NL8602575A - DICHLOROANILINE DERIVATIVES. - Google Patents

Description

t VO 8410

Dichloroaniline derivatives.

The invention relates to dichloroaniline derivatives having a stimulatory effect on (-adrenorceptors), methods of preparation thereof, pharmaceutical compositions containing them, as well as their use in medicine.

Dihaloaniline derivatives have been described as bronchodilators that stimulate β-adrenoreceptors.

British Patent 1,178,191 discloses compounds having the general structure of Formula 10 wherein the substituents Hal represent bromine or chlorine atoms; R1 hydrogen or hydroxy 2 3 4 5

10 proposes? R and R each represent hydrogen or C 1-4 alkyl; and R and R.

each representing hydrogen, C 1 alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, 1-dialkylaminoalkyl, cycloalkyl, phenyl, benzyl or adamantyl, 4 or KR R forming a heterocyclic ring optionally substituted with C 1 -C 2 alkyl groups.

A new group of dichloroaniline derivatives has now been found, differing in structure from the compounds disclosed in British Patent 1,178,191, and having a desirable and useful activity profile.

The present invention provides compounds of the general formula 1, wherein X represents a bond, or a CL, alkylene, CL ken alkenylene or CL alkynyl chain, 1–6 2–0 2—0, and Y represents a bond, or a C 1-4 alkylene, C 1-4 alkenylene or C 1-4 alkynylene chain, with the proviso that the total number of carbon atoms in X and Y taken together does not exceed 8;

Ar represents a phenyl group substituted by one or more substituents selected from nitro, - (CH.) R [where R represents C alkoxy, 3 4 3 4 2 ^ -NR R (where R and R each represent a hydrogen atom or a C 1 -alkyl group 3 4, or -NR R forms a saturated heterocyclic amino group having 5-7 atoms in the ring and optionally containing one or more atoms in the ring selected from -O- or -S- or a group -NH- or -N (CH_) -), 5 6 5 -NR COR (wherein R represents a hydrogen atom or a C alkyl group, 6 3 4 and R represents a hydrogen atom or a C 1-4 alkyl, 4 alkoxy or -NR R - group), and q represents an integer of 1-3], 7 7 5 8 8 35 - (CH_) R [where R represents -NR S0_R (where R is a CL. Alkyl-, 2 r 3 4 52 5 1-4 represents phenyl or NR R group), -NR CO 2 CH 2 N (R) 2 (wherein; each of the 3 S G. 2 5 7 5 -2 groups R 5 is a hydrogen atom or a C 1. alkyl group), 9 9 1-4 34 10 -COR where R represents hydroxy, C 1-4 alkoxy or NR R), -SR (where R 1 represents a hydrogen atom om or a C 1-4 alkyl group, which is optionally substituted by hydroxy, alkoxy or NR 3 R 4), -SOR ^ °, -SO ^ R ^^, -CN, or -NR ^ R ^ 2 (where R ^ and R ^ represent a hydrogen atom or a C-alkyl-***** group, at least one of which represents C 1. alkyl, 3 4 2-4 substituted by a hydroxy, C 1-4 alkoxy or NR R group), and r represents an integer from 0-3], 9 9 -OCH 4 iCCOR (where q and R are the above have meanings), or -0 (CH ^) ^. R ^ ^ [where R ^ 3 stands for hydroxy, NR3R4, NR ^ ^ R ^ 2 or a C ^ -4 alkoxy group, optionally substituted by hydroxy, C ^ 4 alkoxy or NR 1 R 4, and t represents an integer of 2-3]; and 1 2 R and R each represent a hydrogen atom or a C alkyl group, with 1-3 1 2 provided that the total number of carbon atoms in R and R taken together is not more than 4; as well as physiologically acceptable salts and solvates (e.g. hydrates) thereof.

It will be understood that the compounds of the general formula 1 have one or two asymmetric carbon atoms, namely 1 2 the carbon atom of the -CH (OH) group and, when R and R are different groups, the carbon atom to which these are bound.

The compounds of the invention therefore include all enantiomers, diastereoisomers and mixtures thereof, including racemates. Compounds in which the carbon atom in the -CH (OH) group is in the R configuration are preferred.

In the definition of general formula 1, the term alkenylene includes both cis and trans structures.

In one aspect, the invention provides compounds of formula 1, wherein R, R, X, Y, and Ar have the meanings mentioned above 5 5 8 9 10 10 10 and R represents -NR SO R, -COR, -SR, -SOR, -SO R, 11 12 2 30 -CN or -NR R.

For example, in general formula 1, the chain X may represent a bond, -CH2 ~, ~ ^ CH2 ^ 3 "" "" ^ CH2 ^ 4 ~ "" ^ CH2 ^ 5 * "'- (ch2) 6-, -ch2c = c-, - (ch2) 2ch = ch-, - (ch2) 2c = c-, -ch = chch2-, -CH = CH (CH2) - or -CH2C = CCH2-. For example, the chain Y can represent a bond, -CH2-, - (CH ^ -, - (CH ^ -, - (CH2) 4-, -CH = CH-, -C = C-, ch2ch = ch- , or -ch2c = c-.

3 o 0 2 57 5 -3-

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

A preferred group of compounds of formula 1 is where X represents an alkylene chain and Y represents a C 1-4 alkylene chain.

Particular compounds of this type are those in which X stands for - (CH2) 3- or -CCH2) 4- and Y stands for -CH2-, - (CH2) 2 ~ or - (CH ^ -.

In the compounds of formula 1, and R 2 may each represent, for example, methyl, ethyl, propyl or isopropyl groups, except 1 2 that when one of R and R is a propyl or isopropyl group, the other is a hydrogen atom or a methyl group . R1 can be, for example, a hydrogen atom or a methyl, ethyl or propyl group. R can be, for example, a hydrogen atom or a methyl group. R and R are each preferably a hydrogen atom or a methyl group.

1 2

A preferred group of compounds are those wherein R and R

1 2

both represent hydrogen atoms, or R is a hydrogen atom and R.

represents a C, alkyl group, especially is a methyl group.

3 4

When -NR R in compounds of formula 1 represents a saturated heterocyclic amino group, it may contain 5, 6 or 7 atoms in the ring and optionally in the ring contain a hetero atom selected from -O- or -S-, or a group -NH- or -N (CH 3) -. Examples of such 4 -NR R groups are pyrrolidino, piperidino, hexamethylene imino, piperazino, N-methylpiperazino, morpholino, homomorpholino or thiamorpholino.

For example, Ar may be a phenyl group substituted by - (CH.) R E where R represents C alkoxy, for example methoxy,

(J

diC. . alkylamino, for example dimethylamino, morpholino, piperidino, 6 6 piperazino, N-methylpiperazino, -NHCOR (where R stands for C ... alkyl, 7 7

30 for example methyl), and q equals 1 or 2], - (CH) R [where R

5 8 5 2 Σ 'g

stands for -NR SO.R (where R represents hydrogen or methyl, and R

2 5 represents C. alkyl, e.g. is methyl), -NHCOCH N (R) (where 1-4 5 2 2 9

both groups R stand for C,. alkyl, for example methyl), -C0R

9 (where R represents 4 alkoxy, for example ethoxy, amino, diC 4 -4 alkylamino for example dimethylamino, morpholino, piperidino, piperazino 11 12 11 12 or N-methylpiperazino), -NR R (where R and / or R represents a

9% 7 S

4 4 -C 2 4 alkyl group, for example, ethyl group, substituted by a hydroxy or diC 2 -alkylamino group, for example dimethylamino group, and the other represents a hydrogen atom), and r equals zero or 1,990 -CH. COR (where R stands for that. Alkylamino, for example di-2 13 1-413 5 methylamino), or -OiCI ^ ^ R (where R stands for diC1-4 alkylamino, for example dimethylamino).

A preferred group of compounds of the invention are those of formula la, wherein X represents a C 1-4 alkylene chain and Y represents a y alkylene chain, with the proviso that the total number of carbon atoms in X and Y together is 5 or 6; and

Ar represents a phenyl group substituted by a group selected from alkoxymethyl (e.g., methoxymethyl), morpholinomethyl, diC 1 -alkyl amino-C. -alkyl (eg dimethylaminoethyl), -CH.NHCOR5 (where R6 is 2 5 8 2 5 15 for C, alkyl, eg methyl), -NR SO R (where R is hydrogen- 8 2 5 substance or methyl and R represents C. alkyl, e.g. methyl), -NHCOCH_N (R).

5 1-4 2g z

(where both R groups represent CL alkyl, e.g. methyl), -COR

9 -1-4 (where R stands for hydroxy, C alkoxy, eg ethoxy, amino, which. 1-4 9 9 1-4 alkylamino eg dimethylamino, or morpholino), -CH.COR (where R stands for 2 11 12 20 for amino or that .alkylamino, eg dimethylamino), -NR R (where 11 12 1-4 R and R are both hydroxy hydroxy, alkyl, eg hydroxyethyl), 2-4 9

diC. alkylamino-ethylamino (e.g. dimethylamino-ethylamino), -OCH.COR

1-4 9 z (where R stands for those .alkylamino eg dimethylamino), or -O (CH 4) -r (where R (where R stands for diC ^ 4alkylamino, eg dimethy 1-25 amino); as well as physiologically acceptable salts and solvates thereof.

Particularly preferred compounds of formula la are those wherein X and Y have the meanings stated for formula la; and

Ar represents a phenyl group substituted by a group selected from 6 6 8 8 -CH NHCOR (where R is methyl), -NHSO R (where R is methyl), 9 9 ^ 30 -COR (where R is hydroxy, ethoxy, amino or morpholino), or 9-9 -CH2COR (where R is amino or dimethylamino), and physiologically acceptable salts and solvates thereof.

Particularly important compounds according to the invention are: 4- [3 - [[6-C C 2- (4-amino-3,5-dichlorophenyl) -2-hydroxy-ethyl] amino-hydroxy-13-35 oxy] propyl] benzamide; 8802575 * -5-ethyl 4-C3-CC6-CC (4-amino-3,5-dichlorophenyl) -2-hydroxy-ethyl-jaminc-hexyl] oxypropyl 1-benzoate, * N - [[3- [3- [ [6- [C 2- (4-amino-3,5-dichlorophenyl) -2-hydroxy-ethyl] aminol-hydroxyoxypropyl] phenylethyl] acetamide; 4- [4-C5-CC2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethyl] amino] hexyl] oxypentyloxy] buty1] -N, N-dimethylbenzene acetamide; 4- [3 - [[6 - [[2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethyl] amino] hexyl] -oxy] propyl] benzoic acid; 4— [4— [3 - [[6-C 2 - (4-amino-3,5-dichlorophenyl) -2-hydroxy-ethyl] amino-1-hexyl] oxypropyl] benzoyl] morpholine; N-C4- [3 - [[6 - [[2- (4-amino-3,5-dichlorophenyl) -2-hydroxy-ethyl] amino] -hexyl] oxy] ethyl3phenyl] methanesulfonamide; 4- [3 - [[6 - [[2- (4-amino-3,5-dichlorophenyl) -2-hydroxy-ethyl] amino] -hexyluoxy] propylbenzene acetamide; 15 as well as the physiologically acceptable salts and solvates thereof.

Suitable physiologically acceptable salts of the compounds of the general formula 1 include acid addition salts derived from inorganic and organic acids, such as hydrochlorides, hydrobromides, sulfates, phosphates, maleates, tartrates, citrates, benzoates, 4-methoxy-20 benzoates, 2- or 4 -hydroxybenzoates, 4-chlorobenzoates, p-toluenesulfonates, methanesulfonates, sulfamates, ascorbates, salicylates, acetates, fumarates, succinates, lactates, glutarates, gluconates, tricarballylates, hydroxy-naphthalene carboxylates, e.g. 1-hydroxy or 3-hydroxy-2-naphthalene carboxylates, or oleates. The compounds can also form salts with suitable bases. Examples of such salts are alkali metal (e.g. sodium and potassium), and alkaline earth metal (e.g. calcium or magnesium) salts.

The compounds according to the invention have a stimulating effect on B 1 -adrenoreceptors, which furthermore has a particularly advantageous profile. The stimulatory activity was demonstrated in the isolated guinea pig trachea, in which compounds were found to cause relaxation of PGF2a-induced contractions. Compounds according to the invention showed a particularly long duration of action in this test.

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

Q? n * S 7? § p -6-

The compounds of the invention also have an indication of usefulness for the treatment of inflammatory and allergic skin diseases, congestive heart defects, depression, preterm labor, glaucom, and in the treatment of conditions in which it is advantageous to reduce gastric acidity , especially in the case of gastric and duodenal ulcers.

The invention further provides compounds of formula 1 as well as their physiologically acceptable salts and solvates for use in the therapy or prophylaxis of diseases associated with reversible airway obstruction in humans or animals.

The compounds of the invention can be brought into a suitable form for administration in any suitable manner. The invention therefore also includes pharmaceutical compositions comprising at least one compound of formula 1 or a physiologically acceptable salt or solvate thereof formulated for use in human or veterinary medicine. Such compositions can be combined with physiologically acceptable carriers or excipients before use, optionally with additional medicinal agents.

The compounds can be presented 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 of the invention are conveniently delivered in the form of an aerosol spray presentation from pressure packs, using a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas, or from a nebulizer .

In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve that delivers a measured amount.

For administration by inhalation or insufflation, the compounds of the invention may also be in the form of a dry powdered 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 in the form of a dosage unit in, for example, capsules or cartridges of, for example, gelatin, or in. V - - Itcza ifcf * <S> a -ï -7- blister packs from which the powder can be administered using an inhaler or insufflator.

For oral administration, the pharmaceutical composition may be in the form of, for example, tablets, capsules, powders, solutions, syrups or suspensions, which are formulated in the usual manner with acceptable excipients.

For buccal administration, the composition may be in the form of tablets, drops or lozenges, which are on. are composed in the usual manner.

The compounds of the invention can be made suitable for parenteral administration by bolus injection or continuous infusion. Injection formulations can be presented in dosage units in ampoules, or in multi-dose containers with a preservative added. The compositions may be in the form of suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain auxiliary agents such as suspending stabilizers and / or dispersants. Also, the powdered active ingredient can be used for reconstitution prior to use with a suitable vehicle, for example sterile pyrogen-free water.

For topical administration, the pharmaceutical preparations may be in the form of ointments, lotions or creams, which are formulated in a conventional manner, for example with an aqueous or oily base, generally with the addition of suitable thickeners and / or solvents. For nasal administration, the composition may be in the form of a spray formulated, for example, on the basis of 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, for example, those which are conventional suppository bases. such as cocoa butter or other glycerides.

Where pharmaceutical preparations for oral, buccal, rectal or topical administration have been described above, they may be presented in a conventional manner, together with controlled release forms.

A daily dose of the active compound for the treatment of man from 0.005 mg to 100 mg is suggested, which amount is 0602575 rt

* V

-8- can be administered conveniently in one or two doses. The exact dose to be applied will of course depend on the age and condition of the patient and on the route of administration. For example, a suitable dose for inhalation administration is 0.005 mg to 20 mg, 5 for oral administration, 0.02 mg to 100 mg, and for parenteral administration, 0.01 mg to 2 mg for bolus injection administration and 0.01 mg to 25 mg for administration by infusion.

The compounds of the invention can be prepared by various methods, as will be explained below.

In the following description of processes for preparing compounds of formula 1 and intermediates which can be used in their preparation, X, Y, Ar, R and R have the meaning defined for general formula 1, unless otherwise specified. In addition, any substituent in the group Ar may be a precursor substituent, which can be converted to the required substituent by conventional methods.

It will be understood that some of the reactions described below may lead to attack of other groups in the starting material which are desired in the final product; this applies in particular to the reduction methods described, especially when hydrogen and a catalyst are used and when an ethylene or acetylene bridge is required in the compound of the invention. Accordingly, in accordance with conventional practice, care should be taken to use reagents that do not attack such groups, or that the reaction is conducted as part of a sequence avoiding their use when such groups are present in the starting material.

In the preparation of both intermediates and final products, the last step in the reaction may be to remove a protecting group. Conventional protecting groups can be used, as described, for example, in "Protective Groups in Organic Chemistry", Ed. J. F.W. McOmie (Plenum Press, 1973). For example, hydroxy groups can be protected by aralkyl groups such as benzyl, diphenylmethyl or triphenylmethyl, or as tetrahydropyranyl-35 derivatives. Suitable amino protecting groups include aralkyl groups such as benzyl, α-methylbenzyl, diphenylmethyl or triphenylmethyl, and acyl groups such as acetyl, trichloroacetyl or trifluoroacetyl.

Conventional methods can be used to remove protecting groups. For example, aralkyl groups can be removed by hydrogenolysis in the presence of a metal-5 catalyst (e.g. palladium on charcoal). Tetrahydropyranyl groups can be cleaved off by hydrolysis under acidic conditions. Acyl groups can be removed by hydrolysis using an acid such as an inorganic acid, for example hydrochloric acid, or a base such as sodium hydroxide or potassium carbonate, or a group such as trichloro-acetyl can be removed by reduction with, for example, zinc and acetic acid.

In a general method Cl), a compound of the general formula 1 can be prepared by alkylation. Conventional alkylation procedures can be used.

Thus, for example, in one process (a), a compound of the general formula 1 wherein R 1 is a hydrogen atom can be prepared 14 by alkylating an amine of the general formula 2, wherein R represents a hydrogen atom or a protecting group and R 1 ^ is a hydrogen atom), followed by removal of any protecting groups, if any.

The alkylation (a) can be carried out using an alkylating agent of the general formula 3 (wherein L represents a leaving group, for example a halogen atom such as chlorine, bromine or iodine, or represents a hydrocarbylsulfonyloxy group such as methanesulfonyloxy or p-toluenesulfonyloxy).

The alkylation is preferably 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 conducted in a solvent such as acetonitrile or an ether, for example tetrahydrofuran or dioxane, a ketone, for example butanone or methyl isobutyl ketone, 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, V 'J. -Ιο ί, a compound of the general formula 1 wherein R represents a hydrogen atom can be prepared by alkylation of an amine of the general formula 2, as previously defined except that R represents a hydrogen atom or a group that can be reacted therein under the reaction conditions, with a compound of the general formula 4 in the presence of a reducing agent, followed if necessary by removal of any protecting groups.

. 15

Examples of suitable R groups which can be converted into a hydrogen atom are arylmethyl groups such as benzyl, 10α-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 charcoal, using an alcohol, for example ethanol or methanol, or an ester, for example ethyl acetate , or an ether, tetrahydrofuran, or water, as a reaction solvent, 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 atmosphere.

When the R and R are hydrogen atoms, the reducing agent may also be a hydride such as diborane or a metal hydride such as sodium borohydride, sodium cyanoborohydride or lithium aluminum hydride.

Suitable solvents for the reaction with these reducing agents will depend on the hydride used, but will include alcohols such as methanol or ethanol, or ethers such as diethyl ether or tert-butyl methyl ether, or tetrahydrofuran.

14 15

When a compound of formula 2 wherein R and R each represent hydrogen atoms is used, the imine intermediate of formula 5 can be formed.

Reduction of the imine under the conditions described above, followed if necessary by removal of any protecting groups, results in a compound of the general formula 1.

When it is desired that a protected intermediate of the general formula II be used, it is particularly appropriate to use hydrogen 35 and a catalyst as described above, with the 14 protecting group R under these reducing conditions in 8252575. 11- a hydrogen atom can be converted, avoiding the need for a separate step to remove the protecting group. Suitable protecting groups of this type include arylmethyl groups such as benzyl, benzhydryl and α-methylbenzyl.

In another general method (2), a compound of the general formula 1 can be prepared by reduction. Thus, for example, a compound of the general formula 1 can be prepared by reducing an intermediate of the general formula 6, in which at least one 4 12 3 of the symbols Χ, Χ, Χ, Χ and Y represents a reducible group 10 and / whether Ar contains a reducible group and the other or others have a suitable meaning as follows, viz. X stands for -NH-, X stands for 2 14 14 z for -CH (OH) -, X stands for -CH_NR - (wherein R represents a hydrogen atom or a protecting group), X represents -CR RX, and Ar and Y have the meanings given for formula 1, followed, if necessary, by removal of any protecting groups.

4.

Suitable reducible groups include those where X represents 2 1 2 -NO, X represents a group> C = 0, X represents a group -CH ^ NY '- (where Y' represents a group capable of catalytic hydrogenation in hydrogen be converted, for example an arylmethyl group such as benzyl, benzhydryl or α-methylbenzyl), or an imine (-CH = N-) group or 3 12

a group -CONH-, X stands for a group -COX- or a group CR R X

2 3 (where X represents C-alkenylene or C-alkynylene), or -X -X -2 2—0 2—0 represents a group -CH ^ N ^ CR X-, Y represents ^ 2-4 ^ 1 enylene or alkynylene, and Ar represents a phenyl group substituted by a 3 4 17 25 group containing an amide bridge such as - (CS) CONR R or -NHCOR 1 Z 12 (wherein -NHCOR is reducible to the NHR group).

The reduction can be carried out with reducing agents suitable for the reduction of ketones, imines, amides, protected amines, olefins, alkynes and nitro groups. Thus, for example, when X in the general formula 6 represents a nitro group, it can be reduced to an amino group by using hydrogen in the presence of a catalyst as previously described for process (1), part (b).

When X ^ in the general formula 6 represents a> C = © group, it can be reduced to a -CS (OH) group by using hydrogen in the presence of a catalyst as previously described. for method (1) part (b). Also, the reducing agent may 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, if appropriate, an alcohol, for example methanol or ethanol, or an ether such as tetrahydrofuran, or a halogenated hydrocarbon such as dichloromethane.

2

When X in the general formula 6 represents a -CH-NY 'group 2 3 2 or the group is -CH = N-, or -XX - represents -CH.N = CR X-, it can be 2 * 10 is reduced to a -CH2NH- or -CH2NHCHR X group by using hydrogen in the presence of a metal catalyst as previously described for process (1) part (b). Also, when X or 2 3 2 represents -XX - the group -CH = N- or -CH N = CR X-, it can be reduced to a -CH ^ NH- or -CH ^ NHCHR X group by a reducing agent and conditions as just described for the reduction of 1 X when it represents a group> C = 0.

2 3

When X or X in the general formula 6 represent a -CONH or -COX group, or Ar is phenyl substituted by a group containing an amide bridge such as -CH2) ^ _ ^ CONR ^ R ^ or -NHCOR1 (wherein R1 has the meanings mentioned previously), it can be reduced to a group -CH NH- or -CH X-, or to phenyl, substituted by the group o 4 12 - (CH_) NR R or -NHR by a hydride such as diborane or using a complex-2 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.

3 12

When X represents a group CR RX in which X represents C 2 ^ alkenylene or alkylene, X X 4-4 alkenylene or C 2-4 alkylene, it can be reduced to C2 g alkylene or C 2 alkylene, respectively, by hydrogen to be used in the presence of a catalyst as previously described for process (1) part (b). When X stands for C. alkynylene or Y stands for C2 ^ alkynylene, it can also be reduced to ^ 2-sa ^ ^ eny ^ a respectively C2 alkenylene by using, for example, hydrogen and a lead poisoned palladium on calcium carbonate catalyst 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.

8602073 * * - 13-

In a further general process (3) / a compound of the general formula 1 can be prepared by removing the protecting group from a protected intermediate of formula 7, wherein R and R 2 each represent a hydrogen atom or a protecting group and / or optional hydroxy and / or amino substituents in the group Ar are protected, provided that at least one of R 1 and / or R 1 represents a protecting group and / or Ar contains a protecting group.

Suitable protecting groups and methods for their removal are as previously described. For example, R may represent an aralkyl group, for example benzyl, which can be removed by hydrogenolysis in the presence of a metal catalyst (e.g.

16 palladium on charcoal), and / or R may represent an acyl group which can be removed by boiling with a dilute mineral acid (e.g. hydrochloric acid).

Compounds of formula 1 can also be prepared by a process in which one compound of the general formula 1 is converted into another.

For example, a compound of formula 1 wherein Ar represents a 9 phenyl group substituted by the group - (CH) COR wherein 9 ^ 20 R is hydroxy can be prepared by hydrolysis of the corresponding g compound of formula 1 wherein R represents Calkoxy. For example, the hydrolysis can be carried out under basic conditions using, for example, sodium hydroxide.

In the general methods described above, the resulting compound of formula 1 may be in the form of a salt, preferably in the form of a physiologically acceptable salt. If desired, such salts can be converted to the corresponding free acids by using conventional methods.

Physiologically acceptable salts of a compound of the general Formula 1 can be prepared by reacting a compound of the general Formula 1 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, including other physiologically acceptable salts, of the compounds of general formula 1, using conventional methods.

When a specific enantiomer of a compound of the general Formula 1 is required, it can be obtained by separating a corresponding racemate of a compound of the general Formula 1 using conventional methods.

For example, one example is to use a suitable optically active acid to. salt to be formed with the racemate of a compound of the general formula 1. The resulting mixture of 10 isomeric salts can be separated, for example, by fractional crystallization into the diastereoisomeric salts from which the required enantiomer of a compound of the general formula 1 can be isolated by reaction in the required free base.

Also enantiomers of a compound of the general formula 1 can be prepared from the suitable optically active intermediates using any of the general methods described herein.

Specific diastereomers of a compound of formula 1 may be obtained by conventional methods, for example, by synthesis from a suitable asymmetric starting material using any of the methods described herein, or by reaction of a mixture of isomers of a compound of the general formula 1 into appropriate diastereoisomeric derivatives, for example salts which can then be separated by conventional means, for example by fractional crystallization.

Intermediates of the general formula 6 for use in the general method (2) can be prepared by a number of methods, analogous to the methods described in British Pat. No. 2,165,542A.

For example, intermediates of the general formula 6 wherein a group represents> C = 0 can be prepared from a haloketone of the formula 8, by reaction with an amine of the formula 9 (wherein Y 'represents hydrogen or a group capable of containing it be converted by catalytic hydrogenation). The reaction can be carried out in a cold or warm solvent, for example tetrahydrofuran, tert-butylmethyl-35 ether, dioxane, chloroform, dimethylformamide, acetonitrile or a ketone such as butanone or methyl isobutyl ketone, or an ester, for example ethyl-6302373 * S% -15 acetate, preferably in the presence of a base such as diisopropylethylamine, sodium carbonate or another acid scavenger such as propylene oxide.

Intermediates of the general formula 6 wherein X 1 represents a group> C = 0 can be reduced to the corresponding intermediate which represents a group -CH (OH) - by, for example, a metal hydride such as sodium borohydride in a solvent such as ethanol use.

Intermediates of formulas 2, 3, 4, 8 and 9 are either known compounds or can be prepared by methods analogous to those described for the preparation of known compounds.

Suitable methods for preparing intermediates of formulas 3, 4 and 9 are described in British Patent Publication Nos. 2,140,800A, 2,159,151A, 2,165,542A and in the examples below.

The invention is further illustrated by the following examples. The temperatures are in ° C. Dried refers to a drying treatment using magnesium sulfate or sodium sulfate unless otherwise noted. Thin layer chromatography (tic) 20 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 indicated: A-toluene: ethanol: 0 88 ammonia; B-toluene, ethanol: triethylamine; C-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 is 1- (4-amino-3,5-dichlorophenyl) -2-bromoethanone.

Intermediate 2 30 (Z) -N- [4- [3 - [[6 - [(phenylmethyl) amino3hexyl] oxy] -1-propenyl] phenyl] -methanesulfonamide, hydrochloride (Z) -N- [4- [3- [(6-Bromohexyl) oxy] -1-propenylphenyl] methane-sulfonamide (2.0 g) was added to benzylamine (6 ml) at 125 ° C under nitrogen. The reaction mixture was stirred at 125 ° C for 3 hours, cooled to room temperature and added to 2N hydrochloric acid 3302575 4 ^ -16- (50ml) and water (20ml). The resulting white solid was collected by filtration, washed successively with 2N hydrochloric acid, water and ether, then dried under reduced pressure at 50 ° C. The title compound was obtained as a white powder (1.0 g), m.p. 133-134 ° C.

Intermediate 3 (Z) -N- [4-C3- [C6- [C2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethyl3- (phenylmethyl) amino] hexy 13oxy] -1-propenyl] phenyl] methanesulfonamide

A suspension of intermediate 1 (520 mg), intermediate 2 10. (850 mg) and DEA (500 mg) in 25 ml THF was stirred overnight at room temperature. After filtration, the filtrate was concentrated to an oil, which oil was dissolved in 20 ml of methanol, cooled in an ice bath, and treated with 250 mg of sodium borohydride. The light yellow solution was stirred at room temperature overnight, the methanol was evaporated and the residue was partitioned between 25 ml of water and 25 ml of ethyl acetate. The organic phase was washed with water and brine, dried and concentrated to a red oil which was purified by FCC, eluting with System E (75: 25: 1) to afford the title compound as a colorless oil (540 mg). Thin-20 layer chromatography (System E 75: 25: 1) gave Rf 0.09.

Intermediate 4 4-Iodo-N, N-dimethylbenzeneethanamine, hydrochloride 4-Bromo-N, N-dimethylbenzeneethanamine, hydrochloride (0.65g) was partitioned between 10ml ethyl acetate and 10ml 8% sodium bicarbonate. The water layer was extracted with 10 ml of ethyl acetate, and the combined organic extracts were dried and concentrated to give the free base (0.57 g). n-Butyl lithium (1.6M in hexane, 1.72ml) was added to a solution of the free base (0.57g) in 10ml THP at -78 ° C, and the mixture was stirred under nitrogen for 30 minutes stirred. A solution of 0.63 g of iodine in 10 ml of THP was added dropwise and after 10 minutes the reaction mixture was quenched by adding 10 ml of saturated ammonium chloride. The THF was evaporated and the aqueous residue was extracted with 2 x 15 ml ethyl acetate. The organic extracts were washed with 15 ml of 10% sodium thiosulfate and 15 ml of brine, dried and concentrated 8602575 S-17 to give a brown oil. The oil in 10 ml ether and 2 ml dichloromethane was treated with ether hydrochloride and the resulting precipitate was collected by filtration and dried. The title compound was obtained as a white solid (0.54 g).

5 Analyzes found: C 38.77; H 4.87; N 4.39; Cl 11.36; I 40.67.

C10H14IN * HCl requires C 38'55 * H 4.85; N 4.5; Cl 11.38; I 40.73%.

Intermediate 5 N- (4-Iodophenyl) -N-methylmethanesulfonamide

A mixture of N- (4-iodophenyl) methanesulfonamide (4.3g), 50% aqueous sodium hydroxide (25ml), iodomethane (5ml), dichloromethane (10ml) and tetrabutyl ammonium bisulfate (0.5g) was added stirred vigorously for 2 hours. 50 ml of water was added and the mixture was extracted with 3 x 50 ml of ether. The organic extracts were washed with water and brine, dried and concentrated to a solid which was triturated with hexane. Meri obtained the title compound as white crystals (4.1 g), mp 106-107 ° C.

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

Dimethylamine (33% w / w in IMS, 5.85 ml) was added dropwise at QeC under nitrogen to a suspension of [(4-iodophenoxy) acetyl chloride (9.49 g) in 50 ml of triethylamine. The suspension was stirred at 0 ° C for 2 hours and partitioned between 300 ml of ethyl acetate and 300 ml of 8% aqueous sodium bicarbonate. The organic layer was dried and the solvent was evaporated to leave an oil which was purified with FCC, eluting with diethyl ether.

The title compound was obtained as a white solid (3.96 g) with a melting point of 63-65 ° C.

Intermediate 7 4-Iodo-N, N-dimethylbenzene acetamide "1" e - «p—" i - + ...... i ml 30 4-Iodophenylacetyl chloride (5.15 g) was added in portions at QeC to 0, 90 g of dimethylamine in 25 ml of triethylamine. The suspension was stirred at 0 ° C for 2 hours and 100 ml of chloroform was added. The organic phase was washed with 50 ml of 8% aqueous sodium bicarbonate, dried and concentrated to give 5.0 g of a red solid which was purified with FCC eluting 8502575 * -18 with ether followed by ethyl acetate . The title compound was obtained as a yellow solid (2.58 g) with a melting point of 75-77 ° C.

Intermediate 8 Ν, Ν-Dimethyl 4- [4- [5 - [(phenylmethyl) amino] pentyloxy] butyl] benzene 5 acetamide

Intermediate 16 (1.60 g) was added dropwise at 3.5 ° C under nitrogen to 3.5 ml of benzylamine. The solution was stirred at 120 ° C for 3 hours and poured into 65 ml 0.8N aqueous hydrochloric acid.

The aqueous mixture was extracted with 3x30 ml ethyl acetate and the combined extracts were washed with 50 ml 8% aqueous sodium bicarbonate and 50 ml brine, dried and concentrated to give an oil (0.56 g). The combined water phases were extracted again with 2x50 ml ethyl acetate, dried and concentrated to yield 0.92 g of an oil. The two oils were combined and purified by PCC, eluting with ethyl acetate-triethylamine (100: 1). The title compound was obtained as a pale yellow oil (1.00 g), tic (ethyl acetate-triethylamine 100: 1) Rf 0.1.

Intermediate 9 N - [[3- [3 - [[6 - [(phenylmethyl) amino] hexyl] oxy] -1-propynylphenyl] -20 methyl] acetamide

A suspension of N - [(3-iodophenyl) methyl] acetamide (3.91 g), N- [6 - [(2-propynyl) oxy] hexyl] benzenemethanamine (3.48 g), PTPC (100 mg) and copper iodide (60 mg) in 75 ml diethylamine was stirred at room temperature under nitrogen for 20 hours. The reaction mixture was poured into 100 ml diethyl ether and filtered. The filtrate was concentrated to give 6.62 g of an oil which was purified by FCC, eluting with System D (100: 0: 1 - 100: 10: 1).

The title compound was obtained as a red oil (4.60 g), tic (ethyl acetate-triethylamine 100: 1) Rf 0.12.

Intermediates 10-13 were prepared in a similar manner:

Intermediate 10 N, N-Dimethyl-4- [3 - [[6-C (phenylmethyl) amino] hexyl] oxy] -1-propynyl] benzamide 35 From 4-iodo-N, N-dimethylbenzamide (2.5 g) and N- [6 - [(2-propynyl) oxy] hexyl] benzenemethanamine (2.23 g). FCC purification eluting 8602575 1 -19- with ethyl acetate-triethylamine (100: 1) gave the title compound as an orange oil (2.96 g), tic (ethyl acetate + a few drops of triethylamine) Rf 0.15.

Intermediate 11 5 N, N-Dimethyl-2- [4-C3-CC6-C (phenylmethyl) amino] hexyl] oxy] -1-propyny 1-3 - phenoxylacetamide

Git intermediate 6 (3.91 g) and N- [6-C (2-propynyl) oxyhexyl] -benzenemethanamine (3.14 g) FCC purification eluting with System C (83: 17: 1) gave 3, 87 g of a product which was again placed on the column as before but using ethyl acetate-triethylamine (100: 1) as the eluent. The title compound was obtained as an orange-colored oil (1.44 g), tic (ethyl acetate + a few drops of triethylamine) Rf 0.3.

Intermediate 12 15 N-Methyl-N- [4- [3- [C6-C (phenylmethyl) amino3hexyl3oxy3-1-propynyl3-phenyl] methanesulfonamide from intermediate 5 (1.8 g) and N-β-E (2-propynyl) oxyhexyl3 -benzene methanamine (1.5 g), except that triethylamine / THF (1: 1, 50 ml) was used in place of diethylamine. FCC purification eluting with System B (95: 5: 1) gave the title compound as an orange oil (2.0 g) tic (System B 95: 5: 1) Rf 0.13.

Intermediate 13 4-E3-EE6-EE2- (4-Amino-3,5-dichlorophenyl) -2-hydroxyethyl] (phenylmethyl) amino3hexyl3oxy3-1-propynyl) benzamide 25 intermediate 24 (550 mg) and 4-iodobenzamide (250 mg), except diethylamine / THF (4: 1, 10 ml) was used instead of diethylamine, and addition of the reaction mixture to ether followed by filtration was omitted. FCC purification of the concentrated reaction mixture, eluting with System B (90: 10: 1), gave the title compound as a pale yellow oil (540 mg), tic (System B 90: 10: 1) Rf 0.35.

Intermediate 14 N-E4-E3-EE6-EE2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethyl] (phenylmethyl) amino] hexyl] oxy] -1-propynyl3phenyl3-2- (dimethylamino) acetamide 35 A suspension of intermediate 24 (1.0 g), 2- (dimethylamino) -

N- (4-iodophenyl) acetamide (680 mg), dicyclohexylamine (450 mg), BTPC

1 Λ: / Λ 1 1 V j v 5 5 -20 -20 -20-------50-50 -20 en en koper koper koper koper koper koper koper koper koper koper koper koper koper koper koper koper in in in in in in in 3 3 3 3 3 3. 25 25 25. 25 25 25 25 25 25 25 25. 25 25 25 ether precipitate was removed by filtration, the solvent was evaporated and the residue was purified by FCC eluting with 5 System C (50: 50: 1) to give the title compound as a yellow oil (800 mg), tic (System A 80 : 20: 2) Rf 0.53.

Intermediate 15 4- [4- [3 - [[6 - [(phenylmethyl) amino] hexyl 3oxy 3-propynyl-3-benzoyl-3-morpholine 10 4- (4-iodobenzoyl) morpholine (4.0 g) and N- [6 - [(2- propynyl) oxy3-hexylbenzenemethanamine (3.09 g) was reacted according to the method of intermediate 14. FCC purification eluting with ethyl acetate triethylamine (100: 1) gave the title compound as a yellow oil (2.21 g ), tic (ethyl acetate-triethylamine 100: 1) Rf 0.2.

Intermediate 16.4 - [4— C (5-Bromopentyl) oxy] butyl] -N, N-dimethylbenzene acetamide

A mixture of intermediate 7 (2.50 g), 1-bromo-5- (3-butynyloxy) pentane (1.90 g), dicyclohexylamine (1.73 g), BTPC (50 mg) and copper iodide (10 mg) was stirred in 30 ml of acetonitrile 20 under nitrogen for 2 hours. 80 ml of ether were added, the mixture was filtered, the filtrate was concentrated, and the residue was refluxed in 100 ml of ethanol with charcoal and filtered (hyflo).

The solution was hydrogenated over 10% palladium on charcoal (50% paste in water; 1.0 g) for 48 hours, filtered (hyflo) and concentrated to give a residue which was purified with FCC, eluting with ether-ethyl acetate (100: 0- * 80:20). The title compound was obtained as a yellow oil (1.62 g), tic (ether) Rf 0.12.

Intermediate 17 (Z) -N- C [3- [3 - [[6 - [[2- (4-Amino-3,5-dichloropheny1) -2-hydroxyethyl-13-30 (phenylmethyl) amino3hexyl3oxy3-1-propenyl3phenyl3methyl3acetamide

A solution of intermediate 1 (1.44 g), intermediate 9 (2.0 g) and DEA (660 mg) in 20 ml THF was left under nitrogen at room temperature for 20 hours. The precipitate was removed by filtration and the filtrate was concentrated to give an oil which was dissolved in 20 ml of methanol, cooled in an ice bath, and 8602575 / cmteSi.

-21- was treated in portions with 750 mg of sodium borohydride. The reaction. mixture was stirred at room temperature under nitrogen for 2 hours and concentrated to give an oil to which 100 ml of water was added. The mixture was extracted with 3x50 ml ethyl acetate 5 and the combined extracts washed with 50 ml water and 50 ml brine, dried and concentrated to give an oil which was purified by FCC. Elution was performed with System B (95: 5: 1). The title compound was obtained as a yellow oil (1.51 g), tic {System B 95: 5: 1) Rf 0.13.

Intermediates 18-24 were prepared in a similar manner:

Intermediate 18 4- [4- [5-C [2- (4-Amino-3,5-dichlorophenyl) -2-hydroxyethyl] (phenyl-methyl) amino] pentloxy] buty1] -N, N-dimethylbenzene acetamide

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), tic (ethyl acetate-hexane (1: 1) + a few drops of triethylamine) Rf 0.1 .

Intermediate 19 20 (Z) -2- [4- [3-C [6- [C2- (4-Amino-3,5-dichlorophenyl) -2-hydroxyethyl3- (phenylamethyl) amino] hexyl] oxy-1-propenyl] phenoxy] -N, N-dimethylacetamide 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), tic (System B 95: 5: 1) Rf 0.31.

25 Intermediate 20 N- [4- [2-C 6-C [2- (4-Amino-3,5-dichlorophenyl) -2-hydroxyethyl] (phenyl-methyl) amino] hexyl] oxy] methyl] phenyl methanesulfonamide

From intermediate 1 (0.7 g) and N- [4- [2 - [[6 - [(phenylmethyl) amino] -hexyl3oxy] 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), tic (System A 80: 20: 1) Rf 0.47.

860 2 5 7 5 -22-

Intermediate 21 N- [4- [3-C [6-C [2- (4-Amino-3,5-dichlorophenyl) -2-hydroxyethyl]] (phenyl-methyl) amino] hexyl] oxy] -1-propynyl] phenyl] -N-methylmethanesulfonamide From intermediate 1 (660 mg) and intermediate 12 (1.0 g). The sodium borohydride / methanol reaction was continued for 18 hours. PCC purification eluting with System C (33: 66: 1-50: 50: 1) gave the title compound as a pale yellow oil (320 mg), tic (hexane-ether-triethylamine 50: 50: 1) Rf 0 , 04.

Intermediate 22 10 (Z) -4- [3 - [[6 - [[2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethyl] (phenylmethyl) amino] hexyl] oxy] -1- propenyl] -N, N-dimethylbenzamide

From intermediate 1 (1.0 g) and intermediate 10 (1.39 g).

FCC purification eluting with System B (97: 3: 1) gave the title compound as a yellow oil (0.93 g), tic (System B 95: 5: 1) Rf 0.3.

15 Intermediate 23 4— [4— [3-C [6-C [2- (4-Amino-3,5-dichlorophenyl) -2-hydroxyethyl] (phenyme thy1) amino] hexy1] oxy] -1 propyne] benzoyl morpholine

From intermediate 1 (1.0 g) and intermediate 15 (1.53 g).

The sodium borohydride / methanol reaction was continued for 60 hours.

FCC purification eluting with System B (97: 3: 1) gave the title compound as an orange oil (1.54 g), tic (System B 95: 5: 1)

Rf 0.25.

Intermediate 24 4-phimino-3,5-dichloro-α-CC (phenylmethyl) [6-C (2-propynyl) oxy] hexyl] -25 amino methyl methylbenzene methanol

From intermediate 1 (1.0 g) and N- [6- [2-propynyl) oxy] hexyl] -benzenemethanamine (870 mg), performing the first step of the reaction for only 25 minutes. FCC purification eluting with System C (20: 80: 1) gave the title compound as a colorless oil (1.27 g), tic (System C 20: 80: 1) Rf 0.33.

Intermediate 25 N, N-Bis C2-phenylmethoxy) ethyl] -4-iodobenzeneamamine

A mixture of 2,2 '- (4-iodophenylimino) bis-ethanol (2 g), benzyl bromide (2.3 g), tetra-n-butylaromonium bisulfate (0.4 g) and 50% sodium 35 hydroxide ( 20 ml) was stirred vigorously for 5 hours. The mixture was diluted 8302573-23 with 20 ml of water, extracted with 2x20 ml of ethyl acetate and the combined extracts were washed successively with 50 ml of water and 50 ml of brine, dried and evaporated. Purification by FCC eluting with hexane ether (19: 1 9: 1) gave the title compound as 5 a pale yellow oil (2.1 g), tic (hexane ether 1: 1) Rf 0.7.

Intermediate 26 4-Amino-3,5-dichloro-α-CC [6- [Γ3- [4-bis [2- (phenylmethoxy) ethyl] amino 3-phenyl-2-propynyloxy] hexyl3 (phenylmethyl) amino Umethylbenzenemethanol 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: 1, 30 ml) was stirred at room temperature under nitrogen for two days. The solvent was evaporated and the residue was purified by FCC, eluting with System C (20: 80: 1- * 30: 70: 1) to give the title compound as an orange-15 colored oil (1.75 g) , tic (System C 20: 80: 1) Rf 0.17.

Intermediate 27 4-flmino-3,5-dichloro-α-C 6 - [[3- [4- [2- (dimethylamino) ethoxyphenyl] -2-propynyl) oxyhexyl] (phenylmethyl) amino] methyl] benzenemethanol

A solution of 2- (4-iodophenoxy) -N, N-dimethylethanamine 20 (1.57 g), intermediate 24 (2.94 g), BTPC (100 mg) and copper iodide (10 mg) in 30 ml diethylamine and 10 ml of acetonitrile was stirred at room temperature under nitrogen for 16 hours. The solvent was evaporated and the residue was purified by FCC, eluting with System B (95: 5: 1). The title compound was obtained as a red oil (3.57 g), tic (System B 95: 5: 1) Rf 0.26.

Example I

4- [3 - [[6-C [2- (4-Amino-3,5-dichlorophenyl) -2-hydroxyethyl] amino] hexyl] -oxy UpropylHbenzamide

Intermediate 13 (1.3 g) was hydrogenated over 10% palladium-30 oxide on charcoal (50% aqueous paste, 280 mg) in 15 ml of ethanol containing hydrochloric acid (concentrated HCl / EtOH, 1: 9 v / v, 2 ml ). The catalyst was removed by filtration through hyflo, the solvent was evaporated and the residue was partitioned between 25 ml of 8% sodium bicarbonate and 25 ml of ethyl acetate. The water layer was extracted again with 25 ml of ethyl-35 acetate and the combined organic extracts were washed with 8% 8602573 t-24-sodium bicarbonate and brine, dried, and concentrated to a semi-solid. This was triturated with ether / ethyl acetate (M: 1) to give the title compound as an off-white solid (240 mg, 22%), mp 91-94 ° C, tic (System A 5 80: 20: 2. ) Rf 0.25.

Examples II-IX were performed in a similar manner:

Example II

N- [4- [3- [[6- [[2- (4-Amino-3,5-dichlorophenyl) -2-hydroxyethyl 1] amino] -10 hexyl] oxy] propyl] phenylmethanesulfonamide

From intermediate 3 (500 mg). Evaporation of the ethyl acetate extracts gave an oil which was purified by FCC. Elution was carried out with System B (95: 5: 1), followed by trituration with dry ether. Thereby, the title compound was obtained as a white powder (100 mg), mp 62.64 ° C.

Analysis: Found C 54.82; H 7.26; N 7.36.

C24H35C12N304S, 0 * 35C4H10 ° requires C 54.63; H 6.95; N 7.52.

Example III

Ethyl 4- [3 - [[6 - [[(4-amino-3,5-dichlorophenyl) -2-hydroxyethyl] amino-3-20 hexyl] oxy3propylbenzoate

From ethyl 4- [3 - [[6 - [[(4-amino-3,5-dichlorophenyl) -2-hydroxyethyl] - (phenylmethyl) amino] hexyl] oxy] 1-propynyl] benzoate (500 mg) using pre-reduced 10% palladium on charcoal (50% paste in water, 60mg) as the hydrogenation catalyst. The residue, obtained by evaporation of the ethyl acetate extract, was purified by FCC, eluting with System C (50: 50: 1). The title compound was obtained as a white solid (97 mg), mp 66-68 ° C. Tic (System C 50: 50: 1) Rf 0.05.

Example IV

N- [4 »[3 - [[6 - [[2- (4-Amino-3,5-dichlorophenyl) -2-hydroxyethyl] amino] -hexyl] oxy3propyl] phenyl] -2- (dimethylamino) acetamide, (E) -butenedioate- (salt) (1: 1)

From intermediate 14 (750 mg), using concentrated HCl / EtOH, 1: 9 v / v, 2.2 ml. The yellow oil (520 mg), which was obtained after concentration of the ethyl acetate extracts, was dissolved 8 SO 2 57.5 * 25 in 5 ml of methanol and treated with a solution of 120 mg of fumaric acid in 2 ml of methanol. The methanol was evaporated and the residue triturated with ether to give a yellow solid (610 mg). This was recrystallized from 15 ml of isopropanol to give the title compound as a white solid (100 mg), mp 106-110 ° C.

Analysis: found C 56/32; H 6.97; N 7.94; Cl 11.32.

C27H40Cl2N4 ° 3 * C4H4 ° 4 requires C 56'79 '* H 6'76' * N 8'55; Cl 10'82%

Example V

4- [3 - [[6 - [[2- (4-Amino-3,5-dichlorophenyl) -2-hydroxyethyl] amino3-hexyl3oxy] propyl] -N, N-dimethylbenzamide, (E) -butenedioate (salt ) (2: 1)

From intermediate 22 (0.82 g) using pre-reduced 10% palladium on charcoal (50% aqueous paste, 100 mg) as the hydrogenation catalyst. The oil obtained by evaporation of the ethyl acetate extract was purified by FCC, eluting with System B (95: 5: 1) to obtain an oil. The oil (0.42 g) in 2 ml of methanol was treated with (E) -dibutenic acid (47.6 mg) in 2 ml of methanol and the solution was concentrated. The residue was triturated with diethyl ether to afford the title compound 20 as a white solid (0.47 g), mp 107-109 ° C.

Analysis: found C 59.0; H 7.2; N 7.2; Cl 12.6.

C26H37Cl2N303.0.5C4H4O4 requires C 59.2; H 6.9; N 7.4; Cl 12.5%.

Example VI

4- [4-C3-CC6-CC2- (4-Amino-3,5-dichlorophenyl) -2-hydroxyethyljamino] -hexyl] oxy-propylbenzoyl] morpholine

From intermediate 23 (0.70 g) using previously reduced 10% palladium on charcoal (50% aqueous paste, 80 mg) as the hydrogenation catalyst. Evaporation of the ethyl acetate-30 extract gave an oil which was purified by FCC, eluting with System B (95: 5: 1). The title compound was obtained as a yellow oil (391 mg). A solution of the title compound (390 mg) in 2 ml of methanol was treated with (E) -dibutenic acid (41.1 mg) in 2 ml of methanol, and the solvent was evaporated to give an oil which was triturated with diethyl ether the (E) -butenedioate salt 8502575 t * -26- (2: 1) of the title compound gave as a white matter (40 mg), mp 114-116 ° C.

Analysis: Found C 58.7; H 6.0; N 6.7; Cl 11.9.

(C28H39C12N304,2 * C4H404 requires C 59'0t H 6'8 '* N 6'9; C1 n'6% · 5 Example Vil N- C [3- [3-C [6 - [[2- (4 -Amino-3,5-dichlorophenyl) -2-hydroxyethyl] amino] -hexyl] oxy] propyl] phenyl] methyl] acetamide

From intermediate 17 (1.40 g) using previously reduced 10% palladium on charcoal (50% aqueous paste, 170 mg) as the hydrogenation catalyst. The solid obtained from the ethyl acetate extracts was triturated with diethyl ether to afford the title compound as a white solid (0.76 g) mp 91-94 ° C, tic (System A 80: 20: 2) Rf 0.45 .

Analysis: Found C 60.7; H 7.5; N 7.9; Cl 13.9.

C - H _C1_N_0_ requires C 61.2; H 7.3; N 8.2; Cl 13.9%.

26 37 233

Example VIII

2- [4- [3 - [[6-C [2- (4-Amino-3,5-dichlorophenyl) -2-hydroxyethyl] amino-3-hexyloxy-3-propyl-3-phenoxy 3, Ν, Ν-dimethyl-acetamide (E) -butenedioate (salt) (2: 1) From Intermediate 19 (0.99 g) using previously reduced 10% palladium on charcoal (50% aqueous paste, 115 mg) as the hydrogenation catalyst. Concentration of the ethyl acetate extract gave an oil. The oil (0.70 g) in 2 ml of methanol was treated with (E) -dibutenic acid (75.5 mg) in 2 ml of methanol and the solution was concentrated. The residue was triturated with diethyl ether to afford the title compound as a leather-colored solid (0.63 g, mp 116-118 ° C, tic (System B 95: 5: 1) Rf 0.17.

Example IX

N- [4- [3 - [[6 - [[2- (4-Amino-3,5-dichlorophenyl) -2-hydroxyethyl-3-amino-3-hexyl-3-oxypropyl] -phenyl3-N-methylmethanesulfonamide hydrochloride

From intermediate 21 (250 mg) using previously reduced 10% palladium oxide on charcoal (50% aqueous paste, 50 mg) as the hydrogenation catalyst. Concentration of the ethyl acetate extract gave an oil which was purified by FCC. In addition, elution was carried out with System B (99: 1: 1 ^ -95: 5: 1) to obtain a yellow oil (130 mg) 8602575 -27-. The oil in 5 ml ether was treated with ether hydrochloride and the resulting oil triturated with dry ether to give the title compound as a yellow solid (90 mg), tic (System B 95: 5: 1) Rf 0.56 .

Analysis: Found C 51.14; H 7.02; N 6.87; Cl 17.82; S 5.00.

C25H37C12N3 ° 4S "HC1 requires c 51'50" H 6 * 57; n 7.21; Cl 18.24; S 5.50%.

Example X.

4-Amino-3,5-dichloro-a- [C [6-C3- [4-C2- (dimethylamino) ethyl] phenyl] propoxyhexy13amino methyl methylbenzene methanol 1 A solution of intermediate 4 in the form of its free base (1, 54 g), intermediate 24 (2.94 g), BTPC (100 mg) and copper (I) iodide (10 mg) in diethylamine (30 ml) and 10 ml acetonitrile were stirred under nitrogen for 18 hours. The solution was concentrated under reduced pressure to obtain a brown oil. This was purified by FCC eluting with System B (95: 5: 1). A yellow oil (2.4 g) was obtained. The oil (2.3 g) was hydrogenated over 10% palladium oxide on carbon (50% aqueous paste, 500 mg) in 20 ml ethanol containing hydrochloric acid (concentrated HCl / EtOH; 1: 9 v / v, 6.9 ml) . The catalyst was removed by filtration with hyflo, the ethanol was evaporated and the residue was partitioned between 20 ml of 8% sodium bicarbonate and 20 ml of ethyl acetate. The water layer was extracted again with 20 ml of ethyl acetate and the combined organic extracts were washed with 20 ml of sodium bicarbonate and 20 ml of brine, dried and concentrated to a yellow oil. The oil was purified with FCC, eluting with System B (98: 2: 1) to give a light yellow oil (1.2 g). This was triturated with hexane to afford the title compound as a white solid (1.1g) mp 41.5-43.5 ° C.

Analysis: Found C 63.23; H 8.37; N 8.10; Cl, 13.69.

C27H40Cl2N3O2 requires C 63.64; H 7.91; N 8.25; Cl, 13.92%.

Example XI

4- [4-C5 - [[2- (4-Amino-3,5-dichloropheny1) -2-hydroxyethy1] -amino1-pentyloxy-3-buty13-N, N-dimethylbenzene acetamide

Intermediate 18 (1.00 g) in 20 ml of ethanol containing hydrochloric acid-35 te (concentrated HCl / EtOH, 1: 9 v / v, 1.48 ml) was hydrogenated above '8602575 ψ * -28- * pre-reduced 10 % palladium on charcoal (150 mg, 50% paste in water). The reaction mixture was filtered (hyflo) and the filtrate was concentrated. The residue was partitioned between 100 ml of ethyl acetate and 2x50 ml of 8% aqueous sodium bicarbonate. The dried organic layer 5 was concentrated and the residual oil was purified with FCC 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 2 ml of methanol was treated with (E) -dibutenic acid (51.9 mg) in 2 ml of methanol. The solution was concentrated to give an oil which was triturated with diethyl ether. The (E) -butenedioate salt (2: 1) of the title compound (407 mg), mp 107-110 ° C, was obtained.

Analysis: found C 59.9; H 7.4; N 7.0; Cl 12.0.

C27H39Cl2N3O3.0.5C4H4O4 requires C 59.8; H 7.1; N 7.2; Cl 12.2%.

Example XII

N— [4— C 3— C [6-C [2— (4-Amino-3,5-dichlorophenyl) -2-hydroxyethyl] amino] -hexyl] oxy] ethyl] phenyl] methanesulfonamide

Intermediate 20 (1.2 g) was hydrogenated as in Example XI, using previously reduced 10% palladium oxide on carbon (50% aqueous paste, 150 mg) as the catalyst. Evaporation of the ethyl lactate extract gave a yellow oil which was purified with FCC, eluting with System B (92: 8: 1). A pale yellow oil was obtained which, on trituration with ether, gave the title compound gas as a white solid (445 mg), mp 62-65 ° C.

Analysis: Found C 52.94; H 6.40; N 7.79; Cl 13.96; S 6.17.

CH1 ClNOS requires C 53.28; H 6.42; N 8.10; Cl, 13.68; S 6.18%.

wj & «5 fs

Example XIII

4- [3-C [6 - [[2- (4-Amino-3,5-dichlorophenyl) -2-hydroxyethyl-amino-3-hexyl] oxyHpropylobenzeneacetamide 30 4— [3 - [(6-Bromohexyl) oxy] propyl] benzenetacetamide (950 mg) was added at 100 ° C under nitrogen to a stirred solution of 4-amino-ot- (aminomethyl) -3,5-dichlorobenzene-methanol (900 mg) and DEA (650 mg) in DMF (10 ml). After 1 hour, the solvent was evaporated and the residue was partitioned between 20 ml of 8% sodium bicarbonate and 20 ml of ethyl-35 acetate. The organic layer was washed with water and brine, 8902575 *? 1-29- dried and concentrated under reduced pressure to give a yellow solid. This was triturated with ether to afford the title compound as an off-white powder (510mg) mp 104-106 ° C.

Analysis: Found C 60.58; H 7.35; N 8.11; Cl 13.83.

C-H-ClNO requires C 60.48; H 7.11; N 8.46; Cl, 14.28%.

25 35 233

Example XIV

4-amino-3,5-dichloro-a - [[[6-C3- [4- (methoxymethyl) phenyl-propoxy] -hexyl-amino-methyl-benzene-methanol, (E) -butenedioate (2: 1) (salt) 10 l- [3- [ (6-Bromohexyl) oxy] propyl] -4- (methoxymethyl) benzene (1.0 g) and 4-amino-a- (aminomethyl) -3,5-dichlorobenzene methanol (1.0 g) was reacted according to the method of example XIII. Concentration of the ethyl acetate extract gave an oil which was purified by FCC eluting with System B (90: 10: 1). 620 mg of a yellow oil were obtained.

The oil was treated in 5 ml isopropanol with a hot solution of fumaric acid (20 mg) in 2 ml isopropanol and after 1 hour the two-phase system was stirred vigorously leaving a pale yellow precipitate. This was collected by filtration and dried under reduced pressure. The title compound was obtained as a light yellow powder 20 (550 mg) mp 110-112 ° C, tic (System A 80: 20: 2) Rf 0.43.

Analysis: Found C 59.33; H 6.87; N 4.88; Cl, 13.31.

C.cH, tCl LÖ ,. 0.5C .H .0. requires C 59.89; H 7.07; N 5.17; Cl 13.09%.

25 36 223 4 4 4

Example XV

4- [3-C [6 - [[2- (4-Amino-3,5-dichlorophenyl) -2-hydroxyethyljamino 3hexy13-25 oxy Hpropy1] benzoic acid

The product of Example III (600 mg) in 8 ml of ethanol was treated with 4 ral 2N sodium hydroxide and stirred at reflux temperature for 1 hour. The ethanol was evaporated, 20 ml of water was added to the residue and the mixture was neutralized with 2N hydrochloric acid. Ethyl acetate (25 ml) was added and the two-phase mixture was stirred vigorously for 10 minutes. The resulting precipitate was collected by filtration, washed with ethyl acetate and dried to obtain a cream-colored solid (450 mg), which was triturated with warm methanol (10 ml) and filtered. The title compound was obtained as a white powder (290 mg) mp 190-191 ° C.

8/30 2573 -30-

Analysis: Found C 59.22; H 6.82; N 5.62; Cl 14.40.

CoaH "5" 7C1'7N'3C) 4 requires c 59.63; H 6.67; N 5.79; Cl, 14.67%.

<& TC Yes a 6 4

Example XVI

4-Amino-3,5-dichloro-a - [[[6- [3- [4 - [(4-morpholinyl) methylphenyl] -5 propoxy] hexyl] amino] methylbenzenemethanol

The product of Example VI (0.67 g) in 10 ml of benzene was added dropwise at room temperature under nitrogen to 300 mg of lithium aluminum hydride in 15 ml of dry diethyl ether. The suspension was stirred at room temperature for 18 hours and after treatment with 0.3 ml of water, 0.6 ml of 2N aqueous sodium hydroxide and 0.6 ml of water, a precipitate was obtained which was filtered off (hyflo). The filtrate was concentrated to give an oil. This was purified by FCC eluting with System B (95: 5: 1). The title compound was obtained as a white solid (318 mg), mp 57-59 ° C, tic (System B 95: 5: 1) Rf 0.22.

Example XVII

4-Amino-3,5-dichloro-a- [C [6- [3-C4 - [[2- (dimethylamino) ethyl] amino] -phenyl] propoxy] hexyl] amino] methyl] benzenemethanol- (E) - butenedioate (2: 3) (salt) The product of Example IV in the form of its free base (440 mg) was treated with 420 mg of lithium aluminum hydride according to the method of Example XVI. After 7 days, 1 ml of water, 2 ml of 2N aqueous sodium hydroxide and 1 ml of water were successively added, the precipitate was removed by filtration via hyflo and the ether was evaporated to leave a brown oil. A solution of the oil (320 mg) and fumaric acid (78 mg) in 3 ml of methanol was concentrated to an oil which was triturated with ether to give the title compound as a brown solid (230 mg), mp 41-45 ° C .

Analysis: Found C 56.59; H 7.35; N 7.30; Cl 9.61.

C27H42Cl2N 0.1.5C4H404 requires C 56.66; H 6.91? N 8.01; Cl 10.13%.

Examples XVIII and XIX were performed according to the method of Example I:

Example XVIII

4-Amino-3,5-dichloro-a - [[[6- [3- [4- [bis- (2-hydroxyethyl) amino] -phenyl) propoxy] hexyl] aminoImethylbenzene methanol 8802575 -31-

From intermediate 26 (402 mg), using concentrated HCl / EtOH 1: 9 v / v 0.09 ml. Evaporation of the ethyl acetate extracts gave a brown oil which was purified by PCC eluting with System B (95: 5: 1 ^ -80: 20: 1) to give the title compound 5 as a pale yellow oil (85 mg ), tic (System A 80: 20: 2)

Rf 0.33. δ (CDCl3) 1.2-1.63 and 1.84 (-CE ^ -); 3.4 (-OCH -), * 3.54 and 3.81, 8H, (-CH 1 CH 2 OH) 2; 6.62 and 7.04, 4H, (CH of phenyl ring); 7.17, 2H, (CH of dichloroanilination). -

Example XIX

10 4-amino-3,5-dichloro-α-C [[6- [| 3- [4- [2- (dimethylamino) ethoxy] phenyl] propoxy) hexylaminoethylmethylbenzenemethanol

From intermediate 27 (3.42 g), using previously reduced 10% palladium on charcoal (50% paste in water, 750 mg) as the catalyst for the hydrogenation, in 30 ml of ethanol containing hydrochloric acid (concentrated HCl / EtOH 1: 9 v / v, 10.1 ml), The oil obtained by evaporation of the ethyl acetate extracts was purified by FCC eluting with System A (80: 20: 2), followed by further FCC chromatography of the crude fractions eluting with System B (95: 5: 1). The resulting oils combined (493 mg) in 5 ml of methanol were treated with 109 mg of (E) -dibutenic acid in 5 ml of methanol. The solution was concentrated and the remaining foam was triturated with diethyl ether. The title compound was obtained as a light yellow foam (0.361 g), tic (System A 80: 20: 2) Rf 0.5.

Analysis: Found C 56.1, H 7.2; N 6.2; Cl 11.0.

C27H41C12N303.1,25C4H404.0,8H2O requires C 56.0; H 7.0; N 6.1; Cl 10.3%.

The following are examples of suitable compositions of compounds of the invention. The term "active ingredient" used herein represents a compound of the invention.

Tablets (Direct Compression) 30 mg / tablet

Active ingredient 2.0

Microcrystalline cellulose USP 196.5

Magnesium stearate BP 1.5

Compression weight 200.0 8602575 -32-

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

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

The tablets can be film coated using suitable film-forming materials such as hydroxypropylmethyl cellulose, using standard techniques. The 10 tablets can also be coated with sugar.

Syrup (Sucrose-free) mg / 5ml dose

Active ingredient 2.0 mg

Hydroxypropylmethylcellulose USP

15 (viscosity type 4000) 22.5 mg

Buffer)

Flavor j

Pigment ) , .

. as required

Preservative ^ 20 '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 composition. The resulting solution is made up to volume and mixed. The syrup is clarified by filtration.

Measured pressure aerosol dose A. Suspension aerosol mg / measured dose per can 30 Active ingredient Λ. 0.100 26.40 mg micromromed

Oleic acid BP 0.100 2.64 mg

Trichlorofluoromethane BP 23.64 5.67 g

Dichlorodifluoromethane BP 61.25 14.70 g 8302575 -33-

The active ingredient was micronized in a fluid energy medium to a range of fine particle sizes. The oleic acid is mixed with the trichlorofluoromethane at a temperature of 10-15 ° C and the micronized drug is mixed in the solution using a high shear mixer. The slurry is metered into aluminum aerosol cans, and appropriate metering valves delivering 85 mg of suspension are shrink-mounted to the cans and the cans are filled under pressure with dichlorodifluoromethane.

10 b. Solution aerosol mg / metered dose per can Active ingredient 0.055 13.20 mg

Ethanol BP 11,100 2.66 g

Dichlorotetrafluoroethane BP 25,160 6.04 g 15 Dichlorodifluoromethane BP 37,740 9.06 g

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

The active ingredient is dissolved in the ethanol, together with the oleic acid or surfactant when used. The alcoholic solution is placed in suitable aerosol containers, followed by the dichlorotetrafluoroethane. Suitable metering valves are attached to the containers by shrinking and the containers are filled under pressure with dichlorodifluoromethane through the valves.

Injection for intravenous administration 25 mg / ml

Active ingredient 0.5 mg

Sodium chloride BP as needed

Water for injections BP up to 1.0 ml

Sodium chloride can be added to adjust the tonicity of the solution and the pH can be adjusted using acid or base to that value corresponding to optimal stability and / or facilitate dissolution of the active ingredient. Suitable buffer salts can also be used.

The solution is prepared, clarified and placed in appropriately sized ampoules, which are closed by fusing the glass. The injection preparation is sterilized by autoclaving using one of the acceptable cycles. The solution can also be sterilized by filtration and by placing the solution in sterile ampoules under aseptic conditions. The solution can be packaged under an inert atmosphere of nitrogen or other suitable gas.

Cartridges for inhalation mg / cartridge

Active ingredient micronized _ 0.200

Lactose BP up to 25.0 The active ingredient is micronized in a floppy energy mill to an area of fine particle size before being mixed with normal tableting grade lactose in a high energy mixer. The powder mixture is placed in No. 3 hard gelatin capsules on a suitable capsule filler. The contents of the cartridges are administered using a powder inhaler such as the Glaxo Rotahaler.

8502575 .................: j

Claims (10)

1. Compounds of the general formula 1, wherein X represents a bond, or a C 1-4 alkylene, C 2-8 alkenylene or alkynylene chain, and Y represents a bond, or a C 1-4 alkylene, C 2-4 alkenylene or C2-4 alkyny -5 represents a loan chain, it being understood that the total number of carbon atoms in X and Y taken together does not exceed 8; Ar represents a phenyl group substituted by one or more substituents selected from nitro, - (CH) R [where R represents C. alkoxy, 3 4 3 4 2 q 1-3 -NR R (where R and R each represents a hydrogen atom or a C 4 alkyl group 3 4 1 - 4 10, or -NR R forms a saturated heterocyclic amino group having 5-7 atoms in the ring and optionally containing one or more atoms in the ring selected from - 0- or -S- or a group -NH- or -N (CH) -), 5 6 5 ^ -NR COR (where R represents a hydrogen atom or a C 4 alkyl group, 6 1-4 3 4 and R a hydrogen atom or a C 1-4 alkyl, C 1-4 alkoxy or -NR R - 15 group), and q represents an integer of 1-3], 7 7 5 8 8 - (CH_) R [where R is for -NRSO 4 R (where R represents a C 1 -alkyl, 2 R 3 4 52 5 - 1-4 phenyl or NR R group), -NR CO 2 N 2 (R) 2 (wherein: each of the groups R5 represents a hydrogen atom or a C alkyl group), 9 9 1—4 34 10 -COR where R represents hydroxy, C 1-4 alkoxy or NR R), -SR (where 20 is for a hydrogen atom or a 4 alkyl group, which is optionally substituted by hydroxy, C 1-4 alkoxy or NR ^ R 4), -SOR ^, -SO2R ^, -CN, or -NR ^ R ^ 2 (where R * 1 and R ^ 3 represent a hydrogen atom or a C 1-4 alkyl group, at least one of which represents C 4 alkyl, 3 4 2-4 substituted by a hydroxy, C 1-4 alkoxy or NR R group), and r 25 is a whole represents number from 0-3], 9 9 '-O (CH_) qC0R (where q and R have the meanings given above «*« <· aa 1 Ί 1 Λ' ben), or -0 (CH) R [ wherein R represents hydroxy, NR R, NR R or a C 1-4 alkoxy group, optionally substituted by hydroxy, C 1-4 alkoxy or NR 3 R 4, and t represents an integer of 2-3]; and 1 2 30. and R each represents a hydrogen atom or a C 1 alkyl group, with 1-3 1 2 provided that the total number of carbon atoms in R and R taken together is not more than 4; as well as physiologically acceptable salts and solvates (e.g., hydrates) thereof. 8602575 t S '-36- 2 J. 4 g 2 represents hydrogen or methyl, and R represents C alkyl), 5 5 -NHCOCH N (R) (where both groups represent R C 1-4 alkyl), 9 2 2 g x — 4 -COR (where R represents hydroxy, C, .alkoxy, amiono diC. Alkyl- 9 g 1-4 amino, or morpholino), -CH COR (where R anu.no or diC alkylamino 11 12 ^ 11 12 ^ -4 represents -NR R (where R and R both represent hydroxy C 1-9 alkyl), which is alkylaminoethylamino, -OCH COR (wherein R is diC, alkyl 1-4 13 13 ^ 13 ”4 amino) ; or -0 (CH2) 2 R wherein R is dic ^ alkylamo, as well as physiologically acceptable salts and solvates thereof. 8602575 JV. £ -37- Compounds according to claim 1, wherein the total number of carbon atoms in the -X- and -Y- chains is 4, 5, 6 or 7. Compounds according to claim 1 or 2, wherein X stands for - (CH 2) or - {CH 2) 4 ', and Y stands for -CH 2, - (CH 2) 2 or - (CH 2 -). 4-C3-C [6-C [2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethyl-3-amino-hexyl] -oxypropy1] benzamide? ethyl 4-C3-HC6-CC (4-amino-3,5-dichlorophenyl) -2-hydroxyethyl3amino-1-hexyl] oxy3propylbenzoate; N - [[3- [3 - [[6 - [[2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethyl3amino3-hexyl] oxy3propy13phenyl3methyl13acetamide; 4-C4-C5-CC2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethyl 3 amino 3hexyl3-oxy 3pentyloxy 3buty13-N, N-dimethylbenzene acetamide; 4- [3 - [[6-C [2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethyl 3 amino 3-hexyl3oxy3propylbenzoic acid; 4- [4-C3-C [6 - [[2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethyl-3-amino-hexyl-3-oxy-propyl-3-benzoyl-morpholine; N-C4-C3- [t6-C [2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethyl3amino3-20 hexyl3oxy3ethyl3phenyl3methanesulfonamide; 4- [3-C 6- [E2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethyl3amino] -hexyl3oxy3propyl3benzene acetamide; as well as physiologically acceptable salts and solvates thereof. Compounds according to one or more of claims 1 to 3, wherein 12. R and R both represent hydrogen atoms or R is a hydrogen atom 2 and R represents a C 1-3 alkyl group. Compounds according to any of claims 1 to 4, wherein Ar represents a phenyl group substituted by - (CH) R [where R δ q 10 represents C, alkoxy, die. .alkylamino, morpholino, piperidino, pipe-gg razino, N-methylpiperazino, -NHCOR (where R is C._. alkyl), and 77 5 5 q is 1 or 2], - (CH.) R (where R is for -NR SO.R (where R 2 represents 0 ^ g hydrogen or methyl, and R represents C 1 alkyl -NHCOCH 5 N (R) 5 ^ Λ (where both groups represent RC 1 4 alkyl), -COR ( where R stands for C. alkoxy, amino diC1alkylamino, morpholino, piperidino, pipe 1-4 1-4 11 12 11 12 razino or N-methylpiperazino), -NR R (where R and / or R stands for a C2_4 alkyl group, substituted by a hydroxy or diC ^ alkylamino group and the other represents a hydrogen atom), and r is 9 9 13 0 or 1], -OCH COR (where R is diC. alkylamino), or -0 (CH) R 13 2 1-4 20 (where R is diC 1 -C 4 alkyl amino). 6. Compounds of the general formula la, wherein X represents a C 1-3 alkylene chain and Y represents a C 1-3 alkylene chain, with the proviso that the total number of carbon atoms in X and Y taken together is equal to 5 or 6; and Ar represents a phenyl group which is substituted by a group selected from C alkoxymethyl, morpholinomethyl, diC alkylaminoC 1 6 6 8 8 alkyl, -CH NHCOR (where R represents C alkyl), NR SO K (where R Compounds according to claim 6, wherein Ar represents a phenyl group-6-6 / substituted by a group selected from -CH NHCOR (wherein R 8 represents 8 ^ 9 methyl}, -NHSCLR (wherein R represents methyl), -COR (where 9 2 9 R stands for hydroxy, ethoxy, amino or morpholino, or -CH.COR (where g represents 2 5. amino or dimethylamino). 8. The connections: A method of preparing compounds according to any of claims 1 to 8 or a physiologically acceptable salt or solvate thereof, comprising: (1a) for the preparation of a compound of formula 1 wherein R 1 represents a hydrogen atom, the alkylation of an amine of general 14 formula 2 (wherein R represents a hydrogen atom or a protecting group and R is a hydrogen atom) with an alkylating agent of formula 3, (wherein L represents a leaving group and R, X , Y and Ar have the meanings set forth in claim 1), followed, if necessary, by removing any protecting groups present; or (lb) for the preparation of a compound of formula 1 wherein R 1 represents a hydrogen atom, alkylating an amine of the general formula 2 as defined above except that R represents a Q 0 U A. fj * t? -38- hydrogen atom or a group capable of being reacted therein under the reaction conditions, with a compound of the general formula 4 (wherein R, X, Y and Ar have the meanings set out in claim 1) in the presence of a reducing agent, followed as necessary by removing any protecting groups present; or (2) reducing an intermediate of the general formula 6 wherein X1 represents -CH (OH) - or a group convertible therein by reduction; 2 14 14 X represents -CH 2 NR - (wherein R represents a hydrogen atom or a protecting group) or a group convertible therein by reduction; 3 12 X stands for -CR R X- or a group convertible therein by reduction 1 2 (wherein R and R have the meanings set forth in claim 1); 4 X stands for -NH2 or a group which can be converted therein by -15; and Y and Ar have the meanings set forth in claim 1 or are groups that can be converted therein by reduction; wherein at least one 12 3 4 of X, X, X and X represents a reducible group and / or Y represents a reducible group and / or Ar contains a reducible group, followed if necessary by removing any protecting groups present; or (3) removing the protecting group from a protected intermediate of the general formula 7 wherein R, R, X, Y and Ar have the meanings set out in claim 1, R14 and R16 each having a hydrogen atom or represent a protecting group and / or any hydroxy and / or amino substituents in the group Ar are protected, provided that at least one of R and R represents a protecting group or Ar contains a protecting group; or 30 (4) for the preparation of a compound of formula 1 wherein Ar represents a 9 phenyl group which is substituted by the group - (CEL) COR 9. r wherein r has the meanings set forth in claim 1 and R represents hydroxy, hydrolyzing the corresponding compound of formula 9 wherein R represents alkoxy; and, if desired, converting the obtained compound of the general formula 1 or a salt thereof into a physiologically acceptable salt or solvate thereof. 8302573 -39- A pharmaceutical composition comprising at least one compound of the general formula 1 as defined in any one of claims 1 to 8, or a physiologically acceptable salt or solvate thereof, together with a physiologically acceptable carrier or excipient. 3502575 VER ££ NKiD £ PATENT BUREAUX a.o.no. 8602575 • vchavwhagi (hollamd) beak. when writing dd. February 2, 1987 Lu / 632 - ^ 0 - Change (es) Tan erratnaCa) in the description pertaining to patent application no. 8602575 proposed by applicant {ster) under date 2 February 1987 -ooo— On page 5, lines 5-6 and on page 37, lines 13-14: "hexyl] -oxyJ" should be deleted so that the name of the compound in question matches the name given in Example XI 5. ft «n 2 ij 7 5 V» “V · * w