NO844658L - PROCEDURE FOR THE PREPARATION OF URINE COMPOUNDS - Google Patents

Description

The invention relates to a method for production

of 3-(ureido- and thioureido-cyclohexylamino)-propane-1,2-diol compounds which have been shown to be pharmaceutically valuable agents, e.g. as antihypertensives with both a- and b-receptor blocking properties. They are therefore administered to primates and also humans alone or in combination with other agents, distinctly valuable for the treatment of and prevention against cardiovascular disorders, such as hypertension and heart diseases, especially myocardial infarction (myocardial infarction), rhythm disturbances and coronary insufficiency ( angina pectoris). Furthermore, the compound according to the invention can also be used for treatment or prevention against other diseases, which respond to islet receptor blockade, e.g. diseases of the nervous system, such as tension or depressed

heat, or glaucoma, migraine, arteriosclerosis etc.

The process for the preparation of these compounds

is aimed at the formation of the ureido and thioureido groups.

In particular, the invention relates to a new method for the preparation of compounds with formula

wherein Ar means a monocyclic or optionally partially saturated bicyclic, carbocyclic or heterocyclic aromatic

1 2

residue, R means hydrogen, alkanoyl or aroyl, R and R

means independently of each other, hydrogen or lower alkyl, or R 1 and R 2 together mean the alkyl with 2-7 carbon atoms,

which separates the two nitrogen atoms to which they are bound,

3 4

with 2-4 carbon atoms, R and R independently mean hydrogen or lower alkyl, and X means oxo (O) or thio (S), as well as their salts, especially pharmaceutically usable salts.

The definitions and general terms used have the following meaning within the scope of the invention: An aromatic residue preferably means phenyl, naphthyl, pyridyl, quinolyl, isoquinolyl, indolyl or 1,2,5-thiadiazolyl.

A partially saturated bicyclic, carbocyclic or heterocyclic aromatic residue is preferably tetrahydronaphthyl, tetrahydroquinolyl or tetrahydroisoquinolyl. The substituents optionally present at the phenyl or phenylendene parts of the above-mentioned residues are preferably lower alkoxy, e.g. methoxy, lower alkyl, e.g. methyl, halogen, e.g. chlorine, hydroxy or trifluoromethyl. The optionally present substituents in the heterocycle or on the partially saturated ring of the bicyclic residues preferably comprise lower alkoxy, lower alkyl, halogen, hydroxy, cyan, carbamoyl, substituted amino, (alkylene-, oxaalkylene- or thiaalkylene-)imino, e.g. morpholino, and oxo in some cases the above-mentioned partial saturated bicyclic residues.

An alkenyl residue present as such or as an example

in alkenyloxy, preferably means alkenyl with up to 7 carbon atoms, e.g. 2-propenyl (allyl), 2-butenyl, 2-methyl-2-propenyl or 2-methyl-2-butenyl.

An alkenyl residue present as such or as an example

in alkenyloxy, preferably means alkenyl with up to 7 carbon atoms, e.g. 2-propionyl (propargyl), 2-butynyl or 2-pentynyl.

The term "lower" defines in the above and below mentioned organic residues or compounds, such with a maximum of 7, preferably with up to 4, and especially with 1 or 2 carbon atoms.

Lower alkyl preferably contains 1-4 carbon atoms and means e.g. ethyl, propyl, butyl or especially methyl. Lower oxycarbonyl preferably contains 1-4 carbon atoms in the alkoxy part, and means e.g. methoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl or especially ethoxycarbonyl.

The lower alkylene preferably contains 1-7 carbon atoms and means in particular 1,2-ethylene, 1,3-propylene, 1,4-butylene or 1,5-pentylene.

Cycloalkyl is preferably cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl. Oxaalkylenimino is preferably morpholino; thiaalkylenimino preferably means thiomorpholino, lower alkylenimino preferably means pyrrolidone or piperidino.

Aroyl is preferably benzoyl or with 1-3 residues of the type lower alkyl, lower alkoxy, halogen or trifluoromethyl substituted benzoyl, or heteroaroyl, e.g. nicotinoyl.

Lower realkanoyl is preferably acetyl, propionyl or butyryl.

Lower oxy is preferably ethoxy, propoxy, isopropoxy or especially methoxy.

Lower alkylthio is preferably ethylthio, propylthio or especially methylthio. Lower alkylsulfinyl is preferably ethylenesulfinyl, propylsulfinyl or especially methylsulfinyl. Lower alkylsulfonyl is preferably ethylsulfonyl, propylsulfonyl or especially methylsulfonyl.

Lower oxycarbonylamino is preferably ethoxycarbonylamino or methoxycarbonylamino.

Halogen is preferably fluorine or chlorine, but can also be bromine or iodine.

Alkylamino is preferably mono- or di-(methyl, ethyl, propyl)-amino. Alkylcarbamoyl is preferably mono- or di-N-(methyl, ethyl, propyl)-carbamoyl. Alkylsulfamoyl is preferably mono- or di-N-(methyl, ethyl, propyl)-sulfamoyl.

Alkanoylamino is preferably acetylamino or propionylamino.

Alkylsulfonylamino is preferably methylsulfonylamino or ethylsulfonylamino.

The compounds of formula I form acid addition salts which are preferably therapeutically usable salts of inorganic or organic acids, such as, for example, of strong mineral acids, e.g. halogenated acids, e.g. hydrochloric acid or hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid or perchloric acid, or aliphatic or aromatic carboxylic acids or sulphonic acids. E.g. formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, glyconic acid, citric acid, maleic acid, fumaric acid, pyruvic acid, phenylacetic acid, benzoic acid, 4-aminobenzoic acid, anthranilic acid, 4-hydroxybenzoic acid, salicylic acid, 4-aminosalicylic acid, pamoic acid, nicotinic acid , methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, sulfanilic acid, cyclohexylsulfamic acid, or of ascorbic acid.

In addition to the method for producing the above-mentioned pharmaceutically usable salts, the invention also includes the method for producing some "prodrug" derivative, e.g. a therapeutically usable ester of the alcohol according to the invention, (compounds of formula I in which R means hydrogen), which by solvolysis or under physiological conditions can be converted into the aforementioned alcohols.

Such esters are preferably lower alkanoyl esters, for example the acetyl or isobutyl ester, the aroyl ester, e.g. the benzoyl or nicotinoyl ester, the carbamoyl ester (carbamater), e.g. N-ethylcarbamoyl or N-methylcarbamoyl ester.

The compounds that can be produced by the method according to the invention show valuable pharmacological properties, primarily cardiovascular, for example antihypertensive and heart-influencing effects, i.a. due to their inhibitory effect on B receptors. This inhibition is attributed to the strong affinity of the compound according to the invention to e-receptors. The compounds according to the invention which have no or only little 6-receptor stimulating activity, achieve by their affinities B-receptors where a strong inhibitory effect. In addition, the compounds according to the invention have inhibitory effects on α-receptors, which can also contribute, e.g. to their antihypertensive effect, without, however, usually causing orthostatic hypotension.

The above-mentioned pharmacological properties can be demonstrated in vitro or in vivo, preferably using mammals such as rats, cats, dogs or their isolated organs as test subjects. The animals can be normotensive or hypertensive, e.g. genetically hypertensive rats, or renally hypertensive rats, or dogs, or dogs whose sodium has been removed. In said compounds, they can be administered enterally or parenterally, preferably orally or intravenously, e.g. gelatin capsules or in the form of starch-containing suspensions or aqueous solutions. The dose used can lie in a range of approximately between 0.01 and 100 mg/kg/day, preferably between approx. 0.05 and 50 mg/kg/day, especially between approx. 0.1 and 30 mg/kg/day.

The in vivo blood pressure-lowering effect is recorded either directly with a catheter such as is introduced into a dog's femoral artery, or indirectly using rat tail sphygmomanometry and a transfer instrument. Blood pressure is determined before and after administration of the active substance in mm Hg. Thus, e.g. representative compounds according to the invention which are mentioned in the examples are very effective on hypertensive rats or dogs already in oral doses of 10 mg/kg/day or lower.

Thus, the anti-hypertensive effect and the lowering of the heart rate in spontaneously hypertensive rats can be demonstrated, by indirectly measuring the systolic pressure by sphygmomanometry on the rat's tail. Awake rats are locked individually in cages, which are located in a comfortably warm room. After blood pressure and heart rate control values have been measured, the test compounds are administered orally once daily for 2 or 4 consecutive days. Blood pressure is usually determined 24 hours after the first dose, and then each time 2.0, 4.0 and 24 hours after each daily dose. The effect compared to this in rats treated only with vehicle.

The antihypertensive and bradycardic effect is also examined in awake, chronically hypertensive dogs, the hypertension is therefore due to a weakening of the kidney function. The arterial pressure is recorded by means of direct percutaneous puncture of the femoral artery, using a needle connected to a transfer instrument. After establishing control values, the dogs are treated for 4 days once daily, orally, with capsules containing the test compound. Blood pressure and heart rate are determined respectively 1.5, 3, 6 and 24 hours after each daily dose, and the results are compared with the control values obtained before the treatment. The properties of binding to 3-receptors that show a B-receptor effector, e.g. blocking effect of the mentioned new compounds is determined in a B-receptor binding test in vitro after a modification of the method described Life Sciences 17, 993 (1975).

<3>H-dihydroalprenolol is specifically bound by brain membrane preparations, and this interaction is prevented by known agonists and antagonists of B receptors.

For the binding test, 2 ml sample of the suspension of a membrane preparation (which roughly corresponds to 20 mg of calf heart caudate) in ice-cooled test tubes, containing<3>H-dihydroalprenolol with or without the test compound, has been freshly dissolved in 0.1% ascorbic acid. The final concentration of <3>H-dihydroalprenolol is 1.0 nM. The test compounds are examined within a wide concentration range. The test tubes are incubated for 10 minutes at 37°C and the suspension is then immediately filtered under vacuum through a fiberglass filter. The filters are washed with 15 ml of cold 50 mM tris-HCl (pH 7.9 at 25°C),

have together with 20 ml of scintillation solution in scintillation ampoules, first shake for 90 minutes and then examine the radioactivity with a counting tube.

The IC^q value indicates the concentration of the test compounds which is necessary to reduce the specific binding of 1.0 nM<3>H-dihydroalprenolol solution by around 50%. They are determined graphically. The compounds according to the invention inhibit the binding of dihydroalprenolol to B-receptors with an IC^q value of only 5 nM (5 x 10 ^M) or lower.

The antagonistic effect of the compounds according to the invention on B receptors can be shown in vitro by antagonism of the adrenaline activation of an adenylate cyclase preparation, originating from the cerebellum of a guinea pig (J. Neurochemistry, 22, 1031 (1974)).

The ability to bind to α-receptors is a reference to the inhibitory effect on α-receptors, e.g. demonstrated in vitro by the inhibition of the binding of the known α-blocker Prazosin (^H-Prazosin) to a synaptosomal membrane preparation from rat forebrain (Naunyn-Schmiedeberg's Arch. Pharmacol. 308, 223

(1979)).

The effect of the compounds according to the invention against glaucoma can be read from the intraocular pressure reduction that can be detected in mammals, e.g. on normotensive rabbits, essentially following that of D.E. Potter and J.M. Rowland in Experimental Eye Research 27, 615-625 (1978) described method. The intraocular pressure drop is determined as follows: two 50 µl portions of a solution of the test compound in sterilized water of different concentration are applied to male New Zealand albino rabbits weighing 3-4 kg to one eye, and two 50 µl portions of vehicle material are applied for control to the contralateral eye. The intraocular pressure (in mm Hg) in each eye is measured directly before treatment chronometrically, and then 1, 2 and 3 hours after administration. The difference in the intraocular pressure between the treated eye and the control eye is determined.

The preparation of compounds with formula is preferred

I, in which Ar means optionally substituted /phenyl, pyridyl, naphthyl, tetrahydronaphthyl, 3,4-dihydro-1(2H)-naphthalenoyl, 3,4-dihydro-2(1H)-quinolonyl, 3,4-dihydro-1( 2H)-isoquinolonyl,

12 3 4

indolyl or 1,2,5-thiadiazolyl/, R, R , R , R , R and X have the indicated meanings, as well as their salts, especially their pharmaceutically usable salts.

Highly preferred is a method for production

of compounds of formula I, wherein Ar means 1-naphthyl, 1(2H)-oxo-3,4-dihydronaphth-5-yl, 5,6,7,8-tetrahydro-cis-6,7-dihydroxynaphth-1- γ1, 4-indolyl, 3,4-dihydro-2(1H)-quino-lon-5-yl, 3-cyano-2-pyridyl or 4-(4-morpholino)-1,2,5-12 3 4

thiadiazol-3-yl, R, R , R , R , R and X have the indicated meanings, as well as their salts, especially their pharmaceutically usable salts.

Particularly preferred is a method for the preparation of compounds of formula I, in which Ar means phenyl which is optionally substituted by one to three substituents from the lower group (alkyl, alkenyl, alkynyl, alkanoyl, raono- or dialkylamino, alkanoylamino, alkylsulfonylamino, alkoxycarbonyl, alkylcarbamoyl , alkylsulfamoyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkenyloxy or

alkynyloxy), hydroxy, cyan, halogen, pyrrolyl, anino,

5-, 6- or 7-membered (alkylene-, oxaalkylene-, thiaalkylene)-imino, benzyloxy, phenyl, 5-, 6- or 7-membered cycloalkyl, carbamoyl, sulfamoyl or with 3-7-membered cycloalkyl-, phenyl -, hydroxy-, lower alkoxy-, lower alkoxycarbonylamino-, lower alkylthio-, lower alkylsulfinyl-, lower alkylsulfonyl- and carbamoyl-substituted (lower alkyl or lower alkoxy), R means hydrogen, lower alkanoyl or

12 1 aroyl, R and R mean hydrogen or lower alkyl, and R and R 2 together mean the alkyl with 2-5 carbon atoms, which separates the two nitrogen atoms, to which they are bound, by 2-4 carbon atoms, R<3> and R 4 mean hydrogen or lower alkyl, and X means 0 or S, as well as their salts, especially their pharmaceutically usable salts. Particularly preferred is a method for the preparation of the above-mentioned compounds of formula I, in which 1 2 R means hydrogen, R and R together mean the alkylene with 2-4 carbon atoms, whereby 5-, 6- or 7-membered 3 4 rings, R and R are hydrogen or lower alkyl, and X is 0 or S, as well as their salts, especially their pharmaceutically usable salts. First and foremost preferred is a method for preparing compounds of formula

in which R means hydrogen or lower alkanoyl, each of the symbols R and R means hydrogen, or R and R together means unbranched alkylene with 2-4 carbon atoms, R 3 and R<4>

independently means hydrogen or lower alkyl,

R 5 and R 6 independently mean hydrogen, lower (alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy or alkynyloxy), hydroxy, cyan, halogen, amino, lower (mono- or dialkylamino, alkanoylamino, alkylsulfonylamino, alkylthio, alkylsulfinyl or alkylsulfonyl ), morpholino,

1- or 2-pyrrolyl, phenyl, 5- to,7-membered cycloalkyl, lower alkanoyl, lower alkoxycarbonyl, carbamoyl or sulfamoyl, R also means lower alkyl or lower alkoxy, rest residues may be substituted with a substituent from the cycloalkyl group with 3 to 6 carbon atoms, phenyl, lower alkoxy, hydroxy, lower alkoxycarbonylamino, lower alkyl-(thio, sulfinyl or sulfonyl), or with carbamoyl, X means 0 or S, as well as their salts, especially their pharmaceutically usable salts.

A method for production is also preferred

3 4 5

of compounds of formula II, wherein R , R and R are hydrogen, R is lower alkyl, lower alkeny1, lower alkynyl, lower alkyl-(thio, sulfinyl or sulfonyl), lower alkoxy, lower alkenyloxy, lower alkynyloxy, cyano, lower alkoxycarbonyl, carbamoyl, lower alkanoylamino, morpholino, pyrrolyl or 5- to 7-membered cycloalkyl, R also means lower alkyl or lower alkoxy, which residues are substituted with cycloalkyl with 3-5 carbon atoms, phenyl, lower alkoxy or with carbamoyl, X means 0 as well as their salts, especially their pharmaceutically usable salts.

Of particular interest is a process for preparing compounds of formula III

3 7

where R means hydrogen or lower alkyl, R means cyan,

lower alkoxycarbonyl, pyrrolyl, morpholino, alkenyloxy of 3-6 carbon atoms, alkynyloxy of 3-6 carbon atoms or alkoxy of 1-3 carbon atoms, which is substituted by cyclopropyl, as well as their salts, especially their pharmaceutically usable salts.

The compounds with the formulas I, II and III can be present in

two isomeric forms, in which the two substituents on the cyclohexane ring are either cis or trans to each other. Furthermore, the asymmetric carbon atom which has the OR residue (hydroxy, alkanoyloxy or aroyloxy) in the compounds according to the invention can either have S or R configuration. Therefore, the compounds with the formulas I, II and III can appear in the form of stereoisomers, e.g. as geometric isomers, racemates purely enantiomers or mixtures thereof, all of which are covered by the invention.

Preferred are compounds with the formulas I, II and III, in which the two 1,4-cyclohexane substituents are cis to each other. Further preferred are enantiomers, in which the carbon atom which has the hydroxy, alkanoyloxy or aroyloxy group has the S configuration.

Of particular interest is a process for the preparation of compounds of formula III, in which R 3 means hydrogen, and R 7 means allyloxy, propargyloxy or cyclopropylmethoxy, their stereomers and enantiomers and their salts, especially their pharmaceutically usable salts. Particular preference is thereby given to cis stereoisomers and the S-enantiomers.

The method according to the invention for the preparation of compounds of formula I is characterized by reacting two compounds with each other or cyclizing a compound, these compounds or compounds respectively having the formula

12 3 4

wherein Ar, R, R , R , R and R have the above meaning,

1 2

and wherein one of the groups X and X is hydrogen, and the other acyl radical of a carboxylic acid half-derivative, or

1 12 2

in which either X together with R or X together with R,

means the group with formula =C=X (IVa), since X means 2

2

hydrogen and R means hydrogen or lower alkyl, or X"*" means hydrogen and R"*" means hydrogen or lower alkyl,

and since in the starting compound(s) of formula IV functional groups that do not participate in the reaction may be present in protected form, and possibly protected functional groups are transferred into free functional groups, and if desired, a formed compound of formula I is converted into another compound with formula I, and/or if desired, comforms a formed, free compound to a salt or a formed salt to a free compound or another salt, and/or if desired, splits the isomer mixture formed into the individual isomers.

In a starting material of formula IV, especially in a wherein

R 1 and R 2 together mean an alkylene group, the acyl radical of a carboxylic acid half-derivative X 1 or X 2 , e.g. corresponding radical of a carboxylic acid half-ester such as lower alkoxycarbonyl, e.g. methoxycarbonyl or ethoxycarbonyl, a carboxylic acid half-halide, such as halocarbonyl, e.g. chlorocarbonyl or bromocarbonyl, or a carboxylic acid hemiamide, e.g. 1-imidazolylcarbonyl.

One of the starting materials of formula IV, where R"<*>"andX"<*>"together or R<2>and X 2 together form a group of formula IVa, is an isocyanate or isothiocyanate, while the other

2 1 2

is an amine, in which X or X represents hydrogen, and R or R"'" represents hydrogen or lower alkyl.

In the starting material or materials of formula IV, functional groups present which could be reactive under the reaction conditions can be present in a protected form to avoid side reactions. The protecting groups are then removed again or cleaved off during the reaction.

Therefore, in all cases in which OR means hydroxy or Ar has a free hydroxy group, such a hydroxy group can e.g. protected as esterified hydroxy, e.g. as acyl-oxy, e.g. as lower alkanoyloxy, benzyloxy, carbonyloxy or lower alkoxycarbonyloxy or as etherified hydroxy, e.g. such as 2-tetrahydropyranoyloxy or benzyloxy. The protective group can then be removed and replaced with hydrogen, e.g. by means of solvolysis such as hydrolysis, alcoholysis or acidolysis, or by reduction as also by hydrogenolysis.

In a similar way, a free amino group can be protected, e.g. as an easily cleavable acyl derivative, e.g. as benzyloxycarbonylamino or as t-butyloxycarbonylamino, or as some easily cleavable amino protecting group,

as it usually finds application in peptide chemistry.

The protected amino group can then be released, e.g. by solvolysis such as hydrolysis or acidolysis, or by reduction such as hydrogenolysis.

The cyclization is carried out in the absence or presence of a solvent or diluent, and if necessary, in the presence of a condensing agent, preferably a basic condensing agent such as an alkali metal or alkaline earth metal hydroxide, carbonate, hydrogen carbonate or low-alkaline alkoxide, further by an organic base, such as a tertiary amine or a base of the pyridine type under cooling,

at room temperature or during heating, e.g. within a temperature range between approx. 0° and 150°C in a closed vessel and/or under a protective atmosphere.

Starting compounds of formula IV, especially those in which R 1 and R 2 together preferably mean lower alkylene, are prepared according to methods known per se, especially in situ, e.g. when converting a compound with formula

1 2

IV, wherein X and X are hydrogen, with a reactive derivative of carbonic acid. Reactive derivatives of carbonic acid are corresponding diesters, such as dilave alkyl carbonates, e.g. diethyl carbonate or diphenyl carbonate, or dihalides, such as phosgene, as also halocarbon esters, e.g. corresponding lower alkyl esters, such as chlorocarbonic acid lower alkyl esters, e.g. chlorocarbonic acid ethyl ester or chlorocarbonic acid isobutyl ester, further chlorocarbonic acid phenyl ester, or halocarbonic acid amides, e.g. chlorocarbonic acid amides or ureas, such as N,N'-carbonyldiimidazole. 1 2 The starting amine compounds of formula IV, in which X and X 1 2 mean hydrogen, and especially those in which R and R together mean lower alkylene, can e.g. is obtained when an N-(4-nitro-phenyl)-N'-R^ alkylenediamine is acylated with e.g. an alkanoyl halide or an anhydride, whereby a N-(4-nitro-phenyl)-N<1->R^-N,N'-diacylalkylenediamine is obtained, that the formed N-(4 -aminocyclohexyl)-N'-R 3-N,N1-diacylalkylenediamine is optionally mono-alkylated, e.g. with a reactive ester of a lower alkanol, is condensed with a 3-ArO-1,2-epoxypropane, and compounds of formula IV are obtained, in which X and X mean acyl, and this diacyl derivative is hydrolyzed. 12" The starting amine compounds of formula IV, wherein X and X 1 2

means hydrogen and especially those in which R and R together mean lower alkylene, can also be obtained by e.g. transfers 4-aminocyclohexanol to 4-aminocyclohexanol, reacts 4-aminocyclohexanone with 3-ArO-1,2-epoxypropane, and converts the carbonyl group in the ketone formed intermediate the desired amino group preferably by reacting this ketone with an N-R -lower alkylenediamine or with an X ^-lower alkylamine, in which X"^ is a group which can be transferred to an amino group of formula -NH-R 3 (Va) under simultaneous

subsequent treatment with a reducing agent, such as catalytically activated hydrogen, or a suitable reducing hydride reagent, e.g. sodium cyanoborohydride. With a formed intermediate step with a group X 3 which can be transferred through the amino group -NH-R 3 , this conversion is carried out and, if desired, its free secondary hydroxy group can be transferred in a manner known per se into a substituted RO group. Groups X 3 which can be transferred to the amino group -NH-R 3 are e.g. hydroxy or cyan, their conversion to a group of formula Va is carried out according to known methods. Thus a hydroxy compound is transferred, e.g. to a reactive, esterified hydroxy compound, e.g. to a halogen or an organic sulfonyloxy compound, treating it e.g. with a suitable esterifying agent such as thionyl halide or halide of an organic sulfonic acid, the reactive ester intermediate is then treated with an amine of formula H2N-R^ (V), while a cyan intermediate is transferred by reduction to the corresponding N-unsubstituted aminomethyl compound,

in a formed aminomethyl compound, the amino group can be mono-substituted with lower alkyl.

Isocyanate and isothiocyanate starting compounds in which and

In 2 2

R together (or instead X and R together) form a group of formula IVa, can be prepared, for example, by treatment with phosgene or thiophosgene, from the amines formed, in which

II 2 2

X and R (or instead of X and R ) mean hydrogen.

The preparation of the starting compounds, and if the starting compounds are formed in situ, the compound of formula I, takes place in the usual way, usually in the presence of an inert solvent, and if necessary, using a condensing agent, e.g. a basic condensing agent such as an alkali metal or alkaline earth metal hydroxide, carbonate or bicarbonate, e.g. sodium or potassium hydroxide, carbonate or hydrogen carbonate, or an alkali metal lavereal alkanolate, e.g. sodium methanolate or potassium tert-butylate, or an organic tertiary nitrogen base such as a tri-lower alkylamine, e.g. trimethylamine or triethylamine or pyridine, while cooling at room temperature or while heating, e.g. within a temperature range between approx. 0° and approx. 150°C, in a closed vessel and/or in an inert gas atmosphere.

The compounds which can be obtained by the method according to the invention can be transferred into one another according to conventional methods, since substituents which should not react in such conversions can be present in protected form.

For example, compounds of formula I, in which R means alkanoyl or aroyl, can be converted by hydrolysis with e.g. aqueous acid, such as hydrochloric acid or with an aqueous base,

as sodium hydroxide, to compounds of formula I in which R is hydrogen.

Conversely, compounds of formula I in which R means hydrogen can e.g. by condensation with a corresponding carboxylic acid or one of its reactive derivatives according to esterification procedures known in the art, preferably under non-basic conditions, are converted into compounds of formula I, in which R means alkanoyl or aroyl.

Furthermore, compounds of formula I, in which R 4 means hydro-

4

gene, is converted into a compound of formula I, in which R means lower alkyl, as they e.g. is reacted with a reactive esterified lower alkanol as a lower alkyl halide, or by carrying out a reductive alkylation, e.g. with formaldehyde and formic acid, resulting in a compound

4

of formula I, wherein R is methyl.

Compounds of formula I, where R 3 means hydrogen, can be converted into compounds of formula I, where R 3 means lower alkyl, by reacting them with a reactive derivative of a lower alkanol, e.g. with a lower alkyl iodide in the presence of a strong base such as sodium hydride in an inert solvent such as dimethylformamide.

Compounds of formula I which have a cyano group in the residue Ar can be converted into the corresponding carbamoyl compounds, e.g. in a basic or preferably in an acidic medium, especially in the presence of a strong mineral acid, such as e.g. concentrated hydrochloric acid.

In compounds of formula I which contain Ar in the residue

an amino group, the amino group can by reaction with a corresponding lower alkanesulfonic acid e.g. methanesulfonic acid optionally in the presence of a suitable condensation agent, e.g. N,N'-dicyclohexylcarbodiimide is converted to lower alkylsulfonyl amino. Instead of the free acid, a reactive derivative thereof can also be used, e.g. a halide such as chloride or bromide, or an acid anhydride.

Furthermore, a compound of formula I, as in the residue Ar

has a hydroxy group, this group is converted to lower alkyloxy, lower alkenyloxy or cycloalkyl-lower alkyloxy. The compounds or a salt thereof, such as an alkali metal, e.g. sodium salt, is thereby reacted with a reactive ester of an alcohol, which introduces said residues.

Furthermore, compounds of formula I in which X means oxygen, by sulphurizing agents, such as e.g. phosphorus pentasulphide, is converted into compounds, in which X means sulphur.

Depending on the selected starting materials and methods, the compounds may exist as one of the possible pure isomers or as isomeric mixtures, e.g. as pure geometric isomers (cis or trans), as pure optical isomers such as antipodes or as mixtures of optical isomers, such as e.g. racemates or as mixtures of geometric isomers.

Formed geometric or diastereomeric isomeric mixtures

of the above-mentioned compounds can be separated into the individual racemic or optically active isomers by methods known per se, e.g. by fractional distillation, crystallization and/or chromatography. Racemic products can be resolved to the optical antipodes, e.g. by separation of diastereomeric derivatives which according to J. Org. Chem. 43, 3803

(1978), e.g. by fractional crystallization of d- or 1-(tartrates, mandelates, camphor sulphonates or 1-naphthyl-f1-ethyl isocyanate derivatives) of compounds of formula I. Preferably, respectively, the most effective isomer and/or the most effective antipode of the compound according to the invention is isolated.

The compounds according to the invention are obtained either free or

in the form of their salts. Each free compound can be converted to a corresponding acid addition salt, preferably using an acid or an ion exchanger. Formed salts can be converted into the corresponding free compounds, for example using a base, for example a metal, especially ammonium hydroxide, or a basic salt, e.g. an alkali metal hydroxide or carbonate, or a cation exchanger. These or other salts, e.g. picrates, can also be used in the purification of the formed bases, as one transfers the bases into salts, separates and purifies them, and from the salts releases the bases again. Due to the close relationship between the free compounds and their salts, it is in this connection with free compounds, where possible and appropriate, to also understand the corresponding salts.

The compounds and their salts can also be obtained in the form of their hydrates or they can contain others, e.g. the solvents used for crystallization.

The invention also relates to modifications of the method according to which an intermediate product formed at one or other step of the method is used as starting material, and the remaining method steps are carried out or the method is interrupted at one or another step,

or according to which a starting material is formed under the reaction conditions, or in which a starting material is used in the form of a derivative, e.g. a salt or in the form of isomeric mixtures or pure isomers.

In the process, starting materials are preferably used which lead to the compounds of formula I mentioned above as particularly preferred. The preferred starting materials of formula IV are the respective cis isomers.

The compounds of formula I and their pharmaceutically acceptable non-toxic acid addition salts can be used as medicaments which can be administered enterally, orally, 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 suitable carriers.

Preferred pharmaceutical compositions are tablets

and gelatin capsules comprising the active ingredient together with a) diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine, b) lubricants, e.g. silicon dioxide, talc, stearic acid, or its magnesium or calcium salt, and/or polyethylene glycol,

for tablets also c) binders, e.g. magnesium aluminum silicate, starch pastes, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose and/or polyvinyl pyrrolidone, if desired d), disintegrating agent, e.g. starches, agar, alginic acid or its sodium salt, or foaming mixtures, and/or e), absorbents, coloring agents, flavoring agents and sweetening agents. Injectable preparations are preferably aqueous isotonic solutions or suspensions, and suppositories are preferably prepared from fat emulsions or suspensions. These compositions may be sterilized and/or contain auxiliary

substances such as preservatives, stabilisers, wetting and emulsifying agents, solubilizers, salts for regulating the osmotic pressure and/or buffers. In addition, they may also contain other therapeutically valuable substances. These preparations are produced according to the usual mixing, granulating or coating methods, and contain approx. 0.1

to 75%, preferably approx. 1 to 50% of the active ingredient.

The invention will be explained in more detail with the help of some examples. The temperatures are indicated in °C. When nothing else is mentioned, all evaporations are carried out under reduced pressure, preferably approx. 15 and 100 mm Hg.

Example 1.

A solution of 18 g of 1-[(4-(12-aminoethyl)-amino]-cyclohexyl [-amino_)-3-(2-allyloxy-phenoxy)-2-propanol (prepared as indicated below) in 100 ml of tetrahydrofuran, is treated with 8.5 g of N,N'-carbonyldiimidazole. The mixture is stirred for 4 hours under reflux, the tetrahydrofuran is removed under reduced pressure, and the residue is taken up in acetic acid. The solution is washed repeatedly with water, dried and evaporated under reduced pressure. The residue is taken up in 100 ml of isopropanol and heated under reflux. While stirring, 2.9 is added

g fumaric acid. It is stirred further until the fumaric acid has completely dissolved. On standing and cooling, the hemifumarate of cis-1-4-//3-(2-allyloxyphenoxy)-2-hydroxypropyl7-amino/-cyclohexyl}-2-imidazolidinone crystallizes out.

After recrystallization from ethanol, the pure cis-isomer is obtained, m.p. 156-157°C.

A solution of 1575 g of this salt in 7875 ml of water is mixed with a solution of 4.356 mol of potassium carbonate in 790 ml of water. cis-1-4-//3-(2-allyloxyphenoxy)-2-hydroxypropyl/-amino/-cyclohexyl3-2-imidazolidinone is obtained as an oil. As discussed above, it can be transferred to a salt as in a hemifumarate of great purity.

The starting material can be prepared as follows: 36.2 g of N-(4-nitrophenyl)-ethylenediamine (F.Linsker and R.L. Evans,

J. Org. Chem. 10, 283 (1945)) is heated slowly at room temperature to a solution of 30 g of acetic anhydride in 100 ml of 1,2-dimethoxyethane. The mixture is then heated for 1 hour on a steam bath. After cooling, the mixture is evaporated under reduced pressure. The residue is taken up in methylene chloride and water, then adjusted by adding 5N caustic soda to pH 9-10. The methylene chloride phase is washed with a 10% aqueous sodium carbonate solution, dried and evaporated to dryness. The crude N-(2-acetylamino-ethyl)-N-(4-nitrophenyl)-acetamide is obtained, which is used without further purification.

25g of 5% rhodium on charcoal (water content from 50%) is added to a mixture of N-(2-acetylaminoethyl)-N-(4-nitrophenyl)-acetamide and 500 ml of water. The mixture is hydrogenated within a temperature range of 46-50°, and under a pressure of 3 atmospheres, until approx. 0.9 moles of hydrogen. The mixture is filtered and evaporated under reduced pressure. A viscous residue is obtained which consists of a mixture of cis- with smaller amounts of trans-N-(2-acetylaminoethyl)-N-(4-aminocyclohexyl)-acetamide.

A solution of 24 g of N-(2-acetylaminoethyl)-N-(4-amino-cyclohexyl)-acetamide (predominantly cis-isomers) and 21 g of 1-(2-allyloxyphenoxy)-2,3-epoxypropane in 200 ml of isopropanol , stirred for 6 hours and heated under reflux, then evaporated to dryness. The residue is taken up in 400 ml of 50% aqueous ethanol, in which it has previously been dissolved 24

g of sodium hydroxide. The mixture is refluxed for 4 hours, then partially evaporated to remove ethanol. After adding 20 g of sodium chloride, the mixture is extracted again with methylene chloride. The organic phase is washed with water, dried and evaporated under reduced pressure. The crude 1-[(4-(T2-aminoethyl)-amino/-cyclohexyl7-amino.3 ~ 3-(2-allyloxyphenoxy)-2-propanol (predominantly cis isomers) is obtained.

The following compounds can be prepared according to the method described in example 1, selecting the suitable starting compounds.

2.1 cis-1-[4-(2-cyclopropylmethoxy-phenoxy)-2-hydroxy-propyl-7-amino-7-cyclohexyl-2-imidazolidinone, m.p. of hemifumarates 168-170°C (from ethanol) by reaction of cis-1-^"/4~-/T2-aminoethyl)-amino7-cyclohexyl7_aminoJ - 3-( 2-cyclopropylmethoxyphenoxy)-2-propanol with N,N' -carbonyldiimidazole;

2.2 (S)-cis-1-f4-(73'-(2-cyclopropyl-methoxy-enoxy)-2-hydroxypropyl-7-amino-7-cyclohexyl}-2-imidazolideinone, m.p.

of hemifumarates 147-149°C; / a. 7^ 5 = -8.41° (c = 1.35 in methanol), by reaction of (S)-cis-1-fr/3-/T2-aminoethyl 1)-amino7-cyclohexyl7-aminoJ- 3-(2-cyclopropylmethoxyphenoxy)-2-propanol with N,N'-carbonyldiimidazole;

2.3.

--25

of the hemifumarate 150-152°C during decomposition, Z<i./D = +8.26°

(c = 1.36 in methanol), by reaction of (R)-cis-1-//4-(2-aminoethyl)-amino7-cyclohexyl7-aminoq}-3-(2-cyclopropyl-methoxyphenoxy)-2 -propanol with N,N<1->carbonyl-diimidazole;

2.4 trans-1-{4-[73-(2-cyclopropylImethoxyphenoxy)-2-hydroxy-propyl7-amino7-cyclohexylJ-2-imidazolidinone, m.p. of the hemifumarate 178-180°C (from isopropanol), by reaction of trans-1-//5-/T2-aminoethyl)-amino7~cyclohexy17-amino}-3-(2-cyclopropylmethoxyphenoxy)-2-propanol with N, N'-carbonyldiimidazole;

2.5 cis-1-[4/73-(2-methoxyphenoxy)-2-hydroxypropyl-7-amino7-cyclohexyl-2-imidazolidinone, m.p. of the hemifumarate 190-192°C (from a mixture of isopropanol and methanol),

by reacting cis-1-((β-aminoethyl)-amino7-cyclohex-syl7-aminoqj-3-(2-methoxyphenoxy)-2-propanol with N,N'-carbonyl-diimidazole;

2.6 cis-1-{4-(β3-(2-propargyloxyphenoxy)-2-hydroxypropyl7-amino7-cyclohexyl}-2-imidazolidinone, m.p. of the hemifumarate 168° (from 95% ethanol), by reaction of cis-1-f/4-/T2-aminoethyl)-amino/-cyclohexyl/-aminoJ-3-(2-propargyloxyphenoxy)-propanol with N,N' -carbonyl-diimidazole;

2.7 trans-1-(4-//3-propargyloxyphenoxy)-2-hydroxypropyl/-amino/-cyclohexyl-2-imidazolidinone, m.p. of hemifumarate 92-98°C, by reaction of trans-1-f74-(72-aminoethyl)-amino/- cyclohexyl/-aminoJ -3-(2-propargyloxyphenoxy)-2-propanol with N,N<1-> carbonyldiimidazole;

2.8 cis-1-f4-[73-(3-propargyloxyphenoxy)-2-hydroxypropyl]amino]-cyclohexyl-2-imidazolidinone, m.p. of hemifumarate 177°C (from ethanol), by reaction of cis-1-//4-/(2-aminoq/_ cyclohexyl7-amino_}-3-( 3-propargyloxyphenoxy)-2-propanol with N,N< 1->carbonyl-diimidazole;

2. 9 cis-1- [ 4-/_ 7_ 3-( 4-propargyloxyphenoxy)-2-hydroxypropyl7_

amino7-cyclohexylJ-2-imidazolidinone, m.p. of the 1:1 fumarate 95-100°C (isopropane solvate from isopropanol) by reaction of cis-1-f/ 4-/r2-aminoethyl)-amino/-cyclohexy 1/-amino}-3-(4-propargyloxyphenoxy)- 2-propanol with N,N<1->carbonyl-diimidazole;

2.10 cis-1-2r4-//3-(2-cyanophenoxy)-2-hydroxypropyl7-amino7-cyclohexyl-2-imidazolidinone, m.p. of the hemifumarate 192°C during cleavage from ethanol), by reaction of cis-1-((74-/T2-aminoethyl)-amino7-cyclohexyl7-aminoJ-3-(2-cyano-phenoxy)-2-propanol with N,N <1->carbonyl-diimisazole;

2. 11 trans-1-^4-[73-(2-cyanophenoxy)-2-hydroxypropyl7~

amino7-cyclohexyl}-2-imidazolidinone, m.p. of the hemifumarate 215-216°C (from ethanol), by reaction of trans-1-/"/4-/T2-aminoethyl)-amino7-cyclohexyl7-aminoJ-3-(2-cyanophenoxy)-2-propanol with N, N'-carbonyldiimidazole;

2. 12 cis-1-{4-[73-/2-(1-pyrrolyl)phenoxy_/-2-hydroxy-propyl/-amino/-cyclohexyl}-2-(imidazolidinone, m.p. of the hemifumarate 144°C with decomposition (from ethanol), by reaction of cis-1-[(4-[72-aminoethyl)-amino]^cyclohexyl[^-amino]-3-(2-(1-pyrrolyl)-phenoxy)-2-propanol with N,N'-carbonyldiimidazole; 2. 13 cis-1-(4-(2-pyrrolyl)-phenoxy7-2-hydroxypropyl-(amino)-cyclohexyl)-2-imidazolidinone, m.p. of the hemifumarate 130-134°C (from ethanol) by reaction of cis-1-f/4-(T2-aminoethyl)-amino7-cyclohexyl7-aminoq}-3-(2-pyrrolyl)-phenoxy7-2-propanol with N ,N<1->carbonyldiimidazole; 2. 14 cis-1-A-//3-/2-(4-morpholino)-phenoxy7-2-hydroxy-propyl7-amino7-cyclohexyl}-2-imidazolidinone, m.p. of the hemifumarate 114-118°C (from ethanol), by reaction of cis-1-//4-/12-aminoethyl)-amino7-cyclohexyl7-aminoJ-3-/2-(4-morpholino)-phenoxy7~2- propanol with N,N<1->carbonyl-diimidazole; 2.15 cis-1-/"4-//3-/4-( 2-me toc sy e ty 1) - phenoxy 7~ 2-hydroxy propyl7_amino7-cyclohexylJ-2-imidazolidinone, m.p. of the hemifumarate 166- 168°C (from isopropanol), by reacting cis-1-[4-(12-aminoethyl)-amino7-cyclohexyl]-amino}-3-(4-(2-methoxyethyl)-phenoxy7-2-propanol with N,N<1->carbonyl-diimidazole ; 2. 16 cis-1-(4-//3-(2-benzyloxyphenoxy)-2-hydroxypropyl7~amino7-cyclohexyl}-2-imidazolidinone, m.p. of the hemifumarate 141- 146°C (from ethanol), by reaction of cis-1-//4-/T2-aminoethyl)-amino7-cyclohexyl7_aminoJ - 3-(2-benzyloxyphenoxy)-2-propanol with N,N<1-> carbonyl-diimidazole; 2.17 cis-1-f4-//3-(2-carbamoylphenoxy)-2-hydroxypropyl 1/amino7-cyclohexyl-2-imidazolidinone, m.p. of the hemifumarate 110°C, by reaction of cis-1 -//4-/T2-aminoethyl)-amino/- cyclohexyl7_aminoJ - 3-(2-carbamoylphenoxy)-2-propanol with N,N<1->carbonyl-diimidazole; 2.18 cis-1-/4-/23-Z2 -(2-methylpropoxy)-phenoxY/-2-hydroxy-propyl/-amino/-cyclohexylJ-2-imidazolidinone, mp of the hemifumarate 170-172°C (from ace ton), by reaction of cis-1-(/_$-/_{ 2-aminoethyl)-aminoq/-cyclohexy 1/-amino}-3-/2-( 2-methylpropoxy)-phenoxy_/-2- propanol with N,N'-carbonyl-diimidazole; 2.19 cis-1-{4-/_/ 3-(2-cyclohexylphenoxy)-2-hydroxypropyl/- aminoq/-cyclohexyl}-2-imidazolidinone, m.p. of the hemifumarate 117-120°C (hydrate from a mixture of isopropanol and acetone), by reaction of cis-1-^/4-/(2-aminoethyl)-aminoq/-cyclohex-syl/-amino3-3-(2 -cyclohexylphenoxy)-2-propanol with N,N'-carbonyldiimidazole; 2. 20 cis-1-(4-//J-(2-methoxycarbonylphenoxy)-2-hydroxy-propyl/-amino/-cyclohexyl3-2-imidazolidinone, m.p. of the hemifumarate 135-138°C (from a mixture of isopropanol and acetone), by reaction of cis-1-/'/4-/r2-aminoethyl)-amino/- cyclohexyl/-aminoJ-3-(2-methoxycarbonylphenoxy) -2-propanol with N,N<1->carbonyl-diimidazole; 2. 21 cis-1-/"4-//3-(2-phenylphenoxy)-2-hydroxypropyl 1/amino7-cyclohexylJ-2-imidazolidinone, m.p. of the hemifumarate 146-148°C (from isopropanol), at reaction of cis-1-(1_4-1_(2-aminoethyl)-amino/-cyclohexyl/-aminoq}-3-(2-phenyl-phenoxy)-2-propanol with N,N'-carbonyl-diimidazole; 2.22 cis-1-^4-//3-(4-benzoyloxyphenoxy)-2-hydroxypropyl/- amino/-cyclohexyl}-2-imidazolidinone, m.p. of the hydrochloride 159-161°C (from ethanol), by reaction of cis -1-f/4-((T2-aminoethyl)-amine/-cyclohexyl/-aminoJ -3-(4-benzyloxy-phenoxy)-2-propanol with N,N'-carbonyl-diimidazole; 2. 23 trans-1-{ 4-//3-(2-allyloxyphenoxy)-2-hydroxypropyl/-amino/-cyclohexylJ-2-imidazolidinone, m.p. of the hemifumarate 149-150°C (from ethanol), by reaction of trans-1-/"/ 4-((T2-aminoethyl)-amino7-cyclohexyl)-aminoJ-3-(2-allyloxy-phenoxy)-2-propanol with N,N<1->carbonyl-diimidazole; 2. 24 cis-1-/"4-/73-( 2-allylphenoxy)-2-hydroxypropyl/-amino/-cyclohexyl3-2-imidazolidinone, m.p. of the hemifumarate 158-159°C (from a mixture of isopropanol and acetone), by reaction of cis-1-((74-)(T2-aminoethyl)-amino/-cyclohexyl7-aminoj-3-(2-allylphenoxy)-2-propanol with N,N'-carbonyl-diimidazole; 2. 25 cis-1-/*4-//3-( 2-cyclopropyl Ime to syphenoxy)-2-hydroxypropyl7_amino7-cyclohexyl}-3-methyl-2-imidazolidin-one, m.p. of the hemifumarate 145-147°C , by reaction of cis-1-[74-(12-methylaminoethyl)-amino7-cyclohexyl7-aminoJ-3-(2-cyclopeopylmethoxyphenoxy)-2-propanol with N,N'-carbonyl-diimidazole ; 2. 26 cis- 1-/"4-/N-/3-(2-allyloxyphenoxy)-2-hydroxypropyl7-N-methylamino7-cyclohexyl}-2-imidazolidinone, m.p. by at the hydrochloride 80°C during cleavage (from acetic acid ester), by reaction of cis-1-fN-/4-/T2-aminoethyl)-amino7~cyclohexyl7_N-methylaminoq}-3-(2-allyloxyphenoxy)-2-propanol with N,N<1->carbonyldiimidazole; 2. 27 cis-1-(4-//3-(4-chloro-1,2,5-thiadiazol-3-yloxy)-2-hydroxypropyl7_amino7_cyclohexyl}-2-imidazolidinone, m.p. from the hemifumarate 163°C (from isopropanol), by reaction of cis-1-f/4-(T2-aminoethyl)-amino7_cyclohexyl7_aminoJ - 3-(4-chloro-1,2,5-thiadiazol-3-yloxy)-2 -propanol with N,N'-carbonyldiimidazole; 2. 28 cis-1-/"4-/73- (1-naphthylocsy)-2-hydroxypropyl7-amining7-cyclohexylj-2-imidazolidinone, by reaction of cis-1-^"/4-/T2- aminoethyl)-amino7-cyclohexyl7-aminoJ-3-(1-naphthyloxy)-2-propanol with N,N'-carbonyl-diimidazole; 2. 29 cis-1-/4-//3-(4-indolyloxy)-2-hydroxypropyl7-amino7-cyclohexyl-2-imidazolidinone, by reaction of cis-1-{/ 4-/ T2-aminoethyl)-amino7 -cyclohexyl-7-aminoq-3-(4-indolyl-oxy)-2-propanol with N,N'-carbonyl-diimidazole; 2. 30 cis-1-f4-[73-(3-cyano-2-pyridyloxy)-2-hydroxy-propyl7-amino7-cyclohexyl3-2-imidazolidinone, by reaction of cis-1- //4-/r2- aminoethyl)-amino7-cyclohexyl7-aminoJ-3-(3-cyano-2-pyridyloxy)-2-propanol with N,N'-carbonyl-diimidazole; 2. 31 cis-1-{4-/73-(4-carbamoylmethylphenoxy)-2-hydroxy-propyl7-amino7-cyclohexyl3-2-imidazolidinone, by reaction of cis-1-//4-/T2-aminoethyl)- amino7_cyclohexyl7-aminoJ - 3-(4-carbamoylmethylphenoxy)-2-propanol with N,N<1->carbonyl-diimidazole; and 2. 32 cis-1-(4-//3-(2(1H)-oxo-3,4-dihydro-5-quinolinyloxy)-2-hydroxypropyl7-amino7-cyclohexyl-2-imidazolidinone,

by reacting cis-1-[(4-([2-aminoethyl)-amino7~cyclohexyl7-amino]-3-(2(1H)-oxo-3,4-dihydro-5-quinolinyloxy)-2-propanol with N,N<1->carbonyl-diimidazole.

Example 3.

On treatment of 1-(4-aminocyclohexyl)-amino-3-(2-allyloxyphenoxy)-2-propanol with ethyl isocyanate, 1-{4-/73-(2-allyloxyphenoxy)-2-hydroxypropyl7_amino7-cyclohexyl}-3 is obtained - ethyl urea, whose hemifumarate after washing with a little acetone/methanol (9:1) melts at 159-160°C.

Example 4.

On treatment of cis-1-/4-/73-(2-cyclopropylmethoxy-phenoxy)-2-hydroxypropyl7-amino7-cyclohexyl-2-imidazo-lidinone with benzoyl chloride in the presence of pyridine, cis-1-/4-/73 is obtained -(2-cyclopropylmethoxyphenoxy)-2-benzoyloxypropyl7-amino7_cyclohexyl}-2-imidazolidinone.

In an analogous manner, treatment of cis-1-<f4-(2-cyclopropylmethoxyphenoxy)-2-hydroxypropyl7-amino7-cyclohexyl-2-imidazolidinone with nicotinoyl chloride in the presence of pyridine gives cis-1-/4- /73-(2-cyclopropylmethoxyphenoxy)-2-(3-pyridylcarbonyloxy)-propyl7-amino/-cyclohexyD-2-imidazolidinone and by treatment of cis-1-/"4-//3 - ( 2- allyloxy enoxy)-2-hydroxypropyl/-amino7-cyclohexyl}-2-imidazolidinone with acetyl chloride in the presence of pyridine, cis-1-/"4-/<7>3-(2-allyloxyphenoxy)-2-acetyloxypropyl/- amino[-cyclohex-syl}-2-imidazolidinone.

Example 5.

Tablets with a content of each 10 mg of the active substance according to example 1:

Ingredients for 10,000 tablets:

Procedure: Sieve all powdery ingredients with a sieve of 0.6 mm mesh size. The active substance is then mixed with milk sugar, talc, magnesium stearate and with half of the starch in a suitable mixer. The other starch half is suspended in 40 ml of water, and the suspension is added to the boiling solution of polyethylene glycol in 150 ml of water. The resulting paste is made into powders, and possibly granulated with the addition of a further amount of water. The granulate is dried for 16 hours at 35°C, driven through a sieve of 1.2 mm mesh size, and pressed into tablets with a diameter of 6.4 mm which have a breaking drill.

Claims (13)

1. Process for the preparation of compounds of formula in which Ar means a monocyclic or optionally partially saturated bicyclic carbocyclic or heterocyclic aromatic residue, R means hydrogen, alkanoyl or aroyl, R and R 2 independently mean hydrogen or lower alkyl, or R 1 and R<2> together mean the alkylene with 2 -7 carbon atoms, which separate the two nitrogen atoms to which they are bound, 3 4 with 2-4 carbon atoms, R and R independently mean hydrogen or lower alkyl, and X means oxo (0) or thio (S) and their salts, characterized in that two compounds react with each other or are cyclized in a compound, as these compounds or compound, respectively, have the formula 12 3 4 in which Ar, R, R , R , R and R have the above meaning, 1 2 andwherein one of the groups X and X means hydrogen, and the other acyl radical of a carboxylic acid half-derivative, or 1 12 2 in which either X together with R or X together with R be represents the group of formula =C =X (IVa), since X 2 means hydrogen and R 2 means hydrogen or lower alkyl, or X <1> means hydrogen and R"*" means hydrogen or lower alkyl, and while in the starting compound or compounds with formula IV functional groups that do not participate in the reaction are in protected form, optionally protected functional groups are transferred into free functional groups, and if desired, a formed compound of formula I is converted into another compound of formula I, and/or if desired, a formed free compound is converted into a salt or a formed salt into a free compound or another salt, and/or if desired, a formed isomer mixture is separated into its isomers. 2. Method according to claim 1, in that in the starting material 1 2 als of formula IV, in which R and R together preferably form an alkylene group as defined in claim 1, means acyl-1 2 radical of a carboxylic acid half-derivative, X or X means the corresponding radical of a carboxylic acid half-ester, a carboxylic acid half-halide or a carboxylic acid half amide. 3. Method according to claim 1, in which an initial 1 2 bond with formula IV, in which R and R together form an alkylene group as defined in claim 1, is formed by reacting a starting compound with formula IV, in which both X" <*> " and X 2 mean hydrogen, m situ with a reactive derivative of the carbonic acid. 4. Method according to claim 3, where a reactive derivative of carbonic acid is a corresponding diester such as a dilower alkyl carbonate, a dihalide such as phosgene, a halocarbonic acid ester such as a halocarbonic acid lower alkyl ester, a halocarbon amide or a urea, such as N,N'-carbonyldiimidazole. 5. Process according to one of claims 1-4, characterized in that compounds of formula I or their salts are prepared, in which Ar means optionally substituted /phenyl, pyridyl, naphthyl, tetrahydronaphthyl, 3,4-dihydro-1(2H)-naphthalenonyl , 3,4-dihydro-2-(1H)-quinolony1, 3,4-dihydro-1(2H)-isoquinolonyl, indolyl 12 3 4 or 1,2,5-thiadiazolyl/, and R, R , R , R , R and X have the meaning specified in claim 1. 6. Process according to one of claims 1-4, characterized in that compounds of formula I or their salts are prepared, in which Ar means phenyl, optionally substituted with 1-3 substituents from the groups (alkyl, alkenyl, alkynyl, alkanoyl, mono- or dialkylamino, alkanoylamino, alkylsulfonylamino, alkoxycarbonyl, alkylcarbamoyl, alkylsulfamoyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkenyloxy or alkynyloxy), hydroxy, cyan, halogen, pyrrolyl, amino, 5-, 6- or 7-membered (alkylene-, oxaalkylene- . -, lower alkylsulfonyl- and carbamoyl substituted (lower alkyl or lower alkoxy), R means hydrogen, lower alkanoyl or aroyl; R 1 and R <2> mean hydrogen or lower alkyl, or R 1 and R 2 together mean the alkylene of 2-5 carbon atoms, which separates the two nitrogen atoms to which they are attached, of 2-4 carbon atoms, R <3> and R 4 mean hydrogen or lower alkyl, and X means 0 or S. 7. Process according to one of claims 1-4, characterized in that compounds of formula I or their salts are prepared, in which Ar has the meaning stated in claim 6, R means hydrogen, R" <*> " and R 2 together mean the alkyl with 2-4 carbon atoms, whereby 3 4 5-, 6- or 7-membered rings are formed, R and R mean hydrogen or lower alkyl, and X means 0 or S. 8. Method according to one of claims 1-4, characterized in that compounds with formula are prepared or their salts, in which R means hydrogen or lower alkanoyl, each of the symbols R and R <2> means hydrogen or R 1 and R 2 together means unbranched alkylene of 2-4 carbon-3 4 atoms,.R and R independently mean hydrogen 5 6 or lower alkyl, R and R independently mean hydrogen, lower (alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy or alkynyloxy), hydroxy, cyan, halogen, amino, lower (mono- or dialkylamino, alkanoylamino, alkylsulfonylamine, alkylthio, alkylsulfinyl or alkylsulfonyl), morpholino, 1- or 2-pyrrolyl, phenyl, 5 to 7-membered cycloalkyl, lower alkanoyl, lower alkoxycarbonyl, carbamoyl or sulfamoyl, R^ also means lower alkyl or lower alkoxy, which residues may be substituted with a substituent from the cycloalkyl group with 3-6 carbon atoms, phenyl, lower alkoxy, hydroxy, lower alkoxycarbonylamino, lower alkyl(thio), sulfinyl or sulfonyl), or with carbamoyl, and X means 0 or S. 9. Method according to one of claims 1-4, characterized in that compounds of formula II according to claim 8 are prepared, or:: their salts, in which R, R 1 and R 2 have the meaning stated in claim 8, R"^, R4 and R5 mean hydrogen, R means lower alkyl, lower alkenyl, lower alkynyl, lower alkyl-(thio, sulfinyl or sulfonyl), lower alkoxy, lower alkenyloxy, lower alkynyloxy, cyano, lower alkoxycarbonyl, carbamoyl, lower alkanoylamino, morpholino, pyrrolyl or 5- to 7-membered cycloalkyl, R <6> also means o lower alkyl or lower alkoxy, which residues are substituted with cycloalkyl with 3-5 carbon atoms, phenyl, lower alkoxy or with carbamoyl, and X means 0. 10. Method according to one of claims 1-4, characterized in that compounds with formula are prepared 3 or their salts, wherein R is hydrogen or lower alkyl, and R 7 is cyano, lower alkoxycarbonyl, pyrrolyl, morpholino, alkenyloxy of 3-6 carbon atoms, alkynyloxy of 3-6 carbon atoms, or alkoxy of 1-3 carbon atoms, which is substituted by cyclopropyl . 11. Process according to one of claims 1-4, characterized in that cis-1-f4-//3-(2-allyloxyphenoxy)-2-hydroxypropyl/-amino/-cyclohexyl}-2-imidazolidinone or a salt thereof is prepared . 12. Method according to one of claims 1-4, characterized in that cis-1- /4-//3-(2-cyclopropylmethoxyphenoxy)-2-hydroxy-propyl7-amino/-cyclohexyl-2-imidazolidinone or a salt is prepared of this. 13. Process according to one of claims 1-4, characterized in that it is produced. (S)-cis-1-A-//3-(2-cyclopropylmethoxyphenoxy)-2-hydroxy-propyl7-amino/-cyclohexyl]-2-imidazolidinone or a salt thereof.