GB2097385A - Heterocyclic prostaglandin analogues - Google Patents

Abstract

Compounds of the general formula <IMAGE> (wherein A represents a group formula -CH=CH- (in either the cis- or trans-configuration), -(CH2)2- or -(CH2)3-; and Z represents a C4-6alkyl group or a group of formula <IMAGE> in which R represents a C5-7alkyl or C5-7 cycloalkyl group) and salts have been found to have an inhibitory effect on blood platelet aggregation and are therefore useful in medical therapy e.g. for the treatment of thrombo- embolic conditions.

Description

SPECIFICATION Heterocyclic prostaglandin analogues The present invention relates to novel 1 ,2,4-triazolidine-3,5-dione prostaglandin analogues having valueable pharmacological properties, and to novel intermediates of use in the preparation thereof.

Belgian Patent Specification No. 861957 describes compounds of the general formula

in which n is 1 to 5 Y represents -CH2-CH2- or -CH=CH- R1 is hydrogen or CO2R, represents an ester group in which R, contains 1 to 12 carbon atoms, R2 is hydrogen, C14 alkyl or phenyl, R3 is a hydroxy or protected hydroxy group R4 is hydrogen, Cis alkyl, C38 cycloalkyl, C38 cycloalkyl-C16 alkyl, phenyl, phenyl-C1-6 alkyl, naphthyl, naphthyl-C,~6 alkyl, any of the phenyl or naphthyl groups being optionally substituted by one or more halogen, trifluoromethyl, C16 alkyl, hydroxy, C16 alkoxy, phenyl-C1-6 alkoxy or nitro groups, R5 is hydrogen, C16 alkyl, C5S cycloalkyl, phenyl, phenyl-C1-6 alkyl or phenyl-C3~6 cycloalkyl, any of the phenyl groups being optionally substituted by one or more halogen, trifluoromethyl, C16 alkyl, C1-6 alkoxy or nitro groups, or R2 and R4 together with the carbon atom to which they are attached form a C5B cycloalkyl group.

In the above-mentioned Specification the compounds of formula (I) specifically disclosed have either an ester group as the --CO2R1 group and/or a R5 substituent group which is other than hydrogen.

We have now discovered a new class of 1 ,2,4-triazolidine-3,5-dione prostaglandin analogues, falling within the broad scope of formula (A) above, which have advantageous pharmacological properties as described in more detail below. These new compounds are characterised inter alia by the absence of any substituent at the 4-position of the triazolidine ring and by the presence of a terminal carboxy group in the side chain substituting the 1-position of the triazolidine ring.

The new compounds may be represented by the general formula

wherein A represents a group of formula -CH=CH- (in either the cis- or trans-configuation), -(CH2)2- or -(CH2)3-; and Z represents a C45 alkyl group or a group of formula

in which R represents a C57 alkyl or C57 cycloalkyl group.

In formula (I), Z preferably represents an n-pentyl group or a group of formula

in which R is n-pentyl, 1,1 -dimethylpentyl, cyclopentyl or cyclohexyl.

The invention also includes salts of the compounds of formula (I) and references hereinafter to compounds if formula (I) may be taken to include references to the salts thereof unless there is any indication to the contrary. Particularly valuable salts for medical purpose are those having a physiologically acceptable cation such as an alkali metal e.g. sodium and potassium, an alkaline earth metal e.g. calcium and magnesium, ammonium or an organic base, particularly an amine such as ethanolamine. Salts having non-physiologically acceptable cations are included within the ambit of this invention as useful intermediates for the production of physiologically acceptable salts, and of the acids of formula (I).

Except when there is clear indication to the contrary, formula (I) and other formulae in the specification embrace both stereoisomers represented therein. In particular such formulae include the enantiometicforms and racemates. An advantage of the compounds of formula (I) over for example corresponding hydantoin prostaglandin analogues, which are known in the literature is that the former compounds have one less asymmetric carbon atom than the latter compounds and therefore fewer stereoisomers to separate.

The compounds of formula (I) are of value in having pharmacological properties related to those of natural prostaglandins; thus, the compounds may mimic or antagonise the biological effects of members of the prostaglandin (PG) 'A', 'B', 'C', 'D', 'E' and 'F' series. For example, compounds of formula (I) have been found to mimic the anti-aggregatory effect of PGE, on blood platelets.

By reason of their prostaglandin-relatad properties, the compounds of formula (I) are useful in the pharmacological 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 compounds of formula (I) are also of value as therapeutic agents. According to a further feature of the present invention we provide compounds of formula (I) (as defined above) and physiologically acceptable salts thereof for use in a method of treatment of the human or animal body by therapy, e.g.

in the treatment or prophylaxis of thrombo-embolic conditions in a mammal. Compounds of formula (I) such as the preferred classes of compounds described above have a potent anti-aggregatory effect on blood platelets and are useful whenever it is desired to inhibit platelet aggregation or to reduce the adhesive character of platelets, for example in the treatment or prevention of the formation of thrombi in mammals, including man. The compounds are particularly useful in the treatment and prevention of myocardial infarcts, thromboses, and strokes. The compounds may also be used to promote patency of vascular grafts following surgery, and to treat complications of arteriosclerosis and conditions such as atherosclerosis, blood clotting defects due to lipidemia, and other clinical conditions in which the underlying aetiology is associated with lipid imbalance or hyperlipidermia.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. The compounds of formula (I) may also be used in the treatment of peripheral vascular disease and angina pectons.

In experiments which have been carried out on the rat, compounds of formula (I) have been shown to have a very low or negligible hypotensive effect which may be of advantage in clinical cases where a hypotensive or vasodilatory effect is undesirable.

Compounds of formula (I) which inhibit pentagastrin-induced gastric acid secretion and reduce the formation of indomethacin-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 gastro-intestinal tract whether such ulcers arise spontaneously or as a component of polyglandular adenoma syndromes.

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 psoriassis, atopic dermatitis, nonspecific dermatitis, primary irritant contact dermatitis, allergic contact dermatitis, basal and squamous cell carcinomas of the skin, lamellar icthyosis, 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 topicaliy to the affected skin.Alternatively they may be administered by an intradermal or intramuscular injection, for example directiy 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 jig to 20 mg per kilogram bodyweight. For example, an intravenous dose may lie in the range of from 5 jig to 1 mg/kg which may conveniently be administered as an infusion of from 0.01 to 50 jig per kilogram per minute. Infusion fluids suitable for this purpose may contain from 0.001 to 100, for example from 0.01 to 10 jig per millilitre, preferably 1 to 10 ,ug/ml. Unit doses may contain from 10 yg to 100 mgofa 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 20 mg. Such dosage units may be administered for example, 1, 2, 3 or 4 times per day, separately or in multiples thereof.

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 1 jig, to 10 mg, for example from 10 jig to 1 mg, per litre.

The abovementioned doses refer to the acids 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, compounds of formula (I) and their physiologically acceptable salts (hereinafter referred to as the "active ingredient") may be presented with a pharmaceutical carrier therefor as a pharmaceutical formulation in accordance with the invention. 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 compound of formula (I) as a unit-dose formulation, for example a tablet, which may contain from 0.05% to 95% by weight of the active ingredient.Other pharmacologically active substances may also be present in formulations of the present invention for example /3-adrenoceptor blocking agents such as propranolol. The compound of formula (I) may be incorporated in the formulations either in the form of an acid or a salt 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, (e.g. buccal such as sub-lingual) or parenteral (e.g. subcutaneous, intramuscular or 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 active 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 the active compound; as powders or granules; as solutions or suspensions in aqueous or non-aqueous liquids; as oil-in-water emulsions; or as water-in-oil liquid emuisions. Such formulations may be prepared by any of the methods of pharmacy but all methods include the step of bringing into association the active ingredient with the carrier which comprises one or more appropriate ingredients. In general, the formulation may be prepared by uniformly and intimately admixing the active ingredient with liquids 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 active ingredient, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient 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 active ingredient moistened with an inert liquid diluent.

Formulations suitable for buccal (e.g. sub-lingual) administration include lozenges comprising the active ingredient compound in a flavoured base, e.g. sucrose and acacia or tragacanth; and pastilles comprising the active ingredient in an inert base such as gelatin and glycerin; or sucrose and acacia.

Formulations of the present invention suitable for parenteral administration conveniently comprise sterile aqueous preparations of the active ingredient, 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 active ingredient 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 active ingredient with one or more conventional solid carriers, forming the suppository base for example cocoa butter, and shaping of the resulting mixture.

Formulations suitable for topical application to the skin preferably take the form of an ointment, cream, lotion, paste, gel, spay, aerosol or oil. Carriers which may be used in such formulations include petroleum jelly, lanolin, polyethylene glycols, alcohols and combinations thereof. The active ingredient is generally present in a concentration of from about 0.1 to 1 5% w/w of the composition, for example from about 0.5 to about 2%.

In the above-mentioned Belgian Patent Specification, the compounds of formula (A) are prepared in principle by introducing into a 1 ,2,4-triazolidine-3,5-dione ring system the appropriate side chains in the 1- and 2-positions (in either order). This mode of synthesis may be satisfactory when the 4-position is substituted, as is the case with the majority of the compounds specifically exemplified in the Specification. However, when the 4-position is unsubstituted, as is the case with the compounds of formula (I) according to the present invention, considerable difficulties may arise in ensuring that the side chains are inserted in the correct positions in the ring system. Thus, for example, undesired substitution of the 4-position may readily occur.

It is an object of the present invention to provide a new and advantageous synthesis for the compounds of formula (I) which avoids the difficulties noted above. This synthesis will be described in detail below.

According to a feature of the present invention, we provide a process for the preparation of compounds of formula (I) (as defined above) and salts thereof which comprises cyclising a compound of formula.

The compounds of formula (I) may be prepared from a corresponding compound of formula

(wherein G is carboxyl or a derivative thereof such as the ethyl ester, and A and Z are as defined above) or an ester thereof (i.e. a corresponding compound in which the terminal carboxyl group of the side chain in the 2-position is esterified, for example, as an alkyl (e.g. ethyl ester group), by cyclisation, e.g.

under acidic conditions or by heating alone; if necessary, hydrolysing any resulting ester, e.g. under alkaline conditions, to form a compound of formula (I) which is optionally converted into a salt thereof.

Alternatively, where G is alkoxycarbonyl, cyclisation may be effected in the presence of a suitable base, for example an alkoxide such as sodium ethoxide, or 1 ,5-diazabicycloundec-5-ene.

Compounds of formula (II) are conveniently prepared from a compound of formula

(wherein A, G and Z are as defined above) or an ester thereof, by reaction with cyanic acid.

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 (III) wherein G is carboxyl. 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.

Compounds of formula (III) wherein Z represents a group of formula

(in which R is as defined above) may be prepared by reacting a compound of formula

(wherein A and G are as defined above) or an ester thereof with a compound of formula H2C=CHCOR (V) (wherein R is as defined above) followed by reduction of the carbonyl group, e.g. using sodium borohydride to form a compound of formula (III). The reaction of the compounds of formulae (IV) and (V) may be effected in the presence or absence of an inert solvent and at room temperature or optionally with heating.

The compounds of formula (Ill) may also be conveniently prepared by reaction of a compound of formula (IV), as defined above, or an ester thereof, with a compound of formula

(wherein Hal is a halogen atom (preferably a bromine atom) and Z is as defined above). 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.

Compounds of formula (Ill) wherein Z represents a C46 alkyl group and A is a group of formula -(CH2)2- or -(CH2)3-, may be prepared by reacting an appropriate compound of formula (IV) with an appropriate alkanal accompanied by hydrogenation in the presence of a noble metal catalyst, e.g.

palladium/charcoal.

The compounds of formula (lV) (as defined above) and esters thereof are new compounds and constitute a further feature of the present invention. These compounds are useful as intermediates not only for the synthesis of compounds of formula (I) by the route outlined above but also for the synthesis of other heterocyclic prostaglandin analogues, e.g. the compounds of formula (A) in the abovementioned Belgian Patent Specification.

Compounds of formula (IV) (wherein A represents a group of formula -(CH2)2 or-(CH2)3-) may be prepared by hydrogenolysis, e.g. using palladium/charcoal, of a corresponding compound of formula

(wherein Ar represents a phenyl group which may optionally be substituted, A represents a group of formula -(CH2)2- or -(CH2)3-, and G is as defined above) or an ester thereof.

Alternatively, a compound of formula (VII) (wherein A and G is as defined above, and A represents a group of formula -CH=CH- (in the cis- or trans-configuration), -(CH2)2- or -(CH2)3-) may be subjected to acid-catalysed solvolysis to yield a compound of formula (IV).

The compounds of formula (VII) and the esters thereof may be prepared by reacting a compound of formula

(wherein G and Ar are as defined above) with a compound of formula

(wherein X is a halogen atom selected from bromine, chlorine or iodine and A is as defined above) or an ester thereof under basic conditions serving to provide a carbanion corresponding to the compound of formula (VIII), e.g. in salt form, particularly an alkali metal salt such as the sodium salt. Thus, for example, the last-mentioned reaction may be effected in the presence of sodium hydride, conveniently in an organic solvent, e.g. an ether such as dioxan. Hexamethylphosphoramide is preferably a catalyst in the reaction.

The compound of formula (VIII) above may be prepared by reaction of a compound of formula

(wherein G is as defined above) with a compound of formula ArCHO (wherein Ar is as defined above).

It should be noted that the present invention extends to all novel compounds, compositions, processes and reaction steps herein disclosed.

The following Examples illustrate the present invention.

Example 1 Ethyl 3-benzylidenecarbazate To a solution of ethyl carbazate (62.4 g, 0.60 mol) in warm ethanol (300 ml) was added benzaldehyde (64.2 g, 0.60 mol) in one portion. The suspension was refluxed for 2 hours; on cooling, a colourless crystalline solid was formed which was removed by filtration and recrystallised from ethanol to give ethyl 3-benzylidenecarbazate, m.p. 136c.

Example 2 Ethyl 3-benzylidene-2-(6-ethoxycarbony'Ihexyl)carbazate To a stirred suspension of sodium hydride (80% dispersion in mineral oil, 12.10 g, 0.40 mol) in dry tetrahydrofuran (650 ml) under at atmosphere of dry nitrogen was added ethyl 3benzylidenecarbazate (76.9 g, 0.40 mol) in portions. After evolution of hydrogen ceased, dry hexamethylphosphoramide (75 ml) and solid sodium iodide (62 g, 0.41 mol) were added followed by ethyl 7-bromoheptanoate (96.0 g, 0.41 mol) in a little tetrahydrofuran. The suspension was stirred at room temperature for 24 hours then refluxed for 6 hours. The cooled mixture was poured into icewater and the product extracted into ethyl acetate.The combined extracts were dried (MgSO4) and the solvent removed in vacuo and the residue was purified by column chromatography (silica, eluted with chloroform) to give ethyl 3-benzylidene-2-(6-ethoxycarbonylhexyl)carbazate as a pale yellow syrup, a 2.23 (2H, t, J=7 Hz, -cK2-CO2Et),7.83 (1H,s,CH=N).

Example 3 Ethyl 3-benzylidene-2-(7-ethoxywarGatnyllhe l)carbazate When ethyl 3-benzylidenecarbazate was alkylated with ethyl 8-bromo-octanoate (obtained by the procedure of R. Toubiana and J. Asselinear, Ann. Chim., 7, 593), the title compounds was obtained as a pale yellow syrup, M/e 362 (M+, C20H30N204), u max. i 735 1705, 1 609 and 1 573 cm-, S 1.18 and 1.31 (each 3H, t, 2xOCH2CH3), 1.30-1.65 (10H, m, 5xCH2), 2.23 (2H, t, CH2CO2Et), 4.10 (6H, m, 2xOCH2 and NCH2), 7.31 and 7.65 (5H, m, aromatic protons) and 7.83 (1 H, s, CH=N).

Example 4 Ethyl 2-(6-ethoxycarbonylhexyl)carbazate Ethyl 3-benzylidene 2-(6-ethoxycarbonylhexyl)carbazate (25 g, 0.072 mol) and 10% palladium on charcoal (3.33 g) in absolute ethanol (250 ml) was agitated under 100 p.s.i. of hydrogen for 17 hours at room temperature.The catalyst was removed by filtration (Celite) and the solvent removed in vacuo giving ethyl 2-(6-ethoxycarbonylhexyl)carbazate as a colourless oil, b.p. 106-8V0.01 mm, m/e 260(M+, C,2H24N204)- Example 5 Ethyl 2-(7-ethoxycarbonylheptyl)carbazate In an analogous manner to that described in Example 4, the title compound was obtained as a colourless oii, b.p. 1 32-5V0.01 mm, M/e 274 (M+, C,3H26N204), V max. 3340, 3220, 1735 and 1695 cm-', 6 1.27 (6H, t, 2xOCH2CH2), 1.0-1.80 (1 OH, m, 5xCH2), 2.31 (2H, t CH2CO2Et), 3.40 (2H, t, NCH2), 3.90 (2H, s, exch., NH2) and 4.18 (4H, q, 2xOC,'2CH3).

Example 6 Ethyl 3-(3-cyclohexyl-3-oxopropyl)-2-(6-ethoxycarbonylhexyl)carbazate Ethyl 2-(6-ethoxycarbonylhexyl)carbazate (5.20 g, 20 mmol) and cyclohexylvinyl ketone (2.80 g, 20 mmol) were mixed and set aside at room temperature for 6 days. The resulting syrup was purified by column chromatography (silica, elution with 7:3 ether:hexane) giving ethyl 3-(3-cyclohexyl-3oxopropyl)-2-(6-ethoxycarbonylhexyl)carbazate as a pale yellow oil, a 3.0-3.5 (4H, m, 2xNCH2), 4.13 (2H, q, J=7 Hz, OCH2), 4.16 (2H, q, J=7 Hz, OCH2), 4.45 (1 H, br.s, NH, exchangeable).

Example 7 Ethyl 3-(3-cyclohexyl-3-hydroxypropyl)-2-(6-ethoxycarbonylhexyl)carbazate Ethyl 3-(3-cyclohexyl-3-oxopropyl)-2-(6-ethoxycarbonylhexyl)carbazate (11.1 g, 28 mmole) in ethanol (120 ml) was stirred and cooled in an ice-bath and sodium borohydride (0.8 g, 21 mmole) was added in portions over 1 5 min. The reaction mixture was stirred a further 1 5 min and then allowed to stand at room temperature overnight. The solvent was removed in vacuo, the residue diluted with water (120 ml), and the oil extracted with ether. The combined extracts were dried over MgSO4 and the solvent removed in vacuo to give ethyl-3-(3-cyclohexyl-3-hydroxypropyl)-2-(6- ethoxycarbonylhexyl)carbazate as a colourless syrup Rf 0.38, chloroform-ethanol, 98:2.

Example 8 1 -(3-Cyclohexyl-3-hydroxypropyl)-2-(6-ethoxycarbonylhexyl )-1 ,2,4-triazolidine-3,5-dione Ethyl (3-cyclohexyl-3-hydroxypropyl)-2-(6-ethoxycarbonylhexyl)carbazate (3.73 g, 9.3 mmole) in ethanol (20 ml) and 2N hydrochloric acid (10 ml, 20 mmole) was stirred and cooled in an ice-bath and treated dropwise with potassium cyanate (1.62 g, 20 mmole) in water (5 ml). After addition was complete the reaction mixture was stirred at room temperature for 24 hours. The solvent was then removed in vacuo, the residue diluted with water (60 ml) and the oil extracted with ether. The combined extracts were dried over MgSO4 and the solvent removed in vacuo to give crude ethyl 3 carbamoyl-3-(3-cyclohexyl-3-hydroxypropyl)-2-(6-ethoxycarbonylhexyl)carbazate as a pale yellow syrup.This was treated with 1 ,5-diazabicycloundec-5-ene (2 drops) and heated on a steam bath for 12 hours giving 1 -(6-ethoxycarbonylhexyl)-2-(3-cyclohexyl-3-hydroxypropyl)- 1 ,2,4-triazolidine-3,5-dione as a brown syrup, Rf 0.4, silica, chloroform methanol (19:1).

Example 9 1 -(6-Carboxyhexyl-2-(3-cyclohexyl-3-hydroxypropyl)-1 ,2,4-triazolidine-3,5-dione Crude 1 -(6-ethoxycarbonylhexyl)-2-(3-cyclohexyl-3-hydroxypropyl)- 1 ,2,4-triazolidine-3,5-dione (3.9 g) and 2N aqueous sodium hydroxide (30 ml) were stirred at room temperature for 3 hours. The reaction mixture was then washed throughly with ether and the residual aqueous solution acidified with 2N hydrochloric acid. The liberated oil was extracted with ethyl acetate, the combined organic layers dried over MgSO4 and the solvent removed in vacuo to give a pale yellow gum.Purification by column chromatography from ethyl acetate-hexane gave 1 -(6-carboxyhexyl)-2-(3-cyclohexyl-3hydroxypropyl)-1 ,2,4-triazolidine-3,5-dione as a colourless solid, m.p. 104107 . Anal. found C, 58.73; H, 8.66; N, 11.23%. C18H31N305 requires C, 58.52; H, 8.46; N, 11.37%.

Example 10 In an analogous manner to that described above for the synthesis of the compound of Example 9, the following compounds were prepared: (a) 1 -(6-carboxyhexyl)-2-(3-cyclopenl-3-hydroxyprnpyl)-1 ,2,4-triazolidine-3,5-dione as a colourless wax RF 0.49 (SiO2; CHCl3-MeOH-HOAc, 90:5:5), v max. 3400 br, 31 50 br, 1750 and 1700 cm-1, S 1.02.1 (1 9H, m, 9xCH2+CH), 2.40 (2H, t CH2-CO2H), 3.25-4.25 (5H, m, 2xNCH2 and CHOH), 6.0-7.0 br (2H, exch., CO2H and NH); (b) 1 -(6-carboxyhexyl)-2-(3-hydroxy-4,4-dimethyloctyl)-1 ,2,4-triazolidine-3 ,5-dione as a colourless gum RF 0.55 (SiO2; CHCl3-MeOH-HOAc, 90:5::5), V max. 3400 bur,3 150 br, 1 760 and 1705 cm-1,S 6 1.05 (9H, m,3xCH3), 1.10-2.0(16H, m, 8xCH2),2.42 (2H,t,CH2CO2H),3.35 (1H, dxd, J 9.5 and 2.5 Hz, CHOH), 3.50-4.10 (4H, m, 2xNCH2), 6.7-7.3 br (2H, exch., CO2H and NH); (c) 1 -(7-carboxyheptyl)-2-(3-cyclohexyl-3-hydroxypropyl)- 1 ,2,4-triazolidine-3 ,5-dione (using the intermediates of Examples 3 and 5) as a colourless gum RF 0.54 (SiO2; CHCl3-MeOH-HOAc, 90:5::5), max. 3400 br,31 50 br, 1750 and 1710 cm-1, S 1.0-2.0 (23H, m, 1 2xCH2 and CH), 2.20 2H, t, CH2CO2H), 3.37-4.0 (5H, m, 2xNCH2 and CHOH) 6.0-6.5 br (2H, exch., CO2H and NH).

Example 11 Ethyl 2-(6-ethoxycarbonylhexyl)-3-octylcarbazate Ethyl 2-(6-ethoxycarbonylhexyl)carbazate (5.20 g, 20 mmole), octanal (2.56 g, 20 mmole).

ethanol (120 ml), and 10% palladium-charcoal (0.8 g) were agitated under hydrogen (1 atmosphere pressure) until uptake ceased (ca. 6 hours at room temperature). The catalyst was filtered off (Celite), the solvent removed in vacuo and the residue distilled yielding ethyl 2-(6-ethoxycarbonylhexyl)-3octylcarbazate as a colourless syrup, b.p. 164-1 68a/0.01 mm, m/e 372 (M+, C20H4ON204).

Example 12 1 -(6-Carboxyhexyl)-2-octyl-1 ,2,4-triazolidine-3,5-dione A stirred solution of the carbazate obtained in Example 11(2.5 g; 6.7 mmol) in ethanol (20 ml) and 2N hydrochloric acid (7 ml; 14 mmol) was cooled in an ice-bath and treated dropwise with potassium cyanate (1.1 g; 13.6 mmol) in water (4 ml). The reaction mixture was stirred at room temperature for 24 hours, the solvent was removed in vacuo and the residue was treated with water (50 ml); the oil was extracted into ether, the combined extracts were dried (MgSO4) and the solvent was removed in vacuo, to give crude ethyl 3-carba moyl-2-( 6-ethoxycarbonylhexyl)-3-octylca rbazate as a pale yellow syrup.This was heated with 1 ,5-diazabicyclo/5,4,0/undec-5-ene (2 drops) on the steam bath for 12 hours, yielding crude 1 -(6-ethoxycarbonylhexyl)-2-octyl-1 ,2,4-triazolidine-3,5-dione as a brown syrup (2.8 g) which was stirred with 2N aqueous sodium hydroxide (28 ml) at room temperature for 3 hours. Insoluble impurities were removed by washing thoroughly with ether and the clear aqueous solution was acidified with 2N hydrochloric acid; the liberated carboxylic acid was extracted into ethyl acetate, the combined extract was dried (MgSO4) and the solvent was removed in vacuo, to leave a pale yellow solid.Crystallisation from ethyl acetate-hexane gave the title compound as colourless crystals (620 mg), m.p. 7678 (Found: C, 59.9; H, 9.35; N, 12.3 C17H31N3O4 requires C, 59.8; H, 9.15; N, 12.3%), u,K: 3470 br, 3150 br, 1720 and 1695 cm-', S 0.87 (3H, t, CH,), 1.10-- 1.80 (20H, m, 1 OxCH2), 2.33 (2H, t, CH2CO2H), 3.54 (4H, t, 2xNCH2) and 9.0 br (2H, exch., C02H and NH).

Example 13 Ethyl 2-(6-ethoxycarbonylhexyl)-3-(3-oxo-octyl)carbazate A mixture of ethyl 2-(6-ethoxycarbonylhexyl)carbazate (7.8 g, 0.03 mol) with oct-l -en-3-one (3.78 g, 0.03 mol) was set aside at room temperature for 5 days. The resulting syrup, a mixture of the mono- and bis-adducts, RF 0.55 and 0.63 (SiO2; Et2O-hexane, 7::3), respectively, was purified by chromatography to give ethyl 2-(6-ethoxycarbonylhexyl)-3-(3-oxo-octyl)carbazate (6.7 g, 58%) as a pale yellow oil, S 0.90 (3H, t, CH2-CH2CH3), 1.23 (3H, t, OCH2CH3), 1.26 (6H, t, 2xOCH2CH3), 1.21.9 (1 4H, m, 7xCH2), 2.26 (2H, t, CH2CO2Et), 2.40 (2H, t, COCH2Bu), 2.51 (2H, t, NHCH2-CH2CO), 3.06 (2H. t. NHCH2CH2CO' 3.28 (2H,t, EtO2C---NCH2),4.10 (2H,q,OCH2CH3),4.13 (2H,q, OCH2CH3) and 4.50 br(1H,s, NH).

Example 14 Ethyl 2-( (3-ethoxycarbonyl hexyl )-3-(3-hydroxyoctyl )carbazate Sodium borohydride (320 mg, 8.6 mmol) in ethanol (40 ml) was added during 15 minutes to a stirred, ice-cooied solution of the oxo-octylcarbazate obtained in Example 13 (3.0 g, 7.8 mmol) in ethanol (40 ml) and the mixture was stirred at room temperature overnight. The solvent was evaporated in vacuo, the residue was shaken with water and ether, and the ethereal phase was dried (MgSO4) and evaporated.Purification of the residual syrup by column chromatography (SiO2; Et2O- hexane, 4:1) gave the title compound (2.03 g, 68%) as a pale yellow syrup, RF 0.34 (SiO2; CHCl3- EtOH, 98.2), 60.89 (3H,t,CH2CH2CH3), 1.23 (3H, t, OCH2CH3),1.26(3H, t, OCH2CH3), 1.2-1.7 (18H,m, 9xCH2), 2.27 (2H, t, OCH2CO2Et), 2.7-3.8 (7H, m, 2xNCH2, CHOH, and NH), 4.06 (2H, q, OCH2CH3) and 4.1 1 (2H, q, OCH2CH3).

Example 15 1 -(6-Carboxyhexyl)-2-(3-hydroxyoctyl)-1 ,2,4-triazolidine-3,5-dione In an analogous manner to that described in Example 12, the carbazate obtained in Example 14 was converted into the crude triazolidinedione ester which, after saponification and purification by column chromatography (SiO2; CHCl3-MeOH, 1 9:1), gave the title compound as a colourless gum (400 mg, 42%), RF 0.5 (SiO2; CHCl3-MeOH-HOAc, 90:5:5), V max. 3400 br, 3150 br, 1760 and 1705 cm~1, a 1.00 (3H, t, CH3), 1.10-2.0 (1 8H, m, 9xCH2), 2.40 !2H, t, CH2CO2H), 3.3O.25 (5H, m,2xNCH2 and CHOH), 6.0-7.0 br (2H, exch., C02H and NH).

Example 16 Ethyl 3-benzylidene-2-[(Z)-6-methoxycarbonylhex-2-enyl]carbazate To a stirred suspension of sodium hydride (80% dispersion in mineral oil, 1.55 g, 52 mmole) in dry THF (12.5 ml) under an atmosphere of dry nitrogen was added ethyl 3-benzylidenecarbazate (9.61 g, 50 mmole) in portions. After evolution of hydrogen ceased (Z)-methyl 7-bromohept-5-enoate (1 1.4 g, 52 mmole) in dry THF (25 ml) was added, the suspension stirred at room temperature overnight, then refluxed 6 hours. The cooled mixture was poured into ice-water containing sodium dihydrogen phosphate (20 g) and the product extracted into ethyl acetate.The combined extracts were dried over MgS04, the solvent removed in vacuo and the residual oil purified by column chromatography (silica, eluted with chloroform) to give ethyl 3-benzylidene-2-[(Z)-6-methoxycarbonylhex-2-enyl]carbazate as pale yellow syrup, m/e 332 (M+, C18H24N204).

Example 17 Ethyl 2-[(Z)-6-ethoxycarbonylhex-2-enyl]carbazate Ethyl 3-benzylidene-2-[(Z)-2-(6-methoxycarbonylhex-2-enyl)]carbazate (14.0 g, 42 mmole) and ethanolic hydrogen chloride (12% w/v, 300 ml, 1 mole) were refluxed for 24 hours. The dark solution was cooled to room temperature, the solvent removed in vacuo, and the residual oil purified by column chromatography (silica, eluted with chloroform-ethanol 98:2) giving ethyl 2-[(Z)-6-ethoxycarbonylhex2-eny]carbazate as a colourless oil, b.p. 12O1250/0.02 mm, m/e 258 (M+, C,2H2404).

Example 18 1 -[(Z)-6-Carboxyhex-2-enyl]-2-(3-cyclohexyl-3-hydroxypropyl)-1 ,2,4-triazolidine-3,5-dione A mixture of the carbazate obtained in Example 17 (1.6 g, 6.2 mmol) with 1-cyclohexylprop-2- en-1-one (0.86 g, 6.2 mmol) was set aside at room temperature for 6 days.The resulting syrup was purified by chromatography (SiO2; CHCl3-Et0H, 98:2) to give ethyl 3-(3-cyclohexyl-3-oxopropyl-2 [(Z)-6-ethoxyhex-2-enyl]carbazate (1.9 g) as a pale yellow oil, RF 0.5 (SiO2; CHCl 3-EtOH, 98:2), V max. 3380, 1732 and 1708 cell, 1.0-2.0 (1 2H, m, 6xCH2), 1.23 (6H, t, 2xOCH2CH3), 2.22 (4H, m, CH2CO2Et and CH=CHCH2CH2), 2.56 (3H, m, CH2COCH), 3.08 (2H, t, NHCH2), 4.07 (6H, m, NCH2CH= and 2xOCH2CH3) and 5.49 (2H, m, CH=CH). Sodium borohydride reduction of the above ketone afforded ethyl 3-(3-cyclohexyl-3-hydroxypropyl)-2- [(Z)-6-ethoxycarbonylhex-2-enyl]ca rbazate as a colourless oil, RF 0.4 (SiO2; CHCl3-EtOH, 98::2), V max. 3450 br, 3405, 1 734 and 1700 cm-', a 1.02.0 (1 5H, m, 7xCH2 and CH), 1.23 (6H, t, 2xOCH2CH3), 2.22 (4H, m, CH2CO2Et and CH=CHCH2CH2), 3.06 and 3.45 (each 1 H, m, non-equiv. NHCH2), 4.07 (7H, m, NCH2CH=, CHOH and 2xOCH2CH3) and 5.49 (2H, m, CH=CH).

In an analogous manner to that described in Example 14, the carbazate obtained in the last stage afforded a triazolidinedione ester. The derived carboxylic acid was purified by preparative t.l.c./RF 0.5 (SiO2; CHCl3-MeOH-HOAC, 90:5:5)/and crystallisation from ethyl acetate-hexane, to give 1-[(Z)-6 carboxyhex-2-enyl]-2-(3-cyclohexyl-3-hydroxypropyl)-1 ,2,4-triazolidine-3 ,5-dione as a colourless solid, no sharp m.p. (Found:C, 59.1; H, 7.75; N, 11.2. C,8H29N30s requires C, 58.85; H, 7.95; N, 11.45%), V max. 3410 br, 1712 and 1570 cm-l, S ([2H6]DMSO, 1000C) 1.0-2.0 (15 H, m, 7xCH2 and CH), 2.17 (4H, m, CH2CO2H and CH=CHCH2CH2), 3.39 (3H, m, NCH2CH2 and CHOH), 4.03 (2H, br t, NCH2CH=) and 5.47 (2H, m, CH=CH).

The following Examples illustrate pharmaceutical compositions according to the present invention wherein the "active ingredient" is a compound of formula (I) as defined above or a physiologically acceptable salt thereof, 1 -(6-carboxyhexyl-2-(3-cyclohexyl-3-hydrnxyprnpyl)-1 ,2,4- triazolidine-3,5-dione.

Example A Tablet In one Tablet Active ingredient 5.0 mg Lactose B.P. 82.0 mg Starch B.P. 10.0 mg Povidone B.P.C. (polyvinylpyrrolidone) 2.0 mg Magnesium stearate 1.0 mg Mix together the active ingredient, 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 B Capsule In one Capsule Active ingredient 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 C 1 flbg/ml lnjection Active ingredient 100 jig Water for injection to 100 ml Dissolve the active ingredient in the Water for Injection. Sterilise the solution by filtration through a membrane filter, 0.22 jim 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 D 10 /ug/ml Injection Active ingredient 1 mg Ethyl alcohol 10 ml Propylene glycol 30 ml Water for injection to 100 ml Dissolve the active ingredient in the Ethyl Alcohol, add the Propylene Glycol and dilute to volume with Water for Injection.

Sterilise the solution by filtate through a membrane filter, 0.22 jim 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 (13)

Claims

1. Compounds of the general formula

(wherein A represents a group of formula -CH=CH- (in either the cis- or trans-configuration), -(CH2)2- or -(CH2)3-; and Z represents a C45 alkyl group or a group of formula

in which R represents a C57 alkyl or C5~7 cycloalkyl group) and salts thereof.

2. Compounds as claimed in Claim 1 wherein Z represent an n-pentyl group or a group of formula

in which R represent an n-pentyl, 1,1 -dimethylpentyl, cyclopentyl or cyclohexyl group.

3. Compounds as claimed in Claim 1 or Claim 2 wherein A represents a group of formula -(CH2)2-.

4. 1 -(6-Carboxyhexyl-2-(3-cyclohexyl-3-hydroxypropyl)-1 ,2,4-triazolidine-3,5-dione and physiologically acceptable salts thereof.

5. A process for the preparation of compounds of formula (I) (as defined in Claim 1) which comprises cyclising a compound of formula

(wherein A and Z are as defined in Claim 1 and E is a carboxyl group or a functional equivalent thereof) or an ester thereof; and, if necessary hydrolysing any resulting ester, to form a compound of formula (I) which is optionally converted into a salt thereof.

6. A process for the preparation of compounds of formula (11) (as defined in Claim 5) which comprises reacting cyanic acid with a compound of formula

(wherein A and Z are as defined in Claim 1 and G is as defined in Claim 5).

7. A process for the preparation of a compound of formula (III) shown in Claim 6 (wherein Z represents a group of formula

(in which R is as defined in Claim 1) which comprises reacting a compound of formula

(wherein A is as defined in Claim 1 and E is as defined in Claim 4) or an ester thereof with a compound of formula H2C=CHCOR (V) (wherein R is as defined in Claim 1) followed by reduction of the carbonyl group.

8. A process for the preparation of a compound of formula (III) (as defined in Claim 6) which comprises reacting a compound of formula (IV) (as defined in Claim 7) or an ester thereof, with a compound of formula

(wherein Hal represents a halogen atom and Z is as defined in Claim 1)

9. Pharmaceutical formulations comprising, as active ingredient, at least one compound of formula (I) (as defined in Claim 1) or a physiologically acceptable salt thereof, together with a pharmaceutical carrier therefor.

10. Compounds of formula (I) (as defined in Claim 1) and physiologically acceptable salts thereof for use in a method of treatment of the human or animal body by therapy.

11. Compounds of formula (I) (as defined in Claim 1) and physiologically acceptable salts thereof for use in the treatment or prophylaxis of thrombo-embolic conditions in a mammal.

12. Compounds of formula (I) (as defined in Claim 1) and physiologically acceptable salts thereof for use in the treatment or prophylaxis of myocardial infarcts, thromboses, strokes, peripheral vascular disease or angina pectoris.

13. Compounds of the general formula

(wherein A is as defined in Claim 1 and G is as defined in Claim 5) and esters thereof.