CH645631A5 - Process for the preparation of hydantoin derivatives - Google Patents

Description

The invention relates to the production of hydantoin derivatives. The hydantoin derivatives, which are defined in more detail below as compounds of the formula I, have pharmacological properties which are related to those of the natural prostaglandins. This is reflected in their ability to mimic or counteract the physiological effects of natural prostaglandins in various biological preparations. In particular, it has been found that certain compounds of the formula I inhibit platelet aggregation as effectively as the prostaglandin egg.

In the compounds of formula I

0

z-n

0

mean

Z is hydrogen or alkyl; one of the groups Z1 and Z2 the group -ŒL-X-X ^ X2, wherein

X is phenylene, -C = C-, ice or trans-CH = CH- or -CH2-CQ2-, where each Q is independently hydrogen and alkyl, such as ethyl, or the two Q together are an alkylene group with 4, 5 or 6 Represent carbon atoms;

XI is a covalent bond or a straight-chain or branched-chain alkylene chain having 1 to 6 carbon atoms, in which one of its methylene groups may be replaced by a 0xa (-0-) group, provided that at least one carbon atom has the oxa group of a -C = C -, -CH = CH or -CO group separates; and

X2 is 5-tetrazolyl, carboxyl, carboxamide, hydroxymethylene or alkoxycarbonyl, and the other of the groups Z1 and Z2 is the group -Y-Y'-Y2-Y3, in which

Y is -CR2-CH2-, where each R is independently hydrogen and methyl;

Y1 carbonyl, methylene, one by hydroxy or by

Hydroxy and alkyl substituted methylene group; Y2 is a covalent bond or a straight- or branched-chain alkylene group having 1 to 7 carbon atoms, which may optionally be substituted on the carbon atom adjacent to Y1 by one or two independent alkyl, bicycloalkyl or cycloalkyl groups;

Y3 is hydrogen, hydroxy, alkoxy having 1 to 7, preferably 1 to 4, carbon atoms, cycloalkyl, bicycloalkyl, phenyl, benzyl, phenoxy or benzyloxy, wherein each of the groups phenyl, benzyl, phenoxy and benzyloxy in the benzene ring through one or more of the groups hydroxy , Halogen, nitro, amino, acylamino, alkenyl, alkoxy, phenyl and alkyl, which in turn can be substituted by one or more halogens; or

Y is a bond, -CH2- or -CH2.CH2-; and

Y1, Y2 and Y3 together form a cycloalkyl group which is substituted by a hydroxyl group and preferably has 3 carbon atoms which separate them from the hydantoin ring,

mean.

Unless otherwise stated, in the present description, in the compounds of the formula I and in compounds of the other formulas, the alkyl groups preferably denote methyl, ethyl, propyl, butyl, pentyl and hexyl, including all of their isomers. For example, in the definitions of Y1 and Y2, the alkyl groups in particular mean methyl and the alkyl portion of the alkoxycarbonyl group in particular methyl or ethyl. So alkenyl groups with 2 to 4 carbon atoms, for example vinyl, are likewise preferred.

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In the compound of formula I, the cycloalkyl groups preferably have 3 to 10 carbon atoms and the bicycloalkyl groups preferably 4 to 10 carbon atoms, for example adamantyl.

In a compound of formula I the bond of the divalent phenylene group can be ortho, meta or para and the oxa group is preferably adjacent to phenylene or, if X is other than phenylene, X1 is preferably -CH2-0-CH2-.

The compounds of formula I also include the salts of the corresponding carboxylic acids and tetrazoles when X2 is carboxyl or tetrazolyl, and the salts which can also be formed when Z is hydrogen. Particularly valuable salts for medical purposes are salts which have a pharmaceutically acceptable cation, such as ammonium, or a cation of an alkali metal, such as sodium or potassium, an alkaline earth metal, such as calcium and magnesium, or an organic base, in particular an amine. such as ethanolamine. Salts without a pharmaceutically acceptable cation also fall within the scope of the present invention since they are useful as intermediates for pharmaceutically acceptable salts or acids or esters of the compound of formula I.

Unless expressly stated otherwise, all stereoisomers are included in the compounds of the formula I and all other compound formulas mentioned in the description. In particular, these formulas include the enantiomeric forms, these mixtures are called racemates, and the diastereoisomers.

It has been found that the compounds of the formula I in which Z is hydrogen or alkyl having 1 to 4 carbon atoms, for example methyl or butyl; one of the groups and Z2 -CHrX-X ^ X2-, in which and X1 together is an alkylene having 3 to 7, preferably 5, carbon atoms; and

Alkoxycarbonyl, carboxyl or a salt thereof, and the other of the groups and Z2 -Y-Y ^ -Y3-, wherein Y1 and Y2 have the meaning as above; and represents hydrogen, cycloalkyl having 4 to 7 carbon atoms, phenyl or benzyl,

mean, are compounds which have particularly interesting prostaglandin-related properties. This definition includes a subclass in which Z is hydrogen and Z1 is -CHo-X-X ^ X2-.

The compounds of formula I can be prepared in the manner known for compounds of analogous structure.

According to the invention, they are obtained from the corresponding derivatives of hydantoic acid of the formula II

Z1 X

X2

Z1 Y,

Y3

(ii),

wherein

G is carboxyl or one of its functional derivatives, such as an amide or ester, especially an alkyl ester; and Z, Z1 and Z2 have the meaning given above, produced by cyclization.

The cyclization is preferably carried out under acidic conditions or by heating alone. The reaction can be carried out in the absence of a solvent, but an inert solvent, e.g. a hydrocarbon, e.g. B. gasoline can be used. On the other hand, when G is alkoxycarbonyl, the cyclization can be carried out in the presence of a suitable base, for example an alkoxide, such as sodium ethoxide.

According to the invention, the compounds of the formula II are prepared by the processes specified in claims 12 and 16.

If cyanic acid is used in the process according to claim 12, it is usually used in situ using an alkali metal cyanate, e.g. As potassium cyanate, and an acid prepared, which may be present as an acid addition salt of the compound of formula III 'or as a free acid of formula III', wherein 15 either one or both groups R and X2 are hydrogen. On the other hand, an equivalent amount of a mineral acid or an organic acid can be added to the reaction medium. The reaction can be carried out in the absence of a solvent, but if necessary an inert solvent can also be used, which is preferably polar, such as water, or a mixture of water with acetone, dimethylformamide, dimethyl sulfoxide or a lower alcohol, such as ethanol . As a solvent e.g. but also a hydrocarbon, an ether or a halogenated hydrocarbon, e.g. Chloroform. If necessary, if, for example, no solvent is used, the reaction can also be accelerated by heating the reactants.

Similar reaction conditions can be used in the process of claim 16, in which an alkyl isocyanate is used, it being unnecessary to provide an equivalent amount of acid, as an acid addition salt or as another compound, as a reactant.

Instead of using a cyanate, a compound of the formula III 'can also be reacted in process 35 according to claim 12 with urea, nitrourea or an N-alkylurea as required. A solvent is not necessary, but an inert solvent, for example one of those mentioned above, can be used if desired. The reaction is preferably carried out at elevated temperature, for example at 100 to 125 ° C, but temperatures up to 150 ° C can also be used.

In the production process described above, the intermediates of the formula II need not be isolated from the reaction mixture 45 and can be converted directly into the compounds of the formula I under the reaction conditions described.

An intermediate product of the formulas III 'and III "specified in claims 12 and 16" can be obtained in a simple manner by reacting a compound of formula IV with a compound of formula V

55

(iv)

60

Q

(v)

wherein

G ', Z1 and Z2 have the same meaning as in formula III'; and in which one of groups 65 Q1 and Q2 amino and the other a halogen, preferably bromine,

mean be manufactured. The implementation can e.g. B. by heating in the absence of a solvent or in counter

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an inert solvent such as ethanol.

The intermediates of the formulas III 'or III ", in which Z2 is -Y-Y'-Y ^ Y3 when Y1 is carbonyl, can also be reacted, for example, by reacting an amine of the formula IV in which Q1 is amino with an unsaturated ketone Formula VI

CR2 = CH.CO.Y2.Y3 (VI),

wherein

Y2 and Y3 have the same meaning as in formulas III 'and III ", respectively. The reaction is carried out in the presence or in the absence of an inert solvent, preferably at room temperature or, if appropriate, with heating.

According to the invention, the hydantoins of the formula I are also obtained by cyclization of a compound of the formula VII

z-n '

2nd

wherein

Z, Z1 and Z2 have the same meaning as in formula I; and G carboxyl or one of its active functional derivatives such as alkoxycarbonyl, e.g. B. ethoxycarbonyl means. The compounds of formula VII can be cyclized under conditions similar to those of a compound of formula II. Usually the method to be used to prepare a compound of formula VII is chosen so that the prevailing reaction conditions allow spontaneous cyclization.

According to the invention, the intermediates of formula VII by reacting a compound of formula V with a compound of formula VIII

q2-z2 (v)

0

g wherein either

Q1 or Q2 is a halogen, preferably chlorine or bromine, and the other group is amino; and Z, Z1, Z2 and G have the same meaning as in formula VII. The reaction can e.g. B. by mixing the reactants or it can e.g. an inert solvent is used and the mixture is heated. Suitable solvents include alkanols, ethers, hydrocarbons and 'halogenated hydrocarbons.

The compounds of formula VIII in turn can e.g. by reacting a corresponding carbamic acid derivative, for example an alkyl ester, with a compound of the formula IV under the conventional conditions.

In a process similar to the production process described above, the hydantoins of the formula I are reacted according to the invention by reacting a compound of the formula IX

0

z z

wherein

Z, Z1 and Z2 have the meaning as in formula I,

made with a carboxylic acid derivative. All known and suitable carboxylic acid derivatives can be used, for example phosgene, diphenyl carbonate or an alkyl haloformate, such as, for example, chlorinated carbonate. The reaction is preferably carried out in the presence of a base, for example an amine, such as triethylamine or di-iso-propylethylamine, and using an inert aprotic solvent, for example toluene, dimethylformamide or an ether, for example diethyl ether. The implementation can e.g. B. at room temperature, if necessary, the reaction mixture can be heated.

The intermediates of formula IX can be prepared analogously to the methods described for the preparation of the compounds of formula III 'or III ".

The tetrazoles of the formula I can also be obtained from the corresponding compounds, in which the group X2 is represented by the group -C = N, in which X3 and X4 together form a bond (nitrii)

X4 X3

mean, X3 is hydrogen or alkyl and X4 is alkoxy (imido-ester), alkylthio (imidothioester), -NH-NH2 (amidrazone) or amino (amidine), or R3 is hydroxy and R4 is amino (amidoxime). The reaction is preferably carried out in a polar aprotic liquid medium, such as dimethylformamide, using a salt of a hydrochloric acid, for example sodium azide. However, if X2 is replaced by an amidine or amidrazone, a suitable reagent, e.g. B. nitric acid. If an amidine is reacted with nitrous acid, the reduction of the nitrosation intermediate with or without isolation using, for example, sodium amalgam is necessary to give the corresponding tetrazole. The tetrazole precursor can be obtained in a known manner. So z. B. Nitrii can be prepared by dehydrogenation of the corresponding amide.

The alcohols of the formula I in which X2 denotes hydroxymethylene can likewise be obtained from the corresponding acid, ester, acid halide, acid anhydride or aldehyde by reduction with an appropriate reducing agent. The corresponding reducing agent depends on the particular reactant, but mostly sodium in ethanol can be used. For example, a carboxylic acid e.g. with chlorinated carbonate in the presence of a base such. As triethylamine, are converted into a corresponding mixed anhydride and then reduced to the alcohol using, for example, sodium borohydride. In the same way, an ester can be converted to an alcohol, for example using diisobutylaluminum hydride in an inert solvent, e.g. Ether or a hydrocarbon such as As hexane or benzene, can be reduced. These alcohols can also be produced by catalytic hydrogenation.

On the other hand, the alcohols of the formula I in which X2 is hydroxymethylene can be prepared by hydrolysis of an appropriate halide with a suitable reagent. A hydroxide can be used for this purpose,

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for example an aqueous alkali hydroxide, or a suspension of silver oxide in water.

When preparing the hydantoins of the formula I with a hydroxyl group in a side chain, it may be desirable to protect them during the course of the reaction. This can easily be done in a known manner by a protecting group, e.g. B. by acyl, aroyl, tetrahydropyran-2-yl, 1-ethoxyethyl or aralkyl, e.g. B. Benzyl.

The protective groups can be removed by suitable known methods, for example an acyl group can be removed by acid or base hydrolysis and a benzyl group by reducing cleavage.

In addition, a ketone of formula I, wherein Y1 is carbonyl, can be incorporated into the corresponding secondary alcohol by reduction with a suitable reducing agent, e.g. Sodium borohydride. An alcohol of the formula I in which Y1 is -CH2OH- can also be oxidized to the corresponding ketone using Jones reagent, acid dichromate or another suitable reagent.

In the same way, the compounds of the formula I which have a —C = C or —CH = CH bond can be converted into the corresponding ethylene or saturated compounds by means of conventional hydrogenation processes, for example according to Lindlar or with an Adams catalyst .

The hydantoin derivatives of the formula I have an asymmetric 5-carbon atom and in the compounds of the formula I in which Y1 contains a hydroxyl group there is another asymmetric center. These alcohols therefore exist as four isomers which can be separated into two diastereomers by thin layer chromatography or high performance liquid chromatography (HPLC), each of which is a racemic mixture of two isomers. When the diastereomers are separated, a diastereomer can be converted into a mixture of the four isomers by adding a base, for example an alkali metal hydroxide, and then "reseparated" again to two diastereomers. Repeated use of this technique enables the actual conversion of one diastereomer to the other. This may be desirable if one diastereomer has a preferred biological activity over the other.

The corresponding alcohols of the formula III 'or III "also exist in four isomeric forms. If necessary, these can be separated into two diastereomers. The subsequent cyclization to a compound of the formula I maintains the stereochemical configuration.

With all the preceding chemical processes, it is of course clear that the choice of the reactant is determined in part by the functional groups present in the material and that if necessary, reactants must be used which have a suitable selective mode of action.

The hydantoin derivatives of the formula I have valuable pharmacological properties which are related to those of the natural prostaglandins. This means that the hydantoin derivatives mimic or counteract the biological effects of prostaglandins (PG) "A", "B", "C", "D", "E" and "F" series. It has been found that the hydantoin derivatives of the formula I have the same inhibitory effect on the aggregation of platelets as the PGE and that they have the contraction induced by PGE2 or PGF2 on the smooth muscles of rat stomach, rat intestine, the rectum of chickens and the trachea of guinea pigs counteract. In general, the antagonistic properties, as opposed to the mimicking ones, were observed when larger doses of the hydantoin derivatives were used. The pharmacological "profile", which is understood to mean the relative modes of action, namely the mimicking ones

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or the antagonistic, compared to the natural prostaglandins, of course varies depending on the specific hydantoin derivative under consideration.

Due to their properties related to prostaglandin, the hydantoin derivatives of the formula I are useful in the pharmacological characterization and differentiation of the biological effects of the natural prostaglandins and their receptors. Further understanding of the physiological effects of prostaglandins is of course of great value in the search for new and improved therapeutic substances.

The hydantoin derivatives of the formula I are also of great use as therapeutic active ingredients. In particular, the above-described hydantoin derivatives with an inhibitory effect on the aggregation of platelets are useful when platelet aggregation is to be inhibited or to reduce the ability of the platelets to stick. They can be used to treat or prevent thrombosis in mammals, including humans. 20 For example, the present compounds are useful in the treatment and prevention of myocardial infarctions, for the treatment and prevention of thromboses, and for improving the patency of vascular grafts after surgical interventions. They are also suitable for the treatment of arterioskle-25 rose and conditions such as atherosclerosis, disorders of blood clotting due to lipaemia and other clinical conditions in which the cause of the disease is related to an impaired lipid balance or hyperlipidemia. These compounds can furthermore be used as additives to blood and other liquids which are used for the artificial maintenance of a circulation outside the body or for the flushing of isolated parts of the body.

A group of compounds which have proven particularly valuable as inhibitors of platelet aggregation are the compounds of the formula I in which Z is hydrogen, Z1 is carboxylalkylene in which the alkylene part has 3 to 9 carbon atoms and Z2 is a group - (CH2 ) 2. CH. OH. Y2. Y3, wherein Y2 has a branched chain alkylene with a tertiary carbon atom adjacent to the 40 hydroxy-substituted carbon, and Y3 has the meaning as in formula I. The compounds in which Z1 is carboxyhexyl and Y3 are cycloalkyl having 4 to 7 carbon atoms have proven particularly effective in this group.

45 Furthermore, it has been found that the hydantoin derivatives of the formula I bring about a relaxation of the vascular smooth muscles in a similar way to the prostaglandins of the groups "A" and "E". Examples of these compounds are the 5- (6-carboxyhexyl) -l- (3-hydroxy-4,4-dimethyloctyl) -hydantoin and the 5- (6-carboxyhexyl) -l- (3-hydroxy-4,4) -dimethyl-5-phenylpentyl) hydantoin. The compounds that relax the vascular smooth muscles therefore have a vasodilatory effect and thus antihypertensive properties and can therefore be used to lower blood pressure in mammals and 55 in humans. They can be administered either alone or with an agent blocking the adrenaline-ß receptors or another antihypertensive agent for the treatment of all types and strengths of elevated blood pressure including the essential, malignant and secondary hyper-60 tension.

The compound 5- (6-carboxyhexyl) -1- (3-hydroxy-4,4-dimethyloctyl) hydantoin also has the same effect as PGE, namely to counteract the bronchial constrictions caused by histamine. The hydantoin derivatives of formula I 65 which possess these properties can be used for the treatment or prophylaxis of bronchial asthma and bronchitis by eliminating the bronchial constriction associated with these clinical pictures.

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The hydantoin derivatives of the formula I, such as, for example, the 5- (6-carboxyhexyl) -1- (3-hydroxyoctyl) hydantoin, the 5- (6 ~ carboxyhexyl) -3-methyl-1- (3-oxooctyl) hydantoin, the 5- (6-carboxyhexyl) -l- (3-oxo-octyl) -hydantoin and the 5- (6-carboxy-hexyl) -l- (4-phenoxybutyl) -hydantoin, which caused those caused by penta-5 gastrin Inhibiting gastric acid secretion and reducing the formation of aspirin-related gastric ulcers in rats can serve to reduce excess gastric secretion, to reduce or prevent the formation of gastrointestinal ulcers or to heal such ulcers and damage that are already present in the gastrointestinal tract , to accelerate. This can occur either with spontaneous ulcers or with ulcers that are associated with polyglandular adenoma syndrome. 15

It has also been found that intravenous infusions of certain hydantoin derivatives of the formula I, for example 5- (6-carboxyhexyl) -1- (3-hydroxyoctyl) hydantoin, increase the urine volume in dogs, which indicates a possible use of these derivatives as diuretics . This application enables the treatment of oedemas, such as those that occur in heart defects, liver or kidney damage in humans or mammals.

Another use of the hydantoin derivatives of the formula I, the effect of which is similar to the action on the smooth muscles of the uterus of PGE2 and PGF2c, is the action as an antifertility agent, in particular as an abortivum.

The amount of a compound of the formula required to achieve the desired biological effect naturally depends on a number of factors, for example the type of compound chosen, the particular use, the dosage form and the recipient. In general, daily doses can range from 1 jig to 20 mg / kg body weight. For example, an intravenous dose may range from 5 µg to 1 mg / kg body weight, which can generally be administered as an infusion of 0.01 to 50 µ, mg / kg and per minute. The infusion solutions suitable for this purpose can generally contain 0.001 to 100, for example 0.01 to 10 μg / ml. Single doses generally contain 10 [Xg to 100 mg of a compound of formula I. Ampoules for injection can, for. B. 0.01 to 1 mg and orally administrable single-dose preparations, such as tablets or capsules, can generally 0.1 to 50 mg, e.g. B. 2 to 20 mg of the active ingredient.

If a compound of formula I is to be used to inhibit platelet aggregation, it is generally indicated to have a concentration in the appropriate fluid, either in the patient's blood or in a perfusion fluid, of about 1 to 10 mg. for example, 10 (xg to 1 mg, per liter.

The above doses relate to the acids,

Amides, esters, alcohols and tetrazoles of the formula I. If a salt is used, the dose should be chosen based on the corresponding anion.

For the treatment or prophylaxis of the 55 states described above, the hydantoin derivatives can be administered as a crude product, but their administration in the form of pharmaceutical preparations with a suitable carrier is preferred. The carrier must of course be "acceptable" in the sense that it is compatible with the other components of the preparation and is not harmful to the recipient. The carrier can be either solid or liquid and is produced with a hydantoin derivative, preferably as a single dose preparation, for example as a tablet, which can generally contain 0.05 to 95% by weight of the hydantoin derivative. Other pharmacologically active substances can also be present in the preparations. The hydantoin derivatives can either in

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be processed in their acid form or as a salt or ester. The preparations can be prepared in all ways known in pharmacy, essentially mixing the components of the preparations together.

Suitable preparations are, for example, those for oral, rectal, local (e.g. buccal, such as sub-lingual), parenteral (that is to say subcutaneous, intramuscular and intravenous) administration, the appropriate dosage form depending on the type and severity of the treating disease and depends on the type of hydantoin derivative.

Preparations for oral administration can be in divided single doses, such as capsules, cachets, lozenges or tablets, each unit containing a predetermined amount of the hydantoin derivative. Furthermore, the preparations can be in the form of powders or granules, as a solution or suspension in an aqueous or non-aqueous liquid, furthermore as an oil-in-water emulsion or as a water-in-oil emulsion. These formulations can be prepared in any manner known in pharmacy, the hydantoin derivative being mixed with the carrier which consists of one or more ingredients. In general, they are prepared by uniformly and intimately mixing the hydantoin derivative with the liquid or finely divided solid carrier or with both, and then brought into the desired dosage form as required. For example, tablets can be produced by pressing or molding a powder or granulate of the hydantoin derivative, optionally with one or more auxiliaries. Pressed tablets can be obtained by pressing the active component in a free-flowing form, e.g. B. as a powder or in the form of granules, optionally mixed and pressed with a binder, lubricant, inert diluent, surface-active agent or dispersant using a suitable machine. Molded tablets can be molded by molding the powdered hydantoin derivative moistened with an inert liquid diluent using a suitable machine.

Preparations for buccal (sub-lingual) administration are mostly lozenges which contain a hydantoin derivative in a flavor base, usually sucrose, gum arabic cum or tragacanth. Furthermore, for this administration, lozenges can also be present which contain the hydantoin derivative in an inert basis, such as, for example, gelatin and glycerol, or sucrose and gum arabic.

The preparations intended for the parental dosage form contain sterile aqueous preparations of a hydantoin compound, which are preferably isotonic with the blood of the recipient. These preparations are preferably administered intravenously, although the administration can also take place as a subcutaneous or intramuscular injection. These preparations can usually be prepared by mixing the hydantoin derivative with water and sterilizing and by producing the isotonicity with the blood.

Preparations for rectal administration are preferably in single dose suppositories. These can be prepared by mixing the hydantoin derivative with one or more of the conventional solid carriers, such as cocoa butter, and shaping the resulting mixture.

In summary, the main effects of the new compounds of the formula I are listed once again:

Lowering blood pressure in mammals, including humans, treatment or prophylaxis of thrombosis in humans and mammals or mammalian tissues, vasodilation in humans and mammals, treatment and prophylaxis of gastrointestinal lesions in humans and mammals, bronchial dilation in humans and mammals,

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Treatment and prophylaxis of allergic conditions in humans and mammals, abortion of a fetus in humans and mammals, infertility in humans and mammals, with the administration of a non-toxic, effective amount of a compound of formula I.

The following examples serve to illustrate the invention without restricting it.

example 1

Preparation of 5- (6-carboxylhexyl) -1- (3-hydroxy-4,4-dimethyl-5-phenylpentyl) hydantoin

A. Diethyl 2-amino nonanoate

16.7 g of diethyl acetamidomalonate and 16.6 g of ethyl 7-bromheptanoate were dissolved in ethanolic ethoxide (prepared from 1.51 g of sodium and 30 ml of absolute ethanol) and the mixture was heated under reflux for 27 hours. The cooled solution was poured into ice water, the product extracted into ether and the dried extract evaporated, after which crude diethyl acetamido (6-ethoxycarbonylhexyl) maonate resulted as a pale yellow oil 52.2 (3H, singlet, -CÖCH3), 4.17 (6H, Multiple «, 3 x -OCH2-CH3. This amide was heated under reflux with 111 ml of concentrated hydrochloric acid for 5Ì4 h, the cooled solution was washed with ether and the aqueous layer was decolorized with activated carbon and evaporated to dryness in vacuo The remaining colorless mass was dissolved in the minimum amount of absolute ethanol and added dropwise to a stirred, cooled (-10 ° C) mixture of 125 ml of absolute ethanol and 15.7 g of thionyl chloride. The resulting solution was set aside at room temperature for 1 hour. 1'A h heated under reflux, cooled and poured into ice water, the pH being adjusted to 9 with aqueous sodium hydroxide solution. The mixture was extracted with ether and the get rocknete extract concentrated and distilled, whereby diethyl 2-aminononanedioat (55% yield) resulted as a colorless oil.

Boiling point: 114 to 115 ° C / 0.02 to 0.03 mm Hg.

B. Diethyl 2 - ((4,4-dimethyl-3-oxophenylpentyl) amino) nonandioate

3.95 g of 4,4-dimethyl-5-phenylpent-1-en-3-one was added dropwise to 5.18 g of diethyl 2-aminononanedioate with cooling and stirring. The mixture was left at room temperature for 21 hours to give diethyl 2 - ((4,4-dimethyl-3-oxo-5-phenylpentyl) amino) nonanedioate.

C. Diethyl-3 - ((3-hydroxy-4,4-dimethyl-5-phenylpentyl) amino) -

nonandioat

5.1 g of the previous crude ketone was dissolved in 70 ml of absolute ethanol and the solution was stirred in an ice bath while gradually adding 380 mg of sodium borohydride. The solution was stirred in the ice bath for an additional 10 minutes and then allowed to stand at room temperature for 5 hours. Most of the alcohol was evaporated, water was added and the solution was acidified to pH 6. The insoluble oil was extracted with ether and the ether solution was dried and evaporated, whereupon diethyl 2 - ((3-hydroxy-4,4-dimethyl-5-phenylpentyl) amino) nonanedioate resulted as a pale yellow oil, which without further cleaning was used.

D. 5- (6-ethoxycarbonyl-hexyl) -l- (3-hydroxy-4,4-dimethyl-5-

phenylpentyl) hydantoin and the corresponding acid

A solution of 8.45 g of the above alcohol in 37.6 ml of ethanol and 18.8 ml of 2N hydrochloric acid was stirred and cooled in ice while dropwise adding a solution of 3.05 g of potassium cyanate in 5.6 ml of water. The mixture was left at room temperature for 18 hours, then the alcohol was evaporated, water was added and the insoluble oil was added

Ether extracted. The dried ether solution was evaporated to give a viscous oil, which was heated on the steam bath for 6 hours, after which the 5- (6-ethoxycarbonylhexyl) -l- (3-hydroxy-4,4-dimethyl-5-phenylpentyl) -hydantoin 5 resulted as a viscous, pale yellow oil.

This ester was added to a mixture of 25 ml of 2N sodium hydroxide and 60 ml of water, and the resulting cloudy solution was left to stand at room temperature for 2 hours. The solution was washed out with ether and the clear, alkaline solution was acidified with 2N hydrochloric acid and the oil which had precipitated was extracted with ether. After evaporation of the dried ether solution, 6.8 g of a viscous oil resulted, which was chromatographed on a silica gel column. This resulted in 5- (6-carboxyhexyl) -l- (3-hydroxy-4,4-dimethyl-5-phenyl-15 pentyl) hydantoin as a colorless viscous oil, which solidified. Melting point about 115 ° C, shrinking from about 90 ° C because a mixture of diastereomers was present. Repeated recrystallization from a mixture of ethanol acetate and light petroleum (boiling point 60 to 80 ° C) gave one of the 20 diastereomers as thin needles, melting point 135 to 137 ° C.

Example 2

Preparation of 5- (6-carboxyhexyl) -l- (3-hydroxyoctyl) -25 hydantoin

A. Diethyl 2- (3- (tetrahydropyran-2-yloxy) octylamino) nonanedioate

Dry ethereal hydrogen bromide made from 200 ml ether and 26.8 g hydrogen bromide at 0 ° C was added dropwise to a stirred solution of 19.15 g acrolein in 100 ml ether cooled to -25 ° C. The stirred mixture was kept at this temperature for 1 hour, then brought to 0 ° C., stirred at this temperature for 1 hour and then dropwise to pentylmagnesium bromide 35 (prepared from 54 g of 1-bromopentane, 8.8 g of magnesium and 120 ml Ether) was added while maintaining a constant reflux temperature. The reaction mixture was mixed with saturated aqueous ammonium chloride and extracted with ether, the dried extract was evaporated down and distilled, 40 using 1-bromo-3-hydroxyoctane as a colorless oil with a boiling point of 68.5 to 72.5 ° C / 0.08 mm Hg received. A solution of 20.9 g of this bromoalcohol in 17.0 g of dihydropyran was mixed with 500 mg of p-toluenesulfonic acid in a little ether, left to stand at room temperature for 18 hours and washed out with aqueous 45 sodium bicarbonate solution. The organic layer was percolated through silica in an ether / hexane mixture (1: 9) and the solvent removed in vacuo to give l-bromo-3- (tetrahydropyran-2-yloxy) octane as a colorless oil, 00.88 ( 3H, triplet, -CH3) and 4.62 (1H, broad, 50 -0-CHR-0-). A solution of 15.0 g of this tetrahydropyranyl intermediate and 13.0 g of diethyl 2-aminononanedioate in 100 ml of absolute ethanol was heated under reflux for 18 hours, then the ethanol was removed in vacuo and the residue was washed with water, which sodium carbonate in light Over-55 shots included, diluted. The mixture was extracted with dichloromethane, the extract was dried over sodium sulfate and evaporated and the residue was purified by column chromatography on silica in a hexane / ether mixture (1: 4). The result was diethyl 2- (3- (tetrahydropyran-2-yloxy) octyl-60 amino) nonanedioate as a colorless viscous oil, 00.88 (3H, triplet -CH3), 2.28 (2H, triplet, - CH2-C02Et), 2.61 (2H, multiple «, -CH2-N), 3.20 (1H, triplet, N-CHR-CO, Et), 4.13 (4H, multiple«, 2 X -0 -CH2-CH3), 4.60 (1H, broad, -O-CHR-O).

The above amino diester, on the other hand, was prepared in the following 65 ways: 10.40 g of diethyl 2-aminononanedioate and 5.04 g of oct-1-en-3-one were slowly mixed at 0 ° C with stirring and allowed to stand at room temperature for 3 hours. The result was diethyl 2- (3-oxooctylamino) nonanedioate as a colorless oil,

645 631 12

62.3 (4H, multiplet, -CH> -CO-, Et and NCH-> CH2CO-), exchangeable, -C02H, -OH), about9.0 (IH, broad, exchangeable,

3.16 (IH, triplet, Et02C-CHR-N), 4.11 (2H, quartet, NH).

-0-CH2-CH3), 4.17 (2H, quartet, -0-CH2-CH3). A stirred using the procedure of Example 1, the solution of 13.5 g of this ketone in 140 ml of absolute ethanol identified hydantoin above was also added dropwise at 0 ° C with 665 mg of sodium borohydride in 70 5 diethyl-2 - ((3rd -hydroxyoctyl) amino) nonanedioate, ml of absolute ethanol was added, then left to stand for 3 to 4 hours at room temperature and concentrated at 40 ° C in a vacuum. The residue dissolved in D. separation of the diastereomeric water was brought to pH 5 using n-hydrochloric acid and then extracted carefully with chloroform, the hydantoin provided was a viscous oil, which was washed out with water using the extract, dried and evaporated , "HPLC from a silica column with a mixture of chloro, after which diethyl 2- (3-hydroxy-octylamino) nonanedioate was obtained as formal methanol and acetic acid (97: 2.5: 0.5) as a solvent in colorless oil. The latter was separated into the two diastereomers without further purification, and both diastereomers, 14.0 ml of dihydropyran to which 10 ml of ether had been added, formed small, colorless needles with melting points 76 to followed by portionwise addition of 6.72 g of p- Toluene sulfone- 78 ° C or 63-65 ° C.

acid and the whole for 18 h at room temperature- «The same diastereomers were released by cyclization of the. The reaction solution was diluted with ether, prepared using speaking diastereomers of the formula 3. The aqueous sodium carbonate and then washed out with water means that the mixture of the diastereomers of diethyl 2-dried and evaporated and the residue by means of [(3-hydroxyoctyl) amino] nonanedioate, prepared in Example 1, column chromatography was dissolved on silica in a hexane / ether-ethanol and then an ethereal solution of mixture (1: 4) was cleaned. The result was that diethyl 2- (3- (tetrahy-20 hydrogen chloride) was added. The solution became trok-dropyran-2-yloxy) octylamino) nonanedioate, which was evaporated with the kene and the mixture of diastereo-top resulted Compound prepared was identical (NMR, IR meren hydrochloride as a viscous oil, which can be found in the case of mixed thin-layer chromatography). leave partially solidified. Then ether was added and

“The mass stirred and cooled, being a crystalline solid

B. 5- (6-Carboxyhexyl) -l- (3-tetrahydropyran-2-yloxy) octyl) - resulted, which was collected, washed with ether and dried hydantoin. The solid was recrystallized from ethyl acetate and

A solution of 7.8 g of diethyl 2- (3-tetrahydropyran-2-) gave small, colorless plates of the pure hydrochloride with yloxy) octylamino) nonanedioate in 32 ml of ethanol, which had a melting point of 95 to 96.5 ° C. This salt was in

Solution of 3.0 g of potassium cyanate in 6 ml of water was added. The 3Q dilute sodium hydroxide solution was suspended and the suspension resulting with ether was stirred and shaken out during the step-washing out of the separated ether solution,

have addition of 16.7 ml of 2N hydrochloric acid cooled. The solution dried and evaporated. One received one of the diastereo-

was left at room temperature for 22 h, the mere (A) of diethyl (2 - [(3-hydroxyoctyl) amino] nonanedioate

Most of the ethanol evaporated, water added and that as a colorless oil.

insoluble oil extracted with ether. The ether solution was treated with 3J Das after collecting the original solid hydrochloride.

Washed out water, dried over magnesium sulfate and the remaining ether filtrate was evaporated and it resulted.

evaporated. The 8.0 g of the yellow oil obtained in this way formed an oily hydrochloride, which, as described above, was dissolved in light petroleum (boiling point 60 to 80 ° C.) and the base was converted. The result was almost pure

The solution was heated under reflux for 4 h, then the second diastereomer (B) of diethyl-2 - [(3-hydroxyoctyl) - was dried.

evaporated and the remaining oil on the steam bath for 2 h 4Q amino] nonanedioate as a colorless oil.

heated. 7.3 g of 5- (6-ethoxycarbonylhexyl) -1- resulted. In the manner described in Example 1, the above

(3- (tetrahydropyran-2-yloxy) octyl) hydantoin as a yellow oil, diastereomer A in a single diastereomer of 5- (6-carboxy-

which was used without cleaning. hexyl) -l- (3-hydroxyoctyl) hydantoin, which consists of

A solution of 6.2 g of the ester in 80 ml of 0.5N sodium - a mixture of ethyl acetate and mineral spirits (boiling point hydroxide solution was standing at room temperature for 2 hours - 60 to 80 ° C) as small colorless needles with a melting point. The solution was then washed out with ether, which crystallized from 63 to 65 ° C.

aqueous layer acidified with 2N hydrochloric acid and the precipitated In the same way, the above diastereomer B was extracted into the oil with ether. The washed and dried ether - second diastereomer of 5- (6-carboxyhexyl) -l- (3-hydroxyoc-

The extract was evaporated and the 5- (6-carboxy-tyl) -hydantoin resulted, which consists of ethyl acetate / light benzene.

hexyl) - l- (3-tetrahydropyran-2-yloxy) octyl) hydantóin as gelatin (boiling point 60 to 80 ° C) as small colorless needles with a particular oil. Melting point crystallized from 76 to 78 ° C.

E. Conversion (interconversion) of the diastereomers

C. 5- (6-Carboxyhexyl) -l- (3-hydroxyoctyl) -hydantoin A solution of 100 mg 5- (6-carboxyhexyl) -l- (3-hydroxyoc-

3.55 g of this tetrahydropyranyloxy compound were in tyl) -hydantoin (diastereomer with a melting point of 76 to

28 ml of tetrahydrofuran and 7 ml of 5N hydrochloric acid dissolved and the 55 78 ° C) in 3 ml of n-sodium hydroxide solution was at room temperature

Let the solution stand at room temperature for 314 hours. Then left to stand for 19 hours. The solution was acidified and refluxed for 30 minutes. Most of the and extracted with ether and the ether extract with water solvent was evaporated, then water was added and washed, dried and poured into a viscous oil.

the insoluble oil extracted with ether. The ether solution was steamed. Using HPLC (high performance liquid chromatographic

washed out with water, dried over magnesium sulfate 60 phy) this oil was divided into the two diastereomers of 5- (6-carbo-

and evaporated, after which 3.15 g of a viscous yellow oil oxyhexyl) -l- (3-hydroxyoctyl) hydantoin was separated. The two resulted. The oil was purified by chromatography on a diastereomer, melting point 76 to 78 ° C, identical to silica gel column, first with chloroform and then with the starting material (approx. 40 mg) and melting point 63

eluted with a mixture of chloroform and methanol (19: 1) up to 65 ° C (approx. 40 mg), identical to that described above. The result was 5- (6-carboxyhexyl) -l- (3-hydroxyoc- 65 diastereomer A).

tyl) -hydantoin as a very viscous, almost colorless oil, 00.89 (3H, in the same way the diastereomer with the melting

Triplet, -CH3), 2.34 (2H, triplet, -CH2-C02H), 2.9-4.2 (4H, point from 63 to 65 ° Cin a mixture of approximately the complex, -CH2-N, CH -N, CH-OH), about 5.6 (2H, broad, equal amounts of the diastereomer with the melting point of

76 to 78 ° C and transferred to him and then isolated the pure diastereomers by HPLC.

Examples 3 to 27 The following compounds were prepared by a series of reactions analogous to the reactions described in Example 1 and using the corresponding vinyl ketones as starting materials: 3a) diethyl 2 - ((3-oxopentyl) amino) nonanedioate; 4a) diethyl 2 - ((3-oxo-4,4-dimethylpentyl) amino) nonanedioate; 5a) diethyl 2 - ((3-oxo-4-methylpentyl) amino) nonanedioate; 6a) diethyl 2 - ((3-oxononyl) amino) nonanedioate; 7a) Diethyl 2 - ((3-oxo-4-methyloctyl) amino) nonanedioate; 8a) diethyl 2 - ((3-oxodecyl) amino) nonanedioate; 9a) Diethyl 2 - ((3-oxo-4,4-dimethyloctyl) amino) nonanedioate; 10a) diethyl 2 - ((3-oxo-4-ethylhexyl) amino) nonanedioate; IIa) diethyl 2 - ((3-cyclobutyl-3-oxopropyl) amino) nonanedioate; 12a) diethyl 2 - ((3-cyclopentyl-3-oxopropyl) amino) nonanedioate;

13a) Diethyl 2 - ((3-oxo-4,4-dimethyl-5- (3-trifluoromethylphenyl) pentyl) amino) nonanedioate;

14a) diethyl 2 - ((3-cyclohexyl-3-oxopropyl) amino) nonanedioate; 15a) Diethyl 2 - ((3-cycloheptyl-3-oxopropyl) amino) nonanedioate;

16a) Diethyl 2 - ((3-oxo-3-phenylpropyl) amino) nonanedioate;

17a) Diethyl 2 - ((3-oxo-4-phenylbutyl) amino) nonanedioate;

18a) diethyl 2 - ((3-oxooctyl) amino) pentanedioate;

19a) Diethyl 2 - ((3-oxooctyl) amino) undecanedioate;

20a) ethyl 2 - ((3-oxooctyl) amino) -3-ethoxycarbonylmethoxy-

phenyl) propionate;

21a) ethyl 2 - ((3-oxo-4-4, dimethylpentyl) amino) -3- (3-ethoxycarbonylmethoxyphenyl) propionate;

22a) ethyl 2- (3-oxooctylamino) -3- (3- (2-ethoxycarbonylethyl) phenyl) propionate;

23a) ethyl 2- (3-cyclobutyl-3-oxopropylamino) -3- (3- (2-ethoxycarbonylethyl) phenyl) propionate;

24a) ethyl 2- (3-cyclopentyl-3-oxopropylamino) -3- (3- (2-ethoxycarbonylethyl) phenyl) propionate;

25a) ethyl 2- (3-cyclohexyl-3-oxopropylamino) -3- (3- (2-ethoxycarbonylethyl) phenyl) propionate; 26a) diethyl 2- (3-oxooctylamino) -7-oxanonane and 27a) diethyl 2- (3-cyclopentyl-3-oxopropylamino) -7-oxanone andioate, which were converted into the corresponding hydroxy compounds:

3b) diethyl 2 - ((3-hydroxypentyl) amino) nonanedioate; 4b) diethyl 2 - ((3-hydroxy-4,4-dimethylpentyl) amino) nonanedioate;

5b) diethyl 2 - ((3-hydroxy-4-methylpentyI) amino) nonanedioate;

6b) diethyl 2 - ((3-hydroxynonyl) amino) nonanedioate; 7b) diethyl 2 - ((3-hydroxy-4-methyloctyl) amino) nonanedioate; 8b) diethyl 2 - ((3-hydroxydecyl) amino) nonanedioate; 9b) diethyl 2 - ((3-hydroxy-4,4-dimethyloctyl) amino) nonanedioate;

10b) diethyl 2 - ((3-hydroxy-4-ethylhexyl) amino) nonanedioate; IIb) diethyl 2 - ((3-cyclobutyl-3-hydroxypropyl) amino) nonanedioate;

12b) diethyl 2 - ((3-cyclopentyl-3-hydroxypropyl) amino) nonanedioate;

13b) Diethyl-2 - ((3-hydroxy-4,4-dimethyl-5- (3-trifluoromethyl-

phenyl) pentyl) amino) nonanedioate;

14b) Diethyl-2 - ((3-cyclohexyl-3-hydroxypropyl) -amino) -

nonandioat;

15b) diethyl 2 - ((3-cycloheptyl-3-hydroxypropyl) amino) nonanedioate;

16b) diethyl 2- ((3-hydroxy-3-phenylpropyl) amino) nonanedioate;

17b) diethyl 2 - ((3-hydroxy-4-phenylbutyl) amino) nonanedioate;

13 645 631

18b) diethyl 2 - ((3-hydroxyoctyl) amino) nonanedioate; 19b) Diethyl 2 - ((3-hydroxyoctyl) amino) undecanedioate; 20b) ethyl 2 - ((3-hydroxyoctyl) amino) -3- (3-ethoxycarbonyl-methoxyphenyl) propionate; 5 21b) ethyl 2 - ((3-hydroxy-4,4-dimethylpentyl) amino) -3- (3-ethoxycarbonylmethoxyphenyl) propionate; 22b) Ethyl 2 - ((3-hydroxyoctylamino) -3- (3- (2-ethoxycarbonylethyl) phenyl) propionate;

23b) ethyl 2 - ((3-cyclobutyl-3-hydroxypropylamino) -io 3- (3- (2-ethoxycarbonylethyl) phenyl) propionate; 24b) ethyl 2 - ((3-cyclopentyl-3-hydroxypropylamino- 3- (3- (2-ethoxycarbonylethyl) phenyl) propionate; 25b) ethyl 2- (3-cyclohexyl-3-hydroxypropylamino) -3- (3- (2-ethoxycarbonylethyl) phenyl) propionate; 15 26b ) Diethyl 2- (3-hydroxyoctylamino) -7-oxanonanedioate and 27b) diethyl 2- (3-cyclopentyl-3-hydroxypropylamino) -7-oxa-nonandioate,

from which the following hydantoins of the formula I were prepared, which, as listed, were separated into the two stereo-20 isomers by HPLC and had the melting points listed:

3c) 5- (6-carboxyhexyl) -l- (3-hydroxypentyl) hydantoin, a colorless oil, diastereomers 71 to 73 ° C and 56 to 58 ° C; 4c) 5- (6-carboxyhexyl) -l- (3-hydroxy-4,4-dimethylpentyl) -25 hydantoin, diastereomers 114 to 115 ° C and 144 to 146 ° C; 5c) 5- (6-carboxyhexyl) -l- (3-hydroxy-4-methylpentyl) hydantoin, melting point approx. 70 to 80 ° C, diastereomers 73 to 76 ° C and HO to 111 ° C; 6c) 5- (6-carboxyhexyl) -l- (3-hydroxynonyl) hydantoin, a viscous oil;

7c) 5- (6-carboxyhexyl) -l- (3-hydroxy-4-methyloctyl) hydantoin, a viscous oil; 8c) 5- (6-carboxyhexyl) -l- (3-hydroxydecyl) hydantoin, a viscous oil, diastereomers 68 to 70 ° C and 82 to 83 ° C; 35 9c) 5- (6-carboxyhexyl) -l- (3-hydroxy-4,4-dimethyloctyl) hydantoin as colorless crystals, melting point 90 to 98 ° C; a diastereomer isolated by crystallization from ethyl acetate, melting point 103 to 104 ° C;

10c) 5- (6-carboxyhexyl) -l- (3-hydroxy-4-ethylhexyl) hydantoin, 40 melting point 70 to 80 ° C, diastereomers 82 to 84 ° C and 120 to 122 ° C;

11c) 5- (6-carboxyhexyl) -l- (3-cyclobutyl-3-hydroxypropyl) hydantoin, diastereomers 114 to 116 ° C and 103 to 105 ° C; 12c) 5- (6-carboxyhexyl) -l- (3-cyclopentyl-3-hydroxypropyl) -45 hydantoin, diastereomers 116 to 117 ° C and 97 to 99 ° C; 13c) 5- (6-carboxyhexyl) -1- (3-hydroxy-4,4-dimethyl-5-m-tri-fluoromethylphenylpentyl) hydantoin, diastereomers 118 to 120 ° C and 145 to 147 ° C;

14c) 5- (6-carboxyhexyl) -l- (3-cyclobutyl-3-hydroxypropyl) -50 hydantoin, diastereomers 96 to 98 ° C and 124 to 126 ° C; 15c) 5- (6-carboxyhexyl) -l- (3-cycloheptyl-3-hydroxypropyl) hydantoin, melting point approx. 70 to 76 ° C, diastereomers 107 to 109 ° C and 107 to 109 ° C;

16c) 5- (6-carboxyhexyl) -l- (3-hydroxy-3-phenylpropyl) hydan-55 toin, the diastereomers both formed colorless viscous oils; 17c) 5- (6-carboxyhexyl) -l- (3-hydroxy-4-phenylbutyl) hydantoin, diastereomers 102 to 104 ° C and 61 to 63 ° C; 18c) 5- (3-carboxypropyl) -l- (3-hydroxyoctyl) hydantoin, the diastereomers both formed colorless viscous oils; 60 19c) 5- (8-carboxyoctyl) -l- (3-hydroxyoctyl) hydantoin, diastereomers 57 to 60 ° C and 69 to 71 ° C; 20c) 5- (3-carboxymethoxybenzyl) -l- (3-hydroxyoctyl) hydantoin, a colorless, foamy mass; 21c) 5- (3-carboxymethoxybenzyl) -1- (3-hydroxy-4,4-dimethyl-65-pentyl) -hydantoin, diastereomers of the corresponding ethyl ester, mp. 103 and 151 to 154 ° C .; 22c) 5- (3- (2-carboxyethylbenzyl)) - 1- (3-hydroxyoctyl) ~ hydantoin, a diastereomer, melting point 82 to 86 ° C;

645 631

14

23c) 5- (3- (2-carboxyethylbenzyl)) - 1- (3-cyclobutyl-3-hydroxypropyl) hydantoin, a diastereomer, melting point 118 to 121 ° C;

24c) 5- (3- (2-carboxyethylbenzyl)) - 1- (3-cyclopentyl-3-hydroxypropyl) hydantoin, a diastereomer, melting point 140 to 143 ° C;

25c) 5- (3- (2-carboxyethylbenzyl)) - 1- (3-cyclohexyl-3-hydroxypropyl) hydantoin;

26c) 5- (4-carboxymethoxybutyl) -l- (3-hydroxyoctyl) hydantoin, and

27c) 5- (4-carboxymethoxybutyl) -1- (3-cyclopentyl-3-hydroxypropyl) hydantoin;

all compounds were obtained via the corresponding ethyl ester.

The starting compounds used for the above processes were prepared as follows:

The dried extract was concentrated in vacuo and a yellow oil resulted, which was purified by column chromatography on silica by elution with a mixture of ether / hexane (1: 1). The result was t-butyl-3- (3-bromine

5 thyIphenyl) propionate as a colorless oil. Using the method described in the previous paragraph, this substance was converted to the desired diester, which was used in Examples 22 to 25.

10 D. Diethyl 2-amino-7-oxa-nonandioate

This compound was prepared from ethyl 4-bromobutoxyacetate (Merck, DT-OS 2354085) by a series of reactions analogous to that described in paragraph B above and was obtained as a colorless oil, boiling point 120 to 121 ° C / 0.005 mm Hg.

15 The compound was used in Examples 26 and 27.

A. For Examples 18 and 19

Using the procedure described in Example 1A, the diethyl 2-aminopentanedioate, boiling point 93 to 96 ° C / 0.02 mm Hg, nd 1.4425 and the diethyl 2-aminoundecanedioate, boiling point 160 ° C / 0.1 mm Hg, which were used in Examples 18 and 19. 25th

B. Ethyl 2-amino-3- (3-ethoxycarbonylmethoxyphenyl) propionate

2.60 g of diethylacetamidomalonate and 2.39 g of ethyl 3- (chloromethyl) phenoxyacetate [Robertson, J. Chem. Soc., 492 (1933), US-30 PS 3 933 895] were prepared in ethanolic ethoxide ( dissolved in 230 mg sodium and 10 ml absolute ethanol) and the mixture heated under reflux for 19 h. The cooled solution was poured into ice water, the product extracted into ether and the dried extract evaporated. The remaining 35 rubber-like substance was recrystallized from ether / hexane and gave the diethylacetamido (3-ethoxycarbonylmethoxyphenyl) malonate as white prisms, melting point 98.5 to 101.5 ° C. 1.90 g of this derivative were mixed with 25 ml 10% aqueous hydrochloric acid 3 '/; Heated under reflux and the 40 cooled solution evaporated to dryness in vacuo. The remaining white solid was dissolved in the minimum amount of absolute ethanol and added dropwise to a stirred, cooled (-10 ° C) mixture of 15 ml of absolute ethanol and 1.64 g of thionyl chloride. The resulting solution 45 was set aside at room temperature for 18 hours, then heated under reflux for 1 hour, cooled, poured into ice water, and the pH was adjusted to 9-10 with aqueous sodium hydroxide solution. The mixture was extracted with ether and the dried extract was concentrated. The ethyl 50 2-amino-3- (3-ethoxycarbonylmethoxyphenyl) propionate resulted as a colorless oil, which was used in Examples 20 and 21 without further purification.

55

C. Ethyl 2-amino-3- (3- (2-ethoxycarbonylethyl) phenyl) propionate

A solution of 4.04 g of di-isopropylamine and 25 ml of butyl-lithium (1.60 mol in hexane) in 40.0 ml of dry tetrahydrofuran, stirred under dry nitrogen at -78 ° C, was stirred for 4 minutes with 4 , 64 g of t-butyl acetate are added. A solution of 11.60 g of a, cc'-dibromo-m-xylene and 1.42 g of dry hexamethylphosphoramide in 8.0 ml of dry tetrahydrofuran was added to this solution 60 over a further 5 min. The resulting yellow solution was stirred at -78 ° C for half an hour and warmed to room temperature for an additional three hours. Excess ice water was then added and the mixture extracted with ether, the extract washed with 60 ml of 1N hydrochloric acid and then with water. The

Example 27b

Preparation of 5- (6-carboxyhexyl) -l- (3-oxooctyl) hydantoin

Potassium cyanate and hydrochloric acid were added to 7.7 g of diethyl 2- (3-oxooctylamino) nonanedioate, prepared in the manner described in Example 1B, and 5- (6-ethoxycarbo-nylhexyl) -l- (3-oxo-octyl) resulted ) -hydantoin. Hydrolysis of the ester using a sodium hydroxide solution gave the 5- (6-carboxyhexyl) -l- (3-oxo-octyl) hydantoin as a viscous oil which crystallized to a low melting solid.

Example 28

Preparation of 5- (6-carboxyhexyl) -l- (5-phenylpentyl) hydantoin

A mixture of 25.9 g of diethyl 2-aminononanedioate and 22.7 g of 5-phenylpentyl bromide was heated in a water bath at 100 ° C for 3 hours. After cooling, 100 ml of ether was added to the mixture, which was then left to stand at 0 ° C for 2 hours. 21.95 g of the colorless solid that crystallized out was collected and dried. This diethyl (2 - ((5-phenylpentyl) amino) nonanedioate hydrobromide melted at 70 to 72 ° C.

A solution of 4.86 g of this hydrobromide in 20 ml of ethanol and 5 ml of 2N hydrochloric acid was cooled in ice and stirred while gradually adding a solution of 1.62 g of potassium cyanate in 5 ml of water. The solution was then left to stand at room temperature for 18 hours. The alcohol was evaporated, water was added and the insoluble oil extracted with ether, the ether extract dried and evaporated. A slightly yellow oil resulted. This was heated on a steam bath for 6 hours and the 5- (6-ethoxycarbonylhexyl) -1- (5-phenylpentyl) hydantoin resulted.

4.0 g of the above ester was hydrolyzed by adding dilute sodium hydroxide solution and the product was purified by chromatography on silica gel. The result was 5- (6-carboxyhexyl) -l- (5-phenylpentyl) hydantoin, which crystallized from ethyl acetate / light petrol (boiling point 60 to 80 ° C) in colorless prismatic needles, melting point 90 to 92 ° C.

Examples 29 to 35

The following compounds were prepared by a series of reactions analogous to those described in Example 28 and using the corresponding alkyl halides:

29a) diethyl 2-octylaminononanedioate; 30a) diethyl 2- (4-propoxybutyl) -aminononanedioate; 31a) diethyl 2- (4-phenoxybutyl) aminononanedioate; 32a) diethyl 2- (4-m-trifluoromethylphenoxybutyl) amino nonanedioate;

33a) diethyl 2- (3-m-tolyloxypropyl) -aminononanedioate;

15

645 631

34a) diethyl 2- (3-hydroxypropyl) aminononanedioate, and 35a) diethyl 2- (3-hydroxy-3-methyloctyl) aminononanedioate, which were converted into the desired hydantoins: 29b) 5- (6-ethoxycarbonylhexyl) - l-octylhydantoin, melting point 46 to 48 ° C;

29c) 5- (6-carboxyhexyl) -l-octylhydantoin, melting point 88 to 89 ° C;

30b) 5- (6-carboxyhexyl) -l- (4-propoxybutyl) hydantoin, melting point 72 to 74 ° C;

31b) 5- (6-carboxyhexyl) -l- (4-phenoxybutyl) hydantoin, melting point 88 to 90 ° C;

32b) 5- (6-carboxyhexyl) -l- (4-m-trifluoromethylphenoxybutyl) hydantoin, melting point 51 to 54 ° C; 33b) 5- (6-carboxyhexyl) -1- (3-m-tolyloxypropyl) hydantoin, a colorless viscous oil;

34b) 5- (6-carboxyhexyl) -l- (3-hydroxypropyl) hydantoin, melting point 111 to 113 ° C, and

35b) 5- (6-Carboxyhexyl) -l- (3-hydroxy-3-methyloctyl) hydantoin, a viscous oil.

Example 36

Preparation of 1- (6-carboxyhexyl) -5-octyl-hydantoin 16.0 g2-aminocapric acid [J. At the. Chem. Soc., 68 (1946), 450] was added in portions to a cooled (-10 ° C) mixture of 70 ml of absolute ethanol and 6 ml of thionyl chloride with stirring. The resulting solution was set aside for 2 hours at room temperature, then heated under reflux for 1 hour, cooled, poured into ice water, and the pH of the solution was adjusted to 9 with aqueous sodium hydroxide solution. The mixture was extracted with ether, the extract was dried, concentrated and distilled. The ethyl 2-amino decanoate (75%) resulted as a colorless oil, boiling point 82 to 84 ° C / 0.2 mm Hg.

A solution of 18 g of the above amino ester and 20 g of ethyl 7-bromheptanoate in 50 ml of absolute ethanol was heated under reflux for 24 hours and then the ethanol was evaporated. The addition of ether precipitated a hydrobromide salt, melting point 98 ° C., which was dissolved in a little dichloromethane, one equivalent of triethylamine was added, and the mixture was washed thoroughly with water and dried. After removing the solvent, the ethyl 2- (6-ethoxycarbo-nylhexylamino) decanoate (52%) resulted as a colorless viscous 01, boiling point 142 to 144 ° C / 0.001 mm Hg.

7.4 g of ethyl 2- (6-ethoxycarbonylhexylamino) decanoate was reacted with potassium cyanate and hydrochloric acid and the result was l- (6-ethoxycarbonylhexyl) -5-octylhydantoin, which consists of light petrol (boiling point 60 to 80 ° C) colorless crystals with a melting point of 68 to 70 ° C.

4.0 g of this ester were hydrolyzed with a sodium hydroxide solution and gave l- (6-carboxyhexyl) -5-octylhydantoin, which consists of a mixture of ethyl acetate and light petroleum (boiling point 60 to 80 ° C) as colorless needles, melting point 65 to 66 ° C, crystallized.

Example 37

Preparation of 5- (6-carboxyhexyl) -3-methyl-1-octyl-hydantoin A solution of 742 mg of diethyl 2-octylaminononanedioate and 120 mg of methyl isocyanate in 7.5 ml of dry ether was left at room temperature for 48 hours. After this time the ether was evaporated and 800 mg of a pale yellow oil resulted. The oil was heated on the steam bath for 2 hours and 5- (6-ethoxycarbonyl) -3-methyl-1-octylhydantoin was obtained as a yellow oil.

650 mg of the ester was hydrolyzed by standing in solution of 2.4 ml of ethanol and 0.6 ml of 5N sodium hydroxide solution for 3 hours at room temperature. After evaporation of the ethanol, the acidic product was extracted with

30 -

Ether isolated and purified by chromatography on a silica gel column. The 5- (6-carboxyhexyl) -3-methyl-1-octylhydantoin was obtained as a colorless oil.

s Example 38

Preparation of 5- (6-carboxyhexyl) -3-methyl-l- (3-hydroxyoctyl) hydantoin Diethyl 2 - ((3-oxooctyl) amino) nonanedioate (Example 28) 10 was based on that described in Example 37 Reacted with methyl isocyanate and gave 5- (6-ethoxycarbonylhexyl) -3-methyl-l- (3-oxooctyl) -hydantoin, which to 5- (6-carboxyhexyl) -3-methyl-l- (3-oxooctyl) - hydantoin was hydrolyzed as a colorless oil.

1.23 g of this keto acid was dissolved in 15 ml of O, 25N sodium hydroxide solution and the solution was dissolved in an ice bath while adding 63 mg of sodium borohydride. After stirring for 3 hours at room temperature, the solution was acidified and ether extracted. The washed and dried Ätherex-20 tract was evaporated to give an oil which was purified by column chromatography on silica using chloroform and methanol (50: 1) as the eluent. The 5- (6-carboxyhexyl) -3-methyl-l- (3-hydroxyoctyl) hydantoin resulted as a colorless viscous oil.

25th

Example 39

Preparation of 1- (6-carboxyhexyl) -3-methyl-5-octylhydantoin

In the manner described in Example 37, ethyl 2- (6-ethoxycarbonylhexylamino) decanoate (Example 36) was converted into the 1- (6-ethoxycarbonylhexyl) -3-methyl-5-octylhydantoin and then hydrolysed into the 1- (6th -Carboxyhexyl) -3-methyl-5-octylhydantoin, which was isolated as a colorless oil.

Example 40

Preparation of 3-butyl-5- (6-carboxyhexyl) -l-octylhydantoin 5- (6-ethoxycarbonylhexyl) -l-octylhydantoin (see Example 40 29b) was added to a solution of 308 mg sodium in 40 ml ethanol, followed by 1 , 8 g of butyl bromide were added and the solution was heated under reflux for 24 h. The solvent was evaporated, water was added and the insoluble oil was extracted with ether. The washed-out and dried extract was evaporated to give 3- (butyl-5- (6-ethoxycarbonyl-45 hexyl) -l-octylhydantoin.

3.2 g of this ester was dissolved in 15 ml of ethanol and 15 ml of 2N sodium hydroxide solution and left at room temperature for 1 hour. The acidic product was isolated by extraction with ether and purified by chromatography on silica gel 50, whereupon the 3-butyl-5- (6-carboxyhexyl) -l-octyl-hydantoin resulted as a colorless oil.

Example 41

Preparation of 3-butyl-1- (6-carboxyhexyl) -5-octylhydantoin In the manner described in Example 40, 1- (6-ethoxycarbonylhexyl) -5-octylhydantoin (see Example 36) was added to the 3-butyl-1 - (6-ethoxycarbonylhexyl) -5-octylhydantoin, which was converted into the 3-butyl-l- (6-carboxyhexyl) -5-octylhydantoin as a colorless oil by hydrolysis.

35

55

60

Example 42

Preparation of 5- (6-carboxyhex-2-ynyl) -l- (3-hydroxyoctyl) hydantoin

65 Under the reaction conditions from Example 1A, diethyl acetamidomalonate and methyl 7-bromhept-5-inoate were reacted and the diethyl acetamido (6-methoxycarbonylhex-2-ynyl) malonate resulted as a yellow oil.

645 631 16

This crude product was left to stand by boiling with 5N hydrochloric acid and again for 15 min. Then the crystals were hydrolyzed and the product was re-esterified to give diethyl, washed with water, dried in vacuo,

2-aminonon-4-indioate, which was distilled and a colorless suspended in 3 ml of ether and collected again. The result was an oil, boiling point 116 ° C / 0.01 mm Hg, n'ß 1.4703. 0.74gl- (6-carboxyhexyl) hydantoin-5-carboxaldehyde,

The above amino derivative was with oct-l-en-3-one to the Di- 5 melting point 223.5 to 225 ° C.

Ethyl-2 - ((3-oxooctyl) amino) non-4-indioate implemented, which with elemental analysis

Sodium borohydride was reduced and the diethyl-2 - ((3-hydro- for c Hl6N, 05: C 51.56; H 6.29; N 10.93%

xyoctyl) -ammo) -non-4-mdioate. found: "C 51.86; H 6.66; N 10.62%

If this compound is mixed with potassium cyanate and hydrochloric acid and the hydantoin ester thus prepared is hydrolyzed, so 10 In dimethyl sulfoxide-d6, a light brown oil predominantly existed as a masked product. Purification using column chro aldehyde, l- (6-carboxyhexyl) -5-hydroxymethylene-hydantoin. Matography on silica with a mixture of chloroform methanol (30: 1) as eluent gave the 5- (6-carboxyhex- C. 1- (6-carboxyhexyl) -5 - ((E) -3-oxo-octylidene) -hydantoin 2 -inyI) - (3-hydroxyoctyl) -hydantoin, a mixture of the diastereo- A mixture of 20 mg l- (6-carboxyhexyI) -hydantoin-5-carb-mere, which gave two spots. Rf. 0,38,0,44 when running on 15 oxaldehyde with59mg2-oxoheptylidene-triphenyl-phosphorane a thin layer chromatography on silica with chloro- (see J. Org. Chem. 37 [1972], 1818) and a drop of benzene form / methanol / Acetic acid (90: 5: 5) as eluent. Under was heated under nitrogen at 100 ° C. for 35 min and using HPLC one of the diastereomers (TLC, resulting rubbery substance in ethyl acetate - Rf. 0.38) was isolated as a colorless oil; NMR (CDCI3) 00.89 (3H, men. The product was dissolved in dilute aqueous sodium

Triplet, -CH3), 2.2 to 2.4 (6H, multiple «, -CH2, C = C.CH2- + 20 bonate solution, extract extracted with ethyl acetate - CH2.C02H), 3.54 (2H , Triplet,> N.CH2-), approx. 3.6 (IH, multi-view and plotted against Congorot with aqueous n-hydrochloric acid,> CH.OH), 4.11 (1H, triplet,> N. CH.CO-). acidifies and the released carboxylic acid extracted with ether.

The ethereal solution was washed out with water, dried over 5- (6-carboxyhex-2-enyl) -l- (3-hydroxyoctyl) -hydantoin magnesium sulfate and evaporated to give a hydrogenation. The corresponding saturated ver 25 mg of a rubber-like substance which was produced by means of HNMR binding, which is identical to the title compound spectroscopy as l- (6-carboxyhexyl) -5 - ((E) -3-oxo-octylidene) -dung from Example 2 proved. hydantoin was identified (characteristic signals at 65.72

[IH, triplet, = CH-] and 3.93 [2H, doublet, = CH-CH2-CO] with example 43 ^ j 7 j Hz, in deuterochloroform).

A. 2- (Dibutoxymethyl) glycine ethyl ester N-formylglycine ethyl ester was based on that from Harman and D "l- (6-carboxyhexyl) -5 - ((E) -3-hydroxyoctylidene) hydantoin

Hutchinson in J. Org. Chem., 40 (1975), 3474, C-formylated and a stirred solution of 20 mg l- (6-carboxyhexyl) -5 - ((E) -3-the resulting compound in the 2- (Dibutoxymethyl) -glycine-oxo-octylidene) -hydantoinin 1.5 ml H20, which is a light ethyl ester using the in Chemistry of Penicillin, Eds. 35 excess sodium bicarbonate was mixed with 5 mg H.T. Clarke, published by Princetown University Press, added sodium borohydride. After 60 minutes, the New Jersey solution, 1949, page 517, was transferred. acidified against Congorot with aqueous n-hydrochloric acid, the liberated carboxylic acid extracted into ethyl acetate and the ethyl acetate-B. l- (6-Carboxyhexyl) -hydantoin-5-carboxaldehyde solution was washed three times with water and

A mixture of 2.0 g of 2- (dibutoxymethyl) glycine ethyl ester 40 smmsulfate dried. After evaporation of the ethyl acetate with 1.82 g of ethyl 2-bromheptanoate, a pale yellow rubber-like substance (14 mg) was left under nitrogen in a water bath at 100 ° C. for 3 h and gave the crude middle sH.NM R . -Spectroscopy as (6-carboxyhexyl) -5 - ((E) -ethyl-7 - ((2,2-dibutoxy-l-ethoxycarbonylethyl) amino) -3-hydroxyoctylidene) hydamomid heptanoate hydrobromide. A stirred solution of 3.28 g of this slS "ale 1 ô5'61 t1H <TnPlett = CH-, J 7.1 Hz] m hydrobromide in 13 ml of ethanol was cooled in ice water and" 5 euteroc oro).

followed by a solution of 1.34 g of potassium cyanate in 4 ml of water,

of 3.63 ml of 2N aqueous hydrochloric acid. The cooling bath was removed E- l- (6-carboxyhexyl) -5- (3-hydroxyoctyl) -hydantoin and stirring continued at room temperature for 22 hours. The product described in paragraph C then became

Then the ethanol was evaporated in vacuo, the back l- (6-carboxyhexyl) -5- (3-octooctyl) hydantome and the title mind were shaken out with water and ether and the etheric bond was reduced, which turned out to be with separated the solution, washed with water and were identical over Magne title compounds of Examples 28 and 2, dried sodium sulfate (MgSO4). After removing the ether, an oil resulted, which under nitrogen at 100 ° C for 3 h ^ 44

was heated and gave 2.94 g of 5-dibutoxymethyl I-1- (6-ethoxycarbonyl-p hexyl) -hydantoin. This was done in 6 ml of ether with 48 ml of 55 producing 5- (6-carboxyhex-2Z-enyl) -l- (3-cyclohexyl-water and 24.9 ml of n-aqueous sodium hydroxide solution with 3-hydroxypropyl) -hydantoin

Room temperature stirred for 1 'Ah and after the addition of cis-methyl-7-bromhep-5-enoate (prepared according to the process

50 ml of ether, the aqueous phase was separated off, cooled in ice water, the GB-PS 1355 991) and diethyl acetamidomalonate were stirred with fresh ether, reacted with aqueous n-hydrochloric acid and Con- under the conditions described in Example 1A, acidified as a red indicator . The ethereal solution of the 60 and gave the diethyl acetamido (6-methoxycarbonylhex-2-

Carboxylic acid was washed three times with water, over enyl) malonate as a yellow oil.

Magnesium sulfate dried and evaporated. This resulted in this crude product being boiled with 5N hydrochloric acid

2.15 g of l- (6-carboxyhexyl) -5-dibutoxymethylhydantoin as chewed hydrolyzed and the product as described in Example 1A from the Schukose substance. After cooling 1.89 g of the latter diethyl 2-aminonon-4-endioate esterified as a colorless oil, boiling substance and stirring with 8.5 ml of concentrated aqueous salt - 65 point 118 to 123 ° C / 0.05 mm Hg, nò9'5 1.4620.

Acid makes the resulting solution spontaneously a suspension The reaction of this amino compound with 1-cyclohexyl of colorless crystals. The suspension was set aside for zim-prop-2-enone according to Example 2B and the reduction in diethyl 2-mer temperature 1 * h, diluted with 10 ml of water ((3-cyclohexyl-3-oxopropyl) -amino) -non -4-endioats with

Sodium borohydride as in Example 2C gave diethyl 2 - ((3-cyclohexyl-3-hydroxypropyl) amino) non-2-endioate.

Adding potassium cyanate and hydrochloric acid to this compound and hydrolysing the resulting hydantoin ester in the manner described in Example 2D gave the 5- (6-carboxyhex-2Z-enyl) -l- (3-cyclohexyl-3-hydroxypropyl) hydantoin as a yellow oil which tended to solidify. Using HPLC, this compound was separated into its diastereomers, one of which formed colorless prisms with a melting point of 95 to 97 ° C and the other colorless needles with a melting point of 108 to 110 ° C.

In analogy to the methods described in Examples 1 and 2, the following compounds were also prepared using suitable vinyl ketones as starting material:

45a) diethyl 2- (3-oxo-5,5-dimethylhexyl) -aminononanedioate; 46a) diethyl 2- (3-oxo-5-methylhexyl) -aminononanedioate; 47a) diethyl 2- [3-oxo-3- (p-tolyl) propyl] aminononanedioate; 48a) diethyl 2- (3-oxo-4-cyclopentylbutyl) aminononanedioate; 49a) diethyl 2- (3-oxo-4-cyclohexylbutyl) -aminononanedioate; 50a) diethyl 2- (3-oxo-6-cyclohexylhexyl) -aminononanedioate; 51a) diethyl 2- (3-oxo-5-ethoxypentyl) -aminononanedioate; 52a) diethyl 2- [3-oxo-4- (3-trifluoromethylphenoxy) butyl] aminononanedioate;

53a) diethyl 2- [3-oxo-3- (4-chlorophenyl) propyl] amino-nonanedioate;

54a) diethyl 2- [3-oxo-3- (4-methoxyphenyl)] aminononanedioate;

55a) ethyl 2- (3-oxo-3-cyclohexylpropyl) amino-6-ethoxy

carbonyl methoxyhexanoate;

56a) ethyl 2- (3-oxo-3-cyclopentylpropyl) amino-6-ethoxycarbonyl methoxyhexanoate;

57a) ethyl 2- (3-oxooctyl) amino-6-ethoxycarbonyl methoxy hexanoate;

58a) diethyl 2- (3-oxo-5,5-dimethylhexyl) aminonone-4Z-en-dioate;

59a) diethyl 2- (3-oxo-3-cyclopentylpropyl) aminonone-4Z-en-dioate;

60a) diethyl 2- (3-oxo-3-cyclohexylpropyl) aminononon-4E-en-dioate;

61a) diethyl 2- (3-oxo-4-cyclopentylbutyl) aminonon-4Z-en-dioate;

62a) diethyl 2- (3-oxo-4,4-dimethyl-5-phenylpentyl) -aminonon-4Z-en-dioate;

63a) diethyl 2- (3-oxo-5-cyclopentylpentyl) aminonone-4Z-en-dioate;

64a) ethyl 2- (3-oxo-3-cyclohexylpropyl) amino-6-ethoxy-carbonylmethoxyhex-2Z-enoate; 65a) ethyl 2- (3-oxo-3-cyclohexylpropyl) amino-6-ethoxy-carbonylmethoxyhex-2E-enoate; and

66a) diethyl 2- (3-oxo-3-cyclohexylpropyl) aminonon-4-in-dioate; which were converted into the corresponding alcohols: 45b) diethyl 2- (3-hydroxy-5,5-dimethylhexyl) amine-ononanedioate;

46b) diethyl 2- (3-hydroxy-5-methylhexyl) aminononanedioate; 47b) diethyl 2- [3-hydroxy-3- (p-tolyl) propyl] aminononanedioate; 48b) diethyl 2- (3-hydroxy-4-cyclopentylbutyl) amino nonandioate;

49b) diethyl 2- (3-hydroxy-4-cyclohexylbutyl) amino nonanedioate;

50b) diethyl 2- (3-hydroxy-6-cyclohexylhexyl) amino nonanedioate;

51b) diethyl 2- (3-hydroxy-5-ethoxypentyl) aminononanedioate; 52b) diethyl 2- [3-hydroxy-4- (3-trifluoromethylphenoxy) butyl] aminononanedioate;

53b) diethyl 2- [3-hydroxy-3- (4-chlorophenyl) propyl] amino-nonanedioate;

54b) diethyl 2- [3-hydroxy-3- (4-methoxyphenyl) propyl] amino-nonanedioate;

17 645 631

55b) ethyl 2- (3-hydroxy-3-cyclohexylpropyl) amino-6-ethoxycarbonyl methoxyhexanoate;

56b) ethyl 2- (3-hydroxy-3-cyclopentylpropyl) amino-6-ethoxycarbonyl methoxyhexanoate; 5 57b) ethyl 2- (3-hydroxyoctyl) amino-6-ethoxycarbonyl methoxy hexanoate;

58b) diethyl 2- (3-hydroxy-5,5-dimethylhexyl) aminonone-4Z-enedioate;

59b) diethyl 2- (3-hydroxy-3-cyclopentylpropyl) -aminonon-4Z-io en-dioate;

60b) diethyl 2- (3-hydroxy-3-cyclohexylpropyl) aminonon-4E-en-dioate;

61b) diethyl 2- (3-hydroxy-4-cyclopentylbutyl) aminonon-4Z-en-dioate;

15 62b) diethyl 2- (3-hydroxy-4,4-dimethyl-5-phenylpentyl) amino-non-4Z-en-dioate;

63b) diethyl 2- (3-hydroxy-5-cyclopentylpentyl) aminonone-4Z-en-dioate;

64b) ethyl 2- (3-hydroxy-3-cyclohexylpropyl) amino-6-ethoxy-20 carbonylmethoxyhex-2Z-enoate; 65b) ethyl 2- (3-hydroxy-3-cyclohexylpropyl) amino-6-ethoxy-carbonylmethoxyhex-2E-enoate, and 66b) diethyl-2- (3-hydroxy-3-cyclohexylpropyl) aminonon-4-in -dioat,

25th

from which the desired hydantoins were obtained as a mixture of diastereomers, which were separated if possible and gave the individual diastereomers with the melting points indicated: 30 45c) 5- (6-carboxyhexyl) -l- (3-hydroxy-5,5- dimethylhexyl) hydantoin, 86 to 88 ° C, 107 to 110 ° C; 46c) 5- (6-carboxyhexyl) -l- (3-hydroxy-5-methylhexyl) hydantoin, 100 to 101 ° C, 102 to 103 ° C; 47c) 5- (6-carboxyhexyl) -1- [3-hydroxy-3- (p-tolyl) propyl] -35 hydantoin;

48c) 5- (6-carboxyhexyl) -l- (3-hydroxy-4-cyclopentylbutyl) hydantoin, 101 to 104 ° C, 75 to 78 ° C; 49c) 5- (6-carboxyhexyl) -l- (3-hydroxy-4-cyclohexylbutyl) hydantoin, 92 to 94 ° C, 109 to 111 ° C; 40 50c) 5- (6-carboxyhexyl) -1- (3-hydroxy-6-cyclohexylhexyl) hydantoin, 84 to 86 ° C;

51c) 5- (6-carboxyhexyl) -l- (3-hydroxy-5-ethoxypentyl) hydantoin, 68 to 70 ° C;

52c) 5- (6-carboxyhexyl) -1- [3-hydroxy-4- (3-trifluoromethyl-45 phenoxy) butyl] hydantoin, 105 to 107 ° C, 118 to 120 ° C; 53c) 5- (6-carboxyhexyl) -1- [3-hydroxy-3- (4-chlorophenyl) propyl] hydantoin, 93 to 94 ° C, 101 to 102 ° C; 54c) 5- (6-carboxyhexyl) -1- [3-hydroxy-3- (4-methoxyphenyl) propyl] hydantoin, 93 to 94 ° C, 102 to 103 ° C; 50 55c) 5- (4-carboxymethoxybutyl) -l- (3-hydroxy-3-cyclohexyl-propyl) hydantoin, 88 to 94 ° C;

56c) 5- (4-carboxymethoxybutyl) -l- (3-hydroxy-3-cyclopentyl-propyl) hydantoin, 107 to 108 ° C;

57c) 5- (4-carboxymethoxybutyl) -l- (3-hydroxyoctyl) hydantoin, 55 79 to 81 ° C;

58c) 1- (3-hydroxy-5,5-dimethylhexyl) -5- (6-carboxyhex-2Z-enyl) -hydantoin, 66 to 71 ° C, 148 to 150 ° C; 59c) 1- (3-hydroxy-3-cyclopentylpropyl) -5- (6-carboxyhex-2Z-enyl) hydantoin, 74 to 76 ° C, 105 to 107 ° C; 60 60c) 1- (3-hydroxy-3-cyclohexylpropoyl) -5- (6-carboxyhex-2E-enyl) hydantoin, 60 to 63 ° C;

61c) 1- (3-hydroxy-4-cyclopentylbutyl) -5- (6-carboxyhex-2Z-enyl) hydantoin, 114-116 ° C;

62c) l- (3-hydroxy-4,4-dimethyl-5-phenylpentyl) -5- (6-carboxy-65 hex-2Z-enyl) hydantoin, 68 to 70 ° C, 116 to 117 ° E, 63c) 1- (3-hydroxy-5-cyclopentylpentyl) -5- (6-carboxyhex-2Z-enyl) hydantoin, 100 to 102 ° C, 76 to 78 ° C; 64c) 1- (3-hydroxy-3-cyclohexylpropyl) -5- (4-carboxymethoxy-

645 631

18th

but-2Z-enyl) hydantoin. each diastereomer was a glassy colorless mass;

65c) 1- (3-hydroxy-3-cyclohexylpropyl) -5- (4-carboxymethoxy-but-2E-enyl) hydantoin, 97 to 101 ° C; and 66c) 1- (3-hydroxy-3-cyclohexylpropyl) -5- (6-carboxyhex-2-ynyl) hydantoin, 84 to 86 ° C, 147 to 148 ° C.

Example 67

Preparation of 5- (6-carboxyhexyl) -l- (3-hydroxy-3-cyclohexyl-propyl) hydantoin

A stirred solution of 10 g of diethyl 2-aminononanedioate in 77 ml of ethanol was cooled in ice water and treated first with 38.6 ml of 2N hydrochloric acid and then with a solution of 6.255 g of potassium cyanate in 20 ml of water. The cooling bath was removed and the suspension was stirred at room temperature for 7 hours and then left to stand overnight. The ethanol was evaporated in vacuo and the residue was shaken with water and chloroform. The chloroform phase was separated, washed with water, dried over magnesium sulfate and the chloroform was evaporated. An oil was obtained which was heated on a steam bath for 6 hours. The oil obtained crystallized on standing at room temperature. The crystals were stirred with ether and collected to give pure diethyl 2-ureidononanedioate, melting point 79 to 80 ° C.

A mixture of 8 g of diethyl 2-ureidononanedioate and 1.28 g of diazabicyclonones (DBN) was heated in a bath at 100 ° C. for 1 h and the reaction mixture was shaken with chloroform and a small excess of dilute hydrochloric acid. The chloroform phase was separated, washed with water, dried over magnesium sulfate and the chloroform was evaporated. A crystalline residue was obtained. The crystals were suspended in ether, collected and yielded 5- (6-ethoxycarbonylhexyl) hydantoin with a melting point of 110 to 110.5 ° C.

A mixture of 200 mg of 5- (6-ethoxycarbonylhexyl) hydantoin, 97 mg of diazabicyclonones (DBN) and 108 mg of cyclohexylvinylyl ketone was heated in a bath at 100 ° C. for 5 hours. A stirred solution of the oil obtained in 2.5 ml of ethanol was treated with 30 mg of sodium borohydride and after 3 hours the solution was diluted with 40 ml of water, treated with 3 ml of 1N hydrochloric acid and shaken with ether. The ethereal phase was washed with water, dried over magnesium sulfate, concentrated and gave a suspension of the solid. The solid was collected and the ethereal filtrate was evaporated. A resin remained which was stirred for 114 hours with 6.2 ml of 0.35N aqueous sodium hydroxide and 0.75 ml of ether. After adding water and ether and after shaking, the aqueous phase was separated off, washed with ether and acidified with 2N hydrochloric acid. The released product was extracted into ether, the ethereal solution washed with water, dried over magnesium sulfate and evaporated. 90 mg of a resin were obtained. After purification of this resin by column chromatography on silica (15 g) in chloroform / methanol / acetic acid (96: 2: 2), observing the elution of the product by means of its absorption at 250 nm, a mixture of equal parts of the two diastereomers of 5- (6-carboxyhexyl) -l- (3-cyclohexyl-3-hydroxypropyl) hydantoin. These diastereomers were separated by HPLC and proved identical to the diastereomers described in Example 58c).

Example 68

Preparation of 5- (6-ethoxycarbonylhexyl) -l- (3-hydroxy-3-cy-clohexylpropyl) hydantoin

A solution of 4 g of 5- (6-carboxyhexyl) -l- (3-hydroxy-3-cyclohexylpropyl) hydantoin (diastereomer with a melting point of 96 to 98 ° C.) in 60 ml of ethanol and 1.6 ml of concentrated sulfuric acid was added for 18 hours Leave room temperature.

The alcohol was evaporated, water was added and the precipitated oil was extracted with ether. The ether solution was washed with sodium bicarbonate solution and water, dried over magnesium sulfate and evaporated. A single diastereomer of 5- (6-ethoxycarbonylhexyl) -1- (3-hydroxy-3-cyclohexyl) hydantoin was obtained as a colorless oil which soon solidified and crystallized from cyclohexane in fine platelets, melting point 62 to 63 ° C.

Similarly, the other diastereomer (melting point 124-126 ° C) of 5- (6-carboxyhexyl) -l- (3-hydroxy-3-cyclohexylpropyl) hydantoin was converted to its ethyl ester, melting point 101-102 ° C.

15

Example 69

Separation of the diastereomers from diethyl-2 - [(3-hydroxy-3-

cyclopentylpropyl) amino] nonandioate The mixture of diastereomers was dissolved in ether, the solution treated with a slight excess in ethereal chlorine-2Q hydrogen, stirred and gave a solid which was collected and washed with ether. This mixture of diastereomeric hydrochlorides had a melting point of 91 to 94 ° C. Fractional crystallization from ethyl acetate or a mixture of ethyl acetate and 25 ether gave two pure hydrochlorides, one of which was a fine colorless plate with a melting point of 112 to 114 ° C. and the other colorless needles of melting point 86 to 87 ° C formed.

Similarly, the two diastereomers of 30 diethyl 2 - [(3-hydroxy-3-cyclohexylpropyl) amino] nonanedioate were separated as their hydrochlorides, melting point 117-118 ° C and 67-69 ° C.

35

Example 70

Preparation of 5- (6-carboxyhex-2- (Z) -enyl) -l- (3-cyclohexyl-3-hydroxypropyl) hydantoin cis-methyl-6-bromhept-5-enoate (prepared according to the method described in GB-PSNr 1355991) and diethylacet-40 amidomalonate were reacted under the conditions described in Example 1A to give diethylacetamido (6-methoxycarbonylhex-2-enyl) malonate as a yellow oil.

This crude product was hydrolyzed by boiling with 5N hydrochloric acid and the product was esterified 45 as described in Example 1A. Diethyl 2-amino-4-endioate was obtained as a colorless oil, boiling point 118 to 123 ° C / 0.05 mmHgnì) 9'5 = 1.4620.

The reaction of this amino compound with 1-cyclohexyl-prop-2-enone as in reference example 2B and reduction of the 50 diethyl 2 - [(3-cyclohexyl-3-oxopropyl) amino] non-4-en-dioate with sodium borohydride as in example 2C provided diethyl 2 - [(3-cyclohexyl-3-hydroxypropyl) amino] non-2-enedioate.

Treatment of this compound with potassium cyanate and hydrochloric acid and hydrolysis of the hydantoin ester obtained as in Example 2D gave 5- (6-carboxyhex-2 (Z) -enyl) -l- (3-cyclohexyl-3-hydroxypropyl) hydantoin as a yellow oil which tended to solidify. This compound was separated into its diastereomers by means of HPLC. One formed fine colorless prisms from melting point 97 to 99 ° C and the other colorless 60 needles from melting point 108 to 110 ° C.

Mutual converters of the diastereomers 3.1 g of the diastereomer of melting point 108 to 110 ° C. were dissolved in 50 ml of n-sodium hydroxide solution and the solution was left to stand at room temperature for 18 hours. The solution was acidified and extracted with ether. The ether solution was washed with water, dried, evaporated and gave 3.1 g of a colorless glassy mass. According to thin layer chromatography it turned out to be a mixture of the

55

19th

645 631

Starting material with the other diastereomer. Separation of the mixture by HPLC gave the diastereomers of melting point 97 to 99 ° C (1.34 g) and melting point 108 to 110 ° C (1.33 g), which are identical to those described above.

Example 71

Preparation of 5- (6-ethoxycarbonylhexyl) -l- (3-cyclohexyl-3-hydroxypropyl) hydantoin A solution of 4 g of 5- (6-carboxyhexyl) -l- (3-cyclohexyl-3-hydroxypropyl) hydantoin (diastereomer from Melting point 96 to 98 ° C, Example 67) in 60 ml of ethanol and 1.6 m of concentrated sulfuric acid was left for 18 h at room temperature. The alcohol was evaporated, water was added and the precipitated oil was extracted with ether. The ether solution was washed with sodium bicarbonate solution and water, dried over magnesium sulfate and evaporated. A single diastereomer of 5- (6-ethoxycarbonylhexyl) -1- (3-cyclo-hexyl-3-hydroxypropyl) hydantoin was obtained as a colorless oil which soon became solid and crystallized from cyclohexane in fine colorless platelets, melting point 62 to 63 ° C.

Example 72

Preparation of 1- (3-Cyclohexyl-3-hydroxypropyl) -5- (7-hydroxyheptyl) hydantoin A solution of 108.5 mg ethyl chloroformate in 0.5 ml tetra-hydrofuran was added to a stirred solution of 368 mg 5- (6 -Carboxyhexyl) -l- (3-cyclohexyl-3-hydroxypropyl) hydantoin (mixture of diastereomers, Example 67) and 101 mg of triethylamine were added and the mixture was cooled to -5 ° C. for 15 min. After a further hour at 0 ° C the solid was collected and washed with 1 ml of tetrahydrofuran.

The combined filtrate and washing liquid were added dropwise over 30 minutes to a solution of 100 mg sodium borohydride in 1 ml water at 15 ° C. After the addition was complete, the solution was stirred at room temperature for 2 hours. Then water was added, the solution acidified with 2N hydrochloric acid and extracted with ether. The ether solution was washed with sodium bicarbonate solution and then with water, dried over magnesium sulfate and evaporated. 330 mg of a colorless, viscous oil remained.

Chromatography of 300 mg of this oil in water-saturated ethyl acetate over a column of silica gave 250 mg of an oil which, after thin-layer chromatography on silica, showed only two spots in a mixture of chloroform, methanol and acetic acid (ratio 90: 5: 5), Rr 0.60.0.63 attributable to the diastereomers of 1- (3-cyclohexyl-3-hydroxypropyl) -5- (7-hydroxyheptyl) hydantoin. The diastereomers were separated by means of HPLC. The less polar isomer solidified, melting point 73 to 77 ° C, the less polar was obtained as a viscous oil.

Example 73

Preparation of 5- (6-carboxyhexyl) -l- (3-cyclohexyl-3-hydroxypropyl) hydantoin 500 mg 5- (6-ethoxycarbonylhexyl) -l- (3-cyclohexyl-3-hydro-xypropyl) hydantoin (single diastereomer) were dissolved in 2.5 ml of aqueous ammonium hydroxide solution (specific weight 0.880) and the solution was heated in a closed vessel at 100 ° C. for 2 hours. After cooling, the solution was acidified with 2N hydrochloric acid and the precipitated resin was extracted first with ether, which dissolved part of the resin, and then with chloroform. The chloroform extract was washed with sodium bicarbonate solution and then with water, dried over magnesium sulfate and evaporated. He provided the mixed diastereomers of the title compound as a colorless solid, melting point 110 to 120 ° C (thin layer chromatography over

Silica in chloroform / methanol / acetic acid (90: 5: 5) showed two spots, Rr value 0.37, 0.41).

5 Example 74

Preparation of 5- (6-carboxyhexyl) -l- (3-hydroxy-3-cyclohexylbutyl) hydantoin

A solution of 6.9 g of 3-cyclohexylprop-l-en-3-one in 10 ml of dry ether was cooled to 0 ° C. and stirred while adding a solution of 4 g of hydrogen bromide in 20 ml of ether, whereupon the solution was dissolved in left in a refrigerator overnight.

This bromine-ketone solution was gradually added at room temperature to a stirred solution of methylmagnesium iodide, 15 made from 1.5 g magnesium and 8.5 g methyl iodide in 35 ml dry ether. After stirring for a further 2 hours, the mixture was poured into a cold solution of 5 g of ammonium chloride in 50 ml of water. The mixture was filtered, the ether layer separated, dried and evaporated. After distillation of the residue, 5.6 g of 4-bromo-2-cyclohexylbutan-2-ol were obtained, boiling point 86 to 88 ° CI 0.04 mm Hg, melting point 31 to 33 ° C.

A mixture of 4.9 g of the above-mentioned bromoalko-25 hols and diethyl 2-aminononanedioate was heated at 100 ° C. for 4 hours. The mixture was made basic with dilute sodium hydroxide solution and the insoluble oil extracted with ether. The ether extract was dried, evaporated to give 8.4 g of diethyl 2 - [(3-hydroxy-3-cyclohexylbutyl) amino] nonanedioate as an oil which was used without further purification.

Treatment of this amino diester with cyanic acid and subsequent alkaline hydrolysis of the hydantoin ester thus prepared as described in Example 1D produced 5- (6-35 carboxyhexyl) -l- (3-hydroxy-3-cyclohexylbutyl) hydantoin, which, as in Example 2D described, was split into diastereomers of melting point 173 to 174 ° C and melting point 109 to 111 ° C.

40 Example 75

Preparation of 5- (6-carboxyhexyl) -l- (3-cyclohexyl-3-oxopropyl) hydantoin The reaction of 20.8 g of diethyl 2 - [(3-cyclohexyl-3-oxo-45 propyl) amino] nonandioate with Cyanic acid using the general procedure described in Example 1D and subsequent treatment with alkali provided 7.2 g of 5- (6-carboxyhexyl) -l- (3-cyclohexyl-3-oxopropyl) hydantoin as a colorless resin . After crystallization from ether at 0 ° C., crystals of the pure compound with a melting point of 77.5 to 78.5 ° C. were obtained.

Example 76

Preparation of 5- (6-carboxyhexyl) -1- [3-hydroxy-55 3- (p-biphenylyl) propyl] hydantoin

A solution of 5 g of diethyl 2- [3-hydroxy-3- (p-bi-phenylyl) propylamino] nonandioate, which is obtained via diethyl 2- [3-oxo-3- (p-biphenylyl) propylamino] nonandioate the appropriate vinyl ketone using the procedure of Example 60 2, in 20 ml of absolute ethanol was heated at 60 ° C while 1.12 g of nitrourea was added in portions.

The mixture was then refluxed for 20 minutes, the solvent evaporated to give a viscous oil. The oil 65 was then heated on a steam bath for 6 hours to give 5- (6-ethoxycarbonylhexyl) -l- [3-hydroxy-3- (p -biphenylyl) propyl] hydantoin as a viscous light yellow oil which has been converted into the corresponding carboxylic acid.

645 631

20th

Example 77

The procedure of Example 76 was used to prepare the following compounds:

77a) diethyl-2-j [3-oxo-3- (4,4-dimethylaminophenyl) propyl] amino | nonanedioate;

77b) diethyl 2- {[3-hydroxy-3- (4,4-dimethylaminophenyl) propyl] amino [--nonanedioate; and therefrom 77c) 5- (6-carboxyhexyl) -1- [3-hydroxy-3- (4,4-dimethylaminophenyl) propyl] hydantoin.

Examples 78 to 80 The following compounds were also prepared by the procedure of Example 76:

78a) diethyl 2 - [(cycloheptan-2-onylmethyl) amino] nonandioate; 79a) diethyl 2-] [3-oxo-3- (4-hydroxyphenyl) propyl] amino \ nonanedioate; and

80a) diethyl-2-j [3-oxo-3- (5-nitrophenyl) propyl] amino} ■ nonanedioate;

which have been converted to:

78b) diethyl 2 - [(2-hydroxycycloheptylmethyl) amino] nonanedioate;

79b) diethyl 2-j [3-hydroxy-3- (4-hydroxyphenyl) propyl] amino j-nonanedioate; and

80b) diethyl 2-j [3-hydroxy-3- (4-nitrophenyl) propyl] amino-j nonanedioate;

which have been converted to:

78c) 5- (6-carboxyhexyl) -1- (2-hydroxycycloheptylmethyl) hydantoin;

79c) 5- (6-carboxyhexyl) -1- [3- (4-hydroxyphenyl) -3-hydroxypropylhydantoin; and

80c) 5- (6-carboxyhexyl) -1- [3- (4-nitrophenyl) -3-hydroxypropylhydantoin.

Example 81

Preparation of 5- (6-carboxyhexyl) -1- [3- (4-hydroxyphenyl) propyl] hydantoin This compound, which has a melting point of 107 to 108 ° C., was prepared by a process analogous to that described in Example 76, the corresponding alkyl halide being preferred instead of the vinyl ketone. The intermediate product diethyl 2- [3- (4-hydroxyphenyl) propyl] aminononanedioate was obtained.

Example 82

Preparation of salts of 5- (6-carboxyhexyl) -l- (3-hydroxy-3-cyclohexylpropyl) hydantoin Two series of salts are possible:

1) those in which the hydrogen atom in the 6-carboxy group is replaced by a metal ion; and

2) Those in which both the hydrogen atom in the 6-carboxy group and the hydrogen atom in the 3-position of the hydantoin ring are replaced.

The following series 1) salts were prepared by the following procedure:

Salts: sodium, potassium and magnesium

method

To a stirred solution of 1.0 mmol of a mixture of the two diastereomers of the title hydantoin in the ratio 50:50 in 5 ml of methanol was slowly added a solution of 1.0 mol equivalent of the appropriate metal bicarbonate (carbonate suspension for magnesium) in 2 ml of water. The reaction mixture was evaporated, finally under high vacuum (80 ° C), to give the monometal salt (semimetal salt for magnesium) as a hygroscopic foam.

10th

The following series 2) salts were prepared by the following procedure:

Salts: sodium, potassium and magnesium

method

A solution of 2.1 molar equivalents of metal bicarbonate (carbonate suspension for magnesium) in 5 ml of water was added to 1.0 mmol of a mixture of the two diastereomers of the title hydantoin in a ratio of 50:50 and the aqueous solution obtained was evaporated to dryness. The residue was treated with 10 ml of ethanol, filtered and the filtrate evaporated. It gave the bis metal salt (monometal salt for magnesium) as a hygroscopic foam.

The same procedures can be used to prepare the salts of the 15 separated diastereomers, especially those with the lower melting point.

The hydantoins used in carrying out the pharmacological tests corresponding to Examples 1A to 1F are designated as follows:

Compound 2: 5- (6-carboxyhexyl) -1- (3-hydroxyoctyl) hydantoin;

Compound 4: 5- (6-carboxyhexyl) -1- (3-hydroxy-4,4-dimethylpentyl) hydantoin;

Compound 6: 5- (6-carboxyhexyl) -1- (3-hydroxynonyl) hydantoin;

Compound 9: 5- (6-carboxyhexyl) -1- (3-hydroxy-4,4-dimethyloctyl) hydantoin;

Compound 11: 5- (6-carboxyhexyl) -l- (3-hydroxy-3-cyclo-butylpropyl) hydantoin;

Compound 12: 5- (6-cyclohexyl) -1- (3-hydroxy-3-cyclopentylpropyl) hydantoin;

Compound 14: 5- (6-carboxyhexyl) -1- (3-hydroxy-3-cyclo-hexylpropyl) hydantoin;

Compound 38: 5- (6-carboxyhexyl) -3-methyl-l- (oxooctyl) hydantoin.

If a special diastereomer is used, this is specified with reference to its melting point. Example Ä

Cardiovascular effects in rats

Male rats [strain Wistar (Charles River)] with normal blood pressure and a weight of 250 to 350 g were anesthetized with chloroform before cannulation of the left femoral vein and the anesthesia was maintained by intravenous chloralose 45 (60 mg / kg). Arterial blood pressure was recorded on the left femoral artery using an electronic transducer (Bell and Howewll type 4-327 L221) and the associated pulse rate was measured using a cardiotachometer triggered by the arterial pressure waves 50.

The test compounds were administered as a solution in physiological saline by intravenous injection through the thigh cannula. Between successive administrations, the reactions observed were returned to their 55 values before the injections.

Injections of the carrier alone in the same volume as the injections containing the active ingredient did not bring about a drop in blood pressure.

20th

25th

30th

35

40

60

65

connection

dose

Average drop in blood pressure, mm Hg

PGE,

4 jxg / kg

28

PGE,

16ng / kg

44

Connection 2

10 ng / kg

14

Connection 2

1 mg / kg

42

Connection 6

3 mg / kg

40

Connection 9

3 mg / kg

22

21st

645 631

Example B

Inhibition of platelet aggregation The platelet aggregation in 1 ml of fresh human platelet-rich plasma (PRP) was demonstrated in an Born Born aggregometer.

The compound to be tested was added to the PRP at the desired concentration and the resulting mixture was incubated at 37 ° C 1 min. Thereafter, platelet aggregation was stimulated by adding adenosine diphosphate (ADP) to a concentration of 5 [xMol.

The inhibitory effect of the compound on aggregation was determined by measuring the percentage inhibition of platelet aggregation in the presence of the compound compared to the total absence of the compound.

Compound 12, lactose and starch are mixed together. The powders are granulated using a solution of the povidone in purified water. The magnesium stearate is added to the dry granules and the whole is compressed into tablets of 100 mg.

Example H

io

Capsules

In a capsule

Compound 12 (melting point 116-117 ° C)

10 mg

Lactose

79 mg

Strength

10 mg

Magnesium stearate

1mg

connection

concentration

Inhibition of aggregation (%)

PGE!

15 [Xg / ml

33

PGEj

20 [xg / ml

47

PGEj

30 [xg / ml

63

PGEj

40 [xg / ml

69

Connection 12

1.0ng / ml

25th

(Melting point

116 to 117 ° C)

Connection 12

1.0ng / ml

51

Connection 12

2.0ng / ml

79

Connection 12

4.0ng / ml

94

15

The powders are mixed in a powder mixer, filled into hard gelatin capsules at 100 mg per capsule.

Example I

20th

1 [xg / ml injection

Compound 12 (melting point 116-117 ° C) water for injection

100 ng ad 100 ml

25th

Using comparisons like these, the following relative efficiencies compared to PGEj have been demonstrated. Compound 2 (melting point 76 to 78 ° C), 12.5 x; Compound 4 (melting point 144 to 146 ° C), 0.05 x; Compound 11 (114-116 ° C), 5.2x; Compound 12 (melting point 116-117 ° C), 12.5x; and compound 14 (melting point 96 to 98 ° C), 16x.

Example C

Compound 38 was found to reduce aspirin-induced gastric ulceration in rats; an oral dose of 1 mg / kg provided 80% protection.

Example D

At an intravenous dose of 30 [xg / kg, compound 2 completely inhibited pentagastrin-induced gastric acid secretion in rats.

Example E

It was found that intravenous injection of compound 9 (50 xg / kg) completely counteracted the histamine-induced bronchoconstriction in anesthetized guinea pigs.

30th

Compound 12 is dissolved in the water for injection. The solution is sterilized by filtering through a membrane filter with a pore size of 0.22 μm and the filtrate is collected in a sterile container. Under aseptic conditions, the solution is filled into sterile glass ampoules, 1 ml per ampoule. The ampoule is then sealed.

Example J

35

10 [ig / ml injection

Compound 12 (melting point 116-117 ° C) ethyl alcohol propylene glycol 40 water for injection

1mg 10 ml 30 ml ad 100ml

Compound 12 is dissolved in the ethyl alcohol, the propylene glycol is added and the volume is diluted with water for injection.

The solution is sterilized by filtering through a membrane filter with a pore size of 0.22 µm and the filtrate is collected in a sterile vessel. Under aseptic conditions, the solution is filled into sterile glass ampoule vials, 10 ml per ampoule vial. This is closed with a sterile rubber stopper and secured with an aluminum collar.

Example F

The intravenous infection of compound 2 (melting point 76 55-78 ° C) in a dose of 250 [xg / min showed that an electrically induced arterial thrombosis in anesthetized rabbits reduced.

Example K

100 [xg single dose injection (freeze-dried)

Example G

Compound 12 (melting point 116-117 ° C) 10.0 mg

Mannitol 2.5 g n / 10 sodium hydroxide solution qs ad pH 10.0

61 water for injection ad 100.0 ml

Tablets

In a tablet

Compound 12 (melting point 116-117 ° C)

Lactose B.P.

B.P.

PovidonB.P.C.

Magnesium stearate

5.0 mg 82.0 mg 10.0 mg 2.0 mg 1.0 mg

Compound 12 is suspended in about 20 ml of water. Sufficient sodium hydroxide solution is then added to bring the suspension to pH 10 and stirred to dissolve compound 12. The mannitol is then added and dissolved and made up to the prescribed volume with water for injection.

645 631

The solution is sterilized by filtering through a membrane filter with a pore size of 0.22 µm and filled aseptically into sterile ampoules, 1 ml per ampoule. The solutions are freeze-dried and the containers are sealed with rubber closures under aseptic conditions. Each ampoule contains 100% of Compound 12 as its freeze-dried sodium salt.

The suppository mass is melted at about 40 ° C. Compound 12 is gradually incorporated as a fine powder and the whole is processed into a homogeneous mixture. Then the suppositories are poured into appropriate molds and left to solidify.

Example L

Suppositories

-10

Compound 12 (melting point 116-117 ° C) Massa Esterinum C

3 mg ad 2 mg

Massa Esterinum C is a commercially available supplement base, which consists of a mixture of mono-, di- and tri-glycerides of the saturated vegetable fatty acids. It is distributed by Henkel International, Düsseldorf.

1

M

Claims (34)

645 631 2nd PATENT CLAIMS 1. Process for the preparation of hydantoin derivatives of the formula Q z-n (I), wherein Z is hydrogen or alkyl; one of the groups Z1 and Z2 the group -CH2-X-X1-X2, wherein X is phenylene, -C = C-, ice or trans-CH = CH- or -CH2-CQ2-, wherein each Q independently represents hydrogen and alkyl or the two Q together represent an alkylene group with 4.5 or 6 carbon atoms; XI is a covalent bond or a straight or branched chain alkylene chain having 1 to 6 carbon atoms, in which one of its methylene groups may be replaced by a 0xa (-0-) group, provided that at least one carbon atom has the oxa group of a -C = C -, -CH = CH or -CO group separates; and X2 is 5-tetrazolyl, carboxyl, carboxamide, hydroxymethylene or alkoxycarbonyl, and the other of the groups Z1 and Z2 is the group -Y-Y'-Y ^ Y3, in which Y is -CR2CH2-, where each R is independently hydrogen and methyl; Y1 carbonyl, methylene, one by hydroxy or by Hydroxy and alkyl substituted methylene group; Y2 is a covalent bond or a straight- or branched-chain alkylene group having 1 to 7 carbon atoms, which may optionally be substituted on the carbon atom adjacent to Y1 by one or two independent alkyl, bicycloalkyl or cycloalkyl groups; Y3 is hydrogen, hydroxy, alkoxy of 1 to 7 carbon atoms, cycloalkyl, bicycloalkyl, phenyl, benzyl, phenoxy or benzyloxy, wherein each of the groups phenyl, benzyl, phenoxy and benzyloxy in the benzene ring through one or more of the groups hydroxy, halogen, nitro, amino , Acylamino, alkenyl, alkoxy, phenyl and alkyl can be substituted, which in turn can be substituted by one or more halogens; or Y is a bond, -CH2- or -CH2.CH2-; and Y1, Y2 and Y3 together form a cycloalkyl group which is substituted by a hydroxyl group and separates them from the hydantoin ring, mean, and of their salts, characterized in that a compound of formula II g ^ "z1 (ii), wherein G is carboxyl or one of its functional derivatives, cyclized and optionally converting a compound of formula I obtained into another salt. 2. The method according to claim 1, characterized in that a compound of formula II, wherein G is carboxyl, carboxamide or alkoxycarbonyl, cyclized. 5 3. The method according to claim 1 or 2, characterized in that one carries out the reaction with heating. 4. The method according to any one of claims 1 to 3, characterized in that one carries out the reaction under acidic conditions. 10th 5. The method according to any one of claims 1 to 4, characterized in that one carries out the reaction in the presence of a solvent. 6. The method according to claim 1, 2 or 5, characterized in that a compound of the formula II in which G is alkoxycarbonyl is used and the cyclization is carried out in the presence of a base. 7. The method according to claim 6, characterized in that 20 one uses as base sodium ethoxide. 8. The method according to any one of claims 1 to 7, characterized in that one produces a compound of formula I, wherein 15 25th Z hydrogen X2 is carboxyl or alkoxycarbonyl, and when Y2 and Y3 are taken together they form a cycloalkyl group of 4 to 7 carbon atoms. 9. The method according to any one of claims 1 to 7, characterized in that one produces a compound of formula I, wherein Z is hydrogen; X phenylene, ice -CH = CH- or -CH2-CH2-; X2 carboxyl or alkoxycarbonyl; and 35 R is hydrogen, and wherein Y2 and Y3 together do not form a cycloalkyl group. 10. The method according to any one of claims 1 to 7, characterized in that one produces a compound of formula I, wherein Z is hydrogen; X ice -CH = CH- or -CH2-CH2-; XI is a covalent bond or a straight-chain or branched-chain alkylene group with 1 to 6 carbon atoms; X2 carboxyl or alkoxycarbonyl; Y -CH2-CH2- mean and Y2 and Y3 together do not form a cycloalkyl group and Y3 is hydrogen. 50 11. The method according to any one of claims 1 to 7, characterized in that the following compounds are prepared: 5- (6-carboxyhexyl) -l- (3-hydroxyoctyl) hydantoin; 5- (6-carboxyhexyl) -1- (3-hydroxy-4,4-dimethylpentyl) hydantoin; 5- (6-carboxyhexyl) -l- (3-hydroxynonyl-hydantoin; 5- (6-carboxyhexyl) -l- (3-hydroxy-4,4-dimethyloctyl) hydantoin; 5- (6-carboxyhexyl) -l- (3-hydroxy-3-cyclobutylpropyl) hydantoin; 5- (6-carboxyhexyl) -l- (3-hydroxy-3-cyclopentylpropyl) hydantoin; 5- (6-carboxyhexyl) -l- (3-hydroxy-3-cyclohexylpropyl) hydantoin; 5- (6-carboxyhexyl) -3-methyl-l (3-hydantoinoxooctyl); 60 65 and their salts and esters. 12. Process for the preparation of hydantoin derivatives of the formula I. 3rd 645 631 0 z-n (I) wherein Z is hydrogen or alkyl; one of the groups Z1 and 7} the group -CH.-X-X ^ X2, wherein X is phenylene, -C = C-, ice or trans-CH = CH- or -CH2-CQ2-, wherein each Q independently represents hydrogen and alkyl or the two Q together represent an alkylene group with 4.5 or 6 carbon atoms; XI is a covalent bond or a straight or branched chain alkenyl chain with 1 to 6 carbon atoms, in which one of its methylene groups may be replaced by a 0xa (-0-) group, provided that at least one carbon atom has the oxa group of a -C = Separates C, -CH = CH or -CO group; and X2 is 5-tetrazolyl, carboxyl, carboxamide, hydroxymethylene or alkoxycarbonyl, and the other of the groups 13. The method according to claim 12, characterized in that a metal cyanate is used in the presence of an equivalent amount of acid to prepare a compound of formula II. 5 14. The method according to claim 12, characterized in that one uses urea, nitrourea or N-alkylurea for the preparation of a compound of formula II and carries out the reaction at a temperature up to 150 ° C. 15. The method according to any one of claims 12 to 14, characterized in that the reaction in the presence of a Performs solvent. 16. Process for the preparation of hydantoin derivatives of the formula I. 15 20th 25th 0 z-n n> (I), 0 Z1 Y and Z2 the group -Y-Y ^ Y-Y3, wherein Y1 Y2 -CR2CH2-, where each R is independently hydrogen and methyl; Carbonyl, methylene, a methylene group substituted by hydroxy or by hydroxy and alkyl; a covalent bond or a straight-chain or branched-chain alkylene group having 1 to 7 carbon atoms, which may optionally be substituted on the carbon atom adjacent to the Y1 by one or two independent alkyl, bicycloalkyl or cycloalkyl groups; Hydrogen, hydroxy, alkoxy having 1 to 7 carbon atoms, cycloalkyl, bicycloalkyl, phenyl, benzyl, phenoxy or benzyloxy, in which each of the groups phenyl, benzyl, phenoxy and benzyloxy in the benzene ring through one or more of the groups hydroxyl, halogen, nitro, amino, Acylamino, alkenyl, alkoxy, phenyl and alkyl can be substituted, which in turn can be substituted by one or more halogens; or a bond, -CH2- or -CH2.CH2-; and Y2 and Y3 together form a cycloalkyl group substituted by a hydroxyl group, which separates them from the hydantoin ring, mean, and of their salts, characterized in that a compound of formula III ' (1HT) X 35 X1 40 Y Y1 h wherein G 'is carboxyl or one of its functional derivatives or cyano, with cyanic acid, urea, nitrourea or an N-alkylurea and converting the compound of formula II obtained into a corresponding compound of formula I by the process according to one of claims 1 to 11. wherein Z is hydrogen or alkyl; one of the groups 30 Z1 and Z2 the group -CH2-X-X1-X2, wherein Phenylene, -C = C-, ice or trans-CH = CH- or -CH2-CQ2-, wherein each Q independently represents hydrogen and alkyl or the two Q together represent an alkylene group with 4, 5 or 6 carbon atoms; a covalent bond or a straight or branched chain alkylene chain having 1 to 6 carbon atoms, in which one of its methylene groups may be replaced by a 0xa (-0-) group, provided that at least one carbon atom has the oxa group of a -C = C- , -CH = CH or -CO group separates; and 5-tetrazolyl, carboxyl, carboxamide, hydroxymethylene or alkoxycarbonyl, and the other of the groups and Z2 is the group -Y-Y ^ Y ^ Y3, wherein -CR2CH2-, where each R is independently hydrogen and methyl; Carbonyl, methylene, a methylene group substituted by hydroxy or by hydroxy and alkyl; a covalent bond or a straight-chain or branched-chain alkylene group having 1 to 7 carbon atoms, which may optionally be substituted on the carbon atom adjacent to the Y1 by one or two independent alkyl, bicycloalkyl or cycloalkyl groups; Hydrogen, hydroxy, alkoxy having 1 to 7 carbon atoms, cycloalkyl, bicycloalkyl, phenyl, benzyl, phenoxy or benzyloxy, in which each of the groups phenyl, benzyl, phenoxy and benzyloxy in the benzene ring through one or more of the groups hydroxyl, halogen, nitro, amino, 60 acylamino, alkenyl, alkoxy, phenyl and alkyl can be substituted, which in turn can be substituted by one or more halogens; or Y is a bond, -CH2- or -CH2.CH2-; and Y1, Y2 and Y3 together form a cycloalkyl group which is substituted by a hydroxyl group 65 and which separates them from the hydantoin ring, mean, and of their salts, characterized in that a compound of formula III " X2 z1 45 y 50 55 Y3 645 631 4th Mr (iii "), z-n ' wherein G "is carboxamido or cyano, is reacted with an alkyl isocyanate and the compound of formula II obtained is converted into a corresponding compound of formula I by the process according to one of claims 1 to 11. 17. The method according to claim 16, characterized in that one carries out the reaction in the presence of a solvent. 18. Process for the preparation of hydantoin derivatives of the formula I q (VII), z-n (I) n> 0 wherein 10th in which G is carboxyl or one of its functional derivatives, cyclizes and, if appropriate, converts a compound of the formula I obtained into another salt. 19. The method according to claim 18, characterized in that a compound of formula VII, wherein G is carboxyl or alkoxycarbonyl, is cyclized. 20. The method according to claim 18 or 19, characterized in that the reaction is carried out under acidic conditions. 21. The method according to any one of claims 18 to 20, characterized in that one produces a compound of formula I, wherein Z is hydrogen; X2 is carboxyl or alkoxycarbonyl, and when Y2 and Y3 are taken together they form a cycloalkyl group of 4 to 7 carbon atoms. 25th z z1 X X1 Hydrogen or alkyl; one of the groups and Z2 the group -CHz-X-X'-X2, in which phenylene, -C = C-, ice or trans-CH = CH- or -CH2-CQ2-, in which each Q is independently hydrogen and alkyl or the two Q together represent an alkylene group of 4.5 or 6 carbon atoms; a covalent bond or a straight or branched chain alkylene chain having 1 to 6 carbon atoms, in which one of its methylene groups may be replaced by a 0xa (-0-) group, provided that at least one carbon atom has the oxa group of a -C = C- , -CH = CH or -CO group separates; and 5-tetrazolyl, carboxyl, carboxamide, hydroxymethylene or alkoxycarbonyl, and the other of the groups and Z2 is the group -Y-Y'-Y2-Y3, wherein -CR2CH2-, each R being independently hydrogen and methyl; Carbonyl, methylene, a methylene group substituted by hydroxy or by hydroxy and alkyl; a covalent bond or a straight-chain or branched-chain alkylene group having 1 to 7 carbon atoms, which may optionally be substituted on the carbon atom adjacent to the Y1 by one or two independent alkyl, bicycloalkyl or cycloalkyl groups; Hydrogen, hydroxy, alkoxy having 1 to 7 carbon atoms, cycloalkyl, bicycloalkyl, phenyl, benzyl, phenoxy or benzyloxy, in which each of the groups phenyl, benzyl, phenoxy and benzyloxy in the benzene ring through one or more of the groups hydroxyl, halogen, nitro, amino, Acylamino, alkenyl, alkoxy, phenyl and alkyl can be substituted, which in turn can be substituted by one or more halogens; or a bond, -CH2- or -CH2-CH2-; and Y2 and Y3 together form a cycloalkyl group substituted by a hydroxyl group, which separates them from the hydantoin ring, mean, and of their salts, characterized in that a compound of formula VII 30th 35 40 X2 Y2 45 X XI X2 Y Y Y1 22. The method according to any one of claims 18 to 20, characterized in that one produces a compound of formula I, wherein Z is hydrogen; X is phenylene, cis-CH = CH- or -CH2-CH2-; X2 carboxyl or alkoxycarbonyl; and R is hydrogen, and wherein Y2 and Y3 together do not form cycloalkyl groups. 23. The method according to any one of claims 18 to 20, characterized in that one produces a compound of formula I, wherein Z is hydrogen; cis-CH = CH- or -CH2-CH2-; a covalent bond or a straight or branched chain alkylene group having 1 to 6 carbon atoms; Carboxyl or alkoxycarbonyl; -CH2-CH2- mean and Y2 and Y3 together do not form a cycloalkyl group and Y3 is hydrogen. 50 24. The method according to any one of claims 18 to 20, characterized in that the following compounds are produced: 5- (6-carboxyhexyl) -l- (3-hydroxyoctyl) hydantoin; 5- (6-carboxyhexyl) -l- (3-hydroxy-4,4-dimethylpentyl) -55 hydantoin; 5- (6-carboxyhexyl) -l- (3-hydroxynonyl) hydantoin; 5- (6-carboxyhexyl) -l- (3-hydroxy-4,4-dimethyloctyl) hydantoin; 5- (6-carboxyhexyl) -l- (3-hydroxy-3-cyclobutylpropyl) -60 hydantoin; 5- (6-carboxyhexyl) -l- (3-hydroxy-3-cyclopentylpropyl) hydantoin; 5- (6-carboxyhexyl) -l- (3-hydroxy-3-cyclohexylpropyl) hydantoin; 65 5- (6-carboxyhexyl) -3-methyl-l (3-hydantoinoxooctyl); and their salts and esters. 25. Process for the preparation of hydantoin derivatives of the formula I. 5 645 631 z-n (I), 26. The method according to claim 25, characterized in that G is alkoxycarbonyl, Q1 amino, Q2 bromine and Z is hydrogen. 27. Process for the preparation of hydantoin derivatives of the formula 5 q 10th z-n Y2 wherein Z is hydrogen or alkyl; one of the groups Z1 and Z2 the group -CHj-X-X ^ X2, wherein X is phenylene, -C = C-, ice or trans-CH = CH- or -CH2-CQ2-, wherein each Q independently represents hydrogen and alkyl or the two Q together represent an alkylene group with 4, 5 or 6 carbon atoms; XI is a covalent bond or a straight or branched chain alkylene chain with bisbis carbon atoms, in which one of its methylene groups may be replaced by a 0xa (-0-) group, provided that at least one carbon atom has the oxa group of a -C = C-, -CH = Separates CH or -CO group; and X2 is 5-tetrazolyl, carboxyl, carboxamide, hydroxymethylene or alkoxycarbonyl, and the other of groups 7} and 7} is the group -Y-Y'-Y ^ Y3, where Y is -CR2CH2-, where each R is independently hydrogen and methyl ; Y1 carbonyl, methylene, a methylene group substituted by hydroxy or by hydroxy and alkyl; a covalent bond or a straight-chain or branched-chain alkylene group having 1 to 7 carbon atoms, which may optionally be substituted on the carbon atom adjacent to the Y1 by one or two independent alkyl, bicycloalkyl or cycloalkyl groups; Hydrogen, hydroxy, alkoxy having 1 to 7 carbon atoms, cycloalkyl, bicycloalkyl, phenyl, benzyl, phenoxy or benzyloxy, in which each of the groups phenyl, benzyl, phenoxy and benzyloxy in the benzene ring through one or more of the groups hydroxyl, halogen, nitro, amino, Acylamino, alkenyl, alkoxy, phenyl and alkyl can be substituted, which in turn can be substituted by one or more halogens; or a bond, -CH2- or -CH2.CH2-; and Y2 and Y3 together form a cycloalkyl group substituted by a hydroxyl group, which separates them from the hydantoin ring, mean, and of their salts, characterized in that a compound of formula V with a compound of formula VIII (v, n, (I) 15 0 where Z 7} X Y Y1 z-n (viii), 20th 25th 30th Hydrogen or alkyl; one of the groups and 7} the group -CH2-X-X1-X2, in which phenylene, -C = C-, ice or trans-CH = CH- or -CH2-CQ2-, in which each Q is independently hydrogen and alkyl or the two Q together represent an alkylene group with 4, 5 or 6 carbon atoms; X1 is a covalent bond or a straight or branched chain alkylene chain with 1 to 6 carbon atoms, in which one of its methylene groups may be replaced by a 0xa (-0-) group, provided that at least one carbon atom has the oxa group of a -C = C -, -CH = CH or -CO group separates; and X2 is 5-tetrazolyl, carboxyl, carboxamide, hydroxymethylene or alkoxycarbonyl, and the other of groups 7} and 7} is the group -Y-Y'-Y ^ Y3, where Y is -CR2CH2-, each R independently being hydrogen and methyl is; Carbonyl, methylene, a methylene group substituted by hydroxy or by hydroxy and alkyl; a covalent bond or a straight-chain or branched-chain alkylene group having 1 to 7 carbon atoms, which may optionally be substituted on the carbon atom adjacent to the Y1 by one or two independent alkyl, bicycloalkyl or cycloalkyl groups; Hydrogen, hydroxy, alkoxy with 1 to 7 carbon atoms, cycloalkyl, bicycloalkyl, phenyl, benzyl, phenoxy or benzyloxy, in which each of the groups phenyl, benzyl, phenoxy and benzyloxy in the benzene ring by one or more of the groups hydroxyl, halogen, nitro, Amino, acylamino, alkenyl, alkoxy, phenyl and alkyl can be substituted, which in turn can be substituted by one or more 50 halogens; or a bond, -CH2- or -CH2.CH2-; and Y2 and Y3 together form a cycloalkyl group substituted by a hydroxyl group, which separates them from the hydantoin ring, 55 and their salts, characterized in that that a carboxylic acid derivative with a compound of formula IX 35 y1 Y2 40 45 Y Y1, 60 wherein either Q1 or Q2 is halogen and the other group is amino, and the compound of formula VII obtained is converted into a corresponding compound of formula I by the process according to any one of claims 18 to 24. 65 (ix), is reacted and, if appropriate, a compound of the formula I obtained is converted into another salt. 645 631 6 28. The method according to claim 27, characterized in that one carries out the reaction in the presence of a base. 29. The method according to claim 28, characterized in that an amine is used as the base. 30. The method according to claim 28 or 29, characterized in that the base used is triethylamine or di-iso-propyl-ethylamine. 31. The method according to any one of claims 27 to 30, characterized in that phosgene, diphenyl carbonate and chlorinated carbonate are used as the carboxylic acid derivative. 32. The method according to any one of claims 27 to 31, characterized in that one carries out the reaction in the presence of an inert aprotic solvent. 33. The method according to any one of claims 27 to 32, characterized in that one produces a compound of formula I, wherein Z is hydrogen; X2 is carboxyl or alkoxycarbonyl, and when Y2 and Y3 are taken together they form a cycloalkyl group of 4 to 7 carbon atoms. 34. The method according to any one of claims 27 to 32, characterized in that one produces a compound of formula I, wherein Z is hydrogen; X is phenylene, cis-CH = CH- or -CH2-CH2-; X2 carboxyl or alkoxycarbonyl; and R is hydrogen, and wherein Y2 and Y3 together do not form a cycloalkyl group. 35. The method according to any one of claims 27 to 32, characterized in that one produces a compound of formula I, wherein Z is hydrogen; X cis-CH = CH- or -CH2-CH2-; XI is a covalent bond or a straight or branched chain alkylene group having 1 to 6 carbon atoms; X2 carboxyl or alkoxycarbonyl; Y is -CH2-CHr and Y2 and Y3 together do not form a cycloalkyl group and Y3 is hydrogen. 36. The method according to any one of claims 27 to 32, characterized in that the following compounds are produced: 5- (6-carboxyhexyl) -l- (3-hydroxyoctyl) hydantoin; 5- (6-carboxyhexyl) -1- (3-hydroxy-4,4-dimethylpentyl) hydantoin; 5- (6-carboxyhexyl) -l- (3-hydroxynonyl) hydantoin; 5- (6-carboxyhexyl) -l- (3-hydroxy-4,4-dimethyloctyl) hydantoin; 5- (6-carboxyhexyl) -l- (3-hydroxy-3-cyclobutylpropyl) hydantoin; 5- (6-carboxyhexyl) -l- (3-hydroxy-3-cyclopentylpropyl) hydantoin; 5- (6-carboxyhexyl) -l- (3-hydroxy-3-cyclohexylpropyl) hydantoin; 5- (6-carboxyhexyl) -3-methyl-l (3-hydantoinoxooctyl); and their salts and esters. 37. The method according to any one of claims 1 to 36, characterized in that alkylating a compound of formula I, wherein Z is hydrogen.