NO861370L - PROCEDURES FOR THE PREPARATION OF THERAPEUTIC ACTIVRANILIN DERIVATIVES. - Google Patents

Description

This invention relates to a method for

position of dichloroaniline derivatives with a stimulating effect on 32~ac^renoresePtors•

The present invention thus provides a method for the preparation of compounds according to the general formula (I):

where

X represents a C 1 -3 alkylene or C 1 -alkynylene chain;

Y represents a C 1 --alkylene chain;

12

R and R each represent hydrogen or methyl; and Ar represents a phenyl group optionally substituted with a fluorine atom, a group selected from amino, C 1 -alkyl (e.g.

methyl), C 1-2 -alkyl (e.g. methoxy), hydroxy-C 1-2 -alkyl (e.g. hydroxymethyl), morpholino, hydroxy or -NHCOR^ where R is C 1-2 -alkyl (e.g. methyl), or Ar is a phenyl group substituted with hydroxyl groups in the 3- and 5-positions; and physiologically satisfactory salts and solvates thereof.

It will be understood that the connections according to the general

formula (I) has one or two asymmetric carbon atoms, viz

1 2

the carbon atom in the -CH group and where R and R are different

OH

groups, the carbon atom to which these are attached.

The compounds produced according to the invention thus include all enantiomers, diastereoisomers and mixtures thereof, including racemates. Compounds where the carbon atom in the -CH group is in the R configuration are preferred.

OH

A particularly preferred group of compounds according to

formula (I) are those where Ar is a phenyl group which optionally contains one substituent, more preferably an amino, methoxy, NHAcetyl or morpholino group.

Particularly important compounds produced according to the invention are: 4-amino-3,5-dichloro-a-[[[6-[2-[4-(4-morpholinyl)phenyl]-ethoxy]-hexy1]amino]methyl]benzenemethanol; N-[4-[2-t[6-[[2-(4-amino-3,5-dichlorophenyl)-2-hydroxyethyl]amino]hexyl]oxy]ethyl]phenyl]acetamide;

4-amino-3,5-dichloro-α-[[[5-[2-(4-methoxyphenyl)ethoxy]pentyl]-amino]methyl]benzenemethanol;

and the physiologically satisfactory salts and solvates thereof.

Suitable physiologically acceptable salts of the compounds of general formula (I) include acid addition salts derived from inorganic and organic acids, such as hydrochlorides, hydrobromides, sulfates, phosphates, maleates, tartrates, citrates, benzoates, 4-methoxybenzoates,

2- or 4-hydroxybenzoates, 4-chlorobenzoates, p-toluenesulfonates, methanesulfonates, sulfamates, ascorbates, salicylates, acetates, fumarates, succinates, lactates, glutarates, gluconates, tricarballylates, hydroxynaphthalene carboxylates, e.g. 1-hydroxy- or 3-hydroxy-2-naphthalene carboxylates or oleates. The compounds can also form salts with suitable bases. Examples of such salts are alkali metal salts (eg sodium and potassium salts) and alkaline earth metal salts (eg calcium or magnesium salts).

The compounds produced according to the invention have a stimulating effect on 32-α<3 renoreceptors which also have a particularly advantageous profile. The stimulatory effect was demonstrated on the isolated guinea pig trachea, where the compounds were shown to cause relaxation of PGF2a-induced contractions. Compounds produced according to the invention have shown a particularly long-lasting effect in this test.

The compounds produced according to the invention can be used in the treatment of diseases associated with reversible airway obstruction such as asthma and chronic bronchitis.

The compounds produced according to the invention are also indicated to be suitable for the treatment of inflammatory and allergic skin diseases, congestive heart failure, depression,

for early labor pains and glaucoma and in the treatment of conditions where it is beneficial to reduce gastric acidity, especially in the case of gastric and peptic ulcers.

The invention consequently further provides a method for the preparation of compounds according to formula (I) and physiologically satisfactory salts and solvates thereof for use in therapy or prevention of diseases associated with reversible airway obstruction in humans or animals.

The compounds of the invention may be formulated for administration by any suitable means. The invention therefore includes within its scope the production of pharmaceutical preparations comprising at least one compound according to formula (I) or a physiologically satisfactory salt or solvate thereof designed for use in human or veterinary medicine. Such preparations can be presented for use with physiologically satisfactory carriers or additives, possibly with supplementary medicinal products.

The compounds may be formulated in a form suitable for administration by inhalation or inhalation, or for oral, buccal, parenteral, topical (including nasal) or rectal administration. Administration by inhalation or inhalation is preferred.

A suggested daily dosage of active compound for the treatment of humans is from 0.005 to 100 mg, which may conveniently be administered in one or two doses. The exact dose used will of course depend on the patient's age and condition and on the method of administration.

The compounds produced according to the invention can be produced by a number of methods, as described therein

1 2

the following, where X, Y, Ar, R and R are as indicated for the general formula (I) unless otherwise specified. It will be understood that some of the reactions described below can affect other groups in the starting material that are desirable in the final product; this applies in particular to the reduction processes described, especially where hydrogen and a catalyst are used, and when an acetylene bond is required in the compound produced according to the invention. One must therefore, according to conventional practice, be careful either to use reagents that will not affect such groups or to carry out the reaction as part of a sequence that avoids their use when such groups are present in the starting material.

In the production of both intermediates and final products, the final step in the reaction may be the removal of a protecting group. Conventional protecting groups can be used, such as e.g. described in. "Protective Groups in Organic Chemistry", ed. J. F. W. McOmie (Plenum Press, 1973). Thus, hydroxyl groups can e.g. are protected with aralkyl groups such as benzyl, diphenylmethyl or triphenylmethyl, or as tetrahydropyranyl derivatives. Suitable amino-protecting groups include aralkyl groups such as benzyl, α-methylbenzyl, diphenylmethyl or triphenylmethyl, and acyl groups such as acetyl, trichloroacetyl or trifluoroacetyl.

Conventional methods for uncovering can be used. Thus, e.g. aralkyl groups are removed by hydrogenolysis in the presence of a metal catalyst (e.g. palladium on charcoal). Tetrahydropyranyl groups can be cleaved by hydrolysis under acidic conditions. Acyl groups can be removed by hydrolysis with a base such as sodium hydroxide or potassium carbonate, or a group such as trichloroacetyl can be removed by reduction with e.g. zinc and acetic acid.

In one general method (1), a compound according to the general formula (I) can be prepared by alkylation. Conventional alkylation methods can be used.

Thus, it can e.g. in one method (a), a compound according to the general formula (I) where R"*" is a hydrogen atom is prepared by alkylating an amine according to the general formula (II)

(where R^ is a hydrogen atom or a protecting group and R^

is a hydrogen atom) followed by removal of any protecting group(s).

The alkylation (a) can be carried out using an alkylating agent according to the general formula (III):

(where L is a leaving group, eg a halogen atom such as chlorine, bromine or iodine, or a hydrocarbylsulfonyloxy group such as methanesulfonyloxy or p-toluenesulfonyloxy).

The alkylation is preferably carried out in the presence of a suitable acid scavenger, e.g. inorganic bases such as sodium or potassium carbonate, organic bases such as triethylamine, diisopropylethylamine or pyridine, or alkylene oxides such as ethylene oxide or propylene oxide. The reaction is conveniently carried out in a solvent such as acetonitrile or an ether, e.g. tetrahydrofuran or dioxane, a ketone, e.g. butanone or methyl isobutyl ketone, a substituted amide, e.g. dimethylformamide, or a chlorinated hydrocarbon, e.g. chloroform, at a temperature between ambient temperature and the reflux temperature of the solvent.

According to another example (b) of an alkylation method, a compound according to the general formula (I) where R"*" represents a hydrogen atom can be prepared by alkylating an amine according to the general formula (II), as previously described , except that R^ is a hydrogen atom or a group which can be converted into this under the reaction conditions, with a compound according to the general formula (IV):

in the presence of a reducing agent, where necessary followed by removal of any protecting groups.

Examples of suitable R groups which can be converted into a hydrogen atom are arylmethyl groups such as benzyl, α-methylbenzyl and benzhydryl.

Suitable reducing agents include hydrogen in the presence of a catalyst such as platinum, platinum oxide, palladium, palladium oxide, Raney nickel or rhodium on a support such as charcoal, using alcohol, e.g. ethanol or methanol, or an ester, e.g. ethyl acetate, or an ether, e.g. tetrahydrofuran, or water as reaction solvent, or a mixture of solvents, e.g. a mixture of two or more of those just described, at normal or elevated temperature and pressure, e.g. at from 20 to 100°C and from 1

to 10 atmospheres.

7 8

When one or both of R and R are hydrogen atoms, alternatively the reducing agent may be a hydride such as diborane or a metal hydride such as sodium borohydride, sodium cyanoborohydride or lithium aluminum hydride. Suitable solvents for the reaction with these reducing agents will depend on the particular hydride used, but will include alcohols such as methanol or ethanol, or ethers such as diethyl ether or tert-butyl methyl ether or tetrahydrofuran.

When a compound according to formula (II) is used

where R 7 and R 8 are each hydrogen atoms, the intermediate imine according to formula (V) can be formed:

Reduction of the imine using the conditions described above, where necessary followed by removal of any protecting groups, gives a compound of general formula (I).

Where it is desirable to use a protected intermediate according to the general formula (II), it is particularly suitable to use hydrogen and a catalyst as described above, with protective groups R 7 which can be converted into a hydrogen atom under these reducing conditions, thus avoiding the need for a separate detection step. Suitable protecting groups of this type include arylmethyl groups such as benzyl, benzhydryl and α-methylbenzyl.

In another general method (2), a compound according to the general formula (I) can be prepared by reduction. Thus, e.g. a compound according to the general formula (I) is prepared by reduction of an intermediate according to the general formula (VI):

4 12 3 where at least one of X , X , X , X and Y represents a reducible group and/or Ar contains a reducible group and the 4 1 others have the appropriate meaning as follows: X is -NH2 , X is -CH(OH)-, X<2> is -CH2NR<7-> and X3 is -CR<1>R<2>X - where necessary followed by removal of any protecting groups.

Suitable reducible groups include those where X 4 is

1 2 -NO2, X is a -C=0 group, X is a -CH2NY<1> group (where Y' represents a group which can be converted to hydrogen by catalytic hydrogenation, e.g. an arylmethyl group such as benzyl, benzhydryl or α-methylbenzyl), or an imine-(CH=N) group or a -CONH group, X<3>is a -COX group or a CR 1 R 2X group (where X is C-, .<->alkenylene or C,

2 3 2

alkynylene) or -X -X - is a -CH2N=CR X group, Y is C2_3~alkenylene or -alkynylene and Ar is a phenyl group substituted mgerd uppen e hnviotr rogR r9 upepr e hyedlrleogr emn ed elelen r -CeHn O-aglkryuplp - e (efl.elker s. en C1_-C3O~a z-R lk9y-l-)

group.

The reduction can be carried out using reducing agents which are suitably used for the reduction of carboxylic acids, aldehydes, esters, ketones, imines, amides, protected amines, alkenes, alkynes and nitro groups. When, for example, X 4 in the general formula (VI) represents a nitro group, or the phenyl group Ar contains a nitro substituent, this can be reduced to a -NH2~ group using hydrogen in the presence of a catalyst as previously described for method (1)

part (b).

When X"*" in the general formula (VI) represents a C=0 group, this can be reduced to a -CH(OH) group using hydrogen in the presence of a catalyst as previously described for method (1) part (b). Alternatively, the reducing agent can e.g. be a hydride such as diborane or a metal hydride such as lithium aluminum hydride, sodium bis(2-methoxyethoxy)aluminum hydride, sodium borohydride or aluminum hydride. The reaction can be carried out in a solvent, suitably an alcohol, e.g. methanol or ethanol, or an ether such as tetrahydrofuran or a halogenated hydrocarbon such as dichloromethane.

When X 2 in the general formula (VI) represents a

-CH„z NY' group or the group -CH=N-, or -X 2 -X<3->represents -CH^N=CR X-, this can be reduced to a -CH2NH- or -CH2NHCHR X group using hydrogen in the presence of a metal catalyst as previously described for method (1) part (b). Alternatively, when X<2>or -X<2->X<3->is the group -CH=N-or -CH2N=CR<2>X-, this can be reduced to a -CH2NH- or -CH_NHCHR X- group using a reducing agent and conditions as just described for the reduction of X when this represents a -C=0 group. When X 2 or X 3 in the general formula (VI) represents a -CONH or -COX group, this can be reduced to resp. a -CH2NH- or -CH-jX group using a hydride such as diborane or a complex metal hydride such as lithium aluminum hydride or sodium bis(2-methoxyethoxy)aluminum hydride in a solvent such as an ether, e.g. tetrahydrofuran or diethyl ether.

When X 3 represents a CR 1R 2X group where X is ^ 2- 4~ alkenyl or C-^^-alkynyl, or Y represents ^ 2- 3~ alkenyl or C 2_3~ alkynyl, this can be reduced to resp. C 3 -alkylene or C 3 -alkylene using hydrogen

in the presence of a catalyst as previously described for method (1) part (b).

group Nhår voAr r R e9 r is phenhyidl rosugben stietluelerr t amlked yle, n ka-Cn HO- denne ller du-CsOer~zR es q-til phenyl substituted with a hydroxymethyl group using e.g. a complex metal hydride such as lithium aluminum hydride or sodium borohydride.

In the general methods described above, the obtained compound according to formula (I) can be in the form of a salt, suitably in the form of a physiologically satisfactory salt. Where desired, such salts can be converted into the corresponding free base using conventional methods.

Physiologically satisfactory salts of the compounds according to the general formula (I) can be prepared by reacting a compound according to the general formula (I) with a suitable acid or base in the presence of a suitable solvent such as acetonitrile, acetone, chloroform, ethyl acetate or an alcohol , e.g. methanol, ethanol or isopropanol.

Physiologically satisfactory salts can also be prepared from other salts, including other physiologically satisfactory salts, of the compounds according to the general formula (I) using conventional methods.

When a specific enantiomer of a compound of general formula (I) is required, this can be obtained by resolving a corresponding racemate of a compound of general formula (I) using conventional methods. Alternatively, enantiomers of a compound of general formula (I) may be synthesized from the appropriate optically active intermediates using any of the general methods described herein.

Specific diastereoisomers of a compound according to formula (I) can be obtained by conventional methods, e.g. by synthesis from a suitable asymmetric starting material using any of the methods described herein, or by converting a mixture of isomers of a compound of general formula (I) into suitable diastereoisomeric derivatives, e.g. . salts which can then be separated by conventional aids, e.g. by fractional crystallization.

The intermediate products used in the above-mentioned general methods are either known compounds or they can be prepared by methods analogous to those described for the production of known compounds. Suitable methods are described in British Patent Specifications Nos. 2140800A and 2159151A and in the exemplary material included below.

The following examples illustrate the invention.

Temperatures are in °C. "Dried" refers to drying

using magnesium sulfate, except where otherwise indicated. Thin layer chromatography (t.l.c.) was performed over SiC^. Flash column chromatography

(FCC) was performed on silica (Merck 9385). The following abbreviations are used: THF - tetrahydrofuran; EA - ethyl acetate; ER - diethyl ether; CX - cyclohexane; H-hexane; DMF - dimethylformamide; DCM - dichloromethane; TE - triethylamine; ME - methanol;

T - toluene; ET - ethanol.

Intermediate 1 discussed below is 1-(4-amino-3,5-dichlorophenyl)-2-bromo-1-ethanone.

Intermediate product 2

[2-[(5-bromo-2-pentynyl)oxy]ethyl]benzene

(i) [ 2- [ ( 2- propynyl) oxy] ethyl] benzene

A mixture of benzeneethanol (12.2 g), 3-bromo-1-propyne (12.0 ml), 40% aqueous sodium hydroxide (20 ml) and tetrabutylammonium bisulfate (1 g) was stirred overnight. Water (100 mL) was added and the mixture was extracted with ER (2x100 mL).

The organic extracts were washed with water and brine, dried and concentrated to a dark oil, which was purified by FCC eluting with CX-ER (19:1) to give the title compound as a pale yellow oil (12.3 g). T.l.c. (CX-ER 19:1 Rf 0.50.

(i i) 5-(2-phenylethoxy)-3-pentyl-1-ol

n-Butyllithium (1.6M in hexane, 35 mL) was added to a stirred solution of the product from step (i) (8.0 g) in dry THF (50 mL) at -78° under nitrogen. Boron trifluoride etherate

(6.8 mL) was added and the mixture was stirred at -78° for 30 min. Oxirane (7 mL) was added and the mixture was stirred at -78°

for 1 hour, treated with saturated aqueous ammonium chloride (100 ml), allowed to warm to room temperature and was extracted with ER (2x100 ml). The organic extracts were washed with water and brine, dried and concentrated to an orange oil, which was purified by FCC eluting with H-ER (2:1) to give the title compound as a pale yellow oil (3.95 g). T.l.c. (H-ER 2:1) Rf 0.10.

(iii) [ 2-[( 5- bromo- 2- pentynyl) oxy]- ethyl] benzene

A solution of triphenylphosphine (5.25 g) in dry DCM

(15 mL) was added to a solution of the product from step (ii) (3.9 g) and carbon tetrabromide (6.63 g) in dry DCM (25 mL) at 0° over 10 min. The yellow solution was stirred at 0° for 30 min., evaporated onto silica (Merck 9385) and purified by FCC eluting with H -> H-ER (3:1) to give the title compound as a colorless oil (2, 7g). T.l.c. (H-ER 2:1)

Rf 0.69.

Intermediate product 3

N-[1-methyl-5-(2-phenylethoxy)pentyl]-benzenemethanamine

(i) 6-(2-phenylethoxy)-2-hexanone

[2-(4-Bromobutoxy)ethyl]benzene (10.0 g) in dry ether (80 mL) was added dropwise to magnesium turnings (0.946 g) under nitrogen with stirring, obtaining a slight reflux. The reaction mixture was refluxed for 1 hour, allowed to cool to room temperature and was added dropwise to acetic anhydride (8.07g) in dry ether (55ml) at -70° under nitrogen with stirring over 1.5 hours. The reaction mixture was stirred at -70° for 2 hours, allowed to warm to -10° and then treated with saturated ammonium chloride (100 mL). The organic phase was separated and the aqueous phase was re-extracted with ER (150 mL). The combined organic extracts were washed with 2N aqueous sodium hydroxide (150 mL) and brine (150 mL), dried and evaporated to give an oil (7.54 g), which was purified by FCC eluting with ER-CX (1 :3), giving the title compound as a colorless oil (4.34 g). T.l.c. (ER-CX 1:3) Rf 0.25.

(i i) N-[1-methyl-5-(2-phenylethoxy)pentyl]benzenemethanamine

The product from step (i) 4.16 g) and benzylamine (2.03 g) in toluene (50 ml) were refluxed using a Dean-Stark apparatus for 1 hour. The toluene solution in ethanol (100 ml) was hydrogenated over pre-reduced 5% platinum oxide on charcoal (0.40 g). The reaction mixture was filtered ("hyflo") and evaporated to give an oil (5.73 g), which was purified by FCC eluting with EA-CX (1:4) + 1% TE, as

the title compound was obtained as a yellow oil (4.51 g).

T.l.c. (EA-CX 1:4 + a few drops of TE) Rf 0.11.

Intermediate product 4

2, 2, 2- trifluoro- N-[ 6-[ 2-[ 4-( 4- morpholinyl) phenyl] ethoxy] hexyl]- N -(phen<y>lmet<y>l)- acetamide

A solution of N-[6-[2-(4-aminophenyl)ethoxy]hexyl]-2,2,2-trifluoro-N-(phenylmethyl)acetamide (10.0 g), 2-chloroethyl ether (3.38 g ), N,N-diisopropylethylamine (6.14 g) and sodium iodide (7.11 g) in DMF (500 mL) was stirred at 100° for 2 days under nitrogen. The solvent was evaporated and water (200 mL) was added to the residue. The mixture was extracted with EA

(3 x 200 mL), and the combined dried (Na 2 SO 4 ) extracts were concentrated to give an oil (16.5 g), which was purified by FCC eluting with ER-CX (1:2) to give the title compound as an orange oil (3.49 g). T.l.c. (ER-CX 1:1) Rf 0.26.

Intermediate 5

N-[ 6-[ 2-[ 4-( 4- morpholinyl) phenyl] ethoxy] hexyl] benzenemethanamine

Intermediate 4 (3.25 g) in methanol (40 mL) was stirred under nitrogen for 16 h with potassium carbonate (9.0 g). More potassium carbonate (4.5 g) was added and after 24 hours water (50 ml) was added. The mixture was extracted with EA (3 x 50 mL), and the combined extracts were washed with water (50 mL) and brine (50 mL), dried (Na 2 SO 4 ) and concentrated to give the title compound as an orange oil (2.59 g) .

T.l.c. (EA + a few drops of TE) Rf 0.18.

Intermediate 6

N-[ 4-[ 2-[[ 6-[( phenylmethyl) amino] hexyl] oxy] ethyl] phenyl] acetamide

Acetic anhydride (1.53 g) in DCM (25 mL) was added dropwise to an ice-cooled solution of N-[6-[2-(4-aminophenyl)ethoxy]hexyl]-2,2,2-trifluoro-N (phenylmethyl)acetamide (6.34 g) in pyridine (1.19 g) and DCM (25 mL) under nitrogen. After 4 hours at room temperature, the solvent was evaporated and the residual oil in methanol (40 mL) was stirred under nitrogen with potassium carbonate (9.0 g) for 40 hours, with more potassium carbonate (4.0 g) being added after 24 hours. The mixture was diluted with water (100 mL) and extracted with EA (3 x 100 mL). The combined extracts were washed with water (100 mL) and brine (100 mL), dried (Na 2 SO 4 ) and concentrated to an oil (5.19 g), which was purified by FCC eluting with EA-TE (100: 1), giving the title compound as an orange oil (2.94 g). T.l.c. (EA + a few drops of TE) Rf 0.15.

Intermediate product 7

N-[ 6-[ 2-( 4- nitrophenyl) ethoxy] hexyl] benzenemethanamine

The title compound was prepared as an orange oil, t.l.c. (EA-CX 1:2 with a few drops of TE) Rf 0.33, by a conventional reaction sequence using 4-nitrobenzene-ethanol, 1,6-dibromohexane and benzylamine as starting materials.

Intermediate 8

1,1-dimethyl-5-[2-[4-(4-morpholinyl)phenyl]ethoxy]pentanamine

(i) 4-(4-morpholinyl)benzeneethanol

4-Aminobenzeneethanol (20.2 g), 2-chloroethyl ether (21.1 g), N,N-diisopropylethylamine (38.1 g) and potassium iodide (48.8 g) in DMF were heated to 80° under nitrogen for 60 hours. The solvent was evaporated and the residue (~143 g) was purified by FCC eluting with ER-CX (1:1-»1:0) to give the title compound as a pale red-white solid (17.7 g) , m.p. 57°.

(ii) 4-[ 4-[ 2-[( 4- bromobutyl) oxy] ethyl] phenyl] morpholine

The product from step (i) (17.6 g), 1,4-dibromobutane (30 mL), 12.5 M aqueous sodium hydroxide (100 mL) and tetra-n-butylammonium bisulfate (2.0 g) were stirred rapidly at room temperature for 16 hours. The mixture was diluted with water (400 mL), extracted with ER

(3x400 ml) and the combined extracts were washed with water (400 ml) and brine (400 ml) successively, dried and concentrated to give an oil (53.5 g), which was purified by FCC eluting with ER -CX (0.1-»1:5), giving the title compound as an orange oil (20.1 g). T.l.c. ER-hexane (1:5) Rf 0.1.

(iii) 2,2-Dimethyl-6-[2-[4-(4-morpholinyl)phenyl]ethoxy]hexanoic acid n-butyllithium i. Hexane (1.53M, 113.5 mL) was added dropwise to N,N -diisopropylamine (17.9 g) in THF (100 ml) at

-78° under nitrogen. The mixture was warmed to 0°, stirred i

1 hour and treated dropwise with isobutyric acid (7.65 g) in THF

(20 ml). The resulting suspension was stirred at room temperature for 3 hours, and the product from step (ii) (20.0 g) was added dropwise. The reaction mixture was stirred for 16 hours at room temperature, and the solvent was evaporated. The resulting oil was partitioned between EA (250 mL) and water (250 mL). The aqueous phase was acidified to pH 6 with 2N aqueous hydrochloric acid, and the organic extract was separated. The aqueous phase was extracted with EA (250 mL) and the combined extracts were concentrated to recover the title compound as an orange oil (20.4 g). T.l.c. (ER) Rf 0.53.

(iv) (phenylmethyl)-[ 5-[ 2-[ 4-( 4- morpholinyl) phenyl] ethoxy]-pentyl ] ' kar barnat

Ethyl chloroformate (3.29 g) in acetone (10 mL) was added dropwise to a solution of the product from step (iii) (10.0 g) and triethylamine (3.0 g, 30 mmol) in acetone (100 mL) and water

(10 ml) at 0°. The mixture was stirred at 0° for 40 min and sodium azide (2.0 g) in water (25 ml) was added dropwise. The resulting suspension was stirred at room temperature for 45 min, diluted with water (200 mL) and extracted with T (2x200 mL).

The dried (Na 2 SO 4 ) extract was heated at 75-80° i

2.5 hours and evaporated. The residue was treated with benzyl alcohol (20 mL), and heated at 75-80° for 60 hours, and the benzyl alcohol was removed by distillation (~1 mm Hg). The resulting oil was purified on a column of silica (Merck 9385) eluting with ER-CX (1:2) to give the title compound as a yellow oil (4.74 g). T.l.c. ER-CX (1:2) Rf 0.13. (v) 1,1-dimethyl-5-[2-[4-(4-morpholinyl)phenyl]ethoxy]pentanamine The product from step (iv) (7.50 g) in ethanol (80 ml) was hydrogenated over 10% palladium on charcoal (50% paste in water,

1.0 g). The reaction mixture was filtered ("hyflo") and the solvent was evaporated to give an oil (5.99 g), which was purified by FCC eluting with EA-ME-TE (66:33:1), giving the title compound was obtained as a yellow oil (2.84 g). T.l.c. EA-ME-TE (66:33:1) Rf 0.26.

Intermediate 9

N-[ 5-[ 2-[ 4- methoxyphenyl] ethoxy] pentyl] benzenemethanamine hydrochloride

(i) 1-[ 2-[( 5-bromopenty1)oxy]ethy1]- 4- methoxybenzene

A mixture of 4-methoxybenzeneethanol (7.0 g), 1,5-dibromopentane (20 mL), 50% aqueous sodium hydroxide (30 mL) and tetra-butylammonium bisulfate (1 g) was stirred at room temperature overnight, water (100 mL ) was added and the mixture was extracted with ER (2x100 mL). The organic extracts were washed with water and brine, dried and concentrated in vacuo to give an oil, which was purified by FCC eluting with hexane-*hexane-ER (9:1) to give the title compound as a colored loose liquid (10.5 g). T.l.c. hexane-ER (9:1) Rf 0.28.

(i i) N-[ 5-[ 2-[ 4- methoxyphenyl] ethoxy] pentyl] benzenemethanamine hydrochloride

The product from step (i) (5 g) was added to benzylamine (15 ml) at 140° under nitrogen. After 2 hours, the reaction mixture was poured into 2N hydrochloric acid (150 ml) and water (150 ml). The supernatant was collected by filtration, washed with water and ER and then dried under vacuum at 50° to give the title compound as a white solid (3.4 g), m.p. 123-126°.

Intermediate 10

(a) 4- amino- 3, 5- dichloro- a-[[[ 6-[ 2-( 4- nitrophenyl) ethoxy] hexyl]-(phenylmethyl) amino] methyl] benzenemethanol

Intermediate 1 (794 mg), intermediate 7 (1.0 g) and N,N-diisopropylethylamine (400 mg) in THF (15 mL) were allowed to stand at room temperature overnight. The mixture was filtered and the filtrate was concentrated in vacuo to an oil, which was dissolved in methanol (10 mL), cooled in an ice bath, treated with sodium borohydride (200 mg) and stirred overnight at room temperature. Water (25 mL) was added and the mixture was extracted with EA

(3 x 20 ml). The organic extracts were washed with brine, dried (Na 2 SO 4 ) and concentrated to an oil, which was purified by FCC eluting with CX-EA-TE (80:20:1),

giving the title compound as an orange oil (1.3 g). T.l.c. (CX-EA-TE 80:20:1) Rf 0.21.

The following compounds were prepared in a similar manner:

(b) 4- amino- 3, 5- dichloro- a-[[[ 6-[ 2[ 4-( 4- morpholinyl)- phenyl]-ethoxy]hexyl](phenylmethyl)amino] methyl] benzenemethanol (1.75 g) as a viscous oil (t.l.c. H-EA (4:1) Rf 0.11 from Intermediate 1 (1.0 g) and Intermediate 5 (1.5 g). For treatment with sodium borohydride, the residue was dissolved in ME ( 40 mL) and THF (10 mL), and after the reaction the mixture was concentrated to an oil, which was partitioned between EA (50 mL) and water (50 mL). Final purification by FCC eluting with H-EA (9:1 -* 4:1). (c) N-[ 4-[ 2-[[ 6-[[ 2-( 4- amino- 3, 5- dichlorophenyl)- 2- hydroxyethyl]( phenylmethyl) amino] hexyl] oxy ] ethyl] phenyl] acetamide (1.13 g) as a yellow oil (t.l.c.EA-CX (1:1) + a few drops of TE

Rf 0.2), from Intermediate 1 (1.00 g) and Intermediate 6 (1.30 g). The sodium borohydride-methanol reaction mixture was stirred under nitrogen for 24 hours. Final purification by FCC eluting with EA-CX-TE (50:50:1). (d) 4- amino- 3, 5- dichloro- a-[[[ 5-[ 2-( 4- methoxyphenyl)- ethoxy]-pentyl] ( f enyImety1) amino] methy1]- benzenemethano1 (240 mg) as a colorless oil, t.l.c. (hexane-EA-TE 80:20:1) Rf 0.28, from Intermediate 1 (325 mg), Intermediate 9 (430 mg) and N,N-diisopropylethylamine (300 mg), except that the reaction with sodium borohydride was carried out for only 6 h, after which the solvent was evaporated and the residue partitioned between 8% aqueous sodium bicarbonate (25 mL) and ethyl acetate (25 mL). Purification by FCC using hexane-EA-TE (90:10:1) as eluent. T.l.c. silica (hexane-EA-TE 80:20:1) Rf 0.28.

Intermediate 11

The following compounds were prepared by a conventional reaction sequence from Intermediate 1 and the other starting materials as indicated: (a) 4-amino-3,5-dichloro-a-[[[-6-(2-phenylethoxy)hexyl]-( phenylmethyl) amino] methyl] benzenemethanol as a colorless oil, m.p. (CX-EA-TE 80:20:1) Rf 0.23, using !2-[(6-bromohexyl)oxy]ethyl]benzene and benzylamine. (b) 4- amino- 3, 5- dichloro- a-[[[ 5-( 2- phenylethoxy) pentyl]-( phenylmethyl) amino] methyl] benzenemethanol as a colorless oil, m.p. (CX-EA-TE 66:33:1) Rf 0.25, using [2-[(5-bromopentyl)oxy]ethyl]benzene and benzylamine. (c) 4-ami. no- 3 , 5- dichloro- a- [ [ [ 6- ( 4- f phenylbutoxy) hexyl] -

(phenylmethyl)amino]]methyl]benzenemethanol as a yellow oil,

t.l.c. (EA-CX (1:4) + a few drops of TE) Rf 0.3, using N-[6-(4-phenylbutoxy)hexyl]benzenemethanamine.

(d) 4-amino-3,5-dichloro-α-[[[1-methyl-5-(2-phenylethoxy)pentyl]-(phenylmethyl)amino]methyl]benzenemethanol as a colorless oil, m.p. CX-EA-TE (80:20:1) Rf 0.58, using Intermediate 3. (e) 4- amino- 3, 5- dichloro- a-[[[ 5-[ 2-( 4- fluorophenyl ) ethoxy]-pentyl]( phenylmethyl) amino] methyl] benzenemethanol as a colorless oil, m.p. (EA-CX-TE 20:80:1) Rf 0.27, using 1-[2-[(5-bromopentyl)oxy]ethyl]-4-fluorobenzene and benzylamine. (f) 4- amino- 3, 5- dichloro- a-[[[ 5-[ 2-( 4- methylphenyl) ethoxy]-pentyl] (phenylmethyl) amino] methyl] benzenemethanol as a colorless oil, m.p. EA-CX-TE (20:80:1) Rf 0.37, using 4-methylbenzeneethanol, 1,5-dibromopentane and benzylamine. (g) 4- amino- a-[[[ 5-[ 3-[ 3, 5- bis(phenylmethoxy) phenyl] propoxy]-pentyl]( phenylmethyl) amino] methyl]- 3, 5- dichlorobenzenemethanol as a yellow oil , t.l.c. (EA-CX (1:4) + a few drops of TE) Rf 0.23, using 3,5-bis(phenylmethoxy)benzenepropanol-1,5-dibromopentane and benzylamine. (h) 4-amino-3,5-dichloro-α-[[[ 5-[ 3-(4-methoxyphenyl)propoxy]-pentyl](phenylmethyl)amino]methyl]benzenemethanol as a colorless oil, m.p. CX-EA (9:1) Rf 0.36, using 1-[3-[(5-bromopentyl)oxy]propyl]-4-methoxybenzene and benzylamine.

Intermediate 12

Ethyl- 4- [ 3- [ [ 6- [ [ ( 4- amino- 3 , 5- di. chlorophenyl) - 2- hydroxyethyl] - amino] hexyl] oxy] propyl] benzoate

The title compound was prepared as a white solid, m.p. 66-68°, by a conventional reaction sequence using ethyl 4-iodobenzoate, N-[6-[(2-propynyl)oxy]-hexyl]benzenemethanamine and Intermediate 1 as starting materials.

Example 1

N-[ 4-[ 2-[[ 6-[[ 2-( 4- amino- 3, 5- dichlorophenyl)- 2- hydroxy- ethyl]-amino] hexyl] oxy] ethyl] phenyl] acetamide

Intermediate 10 (c) (1.08 g) in ethanol (20 mL) and concentrated hydrochloric acid in ethanol (1:9 v/v, 1.72 mL) were hydrogenated over pre-reduced 10% palladium on charcoal (100 mg). The catalyst was removed by filtration ("hyflo"), the filtrate was concentrated and the residue was partitioned between EA (50 mL) and 8% aqueous sodium bicarbonate (2x50 mL). The organic phase was washed with brine (50 mL), dried (Na 2 SO 4 ) and concentrated to give a solid, which was triturated with a small amount of ether to give the title compound as a white solid (0.60 g), m.p. . 98-100°.

Found: C, 59.7; H, 6.9; N, 8.4; Cl, 14.6 C24H33C12N3°3 requires: C'59.8; H, 6.9; N, 8.7; Cl, 14.7%

Example 2

(a) 4- amino- 3, 5- dichloro- a-[[[ 6-( 2- phenylethoxy) hexyl]-amino]-methyl] benzenemethanol

Intermediate 11(a) (300 mg) was hydrogenated over pre-reduced 10% palladium oxide on carbon (50% aqueous paste 40 mg)

in ethanol (20 mL) containing hydrochloric acid (0.6 mmol). After 1.5 hours, the catalyst was removed by filtration through "hyflo" and the filtrate was concentrated in vacuo. The residue was dissolved in EA (20 mL) and washed with 8% aqueous sodium bicarbonate and brine, dried (Na 2 SO 4 ) and evaporated to an oil. Purification by FCC eluting with EA-ME-TE (90:10:1) gave the title compound as a white powder (120 mg), m.p. 60-63°. T.l.c.

(EA-ME-TE 80:20:1) Rf 0.42.

(b) 4-amino-3,5-dichloro-α-[[[5-(2-phenylethoxy)-pentyl] amino]-methyl] benzenemethanol, a cream-colored solid (370 mg), m.p. 64-65°, t.l.c. (EA-ME-TE 80:20:1) Rf 0.40 was similarly prepared from Intermediate 11(b) (650 mg).

Example 3

4- amino- a-[[[ 6[ 2-( 4- aminophenyl) ethoxy] hexyl]- amino] methyl]-3, 5- d i chlor ben z e nme tan o 1

Intermediate 10(a) (300 mg) was hydrogenated over pre-reduced 10% palladium oxide on carbon (50% aqueous paste, 60 mg)

in ethanol (20 ml) containing hydrochloric acid (1:9 conc. HCl/ethanol,

1 ml). The catalyst was removed by filtration through hyflo and the ethanol was removed under vacuum. 8% aqueous sodium bicarbonate (20 mL) was added to the residue, which was then extracted with EA (2x20 mL). The organic extracts were washed with water and brine, dried (Na 2 SO 4 ) and concentrated to a yellow oil, which was purified by FCC eluting with EA-ME-TE (80:20:1) to give a solid. Trituration with ER afforded the title compound as a warm-white powder (160 mg), m.p. 71-73°. T.l.c. (EA-ME-TE 80:20:1) Rf 0.32.

Example 4

(a) 4- amino- 3, 5- dichloro- a-[[[ l- methyl- 5-( 2- phenylethoxy)-pentyl] amino] methyl] benzenemethanol

Intermediate 11(d) (890 mg) was hydrogenated over pre-reduced 10% palladium oxide on carbon (50% aqueous paste, 100 mg)

in ethanol (20 ml) which contained hydrochloric acid (conc. HCl/ethanol,

1:9 parts by volume, 1.6 ml). The catalyst was removed by filtration through hyflo and the ethanol was evaporated. The residue was partitioned between 8% aqueous sodium bicarbonate and EA. The aqueous phase was re-extracted with EA and the combined organic extracts were washed with brine, dried (Na 2 SO 4 ) and concentrated to give a yellow oil, which was purified by FCC eluting with EA-TE (99:1) , giving the title compound as a colorless oil (580 mg). T.l.c. (EA-TE 99:1) Rf 0.16.

b) 4-ami. no-3,5-dichloro-α-[[[6-(4-phenylbutoxy)hexyl]-amino]-methyl]benzenemethanol was prepared in the same way from Intermediate II(c) (320 mg). Purification by FCC eluting with EA-ME-TE (80:20:1) followed by trituration with dry ER and drying

in vacuo gave the title compound as a white powder (180 mg),

m.p. 74-76°.

Found: C 63.38 H 7.59 N 6.06 Cl 15.47. C24H34C12N2°2 requires: c 63.57 H 7.56 N 6.18 Cl 15.64%.

Example 5

4-amino-3, 5-dichloro-α-[[[1,1-di. methyl- 5- [ 2- [ 4- ( 4- morpholinyl) - phenyl] ethoxy] pentyl] amino] methyl] benzenemethanol-( Z)- butenedioate ( salt) 1:1

A solution of 4-amino-3,5-dichloro-α-oxo-benzeneacet-

aldehyde (1.9 g) and Intermediate 8 (2.5 g) in benzene (50 ml)

was refluxed in a Dean-Stark type apparatus for 1 hour. The solvent was evaporated and the residual oil was dissolved in methanol (50 ml), cooled in an ice bath and treated portionwise with sodium borohydride (1.5 g). The yellow mixture was stirred at room temperature overnight and then concentrated to an oil, which was partitioned between water (100 mL) and EA (100 mL). The organic phase was washed with water and brine, dried (Na 2 SO 4 ) and concentrated to an oil, which was purified by FCC eluting with T-ET-ammonia (80:20:1) to give a pale yellow oil (2, 5g). T.l.c. (T-ET-ammonia 80:20:1)

Rf 0.53. A sample of the oil (150 mg) in methanol (2 ml) was treated with a solution of maleic acid (150 mg) in methanol (2 ml). The solvent was removed under vacuum and the residue triturated with ER to give the title salt as a white powder (180 mg), m.p. 110-115° (dec.).

Analysis: found: C 57.28 H 6.71 N 6.32 Cl 10.83. C27H39C12N3°3'C4<H>4°4,<1//>2 H2° requires: C 57.32 H 6.83 N 6.47 Cl 10.92%.

Example 6

4- amino- 3, 5- dichloro- a-[[[ 6-[ 2-[ 4-( 4- morpholinyl) phenyl] ethoxy]-hexyl] amino] methyl] benzenemethanol

Intermediate 10(b) (1.2 g) was hydrogenated over pre-reduced 10% palladium oxide on carbon (50% aqueous paste, 250 mg) in ethanol (25 mL) containing hydrochloric acid (conc. hydrochloric acid/ethanol 1:9 v/v , 2.0 ml). The catalyst was removed by filtration through hyflo, the ethanol was evaporated and the residue was partitioned between EA (50 mL) and 8% aqueous sodium bicarbonate (50 mL). The organic phase was washed with water and brine, dried (Na 2 SO 4 ) and concentrated to a solid, which was triturated with ER to give the title compound as a warm-white powder (820 mg), m.p. 102-103°.

Found: C 61.00 H 7.25 N 8.07 Cl 13.65. C26H37C12N3°3 requires: c 61.17 H 7.31 N 8.23 Cl 13.89%.

Example 7

(a) 4- amino- 3, 5- dichloro- a-[[[ 5-[ 2[ 4-( methylphenyl) ethoxy]-pentyl] amino] methyl] benzenemethanol

Intermediate 11(f) (0.92 g) was hydrogenated over pre-reduced 10% palladium on charcoal (100 mg) in ethanol (20 mL)

which contained hydrochloric acid (conc. hydrochloric acid/ethanol, 1:9 v/v, 1.62 mL), and the catalyst was removed by filtration ("hyflo"). The filtrate was concentrated, and the residue was partitioned between EA

(50 ml) and 8% aqueous sodium bicarbonate (2x50 ml). The organic phase was washed with brine (50 mL), dried (Na 2 SO 4 ) and concentrated to give an oil (0.7 g), which was purified by FCC eluting with EA-TE (100:1), followed by Trituration with ether gave the title compound as a white solid (0.46 g), m.p. 78-79°.

Found: C 62.2 H 6.9 N 6.5 Cl 16.8. C22H30C12N2°2 requires: c 62.1 H 1 r1 N 6 >6 cl 16.07%. (b) 4- amino- 3, 5- dichloro- a-[[[ 5-[ 3-( 4- methoxyphenyl) propoxy]-pentyl] amino] methyl] benzenemethanol was prepared in the same way from Intermediate 11(h) (450 mg) using pre-reduced 10% palladium oxide on carbon (50% aqueous paste, 100 mg) as catalyst. Purification by FCC eluting with T-ET-TE (90:10:1) followed by trituration with dry ER afforded the title compound as a white solid (150 mg), m.p. 63-64°.

Found: C 60.30 H 7.13 N 6.03 Cl 15.74. C23H32C12N2°3 requires: c 60.66 H 7.08 N 6.15 Cl 15.57%. (c) 4- amino- 3, 5- dichloro- a-[[[ 5-[ 2( 4- fluorophenyl) ethoxy]-pentyl] amino] methyl] benzenemethanol was similarly prepared from Intermediate 11(e) ( 0.783 g) using 10% palladium on charcoal (100 mg) as catalyst. Final trituration with hexane gave the title compound as a white solid (0.225 g), m.p. 75-76°.

Analysis, found: C 59.0 H 6.5 N 6.5 Cl 16.4. C21H27C12FN2°2 requires: C 58.8 H 6.3 N 6.5 Cl 16.5%.

Example 8

[ 3-[[ 5-[[ 2-(4-amino-3, 5-di.chlorophenyl)- 2- hydroxyethyl]-amino]-penty1] oxy]propyl]- 1,3-benzenedi o 1

Intermediate 11(g) (2.20 g) was hydrogenated over pre-reduced 10% palladium oxide on charcoal (200 mg) in ethanol (30 mL) containing hydrochloric acid (conc. HCl/ET 1:9 v/v, 2.75 mL ). The catalyst was removed by filtration ("hyflo"). The filtrate was concentrated and the residue was partitioned between EA (50 mL) and 8% aqueous sodium bicarbonate (2x50 mL). The organic phase was washed with brine (50 mL), dried (Na 2 SO 4 ) and concentrated to give an oil (1.05 g), which was purified by FCC eluting with EA-ME-TE (90:10:1 ), giving the title compound as a white foam (0.369 g). T.l.c.

(EA-ME-TE 90:10:1) Rf 0.2.

Found: C 57.4 H 6.7 N 5.9 Cl 15.1. C22H30C12N2°4 requires: c 57'8 H 6.6 N 6.1 cl 15.5%.

Example 9

4- amino- 3, 5- dichloro- g-[[[ 5-( 2- phenylethoxy)- 3- pentynyl]-amino] methy1] benz enme t ano1

Intermediate 2 (80 2 mg) in DMF (2 mL) was added to a stirred solution of 4-amino-α-(aminomethyl)-3,5-dichlorobenzene-methanol (1.0 g) and N,N-diisopropylethylamine ( 6 50 mg) in DMF

(20 ml) at 100° under nitrogen. After 2 hours the solvent was evaporated and the residue was purified by FCC twice eluting with T-ET-TE (9:5:1) to give a pale yellow oil which was triturated with H to give the title compound as a white solid (80 mg), m.p. 62.5-63°.

Found: C 61.39 H 5.93 N 6.79 Cl 17.37. C21H24C12N2°2 requires: c 61.92 H 5.94 N 6.88 Cl 17.41%.

Example 10

4- amino- 3, 5- dichloro- g-[[[ 5-[ 2-( 4- methoxyphenyl) ethoxy] pentyl]-amino] methyl] benzenemethanol hydrochloride

Intermediate 10(d) (230 mg) was hydrogenated over 10% palladium oxide on carbon (50% aqueous paste, 40 mg) in ethanol

(10ml). The catalyst was removed by filtration through hyflo and the ethanol was evaporated to give a green solid which was triturated with dry ether to give the title

the compound as a pale green powder (170 mg), m.p. 134-137° (dec.).

Analysis, found: C 54.28 H 6.45 N 5.58 Cl 21.35. C22H30C12N2°3 *HC1'1/2H2° requires: C 54.27 H 6.62 N 5.75 Cl 21.85%.

Example 11

4- amino- 3, 5- dichloro- a-[[[ 6-[ 3-[ 4-( hydroxymethyl) phenyl]-propoxy] hexyl] amino] methyl] benzenemethanol

Compound Intermediate 12 (88 mg) in ER (4 mL) was added dropwise to a stirred suspension of lithium aluminum hydride (50 mg) in ER (4 mL) under nitrogen. The reaction mixture was stirred for 2.5 hours at room temperature and treated dropwise with water (0.05 mL), 2N aqueous sodium hydroxide (0.1 mL) and water (0.1 mL). The mixture was filtered ("hyflo") and the filtrate was concentrated to give a colorless oil (64 mg), which on trituration with ER gave the title compound as a white solid, m.p. 56-59°. T.l.c. (T-ET-NH^ 39:11:1) Rf 0.44.

Claims (5)

1. Process for the preparation of compounds according to the general formula (I) where X represents a C 1 -3 alkylene or C 1 -alkynylene chain; Y represents a C 1 -6 alkylene chain; 1 2 R and R each represent hydrogen or methyl; and Ar represents a phenyl group optionally substituted with a fluorine atom, a group selected from amino, C 1-3 -alkyl, C 1-3 - alkoxy, hydroxy-C 1 -alkyl, morpholino, hydroxy or -NHCOR 6 where R 6 is C 1 -3 -alkyl, or Ar is a phenyl group substituted with hydroxyl groups in the 3- and 5-positions; and physiologically satisfactory salts and solvates thereof, characterized by: (la) for the preparation of compounds according to formula (I) where R<1> is a hydrogen atom, alkylation of an amine according to the general formula (II) (where R 7 is a hydrogen atom or a protecting group and R g is a hydrogen atom) with an alkylating agent according to the general formula (III) (where L is a leaving group), if necessary followed by removal of any protecting groups; or (lb) for the preparation of compounds according to formula (I) where R"'" is a hydrogen atom, alkylation of an amine according to the general formula (II) where R 7 is a hydrogen atom or a protecting group and R gives a hydrogen atom or a group which can be converted into this under the reaction conditions, with a compound according to the general formula (IV) in the presence of a reducing agent, if necessary followed by removal of any protecting groups; or (2) reduction of an intermediate according to the general formula (VI) where X is -CH(OH)- or a group that can be converted to this by reduction, X 2 is -CH»NR 7- or a group that can be converted to this by reduction, X 3 is -CR 1R 2X- or a group which can be converted thereto by reduction, X^ is -NH2 or a group which can be converted thereto by reduction, Y is as defined above or a group which can be converted thereto by reduction and Ar is as defined above or a group which can 12 3 4 is converted to this by reduction, with at least one of X , X , X , X , Y and Ar contains a reducible group, if necessary followed by removal of any protecting groups; and if desired converting the resulting compound of general formula (I) or a salt thereof into a physiologically satisfactory salt or solvate thereof. 2. Method according to claim 1, characterized by the preparation of compounds where Ar is a phenyl group which optionally contains one substituent at the 4-position which is an amino, methoxy, -NHAcetyl or morpholino group. 3. Method according to claim 1, characterized by the preparation of the compound 4-amino-3,5-dichloro-a-[[[-6-[2-[4-(4-morpholinyl)-phenyl]ethoxy]hexyl]amino] methyl]-benzene-methanol or a physiologically satisfactory salt thereof. 4. Process according to claim 1, characterized by the preparation of the compound N-[4-[2-[[6-[[-2-(4-amino-3,5-dichlorophenyl)-2-hydroxyethyl]amino]hexyl]oxy ]ethyl]phenyl]acetamide or a physiologically satisfactory salt thereof. 5. Method according to claim 1, characterized by the preparation of 4-amino-3,5-dichloro-a-[[[5-[2-(4-methoxyphenyl)ethoxy]pentyl]amino]methyl]benzenemethanol or a physiologically satisfactory salt hence.