DE2153024B2 - Ureidophenoxyalkanolamines and process for their preparation - Google Patents

Description

JC ₁ M ₇ H 2.6 3.1 2.01 - no + 8 "/ (i + 4 "/ (i + 3 3 "/ (i i-CiH? CH ₁ 1.3 0.43 2.06 - no + 5% + 5% + 8 "/ (i i-cill; C ₂ \ U 1.8 1.4 1.52 - no + 9% + 14% + 53% 1-C ₄ H ₄ CH ₁ 0.92 1.0 0.82 - no + 8% + 9% + 42% tC ₄ H ₄ C ₂ H ■ -, 0.72 0.29 0.68 5.0 no - 2 "/ (i + 2% - 6% tC ₄ H ₄ cyclohexyl 0.6b 0.18 0.10 20.0 10-20 + 2 "/ (i + 1% -10% 1 - (4-acetaminophenoxy) - 4.8 1.8 0.55 5.0 no -6% - 3% - 2% 2-hydroxy-3-isopropyl aminopropane

In the table:

Column 1: Chemical compound of the general formula I characterized by the costs Ki and R_> or name of the comparison

subslance.

Column 2: ED 50 of the inhibition of the positive chronological isoprenaline effect (1 tig / kg) in mg / kg iv
Column 3: F.Di »the inhibition of the positive inotropic isoprenaline effect (lng / kg) in mg / kg iv
Column 4: Ki>, o the inhibition of the positive inotropic isoprenaline effect (0.015 (ig / ml) in niolH) 'on the isolated atrial

preparai.

Column 5: Dose in mg / kg with ip application of the incipient 8-blockade to the bronchial system of the guinea pig.
Column 6: aconiline arrhythmia in rats, dose in mg / kg which inhibits the arrhythmia by 73%.

Column circulatory side effects after intravenous injection of 2.5 mg / kg in the cat as a percentage of the initial value. 7-9:

Column 7: frequency.
Column 8: Systolic blood pressure.
Column 9: dp / dt max.

As the results in Table 1 show, the ureidophenoxyalkanolamine derivatives have the general Formula 1 has a ß-adrenergic blocking effect, which only inhibits the positive inotropic and chronotropic effects of isoprenaline. The one through isoprenaline The lowering of blood pressure is also induced in a dosage which corresponds to 20 times the amount of the ED50.

not influenced, while / J-receptor blockers of the 1-isupropylamino-3- (l-naphthyloxy) -propane-2-ol type block the peripheral vascular effects of isoprenaline most strongly. Likewise, the action 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 l- [4- (3-Cyclohexylureido) -phenoxy] -2-hydroxy-3-isopropylamino-propane that by isopienalin [D, l.-l- (3,4-dihydroxyphenyl) -2- isopropylaminoälhanol] caused Frequen / -Increase by 50 ¹ and Vo caused by Isoprcnalin positive inotropic effect by 76% are gchemml.

With regard to the potency of the compounds of general l ^are: Ormel / kg no antiarrhythmic effect has from 1 to 1- (4-Acetaminophcnoxy) -2-hydroxy-3-isopropylamino-propane superior While the latter compound, for example, on Akonitintcst rat mg to 40 Some derivatives of the ureidophenoxyalkanolamine compounds of the general formula I are effective.

The circuit side effects of the connections of the general funnels I are small. While that 1-isopropylamino-3- (1-naphthyloxy) -propane-1-oil already at 0.5 mg / kg i.p. v. marked bradycardia in the cat. Lowering blood pressure and decreasing the force of contraction has, these disadvantageous side effects are absent in the compounds of general formula I. Some compounds of general formula 1 even have a clear positive-chronotropic and inotropc intrinsic effect.

On the basis of these results it is justified to assume a specific effect of the compounds of the general Formula I to speak. This specific ^ receptor blockade is for therapeutic use of great importance. There is once the possibility of using the links of the general Formula I a therapy with / J-receptor blockers if bronehial obstrictions exist at the same time or, on the other hand, the cardiac side effects in the treatment of mil / J stimulators turn off. In states of shock, mobilization of endogenous catecholamines can lead to blockages Circulation dysregulation in the peripheral vascular system occur when using the specific / i-receptor blockers of the general formula I is avoided, since a predominance of the a-sympathetic tone in the peripheral vascular system cannot occur.

According to the invention see the compounds of general formula I on various Build ways.

So you can

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

Ml;

(lh

R ¹ N CII; CH CII; O

A ¹ O \ ^:

with a compound of the general formula

R-N C-O

! I.

R ³ R ⁴

in which R ¹ and R ^{2 have} the meaning given.

(Uli R 'is a hydrogen atom and R * is a Ci-Q-alkoxy group, an optionally substituted phenoxy group, a Ci-CV-alkylthio group, an optionally substituted l'licnylthio group, an unsubstituted or substituted by R-' amino group, a hydrazino group or an Ilalogenatom or R 'and R ⁴ together have an additional CN bond and A ¹ and A- 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 the benzyl group, an alkoxycarbonyl group. / um For example the lcri-butoxycarbony group, a cycloalkyloxy-carbony group, for example the Cydopentylowcarbonylgruppe or the Cyclohexyloxverbonylgruppe. or a / x-aralkyloxycarbonyl group c. For example the benzyloxycarbonyl group, or A ¹ and A ^: together a hydrolytically cleavable protective group, such as the carbonyl, oxalyl, alkylidene or cycloalkylene group. mean, implements and, if necessary, splits off existing protective groups.

According to the definition of the radicals R 'and R ¹ , the compounds of the general formula III represent 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 111 takes place in a manner known per se for these reactions Manner, expediently in an inert organic solvent and, if desired, with heating.

In those cases in which A ¹ denotes a hydrogen atom, 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. like 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, be performed. The hydrogenolysis can be achieved by the presence of a catalyst, for example Hydrochloric acid or oxalic acid, accelerated or completed when using noble metal catalysts Hydrogenation can be used.

The hydrolysis of the protecting groups can be carried out in an acidic or alkaline medium in the customary manner ι.

But you can also

b) a phenoxyalkanolamine of the general formula

R ¹ - N CH, CH CH, - {) - <f Λ ¹ ΟΛ-

-N- C ()
R ⁵ Κ

Ι I V)

with an Amiii ilc / iillueiiie an I-Ormel

Nile·

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

According to the definition of the radicals R ^r> and R ^b , the compounds of the general formula IV represent carbamic acid esters, thiocarbamic acid esters, semicarbazides, carbamic acid halides, isocyanates or, if R ^{2 is} other than hydrogen, also ureas.

The reactions of the compounds of the general formula IV with the compounds of the general For mel V take place in known per se for these reactions ter way, expediently in an indifferent organi see small solution and, if desired, under He heat. Instead of a solvent, an excess of the amine used can also use the more general one 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. Semicarb acidic. Carbamic acid halides and isocyanates customary methods, for example from Verbin fertilize the general formula II done.

But you can also

c) in appropriately substituted phenoxyalkanol amines of the general formula

R ¹ X CH, CH Cll

Ml C NH

(VIl

in which R ¹ , R ² , A ¹ and A ^{2 have} the specified denotation, and in their corresponding isolhiourea 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 the general formula VI, for example with the help of oxides or salts of sword metals or by using oxidizing agents such as hydrogen peroxide, sodium peroxide, Potassium peroxide or nitrous acid can be carried out.

Similar to thioureas, the corresponding decay Isothiourea ether, which in the sense of the invention as starting materials for the desulfurization reactions are on an equal footing with them.

The compounds of the general formula VI can also be obtained by treatment with phosgene or phos phosphorus pentachloride can be desulfurized. The chloroformic acid obtained thereby al: intermediates amidines or carbodiimides can de by saponification or addition of water in the compounds general formula I are converted.

But you can also

d) a phenoxyalkanolamine of the general form

ν eil · cn eil · ο

Λ ¹ O A ¹

NH CNR ²

(VIII

in which R ¹ , R ', 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 ⁷ , the compounds of the general formula VII represent haloformic acid amidines, isourea esters, isothiourea esters, isourea ethers and isothiourea ethers.

The hydrolysis of the compounds of the general formula VII used as starting materials succeed 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

R ¹ N - CI I, CH Cll

Λ ¹ OA ²

NR ¹

(VIIIl

in which R ¹ , R ² , A ¹ and A ^{2 have} the meaning given, splitting off water protective groups.
But Wan can too

attach and any existing ones

809 583/13!

f) a phenoxyalkanolamine of the general formula

R'-ΛΙ-CH, -CH -CH, -O - ^{/ y}

I "I

Λ ¹ Ο — Λ-

NH

! I

Nil-C-NH

UX)

in R ¹ , R ² , A ¹ and A ^2, the meaning given is in an alkaline medium.

sit, hydrolyze and possibly existing κι But you can also

Split off protective groups. The hydrolysis of the compound g) a phenoxyalkanolamine of the general formula

fertilization of the general formula IX is expedient

R ¹ -N CU, -CH CH, -O

/ V

O- Λ-

J '

R-

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

R ¹ N CH, C]] C] U

Λ 'OA ^J

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

R- Nile,

IV)

in which R ^{2 has} the meaning given, allow to react, whereupon any Schulz groups present are split off.

In this reaction it is advisable to use an excess on the amine of the general formula V used, for example 2 to 3 moles of amine per mole of one Compound of the general formula Xl to use.

The reaction may be the solvent are carried out in an inert organic solvent at temperatures between 0 ^'1 C and the boiling temperature.

The phenoxyalkanolamine of the general formula Xl used as the starting product can, 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 CS2 in the presence of alkali and subsequent addition of ethylene chlorohydrin in one .! Indifferent organic solvents such as dimethylformamide, whereby first the correspondingly substituted phenyldithiocarbamic acid - /? - hydroxyethyl ester is obtained, which is then reacted with ethyl chloroformate in NaOH.

But you can also

i) a ureidophenyl derivative of the general formula

O CH, R "

(XII)

R- NCN ■ ''

I Il I
H ¹ O H ¹

in which R ^{2 has} the meaning given, B ¹ and B ² Λ)
S.

(Xl)

each 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 ^K the groups

(Il

CII.

(XlIiM)

CII CII. R "(XIIIbI

represents, in which R ' ^{1 represents} a halogen atom or the radical of a sulfonic acid, for example benzenesulfonic acid or p-toluenesulfonic acid, or a mixture of compounds in which R ^{8 has} the meanings given, with an amine of the general formula

R ¹ Nile A ¹

(XIV)

in which R ¹ and A ^{1 have} the meaning given, implement and split off any protective groups present.

If R ^{8 represents} the 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 the supply of heat will. 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. As a diluent or solvent, one can optionally also use the amine of the general formula XIV in excess.

If A ¹ represents an acyl group in the amine of the general formula XIV, it is advantageous to use the amine in the form of its alkali metal 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 will.

But you can also

j) a ureidophenyl derivative of the general formula

(XV)

R ² NCN- -OH

! 1Ii

B ¹ () 15-iii of R ² , B ¹ and B ^{2 have} the meaning given, with a compound of the general formula

R "CiI, ΠΙ Cll · N R '

I i (XVIi

() Λ- Λ ¹

or

CiI, CII Cll · NR ¹

! (XVIIl

OA ¹

in which R ¹ , R ⁹ , A ¹ and A- have the meaning given, or allow mixtures thereof to react and split off any protective groups present.

The reaction can expediently in the presence of an acid acceptor, such as potassium carbonate or sodium carbonate, be performed. On the other hand, one can also use an alkali salt of the phenol in question, for example the sodium or potassium salt, use as the starting compound. The reaction can take place in an inert Solvents or diluents, such as ethanol, carried out and accelerated by the supply of heat or brought to a conclusion.

But you can also

k) a ureidophenyl derivative of the general formula

R- N

O Cll · CH Cll · Nil A ¹

(Wl

in which R ² , A ² , B ¹ and B ^{2 have} the meaning given and A ^{1 is} a hydrogen atom or an optionally substituted benzyl resl, with a carbonyl compound of the general formula

R ¹ "CR"

(XIXl

in which R ¹ ″ and R ″ 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 slot groups that may be present.

Suitable reducing conditions are, for example, the presence of formic acid the method of Leuckart-Wallach.

^{If A 1 is} a hydrogen atom, suitable reducing conditions are 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 ¹⁰ and R ″ denote alkyl radicals or, together with the C atom of the carbonyl group, a cycloalkyl radical, an excess of the carbonyl compound of the general formula XlX can also be used as the solvent.

^{If A 1 is} a hydrogen atom, suitable reducing conditions are also created by the presence of di-metal hydrides, such as alkali borohydride, 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 should not be hydrogenated, it is advisable to reduce with di-metal hydrides such as alkali borohydride.

The compounds of the general formula XVIII used as starting compounds can of ^{course also be generated in situ if A 2} and A ^{1 are} hydrogen, for example by reducing the corresponding nc-diazoketones, (X-azidoketones, <YC) ximinoketonc, ix -Nitroketones, (\ -nitrosoketones, rv-nitro alcohols, cyanohydrins or acyl cyanides.

But you can also

1) a ureidophenyl derivative of the general formula

O A-

R- NCN

I Il I

B 'O B ²

O Cll · CH Cll · Nil 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 , _{χ (χχ])}

in which R ^{1 has} the meaning given and X is a halogen atom, an alkylsulfal radical or the radical of a sulfonic acid, such as the benzenesulfonyl or toluenesulfonyl radical, react and split off any protective groups present.
If A ^{1 is} an acyl group, the ver

bonds of the general formula XX can also be used in the form of their alkali salts.

An acid acceptor, 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 Äihunol. carried out and accelerated by the supply of heat or / u to the end.

But you can also

m) a ureidophenyl derivative of the general formula

R ² - NCN -

■ i:

B ¹ O Ii ²

OR ¹

O CU, C CH, N .V

(XXIlI

in which R ¹ , R ² , A ¹ , B ¹ and B ^{2 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 Dr 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 isopropoxide or magnesium isopropoxide. be carried out according to the method of Meerwein-Ponndorf-Verley or its modifications.

But you can also

n) a Üreidophernl derivative of the general formula

R ^: NCN
H ' () B ^:

O CH.

NO'
Y

(XXIIIi

in the R ¹ , R ² . 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 ¹ -

\ /
C.

R '

(XXIVi

means in which R ¹² and R ^IJ each have a hydrogen atom or a Ci-C-alkyl radical or R ¹² and R ^1! together denote the group - (CH2) ,, -, where η stands for the m numbers 4 to 6, subject to hydrolysis and split off any protective groups present.

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 XXlII can be carried out both in an alkaline as well as an acidic medium can be carried out during the hydrolysis of the Oxazolidines 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 ^: NH C - Ml

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 a Λ-arylalkyl group, such as the benzyl group, an alkoxycarbonyl group, a cycloalkyloxycarbonyl group or a Λ-aralkyloxycarbonyl group, and where at least one of R ¹⁴ and R ^{15 is} a hydrogenolytically cleavable group, R ¹

O CHj CII Cll · NR '
OR ¹⁴

(XXVl

subject to hydrogenolysis. The hydrogenolysis of the compounds of the general formula XXV can by means of hydrogen in the presence of a hydrogenation catalyst such as platinum, palladium or Raney nickel, be performed.

But you can also

p) a ureidophenyl derivative of the general formula

R ¹

R ² NC - N

: Γ 1

B ¹ O ti ¹

■ Ο — CH ₂ CH -CH ₂ - NR '
OR ¹ "

(XXVIl

in which R ¹ , R ² , B 'and B ^{2 have} the meaning given and R ¹⁶ and R ¹⁷ each represent a hydrogen atom or a hydrolytically cleavable 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 cyclohexyloxycarbonyl group, or an aralkyl

oxycarbonyl group, for example the benzyloxycarbonyl 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 either in an acidic or in an alkaline medium.

But you can also

q) a ureidophenyl derivative of the general formula

R ² -N-C-N
R ^1S OR ^{| q)} -CH ₂ -CHOH-CH ₂ -NH-R ¹

(XXVII)

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

and R ' ⁸ and R ¹⁹ each represent a hydrogen atom or an acyl group, for example an aliphatic or aromatic acyl group, and where at least one of the radicals R ¹⁸ and R ^{19 represents} an acyl group.

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

R ² -N-C-N ~ <>

I Il I ^x = ^/

B ¹ OB ²

in which R ² , R ¹⁰ , R ″, 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,

O-CH, -NH R ¹ "
R "

(XXVlII)

be performed.

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

R ² —N — C — N — f? —O — CH, -CHOH-C —NH,

I Il I

B ^! OB ² (XXIX)

in which R ² , B ¹ and B ^{2 have} the specified meaning of the general formula XV, in which R ² , B ¹ and B ^{2 have} the

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

But you can also

s) a ureidophenyl derivative of the general formula

OA ² R ¹

R ² —N— C—

I Il I

B ¹ OB ²

I!

O-CH ₂ -CH-CNA ³
O

(XXX)

in which R ', R ² , A ² , A ³ , B' and B ² the specified meaning The ureidophenyl used as the starting product

own, hydrogenate and optionally present 50 derivative of the general formula XXX can be used for

split off protective groups. game by implementing a connection of the general

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

O-A ²
0-CH ₂ -CH-COOR ²⁰

B ¹

B ²

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

R ¹ —NH-A ³ CXXXl)

represents, with

(XXXII)

in which R ¹ and A ^{3 have} the meaning given, are obtained. But you can also

2?

t) a ureidophenyl derivative of the general formula

R ² —Ν — C -
B 'B ²

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

R'-NH-A ^J

(XXXIl)

in which R 'and A ^{3 have} the meaning given, bring them to reaction under reducing conditions and split off any protective groups present.

Suitable reducing conditions provide the presence of formic acid according to the method von Leuckart-Wallach.

O
R ² -N-C-N

I I

B 'B ²

in which Ri, R ² , A ² , B ¹ and B ^{2 have} the meaning given, reduce and split off any protective groups 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

R ² -N-C-N
B ¹ B ²

Ο — Λ ²

O-CH ₁ -CH-CHO

(XXXlIl)

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

^{If A 3 is} a hydrogen atom, suitable reducing conditions are 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 also

u) a ureidophenyl derivative of the general formula

Ο-Λ ²

CH, - CH-CH = NR ¹

(XXXlV)

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 solvent or diluent.

But you can also

v) a ureidophenyl derivative of the general formula

O-A ²

VQ-CH ₂ -CH-CH ₂

R "

R "

CKXXV)

in which R ² , A ² , B 'and B ² as well as Ri ″ and R ^{11 have} the meaning given, reduce and split off any protective groups 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, 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 Solvents or diluents are carried out.

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 widely, with finding the optimal one in each case Conditions is professional

Depending on the character of the starting materials, one or the other of the processes described can be

In some 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 by selecting suitable protective groups and thus to

V) to increase the yield or to manufacture the product using 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 in their acid addition

b5 salts are transferred.

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

If racemic compounds of the general formula I are obtained, they can be broken down into their optically active forms by known methods. Also, optically active compounds can be obtained in the reaction of the formula I but also through the use ^r> optically active starting compounds.

example 1

35.5 g of l- (4-ureidophenoxy) -2,3-epoxypropane and ι ο 142 ml of isopropylamine were stirred at room temperature for 40 hours. Then the excess of isopropylamine was distilled off, the residue dissolved in dilute hydrochloric acid, the solution is filtered and precipitated blank the dissolved base by adding solid potassium carbonate · ι ~>. The precipitate, which consists of 1- (4-ureidophenoxy) -2-hydroxy-3-isopropylaminopropane, had a melting point of 141.5 to 142.5 ° C. after recrystallization from ethanol.

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, by adding μ ethereal hydrochloric acid, the 1- (4-ureidophenoxy) -2-hydroxy-3-tert-butylaminopropane hydrochloride was precipitated, which after recrystallization from aqueous methanol at 207 ⁰ C (decomp.) Melted.

B is ρ ie 1 3 ^! '

26 g of N-methyl-N '- [4- (2,3-epoxypropoxy) phenyl] urea, 50 ml of isopropylamine and 100 ml of isopropanol were refluxed for 5 hours. After distilling off the solvent and the Excess isopropylamine obtained residue was dissolved in dilute hydrochloric acid, the solution filtered and the dissolved substance precipitated by adding solid potassium carbonate. After recrystallization the 1 - [4- (3-methylureido) phenoxy] -2-hydroxy-3-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:

A mixture of 49.8 g of N-methyl-N '- (p-hydroxyphenyl) urea, 150 ml of 5N-KOH and 166 g of epichlorohydrin was stirred for fi hours at room temperature. Then, the precipitated N-methyl-N 'was - [4- (2,3-epoxypropoxy) -phenyl] -urea suction filtered washed with water and dried The crude product, melting at 139-143 ⁰ C, was used without further purification

Example 4

10 g of N-ethyl-N '- [4- (23-epoxypropoxy) phenyl] urea and 50 ml of tert-butylamine were refluxed for 8 hours after the distillation of the excess tert-butylamine obtained residue was dissolved in dilute hydrochloric acid, the undissolved material filtered off, the base, precipitated with potassium carbonate, filtered off with suction, dried and, for purification, from butyl acetate recrystallized that produced in this way

60

65 L- [4- (3-Ethylureido) phenoxy] -2-hydroxy-3-tert-butylaminopropane melted at 122-124 ° C.

The N-ethyl-N '- [4- (2,3-epoxypropoxy) phenyl] urea used as the starting product, which melted after recrystallization from ethanol at 154 to 156.5 ° C, was analogous to the N-methyl-N '- [4- (2,3-epoxypropoxy) phenyl] urea manufactured.

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. The excess cyclohexylamine was then distilled off, the residue that remained was dissolved in dilute hydrochloric acid and the solution was filtered. Which was [4- (3-cyclohexylureido) -phenoxy] -2-hydroxy-3-isopropylaminopropan precipitated by addition of sodium hydroxide l- which melted after recrystallization from isopropanol at 157-160 ⁰ C.

Example 6

A mixture of 3 g of N-methyl-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 was 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-butyiaminopropane from, which melted after recrystallization from isopropanol at 140 to 143 ° C.

Example 7

0.5 g 1- (4-aminophenoxy) -2-hydroxy-3-isopropylaminopropane 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 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 is dissolved in water and 86 ml of 1N hydrochloric acid and the solution is filtered by adding 1- [4- (3-CyclohexyIureido) -phenoxy] -2-hydroxy-3-tert-butylaminopropane was sodium hydroxide solution precipitated which, after recrystallization from isopropanol, melted 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:

92.5 g were added to a solution of 40 g of N-cyclohexyl-N '- (p-oxyphenyl) urea in 50 ml of 5η potassium hydroxide solution Epichlorohydrin given and the whole thing for 16 hours

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

Example 9

A mixture of 10 g of 1- (4-ureidophenoxy) -2-hydroxy-3-isopropylaminopropane and 10 g of n-hexylamine hydrochloride were heated to 150 ° C. for 3 hours. The reaction product was dissolved in 150 ml 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 fell which melted after recrystallization from ethanol - water i: 1 at 146 to 149 "C.

Example 10

1.175 g of 1- (4-phenoxycarbonylaminophenoxy) -2-hydroxy-3-tert-butylaminopropane hydrochloride, 8 ml of methanol, 2.93 ml of methanolic sodium methylate solution (1 normal) and 2.67 ml of methanolic cyclohexylamine solution (1 normal) were combined and stirred for 8 hours at room temperature. After standing overnight, the mixture 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 1η hydrochloric acid. Then, 1- [4- (3-cyclohexylureido) phenoxy] -2-hydroxy-3-tert-butylaminojo propane precipitated by addition of sodium hydroxide to pH 12, which is melted after the Ümkristallisation from isopropanol at 143-144 ⁰ C.

The 1- (4-phenoxycarbonylaminophenoxy) -2-hydroxy-3-tert-butylaminopropane hydrochloride used as the starting product was made 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 l- (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 were methanol and excess amine is distilled off, the residue is dissolved in water with the addition of hydrochloric acid at pH 4, the The solution is filtered and the base is precipitated by adding sodium hydroxide solution to pH 12. The precipitate that came out 1- [4- (3-Isopropylureido) phenoxy] -2-hydroxy-3-isopropylaminopropane was recrystallized from isopropanol and then melted at 154-156 ° C

The following compounds ω manufactured:

1- [4- (3-allylureido) phenoxy] -2-hydroxy-3-isopropylaminopropane, M.p. 145 to 147 ° C

1 - [^ - (S-sec-ButylureidoJ-phenoxy ^ -hydroxy-3-isopropylaminopropan it, F. 141.5 to 143 ^C 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:

20 g of l- (4-aminophenoxy) -2-hydroxy-3-isopropylaminopropane were dissolved in 100 ml of acetone with the addition of 7 ml Dissolved glacial acetic acid and a solution of 13.9 g of phenyl chloroformate in 50 ml within 40 minutes Acetone was added dropwise. The temperature was kept below 30 ° C. The mixture was then stirred for a further 1 hour and then the deposited l- (4-phenoxycarbonylaminophenoxy) -2-hydroxy-3-isopropylamino- Propane hydrochloride is filtered off, which melted after recrystallization from methanol at 199 to 202 ° C.

Example 12

2 g of l- (4-phenoxycarbonylaminophenoxy) -2-hydroxy-3-isopropylaminopropane hydrochloride, 10 ml of methanol and 2.5 ml of crotylamine were refluxed for 50 minutes. 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) and the solution filtered. After adding sodium hydroxide solution to pH 12, the 1- [4- (3-CrotyI-ureido) -phenoxy] -2-hydroxy-3-isopropylaminopropane became precipitated, which melted at 140.5 to 143.5 ° C. after recrystallization from isopropanol.

Using cyclopentylamine instead of crotylamine obtained according to the above procedure, the 1 - [4- (3-Cyclopentylureido) -phenoxy] -2-hydroxy-3-isopropylaminpropan a melting point of 157.5 to 16O ⁰ C.

Example 13

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 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 after recrystallization from isopropanol at 145 to 148.degree melted.

Following the same procedure using the appropriate amines, the following compounds were obtained of the general formula I prepared: 1- [4- (3-Cyclopropylureido) -phenoxy] -2-hydroxy-3-isopropyl-aminopropane, M.p. 141 to 143.5 ° C 1- [4- (3-hexen- (2) -yl-ureido) -phenoxy] -2-hydroxy-3-isopropyl-aminopropane, M.p. 157.5 to 159.5 ° C

Example 14

10 g of N-cyclohexyl-N '- [4- {23-epoxypropoxy) phenyl] urea, 10 ml of isopropylamine and 50 ml of methanol 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 up to pH 12 was 1- [4- (3-cyclohexylureido) phenoxy] -2-hydroxy-3-isopropylaminopropane precipitated which after recrystallization from ethanol at 157 melted to 160 ° C.

Using N-cyclohexyl-N '- {4- (2,3-epoxypropoxy) phenyl] urea and suitable amines in an analogous manner were the following compounds made of the general formula I:

l- [4- (3-cyclohexylureido) -phenoxy] -2-hydroxy-3-sec-butylaminopropan, F. 127-130 ⁰ C.

l- [4- (3-cyclohexylureido) -phenoxy] -2-hydroxy-3-isoamyiaminopropan, F. 157-159 ⁰ C.

1- [4- (3-Cyclohexylureido) phenoxy] -2-hydroxy-3- (i, l, 3,3-tetramethylbutyl) aminopropane, F. 131 to 133.5 "C

l - ^ - p-CyclohexylureidoJ-phenoxyJ ^ -hydroxy-S-isopropylaminopropane, F. 157 to 160 ° C.

Example 15

5 g l-l / l-p-CyclohexylureidoJ-phenoxy ^ -hydroxy-3- (N-benzyl-N-tert-butylamino) -propane, 100 ml of glacial acetic acid and 0.5 g of platinum dioxide were added for 6 hours at room temperature in a hydrogen atmosphere shaken The catalyst was then filtered off with suction, the glacial acetic acid was distilled off in vacuo and the the remaining residue was dissolved in 250 ml of water with the addition of hydrochloric acid (pH 2). The solution was filtered and by adding sodium hydroxide solution to pH 12 that

butylaminopropane precipitated, which melted after recrystallization from isopropanol at 142 to 144.5 ° C.

The debenzylation of l- [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 l- [4- (3-cyclohexylureido) phenoxy] -2-hydroxy-3- (N-benzyl-N-tert- butylamino) propane was produced as follows:

39.8 g of N-cyclohexyl-N '- [4- (2,3-epoxypropoxy) phenyl] urea, 24.5 g of N-benzyl-N-tert-butylamine and 150 ml of ethanol were refluxed for 17 hours The solvent was then distilled off, the 1 - [4- (3-Cydohexylureido) phenoxy] -2-hydroxy-3- (N-benzyI-N-tert-butylamino) propane remained as resin, 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 l- [4- (3-Cyclohexylureido) phenoxy] -2-hydrox> '- 3-aminopropane hydrochloride, 20 ml of acetone and 1.42 ml of methanolic sodium methylate solution (1 normal) were combined and refluxed for 1 hour. Then, while cooling with ice, 2 g of sodium borohydride were added, the mixture was stirred for 10 minutes and after standing The excess sodium borohydride was destroyed with 10 ml of dilute hydrochloric acid overnight Methanol is distilled off, the residue dissolved in 50 ml of water, the solution filtered and the 1- [4- (3-cyclohexylureido) phenoxy] -2-hydroxy-3-isopropylaminopropane precipitated by adding sodium hydroxide solution to pH 12, which after recrystallization from isopropanol b-.i ij7 melted to 160 ° C.

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

2A g of N-cyclohexyl-N '- [4- (23-epoxypropoxy) -phenylj-urea and 800 ml of a solution of ammonia in methanol (18.5 g of ammonia / 100 ml of solution) were then heated ^{to 50 ° C. for 32 hours} 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- ^ -p-cyclohexylureidoJ-phenoxyj ^ -hydroxy-S-ainopropane hydrochloride precipitated , which melted after recrystallization from dimethylformamide at 220 to 222 ° C.

Example 17

3.3 g of 1 - [4- (3-CycIohexylureido) phenoxy] -2-hydroxy-3-chloropropane, 5.9 g of isopropylamine and 50 ml of methanol were heated to 100 ° C. in an autoclave for 12.5 hours The solvent and excess isopropylamine are 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 pH 12. A precipitate of 1- [4- (3-cyclohexylureido) phenoxy] -2 fell -hydroxy-3-isopropyl-aminopropane, which melted ^{at 157 to 160 0 C after recrystallization from isopropanol.}

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

30 g of N-cyclohexyl-N '- [4- (2,3-epoxypropoxy) phenyl] urea, 60 ml of methanol and 20 ml of concentrated hydrochloric acid were combined and stored for 24 hours at room temperature ditched. Then by addition

jo of 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.degree 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, along with the alcohol and excess isopropyl bromide distilled off and the deposited 1- [4- (3-cyclohexylureido) phenoxy] -2-hydroxy-3-isopropylamino- Filtered off propane, which melted at 156 to 159 ° C after recrystallization from isopropanol.

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 were heated to the boil, resulting in a bright solution. When cooling down The l- [4- {3-Cyclohexylureido) phenoxy] -2-hydroxy-3-tert-butylaminopropane benzoate separated from melting point 194 to 198 ° C.

If 0.2 g of succinic acid is used instead of 0.4 g of benzoic acid, one obtains in an analogous manner the neutral.! - ^ - (S-CyclohexylureidoJ-phenoxyJ ^ -hydroxy-3-tert-butylaminopropane succinate from melting point 202 to 204 ° C.

bo When using 03 g of tartaric acid instead of 0.4 g of benzoic acid is obtained in a similar manner to the neutral 1- [4- (3-cyclohexylureido) phenoxy] -2-hydroxy-3-tert-butylaminopropane tartrate from melting point 213 to 215 ° C.

B e i s ρ i e 1 20

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

809 583/135

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

If 0.4 g of salicylic acid is used instead of 0.2 ml of glacial acetic acid, this is obtained in an analogous manner 1- [4- (3-Cyclohexylureido) phenoxy] -2-hydroxy-3-tert-butylaminopropane salicylate after recrystallization from isopropanol at 133 to 135 ° C melts ι ο

Example 21

7.2 g of l-l / HS-CyclohexyhireidoJ-phenoxyj ^ -hydroxy-3-tert-butylaminopropane, 36 ml of water and 10 ml of 2N nitric acid were heated to 80 ° C. The solution filtered and cooled. The 1- [4- (3-cyclohexylureido) phenoxy] -2-hydroxy-3-tert-butylaminopropane nitrate separated out, which after recrystallization from isopropanol / water 98: 2 at 172 to 176 ° C melted.

Use 2N nitric acid instead of 10 ml 2 ml of concentrated hydrochloric acid, then the 1- [4- (3-cyclohexylureido) phenoxy] -2-hydroxy-3-tert-butylaminopropane hydrochloride is obtained, which after recrystallization from isopropanol-water 98: 2 at 208 melts up to 212.5 ° C

Example 22

10 g of 1- [4- (3-cyclohexylureido) phenoxy] -2-hydroxy-3-tert-butylaminopropane were dissolved in 50 ml of methanol solved. 1.55 ml of 17.8 N sulfuric acid were added to the solution admitted. The neutral l- [4- (3-cyclo-

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

Example 23

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

Example 24

A mixture of 2.4 g of 1- (4-aminophenoxy) -2-hydroxy-3-tert-butylaminopropane, 24 ml of acetone and 1.25 g of cyclohexyl isocyanate was refluxed for 1 hour. Then the solvent was removed 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, the 1- [4- (3-cyclohexylureido) phenoxy] -2-hydroxy-3-tert-butylaminopropane was then precipitated, which after recrystallization from isopropanol at 142 to 143.5 ° C melted.

The same result is achieved if the reaction is carried out in the presence of glacial acetic acid. Per Mol of 1 - (4-aminophenoxy) -2-hydroxy-3-tert.-butyl-

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

Example 25

4.8 g of l- (4-aminophenoxy) -2-hydroxy-3-tert-butylaminopropane were added with stirring at room temperature in a mixture of 48 ml of water and 20 ml 1 η-hydrochloric acid dissolved. Then 2.5 g of cyclohexyl isocyanate were added and the whole for 15 hours

30th

35 Stirred at room temperature. Then the solution was sucked in and the 1- [4- {3-cyclohexylureido) phenoxy] -2-hydroxy-3-tert-butylaminopropane 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-hydroxy-3-isopropylaiTiino-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 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, the l- (4-

Ureidophenoxy) -2-hydroxy-3-isopropylaminopropane precipitated which melted after recrystallization from isopropanol at 141 to 142 ° C.

Example 27

13 g of glycid-p-toluenesulfonic acid ester, 1.35 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. The methanol was then distilled off in a water jet pump vacuum, and the residue obtained was 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 The residue was extracted in the cold with a mixture of 30 ml of water and 5 ml of 1η hydrochloric acid. The solution was vacuumed clean and the 1- [4- (3-cyclohexylureido) phenoxy] -2-hydroxy-3-tert-butylaminopropane was precipitated by adding dilute sodium hydroxide solution after recrystallization from isopropanol at 142 to 144 ° C melted.

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 at room temperature for 24 hours, the deposited l- [4- (3-Cyclo-

hexylureido) phenoxy] -2-hydroxy-3-tert-butylaminopropane 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 out.

Claims (9)

Claims: Ureidophenoxy-alkanolamines of the general funnel R ¹ Nile C - Nile ^{; /} Il ο ,. O ClI. CHOIl CH> Nile R ' in which R ^{1 is} a branched Ci-Cn-alkyl radical and R- is a hydrogen atom, a Ci-Cb-n-alkyl radical, a branched C ₍ —Cs-alkyl radical, a Ci-C? - cycloalkyl radical or a Cj-C-alkenyl radical , 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-byroxy-3-isopropylaminopropane. 4. 1 [4- (3-Ethylureido) -pherioxy] -2-hydroxy-3-liter-butylaminopropane. 5. 1- [4- (3-Methylureido) -phynoxy] -2-hydroxy-3-tert-butylaminopropane. 6. 1 [4- (3-Ethylureido) phenoxy] -2-hydroxy-3-isopropylaminopropane. 7. 1 [4- (3-Cyelohexylureido) phenoxy] -2-hydroxy-3-tert-butylaminopropane. 8. Process for the preparation of ureidophenoxyalkanolamines, their optically active forms and their salts with physiologically compatible inorganic or organic acids according to Claims 1 to 7, characterized in that either a) a phenoxyulkanolamine of the general formula R 'N dl CIl CIl, Λ ¹ () / V Nile, with a compound of the general formula R- i I R ¹ R ⁴ C o in which R ¹ and R ^{2 have} the meaning given, R ^{1 is} a hydrogen atom and R ^{4 is} a Ci-Ct-alkoxy group, an optionally substituted phenoxy group, cine Ci - CVAIkylthiogruppe, an optionally substituted phenylthio group, an unsubstituicrtc or amino group substituted ^{by R 2, a} Hydrazinogruppc or a halogen atom or R 'and R ⁴ together represent an additional CN bond and Λ ¹ and Λ- each represent a hydrogen atom or a hydrolytically or hydrogenolyiisch cleavable school / group or A ¹ and A- together represent a hydrolytically cleavable protective group optionally existing protective groups are split off, or that one b) a phenoxyalkariolamine of the general formula R 'N (II, CII, CII W o N C R " UVi mil Amiii i \ i: r alliicincinen Immcl R ¹ Ml, in which R ¹ , R-, Λ ¹ and Λ- have the meaning given, R 'is a hydrogen aiom and R' ^{1 is} a Ci - d-Alkoxygnippe, an optionally substiliiierle phenoxy group, a (ι - Ci-alkylthio group, an optionally substituted l'henylthio group, a llydra / inognippe or a lalugeuaioin. oiler, if R- 'is different; ils hydrogen also means an amino group oiler R' and R "/ i together mean an additional C -N bond, around and around v <absent school fluids split off, or where one c) in appropriately substituted phenoxyalkanolaniines of the general formula R ' N CU, CU i! CH ₂ Nile C NH Il s (Vl) in which R ', R-', A ¹ and A- 'have the meaning given, and their corresponding m isothiourea ethers replace the sulfur or the thioether group with oxygen and R ¹ N CII. CIl CH. Λ ^; in the R ¹ . R-, A ¹ and A- have the meaning given and R ^{7 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 have 1 to 4 carbon atoms, optionally existing protecting groups are split off, or that one d) a phenoxyalkanolamine of the general formula NII ι
C. N
R- (VHi indicates, hydrolysed and possibly existing groups of scuffs abspaliel, or that man e) to a phenoxyalkanolamine of the general formula R 'N CII, CII CW, ι "ι Λ ¹ (') Λ- in which R ¹ , R-, A ¹ and A- have the meaning given. Water systems and splitting off any protective groups that may be present. N C NR ' (VHIl R ¹ N CII, CII CH, Λ ¹ Ο V ' in the Ri, R- '. A ¹ and A- have the meaning given, hydrolyzed and split off any protective grips that are present! Or or that one f) a phenoxyalkanolamine of the general formula NII Ii Nile C Nile R ' that he g) a phenoxyalkanolamine of the general formula R ¹ N CII, CII CII. O Λ ' IXl in which R ¹ , R-, A ¹ and A- 'have the meaning given, split off stranded and any protective group present!), or that h) a phenoxyalkanolamine of the general formula R ¹ N CII. CIi CH, O V IXIl in which R ¹ , Λ ¹ and A- have the meaning given, with an amine of the general formula R 'Nile. (Vi in which R- has the meaning given, react, whereupon one which may be present Protection group)! split off, or dal! man i) a ureidophenyl derivative of the general formula R- NC \
H '() U- ixiii in which R- has the meaning given, B ¹ and B ² each individually a hydrogen atom or a hydrolytically removable protective group or B ¹ and B- together a hydrolytically removable protective group and R ⁸ the groups CII CiI, or CM
O CH, R " (XIIhD
(XIII St. represents, in which R ^q 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 Λ ' (XIYi in which R ¹ and A ^{1 have} the meaning given, reacts and spies out any protective groups present, or j) a ureidophenyl derivative of the general Torrn el RNCN
H ¹ O H ¹ Oll (XYl in which R-, B ¹ and B- have the meaning given, with a compound of the general formula R "Cll • CH (H;
ο V or (H ("ff (fl \ R ¹ (XYIi R '
(XYIIi in the R '. R ^M. A ¹ and A- have the meaning given, or can be reacted with mixtures of compounds of the general formulas XVI and XVII and any protective groups present are split off, or one can k) a ureidophene derivative of the general formula R ^: --NC -N
B 'O B- O CII; CII CII-NH V IXY! in which R ² , A ² , B ¹ and B ^{2 have} the abovementioned meaning and A ³ denotes a hydrogen atom or an optionally substituted benzyl radical, with a carbonyl compound of the general formula O
R ¹ "CR" IXIXI 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, reacts under reducing conditions and eliminates any protective groups present, or that one
I) a ureidophenyl derivative of the general formula R- -N -C-N-- i ii ί
B ¹ OB ^: O Λ- ■■ () ■ CH, (H -CM, NH A ¹ (XXl in which R ² , A ', A-', B ¹ and B ^{2 have} the meaning given, with an alkylating agent of the general formula R ¹ X (XXlI in which R ^{1 has} the meaning given and X denotes a halogen atom or an alkyl sulfate residue or the residue of a sulfonic acid, converts and removes any protective reds which may be present. or that one R- NCNH ¹ () U- in the K ¹ , R-. Λ ¹ . H ¹ and B- have the meaning given, hydrogenated and splitting off any slot groups present, or in) an Ireidophenyl derivative of the general formula OR ¹ ; l ') CM, (' ■ CII, N (XXII) that he n) a Ireidophenyl derivative of the general formula \ CNH ¹ () Ii '\ R ¹ O Cll IXXIIIl 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 Cj group means in which R ¹ - and R ^1! each a hydrogen atom or a (Ί - CVAIkylrest or R ¹ - and R "together represent the group - (CM;) ,, -, where /) stands for the numbers 4 to 6, is subjected to hydrolysis and optionally before- (XXIVi R " handcne. Protective groups split off, or because: man o) a urcidophenyl derivative of the more general formula Nil C Ml O Cll · CM (II; N
OR " (XXVi in which R ¹ and R- have the meaning given and R ¹ 'and R ^r> each denote a water loffate or a hydrogenolytically cleavable group and where at least one of the radicals R ¹⁴ and R ^r> denotes a hydrogenolytically cleavable group which is subjected to hydrogenolysis, or that p) a ureidophenyl-Dc rival of the general formula R ^: NCNB '() BR ¹ O CII; CM CH; N O R '"R ¹ " IXXVI) in the R ¹ . R-, B ¹ and H- have the meaning given and R ^lb and R ¹⁷ each represent a hydrogen atom or a hydrolytically cleavable group and where at least one of the radicals R ^lf> and R ¹⁷ denotes a hydrolytically cleavable group which is subjected to hydrolysis and optionally splitting off any protective groups present, or q) a ureidophenyl derivative of the general formula R ² NCN ί Il I R ^lv OR ¹ "O ClN CHOH-CH, NH-R ¹ (XXVII) in which R ¹ and R ^{2 have} the meaning given and R ¹⁸ and R ¹⁹ each denote a hydrogen atom or an acyl group and where at least one of the radicals R ¹⁸ and R ¹⁹ denotes an acyl group, is subjected to hydrolysis, or that one r) a Ireidophenyl derivative of the general formula IO R- 'NC N \ Ii I} ¹ OH ^J O CII, NII R ¹ " IXXVI in which R ² , R "', R", H ¹ and B ^? have the stated η meaning, hydrogenated and optionally splitting off Schui groups, or that one s) a ureidophenyl derivative of the general formula R ^J NCN i Ü ^: B ¹ OH ^J O A 'R' o cn., cn c ν OA ¹ IXXXl in which R ¹ , RJ, Λ- ', Λ', Ii 'and IP have the meaning given, hydrogenated and possibly splitting off existing school / groups, oiler dal.! man 1) a ureidophenyl derivative of the general formula R- 'NC N
B ¹ O IV OA ¹ o cn. cn (iio IXXXIIII in which R- ', A-', B ¹ and B- have the meaning given, with an amine of the general formula _K , _{N || v} , XXXIi, in which R ¹ and Λ ^{1 have} the meaning given, reacts under reducing conditions and splitting off any protective groups present, or that one
u) a jreidophenyl derivative of the general formula R ' NC N i il i B ¹ OB o (ii, cn cn ν r ¹ iXXXIVi in which R ', R ² , A ² , B ¹ and B ^{2 have} the meaning given, reduced and any protective groups present, or R- N C B'O that he
ν) a ureidophenyl derivative of the general IXXXV) splits, or O CII .. l-ormel II. N C. R " () A ' R " M ■ ·
I.
ι
B- cn ( in which R ² , A ", B ¹ and B ² and R ¹⁰ and R" have the meaning given, reduced and any protective groups which may be present are split off and the compounds of general formula 1 obtained with physiologically compatible ones inorganic or organic acids in their acid addition salts or obtained Acid addition salts of compounds of the general formula I with inorganic bases are converted into the free compounds and optionally Raccmatc broken down 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.