DE2153024C3 - Ureidophenoxyalkanolamines and process for their preparation - Google Patents

Description

it

The invention relates to ureidophenoxyalkanolamines of the general formula

R ² —NH-C-NH—

O -CH ₁ -CHOH-CH ₂ -NH-R ¹

in which R ^{1 is} a branched Cj-Ce-alkyl radical, in particular the isopropyl, isobutyl, tert-butyl, isoamyl, tert-amyl or isohexyl radical and R ^{2 is} a hydrogen atom, an n —Ci-Cö- Alkyl radical, a branched Cj -Ce -alkyl radical, in particular the isopropyl, isobutyl, tert-butyl, isoamyl, tert-amyl or isohexyl radical, a Cj -Cz cycloalkyl radical, especially the cyclopropyl, cyclobutyl , Cyclopentyl, cyclohexyl or the cycloheptyl radical, or a Cj-Ce-alkenyl radical, in particular the allyl, methallyl or the crotyl radical, their optically active forms, l ^ Γΐ juiZCn

Hill piiySiCiGgi.jt-ii * wi κ ugiiCuCii 2 "Ci gu" '-

see or organic acids and process for their Manufacturing.

As examples of physiologically compatible inorganic and organic acids that are suitable for salt formation are, be hydrochloric acid, hydrobromic acid, hydriodic 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, citric acid or ascorbic acid.

The definition of the compounds of the general formula I includes both the pure stereoisomeric forms as well as mixtures of the same.

Table 1

The compounds of general formula I have a significantly stronger, specific / 9-adrenergic blocking effect Effect when they were by D. D u η Ι ο ρ and R. G. Shanks (Brit. J. Pharmac. Chemother. 32, 201-210 [1968]) for 1- (4-acetaminophenoxy) -2-hydroxy-3-isopropylaminopropane has been described.

The compounds were tested on the cat anesthetized with chloralose urethane. The contraction force was recorded using the maximum rate of pressure increase (dp / dt max) in the left ventricle using a steel catheter. The systolic and d! 2sto! Ic blood pressure i ^{| n} d dip Ηργ / ΙΥρπιιρπ / were recorded simultaneously. The investigations on the spontaneously beating atrial specimen of guinea pigs were carried out according to the method of W. Schaumann, R. Bodem and W. Bartsch (Arch. Exp. Pharmak. U. Path. 255, 328 [1966]), modifying the recording technique with isometric transfer Semiconductor strain gauges carried out on the Dynograph type R 611 (Beckmann). The blockade of the isoprenaline effect on the bronchial system was determined using the histamine spasm of guinea pigs and the antiarrhythmic effect was tested using the aconitin test in rats.

The results are shown in Table 1.

I. R ² 2 3 4th 5 6th 7th 8th 9 R ¹ H iC ₃ H ₇ CH ₃ 2.6 3.1 2.01 no + 8% + 4% + 33% iC ₃ H ₇ C ₂ H ₅ 1.3 0.43 2.06 - no + 5% + 5% + 8% iC ₃ H ₇ CH ₃ 1.8 1.4 1.52 no + 9% + 14% + 53% tC ₄ H ₉ C ₂ H ₅ 0.92 1.0 0.82 no + 8% + 9% + 42% tC ₄ H ₉ Cyclohexyl 0.72 0.29 0.68 5.0 no -2% + 2 "Io - 070 IC ₄ H ₉ 1 - (4-acetaminophenoxyV 0.66 0.18 0.10 20.0 10-20 + 2% + 1% -10% 4.8 1.8 0.55 5.0 no -6% - 3% - 2%

2-hydroxy-3-isopropylaminopropane

In the table:

Column 1: Chemical compound of the general formula I characterized by the radicals Ri and R ₂ or the name of the reference substance.

Column 2: ED50 of the inhibition of the positive chronotropic effect of isoprenaline (1 Hg / kg) in mg / kg i.v.

Column 3: ED50 of the inhibition of the positive inotropic effect of isoprenaline (1 μg / kg) in mg / kg i.v.

Column 4: ED50 of the inhibition of the positive inotropic effect of isoprenaline (0.015 μg / ml; in moi ■ 10 ⁵ on the isolated atrial preparation.

Dose in mg / kg with i.p. Application of the beginning Ö blockade to the bronchial system of the guinea pig. Aconitin arrhythmia in rats, dose in mg / kg which inhibits the arrhythmia by 73%. Circulatory side effects after intravenous injection of 23 mg / kg at the Xatze as a percentage of the initial value.

Column 5:
Column 6:
columns
7-9:
Column 7:
Column 8:
Column 9:

Frequency.

Systolic blood pressure.
ApIAt max:

As the results of Table 1 show, the ureidophenoxyalkanolamine derivatives of the general formula I have a / 3-adrenergic blocking effect, which exclusively inhibits the positive inotropic and chronotropic isoprenaline effect corresponds to the ED50, not influenced, while O-receptor blockers of the l-isopropylamino-3- (l-naphthyloxy) -propane-2-0I type block the peripheral vascular action of isoprenaline most strongly. Likewise, the ^ -stimulating effect of isoprenaline on the bronchial system is only influenced in very high doses
Even with enteral application (5 mg / kg),

the cat, for example, by 1- [4- (3-cyclohexylureido) phenoxy] -2-hydroxy-3-isopropylamino-propane by isoprenaline [D, L-1- (3,4-dihydroxyphenyl) -2-isopropylaminoethanol] caused frequency increase of 50% and that caused by isoprenaline positive inotropic effect 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, none Some derivatives of urcidophenoxyalkanolamine compounds have antiarrhythmic effects of the general formula I effective.

The circulatory side effects of the compounds of general formula I are very slight. While that l-Isopropylamino-3- (l-naphthyloxy) -propan-l-ol already at 0.5 mg / kg i. v. a noticeable one on the cat Bradycardia, hypotension, and decrease in contractile force are absent from the compounds of the general formula I these adverse side effects. Some compounds of general formula I. even have a clear positive-chronotropic and inotropic intrinsic effect.

R ^{3 is} a hydrogen atom and R ^{4 is} a Ci-Gt-alkoxy group, an optionally substituted phenoxy group, a Ci-Gi-AIk _- , ithiogruppe, an optionally substituted phenylthio group, an unsubstituted or ^{substituted by R 2} amino group, a hydrazino group or a halogen atom or R ³ and R ⁴ together form an additional C — N bond and A ¹ and A ² each have a hydrogen atom, a hydrolytically cleavable 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 cycloalkyloxycarbonyl group, for example the cyclopentyloxycarbonyl group and the cyclohexylcarbonyl group, or an aralkyloxycarbonyl group, for example the benzyloxycarbonyl group, or a hydrogenolytically cleavable protective group, for example a arylalkyl group Example the benzyl group, an alkoxycarbonyl group. for example the tert-butoxycarbonyl group, a cycloalkyloxy-carbonyl group, for example the cyclopentyloxycarbonyl group or the cydohexyloxycarbonyl group, or an α-aralkyloxycarbonyl group. for example the benzyloxycarbonyl group, or A ¹ and A ² together form a hydrolytic group

to speak of a specific effect of the compounds of general formula I. This specific ^ -Receptor blockade is u ': r the therapeutic application of great importance. There is once the possibility of using the links of the general Formula I therapy with ß-receptor blockers in the presence of bronchial obstruction to carry out or, on the other hand, the cardiac side effects in the treatment with ^ simulators turn off. In states of shock, endogenous catecholamines can be mobilized in the case of j3 blockade Circulatory dysregulation can occur in the peripheral vascular system, which occurs when the specific / i-receptor blockers of the general formula i is avoided, since a predominance of the "-Sympathico-alkylidene or cycloalkylidene group, mean, implements and splitting off any protective groups that may be present.

According to the definition of the radicals R ^! and R ⁴ represent the compounds of the general formula III carbamic acid esters, thiocarbamic acid esters, urea, mono- or symmetrically disubstituted ureas. Semicarbazides, carbamic acid halides or isocyanates.

The reaction of the compounds of the general formula II with the compounds of the general formula III takes place in a manner known per se for these reactions, expediently in an indifferent organic Solvent and, if desired, with heating.

f ö ftci / ctom

ailfti-i »rnn

Ir, rlor,

ccorctnffiitri

According to the invention, the compounds of general formula I can be different Build ways.

So you can

a) prepare the compounds of general formula I by adding a phenoxyalkanolamine general formula

R'-N—

V-NH,

A ¹ O-A ²

with a compound of the general formula R ² —Ν — C = O

R ³ R ⁴
in which R ¹ and R ^{2 have} the meaning given,

(HD suggests, it can be advantageous to carry out the reaction of the compounds of the general formula II with the compounds of the 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 the presence of Raney nickel in an inert diluent or solvent suitable for the particular catalyst, for Example alcohol, aqueous alcohol, dioxane or glacial acetic acid can be carried out. Hydrogenolysis can accelerated or completed by the presence of a catalyst, for example hydrochloric acid or oxalic acid when noble metal catalysts are used for hydrogenation.

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

But you can also

b) a phenoxyalkanolamine of the general formula

R ¹ —N — CH, -CH-CH, -O-

A ¹

OA ² -NC = O

i I

R ⁵ R "

(IV)

with an amine of the general formula

R-NH ₁ (V)

in which R ', R ¹ , A' and A ^{2 have} the meaning given, R ^{5 is} a hydrogen atom and R ^{6 is} a Ci-C ₄ alkoxy group, an optionally substituted phenoxy group, a C | -CU alkylthio group, an optionally substituted one A phenylthio group, a hydrazino group, a halogen atom or, if R ² denotes other than hydrogen, also an amino group or R ⁵ and R ⁶ together denote an additional C — N bond and remove any protective groups that may be present.

According to the definition of the radicals Rs and R ⁶ , the compounds of the general formula IV represent carbamic acid esters, thiocarbamic acid esters, semicarbazides, carbamic acid halides, isocyanates or, if nn R ^; other than hydrogen means, also represents urea.

The implementation of the connections of the general Formula IV with the compounds of general formula V are carried out in a manner known per se for these reactions Manner, expediently in an inert organic solvent and, if desired, with heating. Instead of a solvent, it is also possible to use an excess of the amine used in general Formula V can be used.

The preparation of the compounds of the general formula IV used as starting materials can by using the for the production of carbamic acid esters, thiocarbamic acid esters, semicarbazides, Carbamidsäurehalogenideii and isocyanates customary methods, for example from compounds of the general formula II.

But you can also

c) in appropriately substituted phenoxyalkanolamines the general formula

R'-N-CH ₂ -CH-CH ₁ -O Λ ¹ O-A ²

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

The replacement of the sulfur atom by an oxygen atom in the compounds of 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 carried out will.

The ent behave analogously to thioureas

R'-N-CH ₂ -CH-CH ₂ NH-C-NH-R ²

(VI)

Talking isothiourea ethers, which in the context of the invention are treated as starting materials for the desulphurisation reactions.

The compounds of the general formula VI can also be prepared by treatment with phosgene or phosphorpene tachloride desulphurized. The chloroformic acid amidines obtained as intermediate products or carbodiimides can by saponification or addition of water in the compounds of general formula I are converted.

But you can also
4 (id) a phenoxyalkanolamine of the general formula

// X

R ⁷

NH-C = NR ²

(VIl)

A ¹

Ο — Λ ²

in which R ¹ , R ² , A ¹ and A ^{2 have} the meaning given and R ^{7 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 1 to 4 Having carbon atoms means hydrolyzing and splitting off any protective groups that may be present.

According to the definition of the radical R ', the compounds of the general formula VN are haloformic acid amidines, Isourea esters, isothiourea esters, isourea ethers and isothiourea ethers represent.

R '- N-CH ₂ -CH-CH ₂ -Λ ¹ Ο -Λ ²

The compounds of the general formula VIl used as starting materials are hydrolyzed expediently in an alkaline medium. The isourea esters, isothiourea esters, isourea ethers and isothiourea ethers of the general formula VII can also be used with good success in an acidic medium be hydrolyzed.

But you can also

e) to a phenoxyalkanolamine of the general formula

N = C = N - R ²

(VIII)

in which R ¹ , R ² , A ¹ and A ^{2 have} the following meanings, add water and split off any protective groups present. But you can also

909 637 / UO

f) a phenoxyalkanolamine of the general formula

R ¹ -N-CB, -CH-CH ₁ -O ^

T ,

-NH-C-NH-R ²

(IX)

in which Ri, R ² , A 'and A ^{2 have} the meaning given, hydrolyze and split off any protective groups present. The hydrolysis of the compounds of the general formula IX is expedient in an alkaline medium. But you can also g) a phenoxyalkanolamine of the general formula

R ¹ —N — CH ₂ —CH — CH ₂ —O A ¹ Ο — Α ²

in which R ', R ² , A ¹ and A ^{2 have} the meaning given, saponify and split off any protective groups present. The saponification of the compounds of the general formula X is expedient in an alkaline medium. But you can also h) a phenoxyalkanolamine of the general formula

R ¹ - N- CH ₂ - CH-CH ₂ -A ¹ A ² O-

in which R ¹ , A ¹ and A ^{2 have} the meaning given, with an amine of the general formula

R ² -NH ₂

(V)

in which R ^{2 has} the meaning given, allow to 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 one Compound of the general formula XI to use.

The reaction can be carried out in an inert organic solvent at temperatures between ⁰ ° C. and the boiling point of the solvent.

The phenoxyalkanolamine of the general formula XI used as the starting material can be prepared, for example, from a phenoxyalkanolamine of the general formula II, in which R ¹ , A ¹ and A ^{2 have} the meaning given, by reaction with CS ₂ in the presence of alkali and subsequent addition of ethylene chlorohydrin in an inert organic solvent such as dimethylformamide, initially forming the correspondingly substituted phenyldithiocarbamic acid / hydroxyethyl ester, which is then reacted with ethyl chloroformate in NaOH.

But you can also

i) a ureidophenyl derivative of the general formula

(XII)

R ² —N — C — N— <f VO-CH ₂ -R *

I Il I ^x = ^/

B ¹ OB ² in which R ^{2 has} the meaning given, B ¹ and B ²

b5 (XI)

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 oxal group and R ⁸ the groups

40

-CH CH ₂

P (IIIa)

or

-CH-CH ₂ -R "(XIIIb)

O-A ²

represents, in which R ^{9 represents} a halogenated or the residue of a sulfonic acid, for example benzenesulfonic acid or p-toluenesulfonic acid, or a mixture of such compounds, in which R ^{8 has} the meanings given, with an amine of the general formula

R ¹ -NH-A ¹

(XIV)

in which R <and A <have the meaning given, implement and split off any existing protective groups.

If R ⁸ represents group XIII b, the reaction can expediently be carried out 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 carried out under atmospheric pressure or under increased pressure, for 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 im can optionally also be used as a diluent or solvent Use excess.

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

The compounds of general formula XII used as starting materials can be obtained by reaction of the corresponding phenol with an epihalohydrin, for example epichlorohydrin. the Compounds of the general formula XII can be isolated. However, they can also be processed further in accordance with this invention in the production medium.

But you can also

j) a ureidophenyl derivative of the general formula with a compound of the general formula
R ⁹ -CH ₂ -CH-CH ₃ -NR ¹
O - A ² A ¹

P (Vl)

or

IU

CH ₂ - CH-CH ₂ -NR ¹

O A '

R ² -N-CNB ¹ OB ²

in which R ² , B ¹ and B ^{2 have} the meaning given in which R ', R ⁹ , A' and A ^{2 have} the meaning given, or allow mixtures thereof to react and split off any protective groups present. The reaction can expediently be carried out in the presence of an acid acceptor such as potassium carbonate or sodium carbonate. On the other hand, an alkali salt of the phenol in question, for example the sodium or potassium salt, can also be used as the starting compound. The reaction can be carried out in an inert solvent or diluent, such as, for example, P ^ V) ethanol, and accelerated or brought to a conclusion by supplying heat. But you can also

k) a ureidophenyl derivative of the general formula

O-A ² -CH ₂ -CH-CH ₂ -NH-A ³

PiVIII)

in which R ² , A ² , B 'and B ^{2 have} the meaning given and A ^{3 is} a hydrogen atom or an optionally substituted benzyl radical, with a carbonyl compound of the general formula

OR ¹⁰ —C — R "

(XlX)

in which R ¹⁰ and R ″ together with the connecting carbon atom represent a ^{radical which can be converted into the group R 1} by hydrogenation, react them 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-Wallach.

Suitable reducing conditions are, if A ^{3 is} a hydrogen atom, also the presence of hydrogen and a hydrogenation catalyst such as platinum, palladium or Raney nickel, it being possible to work in an inert solvent or diluent, for example ethanol.

If R ^(o and R ^{11 are} alkyl radicals or, together with the C atom of the carbonyl group, a cycloalkyl radical mean, can also be an excess as a solvent

J5 of the carbonyl compound of the general formula XIX can be used.

Suitable reducing conditions are, if A ^{3 is} a hydrogen atom, also by the presence of di-light metal hydrides, such as alkali boron hydride, created in an inert solvent or diluent such as hydrous methanol, it being possible to use an excess of the carbonyl compound of the general formula XIX. If R ^{2 is} an alkenyl radical that is not with is to be hydrogenated, it is recommended to use Di-Leicht metal hydrides, such as alkali borohydride, to reduce.

The compounds of the general formula XVIII used as starting compounds can, if A ² and A ^{3 represent} a hydrogen atom, even can also be generated in situ, for example by reducing the corresponding «-diazoketones, Λ-azidoketones,« -oximinoketones, «-nitroketones, "-Nitrosoketones," -nitro alcohols, cyanohydrins or acyl cyanides.

But you can also

1) a ureidophenyl derivative of the general formula

O-A ²

R ² - N - C - N 1 / ~ \ - O - CH ₂ - CH - CH ₂ --NH - A ¹

(XX)

B ¹ OB ²

in which R ² , A ¹ , A ² , B "and B ^{2 have} the specified meaning halogen atom, an alkyl sulfate radical or the radical of one, with an alkylating agent of the general sulfonic acid, such as the benzenesulfonyl or the toluene

Formula ni χ fXXI) sulfonyl radical, means convert and optionally

split off existing protecting groups, in which R 'has the meaning given and X is a If A ^{1 is} an acyl group, the Ver

Look for bonds of the general formula XX in shape their alkali salts are used,

A slureacceptor, such as alkali metal carbonate, can also advantageously be used in the reaction. the Reaction can expediently in the presence of an inert

Diluent or solvent, such as ethanol, performed and accelerated or completed by the supply of heat.

But you can also

m) a ureidophenyl derivative of the general formula

OR ¹

R ² -N-C-N- <f% -O-CH ₁ -C-CH ₁ -NA ¹

111

B ¹ OB ²

(XXII)

in which R ', R ² , A ¹ , B ¹ and B * have the meaning given, hydrogenate and split off any protective groups present.

The hydrogenation can, for example, by catalytic hydrogenation, for example in the presence of platinum, Palladium or Raney nickel, and in an inert solvent or diluent. The hydrogenation can also be advantageous with di-light metal hydrides, such as lithium aluminum hydride, or sodium borohydride, in a solvent or diluent such as aqueous methanol, or with Alcoholates, such as aluminum isopropylate or magnesium isopropylate, according to the method of Meerwein-Ponndorf-Verley or her treatises.

But you can also

n) a ureidophenyl derivative of the general formula

-CH ₁

Ν — R ¹

(XXIII)

in which R ', R ^J , B ¹ and B ^{2 have} the meaning given and Y is a hydrolytically cleavable group, such as the carbonyl group, the oxalyl group or the group

R ¹² - ^X CR ¹³

(XXIV)

denotes in which R ¹² and R ¹³ each represent a hydrogen atom or a Ci-Ce alkyl radical or R ¹² and R ' ³ together denote the group - (CHz) _n -, where η stands for the numbers 4 to 6, subject to hydrolysis and

R ² -NH-C -NH-O

in which R ¹ and R ^{2 have} the abovementioned meaning and R ¹⁴ and R ¹⁵ 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 ot-aralkyloxycarbonyl group, and where, at least one of the radicals R ¹⁴ and R ¹⁵ denotes a hydrogenolytically cleavable group, any protective groups present are cleaved off.

The compounds of the general formula XXIII

thus represent oxazolidones, oxazinediones and oxazolidines The hydrolysis of the oxazolidones and the oxazinediones of the general. Formula XXIII can be used in an alkaline as well as an acidic medium can be carried out during the hydrolysis of the Oxazolidine of the general formula XXIII is preferably carried out in an acidic medium.

But you can also

o) a ureidophenyl derivative of the general formula

R ¹⁵

-CH ₂ -CH-CH ₂ -NR ¹
O-R ¹⁴

(XXV)

50

55 subject to hydrogenolysis. The hydrogenolysis of the compounds of the general formula XXV can be carried out using hydrogen in the presence of a hydrogenation catalyst such as platinum, palladium or Raney nickel.

But you can also

p) a ureidophenyl derivative of the general formula

R ¹

R ² —N — C— N— «
B ¹ OB ²

0-CH ₂ -CH-CH ₂ -NR ¹
O — R "'

iXXVI)

in which R ¹ , R ² , B ¹ and B ² the given meaning is benzoyl group, an alkoxycarbonyl group, for sitting and R ¹⁶ and R ¹⁷ each have a hydrogen atom 65 plays the tert-butoxycarbonyl group, the ethoxycar-

or a hydrolytically cleavable group, such as an aliphatic acyl group, for example the acyl group, an aromatic acyl group such as the bonyl group, etc., a cycloalkyloxycarbonyl group, for example the cyclopentyloxycarbonyl group and the cyclohexyloxycarbonyl group, or an aralkyl

oxycarbonyl group, for example the benzyloxyearbonyl group, and where at least one of the radicals R ¹⁶ and R ^{17 is} a hydrolytically cleavable group, subject to hydrolysis and remove any protective groups that may be present. the

Hydrolysis can be carried out in both an acidic and an alkaline medium.

But you can also

q) a ureidophenyl derivative of the general form

R- N -C-N--

I Il I

R ^IS O R '"O ClI, CHOII CII, NH R'

IXXVIIi

in which R ¹ and R ² have the meaning given, subject to hydrolysis.

and R ¹⁸ and R ^{| q} each represent a hydrogen atom or an acyl group, for example an aliphatic or aromatic acyl group, and where at least one of R ¹⁸ and R ^{| q represents} an acyl group.

The hydrolysis can be carried out either in an acidic or in an alkaline medium. But you can also
r) an Ireidophenyl derivative of the general formula

R ^: NCN ■
IV () IV

in the R ² , R ¹⁰ . R ¹ ', B ¹ and B ^{2 have} the meaning given, hydrogenate and split off any protective groups present.

The hydrogenation can, for example, with a di-light metal hydride, such as lithium aluminum hydride,

R ^: Nt N

I ii

O CII, R ¹ "

IXX VH I)

be performed.

The compounds of the general formula XXVIII can d < ~ ch condensation of compounds of the general formula XIX with an amide of the general formula

O CII, CHOII C-- NII,

(XXIXl

in which R ² , B ¹ and B ^: the given meaning has the general formula XV, in which R ² , B ¹ and B ² the

zen. The compounds of the general formula XXIX in turn can, for example by reacting a compound of the general formula XV or an alkali metal salt of a compound Have given meaning, can be obtained with 2,3-epoxypropionamide.

But you can also

s) a ureidophenyl derivative of the general formula

O Λ-

R ¹

R ^: NC N

O CH, ClI-C-N-V

(XXXl

in the Ri, R ² . A ² , A ³ , Bi and B ^{2 have} the meaning given, hydrogenate and split off any protective groups present.

The hydrogenation is expediently carried out with di-light metal hydrides, such as lithium aluminum hydride.

The ureidophenyl derivative of the general formula XXX used as starting product can play a compound for Fn by reacting the general formula

ii

R ² - N - CN

! I.

B ¹ B ²

Ο —Λ-

; - O —CH, - CH- COOR '

in which R ² , A ² , B ¹ and B ^{2 have} the meaning given and R ^{20 is} a C 1 -C 4 -alkyl radical an amine of the general formula

(XXXI)

represents, mi)

R'— NH- (XXXII)

in which R 'and A ^{3 have} the meaning given, are obtained. But you can also

% s

t) a ureidophenyl derivative of the general formula

Il

R ² --Ν —C - N ·? '

C) - Λ ²

O CU, CIl CIIO

(XXXIII)

B ¹

B ²

in which R ² , A ² , B ¹ and B ^{2 have} the meaning given, with an amine of the general formula

R ¹

NH Λ ¹

(XXXII)

in which R ¹ and A * have the meaning given, react them under reducing conditions and split off any protective groups present.

Suitable reducing conditions are when A ^!

in a hydrogen atom means, also in the presence of Hydrogen and a hydrogenation catalyst such as platinum. Palladium or Raney nickel in an inert Solvents or diluents, for example ethanol.

ι-, Suitable reducing conditions, if A ^J denotes a hydrogen atom, also through the presence of di-light metal hydrides, such as alkali borohydrides, in an inert solution or diluent

Condition ^ UH ^ T! ^c t ^p !! en di ° C \ p- medium, u / ip u / accprhaltiapm Mpthannl. pp.srhnffpn.

presence of formic acid according to the method of Leuckart-Wallach.

il * · ■■

R ² NCN ^y '
B ¹ B ²

in which R ^1, R-, A ', B ¹ and B ^{2 have} the meaning given, reduce and, if appropriate, split off protective groups that are present.

Formic acid, for example, is suitable for the reduction. However, the reduction can also be carried out using hydrogen in the presence of suitable hydrogenation catalysts but can also

u) a ureidophenyl derivative of the general formula

O- Λ ²

O CH, CH ClI -N R ¹

(XXXIV)

O
R ² - N ■■ (· -N

I I

B ¹ B ²

gates, such as platinum, palladium or Raney nickel, or by means of di-light metal hydrides, such as alkali borohydrides or lithium aluminum hydride, in an inert solution or diluents can be carried out.

But you can also

v) a ureidophenyl derivative of the general formula

O- / VR ¹ "

y /

O Cl l • ClI CII ₂ NC

R "

(XXXV)

in the R ² . A ² . B ¹ and B ² and R '»and K" have the meaning given, reduce and split off any protective groups present.

Formic acid, for example, is suitable for the reduction. The reduction can also be carried out by means of hydrogen in the presence of suitable hydrogenation catalysts, such as platinum, palladium or Raney nickel, or by means of di-light metal hydrides such as alkali borohydrides or lithium aluminum hydride, in an inert solvent or diluent! carried out will.

The embodiments of the method according to the invention can in general with regard to the Reaction conditions can be varied widely and adapted to the respective conditions.

For example, the reactions in the absence or in the presence of inert solvents or diluents, at room temperature or be carried out 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 reactants, the optimal conditions with regard to Temperature and solvent vary throughout, with finding the optimal one in each case Conditions is professional

Depending on the character of the raw materials, this can be one or the other of the processes described in individual cases a compound of the general formula I only deliver in low yields. In such cases it is not difficult for the person skilled in the art to either to prevent side reactions and thus the yields by selecting suitable protective groups to increase or to manufacture the product in another of the process routes described.

The preparation of the compounds used as starting materials in the individual processes can, Unless specifically described, it is carried out using known methods and is professional.

The compounds of general formula I obtained can be mixed with physiologically acceptable inorganic compounds or organic acids such as hydrochloric acid, hydrobromic acid, hydriodic acid, Sulfuric acid, nitric acid, phosphoric acid, acetic acid, propionic acid, dichloroacetic acid, Benzilic acid, salicylic acid, oxalic acid, malonic acid, adipic acid, maleic acid, fumaric acid, tartaric acid, citric acid, or ascorbic acid can be converted into its acid addition salts.

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

As far as racemic compounds of the general Formula I are obtained, they can be broken down into their optically active forms by known methods will. Likewise, you can optically active compounds of the general formula I but also by using -> obtained optically active starting compounds in the reaction.

Example I.

35.5 g of 1- (4-ureidophenoxy) -2,3-epoxypropane and 142 ml of isopropylamine were added at room temperature Stirred for 40 hours. Then the excess isopropylamine was distilled off, the residue in dilute Dissolved hydrochloric acid, the solution filtered blank and the dissolved base by adding solid potassium carbonate π failed. The precipitate from l- (4-ureidophenoxy) -2-hydroxy-3-isopropylaminopropane consists, had a melting point after recrystallization from ethanol from 141.5 to 14? VC

_'o example 2

10 g of 1- (4-ureidophenoxy) -2,3-epoxypropane 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-ureidophenoxy) -2-hydroxy-3-tert-butylaminopropane hydrochloride was precipitated by the addition of ethereal hydrochloric acid ⁰ C (decomp.) Melted.

Example 3 ^{! L}

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 the .m Excess isopropylamine obtained residue was dissolved in dilute hydrochloric acid, the solution fiiirieri and the geiosted substance clurcn /. addition of solid potassium carbonate precipitated. After recrystallization the 1- [4- (3-methylureido) phenoxy] -2-hydroxyj-isopropylaminopropane thus obtained melted from dilute alcohol at 154 to 156 ° C.

The N methyl-N '- [4- (2,3-epoxypropoxy) phenyl] urea used as the starting compound was made as follows:, n

A mixture of 49.8 g of N-methyl-N '- (p-hydroxypheny!) - urea, ! 5Om! Sn-KOH and 166 g Epi chlorohydrin were stirred for 6 hours at room temperature. Then the precipitated N-methyl-N '- [4- (2,3-epoxypropoxy) phenyl] urea became Aspirated, washed with water and dried. The raw product, that melted at 139 to 143 ° C became without further cleaning processed.

Example 4

^v mi

10 g of N-ethyl-N '- [4- (2,3-epoxypropoxy) -phenyI] -urea and 50 ml of tert-butylamine were refluxed for 8 hours. The one after distilling off of the excess tert-butylamine obtained residue was dissolved in dilute hydrochloric acid, the Unt,:> dissolved abfütriert, the base precipitated with potassium carbonate, suctioned off, dried and recrystallized for cleaning from 3utyl acetate. The one made in this way 1- [4- (3-Ethylureido) -phenoxy] -2-hydroxy-3-tert-butylaminopropane melted at 122 to 124 ° C.

The N-ethyl-N '- [4- (2,3-epoxypr <jpoxyJ-phenyl] urea, after recrystallization from ethanol at 154 to 156.5 ° C melted, was prepared analogously to the N-methyl-N '- [4- (2,3-epoxypropoxy) -phenyl] -urea.

Analogously from N-ethyl-N '- [4- (2,3-epoxypropoxy) -phenyl] -urea by reaction with isopropylamine l- [4- (3-Ethylureido) phenoxy] -2-hydroxy-3-isopropylaminopropane obtained, which after recrystallization from ethanol / water 1: 1 at 155 to Melting 157 ° C.

Example 5

1 g of 1- (4-ethoxycarbonylaminophenoxy) -2-hydroxy-3-isopropylaminopropane and 5 ml of cyclohexylamine were refluxed for 2 hours. Then the excessively hot hexylamine was distilled off. the the remaining residue was dissolved in dilute hydrochloric acid and the solution was filtered. By adding caustic soda became the 1- [4- (3-cyclohexylureido) phenoxy] -2-hydroxy-3-isopropylaminopropane precipitated, which melted after recrystallization from isopropanol at 157 to 160C.

Example 6

A mixture of 3 g of NMethyl-N '- (p-oxyphenyl) urea, 3 ml of tert-butyl (2.3-epoxypropyl) amine, 20 ml of water and 0.2 ml of concentrated sodium hydroxide solution Stirred for 6 hours at room temperature and then left to stand for 18 hours. It had turned out to be resinous Precipitate formed which was digested with water and then dissolved in acetone. From the acetone Solution crystallized 1- [4- (3-methylureido) -phenoxy] -2-hydroxy-3-tert-butylaminopropane from, which after recrystallization from isopropanol at 140 to 143 ° C melted.

Example 7

0.5 g of 1- (4-aminophenoxy) -2-hydroxy-3-isopropylaminopropane were geiost and u, jg cyclohexyl isocyanate in a mixture of 2.2 ml of n-acid and 5 ml of acetone admitted. After 16 hours, the acetone was distilled off, 5 ml of water were added and the Solution filtered. The 1 - [4- (3-cyclohexylureido) phenoxy] -2-hydroxy-3-isopropylaminopropane was obtained by adding sodium hydroxide solution precipitated, which after recrystallization from isopropanol at 156 to 158.5 ° C melted.

Example 8

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. Then the solvent was distilled off, the remaining one The residue was dissolved in 3 l of water and 86 ml of 1N hydrochloric acid and the solution was filtered. By adding The 1- [4- (3-cyclohexylureido) phenoxy] -2-hydroxy-3-tert-butylaminopropane was sodium hydroxide solution precipitated, which melted after recrystallization from isopropanol at 143 to 145 ° C.

The N-cyclohexyl-N '- [4- (23-epoxypropoxy) phenyl] urea used as the starting product was made in the following way:

To a solution of 40 g of N-cyclohexyl-N '- (p-oxyphenyl) urea 92.5 g of epichlorohydrin were added to 50 ml of 5N potassium hydroxide solution and the whole was added for 16 hours

Stirred at room temperature. The precipitated N-cyclohexyl-N '- [4- (2,3-epoxypropoxy) -phenyij-urea was then Sucked off, washed with water and dried. The crude product that has a melting point from 170 to 174 ° C, was processed further without purification.

Example 9

A mixture of 10 g l- (4-Ureidophcnoxy) -2-hydroxy-3-isopropylaminopropan and 10 g of n-Hexylaminhydrochlorid were heated for 3 hours at 15O ⁰ C. The reaction product was dissolved in 150 ml of water with the addition of hydrochloric acid, and the solution was filtered. After the addition of sodium hydroxide solution, the 1- [4- (3-n-hexyl ureido) phenoxy] -2-hydroxy-3-isopropylaminopropane precipitated, which melted 1: 1 at 146 to 149 ° C. after recrystallization from ethanol-water .

Example 10

1.175 g of 1 - (4-phenoxycarbonylaminophenoxy) -2-hydroxy-j tert-butylaminopropane hydrochloride, 8 ml of methanol, 2.93 ml of methanolic sodium methylate solution (! normal) and 2.67ml methanolic cyclohexylamine solution (1 normal) were combined and 8 hours at Room temperature stirred. After standing overnight, the solvent was refluxed for 1 hour distilled off and the residue dissolved in 20 ml of water and 3.8 ml of 1 η-hydrochloric acid. Then was through Addition of caustic soda up to pH 12 the l- [4- (3-cyclo-

hexylureido) phenoxy] -2-hydroxy-3-tert-butylaminopropane precipitated, which after recrystallization melted from isopropanol at 143-144 ° C.

The 1- (4-phenoxycarbonylaminophenoxy ^ -hydroxy-S-tert-butylaminopropane hydrochloride used as the starting product was produced 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, one Stirred for a further hour and so much 1N sodium hydroxide solution was added dropwise that the pH was 6 to 7. It fell the 1- (4-phenoxycarbonylaminophenoxy) -2-hydroxy-3-tert-butylaminopropane hydrochloride which melted after drying at 127 to 130 ° C.

Example 11

2 g of 1- (4-phenoxycarbonylaminophenoxy) -2-hydroxy-3-isopropylaminopropane hydrochloride, 2 ml of isopropylamine and 10 ml of methanol were left to stand at room temperature for 2 days. Then methanol and excess amine were removed, the residue was dissolved in water with the addition of hydrochloric acid at pH A , the solution was filtered and the base was precipitated by adding sodium hydroxide solution to pH 12. The precipitate-3-hydroxy -2-isopropylaminopropan consisted of l- [4- (3-isopropylureido) phenoxy] was recrystallized from isopropanol and then melted at 154 to 156 ⁰ C.

Following the same procedure using appropriate amines, the following compounds were obtained manufactured:

1- [4- (3-AHylureido) phenoxy] -2-hydroxy-3-isopropylaminopropane, F. 145 to 147 ° C.

1- [4- (3-sec-butylureido) -phenoxy] -2-hydroxy-3-isopropylaminopropane, F. 141.5 to K3 ° C.

1- [4- (3-i-Amylureido) phenoxy] -2-hydroxy-3-isopropylaminopropane, F. 124 to 127 ° C The l- (4-phenoxycarbonylaminophenoxy) -2-hydroxy-3-isopropylamino- Propane hydrochloride was produced in the following way:

-, 20g 1- (4-aminophenoxy) -2-hydroxy-3isopropylaminopropane were dissolved in 100 ml of acetone with the addition of 7 ml of glacial acetic acid and a solution within 40 minutes 13.9 g of phenyl chloroformate in 50 ml of acetone were added dropwise. The temperature was below

held at 3O ⁰ C. The mixture was then stirred for a further 1 hour and then the precipitated 1- (4-phenoxycarbonylaminophenoxy) -2-hydroxy-3-isopropylaminopropane hydrochloride, which melted at 199-202 ° C. after recrystallization from methanol.

'' Example 12

2 g of l- (4-phenoxycarbonylaminophenoxy) -2-hydroxy-3-isopropylaminopropane hydrochloride, 10ml metha-

PiGi üpiu 2.5 n \ i ^ roiyiafptipi "wiirucn 50 mifi'üicM üi'lici

: n refluxed. Then were methanol and excess Crotylamine is distilled off, the residue in 100 ml of water with the addition of dilute hydrochloric acid (pH 4) dissolved and the solution filtered. After adding sodium hydroxide solution to pH 12, the 1- [4- (3-crotyl-

2; ureido) -phenoxy] -2-hydroxy-3-isopropylaminopropane which, after recrystallization from isopropanol, melted at 140.5 to 143.5 ° C.

Using cyclopentylamine instead of crotylamine, one obtains according to the above procedure

jn writing the l- [4- (3-CycIopentylureido) -phenoxy] -2-hydroxy-3-isopropylaminpropan a melting point of 157.5 to 16O ⁰ C.

Example 13

j-, a mixture of 342 mg cycloheptylamine, 1 g l- (4-phenoxycarbonylaminophenoxy) -2-hydroxy-3-isopropylaminopropane hydrochloride, 2.6 ml of methanolic sodium methylate solution (1 normal) and 10 ml of methanol were left to stand at room temperature for 16 hours and then refluxed for 30 minutes. The solvent was then distilled off, the The residue was taken up in 50 ml of water with the addition of dilute hydrochloric acid (pH 4) and the solution filtered. By adding sodium hydroxide solution to pH 12, the 1- [4- (3-cycloheptylureido) phenoxy] -2-hydroxy-3-isopropylaminopropane became precipitated, which melted after recrystallization from isopropanol at 145 to 148 ° C.

The following compounds were prepared by the same procedure using the appropriate amines. prepared gene of the general formula I: i- [4- (3-Cyciopropyiureido) -phenoxy] -2-hydroxy-3-isopropyl-aminopropane, mp 141 to 143.5 ° C 1- [4- (3-hexene- (2) -yl-ureido) -phenoxy] -2-hydroxy-3-isopropyl-aminopropane, F. 157.5 to 159.5 ⁰ C.

Example 14

10 g of N-cyclohexyl-N '- [4- (23-epoxypropoxy) phenyl] urea, 10 ml isopropylamine and 50 ml methyl

bo thanoi were refluxed for 25 hours Then the solvent and excess amine were distilled off, the remaining residue in 800 ml Dissolved water with the addition of hydrochloric acid (pH 3 to 5) and the solution filtered by adding sodium hydroxide solution

b5 until the pH was -2-hydroxy-3-isopropyiaminopropan precipitated l- [4- (3-cyclohexylureido) phenoxy] 12, which melted after recrystallization from ethanol at 157 to 16O ⁰ C.

IO

15th

25th

JO

Using N-Cyc | ohexyl-N '- [4- (2 ^ - epoxypropoxy) -phenyl] -h3rnstoff and suitable Amines were prepared in an analogous manner to the following compounds of general formula I:

l-fjl-P-CyclohexylureidoJ-phenoxyl ^ -hydroxy-S-sec-butylaminopropan, F. 127-130 ⁰ C.

! - [4- (3-Cyclonexylureido) phenoxy] -2-hydroxy-3-isoamylaminopropane, mp 157-159 ° C

1- ^ ß-CyclohexylureidoJ-phenoxyJ ^ -hydroxy-S- (1,333-tetramethylbutyl) -aminopropane, F. 131 bis 133.5 "C

l- [4- (3-CycIohexylureido) -phenoxy] -2-hydroxy-3-isopropylaminopropan, F. 157-160 ⁰ C.

Example 15

5 g! - [^ (S-CycIohexylureidoJ-phenoxyJ ^ -hydroxy-3- (N-benzyl-N-tert-butylamino) propane, 100 ml glacial acetic acid and 0.5 g platinum dioxide were added for 6 hours Shaken at room temperature in a hydrogen atmosphere *. Then the catalyst was sucked off, the glacial acetic acid is distilled off in vacuo and the remaining residue in 250 ml of water with addition dissolved by hydrochloric acid (pH 2). The solution was filtered and by adding sodium hydroxide solution to pH 12 the 1- [4- (3-Cyclohexylureido) phenoxy] -2-hydroxy-3-tert-butylaminopropane precipitated, which melted at 142 to 144.5 "C after recrystallization from isopropanol.

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 100 ml of glacial acetic acid and 1 g of palladium- ^{carbon for 8 hours at 50 °} C. and 50 atm

The 1 - [4- (3-Cyclo- j-, hexyIureido) phenoxy] -2-hydroxy-3- (N-benzyl-N-tert-butylamino) propane was prepared as follows: 39.8 g of N-cyclohexyl-N '- [4- (23-epoxypropoxy) phenyl] urea, 24.5 g of N-benzyl-N-tert-butylamine and 150 ml of ethanol were refluxed for 17 hours. Then the solvent was distilled off, wherein the 1- [4- (3-CyclohexyIureido) -phenoxy] -2-hydroxy-3- (N-benzyl-N-tert-butylamino) -propane as resin remained which was used for debenzylation without purification. The compound was called fumarate ^ characterized, which melted after recrystallization from ethanol at 142 to 145 ° C.

Example 16

1 g of 1- [4- (3-Cyc! Ohexylureido) phenoxy] -2-hydroxy-ν S-aminopropane hydrochloride, 20 ml of acetone and 1.42 ml of methanolic sodium methylate solution (1 normal) were combined and refluxed for 1 hour cooked. Then, while cooling with ice, 2 g of sodium borohydride were added, the mixture was stirred for 10 minutes and, after standing - overnight - 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 was filtered and the 1- [4- (3-cyclohexylureido) phenoxy] -2-hydroxy-3-isopropylaminopropane was precipitated by adding sodium hydroxide solution to pH 12 , which melted at 157 to 160 ^{0 C after recrystallization from isopropanol.}

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

29 g of N-cyclohexyl-N '- [4- (2,3-epoxypropoxy) phenyl] urea and 800 ml of a solution of ammonia in methanol (18.5 g of ammonia / 100 ml of solution) were heated to 50 ° for 32 hours C. 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 was added to pH 1, the 1 - [4- (3-CyclohexyIureido) phenoxy] -2- hydroxy-3-aminopropane hydrochloride precipitated which, after recrystallization from dimethylformamide, melted at 220 to 222.degree.

Example 17

33 g of l-IH-p-cyclohexylureidoJ-phenoxyJ ^ -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. Then the solvent and excess isopropylamine were distilled off The residue is dissolved in 200 ml of water with the addition of hydrochloric acid (pH 4), the solution is filtered and sodium hydroxide solution is added to a pH of 12. A precipitate of 1- [4- (3-cyclohexylureido) phenoxy] -2-hydroxy-3-isopropyl-aminopropane precipitated out, which after recrystallization from isopropanol melted at 157 to 160.degree.

The starting product used was 1- [4- (3-cyclohexylureido) phenoxy] -2-hydroxy-3-chloropropane manufactured as follows:

30 g of N-cyclohexyl-N '- [4- (2,3-epoxypropoxy) -phenyl] -urea, 60 m! Methanol and 20 ml concentrated Hydrochloric acid were combined and left at room temperature for 24 hours. Then by addition from 70 ml of water the 1 - [4- (3-cyclohexylureido) phenoxy] -2-hydroxy-3-chloropropane precipitated which after Recrystallization from ethyl acetate at 136 to 139 ° C melted.

Example 18

1.8 g of 1- [4- (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 iodide were added Stirred at 70 ^° C. for 16 hours. Then 50 ml of water and 5 ml of 1N sodium hydroxide solution were added, the alcohol and excess isopropyl bromide were distilled off and the separated 1- [4- (3-cyclohexylureido) phenoxy] -2-hydroxy-3-isopropylaminopropane was filtered off, which melted after recrystallization from isopropanol at 156 to 159 ° C.

Example 19

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 the boil, a clear solution being formed. On cooling, the 1- [4- (3-cyclohexylureido) phenoxy] -2-hydroxy-3-tert-butyIaminopropan benzoate different from a melting point of 194-198 ⁰ C.

If 0.2 g of succinic acid is used instead of 0.4 g of benzoic acid, the neutral 1 - [4- (3-cyclohexylureido) phenoxy] -2-hydroxy-3-tert-butylaminopropane succinate with a melting point of 202 is obtained in an analogous manner to 204 ⁰ C.

If 0.3 g of tartaric acid is used instead of 0.4 g of benzoic acid, this is obtained in an analogous manner Neutral 1 - ^ - p-CyclohexylureidoJ-phenoxyJ ^ -hydroxy-3-tert.-butylaminopropane tartrate with a melting point of 213 to 215 ° C.

Example 20

A mixture of 1 g of 1- [4- (3-cyclohexylureido) phenoxy] -2-hydroxy-3-tert-butylaminopropane, 0.2 ml

909 637/140

Glacial acetic acid and 5 ml of isopropanol were briefly heated to the boil. On cooling, the 1- [4- (3-Cydoureido) phenoxy] -2-hydroxy-3-tert-butylaminopropane acetate separated out, which after recrystallization from isopropanol at 162 to 165.5 ⁰ C melted.

When using 0.4 g of salicylic acid instead of 0.2 ml of glacial acetic acid is obtained in analogous manner the l- [4- (3-CycIohexy | ureido) -phenoxy] -2-hydroxy-3-tertbutylaminopropan salicylate from the after recrystallization Isopropanol melts at 133 to 135 ° C

Example 21

7.2 g of 1- [4- (3-CycIohexyIureido) phenoxy] -2-hydroxy-3-tert-butylaminopropane, 36 ml of water and 10 ml of 2N nitric acid were ^{heated to 80 °} C., the solution was filtered and cooled the l- [4- (3-CycIo-

hexylureido) phenoxy] -2-hydroxy-3-tert-butylaminopropane nitrate which, after recrystallization from isopropanol / water 98: 2, melted at 172 to 176 ° C.

If one uses instead of 10 ml 2 η-nitric acid jo 2 πι! concentrated hydrochloric acid, then you get that 1- [4- (3-Cyclohexylureido) -phenoxy] -2-hydroxy-3-tert-butylaminopropane hydrochloride, which after recrystallization from isopropanol-water 98: 2 at 208 melts up to 212.5 ° C.

Example 22

10 g of 1 - [4- (3-CycIohexylureido) phenoxy] -2-hydroxy-3-tert-butylaminopropane were dissolved in 50 ml of methanol solved. 1.55 ml of 17.8 η-sulfuric acid in admitted. The neutral I- [4- (3-cyclo-

hexylureido) phenoxy] -2-hydroxy-3-tert-butylaminopropane sulfate, which melted from 245 ° C.

Example 23 ₍ .

A solution of 10 g of I [4- (3-cyclohexylureido) phenoxy] -2-hydroxy-3-tert-butylaminopropane in 50 ml of methanol was admixed with 13.8 mmol of 85% phosphoric acid. After a short time the secondary phosphate of the above-mentioned base precipitated which, after recrystallization from m methanol-water 5: 1 at 210 to 212.5 ⁰ C melted.

Example 24

A mixture of 2.4 g of l- (4-aminophenoxy) -2-hydroxy-3-tert-butylaminopropane, 24 ml of acetone and r, 1.25 g of cyclohexyl isocyanate were refluxed for 1 hour. Then the solvent became distilled off, the residue dissolved in water with the addition of dilute hydrochloric acid to pH 4 and the solution filtered By adding sodium hydroxide solution to pH 12, < > Then the 1- [4- (3-cyclohexylureido) phenoxy] -2-hydroxy-3-tert-butylaminopropane was precipitated after recrystallization from isopropanol at 142 to 143.5 ° C melted.

The same result is achieved when the r, reaction is carried out in the presence of glacial acetic acid. Per Mol I - (4-aminophenoxy) -2-hydroxy-3-tert.-butyl-

aminopropane 1 to 2 moles of glacial acetic acid were added.

Example 25

^K Wl

4.8 g of I - (4-aminophenoxy) -2-hydroxy-3-tert-butylaminopropane were added to a mixture of 48 ml of water and 20 ml at room temperature with stirring I nSal / acid dissolved. Then 2.5 g of cyclohexyl isocyanate were added and the whole thing for 15 hours at ι, ·, Then the solution was vacuumed clean and the j- [4- (3-Cycloneexylureido) phenoxy] -2-hydroxy-3-tert-butylani) nopropane precipitated by adding sodium hydroxide solution to pH 12, -, which after recrystallization from isopropanol at 142 melted to 144 "C,

Example 26

2 g of 1- (4-phenoxycarbonylaminophenoxy) -2-hydroxyiii 3-isopropylamino-propane hydrochloride were in Dissolved 20 ml of methanol at ambient temperature and the solution with 5 ml of aqueous concentrated Ammonia added. After a reaction time of 16 hours at ambient temperature, the solvent became ι -, distilled off in vacuo, the residue dissolved in 40 ml of water with the addition of hydrochloric acid to pH 4, the solution filtered and adjusted to pH 12 with sodium hydroxide solution. By adding solid potassium carbonate, uas 1 (4-

Ureidophenoxy) -2-hydroxy-3-isopropylaminopropane jo precipitated which after recrystallization from isopropano! at 14! melted to 142 ° C.

Example 27

j-, 13 g of glycid-p-toluenesulfonic acid ester, 135 g of N-cyclohexyl-N '- (p-oxyphenyl) urea, 5.7 ml of 1N sodium methylate solution in methanol and 60 ml of methanol were refluxed for 8 hours Then the methanol was distilled off in a water pump vacuum

m liert, the residue obtained with 50 ml of water washed out, dried and then with 1.53 ml of tert-butylamine and 14 ml of methanol for 24 hours The solution was then filtered off with suction, the solvent was distilled off and the one obtained

, -, residue with a mixture of 30 ml of water and 5 ml of 1 η-hydrochloric acid extracted in the cold. The solution was sucked clean and diluted by adding Sodium hydroxide solution precipitated the 1- [4- (3-cyclohexylureido) phenoxy] -2-hydroxy-3-tert-butylaminopropane, which

i "after recrystallization from isopropanol at 142 to Melted 144 ° C.

Example 28

4.68 g of N-cyclohexyl-N '- (p-hydroxyphenyl) urea were dissolved in 60 ml of 1 η sodium hydroxide solution at room temperature with stirring and then 4.04 g of N-tert-butyl-N- (2-hydroxy-3-chloropropyl) amine hydrochloride admitted. The mixture was then stirred for 24 hours at room temperature, and the 1 [4- (3-cyclohexylureido) phenoxy] -2-hydroxy-3-tert-butylaminopropane which had separated out was filtered off with suction and washed with water. It melted after recrystallization from isopropanol at 142 to 144 ° C.

The N-tert-butyl-N- (2-hydroxy-3-chloropropyl) amine hydrochloride used as the starting product was manufactured as follows:

To a mixture of 78 ml of tert-butylamine, 100 ml of methanol and 1 ml of water, 39.2 ml of epichlorohydrin were added dropwise with stirring at room temperature over the course of 20 minutes. After a reaction time of 16 hours at room temperature ethereal hydrochloric acid was added dropwise until an acidic reaction at a temperature of +10 ⁰ C. An oil which soon crystallized and which, after recrystallization from isopropanol, melted at 163 to 166.degree. C. precipitated.

Claims (9)

Palenliin sayings: Ureidophenoxy-alkanolamines of the general formula R ² -NH-C-NH-O > -O-CH, -CHOH-CHi-NH-R ¹ (D in which R ^{1 is} a branched C3-Ce-alkyl group and R- is a hydrogen atom, a Q-Ce-n-alkyl group, a branched C3-Ce-alkyl group, a C3-C7-cycloalkyl group or a C ₃ -Q-alkenyl group, their optically active forms and their salts with physiologically compatible inorganic or organic acids. 2.1 - (4-ureidophenoxy) -2-hydroxy-3-isopropylaminopropane. 3. 1 - [4- (3-Methylureido) phenoxy] -2-hydroxy-3-isopropylaminopropane. 4. 1 - [4- (3-Ethylureido) phenoxy] -2-hydroxy-3-tert-butylaminopropane. 5. 1- [4- (3-Methylureido) -phenoxyj-2-hydroxy-3-tert-butylaminopropane. 6. 1 - [4- (3-Ethylureido) phenoxy] -2-hydroxy-3-isopropylaminopropane. 7. 1 - [4- (3-Cyclohexylureido) phenoxy] -2-hydroxy-3-tert-butylaminopropane. 8. Process for the preparation of ureidophenoxyalkanolamines, their optically active foi.nen and their salts with physiologically compatible inorganic or organic acids according to the Claims 1 to 7, characterized in that either a) a phenoxyalkanolamine of the general formula N-dl · -CH-CHi - () - <f ! i Λ ¹ C) · ■ A ² (11) with a compound of the general formula R- R- ' (III) in which R ¹ and R ^{2 have} the meaning given, R ^{3 is} a hydrogen atom and R ^{4 is} a Ci-Ct-alkoxy group, an optionally substituted phenoxy group, a Ci-C4-alkylthio group, an optionally substituted phenylthio group, an unsubstituted or ^{substituted by R 2} amino group , a hydrazino group or a halogen atom or R ³ and R ⁴ together represent an additional CN bond and A ¹ and A ² each represent a hydrogen atom or a hydrolytically or hydrogenolytically removable protective group or A 'and A ² together represent a hydrolytically removable protective group, and optionally splitting off existing protective groups, or that one b) a phenoxyalkanolamine of the general formula R ¹ -N CH, -CH- C O Λ- with a Λ min of the general formula -O R- Nl! R ⁵ O I Il -N-C- R " (IV) (V) in which R ¹ , R ² , A ¹ and A ^{2 have} the meaning given, FO a hydrogen atom and R ⁶ a Ci - C «alkoxy group, an optionally substituted phenoxy group, cmc Ci-CVAIkylthiogruppc. an optionally substituted phenylthio group, a hydra / amino group or a halogen atom, or, if R ^{2 is} other than hydrogen, also an amino group or R5 and R ⁶ together represent an additional C —N bond, and splitting off any protective groups that may be present, or that he 21 53 024
3 4
c) in appropriately substituted phenoxyalkanolamines of the general formula O— / ~ y ~ NH — C — NH- R ² (Vl)
\ - / Il R ¹ —Ν — CH ₁ -CH-CH, -
I "I Il
S. A ¹ OA ² any protecting groups that may be present
splits, or that one
d) a phenoxyalkanolamine of the general
formula in which R ', R ² , A ¹ and A ² the given Be
have meaning, and their corresponding u,
Isothiourea ethers the sulfur or the
Thioether group replaced by oxygen and R ⁷ - Ο ^ ζ \ —NH-C = N (VII) R '- N-CH ₂ -CH-CH R ² I.
Λ 'Ο-Λ ² indicates, hydrolyzes and, if necessary, before
splits off existing protecting groups, or that
man
e) to a phenoxyalkanolamine of the general
formula in the R ¹ . R '. A ¹ and A ^{2 have} the specified value
Have meaning and R ^{7 is} a halogen atom, a
O-acyl group, an O-alkyl group, a
S-acyl group or an S-alkyl group in which
the alkyl groups have 1 to 4 carbon atoms, be , - O - ^^^ N = C = -NR ² (VIII) R'-N-Cfl, -CiI-CH
I - ι II
Λ 'Ο - Λ- or that one
f) a phenoxyalkanolamine of the general
formula in which R ¹ , R ', A ¹ and A ² the specified Be
have meaning, water anlat, rt and gege
splitting off any existing protection groups, NII
Η O ^ 'y -NH- C NH R ² (IX) R ¹ N-CH, - CH CII,
I. I.
A ¹ O - A ² that he
g) a phenoxyalkanolamine of the general
formula in which R ¹ , R ² , A ¹ and A ² the given Be
have meaning, hydrolyzed and given
| i if existing protecting groups are split off, or O R-
/ te
I. ■■ () ^{v /} / -N -. (X) £ ;.
} R ¹ -N - CH, - CH CII,
I "I O ; ■ I I
ΐ: A ¹ Ο-Λ ² man
h) a phenoxyalkanolamine of the general
formula in which R ¹ , R ² , A ¹ and A ² the given Be
have meaning, saponified and possibly τ>
splits off existing protective groups, or that , - ■ () ■ - </ -Ν = - ·. J (XIl
S. R ¹ "N-CH, -CU-C II Λ ¹ Ο Λ- in which R ^{2 has} the meaning given,
lets react to what you may do before
splits off existing protecting groups, or that
man in R ¹ , A ¹ and A ² the given meaning- »·,
Hinged with an amine of general
formula
R- 'Nil, (Vl i) a ureidophenyl derivative of the general formula R ² - C - N
B ¹ OB ² -O — CH ₂ -R " (XII) in which R ^{2 has} the meaning given, B 'and B ² each individually a hydrogen atom or ι ο a hydrolytically removable protective group or B' and B ² together a hydrolytically removable protective group and R ⁸ the groups -CH- -CH, -CH-CH ₂ -R "
Ο-Λ ² (XIIIa)
(XIIIb) 21) represents, in which R ⁹ denotes a halogen atom or the radical of a sulfonic acid, or a mixture of compounds of the general formula XII, in which R ^{8 has} the two meanings given, with an amine of the general formula R ¹ -NH- / V (XlV) in which R ¹ and A ^{1 have} the meaning given R ² - N - C - N - <f I Il I '- B ¹ C) B ² j) have, reacts and splits off any protective groups present, or that one
a ureidophenyl derivative of the general formula (XV) in which R ² , B ¹ and B ^{2 have} the meaning given, with a compound of the general formula R ⁴ -CH ₂ -CH -CH ₂ -NR ¹ Ο — Λ- (XVI) A ¹ or CH, - (XViii A ¹ in which R ¹ , R ⁹ , A ¹ and A ^{2 have} the meaning given, or are allowed to react with mixtures of compounds of the general formulas XVl and XVlI and any protective groups present are split off, or that one a ureidophenyl derivative of the general formula Ο - Λ ² .- () - CH- - <"H -CH, -NH (XVIIIi in which R ² , A ² , B ¹ and B ^{2 have} the abovementioned meaning and A ^{3 is} a hydrogen atom or an optionally substituted benzyl radical, with a carbonyl compound of the general formula I! R ¹ "- CR" (XIXl in which R ¹⁰ and R "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 any protective groups present are split off, or that one
I) a ureidophenyl derivative of the general formula R ² -N-CN- ^ ' I Il I B 'O I3 ^: O CH, -CH-CH ₁ -NH-A ¹ (XX) in which R ² , A ¹ , A ² , B ¹ and B ^{2 have} the meaning given, with an alkylating agent of the general formula R ¹ X (XXh in which R ^{1 has} the meaning given and X is a halogen atom or an alkyl sulfate radical or the radical of a sulfonic acid, converts and eliminates any protective earths that may be present. or that one m) a ureidophenyl derivative of the general formula R ² NC N - · '■
I) 'O U' in the R ¹ , R ² . A ¹ . B ¹ and I? - 'the given meaning bcsit / en. hydrogenated and splitting off any protection / groups present, or OR ^! C CW: \ Λ ¹ (NXIh that he Ii) a ureidophenyl derivative of the more general I ormel R ^: NCN
I) '(ι Ii' O Cll · NR ¹
Y (Willi in the R ¹ . R-. B ¹ and B- 'have the meaning given and Y is a hydrolytically cleavable group such as the carboxyl group, the oxalyl group or the group IXMV] denotes in which R ¹ - 'and R ¹ ' each represent a hydrogen atom or a Ci - Ch-alkyl radical or R ¹² and R ^H together denote the group - (CH;), -, where η stands for the numbers 4 to b, subjected to hydrolysis and optionally before-R ¹ existing protection groups are split off, or because: man o) a ureidophenyl derivative of the general formula R- NU C "NIl in which R ¹ and R- 'have the meaning given and R ¹⁴ and R ¹⁵ each represent a hydrogen atom or a hydrogenolytically cleavable group and where at least one of the radicals R ^M and R ^{15 is} a hydrogen atom R ^: NC "N B ¹ OB ^: O Cl 1; (11 -CH; N OR ^M (XXYl Lytically cleavable group means the Hy subject to drugolysis, or that one p) a ureidophenyl derivative of the more general formula R '
-O CIl; CH CH; N OR ¹ "R ^r (XXVl in which R ¹ , R ² , B ¹ and B ^{2 have} the meaning given and R ¹⁶ and R ¹⁷ each represent a hydrogen atom or a hydrolytically removable group and where at least one of the radicals R ' ⁶ and R' ^{7 represents} a hydrolytically removable group , which is subjected to hydrolysis and any protective groups present are split off, or q) a ureidophenyl derivative of the general formula R ^: —N - C - N- ί Si! R ¹⁸ OR ¹ 'VO - CH -, - CHf) H - CH, - NH-R ¹ (XXVII) in which R ¹ and R ^{2 have} the meaning given and R ¹⁸ and R ' ⁹ each represent a hydrogen atom or an acyl group and where at least one of the radicals R ¹⁸ and R ^{1 is} an acyl group, subject to hydrolysis. or that one r) a ureidophenyl derivative of the general formula R2 N C N --- '' ' I ^! i! B ¹ OB ² in which R ² , R ¹⁰ , R ″, B ¹ and B ^{2 have} the specified n: meaning, hydrogenated and splitting off any protective groups that may be present, or R ^: N CN B ¹ () B ² O C CI O
IL
O NFI
, JR "
R ¹ " R ¹ N ^ Λ ¹ (XXVIII) that he
s) a ureidophenyl derivative
formula the general IXXX) ο Λ ² cn c
Ij Il
O in which R ¹ , R ² , A ² , A ³ , B ¹ and B ² are as defined, hydrogenated and any protective groups present are eliminated. R ² ■ N CN B ¹ (') B ~ or that one t) a ureidophenyl derivative of the general formula O -Λ ¹ I.
■■ ο — πι, - cn-Clio (XXXIlI) in which R ² , A ² , B ¹ and B ^{2 have} the meaning indicated, with an amine of the general formula R ¹ -NH-A- ' (XXXII) in which R ¹ and A ^{3 have} the meaning given, reacts under reducing conditions and splitting off any protective groups present, or that one
u) a ureidophenyl derivative of the general formula R ² -NC- NI Ii I B 'OB ² -A ²
O (H, CH CH-NR ¹ (XXXIV) in which R ¹ , R ² , A ² , B ¹ and B ^{2 have} the meaning given, reduced and any protective groups present, or R ² - NC- N B ¹ OB ² that he v) a ureidophenyl derivative of the general formula C) -A ² R '" I / CH ₂ - CFI - CFI ₂ - N - C R " (XXXV) in which R ² , Ai, B ¹ and B ² and R ' ⁰ and R "have the meaning given, reduced and optionally splitting off protective groups and the resulting compounds of the general formula I with physiologically acceptable inorganic or organic acids in their acid addition salts or obtained Acid addition salts of compounds gene of the general formula I converted into the free compounds with inorganic bases and optionally broken down racemates into their optically active forms. 9. The method according to claim 8, characterized in that the starting compounds with asymmetric carbon atom used as optically active forms.