GB1599740A

GB1599740A - Hydantoin derivatives

Info

Publication number: GB1599740A
Application number: GB25575/78A
Authority: GB
Original assignee: Wellcome Foundation Ltd
Current assignee: Wellcome Foundation Ltd
Priority date: 1978-05-31
Filing date: 1978-05-31
Publication date: 1981-10-07
Also published as: BE876670R; IL57436A0; AU4762579A; IT7949253A0; NL7904311A; JPS554371A; ZA787354B; FR2427331B2; DE2922070A1; SE7904700L; FR2427331A2; IT1164693B

Description

(54) HYDANTOIN DERIVATIVES (71) We, THE WELLCOME FOUNDATION LIMITED, of 183-193 Euston Road, London, N.W.I., 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 it 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.

In the complete specification of our co-pending patent application Nos. 42024/77 and 8011278 (Serial Nos. 1,595,694, 1,595,695) we describe certain hydantoin derivatives, defined hereinbelow in formula (I), which 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 Zl and ZZ is represented by the group --CH,,--X--X'-XZ wherein X is phenylene, -=c-, cis or trans H=CH- or H2Q2- 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; Xl 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(--OO-) 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, carboxamide, hydroxymethylene and alkoxycarbonyl; and the other of Z1 and Z2 is represented by the group -Y-Y1-Y2-Y3 wherein Y is -CR2-C112- 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 independently selected from alkyl, bicycloalkyl and cycloalkyl: Y3 is hydrogen, hydroxy, alkoxy having I to 7, preferably 1 to 4, carbon atoms; cycloalkyl, bicycloalkyl, phenyl, benzyl, phenoxy, or benzyloxy, wherein each of phenyl, benzyl, phenoxy and benzyloxy may be substituted in the benzene ring by one or more groups selected from hydroxy, halogeno, nitro, amino, acylamino, alkenyl, alkoxy, phenyl and alkyl which may itself be substituted by one or more halogeno groups; or Y is a bond, -CH2-, or H2. CH2- and yl, y2 and Y3 taken together form a cycloalkyl group substituted by a hydroxyl group which preferably has three carbon atoms separating it from the hydantoin ring.

Unless otherwise stated, in formula (I) alkyl moieties are selected from methyl, ethyl, propyl, butyl, pentyl and hexyl, including all isomers thereof; for example, in the definitions of Y1 and y2 the alkyl group 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.

In a compound of formula (I) the bonding of the divalent phenylene group may be ortho, meta orpara, and the oxa group is preferably adjacent the phenylene or when X is other than phenylene then Xl may be CHz-OCH2-.

Included in the meaning of compounds of formula (1)- are the salts corresponding to the carboxylic acids and tetrazoles when XZ 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, an alkaline earth metal e.g. 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 (1).

Except when there is a clear indication to the contrary, formula (I) embrace all stereoisomers represented therein. In particular the formula includes 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, and in particular by the methods described in the abovementioned patent specifications.

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 inhibit blood platelet aggregation. relax vascular smooth muscle, antagonise histamine induced bronchoconstriction, inhibit pentagastrin induced acid secretion and promote diuresis. The medicinal uses to which such compounds may be put are more fully explained in our earlier applications together with appropriate doses, modes of administration and pharmaceutical compositions therefor.

The present invention provides further compounds of formula (I) as hereinafter exemplified: Reference Preparation 1 Preparation of 5-(6-Carboxylhexyl)-1-(3-hydroxy-4,4- dirnethyl-5-phenylpentyl)hydantoin A. Diethyl 2-aminononanedioate Diethyl acetamidomalonate (16.7 g) and ethyl 7-bromoheptanoate (16.6 g) were dissolved in ethanolic ethoxide (prepared from sodium (1.51 g) and absolute ethanol (30 ml) and the mixture was refluxed for 27 hours. The cooled solution was poured into ice-water, the product was extracted into ether, and the dried extract was evaporated to give crude diethyl acetamido - (6 - ethoxycarbonylhexyl)malonate as a pale yellow oil, a2.2(3H, singles, --COCH,), 4.17(6H, multiplet, 3x-OCH2-CH). This amide was refluxed with concentrated hydrochloric acid (111 ml) for 5+ hours, the cooled solution was washed with ether, and the aqueous layer was decolorised with activated charcoal and evaporated to dryness in vacuo.

The residual colourless glass was dissolved in the minimum quantity of absolute ethanol and added dropwise to a stirred, cooled (-10"C) mixture of absolute ethanol (125 ml) and thionyl chloride (15.7 g). The resulting solution was set aside at room temperature for I hour, refluxed for 1+ hours, cooled, and poured into icewater, adjusting the pH to 9 with aqueous sodium hydroxide. The mixture was extracted with ether, and the dried extract was concentrated and distilled, giving diethyl 2-amino-nonanedioate (55 " yield) as a colourless oil, b.p.

I1A 1150/0.02--03 mm.

B. Diethyl 2-((4,4-dimethvl-3-oxo-phenylpentyl)amino)nonanedioate To diethyl 2-aminonónanedioate (5.18 g) was added dropwise 4,4-dimethyl-5 phenylpent-l-en-3-one (3.95 g) with cooling and stirring. The mixture was allowed to stant at room temperature for 21 hours to give diethyl 2 - (4,4 - dimethyl - 3 oxo - 5 - phenylpentyl)amino)nonanedioate.

C. Diethyl 2 - (3 - hydroxy - 4,4 - dimethyl - 5 - phenylpentyl)amino) nonanedioate The foregoing crude ketone (5.1 g) was dissolved in absolute ethanol (70 ml) and the solution was stirred in an ice-bath during the gradual addition of sodium borohydride (380 mg). The solution was stirred in the ice-bath for a further 10 minutes and then left to stand at room temperature for 5 hours. Most of the alcohol was evaporated, water was added, and the solution acidified to pH 6. The insoluble oil was extracted with ether. and the ether solution was dried and evaporated to leave diethyl 2 - (3 - hydroxy - 4,4 - dimethyl - 5 - phenylpentyl) amino)nonanedioate as a pale yellow oil which was used without further purification.

D. 5 - (6 - Ethoxycarbonyl - hexyl) - 1 - (3 - hydroxy - 4,4 - dimethyl - 5 phenylpentyl)hydantoin and the corresponding acid A solution of the above alcohol (8.45 g) in ethanol (37.6 ml) and 2N hydrochloric acid (18.8 ml) was stirred and cooled in ice during the dropwise addition of a solution of potassium cyanate (3.05 g) in water (5.6 ml). The mixture was allowed to stand at room temperature for 18 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 6 hours to give 5 - (6 - ethoxycarbonylhexyl) - 1 - (3 - hydroxy 4,4 - dimethyl - 5 - phenylpentyl)hydantoin as a viscous pale yellow oil.

This ester was added to a mixture of 2N-sodium hydroxide (25 ml) and water (60 ml) and the resulting cloudy solution 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 - (6 - carboxyhexyl) - 1 - (3 hydroxy - 4,4 - dimethyl - 5 - phenylpentyl)hydantoin as a colourless viscous oil which solidified, m.p. ca. 1150C, shrinking from ca. 90"C being a mixture of diastereomers. Recrystallisation several times from a mixture of ethyl acetate and light petroleum (b.p. 60--80"C) gave one of the diastereomers as small needles, m.p. 135--1370C.

Reference Preparation 2 Preparation of 5-(6-Carboxyhexyl)- I -(3-hydroxyoctyl)hydantoin A. Diethyl 2-(3-tetrahydropyran-2-yloxy)octylamino)nonanedioate Dry ethereal hydrogen bromide, prepared from ether (200 ml) and hydrogen bromide (26.8 g) at OOC, was added dropwise to a stirred solution of acrolein (19.15 g) in ether (100 ml) cooled to -25"C. The stirred mixture was kept at this temperature for I hour, allowed to come to OOC, stirred for 1 hour, at OOC and then added dropwise to ethereal pentyl magnesium bromide (prepared from 1 bromopentane (54 g) magnesium (8.8 g) and ether (120 ml)), maintaining constant reflux. The reaction mixture was decomposed with saturated aqueous ammonium chloride and extracted with ether, and the dried extract was concentrated and distilled, giving l-bromo-3-hydroxyoctane as a coloureless oil, b.p.

68.S72.50C/0.08 mm. A solution of this bromo-alcohol (20.9 g) in dihydropyran (17.0 g), was treated with p-toluenesulphonic acid (500 mg) in a little ether, set aside at room temperature for 18 hours, and washed with aqueous sodium bicarbonate. The organic layer was percolated through silica in 1:9 ether/hexane and the solvent was removed in "acuo, giving l-bromo-3-(tetrahydropyran-2 yloxy)octane as a colourless oil, 80.88 (3H, triplet, -CR3) and 4.62 (1H, broad, mO-cHR). A solution of this tetrahydropyranyl intermediate (15.0 g) and diethyl 2-aminononanedioate (13.0 g) in absolute ethanol (l00ml) was refluxed for 18 hours, the ethanol was removed in vacuo, and the residue was diluted with water containing a slight excess of sodium carbonate. The mixture was extracted with dichloromethane. the extract was dried over sodium sulphate and evaporated, and the residue was purified by column chromatography on silica in 1:4 hexane/ether, giving diethyl 2 - (3 - (tetrahydropyran - 2 - yloxy)octylamino)nonanedioate as a colourless viscous oil, b0.88 (3H, triplet -CH3), 2.28 (2H, triplet, -CH2-CO2Et), 2.61 (2H, multiplet, -CH2-N), 3.20 (IH, triplet, N-CHR-CO2Et), 4.13 (4H, multiplet, 2x-O-CH2-C113), 4.60 (IH, broad -O-CHR-O-).

The above aminodiester was alternatively prepared in the following manner.

Diethyl 2-aminononanedioate (10.40 g) and oct-l-en-3-one (5.04 g) were mixed slowly at OOC. with stirring, and set aside at room temperature for 3 hours, giving diethyl 243-oxooctylamino)nonanedioate as a colourless oil, b2.3 (4H, multiplet, --CH,CO,Et and NCH2CH2CO), 3.16 (1H, triplet, EtO2C-CHR-N), 4.11 (2H, quartet, --OO-CH,CH,), 4.17 (2H, quartet, -O-CH2-CH3). A stirred soluton of this ketone (13.5 g) in absolute ethanol (140 ml) was treated dropwise at 0 C with sodium borohydride (665 mg) in absolute ethanol (70 ml), then kept for 3z hours at room temperature, and concentrated at 400C in vacuo. The residue, dissolved in water, was brought to pH5 with N-hydrochloric acid and extracted thoroughly with chloroform, the extract was washed with water, dried, and evaporated, giving diethyl 2-(3-hydroxyoctylamino)nonanedioate as a colourless oil. Without further purification, the latter was dissolved in dihydropyran (14.0 ml), treated with ether (10 ml) followed byp-toluenesulphonic acid (6.72 g) in portions, and set aside at room temperature for 18 hours. The reaction solution was diluted with ether, washed with aqueous sodium carbonate then water, dried, and evaporated, and the residue was purified by column chromatography on silica in 1:4 hexane/ether, giving diethyl 2 - (3 - (tetrahydropyran - 2 yloxy)octylaminno) - nonanedioate identical (n.m.r., i.r. mixed t.l.c.) with that prepared previously.

B. 5 - (6 - Carboxylhexyl) - I - (3 - (tetrahydropyran - 2 - yloxy)octyl hydantoin To a solution of diethyl 2 - (3 - (tetrahydropyran - 2 - yloxy)octylamino)nonanedioate (7.8 g) in ethanol (32 ml) was added a solution of potassium cyanate (-3.0 g) in water (6 ml). The resulting suspension was stirred and cooled during the gradual addition of 2N-hydrochloric acid (16.7 ml). The solution was allowed to stand at room temperature for 22 hours, most of the ethanol was evaporated, water was added, and the insoluble oil was extracted with ether. The ether solution was washed with water, dried over magnesium sulphate, and evaporated. The yellow oil so obtained (8.0 g) was dissolved in light petroleum (b.p. 6809C) and the solution was refluxed for 4 hours, evaporated to dryness, and the residual oil was heated on the steambath for 2 hours to give 5 - (6 - ethoxycarbonylhexyl) - 1 - (3 - tetrahydropyran-2-yloxy)octyl-hydantoin as a yelow oil (7.3 g) which was used without further purification.

A solution of the ester (6.2 g) in 0.5N-sodium hydroxide solution (80 ml) was allowed to stand at room temperature for 22 hours after which the solution was washed with ether, the aqueous layer was acidified with 2N-hydrochloric acid, and the precipitated oil was extracted with ether. The washed and dried ether extract was evaporated to give 5 - (6 - carboxyhexyl) - I - (3 - tetrahydropyran - 2 yloxy)octyl)hydantoin as a yellow oil.

C. 5-(6-Carboxyhexyl)-l-(3-hydroxyoctyl)hydantoin This tetrahydropryanyloxy compound (3.55 g) was dissolved in tetrahydrofuran (28 ml) and SN-hydrochloric acid (7 ml) and the solution was left at room temperature for 3T hours, and then refluxed for 30 minutes. Most of the solvent was evaporated, water was added and the insoluble oil was extracted with ether. The ether solution was washed with water, dried over magnesium sulphate and evaporated to give 3.15 g) of viscous yellow oil. The oil was purified by chromatography on a column of silica gel, elution first with chloroform and then with a mixture of chloroform and methanol (19:1) giving 5 - (6 - carboxyhexyl) 1 - (3 - hydroxyoctyl)hydantoin as a very viscous almost colourless oil, a0.89 (3H, triplet, --CH,), 2.34 (2H, triplet, -CH2-CO2H), 2.9--4.2 (4H, complex, -CH2-N, CH-OH), ca.5.6(2H, broad, exchangeable, -CO2H, -OH), ca. 9.0 (1H, broad, exchangeable, NH).

Using the method of Reference Preparation 1 the above identified hydantoin was also prepared via the corresponding diethyl 2 - (3 hydroxyoctyl)amino)nonanedioate.

D. Separation of Diastereomers The hydantoin resulting from the above described preparations was a viscous oil which by use of HPLC on a column of silica with a mixture of chloroform, methanol and acetic acid (97:2.5:0.5) as solvent was separated into two diastereomers, both of which formed small colourless needles of m.p. 76--780C and 63v5 C respectively.

The same diastereomers were prepared by cvclisation of the corresponding diastereomers of formula (III). That is, the mixture of diastereomers of diethyl 2 ((3 - hydroxyoctyl)amino)nonanedioate. prepared as in Reference Preparation I was dissolved in ethanol and an ethereal solution of hydrogen chloride was added.

The solution was evaporated to dryness to leave the mixture of diastereomeric hvdrochlorides as a viscous oil, which partly solidified on standing. Ether was added and the mass stirred and cooled to give a crystalline solid, which was collected, washed with ethcr, and dried. The solid was crystallised from ethyl acetate to give small colourless plates, m.p. 9596.5 , of a pure hydrochloride.

This salt was suspended in dilute sodium hydroxide solution and shaken with ether, and the separated ether solution was washed, dried and evaporated to give one of the diastereomers (A) of diethyl 2-((3-hydroxyoctyl)amino)nonandioate as a colourless oil.

The ether filtrate remaining after collection of the original solid hydrochloride was evaporated to leave an oily hydrochloride, which was converted to base as described above to give the almost pure second diastereomer (B) of diethyl 2 ((3 - hydroxyoctyl)amino)nonanedioate as a colourless oil.

Bv the method described in Reference Preparation 1, the above diastereomer (A) was converted into a single diastereomer of 5 - (6 - carboxyhexyl) - 1 - (3 hydroxyoctyl)hydantoin, which crystallised from a mixture of ethyl acetate and light petroleum (b.p. 6080 ) as small colourless needles m.p.). 6365 .

Similarly the above diastereomer (B) was converted into the second diastereomer of 5-(6-carboxyhexyl)- l-(3-hydroxyoctyl)hydantoin, which crystallised from ethyl acetate light petroleum (b.p. 6080 ) as small colourless needles, m.p. 7678 .

E. Interconversion of the diatereomers A solution of 5 - (6 - carboxyhexyl)- 1 - (3 - hydroxyoctyl)hydantoin (diastereomer of m.p. 7678") (100 mg) in N-sodium hydroxide solution (3 ml) was allowed to stand at room temperature for 19 hours. The solution was acidified and extracted with ether, and the ether extract was washed with water, dried and evaporated to leave a viscous oil. By means of high performance liquid chromatography this oil was separated into the two diastereomers of 5-(6 carboxyhexyl)-1-(3-hydroxyoctyl)hydantoin, m.p. 76--78"C identical with the starting material (ca. 40 mg) and m.p. 63650C (ca. 40 mg) identical with the diastereomer (A) described above.

In similar fashion, the diastereomer of m.p. 63--65"C was converted into a mixture of approximately equal quantities of itself with the diastereomer of m.p.

76-780C, and the pure diastereomers were isolated by means of high performance liquid chromatography.

Examples 1 to 14 By a series of reactions analogous to that described in the preceding Reference Preparations and using the appropriate vinyl ketones starting materials, were prepared: la) diethyl 2 - (3 - oxo - 5 - methylhexyl)aminononanedioate; 2a) diethyl 2 - (3 - oxo - 3 - (p - tolyl)propyl)aminononanedioate: 3a) diethyl 2-(3 - oxo - 4 - cyclopentylbutyl)aminononanedioate; 4a) diethyl 2 - (3 - oxo - 3 - (4 - chlorophenyl)propyl)aminononanedioate; Sa) diethyl 2 - (3 - oxo - 3 - (4 - methoxyphenyl)aminononanedioate: 6a) ethyl 2 - (3 - oxo - 3 - cyclohexylpropyl)amino - 6 ethoxycarbonylmethoxyhexanoate; 7a) diethyl 2- (3 - oxo - 5*5 - dimethylhexyl)aminonon - 4Z- enedioate: 8a) diethyl 2 - (3 - oxo - 3 - cyclopentylpropvl)aminonon - 4Z - enedioate: 9a) diethyl 2 - (3 - oxo - 3 - cyclohexylpropyl)aminonon - 4E - enedioate: 10a) diethyl 2 - (3 - oxo - 4 - cyclopentylbutyl)aminonon - 47 - enedioate: l la) diethyl 2 - (3 - oxo - 5 - cyclopentylpentyl)aminonon - 4Z - enedioate: 12a) ethyl 2 - (3 - oxo - 3 - cyclohexylpropyl)amino - 6 ethoxycarbonylmethoxyhex - 2Z - enoate; 13a) ethyl 2 - (3 - oxo - 3 - cyclohexylpropyl)amino - 6 ethoxycarbonylmethoxyhex - 2E - enoate; and 14a) diethyl 2 - (3 - oxo - 3 - cyclohexylpropyl)aminonon - 4 - ynedioate; which were converted to the corresponding: lb) diethyl 2 - (3 - hydroxy - 5 - methylhexyl)aminononanedioate; 2b) diethyl 2 - (3 - hydroxy - 3 - (p - tolyl)propyl)aminononanedioate; 3b) diethyl 2 - (3 - hydroxy - 4 - cyclopentylbutyl)aminononanedioate: 4b) diethyl 2 - (3 - hydroxy - 3 - (4 - chlorophenyl)propyl)aminonononedioate: Sb) diethyl 2-(3-hydroxy-3-(4-methoxyphenyl )propyl)aminonononedioate: 6b) ethyl 2 - (3 - hydroxy - 3 - cyclohexylpropyl)amino - 6 ethoxycarbonylmethoxyhexanoate: 7b) diethvl 2 - (3 - hydroxy - 5,5 - dimethylhexyl)aminonon - 4Z - enedioate: 8b) diethyl 2 - (3 - hydroxy - 3 - cyclopentylpropyl)aminonon - 4Z - enedioate; 9b) diethyl 2 - (3 - hydroxy - 3 - cyclohexylpropyl)aminonon - 4 - enedioate: 10b) diethyl 2 - (3 - hydroxy - 4- cyclopentylbutyl)aminonon - 4Z - enedioate: 11b) diethyl 2 - (3 - hydroxy - 5 - cyclopentylpentyl)aminonon - 4Z enedioate: l2b) ethyl 2 - (3 - hydroxy - 3 - cyclohexylpropyl)amino - 6 ethoxycarbonylmethoxyhex - 2Z - enoate; l3b) ethyl 2 - (3 - hydroxy - 3 - cyclohexylpropyl)amino - 6 ethoxvcarbonylmethoxyhex - 2E - enoate; and 14b) diethyl 2 - (3 - hydroxy - 3 - cyclohexylpropyl)aminonon - 4 ynedioate; from which were obtained the desired hydantoins as a mixture of diastereomers which were separated where possible to provide the individual diastereomers having the stated melting point(s): Ic) 5 - (6 - carboxyhexyl) - 1 - (3 - hydroxy - 5 - methylhexyl)hydantoin, 100-101 , 102-103 C; 2c) 5 - (6 - carboxyhexyl) - I - (3,3 - hydroxy-(p - tolyl)propyl)hydantoin, 3c) 5 - (6 - carboxyhexyl) - 1 - (3 - hydroxy - 4 cyclopentylbutyl)hydantoin, 101-104 75-78 ; 4c) 5 - (6 - carboxyhexyl) - 1 - (3 - hydroxy - 3 - (4 - chlorophenyl)propyl)hydantoin, 93940, 101-102 ; 5c) 5-(6-carboxyhexyl) - 1 - (3 - hydroxy - 3 - (4 methoxyphenyl)propyl)hydantoin, 93-942, 102-103 ; 6c) 5 - (4-carboxymethoxybutyl) - I - (3 - hydroxy - 3 cyclohexylpropyl)hydantoin, 88-94 7c) 1 - (3 - hydroxy - 5,5 - dimethylhexyl) - 5 - (6 - carboxyhex - 2Z enyl) - hydantoin, 66-71 , 148-150 ; 8c) 1 - (3 - hydroxy - 3 - cyclopentylpropyl) - 5 - (6 - carboxyhex - 2Z enyl)hydantoin, 74-76 , 105-107 ; 9c) I - (3 - hydroxy - 3 - cyclohexylpropyl) - 5 - (6 - carboxyhex - 2E enyl)hydantoin, 60-63 ; l0c) I - (3 - hydroxy - 4 - cyclopentylbutyl) - 5 - (6 - carboxyhex - 2Z enyl)hydantoin, 114-116 ; l lc) I - (3 - hydroxy - 5 - cyclopentylpentyl) - 5 - (6 - carboxyhex - 2Z enyl)hydantoin, 100102 , 7--78"; 12c)l - (3 - hydroxy - 3 - cyclohexylpropyl) - 5 - (4 - carboxymethoxybut 2Z - enyl)hydantoin, each diastereomer a colourless glass; 13c) 1 - (3 - hydroxy - 3 - cyclohexylpropyl) - 5 - (4 - carboxymethoxybut 2E - enyl)hydantoin, 97-101 ; and 14c) I - (3 - hydroxy - 3 - cyclohexylpropyl) - 5 - (6 - carboxyhex - 2 ynyl)hydantoin, 84-86 , 147-148 ; Example 15 Preparation of 5-(6-carboxyhexyl)- 1 -(3-hydroxy-3-cyclohexylbutyl)hydantoin A solution of 3-cyclohexylprop-l-en-3-one (6.9 g) in dry ether (10 ml) v as cooled to 0 and stirred during the addition of a solution of hydrogen bromide (4 g) in ether (20 ml), after which the solution was allowed to stand in the refrigerator overnight.

This bromo-ketone solution was added gradually at room temperature to a stirred solution of methyl magnesium iodide (prepared from magnesium (1.5 g and methyl iodide (8.5 g) in dry ether (35 ml)). After a further 22 hours stirring. the mixture was poured into a cold solution of ammonium chloride (5 g) in water (50 ml). The mixture was filtered and the ether layer was separated, dried and evaporated. Distillation of the residue gave 4 - bromo - 2 - cyclohexylbutan - 2 ol (5.6 g). b.p. 86-88 /0.04 mm, m.p. 3133 .

A mixture of the foregoing bromo-alcohol (4.9 g) and diethyl 2aminononanedioate was heated at 100" for 4 hours. The mixture was basified with dilute sodium hydroxide solution and the insoluble oil was extracted with ether.

The ether extract was dried and evaporated to give diethyl 2 - ((3 - hydroxy - 3 cyclohexylbutyl)aminononanedioate (8.4 g) as an oil which was used without further purification.

By treatment of this amino-diester with cyanic acid, followed by alkaline hydrolysis of the hydantoin ester so produced, as described in Reference Preparation 1 D, was prepared 5-(6-carboxyhexyl)- 1 -(3-hydroxy-3-cyclohexyl- butyl)hydantoin which was separated as described in Reference Preparation 2 D, into diastereomers of m.p. 173174 and m.p. 109111 .

Example 16 Preparation of 5-(6-Carboxyhexyl)- 1 -(3-cyclohexyl-3-oxopropyl)hydantoin Reaction of diethy

Example 22 Preparation of 5-(6-carboxyhexyl )- 1 (3-(4-hydroxyphenyl)propyl)hydantoin This compound, m.p. 107-l080C, was prepared by a method analogous to that used in Reference Preparation 2 only using the appropriate alkylhalide, rather than vinylketone, to prepare the intermediate diethyl 2 - (3 - (4 hydroxyphenyl)propyl)aminononanedioate.

Example A Inhibition of Platelet Aggregation Aggregation of platelets in I 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 37"C for 1 minute after which platelet aggregation was stimulated by the addition of adenosine diphosphate (ADP) to a concentration of 5 uM.

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 - (6 - carboxyhex - 2Z - enyl - I - (3 cyclohexyl - 3 - hydroxypropyl)hydantoin were tested in this way and the latter was found to be about 20 to 25 times more potent than PRE1.

In the following Examples the "Compound" is 5-(6-carboxyhex-2Z-enyl)-1-(3cyclohexyl-3-hydroxypropyl)hydantoin.

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 I ug/mol Injection Compound 100 ug Water for Injection to . 100 ml Dissolve the Compound in the Water for Injection. Sterilise the solution by filtration through a membrane filter, 0.22 Nm pore size, collecting the filtrate in a sterile receiver. Under aseptic conditions, fill the solution into sterile glass ampoules, I ml per ampoule. Seal by fusion of the glass.

Example E 10 ug/ml Injection Compound I 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 am 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.

WHAT WE CLAIM IS: 1. 5 - (6 - Carboxyhexyl) - I - (3 - hydroxy - 5 - methylhexyl)hydantoin.

2. 5 - (6 - Carboxyhexyl) - 1 - (3 - hydroxy - 3 - (p - tolyl)propyl)hydantoin.

3. 5 - (6 - Carboxyhexyl) - I - (3 - hydroxy - 4 - cyclopentylbutyl)hydantoin.

4. 5 - (6 - Carboxyhexyl) - 1 - (3 - hydroxy - 3 - (4 chlorophenyl)propyl)hydantoin.

5. 5 - (6 - Carboxyhexyl) - 1 - (3 - hydroxy - 3 - (4 methoxyphenyl)propyl)hydantoin.

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

7. 5 - (6 - Carboxyhexyl) - 1 - (3 - hydroxy - 3 - (p biphenylyl)propyl)hydantoin.

8. 5 - (6 - Carboxyhexyl) - 1 - (3 - hydroxy - 3 - (4 dimethylaminophenyl)propyl)hydantoin.

9. 5 - (6 - Carboxyhexyl) - 1 - (3 - hydroxy - 3 - (4 hydroxyphenyl)propyl)hydantoin 10. 5 - (6 - Carboxyhexyl) - 1 - (3 - hydroxy - 3 - (4 - nitrophenyl)propyl)hydantoin.

11. 5 - (4 - Carboxymethoxybutyl) - I - (3 - hydroxy - 3 cyclohexylpropyl)hydantoin.

12. 5 - (6 - Carboxyhex - 2Z - enyl) - 1 - (3 - hydroxy - 5,5 dimethylhexyl)hydantoin.

13. 5 - (6 - Carboxyhex - 2Z- enyl) - I - (3 - hydroxy - 3 cyclopentylpropyl)hydantoin.

14. 5 - (6 - Carboxyhex - 2E - enyl) - 1 - (3 - hydroxy - 3 cyclohexylpropyl)hydantoin.

15. 5 - (6 - Carboxyhex - 2Z - enyl) - 1 - (3 - hydroxy - 4 cyclopentylbutyl)hydantoin.

16. 5 - (6 - Carboxyhex - 2Z - enyl) - 1 - (3 - hydroxy - 5 cyclopentylpentyl)hydantoin.

17. 5-(4-Carboxymethoxybut - 2Z - enyl) - 1 - (3 - hydroxy - 3 cyclohexylpropyl)hydantoin.

18. 5 - (4 - Carboxymethoxy - but - 2E - enyl) - I - (3 - hydroxy - 3 cyclohexylpropyl)hydantoin.

19. 5 - (6 - Carboxyhex - 2 - ynyl) - I - (3 - hydroxy - 3 cyclohexylpropyl)hydantoin.

20. 5 - (6 - Carboxyhexyl) - I - (3 - cyclohexyl - 3 - oxopropyl)hydantoin.

21. 5 - (6 - Carboxyhexyl) - 1 - (2 - hydroxycycloheptylmethyl)hydantoin.

22. 5 - (6 - Carboxyhexyl) - I - (3 - (4 - hydroxyphenyl)propyl)hydantoin.

23. The diastereomer of a compound claimed in any preceding claim which diastereomer is shown to be the less polar by thin layer chromatography using silica gel and a solvent system of chloroform:methanol:acetic acid in the proportions of 90:5:5 v/v/v.

24. A pharmaceutical composition comprising a compound according to any preceding claim in association with a pharmaceutically acceptable carrier.

25. A composition as claimed in claim 24 wherein the carrier is a liquid.

26. A composition as claimed in claim 24 or 25 in the form of a sterile injectable solution.

27. A composition as claimed in claim 26 comprising from 0.001 to 100,ug of a compound of formula (I) per millilitre.

28. A composition as claimed in claim 24 or 25 in the form of a unit dose comprising from 0.01 to 1 mg of a compound of formula (I). 29. A composition as claimed in claim 24 or 25 wherein the carrier is a solid.

30. A composition as claimed in claim 24. 25 or 29 in the form of a unit dose.

31. A composition as claimed in claim 24. 25, 29 or 30 in the form of tablet, capsule. cachet or suppository.

32. A composition as claimed in claim 30 or 31 comprising from 0.1 to 50 mg of a compound of formula (I).

33. A method of preparing a compound according to any of claims 1 to 22

**WARNING** end of DESC field may overlap start of CLMS **.

Claims

**WARNING** start of CLMS field may overlap end of DESC **. Sterilise the solution by filtration through a membrane filter, 0.22 am 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. WHAT WE CLAIM IS:

1. 5 - (6 - Carboxyhexyl) - I - (3 - hydroxy - 5 - methylhexyl)hydantoin.

2. 5 - (6 - Carboxyhexyl) - 1 - (3 - hydroxy - 3 - (p - tolyl)propyl)hydantoin.

3. 5 - (6 - Carboxyhexyl) - I - (3 - hydroxy - 4 - cyclopentylbutyl)hydantoin.

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

9. 5 - (6 - Carboxyhexyl) - 1 - (3 - hydroxy - 3 - (4 hydroxyphenyl)propyl)hydantoin

10. 5 - (6 - Carboxyhexyl) - 1 - (3 - hydroxy - 3 - (4 - nitrophenyl)propyl)hydantoin.

20. 5 - (6 - Carboxyhexyl) - I - (3 - cyclohexyl - 3 - oxopropyl)hydantoin.

21. 5 - (6 - Carboxyhexyl) - 1 - (2 - hydroxycycloheptylmethyl)hydantoin.

22. 5 - (6 - Carboxyhexyl) - I - (3 - (4 - hydroxyphenyl)propyl)hydantoin.

25. A composition as claimed in claim 24 wherein the carrier is a liquid.

28. A composition as claimed in claim 24 or 25 in the form of a unit dose comprising from 0.01 to 1 mg of a compound of formula (I).

29. A composition as claimed in claim 24 or 25 wherein the carrier is a solid.

30. A composition as claimed in claim 24. 25 or 29 in the form of a unit dose.

33. A method of preparing a compound according to any of claims 1 to 22

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, Z1 and Z2 has the same meaning as in formula (I), as hereinbefore defined.

34. A method of preparing a compound according to any of claims 1 to 22 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), as hereinbefore defined.

35. A method of preparing a compound according to any of claims 1 to 22 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), as hereinbefore defined.

36. A method of preparing a compound according to any of claims 1 to 22 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, Jl is hydrogen or Zl, J2 is hydrogen or Z2 and J3 is alkyl, Zl or Z2 provided that one of J, J' and J2 is hydrogen and J3 does not have the same value as J, Jl or J2: in the definition of Jl, J2 and J3 each of Zl and Z2 has the same meaning as in formula (I), as hereinbefore defined.

37. A method of preparing a compound according to any of claims I to 22 comprising reduction of a compound of formula (XI)

wherein either Z3 is =CR-CH2-Y1-Y2-Y3 and Z4 is -CH2-X-X1-X or Z3 is =C11-X-X1-X2 and Z4 is -Y-Y-Y-Y in which each of R. X to X2, Y to Y3 and Z is as defined in formula (I), as hereinbefore defined.

38. A compound according to any of claims I to 22 when prepared by a process defined by any of claims 33 to 37.

39. 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 according to any of claims 1 to 22.

40. A method for the treatment of prophylaxis of thrombosis in a mammal or mammalian tissue. excluding human, which comprises administration of a nontoxic, effective antithrombotic amount of a compound according to any of claims 1 to 22.

41. 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 according to any of claims 1 to 22.

42. A method for inducing bronochodilation in a mammal, excluding man, comprising administration to said mammal of a non-toxic, effective bronchodilatory amount of a compound according to any of claims 1 to 22.

43. A method as claimed in any of claims 39 to 42 wherein the compound is administered at a daily dose of from 1 Elg to 20 mg per kilogram of the mammal.

44. A method as claimed in any of claims 39 to 42 which comprises an intraveneous infusion of the compound.

45. The preparation of a compound according to any of claims 1 to 22 by a method substantiallv as hereinbefore described with particular reference to Examples I to 22.