CH618417A5 - Process for the preparation of novel hydroxyamines - Google Patents

Description

The present invention relates to a method for which diseases can serve. The new compounds have the position of new hydroxy amines with a blocking effect on the formula I the / 5 receptors which are used for the treatment of cardiovascular

R7

OUR3 R5 L ^ r0

(R1) (R2) ArOCM_ÌHCHN - C - (CH-) - Y— (f, 7 ^ (I),

2 A «rb 2n ^ = Y q

(CH.) R

/. m in which R1 in the 2- or 3-position is the group -CH2CH = CH2, -OCH2CH = CH2, -OCH2C = CH, alkoxyalkyl, H0CH2CH2NHC0CH20, CH30CH2CH2NHC0CH20- or -CH = NOR, with R being hydrogen or alkyl having 1 to 6 carbon atoms , R2 hydrogen, halogen, alkyl or alkoxy, R3 hydrogen, R4 hydrogen, R5 hydrogen or methyl and R6 hydrogen, R7 and R8 hydrogen, R9 hydrogen or-CONR10Rn, with R10 and R11 individually hydrogen, Y -O- or -CH2- , n is an integer from 0 to 5, m is an integer from 0 to 2 and Ar is the phenyl group.

R1 as alkoxyalkyl has up to 7 carbon atoms, preferably up to 4 carbon atoms in each alkyl chain and each alkyl can be straight-chain or branched. Alkoxyalkyl R1 is therefore, for example, methoxymethyl, methoxyethyl, ethoxyethyl, isopropoxyethyl, n-propoxymethyl or 60 tert-butyloxymethyl.

R1 can be —CH = NOR, where R is hydrogen or an alkyl group with 1 to 6 carbon atoms, for example isonitrosomethyl, methylisonitrosomethyl, ethylisonitrosomethyl, n-propylisonitrosomethyl, isopropylisonitro-65 somethyl.

R2 as halogen is, for example, chlorine, fluorine or bromine.

R2 as alkyl has up to 7, preferably up to 4 carbon atoms and is straight-chain or branched and can be

3rd

618 417

for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl.

R2 as alkoxy has up to 7 carbon atoms, preferably up to 4 carbon atoms and is straight-chain or branched and can be, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy or tert-butoxy.

m is preferably 0 or 1.

n is preferably 1 or 2.

The state of the art is described, for example, by BE patent specification No. 750 450, NL patent application no. 7 106 642 and DE laid-open specifications 2 135 678 and

2,357,849.

In these publications, β-receptor blocking compounds are described which have a carbamyl-substituted phenoxyethylamino group.

The inventive method for the preparation of new hydroxy amines of formula I is defined in claim 1.

The new compounds obtainable according to the invention have valuable pharmacological properties. For example, they block the heart /? - receptors, which is determined by determining the antagonism of tachycardia after intravenous injection of 0.5 ng / kg of d / l-isoproterenol sulfate in an anesthetized cat at an intravenous dose of

3 mg / kg or more can be shown. They are therefore selective for the heart.

The new compounds obtainable according to the invention can be used as cardioselective antagonists of adrenergic / 3-receptor stimulators, for example for the treatment of exogenous or endogenously caused arrhythmias and angina pectoris. They can also be used as intermediates for the preparation of other valuable pharmacologically active compounds.

The following compounds are particularly preferred:

1. l- [2- (4-carbamylphenoxy) ethylamino] -3- (2-allylphenoxy) propanol- (2),

2. l- [2- (4-carbamylphenoxy) ethylamino] -3- (2-meth-oxyethyl) phenoxy-propanol- (2),

3. 1 - [1-methyl-2 - (4-carbamylphenoxy) ethylamino] -3 - (2 -allylphenoxy) propanol- (2),

4. 1 - [1-methyl-2- (2-methylphenoxy) ethylamino] -3- (2-allylphenoxy) propanol- (2),

5. l- [l-methyl-2- (4-methylphenoxy) ethylamino] -3- (2-allylphenoxy) propanol- (2),

6. l- [l-methyl-2- (4-carbamylphenoxy) ethylamino] -3- (2-methylisonitrosomethylphenoxy) propanol- (2),

7. l- [2- (4-Carbamylphenoxy) ethylamino] -3- (3-allylphenoxy) propanol- (2).

A reactive, esterified hydroxyl group is in particular a hydroxyl group which is mixed with a strong, inorganic or organic acid, preferably a hydrohalic acid, in particular hydrochloric acid, hydrobromic acid or hydroiodic acid, or sulfuric acid or a strong organic sulfonic acid, in particular a strong aromatic sulfonic acid, particularly preferably benzene sulfonic acid , 4-bromobenzenesulfonic acid or 4-toluenesulfonic acid, is esterified. Z is therefore preferably chlorine, bromine or iodine.

The reaction is carried out in a conventional manner. If a reactive ester is used as the starting material, the reaction is preferably carried out in the presence of a basic condensing agent and / or with an excess of amine. Suitable basic condensing agents include alkali metal hydroxides, in particular sodium or potassium hydroxide, alkali metal carbonates, preferably potassium carbonate, and alkali metal alcoholates, in particular sodium methylate, potassium ethylate or potassium tert-butoxide.

Within the definition of the end products, the sub-

Stituents of the compounds are varied, just as the compounds obtained can be introduced, split off or converted into other end products by methods known per se.

For example, it is possible to use C = C double bonds or C = C triple bonds using hydrogen in the presence of a hydrogenation catalyst, e.g. B. platinum, palladium or nickel, preferably Raney nickel, to catalytically hydrogenate to C — C single bonds. Care must be taken not to reduce other reducible groups.

In compounds obtained which contain a C = C triple bond, this can be converted into C = C double bonds and, if desired, hydrogenated stereospecifically to C = C-cis or C = C-trans double bonds. The hydrogenation of a C = C triple bond to a C = C double bond can be carried out, for example, using one mole of hydrogen in the presence of a less active hydrogenation catalyst, for example using iron or palladium, e.g. B. Raney iron or palladium with barium sulfate, preferably at elevated temperature. The hydrogenation to a C = C double bond can, for. B. with a mole of hydrogen and a deactivated catalyst, z. B. with palladium on activated carbon and in the presence of quinoline, with palladium on calcium carbonate in the presence of lead salts or with Raney nickel.

The hydrogenation to a C = double bond can be carried out using sodium in liquid ammonia, with short reaction times being used with regard to other reducible groups and an excess of reducing agent being avoided, preferably an aluminum halide, in particular ammonium chloride, can be added as a catalyst.

With the reduction mentioned above, care must be taken that other reducible groups are not reduced. When reducing using Raney nickel and hydrogen, special care must be taken to ensure that a halogen atom that may be present on the aromatic ring is not replaced by hydrogen. Furthermore, one must pay attention to any thioether groups present in all reductions, especially in the case of catalytic hydrogenations. Catalysts which are resistant to sulfur are preferably used, and in practice the volume of hydrogen to be taken up is calculated and the reduction is terminated when the calculated amount of hydrogen has been taken up.

Furthermore, from a compound of the formula I,

wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, Y, m, and n have the meanings given above, in which the nitrogen atom of the amino group and / or the hydroxyl group have a radical which can be removed, and a radical is removed .

Such cleavable residues are in particular those which can be cleaved by solvolysis, reduction, pyrolysis or fermentation.

Residues that can be split off by solvolysis are preferably residues that can be split off by hydrolysis or ammonolysis.

Residues which can be split off by hydrolysis are, for example, an acyl residue which, if present, contains functionally modified carboxyl groups, e.g. B. oxycarbonyl, such as alkoxycarbonyl, z. B. tert-butoxycarbonyl, or ethoxycarbonyl, aralkoxycarbonyl, such as phenyl-lower alkoxycarbonyl, e.g. B. a carbobenzyloxy, halogen-carbonyl, z. B. a chlorocarbonyl radical, further arylsulfonyl radicals, such as toluenesulfonyl or bromobenzenesulfonyl radicals and possibly halogenated, such as fluorinated lower alkanoyl radicals, such as formyl, acetyl or trifluoroacetyl radical or a benzyl radical or cyano groups or silyl radicals, such as trimethylsilyl radical.

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

618 417

4th

Of the above-mentioned residues on the hydroxyl groups which can be split off by hydrolysis, the oxycarbonyl residues and the lower alkano-oyl residues or the benzoyl residues are preferably used. In addition to the radicals mentioned above, double-bonded radicals can also be used which can be split off from the amino group by hydrolysis, e.g. B. alkylidene radicals or a phosphorylidene group, for. B. a triphenylphosphorylidene group, whereby the nitrogen atom receives a positive charge. In addition, radicals which can be removed from the hydroxyl group and the amino group by hydrolysis are divalent radicals, such as, where appropriate, substituted methylene. Any organic radicals can be used as the substituent on the methylene radicals, it being irrelevant for the hydrolysis which compound is the substituent on the methylene radical. As methylene substituents, for example aliphatic or aromatic radicals, such as the above-mentioned alkyl, aryl, z. As phenyl or pyridyl can be used. The hydrolysis can be carried out in a conventional manner, in a basic or, preferably, in an acidic medium.

Compounds with radicals which can be split off by hydrolysis are also compounds of the formula VIII if R4 is hydrogen,

(R1HR2) ArOCH_CH CH7

2 | I.

0 NO

wherein Ar, R1 and R2 have the meanings given above, R13 is a group of the formula IX

(ix)

R5 R8

A, cV ", -f \

i «,

CCIH-lfV

2 m and Xs represents a carbonyl or thiocarbonyl group.

The hydrolysis is carried out in an analogous manner, e.g. B. in the presence of a hydrolysis agent, e.g. B. in the presence of an acidic agent, such as dilute mineral acid, preferably sulfuric acid or hydrohalic acid, or in the presence of basic agents, such as alkali metal hydroxides, preferably sodium hydroxide. Oxydecarbonyl residues, arylsulfonyl residues and cyano groups can be split off in a suitable manner with acidic agents, for example with a hydrohalic acid, in particular hydrobromic acid. Preferably, the cleavage and use of dilute hydrobromic acid may be carried out in admixture with acetic acid. Cyano groups are preferably split off with hydrobromic acid at an elevated temperature, for example in boiling hydrobromic acid, using the so-called “bromine cyanide method” (von Braun). Furthermore, for example, a tert-butoxycarbonyl radical under anhydrous conditions by treatment with a suitable acid, e.g. B. Trifluoroacetic acid, be split off. Acidic agents are preferably used in the hydrolysis of the compounds of the formula VI.

Residues that can be split off by ammonolysis are in particular the halocarbonyl residues, such as, for. B. the chlorocarbonyl radical. The ammonolysis can be carried out in a conventional manner, e.g. B. by means of an amine containing at least one hydrogen bonded to the nitrogen atom, such as a mono- or di-lower alkylamine, e.g. B. methylamine or dimethylamine or especially ammonia, preferably 5 is carried out at elevated temperature. Instead of ammonia, one can use an agent that provides ammonia, for example hexamethylenetetramine.

Residues which can be removed by reduction are, for example, an a-arylalkyl radical, such as, for. B. a benzyl radical or an a-Aral-lo koxycarbonylrest, such as. B. a benzyloxycarbonyl radical, which can be split off in a conventional manner by hydrogenolysis, in particular with catalytically activated hydrogen, such as. B. hydrogen in the presence of a hydrogenation catalyst, e.g. B. Raney nickel. Other radicals which can be split off by hydrogenolysis are 2-haloalkoxycarbonyl radicals, such as, for. B. 2,2,2-trichloroethoxycarbonyl residues or 2-iodoethoxy or 2,2,2-tribromoethoxycarbonyl residues, which can be split off in a conventional manner, for example by a metal reduction (so-called nascent hydrogen). Nas-20 emitting hydrogen can by the action of metal or metal alloys such. B. amalgan, on compounds which release hydrogen, for example carboxy acids, alcohols or water, in particular zinc or zinc alloys can be used together with acetic acid. Hydrogenolysis of 2-haloalkoxycarbonyl residues can also be carried out using chromium or chromium (II) compounds, e.g. B. chromium (II) chloride or chromium (II) acetate.

A residue that can be removed by reduction can also be an arylsulfonyl residue, for example a toluenesulfonyl group, which can be removed in a conventional manner by reduction using nascent hydrogen, e.g. B. by means of an alkali metal, preferably lithium or sodium, in liquid ammonia; such a group 35 can in particular be split off from a nitrogen atom. When carrying out the reduction, it must be ensured that other reducible groups are not influenced.

Residues which can be split off by pyrolysis, in particular residues which can be split off from the nitrogen atom, are, where appropriate, substituted or preferably unsubstituted carbamoyl groups. Suitable substituents are e.g. B. lower alkyl or aryl-lower alkyl, e.g. B. methyl or benzyl, or aryl, e.g. B. Phenyl. Pyrolysis is carried out in a conventional manner, 45 taking care that other groups sensitive to heat are not affected.

Residues that can be split off by fermentation, in particular residues that can be split off from the nitrogen atom, are substituted, but preferably unsubstituted, carbamoyl groups. Suitable substituents are, for example, lower alkyl or aryl-lower alkyl, such as methyl or benzyl, or aryl, such as. B. Phenyl. The fermentation is carried out in a conventional manner, e.g. B. by means of the enzyme urease or by means of soybean extract, at a temperature of about 55 20 ° C or at a slightly elevated temperature.

Furthermore, a Schiff base of the formula X or XI, when R4, R5 and R6 are hydrogen,

60

65

0M RJ

12 I

IR HR) Ar0CHzCH-C «N-R

OH R *

(x)

i 2 '' 13

CR HR) Ar-0CH2CR-CH-N = R (xi)

5

618 417

or a tau tomer corresponding to formula XI or formula XII

(R1) CR '

) Ar-0CH2CH-

• CHR-

NH

(xii)

R

/ '

1 3

wherein Ar, R1, R2, R3 and R13 have the meanings given above and R13 'H has the same meaning as R13

(R1) (R2) Ar 0CH2C

0 R "

10th

and wherein the compounds of the formulas XI and XII can also coexist. This reduction can be carried out in a conventional manner, e.g. B. using a di-light metal hydride, such as sodium borohydride or lithium aluminum hydride, using a hydride such as boranate with formic acid or by means of catalytic hydrogenation, such as with hydrogen in the presence of Raney nickel. The reduction must ensure that other groups are not adversely affected.

Furthermore, the oxo group of a compound of formula XIII

R '

CHN - C - (CH-1 Y-

I «'b

Rq R

(XIII)

1 9

(CH,) R 2 m in which Ar, R1, R2, R3, R4, R5, R6, R7, R8, R9, m, n and Y have the meanings given above, are reduced to a hydroxyl group. This reduction can be carried out in a conventional manner, in particular using a di-light metal hydride as mentioned above, or according to the "Meerwein-Pondorf-Verley" method or a modification thereof, preferably using an alkanol as a reaction component and as a solvent , such as isopropanol, and using a metal alkanolate, such as. B. metal isopropoxide, e.g. B. aluminum isopropanolate.

Furthermore, in a compound of formula XIV

R3 R5

(X2) "2

R Ar 0CH ~ CHCHCHN-C- (CH_) Y-

2 I 2

• û I fi r4R6

in which Ar, R2, R3, R4, Rs, R6, R7, R8, R9, m, n and Y have the meanings given above and in which X2 is a radical which can be converted to a radical R1 having the same meaning as above, convert the rest of X2 to R1.

A radical X2 which can be converted into R1 is, for example, a radical X2 which can be converted into an alkoxyalkyl radical R1, e.g. B. a Z1 alkyl radical. A compound of the formula XIV which has such a Z1-alkyl radical as X2 can be reacted in a conventional manner with a compound alkyl-Z2, one group Z1 or Z2 being a hydroxyl group and the other group being Z with the meaning given above . For example, either a compound of formula XV

r-, 3rd

(xv)

H0-a'lkyl- (R2) Ar OCHUCHOHCHNR1 3

2 I

'4 rows

1 4

Rq

(XIV)

(ch9) r-

2. react with a compound alkyl-OH, where R2, R3, R4, - R13 and Z have the meanings given above. The reaction can be carried out in a conventional manner, such as, for example, reacting a compound of formula 45 with II with an amine of the formula R4-NH-R13.

A radical X2 which can be converted into R1 is, for example, a radical X2 which can be converted into an alkoxyalkoxy radical R1, such as for example a radical ZJ-alkyl-Ó- or a hydroxyl group.

A compound of the formula XIV which has such a radical Z1-alkyl-0- as X2 can be reacted in a conventional manner with a compound alkyl-Z2, one of the radicals Z1 or Z2 being the hydroxyl group and the other Z being of the meaning given above.

For example, a connection of the For-55 mei XVII 3

HO-alkyl-O (R2) Ar OCH ^ CHOHCl- ^ NR1 3

60

react with a compound alkyl-Z or a compound of formula XVI

R3

Z-alkyl (R2) Ar 0CH2CH0HCHNR13 ®

XVII)

R

(XVI)

with a compound alkyl-Z or a compound of formula XVIII -5

I.

Z-alkyl-0 (R2) Ar 0CH2CH0HCHNR13 (XVIII) i, 4

618 417

6

with a compound alkyl-OH, where R2, R3, R4, R14 and Z have the meanings given above. The reaction can be carried out in a conventional manner, e.g. B. as a reaction of a compound of formula II with an amine of formula R4-NH-R13.

A compound of formula XIV, which has a hydroxyl group as radical X2, can be reacted in a conventional manner with a compound alkoxyalkyl-Z, in which Z has the meaning given above.

So you can a compound of formula XIX

R *

H0-R2) Ar 0CH2CH0HCHNR13

(xix)

R

with a compound alkoxyalkyl-Z, wherein R2, R3, R4, R13 and Z have the meanings given above. The reaction can be carried out in a conventional manner, for example the reaction of a compound of the formula II with an amine R4 ~ NH-R13.

Furthermore, the oxo group of a compound corresponding to that of formula I, i.e. H. in cases where R3, R5 and R6 are hydrogen and which has an oxo group on a carbon atom attached to a nitrogen atom are reduced to two hydrogen atoms. The radical R1 is preferably not one of the radicals which contains a carbonyl group.

The compounds mentioned are, for example, those of the formula XX

(R

) (R2) Ar

OCH.

0

il 13

.CHOHCNR

(xx)

wherein R1, R2, R4 and R13 have the meanings given above when R3 is hydrogen.

The reduction can be carried out by any of the methods described above, using complex metal hydrides, e.g. As lithium aluminum hydride, or diisobutyl aluminum hydride can be used. Preferably, this reaction is carried out in an inert solvent such as an ether, e.g. B. diethyl ether or tetrahydrofuran.

So you can a compound of formula XIX

HO (R2) Ar-0CH_CH0HCHNR13 (XIX)

u

R

react with an alkoxycarbonylamino-Z, where R2, R3, R4, R13 and Z have the meanings given above. The reaction can be carried out in a conventional manner, for example as mentioned for the reaction of a compound of formula III with an amine of formula R4-NH-R13.

A radical X2 which can be converted into R1 is, for example, a radical X2 which can be converted into an alkoxycarbonylaminoalkoxy radical, for example H2N-alkoxy.

A compound of formula XIV, which has such a radical H2-alkoxy, can in the conventional manner with a

Alkoxycarbonyl chloride be implemented. So you can a compound of formula XXI

R3

H2N-alkoxy (R2) Ar-0CH2CH0HCHNR13

(XXI)

R

io react with an alkoxycarbonyl chloride, where R2, R3, R4, R13 have the meanings given above. The reaction can be carried out in a conventional manner, as described, for example, for the reaction of the compound of the formula III with an amine of the formula R4-NH-R13. 15 A radical which can be converted into R1 is, for example, a radical X2 which can be converted into an alkoxycarbonylaminoalkoxy radical, for example Z1-CO-NH-alkoxy.

A compound of the formula XIV which has such a radical Z1-CO-NH-alkoxy as X2 can be reacted in a conventional manner with a compound alkyl-Z1, where Z1 and Z2 have the meanings given above.

So you can a compound of formula XXII

3rd

R *

25 I

Z "'" -CO-NH-a 1 koxy (R2) Ar-0CH2CH0HCHNR

13

(XXII)

R

30 react with a compound alkyl-Z2, where R2, R3, R4, R13, Z1 and Z2 have the meanings given above. A radical X2 which can be converted into R1 is, for example, a radical X2 which can be converted into an alkoxycarbonylaminoalkyl radical, for example an H2N-alkyl radical.

35 A compound of formula XIV which has such an H2N-alkyl radical can be reacted in a conventional manner with an alkoxycarbonyl chloride.

So you can a compound of formula XXIII

d3

40 R

H ~ N-alkyl (R2) Ar-0CHoCH0HCHNR13

2 2 |

45 (XXIII) R4

react with an alkoxycarbonyl chloride, where Ar, R2, R3, R4 and R13 have the meanings given above. The reaction can be carried out in a conventional manner, for example as described for the reaction of a compound of formula III with an amine R4-NH-R13.

A radical which can be converted into R1 is, for example, a radical X2 which can be converted into an alkoxycarbonylaminoalkyl radical, for example Z1-CO-NH-lower alkyl.

55 A compound of the formula XI which has such a radical Z2-CO-NH-alkyl as X2 can be reacted in a conventional manner with a compound alkyl-Z2, where Z1 and Z2 have the meanings given above.

So you can a compound of formula XXII

60

Ru

Z] -C0-NH-alkyl (R2) Ar-GCH2CH0HCHNR13

65

(XXII)

l-

react with a compound alkyl-Z2, where Ar, R2, R3, R4, R13, Z1 and Z2 have the meanings given above.

7

618 417

A radical X2 which can be converted into R1 is, for example, a radical X2 which can be converted into an alkoxycarbonylaminoalkenyl radical, for example a radical Z-alkenyl.

A radical X2 which can be converted into R1 is, for example, a radical X2 which can be converted into an alkoxycarbonylaminoalkenyl radical, for example a radical H2N-alkenyl.

A compound of the formula XIV which contains such a radical H2N-alkenyl can be reacted in a conventional manner with an alkoxycarbonyl chloride.

So you can a compound of formula XXIV

H-, N-alkeny 1 (R) Ar-OCh ^ CHOHCH

W. A

13

(xxiv)

react with an alkoxycarbonyl chloride, where R2, R3, R4 and R13 have the meanings given above. The reaction can be carried out in a conventional manner, for example as described for the reaction of a compound of formula III with an amine of formula R4-NH-R13.

Alkoxycarbonylaminoalkenyl radical convertible radical X2, for example a radical Z1-CO-NH-alkenyl.

A compound XII, which has such a residue ZMIO-NH-alkenyl as X2, can be reacted in a conventional manner with a compound alkyl-Z2, where Z1 and Z2 have the meanings given above.

A radical which can be converted into R1 is, for example, one into a 20 A compound of the formula XXV

«

Z1 - CO-NH- a 1 keny 1 (R2) Ar- 0CH2CH0hI: HNR1 3

I A

(xxv)

react with a compound alkyl-Z2, where R2, R3, R4, R13, Z1 and Z2 have the meanings given above. Furthermore, in a compound of formula XXVI

EAR"

r "

(X3) (R1) Ar-0-CH-CHCHN-C- (CH_) -Y-

c. Ii £ n

(xxvi)

(CH-) R "2 m in which Ar, R1, R3, R4, R5, R6, R7, R8, R9, m, n and Y have the meanings given above and X3 can be converted into a radical R2 with the meaning given above Residue means the residue X3 will be converted to R2.

So you can a compound of formula XXVII

A compound of formula XXX, which has a hydroxyl group as X3, can be reacted in a conventional manner with a compound alkyl-Z, in which Z has the meaning given above 45.

r-

HO- (R) Ar-0CH2CH0HCHNR

13

(xxvii)

R

react with a compound alkyl-Z, wherein Ar, R1, R3, R4, ss R13 and Z have the meanings given above. The reaction can be carried out in a conventional manner, for example as indicated for the reaction of a compound of the formula III with an amine of the formula R4-NH-R13. 60 Furthermore, in a compound of formula XXVIII

OHR3

(R1) (R2) Ar-0CH2CHCHNX4 (XXVIII) 65

in which Ar, R1, R2, R3 and R4 have the meanings given above and in which X4 is a radical which can be converted into a radical R13 with the meaning given above, the radical X4 is converted into R13.

A radical X4 which can be converted into R13 is, for example, a radical X4 which can be converted into a (subst.) Phenoxyalkyl radical, for example a Z3 alkyl radical. A compound XXXII, which has such a Z3-alkyl radical as X4, can be reacted in a conventional manner with a compound (subst.) - phenyl-Z4, one of the Z3 or Z4 radicals being a hydroxyl group and the other Z having the meaning given above. So you can either a compound of formula XXIX

618 417

1A 1

R -C- (CH.,) -OH (XXIX)

I 2 n

R6

with a compound (subst.) - Phenyl-Z or a compound of formula XXX

R5

R14-C- (CH0) -Z (XXX)

React I 2 n with a compound (subst.) - phenyl-OH, where Rs, R6 and n have the meanings given above and R14

5 (R1) (R2) Ar — OCHCHOHCH (R3) N—

R4

wherein Ar, R1, R2, R3 and R4 have the meanings given above. The reaction can be carried out in a conventional manner, for example as indicated for the reaction of a compound of formula II with an amine of formula III, R4-NH-R13.

Furthermore, in a compound of formula XXXI

, 6th

3 5 EAR R °

(R1) (R2) Ar-0CH2CHCHN-C-

.k

(CH2) n-

R <R6

(XXXI)

wherein Ar, R1, R2, R3, R4, Rs, R6, R8, R9, Y, n and m have the meanings given above and X6 is a radical which can be converted into R7 with the meaning given above, X6 are converted into R7.

A radical X6 which can be converted into R7 is, for example, a radical which can be converted into an alkoxy radical, for example a radical

React 2s with a compound alkyl-OH, where R1S, R8, R9 and m have the meanings given above.

Furthermore, in a compound of formula XXXIV

R '

30th

where R1

(Choir' /. m r? 5 //

\ = t = /

(XXXIV)

35

(CH9) R9 £. m

R

I.

R OH

i •

R

i is.

-Y- (CH-) -C — NCHCHCHo0Ar 2 11 R6 R4 2 R2

A compound which contains such a radical X6 can be reacted in a conventional manner with a compound alkyl-Z2, where Z1 and Z2 have the meanings given above.

So you can either use a compound of formula XXXII _

PB

45

HO

- (CH9) R 'c m

(XXXII)

ir-

with a compound alkyl-Z or a compound of formula XXXIII

R

8th

where R15, R7, R9 and m have the meanings given above and X7 is a radical which can be converted into R8, where R8 has the meaning given above, X7 are converted into R8.

A radical X7 which can be converted into R7 is, for example, a radical X7 which can be converted into an alkoxy radical, for example a radical

(CH->) R9

\ £. m

50

A compound which has such a radical as X7 can be reacted in a conventional manner with a compound alkyl-Z2 55, where Z1 and Z2 have the meanings given above.

So you can either use a compound of formula XXXV

CCVmR9

ho r \ -

(XXXV)

4 CH.,) R (XXXIII)

2 m

65

15

with a compound alkyl-Z or a compound of formula XXXVI

9

618 417

(CH.,) R '2 m

(xxxvi)

react with a compound alkyl-OH, where R15, R7, R9 m and Z have the meanings given above.

Furthermore, in a compound of formula XXXVII

(xxxvii)

20th

wherein R15 and R7 have the meanings given above and X8 is a radical which can be converted into - (CH2) mR9, wherein m and R9 have the meanings indicated above, Xe are converted to - (CH2) mR9.

A residue X8 which can be converted to - (CH2) mR9 is e.g. B. a residue which can be converted to - (CH2) mCONR10R11 or - (CH2) mCONHNR10R11 when R10 and Ru together with the nitrogen atom form a morpholinyl or piperazinyl group, such as a residue

Z1CH2CH2

^ N (NH) C0 (CH9) -

Z -CH2CH ^ m or a remainder h2nch2ch2

\

zch2CH ^

> l (l \ IH) C0 (CH „) - 2 m

r! 5

10th

wherein R7, R8, R9, R15, m, Z, Z1 and Z2 have the meanings given above. These residues are each subjected to ring closure in a conventional manner, e.g. B. how the reaction between a compound of formula II with a 15 compound of formula III.

A residue X8 which can be converted to - (CH2) mR9 is e.g. B. a residue that can be converted to - (CH2) mCONR10R11 or - (CH2) mCONHNR10R11, for example a residue

8th

ZCO (CH-) 2 m

30th

R

15

which is implemented in a conventional manner with a compound R10RnN-H 35 or a compound R10R11NNH2.

The reaction can be carried out in the same way as the reaction between a compound of the formula II and a compound of the formula III.

A radical X8 which can be converted to (CH2) n, R9 is, for example, a radical which can be converted to an alkoxycarbonylaminoalkyl (CH2) m radical. These reactions and residues are the same as when X2 is a residue that can be converted into an alkoxycarbonylaminoalkyl residue R1 45.

Furthermore, in a compound of formula XL

OH

r '

ß '

(R2) (R2) Ar-GCH0CHCHNC- (CH0) -Y

jTkrK

R

10th

n w

(xl)

(CH0) R "2 m in which Ar, R1, R2, R3, R5, R6, R7, R8, R9, Y, m and n have the meanings given above and X10 is a radical which can be converted to R4, X10 is converted to R4 .

A radical X10 that can be converted to a radical R4 = hydrogen is, for example, benzyl or alkanoyl, which is hydrolyzed.

The above-mentioned implementations may possibly be carried out simultaneously or in any order one after the other.

60

65

The reactions mentioned above can be carried out in a manner known per se in the absence or in the presence of diluents and / or condensing agents and / or catalysts, at room temperature or at an elevated temperature, possibly in a closed vessel.

Depending on the process conditions and the starting materials used, the end product is either in free form or in the form of its acid addition salt, which in the

618 417

10th

Protection scope of the present invention is included.

For example, basic, neutral or mixed salts and hemiamino, sesqui or polyhydrates can be obtained. The acid addition salts of the compounds obtained according to the invention can be converted into the free compounds in a manner known per se by, for. B. basic agents such as alkalis, or ion exchangers can be used. On the other hand, free bases obtained can form salts with organic or inorganic acids. In the production of acid addition salts, preference is given to using those acids which form suitable therapeutically permissible salts. Such acids are, for example, hydrochloric acids, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, aliphatic, alicyclic, aromatic or heterocyclic carboxylic or sulfonic acids, such as, for example, formic, acetic, propionic, amber, glycolic, lactic, apple, wine -, Ci-tronen-, ascorbic, maleic, hydroxymaleic, pyruvic, phenylacetic, benzoic, p-aminobenzoic, anthranilic, p-hyroxybenzoic, salicylic, p-aminosalicylic or embonic acid, Methanesulfonic, ethanesulfonic, hydroxyethanesulfonic or ethylenesulfonic acids, halobenzenesulfonic, toluenesulfonic or naphthylsulfonic acids or sulfanilic acid, methionine, tryptophan, lysine or arginine.

These or other salts of the new compounds obtainable according to the invention, such as picrates, can serve as cleaning agents for the free bases obtained by converting the free bases into salts, separating them and then releasing the bases from these salts. Due to the close relationship between the new compounds in free form and in the form of their salts, it is understood that the corresponding salts can be used instead of the free compounds if possible.

According to a preferred embodiment of the process according to the invention, it is possible to start from any compound which has been obtained as an intermediate and then to carry out the process steps which are still missing, or to abort the process at any stage, or to start the starting material under the reaction conditions leave or add a reaction component, if possible in the form of their salts.

So you can an aldehyde of the formula XXXVIII

(R1) (R2) Ar — OCH2CHOHCHO (XXXVIII)

wherein R1 and R2 have the meanings given above, with an amine of the formula R4-NH-R13, wherein R4 and R13 have the meanings given above, in the presence of a suitable reducing agent, for example one of the abovementioned. In this way, a compound of formula X is obtained as an intermediate, which can then be reduced according to the invention.

Furthermore, an amine of the formula III can be reacted in a manner known per se with an aldehyde or a ketone of the formula 0 = R13 ', in which R13' has the meaning given above, in the presence of a suitable reducing agent, for example one of the abovementioned. In this way, a compound of formula XI or XII is obtained as an intermediate, which can then be reduced according to the invention.

Furthermore, a phenol of the formula V with an acetidinol of the formula XXXIX can be known

ch2-n-r13 (xxxix)

ho-Ìh Ìh2

wherein R13 has the meaning given above, to a compound of formula I. This implementation is carried out in a conventional manner. Thus, the reaction can be carried out under alkaline conditions in a suitable solvent, such as benzyl alcohol, by heating the reaction mixture to boiling for a few hours. In this way, the phenol is first converted to the metal phenolate, for example the alkali phenolate, before it is added to the acetidinol of the formula XXX.

From the methods described above for the preparation of the active compounds, it follows that the different substituents can be introduced by different analogy methods. Thus the introduction of —0-CH2CH = CH2 and —0-CH2C = CH groups as substituent R1 can be carried out in the same way as the introduction of alkoxy groups as radicals R2. Analogously, alkoxy groups R7 and R8 can be introduced in the same way as alkoxy groups R2. Similar analogies apply to other radicals.

Depending on the choice of the starting materials and the processes, the new compounds obtainable according to the invention can be in the form of optical antipodes or racemates or, if they contain at least one asymmetric carbon atom, they can be present as a mixture of isomers (racemate mixture). The isomeric mixtures (racemic mixtures) which are obtained can be separated into the two stereoisomeric (diastereomeric) forms, depending on the physico-chemical differences between the components, for example by chromatography and / or fractional crystallization.

The racemates obtained can be separated by methods known per se, for example by recrystallization from an optically active solvent, by means of microorganisms or by reaction with optically active acids, the salts of the compound being formed, which then, for example, owing to their different solubility in the Diastereomers are separated, from which the antipodes are released by suitable means. Suitable optically active acids are e.g. B. the L and D forms of tartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphor sulfonic acid or quinic acid. The more active part of the two antipodes is preferably isolated.

To carry out the process according to the invention, preference is given to using starting materials which lead to groups in the end products which are primarily particularly desirable and in particular lead to the specifically described and preferred end products.

The starting materials are known per se or, if they are new, can be obtained by methods known per se.

In clinical use, the compounds obtainable according to the invention can normally be administered orally, rectally or by injection in the form of a pharmaceutical preparation which contains an active compound either as a free base or as a pharmaceutically acceptable, non-toxic acid addition salt, e.g. B. contains the hydrochloride, lactate, acetate, sulfamate or the like, in combination with a pharmaceutically acceptable carrier. The mention of the new compounds obtainable according to the invention relates either to the free amine base or the acid addition salts of these bases, even if the compounds are generally mentioned or specifically described, provided that the context in which these terms are used, e.g. B. in the examples, agrees with this broad interpretation. The carrier can be a solid, semi-solid or liquid diluent or a capsule. Usually the amount of active compound is from 0.1 to 95% by weight of the preparation, preferably from 0.5 to

5

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15

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30th

35

40

45

50

55

60

65

11

618 417

20% by weight for preparations for injection and 2 to 50% by weight for preparations for oral administration.

In the preparation of the pharmaceutical preparations which contain a compound according to the invention in the form of a unit dose for oral administration, the selected compound can be mixed with a solid, powdery carrier, for example with lactose, sucrose, sorbitol, mannitol, starch, for example potato starch, corn starch or amylopectin, cellulose derivatives or gelatin, or also together with a lubricant, such as magnesium stearate, calcium stearate, polyethylene glycol waxes or the like; the mass can then be compressed into tablets. If dragées are to be produced, the cores prepared as above can be coated with concentrated solutions of sugar. These solutions can also contain, for example, gum arabic, gelatin, talc, titanium dioxide or the like. In addition, the dragées can be coated with a lacquer dissolved in a volatile organic solvent or mixture of solvents. A dye can be added to these coatings to enable easy distinction between tablets with different active compounds or with different amounts of active compound.

In the production of soft gelatin capsules (pearl-shaped, closed capsules) consisting of gelatin and, for example, glycerol, or in the production of similar closed capsules, the active compound can be mixed with a vegetable oil. Hard gelatin capsules can contain granules of the active compound in combination with a solid, powdery carrier, for example with lactose, sucrose, sorbitol, mannitol, starch (e.g. potato starch, corn starch or amylopectin), cellulose derivatives or gelatin.

Unit dosage forms for rectal administration can be prepared in the form of suppositories containing the active substance in admixture with a neutral fat base, or in the form of gelatin rectal capsules containing the active substance in admixture with a vegetable oil or paraffin oil.

Liquid preparations for oral administration can be in the form of syrups or suspensions, e.g. B. solutions containing about 0.2 to about 20 wt.% Of active substance, the remainder consisting of sugar and a mixture of ethanol, water, glycerol and propylene glycol. If desired, such liquid preparations can contain colorants, flavorings, saccharin and / or carboxymethyl cellulose as thickeners.

Solutions for parenteral administration by injection can be prepared in the form of an aqueous solution of a water-soluble pharmaceutically acceptable salt of the active compound, preferably in a concentration of about 0.5 to about 10.0% by weight. These solutions can also contain stabilizing agents and / or buffer substances and can be obtained in ampoules with different doses.

example 1

1.9 g of l, 2-epoxy-3- (allylphenoxy) propane and 1.8 g of 4- (2-aminoethoxy) benzamide were refluxed in 25 ml of isopropanol for 1.5 hours. The reaction mixture was evaporated in vacuo, the residue was dissolved in acetone and the hydrochloride of l- [2- (4-carbamylphenoxy) ethylamino] -3- (2-allylphenoxy) ~ propanol- (2) was added by adding hydrochloric acid ether failed; F. 211 ° C. The structure was confirmed by means of the NMR spectrum.

Example 2

2.8 g of l, 2-epoxy-3- [2-chloro-5-methylphenoxy] propane and 2.7 g of 4- (2-aminoethoxy) benzamide were refluxed in 25 ml of isopropanol for 5 hours. The mixture was evaporated in vacuo and the residue was dissolved in acetone. The hydrochloride of l- [4-carbamylphenoxy-ethylamino] -3- (2-chloro-5-methylphen-oxy) -propanol- (2) was precipitated by adding ether containing hydrogen chloride; F. 250 ° C (dec.). The structure was confirmed by NMR spectrum.

Example 3

2.1 g l, 2-epoxy-3- [4- (2-methoxyethyl) phenoxy] propane and 1.8 g 4- (2-aminoethoxy) benzamide were reacted with one another in accordance with Example 1. The melting point of l- [2- (4-carbamylphenoxy) ethylamino] -3- (2-methoxyethyl) -phe-noxypropanoI- (2) -hydrochloride was 105 ° C. The structure was confirmed by NMR spectrum.

Example 4

0.4 g of 3- (1,2-epoxy-3-propoxy) -4-chlorothiazole and 0.4 g of 4- (2-aminoethoxy) benzamide were reacted with one another in accordance with Example 1. The hydrochloride of l- [2- (4-carbamylphenoxy) ethylaminoj-3- (4-chloro-2-thiazoloxy) propanol- (2) decomposed at 215 ° C. The structure was confirmed by NMR spectrum .

Example 5

1.9 g l, 2-epoxy-3- (2-allylphenoxy) propane and 2.5 g 4- (2-aminopropoxy) benzamide were reacted with one another in accordance with Example 1. The hydrochloride of l- [l-methyl-2- (4-carbamylphenoxy) ethylamino] -3- (2-allylphenoxy) -propa-nol- (2) melted at 94 ° C. The structure was confirmed by NMR spectrum .

Example 6

3.8 g l, 2-epoxy-3- (2-allylphenoxy) propane and 3.3 g 1- (2-methylphenoxy) -2-propylamine were reacted with one another in accordance with Example 1. The hydrochloride of l- [l ~ methyl-2- (2-methylphenoxy) ethylamino] -3- (2-allylphenoxy) propa-nol- (2) melted at 142 ° C. The structure was confirmed by NMR spectrum .

Example 7

3.8 g l, 2-epoxy-3- (2-allylphenoxy) propane and 3.3 g 1- (4-methylphenoxy) -2-propylamine were reacted with one another in accordance with Example 5. The hydrochloride of l- [l-methyl-2- (4-methylphenoxy) ethylamino] -3- (2-allylphenoxy) -propa-nol- (2) melted at 146 ° C. The structure was confirmed by NMR spectrum .

Example 8

1.8 g of l-amino-3- (2-methylisonitrosomethylphenoxy) -pro-panol- (2) and 1.55 g of 4-methylcarbonylmethoxybenzamide were dissolved in 25 ml of methanol and cooled to 0 ° C. 1.8 g NaBH4 was then added over a half hour period. Then 50 ml of water was added and the product was extracted with ethyl acetate. The ethyl acetate phase was evaporated in vacuo and the substance, 1 - [1-methyl 1- 2- (4-carbamoylphenoxy) ethylamino] -3 - (2-methylisonitrosomethylphenoxy) propane- (2) was treated with ether and ethyl acetate washed; Mp 106 ° C (HCl).

Example 9

According to the procedure according to Example 1, 1- [4- (2- (2-methoxycarbonylamino) ethyl] phenoxyethylamino} -3- (2-methylphenoxy) propanol- (2) was obtained from 1,2-epoxy-3- ( 2-methyl-phenoxy) propane and l- (4-methoxycarbonylaminoethylphenoxy) -2-ethylamine; F. 93 ° C (as base).

5

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15

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35

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45

50

55

60

65

618 417

Example 10

According to the procedure according to Example 1, 1- [2- (4-carbamylphenoxy) ethylamino] -3- (3-allylphenoxy) -propa-nol- (2) was obtained from 1,2-epoxy-3- (3-allylphenoxy) -propane and 4-amino-ethoxybenzamide; F. 228 ° C (as hydrochloride).

Example 11

According to the procedure according to Example 1, 1- [2- (4-carbamoylphenoxy) ethylamino] -3- (2-chlorophenoxy) propa-nol- (2) was obtained from 1,2-epoxy-3- (2-chlorophenoxy) -propane and 4-aminoethoxybenzamide; F. 228 ° C (as hydrochloride).

Example 12

According to the procedure of Example 1, l- [2- (4-carbamylphenoxy) ethylamino] -3- (2,3-dichlorophenoxy) propanol- (2) was obtained from 1,2-epoxy-3- (2, 3-dichlorophenoxy) propane and

4-aminoethoxybenzamide produced; F. 245 ° C (as hydrochloride) and 156 ° C (as base).

Example 13

250 g l- [2- (4-carbamylphenoxy) ethylamino] -3- (2-chloro

5-methylphenoxy) propanol (2) hydrochloride was mixed with 175.8 g lactose, 169.7 g potato starch and 32 g colloidal silica. The mixture was moistened with a 10% solution of gelatin and granulated through a sieve with a mesh size of 1.68 mm (12 mesh). After drying, 160 g of potato starch, 50 g of talc and

5 g of magnesium stearate were added, and the mixture thus obtained was pressed into tablets (10,000), each containing 75 mg of active substance. The tablets are placed on the market with a notch to allow a dosage other than 25 mg or multiples thereof if the tablets are broken.

Example 14

From 250 g l- [2- (4-carbamylphenoxy) ethylamino] -3- (2-2-methoxyethyl) phenoxypropanol (2) hydrochloride, 175.9 g lactose and an alcoholic solution of 25 g polyvinyl pyrrolidone granules were made. After drying, the granules were mixed with 25 g of talc, 40 g of potato starch and 2.50 g of magnesium stearate and pressed into 10,000 biconvex tablets. These tablets are first coated with a 10% alcoholic solution of shellac and then with an aqueous solution containing 45% sucrose, 5% gum arabic, 4% gelatin and 0.2% colorant. Talc and powdered sugar are used for dusting after the first 5 coatings. The coating was then coated with a 66% sugar syrup and polished with a 10% carnauba wax solution in carbon tetrachloride.

Example 15

1 g of l- [2- (4-carbamylphenoxy) ethylamino] -3- (4-chloro-3-thiazoloxy) propanoI- (2) hydrochloride, 0.8 g of sodium chloride and 0.1 g of ascorbic acid were so obtained lots of water dissolved that

100 ml of solution were obtained. This solution, containing 10 mg of active substance per ml, was used to fill ampoules, which were then sterilized by heating at 120 ° C for 20 minutes.

The β-receptor blocking agents obtainable according to the invention were tested with regard to their biological properties. All compounds were pretreated on anesthetized cats (male and female weighing 2.5 to 3.5 kg) that had been pretreated with re-serpin (5 mg / kg body weight, administered intramuscularly) approximately 16 hours before the experiments , tested. The animals were pretreated with reserpine to eliminate endogenous sympathetic heartbeat control and vascular smooth muscle tone.

The cats were anesthetized with pentobarbital (30 mg / kg body weight, administered intraperitoneally) and artificially ventilated with room air. A bilateral vagotomy was performed on the neck. Blood pressure was measured with a cannula in the carotid artery and the heartbeat was recorded with a cardiotachometer triggered by the electrocardiogram (ECG). The actual beta-mimetic effectiveness on the heart was indicated by an increased heartbeat after the administration of the agent. The test compounds were administered intravenously in logarithmically increased doses. The values obtained were recorded as dose-effect curves, from which the effectiveness values (ED50) (affinity values) were determined. At the end of each trial, high doses of isoprenaline were given to get the maximum heartbeat effect.

The compounds were also tested on conscious dogs. Beagles were trained to lie still and to stand upright for 2 minutes by placing their front paws on a table. Arterial blood pressure was recorded using a blood pressure transmitter attached to the heart. The heartbeat was determined by the EKG. All dogs were pretreated with methylscopolamine to eliminate vagus effects. Recordings were made before and 15 and 75 minutes after test compound administration, first with the dogs on their backs for 2 minutes and in an upright position for 2 minutes. The test compounds were administered at 2 hour intervals in increasing doses.

Table 1 below shows the effective amounts (affinity values) and the real (intrinsic) /? - mimetic activity of the compounds obtainable according to the invention on reserpined cats and the effects on the blood pressure of dogs that were conscious. Corresponding values for propanolol, (l-isopropylamino-3- (l-naphthoxy) -propa-nol- (2)], practolol, [4- (2-hydroxy-3-isopropylaminopropoxy-oxy) acetanilide], metoprolol, { l-isopropylamino-3- [4- (2-meth-oxyethyl) phenoxy] propanol (2)}, tolamolol, {4- [2- (2-hydroxy-3-o-tolyloxypropylamino) ethoxy ] -benzamid} and AH 5158 {5- [1 -Hydroxy-2] - (l-methyl-3-phenylpropyl) -aminö- [ä-thyl] -salicylamide} are given for comparison.

12

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55

13

Table 1

618 417

connection

Reserpined cat

Conscious

dogs

Isoprene block

Specific

À blood pressure in torr

EDS0 mg / kg

Activity after 1.5 mg / kg IV

MR

PR

Beats / min.

lying upright

Propranolol

0.1

0.1

0

+ 5

0

Practolol

0.3

35

+ 15

Metoprolol

0.2

4.7

0

- 5th

- 3rd

Tolamolol

0.1

1.5

+ 9

-23

-32

AH 5158

0.2

0.6

+ 21

-38

-67

example 1

0.3

1.8

0

-28

-45

Example 2

0.3

4.6

0

Example 3

1.1

8.5

0

Example 5

0.05

0.2

+ 15

-43

-42

Example 6

0.5

0.5

+ 24

Example 9

0.3

2.4

+ 40

Example 11

0.05

1.0

+ 16

-28

-20

Example 17

0.1

1.5

+ 8

-23

-46

Example 18

0.04

0.3

+ 13

Example 19

1.7

> 8.5

0

Example 20

0.03

> 8.5

+ 11

The experiments prove that the compounds investigated are effective β-receptor antagonists, with or without real β-mimetic activity. The compounds also lower blood pressure in conscious dogs 30 years old, significantly more than propranolol, practolol and metoprolol, and to the same extent as tolamolol. The orthostatic

Effects of the new compounds obtainable according to the invention are not as pronounced as those of AH 5158, i.e. H. the blood pressure does not drop appreciably from the lying to the upright position.

The following compounds were also made according to the invention:

R

I.

ArOCH „CHOHCH„ NHCH (CH0) O 2 2 2. n

(CH2) mR-

example

Ar r1

r2

r5

n m

r9

F. (° C)

17th

Phenyl

2-CH2 = CH-CH20-

H

H

1

0

4-NH2CO-

136-7

(HCl)

18th

Phenyl

2-CH = C-CH20—

H

H

1

0

4-NH2CO—

215

(HCl)

19th

Phenyl

2-NHzCOCH2—

H

H

1

0

4-NH2CO—

176

(HCl)

20th

Phenyl

2-hoch2ch2nhcoch2o-

H

H

1

0

4-NH2CO—

66

(p-OH-

Benzoate)

21st

Phenyl

2-CH2 = CH-CH20—

H

H

2nd

0

4-NH2CO—

200

(HCl)

22

Phenyl

2-CH2 = CH-CH20—

H

H

4th

0

4-NH2CO—

01

(HCl)

23

1,2,5-thiadiazolyl

4-C1

H

1

0

4-NH2CO—

> 250

(HCl)

S

Claims (3)

618 417 1. l- [2- (4-carbamylphenoxy) ethylamino] -3- (2-allylphenoxy) propanol- (2), l- [2- (4-carbamylphenoxy) ethylamino] -3- (2-meth-oxyethyl) phenoxy-propanol- (2), l- [l-methyl-2- (4-carbamylphenoxy) ethylamino] - 3- (2-allylphenoxy) propanol- (2), 4. l- [l-methyl-2- (2-methylphenoxy) ethylamino] -3- (2-allylphenoxy) propanol- (2), 5. 1 - [1-methyl-2- (4-methylphenoxy) ethylamino] -3- (2-allylphenoxy) propanol- (2), 6. l- [l-methyl-2- (4-carbamylphenoxy) ethylamino] -3- (2-methylisonitrosomethylphenoxy) propanol- (2), 7. l- [2- (4-carbamylphenoxy) ethylamino] -3- (3-allylphenoxy) propanol- (2), or a therapeutically acceptable salt of the listed compounds is prepared. 2nd 2. The method according to claim 1, characterized in that the isomeric mixtures of the compounds obtained are separated into the pure isomers and / or the racemate of the compounds obtained are separated into the optical antipodes. 3. The method according to claim 1, characterized in that 2 n (I. f LH -,) R 'rn 20th 25th wherein Ar, R1, R2 and R3 have the meanings given above, X1 is the hydroxyl group and Z is a reactive, esterified hydroxyl group or X1 and Z together form an oxy group, with an amine of the formula III m in which R4, Rs, R6, R7, R8, R9, Y, n and m have the meanings given above, is implemented and that, if necessary, the free bases obtained are converted into their therapeutically permissible acid addition salts. 2nd ) ArUCH ^ CI ICH- Z U.N 15 HM-C- (CH_) -V ? n (C H) R (CH,) 2 U 1 6 R R wherein R1 in the 2- or 3-position is the group -CH2CH = CH2, -OCH2CH = CH2, —OCH2C = CH, alkoxyalkyl, H0CH2CH2NHC0CH20, CH30CH2CH2NHC0CH20- or -CH = NOR with R hydrogen or alkyl with 1 to 6 carbon atoms, R2 Hydrogen, halogen, alkyl or alkoxy, R3 hydrogen, R4 hydrogen, Rs hydrogen or methyl, R6 hydrogen, R7 and R8 hydrogen, R9 hydrogen or -CONR10R ", with R10 and R11 individually hydrogen, YO-or -CH2-, n a integer from 0 to 5, m is an integer from 0 to 2 and Ar is the phenyl group, and also of therapeutically permissible acid addition salts of these compounds, characterized in that a compound of the formula II X ^ R I I (R1 HR 2nd PATENT CLAIMS 1. Process for the preparation of new hydroxy amines of the formula I. ÜHR3 R5 12 I '' R H R) A rOCIUCHCHN - C - 3rd