HU193280B - Process for preparing novel hidantane derivatives and compositions comprising the same as active substance - Google Patents

Abstract

The present invention relates to novel hydantoin derivatives of formula (I) and to pharmaceutical compositions containing them. Wherein Z is hydrogen or alkyl, Z1 is carboxylic acid and Z2 is substituted amino. The process involves reacting a compound of formula (II) with a compound of formula (III) and, if desired, converting the compound of formula (I) to another compound of formula (I). The compounds of formula (I) have pharmacological properties similar to natural prostaglandins, as mimetics or antagonists thereof. -1-

Description

The present invention relates to a process for the preparation of novel hydantoin derivatives of formula (I) and to pharmaceutical compositions containing the compounds of formula (I) as an active ingredient.

British Patent Nos. 1,595,694, 1,595,695, 1,599,740, and 1,603,407 disclose hydantoin derivatives having pharmacological properties similar to natural prostaglandins. These compounds have been shown to mimic or inhibit the physiological effects of natural prostaglandins in various biological preparations.

A novel group of hydantoin derivatives represented by the general formula (I) has been found to have particularly advantageous pharmacological properties, as described below.

In the formula (I), - Z is hydrogen or (C1-C4) -alkyl;

- Z ¹ is -CH ₂ -X-X'-X ² wherein

- X is - (CH ₂ ) ₂ -

---- X ¹ is a C 1-6 straight or branched alkylene group,

--- X ² is carboxyl or (C 1 -C 4) alkoxy) carbonyl and - Z ² is -NH-CH ₂ -R and -N = CH-R where - R is -COY or ( a) wherein:

- Y is C 3 -C 8 alkyl, phenyl-C 1 -C 4 alkyl, phenyl or C 4 -C 8 cycloalkyl, and

- Y ¹ is hydrogen, hydroxy, (C 1 -C 4) alkoxy or (C 1 -C 4) alkanoyloxy -,

Unless otherwise indicated herein, any reference to further hydantoin is to be understood as meaning the hydantoin derivative of formula (1) and esters thereof. For use in human or veterinary medicine, esters are meant to be used in medical applications. Furthermore, in the general formula (I), unless otherwise expressly stated, alkyl or an alkyl-containing moiety, for example an alkanoyl-alkyl moiety, is a straight-chain or branched C 1 -C 4 group.

Unless otherwise indicated, all stereoisomers of the compound are encompassed by Formula I and other formulas herein. In particular, the formulas include geometric isomers, diastereoisomers, individual enantiomers, and racemic mixtures thereof, which may have color and anti-configuration depending on the position of their -N = CH group.

Those compounds of formula (1) are preferred on the basis of their useful pharmacological properties, Z is H, Z is ^-CH2-L-X X'-X ^2, wherein X is - (CH2) ₂ group, X ¹ is 2- C 4 alkylene chain and X ² is carboxyl group (or corresponding C 1 -C 4 alkyl ester) and Z ² is -NH-CH ₂ -R or -N = CH-R where R is group, wherein Y ¹ is hydroxy and Y is phenyl or C 3-8 alkyl or 4-8 carbon atoms, preferably 6 carbon atoms.

Within the scope of the present invention, there is a subgroup for the preparation of hydantoin of formula I wherein Z ² is as defined above -NH-CH ₂ -R and for the preparation of hydantoin of formula I wherein Z ² is as defined above -N = CH-R.

Among the hydantoin produced according to the present invention, 5- (6-carboxyhexyl) -1- (2-cyclohexyl-2-hydroxyethylamino) hydantoin is preferred.

5- (6-Carboxy-hexyl) -1- (2-cyclohexyl-2-hydroxy-ethylideneamino) -hydantoin, 5- (6-carboxy-hexyl) -1- (2-hydroxy-2-phenyl-ethylidene) -amino) hydantoin and their C 1 -C 4 alkyl esters. The parent compounds may be in any of the two isomeric forms, the first two of which are diastereoisomers in the form of a viscous oil at 21 ° C and a solid crystalline state at 21 ° C, of which particularly preferred.

The following hydantoin and their esters are also preferred:

5- (6-carboxy-hexyl) -1- (2-cyclohexyl-ethyl-1-amino) -hydantoin,

5- (6-carboxy-hexyl) -1- (2-hydroxy-heptylideneamino) -hydantoin,

5- (6-carboxyhexyl) -1- (2-hydroxy-2-phenylethylamino) hydantoin,

5- (6-Carboxyhexyl) -1- (2-cyclohexyl-2-hydroxyethylamino) -3-methylhydantoin.

Like other known hydantoin, the hydantoin of formula I has pharmacological properties similar to natural prostaglandins and is capable of, for example, mimicking or antagonizing prostaglandin (PG) "A", "B," C, "D," in their broad pharmacological profile. The biological effects of members of groups E, F and 1.

The pharmacological profile of the hydantoin produced by the process of the present invention is advantageous for its duration of action, which is much longer lasting than known hydantoin derivatives, and / or for its greater than expected activity. In this regard, 5- (6-carboxyhexyl) -1- (2-cyclohexyl-2-hydroxyethylideneamino) hydantoin and 5- (6-carboxyhexyl) -1- (2-hydroxy-2 -phenylethylidene-aminoamino) -hydantoin and their (C 1 -C 4) alkyl esters are outstanding with exceptionally long duration of action. In general, compounds of formula I wherein Ϋ ¹ is hydroxy have a long duration of action of 2193280 and those in which Y ¹ is hydrogen are more than expected, although many compounds may exhibit both properties simultaneously. The pharmacological profile, which is understood to be a relative mimetic or antagonistic effect similar to that of natural prostaglandins, will, of course, vary with each particular hydantoin. Therefore, given the wide spectrum of natural prostaglandins, their potential use as antagonists and mimetics is wide. Thus, the hydantoin compounds of formula (I) of the present invention may be used in human and veterinary medicine for prophylaxis or treatment, in particular when the use of a prostaglandin antagonist or mimetic is recommended, such as in any of the following clinical conditions.

A particular advantage of the hydantoin derivatives of the present invention is that they permanently and effectively inhibit platelet aggregation. Thus, these hydantoin are useful in inhibiting platelet aggregation or in reducing the adhesiveness of platelets, respectively, for preventing or treating thromboembolic disorders in mammals, including humans. "Thromboembolic disorder refers to disorders associated with increased undesirable aggregation of platelets. It is believed that the hydantoin of formula (I) has a greater platelet-binding activity than known hydantoin derivatives to exert this effect. Hydantoin are useful, for example, in the prevention and treatment of myocardial infarction, thrombotic conditions, peripheral vascular disease and angina, and in ensuring postoperative vascular permeability, and in the treatment of arteriosclerosis and lipemia, such as in the treatment of atherosclerosis, the etiology of which is due to lipid imbalance or hyperlipidemia. A further application of these compounds is the use as an additive to prevent platelet aggregation in blood or other fluid used to provide artificial extracorporeal circulation of isolated body parts.

The hydantoin produced according to the present invention, like members of the prostaglandin _c "A and" E groups, causes relaxation of vascular smooth muscle. Compounds that cause vascular smooth muscle relaxation are simultaneously vasodilating, thereby acting against hypertension, and are useful in lowering blood pressure in mammals, including humans. Such compounds, alone or in combination with a β-adrenoceptor blocking agent or other antihypertensive agent, are useful in the treatment of all types of hypertension, including essential, malignant and secondary hypertension. The use of sustained release drugs in the treatment of hypertension is advantageous, and the hydantoin produced according to the present invention is valuable for such purpose in clinical practice due to its aforementioned sustained action. Their vasodilatory activity observed in experimental animals is significantly longer than that of previously known prostaglandin mimetics of similar structure. In addition, observing the effect profile, it has been found that the retention time of the vasodilator effect is much longer with respect to known agents than would be expected based on half-life. The hydantoin of Formula I, which inhibit pentagastrin-induced gastric acid secretion in rats and induce indomethacin-induced gastric lesion, are useful in reducing or eliminating gastric-intestinal-induced gastric ulceration, whether the ulcer is spontaneous or is part of a polyglandular adenoma syndrome.

In addition, the hydantoin of Formula I is also useful in the treatment of proliferative skin disorders, such as the treatment of excessive cell division in the epidermis or dermis, possibly accompanied by imperfect cell differentiation.

A further application of the hydantoin of formula (1) is inhibition of the bronchial joint, such as histamine or 5-hydroxytryptamine (5-HT) -induced bronchial joint. Hydantoin with this property is useful in the prevention and treatment of lung asthma and bronchitis by alleviating their associated bronchoconstriction. Hydantoin capable of inhibiting the effects induced by histamine or 5-HT are generally useful in the prevention or treatment of allergic shock reactions such as response to allergens.

The hydantoin of formula (I), which mimics the effect of PGE ₂ and PGF _{2 on} uterine smooth muscle, can be used as fertility inhibitors, in particular as an abortifacient.

For some applications, it may be necessary to potentiate one or more effects other than the vasodilator effect of hydantoin, such as the platelet aggregating effect over the vasodilator. It has been found that this can be achieved by the preparation of formulations containing the hydantoin of the formula I together with a cyclic AMP phosphodiesterase inhibitor, hereafter referred to as the phosphodiesterase inhibitor for the sake of brevity.

The following phosphodiesterase inhibitors or their pharmacologically acceptable salts are useful for potentiating the platelet aggregating effect of hydantoin:

-3193280

the. ) xanthine derivatives such as:

theophylline (3,7-dihydro-1,3-dimethyl-1H-purine-2,6-dione), caffeine (3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione) ) and aminophylline (a 2: 1 adduct of theophylline and 1,2-ethanediamine);

b. ) isoquinoline derivatives such as:

papaverine (1 - [(3,4-dimethoxyphenyl) methyl] -6,7-dimethoxyisoquinoline);

c. ) derivatives of pyrimido [5,4-d] pyrimidine, for example:

dipyridamole. (2,2 ', 2 ", 2"' - [(4,8-dipiperidinopyrimido [5,4-d] pyrimidin-2,6-diyl) dinitrile] tetraethanol) and its salts;

d. ) thieno [3,2-d] pyrimidine derivatives such as N- [4- (4-morpholinyl) thieno [3,2-d] pyrimidin-2-yl] -1,2-ethanediamine;

e. ) derivatives of pyrazolo [3 ', 4': 2,3] pyrido [4,5-b] - [1,5] benzodiazepin-6- (3H) -one, e.g.

3-ethyl-7,12-dihydro-7,12-dimethylpyrazolo] 4 ', 3': 5,6] -pyrido [4,3-b] benzodiazepin-6- (3H) -one;

f. ) 1H or 2H-pyrazolo [3,4-b] pyridine derivatives, for example: 4- (butylamino) -1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-carboxylic acid ethyl- ester and 2-methyl-6-phenyl-4- (1-piperidinyl) -2H-pyrazolo [3,4-b] pyridine;

g. ) Derivatives of 5H-furo- [3,4-e] pyrazolo [3,4-b] pyridin-5-one, e.g.

4- (Butylamino) -1-ethyl-1,7-dihydro-7-hydroxy-5H-furo [3,4-e] pyrazolo [3,4-b] pyridin-5-one and

h. ) 1- (2H) -naphthalenone derivatives, e.g.

2- (dimethylamino) methyl-3,4-dihydro-7-methoxy-1- (2H) -naphthalenone.

The amount of hydantoin required to achieve the desired biological effect will, of course, vary depending on many factors. Such factors include the compound chosen, the purpose of administration, the route of administration and the patient being treated. The daily dose is generally in the range of 1 ng to 20 mg / kg body weight. For example, the intravenous dose may be in the range of 10 ng to 1 mg / kg, which may conveniently be administered as an infusion of 0.1 ng to 50 pg / kg / min. Suitable infusion solutions may contain 0.01 ng to 100 pg, for example 0.1 ng to 100 pg hydantoin per milliliter. The unit dosage form may contain from 100 ng to 100 mg of a compound of formula I, e.g., ampoules for injection of 100 ng / ml to 1 mg / ml, formulations suitable for oral administration such as tablets or capsules 0.001 to 50, e.g. 0.02 —20 mg / ml.

Specifically, when used to inhibit platelet aggregation, hydantoin is desirably to be present in the appropriate fluid at a concentration of 10 ng / l to 10 mg / l, e.g. 100 ng / l to 1 mg / l in the patient's blood or perfusion fluid. be present.

The above values apply to the use of the acid and ester of the formula I, and in the case of a salt, the dosage should be considered in relation to the appropriate anion.

The hydanthines of formula (I) may be used alone for the prevention and treatment of the foregoing conditions, but are preferably formulated with pharmaceutically acceptable carriers. The carrier must, of course, be suitable in the sense of being compatible with the ingredients of the formulation and not deleterious to the patient. The carrier may be solid or liquid. Preferred formulations of hydantoin are those containing 0.05 to 95% by weight of a hydantoin of the formula I in a unit dosage form such as a tablet. The pharmaceutical composition, as described above, may also contain other pharmacologically active compounds. The hydantoin derivatives may be in the form of an acid, ester or salt of the composition and may be prepared by any of the methods well known in the art of pharmacy, comprising mixing the components of the composition.

The compositions may be oral, rectal, topical, orally absorbable (e.g., sublingual), parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous), the preferred route being the nature and severity of the condition being treated, and the nature of the compound employed. .

Formulations for oral administration may be presented as discrete units such as capsules, cachets, lozenges, or tablets, each containing a predetermined amount of hydantoin derivatives; they may be prepared in the form of powder or granules; as a solution or a suspension in an aqueous or non-aqueous medium and as an oil-in-water or water-in-oil emulsion. Any of the methods customary in the pharmaceutical art may be used to prepare the formulations, but in each case the hindatoin derivative, which carrier consists of one or more accessory ingredients, is combined with a carrier. In general, the compositions are prepared by uniformly and intimately admixing the hydantoin derivative with a liquid or finely divided solid carrier, or both, and optionally shaping the composition. For example, tablets may be prepared by compressing or compressing a powder or granule of hydantoin derivative optionally with one or more accessory ingredients. Compressed tablets may be made by compressing a hydantoin derivative in a free-flowing state, for example in powder or granule form, optionally with a binder, a lubricant, an inert diluent, a surfactant or a dispersing agent. Compressed tablets may be made on a compression machine by moistening the powdered hydantoin derivative with a liquid inert diluent.

Orally absorbable (sublingual) formulations include hydantoin derivatives in a flavored carrier such as sucrose, acacia or tragacanth.

Lozenges containing -4193280 and lozenges containing hydantoin derivative in an inert carrier such as gelatin, glycerol, sucrose or acacia.

The sanitary compositions of the present invention preferably contain the hydantoin derivative in sterile water. These compositions are preferably isotonic with the patient's blood. These compositions are preferably administered intravenously, although they may also be administered by subcutaneous, intramuscular and intradermal injection. These compositions may conveniently be prepared by mixing hydantoin derivatives with water and rendering the sterile composition isotonic with blood. Injectable compositions according to the invention generally contain from 0.1 to 5% by weight of the active ingredient.

Formulations for rectal administration are preferably presented in the form of suppositories per dosage unit. These suppositories are prepared by mixing the hydantoin derivatives with one or more conventional carriers, such as cocoa butter, and form the resulting mixture.

Formulations for topical application to the skin are preferably formulated as ointments, creams, lotions, pastes, gels, sprays, aerosols and oils. Suitable carriers include, for example, petroleum jelly, lanolin, polyethylene glycol, alcohols and combinations. The active ingredient is generally present in these formulations in a concentration of 0.1 to 15% by weight, for example 0.5 to 2% by weight.

The hydantoin of formula I wherein Z ² is -N = CH-R wherein R is as defined above, a compound of formula II wherein Z and Z ¹ are as defined above is a compound of formula III ), wherein R is as defined above, and optionally one or more of the following conversions are carried out in any order:

i. converting the resulting hydantoin in the form of the ester of the formula I into the corresponding acid; and / or ii. ) converting the resulting hydantoin of formula (I) containing Z into hydrogen into a hydantoin having from 1 to 4 carbon atoms in Z and / or (iii) the resulting radical of formula (a) from R in which Y ¹ is C 1-4 alkanoyl converting a hydantoin of formula (I) containing an oxy group and Y into the corresponding hydantoin of formula (I) having a hydroxy group in Y ¹ and / or (iv) the resulting R substituent is -CO-Y converting the hydantoin of formula (I) into the corresponding hydantoin having the formula -CH (OH) -Y as R; and / or

v.) converting the resulting hydantoin of formula (I) into a corresponding hydantoin containing the group -NH-CH ₂ -R in the meaning of Z ² where R is as defined above.

The reaction of the compounds of the formulas II and III is carried out in a suitable solvent such as methanol.

If one or both diastereoisomers of the compound of formula (I) present in the isomeric mixture are to be separated in the above process, it is convenient to separate the isomers by conventional means, such as high performance liquid chromatography.

Compounds of formula (II) are prepared by hydrogenation of compounds of formula (IX) wherein Z and Z ¹ are as defined above, Ph is phenyl, under suitable conditions.

The compound of formula (II) may be prepared from the compound of formula (X) wherein G is a carboxyl group or a derivative thereof, such as an amide derivative such as a carbamoyl group or an ester thereof, in particular an alkyl ester; or cyano group, with cyanic acid or alkyl isocyanate, depending on the meaning of the Z substituent hydrogen or alkyl group.

If cyanic acid is used, it is conveniently prepared in situ from an alkali metal cyanate such as potassium cyanate with an acid which may be present in the form of an acid addition salt of a compound of formula (X) or as a free acid of formula (X). Alternatively, an equivalent amount of mineral acid and thus organic acid may be added to the reaction mixture. The reaction may be carried out in the absence of a solvent or in an inert solvent, preferably a porous solvent such as water or a mixture of water with acetone, dimethylformamide, dimethylsulfoxide or a lower alkanol such as ethyl alcohol, or else hydrocarbon, ether or halogenated hydrocarbon such as chloroform. If desired, for example when no solvent is used, the reaction may be facilitated by heating the reagents.

Similar reaction conditions may be used when alkyl isocyanate is used, except that it is not necessary to add the equivalent amount of acid in the form of an acid addition salt or in any other form to the reagents.

Instead of using cyanate or isocyanate, the compound of formula (X) may be reacted with urea, nitrocarbamide or N-alkylcarbamide, as defined in Z. It is not necessary to use a solvent, but if desired, the inert solvents described above may be used. The reaction is preferably carried out at a higher temperature, for example 100-125 ° C, but the temperature can be raised to 150 ° C.

Compounds of formula IX are compounds of formula IV, wherein the substituents are as defined above, compounds of formula XI: wherein Z is

-5193280 is prepared as described above and Ph is phenyl.

The compounds of formula (IV) are suitably provided by Schwenk and Papa [J. Amer. Chem. Soc., 70, 3626, (1948).

Compounds of formula (X) are prepared by reacting a compound of formula (IV) with an excess of hydrazine hydrate under suitable conditions, for example, in a suitable solvent such as ethanol.

Compounds of formula III are Tiffany et al. [J. Amer. Chem. Soc. 79, 1682 (1957)] or Royals and Robinson [J. Chem. Soc., 78, 4161 (1956).

In the conversion step i), the reaction is preferably carried out by hydrolysis, for example in the presence of a basic medium such as sodium hydroxide. Similar hydrolysis can be carried out in the conversion step iii), where Y ¹ alkanoyloxy can be converted to Y ^{1 * *} hydroxyl.

In the conversion step ii), the reaction is preferably carried out by treatment with a suitable alkylating agent such as an alkyl halide such as an alkyl iodide in the presence of a suitable base such as sodium hydroxide.

In the conversion step iii), the deacylation is carried out by a conventional procedure such as treatment with sodium hydroxide.

The conversion step (iv) may be carried out by a conventional reduction procedure, for example using sodium borohydride as a reducing agent in an alkaline medium.

In the conversion step (v), the reaction may be carried out with a suitable reducing agent, for example an appropriate borohydride or cyanoborohydride of an alkali metal such as sodium or lithium. The reaction must be carried out under suitable conditions, which, for example when cyanoborohydrides are used, means the presence of an acid such as acetic acid.

In general, the reactions and the conversion steps described above may be carried out in the usual manner using known procedures for the preparation of analogous compounds.

The compounds of formulas II and IX described above are novel.

In all of the chemical processes described above, it is natural that the choice of reagents is partially determined by the functional groups present in the substrate, and where appropriate, reagents having a sufficiently selective action should be selected.

The following examples illustrate the invention.

Example 1

Preparation of 5- (6-Carboxyhexyl) -1- (2-cyclohexyl-2-hydroxyethylideneamino) hydantoin

a.) Preparation of 1-Benzylideneamino-5- (6-ethoxycarbonylhexyl) hydantoin

A solution of sodium ethyl acetate (4.6 g) in ethyl alcohol (100 ml) was prepared. A suspension of benz6 aldehyde semicarbazone (16.3 g) in a mixture of 50 ml of sodium ethylate and 20 ml of ethyl alcohol was heated to reflux for 15 minutes. Diethyl 2-bromo nonanedioate (16 g) was added and the mixture was refluxed for 30 minutes. Sodium ethylate (25 mL) was added, the mixture was refluxed for 5 minutes, then bromide diester (8 g) was added and the mixture was refluxed for another 30 minutes. The remaining 25 ml of sodium ylate solution and 8 g of bromide diester are added and the mixture is refluxed for another hour. Most of the ethyl alcohol was evaporated in vacuo and the residue partitioned between dilute hydrochloric acid and ether. The remaining 5.4 g of benzaldehyde semicarbonate is filtered off, the ether solution is washed with water, dried over magnesium sulfate and evaporated. The remaining semi-solid residue was treated with a little ether. 13.0 g of 1-benzylideneamino-5- (6-ethoxycarbonylhexyl) hydantoin crystallize from cyclohexane as colorless needles. 92-94 ° C.

b. ) Preparation of 1-Amino-5- (6-ethoxycarbonylhexyl) hydantoin

A.) From Step benzylidene-amino compound of 5.8 g in 100 ml of ethanol was hydrogenated over 1 hour at 50 ° C, 9,8.10 ⁵ Pa, 10% palladium on carbon in the presence of. The catalyst was filtered off and the solvent was evaporated. This gave 4.3 g of the title compound, which was recrystallized from ethyl acetate, light oil (b.p. 60-80 ° C) to give colorless needles. The product obtained has a melting point of 80-82 ° C.

c. ) Preparation of 5- (6-Carboxyhexyl) -1- (2-cyclohexyl-2-hydroxyethylideneamino) hydantoin

Procedure A)

270 mg of 1-amino-5- (6-ethoxycarbonylhexyl) hydantoin and 140 mg of cyclohexylglyoxal hemihydrate, prepared by the method of Tiffany et al., J. Amer. Chem. Soc., 79, 1682 (1957). Pre-solution of 1.5 ml of methanol is refluxed for 1 hour. Water was added and the precipitated solid (330 mg) was recrystallized from aqueous methanol. 5- (6-Ethoxycarbonylhexyl) -1- (cyclohexylcarbonylmethyleneamino) hydantoin (Compound No. 1) is obtained as colorless plates. M.p. 88-90 ° C.

The resulting ester (790 mg) was hydrolyzed with 4 ml of 0.5 N sodium hydroxide solution at room temperature for 1 hour. The solution was washed with ether, acidified with n hydrochloric acid and the precipitated gum was extracted into ether. The ethereal solution was washed, dried and evaporated to give 730 mg of a colorless solid, which was crystallized from aqueous methanol 6193280. 5- (6-Carboxyhexyl) -1- (cyclohexylcarbonylmethyleneamino) hydantoin (Compound # 2) was obtained as colorless plates. 150-152 ° C. 5

1 g of ketoic acid was dissolved in 13.7 ml of 0.5 N sodium hydroxide solution and reacted in portions with 52 mg of sodium borohydride added at room temperature for 3 hours. The mixture was then acidified with 2N hydrochloric acid and the precipitated oil was extracted with chloroform. The extract was washed with water, dried and evaporated. This gave 700 mg of a colorless viscous oil which was treated with ether to give a solid. This material was recrystallized from methanol to give one of the diastereoisomers of 5- (6-carboxyhexyl) -1- (2-cyclohexyl-2-hydroxyethylidene-amino) -hydantoin (Compound 3) as colorless plates. The resulting ² θ compound had a melting point of 84-86 ° C.

NMR (CDCl ₃ ): δ 2.34 (2H, t, CH ₂ CO ₂ H), 4.16 (1H, t, CHOH), 4.37 (1H, t, COCHN), 8.37 (1H, d, N = CH).

Procedure B

3.0 g of 1-amino-5- (6-ethoxycarbonylhexyl) -hydantoin and 2.24 g of 2-acetoxy-2-cyclohexylacetaldehyde, as described by Ross et al., J. Med. Chem., 22, 412 (1979) prepared a solution of -20 ml of methanol under reflux for 1 hour. The methanol is then evaporated from the solution and the residue is dissolved in ether, the ethereal solution is washed with n-35 hydrochloric acid, water, and dried. The oil remaining after evaporation of the ethereal solution is purified by chromatography on a silica column. The eluent was eluted with 40: 1 chloroform: methanol. This gave 4.9 g of a colorless oil, which was run on silica with 95: 4: 1 chloroform: methanol: acetic acid (95: 4: 1) to give two spots having a retention factor of 0.46 and 0.50 respectively. 1.5 g of this oil were separated by HPLC (silica, dichloromethane: methanol: methanol: acetic acid 98.5: 1.0: 0.5), the two diastereoisomers separated. - 50 because we win:

both diastereoisomers of 1- (2-acetoxy-2-cyclohexyl-ethylideneamino) -5- (6-ethoxycarbonylhexyl) -hydantoin are in the form of a colorless viscous oil, 625 mg Rf = 0.50 (Compound 4). and 850 mg of product are obtained with Rj = 0.46 (compound 5).

The pure isomer (Rf = 0.50 mg, 100 mg) was dissolved in 2 ml of 0.5 N sodium hydroxide solution and the solution was kept at room temperature for 1 hour, then acidified with n-hydrogen chloride solution and the precipitated oil in chloroform. extracted. The chloroform extract is washed, dried and _R bepárol- Juk. Thus, 5- (6-carboxyhexyl) -1- (2- ^bb)

One of the almost pure diastereoisomers of -cyclohexyl-2-hydroxyethylideneamino) -hydantoin (Compound 6) was obtained as a colorless, viscous oil.

NMR (CDCl ₃ ): δ 2.32 (2H, t, CH ₂ CO ₂ H), 4.17 (1H, t, CHOH), 4.39 (1H, t, COCHN), 8.23 (1H, d, N = CH).

Similarly, the other diastereoisomer R = 0.46 is hydrolyzed to give the other diastereoisomer of 5- (6-carboxyhexyl) -1- (2-cyclohexyl-2-hydroxyethylideneamino) -hydantoin, which identical to the compound obtained according to Method A (Compound 3). Melting point 84-86 ° C.

Example 2

Preparation of 5- (6-Carboxyhexyl) -1- (2-cyclohexylethylidene) amino-hydantoin

A solution of 1-amino-5- (6-ethoxycarbonylhexyl) hydantoin (271 mg) and cyclohexylacetaldehyde (126 mg) in methanol (4 ml) was heated to reflux for 2 hours. The solvent was evaporated and the residue was crystallized from methanol. 1- (2-Cyclohexylethylideneamino) -5- (6-ethoxycarbonylhexyl) hydantoin (Compound 7) was obtained as colorless needle crystals. 95-97 ° C.

The resulting ester (380 mg) was dissolved in 11 ml of 0.2 N sodium hydroxide solution and allowed to stand at room temperature for 2 hours. The solution is then washed with ether, acidified with 2N hydrochloric acid and the precipitated oil is extracted into ether. The ethereal solution was washed with water, dried over magnesium sulfate and evaporated. The resulting 5- (6-carboxyhexyl) -1- (2-cyclohexylethylidene) amino-hydantoin (Compound 8) was recrystallized from diisopropyl ether light oil (boiling point 6080 DEG C.) to give colorless needles. 90-92 ° C.

Example 3

Preparation of 5- (6-Carboxyhexyl) -1- (2-hydroxy-2-phenylethylidenediamino) hydantoin

Procedure A)

1.95 g of 1-amino-5- (6-ethoxycarbonylhexyl) hydantoin and 1.3 g of Riehl and Fourgerousse, Bull. Soc. Chim., 1968, 4083 A solution of α-acetoxyphenylacetaldehyde in 15 ml of methanol is refluxed for 2 hours. The solvent is then evaporated from the solution and the residual pale yellow oil is purified by chromatography on a silica column. Elution was carried out with a 50: 1 mixture of chloroform: methanol. In this way, a mixture of the diastereoisomers of 5- (6-ethoxycarbonylhexyl) -1- (2-acetoxy-2-phenylethylideneamino) hydantoin is obtained in the form of an oily substance. The material was obtained by thin layer chromatography on silica

Rf.7193280 in a 50: 1 mixture of roforrylmethyl alcohol yields two spots having Rj values of 0.28 (compound 9) and Rj 0.31 (compound 10). The diastereoisomers were separated by column chromatography on silica gel using dichloromethane: methanol (100: 1) as eluent.

Less Polar Compound (Compound # 10): NMR (CDCl ₃ ): δ 2.33 δ (5H, m, CH ₂ CO ₂ and COCH ₃ ), 4.11 (2H, qu, CO ₂ CH ₂ CH). ₃ ), 4.38 (1H, t, N-CH), 6.41 (1H, d, CH-O), 7.38 (5H, s, Ph), 8.44 (1H, d, N = CH);

The more polar compound (Compound 9) had 15 characteristics: NMR (CDCl ₃ ): δ 2.21 (5H, m, CH ₂ CO ₂ and COCH 3, 4.11 (2H, qu, CO ₂ CH ₂ CH 3, 4). 43 (1H, t, N-CH), 6.40 (1H, d, CH-O),

7.38 (5H, s, Ph), 8.35 (1H, d, N = CH).

A volume of 170 mg of pure, less polar acetoxy ester ² θ is hydrolyzed in 6.5 ml of 0.2 N sodium hydroxide solution at room temperature for 1 hour.

The solution was then washed with ether and then acidified with 2N hydrochloric acid. The precipitate was extracted into ethyl acetate and the extract was washed with ether, dried over magnesium sulfate and evaporated. The resulting colorless oil was crystallized from ethyl acetate, light oil (boiling point 60-80 ° C) in the form of needle crystals melting at 112-114 ° C with 5- (6-carboxyhexyl) -1- (2-hydroxy-2-). yielding one of the diastereoisomers of phenylethylidene amino) hydantoin (Compound 11).

Likewise, the more polar acetoxy ester ^{35 is} hydrolyzed to give another diastereoisomer of 5- (6-carboxyhexyl) -1- (2-hydroxy-2-phenylethylideneamino) -hydantoin (Compound 12), which is ethyl acetate. , light oil (b.p. 60-80 ° C) mixture of small colorless mono hydrate ⁴³ precipitated as needles. M.p. 70-73 ° C.

Procedure B

Described in example 1) part c) mO Don ₄₅ 1.08 g of 1-amino-5- (6-ethoxycarbonyl hexyl) hydantoin and 608 mg of phenylglyoxal monohydrate is reacted with 10 ml of methyl alcohol is 5- 6-Ethoxycarbonylhexyl-1- (phenacylideneamino) hydantoin (Compound 13) was obtained, m.p. 77-79 ° C.

The resulting ester solution (1.45 g) was hydrolyzed in 22.0 mL of 0.5 N sodium hydroxide solution at room temperature for 1 hour. The resulting solution was washed with ether and acidified with dilute hydrochloric acid. This gave 5- (6-carboxyhexyl) -1- (phenacylideneamino) hydantoin (Compound 14), which was recrystallized from ethyl acetate, light oil (boiling point 60-80 ° C) at 84-86 ° C. melting point almost θθ len prisms are obtained.

Reduction of the above ketoic acid according to Example 1 c), Process A, affords the same diastereoisomers, Compounds 11 and 12, as described above in Example A of this Example. ⁶⁵

Example 4

Preparation of 5- (6-Carboxy-hexyl) -1- (2-hydroxy-heptylideneamino) -hydantoin

A.)

271 mg of 1-amino-5- (6-ethoxycarbonylhexyl) hydantoin and Riehl and Fougerousse Bull. Soc. Chim., 1968, 4083 A solution of α-acetoxyheptaldehyde in 4 ml of methanol is refluxed for 2 hours. The solvent is then evaporated from the solution and the residue is purified by chromatography on silica, eluting with a 50: 1 mixture of chloroform: methanol. In this way, a mixture of the diastereoisomers of 1- (2-acetoxyheptylideneamino) -5- (6-ethoxycarbonylhexyl) hydantoin was obtained as a colorless oil. TLC (silica, 50: 1 chloroform: methanol) gave two spots, Rf = 0.47 (Compound 15) and R / 0.51 (Compound 16). values. The resulting material (the two diastereoisomers) has the following characteristics:

NMR (CDCl ₃ ): δ 2.21 (5H, m, CH ₂ CO ₂ and COCH 3), 4.11 (2H, qu, CO ₂ CH ₂ CH ₃ ), 4.36 (1H, t, N-CH ), 5.28 (1H, m, CHO), 8.13 and 8.23 (1H, 2d, N = CH)

The above mixture of acetoxy ester (213 mg) was hydrolyzed with 8.0 ml of 0.2 N sodium hydroxide solution at room temperature for 3 hours. The solution was then washed with ether and then acidified with 2N hydrochloric acid. The resulting oil was extracted into ether, the extract was washed with water, dried over magnesium sulfate and evaporated. This gave 180 mg of a diastereoisomer of 5- (6-carboxyhexyl) -1- (2-hydroxy-heptylidene) amino-hydantoin, which was subjected to thin layer chromatography on silica, chloroform: methyl alcohol / acetic acid 90: Running 5: 5 gives two spots, R _f = 0.41 (Compound 17) and R _? = 0.44 (Compound 18). This mixture was dissolved in ether and kept at 5 ° C overnight to crystallize the pure diastereoisomer R (= 0.41) (Compound 17). The product obtained has a melting point of 73.5 ° C. NMR (CDCl ₃ ): δ 2.35 (2H, t, CH ₂ CO ₂ ), 4.37 (2H, m, N-CH and CH-O) 8.21 (1H, d, N = CH).

Procedure B

1.8 g of l-amino-5- (6-ethoxycarbonylhexyl) hydantoin and 1.1 g of the method of Royals and Robinson [see, e.g. J. Amer. Chem. Soc., 78, 4161 (1956)] was allowed to stand at room temperature for 40 hours in 18 ml of methyl alcohol. The solvent was evaporated from the solution and the residue was dissolved in ether and the solution was washed with 0.5 N hydrochloric acid, then water, dried over magnesium sulfate and evaporated. The residue was purified by chromatography on silica, eluting with chloroform. Thus, 5- (6-ethoxycarbonylhexyl) -1- (hexanoylmethyleneamino) hydantoin

Recrystallization from ether / light oil (b.p. 40-60 ° C) gave colorless needle crystals. M.p. 52-55 ° C.

1.0 g of the ester obtained was left in 12.8 ml of 0.5 N sodium hydroxide solution for 1 hour at room temperature. The solution is then washed with ether, acidified with dilute hydrochloric acid and the resulting oil is extracted into ether. The ether extract was washed, dried and evaporated. This gives a viscous yellow oil which is purified by minor chromatography on silica, eluting with a 50: 1 mixture of chloroform: methanol: silica. Pure 5- (6-carboxyhexyl) -1- (hexanoylmethylene amino) hydantoin (Compound 20) forms a hemihydrate. M.p. 84-85 ° C.

Reduction of the above ketoic acid according to Example 1 (c), Method A, affords a diastereoisomeric mixture of compounds 17 and 18, which are the same as in Process A above.

Example 5

Preparation of 5- (6-Carboxyhexyl) -1- (2-hydroxy-3-phenylpropylidene) amino hydydoin

A solution of 1.9 g of 1-amino-5- (6-ethoxycarbonylhexyl) hydantoin and 1.35 g of 2-acetoxy-3-phenylpropanal in 28 ml of methanol is refluxed for 5 hours. The solvent was evaporated and the residue was purified by chromatography on silica (50: 1 chloroform: methanol). 1- (2-Acetoxy-3-phenylpropylideneamino) -5- (6-ethoxycarbonylhexyl) hydantoin is obtained in the form of a colorless oil. TLC (silica, 50: 1 chloroform: methanol) gave two diastereoisomers R f = 0.54 (Compound 21 and Rf = 0.60 (Compound 22)). The two isomers were separated by high performance liquid chromatography (silica, 5: 1 chloroform: dichloromethane).

The more polar diastereoisomer has the following characteristics: NMR (CDCl ₃ ): δ 2.06 (3H, s, COCH ₃ ), 2.28 (2H, t, CH ₂ CO ₂ ), 3.12 (2H, d, CH ₂ Ph). , 4.13 (2H, qu, CO ₂ CH ₂ CH ₃ ), 4.32 (1H, t, N-CH), 5.56 (1H, m, CH-O), 7.28 (5H, s , Ph), 8.23 (1H, d, N = CH).

The less polar diastereoisomer has the following characteristics:

NMR (CDCl ₃ ): δ 2.05 (3H, s, COCH ₃ ), 2.28 (2H, t, CH ₂ CO ₂ ), 3.12 (2H, d, CH ₂ Ph), 4.12 ( 2H, qu, CO ₂ CH ₂ CH ₃ ), 4.32 (1H, t, N-CH),

5.58 (1H, m, CH-O), 7.27 (5H, s, Ph), 8.09 (1H, d, N = CH).

The diastereoisomeric mixture of the above acetoxyester diastereoisomeric mixture was hydrolyzed according to Example 3 (A) to give a diastereoisomeric mixture of 5- (6-carboxyhexyl) -1- (2-hydroxy-3-phenylpropylideneamino) hydydoin (23 and 24). The diastereoisomer mixture was characterized by NMR [(CD ₃ ) ₂ SO, 80 ° C]: δ 2.20 (2H, t, CH ₂ CO ₂ ), 4.40 (2H, m, N-CH and CH-O), 7.25 (5H, s, Ph), 8.64 and 8.80 (1H, 2d, N = CH)

Similarly, the more polar acetoxy ester (Compound 22) is hydrolyzed to give one of the diastereoisomers of 5- (6-carboxyhexyl) -1- (2-hydroxy-3-phenylpropylideneamino) -hydantoin, which is ethyl. Recrystallization from acetate gave colorless needles (compound 23). 116-118 ° C.

Example 6

Preparation of 5- (6-carboxyhexyl) -1- (2-cyclohexyl-2-hydroxyethylideneamino) -3-methylhydantoin

350 mg of a diastereoisomeric mixture of 5- (6-carboxyhexyl) -1- (2-cyclohexyl-2-hydroxyethylidene-amino) -hydantoin - compounds 1 and 6 of Example 1 - 4.2 ml of methyl alcohol, 1.05 ml of 2N sodium hydroxide solution, then 0.18 ml of methyl iodide are added and the mixture is allowed to stand at 20 ° C for 44 hours. The solvent was evaporated and water was added to the residue and washed with ether. The aqueous solution was acidified and the resulting oil was extracted into ether. The ether extract was washed, dried and evaporated. The resulting oil is purified from traces of impurity by chromatography on a silica column, eluting with a 30: 1 mixture of chloroform / methyl alcohol. The resulting 5- (6-carboxyhexyl) -1- (2-cyclohexyl-2-hydroxyethylideneamino) -3-methylhydantoin was subjected to thin layer chromatography on silica, ether: light oil (60-80 ° C). Boiling point C: methanol: acetic acid 55: 35: 5: 5, eluting with two spots R _f = 0.39 (Compound 25) and R _f = 0.43 (Compound 26) values, which spots correspond to the two diastereoisomers.

NMR (CDCl ₃ ): δ 2.35 (2H, t, CH ₂ CO ₂ ), 3.05 (3H, s, N-CH ₃ ), 4.19 (1H, t, CH-O), 4, 35 (1H, t, N-CH), 8.22 and 8.27 (1H, 2d, N = CH).

Example 7

Preparation of 5- (6-carboxyhexyl) -1- (2-cyclohexyl-ethylamino) -hydantoin

1- (2-Cyclohexylethylidene-amino) -5- (6-ethoxycarbonylhexyl) hydantoin (190 mg in Example 2) and 35 mg sodium cisnoborohydride (190 mg) in 3.8 ml methanol in 0.2 ml acetic acid was allowed to stand at room temperature for 5 days. Water and ether are added and the ether phase is separated off, washed with sodium bicarbonate and then with ether, dried over magnesium sulfate and evaporated. 5- (6-Ethoxycarbonyl-hexyl) -1- (2-cyclohexyl-ethyl-1-amino) -hydantoin (Compound 27) was obtained as a colorless oil.

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The resulting ester (185 mg) was hydrolyzed with 5.5 ml of 0.2 N sodium hydroxide solution at room temperature for 3 hours. After neutralizing the solution and extracting with ether, it was crystallized from a mixture of 5- (6-carboxyhexyl) -1- (2-cyclohexylethylamino) -hydantoin (Compound 28), ether, light oil (boiling point 60-80 ° C). . Colorless, tiny needle crystals are obtained. 89-91 ° C.

Example 8

Preparation of 5- (6-carboxyhexyl) -1- (2-cyclohexyl-2-hydroxyethylamino) -hydantoin mg mg of 5- (6-carboxyhexyl) -1- (2-cyclohexyl-2-hydroxy) A solution of ethylideneamino) hydantoin (Compound No. 3 in Example I) and 1.6 mg of sodium cyanoborohydride in 1.5 ml of methanol and 0.1 ml of acetic acid was added at 20 ° C. leave for 4 days. The product is then isolated by extraction with ether and crystallized from ethyl acetate, a light oil (boiling point 60-80 ° C). One of the diastereoisomers of 5- (6-carboxy-hexyl) -1- (2-cyclohexyl-2-hydroxyethylamino) -hydantoin (Compound 29) is thus obtained in the form of tiny prism crystals. 103-105 ° C.

Reduction of the compound of Example 1 in a similar manner gave the other diastereoisomer of 5- (6-carboxyhexyl) -1- (2-cyclohexyl-2-hydroxyethylamino) -hydantoin (Compound 30). , in the form of a viscous oil.

NMR [(CD ₃ ) ₂ SO]: δ 2.18 (2H, t, CH ₂ CO ₂ ), 2.82 (2H, m, N-CH ₂ ), 3.25 (1H, m, CH-O). ), 4.05 (1H, t, N-CH).

Example 9

Preparation of 5- (6-carboxyhexyl) -1- (2-hydroxy-2-phenyl-ethylamino) -hydantoin

A.)

5- (6-Ethoxycarbonylhexyl) -1- (2-acetoxy-2-phenylethylideneamino) hydantoin (a mixture of 9 and 10 of Example 3).

Example 8 was reduced with sodium cyanoborohydride. The product obtained is a colorless viscous oil containing both diastereoisomers of 5- (6-ethoxycarbonylhexyl) -1- (2-acetoxy-2-phenylethylamino) hydantoin (compounds 31 and 32). .

NMR (CDCl 3): δ 2.1 (3H, s, COCH ₃ ), 2.28 (2H, t; CH ₂ CO ₂ ), 3.32 (2H, tn, N-CH ₂ ), 3.95 ( 1 H, t, N-CH), 4.14 (2H, qu, CO ₂ CH ₂ CH ₃ ), 5.86 (1H, m, CH-O), 7.35 (5H, s, Ph).

The resulting acetoxy ester is hydrolyzed with dilute sodium hydroxide as described in Example 7 to give 5- (6-carboxy-hexyl) -1- (2-hydroxy-2-phenylethylamino) -hydantoin as a viscous oil. The product obtained is a mixture of the two diastereoisomers (Compounds 33 and 34).

NMR [(CD ₃ ) ₂ SO]: δ 2.16 (2H, t, CH ₂ CO ₂ ),

2.8-3.2 (2H, m, _N-CH2), 3.97 (1H, m, N-CH), 4.57 (1H. M, CH-O), 7.32 (5H, s, Ph).

B.)

One of the diastereoisomers of 5- (6-carboxyhexyl) -1- (2-hydroxy-2-phenylethylideneamino) -hydantoin (Compound 11 of Example 3) was reduced with sodium cyanoborohydride. in the same manner as in Example. The resulting viscous oil is one of the diastereoisomers of 5- (6-carboxyhexyl) -1- (2-hydroxy-2-phenylethylamino) hydantoin (Compound 33).

NMR [(CD ₃ ) ₂ SO]: δ 2.18 (2H, t, CH ₂ CO ₂ ), 2.87 and 3.06 (all 1H, m, not equivalent to NCH ₂ ), 4.07 (1H, t, N-CH), 4.60 (1H, m, CHO), 7.33 (5H, m, Ph).

The other diastereoisomer of 5- (6-carbohexyl) -1- (2-hydroxy-2-phenylethylideneamino) -hydantoin (Compound 12 of Example 3) was similarly reduced to 5- (6-carboxyhexyl) 1 - ( Another diastereoisomer of 2-hydroxy-2-phenylethylamino) -hydantoin (Compound 34) was obtained. 112-114 ° C.

Example 10

Preparation of 5- (6-carboxy-hexyl) -1- (2-hydroxy-heptylamino) -hydantoin

5- (6-Carboxy-hexyl) -1- (2-hydroxy-heptylideneamino) -hydantoin (a mixture of compounds 17 and 18 of Example 4) is reduced with sodium cyanoborohydride in Example 8. as specified. 5- (6-Carboxy-hexyl) -1- (2-hydroxy-heptylamino) -hydantoin (a mixture of compounds 35 and 36) is obtained in the form of a viscous oil.

NMR [(CD ₃ ) ₂ SO 6: δ 2.17 (2H, t, CH ₂ CO ₂ ), 2.71 and 2.81 (2H, 2m, N-CH ₂ ), 3.45 (1H, br, CH-O), 4.05 and 4.08 (1H, 2t, N-CH).

One of the diastereoisomers of 5- (6-carboxy-hexyl) -1- (2-hydroxy-heptylideneamino) -hydantoin (Compound 17) was similarly reduced with sodium cyanoborohydride, m.p. A diastereoisomer of 5- (6-carboxy-hexyl) -1- (2-hydroxy-heptylamino) -hydantoin (Compound 35) was obtained. M.p. 78-81 ° C.

NMR [(CD ₃ ) SO]: δ 2.18 (2H, t, CH ₂ CO ₂ ) 2.72 and 2.82 (2H, 2m, N-CH ₂ ), 3.45 (1H.br, CH -O), 4.07 (1H, t, N-CH).

Example 11

Preparation of 5- (6-Carboxyhexyl) -1- (2-cyclohexyl-2-hydroxyethylamino) -3-methylhydantoin

5- (6-Carboxy-hexyl) -1- (2-cyclohexyl-2-hydroxy-ethylideneamino) -3-methyl-hydantoin (mixture of diastereoisomers 25 and 26 of Example 6), sodium cyano with borohydride as in Example 8. The product was purified by chromatography on silica using 50: 1 chloroform: methanol as eluent. In this way, a mixture of diastereoisomers of 5- (6-carboxyhexyl) -1- (2-cyclohexyl-2-hydroxyethylamino) -3-methylhydantoin (Compounds 37 and 38) is obtained as a colorless viscous oil. form.

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NMR (CDCl ₃ ): δ 2.33 (2H, t, CH ₂ CO ₂ ), 2.6-3.0 (2H, m, N-CH ₂ ), 3.05 (3H, s, N-CH ₃ ), 3.40 (1H, br, CH-O), 4.02 (1H, t, N-CH).

Example 12

Preparation of 5- (6-carboxyhexyl) -1- (2-hydroxy-3-phenylpropylamino) hydantoin

5- (6-Ethoxycarbonylhexyl) -1- (2-acetoxy-3-phenylpropylideneamino) hydantoin (Compound 21 and 22 of Example 5) Sodium Cyanoboron hydride was reduced as in Example 8. A mixture of 5- (6-ethoxycarbonylhexyl) -1- (2-acetoxy-3-phenylpropylamino) hydantoin diastereoisomers (Compounds 39 and 40) was obtained as a viscous oil.

NMR (CDCl ₃ ): δ 2.05 (3H, S, COCH ₃ ), 2.28 (2H, t, CH ₂ CO ₂ ), 2.92 (2H, d, CH ₂ Ph), 3.10 ( 2H, d, N-CH ₂ ), 4.11 (2H, q, CO ₂ CH ₂ CH ₃ ), 4.35 (1H, t, N-CH), 5.15 (1H, m, CH-O). ), 7.25 (5H, s, Ph).

The above 140 mg ester mixture was hydrolyzed with 5 ml of 0.2 N sodium hydroxide solution at room temperature for 3 hours. The al mixture was then neutralized with 0.5 ml of 2N hydrochloric acid and the residual oil was extracted into ether. The ether extract was washed, dried and evaporated. This gives a diastereoisomeric mixture of 5- (6-carboxyhexyl) -1- (2-hydroxy-3-phenylpropylamino) hydantoin (Compounds 41 and 42) as a viscous oil.

NMR t (CD ₃ ) ₂ SO)]: δ 2.18 (2H, t, CH ₂ CO ₂ ), ca 2.6-2.85 (4H, m, PhCH ₂ + N-CH ₂ ), 3, 17 (1H, m, CHO), 4.04 (1 / 2H, t, one isomer N-CH), 4.09 (1 / 2H, t, one isomer N-CH), 7.23 (5H, m , Ph).

The above diastereoisomeric pair is crystallized from one of the pure diastereoisomers (Compound 41) when dissolved in a mixture of ethyl acetate and light oil (boiling point 60-80 ° C) overnight in a refrigerator. M.p. 93-95 ° C.

NMR 1 (CD ₃ ) ₂ SO]: δ 2.17 (2H, t, CH ₂ CO ₂ ), ca 2.6-2.85 (4H, m, PhCH ₂ + NCH ₂ ), 3.17 (1H , m, CHO), 4.09 (1H, t, N-CH), 7.22 (5H, m, Ph).

Example 13

Preparation of 5- (6-carboxyhexyl) -1- (2-methoxy-2-phenylethylidenediamino) hydantoin

-amino-5- (6-ethoxycarbonylhexyl) hydantoin and α-methoxyphenylacetaldehyde (prepared according to the procedure of Dornow and Müller, Chem. Ber., 93, 320/1960). with each other under the conditions described in Example 3 (A). This gives a diastereoisomeric mixture of 5- (6-ethoxycarbonylhexyl) -1- (2-methoxy-2-phenylethylidene) -hydantoin as an oily substance. Thin layer chromatography on silica using a 19: 1 mixture of chloroform / methyl alcohol as the eluent afforded two spots with Rf = 0.52 (ve20 strand 20) and Rf = 0.56 (Compound 44 | pf \ prfpkpknpi

NMR (CDCl ₃ ): δ 2.24 (2H, t, CH ₂ CO ₂ ), 3.40 (3H, S, OCH ₃ ), 4.12 (2H, qu, CO ₂ CH ₂ CH ₃ ), δ , 39 (1H, m, N-CH), 4.83 (1H, d, CH-O), 7.36 (5H, s, Ph), 7.83 and 7.87 (1H, 2d, N = CH) (diastereoisomeric pair).

The above ester mixture was hydrolyzed with aqueous sodium hydroxide as described in Example 2 to a diastereoisomeric mixture of 5- (6-carboxyhexyl) -1- (2-methoxy-2-phenylethylenediamino) hydantoin (45 and 46). (Compounds No. 3) are obtained in the form of a viscous oil.

NMR (CDCl ₃ ): δ 2.30 (2H, m, CH ₂ CO ₂ ), 3.42 (3H, S, OCH ₃ ), 4.40 (1H, m, N-CH), 4.86 ( 1H, d, CH-O), 7.36 (5H, s, Ph), 7.77 and 7.84 (1H, 2d, N = CH) (two diastereoisomers).

Example 14

Preparation of 5- (6-carboxyhexyl) -1- (2-methoxy-2-phenylethylamino) hydantoin

5- (6-Carboxyhexyl) -1- (2-methoxy-2-phenylethylideneamino) hydantoin (a mixture of compounds 45 and 46 according to Example 13) was reduced with sodium cyanoborohydride. as in Example 8. The diastereoisomeric mixture of 5- (6-carboxyhexyl) -1- (2-methoxy-2-phenylethylamino) -hydantoin (Compounds 47 and 48) was obtained as a viscous oil.

NMR (CDCl ₃ ): δ 2.33 (2H, t, CH ₂ CO ₂ ), 2.87 and 3.02 (2H, 2d, NHCH ₂ ), 3.26 (3H, s, OCH ₃ ), δ , 01 (1H, t, N-CH), 4.30 and 4.39 (1H, 2d, CH-O), 7.30 (5H, s, Ph).

In vitro activity

Inhibition of platelet aggregation

Freshly collected human blood is transferred into a 3.15% trisodium citrate silicone-coated (Siloclad; Clay Adams) plastic (Sterilin Ltd.) tube. The volume ratio of buffer to blood is 0.1: 0.9. The blood-buffer mixture was centrifuged at room temperature for 200 minutes for 15 minutes. Plasma rich plasma is then returned to the plastic container and stored at room temperature. Inhibition of platelet aggregation was determined using a Born-type aggregometer. 0.5 ml of platelet rich plasma is incubated with and without hydantoin for 1 min at 37 ° C and then enough adenosine diphosphate (ADP) or other aggregating agent is added to induce non-reversible aggregation of the control. A dose-inhibition curve is plotted for each compound and the ID ₅₀ value (50% inhibition) is calculated as the dose that produces a 50% reduction in aggregation relative to the control. The results show the effect after one minute of incubation and the effect after 5 minutes of incubation in platelet rich plasma c by comparison with 5- (6-carboxyhexyl) -1- (3-) described in British Patent No. 1,595,694. cyclohexyl-3-hydroxypropyl) hydantoin (Compound X) (Table 1).

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22

Table I

Compound shit IC _S0 (ng / ral) Effect compared to PC1 ₂ incubation 5 course increase (minutes) 10 3 16 0.02 X 7 x 20 6 2 0.30 X 5 x 20 8 24 0.05 - - 11 1 0.53 X 8 - 17 131 0.01 X 2 - 17/18 8 0.12 X 2 - 25/26 13 0.06 X 6 - 29 6 0.16 X 7 - 30 0.9 0.64 X 6 - 33 5.3 0.07 X 2 34 175 0,003 - - 33/34 6 0.17 X 2 - 35 12.7 0.05 X 1.5 - 35/36 1.27 0.49 X 1.5 - 37/38 3 0.18 X 7 - X 1.5 0.21 X 2 x 3

Ex carrier activity

Investigation of rabbit platelet aggregation and associated changes in systemic blood pressure.

Male rabbits weighing 2-2.5 kg are dosed at 30 mg / kg followed by a maintenance dose of 3 mg / kg i.v. After administration of sodium pentobarbitone, systemic arterial blood pressure was measured through a cervical artery cannula filled with 5 units / ml heparin-mixed saline. The animal is not given heparin. The hydantoin to be tested is administered via cannula into the femoral vein. Blood samples (1.5 ml) were slowly collected through a femoral artery cannula into a 0.15 ml syringe containing 3.18% sodium citrate. Blood and citrate were gently shaken and transferred to an Eppendorf plastic tube and centrifuged in an Eppendorf centrifuge (Model 5412, max. Centrifugation at 10,000 g) for 2 seconds. Platelet-rich plasma is collected and an aliquot of 0.35 ml is transferred to the aggregometer and incubated at 37 ° C for 1 minute before adding ADP (20 pmoles) sufficient to induce near-maximal aggregation. the time between the introduction of plasma into the aggregometer was less than 1.5 minutes.

₅₅ Once the rabbit's blood pressure steady - 10-20 minutes after preparative surgical procedure - are bled 10 min intervals. After three control blood samples and three platelet aggregation control measurements, the hydantoin was administered intravenously over 15 minutes using a Braun slow infusion device. Blood samples are taken 10 minutes after the start of the infusion. Every 10 minutes, two additional blood samples were also taken after infusion, additional infusion begins before ^b5 formation.

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Table 2 shows the ED ₅₀ values and the change in blood pressure. the results for PGI ₂ and Compound X are also reported for comparison.

Table 2

Compound Ed Blood Pressure

Pg / kg / min Hgmm

3. 2.0 0

6. 0.15 0

X 3.3 -5

PGI ₂ 0.2 -20

The above results show that the _ED50 values of the compounds 3 and 6 are comparable to the value of the compound X and the ED _5o PGI _2, 3 and 6 but using the compounds in such dosage forms - in contrast to agents known - does not cause a fall in blood pressure .

Carrier activity

(a) Cardiovascular effects in rat

Male Wistar rats weighing 250-300 g body weight are anesthetized with 30 mg / kg iv of sodium pentobarbitone administered and 3 mg / kg of sodium pentobarbitone administered as needed. Arterial blood pressure is recorded on the femoral artery with cannula, and heart rate is recorded from the arterial pulse. The body temperature of the animals is controlled by a thermistor-controlled radiant heat such that it is measured in the rectum at 37 ° C. Each compound was injected in a volume of 0.25 mL into the femoral vein and then rinsed with 0.2 mL of 0.9% w / v saline. The dose-response relationship of the mean systemic hypotension induced by the administration of hydantoin was measured and compared with the values obtained using PGI ₂ and PGE in a similar manner in the same animal. The antihypertensive duration index of each compound is given in Table 3 with the time from peak to half-maximal effect (t 1/2 min) and values for Compound X and PGl ₂ are also compared.

Table 3

Compound Blood pressure drop ratio pgi ₂ PGE, t 1/2 (min) Third 0.027 0.324 11.0 6th 0.041 0.5 17.0 8th 0.01 0.11 1.0 yl. 0.1 '1.1 16.0 17th 0.01 to 0.12 3.5 17./18. 0.04 0.48 10-19 25./26. 0.09 1.08 9 29th 0.02 0.24 37 30th 0.02 0.24 28 33./34. 0.02 0.24 6 35th 0.01 - 1.3 35./36. 0.06 - 0.1 37./38. 0.03 0.36 17 X 0.06 0.72 4.0 pgi ₂ 11.0 0.3

b.) Cardiovascular effects in dogs

For dogs weighing 10-15 kg, 80 mg / kg

arc. dosing with chloralose added and, if necessary, subcutaneous injections of 3 mg / kg pentobarbitone. The test compounds are administered as a bolus injection into the femoral vein and the blood pressure in the right femoral artery is recorded. The results in Table 4 show the antihypertensive effect in the vessel as well as the t 1/2 duration, comparing with the value obtained for Compound X.

Table 4 Compound Dose Blood pressure t 1/2  (Pg / kg) (MmHg) (Min) X 1.25 -45 2.8 2.5 -56 6.2 6 0,625 -54. 60 1.25 -65 > 60 29th 0,625 -26 > 30 1.25 -51 > 60

c.) Inhibition of gastric lesion in rats

Inhibition of gastric lesion induced by acid-ethyl alcohol mixture (cell protection) was measured in rats by oral administration of hydantoin at various doses. For the sake of comparison, the results for Compound X are also shown in Table 5.

Table 5

Compound Dose (pg / kg) % inhibition 4./5. 50 90 ± 6 6th 10 31 ± 20 25 50 ± 21 50 69 ± 8 8th 25 71 ± 6 50 76 ± 11 X 5 46 ± 26 10 80 ± 9 25 89 ± 6 23./24. 10 55 ± 15 30th 25 65 ± 17 37./38. 10 71 ± 1

The above compounds exhibit an oral ulcer activity similar to that listed above in the presence of indomethacin at 20 mg / kg for 3 hours with gastric erosion.

The following examples illustrate the preparation of pharmaceutical compositions containing an active ingredient of the present invention.

In Examples A-D, the term "active compound" refers to hydantoin derivatives of formula (I) which are solid at room temperature. In Examples Ε and F, the active compound is either solid or at room temperature

-13193280 refers to liquid hydantoin derivatives of formula (I). In Examples G-I, the term "active compound" refers to hydantoin derivatives of formula (I) in liquid form at room temperature, such as an oil. Such liquid compounds are compounds 4-6, 9, 10, 15, 16, 21, 22, 25-27, 30-36, 37 and 38, or mixtures thereof.

The Example

Preparation of tablet per tablet (mg)

Active Compound 5.0

Lactose B.P. 82.0

Starch B.P. 10.0

Povidon B.P.C (Polyvinylpyrrolidone) 2.0

Magnesium stearate 1.0

The active compound is mixed with lactose and starch. The powder is granulated by adding povidone dissolved in purified water. The granules are dried, then magnesium stearate is added and 100 mg tablets are compressed.

Example B

Preparation of capsule per capsule (mg)

Active compound

Lactose 79

Starch 10

Magnesium stearate 1

The powder is mixed in a blender and filled into a hard gel capsule every 100 mg.

Example C Preparation of pg / ml injection

Active compound 100 pg

Injection quality water for addition to 100ml

The active compound is dissolved in water for injection. The solution was sterile filtered through a 0.22 µm pore size membrane and the filtrate collected in a sterile receiver. The solution is aseptically filled into sterile glass ampoules at a rate of one ml per ampoule. The vial is sealed by sealing the vial.

Example D Preparation of pg / ml injection

The active compound is 1 mg

Ethyl alcohol 10 ml

Propylene glycol 30 ml

Water for injections up to 100 ml

The active compound is dissolved in ethyl alcohol, propylene glycol is added and diluted to 100 ml with water for injection.

The solution is sterile filtered through a 0.22 µm pore size membrane and the filtrate is collected in a sterile receiver. Aseptically, the solution is filled into a sterile glass vial at a volume of 10-10 ml per vial. The vial is sealed with a sterile rubber stopper and sealed with an aluminum ring.

This Example is a single dose injection (freeze-dried) of 100pg

The active compound is Mannitol

0.1 N Sodium hydroxide solution, θ Water for injection, 2.5 mg

qs pH 10.0

To 100.0 ml to make up

The active compound is dissolved in about 20 ml of water for injection (or, in the case of compound all, mixed with water to form a crude emulsion). Add enough sodium hydroxide solution to adjust the pH to 10 and stir until dissolved. The solution is added and dissolved in mannitol and diluted to 100 ml with water for injection.

The solution is sterilized by passing through a 0.22 µm pore size membrane filter and aseptically distributed into 1 ml sterile vials. The solution is freeze-dried and the vials are sealed with aseptic sealing caps. Each vial contains 100 µg of active compound in the form of its sodium salt in freeze-dried state.

Example F Making a cone

Active compound Esterinum C mass per mg supplement

The suppository stock is heated to about 40 ° C and the finely powdered active compound is gradually added to form a homogeneous mixture. Pour into proper shape and allow to freeze.

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

Example G

Making a tablet

Per tablet (mg)

Active compound 0.5

Microcrystalline Cellulose Carrier 50.0 Lactose B.P. 36.5

Starch B.P. 10.0

Povidon B.P.C. 2.0

Magnesium stearate 1.0

The active compound is dissolved in a suitable solvent, distributed over the microcrystalline cellulose carrier, dried, and mixed with lactose and starch.

The powder is granulated using povidone dissolved in purified water. The granules are dried, magnesium stearate is added and 100 mg tablets are compressed.

-14193280

Example H

Preparation of capsules

Per capsule (mg)

The active compound is 0.5 mg

Corn oil 99.5 mg

The active compound is dissolved in corn oil and placed in an amount of 100-100 mg in soft gelatin capsules.

Example I Preparation of pg / ml injection

Active compound 100 pg

Polysorbate 80 B.P. 0.1% w / v to the final volume

Water for injections up to 100 ml

Polysorbate 80 is mixed with water for injection and the active compound is added to form an emulsion. The emulsion was sterilized by passing through a 0.22 µm pore size membrane filter and the filtrate was collected in a sterile receiver. Aseptically, the solution is filled into sterile glass ampoules every 1 ml. The vials are sealed.

Example J Preparation of pg / ml injection

The active compound is 1 mg

Ethyl alcohol 10 ml

Propylene glycol 30 ml

Polysorbate 80 B.P. 0.1% (w / v) volume of water for injection to make up 100 ml of water for injections

Polysorbate 80 is mixed with 20 ml of water for injection and mixed with the active compound to form an emulsion. Ethyl alcohol and propylene glycol are added to the emulsion, then thoroughly mixed and diluted to 100 ml with water for injection. The mixture is sterilized by passing through a 0.22 µm membrane filter and the filtrate is collected in a sterile receiver. Aseptically, the solution is filled into sterile glass vials every 10 ml, sealed with a sterile rubber stopper and sealed with an aluminum ring.

Claims (7)

PATENT CLAIMS A process for the preparation of new hydantoin derivatives of the formula I and their stereoisomers wherein Z is hydrogen or C 1 -C 4 alkyl; - Z ¹ is -CH ₂ -X-X'-X ² wherein - X is - (CH ₂ ) ₂ - - X ¹ is a linear alkylene group having 1 to 6 carbon atoms, X ² is a carboxyl group or a (C 1 -C 4 alkoxy) carbonyl group and - Z ² is -NH-CH ₂ -R and -N = CH-R, wherein R is -COY or a group of formula (a) wherein --- Y is C 3 -C 8 alkyl, phenyl-C 1 -C 4 alkyl, phenyl or C 4 -C 8 cycloalkyl, and --- Y ¹ is hydrogen, hydroxy, (C 1 -C 4) alkoxy or (C 1 -C 4) alkanoyloxy - characterized in that Z ^{2 is} -N = CH-R - wherein R is as defined in the foregoing, for the preparation of a compound of formula I having a compound of the formula II in which Z and Z ¹ are as defined in the preamble, with a compound of the formula III in which R is as defined Reacting and optionally subjecting the resultant product of formula (I) to one or more of the following conversion steps, selecting the sequence of steps as desired: i) converting the resulting hydantoin of the formula (I) (C 1 -C 4) alkyl ester to the corresponding acid; and / or (ii) converting the resulting hydatoin derivatives of formula (I) wherein Z is hydrogen into the corresponding compound of formula (I) having from 1 to 4 carbon atoms as Z substituents; ) hydantoin derivatives of formula (i) wherein R is a group of formula (a) wherein Y is as defined in the foregoing, Y ¹ is (C 1 -C 4) -alkanoyloxy, the corresponding Y ¹ converting it into a compound of formula (Γ) containing a hydroxy group; and / or iv. ) converting hydantoin derivatives of formula (I) wherein R is -COY - Y is as defined herein - into the corresponding compound of formula (I), wherein R is -CH (OH) Y, and /obsession v. ) Hydantoin derivatives of formula (I) ^{Z, Z} = group represented by formula -N = CH-R - R is as defined above - General containing _-NH-CH2 -R group of the formula to the corresponding Z ² substituent (I) converting to a compound of the formula; and optionally separating one or two of the diastereoisomers of the compound of formula (I) obtained. -15193280 Process according to claim 1, characterized in that the reaction is carried out in a solvent such as methanol. A process for the preparation of hydantoin derivatives of formula I according to claim 1 or 2, wherein Z ² is -NH-CH ₂ -R - R and the other substituents are as defined in claim 1 - and reacting a compound of formula (II), as defined in claim 1, with a compound of formula (III), as defined in claim 1, and reducing the nitrogen-carbon double bond in the resulting compound. A process for the preparation of hydantoin derivatives of formula I according to claim 1 or 2, wherein Z ² is -N = CH-R, R and the other substituents are as defined in claim 1, characterized in that: reacting a compound of formula II with substituents as defined in claim 1 with a compound of formula III. 5. A process for the preparation of hydantoin derivatives of formula I according to any one of claims 1 to 5, wherein Z is hydrogen, Z 'is -CH ₂ X-X'-X ² - wherein X is - (CH 2) 2 -, X ¹ is 2-. 4 carbon atoms, and X ² represents a carboxyl group or a C 1-4 alkyl group, - Z 2 are as defined in claim 1 and R is (a) a group of formula, Y ¹ represents hydroxy, and Y is phenyl, C3-8, alkyl or a C 4 -C 8 cycloalkyl group, wherein a compound of formula II is as defined in the present disclosure, with a compound of formula III: wherein R is a compound of general formula (a); formula, in which Y ¹ is hydroxy and Y is phenyl, ¹ θ 3-8 carbon atoms or 4-8 carbon atoms, preferred and, if desired, reduce the nitrogen-carbon double bond of the resulting compound. 6. Method according to claims 5- (6-carboxy-hexyl) -l- for preparing a compound of formula ¹⁵ (S) [2-cyclohexyl-2- (hydroxyethyl) amino] - hydantoin, 5- (6-karoxi hexyl) -1-l2-cyclohexyl-2- (hydroxy-ethylidene) amino] hydantoin, 5- (6-carboxy-hexyl) ^-l-20 - [2 hydroxy-2- (phenyl-ethylidene) amino] hydantoin or a (1-4C) alkyl acetoacetate preparation, characterized in that a compound with an appropriately substituted formula (II) are reacted with an appropriately substituted ²⁵ (III), followed, if necessary, the resulting nitrogen-carbon double bond containing the compound. 7. A process for the preparation of a pharmaceutical composition comprising combining as active ingredient one or more hydantoin derivatives of the formula I as claimed in claim 1 and / or ³⁵ excipients with a carrier and / or other excipients to form a pharmaceutical composition. .