DD202286A5 - PROCESS FOR THE PREPARATION OF DERIVATIVES OF 3-AMINO-1,2-PROPANDIOL - Google Patents

Abstract

The invention relates to a process for the preparation of derivatives of 3-amino-1,2-propanediol for use as medicaments, for example for the treatment of angina pectoris, cardiac arrhythmias and hypertension. The aim of the invention is the preparation of compounds with specific action on beta-adrenergic receptors. According to the invention, derivatives of the 3-amino-1,2-propanediol of the formula I are prepared in which R 11 is polyhydroxy lower alkyl, lower alkyl alkoxy lower alkyl, lower alkyl sulfonylamino linked in the 4 position or 1-lower alkylcarbamoyl-2-vinyl linked in the 4 position, and alk radicals of formulas -CH deep 2-CH deep 2-or CH-CH deep 2 -, and salts of such compounds.

Description

Berlin, December 10, 1981

23 2 5 2 8 8 ~ ^ ^AP ° ° ^{7 c / 232 52B}

A process for the preparation of derivatives άβ3 3-Ainino-1, 2- propanediol

Field of application of the invention

The invention relates to a process for the preparation of novel derivatives of 3-amino-1,2-propanediol, pharmaceutical preparations containing such compounds and their use for the preparation of pharmaceutical preparations or as pharmacologically active compounds.

The compounds prepared according to the invention act in a specific manner on β-adrenergic receptors. They are used, for example, for the treatment of angina pectoris and cardiac arrhythmias, and as antihypertensive agents.

Characteristic of the known technical solutions

There is no information available on which compounds have been used hitherto for the treatment of jellon-angina pectoris _r -r rhythm disorders or hypertension. There are also no details of processes for the preparation of 3-amino-1,2-propanediols or derivatives thereof known.

Object of the invention

The aim of the invention is the provision of novel compounds with effect on ß-adrenergic receptors, which are suitable for the treatment of angina pectoris, cardiac arrhythmias and hypertension.

ι λ

10. 12. 1981

0 Π O C Q Q AP C 07 C / 232 528

1 ό ID LQ O - _1β - 59 516 12

Indung Principle of the, Erf

The invention has for its object to find new Verbindun conditions with the desired properties and processes for their preparation,

According to the invention, new derivatives of 3-amino-1,2-propanediol of the formula

R ₁₁ OH

4 ² y

jj ^d (I)

oh η \ y

in which R _{11 is} polyhydroxy-lower alkyl, cycloalkyl-lower alkoxy-lower alkyl, lower-alkylsulfonylamino bonded in the 4-position or i-lower-alkylcarbamoyl-2-vinyl bonded in the 4-position, and alk radicals of the formulas

-CH ₂ -CH ₂ or -CH-CH ₂ - means

The invention also includes salts of such compounds.

The radicals and compounds referred to as "lower" in the context of the present description preferably contain up to 7 and primarily up to 4 carbon atoms,

Cycloalkyl has 3-7, in particular 3-5 carbon atoms as ring members. Eiederalkyl is z. As methyl, ethyl, n-propyl, isopropyl, η-butyl, isobutyl or tert-butyl, Polyhydroxyniederalkyl can occupy any of the possible positions in the phenyl ring and is z "B. di- or Trihydroxyniederalkyl, such as 1,2-D! hydroxy or 2,3-dihydroxy-lower alkyl, e.g. For example, 1,2-dihydroxy or 2,3-dihydroxypropyl.

232528

Cycloalkyl-lower alkoxy-lower alkyl may substitute any of the possible positions in the phenyl ring and is, for example, cycloalkyl-lower alkoxymethyl or 1- or 2- (cycloalkyl-lower-alkoxy) -ethyl. Niederalkylsulfonylamino corresponds to the formula Niederalky1-SO ₂ -N (R) -, wherein R _{19 is} hydrogen or lower alkyl, and accordingly represents, for example, ethylsulfonylamino and especially methylsulfonylamino, but also also N-methyl-methylsulfonylamino. L-lower alkylcarbamoyl-2-vinyl · is, for example, 1-ethylcarbamoyl and especially 1-methylcarbamoyl-2-vinyl.

The phenyl bearing the amide and hydroxy groups is attached to the. ^the remaining molecule is attached in such a way that the latter is attached in the 4-position of said phenyl, ie in the para position to the amide group, and especially in the 5-position of said phenyl, (ie in para position to the hydroxy group) is.

The novel compounds may be present in the form of their salts, such as their acid addition salts and, in the first place, their pharmaceutically acceptable non-toxic acid addition salts. Suitable salts are, for example, those cycloaliphatic with inorganic acids such as Halogenwä's'sers'tor'fsäuren, for example, hydrochloric acid or hydrobromic acid, sulfuric acid, or phosphoric acid, or with organic acids such as aliphatic, j, aromatic or heterocyclic carboxylic or sulfonic acids, for example formic , Acetic, propionic, succinic, glycolic, lactic, acetic, tartaric, citric, maleic, hydroxymalein, pyruvic, fumaric, benzoic, 4-aminobenzoic, anthranilic, 4- Hydroxybenzoic, salicylic, Embon, methanesulfonic, Aethansulfon-, 2-Hydroxyäthansulfon-, Aethylensulfon-, toluenesulfone, naphthalenesulfonic or SuIfanilsäure, or with other acidic organic substances, such as ascorbic acid.

The new compounds have valuable pharmacological properties. In particular, they specifically act on adrenergic receptors. This effect is a common feature

2 £ JUL.1982 * 02488i

LOL 'JL u υ

the compounds of the formula I based on the affinity for these receptors, which in the absence of or very little stimulating effect as pure blockade, with low to moderate stimulatory effect as a blockade with simultaneous ISA, i. intrinsic sympathomimetric activity, expresses.

The compounds of formula I exhibit blocking activity on adrenergic β-receptors with pronounced cardioselectivity, which is particularly evident in those substances which are in the 4-position of the phenyl ring by lower alkylsulfonylamino, e.g. ,

) Methylsulfonylamino, or by 1-lower-alkylcarbamoyl-2-vinyl, e.g. 1-methylcarbamoyl-2-vinyl, while those whose phenyl ring is replaced by cycloalkyl-lower alkoxy-lower alkyl, e.g. Cyclopropylmethoxyäthyl, substituted, have a less pronounced cardioselectivity. The compounds of the formula I furthermore effect a blockade of vascular β receptors which can be detected, in particular, with the substances whose phenyl ring is substituted by polyhydroxy-lower alkyl, for example 2,3-dihydroxypropyl, or by cycloalkyl-lower alkoxy-lower alkyl, for example cyclopropylmethoxyethyl, in which both these compounds but also those which in the 4-position of the phenyl ring, a Niederalkylsulfonylamino-, for example a methylsulfonylamino group, or a 1-

) Lower alkylcarbamoyl-Z-vinyl, about a l-methylcarbamoyl-2-vinyl group wear, as an additional effect a more or less pronounced blockade of tracheal ß-receptors is present.

Compounds of formula I with a Polyhydroxyniederalkyl-, such as a 2,3-dihydroxypropyl group, also show a more or less pronounced ISA, which is to call a blood pressure reduction as an additional effect. This latter activity can also be demonstrated on compounds with a .Niederalkylsulfonylamino-, such as a methylsulfonylamino group in the phenyl ring.

The above information regarding pharmacological properties is based on the results of corresponding phannacological tests in standard test procedures. Thus, the novel β-blocking compounds exhibit inhibition of isoproterenol-induced tachycardia on isolated guinea pig hearts in a concentration range of about 0.001 μg / ml to about 3 μg / ml, and on the anesthetized reserpine pretreated cat in a dose range of about 0.001 mg / kg to about 10 mg / kg when given intravenously. Blockade of vascular β-receptors is inhibited by isoproterenol-induced vasodilation in the vascular area of the femoral artery on the anesthetized reserpine pretreated cat when given intravenously in a dose range of about 0.003 mg / kg to about 30 mg / kg detectable.

The imbalance of the tracheal β receptors caused by the compounds of the formula I can be detected by inhibition of the isoprenaline-induced relaxation on the isolated guiantena trachea in a concentration range of about O, dt) 1 μ mol / liter to about 30 μ mol / liter ,

The ISA of the β-blocking compounds of the formula I results from the increase in the basal heart rate in the anesthetized, pre- J pin pretreated cat, which is evident, for example, when intravenous administration of 1- [2- (3-carbamoyl-4-hydroxy phenoxy) ethylamino] -3- [2- (2,3-dihydroxypropyl) phenoxy] -2-propanol in a dose range of from about 0.001 mg / kg to about 1 mg / kg.

The novel beta-blocking compounds also cause i.v. in a dose range of from about 0.03 mg / kg to about 30 mg / kg. a lowering of the arterial blood pressure in the anesthetized cat.

Accordingly, the novel compounds of the formula I can be used as partially cardioselective β-receptor blockers, e.g. used for the treatment of cardiac arrhythmias, angina pectoris and hypertension.

L ό I D L Ö

D -

The compounds of general formula I can also be used as valuable intermediates for the preparation of other valuable, in particular, pharmaceutically active compounds.

The invention particularly relates to compounds of the formula I, wherein R-. Di- or trihydroxy-lower alkyl, cycloalkyl-lower alkoxy-lower alkyl having up to 4 carbon atoms in the lower alkyl portion, lower alkylsulfonylamino or lower N-lower alkyl-lower alkylsulfonylamino having up to 4 carbon atoms in each lower alkyl portion bonded in the 4-position,. or l-lower alkylcarbamoyl-2-vinyl bonded in 4-step with up to 4 carbon atoms in the lower alkyl part and alk radicals of the formulas

CH is -CH-CH- or 3, or salts, in particular

-CH-CH-

Acid addition salts, especially pharmaceutically acceptable non-toxic acid addition salts thereof.

The invention relates in particular to compounds of the formula I in which R _{1 is} 1,2-dihydroxy- or 2,3-dihydroxy-lower alkyl, cycloalkyl-lower alkoxymethyl or 1- or 2- (cycloalkyl-lower-alkoxy) -ethyl, lower alkylsulfonylamino having up to 4 carbon atoms and bonded in the 4-position, wherein R _{12 is} hydrogen or 4-position linked r-Aethylcarbamoyl-2-vinyl or 1-methylcarbamoyl-2-vinyl. "and alk

J radicals of the formulas -CR -CEy- or CH

-CH-CH-, or salts, in particular acid addition salts, especially pharmaceutically acceptable non-toxic acid addition salts thereof.

More particularly, the invention relates to compounds of the formula I wherein ^r R is 1,2-dihydroxy or 2,3-dihydroxy-lower alkyl. with up to 4 carbon atoms, eg 1,2-dihydroxy- or 2,3-dihydroxypropyl, 1- or 2- (cycloalkyl-lower-alkoxy) -ethyl having 3-5 carbon atoms in the cycloalkyl part, eg 1- or 2- (cyclopropylmethoxy) -ethyl, 4-position-linked lower alkylsulfonylamino having up to 4 carbon atoms, wherein R _1? Is hydrogen, for example methylsulfonylamino, or 1-methyl

carbamoyl-2-vinyl, and alk radicals of the formulas -CH "-CH" - or 9 ^H 3

²² -CH-CH ₂ -

means, or salts, in particular acid addition salts, especially pharmaceutically acceptable, non-toxic acid addition salts thereof.

The novel compounds of the formula I are prepared in a manner known per se. You can use it e.g. obtained by adding a compound of the formula

./11 x / X., 1 (ID

I II. ^ - 0-CH ₂ -CH-CH ₂ -Z ₁

with a compound of the formula

(III)

wherein one of Z ₁ and Z _{9 represents} a reactive esterified hydroxy group and the other represents the primary amino group and X represents hydroxy, or wherein X ₁ and Z ₁ together represent the epoxy group and Z represents the primary amino group, and if desired, converting a resulting free compound into a salt or a resulting salt into a free compound, and / or, .. if desired, a resulting mixture of isomers is separated into the isomers, or J resolving a racemate obtained into the antipodes.

A reactive esterified hydroxy group Z or Z "is one represented by a strong acid, in particular a strong inorganic acid, such as a hydrohalic acid, especially hydrochloric, hydrobromic or hydroiodic acid, or sulfuric acid, or a strong organic acid, especially a strong organic sulfonic acid, such as an aliphatic or aromatic sulfonic acid, eg Methanesulfonic acid, 4-methylphenylsulfonic acid or 4-bromophenylsulfonic acid, esterified hydroxy group, and is primarily halogen, e.g. Chlorine, bromine or iodine, or aliphatically or aromatically substituted sulfonated

fonyloxy, e.g. Methylsulfonyloxy or 4-methylphenylsulfonyloxy.

The above reaction is carried out in a manner known per se, wherein, especially when using a starting material having a reactive esterified hydroxy group, advantageously in the presence of a basic agent such as an inorganic base, for example an alkali metal or alkaline earth metal carbonate or hydroxide, or an organic basic agent, such as a Alkalimetallniederalkanolats, and / or an excess of the basic reactant and usually in the presence of a solvent J or solvent mixture and, if necessary, while cooling or heating, for example in a temperature range of about -20 ⁰ C to about +150 ⁰ C , in an open or closed vessel and / or in an inert gas atmosphere, eg in a nitrogen atmosphere, works.

Starting materials of the formula II are known or can be prepared in a manner known per se.

Starting materials of formula III can be obtained eg by reacting a Hydroxysalicylamids with one of the meaning of alk appropriate dihaloalkane, such as a Chlorbrom- or dibromoalkane in the presence of an alkaline condensing agent such as an alkali carbonate). These reactions are carried out in a conventional manner, wherein protective groups which are attached to the hydroxyl groups are split off simultaneously or, as described below, subsequently.

The compounds of formula I can be further prepared by reacting in a compound of formula

, Ai ⁹ ~ ^x

^ x

/ - 0-CH -CH-CH -N-alk-0 - + - '^"00 N _n (IV), II

Ox ₂ X ₃

ΙόΙΏ LO O

wherein R 'has the meaning of R .., or in 4-membered, substituted on the nitrogen by a hydrogen-substitutable substituent substituted lower alkylsulfonylamino, X, X, X and X

i · O ^ T .J

in each case hydrogen or a substituent substitutable by hydrogen, or X. and X_ and / or X. and X. together represent one

2 3 4 5

mean divalent, substitutable by two hydrogen atoms, with the proviso that at least one of X ₇₃ X ,, X, and X_ is different from hydrogen, or at least R 'in the 4-position bonded to the nitrogen atom by a hydrogen substitutable substituent substituted lower alkylsulfonylamino, j or at least X and X, together or X, and X_ together represent a divalent radical, which can be replaced by two hydrogen atoms, or in a salt thereof, the groups other than hydrogen X, X, X, and X ,. or X and X together and / or X, and X together split off and replaced by hydrogen atoms, and / or replaced by a substitutable on the nitrogen atom of the 4-position lower alkylsulfonylamino R 'hydrogen substituents, and, if desired, performs the additional method steps subsequently to the first method.

The cleavage of the groups X, X_, X, or X "or in each case X" and X

and / or X, and X together, and that in a 4-lower alkylsulfonyl

J amino group on the nitrogen atom substituent is carried out by solvolysis, such as hydrolysis, alcoholysis or acidolysis, or by reduction, including hydrogenolysis.

A particularly useful leaving group X, or X, or a protecting group attached to the nitrogen atom in a 4-lower alkylsulfonylamino group is primarily a hydrogenolytically cleavable a-aryl-lower alkyl group, such as an optionally substituted 1-polyphenyl-lower alkyl or 1-phenyl-lower alkyl group, wherein substituents, especially of the Phenylteil, eg Lower alkyl, such as methyl, or lower alkoxy, such as methoxy, and primarily

Benzyl. A group X_ and in particular X- and X and a nitrogen protecting group in a 4-lower alkylsulfonylamino group may also have a solvolytic, such as hydrolytic or acidolytic, furthermore a reductive, including hydrogenolytic, cleavable radical, in particular a corresponding acyl radical, such as the acyl radical of an organic carboxylic acid , eg Lower alkanoyl such as acetyl, or aroyl such as benzoyl, further the acyl radical of a monoester of carbonic acid such as lower alkoxycarbonyl, e.g. Methoxycarbonyl, ethoxycarbonyl or tert-butyloxycarbonyl, 2-halo-lower alkoxycarbonyl, z.-B. 2,2,2-trichloroethoxycarbonyl or 2-iodoethoxycarbonyl, optionally sub-) substituted 1-phenyl-lower alkoxycarbonyl, for example benzyloxycarbonyl or diphenylmethoxycarbonyl, or aroylmethoxycarbonyl, for example phenacyloxycarbonyl, furthermore an optionally substituted 1-polyphenyl-lower alkyl group, in which substituents, in the first instance of the phenyl moiety, For example, have the meaning given above, and in the first place trityl present.

One by X and X_ and / or X, and X ,. together formed, cleavable radical is primarily a hydrogenolytically cleavable group, such as optionally substituted 1-phenyl-lower alkylidene, wherein substituents, in particular of the phenyl moiety, for example lower alkyl or lower alkoxy may be, and in particular benzylidene, and j solvolytic, in particular hydrolytically cleavable groups, such as lower alkylidene, for example methylene or isopropylidene, or 1-phenyl-lower alkylidene, the phenyl part of which is optionally substituted by lower alkyl, such as methyl or lower alkoxy, such as methoxy, in particular benzylidene, or cycloalkylidene, for example cyclopentylidene or cyclohexylidene.

Starting materials useful in the form of salts are primarily in the form of acid addition salts, e.g. used with mineral acids, as well as with organic acids.

ν "?

Hydrogenolytically removable radicals X, Χ, Χ and / or X ₁ , in particular optionally substituted 1-phenyl-lower alkyl groups, furthermore also suitable acyl groups, such as optionally substituted 1-phenyl-lower alkoxycarbonyl, and together formed by the groups X and X and X and X_, Optionally substituted 1-Phenylniederalkylidengruppen, and standing in a 4-Niederalkylsulfonylaminogruppe nitrogen on protecting groups of this type can be cleaved by treatment with catalytically activated hydrogen, for example with hydrogen in the presence of a nickel catalyst, such as Raney nickel, or a suitable noble metal catalyst.

Hydrolytically removable groups X, X, X, and / or X, such as acyl radicals of. organic carboxylic acids, for example lower alkanoyl, and half esters of carbonic acid, eg lower alkoxycarbonyl, furthermore trityl radicals, as well as by the radicals X "and X, and / or X, and X_ together formed Niederalkyliden-, 1-phenyl-niederalkyliden- or Cycloalkylidengruppen and in a 4-Niederalkylsulfonylaminogruppe existing nitrogen protecting group of this type may, depending on the nature of such radicals by treatment with water under acidic or basic conditions, for example in the presence of a mineral acid such as hydrochloric or sulfuric acid, or an alkali metal or alkaline earth metal hydroxide or carbonate or a Amines, such as J isopropylamine, are split off.

Acidolytically removable radicals X ", X, X ^ and / or X" and / or a nitrogen protecting group present in a 4-lower alkylsulfonylamino group are, in particular, certain acyl radicals of half-esters of carbonic acid, e.g. tert.-lower alkoxycarbonyl or optionally substituted diphenylmethoxycarbonyl radicals, and also the tert.-lower alkyl radical; such radicals may be prepared by treatment with suitable strong organic carboxylic acids, such as optionally substituted by halogen, in particular fluorine, substituted lower alkanecarboxylic acids, primarily with trifluoroacetic acid (if necessary, in the presence of an active compound).

- II -

four-agent, such as anisole), as well as with formic acid are split off.

By reductively cleavable radicals X ", X, X and / or X and / or a nitrogen protecting group in a 4-Miederalkylsulfonylaminogruppe are also understood such groups which upon treatment with a chemical reducing agent (in particular with a reducing metal or a reducing metal compound) be split off. Such radicals are especially 2-halo-lower alkoxycarbonyl or arylmethoxycarbonyl, e.g. upon treatment with a reducing heavy metal, such as zinc, or with a reducing heavy metal salt, such as a chromium (II) salt, e.g. chloride or acetate, usually in the presence of an organic carboxylic acid, such as formic acid or acetic acid, and can be cleaved from water.

Nitrogen protecting groups which are on the nitrogen atom of a 4-Niederalkylsulfonylaminogruppe R 'correspond to the aforementioned and can be removed by the methods described and replaced by hydrogen groups, such groups are cleaved in the course of the described method simultaneously with other groups or subsequently in a separate process measure ,

J The above reactions are usually carried out in the presence of a solvent or solvent mixture, suitable reactants may function as such the same time, and, if necessary, while cooling or heating, for example a in an open or closed vessel and / or in the atmosphere

Inert gases, e.g. Nitrogen.

The starting materials of formula IV can be obtained analogously to the process modifications described above, e.g. by treating a compound of the formula

V *

11 ·. "-QH or a salt thereof, with a connection

the formula

0 -

X ° -CH-C "-CH-N-alk-0 - + l]" ^C ° V (IVa)

^0X 2 ^X 3

wherein X * represents the group X ", wherein at least one of the groups X and X ° is other than hydrogen, and X ° represents a reactive esterified hydroxy group, or X ^ and X ° together represent a carbon-oxygen bond, or wherein X and X ^ together represent a cleavable radical replaceable by two hydrogen atoms linked to the oxygen or nitrogen atom, respectively, and X ° represents a reactive esterified hydroxy group, or by treating a compound of the formula

11

H-Y, (IVb)

_x ^ ₂₁ OX "

with a compound of the formula

0-X,

Y ₂ -alk-0 4- II ^WW1 \ _T (IVc)

wherein X ° has the meaning given above for X ", and one of the groups Y and Y represents a reactive esterified hydroxy group, and the other represents the group of the formula -NH (X), wherein X has the meaning given above, with the That at least

£ 3 ZD Δ®

one of the groups X and X "is other than hydrogen, or wherein X ° and Y form an oxygen-carbon bond and Y is the group of the formula -NH (X") and X is other than hydrogen. The above reactions are carried out in a manner known per se, e.g. as described under the first method according to the invention.

It is also possible to e.g. by reacting a compound of the formula

[ ¹ JQ-QfJ -QJ-CU _j> fjj (IVd)

V / 2,22

with a carbonyl compound of the formula

(IVe)

wherein R represents a alkylene radical alk, one separated from the oxygen atom by a carbon atom

Carbonylgruppe containing alkyl radical, and X and X_ Λ or X, and X, - together represent one of the specified protective groups, formed Schiff base with a borohydride, such as sodium borohydride to reduce the compound of formula IV. The reduction can also be carried out by means of activated hydrogen in the presence of a hydrogenation catalyst, e.g. a platinum-on-carbon catalyst.

Carbony compounds of the formula (IVe) in turn can be prepared by reacting a compound of the formula

HO _A

with a compound of the formula R-Hal (IVg), wherein R has the above meaning and e.g. a haloketone, such as chloroacetone, can be obtained in a conventional manner.

The novel compounds of formula I can also be obtained) by reacting, in a compound of formula

--O - CH - CH - X - C - ^L - "" * '"° ^(V)>

\ / ² ι ⁶

OX ₇

where X _{r is} a reducible group of the formulas 6

- CH = N - alk - (Va), resp

-CH ₂ -N = alk _x - (Vb)

where alk is an alkylylidene radical corresponding to the radical alk and X is hydrogen or a radical which can be replaced by hydrogen under the conditions for the reduction of X,

R 'is the meaning of R ₁₁ , or in the 4-position, substituted on the nitrogen atom by a hydrogen-substitutable substituent X ₇ substituted lower alkylsulfonylamino, wherein X, as defined above, wherein always X ^ is a reducible

Group Va or Vb is to reduce this group and at the same time split off the group X other than hydrogen and replace it with hydrogen and, if desired, carry out the additional process steps subsequently mentioned in the first method.

«- ν £. s / (L V W

A hydroxy-cleavable group X is primarily an α-aryl-lower alkyl group such as an optionally substituted 1-phenyl-lower alkyl group wherein substituents of the phenyl moiety, e.g. Lower alkoxy, such as methoxy, and especially benzyl.

Nitrogen protective groups X in a 4-lower alkylsulfonylamino group R 'correspond to the groups mentioned above for X ₇ which can be eliminated by the methods described and replaced by hydrogen, where such groups are split off simultaneously with other groups or subsequently in a separate process ,

Starting materials of the formula V with a group X of the formula Vb can

also in the isomeric form of ring tautomers of the formula

• _x ^ iO-CH-CH CH ₂ O-X ₇

wherein alk corresponds to the meaning of alk and oxygen and J is nitrogen atom of the ring on the same carbon atom are bonded, are present.

An alkyl-ylidene alk is e.g. Methine or ethyl ylidene, while an alkylidene group represents <methyl ethylidene.

while an alkylidene group alk. Methylene, ethylidene or 1-

The reduction of the nitrogen-carbon double bond in starting materials of the formula V, which contain as X a group Va or Vb,

while X has the meaning given under the formula V, to the nitrogen-carbon single bond can be prepared in a conventional manner, e.g. by treatment with catalytically activated hydrogen, such as

Hydrogen in the presence of a suitable hydrogenation catalyst, such as a nickel, platinum or palladium catalyst, carried out, wherein hydrogenolytically cleavable groups X _{7 are also} eliminated and replaced by hydrogen; or working with a suitable hydride reducing agent, such as an alkali metal borohydride, eg sodium borohydride. When hydride reducing agents are used, acyl radicals of carboxylic acids, such as, for example, acetic acid, which are bonded to oxygen, can also be present as radicals X ₇ and be split off in the same operation.

A starting material of the formula V can be prepared in a manner known per se, if appropriate in situ, i. under the conditions of the process described. So you can use a compound of the formula

• _x -O-CH-CH-CHO (Ve)

OH

with an amine of the formula

Λ ⁷

H ₂ N-EIk-O- / V ^C0NH 2. (Vf) V *

to a starting product of the formula V with the group X _{c of} the formula

Va implement.

By reacting a compound of the formula

• _x / '- O-CH ₂ -CH-CH ₂ -NH ₂ (Vh) OH

L · ^ L * J i- υ u

- 17 with a carbonyl compound of the formula

Λ ⁷

¹ V

can be converted to starting materials of the formula V with a group X of

Get formula (Vb). A modification of these reactions consists in reacting a einer dibenzylamino compound corresponding to a compound of the formula (Vh) with the oxo compound of the formula (VI) under the reducing conditions of the process. Catalytically activated hydrogen, for example hydrogen in the presence of a Schwennetallhydrierkatalysators or a mixture thereof, such as a palladium and / or platinum catalyst is used as the reducing agent in the first place. Under such reaction conditions, hydrogenolytically removable groups X ₇ , for example benzyl groups, are split off, and at the same time the nitrogen-carbon double bond is reduced to the corresponding nitrogen-carbon single bond.

Oxo compounds of formula (Vi), in turn, are e.g. by reacting a compound of the formula

^) 0-X

1 ^;

HOl \ - ^QOm 2 (Vk)

with a haloalkanone compound of the above formula R - Hal (IVf), e.g. Ghloraceton, in the presence of an alkaline condensing agent, such as potassium carbonate, or an organic base, such as triethylamine, available.

The novel compounds of formula I can also be obtained by reacting a compound of the formula

ά. * JLUL » W

in which R '' has the meaning of R, or in the 4-position bonded, optionally substituted on the nitrogen atom by a cleavable by means of ammonolysis and substituted by a hydrogen substitutable substituents \ substituted Niederalkylsulfonylamino, X "is hydrogen or a leaving removable by Ämmonolyse group, or reactive derivative of one of the carboxylic acids defined in formula VI, with ammonia (VII), and at the same time optionally present radicals X or on the nitrogen of a 4-lower alkylsulfonylamino group

eliminates standing substituents and replaced by hydrogen, and if desired, then performs the 'mentioned in the first method additional process steps.

Ammonolytisch cleavable substituents and radicals X _Q are acyl radicals

of organic carboxylic acids, e.g. Aroyl, such as benzoyl, or lower alkanoyl, such as acetyl.

Reactive derivatives of the carboxylic acids defined in formula VI are e.g. the halides, such as the chlorides or bromides, further the azides, as well as acid anhydrides, in particular mixed acid anhydrides with e.g. Lower alkanecarboxylic acids such as acetic acid or propionic acid, lower alkoxyalkanecarboxylic acids such as 2-methoxyacetic acid. Reactive derivatives of carboxylic acids of formula VI are in particular esters, e.g. with lower alkanols such as methanol, ethanol, isopropanol, tert-butanol, further with aryl-lower alkanols, such as optionally lower alkyl, e.g. Methyl, or lower alkoxy e.g. Methoxy, substituted benzyl alcohol, or phenols optionally activated by suitable substituents, e.g.

£. ^ L · <JL · U Q

by halogen, such as 4-halo, such as 4-chloro, lower alkoxy, about 4-lower alkoxy, such as 4-methoxy, 4-nitro or 2,4-dinitro, such as 4-chlorophenol, 4-mathoxyphenol, 4-nitro or 2 , 4-Dinitrophencl, further with cycloalkanols, such as cyclopentanol or cyclohexanol, which may optionally be substituted by lower alkyl, for example methyl. The reaction is carried out in a conventional manner, usually in the presence of an inert solvent, for example in a temperature range of about -10 ° to +50 ⁰ C in a closed vessel.

The starting materials of the formula VI can be obtained in a manner known per se by reacting a compound of the formula (II) in which X and Z together denote the epoxy group with an amino compound of the formula

H N-alk-0 Ϊ-u- ^C0OH (VIa)

V *

wherein X has the meaning indicated, or a reactive derivative thereof, is reacted.

^ >> It is also possible to react by reacting a compound of the formula ... "

OH

with a carbonyl compound of the formula

0-X ₈

Ro £ Y ^{C00H (VIc)} >

wherein R is the alkyl radical corresponding to Alk, an oxo radical containing alkyl radical in place of its free valence, reduced with a borohydride, such as sodium borohydride · The reduction may also be carried out by means of activated hydrogen in the presence of a hydrogenation catalyst, e.g. a platinum-on-carbon catalyst.

Carbony compounds of the formula (VIc) in turn can be prepared by reacting a compound of the formula

ο ρ

HC- / Y ^C00H (VId)

with a compound of the above-explained formula

R-HaI (IVg),

wherein Hal is halogen, in particular chlorine, are obtained in a conventional manner.

The novel compounds of formula I can also be obtained by J in a compound of formula

OH H

wherein one or all of the hydroxy groups and / or the secondary nitrogen atom and / or lower-alkylsulfonylamino R.sub.4 attached in the 4-position is optionally substituted on the nitrogen atom by such groups which can be eliminated by hydrolysis and replaced by hydrogen, which cleaved under the conditions of the process and replaced by hydrogen be converted, the group -CN by hydrolysis in the group -COM and at the same time optionally on the nitrogen atom of a

cleaved in the 4-position Niederalkylsulfonylaminogruppe and / or on one or all of the hydroxyl groups and / or on the secondary nitrogen protecting groups and replaced by hydrogen, and, if desired, the then referred to the first method 'performs additional method steps.

The above reactions are carried out in a manner known per se. The hydrolysis is carried out in a basic or advantageously in an acid medium, in particular in the presence of concentrated aqueous mineral acid, such as conc. Hydrochloric acid, and if necessary, ) under cooling or heating, for example in a temperature range of about 0 to 60 °, preferably from about 40-50 °, carried out in an open or closed vessel and / or in an inert gas atmosphere, for example in a nitrogen atmosphere.

The starting materials of formula VII can be e.g. by reacting a compound of the formula

/ X ° ^H (VIIa)

• _x ^ - O-CH-CH-CH-NH ₂

with a compound of the formula

Hal-alk-0 V-Il (VIIb)

wherein Hal represents chlorine, bromine or iodine. The reaction is advantageously carried out in the presence of a basic agent in a conventional manner.

In turn, the compound VIIb can be obtained by the action of acetic acid on the oxime corresponding to the cyanide. This is conveniently done by boiling under reflux. The oxime can in turn be prepared from the corresponding aldehyde by boiling with

^ 32528 8

Hydroxylamine hydrochloride in the presence of alcoholic sodium carbonate solution are prepared under reflux. The resulting aldehyde, in turn, can be prepared by reacting 2,4-dihydroxybenzaldehyde with an a, LO dihalo-lower alkane, preferably in the presence of a basic agent. But you can also in an analogous manner, a hydroxysalicylonitrile, for example, the 2,4-dihydroxybenzonitrile [Chem. Ber. 24, 3657 (1891)] or the 2,5-dihydroxybenzonitrile [HeIv. Chim. Acta 30, 149, 153 (1947)] with a non-geminal Dihalogenniederalkan to a compound of formula VIIb implement.

The novel compounds of formula I can also be obtained by reacting a compound of formula

with a compound of the formula.

'' "'" OH

OH (VIII),

-ΓΟΝΗ

-N-alk-Of-IJ 2 ( _Ιχ)

X ₁ -

wherein Z is a reactive, esterified hydroxy group and X is hydroxy, or wherein Z and X ₁ together represent the epoxy group, or with a corresponding ring-closed compound of the formula

X ,, 0- ·

OH

L ^ Y ^C0NH 2

wherein R and alk each have the meaning given, and X is hydrogen or a cleavable under the conditions of the process and with the hydroxy group of a compound of formula X capable of forming the ether bond capable group, reacting, and, if desired, the subsequent to the performs the first method described method steps. Cleavable and capable of forming the ether bond groups X as mentioned above are e.g. Lower alkyl, wherein aryl e.g. is naphthyl, such as 1-naphthyl, and in particular phenyl, which is optionally substituted by lower alkyl, lower alkoxy, hydroxy, halogen, trifluoromethyl and / or nitro. Accordingly, groups X defined above are, in particular, benzyl, furthermore lower alkoxymethyl, e.g. Methoxymethyl.

A reactive esterified hydroxy group Z is one represented by a strong acid, in particular a strong inorganic acid such as a hydrohalic acid, in particular hydrochloric, hydrobromic or hydroiodic acid, or sulfuric acid, or a strong organic acid, in particular a strong organic sulphonic acid such as aliphatic or aromatic sulfonic acid, z.3. Methanesulfonic acid, 4-methylphenylsulfonic acid or 4-bromophenylsulfonic acid, esterified hydroxy group, and is primarily halogen, e.g. Chlorine, bromine or iodine, or aliphatically or aromatically substituted SuI-fonyloxy, e.g. Methylsulfonyloxy or 4-methylphenylsulfonyloxy.

The reaction of a compound of formula VIII with such a formula IX is carried out in a manner known per se, wherein, especially when using a starting material of the formula XI with a reactive esterified hydroxy group, advantageously in the presence of a basic agent such as an inorganic base, e.g. an alkali metal or alkaline earth metal carbonate or hydroxide, or an organic base such as an alkali metal lower alkoxide, and / or an excess of the basic reactant. The compound of the formula X.

may also be used as a salt, such as an alkali salt, e.g. present as the sodium salt.

The reaction of a compound of the formula VIII with a compound of the formula X is usually carried out in the presence of a basic catalyst, such as an alkali metal hydroxide, for example potassium hydroxide, or an organic base, for example triethylamine, or an acidic catalyst, such as trifluoroacetic acid.

These reactions are carried out in a manner known per se and usually in the presence of a solvent or solvent mixture and, if necessary, with cooling or heating, for example in a temperature range from about + 20 ° to about + 200 °. preferably from about +100 to about + 180 ° in an open or closed vessel and / or in an inert gas atmosphere, eg in a nitrogen atmosphere.

Starting materials of the formula ΐχ wherein Z- is a reactive esterified hydroxy group, e.g. Is chlorine, and X is hydroxy, by reacting an amine with optionally protected hydroxy group of the formula

OH

IH "- _alk -o- ^ Y ^C0 ™ 2 M

with epichlorohydrin in a conventional manner, while a starting material of formula IX, wherein Z and X together represent the epoxy group, from an amine of formula IXa with epichlorohydrin in the presence of a basic agent, e.g. an alkali or alkaline earth metal hydroxide or carbonate, such as sodium hydroxide or carbonate, or calcium hydroxide or carbonate. A protected hydroxy group is e.g. one by means of a reduction including hydrogenolysis, e.g. an α-aryl-lower alkyl group such as a 1-phenyl-lower alkyl group optionally substituted as above, e.g. a benzyl group, or a hydrolysis-releasable and hydrogen-substitutable group, e.g. an acyl radical, for example

«- ** dm * J l ~ UO

a lower alkanoyl group such as an acetyl group, substituted hydroxy group. Such protecting groups are obtained by reduction, including hydrogenolysis, or hydrolysis, in the usual manner simultaneously or in a separate reaction step, e.g. as described, split off and replaced by hydrogen.

Starting materials of the formula X can be prepared in a manner known per se by reacting a compound of the formula

CH OH I

XO - CH (Xa),

¹ I

wherein the two hydroxy groups are preferably in reactive, esterified form, e.g. may be present as halogen, such as chlorine, or as sulphonyloxy, such as methanesulphonyloxy, and X.sup.- is preferably different from hydrogen and, for example, as described

optionally substituted benzyl group, with a compound of the formula

-CONH ₂

wherein alk has the meaning given, can be obtained. These reactions are usually carried out in a solvent or solvent mixture, and, if necessary, while cooling or heating, for example in a temperature range of about -20 ° to about +150 ⁰ C, preferably from about + 60 ° to about +100 ⁰ C, in an open or closed vessel and / or in an inert gas atmosphere, for example in a nitrogen atmosphere performed. If, in a starting material of the formula so obtained in this way, the group X represents an optionally substituted benzyl group, for example as described, this may be effected, for example, by means of catalytically activated hydrogen, for example hydrogen in the presence of a noble metal catalyst, such as a palladium-on-carbon catalyst, cleaved in the usual manner and replaced by hydrogen, wherein a starting material of the formula X, wherein X-, is hydrogen, is obtained.

The reactions described above may, if desired, be carried out simultaneously or successively, furthermore in any order. If necessary, they are carried out in the presence of diluents, condensing agents and / or catalytic agents, at reduced or elevated temperature, in a closed vessel under pressure and / or in an inert gas atmosphere.

Depending on the process conditions and starting materials, the novel compounds are obtained in free form or in the form of their salts also encompassed by the invention, it also being possible for the novel compounds or salts thereof to be present as Heini, mono, sesqui or polyhydrates thereof. Acid addition salts of the novel compounds can be prepared in a manner known per se, e.g. by treatment with basic agents, such as alkali metal hydroxides, carbonates or bicarbonates or ion exchangers are converted into the free compounds. On the other hand, free bases obtained can be treated with organic or inorganic acids, e.g. form with the acids mentioned, acid addition salts, in particular those acids are used for their preparation, which are suitable for the formation of pharmaceutically acceptable salts.

These or other salts, especially acid addition salts of the new compounds, e.g. Oxalate.oder perchlorates, can also serve to purify the resulting free bases by converting the free bases into salts, separating and purifying them, and in turn releases the bases from the salts.

Depending on the choice of starting materials and procedures, as optical antipodes or racemates, or if they contain at least two asymmetric carbon atoms, the novel compounds may also be present as racemate mixtures. The starting materials can also be used as specific optical antipodes.

2 3 2 b 1 8 8

Obtained racemic gels may, due to the physico-chemical differences of the diastereoisomers in a known manner, e.g. by chromatography and / or fractional crystallization, are separated into the two stereoisomeric (diastereomeric) racemates.

Obtained racemates can be broken down by methods known per se into the antipodes, z.3. by recrystallization from an optical

active solvents, by treatment with suitable microorganisms or by reaction with an optically active substance which forms salts with the racemic compound, in particular acids, and separation of the salt mixture obtained in this way, e.g. due to different solubilities, in the diastereomeric salts from which the free antipodes can be released by the action of suitable Mittal. Particularly common optically active acids are e.g. the D and L forms of tartaric acid, di-O, O- (p-toluoyl) tartaric acid, malic acid, mandelic acid, camphorsulfonic acid, glutamic acid, aspartic acid or quinic acid. Advantageously, one isolates the more effective of the two antipodes.

The invention also relates to those embodiments of the method according to which starting from a compound obtainable as an intermediate at any stage of the process and carrying out the missing process steps, or terminating the process at any stage, or wherein forming a starting material under the reaction conditions, or in which a reaction component is optionally present in the form of their salts.

Appropriately used for carrying out the inventive reactions, such starting materials, which lead to the above-mentioned groups of end products and especially to the specifically described or highlighted end products.

The starting materials are known or, if they are new, may be prepared by methods known per se, as above, e.g. analogous to the case

232528 8

- 28 games to be described.

The new compounds may e.g. find use in the form of pharmaceutical preparations containing a pharmacologically effective amount of the active substance, optionally together with pharmaceutically acceptable excipients which are enteral to z.3. oral or parenteral administration, and may be inorganic or organic, solid or liquid. Thus, tablets or gelatin capsules containing the active ingredient together with diluents, e.g. Lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycerol and / or lubricants, e.g. Silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and / or polyethylene glycol have. Tablets may also contain binders, e.g. Magnesium aluminum silicate, starches such as corn, wheat, rice and arrowroot starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone, and, if desired, disintegrants, e.g. Starches, agar, alginic acid or a salt thereof, such as sodium alginate, and / or effervescent mixtures, or adsorbents, dyes, flavorings and sweeteners. Furthermore, one can use the new pharmacologically active compounds in the form of parenterally administered preparations or infusion solutions. Such solutions are preferably isotonic aqueous solutions or suspensions, e.g. for lyophilized preparations containing the active ingredient alone or together with a carrier material, e.g. Mannitol, can be prepared before use. The pharmaceutical preparations may be sterilized and / or adjuvants, e.g. preservatives,

Stabilizers, wetting agents and / or emulsifiers, solubilizers, salts for regulating the osmotic pressure and / or buffers. The present pharmaceutical preparations which, if desired, may contain further pharmacologically active substances, are prepared in a manner known per se, for example. by means of conventional mixing, granulating, coating, dissolving or lyophilization processes, and containing from about 0.1% to 100%, in particular from about 1% to about 50%, lyophilizates up to 100% of the active substance.

The dosage may depend on various factors, such as route of administration, species, age and / or individual condition. Thus, the doses to be administered daily in one or more, preferably at most 4, single doses to warm-blooded animals for β-receptor blocker of formula I are between 0.03 and 3 mg / kg and for warm-blooded animals of about 70 kg preferably between about 0.005 and about 0.3 g.

The following examples serve to illustrate the invention; Temperatures are given in degrees centigrade.

Example 1: A solution of 20.0 g of crude 1- [N- [2- (4-carbamoyl-3-hydroxy-phenoxy) -1-methyl-ethyl] -benzylamino] -3- (4-methanesulfonyl)

aminophenoxy) -2-propanol in 250 ml of methanol is hydrogenated after addition of 2.5 g of Pd / C catalyst (5%) under normal conditions until the debenzylation is complete, (TLC control), to which an addition of another 1.0 g of the catalyst is needed. The catalyst is filtered off, the filtrate evaporated and the remaining OeI dissolved in a little hot isopropanol. After cooling, crystalline l- [2- (4-carbamoyl-3-hydroxy-phenoxy) -1-methyl-ethylamino] -3- (4-methanesulfonylamino-phenoxy) -2-propanol is obtained

of the mp. 147-150 ° (diastereomer mixture).

The starting material is obtained in the following manner:

_a ) According to the method described by Irvine et al., Synthesis 1972 , 56S, 2,4-dihydroxybenzamide is converted to the 2,3-dihydro-2, 2-din-ethyl-7-hydroxy-4H by using an excess of acetone -l, 3-benzoxazin-4-one, mp. 249-251 ° converted.

Ib) From 168 g of 2,3-dihydro-2,2-dimethyl-7-hydroxy-4H-l, 3-benzoxazin-4-one, 305 g of potassium carbonate and 88 ml of chloroacetone in 1.2 liters of acetonitrile is obtained by boiling during 28 hours and subsequent workup, the 2,3-dihydro-2,2-dimethyl-7- (2-oxopropoxy) -4H-l, 3-benzoxazin-4-one, mp. 160-162 ° (from isopropanol).

Ic) A solution of 75 g of crude 2,3-dihydro-2,2-dimethyl-7- (2-oxopropoxy) -4H-l, 3-benzoxazin ~ 4-one and 32 g of benzylamine in 1000 ml of methanol is added of 0.75 g conc. Sulfuric acid and 1.6 g of Pt / C catalyst (5%) hydrogenated to standstill of hydrogen uptake under normal conditions. After filtering off the catalyst and evaporating off the solvent, the oily residue is partitioned between 300 ml of ethyl acetate and 500 ml of 2N hydrochloric acid. From the aqueous phase is isolated by mixing with conc. Ammonia (ice cooling) and extraction with ethyl acetate crude 2,3 ~ dihydro-2,2-dimethyl-7 - [(2-benzylamino) -propoxy] -4H-l, 3-benzoxazin-4-one as OeI, which continues to use raw can be.

Id) A mixture of 100 g of crude 2,3-dihydro-2,2-dimethyl-7 - [(2-benzylamino) -propoxy] -4H-1,3-benzoxazin-4-one, 100 ml of isopropanol and 100 ml Isopropylamine is refluxed for 1 hour and then evaporated. The remaining OeI crystallizes on trituration with ether. The crystals are filtered off with suction and washed with a little isopropanol. This gives 4- [2- (benzylamino) -propoxy] -salicylamid, mp 121-123 °.

LOLJL · UU

le) A solution of 19.0 g of 4- [2- (3-benzylamino) -propoxy! -salicylamide.

and 12.4 g of 4- (2,3-epoxypropoxy) -nitrobenzene in 300 ml of isopropanol is refluxed for 20 hours. After addition of another 1.2 g of 4- (2,3-epoxypropoxy) -nitrobenzene is heated for a further 20 hours under reflux. Subsequently, the solvent is partially evaporated off, whereupon 1- [N- [2- (4-carbamoyl-3-hydroxyphenoxy) -l-methyl-ethyl] -benzylamino] -3- (4-nitrophenoxy) -2-propanol of the mp 160.-164 ° (diastereomer mixture) crystallized out.

If) A solution of 19.0 g of the resulting compound in 380 ml of dioxane is hydrogenated with the addition of 18 g of Raney nickel in 4 portions under normal conditions until the intake of 3 moles of hydrogen equivalent. After filtration and evaporation of the filtrate remains crude 1- [N- [2- (4-carbamoy1-3-hydroxy-phenoxy) -1-methyl-ethyl] -benzylamino] -3- (4-amino-phenoxy) -2- propanol as an orange-brown oil, which is further processed without further purification.

Ig) 16 g of the resulting compound are dissolved in 90 ml of anhydrous pyridine, and thereto dropwise added with cooling to 5-10 ° 4.4 g Methansulf onsäurechlorid. The reaction mixture is stirred for 4 hours at room temperature, the solvent was evaporated

and the residue is partitioned between 400 ml of ethyl acetate and 50 ml of water. The organic phase is washed three more times with 50 ml of water, dried over magnesium sulfate, treated with charcoal and evaporated, after which crude 1- [N- [2- (4-carbamoyl-3-hydroxy-phenoxy) -1-methyl- ethyl] -benzylamino] -3- (4-methanesulfonylamino-phenoxy) -2-propanol as an orange oil, which is further processed without further purification.

Example 2: A solution of 30 g of crude 1- [N- [2- (3-carbamoyl-4-hydroxy-phenoxy) -ethyl] -benzylamino] -3- [4- [2- (cyclopropylmethoxy) -ethyl] - phenoxy] -2-propanol in 600 ml of methanol is hydrogenated under normal conditions with the addition of 4 g of Pd / C catalyst (5/0 until 1 mole equivalent of hydrogen is taken up by addition of dioxane and heating to give the already crystallized product The catalyst is filtered off, the filtrate is filtered off and, after recrystallization from isopropanol, then from methanol, pure 1- [2- (3-carbamoyl-4-hydroxy-phenoxy) -ethylamino] -3- [4-] is obtained. [2- (cyclopropylmethoxy) ethyl] phenoxy] -2-propanol of mp. 149-150 °.

The starting material is prepared in the following manner:

2a) According to the method described by Irvine et al., Synthesis 1972, 568. Converted 2,5-dihydroxy-benzamide using an excess of acetone in 2,3-dihydro-2,2-dimethyl-6-hydroxy-4H-l, 3-benzoxazin-4-one, m.p. 215-216 °.

2b) 70 g of 2,3-dihydro-2, 2-dimethyl-6-hydroxy-4H-l, 3-benzoxazin-4-one are stirred in 400 ml of acetonitrile with 100 g of potassium carbonate and 32 ml of chloroacetone for 30 hours under reflux , After addition of a further 3.2 ml of chloroacetone, the reaction mixture is heated for an additional 15-20 hours. The still warm reaction mixture is filtered, the residue washed thoroughly with acetone and

  the combined filtrate evaporated. The crystalline residue is recrystallized from toluene to yield the 2,3-dihydro-2,2-dimethyl-6- (2-oxopropoxy) -4H-1,3-benzoxazin-4-one of mp 125-126 °.

232528

2c) 74 g of the resulting 2,3-dihydro-2,2-dimethyl-6- (2-oxo-propoxy) -4H-l, 3-benzoxazin-4-one are dissolved in a mixture of 150 ml of dioxane and 450 ml 2N hydrochloric acid heated for 45 minutes on a water bath. The solvent is evaporated and the crystalline residue triturated with water and then filtered with suction. Recrystallization from isopropanol gives the 5- (2-oxo-propoxy) -Salicylamid, mp 152-154 °.

2d) A solution of 104.5 g of 5- (2-oxo-propoxy) -salicylamide in 1000 ml of methanol with 55 g of benzylamine and 1.25 g of conc. Sulfuric acid and hydrogenated in the presence of 3.0 g of Pt / C catalyst under normal conditions until the absorption of 1 equivalent of hydrogen. The catalyst is filtered off, the solution is stirred with about 10 g of powdered calcium carbonate, filtered again and evaporated. The remaining OeI crystallizes from isopropanol. Recrystallization from isopropanol gives 5- [2- (3-enylamino) -propoxy] -salicylamide, mp. 102-104 °,

2e) A solution of 14.3 g of 1- [2- (cyclopropylmethoxy) ethyl] -4- (2,3-epoxypropoxy) benzene (DE-OS 26 49 605) and 16.3 g of 5- [ 2- (Benzylamino) -propoxy] -salicylamide in 200 ml of isopropanol is boiled under reflux for 18 hours. Evaporation of the reaction mixture gives crude 1- [N- [2- (3-carbamoyl-4-hydroxy-phenoxy) ethyl] benzylamino] -3- [4- [2- (cyclopropylmethoxy) ethyl] phenoxy ] -2-propanol as a brown oil, which is processed further without further purification.

Example 3: A solution of 50 g of crude 1- [N- [2- (3-carbamoyl-4-hydroxy-phenoxy) -zyl] -ber.zylami.no] -3- (4-methanesulfonylamino-phenoxy) After addition of 6 g of palladium-on-carbon catalyst (5%), 2-propanol in 550 ml of methanol is hydrogenated under normal conditions until hydrogen uptake has come to a standstill. The already crystallized product is brought by addition of dioxane and heating in solution, the catalyst was filtered off and the filtrate was evaporated. The crystalline evaporation residue yields after recrystallization from ethanol, then from methanol with the addition of activated carbon, the 1- [2- (3-carbamoyl-4-hydroxy-phenoxy) -ethylamino] -3- (4-raethansulfonylaminophenoxy) -2- Propanol of mp 152-153 °.

The starting material is produced in the following way:

3a) 19.5 g of 4- (2,3-epoxypropoxy) -nitrobenzoyl · and 28.6 g of 5- (2-benzylaminoethoxy) -salicylamide are refluxed in 400 ml of isopropanol for 20 hours. The crude l- [N- [2- (3-carbamoyl-4-hydroxy-phenoxy) -ethyl] -benzylamino] -3- (4-nitro-phenoxy) -2-propanol obtained as a viscous OeI after evaporation of the reaction mixture will be processed as such.

3b) 50 g of the crude compound obtained according to Example 3a) are dissolved in 500 ml of ethanol and hydrogenated in the presence of 5 g of Raney nickel. There are still 2 additions of 10g Raney nickel needed until the calculated amount (3 moles equiv.) Of hydrogen is added. After filtering off and evaporating the filtrate, crude '1- [N- [2- (3-carbamoyl-4-hydroxy-phenoxy) -ethyl] -benzylamino] -3- (4-amino-phenoxy) -2-propanol is obtained as a brown OeI.

3c) 44 g of the crude compound obtained according to Example 3b) are dissolved in 300 ml of anhydrous pyridine and added dropwise with stirring and cooling at 10-20 ° with 11.4 g of methanesulfonyl chloride. The reaction mixture is stirred overnight at room temperature, evaporated and between 500 ml of ethyl acetate and 100 ml

Δύ I 3 L OO

Water is distributed. The organic phase is separated, washed twice with 100 ml of water, dried over magnesium sulfate and evaporated. The crude 1- [N- [2- (3-carbamoyl-4-hydroxy-phenoxy) -ethyl] -benzylamino] -3- (4-methanesulfonylamino-phenoxy) -2-propanol so obtained as a tough OeI is purified without further purification further processed.

Example 4: A mixture of 11.5 g of 4- (2,3-epoxypropoxy) cinnamic acid N-methylamide and 7.4 g of 5- (2-aminoethoxy) salicylamide in 50 ml to about 80 ° dissolved solution of dimethylsulfoxide, the solution stirred for 1 hour at 75-85 ° and then poured into 500 ml of water. The precipitating resinous product is separated and stirred with 150 ml of ethyl acetate. The precipitated crystals are filtered off and recrystallized from a little isopropanol, after which 4- [3- [2- (3-carbamoyl-4-hydroxy-phenoxy) ethylamino] -2-hydroxy-propoxy] -N-methylzimtsäureamid of mp 170-171 ° (sinters from 148 °).

Example 5 : A solution of 41 g of crude 1- [N- {2- (3-carbamoyl-4-hydroxy-phenoxy) -ethyl] -benzylamino] -3- [4- (N-methylmethanesulfonylamino) -phenoxy] 2-Propanol in 410 ml of methanol is hydrogenated and worked up analogously to Example 3 in the presence of 4 g of palladium-on-carbon catalyst. Obtained after recrystallization from ethanol and methanol, the l- [2- (3-caramoyl-4-hydroxy-phenoxy) ethylamino] -3- [4- (N-methylmethanesulfonylamino) phenoxy] -2-propanol of mp. 120-121 °.

The starting material is prepared in the following manner:

5a) A solution of 103.7 g of 4-methylaminophenol sulfate in 330 ml of pyridine and 102 ml of N, N-Diisopropyläthylamin is added dropwise with ice cooling and stirring with 77 ml of methanesulfonyl chloride for about 30 minutes and stirred at room temperature overnight. The volatile constituents are evaporated off, the evaporation residue is partitioned between ethyl acetate and water, the organic phase is separated off and concentrated by evaporation, and the crystalline residue is removed.

stood with 300 ml of 6-n. Sodium hydroxide heated to complete dissolution on a water bath. The solution is filtered and adjusted to pH 2 with concentrated hydrochloric acid. In this case, the 4- (N-methylsulfonylamino) phenol crystallizes out. It is filtered off and dried in vacuo at 80 °; Mp 135-136 °.

5b) A mixture of 34.2 g of the compound obtained according to Example 5a), 35.2 g of potassium carbonate and 125 ml of epichlorohydrin is boiled for 2 hours with stirring and reflux. The suspension is filtered, the filtrate evaporated, partitioned between ethyl acetate and water, the organic phase separated, dried over magnesium sulfate and evaporated. The 4- (2,3-epoxy-propoxy) -N-methyl-methanesulfonanilide, mp. 96-100 ° (from methanol), is obtained.

5c) A solution of 19.0 g of the compound obtained according to Example 5b) and 21.4 g of 5- {2-Benzylaminoäthoxy) -salicylamide in 350 ml of isopropanol is refluxed for 5 hours. Evaporation gives crude 1- [N- (2- (3-carbamoyl-4-hydroxy-phenoxy) ethyl] benzylamino] -3- [4- (N-methyl-1-methanesulfonylamino) -phenoxy] -2- propanol as a viscous oil, which is further processed as such.

Example 6 A mixture of 13.9 g of 1- (4-methanesulfonylamino-phenoxy) -3-amino-2-propanol and 10.5 g of 4- (2-oxo-propoxy) -salicylamide is dissolved in ml of toluene with the addition of boiled a few drops of acetic acid on a water separator. After stopping the dehydration (-2-3 hours), the solution is evaporated, the dark red residue dissolved in 300 ml of ethanol and treated portionwise with stirring with a total of 5.7 g of sodium borohydride. The temperature rises up to 36 °. The reaction mixture is still 2 hours. 20-30 ° further stirred and

stand overnight. Under ice cooling, it is then with about ö n. Hydrochloric acid brought to pH 3-4, filtered and evaporated. The evaporation residue is partitioned between 100 ml of water and ethyl acetate, the aqueous phase is separated off, treated with conc. Ammonia made alkaline and extracted with 200 ml of ethyl acetate. After washing the organic phase with water, drying over sodium sulfate and evaporation of the solvent gives -l- [2- (4-carbamoyl-3-hydroxyphenoxy) -l-methyl-ethylamino] -3- (4-methanesulfonylamino-phenoxy) 2-propanol as a mixture of diastereomers, which is recrystallized from a little hot isopropanol; M.p. 147-150 °.

The required as starting material l- (4-methanesulfonylamino-phenoxy) -3-amino-2-propanol is prepared as follows:

6a) A mixture of 18.7 g of 4-methanesulfonylamino-phenol, 8.5 g of epichlorohydrin, 7 g of potassium carbonate and 70 ml of isopropanol is stirred for 2.5 hours at 90 °. The reaction mixture is filtered hot, the residue washed with isopropanol and the filtrate is concentrated under reduced pressure, finally at 0.03 Torr on the water bath, which is obtained as a residue, the 4-Methansulfonylamino- (2,3-epoxypropoxy) phenol.

A solution of 24.3 g of the product obtained in 170 ml of dioxane is treated with a solution of about 2 g of dry ammonia gas in 110 ml of dioxane and allowed to stand the reaction mixture in a sealed flask for 24 hours at room temperature. After removal of the excess ammonia and evaporation of the solvent under reduced pressure, crude 1- (4-methanesulfonylaminophenoxy) -3-amino-2-propanol is obtained, which is further processed as such.

Example 7; 23.2 g of 1- [2- (4-MeChoxycarbonyl-3-hydroxy-phenoxy) -1-methyl-1-ethylamino] -3- (4-methanesulfonylamino-phenoxy) -2-propanol are mixed with a mixture of 50 ml of dioxane and 500 ml conc. Ammonia solution added. The reaction mixture is stirred for 1-2 hours and, when it has become homogeneous, allowed to stand for 3 days at 20-30 °. Evaporation gives crude 1- (4-carbamoyl-3-hydroxy-phenoxy) -3- [2- (4-methanesulfonylamino-phenoxy) -l-methyl-ethylamino] -2-propanol as a mixture of diastereomers. This is dissolved in a little hot isopropanol and the solution is then cooled to give the compound pure, mp. 147-150 °.

The starting material can be obtained in the following manner:

7a) A solution of 24.3 g of 4- (2,3-epoxy-propoxy) -methanesulfonylaminophenol and 30 g of 4- (2-benzylamino-propoxy) -methoxycarbonyl-3-hydroxybenzene in 200 ml of isopropanol is refluxed for 24 hours , The crude product obtained after evaporation is between 2-n. Distributed hydrochloric acid and ether, the aqueous phase separated and treated with conc. A mm oniaklösung made alkaline. Exhaustive extraction with ethyl acetate, washing of the organic phase with water, drying over magnesium sulfate and evaporation gives crude 1- [N- [2- (4-carbomethoxy-3-hydroxy-phenoxy) -l-methyl-ethyl] -benzylamino]. -3- (4-methanesulfonylamino-phenoxy) -2-propanol, which is further processed as such in the next step.

7b) A solution of 46 g of l- [N- [2- (4-methoxycarbonyl -3-hydroxy-phenoxy) -1-methyläthy1] -benzyl-amino] -3- (4-methansulfο τψ lamino-phenoxy) -2 -propanol in 500 ml of methanol is hydrogenated with the addition of 5 g of palladium-on-carbon catalyst (5% strength) under normal conditions until the intake of 1 molar equivalent of hydrogen. The solution is filtered from the catalyst and the filtrate is concentrated to dryness, which gives crude 1- [2- (4-methoxycarbonyl-3-hydroxy-phenoxy) -1-methyl-ethylamino] -3- (4-methanesulfonylamino-phenoxy) -. 2-propanol, which is further processed as such.

£ D L

Example 8: A solution of 3.7 g of 1- [2- (3-cyano-4-hydroxy-phenoxy) -ethylamino] -3- [4-methanesulfonylaminophenoxy] -2-propanol in a mixture of 15 ml of conc , Hydrochloric acid and 25 ml of dioxane are kept at a temperature of 15 hours. 20-25 ° stirred. The reaction mixture is then evaporated and made alkaline with 10% aqueous ammonia solution. The deposited after several hours standing crude 1- [2- (3-carbamoyl-4-hydroxy-phenoxy) ethylamino] -3- [4-methanesulfonylamino-phenoxy] -2 - propanol is filtered off and from ethanol, then from Methanol recrystallized; Mp 152-153 °.

The required as starting material l- [2- (3-cyano-4-hydroxy-phenoxy) ethylamino] -3- [4-methanesulfonylamino-phenoxy] -2-propanol can be obtained as follows:

8a) A mixture of 6.5 g of 5- (2-bromoethoxy) -2-hydroxy-benzonitrile and 9.7 g of the obtained according to Example 6a) 1- (4-Methansulfonylaminophenoxy) -3-amino-2-propanol is in Oelbad melted at 100 ° and stirred magnetically for 1 hour. The melt is then boiled with 100 ml of isopropanol, the solution was filtered and the filtrate was evaporated. The evaporation residue is between 400 ml of ethyl acetate and 50 ml of 2-n. Potassium bicarbonate solution, the organic phase separated, washed with water, dried over magnesium sulfate and evaporated to give crude 1- [2- (3-cyano-4-hydroxy-phenoxy) -ethylamino] -3- [4-methanesulfonylaminophenoxy]. -2-propanol, which is further processed as such.

Example 9: 2.3 g of sodium metal are reacted with 45 ml of methanol. After the reaction has ended, the solution of 19.2 g of 4- (2-cyclopropylmethoxyethyl) phenol (German Offenlegungsschrift No. 2,649,605) in 110 ml of methanol is added and the mixture is refluxed for 1 hour on the water bath. Subsequently, the reaction mixture is evaporated to dryness under reduced pressure and the resulting sodium salt in 110 ml

LO L ^r JLQ O

Dimethylformamide slurried. To this is added a solution of 28.85 g of 5- [N- (3-chloro-2-hydroxy-propyl)] -aminoethoxysalicylamide in dimethylformamide (170 ml), and the mixture is heated for 3 hours with stirring on the boiling water bath. The solvent is removed under reduced pressure and the residue with. 200 ml of water, filtered off and the filter residue from isopropanol, then recrystallized from methanol, after which pure l- [2- (3-carbamoyl-4-hydroxyphenoxy) ethylamino] -3- [4- [2- (CyclopropyImethoxy) - äthy1] -phenoxy] -2-propanol of mp. 149-150 °.

The 5- [N- (3-chloro-2-hydroxypropyl)] - aminoethoxy-salicylamide required as starting material can be prepared as follows:

9a) A mixture of 48.2 g of 2,3-dihydro-2,2-dimethyl-6-hydroxy-4H-lj3-benzoxazin-4-one, 70 g of potassium carbonate and 250 ml of 1,2-dibromoethane is added with stirring and Reflux cooked for 4 hours. The slurry reaction mixture is extracted 3-4 times with 1 liter of methanol each time, the combined methanol extracts are evaporated and the residue is recrystallized from methanol. This gives 6- (2-3-methoxy-2,3-dihydro-2, 2-dimethyl-4H-1,3-benzoxazin-4-one, mp 190-195.

9b) A mixture of 60 g of 6- (2-bromoethoxy) -2,3-dihydro-2,2-dimethyl-4H-1,3-benzoxazin-4-one and 110 ml of benzylamine is placed in a bath of 80 ° stirred for 30 minutes. The reaction mixture is then on with ice cooling with conc. Hydrochloric acid brought to pH 3-4 and allowed to crystallize. To. The crystals are filtered off with suction for 2-4 hours, washed with 50 ml each of water and ethyl acetate and dried. The resulting 5- (2-benzylaminoethoxy) salicylamide hydrochloride melts at 214-216 °. The liberated base melts at 107-108 ° (from ethyl acetate-ether).

D L ö

9c) The 5- (2-aminoethoxy) salicylamide can be prepared by debenzylation using hydrogen in the presence of a Pd / C catalyst (5% strength) of the corresponding N-benzyl compound obtained according to Example 9b) in methanol: mp. 140 °.

9d) A solution of 19.6 g of 5- (2-aminoethoxy) salicylamide in 80 μl of methanol is added slowly to a solution of 9.25 g of epichlorohydrin in 30 ml of methanol, and the reaction mixture is stirred for 3 hours at 25 °. After evaporation of the solvent maa crude 5- [N- (3-chloro-2-hydroxy-propyl)] - aminoethoxy-salicylamid receives, which is further processed as such.

Example 10: To a mixture of 19.2 g of 4- (2-cyclopropylmethoxyethyl) phenol and 25.2 g of 1- [2- (3-carbamoyl-4-hydroxy-phenoxy) -ethyl] -3-azetidinol are added 0.4 g of solid potassium hydroxide and heated the mixture for 22 hours at 150 ° in a nitrogen atmosphere. After cooling, the reaction mixture with 2-n. Hydrochloric acid neutral, extracted with 100 ml of ether, the ethereal phase separated

and extracted with 2N hydrochloric acid. The aqueous phase is separated, concentrated with conc. Adjusted sodium hydroxide solution to neutrality and extracted the mixture with methylene chloride. After washing the organic phase with water and evaporation of the solvent, the residue obtained is recrystallized from isopropanol, then from methanol, after which the 1- [2- (3-carbamoyl-4-hydroxy-phenoxy) -ethylamino] -3- [ To obtain 4- [2- (cyclopropylmethoxy) ethyl] phenoxy] -2-propanol; Mp 149-150 °.

The required as starting material l- [2- (3-carbamoyl-4-hydroxyphenoxy) ethyl] -3-azetidinol can be obtained in the following manner:

10a) To a solution of 40 g of 5- (2-aminoethoxy) -2-benzyloxy-benzamide in 250 ml of 80% ethanol heated to 80 °, a solution of 15.4 g of 2-benzyloxy- add dropwise l, 3-dibromopropane in 95% ethanol and stir on the

temperature is still 12 hours. Subsequently, the solvent is largely removed, the residue with 2-n. Alkaline sodium hydroxide solution and the mixture extracted with ethyl acetate. The ethyl acetate solution is extracted with 2N hydrochloric acid until the reaction is acid, the organic phase is washed with water, dried over magnesium sulfate and evaporated to dryness, which gives crude 1- [2- (3-carbamoyl-4-benzyloxyphenoxy). ethylamino] -3-benzylazetidinol.

Hydrogenolysis by means of hydrogen in the presence of a palladium on carbon catalyst in methanolic solution until the absorption of 2 molar equivalent of hydrogen gives the said compound the 1- [2- (3-carbamoyl-4-hydroxy-phenoxy) -ethylamino] 3-azetidinol, which is further processed as such.

Example 11 Tablets containing 20 mg of active substance are prepared in the usual way in the following composition:

Composition:

1- [2- (3-carbamoyl-4-hydroxy-phenoxy) -

ethylamino] -3- [4- [2- (cyclopropyImethoxy) -äthy1] -

phenoxy] -2-propanol Wheat Starch Milk Sugar Colloidal Silica Talc

magnesium stearate

, 20 mg 60 mg 50 mg 5 mg 9 mg 1 mg

145 mg

Preparation: 1- [2- (3-carbamoyl-4-hydroxy-phenoxy) -ethylamino] -3- (4- [2- (cyclopropylmethoxy) -ethyl] -phenoxy] -2-propanol is mixed with a portion of the wheat starch, mixed with milk sugar and colloidal silica, and the mixture is passed through a sieve, another part of the wheat starch is gelatinized with 5 times the amount of water on the water bath, and the pulp mixture is kneaded with this paste until a slightly plastic mass is formed.

The plastic mass is forced through a sieve of about 3 mm mesh size, dried and the obtained dry granules are again driven through a sieve. Then the remaining wheat starch, talc and magnesium stearate are added and the mixture is compressed into tablets of 145 mg weight with score.

Example 12 Tablets containing 1 mg of active substance are prepared in the usual manner in the following composition:

Composition :

1- [2- (4-carbamoyl-3-hydroxy-phenoxy) -l-methyl-ethylamino] -3- (4-methanesulfonylaminophenoxy) -2-propanol 1 mg

Wheat starch 60 mg

• lactose 50 mg

Colloidal silica 5 mg talc 9 mg

Magnesium stearate 1 mg

126 mg

232528 8

Preparation: 1- [ 2- (4-Carbamoyl-3-hydroxy-phenoxy) -1-ethyl-ethylamino] -3- (4-methanesulfonyl-amino-phenoxy) -2-propanol is added to a portion of the wheat starch, with lactose and mixed colloidal silica and the mixture is forced through a sieve. Another part of the wheat starch is gelatinized with 5 times the amount of water on the water bath and the powder mixture kneaded with this paste until a weakly plastic mass is formed.

The plastic mass is forced through a sieve of about 3 mm mesh size, dried and the obtained dry granules are again driven through a sieve. Then the remaining wheat starch, talc and magnesium stearate are added and the mixture is compressed into tablets of 126 mg weight with score.

Example 13: Capsules containing 10 mg of active substance are prepared in the usual manner as follows:

Composition: 1- [2- (3-carbamoyl-4-hydroxy-phenoxy) -ethylamino] -3- [2- (2,3-dihydroxypropyl) -phenoxy] -2-propanol 2500 mg talc 200 mg

Colloidal silica 50 mg

Preparation: The active substance is intimately mixed with talc and colloidal silica, the mixture is forced through a sieve of 0.5 mm mesh size and this is filled into portions of 11 mg each into hard gelatine capsules of suitable size.

Example 14 : A sterile solution of 5.0 g of 1- [2- (3-carbamoyl-4-hydroxyphenoxy) ethylamino] -3- [2- (2,3-dihydroxypropyl) phenoxy] -2-propanol hydrochloride in 5000 ml distilled water is filled into 5 ml ampoules containing 5 mg of active ingredient in 5 ml of solution.

Example 15 Instead of the substances used as active substances in Examples H to 14, the following compounds of the formula I or their pharmaceutically usable non-toxic acid addition salts can also be used as active substances in tablets, dragees, capsules, ampoule solutions, etc. 2- (3-carbamoyl-4-hydroxyphenoxy) ethylamino] -3- (4-methylsulfonylamino) -phenoxy-2-propanol, 4- [3- [2- (3-Ca-bromoyl-4- hydroxy-phenoxy) -ethyl (2-hydroxypropoxy) -N-methylcinnamic acid amide or the 1- [2- (3-carbamoyl-4-hydroxy-phenoxy) ethylamino] -3- [4- (N-methyl-methanesulfonylamino) -phenoxy] -2-propanol.

Claims (6)

232528 8 Erf inctosgsanspruch 1. A process for the preparation of derivatives of 3-amino-l, 2-propanediol of the formula ? ^H ί OH H in which R Polyhydroxyniederalkyl, Cycloalkylniederalkoxyniederalkyl, in the 4-position bound Niederalkylsulfonylainino or 4 in abutment condition bound l-lower alk-2-vinyl and radicals of the formulas -CH.-CH - or 3, characterized in that ^f -CH-CH that he a) a compound of the formula X ₁ , 1 (II) with a compound of the formula OH _z - _alk - ^o i Y ^C0NH 2 (HD L O L Ό L O O wherein one of Z and Z is a reactive esterified Hydroxy group and the other for the primary amino group and X is hydroxy, or wherein X and Z together are the Epoxy group and Z is the primary amino group, and R ^ ₁ and alk have the above meaning, or b) in a compound of the formula ί -O-CH ₂ -CH-CH-N-alk-C-1 • - IJ ^ N ₃ (IV), Ox ₂ X ₃ in which R 'has the meaning of R or is lower alkylsulfonylamino which is bonded in the 4-position and is substituted on the nitrogen atom by a hydrogen-substitutable substituent, X_, X, X and X_ are each hydrogen or a substituent which can be replaced by hydrogen or X and X, and / or X, and X_ 2 3 4 D together represent a divalent radical which can be replaced by two hydrogen atoms, with the proviso that at least one of the radicals X, X_, X, and X. is different from hydrogen, or at least R '3 4 J 11 4-membered lower alkylsulfonylamino substituted on the nitrogen atom by a hydrogen-substitutable substituent, or at least X and X together or X and X together represent a bivalent group substitutable by two hydrogens, or in a salt thereof, that of hydrogen different groups X, X, X and X_ or X and X together and / or X and X together split off and replaced by hydrogen atoms, and / or a substituent substituted on the nitrogen atom of the 4-position lower alkylsulfonylamino R 'hydrogen substitutable by hydrogen replaced, or, L · Ό Ο c) in. A compound of the formula O - \ IO-CH -CH-X _n -C-4- 'r ^LOm 2' W. OX. wherein X is a reducible group of formulas 6 -CH-N-alk - (Va), or
-CH ₂ -N = alkj - (Vb) where alk is an alkylylidene radical corresponding to the radical alk and X is hydrogen or a radical which can be replaced by hydrogen under the conditions for the reduction of X, R 'represents the meaning of R, or lower-alkylsulfonylamino, bonded in 4-membered form, substituted on the nitrogen atom by a hydrogen-displaceable substituent X, in which X has the meaning given above, where X _{c is} always a re-7 o ducible group Va or VIi, this group reduces and at the same time that of hydrogen
Replaced hydrogen, or d) a compound of the formula early split off the non-hydrogen group X and through If 11 V "-O-CH-CH-CH.-N-alk-Ol · - ΐΓ ^{0ΟΟΗ (VI>>} \ / ² i ² | OH H in which R "has the meaning of R or in the 4-position bonded to the nitrogen atom by a by means of ammonolysis by a hydrogen-substitutable substituent substituted lower alkylsulfonyl represents amino, X hydrogen or one by means of ammonolysis cleavage or a reactive derivative of one of the carboxylic acid defined in formula VI, with ammonia (VII) is reacted, and at the same time optionally eliminates any residues present X ₀ and replaced by hydrogen, or e) in a compound of the formula OH in which one or all of the hydroxyl groups and / or the secondary nitrogen atom and / or lower alkylsulfonylamino R bonded to the nitrogen atom is optionally substituted by such groups which can be eliminated by hydrolysis and replaced by hydrogen, which are split off under the conditions of the process and hydrogen be replaced, the group -CN by hydrolysis into the group -CONH converts, and at the same time optionally on the nitrogen atom of a 4-linked lower alkylsulfonylamino group and / or on one or all hydroxy groups and / or on the secondary nitrogen atom protecting groups, and replaced by hydrogen , or f) a compound of the formula (VIII) 232528 with a compound of the formula OH.
I Z.-CH-CH-CH-N-alk-0 - + - || - ^C0NH 2
' ² I ² I% / wherein Z is a reactive, esterified hydroxy group and X is hydroxy, or wherein Z and X together represent the epoxy group, or with a corresponding ring-closed compound of the formula OH wherein R. and alk each have the meaning given, and X is hydrogen, or a group which can be split off under the conditions of the process and is capable of reacting with the hydroxy group of a compound of the formula X to form the ether bond, is reacted _, but without _; if desired, converting a free compound obtained into a salt or a salt obtained into a free compound, and / or, if desired, separating a mixture of isomers obtained into the isomers or a racemate obtained into the anti-iodine. » 2. The method according to item 1, characterized in that 1- [N- [2- (4-carbamoyl-3-hydroxy-phenoxy) -l-methyl-ethyl] benzylamino] -3- (4-methanesulfonylamino-phenoxy ) -2-propanol hydrogenated by means of hydrogen to l- [2- (4-carbamoyl-3-hydroxy-phenoxy) -l-methyl-ethylamino] -3- (4-methanesulfonylamino-phenoxy) -2-propanol. Loose D IO C 3. Method according to point 1, characterized in that l- [N- [2- (3-Ca.rbamoyl-4-hydro: -cy-phenoxy) -ethyl] -ben2ylainino-3 ~ [4- [2- Cyclopropylmethoxy) ethyl] phenoxy] -2-propanol using hydrogen to give 1- [2- (3-carbamoyl-4-hydroxy-phenoxy) ethylamino] -3- [4- [2-cyclopropylmethoxy) ethyl] phenoxy] -2-propanol hydrogenolyzed. 4. Method according to item '- 1, characterized in that l- [N- [2- (3-carbamoyl-4-hydroxy-phenoxy) -ethyl] -benzylamino] -3- (4-methanesulfonylamino-phenoxy) - 2-propanol is hydrogenolyzed by hydrogen to l- [2- (3-carbamoyl-4-hydroxy-phenoxy) ethylamino] -3- (4-methanesulfonyl-in-nophenoxy) -2-propanol. 5. The method according to 'item' 1, characterized in that 4- (2, '3-epoxy-propoxy) cinnamic acid-N-methylamide with 5- (2-Aminoäthoxy) -salicylamid 4- [3- [2- (3-carbamoyl-4-hydroxy-phenoxy) ethylamino] -2-hydroxy-propoxy] -N-methyl-cinnamamide. 6. The method according to one of -ptaakt- 1 ~ ^5, characterized in that one converts a compound of formula I obtained in a pharmaceutically acceptable non-toxic Säureaddxxonssalz.