HU193303B - Process for preparing urea derivatives - Google Patents

Abstract

The invention relates to a process for the preparation of antihypertensive and cardiopulmonary compounds of the formula wherein Ar is a monocyclic or optionally partially saturated bicyclic, carbocyclic or heterocyclic aromatic radical, R is hydrogen, alkanoyl or aroyl, R 1 and R 2 independently of one another are hydrogen or lower alkyl or R 1 and R 2 together denote alkylene of 2 to 7 carbon atoms which separates the two nitrogen atoms to which it is attached by 2 to 4 carbon atoms, R 3 and R 4 independently represent hydrogen or lower alkyl, and X represents oxo (O) or thio (S ), and their salts, which is directed to the formation of the ureido or thioureido group.

Description

The present invention relates to a process for the preparation of 3- (ureido-cyclohexylamino) -propane-1,2-diol derivatives.

These compounds are of great pharmaceutical value, namely antihypertensive agents, which have both α-receptor and β-receptor blocking properties. These compounds can therefore be used alone or in combination with other active ingredients in mammals, including humans, and are particularly valuable agents for cardiovascular disorders such as hypertension, certain heart diseases, particularly myocardial infarction and myocardial infarction, for the treatment or prevention of coronary insufficiency (angina pectoris). The compounds of the present invention are also useful in the treatment and prevention of diseases which respond to the biocade of β-receptors; for example, certain diseases of the nervous system, such as tension and anxiety, and glaucoma, migraine, atherosclerosis, and the like.

The process for preparing the compounds in question is directed to the preparation of the ureido group.

The present invention relates to a process for the preparation of the novel compounds of the formula I and their salts, in particular their pharmaceutically acceptable salts. In the general formula (I)

Ar is substituted with halogen

A 1,2,5-thia-diazolyl group or a phenyl group having a C2-C6 alkenyl group, a C1-C4 alkoxycarbonyl group, a C1-C7 alkoxy group, a C2-C6 alkenyloxy group, a 2- C 6 -C 6 alkynyloxy, cyano, pyrrolyl, morpholino, 5-, 6- or 7-membered cycloalkyl, carbamoyl, C 3 -C 6 cycloalkyl-C 1 -C 4 alkoxy, or C 1 -C 4 alkoxy; Monosubstituted with (C 1 -C 4) alkyl,

R ¹ and R ² are hydrogen or R ¹ and R ² together form ethylene,

R ³ and R ⁴ are each independently hydrogen or C 1-5 alkyl.

The above definitions and general terms have the following meanings within the scope of the present invention:

The alkenyl group, either as such or e.g. as part of an alkenyloxy group, it is a group containing from 2 to 6 carbon atoms; such as 2-propenyl (allyl), 2-butenyl, 2-methyl-2-propenyl and 2-methyl-2-butenyl.

The alkynyl group, either as such or e.g. as part of an alkynyloxy group means a group containing from 2 to 6 carbon atoms. Such groups include e.g. 2-propynyl (propar 2 -glyl), 2-butynyl or 2-pentynyl.

The term "lower carbon" means that such a group or compound is labeled with up to 7 carbon atoms, preferably up to 4 carbon atoms, and in particular 1 or 2 carbon atoms.

Unless otherwise stated, alkyl is preferably C 1 -C 4 and is e.g. ethyl, propyl, butyl or particularly preferably methyl.

Said alkoxycarbonyl group contains from 1 to 4 carbon atoms in the alkoxy moiety and thus includes, for example, a methoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group or, more preferably, an ethoxycarbonyl group.

Cycloalkyl may be cyclopentyl, cyclohexyl or cycloheptyl.

C 1-7 -alkoxy is preferably ethoxy, propoxy, isopropoxy, or especially methoxy.

Preferably the halogen atom may be fluorine or chlorine, but the bromine or iodine atom may also be present.

The compounds of formula (I) may be converted into acid addition salts, with pharmaceutically acceptable salts of inorganic or organic acids being preferred. Such acids are, for example, strong mineral acids such as hydrogen halides such as hydrochloric or hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid or perchloric acid, or aliphatic or aromatic carboxylic acids and sulfonic acids, e.g. formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, gluconic acid, citric acid, maleic acid, fumaric acid, pyruvic acid, phenylacetic acid, benzoic acid, amino benzoic acid, anthranilic acid, 4-hydroxybenzoic acid, salicylic acid, amino salicylic acid, embonic acid, nicotinic acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethane sulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, stilanyl acid, cyclohexylsulamic acid and ascorbic acid.

The compounds of the present invention possess valuable pharmacological properties. These properties, in particular, are based on the cardiovascular effects, such as antihypertensive activity and cardiac effects, among others, on the inhibitory effect of these compounds on β-receptors. The inhibitory effect can be attributed to the fact that the compounds of the invention have a strong affinity for the β-receptors. Compounds of the present invention that exhibit no or only moderate β-receptor stimulating activity exhibit a potent inhibitory activity there due to their affinity for β-receptors. In addition, the compounds of the present invention also exert some inhibitory activity on α-receptors and may also contribute, for example, to the antihypertensive effect of the compounds, but without inducing orthostatic hypotension, which normally occurs.

The above pharmacological properties may be demonstrated in vitro or in vivo, and preferably include mammalian animals such as mice. rats, cats, dogs, or organs isolated from them. Animal tension may be normal or high, for example, genetically hypertensive rats or renally hypertensive rats or dogs, or dogs deprived of sodium. The compounds of the invention may be administered enterally or parenterally; oral and intravenous administration are preferred. The application may take the form of, for example, gelatin capsules or starch-containing suspensions or aqueous solutions. The dose used is about 20 mg / kg. 0.01 to 100 mg / kg / day, preferably ca. 0.05 to 50 mg / kg / day, and particularly preferably ca. It may be in the range of 0.1-30 mg / kg / day.

The antihypertensive effect is measured in vivo either directly using a catheter inserted into the femoral artery of the experimental dog or indirectly by means of a sphygmomanometer on the tail of the experimental rat and recorded in each case with a suitable device. Blood pressure in mm Hg is determined before and after application of the active ingredient. For example, the most representative compounds of the present invention, as described in the Examples, are highly effective at doses of 10 mg / kg / day orally administered to high blood pressure rats or dogs.

The antihypertensive effect and decrease in heart rate can be demonstrated in spontaneously hypertensive rats by measuring systolic pressure in rat tails by indirect methods such as sphygmomanometry. The awake rats are individually housed in cages that are housed in a pleasantly warm environment. After determining blood pressure and heart rate control value, the test compound is administered orally to the animal for two or four consecutive days and once daily. Blood pressure is usually measured 24 hours after the first dose and then 2.0, 4.0 and 24 hours after the respective daily dose. The effect is compared with that observed in vehicle-only rats.

The antihypertensive and bradycardic effects can also be investigated in alert and chronically hypertensive dogs, whose hypertension is based on impaired renal function. Arterial blood pressure is measured after direct percutaneous puncture of the femoral artery of the animals using a needle attached to a recording device. After the control values were determined, the dogs were treated with capsules orally once daily for four days containing the active ingredient to be tested. Blood pressure and heart rate were determined at intervals of 1.5.3.6 and 24 hours after each daily dose and compared with control values prior to commencement of treatment.

The ability of these novel compounds to bind to β-receptors and thus to act on β-receptors, such as their blocking activity, was determined in vitro by a β-receptor binding assay, Life Sciences 17, 993 (1975). ) with a modified version of the procedure described in the literature.

³ H-dihidroalprenololt brain membrane preparation using specific binding partner and this interaction inhibited β-receptor antagonists and agonists are known.

During the binding assay, 2 ml of the membrane preparation suspension is added to ice-cooled test tubes containing ³ H-dihydroalprenolol, freshly dissolved in 0.1% ascorbic acid, with or without the test compound (membrane preparation approx. 20 mg, from calf). corresponding to nucleus caudatus). The ³ H-dihidroalprenolol final concentration of 1.0 nM. The compounds to be tested are tested over a wide concentration range. The tube is incubated for 10 minutes at 37 ° C and the suspensions are immediately filtered through a glass filter under vacuum. Each filter was then washed with 15 mL of cold 50 mM Tris-HCl buffer (pH 7.9 at 25 ° C) and the resulting liquids were filled with 12 mL of scintillation solution into scintillation vials, which were shaken for 90 minutes, and the radioactivity was measured using a counting tube.

The IC ₅₀ values represent the concentrations of test compounds required to reduce the specific binding of the 1.0 N ³ H-dihydroalprenolol solution by 50%. These values are determined graphically. The compounds of the present invention inhibit the binding of dihydroalprenolol to the β-receptor with an IC _{50 of} only 5 nM (i.e., 5 x 10 ⁹ moles) or less.

The β-receptor antagonistic activity of the compounds of the present invention can be demonstrated in vitro by antagonizing the adenylate cyclase preparation of guinea pig cerebellum to adrenaline activation [J. Neurochemistry, 22, 1031 (1974)].

Binding to α-receptors is an ability that indicates the existence of an inhibitory effect on α-receptors. This can be demonstrated in vitro binding of the known α-blocker prazosin ⁽³ H-Prazosin) in rat synaptosomal membrane preparation prepared előagyából inhibition [see Nau3

-3193303 nyn-Schmiedebergs Arch. Pharmacol. 308, 223 (1979)].

The anti-glaucoma activity of the compounds of the present invention can be demonstrated by measuring the reduction in intraocular pressure in which mammalian animals, such as the normal tensile rabbits are used and essentially D.E. Potter and J.M. Employing the method described by Rowland; it is described in Experimental Eye Research 27, 615-625 (1978). The reduction in intraocular pressure was determined as follows: one eye of New Zealand albino rabbits weighing 3 to 4 kg was treated with a solution of the test compound in sterile water, while the other eye was treated with vehicle alone for control purposes. The drug-containing solution was used in the form of two solutions of different concentrations and 50 μΐ volume, while the control vehicle was also used at 50 μΐ and twice. The intraocular pressure (in mmHg) of each eye was measured with a tonometer immediately before and 1, 2, and 3 hours after application of the preparation, and the difference between the intraocular pressure of the treated eye and the control eye was determined.

Preferred compounds of the formula I are the compounds of the formula II and their salts, in particular their salts for pharmaceutical purposes; in formula (II) R ¹ and R ^z both represent hydrogen atoms, or represents an ethylene group, ^R1 and ^R2 together; R ⁵ and R ⁴ are independently hydrogen or C 1-4 alkyl; R ^{5 is C} 2 -C 6 alkenyl, C 1 -C 7 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, cyano, morpholino, 1-pyrrolyl, 2-pyrrolyl, phenyl, 5- 7-membered cycloalkyl, C 1 -C 4 alkoxycarbonyl, carbamoyl, C 3 -C 6 cycloalkyl (C 1 -C 4 alkoxy) or C 1 -C 4 alkoxy (C 1 -C 4 alkyl).

Particularly preferred are the compounds of formula III and their salts, especially pharmaceutically acceptable salts thereof, wherein R ^{3 is} hydrogen or C 1-4 alkyl and R ⁷ is cyano, C 1-4 alkoxycarbonyl, pyrrolyl, morpholino, C3-C6 alkenyloxy, C3-C6 alkynyloxy or C1-C3 alkoxy substituted with a cyclopropyl group.

The compounds of formula (I), (II) and (III) may exist in two isomeric forms, the two substituents on the cyclohexane ring being either in the cis or trans position; in addition, the asymmetric carbon atom bearing the hydroxyl group in the compounds of the invention is either 4 or 4;

It has S or R configuration. The compounds of formula (I), (II) (III) may therefore be in the form of stereoisomers, such as geometric isomers, racemates, pure enantiomers, or mixtures thereof, and are all within the scope of the present invention.

Preference is given to compounds of formulas I, II and III in which the substituents at the 1- and 4-positions of the cyclohexane ring are cis relative to each other, more preferably the enantiomers wherein the carbon atom bearing the hydroxyl group is in the S configuration.

Of particular interest are the compounds of formula (III) as well as their stereoisomers and enantiomers and their salts, especially pharmaceutically acceptable salts thereof, wherein R ^{3 is} hydrogen, and R ^{7 is} allyloxy, propargyloxy, or cyclopropylmethoxy. -group. Particularly preferred are cis-stereoisomers and S-enantiomers.

The preparation of compounds of formula (I) according to the invention is characterized by reacting two compounds or cyclizing one compound (Yen), wherein said starting compound (s) are of formula (IV) wherein Ar, R ¹ , R ² , R ³ and R ⁴ are as defined above, one of X ¹ and X ² being a hydrogen atom and the other being an acyl radical of a semi-carbonic acid, or X ¹ and R ¹ together or X ² and R ² together being = C ^ ZQ (IVa) to form groups of the formulas, 'whereby the latter, if desired, a salt or a resulting salt X ² is hydrogen and R ² is hydrogen, or in the latter case, X ¹ is hydrogen and R ¹ is hydrogen and desired, the free compound obtained is, if case, it is converted to the free compound or other salt.

A general Formula III starting vegyülelben (IV), especially those wherein R ¹ and R ² represents an ethylene group together, X 'or X ² substituents as a szérisav-half derivative acyl radical e.g. corresponding radical of a carbonic acid semiester, such as a lower alkoxy a carbonyl group such as methoxycarbonyl or ethoxycarbonyl; and a suitable radical of a carbonic acid halide such as a halocarbonyl group such as chlorocarbonyl or bromocarbonyl and a carbonic acid group. semiamide is a suitable radical such as 1-imidazolylcarbonyl.

One of the starting compounds of formula (IV), wherein R ¹ and X ¹ together or R ² and X ² together represent a group of formula (IVa), is an isocyanate, while the other starting compound is an amine, wherein X ² or X ¹ is hydrogen and R ² or R ¹ is hydrogen.

The cyclization reaction in the presence of a solvent or diluent or without the use of any _guide and, if necessary, of a coupling reagent, preferably a savory bases 4193303 condensing agent, eg. an alkali metal hydroxide, carbonate, bicarbonate or (lower) alkanolate or an alkaline earth metal hydroxide, carbonate, bicarbonate or (lower) alkanolate, and an organic base such as a tertiary amine , or in the presence of a pyridine-type base and under cooling or at room temperature or under heating, e.g. The temperature is between 0 ° C and 150 ° C, in a closed vessel and / or under an inert gas atmosphere.

The starting compounds of formula (IV), in particular those in which R 'and R ² together are ethylene, are prepared by known methods, preferably in situ. For example, a compound of formula IV wherein X ¹ and X ^{2 are} hydrogen is reacted with a reactive derivative of carbonic acid. Such reactive carbonic acid derivatives include the corresponding diesters, such as di- (lower) alkyl carbonates, e.g. diethyl carbonate and diphenyl carbonate; dihalides such as phosgene; halogen-carbonic acid esters are thus suitable lower alkyl esters, e.g. chloro-lower alkyl esters, for example ethyl chloro-carbon or isobutyl chloro-carbon, and phenyl-chloro-carbon; halogenated carbonic amides such as chloro-carbonic amide; and urea, and derivatives thereof, e.g. Ν, Ν'-carbonyldiimidazole.

The starting amines of formula (IV) wherein X ¹ and X ^{2 are} hydrogen, R ¹ and R ^{2 taken} together are ethylene, may be prepared, for example, by the following procedure: A N- (4-nitrophenyl) -N'-R For example, ^3- ethylenediamine is acylated with an alkanoyl halide or an anhydride. In this way, N- (4-nitrophenyl) -N'-R ³ -N, N'-diacylalkylenediamine is obtained and is preferably reduced by catalytic hydrogenation. The resulting N- (4-aminocyclohexyl) is obtained. -N'-R ³ -N, N'-diacyl ethylenediamine, optionally e.g. monoalkylated with the reactive ester of a lower alkanol and then condensed with 3-ArO-1,2-epoxypropane. Thus, a compound of formula IV is obtained wherein X ¹ and X ^{2 are} acyl groups and finally this diacyl derivative is hydrolyzed.

The starting amine compounds of formula (IV) wherein X ¹ and X ^{2 are} hydrogen hydrogen and wherein R 1 and R ² together represent ethylene may be prepared in other ways. For example, 4-aminocyclohexanol is converted to 4-aminocyclohexanone and then 4-aminocyclohexanone is reacted with 3-ArO-1,2-epoxypropane. The carbonyl group of the resulting ketone intermediate is then converted to the desired amino group by converting said ketone with an NR ³ -ethylenediamine or an X ³ -ethylamine, in which X ^{3 is} an amino group of formula (Va) -NH-R ^3. is reacted with, or simultaneously with, a reducing agent such as catalytically activated hydrogen or a suitable reducing hydride reagent such as. and treatment with sodium cyanoborohydride. The resulting intermediate is subjected to the conversion of the X ³ group to the amino group -NH-R ³ and the free secondary hydroxyl group of the intermediate is converted to the substituted RO group by a known method. Examples of the R ³ -NH- convertible amino group X ³ include hydroxyl and cyano, which can be converted to Va using known methods. For example, the hydroxy compound is converted to a reactively esterified hydroxy derivative, such as, e.g. a halogen derivative or an organic sulfonyloxy compound, e.g. by treatment with a suitable esterifying agent such as a thionyl halide or an halide of an organic sulfonic acid. The reactively esterified intermediate is then reacted with an amine of formula H ₂ NR ³ (V). Conversely, the cyano-containing intermediate can be converted to the corresponding N-unsubstituted aminomethyl compound by reduction, and the amino group of the resulting aminomethyl compound can then be replaced singly by the addition of an alkyl group.

The isocyanates used as starting materials in which X ¹ and R 'together or alternatively X ² and R ² together represent a group of formula IVa can be prepared, for example, from the corresponding amines where X ¹ and R ¹ (or X ² and R ² ) is hydrogen. We deal with the said amines with phosgene. reacted.

The starting compounds and, if prepared in situ, the starting compounds are prepared under conventional conditions, usually in the presence of an inert solvent and, if necessary, a condensing agent or an organic tertiary nitrogen base. By way of example, a condensing agent may be a basic condensing agent such as an alkali metal or alkaline earth metal hydroxide, carbonate or bicarbonate, e.g. sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate or potassium bicarbonate, or an alkali metal (lower) alkanolate, e.g. sodium methanol or potassium tert-butylate, while the organic tertiary base is a tri- (lower) alkylamine, e.g. trimethylamine or triethylamine or pyridine may be used. The operation may be carried out under cooling or at room temperature or may be carried out by heating, e.g. 0 ° C to approx. We operate at temperatures up to 150 ° C

-5193303 and the reaction is carried out in a closed vessel and / or under an inert gas atmosphere.

Depending upon the choice of starting materials and methods employed, the compounds of the present invention may be in the form of a possible pure isomer or a mixture of isomers such as pure geometric isomers (cis or trans isomers), pure optical isomers such as antipodes, mixtures of optical isomers. racemates, and desire in the form of mixtures of geometric isomers.

Mixtures of isomers of optical or diastereomeric isomers of the compounds can be separated into the individual racemic or optically active isomers by methods known per se. Separation can take place, for example, by fractional distillation, crystallization and / or chromatography. The resulting racemic products can be cleaved into optical antipodes, for example by separation of diastereomeric derivatives [see J. Org. Cehm, 43, 3803 (1978)], such as fractional crystallization of d- or 1-tartrates, mandelates, camphorsulfonates or 1-naphthyl-1-ethylisocyanate derivatives of the compounds of formula (I). Preferably, the more potent isomer and / or more potent antipode of the compounds of the invention is always isolated.

The compounds of the present invention are obtained either as free compounds or salts thereof. Any free compound can be converted to the corresponding acid addition salt, preferably by an acid or an anion exchanger. Conversely, the resulting salts can be converted to the free compounds, for example by reaction with a base such as a metal hydroxide or ammonium hydroxide, and a basic salt such as a base. with an alkali metal carbonate or with a cation exchanger. These salts and other salts, e.g. the picrates can also be used to purify the resulting bases, if the bases are formed into salts, separated and purified, and finally the bases are liberated again. Because of the close association between the free compounds and their salts, the corresponding salts should be understood as meaning, where appropriate and appropriate, the corresponding salts.

The compounds and their salts may also be obtained in the form of hydrates or they may also bind other solvents, such as those used in the crystallization process.

The invention also relates to variants of the process, wherein any of the starting materials is prepared under the reaction conditions, or the starting material is used in the form of a derivative such as a salt or a mixture of isomers or a pure isomer.

The process preferably utilizes starting materials from which the compounds of formula (I), which are particularly preferred above, may be prepared. Of all the starting compounds of formula (IV), cis isomers are preferred.

The compounds of formula I and their pharmaceutically acceptable non-toxic acid addition salts can be used as active ingredients in pharmaceutical formulations. The compositions may be enteral, such as orally or rectally, or parenterally, and contain an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, alone or in admixture with one or more pharmaceutically acceptable carriers.

Preferred dosage forms are tablets and gelatin capsules, which may contain, in addition to the active ingredient: a) diluents, e.g. lactose, dextrose, sucrose, mannitol sorbitol, cellulose and / or glycine; b) lubricants such as lubricants; S2.silicon dioxide, talc, stearic acid, magnesium or calcium stearate and / or polyethylene glycol; the tablets may also contain: c) binders, e.g. magnesium 2: aluminum aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone; and, if desired, d) disintegrating agents, e.g. starch, agar, alginic acid or its sodium salt, and effervescent additives; and / or e) adsorbents, colorants, flavors, and sweeteners. Injectable compositions include aqueous, isotonic solutions or suspensions. Suppositories are preferably prepared from fat emulsions or fat suspensions. Each formulation may be sterilized and / or may contain auxiliaries such as preserving, stabilizing, wetting or emulsifying agents, as well as solubilizers, salts and / or buffers for controlling osmotic pressure, and other therapeutically valuable substances. These formulations are prepared by conventional mixing, granulating, and coating processes, and are prepared in an amount of about 1 to about 10 minutes. 0.1-75%, preferably ca. They contain 1-50% active ingredient.

The following examples further illustrate the invention. Temperature data are given in ° C. Unless otherwise noted, all evaporation operations are carried out under reduced pressure, preferably for approx. 2-13.3 kPa.

Example 1 g 1 - {[(4 - [(2-Aminoethyl) amino] -cyclohexyl] -amino} -3- (2-yl-1-oxy-phenoxy) -2-propanol (Preparation of the compound) (below) was treated with 8.5 g of Ν, Ν'-carbonyldiimidazole in 100 ml of tetrahydrofuran solution and stirred for 4 hours under reflux, and the residue was taken up in ethyl acetate under reduced pressure. The solution was washed several times with water, dried and evaporated under reduced pressure, the residue was taken up in 100 ml of isopropanol, refluxed, 2.9 g of fumaric acid was added with stirring, and the mixture was further stirred until the fumaric acid was completely dissolved. and allowing to stand, whereby the hemifumarate of cis-1- {4 - [[3- (2-allyloxy-phenoxy) -2-hydroxy-propyl] -amino] -cyclohexyl} -2-imidazolidone crystallizes out. After purification, the pure cis isomer, m.p. 156-157 °, is obtained.

Dissolve 1575 g of the above salt in 7875 ml of water and add 4,356 moles of potassium carbonate in 790 ml of water to give cis-1- {4 - [[3- (2-allyloxyphenoxy) - 2-Hydroxypropyl] amino] cyclohexyl} -2-imidazolidinone is obtained. This can be converted to a salt such as the more pure hemifumarate as described above.

The starting material may be prepared as follows:

36.2 g of N- (4-nitrophenyl) ethylene diamine [see F. Linsker and R.L. Evans, J. Org. Chem. 10, 283 (1945)] is slowly added at room temperature to 30 g of acetic anhydride in 100 ml of 1,2-dimethoxyethane and the mixture is heated on a steam bath for 1 hour. After cooling, the mixture was concentrated under reduced pressure. The residue obtained is taken up in water and dichloromethane and the pH is adjusted to 9-10 by addition of 5N sodium hydroxide solution. The methylene chloride layer was washed with 10% aqueous sodium carbonate solution, then dried and evaporated to dryness. This gives crude N- (2-acetylaminoethyl) -N- (4-nitrophenyl) acetamide which is used without further purification.

To a mixture of N- (2-acetylaminoethyl) -N- (4-nitrophenyl) acetamide and 500 ml of water was added 25 g of 5% rhodium on carbon (water content: 50%). The reaction mixture is hydrogenated at a temperature of 40-50 ° C and a pressure of 300 bar ( ³ bar) until the mixture is cooled to ca. It takes up 0.9 moles of hydrogen. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. In this way, a viscous residue is obtained, consisting mainly of a mixture of cis and a small amount of trans-N- (2-acetylaminoethyl) -N- (4-aminocyclohexyl) acetamide.

g of N- (2-acetylaminoethyl) -N- (4-aminocyclohexyl) acetamide (predominantly cis isomer) and 21 g of 1- (2-allyloxy-phenoxy) -2,3-epoxy propane in 200 ml of isopropanol was stirred for 6 hours under reflux and the mixture was evaporated to dryness. The residue was taken up in 400 ml of 50% aqueous ethanol in which 24 g of sodium hydroxide was previously dissolved. The reaction mixture is refluxed for 4 hours and then partially evaporated to remove the ethanol. After adding 20 g of sodium chloride, the mixture is extracted several times with dichloromethane. The organic layer was washed with water, dried and concentrated under reduced pressure. This gives crude 1 - {[4 - [(2-aminoethyl) amino] -cyclohexyl] -amino) -3- (2-allyloxyphenoxy) -2-propanol, which is predominantly cis- isomer.

Example 2

From the appropriate starting compounds, the following compounds of the invention are prepared according to the procedure described in Example 1:

2.1 cis-1- [4 - [[3- (2-Cyclopropylmethoxy-phenoxy) -2-hydroxy-propyl] -amino] -cyclohexyl} -2-imidazolidinone, m.p. 168-170 ° from hemifumarate. The compound was prepared from cis-1 - {[4 - [(2-aminoethyl) amino] -cyclohexyl] -amino} -3- (2-cyclopropylmethoxy-phenoxy) -2-propanol as, Ν-carbonyl-. reaction with diimidazole.

2.2 (S) -cis-1- {4 - [[3- (2-Cyclopropylmethoxy-phenoxy) -2-hydroxy-propyl] -amino] -cyclohexyl} -2-imidazolidinone, m.p. 147-149 °; [a] £ ⁵ = -8.41 ° (c = 35, methanol). The compound was prepared from (S) -cis-1 - {[4 - [(2-aminoethyl) amino] -cyclohexyl] -amino} -3- (2-cyclopropylmethoxyphenoxy) -2-propanol, It is prepared by reaction with? -Carbonyldiimidazole.

2.3 (R) -cis-1- {4 - [[(2-Cyclopropylmethoxy-phenoxy) -2-hydroxy-propyl] -amino] -cyclohexyl} -2-imidazolidinone, melting point (decomposition) of hemifumarate; 150-152 °; [?] D ⁵ = + 8.26 ° (c = 1.36, methanol). The compound was prepared from (R) -cis-1 - {[4 - [(2-aminoethyl) amino] -cyclohexyl] -amino) -3- (2-cyclopropylmethoxyphenoxy) -2-propanol, It is prepared by reaction with N'-carbonyldiimidazole.

2.4 trans-1- {4 - [[3- (2-Cyclopropylmethoxy-phenoxy) -2-hydroxy-propyl] -amino] -cyclohexyl} -2-imidazolidinone, melting point of hemifumarate (from isopropanol): 178-180 ° . The compound was prepared from trans-1 - {[4 - [(2-aminoethyl) amino] cyclohexyl] amino} -3- (2-cyclopropylmethoxyphenoxy) -2-propanol, Ν, Ν'-carbonyl. reaction with diimidazole.

2.5 cis-1- {4 - [[3- (2-Methoxyphenoxy) -2-hydroxypropyl] amino] cyclohexyl} -2-imidazolidinone, m.p. 190-192 ° from hemifumarate (isopropanol / methanol). The compound was treated with Ν, Ν'-carbonyldiimidazole starting from cis-1 - {[4 - [(2-aminoethyl) amino] -cyclohexyl] -aminol-3- (2-methoxyphenoxy) -2-propanol. reaction.

2.6 cis-1- {4 - [[3- (2-Propargyloxy-phenoxy) -2-hydroxy-propyl] -amino] -cyclohexyl} -2-imidazolidinone, hemifumarate melting point (from 95% ethanol): 168 °. The compound was prepared from cis-1 - {[4 - [(2-aminoethyl) amino] cyclohexyl] amino} -3- (2-propargyloxyphenoxy) propanol with Ν, Ν'-carbonyldiimidazole. reaction.

-7193303

2.7 trans-1- {4 - [[3- (2-Propargyloxy-phenoxy) -2-hydroxy-propyl] -amino] -cyclohexyl} -2-imidazolidinone, m.p. 9298 °. The compound was prepared from trans-1 - {[4 - [(2-aminoethyl) amino] -cyclohexyl] -amino} -3- (2-propargyloxy-phenoxy) -2-propanol, N, N'-carbonyl- reaction with diimidazole.

2.8 cis-1- {4 - [[3- (3-Propargyloxy-phenoxy) -2-hydroxy-propyl] -amino] -cyclohexyl] -2-imidazolidinone, m.p. 177 ° from hemifumarate (from ethanol). The compound was prepared from cis-1 - {[4 - [(2-aminoethyl) amino] -cyclohexyl] amino} -3- (3-propargyloxyphenoxy) -2-propanol with Ν, Ν'-carbonyldiimidazole. reaction.

2.9 cis-1- {4 - [] 3- (4-Propargyloxy-phenoxy) -2-hydroxy-propyl] -amino] -cyclohexyl-2-imidazolidinone, 1: 1 fumarate melting point (isopropanol solvate), from isopropanol): 95-100 °. The compound was prepared from isz, Ν'-carbonyl starting from cis-1 - {[4 - [(2-aminoethyl) amino] cyclohexyl] amino} -3- (4-propargyloxyphenoxy) -2-propanol. reaction with diimidazole.

2.10 cis-1- {4 - [[3- (2-Cyanophenoxy) -2-hydroxypropyl] amino] -cyclohexyl} -2-imidazolidinone, hemifumarate melting point (ethanol): 192 ° (dec.) . The compound was prepared from cis-1 - {[4-] (2-aminoethyl) amino] -cyclohexyl] -amino} -3- (2-cyanophenoxy) -2-propanol with Ν, Ν'-carbonyldiimidazole. reaction.

2.11 trans-1- {4 - [[3- (2-Cyanophenoxy) -2-hydroxypropyl] amino] -cyclohexyl] -2-imidazolidinone, hemifumarate, m.p. 215-216 °. The compound was reacted with N, N'-carbonyldiimidazole starting from trans-1 - ([4- (2-aminoethyl) amino] -cyclohexyl] -amino} -3- (2-cyanophenoxy) -2-propanol. we produce it.

2.12 cis-1- {4 - [[3- [2- (1-Pyrrolyl) phenoxy] -2-hydroxypropyl] amino] -cyclohexyl] -2-imidazolidinone, hemifumarate melting point (ethanol): 144 ° (dec.) while). The compound was prepared from cis-1 - {[4 - [(2-aminoethyl) amino] -cyclohexylamino} -3- [2- (1-pyrrolyl) phenoxy] -2-propanol, Ν, Ν'-carbonyl. reaction with diimidazole.

2.13 cis-1- {4 - [[3- [2- (2-pyrrolyl) phenoxy] -2-hydroxypropyl] amino] cyclohexyl) -2-imidazolidinone, hemifumarate melting point (from ethanol): 130-134 °. The compound was prepared from cis-1 - [[4 - [(2-aminoethyl) amino] cyclohexyl] amino} -3- [2- (2-pyrrolyl) phenoxy] -2-propanol, N, N'- by reaction with carbonyldiimidazole.

2.14 cis-1- (4 - [[3- [2- (4-Morpholino) phenoxy] -2-hydroxypropyl] amino] -cyclohexyl] -2-imidazolidinone, hemifumarate melting point (from ethanol): 114-118 ° The compound was prepared from cis-1 - {[4 - [(2-aminoethyl) amino] cyclohexyl] amino} -3- [2- (4-morpholino) phenoxy] -2-propanol Ν, Ν prepared by reaction with 'carbonyldiimidazole.

2.15 cis-1- {4 - [[3- (2-AA-ethoxyethyl) phenoxy] -2-hydroxypropyl] amino] -aclohexyl] -2-imidazolidinone, hemifumarate melting point (from isopropanol): 166-168 ° . Starting from cis-1 - {[4 - [(2-aminoethyl) amino] cyclohexyl] amino} -3- [4- (2-methoxyethyl) phenoxy] -2-propanol Ν, Ν prepared by reaction with '-carbonyldiimiclazole.

2.16 Cis-1- {4 - [[3- (2-Benzyloxy-phenoxy) -2-hydroxy-propyl] -amino] -cyclohexyl-2-imidazolidinone, m.p. 141-146 ° from hemifumarate . The compound was prepared from cis-1 - {[4 - [(2-aminoethyl) amino] -cyclohexyl] -amino} -3- (2-benzyloxy-phenoxy) -2-propanol, N, N'-carbonyl- diimidazole.

2.17 cis-1 - {4- [[3- (2-Carbamoyl-phenoxy) -2-hydroxy-p ^r piperidinopropyl] amino] cyclohexyl-2-imidazolidinone, the hemifumarate mp 110 DEG. The compound was treated with Ν, Ν'-carbonyldiimidazole starting from cis-1 - {[4 - [(2-aminoethyl) amino] cyclohexyl] amino} -3- (2-carbamoylphenoxy) -2-propanol. reaction.

2.18 cis-1- {4 - [[3- [2- (2-Methyl-propoxy) -phenoxy] -2-hydroxy-propyl] -amino] -cyclohexyl) -2-imidazolidinone, hemifumarate melting point (from acetone): 170 -172 °. Starting from cis-1 - {[4- (2-aminoethyl) amino] -cyclohexyl] -amino} -3- [2- (2-methylpropoxy) -phenoxy] -2-propanol, N, N ' reaction with carbonyldiimidazole.

2.19 Cis-1- {4 - [[3- (2-Cyclohexyl-phenoxy) -2-hydroxy-propyl] -amino] -cyclohexyl-2-imidazolidine, Hemifumarate Melting Point (Hydrate, Isopropanol-Acetone): 117- 120 °. The compound was treated with N, N'-carbonyldiimidazole starting from cis-1 - {[4 - [(2-aminoethyl) amino] cyclohexyl] amino} -3- (2-cyclohexylphenoxy) -2-propanol. reaction.

2.20 Cis-1- {4 - [[3- (2-Methoxycarbonyl-phenoxy) -2-hydroxy-propyl] -amino] -cyclohexyl] -2-imidazolidinone, Hemifumarate Melting Point (Isopropanol-Acetone): 135 -138 °. The compound was prepared from isz, Ν'-carbonyl starting from cis-1 - {[4 - [(2-aminoethyl) amino] cyclohexyl] amino} -3- (2-methoxycarbonylphenoxy) -2-propanol. reaction with diimidazole.

2.21 Cis-1- [4 - [[3- (2-Phenyl-phenoxy) -2-hydroxy-propyl] -amino] -cyclohexyl] -2-imidazolidinone, m.p. 146-148 ° from hemifumarate. The compound was reacted with N, N'-carbonyldiimidazole starting from cis-1 - {[4 - [(2-aminoethyl) amino] -cyclohexyl] -amino} -3- (2-phenyl-phenoxy) -2-propanol. we produce it.

2.22 cis -1-) 4 - [[(4-Benzyloxy-phenoxy) -2-hydroxy-phenyl] -amino] -cyclohexyl] -2-imidazolidinone, m.p. 159-161 ° C (from ethanol). The compound was prepared from cis-1 - {[4 - [(2-aminoethyl) amino] -cyclohexyl] -amino} -3- (4-benzyloxyphenoxy) -2-propanol. by reaction with carbonyldiimidazole.

2.23 trans-1- {4 - [[3- (2-Allyloxy-phenoxy) -2-hydroxy-propyl] -amino] -cyclohexyl) -2-imidazolidinone, m.p. of hemifumarate (from ethanol-8193303): 149 -150 °. The compound was prepared from trans-1 - ([4 - [(2-aminoethyl) amino] -cyclohexyl] -amino) -3- (2-allyloxy-phenoxy) -2-propanoate. by reaction with carbonyldiimidazole.

2.24 cis-1- {4 - [[3- (2-Allyl-phenoxy) -2-hydroxy-propyl] -amino] -cyclohexyl) -2-imidazolidinone, hemifumarate melting point (from isopropanol / acetone): 158- 159 °. The compound was prepared from cis-1 - {[4 - [(2-aminoethyl) amino] -cyclohexyl] -amino) -3- (2-allyl-phenoxy) -2-propanol-bromo with Ν, Ν'-carbonyldiimidazole. reaction.

2.25 cis -1-] 4 - [[3- (2-Cyclopropylmethoxy-phenoxy) -2-hydroxy-propyl] -amino] -cyclohexyl-3-methyl-2-imidazolidinone, m.p. 145-147 ° C. . The compound was prepared from cis-1 - {[4 - [(2-methylaminoethyl) amino] -cyclohexyl] -amino} -3- (2-cyclopropylmethoxy-phenoxy) -2-propanol Ν, It is prepared by reaction with? -Carbonyldiimidazole.

2.26 Cis-1- {4- [N- [3- (2-Allyloxy-phenoxy) -2-hydroxy-propyl] -N-methyl-amino] -cyclohexyl} -2-imidazolidinone, m.p. (acetate): 80 ° (with decomposition). The compound was cis-1- {N- [4 - [(2-aminoethyl) amino] -cyclohexyl] -N-methylammonio} -3- (2-alpha-11-oxy-phenoxy) -2-. starting from propanol by reaction with N, N'-carbonyldiimidazole.

2.27 Cis-1- {4 - [[3- (4-Chloro-1,2,5-thiadiazol-3-yl] oxy) -2-hydroxypropyl] amino] cyclohexyl} -2- imidazolidinone, hemifumarate melting point (from isopropanol): 163 °. The compound was cis-1- [4- [(2-aminoethyl) amino] -cyclohexyl] -amino} -3- (4-chloro-1,2,5-thiadiazol-3-yloxy). ) Is prepared from 2-propanol by reaction with Ν, Ν'-carbonyldiimidazole.

Example 3

- [(4-aminocyclohexyl) amino] -3- (2-allyloxy-phenoxy) -2-propanol is reacted with ethyl isocyanate to give 1- {4 - [[3- (2-allyloxy) (phenoxy) -2-hydroxypropyl] amino] cyclohexyl) -3-ethylurea is obtained. The compound hemifumarate melts at 159-160 ° C after washing with a little acetone-methanol (9: 1).

Example 4

Composition for 10,000 tablets:

cis'z-1-14- [[3- (2-Auil- (oxy-phenoxy) -2-hydroxy-propyl] -amino] -cyclohexyl-2- imidazolidine hemifumarate 100 g Lactose 1157 g corn starch 75g Polyethylene glycol 6000 75g talc 75g Magnesium stearate 18 yrs Cleaned water qs

process

Each powder component is sieved through a 0.6 mm mesh screen. Then the drug substance is mixed with a suitable mixer with the lactose, the talc, the magnesium stearate and half of the starch vei ^{2 Cl.} The other half of the starch is suspended in 40 ml of water and this suspension is added to a solution of polyethylene glycol in 150 ml of water and boiling. The resulting paste is added to a mixture of the powdered components and granulated, optionally with additional water. The granulate is then dried for 16 hours at 35 °, processed through a sieve with a mesh size of 1.2 mm and finally pressed into tab30 sheets with a diameter of 6.4 mm. The tablets are scored.

Effect of Compounds of the Invention on Systolic Blood Pressure (BP, mmHg) in Spon ³⁵ Hypertensive Rats In the above method, wake rats were individually caged. We placed. First, blood pressure control values were determined, and each test compound was administered orally once daily for two consecutive days.

The results show s until the blood pressure falls on the second day, 2 hours after drug administration.

The active ingredient is the compound of Example 1 As described above tablets containing 10 mg of the drug are shown below - compounds biak we make: 50 ményezte: The following is an example Dose BP-c: compound mg / kg po MmHg 1 50 -79.3 2.5 50 -39.3 2.11 50 -33.0 2.10 50 -11.0 2.7 50 -30.0 2.12 50 -68.0 2.8 50 -52.3 2.15 50 -17.6 2.2 30 -75.5

exam to choose-

Claims (9)

PATENT CLAIMS 1. A process for the preparation of compounds of the formula I, their stereoisomers and their salts Ar is substituted with halogen A 1,2,5-thiadiazolyl group or a phenyl group having from 2 to 6 carbon atoms alkenyl, C1 to 4 alkoxycarbonyl groups, C1 to 7 alkoxy groups, C2 to C6 alkenyloxy groups, cyano groups, pyrrolyl groups, morpholino, benzyloxy, phenyl, 5-, 6- or 7-membered cycloalkyl, carbamoyl, C3-C6 cycloalkyl-C1-C4 alkoxy or C1-C4 alkoxy- Monosubstituted with C4 alkyl), R ¹ and R ² are hydrogen or R 1 and R ² together form ethylene, R ³ and R ⁴ are independently hydrogen or C 1 -C 5 alkyl, characterized by reacting two compounds or cyclizing a single compound, said compound (s) being optionally prepared in situ from general formula (IV); wherein Ar, R ¹ , R ² , R ³ and R ⁴ are as defined above, one of X ¹ and X ² being hydrogen and the other being an acyl radical of a semi-carbonic acid, or X 'and R ¹ together, or X ² and R ² together form a group = C = O (iVa) wherein X ^{2 is} hydrogen and R ^{2 is} hydrogen, and X ^{1 is} hydrogen and R ^{1 is} hydrogen, and the resulting free compound is optionally salted or the resulting salt is optionally converted to the free compound or other salt. Process according to Claim 1, characterized in that the starting compound of the formula (IV) is used, wherein R ¹ and R ² together preferably represent ethylene, and the acyl radical of the half-derivative of X ¹ or X ^{2 is} a half-ester of carbonic acid, means a suitable radical of a carbonic acid halide or carbonic acid amide. 3. A method according to claim 1, characterized in that it is used in the formula (IV) is a starting compound of formula wherein R ¹ and R ² together represent an ethylene group, and that of Formula a hydrogen atom ^two substituent (IV), X 'and X Starting from compound I, it is prepared in situ by reaction with a reactive carbonic acid derivative. The process according to claim 3, wherein the reactive derivative of carbonic acid is a suitable ester such as a di (lower) alkyl carbonate, a di halide such as phosgene, a halogenated carbonic acid ester such as a halogen a (lower) alkyl ester of carbonic acid, a halogenated carbonic amide or urea, or a derivative thereof such as N, N'-carbonyldiimidazole. 5. A process according to any one of claims 1 to 6 for the preparation of compounds of formula II and salts thereof: wherein R 1 and R ² are both hydrogen or R 1 and R ² together represent ethylene; R ³ and R ⁴ 10 is independently hydrogen or (1-4C) alkyl; R ^{5 is C} 2 -C 6 alkenyl, C 1 -C 7 alkoxy, C 2 -C 6 alkenyloxy group, cyano group, morpholino group, 1-pyrrolyl group, 2-pyrrolyl group, phenyl group, 5-7 membered cycloalkyl group, C 1 -C 4 alkoxy group. carbonyl, carbamoyl, 3-6 carbon? atomic cycloalkyl (C 1-4 alkoxy), or C 1-4 alkoxy (1-4) (C 20 alkyl) group, wherein the starting compound is the compound (s) of formula (IV) substituted as defined in the present claim. 6. A process for the preparation of compounds of formula (III) and salts thereof according to any one of claims 1 to ³ , wherein R ^{3 is} hydrogen or C 1 -C 4 alkyl and R ⁷ is cyano, C 1 -C 4 alkoxycarbonyl, 130 or 2-pyrrolyl. , morpholino, C3-6 alkenyloxy group, C3-6 alkynyloxy group or a C1-3 alkoxy group which is substituted by one ciklopropilcsópoittal _f wherein characterized ve to be substituted as defined in the present claim (IV) starting from the compound (s) of the general formula. 7. Process for the preparation of cis-1- {4 - [[3- (2-allyloxyphenoxy) -240-hydroxypropyl] amino] -cyclohexyl] -2-imidazolidinone or a salt thereof according to any one of claims 1 to 4 starting from the compound (s) of the formula (IV) substituted according to the subject compound. 8. Process for the preparation of cis-1- {4 - [[3- (2-cyclopropylmethoxy-phenoxy) -2-hydroxypropyl] -amino] -cyclohexyl} ^-5 θ -2-imidazolidinone or a salt thereof as claimed in any one of claims 1 to ⁵ that is a compound of formula (IV) substituted according to the subject compound. 9. A process according to any one of claims 1 to 4, (S) -cis-1- (4 - [[3- (2-cyclopropylmethoxyphenoxy) -2-hydroxypropyl] amino] -cyclohexyl] -2-imidazolidinone; salt ⁶⁰ , characterized in that the compound (s) of the formula (IV) substituted according to the compound of the present invention are used.