FI62061C - FOERFARANDE FOER FRAMSTAELLNING AV NYA BETA-RECEPTORER BLOCKERANDE 2-HYDROXI-3- (2-OXYIMINO-4-UREIDO-PHENOXY) -PROPYLAMINDERIVAT SAMT DERAS SALTER - Google Patents

Description

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(22) Htkemtapihrt — Aiwttkntnpdit 17.12.7U

(23) AlkupiM — GIWgH «ttdt | 17.12.71+ (41) Translators Public · k * l - BIMt offamllg 22.06.75

National Board of Patents and Registration / «) N« httv »lul,» non). kuL | ulw », n pv ™ .-, n n 'fi9

Patent- och raglstarstyraisan v AimMcm utlagd «eh uti ^ krtften pubikarad (32) (33) (31) * ΥΤ *« * Τ «tuolluus — Begird prior * ·» 21.12.73 20.11.71+, 22.II.7I +, 25.11.71+ Austria-Österrike (AT) A 10718/73, A 9308/71 +, A 9391/71 +, A 9I + 36/71 + (71) Chemie Linz Aktiengesellschaft, St.-Peter-Strasse 25, Linz , Austria-Österrike (AT) (72) Gerhard Zölss, Linz, Heribert Pittner, Gmund, Heimo Stormann-Menninger-Lerchenthal, Linz, Irmgard Lindner, Linz, Austria-Österrike (AT) (7I +) Leitzinger Oy (5I +) Method for new For the preparation of β-receptor blocking 2-hydroxy-3- (2-oxyimino-1 + -ureidophenoxy) -propylamine derivatives and their salts - For the preparation of 2-hydroxy-3- (2-oximino) blockers (U-urophenoxy) -propylamine derivatives are obtained

Substances with β-receptor blocking activity have become increasingly important in therapies in the treatment of various heart diseases, which can be causally or symptomatically explained by excessive circulatory loading of the body's own catecholamines. Substantial progress has been made in finding so-called cardioselective β-blockers - substances which 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 used, namely 1'-C4-acetamino-phenoxy- (2'-hydroxy-3'-isopropylamino) -J-propane, which is described in Austrian Patent Publication 261,582, so that there are still there is a great need to find actually useful, cardioselective / i-blockers. However, many β-blockers have the disadvantage of an adverse cardiodepressant effect, often associated with a β-blocking effect.

A patent is also known from the literature for carioselectively active phenoxypropylamine derivatives having a propylamine in the primary chain disubstituted at the β-position by a disubstituted ureido group (DOS 2100313) and which in the core may be substituted by hydrocarbon groups, halogenated fluorine, ether groups, ether groups cyano groups, as well as cardioselectively active β-blockers having a phenoxypropylamine structure and having an oxime side chain in the o-position relative to the propylamine side chain and which may be optionally substituted at the nucleus at any position by one or more haloalkyl, aro, - or an alkoxy group, see Austrian Patent Publication 286,963.

In addition, Finnish patent application 3612/74 describes phenoxypropylamine derivatives having a specific-blocking effect, in which the compounds have an acyl group in the o-position relative to the propylamino chain and an ureido group in the p-position.

It has now surprisingly been found that with 2-hydroxy-3- (2-oxyimino-4-ureidophenoxy) -propylamine derivatives of the formula Rn 'NH-CO-N i A, X -O-r 4 (i) O-CH 2 "CH-CH 2" NH-R 3

OH

wherein R is hydrogen or a straight-chain or branched alkyl group having 1 to 6 carbon atoms 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 represent an alkylene group having 4 to 7 carbon atoms, wherein one of these carbon atoms may be replaced by oxygen, R 2 represents hydrogen, alkyl having 1 to 6 carbon atoms or a phenyl group, R 3 represents a branched alkyl group having 3 to 6 carbon atoms and R 4 represents hydrogen , an alkyl group having 1 to 6 carbon atoms, or a benzyl group, and their pharmaceutically acceptable salts have a strong β-blocking effect and a surprisingly good cardioselectivity and a certain oral effect. The latter was determined by the method of Dunlop and Shanks, 3,62061, 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., Cardiology 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 inhibitory effect of the non-esterified fatty acids in rats (f ^ effect), while hardly any effect on the increased lactant and glucose values with isoprenaline was observed (82 ~ effect) · Despite the large effect of the compounds of general formula I -blocking effect in the study of heart rate in awake dogs according to Barrett and Carter, Brit. J. Pharmaco. 40, 373-81 (1970), they do not lower the heart rate at all after oral administration of the agents, suggesting 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 the commercially available 8-blocker.

The compounds of the formula I are prepared in such a way that the 2-acylphenoxypropylamine derivative of the general formula IIa / R '', NH. CO -

Jk R * \ c - R0 h 2 Ha I o

0CH2 - CH - CH2 - NHR3 OH

wherein R 1, R 2, R 2 and R 2 are as defined above, or a salt thereof is reacted with hydroxylamine or a derivative thereof of general formula IIIa H 1 N - OR. Range 2 4 4 62061 where means the same as in formula I.

The reaction is conveniently carried out at room temperature in a polar solvent, for example a mixture of a lower aliphatic alcohol such as methanol or ethanol and water or a secondary or tertiary amine such as pyridine. Hydroxylamine or a derivative thereof is suitably used in excess. If starting from salts of compounds of formula III, which is preferred, this salt is suitably added as an aqueous solution to the compound of formula II. The compound of formula I then precipitates as a salt if no amine was used as solvent and can be isolated as such or after conversion to a base.

If both compounds of formula IIa and compounds of formula IIIa are added as salts, it is advisable to act in a medium which buffers the liberated acids derived from the hydroxylamine salts of formula IIIa.

However, it is also possible to select the compounds of the formula Hb NH2 I ^ f ~ 12 IIb T 0 as starting material

OCH2 - CH - CH2 - NHR3 OH

wherein R 2 and R 2 are as defined above. These are first reacted with hydroxylamine or its derivatives of formula IIIa, followed by the addition of a ureido group by reaction with compounds of formula IV.

R,. CO - N 'IV

Where Rg represents a halogen atom, R and R4 then have the same meaning as above, or in the case where IR is hydrogen, the reaction is carried out with an isocyanate of the formula O = C = N - Rx IVa in which R 2 is as defined above.

The reaction conditions between the compounds of formula Hb and its compounds of formula IIIa are similar to those of the reaction between the compounds of formula IIa and compounds of formula IIIa.

When urea acid halides of the formula IV are used for the attachment of the ureido group, the reaction is conveniently carried out in the presence of an acid acceptor, for example using pyridine as solvent.

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

NH-C-Y

✓AJ

[J_c-r2 I «n“ ° “R4 Ile O-CH2-CH-CH2-NH-R3

OH

wherein Y is an alkoxy, aryloxy, aralkyloxy, alkylthio, arylthio or aralkylthio group, and R 2, R 3 and R 4 are as defined above, are reacted with amines of formula mb

Rn is NH I mb where R and R1 are as defined above, at room temperature or at elevated temperature. Preferred starting materials are compounds of the formula Ile 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.

6 62061

The above-mentioned polar solvents are also suitable as media, in which case mixtures of lower aliphatic alcohols and water are particularly good. Amines of formula IIIb are also suitable solvents when used in a corresponding excess.

The choice of reaction conditions is determined by the chemical nature of the compounds of formula Ile. If Y is an aromatic, for example 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 used a solvent, for example pyridine.

If it is desired to prepare compounds of the formula I in which R1 is not hydrogen, this is also possible by reacting the urea derivatives of the general formula Ild NH - CO - NH2 NOR. Ild '4 O - ch2 - CH - ch2 - nhr3

OH

wherein R 2 and R 2 are as defined above, to react with amines of formula IIIc R '' HN J IIIc R '' 8 wherein R is as defined above, R 8 is an optionally branched alkyl group having up to 10 carbon atoms, a cyclopentyl or cyclohexyl group , a benzyl or phenyl group or, together with the group R, a divalent, optionally branched hydrocarbon group having 4 to 7 carbon atoms in the main chain, one or two of these 7 62061 carbon atoms being replaced by oxygen, sulfur or nitrogen.

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 polar solvents, especially mixtures of lower aliphatic alcohols with water, are still considered to be the best reaction media. If the amines are volatile at the reaction temperature, proceed in a closed vessel. If amine salts are used, an equivalent amount of alkali hydroxide must be added.

Also the β-amino derivative of the formula Ile NH - C - N 1 I S ^ v

(S

jf 2 Ile I N - 0 - R4

och2 - X

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

O OH

can be reacted with amines of general formula IIld H 2 N - R 3 IIId wherein R 1 is as defined above to give compounds of formula I.

The reaction is conveniently carried out at an elevated temperature, namely at about 30 to 150 ° C, with an aggravation of 30 to 120 ° C. Also in this case, it is expedient to operate in a polar solvent and in the presence of water, in which case water still accelerates the reaction. Suitable polar solvents are in particular lower aliphatic alcohols, such as methanol, ethanol, further dimethylformamide, dioxane, 362061 tetrahydrofuran and acetonitrile. It is also possible to use the amine of the formula IIId as solvent. Based on the polar solvent, the amount of water added may be from a few percent up to an amount where the homogeneity of the reaction mixture can still be achieved during the reaction.

If the amine of formula IIId is volatile at the reaction temperature used, the reaction must be carried out in a closed system.

In principle, it can be said that the epoxides of the formula Ile are more reactive than the halohydrins of the formula Ile, which must be taken into account under the reaction conditions.

Instead of the compounds of the formula Ile, it is also possible to use the compounds of the formula Ilf 6 -, -, l nf I nor4

OCH2 - X

wherein R 2, R 4 and X are as defined above, may be reacted with amines of formula IIId. The resulting compounds must then be coupled with a ureido group by reaction with compounds of formula IV, the conditions given above being suitable.

The isolation of the compounds of the formula I takes place in the usual manner. If these are present in the reaction mixture as salts, it is advisable to liberate the base by alkalizing and isolating these as such or by extraction as an organic solvent. The bases can then be converted to salts.

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.

Of the compounds of formula I, those compounds in which R is a hydrogen atom or a straight-chain or branched alkyl group having 6, preferably up to 4, carbon atoms have a particularly favorable effect. In the case of compounds having a particularly favorable effect, means a hydrogen atom, optionally a branched alkyl group having up to 6, preferably up to 4 carbon atoms, a benzyl or phenyl group. Compounds in which R and R1 together with the nitrogen atom of the ureido group in the terminal position also represent a pyrrolidino, diazolidino, for example imidazolidino, diazolidino, oxazolidino, piperidino, morpholino, tetrahydro-diazino, for example tetrahydropyrimidino, tetrahydropyrimidino, or a homopiperazino group. The pyrrolidino, piperidino and morpholine groups are preferred.

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

The compounds of formula I may be used in the preparations either as bases or as pharmaceutically acceptable salts; such pharmaceutically acceptable salts include, for example, hydrohalides, especially hydrochloride and hydrobromide, further sulfate, phosphate, acetate, fumarate, succinate, cyclohexyl sulfamate, tartrate and citrate. Such salts are prepared by reacting the bases with an equivalent amount of the corresponding acid.

6 2 0 61 ίο

Pharmacological comparative tests

The experiments have compared the pharmacological properties of the compounds of the formula I with the compounds of the Austrian patent publication 286,963. The experiments have observed the effect of the compounds on the positive chronotropic isoprenaline effect in narcotic rats to determine the β-blocking effect and the effect of the compounds on the cardiac depressant ability of electrically irritated guinea pigs to determine the cardiodepressant effect of the compounds. The compounds described in Austrian Patent Publication 261,582, a product called Practolol, were also used as a control in the experiments.

The following compounds were used in the experiments: N- [3- (1'-hydroxyimino) -ethyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N'-diethylurea code ST 1373 N- E 3- (1'-hydroxyimino) -ethyl-4- (31-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N'-dimethylurea> code ST 1332 N- [3- (1'- hydroxyimino) methyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N'-dimethylurea code ST 1399 N- [3- (1'-hydroxyimino) ethyl] 4- (3'-tert-Butylamino-2'-hydroxy) -propoxy] -phenyl-N'-tetramethyl- (1,4) -urea code ST 1363 N-13- (1'-hydroxyimino) -ethyl- 4- (3'-tert-Butylamino-2'-hydroxy) -propoxy] -phenyl-N'-methylurea code ST 1371 N-13- (1'-hydroxyimino) -ethyl-4- (3'-sec. butylamino-2'-hydroxy) -propoksiJ-phenyl-N'-dimethylurea; code ST 1375 N- [3- (1'-butoxyimino) -ethyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N'-dimethylurea; code ST 1351 N- [3- (1'-hydroxyimino) -ethyl-4- (3'-tert-butylamino-21-hydroxy) -propoxy] -phenyl-N'-methyl-N'-n-butylurea; code ST 1388 11 62061 N- ¢ 3- (1'-Benzyloxyimino) -ethyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N'-diethylurea> code ST 1398

Reference Compounds a) Compound of AT Patent Publication 286,963: N- ¢ 3- (1'-hydroxyimino) -ethyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenylacetamide; code ST 1359 b) Compound of AT Patent Publication 261,581: 1'-14-acetamino-phenoxy- (2'-hydroxy-3'-isopropylamino) -3-propane; "Practolol"

All compounds were used in the form of an aqueous solution of their salts. Experimental methods: 1. effect on positive chronotropic isoprenaline effect.

Male and female rats weighing 200-300 g and anesthetized with pentobarbital (30 mg / kg ip} were used in the experiment. The test compound was administered intraperetoneally at doses of 40 mg / kg or intraduodenally at doses of 60 mg / kg. 100 mg / kg isoprenaline was initiated after dosing and 30 minutes after id dosing. as a percentage of the above isoprenaline value.

The change in heart rate is a good indication of the 3-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 approximately 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 on 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.

Table

Isoprenaline effect (5) Change in contractile capacity Compound Isoprenaline = 100% code_i, p._i, d._output value = 100% ST 1373 2 18 - 7 ST 1332 4 16 - 13 ST 1399 4 11 - 14 ST 1363 6 33 - 16 ST 1371 6 39 +19 ST 1375 12 31 + 18 ST 1351 12 31 +4 ST 1388 5 18 - 6 ST 1398_0_37_- 12_ ST 1359 0 53 - 26 "Practolol" _6_24_- 25_ 13 6 2 0 6 ';

The results obtained show that the compounds of formula I have a more favorable isoprenaline effect when administered intraduodenally, whereas intraperitoneally the compounds of formula I and the reference compound have a similar effect. The cardioprotective effect of the compounds shows that the compounds of formula I have a significantly weaker contractile-reducing effect than the reference compounds. Since the cardiodepressant effect of β-blockers is an undesirable side effect, this means in practice that the compounds of the formula I have a much more advantageous effect than the reference compounds.

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

Example 1: 44.8 g of hydroxylamine hydrochloride are dissolved in 90 ml of water, a solution containing 75.5 g of N-dimethyl-N '- / 3-acetyl-4- (31-tert-butylamino-21- hydroxy) -propoxy / phenylurea in 750 ml of methanol, and allowed to stand for 26 hours at room temperature. The solvent is distilled off in vacuo, the residue is taken up in 200 ml of water, basified with 162 ml of 4N sodium hydroxide, seed crystals are added, the precipitated base is filtered off with suction, washed with water and dried over phosphorus pentoxide.

Yield of N-dimethyl-N '- [3- (1'-hydroxyimino) -ethyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenylurea: 76.0 g, i.e. 96.6% of theory.

Melting point: 183-187 ° C.

66.0 g of the N-dimethyl-N '- [3- (1'-hydroxyimino) -ethyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenylurea thus obtained are suspended heated to 500 ml of ethanol, a solution of 10.5 g of fumaric acid in 250 ml of ethanol is added, 150 ml of water are added, filtered and the filtrate is evaporated in vacuo to about 200 ml. 1000 ml of acetone are slowly added to the residue, the precipitated crystals are filtered off with suction, washed with acetone and ether and dried in vacuo at 80 ° C.

14 62061

Yield of fumarate: 76.2 g or 99.6% of theory Melting point: 210-212 ° C

In the usual manner, the melting point of the hydrochloride obtained from the base is 208 to 211 ° C.

The starting N-dimethyl-N1- [3-acetyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenylurea is obtained as follows: 3-Acetyl-4-hydroxy-aniline is converted to pyridine. in solution and at room temperature to react with dimethylcarbamoyl chloride to give N-dimethyl-N1- (3-acetyl-4-hydroxy) -phenylurea, which is obtained as crystals, m.p. 160-162 ° C, after evaporation of the pyridine, the residue is taken up in chloroform and evaporated. Reaction of this with an aqueous alkaline solution of epichlorohydrin gives N-dimethyl-N1- [3-acetyl-4- (21,31-epoxy) -propoxy] -phenylurea, m.p. 98-102 ° C, which further reacts with excess tert-butylamine. in aqueous solution at room temperature to N-dimethyl-N '- [3-acetyl-4- (31-tert-butylamino-2'-hydroxy) -propoxy] -phenylurea, melting point: 120-122 ° C.

Example 2: 3.8 g of N-diethyl-N '- [3-acetyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenylurea, melting point: 105-109 ° C, are dissolved To 40 ml of methanol, a solution of 2.1 g of hydroxylamine hydrochloride in water is added and the mixture is allowed to react at room temperature for 20 hours. The methanol is distilled off in vacuo, 10 ml of water are added to the residue, the mixture is made alkaline with 7.5 ml of 4N sodium hydroxide, the separated base is extracted with ethyl acetate, the organic phase is dried over sodium sulfate and the solvent is distilled off in vacuo. The residue crystallizes after trituration with acetone. The yield of N-diethyl-N '- [3- (11-hydroxyimino) ethyl] -4- (31-tert-butylamino-21-hydroxy) propoxy] phenylurea is 3.2 g or 81.0% of the theoretical. Melting point: 148-152 ° C.

Fumarate can be prepared from bases by adding a calculated amount of fumaric acid (in ethanol).

Melting point: 209-212 ° C.

15 6 2 C 6 "i

Example 3: 3-Acetyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxyaniline (melting point 115-117 ° C) is dissolved in ethanol and aqueous hydroxylamine hydrochloride is added. After reacting for 20 hours at room temperature, 3- (1'-hydroxyimino) -ethyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxyaniline is isolated according to Example 1 and reacted with dimethyl carboxylate. with bamic acid chloride in pyridine at room temperature. The reaction mixture is evaporated in vacuo, the residue is taken up in water and the aqueous phase is extracted with ethyl acetate. The ethyl acetate phase is separated, dried and evaporated in vacuo. The residue thus obtained crystallizes on trituration with ether. There is thus obtained crude N- [3- (1'-hydroxyimino) -ethyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N'-dimethylurea, which as given in Example 1 can be converted to fumarate having a melting point of 210-212 ° C.

Example 4: 1.03 g of N- [3- (1'-hydroxyimino) -ethyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-carbamic acid phenyl ester which is prepared by reacting N- [3-acetyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-carbamic acid phenyl ester with hydroxylamine hydrochloride in methanol / water, adding 0.76 g of piperidine and 4 ml of water and allowed to react for 17 hours at room temperature. The solvent is then distilled off under reduced pressure, water is added to the residue, the oily precipitate is added as seed crystals, the crystals formed are filtered off with suction, washed with water and dried over phosphorus pentoxide.

Yield of N- [3- (11-hydroxyimino) -ethyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N1-pentamethylene (1,5) -urea: 0 , 8 g = 86.0 S of theory.

Melting point of fumarate: 170-173 ° C.

Example 5: 1.03 g of N- [3- (1'-hydroxyimino) ethyl) -4- (3'-tert-butylamino 2'-hydroxy) propoxy] phenylcarbamic acid phenyl ester prepared by reacting N- [3-acetyl-4- (3'-tert-butyl-16 6 2 0 61 amino-2'-hydroxy) -propoxy] -phenylcarbamic acid phenyl ester with hydroxylamine hydrochloride in methanol, 10 ml of ethanol and 5 ml of water and 0.81 g of diethylamine and allowed to react for 20 hours at room temperature. The solvent is distilled off in vacuo, the residue is made alkaline with 1N sodium hydroxide, the separated base is extracted with ethyl acetate and the organic phase is worked up as usual.

Yield of N- [3- (1'-hydroxyimino) -ethyl-4- (31-tert-butylamino-21-hydroxy) -propoxy] -phenyl-N'-diethylurea: 0.85 g = 94.15 % of theoretical.

Dissolving acetone and adding an acetone solution of fumaric acid gives crystalline fumarate.

Melting point: 209-212 ° C.

Example 6: 0.40 g of N- [3- (1'-hydroxyimino) ethyl-4- (3'-tert-butylamino-2'-hydroxy) propoxy] phenyl urea, 5.0 ml of diethylamine and 0.05 ml of water are reacted in an autoclave for 3 hours at 130 ° C. The reaction mixture is then evaporated in vacuo.

Yield of N- [3- (1'-hydroxyimino) -ethyl-4- (3'-tert-butylamino-21-hydroxy) -propoxy] -phenyl-N'-diethylurea: 0.40 g = 85, 8% of theory.

Crystalline fumarate can be prepared from a base in an acetone-containing solution by adding a calculated amount of fumaric acid.

Melting point: 209-212 ° C.

The starting material used is prepared as follows: 5.0 g of N- [3-acetyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenylurea are dissolved in 50 ml of methanol, a solution of is 3.25 g of hydroxylamine hydrochloride in 5 ml of water and is allowed to react for 20 hours at room temperature. The solvent is distilled off in vacuo, 30 ml of water are added to the oily residue, the mixture is made alkaline with 12 ml of 4N sodium hydroxide, the separated base is dissolved in ethanol, filtered and a solution containing the calculated amount of fumaric acid is added. Allow to stand overnight and separate the separated crystals by suction.

6 2 0 6 1 17 N- [3- (1'-hydroxyimino) ethyl 4- (3'-tert-butylamino-2'-hydroxy) propoxy] phenylurea fumarate: 3.5 g = 57.1% of theory Melting point: 217 - 220 ° C.

Example 7: 1.0 g of N- [3- (11-hydroxyimino) ethyl 4- (3'-tert-butylamino-2'-hydroxy) propoxy] phenylurea fumarate is heated at reflux for 7 hours in 10 ml: in piperidine. The reaction mixture is evaporated in vacuo, a small amount of water and a calculated amount of 1N sodium hydroxide are added to the residue and extracted several times with ethyl acetate. The ethyl acetate solution is distilled after drying to leave N- [3- (1'-hydroxyimino) -ethyl-4- (3'-tert-butylamino-21-hydroxy) -propoxy] -phenylate formed as a crystalline residue. N'-penta-methylene (1,5) -urea base.

Yield: 0.55 g = 53.7% of theory Fumarate melting point: 170-173 ° C.

Example 8: 3.0 g of N- [3- (1'-hydroxyimino) -ethyl-4- (31-chloro-2'-hydroxy) -propoxy] -phenyl-N'-diethylurea, m.p. 123-125 ° C , is reacted at room temperature for 16 hours with a mixture of 7.5 ml of tert-butylamine and 7.5 ml of water.

The excess amine is then distilled off in vacuo, the oily residue is triturated with water, the crystals formed are filtered off with suction, washed with water and dried over phosphorus pentoxide. 2.4 g of N- [3- (11-hydroxyimino) ethyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] phenyl-N1-diethylurea are obtained, which is 72.5% of theory.

Crystalline fumarate can be prepared from a base by adding a calculated amount of fumaric acid.

Melting point: 209-212 ° C.

18 62061 The hydrochloride used as starting material is prepared as follows: 10.0 g of N- [3-acetyl-4- (31-chloro-2'-hydroxy) -propoxy] -phenyl-N1-diethylurea (melting point: 144-146 ° C) ) is dissolved in 170 ml of methanol, a solution of 2.2 g of hydroxylamine hydrochloride in 10 ml of water is added and the reaction is allowed to proceed for 15 hours at room temperature. The methanol is then distilled off in vacuo, water and a little ether are added, seed crystals are added, the precipitated crystals are filtered off with suction, washed with water and dried over phosphorus pentoxide.

Yield of N- [3- (1'-hydroxyimino) -ethyl-4- (3'-chloro-2'-hydroxy) -propoxy] -phenyl-N'-diethylurea 9.0 g = 86.3% of theory , melting point 123-125 ° C.

It can also be prepared as follows: 1.0 g of N- [3-acetyl-4- (21,3'-epoxy) -propoxy] -phenyl-N'-diethylurea (melting point: 72-74 ° C) is dissolved in 10 ml. methanol, 0.25 g of hydroxylamine hydrochloride dissolved in 1 ml of water are added and allowed to react for 17 hours at room temperature. The methanol is distilled off in vacuo, the oily residue is triturated with methylene chloride while adding water, the crystals formed are filtered off with suction, washed with water and dried over phosphorus pentoxide. Yield of N- [3- (1'-hydroxyimino) -ethyl-4- (3'-chloro-2'-hydroxy) -propoxy] -phenyl-N'-diethylurea: 0.7 g = 60% of theory. Melting point: 123-125 ° C.

Example 9: 3.2 g of N- [3- (1'-hydroxyimino) -ethyl-4- (21,31-epoxy) -propoxy] -phenyl-N'-diethylurea is reacted at room temperature for 4 hours with stirring. with 10 ml of tert-butylamine and 10 ml of water. The excess amine is then distilled off in vacuo, water is added to the oily residue, seed crystals are added, the mixture is allowed to stand overnight, the crystals formed are filtered off with suction, washed with water and dried over phosphorus pentoxide.

Yield of N- [3- (11-hydroxyimino) -ethyl-4- (31-tert-butylamino-21-hydroxy) -propoxy] -phenyl-N'-diethylurea 2.7 g = 68.7% of theory , melting point of fumarate: 209-212 ° C.

62061 19 The starting material is prepared as follows: 3.05 g of N- [3-acetyl-4- (2 ', 3'-epoxy) -propoxy] -phenyl-N'-diethylurea are dissolved in 30 ml of methanol and the solution is added. with 0.8 g of hydroxylamine hydrochloride in 3 ml of water. To this is added, with stirring, 1N sodium hydroxide so that the pH of the reaction mixture remains at 6. After 2 hours, the addition of the hydroxide is complete, at which point a stoichiometric amount is consumed. Stir for a further 1 hour, distill off the methanol in vacuo, shake the aqueous solution with ethyl acetate, dry the organic phase over anhydrous sodium sulphate and evaporate in vacuo. Yield: 3.2 g of N- [3- (1'-hydroxyimino) -ethyl-4- (2 ', 3'-ethoxy) -propoxy] -phenyl-N'-diethylurea.

Example 10: 0.2 g of N- [3- (1'-hydroxyimino) -ethyl-4- (31-chloro-2'-hydroxy) -propoxy] -phenyl-N'-methylurea is reacted at room temperature 16 over 1 hour with a mixture of 2 ml of tert-butylamine and 2 ml of water. Further work-up is carried out as in Examples 8 and 9. N- [3- (1'-hydroxyimino) -ethyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl- Yield of N'-methylurea: 0.2 g = 89.4% of theory, melting point: 104-106 ° C.

The starting compound is prepared as follows: To 1.3 g of N- (3-acetyl-4- (2 ', 3'-epoxy) -propoxy] -phenyl-N'-methylurea is added 0.4 g of hydroxylamine hydrochloride (3 ml in water) and allowed to react for 18 hours at room temperature. The methanol is distilled off in vacuo, water is added to the residue, shaken with ethyl acetate, the organic phase is dried over anhydrous sodium sulfate and evaporated in vacuo.

Yield: 0.8 g

By trituration with acetone, crystalline N- [3- (11-hydroxyimino) -ethyl-4- (3'-chloro-2'-hydroxy) -propoxy] -phenyl-N'-methylurea can be prepared therefrom.

Melting point: 147-151 ° C.

20 6 2 0 61

Example 11: 1.0g N- [3- (1'-Hydroxyimino) -ethyl-4- (3 · -chloro-2'-hydroxy) -propoxy] -phenyl-N'-dimethylurea is reacted at room temperature 23 over 1 hour with a mixture of 5 ml of sec-butylamine and 5 ml of water. The reaction mixture is then evaporated in vacuo, acetone is added to the oily residue, allowed to stand overnight at room temperature, a little ethanol is added and the crystals thus obtained are filtered off with suction.

Yield of N- [3- (1'-hydroxyimino) -ethyl-4- (3'-sec-butylamino-2'-hydroxy) -propoxy] -phenyl-N'-dimethylurea: 0.45 g = 40 .5% of theory, melting point of fumarate: 192-195 ° C.

Example 12: 1.85 g of N- [3- (1'-hydroxyimino) -propyl-4- (2 ', 3'-epoxy) -propoxy] -phenyl-N'-diethylurea is dissolved in a mixture of 10 ml of ethanol and 10 ml of water, 2.02 g of tert-butylamine are added and the mixture is heated to reflux for 30 minutes. The solvent is then distilled off, water is added to the residue, it is acidified with 1N hydrochloric acid, shaken several times with ethyl acetate, the aqueous solution is made alkaline with 1N sodium hydroxide and extracted again with ethyl acetate. The organic phase is dried over sodium sulfate, filtered and distilled in vacuo.

Yields of N- [3- (1'-hydroxyimino) -propyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N'-diethylurea: 1.45 g = 64 .5% of theoretical.

The fumarate can be crystallized from the base in an acetone-containing solution by adding fumaric acid.

Melting point: 210-212 ° C.

Example 13: 1.0 g of 3- (1'-hydroxyimino) ethyl-4- (3'-chloro-2'-hydroxy) propoxyaniline is reacted with a mixture of 4.0 g over 7 hours. ml of tert-butylamine and 3 ml of water. The excess amine is distilled off in vacuo, the residue is extracted several times with ethyl acetate, the organic phase is dried over anhydrous sodium sulfate and evaporated in vacuo, the oily residue crystallizes on trituration with ether.

Yield of 3- (1'-hydroxyimino) -ethyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxyaniline: 0.95 g = 83.2% of theory, melting point (acetone) : 138 - 140 ° C.

To 0.5 g of 3- (1'-hydroxyimino) -ethyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxyaniline thus obtained in 5 ml of pyridine is added 0.25 g of diethylcarbamic acid chloride. and allowed to react at room temperature for 48 hours. The solvent is distilled off in vacuo, the residue is taken up in water, extracted with ethyl acetate, the organic phase is dried over anhydrous sodium sulfate and distilled in vacuo.

Yield of N- [3- (1'-hydroxyimino) -ethyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N'-diethylurea: 0.3 g = 45.0 % of theoretical.

From the base thus obtained, fumarate can be prepared in a conventional manner.

Melting point: 209-212 ° C.

The starting material is prepared as follows: To 3.0 g of 3-acetyl-4- (3'-chloro-21-hydroxy) -propoxyaniline in 30 ml of methanol is added 2.55 g of hydroxylamine hydrochloride in 3 ml of water and allowed to react. at room temperature for 17 hours.

The methanol is then distilled off in vacuo, 10 ml of water are added to the residue and the clear solution is made alkaline with 9.0 ml of 4N sodium hydroxide. Seed crystals are added to the separated base, and after some time the crystals formed are separated by suction. Yield of 3- (1'-hydroxyimino) -ethyl-4- (31-chloro-2'-hydroxy) -propoxyaniline: 2.45 g = 76.9% of theory.

Melting point (ethanol / ether): 114-117 ° C.

Example 14: 0.5 g of 3- (1'-hydroxyimino) -ethyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxyaniline prepared according to the above example in 20 ml of absolute ethanol is reacted with 0.22 g of phenyl isocyanate at room temperature for 4 days. The reaction mixture is evaporated in vacuo, the residue is dissolved in acetone, a calculated amount of fumaric acid is added, the mixture is evaporated and triturated with ether. The resulting crystals are extracted with ethanol at reflux and the insoluble matter is separated by suction.

Yield of N- [3- (1'-hydroxyiminool-ethyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N'-phenylurea fumarate: 0.35 g = 43.8% of theory.

M.p .: 167-70 ° C.

According to Examples 1, 2 or 3 above, the following compounds were prepared in an analogous manner to process variant a).

Starting material: N- [3-acetyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N'-tetramethylene (1,4) -urea

Product: N- [3- (1 * -hydroxyimino] ethyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N'-tetramethylene (1,4) -urea, SP 185-188 ° C.

Starting material: N- [3-acetyl-4- (3'-isopropylamino-2'-hydroxy) -propoxy] -phenyl-N'-dimethylurea

Product: N- [3- (1'-Hydroxyimino] -ethyl-4- (3'-isopropylamino-2'-hydroxy) -propoxy] -phenyl-N'-dimethylurea Fumarate mp 175-178 ° C.

Starting material: N- [3-acetyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenylurea

Product: N- [3- (1'-Hydroxyimino] -ethyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenylurea Fumarate mp 217-220 ° C.

Starting material: N- [3-acetyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N'-ethylurea

Product: N- [3- (11-hydroxyimino] -ethyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N'-ethylurea M.p .: 108-110 ° C.

23,62061 Starting material: N- [3-acetyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N'-dimethylurea

Product: N- [3- (1'-Butoxyimino] -ethyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N'-dimethylurea Fumarate M.p .: 163-166 ° C .

Starting material: N- [3-acetyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N'-di-n-propylurea

Product: N- [3- (1'-Hydroxyimino] -ethyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-di-n-propylurea Fumarate M.p .: 163-166 ° C.

Starting material: N, N-acetyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N'-sec-butylurea

Product: N- [3- (1'-Hydroxyimino] -ethyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N'-sec-butylurea Fumarate M.p .: 225-228 ° C.

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

Product: N- [3- (1'-hydroxyimino] -ethyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N'-n-butylurea M.p .: 93-95 ° C.

Starting material: N- [3-acetyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N'-tert-butylurea

Product: N- [3- (1'-hydroxyimino] -ethyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N'-tert-butylurea Fumarate M.p .: 222 - 225 ° C.

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

Product: N- [3- (1'-hydroxyimino] -ethyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N * -di-n-butylurea

Fumarate M.p .: 171-174 ° C.

62061 24 Starting material: N- [3-acetyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N'-isopropylurea

Product: N- [3- (1 * -hydroxyimino] -ethyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N'-isopropylurea M.p .: 189-191 ° C.

Starting material: N- [3-acetyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N'-dimethylurea

Product: N- [3- (1'-Methoxyimino] -ethyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N'-dimethylurea Fumarate m.p .: 163-167 ° C .

Starting material: N- [3-acetyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N'-methyl-N'-isopropylurea

Product: n- [3- (1'-Hydroxyamino) -ethyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N'-methyl-N'-isopropylurea M.p .: 145 - 148 ° C.

Starting material: N- [3-acetyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N'-methyl-N'-n-butylurea

Product: N- [3- (1'-Hydroxyimino] -ethyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N'-methyl-N'-n-butylurea Fumarate Sp Mp: 137-139 ° C.

Starting material: N- [3-acetyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N'-methyl-N'-ethylurea

Product: N- [3- (1'-Hydroxyimino] -ethyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N'-methyl-N'-ethylurea Fumarate S .: 212-216 ° C.

Starting material: N- [3-acetyl-4- (3'-isopropylamino-2'-hydroxy) -propoxy] -phenyl-N'-diethylurea

Product: N- [3- (1'-Hydroxyimino] -ethyl-4- (3'-isopropylamino-2'-hydroxy) -propoxy] -phenyl-N'-diethylurea M.p .: 127-128 ° C.

6 2 0 61 25 Starting material: N- [3-acetyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N'-dimethylurea

Product: N- [3- (1'-Benzyloxyimino] ethyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N'-dimethylurea Fumarate M.p .: 164-167 ° C.

Starting material: N- [3-formyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N'-dimethylurea

Product: N- [3- (1'-hydroxyimino] -methyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N'-dimethylurea M.p .: 169-172 ° C.

Starting material: N- [3-formyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N'-diethyl urea

Product: N- [3- (1'-hydroxyimino] methyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N'-diethyl urea M.p .: 155-161 ° C .

Starting material: N- [3-acetyl-4- (3'-tert-butylamino-2, -hydroxy) -propoxy] -phenyl-N'-ethyl-N'-n-propylurea

Product: N- [3- (1'-Hydroxyimino] -ethyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N'-ethyl-N'-n-propylurea Fumarate Sp Mp: 205-206 ° C.

Starting material: N- [3-butyryl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N'-diethylurea

Product: N- [3- (1'-Hydroxyimino] -butyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N'-diethyl urea Fumarate M.p .: 178-180 ° C.

Starting material: N- [3-propionyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N'-pentamethylene (1,5) -urea

Product: N- [3- (1'-Hydroxyimino] -propyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N'-pentamethylene (1,5) -urea Fumarate Sp .: 156 - 158oc.

26 62061 Starting material: N- [3-propionyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N'-dimethylurea

Product: N- [3- (1'-Hydroxyimino] -propyl-4- {3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N * -dimethylurea M.p. 86-88 ° C.

Starting material: N- [3-butyryl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N'-pentamethylene (1,5) -urea

Product: N- [3- (1'-Hydroxyimino] -butyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N * -pentamethylene (1,5) -urea Fumarate Sp Mp: 148-150 ° C.

Starting material: N-C3-acetyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N'-methyl-N'-cyclohexylurea

Product: N- [3- (1'-Hydroxyimino] -ethyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N'-methyl-N1-cyclohexylurea Fumarate M.p .: 166 - 168 ° C.

Starting material: N- [3-acetyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N'-methyl-N'-benzylurea

Product: N- [3- {1'-Hydroxyimino] -ethyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N'-methyl-N'-benzylurea M.p .: 108 - 110 ° C.

Starting material: N-C3-propionyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N'-3 "-oxapentamethylene (1,5) -urea Product: N- £ 3- ( 1'-Hydroxyimino-propyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N'-3 "-oxapentamethylene (1,5) -urea M.p .: 110-112 ° C.

Starting material: N- [3-benzoyl-4- (3'-tert, butylamino-2'-hydroxy) -propoxy] -phenyl-N'-pentamethylene (1,5) -urea

Product: N- [3- (1'-hydroxyimino] benzyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N'-pentamethylene (1,5) -urea M.p. : 143 - 146 ° C.

62061 27

According to Example 12, in a manner analogous to process variant e), the starting material was prepared: N- [3- (1'-hydroxyimino-propyl-4- (2 ', 3'-epoxy) -propoxy] -phenyl-N'-diethylurea

Import: N- [3- (1'-hydroxyiminol-propyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N'-diethylurea Fumarate M.p .: 210-212 ° C.

Example 15 1.0 g of N-β-yl'-hydroxyimino-ethyl-β-β'-tert-butylamino-4'-hydroxy) propoxy-phenyl-carbamic acid ethyl ester, (prepared by carrying N-β-acetyl-4 - (3'-tert-Butylamino-2'-hydroxy) -propoxy] -phenyl-carbamic acid ethyl ester to react with hydroxylamine hydrochloride in methanol / water.) Heat with 30 ml of piperidine for 24 hours at reflux. Excess piperidine was distilled off in vacuo, water was added to the residue, and the formed crystals were separated by suction.

N £ 3- (1'-hydroxyimino) -ethyl-4- (3--tert.butyyliamino 2, -hydrok-Si) -propoksiJ-phenyl-N'-pentamethylene (l, 5) -urea the yield was 0.55 g * 49.7% of theory and the fumarate Sp. was 170-173 ° C.

Example 16 0.5 g of n- [3- (1,1-hydroxyimino) -ethyl-4- (3, -tert-butylamino-2'-hydroxy) -propoxy] -phenyl-carbamic acid benzyl ester (prepared by reacting N- -acetyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-carbamic acid benzyl ester to react with hydroxylamino-hydrochloride in methanolic solution) and 5 ml of piperidine were heated to reflux with stirring for 10 hours. Excess piperidine was distilled off in vacuo, the oily residue was dissolved in water, and the formed crystals were separated by suction.

28 6206 1

N- [3- (1'-Hydroxyimino) -ethyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenyl-N'-pentamethylene- (1,5) -urea was 0.22 g »46.55% of theory and the m.p. 170-173 ° C

Example 17 2.0 g of 3- (1'-hydroxyimino) -ethyl-4- (3'-tert-butylamino-2'-hydroxy) -propoxyaniline (Base M.p. 135-138 ° C) was dissolved in 10 ml of pyridine and 1.5 g of monothioic acid S-phenyl ester chloride were added over 1 hour at r90 ° C. The solvent was then distilled off in vacuo.

The crude N-3- (1'-hydroxyimino) -ethyl 4- (3'-tert-butylamino-2'-hydroxy) -propoxy] -phenylcarbamic acid thiophenyl ester thus obtained was dissolved in 20 ml of ethanol and 10 ml of water, and 4.9 g of diethylamine and the mixture was allowed to stand for 21 hours at room temperature. The alcohol was then distilled off in vacuo, the aqueous solution was made alkaline with 1N sodium hydroxide, the separated base was extracted with ethyl acetate and the organic phase was evaporated in vacuo. The oily residue was taken up in acetone, evaporated and allowed to stand at room temperature to complete crystallization. Finally, the crystals were filtered off with suction and washed with acetone / ether and ether.

The yield of N- [3- (1'-hydroxyimino) ethyl] -4- (3'-tert-butylamino-2'-hydroxy) propoxy] phenyl-N'-diethylurea was 1.45 g = 54 , 3% of theoretical and fumarate Sp. was 209-212 ° C.

Claims (3)

1 N - O - R4 O - CH2 - CH - CH2 - NH - R3 OH saatetaan reagoimaan kaavan IIIc mukaisten amiinien kanssa 32 6206 1 HN IIIC \ E / R8 tai e) kaavan Ile mukaiset p-aminophenolijohdannaiset R - NH - C - N , A Rl "I C - R0 He II 2 IN - 0 - R4 OCH2 - X saatetaan reagoimaan yleiskaavan Illd mukaisten amiinien odds H2N - R3 HId tai f) kaavan Ilf mukaiset p-aminophenolijohdannaiset nh2 (SIN - 0 - R4 O - CH2 - X saatetaan reagoimaan kaavan HId muan r3 HId 620 61 33 yes saatuihin yhdisteisiin liitetään ureidoryhmä saattamalla reagoimaan kaavan IV mukaisten yhdisteiden odds Rc. CO - N IV ^ B R1 tai siinä tapauksessa, etä kaavassa IR on vety, saatetaan reagoimaan isosyanaatin odds - = Rx IVa jolloin näissä kaavoissa R, R ^, R2 »R3 ja R4 tarkoittavat same kuin noble, Rg tarkoittaa halogenatiomia, Rg tarkoittaa alkyyli-ryhmää, jossa on 1-6 hiiliatomia, cyclohexylyh , jossa on pääketjussa 4-7 hiiliatomia, jolloin yks näistä hiiliatomeista voi olla korvattu hapella, X tarkoittaa ryhmää -CH - CH, tai -CH - CHo - Hai, jossa Hai on kloori-, bromi- tai ^ 0 OH iodomy, yes Y on alkoxy-, aryloxy-, aralkyyl-oxy- tai aryy-lithioryhmä, minkä jälkeen saadut kaavan I mukaiset yhdisteet eristetään emäksinä tai suoloina. Process for the preparation of β-receptors blocking 2-hydroxy-3- (2-oxyimino-4-ureidophenoxy) -propylamine derivatives of the formula / R \ NH-CO-N f λ "l-c-r2 ητ in no-r4 (IN) Wherein R is hydrogen or a straight or branched alkyl group of 1-6 carbon atoms, R 2 is a hydrogen atom, a straight or branched alkyl group of 1-6 carbon atoms, a cyclohexyl, benzyl or phenyl group, or R and R 2 together represent an alkylene group of 4-7 carbon atoms, one of which can be replaced by oxygen, R2 is hydrogen, an alkyl of 1-6 carbon atoms or a phenyl group, R3 is a branched chain. alkyl group having 3-6 carbon atoms and R4 is hydrogen, an alkyl group having 1-6 carbon atoms or a benzyl group, and their pharmaceutically suitable acid addition salts, characterized in that a) 2-acylphenoxypropylamine derivatives of the general formula Ha '' NH - CO - N Λ Ila λ— c - R2 ίΓ 0 0CHo- CH - CH0 - NH - R0 2 I 2 3 OH or their salts are reacted with hydroxylamine or its derivatives of the general formula IIa NH 2 - OR 2 Ilia or with their salts, or b) acylphenoxypropylamine derivative of the general formula lib nh2 Λι [+ __c. or their salts are reacted with hydroxylamine or its derivatives of the formula IIia NH2 - o - r4 or with their salts and then an ureido group is combined with the reaction product by react with the compounds of formula IV 36 6 2 0 61 R Rg · CO - N '(IV) \ / R1 or in the case that R 0. C = N - R] (IVa) or (c) carbonic or thiocolic acid derivatives of the general formula Ile NH O-CH 2 -CH-CH 2 -NH-R 3 the formula Ild NH-C-NH2 11 11 is -N-0-R4 (Hd) O-CH ) p-aninophenol derivatives of formula Ile, II / Λ, ° r I Ile II 2 YN - 0 - Rh and 2 - X are reacted with amines of general formula IIId H2N - R3 IHd or f) p-aminophenol derivatives of formula IIf nh2 I iif \ Υ ^ · ίΐ 'K2 IN - 0 - R4 0. CH2 - X is reacted with amines of the formula Hid NH2 - R3 IIIq