DD266797A5 - PROCESS FOR THE PREPARATION OF AMID DERIVATIVES - Google Patents

Abstract

The invention relates to a process for the preparation of amide derivatives. According to the invention, amide derivatives of the formula I are prepared in which, for example: R 1 is hydrogen or fluorine; R 2 is optionally substituted phenyl, C 3 -C 6 -cycloalkyl, C 1 -C 4 -alkyl and the like. al .; R3 is hydrogen, methyl or ethyl or R2 and R3 together form a C4-C7 polymethylene group in which one methylene moiety may be replaced by oxygen or sulfur which is at least 2 carbon atoms away from the nitrogen atom of the NR2R3 group and wherein two adjacent methylene moieties are substituted by 2 Carbon atoms of a benzene ring which is fused with the C4-C7 polymethylene group and which may itself carry a halogen, C1-C4 alkoxy, C1-C4 alkyl, trifluoromethyl, cyano or nitro substituent or a pharmaceutically usable acid addition salt thereof. Formula I

Description

Field of application of the invention

The present invention relates to an ancestor for the preparation of novel amide derivatives, especially new Phonoxyacotamiddorivato containing a 2-hydroxy-3-phonoxy-propylamlnogruppo, which amides stimulate the Thermogeneso in warm-blooded animals and e.g. have been used to treat obesity and similar conditions, such as obesity of early onset diabetics. The invention also encompasses pharmaceutical compositions useful for administering the amiddorivato dor invention to warm-blooded animals and the use of said derivatives for the treatment of (and / or production of thermogenic medicaments for the treatment of obesity and related conditions.

Characteristic of the known state of the art

In EP-OS No. 171760 is a series phonolischer Phonoxyacotamiddorivato boschriebon, wolche useful ionotropo agents for the treatment koiigostivor heart disease should be.

Object of the invention

It is an object of the present invention to provide novel amide derivatives having valuable pharmacological properties, but different from amide dorivaton.

Principle of invention dor

The invention has for its object to find nouo amide derivatives with don gowünschton properties and ancestors for their preparation.

Surprisingly, certain novel amide dorivato of the unton angogobonone Formol I were found to differ from the known precursors in the literature due to the lack of phonolischon hydroxygruppo, to possess highly modulatable potency at doses which cause relatively little cardiac stimulation, but the selectivity of the thermogenic effect an important requirement for a useful agent for treatment eg of obesity and related conditions.

According to the invention, an amide derivative of Formol I is provided (the formulas are shown in the end for all the precursor radicals designated by Roman numerals) in which R ^{1 is} hydrogen or fluoro, R ^{2 is} a phenyl group containing a halogen, C) - C ₄ alkyl, C ₁ -C ₄ alkoxy, trifluoromethyl, cyano or Nitrosubstituonton, a Cj-Ce-cycloalkyl group, a Ci-C ^ -Alkylgruppo, in which the carbon atom don don nitrogen NR ² R ³ -Grouppo, one or two Wasserstoffatomo bears, or o is C ₃ -C ₄ alkenyl, wherein jode the latter groups a hydroxy, carbamoyl, C ₁ -C ₄ -Akoxy-, phenyl or And R ^{3 is} hydrogen, methyl or ethyl, or R 'and R ³ together form a C ₄ -C ₇ polymothylonegroup, wherein oino may be methyloneinhoite by oxygen or sufrofol, which may be substituted by at least two carbon atoms of the nitrogen atom of the nucleus NR ² R ³ -Group is removed, and wherein two 3-jfflinanderfolgondi) Mothylonoinhoiten may be replaced by two carbon atoms of a ring bosses, which referred to dio C ₄ -C 7 group is anolliort and, in turn, a halogen, C ₁ -C ₄ -AIkOXy-, C ₁ -C ₄ -alkyl -, trifluoromethyl, cyano or Nitrosubstituonton can carry; or a pharmaceutically acceptable addition salt thereof with acid chloride. It should be noted that the compounds dor Formol I odor mehroro asymmetric Kohlonstoffatomo contain and as optically active enantiomers or optically inactive Racemato oxistioron can. The present invention includes

each enantiomer, racemate and / or (when two or more asymmetric carbon monoxide> mo are present) diastore omor which has thermogenic properties in warm blooded animals, whereas in chemistry it is known how to display the individual enantiomers, e.g. By racemate formation or by storoospo-cific synthesis, and how the thormogonone properties are determined, for example by using the standard borritiobonon-based woitor below.

The group -OCH ₂ CO-NR ² R ³ is in principle m- or p-donation to the oxyethylamino-Seitonketio, the dio-p-position is preferred.

For R *, hydrogen is preferred.

When R ^{2 is} a C 1 -C ₄ alkyl group or a C ₃ -C ₄ alkynyl group as defined above, specific examples are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, allyl or 2-methyl-allyl each may have a substituent tragon, which may be hydroxy, carbamoyl, C ₁ -C ₄ -alkoxy (such as mothoxy or ethoxy), phenyl and chlorophenyl (especially p-chloro-phonyl).

When R ^{2 is} phenyl, specific examples are unsubstituted phenyl or phenyl having a substituent selected from fluoro, chloro, bromo, methoxy, ethoxy, methyl, ethyl, trifluoromethyl, cyano and nitro.

When R ^{2 is} C 1 -C 12 cycloalkyl, specific examples are cyclobutyl, cyclopentyl and cyclohexyl.

Specific examples of optional substituents which are present when R ^{2 is} phenyl or when a Toil of R ² and R ³ together is a benzene moiety as defined above

for halogen: fluorine, chlorine and bromine;

for C 1 -C ₄ alkoxy: methoxy, ethoxy, propoxy and isopropoxy;

for C 1 -C ₄ -alkyl: methyl, ethyl, propyl, isopropyl and tert-butyl.

A specific example of R ³ is hydrogen.

When R ² and R ³ together form a C ₄ -C ₇ polymethylone group, specific examples are tetramethylone or pentamethylene, and when taken together form a CHV polymothylon group in which a Mothylon unit is replaced by oxygen or Schwotol, specific examples are ethyleneoxyethylone or ethylene thioethylene.

Specific examples of the group NR ² R ³ are anilino, benzylamino, allylamines, cyclohexylamines, cyclopontylamino, morpholino, piperidino, pyrrolidino, dimethylamines, diothylamino, mothylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, 2-hydroxyethylamino, 3 Hydroxypropylamino, 2-methoxy-othylamino, indolin-1-yl, 1,2,3,4-tetrahydroisoquinolin-2-yl and 1,2,3,4-tetrahydroquinolin-i-yl.

A preferred group of Vorbindungen the invention comprises the compounds of formol I wherein R 'water Stuff and the group NR ² R ³ C _t -C ₄ alkyl & mlno (wherein C _{(-C 4} alkyl is as defined above) (especially Mothylamino or ethylamino), benzylamino, piperidino, pyrrolidino, C 1 -C 4 -alkenylamino, morpholino or C 1 -C 4 -atrifluoro-quinoline-1-ylyl and the groups -OCH ₂ -CO-NR ² R ³ and -O-CH ₂ CH ₂ -NH- In the p-position vorknüpft are, as well as the pharmaceutically acceptable addition salts with acid of these compounds.

A further preferred group of compounds comprises the compounds of the formula I in which R ^{1 is} hydrogen, the group NR ² R ^{3 is} methylamino, ethylamino, propylamino, isopropylamino, 2-hydroxy-othylamino, 3-hydroxy-propylamino, 2-mothoxyethylamino, 3-methoxy-propylamino or 1,2,3,4-tetrahydroisoquinolin-2-yl and the groups -OCHj-CO-NR ² R ³ and -O-CH ₂ CH ₂ -NH- are linked in the p-position, and the pharmaceutically prewondered addition salts of these compounds with acids.

Typical compounds of formula I have been set forth in the accompanying examples. Compounds of particular Intorosso are those of Examples 1,2,5,7,16,19 and 21 which, together with their pharmaceutically acceptable addition salts with acids, are set forth as a particular ingredient of the invention.

The precursors of formula I are basic and can be isolated and used ontwoder in the form of the free base or as a pharmaceutically acceptable addition salt with acids thereof. Specific examples of pharmaceutically acceptable addition salts with acids include salts with inorganic acids such as hydrohalides (especially hydrochlorides or hydrobromides), sulfates and phosphates and salts with organic acids such as succinate citrates, lactato, tartrates, oxalates and derivatives derived from acidic polymeric resins such as the free acid form of sulfonated! Polystyron.

The new compounds of formula I can be prepared by conventional methods known in organic chemistry. A method for the manufacture of structurally analogous precursors, as set forth, for example, in British Patent Specification 1,455,116. These processes are to be regarded as a further part of the invention and have been illustrated by the following processes, wherein R ¹ , R ² and R ^{3 have the} previously defined meaning.

(a) An ester of the formula II in which R ^{4 is} a C 1 -C ₄ -alkoxy group, phenoxy or benzyloxy is reacted with an amine of the formula HNR ² R ³ .

Especially suitable examples of R ⁴ are mothoxy or ethoxy. The ancestor is generally in a suitable inert solvent or diluent, for. Example, in a C, -C ₄ alkanol such as methanol or ethanol and boi a Tompe rat ir in ·· range of otwa 0 ° C-60 ° C and carried out in a pressure vessel, a volatile amir such as methylamine wounded becomes. The amine of the formula NHR ² R ³ is expediently used in excess. The required starting esters can be converted by a Phonoldor !. .ito of formula III can be obtained with an alkylating agent of the formula X-CH ₂ -CO-R ⁴ wherein X is a suitable leaving group, e.g. As chlorine, bromine or iodine, and R ^{4 has} the meaning given above, in Gegenv.art a base, for. B, as described in the attached examples. It will be noted that this ancestor is analogous to the following process (b) and that basically similar reaction conditions and bases can be used.

(b) A phenol derivative of formula III is reacted with an alkylating agent of the formol X-CH ₂ -CO-NR ² R ³ , wherein X is a suitable leaving group, e.g. For example, chlorine, bromine, iodine, methanesulfonyloxy or p-Toluerisulfonyloxy reacted.

The process is conveniently carried out in the presence of an external base, e.g., an inorganic base such as an alkali metal carbonate or acetate (e.g., potassium carbonate or sodium acetate) or an alkali metal hydride (e.g., sodium hydride) at a temperature in the range of otwa 1ObIs 12O ⁰ C performed. Conveniently, a suitable solvent or diluent, e.g. For example, acetone, butan-2-one, propan-2-ol, 1,2-dimothoxy-othane or tort-butylmothyl ether may be prewired. In order to suppress noise reactions, the process may also be carried out by first grafting the Phe III III with a suitable base to the corresponding salt, then adding it to the alkylating agent or formula X-CH ₂ -CO-NR ² R ³ becomes.

The starting phenol derivatives of formula III can be obtained by conventional ancestor organic chemistry. So z. Example, by reacting a phenol of the formula IV with an epoxide of the formol V in elnom gooignoten solvent or diluent, z, B. an alcohol such as ethanol or propan-2-ol in a temperature range of about 10-110 ⁰ C, suitably b ^"1 η Sledopunkt odor are obtained near the boiling point dos Roaktionsgomischos. Dio Epoxido the formol V are known as such, but can also be prepared by reaction of phenol or o-phenol fluorine with epichlorohydrin or epibromohydrin in the presence of a goolgneton base such as oinom alkali metal hydroxide, Piperidine, morpholine or N-methylmorpholine In a suitable solvent, methanol, ethanol or propan-2-ol was conveniently prepared at the boiling point or near the boiling point of the ronglucose mixture.

In general, it is preferred to react the epoxide of formula V with a goschützton phenol derivative of formula VI wherein Q is a suitable protecting group such as bonzyl. In this case, after the reaction of compounds V and Vl, the protecting group will degrade, e.g. B. in the case of Bonzyl by hydrogenolysis, for. By hydrogoning at a pressure in the oinom range of about 3-30bflr i. ι presence of a palladium / cohort catalyst in an inorton Vordünnungsodor solvent, eg oinem C ₁ -C ₄ -AlkOnOl (such as methanol, ethanol or tert-butyl alcohol) or a C, -C ₄ alkanoic acid (wlo acetic acid) and at oiner temperature from about 20-80 ⁰ C

 The epoxides of Formol V can be used in their racemic or their onantiomorphic forms.

(c) reacting an amindoori of Furmoi VII wirii with an epoxide of formula V.

It is to be understood that this reaction is a modification of the above described method for the preparation of the starting materials of formula III and that therefore generally similar conditions of roughening may be employed.

Dio starting amine derivatives of formol VII may be prepared from the corresponding phenols of formula IV by reaction with a precursor of formula X-CH ₂ -CONR ² R ³ onsprochond as defined under analogous reaction conditions as described in process (b).

(d) A protected derivative of Formol VIII wherein Q is a suitable protecting group is protected.

A geoigneto protecting group is, for example, a hydrogeriol-siorable group such as benzyl, 4-methoxycarbonyl or 3,4-dimethoxybenzyl, e.g. B. can be removed by hydrogelling under similar Roaktlonsbodingungon as for the representation of Ausgangsmaterialion for ancestors (b). A hydrogen pressure of about 3-30bar at the usual temperatures of about 20-80 ⁰ C may be used.

The protected derivatives of the formula VIII can be obtained by process (b) or (c) with appropriate starting material ion, boi denon dio amino group protected with oO gooignoten protective group. When Q is benzyl, the corresponding starting enzyme-containing starting materials analogous to formula VII can conveniently be obtained e.g. B. by reductive alkylation of the compounds of formula VII with benzaldehyde in the presence of sodium borohydride in oinem solvent or diluent such as methanol at 0-25 ⁰ C orhalton been.

If a pharmaceutically acceptable acid addition salt is desired, then the precursor of formula I in the form of the free base is reacted with the corresponding acid according to a conventional method. If e.g. a hydrohalide is desired, this may conveniently be orhalton by hydrogenation of the free base together with the stoichiometric amount of the corresponding benzyl halide.

If eil Enantlomor is needed, then the corresponding racemate can be separated, for. B. by reaction with a suitable optical acid according to a conventional incident on. However, it is also possible to carry out oinos of the above ancestors with an optically active starting material.

As stated, the compounds of the formula I have properties and are used for the treatment of obesity and / or related diseases of the metabolic disorder, such as diabetes mellitus spezioll dos adulton occurrence. In addition, in some cases, the compounds of formula I may be useful for modifying the skeletal composition, e.g. B. by increased Fettkatabollsmus in Flsischproduzierendon animals wio cattle, pigs, sheep, goats and / or rabbits of value.

The thermogenic effects of compounds of formula I can be demonstrated by one or more of the following standard tests:

(n) rats are kältoadaptiert by be (4 ⁰ C) for 10 days brought it in a cold environment in order to increase their ability to Thermogenoso. Then they are placed in a thermoneutral environment (29 ⁰ C). Three hours later, the internal tempature is measured to obtain a base value. Then the test compound is administered subcutaneously or orally as a suspension or solution in 0.45% w / v. of aqueous sodium chloride and 0.25% w / v. Polysorbate 80 administered. After one hour, the internal tempatures will be renewed; gemoösen. In this test, a compound which is dio, causes einon statistically significant increase in internal temperature of about 0.3 ⁰ C or more at e'nor subcutaneous dose of 15 mg / kg (or less) is regarded as significantly active. This test serves as a model for low-level thermogenesis that occurs during dieting.

(b) Rats are cold-adapted to 4 hours boi 4 ⁰ C to enhance their ability to horseradish. They were then placed in a warm environment of 23 ° C for 2 days. The following day, oostomy is administered subcutaneously or orally as described in (a). After one hour, the animals are killed and the interscapular brown adipose tissue (BAT) is removed. The BAT mitochondria are prepared by differential centrifugation and GDP binding (Holloway et al., International Journal of Obesity, 1984, 8955) as a measure of thermogenic activation. Each test includes a control that is dosed only with the solvent or suspending agent and a positive control dosed with 1 mg / kg isopronaline (as sulfate). The test compounds are routinely dosed at 0.1, 0, 3, 0, 0, 3, 0, and 10 mg / kg, and the results are related to those due to isoprenaline effect on GDP binding. From these results, the effective dose (ED ₀₀ ), which produces 50% of the isoprene allotment, is calculated by linear regression analysis. The compounds are considered active in this assay if they cause a significant increase in GDP binding compared to the controls. This test serves to prove that the thermogenic effects observed in test (a) are caused by an increase in the effect on the BAT and not by any unspecific or toxic mechanisms.

(c) Rats were adapted to a hormone-neutral environment (29 ° C) for 2 weeks to reduce their ability to BAT-sturt, non-tremor-induced thormogenesis. During three days, the animals are accustomed to a device for measuring the heartbeat by external electrodes attached to the balls of the foot, which are connected to an f-KG integrator, which permits continuous horzfroquency separation. The pre-prime is subcutaneously pre-administered with ED ₆ O determined according to test (b), and the frequency of hearing is determined 15-30 min after the administration. The process is then repeated in further tests using increasing multiples of the by Tost (b) bestimmton ED _W until the heart rate ODNR reached 500 beats per minute exceeds, thus dio (to achieve einor heart rate of 500 Schlägsn per minute bonötigte dose D ₆ O ₀ ) can be calculated.

The ratio of De ₀₀ to ED ₆₀ after test (b) can be defined as selectivity (SI) and represents a measure of the selectivity of the compound over dom BAT in contrast to the Horz-Kroislauf systome; prefixes with oinom SI> 1 becomes one attributed to distinct selectivity. Non-selective compounds have an SI <1 (eg isoprenaline - 0.06).

(d) rats werdon 4 days boi 4 ⁰ C cold adapted in order to increase their ability to Thormogonese. Then they are placed in a warm environment bsi 23 ⁰ C for 2 days. The following day, the basal metabolic rate of animals is compared with a closed-loop, acid-consuming consuming device according to Arundol et al., J. Appl. Physiol. Respirat. Environ. Exerciso Physiol., 1984, 57 (5), 1591-1593. The Ratton is then (orally or subcutaneously) tested at about 10 mg / kg as a solution or suspension in 0.45% w / v. aqueous sodium chloride and 0.25% Gow./Vol. Polysorbate 80 administered. The metabolic rate is then determined at least 1 hour after dosing. In this test, the compounds are considered to be active if they cause a marked increase in metabolic wasturn in comparison with control animals (Student's t-test: ρ <0.5) to which only the solvent or suspending agent was administered.

In the above tests, the compounds of formula I generally have effects of the following order of magnitude without exhibiting visible toxicity:

Test (a): Increase of internal temperature by otwaO, 5 ° C (or more) after subcutaneous administration of <15mg / kg; Tost (b): subcutaneous ED _{60 for} GDP binding in BAT mitochondria of 0.01-μg / kg; Test (c): SH> 50.

For example, the crude compound in Example 1 below had the following effects in the above tests:

(a) 2.25 ° C at a subcutaneous dose of 10 mg / kg;

(b) subcutaneous ED ₆₀ : 0.133 mg / kg; oralo ED _W : 1.18 mg / kg;

(c) D ₆ oo:> 13.3 mg / kg (subcutaneously); SI> 100 (subcutaneously); SI> 50 (oral).

In contrast, the known structurally related compound described in Example 2 of European Patent Application No. 171760 caused N-phenyl-p- [2- (2-hydroxy-3- (p-hydroxy-phonoxy) -propylamino] -ethoxy) -phonoxyacetamide in test (a). a temperature increase of 1.24 ° C and in the test (b) no noticeable effect, but produced a significant increase in the heart rate.

When used to produce thermogenic effects in warm-blooded animals, including humans, a compound of formula I or, if desired, a pharmaceutically acceptable salt thereof is pre-administered such that a dose of 0.002-20mg / kg, preferably in Boroich, of 0.02 ~ 10mg / kg administered daily in one dose or divided into several doses as needed. However, it will be appreciated by those skilled in the art that the dose must be varied according to the dose of the substance, the swaths of the condition to be treated and the age and sex of the pationton, as well as well-known medical principles.

The compounds of formol I are generally used for medical (or veterinary) purposes in the form of preparations containing a compound of formula I or a pharmaceutically (or veterinarily) acceptable salt thereof as an active ingredient and a pharmaceutically (or veterinarily medicinal) diluent or Carrier included. Such preparations are part of the invention and are typically prepared for oral administration (eg, tablets, capsules, pills, powders, solutions, suspensions, etc.) or paronteral administration (including sterile solutions, suspensions, and emulsions). Preparations for oral administration are generally preferred.

The preparations can be prepared by standard excipients and by methods generally bocarnit. One dosage unit such as tablet or capsule usually contains e.g. 0.1-250 mg active substance. The compositions may also contain other active ingredients known for use in the treatment of obesity and related conditions, e.g. As appetite suppressants, vitamins and hypoglycemic agents.

Ausfuhrungsbelsplel

The invention is illustrated below by the following examples in which, unless stated otherwise

a) all operations at room temperature, d. H. boi be carried out at a temperature in the Boreich of 18-26 ° C;

b) evaporations are carried out at reduced pressure in a rotary evaporator;

c) chromatography on Merck Kieselgel (Article 7734) by Merck, Darmstadt, Federal Republic of Germany; el) the yields are given by way of illustration only and are not to be regarded as achievable as a boi optimized production run;

e) nuclear magnetic resonance spectrometry (NMR) at 200 MHz in O ₆ -DMSO as solvent with tetramethylsilane (TMS) as internal standard and expressed in delta words (parts per million) for protons relative to TMS, conventional abbreviations describing the Signal be used and

f) all crystalline end products have satisfactory microanalyses and NMR spectra.

At iplel 1

A mixture of p- | 2- (2-hydroxy-3-phenoxy-propylamino) ethoxy) -phenoxy-oxyacetic acid methyl ester (0.38g) in methanol (20ml) and a 33% w / v solution of methylamine in ethanol (10ml ) is allowed to stand at room temperature for 3 hours. The solvent is evaporated off and the residue is recrystallised from ethyl acetate to give N-methyl-p- [2- (2-hydroxy-3-phenoxy-)

Propylaminoj-ethoxylphenoxyacetamld (0.24g), mp 11B ⁰ C is obtained. Microanalysis: found 63.9; H 7.0; N 7.3%; C ₂ OH ₂₈ N ₂ O ₆ requires C 64.2; H 7.0; N 7.5%; NMR: 1.84 (br 8.1H, NH); 2.68 (m, 5H, CH (OH) CH ₂ NH + NHCH ₃ ); 2.86 (t, 2H, NHCH ₂ CH ₂ O); 3.90 (m, 5H, OCH ₂ CH (OH) + OCH ₂ CH ₂ ); 4.38 (s, 2H, OCH ₂ CO); 4.80 (br s, 1H, OH): 6.80-7.00 (m, 7 aromatic H); 7.25 (m, 2 aromatic H); 7.80 (br s, 1H, CONH)

 Ons initial matorial wurclo obtained as follows:

A mixture of N -bonyl N- [2- (p-hydroxy-phenoxy) othyl] -2-hydroxy-3-phonoxy-propylamine (4.0g), bromo-oxydiuremothylosthor (1.56g), anhydrous potassium carbonate (1.7g and potassium iodide (0.05 g) is stirred in dry acetone (60 ml) under reflux for 24 h. The crude mixture is cooled, the solid is filtered off and the solvent is evaporated off. The residue of p · [2- (N-Bθn7yl · 2-hydroxy-3-phonoxy-propylamino) -thoxy) -phenoxyacetic acid methyl ester is dissolved in methanol (90 ml) and acetic acid (30 ml). The resulting solution is in the presence of 10üow .-% palladium on carbon (0.4 g) at 20 bar hydriort and 6O ⁰ C 48h. The mixture is cooled, the solid filtered off and the solvent evaporated. The refluxing oil is dissolved in methanol and treated with a solution of chlorosurfactant. The precipitate is recrystallized twice from methanol to give p- | 2- (2-hydroxy-3-phonoxypropylaminolothoxylphonoxyosslgsäuremothyloster hydrochloride, 0.22 g, mp 170 ⁰ C; Microanalysis: Found C, 58.2; H, 6.3; N 3.6, Cl 8.8%, C ₂₀ H ₂₈ CINO ₀ requires C 68.3, H 0.3, N 3.4, Cl 8.6%, NMR: 3.08 (dd, 1H, CHCH ₂ NH), 3.26 (dd, 1H, CHCH ₂ NH), 3.36 (t, 2H, NHCH ₂ CH ₂ ), 3.7 (s, 3HCO ₂ CH ₃ ), 4.0 (d, 2H , OCH ₂ CH), 4.25 (m, 3H, OCH ₂ CHOH-), 4.74 (s, 2H, OCH ₂ CO), 6.8-7.05 (m, 7 aromatic H), 7, 31 (m, 2 aromatic H) The hydrochloride is partitioned between a 5% (w / v) aqueous sodium bicarbonate solution (50 ml) and dichloromethane (50 ml), dried organic (MgSO ₄ ) and the solvent evaporated vorbleibende solid is recrystallized from methanol to give p- (2- (2-hydroxy-3-phenoxy-propylamlnojethoxylphenoxyosslgsäuremothylester (1.67 g), mp 116-118 ⁰ C. Dos is Propyleminderivat-Au.sgangsmaterlal folgenderma en get:

(a) A stirred mixture of 2- (p-hydroxy-phenoxy) ethylamine (4.0 g) and benzaldehyde (O ₁ Og) in methanol (50 mL) is ice-cooled and sodium borohydride (2.0 g) is added in portions over 1 h. After stirring for a further 18h, the solvent is evaporated. The residue is partitioned between 2M hydrochloric acid (200ml) and ethyl acetate (100ml). The Säuroschicht is abgotrennt, made alkaline with potassium carbonate and then extrahiort with Essigoster. Dio extracts are dried (MgSO ₄ ) and evaporated. The remaining oil is dissolved in Essigoster and dry hydrogen chloride passed through the solution until no solid precipitates. The precipitate is abgotrennt and recrystallized from methanol and Esslgostor and provides N-benzyl-2- (p-hydroxy-phenoxy) othylamin-hydrochloiid · (2.3 g), mp 182-184 ⁰ C.

(b) N-Benzyl-2- (p-hydroxy-phonoxy) ethylamine hydrochloride (3.5g) is shaken with 1M sodium hydroxide solution (20ml) and dichloromethane (20ml). The organic layer is separated and washed with water (10 ml), dried (MgSO ₄ ) and the solvent evaporated to give N-bonyl-2- (p-hydroxy-phenoxy) othylamine as an oil.

(c) A mixture of N-benzyl-2- (p-hydroxy-phenoxy) ethylamine (2.5g) and 1,2-epoxy-3-phenoxy-propane (1.54g) in propan-2-ol (50ml ) is refluxed for 72 h. The solvent is evaporated off to give N-benzyl-N- [2- (p-hydroxy-pentoxy) -ethyl] -2-hydroxy-3-phonoxy-propylamine as an oil which, after identification by thin layer chromatography (TLC) (with silica gel plates and 5 % Methanol in dichloromethane as eluent) is fairly pure and will continue to be used without purification.

The starting material N-bonyl-tp-hydroxy-phenyldothylamine hydrochloride can also be obtained as follows: A mixture of p- (2-bromo-ethoxy) phenol (2.2 g), benzylamine (1.07 g) and triethylamine (1 , 01 g) in ethanol (30 ml) is heated under reflux for 18 h. The solvent is evaporated and the residue partitioned between 2M hydrochloric acid (COOmI) and ethyl acetate (50 ml). The acid layer is filtered off, made alkaline with potassium carbonate and then extracted with ethyl acetate. The extracts are dried (MgSO ₄ ) and the solvent evaporated. The remaining oil is dissolved in Essigoster. Then dry hydrogen chloride is passed through the solution until solid mohr fails. The solid is filtered off and umkristallisiort from a mixture of methanol and Essigester and provides N-benzyl-2- (p-hydroxy-phenoxy) ethylamine hydrochloride, 0.9g, m.p. 182-184 ⁰ C.

Example 2

The procedure described in Example 1 is repeated with the (-) - form of p- | 2- (2-hydroxy-3-phenoxypropylamino) ethoxy] phenoxyacetic acid methylstyrene (Z) (0.66 g), the corresponding optically active form of N methyl-p- (2- (2-hydroxy-3-phenoxypropylamino) is erhalton othoxylphonoxyacatamid (0.50 g), mp 114-115 ⁰ C, [a] jj ⁶ = - 8.1 ° (c = 0, 97, ethanol).

The starting material (Z) is available as follows:

A mixture of p- [2- (2-hydroxy-3-phenoxy-propylamino) othoxy] -phonoxyacetic acid (0.92g), (-) - di-p-toluoyltartaric acid monohydrate (0.991g) in methanol (15ml) evaporated under boiling to a final volume of 5 ml. Acetic methyl ether (10 ml) is added and the mixture is concentrated again to a volume of BmI. This ancestor is repeated again. The mixture is allowed to stand at room temperature for 18 hours. The resulting solid is separated and recrystallized from methanol and acetic acid ethyl ester to give (-) - p- (2- (2-hydroxy-3-phenoxypropylamino) ethoxy] phenoxyacetic acid methyl ester - (-) - di-p-toluoyltartrate (0.337g). F 146-148 ⁰ C; \ a] l ^b - - 80.3 ° (c = 0.97, methanol).

(-) - p- [2- (2-Hydroxy-3-phenoxy-propylamino) -ethoxy] -phenoxy-oxy-methacrylate - (-) - di-p-toluoyl tartrate (0.33 g) is added between 5% (w / v) sodium bicarbonate solution (10ml) and dichloromethane (10ml). The organic layer is separated, dried (MgSO ₄ ) and the solvent evaporated. The vorbleibendo solid (0,148g), mp 114-116 ⁰ C; [o.lo ³ = - 7.8 ° (c = 0.97, dichloromethane) is dissolved in acetic acid ester. Dry hydrochloric acid is passed through the solution until more solid precipitates out. The precipitate is separated and umkristallisiort of methanol and Essigsäuremethylestor and provides (-) - p- [2- (2-hydroxy-3-phenoxypropylamirio) othoxy] |> honoxyessigsäuremothylester hydrochloride (0,092g), mp 156-157 ⁰ C; (α) "= - 12.1 ° (c = 1.0, methanol).

Examples 3-16

After similar ancestors as described in Example 1 (but with the corresponding amine of the formula HNR ² R ³ and untor execution of the reaction to almost complete conversion, as indicated by thin layer chromatography on silica gel), the following compounds of formula IX in yield of 60 -90% obtained and ontwoder as freio bases or as hydrochloride or oxalate - or by Roaktion dor free base with etherealom hydrogen chloride or oxalic acid and recrystallization from the angegobenen solvents - isolated.

example R ² R ³ N-- F.ing- F. ( ⁰ C) solvent position to the crystal lisa tion Third dimethylamino 4 84-85 EtOAc 4th methylamines 3 184-186 · Mooh / EtOAc 5th 2-hydroxy-othylamino 4 121 to 121.5 MoOAc 6th benzylamino 4 111-113 MeOAc 7th isopropylamino 4 110-111 Mr, OAc / Hoxan 8th. piperidino 4 68-69 E ₁ OAc 9th 2-methoxy-ethylamino 4 96-97 EtOAc 10th cyclopentylamino 4 103-104 EtOAr 11th pyrrolidino 4 66-67 EtPMc / hexane 12th 1,2,3,4-Totrahydro- 4 154-156 " MeOH / MoOAc isoquinolin-2-yl 13th morpholines 4 168-169 " MeOH 14th Butylamlno 4 106-107 EtOAc 15th isobutylamino 4 104-105 EtOAc 16th propylamino 4 105-106 EtOAc Remarks: * Hydrochloride ·· Oxalate MeOH methanol MeOAc acetic acid ester EtOAc vinegar

The starting ester for Example 4 is obtained as follows:

(i) A mixture of resorcinol (88g), 1,2-dibromoethane (180g) and potassium hydroxide (44.8g) is stirred at reflux in methanol (600ml) for 24 hours. The reaction mixture is cooled. The remaining solid is filtered off and the filtrate is evaporated, yielding 3- (2-bromo-ethoxy) phenol as an almost pure oil after TLC (with silica gel plates and 10% methanol in dichloromethane as the eluting solvent), without further purification , (ii) A mixture of 3- (2-bromoethoxy) phonol (40g) and benzylamine (39.2g) is stirred at reflux for 18h in ethanol (800ml). The reaction mixture is cooled and the solvent evaporated. The remaining oil is dissolved in ethyl acetate (200ml). The solution is washed with 2 M hydrochloric acid (100 ml). The aqueous layer is made alkaline with solid potassium carbonate and extracted with ether (2 x 100 ml). The extracts are washed successively with water (50 ml) and brine (50 ml) and then dried (MgSO ₄ ). The dry ethereal solution is treated with a saturated solution of hydrogen chloride in ether. The precipitated solid is recrystallized twice from a mixture of methanol / ethyl acetate to give N-benzyl-n-hydroxy-phenoxyethylamine hydrochloride (19.2 g), m.F. 148-149 ° C; NMR: 3.2 (t, 2H, CH ₂ NH), 4.22 (s + t, 4H, CHiO, NCH ₂ Ph), 6.4 (m, 3 aromatic H), 7.1 (t, 1 aromatic H), 7.3-7.8 (m, 5 aromatic H). (iii) A mixture of N-benzyl-2- (rn-hydroxy-phenoxy) ethylamine hydrochloride (2.79g), 1 ^ -epoxy-S-phenoxy-propane (1.5g) and anhydrous potassium carbonate (2.0g) heated under reflux for 18 h in propan-2-ol. The reaction mixture is cooled and the solvent evaporated to yield N-benzyl-N- [2- (m -hydroxy-ph3noxy) -thyl-2-hydroxy-3-phonoxy-propylamine as a nearly pure oil, as by TLC (with silica gel plates and 5% methanol in dichloromothane as the eluent), which is used further without purification.

(iv) N -Benzyl-N- [2- (m -hydroxy-phenoxy) ethyl] -2-hydroxy-3-phenoxy-propylamine (1.6 g) is added methyl bromoacetate (0.5 g), anhydrous potassium carbonate (0 , 6g) and potassium iodide (0.05g) in acetone (80ml) using a similar procedure to the starting ester in Example 1 with isolation of the intermediate m- [2- (N-benzyl-2-hydroxy-3-phenoxypropylamino) ethoxy] phenoxyacetic acid methyl ester (1.1 g) is used. M- obtained | 2- (2-hydroxy-3-phenoxypropylamirio) ethoxy) phenoxyessigsäuremethylesier-nydiuchlond (0.35 g), mp 164-167 ⁰ C; Microanalysis: found C 58.0; H 6.5; N 3.3; Cl 8.7%; C ₂₀ H ₂₆ CINO requires C 58.3; H 6.4; N 3,4; Cl 8.6%; NMR: 3.1 (dd, 1H, CHCH ₂ NH), 3.25 (dd, 1H, CHCH ₂ NH), 3.4 (t, 2H, NHCHjCH ₂ ), 3.7 (s, 3H, CO ₂ CH ₃ ), 3.9-4.1 (m, 2H, OCH ₂ CH), 4.2-4.4 (m, 3H, OCH ₂ CHOH-), 4.78 (s, 2H, OCH ₂ CO ), 5.98 (el, 1H, CHOH), 6.5-6.7 (m, 3 aromatic H), 6.9-7.0 (m, 3 aromatic H), 7.1-7.4 (m, 3 aromatic H), 9.1 (s, 2H, NH ₂ ⁺ ).

Examples 17-18

By similar procedures as described in Examples 3-16, but with p- [2-l3- (o-fluoro-phenoxy) -2-hydroxypropylamino] -ethoxy] phenoxyessigsäuremethylester as starting compound are obtained in yield of about 80-90%:

(Example 17): N-methyl-p- [2- (3- (o-fluorophenoxy) -2-hydroxypropyl] amino] ethoxy) phenoxyac. Tamid as hydrochloride, mp 168 to 169 ⁰ C (recrystallized from methanol / ethyl acetate) and

(Example 18): N-Piporidino-p - ^ - IS-lo-fluoro-phenoxyl ^ -hydroxypropylaminolothoxylphenoxyacetamid as hydrochloride, m.p. 144 to 146 ⁰ C (recrystallized from ether / methanol).

Dor Required Exposure Mothyloster is obtained as follows:

(I) A mixture of N-benzyl-1-p-hydroxy-phenoxy-jjylamine hydrochloride (see Example 1) (5.6 g), 1,2-epoxy-3- (o- (luorophenoxy) propane (3.6 g) and anhydrous potassium carbonate (2.7 g) is heated at reflux in propan-2-ol (100 ml) for 24 h, the reaction mixture is cooled, the solid is filtered off and the solvent is evaporated off from the pellet The remaining oil is filtered wild by chromatography on kiosolgol with 1% by volume of methanol Purified in dichloromethane as Elutioiisinittcl and provides N-benzyl-NU-lp-hydroxy-phenoxylethyll-S-fo-fluoro-phonoxyl ^ -hydroxy-propylamine as without oil, NMR: 2.27-3.16 (m, 4H, CH ₂ NCH ₂ ), 3.8 (dd, 2H, NCH ₂ Ph), 3.9-4.2 (m, BH, OCH ₂ CHOH, O-F-Ph-OCH ₂ ), 6.7 (s, 4 aromatic H), 6.8-7.1 (m, 4 aromatic H), 7.3 (m, 6H, CH ₂ Ph).

(Ii) A group of N -bonyl-N- [2- (p-hydroxy-phor.oxy) othyl] -3- (o-fluorophenoxy) -2-hydroxy-propylamine (5.4g), bromosulphonic acid methylosthor ( 2.0 g), water-free potassium carbonate (1.79 g) is stirred under reflux for 24 h in dry acetone (80 ml). The reaction mixture is cooled, the solid is filtered off and the solvent is evaporated off. Dissolve the residue in dichloromethan (40ml) and wash successively with 10% IgG (Gow./vol.) Notriquorhydrogencarbonate solution (20ml) and water (20ml) then dried (MgSO ₄ ) and one solvent evaporated. The resulting oil (6.18g ) is purified by chromatography on kiosolgol with 1% by volume of methanol in dichloromethane as eluent, yielding p- [2- [N-benzyl-3- (o-fluorophenoxy) -2-hydroxypropylamino) ethoxy] phenoxyossic acid methyl ester colorless oil. This is dissolved in methanol (100 ml) and stirred for 1 h with charcoal (1 g). The activated carbon is filtered off and the filtrate is hydrogenated in the presence of benzyl chloride (0.71 g) and 10Gow .-% palladium / carbon at atmospheric pressure for 2 h. The catalyst is filtered off and the solvent is evaporated from the filtrate. The residual solid is recrystallized twice from a mixture of methanol and ether, and supplies warsorfroiom p- [2- [3- (o-fluoro-phenoxy) -2-hydroxy-propyl ^l amino] ethoxylphonoxyosslgsäurohydrocnlorid (0.55 g), m.p. 12ü -122 ° C; Microanalysis: found C 55.7; H 5.9; N 3.2; Cl 8.3%; C ₂₀ H ₂₆ CIFNO ₈ requires C 55.9; H 5.9; N 3.3; Cl 8.2%; NMR: 3.1 (dd, 1H, CHCH ₂ NH), 3.27 (m under HOD peak, 1H, CHCH ₂ NH), 3.41 (t, 2H, NHCH ₂ CH ₂ ), 3.68 ( s, 3H, COjCH ₃ ), 4.05 (d, 2H, OCH ₂ CH), 4.25 (d + m, 3H, OCH ₂ , CHCH), 4.71 (s, 2H, OCH ₂ CO), 5.93 (d, 1H, CHOH), 6.8-7.0 (m, 5 aromatic H), 7.1-7.3 (m, 3 aromatic H), 9.12 (broad s, 2H ₁ NH ₂ ⁺ ).

Bolsplel 19

By a similar procedure as described in Example 2, the (-) - phonoxyacetate (Z) (0.6 g) is converted into N- (2-hydroxy-othyl) -p- [2- (2-hydroxy-3-phenoxy-propylamino ) ethoxy] phencxyacetamld (0.32 g) was converted, F. 111-113 ⁰ C, | α) έ = ⁵ - 7.1 ° (c = 0.99; ethanol), wherein instead of methylamine ethanolamine is used.

-9- 266 7 ·.

NM CHjCH ₁ O- ('

OCH ₁ CO-NR '

II

ο-

OCHiCH CH ₁ NH

ql

OH> IV

OH Q, OH

CCH _x CH-CH _x Y

UCH ₁ CO.

YFI OCM _x CO ₁ NIR ²

H CH ₁ ISH Cm ₁ CH ₂ O

IX

Examples 20-27

Following a procedure similar to that described in Example 1 (but with prewound of the corresponding amine of formula HNR ² R ³ and almost complete reaction as exemplified by kiosolgol on TLC analysis), the subsequent precursors of formol IX (the substituent OCHjCONR ² R ^{3 was found to be} present in 4-membered ring X) in yields of 55 to 85%, and free bases were recovered from the indicated solvents after recrystallization.

example R ² R ³ N- F. ( ⁰ C) Solvent for Umkristalüsation 20 ethylamino 104-105 EtOAc 21 allylamines " 97-98 EtOAc 22 2-Phonyl-othylamino 134-136 MeOH 23 4-chloro-bonzylamino 12S-127 Mooh 24 3-Hydroxy-propylamino 103-104 MeOH / EtOAc 25 3-Methoxy-propylamino 88-89 EtOAc 26 Carbamoylmothylamino 208-209 Mooh 27 1-phenyl-othylamino 132-133 EtOAc

Example 28

To p- [2- (2-hydroxy-3-phenoxy-propylamino) -ethoxy) phenol (1, 0g) in dry dimethylformamide (DMF) (50 ml) is added sodium hydroxide (0.132 g of a 60% by weight suspension in mineral oil). The resulting suspension is stirred for about 30 minutes, a clear solution is obtained. Then a solution of N-phonyl-chloro-acotamide (0.559g) in dry DMF (20ml) is added and the mixture is stirred for 18h then poured into water (150ml). The obtained Gomisch is oxy-bleached with dichloromethane (2 × 100 ml). The extract was washed with water (6 × 100 ml), then gotrocknot (MgSO ₄ ) and the solvent evaporated. The residue is umkristallisiort from Essigestor and provides N-phenyl-p- [2- (2-hydroxy-3-phenoxy-propylamino) othoxy) phenoxyacetamide (0,365g), mp 119-121 ⁰ C; Microanalysis: found C 68.7; H 6.5; N 6.3%; C ₂₆ HnN ₂ O ₆ requires C 68.8; H 6.4; N 6.4%; the NMR spectrum corresponds to that indicated structure. The starting phenol is obtained as follows:

(i) A mixture of p- (2-amino-ethoxy) phenol hydrochloride (1.89 g), Tiiethylamine (1.01 g) and i ^ -epoxy-S-phonoxy-propane (1.5 g) is allowed to stand for 24 h heated to reflux. The reaction mixture is cooled and the solvent is evaporated off. The residue is partitioned between dichloromethane (100 ml) and 10% (Gow./vol.) Potassium carbonate solution. The organic layer is separated, dried (MgSO ₄ ) and the solvent evaporated. The remaining oil is dissolved in Essigoster and dried hydrochloric chloride through the solution golnitet until no more solid precipitates. The precipitate is abgotronnt and umkristallisiort of methanol and Essigester and provides p- [2- (2-hydroxy-3-phonoxy-propylamino) ethoxy) phenol hydrochloride (0.53 g), mp 171-172 ⁰ C; Microanalysis: gof indon C 60.3; H 6,7; N 4.0%; Cl 10.6%; C ₁₇ H ₁₂ CINO ₄ orfordort C 60.1; H 6.5; N 4.1; Cl 10.5%. (ii) The ancestors by (i) erhaltone Hyclrochlorid (1.5g) wi ^r d is between 5% (Gow./Vol) aqueous Natriumhydrogencorbonatlösung (15ml) and dichloromethane (15ml) vortoilt. The organic phase is abgotronnt grockrocknot (MgSO ₄ ) and the solvent is evaporated and gives p- [2- (2-hydroxv-3-phonoxy-propylamino) nthoxy] ph9nol as zähon syrup (1.1 g), which used without further purification becomes

 N-Phonyl-1-chloro-acetamide is obtained as follows:

A mixture of aniline (9.3 g) and triethylamine (10.1 g) in dichloromethone (40 ml) is added dropwise over 1 h to an ice-cold solution of chloroacotyl chloride (11.3 g) in dichloromethane (40 ml). The Gomisch is stirred for another 18h. The organic phac? is filtered off, washed with water (3 × 50 ml), dried (MgSO ₄ ) and the solvent evaporated to give N-phenyl-2-chloro-n-c-amide (6.1 g) as a white solid, mp 128-129 ⁰ C. which continues to be used without purification.

Example 29

By analogous procedures as described in Example 28, but using N-propyl-2-chloro-acet8mid (0.447 g) in place of N-phenyl-2-chloroacetamide with N'-propyl-p- (2- (2 -hydroxy-3-phonoxy-propylamino) ethoxy-phenoxyacotamide (0.47g), mp 105-107 ° C (recrystallized from ethyl acetate), which is essentially identical to any material containing dom in Example 16.

The starting material N-propyl-Z-chloro-acotamide is obtained in an analogous manner as N-phenyl-chloro-acetic acid, i. H. by reaction of propylamine with chloroacetyl chloride. Ee is preserved as oil, wolchos oingosotzt without woitore cleaning.

Example 30

As stated above, suitable pharmaceutical compositions of compounds of formula I defined above can be obtained by standard production methods.

A typical tablet formulation for oral administration to warm-blooded animals contains as an active ingredient a precursor of formula I or a pharmaceutically-acceptable salt thereof as defined above (e.g., as described in any of the preceding examples) in finely divided form, and can be obtained by direct pre-pressing with very finely divided lactose containing a standardized separating agent and / or lubricant. If tablets with a small proportion of the active ingredient (eg 0 ₍ 5-10 mg) are required, the active ingredient together with lactose can be finely disintegrated at a ratio of 1:10, and this material can then be refined with additional lactose or mikiocrystalline Cellulose containing 0.6% by weight of a lubricant (such as magnesium stearate) and 5% by weight of a release agent (wio crosslinked sodium carboxymethylcellulose or sodium starch glycolate).

Cla

NMCHiCH ₂ O-

y VoCH _x O-!

CHx CM - CHx

OH Gl OCWxCHCM _x N.

OCH _x CO.

VJU

Claims (9)

A process for the preparation of amide derivatives of the formula I (indicated below) in which R ^{1 is} hydrogen or fluorine, R ^{2 is} phenyl which is a halogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy , Trifluoromethyl, cyano or nitro substituents, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ alkyl, in which the carbon atom bound to the nitrogen of the NR ² R ³ group, one or two Is hydrogen or C; r C ₄ alkenyl, each of the latter groups being capable of bearing a hydroxy, carbamoyl, C ₁ -C ₄ alkoxy, phenyl or chlorophenyl substituent; R ^{3 is} hydrogen, methyl or ethyl or R ² and R ³ together form a C ₄ -C ₇ polymethylene group in which a methylene unit may be replaced by oxygen or sulfur which is at least 2 carbon atoms from the nitrogen atom of NR ² R ³ - And two adjacent moiety units may be replaced by 2 carbon atoms of a benzene ring fused to said C ₄ -C ₇ polymethylene group and which itself is a halogen, C ₁ -C ₄ alkoxy, C ₁ - C ₄ -AlkYl-, trifluoromethyl, cyano or nitro substituent can carry; or a pharmaceutically acceptable acid addition salt thereof, and optionally the pharmaceutical administration form thereof, characterized in that (a) reacting an ester of formula II, wherein R ^{4 is} C ₁ -C ₆ -alkoxy, phenoxy or benzyloxy, with an amine of formula HNR ² R ³ ; (b) reacting a phenol derivative of formula III with an alkylating agent of the formula X-CH ₂ -CO-NR ² -R ³ wherein X is a leaving group; (c) reacting an amine derivative of formula VII with an epoxide of formula V; or (d) deprotecting a protected derivative of formula VIII wherein Q is a protecting group; whereafter, when a pharmaceutically acceptable acid addition salt is desired, the compound of the formula I in the form of the free base is reacted with the corresponding acid according to a conventional method; and when an enantiomer of a compound of formula I is desired, the corresponding racemate can be resolved or one of the above processes (a) - (d) can be carried out with an optically active starting material; and optionally, the compounds prepared by this process with a pharmaceutical carrier or diluent can be made into pharmaceutical dosage forms and wherein formulas II, III, VII, VII and VIII are given below. 2. The method according to claim 1, characterized in that compounds of formula I are prepared, wherein R ^{2 is} phenyl which is a substituent, from the group fluorine, chlorine, bromine, methoxy, ethoxy, methyl, ethyl, Trifk'ormethyl, cyano and may contain nitro, cyclobutyl, cyclopentyl or cyclohexyl; or methyl, ethyl, propyl, isopropyl, butyl, isobutyl, allyl or 2-methyl-prop-2-enyl, which may carry a substituent selected from the group consisting of hydroxy, carbamoyl, methoxy, ethoxy, phenyl and p-chlorophenyl; or R ² and R ³ together are ethyleneoxyethylene or ethylenethioethylene or together are tetramethylene or pentamethylene, of which two adjacent methylene units may be replaced by two carbon atoms of a benzene ring fused with said tetramethylene or pentamethylene, which benzene ring is itself a fluoro, chloro, bromo -, methoxy, ethoxy, methyl, ethyl, trifluoromethyl, cyano or nitro substituents can carry. 3. The method according to claim 1 or 2, characterized in that compounds of formula I are prepared in which the group NR ² R ³ from the group anilino, benzylamino, allylamino, cyclohexylamines, cyclopentylamino, morpholino, piperidino, pyrrolidino, dimethylamines, diethylamino, Methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, 2-hydroxyethylamino, 3-hydroxy-propylamino, 2-methoxy-othylamino, indolin-1-yl, 1-methyltetrahydroisoquinoline-1-yl and 1,2,3, 4-tetrahydroquinolin-1-yl is chosen. 4. The method according to any one of claims 1 to 3, characterized in that compounds of formula I are prepared, wherein the groups -OCH ₂ -CO-NR ² R ³ and -O-CH ₂ CH ₂ -NH- are linked in the para position , 5. The method according to claim 1, characterized in that compounds of formula I are prepared, wherein R ^{2 is} a Cv ^ alkyl group which can carry a hydroxy or Cv-C ₄ alkoxy substituent and in which the nitrogen of the NR ² R ³ group bonded carbon atom carries one or two hydrogen atoms; R ^{3 is} hydrogen, methyl or ethyl or R ² and R ³ together form a C ₄ -C ₆ polymethylene group in which one methylene moiety may be replaced by oxygen or sulfur which is at least 2 carbon atoms from the nitrogen atom of NR ² R ^? Group are removed. A process according to claim 1, characterized in that compounds of the formula I wherein R ^{1 is} hydrogen, the group NR ² R ³ benzylamino, piperidino, pyrrolidino, C ₃ -C ₄ -alkenylamino, morpholino, 1,2, 3,4-tetrahydroisoquinolin-2-yl or C V Ct -alkylamino, in which the carbon atom bound to the nitrogen atom carries one or two hydrogen atoms and the groups -OCHr-CO-NR ² R ³ and -O-CH ₂ CH ₂ -NH- are linked in the para position; or a pharmaceutically acceptable acid addition salt thereof. 7. The method according to claim!, Characterized in that a compound of formula I (given below) is prepared, wherein R ^{1 is} hydrogen, the group NR ² R ³ methylamino, ethylamino, propylamino, isopropylamino, 2-hydroxy-ethylamino, 3 -Hydroxy-propylamino, 2-methoxyethylamino, 3-methoxy-propylamino or 1,2,3,4-tetrahydroisoquinolin-2-yl, and dio-OCH ₂ -CO-NR ² R ³ and -O-CH ₂ CH _{2 groups} -NH- are linked in the para position; or a pharmaceutically acceptable acid addition salt thereof. 8. The method according to claim 1, characterized in that compounds are prepared selected from N-methyl, N-propyl, N- (2-hydroxyethyl) - and N-allyl-p- [2- (2- hydroxy-3-phenoxypropylamino) -ethoxy) phenoxyacetamide and from pharmaceutically acceptable acid addition salts thereof. Process according to any one of the preceding claims, characterized in that a salt is prepared according to one of the preceding claims with an inorganic or organic acid containing a pharmaceutically acceptable anion.