GB1595695A - Hydantoin analogues - Google Patents

Description

(54) HYDANTOIN ANALOGUES (71) We, THE WELLCOME FOUNDATION LIMITED, of 183-193 Euston Road, London NW1, a company incorporated in England do hereby declare that the invention for which we pray that a Patent may be granted to us and the method by which is performed, to be particularly described in and by the following statement:- This invention relates to heterocyclic compounds, their synthesis, compositions containing them, and their use in medicine Hydantion 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 antiplatelet aggregatory properties of prostaglandin E.

In formula (I)

Z is hydrogen or alkyl; one of Z' and Z2 iS represented by the group -CH2-X-X1- X2 wherein X is phenylene, -C=-C-, cis or trans -CH=CH- or -CH2-CQ2- in which each Q 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; X' is a covalent bond or a straight or branched alkylene chain having 1 to 6 carbon atoms optionally having one of its methylene groups replaced by oxa(-O-) provided that at least one carbon atom separates the oxa group from a -C-C-, -CH=CH- or -CO- group; and X2 is selected from 5 tetrazolyl, carboxyl, carbamoyl, hydroxymethyl and alkoxycarbonyl; and the other of Z' 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 hydroxy or methylene substituted by hydroxy 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 independently selected from bicycloalkyl (as hereinafter defined), cycloalkyl (as hereinafter defined), tetrahydrofuranyl and tetrahydropyranyl; Y3 iS hydrogen, hydroxy, alkoxy having I to 7, preferably 1 to 4, carbon atoms, bicycloalkyl (as hereinafter defined), cycloalkyl (as hereinafter defined), tetrahydropyranyl, tetrahydrofuranyl, phenyl, benzyl, phenoxy or benzyloxy, wherein each of phenyl, benzyl, phenoxy and benzyloxy may be substituted in the benzene ring by one or more groups selected from hydroxy, halo, nitro, amino, acylamino, alkenyl, alkoxy, phenyl and alkyl which may itself be substituted by one or more halo groups; provided that, when Y2 is a covalent bond then Y3 is not hydroxy when Y includes hydroxy; or y2 and Y3 together form straight or branched alkyl having 1 to 7 carbon atoms having one or more hydrogens thereof replaced by fluoro; or Y is a bond -CH2- or -CH2.CH2- and Y', Y2 and Y3 taken together form a cycloalkyl group substituted by a hydroxy group which preferably has three carbon atoms separating it from the hydantoin ring; Provided that at least one of Z, X, X2 and Y to Y3 has one of the definitions as ascribed below: (a) Z is alkyl; (b) X is -C-C-, trans -CH=CII- or -CH2-CQ2- provided that at least one Q is other than hydrogen; (c) X2 is 5-tetrazolyl, carbamoyl or hydroxymethyl; (d) Y is -CR2-CH2- provided that at least one R is other than hydrogen; (e) y2 is alkylene substituted on the carbon adjacent Y by at least one group selected from pentyl, hexyl, cycloalkyl, bicycloalkyl, tetrahydrofuranyl and tetrahydropyranyl; (f) Y3 is cycloalkyl, bicycloalkyl, tetrahydropyranyl, tetrahydrofuranyl or phenyl, provided that when y2 is a covalent bond then Y3 iS other than cycloalkyl having 4 to 7 carbon atoms; or Y3 is phenyl, benzyl, phenoxy, or benzyloxy substituted by pentyl or hexyl which may be substituted by halo; (g) Y2 and Y3 taken together form alkyl having one or more hydrogen atoms thereof replaced by fluoro; (h) or Y is a bond, -CH2- or -CH2. CH2- and Y1, Y2 and Y3 taken together form a cycloalkyl group substituted by a hydroxy group.

Unless otherwise stated, in formula (I) and other formulae in this specification, alkyl moieties are selected from methyl, ethyl, propyl, butyl, pentyl and hexyl, including all isomers thereof; For example, in the definitions of Y and Y2 the alkyl groups are preferably methyl; and the alkyl moiety of alkoxycarbonyl is desirably methyl or ethyl. Similarly alkylene groups have 2 to 4 carbon atoms for example vinyl.

In formula (I) cycloalkyl groups have 3 to 10 carbon atoms and bicycloalkyl groups have 4 to 10 carbon atoms for example adamantyl, and such groups may be substituted by one or more alkyl groups, and cycloalkyl groups may have one or more of their hydrogen atoms replaced by fluoro.

In a compound of formula (I) the bonding of the divalent phenylene groups may be ortho, meta or para and the oxa group is preferably adjacent the phenylene or when X is other than phenylene then X' may be -C H 2-O-CH2-.

Included in the meaning of compounds of formula (I) are the salts corresponding to the carboxylic acids and tetrazoles when X2 is carboxyl or tetrazolyl respectively, and the salts which may also be formed when Z is hydrogen. Particularly valuable salts for medical purposes are those having a pharmaceutically acceptable cation such as ammonium or that of an alkali metal eg.

sodium and potassium, an alkaline earth metal eg. calcium and magnesium, or an organic base, particularly an amine such as ethanolamine. Salts having nonpharmaceutically acceptable cations are included within the ambit of this invention as useful intermediates to pharmaceutically acceptable salts, or the acids or esters of formula (I).

Except when there is clear indication to the contrary, formula (I) and other formulae in the specification embrace all stereoisomers, represented therein. In particular such formulae include the enantiomeric forms, such mixtures as are designated racemates, and diastereoisomers.

It has been found that compounds of formula (I) wherein Z is hydrogen or alkyl having 1 to 4 carbon atoms, for example methyl or butyl; one of Z' and Z2 is -CH2-X-X1-X2- wherein X and X' taken together form alkylene of 3 to 7 in particular 5 carbon atoms, and X2 is alkoxycarbonyl, carboxyl or a salt thereof; and the other of Z' and Z2 is -Y-Y1- Y2-Y3- wherein Y, Y and y2 are as hereinbefore defined and Y3 is hydrogen, phenyl, benzyl, or cycloalkyl of 4 to 7 carbon atoms; provided that at least one of Z and Y3 have the definitions ascribed to them below: (a) Z is alkyl (b) Y3 is phenyl have particularly interesting prostaglandinrelated properties. Within this definition are included the subclass wherein Z is hydrogen and Z' is C112-X-X1-X2- as defined.

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 according to any of the methods described in our co-pending UK application No 42024/77, (Serial No 1595694) wherein Z, Z' and Z2 therein have the definitions ascribed to them in formula (I) above.

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, 52 is hydrogen or z2 and 53 is alkyl, Z' or Z2, provided that one of J, J' and J2 is hydrogen and 53 does not have the same value as J, J' or 52; in the definition of Jr, 52 and 53 each of Z' and Z2 has the same meaning as in formula (I); according to the method described in our co-pending UK application No 42024/77 for the alkylation of compounds of analogous structure.

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 methods described in our co-pending UK application No 42024/77 (Serial No 1595694). The compounds of formula (X) may further be prepared by adaptation of methods already known in the art (see for example Chemical Reviews (1950) 46, p 403-425).

Tetrazoles of formula (I) may be prepared from corresponding compounds wherein the group -X2 is replaced by

wherein X3 and X4 together form a bond (nitrile), X3 iS hydrogen or alkyl and X4 iS alkoxy (imidoester), alkylthio (imidothioester), -NH-NH2 (amidrazone), or amino (amidine) or X3 iS hydroxy and X4 iS amino (amidoxime). The reaction is preferably carried out in a polar aprotic liquid medium such as dimethylformamide using a salt of a hydrazoic acid e.g. sodium azide. However, when X2 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 X2 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 by 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 diethyl ether or hydrocarbon such as hexane or benzene. Such alcohols may also be prepared by catalytic hydrogenation.

Alternatively the alcohols of formula (I) wherein X2 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 synthesis of hydantoins of formula (I) having a hydroxy 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, I-ethoxyethyl or aralkyl, for example benzyl.

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

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 hydroxy 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 mixture of the four isomers by treatment with a base, such as an alkali metal hydroxide, and subsequently reseparated 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.

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

The hydantoins of formula (I) are of value in having pharmacological properties related to those of natural prostaglandins, similar to those described in our co-pending UK application No 42024/77 (Serial No 1595694) for the hydantoins disclosed therein.

For example, a hydantoin of formula (I) causing relaxation of vascular smooth muscle in a way similar to members of the prostaglandin 'A' and 'E' series is 5 - (6 carboxyhexyl) - 1 - (3 - hydroxy - 4,4 dimethyl - 5 - phenyl - pentyl)hydantoin.

Compounds relaxing vascular smooth muscle are capable of inducing vasodilation and therefore have antihypertensive properties and are useful in lowering blood pressure in mammals, including man, and may be used alone or in combination with a p-adrenoceptor blocking agent or another antihypertensive substance for the treatment of all grades of hypertension including essential, malignant and secondary hypertension.

Some compounds 5 - (6 carboxyhexyl) - 1 - (3 - hydroxy - 4,4 dimethyl - octyl)hydantoin also mimic the effect of PGE1 of antagonising histamine induced broncho-constriction. The hydantoins of formula (I) having this property may be used in the treatment or prophylaxis of bronchial asthma and bronchitis by alleviating the bronchoconstriction associated with this condition.

Hydantoins of formula (I), such as 5 - (6 carboxyhexyl) - 3 - methyl - 1 - (3 - oxo octyl)hydantoin, - 1 - (3 - oxo - oct 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 certain hydantoins of formula (I) to dogs has been found to increase urine volume indicating a potential utility for such compounds as diuretic agents, the uses of which include the treatment of oedema for example 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 PG F2 is as anti-fertility agents in particular as abortifacients.

The amount of a compound of formula (I) required to achieve the desired biological effect is described in our co-pending UK application No 42024/77 Serial No 1595694 and will of course depend on a number of factors.

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 formulations are described in our copending application No 42024/77 (Serial No 1595694) and include those suitable for oral, rectal, topical (buccal-e.g. sub-lingual), and 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.

It will be appreciated from the foregoing that what we will claim may comprise for example: (a) The novel compounds of formula (I) as hereinabove define (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 excluding 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 or prophylaxis of thrombosis in a mammal or mammalian tissue, excluding 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, excluding man, comprising administration to said mammal of a nontoxic effective vasodilatory amount of a compound of formula (I).

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

(h) A method for inducing bronchodilation in a mammal, excluding 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, excluding man, comprising administration to said mammal of a nontoxic effective prophylactic or therapeutic amount of a compound of formula (I).

(j) A method of inducing abortion of a foetus in a mammal excluding 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 excluding human comprising administration to said mammal of a nontoxic effective contraceptive amount of a compound of formula (I).

Example 1 5-(6-Carboxyhexyl)-l-[(3-hydroxy-3 phenyl)-propyl]hydantoin By a series of reactions analogous to that described in Reference Example A of our co-pending UK application No 42024/77 (Serial No 1595694), and using the appropriate vinyl ketone was prepared: (a) diethyl 2 - [(3 - oxo - 3 phenylpropyl)amino]non nedioate; which was converted to; (b) diethyl 2 - [(3 - hydroxy - 3 phenylpropyl)amino]nonanedioate; from which was prepared the following hydantoin of formula (I) which was separated by HPLC to provide two diastereomers; (c) 5 - (6 - carboxyhexyl)- 1 - [(3 - hydroxy - 3 - phenyl)propyl]hydantoin, both forming colourless oils.

Example 2 Preparation of 5-(6-carboxyhexyl)-3 methyl- 1 -octyl-hydantoin A solution of diethyl 2 octylaminononanedioate (742 mg) and methyl isocyanate (120 mg) in dry diethyl ether (7.5 ml) was allowed to stand at room temperature for 48 hours, after which time the diethyl ether was evaporated to leave a pale yellow oil (800 mg). The oil was heated on the steam bath for 2 hours to give 5 - (6 ethoxycarbonylhydroxy) - 3 - methyl - 1 octylhydantoin as a yellow oil.

The ester (650 mg) was hydrolysed by standing in solution methanol (2.4 ml) and SN-sodium hydroxide solution (0.6 ml) for 3 hours at room temperature. After evaporation of the ethanol, the acidic product was isolated by extraction with diethyl ether, and purified by chromatography on a column of silica gel to give 5 - (6 - carboxyhexyl) - 3 - methyl 1 - octylhydantoin as a colourless oil.

Example 3 Preparation of 5-(6-carboxyhexyl)-3 methyl -(3-hydroxyoctyl)hydantoin Diethyl 2 - ((3 - oxooctyl)amino)nonanedioate (prepared according to Example 2A of our co-pending UK application No 9171/76 (Serial No 1595693) was allowed to react with methyl isocyanate as described in Example 2 to give 5 - (6 - ethoxycarbonyl - hexyl) - 3 methyl - 1 - (3 - oxooctyl)hydantoin, which was hydrolysed to 5 - (6 - carboxyhexyl) 3 - methyl - 1 - (3 - oxooctyl)hydantoin a colourless oil.

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

Example 4 Preparation of 1-(6-Carboxyhexyl)-3 methyl-5-octylhydantoin By the method described in Example 2, ethyl 2 - (6 - ethoxy carbonylhexylamino)decanoate (prepared according to Example 36 of our co-pending UK application No 9171/76 (Serial No 1595693) was converted into 1 - (6 - ethoxycarbonylhexyl) - 3 - methyl - 5 octylhydantoin, and thence by hydrolysis into 1 - (6 - carboxyhexyl) - 3 - methyl 5 - octylhydantoin, isolated as a colourless oil.

Example 5 Preparation of 3-Butyl-5-(6 carboxyhexyl)- 1 -octylhydantoin To a solution of sodium (308 mg) in ethanol (40 ml) was added 5 - (6 ethoxycarbonylhexyl) - 1 - octylhydantoin (see Example 28 of our co-pending UK application No 42024/77) (Serial No 1595694) followed by butyl bromide (1.8 g), and the solution was refluxed for 24 hours. The solvent was evaporated, water was added and the insoluble oil was extracted with diethyl ether The washed and dried extract was evaporated to give 3 - butyl - 5 - (6 ethoxycarbonylhexyl) - I - octylhydantoin.

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

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

Example 6 Preparation of 3-Butyl-l-(6-carboxyhexyl)- 5-octylhydantoin By the method of Example 5, 1 - (6 ethoxycarbonylhexyl) - 5 - octylhydantoin (see Example 35 of our co-pending UK application No 42024/77) (Serial No 1595694) was converted into 3 - butyl - 1 (6 - ethoxycarbonylhexyl) - 5 octylhydantoin, which was hydrolysed to give 3 - butyl - 1 - (6 - carboxyhexyl) - 5 octyl - hydantoin as a colourless oil.

Example 7 Preparation of l-(3-cyclohexyl-3-hydroxy- propyl)-5-(7-hydroxyheptyl)hydantoin A solution of ethyl chloroformate (108.5 mg) in tetrahydrofuran (0.5 ml) was added to a stirred solution of 5 - (6 carboxyhexyl) - 1 - (3 - cyclohexyl - 3 hydroxypropyl) - hydantoin (mixture of diastereomers) (Example 13 of our copending UK application No. 42024/77 Serial No 1595694) (368 mg) and triethylamine (101 mg), cooled to -5 , over a period of 15 minutes. After a further 1 hour at 0 , the solid was collected and washed with tetrahydrofuran (1 ml).

The combined filtrate and washing was added dropwise over about 30 minutes to a solution of sodium borohydride (100 mg) in water (1 ml) at 15 . After addition was complete, the solution was stirred at room temperature for 2 hours. Water was added, the solution was acidified with 2Nhydrochloric acid and extracted with diethyl ether. The ether solution was washed with sodium bicarbonate solution and then with water, dried (MgSO4) and evaporated to leave a colourless, viscous oil (330 mg).

Chromatography of this oil (300 mg) in ethyl acetate saturated with water on a column of silica gave an oil (250 mg) which on thin-layer chromatography on silica in a mixture of chloroform, methanol and acetic acid (90:5:5) showed only 2 spots, Rf 0.60, 0.63, attributable to the diastereomers of 1 (3 - cyclohexyl - 3 - hydroxypropyl) - 5 (7 - hydroxyheptyl)hydantoin. By use of HPLC, the diastereomers were separated; the less polar isomer solidified, m.p. 73 77", the more polar remaining as a viscous oil.

Example 8 Preparation of 5-(6-carbamoylhexyl)-1 (3-cyclohexyl-3-hydroxypropyl)hydantoin 5 - (6 - Ethoxycarbonylhexyl) - I - (3 cyclohexyl - 3 - hydroxy propyl)hydantoin (single diastereomer) (see Example 42 of our co-pending UK application No 42024/776 (Serial No 1595694) (500 mg) was dissolved in aqueous ammonium hydroxide solution (s.g. 0.880) (2.5 ml) and the solution was heated in a closed vessel at 100C for 2 hours. After cooling, the solution was acidified with 2Nhydrochloric acid and the precipitated gum was extracted first with ether, which dissolved a part of the gum and then with chloroform. The chloroform extract was washed with sodium bicarbonate solution and then with water, dried (MgSO4) and evaporated to leave the mixed diastereomers of the title compound as a colourless solid, m.p. 110120 (T.l.c. on silica in chloroform-methanol - acetic acid (90:5:5 v/v/v showed two spots, Rf 0.37, 0.41).

Examples 9-12 By the method of Example 1 were prepared: 9a diethyl 2 - ((4 - cyclohexyl - 3 oxobutyl)amino) - nonanedioate; 10a diethyl 2 - ((6 - cyclohexyl - 3 oxohexyl)amino) - nonanedioate; lla diethyl 2 - ((3 - oxo - 3 - (4 tetrahydropyranyl)propyl) - amino)nonanedioate; 12a diethyl 2 - ((3 - (I - adamantyl) - 3 oxopropyl)amino) - nonanedioate; 9b diethyl 2 - ((4 - cyclohexyl - 3 hydroxybutyl)amino) - nonanedioate; 10b diethyl 2 - ((6 - cyclohexyl - 3 hydroxyhexyl)amino) - nonanedioate; llb diethyl 2 - ((3 - hydroxy - 3 - (4 tetrahydropyranyl) - propyl)amino)nonanedioate; 12b diethyl 2 - ((3 - (I - adamantyl) - 3 hydroxypropyl) - amino)nonanedioate; 9c 5 - (6 - - carboxyhexyl) - 1 - (4 - cyclohexyl - 3 - hydroxy - butyl)hydantoin, diastereomers, m.p. 9294 and 109111 ; 10c 5 - (6 - carboxyhexyl) - 1 - (6 - cyclohexyl - 3 - hydroxyhexyl) hydantoin, diastereomers, m.p. 8486 and 9092 llc 5 - (6 - carboxyhexyl) - 1 - (3 - hydroxy - 3 - (4 - tetrahydro pyranyl)propyl)hydantoin, diastereomers, m.p. 106108 and 101103 ; 12c 5 - (6 - carboxyhexyl) - 1 - (3 - (I adamantyl) - 3 - hydroxy propyl)hydantoin, one diastereomer, m.p.

155157 In the following example the hydantoin is designated thus: Compound 3: 5 - (6 Carboxyhexyl) - 3 - methyl - I - (3 oxooctyl) - hydantoin Example A Compound 3 was found to reduce aspirininduced gastric ulceration in rats: an oral dose of 1 mg/kg gave 80% protection.

Example 13 Preparation of 5-(6-Carboxyhex-2-ynyl)- 1- (3-hydroxyoctyl)hydantoin Diethyl 2 - ((3 - hydroxyoctyl)amino) non - 4 - ynedioate, prepared according to Example 37 of our co-pending UK application No 9171/76 was treated with potassium cyanate and hydrochloric acid, and hydrolysis of the hydantoin ester so produced gave a light brown oil.

Purification by chromatography on a column of silica with a mixture of chloroform and methanol (30:1) as eluant gave 5 - (6 - carboxyhex - 2 - ynyl) - 1 (3 - hydroxyoctyl) - hydantoin as a colourless oil, (mixture of diastereomers) showing two spots, Rf 0.38, 0.44, when run in a chloroform, methanol, acetic acid (90:5:5) mixture on a thin layer of silica. By use of HPLC, one of the diastereomers (TLC, Rf 0.38) was isolated as a colourless oil; NMR (CDCl3) S0.89 (3H, triplet, -CH3), 2.2-2.4 (6H, multiplet, -CH2, C-C.CH2+CH2.CO2H), 3.54 (2H, triplet, N.CH2), ca 3.6 (1H, multiplet, > CH.OH) 4. I I (1H,

Claims (58)

**WARNING** start of CLMS field may overlap end of DESC **. non - 4 - ynedioate, prepared according to Example 37 of our co-pending UK application No 9171/76 was treated with potassium cyanate and hydrochloric acid, and hydrolysis of the hydantoin ester so produced gave a light brown oil. Purification by chromatography on a column of silica with a mixture of chloroform and methanol (30:1) as eluant gave 5 - (6 - carboxyhex - 2 - ynyl) - 1 (3 - hydroxyoctyl) - hydantoin as a colourless oil, (mixture of diastereomers) showing two spots, Rf 0.38, 0.44, when run in a chloroform, methanol, acetic acid (90:5:5) mixture on a thin layer of silica. By use of HPLC, one of the diastereomers (TLC, Rf 0.38) was isolated as a colourless oil; NMR (CDCl3) S0.89 (3H, triplet, -CH3), 2.2-2.4 (6H, multiplet, -CH2, C-C.CH2+CH2.CO2H), 3.54 (2H, triplet, N.CH2), ca 3.6 (1H, multiplet, > CH.OH) 4. I I (1H, triplet, > N.CIlCO ). WHAT WE CLAIM IS:

1. A compound of formula (I)

wherein Z is hydrogen or alkyl; one of Z' and Z2 is represented by the group -CH2- XXX wherein X is phenylene, -C=-C-, cis or trans -CH--CH- or -CH2-CQ2- in which each Q is independently selected from hydrogen and alkyl or the two Q's together form an alkylene radical having four, five or six carbon atoms X' is a covalent bond or a straight or branched alkylene chain having 1 to 6 carbon atoms optionally having one of its methylene groups replaced by oxa (-0-) provided that at least one carbon atom separates the oxa group from a -C=C- -CH=CH- or -CO- group; and X2 is selected from 5tetrazolyl, carboxyl, carbamoyl, hydroxymethyl and alkoxycarbonyl; and the other of Z' and Z2 iS represented by the group ---YY-YY'--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 hydroxy or methylene substituted by hydroxy 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 independently selected from bicycloalkyl (as hereinbefore defined), cycloalkyl (as hereinbefore defined), tetrahydrofuranyl and tetrahydropyranyl; Y3 is hydrogen, hydroxy, alkoxy having 1 to 7 carbon atoms, bicycloalkyl (as hereinbefore defined), cycloalkyl (as hereinbefore defined), tetrahydropyranyl, tetrahydrofuranyl, phenyl, benzyl, phenoxy or benzyloxy, wherein each of phenyl, benzyl, phenoxy and benzyloxy may be substituted in the benzene ring by one or more groups selected from hydroxy, halo, nitro, amino, acylamino, alkenyl, alkoxy, phenyl and alkyl which may itself be substituted by one or more halo groups; provided that, when Y2 iS a covalent bond then Y3 is not hydroxy when Y includes hydroxy; or Y2 and Y3 together form straight or branched alkyl having 1 to 7 carbon atoms having one or more hydrogens thereof replaced by fluoro; or Y isabond, -CH2- or --CH,.CH,,- and Y', Y2 and Y3 taken together form a cycloalkyl group substituted by a hydroxy group; Provided that at least one of Z, X, X2 and Y to Y3 has one of the definitions as ascribed below: (a) Z is alkyl; (b) X is -C-C-, trans -CH=CH- or -CH2-CQ2- provided that at least one Q is other than hydrogen; (c) X2 is 5-tetrazolyl, carbomoyl or hydroxymethyl; (d) Y is -CR2-CH2- provided that at least one R is other than hydrogen; (e) Y2 is alkylene substituted on the carbon adjacent Y' by at least one group selected from pentyl, hexyl, cycloalkyl, bicycloalkyl, tetrahydrofuranyl and tetrahydropyranyl; (f) Y3 iS cycloalkyl, bicycloalkyl, tetrahydropyranyl, tetrahydrofuranyl or phenyl, provided that when Y2 iS a covalent bond then Y3 iS other than cycloalkyl having 4 to 7 carbon atoms; or Y3 is phenyl, benzyl, phenoxy, or benzyloxy substituted by pentyl or hexyl which may be substituted by halo; (g) Y2 and Y3 taken together form alkyl having one or more hydrogen atoms thereof replaced by fluoro; (h) or Y is a bond, -CH2- or -CH2.CH2- and Y1, y2 and Y3 taken together form a cycloalkyl group substituted by a hydroxy group; or a salt thereof (as hereinbefore defined).

2. A compound according to claim I, wherein 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 independently selected from bicycloalkyl or cycloalkyl; Y3 is hydrogen, hydroxy, alkoxy having 1 to 7 carbon atoms, cycloalkyl, bicycloalkyl, phenyl, benzyl, phenoxy or benzyloxy, wherein each of phenyl, benzyl, phenoxy or benzyloxy may be substituted in

the benzene ring by one or more groups selected from hydroxy, halo, nitro, amino, acylamino, alkenyl, alkoxy, phenyl and alkyl which may itself be substituted by one or more halo groups; or Y is a bond, -C112-, or -CH2.CH2- and Y, Y2 and Y3 taken together form a cycloalkyl group substituted by a hydroxy group.

3. A compound according to claim 1 or claim 2, wherein X2 is carboxyl or alkoxycarbonyl; Y2 is a covalent bond or straight or branched alkylene having 1 to 7 carbon atoms; Y3 is hydrogen, hydroxy, alkoxy having 1 to 7 carbon atoms, phenyl, benzyl, phenoxy or benzyloxy, wherein each of p enyl, benzyl, phenoxy or benzyloxy may be substituted in the benzene ring by one or more groups selected from hydroxy, halo, nitro, amino, acylamino, alkenyl, alkoxy, phenyl and alkyl which may itself be substituted by one or more halo groups; or Y2 is a covalent bond and Y3 is a cycloalkyl group having from 4 to 7 carbon atoms.

4. A compound according to claim 1 Provided that at least one of X to X2 and Y to Y3 has one of the definitions as ascribed below: (a) X is -C=-C-, trans -CH=CH- or -CH2-CQ2- provided that is least one Q is other than hydrogen; (b) X2 is 5-tetrazolyl, carbamoyl or hydroxymethyl; (c) Y is -CR2-C112- provided that at least one R is other than hydrogen; (d) Y2 is alkylene substituted on the carbon adjacent Y' by at least one group selected from pentyl, hexyl, cycloalkyl, bicycloalkyl, tetrahydrofuranyl and tetrahydropyranyl; (e) Y3 iS cycloalkyl, bicycloalkyl, tetrahydropyranyl, tetrahydrofuranyl or phenyl, provided that when Y2 is a covalent bond then Y3 is other than cycloalkyl having 4 to 7 carbon atoms; or Y3 is phenyl, benzyl, phenoxy, or benzyloxy substituted by pentyl or hexyl which may be substituted by halo; (f) Y2 and Y3 taken together form alkyl having one or more hydrogen atoms thereof replaced by fluoro; (g) or Y is a bond, -CH2- or -CH2.CH2- and yl, Y2 and Y3 taken together form a cycloalkyl group substituted by a hydroxy group.

5. A compound according to claim 1, Provided Additionally that at least one of X1, Y and Y3 has one of the definitions as ascribed below: (a) X1 is a covalent bond or a straight or branched hexylene chain, or a straight or branched alkylene having from 1 to 6 carbon atoms having one of any methylene groups replaced by an oxa group; (b) Y is carbonyl; (c) Y3 is hydroxy, alkoxy having from 1 to 7 carbon atoms, a cyclic radical other than cycloalkyl having from 5 to 8 carbon atoms, phenoxy, or phenyl, benzyl, phenoxy or benzyloxy each of which is substituted in the benzene ring by one or more groups at least one of which is selected from hydroxy, amino, acylamino, alkenyl, or alkyl substituted by one or more halogeno groups other than trifluoromethyl.

6. 5 - (6 - Carboxyhexyl) - 1 - (3 - hydroxy - 3 - phenylpropyl) - hydantoin.

7. 5 - (6 - Ethoxycarbonylhexyl) - 3 methyl - 1 - octylhydantoin.

8. 5 - (6 - Carboxyhexyl) - 3 - methyl I - octylhydantoin.

9. 5 - (6 - Ethoxycarbonylhexyl) - 3 methyl - 1 - (3 - oxooctyl) - hydantoin.

10. 5 - (6 - Carboxyhexyl) - 3 - methyl I - (3 - oxooctyl)hydantoin.

11. 5 - (6 - Carboxyhexyl) - 3 - methyl 1 - (3 - hydroxyoctyl) - hydantoin.

12. 1 - (6 - Ethoxycarbonylhexyl) - 3 methyl - 5 - octylhydantoin.

13. 1 - (6 - Carboxyhexyl) - 3 - methyl 5 - octylhydantoin.

14. 3 - Butyl - 5 - (6 ethoxycarbonylhexyl) - I - octylhydantoin.

15. 3 - Butyl - 5 - (6 - carboxyhexyl) - octylhydantoin.

16. 3 - Butyl - 1 - (6 ethoxycarbonylhexyl) - 5 - octylhydantoin.

17. 3 - Butyl - 1 - (6 - carboxyhexyl) 5 - octylhydantoin.

18. 1 - (3 - Cyclohexyl - 3 hydroxypropyl) - 5 - (7 - hydroxy heptyl)hydantoin.

19. 5 - (6 - Carbamoylhexyl) - 1 - (3 - cyclohexyl - 3 - hydroxy) - hydantoin.

20. 5 - (6 - Carboxyhexyl) - 1 - (4 - cyclohexyl - 3 - hydroxy - butyl)hydantoin.

21. 5 - (6 - Carboxyhexyl) - 1 - (6 - cyclohexyl - 3 - hydroxy - hexyl)hydantoin.

22. 5 - (6 - Carboxyhexyl) - I - (3 hydroxy - 3 - (4 - tetra hydropyranyl)propyl)hydantoin.

23. 5 - (6 - Carboxyhexyl) - 1 - (3 - (1 adamantyl) - 3 - hydroxy propyl)hydantoin.

24. 5 - (6 - Carboxyhex - 2 - ynyl) - 1 (3 - hydroxyoctyl)hydantoin.

25. A derivative of a compound according to any of claims 6 to 24 selected from an ester, amide or alcohol.

26. a salt, as hereinbefore defined, of a compound according to any of claims 6 to 25.

27. A compound according to any of claim 1 to 26 which is a mixture of the diastereomer having the higher melting point together with the diastereomer having the lower melting point.

28. A compound according to any of claim I to 26 which is the diastereomer having the higher melting point.

29. A compound according to any of claims 1 to 26 which is the diastereomer having the lower melting point.

30. A composition comprising a compound of formula (I) as defined in any of claims 1 to 29 in association with a pharmaceutically acceptable carrier.

31. A composition as claimed in claim 30 wherein the carrier is a liquid.

32. A composition as claimed in claim 30 or 31 in the form of a sterile injectable aqueous solution.

33. A composition as claimed in claim 31 or 32 comprising from 0.001 to 100 g of a compound of formula (I) per millilitre.

34. A composition as claimed in any of claims 31 to 33 in the form of a unit dose comprising from 0.01 to 1 mg of a compound of formula (I).

35. A composition as claimed in claim 30 wherein the carrier is a solid.

36. A composition as claimed in claim 35 in the form of a unit dose.

37. A composition as claimed in claim 35 or 36 in the form of a tablet, capsule, cachet or suppository.

38. A composition as claimed in any of claims 35 to 37 comprising from 0.1 to 50 mg of a compound of formula (I).

39. A method of preparing compound of formula (I) as defined in any of claims 1 to 29 comprising cyclisation, under acidic conditions or by heating, of a compound of formula (II)

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

40. A method of preparing a compound of formula (I) as defined in any of claims 1 to 29 comprising cyclisation under acidic conditions or by heating, of a compound of formula (VII)

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

41. A method of preparing a compound of formula (I) as defined in any of claims 1 to 29 comprising reaction of a carbonic acid derivative with a compound of formula (IX)

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

42. A method of preparing a compound of formula (I) as defined in any of claims 1 to 29 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 Zi, 52 is hydrogen or Z2 and 53 is alkyl, Z' or z2 provided that one of J, J' and 52 is hydrogen and 53 does not have the same value as J, J' or J2, in the definition of Ji, J2 and 53 each of Z' and z2 has the same meaning as in formula (I).

43. A method of preparing a compound of formula (I) as defined in any of claims 1 to 29 comprising reduction of a compound of formula (XI)

wherein either Z3 iS =CR-CH2-Y1-Y2 Y3 and Z4 is -CH2-X-X1-X2 or Z3 is =CH--XX-XX'-X2 and Z4 is -Y-Y1-Y2 yi in which each of R, X to X2, Y to Y3 and Z is as defined in formula (I).

44. A method of preparing a compound of formula (I) as defined in claim I wherein X2 is hydroxymethyl comprising reduction of a corresponding acid, ester, acid halide, acid anhydride or aldehyde.

45. A method of preparing a compound of formula (I) as defined in claim I wherein X2 is hydroxymethyl comprising hydrolysis of a corresponding halide.

46. A compound of formula (I) as defined in any of claims 1 to 29 when prepared by a process defined by any of claims 39 to 45.

47. A method of inhibiting the aggregation of platelets which comprises the bringing of said platelets into association with an effective platelet aggregation inhibitory amount of a compound of formula (I) as defined in any of claims 1 to 29.

48. A method for the treatment or prophylaxis of thrombosis in a mammal or mammalian tissue, excluding human, which comprises administration of a non-toxic, effective antithrombotic amount of a compound of formula (I) as defined in any of claims 1 to 29.

49. A method of lowering blood pressure in a mammal, excluding man, which comprises administration to the mammal of an effective hypotensive, non-toxic amount of a compound of formula (I) as defined in any of claims 1 to 29.

50. A method for inducing vasodilation in a mammal, excluding man, comprising administration to said mammal of a nontoxic effective vasodilatory amount of a compound of formula (I) as defined in any of claims 1 to 29.

51. A method for the treatment or prophylaxis of gastric lesions in a mammal, excluding man, comprising administration to said mammal of a non-toxic effective prophylactic or therapeutic amount of a compound of formula (I) as defined in any of claims 1 to 29.

52. A method for inducing bronchodilation in a mammal, excluding man, comprising administration to said mammal of a non-toxic, effective bronchodilatory amount of a compound of formula (I) as defined in any of claims I to 29.

53. A method for the treatment or prophylaxis of an allergic condition in a mammal, excluding man, comprising administration to said mammal of a nontoxic effective prophylactic or therapeutic amount of a compound of formula (I) as defined in any of claims 1 to 29.

54. A method of inducing abortion of a foetus in a mammal, excluding human, comprising administration to said mammal of a non-toxic effective abortifacient amount of a compound of formula (I) as defined in any of claims 1 to 29.

55. A method of inducing infertility in a mammal, excluding man, of a non-toxic effective contraceptive amount of a compound of formula (I) as defined in any of claims 1 to 29.

56. A method as claimed in any of claims 47 to 55 wherein the compound of formula (I) is administered at a daily dose of from I g to 20 mg per kilogram of the mammal.

57. A method as claimed in any of claims 47 to 55 which comprises an intravenous infusion of the compound of formula (I).

58. The preparation of a compound of formula (I) as defined in claim 1 by a method substantially as hereinbefore described with particular reference to Examples 1 to 13.