NO853151L - PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE PHENETANOLAMINE DERIVATIVES. - Google Patents

Abstract

The invention relates to a process for the preparation of compounds of general formula (I). wherein R represents a hydrogen atom or a straight chain Calkyl group and n is 1 or 2, and physiologically acceptable acid addition salt derivatives and metabolically labile esters thereof. The compounds are suitable for the treatment of heart failure, cardiogenic shock or ischemic heart disease.

Description

This invention relates to a method for manufacturing

of phenethanolamine derivatives with cardiotonic and vasodilatory effects that make them suitable for medical use, especially in the treatment of heart failure.

Heart failure is characterized by the heart being unable to pump blood in sufficient quantities for the body's needs. This causes a reflexive increase in the sympathetic drive mechanism for the heart and vascular system, which leads to increased heart rate and contractility and to increased vascular resistance. The increased resistance further counteracts an already compressed heart,

and an interaction occurs whereby the increase in resistance (to maintain cerebral blood flow) progressively worsens the condition.

The therapy for heart failure generally consists of increasing

of the contractility of the heart or reduction of resistance in the peripheral vascular system. Until now, the most common agents for the treatment of heart failure have been digitalis glycosides, which increase the contractility of the heart, i.e. improve the pumping action. However, these cardiotonic agents have the disadvantage that they are quite toxic. Other agents such as dopamine and dobutamine have the disadvantage that, like isoprenaline, adrenaline and norepinephrine, they have a short duration of action, are ineffective when administered orally or cause unwanted side effects.

It has been shown relatively recently that the use of vasodilators to reduce peripheral vascular resistance (ie to reduce the blood vessels' resistance to the pumping action of the heart) is beneficial in the treatment of heart failure. However, a common side effect of vasodilators such as nitroprusside and hydralazine is that they cause unwanted side effects, such as headache and reflex tachycardia.

Combination of a cardiotonic agent and a vasodilator is particularly beneficial in the treatment of heart failure. When such a combination of active agents is given, it is desirable that they have similar pharmacokinetic profiles so that both agents are effective in the same time periods. This is often very difficult to achieve with compounds that have different structures.

Compounds with low toxicity which increase the contractility of the heart and decrease the peripheral vascular resistance without significantly affecting the heart rhythm and which have a long duration of action would therefore be very valuable in the treatment of heart failure. Effect after oral administration would also be desirable.

Phenethanolamines with a wide variety of substituents on the phenyl ring and in the amino group are known. Such compounds are attributed a number of different effects, such as 3-adrenoreceptor-blocking, vasodilating, broncho-dilating and local anesthetic effects. Areas of use have been found for a number of these agents in the treatment of such disorders as hypertension, cardiac arrhythmias, heart insufficiency, angina, asthma and glaucoma.

We have now found a small group of phenethanolamines with a special combination of substituents in the phenyl ring and the amino group, which increase cardiac contractility and reduce peripheral vascular resistance. This particular group of phenethanolamines has not previously been described in the literature, and we have found that the compounds are cardiotonic agents that act as vasodilators and can be used for the treatment of heart failure.

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

where R means a hydrogen atom or a straight-chain C^^alkyl group and n is 1 or 2, and physiologically acceptable acid addition salts, solvates and metabolically labile esters thereof.

The compounds produced according to the invention have an asymmetric carbon atom, namely - the CE(OH) group, and two optically active enantiomers with the general formula (I) are therefore possible. The production of both individual isomeric forms of compound (I) and all mixtures of such enantiomers is covered by the invention.

The physiologically acceptable acid addition salts of compounds of formula (i) can be derived from inorganic or organic acids. Examples of such salts are hydrochlorides, hydrobromides, sulfates, phosphates, benzoates, p-toluene sulfonates, methanesulfonates, sulfamates, ascorbates, tartrates, citrates, maleates, salicylates, fumarates, succinates, lactates, glutarate, glutaconates, acetates or tricarbalylates. Preferred acid addition salts are the hydrochlorides, fumarates and phosphates.

Physiologically acceptable metabolically labile ester derivatives

can be formed by acylation of any of the hydroxyl groups in the parent compound (I). Such esters include lower alkanoates, such as acetates or pivaloates. In addition to the aforementioned ester derivatives, the invention includes the preparation of compounds of formula (I) in the form of other equivalent physiologically acceptable, i.e. physiologically acceptable compounds which, like the metabolically labile esters, are converted in vivo to the parent compounds (I) . The production of solvates, especially hydrates of compounds of formula (I), is also covered by the invention.

Studies on experimental animals have shown that small doses of compounds of formula (I) increase the contractility of the heart muscle and decrease the total peripheral resistance. The compounds are potent stimulants of myocardial function and act as vasodilators. The compounds produced according to the invention also have special advantages over known cardiotonic agents such as isoprenaline and dobutamine, in that they have a longer-lasting effect and in that they are also absorbed from the gastro-intestinal tract, which is shown by their effect after oral administration. We have discovered that the compounds of formula (I) selectively block vascular ?-adrenoceptors and stimulate myocardial 3?-adrenoceptors. The compounds show no signs of toxicity at the highest investigated doses.

According to a feature of the present invention, compounds of formula (I) can be prepared, where R means a hydrogen atom, a methyl group or an ethyl group and n is 1

or 2, and physiologically acceptable acid addition salts, solvates

and metabolically labile esters thereof.

A preferred group consists of compounds of formula (I), where n is 1.

Another preferred group consists of compounds of formula (I), where R stands for a hydrogen atom.

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

Compounds produced according to the invention can be used for the treatment of heart failure, cardiogenic shock or ischemic heart disorders.

The compounds of formula (I) and their physiologically acceptable acid addition salts and metabolically labile esters have therapeutic or prophylactic value in heart failure in humans and animals.

The compounds of formula (I) and their physiologically acceptable acid addition salts and metabolically labile esters can be included

in preparations in appropriate preparation forms. Such pharmaceutical preparations comprise at least one compound of formula (I) or a physiologically acceptable salt, solvate or a metabolically labile ester thereof, intended for use in human or veterinary medicine. Such preparations can be prepared in a conventional manner in admixture with one or more physiologically acceptable carriers or excipients.

The compounds produced according to the invention can thus be prepared for peroral, buccal, parenteral or rectal administration or in a suitable form for inhalation or inhalation. Oral administration is preferred. Tablets and capsules for oral administration may contain conventional excipients such as binders, for example syrup, acacia, gelatin, sorbitol, tragacanth, starch or polyvinylpyrrolidone; bulking agents, for example lactose, sugar, microcrystalline cellulose, corn starch, calcium phosphate or sorbitol; smoothing agents, for example magnesium stearate, stearic acid, talc, polyethylene glycol or silica; blasting agents, for example potato starch or sodium starch glycolate; or humectants such as sodium lauryl sulfate. The tablets can be coated according to well-known methods. Oral liquid preparations can, for example, take the form of

aqueous or oil-based suspensions, solutions,

emulsions, syrups or mixtures, or consist of a dry product which is reconstituted before use with water or another suitable carrier. Such liquid preparation forms can 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; emulsifiers, for example lecithin, sorbitan mono-oleate or acacia; non-aqueous carriers (including edible oils), such as almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol; as well as preservatives, for example methyl- or propyl-p-hydroxybenzoates or sorbic acid. The compounds, possibly their salts or esters, can also be included in suppositories, such as e.g. contain conventional suppository base materials, such as cocoa butter or other glycerides.

For buccal administration, the preparations can be prepared in a known manner as tablets or lozenges.

The compounds of formula (I) and their physiologically acceptable acid addition salts and metabolically labile esters can also be prepared for parenteral administration by injection or continuous infusion. Injection preparations can be prepared as unit doses in ampoules or in vials with added preservative. The preparations may take the form of suspensions, solutions or emulsions, in oily or aqueous carriers, and may contain suspending, stabilizing and/or dispersing agents. As an alternative, the active ingredient can be in the form of a powder which is reconstituted before use with a suitable carrier, e.g. sterile, pyrogen-free water.

For administration by inhalation, the compounds can be prepared in the form of an aerosol spray in pressurized containers with suitable propellants, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gases, or on nebulizers. When it comes to aerosol containers, the dosage unit can be determined by providing the container with a valve that delivers a measured amount.

For inhalation administration, the compounds produced according to the invention can have. form of a dry powder preparation, for example a powder mixture of the compound and a suitable powder base, such as lactose or starch. The powder preparation can, for example, be included in gelatin capsules or "blister" packs from which the powder is given by means of an inhalation or inhalation device.

When the preparations consist of unit doses, each unit preferably contains 5-500 mg, in the case of oral administration 25-400 mg, of active substance. The daily dose for an adult may vary from 5 mg to 3 g, preferably from 25 mg to 1 g, which can be given in 1-4 doses depending on the method of administration and the patient's condition.

Compounds of formula (I) and their physiologically acceptable acid addition salts and metabolically labile esters may be administered in combination with other therapeutic agents.

The compounds of formula (I) can be prepared by means of

one of the methods described below.

According to a general process (1), the compounds (I) are prepared by an alkylation reaction between a compound of formula (II)

(where -NA means -NHR 5, ■

where R<2>, R<3>, R<4>and R<5> stand for a hydrogen atom or a protecting group and X is an atom or a group that can easily be displaced)

and a compound of formula (III)

(where R and n are as defined for formula (I), R 1 is a hydrogen atom or a protecting group and Y means hydrogen when -NA means -NR<5>CH2CH2X,

or Y means the group

CH2CH2X, where X is as previously indicated when -NA means -NHR<5>), with a subsequent removal of any protecting groups, as described later.

Examples of X are halogen atoms such as chlorine, bromine or iodine or a hydrocarbylsulfonyloxy group, such as methanesulfonyloxy or p-toluenesulfonyloxy. When X is chlorine or bromine, the reaction can be facilitated by the addition of an iodide such as sodium iodide.

In a particular embodiment of the process, compounds of formula (I) can be prepared by alkylating an amine of formula (IV)

with an alkylating agent (V)

after which any protecting groups are removed as described later.

The reaction is preferably carried out in the presence of a base, such as an alkali metal bicarbonate or carbonate, e.g. sodium bicarbonate or potassium carbonate or an amine, e.g. diisopropylethylamine or silver oxide, and in a solution at a temperature in the range -20° to +100°C. Suitable solvents for the reaction are ethers, e.g. dioxane, acetonitrile, substituted amides, e.g. N,N-dimethylformamide, and hydrocarbons, e.g. benzene.

In another embodiment of the process, the compounds (I) can be prepared by alkylating a phenol of formula (VI)

with an alkylating agent of formula (VII)

after which any protecting groups are removed as described later.

Compounds of formula (VII) can alternatively take the form of an aziridine: or an aziridinium salt:

where A means an anion, e.g. a halide ion.

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. The compounds of formula (VI) can be used in the form of a phenolate salt, e.g. sodium salt. The reaction can be carried out in water, acetonitrile, in an alcohol, e.g. methanol or a ketone, e.g. acetone or methyl isobutyl ketone, at a temperature in the range from -20° to 150°C, preferably from 20° to 100°C.

According to another general process (2), the compounds (I) can be prepared by reacting a compound (VIII)

(where R 2 and R 3 are as previously indicated under the general process (1) and R 6 means a group where R 4 and X are as previously indicated under the general process (1)) with an amine (IX)

(where R, R 1 , R 5 and n are as indicated under the general process (1)), after which any protecting groups are removed as described later.

This reaction can be carried out in or without the presence of a solvent at a temperature of 0-150°C, preferably 20-100°C. Suitable solvents include alcohols, e.g. methanol or ethanol; halogenated hydrocarbons, e.g. chloroform or dichloromethane; substituted amides, e.g. N,N-dimethylformamide; ethers, e.g. diethyl ether or tetrahydrofuran; acetonitrile; esters, e.g. ethyl acetate, as well as water and mixtures of these solvents.

When R means the group

, the reaction can be carried out in the presence of sodium carbonate, potassium carbonate, sodium hydroxide or an organic base, e.g. pyridine. An excess of the amine (IX) can alternatively be used. According to another general process (3), the compounds (I) can be prepared by reductive alkylation. Thus, a compound (X) (where R 7 means the group -COCHO or f— 2 3 4 and R , R , R and R are as indicated under the general process (1)), can be reacted with a compound of formula (XI) 7 (where Z means the group CHO when R is -

or where Z

means the group CP^NHR when R is -COCHO and R, R , R and n are as indicated under the general process (1)), in the presence of a reducing agent, after which any protecting groups are removed as described later.

In a particular embodiment of the general process (3),

7

a compound of formula (X), where R is CH(OR 4 )CH^NHR 5 , is reacted with a compound of formula (XI), where Z is CHO, in the presence of a reducing agent. Suitable reducing agents are, for example, alkali metal or alkaline earth metal borohydrides or cyanoborohydrides, such as sodium borohydride or cyanoborohydride, in an alcohol, e.g. ethanol or propanol, as solvent. Hydrogen in the presence of a catalyst such as Raney nickel, platinum, platinum oxide, palladium or rhodium in an alcohol, e.g. ethanol; an ether, e.g. dioxane or an ester, e.g. ethyl acetate, as a solvent, is also suitable as a reducing agent. The catalyst can be placed on activated carbon or be a homogeneous catalyst, such as tris-triphenyl-phosphine-rhodium chloride. The reduction can be carried out at temperatures from -20 to 100°C, preferably 0-50°C.

The reaction can proceed via the imine (XII)

12 3 4

(where R, R, R, R, and n are as indicated under the general process (1)) and it may be possible to isolate the intermediate product. Reduction of the imine under the above conditions and subsequent removal of any protecting groups leads to a compound of formula (I).

In another embodiment of the general process (3), a compound (X), where R 7 is COCHO, is reacted with a compound (XI), where Z is Cr^NHR"^, in the presence of a reducing agent. The reducing agents described in connection with the first embodiment of the reductive alkylation, is suitable for the purpose.

This reaction can proceed via the imine (XIII)

12 3

(where R, R , R , R and n are as indicated under the general process (1)) and it may be possible to isolate the intermediate product. The compound can also be reduced by using the reagents described in the first embodiment of the reductive alkylation, after which any protecting groups are removed to give a compound of formula (I).

According to another general process (4), compounds of formula (I) can be prepared by reduction of a compound (XIV)

(where R, R 1, R 2 , R 3 , R 5 and n are as indicated under the general process (1)), after which any protecting groups are removed as described later. The reduction can be carried out with alkali metal or alkaline earth metal borohydride, such as sodium borohydride, or with hydrogen in the presence of a catalyst, such as palladium or platinum, which can be placed, for example, on activated carbon. Stereoselective reduction can be achieved by using an optically active borane, such as alpine borane (9-(2,6,6-trimethyl-bicyclo[3.1.1]hept-3-yl)-9-boranebicyclo[3.3.1] nonane).

The reaction can be carried out in an organic solvent, such as an ether, e.g. tetrahydrofuran, or an alcohol, e.g. methanol or ethanol, at a temperature of 20-80°C.

According to another general process (5), the new compounds can be prepared by amination of a compound of formula (XV)

(where R , R , R , R and n are as indicated under the general process (1), and R gdenotes a carboxyl group or a salt or reactive derivative thereof, for example an acid halide, e.g. acid chloride, an acid anhydride which for example is formed with an acid chloride, for example pivaloyl chloride or chloroformate, or an ester, for example a C 1 -(C 1 -alkyl ester), after which any protective groups are removed as described later. The reactive derivative can also be formed in situ by treating the acid or salt with a condensing agent, such as N,N<1->dicyclohexylcarbodiimide or N,N<1->carbonyldiimidazole.

The amination will generally be carried out with an amine RNH2 (where R is as indicated under formula (I)).

The reaction can be carried out in an organic solvent, such as an alcohol, e.g. methanol or ethanol; an ether, e.g. tetrahydrofuran; an amide, e.g. N,N-dimethylformamide; or a halogenated hydrocarbon, e.g. methylene chloride, optionally in the presence of a catalyst such as silicon or rhodium trichloride at a temperature of 0-150°C, preferably 50-100°C. When ammonia is used in the reaction (ie R is hydrogen), it may be desirable to carry out the reaction under high pressure, preferably with water or an alcohol, such as methanol or ethanol, as solvent.

g

Compounds of formula (XV), where R is a carboxyl group and salts and esters (e.g. alkyl esters) thereof, are new compounds which constitute valuable intermediates, and the preparation of these is also covered by the invention.

An interesting class consists of compounds of formula (XV), where R<2>, R<3>, R<4> and R<5> are hydrogen atoms.

A particularly interesting class is the connections with

2 3 4 5 8 formula (XV), where R , R , R and R are hydrogen atoms and R means a carboxyl group or an _5 alkyl ester thereof (e.g. a methyl or isopropyl ester). 2 3 4 5 Compounds of formula (XV), where R , R , R and R are hydrogen atoms and R g means a carboxyl group, are particularly interesting, especially when n is 1. According to another general process (6), can compounds of formula (I), where R means hydrogen, are prepared by hydrolysis of a compound of formula (XVI)

2 3 4 5

(where R , R , R , R and n are as indicated under the general process (1) with subsequent removal of any protecting groups, as described later. The hydrolysis can be carried out under acidic or basic conditions, using an aqueous acid, e.g. eg polyphosphoric acid, hydrochloric acid or sulfuric acid, or a

base, such as an alkali metal hydroxide, e.g. potassium hydroxide, at a temperature of 0-100°C. The reaction can be carried out in a solvent which is miscible with water, e.g. an alcohol, such as t-butanol or methanol, a ketone, e.g. acetone, or by means of acetic acid, preferably in the presence of water.

According to another general method (7), compounds of formula (I) can be prepared by removing the protecting group in a compound of formula (XVII)

1 2 3 4 5

where R,R,R,R,R,R are as indicated under the general process (1), or where R 4 and R 5 together constitute a protecting group, provided that at least one of R 1 , R 2 ,

3 4 5

R , R and R constitute a protecting group.

1 2 3 4 5 The protective groups R , R , R , R or R can be any conventional protective group, for example one of those described in "Protective Groups in Organic Chemistry", ed. J. F. W. McOmie (Plenum Press, 1973). Examples of suitable 2 3 4 hydroxyl 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 1 are aralkyl groups, such as benzyl, diphenylmethyl or triphenylmethyl, and acyl groups such as dichloroacetyl. Examples of suitable amide protecting groups represented by R are t-butoxycarbonyl and 2,2,2-trichloroethoxycarbonyl groups.

The protecting groups R , R , R , R and/or R can be removed by conventional technique to obtain compound (I). An aralkyl group such as benzyl can, for example, be cleaved by hydrogenolysis in the presence of a noble metal catalyst (eg palladium or palladium oxide on charcoal); an acyl group such as dichloroacetyl can be removed by reduction with zinc and acetic acid; an alkyl or heterocyclic group to protect a hydroxyl group, can be cleaved 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 process, the groups R 4 and R 5 can together form a protecting group as in the compound

(XVIII)

12 3

(where R, R, R, R and n are as indicated under the general process (1), and Y means a carbonyl or thiocarbonyl radical or a bivalent radical formed from an aldehyde or ketone, such as acetaldehyde or acetone A compound of formula (XVIII) can be converted into a compound of formula (I) by hydrolysis under acidic or basic conditions, for example with hydrochloric or sulfuric acid or with sodium hydroxide, optionally followed by removal of other protecting groups, by means of the above described methods.

The substituent on the amino group can alternatively serve as an internal protecting group for the hydroxy group in the ethylene moiety, such as in compound (XIX) where R, R 1, R 2 , R<3>, R<5> and n are as indicated under the general procedure ( 1). The compound of formula (XIX) can be converted into a compound of formula (I) by reduction with the reagents mentioned under the general process (3), after which any other protecting groups are removed by means of the methods described above.

When it is desired to prepare an acid addition salt from

a compound (I), the product of any of the above-mentioned processes can be converted into a salt by treating the resulting free base with an appropriate acid using conventional methods.

Physiologically acceptable salts of the compounds of formula

(I) can be prepared by reacting a compound (I), in the form of the free base, with a suitable acid in the presence of a suitable solvent, such as acetonitrile, acetone, chloroform, ethyl acetate or an alcohol, e.g. methanol, ethanol or isopropanol. Physiologically acceptable salts can by means of conventional methods also be prepared from other salts, including other physiologically acceptable salts of compounds of formula (I) •

Optically active enantiomers of compounds of formula (I) can be obtained from intermediates with the required chirality. Such enantiomers can alternatively be obtained by cleaving corresponding racemic compounds in a conventional manner,

for example, using an optically active acid; see, for example, "Stereochemistry of Carbon Compounds" by E. L. Eliel (McGraw Hill 1962) and "Tables of Resolving Agents" by S. H. Wilen.

Examples of optically active acids that can be used to form salts with the racemic compounds include the (R) and (S) forms of organic carboxylic acids and sulfonic acids, such as tartaric acid, di-p-toluoyltartaric acid, camphorsulfonic acid and lactic acid.

The resulting mixtures of isomeric salts can, for example,

by fractional crystallization, separated into the diastereoisomers,

and the desired optically active isomers are optionally converted to the free base form.

According to another method, optically active enantiomers can be obtained by separating optically active derivatives of the compounds. Thus, for example, derivatives of compounds of formula (I) can be prepared, where one of the groups R 1 , R 2 , R<3>, R<4> and R in compounds of formula (XVII) represents a chiral protecting group. R 2 , R 3 or R 4 can for example be an optically active sugar residue, such as 3-D-glucopyranosidyl 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 separation of the enantiomers, using the methods described under the general process (7).

Each of the methods just mentioned for preparing compounds of formula (I) can be used as the last main step in the synthesis. The same general methods can be used for introducing the desired groups at intermediate stages or combined in different ways in these multi-stage processes.

The compounds of formula (VIII), where R^ means the group

can be prepared from a compound of formula (XX)

2 3 1

(where R and R are as above and X is a halogen atom), by treatment, for example, with sodium borohydride, whereby the halohydrin that is formed is treated with a base, such as potassium carbonate or sodium hydroxide. The reaction can be carried out in dimethylformamide or in an alcohol, such as methanol or ethanol, or in water at temperatures from room temperature to the boiling point of the solvent.

The compounds (VIII), where R6 means -CH(OR<4>)CH2X (where R<4> and X are as indicated under formula (I)), can be prepared by treating the corresponding epoxides with hydrogen halide or p-toluenesulfonic acid, after which a protection group is possibly introduced.

The compounds (x), where R 7 is COCHO, can be prepared from compounds of formula (XXI)

2 3 1

(where R , R and X are as previously indicated), by reaction with an alkoxide, such as sodium methoxide, in methanol and subsequent treatment with an acid, e.g. hydrochloric acid.

The compounds of formula (XX) are known compounds.

The compounds of formula (XXI) can be prepared by halogenation of a compound of formula (XXII)

(where R 2 and R 3 are as previously indicated), for example by using a halogen (e.g. chlorine) or an N-halogenosuccinimide (e.g. N-bromosuccinimide).

The compounds of formula (X), where R 7 is COCHO, can also be prepared directly from a compound (XXII) by oxidation, e.g. with selenium dioxide.

The compounds of formula (XIV) can be prepared by reacting a compound (XX) with an amine (IX) under the reaction conditions described for the general process (2).

Compounds of formula (XVII) can be prepared using one of the previously described processes 1-4.

The compounds of formula (VII) can be prepared by reacting a compound (VIII) with an amine of formula

(where R 5 and X are as previously indicated). When the compounds (VII) are in the form of an aziridine or aziridinium salt, they can be prepared by reacting compound (VIII) with an amine of the formula

(where R^ is as previously indicated), using the conditions described under the general process (1).

Compounds of formula (IX) can be prepared from compounds of formula (V) by reacting an amine of formula

5 5

R NH2 (where R is as previously indicated), using the reaction conditions for the general process (1).

Compounds of formula (V) can be prepared from compounds of formula (VI) by reaction with a compound XCH 2 CH 2 X (where X is as previously indicated).

Compounds of formula (XI), where Z is CHO, can be prepared by alkylating the phenol (VI) with an alkylating agent of formula HCOCH 2 X (where X is as previously indicated), or preferably by means of a protected derivative thereof, e.g. an acetal such as diethyl acetal.

Compounds of formula (XVI) can be prepared by reacting a compound (XX) with a nitrile (XXIII)

(where R and n are as previously indicated) and subsequent treatment with a reducing agent such as sodium borohydride. Compounds of formula (XV), where R Q is a carboxyl group or a salt or ester thereof, can be prepared by reacting compounds of formula (XXIV)

(where R 5 , R 8 and n are as previously indicated), with a compound (XX) and subsequent treatment with a reducing agent, such as sodium borohydride, after which any protective groups can be removed as previously described.

g

Compounds of formula (XV), where R is a carboxyl group, can be prepared by hydrolysis of a corresponding ester, after which any protective groups are removed as described later. The hydrolysis can be carried out under acidic or basic conditions by using e.g. polyphosphoric acid, hydrochloric or sulfuric acid or a base, such as an alkali metal hydroxide, e.g. sodium hydroxide, at a temperature of 0-100°C. The reaction can be carried out in a solvent which is miscible with water, e.g. an alcohol such as methanol.

8

Compounds of formula (XV), where R is a reactive derivative of a carboxylic acid, e.g. an acid chloride or acid anhydride, can be prepared in a conventional manner.

g

Compounds of formula (XV), where R is a carboxyl group or a salt or ester thereof, and n is 2, can be prepared by reduction of the corresponding α-3-ethylene carboxylic acid, possibly as a salt or ester, by means of the previously described suitable hydrogenation methods. The unsaturated starting material can be prepared according to methods which are analogous to the methods according to the invention, for example by alkylation according to the general process (1) which is illustrated in the examples.

Compounds of formula (XXIII) and (XXIV) can be prepared by reacting a compound (XXV)

(where n is as previously stated and R 9 means the group C=N, COOH or a carboxylic acid ester according to the definition for R 8), with a compound XCH9CH„Br (where X is as previously stated), and subsequent amination with R 5 NH^ (where R 5 is as previously indicated).

Compounds of formula (XVIII) can be prepared from a 12 3

compound (XVII), where R, R , R , R and n are as indicated below

4 5

the general process (1) and R and R are hydrogen atoms, by reaction with 1,1'-carbonyldiimidazole or 1,1'-thiocarbonyldiimidazole.

Compounds of formula (XIX) can be prepared by reaction between a compound (IV) and a compound (XI), where Z means the group CHO.

In the following examples, temperatures are indicated in °C. "Dried" refers to drying with magnesium sulfate unless otherwise stated. Thin layer chromatography (TLC) was performed on silica gel plates. FCC - "Flash" column chromatography was performed on silica gel (Merck 9385).

Otherwise, the following abbreviations are used:

EA - ethyl acetate; ER - diethyl ether; PE - petroleum ether; ME - methanol; MC - methylene chloride; T - toluene; ET - ethanol; A - 0.88 ammonia solution; H - hexane; DMF - dimethylformamide; THF - tetrahydrofuran; 9-BBN 9-boranebicyclo[3:3:1]nonane; Pd-C palladium on carbon; PdO-C palladium oxide on charcoal.

Intermediate 1

Methyl 2-(2-bromomethoxy)benzene acetate

A mixture of methyl 2-hydroxybenzene acetate (50.0 g), anhydrous potassium carbonate (84.0 g) and dibromoethane (500 mL) in dry ME

(2 litres), was refluxed for 111 hours. The resulting mixture was evaporated, the residue dissolved in chloroform (500 mL), washed with water (2 x 250 mL) and brine (250 mL), dried (Na 2 SO 4 ) and evaporated. The resulting oil (82 g) was purified by FCC eluting with T to give the title compound as a yellow oil (32.5 g).

Analysis calculated for C^<H>^<Br>03:

C, 48.4; H, 4.8%

Found: C, 48.5; H, 4.8

Intermediate product 2

Methy1- 2-[ 2-[( phenylmethyl) amino] ethoxy] benzene acetate

A mixture of Intermediate 1 (15 g), benzylamine (58.7 g) and sodium iodide (16.4 g) in dry acetonitrile (400 ml) was refluxed for 4 hours. The inorganic solid was filtered off and the filtrate evaporated. A solution of the residue in EA (200 ml) was washed with water (50 ml) and brine (50 ml), dried and evaporated. The residue was purified by FCC eluting with EA to give the title compound as an orange oil (13.2 g).

Analysis calculated for C^gH^^NO^:

C, 72.2; H, 7.1; N, 4.7%

Found: C, 72.4; H, 7.2; N, 4.8

Intermediate product 3

2-(2-Bromoethoxy)benzeneacetamide

A solution of 2-hydroxybenzeneacetamide (1.06 g), potassium carbonate (1.9 g) and tris[2-(2-methoxyethoxy)ethyl]amine (0.11 g) in dibromoethane (50 mL) was refluxed for 21 hours and evaporated. The resulting solid was dissolved in EA (75 mL), washed with water, dried and evaporated. The residue was purified by FCC eluting with ER and then with EA

to give the title compound as a white solid (0.9 g),

m.p. 84-86°C.

Intermediate product 4

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

A solution of Intermediate 2 (5.0 g) in ME (10 ml),

was heated in an autoclave with liquid ammonia (15 ml) at 75° for 45 hours. The solvent was evaporated and the residue purified by FCC eluting with EA-ME (9:1) to give the title compound as an off-white solid (2.60 g), m.p. 89-90°.

Intermediate 4 (alternative production)

A solution of Intermediate 3 (52 g), benzylamine

(218 ml) and sodium iodide (60 g) in acetonitrile, was refluxed for 18 hours, filtered and evaporated. The residue was dissolved in EA (300 ml), washed with aqueous sodium carbonate (2M) and water, dried and evaporated. The resulting brown oil was purified twice with FCC eluting with ER and then with EA to give the title compound as a white solid (12 g), m.p. 8 5-8 7°C.

Intermediate 5

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

A solution of 1-[3,5-bis(phenylmethoxy)phenyl]-2-bromoethanone<1> (1.37 g) in dry DMF (25 mL) was added over 5 min to a stirred solution of Intermediate 2 (1.0 g)

and diisopropylethylamine (0.432 g) in dry DMF (25 mL). The mixture was stirred at room temperature for 3.5 hours under nitrogen and evaporated. Sodium borohydride (0.5 g) was added over 10 minutes to a solution of the residue in absolute ET (130 mL). The mixture was stirred at room temperature for 18 hours and concentrated under vacuum. Water (5 mL) and ME (100 mL) were added and the solution evaporated. A solution of the residue in EA (50 mL) was washed with water (25 mL) and brine (25 mL), dried and evaporated to give the title compound as a yellow oil (2.13 g) TLC (EA) Rf 0.7 .

^ S. N. Quessy and L. R. Williams Aust. J. Chem. , !32, 1317,

(1979).

Intermediate 6

2-(2-aminoethoxy)benzeneacetamide

A solution of Intermediate 4 (2.5 g) in absolute ET

(25 ml), was hydrogenated over 10% PdO-C until absorption ceased. The catalyst was filtered off and the filtrate evaporated under reduced pressure to give a pale yellow oil which was purified by FCC eluting with dichloromethane-ET-A 100:8:1 to give the title compound as a colorless oil which crystallized on standing (1.3 g), m.p. 92-94°.

Intermediate product 7

α-(aminomethyl)-3,5-bis(phenylmethoxy)benzenemethanol

A mixture of 3,5-bis(phenylmethoxy)benzaldehyde (31.8 g), trimethylsilyl cyanide (9.92 g) and zinc iodide (0.4 g) in dry benzene (50 mL) was stirred for 4 hours under nitrogen. The resulting solution was added to an ice-cooled solution of lithium aluminum hydride (7.6 g) in dry THF (500 mL) and the mixture stirred for 18 h at room temperature. The reaction mixture was cooled in an ice bath and water (7.6 mL) added dropwise, followed by 2N sodium hydroxide solution (15.2 mL) and water (22.8 mL). The inorganic solid was filtered off and the filtrate evaporated to give a red gummy product which was purified by FCC eluting with EA-ME 7:1 to give the title compound as a colorless solid (21.8 mg), m.p. 89-90°.

Intermediate 8

2-(2-Bromoethoxy)benzeneacetonitrile

A mixture of 2-hydroxybenzeneacetonitrile (1.6 g) and potassium carbonate (3.3 g) in dibromoethane (15.5 ml) was heated to 120° for 2 days. The solvent was evaporated, the residue added to EA, the organic solid filtered off and the filtrate evaporated to a brown gummy product. The product was purified by FCC eluting with ER-PE (1:1) to give the title compound as an orange oil (2.2 g). TLC (ER-PE 2:1) Rf 0.4.

Intermediate 9

2-[ 2-[( phenylmetoxy) amino] ethoxy] benzeneacetonitrile

A mixture of Intermediate 8 (5.0 g), benzylamine (11 g), potassium carbonate (5.8 g) and sodium iodide (4.7 g) in acetonitrile (100 ml) was refluxed for 3 hours. The inorganic solid was filtered off and the filtrate evaporated. The residue was purified by FCC eluting with EA to give the title compound as a yellow oil (4.8 g). TLC (EA) Rf 0.25.

Intermediate 10

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

A solution of 1-[3,5-bis(phenylmethoxy)phenyl]-2-bromoethanone (5.96 g), Intermediate 9 (4.00 g) and diisopropylethylamine (2.61 mL) in DMF (30 mL ), was stirred at room temperature for 2.5 hours and evaporated. The gummy residue was dissolved in ME (30 mL) and treated with sodium borohydride (1.9 g) for 16 h at room temperature. The reaction mixture was evaporated, treated with ME (50 mL), re-evaporated and partitioned between chloroform (2 x 100 mL) and water (100 mL). The organic phase was dried and evaporated leaving a yellow gum which was purified by FCC eluting with T-ER (19:1) to give the title compound (5.60 g) as a yellow gum. TLC (T-ER 19:1) Rf 0.24.

Intermediate 11

1- methylethyl- 2- hydroxybenzene acetate

A solution of o-hydroxyphenylacetic acid (3.04 g) in isopropanol (20 mL) was treated with sulfuric acid (18M; 0.1 mL) at room temperature for 6 h, refluxed for 3 h and evaporated. The residue was partitioned between EA (50 mL) and aqueous sodium bicarbonate (1M; 2 x 20 mL). The organic phase was dried and evaporated to leave the title compound (3.45 g),

as a yellow oil which later turned into solid form. TLC (ER)

Rf 0.52.

Intermediate 12

1- methylethyl- 2-( 2- bromomethoxy) benzene acetate

A mixture of Intermediate 11 (1.94 g), potassium carbonate (2.8 g), dibromoethane (20 ml) and isopropanol (50 ml) was refluxed for 16 h, filtered and evaporated to a light brown oil (3, 00 g). TLC (PE-20%ER) Rf 0.26.

Intermediate 13

(iii) 1- methylethyl- 2-[ 2-[( phenylmethyl) amino] ethoxy] benzene acetate

A mixture of Intermediate 12 (80 g), benzylamine (300 ml), potassium carbonate (74 g) and sodium iodide (80 g) in acetonitrile (1 liter) was refluxed for 20 hours. The inorganic solid was filtered off and the filtrate evaporated. The residue was purified by FCC eluting with ER to give the title compound as a pale yellow oil (70 g).

TLC (ER) Rf 0.4.

Me11omproduct 14

1- methylethyl- 2-[ 2-[[ 2-[ 3, 5- bis( phenylmethoxy) phenyl]- 2- hydroxyethyl]( phenylmethyl) amino] ethoxy] benzene acetate

A solution of 1-[3,5-bis(phenylmethoxy)phenyl]-2-bromoethanone (5.0 g) in dry DMF (15 mL) was added to a solution of Intermediate 13 (4.0 g) and diisopropylethylamine

(4.5 mL) in DMF (50 mL) and the solution stirred at room temperature for 3 hours. The solvent was evaporated and the residue* redissolved in ET (80 ml) and treated with sodium borohydride (2.5 g). The mixture was stirred for 2 hours, water (20 mL) was added and the mixture was stirred for another 0.5 hour. ET. was evaporated, the residue acidified with 2N hydrochloric acid and the mixture heated on

a steam bath for 20 minutes. The solution was then neutralized with 8% sodium bicarbonate and extracted with EA (3 x 80 mL). The combined extracts were washed with brine (50 mL), dried and evaporated. The residue was purified by FCC eluting with ER-PE (1:1) to give the title compound as a pale yellow oil (5.6 g). TLC (ER-PE 1:1) Rf 0.35.

Intermediate 15

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

A solution of Intermediate 14 (56.1 g) and 2N sodium hydroxide (223 mL) in ME (400 mL) was refluxed for 16 hours. The ME was evaporated and the aqueous phase acidified to pH 6 with glacial acetic acid (20 mL) and extracted with EA (3 x 100 mL). The combined extracts were washed with water and brine, dried and evaporated. The residue was purified by FCC eluting with EA-PE (7:3) to give the title compound as a white foam (32.8 g). TLC (EA-PE 7:3) Rf 0.25.

Intermediate 16

2-[ 2-[[ 2-( 3, 5- dihydroxyphenyl)- 2- hydroxyethyl] amino] ethoxy] benzeneacetic acid

A solution of Intermediate 15 (2.0 g) in a mixture of ET (50 mL) and ME (50 mL) was hydrogenated over 10% Pd-C (0.2 g). After uptake, the catalyst was filtered off and the filtrate evaporated to give the title compound as a colorless solid (0.96 g), m.p. 225°.

TLC (dichloromethane-ET-water-acetic acid, 5:5:1:1) Rf 0.74.

Analysis calculated for C^g?^^NO^•H^O:

C, 60.7; H, 6.2; N, 3.9%

Found: C, 60.5; H, 6.3; N, 3.8

Example 1

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

A solution of Intermediate 5 (2.02 g) in ME (25 ml) and liquid ammonia (25 ml) was heated in an autoclave to 65-75° for 65 hours. The solution was evaporated and the residue purified by FCC eluting with EA-PE (3:2) to give the title compound as an off-white solid (1.23 g),

m.p. 123-125°.

(ii) 2-[ 2-[[ 2-( 3, 5- dihydroxyphenyl)- 2- hydroxyethyl] amino] - ethoxy] benzeneacetamide hydrochloride

The product from step (i) (1.08 g) in absolute ET (150 mL) was hydrogenated over Pd-C (350 mg). The catalyst was filtered off and the filtrate evaporated. The residue was purified by FCC eluting with T-ET-A (78:20:2 and 68:30:2). The product was treated with hydrogen chloride in ether to give the title compound as a tan hygroscopic solid (190 mg), m.p. 86-88°C (decomp.).

Analysis calculated for C18H22N2°5"HCl 0.33 CH3C02C2H5°'5H20: C, 55.1; H, 6.4; N, 6.65%

Found: C, 55.2; H, 6.6; N, 6.5

t (D4 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 (2H, t); 6.38 (2H, s); 6.44 (2H, t); 6.60-6.90 (2H, ABX).

Example 2

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

A solution of 1-[3,5-bis(phenylmethoxy)phenyl]-2-bromo-ethanone (7.23 g) in dry DMF (80 mL) was added dropwise to a solution of Intermediate 4 (5.0 g) and diisopropylethylamine (2.27 g) in dry DMF (80 mL) under nitrogen, whereupon the mixture was stirred at room temperature for 23 h. The solvent was evaporated and a solution of the residue in absolute ET (400 mL) was treated with sodium borohydride (2.64 g) and the mixture stirred at room temperature for 18 h. Water (40 mL) and ME (200 mL) were added and the mixture concentrated. Water was added and the suspension extracted with EA (3 x 100 mL). The combined extracts were washed with water (50 mL), brine (50 mL), dried and evaporated. The residue was crystallized from EA-PE to give the title compound as a white solid (8.37 g),

m.p. 121-123°.

(ii) 2-[ 2- 1[ 2-( 3, 5- dihydroxyphenyl)- 2- hydroxyethyl3 amino]-ethoxy] benzeneacetamide hemifumarate

The product from step (i) (8.13 g) in absolute ET (850 mL) was hydrogenated over Pd-C (2.0 g). The catalyst was filtered off and the filtrate evaporated. The residue (4.0 g) was dissolved in absolute ET (30 mL) and a solution of fumaric acid (670 mg) in absolute ET (30 mL) added. The precipitated solid was filtered off, crystallized from ET and recrystallized from ME/EA to give an off-white solid (2.39 g), m.p. 110-115° (decomp.).

A portion (1 g) was slurried in absolute ET, filtered off and dried under vacuum at 70° to give the title compound as an off-white solid (650 mg), m.p. 212-213° (decomp.).

Analysis calculated for (<C>^3H22<N>2°5^2<C>4<H>4°4<:>

C, 59.4; H, 6.0; N, 6.9%

Found: C, 59.1; H, 5.9; N, 6.6

Example 3

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

A stirred solution of Intermediate 10 (0.1 g) in t-butanol (2 ml) was treated with finely divided potassium hydroxide (0.2 g) and the mixture stirred under reflux conditions for 30 minutes. The mixture was diluted with saturated sodium chloride solution (15 mL) and extracted with EA (3 x 5 mL). The combined extracts were dried and evaporated under reduced pressure to give a pale yellow gum which was purified by FCC eluting with T-ET-A 79:19:2 to give a pale yellow glass which was triturated under ER to give the title compound as a white powder (20 mg), m.p. 120-121°. TLC (T-ET-A 79:20:1) Rf 0.5.

Example 4

R(-)- 2-[ 2-[[ 2-( 3, 5- dihydroxyphenyl)- 2- hydroxyethyl] amino]-ethoxy] benzene acetamide hemifumarate

(i) R(-)-a-(bromomethyl)-3,5-bi6(phenylmethoxy)benzenemethanol

A solution of 1-[3,5-bis(phenylmethoxy)phenyl]-2-bromoethanone (8 g) in THF (6 mL) was added to a newly prepared alpine borane (from 9-BBN (4, 9 g) and (+)-g-pinene (7 ml)) at 60° under nitrogen. The solution was stirred overnight and then kept at room temperature over a weekend. Acetaldehyde (4 mL) was added and the solvent evaporated. The residue was dissolved in ER (50 ml) and ethanolamine (2.6 ml) was added. The mixture was stirred at 0° for 15 minutes and the solid filtered off. The filtrate was washed with brine, dried and evaporated to a pale yellow gummy product (10 g). This was purified by FCC eluting with T and crystallized from ER and then recrystallized from ER-H to give the title compound as colorless needles (3.4 g), m.p. 81°.

(ii) R(-) [ 3, 5- bis( phenylmethoxy) phenyl] oxirane

A mixture of the product from step (i) (3.3 g) and potassium carbonate (1.5 g), ME (40 ml) and water (30 ml) was stirred and refluxed for 1 hour. The ME was evaporated and the residue extracted with ER (2 x 40 mL). The extracts were washed with brine, dried and evaporated to give the title compound as a colorless gummy material (2.6 g).

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

A solution of the product from step (ii) (2.5 g) and Intermediate 4 (1.8 g) in ME (40 ml) was refluxed overnight. A further portion of Intermediate 4 (0.4 g) was added and the solution refluxed for 24 hours. The solvent was removed and the residue triturated with a mixture of ER and EA to give a white solid (1.9 g). The filtrate was evaporated and the residue purified by FCC eluting with ER to give a colorless gum which was triturated with ER to give a white solid (1.0 g).

The aforementioned fractions were combined with 450 mg of white solid prepared in the same way in a separate experiment, and recrystallized from EA-ER to colorless crystals (3.0 g), m.p. 94-95°.

(iv) R(-)- 2-[ 2-[[ 2-( 3, 5- dihydroxyphenyl)- 2- hydroxyethyl]-amino] ethoxyJbenzeneacetamide hemifumarate

A suspension of the product from step (iii) (2.9 g) in ET (70 mL) was hydrogenated over 10% Pd-C (0.3 g) for 16 h. Catalyst and solvent were removed to give the free base of the title compound as a white solid (1.6 g). The free base was dissolved in warm ET (20 mL) and treated with a solution of fumaric acid (270 mg) in warm ET

(10ml). On cooling, an oil precipitated, and after evaporation to dryness of the mixture, a white glass remained. This

was dissolved in ME (15 mL) to which was added a crystallisation buffer to give the title compound as colorless microcrystals (1.3 g), m.p. 199-200°.

Analysis calculated for [C^8H22N2°5^2C4H4°4:

C, 59.4; H, 6.0; N, 6.9%

Found: C, 59.3; H, 6.0; N, 6.8

Example 5

S(+)- 2-[ 2-[[ 2-( 3, 5- dihydroxyphenyl)- 2- hydroxyethyl] amino]-ethoxy] benzeneacetamide

(i) S(+)-α-(bromomethyl)-3,5-bis(phenylmethoxy)benzenemethanol

A solution of 1-[3,5-bis(phenylmethoxy)phenyl]-2-bromoethanone (20 g) in dry tetrahydrofuran (15 ml) was added to

a newly prepared alpine borane [from 9-BBN (12.25 g) and (-)-g-pinene (17.5 ml)] and heated to 65° for 5 h under nitrogen. The mixture was stirred at 60° overnight under nitrogen, after which the solution was cooled in an ice bath. Acetaldehyde (10 mL) was added and the solution stirred at 20° for 0.5 h and evaporated under vacuum. The residue was dissolved in ER (125 mL) and added

ethanolamine (6.5 mL). The mixture was stirred at 0° for 0.25 hours and the resulting solid filtered off. The filtrate was washed with brine (100 mL), dried and evaporated to a pale yellow semi-solid. Purification by FCC eluting with T and recrystallization twice from ER gave the title compound as white airy crystals (1.77 g), m.p. 78-80°.

(ii) S(+)[ 3,5-bis(phenylmethoxy)phenyl]oxirane

A mixture of the product from step (i) (1.77 g), potassium carbonate (805 mg) in ME (21 ml) and water (16 ml) was refluxed and stirred for 1 hour. The mixture was then allowed to cool, after which the solvent was evaporated. The residue was extracted with ER (3 x 25 mL). The combined extracts were dried and evaporated to leave the title compound as a clear oil (1.39 g).

Analysis calculated for C22H20^3<:>

C, 79.49; H, 6.06%

Found: C, 79.56; H, 6.26

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

A mixture of the product from step (ii) (1.32 g) and Intermediate 4 (1.16 g) in ME (30 ml) was refluxed for 24 h under nitrogen. The solution was concentrated in vacuo and the residue purified by FCC eluting with ER to give the title compound as a white crystalline solid (1.2 g), m.p. 96-96.5°.

(iv) S(+) 2-[ 2-[[ 2-( 3, 5- dihydroxyphenyl)- 2- hydroxyethyl] amino]-ethoxy] benzeneacetamide

A solution of the product from step (iii) (1.2 g) in ethanol (50 ml) was hydrogenated over 10% Pd-C catalyst (120 mg) until hydrogen uptake occurred (139 ml). The catalyst was filtered off through hyflo and the filtrate evaporated under vacuum to a pale yellow oil which was then triturated under ER

(20 mL) to give the title compound as a white crystalline solid (580 mg), m.p. 154-155°.

Analysis calculated for Cj8<H>22N2°5"<0>'<2>Et0H:

C, 62.16; H, 6.53; N, 7.88. %

Found: C, 61.84; H, 6.33; N, 7.88.

Example 6

2-[2-[[ 2-( 3, 5- dihydroxyphenyl)- 2- hydroxyethyl] amino] ethoxy] benzeneacetamide

A suspension of 2-[2-[[2-[3,5-bis(phenylmethoxy)phenyl]-2-hydroxyethyl](phenylmethyl)amino]ethoxy]benzeneacetamide (18.2 g)

in ET (150 mL), was hydrogenated over 10% Pd-C (1.8 g). After the hydrogen uptake had subsided, the mixture was diluted with ME to dissolve the precipitated product, after which the resulting mixture was filtered. A colorless solid crystallized from the filtrate on standing. The solid was filtered off and dried to give the title compound as a crystalline solid (4.2 g), m.p. 106-107°.

Analysis calculated for C18<H>22<N>2°5"C2H5OH:

C, 61.2; H, 7.2; N, 7.1%

Found: C, 61.5; H, 7.3; N, 7.0.

Example 7

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

A solution of Intermediate 3 (2.58 g) in dry DMF (10 mL) was added over 10 minutes to a stirred solution of Intermediate 7 (5.24 g) and N,N-diisopropylethylamine (3.88 g) in dry DMF (40 mL) at 90° under nitrogen. Stirring was continued for 1 hour, after which the solution was evaporated onto sand. and purified by FCC eluting with MC-ET-A (150:8:1) to give the title compound as a white solid (3.37 g),

m.p. 105.5-107°.

Analysis calculated for C32<H>34N2°5'0'3H20:

C, 72.2; H, 6.6; N, 5.3%

Found: C, 71.7; H, 6.3; N, 5.1.

Example 8

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

A solution of Intermediate 6 (0.95 g) in ET (15 mL) was slowly added to a solution of 3,5-[bis(phenylmethoxy) ]-α-oxo-benzeneacetaldehyde (1.7 g) in ET ( 15 ml) and the mixture boiled under reflux for 2 hours. To the cooled solution was added sodium borohydride (0.37 g), after which the mixture was stirred for 18 hours. ME (25 mL) was added and the solution heated to 40°C for 10 minutes. The solvent was evaporated and the residue purified by chromatography on a short silica gel column (Merck 7747) eluting with MC-ET-A (200:8:1) to give the title compound (10 mg) which was identical to the product of Example 7.

Example 9

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

Pivaloyl chloride (0.57 g) was added to a solution of Intermediate 15 and triethylamine (4.26 g) in dry THF (50 mL) and stirred under nitrogen at 0°. After 5 minutes, ethylamine hydrochloride (0.66 g) was added, after which the reaction flask was closed and the solution stirred at room temperature for 16 hours. The solution was evaporated and partitioned between water (80 mL) and

EA (3 x 80 ml). The organic extracts were combined, dried and evaporated to an orange oil. Purification by FCC eluting with ER afforded the title compound as a colorless gummy product (0.58 g). TLC (EA) Rf 0.53.

(ii) 2-[ 2-[[ 2-( 3, 5- dihydroxyphenyl)- 2- hydroxyethyl] amino]-ethoxy]- N- ethylbenzeneacetamide hemifumarate

A solution of the product from step (i) (0.56 g) in ET (40 ml) was hydrogenated over dry 10% Pd-C catalyst (0.10 g) until hydrogen uptake occurred (63.0 ml). The catalyst was filtered off through hyflo and washed with hot ME (50 mL). The filtrate was treated with a solution of fumaric acid (0.05 g) in ME (5 mL) and evaporated to a colorless gummy material. This residue was triturated under ER (20 mL) for 4 h and filtered to give the title compound as a cream yellow solid (0.30 g). TLC (MC-ET-A 25:8:1) Rf 0.31.

Analysis calculated for (c2oH26N2°5)2C4H4°4* 0'8H20+1»8c2h5OH:

C, 59.4; H, 7.2; N, 5.8%

Found: C, 59.4; H, 6.9; N, 5.5

Example 10

2-[ 2-[[ 2-( 3, 5- dihydroxyphenyl)- 2- hydroxyethyl] amino] ethoxy]-benzeneacetamide- phosphate- hemihydrate

2-[2-[[2-(3,5-dihydroxyphenyl)-2-hydroxyethyl]amino]-ethoxy]benzeneacetamide hemifumarate (16.1 g), was suspended in water (40 mL), treated with 85% phosphoric acid (2.64 ml) and heated to 60° to obtain solution. The solution was stirred and cooled to 0° for 1 hour. The fumaric acid was filtered off and the filtrate evaporated under vacuum to a total volume of 30 ml. After heating to dissolve the solid, ET (80 mL) was added and the solution stirred and cooled to 0°. The crystalline solid was filtered off, washed with ET (20 ml) and dried at 50° under vacuum to give the title compound (16.8 g), m.p. 138-140°.

Analysis calculated for C18H22N2°5"H3P04"0'5H2o+0 >4C2H5OH:

C, 48.1; H, 6.1; N, 5.9; P, 6.5% Found: C, 47.8; H, 6.15; N, 5.85; P, 6.4

Example 11

(i) 2-[ 2-[ 5-[ 3, 5- bis( phenylmethoxy) phenyl]- 2- oxo- 3- oxazolidinyl] ethoxy] benzeneacetamide

A solution of 1,1<1->carbonyldiimidazole (0.68 g) in dry THF (5 mL) was added to a stirred solution of 2-[2-[[2-[3,5-bis(phenylmethoxy) phenyl]-2-hydroxyethyl]amino]ethoxy]benzeneacetamide (1.0 g) in dry THF (7 mL) at 50° under nitrogen. Stirring was continued for 18 hours, after which the solution was evaporated. The residue was dissolved in EA (50 mL), washed with water (2 x 25 mL), brine (25 mL), dried and evaporated to give a white solid. Purification by FCC eluting with MC-ET-A, first (150:8:1) and then (100:8:1) gave the title compound as a white solid (0.30 g), m.p. 145-146°.

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

A suspension of the product from step (i) (40 mg) in 2N sodium hydroxide solution (0.8 mL) and ET (1.6 mL) was stirred at 60° for 8 h. The ET was evaporated and the remaining solution extracted with EA (3 x 5 mL). The organics were combined, dried and evaporated to give a white solid. Purification by FCC eluting with MC-ET-A (100:8:1) gave the title compound as a white solid (5 mg) identical to the product of Example 7.

Example 12

2-[ 2-[[ 2-( 3, 5- dihydroxyphenyl)- 2- hydroxyethyl] amino] ethoxy]-N- propylbenzeneacetamide

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

A solution of Intermediate 15 (3.0 g) in DMF (40 mL) and 1,1-carbonyldiimidazole (0.87 g) was stirred under nitrogen at room temperature for 2.5 h, n-propylamine (0.316 g) was added and the reaction mixture stirred at room temperature for 21 hours. The solution was evaporated and the residue dissolved in EA. The solution was washed with 8% sodium bicarbonate, water and brine, dried and evaporated. The residue was purified by FCC eluting with EA-PE 1:1 to give the title compound as a colorless oil (1.3 g). TLC (EA-PE) 1:1 Rf 0.25.

(ii) 2-[ 2-[[ 2-( 3, 5- dihydroxyphenyl)- 2- hydroxyethyl] amino]-ethoxy]- N- propylbenzeneacetamide

A solution of the product from step (i) (1.24 g) in absolute ET (50 mL) was hydrogenated over 10% Pd-C (400 mg). The catalyst was filtered off through hyflo and the ethanolic filtrate evaporated. The residue was purified by chromatography on a short silica column (Merck 774 7) eluting with EA-isopropanol 7:3 to give the title compound as a white foam (187 mg). TLC (EA-isopropanol 7:3) Rf 0.35.

6(D 4 methanol) 0.88 (3H, t, CH 2 CH 2 CH_ 3 ). , 1.51 (2H, m, CH2CH2CH3), 2.75-2.90 (2H, AB part ABX, CH(OH)CH2N), 3.13 (2H, t, CH2CH2CH3), 3.22 (2H, m, NHCr^CHj, 3.48 (2H, s, ArCH2CO) , 4.11 (2H, t, NHCH2CH2O), 4.67 (2H, dd, NHCH2CHOH), 6.1-7.3 (7H, m , aromatic).

Example 13

2-[ 2-[[ 2-[ 3, 5-( dihydroxy) phenyl]- 2- hydroxyethyl] amino] ethoxy] benzenepropanamide

(i) Methyl-2-hydroxybenzenepropenoate

A solution of 2-hydroxybenzenepropenoic acid (16.42 g) and sulfuric acid (18M; 0.1 mL) in ME (100 mL) was refluxed for 70 h, cooled and filtered to give a light brown solid (10.9 g). The filtrate was evaporated, the residue partitioned between dichloromethane (2 x 50 ml) and aqueous sodium bicarbonate (1M; 50 ml) and the undissolved material (4.7 g) collected. The organic phase was dried and evaporated to leave a light brown solid (2.90 g). The three product fractions were combined to give the title compound in a total yield of 18.5 g,

m.p. 133-137°.

(ii) Methyl 2-(2-bromoethoxy)benzenepropenoate

A mixture of the product from step (i) (10.69 g), potassium carbonate (9.66 g) and tris 2-(2-methoxyethoxy)ethyl]amine (1 g) in dibromoethane (100 ml) was refluxed for 72 hours, filtered, evaporated, dissolved in T, filtered through silica (Merck 938 5) and evaporated to give the title compound as a white solid (13.22 g), m.p. 57-59°.

(iii) Methyl 2-[ 2-[[ 2-( 3, 5- dihydroxyphenyl)- 2- hydroxyethyl]-amino] ethoxy] benzenepropenoate

A solution of α-(aminomethyl)-3,5-dihydroxybenzene-methanol (3.5 g), sodium iodide (3.0 g) and diisopropylethylamine (3.5 ml) in DMF (80 ml) was treated at 80° with a solution of the product from step (ii) (5.7 g) in DMF (20 ml) for 1 hour and then evaporated. The resulting gummy material was adsorbed onto sand and purified twice by chromatography on silica (Merck 9385) to give the title compound as a brittle off-white solid (1.45 g). TLC (T-ET-A 79:20:1) Rf 0.13.

(iv) Methyl 2-[ 2-[[ 2-[ 3, 5-( dihydroxy) phenyl]- 2- hydroxyethyl]-amino] ethoxy] benzenepropanoate

A mixture of the product from step (iii) (2.2 g) and 10% PdO-C (0.5 g) in absolute ET (50 ml) was hydrogenated until absorption had occurred. The catalyst was removed by filtration and the filtrate evaporated under reduced pressure. The residue was purified by FCC eluting with dichloromethane-ET-A (100:8:1) to give the title compound as a light brown oil (1.6 g). TLC. Dichloromethane-ET-A (100:8:1) Rf 0.35.

(v) 2-[ 2-[[ 2-[ 3, 5-( dihydroxy) phenyl]- 2- hydroxyethyl] amino]-ethoxy] benzenepropanamide

A mixture of the product from step (iv) (1.5 g) ME (30 ml) and liquid ammonia (20 ml) was heated to 80° in an autoclave (50 ml) for 16 hours. The solution was evaporated under reduced pressure and the residue purified by FCC eluting with dichloromethane-ET-A (50:8:1) to give the title compound as a light brown foam (0.4 g). TLC Dichloromethane-ET-A (50:8:1) Rf 0.15. Analysis calculated for C19H24N2°5'0'75H2°'0'5Et0H: C, 60.5; H, 7.2; N, 7.1%

Found: C, 60.1; H, 6.9; N, 7.2

Example 14

2-[ 2-[[ 3, 5-( dihydroxyphenyl)- 2- hydroxyethyl] amino] ethoxy]- N-methylbenzeneacetamide

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

A mixture of Intermediate 5 (1.5 g), ET (20 mL) and 33% methylamine in ethanol (20 mL) was heated to 95° in an autoclave for 16 hours. The solvent was evaporated leaving a gummy material (1.5g) which was purified by FCC eluting with ER to give the title compound as a colorless gummy product (1.1g).

(ii) 2-[ 2-[[ 3, 5-( dihydroxyphenyl)- 2- hydroxyethyl] amino]-ethoxy]- N- methylbenzeneacetamide

A solution of the product from step (i) (1.0 g) in absolute ET (70 mL) was hydrogenated over 10% Pd-C (300 mg). The catalyst was filtered off and the filtrate evaporated. The residue was purified by FCC eluting with EA-ME (8:2) to give the title compound as an off-white solid (387 mg),

m.p. 8 2-85°.

Analysis calculated for C^ o,H24N2°5 * 0 ' 5H20:

C, 61.8; H, 6.8; N, 7.6%

Found: C, 61.9; H, 6.2; N, 7.7

In the following, examples of suitable formulations of compounds produced according to the invention are given. The term "active ingredient" here stands for one of these compounds, which can for example be the compound 2-[2-[[2-(3,5-dihydroxy-phenyl)-2-hydroxyethyl]amino]ethoxy]benzeneacetamide.

Example A - Tablets - Direct pressing

The active substance was sieved through a 250 µm sieve, mixed with the excipients and pressed using 8.5 mm punches.

Tablets of different strengths can be produced by changing the weight of the pressing mass and using suitable punches.

Example B - Tablets - Wet granulation

The active substance is sieved through a 250 µm sieve and mixed with lactose, starch and pre-gelatinized starch. The powder mixture is moistened with purified water and granulated, dried, sieved and mixed with the magnesium stearate. The lubricated granules are pressed into tablets as described in Example A.

The tablets can be coated with suitable film-forming materials, e.g. methylcellulose or hydroxypropylmethylcellulose, in a conventional manner.

Example C - Capsules

<*>A form of direct compressible starch from Colorcon Ltd, Orpington, Kent, UK.

The active substance is sieved through a 250 µm sieve and mixed with the other materials. The mixture is filled onto hard gelatin capsules No. 1 using a suitable filling machine. Other doses can be prepared by changing the filling weight and, if necessary, the capsule size.

Example D - Sucrose syrup

The active substance, buffer, flavoring agent, coloring agent and preservative are dissolved in some of the water, after which the glycerin is added. The remaining water is heated to dissolve the sucrose and then cooled. The two solutions are combined, brought up to the correct volume and mixed. The syrup obtained is clarified by filtration.

Example E - Sucrose-free syrup

The hydroxypropylmethylcellulose is dispersed in hot water, cooled and mixed with an aqueous solution containing the active ingredient and the other components. The resulting solution is adjusted to the correct volume and mixed. The syrup obtained is clarified by filtration.

Example F - Suppositories

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

Example G - Injection solution for intravenous administration

Sodium chloride can be added to achieve isotonic solutions, and the pH can be adjusted for maximum stability and/or to facilitate the solubility of the active ingredient using dilute acids, alkalis or buffer salts. Antioxidants and chelating salts can also be used.

The solution is prepared, clarified and filled into suitable ampoules which are sealed by melting the glass. The injection solution is sterilized by heating in an autoclave. Alternatively, the solution can be sterilized by filtration and then filled into sterile ampoules under aseptic conditions. The solution can be packaged under an inert nitrogen atmosphere.

Example 15

2-[ 2-[[ 2-( 3, 5- dihydroxyphenyl)- 2- hydroxyethyl] amino] ethoxy] benzeneacetamide

A solution of 2-[2-[[2-[3,5-bis(phenylmethoxy)phenyl]-2-hydroxyethyl]amino]ethoxy]benzeneacetamide (0.6 g) in ET (20 mL) was hydrogenated over 10 % Pd-C (0.06 g) until hydrogen uptake had occurred (58 ml). The catalyst was filtered off through hyflo and washed with ET (20 mL). The volume of ET was reduced to 10 mL under reduced pressure, whereupon the title compound crystallized as a white solid (0.23 g), m.p. 105-107°. The product was identical to that obtained in Example 6.

Claims (5)

1. Process for the preparation of compounds of the general formula (I) where R means a hydrogen atom or a straight-chain C^^alkyl group and n is 1 or 2, as well as physiologically acceptable acid addition salts, solvates and metabolically labile esters thereof, characterized by (1) an alkylation reaction between a compound with formula (II) 5 5 where -NA means a group -NHR , -NR CH2 CH2 X, 2 3 4 5 R , R , R , and R each represent a hydrogen atom or a protecting group and X is an atom or group that is readily displaceable, and a compound of formula (III) wherein R and n are as indicated for formula (I), R 1 is a hydrogen atom or a protecting group and Y means hydrogen when -NA means -NR <5> CH2 CH2 X, . or Y means the group CH 2 CH 2 X, where X is an atom or group readily displaceable when -NA means -NHR^, followed, if necessary, by removal of any protecting groups; or (2) conversion of a compound of formula (VIII) 2 3 6 where R and R are as indicated above under process (1) and R means a group where R 4 and X are as indicated under process (1), with an amine (IX) 1 5 where R and n are as set forth in formula (I ) and R and R are as set forth above under process (1), followed, if necessary, by removal of any protecting groups; or (3) conversion of a compound of formula (X) where R 7 means the group -COCHO or in 2 3 4 and R , R , R and R are as indicated above under process (1), with a compound (XI) where Z means the group CHO when R 7 is or where Z 5 o 7 means the group CH-NHR when R is -COCHO, R and n are as defined in formula (I) and R 1 and R 5 are as defined above in process (1), in the presence of a reducing agent, followed, if necessary, by removal of any protecting groups; or (4) reduction of a compound of formula (XIV) 12 3 5 wherein R and n are as defined in formula (I) and R , R , R , and R are as defined above under process (1), followed, if necessary, by removal of any protecting groups; or (5) amination of a compound of formula (XV) 2 3 4 5 where n is as indicated in formula (I), R , R , R and R are as indicated above under process (1) and R g means a carboxylic acid group or a salt or reactive derivative thereof, with an amine RNH2 / where R is as indicated in formula (I), followed, if necessary, by removal of any protecting groups; or (6) for the preparation of compounds of formula (I), where R is hydrogen, hydrolysis of a compound of formula (XVI) 2 3 4 5 where n is as set forth in formula (I) and R , R , R , and R are as set forth above under process (1), followed, if necessary, by removal of any protecting groups; or (7) cleavage of a protecting group from a for- 1 2 3 4 5 where R and n are as indicated in formula (I) and R , R , R , R and R are as indicated above under process (1), provided that at least one 2 3 4 5 of R , R , R , R and R represent a protecting group; and optionally converting a compound of formula (I) or a salt thereof into a physiologically acceptable acid addition salt, solvate or a metabolically labile ester thereof. 2. Method according to claim 1, characterized by the preparation of compounds where n is 1. 3. Method according to claim 1 or 2, characterized by the preparation of compounds where R means a hydrogen atom. 4. Process according to claim 1, characterized by the production of 2-[2-[[2-(3,5-dihydroxyphenyl)-2-hydroxyethyl]amino]ethoxy]benzeneacetamide and physiologically acceptable acid addition salts thereof. 5. Process according to claim 1, characterized by the preparation of compounds where R means a hydrogen atom, a methyl or ethyl group and n is 1 or 2.