DD210266A5 - PROCESS FOR PREPARING 3- (UREIDOCYCLOHEXYLAMINO) PROPANE-1,2-DIOLDERIVATE - Google Patents

Abstract

The invention relates to cardiocasculatory compounds of the formula I, wherein Ar is a (monocyclic or optionally partially hydrogenated bicyclic) carbocyclic or heterocyclic, optionally substituted aromatic radical, R is hydrogen, alkanoyl o.Aroyl, R deep1 uR deep2 independently of one another hydrogen or lower alkyl or R deep1 and R deep2 together represent alkylene having 2 to 7 carbon atoms, which mean the two nitrogen atoms of 2 to 4 carbon atoms separating the two nitrogen atoms by 2 to 4 carbon atoms, R deep3 and R deep 4 independently of one another hydrogen or lower alkyl and X is oxo (O) o.Thio (S), their salts, in particular therapeutically usable salts, as well as processes for their preparation, pharmaceutical preparations containing these compounds, as well as their therapeutic use. They can, for example, by reduction of a corresponding formula I. Verbind.worin instead of the 1,4-cyclohexyle nrestes is a 1,4-phenylene radical can be prepared.

Description

Berlin, 13,10,1983

AP C 07 D / 2 51 330/5 62 512/11

Process for the preparation of nsuen 3- (ureidocyclohexylaraino) -propane-1,2-diolderivatan

Field of application of the invention

The invention relates to a process for the preparation of 3- (ureidocyclohaxylaminoypropane-1,2-diol derivatives having valuable pharmacological, especially cardiovascular, z, 3, antihypertensive properties *

The compounds prepared according to the invention are used as medicaments, for example for the treatment, handling and prevention of cardiovascular conditions, such as hypertension or cardiac disorders, such as i-cardiac arrest, cardiac arrhythmia or angina pectoris.

Characteristic of the known technical solutions

In the US-PS 4 632 26C are 1-heterocyclyloxy or 1-aryloxy-3 ~ described amidoalkylainino-2-propanol derivatives which 'are used as S-31ocker.

No compounds of the type registration are abar is in the open literature present been found "

The aim of the invention is the provision of new compounds with cardiovascular, z, 3 "anti-hypertensive Wirkun conditions.

Explanation of the essence of the invention

The invention is based on the object, r, eua compounds

13.10.1983 A? C 07 D / 251 330/6 - la - 62 512/11

with the desired properties and processes for their preparation aufzufindan.

According to the invention, novel compounds of the formula I

i Cj - \ r

ArG-CH ₀ -CH-CH ₀ -M- / * -NN-R "(I) 2 2 ^ j ^ _c ^ 5

wherein Ar is a (monocyclic or optionally partially hydrogenated bicyclic) carbocyclic or heterocyclic, optionally substituted aromatic Rast, R is hydrogen, alkanoyl or aroyl, R ^ and Rp are independently hydrogen or Niaderalkyl or R ₁ and R ₀ together with alkylene 2 to 7 carbon atoms separating the two nitrogen atoms by 2 to 4 carbon atoms, R "and R are unabhänoia represent hydrogen or lower alkyl, and X is oxo (0) or thio (3) means, as well as their salts, especially therapeutically useful salts

The above compounds of formula I are preferred wherein Ar ₁ is optionally substituted /! Phenyl, pyridyl, naphthyl, Tet ranydronapht hy 1, 3, 4-0ihydro-l- (2H) -naphthalenone _i 3,4-dihydro-2- (IH ) quinolone _f 3,4-dihydro-i (2H) -isocene inolone, indolyl or i _} 2 , 5-thiadiazolyl], and their salts, in particular their therapeutically acceptable salts *

Very particular preference is given to compounds of the formula I in which Ar 1-naphthyl, 1 (2H) -oxo-3,4-dihydronaphth-6-yl, 5,5,7,8-tetra-2-hydroxy-cis-6, 7-dihydroxy-

naphth-1-yl, 4-indolyl, 3,4-dihydro-2 (1H) -quinolone-5-yl, 3-cyano-2-pyridyl or 4- (4-morpholinyl) -l, 2, -5- thiadia2ol-3-yl, and their salts, especially their therapeutically acceptable salts.

Particular preference is given to compounds of the formula I in which Ar is optionally substituted by one to three substituents of the group lower (alkyl, alkenyl, alkynyl, alkanoyl, mono- or dialkylamino, alkanoyl-amino, alkylsulfonylamino, alkoxycarbonyl, alkylcarbanioyl, alkylsulfamoyl, alkoxy, alkylthio , Alkylsulfinyl, alkylsulfonyl, alkenyloxy or alkynyloxy), hydroxy, cyano, halogen, pyrrolyl, amino, 5-, 6-odar 7-membered (alkylene, oxaalkyiene, thiaalkylene) imino, benzyloxy, phenyl, 5-, 6- or 7-membered cycloalkyl, carbamoyl, sulfamoyl or by 3- to 7-membered cycloalkyl, phenyl, hydroxy, lower alkoxy, Miederalkoxycarbony! Amino, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl and carbamoyl-substituted (lower alkyl or lower alkyl ) substituted phenyl, R is hydrogen, lower alkylanoyl or aroyl; R and R _? Or R and R ^ together are alkylene having 2 to 5 carbon atoms, R ~ and R _{A are} hydrogen or lower alkyl · and X is O or S and their salts, in particular their therapeutically acceptable salts.

Very particular preference is given to the abovementioned compounds of the formula I in which R is hydrogen; R-. and R together represent alkylene of 2 to 4 carbon atoms to form 5-, 6- or 7-membered rings; R and R _{A are} hydrogen or lower alkyl, and X is _O or 5, and their salts, in particular their therapeutically acceptable salts.

Most preferred are compounds of formula II

- Q -

wherein R represents hydrogen or lower alkanoyl; each of R ₁ and R _{9 is} hydrogen or R ₁ and R ₁ together are unbranched alkyl having 2 to 4 carbon atoms; R ^ and R independently represent hydrogen or lower alkyl; R, and R independently of one another are hydrogen, lower (alkyl, alkenyl or alkynyl), lower (alkoxy, alkenyloxy or alkynyloxy), hydroxy, cyano, halogen, amino, lower (mono- or dialkyiamino, alkanoyl-amino or alkylsulfonylamino), lower Alkylthio, alkylsulfinyl or alkylsulfonyl), morpholine, 1- or 2-pyrrolyl, phenyl, 5- to 7-membered cycloalkyl, lower alkanoyl, lower alkoxycarbonyl, carbamoyl or sulfamoyl; R 1 - also lower alkyl or lower alkoxy means which radicals may be substituted by a substituent of the group cycloalkyl having 3 to 6 carbon atoms, phenyl, lower alkoxy, hydroxy, lower alkoxycarbonyl, lower alkyl (thio, sulfinyl or sulfonyl), or by carbamoyl; X is 0 or S-; and their salts, especially their therapeutically acceptable salts.

Preference is furthermore given to compounds of the formula II in which each of the symbols R_ and R _{A is} hydrogen; R is hydrogen; R, lower alkyl, lower alkenyl, lower alkynyl, lower alkane, -! - (thio, sulfinyl or sulfonyl), lower alkoxy, lower alkenyloxy, lower alkynyloxy, cyano, lower alkoxycarbonyl, carbamoyl, lower alkanoylanino, morpholino, pyrrolyl or 5- to 7-membered cycloalkyl; R ,. also represents lower alkyl or lower alkoxy, which radicals are substituted by cycloalkyl having 3 to 5 carbon atoms, by phenyl, by lower alkoxy or by carbamoyl; X 0 and their salts, in particular their therapeutically acceptable salts.

Of particular interest are compounds of formula III

OH H

A / CH ₂ -CH-CH ₂ -N-> 4 _x yiR ₃ (III)

wherein R_ is hydrogen or lower alkyl; R_ is cyano, lower alkoxycarbonyl, pyrrolyi, morpholino, alkenyloxy of 3 to 6 carbon atoms, alkynyloxy of 3 to 6 carbon atoms or alkoxy of 1 to 3 carbon atoms substituted by cyclopropyl; and their salts, especially their therapeutically acceptable salts.

The compounds of the formulas I, II and III can be present in two isomeric forms in which the two radicals on the cyclohexane ring (ie the two 1,4-cyclohexylene-5-substituents), either cis or trans, are constantly to one another. Further, the asymmetric carbon atom bearing the OR radical, which may be hydroxy, alkanoyloxy or aroyloxy, may have either S or R configuration in compounds of this invention. Therefore, the compounds according to the invention can occur in the form of stereoisomers, for example as geometric isomers, racemates, pure enantiomers or mixtures thereof, all of which are within the scope of the present invention.

3evorzugt are compounds of the invention, for example those of the formulas I, II or III wherein the two l, 4-cyclohexylene 5ubsticuenten cis to each other are Constantly.

Further preferred are the enantiomers in which the carbon atom bearing the hydroxy, alkaloyloxy or aroyioxy group has an S configuration.

Of particular interest are compounds of formula III wherein R 1 is hydrogen and R 1 is allyloxy, propargyloxy or cyclopropylmethoxy; the stereoisomers and enantiomers ^ thereof; and their salts, especially their therapeutically acceptable salts. Especially

zugt are the cis stereoisomers and S-enantiomers.

The general terms used to define the compounds according to the invention have in the. Within the scope of the present invention, the following meaning.

An aromatic radical is preferably phenyl, naphthyl, pyridyl, quinolyl, isoquinolyl, indolyl or 1,2,5-tnadiazolyl. A partially hydrogenated bicyclic, carbocyclic or heterocyclic aromatic radical is preferably tetrahydronaphthyl, tetrahydroquinolyl or tetrahydroisoquinolyl. The substituents optionally attached to the phenyl or phenylene portion of the above-mentioned bicyclic groups are preferably lower alkoxy, e.g. methoxy; Lower alkyl, e.g. Methyl; Halogen, z.3. Chlorine; hydroxy; or trifluoromethyl. The substituents optionally attached to the heterocycle or the partially hydrogenated ring of the bicyclic groups preferably include lower alkoxy, lower alkyl, halogen, hydroxy, cyano, carbamoyl, substituted amino, (alkylene, oxaalkylene or thiaalkylene) -imino, e.g. Morpholino, and oxo in the case of the above-mentioned partially hydrogenated bicyclic radicals.

An alkenyl radical, as such or as present in, for example, alkenyloxy, means straight or branched alkenyl, preferably having up to 7 carbon atoms, e.g. 2-propenyl (A) IyI), 2-3utenyl, 2-methyl-2-propenyl or 2-methyl-2-butenyl.

An alkynyl group, as such or as present in, for example, aikinyloxy, means straight or branched alkynyl, preferably having up to 7 carbon atoms, e.g. 2-? Ropinyl (propargyl), 2-3utinyl or 2-pentynyl.

The term "lower" defines in the organic radicals or compounds mentioned above or below those having at most 7, preferably 4, in particular 1 or 2, carbon atoms.

A lower alkyl group preferably contains 1 to 4 carbon atoms and means, for example, ethyl, propyl, butyl or especially methyl.

A lower alkoxycarbonyl group preferably contains 1 to 4 carbon atoms in the alkoxy moiety and means, for example, methoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl or, in particular, ethoxycarbonyl.

A lower alkylene group may be branched or unbranched, preferably contains 1 to 7 carbon atoms and is in particular 1,2-ethylene, 1,3-propylene, 1,4-butylene or 1,5-pentylene.

Cycloalkyl is preferably cyclopropyl, glylopentyl, cyclohexyl or cycloheptyl. Oxaalkyleniraino is preferably morpholino; Thiaalkyleneimino is preferably thiomorpholino; Lower alkylerimino preferably denotes pyrrolidino or piperidino,

Aroyl is preferably benzoyl; benzoyl or heteroaroyl substituted with 1 to 3 lower alkyl, lower alkoxy, halogen or trifluoromethyl radicals, e.g. Nicotinoyl.

Lower alkanoyl is preferably acetyl, propionyl or butyryl.

Lower alkoxy is preferably ethoxy, propoxy, isopropoxy or especially methoxy,

Lower alkylthio is preferably ethyltnio, propylthio or especially methylthio.

Corsage alkylsulfinyl is preferably ethylsulfinyl, propylsulfinyl or especially methylsulfinyl.

Lower alkylsulfonyl is preferably ethylsulfonyi, propylsulfonyl or, in particular, methylsulfonyl.

Lower alkoxycarbonylamino is preferably ethoxycarbonylamino or methoxycarbonylamino.

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

Alkylamino is preferably mono- or di- (methyl, ethyl, oropyl) -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 metylsulfonylamino or ethylsulfonylamino.

The gene compounds of formula I form acid addition salts, which are preferably those of therapeutically useful inorganic or organic acids, such as strong mineral acids, for example hydrohalic acids, e.g. Hydrochloric or hydrobromic acid; Sulfuric, phosphoric, nitric or perchloric acid; aliphatic or aromatic carboxylic acids or sulfonic acids, e.g. Ants, vinegar, propion, amber, glycol, milk, asp. Wine, glucon, citric, maleic, fumaric, pyruvic, phenylacetic, benzoic, 4-aminobenzoic, anthranilic, 4-hydroxybenzoic, salicylic, 4-aminosalicyl, pamoic, nicotinic ; Methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, benzenesulfonic, ρ -toluenesulfonic, naphthalenesulfonic, suifanilic, cyclohexylsulfamic acids; or ascorbic acid.

In addition to the abovementioned pharmaceutically acceptable salts, all "prodrug" derivatives, for example therapeutically used, are also suitable.

bare esters of the alcohols according to the invention (compounds of the formula I in which R is hydrogen), which can be converted by solvolysis or under physiological conditions to give the alcohols mentioned, the subject of the present invention.

Such esters are preferably lower alkanoyl esters, for example the acetyl or isobutyryl ester; Aroyl ester, z.3. the benzoyl or nicotinoyl ester; Carbamoyl ester (carbamate), z.3. the N-Ae thylcaroamoyl- or N-methylcarbamoyl ester.

The compounds of the present invention exhibit valuable pharmacological properties, primarily cardiovascular, for example, antihypertensive and cardiac effects, which they produce, inter alia, due to their ability to hinder β-adrenergic receptors. This interaction is attributed to the strong affinity of the compounds according to the invention for β-adrenergic receptors. As compounds of this invention having little or no intrinsic 3-stimulating activity, this β-receptor andrenergic receptor affinity results in a strong adrenergic inhibitory effect. In addition, the compounds according to the invention have α-adrenergic blocking properties, which are likewise met. contribute to their antihypertensive effect, with little tendency to cause orthostatic hypotension.

The above-mentioned pharmacological properties can be demonstrated by means of in vitro or in vivo animal experiments, preferably on mammals, such as rats, cats, dogs or their isolated organs, as test objects. The animals may be either nor-notensive or hypertensive, e.g. genetically hypertensive rats, or renal, hypertensive rats or dogs, and dogs deprived of sodium. The compounds mentioned can be administered enterally or parenterally, preferably orally or intravenously, 2.3. by gelatin capsules or in

Form starch-containing suspensions or aqueous solutions. The dose used may range from about 0.01 to 100 mg / kg / day, preferably about 0.05 to 50 mg / kg / day, more preferably about 0.1 to 30 mg / kg / day.

The in vivo antihypertensive effect is administered either directly with a catheter, e.g. is introduced into the fumoral artery of a dog, or indirectly registered by soy gyroometry on the rat's tail, and a transmission instrument. The bluing pressure is determined before and after administration of the active ingredient in mmHg. Thus, e.g. the representative compounds of this invention illustrated in the Examples are very effective in hypertensive rats or dogs even when administered in low oral doses of 10 mg / kg / day or less.

Thus, the antihypertensive effect and the reduction of the heart rate in spontaneously hypertensive rats can be detected by indirectly measuring the systolic pressure by sphygmomanometry on the rat's tail. Guard rats are individually locked in cages, which are in a pleasantly 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. The blood pressure is usually determined 24 hours after the first dose and then every 2.0, 4.0 and 24 hours after each daily dose, and the effect compared with that in such rats treated with the carrier material.

As typical representatives of the compounds of the invention, the compounds of Examples -1, 2 and 3m have marked antihypertensive and bradycardic (ie, heart rate decreasing) effects when administered spontaneously to hypertensive rats in low doses of 10 mg / kg or below.

- 10 -

The antihypertensive and bradycardic effects are also studied in conscious, chronically hypertensive dogs; Hypertension is produced by a weakening of kidney function. Arterial pressure is registered by direct percutaneous puncture of the fetal artery, using a needle attached to a transfer instrument. Upon taking control data, the dogs are treated orally once daily for 4 days with capsules containing the test compound. Blood pressure and heart rate are determined at 1.5, 3, 6 and 24 hours after the daily dose, respectively, and the results are compared with the control values obtained before the treatment.

For example, the compounds of Examples 1 and 3m, when administered at an oral dose of 10 mg / kg, can cause an uninterrupted reduction in mean arterial pressure and decrease heart rate in renal hypertensive dogs.

The β-adrenergic receptor binding properties indicative of 8-adrenergic regulatory, eg, blocking, activity of said new compounds are determined in a test of 8-S-acetate binding in vitro after a modification of the method as described in Life Sciences 1], 993 (1975).

~ H-Dihydroalprenolol is specifically bound by brain membrane preparations, and this effect is inhibited by known agonists and antagonists of 3-adrenergic receptors.

In the binding assay, 2 ml of the suspension of a membrane preparation (which corresponds to about 20 mg of calf brain caudate) are placed in ice-cold test tubes containing H-dihydroalprenolol with or without a test compound, freshly dissolved in 0.1% ascorbic acid.

The Snd concentration of H-dihydroalprenolol is 1.0 nM. The test compounds are tested within a wide concentration range. The test tubes are incubated for 10 minutes at 37 ⁰ C, and the

Suspensions then immediately filtered under vacuum through fiberglass filters. The filters are washed with 15 ml of cold 50 mM Tris-HCl (pH 7.9 at 25 ° C), placed in scintillation vials together with 12 ml of scintillation solution, shaken first for 90 minutes and then assayed for radioactivity with the counting tube.

The IC values (which indicate the concentration of test compounds needed to reduce the specific binding of the 1.0 nM H-dihydrcaiprenolol solution by 50%) are determined graphically.

The compounds according to the invention inhibit β-receptor formation of the

-9 dihydroalprenolols with ICL values as low as 5 nM (5 χ 10 M) or below. For example, the compounds of Examples 1, 2a, 3b and 3c have IC values of about 80, 5, 50 and 4 nM, respectively.

The antagonistic effect of the compounds according to the invention on β-adrenergic receptors can be demonstrated in vitro by the antagonism of the epinephrine activation of an adenylate cyclase preparation which originates from the guinea pig's cerebellum. [J. Neurochemistry, 22, 1031 (1974)]. For example, the inventive compounds of Examples 1, 2a and 3b show an IC value of about 3-5 nM (3-5 χ 10 M), demonstrating strong S-adrenergic blockade.

The a-adrenergic receptor binding properties which indicate the a-receptor blocking properties are described e.g. in vitro

Figure 3 shows the inhibition of binding of the known Ci-blocker prazocin (H-razocin) to a synaptosonal membrane preparation from the rat front dermis [Naunyn-Schmiedebergs Arch. Pharmacol, 308, 223 (1979)].

For example, the compounds of Examples 1, 2a, 3b and 3m act in the above-described α-receptor binding assay with IC values that are at 1 /> M (1 · 10 ~ ° M).

~ 12 -

The anticlaucoma activity of the compounds of the invention can be seen in the intraocular pressure reduction detected on mammalian animals, eg normotensive rabbits, essentially according to the methodology described by DE Potter and JM Rowland in Experimental Eye Research _2_7, 615-625, (197S) can. The intraocular pressure reduction is determined as follows: 2 × 50 μl of a solution of the test compound in sterilized water of different concentration are applied to one eye in male New Zealand albino rabbits weighing 3-4 kg each and 2 × 50 μl of the carrier material are applied to the contralateral eye for control. The intraocular pressure (in mm Hg) in each eye is measured tonometrically immediately before treatment, and then at 1.2 and 3 hours after administration, respectively. The difference of intraocular pressure between treated eye and control eye is determined.

For example, the inventive compounds of Examples 1 and 2a, at a concentration of about 20 and 6.4 nM, a significant reduction in intraocular pressure in rabbits.

Accordingly, the compounds of the present invention can be used in mammals as α- and β-adrenergic blocking agents, as well as cardiovascular drugs, particularly antihypertensive and cardiac frequency depressants, for example in the treatment, management and prevention of cardiovascular conditions such as hypertension or cardiac disorders such as Myocardial infarction, cardiac arrhythmia or angina pectoris, and / or other conditions that responded to, inter alia, a ß-adrenergic blockade, such as excitability, anxiety, glaucoma or migraine. They can also be used as intermediates for the preparation of other valuable products, in particular pharmacologically active preparations.

The present invention also relates to methods of preparing the compounds of formula I. Unless defined otherwise below, Ar, R, R to R, and X have the same meaning as defined above

of formula I indicated.

The compounds of the present invention are prepared by methods known per se, by

a-) a compound of the formula IV

ArO-CH ₉ -6H-CH ₉ -Z ₁ (IV) with a compound of the formula V

Il 'X

in which one of Z and Z _{9 is} a reactive esterified hydroxy group and the other is NHR _x , and Y-. is hydroxy, alkanoyloxy or aroyloxy; or in which Y, and Z together represent an epoxy group, Z _{0 is} the amino group NHR, and Ar, R ₁ , R ₉ , R-, R, and X have the meanings given above; and if desired, converting a compound of formula I obtained into another compound of formula I; and / or, if desired, converting a resulting free compound into a salt or a salt obtained, into a free compound or other salt; and / or, if desired, a resulting isomer mixture is separated into the isomers or a resulting racemate is split into the two enantiomers.

A reactive esterified hydroxy group Z ₁ or Z ₉ is a hydroxy group esterified by a strong acid, in particular by a strong inorganic acid such as a hydrohalic acid, z. Hydrochloric acid, hydrobromic or hydroiodic acid, or sulfuric acid, or by a strong organic acid, in particular by a strong organic sulphonic acid such as an aliphatic or aromatic sulphonic acid, z.3-methanesulphonic acid, 4-methylphenylsulphonic acid or 4-bromophenyisulphonic acid.

- II ;. -

The said reactive esterified hydroxy group is in particular halogen, z.3. Chlorine, bromine or iodine, or aliphatically or aromatically substituted sulfonyloxy, z.3. Phenylsulfonyloxy or 4-methylphenylsulfonyloxy (tosyloxy).

The above reaction is carried out in manner known per se, usually in the presence of a solvent or a mixture of several solvents and, if necessary, under cooling or with heating, for example in a temperature range of from about -2O ⁰ C to about 150 ° C, in an open or closed vessel and / or an inert gas, for example in a nitrogen atmosphere. If a starting material is used which has a reactive esterified hydroxy group, the reaction is advantageously carried out under basic conditions, for example in the presence of an inorganic base, z.3. an alkali metal or alkaline earth metal carbonate or hydroxide or in the presence of an organic base such as an alkali metal lower alkoxide and / or in an excess of the basic reactant.

In particular, compounds of the formula I are prepared by reacting an oxirane of the formula VI

ArO-CH CH-CH ₇ (VI)

with an amine of formula VII

₄ > _x / ₃ · - · C

Il X

or one of its stereoisomers, wherein R ₁ and R 1 independently represent hydrogen or lower alkyl; or R- and R, together represent 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 _Q and R independently of one another are hydrogen or

Lower alkyl, and X is oxo or thio.

Preferred intermediates of formula VII are the compounds of formula VIII

α - c β - ο

R ₄ NH- ^^ = - N / ^ "^ 3 (VIII)

il

0 ·

or their stereoisomers, advantageously the cis isomers, in which R and R _{4 are} hydrogen or lower alkyl.

The starting materials of formula IV (and for example VI) are known in the literature or can be prepared by methods known per se, e.g. as illustrated in the examples of this invention. For example, racemic or optically active starting compounds of formula IV are prepared by first reacting compounds of the formula ArOH or their alkali metal derivatives with e.g. racemic or optically active epichlorohydrin or benzyl-2,3-epoxypropylather condensed and the products obtained hydrogenolyzed, acylated and / or cyclized.

The starting materials of the formulas VII and VIII (compounds of the formula V where Z _n = NHR 1) are preferably prepared by mixing, for example, compounds of the formula IX

V \> - \ / - ^R 3 ^(IX)

Ii X

wherein Z _{n is} R, NH, nitro or Acvl-NHR; R _n , R _n , R _n . j 4. '-τ ι L _>'

R ₁ and X have the meanings defined above; Acyl-NHR, acylated NHR, is, for example, (alkoxycarbonyl or aralkoxycarbonyl, eg tert-butyloxycarbonyl, carbobenzoxy, lower alkanoyl ·, eg acetyl or trifluoroacetyl) -substituted NHR. ·

The hydrogenation of compounds of the formula IX is carried out by methods known per se, preferably with catalytically activated

Hydrogen, such as hydrogen in the presence of e.g. a platinum, palladium, nickel, preferably a rhodium catalyst, in a solvent such as e.g. Water, acetic acid or ethanol, at room temperature or at elevated temperature, and at normal or elevated pressure, e.g. at a pressure of 3 atmospheres.

The compounds obtained by hydrogenation of the compounds of formula IX wherein Z _? Acyi-NHR ^ is converted to compounds of formula VII (that is compounds of formula V with Z = NHR,) by cleaving the Acy! Protecting group, for example by hydrolysis with an aqueous base such as caustic soda or an aqueous acid such as hydrochloric acid, or by hydrogenation with hydrogen in the presence of a catalyst such as palladium.

Further, the corresponding intermediates of formulas VII and VIII wherein R is hydrogen can be converted to intermediates of formula VII or VIII wherein R is lower alkyl, for example, by alkylation with a reactive vsrestartan, lower alkyl halide, such as a lower alkyl halide or below Conditions of the reductive alkylation, eg with formaldehyde in the presence of formic acid, or with acetone in the presence of sodium cyanoborohydride.

The intermediates of the formulas V, VII and VIII can be obtained as cis or trans isomers or as cis / trans mixtures. When a cis / trans isomeric mixture is obtained, the isomers can be separated by methods known in the art, e.g. by chromatography or crystallization. Advantageously, the cis isomers of the amines of formulas VII and VIII are isolated leading to the preferred compounds of the present invention, either as free bases or as acid addition salts.

Another process for the preparation of compounds of the formula I.

is that one

b) a compound of the formula ArOH, preferably in the form of a metal salt, z.3. an alkali metal derivative, with a compound of

^{Formula X} YR, R ₁ -R ₉

CHCHN \ / ^{R (X)}

wherein Z is reactive esterified hydroxy and Y is OR; or Z and Y together form an epoxy group; and Ar, R, R-. , R ", R_, R, and X have the meanings defined above, and wherein the amino and hydroxy groups. optionally present in protected form, condensed or with a compound of formula XI and other functional groups

^HU \. _e _ R ₁ R ₉

' -N ⁷ - « _x / ~ \ / ^IR 3 (XI) ,

Π X

wherein R, R ₉ , R _n and X have the meanings defined above and wherein hydroxy may optionally be present in protected form, condensed and, if desired, a compound of formula 1 is converted into another inventive compound.

The above condensations can be carried out under conditions known per se, advantageously in an inert solvent, at room temperature or elevated temperature, and preferably in an inert gas atmosphere.

Intermediates of formula XI can be obtained by cyclization of a compound of formula X wherein Z is reactive esterified hydroxy, Y is hydroxy and hydrogen. Intermediates of the formula X can be prepared by condensation of the amines of the formula VII with z. Epichlorohydrin.

"Ι ο"

j- O

Another possibility for the preparation of compounds of formula I is that

c) a compound of the formula XII

OR R.

II ⁴ / ~ \ !

OR R. H " ^R 2 ⁴ / ~ \ ! Γ

₂₉ ^ ) \ / ^N "" ^R ₃ ⁽

C Il X

or, if R, is hydrogen, one of the tautomers is reduced, wherein Ar, R, R ,, R _0, R, Rz ₁ and X have the meanings given above, and, if desired, a resulting compound of formula I converted into another compound of the invention.

The reduction can be carried out either by catalytic hydrogenation, for example with hydrogen in the presence of Raney nickel as catalyst, or by a reducing agent such as matrium cyanoborohydride, the reaction being carried out by methods known per se, for example in a solvent such as ethanol, preferably at room temperature or slightly elevated temperature.

Intermediates of formula XII, wherein R is hydrogen, may be used as isomers, as in formula XIIa

ArO-CH ₇ -CK-O - I ¹ 'I ² '

- I; </ -N _x / -R ₃ (XIIa)

^R 4

shown present.

The intermediates of formulas XII and XIla can, z.3. in situ, by condensation of an amine of formula XIII

OR

ArO-CH ₀ -CH-CH ₀ -NHR. (XIII)

/ 2 4

with a ketone of formula XIV

2 4

il X

_s are prepared wherein such condensation occurs either spontaneously or preferably in the presence of a dehydrating agent such as boron trifluoride, magnesium sulphate or molecular sieve.

The amines of formula XIII, starting from, can be obtained by condensation of a compound of formula VI with R ₇ NH ₀ under the standard conditions of an aminolysis. Ketones of formula XIV can then be prepared by oxidation of compounds of formula VII, for example with an alkali metal hypochlorite, preferably under the conditions of phase transfer catalysis as described in Tetrahedron Letters 1976 , 1641.

Further, compounds of the present invention can be prepared by

d) a compound of the formula XV

OR R, R --- R

II ¹⁺ / ~ VI ^l i ²

ArO-CH ₀ -CH-CON-- / ~ ^N \ ß ~ ^R 2 ( ^sv )

c '

II X

and, if desired, converting a compound of formula I obtained into another compound of the invention.

The reduction is carried out, for example, with simple or complex light metal hydrides, e.g. Alan, borane or lithium aluminum hydride, according to methods well known in the art.

In turn, intermediates of formula XV may be prepared by condensation of an acid of formula XVI

OR

ArO-CH ₉ -CH-COOH (XVI),

if R represents hydrogen, optionally in protected form or one of its reactive functional derivatives, e.g. an acid chloride or a mixed anhydride, an Arnin of the formula VII according to well-known processes for the preparation of amides.

The condensation of a free carboxylic acid of formula XVI with an amine of formula VII is preferably carried out in the presence of a coupling reagent, such as dicyclohexylcarbodiimides or 1,1'-carbonyldiimidazole, according to methods well known in the art.

The condensation of a reactive functional derivative of a compound of formula XVI with an amine of formula VII proceeds spontaneously or in the presence of bases such as potassium carbonate, pyridine or triethylamine in an inert solvent such as mathvinyl chloride, at room temperature or elevated temperature.

The acids of the formula XVI can essentially be prepared by the process described in US Pat. No. 3,699,097, for example by condensation of ArOH with chlorosilicic acid in aqueous sodium hydroxide solution.

Furthermore, the compounds of the present invention can be prepared by

e) a compound of the formula XVII

OR R, Rt - R-

Ar0-CH _o -CH-CH "-N- <" - NR NO. (.XVII)

C il X

and, if desired, converting a compound of formula I into another compound of the invention.

The reduction is advantageous z.S. by selective catalytic hydrogenation with hydrogen in the presence of a catalyst such as

Nickel, rhodium or platinum, preferably in an acidic medium such as acetic acid or ethanol in the presence of a mineral acid. The said reduction is particularly useful when Ar represents a residue that is relatively resistant to hydrogenation conditions.

The starting compounds XVIII can be prepared by condensing a compound of formula IV with a compound of formula IX wherein Z is R, NH, the conditions being similar to those used for the condensation of compounds of formula IV with compounds of the formula V wherein Z is "MHR.

Another method for the preparation of compounds of formula I is that

f) in a compound of the formula XVIII

OR aR

₉ -CH-CH ₂ -N- ^ \

a _R R is ArO-CH ₉ -CH-CH ₂ -N- ^ -N-C 1 -NR ₃ (XVIII),

"1 11 X

wherein X represents a removable hydrogen-substitutable radical, replacing it with hydrogen, and, if desired, converting a compound obtained to another compound of the invention,

The cleavable group X. may be solubilized by solvolysis, such as hydrolysis, alcoholysis or acidolysis, or by reduction, including hydrogenolysis by hydrogen. A suitable group which can be split by hydrogenolysis X ₁ is an α-aryl-lower alkyl group, preferably a 1-phenyl-lower alkyl group, in particular benzyl. Sine group X ₁ can also be a radical which can be eliminated by solvolysis, such as hydrolysis or acidolysis, or else reduction. Such a radical is a corresponding acyl radical, such as the acrylic radical of an organic carboxylic acid, such as A-cetyl or aroyl, such as benzoyl, and also the acyl radical of a monoester of carbonic acid, such as Niederalkoxycar-

bonyl, e.g. Methoxycarbonyl, ethoxycarbonyl or tart-butyloxycarbonyl, 2-halo-lower-alkoxycarbonyl, z.3. 2,2,2-trichloroethoxycarbonyl or 2-iodoethoxycarbonyl, optionally substituted 1-phenyl-lower alkoxycarbonyl, e.g. Benzyloxycarbonyl or diphenylmethoxycarbonyl, or aroylmethoxycarbonyl, e.g. Phenacyloxycarbonyl, further an optionally substituted 1-polyphenyl-lower alkyl group, wherein substituents, primarily the phenyl moiety, e.g. have the meaning given above, and represent trityl in the first place.

Hydrogenolytically removable radicals X, in particular optionally substituted i-phenyl-lower alkyl groups, and also suitable acyl groups, such as optionally substituted 1-phenyl-lower alkoxycarbonyl, can be prepared by treatment with catalytically activated hydrogen, e.g. with hydrogen in the presence of a nickel catalyst, such as Raney-Nickei, or a suitable Kdalmetallkatalysators split off.

Hydrolytically cleavable groups X, such as acyl radicals of organic carboxylic acids, e.g. Lower alkanoyl, and halocarbons of carbonic acid, e.g. Lower alkoxycarbonyl, further e.g. Trityl radicals may, depending on the nature of such radicals, be treated by treatment with water under acidic or basic conditions, e.g. in the presence of a mineral acid such as hydrochloric or sulfuric acid, or an alkali metal or alkaline earth metal hydroxide or carbonate or an amine such as isopropylamine, are cleaved off.

Acidolytically removable radicals X ₁ are, in particular, certain A.cyl radicals of half-esters of carbonic acid, such as, for example, tert.-lower alkoxycarbonyi or optionally substituted diphenylmethoxycarbonyl radicals, and also the tert.-lower alkyl radical; such radicals can be eliminated by treatment with suitable strong organic carboxylic acids, such as optionally with calcine, especially fluoro, substituted cermet alkanecarboxylic acids, primarily with trifluoroacetic acid (if necessary in the presence of an activating agent such as anisole), as well as with formic acid.

By reductively cleavable radicals X are also understood those groups which are cleaved off on treatment with a chemical reducing agent (in particular with a reducing metal or a reducing metal compound). Such radicals are especially 2-halo-lower alkoxycarbonyl or arylmethoxycarbonyl, e.g. upon treatment with a reducing heavy metal, such as zinc, or with a heavy duty reducing salt, such as a chromium (TI) salt, e.g. chloride or acetate, usually in the presence of an organic carboxylic acid, such as formic acid or acetic acid, and can be cleaved from water.

The starting materials of the formula XVIII can be prepared analogously to the process variants described above. So can 2.S. a compound of the formula ArOH or a salt thereof, with a compound of the formula Xa

OR R --- R ₉

I / - I- ² Z-CH 1 -CH-CH ₀ -N- ", -N NR _n (Xa),

i 2. \ _y \ _n s 3

^X i_ i!

wherein Z represents a reactive esterified hydroxyl group, and wherein the functional groups are optionally present in protected form.

The novel compounds of the formula I can also be obtained by reacting

g) a Schiff's base of formula XIX OR R --- R

1 · - * > L

9 ι -

Il X

and, if desired, converting a compound obtained into another compound of the invention.

The reduction of the nitrogen-carbon double bond in, starting materials of Formal XIX to the nitrogen-carbon single bond can

in a manner known per se, z.3. by treating with catalytically activated hydrogen, such as hydrogen in the presence of a suitable hydrogenation catalyst, e.g. a nickel, platinum or palladium catalyst, or one works with a suitable hydride reducing agent such as an alkali metal borohydride, e.g. Sodium borohydride. When using Kydridreduktionsmitteln, also bound to oxygen acyl radicals of carboxylic acids, such as z.3. of acetic acid, are present in the OR group and cleaved in the same operation.

A starting material of the formula XIX can be prepared in a manner known per se, if appropriate in situ, i. under the reaction conditions of the process described. So can a connection of the

Formula XIXa ° ^R

ArO-CH ₉ -OH-CHO (XIXa)

with an amine of formula XIXb

R --- R, H ₂ N- () · -Ν _χ ^ MR ₃ (XIXb)

Il X

for the preparation of the starting material of formula XIX be implemented.

Another method for the preparation of compounds of formula I is that

h) in a compound of formula XX

ArO-CH ₀ -CH "CH R _T -R

^(XX)

H X

or in a salt thereof, wherein X is a divalent radical which is replaceable by two hydrogen atoms, which cleaves this radical Y, and converts a compound obtained into another compound of the invention.

A cleavable radical Y ₉ is primarily a hydrogenolytically cleavable group, such as optionally substituted 1-phenyl-niederalkyliaen, wherein substituents, in particular of the phenyl moiety, for example lower alkyl, such as tert-butyl, hydroxy, lower alkoxy, halogen and / or nitro be can, and in particular benzylidene, as well as solvolytic, in particular hydrolytically cleavable groups, such as lower alkylidene, for example methylene or isopropylidene, or Cycloaikyliden, eg cyclohexylidene. Another radical is the diacyl radical of carbonic acid or thiocarbonic acid, ie the carbonyl or thiocarbonyl group.

Starting materials useful in the form of salts are primarily in the form of acid addition salts, e.g. Mineral acids, as well as of organic acids used.

The cleavage of the residue Y ₉ is carried out analogously to the reactions described for process f).

The starting materials of the formula ICX can be prepared by methods known per se, e.g. according to the method b) analogous reaction, i. by condensation of a compound of the formula ArOH with a compound of the formula XXa OR

Z-CH ₂ -CH-CH-CH _{2 /} - ' _x * i "' * 2

Oi - \ / - \ / ~ ^R 3

2 ff

wherein Z represents a reactive esterified hydroxy group, and wherein the functional groups are optionally present in protected form.

The novel compounds of formula 1 can also be prepared by

i) in a compound of formula XXI

/ \ ί ¹ ι ²

ArO-CH ₉ -C-CH ₂ -N- * / "\ / ^Ν " ~ ^R 3 ^ ¹ ^ '· · C

il X

.worin Z _{7 represents} a hydrogen atom together with a group OZ ^, wherein Z is ₁ . stands for a cleavable radical; or Z, represents an oxygen atom; converts R, to a hydrogen atom together with a hydroxy group, and converts, if desired, a compound obtained into another compound of the invention.

The group OZ, is a protected by conventional methods hydroxy group. Thus, the hydroxy group may be in the form of an ester, e.g. an acyl derivative, such as a lower alkanoyl, benzyloxycarbonyl or lower alkoxycarbonyl ester, or in the form of an ether, ζ.3. be protected as a 2-tetrahydropyranyl or benzyl ether. The cleavable radical R ^ can be known per se by hydrogen

Methods, z.3. be replaced by solvolysis, in particular hydrolysis with an acid, or by reduction, preferably by hydrogenolysis, by a hydrogen atom.

The oxygen atom (Z, = 0) can be replaced by hydrogen together with a hydroxy group by reduction according to methods known per se. Thus, the reduction is carried out, for example, with catalytically activated hydrogen, for example in the presence of Raney nickel, palladium black or a platinum catalyst. It is preferable to use complex hydrides, for example, alkali metal borohydrides such as sodium borohydride, 3orwasser- _; Substance compounds, such as diborene, or alkali metal aluminum hydrides, such as lithium aluminum hydride, and in particular alkali metal triiederalkylborhydride and related boron compounds such as potassium tris (sec-butyl) -. Borohydride or lithium tris (triamyisilyl) -borohydride, which in an inert solvent Etheric character, such as dioxane, diethyl ether or tetrahydrofuran in particular, or in the case of the use of sodium borohydride in an anhydrous alkanol or its mixture with tetrahydrofuran, or in rässerig-lower alkanol

Solution can be applied.

The starting materials can be prepared by methods known to them. Thus, for example, Compounds in which Z, an oxygen atom, by reacting a compound of formula Ar-OH or its salts, with a 1,3-dihaloacetone and condensation of the obtained monohalo-acetone compound with a Amiη of formula XXIa

HN- ^ \ -SF _N / NR ₃ (XXIa)

il X

produce.

Starting materials which contain the protected hydroxy group OZ can be prepared in an analogous manner. In this case, instead of the 1,3-dihaloacetone, a corresponding 1,3-dihalogenopropane compound is used, which in the 2-position has a group OZ.

Compounds of the invention obtained by any of the methods described above may be converted to other conventional methods or, for example, as illustrated below.

For example, compounds of formula I wherein R is alkanovol or aroyl can be prepared by hydrolysis with e.g. aqueous acid, such as hydrochloric acid or aqueous alkali, such as lithium or sodium hydroxide, into compounds of formula 1 wherein R is hydrogen.

Conversely, compounds of formula I wherein R is hydrogen may be converted by condensation with a corresponding carboxylic acid or its reactive derivatives, according to esterification methods well known in the art, advantageously under non-basic conditions, to compounds of formula I wherein R is alkanoyl or aroyl become.

Further, compounds of formula I wherein R is hydrogen may be converted to a compound of formula I wherein R _{x is} lower alkyl, by reacting with a reactive esterified lower alkanol, for example a lower alkyl halide, the corresponding compound of the formula I is preferably isolated as an acid addition salt, or by carrying out a reductive alkylation, for example with formaldehyde and formic acid, wherein a compound of formula I, wherein R, is methyl.

Compounds of formula I, optionally in protected form, wherein R 1 is hydrogen may be converted into compounds of formula I wherein R 10 is lower alkyl by reacting with a reactive derivative of a lower alkanol, eg with a lower alkyl iodide, in the presence of a strong Base such as Sodium hydride are reacted in an inert solvent such as dimethylformamide.

Unsaturated compounds, for example those bearing an alkenyl or alkynyl radical, can also be hydrogenated with catalytically activated hydrogen, compounds of formula 1 or intermediates bearing a corresponding alkyl radical being obtained.

Compounds of the formula I, optionally in protected form, which have a cyano group in the radical Ar, may be converted into the corresponding carbamoyl compounds, e.g. in a basic or preferably in an acidic medium, in particular in the presence of a strong mineral acid, ζ.3. conc. Hydrochloric acid to be converted.

When a compound of formula I contains a protected hydroxy-lower alkyl group or a protected hydroxy group, the protecting group may be e.g. be replaced by solvolysis, such as hydrolysis, alcoholysis or acidolysis, or by reduction, including hydrogenolysis, as already described above, by hydrogen.

In compounds of the formula I which contain an amino group in the radical Ar, the amino group in Niederaikylsulfonylamino by reaction with a corresponding. Niedaralkanesulfonic acid, e.g. Me sulfonic acid, optionally in the presence of a suitable Kondensationsmittals, e.g. N, N'-dicyclohexylcarbodiimide. Instead of the free acid, a reactive derivative thereof, e.g. a halide such as chloride or bromide, or an acid anhydride can be used. The further reactive substituents of a product of the formula I may be present in protected form in these conversions.

Further, in a product of the formula I which has a hydroxy group in the radical Ar, this group can be converted into lower alkoxy, lower alkenyloxy or lower cycloalkyl-lower alkoxy. The product or its alkali metal, z.3. Sodium salt is reacted with a reactive ester of an alcohol which introduces the radicals mentioned. If necessary, the further reactive substituents of the product of the formula I can be present in protected form in these reactions.

Further, optionally protected compounds of formula I or intermediates wherein X is oxygen may be substituted by sulfur-introducing reagents such as e.g. Phosphorus pentasulfide are converted into compounds wherein X is sulfur.

With respect to the reactions listed above, the term "protected" means potentially reactive substituents, eg. Amino, hydroxy and other interfering groups, in accordance with protective techniques well known in the art, z.3. as illustrated below, suitably protected so as to avoid side reactions. This can be achieved by protecting such substituents from a desired reaction and then deprotecting them or during the reaction of a process, if necessary

whereby the desired compounds, z.3. those of the formula I can be obtained.

Thus, in all instances where OR represents hydroxy or Ar carries a free hydroxy group, such a hydroxy group may be termed an ester, e.g. as an acyl derivative, such as a lower alkanoyl, benzyloxycarbonyl or lower alkoxycarbonyl ester; or as an ether, for example as 2-tetrahydropyranyl or benzyl ether.

Similarly, a free basic amino group or the (-NR, -) group, when carrying at least 1 hydrogen on the nitrogen, can be readily cleaved amide, for example as an acyl derivative, such as benzyloxycarbonyl (carbobenzyloxy) - or as t-butyloxycarbonyl derivative, or with any other readily cleavable N-protecting group as commonly found in peptide chemistry.

In a suitably protected compound of formula I or an intermediate in which one or more functional groups are protected, the protected functional groups, z.3. Amino or hydroxy groups are released in a conventional manner, for example by solvolysis, in particular acid hydrolysis, or by reduction, in particular hydrogenolysis.

The abovementioned reactions are carried out by methods known per se, in the presence or absence of diluents, preferably those which are inert towards the reagents and which dissolve them, catalysts, condensation agents or other agents mentioned above, and / or in an inert atmosphere, under cooling, at room temperature or at elevated temperature, preferably at the boiling point of the solvent used, at normal or elevated pressure.

The invention also relates to modifications of the present

according to which an intermediate obtained at any stage of the process is used as starting material and the remaining process steps are carried out, or the process is stopped at any stage, or after which a starting material is formed under the reaction conditions, or wherein a starting material in the form of a salt or optically pure antipodes is used. Whenever desired, the above procedures are not performed until all potentially interfering reactive functional groups are suitably protected, as illustrated above and in the Examples.

In the reactions mentioned, such starting materials are advantageously used, which are among the. in the above described as particularly preferred compounds. The preferred starting materials of formulas VII and VIII are the respective cis isomers.

The invention also relates to novel starting materials and processes for their preparation.

Depending on the starting materials and methods chosen, the new compounds may be present as one of the possible isomers or isomer mixtures, for example as pure geometric isomers (cis or trans), as pure optical isomers such as antipodes or as mixtures of optical isomers such as Racemates or as mixtures of geometric isomers.

Resultant geometric or diastereomeric mixtures of isomers of the above compounds or intermediates 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 also be cleaved into the optical antipodes, e.g. by separation of their diastereomeric salts, as described in J. Org. Chem. 4 · 3_, 3803 (1973), z, 3, by fractional crystallization of d- and! - (tartrates,

camphorsulfates or 1-naphthyl-1-ethyl isocyanates) of compounds which have a basic, salt-forming group or of d- and [alpha] - (alpha-methylbenzylamine, cinchonidine, quinine, quinidine, ephedrine, dehydroabietylamine, brucine or strychnine) Salts of compounds having an acidic, salt-forming group.

Advantageously, in each case the more active isomer and / or the more effective antipode of the compounds according to the invention are isolated.

The compounds of the present invention are finally obtained either in free or in the form of their salts. Any base obtained may be converted to a corresponding acid addition salt, preferably using a therapeutically acceptable acid or an anion exchanger. Salts obtained may be converted to corresponding free bases, for example using a stronger base, for example a metal or ammonium hydroxide or a basic salt, e.g. an alkali metal hydroxide or carbonate, or a cation exchanger. These or other salts, such as picrates, can also be used to purify the resulting bases by salifying the bases, separating and purifying them, and releasing the base from the salts. As a result of the close relationship between the free compounds and their salts, free and meaningful and expedient, if appropriate, always also include the corresponding salts in this connection.

The compounds and their salts may also be obtained in the form of their hydrates, or they may include other solvents used for crystallization.

The present invention further relates to compounds of the formula I and their therapeutically acceptable, non-toxic acid addition salts for use as medicaments, in particular as et- and S-adrenergic blockers, for example as hypotensive, antihypertensive and

cardiac influencing agents, e.g. for the treatment of elevated blood pressure, cardiac disorders and other diseases responsive to andrenergic receptor blockade; and in particular for use in the manufacture of pharmaceutical preparations, in. special preparations having an anti -ergic receptor blocking effect, especially an antihypertensive or cardiac effect.

The preparations according to the invention are those for enteral, such as oral or rectal administration, as well as for parenteral administration to mammals, including humans. The pharmaceutical preparations according to the invention contain at least one compound of the formula I, or one of its therapeutically acceptable salts as active ingredient, optionally together with one or more therapeutically acceptable excipients.

The pharmacologically useful compounds of the present invention can be used for the preparation of pharmaceutical preparations containing an effective amount of the active ingredient together or in admixture with excipients suitable for enteral or parenteral administration. Preferably, tablets or gelatin capsules containing the active ingredient together with diluents, e.g. Lactose, dextrose, cane sugar, mannitol, sorbitol, cellulose and / or glycine, and lubricants, e.g. Silica, talc, stearic acid or salts thereof, such as magnesium or calcium tearate, and / or polyethylene glycol; Tablets also contain binders, e.g. Magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone, and, if desired, disintegrants ·, e.g. Starches, agar, alginic acid or a salt thereof, such as sodium alginate and / or effervescent mixtures, or adsorbents, dyes, flavorings and sweeteners. Injectable preparations are preferably isotonic solutions or suspensions, and suppositories primarily fat emulsions or suspensions. The pharmacological preparations may be sterilized and / or. Adjuvants, z.3. preservatives,

13.10.1983 AP C 07 D / 251 330/8 - 34 - 52 512/11

Stabilizing, Metz and / or emulsifying agents, Löslichkeitsvermittier, salts for regulating the osmotic pressure and / or buffer containing, The present pharmaceutical preparations, which, if desired, may contain other pharrnakologisch valuable substances are in a conventional manner, z, 3 "by conventional mixing, granulation or coating methods, and contain from about 0.1 % to etv / a 75 %, in particular from about 1 % to eta; a 50 %, of the active material.

In particular, the present invention relates to methods for the treatment of cardiovascular diseases. The dosage of the active substance depends on the vascular species, its body weight, age and individual condition, as well as the application prognosis. Single doses for nipples weighing about 50 to 70 kg may contain between about 10 to 200 mg of the active ingredient.

Ausführunosbgispiel

The following examples serve to illustrate the invention; however, they are to be limited in scope by kainer. Temperatures are., In Celsius degrees indicated. Unless otherwise stated, all evaporation operations are carried out under reduced pressure, preferably between about 15 and 100 mm Hg.

Example 1 : A mixture of 657.6 g of 92% o- (allyloxy) -phenoxymethyloxirane (U.S. Patent 3,483,221) and 512 g of cis-1- (4-aminocyclohexyl) -2-imidazolidinone in 6,000 ml of isopropanol. stirred and boiled under reflux for 6 hours. This hot reaction mixture is treated with 162.1 g of fumaric acid and stirred overnight at room temperature. The crude product is filtered off and washed with 1000 ml of isopropyl alcohol. The obtained wet solid material is first recrystallized from 5000 ml of isopropyl alcohol and then dried under vacuum at 65 ° to a constant weight. A white crystalline product is obtained which melts at 154-155 °. Recrystallization of 1781 g of the obtained salt from 9700 ml of anhydrous ethanol gives the cis-1- (4- [3- (o-allyloxyphenoxy) -2-hydroxypropylamino] -cyclohexyl) -2-imidazolidinone hemifumarate. F. 156-157 °. This is the cis compound of Formula III wherein R is hydrogen and R _{7 is} allyloxy in its hemifumarate salt form.

A solution of 1575 g of the above salt in 7875 ml of water is basified with a solution of 4.537 mol of potassium carbonate in 790 ml of water. The cis-1- (4- [3- (o-allyloxyphenoxy) -2-hydroxypropylamino] cyclohexyl) -2-imidazolidinone is obtained as an OeI. This is converted into the hemifumarate of higher purity as described above.

The starting material is prepared as follows: A solution of 1800 g of p-amino acetanilide in 7000 ml of dimethylformamide is stirred at room temperature and then cooled to 10-15 ° in an ice-water bath. 1440 g of 2-chloroethyl isocyanate are added to the stirred, cooled solution within 50 minutes, keeping the reaction mixture at a temperature between 20 and 25 °. The mixture is stirred at room temperature for 90 minutes and treated within 20 minutes with 8000 ml of ice water. It is stirred for a further 2 hours. The solid material is filtered off and washed with 4000 ml of water. The crude product is slurried in 7000 ml of 95% alcohol. The solid material is filtered off and dried in air at room temperature overnight.

net. This gives the 1- (p-acetamidophenyl) -3- (2-chloroethyl) urea, which melts with decomposition at 207-209 °.

A mixture of 1600 g of - (p-Acetamidophenyl-S - ^ - chloroethyl) urea in 7200 ml of dimethylformamide is stirred in a nitrogen atmosphere at room temperature. To the solution obtained, a solution of 400 g of sodium methoxide in 2000 ml of water-free methyl alcohol is added within 90 minutes, during which the temperature rises. The reaction mixture is stirred for a further 20 minutes, then heated to 70-75 ° and held at this temperature for 1 hour. Then, the reaction mixture is allowed to cool slowly, within about 3 hours, with stirring to 32 °. Then you quickly add 5000 ml of ice water. Stirring is continued at room temperature for 4 hours and the mixture allowed to stand at room temperature overnight. The solid material is filtered off, with 3000 nil. Water and dried in air for about 2 days at room temperature. This gives the 1- (p-acetamidophenyl) -2-imidazolidinone. F. 270-273 °.

A mixture of 4213 g of 1- (p-acetamidophenyl) -2-imidazolidinone in 39,000 ml of water and 2930 g of 5% rhodium on carbon catalyst (50% wet with water) is hydrogenated at 40 °. The Hydriarungsgemisch is filtered and the filtrate evaporated to dryness in vacuo. The resulting solid material is dried in air and then pulverized. The crude product is recrystallized from 12000 ml of acetone. The 1- (4-acetamiaocyclohexyl) -2-imidazolidinone is obtained as a mixture of cis and trans isomers. F. 211-230 °.

A solution of 3271 g of sodium hydroxide in 33,000 ml of water is displaced with 3271 g of 1- (4-acetamidocyclohexyl) -2-imidazolidinone. The mixture is stirred and boiled under reflux for 4 hours. The Raaschegemisch is cooled to room temperature and treated with stirring with 3271 g of sodium chloride. The reaction mixture is extracted ten times with a total of 93,000 ml of methylene chloride. The methylene chloride extract containing the product is concentrated in vacuo to approximately 5000 ml.

trated. This solution is mixed with 300 g of anhydrous magnesium sulfate. The mixture is stirred at room temperature for about 3 hours, filtered and the filtrate evaporated to dryness in vacuo. The residue obtained is dried under high vacuum to constant weight. The 1- (4-aminocyclohexyl) -2-imidazolidinone is obtained as an isomer mixture which crystallizes on standing at room temperature.

A mixture of 9500 ml of anhydrous ethyl alcohol and 2323 g of 1- (4-aminocyclohexyl) -2-imidazolidinone is heated to produce a solution. The solution is cooled to room temperature and adjusted to pH 1 with 9200 ml of saturated solution of anhydrous hydrogen chloride gas in ethyl acetate. The temperature of the mixture rises to 60 ° and the product crystallizes out. The mixture is cooled to 10 °, the crude product filtered off, washed with 3500 ml of anhydrous ethyl alcohol and dried in vacuo for 2 days at 50-60 °. The crude hydrochloride is recrystallized twice from anhydrous methanol-ethyl ether (approximately 1: 1). The cis-1- (4-aninocyclohexyl) -2-imidazolidinone monohydrochloride is obtained. F. 327-328 °.

A solution of 630 g of cis-1- (4-aminocyclohexyl) -2-imidazolidinone monohydrochloride and 155 g of fumedium oxide in 6000 ml of anhydrous methanol is stirred in a nitrogen atmosphere at room temperature for about 24 hours. The reaction mixture is cooled in an ice bath and the sodium chloride is filtered off. The methanol filtrate is evaporated to dryness in vacuo. The residue is dissolved in 1700 ml of dichloromethane with heating. The mixture is cooled in an ice bath and filtered with a hyphlo filter. The filter cake is washed with 750 ml of dichloromethane. The dichloromethane filtrate is evaporated to dryness in vacuo and the residue is dried under high vacuum to constant weight. The cis-1C-4-aminocyclohexyl) -2-imidazolidinone is obtained. F. 121-123 °.

Example 2

a) A solution of (S) - [o- (cyclopropyl-ethoxy) -phenoxy] -methoxyoxirane (25.77 g) and cis-1- (4-aminocyclohexyl) -2-imidazolidinone (23.6 g, Example 1) in 300 ml of isopropanol is refluxed in a nitrogen atmosphere with stirring for 5 1/2 hours. The solution is allowed to stand at room temperature for 16 hours and then evaporated under reduced pressure. The residue is dissolved in 300 ml of acetic acid and acidified to pH 1 with a solution of hydrogen chloride gas in ethyl acetate. The amorphous solid precipitate is filtered off and washed with ethyl acetate. The solid material is dissolved in warm water, the solution is cooled to room temperature, washed with ethyl acetate (2 × 100 ml), basified with excess 10% aqueous sodium carbonate solution and extracted with ethyl acetate (2 × 200 ml). The organic extract is washed with 10% aqueous sodium carbonate solution and water = The organic layer is dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue is dried briefly in a high vacuum. A viscous oil is obtained.

The OeI is converted to hemifumarate by dissolving 40.86 g of OeI in 350 mL of hot isopropanol and adding fumaric acid (5.3 g). The solution is slowly cooled to room temperature, whereupon the product crystallizes out. The mixture is further cooled in an ice bath, the solid material is filtered off and washed with cold isopropanol. The solid material is dried under high vacuum at 50 ° to obtain the crude hemifumarate salt. This is purified by treatment with Aethyia alcohol. The chiral product is more soluble than the racemate. Repeated crystallization and removal of the racemate (which is less soluble) by filtration, after evaporation of the filtrate leads to the isolation of (S) -cis-1- (4- [3- (o-Cyclopropylinethoxyphenoxy) -2-hydroxypropylamino] cyclohexyl) -2-imidazolidinone hemifumaracs (salt of the S enantiomer). F. 147-149 °. [α] "= -8.41" (c = 1.35 in methanol). This product is the salt of

cis- (S) -compound of formula III, wherein R _{7 is} cyclopropylmethoxy and R 1 is hydrogen

 j

The optical purity is determined by NMR in the presence of a chiral shift-Reägenses and is greater than 95%.

b) Analogously, the condensation of (R) - [o- (cyclopropylmethoxy) -phenoxy] -methyloxirane (33.69 g) with cis-1- [4-aminocyclohexyl] -2-imidazolidinone gives the (R) -cis -l- (4- [3- (o-Cyclopropylmethoxy) -2-hydroxypropylamino] -cyclohexyl) -2-imidazolidinone hemifumarate (salt of the R-enantiomer of the cis-compound of formula III wherein R "is cyclopropylmethoxy). F. 150-152 ° (decomposition). • [α] β ⁵ = + 8.26 ° (c = 1.36 in methanol).

The starting material is prepared as follows: A mixture of 42.5 g of (R) -epichlorohydrin [described in J. Organic Chemistry 4_3_, 4876 (1978)], 36.8 g of o- (cyclopropylmethoxy) phenol and Γ64 ml of acetone and 10 ml of hexane is mixed with 30.9 g of powdered potassium carbonate 'and boiled under stirring in a nitrogen atmosphere for 42 hours under reflux. The mixture is cooled to room temperature, the solid material separated and washed with acetone. The filtrate is carefully evaporated in a high vacuum at room temperature. The residue is dissolved in ether (200 ml), washed with ice cold 1N sodium hydroxide solution (2 × 50 ml) and water (2 × 50 ml). The solution is dried over anhydrous sodium sulfate, filtered off and evaporated under reduced pressure. The residue is distilled in vacuo and the main fraction, boiling at 108-121VO, 2 mmHg, collected. It consists of (S) - [o- (cyclopropylmethoxy) phenoxy] methyl oxirane. [ci] ^ ⁵ = +10.10 (c = 2.4 in methanol).

The (R) - [o- (cyclopropylmethoxy) phenoxy] methoxy oxirane is obtained analogously from (3) -pichlorohydrin. Boiling point 120-127 ° / 0.2 mmHg, [α] '"= -9.76 ° (c = 1.58 in methanol.

The (S) - [o- (cyclopropylmethoxy) -phenoxy] -methyloxirane is also prepared as follows:

- 40 -

A mixture of (S) -3-benzyl-2,3-epoxypropyl ether (8.95 g), [described in Heterocycles, Vol. 16, 381, (1981)], o-cyclopropylmethoxyphenol (8.95 g) in 36 Powdered potassium carbonate (6.9 g) is added to ml of acetone and 4 ml of hexane and refluxed in a nitrogen atmosphere with stirring for 74 hours. The mixture is cooled to room temperature, the solid material is filtered off and washed with acetone. The filtrate is evaporated under reduced pressure, the residue dissolved in ether, the solution washed twice with water, over anhydrous. Dried sodium sulfate, filtered and the filtrate evaporated to dryness. The crude oil is distilled in vacuo at 199-212 ° / 0.2 mmHg. The (S) -1-benzyloxy-3- [o-cyclopropylmethoxy) phenoxy] -2-hydroxypropane is obtained.

A solution of (S) -1-benzyloxy-S-fo-cyclohexyltriethoxy) -phenoxy] -2-hydroxypropane (10.97 g) in 100 ml of ethanol is added with 3.5 g of 10% palladium on carbon catalyst Room temperature and 3.06 atmospheres pressure until hydrogen uptake ceases (approximately 10 minutes). The catalyst is filtered off, washed with ethanol and the filtrate is evaporated under reduced pressure. The resulting crystalline residue is recrystallized from 35 ml of ethanol. The (S) -3- [o- (cyclopropylmethoxy) -phenoxy] -l, 2-propanediol is obtained. F. 95-97 °, [aj ^ ⁵ = 5.32 ° (c = 0.99 in methanol).

A solution of 3- [o- (cyclopropylmethoxy) -phenoxy] -1,2-propanediol (5.82 g) in 15 ml of dry pyridine is cooled to 5 ° in a nitrogen atmosphere and treated with p-toluenesulfonyl chloride (4.7 g ) with stirring, within 10 minutes. The mixture is stirred at 5 ° for 1 1/2 hours and then allowed to stand overnight in a refrigerator at about 5 °. Aether (15 ml) is added to the mixture, allowed to stand at 5 ° C. for a further hour, the resulting solid material is filtered and washed with ether. The fitrate is evaporated to dryness at low temperature. The residue is taken up in ether, the solution washed with ice-cold water and then treated all at once with saturated solution of sodium bicarbonate. The solution is over

dried water-sodium sulfate, filtered and concentrated under reduced pressure and under high vacuum. The (S) -3- [o-cyclopropylmethoxy) -phenoxy] -l, 2-propanediol-1-tosylate is obtained as sin OeI. [ct] ^ = -8.49 ° (c = 1.26 in methanol).

A solution of 3 ~ [o- (cyclopropylmethoxy) -phenoxy] -l, 2-propanediol ltosylat (8.1 g) in 25 ml of methanol and 12 ml of ether with stirring in a nitrogen atmosphere, with cooling to 5 °, with 0.47 g sodium in small pieces within 30 minutes. The mixture is further stirred at 5 ° for two hours. By introducing carbon dioxide, the pH of the mixture is adjusted to 8. The mixture is filtered and the filtrate evaporated in a warm water bath under reduced pressure. Then add ether and sis water. The layers are separated, the organic layer is washed again with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting crude material is distilled in vacuo. The (S) - [o- (cyclopropylmethoxy) -phenoxy] -methyloxirane is obtained, which is identical to the product described above. Upon standing at room temperature, the product yields waxy, low-melting crystals.

EXAMPLE 3 In a manner analogous to the methods described above, the following racemic compounds of the formula II are obtained in which R, R, R and R are hydrogen, X is oxygen and R ₁ and R "together are -CK ₇ CH ₉ - mean. Unless otherwise stated, all products are obtained as hemifumarates.

R_OR R ₇ R ₁ -R ₉

5 \ · ι .4 · - ·. i, i

. *. -OCH ₂ -CH-CH ₂ -N-. _N / - ^ / R ₃

Λ 'π

V ^x

_ Λ 9 -

Connection ^R 6 3 / a o-methoxy 3 / b p-propargyloxy 3 / c o-propargyloxy 3 / d m-propargyloxy 3 / e p-propargyloxy (1: 1 fumarate salt) 3 / f o-cyano 3 / g o-cyano 3 / h o- (l-pyrrolyl) 3 / i o- (2-pyrrolyl) 3 / j o-morpholino 3 / k p- (2-methoxyethyl) 3.1 o- (Cyclopropylniethoxy) 3 / m o- (Cyclopropylinethoxy) 3 / n o-3enzyloxy 3/0 o-Carfaanioyl 3 / p o- (2-Methylpropcxy) 3 / q o-cyclohexyl 3 / r o-methoxycarbonyl 3 / s O-phenyl 3 / t p-benzyloxy (HCl salt) 3 / u o-allyloxy 3 / v o-Allvl

The Umkristalli isomer is siert out

CIS ice

trans ice

ice

ice

trans ice ice ice ice

trans ice ice ice ice ice

ice ice ice trans ice

iPrOH / CH OH 95% AetOH

AetOH iPrOH

AetOH AetOH AetOH AetOH AetOH iPrOH iPrOH AetOH AetOH

Acetone iPrOH / acetone

iPrOH / acetone

iPrOH

EtOH

AetOH iPrOH / acetone

190-2 ° 168 ° 92-8 ° 177 °

95-100 ° (iPrOH solvate).

192 ° Zers.

215-6 °

144 °

130-4 °

114-9 °

166-8 °

173-80 °

168-170 ° '

141-6 °

110 °

170-2 °

117-120 (hydrate)

135-8 °

146-8 °

159-61 °

159-50 °

158-9 °

iPrOH = isopropyl alcohol; AetOH = ethyl alcohol; Dec. = Decomposition.

The following known starting materials of formula VI have been prepared as described in the readily available chemical literature.

0 ArO-CH ₉ -CH-CH ₉ (VI)

Ar Ar

o-methoxyphenyl p-benzyloxyphenyl

o-Propargyioxyphenyl p- (2-methoxyethyl) -phenyl

m-Propargyloxyphenyl o- (benzyloxyphenyl

ρ-propargyloxyphenyl o-carbamoylphenyl

o-cyanophenyl o-biphenyl

o- (1-pyrrolyl) -phenyl o -methoxycarbonylphenyl o- (2-pyrrolyl) -phenyl o-allylphenyl o-morpholinophenyl

The following starting materials are prepared as follows:

1) Catechol (110 g) is dissolved in 800 ml of isopropanol, first treated with a solution of sodium hydroxide (41 g) in 45 ml of water and then with cyclopropylmethyl chloride (155 g, 70% pure) and potassium hydroxide (5 g). The reaction mixture is stirred in a Stickstoffatmopshäre and boiled under reflux for 16 hours. The mixture is cooled to room temperature, the solid material is filtered off and washed with isopropanol. The filtrate is evaporated under reduced pressure, the brown residue dissolved in toluene (600 ml) and adjusted to pH 1 with 3N hydrochloric acid. The organic phase is washed with water (4 × 700 ml), with aqueous matrium bisulphite solution and with water (3 × 100 ml). The organic layer is dried over anhydrous sodium sulfate, filtered through basic alumina (300 g) to remove the remaining catechol and evaporated under reduced pressure. The residue is distilled in vacuo through a Vigreux column (fitted with a reflux attachment). The 2- (cyclopropylmethoxy) phenol is obtained, which boils at 66-68VO, 1 mm.

A solution of 6.92 g of sodium hydroxide in 28 ml of water is added with 200 ml of ethanol, 24.6 g of 2- (Cyclopropyiinethoxy) phenol and 83.25 g of epichlorohydrin. The reaction mixture is stirred at 25 ° under nitrogen for 24 hours and then allowed to stand for 36 hours. The mixture is filtered off from sodium chloride and evaporated in vacuo. The residue is partitioned between ether and water. The ether solution is washed three more times with water, dried and evaporated. The residue is distilled in vacuo. The between 133 and 114 ° /

0.5 mmHg boiling fraction corresponds to the o- (cyclopropylmethoxy) phenoxymethyl oxirane of the compound of the formula VI in which Ar is o- (cyclopropylmethoxy) -phenyl.

2) If, in the above reactions, the cyclopropylmethyl chloride is replaced by 1-3-rom-2-methylpropane, the o- (2-methylpropoxy) phenoxymethyl-oxirane, the compound of the formula VI in which Ar o- (2- Methylpropoxy) -phenyl, prepared,

3) A solution of 4.6 g of sodium hydroxide in 19 ml of water is mixed with 150 ml of ethanol, 17.7 g of 2-cyclohexylphenol and 55.5 g of epichlorohydrin. The reaction mixture is stirred overnight, filtered and evaporated in vacuo. The residue is distilled in vacuo. The fraction boiling at 127-133 ° / 0.2 mmHg corresponds to the o- (cyclohexyl) -phenoxymethyloxirane, the compound of the formula VI in which Ar is o- (cyclohexyl) -phenyl.

4) The trans-1- (4-aminocyclohexyl) -2-imidazolidinone hydrochloride is prepared as follows: A solution of crude i- (4-aminocyclohexyl) -2-imidazolidinone monohydrochloride (66 g) (obtained by evaporation of mother liquors from the preparation and purification of the cis-1- (4-aminocyclohexyl) -2-imidazolidinone hydrochloride in Example 1 and which consist mainly of the trans isomer) in 1200 ml of ethanol and 600 ml of methanol is heated to boiling. The insoluble material (5.5 g, mainly the cis isomer) is filtered off and the hot filtrate is cooled in an ice bath. The crystallized on cooling material is filtered off and dried. This gives 9. 1 g

of the solid mainly consisting of the trans isomer. F. 326-328 ° (decomposition). The solid material is recrystallized by dissolving in 100 ml of hot methanol and adding 100 ml of ether. The crystalline material obtained after cooling to room temperature is separated and dried. The trans-1- (4-aminocyclohexyl) -2-imidazolidinone monohydrochloride is obtained. F. 328-329 ° (decomposition). The hydrochloride salt is converted to the free base to which trans-1- (4-aminocyclohexyl) -2-imidazolidinone melts at 168-170 °.

EXAMPLE 4 Analogously to the processes described in Examples 1 and 2, the condensation of cis-1- (4-aminocyclohexyl) -3-methyl-2-imidazolidinone with o- (cyclopropylmethoxy) -phenoxymethyloxirane (see Example 3) gives the cis-l- (4 ~ [3- (o-cyclopropyl-methoxyphenyl) -2-hydroxypropylamino] -cyclohexyl) -3-methyl-2-imidazolidinone hemifumarate salt. F. 145-147 °,

The starting material is prepared as follows: It is stirred in a nitrogen atmosphere p-nitroaniline (40 g) in 200 ml Dimethoxyäthan and it is mixed with chloroethyl isocyanate (45.8 g) in three portions within 4 1/2 hours. After adding the first portion of approximately 65%, the solution is refluxed for 1 1/2 hours. Then add another 20% and boil for 1 1/2 hours under reflux. After adding the remainder of the isocyanate, continue boiling under reflux for 1 1/2 hours. The dark solution is cooled to room temperature, filtered and the filtrate evaporated under reduced pressure. The residue is taken up in toluene and the mixture re-evaporated to remove the unreacted chloroethyl isocyanate. The substantially solid residue is treated with ethyl acetate (400 ml) and water (200 ml) and the layers are separated. The organic layer is washed with water, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The solution of the crude 1- (p-nitrophenyl) -3- (2-chloroethyl) - "urea in 300 ml of methanol and 75 ml of dimethylformamide is filtered

and the filtrate used directly in the next step.

The above solution is stirred in a nitrogen atmosphere and treated with a solution of sodium methoxide (prepared from 7.4 g of sodium in 125 ml of methanol) over 20 minutes. The reaction mixture is refluxed for 2 hours, cooled to room temperature, diluted with 300 ml of water and stirred. The precipitate is filtered off, washed first with methanol / water (1: 1, 150 ml) and then with water (100 ml). The solid material is stirred in ethanol (150 ml) for a few minutes, filtered and dried. This gives the 1- (p-nitrophenyl) -2-imidazolidinone. F. 243-245 °.

A solution of 1- (p-nitrophenyl) -2-imidazolidinone (25 g) in 450 ml of dimethylformamide is stirred under nitrogen and sodium hydride (50%, 6.4 g) added in small portions. The mixture is stirred at 50 ° for 1 1/2 hours, cooled to room temperature and treated with methyl iodide (25 g). After further stirring for 2 hours, the pH of the reaction mixture is 9. An additional amount of methyl iodide (4 g) is added over 6 hours until the pH of the mixture is about 8. The mixture is treated with water (150 ml), the precipitate is filtered off, washed first with dimethylformamide / water (1: 1) and then with water (2 × 150 ml) and dried. This gives the 1- (p-nitrophenyl) -3-methyl-2-imidazolidinone. F. 207-208 °.

A solution of l- (p-Mitrophenyi) -3-methyl-2-imidazolidinone (12.45 g) in 150 ml of glacial acetic acid is added to 6 g of 5% rhodium on alumina and hydrogenated at 50 ° and 3.06 atmospheres pressure , The catalyst is filtered off and the filtrate is evaporated under reduced pressure. The residue is added with water (25 ml) and basified with cooling in an ice bath with 50% aqueous sodium hydroxide solution. After extraction with methylene chloride (5 × 70 ml), drying of the extracts with anhydrous sodium sulfate, filtration and evaporation under reduced pressure gives the 1- (4-aminocyclohexyl) -3-methyl-2-imidazolidinone. The OeI is dissolved by dissolving in 100 ml of isopropanol and adding a saturated solution of hydrogen chloride

converted into the hydrochloride salt in ethyl acetate. Aether (50 ml) is added and the salt crystallizes upon cooling to room temperature. The mixture is further cooled in a refrigerator. The precipitate is filtered off and dried. The cis-1- (4-aminocyclohexyl) -S-methyl-Z-imidazolidinone hydrochloride is obtained. F, 287-298 °.

The hydrochloride salt is converted to the free base by dissolving 3.2 g of salt in 50 ml of water, adding 20 ml of 50% aqueous sodium hydroxide solution and extraction with methylene chloride (5 × 40 ml). The methylene chloride solution is dried over anhydrous sodium sulfate, filtered and evaporated. Cis-1- (4-Aininocyclohexyl) -3-methyl-2-imidazolidinone is obtained. F. 81-87 °.

Example 5: A mixture of cis-1- (4- [3- (o-allyloxyphenoxy) -2-hydroxypropylamino] cyclohexyl) -2-imidazolidinone (4.4 g) in 15 ml of isopropanol, 37.5% aqueous Formaldehyde (0.671 g) and formic acid (2.6 g) are refluxed for 19 hours. The solution is cooled to room temperature, with 1 ml of conc. Hydrochloric acid and the mixture was evaporated to dryness. The glassy residue is dissolved in 100 ml of water, made basic with excess 25% aqueous sodium hydroxide solution and extracted with methylene chloride (1 × 50 ml, 1 × 25 ml). The extract is dried, filtered and evaporated. A residue is obtained which is purified by preparative thin layer chromatography [on silica gel using ethyl acetate: diethanol-ammonium hydroxide (90: 5: 5) as eluent]. The cis-1- (4- [3- (o-allyioxyphenoxy) -2-hydroxy-N-methylpropylamino] cyclohexyl) -2-imidazolidinone is obtained as an OeI. The hydrochloride salt melts at 80 ° (decomposition). It is prepared by dissolving 2.3 g of the acid in 50 ml of ethyl acetate, adding a saturated solution of hydrogen chloride gas in ethyl acetate and separating the resulting salt.

Example 6 : A mixture of 3.0 g of cis-1- (4-aminocyclohexyl) -2-imidazolidinone, 3.2 g of 3-chloro-4- (oxiranylmethyloxy) -1,2,5-chiadiazole and 40 ml of isopropanol stirred and boiled under reflux for 7 hours. The reaction mixture is filtered and the filtrate is acidified with a solution of anhydrous hydrogen chloride in ethyl acetate. The hydrochloride salt precipitates as an amorphous solid material. After cooling, decant the above solution and dissolve the crude hydrochloride salt in 50 ml of water. The solution is filtered, basified by adding 2N sodium hydroxide solution and the free base extracted with methylene chloride. The methylene chloride solution is dried and evaporated in vacuo. A solution of the free crude base in 18 ml of isopropanol is boiled under reflux and treated with 0.27 g of fumaric acid. Crystallization of the product gives the cis-1- (N- [3- (4-chloro-1, 2,5-thiadiazol-3-yloxy) -2-hydroxypropylamino] -cyclohexyl) -2-imidazolidinone hemifumarate. F. 163 °. The solvent for the recrystallization is isopropanol.

Treatment with morpholine at 125-130 ° gives the cis-1- (N- [3- (4-morpholinyl-1,2,2-thiadiazol-3-yloxy) -2-hydroxypropylamino] -cyclohexyl) -2-imidazolidinone ,

The starting 3-chloro-4 - (oxiranyimethyloxy) -l, 2,5-thiadiazole is used as described in J. Med. Chem. 15, 651 (1972).

Example 7: The following compounds of the formula I, wherein R ₁ and R

taken together, are ethyl, R- and R _{7 are} hydrogen, and X is oxygen can be prepared according to the methods described in the preceding examples.

H ice U Li ice H ice H ice H ice

Senzoyl CIS nicotinoyl ice acetyl ice

- 49 -

Example Ar R Stereochemistry

7 / a 1-naphthyl

7 / b 4-indolyl

7 / c 3-cyano-2-pyridyl 7 / d p- (carbamoylmethyl) -phenyl

7 / e '3,4-dihydro-2 (1K) -quinolone-5-yl

7 / f. 5,6,7,8-tetrahydro-cis-6,7

dmydroxynäpnth-1-yl

7 / g cis-o- (cyclopropylmethoxy) phenoxy

7 / h cis-o- (cyclopropylmethoxy) phenoxy

7 / i cis-o- (allyloxy) phenoxy

The appropriately substituted, optionally protected oxirane starting materials for the compounds 7 / a-7 / f are described in the literature.

The compounds 7 / g-7 / i can be prepared by acylation of compounds of Examples 1 and 3 / m with benzoyl chloride, nicotinoylochloride or acetyl chloride, respectively, in a pyridine solution.

Example 8 : A solution of 3.7 g of o- (allyloxy) -phanoxymethyioxirane and 3.4 g of 1- (4-aminocyclohexyl) -3-ethylurea in 50 ml of isopropyl alcohol is stirred at reflux for 3 1/2 hours. The solution is evaporated in vacuo. The resulting crude product is purified by column chromatography on silica gel using methylene chloride / methyl alcohol (first 200: 15, then 1: 1) as eluent. The slowly migrating main component is dissolved in 30 ml of isopropanol and admixed with 0.4 g of fumaric acid. The solution is evaporated to dryness and treated with 25 ml of acetone. This is decanted, the residue dissolved in 25 ml of acetone and 2 ml of methyl alcohol and the solution clarified by filtration. The crystallized product is filtered off, washed with a little acetone / methyl alcohol (9: 1) and dried at 90 ° under high vacuum.

The 1- (4- [3- (o-allyloxyphenoxy) -2-hydroxypropylamino] cyclohexyl) -3-ethylurea hemifuinarac is obtained. F. 159-160 °,

The starting material is prepared as follows: A solution of 6.3 g of 1-ethyl-3- (p-nitrophenyl) urea in 75 ml of glacial acetic acid is mixed with 3.2 g of 5% rhodium on alumina and the mixture at 3 atmospheres Pressure and 50 ° hydrogenated for 3 1/2 hours. The catalyst is filtered off and the filtrate is evaporated to dryness. The residue is basified with 6N sodium hydroxide solution and extracted with methylene chloride (5 × 50 ml). The methylene chloride extract is evaporated to dryness, the residue dissolved in 30 ml of isopropanol and adjusted to pH 1 with a solution of hydrogen chloride in ethyl acetate. After adding 60 ml of ether, l- (4-itainocyclohexyl) -3-ethylhydrogen hydrochloric acid crystallizes! out. F. 230-232 °.

A solution of 1.5 g of 1- (4-aminocyclohexyl) -2-ethylurea hydrochloride in 20 ml of methyl alcohol is treated with 0.36 g of Na.trium-nethoxide. After usual workup receives mar. the 1- (4-aminocyclohexyl) -3-ethylurea as an OeI which is used directly in the above condensation.

Example 9: A solution of 2.67 g of 1- (4- [3- (o-cyclohexylphenoxy) -2-hydroxypropylamino] -phenyl) -2-imidazolidinone in 50 ml of acetic acid is charged with 1.75 g of 5% rhodium Alumina added and hydrogenated at 50 ° and 3 atmospheres pressure for 5 hours. After cooling to 20 °, the catalyst is filtered off and the filtrate is evaporated to dryness. The residue is dissolved in 50 ml of water, the solution basified with 6N sodium aqueous sodium hydroxide solution under cooling in an ice bath and extracted with 75 ml of methylene chloride. The Methylanchloridextrakt is washed twice with 25 ml of water, dried over anhydrous sodium sulfate, filtered and evaporated to dryness. A dark oil is obtained, which is dissolved in 30 nil of ethyl acetate and treated with a solution of hydrogen chloride gas in ethyl acetate on the

pH value 1 is set. The obensteh.de solution is decanted from the rubbery precipitate and the rubber dissolved in water. The aqueous solution is washed with ethyl acetate, the aqueous layer basified with 10% aqueous sodium carbonate solution and extracted twice with 25 ml Essxgsäureäthylester. The Essigsäureäthylesterextrakt is washed twice with water, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. A viscous oil is obtained. Dissolve 0.94 ml of the oil in 10 ml of hot acetone and add 0.13 g of fumaric acid. It precipitates a gum, which is dissolved by adding 2 ml of methyl alcohol and treated with 0.5 ml of water. The crystallized product is filtered off and dried in vacuo at 45 °. The cis-1- (4- [3- (o-cyclohexylphenoxy) -2-hydroxypropylamino] -cyclohexyl) -2-imidazolidinone hemifumarate hydrate, which melts at 117-120 °, is obtained. The product is identical to that of Example 3 / q.

The starting material is prepared as follows: A mixture of 10 g of 1- (p-acetamidophenyl) -2-imidazolidinone (see Example 1), 10 g of sodium hydroxide and 100 ml of water is refluxed for 4 hours. After cooling, the product crystallizes out, which is' separated and recrystallized from ethanol. The 1- (4-aminophenyl) -2-imidazolidinone is obtained. F. 170-172 °.

A solution of 3.24 g of o- (cyclohexyl) -phenoxymethyloxirane (see Example 3) and 2.65 g of 1- (4-aminophenyl) -2-imidazolidinone in 60 ml of isopropanol is refluxed for 18 hours. The reaction mixture is filtered and the filtrate is evaporated in vacuo. The residue is dissolved in 50 ml of ethyl acetate and adjusted to pH 1 with a solution of hydrogen chloride gas in ethyl acetate. The above solution is decanted from the resulting dark gum and the residue is treated with ethyl acetate and 5% aqueous sodium carbonate solution. The ethyl acetate solution is separated, washed with 10% aqueous sodium carbonate solution and twice with water. The solution is dried over anhydrous sodium sulfate, with

· - 52 -

Activated charcoal, filtered and evaporated in vacuo. A dark viscous gum is obtained, which is chromatographed on a silica gel column and eluted with methylene chloride / methyl alcohol. The resulting 1- (4- [3- (o-cyclohexylphenoxy) -2-hydroxypropylamino] phenyl) -2-imidazolidinone is used directly in the next step.

Example 10 Preparation of 10,000 Tablets with a Content of 10 mg of the Active Substance of Example 1

ingredients:

Cis-l- (4 - [ '3- (o-allyloxyphenoxy) -2-hydroxypropyl-amino] -

cyclohexyl) -2-imidazolidinone hemifumarate 100 g

Lactose 1157 g

Cornstarch 75 g

Polyethylene glycol 6000 75 g

Talcum powder 75 g

Magnesium stearate 18 g

purified water q.s.

Procedure :

All powdery ingredients are combined with a. Sieve of 0.6 mesh sieved. Then the active ingredient is mixed with milk sugar, talc, magnesium scearate and half of the starch in a suitable mixer. The other half of the starch is suspended in 40 ml of water and the suspension added to the boiling solution of polyethylene glycol in 150 ml of water. The resulting paste is added to the powders and optionally granulated with the addition of another amount of water. The granules are dried overnight at 35 °, forced through a sieve of 1.2 mesh size and pressed into 6.4 mm diameter tablets having a score line.

Example 11 Preparation of 10000 Capsules Containing 10 mg of Active Substance of Example 2

Ingredients :

(S) -cis-1- (4- [3- (o-Cyclopropylmethoxyphenoxy) -2-hydroxypropylamino] -cyclohexyl) -2-imidazo-Lidinone hemifumarate 100g

Milk sugar 1800 g

Talcum powder. 100 g

Method:

All powdery ingredients are sieved with a sieve of 0.6 mm mesh size. Then the active ingredient is first homogenized with talc and subsequently with lactose in a suitable mixer. Capsules no. 3 are filled with 200 mg of the mixture each with a filling machine. ,

In an analogous manner, tablets or capsules of other compounds of the invention, e.g. those exemplified herein in the further examples.

Example 12: A solution of 3.7 g of cis-l- (4-Ainir-ocyclohexyl ^N> -2-imidazolidinone and 4.7 g of p-CCyclopropylmethoxy) -phenoxymethyloxiran in 50 ml of isopropanol is refluxed for δ hours. The solution is allowed to stand at room temperature for 16 hours, 1.17 g of fumaric acid is added thereto and refluxed for 30 minutes. There is a precipitate. The reaction mixture is cooled to room temperature, the product is filtered off, washed with isopropanol and dried at 65 ° in vacuo. The cis-1- (4- [3- (p-cyclopropylmethoxyphenoxy) -2-hydroxypropylamino] -cyclohexyl) -2-imidazolidinone hemifumarate is obtained. F. 163-165 °.

The starting material is prepared as follows: A mixture of 11.0 g of hydroquinone, 80 ml of isopropanol, 4.1 g of sodium hydroxide in 4.5 ml of water, 9.9 g of cyclopropylmethyl chloride and 0.5 g of potassium iodide is refluxed for 12 hours. The solvent is evaporated and the residue extracted with ether. The ether extract is washed successively with water, sodium bicarbonate solution, dilute sodium bisulfite solution,

Washed water and sodium chloride solution and dried. The crude product obtained after evaporation of the solvent is purified by preparative chromatography [first using toluene and then toluene-ethyl acetate (90: 5 to 85:15) as eluent]. The (p-cyclopropyirnethoxy) phenol is obtained. F. 49-52 °.

A mixture of 0.46 g of sodium hydroxide in 1.3 ml of water and 14 ml of ethanol, 1.64 g of ρ- (cyciopropylinethoxy) phenol and 5.54 g of epichlorohydrin is stirred in a nitrogen atmosphere at room temperature for 24 hours and at room temperature 2 1 / 2 days left. The solvent is evaporated in vacuo, the residue taken up in ether, washed with water and sodium chloride solution. The solution is dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The o- (cyclopropylmethoxy) -phenoxymethyloxirane, which is used directly in the condensation, is obtained.

Example 13 : A suspension of 3.3 g of lithium aluminum hydride in 100 ml of tetrahydrofuran is concentrated with 3.6 g. Sulfuric acid at -5 to -10 ° added dropwise. The mixture is further stirred for 1 hour at -5 ° and then with stirring within 5 to 10 minutes with 6.5 g of 3- (o-allyloxyphenoxy) -2-hydroxy-N- [4- {imidazolidin-2-one-l -yl) -cyclohexyl] -propionamide. The reaction mixture is allowed to warm to room temperature, stirred for an additional 1 hour, and finally boiled under reflux for 1 hour. After cooling, the mixture is first treated with ethyl acetate, then with water and sodium hydroxide, filtered and concentrated in vacuo. The residue is dissolved in ethyl acetate, the solution washed with water, dried and concentrated. The residue is dissolved in isopropanol and treated with stirring and boiling under reflux with 0.9 g of fumaric acid. After cooling, the cis-1- (4- [3- (o-allyloxyphenoxy) -2-hydroxypropylamino] -cyclohexyD-Z-imidazolidinone hemifumarate salt crystallises out The product is identical to that of Example 1.

The starting material is prepared as follows: A mixture of 62 g of racemic chlorosilicic acid, 82 g of o-ailyloxyphenoi and 90 g of 50% solution of sodium hydroxide in 500 ml of water is heated to 80-90 ° with stirring for 2 hours. The hot mixture is treated with conc. Acidified hydrochloric acid, wherein the crude product precipitates. After cooling, it is filtered off and washed with water. The resulting 2- (o-allyloxyphenoxy) -2-hydroxypropionic acid can be recrystallized from a mixture of alcohol and water.

A solution of 40 g of phosgene in 100 ml of tetrahydrofuran is cooled to 10 ° and added to a solution of 48 g of 3- (o-allyloxyphenoxy) -2-hydroxypropionic acid in 250 ml of tetrahydrofuran at room temperature with stirring. The reaction mixture is allowed to stand for 18 to 24 hours at room temperature and evaporated in vacuo at 40 °. The residue is dissolved in acetone and cooled to -10 °. A solution of 37 g of cis-1- (4-aminocyclohexyl) -2-imidazolidinone and 34 g of sodium bicarbonate in water is slowly added with stirring. The reaction mixture is stirred for 2 hours at 20 °, concentrated in vacuo to remove the acetone bulk and then extracted several times with methylene chloride. The methylene chloride solution is washed with water, dried and evaporated in vacuo. The 3- (o-allyloxy-phenoxy) -2-hydroxy-N- [4- (imidazolidin-2-one-1-yl) cyclohexyl] -propionamide is obtained.

Example 14: A solution of 2.5 g of 3- (o-allyloxyphenoxy) -2-hydroxypropylamine and 1.8 g of 1- (4-oxocyclohexyl) -2-imidazolidinone in 40 ml of anhydrous methanol is added with sodium cyanoborohydride (0.6 g ), 0.6 ml of glacial acetic acid and 3 g of molecular sieve. The reaction mixture is stirred for 72 hours and the pH is maintained at 4-5 during this time. The molecular sieve is filtered off, the filtrate with dilute hydrochloric acid to pH 2 and the methanol evaporated in vacuo. The residue is extracted with ethyl acetate. The aqueous layer is basified with 6 N aqueous sodium hydroxide solution and extracted several times with ethyl acetate. The ethyl acetate is evaporated in vacuo, the residue

was dissolved in isopropanol and converted into the hemifumarate salt by adding 0.6 g of fumaric acid.

The resulting mixture of cis and trans isomers of 1- (4- [3- (o-allyloxyphenoxy) -2-hydroxypropylamino] cyclohexyl) -2-imidazolidinone hemifumarate is separated by recrystallization from isopropanol and / or ethanol. The cis compound of Example 1 is obtained.

The mixture of cis and trans isomers of the free amine can first be separated by preparative chromatography and then the free cis-amine converted to the hemifumarate of Example 1.

The S-Co-allyloxyphenoxy-Z-hydroxy-propanolanine starting material is prepared as follows: A mixture of 50 g of o- (allyloxy) -phenoxyniettryloxirane, 250 ml conc. Ammonium hydroxide and 150 ml of isopropanol are stirred for one week at room temperature. The reaction mixture is filtered, the filtrate evaporated to a small volume, extracted with ethyl acetate, and the extract evaporated. The residue is dissolved in hot isopropanol and sit 4 normal hydrochloric acid acidified in ethanol. The 3- (o-allyloxyphenoxy) -2-hydroxypropylamine hydrochloride is obtained. F. 106-108 °. The free base is obtained from this hydrochloride salt by treatment with ammonium hydroxide, extraction with methylene chloride and evaporation of the solvent. F. 31-84 °.

The 1- (4-oxocyclohexyl) -2-imidazolidinone starting material is prepared as follows: A mixture of 18.3 g of 1- (4-aminocyclohexyl) -2-imidoazolidinone as a mixture of cis and trans isomers, 2.0 g benzyltributylammonium chloride, 250 ml of ethyl acetate and 3 60 ml of a 10% aqueous potassium hypochlorite solution [according to the method described by CA. Meyers in J. Org. Chem. 26, 1046 (1961)] is stirred for 1 1/2 hours at room temperature. The organic layer is separated and the aqueous layer extracted with ethyl acetate. The combined organic phases are washed with water, sodium bicarbonate solution and dilute hydrochloric acid, dried and evaporated to dryness. The 1- (4-oxocyclohexyl) -2-imidazolidinone is obtained.

Example 15: Eye drops containing 0.1% of the active compound:

Cis-l- (4 - [(3-o-allyloxyphenoxy) -2-hydroxypropyl-amino] -

cyclohexyD-Z-imidazolidinone hemifumarate 1.0 g

O ₅ Ol M citric acid 370.0 nil

0.02 M 'disodium phosphate' 620.0 ml

Disodium metabisulfite 1.0 g

Benzalkonium chloride 0.1 g

Hydroxypropylmethylcellulose 5.0 g

Distilled water to make up to 1000,0 ml.

The ingredients are mixed at room temperature, the resulting solution filtered, sterilized and placed under sterile conditions in dropper bottles containing 15 ml of solution.

Effect of compounds of the invention on systolic blood pressure (BP, mm Hg) in spontaneously hypertensive rats.

According to the method described above, conscious rats are housed individually in cages First, the control values of the blood pressure are determined, and then the individual test compounds are orally administered once a day for two consecutive days.

The results show the decrease in the average pressure on the second day, hours after administration of the drug.

In the test described above, a selection of the new compounds gives the following values.

Results dose Decrease of the impression connection mg / kg p = o. now. hg of the example 50 -79.3 1 50 -39.3 3a 30 -47.8 3b 50 -33.0 3g 50 -11.0 3f 50 -30.0 3c 50 -68.0 3h 50 -52.3 3d 50 -17.6 3k 30 -75.5 2a

Claims (11)

13.10.1983 AP C 07 D / 2 51 330 / £ - 5S - 52 512/11; rr inaunasansprucn 1, Process for the preparation of novel 3- (ureidocyclohexylamino) -propane-l, 2-diol derivatives of Formal 1 R m. ~ »R" OR Y J wherein Ar is a (monocyclic or optionally partially hydrogenated oicyclic) carbocyclic or heterocyclic j optionally substituted aromatic Rast, R is hydrogen, alkanoyl or Aroyl staht, R. and R _{0 are} independently hydrogen or Niadaralkyl or R and R _p together alkylene with 2 to 7 carbon atoms, Kelchs dia two nitrogen atoms by 2 to 4 carbon atoms separate, mean, R_ and R independently represent hydrogen or Nieder'alkyl, and X is oxo (O) or thio (S), and their salts, characterized in that one a) a compound of formula IV
with a compound of formula V j- # * -N M-R-, (V) 13.10.1933 AP C 07 D / 2Si 330/5 - 59a - 52 512/11 in which one of the radicals Z ₁ and Z _{9 is} one reactive esterified hydroxy group and the other is the group NHR _{11 /} and Y is hydroxy , alkanoyloxy or aroyloxy; or in which Y 1 and Z ₁ together represent an epoxy group, Z _{0 is the} amino group NHR 1; and Ar, R ₁ ,. ^r ' _o , R_, R _A and X are the above * T * - i- W 'T' given meanings; or 60 - b) · a compound of Fornel ArOK or its metal salts, never a compound of formula X. Y κ R; - R. 4 ι 2 M-R (ν) 2, Process according to item 1, characterized in that compounds of formula I, wherein Ar is optionally substituted [ phenyl, pyridyl, Naphtny ^, tetrahydronaphthyl , 3,4-oihydro-i (2H) -naphthalenone, 3,4-dihydro -2- (IH) chinoion, 3 _/ 4-oihydro-l (2h ') - isoquinolone, indolyl or 1,2,5-T'niadiazoiylj, and the other symbols dia have the meaning given in item 1, and theirs Salts produces .. 2) if a compound is desired in which R is alkanoyl or aroyl, in a compound of Foras 1 I, in which R is hydrogen, converts it into the named groups, and / or 3, method according to item 3, characterized in that daiä compounds of formula I, wherein Ar is optionally substituted by 13 * 10.1983 AP C 07 D / 251 33 0/6 64 - 62 512/11 one to three substituents on the group lower (alkyl, alkenyl, alkynyl, mono- or oxyalkyl) amino, alkanoylamino, alkylsulfonylamino, alkoxycaroonyl, alkyicarbamoyl, aikylsulfamoyl, alkoxy, alkylthio, alkylsulfinyl , alkylsulfonyl, alkenyloxy or alkynyloxy), hydroxy, cyano, halogen , Pyrrolyl, amino, 5-, S- or 7-membered (Aikylsn-, Oxaalkylan-, Thiaalkyien) imino, sanzyloxy, phenyl, 5-, 5- or 7g] Jedrig3S cycloalkyl, carbamoyl, sulfarnoyl or 3- to 7-membered cycloalkyl !, phenyl, hydroxy, Niaderalkoxy-, Niederalkoxycarbonylamino-, Miederalkylthio-, Misdaralkylaulfinyl-, Niederalkyisulfonyl- and carbamoyl-substituted (Miederalkyl or Niaderalkoxy) substituted phenyl, R is hydrogen, lower alkanoyl or _aroyl}; R ₁ and R "are hydrogen or Miaderalkylj or R, and R ₂ together are alkylene having 2 to 5 carbon atoms, R-. and R, are hydrogen or niaderalkyl, and X is O or S and produces their salts, 3) when a compound in which the group Ar has a lower alkylsulfonylamino substituent is desired in a compound having an arnino substituent, converts it into said radical, and / or 3) when a compound in which R _{A is} lower alkyl is desired, in a compound wherein R /. Is hydrogen, introduces a remainder, and / or, 3 ' x wherein Z is reactive esterified hydroxy and Y is OR; or Z and Y Susannen form an epoxy group; and Ar, R, R, R, R, R _, and X have the meanings just defined; or sit a connection of the Fonsei XI ^H ° \ -. .-. * i h Il X · wherein R .., R ^, Rt and X have the meanings defined above, condensed, or c) a compound of Fomel XII OR R, Ri "^ Ar0-CH ₂ -CH-CH, -N-- () _-Ν χ ^ -R ₃ (XU) Il • X or, when R, is hydrogen, one of its tautoserene, reduced, wherein Ar, R, R ₁ , R ₉ , R ^, R ₇ and X have the meanings indicated, or d) a compound of the formula XV OR R, Rt - 3 "[! ⁴ / - \ | 1 | 2. ArO-CH ₂ -CH-CON- / _/ · -Ν _χ ^ NS ₃ (XV) reduced, or ArO-CH _? -CH-CH ₇ -N - (> -N / -R ₃ (XVII) - 61 - e) one compound of Formal XVII OR R reduced, or f) in a compound of Fornel XVIII OR ^R "" ^R 7 il X (XVIII) , wherein X, a cleavable, substitutable by hydrogen radical, replaced by hydrogen, or g) a Schiff's 3ase of the formula XIX OR ' ^R r ~ ^R 7 ArO-Cn ₂ -CH-CH, -Nr ) - reduced, or h) in a compound of the formula MX ArC-CK ₂ -CH "CH ₂ _R ₁ -R or in a salt thereof, wherein Y, a divalent radical, which is replaceable by two hydrogen atoms, means this radical Y _? splits off, or i) in a compound of Fc-el XXI C X - 62 - in which Z, a hydrogenone is taken together with a Gruooe OZ. means, wherein Z. stands for a cleavable rest; or Z ^ sin oxygen atom; this radical R ,, into a hydrogen atom: usars = n with a * hydroxy group, and if in all these processes a) to i) it is necessary to protect a reactive group, including side reactions, or if necessary, one present in protected form ·: group, during the process or subsequently, splits off, and / or Dwenn a compound of formula I is desired, wherein R is hydrogen, in a compound of formula I, wherein R is alkanoyl or aroyl, these groups converts to hydrogen, and / or, 4, Method according to item 1, characterized in that compounds of the formula II r-, -'R R "R" s »« »R, ^ - « R
ö where R is hydrogen or lower alkanoyl; each of the symbols R ₁ and R _{9 is} hydrogen, or R ₁ and Rp together are unsubstituted, veig tes alkylene having 2 to 4 carbon atoms; R_ and R. independently of each other j 4 - - 13.10.1933 AP C 07 0/251 33G / 5 - 55 - 52 512/11 or lower alkyl; R ,. and R 1 independently of one another are hydrogen, lower (alkyl- _t- alkenyl or alkynyl), lower (alkoxy, alkenyloxy or alkynyloxy), hydroxy, cyano, halogen, amino, lower (mono- or o-alkylamino, alkanoylaurio or alkylsulfonylamino), lower (alkylthio, alkylsulfinyl) or alkylsulfonyl), morpholino, 1- or 2-pyrrolyl, phenyl, 5-7-membered cycloalkyl, lower-alkanoyl, lower-alkoxycarbonyl, carbamoyl or sulfamoyl; R, _ also Miederalkvl or arylalkoxy means which radicals may be substituted by one substituent of the group cycloalkyl of 3 to 5 carbon atoms, phenyl, lower alkyl , hydroxy, lower alkylcarbonylamino, lower alkyl (thio, sulfinyl or sulfonyl) or carbamoyl; X is 0 or S; and their salts. 4) when a compound of the formula I in which R is lower-alkyl is desired, into a compound in which R, is hydrogen, introduces a radical mentioned, and / or 5. The method according to item i, characterized in that V'erbindunaen of formula III OH H
CH-CH ₀ -IM- * \ -h \ ² w wherein R_ is hydrogen or Niedsralkvl; R 1 is cyano, lower alkoxycarbonyl, pyrrolyl, morpholino, alkenyloxy of 3 to 6 carbon atoms, alkynyloxy of 3 to 6 carbon atoms or alkoxy of 1 to 3 carbon atoms substituted by cyclopropyl; and their salts. 13.10.1983 AP C 07 D / 251 330/5 - Sun - 52 512/11 δ. Process according to item 1, characterized in that compounds of items 4 and 5, in which the zirconium substituents of cis-stalactite are present, and in salts, are prepared. 5) when a compound is desired wherein the substituent of the group Ar is alkyl, a compound wherein the substituent is alkenyl or alkynyl is reduced, and / or 6) when a compound is desired in which the substituent of Ar is carbarjoyl, in a compound wherein the substituent is cyano, this radical is carmally notransformed, and / or 7, Method according to item 1, characterized in that compounds of the formula III shown in point 5, in which the hydroxyl group traganda carbon atom has the cis configuration, and their salts. 7) when a compound is desired in which the group .Ar contains a hydroxy or hydroxy-lower alkyl substituent in a compound in which these groups are in protected form,: releases, and / or 13.10.1983 AP C 07 D / 251 330/5 - 53 - 52 512/11 8, Process according to item 1, characterized in that compounds of the formula IU ₁ shown in point 5 in which R-, is hydrogen, R ^ is allyloxy, propargyloxy or cyclopropylmethoxy, their stereoisomers and snantiomers, and salts of these compounds, 9, process according to item 1, characterized in that cis-1- {4- (3- (o -allyloxyphenoxy) -2-hydroxypropylamino] cyclohexyl) -2-imidazolidirine, and its salts are prepared » 9) wenη one compound is desired in which whether Ar group has a niaderalkoxy, Niederalkenyloxy- or lower cycloalkyl-niedaralkoxy substituent, a hydroxy 'substituent converted to said radical, and / or 10, process according to item I _1, characterized in that cis -i {4- [3- (o-Cyclopropyirasthoxyphenoxy) -2-hydroxypropylatTiino'j-cyclohexyl) -2-imidazolidinone which produces S-enantiomers and their salts, 10) when a compound in which X is a sulfur atom is desired, in a compound wherein X is oxygen, converts it to sulfur, and / or, if desired, converts a compound of formula I obtained into another compound of the invention, and / or / z / if desired, converting a resulting free compound into a salt or a salt obtained into the free compound or into another salt, and / or, if desired, a resulting mixture of isomers or racemates in the individual isomers or Racetnats aftrennt, and / or, if desired, obtained racemate in dis optical antipodes. 11, method according to item I _1, characterized in that one prepares cis-i- (4- [3- (o-pyrrolylphenoxy) -2-hydroxypropylamino-3-cyclohexyl) -2-imidazolidinone and its salts.