DE2724948A1 - HYDANTOIN DERIVATIVES, THE PROCESS FOR THEIR MANUFACTURING AND THEIR USE IN PHARMACEUTICAL PREPARATIONS - Google Patents

Description

DR. BERG DIPL-INCi. STAr ¹ F DIPL-ING. SCHWABE DR. OR. MNDVAIR

P.O. Box 860245, 8000 Munich 86

Lawyer File 28 Ή1
Be / Sch

The Wellcome Foundation Ltd. London / England

"Hydantoin derivatives, process for their production and their use in pharmaceutical preparations"

This invention relates to heterocyclic compounds, their Manufacture, preparations containing them and their use in medicine.

Hydantoin derivatives as defined below in the general formula (I) have pharmacological properties similar to those natural prostaglandins are related, as evidenced by this

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their ability to mimic or antagonize the physiological effects of natural prostaglandins in various biological preparations. In particular, certain compounds of the general formula (I) have very strong mimicking properties of the platelet anti-aggregation properties of prostaglandin E _x,.

The compounds according to the invention have the general formula (I) on

No. ¹

N I (I),

in which Z is a hydrogen atom or an alkyl group, one of the radicals z ' ¹ and Z by the group -CH ₂ -XI ¹ -r, in which X is phenylene-, -CSC-, cis- or trans -CH-CH- or -CHg -CQg group, in which each radical Q, independently of the other, is hydrogen and alkyl such as ethyl or the two Q radicals together form an alkylene radical having 4, 5 or 6 carbon atoms, the radical X is a covalent bond or a straight bond or branched alkylene chain having 1 to 6 carbon atoms, in which one of its methylene groups is optionally replaced by an oxa (-O -) group, with the proviso that at least one carbon atom is the oxa group of a -CC-, -CH-CH- or -CO group separates and X ^{2 is} a 5-tetrazolyl, carboxyl, carboxamide, hydroxymethylene or alkoxycarbonyl group

P ^{e i8t} '709850/1083

and the other of the radicals Z ¹ and Z ² by the group

272A948

-Y-Y-Y -Y ^ is displayed,

where T is a -CR ₂ -CHo group in which each radical R, independently of the other, is hydrogen and / or methyl, Y is a carbonyl, methylene, methylene substituted by a hydroxyl group or a hydroxyl and alkyl group -

P.
tuated methylene group, Y is a covalent bond or a straight or branched alkylene group with 1 to 7 carbon atoms, which is optionally substituted on the carbon atom adjacent to the radical Y by one or two independent alkyl, bicycloalkyl or cycloalkyl groups, Y * is hydrogen -, Hydroxy, Akoxygruppe with up to 7 », preferably 1 to 4 carbon atoms, cycloalkyl, bicycloalkyl, phenyl, benzyl, phenoxy or benzyloxy group, in which each phenyl, benzyl, phenoxy and / or benzyloxy group in the benzene ring can be substituted by one or more hydroxy, halogen, nitro, amino, acylamino, alkenyl, alkoxy, phenyl and alkyl groups, which can themselves be substituted by one or more halogen groups or Y is a bond, a -CH ₂ - or -CH ₂ .CH ₂ group and the radicals Y, Y and Y together form a cycloalkyl group which is substituted by a hydroxyl group, preferably with 3 carbon atoms, which si Separate e from the hydantoin ring.

Unless otherwise indicated, in formula (I) and in other formulas in this description, the alkyl parts are methyl, ethyl, propyl, butyl, pentyl and hexyl groups, including all of their isomers.

For example, in the definitions for Y ¹ and Y ^2, the alkyl groups are preferably methyl groups and the alkyl moiety is

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The alkoxycarbonyl group is desirably a methyl or ethyl group. Similarly, the alkylene groups have 2 to M carbon atoms and are, for example, vinyl groups.

In the general formula (I), the cycloalkyl groups have 5 to 10 and bicycloalkyl groups 4 to 10 carbon atoms, for example Adamantyl groups.

In a compound of the general formula (I) the bond of the divalent phenylene group can be in the ortho, meta or para position and the oxa group is preferably adjacent to the phenylene group or if X has a meaning other than phenylene, the radical X can be -CH ₂ -O-CH ₂ -.

Included in the meanings of the links of the general Formula (I) are the salts of the corresponding carboxylic acids and tetrazoles when X ^ is a carboxyl or tetrazolyl group and the salts which can also be formed when Z is hydrogen. Particularly valuable for medical purposes Salts have a pharmaceutically acceptable cation such as ammonium or that of an alkali metal, for example sodium or potassium, an alkaline earth metal, for example calcium and magnesium, or an organic base, in particular an amine such as ethanolamine. Salts with non-pharmaceutical Compatible cations also fall within the scope of the invention as valuable intermediate products for production pharmaceutically acceptable salts or the acid or ester of the general formula (I).

7 0 Q 0 5 0/1 0 8 3

-> β- 2 7 2 Λ 9 Λ

Unless a clear statement indicates otherwise, the includes general formula (I) and the other formulas in this description all stereoisomers represented therein “In particular the formulas include the enantiomeric forms, such mixtures, which are referred to as racemates, and diastereoisomers.

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It was found that compounds of the general formula (I), wherein

Z is hydrogen or an alkyl group with 1 to 4 carbon atoms, for example methyl or butyl, one of the radicals Z ¹ and Z ² -CH ₂ -XX ^ -X-, wherein X and x ' ¹ together are an alkylene group with 3 to 7, im special 5 Koh-

Forming fuel atoms and X is an alkoxycarbonyl, carboxyl group is or a salt thereof,

ι? Ί? 'S and the other of Z ¹ and Z is -YYYY ^, wherein

1 2 -5

Y, Y and Y has the meaning defined above and Y ^ is hydrogen, a phenyl or benzyl group or a cycloalkyl group with 4 to 7 carbon atoms ,

properties related to prostaglandin of particular interest exhibit. Within this definition, the subclass is

1 Ί 2

hold, wherein the radical Z is hydrogen and Z is -CH ₂ -XX -X ₁ as defined.

The compounds of the general formula (I) can be prepared for the preparation of compounds by any of the processes known to the person skilled in the art analog structure can be produced. For example, they can be prepared by having the appropriate Derivatives of hydantoic acid of the general formula (II)

No. ¹

ZN N

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wherein G is a carboxyl group or a derivative thereof such as an amide or an ester, especially an alkyl ester, and

1 2
each of the radicals Z, Z and Z has the same meaning as in the general formula (I), cyclized under acidic conditions or heated alone. The reaction can be carried out in the absence of a solvent, however, if desired, an inert solvent, for example a hydrocarbon such as gasoline, can be used. However, if G is an alkoxycarbonyl group, the cyclization can optionally be effected in the presence of a suitable base, for example an alkoxide such as sodium ethoxide.

The compounds of general formula (II) are expedient produced by an amino acid derivative of the general formula (III)

GZ ¹

(in),

HN

Ί 2

wherein G, Z and Z have the meanings defined in the general formula (I), with the proviso that G as Ni, is tril with cyanic acid or an alkyl isocyanate depending upon whether Z is a hydrogen atom or an alkyl group is reacted, .

If cyanic acid is used, the cyanic acid is expediently formed in situ using an alkali metal cyanate, for example potassium cyanate, and an acid which is used as the acid addition salt of the compound of the general formula (III)

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or as a free acid of the general formula (III)

ρ can be where one or both of R and X are hydrogen. However, an equivalent amount of mineral acid can also be used or organic acid can be added to the reaction medium. The reaction can take place without a solvent, however desirably an inert solvent is used which is preferably polar, such as water or a mixture of water with acetone, dimethylformamide, dimethyl sulfoxide or a lower alkanol, v / ie ethanol or it can be a hydrocarbon, an ether or a halogenated hydrocarbon, like chloroform. If desired, for example, if no solvent is used, the reaction can be carried out by heating the reactants.

Similar reaction conditions can be used when an alkyl isocyanate is used, except that it is unnecessary to introduce an equivalent amount of acid, such as an acid addition salt or otherwise, into the reactants.

Instead of using a cyanate or isocyanate, a compound of the general formula (III) can be reacted with urea, nitrourea or an N-alkylurea, depending on suitability. A solvent is not essential but if desired an inert solvent, are venvendet as mentioned above, wherein the reaction is preferably carried out at an elevated temperature, for example from 100 to 125 ° C is effected, but temperatures are used up to 150 ⁰ C. can.

In the procedure described above, the intermediary

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products of the general formula (11) cannot be isolated from the reaction mixture and can be converted directly into the compounds the general formula (i) under the conditions described be convicted.

An intermediate product of the general formula (lii) can zv / ecklich be prepared by a compound of the general formula (IV) with a prebindun ;; eggs general Formula (V)

G ¹

V 2

J (IV) Q-Z "(V ;,

Ί 2
in which the radicals G, Z and Z are defined in the formula (Hj)

Ί have 2nd meaning, one of the radicals ψ and Q is an amino group and the other a halogen group, preferably bromo i.ct, implements. The reaction can be carried out by heating without solvents or in the presence of an inert solvent such as achanol, be performed.

The intermediates of the general formula (TlE), where Z ^£ "

Ί 2 ⁷ J 1

-Υ-Ϊ -x -1 ^J , can, if 1 is a carbonyl group, also be prepared by an amine of the general formula (IV), in which Q is an amino group, with an unsaturated ketone of the general formula (Vl )

GR ₂ = GlLCO. Ϊ ² . Y ⁵ (Vx),

2 3
wherein Y and Y ^ have the same meaning as in the general formula (III), reacts, the reaction in counter

709850/1083 ORIGINAL BATHROOM

was or without an inert solvent at room temperature or optionally effected with heating.

The hydantoins of the general formula (I) can also be prepared by adding a compound of the general formula Formula (VlI)

(VII), G.

wherein Z, Z and Z are those defined in the general formula (I) Have meaning and G is a carboxyl group or a reactive derivative thereof, such as an alkoxycarbonyl group, ζφη example is ethoxycarbonyl, cyclized. The connections of the general formula (VII) can be cyclized under conditions similar to those of a compound of the general formula (II) and conveniently the process used for the preparation of a compound of the general formula (VII) selected so that the prevailing reaction conditions permit spontaneous cyclization.

For example, the intermediates of the general formula (VII) can be prepared by adding a compound of the general formula (V) with a compound of the general formula (VIII)

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_Q 2_ _Z 2 _(v) ZN 1 (VIII),

1 2
wherein one of the radicals Q and Q is halogen, preferably chlorine or bromine and the other is an amino group and each of the

Ί 2 1
Z, Z, Z and G radicals have the same meanings as in the general formula (VII). The reaction can be effected by mixing the reactants or, if necessary, an inert solvent is used and the mixture is heated. Suitable solvents include alkanols, ethers, hydrocarbons and halogenated hydrocarbons.

The compounds of the general formula (VIII) can be prepared as such by adding a suitable carbamic acid derivative, for example an alkyl ester, with a compound of the general formula (IV) using general, implements methods known to the person skilled in the art.

In a process related to those described above, the hydantoins of the general formula (I) can be prepared thereby be. that one is a compound of the general formula (IX)

ZN
H

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Λ ?
wherein each of the radicals Z, Z and Z "has the same meaning as in the general formula (1), is reacted with a carbonic acid derivative. Any carbonic acid derivative known to the person skilled in the art can be used, such as, for example, phosgene, diphenyl carbonate or a The reaction is desirably effected in the presence of a base such as an amine such as triethylamine or diisopropylethylamine and using an inert aprotic solvent such as toluene, dimethylformamide or an ether such as diethyl ether. The reaction can be carried out at room temperature but, if desired, the reaction mixture can be heated.

The intermediates of the general formula (IX) can with Use of processes analogous to those described above for the preparation of the compounds of the general formula (III), produced v / earth.

The hydantoins of the general formula (I) in which Z is an alkyl group is can also be prepared by using an alkylating agent that acts as a reactive Ester derivative of an alcohol J .OH can be designated a compound of the general formula (X)

NOTHING)

.N

\ j ²

alkylated, where J is hydrogen or alkyl, j ' ^{1 is} hydrogen or

709850/1083

Z, J is hydrogen or Z and J ^y alkyl, Z or Z, with the proviso that one of the ties te J, J and J is water toi 'f and J must not have the same meaning as J, u and J ^ ,

1 ° ο 1

where in the definition of ύ, J "" and J, ieder der ;; cüte '/, and Z has the same meaning as in the general j'or.-nel (J). Suitable reactive ester derivatives include chlorides, bromides, iodides and sulfonates such as p-1'oluenesulfonate, methanesulfonab and benzene sulfonate. The alkylation can be effected using reaction conditions which include -.ion. ? i 'Achmann as such as r; ^eei:; net are known beispielsv / else in Gegenv / art a base ■ .: ic a Alkalinietalltiydrids, Ali: alimetallamids or alkali metal alkoxide, typically sodium hydride or ilatriumalkoxid, for r> ei.sj ) iel nutriuiiiinethoxid. The reaction is expediently carried out in an inert ij5sun -; sniittel, which / in some cases serves as a diluent for the reaction partner, such as in toluene, dioxane, ether, methylformamide, tetrahydrofuran, dimethyl sulfoxide or aceronitrile or it can if the base is an alkali metal alkoxide the corresponding alkanol can be used.

It should be noted that the intermediate products of the general formula (X), in which J is hydrogen, also compounds of the general formula (I) and can be prepared by one of the preceding processes. The connections of the general formula (X) can furthermore be prepared by adapting processes already known to the person skilled in the art (see, for example, Chemical Heviews (1950) 4-6, pp. 403-425).

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The compounds of the general formula (I) can also be prepared by having a corresponding unsaturated Compound of general formula (XI)

L

, 3

Z N I (XI),

4 Z

wherein either the radical Z ⁵ = Cfi-CH ₂ -Y ¹ -Y ² -Y ^ and Z ^ -GHp-XX ¹ -X ^ or the radical T? = CH-XX ¹ -X ² and Z ⁴ -YY ¹ -Y ² -Y ⁵ , in which each of the radicals R, X to X ² and Y to Y * have the meaning defined in the general formula (I), with a suitable reducing agent.

A suitable reducing agent is tin (II) chloride, which is found in an aqueous solution, optionally in the presence of a dilute one Mineral acid can be used or the catalytic hydrogenation in the presence of, for example, Raney nickel, Platinum, palladium, ruthenium or rhodium. The choice of reducing agent in a given Situation becomes naturally reactive by the present / the other Groups in the molecule which as such can be accessible to reduction are determined.

The intermediates of the general formula (Xl) can by means of the following reaction sequences can be established:

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\ S * ^ 4 4

CH + G-Z> CH

NH ₂ NH

(XII)

^{H +}

ZN

^N z ^

(XIV) (XIII)

(XI)

In the preceding formulas, the radicals Z, Z, Z and G have the same meanings as in the general formulas (XI) and (III), where G * is an alkyl group, for example an n-butyl group, and G is halogen, such as bromine . The formation of the compound of the general formula (XIII) takes place analogously to the ring closure of a compound of the general formula (II) and the compounds of the general formula (XIV) are prepared using concentrated mineral acid, such as hydrochloric acid.

The tetrazoles of the general formula (I) can be prepared from the corresponding compounds in which the group -X ^{2 is} replaced by the group -Q- * N in which the radicals

P 709880/1083

X * and X together form a bond (nitrile), 1? Hydrogen or alkyl and X is alkoxy (imidoester), alkylthio (imidothioester), -NH-NH ₂ (amidrazone) or amino (amidine) or R- ^ hydroxy and R is amino (amidoxime). The reaction is preferably carried out in a polar aprotic liquid medium, such as dimethylformamide, using a salt of a hydrazoic acid, for example sodium azide. However, if XT is replaced by an amidine or amidrazone, nitrous acid is a suitable reagent. If an amidine is reacted with nitrous acid, then reduction of the nitrosation intermediate, with or without isolation, using, for example, sodium amalgam, is required to form the corresponding tetrazole . The tetrazole precursor can be obtained by known methods, for example the nitrile by dehydrating the corresponding amide.

The alcohols of the general formula (I) in which λ is hydroxymethylene is, can also by reduction with a suitable reducing agent of the corresponding acid, the ester, Acid halide, acid anhydride or aldehyde can be obtained. The appropriate reducing agent will depend on the particular substrate dependent, however, reactants that can be used are sodium in ethanol · In particular can, for example, a carboxylic acid to a corresponding mixed anhydride with ethyl chloroformate in the presence of a Base, such as triethylamine, and then reduced to an alcohol using sodium borohydride. In a similar way, an ester can be converted into an alcohol

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in turn of 1) isobutylaluminum hydride in a medium solvent, like ether, or hydrocarbons like hexane or benzene, be reduced. Such alcohols can also pass through catalytic hydrogenation can be produced.

Optionally, the alcohols of the general li'oi.'inel (ι.), Wherein X is an itydroxymethylene group by means of hydrolysis of one corresponding halide produced with a suitable agent v / earth. For this purpose a L yd rox ixi, he isi> can be used An aqueous alkali or a suspension of silver oxide used in water.

For the production; the hydantoine of all ¹ oniei nen i / ormel (.i} with a hydroxyl group in a side chain It is desirable to protect this during the course of the lieaktion.This can easily be done in a known manner using a protecting group such as an acyl, aroyl -, tetrahydronn-2-yl, 1-ethoxyethyl or araikyi, for example üensyl group.

The removal of the protective group can be carried out by means of methods known to the person skilled in the art; for example can
an acyl group by acid odex · base hydrolysis and a
Benzyl group can be removed by reductive cleavage.

Furthermore, a ketone of the general i'Ormel (I), wherein
Y is a carbonyl group to the corresponding secondary
Alcohol can be converted by reduction with a suitable reducing agent, for example sodium borohydride.

7098 50/1083 BATH ORIGINAL

j ₁ 272A948

Furthermore, an alcohol of the general formula (I), wherein Y ^ is a -CH.OH group to the (Corresponding ketone under Oxidized using Jones reagent, acid dichromate, or any other suitable reagent.

Similarly, provided the compounds of general Formula (I) have a -C ^ C- or -CH = CH- bond, these by means of conventional hydrogenation processes, for example using a catalyst of the Lindlar or Adams type, to the corresponding ethylenic or saturated compound, depending on the suitability.

The hydantoins of the general formula (I) are asymmetrical 5-carbon atom and another asymmetric center are contained in the compounds, in which Y is a hydroxyl * * group has. Such alcohols accordingly exist as four isomers, by means of thin-layer chromatography or high-performance liquid chromatography are separable into two diastereomers, each of these two being a racemic mixture of ζweisomere is. A diastereomer can be used to separate the diestereomers to a mixture of four isomers by treatment with a base such as an alkali metal hydroxide, and then again Separation converted to form two diastereomers will. Repeated use of this procedure enables efficient conversion of one diastereomer to the other; this may be desirable when one diastereomer has a preferred biological activity over the other.

The corresponding alcohols of the general formula (III) are

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also exist in four isomeric forms. If desired, these can be separated into two epimers and then made into one compound of the general formula (I) are cyclized while maintaining the stereochemical configuration.

In all of the processes described above, it is of course clear that the selection of the reactant is partial is dictated by the functional groups present in the substrate and, if necessary, reactants must can be used with an appropriate selectivity of action.

The hydantoins of the general formula (I) are valuable in terms of their pharmacological properties, which are related to those of the natural prostaglandins, ie that the hydantoins enhance the biological effects of the various prostaglandins (PG) of the ¹ A ¹ -, ¹ B'-, ¹ C- Mimic or antagonize, ¹ D ¹ , ¹ E ¹ , and 'F' rows. For example, it has been found that the hydantoins of the general formula (I) _{mimic the antiaggregatory effect of PGE 11} on blood platelets and the PGE2 or PGF _2- induced contraction of the smooth muscles that affect the stomach of rats, the large intestines of rats, the rectum from chicks and guinea pig trachea antagonize. In general, antagonistic as opposed to mimetic properties were observed when larger doses of the hydantoins were used. The pharmacological profile, by which the relative efficacy, mimetic or antagonistic, is to be understood in comparison to the natural prostaglandins for ? F & a eWjr ^ i M ¹ S * ¹³ - ^{011 of the s} P ^ezi fi

see eligible hydantoin being dependent.

With regard to their prostaglandin-related properties are the hydantoins of the general formula (I) in terms of pharmacological characterization and differentiation the biological activities of the natural prostaglandins and their "receptors". Further understanding of the The physiological role of prostaglandins is natural in terms of finding new and improved therapeutic ones Substances valuable.

The hydantoins of the general formula (I) are also valuable as therapeutic agents. In particular, hydantoins are as previously described with a strong antiaggregatory effect on platelets, valuable if so desired becomes, the blood platelet (thrombocyte) aggi'egat ion to inhibit or reduce the adhesive nature of platelets and they can be used to treat or prevent the Thrombosis formation in mammals, including humans, can be used. For example, the compounds are suitable for the treatment and prevention of myocardial infarctions, for the treatment and prevention of thrombosis, for promotion the open or patency of vascular grafts after surgery and to treat complications of atherosclerosis and conditions such as atherosclerosis, blood clotting defects as a result of lipemia and other clinical conditions that are related to the underlying etiology is associated with an impaired lipid balance or hyperlipidemia. Another use of such compounds is

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as an additive to blood and other fluids used for artificial Circulation and perfusion outside the body can be used by isolated body parts.

A group of compounds which are particularly useful as inhibitors of platelet aggregation are those of the general Formula (I), wherein Z is hydrogen, Z is carboxyalkylene, where-

2 rin the alkylene part has 3 to 9 carbon atoms, and Z one

Group - (CH ₂ ) ₂ .CH.OH.Y ² .Y ^ is where Y ^{2 is} a branched alkylene having a tertiary carbon atom adjacent to the hydroxy-substituted carbon and Y has the meaning defined in the general formula (I). It has been found that within this group of compounds, those in which Z is a carboxyhexyl group and the radical Y * is a cycloalkyl group having 4 to 7 carbon atoms are particularly effective.

It has further been found that the hydantoins of the general formula (I) is a relaxation of the vascular smooth muscle in a similar way as cause the members of the prostaglandin ¹ A ¹ - and 'E' series. Examples of such compounds are 5- (6-carboxyhexyl) -1- (3-hydroxy-4,4-dimethyloctyl) hydantoin and 5- (6-carboxyhexyl) -1- (3-hydroxy-4,4-dimethyl-5-pbenylpentyl) - hydantoin. Compounds that relax the vascular smooth muscles are suitable for inducing vasodilation and accordingly have antihypertensive properties and are suitable for lowering blood pressure

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pressure in mammals, including humans, and can be used alone or with a ß-adrenoceptor blocking agent or another antihypertensive substance used to treat all Levels of hypertension including essential, malignant, and secondary hypertension can be used.

The compound 5- (6-carboxyhexyl) -1- (3-hydroxy-4-.4-dimethyloctyl) hydantoin mimics the effects of PGE. with regard to the Antagonization of histamine-induced bronchial constriction after. The hydantoins of the general formula (I) with this Property can be used to treat or prevent bronchial asthma and bronchitis by providing relief with these Conditions related bronchoconstriction can be used.

The hydantoins of the general formula (I), such as 5- (6-carboxyhexyl) -1- (3-hydroxyoctyl) hydantoin, 5- (6-carboxyhexyl) -3-methyl-1- (3-oxooctyl) hydantoin, 5- (6-carboxyhexyl) -1- (3-oxooctyl) hydantoin and 5- (6-carboxyhexyl) -1- ( ^/ 4-phenoxybutyl) hydantoin, which inhibit pentagastrin-induced gastric acid secretion and the formation of aspirin reduce induced gastric damage in rats are valuable for reducing excessive gastric acid secretion, reducing and preventing the formation of gastric and intestinal ulcers, and accelerating the healing of such ulcers that are already present in the gastrointestinal tract, whether spontaneous or spontaneous as a component of polyglandular adenoma syndromes.

It has been found that intravenous infusions are certain

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Hydantoins of the general formula (I), typically from 5- (6-carboxyhexyl) -1- (3-hydroxyoctyl) hydantoin, increase the volume of urine in dogs, which results in the potential utility of such compounds as diuretics; their use in the treatment of edema, for example edema associated with heart, liver or kidney failure in humans or other mammals.

Another use of the hydantoins of general formula (I), which _{mimic the uterine smooth muscle effects} of PGE ₂ and PGF 2o, is as an anti-fertility agent, for example as an abortion agent.

The amount of a compound of general formula (I) required to achieve the desired biological effect will of course depend on a number of factors, for example the specific compound selected, the use for which the compound is intended, the mode of administration and the like Recipient. In general, the daily dose can be expected to range from about 1.0 µg to 20 mg per kg of body weight. For example, an intravenous dose can be in the range from 5 / Ug to 1 mg / kg, whereby it should expediently be administered as an infusion at 0.01 to 50 / Ug per kg / minute. Suitable infusion liquids for this purpose can contain 0.001 to 100, for example 0.01 to 10 ^ ug per ml. Unit doses can contain 10 / Ug to 100 mg of a compound of the general formula (I) and , for example, ampoules for injection 0.01 to 1 mg and orally administrable dosage units such as

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Tablets or capsules, 0.1 to 50, for example 2 to 20 mg Contain active ingredient.

When a compound of the general formula (I) is used in particular for inhibiting platelet aggregation
it is generally desirable to have a concentration in the corresponding liquid, whether it is the blood of a
Patient or a perfusion fluid, of about 1 / Ug
to 10 mg, for example 10 / Ug to 1 mg per liter.

The doses given above relate to the acids, amides, lister, alcohols and tetrazoles of the general formula (I); If a salt is used, the dose depends on it
the corresponding anion.

For the treatment or prophylaxis of the abovementioned conditions, although the hydantoin compounds can be used as such, they are presented as a pharmaceutical formulation with a carrier suitable for this purpose. The carrier
must of course be "suitable" in the sense that he is compatible with the
is compatible with other components of the formulation and
exerts no adverse influence on the recipient. Of the
Carrier may be a solid or a liquid and is preferably formulated with a hydantoin compound as a unit dose, for example as tablet which may contain from 0.05% hydantoin compound to 95 wt.. Other pharmacologically active substances can also be present in the formulations of the present invention as indicated above. The hydantoin compounds a icöiKi * a ia jdÄÄ formulations

ORfGINAL INSPECTED

which in the form of the acid or as its salts or ii ^ tcr oin: _. · & - and the formulation can be rounded by means of all methods known in the field of pharmacy, i.e. in the following: - by mixing the components of the formulation will.

The formulations as such can be used for oral, rectal, local (buccal, for example sub-1 in; ualenj, paret net be obv / OHL the zweckmäijifsce ,; GR in a i '.- ESS ^- depen planar case ^ i ^, will be of the haüur and dm · pivoting the re intended for treatment Bedin; _un;; and dor i .utur of hydantoin pre-binding.

The formulations suitable for oral administration can presented as separate i'Jinheitori, like air. Karvjcin, Cachettes, lozenges, or tablets, each of which has a predetermined definition of the hydantoin compound; enUhalts; as powder or granules; as a solution; or suspension in a wüijri,; eii Liquid or in a non-aqueous liquid; as one Oil-in-water emulsion or as a jasser-in-oil emulsion. Such Formulations can be prepared by any of the methods known in the pharmaceutical field, although all of these processes include the step of bringing together the liydantoin compound with the carrier, which forms one or more additional components. Generally will by uniformly and intimately mixing the hydantoin compound with liquid or finely divided solid carriers or with both and then, if necessary, aas

709850/1083 BAD OFHG » ^NAL

-γ. · 272Α948

Product brought into the desired shape. For example, can a tablet can be produced by optionally using a powder or granules of the hydantoin compound one or more additional components pressed or deformed. Compressed tablets can be compressed, in a {suitable device, the hydantoin compound in a free fixing form, such as a powder or granules, if appropriate mixed with a binder, lubricant, inert diluent, surfactant or dispersant getting produced. Molded tablets can be made by in a suitable machine the powdered hydantoin compound moistened with an inert liquid diluent.

For formulations intended for buccal (sub-lingual) administration suitable include lozenges, which are a hydantoin compound in a flavor base, usually sucrose and Acacia or tragacanth contain} as well as lozenges that contain a hydantoin compound in an inert base, such as gelatin and contain glycerin, or sucrose and acacia.

The formulations of the present invention which are used for parenteral Suitable for administration include suitably sterile aqueous preparations of a hydantoin compound, the Preparations are preferably isotonic with the blood of the intended recipient. These preparations are preferably intravenous administered, although administration can also be by subcutaneous or intramuscular injection. Such Preparations can expediently be produced by

709850/108 3

that you mix the hydrant compound with water and that Makes product sterile and isotonic with blood.

Formulations suitable for rectal administration, are preferably presented as unit dosage suppositories. These can be prepared by the hydantoin compound with one or more of the usual solid Carriers, for example with cocoa butter, mixes and gives the resulting mixture the desired shape.

In summary, it should be pointed out that after the description, the invention, the following subjects, in the first place Line includes, for example, but not limited to:

(a) The new compounds of the general formula (I) as defined above.

(b) A process for the preparation of the new compounds of the general formula (I) as described above.

(c) A pharmaceutical formulation comprising a compound of the general formula (I) together with a pharmaceutical suitable carrier, as well as methods of making such formulations.

(d) A method of lowering blood pressure in mammals, including Humans, to which the mammal is given an effective hypotensive, non-toxic amount of a general compound Formula (I) administered.

(e) A method of treatment or prophylaxis of thrombosis in mammals or mammalian tissues, including humans,

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including a non-toxic, effective antithrombotically effective amount of a compound of the general formula (I) administered.

(f) A method of causing vasodilation in mammals, including humans, by providing the mammal with a non-toxic v / effective vasodilator amount of a compound of the general formula (I) administered.

(rc) Method for the treatment or prophylaxis of gastric damage in mammals, including humans, for what purpose Teat a non-toxic effective prophylactic or therapeutic amount of a compound of the general formula (I) administered.

(h) A method of causing bronchodilation in mammals, including humans, by giving the nipple a administered non-toxic, effective bronchodilator amount of a compound of the general formula (I).

(i) A method of treatment or prophylaxis of allergic Conditions in mammals, including humans, of which the teat is given a non-toxic effective prophylactic or a therapeutic amount of a compound of the general formula (I) is administered.

(j) A method of causing the abortion of a fetus in a mammal, including humans, by providing the mammal with a non-toxic effective abortion-causing amount of a compound of the general formula (I) administered.

(k) Methods of inducing infertility in mammals, including humans, which are not given to the suckler

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administered toxic effective contraceptive amount of a compound of the general formula (I).

(1) A compound of the general formula

J ¹

1 2 wherein two of J, J and J are the same as

1 2 zv / ei of the radicals Z, Z and Z, as above in the formula

(I) and the other is hydrogen.

(m) A compound of the general formula

Z — N \

Y ^ z *

wherein M is a> C = Z ^ -,> CH-CHO- or> CH-CH (OG ^) ₂ ~ group and Z, Z ^, Z and G * are those defined in formulas (XI) and (XII), respectively Have meanings.

(n) A compound of the general formula

1 1 p

wherein M -Q as defined in formula (VIII), or -NH-Z

and Z, Z ¹ , Z and G ¹ are as defined in formula (VII), except that G can also be hydrogen.

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The invention is further illustrated by the following examples.

example 1

Production of 5- (6-carboxylhexyl) -1- (3-hydroxy-4-.4 - dimethyl-5-phenylpentyl) -hydant oin
A. Diethyl 2-aminononanedioate

Diethylacetamidomalonate (16.7 g) and ethyl 7-bromoheptanoate (16.6 g) are dissolved in ethanolic ethoxide (prepared from sodium (1.51 s) and absolute ethanol (30 ml)) and the mixture is refluxed for 27 hours . The cooled solution is poured onto ice water, the product extracted into ether and the dried extract evaporated to give crude diethylacetamido (6-ethoxycarbonylhexyl) malonate as pale yellow 01, ^ 2.2 (3H, singlet, -COCH ₃ ), 4.17 (6H , Multiplet, 3 x -OCH ₂ -CH,). This amide is refluxed for 5 1/2 hours with concentrated hydrochloric acid (111 ml), the cooled solution is washed with ether, the aqueous layer is decolorized with activated charcoal and evaporated to dryness in vacuo. The colorless glass obtained as residue is dissolved in the minimum amount of absolute ethanol and there is added dropwise with stirring to a cooled (-10 ⁰ C) mixture of absolute ethanol (125 ml) and thionyl chloride (15 »7 g). The solution obtained is set aside at room temperature for 1 hour, refluxed for 11/2 hours, cooled and poured into ice water which is adjusted to p = 9 with aqueous sodium hydroxide. Extract the mixture with ether and concentrate the dried extract and distill to give diethyl 2-aminononanedioate (55 # yield) as

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272Λ9Α8

colorless oil, boiling point 114 to 115 ° C / O, O2-O, 3 Torr.

B. Diethyl 2- ((4,4-dimethyl-3-oxo-phenylpentyl) -amino) -nonanedioate

To diethyl 2-aminononanedioate (5.18 g) is added dropwise 4.4-Dimethyl-5-phenylpent-1-en-3-one (3.95 g) with cooling and stirring. The mixture is left at room temperature for 21 hours and receives diethyl 2- (4,4-dimethyl-3'oxo-5-phenylpentyl) amino) nonanedioate.

C. Diethyl 2- (3-hydroxy-4,4-dimethyl-5-phenylpentyl) amino) nonanedioate

The crude ketone obtained beforehand (5.1 g) is dissolved in absolute Ethanol (70 ml) and stir the solution in an ice bath while gradually adding sodium borohydride (380 mg). Man stir the solution in the ice bath for a further 10 minutes and leave it to stand for 5 hours at room temperature. One vaporizes the largest one Part of the alcohol, add water and acidify the solution to Pu 6. The insoluble oil is extracted with ether and dried the ethereal solution and evaporates to form diethyl 2- (3-hydroxy-4-.4-dimethyl-5-phenylpentyl) -amino) -nonanedioate as a pale yellow oil that is used without further purification.

D. 5- (6-Ethoxycarbonylhexyl) -1- (3-hydroxy-4,4-dimethyl-5-phenylpentyl) hydantoin and the corresponding acid

A solution of the above alcohol (8.45 g) in ethanol (37.6 ml) and 2N hydrochloric acid (18.8 ml) is stirred and cooled in ice while a solution of potassium cyanate (3.05 g) in water is added dropwise

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ser (5.6 ml) is added. The mixture is left at room temperature Stand for 18 hours, then evaporate the alcohol, add water and extract the insoluble oil with ether. The dried one Ether solution is evaporated and a viscous Cl is obtained, which is heated on the steam bath for 6 hours, whereby 5- (6-ethoxycarbonylhexyl) -1- (5-hydroxy-4,4-dimethyl-5-phenylpentyl) hydantoin obtained as a viscous pale yellow oil.

This sterile is added to a mixture of 2N sodium hydroxide (25 ml) and water (60 ml) and the cloudy solution obtained is left to stand at room temperature for 2 hours. The solution is washed with ether and the clear alkaline solution is acidified with 2N hydrochloric acid and the precipitated oil is extracted with ether. Evaporation of the dried ethereal solution gives a viscous oil (6.8 g) which is chromatographed on a column of silica gel to give 5- (6-carboxyhexyl) -1- (3-hydroxy-4,4-dimethyl-5-phenylpentyl ) -hydantoin as a colorless, viscous oil that solidifies, melting point approx. 115 ° C, reluctantly approx. 90 ° C, whereby it is a mixture of diastereomers. By repeated recrystallization from a mixture of ethyl acetate and light petroleum (b.p. 60-80 ° C) yields one of the Diaster.eomeren as small needles, melting point 135-137 ⁰ G.

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

hydantoin

A. Dieth.yl-2- (3-tetrahydropyran-2-yloxy) -octylamino) -nonan-

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dioat

Dry ethereal hydrogen bromide, prepared from ether (200 ml) and hydrogen bromide (26.6 g) at ⁰ ° C., is added dropwise with stirring to a solution of acrolein (19.15 g) in ether (100 ml), which is then added -25 ⁰ C has cooled. The mixture is kept under stirring for 1 hour at this temperature, it is then possible to to ⁰ ° C to warm, stirred for 1 hour at ⁰ C and then added dropwise essential pentylmagnesium bromide (prepared from 1-bromopentane (5 ^ g), magnesium (8 , 8 g) and ether (120 ml)), maintaining at constant reflux. The reaction mixture is decomposed with saturated aqueous ammonium chloride and extracted with ether. The dried extract is concentrated and distilled, and 1-bromo-3-hydroxyoctane is obtained as a colorless oil, boiling point, 5--2.5 ° C / 0.08 Torr. A solution of this bromine alcohol (20.9 P.) in dihydropyran (17, Og) is treated with p-toluenesulfonic acid (500 mg) in a little ether, the mixture is left to stand at room temperature for 18 hours and washed with aqueous sodium bicarbonate. The organic layer is percolated through silicon dioxide in a 1: 9 ether / hexane mixture and the solvent is removed under vacuum, whereby 1-bromo-3- (tetrahydropyran-2-yloxy) octane is obtained as a colorless oil; £ 0.88 (3H, Triplet, -CH ₅ ) and 4.62 (1h, broad, -0-CIiK-O-). A solution of this tetrahydropyranyl intermediate (15.0 g) and diethyl 2-aminononanedioate (13.0 g) in absolute ethanol (100 ml) is refluxed for 18 hours, the ethanol is removed under vacuum and the residue is diluted with water and the sodium carbonate contains in slight excess. The mixture is extracted with dichloromethane, the extract is dried over Na-

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trium sulfate and evaporated. The residue is purified by column chromatography on silicon dioxide in 1: 4 hexane / ether and diethyl 2- (3-tetrahydropyran-2-yloxy) octylamino) nonanedioate is obtained as a colorless, viscous Gl, do, 88 (3H, triplet -CH ₅ ), 2.28 (2Ii, triplet, -CH ₂ -GO ₂ At), 2.61 (2H, MuI tipi et, -CH ₂ -K), 3.20 (1H, triplet, N-CHH-CO ₂ At), 4.13 (4H, multiplet, 2 χ -0-CIi ₂ -CIU), 4.60 (1H, broad, -0-CHK-O-).

The amino diester prepared above can also be prepared in the following manner. Diethyl 2-aminononanedioate (10.40 g) and oct-1-en-3-one (5.04 g) are ^{mixed slowly at 0} ° C. with stirring and the mixture is left to stand for 3 hours at room temperature. This gives diethyl 2- (3-oxooctylamino) nonanedioate as a colorless oil / 2.3 (4H, multiplet, -CH ₂ -CO ₂ At and NCH ₂ CH ₂ CO-), 3.16 (111, triplet, AtO ₂ C-CHR-N), 4.11 (211, quartet, -0-CH ₂ -CH,), 4.17 (2H, quartet, -0-CH ₂ -CH ^). A solution of this ketone (13.5 g) in absolute ethanol (140 ml) is treated with stirring dropwise at ⁰ ° C. with sodium borohydride (665 mg) in absolute ethanol (70 ml), then the mass is kept 3 1/2 Hours at room temperature and concentrated under vacuum at 40 ^° C. The residue, dissolved in water, is brought to p ^ 5 with N hydrochloric acid and extracted thoroughly with chloroform, the extract is washed with water, dried and evaporated. Diethyl 2- (3-hydroxyoctylamino) nonanedioate is obtained as a colorless oil. Without further purification, this is dissolved in dihydropyran (14.0 ml), treated with ether (10 ml), then in portions with p-toluenesulfonic acid (6.72 g) and left to stand for 18 hours at room temperature. The reaction solution is diluted with ether, washed with aqueous sodium carbonate, then with water, dried and

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steams. The residue is purified by column chromatography on silicon dioxide in 1: 4 hexarl / ether and diethyl 2- (3- (tetrahydropyran-2-yloxy) octylamino) nonanedioate is obtained
identical (KMR, IR mixed TLC) as prepared above.

B. 5- (6-Carboxyhexyl) -1- (3- (tetrahydropyran-2-yloxy) -oct.yl) -hydantoin

To a solution of diethyl 2- (3- (tetrahydropyran-2-yloxy) octylamino) nonanedioate (7.0 g) in ethanol (32 ml) is added
a solution of potassium cyanate (3.0 g) in water (6 ml). the
The resulting suspension is stirred and cooled during the gradual addition of 2N hydrochloric acid (16.7 ml). The solution is left to stand at room temperature for 22 hours and evaporated
most of the ethanol, add water and extract the insoluble oil with ether. The ether solution is washed with water, dried over magnesium sulfate and evaporated. The yellow oil thus obtained (8.0 g) is dissolved in light petroleum (boiling point 60 ° -80 ° C.) and the solution is refluxed for 4 hours.
It is evaporated to dryness, the residue oil is heated on the steam bath for 2 hours and 5- (6-ethoxycarbonylhexyl) -1- (3- (tetrahydropyran-2-yloxy) octyl) hydantoin is obtained as a yellow oil
(7 »3 g), which is used without further purification.

A solution of the ester (6.2 g) in 0.5N sodium hydroxide solution (80 ml) is allowed to stand at room temperature for 2 1/2 hours, after which time the solution was washed with ether, the aqueous layer was acidified with 2N hydrochloric acid and the precipitated oil was extracted with ether will. The washed and dried ether extract is evaporated to form 5- (6-carboxyhexyl) -1- (3- (tetra-

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hydropyran-2-yloxy) octyl) hydantoin as a yellow oil.

C. 5- (6-Carboxyhexyl) -1- (3-hydroxyoctyl) hydantoin This tetrahydropyranyloxy compound (3.55 s) is dissolved in tetrahydrofuran (28 ml) and 5 ^ hydrochloric acid (7 ml), the solution is left at room temperature for 3 Stand for 1/2 hour and reflux for 30 minutes. Most of the solvent is evaporated, water is added and the insoluble oil is extracted with ether. The ether solution is washed with water, dried over magnesium sulfate and evaporated to give 3-15 g of a viscous yellow oil. The oil is purified from silica gel by chromatography on a column, eluting first with chloroform and then with a mixture of chloroform and methanol (19: 1). This gives 5- (6-carboxyhexyl) -1- (3-hydroxyoctyl) - hydantoin as a very viscous, almost colorless oil, dO.89 (3H, triplet, -CH ,.), 2.34 (2H, triplet, -Cli ₂ -CO ₂ H), 2.9-4.2 (4H, complex , -CH ₂ -N, CH-M, CB- (JH), approx. 5.6 (2H, broad, interchangeable, -CU ₂ H, -OH), approx. 9.0 (1H, broad, interchangeable, NH).

Using the procedure of Example 1, the hydantoin identified above is also placed over the corresponding one Diethyl 2- ((3-hydroxyoctyl) amino) nonanedioate.

D. Separation of the diastereomers

The one obtained according to the manufacturing process described above Hydantoin is a viscous oil that is produced using high performance liquid chromatography on a column of Silicon dioxide with a mixture of chloroform, methanol and acetic acid (97: 2.5: 0.5) as a solvent in two diastereo-

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kidneys are separated, both of which form small colorless needles; Melting point 76-78 ⁰ G or 63-65 ° C.

The same diastereomers can be prepared in such a way that the corresponding diastereomers of the general Formula (III) cyclized. To this end, the mixture of the diastereomers of diethyl 2- / X3-hydroxyoctyl) amino7-nonanedioate is dissolved, prepared as in Example 1, in ethanol and adding an ethereal hydrogen chloride solution. You vaporize them Solution to dryness and obtain a mixture of diastereomeric hydrochlorides as a viscous oil, which partially dissolves after standing solidified. You add ether, stir! Leave and cool, thereby obtaining a crystalline solid that is collected washes and dries with ether. The solid is recrystallized from ethyl acetate and small, colorless platelets are obtained. Melting point 95-96.5 ° C, from pure hydrochloride. This Salt is suspended in dilute sodium hydroxide solution, shaken with ether, the separated ether solution is washed and dried and evaporated, whereby one of the diastereomers (A) of diethyl 2- / C3-hydroxyoctyl) -amino7-nonanedioate is colorless Receives oil.

The ether filtrate, which is obtained after collecting the solid starting hydrochloride is obtained, it is evaporated and an oily hydrochloride is obtained, which, as described above, is converted to the base with formation of almost pure second diastereomer (B) of diethyl 2- / 3-hydroxyoctyl) -amino7-nonanedioate as a colorless one Oil.

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- S4

According to the method described in Example 1, the above diastereomer (A) is converted into a single diastereomer of 5- (6-carboxyhexyl) -1- (3-hydroxyoctyl) hydantoin, which is obtained from a mixture of ethyl acetate and light petroleum (boiling point 60-8O ⁰ C) as small colorless needles, melting point 63-65 ⁰ C, recrystallized.

Similarly, the diastereomer (B) above may in the second diastereomer of 5- (6-carboxyhexyl) -1- (3-hydroxyoctyl) hydantoin is converted, the one from ethyl acetate-light petroleum (b.p. 60-80 ⁰ C) as small colorless needles, melting point 76-78 ⁰ C, auskristalüsiert.

E. Mutual conversion (interconversion) of the diastereo-

meren

(Having a melting point of 76-78 ⁰ C diastereomer) (100 mg) in N-sodium hydroxide solution (3 ml) is allowed to a solution of 5- (6-carboxyhexyl) -1- (3-hydroxyoctyl) -hydantoin for 19 hours at room temperature stand. The solution is acidified, extracted with ether, the ether extract is washed with water, dried and evaporated, and a viscous oil is obtained. Means high-performance-Plüssigchromatographie this oil is separated in the two diastereomer s of 5- (6-carboxyhexyl) -1- (3-hydroxyoctyl) hydantoin, mp 76-78 ⁰ C, identical to the starting material (ca. mg), and mp 63-65 ⁰ C, identical to the diastereomer described above (about 40 mg) (A).

Similarly, the diastereomer, melting point can 63-65 ⁰ C, in a mixture of approximately equal amounts output Distereomer

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272A9 / .8

with diastereomer melting point 76-7ö ° C converted and it can the pure diastereomers using high-performance liquid chromatography to be isolated.

Examples 3 to 27

Using a series of reactions similar to those described in Example 1, using the appropriate Vinyl ketones are used as starting materials to produce the following compounds:

3a) diethyl 2 - ((3-oxopentyl) araino) nonanedioate; 4-a) Diethyl 2- [(3-OXO-4,4-dimethylpentyl) -amino) -nonanedioate; 5a) diethyl 2- [(3-OXO-4-methylpentyl) -amino) -nonanedioate; 6a) diethyl 2 - ((3-oxononyl) amino) nonanedioate; 7a) diethyl 2 - ((3-oxo-4-methyloctyl) amino) nonanedioate; 8a) diethyl 2 - ((3-oxodecyl) amino) nonanedioate;

9a) diethyl 2- [(3-0X0 ^ -4.4-dimethyloctyl) -amino) -nonanedioate; 10a) diethyl 2 - ((3-oxo-4-ethylhexyl) amino) nonanedioate; 11a) Diethyl 2 - ((3-cyclobutyl-3-oxopropyl) amino) nonanedioate; 12a) diethyl 2 - ((3-cyclopentyl-3-oxopropyl) amino) nonanedioate;

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

14a) diethyl 2 - ((3-cyclohexyl -3-oxopropyl) amino) nonanedioate; 15a) diethyl 2 - ((3-cycloheptyl-3-oxopropyl) amino) nonanedioate; 16a) diethyl 2 - ((3-oxo-3-phenylpropyl) -amino) -nonanedioate; 17a) Diethyl 2 - ((3-oxo-4-phenylbutyl) -amino) -nonanedioate; 18a) diethyl 2 - ((3-oxooctyl) amino) pentanedioate; 19a) diethyl 2 - ((3-oxooctyl) amino) undecanedioate; 20a) Ethyl-2 - ((3-oxooctyl) -amino) -3- (3-ethoxycarbonylmethoxy-

^Phenyl) - ^propionati 70 9850/1083

21a) methyl 2 - ((3-oxo-4,4-diruethylpent, yl) amino) -3- (3-ethoxycarbonylmethoxyphenyl) propionate;

22a) Aühyl-2- (3-oxooctylaraino) -9- (3- (2-ethoxycarbonyleth, yl) -phenyl) -propioriate;

23a) ethyl 2- (3-cyclobutyl-3-oxopropylamino) -3- (3- (2-ethoxy carbonylethyl) phenylpropionate ;

24a) Afchyl-2- (3-cyclopentyl-3-oxopropylamino) -3- (3- (2-ethoxy-

carbonylethyl) phenylpropionate ;
2'va) ethyl 2- (3-cyclohexyl-3-oxopropylamine) -3-O- (2-ethoxycarbonylethyl-phenylpropionate;

2ba) I) iäthyl-2- (3-oxooctylamino) - ^r / -oxanonanedioate and

27a) Diethyl-2- (3-cyclopentyl-3-oxopropylamino) - '/ - oxanonan-

dioate, which is converted to the corresponding hydroxy compounds can be:

3b) L) ethyl 2 - ((3-hydroxypentyl) amino) nonanedioate;

4b) diethyl 2- [(3-byciroxy-4,4-dimethylpentyl) -amino) noriandioate;

5b) i) iäthyl-2- ((3-hydrox y _{t-4-methylpentyl)} amino) -nonandioat; 6b) diethyl 2- ((3-hydroxyrion _t yl) amino) nonanedioate;
Vb) diethyl 2 - ((3-hydroxy-4-methyloctyl) amino) nonanedioate; ob) diethyl 2 - ((3-hydroxydecyl) amino) nonanedioate;

9b) L) ethyl 2- ((3-hydroxy-4,4-dimethyloctyl) amino) nonanedioate;

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

11b) Diethyl 2- ((3-cyclobutyl-3-hydroxypropyl) -amino) -nonanedioate ;

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

13b) Diethyl-2 - ((3-hydroxy-4,4-diraethyl-5- (3-trifluoromethylphenyl) -p entyl) amino) nonanedioate;

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

dioate; 709850/1083

15b) Diafchyl-2- ((3-cyclohept.yl-3-h.ydroxyprop.yl) -amino) -nonanedioab;

16b) diethyl 2- [(3-hydroxy-3-phenylpropyl) -amino) -noiiaiulioate; 1 ^r / b) Üiäthyl-2- ((3-hydroxy-n-phenyl butyl) -amino) -η on and i ο at; 10b) ethyl 2 - ((3-ii.ydroxyoct.yl) amino) pentanedxoate; 19b) Diet 2 - ((3-hydroxyoctyi) amino) undecanedioate;

2Ob) ethyl-2 - ((3-hydroxyoctyl) amiriu) -3- (3-ethoxycarbonylinethoxyphenyl) propionic;

21b) Ethyl-2 - ((3-hydroxy-4.4-dimethylpent; ./! J-amino) -3 - (; '· - ethoxycarbonylmethoxyphenyl) propionafc;

22b) ethyl 2- ((3-hydroxyoc tylamino) -3- (3- (2-ethoxyca.fbonyl ethyl) phenyl propionate ;

23b) ethyl 2- ((3-cyclobutyl-3-h, ydrox.ypropylamino) -3 - (? '- (' - ethoxycarbon, ylethyl) -phen, ylpropionate ;

24b) ethyl 2- ((3-cyclopontyl-3-hydroxypropylamino -. '.) - ( ^{: 7} j- (2- ethoxycarbonylethyl) phenylpropionate ;

25b) Ethy1-2- (3-cyclohexyl-o-hydroxyρropylamino ) -3- (3- (2- ethoxycarbonylethyl) phenylpropionate ;

26b) Uiäthyl-2- (3-hydroxyoct, ylamino) -7-oxanonanedioate and

27b) diet hyl-2- (3-cy el open tyl-3-hydr oxy prop, / l amino) -7-oxanonanedioate,

from which the following hydantoins of the general formula (I) produced v / ground which, where an ^ e:; just, by means of fiochleistunfjS-tliquidchromato ^ raphie p; are separated with the formation of two aastereomers with the specified Melting points.

3c) 5- (D-carboxyhexyl) -1- (3-hydroxypentyl) hydantoin, a colorless oil, diastereomers 71-73 ° C and 56-58 ⁰ G;

5- (6-carboxyhexyl) -1- (3-hydroxy-4,4-dimethylpentyl) hydantoin, Diastereomers 114-115 ° C and

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5c) 5- (6-carboxyhexyl) -1- (3-hydroxy-4-methylpentyl) hydantoin, m.p. ca. 7O-3O ° C, diastereomers 73-76 ⁰ C and 110-111 ° C;

6c) 5- (6-Carboxyhexyl) -1- (3-hydroxynonyl) hydantoin, a viscous oil;

7c) 5- (6-cart) oxyhexyl) -1- (3-hydroxy-4-ir.ethyloctyl) hydantoin, a viscous oil;

8c) 5- (6-carboxyhexyl) -1- (3-hydroxydecyl) hydantoin, a viscous Ul, diastereomers 68-70 ⁰ C and 82-83 ° C;

9c) 5- (6-carboxyhexyl) -1- (3-hydroxy-4,4-dimethyloctyl) hydantoin, colorless crystals, melting point 90 ° -98 ° C., a diastereomer isolated by crystallization from ethyl acetate, melting point 1O3-1O4 ° C;

10c) 5- (6-carboxyhexyl) -1- (3-hydroxy-4-ethylhexyl) hydantoin, Melting point 70-80 ° C, diastereomers 82-84 ° C and 120-122 ° C;

11c) 5- (6-carboxyhexyl) -1- (3-cyclobutyl-3-hydroxypropyl) hydantoin, diastereomers 114-116 ⁰ C and 1O3-1O5 ° C;

12c) 5- (6-carboxyhexyl) -1- (3-cyclopentyl-3-hydroxypropyl) hydantoin, Diastereomers 116-117 ° C and 97-99 ° C;

13c) 5- (6-carboxyhexyl) -1 - (3-hydroxy-4.4-dimethyl-5-ni-trifluormethylphenylpentyl) hydantoin, diastereomers 118-120 ⁰ C and °

14c) 5- (6-carboxyhexyl) -1- (3-cyclohexyl-3-hydroxypropyl) hydantoin, diastereomers 96-98 ° C and 124-126 ⁰ C;

15c) 5- (6-carboxyhexyl) -1- (3-cycloheptyl-3-hydroxypropyl) hydantoin, Melting point approx. 70-76 ° C, diastereomers 107-109 ° C and 107-109 ° C;

16c) 5- (6-carboxyhexyl) -1- (3-hydroxy-3-phenylpropyl) hydantoin, Diastereomers both forming colorless viscous oils;

17c) 5- (6-carboxyhexyl) -1- (3-hydroxy-4-phenylbutyl) hydantoin, diastereomers 102-104 ° C and 61-63 ⁰ C;

18c) 5- (3-carboxypropyl) -1- (3-hydroxyoctyl) hydantoin, both Forming diastereomers of colorless viscous oils;

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19c) 5- (8-carboxyoctyl) -1- (3-hydroxyoctyl) hydantoin, diastereomers 57-6O ⁰ C and 69-71 ° C;

20c) 5- (3-carboxyraethoxybenzyl) -1- (3-hydroxyoctyl) hydant ο in, a colorless herrings;

21c) 5- (3-carboxymethoxybenzyl) -1- (3-hydroxy-4,4-dimethylpentyl) hydantoin, diastereomers of the corresponding ethyl ester, mp 100-103 ⁰ C and 151-154 ⁰ C;

22c) 5- (3- (2-carboxyethylbenzyl)) - 1- (3-hydroxyoctyl) hydantoin, a diastereomer, melting point 82-86 ⁰ C;

23c) 5- (3- (2-carboxyethylbenzyl)) - 1- (3-cyclobutyl-3-hydroxypropyl) hydantoin, a diastereomer, melting point 118-

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

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

26c) 5- (4-carboxymethoxybutyl) -1- (3-hydroxyoctyl) hydantoin and

27c) 5- (4-carboxymethoxybutyl) -1- (3-cyclopentyl-3-hydroxypropyl) hydant oin,

all of which are obtained via the corresponding ethyl ester.

The starting materials used in the foregoing procedures are:

A. Examples 18 and 19

Using the procedure described in Example 1A, diethyl 2-aminopentanedioate, boiling point 93-96 ° C / 0.02, is prepared

24
Torr n _D 1.4425 and diethyl 2-aminodecanedioate, boiling point

160 ° C / 0.1 Torr used in Examples 18 and 19, respectively

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will.

B. Ethyl-2-amino - $ - ($ - ethoxycarbonylmethoxyphenyl) propionate Han dissolves diethylacetamidomalonate (2.60 g) and ethyl 3- (chloromethyl) phenoxyacetate (Robertson, J. Ghem. Soc. (1933)) 492; UU Patent 3,933,895) (2.39 g) in ethanolic ethoxide (made from sodium (230 mg) and absolute ethanol (10 ml)) and the mixture is refluxed for 19 hours. The cooled solution is poured into ice water, the product is extracted into ether and the dry extract is evaporated. The rubber residue is crystallized from ether / hexane and diethylacetamido (3-ethoxycarbonylraethoxyphenyl) malonate is obtained as white prisms, melting point 90, 5-101.5 ° C. This derivative (1.90 g) is refluxed for 3 1/2 hours with 10% aqueous hydrochloric acid (25 ml) and the cooled solution is evaporated to dryness under vacuum. The white solid residue is dissolved in a minimal amount of absolute ethanol and, while stirring, is added dropwise to a cooled (-10 ⁰ g) mixture of absolute ethanol (15 ml) and thionyl chloride (1.64 g). The solution obtained is kept at room temperature for 10 hours, refluxed for 1 hour, cooled and poured into ice water, the p ^ value being adjusted to 9 to 10 with aqueous sodium hydroxide. The mixture is extracted with ether, the dry extract is concentrated and ethyl 2-amino-3- (3-ethoxycarbonylmethoxyphenyl) propionate is obtained as a colorless oil, which is used in Examples 20 and 21 without further purification.

G. Ethyl 2-amino-3- (3- (2-ethoxycarbonylethyl) phenyl) propionate A solution of diisopropylamine (4.04 g) and butyllithium (25

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se

ml, 1.6OM in hexane) in dry tetrahydrofuran (40.0 ml) is stirred at -78 ° G under dry nitrogen and then treated for 5 minutes with t-butyl acetate (4.64 g). A solution of ', ot'-dibromo-mxylene (11.60 g) and dry liexamethylphosphoramide (1.42 g) in dry tetrahydrofuran (8.0 ml) is added to this solution over a period of 5 minutes. The resulting yellow solution is stirred at -78 ⁰ C for 1/2 hour, then allowed to warm to room temperature for 3 hours. Ice water is added in excess, the mixture is extracted with ether and the extract is washed with hydrochloric acid (60 ml), then with water. The dried extract is concentrated under vacuum and a yellow oil is obtained, which is purified by column chromatography on silica, eluted with 1: 1 ether: hexane, whereby t-butyl 3- (3-bromomethylphenyl) propionate is obtained as a colorless oil. Using the procedure described in the last paragraph, this is converted to the desired diethyl ester which is used in each of Examples 22-25.

D. Dieth yl 2-amino-7-oxa-nonanedioate

This is made from ethyl 4-bromobutoxyacetate (Merck, Ger. Open minded. 2,354,085) by means of a series of reactions analogously the procedures described in paragraph B above and obtain a colorless oil, boiling point 120-121 ° C / 0.005 Torr. Man used it in Examples 26 and 27.

Example 28 Production of 5- (6-carboxyhexyl) -1- (5-phenylpentyl) hydantoin

A mixture of diethyl 2-aminononanedioate (25.9 g) and 5-phenyl

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S3

Pentyl bromide (22.7 g) is heated in a bath at 100 ° C. for 3 hours. After cooling, ether (100 ml) is added to the mixture, which is then left to ^{stand at 0} ° C. for 2 hours. The colorless solid (21.95 g) which crystallizes out is collected and dried. It is diethyl 2 - ((6-phenylpentyl) amino> nonanedioate.hydrobromide, melting point ⁰

A solution of this hydrobromide (4.86 g) in ethanol (20 ml) and 2N hydrochloric acid (5 ml) is cooled in ice and stirred while a solution of potassium cyanate (1.62 g) in water (5 ml) is gradually added. The solution is then left at room temperature for 18 hours stand. The alcohol is evaporated, water is added, the insoluble oil is extracted with ether and the ether extract is dried, evaporates and turns into a pale yellow oil. This material is heated for 6 hours on the steam bath, which results in 5- (6-Ethoxycarbonylhexyl) -1- (5-phenylpentyl) hydantoin is obtained.

The preceding ester (4.0 g) is hydrolyzed by treating it with a dilute sodium hydroxide solution and purified by chromatography on silica gel to give 5- (6-carboxyhexyl) -1- (5-phenylpentyl) hydantoin, which is obtained (C 60-80 ⁰⁾ auskristalEeiert from ethyl acetate-light petroleum in the form of colorless prism needles; Melting point 90-92 ° C.

Examples 29 to 35

A number of reactions are carried out analogous to those of Example 28, "where / for the appropriate alkyl halides are used:

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29a) diethyl 2-octylaminononanedioate; 30a) diethyl 2- (4-propoxybutyl) aminononanedioate; 31a) diethyl 2- (4-phenoxybutyl) aminononanedioate;

32a) diethyl 2- (4-m-trifluoromethylphenoxybutyl) aminononanedioate;

33a) diethyl 2- (3-m-tolyloxypropyl) aminononanedioate; 34a) diethyl 2- (3-hydroxypropyl) aminononanedioate and 35a) diethyl 2- (3-hydroxy-3-niethyloctyl) aminononanedioate, which are converted into the desired hydantoins:

29b) 5- (6-ethoxycarbonylhexyl) -1-octylhydantoin, melting point 46-48 ° C;

29c) 5- (6-carboxyhexyl) -1-octylhydantoin, melting point 88-89 ° C;

30b) 5- (6-carboxyhexyl) -1- (4-propoxybutyl) hydantoin, m.p. 72-74 ⁰ C;

31b) 5- (6-carboxyhexyl) -1- (4-phenoxybutyl) hydantoin, Melting point 88-90 ° C;

32b) 5- (6-carboxyhexyl) -1- (4-m-trifluormethylphenoxybutyl) hydantoin, m.p. 51-5 C ^ ^0;

33b) 5- (6-carboxyhexyl) -1- (3-m-tolyloxypropyl) hydantoin, a colorless viscous oil;

34b) 5- (6-carboxyhexyl) -1- (3-hydroxypropyl) hydantoin, Melting point 111-113 ° C and

35b) 5- (6-carboxyhexyl) -1- (3-hydroxy-3-methyloctyl) hydantoin, a viscous oil.

Example 36

Preparation of 1- (6-Carbo3cyhexyl) -5-octylhydantoin 2-Aminodecanonsäure (J. Am. Chem. Soc, 1946, 68, 450) (16.0 g) are added in portions to a cooled (-1O ⁰ C) mixture of absolute ethanol (70 ml) and thionyl chloride (6 ml) under

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Stir too. The solution obtained is left at room temperature for 2 hours stand, reflux it for 1 hour, cool it, pour it into ice water and establish the pg value of the solution 9 with aqueous sodium hydroxide. The mixture is extracted with ether, the extract is dried, concentrated and distilled then and receives ethyl 2-aminodecanoate (75 #) as a colorless oil; Boiling point 82-84 ° C / 0.2 Torr.

A solution of the preceding amino ester (18 g) and ethyl 7-bromoheptanoate (20 g) in absolute ethanol (50 ml) is refluxed for 24 hours and then the ethanol is evaporated. By adding ether, a hydrobromide salt, melting point 98 ^° C., is precipitated, which is dissolved in a little dichloromethane, treated with one equivalent of triethylamine, washed thoroughly with water and dried. After removing the solvent, ethyl 2- (6-ethoxycarbonylhexylamino) decanoate (52 #) is obtained as a colorless, viscous oil, boiling point 142-144 ° C / 0.001 Torr.

Is reacted ethyl-2- (6-äthoxycarbonylhexylamino) decanoate (7 »4 g) with potassium cyanate and hydrochloric acid, thus obtaining 1- (6-Äthoxycarbonylhexyl) -5-octylhydantoin in the form of colorless crystals, mp 68-70 ⁰ C, from Light petroleum (boiling point 60-80 ° C).

This ester (4.0 g) is hydrolyzed with sodium hydroxide solution to form 1- (6-carboxyhexyl) -5-octylhydantoin, which is recrystallized from a mixture of ethyl acetate and light petroleum (boiling point 60-80 ° C) as colorless needles, Melting point 65-66 ° CI

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Example 37

Preparation of 5- (6-carboxyhexyl) -3 - methyl-1-octylh.ydantoin A solution of diethyl 2-octylaminononanedioate (7 ^ 2 mg) and methyl isocyanate (120 mg) in dry ether (7.5 ml) leaves stand for 48 hours at room temperature, after which the ether is evaporated and a pale yellow oil (800 mg) is retained. This oil is heated for 2 hours on the steam bath and 5- (6-ethoxycarbonyl) -3-niethyl-1-octylhydantoin is obtained as a yellow oil.

The ester (650 mg) is hydrolyzed by standing in solution in ethanol (2.4 ml) and 5N sodium hydroxide solution (0.6 ml) 3 hours at room temperature. After evaporation of the ethanol, the acidic product is isolated by extraction with ether and purifies by column chromatography on silica gel with formation of 5- (6-carboxyhexyl) -3-methyl-1-octylhydantoin as colorless oil.

Example 38 Production of 5- (6-carboxyhexyl) -3-methyl-1- (3-hydroxyocty3> »

hydantoin

Diethyl 2 - ((3-oxooctyl) -amino) -nonanedioate (Example

28) with methyl isocyanate, as described in Example 37, to give 5- (6-ethoxycarbonylhexyl) -3-methyl-1- (3-oxooctyl) hydantoin, which is converted into 5- (6-carboxyhexyl) -3-methyl -1- (3-oxo-octyl) -hydantoin _f a colorless oil, hydrolyzed.

This keto acid (1.23 g) is dissolved in 0.25N sodium hydroxide solution (15 ml) and stir the solution in an ice bath while adding sodium borohydride (63 mg). After stirring for 2 hours

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the solution is acidified at room temperature and extracted with Ether. The washed and dried ether extract evaporates and an oil is obtained which, after purification by chromatography on a silica column using a Mixtures of chloroform and methanol (50: 1) as eluent 5- (6-carboxyhexyl) -3-methyl-1- (3-hydroxyoctyl) hydantoin supplies as a colorless viscous oil.

Example 39

Preparation of 1- (6-carboxyhexyl) -3-methyl - 5-octylhydantoin The process described in Example 37 is used to convert ethyl 2- (6-ethoxycarbonylhexylamino) decanoate (Example 36) into 1- (6-ethoxycarbonylhexyl) -3-methyl-5-octylhydantoin and this then by hydrolysis into 1- (6-carboxyhexyl) -3-methyl-5-octylhydantoin, whereby it is isolated as a colorless oil

Example 40

Preparation of 3-butyl-5- (6-carboxyhexyl) -1-octylhydantoin To a solution of sodium (308 mg) in ethanol (40 ml) is added 5- (6-ethoxycarbonylhexyl) -1-octylhydantoin (see Example 29b) , then butyl bromide (1.8 g) and the solution is refluxed for 24 hours. The solvent is evaporated, water is added and the insoluble oil is extracted with ether. The washed and dried extract may evaporate to form 3-butyl-5- (6-ethoxycarbonylhexyl) -1-octylhydantoin.

This ester (3.2 g) is dissolved in ethanol (15 ml) and 2N sodium hydroxide (15 ml) and let the solution stand for 1 hour at room temperature. The acidic product is isolated by Ex-

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traction with ether, purifies by means of chromatography on silica gel and receives 3-butyl-5- (6-carboxyhexyl) -1-octylhydantoin as a colorless oil.

Example 41

Preparation of 3-butyl-1- (6-carboxyhexyl) -5-octylhydantoin Following the procedure of Example 40, 1- (6-ethoxycarbonylhexyl) -5-octylhydantoin (see Example 36) is converted to 3-butyl-1- (6 ethoxycarbonylhexyl) -5-octylhydantoin, which is hydrolyzed to form 3-butyl-1- (6-carboxyhexyl) -5-octylhydantoin as a colorless oil.

Example 42 Production of 5- (6-Carbo3qrhex-2-ynil) -1- (3-hydroxyoctyl) -

hydantoin

According to the reaction conditions as described in Example "IA, if you put diethyl acetamidomalonate and methyl-V-bromhept - ^ - ynoate with the formation of diethylacetamido (6-methoxycarbonylhex-2-ynil) malonate than yellow oil around.

This crude product is hydrolyzed by boiling with 5N hydrochloric acid and the product is esterified again to form diethyl 2-aminonone-4-yndioate, which is distilled to give a colorless oil, boiling point 116 ° C./0.01 Torr nj ⁷ 1,403.

The above-mentioned amino compound is used with oct-1-en-3-one around and receives diethyl 2 - ((3-oxooctyl) -amino) -non-4-yndioate, which is reduced with sodium borohydride to form

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of diethyl 2 - ((3-hydroxyoctyl) amino) non-4-yndioate.

If this compound is treated with potassium cyanate and hydrochloric acid and the hydantoin ester is hydrolyzed, a light brown oil is obtained. After purification by chromatography on a silicon dioxide column with a mixture of chloroform and methanol (30: 1) as the eluent, 5- (6-carboxyhex-2-ynyl) -1- (3-hydroxyoctyl) hydantoin is obtained as a colorless oil (mixture of diastereomers) with two spots, Rf. 0.38, 0.44, after expiration in a chloroform, methanol, acetic acid mixture (90: 5J5) on a thin layer of silicon dioxide. Using high-performance liquid chromatography, one of the diastereomers (TLC, Rf. 0.38) is isolated as a colorless oil; KMR (CDCl ₃ ) i 0.89 (3H, triplet, -CH ₃ ), 2.2-2.4 (6H, multiplet, -CH ₅ , C = CCH ₂ - + -CH ₂ -CO ₂ H), 3-54 (2H, Triplet,> N.CH ₂ -), approx. 3.6 (1H, multiplet,> CH.OH), 4.11 (1H, triplet,> N.CH.CO-).

This compound is then catalytically hydrogenated to the corresponding one 5- (6-carboxyhex-2-enyl) -1- (3-hydroxyoctyl) hydantoin and then to the corresponding saturated compound identified in the heading of Example 2 Connection is identical.

Example 43

A. 2- (Dibutoxymethyl) plycine ethyl ester N-pormylglycine ethyl ester is carried out for the C-formylation by a method as described by Harman and Hutchinson in J. Org.

Chem. 1975 »40, 3474 describes and converts the received

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ne compound in the 2- (dibutoxymethyl) glycine ethyl ester under Using the method as described in "Chemistry of Penicillin", edited by H.T. Clarke et al., Published from Princetown University Press, New Jersey, 19 ^ 9, page 517 is described.

B. 1- (6-Carboxyhexyl) hydant oin-5-carboxaldehyde A mixture of 2- (dibutoxymethyl) glycine ethyl ester (2.0 g) with ethyl 7-bromoheptanoate (1.82 g) is heated under nitrogen in a bath for 3 hours at 100 ⁰ C and of crude 7 - ((2,2-dibutoxy-1-äthoxycarbonyläthyl) amino) -heptanoat.Hydrobromid. A solution of 3 »28 g of this hydrobromide in ethanol (13 ml) is cooled with stirring in ice water and treated with a solution of potassium cyanate (1.34 g) in water (4 ml), then with 2N aqueous hydrochloric acid (3.63 ml); the cooling bath is removed and stirring is continued at room temperature for 22 hours. The ethanol is evaporated off under vacuum, the residue is shaken with water and ether and the ether solution is separated off, washed with water and dried over magnesium sulphate (MgSO ^). After removal of the ether, an oil, which was 3 hours under nitrogen at 100 ⁰ C remains heated to give 1--Dibutoxymethyl-5 (6-äthoxycarbonylhexyl) hydantoin (2.94 g). This is stirred in ether (6 ml) with water (48 ml) and N aqueous sodium hydroxide (24.9 ml) for 1 1/2 hours at room temperature and after the addition of further ether (50 ml) the aqueous phase is separated off and cooled (EiS-H ₂ O), stirred with fresh ether and acidified against Congo Red with N aqueous hydrochloric acid. The ethereal solution of the carboxylic acid is washed three times

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Water, dry (MgEJ (V) and evaporate to give 1- (6-carboxyhexyl) -5-dibutoxymethylhydantoin (2.15 g) as a resin When 1.89 g of this product is cooled in ice water and with concentrated aqueous hydrochloric acid (8.5 ml), the resulting solution suddenly gives rise to a suspension of colorless crystals, which is kept at room temperature for 1 1/2 hours, diluted with water (10 ml) and kept for a further 15 minutes, and the crystals are collected , washed with water, dried under vacuum, suspended in ether (3 ml) and collected again and obtained 1- (6-carboxyhexyl) hydantoin-5-carboxaldehyde (0.74 g), melting point 223, -5-225 ⁰ C (Analysis: Found: C 51.86, H 6.66, N 10.62. Calculated for C ₁₁ H ₁₆ N ₂ O ₅ : C 51.56, H 6.29, N 10.93 #). In Dimethyl sulfoxide-d ₆ , this compound is predominantly in the form of a masked aldehyde, 1- (6-carboxyhexyl) -5-hydroxymethylene hydantoin.

C. 1- (6-Carboxyhexyl) -5 - ((E) -3-oxo-octylidene) -hydantoin A mixture of 1- (6-carboxyhexyl) -hydantoin-5-carboxaldehyde (20 mg) with 2-oxoheptylidene triphenylphosphorane ( 59 mg) (see J. Org. Chem. (1972) 371 1818) and 1 drop of benzene are heated for 35 minutes at 100 ° C. under nitrogen and a resin is obtained which is taken up in ethyl acetate. The product is extracted in dilute aqueous sodium bicarbonate, the extract is washed with ethyl acetate and acidified against Congo red with N aqueous hydrochloric acid and the released carboxylic acid is extracted into ether. The ethereal solution is washed with water, dried (MgSO ^) and evaporated and a resin (25 mg) is obtained, which can be identified as 1- (6-carboxyhexyl) -5 - ((E) -3- ^{by means of 1 H KMR spectroscopy.}

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oxooctylidene) hydantoin identified (characteristic signals at 6 5.72 (1H, triplet, = CH-) and 3.93 (2H, doublet, »CH-CHp-CO) with J 7.1 Hz, in deuterochloroform).

D. 1- (6-Carboxyhe3Qrl) »5 - ((E) -3-hydroxyoctylidene) hydantoin A solution of 1- (6-carboxyhexyl) -5 - ((E) -3-oxooctylidene) hydantoin (20 mg ) in HpO (1.5 ml) containing a slight excess of sodium bicarbonate is treated with sodium borohydride (5 mg) while stirring. After 60 minutes, the solution is acidified against Congo Red with N aqueous hydrochloric acid, the released carboxylic acid is extracted in ethyl acetate, the ethyl acetate solution is washed three times with water and dried. (MgSO ^,). After evaporation of the ethyl acetate, a pale yellow resin (14 mg) is obtained, which is identified as 1- (6-carboxyhexyl) -5 - ((E) -3-hydroxyoctylidene) -hydantoin ^{by means of 1 H KMR spectroscopy (characteristic signal at * 5.61} (1H, triplet, ■ CH-, J 7-1 Hz) in deuterochloroform).

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

The product described in paragraph C is then reduced to 1- (6-carboxyhexyl) -5- (3-oxooctyl) hydantoin and the in Compound designated under the heading which is identical to those given in the headings of Examples 28 and 2, respectively Links·

In the following examples the hydantoins are designated as follows :

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

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Connection 4
Connection 6
Connection 9
Connection 11
Connection 12
Connection 14
Connection 38

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

5- (6-carboxyhexyl) -1- (3-hydroxynonyl) hydantoin

5_ (6-carboxyhexyl) -1- (3-hydroxy-4,4-dimethyloctyl) hydantoin

5- (6-carboxyhexyl) -1- (3-hydroxy-3-cyclobutylpropyl) hydantoin

5- (6-carboxyhexyl) -1- (3-hydroxy-3-cyclopentylpropyl) hydantoin

5- (6-carboxyhexyl) -1- (3-hydroxy-3-cyclohexylpropyl) hydantoin

5- (6-carboxyhexyl) -3-methyl-1- (3-oxooctyl) hydantoin.

When a particular diastereomer is used, this is indicated by reference to its melting point.

Example 44

Preparation of 3- (6-carboxyhexyl) -1- (3-oxooctyl) hydantoin diethyl 2- (3-oxooctylamino) nonanedioate (7 »7 g), prepared by the process as described in Example 1B, is treated with Potassium cyanate and hydrochloric acid and receives 5- (6-ethoxycarbonylhexyl) -1- (3-oxooctyl) hydantoin. By hydrolysing this ester using sodium hydroxide solution, 5- (6-carboxyhexyl) -1- (3-oxooctyl) hydantoin is obtained as a viscous oil which is crystallized to a low-melting solid .

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Example 45

Preparation of 5- (e-Carboxyhex-2Z-enyl) -1- (3-cyclohex.yl-3-hydroxypropyl) hydantoin

Cis-methyl-7-bromhept-5-enoate (produced according to the process British Patent 1,355,991) and diethylacetamidomalonate it is reacted according to the conditions as described in Example 1A, and diethylacetamido-Ce-methoxycarbonylhex-2-enyl) malonate is obtained as yellow oil.

The crude product is hydrolyzed with 5N hydrochloric acid at the boiling point and the product is esterified as described in Example 1A, whereby diethyl 2-aminonone-4-enedioate is obtained as a colorless oil, boiling point 118-123 ° C / O, 0.5 Torr, n ^ ⁹ ' ⁵ 1.4620, received.

By reacting this amino compound with i-cyclohexylprop-2-enone as in Example 2B and reduction of the diethyl 2 - ((3-cyclohexyl-3-oxopropyl) amino) non-4-enedioate thus formed with sodium borohydride, as in Example 2C, diethyl 2 - ((3-cyclohexyl-3-hydroxypropyl) amino) non-2-enedioate is obtained.

If this compound is treated with potassium cyanate and hydrochloric acid and the hydantoin ester obtained is hydrolyzed, as in Example 2D, 5 ~ (6-carboxyhex-2Z-enyl) -1- (3-cyclohexyl-3-hydroxypropyl) hydantoin is obtained as a yellow oil that tends to solidify. Using high performance liquid chromatography one separates this compound into its diastereomers, one of which is small colorless prisms, melting point 95_97 ° C, and the other form colorless needles, melting point 108-110 ° C.

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Example A. Cardiovascular effects in rats

Male rats with normal blood pressure, strain Wistar (Charles River), (250-350 g) are anesthetized with chloroform before the Insertion of the cannula into the left femoral vein and maintain anesthesia by intravenous chloralose (60 mg / kg). The pulsating blood pressure is transmitted via an electronic transmission system (Bell and Howell type 4-327 L221) from the The left femoral artery is recorded and the integrated heart rate is established with a cardiotachometer solid that is triggered by the arterial pressure waves. The compound to be studied is administered as a solution in physiological saline by intravenous injection through the thigh cannula. The noted Reflexes are allowed to return to their pre-injection level between successive administrations.

The injections using the carrier alone in equivalent volumes to those with the drug, do not lead to hypotension.

Average

Compound Dose Blood Pressure Drop ___________ Torr

PGE ₂ 4 / UgAg 28

¹¹ 16 / UgAg 44

Connection 2 10 / UgAg 14

" 1 mgAg 42

Compound 6 3 mgAg 40

Compound 9 _ 3 mg / kg_ _ 22

Example B. Inhibition of platelet aggregation

The aggregation of platelets in 1 ml of fresh platelet-enriched human plasma (PRP) is established in a Born aggregometer.

The compound intended for investigation is added to the PRP in the desired concentration and the mixture obtained incubate at 37 ° C for 1 minute after seeing platelet aggregation by adding adenosine diphosphate (ADP) to a concentration of 5 / uM.

The antiaggregatory effect of the compound is determined by measuring the percentage of inhibition of platelet aggregation in the presence of the test compound as compared with when this compound was not administered.

Connection PGE ₁

Compound 12 (melting point 116-117 ° C)

concentration % Inhibition of
ARRreKation 15 ng / ml 33 20 ng / ml 47 30 ng / ml 63 40 ng / ml 69 0.5 ng / ml 25th 1.0 ng / ml 51 2.0 ng / ml 79 4.0 ng / ml 94

By comparison, gives the following relative effect liabilities in terms of PGE _1: Compound 2 (melting point 76-78 ⁰ C),

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12.5x; Compound 4 (melting point 144-146 ° C), 0.0 |? X; Compound 11 (114-116 ° C), 5.2x; Compound 12 (m.p. 116-117 ⁰ C), 12.5x and Compound 14 (m.p. 96-98 ⁰ C), 16x.

Example C

It was found that compound 38, which induced aspirin gastric ulceration reduced in rats. An oral dose of 1 mg / kg provides 80% protection.

Example D

At an intravenous dose of 30 / Ug / kg the compound is inhibited Figure 2 completely shows pentagastrin-induced gastric acid secretion in rats.

Example E.

It was found that intravenous injection of the compound 9 (50 / Ug / kg) completely the histamine-induced Bronchial constriction antagonized in anesthetized guinea pigs.

Example F

Intravenous infusions of compound 2 (melting point 76-78 ° C) at a dose of 250 / Ug / min. reduce the electrically induced Arterial thrombosis in anesthetized rabbits.

Example G Tablet In a tablet

Compound 12 (melting point

116-117 ⁰ C) 5.0 mg

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Lactose B.P. 82.0 mg

Strength B.P. 10.0 mg

Povidone B.P.G. 2.0 mg

Magnesium stearate 1.0 mg

Mix the compound 12, lactose and starch together, granulate the powder using a solution of povidone in purified water, dries the granules, adds them to magnesium stearate and compresses them into tablets, 100 mg each Tablet.

Example H Capsule In a capsule

Compound 12 (melting point 116-117 G) lactose starch

Magnesium stearate

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

Example I.

1 / Ug / ml injection

Compound 12 (melting point 116-117 ° C) 100, µg Water for injection to 100 ml

The compound 12 is dissolved in the injection water, the solution is sterilized by filtering it through a membrane filter,

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10 mg 79 mg 10 mg 1 mg

0.22 µm pore size, collect the filtrate in a sterile container and fill the solution under aseptic conditions into sterile glass ampoules, 1 ml per ampoule. One closes by melting glass.

Example J
1OyUg / ml injection

Connection 12
(Melting point 116-117 ° C) 1 mg

Ethyl alcohol 10 ml

Propylene glycol 30 ml

Injection water to 100 ml

The compound 12 is dissolved in ethyl alcohol, and propylene glycol is added and dilute the volume with water for injection.

The solution is sterilized by filtering it through a membrane filter, 0.22 / µm pore size, the filtrate collects in one sterile container, fill the solution in sterile glass vials under aseptic conditions, 10 ml per vial. Man closes with a sterile rubber stopper and secures with an aluminum cover.

Example K

100Aig single injection (freeze-dried) compound 12 (melting point 116-117 ⁰ C) 10.0 mg Mannitol 2.5 g

N / 10 sodium hydroxide solution qs to pg 10.0

Water for injection to 100.0 ml

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The compound 12 is suspended in about 20 ml of water, and sufficient sodium hydroxide solution is added to give a p n value of 10 reach and stir to loosen connection 12. The mannitol is added, dissolved and diluted to the desired volume with injection water.

The solution is sterilized by passing it through a membrane filter, 0.22 Å pore size, and distributed aseptically in sterile vials, 1 ml per vial. The solution is freeze-dried and the container is closed under aseptic conditions with rubber seals. Each Vial contains 100 / Ug compound 12 as a freeze-dried sodium salt.

Example L Suppositories

Compound 12 (melting point 116-117 ° C) 3 mg

Massa Esterinum C to 2 mg

Melting the ßuppositoriengrundmaterial at about 40 ⁰ C, is gradually compound 12 in the form of a fine powder and mix until homogeneous. It is poured into suitable molds and allowed to set.

Massa Esterinum C is a commercially available suppository base material and consists of a mixture of mono-, di- and triglycerides of saturated vegetable fatty acids. It is brought onto the market by Henkel International, Düsseldorf.

709850/1083 "Claims-

Claims (33)

Patent claims: Compound of general formula (I) Ν J (D, wherein Z is a hydrogen atom or an alkyl group, one of the Λ ? 12th Radicals Z and Z, through the group -CH ₂ -XX -X, in which X is a phenylene residue, a -C = C-, cis- or trans-CH = CH- or -CHp-CQp- group, in which each residue is Q , independently of the other, is a hydrogen atom and / or an alkyl group or the two Q radicals together form an alkylene radical with 4, 5 or 6 carbon atoms, the radical X is a covalent bond or a straight or branched alkylene chain with 1 to 6 carbon atoms is, in which one of its methylene groups is optionally replaced by an oxa (-O -) group, with the proviso that at least one carbon atom separates the oxa group from a -C ^ C-, -CH = CH- or -CO group and ISr is 5-tetrazolyl, carboxyl, carboxamide, hydroxymethylene and / or alkoxycarbonyl and the other of the radicals Z ^ and Z through the group -Y-Y ^ -Y -Y * is pictured, in which Y is a -CR ₂ ~ CH ₂ group, in which each radical R, independently of the other, is hydrogen and / or methyl, y ' ^{1 is} a carbonyl, methylene, methylene group substituted by a hydroxyl group or a methylene group substituted by a hydroxyl group - and 709850/1083 ORIGINAL INSPECTED - ** - 27249Λ8 ρ is alkyl group substituted methylene group, Y is a covalent group Bond or a straight or branched alkylene group having 1 to 7 carbon atoms, which is optionally attached to the Radical Y adjacent carbon atom by one or two of each other independent alkyl, bicycloalkyl and / or cycloalkyl groups is substituted, Y ^ is a hydrogen, hydroxy, Alkoxy group with 1 to 7 »preferably 1 to 4 carbon atoms, cycloalkyl, bicycloalkyl, phenyl, benzyl, phenoxy or benzyloxy group, in which each phenyl, benzyl, phenoxy and benzyl oxy group in the benzene ring by one or more hydroxy, halogen, nitro, amino, acylamino, alkenyl, Alkoxy, phenyl and / or alkyl groups can be substituted, which themselves are substituted by one or more halogen groups can be, or Y is a bond, -CHg- or 12 "3 -CHg.CHg-S group and the radicals Y, Y and Y ^ together form a cycloalkyl group which is substituted by a hydroxyl group which is preferably separated from the hydantoin ring by 3 carbon atoms
and their salts. 2. A compound according to claim 1, characterized in that Z is hydrogen, one of the radicals Z ¹ and Z ² by the group -CH ₂ -XX ¹ -X ² , wherein X is a phenylene radical, a -CSC-, -CH = CH- , preferably cis, or -CH2-CQ2 ~ group, in which each radical Q, independently of the other, is a hydrogen atom and / or an alkyl group or the two Q radicals together form an alkylene radical with 4.5 or 6 carbon atoms, the ^{X 1} radical is a covalent bond or a straight or branched alkylene chain with 1 7 0 9850/1 * ^BO> "is up to 6 carbon atoms in which one of its methylene groups is optionally replaced by an oxa (-O -) group, with the proviso that at least one carbon atom is the oxa group of _ 2 a -C = C-, -CH = CH- or -CO- group separates and X is a carboxyl or alkoxycarbonyl group and 12 1 9 Ί the other of the radicals Z and Z by the group -Y-Y-Y-Y ^ is pictured, where Y is a -CRp-CHg group i ^ » ^where i ⁿ each radical R, independently of the other, is hydrogen and / or methyl, Y is a carbonyl, methylene, methylene group substituted by a hydroxyl group or a hydroxyl group and p is alkyl group substituted methylene group, Y is a covalent group Bond or a straight or branched alkylene group having 1 to 7 carbon atoms, which is optionally attached to the Radical Y adjacent carbon atom is substituted by one or two alkyl groups, Y is a hydrogen, hydroxy, Alkoxy group with 1 to 7 carbon atoms, phenyl, benzyl, phenoxy or benzyloxy group, in which each phenyl, benzyl, Phenoxy and benzyloxy groups in the benzene ring by one or more hydroxy, halogen, nitro, amino, acylamino, alkenyl, Alkoxy, phenyl and / or alkyl groups may be substituted, which are themselves sub- 2 3 can be substituted, or the radicals Y and Y ^ together form a cycloalkyl group of 4-7 carbon atoms 709850/1083 - 66 - and their salts ₀ 3. A compound according to claim 1, characterized in that Z is hydrogen, one of the radicals Z and Z ² by the group -CH ₂ -XX ¹ -X ² , in which X is phenylene-, -CH = CH-, preferably cis or -CH "-CHp group, X is a covalent bond or a straight or branched alkylene chain with 1 to 6 carbon atoms, one of its ethylene groups being replaced by an oxa - (- O -) group, with the permission that at least one carbon atom separates the oxa group from a -CH = CH- or -CO- group and X a carboxyl and / or alkoxycarbonyl group 12th and the other of the radicals Z and Z through the group -Y-Y - Y ² -Y ^{3 is} shown, where Y is a -CHg-CHg radical, Y is a carbonyl, methylene, a methylene group substituted by a hydroxyl group or a methylene group substituted by a hydroxyl and alkyl group Y is a divalent bond or a straight or branched alkylene group having 1 to 7 carbon atoms, the is optionally substituted on the carbon atom adjacent to the radical Y by one or two alkyl groups, Y is a hydrogen, hydroxyl, alkoxy group with 1 to 7 carbon atoms, Benzyl, phenoxy or benzyloxy group, wherein each benzyl, phenoxy and benzyloxy group in the Benzene ring through a 709850/1083 or more hydroxy, halogen, nitro, amino, acylamino, Alkenyl, alkoxy, phenyl and / or * alkyl groups can be substituted which can themselves be substituted by one or more halogen groups. and the salts thereof. 4. Compound according to claim 1, characterized 1 indicates that Z is hydrogen, one of the radicals Z and Z by the group -CHp-XX ^ -X ² , wherein X is a -CH = CH-, preferably cis-, or -CH ₉ -CHp- group, X a covalent bond or a straight or branched alkylene chain with 1 to 6 carbon atoms and ΊΓ is a carboxyl and / or alkoxycarbonyl group Ί 2 12 and the other of Z and Z is represented by the group -YY -Y - Yr , where Y is a -CHp-CH ^ group, Y is a carbonyl, methylene, a methylene group substituted by a hydroxyl group or a methylene group substituted by a hydroxyl and alkyl group, Y is a straight or branched alkylene group having 1 to 7 carbon atoms, which is optionally substituted on the carbon atom adjacent to Y by one or two alkyl groups and Y * is hydrogen
and their salts. 5 · Connection according to claim 1, characterized that Z is hydrogen or an alkyl group with 1 to 4 carbon atoms, one of the radicals Z ¹ and Z ² -CH ₂ ~ XX ¹ -X ² is ₄ in which the radicals X and X together form an alkylene group with 3 to 7 carbon atoms 272Α948 ρ
atoms form and X is an alkoxycarbonyl, carboxyl group or is a salt of the same, and the other of Z ¹ and Z ^{2 is} -YY ¹ -Y ² -Y ^, wherein the 1 ρ
Y, Y and Y radicals have the previously defined meaning and Y * is hydrogen, phenyl or benzyl or the Y and Y * radicals together form a cycloalkyl ring with 4 to 7 carbon atoms. 6. A compound according to claim 1, 2 or 5, characterized characterized in that Y is a -CtU-CI ^ group, Y a -CH.OH-, -C.CH ^ .OH- or -CO- group, Y an alkylene- P is a group with 3 to 7 carbon atoms or the radicals Y and Y * together represent a cycloalkyl ring having 4 to 7 carbon atoms form. 7 · Compound according to claim 1, 2, 5 or 6, d a d ur c h characterized in that the radicals X and X together form an n-pentylene ring, Y a -CH.OH- or -CCH, .OH- 2 a Group, Y is an alkylene radical with a tertiary carbon atom adjacent to Y or the radicals Y and Y ^ together a cycloalkyl ring with 4 to Form 7 carbon atoms. 8. A compound according to any one of the preceding claims, characterized in that Z ¹ -CH ₂ -XX ¹ -X ² , as previously defined, is. 9. A compound according to any one of the preceding claims, characterized in that Z is hydrogen ^is 709R50 / 1083 10. 5- (6-carboxyhexyl) -1- (3-hydroxyoctyl) hydantoin; 5- (6-carboxyhexyl) -1- (3-bydroxy-4,4-dimethyIpenty1) hydantoin; 5- (6-carboxyhexyl) -1- (3-hydroxynonyl) hydantoin; 5- (6-carboxyhexyl) -1- (3-hydroxy-4,4-dimethyloctyl) hydantoin; 5- (6-carboxyhexyl) -1- (3-hydroxy-3-cyclobutylpropyl) hydantoin; 5_ (6-carboxyhexyl) -1- (3-hydroxy-3-cyclopentylpropyl) hydantoin; 5_ (6-carboxyhexyl) -1- (3-hydroxy-3-cyclohexylpropyl) hydantoin; 5- (6-carboxyhexyl) -3-methyl-1- (3-oxooctyl) hydantoin and their salts and esters. 11. Diastereomer of 5- (6-carboxyhexyl) -1- (3-hydroxy-3-cyclopentyl) hydantoin, as previously identified by its higher melting point. 12. Diastereomer of 5- (6-carboxyhexyl) -1- (3-hydroxy-3-cyclohexyl) hydantoin, as previously identified by its lower melting point. 13 preparation, characterized in that that they contain a compound of formula (I) as defined in any one of claims 1 to 12 together with a pharmaceutical contains suitable carrier. 14-. Preparation according to claim 13, characterized in that the carrier is a liquid. 709850/1083 if 15. Preparation according to claim 13 or 14, characterized in that it is in the form of a sterile injectable solution is present. 16. Preparation according to one of claims 14 or 15 »characterized in that it is 0.001 to Contains 10OyUg of a compound of the general formula (I) per ml. 17. Preparation according to claim 14, 15 or 16, characterized characterized in that it is in the form of dosage units containing 0.01 to 1 mg of a compound of general formula (I) included. 18. Preparation according to claim 13, characterized in that that the carrier is a solid. 19. Preparation according to claim 18, characterized that it is in unit dosage form. 20. Preparation according to claim 18 or 19, characterized characterized in that it is in the form of a tablet, a capsule, a cachette or a suppository. 21. Preparation according to claim 18, 19 or 20, characterized in that it contains 0.1 to 50 ag of a Contains compound of general formula (I). 709850/1083 22. A process for the preparation of a compound of the general formula (I) as defined in any one of claims 1 to 12, characterized in that a compound of the general formula (II) H
ZN No. ¹ O
wherein G is a carboxyl group or a derivative thereof, and each of Z, Z and Z has the meaning defined in the general formula (I), is cyclized. 23. A process for the preparation of a compound of the general formula (I) according to any one of claims 1 to 12, characterized in that a compound is used of the general formula (VII) No. ¹ (VII), G ¹ N where G is a carboxyl group or a derivative thereof, and each _{dep radicals z> Z} 1 _{mia Z} 2 _{d ± e} has the meaning defined in the general formula (I), cyclized. 24. A process for the preparation of a compound of the general formula (I) as defined in one of claims 1 to 12, characterized in that f ffq ^ ifQ ¹ } f O ² S 3 i η et that one ORIGINAL INSPECTED a carboxylic acid derivative with a compound of the general formula (IX) "1 ZN
H N,
H 1 2
wherein each Z, Z and Z radicals are those in the general formula (I) has given meaning, implements. 25. Process for the preparation of a compound of the general Formula (I) according to one of Claims 1, 5 »6, 7» 8 or 10, wherein Z is an alkyl group, characterized in that a compound of general formula (X) J ¹ (X) with a reactive ester derivative of an alcohol of the formula J * .OH wherein J is a hydrogen atom or an alkyl group, J is a hydrogen atom or z \ J> a hydrogen atom or Z and J * is an alkyl group, Z ^ or Z ^, with the proviso that one of the radicals J, J ¹ and Jr is hydrogen and that J * does not have the same value as J, J ^ and J ^, where in the definition for j ' ¹ , J ² and J ^ each radical Z ¹ and 2
Z has the same meaning as in the general formula (I) , alkylated. 709850/1083 272Α9Λ8 26. Process for the preparation of a compound of the general Formula (I) according to one of Claims 1 to 12, characterized in that a compound of the general formula (XI) (XI) reduced, in which either the remainder Ί? = CR-CH ₂ -Y ¹ -Y -Y ³ and Z ⁴ -CH ₂ -XX ¹ -X ² or Z ³ = CH-XX ¹ -X ² and Z ⁴ -YY ¹ -Y ² -Y ³ , wherein each of the radicals R, X to X ^, Y to Y ³ and Z have the meanings defined in the formula (I). 27 · Method of making a compound of general Formula (I) as defined in claim 1, wherein X ^ is Tetrazolyl group is characterized by that the corresponding precursor, in which in the Formula (I) Xr is replaced by -C.X ^ -N.JT ", in which the radicals X * and X7 together form a bond, X * hydrogen or Alkyl and X * is an alkoxy, alkylthio, amino or -NH-NHp group is reacted with nitrous acid or a salt of hydrazoic acid, depending on the suitability 28. A process for the preparation of a compound of the general formula (I) as defined in claim 1, wherein X is a Hydroxymethylene group is characterized that one has a corresponding acid, an ester, an acid halide, acid anhydride or an aldehyde 709850/1083 reduced. -λ 29. Process for the preparation of a compound of the general Formula (I) as defined in claim 1, wherein X is a hydroxymethylene group, characterized that a corresponding halide is hydrolyzed. 30. A compound according to formula (I) as defined in any one of claims 1 to 12, provided that it is according to a method any one of claims 22 to 29 is made. 31. Compound of the general formula wherein J is hydrogen or alkyl, J is hydrogen or Z as in claim 1, and J ^ hydrogen or Z, as in the claim 1, with the proviso that one of J, J and J is hydrogen. 32. Compound of the general formula where M> CZ ³ ,> CH-CHCyjdgrj _g ftffi-ffi £ 0G ³ ) ₂ and Z, Z ³ , ORIGINAL INSPECTED and G * those indicated in claim 26 or in the formula (XII) Have meanings. 33. Compound of the general formula 1 2 wherein M is a halogen, an amino group or -NH-Z and 12 1 Z, Z, Z and G have the meanings defined in claim 23 except that G can also be hydrogen. 709850/1083