 carbon atoms; and Z2 is a group -(CH2)2.CH.0H.Y2.Y3 wherein Y2 is a bond or branched alkylene having a tertiary carbon atom adjacent the hydroxy-sustituted carbon and Y3 is as defined in formula (I).

Within this group of compounds, those wherein Y3 iS cycloalkyl having 4 to 7 carbon atoms are especially active.

The hydantoins of formula (I) also cause relaxation of vascular smooth muscle in a similar way as do members of the prostaglandin 'A' and 'E' series. Compounds relaxing vascular smooth muscle are capable of inducing vasodilation and therefore have antihypertensive properties and are useful in lowering the blood pressure in mammals, including man, and may be used alone or in combination with a p-adrenoceptor blocking agent or another antihypertensive substance for the treatment of all grades of hypertension including essential, malignant and secondary hypertension.

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

Hydantoins of formula (I), which inhibit pentagastrin-induced gastric acid secretion and reduce the formation of aspirin-induced gastric lesions in rats are useful in reducing excessive gastric secretion, reducing and avoiding gastrointestinal 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 hydantoins of formula (I), to dogs increase the urine volume indicating a potential utility for such compounds as diuretic agents, the uses of which include the treatment of oedema for example oedema 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 PGF2, is as antifertility agents, in particular as abortifacients.

In addition the compounds of formula (I) may be used in the treatment of proliferative skin diseases such as are associated with excessive cell division in the epidermis or dermis which may be accompanied by incomplete cell differentiation. Particular conditions which may be alleviated include psoriasis, atopic dermatitis, nonspecific dermatitis, primary irritant contact dermatitis, allergic contact dermatitis, basal and squamous cell carcinomas of the skin, lamellar ichthyosis, epidermolytic hyperkeratosis, premalignant sun induced keratosis, non-malignant keratosis, acne, and seborrheic dermatitis in humans and atopic dermatitis and mange in domestic animals. For the treatment of these conditions the compounds are desirably applied topically to the affected skin.Alternatively they may be administered by an intradermal or intramuscular injection which may be directly into the skin lesion or into the surrounding tissue.

Injectable compositions will generally contain from 0.1 to 0.5% w/v of active ingredient.

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 administration, and the recipient. In general, a daily dose may be expected to lie in the range of from 1 g to 20mg per kilogram bodyweight. For example, an intravenous dose may lie in the range of from 5y9 to 1 mg/kg which may conveniently be administered as an infusion of from 0.01 to 50g per kilogram per minute. Infusion fluids suitable for this purpose may contain from 0.001 to 100, for example from 0.01 to 10fzgper millilitre.Unit doses may contain from 1 Oy9 to 1 OOmg of a compound of formula (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 20mg.

More specifically, when a compound of formula (I) is used to inhibit platelet aggrgation 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 1Ebg to 1 Omg, for example from 1 Oyg to 1 mg, per liter, The abovementioned 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 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-e.g. 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 of 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 nonaqueous liquid; as an oil-in-water emulsion; or as 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 accessory 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 compound 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 suitable for topical applications to the skin preferably take the form of an ointment, cream, lotion, paste, gel, spray, aerosol or oil. Carriers which may be used include vasoline, lanoline, polyethylene glycols, alcohols and combinations thereof. The active ingredient is generally present in a concentration of from 0.1 to 15% w/w of the composition, for example from about 0.5 to about 2%.

Formulations of the present invention suitable for pa renteral 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, 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 for lowering blood pressure in a mammal including man which comprises administration to the mammal of an effective hypotensive, non-toxic amount of a compound of formula (I).

(e) A method for the treatment of prophylaxis of thrombosis in a mammal or mammalian tissue, including human, which comprises administration of a non-toxic, effective anti-thrombotic amount of a compound of formula (I).

(f) A method for inducing vasodilation in a mammal, including man, comprising administration to said mammal of a non-toxic effective vasodilatory amount of a compound of formula (I).

(g) A method for the treatment or prophylaxis of gastric lesions in a mammal including man comprising administration to said mammal of a non-toxic effective prophylactic or therapeutic amount of a compound of a formula (I).

(h) A method for inducing bronchodilation in a mammal, including man, comprising administration to said mammal of a non-toxic, effective bronchodilatory amount of a compound of formula (I).

(i) A method for the treatment or prophylaxis of an allergic condition in a mammal, including man, comprising administration to said mammal of a non-toxic effective prophylactic or therapeutic amount of a compound of formula (I).

(j) A method of inducing abortion of a foetus in a mammal including human comprising administration to said mammal of a non-toxic effective abortifacient amount of a compound of formula (I).

(k) A method of inducing infertility in a mammal including human comprising administration to said mammal of a non-toxic effective contraceptive amount of a compound of formula (I).

(I) A method of treating a proliferative skin disease in a mammal which comprises bringing an effective therapeutic amount into effective proximity of the skin.

(m) A compound of formula (11), (III), (IV), (VI), (all), (veil), (IX), (X), or (Xl) as defined hereinbefore, where novel.

Reference Preparation Preparation of 5-(4-carboxymethylthiobutyl)-l - (3-hydroxy-3-cyclohexylpropyl)hydantoin A. Diethyl 2-amino-7-thianonanedioate Diethyl 4-bromobutylacetamidomalonate (Rec.

Trav. Chim. 1971,874) (35.29) was dissolved in absolute ethanol (150 ml) and a solution of ethyl mercaptoacetate (12.09) in ethanolic sodium ethoxide (from 2.309 sodium and 130 ml ethanol) added dropwise with stirring. A slight exotherm soon subsided, and the resulting cloudy mixture was stirred at room temperature for 24 hours. The mixture was evaporated to low bulk in vacuo, then diluted with water and extracted with chloroform. The dried extract was evaporated giving diethyl acetamido-(4-ethoxycarbonylmethylthio)butyl malonate (42.29) as a colourless gum. This was suspended in 10% aqueous hydrochloric acid (750 ml) and refluxed for 3 hours, cooled, then evaporated to low bulk in vacuo, -using ethanol to remove the last traces of water azeotropically.The residual gum was dissolved in a little ethanol and added to a solution of thionyl chloride (21.0 ml) and ethanol (300 ml) (made up at 100) and the solution stood at +50 for 1 8 hours then refluxed for 1 hour. The cooled solution was evaporated, and the residue partitioned between chloroform and water and the aqueous layer taken to pH-l 0 with sodium carbonate solution. The aqueous layer was extracted thoroughly with chloroform and the combined extracts dried and evaporated, giving diethyl 2-amino-7-thianonanedioate (25.5 g) as a pale yellow oil.

B. Ethyl 2-((3-oxo-3-cyclohexylpropyl)-amino)6-(ethoxycarbonylmethylthio)-hexanoate To diethyl 2-amino7-thianonanedioate (4.16 g) was added dropwise 3-cyclohexylprop-1-en-3- one (2.07 g) with cooling and stirring, The mixture was allowed to stand at room temperature for 21 hours to give ethyl 2-((3-oxo-3-cyclohexyl propyl )a mino)-6-(ethoxycarbonyl methylthio) hexanoate as a pale yellow oil.

C. Ethyl 2-((3-hydroxy-3-cyclohexylpropyl)- amino)-6-(ethoxycarbonylmethylthio)hexanoate The foregoing crude ketone (6.2 g) was dissolved in absolute ethanol (180 ml) and the solution was stirred in an ice-bath during the gradual addition of sodium borohydride (750 mg).

The solution was stirred in the ice-bath for a further 10 minutes and then left to stand at room temperature overnight. Most of the alcohol was evaporated, water was added, and the insoluble oil was extracted with ether, and the ether solution was dried and evaporated to leave ethyl 2-((3-hydroxy-3-cyclohexylpropyl)-amino)-6 (ethoxywarbonylmethylthio)hexanoate as a pale yellow oil which was used without further purification.

D. 5-(4-Carboxymethylthiobutyl)-1 -(3-hydroxy- 3-cyclohexylpropyl)hydantoin A solution of the above alcohol (6.05 g) in ethanol (30 ml) and 2N-hydrochloric acid (15 ml) was stirred and cooled in ice during the dropwise addition of a solution of potassium cyanate (2.609) in water (8 ml). The mixture was allowed to stand at room temperature for 1 8 hours, then the alcohol was evaporated, water was added and the insoluble oil was extracted with ether. The dried ether solution was evaporated to leave a viscous oil which was heated on the steam bath for 19 hours to give 5-(4-ethoxycarbonyl- methylthiobutyl)- 1 -(3-hydroxy-3-cyclohexylpropyl)-hydantoin as a viscous pale yellow oil.

A solution of this ester in 0.5 N-sodium hydroxide (75 ml) was left at room temperature for 2 hours. The solution was washed with ether and the clear alkaline solution was acidified with 2N-hydrochloric acid and the precipitated oil was extracted with ether. Evaporation of the dried ether solution gave a viscous oil (6.8 g) which was chromatographed on a column of silica gel to give 5-(4-carboxymethylthiobutyl)-1 -(3-hydroxy-3cyclohexylpropyl)hydantoin as a viscous oil.

Separation by HPLC on a column of silica with a mixture of chloroform, methanol and acetic acid (97:2.5:0.5) gave the two pure diastereomers, one being obtained as a viscous gum and the other forming colourless crystals, m.p. 104-1080C.

Using the method of the preceding Reference Preparation modified as necessary, were prepared 1 a) ethyl 2-((3-oxo-3-cyclohexylpropyl)amino) 3-(3-ethoxycarbonylpropylthio)propionate; 2a) ethyl 2-(3-oxooctylamino)-3-(3 ethoxycarbonylpropylthio)propionate; and 3a) ethyl 2-((3-oxo-3-cyclopentylpropyl)amino)-3-(3-ethoxycarbonylbutylthio)propionate; which were converted to: 1 b) ethyl 2-((3-hydroxy-3-cyclohexylpropyl) amino)-3-(3-ethoxycarbonylpropylthio)propionate; 2b) ethyl 2-((3-hydroxyoctylamino)-3-(3 ethoxycarbonylpropyl)propionate; and 3b) ethyl 2-((3-hydroxy-3-cyclopentylpropyl) amino-3-(3-ethoxywarbonylbutylthio)propionate; from which were obtained the following hydantoins which, where indicated, were separated to provide individual diastereomers having the stated characteristics:: 1 c) 5-(3-carboxypropylthiomethyl)- 1(3- hydroxy-3-cyclohexylpropyl)hydantoin, 131- 1330, 108-1 100C; 2c) 5-(3-carboxypropylthiomethyl)-1 -(3- hydroxyoctyl)-hydantoin, 44--47 0, 57--600C; and 3c) 5-(4-carboxybutylthiomethyl)-1 -(3- hydroxy-3-cyclopentylpropyl)hydantoin, 80- 82", 91--930C Example A Inhibition of Platelet Aggregation Aggregation of platelets in 1 ml of fresh human platelet rich plasma (PRP) was monitored in a Born aggregometer.

The compound to be tested was added to the PRP at the desired concentration, and the resulting mixture incubated at 370C for 1 minute after which platelet aggregation was stimulated by the addition of adenosine diphosphate (ADP) to a concentration of 5,us.

The anti-aggregatory effect of the compound was assessed by measuring the percentage inhibition of platelet aggregation in the presence of the compound as compared when it was completely absent.

Each of prostaglandin E1 and 5-(4 carboxybutyl-thiomethyl)-1 -(3-cyclopentyl-3hydroxypropyl)hydantoin, diastereomer of melting point 8082 . were tested in this way and the latter was found to be about 0.6 times as potent as PGE.

In the following Examples B to E the "Compound" is 5-(4-carboxybutylthiomethyl)-l- (3-cyclopentyl-3-hydroxypropyl)hydantoin diastereomer of melting point 8082 .

Example B Tablet In one Tablet Compound 5.0 mg Lactose B.P. 82.0 mg Starch B.P. 10.0 mg Povidone B.P.C 2.0 mg Magnesium Stearate 1.0 mg Mix together the compound, lactose and starch. Granulate the powders using a solution of the Povidone in Purified water. Dry the granules, add the Magnesium Stearate and compress to produce tablets, 100 mg per tablet.

Example C Capsule In one capsule Compound 10 mg Lactose 79 mg Starch 10 mg Magnesium Stearate 1 mg Mix the powders in a powder blender, fill into hard gelatin capsules, 100 mg per capsule.

Example D l /lg/ml Injection Compound 100y9 Water for Injection to 1 0O ml Dissolve the Compound in the Water for Injection. Sterilise the solution by filtration through a membrane filter, 0.22 m pore size, collecting the filtrate in a sterile receiver. Under aseptic conditions, fill the solution into sterile glass ampoules, 1 ml per ampoule. Seal by fusion of the glass.

Example E 10 yg/ml Injection Compound 1 mg Ethyl Alcohol 10 ml Propylene Glycol 30 ml Water for Injection to 100 ml Dissolve the Compound in the Ethyl Alcohol, add the Propylene glycol and dilute to volume with Water for Injection.

Sterilise the solution by filtration through a membrane filter, 0.22 4m pore size, collecting the filtrate in a sterile vessel. Under aseptic conditions, fill the solution into sterile glass vials, 10 ml per vial. Close with a sterile rubber plug and secure with an aluminium collar.

Claims (50)

Claims

1. A compound of formula (I)

Z is hydrogen or alkyl; one of Z' and Z2 iS represented by the group -X-X1-X2-X3 wherein X is methylene, oxa (-0-) or thia (-S-), X1 is phenylene, or -CH2-C02- in which each 0 is independently selected from hydrogen and alkyl, such as ethyl, or the two Q's together form an alkylene radical having four, five or six carbon atoms, one of any methylene groups of X1 being replaceable by oxa or thia; X2 is a covalent bond or a straight or branched alkylene chain having 1 to 6 carbon atoms;X3 is selected from 5tetrazolyl, carboxyl, carboxamide, hydroxymethyl and alkoxycarbonyl; with the provisos that X and X' together contain one oxa or thia group and that at least one carbon atom separates the oxa or thia group from a -CO- or 5-tetrazolyl group and from the nitrogen of the hydantoin ring; and the other of Za and Z2 is represented by the group ~y~y1~ y2~y3 wherein Y is -CR2-CH2-in which each R is independently selected from hydrogen and methyl;Y' is carbonyl, methylene, methylene substituted by hydroxyl or methylene substituted by hydroxyl and alkyl; Y2 is a covalent bond or straight or branched alkylene having 1 to 7 carbon atoms optionally substituted on the carbon adjacent Y' by one or two groups each of which may be alkyl or a cyclic radical;Y3 iS hydrogen, hydroxy, alkoxy having 1 to 7 carbon atoms, a cyclic radical, 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, halogeno, nitro, amino, acylamino, alkenyl, alkoxy, phenyl, benzyloxy and alkyl which may itself be substituted by one or more halogeno groups; or Y2 and Y3 together form an alkyl group having 1 to 7 carbon atoms of which at least one hydrogen is replaced by fluoro; or Y is a bond 7CH2-, or H2.C H2- and Y1, Y2 and Y3 taken together form a cycloalkyl or bicycloalkyl group substituted by a hydroxyl group; the cyclic radical being a monovalent radical derived by loss of a ring hydrogen atom from a monocyclic or polycyclic compound having from 3 to 12 ring atoms selected from carbon, nitrogen, oxygen and sulphur, which compound may be saturated or unsaturated and may be further substituted by one or more alkyl groups, but excluding phenyl.

2. A compound according to claim 1 wherein Y2 is alkylene optionally substituted on the carbon adjacent Y1 by one or two groups independently selected from alkyl, bicycloalkyl and cycloalkyl; Y3 is hydrogen, hydroxy, alkoxy, cycloalkyl, bicycloalkyl, phenyl, benzyl, phenoxy or benzyloxy, wherein each of phenyl, benzyl, phenoxy and benzyloxy is optionally substituted; or Y, Y1, Y2 and Y3 taken together have the same meaning as defined in claim 1.

3. A compound according to claim 1 or 2 wherein Z is hydrogen; X' is phenylene, or -CH2-CH2-; X3 iS selected from carboxyl and alkoxycarbonyl; Y is -CH2-CH -; Y2 is a bond or alkylene having 1 to 7 carbon atoms optionally substituted on the carbon adjacent Y' by one or two alkyl groups; Y3 iS hydrogen, hydroxy, alkoxy, benzyl, phenoxy or benzyloxy, wherein each of benzyl, phenoxy and benzyloxy are optionally substituted.

4. A compound according to any one of the preceding claims wherein Z is hydrogen; X' is -CH2-CH2-; X2 is a covalent bond or a straight or branched alkylene chain having 1 to 6 carbon atoms; X3 iS selected from carboxyl and alkoxycarbonyl; Yis-CH2-CH2-; Y2 is alkylene optionally substituted on the carbon adjacent Y1 by one or two alkyl groups, and Y3 is hydrogen.

5. A compound according to claim 1 wherein Y2 is straight or branched alkylene having 1 to 7 carbon atoms and substituted on the carbon adjacent Yr by at least one group selected from cycloalkyl substituted by at least one alkyl, cycloalkyl substituted by at least one fluoro and bicycloalkyl substituted by at least one alkyl, and Y3 is as defined in claim 1; or y2 is as defined in claim 1; and Y3 is cycloalkyl substituted by at least one alkyl, cycloalkyl substituted by at least one fluoro or bicycloalkyl substituted by at least one alkyl; or Y2 and Y3 together form straight or branched alkyl having 1 to 7 carbon atoms having one or more hydrogens replaced by fluoro.

6. A compound according to claim 1,2 or wherein Z is hydrogen or alkyl having 1 to 6 carbon atoms one of Zr and Z2 is H 27X1-X2X3 wherein X' and X2 taken together form oxa-or thiaalkylene of 2 to 6 carbon atoms, and X3 is alkoxycarbonyl, carboxyl or a salt thereof.

and the other of Z1 and Z2 iS V V1 V2 V3 wherein Y, Y' and Y2 are as hereinbefore defined and Y3 is hdrogen, phenyl or benzyl.

7. A compound of according to claim 1, 2, or 6 wherein Y is -CH2-CH2-, Y' is --CHOHH-, (CH)OH- or ,' y2 is a bond or alkylene having 3 to 7 carbon atoms and Y3 is cycloalkyl of 4 to 7 carbon atoms.

8. A compound according to claim 1, 2, 6 or 7 wherein X' and X2 together form n-pentylene; Y1 is -CH0H- or -C(CH3)0H-; Y2 is alkylene having a tertiary carbon atom adjacent Y1; or Y2 is a bond and is cycloalkyl of 4 to 7 carbon atoms.

9. A compound according to any one of the preceding claims wherein Z1 is -CH2-X1-X2- X3 as therein defined.

10. A compound according to any one of the preceding claims wherein Z is hydrogen.

11. A compound according to any one of the preceding claims wherein X2 is -CH2-CQ2- in which the -CH2- has been replaced by oxa or thia, and Q is as defined in claim 1.

12. A compound according to claim 11 wherein X2 is -S-CH2-.

13. 5-(4-carboxybutylthiomethyl)-1 -(3hydroxy-3-cyclopentylpropyl)hydantoin, or a salt or ester thereof.

14. The diastereomer of 5-(4carboxybutylthiomethyl)- 1 -(3-hydroxy-3cyclopentylpropyl)hydantoin identified hereinbefore as having the lower melting point.

1 5. A composition comprising a compound of formula (I) as defined in any one of claims 1 to 14 in association with a pharmaceutically acceptable carrier therefor.

1 6. A composition according to claim 1 5 wherein the carrier is a liquid.

1 7. a composition according to claim 1 5 or 16 in the form of a sterile injectable solution.

18. a composition according to claim 16 or 17 comprising from 0.001 to 100 g of a compound of formula (I) per millilitre.

19. A composition according to claim 1 6, 17 or 1 8 in the form of a unit dose comprising from 0.01 to 1 mg of a compound of formula (I).

20. A composition according to claim 1 5 wherein the carrier is a solid.

21. A composition according to claim 20 in the form of a unit dose.

22. A composition according to claim 20 or 21 in the form of a tablet, capsule, cachet or suppository.

23. A composition according to claim 20, 21 or 22 comprising from 0.1 to 50 mg of a compound of formula (I).

24. A method of preparing a compound of formula (I) as defined in any one of claims 1 to 14 comprising cyclisation of a compound of formula (II)

wherein G is carboxyl or a derivative thereof, and each of Z, Z1 and Z2 has the same meaning as in formula (I)

25. A method of preparing a compound of formula (I) as defined in any one of claims 1 to 14 comprising cyclisation of a compound of formula (Vll)

wherein G1 is carboxyl or a derivative thereof, and each of Z, Z1 and Z2 has the same meaning as in formula (I).

26. A method of preparing a compound of formula (I) as defined in any one of claims 1 to 14 comprising reaction of a carbonic acid derivative with a compound of formula (IX)

wherein each of Z, Z1 and Z2 has the same meaning as in formula (I).

27. A method of preparing a compound of formula (I) as defined in any one of claims 1, 2, 6, 7, 8, 9, 11 or 12 wherein Z is alkyl comprising alkylation of a compound of formula (X):

with a reactive ester derivative of an alcohol of formula J3. OH, wherein J is hydrogen or alkyl; J' is hydrogen or Z1; J2 is hydrogen or Z2; and J3 is alkyl, Z1 or Z2; provided that one of J, J1 and J2 is hydrogen, and that J3 does not have the same value as J, J or J2; in the definitions of J1, J2 and J3 each of Z1 and z2 having the same- meaning as in formula (I).

28. A method of preparing a compound of formula (I) as defined in any one of claims 1 to 14 comprising reduction of a compound of formula (Xl)

wherein either Z3 is =CR-CH2-Y1-Y2-Y3 and Z4 is -CH2-X1-X2-X3 or Z3 iS =CH--X11- X2~X3 and Z4 is ~y~yl~y2~y3 in which each of R, X1 to X3, Y to Y3 and Z is as defined in formula (I).

29. A method of preparing a compound of formula (I) as defined in claim 1 wherein X3 is tetrazolyl comprising reaction of the corresponding precursor, wherein in formula (I) X3 is replaced by --C.X5=N.X4 in which X5 and X4 together form a bond, X5 is hydrogen or alkyl and X4 is alkoxy, alkylthio, amino or -NH-NH2, with nitrous acid or a salt of hydrazoic acid as appropriate.

30. A method of preparing a compound of formula (I) as defined in claim 1 wherein X3 iS hydroxymethyl comprising reduction of a corresponding acid, ester, acid halide, acid anhydride or aldehyde.

31. A method of preparing a compound of formula (I) as defined in claim 1 wherein X3 iS hydroxymethyl comprising hydrolysis of a corresponding X3 halide.

32. A compound of formula (I) as defined in any one of claims 1 to 14 prepared by a process defined by any one of claims 24 to 31.

33. A compound of formula

wherein J is hydrogen or alkyl; J' is hydrogen or Z1 as defined in claim 1; and J2 is hydrogen or Z2 as defined in claim 1; provided that if J is hydrogen, only one of J' and J2 may be hydrogen.

34. a compound of formula

wherein M is > C=Z3, > CH--CHO or > CH- CH(OG3)2 and Z, Z3 and Z4 are as defined in claim 28 and G3 is as defined in formula (XII).

35. A compound of formula

wherein M1 is halo, amino or-NH-Z2 and Z, Z1, Z2 and G1 are as defined in claim 25 except that G' may also be hydrogen.

36. A method of inhibiting the aggregation of platelets which comprises the bringing of said platelets into association with an effective platele aggregatory-inhibiting amount of a compound of formula (I) as defined in any one of claims 1 to 14 and 32.

37. A compound of formula (I) as defined in any one of claims 1 to 14 and 32 as an active agent for the treatment or prophylaxis of thrombosis in a mammal or mammalian tissue, including human.

38. A compound of formula (I) as defined in any one of claims 1 to 14 and 32 as an active agent for lowering blood pressure in a mammal, including man.

39. A compound of formula (I) as defined in any one of claims 1 to 14 and 32 as an active agent for inducing vasodilation in a mammal, including man.

40. A compound of formula (I) as defined in any one of claims 1 to 14 and 32 as an active agent for the treatment or prophylaxis of gastric lesions in a mammal, including man.

41. A compound of formula (I) as defined in any one of claims 1 to 14 and 32 as an active agent for inducing bronchodilation in a mammal, including man.

42. A compound of formula (I) as defined in any one of claims 1 to 14 and 32 as an active agent for the treatment or prophylaxis of an allergic condition in a mammal, including man.

43. A compound of formula (I) as defined in any one of claims 1 to 14 and 32 as an active agent for inducing abortion of a foetus from a mammal, including woman.

44. A compound of formula (I) as defined in any one of claims 1 to 14 and 29 as an active agent for inducing infertility in a mammal, including woman.

45. A method of inducing infertility in a mammal, including woman, which comprises administration of a non-toxic contraceptive amount of a compound according to any one of claims 1 to 14 and 32.

46. A method as claimed in claim 36 or 35 wherein the compound of formula (I) is administered at a daily dose of from 1 y9 to 20 mg per kilogram of the mammal.

47. A method as claimed in claim 36 or 45 which comprises an intravenous infusion of the compound of formula (I).

48. The preparation of a compound of formula (I) as defined in claim 1 by a method substantially as hereinbefore described with particular reference to any one of Examples 1 to 3.

49. A pharmaceutical composition comprising a compound of formula (I) as defined in claim 1 in association with a pharmaceutically acceptable carrier substantially as hereinbefore described with particular reference to any one of Examples B to E.

50. A method of preparing a composition as claimed in claim 49 which comprises admixture of the compound of formula (I) and a pharmaceutically acceptable carrier therefor.