FI62060C - PROCEDURE FOR FRAMSTATION OF BETA-BLOCKING SUBSTITUTES 2-HYDROXY-3- (2-ACYL-4-UREIDO-PHENOXY) -PROPYLAMINDERIVAT - Google Patents

Description

ΓΒΐ5ϊ ^ Π ΓΒΐ f11x «CUULUTU $ PUBLICATION

ΛΓα lBJ (11) UTLÄGGININOSSKRIFT 6 ^ 060 ^ ^ (51) K ¥ .ik? /Int.a3 C 07 C 127/19, C 07 D 295/20 FINLAND — FINLAND (* i) mmmigmimm · —mmmmmmki · 3612 / 71 * (22) Hekemtapllvi — AMeknlnpdtf 13.12.7l * (23) AlkupUvt — GlMgtMtfdag 13.12.7I + (41) Tullut lulkltulcri - MWIt ofUntltg 21.06.7 5

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Patent- och ragistarttyralMn AmMcan tittagd och utUkrtfMn publlcund 30.07.82 (32) (33) (31) Pyydtey ucuolkm · * —e «| and <l priorHm 20.12.73 Ι9.ΙΙ.7Π, 20.11.71+, 25.11.T1 * Austria-Austria (AT) A 10666/73, A 9266/7! +, A 9308/71 * A 9 ^ 36/7 ^ (71) Chemie Linz Aktiengesellschaft, St.-Peter-Strasse 25, Linz, Austria- Österrike (AT) (72) Gerhard Zölss, Linz, Herihert Pittner, Gmund, Heimo Stormann-Menninger-Lerchenthal, Linz, Austria-Österrike (AT) (7I +) Leitzinger Oy (5I +) The process for the preparation of β-blocking substituted 2-hydroxy- 3 - (2-acyl-h-ureido-phenoxy) -propyl-amine derivatives

Substances with β-receptor blocking activity have become increasingly important in therapy in the treatment of various heart diseases, which can be causally or symptomatically explained by excessive circulatory loading of the body's own catechol amines. Substantial progress has been made in finding so-called cardioselective β-blockers - substances that primarily act only on the β-receptors of the heart, but little on the β-receptors of other organs. In this way, adverse side effects, such as spastic effects on the respiratory tract, have been avoided. To date, however, only one of these has been put into practice, namely 1 '- / 4-acetamino-phenoxy- (2'-hydroxy-3'-isopropylamino) / -propane, which is described in Austrian Patent 261,582, so that there is still a great need. to find actually useful, cardioselective β-blockers. However, many β-blockers have the disadvantage of an unfavorable cardidepressant effect, often associated with a β-blocking effect.

2,62060 Also known from the patent literature are cardioselective phenoxypropylamine derivatives which have a ureido group (DT-OS no. , as well as cardioselective phenoxypropylamine derivatives having an alkanoylamide group in the p-position and acyl groups, for example an acetyl group in the o-position relative to the propylamine side chain, see Austrian Patent Publication No. 292,671.

It has now surprisingly been found that substituted phenoxy-2-hydroxy-3- (2-acyl-4-ureido) -propyl derivatives having an ureido group in the p-position and an acyl group in the o-position relative to the phenoxypropylamine chain, preferably a lower alkanoyl group and having the general formula R- NH-CO-N 2 'rAs I 0

OCH2-CH-CH2-NH · R3 OH

wherein R is hydrogen or a straight-chain or branched alkyl group having 1 to 6 carbon atoms, R 1 is a hydrogen atom, a straight-chain or branched alkyl group having 1 to 6 carbon atoms, a cyclohexyl, benzyl or phenyl group, or R and R 1 together are an alkylene group having 4 or 5 carbon atoms or an ethyleneoxyethylene group, R 2 represents alkyl having 1 to 6 carbon atoms, a benzyl or phenyl group, and R 3 represents a branched alkyl group having 3 to 6 carbon atoms, a cyclopropyl group, or 2-cyano-1 -methylethyl group, and their salts have clear cardioselective, / S-blocking properties with very good and reliable oral efficacy. The latter was determined by the method of Dunlop and Shanks, Brit. J. Pharmacol. 32, 201-18, 1968 in awake dogs. The cardioselective effect can be found, for example, that according to the method of Shanks et al., Cardiot 3 62060 logia Suppl. II, 49, 11 (1966) isoprenaline-induced increases in heart rate are inhibited in anesthetized dogs by prior administration of these compounds more strongly than the antihypertensive effect of isoprenaline. This effect can be further observed in the isoprenaline-induced blockade effect of non-esterified fatty acids in rats (g ^ effect), while hardly any effect on isoprenaline-elevated lactant and glucose values was observed (g2 ~ effect).

Despite the fact that the compounds of general formula I have a high B-blocking effect in the study of heart rate in awake dogs according to Barrett and Carter,

Brit. J. Pharmacol. 40, 373-81 (1970), they do not lower the heart rate at all after oral administration of the agents, which suggests that the compounds of formula I do not have an adverse and partially dangerous cardiodepressant effect. The toxicity of the compounds of formula I in mice is equal to or even lower than that of a commercially available β-blocker.

The compounds of the formula I are prepared in such a way that the p-aminophenol derivative of the general formula Ha is NH-CO-N, iJ- c - * 2 <IIa) 11 i °

0CH2X

wherein R 1 and R 2 are as defined above, and X is a group -CH - CH 2 or -CH - CH 2 - Hal, wherein Hal is chlorine, bromine or iodine,

O ^ OH

is reacted with amines of general formula IIIa H2N-R3 (purple) 462060 wherein R1 is as defined above. The reaction may be carried out at room temperature or at an elevated temperature, for example 30 to 150 ° C, preferably below 120 ° C. When using compounds having ureido groups substituted by two alkyl groups, it is preferable to operate preferably at or slightly above room temperature. In this case, it is possible to work in a polar solvent, for example dimethylformamide, acetonitrile, dioxane or tetrahydrofuran, but preferably in lower aliphatic alcohols. The amine of formula lila itself can also act as a solvent. Can also be operated without solvent. If the amine of formula IIIa is volatile at the reaction temperature, the reaction must be carried out in a closed system.

In general, it can be said that the compounds of the general formula IIa in which X represents an epoxy group are more reactive than the corresponding halohydrins. This must be taken into account under the reaction conditions, since in the latter case higher temperatures are used, for example 40 to 120 ° C. In both cases, the addition of water has an accelerating effect on the reaction, which is best seen in the fact that the addition of water can also be carried out at room temperature using the halohydrins of the formula Ha as starting material.

However, the compounds NH2 of the general formula Hb can also be selected as starting materials

rS

IL sj- C - R0 (Hb) 1! I o

0CH2X

wherein R2 and X are as defined above. These are initially reacted with amines of the general formula IIIa, after which a ureido group is reacted by reacting with compounds of the formula IV ✓ R \ R5.CO-N, (IV) \ p R1 5 62060 where R5 represents a halogen atom and R and have the same meaning as above . The reaction conditions between the compounds of formula Hb and the compounds of formula IIIa are the same as in the reaction between the compounds of formula IIa and the compounds of formula IIIa.

Another method of preparation is that the carbon or thioic acid derivative of general formula Ile

NH-C-Y

Ä \ - C "R2

£ <IIc> O-CH2-CH-CH2-NH-R3 OH

wherein Y is an alkoxy, aryloxy, aralkyloxy, alkylthio, arylthio or aralkylthio group, and R 2 and R 3 are as defined above, are reacted with amines of formula IIIb wherein R 1 and R 3 are R 1 wherein R and R 1 has the same meaning as above, at room temperature or at elevated temperature. Preferred starting compounds are then compounds of the formula IIe in which Y is an alkoxy or alkylthio group having up to 4 carbon atoms, a phenoxy or phenylthio group or a benzyloxy or benzylthio group.

The above-mentioned polar solvents can also be used as media, in which case mixtures of lower aliphatic alcohols and water are particularly preferred. An amine of formula IIIb can also be used as a solvent when a corresponding excess is used.

6 62 C 60

The choice of reaction conditions is determined by the chemical quality of the compounds of formula lie. If Y is an aromatic, for example a phenyloxy or phenylthio group, then room temperature is usually sufficient for the reaction. In contrast, compounds of formula Ile in which Y is aliphatic must be heated for several hours at about 100 ° C. The compounds of formula Ile can also be used as a crude reaction mixture obtained by reacting the corresponding compounds having a free amino group with compounds of formula C1-CO-Y in which Y is as defined above and distilling off only the solvent used, for example pyridine.

If it is desired to prepare compounds of the formula I which do not contain hydrogen, this is also possible by converting the urea derivatives of the general formula Ild nh-co-nh2

Cp-? - * 2 <1M>

O-CH2-CH-CH2-NH · R3 OH

wherein R and R 3 are as defined above, to react according to formula IIIc with amines R 1 HN · (IIIC) R 7 wherein R is as defined above and R 1 is an optionally branched alkyl group having 1 to 6 carbon atoms, a cyclohexyl group, benzyl - or a phenyl group, or together with the group R an alkylene group having 4 or 5 carbon atoms or an ethyleneoxyethylene group.

7 62060

The reaction is carried out at temperatures of about 50 to 200 ° C, suitably 50 to 150 ° C and the amine is suitably used in excess. The above-mentioned solvents, especially mixtures of lower aliphatic alcohols and water, are still considered to be the best reaction media.

If the amines are volatile at the reaction temperature, work in a closed vessel. If amine salts are used, an equivalent amount of alkali hydroxide must be added.

Finally, the alkali metal salts of the phenols of the general formula Ile nh-c-nC ^ / I o Ri I (Ile)

L C-R

Il Ä I 0

OH

wherein R, R 1 and R 2 are as defined above, may be reacted with compounds of general formula IIId. a cleavable benzyl group. The latter must later be cleaved off by catalytic hydrogenation.

Alkali salts of phenols of formula IIe may also be formed in situ by adding to the reaction charge s 62060 free phenol of formula IIe and an equivalent amount of alkali hydroxide. The reaction conditions are the same as in the previous methods.

Isolation of the compounds of formula I from the reaction mixture takes place in the usual manner. For example, salts of the compounds of formula I with decarboxylic acids, for example fumarate, oxalate or succinate, have a very good tendency to crystallize, which salts are thus preferred for isolation. Of course, all conventional pharmaceutically acceptable salts can also be prepared, such as hydrohalides, such as hydrochloride and hydrobromide, sulfate, phosphate, acetate, cyclohexyl sulfamate, tartrate or citrate, and the like.

The compounds of formula I have an asymmetric carbon atom. They thus exist in racemic and optically active forms. Separation of the racemate into optically active forms takes place in the usual manner, for example by formation of a diastereomeric salt with optically active acids, for example tartaric acid, camphorsulphonic acid, etc.

The compounds of general formula Ha, b, c, d and e used as starting materials are mostly new. Their preparation is explained in connection with the examples.

Of the compounds of formula I, those compounds in which R is a hydrogen atom or a straight-chain or branched alkyl group having up to 6, preferably up to 4 carbon atoms have a particularly favorable effect.

Particularly advantageous properties are generally obtained by compounds in which R and R 1, which may be the same or different, represent a hydrogen atom or an alkyl group having 1 to 6, preferably 1 to 4 carbon atoms, or both groups together represent tetramethylene, pentamethylene or 3-oxapentamethylene group, R2 represents a lower alkyl group having 1 to 5 carbon atoms, and R3 represents a tertiary butyl group or an isopropyl group.

62060 9

Pharmacological comparative tests

The experiments have compared the pharmacological properties of the compounds of the formula I DE-OS 2,229,241, 2,229,242 and 2,100,323 and the compounds of the formula AT-PS 282,671. The experiments have observed the effect of the compounds on the positive chronotropic isoprenaline effect in anesthetized rats to determine the β-blocking effect and the effect of the compounds on the contractile ability of electrically irritated guinea pigs to determine the cardiodepressant effect of the compounds.

The following compounds were used in the experiments: N, N-acetyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N'-diethylurea; code ST 1396 N- [3-acetyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N'-dimethylurea; code ST 1323 N- [3-acetyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N'-methyl-N1-ethylurea; code ST 1406 N- [3-acetyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N'-methyl-N'-n-butylurea; code ST 1413 N- [3-butyryl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N'-diethylurea; code ST 1410

Comparative compounds Compounds according to DE-OS 2,229,241 a) 1- [2-allyl-4- (3-ethylureido) -phenoxy] -3-isopropylamino-2-propanol; code ST 1463 b) 1- [4- (3-allylureido) -phenoxy] -3-tert-butylamino-2-propanol; code ST 1232 t 62060 ίο c) 1- [2-methyl-4- (3-allylureido) -phenoxy] -3-isopropylamino-2-propanol] code ST 1460 Compounds according to DE-OS 2 229 242 a) l- £ 4 - (3-n-butylureido) -phenoxy] -3-tert-butylamino-2-propanol and code ST 1458 b) 1- [4- (3-n-propylureido) -phenoxy] -3-tert-butylamino-2- propanol and code ST 1459 c) 1- (2-methyl-4- (3-n-propylureido) phenoxy] -3-isopropylamino-2-propanol) code ST 1461 d) 1- [2-methyl-4 - (3-n-butylureido) -phenoxy] -3-isopropylamino-2-propanol> code ST 1462 Compounds according to DE-OS 2 100 323 a) 1-t (P-N'-N "-dimethylureido) -phenoxy ] -2-hydroxy-3-iso-propylamino-propane, code ST 1465 b) 1- [E (o-chloro-p-N ', N'-dimethylureido) -phenoxy] -2-hydroxy-3-iso-propylamino -propane> code ST 1466 c) 1- [E (o-allyl-p-N ', N'-dimethylureido) -phenoxy] -2-hydroxy-3-iso-propylamino-propane} code ST 1467 d) 1 - [( p-N ', N' - (3-oxapentamethylene-1,5) -ureido) -phenoxy] -2-hydroxy-3-isopropylaminopropane> code ST 1468 AT-PS 292 671 y Compound 1- (4'-Butyramido-2'-acetyl-phenoxy) -2-hydroxy-3-isopropylamino-propane, code ST 1358

All compounds were used in the form of an aqueous solution of their salts.

11 62060

Test methods: 1. Effect on positive chronotropic isoprenaline effect.

Male and female rats weighing 250-300 g and anesthetized with Nembutal R (30 mg / kg ip) were used in the experiment. The test compound was administered intraduodenally at doses of 1.4 mg / kg, and 100 μg / kg of isoprenaline was injected after dosing. . Isoprenaline-induced increases in heart rate were measured on an ECG device. When isoprenaline was injected without test compound, the heart rate increased by 149 to 13 beats per minute. Column A of the following table shows the changes in heart rate 30 minutes after dosing.

The change in heart rate is a good indication of the adrenergic blocking effect of the compound, and the less isoprenaline is able to affect the heart rate, the more effective the compound is.

2. Effect on the cardiovascular contractility of electrically irritated guinea pigs.

Female and male guinea pigs weighing about 350 g were used as experimental animals. The test animal was sacrificed and the heart was rapidly removed and the left atrium was cleaned and placed in a suitable bath maintained at 37 + 0.5 ° C, where it was continuously rinsed with Tyrode's solution having the following composition:

NaCl 136.9, KCl 5.4, MgCl 2 1.05 NaHCO 3 11.9, NaH 2 PO 4 0.42, CaCl 2 1.8, glucose 5.5. A gas mixture containing 95% O 2 and 5% CO 2 was further introduced into the bath.

The heart palettes were then irritated 60 times per minute with electric shocks. The contraction caused by these electrical stimuli was measured with stretch strips and the stretch was recorded with a plotter. Each vestibule was biased at 1 g.

All test compounds were added to the rinsing solution at a concentration of 10 ”5 Val / l. 10 minutes after the addition of the test compound, the change in contraction was measured.

The change in contraction is an indication of the cardiodepressant effect of the compound. The smaller the attenuation of contraction, the smaller the cardiodepressive effect of the test compound.

The values obtained in the experiments are given in the following table.

Heartbeat- Contraction

Test compound frequency change __increase_

Isoprenali ini _149 + 13_ FI-pat.hak.

3612/74 ST 1396 54 + 19 + 0 ST 1323 61 + 14 +1 ST 1406 54 + 22 - 5 ST 1413 73 + 20 - 5 _ST 1410_64 + 16 _ + _ 5_ DE-OS ST 1463 104 ± 22 - 15 2 229 241 ST 1232 77 + 18 - 19 ___ST 1460_65 + 12_- 30_ DE-OS ST 1458 70 + 5 - 24 2 229 242 ST 1459 63 + 12 - 13 ST 1461 54 + 9 - 30 _____ST 1462_91 ± 17_- 23_ DE-OS ST 1465 83 + 20 - 27 2 100 323 ST 1466 84 + 24 - 27 ST 1467 89 + 25 - 24 __ST 1468_86 + 23_- 22_ AT-OS 292 671 ST 1359_74 ± 18 _ = _ 7_ ______Practolol (g) 52 + 19_- 25_

The results obtained show that the 3-blocking effect of the reference compounds at the intraduodenal dose is partly similar to that of the compounds of formula I and partly weaker. The cardioprotective effect of the compounds shows that the compounds of formula I have a significantly weaker contraction-reducing effect than the comparator compounds. effect is an undesirable side effect, this means in practice that the compounds of formula I are considerably more advantageous in effect than the reference compounds.

Pharmaceutically acceptable soluble salts which can be converted into stable solutions can be processed into injectable solutions. The salts required for this are obtained from the corresponding bases of the formula I simply by reacting them with an equivalent amount of acid. Both bases and salts can be processed into suppositories in the usual manner.

In humans, the single dose is 100 mg when administered orally and correspondingly less when administered intravenously.

Example 1 172.3 g of N- [3-acetyl-4- (21-31-epoxy) -propoxy] -phenyl-N'-diethylurea and 620 ml of water are mixed and 620 ml of tert-butylamine are added. The reaction mixture warms to about 40 ° C and the added compound dissolves rapidly. Keep for a total of 5 hours at room temperature, then distill on a rotary evaporator under vacuum at 40 ° C.

The residue is dissolved in 124 ml of 4N hydrochloric acid and 500 ml of water, the acidic solution is extracted with ethyl acetate, shaken with charcoal, filtered and 124 ml of 4N sodium hydroxide are added. The separated base is extracted with ethyl acetate, the ethyl acetate solution is dried over sodium sulfate, filtered and evaporated. The residue crystallizes on trituration with ether. The precipitated crystals are filtered off with suction and dried.

Yield: 167.4 g »78% of theory of N- [3-acetyl-4- (31-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N'-diethylurea.

Base melting point: 110-112 ° C.

Example 2

A mixture of 8 ml of tert-butylamine and 8 ml of water is added to 1.0 g of N- [3-acetyl-4- (21-hydroxy-3'-chloro) -propoxy] -phenyl-N'-diethylurea ( melting point = 144-146 ° C) and allowed to stand at 14 62060 for 17 hours at room temperature. The clear reaction solution is evaporated in vacuo, the oily residue is dissolved in 1N hydrochloric acid and extracted with ethyl acetate. The acidic aqueous solution is made alkaline, the separated base is extracted with ethyl acetate, the organic layers are dried and evaporated, and the oily residue crystallizes on trituration with ether.

Yield of N- [3-acetyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N1-diethylurea: 1.0 g = 90.4% of theory. Melting point: 110-112 ° C.

Example 3: 1.0 g of N- [3-acetyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenylcarbamic acid phenyl ester hydrochloride is dissolved in 25 ml of a 1: 1 mixture of ethanol and water ( volume), 0.37 g of diethylamine is added and allowed to stand for 21 hours at room temperature. After the reaction, the alcohol is distilled off in vacuo, the aqueous residue is shaken several times with chloroform, the organic phase is dried over sodium sulfate and evaporated in vacuo. The oily residue is triturated with ether, the crystals formed are filtered off with suction, washed with ether and dried.

Yield of N- [3-acetyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N'-diethylurea: 0.7 g = 80.7% of theory.

Melting point: 110-112 ° C.

The starting N- [3-acetyl-4- (3'-tert-butylamino-21-hydroxy) -propoxy] -phenylcarbamic acid phenyl ester hydrochloride can be obtained as follows: 10.0 g of 3-acetyl-4- (3 ' tert-butylamino-2'-hydroxy) -propoxan-1-amine is dissolved in 100 ml of pyridine, 7 g of carbamic acid phenyl ester are added and allowed to stand for 3 days at room temperature. The clear solution is then concentrated in vacuo, the oily residue is taken up in 20 ml of acetone, seed crystals are added, 200 ml of water are slowly added, the precipitated crystals are filtered off with suction and washed with acetone / water and dried over phosphorus pentoxide.

After recrystallization from acetonitrile, the hydrochloride has a melting point of 176-180 ° C.

15 62060

Example 4: ^ 0.20 g of N- [3-acetyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenylcarbamic acid phenyl ester hydrochloride is dissolved in 4 ml of a mixture of ethanol and water in a volume ratio of 1: 1, 0.1 g of piperidine is added and allowed to react for 19 hours at room temperature. The alcohol is then distilled off in vacuo, the aqueous solution is seeded with crystals, a little ether is added, the crystals formed are filtered off with suction and dried.

Yield of N- [3-acetyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N'-pentamethylene (1,5) -urea: 0.15 g = 83.6 % of theoretical.

Melting point: 132-135 ° C.

Example 5: 0.4 g of N- [3- (acetyl-4- (31-tert-butylamino-2'-hydroxy) -propoxy] -phenylcarbamic acid phenyl ester hydrochloride is dissolved in 8 ml of a mixture containing ethanol and water in a volume ratio of 1: 1, 0.18 g of aniline are added and heated to reflux for 16 minutes, then the alcohol is distilled off in vacuo, the aqueous solution is made alkaline with 1N sodium hydroxide, seed crystals are added, the precipitated crystals are filtered off with suction and washed with water and ether.

Yield of N- [3-acetyl-4- (31-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N'-phenylurea: 0.35 g = 95.6% of theory.

Melting point: 159-164 ° C.

Example 6: 0.5 g of N- [3-acetyl-4- (31-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-carbamic acid ethyl ester is heated at reflux for 24 hours in 20 ml of piperidine. The excess piperidine is then distilled off in vacuo, the residue is triturated with ether with a small amount of acetone, the crystals formed are filtered off with suction and washed with ether / acetone.

ie 6 2 0 6 0 Yield of N- [3-acetyl-4- (3'-tert-butylamino-21-hydroxy) -propoxy] -phenyl-N'-pentamethylene (1,5) -urea: 0.3 g = 54.1% of theory.

After recrystallization from acetone / ether, the melting point is 132-135 ° C.

The starting N- (3-acetyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenylcarbamic acid ethyl ester can be obtained in an analogous manner to the corresponding phenyl ester as follows: 2.4 g of chloroformic acid ethyl ester are added 5.0 to 3 g of 3-acetyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxyaniline in 50 ml of pyridine and stirred for 1 hour at 80 ° C. The pyridine is then distilled off in vacuo, the crystalline residue is dissolved in 30 ml of water, basified with sodium hydroxide, the precipitated crystals are filtered off with suction, washed with water and dried over phosphorus pentoxide.

Yield: 6.2 g = 98.8% of theory.

After recrystallization from ethanol, the compound has a melting point of 148-152 ° C.

Example 7: 2.0 g of N- [3-acetyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-carbamic acid benzyl ester (prepared from the corresponding aniline compound with chloroformic acid benzyl ester; melting point of the hydrochloride: 172-175 °) C) and 20 ml of piperidine are heated at reflux for 9.5 hours with stirring. The excess piperidine is then distilled off in vacuo, the oily residue is taken up in ether, seed crystals are added and allowed to stand at room temperature to complete crystallization. The precipitated N- [3-acetyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N'-pentamethylene- (1,5) -urea is filtered off with suction, washed with ether and dried. Yield: 0.85 g = 44.9% of theory.

Melting point of base: 132-135 ° C.

Example 8: 3.0 g of 3-acetyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxyaniline are dissolved in 15 ml of pyridine, 2.4 g of monothioic acid s-phenyl ester chloride are added and the mixture is stirred. 1 hour at 90 ° C. The solvent is then distilled off in vacuo.

17,62060 The crude N- [3-acetyl- [(3'-tert-butylamino-2'-hydroxy) -propoxy] -phenylcarbamic acid thiophenyl ester thus obtained is dissolved in 30 ml of ethanol and 15 ml of water, 7 ml of , 8 g of diethylamine and allowed to react for 23 hours at room temperature. The alcohol is then distilled off in vacuo, the aqueous solution is made alkaline with sodium hydroxide, shaken several times with methylene chloride, the organic phase is dried over anhydrous sodium sulfate and evaporated in vacuo.

The residue solidifies on trituration with acetone / ether. The N- [3-acetyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N'-diethylurea thus obtained is filtered off with suction and washed with acetone / ether.

Yield: 2.15 g = 52.9% of theory.

Melting point: 110-112 ° C.

Example 9: 20 ml of methanol are added to 0.5 g of N- (3-acetyl-4-hydroxy) phenylurea, a solution of 0.68 g of potassium hydroxide (85%) in 5 ml is added. water, 2.48 g of 1-chloro-2-hydroxy-3- (N-benzyl-N-isopropylamino) -propane are added and the mixture is heated with stirring and boiling for 25 hours. The methanol is then removed in vacuo, the residue is acidified with 1N hydrochloric acid, extracted with chloroform and the chloroform phase is discarded. The acidic aqueous solution is made alkaline and shaken several times with chloroform. The chloroform solution is dried and evaporated. The residue is triturated with ether and the precipitated crystals are filtered off with suction.

Yield of N- [3-acetyl-4- (3'-N-benzylisopropylamino-2'-hydroxy) -propoxy] -phenylurea: 0.6 g = 58.3% of theory. After recrystallization from methyl ethyl ketone, the compound has a melting point of 127-13 ° C.

156 mg of N- [3-acetyl-4- (3'-N-benzylisopropylamino-2'-hydroxy) -propoxy] -phenylurea are added to a prehydrated suspension containing 15.6 mg of Pd carbon (10% ) In 7.0 ml of glacial acetic acid and hydrogenated at room temperature until hydrogen consumption ceases. The connection is broken, the filtrate is evaporated in vacuo, the residue is dissolved in water, basified with sodium hydroxide (pH 10), extracted with chloroform, the chloroform solution is evaporated after drying in vacuo, the oily residue is triturated with acetone, seed crystals are added and the crystals are filtered off with suction. Yield of N- [3-acetyl-4- (3'-isopropylamino-2'-hydroxy) -propoxy] -phenylurea: 72 mg = 59.6% of theory.

Melting point: 124-126 ° C.

The starting N- (3-acetyl-4-hydroxy) -phenylurea can be prepared as follows: 50.0 g of 3-acetyl-4-hydroxyaniline hydrochloride and 43.2 g of potassium cyanate are heated at reflux for 30 minutes in 1350 ml of a mixture containing ethanol / water 1: 1, cooled and allowed to stand overnight for crystallization at -5 ° C.

Yield of N- (3-acetyl-4-hydroxy) -phenylurea: 36.7 g = 71.0% of theory.

Melting point: 218-220 ° C.

1-Chloro-2-hydroxy-3- (N-benzyl-N-isopropylamino) -propane can be prepared as follows.

5.0 g of N-benzylisopropylamine are stirred for 2 hours at 50 [deg.] C. in a mixture of 12 ml of methanol and 5 ml of water. The methanol is distilled off in vacuo at 30 ° C. The separated base is extracted with ether, the ether solution is dried over anhydrous sodium sulfate and evaporated. The residue is quenched in vacuo.

Boiling point 0.05 mm = 91 - 92 ° C.

Yield: 7.0 g = 86.6% of theory.

Example 10: 50 ml of ethanol are added to 1.0 g of N- (3-acetyl-4-hydroxy) -phenylurea, 5.27 g of 1-chloro-2-hydroxy-3- (N-benzyl-N -tert-butylamino) -propane and a solution of 1.36 g of potassium hydroxide (85% KOH) is added. The reaction mixture is heated at reflux for 23 hours under nitrogen, the alcohol is distilled off in vacuo, water is added to the residue, acidified with hydrochloric acid and extracted with chloroform. The aqueous layer is made alkaline and shaken again with chloroform. The extract is dried over anhydrous sodium sulfate, after which the solvent is distilled off in vacuo. The residue is triturated with ether, seed crystals are added and the precipitated crystals are filtered off after some time.

19 620 6 O

Yield of N- [3-acetyl-4- (31-N-benzyl-tert-butylamino-2'-hydroxy) -propoxy] -phenylurea: 1.15 g = 54.0% of theory, melting point (from acetone): 145 - 147 ° C.

From this benzyl compound, N- [3-acetyl-4- (31-tert-butylamino-2'-hydroxy) -propoxy] -phenylurea, melting point (hydrochloride) 195 to 197 ° C, can be obtained according to Example 9.

The starting material was prepared according to Example 9.

The boiling point of 1-chloro-2-hydroxy-3- (N-benzyl-N-tert-butylamino) propane at 0.05 mm is 105-107 ° C.

Example 11: 0.5 g of N- (3-acetyl-4-hydroxy) -phenyl-N'-methyl-urea is dissolved in methanol, a solution of 0.2 g of potassium in 25 ml of water is added, 0.5 g of l -chloro-2-hydroxy-3-tert-butylaminopropane hydrochloride and boil for 45 hours.

The solvent is distilled off in vacuo, the residue is taken up in methylene chloride, the organic phase is shaken with sodium hydroxide and water, dried over sodium sulfate and evaporated in vacuo.

The N- [3-acetyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N'-methylurea thus formed crystallizes after addition of seed crystals and trituration with ether.

Melting point: 132-134 ° C.

Example 12: 18 ml of methanol are added to 1.0 g of N- (3-acetyl-4-hydroxy) -phenyl-N'-pentamethylene (1,5) -urea, 0.8 g of 1-chloro-2- hydroxy-3-tert-butylaminopropane hydrochloride, 0.5 g of potassium hydroxide (85%) and 2 ml of water and stirred for 27 hours at 50 ° C.

The solvent is distilled off in vacuo, the residue is taken up in 1N hydrochloric acid and washed several times with ethyl acetate. The aqueous solution is made alkaline with 4N sodium hydroxide, shaken several times with methylene chloride, the organic phase is dried over sodium sulfate and evaporated in vacuo.

20 62C60 The residue containing the base of N- [3-acetyl-4- (3'-tert-butylamino-21-hydroxy) -propoxy] -phenyl-N'-pentamethylene (1,5) -urea is dissolved in 5 ml acetone for the preparation of fumarate, a solution of 0.1 g of fumaric acid in 5 ml of acetone is added, seed crystals are added, the separated crystals are filtered off, washed with acetone and ether and dried.

Melting point: 211-213 ° C.

Example 13: Preparation of N- [3-acetyl-4- (3'-N-benzyl-N-isopropylamino-2'-hydroxy) -propoxy] -phenyl-N'-diethylurea (melting point of fumarate: 110-112 ° C) takes place according to Example 1.

To catalyze the N-benzyl group by catalytic hydrogenation, 111 mg of N- [3-acetyl-4- (3'-N-benzyl-N-isopropylamino-2'-hydroxy) -propoxy] -phenyl-N'-diethylurea is added to the prehydrated suspension, containing Raney nickel in 6.5 ml of ethanol and Hydrated at room temperature until hydrogen consumption ceases. Reaction time 5 hours.

The catalyst is separated off, the solvent is distilled off under reduced pressure, the oily residue is taken up in ether, seed crystals are added and the precipitated crystals are separated off after some time by suction.

Yield of N- [3-acetyl-4- (3'-isopropylamino-2'-hydroxy) -propoxy] -phenyl-N'-diethylurea: 65 mg = 73% of theory.

Example 14: 2.0 g of N- [3-acetyl-4- (31-tert-butylamino-2'-hydroxy) -propoxy] -phenylurea are heated at reflux in 10 ml of piperidine for 6 hours. The excess amine is then completely distilled off in vacuo, the oily residue is triturated with acetone, seed crystals are added, cooled and allowed to stand overnight. The precipitated crystals are filtered off with suction, washed with ether and dried.

2i 62 0 6 0 Yield of N- [3-acetyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N1-pentamethylene (1,5) -urea: 1.1 g = 45.5% of theory.

Melting point of fumarate: 211-213 ° C.

Dissolve 1 g of the starting material in 20 ml of ethanol, add 1.53 ml of piperidine, react at 130 ° C for 7 hours in an autoclave and evaporate the reaction mixture in vacuo, dissolve the oily residue in acetone, acidify with a solution of fumaric acid in acetone and precipitate the crude N- / 3 -acetyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N'-pentamethylene (1,5) -urea Fumarate is isolated, whereby after recrystallization from the alcohol and separation of the part insoluble in boiling point evaporate the alcoholic filtrate and cool. 0.85 g of N- [3-acetyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N'-pentamethylene (1,5) -urea fumarate is obtained. This corresponds to 61.1% without theoretics.

Preparation of the starting compound: 80 ml of methanol are added to 20.0 g of 3-acetyl-4-hydroxyphenylurea, a solution of 6.4 g of potassium hydroxide (85%) in 50 ml of water is added, 80 ml of ml of epichlorohydrin and the mixture is stirred for 5 hours at 50 ° C.

The reaction mixture is concentrated in vacuo, water is added to the concentrate, cooled and the precipitated crystals are filtered off with suction, washed with water and air-dried.

Yield of N- [3-acetyl-4- (2 ', 31-epoxy) -propoxy] -phenylurea: 24.6 g = 95.8% of theory.

Melting point: 163-166 ° C.

24.6 g of epoxide are stirred for 4 hours at room temperature in a mixture of 115 ml of tert-butylamine and 100 ml of water. The reaction mixture is evaporated in vacuo, 100 ml of water are added to the residue and it is acidified to pH 3 with hydrochloric acid. The acidic solution is extracted with ethyl acetate and alkalized. Some of the formed base crystallizes and is separated by suction. The rest is isolated by extraction of the mother liquor with ethyl acetate. Yield of N- [3-acetyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenylurea: 26.8 g = 84.3% of theory. Melting point of the hydrochloride: 195-197 ° C.

22 62060

Example 15 20 ml of diethylamine are added to 2.0 g of N, N-acetyl-4- (3'-tert-butylamino-2 * -hydroxy) propoxyl phenyl, 0.2 ml of water are added and the mixture is added. react at 130 ° C for 3 hours in an autoclave. The reaction mixture is evaporated in vacuo, the residue is triturated with acetone / ether and the precipitated crystals are filtered off after some time.

Yields of N- [3-acetyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N'-diethylurea: 1.3 g = 55.5% of theory. Melting point of the base: 110-112 ° C.

Example 16 12 ml of water are added to a mixture of 1.0 g of N-C3-acetyl-4- (3 * -tert-butylamino-2'-hydroxy) -propoxy] -phenylurea and 2.1 g of methylamine hydrochloride, 7 g of , 8 ml of 4N sodium hydroxide and reacted at 130 ° C for 1 hour in an autoclave. The reaction mixture is concentrated in vacuo and shaken several times with ethyl acetate. The ethyl acetate solution is dried over anhydrous sodium sulfate, evaporated, the oily residue is triturated with ether, seed crystals are added, the precipitated crystals are filtered off after some time, washed and dried.

Yield of N- [3-acetyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N'-methylurea: 0.65 g * 62.2% of theory. Melting point (acetone / ether): 132-134 ° C.

In analogy to Examples 1 and 2 above, the following compounds were obtained according to process variant a): Starting material: N- [3-acetyl-4- (2 ', 3'-epoxy) -propoxy] -phenyl-N'-dimethylurea.

Product: N- [3-acetyl-4- (3'-tert-butylamino-21-hydroxy) -propoxy] -phenyl-N'-dimethylurea Base M.p .: 121-122 ° C Fumarate M.p .: 205 - 208 ° C

23,62060 Starting material: N- [3-acetyl-4- (2 ', 3'-epoxy) -propoxy] -phenyl-N'-ethylurea.

Product: N- [3-acetyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N'-ethylurea Fumarate M.p .: 196-198 ° C.

Starting material: N, N-acetyl-4- (2 ', 3'-epoxy) -propoxy] -phenyl-N'-1-sopropyl urea.

Product: N- [3-acetyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N'-isopropylurea Base m.p .: 87-90 ° C.

Starting material: N, N-acetyl-4- (2 ', 3'-epoxy) -propoxy] -phenyl-N'-butylurea.

Product: N- [3-acetyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N'-butylurea Base M.p .: 126-129 ° C.

Starting material: N, N-acetyl-4- (2 ', 3'-epoxy) -propoxy] -phenyl-N'-sec-butylurea.

Product: N- [3-acetyl-4- (3'-tert-butylamino-2, -hydroxy) -propoxy] -phenyl-N'-sec-butylurea Base m.p .: 80-82 ° C

Starting material: N, N-acetyl-4- (2 ', 3'-epoxy) -propoxy] -phenyl-N'-tert-butylurea.

Product: N- [3-acetyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N'-dimethylurea Base M.p .: 123-125 ° C.

Starting material: N, N-acetyl-4- (2 ', 3'-epoxy) -propoxy] -phenyl-N'-dimethylurea.

Product: N- [3-acetyl-4- (3'-tert-isopropylamino-2'-hydroxy) -propoxy] -phenyl-N'-dimethylurea Base m.p .: 103-107 ° C.

24 62060 Starting material: N- [3-acetyl-4- (2 ', 3'-epoxy) -propoxyl] phenyl-N'-dimethylurea.

Product: N-C3-acetyl-4- (3'-tert-cyclopropylamino-2'-hydroxy) -propoxy] -phenyl-N'-dimethylurea Base m.p .: 80-83 ° C.

Starting material: N- [3-acetyl-4- (2 ', 3'-epoxy) -propoxy] -methyl-N'-ethylurea.

Product: N- [3-acetyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -methyl-N'-ethylurea Base M.p .: 90-93 ° C.

Starting material: N-C3-acetyl-4- (2 ', 3'-epoxy) -propoxy] -methyl-N'-butylurea.

Product: N, N-acetyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -methyl-N'-butylurea Base m.p .: 84-86 ° C.

Starting material: N- [3-acetyl-4- (2 ', 3'-epoxy) -propoxy] -phenyl-N'-di-n-butylurea.

Product: N- [3-acetyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N'-di-n-butylurea

The base crystallizes in two variants:

Sp. (from ether): 81-83 ° C

Sp. (methanol / water): 113-115 ° C

Starting material: N- [3-acetyl-4- (2 ', 3'-epoxy) -propoxy] -phenyl-N'-di-n-propylurea.

Product: N- [3-acetyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N'-di-n-propylurea Base M.p .: 83-86 ° C.

Starting material: N- [3-acetyl-4- (2 ', 3'-epoxy) -propoxy3-phenyl-N'-diethylurea.

Product: N- [3-acetyl-4- [3 '- (1 "-methyl-2" -cyanoethylamino) -2'-hydroxy-propoxy] -phenyl-N'-diethylurea Base M.p .: 89-92 ° C .

Starting material: N- [3-acetyl-4- (2 ·, 3'-epoxy) -propoxy] -phenyl-N'-tetramethylene (1,4) -urea.

Product: N- [3-acetyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N'-tetramethylene (1,4) -urea Fumarate M.p .: 218-220 ° C .

Starting material: N- [3-propionyl-4- (2 ', 3'-epoxy) -propoxy] -phenyl-N'-phenylurea.

Product: N- [3-propionyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] phenyl-N'-phenylurea Fumarate M.p .: 204-207 ° C.

Starting material: N- [3-propionyl-4- (2 ', 3'-epoxy) -propoxy] -phenyl-N'-methylurea.

Product: N, N-propionyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy-phenyl-N * -methylurea Base m.p .: 134-136 ° C.

Starting material: N-p-propionyl-4- (2 ·, 3'-epoxy) -propoxy] -phenyl-N'-diethylurea.

Product: N- [3-propionyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N'-diethylurea Base M.p .: 107-109 ° C.

Starting material: N- [3-propionyl-4- (2 ', 3'-epoxy) -propoxy] -phenyl-N'-dimethylurea.

Product: N, N-propionyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy-phenyl-N'-dimethylurea Fumarate M.p .: 199-202 ° C.

Starting material: N- [3-propionyl-4- (2 ', 3'-epoxy) -propoxy] -phenyl-N'-tetramethylene (1H) -urea.

Product: N- [3-propionyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N'-tetramethylene (1/4) -urea Fumarate M.p .: 208-211 ° C.

26,62060 Starting material: N- [3-propionyl-4- (2 ', 3'-epoxy) -propoxy] -phenyl-N' - 3-oxa-pentamethylene (1 → 5) urea.

Product: N- [3-propionyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N'-3-oxa-pentamethylene (1,5) -urea Fumarate Sp. : 193 - 195 ° C.

Starting material: N, N-3-butyryl-4- (2 ', 3'-epoxy) -propoxy] -phenyl-N'-pentamethylene (1,5) -urea.

Product: N- [3-butyryl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N * -pentamethylene (1,5) -urea Fumarate M.p .: 167-170 ° C .

Starting material: N- [3-phenylacetyl-4- (2 ', 3 * -epoxy) -propoxy] -phenyl-N'-pentamethylene (1,5) -urea.

Product: N, N-3-phenylacetyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N'-pentamethylene (1,5) -urea Base Base M.p .: 117 - 118 ° C.

Starting material: N, N-benzoyl-4- (2 ', 3'-epoxy) -propoxy] -phenyl-N * -pentamethylene (1,5) -urea.

Product: n- [3-Benzoyl-4- (3'-tert-butylamino-2 * -hydroxy) -propoxy] -phenyl-N'-pentamethylene (1,5) -urea Base m.p .: 120-123 ° C.

Starting material: N, N-acetyl-4- (2 ', 3'-epoxy) -propoxy-phenyl-N'-methyl-N * -isopropylurea.

Product: N- [3-acetyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N'-methyl-N'-isopropylurea Base M.p .: 105-107 ° C.

Starting material: N, N-acetyl-4- (2 ', 3'-epoxy) -propoxy] -phenyl-N'-ethyl-N'-n-propylurea.

Product: N- [3-acetyl-4- (3'-tert-butylamino-2 · -hydroxy) -propoxy] -phenyl-N'-ethyl-N'-n-propylurea Fumarate M.p .: 176-178 ° C .

27 62060 Starting material: N-C3-butyryl-4- (2 ', 3'-epoxy) -propoxy] -phenyl-N'-diethylurea.

Product: N- [3-butyryl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N'-diethylurea Base m.p .: 56-58 ° C.

Starting material: N- [3-acetyl-4- (2 ', 3'-epoxy) -propoxy] -phenyl-N'-methyl-N'-benzylurea.

Product: N- [3-acetyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N'-methyl-N'-benzylurea Base M.p .: 121-123 ° C.

Starting material: N- [3-acetyl-4- (2 ', 3'-epoxy) -propoxy] -phenyl-N'-methyl-N'-cyclohexylurea.

Product: N-t3-acetyl-4- (3'-tert-butylamino-2 · -hydroxy) -propoxy] -phenyl-N'-methyl-N'-cyclohexylurea M.p .: 134-136 ° C.

28 62060

Example 17 2.0 g of 3-acetyl-4- (3'-chloro-2'-hydroxy) -propoxyaniline were mixed with a mixture of 8.6 ml of tert-butylamine and 60 ml of water for 7 hours at 30 °. The clear solution was concentrated in vacuo, the residue was dissolved in water, acidified with hydrochloric acid and extracted with ethyl acetate. the aqueous solution was basified with sodium hydroxide solution, shaken with ethyl acetate, the organic phase dried over sodium sulphate and evaporated in vacuo. The crystalline residue was digested with acetone / ether and the crystals thus obtained were separated by suction.

The yield of 3-acetyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxyaniline was 0.97 g = 42.1% of theory and its m.p. was 117-118 ° C.

1.0 g of the compound thus obtained, 10 ml of acetonitrile and 0.5 g of finely ground potassium carbonate were reacted with 1.16 g of piperidinecarbonyl chloride for 30 hours at 30-40 ° C.

The reaction mixture was concentrated in vacuo, the residue was dissolved in water and acidified with 4N hydrochloric acid, and the acidic solution was extracted with chloroform (pH 4-5). Finally, the solution was made alkaline, the separated base was shaken with chloroform, the chloroform solution was dried and the solvent was evaporated in vacuo.

Ether was added to the oily residue, and the resulting crystals were separated by suction.

The yield of N- [3-acetyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N'-pentamethylene (1,5) -urea was 0.77 g * 55%. theoretical and Sp. was 131-134 ° C.

In a similar manner, according to process variant b), 3-acetyl-4- (3'-chloro-2'-hydroxy) -propoxyaniline was prepared from N- [3-acetyl-4 - (- 3 * -tert-butylamino-2'- hydroxy) -propoxy] -phenyl-N'-dimethylurea with a base melting point of 121-122 ° C.

Claims (2)

Process for the preparation of β-blocking substituted 2-hydroxy-3- (2-acyl-4-ureido-phenoxy) -propylamine derivatives of formula I NH-CO-N 2 IX 2 (I) T 0 OCH 2 -CH -CH2-NH ♦ R3 OH wherein R is hydrogen or a straight-chain or branched alkyl group having 1 to 6 carbon atoms, R1 is a hydrogen atom, a straight-chain or branched alkyl group having 1 to 6 carbon atoms, a cyclohexyl, benzyl or phenyl group, or R 1 and R 2 together are an alkylene group having 4 or 5 carbon atoms or an ethyleneoxyethylene group, R 2 represents alkyl having 1 to 6 carbon atoms, a benzyl or phenyl group and R 3 represents a branched alkyl group having 3 to 6 carbon atoms, a cyclopropyl group, or a 2-cyano-1-methylethyl group, and pharmaceutically acceptable salts thereof, characterized in that a) a p-aminophenol derivative of the general formula Ha 30 62060 NH-CO-N »I v 'Γ ^ Ί 1 J-OR, (IIa) 11 I 0 OCH 2 -X is reacted with amines of general formula IIIa H2N-R 3 (IIIa) or b) a p-aminophenol derivative of general formula Hb NH- Λ (Hb) • O o-ch 2 -x is reacted reacting with amines of general formula IIIa H2N-R3 (purple) and then adding a ureido group by reacting with a urea acid derivative of general formula IV Rc.CO-N (IV) '^ R1- c) a carbon or thioic acid derivative of general formula Ile 31 62060 NH-CY I! O 1 C-R 2 (HO OCH 2 -CH-CH 2 -NH.R 3 OH is reacted with amines of the formula IIIb) R 1'HN 1: (IIIb) V or d) a urea derivative of the general formula IId nh-co-nh 2 (Hd ) * 2 I 0 O-CH2-CH-CH2-NH.R3 OH is reacted with amines of the formula IIIb ^ R HN, '(IIIb) R7 62060 32 or e) alkali salts of phenols of the general formula Ile NH-CN ^ f' Γδ Ri IJ-c- r 2 <”·, HO is reacted with compounds of formula IIIc ^ R 3 X-CH 2 -N 2 - (IIIC) R 4 after which the benzyl group optionally contained in the reaction product is cleaved by catalytic hydrogenation, in which formulas R, R 1, R 2 and R 3 have the same meaning as in formula I, X is a halo-CH 2 -CH- or CH 2 -CH- group, Hal is chlorine, bromine OH 2 O or iodine, R 1 is hydrogen or a benzyl group, and R 5 is a halogen atom, Y is alkoxy, aryloxy, aralkyloxy, alkylthio, arylthio or aralkylthio group, R7 represents a straight-chain or branched alkyl group having 1 to 6 carbon atoms, a cyclohexyl, benzyl or phenyl group or, together with the group R, an alkylene group having 4 or 5 carbon atoms or ethylene- oxyethylene group and the reaction product is isolated free as a base or salt. 33 620 6 0 For the preparation of 3-hydroxy substituents with 2-hydroxy-3- (2-acyl-4-ureido-phenoxy) -propylamine derivatives of formula I R. NH-CO-N »L CR (I) OCH2-CH-CH2 "NH-R3 OH is a linear or linear alkyl group with 1-6 cholatomers, R1 is a hydrogen atom with a linear alkyl group with 1-6 cholatomers, a cyclohexyl-, benzyl- or phenyl, or R and R 4 are alkyl groups having 4 or 5 chelates or ethyleneethylene groups, R 2 is alkyl, 1-6 cholera, benzyl or phenyl, and R 3 is a alkyl group of 3 to 6 chelates of cyclopropyl, or a 2-cyano-1-methyl-ethyl group which is also a pharmaceutically acceptable carrier, which is a compound having the formula (a) p-aminophenolate in the form of Ha / R \ NH-CO-N, XI {Ha) Ν / O »I 0 OCH2-X ring is reacted with amine in the form of Ula 34 62060 H2N-R3 (Ula) or b) p-aminophenolate in the form of lib NH2 Λ 1 j_, R2 (lib) 0 The 0-CH2-X ring is reacted with an amine or a compound of formula IVN H2N-R3 (IIIa) and then the urea group of the genome is reacted with a reaction with a urea-substituted compound IV or R1. Rr c) in the case of thiocholysed derivatives of the formula NH-CY II 0 c-r2 (He) b och2-ch-ch2-nh.r3 OH ring of the reagent with the amine of the formula IIIb / R '> hn: <iiib> \ v '35 62 0 6 ϋ eller d) urea derivative with all the formula NH-CO-NH- Λ II did) o-ch2-ch-ch2-nh · r3 OH ring to react with the amine-formula mb R'n HN \ (IHb) ^ * 7 or e) alkali salts of phenols or all forms of NH-CN) 1 0 ^ Κ1χ / / TT .A. 1 (He) HO rings are reacted with compounds of formula IIIc A3 X-CHo-N (IIIC) variables and reaction products optionally with benzyl groups in the genomic catalytic hydration colors R, R1, R2 and R3