LU86038A1 - PHENETHANOLAMINE DERIVATIVES AND THEIR PREPARATION PROCESS - Google Patents

Description

Phenethanolamine derivatives and process for their preparation * The present invention relates to phenethanolamine derivatives having cardiotonic * and vasodilating activity, the processes for their manufacture, the pharmaceutical compositions containing them and their use in medicine, in particular in the treatment of 'heart failure.

Heart failure is characterized by the heart's inability to pump blood in sufficient quantities for the needs of the body. As a result there is a reflex increase in the sympathetic impulse to the heart and vascular system resulting in an increase in heart rate and contractile force and an increase in vascular resistance. The increased resistance also opposes an already compromised heart and an interaction is established by which the state is progressively exacerbated by the increase in resistance (generated to maintain cerebral flow).

a 20 The treatment of heart failure generally involves increasing contractile force or reducing resistance in the peripheral vascular system. Until now, the most commonly used agents for the treatment of heart failure have been digitalis glucosides which increase the contractile force of the heart, that is to say they improve its pumping action. . Ksis these cardio-tonic agents have the disadvantage of being inappropriately toxic. The disadvantage of other agents, including dopamine and dobutamine, is that. what, like isoprenaline, adrenaline and norepinephrine, they

NOT

2 * a short duration of action and are inactive after oral administration or else cause undesirable side effects.

'More recently, it has been established that the use of 5 vasodilators to reduce peripheral vascular resistance (i.e. to reduce the resistance of blood vessels to the pumping action of the heart) is of interest in the treatment of heart failure. However, a common side effect of vasodilators such as nitroprusside and hydra-lazine is that they cause undesirable effects, for example, headache and reflex tachycardia.

The combination of a cardiotonic agent and a vasodilator is of particular interest in the treatment of heart failure. When administering a combination of such products, it is desirable that the two have similar pharmacokinetic profiles so that both are active * during the same periods. This is often very difficult to achieve for compounds of different structures.

Thus, low toxicity compounds which increase the force of contraction of the heart and decrease peripheral vascular resistance without unduly affecting the heart rate and which have a long duration of action would be of great interest in the treatment of 'heart failure. Activity after oral administration would also be desirable.

Phenethanolamines having a wide variety of substituents on the phenyl ring and on amino group 3 are known. A number of activities have been attributed to these compounds, for example, blocking beta-adrenergic receptors, vasodilation, broncho-dilatation and local anesthesia. Applications have been found for many of these agents in the treatment of conditions such as: hypertension, cardiac arrhythmias, heart failure, angina, asthma and glaucoma.

We have now found a small group of phenethanolamines having a particular combination of substituents on the phenyl ring and on the amino group, compounds which increase the contractile force of the heart and reduce peripheral vascular resistance.

This particular group of phenethanolamines has not been discovered in the prior literature and we have found that these compounds are cardiotonic agents and act as vasodilators and that they can be used in the treatment of heart failure.

Consequently, the invention provides compounds having the general formula (I): • HOv „V pH *

\ H \ ï II I

| j | —CHCH2NHCH2CH20— • · φ

w /. I

J (CH 2) nC0NHR

OH (I) where R represents a hydrogen atom or a straight chain alkyl group and n represents 1 or 2, and their physiologically acceptable acid addition salts, their solvates and their meta-esters labile.

4.:. :: It will be noted that the compounds according to the invention have an asymmetric carbon atom, namely - the group -CH (OH) - and there are thus two optically active enantiomers of the general formula (I). It should be understood that the present invention encompasses the two particular isomeric forms of the compounds of formula (I) and all mixtures of these enantiomers.

The acid addition salts of the compounds of formula (I) can be derived from inorganic or organic acids.

10 Here are examples of such salts: hydrochlorides, bromhydates, sulfates, phosphates, benzoates, ji-toluene-sulfonates, methane sulfonates, sulfamates, ascorbates, tartrates, citrates, maleates, salicylates, fumarates, succinates, lactates, glutarates, glutaconates, acetates or tricarballylates. The preferred acid addition salts are. hydrochlorides, fumarates and phosphates.

The physiologically acceptable metabolically labile ester derivatives can be formed by acylation of any of the hydroxyl groups in the parent compound of general formula (I). Examples of such esters include lower alkanoates, such as acetates or pivaloates. In addition to the above ester derivatives, within the scope of the present invention are compounds of general formula (I) in the form of other physiologically acceptable equivalents, that is to say physiologically acceptable compounds which, like metabolically labile esters, are transformed in vivo into parent compounds of general formula (I).

Also within the scope of the invention are the solvates, in particular hydrates, of compounds of general formula (I).

* 5

Animal tests have shown that the compounds of general formula (I), administered in low doses, increase the force of contraction of the myocardium and decrease the total peripheral resistance. The 5 compounds according to the invention are powerful stimulants of myocardial function and act as vasodilators. In addition, the compounds according to the invention have particular advantages over known cardiotonic agents such as isoprenaline <10 and dobutamine in that they have a longer duration of action and, moreover, they are absorbed from the gastrointestinal tract, as indicated by their activity after oral administration. We have found that the compounds of general formula (I) selectively block the adrenergic receptors of the vessels and stimulate the β ^ adrenergic receptors of the heart. The compounds show no signs of toxicity at the maximum doses tested.

One aspect of the present invention provides layered compounds of formula (I) in which R represents a hydrogen atom, a methyl group or an ethyl group, and n is 1 or 2, and their salts. addition of physiologically acceptable acids, their solvates and their metabolically labile esters.

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

Another preferred group of compounds of formula (I) is that in which R represents a hydrogen atom.

t 6

A particularly preferred compound is 2 - [2 - [[2- (3,5-dihydroxyphenyl) -2-hydroxyethyl] amino] ethoxy] benzene- "acetamide and its physiologically acceptable acid addition salts, -it is to say fumarate or phosphate * 5 advantageously in the form of a racemic mixture of its isomers (R) and (S).

The compounds according to the invention can be used for the treatment of heart failure, cardiogenic shock or ischemic heart disease.

Accordingly, the invention further provides compounds of general formula (I) and their physiologically acceptable acid addition salts and their metabolically labile esters for use in the treatment or prophylaxis of heart failure in a human or animal subject.

The compounds of formula (I) and their physiologically acceptable acid addition salts and their metabolically labile esters can be formulated for administration in a practical manner and therefore also fall within the scope of the invention pharmaceutical compositions comprising at least one compound of formula (I) or a physiologically acceptable salt, a solvate or a metabolically labile ester of this compound, suitable for use in human or veterinary medicine. These compositions can be presented for use in a conventional manner in admixture with one or more vehicles or excipients.

Thus, the compounds according to the invention can be prepared for oral, buccal, parenteral or rectal administration 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, for example, syrup, gum arabic, gelatin, sorbitol, gum tragacanth, starch mucilage or polyvinylpyrrolidone; fillers, for example , lactose, sugar, microcrystalline cellulose, corn starch, calcium phosphate or sorbitol; lubricants, for example, magnesium stearate, stearic acid, talc, polyethylene glycol or silica; disintegrants, for example, apple starch - sodium earth or amyloglycolate, or wetting agents such as sodium laury1-sulfate 15. The tablets can be coated in accordance with methods well known in the profession.

The oral liquid preparations can be, for example, in the form of suspensions, solutions, aqueous or oily emulsions, syrups or elixirs or they can be presented in the form of a dry product for reconstitution with water or another vehicle. suitable before use. These liquid preparations may contain traditional additives such as suspending agents, for example, sorbitol, syrup, methylcellulcse, glucose / sugar syrup, gelatin, hydroxylethylcellulose, carboxymethylcellulose, aluminum stearate gel or hydrogenated edible fats ; emulsifiers, for example, lecithin, sorbitan mono-oleate or gum arabic; non-aqueous vehicles (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-hydroxy benzoates or sorbic acid.

The compounds or their salts or esters can also be formulated as suppositories, that is, containing traditional bases for suppositories, such as cocoa butter or other glycerides.

For oral administration, the composition may take the form of tablets or lozenges formulated in the traditional manner.

The compounds of formula (I) and their physiologically acceptable acid addition salts and their metabolically labile esters can also be formulated for parenteral administration by injection or continuous infusion. Preparations for injection may be presented as single doses in ampoules or in multiple dose containers with the addition of a preservative. The preparations can take forms such as suspensions, solutions or emulsions in oily or aqueous vehicles, and they can contain formulating agents, such as suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient can be in powder form for reconstitution with a suitable vehicle, for example, pyrogen-free, sterile water, before use.

For administration by inhalation, the compounds according to the invention are advantageously provided in the form of aerosol spray presentation in a pressurized container with the use of an appropriate blower, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide. or other suitable gas, or in the form of a nebulizer. In the cal of a pressurized aerosol, the unit of dose can be determined by providing a * valve to deliver a metered amount.

Still further, for administration by inhalation, the compounds according to the invention may take the form of a dry powder composition, for example, a mixture of powders of the compound and a suitable powder base such as lactose. or starch. The powder composition can be presented in the form of a single dose, for example, in capsules or cartridges, in particular of gelatin, or in blister packs from which the powder can be administered using an inhaler. or a resuscitator.

When the compositions comprise units of 15 doses, each unit will preferably contain 5 mg to 500 mg, advantageously when the compounds are intended to be administered orally 25 mg to 400 mg of active compound. The daily dose as used for the treatment of adult humans will preferably be between 5 mg and 3 g, most preferably between 25 mg and 1 g, which can be administered as 1 to 4 doses per day, for example, depending on the route of administration and the patient's condition.

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

10

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

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

Ri \ A Γ '

| j-CHCH2NA

• · \\ / OR3 (II) (where -NA represents a group -NHR ^, -NR ^ CI ^ CH ^ X, -N ^ R5 234 3 or -MA, R, R, R and R are each an atom hydrogen or a protecting group and X is an easily displaceable atom or group).

and a compound of formula (III) / Λ Γ ii • · / w / Y0 · ÎcH2) nC0NRR1 (III) (where R and n are as defined in formula T _ 1 I, R is an atom d hydrogen or a protecting group and Y represents a hydrogen when -NA represents

R

-NR5CH2-CH2X, -N <q or N5 ^, or Y represents the group CH? CH7> where X is as defined above 11 when -NA represents -NHR '') followed by elimination of all protecting groups where they are present as „described below.

* Examples of X include a halogen atom such as a chloride, bromide or iodide atom or a hydrocarbylsulfonyloxy group such as methane sulfonyl-oxy or p-toluene sulfonyloxy. When X is bromo or chloro, the reaction can be facilitated; by the addition of an iodide such as sodium iodide.

In a particular embodiment of the process, the compounds of general formula (I) can be prepared by alkylation of an amine of formula (IV) R 20 · OR * ♦ R 5

\ // \ I I

| dd-CHCH 2NH

• · \\ / • I, OR3 (IV) with an alkylating agent of formula (V)

AT

• X-CHjCHj-O ^ ^ (CH ^ pCONRR1 (V) followed by the removal of all protecting groups where they are present as described below.

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

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

AT

5 î · · / \ // HO · (CH2) nC0NRR1 (VI) with an alkylating agent of formula (VII) R20 · OR1 * R5

\ / \\ I I

H ^ -CHCH2NCH2CH2X

• · \ // r3o (VII) followed by the elimination of all protecting groups where they are present as described below.

Alternatively, the compounds of formula (VII) may be in the form of an aziridine: 13 r \ a r

U | -CHCH2N ^ J

\ // • R30 or an aziridinium salt: r2 ° v / Vv 9R | * r5 \ / ^ I + ^ i

(I | -chch2n ^ J

• · Λ- \ // r3o where A "represents an anion, in particular a halide ion.

The reaction is preferably carried out in the presence of a base. Suitable bases include organic bases such as sodium hydroxide, sodium hydride, potassium carbonate, potassium t-butoxide, organic bases such as diisopropylethylamine and basic ion exchange resins such as the Amberlite. Alternatively, the compound of formula 10 (VI) can be used in the form of a phenolate salt, for example sodium salt. The reaction is advantageously carried out in a medium such as water; Acetonitrile; an alcohol, for example, methanol; or a ketone, for example, acetone or methyl isobutyl ketone and at a temperature within the limits of -20 ° to + 150 ° C, preferably ^ between 20 ° and 100 ° C.

According to another general process' 2), the compounds of formula (I) can be prepared by reacting a compound of formula (VIII) 14 r2 ° \ a / 6 • ·

It i • · \ // R3i (VIII) 2 3 (where R and R are as defined above in the general process (1) and R ^ represents a group

-CH-CH 2 ου -CHCH2X

in which R ^ and X are as defined above in the general process (1)) with an amine of formula (IX)

AT

It î · · 5 / \ // r5nhch2ch2-o · (CH2) nC0NRRl (IX) 1 3 - (where R, R, R and n are as defined previously in the general process (1)), followed by the elimination * of all protecting groups where they are present as described below.

This reaction can be carried out in the presence or

5C

r in the absence of a solvent at a temperature of 0 to 150 ’, preferably 20 ° to 100 ° C. Suitable solvents include alcohols, for example, methanol or ethanol; halogenated hydrocarbons, for example, chloroform or dichloromethane; substituted amides, for example, N, N-dimethylformamide; ethers, for example, diethyl ether or tetrahydrofuran; acetonitrile; esters, for example, ethyl acetate; and water and mixtures of these solvents.

✓ 15 OR4

When R6 represents a -thlCHCH group, the reaction can be carried out in the presence of a base such as car-, sodium bonate, potassium carbonate, sodium hydroxide or an organic base such as pyridine. Or - an excess of the amine of formula (IX) can be used.

According to another general process (3), the compounds of formula (I) can be prepared by reductive alkylation. Thus we can react a compound 10 of formula (X) R 20 · R 7 \ // \ / î il \\ / Γ (x), OR3 OR4 (where R ^ represents the group -C0CH0 or -iHCH ^ NHR ^ and R ^, R4 and R ^ are as defined above in the general process (1)) with a compound of formula (XI) / Λ î î ZCHjO7 "^ (CH2) nCQNRR * (XI) i 16 OR4 7 * 5

(where Z represents the group CHO when R is CHCH „NHR

S 1 1 or Z represents the group CH_NHR when R is -COCHO and 1 ^ R, R, R and n are as defined above in the general process (1)) in the presence of an agent re-- 5 conductor, the reaction being followed by the removal of all protective groups where they are present as described below.

In a particular embodiment of the general process (3), a compound of formula (X) in which R7 is CH (OR4) CH ^ NHR ^ is reacted with a compound of formula (XI) in which Z is CHO, in the presence of 'a reducing agent. Examples of suitable reducing agents include an alkali metal or alkaline earth metal borohydride or cyanoborohydride, especially sodium borohydride or cyanoborohydride, using an alcohol such as ethanol or propanol as the solvent, or hydrogen in the presence of a catalyst, such as Raney nickel, platinum, platinum oxide, palladium or rhodium, using an alcohol, for example, ethanol; an ether, for example, dioxane. or an ester, for example, ethyl acetate as a reaction solvent. nel. The catalyst can be attached to a support, for example, carbon or a homogeneous catalyst such as rhodium chloride tris-triphenylphosphine can be used. The reduction can be carried out advantageously at any temperature between -20 ° and 100 ° C., preferably between 0 ° and 30 ° C.

The reaction can take place via imine (xii) 17 r \ a r Λ. · • -CHCH, N = CHCH, D—. .

"I 2 2 \ // • tf \ // î sf (CHaJnCONRRiR7 (XII) R30 (where R, R ^, R ^, R ^, R ^ and n are as defined above in the general process ( 1)) and it is possible that this intermediate can be isolated Reduction of the imine using the conditions described above followed where necessary by the removal of all protective groups gives a compound of general formula (I).

In another embodiment of the general process (3), a compound of formula (X) in which u R is COCHO is reacted with a compound of formula (XI) in which Z is Ch ^ NHR ^ in the presence of an agent reducer. The suitable reducing agents are those described above in the first embodiment of the reducing alkylation process.

15 This reaction can take place via! the imine of formula (XIII)

! 2 A

R 2o · n. ·

\ / \\ Il II I

j H | -CCH = NCH2CH20- · ^ f · [· · ·; V | cH2) nC0NRRl j R 30 (XIII) 18 12 3 (where R, R, R, R and π are as defined above in the general process (1)) and it is possible that this intermediate. This compound can also be reduced using the reagents - described above in the first embodiment of the reductive alkylation process, this reduction being followed by the removal, where necessary, of all protective groups to obtain the compound of formula (I ).

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

Ri ° \ A 1! S 1 î g | -CCH2NCH2CH20 - · ^ • · · \ // r (CH2) nC0NRR1 rîq (XIV) "(where R, R ^, R ^, R ^, and n such that they are defined previously in the general process (1)), followed by the removal of all protective groups, where they are present, as described below. The reduction can be carried out using a metal borohydride alkaline or an alkaline earth metal, such as sodium borohydride or hydrogen in the presence of a catalyst such as palladium or platinum, which can be fixed on a support, for example, on carbon. Stereoselective can be achieved using an optically active borane such as "alpine" borane (9- (2,6,6-trimethylbicyclo [3.1.1.] hept -3-yl) -9-borabi-25 cyclo [3.3. 1] nonane).

> 19

The reaction is advantageously carried out in an organic solvent such as an ether, for example, tetrahydrofuran, or an alcohol, for example, methanol or ethanol, at a temperature of 20 ° to 80 ° C, for example.

In accordance with another general process (5), the compounds of the invention can be prepared by amination of a compound of formula (XV)

2 h c A

R ° \ A ÏR f T, I

j-CHCH2NCH2CH20-1 ^ y · ÎcH2) nR8 R30 (XV) (where R ^, R "5, R ^, R ^ and n are as defined g in the general process (1) and R represents a carboxyl group or a salt or reactive derivative thereof, for example, a hydracid, especially an acid chloride, an acid anhydride formed for example with an acid chloride, especially pivaloyl chloride or chloro -formate, or an ester, in particular an alkyl ester a C ^ (), followed by the removal of all protective groups 15 where they are present as described below. The reactive derivatives can also be formed in situ by treatment of l acid or its salt with a condensing agent such as N, N'-dicyclohexylcarbodiimide or N, N'-carbonyldiimidazole.

The amination will generally be performed using an amine RNH ^ (where R is already defined in formula I).

/ / __ r * f 20

The reaction is advantageously carried out in a solvent. organic such as an alcohol, for example, methanol or - ethanol; an ether, for example, tetrahydrofuran; an amide, for example, N, N'-dimethylformamide; or a halogenated hydro-carbide, for example, methylene chloride, optionally in the presence of a catalyst such as silica or rhodium trichloride and at a temperature of 0 to 150 ° C, for example, preferably 50 ° at 100 ° C. When ammonia is used for reaction 10 (i.e., R represents hydrogen), it may be desirable to carry out the reaction under elevated pressure, preferably using water or an alcohol such as methanol or ethanol as a solvent.

The compounds of formula (XV) where R is a carboxyl group and their salts and esters (for example, alkyl esters, -) are new compounds which are useful intermediates and constitute another characteristic of the invention.

An interesting class of compounds of formula (XV) is that of compounds in which R ^, R, R ^ and R "* a represent hydrogen atoms.

A particularly interesting class of compounds of formula (XV) is that of compounds in which 2 3 4 5 8 R, R, R and R are hydrogen atoms and R represents a carboxyl group or an alkyl ester of this type. last (for example, a methyl or isopropyl ester).

The compounds of formula (XV) where R ^, R ^, R ^ and R ^ g are hydrogen atoms and R represents a carboxyl group are of particular interest, more particularly when n is 1.

21

According to another general process (6), the compounds of the invention in which R represents „hydrogen can be prepared by hydrolysis of a compound of formula (XVI) OR ** R 5 J \

, He II I

r2o ^ · / chch2nch2ch2o- · ^ ^ • · ·

J * (CH2) nC = N

R3o (XVI) 5 (where R ^, R ^, R ^, and n are as defined above in the general process (1)), followed by the elimination of all protecting groups, where they are present, as described below. The hydrolysis can be carried out under acidic or basic conditions using a hydrated acid, for example, polyphosphoric acid, hydrochloric or sulfuric, or a base such as an alkali metal hydroxide, for example potassium and at a temperature of 0 to 100 ° C. The reaction can advantageously be carried out in a water-miscible solvent, such as an alcohol, for example, n-butanol or methanol, a ketone, for example, acetone or by using acetic acid, preferably in the presence of water.

According to another general process (7), the compounds of formula (I) can be prepared by removing the protections from a compound of formula (XVII) 22

2 U 5 A

R 0 \ / \ Γ f »î | jpCHCH2NCH2CH20- · ^ / f • * · | (CH2) nC0NRR1 R30 (XVII) where R, R ^, R ^, R ^, R ^, R ^ and n are as defined above in the general process (1), where 4 5 R and R represent together a protective group, provided that at least one of the R, R, R, R and 5 R represents a protective group.

1 2 3 4 3

When R, R, R, R or R represents a protective group, it can be any conventional protective group, for example, as described in "Protective Groups in Organic Chemistry", Ed. J.F.W.

10 McOmie (Plenum Press, 1973). Examples of suitable hydroxyl protecting groups 2 represented by R, “3 4 R and R are alkyl groups such as jt-butyl-. or methoxymethyl, aralkyl groups such as benzyl, diphenylmethyl or triphenylmethyl, heterocyclic groups such as tetrahydropyranyl and: acyl desf.groapes such as acetyl. Examples of amino protecting groups represented by R are aralkyl groups such as benzyl, diphenylmethyl or triphenyl-methyl and acyl groups such as dichloroacetyl.

Examples of suitable amide protecting groups Ί R are t-butoxycarbonyl and 2,2,2-trichloroethoxycarbonyl groups.

1 2 3 4- 5

The protecting groups R, R, R, R and / or R can be removed using standard techniques to obtain a compound of formula (I). Thus, for example, an aralkyl group such as a benzyl group can be separated by hydrogenolysis in the presence of a precious metal catalyst (for example palladium or palladium oxide on carbon); an acyl group such as a dichloroacetyl group can be removed by reduction using, for example, zinc and acetic acid; an alkyl group or a heterocyclic group protecting a hydroxyl group can be separated 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 45 groups R and R can represent a protective group 15 as in a compound of formula (XVIII)

R \ Λ A

I rcif T2 II 1 * \ // · 0wM "" CHlCH, 0 - \ / î 'v î R3 ° ÎCH2) nCONRRl (Xvni) 12 3 (where R, R, R, R, and n are as they are defined above in the general process (1) and Y represents a carbony or thiocarbonyl radical or a bivalent radical formed from an aldehyde or a ketone such as acetaldehyde or acetone. A compound of formula (XVIII ) can be converted to the compound of formula (I) by hydrolysis under acidic or basic conditions using, for example, hydrochloric or sulfuric acid / / hydrate or sodium hydroxide and, where necessary, elimination from any other protecting groups present using the methods described above.

Alternatively, the substituent on the amino group can act as a protective group for the hydroxyl group in the ethylenic part as in a compound of formula (XIX) R20 · \ / \\ „! T-C1? - ·. „· 0, N-R®.

Y V \ R3i ch2-o-! I 1 î (CH2) nC0NRR1 (XIX) 12 3 5 where R, R, R, R, R and n are as defined above in the general process (1). The compound of formula (XIX) can be converted into a compound of formula (I) by reduction using the reagents described above * in the general process (3) and, where necessary, removal of all other protecting groups present using the methods described above.

When it is desired to prepare an acid addition salt of a compound of formula (I), the product of any of the above processes can be transformed into a salt by treatment of the resulting free base with an appropriate acid using conventional methods.

Physiologically acceptable salts of the compounds of general formula (I) can be prepared by reacting a compound of general formula (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, for example, methanol, ethanol or isopropanol.

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

Optically active enantiomers of the compounds of the invention can be obtained from intermediates having the desired chirality. Alternatively, such enantiomers can be obtained by resolution of the corresponding racemic compound using traditional means, in particular an optically active resolving acid; see, for example, "Stereochemistry of Carbon 15 Compounds" by E.L. Eliel (McGraw Hill 1962) and "Tables of Resolving Agents" by S.H. Wilen.

Examples of optically active resolving acids * which can be used to form salts with racemic compounds include the forms (R) and (S) acids of organic carboxylic and sulfonic acids such as tartaric acid, di-p-toluoy1-tartaric acid, sulfocamphoric acid and lactic acid. The resulting mixture of isomeric salts can be separated, for example, by fractional crystallization, into diastereoisomers and, if desired, the desired optically active isomer can be converted into the free base.

In another method, the optically active enantiomers of the invention can be obtained by separation of the optically active derivatives of the compounds. Thus, for example, derivatives of the compounds of the invention can be prepared 26 ¥ 26 1 2 in which one of the groups R, R, R ^, R ^ or R "* in the compounds of formula (XVII) 2 3 4 represents a chiral protecting group, R, R or R may, for example, represent an optically active sugar residue such as a BD-glucopyrannosidyl group. An example of a suitable optically active amino 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 above in the general process (7).

The methods which have just been described for the preparation of the compounds of the invention can all be used as the last essential step in a preparative sequence. The same general methods can be used for the introduction of the desired groups at an intermediate stage in the stepwise formation of the desired compound and it will be appreciated that these general methods can be combined in different ways in these multi-step processes.

* 20 The compounds of formula (VIII) in which R ^ represents a group -CH-CH2 can be prepared from the compound of formula (XX) R2 ° \ Λ \ / C0CH2Xl • ·

He I

• · \ // R3i (xx) ft 27 2 3 (where R and R are as defined above and Λ - X is a halogen atom) by treatment with, for example, sodium borohydride to form the halohydrin, followed by treatment with a base, such as potassium carbonate or sodium hydroxide. The reaction is advantageously carried out in a solvent such as dimethylformamide, an alcohol such as methanol or ethanol or water, at a temperature ranging from room temperature to reflux.

The compounds of formula (VIII) in which R ^ represents a group -CHiOR ^ XH ^ X (where R ^ and X are as defined previously in the general formula (I)) can be prepared from epoxides corresponding by treatment with the appropriate reagent such as the hydrochloride or p-toluenesulfonic acid, followed by the introduction of a protecting group if desired.

The compounds of formula (X) in which R ^ is * C0CH0 can be prepared from compounds of formula (XXI) R20 ^ · / C0CH (X1) 2 • ·

He I

• · \ // A (χχι> * 28 2 3 1 (where R, R and X are as defined above) by reaction with an alkoxide such as methoxide, sodium in methanol, followed treatment with an acid such as 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) r2 ° \ A / coch 'ii î • · \ // R 30 (XXII) 2 3 (where R and R are such that (they are defined above) using, for example, a halogen (for example, chlorine) or an N-halosuccinimide (for example, N-bromo-succinimide).

The compounds of formula (X) in which R ^ is COCH0 can be prepared directly from a compound of formula (XXII) by oxidation using an appropriate oxidant such as selenium dioxide.

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

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

29

The compounds of formula (VII) can be prepared by reacting a compound of formula (VIII) with an R5 amine of formula - HNCI ^ CI ^ X (where and X are as defined above) or when compounds of formula (VII) are in the form of an aziridine or an aziridinium salt, by reaction of a compound of formula (VIII)) with an amine of formula R5 x \ ch2-ch2 (where is such that 'it is defined above) using the coaditions described in the general process (1).

Compounds of formula (IX) can be prepared from compounds of formula (V) by reaction with an amine of formula R ^ NH ^ (where is as defined above), depending on the reaction conditions of the process general (1).

The compounds of formula (V) can be prepared from compounds of formula (VI) by reaction with a compound XCh ^ Ct ^ X (where X is as defined above).

The compounds of formula (IX) where Z is CHO can be prepared by alkylation of the phenol of formula (VI) with an alkylating agent of formula HCOCI ^ X (where X is as defined above) or, in in particular, a protected derivative of the latter, for example, an acetal such as a diethylacetal.

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

AT

r5 "î I / \ //

„HNCH2CH20 J

(CH2) nC5N (XXIII) / 30 (where and n are as defined above), followed by treatment with a reducing agent such as sodium borohydride.

g

Compounds of formula (XV) where R is a carboxyl group or its salt or ester can be prepared by reaction of compounds of formula (XXIV)

5 A

f ii î hnch2ch2o- · ^ ^! CH2) nR 8 (XXIV) 5 8 (where R, R and n are as defined above) with compounds of formula (XX), followed by treatment with a reducing agent such as sodium borohydride, followed , where necessary, the removal of all protecting groups as described above.

g

Compounds of formula (XV) where R is a "carboxyl" group can be prepared by hydrolyzing a corresponding ester, the hydrolysis being followed by the removal of all protecting groups, where they are present, as described below. Hydrolysis can be carried out under acidic or basic conditions using a hydrated acid, for example, polyphosphoric acid, hydrochloric or sulfuric acid, or a base such as an alkali metal hydroxide, for example. sodium hydroxide and at a temperature of 0 to 100 ° C. The reaction / / • * 31 can advantageously be carried out in a water-miscible solvent such as an alcohol, for example methanol.

* 8

Compounds of formula (XV) where R is a derivative. carboxylic acid reagent, for example, an acid chloride or an acid anhydride, can be prepared in a conventional manner, for example, by forming an acid chloride or an anhydride 'acid.

g

Compounds of formula (XV) where R is a carboxyl group or its salt or its ester and n is 2, can be prepared by reduction of the α-β-ethylene carboxylic acid or an acid salt or d an ester using appropriate hydrogenation methods as described above. The unsaturated precursor can be obtained by methods analogous to those described here for the preparation of the compounds of the invention, for example, by alkylation as described in the general process (1) and illustrated in the examples.

"

Compounds of formula (XXIII) and (XXIV) can. 20 can be prepared by reaction of a compound of formula (XXV) // il ho- \ / · 9 (cH2) nR9 (XXV).

s 32 g (where n is as defined above and R represents the group C = N, C0_H or an ester of carbo- ^ xylic acid as defined above for R) with a compound of formula XCL ^ Ch ^ Br (where X is as defined above), followed by amination with a compound of formula R ^ NH ^ (where R ^ is as defined above).

Compounds of formula (XVIII) can be prepared from a compound of formula (XVII) where R, R, 2 3 R, R and n are as defined in the general process (1) and R and R "* are hydrogen atoms, by 11 reaction with 1,1 -carbonyldiimidazole or 1,1 - thiocarbonyldiimidazole.

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

The following examples illustrate the invention. The temperatures are in ° C. "Dried" is understood to mean desiccation using magnesium sulfate, unless otherwise indicated. Thin layer chromatography was performed on silica plates. The FCC - fast column chromatography - was carried out on silica (Merck 9385).

/ 33

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; 5 H - hexane; DMF - dimethylformamide; THF - tetrahydrofuran; 9-BBN - 9-barabicyclo [3: 3: 1jnonane; ; Pd-C -palladium on carbon; PdO-C - palladium oxide on carbon.

Intermediate 1 10 Methyl 2- (2-bromoethoxy) ben2ene-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 1) was heated at reflux for 111 h. The resulting mixture was evaporated and the residue was dissolved in chloroform (500 ml), washed with water (2x250 ml) and brine (250 ml), dried (^ £ 50 ^) and evaporated. The oil obtained (82 g) was purified by FCC, eluting with T to obtain the title compound in the form of a yellow oil (32.5 g).

* 20 Analysis

Found: C, 48.5; H, 4.8 C / | 1H13Br03 Theor .: C, 48.4; H, 4.8¾

Intermediate 2 Methyl 2 - [2 - [(phenylmethyl) amino] ethoxy] benzene-acetate 25 A mixture of intermediate 1 (15 g), benzylamine (58.7 g) and sodium iodide (16.4 g ) in dry aceto-nitrile (400 ml) was heated at reflux for 4 h. The inorganic solid was separated by filtration and the filtrate evaporated. A solution of the residue in v 34 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 obtain the title compound • as orange oil (13.2 g).

Analysis Found: C, 72.4; H, 7.2; N, 4.8 C18H21N03 Theor .: C, 72.2; H, 7.1; N, 4.1%

Intermediate 3 2- (2-bromoethoxy) benzene-acetamide

A solution of 2-hydroxybenzene acetamide (1.06 g), potassium carbonate (1.9 g) and tris [(2- (2-methoxyethethoxy) ethyl] amine (0.11 g) in the dibromoethane (50 ml) was heated at reflux for 21 h and evaporated. The resulting solid product was dissolved in EA (75 ml), washed with water, dried and evaporated. The residue was purified by FCC to eluting with ER, then EA to obtain the title compound in the form of a white solid product (0.9 g), mp 84-86 ° C.

Intermediate 4 2- [2 - [(phenylmethyl) aminojethoxyjbenzene-acetamide 20 A solution of intermediate 2 (5.0 g) in ME (10 ml) was autoclaved with liquid ammonia (15 ml) to 75 ° for 45 h. The solvent was evaporated and the residue purified by FCC eluting with EA-ME (9: 1) to obtain the title compound as a solid, slightly dirty white product (2.60 g) Mp 89-90 °.

35

Intermediate 4 (other preparation)

A solution of intermediate 3 (52 g), benzylamine (218 ml) and sodium iodide (60 g) in acetonitrile was refluxed for 18 h, filtered * 5 and evaporated. The residue was dissolved in EA (300 ml), washed in aqueous sodium carbonate solution (2 M) and with water, dried and evaporated. The resulting brown oil was purified twice by FCC eluting with ER and then EA to obtain the title compound as a white solid (12 g) m.p. 85-87 ° C.

Intermediate 5 Methyl 2— [2 - [[2— [3,5-bis (phenylmethoxy) phenyl] -2-hydroxy-ethyl] (phenylmethyl) amino] ethoxy] benzene-acetate 15 A solution of 1- [3,5 -bis (phenylmethoxy) pheny1] -2-bromo-

AT

etnanone (1.37 g) in dry DMF (25 ml) was added over 5 minutes with stirring to a 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 h under nitrogen and evaporated.

Sodium borohydride (0.5 g) was added over 10 min to a solution of the residue in absolute TE (130 ml). The mixture was stirred at room temperature for 18 h and concentrated in vacuo. Water (5 ml) and ME 25 (100 ml) were added and the solution was evaporated.

A solution of the residue in EA (50 ml) was washed with water (25 ml) and brine (25 ml), dried and evaporated to obtain the title compound as a yellow oil (2.13 g). CCM (EA) Rf 0.7.

1 5.N. Quessy and L.R. Williams Aust. J. Chem. 32, 1317, (1979) 36

Intermediate 6 2- (2-aminoethoxy) benzene-acetamide

A solution of Intermediate 4 (2.5 g) in absolute TE (25 ml) was hydrogenated on 10% PdO-C until * 5 until absorption had ceased. The catalyst was removed by filtration and the filtrate was evaporated under reduced pressure to obtain a pale yellow oil which was purified by FCC eluting with a dichloromethane-ET-A 100: 8: 1 mixture to obtain the compound titrated in the form of a colorless oil which crystallized on abandonment (1.3 g), mp 92-94 °.

Intermediate 7 g- (aminomethyl) -3.5-bis (phenylmethoxy) benzene-methanol A mixture of 3,5-bis (phenylmethoxy) benzaldehyde (31.8 g), 15 trimethylsilyl cyanide (9.92 g) and zinc iodide (0.4 g) in dry benzene (50 ml) was stirred for 4 h under nitrogen. The resulting solution was added to an ice-cold solution of lithium aluminum hydride (7.6 g) in dry THF (500 ml) and the mixture was stirred for 18 h at room temperature. The reaction mixture was cooled in an ice bath and water (7.6 ml) was added dropwise, followed by 2N sodium hydroxide solution (15.2 ml) and d water (22.8 ml). The inorganic solid was separated by filtration and the filtrate was evaporated to obtain a red gum which was purified by FCC eluting with EA-ME 7: 1 to obtain the title compound as a colorless solid (21.8 mg) FP 89-90 °.

37

Intermediate 8, 2- (2-bromoethoxy) benzene-acetonitrile

A mixture of 2-h-ydroxybenzene-acetonitrile (1.6 g) and * potassium carbonate (3.3 g) in dibromoethane (15.5 ml) was heated at 120 ° for 2 days. The broth was evaporated, EA was added to the residue, the inorganic solid was removed by filtration and the filtrate was evaporated to obtain a brown gum. The gum was purified by FCC eluting with ER-PE (1: 1) to obtain the title compound 11 as orange oil (2.2 g). TLC (ER-PE 2: 1) Rf 0.4.

Intermediate 9 2- [2 - [(phenylmethoxy) amino] ethoxy] benzene-acetonitrile 15 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 heated at reflux for 3 h. The inorganic solid product was separated by filtration and the filtrate was evaporated.

The residue was purified by FCC eluting with EA to obtain the title compound as a yellow oil (4.8 g). TLC (EA) Rf 0.25.

38

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

A mixture of 1 - [- 3,5-bis (phenylmethoxy) phenyl] -2-bromo- * 5 ethanone (3.96 g), intermediate 9 (4.00 g) and di-isopropylethylamine (2, 61 ml) in DMF (30 ml) was stirred at room temperature for 2.5 h and evaporated. .

The residual gum was dissolved in ME (30 ml) and treated with sodium borohydride (1.9 g) for 10 hrs at room temperature. The reaction mixture was evaporated, treated with ME (30 ml), re-evaporated and distributed between the chloroform phase (2x100 ml) and the water phase (100 ml). The organic phase was dried and evaporated to leave a yellow gum which was purified by FCC 15 eluting with T-ER (19: 1) to give the title compound 11 (5.60 g) as a yellow gum. TLC (T-ER 19: 1) Rf 0.24.

Intermediate 11 1-methylethyl 2-hydroxybenzene-acetate 20 A solution of o-hydroxyphenylacetic acid (3.04 g) in isopropanol (20 ml) was treated with sulfuric acid (18 M; 0.1 ml) at room temperature for 66 h, heated at reflux for 3 h and evaporated. The residue was partitioned between the EA phase (50 ml) and the aqueous sodium bicarbonate phase (1 M; 2x20 ml). The organic phase was dried and evaporated to leave the title compound as a yellow oil which subsequently solidified. CCM rER) Rf 0.52.

39 /

Intermediate 12 t 1-methylethyl 2- (2-bromoethoxy) benzene acetate

A mixture of intermediate 11 (1.94 g), potassium carbonate (2.8 g), dibromoethane (20 ml) and isopropanol (30 ml) was heated at reflux for 16 h, filtered and evaporated to leave a light brown oil (3.00 g). CCM (PE-20? I ER) Rf 0.26.

Intermediate 13 (iii) 1-methylethyl 2- [2 - [(phenylmethyl) amino] ethoxyj 10 benzene-acetate

A mixture of intermediate 12 (80 g), benzylamine (300 ml), potassium carbonate (74 g) and sodium iodide (80 g) in acetonitrile (1 1) was heated at reflux for 8 p.m. The inorganic solid was removed by filtration and the filtrate was evaporated.

The residue was purified by FCC eluting with ER to obtain the title compound as a pale yellow oil (70 g). CCM (ER) Rf 0.4.

Intermediate 14 20 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-bromo-ethanone (3.0 g) in dry DMF (13 ml) was added to a solution of Intermediate 13 (4.0 g) and di-isopropylethylamine ( 4.5 ml) in DMF (50 ml) and the solution was stirred at room temperature for 3 h. The solvent was evaporated and the residue was redissolved V.-

AO

in ET (80 ml) and treated with sodium borohydride (2.5 g). The mixture was stirred for 2 h, water (20 ml) was added and the mixture was stirred further for 0.5 h. The ET was evaporated, the residue was acidified with 2N hydrochloric acid and the mixture was heated in a steam bath for 20 minutes. The solution was then neutralized with 8% sodium bicarbonate and extracted with EA (5x80 rnl). 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 obtain the title compound as a pale yellow oil (5.6 g) TLC (ER-PE 1: 1) Rf 0.35.

Intermediate 15 1 5 Acid 2- [2 - [[2- [3,5-bis (phenylmethoxy) phenyl] -2-hydroxyethyl] (phenylmethyl) amiao] ethoxyjbenzene acetic Intermediate solution 1A (56.1 g ) and 2N sodium hydroxide (223 ml) in ME (A00 ml) was heated at reflux for 16 h. The ME was evaporated and the aqueous phase was acidified to pH 6 with acetic acid glacial (20 ml) and extracted with EA (3x100 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 obtain the title compound 25 as white foam (32.8 g).

TLC (EA-PE 7: 3) Rf-0.25.

/ 41

Intermediate 16

Acid 2 - „[2 - [[2- (3,5-dihydroxyphenyl) -2-hydroxyethyl] amino] ethoxy] benzene-acetic

A solution of intermediate 15 (2.0 g) in a mixture * of ET (50 ml) and ME (50 ml) was hydrogenated on Pd-C

S 10¾ (0.2 g). When the absorption stopped, the catalyst was filtered off and the filtrate was evaporated to obtain the title compound as a colorless solid (0.96 g) m.p. 225 °.

10 CCM (dichloromethane-ET-water-acetic acid, 5: 5: 1: 1)

Rf 0.74.

Analysis Found: C, 60.5; H, 6.3; N, 3.8 C18H21N06’H2 ° Theor .: C, 60.7; H, 6.2; N, 3.9¾

Example 1 15 (i) 2- [2 - [[2- [3,5-bis (phenylmethoxy) phenyl] -2-hydroxyethyl] (phenylmethyl) amino] ethoxy] benzene acetamide An intermediate solution 5 ( 2.02 g) in ME (25 ml) and the liquid ammonia (25 ml) was autoclaved at 65-75 ° for 65 h. The solvent was evaporated and the residue purified by FCC eluting with EA-PE (3: 2) to obtain the title compound as a slightly dirty white solid product (1.23 g) PF 12 3-5 0 C.

(ii) 2- [2 - [[2- (3,5-dihydroxyphenyl) -2-25 hydroxyethyl] an) inojéthcxy] benzene-acetamide hydrochloride

The product of step (i) (1.08 g) in absolute TE (150 ml) was hydrogenated on Pd-C (350 mg). The catalyst was removed by filtration and the filtra was evaporated.

/ i i v .. 42

The residue was purified by FCC eluting with T-ET-A (78: 20: 2 and 68: 30: 2). The product was treated with ethereal hydrpgene chloride to obtain compound 11 titled as a hygroscopic solid product 5 of buff color (190 mg). M.p. 86-88 ° C (dec.).

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

C18H22N2 ^ s HCl 0.33 CH3C02C2H5 Q.5H2Q

Theor .: C, 5 5.1; H, 6.4; N, 6.65% t (D ^ Methanol) 2.66-2.77 (2H, m), 2.92-3.06 '(2H, m), 3.60 10 (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 (phenyl methoxy) phenyl] -2-hydroxy- ^ ^ ethyl] (phenylmethyl) amino3ethoxy3benzene-acetamide

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 and the mixture was stirred at room temperature for 11 p.m. 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 was stirred at room temperature for 18 h. Water (40 ml) and ME (200 ml) were added and the mixture was concentrated. Water was added and the suspension was extracted with EA (3x100 ml). The combined extracts were washed with water (50 ml), brine (50 ml), dried and evaporated.

The residue was crystallized from EA-PE to obtain the title compound as a white solid product (8.37 g) m.p. 121-3 °.

43 * (ii) 2- [2 - [[2- (3,3-dihydroxypheny1) -2- 5 hydroxyethyl] amino] ethoxy] benzene acetamide hemifumarate

The product of step (i) (8.13 g) in 1ΈΤ absolute (830 ml) was hydrogenated on Pd-C (2.0 g). The catalyst was removed by filtration 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 1ΈΤ (30 ml) was added. The precipitated solid product was separated by filtration, crystallized from ET and recrystallized from ME / EA to give a solid product of a slightly dirty white (2.39 g) m.p. 110-115 ° (dec.).

15 A portion (1 g) was diluted in absolute 1ΈΤ, separated by filtration and dried under vacuum at 70 ° to obtain the title compound as a slightly dirty white solid product (650 mg) PF 212- 213 ° (dec.) Analysis - Found: C, 59.1; H, 5.9; N, 6.6 20 (C18H22N2 ° 5) 2C4H4 ° 4 Theor .: C, 59.4; H, 6.0; H, 6.9Â

Example 3 2- [2 - [[2- [3,5-bis (phenylmethoxy) phenyl] -2-hydroxyethyl] (phenylmethyl) amino] ethoxy] benzene-acetamide A stirred solution Intermediate 10 (0.1 g) in 25 t-butanol (2 ml) was treated with finely pulverized potassium hydroxide (0.2 g) and the mixture a / / i / 44 / was stirred at reflux for 30 min. The mixture was diluted with saturated sodium chloride solution (15 ml) and extracted with EA (3x5 ml). The combined extracts were dried and evaporated under reduced pressure to obtain a pale yellow gum which was purified by FCC eluting with T-ET-A 79: 19: 2 to obtain the title compound under white powder form (20 mg) PF 120-121 °.

TLC (T-.ETtA 79: 20: 1) Rf 0.5.

Example 4 R (-) hemifumarate 2 - [2 - [[2- (3,5-dihydroxyphenyl) -2-hydroxyethyl] amino] ethoxy] benzene-acetamide (i) R (-) g- (bromomethyl) - 3,5-bis (phenylmethoxy) benzene methanol A solution of 1- [3,5-bis (phenylmethoxy) phenyl] -2-bromo-ethanone (8 g) in THF (6 ml) was added to borane "alpine" freshly prepared (from 9-BBN (4.9 g) and (+) -rc-pinene (7 ml)) at 60 ° under a stream of nitrogen. The solution was stirred overnight, then left to stand at room temperature over the weekend. Acetaldehyde (4 ml) was added and the solvent was evaporated. The residue was dissolved in the ER (50 ml) and ethanolamine (2.6 ml) was added. The mixture was stirred at 0 ° for 15 min and the solid product was separated by filtration. The filtrate was washed with brine, dried and evaporated to leave a pale yellow gum (10 g). This was purified by FCC eluting with T, crystallized from ER and recrystallized from ER-H to obtain the title compound as colorless needles (3.4 g) mp 81 °.

45 (ii) R (-) [3,5-bis (phenylmethoxy) phenyl] oxirane A mixture of the product of step (i) (3.3 g), potassium carbonate (1.5 g), ME (40 ml) and water (30 ml) was stirred and heated to reflux for 1 h. The ME was evaporated and the residue was extracted with the ER (2x40 ml).

The extracts were washed with brine, dried and evaporated to leave the title compound as a colorless gum (2.6 g).

(i i i) R (-) 2- [2 [[2- [3,5-bis (phenylmethoxy) phenyl] -2-hydroxy-1 o ethyl] (phenylmethyl) amino] ethoxy] benzene-acetamide

A solution of the product of step (ii) (2.5 g) and of intermediate 4 (1.8 g) in ME (40 ml) was heated at reflux overnight. Additional intermediate 4 (0.4 g) was added and the solution was heated at reflux for 24 h. The solvent was removed and the residue was triturated with a mixture of ER and EA to obtain a white solid product (1.9 g). The filtrate was evaporated and the residue was purified by FCC eluting with ER to obtain a colorless gum which was tri-filtered with ER to obtain a white solid product (1.0g). The above fractions were combined with 450 mg of the white solid product prepared in the same way in a separate experiment and recrystallized from EA-ER to give colorless crystals (3.0 g) m.p. 94-95 °.

/ -, 4é (iv) R (-) hemifumarate 2- [2 - [[2- (3,5-dihydroxyphenyl) - 2-hydroxyethyl] amino] ethoxy] benzene-acetamide 4 A suspension of the product of step (ii) (2.9 g) in TE (70 ml) s was hydrogenated on Pd-C at 10¾ (0.3 g) i 5 during 16 h. The catalyst and the solvent were removed to obtain the free base of the title compound as a white solid product (1.6 g). The free base was dissolved in hot TE (20 ml) and treated with a solution of fumaric acid (270 mg) in hot ET 10 (10 ml). An oil separated on cooling and the mixture was evaporated to dryness to leave a white glass. This was dissolved in ME (15 ml) and the solution was seeded to obtain the title compound as colorless microcrystals (1.3 g) 15 m.p. 199-200 °

Analysis Found: C, 59.3; H, 6.0; N, 6.8 tC18H22N2 ° 5 ^ 2C4H404 Theor .: C, 59.4; H, 6.0; N, 6.9¾

Example 5 S (+) 2- [2 - [[2- (3,5-dihydroxyphenyl) -2-hydroxyethyl] amino] ethoxy] benzene-acetamide (i) 5 (+) g- (bromomethyl) -3, 5-bis (phenylmethoxy) benzene methanol

A solution of 1- [3,5-bis (phenylmethoxy) phenyl] -2-bromo-ethanone (20 g) in dry tetrahydrofuran (15 ml) was added to freshly prepared "alpine" borane [from 9-BBN (12.25 g) and (-) - a-pinene (17.5 ml) and heated at 65 ° for 5 h under nitrogen. The mixture was stirred at 60 ° overnight under a stream of nitrogen and the solution was cooled in an ice bath.

L · - 47 Acetaldehyde (10 ml) was added and the solution was stirred at 20 ° for 0.5 h and evaporated in vacuo. The residue was dissolved in the ER (125 ml) and ethanolamine (6.5 ml) was added. The mixture was stirred at 0 ° for 0.25 hr and the resulting solid product was removed by filtration. The filtrate was washed with brine (100 ml), dried and evaporated to leave a semi-solid product of pale yellow color. Purification by FCC eluting with T and double recrystallization from ER 10 gave the title compound as fluffy crystals (1.77 q) m.p. 78-80 °.

(ii) S (-r) [3,5-bis (phenylmethoxy) phenyl] oxirane A mixture of the product of step (i) (1.77 g), potassium carbonate (805 mg) in ME ( 21 ml) and the water (16 ml) was heated to reflux with stirring for 1 h. The mixture was allowed to cool and the solvent was evaporated. The residue was extracted with the ER (3 x 25 ml).

The combined extracts were dried and evaporated to leave the title compound as a limpid oil (1.39 g).

Analysis Found: C, 79.56; H, 6.26 C22H20 ° 3 Theor .: C, 79.49; H, 6.06? Ô (iii) S (+) 2- [2 - [[2- [3,5-bis (phenylmethoxy) phenyl] -2-hydroxyethyl] (phenylmethyl) amino] ethoxy] benzene- acetamide A mixture of the product from step (ii) (1.32 g) and intermediate 4 (1.16 g) in ME (30 ml) was heated at reflux for 24 h under nitrogen. The solution was concentrated in vacuo and the residue was purified by FCC eluting with ER to obtain the title compound 30 as a white crystalline solid (1.2 g) P.F.

96-96.5 °.

48 (iv) S (+) 2- [2 - [[2- (3,5-dihydroxyphenyl) -2-hydroxyethylj. amino] ethoxy] benzene-acetaniide

A solution of the product of step (iii} (1.2 g) in ethanol (50 ml) was hydrogenated on the catalyst - 5 Cd-P at 10% (120 mg) until the stopping of absorption of hydrogen (139 ml). The catalyst was removed by filtration on hyflo and the filtrate was evaporated under vacuum, leaving a pale yellow oil which was triturated with ER (20 ml) to obtain the compound of the title as a white crystalline solid product (580 mg) PF 154-5 °.

Analysis Found: C, 61.84; H, 6.33; N, 7.88 C1oH.J „0c.0,2EtOH Theor .: C, 62.16; H, 6.53; N, 7.88%.

I o LL L j

Example 6 2- 2- [2 - [[2- (3,5-dihydroxyphenyl) -2-hydroxyethyl] amino] ethoxy] benzene-acetamide

A suspension of 2- [2 - [[2- [3,5-bis (phenylmethoxy) phenyl] -2-hydroxyethyl1 (phenylmethyl) amino] ethoxy] benzene-acetamide (18.2 g) in ET ( 150 ml) was hydrogenated on 20 Pd-C at 10% (1.8 g). After stopping the absorption of hydrogen, the mixture was diluted with ME to redissolve the precipitated product and the resulting mixture was filtered. A colorless solid product crystallized from the filtrate after abandonment. The solid product was separated by filtration and dried to obtain the title compound as a crystalline solid product (4.2 g) m.p. 106-7 °.

Analysis Found: 'C, 61.5; H, 7.3; N, 7.0 C18H22N2 ° 5‘C2H50H Theor *: c> 61> 2; H, 7.2; N, 7.1% i ^ ___ 49

Example 7 2- [2 - [[2- [3,5-bis (phenylmethoxy) phenyl] -2-hydroxyethyl3 aminolethoxyjbenzene-acetamide c · - ^ A solution of intermediate 3 (2.58 g) in dry DMF ' (10 ml) was added over 10 minutes with stirring to a solution of intermediate 7 (5.24 g) and N, N-diisopropyl-ethylamine (3.88 g) in dry DMF (40 ml) at 90 ° under nitrogen. Stirring was continued for 1 h, then the 1 q solution was evaporated on sand and purified by FCC eluting with MC-ET-A (130: 8: 1) to obtain the title compound in the form white solid product (3.37 PF 105.5-107 °.

Analysis Found: C, 71.7; H, 6.3; N, 5.1 15 C32H34N2 ° 5 * 0.3H2 ° Theor .: C, 72.2; H, 6.6; N, 5.3¾

Example 8 2- [2 - [[2- [3,5-bis (phenylmethoxy) phenyl] -2-hydroxyethyl3 aminijethoxyjbenzene-acetamide

A solution of intermediate 6 (0.95 g) in ET (15 ml) was added slowly to a solution of 3,5- [bis (phenyl-methoxy) -l-oxo-benzene-acetaldehyde ( 1.7 g) in TE (15 ml) and the mixture was heated at reflux for 2 h. To the cooled solution sodium borohydride (0.37) was added and the mixture was stirred for 18 h. ME (25 ml) was added and the solution was heated at 40 ° C for 10 min. The solvent was evaporated and the residue was purified by short path chromatography on silica gel (Merck 7747) eluting with MC-ET-A (200: 8: 1) to obtain the title compound 30 (10 mg) which was identical to the product of Example 7.

50

Example 9 (i) 2- [2 - [[2- [3,5-bis (phenylmethoxy, phenyl] -2-hydroxy-ethyl] (phenylroethyl) amino] ethoxy] -Ni-ethylbenzene-acetamide 5 Pivaloyl chloride (0.57 g) was added to a solution of Intermediate 15 and triethvlamine (4.26 g) in dry THF (50 ml) and stirred under nitrogen at 0 °, After 5 min of ethylamine hydrochloride (0 , 66 g) was added, the reaction flask was sealed and the solution was stirred at room temperature for 16 h. The solution was evaporated, then partitioned between the water phase (80 ml) and the EA phase ( 3x80 ml) The organic portions were pooled, dried and evaporated to give an orange oil Purification by FCC eluting with ER gave the title compound as a colorless gum (0.58 g). (EA) Rf 0.53.

(ii) 2- [2 - [[2- (3,5-dihydroxyphenyl) -2-hydroxyethyl] amino] ethoxy] N-ethylbenzene-acetamide hemifumarate A solution of the product of step (i) (0.56 g) in the TE (40 ml) was hydrogenated on the dry Pd-C catalyst at 10% (0.10 g) until the absorption of hydrogen was stopped (63.0 ml). The catalyst was removed by filtration on hyflo and washed with hot ME (50 ml). The / b 51 filtrate was treated with a solution of fumaric acid (0.05 g) in ME (5 ml) and evaporated to give a colorless gum. This residue was triturated under ER (20 ml) for 4 h and separated by filtration to obtain the title compound as a solid, cream-colored product (0.30 g). TLC (MC-ET-A 25: 8: 1) Rf 0.31. Analysis Found: C, 59.4; H, 6.9; N, 5.5

(C20H26N2 ° 5) 2C4H4 ° 4 * 0.8H20 + 1.8C2H50H

Theor .: C, 59.4; H, 7.2; N, 5.8¾.

10 Example 10

Phosphate, 2- [2 [[2- (3,5-dihydroxypheny1) - 2-hydroxyethyl] aminojethoxy] benzene acetamide hemihydrate 2- [2 - [[2- (3,5-dihydroxyphenyl)) hemifumarate 2-hydroxy-ethyljaminojethoxy] benzene-acetamide (16.1 g) was suspended in water (40 ml), treated with 85% phosphoric acid (2.64 ml) and heated to 60 ° to obtain a solution. The solution was stirred and cooled to 0 ° for 1 h. The fumaric acid was separated by filtration and the filtrate was evaporated in vacuo to a total volume of 30 ml. After heating to dissolve the solid product, 1ΈΤ (20 ml) was added and the solution was stirred and cooled to 0 °. The crystalline solid product was separated by filtration, washed with ET (20 ml) and dried at 50 ° under vacuum to obtain the title compound (16.8 g) m.p. 138-40 °.

ANalysis Found: C, 47.8; H, 6.15; N, 5.85; P, 6.4

C18H22N2 ° 5'H3P04'0’5H2Q + 0’4C2H50H

Theor .: C, 4 8.1; H, 6.1; N, 5.9; P, 6.5 S5 j 52

Example 11 (1) 2- [2- [5- [3,5-bis (phenylmethoxy) phenyl3-2-oxo-3-oxazolidinyl] ethoxy] benzene-3 ketamide

A solution of 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] benzene-acetamide (1.0 g) in dry THF (7 ml) at 50 ° under nitrogen. The stirring was continued for 18 h and the solution was evaporated. The residue 10 was dissolved in EA (50 ml), washed with water (2x25 ml), brine (25 ml), dried and evaporated to give a white sclid product. Purification by FCC eluting with MC-ET-A first (150: 8: 1) then (100: 8: 1) gave the title compound as a white solid (0.30 g ) Mp 145-146 °.

(ii) 2- [2 - [[2- [3,5-bis (phenylmethoxy) phenyl] -2-hydroxy-ethyl3amino] ethoxy] benzfene-acetamide

A suspension of the product from step (i) (40 mg) in a solution of 2 N sodium hydroxide (0.8 ml) and ET 20 (1.6 ml) was stirred at 60 ° for 8 h. The TE was evaporated and the remaining solution was extracted with EA (3x5 ml). The organic portions were combined, dried and evaporated to give a white solid product.

Purification by FCC eluting with MC-ET-A (100: 8: 1) gave the title compound as a white solid product (5 mg) which was identical to the product of Example 7.

/ ^ __ L. 53

Example 12 2- [2 [[2- (3,5-dihydroxyphenyl) -2-hydroxyethyl] amino] ethoxyl-N-propylbenzene-acetamide (i) 2- [2 - [[2- [3 ', 5-bis (phenylmethoxy) phenylj-2-hydroxy- ^ 5 ethyl] (phenylmethyl) ethoxy] -N'-propylbenzene-acetamide

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-propyl-amine (0.316 g) was added and the reaction mixture was stirred at room temperature for 21 h. 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 obtain the title compound in the form of a colorless oil (1.3 g). TLC (EA-PE) 1: 1 Rf 0.25.

(ii) 2- [2 - [[2- (3,5-dihydroxyphenyl) -2-hydroxyethyljamino] ethoxy] -N-propylbenzene-acetamide

A solution of the product of step (i) (1.24 g) in * 20 absolute TE (50 ml) was hydrogenated on Pd-C at 10¾ (400 mg). The catalyst was removed by filtration on hyflo and the ethanolic filtrates were evaporated. The residue was purified by short path column chromatography on silica gel (Merck 7747) eluting with EA-25 Isopropanol 7: 3 to obtain the title compound as white foam (187 mg). TLC (EA-isopropanol) 7: 3) RF 0.35.

6 (D „Methanol) 0.88 (3H, t, 1.51 {2H, m, CHjÇHjCHg), 2.75-2.90 (2H, AB particABX, CH (0H) ÇH2N), 3.13 30 (2H, t, CH2CH2CH3), 3.22 (2H , m, NHCH2CH2), 3.48 (2H, s,

ArCH2C0), 4.11 (2H, t, NHCH ^ jO), 4.67 (2H, dd, NHCHqCHQH), 6.1-7.3 (7H, m, aromatiuvia).

/ ___ i> 54

Example 13 2- [2 - [[2- [3,5- (dihydroxy) phenyl] -2-hydroxyethyl] amino] ethoxy] benzene-propanamide g mm - - '"——

A solution of 2-hydroxybenzene-propenoic acid 1-5 (16.42 g) and sulfuric acid (18 M; 0.1 ml) in ME (100 ml) was heated at reflux for 70 h, cooled and filtered to obtain a light brown solid product (10.9 g). The filtrate was evaporated, the residue was distributed between the dichloromethane phase 10 (2x50 ml) and the aqueous sodium bicarbonate phase (1 M; 50 ml) and the insoluble substance (4.7 g) was collected. The organic phase was dried and evaporated leaving a solid product of light brown color (2.90 g). The three batches of product were combined to obtain the title compound with a total yield of 18.5 g. Mp 133-137 °.

(ii) Methyl-2- (2-bromoethoxy) benzene-propenoate A mixture of the product of step (i) (10.69 g), potassium carbonate (9.66 g) and tris [2- ( 2-methoxyethoxy) * 20 ethyl] amine (1 g) in dibrcmo-ethane (100 ml) was refluxed for 72 h, filtered, evaporated, dissolved in T, filtered through silica gel (Merck 9385) and evaporated leaving the title compound as a white solid product (13.22 g) PF 57-59 °.

55 (iii) Methyl-2- [2 - [[2- (3,5-dihydroxyphenyl) -2-hydroxy-t ethyl3amino] ethoxy] benzene propenoate

A solution of a- (aminomethyl) -3,5-dihydroxybenzene-methanol (3.5 g)> sodium iodide (3.0 g) and diisopropylethylamine (3.5 ml) in the DMF (80 ml) at 80 ° was treated with a solution of the product of step (ii) (5.7 g) in DMF (20 ml) for 1 h, and evaporated.

The resulting gum was adsorbed on sand and purified twice by chromatography on silica gel (Merck 10 9385) to obtain the title compound as a crumbly solid product of a slightly dirty white (1.45 g) . TLC (T-ET-A 79: 20: 1) Rf 0.13.

(iv) Methyl-2- [2 - [[2- [3,5- (dihydroxy) phenyl] -2-hydroxy-ethyl] amino3ethoxy3benzene-propanoate A mixture of the product of step (iii) (2,2 g) and

PdO-C at 10? 6 (0.5 g) in absolute TE (50 ml) was hydrogenated until the end of absorption. The catalyst was removed by filtration and the filtrate was evaporated under; reduced pressure. The residue was purified by FCC by d * 20 eluting with the dichloromethane-ET-A mixture (100: 8: 1) | to obtain the title compound as a light brown oil (1.6 g, '. TLC dichloromethane-ET-A | (100: 8: 1) Rf 0.35.

j / (56 (v) 2- [2 - [[2- [3,5- (dixhydroxy) phenyl] -2-hydroxyethyl] aminojethoxy1benzene-propanamide

A mixture of the product from step (iv) (1.5 g), ME (30 ml) and liquid ammonia (20 ml) was heated * 5 at 80 ° in an autoclave (50 ml) for 16 h). The solution was evaporated under reduced pressure and the residue was purified by FCC, eluting with a dichloromethane-ET-A mixture (50: 8: 1) to obtain the title compound in the form of a fawn-colored foam (0 , 4 g). TLC dichloro-10 methane-ET-A (50: 8: 1) Rf 0.15.

Analysis Found: C, 60.1; H, 6.9; N, 7.2 Ε19Η24Ν2 ° 5 · 0.75Η20 · ° ’5Ε1: 0Η

Theor .: C, 60, ^ 5; H, 7.2; N, 7.1¾

Example 14 15 2- [2 - [[3,5-dihydroxyphenyl] -2-hydroxyethyl] amino] ethoxy] -N-methylbenzene-acetamide (i) 2- [2 - [[2- [3,5-bis ( phenyltnethoxy) phenyl3-2-hydroxyethyl] (phenylmethyl) amino] ethoxy] -N-methylbenzene-acetamide 20 A mixture of intermediate 5 (1.5 g), ET (20 ml) and ethanolic methylamine at 33 ? ô (20 ml) was heated at 95 ° in an autoclave for 16 h. The solvent was evaporated leaving a gum (1.5 g) which was purified by FCC eluting with the ER to obtain the title compound 11 as a colorless gum (1.1 g).

57 (ii) 2- [2 - [[3,5- (dihydroxyphen}} 1 i-2-hydroxyçthyl] amino] v ethoxy] -N-methylbenzene-acetamide

A solution of the product of step (i) (1.0 g) in absolute TE (70 ml) was hydrogenated on Pd-C at 10¾ (300 mg).

♦ 5 The catalyst was removed by filtration and the filtrate was evaporated. The residue was purified by FCC eluting with EA-ME (8: 2) to obtain the title compound as a slightly dirty white solid product (387 mg). M.p. 82-85 °.

Analysis Found: C, 61.9; H, 6.2; N, 7.7 C19H24N2 ° 5.0.5H2 ° Theor .: C, 61.8; H, 6.8; N, 7.6%

The following are examples of suitable formulations of compounds of the invention. The term "active constituent" is used herein to denote a compound of the invention and it can be, for example, the compound 2- [2 - [[2- (3,5-dihydroxyphenyl) -2-hydroxyethyl] amino ] ethoxv] benzene-acetamide.

w

Example A - Tablets - Direct Compression mg / Tablet

Active ingredient 50.0 20 Microcrystalline cellulose B.P.C. 149.0

Magnesium stearate 1.0 200.0

The active ingredient is sieved through a 250 ju sieve, mixed with the excipients and compressed using 8.5 mm cookie cutters. Tablets with other concentrations can be prepared by varying the compression weight and using suitable cookie cutters.

58

Example B - Tablets - Wet granulation mg / tablet, Active ingredient 50.0

LactoseB.P. 119.0 * B.P. starch 20.0 5 B.P. pregelatinized corn starch 10.0

Magnesium stearate B.P. 1.0

Compression weight 200.0

The active component is sieved through a 250 ju sieve and mixed with lactose, starch, tinized pregela-10 starch. The mixed powders are moistened with purified water, the granules are prepared, dried, sieved and mixed with the magnesium stearate. The lubricated granules are compressed into tablets as described in Example A.

The tablets can be coated with a film with suitable film-forming substances, for example methylcellulose or hydroxypropylmethylcellulose using standard techniques. Or, the tablets can be coated or kera-20 tinized / 5 59

Example C - mg / capsule capsules

Active ingredient 50.0 * Starch 1500 149.0 * 5 Magnesium stearate B.P. 1.0

Filling weight 200.0 * Form of starch which can be compressed: directly, supplied by Colorcon Ltd, Orpington, Kent; R.U.

The active ingredient is sieved through a 250 u% 10 sieve and mixed with the other substances. The mixture is loaded into No. 1 hard gelatin capsules using a suitable filling device. Other doses can be prepared by changing the filling weight and, if necessary, changing the size of the capsules.

15 Example D - Sucrose syrup mg / 5 ml dose

Active ingredient 50.0

Sucrose B.P. 2750.0

Glycerin B.P. 500.0

Tampon) 20 Aroma) as required

Dye)

Conservative )

Purified water B.P. q.s.p. 5.0 ml

The active ingredient, the buffer, the flavor, the color and the preservative are dissolved in a certain amount of water and glycerin is added. The rest of the water is heated to dissolve the sucrose, then cooled. The two solutions are combined, brought to the desired volume and mixed. The syrup obtained is clarified by filtration.

60> · Example E - Syrup without sucrose mg / 5 ml dose 5 Active constituent 50.0

Hydroxypropyl-methyl 1 cellulose USP

(viscosity type 4000} 22.5 fhg

Buffer )

Flavor) 10 Color) as required

Conservative )

Sweetener)

Purified water B.P. q.s.p. 5.0 ml The hydroxypropyl methylcellulose is dispersed in hot water, cooled, then mixed with an aqueous solution containing the active ingredient and the other ingredients of the formulation. The solution obtained is brought to the desired volume and mixed. The syrup obtained is clarified by filtration.

20 Example F - Suppositories

Active ingredient 50.0 mg * Witepsol H15 q.s.p. 1.0 g * Specialty of Adeps Solidus Ph.Eur.

A suspension of the active ingredient in Witepsol H15 25 is prepared and loaded using a suitable apparatus into 1 g suppository molds.

61? Example G - Injection for intravenous administration

- »/ Dp / V

t Active ingredient 1.00

Water for B.P. q.s.p. 100.0

Sodium chloride can be added to adjust the tone of the solution and the pH can be adjusted to that of maximum stability and / or to facilitate the solution of the active ingredient using a dilute acid or alkali or by addition of salts adequate pads.

Antioxidants and metal chelating salts may also be included.

The solution is prepared, clarified and packaged in appropriately sized vials sealed by melting glass. The solution for injection is sterilized by heating in an autoclave using one of the acceptable cycles.

Alternatively, the solution can be sterilized by filtration and packaged in sterile ampoules under aseptic conditions. The solution can be packaged under an inert nitrogen atmosphere.

/ / 62

Example 15: 2- [2 - [[2- (3,5-dihydroxyphenyl) -2-hydroxyethyl] aminoj, ς, ethoxy] ben2ene-acetamide κ, A solution of 2 - * - [2 - [[2- [ 3,5-bis (phenylmethoxy) -phen \ l] - '5 2-hydroxyethyl] amino] ethoxy] benzene-acetamide (0.6 g) in 1ΈΤ (20 ml) was hydrogenated on 10% Pd-C ( 0.06 g) until the absorption of hydrogen is stopped (58 ml). The catalyst was separated by filtration on hyflo and washed with ET (20 ml). The volume of ET was reduced 10 to 10 ml under reduced pressure and the title compound crystallized as a white solid (0.23 g) m.p. 105-107 °. The product was identical to the sample prepared in Example 6.

v

Claims (14)

63 V · * 1. Compounds of general formula (I) HO · OH J \ \ // \ I II I | g — CHCH2NHCH2CH20— · • · · w /, I | (CH2) nCONHR OH (I) where R represents a hydrogen atom or a straight chain alkyl group -j and n represents 1 or 2, and their physiologically acceptable acid addition salts, their solvates and their metabolically labile esters. 2. Compounds according to claim 1, in which n is 1. 3. Compounds according to claim 1 or 2, in which 10. represents a hydrogen atom. 4. (3,5-Dihydroxyphenyl) -2-hydroxyethyl7 amino7 "ethoxy7benzene-acetamide and its physiologically acceptable acid addition salts. 5. Compounds according to claim 1, in which R 15 represents a hydrogen atom, a methyl group or an ethyl group and n is 1 or 2. / - J 64 6. A process for the preparation of compounds of formula: * general (I) according to one of claims 1 to 5, which '£ comprises (1) an alkylation reaction between a compound of formula (II) 4 Ok' R ^ O / v! H u \ ^ \ _ CHCH-NA (II) U OR3 where -NA represents a group -NHR ^, -NR ^ ChLCH „X. 5. L R9 -N ^ jf or N ^ J "R2, R ^, R ^ and R ^ each represent a hydrogen atom or a protecting group and X is an easily displaceable atom or group,, and a compound of formula (III) I (III) Yo 'y' (CH0) CONRR1 - δ n î where R and n are as defined in formula (I), R is a hydrogen atom or a protecting group and Y represents a hydrogen when -NA represents 15 r5 -NR5CH2CH2X, -N ^ J or, or Y represents the group ChLCtLX where X is an atom or a group which can be easily displaced - LL 5 mentally displaced when -NA represents -NHR , followed, if necessary, by the elimination of all the protective groups which are present; or 65 tT ♦, (2) reaction of a compound of formula (VIII) * R20 R6 (VIII) V r3o 2 3 where R and R are as defined in process 5 (d) (R) ^ represents a group ^ "0 \? r4 _CH-ch2 or -CHCH2X 4 where R and X are as defined in process (1), with an amine of formula (IX) 5 J! (IX) R NHCH.CH.-0 Δ ά J (CH_) CONRR1 δ n 10 where R and n are as defined in formula 1 5 (I) and R and R are as defined higher in the process (1), followed, if necessary, by the removal of all the protecting groups which are present; or c. (3) reaction of a compound of formula (X) r2 ° yér ^ r-R? Lj (X)? 4 0RJ OR / *> 66 * where represents the group -C0CH0 or -CHChLNHR ^ and R ^, 3 4 5 L - 0 R, R and R are as defined above S in the process (1), with a compound of formula (XI) 1 (XI) ZCH20 (CH ^ CONRR1 or4 where Z represents the group CHO when R ^ is -CHCH „NHR ^ 5. L or Z represents the group CH ^ NHR when R is -CQCHO and R and n are as defined in formula (I) and R ^ and R ^ are as defined above I® in the process (1), in the presence of a reducing agent, followed, if necessary, by the removal of all the protective groups which are present; or (4) reduction of a compound of formula (XIV) X: r2o? f 15. CC ^ NC ^ C ^ -O ^^ J (XIV) (CH0) CONRR1 o 1 δ n RJ0 C where R and n are as defined in formula 12 3 3 (I) and R, R , R and R are as defined above in process (1), followed, if necessary, by the removal of all protecting groups which are present; or / * J 67 (5) amination of a compound of formula (XV) K * 2 or4 rD R20v / \ '' (XV) (CH2) nR8 5 R30 2 where n is as defined in formula (1), R, 3 4 5 R, R and R are as defined above in process (1) and R represents a group d carboxylic acid or its salt or reactive derivative thereof, with an amine RNh ^ where R is as defined in formula (I), followed, if necessary, by the removal of all protecting groups which are present ; or (6) for the production of compounds of formula (I) UMfc in which R is hydrogen, hydrolysis of a compound * of formula (XVI) 2? R4? 5 Γ "r20 (XVI) (.CH2> nCBN r3o n 20 where n is as defined in formula (I) and R, R, R4 and R? are as defined above in process (1), followed, if necessary, by elimination of all the protective groups which are present; or s “l '·' t 68 ς 1 (7) removal of the protections of a compound of l / formula (XVII) R2n ^ or4 R5 r ^ l R 0 '' I (XVII)> CHCH2n-ch2ch2- ° \ ^ 5 (CH2) nCONRR1 R30 where R and h are as defined in formula (I) and R1, R2, R "5, R4 and R ^ are such that they are defined above in process (1), provided that at least one of R, R, R, R or R5 represents a protective group; and optionally transformation of the compound of formula (I) or its salt to a physiologically acceptable acid addition salt, a solvate or a 1 5 metabolically labile ester. > „7. Pharmaceutical composition comprising a compound l this general formula (ï) or a physiologically acceptable acid addition salt, a solvate or a metabolically labile ester of this compound, together with at least one carrier or physiologically acceptable excipient. 8. Compounds of general formula (XV) J 2 0r4 r5 / yv \ K o v .χν. 1 'I (χν) Nj ^ CHCH2N-CH2CH2-0-kN ^ J 25 (CH2) nR8 r3o 69 2 3 4 5 where n is 1 or 2, R, R, R and R each represents a Q hydrogen atom or a protecting group and R represents a carboxylic group, or a salt or a C 1 -C 4 alkyl ester; of these .composites. * 9. Compounds according to claim 8, in which 2 3 4 5 n is 1 or 2, R, R, R and R each represents a hydrogen atom and R represents a carboxylic group, or an alkyl ester in C1 to C3 of these compounds. 10. 2- / 2 - / ^ 2- (3,5-Dihydroxyphenyl) -2-hydroxy-10 ethyl7amino7 “ethoxy7benzene acetic acid. 1 "v *