HU183046B - Process for producing hydanthoine derivatives - Google Patents

Abstract

Hydantoins and N-alkylhydantoins of formula (I) (I) <IMG> Wherein Z is hydrogen or alkyl; one of Z1 and Z2 is represented by the group -CH2-X-X1-X2; wherein X is phenylene, -C?C-, cis or trans -CH=CH- or -CH2-CQ2- in which each Q is independently selected from hydrogen and alkyl or the two Q's together form an alkylene radical having four, five or six carbon atoms; X1 is a covalent bond or a straight or branched alkylene chain having 1 to 6 carbon atoms optionally having one of its methylene groups replaced by oxa (-O-) provided that at least one carbon atom separates the oxa group from a -C?C-, -CH=CH- or -CO- group; and X2 is selected from 5-tetrazolyl, carboxyl, carbamoyl, hydroxymethyl and alkoxycarbonyl; and the other of Z1 and Z2 is represented by the group -Y-Y1-Y2-Y3; wherein Y is -CR2-CH2- in which each R is independently selected from hydrogen and methyl; Y1 is carbonyl, methylene, methylene substituted by hydroxy or methylene substituted by hydroxy and alkyl; Y is a covalent bond or a straight or branched alkylene having 1 to 7 carbon atoms, unsubstituted or substituted on the carbon adjacent Y1 by one or two groups independently selected from alkyl, bicycloalkyl and cycloalkyl; Y is hydrogen, hydroxy, alkoxy having 1 to 7 carbon atoms, cycloalkyl, bicycloalkyl, phenyl, benzyl, phenoxy or benzyloxy, wherein each of phenyl, benzyl, phenoxy and benzyloxy is unsubstituted or substituted in the benzene ring by one or more groups selected from hydroxy, halo, nitro, amino, acylamino, alkenyl, alkoxy, phenyl and alkyl which may itself be substituted by one or more halo groups; or Y is a bond, -CH2- or -CH2-CH2- and Y1, Y2 and Y taken together form a cycloalkyl group substituted by a hydroxy group, and salts thereof; have biological properties related to those of natural occurring prostaglandins and may be used in medicine, for example, in the treatment of thrombosis.

Description

phenyl, benzyl, phenoxy or benzyloxy, or

Y is a direct bond, -CH 2 - or -CH 2 - -CH 2 -,

Y ¹ , Y ² and Y ³ together represent a C 3-7 cycloalkyl group substituted with a hydroxy group.

These compounds have prostaglandin-like properties and are prepared by known production procedures from appropriately substituted starting materials, for example, cyclization of a compound of formula (II) or (VII), optionally in situ, wherein G or G ¹ represents a carboxyl group or a derivative thereof. by.

The present invention relates to novel nitrogen-containing heterocyclic compounds and to pharmaceutical compositions containing these compounds as active ingredients.

It has now been found that the hydantoin derivatives represented by the following general formula (I)

Z is hydrogen or C1-C4 alkyl,

Z ¹ and Z ² are one of -CH ₂ -XX ¹ -X ² group, and in formula

X is phenylene, -C = C-, cis or trans -CH = CH- or -CH 2 -CO 2 and in the latter two Q are independently hydrogen or C 1 -C 4 alkyl,

X ^I is a covalent bond or a straight or branched chain C1-6 alkylene group ,, wherein the methylene groups is optionally replaced by an -O- oxacsoportra provided that this oxacsoportot separated by at least one carbon atom in the -C-C- , -CH = CH- or -CO-,

X ^{2 is a} carboxyl, carboxamide, hydroxymethylene or alkoxycarbonyl group,

The other of Z ¹ and Z ² is a group of the formula -YY ¹ -Y ² -Y ³ and in it

Y is a group of formula -CL ₂ -CH ₂ - in which the two L are independently hydrogen or methyl,

^Y1 carbonyl, methylene, substituted methylene or substituted methylene group and hydroxy C1-4 alkyl, hydroxy

Y ^{2 is a} covalent bond or a straight or branched C 1 -C 7 alkylene group optionally substituted on one or two carbon atoms adjacent to the Y ¹ substituent independently selected from C 1 -C 4 alkyl,

Substituted with C4-C10 bicycloalkyl or C3-C7 cycloalkyl,

Y represents ³ hydrogen, hydroxy, C 1-7, preferably C 1-4 alkoxy, C 3-7 cycloalkyl, C 4-10 bicycloalkyl, phenyl, benzyl, phenoxy or benzyloxy 2 groups, said phenyl, benzyl, phenoxy or benzyloxy may be substituted on the benzene ring with one or more substituents independently selected from hydroxy, nitro, C 1-4 alkoxy, alkyl or phenyl, trifluoromethyl or halogen; or

Y is a direct bond, -CH ₂ - or -CH ₂ -CH ₂ -,

Y ¹ , Y ² and Y ³ together represent a C 3-7 cycloalkyl group substituted with a hydroxy group, said hydroxyl group being preferably separated by 3 carbon atoms from the hydantoin ring having valuable pharmacological properties similar to those of natural prostaglandins; Thus, these compounds partially mimic and partially antagonize the physiological effects of natural prostaglandins in various biological formulations. In particular, it has been found that some of the compounds of formula (I) greatly mimic the inhibitory effect of prostaglandin-E1 on blood aggregation.

In the definition of formula (I) and other formulas below, alkyl groups, unless otherwise specified, may have from 1 to 6 carbon atoms, i.e., methyl, ethyl, propyl, butyl, pentyl hexyl, and the like. all possible isomers may be present in the place of the alkyl groups mentioned in the definition of each substituent.

Thus, for example, the alkyl groups in the above definitions of Y ¹ and Y ² may be preferably methyl; the alkyl portion of the alkoxycarbonyl groups may preferably be methyl or ethyl.

The alkylene groups in the definitions may have from 2 to 4 carbon atoms; examples of such groups include vinyl.

The cycloalkyl groups mentioned in the above definition of formula I may contain from 3 to 7 carbon atoms and the bicycloalkyl groups may contain from 4 to 10 carbon atoms.

A compound of formula as defined above (I), the divalent phenylene group in the ortho, meta or para linked to the oxacsoport is preferably phenylene adjacent positions, or when X is other than phenylene then X ¹ is a - CH ₂ = O-CH ₂ -.

Groups within the formula as defined above (I) include carboxylic acids - where X ² represents a carboxyl group - the salts, and can be formed from compounds containing hydrogen, Z is a salt. Particularly suitable for therapeutic purposes are salts which contain a pharmaceutically acceptable cation such as ammonium or alkali metal such as sodium or potassium, alkaline earth metal such as calcium or magnesium, or an organic base such as an amine. , e.g., ethanolamine cation. However, it is also within the scope of the present invention to provide salts containing a pharmaceutically unacceptable cation.

183,046 because they can be valuable intermediates for the preparation of pharmaceutically acceptable salts, as well as acids or esters of formula (I).

The compounds of formula (I) and the corresponding compounds of the general formula (I) include all other stereoisomeric forms which are not expressly stated. In particular, enantiomeric forms, racemates containing mixtures thereof, and diastereoisomeric compounds are important in this regard.

Particularly important prostaglandin-like properties are those compounds of formula I wherein each substituent has the following meanings in the above definitions:

Z is hydrogen or C1-C4 alkyl, especially methyl or butyl;

One of Z ¹ and Z ² is a -CH 2 -XX ¹ -X ² group in which X and X ¹ together are C 3 -C 7, especially C 5 -alkylene, and X ² is alkoxycarbonyl, carboxyl or salts thereof;

The other of Z ¹ and Z ² is a -YY ¹ -Y ² -Y ³ group in which Y, Y ^r and Y ² are as defined above and Y ³ is hydrogen, C 4 -C 7 cycloalkyl, phenyl or represents a benzyl group.

Among these preferred compounds, particular mention should be made of those in which Z represents a hydrogen atom and Z ¹ represents a group -CH ² -X-X ¹ -X ^{2 as} defined above.

Compounds of formula (I) as defined above may be synthesized according to the present invention by any of the known methods for preparing such structures. For example, can be carried out by reacting a (Π) hydantoin derivative of formula - wherein G represents a carboxyl group or a derivative thereof, for example amide or ester, especially ester groups, Z, Z ¹ and Z ² is at least equivalent to the As defined in formula (I), it is subjected to a ring closure reaction in an acidic medium or simply by heating. This reaction may be carried out in the absence of a solvent, but it is preferable to use a solvent which is inert to the reaction, such as a hydrocarbon such as gasoline as a solvent. In cases where the starting compound of formula (II) contains an alkoxycarbonyl group at G, the ring closure reaction may be carried out in the presence of a suitable base such as an alkoxide such as sodium ethoxide.

Compounds of the formula being as starting material for use in process (II) of the above process is preferably (III) an amino acid derivative of formula - may be prepared, cyanic acid or a - wherein G, Z ¹ and Z ² is as defined above, but G nitrile can be alkyl isocyanate (depending on whether Z is hydrogen or alkyl in the desired compound).

When the above reaction is carried out with cyanic acid, the cyanic acid is preferably prepared in situ from an alkali metal cyanate, such as potassium cyanate, by reaction with an acid, which is the acid addition salt of the compound of formula (III) or one or both of X and X ² are hydrogen - may also be present as the free acid of formula (III) in the reaction mixture.

In another embodiment of the process, an equivalent amount of a mineral acid or an organic acid may be added to liberate the cyanic acid. The reaction can be carried out without the use of a solvent, but preferably a solvent which is inert to the reaction is preferably polar; examples of such solvents include water or water and mixtures of acetone, dimethylformamide, dimethylsulfoxide or a lower alkanol such as ethanol, and hydrocarbons, ethers or halogenated hydrocarbons such as chloroform. If desired, for example in the absence of a solvent, the reaction may be effected by heating the reaction mixture.

Similar reaction conditions may be used when starting with an alkyl isocyanate, except that no equivalent amount of acid (e.g. in the form of an acid addition salt) is required in the reaction mixture.

Instead of using cyanates or isocyanates, the compounds of formula (III) may also be reacted with urea, nitrocarbamide or N-alkyl urea. In this case, the use of a solvent as a reaction medium is not essential, but it is generally preferred to carry out the reaction in the presence of a reaction-inert solvent, such as one of the foregoing; it is also advantageous to carry out heating, for example at a temperature of 100-125 ° C or up to 150 ° C.

In the synthesis described above, the intermediate of formula (II) does not need to be isolated from the reaction mixture, but may be further reacted directly in the reaction mixture to produce the corresponding compound of formula (I) under the reaction conditions described above.

The starting compounds of formula (III) may conveniently be prepared by reacting a compound of formula (IV) with a compound of formula (V): wherein G, Z ¹ and Z ² are as defined above, Q ¹ and Q ^{One of} which represents an amino group and the other represents a halogen, preferably a bromine atom. This reaction may be carried out by heating the reactants without the use of a solvent or in the presence of a solvent inert to the reaction such as ethanol.

The starting compounds of formula (III) wherein Z ^{2 represents} a -Y-Y ¹ -Y ² -Y ³ group and Y ^{1 is a} carbonyl group may also be prepared by reacting a compound of formula (IV) wherein Q ¹ is an amino group. 3

183,046 is reacted with an unsaturated ketone of formula VI wherein Y ² and Y ³ are as defined above; this reaction may be carried out with or without the use of a solvent which is inert to the reaction, at room temperature or optionally by heating.

The hydantoin derivatives of formula (I) as defined above may also be prepared by reacting a compound of formula (VII) wherein Z, Z ¹ and Z ² are as defined above and G ¹ is a carboxyl group or a reactant thereof a derivative thereof, for example an alkoxycarbonyl group such as an ethoxycarbonyl group, is subjected to a ring closure reaction. The ring closure of compounds of formula (VII) may be performed under conditions similar to those of compounds of formula (II); in preparing the compounds of formula (VII), the reaction conditions are suitably selected so as to permit the spontaneous ring closure of the resulting compound.

For example, compounds of formula VII may be prepared by reacting a compound of formula V with a compound of formula VIII wherein Z, Z ¹ , Z ² and G ¹ are as defined above, Q ¹ and Q ² being one of which is halogen, preferably chlorine or bromine, and the other represents an amino group; this reaction may be carried out by optionally mixing the reacting compounds in the presence of an inert solvent and heating the reaction mixture. Suitable solvents are preferably alkanols, ethers, hydrocarbons or halogenated hydrocarbons.

Compounds of formula (VIII) may be prepared by reacting a suitable carbamic acid derivative, such as an alkyl ester of a carbamic acid, with a compound of formula (IV) as defined above under reaction conditions well known in the art.

Alternatively, a compound of formula (I) as defined above may be prepared by reacting a compound of formula (IX) wherein Z, Z ¹ and Z ² have the same meanings as those of formula (I) is defined as reacting with a carbonic acid derivative. As the carbonic acid derivative, any reactive carbonic acid derivative well known in the art, such as phosgene, diphenyl carbonate or an alkyl halide formic acid, such as ethyl chloroformate, can be used. The reaction may conveniently be carried out in the presence of a base such as an amine such as triethylamine or diisopropylethylamine in an aprotic solvent which is inert to the reaction such as toluene, dimethylformamide or an ether such as diethyl ether. The reaction is also carried out at room temperature, but heating of the reaction mixture is generally preferred.

The starting compounds of formula (IX) as defined above may be prepared by methods analogous to those described above for the preparation of compounds of formula (III).

Hydantoin derivatives of formula (I) wherein Z represents an alkyl group may also be prepared by alkylation from the corresponding compounds of formula (X) wherein R is hydrogen or alkyl, R ^{1 is} hydrogen or a Z ¹ substituent as defined above, R ^{2 represents a} hydrogen atom or a substituent Z ² and R ³ alkyl as defined above or a substituent Z ¹ or Z ^{2 as} defined above, wherein one of R ¹ , R ¹ and R ² represents a hydrogen atom, in particular an alkylating agent. With a reactive derivative of an alcohol of the formula R ³ -OH - wherein R ^{3 represents an} alkyl group or a Z ¹ or Z ² substituent as defined above, wherein R ³ is different from the R, R ¹ and R ² substituent of the compound of formula X meaning digging.

Suitable reactive esters for the above reaction include chloride, bromide, iodide or sulfonate, such as p-toluenesulfonate, methanesulfonate or benzenesulfonate derived from an alcohol of the formula R ³ -OH. The alkylation reaction may be carried out under conventional reaction conditions well known to those skilled in the art, for example a base such as an alkali metal hydride, an alkali metal amide or an alkali metal alkoxide, in particular sodium hydride, sodium alkoxide such as sodium methoxide. presence. The reaction is conveniently carried out in a reaction-inert solvent which also serves as a diluent for the reactants; for example, toluene, dioxane, dimethylformamide, tetrahydrofuran, dimethylsulfoxide or acetonitrile may be used; when an alkali metal alkoxide is used as the base, the corresponding alkanol may also be used as a solvent.

Intermediates of formula (X) wherein R is hydrogen are included in the above definition of formula (I) and may be prepared by the methods described above for the preparation of such compounds of formula (I). The compounds of formula (X) may also be prepared by appropriate adaptation of methods already known in the art, such as Chemical Reviews 46, 403-425 (1950).

Compounds of formula (I) as hereinbefore defined may also be prepared by reacting an appropriate unsaturated compound of formula (XI):

Z ³ is = CL-CH ₂ -Y ¹ -Y ² -Y ³ and

Z ⁴ is -CH ² -XX ¹ -X ² or

Z ³ is = CH-XX ¹ -X ² and

Z ^{4 is} a group -YY ¹ -Y ² -Y ³ , wherein X, X ¹ , X ² , Y, Y ¹ , Y ² Y ³ and L have the same meaning as given in formula (I).

183,046, by a suitable reducing agent.

Suitable reducing agents for the above reaction are, for example, tin (II) chloride in aqueous solution, optionally in the presence of a dilute mineral acid; The reduction may also be effected by catalytic hydrogenation, for example in the presence of Raney nickel, platinum, palladium, ruthenium or radium catalysts. Of course, other reactive groups present in the molecule that may also be attacked by the reducing agent should also be considered when selecting the most appropriate reducing agent.

The intermediates of the general formula (XI) in the above-described processes may be prepared by the reaction steps outlined in Scheme A in the accompanying drawings; in the general formulas of this scheme, Ζ, Ζ ³ , Z ⁴ and G are as defined in formulas XI and III, G ^{3 is} alkyl such as n-butyl and G ^{4 is} halogen, preferably represents bromine and Ph represents phenyl. In the above process, compounds of formula (XIII) may be prepared in a similar manner to the ring closure of compounds of formula (II) above, and compounds of formula (XIV) may be prepared by treating compounds of formula (XIII) with concentrated mineral acid such as hydrochloric acid is obtained.

The alcohols of formula (I) wherein A ² is hydroxymethylene may also be prepared by reduction of the corresponding acids, esters, acid halides, acid anhydrides or aldehydes with a suitable reducing agent. Suitable reducing agents are those known for this purpose; the optional reducing agent may be selected according to the nature of the compound to be reduced. In general, metal sodium in ethanol is well suited for this reaction. For example, the carboxylic acid may be converted to the corresponding mixed anhydride by reaction with ethyl chloroformate with a base such as triethylamine, and the latter reduced with sodium borohydride to the corresponding alcohol. Likewise, the esters may be reduced to the corresponding alcohols, preferably diisobutylaluminum hydride, in a reaction-inert solvent such as an ether or hydrocarbon such as hexane or benzene. However, they can also be prepared by reduction of alcohols by catalytic hydrogenation.

The alcohols of formula I wherein X ² is hydroxymethylene may also be prepared from the corresponding halides by hydrolysis with a suitable reagent. The hydrolyzing agent may be, for example, an aqueous suspension of an alkali metal hydroxide or silver oxide.

In the synthesis of the hydantoin derivatives of formula (I) containing a hydroxyl group in the side chain, it may be desirable to protect this hydroxyl group during the reaction. This can be easily accomplished using standard protecting groups; for each protecting group, for example, acyl, aroyl, tetrahydropyran-2-yl, 1-ethoxyethyl or aralkyl such as benzyl may be used.

Deprotection may be accomplished by methods known to those skilled in the art; for example, the acyl group may be cleaved by acidic or basic hydrolysis and the benzyl group reductively.

The ketones of formula (I) wherein Y ¹ is a carbonyl group can be converted to the corresponding secondary alcohols by reduction with a suitable reducing agent such as sodium borohydride. Alcohols containing Y ¹ -CH (OH) - may be oxidized to the corresponding ketones using, for example, Jones reagent, an acidic dichromate or other suitable oxidizing agent.

Similarly, when the compounds of Formula I contain an unsaturated C-C or -CH = CH- bond, these compounds are suitably ethylenically unsaturated by standard hydrogenation techniques such as using a Lindlar-type or Adams catalyst. to a compound or to the corresponding saturated compound.

The hydantoin derivatives of formula (I) contain an asymmetric carbon atom at position 5; those compounds having one hydroxyl group in Y ¹ have an additional center of asymmetry. Such alcohols therefore exist in four isomeric forms; these can be separated by thin layer chromatography or high performance liquid chromatography into two diastereomeric forms, each consisting of a racemic mixture of two isomers. During the separation of diastereomers, one of the diastereomers is converted into a mixture of 4 isomers by treatment with a base such as an alkali metal hydroxide, and this mixture is again separated into the two diastereomeric forms. By repeating this method, one epimer can be converted to another; this may be desirable in cases where one of the diastereomers exhibits more favorable biological activity than the other.

The corresponding alcohols of formula (III) also exist in four isomeric forms. If desired, they can also be separated into two epimeric forms and then cyclized to the corresponding compound of formula (I) to obtain the desired shape while retaining the stereochemical configuration.

Of course, for all the chemical processes described above, it will be appreciated that the choice of appropriate reactants will also depend on the functional groups present in the compound being processed; if necessary, reagents of sufficient selectivity should be selected for each process.

The hydantoin derivatives of formula (I) have valuable pharmacological properties similar to those of natural prostaglandins, i.e., these hydantoin derivatives either mimic or antagonize the biological activity of the Α-, B-, C-, D-, E- and F-series prostaglandins. effects. For example, it has been observed that hydantoin derivatives of formula I exhibit an inhibitory effect on prostaglandin-E1 blood cell aggregation and antagonize prostaglandin-E2 or -F4 from rat stomach or colon, chicken rectum, or guinea-pig trachea. effect. Generally, it has been found that higher doses of the new hydantoin derivatives are used

At 183,046, antagonizing effects are more likely to prevail. The pharmacological profile of the novel compounds, which is the degree of mimetic or antagonizing activity relative to the action of natural prostaglandins, also depends on the unique nature of each hydantoin derivative.

The novel hydantoin derivatives of formula I, due to their pharmacological properties related to natural prostaglandins, may be useful in pharmacological characterization and differentiation of the biological activity of natural prostaglandins and their receptors. Closer understanding of the physiological role of natural prostaglandins can, of course, also provide valuable insights into research into new and improved therapies of this type.

In addition, the hydantoin derivatives of the formula (I) obtainable by the process of the invention are also valuable drugs. In particular, hydantoin derivatives which have a strong inhibitory effect on blood cell aggregation or which reduce the adhesive properties of blood cells should be highlighted in this regard; these compounds are useful in the treatment or prevention of thromboses in humans and mammals. Thus, such compounds are useful in the treatment or prophylaxis of myocardial infarction and thrombosis, in the treatment of open areas remaining in blood vessels following surgical interventions, and in the treatment of arteriosclerotic complications and atherosclerotic conditions, in the treatment of lipemia and lipid disorders, also in the treatment of clinical conditions associated with hyperlipidemia. Other applications of the novel compounds of the present invention include the addition of these compounds to blood or other fluids used for artificial extracorporeal circulation and perfusion of isolated body parts to prevent coagulation disorders.

A particularly effective inhibition of blood cell aggregation in terms of (I) compounds wherein Z is hydrogen, Z ¹ is an alkylene moiety containing 3-9 carbon atoms carboxy alkylene group, and Z where ^Z is a - (CH2) 2 CHOH-Y ^Z -Y ³

wherein Y ² represents a branched alkylene group containing a tertiary carbon atom adjacent to the carbon atom bearing the hydroxy group and Y ³ has the same meaning as defined in formula (I). Compounds of this group possess particularly preferable activity are those in which Z ¹ represents carboxy-hexyl, Y ³ is C4-7 cycloalkyl.

It has also been found that the novel hydantoin derivatives of formula (I) obtainable by the process of the present invention relax vascular smooth muscle in a manner similar to that of the A and E prostaglandins. Examples of such compounds are 1- (3-hydroxy-4,4-dimethyloctyl) -5- (6-carboxyhexyl) hydantoin and 1- (3-hydroxy-4,4-dimethyl-5-phenyl). pentyl) -5- (6-carboxyhexyl) hydantoin. Compounds that relax vascular smooth muscles also have vasodilator activity and thus have antihypertensive activity, and are therefore useful in the treatment of hypertension in humans and mammals. These compounds can be used for this purpose alone or in combination with β-adrenoreceptor blocking agents or other antihypertensive agents for the treatment of all types of hypertension such as essential, malignant and secondary hypertension.

1- (3-Hydroxy-4,4-dimethyl-octyl) -5- (6-carboxy-hexyl) -hydantoin also has the anti-histamine-induced bronchoconstriction effect of prostaglandin-ee, such as hydantoin of formula (I). derivatives having this property may also be used in the treatment or prevention of bronchial asthma and bronchitis due to their anti-bronchoconstrictive effects.

The hydantoin derivatives of formula (I), such as 1- (3-hydroxyoctyl) -5- (6-carboxyhexyl) -hydrin, 1- (3-oxooctyl) -3 - methyl-5- (6-carboxy-hexyl) -hydantoin, 1- (3-oxo-octyl) -5- (6-carboxy-hexyl) -hydantoin and 1- (4-phenoxy-butyl) -5- ( 6-Carboxyhexyl) hydantoin, which inhibit pentagastrin-induced gastric acid secretion and reduce the formation of aspirin-induced gastric lesions in rats, can be used to reduce excessive gastric secretion, prevent or reduce the incidence of gastric whether it be spontaneous ulcers or ulcers as a component of polyglandular adenoma syndromes.

Administration of certain hydantoin of formula I, such as 1- (3-hydroxyoctyl) -5- (6-carboxyhexyl) -hydantoin, by intravenous infusion in dogs, has been shown to increase the volume of urine, that these compounds are potent diuretic agents which may be used in the treatment of edema such as cardiac insufficiency, edema of the liver or kidney in humans or mammals.

The hydantoin derivatives of formula (I), which also exhibit prostaglandin-E2 and -F2 * activity on uterine smooth muscle fibers, may also be used as contraceptives or abortions.

The amount of the compounds of formula (I) obtainable by the process of the present invention will, of course, depend on various factors such as the particular nature of each compound, the desired mode of action, the mode of administration and the individual characteristics of the subject or animal. Generally, however, the daily dose of the compounds may be between 1 mg and 20 mg per kg of body weight. For example, the dose to be used for intravenous administration is between 5 mg and 1 mg / kg; this amount is conveniently infused at a rate of 0.01 to 50 / kg / kg / minute. Infusion fluids suitable for this purpose may contain the active ingredient in a concentration of 0.001100 µg / ml, preferably 0.01-10 mg / ml. Each dosage unit contains 10 mg and 100 mg of the active ingredient of the formula I

They may contain from about 183,046 to, for example, ampoules for injection, containing from 0.01 to 1 mg, and oral dosage units, such as tablets or capsules, containing from 0.1 to 50 mg, in particular 2 to 20 mg, of active ingredient.

When the compound of formula (I) is used to inhibit blood cell aggregation, it may generally be desirable to have an active agent concentration of about 1 µg to 10 mg, preferably in the blood or perfusion fluid of the subject or animal being treated, preferably Between 10 μg and 1 mg.

The above dosage data given refer to acids, amides, esters, alcohols and tetrazoles of formula I; when the compounds are used in the form of a salt, the anion present in the salt should also be taken into account in determining the dosage.

The hydantoin derivatives used for the treatment and prevention of the above-mentioned pathological conditions can be used for the said purposes in the form of the pure compound, however, it is generally preferred to use these active compounds in the form of the usual pharmaceutical compositions. These pharmaceutical compositions employ pharmaceutically acceptable carriers, which means that the carrier must be compatible with the active ingredient and other ingredients of the composition and must not deleteriously affect the recipient or the animal. The carrier may be solid or liquid; each dosage unit, such as tablets, may contain from 0.05% to 95% by weight of the hydantoin derivative of the Formula I, with the active ingredients mentioned. The compositions may also contain other pharmacologically active compounds. The novel hydantoin derivatives can be used in either the free acid, salt or ester form in these formulations. The preparation of the pharmaceutical compositions may be carried out by methods well known in the art; the essence of these methods is to mix the active ingredient with the other ingredients of the formulation.

Such pharmaceutical compositions may be formulated for oral, rectal, topical (e.g., buccal as sublingual), parenteral (subcutaneous, intramuscular, or intravenous) administration; the most preferred route of administration will also depend upon the nature and severity of the condition to be treated, as well as the nature of the hydantoin derivative of formula (I) optionally employed.

Dosage units for oral formulations may be presented, for example, in the form of tablets, capsules, cachets, or the like; these compositions contain predetermined amounts of the hydantoin derivative of formula (I); or in the form of powders or granules, solutions or suspensions in aqueous or non-aqueous liquids, or in oil-in-water or water-in-oil emulsions. All of these compositions may be prepared by any of the methods conventionally used in the art of pharmacy; an essential feature of each process is that the hydantione derivative used as the active ingredient is mixed with the vehicle and possibly other excipients. Generally, the hydantoin derivative is mixed uniformly and intimately with the liquid or finely divided solid carrier and then brought into the desired shape as needed. For example, tablets are prepared by compressing the hydantoin derivative together with one or more excipients in the form of a powder or particulate mixture to form a suitable formulation. Compression may be carried out in suitable machinery, the hydantoin derivative may be mixed in the form of a free-flowing powder or in granular form, with a binder, a smoothing agent, an inert diluent, a surfactant or a dispersing agent. The tablets may also be made by molding in a suitable device the active ingredient which has been powdered and moistened with an inert liquid diluent.

Tablets or lozenges suitable for buccal (sublingual) administration are prepared with a flavored base, usually sugar, acacia or tragacanth, by mixing with the hydantoin derivatives and shaping them into suitable forms. Alternatively, lozenges may be prepared which contain the hydantoin derivative in an inert base such as gelatin and glycerol or in a mixture of sugar and acacia.

Formulations for parenteral administration are conveniently prepared from a sterile aqueous solution of the hydantoin derivative; these compositions are preferably isotonic with the blood of the subject or animal being treated. Such compositions are preferably administered intravenously, although subcutaneous or intramuscular injection is also possible. Such compositions are conveniently prepared by mixing the hydantoin derivative with water, sterilizing the resulting solution and rendering it isotonic with blood.

For rectal administration, suppositories are conveniently prepared. They are prepared by mixing the hydantoin derivative with one or more conventional solid suppository carriers, such as cocoa butter, and then bringing the mixture into a suitable form.

From the foregoing, it will be appreciated that the present invention includes a number of novel elements, among which:

(a) a process for the preparation of new hydantoin derivatives of formula (I) as defined above;

b) a process for the preparation of pharmaceutical compositions containing the novel compounds of formula I as active ingredients, using pharmaceutically acceptable carriers and / or other pharmaceutical excipients;

c) a method for reducing blood pressure in a human or mammalian animal by administering a non-toxic amount of a novel compound of formula I to produce a hypotensive effect;

d) a method for treating or preventing thrombosis in a human or mammalian animal or tissue thereof by treatment with a non-toxic amount of the hydantoin derivatives of formula I to achieve an antithrombotic effect;

e) a method of dilating blood vessels of a human or mammalian animal by treatment with a non-toxic amount of a hydantoin derivative of the formula I to produce a vasodilating effect;

(f) procedure for stomach injuries in humans and mammals7

183,046 for treating or preventing a medicament by treating with a non-toxic amount of a hydantoin derivative of formula (I) to produce this effect;

g) a method for treating bronchodilation in humans and mammals by administering a hydantoin derivative of formula I to a bronchodilator in a sufficient amount to produce a bronchodilator effect;

h) a method of treating and preventing allergic conditions in humans and mammals by administering therapeutic or prophylactic, non-toxic amounts of hydantoin derivatives of formula I;

(i) a method of inducing abortion in humans and mammals by administering a non-toxic amount of the hydantoin derivatives of formula I to achieve this effect;

j) a method of inhibiting conception in humans and mammals by administering a non-toxic amount of the hydantoin derivatives of formula I to achieve this effect.

In addition to the chemical and pharmaceutical production methods which are the subject of the present invention and which are intended to be protected by the claims, the above list also includes various therapeutic and other uses of the invention; the latter are, of course, not within the scope of the claims.

Among the hydantoin derivatives of the formula I to be prepared according to the invention, the following are particularly preferred:

A compound of formula (X) wherein two of R, R ¹ and R ² are as defined above for Z, Z ¹ and Z ² as defined above for formula (I) and the third represents hydrogen;

2. Compounds of formula (XIV) wherein M represents a group> C = Z ³ ,> CH-CHO or> CH-CH (OG ³ ) ₂ and Z, Z ³ , Z ⁴ and G ³ have the same meanings as As defined in formula (XI) and (XII) respectively;

3. Compounds of Formula XV wherein M ^{1 is} a -Q ¹ substituent or a group -NH-Z ² as defined in Formula VIII, and Z, Z ¹ , Z ² and G ¹ are is as defined in formulas I or VII, except that G ¹ may also represent a hydrogen atom.

Practical embodiments of the process of the invention are illustrated by the following examples, which generally provide compounds of the invention in a yield of 50-70%.

/. Example 1- Preparation of 1- (3-hydroxy-4,4-dimethyl-5-phenylpentyl) -5- (6-carboxyhexyl) hydantoin

A) 2-Amino-nonanedioic acid diethyl ester

16.7 g of acetamidomalonic acid diethyl ester and 16.6 g

Ethyl 7-bromo-heptanoic acid is dissolved in ethanolic sodium ethoxide solution (1.51 g) in metal sodium and 30 ml of absolute ethanol, and the mixture is refluxed for 8 hours. After cooling, the resulting solution is poured into ice water, the product is extracted with ether, the separated ethereal phase is dried and evaporated. The residue was obtained as a pale yellow oil in the form of diethyl acetamido- (6-ethoxycarbonyl-hexyl) -malonic acid; Characteristics of the magnetic resonance spectrum of this compound:

δ = 2.2 (3H, singlet, -COCH3),

4.17 (6H, multiplet, 3X-OCH 2 -CH 3).

The amide obtained above was refluxed with 111 ml of concentrated hydrochloric acid for 5.5 hours, and after cooling, the resulting solution was washed with ether, the aqueous phase was separated, purified by charcoal and evaporated to dryness in vacuo. The resulting colorless glass was dissolved in the minimum amount of absolute ethanol required and added dropwise to a stirred mixture of 125 ml of absolute ethanol and 15.7 g of thionyl chloride cooled to -10 ° C. The resulting solution was then allowed to stand at room temperature for 1 hour, then refluxed for 1.5 hours, cooled, poured into ice water, and the pH of the aqueous mixture was adjusted to 9 with aqueous sodium hydroxide solution. This mixture is extracted with ether, the separated ethereal phase is dried, evaporated and the residue is distilled under reduced pressure. This gives the 2-amino nonanedioic acid diethyl ester (55%) as a colorless oil, boiling at 114-115 ° C at 0.02-0.03 mmHg.

B) 2 - [(3-Oxo-4,4-dimethyl-5-phenyl-pentyl) -amino] -nonanedioic acid diethyl ester

5.19 g of 2-amino nonanedioic acid diethyl ester are added dropwise under cooling and stirring to 3.95 g

4,4-dimethyl-5-phenyl-pent-l-en-3-one. This mixture was allowed to stand at room temperature for 21 hours to give 2 - [(3-oxo-4,4-dimethyl-5-phenylpentyl) amino] nonanedioic acid diethyl ester.

C) Diethyl ester of 2 - [(3-hydroxy-4,4-dimethyl-5-phenylpentyl) amino] nonanedioic acid

The oxo compound (5.1 g) obtained as described in the previous section was dissolved in crude ethanol (70 ml) without further purification, and 380 mg of sodium borohydride was added gradually with stirring in an ice bath. The resulting solution was stirred in the ice bath for an additional 10 minutes and then allowed to stand at room temperature for 5 hours. Most of the ethanol is evaporated, water is added to the residue and the resulting solution is acidified to pH 6. The precipitated oily product is extracted with ether and the ether phase is separated off, dried and evaporated. The residue was 2 - [(3-hydroxy-4,4-dimethyl-5-phenylpentyl) amino] nonanedioic acid diethyl ester as a pale yellow oil. This compound was used in the next step without further purification.

D) 1- (3-Hydroxy-4,4-dimethyl-5-phenylpentyl) -5- (6-ethoxycarbonylhexyl) hydantoin and the corresponding free carboxylic acid

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8.45 g of the 3-hydroxy compound obtained above

A solution of 3.05 g of potassium cyanate in 5.6 ml of water is added dropwise in a mixture of 37.6 ml of ethanol and 18.8 ml of 2N hydrochloric acid solution in an ice bath. After allowing the mixture to stand at room temperature for 18 hours, the ethanol was evaporated, water was added to the residue and the precipitated oily product was extracted with ether. The ether layer was separated, dried and evaporated; The residue was a viscous oil which was heated on a water bath for 6 hours to give 1- (3-hydroxy-4,4-dimethyl-5-phenylpentyl) -5- (6-ethoxycarbonyl) as a pale yellow viscous oil. - hexyl) hydantoin.

To the ester obtained above was added a mixture of 25 ml of 2N sodium 15-hydroxide solution and 60 ml of water and the resulting cloudy solution was allowed to stand at room temperature for 2 hours. The solution is then washed with ether and the now clear aqueous alkaline solution is acidified with 2N hydrochloric acid. The precipitated oily product was extracted with 20 ether. The ether layer was separated, dried and evaporated; 6.8 g of a viscous oil are obtained. This oily product is chromatographed on a silica gel column to give 1- (3-hydroxy-4,4-25-dimethyl-5-phenylpentyl) -5- (6-carboxyhexyl) hydantoin as a colorless viscous oil. which solidifies on standing and melts at about 115 ° C after shrinking at a temperature of about 90 ° C. This product is a mixture of diastereomeric forms; recrystallization from a mixture of ethyl acetate and light naphtha in the boiling range of 60-80 [deg.] C. yields one of the diastereomers in the form of tiny needle crystals, m.p. 135-137 [deg.] C.

Example 2 Preparation of 1- (3-hydroxyoctyl) -5- (6-carboxyhexyl) hydantoin

A) 2- [3- (Tetrahydropyran-2-yloxy) -octylamino] -nonanedioic acid diethyl ester

To a solution of 19.15 g of acrolein in 100 ml of ether and cooled to -25 ° C are added dropwise a solution of 200 ml of ether and 26.8 g of hydrobromic acid in anhydrous ethereal hydrobromide at 0 ° C. The mixture was stirred at -25 ° C for 1 hour with further stirring, then allowed to warm to 0 ° C, stirred at this temperature for an additional 1 hour, then added dropwise from 54 g of 1-bromopentane, 8.8 g. g of a solution of pentylmagnesium bromide in ether (120 g) and ether (120 ml) while refluxing. The reaction mixture was quenched by the addition of a saturated aqueous ammonium chloride solution, extracted with ether, the ether phase separated, dried, evaporated and the residue was distilled under reduced pressure. This gives go l-bromo-3-hydroxyoctane in the form of a colorless oily product at 0.08 mmHg

68.5-72.5 ° C.

20.9 g of the 1-bromo-3-hydroxyoctane obtained above are dissolved in 17.0 g of dihydropyran.

A solution of p-toluenesulfonic acid (500 mg) in a small amount of ether was added and the mixture was allowed to stand at room temperature for 18 hours and then washed with aqueous sodium bicarbonate. The organic solvent layer was separated, percolated over silica gel in ether / hexane (1: 9) and evaporated in vacuo. The residue was 1-bromo-3- (tetrahydropyran-2-yloxy) octane as a colorless oil. Characteristic data for the nuclear magnetic resonance spectrum of this compound;

δ = 0.88 (3H, triplet, -CH 3),

4.62 (1H, broad, -O-CHR-O-).

15.0 g of the tetrahydropyranyl intermediate obtained above are added to reflux for 18 hours with 13.0 g of 2-amino nonanedioic acid diethyl ester in 100 ml of absolute ethanol. The ethanol was then evaporated in vacuo and to the residue was added water containing a slight excess of sodium carbonate, the mixture was extracted with dichloromethane, the dichloromethane phase was separated, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography (hexane: ether = 1: 4). This gives 2- [3- (tetrahydropyran-2-yloxy) -octylamino] -no-nandioic acid diethyl ester as a colorless viscous oil; Characteristics of the magnetic resonance spectrum of this compound:

δ = 0.88 (3H, triplet, -CH ₃ ),

2.28 (2H, triplet, -CH2-COO-C2H5), 2.61 (2H, m, _CH2 -N <),

3.20 (IH, t,> N-CHR-COO-C ₂ H _5), 4.13 (4H, multiplet, _{2x-O-CHI-CH3),} 4.60 (IH, br, O CHR-O-).

The above amino diester can also be prepared in the following manner:

10.40 g of 2-amino-nonanedioic acid diethyl ester and 5.04 g of oct-1-en-3-one are slowly stirred at 0 [deg.] C. and the resulting mixture is allowed to stand at room temperature for 3 hours. This gives 2- (3-oxooctylamino) nonanedioic acid diethyl ester as a colorless oil; characteristic values of the magnetic resonance spectrum of this compound;

δ = 2.3 (4H, multiplet, -CH 2 -COO-C ₂ H 5 and> n-ch ₂ -ch ₂ -co-),

3.16 (1H, triplet, C ₂ H ₅ -OOC-CHR-N <),

4.11 (2H, quadruple, -O-CH ₂ -CH ₃ ),

4.17 (2H, quadruple, -O-CH ₂ -CH ₃ ).

13.5 g of the oxo compound obtained above are dissolved in 140 ml of absolute ethanol and a solution of 665 mg of sodium borohydride in 70 ml of absolute ethanol is added dropwise at 0 DEG C. with stirring, and the mixture is allowed to stand at room temperature for 3.5 hours. and then concentrated in vacuo at 40 ° C. The residue was dissolved in water, adjusted to pH 5 with n hydrochloric acid, extracted well with chloroform, washed with chloroform, dried and evaporated.

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2- (3-hydroxyoctylamino) -nonanedioic acid diethyl ester is obtained as a colorless oil.

The resulting ester is dissolved without further purification in 14.0 ml of dihydropyran, 10 ml of ether are added, and 6.72 g of p-toluenesulfonic acid are added portionwise and the mixture is allowed to stand at room temperature for 18 hours. The reaction mixture was diluted with ether with aqueous sodium carbonate solution, washed with water, dried and evaporated. The residue was purified by silica gel column chromatography (hexane: ether = 1: 4). This gives 2- [3- (tetrahydropyran-2-yloxy) -octylamino] -nonanedioic acid diethyl ester having a nuclear magnetic resonance spectrum, an infrared spectrum and a thin layer chromatogram corresponding to the product obtained by the procedure described in the preceding paragraph.

Β) 1- [3- (Tetrahydropyran-2-yloxy) -octyl] -5- (6-carboxy-hexyl) -hydantoin

7.8 g of 2- [3- (tetrahydropyran-2-yloxy) octylamino] -nonanedioic acid diethyl ester are dissolved in 32 ml of ethanol and to this solution are added 3.0 g of potassium cyanate in 6 ml of water. The resulting suspension was stirred under cooling and 16.7 mL of 2N hydrochloric acid was added gradually. After allowing the mixture to stand at room temperature for 22 hours, most of the ethanol was evaporated, water was added to the residue and the resulting oily product was extracted with ether. The separated ethereal layer was washed with water, dried over anhydrous magnesium sulfate and evaporated. The residue was obtained as a yellow oil (8.0 g) which was dissolved in light petroleum (b.p. 60-80 ° C) and refluxed for 4 hours. The solution was evaporated to dryness and the resulting oily product was heated on a water bath for 2 hours. 7.3 g of 1- [3- (tetrahydropyran-2-yloxy) octyl] -5- (6-ethoxycarbonylhexyl) hydantoin are obtained in the form of a yellow oil which is used without further purification.

6.2 g of the ester obtained above are dissolved in 80 ml of 0.5 N sodium hydroxide solution and allowed to stand at room temperature for 2.5 hours. The aqueous solution was then washed with ether and the separated aqueous layer was acidified with 2N hydrochloric acid and the resulting oily product was extracted with ether. The ether phase is washed, dried and evaporated. 1- [3- (Tetrahydropyran-2-yloxy) -octyl] -5- (6-carboxy-hexyl) -hydantoin is obtained in the form of a yellow oil.

C) 1- (3-Hydroxyoctyl) -5- (6-carboxyhexyl) hydantoin

3.55 g of 1- [3- (tetrahydro-pyran-2-yloxy) -octyl] -5- (6-carboxy-hexyl) -hydantoin, prepared as described in the previous section, are 28 ml of tetrahydrofuran and 7 ml of 5 The mixture was dissolved in a mixture of hydrochloric acid and the solution was allowed to stand at room temperature for 3.5 hours and then refluxed for 30 minutes. Most of the solvent was evaporated, water was added to the residue and the resulting oily product was extracted with ether. The ether layer was separated, washed with water, dried over anhydrous magnesium sulfate and evaporated. 3.15 g of a yellow viscous oil are obtained. This was purified by column chromatography on silica gel, eluting with chloroform followed by 19: 1 chloroform: methanol. 1- (3-hydroxyoctyl) -5- (6-carboxyhexyl) hydantoin is obtained in the form of an almost colorless, highly viscous oil-like product; characteristic values for the magnetic resonance spectrum of this compound:

δ = 0.89 (3H, triplet, -CH ₃ ),

2.34 (2H, triplet, -CH _Z COOH)

2.9-4.2 (4H, complex,

-ch ₂ -n <,> ch-n <,> CH-OH),

Around 5.6 (2H, wide, removable, «

-COOH, -OH),

About 9.0 (1H, broad, interchangeable, -NH-).

The above hydantoin derivative may also be prepared via the corresponding 2 - [(3-hydroxyoctyl) amino] nonanedioic acid diester via the procedure described in Example 1.

D) Separation of diastereomers

The hydantoin derivative obtained by the procedure described in the Examples above is a viscous oil; this product was separated by chromatography on a silica gel column with 97: 2.5: 0.5 chloroform: methanol: acetic acid to give two diastereomeric compounds. Both diastereomers form tiny colorless needle crystals; m.p. 76-78 ° C and 63-65 ° C, respectively.

The same diastereomeric compounds are obtained by cyclizing the two diastereomeric forms of the corresponding starting compound (III) separately.

This can be accomplished by dissolving the 2 - [(3-hydroxyoctyl) amino] nonanedioic acid diethyl ester obtained as a mixture of the two diastereomeric forms in the same manner as in Example 1 and adding ethereal hydrogen chloride solution. The resulting solution was evaporated to dryness to give a mixture of diastereomeric hydrochlorides as a partially solidifying viscous oil on standing. To this is added ether, cooled and stirred to give a crystalline solid, which is collected, washed with food and dried. The resulting solid product was recrystallized from ethyl acetate to give pure hydrochloride, m.p. 95-96.5 ° C, as tiny colorless plate crystals. The hydrochloride obtained is suspended in dilute aqueous sodium hydroxide solution, the suspension is shaken with ether and the separated ethereal solution is washed with water, dried and evaporated to give 2 - [(3-hydroxyoctyl) amino] as a colorless oil. one of the diastereomers (A) of the nonanedioic acid - diethyl ether space.

After the first isolation of the solid hydrochloride described above, the remaining ethereal filtrate was evaporated; converting the resulting oily hydrochloride to the free base as described above to give the diastereomer (2) of 2 - [(3-hydroxyoctyl) amino] -nonanedioic acid diethyl ester in almost pure state as a colorless oil.

The diastereomer (A) thus obtained was prepared according to the procedure described in Example 1 for 1- (3-hydroxyoctyl) -5- (6-101).

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-carboxyhexyl) -hydantoin, which is crystallized from a mixture of ethyl acetate and light naphtha boiling at 60-80 ° C to give tiny colorless needles, m.p. 63-65 ° C.

Similarly, the above diastereomer (B) is converted to another diastereomer of 1- (3-hydroxyoctyl) -5- (6-carboxyhexyl) -hydantoin, which is a mixture of ethyl acetate and light petroleum boiling range 60-80 ° C. crystallized to form tiny colorless needles, m.p. 76-78 ° C.

E) Conversion of diastereomers

100 mg of the dasterereomer of 1- (3-hydroxyoctyl) -5- (6-carboxyhexyl) hydantoin, m.p. 76-78 ° C, were dissolved in 3 ml of sodium hydroxide solution and the resulting solution was stirred at room temperature for 19 hours. leave for an hour. The solution is then acidified, extracted with ether, the ether phase is separated off, washed with water, dried and evaporated. The residue was obtained as a viscous oil, which was separated into two diastereomers of 1- (3-hydroxyoctyl) -5- (6-carboxyhexyl) hydantoin by high performance liquid chromatography; the diastereomer of m.p. 76-78 DEG C. (about 40 mg) is the same as the starting material and the diastereomer of m.p. 63-65 DEG C. (about 40 mg) is the same as the diastereomer (A) described above.

Similarly, diastereomer (A) of m.p. 63-65 ° C is converted to a diastereomeric mixture of the diastereomers (A) and (B) of this compound, from which the same starting material is separated by high performance liquid chromatography (6365 ° C). temperature melting diastereomer A and the pure diastereomer B melting at 76-78 ° C.

3-26. example

Using the reaction sequence described in Example 1, using the appropriate vinyl ketones as starting materials, the following 3a-26a oxo compounds are prepared:

3a 2 - [(3-oxopentyl) amino] -nonanedioic acid diethyl ester,

4a 2 - [(3-oxo-4,4-dimethylpentyl) amino] -nonanedioic acid diethyl ester,

5a 2 - [(3-oxo-4-methylpentyl) amino] nonanedioic acid diethyl ester,

6a 2 - [(3-oxo-nonyl) -amino] -nonanedioic acid diethyl ester,

7a 2 - [(3-O-4-methyloctyl) amino] nonanedioic acid diethyl ester,

8a 2 - [(3-oxo-decyl) -amino] -nonanedioic acid diethyl ester,

9a 2 - [(3-oxo-4,4-dimethyl-octyl) -amino] -nonanedioic acid diethyl ester,

10a 2 - [(3-oxo-4-ethylhexyl) amino] -nonanedioic acid diethyl ester, 1α 2 - [(3-cyclobutyl-3-oxo-propyl) -amino] -nonanedioic acid ^; ester,

12a 2 - [(3-Cyclopentyl-3-oxopropyl) amino] nonanedioic acid diethyl ester,

13a 2 - {[3-Oxo-4,4-dimethyl-5- (3-trifluoromethyl) -phenyl-pentyl] -amino} -nonanedioic acid diethyl ester,

14a 2 - [(3-Cyclohexyl-3-oxo-propyl) -amino] -nonanedioic acid diethyl ester,

15a 2 - [(3-Cycloheptyl-3-oxo-propyl) -amino] -nonanedioic acid diethyl ester,

16a 2 - [(3-Oxo-3-phenyl-propyl) -amino] -nonanedioic acid diethyl ester,

17a 2 - [(3-oxo-4-phenyl-butyl) -amino] -nonanedioic acid diethyl ester,

18a 2 - [(3-oxooctyl) amino] -undecanedioic acid diethyl ester,

19a 2 - [(3-oxooctyl) amino] -3- [3- (ethoxycarbonylmethoxy) phenyl] propionic acid ethyl ester,

20a ethyl 2 - [(3-oxo-4,4-dimethylpentyl) amino] -3- [3- (ethoxycarbonylmethoxy) phenyl] propionic acid,

21a 2 - [(3-oxooctyl) amino] -3- [3- (2-ethoxycarbonylethyl) phenyl] propionic acid ethyl ester,

22a 2 - [(3-Cyclobutyl-3-oxopropyl) amino] -3- [3- (2-ethoxycarbonylethyl) phenyl] propionic acid ethyl ester,

23a 2 - [(3-Cyclopentyl-3-oxopropyl) amino] -3- [3- (2-ethoxycarbonylethyl) phenyl] propionic acid ethyl ester,

24a 2 - [(3-Cyclohexyl-3-oxo-propyl) -amino] -3- [3- (2-ethoxycarbonyl-ethyl) -phenyl] -propionic acid ethyl ester,

25a 2 - [(3-oxooctyl) amino] -7-oxa-nonanedioic acid diethyl ester,

26a 2 - [(3-Cyclopentyl-3-oxo-propyl) -amino] -7-oxa-nonanedioic acid diethyl ester;

these oxo compounds are then converted to the 3b-26b hydroxy compounds in the same manner as in the preceding examples:

3b 2 - [(3-hydroxypentyl) amino] nonanedioic acid diethyl ester,

4b 2 - [(3-Hydroxy-4,4-dimethyl-pentyl) -amino] -nonanedioic acid diethyl ester,

5b 2 - [(3-hydroxy-4-methylpentyl) amino] -nonanedioic acid diethyl ester,

6b 2 - [(3-Hydroxy-nonyl) -amino] -nonanedioic acid diethyl ester,

7b 2 - [(3-Hydroxy-4-methyl-octyl) -amino] -nonanedioic acid diethyl ester,

8b 2 - [(3-Hydroxy-decyl) -amino] -nonanedioic acid diethyl ester,

9b 2 - [(3-Hydroxy-4,4-dimethyl-octyl) -amino] -nonanedioic acid diethyl ester,

10b 2 - [(3-hydroxy-4-ethylhexyl) amino] -nonanedioic acid diethyl ester, 1b 2 - [(3-cyclobutyl-3-hydroxypropyl) amino] -nonanedioic acid diethyl ester,

12b 2 - [(3-cyclopentyl-3-hydroxypropyl) amino] -nonanedioic acid diethyl ester,

13b 2 - {[3-Hydroxy-4,4-dimethyl-5- (3-trifluoromethyl-phenyl) -pentyl] -amino} -nonanedioic acid diethyl ester,

14b 2 - [(3-Cyclohexyl-3-hydroxypropyl) amino] nonanedioic acid diethyl ester,

15b 2 - [(3-Cycloheptyl-3-hydroxypropyl) amino] -nonanedioic acid diethyl ester,

16b 2 - [(3-Hydroxy-3-phenylpropyl) amino] -nonanedioic acid diethyl ester,

-11I

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17b 2 - [(3-Hydroxy-4-phenyl-butyl) -amino] -nonanedioic acid diethyl ester,

18b 2 - [(3-Hydroxyoctyl) amino] -undecandioic acid diethyl ester,

19b 2 - [(3-Hydroxyoctyl) amino] -3- [3- (ethoxycarbonylmethoxy) phenyl] propionic acid ethyl ester,

ZOb 2 - [(3-hydroxy-4,4-dimethylpentyl) amino] -3- [3- (ethoxycarbonylmethoxy) phenyl] propionic acid ethyl ester,

21b 2 - [(3-Hydroxyoctyl) amino] -3- [3- (2-ethoxycarbonylethyl) phenyl] propionic acid ethyl ester,

22b 2 - [(3-Cyclobutyl-3-hydroxypropyl) amino] -3- [3- (2-ethoxycarbonylethyl) phenyl] propionic acid ethyl ester,

23b 2 - [(3-Cyclopentyl-3-hydroxypropyl) amino] -3- [3- (2-ethoxycarbonylethyl) phenyl] propionic acid ethyl ester,

24b 2- [3-Cyclohexyl-3-hydroxypropyl) amino] -3- [3- (2-ethoxycarbonylethyl) phenyl] propionic acid ethyl ester,

25b 2 - [(3-hydroxy-octyl) -amino] -7-oxa-nonanedioic acid diethyl ester,

26b 2 - [(3-Cyclopentyl-3-hydroxy-propyl) -amino] -7-oxa-nonanedioic acid diethyl ester;

from the above compounds, the hydantoin derivatives of formula (I) listed below are also prepared according to the procedure described in the previous examples; of which, for which the melting point of each diastereomer is also given, was separated by high performance liquid chromatography into two diastereomeric forms:

3c 5- (6-Carboxylhexyl) -1- (3-hydroxypentyl) hydantoin, colorless oil, m.p. 7173 ° C and 56-58 ° C,

4c 5- (6-carboxylhexyl) -1- (3-hydroxy-4,4-dimethylpentyl) hydantoin, m.p. 114-115 ° C and 144146 ° C,

5c 5- (6-Carboxyhexyl) -1- (3-hydroxy-4-methylpentyl) hydantoin, m.p. 70-80 ° C, diastereomers m.p. 73-76 ° C and 110-111 ° C,

6c 5- (6-carboxy-hexyl) -1 - (3-hydroxy-nonyl) hydantoin, viscous oil, Rf 0.5 _(SiO2, 9: 1, 71 ° C and 79-81 ° C,

7c 5- (6-carboxy-hexyl) -1 - (3-hydroxy-4-methyl-octyl) hydantoin, viscous oil, Rf 0.5 _(SiO2, 9: 1 chloroform: methanol mixture),

8c 5- (6-Carboxy-hexyl) -1- (3-hydroxy-decyl) -hydantoin, a viscous oil, m.p. 6870 ° C and 82-83 ° C,

9c 5- (6-Carboxyhexyl) -1- (3-hydroxy-4,4-dimethyloctyl) hydantoin, colorless crystals, m.p. 90-98 ° C, diastereomers m.p. 77 ° C and 103-104 ° C,

10c 5- (6-Carboxyhexyl) -1- (3-hydroxy-4-ethylhexyl) hydantoin, m.p. 70-80 ° C, m.p. 8284 ° C and 120-122 ° C 5- (6-carboxyhexyl) -1- (3-cyclobutyl-3-hydroxypropyl) -hydantoin, m.p. 114-116 ° C and 103105 ° C.

12c 5- (6-Carboxyhexyl) -1- (3-cyclopentyl-3-hydroxypropyl) -hydantoin, m.p. 116-117 ° C and 9799 ° C,

13c 5- (6-Carboxy-hexyl) -1- [3-hydroxy-4,4-dimethyl-5- (m-trifluoromethyl-phenyl) -pentyl] -hydantoin, m.p. 118-120 ° C and 145147 ° C,

14c 5- (6-Carboxyhexyl) -1- (3-cyclohexyl-3-hydroxypropyl) hydantoin, m.p. 96-98 ° C and 124126 ° C,

15c 5- (6-Carboxyhexyl) -1- (3-cycloheptyl-3-hydroxypropyl) hydantoin>

op. 70-76 ° C, diastereomers m.p.

107-109 ° C and 107-109 ° C,

16c 5- (6-Carboxyhexyl) -1- (3-hydroxy-3-phenylpropyl) hydantoin, m.p. 72-74 ° C and 67-70 ° C,

17c 5- (6-Carboxyhexyl) -1- (3-hydroxy-4-phenylbutyl) hydantoin, m.p. 102-104 ° C and 6163 ° C,

18c 5- (8-Carboxyoctyl) -1- (3-hydroxyoctyl) hydantoin, m.p. 57-60 ° C and 69-71 ° C,

19c 5- (3-Carboxymethoxybenzyl) -1- (3-hydroxyoctyl) hydantoin, colorless glass; hf = 0.36 (SiO2;

90: 5: 5 chloroform-methanol-acetic acid),

20c 5- (3-Carboxymethoxybenzyl) -1- (3-hydroxy-4,4-dimethylpentyl) hydantoin, m.p. 100-103 DEG C. and 151-154 DEG C. for the corresponding ethyl ester.

21c 5- [3- (2-Carboxyethyl) -benzyl] -1- (3-hydroxyoctyl) -hydantoin, m.p. 82-86 ° C and 9597 ° C,

22c 5- [3- (2-Carboxyethyl) -benzyl] -1- (3-cyclobutyl-3-hydroxypropyl) -hydantoin, m.p. 118-121 ° C, one diastereomer,

23c 5- [3- (2-Carboxyethyl) -benzyl] -1- (3-cyclopentyl-3-hydroxypropyl) -hydantoin, m.p. 140-143 ° C, one diastereomer,

24c 5- [3- (2-Carboxyethyl) benzyl] -1- (3-cyclohexyl-3-hydroxypropyl) hydantoin, m.p. 146-148 ° C and 156.5157 ° C for diastereomers .

25c 5- (4-Carboxymethoxy-butyl) -1- (3-hydroxy-octyl) -hydantoin, diastereomers; 79-81 ° C and colorless glass: hf = 0.31 (SiO ₂ ; 90: 5: 5 chloroform: methanol: acetic acid);

6c 5- (4-Carboxymethoxybutyl) -1- (3-cyclopentyl-3-hydroxypropyl) -hydantoin, m.p. 107-108 ° C, one diastereomer.

All of the compounds 3c-26c listed above are

In a manner similar to that described in detail in Example 1, through the appropriate ethyl ester, the ethyl moieties are then

-121

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Example 1 was prepared by the alkaline hydrolysis described in Section D).

The starting compounds used in the procedure described in the Examples above were prepared as follows:

A) Starting material of Example 18

The 2-aminodecandioic acid diethyl ester was boiled at 160 ° C under 0.1 mm Hg using the procedure described in Example 1 (A). This compound was used as starting material in Example 18.

B) Preparation of ethyl 2-amino-3- [3- (ethoxycarbonylmethoxy) phenyl] propionic acid

2.60 g of acetamidomalonic acid diethyl ester and 2.39 g of 3-chloromethylphenoxyacetic acid ethyl ester, the latter compound being Robertson, J. Chem. Soc. 1933, 492; No. 3,933,895 Prepared according to U.S. Pat. No. 4: dissolved in a solution of 230 mg of sodium metal in 10 ml of absolute ethanol in ethanolic sodium ethoxide and heated under reflux for 19 hours. After cooling, the reaction mixture is poured into ice water, the product obtained is extracted with ether, the ether phase is separated off, dried and evaporated. The resulting resin-like product was crystallized from ether / hexane. This gives the acetamido- [3- (ethoxycarbonylmethoxy) phenyl] malonic acid diethyl ester as white prismic crystals, m.p. 98.5-101.5 ° C.

The malonate derivative (1.90 g) obtained above was refluxed with aqueous 10% hydrochloric acid (25 ml) for 3.5 hours, and the resulting solution was cooled to dryness in vacuo. The residual white solid was dissolved in the minimum amount of absolute ethanol needed and added dropwise to a stirred mixture of 1.64 g of thionyl chloride and 15 ml of absolute ethanol at -10 ° C. The resulting solution was allowed to stand at room temperature for 18 hours, then refluxed for 1 hour, then cooled, poured into ice water and adjusted to pH 9-10 with aqueous sodium hydroxide. The thus-basified mixture was extracted with ether, and the separated ethereal extract was concentrated to give 2-amino-3- [3- (ethoxycarbonylmethoxy) phenyl] propionic acid ethyl ester as a colorless oil which was used without further purification. as starting material in the procedure of Examples 19 and 20.

C) Preparation of 2-amino-3- [3- (2-ethoxycarbonylethyl) phenyl] propionic acid ethyl ester

A solution of 4.04 g of diisopropylamine and 25 ml of a solution of 1.60 molar butyl lithium in hexane in 40.0 ml of anhydrous tetrahydrofuran is stirred at -78 ° C under a dry nitrogen atmosphere and 4.64 g of tert-butyl is added portionwise over 5 minutes. acetate. A solution of 11.60 g of α, α'-dibromo-m-xylene and 1.42 g of anhydrous hexamethylphosphoric amide in 8.0 ml of anhydrous tetrahydrofuran is then added to the resulting solution. The resulting mixture was stirred at -78 ° C for half an hour and then allowed to warm to room temperature over 3 hours. Ice water was added, the mixture was extracted with ether, and the separated ethereal layer was washed with 60 ml of n hydrochloric acid, water, dried and concentrated in vacuo. The residual yellow oil was chromatographed on a silica gel column, eluting with ether: hexane (1: 1), to give 3- (3-bromomethyl-phenyl) -propionic acid tert-butyl ester as a colorless oil. This product is then converted to the desired diethyl ester as described in the preceding paragraph, which is prepared as described in Examples 21-24. The starting material was used in the procedure described in Example 1B.

D) Preparation of 2-amino-7-oxa-nonanedioic acid diethyl ester

Diethyl 2-amino-7-oxa-nonanedioic acid from ethyl 4-bromobutoxy-acetic acid - cf. Merck, No. 2,354,085. Federal Patent Application Publication of the Federal Republic of Germany - prepared above

The reaction sequence described in Section B). The resulting 2-amino-7-oxa-nonanedioic acid diethyl ester is a colorless oil which boils at 120-121 ° C (0.005 mm Hg). This compound was used as starting material in Examples 25 and 26.

Example 27 Preparation of 1- (5-phenylpentyl) -5- (6-carboxyhexyl) hydantoin

A mixture of 25.9 g of 2-amino nonanedioic acid diethyl ester and 22.7 g of 5-phenylpentyl bromide was stirred in a 100 ° C bath for 3 hours. After cooling, ether (100 mL) was added and the mixture was allowed to stand at 0 ° C for 2 hours. The precipitated colorless white crystalline product is isolated and dried. 21.95 g of 2 - [(5-phenylpentyl) amino] nonanedioic acid diethyl ester hydrobromide are obtained, m.p. 70-72 ° C.

Dissolve 4.86 g of the hydrobromide obtained above in a mixture of 20 ml of ethanol and 5 ml of 2N hydrochloric acid, cool the ice and add a solution of 1.62 g of potassium cyanate in 5 ml of water with stirring. The resulting solution was allowed to stand at room temperature for 18 hours. The ethanol was evaporated, water was added to the residue, the oily product was extracted with ether, the ether layer was separated, dried and evaporated. The resulting pale yellow oil was heated in a water bath for 6 hours. 1- (5-Phenyl-pentyl) -5- (6-ethoxycarbonyl-hexyl) -hydantoin is obtained.

The ester obtained above (4.0 g) was hydrolyzed with dilute aqueous sodium hydroxide as described in the preceding examples and the product obtained was purified by chromatography on a silica gel column. This gives 1- (5-phenylpentyl) -5- (6-carboxyhexyl) hydantoin, m.p. 90-92 ° C, when crystallized from a mixture of ethyl acetate and light petroleum boiling at 60-80 ° C.

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28-34. example

The following 28a-34a compounds are prepared by the reaction sequence described in Example 27 using the appropriate alkyl halides:

28a 2-Octylamino nonanedioic acid diethyl ester,

29a 2- (4-Propoxybutyl) amino nonanedioic acid diethyl ester,

30a 2- (4-phenoxybutyl) amino nonanedioic acid diethyl ester, 2- (4-m-trifluoromethylphenoxybutyl) amino nonanedioic acid diethyl ester,

32a 2- (3-m-Tolyloxypropyl) amino nonanedioic acid diethyl ester,

33a 2- (3-hydroxypropyl) amino nonanedioic acid diethyl ester,

34a 2- (3-Hydroxy-3-methyl-octyl) -amino-nonanedioic acid diethyl ester;

these compounds are then converted to the corresponding hydantoin derivatives 28b-34b as described in Example 27:

28b 5- (6-Eloxycarbonylhexyl) -1-octylhydantoin, m.p. 46-48 ° C.

28b 5- (6-Carboxyhexyl) -1-octylhydantoin, m.p. 88-89 ° C.

29b 5- (6-Carboxy-hexyl) -1- (4-propoxy-butyl) -hydantoin, m.p. 72-74 ° C.

30b 5- (6-Carboxy-hexyl) -1- (4-phenoxy-butyl) -hydantoin, m.p. 88-90 ° C, b 5- (6-carboxy-hexyl) -1- (4-m-) trifluoromethylphenoxybutyl) hydantoin, m.p. 51-54 ° C.

32b 5- (6-Carboxyhexyl) -1- (3-m-tolyloxypropyl) hydantoin, colorless viscous oil; Rf = 0.52 (S102; 9: 1 chloroform: methanol),

33b 5- (6-Carboxyhexyl) -1- (3-hydroxypropyl) hydantoin, m.p. 111-113 ° C.

34b 5- (6-Carboxy-hexyl) -1- (3-hydroxy-3-methyl-octyl) -hydantoin, diastereomers, mp 104-107 ° C and colorless viscous oil; Rf = 0.5 (S102; 90: 5: 5 chloroform: methanol: acetic acid).

Example 35

Preparation of (6-carboxyhexyl) -5-octylhydantoin To a mixture of 70 ml of absolute ethanol and 6 ml of thionyl chloride cooled to -10 ° C is added portionwise 16.0 g of 2-aminodecanoic acid (J. Am. Chem.). . Soc. 65,450, 1946). The resulting solution was allowed to stand at room temperature for 2 hours, then refluxed for 1 hour, then cooled, poured into ice water and the pH of the solution was quenched with aqueous sodium hydroxide solution.

Set to 9. The mixture is extracted with ether, the ether phase is separated off, dried, concentrated and distilled under reduced pressure. The 2-aminodecanoic acid ethyl ester thus obtained in the form of a colorless oil is boiled at 8284 DEG C. under 0.2 mm Hg; yield: 75%.

2 g of ethyl 2-amino-decanoic acid obtained above and 20 g of 7-bromoheptanoic acid ethyl ester are dissolved in 50 ml of absolute ethanol and the solution is refluxed for 24 hours and the ethanol is evaporated from the reaction mixture. Ether was added to the residue, which precipitated a hydrobromide salt, m.p. 98 ° C, dissolved in a little dichloromethane, treated with an equivalent amount of triethylamine, washed thoroughly with water and dried. Evaporation of the solvent gave 2- (6-ethoxycarbonylhexylamino) decanoic acid ethyl ester as a colorless viscous oil, boiling at 142-144 ° C (0.001 mm Hg); yield: 52%.

7.4 g of the ethyl 2- (6-ethoxycarbonylhexylamino) decanoic acid ester thus obtained are reacted with potassium cyanate and hydrochloric acid; This gives 1- (6-ethoxycarbonylhexyl) -5-octylhydantoin as a colorless crystalline product, m.p. 68-70 ° C, when crystallized from light naphtha boiling at 60-80 ° C.

4.0 g of the 1- (6-ethoxycarbonylhexyl) -5-octylhydantoin obtained above are hydrolyzed with sodium hydroxide solution to give 1- (6-carboxhexyl) -5-octylhydantoin which is ethyl acetate. crystallized from acetate and boiling range 6080 ° C to form colorless needle crystals melting at 65-66 ° C.

Example 36 Preparation of 1-octyl-3-methyl-5- (6-carboxyhexyl) hydantoin

742 mg of 2-octylamino nonanedioic acid diethyl ester and 120 mg of methyl isocyanate were dissolved in 7.5 ml of anhydrous ether, allowed to stand at room temperature for 48 hours, and then the ether was evaporated. 800 mg of a pale yellow oil are obtained which is heated on a water bath for 2 hours to give 1-octyl-3-methyl-5- (6-ethoxycarbonyl) hydantoin as a yellow oil.

650 mg of the 1-octyl-3-methyl-5- (6-ethoxycarbonyl) hydantoin obtained above were hydrolyzed in 2.4 ml of ethanol, 0.6 ml of 5N sodium hydroxide solution at room temperature for 3 hours. The ethanol is then evaporated and the resulting acidic product is isolated by extraction with ether and purified by column chromatography on silica gel. This gives 1-octyl-3-methyl-5- (6-carboxyhexyl) hydantoin as a colorless oil. Rf = 0.5 (S102; 19: 1 chloroform: methanol).

Example 37 Preparation of 1- (3-hydroxyoctyl) -3-methyl-5- (6-carboxyhexyl) hydantoin

The diethyl 2 - [(3-oxooctyl) amino] nonanedioic acid diethyl ester prepared in Example 27 was reacted with methyl isocyanate as in Example 36 to give 1- (3-oxooctyl) -3-methyl-5 - (6-Ethoxycarbonylhexyl) hydantoin is obtained. This compound is then hydrolyzed as described in Example 36 to give 1- (3-oxooctyl) -3-methyl-5- (6-carboxyhexyl) hydantoin as a colorless oil.

1.23 g of 1- (3-oxooctyl) -3-methyl-141 obtained above

183,046

Example 43 Preparation of 1- (3-cyclohexyl-3-hydroxypropyl) -5- [6-carboxyhex-2 (Z) -enyl] hydantoin

No. 1,355,991. The cis-7-bromo-hept-5-enoic acid methyl ester prepared according to the procedure described in Great Britain is reacted with acetamidomalonic acid diethyl ester as described in Example 1 (A) to give acetamido- (6-methoxycarbonyl) as a yellow oil. hex-2-enyl) -malonate.

This crude product is hydrolyzed by boiling with 5N hydrochloric acid and then esterified as described in Example 1 (A). This gives 2-amino-non-4-enedioic acid diethyl ester as a colorless oil, boiling at 118-123 ° C at 0.05 mm Hg; n ¹ g> ⁵ = 1.4620.

The amino compound obtained in the above manner is exemplified in Example 2

Reaction with 1-cyclohexylprop-2-enone as described in Section B gives 2 - [(3-cyclohexyl-3-oxo-propyl) -amino] -non-4-enedioic acid diethyl ester. ) with sodium borohydride. This gives 2 - [(3-cyclohexyl-3-hydroxypropyl) amino] non-2-enedioic acid diethyl ester.

This compound was treated with potassium cyanate and hydrochloric acid as described in Example 2 (D) and the hydantoin ester thus obtained was hydrolyzed as described. 1- (3-Cyclohexyl-3-hydroxy-propyl) -5- [6-carboxy-hex-2 (Z) -ethyl] -hydanine is obtained in the form of a yellow oil which is liable to solidify. This compound was separated into two diastereomeric forms by high performance liquid chromatography; one of the diastereomers forms tiny colorless prism crystals melting at 95-97 ° C, the other forming colorless needle crystals melting at 108110 ° C.

Example 44 Preparation of 1- (3-oxooctyl) -5- (6-carboxyhexyl) hydantoin

7.7 g of 2- (3-oxooctylamino) -nonanedioic acid diethyl ester, prepared as described in Example 1 (B), are reacted with potassium cyanate and hydrochloric acid as described in the preceding examples to give 1- (3-oxo) octyl) -5- (6-ethoxycarbonylhexyl) hydroxide is obtained.

The ethoxycarbonyl derivative thus obtained is hydrolyzed with sodium hydroxide solution as described in the previous examples; 1- (3-oxo-octyl) -5- (6-carboxy-hexyl) -hydantoin is obtained in the form of a viscous oil which crystallizes on standing to a low melting solid. Yield: 29%.

Example 45

Preparation of 5- (6-carbamoylhexyl) -1- (3-cyclohexyl-3-hydroxypropyl) hydantoin

- Dissolve 500 mg of one diastereomer of (6-ethoxycarbonylhexyl) -1- (3-cyclohexyl-3-hydroxypropyl) -hydantoin in 2.5 ml of 0.880 g / cm ³ ammonium hydroxide solution and add The solution was heated in a closed vessel at 100 ° C for 2 hours. After cooling, the solution is acidified with 2N hydrochloric acid and the precipitated gum is extracted first with ether and then with chloroform. During ether extraction, a part of the gum dissolves. The chloroform extract was washed with sodium bicarbonate solution and water, dried over magnesium sulfate and evaporated. A mixture of diastereomers of the title compound is obtained in the form of a colorless solid, m.p. 110-120 ° C. Rinse the product on silica gel with chloroform: methanol: acetic acid = 90: 5: 5 to give two spots at Rt = 0.37 and Rf = 0.41.

Example 46

- Preparation of (3-cyclohexyl-3-hydroxypropyl) -5- (7-hydroxyheptyl) hydantoin

To a mixture of 368 mg of Example 14c 5- (6-carboxyhexyl) -1- (3-cyclohexyl-3-hydroxypropyl) hydantoin (mixture of diastereomers) and 101 mg of triethylamine cooled to -5 ° C Add in 15 minutes

A solution of 108.5 mg of ethyl chloroformate in 0.5 ml of tetrahydrofuran. After a further hour at 0 ° C, the solid was separated and washed with tetrahydrofuran (1 mL).

The combined mother liquors and washings were added dropwise over 30 minutes to a solution of 100 mg of sodium borohydride in 1 ml of water maintained at 15 ° C. After the addition was complete, the solution was stirred at room temperature for 2 hours, then water was added, acidified with 2N hydrochloric acid and extracted with food. The ethereal solution was washed with sodium bicarbonate solution, then water, dried over magnesium sulfate and evaporated; 330 mg of a colorless viscous oil are obtained.

300 mg of the oil obtained are chromatographed on a silica gel column eluting with water-saturated ethyl acetate to give 250 mg of an oil. This oil was chromatographed on silica gel with chloroform: methanol: acetic acid = 90: 5: 5 to give two spots at Rfs of 0.60 and 0.63 corresponding to 1- (3-cyclohexyl-3-hydroxy). propyl) -5- (7-hydroxy-heptyl) -hydantoin diastereomers. The diastereomers can be separated by high performance liquid chromatography and the less polar isomer is crystallized (m.p. 73-77 ° C) while the more polar isomer is left as a viscous oil.

41-57. example

The following compounds were prepared in analogy to Example 1:

47a 2 - [(3-Oxo-5-ethoxy-pentyl) -amino] -nonanedioic acid diethyl ester;

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48a 2 - {[3-oxo-4- (3-trifluoromethyl-phenoxy) -butyl] -amino} -nonanedioic acid diethyl ester;

49a 2 - {[3-oxo-3- (4-chloro-phenyl) -propyl] -amino} -nonanedioic acid diethyl ester;

50a 2 - {[3-oxo-3- (4-methoxyphenyl) propyl] amino} nonanedioic acid diethyl ester;

51a 2 - {[3-Oxo-3- (4-hydroxy-phenyl) -propyl] -amino} -nonanedioic acid diethyl ester;

52a 2 - {[3-Oxo-3- (4-nitrophenyl) -propyl] -amino} -nonanedioic acid diethyl ester.

These compounds are converted to the corresponding 3-position substituted hydroxy groups, and the following hydantoin is prepared from these hydroxy derivatives, which, as described above, are separated into their diastereomers by HPLC.

47b 5- (6-Carboxyhexyl) -1- [3-hydroxy-3- (1-adamantyl) propyl] hydantoin, 117.5-179.5 ° C and 155-157 ° C;

47c 5- (6-Carboxy-hexyl) -1- (3-hydroxy-5-ethoxy-pentyl) -hydantoin, 68-70 ° C;

48c 5- (6-Carboxy-hexyl) -1- [3-hydroxy-4- (3-trifluoromethyl-phenoxy) -butyl] -hydantoin, 105-107 ° C and 118-120 ° C;

49c 5- (6-Carboxyhexyl) -1- [3-hydroxy-3- (4-chlorophenyl) propyl] hydantoin, 93-94 ° C and 101-

102 ° C;

50c 5- (6-Carboxy-hexyl) -1- [3-hydroxy-3- (4-methoxy-phenyl) -propyl] -hydantoin, 93-94 ° C and 102103 ° C;

51c 5- (6-Carboxy-hexyl) -1- [3-hydroxy-3- (4-hydroxy-phenyl) -propyl] -hydantoin, 118-119 ° C Rt = 0.13) and Rf = 0.12 ;

52c 5- (6-Carboxy-hexyl) -1- [3-hydroxy-3- (4-nitrophenyl) -propyl] -hydantoin, Rf = 0.2 and R1 = 0.25.

Similarly, starting materials 53a-57a can be used to prepare the final products 53c-57c via the 3-hydroxy derivatives and then converting the hydroxy derivatives into hydantoin and separating the hydantoin into their diastereomers:

53a 2 - [(3-Oxo-4-cyclopentyl-butyl) -amino] -nonanedioic acid diethyl ester;

54a 2 - [(3-oxo-4-cyclohexyl-butyl) -amino] -nonanedioic acid diethyl ester;

55a 3 - [(3-Oxo-4-cyclopentyl-butyl) -amino] -onone-4Z-enedioic acid diethyl ester;

56a 2 - [(3-Oxo-4,4-dimethyl-5-phenyl-pentyl) -amino] -one-4Z-enedioic acid diethyl ester;

57a 2 - [(Cycloheptan-2-one-ylmethyl) -amino] -one-4Z-enedioic acid diethyl ester;

53c 5- (6-Carboxy-hexyl) -1- (3-hydroxy-4-cyclopentyl-butyl) -hydantoin, 75-78 ° C and 101-104 ° C;

54c 5- (6-carboxy-hexyl) -1- (3-hydroxy-4-cyclohexyl-butyl) -hydantoin, 92-94 ° C and 109-111 ° C;

55c 5- (6-Carboxyhex-2Z-en-yl) -1- (3-hydroxy-4-cyclopentyl-butyl) -hydantoin, 114-116 ° C;

56c 5- (6-Carboxyhex-2Z-en-yl) -1- (3-hydroxy-4,4-dimethyl-5-phenylpentyl) -hydantoin, 68-70 ° C and 116-117 ° C ;

57c 5- (6-Carboxy-hexyl) -1- (2-hydroxy-cycloheptylmethyl) -hydantoin, TLC (SiO 2 on CHCl ₃ : MeOH: AcOH = 90: 5: 5), R f = 0.60 and 0.57.

Example 58 Preparation of 1- (3-cyclohexyl-3-hydroxy-propyl) -5- (7-hydroxy-heptyl) -hydantoin

The title compound was prepared according to the procedure detailed in Morrison.

R. T., Boyd, R. N., Organic Chemistry, 2nd Edition, Allyn & Bacon Inc., Boston, page 511. Starting with the appropriate chloride, hydrolysis gives the title product, m.p. 73-77 ° C.

Example 59

Preparation of sodium salts of 5- (carboxyhexyl) -1- (3-hydroxy-3-cyclohexylpropyl) hydantoin

a) While stirring, a solution of 1.0 mmol of sodium bicarbonate in 2 mL of water was added slowly from a 50:50 mixture of the two diastereomers of the title compound in 5 mL of methanol. After the addition was complete, the reaction mixture was gradually evaporated to a final evaporation under high vacuum at 80 ° C. This gives the monosodium salt of the title compound on the 6-carboxylic acid in a hygroscopic form.

IR spectrum (ju max, KBr):

3500 cm ^-1 (OH, NH), 1760 and 1705 cm ^-1 (C = O), and 1580 cm ^-1 (CO 2).

Nuclear Magnetic Resonance Spectrum (D2O, delta):

4.2 (IH, m, CHOH), 2.7-4.0 (3H, m, _N-CH2 and N-CH) and 1.0-2.4 (25H, 12 CH _2, CH 1) .

b) To the starting material described in step a) is added a solution of sodium bicarbonate (2.1 mmol) in water (5 mL) and the resulting aqueous solution is evaporated to dryness. To the resulting residue was added ethanol (10 mL), filtration and evaporation of the filtrate. This gives the disodium salt of the title compound on the 6-carboxyl group and the 3-position hydrogen atom in hygroscopic form.

IR spectrum (μαηχ, KBr): 3450 cm ^-1 (OH),

1750 and 1705 cm- ¹ (C = O) and 1570 cm- ¹ (CO ₂ ).

Nuclear Magnetic Resonance Spectrum: identical to the monosodium salt.

The following examples illustrate the pharmacological effects of the compounds of the present invention and the composition and method of preparation of the pharmaceutical compositions prepared from these compounds as active ingredients. For the sake of brevity, the active compounds in each example are numbered as follows:

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183,046

-5- (6-Carboxyhexyl) hydantoin is dissolved in 15 ml of 0.25 N sodium hydroxide solution and this solution is stirred in an ice bath while 63 mg of sodium borohydride is added portionwise. The mixture was then stirred for an additional 3 hours at room temperature, then the resulting solution was acidified and extracted with ether and evaporated. The residue was obtained as an oily product and purified by column chromatography on silica gel; Elution with a 50: 1 mixture of chloroform and methanol gave the eluate by evaporation to give 1- (3-hydroxyoctyl) -3-methyl-5- (6-carboxyhexyl) hydantoin as a colorless viscous oil. Hf = 0.65 (SiO2; 9: 1 chloroform: methanol).

Example 38 Preparation of 1- (6-carboxyhexyl) -3-methyl-5-octylhydantoin

The ethyl 2- (6-ethoxycarbonylhexylamino) decanoic acid ethyl ester prepared as described in Example 35 was converted to 1- (6-ethoxycarbonylhexyl) -3-methyl-5-octylhydantoin according to the procedure described in Example 36. hydrolyze as described in Example 36 to give 1- (6-carboxyhexyl) -3-methyl-5-octylhydantoin as a colorless oil, Hf 0.55 (S102; 19: 1 chloroform: methanol) .

Example 39 Preparation of 1-octyl-3-butyl-5- (6-carboxyhexyl) hydantoin

To a solution of metal sodium (308 mg) in ethanol (40 ml) was prepared 1-octyl-5- (6-ethoxycarbonylhexyl) hydantoin prepared as described in Example 28 (b), followed by addition of 1.8 g of butyl bromide, and the resulting solution was refluxed for 24 hours. The solvent was then evaporated, water was added to the residue and the insoluble oily product was extracted with ether. The ether layer was separated, washed with water and dried and evaporated; The residue was 1-octyl-3-butyl-5- (6-ethoxycarbonylhexyl) hydantoin.

3.2 g of the 1-octyl-3-butyl-5- (6-ethoxycarbonylhexyl) hydantoin obtained above are dissolved in a mixture of 15 ml of ethanol and 15 ml of 2N sodium hydroxide solution, and the solution is allowed to stand at room temperature for 1 hour. forget it. The acidic product obtained is extracted with ether and the crude product obtained by evaporation from the ether phase is purified by chromatography on silica gel. This gave 1-octyl-3-butyl-5- (6-carboxyhexyl) hydantoin as a colorless oil, Hf = 0.7 (S102; 9: 1 chloroform: methanol). Yield: 30%.

Example 40 Preparation of 1- (6-carboxyhexyl) -3-butyl-5-octylhydantoin

The 1- (6-ethoxycarbonylhexyl) -5-octylhydanthine prepared as described in Example 35 was converted to the 1- (6-ethoxycarbonylhexyl) -3-butyl-5-octylhydantoin by the procedure described in Example 39, then hydrolyzing it as described in the previous examples to give 1- (6-carboxyhexyl) -3-butyl-5-octylhydantoin as an oily colorless product. Hf = 0.8 (SiO ₂ ; 9: 1 chloroform: methanol). Yield: 30%.

Example 41 Preparation of 1- (3-hydroxyoctyl) -5- (6-carboxy-hex-2-ynyl) -hydantoin

Acetamido-malonic acid diethyl ester and 7-bromo-hept-5-acetic acid methyl ester are reacted from the starting compounds in the same manner as in Example 1 (A) to give acetamido- (6-methoxycarbonylhex-2-ynyl) malonic acid diethyl ester. in the form of a yellow oil.

This crude product is hydrolyzed by boiling with 5 π-hydrochloric acid and re-esterified to give 2-amino-non-4-indoic acid diethyl ester which is distilled under reduced pressure. This gives 2-amino-non-4-indoic acid diethyl ester as a colorless oil, boiling at 116 ° C at 0.01 mn Hg; n ¹ J = 1.4703.

The amino compound thus obtained is then reacted with oct-1-en-3-one to give diethyl 2 - [(3-oxooctyl) amino] non-4-indoic acid. This compound is then reduced with sodium borohydride to give 2 - [(3-hydroxyoctyl) amino] non-4-indoic acid diethyl ester.

The compound thus obtained is treated with potassium cyanate and hydrochloric acid and the hydantoin ester thus obtained is hydrolyzed as described in the preceding examples. The crude product was purified by chromatography on silica gel. Elution with chloroform / methanol (30: 1) gave 1- (3-hydroxyoctyl) -5- (6-carboxyhex-2-ynyl) hydantoin as a colorless oil. This product is a mixture of diastereomers which shows two spots on a thin layer chromatogram with a 90: 5: 5 mixture of chloroform-methanol and acetic acid; Rf = 0.38 and 0.44. Yield 40% based on diethyl ester of 2-amino-non-4-indoic acid.

The product thus obtained was subjected to high performance liquid chromatography separation to give one of the diastereomers as a colorless oil, having an Rf value of 0.38 as described above. This product has a nuclear magnetic resonance spectrum (in deuterochloroform) of δ = 0.89 (3H, triplet, -CH ₃ ),

2.2-2.4 (6H, m, -CH ₂ -C? C-CH ₂ - _Z + -CH-COOH);

3.54 (2H, t,> N-CH ₂ -),

About 3.6 (1H, multiplet,> CH ~ OH),

4.11 (1H, triplet,> N-CH-CO-).

The compound thus obtained is then converted by catalytic hydrogenation to the corresponding 1- (3-hydroxyoctyl) -5- (6-carboxyhex-2-enyl) hydantoin, followed by conversion to the corresponding saturated compound which is

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183,046 is identical to 1- (3-hydroxyoctyl) -5- (6-carboxyhexyl) hydantoin obtained according to the procedure of Example 2 and shows the characteristic constants given in Example 2.

Example 42

A) Preparation of 2-dibutoxymethyl) glycine ethyl ester

N-formylglycine ethyl ester is described in Harman and Hutchinson, J. Org. Chem., 40, 3474 (1975), and the resulting compound is prepared as described in "Chemistry of Penicillin", Η. 51 Clark, et al., Princetown University Press, New Jersey, 1949, page 517, is converted to 2-dibutoxymethylglycine ethyl ester. 15

Β) Preparation of 1- (6-carboxyhexyl) hydantoin-5-carboxaldehyde

2.0 g of 2- (dibutoxymethyl) glycine ethyl ester and 1.82 g

7-bromo-heptanoic acid ethyl ester mixture of a nitrogen-air circuit, p _2, a bath temperature of 100 ° C for 3 hours using a crude product of 7 - [(2,2-dibutoxy -1 - carboethoxy - ethyl) - amino] - heptanoic acid ethyl acetate hydrobromide was obtained. This compound (3.28 g) was dissolved in ethanol (13 ml) and the solution ( ₂ g) was stirred in an ice bath while a solution of potassium cyanate (1.34 g) in water (4 ml) was added and

3.63 mL of 2N aqueous hydrochloric acid was added. After the addition was complete, the cooling bath was removed and the mixture was stirred at room temperature for an additional 22 hours. The ethanol is then evaporated in vacuo, the residue is shaken with a two-phase mixture of water and ether, the ether phase is separated off, washed with water, dried over anhydrous magnesium sulfate and the ether is evaporated. The resulting oily residue was heated at 100 ° C under nitrogen for ³ hours to give 2.94 g of 1- (6-ethoxycarbonylhexyl) -5-dibutoxymethylhydantoin.

Ülődön product obtained above was dissolved in 6 ml of ether, the solution mixture of ⁴⁰ hydroxide solution was stirred at room temperature for 1.5 hour aqueous sodium in 48 ml of water and 24.9 ml of n, an additional 50 ml of ether was added and the aqueous layer was separated It is cooled with ice-water, stirred with fresh ether and acidified with Congo red by addition of aqueous hydrochloric acid. The ethereal solution was separated, washed three times with water, dried over anhydrous magnesium sulfate and evaporated. 2.15 g of 1- (6-carboxyhexyl) -5-dibutoxymethylhydantoin are obtained as a resinous product. 50

1.89 g of 1- (6-carboxyhexyl) -5-dibutoxymethylhydantoin obtained above are mixed with 8.5 ml of concentrated aqueous hydrochloric acid in an ice-water bath, and the resulting solution is spontaneously converted into a suspension of colorless crystals? This suspension was stirred at room temperature 55

After standing for 1.5 hours, it is diluted with 10 ml of water and allowed to stand again for 15 minutes; the precipitated crystals were collected, washed with water, dried in vacuo, and the crystalline product was suspended in 3 ml of ether and collected again. 0.74 g of 60 1- (6-carboxyhexyl) hydantoin-5-carboxaldehyde is obtained, m.p. 223.5-225 ° C.

Calcd for C11H16N2O5: C, 51.56; H, 6.28; N, 10.93.

Δ 'found: C, 51.86; H, 6.66; N, 10.62.

This compound is predominantly present in d6-dimethylsulfoxide in the form of a coated aldehyde with 1- (6-carboxyhexyl) -5-hydroxymethylene hydantoin.

C) Preparation of 1- (6-carboxyhexyl) -5 - [(E) -3-oxooctylidene] hydantoin mg 1- (6-carboxyhexyl) hydantoin-5-carboxaldehyde and 59 mg 2 -oxo-heptylidene triphenylphosphorane - cf. J. Org. Chem. 37, 1818 (1972), heated with 100 drops of nitrogen to 1 drop of benzene for 35 minutes, and the resulting resin was dissolved in ethyl acetate. The product formed is extracted with dilute aqueous sodium bicarbonate solution from the ethyl acetate phase, the aqueous phase is separated off, washed with ethyl acetate and acidified to pH Congo with aqueous hydrochloric acid. The resulting carboxylic acid is extracted with ether. The ether layer was separated, washed with water, dried over anhydrous magnesium sulfate and evaporated. 25 mg of a resinous product were obtained which was identified by Ή NMR spectroscopy; typical signals (in deuterochloroform):

δ = 5.72 (1H, triplet, = CH-),

3.93 (2H, d, = CH-CH ₂ -CO-), J = 7.1 Hz.

D) Preparation of 1- (6-carboxy-hexyl) -5 - [(E) -3-hydroxyoctylidene] -hydantoin mg 1- (6-carboxy-hexyl) -5 - [(E) -3-oxo -octylidene] -hydantoin Dissolve in 1.5 ml of water with the addition of a slight excess of sodium bicarbonate and add 5 mg of sodium borohydride with stirring. After 60 minutes, the solution was acidified to Congo red with aqueous hydrochloric acid solution, the carboxylic acid liberated so far was extracted with ethyl acetate, the ethyl acetate layer was separated, washed three times with water and dried over anhydrous magnesium sulfate. The ethyl acetate was then evaporated to give 14 mg of a pale yellow resin which was identified by the vegyület NMR spectroscopy as the title compound; typical values in deuterochloroform:

δ = 5.61 (1H, triplet, = CH-), J = 7.1 Hz.

Yield: 26% based on 2-di (butoxymethyl) glycine ethyl ester.

E) Preparation of 1- (6-carboxyhexyl) -5- (3-hydroxyoctyl) hydan'oin

The 1- (6-carboxyhexyl) -5 - [(E) -3-oxooctylidene] -hydartine obtained in the manner described in section (C) is reduced as described in the previous examples to give 1- (6-carboxyhexyl) -5- (3-oxooctyl) hydantoin is obtained and further reduction yields 1- (6-carboxyhexyl) -5- (3-hydroxyoctyl) hydantoin, which is the same as Example 27 and 2, respectively. shows the same properties as the product obtained in Example 2 and the same as those described therein.

-181

183 046 (2): 1- (3-hydroxyoctyl) -5- (6-carboxyhexyl) hydantoin, (4): 1- (3-hydroxy-4,4-dimethylpentyl) -5- (6-carboxy-hexyl) -hydantoin, (6): 1- (3-hydroxy-nonyl) -5- (6-carboxy-hexyl) -hydantoin, (9): 1- (3-hydroxy-4.4) -dimethyl-octyl) -5- (6-carboxy-hexyl) -hydantoin, (11): 1- (3-hydroxy-3-cyclobutyl-propyl) -5- (6-carboxy-hexyl) -hydantoin, (12) ): 1- (3-hydroxy-3-cyclopentyl-propyl) -5- (6-carboxy-hexyl) -hydantoin, (14): 1- (3-hydroxy-3-cyclohexyl-propyl) -5- (6) -carboxy-hexyl) -hydantoin, (38): 1- (3-oxo-octyl) -3-methyl-5- (6-carboxy-hexyl) -hydantoin.

When any of the above compounds were used in one of the diastereomeric forms in the experiments described below, this condition was indicated by the melting point of that compound.

Example A)

Cardiovascular effects in rats

Wistar (Charles River) strains of normotensive male rats weighing 250-300 g were anesthetized with chloroform and cannulated into their left femoral vein and maintained by anesthetization by intravenous administration of 60 mg / kg chlororalose throughout the experiment. Pulse blood pressure was recorded in a left and femoral artery using a Bell and Howell type 4-327 L221 electronic instrument, and integrated heart rate was measured using a cardiotachometer based on arterial pressure waves.

The test compounds were administered to the animals in the form of a physiological saline solution through a cannula inserted into the femoral vein. When recording the drug-induced reaction, we waited for the reaction to return to pre-administration levels before the next administration.

An equal volume of vehicle without control was administered to the animals under the same conditions; none of these control injections resulted in a decrease in blood pressure.

for comparison, prostaglandin-E ₂ (PGE ₂ ) was administered to the animals; the dosage of each active ingredient and the results obtained are shown in the following table:

Compound Dose Average blood pressure- decrease mm Hg PGE ₂ 4 µg / kg 28 pge ₂ 16 mg / kg 44 Compound (2) 10 mg / kg 14 Compound (2) 1 mg / kg 42 Compound (6) 3 mg / kg 40 Compound (9) 3 mg / kg 22

Example B)

Inhibition of blood cell aggregation

Blood aggregation was measured in 1 ml of fresh blood-rich human plasma using a Bom aggregometer.

The test compound was added to the desired concentration of human platelet rich plasma, and the resulting mixture was incubated at 37 ° C for 1 minute, after which the aggregation of the blood cells was promoted by the addition of 5 μιηόΐ of adenosine bisphosphate.

The aggregate inhibitory effect of the test compound was determined by measuring the inhibition of blood cell aggregation observed in the presence of the test compound by comparing it with the amount of aggregation observed under the same conditions but without the addition of the test compound. The concentrations used and the percent inhibition of aggregation are given in the table below; for comparison, prostaglandin E1 (PGE1) was used under the same experimental conditions.

Compound Concentration Aggregáció- inhibition, % PGE! 15 ng / ml 33 20 ng / ml 47 30 ng / ml 63 40 ng / ml 69 Compound (12) 0.5 ng / ml 25 (op: 116- 1.0 ng / ml 51 117 ° C) 2.0 ng / ml 79 4.0 ng / ml 94

Similar comparative experiments were conducted with compounds (2), (4), (11) and (14) under the same conditions, and based on the results obtained, the potency of these compounds relative to prostaglandin-τ was calculated.

The following results were obtained:

Compound 2 (mp 76-78 ° C): 12.5x Compound 4 (mp 144-146 ° C) 0.05x Compound 11 (mp 114-116 ° C) : 5.2x, Compound 12 (m.p. 116-117 ° C): 12.5x, Compound 14 (m.p. 98-198 ° C): 16x.

Example C)

Compound (38) was used to determine the degree of inhibition of acetylsalicylic acid-induced gastric ulcer in rats. The compound exhibited 80% inhibitory activity at 1 mg / kg oral dose.

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183,046

Example D)

Example I)

Compound (2) was tested in rats for inhibition of gastric acid secretion by pentagastrin-tert-butoxycarbonyl-beta-alanyl-tryptophanyl-methionyl-asparagyl-phenylalanine amide. Compound (2) completely inhibited gastric acid secretion at an intravenous dose of 30 mg / kg.

Example E)

Compound (9) was tested for antagonizing the histamine-induced bronchial constriction in anesthetized guinea pigs. A dose of 50 mg / kg of Compound 9 showed a complete antagonizing effect when injected intravenously.

Example F)

Compound (2) (m.p. 76-78 ° C) was tested in anesthetized rabbits for protection against electrically induced arterial thrombosis. The test compound significantly reduced the occurrence of thrombosis when administered as an intravenous infusion of 250 pg / min.

Example U)

Preparation of tablets

The following substances are used as tablets in the following amounts:

Compound 12 (m.p. 116-117 ° C) 5.0 mg milk sugar, 82.0 mg starch, 10.0 mg polyvinylpyrrolidone 2.0 mg magnesium stearate 1.0 mg

Compound (12) is mixed with milk sugar and starch and granulated with a solution of polyvinylpyrrolidone in purified water to form the above powder mixture. The resulting granules are dried, mixed with magnesium stearate and compressed into tablets at a dosage of 100 mg each.

Preparation of Injection Compound ⁵ (12) (m.p. 116-117 ° C) Water for injection per 100 ml water

The active compound (12) is dissolved in water and the resulting solution is sterilized by filtration through a membrane filter (using a membrane filter with a pore size of 0.22 mm). The filtrate is collected in a sterile container and aseptically filled into sterile glass ampoules at 1 ml per ampoule. The vials are then sealed. The formulation thus prepared contains 1 mg of active ingredient per ampoule.

Example J)

Preparation of injection preparation

The following materials are used in the amounts indicated:

Compound 12 (m.p. 116-117 ° C) 1 mg ethyl alcohol 10 ml propylene glycol 30 ml water for injections per 100 ml

The active ingredient (19) is dissolved in ethyl alcohol, propylene glycol is added and the mixture is diluted to 100 ml with water for injection.

The resulting solution is sterilized by filtration through a membrane filter of 0.22 M pore size ³⁵ , collected in a sterile container and aseptically filled into sterile 10 ml glass bottles. The bottles are sealed with a sterile rubber stopper and sealed with an aluminum ring. The ⁴⁰ injection formulations thus prepared contain 10 mg / ml of the active ingredient.

Example K)

Lyophilized product for injection

The following materials are used in the amounts indicated:

Example H)

Production of capsules

The following substances are used in the following amounts per capsule:

Compound 12 (m.p. 116-117 ° C) 10 mg milk sugar 79 mg starch 10 mg magnesium stearate 1 mg

The above powder ingredients are mixed in a powder mixer and filled into hard gelatine capsules at 100 mg per capsule.

Compound 12 (m.p. 116-117 ° C) mannitol n / 10 sodium hydroxide solution for injection water

10.0 mg 2.5 g

q. s. PH 10.0 to 100.0 ml

The active ingredient (12) is suspended in about 20 ml of water for injection. To this suspension is added enough n / 10 sodium hydroxide solution to adjust the pH to 10 and the mixture is stirred until the compound (12) is dissolved. After dissolution, the mannitol is added and dissolved, and the mixture is diluted to 100 ml with water for injection.

The resulting solution was sterilized by filtration through a 0.22 Mm pore size membrane filter and

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183,046 are distributed under aseptic conditions into sterile ampoules of 1 ml per ampoule. The solution in the ampoules is dried by lyophilization and the vials are aseptically sealed with a rubber stopper. The lyophilized preparation thus obtained contains 100 μg of compound (12) per vial.

glaze in the form of a lyophilized sodium salt. Example L) Preparation of suppositories The following substances are used in quantities: the given Compound 12 (m.p. 116-117 ° C) 3 mg Other than Esterinum C 2 mg

"Other Esterinum C" is a commercially available suppository base consisting of a mixture of mono-, di- and triglycerides of saturated vegetable fatty acids. This product is marketed by Henkel International (Düsseldorf).

The "Other Esterinum C" suppository base material is melted at about 40 ° C, then compound (12) is gradually mixed into a fine powder and homogenized by stirring, which is then poured into suppository molds and allowed to solidify.

Claims (68)

Patent claims A process for the preparation of a nitrogen containing heterocyclic compound of formula (I) Z is hydrogen or C1-C4 alkyl, Z ¹ and Z ² are one of a group -CH 2 -X XX ¹ and ² in the formula X is phenylene, -C = C-, cis or trans -CH = CH- or -CH ₂ -CO ₂ , in which latter two Q are independently hydrogen or C 1 -C 4 alkyl, X ^I is a covalent bond or a straight or branched chain C 1-6 alkylene group, wherein the methylene groups is optionally replaced by a -O- oxacsoportra provided that this oxacsoportot separated by at least one carbon atom in the -C = C-, -CH = CH or -CO-, X ^{2 is} carboxyl, carboxamido, hydroxymethylene or C2 -C5 alkoxycarbonyl, The other of Z ¹ and Z ² is a group of the formula -YY ¹ -Y ² - -Y ³ and in it Y is a group of formula -CL2-CH2- and in the latter the two L are independently hydrogen or methyl, ^Y1 carbonyl, methylene, substituted methylene or substituted methylene group and hydroxy C1-4 alkyl, hydroxy Y ^{2 is a} covalent bond or a straight or branched C 1 -C 7 alkylene group optionally substituted with one or two groups independently selected from C 1 -C 4 alkyl on carbon adjacent to Y ¹ ; Substituted with C4-C10 bicycloalkyl or C3-C7 cycloalkyl, Y represents ³ hydrogen, hydroxy, C 1-7, preferably C 1-4 alkoxy, C 3-7 cycloalkyl, C 4-10 bicycloalkyl, phenyl, benzyl, phenoxy or benzyloxy groups, said phenyl, benzyl -, phenoxy or benzyloxy may be substituted on the benzene ring by one or more substituents independently selected from hydroxy, nitro, C 1-4 alkoxy, alkyl or phenyl, or halogen or trifluoromethyl, or Y represents a direct bond, -CH ₂ - or -CH ₂ - -CH ₂ -, together with γ ¹ , Y ² and Y ³ , substituted with a hydroxy group of C 3 -C 7 cycloalkyl, said hydroxy group being preferably separated by 3 carbon atoms - and pharmaceutically acceptable salts thereof, wherein: (a) a ring closure reaction of a compound of formula II, optionally prepared in situ, wherein G represents a carboxyl group or a reactive derivative thereof and Z, Z ¹ and Z ² have the same meaning as defined in formula I or (b) a compound of formula (VII), optionally in situ, wherein G ^{1 is a} carboxyl group or a reactive derivative thereof, and Z, Z ¹ and Z ² are as defined in formula (I); or c) reacting a compound of formula IX: wherein Z, Z ¹ and Z ² are as defined in formula I with a carbonic acid derivative; or d) in the preparation of compounds of formula I wherein Z is alkyl, wherein Z ¹ and Z ² are as defined above, a compound of formula X wherein R is hydrogen or alkyl, R ^{1 is} hydrogen or any of the above Z ¹ , R ² hydrogen, or Z ² and R ³ alkyl as defined above, or Z ¹ or Z ^{2 as} defined above, wherein one of R ¹ , R ¹ and R ² is hydrogen - With a reactive ester derivative of an alcohol of the formula R ³ -OH - wherein R ^{3 represents an} alkyl group or a substituent Z ¹ or Z ^{2 as} defined above, wherein R ³ is different from the R, R ¹ and R ² substituent of the compound of formula X by alkylation or (e) a compound of Formula XI: wherein: Z is = CL-CH ₂ -γΐ-γ2_γ3 and -211 183,046 Z ⁴ is -CH ² ~ XX ¹ -X ² , or Z ³ is = CH-X-X'-X ² and Z ^{4 is} a group represented by the formula: YY ¹ -Y ² -Y ³ , wherein X, X ¹ , Y, Y ¹ , Y ² , Y ³ and L are as defined in formula (I); reduction with a reducing agent, or f) in the preparation of compounds of formula I wherein X ² is hydroxymethylene in one of the groups Z ¹ and Z ^{2 as} defined in formula I, wherein Z is as defined above, an appropriate acid, ester, acid halide , acid anhydride or aldehyde, or a suitable reducing agent g) hydrolyzing a suitable halide to produce a compound of formula I wherein X ² is a hydroxymethylene group in which Z ² and Z ^{2 are as} defined in formula (I); appropriate compound of formula X ² is alkoxycarbonyl carrier (I), carboxamido and / or, if desired, the obtained (I) compound is converted to a pharmaceutically acceptable carrier for salt X ² is appropriate. (Priority: June 2, 1977) 2. A process for the preparation of a group of nitrogen-containing heterocyclic compounds of formula I: wherein: Z is hydrogen, X ² is carboxyl or C 2 -C 5 alkoxycarbonyl, Y ² is a covalent bond or a straight or branched C 1 -C 7 alkylene group which may be optionally substituted on one or two C 1 -C 4 alkyl groups on the carbon atom adjacent to the Y ¹ substituent, Y ³ is hydrogen, hydroxy, C 1 -C 7 alkoxy, phenyl, benzyl, phenoxy or benzyloxy, any of which is phenyl, benzyl, phenoxy and benzyloxy, which may be substituted on the benzene ring by one or more of the following: halogen, hydroxy, nitro, C 1-4 alkoxy, phenyl or C 1-4 alkyl, trifluoromethyl, Y ² and Y ³ together may represent a C 4 -C 7 cycloalkyl group, X, X ¹ , Z ¹ , Z ² , Y, Y ¹ are as defined in the preamble of claim 1, as well as pharmaceutically acceptable salts thereof, wherein: (a) subjecting a compound of formula (II), optionally in situ, where G represents a carboxyl group or a reactive derivative thereof, Z, Z ¹ and Z ² are as defined herein, or (b) a compound of formula (VII), optionally prepared in situ, in which G ^{1 represents a} carboxyl group or a reactive derivative thereof, Z, Z ¹ and Z ² are as defined in the scope22, or c) reacting a compound of formula IX, wherein Z, Z ¹ and Z ² are as defined herein, with a carbonic derivative; or (d) a compound of the formula (XI) or Z ⁴ is = CH-CH ² -Y ¹ -Y ² -Y ³ and Z ⁴ is -CH 2 -Y-X ¹ -X ² or Z ³ is a group of the formula = CH-XX ¹ -X ² and Z ⁴ is a group represented by the formula -Y-Y ¹ -Y ² -Y ³ , wherein X, X ¹ , X ² , Y, Y ¹ , Y ² and Y ³ are as defined in the preceding art, by a suitable reducing agent, and optionally converting the resulting compound of formula I into a salt. (Priority: March 23, 1977) 3. A process for preparing a group of nitrogen-containing heterocyclic compounds of formula (I) Z is hydrogen, X is phenylene, -C 1 -C 2, or cis or trans- CH = CH or -CH ₂ -CH ₂ -, X ² is carboxyl or C 2 -C 5 alkoxycarbonyl, Y is a group of the formula -CH 2 -CH 2 -, Y ² is a covalent bond or a straight or branched C 1 -C 7 alkylene group which may be optionally substituted on one or two C 1 -C 4 alkyl groups on the carbon atom adjacent to the Y ¹ substituent, Y ³ is hydrogen, hydroxy, C 1 -C 7 alkoxy, benzyl, phenoxy or benzyloxy, any of which may be substituted on the benzene ring by one or more substituents selected from halogen, hydroxy, , nitro, C 1-4 alkoxy, phenyl or C 1-4 alkyl or trifluoromethyl, Y ² and Y ³ together may be a C 4 -C 7 cycloalkyl group, X ¹ , Z ¹ , Z ² and Y ¹ are as defined in the preamble of claim 1, or a pharmaceutically acceptable salt thereof, characterized in that: (a) subjecting a compound of formula (II), optionally in situ, where G represents a carboxyl group or a reactive derivative thereof, Z, Z ¹ and Z ² are as defined herein, or b) subjecting a compound of formula VII, optionally prepared in situ, wherein G ^{1 represents a} carboxyl group or a reactive derivative thereof, Z, Z ¹ and Z ² are as defined herein, or c) a compound of Formula IX: wherein Z, Z ¹ and Z ² are as defined herein; 183,046 is given - by reaction with a derivative of carbonic acid, or (d) a compound of the formula (XI) or Z ³ represents a group = CH-CH2-Y ¹ - Y ² -Y ³ group of the formula and Z ⁴ is a group of the formula -CH ² -X-X ¹ -X ² or else Z ³ is = CH-X-X ¹ -X ² and Z ⁴ is a group represented by the formula -Y-Y ¹ -Y ² -Y ³ , wherein X, X ¹ , X ² , Y, Y ¹ , Y ² and Y ³ are as defined hereinabove, by a suitable reducing agent, and optionally converting the resulting compound of formula I into a salt. (Priority: December 2, 1976) 4. A process for the preparation of a group of nitrogen-containing heterocyclic compounds of formula (I) Z is hydrogen, X is cis -CH = CH- or -CH 2 -CH 2 -, X ^I is a covalent bond or a linear or branched alkyl having 1 to 6 carbon atoms, X ² is carboxyl or C 2 -C 5 alkoxycarbonyl, Y, Y ² and Y ³ are each as defined in the scope of claim 3, Y ² and Y ³ together may represent a C 1 -C 7 alkyl group which may be optionally substituted on one or two C 1 -C 4 alkyl groups on the carbon atom adjacent to the Y ¹ substituent, Ζ ¹ , Z ² and Y ¹ are as defined in the preamble of claim 1, or a pharmaceutically acceptable salt thereof, characterized in that: (a) subjecting a compound of formula (II), optionally in situ, where G represents a carboxyl group or a reactive derivative thereof, Z, Z ¹ and Z ² are as defined herein, or b) a compound of general formula optionally prepared in situ from (VII) to e represent G ¹ carboxyl group or a reactive derivative thereof wherein Z, Z ¹ and Z ² are as defined above - is subjected to ring closure reaction, or c) reacting a compound of formula IX, wherein Z, Z ¹ and Z ² are as defined herein, with a carbonic derivative; or (d) a compound of the formula (XI) or Z ³ is = CH-CH ² -Y ¹ -Y ² -Y ³ and Z ⁴ is -CH 2 -X-X ¹ -X ² or Z ³ is = CH-X-X ¹ -X ² and Z ⁴ is a group represented by the formula -Y-Y ¹ -Y ² -Y ³ , wherein X, X ¹ , X ² , Y, Y ¹ , Y ² and Y ³ are as defined in the preceding art, by a suitable reducing agent, and optionally converting the resulting compound of formula (I) into a salt. (Priority: June 3, 1976) 5. The compound of claim 1 process a) embodiment, wherein G is a carboxyl, carboxamide or 2-5 starting compound (II) -alkoxy-carbonyl radical of the general - formula wherein Z, Z ¹ and Z ² represents As used in the preamble of claim I. (Priority: June 2, 1977) 6. A process for the preparation of process a) according to claim 2, characterized in that the starting compound of the formula II wherein G is carboxyl, carboxamide or alkoxycarbonyl, in which Z, Z ¹ and Z ² are As used in the scope of claim 2. (Priority: March 23, 1977) 7. A process according to claim 3 wherein G is a starting material of the formula II wherein Z, Z ¹ and Z ² are a carboxyl, carboxamide or alkoxycarbonyl group. Use as defined in the scope of claim 3. (Priority: December 2, 1976) 8. A process according to claim 4, wherein the starting compound of the formula II wherein G is carboxyl, carboxamide, or alkoxycarbonyl, wherein e, Z ¹ and Z ² are Use as defined in the scope of claim 4. (Priority: June 3, 1976) A process according to claim 1 or a process according to claim 5, characterized in that the reaction is carried out by heating. (Priority: June 2, 1977) The process of claim 2 a) or the process of claim 6 wherein the reaction is carried out by heating. (Priority: March 23, 1977) A process according to claim 3 or a process according to claim 7, wherein the reaction is carried out by heating. (Priority: December 2, 1976) The process of claim a) or the process of claim 8, wherein the reaction is carried out by heating. (Priority: June 3, 1976) 13. Process according to claim 1 or process according to claim 5 or 9, characterized in that the reaction is carried out under acidic conditions. (Priority: June 2, 1977) 14. Process according to claim 2 or process according to claim 6 or 10, characterized in that the reaction is carried out under acidic conditions. (Priority: March 23, 1977) Process a) according to claim 3, or process 7 or 7 II. The process of claim 1, wherein the reaction is carried out under acidic conditions. (Priority: December 2, 1976) Process a) according to claim 4 or 8 or 8 The method of claim 12, -231 183,046, characterized in that the reaction is carried out under acidic conditions. (Priority: June 3, 1976) Processes a) to h) according to claim 1, or A process according to any one of claims 5, 9 or 13, characterized in that the reaction is carried out in the presence of a solvent. (Priority: June 2, 1977) 18. A process according to claim 2, wherein the reaction is carried out in the presence of a solvent. (Priority: March 23, 1977) 19. A process according to claim 3, a) to d) or any of the processes according to claim 7, 11 or 15, characterized in that the reaction is carried out in the presence of a solvent. (Priority: December 2, 1976) A process for carrying out the process according to claim 4, a) to d), or any of the processes according to claim 8, 12 or 16, characterized in that the reaction is carried out in the presence of a solvent. (Priority: June 3, 1976) 21. A process according to claim 1, or a process according to claim 5 or 17, wherein the starting compound of formula II wherein G is an alkoxycarbonyl group, wherein Z, Z ¹ and Z ² is as defined in the preamble of claim 1, and the ring closure is carried out in the presence of a base. (Priority: June 2, 1977) Method a) according to claim 2, or method 6 or 6 The process of claim 18, wherein the starting compound of formula (II) wherein G is alkoxycarbonyl, wherein Z, Z ¹ and Z ² are as defined in the scope of claim 2, is used. ring closure in the presence of a base. (Priority: March 23, 1977) Process a) according to claim 3, or process 7 or 7 Process according to claim 19, characterized in that the starting compound of the formula (II) wherein G is an alkoxycarbonyl group, wherein Z, Z ¹ and Z ² are The compound of claim 3 is used and the ring closure is carried out in the presence of a base. (Priority: December 2, 1976) Process a) according to claim 4, or process 8 or 8 The process of claim 20 wherein G is an alkoxycarbonyl starting material of formula II wherein Z, Z ¹ and Z ² are as defined in the scope of claim 4, and ring closure in the presence of a base. (Priority: June 3, 1976) 25. A process according to claim 21, wherein the base is sodium ethoxide. (Priority: June 2, 1977) 26. The process according to claim 22, wherein the base is sodium ethoxide. (Priority: March 23, 1977) 27. A process according to claim 23, wherein the base is sodium ethoxide. (Priority: December 2, 1976) 28. A process according to claim 24 wherein the base is sodium ethoxide. (Priority: June 3, 1976) 29. Method a) according to claim 1 or method 5, Process according to claims 9, 13, 17, 21 or 25, characterized in that the starting material is a compound of formula (III) as defined in claim 1 in the reaction mixture, wherein » G, Z ¹ and Z ² have the same meaning as given in formulas II or III, but G may be a nitrile group - with cyanic acid, urea, nitrocarbamide, an alkyl isocyanate or N-alkyl urea. using a compound of formula (II) obtained by reaction, which is subjected to an in situ ring closure reaction without prior isolation. (Priority: June 2, 1977) Method a) according to claim 2 or 6, 10, Process according to Claims 14, 18, 22 or 26, characterized in that the starting material is a compound of formula (III) as defined in claim 1, wherein G, Z ¹ and Z ² has the same meaning as given in formula (II) or (III), but G may also be a nitrile group (II) obtained by reaction with cyanic acid, urea, nitrourea, alkyl isocyanate or N-alkylurea. The compound of Formula I is subjected to a ring reaction in situ without isolation. (Priority: March 23, 1977) Process a) according to claim 3 or method 7, 11, Process according to Claims 15, 19, 23 or 27, characterized in that the starting material is a compound of formula (III) as defined in claim 1, wherein G, Z ¹ and Z ² has the same meaning as given in formula (II) or (III), but G may also be a nitrile group (II) obtained by reaction with cyanic acid, urea, nitrocarbamide, an alkyl isocyanate or N-alkyl urea. A compound of formula (I) is used which is subjected to a kneading in situ reaction without prior isolation. (Priority: December 2, 1976) 32. Process a) according to claim 4 or 8, 12, Process for carrying out the process according to claim 16, 20, 24 or 28, characterized in that the starting material is a compound according to the definition given in claim 1, in a suitable reaction mixture. -241 183,046 of the formula (III) - in which G, Z ¹ and Z ² have the same meaning as given in formula (II) or (III), but G may also be a nitrile group - with cyanic acid, urea, nitrourea, using a compound of formula II obtained by reaction with an alkyl isocyanate or N-alkyl urea, which is subjected to a ring closure reaction in situ without prior isolation. (Priority: June 3, 1976) 33. The process according to claim 29, wherein the starting material is a compound of formula (II) prepared in the reaction mixture which has been reacted with an appropriate alkali metal cyanate in the presence of an equivalent amount of an acid. live. (Priority: June 2, 1977) 34. A process according to claim 30 wherein the starting material is a compound of formula II prepared by reacting the corresponding compound of formula III with an alkali metal cyanate in the presence of an equivalent amount of an acid. live. (Priority: March 23, 1977) 35. The process according to claim 31, wherein the starting compound is a compound of formula (II) prepared in the reaction mixture which has been reacted with an appropriate alkali metal cyanate in the presence of an equivalent amount of an acid. live. (Priority: December 2, 1976) 36. The process according to claim 32, wherein the starting compound is a compound of formula II prepared by reacting the corresponding compound of formula III with an alkali metal cyanate in the presence of an equivalent amount of an acid. live. (Priority: June 3, 1976) 37. A process according to claim 29 wherein the starting material is a compound of formula (II) prepared in the reaction mixture which is a compound of formula (III) with urea, nitrocarbamide, or an N-alkyl. reaction with urea at temperatures below 150 ° C. (Priority: June 2, 1977) 38. A process according to claim 30, wherein the compound of formula (II) prepared in the reaction mixture is a compound of formula (III) with urea, nitrourea, or an N-alkylurea at 150 ° C. Reaction was carried out at a temperature below C. (Priority: March 23, 1977) 39. The process according to claim 31, wherein the compound of formula (II) prepared in the reaction mixture is a compound of formula (III) together with urea, nitrocarbamide, or It was prepared by reaction with N-alkylurea at temperatures below 150 ° C. (Priority: December 2, 1976) 40. The process according to claim 32, wherein the compound of formula (II) prepared in the reaction mixture is a compound of formula (III) with urea, nitrocarbamide, or an N-alkylurea at 150 ° C. Reaction was carried out at a temperature below C. (Priority: June 3, 1976) 41. Process a) of claim 1 or method 5, Process for carrying out the process according to claims 9, 13, 17, 21, 25, 29, 33 or 37, characterized in that the reaction is carried out in the presence of a solvent. (Priority: June 2, 1977) 42. Process a) according to claim 2 or 6, 10, Process for carrying out the process according to claims 14, 18, 22, 26, 30, 34 or 38, characterized in that the reaction is carried out in the presence of a solvent. (Priority: March 23, 1977) 43. Process a) according to claim 3, or process Ί. Process for carrying out the process according to claims 15, 19, 23, 27, 31, 35 or 39, characterized in that the reaction is carried out in the presence of a solvent. (Priority: December 2, 1976) 44. Process a) according to claim 4 or 8, 12, Process for carrying out the process according to claims 16, 20, 24, 28, 32, 36 or 40, characterized in that the reaction is carried out in the presence of a solvent. (Priority: June 3, 1976) 45. A process according to claim 1 wherein G ¹ is a starting material of formula VII wherein carboxy or alkoxycarbonyl is G ¹ wherein Z, Z ¹ and Z ² are as defined in claim 1. applies to. (Priority: June 2, 1977) 46. The process of claim 2, wherein the starting compound of formula VII wherein G ¹ is carboxyl or alkoxycarbonyl is wherein Z, Z ¹ and Z ² are as defined in claim 2. is applied. (Priority: March 23, 1977) 47. The process according to claim 3, wherein the starting compound of formula VII wherein G ¹ is a carboxyl or alkoxycarbonyl group, wherein Z, Z ¹ and Z ² are as defined in claim 3. is applied. (Priority: December 2, 1976) 48. The process according to claim 4, wherein the starting compound of formula VII wherein G ¹ is carboxyl or alkoxycarbonyl, wherein Z, Z ¹ and Z ² are as defined in claim 4. is applied. (Priority: June 3, 1976) 49. The process of claim b) or the process of claim 45, wherein the reaction is carried out under acidic conditions. (Priority: June 2, 1977) 50. Process b) according to claim 2 or 46). -251 A process according to claim 183 046, wherein the reaction is carried out under acidic conditions. (Priority: March 23, 1977) 51. The process of claim b) or the process of claim 47, wherein the reaction is carried out under acidic conditions. (Priority: December 2, 1976) 52. The process of claim b) or the process of claim 48, wherein the reaction is carried out under acidic conditions. (Priority: June 3, 1976) 53. The process of claim b) or the process of claim 45 or 49, wherein the starting material is a compound of formula V as defined in claim 1 in the reaction mixture. Compound VIII: wherein one of Q ₁ and Q ₂ represents a halogen atom and the other represents an amino group, and G ¹ , Z, Z ¹ and Z ² have the same meaning as given in formulas I and VII, respectively, using a compound of formula (VII) which is subjected to a ring closure reaction in situ without prior isolation. (Priority: June 2, 1977) 54. The process of claim b) or the process of claim 46 or 50, wherein the starting material is a compound of formula V as defined in claim 1 in the reaction mixture. Compound VIII: in these formulas, one of Q ₁ and Q ₂ represents a halogen atom and the other represents an amino group, and G ¹ , Z, Z ¹ and Z ² have the same meaning as given in formula I or VU - (VII) which is subjected to an in situ ring closure reaction without prior isolation. (Priority: March 23, 1977) 55. The process of claim b) or the process of claim 47 or 51, wherein the starting material is a compound of formula V as defined in claim 1 in the reaction mixture. VIII) a compound of formula - e wherein Qi and _Q2 are one of a halogen atom, the other amino group represented by G \ Z, Z ¹ and Z and ^Z is the same as the formula (I) or prepared optionally by determining in formula (VII) The compound of formula (VII) is used, which is subjected to an in situ ring closure reaction without prior isolation. (Priority: December 2, 1976) 56. The process of claim b) or the process of claim 48 or 52, wherein the starting material is a compound of formula V as defined in claim 1 in the reaction mixture. Compound VIII: in these formulas, one of Q ₁ and Q ₂ represents a halogen atom and the other represents an amino group, and G ¹ , Z, Z ¹ and Z ² have the same meaning as given in formula I or VII of the formula (VII) which is subjected to an in situ ring closure reaction without prior isolation. ^f (Priority 3 June 1976) 57. The process of claim 53, wherein the starting material is a compound of formula VII wherein G ¹ is alkoxycarbonyl, Q ₁ is amino, Q ₂ is bromo, and Z is selected from the group consisting of: is prepared by reacting a compound of formula (V) or (VIII) wherein R ¹ and Z ² are hydrogen, wherein Z ¹ and Z ² are as defined in claim 1. (Priority: June 2, 1977) 58. The process of Claim 54 wherein the starting material is a compound of Formula VII wherein G ¹ is alkoxycarbonyl, Q ₁ is amino, Q ₂ is bromo, and Z is Z. is hydrogen the compounds (V), (VIII) or - that wherein: Z ¹ and Z ² are as defined above were prepared by reacting in claim 2. (Priority: March 23, 1977) 59. The process of claim 55, wherein the starting material is a compound of formula VII wherein G ¹ is alkoxycarbonyl, Q ₁ is amino, Q ₂ is bromo, and Z is hydrogen. is hydrogen the compounds (V), (VIII) or - that wherein: Z ¹ and Z ² are as defined above were prepared by reacting in claim 3. (Priority: December 2, 1976) 60. The process of claim 56 wherein the starting material is a compound of formula VII wherein G ¹ is alkoxycarbonyl, Q ₁ is amino, Q ₂ is bromo, and Z is hydrogen. is hydrogen the compounds (V), (VIII) or - that wherein: Z ¹ and Z ² are as defined above were prepared by reacting in claim 4. (Priority: June 3, 1976) 61. A process according to claim 1, wherein the reaction is carried out in the presence of a base. (Priority: June 2, 1977) 62. A process according to claim 2, wherein the reaction is carried out in the presence of a base. (Priority: March 23, 1977) 63. The process of Claim 3 wherein the reaction is carried out in the presence of a base. (Priority: December 2, 1976) 64. The method c) according to claim 4, is provided 183 046, characterized in that the reaction is carried out in the presence of a base. (Priority; June 3, 1976) '65. The process of claim 61 wherein the base is an amine, preferably triethylamine or di (i-propyl) amine. (Priority: June 2, 1977) 66. The process of claim 62, wherein the base is an amine, preferably triethylamine or di (i-propyl) amine. (Priority: March 23, 1977) 67. The process according to claim 63, wherein the base is an amine, preferably triethylamine or di-i-propyl) -amine. (Priority: December 2, 1976) 68. A process according to claim 64, wherein the base is an amine, preferably triethylamine or di (i-propyl) amine. (Priority: June 3, 1976) 69. The process of claim c) or the process of claim 61 or 65, wherein the carbonic acid derivative is phosgene, diphenylcarbonate or ethyl chloroformate. (Priority: June 2, 1977) 70. The process of claim c) or the process of claim 62 or 66, wherein the carbonic acid derivative is phosgene, diphenyl carbonate or ethyl chloroformate. (Priority: March 23, 1977) 71. The process of claim c) or the process of claim 63 or 67, wherein the carbonic acid derivative is phosgene, diphenyl carbonate or ethyl chloroformate. (Priority: December 2, 1976) 72. The process of claim c) or the process of claim 64 or 68, wherein the carbonic acid derivative is phosgene, diphenyl carbonate or ethyl chloroformate. (Priority: June 3, 1976) 73. Method c) according to claim 1 or 61, Process for carrying out the process according to claim 65 or 69, characterized in that the reaction is carried out in the presence of an inert aprotic solvent. (Priority: June 2, 1977) 74. Process c) according to claim 2 or 62, A process according to claim 66 or 70, wherein the reaction is carried out in the presence of an inert aprotic solvent. (Priority: March 23, 1977) 75. Method c) according to claim 3 or 63, A process according to claim 67 or 71, wherein the reaction is carried out in the presence of an inert aprotic solvent. (Priority: December 2, 1976) 76. Process c) according to claim 4 or 64, The process of claim 68 or 72, wherein the reaction is carried out in the presence of an inert aprotic solvent. (Priority: June 3, 1976) 77. The process of d) according to claim 1, wherein the reaction is carried out in the presence of a base, preferably an alkali metal hydride, amide or alkoxide, most preferably sodium ethoxide. (Priority: June 2, 1977) 78. A process according to claim 2, wherein the reaction is carried out in the presence of a base, preferably an alkali metal hydride, amide or alkoxide, most preferably sodium ethoxide. (Priority: March 23, 1977) 79. The process according to claim 3, wherein the reaction is carried out in the presence of a base, preferably an alkali metal hydride, amide or alkoxide, most preferably sodium ethoxide. (Priority: December 2, 1976) 80. The process of claim 4, wherein the reaction is carried out in the presence of a base, preferably an alkali metal hydride, amide or alkoxide, most preferably sodium ethoxide. (Priority: June 3, 1976) 81. The method d) of claim 1 or the method of claim ΊΊ. The process according to claim 1, wherein the reactive derivative of the alcohol of the formula R ³ -OH, wherein R ³ is as defined in claim 1, is the corresponding chloride, bromide, iodide or sulfonate, preferably the bromide derivative. (Priority: June 2, 1977) 82. The process of claim 2 d) or the process of claim 78, wherein the reactive derivative of the alcohol of the formula R ³ -OH, wherein R ³ is as defined in claim 1, is the corresponding chloride. , bromide, iodide or sulfonate, preferably the bromide derivative. (Priority: March 23, 1977) 83. The process according to claim 3, d) or the process according to claim 79, wherein the reactive derivative of the alcohol R ³ -OH wherein R ³ is as defined in claim 1 is the corresponding chloride. , bromide, iodide or sulfonate, preferably the bromide derivative. (Priority: December 2, 1976) 84. The process according to claim 4, d) or the process according to claim 80, wherein the reactive derivative of the alcohol of the formula R ³ -OH, wherein R ³ is as defined in claim 1, is the corresponding chloride. , bromide, iodide or sulfonate, preferably the bromide derivative. (Priority: June 3, 1976) 85. A process according to claim 1, wherein the reduction is catalytic. -271 183 04 hydrogenation. (Priority: June 2, 1977) 86. A process according to claim 26 wherein the catalyst is Raneynikkel, platinum, palladium, ruthenium or radium. (Priority: June 2, 1977) 87. The process of Claim 1, wherein the reducing agent is tin (II) chloride. (Priority: June 2, 1977) 88. A process for the preparation of process g) according to claim 1, wherein the starting compound containing X ² is a nitrile group, otherwise defined above, and is reacted with sodium azide. (Priority: June 2, 1977) 89. The process according to claim 1, wherein the reducing agent is sodium borohydride and the starting compound is an anhydride or an acid, wherein X ² is a mixed anhydride, otherwise defined in formula (I). employed. (Priority: June 2, 1977) 90. A process according to claim 1 wherein the starting material is an ester as defined in claim 1 g) and the reducing agent is diisobutylaluminum hydride. (Priority: June 2, 1977) 91. The process of claim 1, wherein the hydrolyzing agent is an alkali metal hydroxide or sodium oxide in an aqueous medium. 92. A process for the preparation of a pharmaceutical composition comprising the hydantoin derivative of the formula I as claimed in claim 1, wherein Z, Z ¹ and Z ² are as defined in claim 1, or a salt or ester thereof in solid, liquid or semi-liquid pharmaceutical carrier and / or by mixing with other pharmaceutical auxiliaries is converted to ⁵ suitable for oral, rectal or parenteral administration formulation. (Priority: June 2, 1977) 93. Process for the preparation of pharmaceutical preparations, Characterized in that a compound of formula (I) according to claim 2, wherein Z, Z ¹ and Z ² are as defined in claim 2, or a salt or ester thereof, with a solid, liquid or semi-liquid pharmaceutical carrier; or by mixing with other pharmaceutical excipients to form a composition for oral, rectal or parenteral administration. (Priority: March 23, 1977) * 94. A process for the manufacture of a pharmaceutical composition, Characterized in that a hydantoin derivative of formula (I) according to claim 3, wherein Z, Z ¹ and Z ² are A salt or ester thereof as defined in claim 3, by mixing it with a solid, liquid or semi-liquid pharmaceutical carrier and / or other pharmaceutical excipient to form a composition suitable for oral, rectal or parenteral administration. (Priority: December 2, 1976) 95. A process for the preparation of a pharmaceutical composition comprising the hydantoin derivative of the formula I as claimed in claim 4, wherein Z, Z ¹ and Z ² Or a salt thereof Ester 35 is formulated with a solid, liquid or semi-liquid pharmaceutical carrier and / or other pharmaceutical excipient to form a composition suitable for oral, rectal or parenteral administration.