FI89164C - FRAMEWORK FOR THE DETERMINATION OF THERAPEUTIC DAPLORAN LINES - Google Patents

Description

1 89164

The present invention relates to a process for the preparation of dichloroaniline derivatives (I) which have a stimulatory effect on β 2 -adrenoreceptors.

Dihaloaniline derivatives have previously been described as bronchodilators with stimulatory activity at β-adrenoceptors.

Thus, British Patent Publication No. 1178191 describes compounds having the general formula

Hai 2 ^ - CH - <!: NR4R5 I1 A3

HoN I

Hai wherein the substituent Hal is a bromine or chlorine atom, R * is hydrogen or hydroxyl; R 2 and R 3 are each hydrogen or C 1-6 alkyl; and R 4 and R 3 are each hydrogen, C 1-5 alkyl, alkenyl, alkynyl / hydroxyalkyl, alkoxyalkyl, dialkylaminoalkyl, cycloalkyl, phenyl, benzyl or adamantyl, or NR 4 R 3 forms a heterocyclic ring optionally substituted with C 1-3 alkyl.

We have now found a new class of dichloroaniline derivatives which are structurally different from the compounds described in British Patent Specification No. 1178191 and which have the desired and useful activity profile.

The present invention thus provides a process for the preparation of compounds of general formula I.

2 89164

Cl 'T - \ R1 h2h -P' S - CHCH2NH <!; XCH20CH2YAr (I) OH R2

Cl wherein X is a bond or a C 1-6 alkylene chain and Y is a bond or an alkylene, C 2-4 alkenylene or C 2-4 alkynylene chain, provided that the total sum of the carbon atoms in the groups X and Y is not more than 8;

Ar is a phenyl group substituted with one or more groups selected from the group consisting of: - (CH 2) g R, wherein R is C 1-3 alkoxy, NR 3 R 4, wherein R 3 and R 4 are each a hydrogen atom or a C 1-4 alkyl group, or -NR 3 R 4 forms a morpholino; or NR 3 COR®, wherein R 3 is a hydrogen atom or a C 1-4 alkyl group, and R® is a hydrogen atom or C 1-4 alkyl, and q is an integer from 1 to 3; - (CH2) rR7, wherein R7 is NR3SO2R8, wherein R3 is as defined above and R® is C1-4 alkyl; -COR 9, wherein R 9 is hydroxy, C 1-4 alkoxy or NR 3 R 4, wherein R 3 and R 4 are as defined above; or NR 4 R 12, wherein R 11 and R * 2 both represent hydrogen or a C 1-4 alkyl group, at least one of which represents a C 2-4 alkyl group substituted by hydroxy, C 1-4 alkoxy; or NR3R4, wherein R3 and R4 are as defined above and r is an integer from 0 to 3; -O (CH 2) q CO 9, wherein q and R 9 are as defined above; or -O (CH 2) t R 4 wherein R 13 is hydrogen, C 1-4 alkoxy or NR 3 R 4 wherein R 3 and R 4 are as defined above and t is 2 or 3; and I, 89164 and are each a hydrogen atom or a C 1-3 alkyl group, provided that the total sum of the carbon atoms in the groups R 1 and R 2 is not more than 4; and their physiologically acceptable salts and solvates, for example hydrates.

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

OH

carbon atom, and when R 1 and R 2 are different groups, the carbon atom to which they are attached.

The compounds obtained according to the invention thus comprise all enantiomers, diastereoisomers and mixtures thereof, including racemates. Preferred are compounds in which the carbon atom in the group -CH- is in the R configuration.

OH

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

In the general formula (I), the chain X may be, for example, a bond, -CH2-, - (ch2) 2) -, - (ch2) 3) _ / - (ch2) 4) -, ~ (CH2) 5) - »- (ch2 ) 6) -, -CH2C = C-, - (CH2) 2 CH) CH-, - (CH2) 2C = C-, -CH = CHCH2-, -CH = CH (CH2) 2- or -CH2ChCCH2- . The chain Y can be, for example, a bond -CH2-, - (CH2) 2) -, - (CH2) 3) -, - (CH2) 4) -, -CH = CH-, -CaC-, CH2CH = CH- or - CH 2 C = C-.

The total number of carbon atoms in the chains X and Y is best 4-8. Compounds in which the total number of carbon atoms in the chains X and Y is 4, 5, 6 or 7 are particularly preferred.

In a preferred group of compounds of formula (I), X is a C 1-4 alkylene chain and Y is a C 1-4 alkylene chain. Particular compounds of this type are those in which X is - (CH2) 3) - or - (CH2) 4) - and Y is -CH2- or - (CH2) 3) -.

4 89164

In the compounds of formula (I), R 1 and R 2 may each be, for example, methyl, ethyl, propyl or isopropyl groups, except that if one of R 1 and R 2 is a propyl or isopropyl group, the other is a hydrogen atom or a methyl group. Thus, for example, R1 may be a hydrogen atom or a methyl, ethyl or propyl group. R2 may be, for example, a hydrogen atom or a methyl group. R 1 and R 2 are preferably a hydrogen atom or a methyl group.

A preferred group of compounds are those in which R 1 and R 2 are both hydrogen atoms or R 1 is a hydrogen atom and R 2 is a C 1-3 alkyl group, especially a methyl group.

Ar may be, for example, a phenyl group substituted with - (CH 2) q R [where R is C 1-4 alkoxy, for example methoxy, diC 1-4 alkylamino, morpholino, -NHCOR®, (wherein R® is C 1-4 alkyl, for example methyl), and q is 1 or 2], - (CH 2) r R 7 [wherein R 7 is -NR 5 SO 2 R®, (wherein R 5 is hydrogen or methyl, and R 5 is C 1-4 alkyl, for example methyl), -COR® (wherein R 5 is C 2-4 alkoxy , for example ethoxy, amino, diC 1-4 alkylamino, for example dimethylamino, morpholino, -NR 4 R 2 · 2 (wherein one or both of R 1 and R 12 is C 2-4 alkyl, for example an ethyl group substituted by hydroxy or a diC 1-4 alkylamino, for example a dimethylamino group, and the other is hydrogen atom), and r is 0 or 13.

A preferred group of compounds obtained according to the invention are the compounds of formula (Ia)

Cl H2H -V - CHCH 2 NHCH 2 XCH 2 OCH 2 YAr (Ia)

Ah

Cl

wherein X is an X 3-4 alkylene chain and Y is an X 3 alkylene chain, provided that the total number of carbon atoms in the groups X and Y

li 5 89164 is 5 or 6; and Ar is a phenyl group substituted with a group selected from C 1-4 alkoxymethyl (e.g. methoxymethyl), morpholinomethyl, diC 1-4 alkylaminoC 1-2 alkyl (e.g. dimethylaminoethyl), -CH 2 NHCOR 6 (wherein R® is C 1-4 alkyl (e.g. wherein R 9 is hydroxy, C 1-4 alkoxy (e.g. ethoxy, amino, diC 1-4 alkylamino, e.g. dimethylamino, or morpholino), CH 2 COR 9 (wherein R 9 is amino or diC 1-4 alkylamino, e.g. dimethylamino), -NR 1-4 alkyl; (wherein R 1 and R 2 are both hydroxy C 2-4 alkyl (e.g. hydroxyethyl), diC 1-4 alkylaminoethylamino (e.g. dimethylaminoethylamino), -OCH 2 COR 9 (wherein R 9 is diC 1-4 alkylamino, e.g. dimethylamino), or -O (CH 2) 2 R 13 (wherein R 13 is diC 1-6 alkylamino, for example dimethylamino), and their physiologically tolerable salts and solvates.

Particularly important compounds of the invention are: 4- [3 - [[6 - [[2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethyl] amino] hexyl] propyl] benzamide; ethyl 4- [3 - [[6 - [[(4-amino-3,5-dichlorophenyl) -2-hydroxyethyl] amino] hexyl] propyl] benzoate; N - [[3- [3 - [[6 - [[2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethyl] amino] hexyl] propyl] phenyl] methyl] acetamide; 4- [4- [5-t [2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethyl] -aminojpentyylioksi] bytyyli] -N, N-dimetyylibentseeniasetamidi; 4- [3 - [(6 - [[2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethyl] amino] hexyl] oxy] propyl] benzoic acid; 4- [4- [3 - [[ 6 - [[2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethyl] amino] hexyl] propyl] benzoyl] morpholine; N- [4- [3 - [[6 - [[2- ( 4-amino-3,5-dichlorophenyl) -2-hydroxyethyl] amino] hexyl] ethyl] phenyl] methanesulfonamide, 4- [3 - [[6 - [[2- (4-amino-3,5- dichlorophenyl) -2-hydroxyethyl-1-amino] hexyl] propyl] benzeneacetamide, and their physiologically tolerable salts and solvates.

Suitable physiologically acceptable salts of the compounds of general formula (I) include acid addition salts derived from inorganic or organic acids, such as hydrochlorides, hydrobromides, sulphates, phosphates, maleates, tartrates, citrates, benzoates or benzoates, 4-methoxybenzate, 4-methoxybenzate. , 4-chlorobenzoates, p-toluene sulphonates, methanesulphonates, sulphamates, ascorbates, salicylates, acetates, fumarates, succinates, lactates, glutarates, gluconates, tricarbalylates, 1-hydroxy-carboxylates, hydroxy-naphthalene-carboxylates - 2-naphthalenecarboxylates or oleate. The compounds may also form salts with suitable bases. Examples of such salts are precious metal (e.g. sodium and potassium) and alkaline earth metal (e.g. calcium or magnesium) salts.

The compounds have a stimulatory effect on β 2 -adrenoceptors, which in addition has a particularly advantageous profile. The stimulatory effect was demonstrated in isolated guinea pig trachea, with the compounds shown to relax PGG2a-induced contractions. The compounds of the invention have been shown to have a particularly long duration of action in this test.

The B2 stimulating effect of the compounds according to the invention and the compounds known from GB 208873 has been compared. The following are the test results. An activity value of 5 and below indicates effective activity as a fl2 stimulant, while a value of 40 and above indicates weak activity. Both known compounds clearly have low activity, while the compounds according to the invention have excellent activity and, in addition, a very long potency.

Power versus The effect of power on the wheel

Compound Release for prenaline (Rtsg min) RCH (CH2) 27 GB2088873A> 100 not tested | \ - / (Ex. 129) ch3

II

7 89164 rch (ch2) 2 v / \ y F GB2088873A> 3840 not tested | (not examples) CH3 where R is H2H - ^ ^ - CHOHCH2NH -

Compound H2H chohch2nh (ch2) xo (ch2) y -Q *

Present Power Compar- Power Application Tuna Isopre- Effect on XYA Nalin (Rt50 min) 1 63 4-CONH2 0.2> 490-> 600 2 63 4-NHSO2CH3 0.84> 510 3 63 4-CO2Et 0.39> 625-> 720 5 63 4-CONMe2 1.5> 540 6 6 3 4-CO-N2 \ 0.15 402 7 63 3-CH2NHAc 0.12> 600-> 700 8 63 4-OCH2CONMe2 0.17 415 10 63 4- (CH2) 2NMe2 3.9> 200,> 640 .11 54 4-CH2CONMe2 1.7> 580-> 640 12 62 4-NHSO2CH2 1.7> 440-> 660 13 63 4-CH2CONH2 0, 19> 625 14 63 4-CH2OCH2 0.34> 420-> 672 15 63 4-CO2H 0.2> 97-> 580 17 63 4-NH (CH2) 2NMe2 2.5> 44-> 710

The compounds of the invention may be used in the treatment of diseases associated with reversible airway obstruction, such as asthma and chronic bronchitis.

s 89164

Useful indications for use of the compounds of the invention also include the treatment of inflammatory and allergic skin diseases, congestive heart failure, depression, preterm labor pain and glaucoma, and the treatment of conditions in which it is advantageous to reduce gastric acidity, especially gastric ulcer and indigestion.

The invention thus provides compounds of formula (I) and their physiologically acceptable salts and solvates for use in the treatment or prophylaxis of diseases involving reversible airway obstruction in human and animal subjects.

The compounds of the invention may be formulated for administration by any suitable route. The invention therefore includes pharmaceutical compositions containing at least one compound of the formula (I) or a physiologically acceptable salt or solvate thereof formulated for use in human or veterinary medicine. Such compositions may be formulated so as to provide physiologically acceptable carriers or excipients, optionally in combination with complementary drugs.

The compounds may be formulated for administration by inhalation or inhalation, or for oral, buccal, parenteral, topical (including nasal) or rectal administration. Administration by inhalation or inhalation is preferred.

For administration by inhalation, the compounds of the invention are conveniently administered as an aerosol spray formulation from pressurized packs using a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoromethane, carbon dioxide or otherwise a suitable gas, or from a nebulizer. In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount.

I; 9 89164

For administration by inhalation or insufflation, the compounds of the invention may alternatively be in the form of a dry powder mixture, for example a powder mixture of the compound and a suitable powder base such as lactose or starch. The powder mixture may be in unit dosage form, for example, as capsules or cartridges made of, for example, gelatin, or as blister packs from which the powder may be administered by means of an inhaler or insufflator.

For oral administration, the pharmaceutical compositions may take the form of, for example, tablets, capsules, powders, solutions, syrups or suspensions prepared by conventional means with acceptable excipients.

For buccal administration the mixture may take the form of tablets, drops or lozenges formulated in conventional manner.

The compounds of the invention may be formulated for parenteral injection from a vial or by continuous infusion. Injectable formulations may be presented in unit dosage form in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

For topical administration, the pharmaceutical compositions may take the form of creams, solutions or creams formulated in a conventional manner, for example, using an aqueous or oily base, generally with the addition of suitable thickeners and / or solvents. For nasal application, the compositions may take the form of a spray formulated, for example, as an aqueous solution or suspension or as an aerosol using a suitable propellant.

The compounds of the invention may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.

The pharmaceutical compositions described above for oral, buccal, rectal or topical administration may be formulated in conventional, controlled release forms.

The recommended daily dose of the active compound for human treatment is 0.005 to 100 mg, which may conveniently be administered in a single dose or in two doses. The exact dose used will, of course, depend on the age and condition of the patient and the route of administration. Thus, a suitable dose for administration by inhalation is 0.005 to 20 mg, for oral administration 0.02 to 100 mg and for parenteral administration 0.01 to 2 mg given as a syringe and 0.01 to 25 mg for infusion.

The compounds of the invention can be prepared by a variety of methods described below. In the following description of the processes for the preparation of the compounds of formula (I) and intermediates which can be used for their preparation, X, Y, Ar, R 1 and R 2 have the same meaning as in the general formula (I), unless otherwise stated. In addition, each substituent on Ar may be a precursor substituent that can be converted to the desired substituent by conventional methods.

It should be noted that some of the reactions described below may affect other groups of starting materials desired in the final product; this applies in particular to the reduction processes described, in particular when hydrogen and a catalyst are used and when an ethylene or acetylene bond to the compound of the invention is desired. Therefore, it is standard practice

II

11 89164 care must be taken either to use reagents which do not affect such groups or to carry out the reactions as part of a series of reactions which avoid their use when such groups are present in the starting material.

In the preparation of both intermediates and final products, the final step in the reaction may be deprotection. Conventional protecting groups described, for example, in "Protective Groups in Organic Chemistry", ed. J.P.W. McOmie (Plenum Press, 1973). Thus hydroxyl groups such as benzyl, diphenylmethyl or triphenylmethyl or as tetrahydropyranyl derivatives. Suitable amino protecting groups may include aralkyl groups such as benzyl, α-methylbenzyl, diphenylmethyl or triphenylmethyl and acyl groups such as acetyl, trichloroacetyl or trifluoroacetyl.

Conventional deprotection methods can be used.

Thus, for example, aralkyl groups can be removed by hydrogenolysis in the presence of a metal catalyst (e.g. palladium / carbon). Tetrahydropyranyl groups can be cleaved by hydrolysis under acidic conditions. The acyl groups may 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 may be removed by reduction with, for example, zinc and acetic acid.

In the general method (1), the compound of the general formula (I) can be prepared by alkylation. Conventional alkylation methods are useful.

Thus, for example, in process (a), a compound of general formula (I) in which R 1 is a hydrogen atom can be prepared by alkylating an amine of general formula (II) 12 89 1 64 h 2 N 2 -

W I

Cl ^ OH

(wherein R 1 · 4 is a hydrogen atom or a protecting group and R 1 is a hydrogen atom), after which any protecting groups present are removed.

The alkylation (a) can be carried out using an alkylating agent of general formula (III): LCHXCH 2 OCH 2 YAr L (111) R 2 (wherein L is a leaving group, for example a halogen atom such as chlorine, bromine or iodine or a hydrocarbylsulfonyloxy group such as methanesulfonyloxy or p-toluenesulfonyloxy).

The alkylation is best carried out in the presence of a suitable acid scavenger, for example inorganic bases such as sodium or potassium carbonate, organic bases such as triethylamine, diisopropylethylamine or pyridine, or alkylene oxides such as ethylene oxide or propylene oxide.

The reaction is conveniently carried out in a solvent such as acetonitrile or ether, for example tetrahydrofuran or dioxane, a ketone, for example butanone or methyl isobutyl ketone, a substituted amide, for example dimethylformamide, or a refluxing hydrocarbon, for example chloroform at ambient temperature, at ambient temperature.

In another example (b) of the alkylation process, a compound of general formula (I) in which R * is a hydrogen atom can be prepared by alkylating an amine of general formula (II) otherwise similar to that already defined except that R * 5 Qn is a hydrogen atom. or a group which can be converted into this atom under reaction conditions with a compound of general formula (IV) in the presence of a reducing agent R2COXCH2OCH2YAr (IV), followed, if necessary, by the removal of any protecting groups.

Examples of suitable R15 groups that can be converted to a hydrogen atom include arylmethyl groups such as benzyl, α-methylbenzyl and benzhydryl.

Suitable reducing agents include 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 using an alcohol such as ethanol or methanol as the reaction solvent or an ester such as ethyl acetate or ether, e.g. or water or a mixture of solvents, for example a mixture of two or more of the solvents just described, at normal or elevated temperature and pressure, for example at 20 to 100 ° C and 1 to 10 atmospheric pressure.

When one or both of R * · * and R * ® are hydrogen atoms, the reducing agent may alternatively be a hydride such as diborane or a metal hydride such as sodium borohydride, sodium cyanoborohydride or lithium aluminum hydride. Suitable solvents when carrying out the reaction using these reducing agents depend on the hydride used in each case, but include alcohols such as methanol or ethanol or ethers such as diethyl ether or tert-butyl methyl ether or tetrahydrofuran.

When a compound of formula (II) is used in which both R ** and R * 5 are hydrogen atoms, an imine intermediate of formula (V) may be formed 14 891 64 _ H2N -XV-CHCH2N = CXCH2OCH2YAr (V) y = / il cr OH R2

The compound of general formula (I) is obtained by reducing the imine using the conditions described above and then, if necessary, removing any protecting groups.

If it is desired to use a protected intermediate of general formula (II), it is particularly convenient to use hydrogen and the catalyst described above together with a protecting group R 1 · 4 which can be converted to a hydrogen atom under these reducing conditions without 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 method (2), a compound of general formula (I) can be prepared by reduction. Thus, for example, a compound of general formula (I) may be prepared by reduction of an intermediate of general formula (VI).

Cl 1 - X 4 - {/ y - X 1 -X 2 -X 3 -CH 2 OCH 2 YAr (VI) cr 'wherein at least one of X 4, X 1, X 2, X 3 and Y is a reducing group and / or Ar contains a reducing group and the other groups have the following suitable meanings are: X 4 is -NH 2, X 1 is -CH (OH) -, X 2 is -CH 2 NR 4 -4 (wherein R 4 is a hydrogen atom or a protecting group, X 3 is -CR * R 2 X, and Ar and Y have the same meaning as in formula (I), followed, if necessary, by the removal of any protecting groups.

li is 39164

Suitable reducing groups include those in which X 4 is -NO 2, X 4 - is a group> C = O, X 2 is a group -Cl 2 NY '- (wherein Y * is a group which can be converted to hydrogen by catalytic hydrogenation, for example an arylmethyl group such as benzyl , benzhydryl or? -methylbenzyl) or an imine (-CH = N-) group or a group -CONH-, X 3 is a group -COX- or a group CR 1 R 2 X (where X is C 2-8 alkenylene or C 2-5 alkynylene), or -X 2 -X 3 - is a group -CH 2 N = CR 2 X-, Y is C 2-4 alkenylene or -alkynylene, and Ar is a phenyl group substituted with a group containing an amide bond such as - (CH 2) q -CONR 3 R 4 or -NHCOR 17 (where -NHCOR ^ 7 can be reduced to NHR12).

The reduction can be carried out using reducing agents suitably used to reduce ketones, imines, amides, protected amides, alkenes, alkynes and nitro groups. Thus, for example, when X4 in the general formula (VI) is a nitro group, this can be reduced to an amino group using hydrogen in the presence of the catalyst described in connection with part (b) of process (1) above.

When X * in the general formula (VI) is a> C = O group, this can be reduced to a -CH (OH) group using hydrogen in the presence of the catalyst described in connection with part (b) of process (1) above. Alternatively, the reducing agent may be 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 may be carried out in a solvent, optionally an alcohol, for example methanol or ethanol, or an ether, such as tetrahydrofuran, or a halogenated hydrocarbon, such as dichloromethane.

When X 2 in the general formula (VI) is a -C 1 NY 'group or a group -CH = N-, or -X 2 -X 3 is -CH 2 N = CR 2 X-, this can be reduced to a group -CH 2 NH- or a group -CH 2 NHCHR 2 X- using hydrogen when the metal catalyst described above in connection with part (b) of process (1) is included. Alternatively, when X 2 or -X 2 -X 3 is -CN = N- or -CH 2 N = CR 2 X-, this can be reduced to ie 89164 -CH 2 NH- or to -CH 2 NHCHR 2 X- using a reducing agent and the conditions just described above for the reduction of group X *. when this is a> C = O group.

When X 2 or X 3 in the general formula (VI) is a -CONH- or -COX group, or Ar is phenyl substituted with a group containing an amide bond, such as - (CH 2) q -CONR 3 R 4 or -NHCOR 17 (wherein R 17 is as defined above) ), this can be reduced to -CH 2 NH- or -CH 2 X-, or to phenyl substituted with - (CH 2) q NR 3 R 4 or -NHR 12 using a hydride such as diborane or a complex metal hydride such as lithium aluminum hydride or sodium bis (2-methoxyethoxy) to aluminum In a solvent such as ether, for example tetrahydrofuran or diethyl ether.

When X 3 is a group CR 1 R 2 X wherein X is C 2-8 alkenylene or C 2-6 alkynylene or Y is C 2-4 alkenylene or C 2-4 alkynylene, this may be reduced to C 2-8 alkenylene or C 2-4 alkynylene, respectively, using hydrogen in the presence of process (1) above (b) above. ). When X is C 2-4 alkynylene or Y is C 2-4 alkynylene, this may alternatively be reduced to C 2-6 alkenylene or C 2-4 alkenylene, respectively, using, for example, hydrogen and a lead-poisoned palladium / calcium carbonate catalyst in a solvent such as pyridine, ° C.

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

Cl ^ R1 R16NH — r \ —CHCH2NR14CXCH2OCH2YAr (VII)

X = J I L

Wherein R14 and are each a hydrogen atom or a protecting group, and / or each hydroxy and / or amino substituent in the group Ar is protected, provided that at least one of the groups R14 and / or R16 is a protecting group and / or Ar contains a protecting group .

Suitable protecting groups and methods for their removal are the same as described above. Thus, for example, R * 4 may be an aralkyl group, for example benzyl, which may be removed by hydrogenolysis in the presence of a metal catalyst (for example palladium / carbon), and / or may be an acyl group, which may be removed by boiling with dilute mineral acid (for example hydrochloric acid).

Compounds of formula (I) may also be prepared by a process in which a compound of general formula (I) is converted into another.

Thus, for example, a compound of formula (I) wherein Ar is a phenyl group substituted with - (CH 2) RCOR 4 where R 9 is hydroxy may be prepared by hydrolysis of the corresponding compound of formula (I) wherein R 10 is C 1-4 alkoxy. For example, the hydrolysis can be performed under basic conditions using, for example, sodium hydroxide.

In the general methods described above, the compound of formula (I) obtained may be in the form of a salt, conveniently as a physiologically acceptable salt. If desired, such salts can be converted to the corresponding free acids by conventional methods.

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 alcohol, for example methanol, ethanol or isopropanol.

89164 BC

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

When a particular enantiomer of a compound of general formula (I) is desired, this may be obtained by resolution of the corresponding racemate of a compound of general formula (I) using conventional methods.

Thus, in one example, a suitable optically active acid may be used to form salts with a racemate of a compound of general formula (I). The resulting mixture of isomeric salts can be separated, for example, by fractional crystallization to diastereoisomeric salts, from which the desired enantiomer of the compound of general formula (I) can be isolated by conversion to the desired free base.

Alternatively, enantiomers of a compound of general formula (I) may be synthesized from suitable optically active intermediates using any of the general methods described herein.

Specific diastereoisomers of a compound of formula (I) may be obtained by conventional methods, for example by synthesis from a suitable asymmetric starting material using one of the methods described herein or by converting a mixture of isomers of a compound of general formula (I) into suitable diastereoisomeric derivatives, e.g. by fractional crystallization.

The intermediates of general formula (VI) used in the general process (2) can be prepared by a variety of methods analogous to those described in UK Patent 2165542A.

li 19 89164

Thus, for example, intermediates of general formula (VI) in which χΐ is a group> C = O can be prepared from a haloketone of formula (VIII) h2n— \ y— COCH2Hal (VIII)

Cl 1 'by reacting it with an amine of general formula (IX) R 1 Y'NHCXCH 2 OCH 2 YAr (IX)> 2 R 2 (wherein Y' is hydrogen or a group which can be converted to hydrogen by catalytic hydrogenation). The reaction may be carried out in a cold or hot solvent, for example tetrahydrofuran, tert-butyl methyl ether, dioxane, chloroform, dimethylformamide, acetonitrile or a ketone such as butanol or methyl isobutyl ketone, or an ester such as ethyl acetate, preferably in the presence of ethyl acetate, preferably when sodium carbonate or another acid scavenger such as propylene oxide.

Intermediates of general formula (VI) in which χΐ is a group> C = O can be reduced to the corresponding intermediate in which χΐ is a group -CH (OH) - using, for example, a metal hydride such as sodium borohydride in a solvent such as ethanol.

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

20 89 1 64

Suitable methods for preparing intermediates of formulas (III), (IV) and (IX) are described in UK Patents 2140800A, 2159151A, 2165542A and the following examples.

The following examples illustrate the invention. Temperatures are ° C. "Dried" means drying using magnesium sulfate or sodium sulfate, unless otherwise noted. Thin plate chromatography (TLC) was performed on SiO 2 and flash column chromatography (FCC) was performed on silica (Merck 9385) using one of the following solvent systems, unless otherwise noted: A-toluene: ethanol: 0.88 ammonia; B-toluene: ethanol: triethylamine; C, from ethyl acetate: hexane: triethylamine; D-ethyl acetate: methanol: triethylamine; E-cyclohexane: ethyl acetate: triethylamine. The following abbreviations have been used: THF - tetrahydrofuran; DMF - dimethylformamide; BTPC - bis (triphenylphosphine) palladium (II) chloride; DEA - N, N-diisopropylethylamine.

Intermediate 1 is 1- (4-amino-3,5-dichlorophenyl) -2-bromoethanone Intermediate 2 (Z) -N-Γ4-Γ3-ΓΓ6- [(phenylmethyl) amino] hexyloxy] -1-propenylphenylmethylsulfonamide. Hydrochloride (Z) -N- [4- [3 - [(6-bromohexyl) oxy] -1-propenyl] phenyl] methanesulfonamide (2.0 g) was added under nitrogen to benzylamine (6 ml) at 125 ° C. :in. The reaction mixture was stirred for 3 hours at 125 ° C, cooled to room temperature and added to 2N hydrochloric acid (50 ml) and water (20 ml). The resulting white solid was collected by filtration, washed alternately with 2N hydrochloric acid, water and ether and dried in vacuo at 50 ° C to give the title compound as a white powder (1.0 g), m.p. 133-134 ° C.

Intermediate 3 (Z 1 -W-Γ 4-Γ 3-Γ Γ 6-Γ Γ 2- [4-amino-3,5-dichlorophenyl) -2-hydroxy-ethyl] (phenylmethyl) amino] hexyl-oxy-1- Prohenyl-1-phenylmethanesulfonamide A suspension of Intermediate 1 (520 mg), Intermediate 2 (850 mg) and DEA (500 mg) in tetrahydrofuran (25 ml) was stirred at room temperature overnight. After filtration, the filtrate was concentrated to oils, which were dissolved in ice-cooled methanol (20 mL) and treated with sodium borohydride (250 mg). The pale yellow solution was stirred overnight at room temperature, the methanol was evaporated and the residue partitioned between water (25 ml) and ethyl acetate (25 ml). The organic phase was washed with water and brine, dried and concentrated to a red oil which was purified by FCC chromatography eluting with System E (75: 25: 1) to give the title compound as a colorless oil (540 mg). TLC (System E 75: 25: 1) Rf 0.09.

Intermediate 4 4-Iodo-N, N-dimethylbenzeneethanamine. hydrochloride 4-Bromo-N, N-dimethylbenzeneethanamine hydrochloride (0.65 g) was partitioned between ethyl acetate (10 ml) and 8% sodium bicarbonate (10 ml). The aqueous layer was extracted with ethyl acetate (10 mL) and the combined organic extracts were dried and concentrated to the free base (0.57 g). To a solution of the free base (0.57 g) in tetrahydrofuran (10 mL) at -78 ° C was added n-butyllithium (1.6M in hexane, 1.72 mL) and the mixture was stirred under nitrogen for 30 minutes. A solution of iodine (0.63 g) in tetrahydrofuran (10 ml) was added dropwise and after 10 minutes the reaction was quenched by the addition of saturated ammonium chloride (10 ml). The THF was evaporated and the aqueous residue was extracted with ethyl acetate (2 x 15 ml). The organic extracts were washed with 10% sodium sulfate (15 mL) and brine (15 mL), dried and concentrated to a brown oil, the oil in ether (10 mL) and dichloromethane 22 89164 (2 mL) was treated with ethereal hydrogen chloride and the resulting precipitate was collected. and dried to give the title compound as a white solid (0.54 g). Analysis found: C, 38.77; H, 4.87; N, 4.39; Cl, 11.36; I, 40.67.

c10H14N.HCl, Calc'd: C, 38.55; H, 4.85; N, 4.5; Cl, 11.38; I, 40.73%.

Selected N- (4-1H-phenyl) -N-methylmethanesulfonamide N “(4-iodophenyl) methanesulfonamide (4.3 g) in 50% aqueous sodium hydroxide (25 ml), iodomethane ( 5 ml), dichloromethane (10 ml) and tetrabutylammonium bisulphate (0.5 g) were stirred vigorously for 2 hours. Water (50 ml) was added and the mixture was extracted with ether (3 x 50 ml). The organic extracts were washed with water and brine, dried and concentrated to a solid which was triturated with hexane to give the title compound as white crystals (4.1 g) m.p. 106-107 ° C.

Intermediate 6 2- (4-iodophenoxy) -N, N-dimethylacetamide

Dimethylamine (33% w / w) in IMS, 5.85 mL) was added dropwise to a suspension of [(4-iodophenoxy) acetyl] chloride (9.49 g) in triethylamine (50 mL) at 0 ° C under nitrogen. The suspension was stirred for 2 hours at 0 ° C and partitioned between ethyl acetate (300 ml) and 8% aqueous sodium bicarbonate (300 ml). The organic layer was dried and the solvent was evaporated. The residual oil was purified by FCC chromatography eluting with diethyl ether to give the title compound as a white solid (3.96 g), m.p. 63-65 ° C.

li 23 8 91 64 Intermediate 7 4- [3-Iodo-N, N-dimethylbenzeneamamide 4-Iodophenylacetyl chloride (5.15 g) was added portionwise to dimethylamine (0.90 g) in triethylamine (25 ml) at 0 ° C. The suspension was stirred for 2 hours at 0 ° C and chloroform (100 ml) was added. The organic phase was washed with 8% aqueous sodium bicarbonate (50 mL), dried and concentrated. The resulting red solid (5.0 g) was purified by FCC chromatography eluting with ether followed by ethyl acetate to give the title compound as a yellow solid (2.58 g), m.p. 75-77 ° C.

Intermediate 8 N, N-Dimethyl-4--4-imet5-Γ (phenylmethyl) amino] pentyl] 1-butylbenzeneacetamide Intermediate 16 (1.60 g) was added dropwise to benzylamine (3.5 ml) at 120 ° C under nitrogen. The solution was stirred for 3 hours at 120 ° C and poured into 0.8N aqueous hydrochloric acid (65 ml). The aqueous mixture was extracted with ethyl acetate (3 x 30 mL) and the combined extracts were washed with 8% aqueous sodium bicarbonate (50 mL) and brine (50 mL), dried and concentrated to an oil (0.56 g). The combined aqueous phases were re-extracted with ethyl acetate (2 x 50 ml), dried and concentrated to an oil (0.92 g). The two oils were combined and purified by FCC chromatography eluting with ethyl acetate-triethylamine (100: 1) to give the title compound as a pale yellow oil (1.00 g), TLC (ethyl acetate-triethylamine 100: 1) Rf 0.1.

Intermediate 9 Ν-ΓΓ3-Γ3-ΓΓ 6-Γ (phenyl) methylamine 1-propyl-1-propylmethylacetamide N - [(3-iodophenyl) methyl ] a suspension of N- [6 - [(2-propynyl) oxy] hexyl] benzenemethane (3.48 g), BTPC 24 891 64 (100 mg) and copper iodide (60 mg) in acetamide (3.91 g) in diethylamine (75 ml) was stirred at room temperature under nitrogen for 20 hours. The reaction mixture was poured into triethyl ether (100 mL) and filtered. The filtrate was concentrated to an oil (6.62 g) which was purified by FCC chromatography eluting with System D (100: 0: 1 → 100: 10: 1) to give the title compound as a red oil (4.60 g), TLC (ethyl acetate-triethylamine). (100: 1) Rf 0.12.

Intermediates 10-13 were prepared in a similar manner: Intermediate 10 N, N-dimethyl-4- [3- [3- [6-] (phenylmethyl) amino] hydroxy] -1-propyl] benzamide 4-Iodo-N, N-dimethylbenzamide (2.5 g) and & [6 - [(2-propynyl) oxy] hexyl] benzenemethanamine (2.23 g) was purified by FCC chromatography eluting with ethyl acetate-1-triethylamine 11a (100: 1) as an orange oil. (2.96 g), TLC (ethyl acetate + a few drops of triethylamine) Rf 0.15.

Intermediate 11 N, N-Dimethyl-2- [4- [3- [3-6-] (phenylmethyl) amino] oxy] oxy] -1-propyl] phenoxy] benzamide From Intermediate 6 (3.91 g) and N- [6 - [(2-propynyl) oxy] ] hexyl] benzenemethanamine (3.14 g) FCC purification by elution with System C (83: 17: 1) gave the product (3.87 g) which was reprocessed on a column in the same manner as above using now ethyl acetate-triethylamine (100: 1) as eluent to give the title compound as an orange oil (1.44 g), TLC (ethyl acetate + a few drops of triethylamine) Rf 0.3.

Il 25 891 64 Intermediate 12 N-Methyl-N-Γ4-Γ3-Γ Γ 6 - [(phenylmethyl) aminohexyloxy] -1-propynyl 1-phenylmethanesulfonamide From Intermediate 5 (1.8 g) and N- [6 - [( 2-propynyl) oxy] hexyl-1-yl] benzenemethanamine (1.5 g) using triethylamine / tetrahydrofuran (1: 1, (50 mL)) instead of diethylamine, FCC purification and elution with System B (95: 5: 1) afforded the title compound as an orange oil (2.0 g), TLC (System B) 5: 5: 1) Rf 0.13.

Intermediate 13 4- (3-1 (6- (12- (4-amino-3,5-dichlorophenyl) -2-hydroxyethyl 1- (phenylmethylamino] hexyloxy] -1-propynyl) benzamide From Intermediate 24 (550 mg) and 4-iodobenzamide (250 mg ), but diethylamine / tetrahydrofuran (4: 1, 10 mL) was used instead of diethylamine and the addition of the reaction mixture to ether following filtration was omitted. FCC purification of the concentrated reaction mixture eluting with System B (90: 10: 1) afforded the title compound as a pale yellow oil (540 mg). , TLC (System B 90: 10: 1) Rf 0.35.

Intermediate 14 N- [4- [3- [6- [2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethyl] phenyl] amino] -1-propionyl] -1-propionyl] phenyl] -1H- (dimethylamino) acetamide Intermediate 24 (1.0 g) 2- (dimethylamino) -N- (4-iodophenyl) acetamide (680 mg), dicyclohexylamine (450 mg), BTPC (50 mg) and a suspension of copper (I) iodide (10 mg) in acetonitrile (15 ml) was stirred under nitrogen for 3 hours, ether (25 ml) was added and the precipitate was removed by filtration The solvent was evaporated and the residue was purified by FCC chromatography eluting with System C (50:50 : 1) to give the title compound as a yellow oil (800 mg), TLC (System A 80: 20: 2) .ff 0.53.

26 891 64 Intermediate 15 4- [4-Γ3-ΓΓ6-Γ (phenylmethyl) amino] hexyloxy] -1-propynylbenzoylmorpholine Olin 4- (4-iodobenzoyl) morpholine (4.0 g) and N- [6 - [(2-propynyl) -li) oxy] hexyl] benzenemethanamine (3.09 g) was reacted by the method of intermediate 14. FCC purification using ethyl acetate-triethylamine (100: 1) afforded the title compound as a yellow oil (2.21 g), TLC (ethyl acetate-triethylamine 100: 1) Rf 0.2.

Intermediate 16 4- [4 - [(5-Bromopentyl) oxy] butyl] -NN-dimethylbenzeneacetamide Intermediate 7 (2.50 g), 1-bromo-5- (3-butynyloxy) pentane (1.90 g), dicyclohexylamine ( 1.73 g), a mixture of BTPC (50 mg) and copper iodide (10 mg) was stirred in acetonitrile (30 ml) under nitrogen for 2 hours. Ether (80 ml) was added, the mixture was filtered, the filtrate was concentrated and the residue was refluxed in ethanol (100 ml) together with carbon and filtered (Hyflo). The solution was hydrogenated with 10% palladium / carbon catalyst 11a (50% paste in water; 1.0 g) for 48 hours, filtered (Hyflo) and concentrated. The resulting residue was purified by FCC chromatography eluting with ether-ethyl acetate (100: 0-> 80:20) to give the title compound as a yellow oil (1.62 g), TLC (ether) Rf 0.12.

Intermediate 17 (Ζ) -Ν-Γ Γ3-Γ 3-Γ Γ 6-Γ Γ 2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethylphenylmethyl 1 amino Ί-1-Propenyl 1-phenylmethylacetamide A solution of intermediate 1 (1.44 g), intermediate 9 (2.0 g) and DEA (660 mg) in tetrahydrofuran (20 ml) was allowed to stand for 20 hours at room temperature under nitrogen. The precipitate was removed by filtration and the filtrate was concentrated. The oil obtained

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27 8 91 64 was dissolved in methanol (20 ml), cooled in an ice bath and treated portionwise with sodium borohydride (750 mg). The reaction mixture was stirred at room temperature under nitrogen for 2 hours and concentrated. To the resulting oil was added water (100 mL). The mixture was extracted with ethyl acetate (3 x 50 mL) and the combined extracts were washed with water (50 mL) and brine (50 mL), dried and concentrated. The resulting oil was purified by FCC chromatography eluting with System B (95: 5: 1) to give the title compound as a yellow oil (1.51 g), TLC (System B 95: 5: 1) Rf 0.13.

Intermediates 18-24 were prepared in a similar manner.

Intermediate 18 4- {4- [5- [2- (4-Amino-3,5-dichlorophenyl) -2-hydroxyethyl] 1- (phenylmethyl) aminopentyloxy] butyl] -N, N-dimethylbenzeneacetamide From Intermediate 1 (690 mg) and intermediate 8 (1.01 g). The sodium borohydride / methanol reaction was continued for 24 hours. FCC purification eluting with System C (50: 50: 1) gave the title compound as a yellow oil (1.12 g), TLC (ethyl acetate-hexane (1: 1) + a few drops of triethylamine) Rf 0.1.

Intermediate 19 (Ζ) -2-Γ4-Γ3-ΓΓ6-ΓΓ2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethyl] phenylmethyl) amino hexyl 1 - 1-propenyl 1 - phenoxy 1-N, N-dimethyl from Intermediate 1 (951 mg) and Intermediate 11 (1.42 g). FCC purification eluting with System B (97: 3: 1) gave the title compound as a yellow oil (1.11 g), TLC (System B 95: 5: 1) Rf 0.31.

28 8 91 64 Intermediate 20 Ν-Γ4-Γ2-Γ Γ6-Γ Γ2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethyl Hphenyl over 1 amino Ixyloxy f enw li Imet aa-nisulfonamide From intermediate 1 (0.7 g) and N- [4- [2 - [[6 - [(phenylmethyl) amino] hexyl] oxy] ethyl] phenyl] methanesulfonamide (1 g). FCC purification eluting with System B (98: 2: 1) gave the title compound as a yellow oil (1.2 g) by TLC (System A 80: 20: 1) Rf 0.47.

Intermediate 21 Ν-Γ4-Γ3-ΓΓ6-ΓΓ 2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethyl) (phenylmethyl) amino-1-propynylphenyl-1-propylphenyl-N-methylmethanesulfonamide From Intermediate 1 (660 g) and intermediate 12 (1.0 g). The sodium borohydride / methanol reaction was continued for 18 hours. FCC purification eluting with System C (33: 66: 1-> 50: 50: 1) gave the title compound as a pale yellow oil (320 mg), TLC (hexane-ether-triethylamine 50: 50: 1) Rf 0.04.

Intermediate 22 (Ζ) -4--3-ΓΓ6-ΓΓ2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethyl-11-phenylphenylamino-11-propenyl] -N. dimethylbenzamide from Intermediate 1 (1.0 g) and Intermediate 10 (1.39 g) FCC purification by elution with System B (97: 3: 1) gave the title compound as a yellow oil (0.93 g), TLC (System B). 95: 5: 1) Rf 0.3.

Il: 29 891 64 Intermediate 23 4-—4-Γ3-ΓΓ6-ΓΓ2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethyl-11 (phenylmethyl) aminohexyl] oxy 1 -1 Propionyl 1-benzoylmorpholine From Intermediate 1 (1.0 g) and Intermediate 15 (1.53 g) The reaction with sodium borohydride / methanol was continued for 60 hours FCC purification by elution with System B (97: 3: 1) gave the title compound as an orange oil (1.54 g), TLC (System B 95:51) Rf 0.25.

Intermediate 24 4-Amino-3,5-dichloro-α-ΓΓ (phenylmethyl) Γ 6 - Γ (2-propyl) oxyhexylamino Nursing benzene methane From intermediate 1 (1.0 g) and N- [6 - [(2-propynyl) ) oxy] hexyl-1i] benzenemethanamine (870 mg). The duration of the first step of the reaction was only 25 minutes. FCC purification eluting with System C (20: 80: 1) gave the title compound as a colorless oil (1.27 g), TLC (System C 20: 80: 1) Rf 0.33.

Intermediate 25 N, N-Bis [2- (phenylmethoxy) ethyl] -4-iodobenzeneamine 2,2 '- (4-iodophenylimino) bis-ethanol (2 g), benzyl bromide (2.3 g), a mixture of tetra-n-butylammonium bisulfate (0.4 g) and 50% sodium hydroxide (20 ml) was stirred vigorously for 5 hours. The mixture was diluted with water (20 ml), extracted with ethyl acetate (2 x 20 ml) and the combined extracts washed successively with water (50 ml) and brine (50 ml), dried and evaporated. FCC purification eluting with hexane-ether (19: 1-> 9: 1) gave the title compound as a pale yellow oil (2.1 g), TLC (hexane-ether 1: 1) Rf 0.7.

30 8 9 1 64 Intermediate 26 4-Amino-3,5-dichloro-.alpha.-trans-6-β-β-ibis-[2- (phenylmethoxy-1-ethylamino) phenyl] -2-propyl] oxy A solution of intermediate 24 (1.9 g), intermediate 25 (1.75 g), BTPC (90 mg) and copper (I) iodide (9 mg) in diethylamine / tetrahydrofuran (4 g) was obtained. : 1.30 ml) was stirred at room temperature under nitrogen for 2 days, the solvent was evaporated and the residue was purified by PCC chromatography eluting with system C (20: 80: 1-> 30: 70: 1) to give the title compound as an orange oil. 75 g), TLC (system C 20: 80: 1)

Rf 0.17.

Intermediate 27 4-Amino-3,5-άί-οοΓί-α-Γ [6-ΓΓ3-Γ4-Γ 2- (dimethylaminoethoxy 1-phenyl-2-propynyloxyloxy) hexyl (phenylmethyl) amino] methyl A solution of 2- (4-iodo-phenoxy) -N, N-dimethylethanamine (1.57 g), intermediate 24 (2.94 g), BTPC (100 mg) and copper iodide (10 mg) in diethylamine (30 ml) was prepared. ) and acetonitrile (10 ml) were stirred at room temperature under nitrogen for 16 hours The solvent was evaporated and the residue was FCC purified by elution with System B (95: 5: 1) to give the title compound as a red oil (3.57 g), TLC (System B 95 : 5: 1) Rf 0.26.

Example 1 4- [3- [6-6- (4-Amino-3,5-dichlorophenyl) -2-hydroxyethyl] amino] hexyloxy] propyl] benzamide Intermediate 13 (1.3 g) was hydrogenated with 10% palladium oxide / carbon (50% aqueous paste, 380 mg). in ethanol (15 mL) containing hydrochloric acid (concentrated HCl / ethanol, 1: 9 v / v, 2 mL). The catalyst was removed by filtration through hyflon, the solvent was evaporated and the residue partitioned between 8% sodium bicarbonate (25 ml) and ethyl acetate (25 ml). The aqueous layer

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3i 89164 was re-extracted with ethyl acetate (25 ml) and the combined organic extracts were washed with 8% sodium bicarbonate and brine, dried and concentrated to a semi-solid which was triturated with ether / ethyl acetate (ca. 4: 1) to give the title compound as an impure white solid ( 240 mg, 22%), m.p. 91-94 ° C, TLC (System A 80: 20: 20: 2) Rf 0.25.

Examples 2-8 were prepared in the same manner.

Example 2 N- [4- [3- [4- [2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethyl] amino] hydroxy] propyl] phenyl] methanesulfonamide ”from Intermediate 3 (500 mg). Evaporation of the ethyl acetate extracts gave an oil which was FCC purified by elution with System B (95; 5; 1) followed by trituration with dry ether to give the title compound as a white powder (100 mg), m.p. 62-64 ° C.

Analysis found: C, 54.82; H, 7.26; N, 7.36 C 24 H 35 Cl 2 N 3 O 4 S.0.35C 4 H 2 O: H * Calculated C, 54.63; H, 6.95; N, 7.52%

Example 3

Ethyl 4- [3 - [[6 - [(4-amino-3,5-dichlorophenyl) -2-hydroxyethyl] amino] hexyloxy] propyl] benzoate

Ethyl 4- [3 - [[6 - [[(4-amino-3,5-dichlorophenyl) -2-hydroxyethyl] (phenylmethyl) amino] hexyl] oxy] -1-propynyl] Benzoate (500 mg) using preheated 10% palladium / carbon (50% paste in water, 60 mg) as hydrogenation catalyst. The residue obtained by evaporation of the ethyl acetate extract was FCC purified eluting with System C (50: 50: 1) to give the title compound as a white solid (97 mb), m.p. 66-68 ° C, TLC (System C 50: 50: 1) Rf 0.05.

32 8 9 1 6 4

Example 4 4- [3- [3-6- [7- (4-Amino-3,5-dichlorophenyl) -2-hydroxyethyl] amino] hydroxy] propyl] -N, N-dimethylbenzamide.

(E) -butenedioate (salt) (2: 1) From intermediate 22 (0.82 g) using pre-reduced 10% palladium / carbon (50% water paste, 100 mg) as hydrogenation catalyst. Evaporation of the ethyl acetate extracts gave an oil which was FCC purified by elution with System B (95: 5: 1) to give an oil. This oil (0.42 g) in methanol (2 ml) was treated with (E) -butenedioic acid (47.6 mg) in methanol (2 ml) and the solution was concentrated. The residue was triturated with diethyl ether to give the title compound as a white solid (0.47 g), m.p. 107-109 ° C.

Analysis found: C, 59.0; H, 7.2; N, 7.2; Cl, 12.6 c2 6h37c ^ 2n3 ° 3 · 0 · 5C4H4O4: Calculated: C, 59.2; H, 6.9; N, 7.4; Cl, 12.5%

Example 5 4- [4- [3- [3-6- [2- (4-Amino-3,5-dichlorophenyl) -2-hydroxy-ethyl] amino] hexyl] -propyl] -benzow]] -morpholine From intermediate 23 (0.70 g) using a pre-reduced hydrogenation catalyst. % palladium / carbon (50% water paste (80 mg). Evaporation of the ethyl acetate extracts gave an oil which was FCC purified by elution with System B (95: 5: 1) to give the title compound as a yellow oil (391 mg). mg) in methanol (2 ml) was treated with (E) -butenedioic acid (41.1 mg) in methanol (2 ml) and the solvent evaporated to give an oil which was triturated with diethyl ether to give the (E) -butenedioate salt of the title compound (2 ml). : 1) as a white solid (40 mg), mp 114-116 °.

Analysis found: C, 58.7; H, 6.0; N, 6.7; Cl, 11.9 (^ 28 ^ 39 ^ 2 ^ 3®4) 2 · C4H4O4 Calcd: C, 59.0; H, 6.8; N, 6.9; Cl, 11.6% and 33 89164

Example 6 Ν-ΓΓ3-Γ3-ΓΓ6-ΓΓ2- (4-amino-3,5-dichlorophenyl) -2-hydroxy-ethylamino-hexylphenyl 1-phenylmethylacetamide From intermediate 17 (1.40 g) was used as a hydrogenation catalyst. 10% palladium / carbon (50% water paste, 170 mg). The solid from the ethyl acetate extracts was triturated with diethyl ether to give the title compound as a white solid (0.76 g), m.p. 91-94 ° C, TLC (System A 80: 20: 2) Rf 0.45.

Analysis found: C, 60.7; H, 7.5; N, 7.9; Cl, 13.9 Calculated for C 26 H 37 Cl 2 N 3 O 3: C, 61.2; H, 7.3; N, 8.2; Cl, 13.9%

Example 7 2- [4-Γ3-Γ Γ 6-Γ Γ2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethylamino] hexoxyl] phenoxy 1-N, N-dimethylacetamide (E) -butenedioate (salt) ( 2: 1) From intermediate 19 (0.99 g) using pre-reduced 10% palladium / carbon (50% water paste, 115 mg) as hydrogenation catalyst. Concentration of the ethyl acetate extracts gave an oil, the oil (0.70 g) in methanol (2 mL) was treated with (E) -butenedioic acid (75.5 mg) in methanol (2 mL) and the solution was concentrated. The residue was triturated with diethyl ether to give the title compound as a tan solid (0.63 g), m.p. 116-118 °, TLC (System B 95: 5: 1) Rf 0.17.

Example 8 Ν-Γ4-Γ3-ΓΓ6-ΓΓ2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethylamino] hexyloxy] propylphenylphenyl-N-methylmethanesulfonamide hydrochloride / carbon (50% water paste, 50 mg). Concentration of the ethyl acetate extracts gave 34 89164 oil which was FCC purified by System B (99: 1: 1-> 95: 5: 1) to give a yellow oil, the oil in ether (5 mL) was treated with ethereal hydrogen chloride and the resulting oil was triturated with dry ether. to give the title compound as a yellow solid (90 mg), TLC (System G 95: 5: 1) RF 0.56.

Analysis found: C, 51.14; H, 7.02; N, 6.87; Cl, 17.82; S 5.00 Calculated for C 25 H 37 Cl 2 N 3 O 4 S.HCl: C, 51.50; H, 6.57; N, 7.21; Cl, 18.24; S 5.50%

Example 9 4-Amino-3,5-dichloro-.alpha.-trans-r3- [4- (2- (dimethylamino) ethyl] phenylpropoxyhexyl] aminomethylbenzene] methanol

A solution of intermediate 4 free base (1.54 g), intermediate 24 (2.94 g), BTPC (100 mg) and copper (I) iodide (10 mg) in diethylamine (30 ml) and acetonitrile (10 ml) the mixture was stirred under nitrogen for 18 hours. The solution was concentrated in vacuo to a brown oil which was FCC purified by System B (95: 5: 1) to give a yellow oil (2.4 g), the oil (2.3 g) being hydrogenated with 10% palladium oxide / carbon (50%). aqueous paste, 500 mg) in ethanol (20 mL) containing hydrochloric acid (concentrated HCl / EtOH; 1: 9 v / v, 6.9 mL). The catalyst was removed by filtration through hyflon. The ethanol was evaporated and the residue partitioned between 8% sodium bicarbonate (20 ml) and ethyl acetate (20 ml). The aqueous layer was re-extracted with ethyl acetate (20 mL) and the combined organic extracts were washed with sodium bicarbonate (20 mL) and brine (20 mL), dried and concentrated to a yellow oil, the oil was FCC purified by eluting with System B (98: 2: 1) to give a pale yellow oil. (1.2 g). This was triturated with hexane to give the title compound as a white solid (1.1 g), m.p. 41.5 to 43.5 °.

Analysis found: C, 63.23; H, 8.37; N, 8.10; Cl, 13.69; Calcd for C27H40Cl2n3 ° 2: C, 63.64; H, 7.91; N, 8.25; Cl, 13.92%

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35 89164

Example 10 4- [4-Γ5--2- (4-amino-3,5-di-1-triphenyl) -2-hydroxyethyl] -amino] pentoxy] Butyl 1 -W. N-Dimethylbenzene as acetamide Intermediate 18 (1.00 g) in ethanol (20 ml) containing hydrochloric acid (concentrated HCl / EtOH, 1: 9 v / v, 1.48 ml) was hydrogenated with pre-reduced 10 % palladium / carbon (150 mg, 50% paste in water). The reaction mixture was filtered (Hyflo) and the filtrate was concentrated. The residue was partitioned between ethyl acetate (100 mL) and 8% aqueous sodium bicarbonate (2 x 50 mL). The dried organic layer was concentrated and the residual oil was FCC purified by eluting with System D (100: 0: 1-> 90: 10: 1) to give the title compound as a yellow oil (0.69 g). The title compound (469 mg) in methanol (2 ml) was treated with (E) -butenedioic acid (51.9 mg) in methanol (2 ml). The solution was concentrated to an oil which was triturated with diethyl ether to give the (E) -butenedioate salt of the title compound (2: 1) (407 mg), m.p. 107-110 °.

Analysis found: C, 59.9; H, 7.4; N, 7.0; Cl, 12.0 Calcd for C 27 H 39 Cl 2 N 3 O 3 · 0.5C 4 H 4 O 4: C, 59.8; H, 7.1; N, 7.2; Cl, 12.2%

Example 11 Ν-Γ 4-Γ3-Γ Γ 6-ΓΓ 2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethyl-11-amino-hexyloxyethylphenylmethanesulfonamide Intermediate 20 (1.2 g) was hydrogenated according to Example 10 using 10% catalyst as a catalyst. pal 1 -dioxide / carbon (50% aqueous paste, 150 mg). Evaporation of the ethyl acetate extract gave a yellow oil which was FCC purified by elution with System B (92: 8: 1). The resulting pale yellow oil was triturated with ether to give the title compound as a white solid (445 mg), m.p. 62-65 °

Analysis found: C, 51.94; H, 6.40; N, 7.79; Cl, 13.96; S, 6.17 36 891 64 Calcd for C 23 H 33 Cl 2 M 3 O 4 S: C, 53.28; H, 6.42; N, 8.10; Cl, 13.68; S, 6.18%

Example 12 4- [3- [6-6- (4-Amino-3,5-dichlorophenyl) -2-hydroxyethyl] -amino] hexoxypropylbenzeneacetamide

Added to a stirred solution of 4-amino-α- (aminomethyl) -3,5-dichlorobenzenemethanol (900 mg) and DEA (650 mg) in dimethylformamide (10 mL) at 100 ° under nitrogen. After 1 hour, the solvent was evaporated and the residue partitioned between 8% sodium bicarbonate (20 ml) and ethyl acetate (20 ml). The organic layer was washed with water and brine, dried and concentrated in vacuo. The resulting yellow solid was triturated with ether to give the title compound as an off-white powder (510 mg), m.p. 104-106 °. Analysis found: C, 60.58; H, 7.35; N, 8.11; Cl, 13.83 C 25 H 35 Cl 2 N 3 O 3: Calc'd: C, 60.48; H, 7.11; N, 8.46; Cl, 14.28%

Example 13 4-Amino-3,5-dichloro-g-ΓΓΓ6-Γ3- Γ 4- (methoxymethylphenyl) -propoxyhexylamino] methylbenzenethanol, (E) -butenedioate (2: 1) (salt) 1- [3-C (6- bromohexyl) oxy] propyl] -4- (methoxymethyl) benzene (1.0 g) and 4-amino-α- (aminomethyl) -3,5-dichlorobenzenemethanol (1.0 g) were reacted according to Example Concentration of the ethyl acetate extract gave an oil which was FCC purified by elution with System B (90: 10: 1) to give a yellow oil (620 mg), the oil in isopropanol (5 mL) was treated with a hot solution of fumaric acid (20 mg) in isopropanol ( 2 ml) and after one hour the biphasic system was stirred vigorously to leave a pale yellow precipitate which was collected by filtration and dried in vacuo to give the title compound as a pale yellow powder (550 mg), mp 110-112. °, TLC (System A 80: 20: 2) Rf 0.43.

Analysis found: C, 59.33; H, 6.87; N, 4.88; Cl, 13.31 C 25 H 36 Cl 2 N 2 O 30 • 5C 4 H 4 O 4: Calculated: C, 59.89; H, 7.07; N, 5.17; Cl, 13.09%

Example 14 4- [3- [6-6- (4-Amino-3,5-dichlorophenyl) -2-hydroxyethyl] -amino] hexyl] propyl] benzoic acid

The product of Example 3 (600 mg) in ethanol (8 ml) was treated with 2N sodium hydroxide (4 ml) and stirred for 1 hour. The ethanol was evaporated, water (20 ml) was added to the residue and the mixture was neutralized using 2N hydrochloric acid. Ethyl acetate (25 ml) was added and the biphasic mixture was stirred vigorously for 10 minutes. The resulting precipitate was collected by filtration, washed with ethyl acetate and dried to give a cream solid (450 mg). This was triturated with warm methanol (10 ml) and filtered to give the title compound as a white powder (290 mg), m.p. 190-191 °.

Analysis found: C, 59.22; H, 6.82; N, 5.62; Cl, 14.40 C 24 H 32 Cl 2 O 2 N 2 O 4: Calculated: C, 59.63; H, 6.67; N, 5.79; Cl, 14.67%

Example 15 4-Amino-35-dichloro-α-β-β-β-β-β (4-morpholinylmethyl-1-phenylpropoxy) Laminolmethylbenzene methanol

The product of Example 5 (0.67 g) in benzene (10 ml) was added dropwise to lithium aluminum hydride (300 mg) in dry diethyl ether (15 ml) at room temperature under nitrogen. The suspension was stirred for 18 hours at room temperature. Treatment with water (0.3 ml), 2N aqueous sodium hydroxide (0.6 ml) and water (0.6 ml) gave a precipitate which was separated by filtration (Hyflo). The filtrate was concentrated to an oil which was FCC purified by System B (95: 5: 1) to give the title compound as a white solid (318 mg), m.p. 57-59 °, TLC (System B 95: 5: 1) Rf 0.22.

Example 16 4-Amino-3,5-dichloro-ΓΓ6-C3- Γ4- [Γ2- (dimethylaminolethylaminophenylpropoxy) 1-amino] iminylbenzenemethanol (E) -butenedioate (2: 3) ( salt) NC 4 -C 3 -C [6 - [[2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethyl] amino] hexyl] oxy] propyl] phenyl] -2-dimethylaminoacetamide as the free base (440 mg) was treated with lithium aluminum hydride (420 mg) according to the procedure of Example 15. After 7 days, water (1 ml), 2N aqueous sodium hydroxide (2 ml) and water (1 ml) were added successively, the precipitate was removed by filtration through hyflo and the ether was evaporated to leave a brown oil, a solution of the oil (320 mg) and fumaric acid (78 mg) in methanol (31) was concentrated to an oil which was triturated with ether to give the title compound as a brown solid (8230 mg), m.p. 41-45 °. Analysis found: C, 56.59; H, 7.35; N, 7.30; Cl, 9.61 Calcd for C27H42Cl2N4O2.1.5C4H4O4: C, 56.66; H, 6.91; N, 8.01; Cl, 10.13%

Examples 17 and 18 were performed according to the method of Example 1.

Examples 17 4-Amino-3,5-dichloro-α-ΓΓΓ6-Γ3- Γ 4-Tbis (2-hydroxyethyl) -aminoenyl] propoxyhexylamino] methylbenzenemethanol From intermediate 26 (402 mg) using a mixture of concentrated hydrochloric acid and ethanol (1: 9 v / v) v, 0.9 ml). Evaporation of the ethyl acetate extracts gave a brown oil which was FCC purified by elution with System B (95: 5: 1 80: 20: 1) to give the title compound as a pale yellow oil (85 mg), TLC (System A 80: 20: 2) Rf 0 , 33. Δ (CDCl 3) 1.2-1.63 and 1.84 (-CH 2 "); 3.54 39 S 9 1 6 4 and 3.81, 8H, (-CH 2 cH 2 OH) 2 '6.62 and 7.04, 4H, (CH of the phenyl ring), 7.17, 2H, (CH of the dichloroaniline ring).

Example 18 4-Amino-3,5-dichloro-α-ΓΓΓ6-Γ3-Γ4-Γ 2- (dimethylaminoethoxy-1-phenylnropoxyhexyl) amino Imetylbenzenemethanol From intermediate 27 (4.32 g) using 10% pre-reduced hydrogenation catalyst palladium / carbon (50% paste in water, 750 mg) in ethanol (30 ml) containing concentrated hydrochloric acid (concentrated HCl / ethanol 1: 9 v / v, 10.1 ml), oil obtained by evaporation of ethyl acetate extracts, FCC- was purified by elution with System A (80: 20: 2), after which the crude fractions were further FCC chromatographed eluting with System B (95: 5: 1) The resulting combined oils (493 mg) in methanol (5 mL) were treated with (E) - butenedioic acid (109 mg) in methanol (5 ml) The solution was concentrated and the residual foam was triturated with diethyl ether to give the title compound as a pale yellow foam (0.361 g), TLC (System A 80: 20: 2) Rf 0.5.

Analysis found: C, 56.1; H, 7.2; N, 6.2; Cl, 11.0 calculated for C27h41c12n3O3 · 1 / 25C4H4O4.0.8H2O: C, 56.0; H, 7.0; N, 6.1; Cl, 10.3%

The following examples provide suitable formulations of the compounds of the invention. As used herein, the term "active ingredient" means a compound of the invention.

Tablets (straight length) mg / tablet

Active Ingredient 2.0

Microcrystalline cellulose USP 196.5

Magnesium stearate BP 1.5

Compression weight 200.0 40 3 91 6 4

The active ingredient is sieved through a suitable sieve, mixed with excipients and compressed using 7 mm diameter pistons.

Tablets of other strengths can be prepared by varying the ratio of active ingredient to microcrystalline cellulose or compression weight and using suitable pistons.

The tablets may be film-coated with suitable film-forming materials such as hydroxypropylmethylcellulose using concentrated methods. Alternatively, the tablets may be sugar coated.

Syrup (sucrose-free) ma / 5 ml dose

Active ingredient 2.0 mg

Hydroxypropylmethyl selenium USP (viscosity 4000) 22.5 mg

Bumpers)

Plavori) color) as needed Preservative)

Sweetener

Purified water BP to 5.0 ml

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

Pressure aerosol delivering said dose A. Suspension aerosol ma / measured dose Per jar

Active ingredient, atomized 0.100 26.40 mg oleic acid BP 0.100 2.64 mg

Trichlorofluoromethane BP 23.64 5.67 g

Dichlorodifluoromethane BP 61.25 14.70 g li 4i 89164

In liquid energy sales, the active ingredient is atomized into fine particles. The oleic acid is mixed with trichlorofluoromethane at 10-15 ° C and the atomized drug is mixed into the solution with a high shear mixer. The suspension is dispensed into aluminum aerosol cans and suitable dispensing valves are pressed onto the cans to give 85 mg of suspension. The dichlorodifluoromethane is pressure filled into the jars through a valve.

B. Solution aerosol mg / measured dose Per jar Active ingredient 0.055 13.20 mg

Ethanol BP 11,100 2.66 g

Dichlorotetrafluoromethane BP 25.160 6.04 g

Dichlorodifluoromethane BP 37.740 9.06 g

Oleic acid, BP, or a suitable surfactant, for example Span 85 (sorbitan trioleate), may also be included.

The active ingredient is dissolved in ethanol together with any oleic acid or surfactant used. The alcoholic solution is metered into suitable aerosol containers followed by dichlorotetrafluoroethane. Suitable dosing valves are pressed onto the vessels and the dichlorodifluoromethane pressure is filled into the vessels through the valves.

Intravenous injection mq / ml

Active ingredient 0.5 mg

Sodium chloride BP as needed

Water for injections BP to 1.0 ml

The tonicity of the solution can be adjusted by adding sodium chloride and the pH can be adjusted with an acid or alkali to a value which is optimal for the stability of the active ingredient, or 42 89164 to facilitate the dissolution of the active ingredient. Alternatively, buffer salts may be used.

The solution is prepared, clarified and filled into suitably sized ampoules which are sealed by melting the glass. The injection is sterilized by heating in an autoclave using some suitable cycle. Alternatively, the solution can be sterilized by filtration and filled into sterile ampoules under aseptic conditions. The solution may be packed under an inert nitrogen gas or other suitable gas.

Inhalation cartridges mg / cartridge

Active ingredient, atomized 0.200

Lactose BP to 25.0

In liquid energy sales, the active ingredient is atomized into fine particles before it is mixed with normal tableting-grade lactose in a high-energy mixer. The powder mixture is filled into a No. 3 hard gelatin capsule in a suitable encapsulation machine. The contents of the cartridges are administered using a powder inhaler such as a Glaxo Rotahaler inhaler.

Il

Claims (2)

43 89 1 64 A process for the preparation of therapeutically valuable dichloroaniline derivatives of the general formula I Cl 1 R 1 h 2h - (/% _ CHCH 0 NH 4 XCH 2 OCH 2 YAr (I) Ah A 2 c 1 wherein X is a bond or a C 1-6 alkylene chain and Y is a bond or C A C 1-4 alkylene, C 2-4 alkenylene or C 2-4 alkynylene chain, provided that the total number of carbon atoms in the groups X and Y is not more than 8. Ar is a phenyl group substituted by one or more groups selected from the group consisting of: - (CH 2) q R, wherein R is C 1-3 alkoxy, NR 3 R 4 wherein R 3 and R 4 are each a hydrogen atom or a C 1-4 alkyl group, or -NR 3 R 4 forms a morpholino, or NR 3 COR 3 wherein R 3 is a hydrogen atom or a C 1-4 alkyl group, and R 6 is a hydrogen atom or C 1-4 alkyl, and q is an integer from 1 to 3, - (CH2) rR7, wherein R7 is NR3SO2R®, wherein R3 is as defined above and R8 is C1-4 alkyl, -COR9, wherein R9 is hydroxy, C1-4 alkoxy or NR3R4, wherein R 3 and R 4 are as defined above, or NR 2 -R * 2, where R ** and R * 2 are both hydrogen or O A C 1-4 alkyl group, at least one of which is a C 2-4 alkyl group substituted by hydroxy, C 1-4 alkoxy; or NR3R4, wherein R3 and R4 are as defined above and r is an integer from 0 to 3; -O (CH 2) q CO 9, wherein q and R 9 are as defined above; or <4 891 64 -O (CH 2) t R 13 where R 13 is hydrogen, C 1-4 alkoxy or NR 3 R 4 wherein R 3 and R 4 are as defined above and t is 2 or 3; and R 1 and R 2 are each a hydrogen atom or a C 1-3 alkyl group, provided that the total sum of the carbon atoms in the groups R 1 and R 2 is not more than 4; and their physiologically tolerable salts and solvates, for example hydrates, characterized in that the compound of formula (I) in which R 3 · is a hydrogen atom is prepared by alkylation of an amine of formula (II) Cl h9h -υ NV-chch2nr14r15 (ii)> = / Ah Cl (where R14 is a hydrogen atom and a protecting group and R * 3 is a hydrogen atom) with an alkylating agent of formula (III) LCHXCH2OCH2YAr (III) (where L is a leaving group and R2, X, Y and Ar have the same meaning as above), followed by if necessary, remove any protecting groups present; or (1b) for the preparation of a compound of formula (I) wherein R 3 · is a hydrogen atom, an amine of general formula (II) is otherwise alkylated except that R 13 is a hydrogen atom or a group which can be converted to hydrogen under reaction conditions by general formula (IV) with R 2 COXCH 2 OCH 2 YAr (IV) II 45 8 9 1 64 (wherein R 2, X, Y and Ar are as defined above) in the presence of a reducing agent, followed, if necessary, by the removal of any protecting groups present; or (2) reducing an intermediate of general formula (VI) Cl X 4 - ^ X 1 -X 2 -X 3 -CH 2 OCH 2 Y-Ar (VI) Cl wherein X 1 is -CH (OH) - or a group which can therefore be converted by reduction; X 2 is -CH 2 NR 14 - (wherein R 14 is a hydrogen atom or a protecting group) or a group which can therefore be converted by reduction; X3 is -CR1R2X- or a group which can therefore be converted by reduction (where R1 and R2 are as defined above; X4 is -NH2 or a group which can therefore be converted by reduction; and Y and Ar are as defined above or are groups which can be at least one of X *, X2, X3 and X4 is a reducing group and / or Y is a reducing group and / or Ar contains a reducing group, followed, if necessary, by the removal of any protecting groups present; (3) deprotection of the general formula (VII); wherein R 1, R 2, X, Y and Ar are as defined above, R 14 and R 16 are each a hydrogen atom or a protecting group and / or an optionally hydroxy, from the intermediate Cl 1 -R 1 R 16 NH-f 2 -CHCH 2 NR 14 OCH CH 2 OCH 2 YAr (VII) / OH OH - and / or the amino substituent in the group Ar is protected provided that at least one of R 4 and R * · ® is a protecting group or Ar contains a protecting group, or (4) a compound of formula (I), wherein Ar is a phenyl group substituted with a group - (CH 2) RCOR 4, wherein r is as defined above and R 1 is hydroxy, to prepare a corresponding compound of formula (I) wherein R 1 is C 1-4 alkoxy; and, if desired, converting the obtained compound of general formula (I) or a salt thereof into a physiologically acceptable salt or solvate thereof. Process for the preparation of compounds according to Claim 1, characterized in that the compound prepared is: 4- [3 - [[6 - [[2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethyl] amino] hexyloxy] propyl] benzamide; Ethyl 4- [3 - [[6 - [[(4-amino-3,5-dichlorophenyl) -2-hydroxyethyl] amino] hexyl] oxy] propyl] benzoate; N - [[3- [3 - [[6 - [[2- (4-amino-3,5-dichloro-phenyl) -2-hydroxy-ethyl] amino] hexyl] oxy] propyl] phenyl] methyl] acetamide; 4- [4- [5 - [[2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethyl] amino] pentyloxy] bytyyli] -N, N-dimetyylibentseeniasetamidi; 4- [3 - [[6 - [[2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethyl] amino] hexyl] oxy] propyy1i] benzoic acid; 4- [4- [3 - [[6 - [[2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethyl-yl] amino] hexyl] oxy] propyl] benzoyl] morpholine; N- [4- [3 - [[6 - [[2- (4-amino-3,5-dichloro-phenyl) -2-hydroxy-ethyl] amino] hexyl] oxy] ethyl] phenyl] methanesulphonamide; 4- [3 - [[6 - [[2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethyl] amino] hexyl] oxy] propyl] benzeneacetamide; and physiologically acceptable salts and solvates thereof. Il: 47 89 1 64