DE2153024A1 - Process for the preparation of ureidophenoxyalkanolamine derivatives - Google Patents

Description

2153Ρ24

Process for the preparation of ureidophenoxy-alkanolamine

Derivatives

The invention relates to processes for the preparation of ureidophenoxyalkanolamine derivatives of the general formula

R ₂ -HH-CO-HH-

O - CH ₂ - CHOH - CH ₂ - BH -

wherein R- is an unbranched lower alkyl radical with 1 to 6 Carbon atoms, a branched lower alkyl radical with 3 to 8 carbon atoms, such as isopropyl, isobutyl, tert-butyl, Isoamyl, tert-amyl or the isohexyl radical, an alkenyl radical with 3 to 6 carbon atoms, such as the allyl, methallyl or crotyl radical, or a cycloalkyl radical with 3 to 7 carbon atoms, such as the cyclopropyl, cyolobutyl, cyclopentyl, cyclohexyl or cycloheptyl radical, and R «is a hydrogen atom, an unbranched lower alkyl radical with 1 to 6 carbon atoms, a branched lower alkyl radical with 3 to 8 carbon atoms, like the Ieopropyl-, isobutyl-, tert, -butyl-, isoamyl-, tert-amyl- or the Iaohexylrest, a cycloalkyl radical with 3 to C atoms, such as the cyolopropyl, cyolobutyl, cyclopentyl, cyclohexyl or cyoloheptyl radical, or an alkenyl radical with 3 to 6 carbon atoms, such as the allyl, methallyl or the Crotylreet mean and where the urea radical and the Alkanolamines are in the o, »or p position to one another can and their salts with physiologically compatible inorganic or organic acids «

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All examples of physiologically acceptable inorganic and organic acids which are suitable for salt formation are hydrochloric acid, hydrobromic acid, hydrogen iodide acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, dichloroacetic acid, propionic acid, benzilic acid, Salicylic acid, oxalic acid, malonic acid, adipic acid, maleic acid, fumaric acid, tartaric acid, or citric acid Called ascorbic acid

The definition of the compounds of general JFoncel I includes both the pure stereoisomeric forms and mixtures of the same

"The compounds of general formula I exercise an essential stronger, specific ß-adrenergic blocking effect than she by D · DUNLOP and R. G. SHANKS (Brit.J.PharmacChemother. ^, 2o1-2o [1968]) for I-U-acetaminophenoxy) -2-hydroxy-3-isopropylaminopropane has been described

The test of the connections erased on the cat anesthetized with Ghloralee urethane, the recording of the contraction force was carried out via the maximum rate of pressure increase (dp / dt max) in the left ventricle by means of a steel catheter the systolic and diastolic blood pressure wad. the heart rate was recorded simultaneously

W. BARTSCH (Aroh.exp.Phermak. U. Path, 2 ^ g, 328 [1966]) carried out · The · determination of the blookad · the isoprenaline effect on the bronchial syatem is carried out · on the histamine spasm de a Guinea pigs and the examination of the antiarrhythmic effect on aconitinteat of the rat.

The results are given in table 1

BATH ORIGINAL

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Tabel

^R 1

«2

CH

CH

1.3 o, 43 1.19 1.8 1.4 1.57

* 3 ° »92 1» o 1.55

* "- ^σ Α ^Η α ⁰ A °» 72 o, 29 1 »7o 5, o

t-CJBU Cyclohexyl o, 66 o, 18 o, 24 2o, o

1-C ₃ H ₇ H 2.6 3.1 1o, 3

1- (4-Ace t amino-

phenoxy) -2-hydroxy- _{Afl 1ft 19 ς ft}

3-isopropyl-amino- ⁴ » ^{8 1} » ^{8 1} · ^{2 5} · ⁰

propane

no
none none none
1o-2o
no

+5 +9 +8 -2 +2 +8

no -6

+ 5%
+1456

+9 *
+ 2 %
+1 56
+4? 6

-3 56

+ $ 8 6

+ 53 %

+ £ 42

- 6 % -1o £ + 33 %

- 2 56

In table 1:

Column 1: Chemical compound of the general formula I characterized by the residues R- and R ₂ or urine of the reference substance

Column 2: ^ED c _{0 of} the inhibition of the positive chronotropic effect of isoprenaline (1 / ug / kg) in mg / kg iv

Column 3t EDc _{0 of} the inhibition of the positive inotropic isoprenaline effect (1yUg / kg) in mg / kg iv

Column 4 » ^ED 50 ^ ^er inhibition of the positively inotropic isopre-

nalin effect (o, o15, ug / kg) in ^ ug / ml on the isolated Atrial specimen

Column 5χ dose in mg / kg with i.p., application of the beginning ß-blockade to the bronchial system of the guinea pig

Column 6: Aconitin arrhythmia in the rat, dose in mg / kg, which inhibits the arrhythmia by 73%

Columns 7-9 »Circulatory side effects with intravenous

Injection of Z.5 mg / kg to the cat as a percentage of the initial value

Column 7t frequency Column 8t eystolic blood pressure Column 9t dp / dt max

As the results in Table 1 show, the ureidophenoxyalkanolamine derivatives of the general formula I have a 0-adrenergic blooming effect which exclusively inhibits the positive inotropic and chronotropic isoprenaline effect -fahen amount of EDe ₀ corresponds, not influenced, while β-receptor blockers of the 1-Ieopropylamino-3- (i-naphthyloxy) -propan-2-ol block the peripheral vascular effect of isoprenaline the strongest. The ß-stimulating Effect of isoprenaline on the bronchial system only influenced in very high doses.

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Even with enteral administration (jj> mg / kg), the frequency increase caused by isoprenaline by 50 % and the positive inotropic effect caused by isoprenaline can be inhibited by 76% »

With regard to the potency, the compounds of general formula I are 1- (4-acetaminophenoxy) -2-hydroxy-3-isopropylamino-propane think. While the last-mentioned compound, for example, in the aconitin test in rats up to 40 mg / kg has no antiarrhythmic effect, some are derivatives the ureidophenoxyalkanolamine compounds of the general Formula I effective

The circulatory side effects of the compounds of general formula I are very slight · While i-isopropylamino-3- (i-naphthyloxy) -propan-2-ol already at 0.5 mg / kg i »v. marked bradycardia, lowering of blood pressure and in the cat Has a decrease in the force of contraction, the compounds of general formula I do not have these disadvantageous side effects. Some compounds of general formula I even have a distinct positive-chromatic and inotropic Intrinsic effect

On the basis of these results, it is justified to assume that the compounds of general formula I have a specific effect to speak. This specific ß-receptor blockade is for the therapeutic application of great importance · There is five times the possibility of using the compounds of general Formula I to carry out a therapy with ß-receptor blockers in the presence of bronohial obstrictions or on the other hand in the treatment with β-stimulators Eliminate cardiac side effects · In states of shock can by mobilizing endogenous catecholamines in case of ß-blockade circulatory dysregulation in the peripheral vascular system occur that occur when using the specific ß-receptor

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Blocker of the general formula I is avoided, since a predominant α-sympathetic tone in the peripheral vascular system cannot occur.

According to the invention, the compounds of General formula I produce in various ways.

So you can

a) prepare the compounds of general formula 1 by that one is a phenoxyalkanolamine derivative of the general formula

R ₁ - N - CH ₂ - CH - CH ₂ - O - </ ^ J II

A ₄ O - A ^

with a compound of the general formula

R ₀ - ff - C = 0 III

* I I

wherein R ^ and R _{2 have} the meaning given above, R, a hydrogen atom and R * an alkoxy group with 1 to 4 carbon atoms, an optionally substituted phenoxy group, an alkylthio group with 1 to 4 carbon atoms, an optionally substituted phenylthio group, a unsubstituted or _{substituted by R 2} amino group, a hydrazino group or a halogen atom or R ^ and R, together an additional CU bond and A and A ₂ each have a hydrogen atom, a hydrolytically removable protective group, such as an aliphatic acyl group, for example the acetyl group, an aromatic acyl group, for example the benzoyl group, an alkoxycarbonyl group, for example the tert-butoxycarbonyl group, the ethoxycarbonyl group, etc., a cyoloalkyloxycarbonyl group, for example the cyclopentyloxycarbonyl group and the cyclo-

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hexyloarbonyl group, or an aralkyloxycarbonyl group, for example the benzyloxyoarbonyl group, or a hydrogenolytically cleavable protective group, such as an α-arylalkyl group, ZUB example the benzyl group, an alkoxyoarbonyl group, for example the tert-butoxycarbonyl group, or the cycloalkyloxycarbonylcarbonyl group, for example the tert.-butoxycarbonyl group, or the cycloalkyloxycarbonylycarbonyl group, for example the cycloalkyloxycarbonylcarbonyl group, a cycloalkyloxycarbonylcarbonyl group, for example the cycloalkyloxy carbonyl group or an α-aralkyloxyoarbttnylgruppe, for example the benzyloxycarbonyl group, or A ^ and A ₂ zueaaanen mean a hydrolytically cleavable protective group, such as the carbonyl, oxalyl, alkylidene or cyoloalkylidene group, and if necessary splits off existing protective groups.

According to the definition of the radicals R, and Rj represent the Compounds of the general formula III carbamic acid ethers, Thiocarbamic acid ester, urea, mono- or symmetrical disubstituted ureas, semicarbazides, carbamic acid halides or isocyanates

The implementation of the compounds of general formula II with the compounds of the general formula III is carried out in a manner known per se for these reactions, advantageously in one indifferent organic solvent and if desired under heating

In the cases in which A ^ means a hydrogen atom, can it may be advantageous to carry out the reaction of the compounds of general formula II with the compounds of general formula III in the presence of an equimolar amount of acid.

The hydrogenolysis of the protective groups can be carried out by catalytic Hydrogenation, for example by hydrogenation in the presence of a noble metal catalyst such as platinum or palladium, or in Presence τοη Raney nickel in an inert diluent or solvent suitable for the respective catalyst,

BAD ORIGINAL 209823/1179

for example alcohol, aqueous alcohol, dioxane or ice cream, The hydrogenolysis can be carried out by the counter Was a catalyst, for example hydrochloric acid or oxalic acid, accelerated or completed if noble metal catalysts are used for hydrogenation

The hydrolysis of the protective groups can be carried out in a customary manner be carried out in an acidic or alkaline medium

But you can too

b) a rienoxyalkanolamine derivative of the general formula

R ₁ - H - CH ₂ - OH - OH ₂ - O -V ^ ^ IV

A ₁ 0 - A ₂ ^ - "* ^ HCO

_{1 2}

R ₅

with an amine of the general formula

R ₂ -HH ₂ Ύ

wherein R ₁ , R ₂ , A ₁ and A _{2 have} the meaning given above, Rc is a hydrogen atom and Rg is an alkoxy group with 1 to A C atoms, an optionally substituted phenoxy group, j) an alkylthio group with 1 to 4 carbon atoms, an optionally substituted phenylthio group, a hydrazino group, a halogen atom or, if R ₂ denotes other than hydrogen, also an amino group or Rc and Rg together denote an additional CH bond, react and split off any protective groups that may be present «

BAD ORiGINAL

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According to the definition of the radicals Rc and Rg represent the Compounds of the general formula IV carbamic acid ester, Thiocarbamic acid ethers, semicarbazides, carbamic acid halides, Isocyanates or, if Rg is other than hydrogen, also contains urea

The reactions of the compounds of the general formula IV with the compounds of the general formula V are carried out in for these reactions in a manner known per se, expediently in an inert organic solvent and desirable trap with heating. Instead of a solvent, an excess of the amine of the general formula V used can also be used be used·

The production of the compounds used as starting materials of the general formula IV can be obtained by using the for the preparation of carbamic acid esters. Thiocarbamic acid esters, Semicarbazides, carbamic acid halides and isocyanates customary methods, for example from compounds of the general formula II

But you can too

c) in appropriately substituted phenoxyalkanolamine derivatives the general formula

R ₁ - H - CH ₉ - CH - CH ₉ - O 1, -2, 2 A ₁ 0-A ₂

in which R ₁ , R ₉ , A. and A _{2 have} the meaning given above, and in their corresponding isothiourea ethers replace the sulfur or thioether group with oxygen and split off any protective groups that may be present.

NH-C-NH-R ₂

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The replacement of the sulfur atom by an oxygen atom in the compounds of the general formula VI can, for example with the help of oxides or salts of heavy metals or by using oxidizing agents such as hydrogen peroxide » Sodium peroxide, potassium peroxide or nitrous acid are running

The corresponding behave analogously to thioureas Isothiourea ethers, which according to the invention are used as starting materials for the desulfurization reactions are·

The compounds of general formula VI can also by Treatment with phosgene or phosphorpene, desulphurised achloride · The chloroformic acid amidines obtained as intermediate products or · Carbodiimides can be converted into the compounds of the general by saponification or addition of water Formula I to be converted

But you can too

d) a phenoxyalkanolamine-Ιλ. .wat the general formula

VII HR _n

CH ₂ - CH - CH ₂ - 0 -

0-A ₂

in which R ₁ , R ₂ , A- and A ₂ have the meaning mentioned above and R ~ is a halogen atom, an O-acyl group, an S-acyl group, an O-alkyl group or an S-alkyl group, in which the alkyl groups Having 1 bia A C atoms means hydrolyzing and splitting off any protective groups that may be present.

ORiGlMAL BATHROOM

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According to the definition of the radical R ~, the compounds of the general formula VII haloformic acid amidines, Iaourea ester, isothiourea ester, isourea ether and isothiourea ether.

The hydrolysis of all starting materials used compounds of the general formula VII takes place weekly in an alkaline Medium The Isoharnetoffester, Isothiourstoffeter, Isourea ethers and isothiourea affinity to the general Formula VII can also be hydrolyzed with good success in an acidic medium

But you can too

e) to a phenoxyalkanolamine derivative of the general formula

R ₁ - Έ - CH ₂ - CH - CH ₂ - 0 - f \ _{? M}

A ₁ 0 - A ₂ ^{Π ==} ^ ΪΓ = C = N -

wherein R ₁ , R ₂ , A ₁ and Ag have the abovementioned meaning, add water and split off any protective groups that may be present.

But you can too

f) a phenoxyalkanolamine derivative of the general formula

R ₁ - H - CH ₉ - CH - CH ₉ - 0 - {/ \) NH IX A ₁ 0 - A ₂ ^^ KH - C - HH - R ₂

in which R .., R ₂ , A ₁ and A _{2 have} the meaning given above, hydrolyze and split off any protective groups present. The hydrolysis of the compounds of the general formula IX is expediently carried out in an alkaline medium.

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But Han can too

g) a phenoxyalkanolamine derivative of the general formula

R ₁ - H - CH ₀ - OH - CH ₉ - 0 ¹ I -2 I * 2 A ₁ 0 -

NCNR ₂

in which R ₁ , R ₂ * A ₁ and A _{2 have} the meaning given above, saponify and split off any protective groups that may be present.

But you can too

h) a phenoxyalkanolamine derivative of the general formula

R ₁ - I - CH ₂ - CH - CH ₂ - O - </ ^ .0 - CHp ΣΙ

A ₁ 0 - A ₀ ^N - ^C \ I

^{1 d} S-CH ₂

in which R ₁ , A ₁ and A ₂ are as defined above, with an amine of the general formula

R ₂ - HH ₂ V

in which R _{2 has} the meaning given above, react, whereupon any protective groups present are split off.

In this reaction, it is advantageous to use an excess of the amine of the general formula V, for example 2 to 3 moles of amine per mole of a compound of the general formula II to be used

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The reaction can be carried out in an inert organic solvent at temperatures between O * C and the boiling point of the solvent.

The fhenoxyalkanolamine derivative of the general formula XI used as an Auegangeprodukt can, for example, from a phenoxyalkanolamine derivative of the general formula II, in which R ^ A ₁ and Ag have the meaning given above, duroh reaction with OS ₂ in the presence of τοπ alkali lye and subsequent addition of ron Ethylenohlorhydrin in an inert organic solvent such as dimethylformamide, whereby first the correspondingly substituted phenyldithiocarbamic acid ß-hydroxy- "ethyl ester is obtained, which is then reacted in NaOH with ethyl chloroformate.

But you can too

i) a ureidophenyl derivative of the general formula

XII

R ₂ -I- OQ-I-

wherein R _{2 has} the meaning given above, B ₁ and B ₂ each individually a hydrogen atom or a hydrolytically removable protective group, such as an aliphatic or aromatic acyl group, or B ₁ and B ₂ together a hydrolytically removable protective group such as the oxalyl group and R _n the groups

- OH - 0H ₀ or -CH-CH ₉ -R ₀ 0 0 _{-A 2}

XIII a XIII b

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represents wherein Rg is a halogen atom or the remainder of a Sulphonic acid, for example benzenesulphonic acid or the p-Toluenesulfonic acid, or a mixture of such Compounds in which Rg has the meanings given above, with an amine of the general formula

R ₁ -NH-A ₁ HV

in which R ₁ and A _{1 have} the meaning given above, react and split off any protective groups that may be present.

When Rg represents group XIIIb, the reaction may be advantageous in the presence of an acid acceptor such as potassium carbonate or sodium carbonate.

The reaction can be carried out at room temperature or accelerated or terminated by supplying heat. The reaction can be used under atmospheric pressure or under increased pressure Example in a closed vessel, and it can be carried out in an inert diluent or solvent, such as methanol or ethanol. The amine of the general formula XIV can optionally also be used in excess as a diluent or solvent.

If A ₁ represents an acyl group in the amine of the general formula XIV, it is advisable to use the amine in the form of its alkali salt

The compounds of general formula XII used as starting materials can be obtained by reacting the corresponding phenol with an epihalohydrin, for example epichlorohydrin. The compounds of the general formula 3EII can be isolated, but they can also be used in the preparation medium are immediately further processed according to this invention

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But Han can too

$) a ureidophenyl derivative of the general formula

-I- 00 - Έ - (/ \ TT

wherein R ₂ , B ₁ and Bg have the abovementioned meaning, with a compound of the general formula

CH ₅ -OH-CH ₉ -HR ₁ XTII

0 A ₁

wherein R ₁ , R ~, A ₁ and A _{2 have} the meaning given above, or mixtures thereof react .: -u let and split off any protective groups present *

The reaction can sweekaSBig in the presence of an acid aooeptore, such as, potassium carbonate or sodium carbonate, to be carried out On the other hand, an alkali metal of the phenol in question, for example the sodium or potassium salt, can be used as the starting compound to be brought·

_BATH

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But Han can too

k) a ureidophenyl derivative of the general formula

-W-OO-W-

XVIII

0 - CH ₀ - CH - CH ₀ - HH 0 -A ₂ A ₃

in which! U, A ₂ * B. and B _{2 have} the abovementioned meaning and A is a hydrogen atom or an optionally substituted benzyl radical, with a carbonyl compound of the general formula

R ₁₀ - C - R ₁₁ XIX

where R ₁₀ and R ₁₁ together with the connecting carbon atom represent a _{radical which can be converted into the group R 1} by hydrogenation, react under reducing conditions and split off any protective groups that may be present.

Suitable reducing conditions are, for example, the presence of formic acid according to the method of Leuckart gelding dar

Suitable reducing conditions are, if A denotes a hydrogen atom, also the presence of hydrogen and * a hydrogenation catalyst such as platinum, palladium or

Raney-Viokel, it being possible to work in an inert solvent or diluent, for example ethanol

If R ₁₀ and R _{11 are} alkyl radicals or, together with the C atom of the carbonyl group, a cyeloalkyl radical, can also be used as a solvent. an excess of the carbonyl compound of the general formula XIX can be used «

ORIGINAL

209873/1179

When Ao is a hydrogen atom, suitable reducing conditions are also created by the presence of di-light metal hydrides such as alkali borohydride in an inert solution or diluent such as hydrous methanol, with an excess of the carbonyl compound generally Formula XIX can be used «

If R _{2 is} an alkenyl radical that is not to be hydrogenated, we recommend; it is possible to reduce with di-light metal hydrides, such as alkali borohydride

The compounds of the general formula XVIII used as starting compounds can, if kr. and A ^ mean a water off atom, can of course also be generated in situ, for example by reducing the corresponding a-diazoketones, a-azido ketones, α-oximino ketones, α-nitro ketones, α-Bfitrosoketones, a-nitro alcohols, or cyanohydrins Acyleyanide.

But you can too

1) a ureidophenyl derivative based on general formula

N - co - IT - I. I. ^B 1 ^B 2

CH ₂ - BH - A ₁

O - A ₂

O - OH ₂ - OH - CH ₂ - BH -

wherein R ₂ , A ₁ , A ₂ , B ₁ and B _{2 have} the meaning given above, with an alkylating agent of the general formula

R ₁ -I XXI

wherein R. has the abovementioned meaning and X is Halogen atom, an alkyl sulfate residue or the residue of one Sulphonic acid, such as the benzenesulphonyl or toluenesulphonyl radical, means to react and optionally present Split off protective groups

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If A. is an acyl group, the compounds of the general formula XX can also be used in the form of their alkali metal salts.

An acid acceptor, such as alkali metal carbonate, can also advantageously be used in the reaction. The reaction can expediently carried out in the presence of an inert diluent or solvent, such as ethanol, and accelerated or completed by supplying heat

But you can auoh

m) a ureidophenyl derivative of the general formula

R ₂ -I- CO-V-

XZII

O - CH ₂ - CO - CH ₂ - N -

wherein R ₁ , R ₂ * A., B ₁ and B _{2 have} the meaning given above, hydrogenate and split off any protective groups present.

The hydrogenation can be carried out, for example, by catalytic hydrogenation, for example in the presence of platinum, palladium or . Raney nickel, and be carried out in an inert solvent or diluent. The hydrogenation can be advantageous auoh with di-light metal hydrides, such as lithium aluminum hydride, or sodium borohydride, in a suitable solution or Diluents, such as aqueous methanol, or with alcoholates, such as aluminum isopropylate or magnesium isopropylate, according to the Method of Meerwein-Ponndorf-Verley or its modifications.

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But you can auoh

η) a ureidophenyl derivative of the general formula

ΣΧΙΙΙ

0 - CEL - CH - CiL, -2, j *

where R ₁ , IU ₉ B ^ and Bp have the abovementioned meaning and Y is a hydrolytically cleavable group such as the carbonyl group, the oxalyl group or the group

-C -

^l 13 ³ ^

denotes in which R- «and R-., each a hydrogen atom or an alkyl radical with 1 to 6 carbon atoms, or R and R ₁ , together denote the group - (CHp) _n -, where η denotes the numbers 4 to 6 stand, subject to hydrolysis and split off any protective groups present *

The compounds of the general formula XXIII thus represent Oxazolidones, Oxazindiones and Oxazolidines. The hydrolysis of the Oxazolidones and the Qxasindiones of the general formula XXIII can be carried out both in an alkaline and in an acidic medium, while the hydrolysis of the Oxazolidine of the general formula XXIII is preferably carried out in an acidic medium

But you can auoh

o) a ureidopheny! derivative of the general formula

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- 2ο -

¹⁵ XXV

0-CH ₂ -CH-CH ₂ -N-R ₁ O

where R ₁ and R _{2 have} the meaning given above and R ₁₄ and R ₁ K each represent a hydrogen atom or a hydrogenolytically cleavable group, for example an α-arylalkyl group, such as the benzyl group, an alkoxycarbonyl group, a cycloalkyloxycarbonyl group or an a-aralkyloxyearbonyl group and wherein at least one of the radicals R ₁₄ and R ₁ is C a hydrogenolytisoh cleavable group, the hydrogenolysis subject · the hydrogenolysis of the compounds of general formula XXV can by means of hydrogen i _n the presence of a Hydrated 'approximately catalyst such as platinum, palladium or Raney nickel, be performed·

But you can too

p) a ureidophenyl derivative of the general formula

H ₂ -H-CO-H- ^ ς & R ₁₇

⁸ I ³ Z 0 - OH ₂ - OH - CH ₂ - B - R ₁

0 - E ₁₆

wherein R ₁ , R ₂ , B ₁ and B _{2 have} the meaning given above, P and R ../- and R ₁ ™ each have a hydrogen atom or a hydrolytically cleavable group, such as an aliphatic acyl group, for example the acetyl group aromatic acyl group, for example the benzoyl group, an alkoxycarbonyl group, for example the tert-butoxycarbonyl group, the ethoxycarbonyl group, etc., a cycloalkyloxycarbonyl group, for example the cyclopentyloxycarbonyl group and the cyclohexyloxycarbonyl group, or an aralkyloxycarbonyl group, for example the benzyloxyoarbonyl group, for example the R ₁ g and R ₁ γ radicals denote a hydrolytically cleavable group, subject to hydrolysis and

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'Remove any protective group that may be present * The hydrolysis Can be used in both acidic and alkaline Me.Ii to be carried out »

But you can too

q) a ureidophenyl derivative of the general formula

R ₂ -Ii- CO -N - ^^ V XXVII

R ₁₈ R ₁₉ 0 - CH ₂ - CHOH - CH ₂ - HH - R ₁

where R ₁ and R _{2 have} the meaning given above and R ₁ Q and R ₁ Q each represent a hydrogen atom or an acyl group, for example an aliphatic or aromatic acyl group, and at least one of the radicals R ₁ Q and R ₁ Q is an acyl group means subject to hydrolysis.

The hydrolysis can be carried out either in an acidic or in an alkaline medium.

But Mar. can also

r) a ureidophenyl derivative of the general formula

- S - CO - N - </ ^ XXVIII

ι ι

B ₁ B ₂ O-CH ₂ -CH -C = O

O ^R 1o ^R 11

iovin R ₂ , R ₁ , R ₁₁ * B-. and B _{2 have} the meaning given above, hydrogenate and split off any protective groups present ·

The hydrogenation can, for example, with a Di-Leichtmetallhyv'riti, such as lithium aluminum hydride.

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The compounds of the general formula XXVIII can by Condensation τοη compounds of the general formula XIX with an amide of the general formula

XXIX

f " co - H -U
• \ = - ^/ o - CH ₂ - OH OH - HH ₂ ^B 1 * 2

are wherein R _2, B ^ and B ₂ are as defined above possess obtained * The compounds of general formula XXIX can in turn, for example, by reacting a compound of the formula XV or a Alkalisalzeβ a compound of general formula XV wherein R _2, B ^ and B _{2 have} the meaning given above, are obtained with 2,3-epoxypropionic acid amide

But you can too

s) a ureidophenyl derivative of the general formula

-H- CO -H- (/ ^ XXX

ii ^{1 = r} O - CH ₉ - CH - CO - H - R ₁ B ₁ B ₂ ~ 2, j 1

QA ₂ A ₃

wherein R ₁ , R ₂ , A ₂ , A ^, B ₁ and B _{2 have} the meaning given above, hydrogenate and split off any protective groups present.

The hydrogenation is expediently carried out with Dl light metal hydrides, like lithium aluminum hydride

Dae used ureidophenyl derivative as the starting product general formula XXX can, for example, by reacting a

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Compound of the general formula

ZXXI

0 - CH ₂ - CH - COOR ₂₀ 0 -

in which IUt A ₂ , XL and B ₂ are as defined above and Rp _{0 is} an alkyl radical having 1 to 4 carbon atoms, with an amine of the general formula

R ₁ -HH-A ₃ IXXII

where R ₁ and A? have the meaning given above, are obtained *

But you can too

t) a ureidophenyl derivative of the general formula

_ ν _ CO - H - </ ^ XXXIII

B ₁ B ₂ ^ = ^ 0 - CH ₂ - CH - CHO

0-A ₂

wherein R ₂ , A ₂ , B ₁ and B _{2 have} the meaning given above, with an amine of the general formula

R ₁ - NH - A ₃ XXXII

wherein R ₁ and A _{3 have} the meaning given above, react under reducing conditions and split off any protective groups present «

Suitable reducing conditions are the presence of formic acid according to the method of Leuckart-Wallach

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Suitable reducing conditions are when A-j is hydrogen atom means also the presence of hydrogen and a hydrogenation catalyst such as platinum, or palladium Raney nickel in an inert solvent or diluent, for example ethanol,

Suitable reducing conditions become when A-, a hydrogen atom means, also created by the presence of di-light metal hydrides, such as alkali borohydrides, in an inert solvent or diluent, such as hydrous methanol,

But you can too

u) a ureidophenyl derivative of the general formula

XXXIV

0 - CH ₂ - CH - CH = * H - R ₁ 0-A ₂

in which R-, R ₂ , A ₂ , B- and B _{2 have} the meaning given above, reduce and split off any protective groups present.

Formic acid, for example, is suitable for the reduction. the However, reduction can also be carried out by means of hydrogen, in the presence of suitable hydrogenation catalysts, such as platinum or palladium or Raney nickel, or by means of di-light metal hydrides, such as alkali borohydrides or lithium aluminum hydride, in one inert solvents or diluents are carried out.

But you can too

v) a ureidophenyl derivative of the general formula

R ₂ -N- CO-N-

209823/1179

N-CO

B ₁ B ₀ "- '0 - GH ₉ - CH - OH ₀ - TI - C

12 * 2, 2 ν

0 - Ao 11

in which R ₂ , A ₂ , B .. and B ₂ and R ^ ₀ and R ^ have the meaning given above, reduce and split off any protective groups present.

For example, formic acid is suitable for the reduction. The reduction can also be carried out using hydrogen in the presence of suitable hydrogenation catalysts such as platinum, palladium or Raney nickel, or using B1 light metal hydrides such as alkali borohydrides or lithium aluminum hydride ₃ in an inert solvent or diluent.

The embodiments of the methods according to the invention can generally largely with regard to the reaction conditions can be varied and adapted to the respective conditions

For example, the reactions can be carried out in the absence or in the presence of inert solvents or diluents Room temperature or with the supply of heat. If necessary, it can also be placed in a closed vessel Pressure to be worked

Depending on the substituents present in the reaction partners the optimal conditions in terms of temperature and solvent can vary widely, with finding the eats properly in optimal conditions.,

BATH ORIGINAL

209823/1179

Depending on the character of the Auegangeetoffe, one or the other other of the processes described in individual cases a compound of the general formula I only in low yields deliver · In such cases, the skilled person does not have any difficulties, either by selecting suitable protection groups to rerhinder life reactions and thus to increase the yields or the * product on another of the described Establish procedural paths *

The compounds used as starting materials in the individual processes can be prepared, unless special described, carried out using known methods and is professional

The compounds of general formula I obtained can be mixed with physiologically acceptable inorganic or organic Acids, such as hydrobromic acid, hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, phosphoric acid, Acetic acid, propionic acid, diohloroacetic acid, benzilic acid, Salicylic acid, oxalic acid, malonic acid, adipic acid, maleic acid, fumaric acid, tartaric acid, citric acid or ascorbic acid in their acid addition salts are converted

Acid addition salts obtained from compounds can also be obtained of the general formula I with inorganic bases in the free compounds

If racemic compounds of the general formula I are obtained, they can be converted into their by known methods Optically active forms are broken down · Likewise, one can optically active compounds of the general formula I but also by receive the use of optically active output compounds in the reaction «

209823/1179

Example 1:

35i5 g of 1- (4-ureidophenoxy) -2,3-epoxypropane and 142 ml of isopropylamine were stirred at room temperature for 40 hours then the excess isopropylamine was distilled off, the residue is dissolved in dilute hydrochloric acid, the solution is filtered blank and the dissolved base is removed by adding solid Potassium carbonate precipitated, The precipitate, which consists of 1- (4-Ure ido phe noxy) -2-hydroxy-3-isopropylamirio propane, had a melting point of 141.5 - 142.5 ° C after recrystallization from ethanol

Example 2:

10 g of 1- (4-ureidophenoxy) -2,3-epoxypropuι and 100 ml of tert-butylamine were refluxed for 8 hours, the excess tert-butylamine was distilled off and the residue was taken up in dilute hydrochloric acid. The solution was sucked clean and then the base was precipitated by adding solid potassium carbonate. The precipitate was filtered off, dried, dissolved in methanol and the 1- (4 ~ l '; - ^ i) henoxy) -2-hydroxy-3-tert-butylaminopropane hydrochloride precipitated by adding ethereal hydrochloric acid, which was precipitated after recrystallization melted from aqueous methanol at 2o7 ⁹ C with decomposition

Example 3:

26 g of N-methyl-N '- [4- (2,3-epoxypropoxy) phenyl] urea ₁ 50 ml of isopropylamine and 100 ml of isopropanol were refluxed for 5 hours after the solvent and the excess isopropylamine had been distilled off The residue obtained was dissolved in dilute hydrochloric acid, the solution was filtered and the dissolved substance was precipitated by adding solid potassium carbonate. After recrystallization from dilute alcohol, the 1- [4- (3-methylureido) -phenoxy] -2-hydroxy- 3-ieopropylaminopropane at 154-156 ° C.

P * C ORIGINAL

209823/1179

2153Ö24

The N-methyl-N '- [4- (2,3- · epoxypropoxy) -phenylJ-urea used as starting compound was prepared as follows: • ttine mixture of 49 »8 g of N-methyl-N'-Cp-oxyphenyl) urea, 150 ml of 5 ⁿ KOH and I66 g of epichlorohydrin was stirred for 6 hours at room temperature. The precipitated N-methyl-N ^f - [4- (2,3-epoxypropoxy) -phenylJ-urea was then filtered off with suction, washed with water and dried. The crude product, which ^{melted at 139 to 143 °} C., was processed further without further purification.

Example 4:

10 g of N-ethyl-N '- [4- (2,3-epoxypropoxy) -phenylJ-urea and 50 ml of tert-butylamine were refluxed for 8 hours. The residue obtained after the excess tert-butylamine had been distilled off was dissolved in dilute hydrochloric acid, the undissolved material was filtered off, the base was precipitated with potassium carbonate, filtered off with suction, dried and recrystallized from butyl acetate for purification. The thus-prepared 1- [4- (3-Äthylureido) -phenoxyJ-2-hydroxy-3-tert-butylaminopropan melting at 122-124 ⁰ C.

The N-ethyl-N ^f - [4- (2,3-epoxypropoxy) phenyl] urine ^{used as starting product, which melted after recrystallization from ethanol at 154-156 »5 0} C, was analogous to the N-methyl W- [4- (2,3-epoxypropoxy) -phenylI-urea produced.

Example 5:

1 g of 1- (4-ethoxycarbonylaminophenoxy) -2-hydroxy-3-isopropylaminopropane and 5 ml of cyclohexylamine were refluxed for 2 hours. The excess cyclohexylamine was then distilled off, the remaining residue was dissolved in dilute hydrochloric acid and the solution was filtered. [4- (3-cyclohexylureido) -phenoxyJ-2-hydroxy-3-isopropylaminopropan precipitated, which after recrystallization from isopropanol at 157 - - by the addition of sodium hydroxide solution containing 1 was melted I60 C ^0.

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BATH

2153Ö24

Example 61

A mixture of 3 g of N-methyl-N'-Cp-oxyphenyl) urea, 3 ml of tert-butyl (2,3-epoxypropyl) amine, 2o ml of water and 0.2 ml of concentrated sodium hydroxide solution was added for 6 hours Stirred at room temperature and then left to stand for 18 hours. A resinous precipitate had formed, which was digested with water and then dissolved in acetone 1- [4- (3-methylureido) phenoxy] -2-hydroxy-3-tert-butylaminopropane crystallized from the acetone solution, which after recrystallization from isopropanol at 14o - 143 ⁰ C melted.

Example 7:

o # 5 S 1- (4 ~ aminophenoxy) -2-hydroxy-3-iscpropylaminopropane were dissolved in a mixture of 2.2 ml of 1 η hydrochloric acid and 5 ml of acetone and 0.3 g of cyclohexyl isocyanate were added. After 16 hours the acetone was distilled off, 5 ^ 1 water was added and the solution was filtered. By addition of sodium hydroxide solution 1- [4- (3-cyclohexylureido) was -phenoxyJ-2-hydroxy-3-isopropylaminopropan precipitated, which after recrystallization from isopropanol at i ^c 6 - melted 158 »5 ⁰ C.

Example 8 χ

50 g of N-cyclohexyl-N '- [4- (2,3-epoxypropoxy) phenyl] urea, 250 ml of tert-butylamine and 500 ml of isopropanol were refluxed for 11 hours. The solvent was then distilled off, the residue that remained was dissolved in 3 l of water and 86 ml of 1 n hydrochloric acid and the solution was filtered. By addition of sodium hydroxide solution 1- [4- (3-cyclohexylureido) phenoxy] was precipitated -2-hydroxy-3-tert-butylaminopropan, which after recrystallisation from isopropanal at 143 - 145 ⁰ C melted.

The N-cyclohexyl-N '- [4- (2,3-epoxypropoxy) phenyl] urea used as the starting product can be made in the following ways »

_BATH

20987 3/1179

~ ³ ° ~ 2Ί53Ό2Λ

92.5 g of epichlorohydrin were added to a solution of 40 g of S-cyclohexyl-N ^ Cp-oxyphenyl) urea in 50 ml of 5 η potassium hydroxide solution and the whole was stirred for 16 hours at room temperature. The precipitated N-cyclohexyl-N * - [4- (2,3-epoxypropoxy) -phenylJ-urestQff was then filtered off with suction, washed with water and dried further processed

Example 9 *

A mixture of 10 g of 1- (4-ureidophenoxy) -2-hydroxy-3-isopropylaminopropane and 10 g of n-hexylamine hydrochloride was heated to 150 ° C. for 3 hours. The reaction product was dissolved in 1 ^ o nl of water with the addition of hydrochloric acid and the solution was filtered. After adding sodium hydroxide solution, the 1- [4- (3-n-hexylureido) phenoxy] -2-hydroxy-3-isopropylaminopropane precipitated out, which after recrystallization from ethanol-water 1 * 1 at 146 - 149 ⁰ C melted.

209823/1179

Example 1ox

1 | 175 g 1- (4-rienoxy carbonylemino phenoxy) -2-hydroxy-3-tert-butylaminopropane hydrochloride, 8 ml methanol, 2.93 ml methanol! See sodium methylate solution (1 normal) and 2.67 al methanolic Cyclohexylamine solution (1 normal) were combined and stirred at room temperature for 8 hours. The compartment standing overnight was refluxed for 1 hour, the solvent was distilled off and the residue was dissolved in 20 ml of water and 3.8 ml of 1 η hydrochloric acid. The 1- [4- (3-cyclohexylureido ) -phenoxy] -2-hydroxy-3-tert.-butylaminopropane precipitated, which after recrystallization from isopropanol pouted at 143 to 144 * C. The 1- (4-marriage noxycarbonylamino phe noxy) -2-hydroxy used as the starting product -3-tert-butylaminopropane hydrochloride was prepared in the following way. 10 g of 1- (4-aminophenoxy) -2-hydroxy-3-tert-butylaminopropane hydrochloride were dissolved in 80 ml of water at room temperature with stirring. Then 5 $ 7 g of phenyl chloroformate were added dropwise, the mixture was stirred for a further hour and so much 1 η sodium hydroxide solution was added dropwise that the pH was 6-7. The 1- (4-phenoxycarbonylaminophenoxy) -2-hydroxy-3-tert. -butylaminopropane hydrochloride, which melted after drying at 127 - 13o * C.

Example 11t

2 g 1- (4-phenoxycarbonylaminophenoxy) -2-hydroxy-3-isopropylaminopropane hydrochloride, 2 ml isopropylamine and 10 ml Methanol was left to stand at room temperature for 2 days. Then methanol and excess amine were distilled off, the residue dissolved in water with the addition of hydrochloric acid at pH 4, the solution filtered and the base by adding Sodium hydroxide solution precipitated to pH 12 · The precipitate, which consisted of 1 - [4- (3-isopropylureido) phenoxy] -2-hydroxy-i3-ieopropylaminopropane, was recrystallized from isopropanol and then melted at 154 - 136 T

209823/1179 bad

By the same method the appropriate amines the following compounds were prepared using t

1 - [4- (3-Allylureido) -phenoxy] -2-hydroxy-3-isopropylaminopropan F: 145-147 ⁸ C

1- [4- (3-sec-butylureido) -phenoxy] -2-hydroxy-3-isopropylaminopropane, Pt 141 # 5 - 143 * C

1- [4- (3-i-Amylureido) phenoxy] -2-hydroxy-3-isopropylaminopropane, Fi ^{124-127 8} C

The 1- (4-phenoxycarbonylamino phenoxy) -2-hydroxy-3-i-propylamino per pan hydrochloride was made in the following way

20 g of 1- (4-aminophenoxy) -2-hydroxy-3-isopropylaminopropane were dissolved in 100 ml of acetone with the addition of 7 ml of glacial acetic acid and within 40 minutes a solution of 13.9 g of phenyl chloroformic acid in 50 ml of acetone was added dropwise. The temperature was kept below 30 ° C. Then another hour stirred and then the precipitated 1- (4-phenoxycarbonylaminophenoxy) -2-hydroxy-3-isopropylaminopropane hydrochloride filtered off, which melted after recrystallization from methanol at 199-2o2 "C.

S.

Example 12:

2 g of 1- (4.-phenoxycarbonylaminophenoxy) -2-hydroxy-3-isopropylaminopropane hydrochloride, 10 ml of methanol and 2.5 ml of crotylamine were refluxed for 50 minutes. Then methanol and excess crotylamine were distilled off, the residue was dissolved in 100 ml of water with the addition of dilute hydrochloric acid (pH 4) and the solution was filtered. After the addition of sodium hydroxide solution to pH 12 1- [4- (3-Crotylureido) phenoxy] -2-hydroxy-3-isopropylaminopropan precipitated, which after recrystallization from isopropanol at 14o, 5 - 143.5 ⁰ C melted. Using cyolopentylamine instead of crotylamine, the 1- [4- (3-cyclopentylureido) phenoxy] -2-hydroxy-3-isopropylamine propane with a melting point of 157.5 - 160 T.

209823/1179

Example 13 »

A mixture of 342 mg of cycloneptylamine, 1 g of 1- (4-phenoxycarbonylaminophenoxy) -2-hydroxy-3-ieopropylaminopropane hydrochloride, 2.6 al methanolic sodium methylate solution (1 normal) and 10 ml of methanol were left to stand at room temperature for 16 hours and then under reflux for 30 minutes boiled · Then the solvent was distilled off, the residue in ^ o ml of water with the addition of Dilute hydrochloric acid (pH 4) was added and the solution filtered. By adding sodium hydroxide to pH 12, the 1- [4- (3-Oycloheptylureido) phenoxy] -2-hydroxy-3-isopropylaminopropane precipitated, which melted after recrystallization from isopropanol at 145 * - 143 * C Subject same procedure were under. Use of the corresponding amines following compounds of the general Formula I made:

1- [4- (3-Cyoloppopylureido) -phenoxy] -2-hydroxy-3-isopropylaminopropan, P: 141-143 "C 5 ⁰

1- [4- (3-Hexen- (2) -yl-ureido) -phenoxyJ ~ 2-hydroxy-3-isopropylaminopropane, P: 157.5-159 »5" C

Example 14 *

25 g of H-cyclohexyl-H ^t - [2- (2,3-epoxypropoxy) phenyl3-urea, 25 ml of tert-butylamine and 125 ml of methanol were refluxed for 16 hours. Then methanol and excess tert-butylamine were refluxed distilled off, the remaining residue was dissolved in 8oo ml of water with the addition of hydrochloric acid (pH 4), the solution was filtered and the base was precipitated by adding sodium hydroxide solution up to pH 12 - [2- (3-Cyclohexylureido) -phenoxy] -2-hydroxy-3-tert »-butylaminopropane dichloroacetate precipitated, which sulked after recrystallization from ethanol at 188.5 - 191 * 5 * C ·

209873/1179

The N-cyclohexyl-N '- [2- (2,3-epoxypropoxy) -phenyl] -urea used in the above reaction was analogous to the N-cyclohexyl-N ¹ - [4- (2,3-epoxypropoxy) -phenyl] -urea (Example 8) produced · The crude product, which ^{melted at 147-151 8} C, was processed further without purification. After recrystallization from isopropanol, the substance has a melting point of 162-164.5 "C.

Example 15:

5 g of N-cyclohexyl-N '- [3- (2,3-epoxypropoxy) phenyl] urea, 5 ml of tert-butylamine and 25 ml of methanol were refluxed for 16 hours · Then methanol and excess tert # - Butylamine was distilled off, the remaining residue was dissolved in 300 ml of water with the addition of hydrochloric acid (pH 4) and the solution was filtered. By adding sodium hydroxide solution to pH 12, 1- [3- (3-cyclohexylureido) phenoxy] -2-hydroxy -3-tert-butylaminopropane precipitated, which melted after recrystallization from acetone at 1i> 1 - 154 ⁰ C ·

The N-cyclohexyl-N '- [3- (2,3-6poxypropoxy) -phenylj-urea used as starting product became analogous to the N-cyclohexyl-N ¹ - [4- (2,3-epoxypropoxy) -phenyl] -urea (Example 8) The crude product, which melted at 139 - 149.5 * C, was processed further without purification.After recrystallization from methanol-water 3: 1, the melting point was 150 to 152 ¹ C,

Example i6i

10 g of N-Gyolohexyl-N ^f - [4- (2,3-epoxypropoxy) phenyl] urea, 10 ml of n-hexylamine and 50 ml of methanol were refluxed for 25 hours. Then the solvent and excess amine were distilled off, the remaining residue was dissolved in 8oo ml of water with the addition of hydrochloric acid (pH 3-5) and the solution was filtered. The 1- [4- (3-cyclohexylureido) phenoxy] -2-hydroxy- 3-nhexylaminopropane precipitated, which melted after recrystallization from ethanol at 160-163 ° C.

209823/1179

Using τοη H-phenylj-urea and suitable amines were the following compounds of general formula I in an analogous manner manufactured:

1 - [4- (3-Cyclohexylureido) phenoxy] -2-hydroxy-3-methylaminopropane, P: 17o - 172 Ό

1- [4- (3-Cyclohexylureido) phenoxy] -2-hydroxy-3-n-butylaminopropane, Fx 160-163 * C

1- [4- (3-cyclohexylureido) -phenoxy] -2-hydroxy-3-oyclohexylaminopropan, P: 156-158 ⁰ C.

1- [4- (3-Cyclohexylureido) -phenoxy] -2-hydroxy-3-isopropylaminopropane, Pt 157 - I60 * C

1 - [4- (3-Cyc lohexylureido) phenoxy] -2 - hydroxy-3-sec-butylaminopropane, Pz 127 - 13o "C

1 - [4- (3-Cyc lohexylureido) -phenoxy] -2-hydroxy-3-isoamylaminopropane, Pt 157-159 * C

1- [4- (3-Cyclohexylureido) -phenoxy] -2-hydrpxy-3-crotylaminopropane, P: 155 * - 157 * C

1- [4- (3-Cyclohexylureido) -phenoxy] -2-hydroxy-3-cyclopentylaminopropane, P: 142.5-145.5 "C

1- [4- (3-Cyclohexylureido) -phenoxy] -2-hydroxy-3-cycloheptylaminopropane, Pt 131 - 133 »5" C

1- [4- (3-Cyclohexylureido) -phenoxy] -2-hydroxy-3- ( 1,1,3 » 3-tetramethylbutyl) -aainopropane _t Pt 131x-133,5" C 1- [4- (3- Cyolohexylureido) phenoxy] -2-hydroxy-3-hex * n- (2) -ylaminopropane, Pi 156-159 "C

1- [4- (3-Cyclohexylureido) -phenoxy] -2-hydroxy-3-cyclopropylaminopropane, Pt154-156.5 * C

Example 17:

5 g 1- [4- (3-Cyclohexylureido) -phenoxy] -2-hydroxy-3- (H-benzyl-N-tert, -butylamino) -propane, 100 ml egg acid and 0.5 g platinum dioxide were shaken for 6 hours at room temperature in a hydrogen atmosphere the glacial acetic acid is distilled off in vacuo and the remaining residue is dissolved in 250 ml of water with the addition of salic acid

209823/1179

BATH ORIGINAL

Si

(pH 2) dissolved. The solution was filtered, and by adding sodium hydroxide solution to pH 12, the 1- [4- (3-cyclohexylureido) phenoxy] -2-hydroxy-3-tert-butylaminopropane was precipitated, which β after recrystallization from isopropanol at 142 melted to 144 »5 ^{0 C.}

The debenzylation of 1- [4- (3-Cyclohexylureido) -phenoxy] -2-, Hydroxy-3- (N-benzyl-N-tert-butylamino) propane can also be carried out as follows:

5 g of the starting compound are shaken with 1oo ml glacial acetic acid and 1 g of palladium on carbon for 8 hours at 5o C and ⁰ 5a at hydrogen pressure · is then worked up as above oesch rubbed.

P The 1- [4- (3-cyclohexylureido) phenoxy] -2-hydroxy-3- (N-benzyl-N-tert-butylamino) propane used as the starting product was made as follows:

39 | 8 g of N-cyclohexyl-N '- [4- (2,3-epoxypropoxy) -phenyl] -urea, 24.5 g of N-benzyl-N-tert.-butyl ^ ¹ Mn and 150 ml of ethanol were 17 Boiled under reflux for hours. The solvent was then distilled off, the 1- [4- (3-cyclohexylureido) phenoxy] -2-hydroxy-3- (N-benzyl-N-tert-butylamino) propane remaining as resin which was used for debenzylation without purification. The compound was characterized as Pumarat, which after recrystallization from ethanol at 142 - 145 ⁰ C melted ·

ψ Example 18:

1 g of 1- [4-C3 yclohexylureido ^c) -phenoxy] -2-hydroxy-3-aminopropane hydrochloride, 2o ml of acetone and 1.42 ml of methanolic sodium methylate solution (1 were combined cooked und.1 hour under reflux normal). Then, while cooling with ice, 2 g of sodium borohydride were added, the mixture was stirred for 10 minutes and, after standing over a seam, the excess sodium borohydride was destroyed with 10 ml of dilute hydrochloric acid. The methanol was then distilled off, the residue was dissolved in 50 ml of water, the solution

209823/1179

filtered and that 1- [4- (3 ~ cyelohexylureido) phenoxy] -2-hydroxy-3-isopropylaminopropane precipitated by adding sodium hydroxide solution to pH 12, which after recrystallization Ieopropanol melted at 157 - 16o "C ·

The 1- [4- (3-cyclohexylureido) phenoxy] -2-hydroxy-3-aminopropane hydrochloride used as the starting compound was made as follows:

29 g of S-cyclohexyl-li ^l - [4- (2,3-epoxypropoxy) phenyl] urea and 8oo ml of a solution of ammonia in methanol (18.5 g ammonia / 1 oo ml solution) were heated to 5o for 32 hours ⁰ C warmed. Then methanol and excess ammonia were distilled off and the remaining residue was boiled with 400 ml of methanol; The solution was filtered and then concentrated hydrochloric acid to pH 1 was added, the 1- [4- (3-cyelohexylureido) phenoxy] -2-hydroxy-3-aminopropane hydrochloride precipitated, which after recrystallization from dimethylformamide at 22o - 222 "C melted

Example 19 »

3 »3 g of 1- [4- (3-Gyclohexylureido) phenoxy] -2-hydroxy-3-chloropropane, 5» 9 g of isopropylamine and 50 ml of methanol were heated to 100 ° C. in the autoclave for 12.5 hours the solvent and excess isopropylamine are distilled off, the residue is dissolved in 2oo ml of water with the addition of hydrochloric acid (pH 4), the solution is filtered and sodium hydroxide solution is added to pH 12. A precipitate of 1- [4- (3-cyclohexylureido) - phenoxy] -2-hydroxy-3-isopropyl-aminopropane from which after recrystallization from isopropanol at 157 - melted I6O ⁰ C.

All of the initial products used 1- [4- (3-cyclohexylureido) phenoxy] -2-hydroxy-3-chloropropane was made as follows:

30 g of N-cyclohexyl-N ^t - [4- (2,3-epoxypropoxy) phenyl] urea, 60 ml of methanol and 20 ml of concentrated hydrochloric acid were combined and left to stand at room temperature for 24 hours. Then the 1- [4- (3-cyclohexylureido) phenoxy] -2-hydroxy-3-chloropropane was precipitated by adding 70 ml of water,

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33

which melted after the Umkrietallieation from Essigeeter at ^ to 139 ⁰ C, ϊ

Example 2oi

1f8 g 1- [4- (3-Cyclohexylureido) -phenoxy] -2-hydroxy-3-aminopropane hydrochloride, 72 ml isopropanel, 5t4 g isopropyl bromide, 3.6 g potassium carbonate and 0.4 g potassium iodide were 16 hours at 7 o Then 50 ml of water and 50 ml of 1 η hatronlaug were added, the alcohol and excess isopropyl bromide were distilled off and the separated 1- [4- (3-0yelohexylureido) phenoxy] -2-hydroxy-3-propylaminopropane was removed - W filtered, which melted after recrystallization from isopropanol at 156-159 ° C.

Example 21:

1o g IT lthyl-lir ^l - [4- (2,3-epoxypropoxy) phenyl] -harnBtoff and 100 mL of allylamine were incubated for 48 hours at room temperature, allowed to stand. The residue remaining after the excess allylamine had been distilled off was dissolved in 50 ml of water with the addition of hydrochloric acid (pH 4) and the solution was filtered. Then the 1- [4- (3-Ethylureido) -phenoxy] -2-hydroxy-3-allylaminopropane was precipitated by adding sodium hydroxide solution to pH 12, which after recrystallization from ethanol-water 1: 1 at 12o - 123 * C melted

Example 22 » A mixture of 1 g of 1- [4- (3-Cyclohexylureido) phenoxy] -2-

hydroxy-3-tert-butylaminopropane, 0.4 g benzoic acid and 5 ml

Methanol was heated to the boil, leaving a bare solution

originated. The 1- [4- (3-cyclohexyl ure ido) phenoxy] -2-hydroxy-3-tert-butylaminopropane benzoate

from melting point 194 - 198 Ό

When using 0.2 g of succinic acid instead of 0.4 g Benzoic acid is obtained in an analogous manner the neutral · 1- [4-

(3-Cyclohexylureido) -phenoxy] -2-hydroxy-3-t * rt.-butylaaine-

propane suocinate with a melting point of 2o2 - 2o4 * C

BAD ORIGINAL 209823/1179

If 0.3 g of tartaric acid is used instead of 0.4 g of benzoic acid, the neutral 1- [4- (3-cyclohexylureido) phenoxy] -2-hydroxy-3-tert-butylaminopropane tartrate is obtained in an analogous manner with a melting point of 213 - 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 briefly heated to boiling 1- [4- (3-Cyclohexylureido) -phenoxy] -2-hydroxy-3-tert-butylaminopropane acetate, which melted _{after recrystallization from isopropanol at 162-165 f 5 ° C.}

When using 0.4 g of salicylic acid instead of 0.2 ml of glacial acetic acid the 1- [4- (3-cyclohexylureido) phenoxy] -2-hydroxy-3-tert.-butylaminopropane salicylate is obtained in an analogous manner, after recrystallization from isopropanol at 133-135 ° C melts

Example 24:

7.2 g 1- [4- (3-Cyclohexylureai.o; phenoxy] -2-hydroxy-3-tert-butylaminopropane, 36 ml water and 1ο ml 2 η nitric acid were ^{heated to 80 0} C, the solution filtered and The 1- [4- (3-cyclohexylureido) phenoxy] -2-hydroxy-3-tert-butylaminopropane nitrate separated out, which after recrystallization from isopropanol-water 98: 2 at 172-176 Ό melted.

If 2 ml of concentrated hydrochloric acid are used instead of 1 o ml of 2 η nitric acid, the 1- [4- (3-Cyolohexylure ido) phenoxy] -2-hydroxy-3-tert-butylamino per pan hydrochloride is obtained after recrystallization from isopropanol-water 98: 2 at 2o8 - 212.5 ⁰ C melts.

209823/1179

HO

Example 25:

10 g of 1- [4- (3-cyclohexylureido) phenoxy] -2-hydroxy-3-tert-butylaminopropane were dissolved in 50 ml of methanol · To the solution 1.55 nil 17 * 8 η sulfuric acid were added. It was different the neutral 1- [4- (3-cyclohexylureido) phenoxy] -2-hydroxy-3-tert-butylaminopropane sulfate which melted from 245 "C with decomposition.

Example 26:

2.34 g N-cyclohexyl-N'-Cp-oxyphenyl) urea, 2.5 g 2-phenyl

3-n-butyl-5-chloromethyloxazolidine 2o ml of 0.5 η sodium methylate solution in methanol were refluxed for 13 hours. After the solvent had been distilled off, the residue was extracted 3 times with 100 ml of water with the addition of 5 ml of 5 η hydrochloric acid each time, the solution was filtered and the 1- [4- (3-cyclohexylureido) phenoxy] -2-hydroxy-3- nbutylaminopropan precipitated by addition of sodium hydroxide, which after recrystallization from isopropanol at 162 - 164 ⁰ C melted ·

The 2-phenyl-3-n-butyl-5-chloromethyl-oxazolidine used as starting material was prepared as follows: In a 750 ml three-necked flask equipped with a stirrer, dropping funnel, thermometer and reflux condenser, 20 ml of a mixture consisting of 132 g ( o, 82 mol) benzal-N-butylamine and 132 g of epichlorohydrin, warmed to ⁰ 6o C and then treated with o, 5 g anhydrous Zinkohlorid. Within 1.5 hours, the residual mixture was added dropwise and 2o g of zinc chloride was added in small portions so that the reaction temperature is between 9o and 11o ⁸ C was maintained · The mixture was then o, heated for 5 hours at loo ⁰ C and then the 2- phenyl-3-n-butyl-5-chlormethyloxazolidin distilled off in an oil pump vacuum, which has a boiling point of 133 - 137 has ⁰ C at 1.2 mm.

209823/1179

Claims (1)

Patent claims: rl »Process for the production of ureidophenoxyalkanolamine derivatives the general formula O - CH ₂ - CHOH - CH ₂ - NH - R ₁ wherein R _{1 is} an unbranched lower alkyl radical with 1 to 6 carbon atoms, a branched lower alkyl radical with 3 to 8 carbon atoms, an alkenyl radical with 3 to 6 carbon atoms or a cycloalkyl radical with 3 to 7 carbon atoms and R ₂ Hydrogen atom, an unbranched lower alkyl radical with 1 to 6 carbon atoms, a branched lower alkyl radical with up to 8 carbon atoms, a cycloalkyl radical with 3 to 7 carbon atoms or an alkenyl radical with 3 to 6 carbon atoms, the urea radical and the alkanolamine radical can be in o-, m- or p-position to one another, and their salts with physiologically compatible inorganic or organic acids, characterized in that either a) a phenoxyalkanolamine derivative of the general formula R ₁ - Ii - CH ₀ - CH - CH ₉ - 0 - _{v v TT} 1,2, 2 V ^ II A ₁ 0 - A ₂ with a compound of the general formula R ₉ -N-C = 0 III ² ! I.
R ₃ R ₄ 2098? 3/1179 wherein R ₁ and R _{2 have} the meaning given above, R ^ a hydrogen atom and R, an alkoxy group with 1 to 4 carbon atoms, an optionally substituted phenoxy group, an alkylthio group with 1 to 4 carbon atoms, an optionally substituted phenylthio group, a unsubstituted or _{substituted by R 2} amino group, a hydrazino group or a halogen atom or R-, and R, together an additional CN bond and A .. and A ₂ each a hydrogen atom or a hydrolytically or hydrogenolytically cleavable protective group or A ₁ and A ₂ together mean a hydrolytically cleavable protective group, reacts and splits off any protective groups present, or that one P b) a phenoxyalkanolamine derivative of the general formula R ₁ - Ii - CH ₂ - CH - CH _? - 0 - (/ \ IV * 1 'ν with an amine of the general formula R ₂ -NH ₂ V wherein R ₁ , Rp »A ₁ and A _{2 have} the meaning given above, Rc is a hydrogen atom and Rg is an alkoxy group ψ with 1 to 4 carbon atoms, an optionally substituted phenoxy group, an alkylthio group with 1 to 4 carbon atoms, a optionally substituted phenylthio group, a hydrazino group or a halogen atom or, if Ro means other than hydrogen, also an amino group or Rc and Rg together mean an additional CU bond, reacts and splits off any protective groups present, or that one 209823/1178 c) in appropriately substituted phenoxyalkanolamine Derivatives of the general formula R ₁ - N - CH ₂ - CH - CH ₂ - O - A ₁ 0 - A ₂ in which R ₁ , R ₂ , A ₁ and A _{2 have} the abovementioned meaning, and their corresponding isothiourea ethers replace the sulfur or thioether group with oxygen and any protective groups present are split off, or that one d) a phenoxyalkanolamine derivative of the general formula R ₁ - N - CH ₀ - CH - CH ₀ - 0 - </ O) R ₇ VII 1 I 2, "2 \ ₌ ^ C V A ₁ O - A ₂ HH-C = NR ₂ wherein R ₁ , R ₂ , A ₁ and A _{2 have} the meaning given above and Ry is a halogen atom, an O-acyl group, an O-alkyl group, an S-acyl group or an S-alkyl group, in which the alkyl groups are 1 to 4 C- Having atoms, means hydrolyzed and splitting off any protective groups present, or that one e) to a phenoxyalkanolamine derivative of the general formula VIII _ η - Kjtin - υ - ν ν O - A _n N = C = H- . - N - CH ₀ - CH - CH ₀ - O - 1,2, "2 in which R ₁ , R ₂ , A ₁ and A _{2 have} the meaning given above, water is added and any protective groups present are split off, or that one 209823/1179 f) a Hie noacyalkano lamin derivative of the general formula R. - If - CH '- CH - CH ₀ - 0 - </ \> NH IX A ₁ 0 - A ₂ ^{X ==} 'HH-C-NH-R ₂ in which R,., R ₂ , A ₁ and A ₂ are as defined above, hydrolyzed and any protective groups present are split off, or that one g) a phenoxyalkanolamine derivative of the general formula R. N - CH ₀ - CH - CH ₀ - O - </ \> OX Ii VX if A ₁ O -A ₂ NCNR ₂ OC CO wherein R ₁ , R ₂ , A ₁ and A _{2 have} the abovementioned meaning, saponified and any protective groups present are split off, or that one h) a phenoxyalkanolamine derivative of the general formula R ₁ -N- CH ₂ - CH - CH ₂ - 0 - ^^ ^ ₀ - CH ₀ XI S - CH ₂ 0 - A ₂ ^Λ 'N = C in which R ₁ , A ₁ and A ₂ are as defined above, with an amine of the general formula R ₂ -NH ₂ V in which R _{2 has} the meaning given above, react 209823/1179 -H-CO-H- leaves, whereupon any protective groups present are split off, or that one i) a ureidophenyl derivative of the general formula XII - CH ₂ - R ₈ where R _{2 has} the meaning given above, B ₁ and each individually a hydrogen atom or a hydrolytically removable protective group or B ₁ and B ₂ together a hydrolytically removable protective group and Rq the groups - CH - CH ₀ or - CH - CH ₉ - R _Q 0 0 - A ₂ XIII a XIII b represents wherein Rq represents a halogen atom or the remainder of a Means sulfonic acid, or a mixture of compounds of the general formula XII, in which Rg the two above has the meanings mentioned »with an amine of the general formula R ₁ -NH-A ₁ XIV in which R ₁ and A _{1 have} the abovementioned meaning, reacts and splitting off any protective groups present, or that one BAD ORfGiNAL 209823/1179 j) a ureidophenyl derivative of the general formula H - CO - ί ^Β 1 - H - I. ^Β 2 XV OH wherein R ₂ , B ₁ and B ₂ are as defined above, with a compound of the general formula Rq-CH ₂ -CH-CH ₂ -NR ₁ XVI O - A ₂ A ₁ or CH ₀ -CH-CH ₀ -IT-R _n XVII X / * ι ¹ 0 A ₁ in which R ₁ , R _Q , A ₁ and A _{2 have} the abovementioned meaning, or mixtures of compounds of the general formulas XVI and XVII are allowed to react and any protecting groups present are split off, or that one k) a ureidophenyl derivative of the general formula IVIII O -CH ₂ - CH - CH ₂ - HH 0 -A ₂ A ₃ in which R ₂ , A ₂ , B ₁ and B _{2 have} the abovementioned meaning and An denotes a hydrogen atom or an optionally substituted benzyl radical, bit of a carbony compound of the general formula 209823/1179 ο
R ₁₀ -C- R ₁₁ χα wherein R ₁₀ and R ₁₁ together with the connecting C atom represent a _{radical which can be converted into the group R 1} by hydrogenation, reacts under reducing conditions and splits off any protective groups present, or that one 1) a ureidophenyl derivative of the general formula XX R ₂ - N - CO - F - CH 0 - wherein R ₂ , A ₁ , A ₂ , B ₁ and B _{2 have} the meaning given above, with an alkylating agent of the general formula R ₁ -X XXI wherein R _{1 has} the meaning given above and X is a halogen atom or an alkylsulfate radical or the radical of a sulfonic acid, such as the benzenesulfonyl or toluenesulfonyl radical, is reacted and any protective groups present are split off, or that one m) a ureidophenyl derivative of the general formula XXII -F-OO-F- 0 - CH ₂ - CO - CH ₂ - N - wherein R ₁ , R ₂ $ A ₁ , B ₁ and B _{2 have} the meaning given above, hydrogenated and any protective 209823/1179 groups split off, or that one n) a ureidophenyl derivative of the general formula Al - CO - N - " ^xx XXIII £ \ = / ^ O - CH ₂ - CH - CJH ₂ where R ₁ , R ₂ , B ₁ and B _{2 have} the meaning given above and Y is a hydrolytically cleavable group, such as the carbonyl group, the oxalyl group or the group C.
\ XXIV 1? 1 "\ denotes in which R ₁₂ and R ₁₅ each represent a hydrogen atom or an alkyl radical having 1 to 6 carbon atoms or R ₁₂ and R ₁ together denote the group "(CH ₂ ) J ₁ "", where η denotes the numbers 4 to 6 stands, is subjected to hydrolysis and any protective groups present are split off, or that one o) a ureidophenyl derivative of the general formula 0 - CH ₂ - CH - CH ₂ - N - 0 - ^R H wherein R ₁ and R _{2 have} the meaning given above and R ₁₄ and R ₁ C each represent a hydrogen atom or a hydrogenolytically cleavable group and where at least one of the radicals R ₁₄ and R ₁ denotes a hydrogenolytically cleavable group which is subjected to hydrogenolysis, or that one 209823/1179 ρ) a ureidophenyl derivative of the general formula η XXTI fi7 0 - in which R .., R ₂ , B ₁ and B _{2 have} the abovementioned meaning and R ₁ g and R.γ each denote a hydrogen atom or a hydrolytically cleavable group and where at least one of the radicals R ₁ g and R-- is hydrolytically A group which can be split off means which is subjected to hydrolysis and any protective groups present are split off, or · that one q) a ureidäphenyl derivative of the general formula R ₂ -N-CO-N - R ₁₈ R ₁₉ ^{N: = :: = /} n OH ₂ - CHOH - CH ₂ - NH - wherein R ₁ and R _{2 have} the meaning given above and R ₁₈ and R ₁ Q each represent a hydrogen atom or in · aoyl group and where at least one of the radical · R ₈ and R ₁ Q is an acyl group which is subjected to hydrolysis, or that he r) a ureidophenyl derivative of the general formula XXVIII B ₁ B ₉ ^ O - CH ₉ - CH - C »0 12 I I R ₉ - N - CO - N ² II I I ^R 1o 209823/1179 -4σ - where R ₂ IR _{1 β>} R ₁₁ »B ₁ and B _{2 have} the meaning given above» hydrogenated and any protective groups present are split off, or that one s) a ureidophenyl derivative of the general formula - N - CO - N - 0 - CBU - CH - CO - K - "2 ₍ j -V-CO-V- wherein R _1, R ₂ * A _2, A ^, B and B ₂ ψ the above-mentioned loading have significance, hydrogenated and optionally splitting off protecting groups present, or in that t) a ureidophenyl derivative of the general formula ZXXIII 0 - CH ₂ - CH - CHO 0-A ₂ wherein R ₂ , A ₂ , B. and B _{2 have} the meaning given above, with an amine of the general formula * R ₁ -UH-A ₃ XXIII wherein R ^ and A _{3 have} the abovementioned meaning, reacts under reducing conditions and splits off any protective groups present, or that one 209823/1179 S1 u) a uriiophenyl derivative of the general formula -N-C y XXXIV τ, O - CH ₉ - CH - CH = N - R- B ₂ -2 , 1 O - where R-, Rp, Ap * ^ I ^un ^ ^ 2 * ^ ^e ° ^ ^en have the meaning mentioned, reduced and any protective groups present, or that one v) a ureidophenyl derivative of the general formula 0-CH ₉ -CH-CH ₉ -N = C O - A ₂ ^K 11 in which R ₉ , A-, B- and B ₂ as well as R- and R-- have the abovementioned meaning, reduced and any protective groups that may be eliminated and the compounds of general formula I obtained with physiologically acceptable inorganic or organic compounds Acids into their acid addition salts or obtained acid addition salts of compounds of the general Formula I converted into the free compounds with inorganic bases. Process according to Claim 1, characterized in that the acid addition salts of compounds of the general formula I physiologically compatible inorganic or organic acids such as hydrochloric acid, Hydrobromic acid, hydroiodic acid, sulfuric acid, 209823/1179 sz Nitric acid, phosphoric acid, acetic acid, dichloroacetic acid, propionic acid, benzilic acid, salicylic acid, oxalic acid, malonic acid, Adipic acid, maleic acid, fumaric acid, tartaric acid, citric acid or ascorbic acid used 3 · Process according to Claims 1 and 2, characterized in that the reactions are carried out in the absence or presence carried out by solvents or diluents which are inert for the respective reaction. 4. Process according to Claims 1 to 3, characterized in that the reactions are carried out between 0 ⁰ C and 2oo ⁰ C, preferably between room temperature and 150 ⁰ C 5. Process according to Claims 1 to 4, characterized in that the reaction of the compounds of the general formula II with compounds of the general formula III is carried out in the presence of an equi-molar amount of acid. 6. The method according to claims 1 to 4 »characterized in that that the hydrogenolysis of the protective groups by means of catalytic hydrogenation, for example in the presence a noble metal catalyst, such as platinum or palladium, or in the presence of Raney nickel. P 7. Process according to claims 1 to 4 * characterized in that that the hydrolysis of the protective groups is carried out in an acidic or alkaline medium, 8. The method according to claims 1 to 4, characterized in that in the implementation of a compound of the general Formula IV with an amine of the general formula V, the amine is used in excess. 209823/1179 SS - 49 - ■> Process according to claims 1 to 4 »characterized in that the sulfur or the thio ether group in the compounds of the general formula VI and its isothiourea ethers are replaced by means of oxides or salts of soft rivets · c, method according to claims 1 to 4f, characterized in that that one replaces the sulfur or the thio- ^ 'fch ^ rgruppe in the compounds of the general formula VI and their isothiourea ethers by oxidizing agents, such as hydrogen peroxide, E sodium peroxide, potassium peroxide or nitrous acid "is A process according to claims 1 to 4» characterized labeled in ze leans, by treating the compounds of general formula VI or its Isothioharnstoffather with phosgene and saponifying the resulting intermediate. *, Method according to claims 1 to 4 »characterized in that that the compounds of general formula VI or their isothiourea ethers with phosphorus pencachloride treated and added to the intermediate product obtained water. \ The method of claims 1 to At characterized marked *, f ⁵ leans, hydrolyzing the compounds of general formula VII in an alkaline medium · ^! Process according to claims 1 to 4 »characterized in that the isourea ester, isothiourea ^! ; toffester, isoureaether and isothioureaether 'ie r general formula VII in an acidic medium hydro- J v'j'if.-rfc. BATH 209823/1179 15 · Process according to claims 1 to 4 »characterized in that that the hydrolysis of the compounds of the general formulas IX and X is carried out in an alkaline medium will. 16. The method according to claims 1 to 4 »characterized in that that in the reaction of the compounds of general formula XI with an amine of the general Formula V the amine in excess, preferably 2 to 3 moles of amine per mole of a compound of the general formula XI, is used 17 »Process according to claims 1 to 4 _t characterized in that Rq means a Cl or Br atom» 18. The method according to claims 1 to 4 »characterized in that that Rg denotes the residue of an aromatic sulfonic acid, such as benzene or toluene sulfonic acid. 19 · The process according to steps things "^{'λ η} 1 to 4» 17 and 18, characterized in that one uses aas Arnin of the general formula XIV in excess · 20. Process according to claims 1 to 4 and 17 to 19 »characterized in that an amine of the general formula XIV, in which R ^ has the meaning given above and A _{1 is} an acyl group, is used as the alkali metal salt ψ used in the reaction 21. Process according to claims 1 to 4, characterized in that the reaction of compounds of the general formula XII, in which R _Q denotes the grouping of the general formula XIII b, with an amine of the general formula XIV in the presence of an acid acceptor, such as alkali carbonates , is carried out. 209823/1179 SS 22. Process according to claims 1 to 4, characterized in that the reaction τοη compounds of the general formula XV with compounds of the general formulas ZVI or XVII in the presence of an 8 acid acceptor, wit Alkali carbonates, is carried out 23 · Process according to claims 1 to 4 »characterized in that alkali metal compounds of the general formula XV are reacted · 24 * Process according to claims 1 to 4, characterized in that in the implementation τοη compounds of general formula XVIII with compounds of general formula XIX formic acid as reducing condition is applied· 23 · Process according to claims 1 to 4 »characterized in that during the reaction τοη compounds of general formula XVIII with compounds of general formula XIX, if A ^ is a hydrogen atom, hydrogen and the presence of a hydrogenation catalyst such as platinum as the reducing condition, Palladium or Raney nickel, are used 26. The method according to claims 1 to 4, characterized in that the τοη compounds in the implementation general formula XVIII with compounds of the general formula XIX, if A * denotes a hydrogen atom, as a reducing condition di-light metanhydrides, such as Sodium borohydride, are used 27 process according to claims 1 to 4 and 24 to 26, characterized in that when IL ₀ and R _{11 represent} alkyl radicals, the carbonyl compounds of the general formula XIX are used in excess _BAD 209823/11 * 9 28. The method according to claims 1 to 4 and 24 to 27, characterized in that the compounds of the general formula JVIII ₁ when A ₂ and A are a hydrogen atom, are generated in situ, for example
by reducing the corresponding α-diazoketones,
α-azido ketones, α-oximino ketones, α-liit ro ketones, α-nitrosoketones, α-nitro alcohols, cyanohydrins or acyl cyanides 29 · Process according to claims 1 to 4, characterized in that a compound of the general formula XX, in which A «, B .. and B« have the meaning given above and A _{1 is} an acyl group, is used as the alkali metal salt. 3o process according to claims 1 to 4, characterized in that that the alkylation of compounds of the general formula XX with compounds of the general formula XXI in the presence of an acid acceptor, such as alkali carbonate, carried out w "5" l- 31. The method according to claims 1 to 4, characterized in that that the hydrogenation of compounds of the general formula XXII by means of hydrogen in the presence a hydrogenation catalyst such as platinum, palladium or Raney nickel is carried out. 32. The method according to claims 1 to 4, marked by W characterized in that the hydrogenation of the compounds of general formula XXII by means of di-light metal, such as lithium aluminum hydride or sodium borohydride, is carried out. 33 · Process according to Claims 1 to 4, characterized in that that the hydrogenation of the compounds of the general formula XXII by means of alcoholates, such as aluminum isopropylate, Magnesium isopropylate, carried out according to the Meerwein-Ponndorf-Verley method 20987 3/1179 sr 34 · Process according to Claims 1 to 4 »characterized in that that the oxazolidones and the oxazinediones of the general formula XXIII in an acidic or alkaline Medium to be hydrolyzed, 35 · Process according to claims 1 to 4 »characterized in that that the oxazolidines of the general formula XXIII are hydrolyzed in an acidic medium 36 · Process according to Claims 1 to 4 »characterized in that that R- * and / or R-c can be split off as hydrogenolytically Groups an a-Arylalkylgiuppe, an Alkoxy- · carbonyl, a cycloalkoxycarbonyl or an α-arylalkyloxycarbonyl group mean· 37 · Process according to Claims 1 to 4 »characterized in that that the hydrogenolysis of the compounds of the general formula XXV by means of hydrogen in the presence a hydrogenation catalyst, such as platinum, palladium or Raney nickel, is carried out 38. Process according to claims 1 to 4, characterized in that R- c and / or R- «denote as hydrolytically cleavable groups an aliphatic or aromatic acyl group, an alkoxycarbonyl, a cycloalkoxycarbonyl or an aralkyloxycarbonyl group. 39 · Process according to Claims 1 to 4, characterized in that that the hydrolysis of the compounds of general formula XXVI in an acidic or alkaline Medium is carried out « 4o. Process according to claims 1 to 4 »characterized in that that the hydrolysis of the compounds of the general formula XXVII into an acidic or alkaline one Medium is carried out 209823/1179 41 · Process according to claims 1 to 4 »characterized in that R-Q and R .. * all acyl groups denote an aliphatic or aromatic aoyl group · 42 · Process according to claims 1 big 4 #, characterized in that the hydrogenation of the compounds of the general formula XXVIII with a di-light metal hydride, like lithium aluminum hydride, is carried out 43 · Process according to claims 1 to 4t, characterized in that the hydrogenation of the compounds of the general formula XXX by means of di-light metal hydrides, such as Lithium aluminum hydride, is carried out 44. The method naoh the claims 1 to 4 »characterized in that in the reaction of compounds of the general formula XXXIII with compounds of the general Formula XXXII formic acid is applied as reducing condition 45 · Process according to Claims 1 to 4 »characterized in that when compounds of the general formula XXXIII are reacted with compounds of the general Formula XXXII, when A- * means a hydrogen atom, as reducing condition hydrogen and the presence of a hydrogenation catalyst such as platinum, or palladium Raney-Hickel, be used 46 · Process according to claims 1 to 4, characterized in that in the reaction of compounds of the general formula XXXIII with compounds of the general Formula XXXII if A? means a hydrogen atom, as reducing condition di-light metal hydrides, such as sodium borohydride, are used « 209823/1179 47 · The process of claims 1 to 4 _t characterized in that the reduction of the compounds of general formulas XXXV UXIV and is carried out with Ameiseneäure · 48 · Process according to claims 1 to 4 _f, characterized in that the reduction of the compounds of the general formulas XXXIV and XXXV with hydrogen in the presence of a β hydrogenation catalyst such as platinum, palladium or Raney-Hickel is carried out 49 · Process according to claims 1 to 4 »characterized in that the reduction of the compounds of the general formulas TTXIV and XXXV with di-light metal hydrides, wi alkali borohydride or lithium aluminum hydride is carried out 5o · The method of claims 1 to 4, 'characterized in that A ₁ and / or Α "" mean as hydrolytically removable protective groups a ⁺ alipbr specific or aromatic acyl group, an alkoxycarbonyl, a Cycloalkoxyoarbonyl- or an aralkyloxycarbonyl " 51 · Process according to claims 1 to 4, characterized in that A ₁ and / or A ₂ as hydrogenolytically cleavable protective groups denote an a-arylalkyl group, an alkoxycarbonyl, a cycloalkoxycarbonyl or an a-arylalkyloxycarbonyl group « 52 «Process according to claims 1 to 4, characterized in that A ₁ and Ap together all hydrolytically cleavable protective groups are a carbonyl, an oxalyl or an alkylidene group of the general formula \ s ^ p XXIV are, in which R ₁₂ and R ₁ ^ have the meaning given above « 209823/1179 53 · Process according to Claims 1 to 4, characterized in that that B .. and / or Bg aj-s can be split off hydrolytically Protecting groups an aliphatic or aromatic acyl group or B- and Bg together one hydrolytic mean removable protecting group. 54 · Process according to Claims 1 to 4 »characterized in that that the starting compounds, which have an asymmetric carbon atom, as racemates in the Reaction can be used 55 · Process according to claims 1 to 4, characterized in that the starting compounds which have an asymmetric carbon atom are used as optically active forms in the reaction · 56. The method according to claims 1 to 4, characterized in that that racemic mixtures of compounds of general formula I in their optically active forms to be dismantled 51 · Ureidophenojcy-alkanolamine derivatives of the general formula R ₂ -NH-CO-NH- 0 - CH ₂ - CHOH - CH ₂ - NH - wherein R _{1 is} an unbranched lower alkyl radical with 1 to 6 carbon atoms, a branched lower alkyl radical with 3 to 8 carbon atoms, an alkenyl radical with 3 to 6 carbon atoms or a cycloalkyl radical with 3 to 7 carbon atoms and R ₂ Hydrogen atom, an unbranched lower alkyl radical with 1 to 6 carbon atoms, a branched lower alkyl radical with 3 to 8 carbon atoms, a cycloalkyl radical with 3 to 7 carbon atoms or an alkenyl radical with 3 to 6 carbon atoms and their salts with physiologically compatible inorganic or organic acids « 209873/1179 58. 1- (4-ureidophenoxy) -2-hydroxy-3-isopropylaminopropane 59 · 1- (4-ureidophenoxy) -2-hydroxy-3-tert-butylaminopropane 6o · 1- [4- (3-methylureido) phenoxy] -2-hydroxy-3-isopiopylinopropane 61 · 1- [4- (3-Ethylureido) phenoxy] -2-hydroxy-3-tert-butylaminopropane 62 · 1- [4- (3-Cyclohexylureido) phenoxy] -2-hydroxy-3-i-propylaminopropane 63. 1- [4- (3-Methylureido) -phfenoxy] -2-hydroxy-3-tert-butylaminopropane 64. 1- [4- (3-Cyclohexylureido) phenoxy] -2-hydroxy-3-tert · - butylaminopropane 65 x 1- [4- (3-n-hexylureido) phenoxy] -2-hydroxy-3-isopropylamine propane 66 · Compounds of the general formula I as Raoemate. 67 · Compounds of the general formula I in the form of their optically active forms. '68 · Compounds according to claims 57 to 67 in the form of their salts with physiologically compatible inorganic ones or organic acids. 69 · Compounds according to claims 57 to 67 in shape their salts with hydrohalic acids. Sulfuric acid" Nitric acid, phosphoric acid, acetic acid, dichloroacetic acid, propionic acid, benzilic acid, salicylic acid, oxalic acid, Malonic acid, adipic acid, maleic acid, fumaric acid, tartaric acid, citric acid or ascorbic acid. 209823/1179 " Vl k * O S'- ¹ V. 70. 1- / 4- (3-Iaopropylureido) _-1- phenoxy-2-hydroxy-3-isopropylaminopropane 71 · 1 - / "" 4- (3-Allylureido) - _i henoxy _7-2-hydroxy-3-iaopropylaminopropan 72.1 - / "* 4- (3-sec.-Butylureido) - _ir henoxy _- 7-2-hydroxy-3- isopropylaninopropane 73 · 1- ainopropane 74.1 - / "4- (3-crotyltireido) phenoxy 7-2-hydroxy-3-isopropyl arainopropane 7o . 1 - / "4- (3-0yclo _i jentyliareido) - _i henoxy_7-2-hydroxy-3- iaopropylaminopr-jpan 76.1 - / "4- (3-Gycloheptylureidü) -phenoxy _- 7-2-hydroxy-3-iaopropylaminopropane 77. 1- ^ ~ 4- (3-Cycloprüpylureido) -phenoxy _e 7-2-hydroxy-3- iaopropylarainupropane 78. 1- / ~ 4- (3-hexen- (2) -yl-ureido) -phenoxy_7-2-hydroxy-3- 79. 1 - / "2- (3-Cyclohexylureidij) -phenoxy_7-2-hydroxy-3-tert. butylaminopropan 80.1 - / "" 3- (3-Cyc lohexylur eido) -phenoxy_7-2-hydroxy-3-t er t butylaminopropane 81.1 - / "4- (3-cyclohexylureido) -phenoxy_7-2-hydroxy-3-nhexylamino prο pan 82.1 - £ ~ A- (3-Cyclohexylureido) -henoxy_7-2-hydroxy-3- fnyav & xy-3 «} me thy laiaino propane 2098? 3M179 33 β 1 - / "" 4- (3-Cyclohexylureido) -phenoxy_7-2-hydroxy-3-n13Utyl amino propane 34 · 1 / ~ 4- (3-cyclohexylureido) phenoxy _{i (_7-2} ^hYdi-l oxy-3-cyclohexylaminopropane c 1 - / "4- (3-Cyclohexylureido) -phenoxy_7-2-hydroxy-3— isopropylaminopropane 36. 1- £ "4- (3-Cyolohexylureido) -phenoxy_7-2-h.ydroxy-3-seoobutylaminopropane 87. 1- / ~ 4- ^(3-G yclohexylureido) -phenoxy_7-2-hydroxy-3-isoamylaminopropan 33.1 - / "4- (3-Cyclohexylureido) -phenoxy_7-2-hydroxy-3-crotylaminopropane ο 1- / ~ 4- (3-Cycloliexylareido) -phenoxy_7 ~ 2-hydroxy-3-cyclopenuy! aminopropane 90. i _ / - 4- (3-Cyclohexylureido) -phenoxy_7-2-hydroxy-3— cycloheptylaminopropane 91. 1- / "4- (3-Gy clohfixylureido) -phenoxy-7-2-hydroxy-3- (1» 1,3,3-tetramethylbutyl) -aminopropane 2 β 1 - / "4- (3-Cyclohexylureido) -phenoxy_7-2-hydroxy-3-iicxen- ( 2) -yl-aiiiinopropane 93.1 - / "4- (3-Cyclohexy lur eido) -phe.ioxy_7-2-hydroxy-3-cyclopropy! Aminopropane 94. 1- / ~ 4- (3 ~! Tnylureido) -phenoxy_7-2-ii :: droxy-3-allylai ".: Inopropane 20982371179 6H ■ ·. Compounds according to claims 70 to 94 in the form their salts with hydrohalogen acid / sulfuric acid, Nitric acid, phosphoric acid, acetic acid, dichloroacetic acid, propionic acid, benzilic acid, salicylic acid, oxalic acid, Iialonic acid, adipic acid, lialic acid, fumaric acid, Tartaric acid, citric acid or ascorbic acid. BAD ORiGJNAL 209823 / 117.Q