CH646426A5 - Process for the preparation of hydantoin derivatives - Google Patents

Abstract

Hydantoin derivatives of the formula I are prepared by reducing a compound of the formula XI. The substituents in formulae I and XI have the meanings given in Patent Claim 1. The hydantoin derivatives of the formula I possess pharmacological properties which are related to those of the natural prostaglandins. <IMAGE>

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 match those of the natural ones

5

10th

IS

20th

25th

30th

35

40

45

50

55

60

65

Prostaglandins are related to wind. This shows 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

mean

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

X is phenylene, -C = C-, ice or trans-CH = CH- or -CH2-CQ2-, wherein 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 = Separates C, -CH = CH or -CO group; 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 -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-chain 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 mutually 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. Likewise, alkenyl

646 426

groups with 2 to 4 carbon atoms, for example vinyl, are preferred.

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

In a compound of the formula I, the bond of the di-valent phenyl 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 ethanol amine. 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 referred to as 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 Z1 and Z2 -CHz-X-X'-X2, in which

X and X1 together are an alkylene of 3 to 7, preferably

5, carbon atoms; and X2 represents alkoxycarbonyl, carboxyl or a salt thereof, and the other of the groups Z1 and Z2 -Y-Y'-Y2-Y3, where Y, Y1 and Y2 are as defined above; and Y3 is hydrogen, cycloalkyl, having 4 to 7 carbon atoms,

Represents 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 -CH2-X-X1-X2-.

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

According to the invention, the compounds of the formula I are prepared by reducing an appropriate unsaturated compound of the formula XI

0 '

z-n where either

Z3 = CR-CH2-Y1 -Y2-Y3; and

3rd

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

646 426

4th

Z4 -CHz-X-X'OC2; or Z3 = CH-X-X1-X2; and Z4 -Y-Y'-Y2-Y3

mean with a suitable reducing agent.

A suitable reducing agent is, for example, tin chloride, which can be used as an aqueous solution, optionally in the presence of dilute mineral acid. Further e.g. a catalytic hydrogenation in the presence of, for example, Raney nickel, platinum, palladium, ruthenium or rhodium can also be carried out. The choice of reducing agent in a given situation is of course determined by the presence of the other active groups in the molecule, which may themselves be reduced.

The intermediates of formula XI can be prepared according to the following reaction scheme:

ï ch (og3) 2 g chcog3) 2

ch + g4.z4> ch nh2 nh

\

z4

(XII)

0

. +

<3 zn u I

/ A ^ chcog3) ;,

0

z4

(XIV) (XIII).

(XI)

ph3p = «z3

In the formulas of the above reaction scheme, Z, Z3 and Z4 have the same meanings as in formula XI, G means carboxyl or one of its functional derivatives, e.g. an amide or an ester, especially an alkyl ester or a nitrii, G3 means alkyl, e.g. n-butyl, and G4 means halogen, e.g. Bromine.

The formation of the compound of formula XIII can e.g. 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. Gasoline. 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.

The compounds of formula XIV are preferably prepared using concentrated mineral acid, such as hydrochloric acid.

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. by acyl, aroyl, tetrahydropyran-2-yl, 1-ethoxyethyl or aralkyl, e.g. 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.

Furthermore, a ketone of formula I, wherein Y1 is carbonyl, can be converted into the corresponding secondary alcohol by reduction with a suitable reducing agent, e.g. 6o sodium borohydride can be transferred. An alcohol of formula I, wherein Y1 is -CH2OH-, can also be oxidized to the corresponding ketone using Jones reagent, acid dichromate or another suitable reagent.

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

5

646 426

the ethylene or saturated compounds are transferred.

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 means of 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.

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 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", by which one understands the relative modes of action, namely the mimicking or the antagonistic, compared to the natural prostaglandins, naturally varies depending on the specific hydantoin derivative under consideration.

Due to their prostaglandin-related properties, 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. Understanding the physiological effects of prostaglandins is of great value when looking 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 hydantoin derivatives described above 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. Thus, the present compounds are useful in the treatment and prevention of myocardial infarction, for the treatment and prevention of thrombosis and for improving the patency of vascular grafts after surgery. They are also suitable for the treatment of arteriosclerosis and conditions such as atherosclerosis, disorders of blood clotting as a result of lipaemia and other clinical conditions in which the cause of the disease is associated with an impaired lipid balance or with

Hyperlipidemia stands. Furthermore, these compounds can be used as additives to blood and other liquids, which are used for the artificial maintenance of a circulation outside the body or for flushing through 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 carboxyalkylene in which the alkylene part has 3 to 9 carbon atoms and Z2 is a group - (CH2) 2 .CH. .H.Y2.Y3, wherein Y2 is a branched chain alkylene having a tertiary carbon atom adjacent to the hydroxy-substituted carbon, and Y3 is as defined in formula I. The compounds in which Z1 is carboxyhexyl and Y3 is a cycloalkyl having 4 to 7 carbon atoms have proven particularly effective in this group.

It has furthermore 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 5- (6-carboxyhexyl) -1- (3-hydroxy-4,4-dimethyIoctyl) hydantoin and 5- (6-carboxyhexyl) -1- (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 humans. They can be administered either alone or with an adrenaline / 3 receptor blocking agent or other antihypertensive agent for the treatment of all types and strengths of elevated blood pressure, including essential, malignant and secondary hypertension.

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

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-oxooctyl) -hydantoin and the 5- (6-carb-oxyhexyl) -l- (4-phenoxybutyl) -hydantoin, which are the gastric acid secretions caused by pen-tagastrin inhibiting 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 occur as a concomitant symptom of a polyglandular adenoma syndrome.

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 edema, such as those that occur in heart defects, liver or kidney damage in humans or mammals.

A further use of the hydantoin derivatives of the formula I, the effect of which is similar to the effect on the smooth muscles of the uterus of PGE2 and PGF2q, is the effect as an antifertility agent, in particular as an abortivum.

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

646 426

6

The amount of a compound of formula I required to achieve the desired biological effect depends, of course, on a number of factors, for example the type of compound chosen, the particular use, the dosage form and the recipient. In general, the daily doses may range from 1 mg to 20 mg / kg body weight. For example, an intravenous dose may range from 5 mg / kg to 1 mg / kg body weight, generally as an infusion of 0, The infusion solutions suitable for this purpose can generally contain 0.001 to 100, for example 0.01 to 10 / tg / ml. Single doses generally contain 10 / tg to 100 mg of a compound of formula I. Ampoules for injection can contain, for example, 0.01 to 1 mg and orally administrable single-dose preparations, such as tablets or capsules, for example, generally 0.1 to 50 mg, for example 2 to 20 mg, of the active ingredient.

If a compound of formula Ï 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 pg to 10 mg, for example 10 fig 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 conditions 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 preferably 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 be processed in the preparations either 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 (for example buccal, such as sub-lingual), parenteral (that is to say subcutaneous, intramuscular and intravenous) administration, the suitable administration form in each case depending on the type and severity of the disease to be treated 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. 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. Shaped tablets can be shaped 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 miarabicum 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 parenteral 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 be carried out 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, bronchodilation in humans and mammals, treatment and prophylaxis of allergic conditions in humans and mammals, abortion of a fetus in humans and mammals, infertility in humans and mammals, upon administration of a non-toxic, effective amount of a compound of the formula I.

The following example serves to explain the invention without restricting it.

example

A. 2- (Dibut oxymethyl) glycine ethyl ester

N-formylglycine ethyl ester was C-formylated to that of Harman and Hutchinson in J. Org. Chem., 40 (1975), 3474, and the resulting compound in the 2- (dibutoxymethyl) glycine ethyl ester using the in Chemistry of Penicillin, Eds. H.T. Clarke, published by Princetown University Press, New Jersey, 1949, page 517.

B. 1- (6-carboxyhexyl) hydantoin-5-carboxaldehyde

A mixture of 2.0 g of 2- (dibutoxymethyl) glycine ethyl ester with 1.82 g of ethyl 7-bromheptanoate was heated under nitrogen in a water bath at 100 ° C for 3 hours to give the crude ethyl 7 - [( 2,2-dibutoxy-l-ethoxycarbonylethyl) amino] heptanoate hydrobromide. A stirred solution of 3.28 g of this hydrobromide in 13 ml of ethanol was cooled in ice water and with a solution of 1.34 g of potassium cyanate in 4

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

7

646 426

ml of water, followed by 3.63 ml of 2N aqueous hydrochloric acid. The cooling bath was removed and stirring continued at room temperature for 22 hours. The ethanol was then evaporated off in vacuo, the residue was shaken out with water and ether and the ethereal solution was separated off, washed out with water and dried over magnesium sulfate (MgSCU). Removal of the ether resulted in an oil which was heated under nitrogen at 100 ° C for 3 hours and gave 2.94 g of 5-dibutoxymethyl-l- (6-ethoxycarbonylhexyl) hydantoin. This was stirred in 6 ml of ether with 48 ml of water and 24.9 ml of n-aqueous sodium hydroxide solution at room temperature for IV2 hours and, after adding 50 ml of ether, the aqueous phase was separated off, cooled in ice water, stirred with fresh ether, with aqueous n- Acidified hydrochloric acid and Congorot as an indicator. The ethereal solution of the carboxylic acid was washed 3 times with water, dried over magnesium sulfate and evaporated. This resulted in 2.15 g of l- (6-carboxyhexyl) -5-dibutoxymethylhydantoin as a chewing-chewy substance. After cooling 1.89 g of the latter substance and stirring with 8.5 ml of concentrated aqueous hydrochloric acid, the resulting solution spontaneously gave way to a suspension of colorless crystals. The suspension was set aside at room temperature for 1 hour, diluted with 10 ml of water and allowed to stand again for 15 minutes. The crystals were then collected, washed with water, dried in vacuo, suspended in 3 ml of ether and collected again. This gave 0.74 g of l- (6-carboxyhexyl) hydantoin-5-carboxaldehyde, melting point 223.5 to 225 ° C. Elemental analysis for chh16n20j:

calc .: C 51.56 H 6.29 N 10.93 found: C 51.86 H 6.66 N 10.62 In dimethyl sulfoxide-d6 there existed predominantly as masked aldehyde, l- (6-carboxyhexyl) -5- hydroxymethylene hydantoin.

C. 1- (6-Carboxyhexyl) -5 - [(E) -3-oxo-octylidene] hydantoin

A mixture of 20 mg l- (6-carboxyhexyl) hydantoin-

-5-carboxaldehyde with 59 mg of 2-oxoheptylidene triphenyl-phosphorane [see J. Org. Chem. 37 (1972), 1818] and a drop of benzene was heated under nitrogen at 100 ° C. for 35 minutes and the resulting rubbery substance in 5 ethyl acetate added. The product was extracted into dilute aqueous sodium dicarbonate solution, the extract was washed out with ethyl acetate and acidified with Congorot with aqueous n-hydrochloric acid, and the carboxylic acid released was extracted with ether. The ethereal solution was washed with water from-10, dried over magnesium sulfate and evaporated, and there resulted 25 mg of a rubbery substance which by HNMR spectroscopy as l- (6-carboxy-hexyl) -5 - [(E) -3- oxooctylidene] -hydantoin was identified [characteristic signals at 5.72 (IH, triplet, = CH-) and 15 3.93 (2H, doublet, = CH-CH2-CO) with J 7.1 Hz, in deuterochloroform] .

D. 1- (6-carboxyhexyl) -5 - [(E) -3-hydroxyoctylidene] hydantoin

A stirred solution of 20 mg of l- (6-carboxyhexyl) -5-20 - [(E) -3-oxooctylidene] hydantoin in 1.5 ml of H20, which contained a slight excess of sodium bicarbonate, was treated with 5 mg of sodium borohydride , after 60 minutes, the solution was acidified against Congorot with aqueous n-hydrochloric acid, the carboxylic acid released was extracted into ethyl acetate and the 25 ethyl acetate solution was washed 3 times with water and dried over magnesium sulfate. After the ethyl acetate had evaporated off, a pale yellow, rubbery substance remained (14 mg), which was identified by HNMR spectroscopy as l- (6-carboxy-hexyl) -5 - [(E) -3-hydroxyoctylidene) hydantoin 30 (characteristic signals at 55.61 (1H, triplet = CH-, J 7.1 Hz) in deuterochloroform.

E. 1 - (6-Carboxyhexyl) -5- (3-hydroxyoctyl) hydantoin

The product described in paragraph C was then 35 reduced to l- (6-carboxyhexyl) -5- (3-oxooctyl) hydantoin and the title compound.

v

Claims (5)

646 426 2. The method according to claim 1, characterized in that one carries out the reduction by means of catalytic hydrogenation. 2nd PATENT CLAIMS 1. Process for the preparation of hydantoin derivatives of the formula I 0 z-n n- wherein Z is hydrogen or alkyl; one of the groups Z1 and Z2 the group -CTk-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-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 = Separates C, -CH = CH or -CO group; 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-chain 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 mutually independent alkyl, bicycloalkyl or cycloalkyl groups; Y3 is hydrogen, hydroxy, alkoxy having 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 XI 0 z-n where Z3 = CR-CH2-Y1-Y2-Y3; and Z4 -CH2-X-X1-X2; or Z3 = CH-X-X'-X2; and Z4 -Y-Y ^ Y ^ -Y3 mean, reduced with an appropriate reducing agent and optionally converting the compounds of formula I obtained into another desired salt of formula I. 3. The method according to claim 2, characterized in that the reduction is carried out using hydrogen in the presence of Raney nickel, platinum, palladium, ruthenium or rhodium. 4. The method according to claim 1, characterized in that tin (III) chloride is used as the reducing agent. 5. The method according to any one of claims 1 to 4, 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. 6. The method according to any one of claims 1 to 4, 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 R is hydrogen, and wherein Y2 and Y3 together do not form a cycloalkyl group. 7. The method according to any one of claims 1 to 4, 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 or branched chain alkylene group having 1 to 6 carbon atoms; X2 carbonyl or alkoxycarbonyl; Y -CH2-CH2- mean and Y2 and Y3 together do not form a cycloalkyl group and Y3 is hydrogen. 8. The method according to any one of claims 1 to 4, 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) -1- (3-hydroxy-3-cyclobutylpropyl) hydantoin; 5- (6-carboxyhexyl) -1- (3-hydroxy-3-cyclopentylpropyl) hydantoin; 5- (6-carboxyhexyl) -1- (3-hydroxy-3-cyclohexylpropyl) hydantoin; 5- (6-carboxyhexyl) -3-methyl-1- (3-hydantoinoxooctyl); and their salts and esters.