CH669787A5 - - Google Patents

Description

DESCRIPTION

The present invention relates to dichloroaniline derivatives having a stimulating action at p2-adrenergic receptors, processes for their preparation and pharmaceutical compositions containing them.

Dihaloaniline derivatives have previously been described as bronchodilators with stimulating activity at the ß-adrenergic receptors.

Thus, the British patent No. 1178191 describes compounds of general structure

Hal ^ .—. R2

* = j =. R1 R3 Hai in which the substituents Hai represent bromine or chlorine atoms; R1 represents hydrogen or hydroxyl; R2 and R3 each represents hydrogen or a CM alkyl group, and R4 and R5 each represents hydrogen, Cw alkyl, alkynyl, hydroxyalkyl, alkoxyalkyl, dialkylaminoalkyl, cy-cloalkyl, phenyl, benzyl or adamantyl, or NR4R5 forms a heterocyclic ring optionally substituted with C 1-3 alkyl groups.

We have now discovered a new group of dichloroaniline derivatives, the structure of which differs from those described in British Patent No. 1178 191 and which have a desirable and useful activity profile.

Thus, the subject of the present invention is compounds of general formula (I)

H2N — f - ^ HCH2NH (| xCH2QCH2YAr (I)

OH R2

/

Cl in which

X represents a bond, a Cw alkylene chain, C2.6 alkenylene or C2.6 alkynylene and

Y represents a bond, or a C 1-4 alkylene chain, C 2-4 alkenylene or C 2-4 alkynylene, provided that the sum of the sum of the carbon atoms in X and Y does not exceed 8;

Ar represents a phenyl group substituted by one or more substituents chosen from nitro groups, - (CH2) qR [in which R is a C1-3 alkoxy group, —NR3R4 (in which R3 and R4 each represent a hydrogen atom or a Cm alkyl group, or - NR3R4 forms a saturated heterocyclic amino group which has 5-7 members and optionally contains, in the ring, one or more atoms chosen from - O—, —S— or a group --NH— or - N (CH3) -), —NR5COR6 (in which R5 represents a hydrogen atom or a CM alkyl group and R6 represents a hydrogen atom or a CM alkyl, CM alkoxy or —NR3R4, and q represents an integer from 1 to 3], - (CH2) rR7 [in which R7 represents a group - NR5S02R8 (in which R8 represents a CM, phenyl alkyl group or - NR3R4), —NR5COCH2N (R5) 2 (in which each of the groups R5 represents a hydrogen atom or an alkyl group in CM), —COR9 (in which R9 represents a hydroxy, alkoxy group in CM or NR3R4), —SR 10 (in which R10 is a hydrogen atom or a C 4 alkyl group optionally substituted by a hydroxy group, CM alkoxy or NR3R4), —SOR10, —S02R10, —CN or —NRUR12 (in which R11 and R12 represent a hydrogen atom or an alkyl group in CM of which at least one is an alkyl group in C2j) substituted by a hydroxy group, alkoxy in Cm or NR3R4), and r represents an integer from 0 to 3],

—0 (CH2) qC0R9 (in which q and R9 are as defined above), or - 0 (CH2) tR13 [in which R13 represents a hydroxy group, NR3R4, NR1: 1R12 or CM alkoxy optionally substituted by a hydroxy group, CM alkoxy or NR3R4, and t is an integer equal to 2 or 3],

R1 and R2 each represent a hydrogen atom or a C ^ alkyl group, provided that the total sum of the carbon atoms in R1 and R2 does not exceed 4,

and their physiologically acceptable salts and solvates (eg hydrates).

It will be noted that the compounds of general formula (I) have one or two asymmetric carbon atoms, namely the carbon atom of the group

-CH-

I

OH

and, when R1 and R2 are different groups, the carbon atom to which they are attached.

The compounds according to the invention thus include all the enan-tiomers, the diastereoisomers and their mixtures, in particular the ra-cêmates. Preferred are compounds in which the carbon atom of the group

-CH-

I

OH

is in configuration R.

In the definition of general formula (I), the term alkenylene includes both eis and trans structures.

According to one of its aspects, the subject of the invention is compounds of formula (I) in which R1, R2, X, Y and Ar are defined for formula (I) and R7 represents a group —NR5S02R8, —COR9, - SR10, -SOR10, -S02R10, - CN or -NR "R12.

In the general formula (I), the chain X can be, for example, a bond, -CH2-, - (CH2) 2-, - (CH2) 3-, - (CH2) 4-, ~ (CH2) 5 -, - (CH2) fi -, - CH2C = C—, - (CH2) 2CH = CH-, - (CH2) 2C = C-, -CH = CHCH2-, -CH = CH- (CH2) 2- or —CH2C = CCH2 -. The chain Y can be, for example, a bond,

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—CH2—, - (CH2) 2 -, - (CH2) 3—, - (CH2) 4 -, —CH = CH -, -C = C-, -CH2CH = CH- OR -CH2C = C-.

Preferably, the total number of carbon atoms in the X and Y chains is from 4 to 8 inclusive. Compounds in which the total of the sum of the carbon atoms in the chains X and Y is 4, 5, 6 and 7 are particularly preferred.

A preferred group of compounds of formula (I) is that in which X represents an alkylene chain in Q.g and Y represents an alkylene chain in CM. Particular compounds of this type are those in which X represents - (CH2) 3 - or - (CH2) 4— and Y is —CH2—, - (CH2) 2— or - (CH2) 3 -.

In the compounds of formula (I), R1 and R2 may each be, for example, methyl, ethyl, propyl or isopropyl groups, except that, if one of the two groups R1 and R2 is a propyl or isopropyl group, l the other is a hydrogen atom or a methyl group. Thus R1 can be, for example, a hydrogen atom or a methyl, ethyl or propyl group. R2 can be, for example, a hydrogen atom or a methyl group. R1 and R2 are each preferably a hydrogen atom or a methyl group.

A preferred group of compounds is the compounds in which R1 and R2 are both hydrogen atoms, or R1 is a hydrogen atom and R2 is a Q.3 alkyl group, in particular a methyl group.

When —NR3R4, in the compounds of formula (I), represents a saturated heterocyclic amino group, this may have 5, 6 or 7 members and optionally contains, in the ring, a heteroatom chosen from —O—, —S— , or a group - NH— or - N (CH3) -. Examples of these groups - NR3R4 are the pyrrolidino, piperidino, hexamethyleneimino, piperazino, N-methylpiperazino, morpholino, homomorpholino outhiamorpholino groups.

Ar can be, for example, a phenyl group substituted by a group - (CH2) qR [in which R represents a Cj3 alkoxy group for example methoxy, dialkyl (in CM) amino for example dimé-thylamino, morpholino, piperidino, piperazino , N-methylpiperazino, —NHCOR6 (in which R6 is a CM alkyl group, for example methyl), and q is equal to 1 or 2], - (CH2) rR7 [in which R7 represents —NR5S02R8 (in which R5 represents a hydrogen atom or a methyl group, and R8 represents a CM alkyl group, for example methyl), —NHCOCH2N (R5) 2 (in which the two R5 groups represent a CM alkyl group, for example methyl), - COR9 (in which R9 represents a C [_4 alkoxy group, for example ethoxy, amino, dialkyl (in CM) amino, for example dimethylamino, morpholino, piperidino, piperazino or N-methylpiperazino), —NR "R12 (in which one of groups R11 and R12 or both represent a C2a alkyl group, for example an ethyl group substituted by a hydroxy group, or a gr oupe dialkyl (in Cw) amino, for example dimethylamino, and the other represents a hydrogen atom), and r is zero or equal to 1], - OCH2COR9 (in which R9 is a dialkyl (in CM) amino group, for example dimethylamino), or - 0 (CH2) 2R13 (in which R13 is a dialkyl (in CM) amino group, for example dimethylamino).

A group of preferred compounds according to the invention consists of the compounds of formula (la)

Cl

\

H2N — i '- ^ HCH2NHCH2XCH20CH2YAr (la) • OH

/

Cl in which X represents a C3_4 alkylene chain and Y represents a Cw alkylene chain, provided that the total number of carbon atoms in X and Y is 5 or 6; and Ar represents a phenyl group substituted by a group chosen from alkoxy (in CM) methyl (for example methoxymethyl), mor-pholinomethyl, dialkyl (in CM) aminoalkyl (in C, .2) (for example di-methylaminoethyl) groups , - CH2NHCOR6 (in which R6 is a CM alkyl group, for example methyl), —NRsSO2R8 (in which Rs is a hydrogen or a methyl group and Rs is a CM alkyl group, for example methyl), - NHCOCH2N (Rs ) 2 (in which the two R5 groups represent a C14 alkyl group, for example methyl), —COR9 (in which R9 is a hydroxy, 5 C alkoxy group, for example ethoxy, amino, dialkyl (in CM) amino, for example dimethylamino, or morpholino), - CH2COR9 (in which R9 is an amino or dialkyl group (in CM) amino, for example dimethylamino), —NRnR12 (in which R11 and R12 both represent a hydroxyalkyl group in C2j), by example hydroxyethyl), dial-kyl (in CM) aminoethylamino (for example dimethylaminoethyl-amino), - OCH2COR9 (in which R9 e is a dialkyl group (in Clamino, for example dimethylamino) or - 0 (CH2) 2R13 (in which R13 is a dialkyl group (in CM) amino, for example dimethylamino); and their physiologically acceptable salts and solvates. Particularly preferred compounds of formula (la) are those in which X and Y are defined for formula (la); and Ar represents a phenyl group substituted by a group chosen from - CH2NHCOR6 (in which R6 is a methyl group), --NHS02R8 (in which R8 is methyl), --COR9 (in which R9 is a hydroxy, ethoxy, amino group or morpholino), or —CH2COR9 (wherein R9 is an amino or dimethylamino group), and their physiologically acceptable salts and solvates. The particularly important compounds of the invention are:

Le4- [3 - [[6 - [[2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethyl] ami-no] hexyl] propyl] benzamide;

ethyl 4- [3 - [[6 - [[((4-amino-3,5-dichlorophenyl) -2-hydroxyethyl] ami-no] hexyl] oxy] propyl] benzoate;

N - [[3- [3 - [[2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethyl] ami-J0 no] hexyl] oxy] propyl] phenyl] methyl] acetamide;

4- [4- [5 - [[2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethyl] ami-no] pentyloxy] butyl] -N, N-dimethylbenzene-acetamide;

4- [3 - [[6 - [[2- (4-amino-3,5-dichlorophenyl) -2-hydroxy-ethyl] amino] hexyl] oxy] propyl] benzoic acid;

la4- [4- [3 - [[6 - [[2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethyl] -amino] hexyl] oxy] propyl] benzoyl] morpholine;

leN- [4- [3 - [[6 - [[2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethyl] -amino] hexyl] oxy] ethyl] methane-sulfonamide;

[4- [3 - [[6 - [[2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethyl] ami-40 no] hexyl] propyl] benzene-acetamide;

and their physiologically acceptable salts and solvates.

Suitable physiologically acceptable salts of the compounds of general formula (I) include the addition salts with acids derived from mineral and organic acids, such as chlorhy-45 drates, hydrobromides, sulfates, phosphates, maleates, tartrates, citrates, benzoates, 4-methoxybenzoates, 2- or 4-hydroxybenzoates, 4-chlorobenzoates, p-toluene sulfonates, methane sulfonates, sulfamates, ascorbates, salicylates, acetates , fumarates, succinates, lactates, 50 glutarates, gluconates, tricarballylates, hydroxynaphthalene-carboxylates, for example 1-hydroxy- or 3-hydroxy-2-naph-talene-carboxylate, or oleates. The compounds can also form salts with suitable bases. Examples of these salts are the salts of alkali metals (eg sodium and potassium-55 sium) and alkaline earth metals (eg calcium or magnesium).

The compounds according to the invention have a stimulating action at the p2-adrenergic receptors, which also has a particularly advantageous characteristic. The stimulating action has been demonstrated in the tracheae isolated from guinea pigs, where it has been shown that the compounds cause relaxation of the contractions induced by PGF-2a. The compounds according to the invention exhibited a particularly long duration of action in this test.

The compounds according to the invention can be used in the treatment of diseases associated with reversible obstruction of the respiratory tract such as asthma and chronic bronchitis.

The compounds according to the invention are also indicated as being useful for the treatment of inflammatory skin diseases

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669,787

and allergic, congestive heart failure, depression, preterm labor, glaucoma, and in the treatment of conditions in which it is beneficial to lower stomach acid, especially in gastric and peptic ulceration than.

Another subject of the invention therefore relates to the compounds of formula (I) and their physiologically acceptable salts and solvates for use in the treatment or in the prophylaxis of diseases associated with reversible obstruction of the respiratory tract in humans or in humans. 'animal.

The compounds according to the invention can be formulated for administration in any suitable manner. The scope of the invention therefore comprises pharmaceutical compositions comprising at least one compound of formula (I) or one of its physiologically acceptable salts or solvates formulated for use in human and veterinary medicine. These compositions can be presented for use with physiologically acceptable vehicles or excipients, optionally with additional drug agents.

The compounds can be formulated in a form suitable for administration by inhalation or insufflation, or for oral, buccal, parenteral, topical (including nasal) or rectal administration. Administration by inhalation or insufflation is preferred.

For administration by inhalation, the compounds according to the invention are advantageously dispensed in the form of an aerosol spray presentation from pressurized packaging, using a suitable blower, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoromethane, carbon dioxide or other suitable gas, or from a nebulizer. In the case of a pressurized aerosol, the unit dose can be determined by providing a valve intended to dispense a metered amount.

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

For oral administration, the pharmaceutical composition can take the form, for example, of tablets, capsules, powder, solutions, syrups or suspensions prepared by conventional methods with suitable excipients.

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

The compounds of the invention can be formulated for parenteral administration by injection of an embol or continuous infusion. The formulations for injection may be, in unit dose form, presented in ampoules, or in multi-dose containers with the addition of a preservative. The compositions can take forms such as suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formulating agents such as suspending agents, stabilizers and / or dispersants. Alternatively, the active substance may be in the form of a powder to be reconstituted before use with a suitable vehicle, for example pyrogen-free sterile water.

For topical administration, the pharmaceutical composition can take the form of ointments, lotions or creams formulated in a conventional manner, with for example an aqueous or oily base, generally with the addition of suitable thickening agents and / or suitable solvents. For nasal application, the composition may take the form of a spray, formulated for example in aqueous solution or suspension or in aerosol using a suitable blower.

The compounds of the invention can also be formulated in rectal compositions such as suppositories or enemas to keep, for example containing bases for conventional suppositories such as cocoa butter or another glyceride.

When pharmaceutical compositions for oral, buccal, rectal or topical administration are described above, they can be presented in a conventional manner associated with slow-release forms.

A proposed daily dosage of the active compound for the treatment of humans is 0.005 to 100 mg, which can advantageously be administered in one or two doses. The precise dosage employed will of course depend on the age and condition of the patient and the method of administration. Thus, a dosage suitable for administration by inhalation is 0.005 to 20 mg, for oral administration from 0.02 to 100 mg, and for parenteral administration from 0.01 to 2 mg for administration by injection of '' an embol and 0.01 to 25 mg for infusion administration.

The compounds according to the invention can be prepared by a number of methods, as described below. In the following description of the processes for the preparation of the compounds of formula (I) and of the intermediates which can be used in their preparation, X, Y, Ar, R1 and R2 are as defined for the general formula (I), unless otherwise indicated . In addition, any substituent in the group Ar can be a precursor substituent which can be transformed to obtain the substituent required by conventional methods.

It will be noted that some of the reactions described below are capable of affecting other groups in the starting product, groups which it is desired to have in the final product; this applies in particular to the reduction processes described, particularly when hydrogen and a catalyst are used and when an ethylene or acetylene bond is required in the compound of the invention. Care must therefore be taken, according to conventional practices, either to use reagents which will not affect these groups, or to carry out the reaction within a sequence which avoids their use when these groups are present in the product of departure.

In the preparation of both intermediates and final products, the final step in the reaction can be the removal of a protecting group. Conventional protecting groups can be used, such as those described, for example, in "Protective Groups in Organic Chemistry", Ed. J.F.W. McOmie (Plenum Press, 1973). Thus, it is possible, for example, to protect the hydroxyl groups with arylalkyl groups such as a benzyl, diphenylmethyl or triphenyl-methyl group, or in the form of tetrahydropyrannyl derivatives.

Suitable amino protecting groups include arylalkyl groups such as a benzyl, a-methylbenzyl, diphenylmethyl or triphenylmethyl group, and acyl groups such as an acetyl, trichloroacetyl or trifluoroacetyl group.

Conventional deprotection methods can be used. Thus it is possible, for example, to remove arylalkyl groups by hydrogolysis in the presence of a metal catalyst (for example palladium on carbon). Tetrahydropyrannyl groups can be removed by hydrolysis under acidic conditions. Acyl groups can be removed by hydrolysis with an acid, such as a mineral acid, for example hydrochloric acid, or a base such as sodium hydroxide or potassium carbonate, or a group such as trichloroacetyl can be removed by reduction with, for example, zinc and acetic acid.

In a general process (1), a compound of general formula (I) can be prepared by alkylation. Conventional alkylation processes can be used.

Thus, for example, in a process (a) can one prepare a compound of general formula (I), in which R1 is a hydrogen atom, by alkylation of an amine of general formula (II)

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669787

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Cl

\

HjN—. .— (j) HCH2NRll, R15 (II)

0H

Cl

(in which R14 is a hydrogen atom or a protecting group and R15 is a hydrogen atom), followed by the removal of any protecting group present.

The alkylation (a) can be carried out by means of an alkylating agent of general formula (III):

LCHXCH2OCH2YAr (III)

I

R2

(in which L is a leaving group, for example a halogen atom such as chlorine, bromine or iodine, or a hydro-carbylsulfonyloxy group such as a methane-sulfonyloxy or p-toluene-sulfonyloxy group).

The alkylation is preferably carried out in the presence of a suitable acid scavenger, for example mineral bases such as sodium or potassium carbonate, organic bases such as triethylamine, diisopropylethylamine or pyridine, or oxides of alkylene such as ethylene oxide or propylene oxide. The reaction is preferably carried out in a solvent such as acetonitrile or an ether such as tetrahydrofuran or dioxane, a ketone, for example butanone or methylisobu-tylketone, a substituted amide, for example dimethylformamide, or a chlorinated hydrocarbon , for example chloroform, at a temperature between room temperature and the reflux temperature of the solvent.

According to another example (b) of an alkylation process, a compound of general formula (I) in which R1 represents a hydrogen atom can be prepared, by alkylation of an amine of general formula (II), such as defined above, except that R15 is a hydrogen atom or a group which can be transformed into a hydrogen atom under the reaction conditions, with a compound of general formula (IV):

R2COXCH2OCH2YAr (IV)

in the presence of a reducing agent, followed if necessary by the elimination of any protective group.

Examples of R15 groups convertible into a hydrogen atom are arylmethyl groups such as benzyl, a-methylbenzyl and benzhydryl.

Among the suitable reducing agents are hydrogen in the presence of a catalyst such as platinum, platinum oxide, palladium, palladium oxide, Raney nickel or rhodium, on a support such as carbon, with the use of an alcohol, for example ethanol or methanol or of an ester, for example ethyl acetate, or of an ether, for example tetrahydrofuran, or of water, as solvent for the reaction, or of a mixture of solvents, for example a mixture of two or more of those described immediately above, at a normal or elevated temperature and pressure, for example from 20 to 100 ° C and from 1 to 10 atmospheres.

Alternatively, when one or both of R14 and Rls are hydrogen atoms, the reducing agent may be a hydride such as diborane or a metal hydride such as sodium borohydride, sodium cyanoborohydride or lithium aluminum hydride. The solvents suitable for the reaction with these reducing agents will depend on the particular hydride used, but will include alcohols such as methanol or ethanol, or ethers such as diethyl ether or t-butyl methyl ether, or tetrahydrofuran.

When a compound of formula (II) is used, in which R14 and R15 are each hydrogen atoms, the intermediate imine of formula (V) can be formed:

Cl \

"•

// w

H2N—. —Lj: HCH2N = lj: XCH20CH2YAr (V)

s. OH R2

Cl

The reduction of the imine under the conditions described above followed, if necessary, by the elimination of any protective group, io gives a compound of general formula (I).

When it is desired to use a protected intermediate of general formula (II), it is particularly convenient to use hydrogen and a catalyst, as described above, with a protective group R14 which is capable of being transformed as a hydrogen gene under these reducing conditions, and thus avoid the need for a separate deprotection step. Suitable protecting groups of this type include arylmethyl groups such as benzyl, benzhydryl and α-methylbenzyl.

In another general process (2), a compound of general formula (I) can be prepared by reduction. Thus, for example, can a compound of general formula (I) be prepared by reduction of an intermediate of general formula (VI):

Cl \

25 // * \

X * 1-—. — Xl-X2-X3-CH20CH2Y-Ar (VI)

• 1. 1 •

/

Cl

In which at least one of the groups X4, X1, X2, X3 and Y represents a reducible group and / or Ar contains a reducible group and the other (s) take the appropriate meaning as follows: X4 is -NH2, X1 is -CH (OH) -, X2 is —CH2NR14— (where R14 is a hydrogen atom or a protecting group), X3 is 35 - CR1R2X, and Ar and Y are as defined in formula (I),

followed if necessary by the elimination of any protective group.

Suitable reducible groups include those in which X4 is - NO2, X1 is a group> C = 0, X2 is a group - CH2NY '- (where Y' represents a group convertible into hydro-40 gene by catalytic hydrogenation, for example a arylmethyl group such as a benzyl, benzhydryl or —methylbenzyl group), or an imine group (—CH = N—) or a group - CONH—, X3 is a group - COX— or a group CR1R2X (where X is an alkenylene group in Q.6 or C2.6 alkynylene), or —X2 —X3 - is a group - CH2N = CR2X—, Y is an alkenylene or alkynylene group in CM) and Ar is a phenyl group substituted by a group containing a bond amide like - (CH2) q_! CONR3R4 or —NHCOR17 (where - NHCOR17 is reducible to the NHR12 group).

The reduction can be carried out by means of reducing agents 50 advantageously used for the reduction of ketones, imines, amides, protected amines, alkenes, alkynes and nitro groups. Thus, for example, when X4, in the general formula (VI), represents a nitro group, it can be reduced to an amino group by using hydrogen in the presence of a catalyst, as described previously for the part (b) of the process (1).

When X1, in the general formula (VI), represents a group> C = 0, it can be reduced to a group - CH (OH) - by using hydrogen in the presence of a catalyst, as described above for part (b) of the process (1). Alternatively, the reducing agent can be, for example, a hydride such as diborane or a metal hydride such as lithium aluminum hydride, sodium bis (2-methoxyethoxy) aluminum hydride, sodium borohydride or aluminum hydride. The reaction can be carried out in a solvent, depending on the case, an alcohol, for example methanol or ethanol, or an ether such as tetrahydrofuran, or a halogenated hydrocarbon such as dichloromethane.

When X2, in general formula (VI), represents a group —CH2NY 'or the group - CH = N, or when - X2 — X3— represents

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a group - CH2N = CR2X—, it can be reduced to a group —CH2NH— or - CH2NHCHR2X— using hydrogen in the presence of a metal catalyst as described above for part (b) of process (1) . As a variant, when X2 or -X2-X3- is the group -CH = N- or -CH2N = CR2X, it can be reduced to a group - CH2NH— or - CH2NHCHR2X— using a reducing agent and the conditions described immediately below. above for the reduction of X1 when it represents a group> C = 0.

When X2 or X3, in general formula (VI), represents a group - CONH— or - COX—, or when Ar is a phenyl group substituted by a group containing an amide bond, such as - (CH2) q_, CONR3R4 or - NHCOR17 (where R17 is as defined above), it can be reduced to a group - CH2NH— or —CH2X—, or to a phenyl group substituted by the group - (CH2) qNR3R4 or - NHR12, respectively, using a hydride such as diborane or a complex metal hydride, such as lithium aluminum hydride or sodium bis- (2-methoxyethoxy) aluminum hydride, in a solvent such as an ether, for example tetrahydrofuran or diethyl ether.

When X3 represents a group CR1R2X, in which X is a C2.6 alkenylene or C2.6 alkynylene group, or when Y represents a CM alkenylene group or C2.4 alkynylene group, it can be reduced to an alkylene group in C2.6 or into a C2-4 alkylene group, respectively, using hydrogen in the presence of a catalyst as described above for part (b) of process (1). Alternatively, when X is a C2_6 alkynylene group or when Y is a C2J alkynylene group, it can be reduced to a C2-6 alkenylene group or C ^ alkenylene group, respectively, using for example hydrogen and a palladium catalyst poisoned with lead on calcium carbonate, in a solvent such as Pyridine, or lithium aluminum hydride in a solvent such as diethyl ether, at a low temperature, for example 0 ° C.

In another general process (3), a compound of general formula (I) can be prepared by deprotection of a protected intermediate of formula (VII)

Cl

X Ri-

fi ^ \ - (^ HCHjNR ll, (j: XCH20CH2YAr (VII)

OH R2

/

C1 in which R14 and R16 each represent a hydrogen atom or a protective group, and / or any hydroxy and / or amino substituent of the group Ar is protected, provided that at least one of the groups R14 and / or R16 represents a protective group and / or that Ar contains a protective group.

Suitable protecting groups and their removal methods are as previously described. Thus, for example, can R14 represent an arylalkyl group, for example a benzyl group, which can be eliminated by hydrogenolysis in the presence of a metal catalyst (for example palladium on carbon), and / or R16 can represent an acyl group which can be removed by boiling with a dilute mineral acid (for example hydrochloric acid).

The compounds of formula (I) can also be prepared by a process of general formula (I) in another.

Thus, for example, can a compound of formula (I) be prepared, in which Ar represents a phenyl group substituted by the group - (CH2) rCOR9, where R9 is a hydroxy group, by hydrolysis of the compound of formula (I) correspondent in which R9 represents a CM alkoxy group. The hydrolysis can, for example, be carried out under basic conditions using, for example, sodium hydroxide.

In the general methods described above, the compound of formula (I) obtained can be in the form of a salt, advantageously in the form of a physiologically acceptable salt. If desired,

these salts can be transformed into the corresponding free acids, by conventional methods.

The physiologically acceptable salts of the compounds of general formula (I) can be prepared by reacting a compound of general formula (I) with a suitable acid or base 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, especially other physiologically acceptable salts, of the compounds of general formula (I), using conventional methods.

When a specific enantiomer of a compound of general formula (I) is required, it can be obtained by resolution of a corresponding racemate of a compound of general formula (I) using conventional methods.

Thus, in one example, an optically active acid suitable for forming salts with the racemate of a compound of general formula (I) can be used. The resulting mixture of isomeric salts can be separated, for example by fractional crystallization, into the diastereoisomeric salts, from which the required enantiomer of a compound of general formula (I) can be isolated by transforming it into the free base required.

Alternatively, one can synthesize enantiomers of a compound of general formula (I) from suitable optically active intermediates using any method described in the present invention.

Diastereoisomers specific for a compound of formula (I) can be obtained by conventional methods, for example by synthesis of a suitable asymmetric starting material, using any method described in the present invention, or by transformation of a mixture of isomers of a compound of general formula (I) into suitable diastereoisomeric derivatives, for example salts which can be separated by conventional methods, for example by fractional crystallization.

The intermediate compounds of general formula (VI) which can be used in the general process (2) can be prepared by a certain number of processes, analogous to those described in GB patent No. 2165542A.

Thus, for example, can one prepare intermediates of general formula (VI), in which X1 is a group> C = 0, from a halogen ketone of formula (VIII):

Cl

\

H2N— / \ —COCH 2Hal (VIII)

• I. 3 *

/

Cl by reacting an amine of general formula (IX)

R1

I

Y'NHCXCH2OCH2YAr (IX)

I

R2

(in which Y 'is hydrogen or a group convertible into hydrogen by catalytic hydrogenation). The reaction can be carried out in a cold or hot solvent, for example tetrahydrofuran, t-butyl methyl ether, dioxane, chloroform, dimethylformamide, acetonitrile, or a ketone such as butanone or methyl isobutyl ketone, or a ester, for example ethyl acetate, preferably in the presence of a base such as diisopropylethylamine, sodium carbonate or another acid purifier such as propylene oxide.

We can reduce the intermediaries of general formula (VI), in which X1 is a group> C = 0, by the corresponding intermediate

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in which X1 is a group - CH (OH) - using for example a metal hydride such as sodium borohydride, in a solvent, for example ethanol.

The intermediates of formulas (II), (III), (IV), (VIII) and (IX) are known compounds or can be prepared by methods analogous to those described for the preparation of the known compounds.

The processes suitable for the preparation of intermediates of formulas (111), (IV) and (IX) are described in patents GB-A-2140800, GB-A-2159151, GB-A-2165542 and in the examples contained in the after.

The following examples illustrate the invention. Temperatures are in ° C. The term "dried or dehydrated" means drying or dehydration using magnesium sulfate or sodium sulfate, unless otherwise indicated. Thin layer chromatography (TLC) is carried out on Si02 and flash column chromatography (CEC) is carried out on silica (Merck 9385) using, unless otherwise indicated, one of the following solvent systems: A) toluene / ethanol / ammonia 0.88; B) toluene / ethanol / triethylamine; Q ethyl acetate / hexane / triethylamine; D) ethyl acetate / methanol / triethylamine; E) cyclohexane / ethyl acetate / triethylamine. The following abbreviations are used: THF: tetrahydrofuran; DMF: dimethylformamide; BTPC: bis (triphenylphosphine) palladium (II) chloride; DEA: N, N-diisopropylethylamine.

Intermediate 1: this is 1- (4-amino-3,5-dichlorophenyl) -2-bromoethanone.

Intermediate 2

(Z) -N- [4- [3 - [[6 - [(phenylmethyl) amino] hexyl] -oxyJ-1-propenylJphenyl] methane-sulfonamide hydrochloride

2.0 g of (Z) -N- [4- [3 - [(6-bromohexyl] oxy] -1-propenyl] -phenyljmethane-sulfonamide are added to 6 ml of benzylamine at 125 ° under nitrogen. the reaction mixture at 125 ° for 3 h, it is cooled to ambient temperature and it is added to 50 ml of 2N hydrochloric acid and to 20 ml of water The resulting white solid is collected by filtration and washed in turn with 2N hydrochloric acid, water and ether, then dried in vacuo at 50 ° to give 1.0 g of the title compound as a white powder. melting point 133-134 °.

Intermediate 3

(Z) -N- [4- [3 - [[6- [[2- (4-amino-3,5-dichlorophenyl) -2-hydroxy-ethyl] (phenylmethyl) amino Jhexyl] oxy] -l-propenyl ] phenyl] methane-Sulfonamide

A suspension of 520 mg of intermediate 1, 850 mg of intermediate 2 and 500 mg of DEA in 25 ml of THF is stirred overnight at room temperature. After filtration, the filtrate is concentrated to an oil which is dissolved in 20 ml of methanol cooled in an ice bath and which is treated with 250 mg of sodium borohydride. The pale yellow solution is stirred overnight at room temperature, the methanol is evaporated and the residue is partitioned between 25 ml of water and 25 ml of ethyl acetate. The organic phase is washed with water and brine, it is dried and concentrated in a red oil which is purified by CEC, eluting using the system E (75/25/1), which gives 540 mg of the title compound as a colorless oil, TLC (system E 75/25/1) Rf 0.09.

Intermediate 4

4-iodo-N hydrochloride, N-dimethylbenzene-ethanamine

0.65 g of 4-bromo-N, N-dimethyl-benzene-ethanamine hydrochloride is divided between 10 ml of ethyl acetate and 10 ml of 8% solution of sodium bicarbonate. The aqueous layer is extracted with 10 ml of ethyl acetate and it is dried and the combined organic extracts are concentrated to give 0.57 g of free base. 1.72 ml of 1.6M solution of n-butyl lithium in hexane are added to a solution of 0.57 g of the free base in 10 ml of THF at -78 ° C. and the mixture is stirred under nitrogen for 30 min. We add drop to

drop a solution of 0.63 g of iodine in 10 ml of THF and, after 10 min, the reaction is stopped by adding 10 ml of saturated ammonium chloride solution. The THF is evaporated and the aqueous residue is extracted with 2 x 15 ml of ethyl acetate. The ex-5 organic lines are washed with 15 ml of a 10% solution of sodium thiosulfate and 15 ml of brine, they are dried and concentrated, which gives a brown oil. The oil is treated in 10 ml of ether and 2 ml of dichloromethane with ethereal hydrogen chloride and the precipitate obtained is collected by filtration, dried, which gives 0.54 g of the title compound in the form of a solid white.

Analysis for C10H14IN, HC1:

Calculated: C 38.55 H 4.85 N4.5 Cl 11.38 1 40.73% Found: C 38.77 H 4.87 N4.39 Cl 11.36 140.67% 15 Intermediaries

N- (4-Iodophenyl) -N-methylmethane-sulfonamide

A mixture of 4.3 g of N- (4-iodophenyl) methane-sulfonamide, 25 ml of 50% aqueous sodium hydroxide, 5 ml of iodomethane, 10 ml of dichlo is vigorously stirred for 2 h. -20 romethane and 0.5 g of tetrabutylammonium bisulfate. 50 ml of water are added and the mixture is extracted with 3 x 50 ml of ether. The organic extracts are washed with water and brine, dried and concentrated to obtain a solid which is triturated with hexane, which gives 4.1 g of the title compound in the form 25 of white crystals with melting point 106-107 °.

Intermediate 6

2-f4-Iodophenoxy) -N, N-dimethylacetamide 5.85 ml of a solution of dimethyl-amine at 33% by weight in IMS is added dropwise to a suspension of 9.49 g of (4 -iodophenoxy) acetyl in 50 ml of triethylamine, at 0 ° C and under nitrogen. The suspension is stirred for 2 h at 0 ° and is partitioned between 300 ml of ethyl acetate and 300 ml of an 8% aqueous solution of sodium bicarbonate. The organic layer is dried and the solvent is evaporated, which leaves an oil which is purified by CEC eluting with diethyl ether, which gives 3.96 g of the title compound as a solid. white melting point 63-65 °.

40 Intermediate 7

4-Iodo-N, N-dimethylbenzene-acetamide

5.15 g of 4-iodophenylacetyl chloride are added in portions to 0.90 g of dimethylamine in 25 ml of triethylamine at 0 °. The suspension is stirred at 0 ° for 2 h and 100 ml of chloroform are added. The organic phase is washed with 50 ml of 8% aqueous sodium bicarbonate solution, it is dried and concentrated, which gives a red solid (5.0 g) which is purified by CEC eluting with ether, then with ethyl acetate, which gives 2.58 g of the title compound so as a yellow solid with melting point 75-77 °.

Intermediate 8

N, N-Dimethyl-4- [4- [5 - [(phenylmethyl) amino Jpentyl] oxyJbutyl] -55 benzene-acetamide

1.60 g of intermediate 16 are added dropwise to 3.5 ml of benzylamine at 120 ° under nitrogen. The solution is stirred for 3 h at 120 ° C and poured into 65 ml of 0.8N hydrochloric acid. The aqueous mixture is extracted with 3 × 30 ml of ethyl acetate and the combined extracts are washed with 50 ml of 8% aqueous sodium bicarbonate solution and 50 ml of brine, they are dried and concentrated, which gives 0.56 g of an oil. The combined aqueous phases are re-extracted with 2 x 50 ml of ethyl acetate, they are dried and concentrated, which gives 0.92 g of an oil. The two oils are combined and purified by CEC eluting with an ethyl acetate / triethylamine system (100/1), which gives 1.00 g of the title compound as a pale yellow oil; C.C.M. (ethyl acetate / triethylamine 100/1) Rf0, l.

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Intermediate 9

N - [[3-J3 - [[6 - [(Phenylmethyl) amino] hexyl] oxy J-1-propynyl] phenyl] methyl] acetamide

A suspension of 3.91 g of N - [(3-iodophenyl-methyl] acetamide, 3.48 g of N- [8 - [(2-propynyl) is stirred at room temperature under nitrogen for 20 h ) oxy] hexyl] benzene-methanamine, 100 mg of BTPC and 60 mg of copper iodide in 75 ml of di-ethylamine. The reaction mixture is poured into 100 ml of diethyl ether and filtered. filtrate, which gives 6.62 g of an oil which is purified by CEC eluting with system D (100/0/1 - »100/10/1), which gives 4.60 g of the compound of the title in the form of a red oil, TLC (ethyl acetate / triethylamine 100/1) Rf 0.12.

Intermediaries 10 to 13 are prepared in a similar manner.

Intermediate 10

N, N-Dimethyl-4-f3 - [[6-J (phenylmethyl) amino] hexyl] oxy J-1-propy-nyljbenzamide

We start with 2.5 g of 4-iodo-N, N-dimethylbenzamide and 2.23 g of N- [6- [2-propynyl) oxy] hexyl] benzene-methanamine. Purification by CEC eluting with an ethyl acetate / triethylamine system (100/1) gives 2.96 g of the title compound as an orange oil, C.C.M. (ethyl acetate + a few drops of triethylamine) Rf 0.15.

Intermediate 11

N, N-Dimethyl-2-J4-J3- [[6 - [(phenylmethyl) amino Jhexyl] oxy J-1-propynylJphenoxy] acetamide

We start with 3.91 g of intermediate 6 and 3.14 of N- [6 - [(2-propy-nyl) oxy] hexyl] benzenemethane. Purification by CEC eluting with system C (83/17/1) gives 3.87 g of a product which is passed over the column as above, but using as eluent an ethyl acetate / triethylamine system (100/1) to give 1.44 g of the title compound as an orange oil (1.44 g), TLC (ethyl acetate + a few drops of triethylamine) Rf 0.3.

Intermediate 12

N-Methyl-N- [4-f3 - [[6-J (phenylmethyl) aminoJhexyl] oxyJ-1-propy-nyl] phenyl] methane-tallow onamide

We start with 1.8 g of intermediate 5 and 1.5 g of N- [6 - [(2-propynyl) oxy] hexyl] benzene-methanamine, except that 50 ml of a mixture is used. 1: 1 of triethylamine and THF instead of diethylamine. Purification by CEC eluting with system B (95/5/1) gives 2.0 g of the title compound as an orange oil, C.C.M. (system B 95/5/1) Rf 0.13.

Intermediate 13

4- [3 - [[6-J [2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethyl] (phenylmethyl) amino JhexylJoxyJ-1-propynyl) benzamide

We start with 550 mg of intermediate 24 and 250 mg of 4-iodo-benzamide, except that 10 ml of a 4: 1 mixture of diethylamine and THF are used instead of diethylamine, and that the addition of the reaction mixture to ether is not followed by filtration. Purification of the concentrated reaction mixture by CEC, eluting with system B (90/10/1), gives 540 mg of the title compound as a pale yellow oil, C.C.M. (system B 90/10/1) Rf 0.35.

Intermediate 14

N-J4- [3 - [[6-J [2- (4-Amino-3,5-dichlorophenyl) -2-hydroxyethyl] - (phenylmethyl) amino JhexylJ oxy J-1-propynyl] phenylJ-2- (dimethylamino ) acetamide

A suspension of 1.0 g of intermediate 24, of 680 mg of 2- (dimethylamino) -N- (4-iodophenyl) -acetamide, of 450 mg of dicyclohexylamine, of 50 mg of BTPC and 10 mg of copper (I) iodide in 15 ml of acetonitrile. 25 ml of ether are added, the precipitate is filtered off, the solvent is evaporated off and the residue is purified by CEC, eluting with system C (50/50/1), which gives 800 mg of the title compound under form of a yellow oil, TLC (system A 80/20/2) Rf0.53.

Intermediate 15

4- [4- [3 '[[6- [(Phenylmethyl) amino JhexylJ-1-propynylJbenzoyl] -morpholine

14.4.0 g of 4- (4-iodobenzyl) morpholine and 3.09 g of N- [6 - [(2-propynyl) oxy] hexyl] -benzene are reacted according to the intermediate process. methanamine. Purification by CEC eluting with an ethyl acetate / triethylamine system (100/1) gives 2.21 g of the title compound as a yellow oil, C.C.M. (ethyl acetate / triethylamine (100/1) Rf 0.2.

Intermediate 16

4- [4 - [(5-Bromopentyl) oxy Jbutyl] -N, N-dimethylbenzene-acetamide A mixture of 2.50 g of intermediate 7 is stirred, 1.90 g of 1-bromo-5- (3 -butynyloxy) pentane, 1.73 g of dicyclohexylamine, 50 mg of BTPC and 10 mg of copper iodide in 30 ml of acetonitrile and under nitrogen for 2 h. 80 mg of ether are added, the mixture is filtered, the filtrate is concentrated and the residue is brought to reflux in 100 ml of ethanol with charcoal and filtered (Hyflo). The hydrogenation of the solution is carried out on 1.0 g of a paste in water, at 50%, of palladium on carbon at 10%, for 48 h, filtered (Hyflo) and concentrated, which gives a residue which is purified by CEC, eluting with an ether / ethyl acetate system (100/0 -> 80/20), which gives 1.62 g of the title compound in the form of a yellow oil, CCM (ether) Rf 0.12.

Intermediate 17

(Z) -N-J [3-J3 - [[6- [[2- (4-Amino-3,5-dichlorophenyl) -2-hydroxy-ethylJ (phenylmethyl) amino JhexylJoxy J-1-propenyl] phenylJmethylJ-acetamide

A solution of 1.44 g of intermediate 1, 2.0 g of intermediate 9 and 660 mg of DEA in 20 ml of THF is left to stand for 20 h at room temperature, under nitrogen. The precipitate is separated by filtration and the filtrate is concentrated, which gives an oil which is dissolved in 20 ml of methanol cooled in an ice bath, and treated in portions with 750 mg of sodium borohydride. The reaction mixture is stirred at room temperature under nitrogen for 2 h, and concentrated, giving an oil to which 100 ml of water are added. The mixture is extracted with 3 × 50 ml of ethyl acetate and the combined extracts are washed with 50 ml of water and 50 ml of brine, they are dried and concentrated, which gives an oil which is purified by CEC, eluting with system B (95/5/1), which gives 1.51 g of the title compound in forine of a yellow oil, TLC (system B 95/5/1) Rf 0.13. Intermediaries 18 to 24 are prepared in a similar manner.

Intermediate 18

4- [4- [5-JJ2- (4-Amino-3,5-dichlorophenyl) -2-hydroxyethyl] (phenylmethyl) amino JpentylJoxy] butyl] -N, N-dimethylbenzene-acetamide

We start with 690 mg of intermediate 1 and 1.01 g of intermediate 8. The sodium borohydride / methanol reaction is continued for 24 h. Purification by CEC eluting with system C (50/50/1) gives 1.12 g of the title compound in the form of a yellow oil, C.C.M. (ethyl acetate / hexane 1/1 + a few drops of triethylamine) Rf 0.1.

Intermediate 19

(Z) -2- [4-J3-J [6-JJ 2- (4- Amino-3,5-dichlorophenyl) -2-hydroxy-ethyl] (phenylmethyl) amino JhexylJ oxy J-1-propenylJphenoxyJ-N, N-dimethylacetamide

We start with 951 mg of intermediate 1 and 1.42 g of intermediate 11. Purification by CEC eluting with system B

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(97/3/1) gives 1.11 g of the title compound as a yellow oil, C.C.M. (system B 95/5/1) Rf 0.31.

Intermediate 20

N-J4- [2- [[86 - [[2- (4-Amino-3,5-dichlorophenyl) -2-hydroxyethyl] - (phenylmethyl) aminoJhexyl] oxyJethyl] phenyl] methane-tallow onamide

We start with 0.7 g of intermediate 1 and 1 g of N- [4- [2 - [[6 - [(phe-nyhnethyl) ammo] hexyl] oxy] ethyl] phenyl] methane-sulfonamide. Purification by CEC eluting with system B (98/2/1) gives 1.2 g of the title compound in the form of a yellow oil, C.C.M. (system A 80/20/1) Rf 0.47.

Intermediate 21

N- [4- [3 - [[6 - [[2- (4-Amino-3,5-dichlorophenyl) -2-hydroxyethyl] - (phenylmethyl) aminoJhexyl] oxyJ-1-propynyl] phenyl] -N-methylmé -thane-sulfonamide

We start with 660 mg of intermediate 1 and 1.0 g of intermediate 12. The sodium borohydride / methanol reaction is continued for 18 h. Purification by CEC eluting with system C (33/66/1 - 50/50/1) gives 320 mg of the title compound as a pale yellow oil, C.C.M. (hexane / ether / triethylamine 50/50/1) Rf 0.04.

Intermediate 22

(Z) -4- [3 - [[6-JJ 2- (4-Amino-3,5-dichlorophenyl) -2-hydroxyethyl] - (phenylmethyl] aminoJhexylJoxy J-1-propenyl] -N, N-dimethylbenz- amide

1.0 g of intermediate 1 and 1.39 g of intermediate 10 are used. Purification by CEC eluting with system B (97/3/1) gives 0.93 g of the title compound in the form of a yellow oil, TLC (system B 95/5/1) Rf 0.3.

Intermediate 23

4- [4- [3 - [[6 - [[2- (4-Amino-3,5-dichlorophenyl) -2-hydroxyethyl] (phe-nylmethyl) amino JhexylJoxyJ-1-propynylJbenzoylJmorpholine

We start with 1.0 g of intermediate 1 and 1.53 g of intermediate 15. The sodium borohydride / methanol reaction is continued for 60 h. Purification by CEC eluting with system B (97/3/1) gives 1.54 g of the title compound in the form of an orange oil, C.C.M. (system B 95/5/1) Rf 0.25.

Intermediate 24

4-Amino-3,5-dichloro-a- [[(phenylmethyl) [6-J (2-propynyl) oxyJ-hexylJ aminoJmethylJbenzene-methanol

We start with 1.0 g of intermediate 1 and 870 mg of N- [6 - [(2-propynyl) oxy] hexyl] benzene-methanamine, carrying out the first stage of the reaction for only 25 min. Purification by CEC eluting with system C (20/80/1) gives 1.27 g of the title compound as a colorless oil, C.C.M. (C 20/80/1 system) Rf 0.33.

Intermediate 25

N, N-Bis [2- (phenylmethoxy) ethyl] -4-iodobenzene-amine

A mixture of 2 g of 2,2 '- (4-iodophenylimino) bis-ethanol, 2.3 g of benzyl bromide, 0.4 g of tetra-n-butylammonium bisulfate is vigorously stirred for 5 h. 20 ml of 50% sodium hydroxide solution. The mixture is diluted with 20 ml of water, it is extracted with 2 x 20 ml of ethyl acetate and the combined extracts are washed successively with 50 ml of brine, dried and evaporated. Purification by CEC eluting with a hexane / ether system (19/1 -> 9/1) gives 2.1 g of the title compound as a pale yellow oil, C.C.M. (hexane / ether 1/1) Rf 0.7.

Intermediate 26

4-Amino-3,5-dichloro-a- [[[6- [J3-J4-bisJ2- (phenylmethoxy) ethyl] -amino J phenyl] -2-propynylJoxy Jhexyl] (phenylmethyl) aminoJmethylJbenzene-methanol

5 A solution of 1.9 g of intermediate 24, 1.75 g of intermediate 25, 90 mg of BTPC and 9 mg of iodide of iodide is stirred at room temperature under nitrogen for 2 days. copper (I) in 30 ml of diethylamine / tetrahydrofuran mixture (4/1).

The solvent is evaporated off and the residue is purified by CEC, eluting 10 with system C (20/80/1 -> 30/70/1), which gives 1.75 g of the title compound as an oil orange, CCM (C 20/80/1 system) Rf 0.17.

Intermediate 27

15 4- Amino-3,5-dichloro-a - [[6-f [3-J4- [2- (dimethylamino) ethoxy J phenyl] (2-propynyl) oxy Jhexyl] (phenylmethyl) aminoJmethyl / -benzene-methanol

A solution of 1.57 g of 2- (4-iodophenoxy) -N, N-dimethylethanamine, 2.94 g of intermediate 24 and 100 is stirred at room temperature under nitrogen for 16 h. mg of BTPC and 10 mg of copper iodide in 30 ml of diethylamine and 10 ml of acetonitrile. The solvent is evaporated and the residue is purified by CEC eluting with system B (95/5/1), which gives the title compound as a red oil (3.57 g), C.C.M. (system B 95/5/1) Rf 0.26.

Example 1

4- [3-J [5-J [2- (4-Amino-3,5-dichlorophenyl) -2-hydroxyethyl [amino J-hexyl] oxyJpropylJbenzamide

The hydrogenation of 1.3 g of intermediate 13 is carried out on 280 mg of an aqueous paste at 50% of palladium oxide on carbon at 10%, in 15 ml of ethanol containing 2 ml of hydrochloric acid (Concentrated HCl / EtOH, 1/9 by volume). The catalyst is filtered off through a Hyflo filter, the solvent is evaporated and the residue is partitioned between 25 ml of 8% sodium bicarbonate solution and 25 ml of ethyl acetate. The aqueous layer is reextracted with 25 ml of ethyl acetate and the combined organic extracts are washed with an 8% sodium bicarbonate solution and brine, they are dried and concentrated to obtain a semi-solid 40 which is triturated with an ether / ethyl acetate system (~ 4/1), which gives 240 mg (22%) of the tire compound in the form of an off-white solid with melting point 91-94 ° , CCM (system A 80/20/2) Rf 0.25.

Examples 2 to 9 are prepared analogously.

45 Example 2

N-J4- [3 - [[6- [[2- (4-Amino.-3,5-dichlorophenyl) -2-hydroxyethyl] ami-noJhexyl] oxy Jpropyl] phenyl] methane-tallow onamide

We start with 500 mg of intermediate 3. Evaporation of the extracts so in ethyl acetate gives an oil which is purified by CEC eluting with system B (95/5/1), then l triturated with anhydrous ether to obtain 100 mg of the title compound in the form of a white powder with melting point 62-64 °.

Analysis for C24H35C12N304S, 0.35C4H1 () 0:

55 Calculated: C 54.63 H 6.95 N7.52%

Found: C 54.82 H 7.26 N 7.36%

Example 3

60 ethyl 4-J3-JJ6- [J (4-Amino-3,5-dichlorophenyl) -2-hydroxyethyl] aminoJ-hexyl] oxyJpropyl] benzoate

We start with 500 mg of ethyl 4- [3 - [[6 - [[4-Amino-3,5-dichlorophenyl) -2-hydroxyethyl] (phenylmethyl) amino] hexyl] oxy] -1-propynyl] benzoate , using as hydrogenation catalyst 60 mg 65 of an aqueous paste at 50% of prereduced palladium on carbon at 10%. The residue obtained is purified by evaporation of the extract in ethyl acetate by means of a CEC, eluting with system C (50/50/1), which gives 97 mg of the title compound in the form of 'a

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white solid with melting point 66-68 ° C.C.M. (C 50/50/1 system) Rf 0.05.

Example 4

Salt (E) -butene-dioate of N- [4- [3-J [6 - [[2- (4-amino-3,5-dichlorophé-nyl) -2-hydroxyethyl] amiti JhexylJoxy Jpropyl] phenyl] - 2- (dimethylamino) acetamide (1/1)

We start with 750 mg of intermediate 14, using 2.2 ml of concentrated HCl / EtOH mixture (1/9 by volume). 520 mg of the yellow oil obtained after concentration of the extracts in ethyl acetate are dissolved in 5 ml of methanol and treated with a solution of 120 mg of fumaric acid in 2 ml of methanol, the methanol is evaporated and the residue is triturated with ether, which gives 610 mg of a yellow solid which is recrystallized from 15 ml of isopropanol to obtain 100 mg of the title compound in the form of a white solid with a melting point 106-110 °.

Analysis for C27H40Cl2N4O3, C4H4O4:

Calculated: C 56.79 H 6.76 N8.55 Cl 10.82% Found: C 56.32 H 6.97 N7.94 Cl 11.32% Example 5

Salt (E) -butene-dioate of 4-J3-JJ6-JJ2- (4-amino-3,5-dichlorophenyl) -2-hydroxy ethyl] amino JhexylJoxy Jpropyl] -N, N-dimethylbenzamide

(211)

We start with 0.82 g of intermediate 22 using as hydrogenation catalyst 100 mg of an aqueous paste at 50% of palladium prereduced on carbon at 10%. Evaporation of the extracts in ethyl acetate gives an oil which is purified by CEC eluting with system B (95/5/1), which gives an oil. 0.42 g of the oil in 2 ml of methanol is treated with 47.6 mg of acetate (E) -butene-dioic acid in 2 ml of methanol and the solution is concentrated. The residue is triturated with diethyl ether, which gives 0.47 g of the title compound in the form of a white solid with melting point 107-109 °.

Analysis for C2ÖH37C12N303,0,5C4H404:

Calculated: C59.2 H 6.9 N7.4 Cl 12.5%

Found: C 59.0 H 7.2 N 7.2 Cl 12.6%

Example 6

4-J4-J3-JJ6-J J2- (4-Amino-3,5-dichlorophenyl) -2-hydroxyalkoxyJ-amino JhexylJ oxyJpropyl] benzoyl [morpholine

We start with 0.70 g of intermediate 23 using as hydrogenation catalyst 80 mg of an aqueous paste at 50% of palladium prereduced on carbon at 10%. Evaporation of the extract in ethyl acetate gives an oil which is purified by CEC eluting with system B (95/5/1), which gives 391 mg of the title compound in the form of 'a yellow oil. A solution of 390 mg of the title compound in 2 ml of methanol is treated with 41.1 mg of (E) -butene-dioic acid in 2 ml of methanol and the solvent is evaporated, which gives an oil which leads, by trituration with diethyl ether, to 40 mg of the salt (E) -butene-dioate (2/1) of the title compound in the form of a white solid with melting point 114-116 °.

Analysis for (C28H39C12N304) 2, C4H404:

Calculated: C 59.0 H 6.8 N6.9 Cl 11.6% Found: C 58.7 H 6.0 N6.7 Cl 11.9% Example 7

N - [[3-J 3-JJ 6-J [2- (4-Amino-3,5-dichlorophenyl) -2-hydroxyethyl] -amino JhexylJoxy JpropylJphenylJmethylJ acetamide

The starting point is 1.40 g of intermediate 17 using as hydrogenation catalyst 170 mg of an aqueous paste at 50% of palladium prereduced on carbon at 10%. The solid obtained from the ethyl acetate extracts is triturated with diethyl ether, which gives 0.76 g of the title compound in the form of a white solid with melting point 91-94 °, CCM (system A 80/20/2) Rf 0.45.

Analysis for C26H37C12N303:

Calculated: C61.2 H 7.3 N 8.2 Cl 13.9% Found: C 60.7 H 7.5 N7.9 Cl 13.9%

Example 8

Salt (E) -butene-dioate of 2- [4-J3-JJ6- [J2- (4-Amino-3,5-dichlorophé-nyl) -2-hydroxyalkoxy J amino JhexylJ oxy JpropylJphenoxyJ-N, N-di- methylacetamide (2/1)

We start with 0.99 g of intermediate 19 using as hydrogenation catalyst 115 mg of an aqueous paste at 50% of palladium prereduced on carbon at 10%. The concentration of the extract in ethyl acetate gives an oil. 0.70 g of the oil in 2 ml of methanol is treated with 75.5 mg of (E) -butene-dioic acid in 2 ml of methanol and the solution is concentrated. The residue is triturated with diethyl ether, which gives 0.63 g of the title compound in the form of a buff-colored solid with melting point 116-118 ° C.C.M. (system B (95/5/1) Rf 0.17.

Example 9

N-J4- [3-J [6-JJ2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethyl [aminoJhexylJoxyJpropyl [phenyl [-N-methyl-methane-sulfonamide] hydrochloride

We start with 250 mg of intermediate 21 using as hydrogenation catalyst 50 mg of an aqueous paste at 50% of palladium oxide prereduced on carbon at 10%. The concentration of the extract in ethyl acetate gives an oil which is purified by CEC eluting with system B (99/1/1 -> 95/5/1), which gives 130 mg of 'an orange oil. The oil is treated in 5 ml of ether with ethereal hydrogen chloride and the resulting oil is triturated with anhydrous ether to give 90 mg of the title compound as a yellow solid, C.C.M. (system B 95/5/1) Rf 0.56.

Analysis for C25H37C12N304S, HC1:

Calculated: C 51.50 H 6.57 N7.21 Cl 18.24 S 5.50% Found: C 51.14 H 7.02 N6.87 Cl 17.82 S 5.00% Example 10

4- Amino-3,5-dichloro-a - [[J6- [3 * J4- [2- (dimethylamino) ethyl] phenyl [propoxy JhexylJamino Jméthyl [benzene-methanol

A solution of 1.54 g of the base of intermediate 4, 2.94 g of intermediate 24, 100 mg of BTPC and 10 mg of copper iodide (I) is stirred under nitrogen for 18 h. in 30 ml of diethylamine and 10 ml of acetonitrile. The solution is concentrated in vacuo, which gives a brown oil which is purified by CEC, eluting with system B (95/5/1), which gives 2.4 g of a yellow oil. The hydrogenation of 2.3 g of the oil is carried out on 500 mg of an aqueous paste at 50% of palladium oxide on carbon at 10%, in 20 ml of ethanol containing 6.9 ml of acid hydrochloric (concentrated HCl / EtOH, 1/9 by volume). The catalyst is separated by filtration through a Hyflo filter, the ethanol is evaporated and the residue is partitioned between 20 ml of 8% solution of sodium bicarbonate and 20 ml of ethyl acetate. The aqueous phase is re-extracted with 20 ml of ethyl acetate and the combined organic extracts are washed with 20 ml of sodium bicarbonate solution and 20 ml of brine, they are dried and concentrated to give a yellow oil. The oil is purified by CEC, eluting with system B (98/2/1), which gives 1.2 g of a pale yellow oil which is triturated with hexane to obtain 1.1 g of the title compound as a white solid with a melting point 41.5-43.5.

Analysis for C27H40Cl2N3O2:

Calculated: C 63.64 H 7.91 N 8.25 Cl 13.92% Found: C 63.23 H 8.37 N8.10 Cl 13.69%

Example 11

4- [4- [5 - [[2- (4-Amino-3,5-dichlorophenyl) -2-hydroxyethyl [amino J-pentyl [oxyJbutyl] -N, N-dimethylbenzene-acetamide

The hydrogenation of 1.00 g of intermediate 18 is carried out in 20 ml of ethanol containing 1.48 ml of hydrochloric acid (HCl

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centered / EtOH, 1/9 by volume) on 150 mg of an aqueous paste at 50% of pre-reduced palladium on carbon at 10%. The reaction mixture is filtered (Hyflo) and the filtrate is concentrated. The residue is partitioned between 100 ml of ethyl acetate and 2 x 50 ml of 8% aqueous sodium bicarbonate solution. The dehydrated organic layer is concentrated and the residual oil is purified by CEC, eluting with system D (100/0/1 -> 90/10/1), which gives 0.69 g of the title compound in the form of 'a yellow oil. 469 mg of the title compound in 2 ml of methanol are treated with 51.9 mg of (E) -butene-dioic acid in 2 ml of methanol. The solution is concentrated, giving an oil which is triturated with diethyl ether to obtain 407 mg of the salt (E) -butenedioate (2/1) of the title compound, melting point 107-110 °.

Analysis for C27H39C12N303,0,5C4H4.04:

Calculated: C59.8 H 7.1 N7.2 Cl 12.2%

Found: C 59.9 H 7.4 N 7.0 Cl 12.0% Example 12

N- [4- [3 - [[6 - [[2- (4-Amino-3,5-dichlorophenyl) -2-hydroxyethyl) ami-no] hexyl] oxy] ethyl] phenyl] methane-tallow onamide

The hydrogenation of 1.2 g of intermediate 20 is carried out as in Example 11, using as catalyst 150 mg of an aqueous paste at 50% of palladium oxide prereduced on carbon at 10%. Evaporation of the extract in ethyl acetate gives a yellow oil which is purified by CEC eluting with system B (92/8/1), which gives a pale yellow oil which is triturated with ether to obtain 445 mg of the title compound in the form of a white solid with melting point 62-65 °.

Analysis for C23H33CI2N3O4S:

Calculated: C 53.28 H 6.42 N8.10 Cl 13.68 S 6.18%

Found: C 52.94 H 6.40 N 7.79 Cl 13.96 S 6.17% Example 13

4- [3 - [[6 - [[2- (4-Amino-3,5-dichlorophenyl) -2-hydroxyethyl] amino J-hexyl] oxyJpropyl] benzene-acetamide

950 mg of 4- [3 - [(6-bromohexyl) oxy] propyl] benzene-acetamide is added to a stirred solution of 900 mg of 4-amino-a- (amino-ethyl) -3,5-dichlorobenzene-methane. and 650 mg of DEA in 10 ml of DMF, at 100 °, under nitrogen. After one hour, the solvent is evaporated off and the residue is partitioned between 20 ml of an 8% solution of sodium bicarbonate and 20 ml of ethyl acetate. The organic layer is washed with water and brine, dried and concentrated in vacuo to give a yellow solid which is triturated with ether to obtain 510 mg of the title compound under form of an off-white powder with a melting point of 104-106 °.

Analysis for C25H35CI2N3O3:

Calculated: C 60.48 H 7.11 N 8.46 Cl 14.28%

Found: C 60.58 H 7.35 N8, ll Cl 13.83% Example 14

4-amino-3,5-dichloro-a - (E) -butene-dioate salt - [[[6- [3- [4- (meth-oxymethyl) phenyl] propoxyJhexyl] aminoJmethylJbenzene-metha-nol (2/1 )

Reacting according to the method of Example 13.1.0 g of 1- [3 - [(6-bromohexyl) oxy] propyl] -4- (methoxymethyl) benzene and 1.0 g of 4-amino- a- (aminomethyl) -3,5-dichlorobenzene-methanol. The concentration of the extract in ethyl acetate gives an oil which is purified by CEC eluting with system B (90/10/1), which gives 620 mg of a yellow oil. The oil is treated in 5 ml of isopropanol with a hot solution of 20 mg of fumaric acid in 2 ml of isopropanol and, after one hour, the two phases are vigorously stirred, which leaves a yellow precipitate pale which is collected by filtration and dried under vacuum to obtain 550 mg of the title compound in the form of a pale yellow powder with melting point 110-112 °, TLC (system A 80/20/2) Rf0,43.

Analysis for C2SH36C12N203,0,5C4H404:

Calculated: C 59.89 H 7.07 N5.17 Cl 13.09%

Found: C 59.33 H 6.87 N 4.88 Cl 13.31% Example 15

4- [3 - [[6 - [[2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethyl] -aminoJhexyl] oxyJpropylJ benzoic acid

600 mg of the product of Example 3 in 8 ml of ethanol are treated with 4 ml of 2N sodium hydroxide and the mixture is stirred at reflux for 1 h. The ethanol is evaporated, 20 ml of water are added to the residue and the mixture is neutralized using 2N hydrochloric acid. 25 ml of ethyl acetate are added and the two-phase mixture is stirred vigorously for 10 min. The resulting precipitate is collected by filtration, washed with ethyl acetate and dried, which gives 450 mg of a cream which is triturated with 10 ml of hot methanol and which is purified to obtain 290 mg of the title compound in the form of a white powder with a melting point of 190-191 ° C.

Analysis for C24H32Cl2N204:

Calculated: C 59.63 H 6.67 N 5.79 Cl 14.67%

Found: C 59.22 H 6.82 N 5.62 Cl 14.40%

Example 16

4-Amino-3,5-dichlorophenyl-a - [[[6- [3- [4- [(4-morpholinyl) methylJ-phenylJpropoxy JhexylJ amino JmethylJbenzene-methanol

0.67 g of the product of Example 6 is added dropwise in 10 ml of benzene to 300 mg of lithium aluminum hydride in 15 ml of anhydrous diethyl ether, at room temperature, under nitrogen. The suspension is stirred for 18 h at room temperature and treatment with 0.3 ml of water, 0.6 ml of 2N aqueous sodium hydroxide and 0.6 ml of water gives a precipitate which is separated by filtration (Hyflo). The filtrate is concentrated, which gives an oil which is purified by CEC, eluting with system B (95/5/1) to obtain 318 mg of the title compound in the form of a white solid with melting point 57 -59 °, CCM (system B (95/5/1) Rf 0.22.

Example 17

4-amino-3,5-dichloro-a - (E) -butene-dioate salt - [[[6- [3-f 4 - [[2- (dimethylamino) ethyl] amino J phenyl] propoxy Jhexyl] amino JmethylJ -benzene-methanol (2/3)

440 mg of the free base of the product of Example 4 are treated with 420 mg of lithium aluminum hydride following the method of Example 16. After 7 days, 1 ml of water, 2 ml are successively added of 2N aqueous sodium hydroxide and 1 ml of water, and the precipitate is separated by filtration through a Hyflo filter and the ether is evaporated to obtain a brown oil. A solution of 320 mg of the oil and 78 mg of fumaric acid in 3 ml of methanol is concentrated to obtain an oil which is triturated in ether, which gives 230 mg of the title compound in the form of a brown solid with melting point 41-45 °.

Analysis for C27H42C12N402,1,5C4H404:

Calculated: C 56.66 H 6.91 N8.01 Cl 10.13%

Found: C 56.59 H 7.35 N7.30 Cl 9.61%

Examples 18 and 19 are prepared according to the method of Example 1. Example 18

4-Amino-3,5-dichloro-a- [[[6- [3-f 4- [bis (2-hydroxyethyl) amino Jphé-nylJpropoxyJhexylJ amino JméthylJbenzène-méthanol

We start with 402 mg of intermediate 26, using 0.9 ml of concentrated HCl / EtOH at 1/9 by volume. Evaporation of the extracts in ethyl acetate gives a brown oil which is purified by CEC, eluting with system B (95/5/1 -> 80/20/1) to obtain 85 mg of the compound of title as a pale yellow oil, TLC (system A 80/20/2) Rf 0.33. 5 (CDC13) 1.2-1.63 and 1.84 (—CH2—); 3.4 (—OCH2—); 3.54 and 3.81.8H (-CH2CH2OH);

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6.62 and 7.04.4H (CH of the phenyl ring); 7.17, 2H (CH of the dichloroaniline nucleus).

Example 19

4-Amino-3,5-dichloro-a - [[[6-f3-f4- / 2- (dimethylamino) ethoxyJphé-nylfpropoxyJhexyl] amino Jméthyl] benzène-méthanol

We start with 3.42 g of intermediate 27, using as hydrogenation catalyst 750 mg of an aqueous paste at 50% of palladium prereduced on 10% carbon, in 30 ml of ethanol containing 10.1 ml hydrochloric acid (concentrated HCl / EtOH, 1/9 by volume). The oil obtained is purified by evaporation of the ethyl acetate extracts by CEC eluting with system A (80/20/2) then by another CEC chromatography of the impure fractions eluting with system B (95 / 5/1). 493 mg of the combined oils obtained in 5 ml of methanol are treated with 109 mg of (E) -butenedioic acid in 5 ml of methanol. The solution is concentrated and the residual foam is treated with diethyl ether to obtain the title compound in the form of a pale yellow foam (0.361 g), C.C.M. (system A 80/20/2) Rf 0.5.

Analysis for C27H4iCl203, l, 25C4H404,0,8H20:

Calculated: C56.0 H 7.0 N6, l Cl 10.3% Found: C56, l H 7.2 N6.2 Cl 11.0%

The following presents examples of suitable formulations of the compounds of the invention. The term "active substance" is used here to represent a compound of the invention.

Tablets (direct compression)

mg / tablet

Active substance 2.0

Microcrystalline cellulose USP 196.5

Magnesium stearate BP 1.5

200.0

The active substance is sieved through a suitable sieve, mixed with the excipients and compressed using punches 7 mm in diameter.

Tablets of other strengths can be prepared by changing the ratio of active ingredient to microcrystalline cellulose or the weight of the tablet and using appropriate punches.

The tablets can be coated with a film with suitable film-forming materials such as hydroxypropyl methylcellulose, using standard techniques. Alternatively, they can be dra-geified.

Syrup (without glucose)

5 ml dose

Active substance 2.0 mg

Hydroxypropylmethylcellulose USP

(viscosity type 4000) 22.5 mg

Aroma pad

Dye as needed

Conservative

Sweetener

Purified water BP q.s.p. 5.0 ml

The hydroxypropyl methylcellulose is dispersed in hot water, cooled and then mixed with an aqueous solution containing the active substance and the other constituents of the formulation. The volume of the resulting solution is made up and mixed. The syrup is clarified by filtration.

Pressurized aerosol with measured dose A. Aerosol with a mgdose suspension measured by bottle

Active ingredient micronized 0.100 26.40 mg

Oleic acid BP 0.199 2.64 mg

Trichlorofiuoromethane BP 23.64 5.67 g

Dichlorodifluoromethane BP 61.25 14.70 g

The active substance is micronized in a fluid jet disintegrator until a fine particle size is obtained. Oleic acid is mixed with trichlorofluoromethane at a temperature of 10-15 ° C and the micronized drug is mixed in the solution with a high shear mixer. A metered amount of suspension is introduced into aluminum aerosol bottles and suitable metering valves dispensing 85 mg of suspension are fixed on the bottles and the bottles are pressurized by the valves with dichlorodifluoromethane.

B. Aerosol of a mgdose solution measured per bottle

Active substance 0.055 13.20 mg

Ethanol BP 11,100 2.66 g

Dichlorotetrafluoroethane BP 25,160 6.04 g

Dichlorodifluoromethane BP 37.740 9.06 g

BP oleic acid or a suitable surfactant can also be included, for example Span 85 (sorbitol trioleate).

The active substance is dissolved in ethanol with oleic acid or any surfactant. Is introduced into suitable aerosol containers a metered amount of the alcoholic solution, then dichlorotetrafluoroethane. Appropriate metering valves are attached to the containers and pressurized with dichlorodifluoromethane through the valves.

Injection for intravenous administration,,

mg / ml

Active substance 0.5 mg

Sodium chloride BP as required

Water for injection BP 1.0 ml

Sodium chloride can be added to adjust the tone of the solution and the pH can be adjusted, using an acid or an alkali, to the pH of optimal stability and / or to facilitate the solubilization of the active substance. It is also possible to use suitable buffer salts.

The solution is prepared, clarified and introduced into ampoules of suitable capacity sealed by melting the glass. The injection is sterilized by heating in an autoclave using one of the acceptable cycles. The solution can also be sterilized by filtration and introduced into sterile ampoules under aseptic conditions. The solution can be conditioned in an atmosphere of nitrogen or any other suitable gas.

Inhalation cartridges mg / cartridge

Active ingredient micronized 0.200

Lactose BP q.s.p. 25.0

The active substance is micronized in a fluid jet disintegrator until it has a fine particle size before being mixed with normal quality lactose for tablets in a high energy mixer. The sprayed mixture is introduced into hardness No. 3 capsules on a suitable encapsulating machine. The contents of the cartridge are administered using a powder inhaler like Rotahaler from Glaxo.

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Claims (10)

669,787 1. Compounds of general formula (I) Cl \ m // h2N — x " / Cl in which X represents a bond, or a C 1-6 alkylene chain, alkeny-lene or C2-alkynylene, and Y represents a bond, or a Cw alkylene chain, CM alkenylene, provided that the total of the sum of the carbon atoms in X and Y does not exceed 8; Ar represents a phenyl group substituted by one or more substituents chosen from nitro groups, - (CH2) qR, - (CH2) rR7, - 0 (CH2) qC0R9 or -0 (CH2) tR13; R is a C | _3 alkoxy group, - NR3R4 or --NR5COR6; R1 and R2 each represents a hydrogen atom or a C1-3 alkyl group, provided that the total sum of the carbon atoms in R1 and R2 does not exceed 4; R3 and R4 each represents a hydrogen atom or a CM alkyl group, or NR3R4 forms a saturated heterocyclic amino group which has 5-7 members and optionally contains, in the ring, one or more atoms chosen from - O - , —S— or a group —NH— or —N (CH) 3 -; R5 represents a hydrogen atom or a Q-4Ì alkyl group R6 represents a hydrogen atom or a CM alkyl, CM alkoxy or —NR3R4 group; R7 represents a group —NR5SO2R8, —NR5COCH2N (Rs) 2, -COR9, -SR10, -SO2R10, - CNou —NR "R12; R8 represents a CM, phenyl or - NR3R4 alkyl group; R9 represents hydroxy, CM alkoxy or -NR3R4; R10 is a hydrogen atom or a CM alkyl group optionally substituted by a hydroxy, CM alkoxy group or —NR3R4; R11 and R12 represent a hydrogen atom or a CM alkyl group at least one of which is a C2Jt alkyl group substituted by a hydroxy group, C1-4 alkoxy or —NR3R4; R13 represents a hydroxy group, —NR3R4, —NR "R12 or alkoxy in CH optionally substituted by a hydroxy group, alkoxy in CM or NR3R4 q represents an integer from 1 to 3 r represents an integer from 0 to 3 t is an integer equal to 2 or 3 and their physiologically acceptable salts and solvates. 2. Compounds according to claim 1, characterized in that the total of the sum of the carbon atoms in the —X— and —Y— chains is equal to 4, 5, 6 or 7. 2 3 669,787 3. Compounds according to claim 1 or 2, characterized in that X represents - (CH2) 3— or - (CHj) ^ -, and Y represents - CH2—, - (CH2) 2- or - (CH2) 3 ~ . 4. Compounds according to any one of claims 1 to 3, characterized in that R1 and R2 are both hydrogen atoms, or R1 is a hydrogen atom and R2 is a C 1-3 alkyl group. 5. Compounds according to claim 1, characterized in that Ar represents a phenyl group substituted by a group - (CH2) qR in which R represents a C ^ alkoxy, dialkyl (in Clamino, morpholino, piperidino, piperazino, N-methylpiperazino) group, - NHCOR6 where R6 is a CM alkyl group and q is equal to 1 or 2; —OCH; jCOR9 in which R9 is a dialkyl group (in Clamino: —0 (CH2) 2R13 in which R13 is a dialkyl group (in Clamino; - (CH2) SrR7 in which R7 represents —NR5S02R8 where R5 represents a hydrogen atom or a methyl group, and R8 represents a CM alkyl group, R7 represents —NHCOCH2N (Rs) 2 in which the two groups R5 represent a CM alkyl group, or R7 represents —COR9 in which R9 represents a CM alkoxy group, amino-dialkyl (in CM) amino, morpholino, piperidino, piperazino or N-methylpiperazmo, or R7 represents io - NR "R12 in which one of the Ru and R12 groups, or both, represents a CM alkyl group substituted by a hydroxy or dialkyl (CM) amino group and the other represents a hydrogen atom and r is zero or equal to 1. 6. Compounds of general formula (la) according to claim 1 15 Cl \ / * \\ H2N —.— ^ HCH2NHCH2XCH20CH2YAr (la) in which X represents a C34 alkylene chain and Y represents a Cw alkylene chain, provided that the total number of carbon atoms in X and Y is 5 or 6, and Ar represents a phenyl group substituted by a group selected from alkoxy (CM) methyl, morpholinomethyl, dialkyl (C1-4) aminoalkyl (Cw) groups, - CH2NHCOR6 where R6 is a CM alkyl group; —NRsSO2R8 where R5 is hydrogen or methyl, and R8 is C14 alkyl; —NHCOCH2N (R5) 2 where the two R5 groups represent CM alkyl groups; —COR9 where R9 is a hydroxy group, CM alkoxy, amino, dialkyl (C14) amino or morpholino; —CH2COR9 where R9 is an amino dialkyl (CM) amino group; —NR1: 1R12 where R11 and R12 both represent a C24 hydroxyalkyl group; dialkyl (CM) aminoethylamino; —OCH2COR9 where R9 is a dialkyl (CM) amino group; or —0 (CH2) 2R13 where R13 is a dialkyl (CM) amino group; and their physiologically acceptable salts and solvates. 40 7. Compounds according to claim 6, characterized in that Ar represents a phenyl group substituted by a group chosen from the groups - CH2NHCORe where R6 is a methyl group; —NHS02R8 where R8 is a methyl group; - COR9 where R9 is a hydroxy, ethoxy, amino or morpholino group; or - CH2COR9 where 45 R9 is an amino or dimethylamino group. 8. The following compounds according to claim 1: 4- [3 - [[6 - [[2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethyl] ami-no] hexyl] oxy] propyl] benzamide; ethyl le- [3 - [[6 - [[((4-amino-3,5-dichlorophenyl) -2-hydroxyethyl] ami-50 no] hexyl] oxy] propyl] benzoate; leN - [[3- [3 - [[6 - [[2- (4-amino-3,5-dichlorophenyl) -2-hydroxy-ethyl] amino] hexyl] oxy] propyl] phenyl] methyl] acetamide; 4- [4- [5 - [[2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethyl] ami-no] pentyloxy] butyl] -N, N-dimethylbenzene-acetamide; 55 4- [3 - [[6 - [[2- (4-amino-3,5-dichlorophenyl) -2-hydroxy-ethyl] amino] hexyl] oxy] propyl] benzoic acid; la4- [4- [3 - [[6 - [[2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethyl] -amino] hexyl] oxy] propyl] benzoyl] morpholine; N- [4- [3 - [[6 - [[2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethyl] -60 amino] hexyl] oxy] ethyl] phenyl] methane-sulfonamide; [4- [3 - [[6 - [[2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethyl] ami-no] hexyl] oxy] propyl] benzene-acetamide; and their physiologically acceptable salts and solvates. 9. Pharmaceutical composition, characterized in that it takes at least one compound of general formula (I) according to one of claims 1 to 8 or one of its physiologically acceptable salts or solvates, as well as a physiologically vehicle or excipient acceptable. * \\? - ^ HCH 2NHIj: XCH 20CH 2YAr (I) = - OH R2 10. Process for the preparation of the compounds according to one of claims 1 to 8 or of a physiologically acceptable salt or solvate thereof, characterized in that it comprises the reduction of an intermediate of general formula (VI) Cl \ "- ■ • V ", 11 \ —X1-X2-X3-CH, 0CH2Y-Ar (VI) \ _ / m ——— “ / Cl in which X1 is - CH (OH) - or a group which can be transformed into —CH (OH) - by reduction: X2 is —CH2NR14 (where R14 is a hydrogen atom or a protecting group) or a group which can be converted to —CH2NR14 by reduction; X3 is - CR1R2X— or a group which can be transformed into —CR1R2X— by reduction (where R1 and R2 are as defined in claim 1); X4 is - NH2 or a group which can be transformed into —NH2 by reduction, and Y and Ar are as defined in claim 1 or are groups which can be converted to these groups by reduction; at least one of X1, X2, X3 and X4 representing a reducible group and / or Y representing a reducible group and / or Ar containing a reducible group, followed, optionally, by the elimination of any protective group present; the compound being, if desired, isolated as an acceptable salt or solvate for therapeutic use, or transformed into another acceptable salt or solvate.