FI71930B - FARING REFLECTION FOR 1,5-DISPENSION HYDANTOIN WITH AGGREGATION FOR BLODKROPPAR FOERHINDRANDE VERKAN - Google Patents

Description

| ν ^ · Ί ANNOUNCEMENT 71Q7n

$ 3 $ 9 ™ '' UTLÄG G NIN G SSKRIFT / l ^ oU

C (45) 03 1 .0? (51) Kv.lk. * / Lnt.CI. * C 07 D 233/78 (21) Patent application - Patentansökning 771 7 ^ 3 (22) Application date - Ansökningsdag 02.06.77 (Fl) (23) Start date - Giltighetsdag 02.06. 77 (41) Became public - Blivit offentlig 0 ^ 4.12 77

National Board of Patents and Registration Date of publication and publication 28 28 86

Patent and registration authorities Ansökan utlagd och utl.skriften publicerad (86) Kv. application - Int. ansökan (32) (33) (31) Privilege claimed - Begärd priority 03.06.76 02.12.76, 23.Ο3.77 England and England (GB) 22877/76, 503 ^ 0/76, 12145/77 (71) The Wellcome Foundation Limited, 183-193 Euston Road, London, England-England (GB) (72) Albert Gordon Caldwell, West Wickham, Kent,

Norman Whittaker, Beckenham, Kent, Eng 1 anti-Eng 1 and (GB) (74) Oy Koister Ab (5 * 0 Method for the preparation of 1,5 "disubstituted hydantoin having an inhibitory effect on platelet aggregation - Förfarande för framställ-Ning av 1, 5_disubstitue rad hydantoin med aggregation av blodkroppar förhindrande verkan

The invention relates to a process for the preparation of 1,8-disubstituted hydantoin, which has zero inhibitory effect on platelet aggregation.

These hydantoin derivatives of formula (I) according to the invention have been found to have pharmacological properties closely resembling those of natural prostaglandins, as evidenced by their ability to promote or counteract the physiological effects of natural prostaglandins in various biological preparations. In particular, some of the compounds of formula (I) have been found to be effective in inhibiting platelet aggregation in a manner similar to the inhibitory effect of prostaglandin E1.

In this formula (I) J? χ7 '719 30 2

Z-N I

N (X) 12 Z is hydrogen or an alkyl group and one of the symbols Z and Z is 12 · · = -CH0-X-X -X; wherein X is a phenylene group, -C-C-, cis -CH = CH- or -CH 2 -CH 2 - group; X 1 is an alkylene chain of 1 to 6 carbon atoms, wherein one of its methylene groups may be replaced by an oxa - (- O -) - group, provided that at least one carbon atom separates the oxa group -CC-, -CH = CH or -CO- group; and X 1 is 5-tetrazolyl, carboxy, carbamoyl, hydroxymethylene or alkoxycarbonyl; and 1 2 1 2 3 one of Z and Z is -Y-Y ~ -Y-Y; wherein Y is -CP ^ -CH, .-; Y1 is carbonyl, methylene or methylene substituted by a hydroxyl group or substituted by a hydroxyl and alkyl group.

imported methylene; Y is a covalent bond or a straight or branched chain alkylene having 1 to 7 carbon atoms; Y is hydrogen, hyperoxy, ethoxy, phenyl (optionally substituted with methyl, trifluoromethyl, methoxy, hydroxy, nitro, amino or phenyl) and phenoxy (optionally substituted with methyl, 2.3). or a trifluoromethyl group); or Y and Y "together form a cycloalkyl group having 4 to 7 carbon atoms.

Unless explicitly stated otherwise, in formula (I) and other formulas of this application, the alkyl moieties are selected from methyl, ethyl, propyl, butyl, pentyl and hexyl groups, including all isomers thereof.

12 ..

Thus, in the definitions of the symbols Y and Y, the alkyl groups are suitably methyl groups, and the alkyl moiety of the alkoxycarbonyl group is suitably a methyl or ethyl group. The same applies to alkylene groups having 2 to 4 carbon atoms, e.g. a vinyl group.

In the compound of formula (I), the bond of the divalent phenylene group may be in the ortho, meta or para position, and the oxa group is suitably located at the phenylene group, or in the case ... X that other than the phenylene group may X - CH ^ CH ^ O-group.

Compounds of formula (I) also include salts of carboxylic acids and tetrazoles when X represents a carboxylic acid, a tetrazole group, and salts which may form 71930 even if Z represents a hydrogen atom. Particularly valuable salts for medical use are those having a pharmaceutically acceptable cation, such as ammonium, or cations of an alkali metal, e.g. sodium or potassium, an alkaline earth metal, e.g. calcium or magnesium, or organic bases, especially an amine, such as ethanolamine. Also included within the scope of the invention are those salts which do not contain pharmaceutically acceptable cations, as they can still be used as intermediates for the preparation of pharmaceutically acceptable salts or acids or esters of formula (I).

All stereoisomers present are included within the scope of formula (I) and the other formulas set forth in this application, unless expressly stated otherwise. In particular, such formulas include enantiomeric forms, racemic mixtures and diastereoisomers.

It has been found that for those compounds of formula (I) in which Z represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, e.g. a methyl or butyl group, 12. 12 one of the symbols Z and Z represents -CH 2 -XX -X- a group, 1 1 wherein X and X together form an alkylene group having 3-7,. . . 2 "..

especially 5 carbon atoms, and X represents an alkoxycarbonyl or carboxyl group or a salt thereof, 12. 12 3 and one of the symbols X and Z "represents the group -Y-Y -Y" -Y-1.2, where Y, Y and Y have the same meaning as defined above. 3

ty, and Y represents a hydrogen atom, a cycloalkyl group having 4 / carbon atoms, a phenyl or a benzyl group, have particularly interesting properties resembling those of a prostaglandin. This definition also includes a subclass where Z

1 12 represents a hydrogen atom and Z represents a -CH 2 -X-X -X group as defined above.

The compounds of formula (I) are prepared according to the invention as set out in the characterizing part of claim 1 as alternative analogous methods. Thus, they can be prepared from the corresponding derivatives of the hydantoin acid of the following formula (T1) La___ -

B

71930. ζχ

G ~ V

Η! (II) ΖΝ \, Ν X Χζ2 in the formula G represents a carboxy group or a derivative thereof such as an amide or ester group, especially an alkyl ester group,

1. ? . . J

the symbols Z, Z and Z have the same meaning as in formula (I), the preparation of which takes place by cyclization under acidic conditions or by heating one's hands. The reaction may be carried out without a solvent, but if desired, an inert solvent such as hydrogen, such as gasoline, may be used. Alternatively, in the case where G represents an alkoxycarbonyl group, the cyclization may be carried out in the presence of a suitable base, e.g. an alkoxide such as sodium methoxide olleor.

Hydantoin of formula (I) may also be prepared by cyclization of a compound of formula (VII).

i1 N

H \ k?.

wherein Z, Z and 7 / have the same meaning as in formula (I), and G represents a carboxy group or a reactive derivative thereof, e.g. an alkoxycarbonyl group such as ethoxycarbonyl. Compounds of formula (VII) may be cyclized under similar conditions to a compound of formula (II), and a process for preparing a compound of formula (VII) is suitably selected so that the reaction conditions present allow spontaneous cyclization.

By applying a process similar to that described above, hydantoin of formula (I) can be prepared by reacting a compound of formula (IX) with 5,71930 o

! 1 ZN

H; (IX) 2 1 2 in which Z, Z and Z "have the same meaning as in formula (I), to react with a carboxylic acid derivative. Suitably any carboxylic acid derivative known in the art, e.g. phosgene, diphenyl carbonate or alkyl haloformate, such as The reaction is conveniently carried out in the presence of a base, e.g. an amine such as triethylamine or diisopropylethylamine, and using an inert aprotic solvent, e.g. toluene, dimethylformamide or an ether such as diethyl ether, The reaction may be carried out at room temperature, but if desired the reaction mixture may be warmed.

Hydantoin of formula (I) wherein Z represents an alkyl group may also be prepared by alkylation, alkylation. .

by means of a substance which may be called a reactive ester derivative of the alcohol J, a compound of formula (X), 9 J-N | (X) H 90 in which J represents a hydrogen atom or an alkyl group, J represents 12.

represents a hydrogen atom or the same as Z, J represents a hydrogen atom or 2 3.. i is the same as Z, and J is an alkyl group or the same as Z or 2 ..1.2.

Z, provided that one of the symbols J, J and J represents a hydrogen 3 .12 atom and J does not mean the same as J, J or J, in which case the symbol 12 3 12.

In the definition of J, J and J, Z and Z have the same meaning as in formula (I). Suitable reactive ester derivatives include chlorides, bromides, iodides and sulfonates such as p-toluenesulfonate, methanesulfonate and benzenesulfonate. The alkylation may be carried out by applying reaction conditions known in the art to be suitable, e.g. in the presence of a base such as an alkali metal hydride, alkali metal amide or alkali metal alkoxide, suitably sodium hydride or sodium alkoxide such as sodium ethoxide.

719 3 0

The reaction is conveniently carried out in an inert solvent which simply acts as a diluent for the reaction components, such as toluene, dioxane, ether, dimethylformamide, tetrahydrofuran, dimethyl sulfoxide and acetonitrile, while in the case of a base alkali metal alkoxide, the corresponding alkanol may be used.

Intermediates of formula (X) wherein J represents a hydrogen atom are also compounds of formula (I) and may be prepared by applying any of the methods set out above. Compounds of formula (X) may also be prepared by methods known in the art (see, e.g., Chemical Rewiews (1950) 45, pp. 403-425).

Another possibility for the preparation of compounds of formula (I) is the reduction of the corresponding unsaturated compound of formula (XI) by means of a suitable reducing agent 1 k ZN jj (XI) Y "1 '3, in which formula either Z represents = CR-CH2_X" * "- Y ^ -Y ^ and Z4 represents a -CH4 -XX ^ -X ^ group, or represents a = CH-XX ^ -X ^ group and Z4 represents a -YY ^ -Y ^ -Y ^ - 2 3 group, wherein the symbols R, XX and YY have the same meaning as in formula (I).

A suitable reducing agent is stannous chloride, which can be used as an aqueous solution in which dilute mineral acid may be present. Catalytic hydrogenation can also be performed using Raney nickel, platinum, palladium, ruthenium or rhodium as the catalyst. The choice of reducing agent depends in each case on the presence of other reactive groups in the molecule which can themselves be reduced.

Intermediates of formula (XI) can be prepared by applying the following sequence of reactions

II

71930 g ch (og5) 2 c chcog3),

CH 1- G <.Z <-►NiT

I I

NH2 NH

\ «CXII),„ i, / Ym <-... »·, / Y" mh ‘V \. Nr \ <

o ώ O Z

cxfv> CXIII) l * P '«3P- 23 (XI) 3 4.

In the above formulas, Z, Z, Z and G have the same meaning as in formulas (XI) and (III), G represents an alkyl group, 4 e.g. an n-butyl group, and G represents a halogen such as bromine. The formation of compound (XIII) corresponds to a ring closure using a compound of formula (II), and compounds of formula (XIV) are prepared using a concentrated mineral acid, e.g. hydrochloric acid.

2

Alcohols of formula (I) wherein X represents a hydroxy methylene group may also be prepared by reduction with a suitable reducing agent of the corresponding acid, ester, acid halide, acid anhydride or aldehyde. The suitable reducing agent depends on the reaction mixture used in each case, in which case sodium in ethanol can be used as the reaction component. In particular, for example, the carboxylic acid can be converted to the corresponding mixed anhydride in the presence of ethyl chloroformate in a base such as triethylamine, followed by reduction to the alcohol with sodium borohydride. Likewise, the ester can be reduced to the alcohol using diisobutylaluminum hydride in an inert solvent such as ether or a hydrocarbon such as hexane or benzene. Such alcohols can also be prepared from catalytic hydrogenation.

8 71 930

Alternatively, alcohols of formula (I) may be:. . 2) where X represents a hydroxymethylene group, is prepared by hydrolysis of the corresponding halide with a suitable reagent. A hydroxide, e.g. an aqueous alkali solution or an aqueous suspension of silver oxide, can be used for this purpose.

In the preparation of hydantoin of formula (I) having a hydroxyl group in the side chain, it may be advantageous to protect this group during the reaction. This can easily be done by methods known in the art using a protecting group such as an acyl, aryl, tetrahydropyran-2-yl, 1-ethoxyethyl group, or an aralkyl group, e.g. benzyl.

The protecting groups can be removed by methods known in the art. Thus, the acyl group can be removed by acidic or basic hydrolysis, and the benzyl group can be removed by reductive cleavage.

Λ

Furthermore, a ketone of formula (I) in which Y represents a carbonyl group may be converted into the corresponding secondary alcohol by reduction with a suitable reducing agent such as sodium borohydride. Thus, an alcohol of formula (I) wherein Y is -CH.OH may also be oxidized to the corresponding ketone using Jones reagent, acid dichromate or other suitable reagent.

Similarly, in the case where the compounds of formula (I) have a -C-C- or -CH = CH bond, these compounds can be converted to the corresponding ethylene or saturated compound by a conventional hydrogenation method, e.g. using a Lindlar-type or Adams catalyst.

The hydantoin of formula (I) has an asymmetric 5-carbon atom, and a second asymmetric center is present in those compounds in which the symbol Y represents a hydroxyl group. Such alcohols thus exist as four epimers, which can be separated by thin layer chromatography or efficiently by liquid chromatography into two diastereomers, both of which are racemic mixtures of the two epimers. When separating diastereomers, the second diastereomer can be converted to a mixture of four epimers by treatment with a base such as alkali metal hydroxide and then re-separation to give two diastereomers. By repeatedly applying this method, one diastereomer can be changed to another, which may be desirable in the event that one diastereomer has a beneficial biological effect over the other.

9,71930

In all the chemical treatments described above, the choice of the reaction component depends in part on the functional groups in the reaction mixture, so that, if necessary, reaction components having a suitable selective effect must be used.

The hydantoin of formula (I) is valuable because it has pharmacological properties similar to those of natural prostaglandins, so that hydantoin resembles or opposes the Af, 1B *, 'C, fD', T ET and 'prostaglandins (PG). Biological effects of F 'series. Thus, it has been found that the effects of the hydantoin of formula (I) resemble the antiplatelet effect of PGE1 and counteract the contraction induced by PGE2 or PGF1, in smooth muscle taken from rat stomach, rat colon, chicken rectum and guinea pig trachea. In general, adverse effects have been observed, which are thus the opposite of the promoting effects, in the case where hydantoin is used in higher doses. The pharmacological profile, which refers to the relative effects, i.e. the promoting or opposing effects compared to the effects of natural prostaglandins, will, of course, vary depending on the particular hydantoin tested in each case.

Due to their properties resembling the action of prostaglandins, the hydantoin of formula (I) are valuable in the pharmacological identification and differentiation of the biological effects of natural protaglandins and their "receptors". A closer understanding of the physiological function of prostaglandins is, of course, valuable in the pursuit of new and better drugs.

The hydantoin of formula (I) are also valuable drugs. In particular, the hydantonines described above have a strong antiplatelet effect on platelets, so they can be used in the case where it is desired to prevent platelet aggregation or to reduce the adhesion of these platelets. They can thus be used to treat or prevent thrombosis in mammals, including humans. Thus, these compounds can be used in the treatment and prevention of myocardial infarction, in the treatment and prevention of thrombosis, in keeping transplanted vessels open after surgery, and in the treatment of complications and conditions of arterial sclerosis, such as 1C) 71930. under conditions caused by fat imbalance or overweight. The compounds can also be used as additives for blood and other fluids used in artificial extracorporeal circulation and drainage through isolated body parts.

A particularly valuable group of antiplatelet compounds are those compounds of formula (I) in which Z represents a hydrogen atom, Z represents a carboxyalkylene group having 3 to 9 carbon atoms in the alkylene moiety, and Z 2 is - (CH 2) .CH.CH.Y2.Y3 -. A group wherein Y in the formula represents a branched alkylene group having a tertiary carbon atom adjacent to the hydroxy-substituted carbon 3, and Y has the same meaning as in formula (I). Of the compounds of this group .... 1, those compounds in which Z represents a carboxyhexyl group and Y2 represents a cycloalkyl group having 4 to 7 carbon atoms are particularly valuable.

It has also been found that the hydantoin of formula (I) causes the triggering of vascular smooth muscle tension in the same way as the compounds of the Ά’ and Έ series of prostaglandin. Examples of these compounds of the invention include 5- (6-carboxyhexyl) -1- (3-hydroxy-4,4-dimethyloctyl) -hydanine and 5- (6-carboxyhexyl) -1- (3-hydroxy-4 , 4-dimethyl-5-fenyylipen-style) -hydantoin. Compounds that trigger vascular smooth muscle tension states are capable of causing vasodilation, so they have antihypertensive properties so that they can be used to lower blood pressure in mammals, including humans. In this case, they can be used alone or in combination with a /> adrenospector blocking agent or other antihypertensive agent to control all kinds of hypertension diseases, including primary, malignant and secondary hypertension.

The compound 5- (5-carboxyhexyl) -1- (3-hydroxy-4,4-dimethyloctyl) -hydantoin also resembles the effect of PGE4 in that it resists histamine-induced bronchoconstriction. The hydantoin of formula (I) having this property can be used in the treatment or prophylaxis of bronchial asthma and bronchitis by alleviating the bronchoconstriction associated with this condition.

Il 71930 11

Hydanthines of 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 H -phenoxybutylD-hydantoin, which resist pentagastrin-induced gastric acid isolation and reduce the formation of aspirin-induced gastric ulcers in rats, can be used to reduce the secretion of excessive gastric fluid, to reduce and prevent gastric and intestinal ulcers, and to accelerate the healing of such gastrointestinal ulcers, whether spontaneous or multi-glandular.

Some intravenous injections of hydantoin of formula (I), typically 5- (6-carboxyhexyl) -1- (3-hydroxyoctyl) -hydantoin, have been shown to increase urinary excretion, indicating the potential for use of these compounds as diuretic drugs, which uses include the treatment of edema, e.g., the treatment of edema due to heart failure, hepatic or renal failure in humans or other mammals.

Another use of the hydantoin of formula (I), based on the fact that their action is reminiscent of the action of PGE 1 and PGF 2 on uterine smooth muscle, is the use of these compounds as contraceptives, in particular as abortifacients.

The amount of compound of formula (I) required to achieve the desired biological effect will, of course, depend on a number of factors, including the compound selected, its intended use, the mode of administration and the recipient. The daily dose can generally be expected to be in the range of 1 μg to 20 mg / kg body weight. Thus, the intravenous dose may be in the range of 5 μg to 1 mg / kg, which may conveniently be infused intravenously from 0.01 to 50 pg / kg / min. Infusion fluids suitable for this purpose may contain 0.001 to 100, e.g. 0.01 to 10, ug / ml of compound. Unit doses may contain 10 pg to 100 mg of a compound of formula (I), e.g. ampoules may contain 0.01-1 mg, and oral unit doses such as tablets or capsules may contain 0.1-50, e.g. 2-20 mg.

When using a compound of formula (I) to prevent platelet aggregation, it is generally advantageous to achieve this. in the fluid, be it the patient's blood or perfusion fluid, at a concentration of about 1 μg-10 mg / L, e.g., 10 μζ ~ 1 mg / L.

The above dosages apply to acids, amides, esters, alcohols and tetrazoles of formula (I). When using salt, the dose should be calculated based on the corresponding anion.

When the hydantoin compounds of the invention are used in the treatment or prevention of the aforementioned conditions, these compounds may be used as crude chemicals, but are best used in combination with a suitable carrier as a pharmaceutical. The plaintiff must, of course, be "acceptable" in the sense that it adapts to the other components of the mixture and does not harm the recipient. The carrier may be a solid or liquid, suitably mixed with the hydantoin compounds to give a unit dose, e.g. a tablet, which may contain from 0.05 to 95% by weight of the hydantoin compound. Other pharmacologically active substances may also be present in the pharmaceutical compositions according to the invention. The hydantoin compounds can be included in the mixtures as either an acid or a salt or an ester, and the mixtures can be prepared by applying a prior art drug preparation technique based primarily on mixing the components together.

These compositions include those suitable for oral, anal, transdermal (buccal or sublingual), parenteral (i.e., subcutaneous, intramuscular, and intravenous) administration, although in each case the most appropriate route of administration will depend on the nature of the condition being treated and the nature of the hydantoin compound. .

As the pharmaceutical compositions of the invention suitable for parenteral administration, sterile aqueous solutions of the hydantoin compound are suitably used, which are suitably isotonic with the blood of the recipient. These preparations are conveniently administered intravenously, although they may also be administered subcutaneously or intramuscularly. These pharmaceutical compositions are conveniently prepared by adding a hydantoin compound to water, sterilizing the solution and making it isotonic with water.

Suppository suppositories are suitably used as rectal compositions. They can be prepared by mixing the hydantoin compound with one or more conventional ones

II

13 71 930 on a solid support and shaping the resulting mixture into a rod.

In the following examples, hydantoin is labeled as follows: Compound 2: 5- (6-carboxyhexyl) -1- (3-hydroxyoctyl) hydantoin; Compound 4: 5- (6-carboxyhexyl) -1- (3-hydroxy-4,4-dimethylpentyl) hydantoin;

Compound 6: 5- (6-carboxyhexyl) -1- (3-hydroxynonyl) hydantoin; Compound 9: 5- (6-carboxyhexyl) -1- (3-hydroxy-4,4-dimethyloctyl) hydantoin;

Compound 11: 5- (6-carboxyhexyl) -1- (3-hydroxy-3-cyclobutylpropyl) hydantoin;

Compound 12: 5- (6-carboxyhexyl) -1- (3-hydroxy-3-cyclopentyl) -propyl) hydantoin;

Compound 1 * 4: 5- (6-carboxyhexyl) -1- (3-hydroxy-3-cyclohexylpropyl) hydantoin;

Compound 38: 5- (6-carboxyhexyl) -3-methyl-1- (3-oxooctyl) -hydantoin.

In the event that a particular dia-stereomer is used. this is indicated by reference to its melting point. Example A: Effects on cardiovascular in rats

Male normotensive rats of the Wistar strain (Carles River) weighing 250-350 g were anesthetized with chloroform before the cannula was inserted into the left femoral vein, and anesthesia was maintained by intravenous administration of 60 mg / kg chloralose. Pulsed blood pressure was measured in the left femoral artery using an electronic transducer (Bell and Howell Type 4-327 L221), and the integrated heart rate was measured with a heart rate monitor controlled by arterial pressure waves.

The test compound was administered as a solution in physiological saline by intravenous spray through a thigh cannula. The measured deviations between successive injections were allowed to return to pre-injection values.

When the vehicle alone was injected in the same volume as the injections containing the test compound, there was no reduction in blood pressure.

11+ 719 30

Compound Dose Mean reduction in blood pressure mmHg PGE2 4 Ug / kg 28 PGE ^ 16 ug / kg 44

Compound 2 10 ug / kg 14

Compound 2 1 mg / kg 42

Compound 6 3 mg / kg 40

Compound 9 3 mg / kg 22

Example B: Inhibition of platelet aggregation

In a Born-type aggregometer, platelet aggregation was monitored in 1 ml of fresh, platelet-rich human plasma.

The test compound was added to the plasma at the desired concentrations, and the resulting mixture was incubated at 37 ° C for one minute, after which the accumulation of flakes was stimulated by the addition of adenosine diphosphate (ADP) to a concentration of 5 μΜ.

The anticoagulant effect of the compound was determined by measuring the percentage inhibition of platelet aggregation. in the presence of the compound, and compared to the situation without the compound.

Compound Concentration Inhibition of Accumulation% PGE1 15 ng / ml 33 PGE- ^ 20 ng / ml 47 PGE- ^ 30 ng / ml 63 PGE- ^ 40 ng / ml 69

Compound 12 (mp 116-117 ° C) 0.5 ng / ml 25 "1.0 ng / ml 51" 2.0 ng / ml 79 "4.0 ng / ml 94 Using such comparisons, the following relative efficacies for the compound were demonstrated: Compound 2 (Mp: 76-78 °, 12.5 x; Compound 4 (m.p. 144-146 ° C), 0.05 x; Compound 11 (mp 144-116 ° C), 5.2x, compound 12 (mp 116-117 ° C), 12.5x, and compound 14 (mp 96-98 ° C), 16x.

Prostaglandin E 1 and 5- (4-carboxymethoxybutyl) -1- (3-cyclohexyl-3-hydroxypropyl) hydantoin were thus studied. The latter was found to be about 20-25 times more effective than PGE 2.

Prostaglandin E 2 and certain compounds of formula (1) were tested as follows. The results are shown in Table B, where the result for prostaglandin E 1 (PGE 2) is taken as a standard and the results for the compounds of formula (1) are measured as multiples of the result for PGE 3.

71930 15

Table B

Prevention of platelet aggregation

Activity

Compound (with respect to PGE) - PGEX 1 5- (4-carboxymethoxybutyl) -1- (3-cyclohexyl-3-hydroxypropyl) hydantoin 15-23 5- (4-carboxymethoxybut-2Z-enyl) -1 - (3-cyclohexyl-3-hydropropyl) hydantoin 19-22 5- (6-carboxyhex-2Z-enyl) -1- (3-hydroxy-5,5-dimethylhexyl) hydantoin 4.7-6.5 5 - (6-carboxyhex-2Z-enyl) -1- (3-hydroxy-3-cyclopentylpropyl) hydantoin 5,5 5- (6-carboxyhexyl) -1- (3-hydroxy-5-methylhexyl) hydantoin 1 .9 5- (6-carboxyhexyl) -1- (3-hydroxy-4-cyclopentylbutyl) hydantoin 0.95-1.64

Example C.

Compound 38 was found to reduce aspirin-induced gastric ulcer formation in rats: an oral dose of 1 mg / kg provided 80% protection.

Example D

Compound 2 completely inhibited pentagastrin-induced gastric acid secretion in rats when administered intravenously at 30 μg / kg.

Example E

Compound 9 completely inhibited histamine-induced bronchoconstriction in anesthetized guinea pigs when administered intravenously at 50 μg / kg.

Example F

Compound 2 (m.p. 76-78 ° C) was found to reduce electrically induced arterial thrombosis in anesthetized rabbits when administered intravenously at a dose of 250 μg / min.

71930

Example G

Prevention of gastric corrosion

Gastric corrosion was observed in rats 3 hours after administration of indomethacin (20 mg / kg, s.c.), giving each mucosa an corrosion score based on the incidence and severity of the lesions.

Compounds of formula (I) stored in ethanol (10 mg / ml; 13 ° C) were added directly to 50 mM Tris buffer to give a final concentration of 250 μg / ml. Thanks to this method, the less soluble hydantoin of formula (I) was obtained as a fine suspension suitable for subcutaneous administration.

The compounds of formula I were administered at a dose of 500 μg / kg, s.c., and the results are shown in Table G. The% inhibition of gastric corrosion was similarly observed for PGE 2, and the results of this experiment are presented as multiples of PGE 2.

Table G

Prevention of gastric corrosion

Activity

Compound ______ (relative to PGE2) PGE2 1 5- (α-carboxymethoxybutyl) -1- (3-cyclohexyl-3-hydroxypropyl) hydantoin 5- (4-carboxymethoxybutyl) -1- (3-hydroxy-3-cyclopentylpropyl) ) hydantoin 1.5

Example H

Vasodilatory properties Male rats of the Wistar strain (250-303 g) were anesthetized with halothane and maintained on chloralose (75 mg / kg, i.v.) and sodium pentobarbitone (3 mg / kg, i.v.).

Arterial pressure was measured from a femoral vein with a cannula inserted, and heart rate was derived by integrating an arterial pulse. Rectal temperature was maintained at 37 to 0.1 ° C with thermo-square-regulated by heat radiation, each of the class A compound examined was injected into the femoral vein in the concentrate as a series of increasing Oita amount of 0.5 ml / kg and washed through with 0.3 ml 11a 0,93-% saline (w / v).

17 71 930

The test compound of formula (I) was dissolved in 1.25% NaHCO 3 in distilled water (w / v) and stored at 0 ° C; further dilutions were made in the same solvent. An aliquot of each compound was taken up and adjusted to the desired concentration with 1.25% NaHCO 3 solution. For each compound, the dose that caused a diastolic pressure drop of 20 mm Hg was calculated and the relative efficacies relative to PGI2 were determined.

These results are shown in Table H.

Table H

Rat Blood Results - Pressure .Activity

Compound __ (with respect to PGIp) pgi2 1 5- (4-carboxymethoxybutyl) -1- (3-cyclohexyl-3-hydroxypropyl) hydantoin 0.03 5- (6-carboxyhexyl) -1- (3-hydroxy-4 -cyclopentylbutyl) hydantoin 0.013 5- (4- (carboxymethoxybut-2Z-enyl) -1- (3-hydroxy-3-cyclohexylpropyl) hydantoin <0.01 5- (6-carboxyhexyl) -1- (3-hydroxy -5-methylhexyl) hydantoin 0.022 18 71930

Example 1 Preparation of 5- (6-carboxyhexyl) -1- (3-hydroxy-1,4-dimethyl-5-phenylpentyl) -hydantoin A. Diethyl 2-amino-nonane dioate

16.7 g of diethyl acetoamidomalonate and 16.6 g of ethyl 7-bromoheptanoate were dissolved in ethanol ethoxide (prepared using 1.51 g of sodium and 30 ml of absolute ethanol), and the mixture was refluxed for 27 hours. The cooled mixture was poured into ice water, extracted with ether and evaporated, the dried extract to give crude diethyl acetamido (5-ethoxycarbonylhexyl) malonate as a pale yellow oil, <= / "2.2 (3H, s inlet, -COCH 3), 4.17 (6H, multiplet, 3 x -QCH 3 -CH 2) This amide was boiled in 111 ml of concentrated hydrochloric acid for 5 1/2 hours under reflux, the cooled solution was washed with ether and the color removed from the aqueous layer, then evaporated to dryness under reduced pressure. the mass was dissolved in a minimum of absolute ethanol and added dropwise with stirring to a mixture of 125 ml of absolute ethanol and 15.7 g of thionyl chloride cooled to -10 [deg.] C. The resulting solution was allowed to stand at room temperature for 1 hour, then boiled for 1 1 / After refluxing for 2 hours, it was cooled and poured into ice water, and the pH was adjusted to 9 with aqueous sodium hydroxide solution. and the dried extract was evaporated and distilled to give 2-amino-nonanedioate as a colorless oil, b.p. 114-115 ° C / 0.002-0.3 mm Hg, yield 55%.

B. Diethyl 2 - [(4,4-dimethyl-3-oxo-phenylpentyl-amino)] - nonane-dioate

To 5.18 g of 2-aminononane dioate was added dropwise 3.95 g of 4,4-dimethyl-5-phenylpent-1-en-3-one under cooling and stirring. The mixture was allowed to stand at room temperature for 21 hours to give diethyl 2- (4,4-dimethyl-3-oxo-5-phenylpentyl) aminononane dioate.

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

5.1 g of the crude ketone from the above was dissolved in 7 ml of crude ethanol, and the solution was stirred in an ice bath.

II

71930 19 in which 380 mg of sodium borohydride were gradually added. The solution was stirred in an ice bath for an additional 10 minutes, then allowed to stand at room temperature for 5 hours. Most of the alcohol was evaporated, water was added and the solution was acidified to pH = 6. The insoluble oil was extracted with ether, the ether solution dried and evaporated to give diethyl 2- (3-hydroxy-4,4-dimethyl-5-phenylpentyl). ) -amino-nonanedioate as a pale yellow oil which was used as such without purification.

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

A solution of 8.45 g of the alcohol from the preceding paragraph in 37.6 ml of ethanol and 18.8 ml of 2N hydrochloric acid was stirred and cooled in an ice bath, and a solution of 3.05 g of potassium cyanate in 5.6 ml was added dropwise. in water. The mixture was allowed to stand at room temperature for 18 hours, after which the alcohol was evaporated, water was added, and the insoluble oil was extracted with ether. The dried ether solution was evaporated to leave a viscous oil which was heated on a steam bath for 6 hours. There was thus obtained 5- (6-ethoxycarbonylhexyl) -1- (3-hydroxy-4,4-dimethyl-5-phenylpentyl) -hydantoin as a viscous pale yellow oil.

This ester was added to a mixture of 25 ml of 2N sodium hydroxide and 60 ml of water, and the resulting cloudy solution was allowed to stand at room temperature for 2 hours. The solution was then washed with ether and the clear basic solution was acidified with 2N hydrochloric acid, and the precipitated oil was extracted with ether. The dried ether solution was evaporated to give 6.8 g of a viscous oil which was chromatographed on a silica gel column. There was thus obtained 5- (6-carboxyhexyl) -1- (3-hydroxy-4,4-dimethyl-5-phenyl-pentyl) -hydantoin as a colorless viscous oil which solidified, melting point about 115 ° C, shrank to about 90 ° C: which was a mixture of diastereomers. Crystallization several times from a mixture of ethyl acetate and naphtha (boiling point 60-80 ° C) gave one of the diastereomer as small needles, melting point 13 5-137 ° C, 71930 20

Example 2 5- (6-Carboxyhexyl) -1- (3-hydroxyoctyl) -hydantoin A. Diethyl 2- [1- (tetrahydropyran-2-yloxy) -octylamino] -nonane dioate

A dry ethereal hydrogen bromine solution prepared using 2G0 ml of ether and 26.8 g of hydrogen bromine at 0 ° C was added dropwise to a solution of 19.0 g of acrolein in 100 ml of ether cooled to -25 ° C. The mixture was stirred at this temperature for 1 hour, then allowed to warm to 0 ° C, stirred for 1 hour at 0 ° C, then added dropwise to an ethereal solution of pentylmagnesium bromide (54 g of bromopentane, 8.8 g of magnesium and 120 g of ml of ether) and boiled under reflux. The reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted with ether, and the dried ether was evaporated and distilled to give 1-bromo-3-hydroxyoctane as a colorless oil, b.p. 68, 5-72, 5 ° C / 0.08 mm Hg. A solution of 20.9 g of this bromoalcohol in 17.0 g of dihydropyran was treated with a solution of 500 mg of p-toluenesulfonic acid in a small amount of ether, after which the reaction solution was allowed to stand at room temperature for 18 hours and washed with aqueous sodium carbonate solution. The organic layer was chromatographed on a silica gel column using a 1: 9 mixture of ether and hexane as eluent. The solvent was evaporated under reduced pressure to give 1-bromo-3- (tetrahydropyran-2-yloxy) octane as a colorless oil, 0.8 (3K, trilette -CH 2) and 4.62 (1H, broad -O-CHR). 0-). A solution of 15.0 g of this intermediate tetrahydropyranyl and 13.0 g of diethyl 2-aminononanedioate in 100 ml of absolute ethanol was refluxed for 18 hours, the ethanol was evaporated under reduced pressure and the residue was diluted with a small amount of sodium carbonate. The mixture was extracted with dichloromethane, the extract dried over sodium sulphate and evaporated, and the residue was purified by silica gel column chromatography using a 1: 4 mixture of hexane and ether as the eluent to give diethyl 2- [3- (tetrahydropyran-2-yloxy) -octyl] oxy] oxy. nonane dioate as a colorless viscous oil Q. Δ 8 (3H, triplet -CH'3), 2.28 (2H, triplet, -CH2-CH2Et), 21 71930 2.61 (2H, multiplet, -CH2-N), 3.20QH, triplet, N-CHR-CO2Et), 4.13 (4H, multiplet, 2 x -O-CH 2 -CH 2), 4.60 (1H, broad -O-CHR-O-).

Alternatively, the above-mentioned aminodiester was prepared as follows. 10.40 g of diethyl 2-aminononane dioate and 5.04 g of oct-1-en-3-one were slowly stirred at 0 ° C and allowed to stand at room temperature for 3 hours to give diethyl 2- (3-ol). -oxo-octylamino) -nonane dioate as a colorless oil <f2.3 (4H, multiplet, -CH2-CO2Et and NCH2CH2CO-), 3.16Cl (triplet, EtQ2C-CHR-N), 4.1H2H, quartet, -0 -CH2-CH3), 4.17 (2H, quartet, -O-CH2-CH3). 13.5 g of this ketone were dissolved in 140 ml of absolute ethanol and the solution was added dropwise at 0 ° C to a solution of 665 mg of sodium borohydride in 70 ml of absolute ethanol, after which the reaction mixture was allowed to stand for 3 1/2 hours at room temperature and evaporated at 40 ° C. At C and under vacuum. The residue was dissolved in water, adjusted to pH = 5 N with hydrochloric acid, and extracted thoroughly with chloroform, the extract was washed with water, dried and evaporated to give diethyl 2- (3-hydroxyoctylamino) -nonane dioate as a colorless oil. This was dissolved without purification in 14.0 ml of hydropyran, the solution was treated with 10 ml of ether, then 6.72 g of p-toluenesulfonic acid was added in small portions, and the reaction mixture was allowed to stand at room temperature for 18 hours. The reaction mixture was then diluted with ether, washed with aqueous sodium carbonate solution and then with water, dried and evaporated, after which the residue was purified by silica gel column chromatography eluting with hexane-ether 1: 4 to give diethyl 2- [3- (tetrahydropyran-2-yl)]. ) octylamine / nonane dioate, which was identical to the same compound as previously prepared (nuclear magnetic resonance spectrum, infrared spectrum, mixed thin layer chromatography).

B. .5- (6-carboxyhexyl) -1- [3- (tetrahydropyran-2-yloxy) -pyl] -hydantoin

To a solution of 7.8 g of diethyl 2- [3- (tetrahydropyran-2-yloxy) octylamino] nonane dioate in 32 ml of ethanol was added a solution of 3.0 g of potassium cyanate in 6 ml of water. The resulting suspension was stirred and cooled, and 16.7 ml of 2N hydrochloric acid was gradually added. The solution was allowed to stand at room temperature for 22 hours, after which most of the ethanol was evaporated, water was added, and the insoluble oil was extracted with ether. The ether solution was washed with water, dried over magnesium sulfate and evaporated. There was thus obtained 8.0 g of a yellow oil which was dissolved in naphtha (b.p. 60-80 ° C). The solution was refluxed for 4 hours, then evaporated to dryness and the residual oil was heated on a steam bath for 2 hours to give 7.3 g of 5- (6-ethoxycarbonyl-hexyl) -1- (2- (tetrahydropyran-2-yloxy) -octyl] -4- hydantoin as a yellow oil which was used as such without purification.

A solution of 6.2 g of this ester in 80 ml of 0.5 N sodium hydroxide solution was allowed to stand at room temperature for 2 1/2 hours, after which the solution was washed with ether, the aqueous layer was acidified with 2N hydrochloric acid, and the precipitated oil was extracted with ether. The ether extract was washed and dried and evaporated to give 5- (6-carboxyhexyl) -1- [3- (tetrahydropyran-2-yloxy) -octyl] -hydantoin as a yellow oil.

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

3.55 g of the tetrahydropyranyloxy compound from the above was dissolved in 28 ml of tetrahydrofuran containing 7 ml of 5 N hydrochloric acid. The solution was allowed to stand at room temperature for 3 1/2 hours, after which it was boiled for 30 minutes using reflux. Most of the solvent was evaporated, water was added, and the insoluble oil was extracted with ether. The ether solution was washed with water, dried over magnesium sulphate and evaporated to give 3.15 g of a viscous yellow oil. The oil was purified by column chromatography on silica gel, eluting first with chloroform and then with a 19: 1 mixture of chloroform and methanol to give 5- (6-carboxyhexyl) -1- (3-hydroxyoctyl) -hydantoin as a highly viscous, almost colorless oil, <= Γθ, 89 (3Η, triplet, -CH 2), 2.34 (2H, triplet, -CH 2 -C 2 H), 2.9-4.2 (4H, complex, -C 0H), ca. 5.6 (2H, broad, exchangeable, -CO 2 H, -OH), ca. 9/0 (1H, broad, interchangeable, NH).

Applying the procedure of Example 1, the hydantoin identified above was also prepared using the corresponding di-ethyl 2- [3- (3-hydroxyoctyl) amino] nonane dioate.

71930 23 D. Separation of diastereomers

The hydantoin obtained as a result of the reactions described above was a viscous oil which was separated by high performance liquid chromatography on a silica gel column using a mixture of chloroform, methanol and acetic acid 97 as eluent; 2, 5: 0.5, into two diastereomers, both of which formed small colorless needles with melting points of 76-78 ° C and 63-65 ° C, respectively.

The same diastereomers were prepared by cyclizing the corresponding diastereomers of formula (III). That is, a mixture of diastereomers of diethyl 2- ({(3-hydroxyoctyl) amino) nonane dioate prepared according to Example 1 was dissolved in ethanol, and an ethereal hydrogen chloride solution was added. The reaction solution was evaporated to dryness to leave a mixture of the hydrochlorides of the diastereomers as a viscous oil which partially solidified on standing. Ether was added, the mass was stirred, and allowed to cool to form a crystalline solid which was collected, washed with ether and dried. This solid residue was crystallized from ethyl acetate to give pure hydrochloride as small colorless flakes, mp 95-96.5 ° C. This salt was suspended in dilute sodium hydroxide solution, then shaken in ether, washed with the separated ether layer, dried and evaporated to give the second diastereomer (A) of diethyl 2- (X3-hydroxyoctyl) -amino-n-nonane dioate as a colorless oil.

The ether filtrate remaining after recovery of the original solid hydrochloride was evaporated to leave an oily hydrochloride which was basified as described above to give another portion of diethyl 2 - {* (3-hydroxyoctyl) -amino] nonanedioate. diastereomer (B) as an almost pure colorless oil.

The above diastereomer (A) was converted as described in Example 1 to the second diastereomer of 5- (6-carboxyhexyl) -1- (3-hydroxyoctyl) -hydantoin, which crystallized from a mixture of ethyl acetate and light gasoline (b.p. 60-80 ° C) as small colorless needles, melting point 63-65 ° C.

Similarly, the above diastereomer (B) was converted to the second diastereomer of 5- (6-carboxyhexyl) -1- (3-hydroxyoctyl) -hydantoin, which crystallized from a mixture of ethyl acetate and light gasoline (b.p. 60-80 ° C) as small colorless needles. melting point 76-78 ° C.

2 4 71930 E. Exchange of diastereomers

A solution of 100 mg of 5- (6-carboxyhexyl) -1- (3-hydroxyoctyl) -hydantoin (diastereomer having a melting point of 76-78 ° C) in 3 ml of sodium hydroxide solution N was allowed to stand at room temperature for 19 hours. The solution was then acidified and extracted with ether, and the ether extract was washed with water, dried and evaporated to leave a viscous oil. By efficient liquid chromatography, this oil was separated into both diastereomers of 5- (6-carboxy-hexyl) -1- (3-hydroxyoctyl) -hydantoin, one having a melting point of 76-78 ° C, weighing about M-0 mg, and this was identical to the starting compound. About 40 mg of the second diastereomer, melting point 63-65 ° C, was obtained, and this was identical to the diastereomer (A) described above.

Similarly, the diastereomer having a melting point of 63-65 ° C was converted to a mixture of approximately equal amounts of this diastereomer and the diastereomer having a melting point of 76-78 ° C. The pure diastereomers were separated by high performance liquid chromatography.

Examples 3-27 3a) diethyl 2 - [(3-oxopentyl) amino] nonane dioate; 4a) diethyl 2- (β-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) nonane dicate; 8a) diethyl 2 - ((3-oxodecyl) amino) nonanedioate; 9a) diethyl 2 - ((3-oxo-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;

II

7a) diethyl 2 - ((3-oxo-4-phenylbutyl) amino) nonanedioate; 18a) diethyl 2 - ((3-oxooctyl) amino) pentanedioate; 18a) diethyl 2 - ((3-oxooctyl) amino) undecanedioate; 20a) ethyl 2 - ((3-oxooctyl) amino) -3- (3-ethoxycarbonylmethoxyphenyl) propionate; 21a) ethyl 2 - ((3-oxo-4,4-dimethylpentyl) amino) -3- (3-ethoxycarbonylmethoxyphenyl) propionate; 22a) ethyl 2- (3-oxooctylamino) -3- (3- (2-ethoxycarbonylethyl) phenyl) propionate; 23a) ethyl 2- (3-cyclobutyl-3-oxopropylamino) -3- (3- (2-ethoxycarbonylethyl) phenyl) propionate; 24a) ethyl 2- (3-cyclopentyl-3-oxopropylamino) -3- (3- (2-ethoxycarbonylethyl) phenyl) propionate; 25a) ethyl 2- (3-cyclohexyl-3-oxopropylamino) -3- (3- (2-ethoxycarbonylethyl) phenyl) propionate; 26a) diethyl 2- (3-oxooctylamino) -7-oxanonanedioate; and 27a) diethyl 2- (3-cyclopentyl-3-oxopropylamino) -7-oxanonanedioate; which were converted to the corresponding hydroxy compounds.

3b) diethyl 2 - [(3-hydroxypentyl) amino] nonanedioate; 4b) diethyl 2 - ((3-hydroxy-4,4-dimethylpentyl) amino) nonanedioate; 5b) diethyl 2 - ((3- hydroxy-4-methylpentyl) amino) nonanedioate; 6b) diethyl 2 - ((3-hydroxynonyl) amino) nonanedioate; 7b) diethyl 2 - ((3-hydroxy-4-methyloctyl) amino) nonanedioate; 2 - ((3-hydroxydecyl) amino) nonanedioate; 9b) diethyl 2 - ((3-hydroxy-4,4-dimethyloctyl) amino) nonanedioate; 10b) diethyl 2 - ((3-hydroxy-4-ethylhexyl ) amino) nonane dioate; 11b1 diethyl 2 - ((3-cyclobutyl-3-hydroxypropyl) amino) nonane dioate; 12b) diethyl 2 - ((3-cyclopentyl-3-hydroxypropyl) amino) nonane dioate; 13b) diethyl 2 - ((3-hydroxy-4,4-dimethyl-5- (3-trifluoromethylphenyl) pentyl) amino] nonanedioate; 14b) diethyl 2 - ((3-cyclohexyl-3-hydroxypropyl) amino) nonane 15b) diethyl 2 - ((3-cycloheptyl-3-hydroxypropyl) amino) nonane dioate; 16b) diethyl 2 - ((3-hydroxy-3-phenylpropyl) amine amino) nonaanidioaatti; 2,6171930 17b) diethyl 2 - ((3-hydroxy-4-phenylbutyl) amino) nonanedioate; 18b) diethyl 2 - ((3-hydroxyoctyl) amino) pentanedioate; 19b) diethyl 2 - ((3-hydroxyoctyl) amino) undecanedioate; 20b) ethyl 2 - ((3-hydroxyoctyl) amino) -3- (3-ethoxycarbonylmethoxyphenyl) propionate; 21b) ethyl 2 - ((3-hydroxy-4,4-dimethylpentyl) amino) -3- (3-ethoxycarbonylmethoxyphenyl) propionate; 2b) ethyl 2 - ((3-hydroxyoctylamino) -3- (3- (2-ethoxycarbonyl-ethyl) phenyl) propionate; 23b) ethyl 2 - ((3-cyclobutyl-3-hydroxypropyl) amino) -3 - (3- (2-ethoxycarbonylethyl) phenyl) propionate; 24b) ethyl 2 - ((3-cyclopentyl-3-hydroxypropyl) amino-3- (3- (2-ethoxycarbonylethyl) phenyl) propionate; 25b) ethyl 2- (3-cyclohexyl-3-hydroxypropyl) amino) - 3- (3- (2-ethoxycarbonylethyl) phenyl) propionate; 26b) diethyl 2- (3-hydroxyoctyl) amino) -7-oxanonanedioate and 27b) diethyl 2- (3-cyclopentyl-3-hydroxypropyl) amino) -7-oxananedioate of the following formula (I) which were separated as described by efficient liquid chromatography to obtain both diastereomers having the melting points mentioned below.

3c) 5- (6-carboxyhexyl) -1- (3-hydroxypentyl) -hydantorine, colorless oil, from diastereomer 71-73 ° C and 56-58 ° C 4c) 5- (6-carboxyhexyl) -1- (3- hydroxy-4,4-dimethylpentyl) -hydantoin, diastereomers m.p. 114-115 ° C and 144-146 ° C; 5c) 5- (6-carboxyhexyl) -1- (3-hydroxy-4-methylpentyl) hydantoin, m.p. mp 79-80 ° C, diastereomers m.p. 73-76 ° C and 110-111 ° C; 6c) 5- (6-carboxyhexyl) -1- (3-hydroxynonyl) hydantoin, viscous oil; two diastereomers, m.p. 69-71 ° C and 79-81 ° C; 7c) 5- (6-carboxyhexyl) -1- (3-hydroxy-4-methyloctyl) hydantoin, viscous oil, Rf 0.5 (SiO 2: chloroform / methanol i. 9: 1); 8c) 5- (5-carboxyhexyl) -1- (3-hydroxydecyl) hydantoin, viscous oil, diastereomers m.p. 68-70 ° C and 82-83 ° C; 9c) 5- (6-carboxyhexyl) -1- (3-hydroxy-4,4-dimethyloctyl) hydantone, as colorless crystals, m.p. 90-98 ° C, the second diastereomer was isolated by crystallization from ethyl acetate, m.p. 103-104 ° C, second diastereomer m.p. 75-77 ° C; li 27 71 930 10c) 5- (6-carboxyhexyl) -1- (3-hydroxy-4-ethylhexyl) -hydantoin, m.p. 70-80 °, diastereomers m.p. 82-84 ° C and 12 Q-12 2 ° C; 11c) 5- (6-carboxyhexyl) -1- (3-cyclobutyl-3-hydroxypropyl) -hydantoin, diastereomers m.p. 114-116 ° C and 103-105 ° 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-m-trifluoromethylphenylpentyl) hydantoin, diastereomers m.p. 118-120 ° C and 145-147 ° C; me) 5- (6-carboxyhexyl) -1- (3-cyclohexyl-3-hydroxypropyl) -hydantoin, diastereomers m.p. 96-98 ° C and 124-126 ° C; 15c) 5- (6-carboxyhexyl) -1- (3-cycloheptyl-3-hydroxypropyl) -hydantoin, m.p. mp 70-76 ° C, diastereomers m.p. 107-109 ° C and 107-9 ° C; 16c) 5- (6-carboxyhexyl) -1- (3-hydroxy-3-phenylpropyl) hydantoin, both diastereomers forming colorless viscous oils, m.p. 72-74 ° C and 67-70 ° C; 17c) 5- (6-carboxyhexyl) -1- (3-hydroxy-4-phenylbutyl) -hydantoin, diastereomers m.p. 102-104 ° C and 61-63 ° C; 18c) 5- (3-carboxypropyl) -1- (3-hydroxyoctyl) -hydantoin, both diastereomers forming colorless viscous oils; 19c) 5- (8-carboxyoctyl) -1- (3-hydroxyoctyl) -hydantoin, diastereomers m.p. 57-60 ° C and 69-71 ° C; 20c) 5- (3-carboxymethoxybenzyl) -1- (3-hydroxyoctyl) -hydantoin, colorless "meringue" mass, Rf 0.36 (S.iO 2: chloroform / methanol / acetic acid 90: 5: 5); 21c) 5- (3-carboxymethoxybenzyl) -1- (3-hydroxy-4,4-dimethylpentyl) hydantoin, diastereomers of the corresponding ethyl esters, m.p. 100-105 ° C and 151-154 ° C; 22c) 5- (3- (2-carboxyethylbenzyl) -1- (3-hydroxyoctyl) hydantoin; two diastereomers, m.p. 95-97 ° C and 82-86 ° C; 2c) 5- [3- (2-carboxyethylbenzyl) -7- (3-cyclobutyl-3-hydroxy-propyl) hydantoin, second diastereomer m.p. 118-121 ° C; 24c) 5- (3- (2-carboxyethylbenzyl)) - 1- (3-cyclopentyl-3-hydroxypropyl) hydantoin, second diastereomer m.p. 140-143 ° C; 25c) 5- (3- (2-carboxyethylbenzyl)) - 1- (3-cyclohexyl-3-hydroxypropyl) hydantoin, two diastereomers, m.p. 156.5-157 ° C and 146-148 ° C; 28 71 9 30 26c) 5- (4-carboxymethoxybutyl) -1- (3-hydroxyoctyl) hydantoin; two diastereomers, m.p. 79-81 ° C and colorless glass, Rt 0.31 (SiO 2: chloroform / methanol: acetic acid 90; 5: 5); 27c) 5- (4-carboxymethoxybutyl) -1- (3-cyclopentyl-3-hydroxypropyl) hydantoin; isolated second diastereomer, mp 107-108 ° C; all prepared via the corresponding ethyl esters.

The starting materials used in the reactions described above were prepared as follows; A. Examples 18 and 19

Following the procedure described in Example IA, diethyl 2-aminopentane dioate m.p. 93-96 ° C / 0.02 mm n-4 1.4425 and diethyl 2-aminoundecane dioate m.p. 160 ° C / 0.1 mm used in Examples 18, resp. 19.

B. Ethyl 2-amino-3- (3-ethoxycarbonylmethoxyphenyl) propionate

2.60 g of diethyl acetamidomalonate and 2.39 g of ethyl 3- (chloromethyl) phenoxyacetate (Robertson, J. Chem.

Soc. (1933), 492; The U.S. 3,933,895) to ethanol ethoxide prepared using 230 mg of sodium and 10 ml of absolute ethanol, and the mixture was refluxed for 19 hours. After cooling, the solution was poured into ice water, then extracted with ether and the dried extract was evaporated. The residual gum was crystallized from a mixture of ether and hexane to give diethylacetamido (3-ethoxycarbonylmethoxyphenyl) malonate as white prisms, m.p. 98.5 - 101.5 ° C. 1.90 g of this derivative and 25 ml of a 10% aqueous hydrochloric acid solution were boiled under reflux for 3 1/2 hours, after which the solution was cooled and evaporated to dryness under reduced pressure. The residual white solid was dissolved in a minimum of absolute ethanol and added dropwise with stirring to a mixture of 15 ml of absolute ethanol and 1.64 g of thionyl chloride cooled to -10 ° C. The resulting solution was allowed to stand at room temperature for 18 hours, then refluxed for 1 hour, cooled and poured into ice water, and adjusted to pH 9-10 with aqueous sodium hydroxide solution. The mixture was extracted with ether and the dried extract was evaporated to give ethyl 2-amino-3- (3-ethoxycarbonylmethoxyphenyl) propionate as a colorless oil which was used in Examples 20 and 21 without purification.

Il 29 71 9 30 C. Ethyl 2-amino-3- (3- (2-ethoxycarbonylethyl) phenyl) propionate

A solution of 4.04 g of diisopropylamine and 25 ml of lithium hutyl (25 ml, 1.60 M in hexane) in 40.4 ml of dry tetrahydrofuran was stirred at -78 ° C under dry nitrogen gas and treated with over 5 minutes with 4.64 g of t-butyl acetate. To this solution was added a solution of 11.60 over 5 minutes. g, cL-dibromo-m-xylene and 1.42 g of dry hexamethylphosphoramide in 8.0 ml of dry tetrahydrofuran. The resulting yellow solution was stirred at -78 ° C for 1/2 hour, after which the reaction mixture was allowed to warm to room temperature over 3 hours. Excess ice water was added, and the mixture was extracted with ether. The extract was washed with 60 ml of 1 N hydrochloric acid and then with water. The dried extract was evaporated under reduced pressure to give a yellow oil which was purified by column chromatography on silica gel eluting with a 1: 1 mixture of ether and hexane to give t-butyl 3- (3-bromomethylphenyl) propionate as a colorless oil. Applying the procedure described in the previous paragraph, this oil was converted to the desired diethyl ester used in all Examples 22-25.

D. Diethyl 2-amino-7-oxanonane dioate This compound was prepared from ethyl 4-bromobutoxyacetate (Merck, German Offenlegungsschrift No. 2,354,085) by performing a series of reactions similar to those described in B above to give this compound. as a colorless oil, kp. 120-121 ° C / 0.005 mm Hg. This compound was used in Examples 26 and 27.

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

A mixture of 25.9 g of diethyl 2-aminononane dioate and 22.7 g of 5-phenylpentyl bromide was heated in a water bath at 100 ° C for 3 hours. After the mixture was cooled, 100 ml of ether was added thereto, after which the mixture was allowed to stand for 2 hours at 0 ° C. The crystallized colorless solid was collected and dried to give 21.95 g of diethyl 2- [4- (5-phenylpentyl) -amino] -nonane dioate hydrobromide, m.p. 70-72 ° C. Free acid m.p. 90-92 ° C.

3 Γ.

71 930

4.86 g of this hydrobromide were dissolved in a solution of 20 ml of ethanol and 5 ml of 2N hydrochloric acid, and the solution thus obtained was cooled in ice, and a solution of 1.62 g of potassium cyanate in 5 ml of water was gradually added with stirring, followed by allowing the solution to stand at room temperature. 18 hours. The alcohol was evaporated, water was added, the insoluble oil was extracted with ether, after which the ether extract was dried and evaporated to leave a pale yellow oil. The oil was heated on a steam bath for 6 hours to give 5- (6-ethoxycarbonylhexyl) -1- (5-phenylpentyl) hydantoin.

4.0 g of the ester from the previous point were hydrolyzed with a dilute solution of sodium hydroxide, and the obtained product was purified by chromatography on silica gel to give 5 - (C 6 -carboxyhexyl) -1- (5-phenylpentyl) -hydoin, which was crystallized from ethyl acetate and from a mixture of light petrol (b.p. 60-80 ° C), as colorless prismatic needles, m.p. 90-92 ° C;

Examples 29-35

By applying a series of reactions according to Example 28, the corresponding alkyl halides were prepared: 29a) diethyl 2-octylaminonanedioate; 30a) diethyl 2- (4-propoxybutyl) aminononanedioate; 31a) diethyl 2- (4-phenoxybutyl) aminononanedioate; 32a) diethyl 2- (4-m-trifluoromethylphenoxybutyl) aminononane dioate; f 33a) diethyl 2- (3-m-tolyloxypropyl) aminononanedioate; 34a) diethyl 2- (3-hydroxypropyl) aminononanedioate; and 35a) diethyl 2- (3-hydroxy-3-methyloctyl) aminononanedioate; which were converted to the desired hydantoin.

29b) 5- (6-ethoxycarbonylhexyl) -1-octylhydantoin, m.p. 4 6-48 ° C; 29c) 5- (6-carboxyhexyl) -1-octylhydantoin, m.p. 88-89 ° C; 30b) 5- (6-carboxyhexyl) -1- (4-propoxybutyl) hydantoin, m.p. 7 2-74 ° C; 31b) 5- (6-carboxyhexyl) -1- (4-phenoxybutyl) hydantoin, m.p. Δ 8-90 ° C; 32b) 5- (6-carboxyhexyl) -1- (4-m-trifluoromethylphenoxybutyl) -hydantoin, m.p. 51-54 ° C; 31 71930 3 3b) 5- (6-carboxyhexyl) -1- (3-m-tolyloxypropyl) hybridoin, colorless viscous oil, Rf 0.52 (SiO 2: chloroform / methanol 9: 1); 34b) 5- (6-carboxyhexyl) -1- (3-hydroxypropyl) hydantoin, m.p. 111-113 ° C, and 35b) 5- (6-carboxyhexyl) -1- (3-hydroxy-3-methyloctyl) hydantoin; two diastereomers, m.p. 104-107 ° C and a colorless viscous oil, Rf 0.5 (SiO 2: chloroform / methanol.acetic acid 90: 5: 5).

Example 36 Preparation of 1- (6-carboxyhexyl) -5-octylhydantoin

16.0 g of 2-aminodecanoic acid (J. Am. Chem. Soc., 19, 46, 68, 450) were added in small portions to a mixture of 70 ml of absolute ethanol and 6 ml of thionyl chloride cooled to -10 ° C. The resulting solution was allowed to stand at room temperature for 2 hours, then refluxed for 1 hour, cooled, poured into ice water, and adjusted to pH 9 with aqueous sodium hydroxide solution, extracted with ether, dried, evaporated and distilled. ethyl 2-aminodecanoate was obtained in 75% yield as a colorless oil, bp = 82-4 ° C / 0.2 mm.

A solution of 18 g of the amino ester prepared above and 20 g of ethyl 7-bromoheptanoate in 50 ml of absolute ethanol was boiled under reflux for 24 hours, after which the ethanol was evaporated. Ether was added to precipitate the hydrobromide salt. Mp = 98 ° C, which was dissolved in a small amount of dichloromethane, then the solution was treated with an equivalent amount of triethylamine, the reaction mixture was washed thoroughly with water and dried. The solvent was evaporated to give ethyl 2- (6-ethoxycarbonylhexylamino) decanoate in 52% yield as a colorless viscous oil, bp = 148-4 ° C / 0.001 mm.

7.4 g of ethyl 2- (6-ethoxycarbonylhexylamino) decanoate were reacted with potassium cyanate and hydrochloric acid to give 1- (6-ethoxycarbonylhexyl) -5-roctylhydantoin as colorless crystals, m.p. = 68-70 ° C, by crystallization from light petrol (b.p. 60-80 ° C).

4.0 g of this ester was hydrolyzed with aqueous sodium hydroxide to give 1- (6-carboxyhexyl) -5-octylhydantoin, which crystallized from a mixture of ethyl acetate and light gasoline (b.p. 60-80 ° C) as colorless needles, m.p. = 65-66 ° C.

71930

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

A solution of 742 mg of diethyl 2-octylaminononane dioate and 120 mg of methyl isocyanate in 7.5 ml of dry ether was allowed to stand at room temperature for 48 hours, after which the ether was evaporated to leave 800 mg of a pale yellow oil.

This oil was heated on a steam bath for 2 hours to give 5- (6-ethoxycarbonyl) -3-methyl-1-octylhydantoin as a yellow oil.

650 mg of this ester was hydrolyzed by allowing it to be in a solution of 2.4 ml of ethanol and 0.6 ml of 5N aqueous sodium hydroxide solution for 3 hours at room temperature. The ethanol was then evaporated and the acidic product was isolated by extraction with ether and purified by silica gel column chromatography to give 5- (6-carboxyhexyl) -3-methyl-1-octylhydantoin as a colorless oil. (Ester) Rf 0.8 (SiO 2: chloroform / methanol 50: 1). (Acid)

Rf 0.5 (SiO9: chloroform / methanol 19: 1).

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

Diethyl 2 - ['(3-oxo-octyl) -amino] -nonanedioate of Example 28 was reacted with methyl isocyanate as described in Example 37 to give 5- (6-ethoxycarbonylhexyl) -3-methyl- 1- (3-oxo-octyl) -hydantoin, which was hydrolyzed to give 5- (6-carboxyhexyl) -3-methyl-1- (3-oxo-octyl) -hydantoin as a colorless oil.

1.23 g of this keto acid was dissolved in 15 ml of a 0.25 N solution of sodium hydroxide, and the solution thus obtained was stirred in an ice bath, and 63 mg of sodium borohydride was added thereto. After stirring for 3 hours at room temperature, the solution was acidified and extracted with ether. The washed and dried ether extract was evaporated to leave an oil which was purified by column chromatography on silica gel using a 50: 1 mixture of chloroform and methanol as eluent to give 5- (6-carboxyhexyl) -3-methyl-1- (3- hydroxyoctyl) -hydantoin as a colorless viscous oil, (Keto ester) two diastereomers, δ (CDCl 3) 2, 34-2, 80 (6H multiplet, CH 2 CO 2 Et + CH 2 COCH 2), 2.97 (3H, singlet, NCH 3), 3.36 and 3.7 δ (each 1H, multiplet, non-equivalent NCH 9), 4.10

II

33 71930 (2H, quartet, CO 2 CH 2 CH 2), (keto acid) δ (CDCl 3) 2.33-2.80 (6H, multiplet, CH 2 Cl 2> 2H + CH 2 COCH 2), 2.98 (3H, singlet, NCH 2), 3.33 and 3.37 (each 1H, multiplet, non-equivalent NCH 2) and (hydroxy acid) ^ (CDCl 3) 2.31 (2H, triplet, CH 2 Cl 2 H), 2.98 (3H, singlet, NCH 2), about 3.5 (3H, multiplet, NCH 2 + CHOH).

Example 39 Preparation of 1- (6-carboxyhexyl) -3-methyl-5-octylhydantoin

Applying the procedure described in Example 37, the ethyl 2- (6-ethoxycarbonylhexylamino) decanoate of Example 36 was converted to 1- (6-ethoxycarbonylhexyl) -3-methyl-5-octylhydantoin, which was then hydrolyzed to 1- (6-carboxyhexyl). - 3-methyl-5-octylhydantoin, which was isolated as a colorless oil. (Ester) Rf 0.55 (S.iO 2: chloroform / methanol = 50: 1) (Acid)

Rf 0.55 (SiO 2: chloroform / methanol = 19: 1).

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

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

3.2 g of this ester were dissolved in 15 ml of ethanol and 15 ml of a 2N solution of sodium hydroxide, and the resulting solution was allowed to stand at room temperature for one hour. The acidic product was extracted with ether and purified by silica gel column chromatography to give 3-butyl-5- (6-carboxyhexyl) -1-octylhydantoin as a colorless oil. Yield of butyl ester from H-ester = 56% and yield of butyl acid from butyl ester = 53%, Rf = 0.7 (SiO 2: chloroform / methanol = 9: 1),

Example 41 Preparation of 3-butyl-1- (6-carboxyhexyl) -5-octylhydantoin

Applying the procedure of Example 40, 71930 34 of 1- (6-ethoxycarbonylhexyl) -5-octylhydantoin according to Example 36 was converted to 3-butyl-1- (6-ethoxycarbonylhexyl) -5-octylhydantoin, which was hydrolyzed to 3-butyl-1- To (6-carboxyhexyl) -5-octylhydantoin, which is a colorless oil. Yield of butyl ester from H-ester = 60% and yield of butyl acid from butyl ester 51%, Rf 0.8 (SiO 2 chloroform / methanol = 9: 1).

Example 42 Preparation of 5- (6-carboxyhex-2-ynyl) -1- (3-hydroxyoctyl) -hydantoin

Under the reaction conditions of Example 1A, diethyl acetamidomalonate and methyl 7-bromohept-5-ynate were reacted to diethyl acetamido- (6-methoxycarbonylhex-2-ynyl) malonate as a yellow oil.

This crude product was hydrolyzed by boiling in 5 N hydrochloric acid, after which the product was re-esterified to give diethyl 2-aminon-4-yne dioate which was distilled to give a colorless oil, b.p. = 180-182 ° / 1 mm Hg.

The above amino compound was reacted with oct-1-en-3-one to give diethyl 2 - [(3-oxo-octyl) -amino] -non-4-yne dioate, which was reduced with sodium borohydride in diethyl-2-yl. To (3-hydroxy-octyl) -amino} -4-yne dioate.

This compound was treated with potassium cyanate and hydrochloric acid, and the hydantoin ester thus prepared was hydrolyzed to give a light brown oil. Purified by silica gel column chromatography eluting with chloroform-methanol (30: 1) to give 5- (6-carboxyhex-2-ynyl) -1- (3-hydroxyoctyl) -hydantoin as a colorless oil which was a mixture of two diastereomers. two spots, Rf 0.38, 0.44, chloroform, methanol, acetic acid 90: 5: 5 using silica gel thin layer chromatography High performance liquid chromatography isolated one of the diastereomers (thin layer chromatography Rf. 0.38) as a colorless oil NMR 0.89 (3H, triplet, -CH 3), 2.2-2.4 (6H, multiplet, -CH 2, C = C.CH 2 - + -CH 2 CO 2 H), 3.54 (2H, triplet,> N.CH 2 -), ca 3.6 (1H, multiplet,> CH.0H), 4.11 (1H, triplet,> N.CH.CO-).

This compound was then hydrogenated to the corresponding catalytic 5- (6-carboxyhex-2-enyl) -1- (3-hydroxyoctyl) -hydantoin, followed by the corresponding saturated compound, which was found to be identical to the title compound of Example 2.

35 71930

Example 4 3 A. 2- (Dibutoxymethyl) -glycine ethyl ester N-formylglycine ethyl ester was C-formylated using a method based on that described by Harman and Huchinson in J. Org. Chem. 1975 40, 3474 and the resulting compound was converted to 2- (dibutoxymethyl) -glycine ethyl ester using the method described in H.T. Clarke and partner. have explained in "Chemistry of Penicillin", Eds. H. T. Clarke and partner. published by Princetown University Press, New Jersey, 1949, p. 517.

B, 1- (6-Carboxyhexyl) -hydantoin-5-carboxaldehyde A mixture of 2.0 g of 2- (dibutoxymethyl) -glycine ethyl ester and 1.82 g of ethyl 7-bromoheptanoate was heated in a bath under nitrogen and At 100 ° C for 3 hours to give crude ethyl 7- [2- (2,2-dibutoxycarbonylethyl) -amino] -heptanoate hydrobromide. A solution of 3.28 g of this hydrobromide in 13 ml of ethanol was cooled with stirring in an ice bath and treated with a solution of 1.34 g of potassium cyanate in 4 ml of water, followed by 3.63 ml of 2N aqueous hydrochloric acid. Cooling was stopped and stirring was continued at room temperature for 22 hours. The ethanol was evaporated under reduced pressure, the residue shaken in water and ether, and the ether solution separated, washed with water and dried over magnesium sulfate, after which the ether was evaporated to leave an oil. This was heated at 100 ° C under nitrogen for 3 hours to give 2.94 g of 5-butoxymethyl-1- (6-ethoxycarbonylhexyl) -hydantoin. To this were added with stirring 6 ml of ether, 48 ml of water and 24.9 ml of aqueous sodium hydroxide solution at room temperature for 1 1/2 hours, after which a further 50 ml of ether were added, the aqueous phase was separated, cooled with ice water, fresh ether was added and stirred and acidified with hydrochloric acid. N aqueous solution until the solution turned Congo red. The ether solution of the carboxylic acid was washed three times with water, dried over magnesium sulfate and evaporated to give 2.15 g of 1- (6-carboxyhexyl) -5-dibutoxymethylhydantoin as a gum. 1.89 g of this gum were cooled in ice water and mixed with 8.5 ml of concentrated aqueous hydrochloric acid, whereby the resulting solution spontaneously became a suspension of colorless crystals. This suspension was allowed to stand at room temperature for 1 1/2 hours, after which 10 ml of water was added and the mixture was allowed to stand for 1 min. The crystals were then collected and washed with water, dried under reduced pressure, suspended in 3 ml of ether and collected again to give 0.7H g of 1- (6-carboxyhexyl) -hydantoin-5-carboxaldehyde, m.p. = 223.5 - 225 ° C, m.p. 223.5-225 ° C (found: C, 51.86-H, 6.66; N, 10.62. Calculated for C 11 H 16 N 2 O 5: c> 51> 5 6; H, 6.29; N, 10 , 93). In dimethyl sulfoxide-dg this compound exists mainly as silylaldehyde, 1- (6-carboxyhexyl) -5-hydroxymethylene hydantoin.

C. 1- (6-carboxyhexyl) -5 - {(, (E) -3-oxooctylidene) hydantoin

A mixture of 20 mg of 1- (6-carboxyhexyl) -hydantoin-5-carboxaldehyde and 59 mg of 2-oxoheptylidene-triphenylphosphorane (see J. Org. Chem. (1972) 37, 1818) and 1 drop of benzene was heated to 10 ° C. At 37 ° C under nitrogen for 35 min, and the resulting gum was taken up in ethyl acetate. The product was extracted with dilute aqueous sodium bicarbonate, the extract was washed with ethyl acetate and acidified with aqueous hydrochloric acid N until the reaction solution turned Congo red, and the liberated carboxylic acid was extracted with ether. The ether solution was washed with water, dried over magnesium sulfate and evaporated to give 25 mg of a gum which was identified by nuclear magnetic resonance spectrum (characteristic signals: 85.72 (1H, triplet, = CH-) and 3.93 (2H, doublet, = CH-CH 2 -CO). ), J 7.1 Hz, in deuterochloroform) to give 1- (6-carboxyhexyl) -5 - [(E) -3-oxo-octylidene-β-hydantoin.

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

A solution of 20 mg of 1- (6-carboxyhexyl) -5 - {“(E) -3-oxooctylidene] -hydantoin in 1.5 ml of water with a slight excess of sodium bicarbonate was treated with 5 mg of sodium borohydride. After 6 minutes, the solution was acidified with aqueous hydrochloric acid N until the solution turned Congo red, the liberated carboxylic acid was extracted with ethyl acetate, and the ethyl acetate solution was washed three times with water and dried over magnesium sulfate. The ethyl acetate was evaporated to give 14 mg of a pale yellow gum which was identified by nuclear magnetic resonance spectrum (characteristic signal 85.72 (1H, triplet, = CH-) and 3.93 (2H, doublet, = CH-CH2-CO), J 7.1 Hz, in deuterochloroform to give 1- (6-carboxyhexyl) -5 - [(E) -3-hydroxyoctylidene] hydantoin.

li 37 71930 E. 1- (6-Carboxyhexyl) -5- (3-hydroxyoctyl) -hydantoin To a solution of 3.06 g of 1- (6-carboxyhexyl) -5-AE) -3-oxo-octylidene-hydantoin in 60 mL of EtOH , 200 mg of 10% palladium on carbon was stirred at room temperature and under pressure to absorb 1 molar equivalent of hydrogen in 2 hours. The catalyst was filtered off, the filtrate was evaporated in vacuo and the residual rubber was collected to give a mass of colorless crystals. The crystals were suspended in 4 ml of ether and collected to give pure 1- (6-carboxyhexyl) -5- (3-oxooctyl) -hydantoin (2.58 g; 84% yield), m.p. 84.5 to 86 ° C. A stirred suspension of 0.5 g of this compound in 15 ml of water was treated at 0 ° C with 0.36 g of NaHCO 3 and then for 3 minutes with 54 mg of sodium borohydride. After 45 minutes, 54 mg of sodium borohydride was added, and after 1 1/2 hours, the clear solution was placed at room temperature for 1 1/2 hours. The solution was then acidified to Congo red with hydrochloric acid, the liberated carboxylic acid was extracted into chloroform, and the chloroform solution was washed with water and dried over magnesium sulfate. Evaporation of the solvent gave 1- (6-carboxyhexyl) -5- (3-hydroxyoctylene) subjected to high performance liquid chromatography (SiO 2, CHCl 3 / MeOH / HOAc 97, 75: 1.25: 1.0) to give the separate diastereomers as colorless gums (200 mg and 20 mg; yield 81%),

Rf 0.44 and 0.40.

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

Diethyl 2- (3-oxooctylamino) nonane dioate (7.7 g) prepared as described in Example 1B was treated with potassium cyanate and hydrochloric acid to give 5- (6-ethoxycarbonylhexyl) -1- (3-oxo octyl) -hydantoiinia. This ester was hydrolyzed with sodium hydroxide solution to give 5- (6-carboxyhexyl) -1- (3-oxooctyl) -hydantoin as a viscous oil which crystallized as a low melting solid.

Example 45 Preparation of 5- (6-carboxyhex-2Z-enyl) -1- (3-cyclohexyl-3-hydroxypropyl) -hydantoin

Cis-methyl-7-bromohept-5-enoate and diethylacetamidomalonate prepared according to the method disclosed in British Patent No. 1,355,991 39,71930 were reacted under the conditions of Example 1A to give diethylacetamido- (6-methoxycarbonylhexane). -2-enyl) malonate as a yellow oil.

This crude product was hydrolyzed by boiling in 5 N hydrochloric acid, and the resulting product was esterified as described in Example 1A to give diethyl 2-aminonon-4-enedioate as a colorless oil, b.p. 118-123 ° C / 0.05 mm, n ^ 9'5 1.4620.

By reacting this amino compound with 1-cyclohexylprop-2-enone as described in Example 2B and reducing the diethyl 2 - [(3-cyclohexyl-3-oxopropyl) -amino] -n-4-enedioate thus obtained with sodium borohydride in Example 2C as described, diethyl-2- [. (3-Cyclohexyl-3-hydroxypropyl) -amino] non-2-enedioate.

Treatment of this compound with potassium cyanate and hydrochloric acid and hydrolysis of the hydantoin ester thus obtained as described in Example 2D gave 5- (6-carboxyhex-2Z-enyl-1- (1-cyclohexyl-3-hydroxypropyl) -hydantoin as a yellow oil. which tended to solidify.

By efficient liquid chromatography, this compound was separated into its diastereomers, one of which formed small colorless prisms, m.p. 95-97 ° C, and the other formed colorless needles, m.p. 108-110 ° C;

Examples 46-67

Using a reaction procedure analogous to that described in the previous comparative preparations and using the appropriate vinyl ketone starting materials, the following were prepared: 46a) diethyl 2- (3-oxo-5,5-dimethylhexyl) aminononanedioate; 47a) diethyl 2- (3-oxo-5-methylhexyl) aminononanedioate; 48a) diethyl 2- (3-oxo-3- (p-tolyl) propyl) aminononanedioate; 49a) diethyl 2- (3-oxo-4-cyclopentylbutyl) aminononanedioate; 50a) diethyl 2- (3-oxo-4-cyclohexylbutyl) aminononanedioate; 51a) diethyl 2- (3-oxo-6-cyclohexylhexyl) aminononanedioate; 52a) diethyl 2- (3-oxo-5-ethoxypentyl) aminononanedioate; 53a) diethyl 2- (3-oxo-4- (3-trifluoromethylphenoxy) butyl) aminononanedioate; 54a) diethyl 2- (3-oxo-3- (4-chlorophenyl) propyl) aminononanedioate;

II

39 7 1 9 3 0 5 5a) Diethyl 2- (3-oxo-3- (4-methoxyphenyl) aminononanedioate 56a) Ethyl 2- (3-oxo-3-cyclohexylpropyl) amino-6-ethoxycarbonylmethoxy iheksanoaatti; 7a) ethyl 2- (3-oxo-3-cyclopentylpropyl) amino-6-ethoxycarbonylmethoxy hexanoate; 58a) ethyl 2- (3-oxooctyl) amino-6-ethoxycarbonylmethoxyhexanoate; 59a) diethyl 2- (3-oxo-5,5-dimethylhexyl) aminonone-4Z-ene dioate; 60a) diethyl 2- (3-oxo-3-cyclopentylpropyl) aminonon-4Z-ene dioate; 61a) diethyl 2- (3-oxo-3-cyclohexylpropyl) aminonon-4E-ene dioate; 62a) diethyl 2- (3-oxo-4-cyclopentylbutyl) aminonon-4Z-ene dioate; 63a) diethyl 2- (3-oxo-4,4-dimethyl-5-phenylpentyl) aminonone-4Z-enedioate; 64a) diethyl 2- (3-oxo-5-cyclopentylpentyl) aminonone-4Z-enedioate; 5a) ethyl 2- (3-oxo-3-cyclohexylpropyl) amino-6-ethoxycarbonylmethoxyhex-2Z-enoate; 66a) ethyl 2- (3-oxo-3-cyclohexylpropyl) amino-6-ethoxycarbonylmethoxyhex-2E-enoate; and 67a) diethyl 2- (3-oxo-3-cyclohexylpropyl) aminonon-4-yne dioate; which were converted to the corresponding alcohols: 46b) diethyl 2- (3-hydroxy-5,5-dimethylhexyl) aminononane dioate; 47b) diethyl 2- (3-hydroxy-5-methylhexyl) aminononanedioate; 48b) diethyl 2- (3-hydroxy-3- (p-tolyl) propyl) aminononanedioate; 49b) diethyl 2- (3-hydroxy-4-cyclopentylbutyl) aminononane dioate; 0b) diethyl 2- (3-hydroxy-4-cyclohexylbutyl) aminononanediol; 51b) diethyl 2- (3-hydroxy-6-cyclohexylhexyl) aminononane dioate; 52b) diethyl 2- (3-hydroxy-5-ethoxypentyl) aminononanedioate;

HO

719 3 0 5 3b) diethyl 2- (3-hydroxy-4- (3-trifluoromethylphenoxy) butyl) aminononanedioate; 54b) diethyl 2- (3-hydroxy-3- (4-chlorophenyl) propyl) aminononane dioate; 55b) diethyl 2- (3-hydroxy-3- (4-methoxyphenyl) propyl) aminononanedioate; 56b) ethyl 2- (3-hydroxy-3-cyclohexylpropyl) amino-6-ethoxycarbonylmethoxyhexanoate; 57b) ethyl 2- (3-hydroxy-3-cyclopentylpropyl) amino-6-ethoxycarbonylmethoxyhexanoate; 8b) ethyl 2- (3-hydroxyoctyl) amino-6-ethoxycarbonylmethoxy hexanoate; 59b) diethyl 2- (3-hydroxy-5,5-dimethylhexyl) aminonone-4Z-enedioate; 6Ob) diethyl 2- (3-hydroxy-3-cyclopentylpropyl) aminonone-4Z-enedioate; 61b) diethyl 2- (3-hydroxy-3-cyclohexylpropyl) aminonon-4E-enedioate; 62b) diethyl 2- (3-hydroxy-4-cyclopentylbutyl) aminonon-4Z-enedioate; 63b) diethyl 2- (3-hydroxy-4,4-dimethyl-5-phenylpentyl) aminonone-4Z-enedioate; 4b) diethyl 2- (3-hydroxy-5-cyclopentylpentyl) aminonone-4Z-enedioate; 65b) ethyl 2- (3-hydroxy-3-cyclohexylpropyl) amino-6-ethoxycarbonylmethoxy-2Z-enoate; 66b) ethyl 2- (3-hydroxy-3-cyclohexylpropyl) amino-6-ethoxycarbonylmethoxyhex-2E-enoate; and 67b) diethyl 2- (3-hydroxy-3-cyclohexylpropyl) aminonon-4-yne dioate; from which the desired hydantoin was obtained as a mixture of diastereomers, which were separated, if possible, to give separate diastereomers having said melting point (s): 46c) 5- (6-carboxyhexyl) -1- (3-hydroxy-5,5-dimethylhexyl) -hydantoin, 86-88 °, 107-110 °; 47c) 5- (6-carboxyhexyl) -1- (3-hydroxy-5-methylhexyl) -hydantoin, 100-101 °, 102-103 °; 48c) 5- (6-carboxyhexyl) -1- (3-hydroxy-3- (p-tolyl) propyl) -hydantoin, 41,719 30c) 5- (6-carboxylhexyl) -1- (3-hydroxy-4 -cyclopentylbutyl) -hydantoin, 101-104 °, 75-78 °; 5c) 5- (5-carboxyhexyl) -1- (3-hydroxy-4-cyclohexylbutyl) -hydantoin, 92-94 °, 109-111 °; 51c) 5- (6-carboxyhexyl) -1- (3-hydroxy-6-cyclohexyl] hexyl) -hydantoin, 84-86 °; 52c) 5- (6-carboxyhexyl) -1- (3-hydroxy-5-ethoxypentyl) -hydantoin, 68-70 °; 53c) 5- (6-carboxyhexyl) -1- (3-hydroxy-4- (3-trifluoromethylphenoxy) butyl) hydantoin, 10-5-107 °, 118-120 °; 4 4c) 5- (6-carboxyhexyl) -1- (3-hydroxy-3- (4-chlorophenyl) propyl] hydantoin, 9 3-94 °, 101-102 °; 55c) 5- (6-carboxyhexyl) -1- (3-hydroxy-3- (4-methoxyphenyl) propyl) hydantoin, 93-94 °, 102-103 °; 56c) 5- (4-carboxymethoxybutyl) -1- (3-hydroxy-3-cyclohexylpropyl) hydantoin, δ 8-94 °; 5c) 5- (4-carboxymethoxybutyl) -1- (3-hydroxy-3-cyclopentylpropyl) hydantoin, 107-108 °; 5c) 5- (4-carboxymethoxybutyl) -1- (3-hydroxyoctyl) hydantoin, 79-81 °; 59c) 1- (3-hydroxy-5,5-dimethylhexyl) -5- (6-carboxyhex-2Z-enyl) hydantoin, 66-71 °, 148-150 °; 6c) 1- (3-hydroxy-3-cyclopentylpropyl) -5- (5-carboxyhex-2Z-enyl) hydantoin, 74-76 °, 10-5-107 °; 61c) 1- (3-hydroxy-3-cyclohexylpropyl) -5- (6-carboxyhex-2E-enyl) hydantoin, 60-63 °; 6 2c) 1- (3-hydroxy-4-cyclopentylbutyl) -5- (6-carboxyhex-2Z-enyl) hydantoin, 114-116 °; 3c) 1- (3-hydroxy-4,4-dimethyl-5-phenylpentyl) -5- (6-carboxy-hex-2Z-enyl) hydantoin, 68-70 °, 116-117 °; 64c) 1- (3-hydroxy-5-cyclopentylpentyl) -5- (6-carboxyhex-2Z-enyl) hydantoin, 100-102 °, 76-78 °; 6c) 1- (3-hydroxy-3-cyclohexylpropyl) -5- (4-carboxymethoxybut-2Z-enyl) hydantoin, each diastereomer colorless glass; 6c) 1- (3-hydroxy-3-cyclohexylpropyl) -5- (4-carboxymethoxybut-2E-enyl) hydantoin, 97-101 °; and 67c) 1- (3-hydroxy-3-cyclohexylpropyl) -5- (6-carboxyhex-2-2-ynyl) hydantoin, 84-86 °, 147-148 °; _ - TT ______________ k2 71 930

Example 68 Preparation of 5- (6-carboxylhexyl) -1- (3-hydroxy-3-cyclohexylpropyl) hydantoin

A solution of 10 g of diethyl 2-aminononanedioate in 77 ml of ethanol was cooled in ice water and treated with 38.6 ml of 2N hydrochloric acid and then with a solution of 6.255 g of potassium cyanate in 20 ml of water. The cooling bath was removed and the suspension was stirred for 7 hours at room temperature and allowed to stand overnight. The ethanol was evaporated in vacuo and the residue was shaken in water and chloroform. The chloroform phase was separated, washed with water and dried over MgSO 4. The chloroform was evaporated to give an oil which was heated on a steam bath for 6 hours. The resulting oil crystallized on standing at room temperature. The crystals were stirred in ether and collected to give pure 2-ureidononanedioate, m.p. 79-80 ° C.

A mixture of 8 g of diethyl 2-ureidononane dioate and 1.23 g of diazabicyclononene (DBN) was heated in a bath for 1 hour, and the reaction mixture was shaken in chloroform and a small excess of dilute hydrochloric acid. The chloroform phase was separated, washed with water and dried over MgSO 4. The chloroformase was evaporated to give a crystalline residue. The crystals were suspended in ether and collected to give 5- (C-ethoxycarbonylhexyl) hydantoin, m.p. 110-110.5 ° C.

A mixture of 200 mg of 5- (6-ethoxycarbonylhexyl) -hydantoin, 97 mg of diazabicyclononene and 108 mg of cyclohexyl-vinyl ketone was heated in a bath at 100 ° C for 5 hours. A stirred solution of the obtained oil in 2.5 ml of ethanol was treated with 30 mg of sodium borohydride, and after 3 hours the solution was diluted with 10 ml of water, treated with 3 ml of 1N hydrochloric acid and shaken in ether. The ether phase was washed with water. dried over MgSO 4 and concentrated to give a solid suspension The solid was collected and the ether filtrate evaporated to leave a gum to which were added with stirring 6.2 ml of 0.35 N aqueous sodium hydroxide solution and 0.75 ml of ether over 1 1/2 hours. After addition of water and ether and shaking, the aqueous phase was separated, washed with ether and acidified with 2N hydrochloric acid, the liberated product was extracted into ether and the ether solution was washed with water, dried over MgSO 4 and evaporated to give 90 mg of gum. by column chromatography on 15 g of silica gel using a 96: 2: 2 mixture of chloroform, methanol and acetic acid as eluent, and when the product elution was monitored by its absorption at 250 nm to give a mixture of equal parts of 5- (6-carboxyhexyl) -1- (3-cyclohexyl-3-hydroxypropyl) two diastereomers. These diastereomers were separated by high performance liquid chromatography and were found to be identical to the diastereomers described in Example 14c.

Example 69 Preparation of 5- (6-ethoxycarbonylhexyl) -1- (3-hydroxy-3-cyclohexylpropyl) hydantolin

A solution of 4 g of 5- (6-carboxyhexyl) -1- (3-hydroxy-3-cyclohexylpropyl) hydantoin (diastereomer m.p. 96-98 ° C) in 60 ml of ethanol and 1.6 ml of concentrated sulfuric acid was added. stand at room temperature for 18 hours. The alcohol was evaporated, water was added and the precipitated oil was extracted with ether. The ether solution was washed with sodium bicarbonate solution and water, dried over MgSO 4 and evaporated to give one diastereomer of 5- (6-ethoxycarbonyl-hexyl) -1- (3-hydroxy-3-cyclohexyl) hydantoin as a colorless oil which soon solidified and crystallized in sheets, m.p. 62-63 ° C;

Similarly, another diastereomer of 5- (6-carboxyhexyl) -1- (3-hydroxy-3-cyclohexylpropyl) hydantoin (m.p. 125-226 ° C) was converted to its ethyl ester, m.p. 101-102 ° C.

Example 70 Separation of diastereomers of dimethyl 2 - [(3-hydroxy-3-cyclopentylpropyl) amino] nonanedioate

The mixture of diastereomers was dissolved in ether and the solution was treated with a small excess of volatile hydrogen chloride and stirred to give a solid which was collected and washed with ether. The melting point of this mixture of diastereomeric hydrochlorides was 91-94 ° C. Partition crystallization from ethyl acetate or a mixture of ethyl acetate and ether gave two pure hydrochlorides, one of which formed colorless small plates, m.p. 112-114 ° C, and the other formed colorless needles, m.p. 86-87 ° C.

Similarly, the two diastereomers of diethyl 2 - [(3-hydroxy-3-cyclohexylpropyl) amino] -7-nonanedioate were separated into their hydrochlorides, m.p. 117-118 ° C and 67-69 ° C.

719 3 0 44

Example 71 Preparation of 5- (6-carboxyhex-2 (Z) -enyl) -1- (3-cyclohexyl-3-hydroxypropyl) hydantoin cis-methyl-7-bromohept-5-enoate (prepared according to GB Patent 1,355 991) and diethyl acetamidomalonate1 was reacted under the conditions described in Reference Preparation 1Δ to give diethylacetamido- (6-methoxycarbonylhex-2-enyl) malonate as a yellow oil.

This crude product was hydrolyzed by boiling in 5N hydrochloric acid and the product was esterified as described in Reference Preparation 1A to give diethyl 2-aminonon-4-enedioate as a colorless oil, boiling point 118-12 3 ° C / 0.05 mm, n ^ 9 ' 5 1, 4620.

When this amino compound was reacted with 1-cyclohexyl-prop-2-enone as in Reference Preparation 2B, and the diethyl-2 - [(3-cyclohexyl-3-oxo-propyl) amino] non-4-eno-oleate thus formed was reduced with sodium borohydride as in Reference Preparation 2C. diethyl 2 - [(3-cyclohexyl-3-hydroxypropyl) amino] non-2-enedioate was obtained.

When this compound was treated with potassium cyanate and hydrochloric acid and the resulting hydantoin ester was hydrolyzed as in Reference Preparation 2D, 5- (6-carboxyhex-2 (Z) -enyl) -1- (3-cyclohexyl-3-hydroxypropyl) hydantoin was obtained as a yellow oil. which tended to solidify. Using high performance liquid chromatography, this compound was separated into its diastereomers, one of which formed small colorless prisms, mp 97-99 ° C, and the other colorless needles, m.p. 108-110 ° C;

Interconversion of diastereomers 3.1 g of a diastereomer having a melting point of 108-110 ° C was dissolved in 50 ml of N-sodium hydroxide solution, and the solution was allowed to stand at room temperature for 18 hours. The solution was acidified and extracted with ether. The ether solution was washed with water, dried and evaporated to give 3.1 g of a colorless glass which was determined by thin layer chromatography to be a mixture of the starting material and the second diastereomer. Separation of the mixture by high performance liquid chromatography gave 1.34 g and 1.33 g of diastereomers having melting points of 97-99 ° C and 108-110 ° C, respectively, which were identical to those described above.

4:> 71930

Example 72 Preparation of 5- (6-ethoxycarbonylhexyl) -1- (3-cyclohexyl-3-hydroxypropyl) hydantolin

60 ml of a solution of 4 g of 5- (6-carboxyhexyl) -1- (3-cyclohexyl-3-hydroxypropyl) hydantoin (diastereone m.p. 96-98 ° C, Example 66): in ethanol, and in 1.6 ml of concentrated sulfuric acid, was allowed to stand at room temperature for 18 hours. The alcohol was evaporated, water was added and the precipitated oil was extracted with ether. The ether solution was washed with sodium bicarbonate solution and water, dried over MgSO 4 and evaporated to give one diastereomer of 5- (6-ethoxycarbonylhexyl) -1- (3-cyclohexyl-3-hydroxypropyl) -hydantoin as a colorless oil which soon solidified and solidified. in sheets, m.p. 62-63 ° C.

Example 73 Preparation of 1- (3-cyclohexyl-3-hydroxypropyl) -5- (7-hydroxyheptyl) hydantoin

A solution of 108.5 mg of ethyl chloroform in 0.5 ml of tetrahydrofuran was added to a stirred solution of 3 6 8 mg of 5- (6-carboxylic acid) -1- (3-cyclohexyl-3- hydroxypropyl) -hydantoin (mixture of diastereomers, Example 68) and 101 mg of triethylamine, and cooled to -5 ° for 15 minutes. After the solution was allowed to stand for an additional 1 hour at 0 ° C, the solid was collected and washed with 1 mL of tetrahydrofuran.

The combined filtrate and washings were added dropwise over 30 minutes to a solution of 100 mg of sodium borohydride in 1 ml of water at 15 ° C. When the addition was complete, the solution was stirred at room temperature for 2 hours. Water was added, the solution was acidified with 2N hydrochloric acid and extracted with ether. The ether solution was washed with sodium bicarbonate solution and then water, dried over MgSO 4 and evaporated to leave 330 mg of a colorless, viscous oil.

Chromatography of 300 mg of this oil in ethyl acetate saturated with water on a silica gel column gave 250 mg of an oil in which, after thin layer chromatography on silica gel in a mixture of chloroform, methanol and acetic acid 90: 5: 5, there were only 2 spots, 0.60, 0.63 due to 1 -cyclohexyl-3-hydroxypropyl.) - 5- (7-hydroxyheptyl) hydantoin from diastereomers. Diastereomers were separated using high performance liquid chromatography; less polar isomer solidified, mp 73-77 ° C, more polar remained '.6 as a viscous oil, 71,930

Example 7 * 4 Preparation of 5- (6-carbamoylhexyl) -1- (3-cyclohexyl-3-hydroxypropyl) hydantoin 50 mg of 5- (6-ethoxycarbonylhexyl) -1- (3-cyclohexyl-3 -hydroxypropyl) hydantoin (one diastereomer) was dissolved in 2.5 N aqueous ammonium hydroxide (specific gravity 0.880), and the solution was heated in a sealed vessel at 100 ° C for 2 hours. After cooling, the solution was acidified with 2N hydrochloric acid, and the precipitated gum was extracted first with ether, which dissolved part of the gum, and then with chloroform. The chloroform extract was washed with sodium bicarbonate solution and then water, dried over MgSO 4 and evaporated to leave the stirred diastereomers of the title compound as a colorless solid, m.p. 110-120 ° C (thin layer chromatography on a silica column in a mixture of chloroform, methanol and acetic acid 90: 5: 5 showed two spots, Rf. 0.37, 0.41).

Example 75 Preparation of 5- (6-carboxyhexyl) -1- (3-hydroxy-3-cyclohexylbutyl) hydantolin

A solution of 6.9 g of 3-cyclohexylprop-1-en-3-one in 10 ml of dry ether was cooled to 0 ° C and stirred with the addition of a solution of 4 g of hydrogen bromine in 20 ml of ether. after which the solution was allowed to stand in the refrigerator overnight.

This bromo-ketone solution was gradually added at room temperature to a stirred solution of 1.5 g of methylmagnesium iodide made of magnesium and 8.5 g of methyl iodide in 35 ml of dry ether. After stirring for 2 1/2 hours, the mixture was poured into a cold solution of 5 g of ammonium chloride in 50 ml of water. The mixture was filtered and the ether layer was separated, dried and evaporated. The residue was distilled to give 5.6 g of 4-bromo-cyclohexyl.butan-2-ol, boiling point 86-88 ° C / 0.04 mm, m.p. 31-3 3 ° C.

A mixture of 4.9 g of the above bromine alcohol and diethyl 2-aminononanedioate was heated at 100 ° C for 4 hours. The mixture was basified with dilute sodium hydroxide solution, and the insoluble oil was extracted with ether. The ether extract was dried and evaporated to give 8.4 g of diethyl 2 - [(3-hydroxy-3-cyclohexylbutyl) amino] nonanedioate as an oil which was used

II

-f V

719 3π .without 1 father cleaning. By treating this amino diester with cyanic acid followed by alkaline hydrolysis of the hydantoin ester thus prepared as described in Example ID, 5- (6-carboxyhexyl) -1- (3-hydroxy-3-cyclohexylbutyl) hydantoin was prepared, which was separated as described in Example 2D. diastereomers having melting points of 173-17 ° C and 109-111 ° C, respectively.

Example 76 Preparation of 5- (6-carboxyhexyl) -1- (3-cyclohexyl-3-oxopropyl) -hydantoin

Reaction of 2D, 8 g of diethyl 2 - [(3-cyclohexyl-3-oxopropyl) -amino] nonionate with cyanic acid using the procedure described in Example ID, followed by treatment with alkali, gave 7.2 g of 5- (6-carboxyhexyl) diate. ) -1- (3-cyclohexyl-1,1-oxopropyl) hydantoin as a colorless gum. When this was crystallized from ether at 0 ° C, crystals of pure compound were obtained, m.p. 7 7, 5-7 8, 5 ° C.

Example 77 Preparation of 5- (6-carboxyhexyl) -1H-3-hydroxy-3- (p-biphenylyl) propyl] hydantoin

A solution of 5 g of 23-hydroxy-3- (p) -biphenyl) propylamino] nonanedioate prepared via d-ethyl 2- [3-oxo-3- (p-biphenyl) propylamino] nonane dioate from a suitable vinyl ketone using the procedure of Example 2, in 20 ml of absolute ethanol, was heated at 60 ° C by the addition of 1.12 g of nitrocarbamide in portions.

Example 78

The procedure of Example 2 was used to prepare: 78a) diethyl 2-β-oxo-3- (4,4-dimethylaminophenyl) propyl 1-amino] nonanedioate; 7 8b) diethyl 2- [E [3-hydroxy-3- (4,4-dimethylaminophenyl) propyl] amino} nonanedioate; and then 78c) 5- (6-carboxyhexyl) -1- [3-hydroxy-3- (1,4-dimethylamino-phenyl) propyl] hybrid

Examples 79-81

The following was also prepared by the method of Example 2: 71930 79a) diethyl 2 - [(cycloheptane I.-2-ynyl.unyl) 1] amino] nonanedioate; 80a) diethyl n-2 - {[3-oxo-3- (4-hydroxyphenyl) propyl] amino} nonane dioate; and 81a) diethyl 11-2-1 (3-oxo-3- (4-methyl) propyl] amino) nonanedioate; which were converted to: 79b) diethyl 2 - [(2-hydroxycycloheptylmethyl) amino] nonane dioate; 80b) diethyl 2 - {(3-hydroxy-3- (4-hydroxyphenyl) pronyl} amino) noranedioate; and 31b) diethyl 2 - {[3-hydroxy-3- (4-nitrophenyl) propyl] amino} nonanedioate; which were converted to: 7 3c) 5- (6-carboxyhexyl) -1- (2-hydroxycycloheptylmethyl) -hydantoin; 30c) 5- (6-carboxyhexyl) -1- [3- (4-hydroxyphenyl) -3-hydroxypropyl] hydride to antholine; and 81c) 5- (6-carboxyhexyl) -1- (3- (4-nitrophenyl) -3-hydroxypropyl) -hydantoin.

Example 82 Preparation of 5- (6-carboxyhexyl) -1- [3- (4-hydroxyphenyl) propyl] hydantoin This mixture, m.p. 107-108 ° C, was prepared by a method analogous to that used in Example 2 but using the appropriate alkyl i.dia or i.nyl ketetone instead of the appropriate alkyl to prepare the intermediate diethyl 2- [3- (4-hydroxyphenyl) propyl] aminonanedioate.

Il

Claims (2)

71930 49 1. A process for preparing a 1,5-disubstituted hydantoin analog having an inhibitory effect on platelet aggregation and having the formula (I) O Ar ^ 1 ZN N (1) \ 2 li zo 1 2 wherein Z is hydrogen or an alkyl group and another of the symbols Z and Z is a -CH 2 -X-X 1 -X 2 group in which X is phenylene, -CC-, cis -CH = CH- or -CH 9 -CH- group; X 1 is an alkylene chain having 1 to 6 carbon atoms, wherein one of its methylene groups may be replaced by an oxa - (- O -) - group, provided that at least one carbon atom separates the oxa group -CC-, 2 -CH = CH- or -CO, and X is 5-tetrazolyl, carboxy, carbamoyl, hydroxymethylene or alkoxycarbonyl; and one of Z and Z2 is -Y-Y1-Y2-Y3; wherein Y is -CH -CH-; Ί L. L · Y is carbonyl, methylene, or hydroxyl-substituted methylene, or hydroxyl- and alkyl-substituted methylene; Y is a covalent bond or a straight or branched chain alkylene having 1 to 7 carbon atoms; 3 Y is hydrogen, hydroxy, ethoxy, phenyl (optionally substituted with methyl, trifluoromethyl, methoxy, hydroxy, nitro, amino or phenyl) or phenoxy (optionally substituted with methyl, trifluoro, amino or phenyl) with a chloromethyl group); or Y and Y together form a cycloalkyl group having 4 to 7 carbon atoms; and for the preparation of salts of this hydantoin, characterized in that (a) a compound of formula (II) Nν ^ / Ζ1 ZN N (II) Yv ·· in which G represents a carboxy group or a derivative thereof, 1 2 and each of the symbols Z, Z and Z has the same meaning as in formula (I); or 50 71930 (b) cyclizing a compound of formula (VII) 9 1 Z ---- N f LN (VII) G 1 z 2 wherein G represents a carboxy group or a derivative thereof, 1 2 and each of the symbols Z, Z and Z has the same meaning as in formula (I); or (c) reacting phosgene, diphenyl carbonate or alkyl haloformate with a compound of formula (IX) O. Z1 ZN I (IX) HN 9 h "\ z2 1 2 in which each of the symbols Ζ, Ζ and Z has the same meaning as in formula (I); or (d) in the case where Z is alkyl, alkylating a compound of formula (X) O AA J - NI (X) y \ 3 with a reactive ester derivative of an alcohol of formula J .OH, wherein J is hydrogen or alkyl, J is hydrogen or Z, J 2 3 12 is hydrogen or Z, and J is alkyl, Z or Z, provided that one of the symbols 12, J and J represents a hydrogen atom, and J does not mean 12 12 3 has the same meaning as J, J or J, in which case the symbols J, J and J define Z and Z is the same as in formula (I), or (e) reducing a compound of formula (XI) II 51 71 930 o 1 .z3 - Z --- N ^ (XX) "^ z4 O wherein either joko3 is = CH- CH2-Y1-Y2-Y3 and Z4 are -CH2-X-X1-X2, or z3 is = CH-X-X1-X2 and Z4 is -Y-Y1-Y2-Y3, wherein Z, X-X2 and Y -Y3 has the same meaning as in formula (I), with the aid of a suitable reducing agent, or (f) in the case where X is hydroxymethylene, the corresponding acid is reduced, e a sterol, acid halide, acid anhydride or aldehyde with a suitable reducing agent, or (g) in the case where X 1 is hydroxymethylene, the corresponding halide is hydrolysed with a suitable reagent; and optionally converting the compound of formula (I) thus obtained into another desired salt, ester or alcohol of formula (I). Process according to Claim 1, characterized in that the compound of formula (I) thus prepared is 5- (6-carboxyhexyl) -1- (3-cyclohexyl-3-hydroxypropyl) -hydantoin or a salt or ester thereof. 71930 52 1. A compound for the preparation of a 1,5-disubstituted hydantoin analog, which comprises an inverse of the aggregation of the blot-circle, and with the formula (I) OZ - NI (I) • Y * s · i vilken Z betecknar en väteatom eller en alkyl group, and in which 12 12 symbols Z and H are in the group -CH -XX -X-group, color X be- = ^ 1 tecnar en phenylylen-, -CC-, cis -CH = CH- or -C ^ - The C1-6 group, X is an alkyl group having 1-6 colaters, may be optionally substituted with a methyl group attached to the oxa - (- 0 -) - group, under the reaction of the atoms of the cholate group with an oxa group of -CC-, -CH = CH- 2 or -CO-, and X is 5-tetrazolyl, carboxyl, carbamoyl, hydroxymethyl or alkoxycarbonyl? 12 12 3 denotes the symbols Z and Z of the group -Y-Y -Y -Y-group, varvid Y är -Cl ^ -Cl · ^ -; Y is a carbonyl group, a methyl group or a methyl group which is substituted by a hydroxyl group, or a methyl group which is substituted by a hydroxyl group and an alkyl-2 group, Y is a covalent bond or an alkyl group having 1-7 chapters; Y is an atom, hydroxy, ethoxy, phenyl (optionally substituted with methyl, trifluoromethyl, methoxy, hydroxy, nitro, amino or phenyl) or phenoxy (optionally substituted with methyl) or trifluoromethyl); or 2 3 Y and Y are selected from the group consisting of cycloalkyl groups having from 4 to 7 carbon atoms, selected from the group consisting of hydrogen atoms, which are converted into a cyclic alkyl group, (a) being cyclized with compounds of formula (II) GV, 1 H · ( II) Z N. JK, V Xz i vilken G betecknar en carboxygrupp eller et derivat av denna, 1 2 oc Z, Z oc Z z betecknar decamma som i formeln (I), eller 53 71 9 30 (b) man cyclouren en förening of formula (VII) 0 11. 71 Z - N> 'i (VII); ! GH '-Z is selected from the group consisting of G1 betecnar and carboxy groups or derivatives thereof, 1 2 and Z, Z and Z betecnar decamma som i in formula (I), eller (c) to give phosgene, diphenylcarbonate or alkylhaloformate to react with for a compound of formula (IX) II z / \ ^ ZN H (IX) H '\ Zl 1 2 and in the form Z, Z and Z of the radicals of formula (I), or (d) of the radicals of the alkyl group, alkyleric man in the form of a compound of formula (X) 9 t 1 J -NA 3 of a reactive ester derivative of an alcohol with a form of J .OH, of which J is a substituent or an alkyl group, J is a substituent of 12- 3 en väteatom eller Z, och J betecknar 1 2 en alkyl, Z eller Z, under förutsättning att en av symbolerna J, 12 3 J och J betecknar en väteatom och J inte betecknar Decamma som 12 12 3 J, J eller J, varvid i definitions of symbols J, J and J 1 2 In the case of a reduction in formula (I) or (e) a reduction in the formulation (XI) A./*3 Z N (XI) 11 0