FI56374C - FREQUENCY REQUIREMENTS FOR BETA RECEPTOR BLOCKING UREIDOFENOXY ALKANOLAMINDERIVAT - Google Patents

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Patent · And registry office (Nihtivilcip ^ is j. MoonL) foreign date—

Patent · oeh regleteretyreleen '' Anafikan utlagd och utl.tkrtftan publktrad 28.09.79 (32) (33) (31) Pyydetty atuelkeu »-Begird prlorltet 13.H.70

German Democratic Republic-Democratic Republic of Germany (DD) WP 151236 Proven-Styrkt "" (71) VEB Arzneimittelwerk Dresden, Postfach 89/90, 8122 Radebeul, Germany

Democratic. Republic of the Democratic Republic of Germany (DD) (72) Rudolf Eckardt, Radebeul, Ernst Carstens, Radebeul, Klaus Femmer,

Radebeul, German Democratic Republic-Germany (DD) (71 *) Oy Borenius & Co Ab (5 ^) Method for the preparation of β-receptor blocking ureidophenoxyalkanolamine derivatives - Pörfarande för framställning av / S-receptorblockerande virei do enei do fei

The invention relates to a process for the preparation of ureidophenoxyalkanolamine derivatives of the general formula R 2 - NH - CO - NH - ((I) O - CH 2 - CHOH - CH 2 --NH - R 1 -, in which case a lower alkyl group having 1 to 6 A C atom, a branched lower alkyl group having 3 to 8 C atoms, an alkenyl group having 3 to 6 C atoms, or a cycloalkyl group having 3 to 7 C atoms and R2 represents a hydrogen atom, a straight-chain lower alkyl group having 1 to 6 carbon atoms, a branched lower alkyl group having 3 to 8 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms or an alkenyl group having 3 to 8 carbon atoms. .6 a C atom, and wherein the urea group and the alkanolamine group may be in the o, rn or p position relative to each other, and their salts with physiologically acceptable inorganic or organic acids.

2 56374

Examples of physiologically acceptable inorganic and organic acids which are suitable for salt formation, be mentioned hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, dichloroacetic acid, propionic acid, benzilic acid, benzoic acid, succinic acid, formic acid, salicylic acid, oxalic acid, malonic acid, adipic acid, maleic acid, fumaric acid, tartaric acid, citric acid or ascorbic acid.

The compounds of general formula I have a substantially stronger special β-adrenaline blocking effect than that described by D. Dunlop and R.G. Shanks (Brit. J. Pharmac. Chemother. 32, 201-210 (1968)) disclosed the characterization of 1- (4-acetaminophenoxy) -2-hydroxy-3-isopropylaminopropane.

The definition of compounds of general formula I includes both pure stereoisomeric forms and mixtures thereof.

The compounds were tested in a cat anesthetized with chloralose urethane. The contraction force was recorded as the maximum rate of pressure rise (dp / dt max) in the left ventricle using a steel catheter. Systolic and diastolic blood pressure and heart rate were recorded simultaneously. A study of a spontaneously pulsating atrial preparation of a guinea pig was performed according to the method of W. Schaumann, R. Bodem, and W. Bartsh (Arch. Exp. Pharmak. U. Path. 255, 328 (1966)). The determination of the blockade of the isoprenal effect in the bronchial system was performed by guinea pig histamine spasm, and the anti-pulse irregularity effect was tested in the rat aconitine test.

The results are shown in Table 1.

3

563'M

^ ^ T &. No '

00 in * + VO H co CM

cn + + +11+ 1 \ K.

- ^ + ^ ^ OO in Η ΟΊ CM H - + co

+ + + + + + I

^ ^ ^ ^ ^ in cn co c \ j cm oo vo c— + + +1 + + 10 cm

VO · Η · Η Ή * H Ο Ή * H

<D 0) Φ 0) H Q) ®

H O O O

Λ) m I I 1 in ο 1 in ^ cvi 3 'd cn t ~ - in o - + co h m in r ~ cm co cm ·> «M« k f »« k

- + rHi — ΙιΗγΗΟΟ iH

I-I

CO cn CO

+ - + O CM H H CO

ΓΟ · »· * · * · * · * e * ·»

OHHOOCOH CM CM iO

co oo o> c— vo vo oo • k · * «k« k Ok Ä «k CM r-1 I — I O O O CM - + k >> CQ] 1 m m M -π o

CM CO w co {Tj <D COR

«WCMJljTMi! X-H

οοοοοίΐί o a r-ι 1 in 3 Μ ο ό 1

>> - h a f> »* H

r-1 WH τΙΛγΙ a I >>

3 CM> S

-PIP,

O -H

m-H u a f- n- <n cn cn f- a) o fta) H W «« WWW ΙΛΟ sfl M co co M · M1 M1 cO ^ oillPi

O O O O O O P -H O

I i I! 1 1 • H -H -P -P -P -H H CO P, 4 56374

Table 1 means:

Column 1: Compound of general formula I characterized by da da or name of reference substance *

Column 2: ED ^ q inhibition of the positive pulse-regulating lycronotropic effect of isoprenaline (1 μg / kg) expressed as mg / kg i.v. (Intravenously).

Column 3: EDJ0 inhibition of the (inotropic 1) muscle contraction effect of isoprenaline (μg / kg) expressed as mg / kg 1> T.

Column 4: Inhibition of the muscle contraction effect of isoprenaline (0.015 ug / kg) in EDf / ml ug / ml in an isolated atrial preparation.

Column 5: Dose in mg / kg causing onset blockage in the mar s bronchodilator system administered i.p.

Column 6: Aconitine-induced pulse irregularity in rats, dose in mg / kg, which prevents irregularity 73 #.

Columns 7 ^ 9 Side effects of intravenous injection of 2.5 mg / kg into the bloodstream in cats as a percentage of baseline.

Column 7: Impact density

Column 8: Systolic blood pressure

Column 9: dp / dt max

As the results of Table 1 show, the ureldophenoxyalkanolamine derivatives of the general formula I have an adrenaline-blocking effect which exclusively inhibits the positive muscle contraction and heart rate-regulating effect of isoprenaline. Isoprenaline-induced hypotension is not yet induced at a dose equivalent to 20-fold the amount of ED-q, whereas 1-isopropylamino-3- (1-naphthyloxy) -propan-2-ol-type β-receptor blockers are the strongest in blocking the effect of isoprenaline on the outer blood vessels. . Similarly, the stimulatory effect of isoprene-nalin on the bronchial system changes only at very high doses.

Cat via intestinal administration (5 mg / kg) could be, for example, L- (4- (3-sykloheksyyliureido) phenoxy) -2-hydroxy-3-is-opropyyliamino propaanllla curb response to isoprenaline lyöntltlheyden increase of $ 50 and the isoprenaline-induced positive inotropic effect 76 9 &.

In terms of potency, the compounds of general formula I are superior to 1- (4-acetaminophenoxy) -2-hydroxy-3-isopropylaminopropane. When the latter compound does not show any antiarrhythmic effect, e.g. in rat aconites up to 40 mg / kg, some derivatives of the ureidophenoxyalkanolamine compounds of the general formula I are effective.

The circulatory side effects of the compounds of general formula I are very minor. When 1-isopropylamino-3- (1-naphthyloxy) -propan-2-ol was already administered at a dose of 0.5 mg / kg i.v. when administered to a cat causes a clear slow beat, a decrease in blood pressure and a decrease in the contractile force, the compounds of general formula I lack these "adverse side effects.

Some compounds of the general formula I even have a clear positive chronotropic and inotropic effect.

In the light of these results, it is reasonable to speak of the specific action of the compounds of the general formula I. This (3-receptor blockade), which is characteristic of these substances, is of great importance in therapeutic use. The compounds of general formula I make it possible to in blockade causes circulatory disturbances which can be avoided by the use of ice-receptor blockers of general formula I, since the prevalence of X-sympathetic tension in the peripheral vascular system cannot occur.

According to the invention, the compounds of general formula I can be prepared by various methods.

Thus a) compounds of general formula I can be prepared by reacting a phenoxyalkanolamine derivative of general formula R1 - NH - CH2 - CH - CH2 - O - # \ (II) OH \ = / 2 with the general formula, 56374 6

R2 - N * C = O

wherein R 1 and R 8 have the meanings given above and then any protecting groups are cleaved.

The reaction between the compounds of the general formula II and the compounds of the general formula III is allowed to take place in a manner known per se, suitably in an ineffective orgasmic solvent, if necessary with heating.

It may be advantageous to allow the reaction between the compounds of general formula II and the general formula III to take place in the presence of an equimolar amount of acid.

Hydrogenolysis of the protecting groups can be accomplished by catalytic hydrogenation, e.g., by hydrogenation in the presence of a noble metal catalyst such as platinum or palladium or Raney nickel in an ineffective diluent or solvent suitable for each catalyst, e.g., alcohol, aqueous alcohol, dioxane, or dioxane. Hydrogenolysis can be accelerated or completed in the presence of a catalyst such as hydrochloric acid or oxalic acid if a noble metal catalyst has been used in the hydrogenation.

The hydrolysis of the protecting groups can take place conventionally in an acidic or alkaline medium.

But it is also possible to b) react a phenoxyalkanolamine derivative of the general formula R. - NH - CH9 - CH - CH0 - O - V (IV) 1 2.2 C »0 OH - · R6 with the general formula r2 - nh2 (V) With an amine according to 7 563/4, wherein R1 and R2 have the same meaning as above, and R8 is an alkoxy group having 1 to 4 carbon atoms, a phenoxy group, or when R2 is something other than a hydrogen atom, also an amino group, and then any protecting groups are cleaved.

According to the definition of the group Rg, the compounds of the general formula IV are uric acid esters or, if R2 is other than hydrogen, also urea derivatives.

The reaction between the compounds of the general formula IV and V is allowed to take place in a manner known per se, suitably in an ineffective organic solvent, if necessary with heating.

Excess amine of general formula V can also be used instead of solvents.

The compounds of the general formula IV added as starting materials can be prepared by customary methods for the preparation of uric acid esters, thiourea esters, semicarbazides, uric acid halides and isocyanates, for example starting from the compounds of the general formula II.

But it is also possible to c) react a ureidophenyl derivative of the general formula R2 - NH - CO - NH - (VI) Y == ^ 0 - ch2 - r7 with an amine of the general formula R-, nh2 (VIII) in which R1 and R8 are same as above and R 1 represents a group - CH - CH 2 or - CH - CH 2 - R q

'(/ ° H

Vila VIIb wherein R 5 represents a halogen atom or a sulfonic acid residue, e.g. benzenesulphonic acid or p-toluenesulphonic acid, or alternatively 8 56374 a ureidophenyl derivative may be a mixture of such compounds according to VI in which R1 has the two meanings mentioned and cleaves any protecting groups.

When a group VIIb is represented, the reaction may conveniently be carried out in the presence of an acid acceptor such as potassium carbonate or sodium carbonate.

The reaction may be carried out at room temperature or may be accelerated or terminated by the addition of heat. The reaction may take place at atmospheric pressure or elevated pressure, e.g. in a closed vessel, and in an ineffective diluent or solvent, such as methanol or ethanol. Optionally, an excess of an amine of general formula VIII can also be used as a diluent or solvent.

The compounds of general formula VI used as starting materials can be prepared by the reaction of the corresponding phenols with an epihalohydrin, e.g. epichlorohydrin. The compounds of general formula VI can be isolated. But they can also be further processed according to the present invention immediately in their preparation medium.

But it is also possible to d) give the general formula R2 - NH - CO - NH - / ~ \ (IX)

OH

the ureidophenyl derivative to react with the general formula

Rg - CH2 - CH - CH2 - NH - R1 (X)

OH

and / or with a compound according to CH 2 - CH - CH 2 --NH - R 1 (XI) 0 or with them, wherein R 2 as well as R 1, R 8 are as defined above, and then the possible protecting groups are cleaved.

The reaction may conveniently take place in the presence of an acid acceptor such as potassium carbonate 9 56374 or sodium carbonate. On the other hand, an alkali salt of the phenol in question, e.g. a sodium or potassium salt, can also be added as a starting material. The reaction may take place in an ineffective solvent or diluent, such as ethanol, and may be accelerated or completed by heat.

But it is also possible to e) give the general formula ^ R2 - NH - CO - NH - (/ \ (XII) V = 7 ^ 0 - ch2 - OH - ch2 - nh2

OH

• m * of the ureidophenyl derivative react with the general formula 0

With a carbonyl compound of Rg-0 to R10 (XIII) under reducing conditions and then cleaving any protecting groups, wherein R2 is as defined above and wherein R8 and R2 together with the C atom connecting them represent a residue which can be converted to R1 in hydrogenation.

Suitable conditions are provided, for example, by the presence of formic acid, which corresponds to the method of Leuckart-Wallach.

Suitable reducing conditions are also provided in the presence of hydrogen and a hydrogenation catalyst such as platinum, palladium or Raney nickel, in which case an ineffective solvent such as ethanol may be used.

When R 9 and R 10 represent alkyl groups or together with the C atom of the carbonyl group a cycloalkyl group, an excess of a carbonyl compound of the general formula XIII can also be used as a solvent.

Suitable reducing conditions are also obtained in the presence of di-light metal hydrides, such as alkali borohydride, in an inert solvent or diluent, such as aqueous methanol, in which case an excess of the carbonyl compound of general formula XIII may be used.

10 56374

When R 2 represents an alkenyl group which must not be hydrogenated in the reduction, it is suitable to use di-light metal hydrides, such as an alkaliophore hydride, for the reduction.

The compounds of general formula XII used as starting materials can, of course, also be prepared in situ, e.g. j a.

But it is also possible to f) give the general formula R2 - NH - CO - NH - (XIV) O - CH2 - CH - CH2 - NH2

OH

to react a ureidophenyl derivative according to the formula wherein R 2 is as defined above with an alkylating agent of the general formula R 1 to X (XV) wherein R 1 is as defined above and X is a halogen atom, and then optionally cleaving the protecting group.

An acid acceptor such as an alkali metal carbonate can also be advantageously used in the reaction. The reaction may conveniently be carried out in the presence of an ineffective solvent or diluent such as ethanol and may be accelerated or completed by heating.

But it is also possible to g) subject hydrogenolysis to the general formula R? - NH - CO - NH - CH2 (XVI) * O - CH2 - CH - CH2 - N - R1

OH

a ureidophenyl derivative according to claim 1, wherein R 1 and R 2 are as defined above. The hydrogenolysis of the compounds of general formula XVI can take place with hydrogen in the presence of a hydrogenation catalyst such as platinum, palladium or Raney nickel.

But it is also possible to h) reduce the general formula R2 - NH - CO - NH - Rg (XVII) 0 - CH9 - CH - CH ~ - N »^ Λ10

OH IU

a ureidophenyl derivative according to claim 1, wherein R 2 and R 9 and R 10 have the same meaning as above, and then cleave any protecting groups.

Formic acid, for example, is suitable for reduction. But the reduction can also take place with hydrogen in the presence of a suitable hydrogenation catalyst such as platinum, palladium or Raney nickel or with di-light metal hydrides such as alkali borohydrides or lithium aluminum hydride in an inert solvent or diluent.

Embodiments of the process according to the invention can generally be varied widely with respect to the reaction conditions and adapted to the particular conditions.

For example, the reactions may be performed in the presence or absence of inert solvents or diluents, at room temperature or by heating. If necessary, a pressurized closed container can be used.

12 56374

Depending on the substituents in the reaction components, the optimum conditions for temperature and solvents can be varied widely, and it is within the skill of the art to find the most suitable conditions. Due to the nature of the starting materials, one of the methods described can, in individual cases, produce a compound of general formula I only in small yields. In such cases, one skilled in the art will have no difficulty either preventing side reactions by selecting appropriate protecting groups and thus increasing catches or forcing the product by one of the procedures described elsewhere.

The preparation of the compounds used as starting materials in private processes, unless otherwise indicated, can be carried out using known methods and is within the skill of the art.

The resulting compounds of general formula I can be converted into their acid addition salts with physiologically acceptable inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, benzoic acid, benzoic acid, benzoic acid, benzoic acid, dichloroacetic acid, dichloroacetic acid, dichloroacetic acid, dichloroacetic acid, dichloroacetic acid. , malonic acid, adipic acid, maleic acid, fumaric acid, tartaric acid, citric acid or ascorbic acid.

Likewise, the acid addition salts of the compounds of general formula I can be converted into the free compounds by means of inorganic bases.

If the compounds of general formula I are obtained in the form of a racemic mixture, they can be resolved into their optically active forms by known methods. However, optically active compounds of the general formula I can also be obtained by reacting optically active starting materials.

Example 1 35.5 g of 1- (4-ureidophenoxy) -2,3-epoxypropane and 142 ml of isopropylamine were stirred at room temperature for 40 hours. The excess isopropylamine was then distilled off, the residue was dissolved in dilute hydrochloric acid, the solution was filtered clear and the dissolved base was saved by the addition of solid potassium carbonate. The precipitate of 1- (4-ureidophenoxy) -2-hydroxy-3-isopropylaminopropane had a melting point of 141.5 to 142.5 ° C after recrystallization from ethanol.

13 563/4

Example 2 10 g of 1- (4-ureidophenoxy) -2,3-epoxypropane and 100 ml of tert-butylamine were heated under reflux for 8 hours, the excess tert-butylamine was distilled off and the residue was extracted with dilute hydrochloric acid. The solution was clarified with suction and then the base was precipitated by the addition of solid potassium carbonate. The precipitate was filtered off, dried, dissolved in methanol and 1- (4-ureidophenoxy) -2-hydroxy-3-tert-butylaminopropane hydrochloride was precipitated by adding ether hydrochloric acid. After recrystallization from aqueous methanol, the salt melted at 207 ° C with decomposition.

Example 3 26 g of N-methyl-N- (4- (2,3-epoxypropoxy) phenyl) urea, 50 ml of isopropylamine and 100 ml of isopropanol were refluxed for 5 hours. After distilling off the solvent and excess isopropylamine, the obtained residue was dissolved in dilute hydrochloric acid, the solution was filtered, and the solute was precipitated by adding solid potassium carbonate. After crystallization from dilute alcohol, the 1- (4- (3-methylureido) phenoxy) -2-hydroxy-3-isopropylaminopropane thus obtained melted at 154-156 ° C.

The starting N-methyl-N · - (4- (2,3-epoxypropoxy) -phenyl) urea was prepared as follows: A mixture of 49.8 g of N-methyl-N '- (p-oxyphenyl) - urine, 150 ml KOH and 166 g epi-v chlorohydrin were stirred for 6 hours at room temperature. The precipitated N-methyl-N '- (4- (2,3-epoxypropoxy) -phenyl) urea was then suction filtered, washed with water and dried. The crude product, melting between 139-143 ° C, was subjected to further work-up without further purification.

Example 4 10 g of N-ethyl-N '- (4- (2,3-epoxypropoxy) -phenyl) urea and 50 ml of tert-butylamine were refluxed for 8 hours. After distilling off the excess tert-butylamine, the residue obtained was dissolved in dilute hydrochloric acid, the insoluble was filtered off, the base was precipitated with potassium carbonate, filtered off with suction, dried and purified by recrystallization from butyl acetate. The 1- (4- (3-ethylureido) phenoxy) -2-hydroxy-2-tert-butylaminopropane thus prepared melted at 122-124 ° C.

η 56374 The starting material is N-ethyl-N '- (4- (2,3-epoxypropoxy) -phenyl) urea, which, after recrystallization, melts between 154 ...

156.5 ° G, was prepared analogously to N-methyl-N '- (4- (2,3-epoxypropoxy) phenyl) urea.

Example 5 1 g of 1- (4-ethoxycarbonylaminophenoxy) -2-hydroxy-3-isopropylaminopropane and 5 ml of cyclohexylamine were heated under reflux for 2 hours. The excess cyclohexylamine was then distilled off, the residue was dissolved in dilute hydrochloric acid and the solution was filtered. Addition of sodium hydroxide precipitated 1- (4- (3-cyclohexylureido) -phenoxy) -2-hydroxy-3-isopropylaminopropane, which melted between 157-160 ° C after recrystallization.

Example 6

A mixture of 3 g of N-methyl-N'-Cp-hydroxyphenylD-urea in 3 ml of tert-butyl (2,3-epoxypropyl) amine, 20 ml of water and 0.2 ml of concentrated sodium hydroxide solution was stirred for 6 hours. at room temperature and then allowed to stand for 18 hours. A sticky precipitate had formed which was extracted with water and then dissolved in acetone. Opropane of 1- (4- (3-methylureido) phenoxy) -2-hydroxy-3-tert-butyl amine crystallized from acetone solution, melting at 140-143 ° C after recrystallization from isopropanol. Instead of sodium hydroxide solution, alkali carbonates can also be used as acid acceptors with the same result.

Example 7 0.5 g of 1- (4-aminophenoxy) -2-hydroxy-3-isopropylaminopropane was dissolved in a mixture of 2.2 ml of 1N hydrochloric acid and 5 ml of acetone, and 0.3 g of cyclohexyl isocyanate was added thereto. After 16 hours, the acetone was distilled off, 5 ml of water were added and the solution was filtered. After addition of sodium hydroxide solution, 1- (4- (3-cyclohexylureido) -phenoxy) -2-hydroxy-3-isopropylaminopropane precipitated, melting at 156-158.5 ° C after recrystallization from isopropanol.

Example 8 50 g of N-cyclohexyl-N1- (4- (2,3-epoxypropoxy) phenyl) urea, 250 ml of tert-butylamine and 500 ml of isopropanol were refluxed for 11 pounds. The solvent was then distilled off, the residue was dissolved in 3 l of water and 86 ml. 1N hydrochloric acid and the solution was filtered. Addition of sodium hydroxide precipitated 1- (4- (3-cyclohexylureido) -phenoxy) -2-hydroxy-3-tert-butylaminopropane, which melted after recrystallization from isopropanol at 143-145 ° C.

the starting N-cyclohexyl-N '- (4- (2,3-epoxypropoxy) phenyl) urea can be prepared as follows;

To a solution of 40 g of N-cyclohexyl-N '- (p-oxyphenyl) urea in 50 ml of 5N potassium hydroxide was added 92.5 g of epichlorohydrin and the mixture was stirred for 16 hours at room temperature. The precipitated N-cyclohexyl-N '- (4- (2,3-epoxypropoxy) -phenyl) -urea was then separated by suction filtration, washed with water and dried. The crude product had a melting point of 170-174 ° C, was passed without purification for further processing.

Example 9

A mixture of 10 g of 1- (4-ureidophenoxy) -2-hydroxy-3-isopropylaminopropane and 10 g of n-hexylamine hydrochloride was heated at 150 ° C for 3 hours. The reaction product was dissolved in 150 ml of water by adding hydrochloric acid, and the solution was filtered. After addition of sodium hydroxide solution, 1- (4- (3-n-hexylureido) -phenoxy) -2-hydroxy-3-isopropylaminopropane precipitated, melting after recrystallization from ethanol-water at 146-149 ° C.

Example 10 - 1.175 g of 1- (4-phenoxycarbonylaminophenoxy) -2-hydroxy-3-tert-butylaminopropane hydrochloride, 8 ml of methanol, 2.93 ml of a methanolic solution of Na-methylate (1N) and 2.67 ml of methanol of cyclohexylamine · The solution (1 norm.) Was combined and stirred for 8 hours at room temperature. After standing overnight, the mixture was refluxed for one hour, the solvent was distilled off and the residue was dissolved in 20 ml of water and 3.8 ml of 1N hydrochloric acid. 1- (4- (3-Cyclohexylureido) -phenoxy) -2-hydroxy-3-tert-butylaminopropane was then precipitated by adding sodium hydroxide solution until the pH was 12, recrystallized from isopropanol to give a melting point of 143-144 ° C.

The starting 1- (4-phenoxycarbonylaminophenoxy) -2-hydroxy-16 3-tert-butylaminopropane hydrochloride was prepared as follows: 10 g of 1- (4-aminophenoxy) -2-hydroxy-3-tert-butylaminopropane hydrochloride was dissolved in 80 g. to 1 ml of water at room temperature with stirring.

5.7 g of chloroformic acid phenyl ester were then added dropwise, the mixture was stirred for another hour and at the same time enough 1N sodium hydroxide solution was added dropwise to a pH of 6-7. 1- (4-Phenoxycarbonylaminophenoxy) -2-hydroxy-3-tert-butylaminopropane hydrochloride precipitated, melting at 127-130 ° C after drying.

Example 11: 2 g of 1- (phenoxycarbonylaminophenoxy) -2-hydroxy-3-isopropylaminopropane hydrochloride, 2 ml of isopropylamine and 10 ml of methanol were allowed to stand for two days at room temperature. The methanol and excess amine were then distilled off, the residue was dissolved in water by adding hydrochloric acid at pH 4, the solution was filtered and the base was precipitated by adding sodium hydroxide to pH 12. The precipitate of 1- (4- (3-isopropyl-ureido) -phenoxy) -2-hydroxy-3-isopropylaminopropane was recrystallized from isopropanol, melting at 154-156 ° C.

By the same procedure, the following compounds were prepared using the corresponding amines: 1- (4- (3-allylureido) -phenoxy) -2-hydroxy-3-isopropylaminopropane;

M.p .: 145-147 ° C.

1- (4- (3-sek.butyyliureido) phenoxy) -2-hydroxy-3-isopropylamino-propane. M.p .: 141.5-143 ° C.

1- (4- (3-i-amylureido) -phenoxy) -2-hydroxy-3-isopropylaminopropane,

M.p .: 124-127 ° C.

The starting 1- (4-phenoxycarbonylaminophenoxy) -2-hydroxy-3-isopropylaminopropane hydrochloride was prepared as follows: 20 g of N- (4-aminophenoxy) -2-hydroxy-3-isopropylaminopropane was dissolved in 100 ml of acetone by adding 7 ml of glacial acetic acid. and 13.9 g of chloroformic acid phenyl ester dissolved in 50 ml of acetone were added dropwise over 40 minutes. The temperature was then maintained at 30 ° C. It was then stirred for a further 1 hour and then the separated 1- (4-phenoxycarbonylaminophenoxy) -2-hydroxy-3-isopropylaminopropane hydrochloride, which melted after recrystallization from methanol at 199-202 ° C, was filtered off.

Example 12: 2 g of 1- (4-phenoxycarbonylamino phenoxy) -2-hydroxy-3-isopropylaminopropane hydrochloride, 10 ml of methanol and 2.5 ml of crotylamine were boiled for 50 min. under the reflux condenser. Methanol 17 56 37 4 was then distilled

And the excess crotylamine was removed, the residue was dissolved in 100 ml of dilute hydrochloric acid (pH 4) and the solution was filtered. After addition of sodium hydroxide solution until pH 12, 1- (4- (3-crotylureido) -phenoxy) -2- hydroxy-3-isopropylaminopropane, which, recrystallized from isopropanol, melted at 140.5-143.5 ° C. If cyclopentylamine was used instead of crotylamine, 1- (4- (3-cyclopentylureido) -phenoxy) -2-hydroxy # 3-isopropylaminopropane having a melting point of 157.5-160 ° C was obtained by the above procedure.

Example 13:

A mixture of 342 mg of cycloheptylamine, 1 g of 1 - (- (4-phenoxycarbonylaminophenoxy) -2-hydroxy-3-isopropylaminopropane hydrochloride, 2.6 ml of methanolic sodium methylate solution (1N of normal) and 10 ml of methanol gave stand for 16 hours at room temperature and then boil for 30 minutes under reflux · After that the solvent was distilled off, the residue was dissolved in 50 ml of water by adding dilute hydrochloric acid (pH 4) and the solution was filtered · Addition of sodium hydroxide until pH 12 precipitated 1- (4- (3'-Cycloheptylureido) -E-oxy) -2-hydroxy-3-isopropylaminopropane, recrystallized from isopropanol, melted at 145-148 ° C.

By the same procedure but using the corresponding amines the following compounds of general formula I were prepared: 1- (4- (3-cyclopropylureido) -phenoxy) -2-hydroxy-3-isopropylamino-propane, m.p. 141-143.5 ° C.

1- (4- (3-hexen- (2) -yl-ureido) -phenoxy) -2-hydroxy-3-isopropylaminopropane, m.p. 157.5 - 159.5 ° C.

Example 14: 25 g of N-cyclohexyl-N '- (2- (2,3-epoxypropoxy) -phenyl) urea, 25 ml of tert-butylamine and 125 ml of methanol were refluxed for 16 hours. methanol and excess tert-butylmine were distilled off, the residue was dissolved in 800 ml of water by adding hydrochloric acid (pH 4), the solution was filtered and the base was precipitated by adding sodium hydroxide until pH 12. The crude product was dissolved in 5 times ether and dichloroacetic acid was precipitated. (3-Cyclohexylureido) -phenoxy) -2-hydroxy-3-tert-butylaminopropane-18,563 / 4 dichloroacetate, recrystallized from ethanol, melting between 188.5 and 191.5 ° C.

The starting material for the above reaction was N-cyclohexyl-N '- (2- (2,3-epoxypropoxy) phenyl) urea-Alne was prepared analogously to N-cyclohexyl-N' - (4- (2,3-epoxypropoxy) phenyl) urea. with the substance (Example 8) · The crude product, melting between 147 and 151 ° C, was used as such without further purification. The melting point of the substance after crystallization from isopropanol is 162-164.5 ° C.

Example 15: 5 g of N-cyclohexyl-N '- (3- (2,3-epoxypropoxy) phenyl) urea, 5 ml of tert-hutylamine and 25 ml of methanol were refluxed for 16 hours. Methanol and excess tert-hutylamine were then distilled off, the residue was dissolved in 300 ml of water by adding hydrochloric acid (pH 4) and the solution was filtered. After addition of sodium hydroxide to pH 12, 1- (3- (3-cyclohexylureido) -E enoxy) -2-hydroxy-3-tert-butylaminopropane, which, after crystallization from acetone, melted at 151-154 ° C.

Reaction starting material N-cyclohexyl-N '- (3- (2,3-epoxypropoxy) -phenyl) urea was prepared analogously to N-cyclohexyl-n' - (4- (2,3-epoxypropoxy) -phenyl) -urea (Example 8). The crude product, melting between 139 and 149.5 ° C, was subjected to further processing without purification. After recrystallization from aqueous methanol: 3: 1, the melting point was 150-152 ° C ·

Example 16; . 10 g of M-cyclohexyl-N * - (4- (2,3-epoxypropoxy) -phenyl) urea 10 ml of n-hexylamine and 50 ml of methanol were refluxed for 25 hours. The solvent and excess amine were then distilled off, the residue was dissolved in 800 ml of water by adding hydrochloric acid (pH 3-5) and the solution was filtered. By adding sodium hydroxide to pH 12, 1- (4- (3-cyclohexylureido) -phenoxy) -2-hydroxy-3-n-hexylaminopropane precipitated, which, recrystallized from ethanol, melted between 160 and 163 ° C.

Using N-cyclohexyl-N '- (4- (2,3-epoxypropoxy) -phenyl) urea And the appropriate amine, the following compounds of general formula 1 were prepared in an analogous manner: 19 56374 1- (4- (3-cyclohexylureido) - phenoxy) -2-hydroxy-3-methylaminopropane, mp: 170-172 ° C.

3-cyclohexylureido) -phenoxy) -2-hydroxy-3-n-butylamine-propane, m.p .: 160-163 ° C * 1- (4- (3-cyclohexylureido) -phenoxy) -2-hydroxy-3-cyclohexylamino-propane, M.p .: 156-158 ° C.

1- (4- (3-Cyclohexylureido) -phenoxy) -2-hydroxy-3-isopropylamino-propane, mp: 157-160 ° C · 1- (4- (3-cyclohexylureido) -phenoxy) -2-hydroxy-3-sec .-butylaminopropane, mp: 127-130 ° C.

1- (4- (3-cyclohexylureido) -phenoxy) -2-hydroxy-3-isoamylaminopropane, m.p .: 157-159 ° C, 1- (4- (3-cyclohexylureido) -phenoxy) -2-hydroxy-3-crotylaminopropane m.p. 155-157 ° C.

1- (4- (3-Cyclohexylureido) -phenoxy) -2-hydroxy-3-cyclopentylamino-propane, m.p .: 142.5-145.5 ° C · 1- (4- (3-cyclohexylureido) -phenoxy) -2-hydroxy-3-cycloheptylamino - propane, m.p .: 131-133.5 ° C ·

1- (4- (3-cyclohexylureido) -phenoxy-2-hydroxy-3- (1,1,3,3-tetramethyl-butyl) -aminopropane, m.p .: 131-133.5 ° C

1- (4- (3-cyclohexylureido) -phenoxy) -2-hydroxy-3-hexen- (2) -yl-aminopropane, m.p .: 156-159 ° C · 1- (4- (3-cyclohexylureido) -E enoxy) -2-hydroxy-3-cyclopropylaminopropane, m.p .: 154-156.5 ° C.

Example 17: 5 g of 1- (4- (3-cyclohexylureido) -phenoxy) -2-hydroxy-3- (N-benzyl-N-tert-butylamino) -propane, 100 ml of glacial acetic acid and 0.5 g of platinum dioxide were shaken 6 hours at room temperature under a hydrogen atmosphere. The catalyst was then filtered off with suction, glacial acetic acid was distilled off in vacuo and the residue was dissolved in 250 ml of water by adding hydrochloric acid (pH 2). The solution was filtered, and by adding sodium hydroxide solution to pH 12, precipitated 1- (4- (3-cyclohexylureido) -phenoxy) -2-hydroxy-3-tert-hutylaminopropane, which, recrystallized from isopropanol, melted at 142-144.5 ° C. , 20 'S 6 3 7 4 1- (4- (3-Cyclohexylureido) -phenoxy) -2-hydroxy-3- (N-benzyl-N-tert-butylamino) -propane can also be debenzylated as follows: 5 g the starting material is shaken with 100 ml of glacial acetic acid and 1 g of palladium on carbon for 8 hours at 50 ° C and 50 atmospheres of hydrogen pressure. Then continue as above.

Debenzylation of 1- (4- (3-cyclohexylureido) -phenoxy) -2-hydroxy-3-N- (benzyl-N-tert-butylamino) -propane can also take place as follows: 5 g of 1- (4- (3-cyclohexylureido) ) -phenoxy) -2-hydroxy-3-N- (benzyl-N-tert-butylamino) -propane, 100 ml of ethanol and 1 g of Raney nickel catalyst were shaken for 8 hours at 50 ° C and 50 atmospheres of hydrogen pressure . The catalyst was then filtered off, the ethanol was distilled off and the resinous residue was dissolved in 250 ml of water by adding hydrochloric acid. After filtration, 1- (4- (3-cyclohexylureido) -phenoxy) -2-hydroxy-3-tert-butylaminopropane was precipitated, melting at 142-144 ° C after recrystallization from isopropanol.

The starting 1- (4- (3-cyclohexylureido) -phenoxy) -2-hydroxy-3- (N-benzyl-N-tert-butylamino) -propane was prepared as follows: 3.65 g of 1- (4-aminophenoxy) - 2-Hydroxy-3- (N-benzyl-N-tert-butylamino) -propane hydrochloride, 90 ml of water and 1.25 g of cyclohexyl isocyanate were stirred for 16 hours at ambient temperature. The solution was filtered and 1- (4- (3-cyclohexylureido) -phenoxy) -2-hydroxy-3-N- (benzyl-N-tert-butylamino) -propane was precipitated by the addition of sodium hydroxide solution. The pale resinous product thus obtained was used crude for debenzylation.

The starting 1- (4- (3-cyclohexylureido) -phenoxy-2-hydroxy-3- (N-benzyl-N-tert-butylamino) -propane can also be prepared as follows: 39.8 g of N-cyclohexyl-N'- (4- (2,3-epoxypropoxy) -enyl) urea, 24.5 g of N-benzyl-N-tert-butylamine and 150 ml of ethanol were refluxed for 17 hours. (4- (3-Cyclohexylureido) -phenoxy) -2-hydroxy-3- (N-benzyl-N-tert-butylamino) -propane remained as a resin, A · «1 '·' 21 56374 which was purified without debenzylation. was identified as its fumarate, which, recrystallized from ethanol, melted at 142-145 ° C.

Example 18 1 g of 1- (4- (3-cyclohexylureido) phenoxy) -2-hydroxy-3-aminopropane hydrochloride, 20 ml of acetone and 1.42 ml of methanolic sodium methylate solution (1 normal) were combined and boiled for 1 hour. an hour under the reflux condenser. 2 g of sodium borohydride were then added under ice-cooling, stirred for 10 minutes and, after standing overnight, the excess sodium borohydride was decomposed with 10 ml of dilute hydrochloric acid. The methanol was then distilled off, the residue was dissolved in 50 ml of water, the solution was filtered and 1- (4- (3-cyclohexylureido) -phenoxy) -2-hydroxy-3-isopropylaminopropane was precipitated by adding sodium hydroxide solution to pH 12. After recrystallization from isopropanol, the material melted at 157-160 ° C.

The starting 1- (4- (3-cyclohexylureido) -phenoxy) -2-hydroxy-3-aminopropane hydrochloride was prepared as follows: 29 g of N-cyclohexyl-N '- (4- (2,3-epoxypropoxy) -phenyl). urine and 800 ml of methanolic ammonia solution (18.5 g of ammonia / 100 ml of solution) were heated for 32 hours at 50 [deg.] C. The methanol and excess ammonia were then distilled off and the residue was boiled with 400 ml of methanol. then concentrated hydrochloric acid to pH 1 to precipitate 1- (4- (3-cyclohexylureido) -phenoxy) -2-hydroxy-3-aminopropane hydrochloride, which, after recrystallization from dimethylformamide, melted at 220-222 ° C .

Example 19 3.3 g of 1- (4- (3-cyclohexylureido) -phenoxy) -2-hydroxy-3-chloropropane, 5.9 g of isopropylamine and 50 ml of methanol were heated in an autoclave at 100 ° C for 12.5 hours. . The solvent and excess isopropylamine were then distilled off, the residue was dissolved in 200 ml of water by adding hydrochloric acid (pH 4), the solution was filtered and sodium hydroxide solution was added until pH 12. Precipitated 1- (4- (3-cyclohexylureido) -phenoxy) - 2-hydroxyisopropylaminopropane, 22 56374 which, recrystallized from isopropanol, melted at 157-160 ° C.

The starting 1- (4- (3-cyclohexylureido) -phenoxy) -2-hydroxy-3-chloropropane was prepared as follows: 30 g of N-cyclohexyl-N '- (4- (2,3-epoxypropoxy) -phenyl) urine , 60 ml of methanol and 20 ml of concentrated hydrochloric acid were combined and allowed to stand for 24 hours at room temperature. It was then precipitated by adding 70 ml of water 1- (4- (3-cyclohexylureido) -phenoxy) -2-hydroxy-3-chloropropane, which, recrystallized from ethyl acetate, melted at 136-139 ° C.

Example 20 1.8 g of 1 - (- (3-cyclohexylureido) -phenoxy) -2-hydroxy-3-aminopropane hydrochloride, 72 ml of isopropanol, 5.4 g of isopropyl bromide, 3.6 g of potassium carbonate and 0.4 g of potassium iodine stirred for 16 hours at 70 ° C. Then 50 ml of water and 5 ml of 1N sodium hydroxide solution were added, the alcohol and the excess isopropyl bromide were distilled off, and then the separated 1- (4- (3-cyclohexylureido) -phenoxy) -2-hydroxy-3-isopropylaminopropane, which recrystallized from isopropanol, melted 156 ... at 159 ° C.

Example 21 10 g of N-ethyl-N '- (4- (2,3-epoxypropoxy) -phenyl) urea and 100 ml of allylamine were allowed to stand for 48 hours at room temperature. After distilling off the excess allylamine, the residue was dissolved in 500 ml of water by adding hydrochloric acid (pH 4) and the solution was filtered. It was then precipitated by adding sodium hydroxide solution to pH 12 with 1- (4- (3-ethyl-ureido) -phenoxy) -2-hydroxy-3-allylaminopropane, which, recrystallized 1: 1 from ethanol-water, melted at 120-123 ° C.

Example 22

A mixture of 1 g of 1- (4- (3-cyclohexylureido) phenoxy) -2-hydroxy-3-tert-butylaminopropane, 0.4 g of benzoic acid and 5 ml of methanol was heated to reflux to give 23 δ 6 3/4 a clear solution was formed. On cooling, 1- (4- (3-cyclohexylureaido) phenoxy) -2-hydroxy-3-tert-butylaminopropane benzoate with a melting point of 194-198 ° C separated.

Using 0.2 g of succinic acid instead of 0.4 g of benzoic acid, neutral 1- (4- (3-cyclohexylureido) phenoxy) -2-hydroxy-3-tert-butylaminopropane succinate with a melting point of 202 was obtained in an analogous manner. ... 204 ° C.

Using 0.3 g of tartaric acid instead of 0.4 g of benzoic acid, neutral 1- (4- (3-cyclohexylureido) phenoxy) -2-hydroxy-3-tert-butylaminopropane-1-arthrate with a melting point of 213 was obtained in an analogous manner. ... 215 ° C.

Example 23

A mixture of 1 g of 1- (4- (3-cyclohexylureido) phenoxy) -2-hydroxy-3-tert-butylaminopropane, 0.2 ml of glacial acetic acid and 5 ml of isopropanol was heated briefly to boiling. On cooling, 1- (4- (3-cyclohexylureido) phenoxy) -2-hydroxy-3-tert-butylaminopropane acetate separated, melting at 162-165.5 ° C after recrystallization from isopropanol.

Using 0.4 g of salicylic acid instead of 0.2 ml of glacial acetic acid, 1- (4- (3-cyclohexylureido) phenoxy-2-hydroxy-3-tert-butylaminopropane salicylate was obtained in an analogous manner, melting 133 after recrystallization from isopropanol. ..135 ° C.

Example 24 7.2 g of 1- (4- (3-cyclohexylureido) -phenoxy) -2-hydroxy-3-tert-butylaminopropane, 36 ml of water and 10 ml of 2N nitric acid were heated: 24 56374 to 80 ° C , the solution was filtered and cooled. 1- (4- (2-Cyclohexylureido) -phenoxy) -2-hydroxy-3-tert-butylaminopropane nitrate separated, melting between 172-176 ° C after recrystallization from isopropanol water 98: 2.

Using 2 ml of concentrated hydrochloric acid instead of 10 ml of 2N nitric acid gave 1- (4- (3-cyclohexylureido) phenoxy) -2-hydroxy-3-tert-butylaminopropane hydrochloride, which was recrystallized from isopropanol-water 98: 2. melted between 208 ... 212.5 ° C.

Example 25 10 g of 1- (4- (3-cyclohexylureido) -phenoxy-2-hydroxy-2-tert-butylaminopropane were dissolved in 50 ml of methanol, and 1.55 ml of 17.8 N sulfuric acid was added to the solution. - (4- (3-cyclohexyl-ureido) -phenoxy) -2-hydroxy-3-tert-butylaminopropane sulfate, melting with decomposition at 245 ° C.

Example 26

To a solution of 10 g of 1- (4- (3-cyclohexylureido) -phenoxy) -2-hydroxy-3-tert-butylaminopropane and 50 ml of methanol was added 13.8 mmol of 85% phosphoric acid. After a short time, a secondary phosphate of the above base precipitated, melting at 210-212.5 ° C after recrystallization from a 5: 1 mixture of methanol and water.

Example 27 7.2 g of allylamine, 15.7 g of 1- (4-phenoxycarbonylaminophenoxy) -2-hydroxy-3-tert-butylaminopropane hydrochloride and 75 ml of methanol were refluxed for one hour. The mixture was allowed to stand overnight, after which the methanol and excess amine were distilled off, the residue was dissolved in 800 ml of water by adding hydrochloric acid until the pH was 4, the solution was filtered and 1- (4- (3-allylureido) phenoxy) -2-hydroxy -3-tert-butylaminopropane was precipitated by the addition of potassium carbonate. The oily base was collected in chloroform, the chloroform layer was separated, dried over potassium carbonate, and the chloroform was distilled off. The residue was dissolved in 130 ml of ethanol, 2 g of fumaric acid was added to the solution, and 1- (4- (3-allylureido) phenoxy) -2-hydroxy-3-tert-butylaminopropane-4-fumarate was precipitated by adding ether. After recrystallization from ethanol, the compound melted at 196-198 ° C.

25, 563 74

Example 28

A mixture of 2.4 g of 1- (4-aminophenoxy) -2-hydroxy-3-tert-butylaminopropane, 24 ml of acetone and 1.25 g of cyclohexyl isocyanate was refluxed for one hour. The solvent was distilled off, the residue was dissolved in water by adding dilute hydrochloric acid to a pH of 4, and the solution was filtered. By adding sodium hydroxide solution until pH 12, 1- (4- (3-cyclohexylureido) -phenoxy) -2-hydroxy-3-tert-butylaminopropane was precipitated, which, recrystallized from isopropanol, melted at 142 ...

At 143.5 ° C.

The same result was obtained when the reaction was carried out in the presence of glacial acetic acid.

Per 1 mole of 1- (4-aminophenoxy) -2-hydroxy-3-tert-butylaminopropane was added 1.2 moles of glacial acetic acid.

Example 29 4.8 g of 1- (4-aminophenoxy) -2-hydroxy-3-tert-butylaminopropane were dissolved by stirring at room temperature in a mixture of 48 ml of water and 20 ml of 1N hydrochloric acid. 2.5 g of cyclohexyl isocyanate were then added and stirred for 15 hours at room temperature. The solution was then sucked clear and 1- (4 - * (3-cyclohexylureido) -phenoxy) -2-hydroxy-3-tert-butylaminopropane was precipitated by adding sodium hydroxide until pH 12, melting at 142-144 ° C after recrystallization from isopropanol: in.

Example 30 2 g of 1- (4-phenoxycarbonylaminophenoxy) -2-hydroxy-3-isopropylaminopropane hydrochloride were dissolved in 20 ml of methanol at ambient temperature, and 5 ml of ammonia saturated with water was added to the solution. The reaction was allowed to proceed for 16 hours at ambient temperature, after which the solvent was distilled off in vacuo, the residue was dissolved in 40 ml of water by adding hydrochloric acid until the pH was 4, the solution was filtered and the pH was adjusted to 12 with sodium hydroxide solution. Addition of solid potassium carbonate precipitated 1- (4-ureidophenoxy) -2-hydroxy-3-isopropylaminopropane, which, recrystallized from isopropanol, melted at 141-142 ° C.

Example 31 1.3 g of glycidic p-toluenesulfonic acid ester, 1.35 g of N-cyclohexyl-N'-26,563 / 4-p-hydroxyphenyl-urea 11a, 5.7 ml of a 1N solution of sodium methylate in methanol and 60 ml of methanol were refluxed for 8 hours. The methanol was then distilled off using a water-jet vacuum pump, the residue obtained was washed with 50 ml of water, dried and then refluxed for 24 hours in a mixture of 1.53 ml of tert. butylamine and 14 ml of methanol. The solution was sucked clear, the solvent was distilled off and extracted cold with a mixture of 30 ml of water and 5 ml of 1N hydrochloric acid. The solution was sucked clear and 1- (4- (3-cyclohexylureido) -phenoxy) -2-hydroxy-3-tert-butylaminopropane was precipitated by the addition of dilute sodium hydroxide, melting at 142-144 ° G after recrystallization from isopropanol.

Example 32 4.68 g of N-cyclohexyl-N'-Cp-hydroxyphenyl] -dissolved material was dissolved in 60 ml of 1N sodium hydroxide solution with stirring at room temperature, followed by the addition of 4.04 g of N-tert-butyl-N- (2-hydroxy -3-chloropropyl) amine hydrochloride and the mixture was stirred for 24 hours at room temperature. The separated 1- (4- (3-cyclohexylureido) phenoxy) -2-hydroxy-3-tert-butylaminopropane was sucked off and washed with water. After recrystallization from isopropanol, the compound melted at 142-144 ° C.

The starting N-tert-butyl-N- (2-hydroxy-3-chloropropyl) -amine hydrochloride was prepared as follows;

To a mixture of 78 ml of tert-butylamine, 100 ml of methanol and 1 ml of water was added dropwise 39.2 ml of epichlorohydrin over 20 minutes at room temperature with stirring. The reaction was allowed to proceed for 16 hours at room temperature, after which an ethereal solution of hydrochloric acid was added dropwise at + 10 ° C until the acid reaction was obtained. Precipitate crystallizing oil which, when recrystallized from isopropanol, melts at 163-166 ° C.

Example 33 (+) - 1- (4-Nitrophenoxy) -2-hydroxy-3-tert-butylaminopropane-dibenzyl-L (+) - tartrate; 172 g of dibenzyl L (+) - tartaric acid monohydrate and 257 g of (+) - 1- (4-nitrophenoxy) -2-hydroxy-3-tert-butylaminopropane were dissolved by heating in a mixture of 700 ml of acetone and 300 ml of water. "After filtration, 1 L of water was added to the solution and cooled, yielding 183 g of (+) - 1- (4-nitrophenoxy) -2-hydroxy-3-tert-butyl 27,5374 aminopropane-dibenzoyl L (+) - tartrate, melting at 105-111 ° C.

IptJji * - “4-9.2 ° (c = 8, methanol-dimethylformamide 9: 1).

(-) - 1- (4-nitrophenoxy) -2-hydroxy-3-tert-butylaminopropane dibenzoyl L (+) - tartrate:

The solution from which the compound described above was separated was concentrated by evaporation in vacuo, followed by the addition of water. An oil precipitated which was dissolved in 1 L of isopropanol. On standing, the crude (-) - 1- (4-nitrophenoxy) -2-hydroxy-3-tert-butylamino-propane-dibenzoyl-L (+) -tartrate separated, which melted 156 times after recrystallization from isopropanol. .160 ° C.

= -66.5 ° (c = 8, methanol-dimethylformamide 9: 1).

(+) - 1- (4-nitrophenoxy) -2-hydroxy-3-tert. butylaminopropane hydrochloride;

A mixture of 93 g of (+) - 1- (4-nitrophenoxy) -2-hydroxy-3-tert. butylaminopropane dibenzoyl L (+) tartrate, 224 ml of distilled water and 224 ml of chloroform were cooled with stirring to + 5 ° C.

47.5 ml of 5N sodium hydroxide solution were then added with stirring in two equal portions. After the first addition, it was stirred for 10 minutes, after the second for 30 minutes. The chloroform phase was then separated in a separatory funnel, washed with water, dried over potassium carbonate and then the chloroform was distilled off. The residue gave 49.2 g of a yellow resin which was dissolved in 398 ml of isopropanol. To this solution was added isopropanol solution of hydrochloric acid gas until the pH was below 7, whereupon (+) - 1- (4-nitrophenoxy) -2-hydroxy-3-tert-butylaminopropane hydrochloride precipitated, m.p. 184-188 ° C.

- + 13.9 ° (c = 8, methanol).

(-) - 1- (4-nitrophenoxy) -2-hydroxy-3-tert. butyyliaminopropaani-hydro-chloride:

In a similar manner to that obtained above from (-) - 1- (4-nitrophenoxy) -2-hydroxy-3-tert-butylaminopropane-dibenzyl-1 (+) - tartrate (-) - 1- (4-nitrophenoxy) -2 hydroxy-3-tert.butyyliaminopropaani hydrochloride.

2 8 $ 63/4

Melting point 165-167 ° C, resp. 184-186 ° C.

δ = -H, 1 ° (c = 8, methanol).

(-) - 1- (4-aminophenoxy) -2-hydroxy-3-tert.butyyliaminopropaani:

To a suspension of 122 g of (+) - 1- (4-nitrophenoxy) -2-hydroxy-3-tert-butylaminopropane hydrochloride, 610 ml of methanol, 10 ml of aqueous ammonia and Raney nickel From a catalyst prepared from 27 g of an Al / Ni alloy containing 37% by weight of nickel, 150 ml of an aqueous solution of hydrazine (213 g of hydrazine / l) were added with stirring at 50-60 ° C for 30 minutes. After vigorous gas evolution ceased, the mixture was heated to reflux for a further 5 minutes, after which the solution was filtered hot to separate the catalyst. The methanol was distilled off, the residue was dissolved in 10 times the amount of water by adding hydrochloric acid, the solution was filtered, and by adding 5N sodium hydroxide solution, (-) - 1- (4-aminophenoxy) -2-hydroxy-3-tert-butylaminopropane was precipitated as a dark oil. The compound was dissolved in chloroform, the chloroform layer was separated, dried over potassium carbonate, and the chloroform was distilled off. The dark oily residue was then distilled in vacuo to a yellowish solidifying oil having a boiling point of 145-146 ° C and a melting point of 82-83 ° C.

-0.56 ° The dihydrochloride of this compound has a rotation: [α] 25 D = + 11.6 ° (c = 4, water-dimethylformamide 2: 3).

(+) - 1- (4- (3-cyclohexylureido) -phenoxy) -2-hydroxy-3-tert-butylaminopropane hydrochloride: (-) - 1- (4-aminophenoxy) -2-hydroxy-3 The reaction of tert-butylaminopropane with cyclohexyl isocyanate proceeds in the same manner as described in Example 28 for the reaction of racemic 1- (4-aminophenoxy) -2-hydroxy-3-tert-butylaminopropane with cyclohexyl isocyanate. Optically active 1- (4- (3-cyclohexylureido) -phenoxy) -2-hydroxy-3-tert-butylaminopropane melted from isopropanol recrystallized at 167-169 ° C.

To prepare the hydrochloride, the base was purified and dissolved in isopropanol by heating, and a solution of isopropanol in hydrochloric acid gas was added to the solution until the pH was below 7. This gave (+) - 1- (4- (3-cyclohexylureido) -phenoxy) -2-hydroxy -3-tert-butylaminopropane hydrochloride with a melting point of 132-136 ° C (corresponding to 205-208 ° C).

- + 13.3 ° (c = 8, methanol) (_) -1- (4- (3-cyclohexylureido) phenoxy) -2-hydroxy-3-tert-butylaminopropane hydrochloride: (-) - 1 The synthesis of - (4- (3-cyclohexylureido) -phenoxy) -2-hydroxy-3-tert-butylaminopropane hydrochloride took place in a similar manner. The optically active 1- (4-aminophenoxy) -2-hydroxy-3-tert-butylaminopropane obtained from (-) - 1- (4-nitrophenoxy) -2-hydroxy-3-tert-butylaminopropane hydrochloride was obtained in crude form. to react with cyclohexyl isocyanate to give optically active 1- (4- (3-cyclohexylureido) phenoxy) -2-hydroxy-3-tert-butylaminopropane, which, recrystallized from isopropanol, melted at 169 · - · 171 ° C. The base was converted to the hydrochloride in a similar manner as above. Melting point 136-140 ° C (resp. 205-208 ° C).

Z * x_7]) 0 * -13.7 ° (c = 8, methanol).

Claims (2)

A process for the preparation of 3-receptor blocking ureidophenoxyalkanolamine derivatives of the general formula - NH - CO - NH - J - (I) O - CH2 - CHOH - GH2 - NH - R1 wherein Rj represents a straight-chain lower alkyl group, having 1 to 6 carbon atoms, a branched lower alkyl group having 3 to 8 carbon atoms, an alkenyl group having 3 to 6 carbon atoms or a cycloalkyl group having 3 to 6 carbon atoms. 7 C atoms, and R 2 is a hydrogen atom, a straight-chain lower alkyl group having 1 to 6 C atoms, a branched lower alkyl group having 3 to 8 C atoms, a cycloalkyl group having 3 to 7 C atoms an atom or an alkenyl group having 3 to 6 carbon atoms, the urea group and the alkanolamine group being able to be in the o, m or p position relative to each other, and their salts with physiologically acceptable inorganic and organic acids, characterized in that either a) an enoxygen base of the general formula R. - NH - CH „- CH - CH0 - 0 - (II) ά h nh9 OH ά is administered reacting the ol derivative with a compound of general formula R 2 - N = C - O (III), wherein R 1 and R 2 are as defined above, followed by cleavage of any protecting groups, or that h) giving the general formula R 4 - NH - CH 0 - CH - CH9 - O - jT \ (IV) 1 * 1 * V = ^ NH - C - O OH 'r6 to react with an amine of general formula R2 - nh2 (V) 31 56374, wherein and R2 have the same meaning as above and R 1 is an alkoxy group having 1 to 4 C atoms, a phenoxy group, or if R 2 represents a non-hydrogen atom, also an amino group, after which the possible protecting groups are cleaved, or that c) the general formula R 2 - NH - CO - NH - (VI) 0. React the ureidophenyl derivative of the formula CH2 to R1j with an amine of the general formula R1 to NH2 (VIII), wherein R1 and R2 are as defined above and the group - CH - CH9 or - OH - CH0 - Ro \ / 2 '2 ° OH (VIIa) (VIIb) wherein R 9 is a halogen atom or a sulfonic acid residue or alternatively a ureidophenyl derivative is a mixture of compounds of formula VI wherein R 2 has said two meanings, followed by cleavage of any protecting groups, or d) giving Ro - NH - The reaction of a ureidophenyl derivative of the formula CO - NH - (IX) 1 - OH, in which R2 is as defined above, reacts with the general formula Rg - CH2 - CH - CH2 - NH - R1 (X) OH and / or the general formula CH2 - CH - CH2 - NH - R1 (XI) /, wherein R1 and Rq are as defined above for 56374 32, followed by cleavage of any protecting groups, or that e) reacting with the general formula R2 - NH - CO - NH - (XII) A ureidophenyl derivative of the formula CH2 - CH - CH2 - NH2 OH to react under reducing conditions with a carbonyl compound of the general formula 0R9 to C to R10 (XIII), wherein R2 is as defined above and R8 and R2 together with the C atom to which they are attached form by reduction to a group convertible into R 1, followed by cleavage of any protecting groups, or that f) giving the general formula R 2 - NH - CO - NH - (XIV) A reaction of a ureidophenyl derivative of the formula CH2 - CH - CH2 - NH2 OH in which R2 is as defined above with an alkylating agent of the general formula R1 to X (XV) in which R1 is as defined above and X is a halogen atom, followed by cleavage optionally protecting groups, or that g) subjecting to hydrogenolysis a ureidophenyl derivative of the general formula fr'l R9 - NH - CO - NH - - / ~ \, 2 (XVI) c \ _ and O - ch2 - CH - ch2 - N - R1 OH wherein R 1 and R 2 are as defined above or that h) is reduced by the general formula 33 56374 R 2 - NH - CO - NH - R 9 Y = / ^ 0 - CH 9 - CH - CHQ - N = C A ureidophenyl derivative of the formula π Λ10 OH Ίϋ in which R 2 and R 9 and R 10 have the same meaning as above and the possible protecting groups are cleaved and the compounds of the general formula I obtained are converted into their acid addition salts with physiologically acceptable inorganic or organic acids or the compounds of the general formula I salts with inorganic bases to give the free compounds. For example, the β-receptor blocker of the ureudo-phenoxy-alkanolamine derivatives of the formula R2 - NH - CO - NH - / \ (I) \ = λ> - CH2 - CHOH - CH2 - NH - R1 is selected from the group consisting of R1 and alkyl group with 1 ... 6 C-atoms, with an alkyl group having 3 ... 8 C-atoms, with alkenyl groups with 3 .. .6 C-atoms or en cycloalkyl groups with 3 ... 7 C-atoms ooh R2 heteroaten en väteatom, en ogrenad lägre alkylgroup med 1 ... 6 C-atom, en grenad lägre alkylgrupp med 3 ... 8 C-atom, en cycloalkylgroup med 3 .. .7 C-atom or ellenen alkenylgrupp med 3 .. .6 The C-atom, the colored urea group and the alkanol group, may be in the form of o-, m- or p-ställning i förhällande account varandra, but also in the form of physiologically acceptable organic and organic salts, kännetecknat därav, att antingen a) ett phenoxyalkanolamines with the formula R1 - NH - CH0 - CH - CH «- 0 - // ~ \ (II) '\ = / ^ nh9 OH (III) 34 5 6 374 varvid and R2 betecnar sannna som ovan ,; after which a shielding group is optionally added, or b) that the phenoxyalkanolamine derivatives with all the formulas Ri - NH - CH9 - CH - CH9 - 0 - // ¾ (IV) 1 ά% c \ _7— N - G - 0 OH '* 6 rings of a reagent with an amine form in r2 - nh2 (V) colors R1 ooh R2 is a member with the word som ovan, Rg is a member of an alkoxy group with 1,. the amino group is then optionally fused to a shielding group, or c) that the ureido phenyl derivatives with the formula R2 - NH - CO - NH - \ = / O - CH2 - R7 (VI) and R2 are taken as the same as R4 - CH - CH9 or - CH - CH9 - Rp \ / 2, 2¾ 0 OH (Vila) (VIIb) i vilken Rq betecnar en halogenatom or sulfonosyrarest, eller alternative alternatives to ureidophenyl derivatives derived from the bleaching of the compounds of formula VI, varvid Rη har bäda de betydelser som angivits ovan, bringas att reagera med Amin med the substituents of formula R1 - NH2 (VIII) and the same R1 are selected from the group consisting of the same group of compounds of formula R1 - NH2 (VIII) and, optionally, d) and ureidophenyl derivatives of the compounds of formula 35 56374 R2 - NH - CO - NH - (IX) W / "OH In the case of R2, the same mixture is used as a reagent in the form of Rg - CH2 - CH - CH2 - NH - R1 (X) OH and / or CH - ^ CH - CH2 - NH - R1 (XI) 0 and R 1 and R 2 are selected from the group consisting of R9 and N-00-N- (XII) * o - CH 2 - CH - CH 2 --NH 2 OH. i will be R2 in the same phase as the ovary ring of the reactor with carbonylation with all the compounds of formula 0 R g - 8 - R10 (XIII) in which Rg and R10 are substituted with the corresponding C-atom in the genome by hydrogenation to a group R1 for which a reducing group is optionally present in the reaction group, or f) that ureidophenylated with R - NH - CO - NH - (XIV) 2 W * - 0 - oh2 - OH - ch2 - ML, i and R2 in the same phase as in the case of a ring reacting with an alkylation mixture with the formula R-j - X (XV)