NL8502212A - PHENETHANOLAMINE DERIVATIVES. - Google Patents

Description

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Fenethanolamine derivatives *

The invention relates to phenethanolamine derivatives having a cardiotonic and vasodilatory action, to methods for their preparation, to pharmaceutical preparations containing them and their use in medicine, in particular in the treatment of cardiac insufficiency.

Heart failure is characterized by the inability of the heart to pump blood in sufficient quantities according to the body's needs. As a result, a reflexive increase in the sympathetic stimulation of the heart and the vasculature arises, which leads to an increased heart rate and contraction force and to an increased vascular resistance. The increased resistance further counteracts the already compromised heart and an interaction develops, with the increase in resistance (caused to maintain cerebral blood flow) progressively worsening the condition.

Treatment of cardiac insufficiency generally includes an increase in the contraction force of the heart or a decrease in resistance in the peripheral vasculature. Heretofore, the most common agents for the treatment of heart failure have been the digitalis glycosides, which increase the contractile force of the heart, i.e., increase its poap activity. However, these cardiotonic agents have the drawback of being undesirably toxic. Other agents, such as dopamine and dobutamine, have the disadvantage that, like isoprenaline, adrenaline and norepinephrine, they have a% short duration of action and are ineffective when administered orally or have undesirable side effects.

Recently, it has been discovered that the use of vasodilators to reduce peripheral vascular resistance (i.e., to decrease the resistance of the blood vessels to the pumping action of the heart) is valuable in the treatment of heart failure. However, a side effect of vasodilators such as notroprusside and hydralazine is usually that they cause undesirable side effects such as headache and reflex tachycardia.

The combination of a cardiotonic agent and a vasodilator is of particular importance in the treatment of heart failure. At the

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Administration of such a combination of agents is desirable to have similar pharmacokinetic properties so that both agents are effective for equal periods of time. However, this is often difficult to achieve with connections of different structures.

Low toxicity compounds that increase the contraction force of the heart and decrease the peripheral vascular resistance without affecting the heart rate too much and with a long duration of action would therefore be of great importance in the treatment of heart failure. Efficacy after oral administration would also be desirable.

Phenethanolamines are known with a wide variety of substituents on the phenyl ring and on the amino group. A number of different actions have been attributed to such compounds, for example a β-adrenoreceptor blocking activity, a vasodilatory activity, a bronchodilator activity and a local anesthetic effect. Some of these compounds have found utility in the treatment of disease states, such as hypertension, cardiac arrhythmias, heart failure, angina, asthma, and glaucoma.

A small group of phenethanolamines has now been found with a special combination of substituents in the phenyl ring and on the amino group, which compounds increase the contractile force of the heart and decrease peripheral vascular resistance. This particular group of phenethanolamines has not been mentioned in previous literature and these compounds have been found to act as cardio-tone agents and as vasodilators and can be used in the treatment of cardiac insufficiency.

The invention therefore provides compounds of the general formula 1 of the formula sheet, wherein R represents a hydrogen atom or a straight chain alkyl group with 1-3 carbon atoms and η is 1 or 2, and physiologically acceptable acid addition salts, compounds with solvent and metabolically labile esters thereof.

It will be clear that the compounds according to the invention have an asymmetric carbon atom, namely the -CH (OH) group, and thus there are two optically active enantiomers of the general formula 1. The invention includes both individual isomeric forms of the compounds of formula I and any mixtures of such enantiomers.

The physiologically acceptable acid addition salts of the compounds of the formula I can be derived from inorganic or organic acids. Examples of such salts include hydrochlorides, hydrobromides, hydrochlorides, sulfides, sulfates, phosphates, benzoates, p-toluenesulfonates, methanesulfonates , sulfamates, ascorbates, tartrates, citrates, maleates, salicylates, fumarates, succinates, lactates, glutarates, glutaconates, acetates or tri-carballyates. The preferred acid addition salts are the hydroflorides, fumarates and phosphates.

Physiologically acceptable, metabolically labile ester derivatives can be formed by acylation of any of the hydroxy groups present in general formula 1. Examples of such esters include lower alkanoates, such as acetates or pivalates. In addition to the above ester vessels, the invention also includes compounds of the general Formula 1 in the form of other physiologically acceptable equivalents, ie physiologically acceptable compounds, which are converted in vivo into the compounds of the general Formula 1, as are the metabolically labile esters. The invention also includes the compounds with solvent, in particular the hydrates, of the compounds of the general formula 1.

Animal studies have shown that compounds of the general formula 1 in low doses increase the contractile force of the heart muscle and decrease the overall peripheral resistance. The compounds of the invention are potent cardiac stimulants and act as vasodilators. In addition, the compounds of the invention have particular advantages over the known cardiotonic agents, such as isoprenaline and dobutamine, in that they have a longer duration of action and are additionally absorbed from the gastrointestinal tract, as evidenced by their activity after oral administration. It has now been found that compounds of the general formula 1 selectively block vascular alpha-adrenoceptors and stimulate cardiac alpha-adrenoceptors. The compounds do not show any signs of toxicity at the highest doses tested.

According to one aspect of the invention there are provided compounds of formula I wherein R represents a hydrogen atom, a methyl group or an ethyl-30 group, n equals 1 or 2, and physiologically acceptable acid addition salts, compounds with solvent and metabolically labile esters thereof.

A preferred group of compounds of formula 1 is the group wherein n = 1.

Another preferred group of compounds of formula 1 is the group wherein R represents a hydrogen atom.

A particularly preferred compound is 2- (2 - [[2- (3,5- / • ft * -4-dihydroxyphenyl) -2-hydroxyethyl] amino] ethoxy] benzeneacetamide and its physiologically acceptable acid addition salts, e.g. fumarate or phosphate, most simply in the form of a racemic mixture of its (R) and (S) isomers.

Compounds of the invention can be used in the treatment of heart failure, cardiogenic shock or ischemic heart disease.

Accordingly, the invention further provides compounds of the general formula 1 and their physiologically acceptable acid addition salts and metabolically labile esters for use in the treatment or prevention of cardiac insufficiency in humans or animals.

The compounds of formula 1 and their physiologically acceptable acid addition salts and metabolically labile esters can be brought into a dosage form in any suitable manner and the invention therefore includes pharmaceutical compositions comprising at least one compound of the formula 1 or a physiologically acceptable salt, compound containing solvent or metabolically labile ester thereof, adapted for use in human or animal medicine. Such formulations can be conventionally mixed with one or more physiologically acceptable carriers or excipients.

Thus, the compounds of the invention can be presented in an oral, buccal, parenteral or rectal administration form or in a form suitable for administration by inhalation or insufflation. Oral administration is preferred.

Tablets and capsules for oral administration may contain conventional excipients, such as binders, eg syrup, acacia, gelatin, sorbitol, gum tragacanth, starch gum or polyvinylpyrrolidone, fillers, eg lactose, sugar, microcrystalline cellulose, corn starch, calcium phosphate or sorbitol, lubricants for example magnesium stearate, stearic acid, talc, polyethylene glycol or silicon oxide, disintegrants, for example potato starch or sodium starch glycolate, or wetting agents such as sodium lauryl sulfate. The tablets can be coated according to methods known in the art. Liquid oral preparations can be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs or in the form of a dry product, in order to be combined with water or another suitable agent before use. Such liquid; 7 ': i ï i -5- J * .....

Preparations may contain conventional additives, such as suspending agents, for example, sorbitol syrup, methyl cellulose, glucose / sugar syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel or hydrogenated edible fats, emulsifying agents, for example, lecithin, sorbitan monoole acacia, non-aqueous carriers (which may include edible oils), for example, almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol, and preservatives, for example methyl or propyl p-hydroxybenzoates or sorbic acid. The compounds or their salts or esters can also be formulated as suppositories, for example, with a conventional suppository base, such as cocoa butter or other glycerides.

For buccal administration, the composition may be in the form of conventionally prepared tablets or lozenges.

The compounds of formula 1 and their physiologically acceptable acid addition salts and metabolically labile esters can also be formulated for parenteral administration by injection or continuous infusion. Preparations for injection can be presented in unit dose form in ampoules or in multi-dose containers with an added preservative.

The compositions may be in the form of suspensions, solutions or emulsions in oily or aqueous carriers and may contain formulating agents such as suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient may be in powder form to be combined with a suitable carrier, for example sterile pyrogen-free water, before use.

For administration by inhalation, the compounds of the invention are conveniently administered in the form of an aerosol spray from pressurized packages using a suitable propellant, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas, or from an atomizer.

In the case of a pressurized aerosol, the dose unit can be determined with a valve delivering a measured amount.

Alternatively, for inhalation administration, the compounds of the invention may be in the form of a dry powder formulation, for example, a powder mixture of the compounds and a suitable powder base, such as lactose or starch. The powder preparation can be brought in unit dose form, for example in capsules or cartridges of, for example, gelatin, or in blister packs, from which the powder can be administered by means of an inhaler or a blower.

When the compositions comprise dose units, each unit will preferably contain 5-500 mg of the active compound, when the compounds are to be administered orally advantageously 25-400 mg. The daily dose as used for the treatment of an adult human will preferably be between 5 mg and 3 g, most preferably from 25 mg to 1 g, which can be administered in 1-4 daily dose depending, for example, on the mode of administration and the patient's condition.

The compounds of formula 1 and their physiologically acceptable acid addition salts and metabolically labile esters can be administered in combination with other drugs.

The compounds of the invention can be prepared by a number of methods as described below.

According to a general method (1), the compounds of the general formula 1 can be prepared by an alkylation reaction between a compound of the formula 2, in which -NA is a group -NER ^, -C ^ C ^ X or a group with the formula 2a or 2b represents, »2 3 4 5 - R, R, R and R each are a hydrogen atom or a protecting group% 20 and X is an easily removable atom or group, and a compound of the formula 3, wherein R and n have the same meaning as in formula 1, R 1 represents a hydrogen atom or a protected group and 5 Y represents a hydrogen atom when -NA represents -NR CH 1 CH 2 X 25 or a group of the formula 2a or 2b, or • Y represents the group CH'CH-X, wherein X has the previously defined meaning when NA represents -NHR, followed by removal of any protecting groups present, as described below.

For example, X may represent a halogen atom, such as chlorine, bromine or iodine, or a hydroxycarbylsulfonyloxy group, such as methanesulfonyloxy or p-toluenesulfonyloxy. When X is chlorine or bromine, the reaction can be facilitated by adding an iodide such as sodium iodide.

According to a particular embodiment of the process, the compounds of the general formula 1 can be prepared by alkylating an amine of the formula 4 with an alkylating agent of the formula 5, followed by removal of any protecting groups present, such as>> Λ. J1 / J .. J »* Ί» -7- described below.

The reaction is preferably carried out in the presence of a base, such as an alkali metal bicarbonate or carbonate, for example sodium bicarbonate or potassium carbonate or an amine, for example diisopropylethyl.

5 amine or silver oxide, and in solution at a temperature between -20 and + 100 ° C. Suitable reaction solvents include ethers, for example dioxane, acetonitrile, substituted amides, for example N, K-dimethylformamide and hydrocarbons, for example benzene.

In another embodiment of the method, the compounds of formula 1 can be prepared by alkylation of a phenol of formula 6 with an alkylating agent of formula 7, followed by removal of any protecting groups present, as described below.

Alternatively, the compounds of formula 7 may be in the form of an aziridine of formula 7a or an aziridine salt of formula 7b, wherein A represents an anion, such as a halodeion.

The reaction is preferably carried out in the presence of a base. Suitable bases include inorganic bases such as sodium hydroxide, sodium hydride, potassium carbonate or potassium t-butoxide, organic bases such as diisopropylethylamine and basic ion exchange resins such as Amberlite. Alternatively, the compound of formula 6 can be used in the form of a phenolate salt, for example the sodium salt. The reaction is conveniently carried out in a medium such as water, acetonitrile, an alcohol, for example methanol or a ketone, for example acetone or methyl iso-25-butyl ketone and at a temperature in the range from -20 to 150 ° C, preferably from 20 -100 ° C.

According to another general method (2), the compounds of formula 1 can be prepared by the reaction of a compound of formula 8, wherein R 2 and R 3 have the meaning, as in the general method (1) and R 1 a group represents the formula 8a or 8b, wherein 4 R and X have the meaning defined in the general process (1), with an amine of the formula 9 wherein R, R 1 and R 1 and n are the earlier in the general process (1 ) define the meaning followed by removal of any protecting groups present, as described below.

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This reaction can be carried out in the presence or absence of a solvent at a temperature of 0-150 ° C, preferably 20-100 ° C. Suitable solvents include alcohols, for example, methanol or ethanol, halogenated hydrocarbons, for example, chloroform or dichloro-methane, substituted amides, for example, Ν, Ν-dimethylformamide, ethers, for example diethyl ether or tetrahydrofuran, acetonitrile, esters, for example ethyl acetate and water and mixtures of the like solvents.

6

When R represents a group of the formula 8b, the reaction can be carried out in the presence of a base such as sodium carbonate, potassium carbonate, sodium hydroxide or an organic base such as pyridine.

Alternatively, an excess of the amine of the formula 9 can be used.

According to another general method (3), the compounds of formula 1 can be prepared by reductive alkylation. For example, a compound of the formula 10 in which 7 R represents the group -COCHO or a group of the formula 10a and 2 3 4 5 R, R, R and R may be the meaning previously defined in the general process (1) reacting with a compound of formula 11, wherein · 7 20 Z represents the group CHO when R is the group of formula 10a 5 '7 1 or Z represents the group CS 2 NHR when R is -COCHO and R, R, R and n have the meaning previously defined in the general method (1), in the presence of a reducing agent, followed by removal of any protecting groups present, as described below.

In one particular embodiment of the general method (3), a compound of the formula 10, wherein R is CH (OR) CH 2 NHP, is allowed to form. is reacting with a compound of formula 11 wherein Z is CHO in the presence of a reducing agent. Examples of suitable reducing agents include an alkali or alkaline earth metal borohydride or cyanoborohydride, such as sodium borohydride or cyanoborohydride, using an alcohol, such as ethanol or propanol as a solvent, or hydrogen in the presence of a catalyst, such as a Raney nickel, platinum, platinum oxide palladium or rhodium, using an alcohol, for example ethanol and ether, for example dioxane or an ester, for example ethyl acetate as a reaction solvent. The catalyst can be on a carbon support, for example, or a homogeneous catalyst such as tristriphenylphosphine rhodium chloride can be used. The reduction can easily be carried out at a temperature between -20 and 100 ° C, preferably from 0 ° -50 ° C.

12 3 4

The reaction can proceed via the imine 12, wherein R, R, R, R, R and n have the meaning previously defined in the general method (1), and it may be possible to isolate this intermediate. The reduction of the imine using the conditions described above, if necessary followed by removal of protecting groups, gives a compound of the general formula 1.

In a further embodiment of the general method (3), a compound of the formula 10, wherein R is COCHO, is reacted with a compound of the formula 11, wherein Z is CH 2 NHR, in the presence of a reducing agent. Suitable reducing agents have been previously described in the first embodiment of the reductive alkylation process.

This reaction can proceed via the imine of the formula 13, wherein: R 3, R, R, R, R and n have the meaning previously defined in the general process (1) and it may be possible to isolate this intermediate. This compound can also be reduced by the means described above in the first embodiment of the reductive alkylation process, if necessary followed by removal of protecting groups to form a compound of the formula 1.

According to another general method (4), the compounds of the formula 1 can be prepared by reduction of a compound of the formula 14, wherein: 12 3 5 R, R, R, R, R and earlier in the general method (1 ) have defined meaning, followed by removal of any protecting groups present, as described below. The reduction can be carried out using an alkali metal or an alkaline earth metal hydride, such as sodium borohydride or hydrogen in the presence of a catalyst, such as palladium or platinum, for example, on a carbon support.

A stereoselective reduction can be achieved using an optically active borane, such as alpine borane (9- (2,6,6-trimethylbicycloe3.1.1] hept-3-yl) -9-borabicyclo-S3.3.1] nonane).

The reaction is conveniently conducted in an organic solvent, such as an ether, for example, tetrahydrofuran or an alcohol, for example, methanol or ethanol at a temperature of, for example, 20-80 ° C. According to another general method (5), the compounds according to the invention can be prepared by amination of a compound of the formula wherein * - * J. J * Λ - # • / * -10 - 2 3 4 5 R, RR, R and n have the meaning previously defined in the general method (1) and R represents a carboxyl group or a salt or reactive derivative thereof, for example an acid halide, for example an acid chloride, an acid anhydride, formed with for example an acid chloride, For example pivaloyl chloride or chloroformate, or an ester, for example a C 1-6 alkylcester, followed by removal of any protecting groups present, as described below. The reactive derivative can also be formed in situ by treatment of the acid or a salt thereof with a condensing agent such as Ν, Ν'-dicyclohexylcarbodiimide or Ν, Ν'-car-bonyldiimidazole.

The amination is generally carried out using an amine RNH2, wherein R was previously defined in formula 1. The reaction is usually carried out in an organic solvent, such as an alcohol, for example methanol or ethanol, an ether, for example tetrahydrofuran, a amide, for example, Ν, Ν'-dimethylformamide or a halogenated hydrocarbon, for example methylene chloride, if desired in the presence of a catalyst, such as silica or rhodium trichloride, and at an O temperature of, for example, 0-150 ° C, preferably 50-100 ° C. When using ammonia for the reaction (R is then hydrogen) it may be desirable to conduct the reaction at a high pressure, preferably using water or an alcohol, such as methanol or ethanol as the solvent.

Q

Compounds of the formula wherein R is a carbonyl group and salts and esters (eg, C. alkyl esters) thereof are new compounds which are valuable intermediates and form a further aspect of the invention.

An interesting class of compounds of formula 15 are the compounds wherein R2, R2, R1 and R2 are hydrogen atoms.

A particularly interesting class of compounds of the formula 15 2 3 4 5 8

are the compounds wherein R, R, R and R are hydrogen atoms and R.

30 represents a carboxyl group or a -alkyl ester thereof (eg a methyl or isopropyl ester).

2 3 4 5

Compounds of the formula wherein R, R, R and R are hydrogen atoms and R represents a carboxyl group are of particular interest, more particularly when n = 1.

According to another general method (&), compounds according to the invention, wherein R represents a hydrogen atom, can be prepared by hydrolysis of a compound of the formula 16, r »" 1 Λ .- .¾ ώί Λ V · · i * · Ί / 4 * -11- where 2 3 4 5 R, R, R, R and n are defined as · above in the general method (1), followed by removal of any protecting groups present / as described below. The hydrolysis can be carried out under acidic or basic conditions using an aqueous acid, for example, phosphoric, hydrochloric or sulfuric acid or a base, such as an alkali metal hydroxide, for example, potassium hydroxide and at a temperature of 0-100 ° C. readily carried out in a water-miscible solvent, such as an alcohol, for example t-butanol or methanol, a ketone, for example acetone, or using acetic acid, preferably in the presence of water.

According to another general method (7), the compounds of the formula 1 can be prepared by deblocking a compound of the formula 17, wherein: 12 3 4 5 15 R, R, R, R, R, R and n are defined as above in the general method (1) or R and R together represent a protecting group, 1 2 3 4 5 wherein at least one of the groups R, R, R, R and R represents a protecting group.

When R1, R2, R2, R4 or R5 is a protecting group, it may be any conventional protecting group, for example as described in "Protective Groups in Organic Chemistry", edited by J.F.W. McOmie 2 3 4 (Plenum Press, 1973). Examples of suitable hydroxy protecting groups represented by R, R and R are alkyl groups, such as t-butyl or methoxymethyl, aralkyl groups, such as benzyl, diphenylmethyl or triphenylmethyl, heterocyclic groups, such as tetrahydropyranyl and acyl groups, such as acetyl. Examples of suitable amino protecting groups represented by R 2 are aralkyl groups such as benzyl, diphenylmethyl or triphenylmethyl and acyl groups such as dichloroacetyl. Examples of suitable amide protecting groups R * are t-butoxycarbonyl and 2,2,2-trichloroethoxycarbonyl-30 groups.

1234 '5

The protecting groups R, R, R, R and / or R can be removed using conventional techniques to form a compound of formula 1. For example, an aralkyl group such as benzyl can be cleaved by hydrogenolysis in the presence of a noble metal As a catalyst (eg palladium or palladium oxide on carbon), an acyl group such as dichloroacetyl can be removed by reduction using, for example, zinc and acetic acid, an alkyl or heterocyclic v - 'v * 5 # t -12-w * group , which protects a hydroxyl group, can be cleaved off by hydrolysis under acidic conditions. An amide protecting group, for example a t-butoxycarbonyl group, can be removed by acid hydrolysis.

In a particular embodiment of this method, the growth pen R and R together may represent a protecting group, such as m a compound of formula 18 wherein 12 3 R, R, R, R and n are defined as above general method (1) and 10 Y1 represents a carbonyl or thiccarbonyl radical or a bivalent radical formed from an aldehyde or ketone, such as acetaldehyde or acetone. A compound of formula 18 can be converted into a compound of formula 1 by hydrolysis under acidic or basic conditions using, for example, aqueous hydrochloric or sulfuric acid or sodium hydroxide and, if necessary, removal of any other protecting groups present, using the method described above.

Alternatively, the substituent on the amino group can serve as an internal protecting group for the hydroxyl group in the ethylene moiety, such as in a compound of formula 19 wherein: 12 3 5 R, R, R, R, R and n defined as above in the general method (1). The compound of formula 19 can be converted into a compound of formula 1 by reduction using the means described above in the general process (3) and, if necessary, removal of any protecting groups present using the above described methods.

When it is desired to prepare an acid addition salt of a compound of formula 1, the product of any of the above processes can be converted into a salt by treating the resulting free base with a suitable acid according to conventional methods.

Physiologically acceptable salts of the compounds of the general formula 1 can be prepared by reacting a compound of the formula 1 in the form of the free base with a suitable acid in the presence of a suitable solvent, such as acetonitrile, acetone, chloroform, ethyl -35 acetate or an alcohol, for example methanol, ethanol or isopropanol.

Physiologically acceptable salts can also be prepared from other salts, including other physiologically acceptable salts of the compounds —i - * s * ^% * \ / •. J - j% - f - 13 - of the general formula 1, using conventional methods.

Optically active enantiomers of the compounds of the invention can be obtained from tucs products of the desired chirality. Alternatively, such enantiomers can also be obtained by dissolving the corresponding racemic compound by conventional means, such as an optically active dissolving acid. For example, which "Stereochemistry of Carbon Compounds" by E.L. Eliel (McGraw Hill, 1962) and "Tables of Resolving Agents" by S.H. Wanting.

Examples of optically active dissolving acids that can be used to form salts with the racemic compounds include the (R) and (S) forms of organic carboxylic and sulfonic acids, such as tartaric acid, di-p-toluyl tartaric acid, camphor sulfonic acid, and lactic acid . For example, the resulting mixture of isomeric salts can be separated into the diastereoisomers by fractional crystallization and, if desired, the desired optically active isomer can be converted to the free base.

In another method, the optically active enantiomers of the invention can be obtained by separating optically active derivatives from the compounds. For example, derivatives of compounds. according to the invention, wherein one of the groups R 1, 2 3 4 5, 20 R, R, R and R in the compounds of formula 17 represents a chiral protecting group, R, R or R may represent, for example, an optically active sugar residue, such as a β-D-glycolpyranozidyl group. An example of a suitable optically active amine protecting group R ^ is an α-methylbenzyl group. These optically active protecting groups can be removed after the separation of the enantiomers by the methods described above in the general method (7).

The methods just described for the preparation of the compounds of the invention can each be used as the last major step of a preparation sequence. The same general methods can be used to introduce the desired groups at an intermediate stage in the stepwise preparation of the desired compound and it will be appreciated that these general methods can be combined in various ways in such multistage processes.

g

The compounds of formula 8, wherein R represents a group of formula 35a, can be prepared from a compound of formula 20 wherein 2 3 R and R are defined as above and X * is a halogen atom, by treatment with, for example, sodium - * Λ I,,. · ». .1 · "-14- boo rhy dr ide to form the halohydrin, followed by treatment with a base such as potassium carbonate or sodium hydroxide. The reaction is conveniently carried out in a solvent, such as dimethylformamide, an alcohol, such as methanol or ethanol or water, at a temperature from room temperature to reflux temperature.

6 4

The compounds of formula 8 wherein R is a group CH (OR) CH-X

4 1, wherein R and X have the meaning previously defined in formula 1, may be prepared from the corresponding epoxides by treatment with the appropriate reagent, such as hydrogen halide or p-toluenesulfonic acid, if desired followed by introduction of a protecting group .

7

The compounds of formula 10 wherein R is COCHO can be prepared from compounds of formula 21 wherein.

2 3 1 R, R and X have the previously defined meaning, by reaction with an alkoxide, such as sodium methoxide in methanol, followed by treatment with an acid, such as hydrochloric acid.

The compounds of formula 20 are known compounds.

The compounds of formula 21 can be prepared by halogenation of a compound of formula 22 in which: 2 3 R and R have the previously defined meaning, using, for example, a halogen (e.g. chlorine) or an N-halosuccinimide (e.g. N-bromosuccinimide).

7

The compounds of formula 10 wherein R is COCHO may also be prepared directly from a compound of formula 22 by oxidation using a suitable oxidizing agent such as selenium dioxide.

The compounds of formula 14 can be prepared by reacting a compound of formula 20 with an amine of formula 9 using the reaction conditions described earlier in the general method (2).

Compounds of formula 17 can be prepared using any of methods 1-4 as previously described.

The compounds of formula 7 can be prepared by reacting a compound of formula 8 with amine of formula 22a wherein and X have the meaning defined above, or when compounds of formula 7 are in the form of a azeridine or an azeridine salt, by reacting a compound of formula 8 with an amine of formula 22b in which R1 has the previously defined meaning, use · 1 ·. -; i% \ 1; - 1: 1 ', J W \ y j J - -15- using the conditions described in the general procedure (H.

Compounds of formula 9 can be prepared from compounds of formula 5 by the reaction with an amine of the formula R NH 2, wherein R has the previously defined meaning, according to the reaction conditions of the general method (1).

The compounds of formula 5 can be prepared from compounds of formula 6 by the reaction with a compound XCi ^ CE ^ X, wherein X has the previously defined meaning.

The compounds of formula 11, wherein Z is CHO, can be prepared by alkylation of the phenol of formula 6 with an alkylating agent of formula HCOCH 2 X, wherein X has the previously defined meaning, or in particular a protected derivative thereof, for example an acetal , such as a diethyl acetal.

Compounds of formula 16 can be prepared by the reaction of a compound of formula 20 with a nitrile of formula 23, wherein R 1 and n have the previously defined meaning, followed by treatment with a reducing agent, such as sodium borohydride.

g

Compounds of formula 15, wherein R is a carboxyl group or a. % salt or ester thereof, can be prepared by the reaction of compounds of formula 24, wherein R, R and n have the previously defined meaning, with compounds of formula 20, followed by treatment with a reducing agent, such as sodium borohydride if necessary followed by deprotection, as previously described.

8

Compounds of formula 15, wherein R is a carboxyl group, can be prepared by hydrolyzing a corresponding ester, followed by the removal of any protecting groups present, as described below. The hydrolysis can be carried out under acidic or basic conditions using an aqueous acid, for example polyphosphoric, hydrochloric or sulfuric acid, or a base, such as an alkali metal hydroxide, for example sodium hydroxide, and at a temperature of 0-100 ° C. The reaction can be easily carried out in a water-miscible solvent, such as an alcohol, for example, methanol.

g

Compounds of formula 15, wherein R is a reactive derivative of a carboxylic acid, for example an acid chloride or an anhydride, can be prepared in a conventional manner, for example by the formation of an acid chloride or an anhydride.

R

Compounds of formula 15, wherein R ~ is a carboxyl group or a 1 ... ......

· ** »...

Salt or ester thereof and n equal to 2 can be prepared by reduction of the corresponding α-β-ethylene carboxylic acid or salt or ester, using suitable hydrogenation methods, as described previously.

The unsaturated precursor can be prepared by methods analogous to the methods described herein for the preparation of the compounds of the invention, for example, by alkylation as described in the general method (1) and exemplified in the examples.

Compounds of formulas 23 and 24 can be prepared by the reaction of a compound of formula 25, 10 wherein n has the previously defined meaning and 9 R represents the CN group, the COOH or carboxylic acid ester group, as g previously defined for R , with a compound of the formula XCH ^ CH ^ Br, where X has the previously defined meaning, followed by amination with a compound of the formula r5nH2 'where R ^ has the previously defined meaning.

Compounds of formula 18 can be prepared from a compound of formula 17, wherein R, R, R, R and n have the meaning defined in the general method (1) and R and R are hydrogen atoms by the reaction with 1,1,1-carbonyldiimidazole or 1,1,1-thiocarbonyldiimidazole.

Compounds of formula 19 can be prepared by the reaction between a compound of formula 4 and a compound of formula 11, where Z represents a CHO group.

The following examples illustrate the invention. Temperatures are o in C, "dried" refers to drying using magnesium sulfate unless otherwise noted. Thin layer chromatography (TLC) was performed on silica plates. Flash column chromatography (FCC) was performed on silica (Merck 9385).

SV * 70 .¾ * »» v

·.,. · «* ----- - -AJ

-17-

Intermediate 1

Methyl 2- (2-bromoethoxy) benzene acetate

A mixture of 50.0 g of methyl 2-hydroxybenzene acetate, 84.0 g of anhydrous potassium carbonate and 500 ml of dibromoethane in 2 L of dry methanol was refluxed for 111 hours. The resulting mixture was evaporated and the residue was dissolved in 500 ml of chloroform, washed with 2 x 250 ml of water and 250 ml of brine, dried over Na 2 SO 4 and evaporated. The resulting oil (82 g) was purified by flash column chromatography using toluene as the eluent to give 32.5 g of the title compound as a yellow oil.

10 Elemental analysis:

Found: C W, 5; ^, 8

Calculated for C, H ^ H ^ BrO ^: c ^ 8, ^; H k, Q%.

Intermediate 2

Methyl 2- [2 - [(phenylmethyl) amino] ethoxy] benzene acetate. A mixture of 15 g of intermediate 1, 58.7 g of benzylamine and 16 g of sodium iodide was refluxed in 100 ml of dry acetonitrile for 1 hour. The organic solid was filtered off and the filtrate was evaporated. A solution of the residue in 200 ml of ethyl acetate was washed with 50 ml of water and 50 ml of brine, dried and evaporated. The residue was purified by flash column chromatography using ethyl acetate as eluent to give 13.2 g of the title compound as an orange oil. Elemental analysis:

Found: C 72, k; H 7.2; N M

Calculated for C 14 H 14 NO N: C 72.2; H 7.1; N ^, 7 $.

Intermediate 3 2- (2-bromoethoxy) benzeneacetami de

A solution of 1.06 g of 2-hydroxybenzene acetamide, 1.9 g of potassium carbonate and 0.11 g of tris [2- (2-methoxyethoxy) ethyl] amine in 50 ml of dibromoethane was refluxed for 21 hours and evaporated.

The solid obtained was dissolved in 75 ml of ethyl acetate, washed with water, dried and evaporated. The residue was purified by flash column chromatography with diethyl ether and then ethyl acetate as aluents to give 0.9 g of the title compound as a white solid, mp 81i-86 ° C.

TI *> _; / -18-

Intermediate product

2- [2- [(phenylmethyl) amino] ethoxy] benzeneacetamide

A solution of 50 g of intermediate 2 in 10 ml of methanol was heated in an autoclave with 15 ml of liquid ammonia at T5 ° C for b-3 hours.

The solvent was evaporated and the residue was purified by flash column chromatography with ethyl acetate-methanol (9: 1) as the solvent to give 2.60 g of the title compound as an off-white solid, mp 89 ° 90 ° C. .

Intermediate (alternative preparation method) A solution of 52 g of intermediate 3, 218 ml of benzylamine and 60 g of sodium iodide in acetonitrile was refluxed for 18 hours, filtered and evaporated. The residue was dissolved in 300 ml of ethyl acetate, washed with sodium carbonate solution (2M) and water, dried and evaporated. The resulting brown oil was purified twice by flash column-15 chromatography with diethyl ether and then ethyl acetate as a solvent to give 12 g of the title compound as an off-white solid, mp 85-87 ° C.

Intermediate 5

Methyl 2- [2- [[2- [2,5-bis (phenylmethoxy) phenyl] -2-hydroxyethyl] (phenylmethyl) -20 amino] ethoxy] benzene acetate

A solution of 1.37 g of 1- [3,5-bis (phenylmethoxy) phenyl] -3-bromoetha-nonyl in 25 ml of dimethylformamide was added over 5 minutes to a stirred solution of 1.0 g of intermediate 2 and 0 32 g of diisopropylethylamine in 25 ml of dry dimethylformamide. The mixture was stirred under nitrogen for 3.5 hours and then evaporated. 0.5 g of sodium borohydride was added over 10 minutes to a solution of the compound in 130 ml of absolute ethanol. The mixture was stirred at room temperature for 18 hours and concentrated in vacuo, 5 ml of water and 100 ml of methanol were added and the solution was evaporated. A solution of the compound in 50 ml of ethyl 30 acetate was washed with 25 ml of water and 25 ml of brine, dried and evaporated to give 2.13 g of the title compound as a yellow oil. Thin layer chromatography using ethyl acetate as the eluent gave an R 2 value of 0.7.

1 ^ S.N. Quessy and L.R. Williams in: Aust. J. Chem. 32, 1317 (1979) * * ‘J Yes» r -19-

Intermediate 6 2- (2-aminoethoxy) benzene acet amide

A solution of 2.5 g of the intermediate in 25 ml of absolute ethanol was hydrogenated on 10 # 's PdO-C until uptake was stopped. The catalyst was removed by filtration and the filtrate was evaporated under reduced pressure to a pale yellow oil, which was purified by flash column chromatography using dichloromethane-ethanol, 88 ammonia (100: 8: 1) as eluent. as a colorless oil, which crystallized on standing and gave 1.3 crystals with a melting point of 92-9 ° C.

Intermediate 7 a- (aminomethyl) -3,5-bis (phenylmethoxy) benzene methanol

A mixture of 31.8 g of 3,5-bis (phenylmethO2I) benzaldehyde, 9.92 g of trimethylsilyl cyanide and 0.1 g of zinc iodide in 50 ml of dry benzene was stirred under nitrogen for 1 hour. The resulting solution was added to an ice-cooled solution of 7.6 g of lithium aluminum hydride in 500 ml of tetrahydrofuran and the mixture was stirred at room temperature for 18 hours. The reaction mixture was cooled in an ice bath and 7.6 ml of water was added dropwise, followed by 15.2 ml of 2N sodium hydroxide solution and 22.8 ml of water. The inorganic solid was filtered off and the filtrate was evaporated to a red gum, which was purified by flash column chromatography with ethyl acetate-methanol (7: 1) as eluent to give 21.8 g of the title compound as a colorless solid with a mp 89-90 ° C.

Intermediate 8 2- (2-bromoethoxy) benzeneacetonitrile

A mixture of 1.6 g of 2-hydroxybenzeneacetonitrile and 3.3 g of potassium carbonate in 15.5 ml of dibromoethane was heated at 120 ° C for 2 days.

The solvent was evaporated, ethyl acetate was added to the residue, the inorganic solid was filtered off and the filtrate was evaporated to a brown gum. The gum was purified by flash column chromatography using diethyl ether-petroleum ether (1: 1) as eluent to give 2.2 g of the title compound as an orange oil. Thin layer chromatography with diethyl ether-petroleum ether (2: 1) as the eluent gave an R 2 value of 0.1.

· '. ; λ. > - -20-

Intermediate 9 2- [2 - [(phenylmethoxy) amino] ethoxy] benzeneacetonitrile

A mixture of 5.0 g of intermediate 8.11 g of henzylamine, 5.8 g of potassium carbonate and 1.7 g of sodium iodide in 100 ml of acetonitrile was refluxed for 5 hours. The inorganic solid was filtered off and the filtrate was evaporated. The residue was purified by flash column chromatography using ethyl acetate as eluent to give US 8 g of the title compound as a yellow oil. Thin layer chromatography using ethyl acetate as the eluent gave an R 2 value of 0.25.

10 Intermediate 10 2- [2- [[2- [3,5-bis (phenylmethoxy) phenyl] -2-hydroxy] ethyl] amino] ethoxy] benzeneacetonitrile

A solution of 5.96 g of 1- [3,5-tis (phenylmethoxy) phenyl] -2-bromoethanone, * 1.00 g of intermediate 9 and 2.61 ml of diisopropylethylamine in 30 ml of dime-15-methylformamide was added for 2 Stirred at room temperature for 5 hours and evaporated. The remaining gum was dissolved in 30 ml of methanol and treated with 1.9 g of sodium borohydride at room temperature for 16 hours. The reaction mixture was evaporated, treated with 50 ml of methanol, re-evaporated and partitioned between chloroform (2 x 100 ml) and water (100 ml). The organic phase was dried and evaporated to leave a yellow gum, which was purified by flash column chromatography using toluene diethyl ether (19: 1) as eluent to give 5.60 g of the title compound as a yellow gum. Thin layer chromatography with toluene diethyl ether (19: 1) as the eluent gave an R 2 value of 0.2h.

Intermediate 11 1-Methyl-ethyl-2-hydroxybenzene acetate

A solution of 3.0 µg of o-hydroxyphenylacetic acid in 20 ml of isopropanol was treated with 0.1 ml of 18 M sulfuric acid at room temperature for 66 hours, refluxed for 3 hours and evaporated. The residue was partitioned between 50 ml of ethyl acetate and 2 x 20 ml of 1 M sodium bicarbonate solution. The organic phase was dried and evaporated to leave 3.5 g of the title compound as a yellow oil which later hardened. Thin layer chromatography with diethyl ether as the eluent gave a crude value of 0.52.

, r * - »· '·» t *, “s e * ...

• * -21-

Intermediate 12 1-methyl ethyl 2- (2-brocmethoxy) benzene acetate

A mixture of 1.9 g g of intermediate 11, 2.8 g of potassium carbonate, 20 ml of dibromoethylene and 50 ml of isopropanol was heated under reflux for 16 hours, filtered and evaporated to leave 3.00 g of a light brown oil. Thin layer chromatography with petroleum ether-20% diethyl ether as the eluent gave an Rf value of 0.26.

Intermediate 13 1-Methyl-ethyl-2- [2- [(phenylmethyl) amino] ethoxy] benzene acetate 10 A mixture of 80 g of intermediate 12, 300 ml of benzylamine, 7 µg of carbonate and 80 g of sodium iodide in 1 L of acetonitrile was added heated to reflux for 20 hours. The inorganic solid was filtered off and the filtrate was evaporated. The residue was purified by flash column chromatography using diethyl ether as the eluent to give 70 g of the title compound as a pale yellow oil. Thin layer chromatography using diethyl ether as the eluent gave an R 2 value of 0. k.

Intermediate 1¼ 1-Methyl-ethyl-2- [2- [[2- [3,5-bis (phenylmethoxy) phenyl] -2-hydroxyethyl] (phenylmethyl) amino] ethoxy] benzene acetate 20 A solution of 5 g 0 l [3,5-bis (phenylmethoxy) phenyl] -2-brocmethanone in 15 ml of dry dimethylformamide was added to a solution of U, 0 g of intermediate 13 and Us5 ml of diisopropylethylamine in 50 ml of dimethylformamide and the solution was left for 3 hours at stirred at room temperature. The solvent was evaporated and the residue was redissolved in 80 ml of ethanol and treated with 2.5 g of sodium borohydride. The mixture was stirred for 2 hours, 20 ml of water was added and the mixture was stirred for an additional 0.5 hours. The ethanol was evaporated, the residue was acidified with 2N hydrochloric acid and the mixture was heated on a boiling water bath for 20 minutes. The solution was then neutralized with 8% sodium bicarbonate-30 solution and extracted with 3 x 80 ml ethyl acetate. The combined extracts were washed with 50 ml of brine, dried and evaporated. The residue was purified by flash column chromatography using diethyl ether-petroleum ether (1: 1) as eluent to give 5 * 60 g of the title compound as a pale yellow oil. Thin layer chromatography using diethyl ether-ether ether (1: 1) as the eluent 35 gave an R ^ value of 0.35 *> t 4 t '\ * 0 * 9 -22-

Intermediate 15 · 2- [2- [[2- [3,5-bis (phenylmethoxy) phenyl] -2-hydroxyethyl] (phenylmethyl) amino] ethoxy] benzenacetic acid

A solution of 56.1 g of intermediate 1U and 223 ml of 2N sodium hydroxide solution in 100 ml of methanol was refluxed for 16 hours. The methanol was evaporated and the aqueous phase was acidified to pH 6 with 20 ml of glacial acetic acid and extracted with 3 x 100 ml of ethyl acetate.

The combined extracts were washed with water and brine, dried and evaporated. The residue was purified by flash column chromatography using ethyl acetate petroleum ether (7: 3) as eluent to give 32.8 g of the title compound as a white foam. Thin layer chromatography with ethyl acetate-petroleum ether (7: 3) as the eluent gave an R 2 value of 0.25 ·

Intermediate 16 2- [2- [[2- (3,5-dihydroxyphenyl) -2-hydroxyethyl] amino] ethoxy] benzeneacetic acid 15 A solution of 2.0 g of intermediate 15 in a mixture of 50 ml of ethanol and 50 ml methanol was hydrogenated over 0.2 g of 10% Pd-C. When the uptake was stopped, the catalyst was filtered off and the filtrate evaporated to give 0.96 g of the title compound as a colorless solid, mp 225 ° C. Thin layer chromatography with dichloromethane-20 ethanol-water acetic acid (5: 5: 1: 1) as the eluent gave an R ^ value of 0.7 ^. Elemental analyzes:

Found: C 60.5; H 6.3; N 3.8

Calculated for Ο ^ Η ^ ΙΤΟ ^ .Η ^ Ο: C 60.7, H 6.2; H 3.9 #

Example I

(A) 2- [2- [[2- [3,5-bis (phenylmethoxy) phenyl] -2-hydroxyethyl] (phenylmethyl) amino] ethoxy] benzeneacetamide

A solution of 2.02 g of intermediate 5 in 25 ml of methanol and 25 ml of liquid ammonia was heated in an autoclave at 65-75 ° C for 65 hours. The solvent was evaporated and the residue was purified by flash column chromatography using ethyl acetate-petroleum ether (3: 2) as eluent to give 1.23 g of the title compound as an off-white solid, mp 123-125 ° C. .

(B) 2- [2- [[2- (3,5-dihydroxyphenyl) -2-hydroxyethyl] amino] ethoxy] benzene acetamide hydrochloride 1.08 g Product of step (A) in 150 ml absolute ethanol was added l / ..> s -mi J * 1-> -23- 350 mg Pd-C hydrogenated. The catalyst was filtered off and the filtrate evaporated. The residue was purified by flash column chromatography using toluene-ethanol-ammonia (78: 20: 2 and 68: 30: 2) as eluents. The product was treated with ethereal hydrogen chloride to give 190 mg of the title-5 compound as a yellowish hygroscopic solid, mp 86-88 ° C (decomposition).

Elemental analysis:

Found: C 55.2; H 6/6; N 6/5

Found for ci8H22N2 ° 5 * Hcl "0'33CH3CO2C2H5" 0'5H20: c 55/1 'H 6 »4? 10 N 6.65% T (Dj methanol) 2.66-2.77 (2H, m), 2.92-3.06 (2H, m), 3.60 (2H, d), 3.77 ( 1H, t), 5.04 (1H, m), 5.60 (2Ξ, t), 6.38 (2H, s), 6.44 (2H, t), 6.60-6.90 (2H , ABX).

Example II

15 (A) 2- [2 - [[2- [3,5- (phenylmethoxy) phenyl] -2-hydroxyethyl] (phenylraethyl) amino] ethoxy] benzeneacetamide

A solution of 7.23 g of 1- [3,5-bis (phenylmethoxy) phenyl] -2-bromoethanone in 80 ml of dry dimethylformamide was added dropwise to a solution of 5.0 g of intermediate 4 and 2.27 g of diisopropylethylamine in 80 ml of dry dimethylformamide under nitrogen and the solution was stirred at room temperature for 23 hours. The solvent was evaporated and a solution of the residue in 400 ml of absolute ethanol was treated with 2.64 g of sodium borohydride and the mixture was stirred at room temperature for 18 hours. 40 ml of water and 200 ml of methanol were added and the mixture was concentrated. Water was added and the suspension was extracted with 3 x 100 ml ethyl acetate. The combined extracts were washed with 50 ml of water and 50 ml of brine, dried and evaporated. The residue was crystallized from ethyl acetate-petroleum ether to give 8.37 g of the title compound as a white solid, mp 121-123 ° C.

(B) 2- [2 - [[2- (3,5-dihydroxyphenyl) -2-hydroxyethyl] amino] ethoxy] benzene acetamide hemifumarate 8.13 g Product of step (A) in 850 ml absolute ethanol hydrogenated over 2.0 g Pd-c. The catalyst was filtered off and the filtrate evaporated. The residue (4.0 g) was dissolved in 30 ml absolute ethanol and a solution of 670 mg fumaric acid in 30 ml absolute ethanol was added.

The precipitated solid was filtered off, crystallized from ethanol, -24-, and. recrystallized from methanol / ethyl acetate and gas 2.39 g of an off-white solid, m.p. 110 DEG-115 DEG (with decomposition).

A portion (1 g) of this was suspended in absolute ethanol, filtered and dried in vaouo at 70 ° C to give 650 mg of the title compound o 5 as an off-white solid, mp 212-213 C (decomposed).

Elemental analysis:

Found: C 59.1; H 5.9; N 6.6

Calculated for (C.QH N 0) _C H.0: C 59.4? H 6.0? N 6.9% 22ο 22 2 O 2 4 4 4 x

Example III

2- [2- [[2- [3,5-bis (phenylmethoxy) phenyl] -2-hydroxyethyl] (phenylmethyl) amino] ethoxy] benzeneacetamide

A stirred solution of 0.1 g of intermediate 10 in 2 ml of t-butanol was treated with 0.2 g of finely ground potassium hydroxide and the mixture was refluxed for 30 minutes. The mixture was diluted with 15 ml of saturated sodium chloride solution and extracted with 3 x 5 ml of ethyl acetate. The combined extracts were dried and evaporated under reduced pressure to give a pale yellow gum, which was purified, by flash column chromatography using toluene-ethanol-ammonia (79: 19: 2) as eluent and a pale yellow glass which was triturated under diethyl ether and gave 20 mg of the title compound as a white powder, mp 120-121 C. Thin layer chromatography with toluene-ethanol-ammonia (79: 20: 1) gave an R 2 value of 0.5.

Example IV

R (-) 2- [2- [(2- (3,5-dihydroxyphenyl) -2-hydroxyethyl 1] amino] ethoxy] benzeneacetamide amide hemifumarate (A) R (-) a- (bromomethyl) -3 , 5-bis (phenylmethoxy) benzenemethanol.

A solution of 8 g of 1- [3,5-bis (phenylmethoxy) phenyl] -2-bromoethanone in 6 ml of tetrahydrofuran was added at 60 ° C under nitrogen to freshly prepared alpine borane (from 4.9 g of 9-boron bicyclo [3: 3: 1] nonane and 7 ml (+) - α-pinene). The solution was stirred overnight and kept at room temperature over the weekend. 4 ml of acetaldehyde was added and the solvent was evaporated. The residue was dissolved in 50 ml diethyl ether and 2.6 ml o ethanolamine was added. The mixture was stirred at 0 C for 15 minutes and the solid filtered off. The filtrate was washed with brine, dried and evaporated, leaving 10 g of a pale yellow gum.

i

This was purified by flash column chromatography using toluene as elution; .

* -25-agent, crystallized from diethyl ether and recrystallized from diethyl ether-hexane to give 3.4 g of the title compound as colorless needles, m.p. 81 ° C.

(B) R (-) [3,5-bis (phenylmethoxy) phenyl] oxirane 5 A mixture of 3.3 g of the product of step (A), 1.5 g of potassium carbonate, 40 ml of methanol and 30 ml water was stirred and refluxed for 1 hour. The methanol was evaporated and the residue was extracted with 2 x 40 ml diethyl ether. The extracts were washed with brine, dried and evaporated, leaving 2.6 g of the title compound as a colorless gum.

(C) R (-) 2- [2 - [[2- [3,5-bis (phenylmethoxy) phenyl] -2-hydroxyethyl] (phenyl-methyl) amino] ethoxy] benzeneacetamide

A solution of 2.5 g of the product from step (B) and 1.8 g of intermediate 4 in 40 ml of methanol was refluxed overnight. An additional 0.4 g of intermediate 4 was added and the solution was refluxed for 24 hours. The solvent was removed and the residue was triturated with a mixture of diethyl ether and ethyl acetate to give 1.9 g of a white solid. The filtrate was evaporated and the residue was purified by flash column chromatography using diethyl ether. as eluent to give a colorless gum which was triturated with diethyl ether to give 1.0 g of a white solid The above fractions were combined with 450 mg of the white solid prepared in the same way in a separate experiment and recrystallized from ethyl acetate diethyl ether to give 3.0 g of colorless crystals, m.p. 94-95 ° C.

25 (D) R (-). 2- [2 - [[2- (3,5-dihydroxyphenyl) -2-hydroxyethyl] amino] ethoxy] - benzeneacetamide hemifumarate

A suspension of 2.9 g of the product from step (C) in 70 ml of ethanol was hydrogenated at 0.3 g of 10% Pd-C for 16 hours. The catalyst and solvent were removed and 1.6 g of the prepared base of the title compound were obtained as a white solid. The free base was dissolved in 20 ml of hot ethanol and treated with a solution of 270 mg of fume aric acid in 10 ml of hot ethanol. On cooling, an oil separated and the mixture was evaporated to dryness leaving a white glass. This was dissolved in 15 ml of methanol and the solution was seeded to give 1.3 g of the ^ * * ** · w λ VV - ^ J% -26-title compound as colorless microcrystals with a melting point of 199-200 ° C .

Elemental analysis:

Found: C 59 s3; H 6.0; H 6.8 Calculated for C 59.1 H 6.0; N 6.9 #

Example V

S (+) 2- [2- [[2- (3,5-dihydroxyphenyl) -2-hydroxyethyl] amino] ethoxy] benzeneacetamide (A) S (+) a- (bromomethyl) -3,5-bis (phenylmethoxy) benzenemethanol 10 A solution of 20 g of 1- [3,5-bis (-phenylmethoxy) phenyl] -2-bromoethanone in 15 ml of dry tetrahydrofuran was added to freshly prepared alpine borane (from 12.25 g of 9-borabicyclo [ 3: 3: 1] nonane and 17.5 ml (-) - α-pinene) and heated at 65 ° C under nitrogen for 5 hours. The mixture was stirred under nitrogen at 60 ° C overnight and the solution was cooled in an ice bath.

10 ml of acetaldehyde was added and the solution was stirred at 20 ° C for 0.5 hour and evaporated in vacuo. The residue was dissolved in 125 ml diethyl ether and 6.5 ml ethanolamine was added. The mixture was stirred at 0 ° C for 15 minutes and the resulting solid was removed by filtration. The filtrate was washed with 100 ml of brine, dried and evaporated, leaving a pale yellow semi-solid. Purification by flash column chromatography using toluene as the eluent and recrystallization twice from diethyl ether gave 1.77 g of the title compound as fluffy white crystals, m.p. 70 DEG-80 DEG.

(B) S (+) [3,5-bis (phenylmethoxy) phenyl] oxirane. A mixture of 1.77 g of the product of step (A), 805 mg of potassium carbonate in 21 ml of methanol and 16 ml of water was added heated under reflux and stirring for 1 hour. The mixture was allowed to cool and the solvent was evaporated. The residue was extracted with 3 x 25 ml diethyl ether. The combined extracts were dried and evaporated, leaving 1.39 g of the title compound as a clear oil.

Elemental analysis:

Found: C 79 »56; H 6.26

Calculated for C 22 H 20 ° 3: C 79> 9; H 6.06 # Ö f. ° ·> 4 v -27- 4> '(C) s (+) 2- [2 - [[2- [3,5-bis (phenylmethoxy) phenyl] -2-hydroxyethyl] (phenyl-methyl) amino] ethoxy] benzeneacetamide

A mixture of 1.32 g of the product from step (B) and 1.16 g of intermediate in 30 ml of methanol was refluxed for 2b hours under nitrogen. The solution was concentrated in vacuo and the residue was purified by flash column chromatography using diethyl ether as the eluent to give 1.2 g of the title compound as a white crystalline solid, mp 96-96.5 ° C.

(D) S (+) 2- [2- [[2- (3,5-dihydroxyphenyl) -2-hydroxyethyl) amino] ethoxy] -10 benzene acetamide

A solution of 1.2 g of the product from step (C) in 50 ml of ethanol was hydrogenated over 120 mg of 10 # 's Pd-C as a catalyst until the hydrogen uptake was stopped (139 ml). The catalyst was removed by filtration through Hyflo and the filtrate was evaporated in vacuo to a light yellow oil which was triturated under 20 ml of diethyl ether to give 5θ0 mg of the title compound as a white crystalline solid, m.p. 15-155 ° C.

Elemental analysis:

Found: C 62.8U; H 6.33; N 7.88 Calculated for t2 ethanol: C 62.16; H 6.53; N 7,885¾

Example VI

2- [2- [[2- (3,5-dihydroxyphenyl) -2-hydroxyethyl] amino] ethoxy] benzeneacetamide A suspension of 18.2 g 2- [2 - [[2- [3,5-bis ( phenylmethoxy) phenyl] -2-hydroxyethyl] (phenylmethyl) amino] ethoxy] benzeneacetamide in 150 ml ethanol 25 was hydrogenated over 1.8 g 10% Pd-C. When the hydrogen uptake ended, the mixture was diluted with methanol to dissolve the precipitated product and the resulting mixture was filtered. After standing for some time, a colorless solid crystallized from the filtrate. The solid was filtered off and dried to give 0.2 g of the title compound as a crystalline solid, m.p. 106-107 ° C.

Elemental analysis:

Found: C 61.5; H 7.3; N 7.0

Calcd for C 7 H 15 O C 2 H 8 OH: C 61.2; H 7.2; N 7.1 a «A a · '-; I; icS- · - * -28-

Example VII

2- [2- [2- [3,5-bis (phenylmethoxy) phenyl] -2-hydroxyethyl] amino] ethoxy] benzene acet amide

A solution of 2.58 g of intermediate 3 in 10 ml of dry dimethylform-5-amide was added over 10 minutes to a stirred solution of 5.2¼ g of intermediate 7 and 3.88 g of Ν-is-diisopropylethylamine in UO ml of dry dimethylformamide in 90 ° C and under nitrogen. Stirring was continued for 1 hour, then the solution was evaporated on sand and purified by flash column chromatography with methylene chloride-ethanol-ammonia (150: 8: 1) as eluent to give 3.37 g of the title compound as a white solid substance with a melting point of 105 5 * 107 ° C.

Elemental analysis:

Found: C 71.7; H 6.3; N 5.1

Calculated for (yi ^ N 0. O.SHgO: C 72.2; H 6.6; N 5.3 $

Example VIII

2- [2- [[2- [3,5-bis (phenylmethoxy) phenyl] -2-hydroxyethyl] amino] ethoxy] benzene acetamide

A solution of 0.95 g of intermediate 6 in 15 nil of ethanol was slowly added to a solution of 1.7 g of 3,5- [bis- (phenylmethoxy)] - α-oxo-20 henzeneacet aldehyde in 15 ml of ethanol and the mixture was refluxed for 2 hours. 0.37 g of sodium borohydride was added to the cooled solution and the mixture was stirred for 18 hours.

25 ml of methanol was added and the solution was heated to 0 ° C for 10 minutes. The solvent was evaporated and the residue was purified over a short silica gel column (Merck 77 ^ 7) with methylene chloride-ethanol-ammonia (200: 8: 1) as eluent to give 10 mg of the title compound as a substance which was identical to the product of Example VII.

Example IX

(A) 2- [2- [[2- [3,5-bis (phenylmethoxy) phenyl] -2-hydroxyethyl] (phenylmethyl) amino] ethoxy] -N-ethylbenzene acetamide 0.57 g Pivaloyl chloride was added to a solution of intermediate 15 and k, 26 g of triethylamine in 50 ml of dry tetrahydrofuran and stirred at 0 ° C under nitrogen. After 5 minutes, 0.66 g of ethylamine hydrochloride were added, the reaction vessel was closed and the solution was stirred at room temperature for 16 hours. The solution was evaporated and partitioned between 80 ml of water and 3 x 80 ml of ethyl acetate. The organic fractions were combined, dried and evaporated to an orange oil. Purification by,. -. x »1 ƒ>

. * · / I J

.-y J 'J - ^

. sF

-29- flash column chromatography using diethyl ether as eluent gave 0.58 g of the title compound as a colorless gum. Thin layer chromatography using ethyl acetate as the eluent gave an R 3 value of 0.53- (3) 2- [2- [[2- (3,5-dihydroxyphenyl) -2-hydroxy ethyl] amino] ethoxy] -N-ethylbenzene acetamide hemifumarate

A solution of 0.56 g of the product of step (i) in 10 ml of ethanol was hydrogenated over 0.10 g of dry 10% Pd-C as a catalyst until hydrogen uptake had ceased (63.0 ml). The catalyst was removed by filtration through Hyflo and washed with 50 ml of warm methanol. The filtrate was treated with a solution of 0.05 g of fumaric acid in 5 al methanol and evaporated to a colorless gum. This residue was triturated under 20 ml of diethyl ether for 1 hour, filtered off to give 0.30 g of the title compound as a cream-colored solid. Thin layer chromatography with methylene chloride-ethanol-ammonia (25: 8: 1) as the eluent gave an Rf value of 0.31.

Elemental analysis e:

Found: C 59, H 6.9; N 5.5

Calculated for »8C2H5OH: c 59, H 7.2; S 5.8 *

Example X.

2- [2- [[2- (3,5-dihydroxyphenyl) -2-hydroxyethyl] amino] ethoxy] benzene acet amide phosphate hemihydrate 16.1 g 2- [2 - [[2- (3.5 -dihydroxyphenyl) -2-hydroxyethyl] amino] ethoxy] -benzeneaetamide hemifumarate was suspended in 10 ml of water, treated with 2.6k ml of 85% phosphoric acid and heated to a solution at 60 ° C. The solution was stirred and cooled to 0 ° C for 1 hour.

The fumaric acid was filtered off and the filtrate was evaporated in vacuo to a total volume of 30 ml. After heating to dissolve the solid, 80 ml of ethanol was added and the solution was stirred and cooled to 0 ° C. The crystalline solid was filtered off, washed with 20 ml of ethanol and dried in vacuo at 50 ° C, yielding 16.8 g of the title compound, mp 138-100 ° C.

Elemental analysis:

Found: C 1 * 7.8; H 6.15; N 5.85, P 6, U

Calculated for ^ Η ^ Ν ^. ^ ΡΟ ^ .0.5 ^ 0 + 0, kC ^ OH: C 1 * 8.1; H 6.1; ff 5.9; P6.5 * φ ** · - ·.

* / * <-30-

Example XI

(A) 2- [2- [5- [3,5-bis (phenylmethoxy) phenyl] -2-oxo-3-oxazolidinyl] ethoxy] henzeneacetamide

A solution of 0.68 g of 1,1'-carbonyldiimidazole in 5 ml of dry te-trahydrofuran was added to a stirred solution of 1.0 g of 2- [2 - [[2- [3,5- "bis (f enylmethoxy) phenyl] -2-hydroxyethyl] amino] ethoxy] henzeneacetamide in 7 ml dry tetrahydrofuran under 50 ° C under nitrogen, stirring was continued for 18 hours, then the solution was evaporated, the residue was dissolved in 50 ml of ethyl acetate, washed with 2 x 25 ml water, 25 ml brine, dried and evaporated to a white solid Purification by flash column chromatography with methylene chloride-ethanol-ammonia (first 150: 8: 1, then 100: 8: 1) as eluent 0.30 g of the title compound as a white solid, mp 1 ^ 5-1 ^ 6 ° C.

15 '(B) 2- [2- [[2- [3,5-bis (phenylmethoxy) phenyl] -2-hydroxyethyl] amino] ethoxy] henzeneacetamide

A suspension of KO mg of the product from step (A) in 0.8 ml 2N sodium hydroxide solution and 1.6 ml ethanol was stirred at 60 ° C for 8 hours. The ethanol was evaporated and the residual solution extracted with 3 x 5 ml ethyl acetate. The organic phases were combined, dried and evaporated to a white solid. Purification by flash column chromatography with methylene chloride-ethanol-ammonia (100: 8: 1) as eluent gave 5 mg of the title compound as a white solid, which was identical to the product of Example VII.

Example XII

2- [2- [f2- (3,5-dihydroxyphenyl) -2-hydroxyethyl] amino] ethoxy] -N-propylbenzene acetami de (A) 2- Γ2- Γ Γ2- [3,5-bis (phenylmethoxy) phenyl] -2-hydroxyethyl] (phenylmethyl) amino] ethoxy] -N-propylbenzene acetamide 30 A solution of 3 g of intermediate 15 in 10 ml of dimethylformamide and 0.87 g of 1,1-carbonyldiimidazole was added for 2.5 stirred at room temperature under nitrogen for one hour. 0.316 g of N-propylamine was added and the reaction mixture was stirred at room temperature for 21 hours. The solution was evaporated and the residue was dissolved in ethyl acetate. The solution was washed with 8% sodium bicarbonate solution, water and brine, dried and evaporated. The residue was purified by flash column chromatography using ethyl acetate-petroleum ether (1: 1) as eluent to give 1.3 g. * 2 * λ λ; The title compound is as a colorless oil. Thin layer chromatography with ethyl acetate-petroleum ether (1: 1) as the eluent gave an R 2 value of 0.25.

(B) 2- [2 - [[2 ~ (3,5-dihydroxyphenyl) -2-hydroxyethyl] amino] ethoxy] -N-propyl-benzeneacetamide 5 A solution of 1.2k g of the product of step (A) in 50 ml absolute ethanol was hydrogenated over U00 mg of 10 µs Pd-C. The catalyst was filtered through Hyflo and the ethanolic filtrations were evaporated. The residue was purified on a short silica gel (Merck 77 ^ 7) with ethyl acetate-isopropanol (7: 3) as eluent to give 187 mg of the title compound as a white foam. Thin layer chromatography with ethyl acetate-isopropanol (7: 3) as eluent gave an R 2 value of 0.35.

5 (D ^ methanol) 0.88 (3H, t, C ^ CE ^ Sl), 1.51 (2H, m, GHgCB ^ CE ^), 2.75-2.90 (2H, AB partial ABX, CH (0H) CH 2 N), 3.13 (2H, t, CH 2 CH 2 CH 2, 3.22 (2H, m, mca 2 CS 2), 3. k8 (ZR, s, ArCl 2 CO), 4.11 (2H, t, NHCH) 1 CH 2 O), 1 *, 67 (2H, dd, 15 NHCH 2 CHOH), 6.1-7.3 (7H, m, aromatics).

Example XIII

2- [2- [[2- [3,5- (dihydroxy) phenyl] -2-hydroxyethyl] amino] ethoxy] benzenepropane arnide (A) methyl 2-hydroxybenzene propenoate 20 A solution of 16 k2 g of 2-hydroxybenzene propylene carboxylic acid and 0.1 ml of 18 M sulfuric acid in 100 ml of methanol was refluxed for 70 hours, cooled and filtered to give 10.9 g of a light brown solid. The filtrate was evaporated, the residue partitioned between 2 x 50 ml of dichloromethane and 50 ml of 1M aqueous sodium bicarbonate solution and 0.7 g of insoluble material was collected. The organic phase was dried and evaporated to leave 2.90 g of a light brown solid. The three portions of product were combined to give the title compound, m.p. 133-137 ° C, in a total yield of 18.5 g.

(B) Methyl 2- (2-bromoethoxy Jbenzene propenoate) A mixture of 10.69 g of the product of step (A), 9.66 g of potassium carbonate and 1 g of tris [2- (2-methoxyethoxy) ethyl] amine in 100 ml of dibroamethah was refluxed for 72 hours, filtered, evaporated dissolved in toluene, filtered through silica (Merck 9385) and evaporated to leave 13.22 g of the title compound as a white solid, melting point 57 -59 ° C.

J 4 -32- (C) Methyl-2- [2- [[2- (3,5-dihydroxyphenyl) -2-hydroxyethyl] amino] ethoxy] -b-enpropopenoate

A solution of 3.5 g of (- aminomethyl) -3,5-dihydroxybenzene methanol, 3.0 g of sodium iodide and 3.5 ml of diisopropylethylamine in 80 ml of dimethylform-5 amide was treated with a solution for 1 hour at 80 ° C of 5.7 g of the product of step (ii) in 20 ml of dimethylformamide and evaporated. The resulting gum was adsorbed on sand and purified twice by chromatography on silica (Merck 9385) to give 1.1 * 5 g of the title compound as a crumbly, off-white solid. Thin layer chromatography with 10 toluene-ethanol-amminia (79: 20: 1) as the eluent gave an R 2 value of 0.13 · (D) Methyl-2- [2- [[2-3,5- (dihydroxy) f enyl] -2-hydroxyethyl] amino] ethoxy] benzene propanoate

A mixture of 2.2 g of the product from step (C) and 0.5 g of 10 # 's PdO-C in 50 ml of absolute ethanol was hydrogenated until the uptake was stopped. The catalyst was removed by filtration and the filtrate was evaporated under reduced pressure. The residue was purified by flash column chromatography with dichloromethane-ethanol-amminia (100: 8: 1) as eluent to give 1.6 g of the title compound as a light brown oil. Thin layer chromatography using dichloroethane-ethamol-ammonia (100: 8: 1) as the running agent gave an R 2 value of 0.35.

(E) 2- [2 - [[2- [3,5- (dihydroxy) phenyl] -2-hydroxyethyl] amino] ethoxy] benzene-propanamide

A mixture of 1.5 g of the product from step (D), 30 ml of methanol and 20 ml of liquid ammonia was heated in a 50 ml autoclave at 80 ° C for 16 hours. The solution was evaporated under reduced pressure and the residue was purified by flash column chromatography with dichloromethane-ethanol-ammonia (50: 8: 1) as eluent to give 0.1 g of the title compound as a colored foam. Thin layer chromatography with dichloromethane-ethanol-amminia (50: 8: 1) as the eluent gave an R ^ value of 0.15 * 30 Elemental analysis:

Found: C 6θ, 1; H 6.9; N 7.2

Calculated for 0 ^^^ 05.075 ^ 9.9.5 ethanol: C 60.5; H 7.2; N 7.1 # * · * Λ j \. (-¾ i / «jf’ - 3 Λ wc * <-33-

Example ΧΙΥ 2- [2- ΓΓ3,5- (Dihydroxyphenyl) -2-hydroxyethyl] amino] ethoxy] -N-methylbenzene-acetamide (A) 2- [2- Γ [2- | ~ 3. 5-Bis (phenylmethoxy) phenyl] -2-hydroxyethyl] (phenylmethyl) -5 amino] ethoxy] -N-methylbenzeneacetamide

A mixture of 1.5 g of intermediate 5, 20 ml of ethanol and 20 ml of 33% ethanolic methyiamine was heated in an autoclave at 95 ° for 16 hours. The solvent was evaporated to leave 1.5 g of gum, which was purified by flash column chromatography using diethyl ether as eluent, and 1.1 g of the title compound were obtained as a colorless gum.

(B) 2- [2- [[3,5- (dihydroxyphenyl) -2-hydroxyethyl] amino] ethoxy] -imethyl-benzeneacetamide 1.0 g of a solution of the product of step (A) in 70 ml of absolute ethanol was hydrogenated over 300 mg of 10 # 's Pd-C. The catalyst was filtered off and the filtrate evaporated. The residue was purified by. flash column chromatography using ethyl acetate-methanol (8: 2) as the eluent to give 3-7 mg of the title compound as an off-white solid, mp 82-85 ° C.

Elemental Analysis: Found: C 61.9; H 6.2; N 7.7

Calcd for C 7 H N N O 2 H H Q C 61.8; H 6.8; N 7 »6J5

The following are examples of suitable preparations of the compounds of the invention.

The term "active ingredient" is used herein to represent a compound of the invention and may include, for example, the compound 2- [2- [[2- (3,5-dihydroxyphenyl) -2-hydroxyethyl] amino] ethoxy] benzene -acetamide.

Example XV

2- [2 - [[2- (3,5-dihydroxyphenyl) -2-hydroxyethyl] amino] ethoxy] benzeneacet-30 amide

A solution of 0.6 g of 2- [2 - [[2- [3,5-bis (phenylmethoxy) phenyl] -2-hydroxyethyl] amino] ethoxy] benzeneacetamide in 20 ml of ethanol was added over 0.06 g of 10 Hydrogenated Pd-C until hydrogen uptake ceased (58 ml).

The catalyst was filtered through Hyflo and washed with 20 ml of ethanol.

The volume of ethanol was reduced to 10 ml under reduced pressure and 0.23 g of the title compound crystallized as a white solid: '::] 2 -31 + -1 * mp 105-1Q7 ° C The product was identical to the sample prepared in Example VI.

Example A

Tablets - direct pressing 5 mg / tablet

Active ingredient 50.0

Microcrystalline cellulose B.P.C. 1 ^ + 9.0

Magnesium stearate 1.0 200.0 The active ingredient is sieved through a 250 micrometer screen, mixed with the excipients and pressed using 8.5 mm punches. Tablets of a different strength can be prepared by changing the press weight - and with suitable punches.

Example B

15 mg / tablet

Active ingredient 50.0

Lactose B.P. 119.0

Starch B.P. 20.0

Pre-gelled corn starch B.P. 10.0 20 Magnesium stearate B.P. 1.0

Press weight '200.0

The active ingredient is sieved through a 250 micron sieve and mixed with the lactose, starch and pre-gelled starch.

*

The powder mixtures are wetted with pure water, granules are made, dried, checked and mixed with the magnesium stearate. The wetted granules are compressed into tablets as described in Example A.

The tablets can be coated with suitable film-forming materials, for example, methyl cellulose or hydroxypropylmetbyl cellulose, using standard techniques. Alternatively, the tablets can be coated with sugar or coated with the viscera.

Λ * ". ·.» 1 Η Ί '; y

TV V ^ »O..J J

-35-

Example C

♦

Capsules mg / capsule

Active ingredient 50.0 5 ^ Starch 1500 1 ^ 9.0

Magnesium stearate B.P. 1.0

Fill weight 200.0) A form of directly pressable starch supplied by Colorcon Ltd., Orpington, Kent, United Kingdom.

10 The active ingredient is sieved through a 250 micro meter sieve and mixed with the other materials. The mixture is introduced into hard gelatin capsules (No. 1) using a suitable filling machine.

Other doses can be prepared by changing the fill weight and, if necessary, the capsule size.

Example D

15 Glucose syrup mg / 5 ml dose

Active ingredient 50.0 • *

Sucrose B.P. 2T50.0

Glycerin B.P. 500.0 20 Buffer)

Flavoring) _ \ as desired

Pigment )

Preservative)

Pure water BP ad 5.0 ml. The active ingredient, the buffer, the flavoring agent, the coloring agent and the preservative are dissolved in a part of the water and the glycerine is added. The residual water is heated to dissolve the sucrose and then cooled. The two solutions are combined, brought to the correct volume and mixed. The syrup formed is clarified by filtration.

- * «-36-

Example E

Sucrose-free syrup mg / 5 ml dose '

Active "component 50.0

5 Hydroxypropy Imethylc ellulo s e USP

(viscosity type ^ 000) 22.5 mg

Buffer)

Flavoring)

Dye) as desired 10 Preservative)

Sweetener)

Pure water BP ad 5.0 ml

The hydroxypropylmethylcellulose is dispersed in hot water, cooled and then mixed with an aqueous solution containing the active ingredient and the other ingredients of the preparation. The resulting solution is brought to the correct volume and mixed. The syrup formed (is clarified by filtration.

Example F

Suppositories 20 Active ingredient 50.0 mg

Witepsol *) H 15 ad 1.0 g *) A brand of Adeps Solidus Ph. EUR.

A suspension of the active ingredient in Witepsol H15 is prepared and introduced into 1 g suppository forms using a suitable machine.

Example G

Injection for intravenous administration

Wt / Vol .#

Active ingredient 1.00 30 water for injections B.P. ad 100.00

Sodium chloride can be added to make the solution isotonic -37- and the pH can be adjusted to the pH of the greatest stability and / or to facilitate dissolution of the active ingredient, using dilute acid or base or by addition of suitable buffer salts. Anti-oxidants and metal complexing salts can also be added.

The solution is prepared, clarified and placed in appropriately sized ampoules which are sealed by fusion. The injection is sterilized by autoclaving by one of the known methods. Alternatively, the solution can be sterilized by filtration and placed in sterile ampoules under aseptic conditions. The solution can be packaged under an inert nitrogen atmosphere.

Claims (9)

1. Compounds of the general formula 1 of the formula sheet, wherein R represents a hydrogen atom or a straight chain alkyl group and n = 1 or 2, and physiologically acceptable acid addition salts, compounds with solvent and metabolically labile esters thereof. Compounds according to claim 1, wherein n = 1. Compounds according to claims 1-2, wherein R represents a hydrogen atom. H. 2- [2- [[2- (3,5-dihydroxyphenyl) -2-hydroxyethyl] amino] ethoxy] benzene acetamide and its physiologically acceptable acid addition salts. Compounds according to claim 1, wherein R represents a hydrogen atom, a methyl or ethyl group and n = 1 or 2. 6. Process for the preparation of the compounds according to claims 1-5 »comprising: (1) an alkylation reaction between a compound of the formula 2 in which: -NA is a group -NHR5, -NR5CH-CH X 2 2 or a group with formula 2a or 2b 20, 2 3 ^ 5 R, R, R and R each represent a hydrogen atom or a protecting group and X is an easily removable atom or group, and a compound of formula 3, wherein R and n have the same meaning have -25 when in formula 1, R1 is a hydrogen atom or a protecting group and Y represents a hydrogen atom when -NA represents a group -NR ^ CHgCH ^ X »a group of formula 2a or 2b, or Y represents the group CH ^ CH 1 X represents X wherein X is an easily replaceable atom or group when -NA represents -NHR followed, if necessary, by removal of any protecting groups present or (2) reaction of a compound of formula 8 wherein: 2 3 R and RJ have the same meaning as in method (1) and R. R a group of the formula 8a or 8b Q Ti; ; V V v j * v * -39- U. ,. wherein R and X have the same meaning as m method (1J, 'with an amine of the formula 9 wherein R and n have the same meaning as in Formula 1 and R 1 and R 1 have the same meaning as in method (1), if necessary followed by removal of any protecting groups present, or (3) reaction of a compound of formula 10, wherein 7 R represents the group -COCHO or a group of formula 10a and 2 h 5 R, R, R and R ^ have the same meaning as in process (1), 10 with a compound of the formula 11, wherein 7 5 Z represents the group CHO, when R = -CHCH-NHR or Z represents the group 57 * CH-NHR, when R = -COCH0, R and n have the same meaning as in formula 1 and 15 R and have the same meaning as in method (1), in the presence of a reducing agent, if necessary followed by the removal of any protective groups present or (½) reduction of a compound of formula 1U, wherein R e nn have the same meaning as in formula 1 and 12 3 5 R, R, R "5 and R ^ have the same meaning as in the process (1), if necessary followed by the removal of any protective groups present, or (5) amination of a compound of formula 15, wherein n has the same meaning as in formula 1, 2. h 5 R, R, R and R have the same meaning as in process (1) and 8 R ° represents a carboxyl group or a salt or a reactive derivative thereof, with an amine RNH 3, wherein R has the same meaning as in formula 1, if necessary followed by removal of any protecting groups present, or. (6) for the production of compounds of the formula 1 wherein R 30 is hydrogen, hydrolysis of a compound of the formula 16, in which n has the same meaning as in formula 1 and R, R, R and R have the same meaning as in process (1), if necessary followed by the removal of any protecting groups present, or (7) deblocking of a compound of formula 17, wherein 35. and n have the same meaning as in formula 1 and r <R2, R < , RU and R 1 have the same meaning as in method (1), 1 2 3 k 5 wherein at least one of the groups R, R, R, R and R is a protective; :; α v '^ .... ..- represents the -Uo group and, if desired, conversion of the compound of the formula 1 or a salt thereof into a physiologically acceptable acid addition salt, compound with solvent or metabolically labile ester. A pharmaceutical composition comprising a compound of the formula 1 or a physiologically acceptable acid addition salt, compound with solvent or metabolically labile ester thereof, together with at least one physiologically acceptable carrier or excipient. 8. Compounds of general formula 15s where n = 1 or 2, 2 3 1+ 5 R, R, R and R each represent a hydrogen atom or a protecting group and Q R represents a carboxyl group or a salt or an alkyl ester thereof. K 5 9. Compounds according to claim 8, wherein n = 1 or 2, R, E, R and R0 each represent a hydrogen atom and R represents a carboxyl group or a C 1-6 alkyl ester thereof. 10. 2- [2- [2- (3,5-Dihydroxy phenyl) -2-hydroxy ethyl] amino] ethoxy] benzene acetic acid. - Χ9 _ f * - £ * >>, / fc -