HU183047B - Process for preparing biologically active hydantoin derivatives - Google Patents

Abstract

A method for preparing nitrogen-containing heterocyclic compounds of formula (I): ** (Formula) ** wherein Z is hydrogen or alkyl; one of Z1 and Z2 is represented by the group -X-X1-X2-X3 wherein X is methylene, X1 is phenylene, -C = C-, -CH = CH- cis or trans or -CH2-CQ2- in that each Q is independently selected from hydrogen and alkyl or the two Q groups together form an alcohol radical having four, five or six carbon atoms; X2 is a covalent bond or a straight or branched alkylenyl chain having 1 to 6 carbon atoms; X3 is selected from 5-tetrazolyl, carboxyl, carboxamido, hydroxymethylene and alkoxycarbonyl.

Description

The present invention relates to novel hydantoin derivatives of formula (I) and to pharmaceutical compositions containing them, wherein Z is hydrogen,

One of Z ¹ and Z ² is -X-X ¹ -X ² -X ³ and the other is -Y-Y'-Y ² -Y ^{3 in} which

X is methylene,

X ^I is cis or trans -CH = CH- or -CH2-CH2- group,

X ² represents a bond or C1 to C6 linear or branched alkylene group, and

X ³ is a carboxyl group, wherein one of the methylene groups in X ¹ and X ^{2 may} be replaced by a thia group (-S-), provided that the thia group is separated by at least one carbon atom from -CH = CH- or - CO, or the nitrogen atom of the hydantoin ring,

Y is - CR2-CH2- (wherein the two R substituents are each independently hydrogen or methyl),

Y ¹ is methylene substituted with hydroxy or methylene substituted with hydroxy and C 1-6 alkyl,

Y ² is a direct bond or a straight or branched alkylene group of 1 to 7 carbon atoms, and

Y ³ is hydrogen or phenyl, or

Y is -CH 2 -CH 2 -, and

Y ¹ is a hydroxymethyl group,

Y ² and Y ³ together represent C 3-8 cycloalkenyl optionally substituted with 1-4 methyl groups, C 4-6 cycloalkenyl, phenyl, adamantyl, tetrahydropyranyl, furyl, thienyl, 4- benzyloxyphenyl or 2a-hydroxy-1-methyl norbornyl, provided that at least one of (A) X ¹ and X ² is a thia group, or a thia group, or when (Β) X ¹ and X ² is not as defined in (A), then (i) at least one of Y ² and Y ³ contains a cyclic group other than a C 3-8 unsubstituted cycloalkyl group or a C 4-6 unsubstituted cycloalkenyl group, (ii) Y ² and Y ³ together form a 2a-hydroxymethyl norbonyl group, or (ii) Y ³ 4-benzyloxyphenyl; wherein the cyclic moiety is adamantyl, tetrahydropyranyl, furyl, thienyl.

The novel hydantoin derivatives of formula I possess biological activity related to natural prostaglandins; namely, these compounds antagonize or prioritize certain physiological effects of natural prostaglandins in various biological compositions.

Some of the compounds of formula (I) exhibit a marked increase in the activity of prostaglandin E1 in inhibiting platelet aggregation.

In the context of the definition of compounds of formula (I), said cyclic groups may be both saturated and unsaturated and may optionally carry one or more alkyl substituents, however, they may not have a phenyl substituent. Examples of ring groups include the following:

C3-C8 cycloalkyl groups such as cyclopropyl, cyclopentyl, cyclohexyl and cyclooctyl; adamantyl and norbornanyl (bicyclo [2,2,1] heptyl) groups in the brain; C4-C6 cycloalkenyl groups such as 4-cyclopentenyl; heterocyclic groups, e.g. tetrahydropyranyl; and heleroaryl groups such as thienyl, furyl.

Unless otherwise stated, the term " alkyl " with respect to the compounds of formula (I) and the compounds represented by the following general formulas means straight or branched alkyl groups having from 1 to 6 carbon atoms, such as methyl, ethyl, propyl, butyl; , pentyl and hexyl as well as the corresponding isomeric groups. The radicals at the positions Y ¹ and Y ² preferably include methyl as alkyl; and the alkyl chain of the alkoxycarbonyl groups may preferably be methyl or ethyl. The alkylene groups may be C2-C4 groups; an example of which is ethylene.

Unless otherwise stated herein and in the claims, the following formulas refer to all possible stereoisomers of the compounds. Formulas for compounds containing asymmetric carbon atoms include both single enantiomers, enantiomeric mixtures (including racemates), and diastereoisomers.

According to the present invention, a hydantoic acid derivative of the formula (II) - wherein J is a C 2 -C 5 alkoxycarbonyl or carboxyl group; J ¹ is hydrogen or carbamoyl, and Z ¹ and Z ² are as defined for formula (I), optionally in the presence of an inert solvent, by heating in an acidic medium or by reaction with an alkali metal cyanate: a. The compound of formula (II) is prepared by reacting the amino acid derivatives of formula (III) wherein Z ¹ , Z ² are as defined above and G is alkoxycarbonyl or carboxyl having 2 to 5 carbon atoms but G is nitrile. can be represented by a cyano band.

When cyanic acid is used as the reactant, the cyanic acid is preferably formed in the reaction mixture itself by reaction of an alkali metal cyanate (e.g. potassium cyanate) with an acid. It is possible, for example, to add to the reaction mixture an amount of mineral or organic acid equivalent to the alkali metal cyanate; however, the free acids of Formula III itself (i.e., compounds containing R and / or X ^{3 in} the Δ1 chain) or the acid addition salts of the compounds of Formula III may be used to liberate the cyanic acid. The reaction is carried out in the absence of solvent-21

183,047, but preferably in a solvent medium. Suitable solvents include inert polar liquids such as water, aqueous acetone, aqueous dimethylformamide or aqueous dimethylsulfoxide, lower alkanols (e.g. ethanol), hydrocarbons, ethers or halogenated hydrocarbons (e.g. chloroform). If desired (for example, when the reaction is carried out in the absence of a solvent), the reaction can be accelerated by heating the mixture.

The compounds of formula (II) may also be reacted with urea, nitrocarbamide or N-alkyl ureas to form compounds of formula (II). The reaction may be carried out in the absence of a solvent, but if desired, an inert solvent may be added. Suitable solvents are, for example, the above-mentioned materials. The reaction is preferably carried out at elevated temperature. The reaction is usually carried out at 100-125 ° C, but temperatures up to 150 ° C may also be employed.

If desired, the compounds of formula (II) formed in the above operations may be converted directly, without isolation, into the final products of formula (I).

Intermediate compounds of formula (III) may be prepared by reacting compounds of formula (IV) with compounds of formula (V). In these formulas, G, Z ¹ and Z ² are as defined above, while one of Q ¹ and Q ² is amino and the other is halogen (preferably bromine). The reaction is carried out in a solvent-free medium or in the presence of an inert solvent (e.g. ethanol) while heating the mixture.

In some cases, the hydroxy group present in the side chain may be subjected to unwanted side reactions during the preparation of the hydantoin compounds of formula (I) containing a hydroxyl group. To eliminate these side reactions, conventional protecting groups such as acyl, aroyl, tetrahydropyran-2-yl, 1-ethoxyethyl or aralkyl (e.g. benzyl) may be added to the hydroxyl groups in a known manner.

The protecting groups may be removed by methods known per se. For example, the acyl group may be cleaved by acidic or basic hydrolysis, while reductive methods may be used to remove the benzyl group.

The alcohols of formula (I) wherein Y ¹ is -CH (OH) - may be used to form ketones with oxidizing agents such as Jones reagent, acidic dichromate solution or the like.

The compounds of formula (I) containing the -CH = CH- bond can be converted into the corresponding ethylenically unsaturated or saturated derivatives by known hydrogenation techniques, for example using Lindlar catalyst or Adams catalyst.

The hydantoin derivatives of formula I contain an asymmetric carbon atom at the 5-position. Derivatives bearing a hydroxyl group in Y ¹ also have an additional asymmetric center to form these four optically active isomers. The mixture of isomers can be separated into two diastereomers by thin layer chromatography or high performance liquid chromatography, each containing two isomers in the form of a racemic mixture. Treatment of any of the separated diastereomers with a base such as an alkali metal hydroxide yields again a mixture of the four isomers. From this mixture, the individual diastereomers can be separated as described above. By repeating this procedure, one diastereomer may be completely converted to the other diastereoisomer; this procedure is particularly advantageous when converting the less valuable diastereomer to another diastereomer having higher biological activity.

The alcohols of the formula (III) may also exist in four isomers. If desired, these isomers may be separated into a mixture of two epimers. Further reaction steps leading to compounds of formula (I) do not alter the starting material configuration.

It will be appreciated that in the reactions listed above, reaction conditions and reagents must be selected with consideration to other reactive groups present in the starting materials and, where appropriate, care must be taken to carry out the reaction selectively.

The hydantoin compounds of formula (I) have valuable therapeutic activity in relation to natural prostaglandins; more specifically, these compounds promote or antagonize certain biological effects of the prostaglandin A, B, C, D, E, and F series compounds. For example, the compounds of formula (I) potentiate the antiplatelet effect of PGE1; and in the gastrointestinal, rat, rectal, and gonadal esophagus experiments, inhibit smooth muscle contractile activity of PGE ₂ and PGF ₂ . The prostaglandin antagonist activity of the compounds of formula (I), in contrast to the mimetic action, is generally manifested at higher doses. The pharmacological nature of the compounds of formula (I), i.e., the potentiating and antagonistic activity relative to natural prostaglandins, will naturally vary from compound to compound.

The compounds of formula (I) can be used for their pharmacological characterization and modification of their biological activity due to their activity on prostaglandins. It is clear that a more precise exploration of the physiological role of prostaglandins can provide very valuable information for research into new drugs that have a beneficial effect.

In addition, the hydantoin derivatives of formula (I) have other valuable therapeutic effects. Some of these compounds have a very strong inhibitory effect on platelet aggregation. These compounds can be used very advantageously in any situation where it is necessary to prevent platelet aggregation or to reduce their adhesive properties, for example in the formation of blood clots in mammals.

183,047 to overtake or dissolve blood clots already formed. These compounds are used in clinical practice for the prevention and treatment of, for example, myocardial infarction and thrombosis, to prevent occlusion of surgically transplanted vessels, for the treatment of coronary artery calcification disorders, and for the treatment of clinical disorders such as coronary artery disease and lipemia. , where the disorder is causally related to fatty tissue disorders or excess lipid levels in the blood. Said hydantoin derivatives may also be added to blood or other body fluids used for artificial circulation or perfusion of isolated body parts.

Particularly preferred anti-platelet compounds are those compounds of formula I wherein Z is hydrogen, Z is a carboxyalkyl group containing from ^{1 to} 9 carbon atoms in the alkylene chain, and Z ² is - (CH ₂ ) 2 -CH ( OH) -Y ² -Y ³ , wherein Y ^{2 is a} branched alkylene group attached to a carbon atom bearing a tetravalent carbon atom or a hydroxyl substituent and Y ³ is as defined for compounds of formula (I). These compounds are highly effective group are those compounds wherein Z is ¹ karboxihexil group, Y ³ is C4-7 cycloalkyl.

The hydantoin derivatives of formula I furthermore, like the A and E series prostaglandins, release vascular smooth muscle. Compounds that release vascular smooth muscle produce vasodilatation and accordingly have an antihypertensive effect. These compounds, alone or in combination with β-adrenergic blocking agents or other antihypertensive agents, can be used with good results in lowering blood pressure in mammals, including humans. The agents and combinations of agents listed above have been shown to be effective in treating hypertension of a variety of origins, including essential, malignant and secondary.

The compounds of formula (I) also potentiate the anti-bronchoconstriction activity of prostaglandin E1 histamine. These compounds are useful in preventing and treating bronchial asthma and bronchitis by resolving bronchoconstriction.

Some of the hydantoin compounds of formula (1) inhibit pentagastrin-induced excessive gastric acid secretion and, based on experiments in rats, reduce aspirin-induced gastric injury. These compounds can be used to reduce excessive gastric juice secretion, to prevent gastrointestinal ulceration, and to accelerate the healing of ulcers already formed in the gastrointestinal tract, either spontaneously or as a result of glandular tumors.

Compounds of formula (I) increase the volume of urine in dogs by intravenous infusion. Accordingly, these compounds are useful as diuretic agents in the treatment of edema disorders, such as edema of the heart, liver or kidney.

The hydantoin derivatives of formula (I) which enhance the activity of the PGE ₂ and PGF on _the uterine muscle can be used as contraceptives (primarily abortifacients).

The compounds of formula (I) may also be used in the treatment of proliferative skin diseases, such as disorders associated with increased cell division in the epidermis or epidermis, possibly accompanied by imperfect cell separation. These compounds in human medicine include, for example, psoriasis, atopic dermatitis, non-specific dermatitis, primary irritation contact dermatitis, allergic ontact dermatitis, skin cells, scaly skin cells, blister ichthyosis, excessive epidermis, , can be used to treat non-malignant cornea, benign cornea, acne and seborrheic dermatitis, and in veterinary medicine for the treatment of atopic dermatitis and scabies. In the treatment of the above disorders, the active ingredient is preferably applied to the injured skin in the form of a topical formulation. The active ingredient may also be administered in the form of a ritradermal or intramuscular injection; in this case, the active ingredient may be applied directly to the injured dermal tissue or into the surrounding tissue. Injection formulations generally contain from 0.1 to 0.5% by weight of active ingredient.

The required daily dose of the compounds of formula (I) will vary depending on several factors, including the type of compound, the desired biological effect, the mode of administration and the condition of the organism being treated. The required daily dose of the compounds of formula (I) is generally from 1 mg / kg to 20 mg / kg. Intravenous compositions may be administered, for example, at a dose of from 5 mg / kg to 1 mg / kg; these compositions are generally infused at a rate of 0.01 to 50 mg / kg / min. Infusion fluids may generally contain 0.001100 mg / ml, for example 0.01-10 mg / ml of active ingredient. Dosage units will usually contain from 10 mg to 100 mg of the hydantoin derivatives of the formula I; dosage units (e.g., ampoule formulations) may contain between 0.01 and 1 mg of active ingredient, and oral dosage units (e.g., tablets or capsules) may contain between 0.1 and 50 mg (e.g., 2-20 mg) of active ingredient.

When used to inhibit platelet aggregation, the compound of formula (I) is generally present in a concentration of 1 Mg to 10 mg, e.g., 10 Mg and 1 mg per liter of body fluid (e.g., patient's blood or perfusion fluid). mg.

The above dose ranges apply to acids, amides, esters, alcohols, or tetrazoles of formula (I). When the compounds of formula (I) are used in the form of their salts, the dosage is based on the anion.

The invention further relates to a process for the preparation of a pharmaceutical composition comprising the compounds of formula (I)

183 047 for the manufacture of inks. In preparing these pharmaceutical compositions, the active compounds of the formula I, or salts thereof, are pharmaceutically acceptable, i.e., compatible with other ingredients and / or excipients which are harmless to the organism to be treated. Both solid and liquid carriers can be used in the preparation of pharmaceutical compositions. The pharmaceutical compositions are preferably formulated in dosage units containing from 0.05% to 95% by weight of the hydantoin compound. As mentioned above, the pharmaceutical compositions may contain, in addition to the hydantoin compounds (acids, salts, esters, etc.) of the present invention, other therapeutic agents. The pharmaceutical compositions are prepared by known pharmaceutical technology operations.

The pharmaceutical compositions may be, for example, compositions for oral, rectal, topical, buccal (e.g., sublingual) and parenteral (e.g., subcutaneous, intramuscular, or intravenous) administration. The route of administration will be selected according to the type and severity of the disorder being treated and the nature of the hydantoin compound.

Compositions for oral administration include, for example, single dose units (such as tablets, capsules, cachets, lozenges, or chewable tablets containing predetermined amounts of hydantoin), solutions or suspensions in aqueous or non-aqueous liquids, and oil-in-water or water-in-water. in oil type emulsions. These compositions are prepared by methods known per se by contacting the active ingredient with the carrier and, if appropriate, with other excipients to be used. Generally, the hydantoin compound is thoroughly mixed with the liquid and / or finely divided solid carrier, and the mixture is formed if necessary. The tablets are made by compressing or melting a powder mixture or granules containing the hydantoin compound, the carrier and any excipients. For example, compressed tablets may be prepared by mixing the hydantoin compound and other additives (e.g., binder, lubricant, inert diluent, surfactant and / or dispersant) in powder or granules, and compressing the mixture or granulate in a suitable press. In the manufacture of molded tablets, the powdered hydantoin compound is moistened with an inert liquid diluent and melted in a suitable apparatus.

Formulations suitable for buccal (sublingual) administration may be, for example, chewable tablets containing the hydantoin compound together with a flavored base (usually sucrose and acacia or tragacanth). For buccal administration, lozenges may also be prepared; these compositions contain the hydantoin compound distributed in an inert material such as gelatin and glycerol or sucrose and acacia.

Formulations suitable for topical application to the skin include ointments, creams, balms, pastes, gels, sprays, aerosol compositions, or oily compositions. Suitable excipients for the preparation of these compositions are, for example, petroleum jelly, lanolin, polyethylene glycols, alcohols and mixtures of the foregoing. Formulations for topical administration will generally contain from 0.1 to 15% by weight, preferably from about 0.5 to 2% by weight, of the active ingredient.

Formulations suitable for parenteral administration may generally be in the form of a sterile aqueous composition. The osmotic pressure of the compositions is preferably adjusted to the same level as the blood of the organism to be treated. These compositions are preferably formulated for intravenous administration, but injectable formulations for subcutaneous or intramuscular administration may also be prepared. Formulations for parenteral administration are generally prepared by mixing the hydantoin compound with water, then sterilizing the resulting mixture and adjusting its osmotic pressure to the desired value.

Formulations for rectal administration may conveniently be presented in unit dosage form in the form of suppositories. In preparing suppositories, the hydantoin compound is admixed with one or more conventional solid suppository bases (e.g., cocoa butter) and the mixture is shaped.

The following examples illustrate the invention without limiting it.

/. example

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

The step:

Preparation of diethyl 2-amino-nonanedicarboxylic acid In a solution of ethanolic sodium ethoxide in ml of absolute ethanol and 1.51 g of sodium metal, 16.7 g of acetamidomalonic acid diethyl ester and 16.6 g of 7-bromoheptanecarboxylic acid ethyl ester are dissolved in 27 hours. reflux. The solution was cooled, poured into ice water and the product extracted with ether. The extract was dried and evaporated. The crude acetamido (6-ethoxycarbonylhexyl) malonic acid diethyl ester was obtained as a pale yellow oily residue; NMR: δ = 2.2 (3H, s, -COCHs), 4.17 (6H, m, 3 x OCH ₂ -CH ₃₎ ppm.

Concentrated hydrochloric acid (111 mL) was added to the resulting admid and the mixture was refluxed for 5.5 hours. The solution is cooled, washed with ether, the aqueous phase is decolorized with charcoal and finally evaporated to dryness in vacuo. The resulting colorless glassy residue was dissolved in a minimum amount of absolute ethanol and added dropwise to a stirred solution of 125 ml of absolute ethanol and 15.7 g of thionyl chloride at -10 ° C. The resulting solution was kept at room temperature for 1 hour, then refluxed for 1.5 hours, finally cooled, poured into ice water, and the mixture was treated with aqueous sodium hydroxide solution at pH 9.

Alkaline to 183,047. The mixture was extracted with ether. The extract was dried, the solvent was evaporated and the residue was distilled. 2-amino-nonanedicarboxylic acid diethyl ester was obtained as a colorless oil; f. ρ .; 114-115 ° C / 0.02-0.03 mmHg; Yield: 55%.

Step B:

Preparation of diethyl 2 - ([4,4-dimethyl-3-oxophenylpentyl] amino) nonanedicarboxylic acid

5.15 g of 4,4-dimethyl-5-phenylpent-1-en-3-one are added dropwise to 2-amino-nonanedicarboxylic acid diethyl ester with stirring and allowed to stand at room temperature for 21 hours. This gives 2 - ([4,4-dimethyl-3-oxo-5-phenyl-pentyl) -amino) -nonedicarboxylic acid diethyl ester.

Step C:

Preparation of diethyl 2 - ([3-hydroxy-4,4-dimethyl-5-phenylpentyl] amino) nonanoic dicarboxylic acid

5.1 g of crude 2 - ([4,4-dimethyl-3-oxo-5-phenylpentyl] amino) nonanediocarboxylic acid diethyl ester obtained in Step B, in 70 ml of absolute ethanol, under stirring and ice-cooling 380 mg of sodium borohydride are added portionwise. After the addition of the reducing agent, the solution was stirred for an additional 10 minutes in an ice bath and allowed to stand at room temperature for 5 hours. Most of the alcohol was evaporated, water was added to the residue and the resulting mixture was acidified to pH = 6. The precipitated insoluble oil was extracted with ether. The ether extract was dried and the solvent was evaporated. The 2 - ([3-hydroxy-4,4-dimethyl-5-phenylpentyl] amino) nonanedicarboxylic acid diethyl ester obtained as a pale yellow oily residue was used in the next step without further purification.

Step D:

Preparation of 5- (6-Ethoxycarbonylhexyl) -1- (3-hydroxy-4,4-dimethyl-5-phenylpentyl) hydantoin and the corresponding free acid

8.45 g of a solution of 2 - ([3-hydroxy-4,4-dimethyl-5-phenylpentyl] amino) nonanedicarboxylic acid diethyl ester obtained in Step C in 37.6 ml of ethanol

18.8 ml of a 2N aqueous hydrochloric acid solution are added and 3.05 g of potassium cyanate are added under stirring and ice-cooling.

A solution of 5.6 ml of water was added dropwise. After allowing the reaction mixture to stand at room temperature for 18 hours, the alcohol was evaporated, water was added to the residue, and the precipitated insoluble oil was extracted with ether. The ethereal solution was dried and the solvent was evaporated. The viscous oily residue was heated in a boiling water bath for 6 hours. 5- (6-Ethoxycarbonylhexyl) -1- (3-hydroxy-4,4-dimethyl-5-phenylpentyl) hydantoin was obtained as a viscous, pale yellow oil.

The resulting ester was added to a mixture of 25 ml of 2N aqueous sodium hydroxide solution and 60 ml of water and the resulting cloudy solution was allowed to stand at room temperature for 2 hours. The solution was washed with ether and the clear basic aqueous solution acidified with 2N aqueous hydrochloric acid. The oily precipitate was extracted with ether.

'6

The ethereal solution was dried, evaporated to give the product

6.8 g of a viscous oily residue is chromatographed on a silica gel column. 5- (6-Carboxyhexyl) -1- (3-hydroxy-4,4-dimethyl-5-phenylpentyl) hydantoin is obtained. The product, initially isolated as a colorless viscous oil, solidifies on standing. The resulting product, containing two diastereomers, melts at about 115 ° C (shrinks from about 90 ° C). After repeated recrystallization from a mixture of ethyl acetate and petroleum ether (boiling range 60-80 ° C), one of the diastereomers is isolated as tiny needle crystals melting at 135-137 ° C.

Example 2

Preparation of 5-16-Carboxyhexyl) -1- (3-hydroxyoctyl) hydantoin

The step:

Preparation of 2- (3- [Tetrahydro-pyran-2-yloxy] -octylamino) -nonedicarboxylic acid diethyl ester

To a stirred solution of 19.15 gacrolein in 100 ml of ether at -25 ° C was added dropwise a solution of 26.8 g of hydrobromic acid in 200 ml of anhydrous ether at 0 ° C. After the addition of the reagent, the mixture was stirred at the same temperature for 1 hour, then allowed to warm to 0 ° C, stirred for 1 hour at 0 ° C, and finally mixed with 54 g of 1-bromopentane, 8.8 g of magnesium Add dropwise to a solution of pentylmagnesium bromide in ether (120 mL), keeping the solution at reflux. The reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted with ether. The ether extract was dried, the solvent was evaporated and the residue was distilled. 1-bromo-3-hydroxyoctane was obtained as a colorless oil; bp: 68.5-72.5 Γ / 0.08 mmHg.

To a solution of 20.9 g of the 1-bromo-3-hydroxyoctane prepared above in 17.0 g of dihydropyran is added a solution of 500 mg of p-toluenesulfonic acid in a small amount of ether and the mixture is kept at room temperature for 18 hours. The reaction mixture was washed with aqueous sodium bicarbonate solution and the organic phase was passed through a silica gel column and washed with ether: hexane (1: 9). The resulting mixture was evaporated in vacuo. Obtained as a colorless oily residue 1-bromo-3- (tetrahydropyran-2-yloxy) octane; Nuclear Magnetic Resonance Spectrum: δ = 0.88 (3H, triplet, -CH ₃ ) and 4.62 (1H, broad, -O-CHR-O-) ppm.

A solution of 15.0 g of the tetrahydropyranyl compound prepared above and 13.0 g of 2-amino nonanedicarboxylic acid diethyl ester in 100 ml of absolute ethanol is refluxed for 18 hours. The ethanol was evaporated in vacuo and the residue diluted with a small excess of aqueous sodium carbonate. The resulting mixture was extracted with dichloromethane. The extract was dried over sodium sulfate, evaporated and the residue was purified by column chromatography. The adsorbent was silica gel and the eluent was a hexameter mixture (1: 4). 2- (3- [tetrahydropyran-61]) is a colorless, viscous oil

183,047

(2-yl-oxy] octylamino) -nonadicarboxylic acid diethyl ester is obtained.

Nuclear Magnetic Resonance Spectrum: δ = 0.88 (3H, triplet, -CH ₃ ), 2.28 (2H, triplet, -CH ₂ -COOEt), 2.61 (2H, multiplet, -CH ₂ -N), 3.20 (lH, triplet, N-CHR-COOEt), 4.13 (4H, m, 2 x -O-CH ₂ -CH _3), 4.60 (IH, broad line, -O-CHR-O- ) ppm.

The diethyl 2- (3- [tetrahydropyran-2-yloxy] octylamino) nonanoic dicarboxylate can also be prepared by the following procedure:

10.40 g of 2-amino nonanedicarboxylic acid diethyl ester are slowly stirred at 0 [deg.] C. with 5.04 g of oct-1-en-3-one and the mixture is kept at room temperature for 3 hours. 2- (3-Oxooctylamino) -nonandiicarboxylic acid diethyl ester is obtained as a colorless oily substance. NMR: δ = 2.3 (4H, m, - CH ₂ COOEt, and N-CH ₂ -, -CH ₂ -CO-), 3.16 (lH, triplet, EtOOC-CHR-N), 4 11 (2H, quartet, -O-CH ₂ -CH _3), 4.17 (2H, quartet, -O-CH ₂ -CH _3).

To a stirred solution of 13.5 g of the ketone obtained above in 140 ml of absolute ethanol is added dropwise at 0 ° C a solution of 665 mg of sodium borohydride in 70 ml of absolute ethanol. After the addition, the mixture was kept at room temperature for 3.5 hours and then concentrated in vacuo at 40 ° C. The residue was dissolved in water, acidified to pH 5 with 1 N aqueous hydrochloric acid and extracted well with chloroform. The extract was washed with water, dried and finally concentrated. 2- (3-Hydroxyoctylamino) -nonandiicarboxylic acid diethyl ester was obtained as a colorless oily substance. The crude product was dissolved in dihydropyran (14.0 mL), ether (10 mL), p-toluenesulfonic acid (6.72 g) was added portionwise and the mixture was kept at room temperature for 18 hours. The solution was then diluted with ether, washed with aqueous sodium carbonate solution, then water, dried, evaporated and the residue was purified by column chromatography. Silica gel was used as adsorbent and hexane: ether (1: 4) as eluent. The product 2- (3- [tetrahydropyran-2-yloxy] -octylamino) -nonedicarboxylic acid diethyl ester isolated was identical with the compound prepared by TLC based on NMR, IR and TLC.

Step B:

Preparation of 5- (6-Carboxyhexyl) -1- (3- [tetrahydropyran-2-yloxy] octyl) hydantoin

To a solution of 7.8 g of 2- (3- [tetrahydropyran-2-yloxy] octylamino) nonanedicarboxylic acid diethyl ester in 32 ml of ethanol was added 3.0 g of potassium cyanate in 6 ml of water, followed by stirring and cooling, 16.7 ml of 2N aqueous hydrochloric acid were added portionwise. The resulting solution was allowed to stand at room temperature for 22 hours and then the bulk ethanol was evaporated. Water was added to the concentrate and the precipitated insoluble oil was extracted with ether. The ethereal solution was washed with water, dried over magnesium sulfate and finally concentrated. The resulting yellow oily residue (8.0 g) was dissolved in petroleum ether (b.p. 60-80 ° C). The solution was refluxed for 4 hours, then the solvent was evaporated and the oily residue was heated in a boiling water bath for 2 hours. 7.3 g of 5- (6-ethoxycarbonylhexyl) -1- (3- [tetahydropyran-2-yloxy] octyl) hydantoin are obtained as a yellow oil, which is used without further purification.

A solution of 6.2 g of 5- (6-ethoxycarbonylhexyl) -1- (3- [tetrahydropyran-2-yloxy] octyl) hydantoin in 80 ml of 0.5 N aqueous sodium hydroxide was added for 2.5 hours. allow to stand at room temperature. The solution is then washed with ether, the aqueous phase is acidified with 2N aqueous hydrochloric acid and the oily precipitate is extracted with ether. The ethereal solution was washed, dried and finally evaporated. 5- (6-Carboxy-hexyl) -1- (3- [tetrahydro-pyran-2-yloxy] -octyl) -hydantoin is obtained as a yellow oily residue.

Step C:

Preparation of 5- (6-Carboxyhexyl) -1- (3-hydroxyoctyl) hydantoin

3.55 g of the tetrahydropyranyloxy compound obtained in Step b) are dissolved in a mixture of 28 ml of tetrahydrofuran and 7 ml of 5N aqueous hydrochloric acid. The solution is kept at room temperature for 3.5 hours and then refluxed for 30 minutes. The bulk of the solvent was evaporated, water was added to the resulting concentrate and the precipitated insoluble oil was extracted with ether. The ethereal solution was washed with water, dried over magnesium sulfate and finally concentrated. The resulting viscous yellow oily residue (3.15 g) was purified by column chromatography over silica gel; eluting with chloroform followed by 19: 1 chloroform: methanol. 5- (6-Carboxyhexyl) -1- (3-hydroxyoctyl) hydantoin is obtained as a very viscous, almost colorless oil.

Nuclear Magnetic Resonance Spectrum: δ = 0.89 (3H, triplet, -CH ₃ ), 2.34 (2H, triplet, -CH ₂ -COOH), 2.9-4.2 (4H, complex line, -CH ₂ -N, -CH-N, -CH- -OH), ca. 5.6 (2H, broad, exchangeable, -COOH, -OH), ca. 9.0 (1H, broad, interchangeable, -NH) ppm.

This hydantoin derivative can also be prepared by the method described in Example 1 starting from the corresponding diethyl 2 - ([3-hydroxyoctyl] amino) nonanoic dicarboxylate.

Step D:

Separation of diastereoisomers

The viscous oily hydantoin compound of Step C was subjected to high performance liquid chromatography on a silica gel column. Chloroform: methanol: acetic acid (97: 2.5: 0.5) was used as eluent. The separated diastereoisomers form tiny, colorless needle crystals melting at 76-78 ° C and 63-65 ° C, respectively.

The same diastereoisomers may also be prepared starting from the corresponding isomers of the compounds of formula (III) by ring closure of the intermediates. In this case, the following diethyl ester (a mixture of diastereoisomers) of 2 - ([3-hydroxyoctyl] amino) nonanedicarboxylic acid, prepared as described in Example 1, was

Dissolve in 183,047 N and add ethereal hydrochloric acid. The resulting solution was evaporated. A mixture of diastereoisomeric hydrochlorides is obtained in the form of a viscous oil which partially solidifies on standing. Ether was added to the product and the mixture was stirred under cooling. The precipitated crystalline solid was collected, washed with ether, dried and then crystallized from ethyl acetate. The pure hydrochloride salt is obtained in the form of small, colorless, lamellar crystals melting at 95-96.5 ° C. The resulting salt is suspended in dilute aqueous sodium hydroxide solution and the suspension is extracted with ether. The ethereal solution was separated, washed, dried and evaporated. One of the diastereoisomers of 2 - ([3-hydroxyoctyl] amino) -nonedicarboxylic acid diethyl ester, hereinafter referred to as "A isomer", is obtained as a colorless oily residue.

The ethereal filtrate obtained after isolation of the solid hydrochloride salt is evaporated and the base is liberated from the resulting oil salt as above. The other diastereoisomer of 2 - ([3-hydroxyoctyl] amino) nonanoic dicarboxylic acid diethyl ester, hereinafter referred to as "B isomer", is obtained as a colorless oily residue.

The isomer A, prepared as described above, was converted to 5- (6-carboxyhexyl) -1- (3-hydroxyoctyl) -hydantoin according to the procedure of Example 1 and the product was ethyl acetate and petroleum ether (b.p. 60-80). (C). The resulting pure diastereoisomer forms tiny colorless needle crystals melting at 63-65 ° C.

By a similar procedure, the other pure diastereoisomer of 5- (6-carboxyhexyl) -1- (3-hydroxyoctyl) hydantoin is converted from isomer B. After crystallization from ethyl acetate / petroleum ether (b.p. 60-80 ° C), the product forms tiny colorless needles, m.p. 76-78 ° C.

Step E:

Conversion of diastereoisomers

100 mg of 5- (6-carboxyhexyl) -1- (3-hydroxyoctyl) hydantoin (diastereoisomer m.p. 76-78 ° C) were dissolved in 3 ml of 1 N aqueous sodium hydroxide solution and the solution was heated for 19 hours. allow to stand at room temperature. The solution was then acidified, extracted with ether, and the extract was washed with water, dried and evaporated. The resulting viscous oily residue was subjected to high performance liquid chromatography. Approximately 40 mg of 5- (6-carboxyhexyl) -1- (3-hydroxyoctyl) hydantoin diastereoisomer (i.e. starting material), m.p. 76-78 ° C. yielding a melting diastereoisomer identical to that obtained in Step D) from the isomer A.

The diastereoisomer of 5- (6-carboxyhexyl) -1- (3-hydroxyoctyl) -hydantoin, m.p. 63-65 ° C, may be converted to a mixture of the two diastereoisomers in a ratio of about 1: 1 by the procedure described above. The individual diastereoisomers may be separated by high performance liquid chromatography.

Example 3

The following starting carboxylic acid esters were prepared according to the procedure described in Examples 1 and 2:

la) 2 - {(3-oxo-3- [4-tetrahydropyranyl] propyl) amino} nonanoic dicarboxylic acid diethyl ester,

2a) diethyl ester of 2 - ([3-oxo-3-cis-4-methylcyclohexylpropyl] amino) nonanedicarboxylic acid,

3a) 2 - ([3-oxo-3-trans-4-methylcyclohexylpropyl] amino) nonanoic dicarboxylic acid diethyl ester, fa) 2 - {(3-oxo-3- [1-adamantyl] propyl) amino} -nonándikarbonsav acid diethyl ester,

5a) 2 - {(3-oxo-3- [2-thienyl] propyl) amino} nonanedioic acid diethyl ester,

6a), 2 - {(3-β-3- [2-furyl] propyl) amino} nonanedioic acid diethyl ester,

7a) diethyl ester of 2 - {(3-oxo-3- [cyclopent-3-enyl] propyl) amino} nonanedicarboxylic acid,

8a) diethyl ester of 2 - ([norboman-2-on-3-ylmethyl] amino) nonanedicarboxylic acid,

9a) diethyl ester of 2 - {(3-oxo-3- [3,3-dimethylcyclobutyl] propyl) amino} nonanoic dicarboxylic acid,

10a) 2 - {(3-oxo-3- [2,2,3,3-tetramethyl-cyclopropyl] -propyl) -amino} -nonedicarboxylic acid diethyl ester, la) 2 - {(3-oxo-3- [1 methylcyclohexyl] propyl) amino} -nonándikarbonsav acid diethyl ester,

12a) 2 - ([3-oxo-3-trans-4-methylcyclohexylpropyl] amino-non-4Z-ene) dicarboxylic acid diethyl ester,

13a) 2 - ([3-oxo-3-cis-4-methylcyclohexylpropyl] amino) non-4Z-ene dicarboxylic acid diethyl ester,

14a) ethyl 2 - ([3-oxo-3-phenylpropyl] amino) -4- (ethoxycarbonylmethylthio) hexanecarboxylic acid,

15a) 2 - ([3-oxo-3-cyclohexylpropyl] amino) -5-ethoxycarbonylmethylthiopentanecarboxylic acid ethyl ester,

16a) ethyl 2 - ([3-oxo-3-cyclohexylpropyl] amino) -6-ethoxycarbonylmethylthiohex-4Z-ene carboxylic acid,

17a) ethyl 2 - ([3-oxo-3-cyclohexylpropyl] amino) -6-ethoxycarbonylmethylthiohex-4E-ene carboxylic acid,

18a) ethyl 2 - ([3-oxo-3-cyclohexylpropyl] amino) -3- (3-ethoxycarbonylpropylthio) propionic acid,

19a) ethyl 2- (3-oxooctylamino) -3- (3-ethoxycarbonylpropylthio) propionic acid,

20a) ethyl 2 - ([3-oxo-3-cyclopentyl-propyl] -amino) -3- (4-ethoxycarbonyl-butylthio) -propionic acid,

21a) Diethyl ester of 2 - {(3-oxo-3- [3-furyl] propyl) amino} nonanedicarboxylic acid,

22a) 2 - {(3-oxo-3- [4-benzyloxyphenyl] propyl) amino) nonanedicarboxylic acid diethyl ester, and

23a) 2 - ([3-Oxo-3-cyclohexylpropyl] amino) -5- (2-ethoxycarbonylethylthio) pentanoic acid ethyl ester.

The following compounds are converted to the following intermediates:

1b) 2 - {(3-hydroxy-3- [4-tetrahydropyranyl] propyl) amino} nonanedioic acid diethyl ester,

183,047

Physical constants for Example 17c: Elemental analysis for C18H28N2O5S (less polar diastereomer):

c [%] H [%] N [%] calculated: 56.4 7.3 7.3 Found: 56.4 7.3 7.3

NMR data for the more polar diastereomer (δ, ppm, CDCl3):

2.67 (m, 2H, CO (N) CHCH ₂ ),

3.05 (s, 2H, SCH2CO2H),

3.20 (bd, 2H, SCH ₂ CH = CH),

4.19 (m, 1H, COCHN),

5.47 (m, 2H, CH = CH),

5.93 (bs, 2H, OH + COaH) and

9.74 (bs, 2H, NH).

Example 24

- Preparation of (4-Carboxymethylthio-butyl) -1- (3-hydroxy-3-cyclohexyl-propyl) -hydantoin

The step:

Preparation of diethyl 2-amino-7-thia nonanedicarboxylic acid

35.2 g of diethyl 4-bromobutylacetamido-malonic acid diethyl ester (Rec. Trav. Chim. 874 (1971)) are dissolved in 150 ml of absolute ethanol, and 12.0 g of mercaptoacetic acid ethyl ester and 2.30 g of sodium are added under stirring. and a mixture of ethanolic sodium ethoxide solution (130 ml) in ethanol was added dropwise. A slight exothermic reaction occurs, but the mixture ceases to warm rapidly. The resulting cloudy mixture was stirred at room temperature for 24 hours and then concentrated in vacuo to a small volume. The resulting concentrate was diluted with water and extracted with chloroform. The extract was dried and evaporated. 42.2 g of (4-ethoxycarbonylmethylthio-butyl) -acetamido-malonic acid diethyl ester are obtained as a colorless gum. This product is suspended in 750 ml of 10% aqueous hydrochloric acid solution, refluxed for 3 hours, cooled and concentrated in vacuo to a small volume. Traces of water were removed by azeotropic distillation with ethanol. The gummy residue was dissolved in a little ethanol and added to a solution of thionyl chloride (21.0 mL) in ethanol (300 mL) at -10 ° C. The resulting mixture was allowed to stand at + 5 ° C for 18 hours and then refluxed for 1 hour. The solution was cooled, evaporated and the residue partitioned between water and chloroform. The pH of the aqueous phase is adjusted to about 10 with aqueous sodium carbonate solution, and the basic aqueous solution is thoroughly extracted with chloroform. The extracts were dried and evaporated. Obtained as a pale yellow oily product, 25.5 g of diethyl ester of 2-amino-7-thia nonanedicarboxylic acid.

Step B:

Preparation of 2 - ([3-Oxo-3-cyclohexylpropyl] amino) -6- (ethoxycarbonylmethylthio) hexanecarboxylic acid ethyl ester

4.17 g of 2-amino-7-thia-nonanedicarboxylic acid diethyl ester are added dropwise with stirring and cooling, and 2.07 g of 3-cyclohexylprop-1-en-3-one are added dropwise. The mixture was allowed to stand at room temperature for 21 hours. Obtained as a pale yellow oily product 2 - ([3-oxo-3-cyclohexylpropyl] imino) - 6- (ethoxycarbonylmethylthio) hexanecarboxylic acid ethyl ester.

Step C:

Preparation of 2 - ([3-Hydroxy-3-cyclohexylpropyl] amino) -6- (ethoxycarbonylmethylthio) hexanecarboxylic acid ethyl ester

6.2 g of crude ketone prepared in Step B are dissolved in 180 ml of absolute ethanol and 750 mg of sodium borohydride are added portionwise under stirring and ice-cooling. The solution was stirred for an additional 10 minutes on an ice bath and allowed to stand overnight at room temperature. The bulk alcohol is evaporated, water is added to the concentrate and the precipitated insoluble oily substance is extracted with ether. The ethereal solution was dried and evaporated. Obtained as a pale yellow oily residue, ethyl 2 - ([3-hydroxy-3-cyclobexylpropyl] amino) -6- (ethoxycarbonylmethylthio) hexanecarboxylic acid. This product was used in the next step without further purification.

Step D:

Preparation of 5- (4-Carboxymethylthio-butyl) -1- (3-hydroxy-3-cyclohexyl-propyl) -hydantoin

A solution of potassium cyanate (2.60 g) in water (8 ml) was added dropwise to a solution of 6.05 g of the alcohol prepared in Step C in a mixture of 30 ml of this tanol and 15 ml of 2N aqueous hydrochloric acid while stirring under ice-cooling. After allowing the reaction mixture to stand at room temperature for 18 hours, the alcohol was evaporated, water was added to the residue, and the precipitated insoluble oil was extracted with ether. The ethereal solution was dried and evaporated. The resulting viscous oily residue was heated in a boiling water bath for 19 hours. 5- (4-Ethoxycarbonylmethylthio-butyl) -1- (3-hydroxy-3-cyclohexyl-propyl) -hydantoin is obtained as a pale yellow viscous oil.

The resulting ester is dissolved in 75 ml of 0.5 N aqueous sodium hydroxide solution and the solution is kept at room temperature for 2 hours. The solution is then washed with water and the clear alkaline aqueous phase is acidified with 2N aqueous hydrochloric acid. The oily precipitate was extracted with ether. The ethereal solution was dried, evaporated and the viscous oily residue (6.8 g) was chromatographed on a silica gel column. 5- (4-Carboxymethylthio-butyl) -1- (3-hydroxy-3-cyclohexyl-propyl) -hydantoin is obtained as a viscous oily product. The product obtained was subjected to high performance liquid chromatography; silica gel column adsorbent and chloroform: methanol: acetic acid (97: 2.5: 0.5). One is pure

183,047

2b) diethyl ester of 2 - ([3-hydroxy-3-cis-4-methylcyclohexylpropyl] amino) nonanedicarboxylic acid,

3b) diethyl ester of 2 - ([3-hydroxy-3-trans-4-methylcyclohexylpropyl] amino) nonanedicarboxylic acid,

4b) diethyl ester of 2 - {(3-hydroxy-3- [1-adamantyl] propyl) amino} nonanedicarboxylic acid,

5b) diethyl ester of 2 - {(3-hydroxy-3- [2-thienyl] propyl) amino} nonanedicarboxylic acid,

6b) diethyl ester of 2 - {(3-hydroxy-3- [2-furyl] propyl) amino} nonanedicarboxylic acid,

7b) diethyl ester of 2 - {(3-hydroxy-3- [cyclopent-3-enyl] propyl) amino} nonanedicarboxylic acid,

8b) diethyl ester of 2 - ([norboman-2-hydroxy-3-ylmethyl] amino) nonanedicarboxylic acid,

9b) diethyl ester of 2 - {(3-hydroxy-3- [3,3-dimethylcyclobutyl] propyl) amino} nonanedicarboxylic acid,

10b) 2 - {(3-hydroxy-3- [2,2,3,3-tetramethylcycloylpropyl] propyl) amino} nonanedicarboxylic acid, diethyl ester, 11b) 2 - {(3-hydroxy-3 - [l-methyl-cyclohexyl] propyl) amino} -nonándikarbonsav acid diethyl ester,

12b) diethyl ester of 2 - {(3-hydroxy-3-trans-4-methylcyclohexylpropyl) amino} non-4Z-ene dicarboxylic acid,

13b) diethyl ester of 2 - {(3-hydroxy-3-cis-4-methylcyclohexylpropyl) amino} non-4Z-ene dicarboxylic acid,

14b) ethyl 2 - ([3-hydroxy-3-phenylpropyl] amino) -6-ethoxycarbonylmethylthiohexanecarboxylic acid,

15b) 2 - ([3-hydroxy-3-cyclohexylpropyl] amino) -5-ethoxycarbonylmethylthiopentanecarboxylic acid ethyl ester,

16b) 2 - ([3-hydroxy-3-cyclohexylpropyl] amino) -6-ethoxycarbonylmethylthiohex-4Z-ene carboxylic acid ethyl ester,

17b) ethyl 2 - ([3-hydroxy-3-cyclohexylpropyl] amino) -6-ethoxycarbonylmethylthiohex-4E-ene carboxylic acid,

18b) ethyl 2 - ([3-hydroxy-3-cyclohexylpropyl] amino) -3- (3-ethoxycarbonylpropylthio) propionic acid,

19b) ethyl 2- (3-hydroxyoctylamino) -3- (3-ethoxycarbonylpropylthio) propionic acid,

20b) 2 - ([3-hydroxy-3-cyclopentyl-propyl] -amino) -3- (4-ethoxycarbonyl-butylthio) -propionic acid ethyl ester,

21b) 2 - {(3-hydroxy-3- [3-furyl] propyl) amino} nonanedicarboxylic acid diethyl ester. * 22b) 2 - {(3-hydroxy-3- [4-benzyloxyphenyl] propyl ),? -amino} -nonandiicarboxylic acid diethyl ester; and? 23b) 2 - ([3-hydroxy-3-cyclohexylpropyl] amino) -5- (2-ethoxycarbonylethylthio) pentanecarboxylic acid ethyl ester.

The following hydantoin derivatives are prepared from the above intermediates (the individual diastereoisomers are optionally isolated from the hydantoin compounds):

2c) 5- (6-carboxy-hexyl) -1- (3-hydroxy-3-cis [4-methyl-cyclohexyl] -propyl) -hydantoin, m.p. 88-90 ° C and 98-100 ° C;

3c) 5- (6-carboxyhexyl) -1- (3-hydroxy-3-trans [4-methylcyclohexyl] -propyl) -hydantoin, m.p. 87-89 ° C and 99-101 ° C;

4c) 5- (6-Carboxyhexyl) -1- (3-hydroxy-3- [1-adamantyl] propyl) hydantoin, m.p. 155-157 ° C;

5c) 5- (6-Carboxyhexyl) -1- (3-hydroxy-3- [2-thienyl] propyl) hydantoin, m.p. 78-80 ° C;

6c) 5- (6-Carboxyhexyl) -1- (3-hydroxy-3- [2-furyl] propyl) hydantoin;

7c) 5- (6-Carboxyhexyl) -1- (3-hydroxy-3β- [cyclopent-3-enyl] propyl) hydantoin, m.p. 86-87 ° C;

8c) 5- (6-carboxy-hexyl) -1- (2a-hydroxy-norboman-3-ylmethyl) -hydantoin, m.p. 103-107 ° C and 132-136 ° C;

9c) 5- (6-Carboxy-hexyl) -1- (3-hydroxy-3- [3,3-dimethyl-cyclobutyl] -propyl) -hydantoin, m.p. 91-92 ° C and 108-109 ° C;

10c) 5- (6-Carboxy-hexyl) -1- (3-hydroxy-3- [2,2,3,3-tetramethyl-cyclopropyl] -propyl) -25-hydantoin, m.p. 93-95 ° C and 135 ° C. -137 ° C;

le) 5- (6-carboxyhexyl) -1- (3-hydroxy-3- [1-methylcyclohexyl] propyl) hydantoin, m.p. 100-102 ° C and 131-132 ° C;

12c) 5- (6-Carboxyhex-2Z-enyl) -1- (3-hydroxy-330-trans- [4-methyl-cyclohexyl] -propyl) -hydantoin, m.p. 63-65 ° C. -89 ° C;

13c) 5- (6-Carboxyhex-2Z-entyl) -1- (3-hydroxy-3-cis [4-methyl-cyclohexyl] -propyl) -hydantoin, m.p. 63-65 ° C. -89 ° C;

14c) 5- (4-Carboxymethylthio-butyl) -1- (3-hydroxy-3-phenyl-propyl) -hydantoin, m.p. 101-102.5 ° C;

15c) 5- (3-Carboxymethylthio-propyl) -1- (3-hydroxy-3-cyclohexyl-propyl) -hydantoin, m.p. 93-96 ° C;

16c) 5- (4-Carboxymethylthio-but-2Z-enyl) -1- (3-hydroxy-3-cyclohexyl-propyl) -hydantoin, m.p. 117-118.5 ° C and 116.117.5 ° C;

17c) 5- (4-Carboxymethylthio-but-2E-enyl) -1- (3-cyclohexyl-3-hydroxypropyl) -hydantoin;

see below. side;

18c) 5- (3-Carboxypropylthiomethyl) -1- (3-hydroxy-3-cyclohexylpropyl) -hydantoin, m.p. 108-110 ° C;

19c) 5- (3-Carboxypropylthiomethyl) -1- (3-hydroxy50-octyl) -hydantoin, m.p. 44-47 ° C and 57-60 ° C;

20c) 5- (4-Carboxy-butylthiomethyl) -1- (3-hydroxy-3-cyclopentyl-propyl) -hydantoin, m.p. 80-82 ° C and 91-93 ° C;

2cc) 5- (6-Carboxyhexyl) -1- (3-hydroxy-3- [3-furyl] 55-propyl) hydantoin;

22c) 5- (6-Carboxyhexyl) -1- (3-hydroxy-3- [4-benzyloxyphenyl] propyl) hydantoin; mp 70-71 ° C and 130-130.5 ° C; and

23c) 5- (3- [2-Carboxyethylthio] -propyl) -1- (3-hydroxy-60 -3-cyclohexyl-propyl) -hydantoin, m.p. 100.5-102.5 ° C and 95-97 ° C.

c) 5- (6-carboxyhexyl) -1- (3-hydroxy-3- [4-tetrahydropyrantyl] propyl) hydantoin, m.p. 106-108 ° C and 101-103 ° C; 65

-101

183047 diastereoisomer viscous gum (by TLC [silica gel; _CHCl3: MeOH: AcOH = 90: 5: 5] _Rf = 0.48) and one pure diastereoisomer is 104-108 fusible C as colorless crystals ° we separate it.

Example 25

Preparation of 5- (6-Carboxy-hexyl) -1- (3-hydroxy- [3-cyclohexyl] -propyl) -hydantoin salts

Two types of salts can be prepared:

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

b) those in which both the above hydrogen atom and the 3-position hydrogen atom of the hydantoin ring are substituted.

The type (a) salts may be sodium, potassium and magnesium salts.

The procedure:

A 50:50 mixture of the title hydantoin in diastereomer 50:50 (1.0 mmol) was dissolved in methanol (5 ml) and a solution of the corresponding metal bicarbonate (1.0 m equivalent) in water (2 ml) was slowly added with stirring. The reaction mixture was evaporated to give a hygroscopic mono-metal salt (half magnesium salt). The salts of type b) may also be sodium, potassium or magnesium salts.

The procedure:

To a 50:50 diastereomeric mixture of the title hydantoin (1.0 mmol) was added a solution of metal hydrogencarbonate (2.1m) in water (5 mL) and the resulting aqueous solution was evaporated to dryness. The residue was treated with 10 ml of ethanol, filtered and the filtrate was evaporated; This gives a hygroscopic bisphemate salt (mono-magnesium salt).

The diastereomeric salts, in particular the lower melting points, can be prepared in the same manner.

Preparation of starting materials:

15-17. s. used as starting material in the preparation of compound

a) diethyl ester of 2-amino-6-thia-octane dicarboxylic acid,

b) diethyl ester of 2-amino-7-thia-non-4Z-ene dicarboxylic acid;

c) 2-Amino-7-thia-non-4E-ene dicarboxylic acid diethyl ester was prepared from the corresponding malonic acid ester derivatives as described in Example 4, namely

a) 3-chloropropylacetamido-malonic acid diethyl ester (Coll. Czech. Chem. Comm. 33, 3823 (1968)),

b) 4-chloro-but-2Z-enylacetamido-malonic acid diethyl ester (Chem. Eng. Data 205 [1970]);

c) 4-chloro-but-2E-enylacetamido-malonic acid diethyl ester (Chem. Eng. Data 205 (1970)).

No. 20 The S- (4-ethoxycarbonyl-butyl) -L-cysteine ethyl ester used as a starting material in the preparation of Compound IIa is prepared as follows:

To a solution of sodium (4.6 g, 0.20 g) in absolute ethanol (320 ml) was added L-cysteine ethyl ester hydrochloride (18.6 g, 0.10 mol). After stirring for 15 minutes, the solvent was evaporated in vacuo. The resulting sodium salt was dissolved in 200 ml of anhydrous dimethylsulfoxide, and 21.0 g (0.10 mol) of the solution was stirred in one portion.

Ethyl 5-bromo-valeric acid is added. After standing overnight at room temperature, the reaction mixture was heated on a boiling water bath for 5 minutes and finally poured into a solution of 1 g of sodium dihydrogen phosphate in 300 ml of water. The oily precipitate was extracted with ether in three portions. The extracts were combined, washed with water, dried over magnesium sulfate, and finally the solvent was evaporated in vacuo. 24.7 g of S - (4-ethoxycarbonyl-butyl) -L-rysteine ethyl ester are obtained in the form of a pale yellow oil.

18 and 19 are prepared by a similar procedure. S- (3-ethoxycarbonylpropyl) -L-crude ethyl ester used as a starting material in the preparation of compound.

No. 23. The 2-amino-6-thia-nonanedicarboxylic acid diethyl ester used as a starting material in the preparation of Compound IIa is prepared as follows:

Dissolve 18.5 g of 3-chloropropylacetamido-malonic acid diethyl ester (Coll. Czech. Chem. Comm. 33, 3823 (1968)) and 100 mg of sodium iodide in 1 ml of absolute ethanol and mix with 7.96 g.

A mixture of ethyl 3-mercaptopropionic acid and ethanolic sodium ethoxide (1.37 g) in ethanol (75 ml) was added dropwise. The resulting solution was stirred at room temperature for 45 hours and then concentrated in vacuo to a small volume. The concentrate was diluted with water and extracted with chloroform. The extract was dried and evaporated. The crude acetamido -3- (2-ethoxycarbonyl-ethylthio) -propyl-malonic acid diethyl ester (24 g) was obtained as a pale yellow syrupy residue. The resulting crude ester was suspended in 470 ml of 10% aqueous hydrochloric acid and refluxed for 3 hours. The mixture was cooled and concentrated in vacuo to a small volume. Traces of water were removed by azeotropic distillation with ethanol. The gummy residue was dissolved in a small amount of ethanol and added to a solution of thionyl chloride (13.5 mL) in ethanol (200 mL) at -10 ° C. The mixture was allowed to stand at + 5 ° C for 18 hours and then refluxed for 1 hour. The solution was cooled, concentrated, and partitioned between chloroform and aqueous sodium carbonate. The chloroform phase is separated and the aqueous phase is extracted twice more with chloroform. The organic extracts were combined, dried, evaporated and the oily residue chromatographed on a silica gel column. Chloroform containing 7% methanol was used as eluent. Obtained as a pale yellow oily substance, 7.0 g of diethyl ester of 2-amino-6-thia nonanedicarboxylic acid.

The following examples illustrate experiments on the biological activity of compounds of formula I and the preparation of pharmaceutical compositions containing compounds of formula I.

II

-11183.047

Example A)

Investigation of platelet aggregation inhibitory activity

The activity of the compounds was visualized on 1 ml of fresh platelet-rich human plasma using a Bom-type aggregometer.

An appropriate amount of the test compound was added to 1 ml of plasma, incubated for 1 min at 37 ° C, and 5 μπιόΐ of adenosine diphosphate was added to induce platelet aggregation. The inhibitory effect of the compounds on platelet aggregation is expressed as a percentage of the values measured on the drug-free sample.

In this experiment, 5- (4-carboxymethylthiobutyl) -1- (3-cyclohexyl-3-hydroxypropyl) hydantoin was found to be about 20 times more potent than prostaglandin E1.

Example B)

Preparation of tablets

The following tablets are prepared:

5- (4-Carboxymethylthio-butyl) -1- (3-cyclohexyl-3-hydroxypropyl) -hydantoin 5.0 mg

Lactose (British Pharmacopoeia grade) 82.0 mg

Starch (British Pharmacopoeia grade) 10.0 mg

Povidone (British Pharmacopoeia) 2.0 mg

Magnesium stearate 1.0 mg

The active ingredient is thoroughly mixed with lactose and starch, the mixture is kneaded with a solution of povidone in purified water and the resulting mass is granulated. The granulate is dried and then mixed with magnesium stearate and compressed into 100 mg vc tablets.

Water for injection q. s. ad 100 ml

The active ingredient is dissolved in water for injection and the solution is sterilized by filtration through a 0.22 µm pore size membrane filter. The filtrate is collected in a sterile container. Aseptically, the solution is filled into sterile glass ampoules and the ampoules containing 1 ml solution for injection are sealed.

EXAMPLE E Preparation of Injection Formulation containing μ-g / ml

An injection composition having the following composition is prepared:

5- (4-Carboxymethylthio-butyl) -1- (3-cyclohexyl-3-hydroxypropyl) -hydantoin 1 ml

Ethanol 10 ml

Propylene glycol 30 ml

Water for injection q. s. ad 100 ml

The active ingredient is dissolved in ethanol, propylene glycol is added to the solution, and the mixture is diluted with water for injection to the desired final volume.

The resulting solution was filtered through a 0.22 μτη membrane filter for sterilization; collect the filtrate in a sterile container. The solution is aseptically filled into sterile glass vials. The vials containing 10 to 10 ml of solution for injection are stoppered with a sterile rubber stopper and sealed with aluminum tape.

Example C)

Production of capsules

Capsules having the following composition are prepared:

5- (4-Carboxymethylthio-butyl) -1- (3-cyclohexyl-3-hydroxypropyl) -hydantoin 10 mg

Lactose 79 mg

Starch 10 mg

Magnesium stearate 1 mg

The powder components are homogenized in a powder mixer and the homogeneous powder mixture is filled into hard gelatin capsules. Each capsule contains 100 mg of powder mixture.

Example D Preparation of Injection Formulation containing pg / ml of active ingredient

An injection composition having the following composition is prepared:

5- (4-Carboxymethylthio-butyl) -1- (3-cyclohexyl-3-hydroxypropyl) -hydantoin 100 pg

Claims (25)

Patent claims A process for the preparation of hydantoin derivatives of the formula I wherein Z is hydrogen, Z ¹ is a group of the formula X-X ¹ -X ² -X ³ , Z ² is a group of the formula Y-Y ¹ -Y ² -Y ^{3 in} which X is methylene, X ^I is cis or trans -CH = CH- or CH2-CH2-, X ² is a bond or a straight or branched alkylene group containing from 1 to 6 carbon atoms, and X ³ is a carboxyl group in which one of the methylene groups in X ¹ and X ^{2 may} be replaced by a thia group (-S-), provided that the thia group is separated by at least one C atom from the -CH = CH- or CO group or by hydantoin nitrogen of the ring, Y is -CR2-CH2-, wherein the two R substituents are independently hydrogen or methyl, -121 183,047 Y ¹ is methylene substituted with hydroxy or methylene substituted with hydroxy and C 1-6 alkyl, Y ² is a direct bond or a straight or branched alkylene group containing from 1 to 7 carbon atoms, Y ³ is hydrogen or phenyl, or Y is -CH 2 -CH 2 -, Y ¹ is a hydroxymethyl group, and Y ² and Y ³ together are C 3 -C 8 cycloalkyl optionally substituted with 1 to 4 methyl groups, C 4 -C 6 cycloalkenyl, phenyl, adamantyl, tetrahydropyranyl, furyl, thienyl, 4-benzyloxyphenyl, or 2 α-hydroxy-1-methyl norbomyl, provided that at least one of (A) X ¹ and X ² is a thia group, or contains a thia group, or when (Β) X ¹ and X ² have different meanings in (A) then (i) at least one of Y and Y ^{3 is other} than C 3-8 unsubstituted cycloalkyl, or Or (ii) Y ² and Y ³ together form a 2a-hydroxymethyl norbomyl group, or (iii) Y ³ 4-benzyloxyphenyl; wherein the cyclic group is adamantyl, tetrahydropyranyl, furyl, thienyl, characterized in that a compound of formula II wherein J is a C 2 -C 5 alkoxycarbonyl or carboxyl group and J ¹ is a hydrogen atom or carbamoyl, Z ¹ and Z ² are cyclized by heating or an alkali metal cyanate in the presence of the above-mentioned, optionally inert solvent. (Priority: September 5, 1978) A process for the preparation of the hydantoin derivatives of formula (I) according to claim 1, wherein Z is hydrogen, Z ¹ is -X-X ¹ -X ² -X ³ - wherein X is methylene, X ^I is cis or trans -CH = CH- or -CH2-CH2-, X ² is a direct bond or a C 1 -C 6 straight or branched alkylene group wherein one of the methylene groups is optionally substituted by a thia group (-S-), provided that the thia group is separated by at least one carbon atom from the -CH = CH- or - CO, or the nitrogen atom of the hydantoin ring, X ³ represents a carboxyl group, Z ² is -YY ¹ -Y ² -Y ³ -, wherein Y, Y ¹ , Y ² and Y ³ are as defined in claim 1, with the proviso that (A) X ² contains a thia group; or (B) when X ² is different from (A), then (i) at least one of Y ² and Y ³ is not C 3 -C 8 unsubstituted cycloalkyl or C 4 -C 6 cycloalkenyl; or (ii) Y ² and Y ³ together are a 2a-hydroxymethyl norbomyl group, or (iii) Y ³ is a benzyloxyphenyl group, characterized in that a compound of formula (II) wherein J, J ¹ , Z, Z ¹ and Z ² are The cyclization according to claim 1, in the presence of an optional inert solvent, is carried out in an acidic medium by heating or by alkali metal cyanate. (Priority: May 31, 1978) The process of claim 1 for the preparation of hydantoin derivatives of formula I wherein Z is hydrogen, Z ¹ is -X-X ¹ -X ² -X ³ - wherein X is methylene, X ^I is cis or trans -CH = CH 2 group or a -CH 2 group, X ² is a direct bond or a straight or branched alkylene group of 1 to 6 carbon atoms, wherein one of the methylene groups is optionally substituted by a thia group (-S-), provided that the thia group is separated by at least one carbon atom from the group -CH = CH- or - CO, or the nitrogen atom of the hydantoin ring, X ³ is carboxyl; Z ² is -Y-Y ¹ -Y ² -Y ³ -, wherein Y, Y ¹ and Y ² are as defined in claim 1, Y ³ is hydrogen; or Y is - CH ₂ -CH ₂ -, Y ¹ is a hydroxymethyl group, Y ² and Y ³ together represent a substituted cycloalkyl group or a cycloalkenyl group according to claim 1, with the proviso that (A) X ² contains a thia group, or when (Β) X ² is not as defined in (A), then (i) at least one of Y ² and Y ³ contains a cyclic group other than C 3-8 unsubstituted cycloalkyl or C 4-6 cycloalkenyl as defined in claim 1; or (ii) Y ² and Y ³ together are 2a-hydroxymethyl norbomyl, characterized in that a compound of formula II - wherein J, J ¹ , Z, Z ¹ and Z ² The cyclization according to claim 1, in the presence of an optional inert solvent, is carried out in an acidic medium by heating or by alkali metal cyanate. (Priority: December 1, 1977) The process of claim 1 for the preparation of hydantoin derivatives of formula I wherein Z is hydrogen, Z ¹ is -X-Y ¹ -X ² -X ³ - wherein X is methylene, X ^I is cis or trans -CH = CH- or -CH2-CH2-, X ² is a direct bond or a straight or branched alkylene group of 1 to 6 carbon atoms, wherein -131 One of the methylene groups is optionally substituted with thia (-S-), provided that at least one carbon atom is separated from the hydantoin ring and X ³ is a carboxyl group, and Z ² is -Y-Y ¹ -Y ² -X ³ - wherein Y is CR2-CH2-, wherein the two R substituents are independently hydrogen or methyl, Y ¹ is methylene substituted with hydroxy or methylene substituted with hydroxy and C 1-6 alkyl, Y ² is a bond or a C 1 -C 7 straight or branched alkylene group, Y ³ is hydrogen or phenyl, or Y ² and Y ³ together are tetrahydropyranyl, or a substituted cycloalkyl or cycloalkenyl group as defined in claim 1, characterized in that a compound of formula II wherein J, J ¹ , Z, Z ¹ and Z ² are cyclized by heating or an alkali metal cyanate in the presence of a solvent as claimed in claim 1 in an acidic medium. (Priority: September 5, 1977) 5. A process according to claim 1, wherein the starting compound is a compound of formula II wherein J is an alkoxycarbonyl, preferably ethoxycarbonyl. (Priority: September 5, 1978) 6. The process of claim 1, wherein the ring closure reaction is carried out under heating. (Priority: September 5, 1978) 7. A process according to claim 1 wherein the ring closure reaction is carried out in the presence of hydrochloric acid. (Priority: September 5, 1978) 8. The process of claim 1, wherein the ring closure reaction is carried out in the presence of potassium cyanate. (Priority: September 5, 1978) 9. The process according to claim 1, wherein the ring closure reaction is carried out in the presence of an inert solvent, preferably an alcohol, preferably ethanol. (Priority: September 5, 1978) 10. A process according to claim 2 wherein the starting material is a compound of formula II wherein J is alkoxycarbonyl, preferably ethoxycarbonyl. (Priority: May 31, 1978) 11. The process of claim 2, wherein the ring closure reaction is carried out under heating. (Priority: May 31, 1978) 12. The process of claim 2, wherein the ring closure reaction is carried out in the presence of hydrochloric acid. (Priority: May 31, 1978) 13. A process according to claim 2, wherein the ring closure reaction is carried out in the presence of potassium cyanate. (Priority: May 31, 1978) 14. The process according to claim 2, wherein the ring closure reaction is carried out in the presence of an inert solvent, preferably an alcohol, preferably ethanol. (Priority: May 31, 1978) 15. A process according to claim 3 wherein the starting material is a compound of formula II wherein J is alkoxycarbonyl, preferably ethoxycarbonyl. (Priority: December 1, 1977) 16. A process according to claim 3 wherein the ring closure reaction is carried out under heating. (Priority: December 1, 1977) 17. The process of claim 3, wherein the ring closure reaction is carried out in the presence of hydrochloric acid. (Priority: December 1, 1977) 18. A process according to claim 3, wherein the ring closure reaction is carried out in the presence of potassium cyanate. (Priority: December 1, 1977) 19. The process of claim 3, wherein the ring closure reaction is carried out in the presence of an inert solvent, preferably an alcohol, preferably ethanol. (Priority: December 1, 1977) 20. The process of claim 4 wherein the starting material is a compound of formula II wherein J is alkoxycarbonyl, preferably ethoxycarbonyl. (Priority: September 5, 1977) 21. The process of claim 4, wherein the ring closure reaction is carried out under heating. (Priority: September 5, 1977) 22. A process according to claim 4, wherein the ring closure reaction is carried out in the presence of hydrochloric acid. (Priority: September 5, 1977) 23. A process according to claim 4 wherein the ring closure reaction is carried out in the presence of potassium cyanate. (Priority: September 5, 1977) 24. The process according to claim 4, wherein the ring closure reaction is carried out in the presence of an inert solvent, preferably an alcohol, preferably ethanol. (Priority: September 5, 1977) 25. A process for the preparation of a pharmaceutical composition comprising the compound of formula I according to claim 1, wherein Z ¹ and Z ² are as defined in claim 1, using conventional pharmaceutical carriers, diluents and / or excipients. is formulated in a manner known per se into a pharmaceutical composition. (Priority: September 5, 1978)