CA1176261A - Hydantoin derivatives - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

Hydantoins and N-alkylhydantoins of formula (I) (I) Wherein Z is hydrogen or alkyl; one of Z1 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 or the two Q's together form an alkylene radical having four, five or six carbon atoms;
X1 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 Z1 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; Y1 is carbonyl, methylene, methylene substituted by hydroxy or methylene substituted by hydroxy and alkyl; Y is a covalent bond or a straight or branched alkylene having 1 to 7 carbon atoms, unsubstituted or substituted on the carbon adjacent Y1 by one or two groups independently selected from alkyl, bicycloalkyl and cycloalkyl;
Y is hydrogen, hydroxy, alkoxy having 1 to 7 carbon atoms, cycloalkyl, bicycloalkyl, phenyl, benzyl, phenoxy or benzyloxy, wherein each of phenyl, benzyl, phenoxy and benzyloxy is unsub-stituted or substituted in the benzene ring by one or more groups selected from hydroxy, halo, nitro, amino, acyl-amino, alkenyl, alkoxy, phenyl and alkyl which may itself be substituted by one or more halo groups; or Y is a bond, -CH2- or -CH2-CH2- and Y1, Y2 and Y taken together form a cycloalkyl group substituted by a hydroxy group, and salts thereof; have biological properties related to those of natural occurring prostaglandins and may be used in medicine, for example, in the treatment of thrombosis.

Description

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This invention relates to heterocyclic compounds, their synthesis, compositions containing them, and their use in medicine.
Hydantoin derivatives, defined hereinbelow in formula ~I), have been found to have pharmacological properties related to those of natural prostaglandins, as demonstrated by their ability to mimic or antagonise the physiological effects of the natural prostaglandins in various biological preparations. In particular, certain compounds of formLla (I) have been found to be potent mimmetics of the anti-platelet aggregatory prDperties of prostaglandin El.
In formula (I) zl ~ (I) Z - N
N \

O Z ,.

Z is hydrogen or alkyl; one of zl and z2 is represented by the group -CH2-X- ~-X2 wherein X is phenylene, -C~C-, cis or trans -CH-CH- or -CH2-CQ2- in which each Q is independently selected rom 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 car~on atcms optionally haYing one of its methylene g`roups replaced by oxa(-O-) provided that at least one carbon atom separates the oxa group from a -C5C-, -CH=CH- or -CO- group; and x2 is selected ,~ ~

from carboxyl, carbamoyl, hydrox~thyl and aLkoxycarbonyl;
and the other of zl and z2 is represented by the group _y_yl_y2_y3 wherein Y is -CR2-CH2- in which each R is independently selected from hydrogen and methyl; yl is carbonyl, methylene, methylene substituted by hydroxy or methylene substituted by hyd-oxy and alkyl; y2 is a covalent bond or straight or branched aIkylene having 1 to 7 carbon atoms optionally substituted on the carbon adjacent yl by one or two groups independently selected from alkyl, bicycloalkyl and cycloalkyl; Y3 is hydrogen, hydroxy, alkcxy having 1 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, halo, nitro, anino, acylamino, alkenyl, alkoxy, phenyl and aLkyl which may itself be substituted by one or more halo groups; or Y is a bond, -CH2-, or -CH2.CH2- and yl~ ~ and Y3 taken together from a cycloalkyl group substituted by a hydroxy group which preferably has three carbon atoms separating it from the hydantoin ring.
This inyel~tion is particularly concerned with compounds of formula (I) in which Z is hydrogen.
Unless otherwise stated, in formLla (I) and other formwlae in this specification, aIkyl moieties are selected from methyl, ethyl, propyl, butyl, pentyl and hexyl, including all ~somers thereof.

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~or example, in the definitions of yl and y2 the alkyl groups are preferably methyl; and the alkyl moiety of aIkoxy-carbonyl is desirably ~ethyl or ethyl. Similarly aikenyl groups h~ve 2 to 4 carbon atoms for example vinyl.
In formuIa (I~ cycloalkyl groups have 3 to 10 carbon atoms and bicycloalkyl groups have 4 to 10 carbon atoms for example adamantyl~
In a ccmpound of formula (I) the bonding of the divalent phenylene group may be ortho, meta or para, and the oxa group is preferably adjacent the phenylene or when X is other than pheny-lene then ~ may be -CH2-0-CH2 .
Included in the meaning of compounds of formula (I) are the salts corresponding to the carboxylic acids when x2 is carkQxyl, and the salts which may also be formed when Z is hydro-~en. Particul æly valuable salts for medical purposes are those having a ph ænaceutically acceptable cation such as ammonium or that of an alkali metal eg. sodium and potassium, and alkaline earth metal eg. calcium and magnesium, or an organic base, particularly an amine such as ethanolamine. Salts having non-pharmaceutically acceptable cations are included within the ambit of this invention as useful intermediates to pharmaceutically acceptable salts, or the acids or esters of forn~la (I).
Except when there is cl~r indication to the contrary, formLla (I) and other formLlae in the specification embrace all stereoisomers represented therein. In particulæ such formNlae include the enantiomeric fo~ms, such mix*ures as are designated racemates, and diastereoisomers.

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It has been found that the class of co~pounds within fonmlla (I) wherein Z is hydrogen; one of zl and z2 is -CH2-X-~-X wherein X and X taken together form alkylene of 3 to 7 in particular 5 carbon atoms, and ~ i5 alkoxycarbonyl, carboxyl or a salt thereof; and the other of zl and z2 is _y_yl_y2_y3 wherein y, yl and y2 are as hereinbefore defined and Y3 is hydrogen, cycloaLkyl of 4 to 7 carbon atoms, phenyl or benzyl;
have particularly interesting prostaglandin-related properties.
~ithin this definition are included the subclass wherein Z is hydrogen and zl is -CH2-X-~ x2 as defined. The corresponding class of compounds within formula (I) in which Z is alkyl having 1 to 4 carbon atoms, for example methyl or butyl also have parti ularly interesting prostaglandin-related properties.
~ he compounds of formula (I) may be synthesised by any method known in the art for the synthesis of compounds of analogous structure. For example, they may be prepared from the corresponding derivatives of hydantoic acid of formula (II) G ~Z

0 (II) wherein G is carboxyl or a deriyative thereof such as amlde or ester in particular an aIkyl ester, and each of z, zl and z2 has the same me~ling as in formula (I~, by cyclisation under acidic conditions or by heating alone. The reaction may be effected in ,.

7G~2'~

the absence of a solvent, but if desired an inert solve~t may be used, for example a hydrocarbon such as petrol. Alternatively, where G is aIkoxycarbonyl, cyclisati~n may be effected in the presence of a suitable base, for example an alkoxide such as sodium ethoxide.
Cbmpcunds of formula (II) are con~eniently prepared from an amino acid derivative of formLla (III) G
~ (III) HN \
z2 wherein G, zl and z2 are as defined in formula (I) provided that G may also be nitrile by reaction with cyanic acid or an alkyl l -cyanate depending respectively on whether Z is hydrogen or alkyl.
When cyanic acid is used, the cyanic acid is conven-iently produced Ln situ by the use of an aIkali metal cyanate, e.g.
potassium cyanate, and an acid which may be present as an acid addition salt of the comFound of formula (III) or a free acid of formNla (III) wherein either or both of R and X is hydrogen.
Alternatively an equivalent amount of mineral acid or an organic acid may be added to the reaction medium. m e reaction may proceed in the absence of a solvent but desirably an inert solvent is ~sed which is preferably polar such as water or a muxture of water with acetone dimethylfornamide, dimethylsulphoxide or a lower alkanol such as ethanol or it may be a hydrocarbon, an ether or halogenated hydrocarbon such as ~Ihloroform Where ,~` '3 ' '.~".~

lP7~Z~

desired, for example if no solvent is used, the reaction may be promoted by heating the reactants.
Similar reaction conditions may be used when an alkyl iso-cyanate is used except that it is unnecessa~y to pro~ide an equivalent amaunt of acid, as an acid addition salt or otherwise, in the reactants.
Instead of using a cyanate or isocyanate, a compound of formLla (III) may be reacted with urea, nitrourea or an N-alkylurea as appropriate. A solvent is not essential but if desired an inert solvent such as one mentioned above may be used, and the reaction is preferably effected at an elevated temperature, for example frcm 100 to 125C but temperatures up to 150 C may be employed.
In the above described synthesis, the intermediates of formula (II~ need not be isolated from the reaction mixture and may be converted directly to compounds of form~la (I) under the described reaction conditio~s.
An intermediate of formLla tIII) may be conveniently prepared by recaction of a compound of form~la (IV) with a compound of formula (V) G Z

¦ (IV) Q2_Z2 (V) Q
wherein G, Z and Z are as defined in formula (III~, one of Q
and Q is amino and the other is halo, preferably bromo. The .~7~%~

reaction may be carried out by heating in the absence of solvent or in the presence of an inert solvent suc-h as ethanol.
The intermediates of formula (III) wherein Z is -Y-Y -Y -Y3 when ~ is carbonyl may also be prepared by reaction of an amine of formNla (I~) wherein Ql is amino with an unsaturated ketone of formula (Vl) CR2-CH.CO.Y2,Y (Vl~
wherein y2 and ~ have the same meaning as in formula (III); the react~on being effected in the presence or absence of an inert solvent, and at room temperature or optionally with heating.
Hydantoins of formLla (I) may also be prepared by cyclisation of a compound of formLla (VII) O
1~ Zl Z - N ~ (VIn ll N 2 wherein Z, Zl an~ Z are as defined in form~la (I) and ~ is carboxyl or a reactive derivative thereof such as alkoxycarbonyl eg. ethoxycarbonyl. Compour~s of formLla tVII) may be cyclised under similar conditions as a compound of formula (II) and con-veniently the method used to prepare a compound of formula (VII) ~s chosen such that the preYailing reaction conditions permit spontaneous cyclisation~

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For example, the intermediates o~ form~la (VII) may be prepared by reaction a compound o~ formLla (V) with a compound of formula (VIII) O

Q2 z2 (V) ~ - N ~ (VIII) I 1 Ql wherein one of Ql and Q2 is halo, preferably chloro or brcm~ and the other is amino and each of z, zl, z2 and ~ have the same meaning as in formula (VII). The reaction may be effected by admixtNre of the reactants or optionally an inert solvent is used and the mixture is heated. Suitable solvents include alkanols, ethers, hydrocarbons and halogenated hydrocarbons.
The compounds of formula (VIII) may themselves be made by reacting an appropriate carbamic acid derivative, for example ~n alkyl ester, with a compound of formula (IV), using techniques known to those skilled in the art.
In a method related to those described hereinbefore, the hydantoins of form~la (I) may be prepared by reacting a compound ~.

A 49&
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of formula ~IX) O

~/
H (IX) H \ z2 wherein each of z, zl and z2 has the same meaning as in formula ~I~ with a carbonic acid derivative. Any carbonic acid derivative known to those skilled in the art as appropriate may be used, for example phosgene, diphenylcarbonate or an alkyl haloformate such as ethyl chloroformate. The reaction is desirably effected in the presence of a basej for example an amine such as triethylamine or di-iso-propyl ethylamine, and using an inert apro~ic solvent such as toluene, dimetllylformamide or an ether suc,h as diethylether. The reaction may be carried out at room temperature but if desired the reaction mixture may be heated.
The intermediates of formula ~IX~ may be made using methods analogous ~o those described above for the prepal^ation of compounds of formula (III).
The hydantoins of formula ~I3 wherein Z is alkyl may also be prepared by alkylation, using an alky]ating agent which may be designated as a reactive ester derivative of an alcohol J3.OH, of a compound of formula ~X) ~ ' J - N ~ CX3 O \~J2 ~ 8 7'6'~

~hcrcin J is hydrogell or alkyl, Jl is hydrogcn or 71, J2 is llydrogcn or z2 and J3 is al~yl, zl or ZZ, provided that one of J, Jl and J2 is hydrogell and J3 does not have the same value as J, Jl or J2; in thc definition of Jl, J2 and J3 each of zl and z2 has the same meaning as in formula (I). Suitable reactive ester dcrivatives incl.ude chloride, bromide, iodide and sulphonatcs SUC]I
as p-toluenesulphonate, mcthanesulphonate and benzenesulphonate.
The alkylation may be effected using reaction conditions which are known in the art to be suitable, for cxample in the presence of a ) base such as an alkalimetal hydride, al~ali metal amide, or alkali-metal alkoxide, typically sodium hydride or a sodium alkoxide eg.
sodium mcthoxide.
The reaction is conveniently carried out in an inert solvent which simply acts as a diluent for the- re~ctants SUC}l as toluene, dioxan, ether, di.met}lyl-formamide, te~rahydrofuran, dimethylsulphoxide or acetonitrile or when the base is an alkali metal alkoxide then the corresponding alkanol may be uscd.
It will be appreciated that the intermcdiates of formula (x) O where.in J is hydrogen are also compounds of formula ~I) and may be prcpared by one Or the foregoing methods. The compounds of formula (X) may furthcr be preparcd by adapta~ion of methods already kno~
in the art (see for example Chcmical Reviews (1950) 46, p. 403-425j.
furtller prcparation of compounds of formula (I) is by rcducti.o]l of a correspond.i.llg unsaturated compoulld of formula (XI) J~z .~176~631 N ~XI) \ z4 ~Therein eithcr Z3 is -CR-CH2-Yl-Y2-Y3 and Z4 is -Cll -X-Xl-X2 3 i C~l ~ Xl x2 alld Z4 is _~_yl_y2_y3 in which each of R, X to x2 and Y to Y3 is as defined in formula (I), with a suitablc reducing agent.
S A suitable reducing agent is stannous chloride whicll may be used as an aqueous solution optionally in the presence of dilute mineral acid or catalytic hydrogenation may be effected in the presence of for example Raney nickel, platinum, palladium, ruthenium or rhodium. Tlle choice of reducing agent in a given situation will O of course be dictated by the presence of other reactive groups in the molecule whic}l may themselves be susceptible to reduction.
Thc intermedia~es of formula (xI) may be prepared by t]le following series of reactions:
G~ ~ CH(OG )2 + G4 z4 G CH~oG3~2 I I
NH~ N\
z4 XII) O O
~ H* ~ C~l(oG3)2 ZN ~ ZN ~T

O z4 0 Z
(XIV) ~XIII) ~, ~ P~3P= Z3 (XI) ~ 1 the a~ove formLlae Z, Z3, Z4 and G have the same m~anings as in formulae (XI) and (III) respectively, G3 is alkyl for example n-butyl and G is halo such as bromo. The formation of (XIII) is analogous to the ring closure involving a compound of formMla (II) and compou~ds of formula (XIV), are prepared using concentrated mîneral acid such as hydrochloric acid.
If desired tetrazoles of foLmula (I) ~ay be prepared from corresponding compounds wherein the group _x2 is replaced b~ -C--N
~4 ~3 wherein X3 and X4 together form a bond (nitrile), X3 is hydrogen or aIkyl and X is alkoxy (imidoester), alkylthio (imidothioester), -NH-NH2 (amidrazone), or amino (amidine) or R is hydroxy and R4 is amino-(amidoxIme). me reaction is preferably carried out in a polar arpotic liquid medium such as dlmethylformamide using a salt of a hydrazoic acid eg. sodium azide. However, when x2 is replaced by an amidine or amidrazone, a suitable reagent is nitrous acid. If an amldine is reacted with nitrous acid then reduction of the intermldiate nitrosation product, with or without prior isolation, using for example sodium amalgam is required to give the corresponding tetrazole. me 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 formNla (I) wherein x2 is hydroxy-methylene ~ay also be obtained by reduction with an appropriate 1~7~

reducing aaent of the corresponding acid, ester, acid halide, acid anhydride or aldehyde. The appropriate reducing agent will depend on the particular substrate, but reactants which may be used are sodium in ethanol. In particular a carboxylic acid may for example be converted to a corresponding muxed anhydride with ethylchloroformate in the presence of a base such as triethyl-amune, and subsequently reduced to the alcohol using sodium boro-hydride. Similarly an ester may be reduced to the alcohol using di-iso-butyl aluminium hydride in an inert solvent such as ether or hydrocarbon such as hexane or benzene. Such alcohols may also be prepared by catalytic hydrogenation.
Alternatively the alcohols of formula (I) wherein x2 is hydro~ymethylene may be prepared by hydrolysis of a correspon-ding halide with an appropriate reagent. For this purpose a hydroxide may be used for example an aqueous alkali or a suspen-sion of silYer oxide in water.
In the synthesis of hydantoins of formula (I) having a hydroxyl group in a side chain it may be desirable to protect this during the course of the reaction. miS may be readily effected in known ~anner using a protecting group such as acyl, aroyl, tetrahydropyran-2-yl, l-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.

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Furthermore a ketone of formula (I) wherein ~ is c~rbonyl may be converted to the corresponding secondary alcohol by reduction with a suitable reducing agent, such as sodium borohydride Also, an alcohol of fornLla (I) wherein ~
is -CH.OH- may be oxidised to the corresponding ketone using Jones' reagent, acid dichromate or any other suitable reagent.
S~milarly where the campounds of formula (I) have a -C==C- or -CH==CH- bond these may be converted by conventional hydrogenation techniaues, for example using a Lindlar type or Adams catalyst, to the corresponding ethylenic or saturated campounds as appropriate.
me hydantoins of formula (I) have asymmetric 5-carbon atam, and a further asymmetric centre is present in those compounds wherein ~ includes a hydroxyl group. Such alcohols therefore exist as four isamers which are separable by thin layer chroma-tography or high performance liauid chromatography into two diastereomers, each ~f which is a racemic muxture of tWD isomers.
On separation of the diastereomers, one diastereamer may be converted to a mixture of the four isamers by treatment with a base, such as an aIkali metal hydroxide, and subsequently re-separated to pravide two diastereamers. ~epeated use of this technique enables the effectu~l conversion of one diastereomer to the other; this may be desirable when one diastereomer has a biological activity preferred to the other.
me correspond~ng alcohols of formula (III) also exist in four isam~ric forms. If desired, these may be separated into - 14 ~
I'~

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tw~ epimers and subsequent cyclisation to a ccmpound of formwla (I) retains the stereochemical config~ration.
In all of the forego~ng 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 hav~ng 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 prosta-glandins that is, the hydantoins mimic or antagonise the biologicaleffects of members of the prostaglandin (PG) 'A', 'B', 'C', 'D', 'E' and 'F' series. Fbr example, hydantoins of formLla (I) have been found to mimic the antiaggregatory effect of PGEl on blood platelets, and to antagonise the contraction induced by PGæ~ or PGF2 on smooth muscle taken from the rat stomach, rat colonr chick rectum and guinea pig trachea~ In general, antagonistic properties, as opposed to mimetic, have been observed when using larger doses of the hydantoins. The pharmacological profile, by which is meant the relative activities, mimetic or antagonistic, campared with the natural prostaglandins, will of course vary depending on the specific h~dantoin under consideration.
By reason of their prostaglandin-related properties, the hydantoins of formula (I) are useful in the pharmacological characterisation and differentiation of the biological activities of the natural prostaglandins and their 'receptors'. me further understanding of the physiological role of prostaglandins is of '~) 31~76~1 course v~ uable in the search for new and improved therapeutic substances.
The hydantoins of formula (I) are also of value as therapeutic agents. In particular hydantoins such as those described previously as having a potent anti-aggregatory effect on blood platelets æ e useful whenever it is desired to inhibit platelet aggregation or to reduce the adhesive character of plate-lets, and may be used to treat or prevent the formation of thrombi in nammals, including m~n. Fbr example, the co~pounds are useful 1~ in the treatment and prevention of myocardial infarcts, to treat and prevent thrombosis, to promote patency of vascular grafts following surgery, and to treat complications of arteriosclerosis and conditions such as atherosclerosis, blood clotting defects due to lipermia, and other clinical conditions in which the underlying aetiology is associated with lipid imbalance or hyperlipidemia. A further use for such ccmpounds is as an additi~e to blood and other fluids which are used in artificial extra-corporea~ circulation and pPrfusion of isolated body portions.

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USeflll iJI lowering blood pressure in mammals, including man., and may be used alone or in combination with a ~Gadrenoceptor b].ocking agent or another an~illypertellsive substance for the treatment of all grades OL hypertension including essential, malignant and secondary hypertension.
The compound 5-(6-carboxyhexyl)-1-(3-hydroxy-~,4-dimethyl-octyl)hydantoin also mimics the effect of PGE~ of antagonising histamine induced broncho-constriction. The hydantoins of formula (I) ha~ing this property ~.ay he used in the treatrnent or prophylaxis of bronchial asthma and bronchitis by alleviating the bronchoconstriction associated with this condition.
Hydantoins of formula (I), such as 5-(6-carboxyhexyl)-1-~(3-hydroxyoctyl~-hydantoin, 5-~6-carboxyhexyl)-3-methyl-1-(3-oxo-octyl)hydantoin, 5-(6-carboxyhexyl)-1-(3-oxo-octyl)hydantoin and 5-(S-carboxyhexyl)~ -phenoxybutyl)hydantoin, which inhibit pen'cagastrin-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 gastro-intestinal ulcer formation and accelerating the healing of such ulcers already present in the gastrointestinal tract whether such ulcers arise spontaneously or as a component of polyglandular adenoma syndromes.
Intravenous i.n~usions of certain hydantoins of for~nula (I), typically 5-(6-carboxyhe~yl)-1-(3-hydroxyoctyl)hydantoin, to dogs ha.s ~een found to increase urine volume indicating a potential ùtility :Eor such compoullds as diuretic agcnts, the uses of which A ~98 ~7G.26~

useful in lvl~ering blood pressure in mar~mals, including man, and may be used alone or in combination with a ~-adrenoceptor blocking agent or another an~ihyper~e]lsivc substance for the treatmen~ of all grades of hyper~ension including essential, malignant and secondary hypertension.
The compouncl 5-(6-carboxyhexyl)-1-~3-hydroxy-4,4-dime~hyl-octyl)hydantoin also mimics the effect of PGE~ of antagonising histamine induced broncho-constriction. The hydantoins of formula (I) having this property may be used in the treatTnent or prophylaxis of bronchial asthma and bronchitis by alleviating the bronchoconstric~ion associated with this con~ition.
Hydantoins of formula ~I), such as 5-(6-carboxyhexyl)-1-~3-hydroxyoctyl)-hydantoin, 5-~6-carboxyhexyl)-3-methyl-1-(3-oxo-octyl)hydantoin, 5-~6-carboxyhexyl)-1-(3-oxo-octyl)hydantoin and 5-~S-carboxyhexyl~ (4-phenoxybutyl)hydantoin, which inhibit pen'cagastrin-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 gastro-intestinal ulccr formation and accelerating tlle healing of such ~lcers already present in the gastrointestinal tract whether such ulcers arise spontaneously or as a component of polyglandular adenoma syndromes.
Intravenous in~usions of certain hydantoins of forrnula ~
typically 5-(6-carboxyhexyl)-1-(3-hydroxyoctyl)hydantoin, to dogs has been found to increase ur;ne volume indicating a potential ùtility for sllch compowlds as .liuretic agcnts, the uses of ~hich -17 _ ~ ~9~

~.~ 7f~
inc3.ude the treatment of oedema for example oedema associated with hcart failure, liver failure or kidney failure in man or other mammals.
A further use for hydantoins of formula (I) which mimic ~ 5 the uterine smooth muscle effects of PG~2 and PGF2a is as anti-`. fertility agents, in particular as abort;facients.
~ . The amount of a compound of formula tI) 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 dail.y dosc may be expected to lie in the range of . from 1 ~g to 20 mg per kilogram bodyweight. For example, an intravenous dose may lie in the range of from S ~g to 1 mg/kg which may conveniently be adminis~ered as an infusion of from 0.01 to 50 ~g per kilogram per minute. Infusion fluid~ suitable for this purpose may contain from 0.001 to 100, for example from 0.01 to 10 ~g per millititre. Unit doses may contain from 10 ~g to 100 mg of a ~ compound of formula (I), for example ampoules for injection may contain from 0.01 to 1 mg, and orally administrable uni.t dose .~ 20 formulations suc:l- as table~s or capsules may contain from 0.1 to 50, fo.r example 2 to 20 mg.
More spe_ifically, wnen a compound of formula (I) is used to inhibit piatelet aggregatioll i~ is generally desirable ~o achieve a concentrati.on in the appropriate liquid, whether it be the blooc~
of a patient or a perfusion fluid, of about 1 ~Ig to 10 mg, for e~-ampi ~ from 10 -ug tc 1 mg, per liter.

.

~ 498 G2~
1hc abovementioned doses refer to the acids, amides, esters, alcohols ancl tetra~o].es of formula (I); where a salt is used, the dose should be taken as referring to the corresponding anion.
For use in the treafment or prophylaxis Or the conditions rcferred to above, while the hydantoin compounds may be used as the raw chemical they are preferably presented with an acceptable carrier therefor as a pharmaceutical formulation. The carrier must of course be 'acceptable' in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. The carrier may be a solid or a liquid, and is preferably formulated with a hydantoin compound as a unit~dose formulation, for example a tablet, which may contain from 0.05'~ to 95~ by weight of the hydantoin compound. Other pharmacologica.lly active su.bstances may also be present in forr.1ulations of the present invention as indicated above. The nydantoin compound.s may be incorporated in the formulations either in the form of the acid or the salt or ester thereof, and the formulations may be prepared by any of the well-known techniques of pharmacy consisting essentially of admixtu-re of the components of the formulation.
The formulati.ons include those suitable for oral, rectal, topi.
(buccal - eg. sub-lingual), the parentcral ~that is subcutancous, in~ramuscular and intravenous) administration, altl1oug}1 the most suitahle rou~e in any given case lrill depend on the nature and severity of +he condit~on being treated, and on the nature of the _5 hydantcin compound 3L~7~iZ6~
FormulatioIIc suitable IOI` oral administration may be presented as discrete units such as capsules, cachets, lozenges or t~blets each con~aining a predetermined amount of hydantoin compound; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; as an oil-in-water emulsion; or as a water-in-oil liquid emulsion. Such formulations may be prepared by any o~
the methods of pharmacy but all methGds inc].ude the step of bringing into association the hydancoin compound with the carrier which constitutes one or more accessory ingredients. In general they are prepared by uniformly and intimately admixing the hydantoin comi~oun(-i with liquid or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation. For . example a tablet mzy be prepared by compression or moulding a powder or granules of the hydantoin compound~ optionally with one or more accessory ingredients. Compressed tablets may be prepared. by compressing, in a suitable machine~ the hydantoin compound in a free--~lowing form SUC]I as a powder or granules optional].y mixed wi.th a binder, lubricant, inert diluent, sur~ace active or dispersing aclellt~s Moul.ded tablets may be made by moulding in a suitable machine the powdered hydantoin compound moistened with an inert liquid diluent.
Formulation.s suitable for buccal (sub-li.ngual) administratio i.nclude lozenges compr;sing a hydan~oin compound in a fla~oured basis, usually sucrose and acacia or tragacan~h; a.nd pastil.les cemprisi.lig a hydantoin compound in an inert basis such as gelaLi.n ~5 and glycerin; or sucrose ancl acaci.a.

6~6~L

~ormulatiolls of the present invention suitable for parenteral administration conveniently comprise sterile aqueous preparations of a hydantoin compound, whicn preparations are preferably isotonic with the blood of the intended recipient. These preparations are preferably administered intravenously, although administration may also be effected by raeans of subcutaneous or intramuscular injection.
Such preparations may be conveniently prepared by admixing the hydantoin compound ~ith water and rendering thc product sterile and isotonic ~ith the blood.
Formulations suitable for rectal administration are pre~erably presented as unit-dose suppositories. These may be prepared by admixture of the hydantoin compound with one or more of the conventional solid carriers, for example cocoa butter, and shaping of the resulting mi~ture.
1~ It will be appreci~ted from ~he foregoing that ~hat we will claim may comprise any novel feature described herein, principally and not exclusively, for example:-(a) The novel compounds of formula (I) as hereinabove defined.
~b) A method for the preparation of the novel compounds of formula ~I) as hereinabove described.
~c) A pharmaceutical formulation comprising a compound of formula (I) in association with a pharmaceutically accep~able carricr therefor, alld methods for the preparation of such formulations (d3 A method for ]ol~Jering blood pressure in a mammal including man ~lhicll comprises admînistration to tlle mammal of an effect~ve ~ 8 ~7G;~il l~yl)otellsive, non-toxic amount of ~ compound of formula (I).
~e) A met}lod fGr the treatment or prophylaxis of throm~osis in a mammal or mammalian tissue, includi.ng human, which comprises administration of a non-toxic, effcctive anti-thrombotic amount of a compound of formula (I).
~) A method for i.nducing vasodilation in a mammal, including man, comprising administration to said mammal of a non-toxic effective vasodilatory amount of a compound of formula (I~.
~g) A method for the treatment or prophylaxis of gastric lesions in a mammal inc]uding man comprising administration to said mammal of a non-toxic effective prophylactic or therapeutic amount of a compound of formula ~I).
~h) A method ~or inducing bronchodilation in a mammal, including man, comprising administration to said mammal of a non-toxic, effective bronchodilatory amount of a compound of formula ~T~, (i) A method for the treatment or prophylaxis of an allergic condition in a mammal, including man, comprising adminis1:rati.0n to said mammal of a non-toxic effective prophylactic or therapeuti.c amount of a compound of formula (I).
~J) A method of inducing abortion of a foetus in a mammal including human comprising admirlistration to said mammal of a non-toxic effective abortifacien~ amount of a compound of formula (I).
~k) A mcthod of inducing infertility i.n a man~lal i.ncluding hulnan comprising administrati.on ~o said mammal of a non-toxic effective contraceptive amount of a compound of formula (I).

1176~1 (]) ~ compoulld of rormula 0 , J ~ J

~ \J2 wherein t~io of J, Jl ~nd J2 are the same as two of z, zl and z2 as hereinbeforc de~ined in formula (I) respccti~-ely, and the other is hydrogen.
(m) A compound of formula 0 Z- N ~1 N \
O, Z
wherein M represents >C=Z3, >.CH-CH0 or ~C~I-CII~OG3)2 and Z, Z3, Z4 and G3 are as herelnbefore d.efined. in formu~ae (xI) and (XII) respectively.
(n) A-compound of formula 0 J~zl Z~ I I

0 l~herein Ml rcpresents -Ql, as defined in formula (VIIl), or -Nl-l-Z2 and z, zl, z2 and G~ a.re as defined in formula (VII~ except 1.hat Gl may also be hydrogell.

--, -,, .

~7~2~;~

EXAMPLE 1 - Pre ration of 5-(6-Carboxylhexyl)-1-(3-hydroxy-4,4-d~methyl-5-phenylpentyl)hydantoin . Diethyl 2-aminononanediote Diethyl acetamLidomalonate (16.7 g) and ethyl 7-brom~-heptanoate (16.6 g~ were dissolved in ethanolic ethoxide (prepared from sodium (1.51 g) ~nd absolute ethanol (30 ml)) and the m~xture was refluxed for 27 hours. The cooled solution was poured into ice-water, the product was extracted into ether, and the dried extract ~^~as evaporated to give crude diethyl acetamido-(6-ethoxy-carbonylhexyl) malonate as a pale yellow oil, 2.2(3H, singlet,-COCH3), 4.17(6H, multiplet, 3 x -OCH2-CH3). This amide was re-fluxed with concentrated hydrochloric acid (111 ml) for 5~ hours, the cooled solution was washed with ether, and the aqueous layer was decolorised with acti~ated charcoal and evaForated to dryness in vacuo. me resid~al colourless glass was dissolved in the minimum quantity of absolute eth~nol and added dropwise to a stirred, cooled ~-10C) mixture of absolute ethanol (125 ml) and thionyl chloride (15.7 g). The resulting solution was set aside at room temperature for 1 hour, refluxed for 1~ hours, cooled, and poured into ice-water, adjusting the pH to 9 with aqueous sodium hydroxide. The nuLKture was extracted with ether, and the dried extract was concentrated and distilled, giving diethyl 2-aminono-anedioate (55% yield) as a colourless oil, b.p. 114-115 /0.02-03mm.
B. Diethyl 2~((4,4-dimethyl-3-oxo-pher.ylpentyl)amino)non-anediote To diethyl 2-aminonoanedioate (5.18 g) was added drop-wise 4,4-dimethyl-5-phenylpent-1-en-3-one (3.95 g; with cooling and A ~98 stirring. The mixture was ailowed to stand at room temperature for 21 hours to give diethyl 2-(4,4-dimethyl-~-oxo-5-phenylpentvl)amino) onanedioate .

C. Dicthyl 2-~3-_,vdroxy-4,4-dimethyl-5-phenylpentyl)amino) nonanedioate -The foregoing crude ketone (5.1 g3 was dissolved in absolute ethanol (70 ml) and the solution was stirred in an ice-bath during the gradual additlon of sodium borohydride (380 mg). The solution was stirred in thc 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 ~as dried and evaporated to leave diethyl 2-(3-hydroxy-4,4-dimethyl-5-phenylpentyl)amino~nonancdioate as a pale yellow oil which was used without further purification.

D. 5~(6-Ethoxycarbonvl~hexyl)-1-(3-hydroxy-~?4-dimethyl-5-phenylpentyl)hydan~oin and the corresponding acid A solution of the above alcohol ts.~5 g) in ethanol ~37.6 ml) and 2N-hydrochloric acid ~18.8 ml) was stirred and cooled in ice during t]le dropwise addition of a solution of potassium cyanate t3-05 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 insolu~le oil was extracted with ether. The dried ether solution was evap2rated to leave a viscous oil which w~s heated ~7~261 on the steæm 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 nixture of 2N-sodium hydroxide (25 ml) and water (60 ml) and the resulting cloudy solution was left at roam 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 ga~e a viscous oil (6.8 g) which was chrcmatographed on a column of silica gel to gi~e 5-(6-carboxyhexyl)-1-(3-hydroxy-4,4-dimethyl-5-phenylpentyl)-hydantoin as a colourless viscous oil which solidified, m.p. ca.
115 C, shrinking from ca. 90C being a mixture of diastereomers.
Recrystallisation several times from a mixture of ethyl acetate and light p~troleum (b.p. 60-80C) gave one of ~he diastereomers as small needles, m~p. 135-137&.

~ ' 6i EXAMPLE 2 - Preparation of 5-(6-Carboxyhexyl~ (3-hydroxyoctyl) hydantoin A. Diethyl 2-t3-(tetrahydropyran-2-yloxy)octylamino) nonanedioate Dry ethereal hydrogen brcmide, prepared from ether (20Qml) and hydrogen bromide (26.8 g) at 0C, was added dropwise to a stirred solution of acrolein ~19.15 g) in ether (100 ml) cooled to ~25C. The stirred mixture was kept at this temperature for 1 hour, allcwed to come to 0C, stirred for 1 hour, at 0C and then added dropwise to ethereal pentyl magnesium brcmide (prepared from l-bromopentane (54 g) magnesium (8.8 g) and ether (120 ml~), maintaining - 26a ~

' ,,,Z~

~; ~')8 ~7~
constant reflux. The reaction mixture was deeomposed with satur~ted aqueons amlllonium cillol ide and ex-tracted lrith ether, and the dried extract lras eoncentrated a3ld distilled, giving 1-bromo-3-hydroxyoctane as a colourless oil, b.p. 68.5-72.5C/0.08 mm. ~ solution of this bromo-alcohol (20.9 g) in dihyclropyran (17.0 g), was treated with ~-toluenesu]phonic acid ~500 mg) in a little ether, set aside at room temperattlre for lS hours, and washed lrith aqueous sodium biearbonate.
The org.,nic layer was percolated through silica in 1:9 ether/hexane and the solvent lras removed in vaeuo, giving l-bromo-3-(tetrahydro-]0 pyran-2-yloxv)oetane as a colourless oil,~0.88(3H, triplet, -Cll~,) and 4.62(111, bro;ld, -0-CHR-0-). ~\ solu~ioll of this tetrahydropyrallyl intermediate (]5.0 g) and diethyl 2-aminononanedioate (13.0 g) in absolute ethanol (100 ml) was re~luxed for 18 hours, the ethanol lras removed in vacuo, and the residue was diluted ~rith water eontainin~
_ _ .
a slight exeess o~ sodium earbonate. The mixture was extracted ~rith diehloromethane, the extraet was dried over sodium sulphate and evaporated, and the residue was purified by eolumn ehromatograpily on siliea in 1:4 hexane/ether, giving cliet]lyl 2-(3-(te~rahydropyran-2-yloxy)octylamino)nonanedioate as a colourless viscous oil,~0.8S(311, triplet -CH3), 2.2~(2H, triplet, -CH2-C02Et), 2.61(21-1, multiplet, -C112-N), 3.20(111, triplet, N-CIIR-C02Et), 4.13(411, multiplet, 2 x rJll3)~ 4.G0(111, broad -0-CIIR-0-).
~he above aminodiester Iras alternatively prepared in the following manller. I)iethy] 2-an-inonon;lnedioate (10.40 g) and oct-]-en--3-one (5.04 g) ~.rere mixed slo~rly at 0C. lrith stirring, and se~
aside at room tcmpelat-lre -for 3 hours, giving diethyl 2-~3-oxooctyl--- ~7 ~ ~98 `~176~

amir,o)nonalledioatc .as a colourless oil,~2.3(4H, multiplet, ~CI12--C02Et and ~CH2CH2C0~ .16~1~1, triplet, EtO2C-CHR-N~, 4.11(2F~ quarcet~ -0-CH2-CH3), 4.17~2H, quartet, -0-CH2-CH3). A
stirred solution of this ketone (13.5 g) in absolute ethanol (140 ml) was treated dropwise at 0C with sodium borohydride (665 mg) in abso].llte ethanol (70 ml), then kept for 32 hours at room temperature, and concentrated at 40C in vacuo. The residue9 di~ssolved in water, was brought to pH5 with N-hydrochloric acid and extracted thoroughly with chloroform, the extract was washed with water, dri.ed, and evaporated, giving die~hyl 2--~3-hydroxy-octylamino)nonanedioa~e as a colourless oil. Without further purification, the latter was dissolved in dihydropyran (14.0 ml), treated with ether (10 ml~
fol.lowed by ~-toluenesulphonic acid (6.72 g) in portions, and set aside at room ~emperature for 18 hours. The reaction soluti.on was diluted with ether, washed with aqueous sodiu~ carbonate then water, dried, and evaporatcd, and the residue was purified by column chromatography on silica in 1:4 hexanelether, giving diethyl 2-(3-(tetrahydropyran-2-yloxy)octylamino)nonancdi.oate identica.l (n.m.r., i.r. mixed t.l.c.) with thclt prepared previously.

0 B. 5_~6-_arbox~exyl)~ -(tetrahydropyran-2-yloxy)octyl) hydantoin To a solution o~ di.ethyl 2-(3~ etrahydropyran-2-yloxy)octyl-amino)rlona.ncdioate (7.8 g) in ethallol (~2 ml) was added a solution of potassium c)rallate (3.0 g) in waier (6 ml.). The resulting

2~ suspension was s~irred ard. coo].ed during -the ~a.dual addition of ~ 4'.) ilt~2~

2N-hydrochloric acicl ~16.7 ml). The solution was allowed to stand at room temperatur~ for 22 hours, most of tne ethanol ~las evaporatcd, water was added, and the insoluble oil was extracted with ether.
The ether solution was washed with watcr, dried over magnesium sulphate, and evaporated. The yellow oi' so obtained (8.0 g) was dissolved in light petroleum (b.p. 60-80C) and the solution was refluxed for 4 hours, evaporated to dryness, and the residual oil l.ias heated on the steambath for 2 hours to give 5-(6-ethoxycarbonylhe~yl)-1-(3-(tetrahydropyran-2-yloxy)octyl)hydantoin as a yellow 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 hour~;
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)-1-(3-(tetrahydropyran-2-ylox~r) octyl)hydantoin as a yellow oil.

C. _ (6-Carboxyhexy])-1-(3-hydroxyoctyl)hydantoin This tetrahydropyranyloxy-compound (3.55 g) was dissolved in tetrahydrofuran (28 ml) and 5N-hydrochloric acid (7 ml) and the solution was lef~ at room temperature ~or 3'- hollrs, and then refluxed for 30 minutes. i~lost of the solvent was evaporated, water was added, and the insoluble oii was extrac~ed with ether. The ethcr solu~ion was washed with water, dried over magnesium sulp}la~e and evaporated to give 3.15 ~T7, of viscous yello~ oil. The oil was puri-Lied b-~t 4~

chromatography on a coll7~in of si]ica gel, e^lution first with chloroform and the1l with a mixture of ch oroform and methanol (19:l) giving 5-(6-carboxyhe,;yl)-l-(3-hydroxyoccyl)hydantoin as a ~-ery ~iscous almost colourless oil,~O.89(3H, triplet, -CH3), 2.34(21i, tripletg -CH2-CO2H), 2.9-4.2(4H, complex, -CH2-N, CH-N, C11-OH), ca. 5.6(2H, broad, exchangeable, -CO2H, -OH), ca. 9.0(lH, broad, exchangeable, NH).
Using the method of Example l the above identified hydantoin was also prepared via the corresponding diethyl 2-((3-hydroxyoctyl) amino)nonanedioate.
D. ~E~ _ion of Diastereomers -The hydantoin resulting from the above described preparations was a Viscolls oil which by use of HPLC on a column of silica wich a mixture of chloroform, methanol and acetic acid ~97:2.5:0.5) as solvent was separated into ~wo diastereomers, both of which formed small colourless needles of m.p. 75-78C and 63-65C respectively.
The samc diastereomers were prepared by cyclisation of the corresponding diaslereomers of formula (IIl). That is, the mixture of diastereomers of diethyl 2- C3-hydroxyoctyl)amin~ nonanedioate, ~O prepared as in Example l was dissolved in ethanol and an echereal solution of hydrogen chloride was added. The solution was evaporatecl to dryness to ]eave the mixture of diastereo1neric hydrochlorides as a viscous oil, which partly solidified on standing. Ether was ad.led and the mass was stirred and cooled to give a cryscalline solid, w}lirh was collccted, was1led witll ether, and dried. The solid ~1as crys~ca lised frvm ethyl acecate to give small colourlrcs ~lates, m.n. 9~-96.5, of a 1lure~]l3r(!roc1l10rlde. T1lis salt ~ias suspended iII dil~lte sodium hydroxide sollltion and shaken ~it]l ether, and the separated ~ther solution was washed, dried and evaporated to give one o~ the diastereomers (A) of diethyl 2- [(3-hydroxyoctyl)am~ nonanedioate as a colourless oil.
'rhe etller filtrate remaining af+er collection of the original solid hydrochioride was evaporated to leave an oily hydrochloride, ~hicil was converted to base as described above to give the almost pure second diastereomer (B) of diethyl 2- [3-hydroxyoctyl)amin3 ncnanedioate as a coiourless oil.
lo By thc method described in Example 1, the above diastereomer (A~
was converted into a single diastereomer of 5-(6-carboxyhexyl)-1-(3-hydroxyoctyl)hydantoin, which crystallised fror,l a mixture of ethyl acetate and light petroleum (b,p, 60-80) as small colovrless needles~
m.p. 6~-65~
Similarly the above diastereomer (B) was converted into the second diastereomer of 5-(6-carboxyhexyl)-1-(3-hydroxyoctyl)llydantoin~
which crystal]ised f~om et}lyl acetate-lig}lt petroleum (b.p. 60-~0) as small coloulless neeclles, m.p. 76-78 E. Inte-rconversion of the diastereomers A solution o 5-(6-carboxyhexyl)-1-(3-hydroxyoctyl)h3rdantoin (diastereoiner of rll.p. 76-78) (100 mg) in N-sodill1n hydroxide solution (3 ml) was allowed to stand at room temperature for i9 hours. The so]ution was -!cidifiecl and extrac~ed with ether, and the ethcr extr~cr was washed witll wlter, dried and evaporated to lec.~re a ~riscous oil.

1\ 49S

2~

By mcans o~ high perforlhance liquid chromatography this oil was separat~-d into the t~-o diastereomers o~ 5-(6-carl~oxyhexyl)-1-~3-hydroxyoctyl)hydântoi;l~ m.p. 76-78C iclentical l~ith the starting material ~ca. 40 mg) and m.p. 63-65C (ca. 40 mg) identical with the diaste-reo]ner (A) described above.
In similar -fashion7 the diastereomer of m.p. 63-65C was converied into a mixture of approximately equal quantities of itself with the diastereomer of m.p. 76-78C, and the pure diastereomers were isolated by means of high per:Eormance liquid chromatography.

EXAMPLES 3 TO_ By a series of reactions analogous to that described in I~xample 1 using the appropriate vinyl ketones as starting materials were prepal~ed:
3a) diethyl 2-((~-oxopencyl)amino)nonanedioate;
lS 4a) dietllyl 2-~(3~oxo-4,4-dimethylpentyl)amino)nonanedioate;
5z) die~hyl 2- ((3-oxo-4-methylpentyl)amino)nonanedioate;
6a) diethyl 2--((3-oxononyl)amino)nonanedioate;
7a) diethyl 2-((3-oxo~4-methyloctyl)amino)nonanedioate;
ga) diethyl 2-~(3-oxodecyl)amino)nonanedioate;
9a~ diechyl 2-~3-oxo-~,4-dimethyloctyl)amino)nonanedioate;
lQa) diethyl 2-((3-oxo-A-et}lylhexyl)amino)nol-anedioate;
lla~ diethyl 2-~(3-cyclol~utyl-3-ocopropy')amino)nonanedioate;
12a) cliethyl 2-~(3-cyclopentyl-3-o~ opropyl)aminc-)nonanedioa1:e;
13a) diethyl 2-((3-ox;)-4,~-dime~llyl-5-(3-triEluoromethylpllenyl) penty~ ino)llonane(lioate;

~ ~')8 1~7~

l~a) diethyl 2-((3-cyclo}lexyl.-3-oxopropy:L)amino)nonanediaote;
- 15a) diethyl 2-((3-cycloheptyl-3-oxopropyl)amino)nonanedioate;
1.6a) diethyl 2-~(3-oxo-3-phenylpropyl)amino)nonanedioate;
17a) diethyl 2-((3-oxo-4-p}lenylbutyl)amino)nonanedioate;
l&a) diethyl 2-((3-oxooctyl)amino)pentanedioate;
19a) diethyl 2-((3-oxooctyl)amino)ulldecanedioate;
20a) ethyl 2-((3-oxooctyl)amino)-3-(3-ethoxycarbonylmethoxyphenyl) propionatc;
21a) ethyl 2-((3-oxo-4,4-dimetllylpentyl)amino)-3- (3-ethoYycarbonyl-methoxyphcnyl)propionat~e;
22a) ethyl 2-~(3- oxooetylamino)-3-(3-(2-ethoxycarbonylethyl)phenyl) propionate;
23a) ethy]. 2-(3-cyclobutyl-3-oxopropylamino)-3-(3-(2-ethoxycarbonyl-ethyl)p}lenyljpropionate;
1524a) ethy:l. 2-(3-cyclopentyl-3-oxopropylamino)-3-~(3-(2-ethoxycarbony]
ethyl~]lenyl)propionace;
25a) ethyl. 2-(3-cyclohexyl-3-oxopropylamino)-3-(3-(2-ethoxycarbonyl et}~ henyl)propionate;
26a) diethyl 2-(3-oxooctylami.no)-7-oxanonanedioate 7 and 2027a) diethyl 2-(3-cyclopentyl-3-oxopropylclmillo)-7-oYanonanedioclte;
whic}l wer~ converted to the corresponding hydroxy compounds:
3b) diethyl 2-((3-hydroYypentyl)amino)nonanedioate;
4b) diethyl 2--((3-hydroxy-4,4-climetllyl.pentyl)amino)llcnanedioate;
5b) diethyl 2-((3-hydroxy-4-methylpentyl)amino)nonanedi.oate;
2561~) diethyl 2-((3-hydroxynonyl)amino)nollanedioate;
7b~ cli.etlly] 2-((3-hydroxy-4-metllyloctyl)amirlo)llollanedioate;
8b) diethyl 2-(~3-hydroxydccy].).lnlino)llonalledioatc;
9b) diethyl 2-((3-hy(lroxy-l 4-dimcthyloc~:yl)amino)nonancclioate;

~L76.Zgi~
lOb) diethyl 2-((3-hydroxy-4-ethylhexyl)amino)nonanedioate;
llh) diethyl 2-((3-cyclobutyl-3-hydraxypropyl~amino) nonanedioate;
12b) diethyl 2-((3-cyclopentyl-3-hydroxypropyl)amino) nonanedioate;
13b) diethyl 2-((3-hydroxy-4,4-dimethyl-5-(3-trifluorQmethyl-phenyl)pentyl)amino~nonanedioate;
14b) diethyl 2-~3-cyclohexyl-3-hydroxypropyl)a~ino) nonanedioate;
15b) diethyl 2-((3-cycloheptyl-3-hydroxypropyl)amino) nonanedioate;
16b) diethyl 2-((3-hydroxy-3-phenylpropyl)amino)nonanedioate;
17b~ diethyl 2-((3-hydroxy-4-phenylbutly)amino)nonanedioate;
18b) diethyl 2-((3-hydroxyoctyl)amino)pentanedioate;
l9b) diethyl 2-((3-hydroxyoctyl)anuno)undecanedioate;
20b) ethyl 2-(~3-hydroxyoctyl)amino)-3-(3-ethoxycarbonyl-methoxyphenyllpropionate; -~-21b~ ethyl 2-(~3~hydroxy-4,4-dimethylpentyl~amino)-3-(3-ethoxycarbonylmethoxyphenyl)propionate;
22b) ethyl 2-((3-hydroxyoctylaNu~lo)-3-(3-(2-ethoxycarbonyl-ethyl)-phenylipropionate;
23b) ethyl 2-((3-cyclobutyl-3-hydroxypropylamuno~-3-(3-(2-ethoxy carbonylethyl)phenyl)propionate;
24b] ethyl 2-((3-cyclopentyl-3-hydroxypropylamino-3-(3-(2-ethoxycarbonylethyllphenyl)propionate;

~'~

25b) ethyl 2-(3-cyclohex~1-3~hydroxypropy].amino)-3-(3-(2-ethoxycarbonylethyl)phenyl)pro~ionate;
26b) diethyl 2-(3-hydroxyoctyla~ino)7-oxanonanedioate; and 27b) diethyl 2-(3-cyclopentyl-3-hydrcxypropylamino)-7-oxa-nonanedioate from which are prepared the follo~nng hydan-toins of formLla (I) which where indicated were separated by HPLC to provide two diastereomers having the stated melted points.
3c) 5-~6-c æ boxyhexyl)-1-(3-hydroxypentyl)hydantoin, a colourless oil, diasterecmers 71-73 and 56-58i 4c) 5-(6-carboxyhexyl)-1-(3-hydroxy-4,4-dimethylpentyl)hydan-toin, diastereomers 114-115 and 144-146;
5c) 5-(6-carboxyhexyl)-1-(3-hydroxy-4-methylpentyl)hydantoin, m.p. ca. 70-80, diastereomers 73-76 and llo-111;
6c) 5-(6-car~oxyhexy1~-1-(3-hydroxynonyl)hydantoin, a viscous oil;
7c) 5-(6-carboxyhexy1)-1-(3-hydroxy-4~methyloctyl)hydantoin, a ~iscous oil;
8c) 5-(6-carboxyhexyl)-1-(3-hydroxydecyl)hydantoin, a viscous oil, diastereomers 68-70 and 82-83;
9c) 5-~6-c æboxyhexyl)-1-(3~hydroxy-4,4-dimethyloctyl) hydant.oin as colourless crystals, m.p. 90-98, one diastere omer isolated by crystallisation from ethyl acetate m.p. 103-104;
lOc) 5-(6-carboxyhexyl~ (3-hydroxy-4-ethylhexyl)hydantoin, m.p. 70-80, diastereon~rs 82-84 and 120-122;

k`~
~`

2Ei1 llc) 5-(6-carboxyhexyl)-1-(3-cyclobutyl-3-hydroxypropyl) hydantoin, diastereomers 114-116 and 103-105;
12c) 5-(6-carboxyhexy~ (3-cyclopentyl-3-hydroxypropyl)hydan toin, diasterecmers 116-117 and 97-99;
13c) 5-(6-carboxyhexyl)-1-(3-hydroxy-4,4-dimethyl-5~mr trifluorGmethylphenylpentyl)hydantoin, diastereomers 118-120 and 145-147;
14c) 5-(6-carboxyhexyl)-1-(3-cyclohexyl-3-hydroxypropyl)hydan-toin, diastereomers 96-98 and 124-126;
15c) 5-(6-carboxyhexyl)-1-(3-cycloheptyl-3-hydroxypropyl)-hydantoin, m.p. ca. 70-76 , diastereomers 107-109 and 107-109;
16c) 5-(6-carboxyhexyl)-1-(3-hydroxy-3-phenylpropyl)hydantoin, diastereomers both forming colourless viscous oils;
17c) 5-(6-carbQxyhexyl)-1-(3-hydroxy-4-phenylbutyl)hydantoin, diastereom~rs 102-104 and 61-63;
18c) 5-(3-carboxypropyl)-1-(3-hydroxyDctyl)hydantoin, diastereomers both forming colourless viscous oils;
l9c) 5-58-carboxyoctyl)-1-(3-hydroxyoctyl)hydantoin, diastereomers 57-60 and 69-71 ;

'~

~L7~

20c) 5~(3-cæ boxymethoxybenzyl~ (3-hydroxyoctyl)hydantoin, a colourless meringue;
21c) 5-(3-carboxymethoxybenzyl)-1-(3-hydroxy-4,4-dimethylpentyl) hydantoin, diastereomers of corresponding ethyl esters m.p. 100~103 and 151-154;
22c) 5-(3-(2-c æboxyethylbenzyl~)-1-(3~hydroxyoctyl~hydantoin, one diasterecmer m.p. 82-86;
23c) 5-(3-(2-carboxyethylbenzyl))-1-(3-cyclobutyl-3-hydroxy-propyl)hydantoin, one diastereomer m.p. 118-121;
24c) 5-(3-(2-c æ boxyethylbenzy1))-1-(3-cyclopentyl-3-hydroxy-propyl)hydantoin, one diastereomer m.p. 140-143;
25c) 5-(3-(2-carboxyethylbenzyl))-1-(3-cyclohexyl-3-hydroxy-propyl)hydantoin;
26c) 5-(4-carboxymethoxybutyl)-1-(3-hydroxyoctyl)hydantoin; and 27c) 5-(4-carbo~ymethoxybutyl)-1-(3-cyclopentyl-3-hydroxypropyl) hydantoin;
all of which were obtained via the coLrespondi~g ethyl ester.
Startirlg materials used in the above procedures were 20 prepared as follows:

- 36a -.~t ~~;
s ~176Z~il A. EXAMPLES 18 and 19 Using the procedure described in Example lA were prepared diethyl 2-aminopentanedioate, b.p. 93-96/0.02mm nD4 1.4425 and diethyl 2-aminoandecanedioate b.p. 160/O.lmm which were used in Examples 18 and 19 respectively.
B. Ethyl 2-amino-3-(3-ethoxycarbonylmethoxyphenyl)propionate Diethyl acetamidomalonate (2.60 g) and ethyl 3-(chloro-methyl) phenoxyacetate ~Robertson, J. Chem. Soc. (1933), 492;
U.S. 3,933, 895) 2.39 g) were dissolved in ethanolic ethoxide (prepared from sodium (230 mg) and absolute ethanol (10 ml)) and the mixture refluxed for 19 hours. The cooled solution was poured into ice-water, the product was extracted into ether, and the dried extract evaporated. m e residual gum was cr~ystallised from ether~hexane to give diethyl acetamido-(3-ethoxycarbony~-methoxyphenyl)~alonate as white prisms, m.p. 98.5-101.5. mis derivative (1.90 g) was refluxed with 10% aqueous hydrochloric acid (25 ml) for 3~ hours and the cooled solution was evaporated to dryness in vacuo. The residual white solid was dissolved in the ~inimum quantity of absolute ehtanol and added dropwise to a stirre1, cooled (-10 C) mixture of absolute ethanol (15 ml) and thionyl chloride (1.64 g). me resulting solution was set aside at room temperature for 18 hours, refluxed for 1 hour, cooled, and poured into ice-water, adjusting the pH to 9-10 with aqueous sodium hydroxide. m e muxture was extracted with ether, and the dried extract was concentrated, giving ethyl 2-a~ino-3-(3-ethoxy-carbonylmethoxyphenyl)propionate as a colourless oil, which was ~7~2~
used without further purification in EXamples 20 and 21.
C. Ethyl 2-amuno-3-(3-(2-ethoxycarbonylethyl)phenyl) propionate A solution of di-isopropylamine (4.04 g) and butyl-lithium (25 nl, 1.60M in hexane) in dry tetrahydrofuran (40.0 ml), stirred at -78 under dry nitrogen, was treated over 5 nunutes with t-butyl acetate (4.64 g). To this solution was added, over 5 minutes, a solution of ~ ,~ '-dibromo-m-xylene (11.60 g) and dry hexamethylphosphoramide (1.42 g) in dry tetrahydrofuran ~8.0 ml). The resulting yellow solution was stirred at -78 for % hour, then allowed to warm to room temperature over 3 hours.
Excess ice-water was added, and the mixture extracted with ether, and the extract washed with IN hydrochloric acid (60 ml~ then water. The dried extract was concentrated in vacuo, to give a yellow oil which was purified by column chromatography on silica, eluting with 1:1 ether hexane, giving tbutyl 3-(3-bromomethylphenyl)propionate as a colourless oil. Using the method described in the last foregoing paragraph this was converted to the desired diethylester which was used in each of Examples 22 to 25.
D. Diethyl 2-amino-7-oxa-nonanedioate This was prepared from e~hyl 4-bromobutoxyacetate (Merck, Ger. Offen. 2,354,085) by a series of reactions analogous to that described in paragraph B above and was obtained as a colourless oil, b.p. 120-121/0.005mm. It was used in Examples 26 and 27.

- 3& -~'` J~' .

~2~:~
EX~MPLE 27b - Preparation of 5-(6-carboxyhexyl)-1-(3-oxooctyl) hydantoin Diethyl 2-(3-oxooctylamino)nonanedioate (7.7 g) pre-pared by the method described in Example lB was treated with potassium cyanate and hydrochloric acid to give 5-(6-ethoxy-carbonylhexyl)-1-~3-oxo-octyl)hydantoin. Hydrolysis of this ester using sodium hydroxide solution gave 5-(6-carboxyhexyl)-1-(3-oxooctyl)hydantoLn as a viscous oil, which crystallised to a lcw-melting solid.
EXAMPLE 28 - Preparation of 5-(6-carboxyhexyl)-1-(5-phenylpentyl~
hydantoin A mixture of diethyl 2-aminononanedioate (25.9 g) and 5-phenylpentyl bromide (22.7 g) was heated in a bath at 100C
for 3 hours. After cooling, ether (lOOml) was added to the mixture, which was then allowed to stand for 2 hours, at 0C.
The colourless solid (21.95 g) which crystallised was collected and dried. This diethyl 2-((5-phenylpentyl)amino)nonanedioate hydrobrcmide melted at 70-72C.
A solution of this hydrobromide (4.86 g) in ethanol (20 ml~ and 2N~hydrochloric acid (5 ml) was cooled in ice and stirred during the gradual addition of a solution of potassium cyanate (1.62 g) in water (5 ml), after which the solution was allowed to stand at roGm temperature for 18 hours. The alcohol was evaporated, water was added, the insoluble oil was extracted with ether, and the ethereal extract was dried and eva~orated to leave a pale yellow oil. This material was 117~Z~

heated on the steam bath for 6 h~urs to give 5-(6-ethoxy-carbonylhexyl)-l-(5-phenylpentyl)hydantoin.
The foregoing ester (4.0 g) was hydrolysed by treat-ment with dilute sodium hydroxide solution and the product was purified by chromatog~aphy on silica gel, to give 5-(6-carboxy-hexyl)-1-(5-phenylpentyl)hydantoin crystallising from ethyl acetate - light petroleum ~b.p. 60-80C) in colourless prismatic needles, m.p. 90-92& .
EXAMPLES 2~ to 35 By a series of reactions analogous to that described in Example 28 using the appropriate alkyl halides were prepared:
29a) diethyl 2-octylaminononanedioate;
30a) diethyl 2-(4-propoxybutyl)aminononanedioate;
31a) diethyl 2-(4-phenoxybutyl)aminononanedioate;
32a) diethyl 2-(4~m-trifluoromethylphenoxybutyl)aminononan-edioate;
33a) diethyl 2-(3-m-tolyloxypropyl)aminononanedioate;
34a) diethyl 2-(3-hydroxypropyl)aminononanedioate; and 35a) diethyl 2-(3-hydroxy-3-methyloctyl)aminononanedioate which were converted to the desired hydantoins:
29b) 5-(6-ethoxycarbonylhexyl)-1-octylhydantoin, m.p. 46-48;
29c) 5-(6-carboxyhexyl)-1-octylhydantoin, m.p. 88-89;
30b) 5-~6-car~oxyhexyl)-1-(4-propoxybutyl)hydantoin, m.p.
72-74;
31b~ 5-(6-carboxyhexyl)-1-(4-phen~oxybutyl)hydantoin, m.p. 88-90;

~ .~

~ ~ s)~

32b) 5-(6-carbo~yhexyl)~ 4-mrtrif]uorcmethylphenoxybutyl) hydantoin, m.p. 51-54;
33b) 5-(6-carboxyhexyl)-1-(3-m-tolyloxypropyl)hydantoin, a colo~rless viscous oil;
34b) 5-(6-carbcxyhexyl)-1-(3-hydroxypropyl)hydantoin, m.p.
111-113; and 35b) 5-(6-carboxyhexyl)-1-(3 hydroxy-3-methyloctyl)hydantoin, a viscous oil.
EXAMPLE 36 - Preparation of 1-(6-Carboxyhexyl)-5-octyl hydantoin 2-Amunodecanoic acid (J. Am. Chem. Soc., 1946, 68, 450) (16.0 g) was added in portions to a cooled (-10C) mixture of absolute ethanol (70 ml) and thionyl chloride (6 ml) with stirring. The resulting solution was set aside for 2 hours, at room temperature, refluxed for 1 hour, cooled, poured into ice-water, and the pH of the solution was adjusted to 9 with aqueous sodium hydroxide. me mixture was extracted with ether, the extract was dried, concentrated, then distilled, giving ethyl 2-amincdecanoate (75%) as a colourless oil, b.p. 82-4 C/0.2 mm.
A solution of the above aminoester (18 g) and ethyl 7-bromoheptanoate (20 g) in absolute ethanol (50 nl) was refluxed for 24 hours, and the ethanol was then e~aporated.
Additi`on of ether precipitated a hydrobromide salt, m.p. 98 C, which was dissolved in a little dichloromethane, treated with an equivalent of triethylamine, washed thoroug~y with water, and driedi removal of the solvent gave ethyl 2-~6-ethoxycarbonyl-hexylamino)decanoate (52%) as a colourless viscous oil, b.p. 142-4C/0.001 mm~
Ethyl 2-(6-ethoxycarbonylhexylamino)decanoate (7.4 g) was reacted with postassium cyanate and hydrochloric acid to give 1-(6-ethoxycarbonyIhexyl)-5-octylhydantoin which formed colour-less crystals, m.p. 68-70C, from light petroleum (b.p. 60-80C).
This ester (4.0 g) was hydrolysed with sodium hydroxide solution to give l-(6-carbcxyhexyl)-5-octylhydantoin which crystallised from a ~ixture of ethyl acetate and light petroleum (b.p. 60-80C) as colourless needles, m.p. 65-66C.
EXAMæLE 37 - PreFaration of 5-(6-carboxyhexyl)-3-methyl-1-octyl-hydantoin A solution of diethyl 2-octylam m ~n~nanedioate (742 mg) and methyl 1 cyanate (120 m~) in dry ether (7.5 ml) was allowed to stand at room temperature for 48 hours, after which time the ether was evaporated to leave a pale yellow oil (800 ~g). The oil was heated on the steam bath for 2 hours to give 5-(6-ethoxy-carbonyl)-3-methyl-1-octylhydantoin as a yellow oil.
The ester (650 mg) was hydrolysed by standing in solu-tion in ethanol (2.4 ml) and 5N-sodium hydroxide solution (0.61 ml) for 3 hours at room tem~erature. After evaporation of the ethanol, the acidic product was isolated by extraction with ether, and Furified by chrcmatography on a column of silica gel to give 5-(6-carboxyhexyl)-3-methyl-1-octylhydantoin as a colourless oil.

:~7~26~

EXAMPLE 38 - Preparatiorl of 5--(6-carboxyhexyl)-3-methyl-1-(3-hydroxyocty_)hydantoin Diethyl 2-((3-oxooctyl)amino)nonanedioate (Example 28 was allowed to react with methyl isoocyanate as described in Example 37 to give 5-(6-ethoxycarbonylhexy1)-3-methyl-1-(3-o~ooctyl)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) a~d the solution was stirred in an ice-bath during the addition of sodium borohydride (63 mg). After 3hours' stirring at roam temperature, the solution was acidified and extracted with ether. The washed and dried ether extract was evaporated to leave an oil which was purified by chromatography on a column of silica using a mLxture of chloroform ar~d methanol (50:1) as eluant to give 5-(6-carboxyh y l~-3-methyl-1-(3-hydroxyoctyl)hydantoin as a colourless viscous oil.
EX~MPLE 39 - Preparation of 1-(6-Carboxyhexyl)-3-methyl-5-octyl-hydantoin By the method described in Example 37, ethyl 2-(6-ethoxy-carbonylhexylamino)decanoate (EXample 36) was converted into 1-(6 ethoxycarbonylhexyl)-3-methyl-5-octylhydantoin, and thence by hydrolysis into 1-(6-carboxyhexyl)-3-methyl-5-cctylhydantoin, isolated as a colourless oil.
EXAMPLE 40 - Preparation of 3-Butyl-5-(6-carboxyhexyl)-1-octyl-hydantoi To a solution of sodium (308 mg) in ethanol (40 ml) was 1~76~1 added 5-(6-ethoxycarbonylhexyl)-1-octylhydantoin (see Example 29b), 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 ~xtracted with ether. The washed and dried extract was evaporated to give 3-butyl-5-(6-ethoxycarbonyl-hexyl)-l-octyl-hydantoin.
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 ether and purified by cArcmatography on silica gel to give 3-butyl-5-(6-carboxyhexyl)-1-octyl hydantoin as a colourless oil.
EXAMPLE 41 - Preparation of 3-Butyl-1-~6-carboxyhexyl)-5-octylhydantoin By the method of Example 40, 1-(6-ethoxycarbonylhexyl)-5-octylhydantoin (see Example 36) was converted into 3-butyl-1-(6-ethoxycarbonyIhexyl)-5-octylhydantoin, which was hydrolysed to give 3-butyl-1-(6-carboxyhexyl)-3-octyIhydantoin as a colourless oil.
EX~MPLE 42 - Prep~ration of 5-(6-Carboxyhex-2-ynyl)-1-(hydroxy-_tyl) hydantoin Under the reaction conditions described in Example lA
diethyl acetamidcmalonate and methyl 7-bromohept-5-ynoate reacted to give diethyl acetamido-(6-methoxycarbonylhex-2-ynyl)malonate as a yellow oil.
This crude product was hydrolysed by boiling with 5N-hydrochloric acid, and the product was re-esterified to give ~ '~

,.

~17~iZ6~

diethyl 2-aminonon-4-ynedioate, which was distilled to give a colourless oil, bop. 116 /0.0imm, nD 1.4703.
The foregoing amino-compound was reacted with oct-l-en-3-one to give diet~yl 2-((3-oxooctyl)amino)-non-4-yndeioate which was reduced with sodium borohydride to give diethyl 2-((3-hyd mxyoctyl)amino)-non-4-ynedioate.
Treatment of this compound with potassiurn 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 rnLxture of chloroform and rnethanol (30:1) as eluant gave 5-(6-carboxyhex-2-ynyl)-1-(3-hydroxyoctyl) hydantoin as a colourless oil, (mixture of diasterecmers) showing two spots, Rf. 0.38, 0.44, when run in a chloroform, rnethanol, acetic acid (90:5:5) rnixture of a thin layer of silica. By use of HPLC one of the diasterecmers (TLC, Rf. 0.38) was isolated as a colourless oil; NMR (CDC13)~0.89 (3H, triplet, -CH3), 2.2-2-4 (6H, r~lltiplet, -CH2, C=C.CH2- + -CH2.C02H), 3.54 (2H, triplet, ~N.CH2-), ca 3,6 (lH, rmultiplet, ~CH.OH), 4.11 (lH, triplet, ~N.
_.C~) -m is oompound was then catalytically hy~rogenated to the corresponding 5-(6-carboxyhex-2-enyl)-1-(3-hydxoxyoctyl) hydantoin and subsequently to the corresponding saturated oomFound which was found to be identical with the title campound of Example 2.
EXAMPT .T~ 43 A. 2-(Dibutoxy~methyl~glycine ethylester ,~

-~I76Z~

N-Formylglycine ethyl ester was C-formylated using a method based on that described by Harman and Hutchinson in J. Org. Chem. 1975 40, 3474 and the resulting compound converted to 2-(dibutoxymethyl)glycine ethyl ester using the method described in "Chemistry of Pencillinn, Eds. H.T. Clarke et al., published by Princetown Univeristy Press, New Jersey, 1949, p.517.
B. 1-(6-Carboxyhexyl)hydantoin-5-carboxaldehyde A mixture of 2-(dibutoxymethyl)glycine ethyl ester (2.0 g) with ethyl 7-bromoheptanoate (1.82 g.) was heated under nitrogen in a bath at 100C for 3 hr. to give crude ethyl 7-(2,2-dibutoxy-l-ethoxycarbonylethyl)amino)-heptanoate hydrobromide.
A stirred solution of 3.28 g. of this hydrobromide in ethanol (13 ml) was cooled in ice-water and treated with a solution of potassium cyanate (1.34 g) in water (4 ml), followed by 2N aqueous hydrochloric acid (3.63 ml); the cooling bath was removed and stirring was continued at room temperature for 22 hr. me ethanol was eYaporated in vacuo, the residue was shaken with water and ether, and the ethereal solution was separated, washed with water a~d dried over magnesium sulphate (~gSO4); removal on the ether left an oil which was heated under nitrogen at 100C for 3 hr., to give 5-dibutoxymethyl-1-(6-ethoxycarbonylhexyl)hydantoin (2.94 g.). Ihis was stirred in ether (6 ml.) with water (48 n~) and _ aqueous sodium hydroxide (24.9 ml) at room temperature for 1~ hr. and, after the addition of more ether (50 ml), the aqueous phase was separated, cooled (ice-H20), stirred with fresh ether - 45a -. ~
~ ~J

~:17~iZ~

and acidified to Congo Red with N aqueous hydrochloric acid. The ehtereal solution of carboxylic acid was thrice washed with water, dried (MgS~), and evaporated, to leave 1-(6-carboxyhexyl)-5-dibutoxymethylhydantoin (2.15 g.) as a gum. ~hen 1.89 g. of the latter were cooled in ice-water and stirred with concentrated aqueous hydrochloric acid (8.5 ml.~, the resulting solution gave place spontaneously to a suspension of colourless crystals.
me suspension was set aside at roan temperature for 1~ hr., diluted with water (10 ml.) a~d set aside 15 min.; the crystals were then collected, washed with water, dried in vacuo, suspended in ether (3 ml.), and collected again, to give 1-(6-carboxyhexyl) hydantoin-5-carboxyaldehyde (0.74 g.), m.p. 223.5-225C (Found:
C. 51.86- H, 6.66; N, 10,62. CllH16N205 required C, 51.56;
H, 6.29; N, 10.93%). In dImethyl sulphoxide-d6, this compound exists predominantly as the masked aldehyde, l-(6-carboxyhexyl)-5-hydroxymethylene-hydantoin.
C. 1-(6-Carboxyhexyl)-5-((E)-3-oxo-octylidene)hydantoin A mixture of 1-(6-carboxyhexyl)hydantoin-5-carboxal~e-hyde (20 mg.) with 2-oxoheptylidene-triphenylphosphorane (59 mg.) (see J. Org. Chem. (1972) 37, 1818) and 1 drop of benzene was heated under nitrogen at 100 C for 35 ~in., a~ld the resulting i~

:l~L762~
gum ~as take3l up in et]lyl acetatc. rhe procIuct was eXtrclCtCd illtO dilute aqueous sodium bicarbonate, the extract was ~as]Ied ~iit]l et]lyl acetate and acidifi,ed to Congo Red with N a~ueous hydroc]l]oric acid~ and the liberatecl carboxylic acid ~ras extracted into ether. The ethereal soluti,on was ~ashed ~itII ~ater, driecl ~IgS04~, and evaporated, to gi~e a gum (25 mg.) which ~as identified by 'H n.m.r. spectroscopy (characteristic sic,nals at ~5.72 (lH, triplet, -CII-) and 3.93 (2H, doublet~ ~CTI-CH?-C0) with J 7.1 Hz, in deuterocllloroform) I0 as 1-(6-carboxyhexyl)-5-((E)-3-oxo-octylidene)hydantoin.
D. 1-~6-Carboxyhexyl)-5-((E)-3-]lydroxyoctylidene)hydantoin A stirred solution of 1-(6-carboxyhexyl)-5-((E)-3-oxo-octylidene)hydantoin (20 mg.) in H20 (1~5 ml.) containing a sli~ht excess of sodium bicarbonate lYas treated with sodium ~5 borohydride (5 mg.). After 60 min., the solution was acidified to Congo Red ~.~ith N aqueous hydrochloric acid, the liberated carboxylic acid was extracted into ethyl acetate, and the ethyl acetate solution ~as tIlrice washed with water and dried (MgS0~).
Evapor~tion of the etIIyl acetate left a pale yellol~ gum (14 mg.) '~0 which was identified by 'H n.m.r. spectroscopy (cIIaracteristic signal at ~5.61 (lH, triplet =CI-I-, J 7.1 Hz) in deuterochlorofo as 1-(6-carboxyhexyl)-5-((E)-3-IIydroxyoctylidene)Ilydalltoill.

E. _-(G-Carl~oxyIlexyl)-5-(3-r,ydroxyoctyl)llyd;liltoln TIIe prodt.ct described in paragraph C ~as subsequent1y reduced to 1-(6-c~rboxy}Iexyl,)-5-(3-oxooctyl)]lydantoirl and the title compo-Illd ~]Iicll l~ere ~ound tc be identical t~it]I tIle title compounds of Ext]IIp]es 2~, aIId 2 rcs~ectively.

-- ~.7 -117~

EXAMPLF. 41 Preparation of 5-(6-carboxyhex-27-enyl)-1-(3-cyclohexyl-3-hydl-oxy-prop~l)hydantoin.
c -Methyl 7-bromohept-5-enoate (prepared by the method of Brit. Pat. No. 1,355,991) and diethyl acetamidomalonate reacted under the conditions described in Example lA to give diethyl acetamido-(6-methoxycarbonylhex-2-enyl)malonate as a yellow oil.
mis crude product was hydrolysed by boiling with 5N-hydrochloric acid and the product was esterified, as described in Example lA, to give diethyl 2-aminonon-4-enedioate as a colour-less oil, b.p. 118-123 /0.05 mm, nD9 1.4620.
Reaction of this an~no-com~ound with l-cyclohexylprop-2-enone as in Example 2B and reduction of the diethyl 2-((cyclo-hexyl-3-oxopropy~amino)non-4-anedioate so produced with sodium borohydride as in Example 2C gave diethyl 2-((3-cyclohexyl-3-hydroxypropyl)amino)non-2-enedioate.
Treatment of this ccmpound with potassium cyanate and hydrochloric acid and hydrolysis of the resulting hydantoin ester as in Example 2D gave 5-(6-carboxyhex-2Z-enyl)-1-(3-cyclohexyl-3-hydroxypropyl)hydantoin as a yellow oil, tending to solidify. By use of HPLC this compound was separated into its diastereomers, one forming small colourless prisms, m.p. 95-97, and the other forming colourless needles, m.p. 108-110 .

- 47a -~' .

~ 98 In the following examples the hydantoins are designated thus:
Compound 2 : 5-(6-Carboxyhexyl)-1-(3-hydroxyoctyl)hydantoin Compound 4 : 5-(G-Carboxyhexyl~ 3-hydroxy-4,4-dimethyl-pentyl)hydantoin Compound 6 : 5-(6-Carboxyhexyl)-1-(3-hydroxynonyl)hydaIltoin Compound 9 : 5-(6-Carboxyhexyl)-1-(3-hydroxy-4,4-dimethylGctyl) hydantoin Compound 11 : 5-(6-Carboxyhexyl)-1-(3-hydroxy-3-cyclobutylpropyl) hydantoin Compound 12 : 5~-(6-Carboxyhexyl)-1-~(3-hydroxy-3-cyc].opentyl-propyl)hydantoin Compound 14 : 5-(6-Carboxyhexyl)-1-(3-hydroxy-3-cyclohexylpropyl~
hydantoin Compound 38 : 5-(6 Carboxyhexyl)-3-methyl-1-(3-oxooctyl)hydantoi.n.
Where a particular diastereomer is used, this is indica~ed by reference ~o its melting point.

EXAMPLE A - Cardiovascular effects in rats __ Male normotensive rats Wistar (Charles River) strain, (250-350 g) were anesthetised (chloroform) prior to cannulation of the left femoral vei.n and anaesthesia maintained by intravenous chloralose (60 mg/kg). Pulsatile blood pressure was recorded from the left femoral a.rtery with an electronic transducer ~Bel]. and llo~rell Type 4-327 L221) and integrated heart rate was measured with a carclioiacllometer triggered from the arterial press-lre waves.

~r 8 A ~198 1176~

The tes~ compouncL was admi.llistered as a solution in ~hysiological saline by intravenous injection via thc femoral cannula. The responses recorded were allowed to return to the preinjection levels bctween successive administrations.
S Injections of the vehical alone in volumes equi.valent to those containi.ng drug did not produce hypotension.
Mean fall in blood Compound D _ pressure mmHg PGE2 4~g/kg 28 " 16~g/kg 44 Compound 2 lO~g/kg 14 " lmg/kg 42 Compound 6 3mg/kg 40 Compound 9 3mg/kg 22 EX~MPLE B - Inhibition of Platclet Aggregation _. _ _ _ Aggregation of pla.telets in 1 ml. of fresh human platelet rich plasma (PRP) was monitored in a ~orn aggregometer.
The cor.~pound to be tested was added to the PRP at the . desired concentration, and ~he resulting mi~ture incubated at 37~ for 1 minute after which platelet aggregation was stimulated by the addltion of adenosine dip~losphate ~ADP) to a concent.ra- -tioll of 5~
The anti-aggregcltory effect O f the compound was assessed by ~.easuring t}lC- percentage inhibition of platelet aggregation in the presence o the co~ilpou]lcl as compared ~rhen it lras ~7G%~l completely absent.
Com~ound Concentration% Inhibition of Aggregation PGEl 15ng~ml 33 20ng/ml 47 " 30ng/ml 63 " 40ng/ml 69 Ccmpound 120.5ng/ml 25 (m.p. 116-117) " l.Ong/ml 51 " 2.Ong/~1 79 " 4.Ong/ml 94 Using comparisons such as this the following relative potencies were demonstrated with respect to P OE l. Ccmpound 2 (m.p. 76-78), 12.5x; Compound 4 (m.p. 144-146), 0.05x; Ccmpound 11 (114-116), 5.2x; Compound 12 (m.p. 116-117), 12.5x; and Compound 14 (m.p. 96-98), 16x.
EX~MPLE C
Ccmpound 38 was found to reduce aspirin-induced gastric ulceration in rats; an oral dose of lmg/kg gave 80% protection.
EXAMPLE D
At an intravenous dose of 30yg/kg~ Ccmpound 2 completely inhibited pentagastrin-induced gastric acid secretion in rats.
EXAMPLE E
An intravenous injection of Compound 9 (50~g/kg) was found to ccmpletely anatagonise histamine-induced broncho-constriction in anaesthetised guinea-pigs.

~_) ~ 4'J8 ~7~2~

_ A~IPLE_E
Intr2venous ;nfusions of Compound 2 (m.p. 76-78C) at a dose of 250 ~g/min ha~e ~een found to reduce electrically-in~uced arterial thrombosis in anaesthetised rabbits.

EX~IPIE G
Tablet In one tablet Compound 12 ~m.p. 116-117) 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 ~ ix together the Compound 12, lactose and starch.
Granulate the powdcrs using a solution of tlle povi~one in Purlfied Water. Dry the granules, add the Magnesium Stearate and compress to produce tablets, 100 mg per tablei.

EXAMPLE H
_.
Capsule In one capsule Compound 12 (m.p. 116-117) 10 mg Lactose 79 mg Starch 10 mg Magnesilml Stearale 1 mg Mix the po~ders in a powder blendcr, fill in~o hard gclaiin `
capsu3es, 300 Illg pcr capsllle .

Z~l EXA~IPLE I
1 ~g/ml Injection Compoulld 12 (m.p. 116-117) 100 ~g Water for Injection to......... 100 ml Dissolve the Compound 12 in thc l~ater for Injection.
Sterilise the solution by -filtration through a membrane filter, 0.22 ~m pore size, collecting the filtrate in a sterile receiver.
Under aseptic conditions, fill the solution into sterile glass ampoules, 1 ml per ampoule. Seal by fusion of the glass.

_AMPI.E J
1 _ g/ml Injection ,, Compound 12 (m.p. 116-117) 1 mg ~thyl Alcohol 10 ml Propylene Glycol ' ' 30 ml Water for Injection to........ 100 ml Dissolve the Compound 12 in the Ethyl Alcoho], add tlle Propylene glycol and dilute to volume with Water for Injection.
Sterilise l,he solution by filtration through ~ membrane filter, 0.22 ~m pore size, collecting the filtrate in a sterile vessel. Under aseptic conditions, fill the solution into sterile glass vials, 10 ml per vial. Close ~ith a sterile rubber plug and sccure with an aluminium collar.

~ 8 :~76~

E~A~IP~IE K
100 llg Sing]e close in~ect;on (freeze-driedj Compound 12 ~m.p. 116-117) lO.O mg Mannitol 2.5 g N/10 Sodium Hydro~ide Sollltion q5 to pH 10.0 Water for Injection to..................... 100.0 ml Suspend the Compound 12 in approximately 20 ml l~Tater.
Add sufficient Sodium Hydroxide Solution to produce pH 10 and stir to dissolve the 50nlpound 12. Add and dissolve t7ne Mannitol and dilute to volume with Water for Injection.
Sterilise the solution by passage through a membrane filter, 0.22 ~m pore size and distribute aseptically into sterile vials, 1 ml per vial. Freeze dry the solutions and seal the containers under aseptic conditions with rubber closures. Each vial contains 100 ~g Corllpound 12 as its freeze-dried Sodium salt.

EXl~IPI.E L
Suppo S itory Compound 12 ~m.p. :L16-117) 3 mg Massa Esterinum C to....................... 2 mg Melt the suppository base at around D,OC. Gradually incorporate tlle Compound ]2 in fine po~rder and mi~ until hcmogeneoll-Pour into suitable moulds and allo~l to set.
Massa Es~erinum C is a commercia]ly avai]able supposi~o~y -base consis1;ing of a mixt~ e o~ mono-, di- and tri-glyccrid~s o~
2~ saturated vegct.al?le fatty acids. lt is narketed by I-Ienkel Inte~ -tiolla], Dussc]dori.

.

Claims

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A method of preparing a compound of formula (I) (I) wherein Z is hydrogen; one of Z1 and Z2 is repre-sented 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 or the two Q's together form an alkylene radical having four, five or six carbon atoms X1 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-) pro-vided that at least one carbon atom separates the oxa group from a -C?C-, -CH=CH- or -CO- group; and X is selected from carboxyl, carbamoyl, hydroxymethyl and alkoxy-carbonyl; and the other of Z and Z 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, Y1 is carbonyl, methylene, methylene substituted by hydroxy or methylene substituted by hydroxy and alkyl; Y2 is a covalent bond or a straight or branched alkylene having 1 to 7 carbon atoms, unsubstituted or substituted on the carbon adjacent Y1 by one or two groups independently selected from alkyl, bicycloalkyl and 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 and benzyloxy is unsubstituted or substituted in the benzene ring by one or more groups selected from hydroxy, halo, nitro, amino, acylamino, alkenyl, alkoxy, phenyl and alkyl which may itself be substituted by one or more halo groups, or Y is a bond, -CH2- or -CH2-CH2- and Y1, Y2 and Y3 taken together form a cycloalkyl group substituted by a hydroxy group, and salts thereof; comprising (a) cyclising a compound of formula (II):- (II) wherein G is carboxyl or a derivative thereof effective to permit cyclization to a compound of formula (I), and z, z and Z2 are as defined above; or (b) cyclising a compound of formula (VII):- (VII) wherein G1 is carboxy or a derivative thereof effective to permit cyclization to a compound of formula (I), and Z, Z1 and Z2 are as defined above; or (c) reacting a carbonic acid derivative effective to permit cyclization to a compound of formula (I), with a compound of formula (IX):- (IX) wherein Z, Z1 and Z2 are as defined above; or (d) reducing a compound of formula (XI):- (XI) wherein Z3 is =CR-CH2-Y1-Y2-Y3 and Z is -CH2-X-X1-X2, or Z3 is =CH-X-X1-X2 and Z4 is -Y-Y1-Y2-Y3 in which each of R, X to X2 and Y to Y3 is as defined above, with a reducing agent effective to reduce the olefinic unsaturation between the ring and Z3; or (e) when X2 is hydroxymethylene reducing a correspond-ing acid, ester, acid halide, acid anhydride or aldehyde with a reducing agent effective to reduce said corresponding derivative, or (f) when X2 is hydroxymethylene hydrolysing a corresponding ing halide and when desired converting the compound of formula (I) so obtained to a corresponding salt, acid, ester, amide, alcohol or ketone of formula (I).

2. A method according to claim 1, comprising cyclising said compound of formula (II) or said derivative thereof.

3, A method as claimed in claim 2, wherein G is carboxyl, carboxamide or alkoxycarbonyl.

4, A method as claimed in claim 2 or 3, wherein the cyclising is effected by heating.

5, A method as claimed in claim 2 or 3, wherein the cyclising is effected under acidic conditions.

6. A method as claimed in claim 2 or 3, wherein the cyclising is effected in the presence of a solvent.

7, A method as claimed in claim 2, wherein G is alkoxycarbonyl and cyclisation is effected in the presence of a base.

8. A method as claimed in claim 7, wherein the cyclising is carried out in the presence of a solvent.

9. A method as claimed in claim 7 or 8, wherein the base is sodium ethoxide.

10. A method according to claim 1, including a step of converting a compound of formula (I) obtained to a corres-ponding salt, acid, ester, amide, alcohol or ketone of formula (I).

11. A method according to claim 10, including a step of converting a compound of formula (I) obtained to a corres-ponding pharmaceutically acceptable, pharmacologically compatible salt.

12. A method according to claim 10, including a step of hydrolyzing an ester of formula (I) obtained to the corresponding acid of formula (I).

13. A method as claimed in claim 1, wherein Z is hydrogen, X2 is carboxyl or alkoxycarbonyl; Y2is a covalent bond or straight or branched alkylene having 1 to 7 carbon atoms optionally substituted on the carbon adjacent Y1 by one or two alkyl groups, and Y3 is hydrogen, hydroxy, alkoxy having 1 to 7 carbon atoms, phenyl, benzyl, phenoxy or benzyloxy, wherein each of phenyl, benzyl, phenoxy and benzyloxy is unsubstituted or substituted in the benzene ring by one or more groups selected from hydroxy, halogeno, nitro, amino, acylamino, alkenyl, alkoxy, phenyl and alkyl which is unsubstituted or substituted by one or more halogeno groups or Y2 is a covalent bond and Y3 is cycloalkyl having 4 to 7 carbon atoms.

14. A method as claimed in claim 11, wherein each Q is hydrogen; each R is hydrogen; Y is hydrogen, hydroxy, alkoxy having 1 to 7 carbon atoms, benzyl, phenoxy or benzyloxy wherein each of benzyl, phenoxy and benzyloxy is unsubstituted or substituted in the benzene ring by one or more groups selected from hydroxy, halogeno, nitro, amino, acylamino; alkenyl, alkoxy, phenyl and alkyl which is unsub-stituted or substituted by one or more halogeno groups; or Y2 is a covalent bond and Y3 is cycloalkyl having 4 to 7 carbon atoms.

15. A method as claimed in claim 12, wherein X is cis -CH=CH- or -CH2-CQ2-; X1 is a covalent bond or a straight or branched alkylene chain having 1 to 6 carbon atoms; Y2 is a covalent bond and Y3 is cycloalkyl having 4 to 7 carbon atoms.

16. A method according to claim 1, wherein at least one of the following conditions apply:
(a) X is other than -CH2-CH2-;
(b) 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 or thia group;
(c) X2 is carbamoyl, hydroxymethyl, and/or (d) Y is other than -CH2-CH2-;
(e) Y1 is carbonyl;
(f) Y2 is alkylene having from 1 to 7 carbon atoms substituted on the carbon atom adjacent Y1 by one or two groups each of which may be alkyl or a cyclic radical, other than mono- or di-methyl substituted, (g) Y 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, protected hydroxy, amino, acylamino, alkenyl or alkyl substituted by one or more halogeno groups other than trifluoro-methyl, (h) Y2 and Y3 together form an alkyl group, having from 1 to 7 carbon atoms, at least one hydrogen of which is replaced by fluoro, (i) Y is a covalent bond, -CH2-, or -CH2.CH2- and Y1, Y2 and Y3 taken together form a cycloalkyl or bicycloalkyl group substituted by a hydroxy group.

17. A method as claimed in claim 2, wherein G is alkoxy carbonyl.

18, A method as claimed in claim 2, wherein the com-pound of formula (II) is prepared from a corresponding com-pound of formula (III):-(III) wherein G, Z1 and Z2 have the same meaning as in formula (II) and G may also be cyano, by reaction with cyanic acid, urea, nitrourea, an alkyl isocyanate or an N-alkylurea as appropriate.

19. A method as claimed in claim 18, wherein an alkali metal cyanate is used in the presence of an equivalent amount of acid.

20. A method as claimed in claim 18, wherein urea, nitrourea or an N-alkylurea is used and the reaction effected at a temperature up to 150°C.

21. A method as claimed in claim 1(b), wherein the compound of formula (VII) is prepared by reacting a compound of formula (V) with a compound of formula (VIII):- (V) (VIII) wherein one of Q1 and Q2 is halogeno and the other is amino and each of Z, Z1, Z2 and G1 have the same meaning as in formula (VII).

22. A method as claimed in claim 21, wherein G1 is alkoxycarbonyl, Q1 is amino, Q2 is bromo, Z is hydrogen and Z1 and Z2 have the same meaning as in formula (I).

23. A method as claimed in claim 1(c), wherein the reaction is effected in the presence of a base.

24. A method as claimed in claim 23, wherein the base is an amine.

25. A method as claimed in claim 24, wherein the base is triethylamine or di-iso-propylethylamine.

26. A method as claimed in claim 1(c), wherein the carbonic acid derivative is selected from the group con-sisting of phosgene, diphenylcarbonate and ethyl chloro-formate.

27. A method as claimed in claim 1(d), wherein the alkylating is effected in the presence of a base.

28. A method as claimed in claim 1(d), wherein the alkylating is effected in the presence of an alkali metal hydride, amide or alkoxide.

29. A method as claimed in claim 1(d), wherein the alkylating is effected in the presence of sodium ethoxide.

30, A method as claimed in claim 1(d), 27 or 29, wherein the alkylating agent is a chloride, bromide, iodide or sulphonate.

31. A method as claimed in claim 1(d), 27 or 29, wherein the alkylating agent is an alkyl bromide.

32. A method as claimed in claim 1(f), comprising reacting sodium azide with a compound wherein the group -C.X4=N.X3 is nitrile.

33. A method as claimed in claim 1(g), which com-prises reducing an acid anhydride with sodium borohydride.

34, A method as claimed in claim 1(g), which com-prises reducing an ester with di-iso-butyl aluminium hydride.

35. A method as claimed in claim 1(h), wherein the hydrolysing agent is an alkali metal hydroxide or sodium oxide in water.

36. A method as claimed in claim 2, wherein diethyl 2-[1-(3-hydroxyoctyl)ureido]nonanedioate is cyclised to produce 5-(6-ethoxycarbonylhexyl)-1-(3-hydroxyoctyl) hydantoin.

37. A method as claimed in claim 36, including hydrolysing the ethoxy carbonyl compound to produce 5-(6-carboxyhexyl)-1-(3-hydroxyoctyl)hydantoin.

38. A method as claimed in claim 2, wherein diethyl 2-[1-(3-hydroxy-4,4-dimethylpentyl)ureido]nonanedioate is cyclised to produce 5-(6-ethoxycarbonylhexyl)-1-(3-hydroxy-4,4-dimethylpentyl)hydantoin.

39, A method as claimed in claim 38, including hydrolysing the ethoxy carbonyl compound to produce 5-(6-carboxyhexyl)-1-(3-hydroxy-4,4-dimethylpentyl)hydantoin.

40, A method as claimed in claim 2, wherein diethyl 2-[1-(3-hydroxynonyl)ureido]nonanedioate is cyclised to produce 5-(6-ethoxycarbonylhexyl)-1-(3-hydroxynonyl)-hydantoin.

41. A method as claimed in claim 40, including hydrolysing the ethoxycarbonyl compound to produce 5-(6-carboxyhexyl)-1-(3-hydroxynonyl)hydantoin.

42. A method as claimed in claim 2, wherein diethyl 2-[1-(3-hydroxy-4,4-dimethyloctyl)ureido]nonanedioate is cyclised to produce 5-(6-ethoxycarbonylhexyl)-1-(3-hydroxy-4,4-dimethyloctyl)hydantoin.

43. A method as claimed in claim 42, including hydrolysing the ethoxycarbonyl compound to produce 5-(6-carboxylhexyl)-1-(3-hydroxy-4,4-dimethyloctyl)hydantoin.

44. A method as claimed in claim 2, wherein diethyl 2-[1-(3-hydroxy-3-cyclobutylpropyl)ureido]nonanedioate is cyclised to produce 5-(6-ethoxycarbonylhexyl)-1-(3-hydroxy-3-cyclobutylpropyl)hydantoin.

45, A method as claimed in claim 44, including hydrolysing the ethoxycarbonyl compound to produce 5-(6-carboxyhexyl)-1-(3-hydroxy-3-cyclobutylpropyl)hydantoin.

46. A method as claimed in claim 2, wherein diethyl 2-[1-(3-hydroxy-3-cyclopentylpropyl)ureido]nonanedioate is cyclised to produce 5-(6-ethoxycarbonylhexyl)-1-(3-hydroxy-3-cyclopentylpropyl)hydantoin.

47. A method as claimed in claim 46, including hydrolysing the ethoxycarbonyl compound to produce 5-(6-carboxyhexyl)-1-(3-hydroxy-3-cyclopentylpropyl)hydantoin.

48. A method as claimed in claim 2, wherein diethyl 2-[1-(3-hydroxy-3-cyclohexylpropyl)ureido]nonanedioate is cyclised to produce 5-(6-ethoxycarbonylhexyl)-1-(3-hydroxy-3-cyclohexylpropyl)hydantoin.

49. A method as claimed in claim 48, including hydrolysing the ethoxycarbonyl compound to produce 5-(6-carboxyhexyl)-1-(3-hydroxy-3-cyclohexylpropyl)hydantoin.

50. A compound of formula (I), as defined in claim 1, whenever prepared by the method of claim 1 or 2, or by an obvious chemical equivalent.

51. A pharmaceutically acceptable, pharmacologically compatible salt of a compound of formula (I), as defined in claim 1, whenever prepared by the process of claim 11, or by an obvious chemical equivalent.

52. A compound of formula (I), as defined in claim 1, wherein Z is hydrogen, X2 is carboxyl or alkoxycarbonyl, Y2 is a covalent bond or straight or branched alkylene having 1 to 7 carbon atoms optionally substituted on the carbon adjacent Y1 by one or two alkyl groups; and Y3 is hydrogen, hydroxy, alkoxy having 1 to 7 carbon atoms, phenyl, benzyl, phenoxy or benzyloxy, wherein each of phenyl, benzyl, phenoxy and benzyloxy is unsubstituted or substituted in the benzene ring by one or more groups selected from hydroxy, halogeno, nitro, amino, acylamino, alkenyl, alkoxy, phenyl and alkyl which is unsubstituted or substituted by one or more halogeno groups; or Y2 is a covalent bond and Y3 is cycloalkyl having 4 to 7 carbon atoms, whenever prepared by the process of claim 13, or by an obvious chemical equivalent.

53. A compound of formula (I), as defined in claim 1, wherein Z is hydrogen; X2 is carboxyl or alkoxycarbonyl; each Q is hydrogen; each R is hydrogen, Y2 is a covalent bond or straight or branched alkylene having from 1 to 7 carbon atoms unsubstituted or substituted on the carbon adjacent Y1 by one or two alkyl groups; Y3 is hydrogen, hydroxy, alkoxy having 1 to 7 carbon atoms, benzyl, phenoxy or benzyloxy wherein each of benzyl, phenoxy and benzyloxy is unsubstituted or substituted in the benzene ring by one or more groups selected from hydroxy, halogeno, nitro, amino, acylamino, alkenyl, alkoxy, phenyl and alkyl which is unsubstituted or substituted by one or more halogeno groups; or Y2 is a covalent bond and Y3 is cycloalkyl having 4 to 7 carbon atoms, whenever prepared by the process of claim 14, or by an obvious chemical equivalent.

54, A compound of formula (I), as defined in claim 14, wherein X is cis -CH=CH- or -CH2-CQ2-; X1 is a covalent bond or a straight or branched alkylene chain having 1 to 6 carbon atoms; and Y is a covalent bond and Y is cycloalkyl having 4 to 7 carbon atoms whenever prepared by the process of claim 15, or by an obvious chemical equivalent.

A compound of formula (I), as defined in claim 1, wherein at least one of the following conditions apply:
(a) X is other than -CH2-CH2-; and/or (b) 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 or thia group;

(c) X2 is carbamoyl, hydroxymethyl, and/or (d) Y is other than -CH2-CH2-;
(e) Y1 is carbonyl, (f) Y2 is alkylene having from 1 to 7 carbon atoms substituted on the carbon atom adjacent Y1 by one or two groups each of which may be alkyl or a cyclic radical, other than mono-or dimethyl substituted;
(g) Y is hydroxy, alkoxy having from 1 to 7 carbon atoms, a cyclic radical other than cyclo-alkyl 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, protected hydroxy, amino, acylamino, alkenyl, or alkyl substituted by one or more halogeno groups other than tri-fluoromethyl:
(h) Y2 and Y3 together form an alkyl group, having from 1 to 7 carbon atoms, at least one hydrogen of which is replaced by fluoro, (i) Y is a covalent bond, -CH2- or -CH2.CH2- and Y1, Y2 and Y3 taken together form a cyclo-alkyl or bicycloalkyl group substituted by a hydroxy group, whenever prepared by the process of claim 16, or by an obvious chemical equivalent, 56. 5-(6-Ethoxycarbonylhexyl)-1-(3-hydroxyoctyl) hydantoin, whenever prepared by the method of claim 36, or by an obvious chemical equivalent.

57. 5-(6-Carboxyhexyl)-1-(3-hydroxyoctyl)hydantoin, whenever prepared by the method of claim 37, or by an obvious chemical equivalent.

58. 5-(6-Ethoxycarbonylhexyl)-1-(3-hydroxy-4,4-dimethylpentyl)hydantoin, whenever prepared by the method of claim 38, or by an obvious chemical equivalent.

59. 5-(6-Carboxyhexyl)-1-(3-hydroxy-4,4-dimethylpentyll) hydantoin, whenever prepared by the method of claim 39, or by an obvious chemical equivalent.

60. 5-(6-Ethoxycarbonylhexyl)-1-(3-hydroxynonyl)-hydantoin, whenever prepared by the method of claim 40, or by an obvious chemical equivalent.

61. 5-(6-Carboxyhexyl)-1-(3-hydroxynonyl)hydantoin, whenever prepared by the method of claim 41, or by an obvious chemical equivalent.

62. 5-(6-Ethoxycarbonyhexyl)- 1-(3-hydroxy-4,4-dimethyl-octyl)hydantoin, whenever prepared by the method of claim 42, or by an obvious chemical equivalent.

63. 5-(6-Carboxyhexyl)-1-(3-hydroxy-4,4-dimethyl-octyl)hydantoin, whenever pxepared by the method of claim 43, or by an obvious chemical equivalent.

64. 5-(6-Ethoxycarbonyhexyl)-1-(3-hydroxy-3-cyclo-butylpropyl)hydantoin, whenever prepared by the method of claim 44, or by an obvious chemical equivalent.

65. 5-(6-Carboxyhexyl)-1-(3-hydroxy-3-cyclobutyl-propyl)hydantoin, whenever prepared by the method of claim 45, or by an obvious chemical equivalent.

66. 5-(6-Ethoxycarbonylhexyl)-1-(3-hydroxy-3-cyclo-pentylpropyl)hydantoin, whenever prepared by the method of claim 46, or by an obvious chemical equivalent.

67. 5-(6-Carboxyhexyl)-1-(3-hydroxy-3-cyclopentyl-propyl)hydantoin, whenever prepared by the method of claim 47, or by an obvious chemical equivalent.

68. 5-(6-Ethoxycarbonylhexyl)-1-(3-hydroxy-3-cyclo-hexylpropyl)hydantoin, whenever prepared by the method of claim 48, or by an obvious chemical equivalent.

69. 5-(6-Carboxyhexyl)-1-(3-hydroxy-3-cyclohexyl-propyl)hydantoin, whenever prepared by the method of claim 49, or by an obvious chemical equivalent.

A method of preparing a compound of formula (I) wherein Z is hydrogen; Z1 is the group -CH2-X-X1-X2-;
wherein X is -CH2-CH2-; X1 is a covalent bond or a straight alkylene chain having 1 to 5 carbon atoms; and X2 is selected from carboxyl and alkoxycarbonyl;
and Z2 is represented by the group -Y-Y1-Y2-Y3-;
wherein Y is -CH2-CH2-, Y1 is methylene, methylene substituted by hydroxy or methylene substituted by hydroxy and alkyl, and when Y1 is methylene then Y is a covalent bond and Y3 is hydroxy, and when Y1 is methylene substituted by hydroxy or methylene substituted by hydroxy and alkyl, Y2 is a co-valent bond and Y3 is hydrogen, cycloalkyl having from 3 to 8 carbon atoms, phenyl or benzyl, wherein each of phenyl and benzyl is unsubstituted or substituted in the benzene ring by one or more groups selected from hydroxy, halo, nitro, alkoxy, alkyl and trifluoromethyl. or Y2 is a straight or branched alkylene having 1 to 7 carbon atoms optionally substituted on the carbon adjacent Y1 by one or.
two alkyl or cycloalkyl groups, and Y3 is hydrogen or cyclo-alkyl, provided that not more than one of Y2 and Y3 includes cycloalkyl;
or Y is -CH2.CH2- and Y1, Y2 and Y3 taken together form a cycloalkyl group substituted by a hydroxy group, and salts thereof comprising cyclising a compound of formula (II) (II) wherein G is carboxyl or alkoxycarbonyl, and Z, Z1 and Z2 are as defined above, and when desired converting the com-pound of formula (I) obtained to a corresponding salt, acid or ester of formula (I).

71. A method according to claim 70, wherein Y2 is a covalent bond or straight or branched alkylene having 1 to 7 carbon atoms optionally substituted on the carbon adjacent Y1 by one or two alkyl groups, and Y3 is hydrogen, hydroxy or phenyl.

72. A method according to claim 70, wherein Y1 is methylene substituted by hydroxy or methylene substituted by hydroxy and alkyl of 1 or 2 carbon atoms, Y2 is a co-valent bond or a straight or branched alkylene having 1 to 6 carbon atoms optionally substituted on the carbon adjacent Y1 by one or two methyl groups, and Y is phenyl which may be substituted in the benzene ring by up to three groups selected from trifluoromethyl, methyl, ethyl, n-propyl or i-propyl, methoxy, ethoxy, n-propoxy or i-propoxy or nitro.

73. A method according to claim 70, wherein Y1 is methylene substituted by hydroxy or methylene substituted by hydroxy and alkyl of 1 or 2 carbon atoms' Y is a co-valent bond or a straight or branched alkylene having 1 to 6 carbon atoms optionally substituted on the carbon adjacent Y1 by one or two methyl groups, and Y3 is cycloalkyl of from 5 to 8 carbon atoms.

74. A method according to claim 70, wherein is 6-carboxy-n-hexyl and Z2 is 3-hydroxy-3-methyl-n-nonyl.

75, A method according to claim 70, wherein said con, pound of formula (I) is converted to the sodium salt.

76. A compound of formula (I), as defined in claim 70, whenever prepared by the method of claim 70, or by an obvious chemical equivalent.

77 A compound of formula (I), as defined in claim 71, whenever prepared by the method of claim 71, or by an obvious chemical equivalent.

78. A compound of formula (I), as defined in claim 72 whenever prepared by the method of claim 72, or by an obvious chemical equivalent.

79, A compound of formula (I), as defined in claim 73, whenever prepared by the method of claim 73, or by an obvious chemical equivalent.

80. A compound of formula (I), as defined in claim 74, whenever prepared by the method of claim 74, or by an obvious chemical equivalent.

81. A salt of a compound of formula (I), as defined in claim 75 whenever prepared by the method of claim 75, or by an obvious chemical equivalent.

82. A process for the preparation of a compound of formula (III):

where n is 1 to 8, R1 is hydrogen or alkyl of 1 to 4 carbon atoms, R2 is hydrogen or alkyl of 1 to 4 carbon atoms and R4 is hydrogen or alkyl of 1 to 9 carbon atoms which com-prises cyclization of a compound of formula (IV):

and, if desired, converting the compound to a pharmaceutically acceptable salt thereof.

83. The process according to claim 82, where in formula (III) and (IV), n is 5, 6 or 7, R1 is hydrogen or alkyl of 1 to 4 carbon atoms, R2 is hydrogen or methyl and R4 is hydrogen or alkyl of 1 to 9 carbon atoms.

84. The compound of formula (III), as defined in claim 82, and pharmaceutically acceptable salts thereof, when prepared by the process of claim 82, or by an obvious chemical equivalent.

85. The compound of formula (III), as defined in claim 82, whenever n is 5, 6 or 7, R1 is hydrogen or alkyl of 1 to 4 carbon atoms, R2 is hydrogen or methyl and R4 is hydrogen or alkyl of 1 to 9 carbon atoms, when prepared by the process of claim 83, or by an obvious chemical equivalent.

86. A process for the preparation of a compound of formula (III):

where n is 1 to 8, R1 is hydrogen or alkyl of 1 to 6 carbon atoms, R2 is hydrogen or alkyl of 1 to 4 carbon atoms and R4 is hydrogen or alkyl of 1 to 9 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, phenyl, phenyl substituted by at least one substituent selected from the group consisting of hydroxy, halo, nitro, alkoxy, alkyl and trifluoromethyl;
or R2 and R4 together with the carbon atoms to which they are joined may also form a cycloalkyl group which comprises cyclization of a compound of formula IV

wherein R1, R2, R4 and n are as defined above and, if desired, converting the compound to a pharmaceutically acceptable salt thereof.

87. A process according to claim 86, wherein R2 and R4 together with the carbon atoms to which they are joined form a cycloalkyl group.

88. A process according to claim 86, wherein n is 3 to 8.

89. A process according to claim 86 or 88, wherein R4 is hydrogen or alkyl of 1 to 7 carbon atoms and R1 is hydrogen or alkyl of 1 to 4 carbon atoms.

90. The process according to claim 86, where, in formulae (III) and (IV), n is 5, 6 or 7, R1 is hydrogen or alkyl of 1 to 6 carbon atoms, R2 is hydrogen, methyl or ethyl and R4 is hydrogen or alkyl of 1 to 9 carbon atoms.

91. A process according to claim 90, wherein R4 is hydrogen or alkyl of 1 to 7 carbon atoms.

92. A compound of formula (III), as defined in claim 86, whenever prepared by the process of claim 86, or by an obvious chemical equivalent.

93. A compound of formula (III), as defined in claim 86, wherein R2 and R4 together with the carbon atom to which they are joined form a cycloalkyl group, whenever prepared by the process of claim 87, or by an obvious chemical equivalent.

94. A compound of formula (III), as defined in claim 87, wherein n is 3 to 8, whenever prepared by the process of claim 88, or by an obvious chemical equivalent.

95. A compound of formula (III), as defined in claim 86, wherein n is 5, 6 or 7, R1 is hydrogen or alkyl of 1 to 6 carbon atoms, R2 is hydrogen, methyl or ethyl and R4 is hydrogen or alkyl of 1 to 9 carbon atoms, whenever prepared by the process of claim 90, or by an obvious chemical equivalent.

96. A compound of formula (III), as defined in claim 86, wherein n is 5, 6 or 7, R1 is hydrogen or alkyl of 1 to 6 carbon atoms, R2 is hydrogen, methyl or ethyl and R4 is hydrogen or alkyl of 1 to 7 carbon atoms, whenever prepared by the process of claim 91, or by an obvious chemical equivalent.