CH667870A5 - PHENETHANOLAMINE DERIVATIVES, METHODS OF PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM. - Google Patents

Description

DESCRIPTION

The present invention relates to phenethanolamine derivatives having cardiotonic and vasodilatory activity, processes for their manufacture and pharmaceutical compositions containing them.

Heart failure is characterized by the inability of the heart 50 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 leading to an increase in heart rate and contractile force and an increase in vascular resistance. The increased resistance 55 further 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).

Treatment for 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, i.e. they improve its pumping action. However, these cardiotonic agents have the drawback of being toxic. The disadvantage of other agents, including dopamine and dobut-amine, is that, like isoprenaline, adrenaline and norepinephrine, they have a short duration of action and are inactive after

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oral administration or cause unwanted side effects.

More recently, it has been established that the use of 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 treatment of heart failure. However, a common side effect of vasodilators such as nitroprusside and hydralazine is to cause side 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 they both have similar pharmacokinetic profiles so that both are active during the same periods. It 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 the amino group are known. A number of activities have been attributed to these compounds, for example blocking of the P-adrenergic receptors, vasodilation, bronchodilation 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 with a particular association 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):

/ \\

HO • OH.

\ // \ I II I

î il CHCH 2NHCH 2CH 2 ° ° \ // 'W

• • •

W /, I,

• (CH2) nC0NHR

OH

where R represents a hydrogen atom or a straight chain alkyl group CH and n represents 1 or 2, their physiologically acceptable acid addition salts and their solvates.

It will be noted that the compounds according to the invention have an asymmetric carbon atom, namely the group - CH (OH) - and that 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. Here are examples of such salts: hydrochlorides, hydrobromides, sulfates, phosphates, benzoa-tes, p-toluenesulfonates, methanesulfonates, sulfamates, ascorbates, tartrates, citrates, maleates, salicylates, fumarates, succinates, lactates, glutarates, glutaconates, acetates or tricarballylates. Preferred acid addition salts are 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 of general formula (I). Examples of such esters include lower alkanoates, such as acetates or pivaloates. Also within the scope of the invention are solvates, in particular hydrates, of compounds of general formula (I).

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 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 and dobutamine in that they have a longer duration of action and, moreover, that they are absorbed at 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 a! vessels and stimulate the heart's adrenergic receptors. The compounds show no signs of toxicity at the maximum doses tested.

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

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.

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

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

Consequently, 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 patient. 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. This is why also 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 potato starch or sodium amyloglycolate; or wetting agents such as sodium lauryl sulfate. The tablets can be coated in accordance with methods well known in the art. Oral liquid preparations can be, for example, in the form of suspensions, solu

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tions, aqueous or oily emulsions, syrups or elixirs, or r! g. g p U

they can be presented as a dry product for recons- \ // \ T

titution with water or other suitable vehicle before use. f dd-CHCHjNA

These liquid preparations may contain traditional additives • • (H)

such as suspending agents, for example sorbitol, syrup, methane

thylcellulose, glucose / sugar syrup, gelatin, hydroxyethylcellulose, I,

carboxymethylcellulose, aluminum stearate gel or hydrogenated edible fats; emulsifiers, for example lecithin, mo-

sorbitan no-oleate or gum arabic; vehicles not where —NA represents a group —NHR5, —NR5CH2CH2X, - N ^ 1 aqueous (which may include edible oils), for example 10

almond oil, fractionated coconut oil, oily esters, propylene- R5

glycol or ethyl alcohol; and preservatives, for example p- or _

methyl or propyl hydroxybenzoate, or sorbic acid. The 4.NI

compounds or their salts or esters can also be formulated in the form of suppositories, i.e. containing traditional bases R2, R3, R4 and R5 are each a hydrogen atom or a group for suppositories, such as butter cocoa or other glycerides. protector and X is an atom or group that can be easily

For oral administration, the composition can take the displaced,

form of tablets or lozenges formulated in the traditional way * a compound of formula (III):

tional. "

The compounds of formula (I) and their addition salts of physical acids

siologically acceptable and their metabolically labile esters | ||

may also be formulated for parenteral administration by injection or continuous infusion. Preparations for injection Y0 •

can be presented as single doses in ampoules or ^ CONRR *

in multi-dose containers with the addition of a preservative. The preparations can take forms such as suspension,. , „

sions, solutions or emulsions in oily or aqueous vehicles, where R and "are not as defined in the formula ®> R is an. r," xj. jp 1, j hydrogen atom or a protecting group and Y represents one and they may contain formulating agents, such as,

suspending, stabilizing and / or dispersing agents. Or atom of Mrogene 1uand "NA still present, the active constituent can be in the form of powder for 30

constitution with a suitable vehicle, for example pyrogenic water, |

sterile, before use. - NR5CH2CH2X, - N ^ Jou N £ ^ J

For administration by inhalation, the compounds according to the invention

+

ton are advantageously provided in the form of an aerosol in a re- QÙ y represents CH2CH2X where X is as defined, precise under pressure with the use of an appropriate pulser, cediently when -NA represents -NHR5,

example dichlorodifluoromethane, trichlorofluoromethane, dichlo- followed by raimination of all protectors where they are pre-

rotetrafluoroethane, carbon gas or other suitable gas, or in the form of a nebulizer. In the case of a pressurized aerosol, the unit

Examples of X include a halogen atom such that a dosage can be determined by providing a valve for bremide or iodide, or a hydrocarbon group.

ver a quantity of os®e-bylsulfonyloxy such as methanesulfonyloxy or p-toluenesulfonyloxy.

Or, for "administration by inhalation, the compounds T v + u ,,,, .... C M ..,

. ,, * „. . , When X is bromo or chloro, the reaction can be iacintee by according to "invention can take the form of a composition of ,, ,,.,. T

* \,, 1 addition of an iodide, such as 1 sodium iodide.

dry powders, for example a mixture of powders of the compound and, r .. r,, ,,,,,,,

,, t,, t 1 „-i t In a particular embodiment of the process, the compounds of a suitable powder base such as lactose or 1 starch. La c i * »1 / T \ * ** 'n w

*, Ä,, .45 general formula (I) can be prepared by alkylation of a powder composition can be presented as a single dose, - c

. ^ \,, amine of formula (IV):

shut up, for example in capsules or cartridges, in particular gelatin, or blister packs from which R20 "0RlfR5

powder can be administered using an inhaler or insuff- \ H \ T I

flower. sq | || -chch2nh ^

When the compositions include dose units, • •

each unit will preferably contain 5 mg to 500 mg, so

advantageous when the compounds are intended to be administered I 3

orally 25 mg to 400 mg of active compound. The daily dose G "

as used for the treatment of adult man 55 with an alkylating agent of formula (V):

preferably lie within the limits of between 5 mg and 3 g, quite preferably between 25 mg and 1 g, which can be administered in 1 to 4 doses per day, for example, depending on the route of administration and the condition of the patient. I I

The compounds of formula (I) and their addition salts of phy- 60 / \ /

siologically acceptable and their metabolically labile esters X-CH2CH 2-0 d can be administered in combination with other therapeutic agents- (CH2) nC0NRR *

caniques.

The compounds of the invention can be prepared by certain procedures followed by the removal of all of the protecting groups in which there are a number of methods, as described below. 65 present, as described below.

According to a general process (1), the compounds of the reaction preferably carried out in the presence of a base general formula (I) can be prepared by an alkyla- reaction such as a bicarbonate or an alkali metal carbonate , by tion between a compound of formula (II): example sodium bicarbonate or potassium carbonate or a

// \

(V)

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amine, for example diisopropylethylamine or silver oxide, and in solution at any temperature within the limits of -20 ° to + 100 ° C. The suitable reaction solvents include ethers, for example dioxane or acetonitrile, substituted amides, 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):

/ \\

l] f

.A // '(VI)

HO

!

(CH2) nC0NRR:

with an alkylating agent of formula (VII):

r \ / "w r f.

U J-CHCH2NCH2CH2X • •

\ //

(VII)

R 30

followed by removal of all protecting groups where they are present, as described below.

Or, the compounds of formula (VII) can be in the form of an aziridine:

R \ A r ^

H 1-CHCH2NvJ * \ // *

R 30

or an aziridinium salt: R20

\ / W

1 î \ // *

OR 4 I

-CHCH

<1

R30

\ //

R 30

where R2 and R3 are as defined above in the general method (1) and R6 represents a group:

-THIS

'H, or

OR4 I

-chch2x in which R4 and X are as defined above in the general process (1)

with an amine of formula (IX):

AT

r5nhch2ch2-0

J \ //

I

(ix)

(CH2) nC0NRR1

where R, R1, R5 and n are as defined above in the general method (1),

followed by removal of all protecting groups where they are present, as described below.

This reaction can be carried out in the presence or in the absence of a solvent at a temperature of 0 to 150 ° C, 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.

When R6 represents a group:

30

or4 I

-CHCH2X,

the reaction can be carried out in the presence of a base such as sodium carbonate, potassium carbonate, sodium hydroxide or an organic base such as pyridine. 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, a compound of formula (X) can be reacted:

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 r-butoxide, organic bases such as diisopropylethylamine and basic ion exchange resins such as l 'Amberlite. Alternatively, the compound of formula (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, 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):

R20 • R6 \ / W /

R20 "R7 \ // \ /

W /

GOLD'

PO

50

where R7 represents the group - COCHO or OR4 -CHCH2NHR5

and R2, R3, R4 and R5 are as defined above in 55 the general method (1)

with a compound of formula (XI):

(VIII) 65

// \

© 9

I 11

AT /"

ZCH20 j.

(CH2) nC0NRR1

where Z represents the CHO group when R7 is

OR4 I

CHCH2NHR5

(XI)

7

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or Z represents the group CH2NHR5 when R7 is —COCHO and R, R1, R and n are as defined previously in the general process (1)

in the presence of a reducing agent, the reaction being followed by the elimination of all the protective groups in which 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) CH2NHR5, 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 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 reaction solvent. The catalyst can be fixed on a support, for example carbon, or else a homogeneous catalyst such as rhodium chloride tristriphenylphosphine can be used. The reduction can advantageously be carried out at any temperature between -20 ° and 100 ° C, preferably between 0 ° and 50 ° C.

The reaction can take place via the imine (XII):

R 0

y / \ - £ hch2n = chch2o-

OR1

/ W

(XII)

\ //, f

\ //

•

1,,

(CH2) nC0NRRxR7

R 30

where R, R1, R2, R3, R4 and n are as defined above in the general process (1)

and it is possible that we can isolate this intermediary. The reduction of the imine, using the conditions described above, followed, where necessary, by the elimination of all the protective groups, gives a compound of general formula (I).

In another embodiment of the general process (3), a compound of formula (X), in which R7 is COCHO, is reacted with a compound of formula (XI), in which Z is CH2NHRS, in the presence of a reducing agent . The suitable reducing agents are those described above in the first embodiment of the reducing alkylation process.

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

R20

• Q • •

\ / w n n i

<j j-CCH = NCH2CH20 -. ^ y »• •«

\ //

, î

r3O

(ch2) nc0nrr1

where R, R1, R2, R3 and n are as defined above in the general process (1)

and it is possible that we can isolate this intermediary. 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).

In accordance with another general process (4), the compounds of formula (I) can be prepared by reduction of a compound of formula (XIV):

r \ a \ il r {\

u | -cch2nch2ch20 • •

\ //

(XIV)

J

r 3o

(CH2) nC0NRR

R20.

(XIII)

where R, R1, R2, R3, R5 and n are as defined above io in the general method (1),

followed by removal of all protecting groups, where they are present, as described below. The reduction can be carried out using an alkali metal borohydride 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 coal. Stereoselective reduction can be achieved using an optically active borane, such as "Alpine" borane [9- [2,6,6-trimethylbicyclo (3.1.1) hept-3-yl] -9-borabicyclo (3.1 .1) nonane],

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.

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

j qr ** r5 j \

\ / W T I II I

], rC "CH2NCH2CH20-iN ^. ^

V7 (CH2) nR8

R30

Where R2, R3, R4, R5 and n are as defined in the general process (1) and R8 represents a carboxyl group or a salt or a reactive derivative thereof, for example a hydracid, in particular a chloride acid, an acid anhydride formed for example with an acid chloride, in particular pivaloyl chloride or chloro-40 formate, or an ester, in particular a C ^ alkyl ester,

followed by removal of all protecting groups, where they are present, as described below. Reactive derivatives can also be formed in situ by treatment of the acid or its salt with a condensing agent such as N, N'-dicyclohexylcarbodiimide 45 or N, N'-carbonyldiimidazole.

The amination will generally be carried out using an amine RNH2 where R is already defined in formula (I). The reaction is advantageously carried out in an organic solvent such as an alcohol, for example methanol or ethanol; an ether, for example tetrahydro-50 furan; an amide, for example N, N'-dimethylformamide; or a halogenated hydrocarbon, for example methylene chloride, optionally in the presence of a catalyst such as silica or rhodium trichloride, at a temperature of 0 to 150 ° C, for example, preferably from 50 ° to 100 ° C When ammonia is used for the reaction (ie when R represents hydrogen), it may be desirable to carry out the reaction under high pressure, preferably using water or an alcohol such than methanol or ethanol as a solvent.

The compounds of formula (XV), in which R8 is a carboxyl group, 60 and their salts and esters (for example the C1-5 alkyl esters) are interesting intermediates and constitute another characteristic of the invention.

An interesting class of compounds of formula (XV) is that of compounds in which R2, R3, R4 and R5 represent 65 hydrogen atoms.

A particularly interesting class of compounds of formula (XV) is that of compounds in which R2, R3, R4 and R5 are hydrogen atoms and R8 represents a carboxyl group or a

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Q.5 alkyl ester of the latter, for example a methyl or isopropyl ester.

The compounds of formula (XV), where R2, R3, R4 and R5 are hydrogen atoms and R8 represents a carboxyl group, are especially interesting, more particularly when n is equal to 1.

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):

OR4 R5 / \

, He II I

R 0 ^ / CHCH2NCH2CH20 - "^ •

(XVI)

• •

I II

• 9

W /

I

(CH2) nC = N

R 30

where R2, R3, R4, R5 and n are as defined above in the general method (1),

followed by removal 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, hydrochloric or sulfuric acid, or a base such as an alkali metal hydroxide, for example potassium hydroxide, at a temperature from 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 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):

\ // * \ 9 "<?

\ // \ I I II I

d dd-CHCHjNCHjCHjO-. •

(XVII)

• © *

W / î

t (CH2) nCCINRR1

R 30

where R, R1, R2, R3, R4, Rs and n are as defined above in the general method (1), or R4 and R5 together represent a protective group, provided that at least one of R1, R2, R3, R4 and R5 represents a protective group.

When R1, R2, R3, R4 or R5 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. McOmie (Plenum Press, 1973). Examples of suitable hydroxyl protecting groups represented by R2, R3 and R4 are alkyl groups such as r-butyl or methoxymethyl, aralkyl groups such as benzyl, diphenylmethyl or tri-phenylmethyl, heterocyclic groups such as tetrahydropy-rannyl and acyl groups such as acetyl. Examples of amino protecting groups represented by R5 are aralkyl groups such as benzyl, diphenylmethyl or triphenylmethyl and acyl groups such as dichloroacetyl. Examples of suitable amide protecting groups R1 are t-butoxycarbonyl and 2,2,2-trichloroethoxycarbonyl groups.

The protecting groups R1, R2, R3, R4 and / or R5 can be removed using conventional techniques to obtain a compound of formula (I). Thus, 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 groups R4 and R5 can represent a protective group as in a compound of formula (XVIII):

R20 • "

\ / \ / \\

î rcï — îh> 1 1 p ™

• w / - \ A-cw— • e ™ ”

• Y1

R30 (CH2) nC0NRR1

Where R, R1, R2, R3 and n are as defined above in the general process (1) and Y1 represents a carbonyl 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 transformed into

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, removing all other protecting groups present using the methods described above.

25 Or, the substituent on the amino group can act as a protective group for the hydroxyl group in the ethylene part as in a compound of formula (XIX):

R z0

30

\ / W

\ //

H 2

ci N-R5.

W / W

(XIX)

? CH. ®

30 CH, -0-i 'I

\ //

I

(CH2) nC0NRR1

where R, R1, R2, R3, R5 and n are as defined above 40 in the general method (1). The compound of formula (XIX) can be transformed into a compound of formula (I) by reduction using the reagents described above in the general process (3) and, where necessary, elimination of all the 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 Compounds, by 65 E.L. Eliei (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:

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take the forms (R) and (S) of organic carboxylic and sulfonic acids such as tartaric acid, di-p-toluoyltartri-que 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 in which one of the groups R1, R2, R3, R4 or R5 in the compounds of formula (XVII) represents a chiral protective group. R2, R3 or R4 may, for example, represent an optically active sugar residue such as a ß-D-glucopyranosidyl group. An example of a suitable optically active amino protecting group Rs is an α-methylbenzyl group. These optically active protecting groups can be removed, after separation of the enantiomers, using the methods described previously 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.

The compounds of formula (VIII) in which R6 represents a group:

-CH-

• hj can be prepared from the compound of formula (XX):

R2 ° \ / \ / C0CH2Xl

\ //

r4

where R2 and R3 are as defined above and X1 is a halogen atom by treatment with, for example, sodium borohydride, to form the halohydrin, followed by treatment with a base, such as carbonate potassium or sodium hydroxide. The reaction is advantageously carried out in a solvent such as dimethylform-amide, 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 R6 represents a group - CH (OR4) XH2X [where R4 and X are as defined above in the general process (1)], can be prepared from the corresponding epoxides by treatment with the appropriate reagent such as the hydrochloride or the / j-toluenesulfonic acid, followed by the introduction of a protective group, if desired.

The compounds of formula (X) in which R7 is COCHO can be prepared from compounds of formula (XXI):

R20 ^ ^ COCH (X *) 2

\ //

j r3o where R2, R3 and X1 are as defined above by reaction with an alkoxide, such as sodium methoxide, in methanol, followed by treatment with an acid such as hydrochloric acid.

The compounds of formula (XX) are known compounds. The compounds of formula (XXI) can be prepared by halogenation of a compound of formula (XXII):

R \ Awc0ch3

\ //

(XXII)

r3O

where R2 and R3 are as defined above using, for example, a halogen, such as chlorine, or an N-halo-succinimide, such as N-bromosuccinimide.

The compounds of formula (X) in which R7 is COCHO 15 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) 2o 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.

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

R5

HNCH2CH2X

(Where R5 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

(XX)

H,

where Rs is as defined above 40 using the conditions described in the general method (1).

Compounds of formula (IX) can be prepared from compounds of formula (V) by reaction with an amine of formula R5NH2 (where Rs is as defined above), according to the reaction conditions of the general process (1) . The compounds of formula (V) can be prepared from compounds of formula (VI) by reaction with a compound XCH2CH2X, 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 HCOCH2X (where X is as defined above) or, by in particular, a protected derivative of the latter, for example an acetal, such as a diethyl acetal.

Compounds of formula (XVI) can be prepared by reaction of a compound of formula (XX) with a nitrile of formula 55 (XXIII):

AT

(XXI) 60

RS.

I / \ //

HNCH2CH20 £

(XXIII)

ch2) ncsn where R5 and n are as defined above,

followed by treatment with a reducing agent such as sodium borohydride 65.

Compounds of formula (XV), where R8 is a carboxyl group or its salt or its ester, can be prepared by reaction of compounds of formula (XXIV):

667,870

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K • •

HNCH2CH20-ü ^ (XXIV)

(CH2) nR8

where R5, R8 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, by the removal of all protective groups, as previously described.

Compounds of formula (XV), where R8 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 above. The 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, 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 methanol.

Compounds of formula (XV), where R8 is a reactive derivative of the carboxylic acid, for example an acid chloride or an acid anhydride, can be prepared in a conventional manner, for example by formation of a acid chloride or an acid anhydride.

Compounds of formula (XV), where R8 is a carboxyl group or its salt or its ester and n is equal to 2, can be prepared by reduction of a, P-ethylenecarboxylic acid or an acid salt or of 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 formulas (XXIII) and (XXIV) can be prepared by reaction of a compound of formula (XXV):

//%

I II

HG ~ \ / * (XXV)

lcH2) nR9

where n is as defined above and R9 represents the group C = N, C02H or an ester of the carboxylic acid as defined above for R8

with a compound of formula XCH2CH2Br (where X is as defined above), followed by amination with a compound of formula R5NH2, where R5 is as defined above.

Compounds of formula (XVIII) can be prepared from a compound of formula (XVII), where R, R1, R2, R3 and n are as defined in the general process (1), and R4 and R5 are hydrogen atoms, by reaction with Ll'-carbonyldiimidazole or lj'-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. Temperatures are in ° C. The word "dried" applies to drying using magnesium sulfate, unless otherwise indicated. Thin layer chromatography was performed on silica plates. FCC - Fast Column Chromatography - was performed on silica (Merck 9385).

The following abbreviations are used:

EA-ethyl acetate; ER-diethyl ether; PE petroleum ether; ME - methanol; MC - methylene chloride; T - toluene; Summer-

thanol; A-0.88 ammonia solution; H-hexane; DMF-dimé-thylformamide; THF-tetrahydrofuran; 9-BBN-9-borabicyclo- [3: 3: 1] nonane; Pd-C-palladium on carbon; PdO-C-palladium oxide on carbon.

Intermediate 1

Methyl 2- (2-bromoethoxy) 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 (21) was heated at reflux for 111 h. The resulting mixture was evaporated and the residue was dissolved in chloroform (500 ml), washed with water (2 x 250 ml) and brine (250 ml), dried (Na2SO4) 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).

Analysis for C! nH ^ BrC ^:

Calculated: C48.4 H 4.8%

Found: C 48.5 H 4.8%

Intermediate 2

Methyl 2- [2- [(pheny Imethyl) amino Jethoxy] 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 heated at reflux for 4 h. The inorganic solid product was separated by filtration and the filtrate evaporated. A solution of the residue in EA (200 ml) was washed with water (50 ml) and brine (50 ml); it was then dried and evaporated. The residue was purified by FCC eluting with EA to obtain the title compound as orange oil (13.2 g).

Analysis for C18H21N03:

Calculated: C 72.2 H 7.1 N 4.7%

Found: C72.4 H 7.2 N4.8%

Intermediate 3

2- (2-Bromoethoxy J benzene-acetamide

A solution of 2-hydroxybenzene acetamide (1.06 g), potassium carbonate (1.9 g) and tris [(2- (2-methoxyethoxy) ethyl] amine (0.11 g) in 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 eluting with ER , then EA to obtain the title compound as a white solid product (0.9 g), mp 84-86 °.

Intermediate 4

2- [2 - [(Phenylmethyl) amino Jethoxy] benzene-acetamide

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 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 °.

Intermediate 4 (other preparation)

A solution of intermediate 3 (52 g), benzylamine (210 ml) and sodium iodide (60 g) in acetonitrile was heated at reflux for 18 h, filtered and evaporated. The residue was dissolved in EA (300 ml), washed in an aqueous solution of sodium carbonate (2M) and with water, dried and evaporated. The resulting brown oil was purified twice by FCC, eluting with ER, then EA to obtain the title compound as a white solid product (12 g), m.p. 85-87 °.

Intermediate 5

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

A solution of 1- [3,5-bis (phenylmethoxy) phenyl] -2-bromoetha-

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none1 (1.37 g) in dry DMF (25 ml) was added over 5 min 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 h 30 min 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 (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); it was dried and evaporated to obtain the title compound in the form of a yellow oil (2.13 g), TLC (EA), Rf 0.7.

1 S.N. Quessy and L.R. Williams, Aus t. J. Chem., 32.1317 (1979). Intermediate 6

2- (2-Aminoethoxy) benzene-acetamide

A solution of intermediate 4 (2.5 g) in absolute TE (25 ml) was hydrogenated on PdQ-C at 10% until the absorption had stopped. 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 of titled in the form of a colorless oil which crystallized upon abandonment (1.3 g), mp 92-94 °.

Intermediate 7

a- (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) a 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 a solution of 2N sodium hydroxide (15.2 ml) and water ( 22.8 ml). The inorganic solid product 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 product ( 21.8 mg), mp 89-90 °.

Intermediate 8

2- (2-Bromoethoxy) benzene-acetonitrile

A mixture of 2-hydroxybenzene-acetonitrile (1.6 g) and potassium carbonate (3.3 g) in dibromoethane (15.5 ml) was heated at 120 ° for 2 days. The solvent was evaporated, TEA was added to the residue, the inorganic solid was separated 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 as orange oil (2.2 g), TLC (ER-PE 2: 1), Rf 0.4.

Intermediate 9

2- [2- [(Phenylmethoxy) amino Jethoxy] benzene-acetonitrile

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.

Intermediate 10

2- [2 - [[2- [3,5-bis (Phenylmethoxy) phenylJ-2-hydroxy Jethyl] ami-no JethoxyJbenzene-acetonitrile

A mixture of 1- [3,5-bis (phenylmethoxy) phenyl] -2-bromoetha-none (5.96 g), intermediate 9 (4.00 g) and diisopropylethylamine

(2.61 ml) in DMF (30 ml) was stirred at room temperature for 2 h 30 min and evaporated. The residual gum 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 distributed between the chloroform phase (2 x 100 ml) and the water phase (100 ml). The organic phase was dried and evaporated to leave a yellow gum which was purified by FCC eluting with T-ER (19: 1) to give the title compound (5.60 g) in the form of 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 66 h, heated at reflux for 3 h and evaporated. The residue was distributed between the EA phase (50 ml) and the aqueous sodium bicarbonate phase (1M; 2 x 20 ml). The organic phase was dried and evaporated to leave the title compound in the form of a yellow oil which subsequently solidified, TLC (ER), Rf 0.52.

Intermediate 12

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 (50 ml) was heated at reflux for 16 h, filtered and evaporated to leave a light brown oil (3.00 g), TLC (PE-20% ER), Rf 0.26.

Intermediate 13

(iii) 1-Methylethyl 2- [2- [(phenylmethyl) amino Jethoxy] benzene-acetate

A mixture of intermediate 12 (80 g), benzylamine (300 ml), potassium carbonate (74 g) and sodium iodide (80 g) in acetonitrile (11) was heated at reflux for 20 h. The inorganic solid product was separated 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), TLC (ER), Rf 0.4.

Intermediate 14

1-Methylethyl (2- [2 - [[2- [3,5-bis (phenylmethoxy) phenylJ-2-hydroxyethyl] phenylmethyl) amino Jethoxy Jbenzene-acetate

A solution of 1- [3,5-bis (phenylmethoxy) phenyl] -2-bromoetha-none (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 was stirred at room temperature for 3 h. The solvent was evaporated and the residue was redissolved 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 30 min. The TE was evaporated, the residue was acidified with 2N hydrochloric acid and the mixture was heated in a steam bath for 20 min. 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 obtain the title compound as a pale yellow oil (5.6 g), TLC (ER-PE 1: 1 ), Rf 0.35.

Intermediate 15

Acid 2- [2 - [[2- [3,5-bis (phenylmethoxy) phenylJ-2-hydroxyethylJ- (phenylmethyl) amino Jethoxy J benzene-acetic

A solution of intermediate 14 (56.1 g) and 2N sodium hydroxide (223 ml) in ME (400 ml) was heated at reflux for 16 h. The ME was evaporated and the aqueous phase was 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

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salt water, dried and evaporated. The residue was purified by FCC eluting with EA-PE (7: 3) to obtain the title compound as white foam (32.8 g), TLC (EA-PE 7: 3), Rf 0 , 25.

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 over 10% Pd-C (0.2 g). When the absorption stopped, the catalyst was separated by filtration and the filtrate was evaporated to obtain the title compound as a colorless solid product (0.96 g), PF 225 °, TLC (dichloromethane -ET-water-acetic acid, 5: 5: 1: 1), Rf 0.74.

Analysis for Ci8H21N06-H20:

Calculated: 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] benzene-acetamide

A solution of intermediate 5 (2.02 g) in ME (25 ml) and 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 123 -125 °.

(ii) 2- [2 - [[2- (3,5-dihydroxyphenyl) -2-hydroxyeth-yl] amino Jethoxy] 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 filtrate was evaporated. The residue was purified by FCC eluting with T-ET-A (78: 20: 2 and 68: 30: 2). The product was treated with ethereal hydrogen chloride to obtain the title compound as a hygroscopic solid product of buff color (190 mg), m.p. 86-88 ° (dec.).

Analysis for C18H22N205 - HCl 0.33 CH3C02C2H5 0.5H20: Calculated: C55, l 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 jethoxy jbenzene-acetamide

A solution of 1- [3,5-bis (phenylmethoxy) phenyl] -2-bromoetha-none (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 23 h. The solvent was evaporated and a solution of the residue in absolute TE (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 (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 obtain the title compound as a white solid product (8.37 g), mp 121-123 °.

(iii) 2- [2 - [[2- (3,5-dihydroxyphenyl) -2-hydroxy-ethyl] amino J ethoxy J benzene acetamide hemifumarate

The product from step (i) (8.13 g) in absolute TE (850 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 TE

(30 ml) and a solution of fumaric acid (670 mg) in absolute TE (30 ml) was added. The precipitated solid product was separated by filtration, crystallized from ET and recrystallized from ME / EA to give a slightly dirty white solid product (2.39 g), m.p. 110-115 ° (dec.). A portion (1 g) was diluted in absolute TE, separated by filtration and dried under vacuum at 70 ° to obtain the title compound as a solid product of a slightly dirty white (650 mg), PF 212-213 ° (dec.).

Analysis for (C18H22N205) 2C4H404:

Calculated: C 59.4 H 6.0 N 6.9%

Found: C59, W H 5.9 N6.6%

Example 3

2- [2- [[2- [3,5-bis (Phenylmethoxy) phenyl] -2-hydroxyethyl] (phenylmethyl) amino Jethoxy] benzene-acetamide

A stirred solution of intermediate 10 (0.1 g) in t-butanol (2 ml) was treated with finely pulverized potassium hydroxide (0.2 g) and the mixture 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 colored gum which was purified by FCC eluting with T-ET-A 79: 19: 2 to obtain the title compound in the form of a white powder. (20 mg), PF 120-121 °, TLC (T-ET-A 79: 20: 1), Rf 0.5.

Example 4

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

(i) R (-) - a- (bromomethyl) -3,5-bis (phenylmethoxy) benzenemetha-nol

A solution of 1- [3,5-bis (phenylmethoxy) phenyl] -2-bromoetha-none (8 g) in THF (6 ml) was added to freshly prepared "Alpine" borane, starting from 9- BBN (4.9 g) and (+) - a-pinene (7 ml), at 60 ° under nitrogen flow. The solution was stirred overnight, then allowed 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 ethanol-amine (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 in the form of 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), potassium carbonate (1.5 g), ME (40 ml) and water (30 ml) was stirred and heated to reflux for 1 hour. The ME was evaporated and the residue was extracted with the ER (2 x 40 ml). The extracts were washed with brine, dried and evaporated to leave the title compound as a colorless gum (2.6 g).

(iii) R (-) -2- [2 - [[2- [3,5-bis (phenylmethoxy) phenyl] -2-hydroxy-ethyl] (phenylmethyl) amino Jethoxy] 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 triturated with ER to obtain a white solid product (1.0 g). 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), mp 94-95 °.

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

A suspension of the product from step (ii) (2.9 g) in TE (70 ml) was hydrogenated on 10% Pd-C (0.3 g) for 16 h. The catalyst and 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 ml). An oil evaporated 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), m.p. 199-200 °.

Analysis for (C18H22N205) 2C4H404:

Calculated: C59.4 H 6.0 N6.9%

Found: C59.3 H 6.0 N6.8%

Example 5

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

(i) S (-f j-a- (bromomethyl) -3,5-bis (phenylmethoxy) benzenemethanol

A solution of 1- [3,5-bis (phenylmethoxy) phenyl] -2-bromoetha-none (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. Acetaldehyde (10 ml) was added and the solution was stirred at 20 ° for 30 min 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 15 min 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 the ER gave the title compound as fluffy crystals (1.77 g), mp 78-80 °.

(ii) S (+) - [3,5-bis (phenylmethoxy) phenylJoxiranne

A mixture of the product from step (i) (1.77 g), potassium carbonate (805 mg) in ME (21 ml) and 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 clear oil (1.39 g).

Analysis for C22H20O3:

Calculated: C 79.49 H 6.06%

Found: C 79.56 H 6.26%

(iii) S (+) - 2- [2 - [[2- [3,5-bis (phenylmethoxy) phenyl] -2-hydroxy-ethylJ (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 the ER to obtain the title compound as a white crystalline solid (1.2 g), mp 96-96.5 °.

(iv) S (+) - 2- [2 - [[2- (3,5-dihydroxyphenyl) -2-hydroxyethyl] ami-noJethoxy] benzene-acetamide

A solution of the product of step (iii) (1.2 g) in ethanol (50 ml) was hydrogenated on the 10% Cd-P catalyst (120 mg) until the stopping of the absorption of hydrogen (139 ml). The catalyst was removed by filtration on hyflo and the filtrate was evaporated in vacuo leaving a pale yellow oil which was triturated with ER (20 ml) to obtain the title compound as a white crystalline solid product (580 mg), mp 154-155 °.

Analysis for C18H22N2Os • 0.2EtOH:

Calculated: 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 JethoxyJben-zene-acetamide

A suspension of 2- [2 - [[2- [3,5-bis (phenylmethoxy) phenyl] -2-hydroxyethyl] (phenylmethyl) amino] ethoxy] benzene-acetamide (18.2 g) in TE (150 ml) was hydrogenated on 10% Pd-C (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 in 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), mp 106-107 °.

Analysis for C18H22N2Os • C2H5OH:

Calculated: C61.2 H 7.2 N7, l%

Found: C61.5 H 7.3 N7.0%

Example 7

2-J2-JJ2- [3,5-bis (Phenylmethoxy) phenyl] -2-hydroxyethyl] amino] -ethoxy Jbenzene-acetamide

A solution of intermediate 3 (2.58 g) in dry DMF (10 ml) was added over 10 min with stirring to a solution of intermediate 7 (5.24 g) and of N, N-diisopropylethylamine (3 , 88 g) in dry DMF (40 ml) at 90 ° under nitrogen. Stirring was continued for 1 h, then the solution was evaporated on sand and purified by FCC, eluting with MC-ET-A (150: 8: 1) to obtain the title compound in the form of a product. white solid (3.37 g), mp 105.5-107 °.

Analysis for C32H34N205 ■ 0.3H20:

Calculated: C72.2 H 6.6 N 5.3%

Found: C71.7 H 6.3 N5, l%

Example 8

2- [2 - [[2- [3,5-bis (Phenylmethoxy) phenyl] -2-hydroxyethyl] amino] -ethoxy Jbenzene-acetamide

A solution of intermediate 6 (0.95 g) in TE (15 ml) was added slowly to a solution of 3,5- [bis (phenylmethoxy)] - a-oxobenzene-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 g) was added and the mixture was stirred for 18 h. ME (25 ml) was added and the solution was heated to 40 ° 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 (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 Jethoxy J-N-ethylbenzene-acetamide

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 min, 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 distributed between the water phase (80 ml) and the EA phase (3 x 80 ml). The organic portions were combined, dried and evaporated, giving an orange oil. Purification by FCC eluting with ER gave the title compound as a colorless gum (0.58 g), TLC (EA), Rf 0.53.

(ii) 2- [2 - [[2- (3,5-dihydroxyphenyl) -2-hydroxy-ethyljamino JethoxyJ-N-ethylbenzene-acetamide hemifumarate

A solution of the product of step (i) (0.56 g) in the TE (40 ml)

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667,870

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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 MF (50 ml). The 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 in the form of a solid cream-colored product (0.30 g), TLC (MC-ET-A 25: 8: 1), Rf 0.31.

Analysis for (C20H26N2O5) 2C4H4O4 • 0.8H20 + 1.8C2HsOH: Calculated: C 59.4 H 7.2 N5.8%

Found: C 59.4 H 6.9 N 5.5%

Example 10

Phosphate, hemihydrate of 2- [2- [[2- (3,5-dihydroxyphenyl) -2-hydroxyethyl] amino] ethoxy Jbenzene-acetamide

2- [2 - [[2- (3,5-dihydroxyphenyl) -2-hydroxy-ethyl] amino] ethoxy] benzene acetamide hemifumarate (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, the TE (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. 138-140 °.

Analysis for C18H22N205 ■ H3PO4-0.5H2O -} - 0.4C2H5OH: Calculated: C48, l H 6.1 N 5.9 P 6.5%

Found: C47.8 H 6.15 N 5.85 P 6.4%

Example 11

(i) 2- [2- [5-f3,5-bis (Phenylmethoxy) phenyl] -2-oxo-3-oxazolidinyl] -ethoxy Jbenzene-acetamide

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. Stirring was continued for 18 h, then the solution was evaporated. The residue was dissolved in EA (50 ml), washed with water (2 x 50 ml), brine (25 ml), dried and evaporated, giving a white solid 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 product (0, 30 g), mp 145-146 °.

(ii) 2- [2-JJ2-J3,5-bis (Phenylmethoxy) phenyl] -2-hydroxyethyl] ami-no Jethoxy Jbenzene-acetamide

A suspension of the product from step (i) (40 mg) in a solution of 2N sodium hydroxide (0.8 ml) and ET (1.6 ml) was stirred at 60 ° for 8 h. The ET was evaporated and the remaining solution was extracted with EA (3x5 ml). The organic portions were combined, dried and evaporated, giving 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 that of Example 7.

Example 12

2- [2- [[2- (3,5-Dihydroxyphenyl) -2-hydroxyethyl] amino Jethoxy J-N-propylbenzene-acetamide

(i) 2-J2 - [{2- [3,5-bis (Phenylmethoxy) phenylJ-2-hydroxyethyl] (phenylmethyl) ethoxy J-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-propylamine (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 salt water; it was 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-J [2- (3,5-Dihydroxyphenyl) -2-hydroxyethylJ aminoJethoxy J-N-propylbenzene-acetamide

A solution of the product of step (i) (1.24 g) in absolute TE (50 ml) was hydrogenated on 10% Pd-C (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-isopro-panol 7: 3 to obtain the title compound as white foam (187 mg), TLC (EA-isopropanol 7: 3), Rf 0.35.

8 (D4 methanol) 0.88 (3H, t, CH2CH2CH3), 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, NHCH2CH2), 3.48 (2H, s, ArCH2CO), 4.11 (2H, t, NHCH2CH2Q), 4.67 (2H, dd, NHCH2CHOH), 6.1-7.3 (7H, m, aromatics).

Example 13

2- [2-J J2- [3,5-Dihydroxy) phenyl] -2-hydroxyethyl] amino] ethoxyJ-benzenepropanamide

A solution of 2-hydroxybenzenepropenoic acid (16.42 g) and sulfuric acid (18M; 0.1 ml) in ME (100 ml) was heated at reflux for 70 h, cooled and filtered to obtain a product light brown solid (10.9 g). The filtrate was evaporated, the residue was distributed between the dichloromethane phase (2 x 50 ml) and the aqueous sodium bicarbonate phase (1M; 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, m.p. 133-137 °

(ii) Methyl-2- (2-bromoethoxy) benzenepropenate

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 h, filtered, evaporated, dissolved in T, filtered through silica gel (Merck 9385) and evaporated leaving the title compound as a white solid (13.22 g), mp 57-59 °.

(iii) Methyl-2- [2 - [[2- (3,5-dihydroxyphenyl) -2-hydroxyethyl] ami-no Jethoxy Jbenzenepropenoate

A solution of a- (aminomethyl) -3,5-dihydroxybenzenemethanol (3.5 g), sodium iodide (3.0 g) and diisopropylethylamine (3.5 ml) in DMF (80 ml) to 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 9483) to obtain the title compound as a friable solid product of a slightly dirty white (1.45 g), TLC (T-ET-A 79: 20: 1), Rf 0.13.

(iv) Methyl-2- [2-J [2-J3,5- (dihydroxy) phenylJ-2-hydroxyethyllamino JethoxyJbenzenepropanoate

A mixture of the product from step (iii) (2.2 g) and 10% PdO-C (0.5 g) in absolute TE (50 ml) was hydrogenated until the end of the 'absorption. The catalyst was filtered off and the filtrate was evaporated under reduced pressure. The residue was purified by FCC eluting with dichloromethane-ET-A (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.

(v) 2-J 2-J [2-J 3,5-Dihydroxy) phenyl] -2-hydroxyethyl] amino] -ethoxy Jbenzenepropanamide

A mixture of the product from step (iv) (1.5 g), ME (30 ml) and

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667,870

liquid ammonia (20 ml) was heated to 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 dichloromethane-ET-A (50: 8: 1), Rf 0.15.

Analysis for Q9H24H2O5 • 0.75H20 • 0.5EtOH:

Calculated: C60.5 H 7.2 N7, l%

Found: C 60.1 H 6.9 N 7.2%

Example 14

2- [2 - [[3,5-Dihydroxyphenyl] -2-hydroxyethyl] amino Jethoxy J-N-methylbenzene-acetamide

(i) 2-J2 - [[2- [3,5-bis (Phenylmethoxy) phenyl] -2-hydroxyethyl] (phenylmethyl) aminoJethoxyJ-N-methylbenzene-acetamide

A mixture of intermediate 5 (1.5 g), ET (20 ml) and 33% ethanolic methylamine (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 as a colorless gum (1.1 g).

(ii) 2- [2 - [[3,5- (Dihydroxyphenyl) -2-hydroxyethyl] aminoJethoxy] -N-methylbenzene-acetamide

A solution of the product of step (i) (1.0 g) in absolute TE (70 ml) was hydrogenated on 10% Pd-C (300 mg). 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 for C19H24N205 • 0.5H20:

Calculated: C61.8 H 6.8 N7.6%

Found: C61.9 H 6.2 N7.7%

The following are examples of suitable formulations of compounds of the invention. The expression “active constituent” is used here to denote a compound of the invention; it can be, for example, the compound 2- [2 - [[2- (3,5-dihydroxyphenyl) -2-hydroxy-ethyl] amino] ethoxy] benzene-acetamide.

Example A

Tablets - direct compression

Active ingredient Microcrystalline cellulose B.P.C.

Magnesium stearate

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 keratinized.

mg / tablet 50.0 149.0 45

L0

200.0

The active ingredient is sieved through a 250 µi 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.

mg / tablet '50.0 119.0 20.0 10.0 1.0'

Example B

Tablets - wet granulation

Active ingredient Lactose B.P.

Starch B.P.

B.P.Pregelatinized Corn Starch

B.P. magnesium stearate

Compression weight 200.0

The active ingredient is sieved through a 250 n sieve and mixed with lactose, starch, pregelatinized 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.

mg / capsule 50.0 149.0

L0

200.0

Example C Capsules

Active ingredient * Starch 1500 Magnesium stearate B.P.

Filling weight

* Form of starch which can be directly compressed, supplied by Colorcon Ltd., Orpington, Kent, UK

The active ingredient is sieved through a 250 µi 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.

Example D Sucrose Syrup

Active constituent Sucrose B.P. Glyceride B.P. Buffer Aroma Coloring Preservative Purified water B.P.

as needed mgd dose of 5 ml 50.0 2750.0 500.0

5.0 ml q.s.p.

The active ingredient, buffer, flavor, color and 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.

Example E

Syrup without sucrose mgjdose of 5 ml 50.0

as needed

Active constituent

Hydroxypropylmethylcellulose USP

(viscosity type 4000) 22.5

Sweetener Aroma Color Buffer

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

The hydroxypropylmethylcellulose 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.

Example F Suppositories

Active ingredient 50.0 mg

* WitepsolH15 q.s.p. 1.0 g

* Specialty of Adeps Solidus Ph. Eur.

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

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Example G

Injection for intravenous administration

Active constituent 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 by using a dilute acid or alkali or by addition of buffering salts adequate. 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. Or 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.

s Example 15

2- [2- [[2- (3,5-Dihydroxyphenyl) -2-hydroxyethyl] amino] ethoxyJben-zene-acetamide

A solution of 2- [2 - [[2- [3,5-bis (phenylmethoxy) -phenyl] -2-hydroxyethyl] amino] ethoxy] benzene-acetamide (0.6 g) in ET io (20 ml ) was hydrogenated on 10% Pd-C (0.06 g) until the absorption of hydrogen was stopped (58 ml). The catalyst was separated by filtration on hyflo and washed with ET (20 ml). The volume of ET was reduced to 10 ml under reduced pressure and the title compound crystallized as a white solid (0.23 g), mp 105-107 °. The product was identical to the sample prepared in Example 6.

r

Claims (17)

667,870 2 CLAIMS 1. Compounds of general formula (I): ho • oh \ // \ T j u chch2nhch2ch20- • • \\ / • • I oh / \\ »• I I \ // " (CH 2) nC0NHR therapeutic, or transformed into another therapeutically acceptable salt or solvate. 8. Process for the preparation of the compounds of general formula (I) according to claim 1, characterized in that the reaction of a compound of formula (VIII) is carried out: (I) R 20 • R6 \ / W / \ // (VIII) where R represents a hydrogen atom or a C,.} straight chain alkyl group and n represents 1 or 2, their physiologically acceptable acid addition salts, their solvates and their physiologically acceptable lower alkanoates. 2. Compounds according to claim 1, in which n is 1. 3. Compounds according to claim 1 or 2, in which R represents a hydrogen atom. 4. 2- [2 - [[2- (3,5-dihydroxyphenyl) -2-hydroxyethyl] amino] ethoxy] -benzene-acetamide and its physiologically acceptable acid addition salts as compounds according to claim 1. 5. Addition salts according to claim 4, chosen from the group comprising hydrochloride, fumarate and phosphate. 6. Compounds according to claim 1, in which R represents a hydrogen atom, a methyl group or an ethyl group and n is 1 or 2. 7. A process for preparing the compounds of general formula (I) according to claim 1, characterized in that an alkylation reaction is carried out between a compound of formula (II): r where R2 and R3 are as defined in the process according to reis vendication 7 and R6 represents a group: -CHOR4 I CH2 or -CHCH2X Where R4 and X are as defined in the process according to claim 1, with an amine of formula (IX): / w s A // r5nhch2ch2-o • (IX) (ch2) nc0nrr1 Rl \ / A? r ' | dd-chch 2na • • W / • I -or3 where - NA represents a group —NHR5, —NR5CH2CH2X, R5 (ii) Where R and n are as defined in formula (I) of claim I and R1 and R5 are as defined in the process according to claim 7, then any protective group which may be present is removed, the compound being, if desired, isolated as a salt or solvate acceptable for therapeutic use, or transformed into another salt or solvate therapeutically acceptable. 9. Process for the preparation of the compounds of general formula (I) according to claim 1, characterized in that one proceeds to the reaction of a compound of formula (X): R2 \ / A / R7 - <3 ° u <] (x) + R2, R3, R4 and R5 each represent a hydrogen atom or a protective group and X is an atom or a group capable of being eliminated, and a compound of formula (III): // \ Y0 J w / (III) W / I, or3 where R7 represents the group - COCHO or OR4 1 -CHCH2NHRs and R2, R3, R4 and R5 are as defined in claim 7, with a compound of formula (XI): (ch 2) nc0nrr 1 // \ where R and n are as defined in formula (I), R1 is a hydrogen atom or a protecting group and Y represents a hydrogen atom when - NA represents R5 -NRsCH2CH2X, -N ^ J or 53- where Y represents the group CH2CH2X where X is an atom or a group capable of being eliminated when —NA represents —NHR5, then any protective group possibly present is removed, the compound being, if desired, isolated as a salt or solvate acceptable for use (XI) zch20 / ^ j /) (ch2) nc0nrr1 where Z represents the group - CHO when R7 is OR4 5 -CHCH2NHR5 or Z represents the group CH2NHRS when R7 is —COCHO, R and n are as defined in formula (I) according to the claim- 3 667,870 tion 1 and R1 and Rs are as defined in the process according to claim 7, in the presence of a reducing agent, then any protective group which may be present is removed, the compound being, if desired, isolated as salt or solvate acceptable for therapeutic use, or transformed into another therapeutically acceptable salt or solvate. 10. Process for the preparation of the compounds of general formula (I) according to claim 1, characterized in that a compound of formula (XIV) is reduced: r 20. .. // \ • • (XIV) \ / W fl 1 Ì ü | -cch2nch2ch20 • • • W / J X • (ch2) nc0nrr * R30 where R and n are as defined in formula (I) according to claim 1, and R1, R2, R3 and R5 are as defined in the process according to claim 7, then any group is removed protective agent possibly present, the compound being, if desired, isolated as a salt or solvate acceptable for therapeutic use, or transformed into another salt or solvate therapeutically acceptable. 11. A process for preparing the compounds of general formula (I) according to claim 1, characterized in that one proceeds to the amina-tion of a compound of formula (XV): r2 °. , • ^) R ** R5 / W \ r \ r ï î | î | (j-chch 2nch 2ch 20 - * ^ • • • \ // (XV) , 1 r3O (ch 2) nr 8 where n is as defined in formula (I), R2, R3, R4 and R5 are as defined in the process according to claim 7, and Rs represents a carboxylic acid group or its salt or its reactive functional derivative, with an amine RNH2 where R is as defined in formula (I) according to claim 1, then any protective group possibly present is removed, the compound being if desired isolated as an acceptable salt or solvate for therapeutic use, or transformed into another therapeutically acceptable salt or solvate. 12. Process for the preparation of the compounds of general formula (I) according to claim 1, in which R is hydrogen, characterized in that one proceeds to the hydrolysis of a compound of formula (XVI): R20 î r1 / W \ // * \ /CHCH2nch2ch20-.x. w / J r 30 (ch2) nc = n r 0 • or ^ r ® \ // \ I I II I t "-CHCHjnch ^ hoO-., I II \ // (XVII) "• * w / î t (ch2) nc0nrr1 r 30 where R and n are as defined in formula (I) according to re-io vendication 1, and R1, R2, R3, R4 and R5 are as defined in the process according to claim 7, provided that at least one of R1, R2, R3, R4 and R5 represents a protective group, the compound being, if desired, isolated as a salt or solvate acceptable for therapeutic use, or transformed into another salt or thera-15 solvate may be acceptable. 14. Pharmaceutical composition comprising a compound of general formula (I) according to claim 1, or one of its physiologically acceptable acid addition salts or one of its solvates in association with at least one support or excipient 20 physiologically acceptable. 15. Compounds of general formula (XV): R20 jr4 r5 / W (XV) (XVI) where n is as defined in formula (I) according to claim 1, and R2, R3, R4 and R5 are as defined above in the process according to claim 7, then any group is removed protective agent possibly present, the compound being, if desired, isolated as a salt or solvate acceptable for therapeutic use, or transformed into another salt or solvate therapeutically acceptable. 13. Process for preparing the compounds of general formula (I) according to claim 1, characterized in that a compound of formula (XVII) is deprotected: \ / \ ÎK T "I, i îl t-CHCH2NCH2CH20-i ^. • • * \ ' r (ch 2) nr ® R30 As a starting material in the process according to claim 11, where n is 1 or 2, R2, R3, R4 and R5 each represents a hydrogen atom or a protecting group and R8 represents a carboxylic group or a carboxylate group of C ^ Cj alkyl. 16. Compounds according to claim 15 or salts of these compounds, in which n is 1 or 2, and R2, R3, R4 and R5 each represent a hydrogen atom and R8 represents a carboxylic group or an alkyl carboxylate group in Cj to C3. 17. 2- [2 - [[2- (3,5-dihydroxyphenyl) -2-hydroxyethyl] ami-no] ethoxy] benzene-acetic acid as a compound according to the claim 40 tion 15.