HU206869B - Process for producing amino-phenol derivatives and pharmaceutical compositions containing them - Google Patents

Abstract

2-Phenylalkoxyalkyl amino-1-(3-substd.-amino-4 -hydroxy phenyl)ethanol derivs. and analogues of formula (I) and their salts and solvates are new. Ar = Ph opt. substd. by halogen, 1-6C alkyl, 1-6C alkoxy, NO2, (CH2)qR, (CH2)rR10, O(CH2)tR11 or by a O(CH2)pO gp.; R = OH NR3R4, NR5COR6, NR5SO2R7, COR8, SR9, SOR9, SO2R9 or CN; q = 0-3; R3-R5 = H or 1-4C alkyl; or NR3R4 = 5- to 7-membered satd. heterocyclylic amino opt. contg. in the ring one or more O, S, NH or NMe; R6 = H, 1-4C alkyl, 1-4C alkoxy, Ph or NR3R4; R7 = 1-4C alkyl, Ph or NR3R4; R7 = 1-4C alkyl, Ph or NR3R4; R8 = OH, 1-4C alkoxy or NR3R4; R9 = H, 1-4C alkyl or Ph; R10 = 1-4C alkoxy; r = 1-3; R11 = OH or 1-4C alkoxy; t = 2 or 3; p = 1 or 2; R1, R2 = H Or 1-3C alkyl, provided that R1+R2 do not contain over 4C; X = 1-7C alkylene, 2-7C alkenylene or 2-7C alkynylene or 2-6C alkynylene, provided that X-Y contain 2-10C; Q = R12CO, R12NHCO, R12R13NSO2 or R14SO2; R12, R13 = H Or 1-3C alkyl; R14 = 1-4C alkyl.

Description

The present invention relates to aminophenol derivatives and to pharmaceutical compositions containing them as active ingredients. The compounds of the present invention have a 3 ₂ -adrenoreceptor stimulating effect.

More particularly, the process of the present invention relates to the preparation of compounds of formula I and pharmaceutically acceptable salts and hydrates thereof.

In the general formula (I)

X is C 1-7 alkylene or C 2-7 alkynylene,

Y is C 1-6 alkylene, C 2-6 alkenylene or C 2-6 alkynylene, and

The total number of carbon atoms in X and Y is 5, 6 or 7;

R ¹ and R ² are hydrogen or methyl;

Q is formyl, acetyl, carbamoyl, (dimethylamino) sulfonyl or methylsulfonyl; and

Ar is a phenyl group having an amino, dimethylamino, nitro, morpholino,

- (CH ₂ ) _q NHCOR ⁶ - in the formula

R ⁶ is C 1-4 alkyl, such as n-butyl, and q is 1-4, preferably 1-, -NHSO ₂ R ⁷ - wherein

R ⁷ is C 1 -C 4 alkyl, such as butyl, -COR ⁸ - wherein

R ⁸ is C 1 -C 4 alkoxy, such as propoxyl-substituted, -NR ³ R ^{4 in} the latter formula

R ³ and R ⁴ are C 1 -C 4 alkyl, such as ethyl or propyl, or -NR ³ R ^{4 is} piperidino, -CH ₂ CONR ³ R ⁴ - wherein

R ³ and R ⁴ are C 1 -C 4 alkyl, for example ethyl, -SR ⁹

R ⁹ is C 1 -C 4 alkyl, such as methyl, or - (CH ₂ ) _r R ¹⁰ - wherein r is 3 and

R ¹⁰ is C 1-4 alkoxy, for example methoxy, or 3,5-dihydroxyphenyl or 3-methoxy-4-hydroxyphenyl, or when X is alkynyl and / or Y is alkenylene or alkynylene, Ar may also be phenyl optionally substituted by fluorine.

The compounds of formula (I) may have one or two asymmetric carbon atoms, one of the CH (OH) - carbon atom, while the other of R ¹ and R ² are different, the carbon atom to which the two groups are attached.

The enantiomers, diastereomers and mixtures thereof, including the racemates, of formula I are encompassed. Preferred are compounds of formula I wherein a

The carbon atom in the -CH (OH) - group is in the R configuration.

In the definition of compounds of formula I, alkenylene is understood to include both cis and trans.

Preferred compounds are those compounds of formula I wherein X is a C 1-4 alkynylene group such as -CH ₂ C 1 -CCH ₂ - and Y is a C 3 alkylene group; most preferably, X is - (CH ₂ ) ₄ - and Y is - (CH ₂ ) ₃ -.

Another preferred group of compounds of formula (I) are those compounds wherein R ¹ and R ² are a hydrogen atom.

A third preferred group of compounds of formula I are those wherein Q is CH ₃ SO ₂ .

Another preferred group of compounds are those compounds of formula (I) wherein Ar is phenyl substituted with a single substituent, most preferably phenyl substituted with -CON (CH ₂ CH ₃ ) ₂ .

Particularly preferred compounds of the invention are N, N-diethyl-4- [4 - {[6 - {[2-hydroxy-2- {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl] ethyl]. -amino} -hexyl] -oxy} -butyl] -benzamide, and its pharmaceutically acceptable salts and hydrates.

Pharmaceutically acceptable salts of the compounds of Formula I include acid addition salts with organic or inorganic acids such as hydrochlorides, hydrobromides, sulfates, phosphates, maleate, tartrate, citrate, benzoate, 4-methoxybenzoate, 2- -hydroxybenzoates, 4-chlorobenzoates, ptoluenesulfonates, methanesulfonates, sulfamates, ascorbates, salicylates, acetates, fumarates, succinates, lactates, glutarates, gluconates, 1-hydroxy, naphthalene carboxylates or oleate. The compounds of the present invention may also form salts with bases, such as alkali metal salts such as sodium or potassium salts or alkaline earth metal salts such as calcium or magnesium salts.

The compounds of the present invention selectively stimulate β ₂ -adrenoreceptors, and the profile of the above effect is highly advantageous. The stimulatory effect was demonstrated in isolated guinea pig trachea, whereby the compounds of formula I relaxed the PGF2a-induced contraction. In the above assay, the compounds of the present invention exhibit particularly long-lasting activity.

The compounds of the present invention are useful as pharmaceutical active ingredients in the treatment of diseases associated with reversible airway obstruction such as asthma or chronic bronchitis.

The compounds of the present invention may also be used in the treatment of premature birth, depression and congestive heart disease, as well as in the treatment of allergic or inflammatory skin diseases, glaucoma and conditions where

It is advantageous to reduce the level of stomach acid, especially in the case of gastrointestinal ulcers.

The compounds of the present invention, and their pharmaceutically acceptable salts and hydrates, can therefore be used as active ingredients in pharmaceutical compositions for the prevention and treatment of reversible airway obstruction in the field of human and veterinary medicine.

The compounds of the present invention may be formulated into pharmaceutical compositions in conventional manner. The pharmaceutical compositions of the present invention comprise at least one compound of formula (I), or a pharmaceutically acceptable salt or hydrate thereof, in admixture with a pharmaceutically acceptable carrier and / or other excipients, for human and veterinary use. The pharmaceutical compositions may contain, in addition to a pharmaceutically acceptable carrier and / or other excipients, auxiliary therapeutic compounds.

The active compounds of the formula I can be formulated in a form suitable for inhalation or insufflation, or for oral, buccal, parenteral, topical (including nasal) or rectal administration. A preferred route of administration is inhalation or insufflation. !

In human medicine, the active ingredient may be administered at a dose of 0.005100 mg per day, preferably in one or two doses to the individual to be treated. The exact dosage will, of course, depend on the age and condition of the patient and the mode of treatment.

The compounds of formula (I) may be prepared by a variety of methods according to the invention, wherein Q, X, Y, Ar, R ¹ and R ² are as defined above unless otherwise stated. Of course, certain reactions may also include groups present in the starting compounds which are desired in the final product, particularly reductive processes involving the use of a hydride reducing agent to form a final product wherein Q is formyl or acetyl or hydrogen in the presence of a metal catalyst. the desired end product has an ethylene or acetylene bond. In the above cases, the usual procedure is used, that is, either reactants which do not affect the above groups are used, or the reaction pathway is chosen so as to avoid their use if any of the above groups are present in the starting compound. In the final step of the processes of the invention, protecting groups are generally removed, both in the preparation of intermediates and in the final products. Suitable protecting groups and their removal are described in general procedure c).

In one general process, the compounds of formula (I) are prepared by alkylation. Alkylation may be carried out in a manner known per se.

Under a) the alkylation process the compound of formula H (I) are prepared by the ^Rl site (II) amine of the formula: - wherein Q is as defined above and ^R17 is hydrogen - is alkylated.

In alkylation process a), alkylation with an alkylating agent of formula III wherein L is a leaving group such as a halogen such as chlorine, bromine or iodine or a hydrocarbylsulfonyloxy group such as methanesulfonyloxy or p - toluenesulfonyloxy -.

Alkylation is preferably carried out with a suitable acid scavenger such as an inorganic base such as sodium or potassium carbonate; an organic base such as triethylamine, diisopropylethylamine or pyridine; or in the presence of alkylene oxides such as ethylene oxide or propylene oxide. The reaction is conveniently carried out in a solvent such as acetonitrile; or in an ether such as tetrahydrofuran or dioxane; a ketone such as butanone or methyl isobutyl ketone; substituted amide such as dimethylformamide; or in a chlorinated hydrocarbon such as chloroform at a temperature between room temperature and the boiling point of the solvent.

In b) the alkylation process, R ¹ is a compound of formula H (I) may be prepared by reacting a compound (II) is an amine of formula - wherein the substituents are as defined above, except that R ¹⁷ is hydrogen, or a group which can be converted to a hydrogen atom under the reaction conditions employed - alkylated with a compound of formula IV in the presence of a reducing agent.

Examples of protecting groups that can be converted to hydrogen as defined for R ¹⁷ are arylmethyl groups such as benzyl, α-methylbenzyl or benzhydryl.

Hydrogen may be used as the reducing agent in the presence of a catalyst such as platinum, platinum oxide, palladium, palladium oxide, Raney nickel or rhodium catalyst, for example, on a support such as charcoal. The reaction is carried out in a solvent such as an alcohol such as ethanol; or in an ester such as ethyl acetate; or in an ether such as tetrahydrofuran; or in water; or in a mixture of two or more of the above solvents, at room temperature or higher and at normal or higher pressure, for example 20-100 ° C, at 10 x ^{10 5} Pa.

When at least one or both of R ¹⁶ and R ¹⁷ is hydrogen, the reduction is carried out with a hydride such as diborane or a metal hydride such as sodium borohydride, sodium cyanoborohydride or lithium aluminum hydride - we can do it. The reaction solvent is selected depending on the hydride used as the reducing agent, and alcohols, such as methanol or ethanol, or ethers, such as diethyl ether, tert-butyl methyl ether or tetrahydrofuran, may be used.

When starting from a compound of formula II wherein R ¹⁷ is hydrogen, an imine of formula V may be formed as an intermediate.

Reduction of the imine under the conditions described above and, if necessary, removal of the protecting groups present, affords the compound of formula (I).

HU 206 869 B

When a protecting group of the formula II is used as its starting compound, it is particularly advantageous to use hydrogen and a catalyst under the conditions described above.

According to general process (c), compounds of formula (I) are prepared by removal of a protected intermediate of formula (VI) wherein R ¹⁵ and R ^Ie are hydrogen or a protecting group, with the proviso that at least one of them represents a protecting group. the protecting group.

The protecting group may be any known protecting group, e.g., Protective Groups in Organic Chemistry, ed. JFW McOmie, Plenum Press, 1973]. The hydroxyl protecting group represented by the symbol R ¹⁵ is, for example, an arylmethyl group such as benzyl, diphenylmethyl or triphenylmethyl. An example of an amino protecting group represented by R ¹⁶ is arylmethyl groups such as benzyl, amethylbenzyl, diphenylmethyl or triphenylmethyl; and acyl groups such as trichloroacetyl or trifluoroacetyl.

In preparing the compounds of formula I, protecting groups may be removed in a manner known per se. For example, when ^R15 and / or ^R16 is an arylmethyl group, the above protecting groups may be removed by cleavage with hydrogen, a metal catalyst - for example, palladium on charcoal - presence. When R ¹⁵ is tetrahydropyranyl, deprotection can be conducted by hydrolysis under acidic conditions. The acyl groups designated for R ¹⁶ can be removed by hydrolysis with a base such as sodium hydroxide; or, for example, the trichloroacetyl group can be cleaved by reduction such as zinc and acetic acid.

According to general process d), compounds of formula I are prepared by reduction, for example, by reacting a compound of formula VII wherein R ¹⁵ is hydrogen or a protecting group and X ¹ , X ² and X ³ at least one of which is a reducible group and / or Y and / or Ar contains a reducible group while X ¹ is -CH (OH) -, X ² is -CH ₂ NR ¹⁶ and X ³ is -CR ¹ R ² X - protecting group (s) present and, if necessary, removing the protecting group (s) present.

For example, for X ¹ as a reducible group, use \

C = O; X ^{2 for} the group -CH ₂ NY '/

wherein Y ¹ is a group removable by catalytic hydrogenation, such as benzyl, benzhydryl, or x-methylbenzyl, or -CH = N-, or -CONH-; X ³ is -COX- or -CR ¹ R ² X- wherein X is C 2 -C 7 alkenylene or C 2 -C 7 alkynylene; or -X ² -X ³ - is -CH ₂ N = CR ² X-; Y is C 2 -C 6 alkenylene or C 26 alkynylene; and Ar is phenyl substituted by nitro.

In a preferred embodiment, R ¹⁵ is a group that is removable under reduction conditions, such as an arylmethyl group such as benzyl, benzhydryl or α-methylbenzyl.

The reduction may be carried out using reducing agents conventionally used to reduce ketones, imines, amides, protected amines, alkenes, alkines and nitro groups.

For example, if the phenyl group represented by Ar contains a nitro group substituent, the nitro group may be reduced with hydrogen in the presence of a catalyst, as described above for process b).

\

If (VII) wherein C = O / group, said group X ¹ is -CH (OH) - group described above can be reduced with hydrogen in the presence of a catalyst, as b) connection procedure. The reducing agent may also 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 may be carried out in a solvent such as an alcohol such as methanol or ethanol an ether such as tetrahydrofuran or a halogenated hydrocarbon such as dichloromethane.

When X ^{2 in} formula VII is CH ² NY 'or -CH = N-, or -X ² -X ³ -CH ² N = CR ² X-, the above groups are hydrogen, in the presence of a catalyst, -CH ² NH or -CH ² NHCHR. ^{2 may} be reduced to X as described for process b). When X ^{2 is} -CH = N or -X ² -X ³ -CH ₂ -N = CR ² X-, the above groups may be reduced to -CH ₂ -NH- or -CH ₂ NHCHR ² X- by reducing agents and under the reaction conditions mentioned for the reduction of X ¹ C = O.

When X ² or X ^{3 in} formula VII is -CONH- or-COX-, the above groups may be reduced to -CH ₂ NH- or -CH ₂ X- by a hydride reducing agent such as diborane or a complex metal hydride such as lithium aluminum hydride or sodium bis (2-methoxyethoxy) aluminum hydride in a solvent such as an ether such as tetrahydrofuran or diethyl ether.

When X ^{3 in} formula (VII) is -CR'R ² X- and in the latter formula X is C 2 -C 7 alkynylene; or Y is C 2 -C 6 alkenylene or C 2 -C 6 alkynylene, X and / or Y can be reduced to C 2 -C 7 acylene in the presence of a catalyst as described for process b). When Y represents a C2-C7 alkynylene group, it is also possible to reduce the above group to a C2-C7 alkenylene group in the presence of hydrogen, lead-poisoned calcium carbonate palladium catalyst in a solvent such as pyridine; or lithium aluminum hydride in a solvent,

For example, in diethyl ether, at low temperatures, for example, near 0 ° C.

Compounds of formula (I) may also be prepared by converting a compound of formula (I) into another compound of formula (I).

For example, compounds of formula (I) wherein Ar is nitro-substituted phenyl may be reduced to compounds of formula (I) wherein Ar is phenyl substituted with amino. The reduction may be carried out in a conventional manner, for example with hydrogen, in the presence of a catalyst such as a platinum or palladium catalyst on a support such as carbon, in a solvent such as an alcohol such as ethanol.

Compounds of formula (I) wherein X is alkynylene and / or Y is alkenylene or alkynylene may be reduced to compounds of formula (I) wherein X and / or Y are alkylene by hydrogen in the presence of a metal catalyst as in process (b). has already been discussed.

Compounds of formula (I) wherein Y is an alkenylene group may also be prepared by reduction of the corresponding compounds of formula (I) wherein Y is an alkynylene group, already described in process (d).

The compounds of formula (I) prepared according to the general methods described above may also be in the form of a salt, preferably a pharmaceutically acceptable salt. If desired, these salts can be converted into the corresponding free acids in a known manner.

Pharmaceutically acceptable salts of the compounds of formula (I) may be prepared by reacting the compound of formula (I) with the appropriate acid or base in a solvent such as acetonitrile, acetone, chloroform, ethyl acetate, or an alcohol such as methanol, ethanol or isopropanol.

The pharmaceutically acceptable salts may also be prepared from other salts, such as other pharmaceutically acceptable salts, in known manner.

The intermediates used in the processes of the present invention may be prepared analogously to the preparation of known compounds or known compounds. The preparation of intermediates is described, for example, in British Patent Nos. 2140800A and 2159151A, or may be prepared by the methods described below.

The following examples are intended to illustrate the process of the invention in public. In the examples, unless otherwise stated, drying is carried out with magnesium sulfate or sodium sulfate. Thin layer chromatography on silica, flash column chromatography on silica gel (Merck 9385).

Intermediate 1 Preparation of (E) -1 {[4- (6-bromo-hexyl) -oxyl] -2-butenyl} -4-fluorobenzene

5.73 g of intermediate 9, 25.2 g of 1,6-dibromohexane,

A mixture of 1.5 g of tetra (n-butyl) ammonium sulfate and 45 ml of 40% sodium hydroxide solution was stirred for 18 hours, then diluted with 200 ml of water and extracted with 2 x 150 ml of ethyl acetate. The organic layer was washed with water (100 mL), brine (100 mL), dried and concentrated in vacuo. The resulting yellow oil was purified by flash column chromatography eluting with 10: 0 to 9: 1 cyclohexane: ethyl acetate.

8.49 g of the title compound are obtained as a yellow oil. TLC _Rf 0.34 (cyclohexane: ethyl acetate 9: 1 as eluent).

Intermediates 2 and 3 are prepared in a similar manner.

Intermediate 2 Preparation of 1-Bromo-5 - [(3-butynyl) oxy] pentane

Starting material was 50.0 g of 3-butin-1-ol, 414 g of 1,5-dibromopentane, 250 ml of 50% aqueous sodium hydroxide solution and 5.0 g of tetra (n-butyl) ammonium. using sulfate and proceeding as described for Intermediate 1 except that after dilution with water, extraction with diethyl ether. The dried extract was evaporated and dibromo-pentane on a 20 cm Vigreux column at 85 ° C for approx. 6,45xl0 ² Torr to distill off from the mixture, and the crude product was purified by flash column chromatography, eluting with cyclohexane-ether 9:

ratio.

43.5 g of the expected product are obtained in the form of a colorless oil. TLC Rf 0.65 (9: 1 cyclohexane: diethyl ether).

Intermediate 3

Preparation of 4- {4- [4- (4-Bromobutoxy) butyl] phenyl} morpholine

Starting with 6.0 g of intermediate 12, 22.1 g of 1,4-dibromobutane, 40 ml of 50% aqueous sodium hydroxide and 0.85 g of tetra (n-butyl) ammonium sulfate, except that the reaction mixture was stirred under nitrogen for 20 hours, then diluted with water and extracted with diethyl ether, and the product was purified by flash column chromatography eluting first with cyclohexane followed by cyclohexane and diethyl ether. 3: 1 ether. 6.7 g of the expected product are obtained in the form of a pale yellow oil which, on standing, turns into a colorless solid. Melting point: 33-35 ° C.

Intermediate 4 Preparation of (E) -N- [6- {4 - [(4-hydroxy-3-methoxyphenyl) -3-butenyl] oxy} hexyl] benzylamine (1 g) A mixture of [4 - {(6-bromohexyl) oxy} -1-butenyl] -2-methoxyphenol and 1.5 g of benzylamine was stirred at 120 ° C under nitrogen for 2 hours. The mixture was cooled, diluted with 40 mL of methylene chloride and washed with 2 x 20 mL of n hydrochloric acid. The organic layer was washed with 8% sodium bicarbonate solution (2 x 20 mL), dried and evaporated in vacuo. 0.93 g of the expected product is obtained in the form of a brown oil. Vékonyréteg5

I

GB 206 869 B chromatography _Rf value of 0.51 (toluene, ethanol, and 0.88 g / cm ³ density of ammonium hydroxide solution 39: 10: 1 as eluent).

Intermediate 5

Preparation of Propyl 4- [4 - {(5-bromopentyl) oxy} -1-butynyl] benzoate

10.0 g of intermediate 10, 7.7 g of intermediate 2, 0.35 g of bis (triphenylphosphine) palladium (II) chloride, 0.035 g of copper (I) iodide, 50 ml of diisopropylethylamine and 50 ml of tetrahydrofuran were stirred at room temperature under nitrogen for 18 hours, then filtered and evaporated. The residue was purified by flash column chromatography eluting with 19: 1 cyclohexane: diethyl ether. To yield 5.8 g of the title compound as a colorless oil, TLC _Rf value of 0.3 (cyclohexane-diethyl ether 19: 1 as eluent).

Intermediate 6

Preparation of 4- [4 - {(6-bromohexyl) oxy} butyl] -N, N-diethylbenzamide

A solution of 12.0 g of 4- [4 - {(6-bromohexyl) oxy} -1-butynyl] -N, N-diethylbenzamide in 300 ml of ethanol was treated with 2 g of 10% metal palladium on carbon and 2 g of 5% metal. hydrogenated in the presence of platinum on carbon, filtered and evaporated. The residue was purified by flash column chromatography eluting. diethyl ether: cyclohexane (1: 1). 7.5 g of the desired product as a colorless oil, TLC _Rf 0.3 (diethyl ether: cyclohexane 1: 1 as eluent).

Intermediate 7

Preparation of N, N-Dipropyl-4-iodobenzamide

To a mixture of 4.10 g of tripropylamine and 40 ml of triethylamine is added 10.0 g of 4-iodobenzoyl chloride at 20 ° C in several portions. The resulting suspension is stirred at room temperature for 1 hour, then diluted with 150 ml of diethyl ether, filtered and evaporated. 11.51 g of the desired product as an orange oil, TLC _Rf 0.48 (ether).

Intermediate 8

Preparation of N - [(4-Iodophenyl) -ethyl] -pentanamide

To a mixture of 4.2 g of 4-iodobenzylamine and 3.2 g of pyridine in 50 ml of methylene chloride is added dropwise 3.7 g of valeric anhydride at 0 ° C. The solution was stirred at 0 ° C for 10 minutes and then at room temperature for 2 hours, washed with aqueous sodium bicarbonate solution, dried and evaporated. The residue was crystallized from diethyl ether at -78 ° C. 3.7 g of the title compound are obtained in the form of a white solid, m.p. 8081 ° C.

Intermediate 9 Preparation of (E) -4- (4-Fluorophenyl) -3-buten-1-ol

To a solution of (3-hydroxypropyl) triphenylphosphonium bromide (32.1 g) in anhydrous tetrahydrofuran (200 mL) cooled to 0 ° C was added dropwise a solution of n-butyllithium in hexane (100 mL, 1.6 mL) under nitrogen. . A solution of 4-fluorobenzaldehyde (9.93 g) in dry tetrahydrofuran (100 ml) was added dropwise and the mixture was stirred at 0 ° C for 30 minutes and then at room temperature for an additional 1.5 hours. The mixture was carefully diluted with water (25 mL), the solvent was evaporated in vacuo at 40 ° C and the residue was partitioned between diethyl ether (200 mL) and water (200 mL). The aqueous phase is re-extracted with 200 ml of diethyl ether, the organic phases are combined, dried and evaporated in vacuo. The resulting brown oil was purified by flash column chromatography eluting with 1: 1 cyclohexane: diethyl ether. 6.33 g of the desired product as a colorless oil, TLC _Rf 0.13 (cyclohexane: diethyl ether 1: 1 as eluent).

Intermediate 10

Preparation of Propyl 4-iodobenzoate

To a mixture of 15.0 g of 4-iodobenzoic acid, 7.2 g of n-propanol and 0.6 g of 4-dimethylamino-pyridine in 50 ml of methylene chloride at 0 ° C under a nitrogen atmosphere is 13.4 g of dicyclohexylcarbodiimide in a single dose. The mixture was stirred at 0 ° C for 10 minutes and then at room temperature for 3 hours, diluted with 50 ml of diethyl ether, filtered and evaporated. The residue was treated with cyclohexane (50 mL), filtered and the filtrate was evaporated. 16.2 g of the desired product as a pale yellow oil, TLC R _f = 0.8 (cyclohexane-diethyl ether 3: 1 as eluent).

Intermediate 11

Preparation of N - [{4- [4 - {[6 - {(phenylmethyl) amino} hexyl] oxy} -butynyl] phenyl} methyl] pentanamide

3.5 g of intermediate 8, 2.85 g of N- [6 - {(3-butynyl) oxy} hexyl] benzylamine, 0.2 g of bis (triphenylphosphine) palladium (II) chloride, A mixture of 02 g of copper (I) iodide and 50 ml of diethylamine was stirred at room temperature under nitrogen for 18 hours and then concentrated. The residue was partitioned between 50 mL of 1M aqueous sodium bicarbonate solution and 2 x 100 mL of ethyl acetate, and the dried organic layer was evaporated. The residue was purified by flash column chromatography eluting with ethyl acetate. 2.3 g of the title compound are obtained as a yellow solid, m.p. 66-67 ° C.

Intermediate 12

Preparation of 4- (4-Morpholinyl) phenylbutanol

A mixture of 7.5 g of 4-aminophenylbutanol, 6.5 g (5.32 ml) of 2-chloroethyl ether, 11.4 g of diisopropylethylamine and 15.0 g of finely ground potassium iodide in 500 ml of dimethyl formamide at 100 ° C and under nitrogen for 65 hours. After cooling, the solvent was removed in vacuo at 55 ° C and the residue was partitioned between ethyl acetate (250 mL) and water (100 mL). The aqueous phase is extracted with another 100 ml of ethyl acetate, the combined organic phases are washed with 150 ml of brine, dried and 15 g are obtained.

The residue was evaporated on silica gel used for flash column chromatography. The material was applied to a flash chromatography column eluting with diethyl ether: cyclohexane (2: 1). 6.13 g of the title compound are obtained in the form of a waxy cream-colored substance, m.p. 51-52 ° C.

Intermediate 13 Preparation of 1,1-Dimethyl-5- [4- {4- (4-morpholinyl) phenyl} butoxy] pentanamine (I) 2,2-Dimethyl-6- [4- {4- (4- morpholinyl) phenyl} butoxy] hexanoic acid

5.32 g of diisopropylamine in 20 ml of anhydrous tetrahydrofuran are treated with 34.4 ml of 1.5 M n-butyllithium in hexane at -40 ° C under a nitrogen atmosphere. The resulting lithium diisopropylamide solution is stirred at 0 ° C for 15 minutes, 2.32 g of isobutyric acid is added and the mixture is stirred at room temperature for 3 hours. Intermediate 3 (3.0 g) was added and the mixture was stirred at room temperature under nitrogen for 20 hours and the solvent was evaporated in vacuo at 40 ° C. The resulting viscous residue was triturated with water (250 mL), adjusted to pH 6 with 2N hydrochloric acid, and extracted with ethyl acetate (2 x 200 mL). The organic phase was dried and concentrated in vacuo. 5.75 g of the product as a pale brown oil, TLC _Rf 0.6 (diethyl ether).

(ii) (Phenylmethyl) -1,1-dimethyl-5- [4- {4- (4-morpholinyl) phenyl} butoxy] penylcarbamate

To a solution of the product from step (i) (5.5 g) and triethylamine (2.13 ml) in acetone (50 ml) and water (5 ml) was added dropwise ethyl acetate (1.66 g) in acetone (5 ml). After stirring at 0 ° C for 40 minutes, 1 g of sodium azide dissolved in 10 ml of water was added dropwise. The resulting slurry was stirred at room temperature for 45 minutes, diluted with 100 mL of water and extracted with 2x100 mL of toluene. The dried extract was heated at 75-80 ° C under nitrogen for 2 hours and then concentrated at 40 ° C in vacuo. The residual oil was dissolved in benzyl alcohol (10 mL) and the solution was stirred at 7075 ° C under nitrogen for 60 hours and then the excess alcohol was removed in vacuo at 95 ° C. The resulting oil was purified by flash column chromatography eluting with diethyl ether: cyclohexane (1: 2). 5.34 g of the desired product as a pale yellow oil, TLC _Rf 0.23 (ether: cyclohexane 1: 2) Optical rotation.

(iii) Preparation of 1,1-Dimethyl-5- [4- {4- (4-morpholinyl) phenyl} butoxy] pentanamine

A solution of 4.60 g of the product obtained in step (ii) in 75 ml of anhydrous ethanol is hydrogenated at room temperature and atmospheric pressure in 25 ml of anhydrous ethanol on carbon dioxide palladium oxide catalyst (1 g, 10%, pre-reduced in 50% aqueous paste). . The catalyst was filtered through a hyflo-filter and the solvent was evaporated in vacuo at 40 ° C. 3.0 g of the title compound as a colorless oil, TLC _Rf 0.32 (toluene, ethyl acetate, and 0.88 g / cm ³ density of ammonium hydroxide solution 39: 10: 1 as eluent) .

Intermediate 14

Preparation of N, N-Dipropyl-4- [4 - {[{6- (phenylmethyl) amino} hexyl] oxy} -1-butynyl] benzamide g, Intermediate 7, 1.57 g of N- [6 - To a stirred solution of {(3-butynyl) oxy} hexyl] phenylmethanamine and 70 mg of bis (triphenylphosphine) palladium (H) chloride in 30 ml of diethylamine is added 10 mg of copper (I) iodide under a nitrogen atmosphere, and the mixture was stirred overnight under a nitrogen atmosphere. The solution was concentrated in vacuo and the residue was dissolved in methylene chloride (50 mL) and evaporated to silica gel flash chromatography. Elution was carried out with diethyl ether. 1.2 g of the expected product are obtained in the form of an orange oil. Analysis calculated for C ₃ oH _{4 2} 0 2 N ₂ Calc'd:

Calculated: C, 77.9; H, 9.2; N, 6.1;

Found: C, 77.6; H, 9.4; N, 6.3.

Intermediate 75

N- [4- {4 - [{6 - [{2- [3 - {(aminocarbonyl) amino} -4- (phenyl-methoxy) phenyl-2-oxo-ethyl} - (phenylmethyl) Preparation of -amino] -hexyl} -oxy] -butyl} -phenyl] -butanesulfonamide

Starting materials are N- [5-bromoacetyl-2- (phenylmethoxy) phenyl] urea, 1-bromo-6 - [(3-butynyl) oxy] hexane, benzylamine and N- (4-iodo). using phenyl) -butanesulfonamide to give the title product in a known manner. 0.9 g of the desired product as a white foam, TLC _Rf 0.27 (ethyl acetate: cyclohexane 3: 1 as eluent).

Intermediate 16 (E) -N- [5- {2 - [{6 - [{4- (4-Hydroxy-3-methoxyphenyl) -3-butenyl} oxy] hexyl} (phenylmethyl) - Preparation of amino] -1-oxoethyl} -2-phenylmethoxy-phenyl] -methanesulfonamide

0.6 g of a solution of N- [5-bromoacetyl-2- (phenylmethoxy) phenyl] methanesulfonamide, 0.48 g of intermediate 4 and 0.39 g of diisopropylethylamine in 10 ml of tetrahydrofuran are added. keep at room temperature. The precipitated diisopropylamine hydrochloride is filtered off and the filtrate is concentrated in vacuo. The resulting oil was adsorbed on silica gel (5 g) and purified by column chromatography (3: 2 cyclohexane: ethyl acetate). 0.38 g of the title compound, TLC R _f = 0.20 (cyclohexane: ethyl acetate 3: 2 mixture of).

Intermediate 77

N- [5- {2 - [{5- [4- {4- (3-Methoxy-propyl) phenyl} butoxy] pentyl} - (phenylmethyl) amino] -l-oxoethyl} - Preparation of 2- (phenyl-ethoxy) -phenyl] -formamide N- [5-bromo-acetyl-2- (phenylmethoxy) -phenyl] -formamide, Intermediate 2, Benzyl

Using the amine, 1,4-diiodobenzene, propargyl alcohol and dimethyl sulfate, the title product is obtained in a known manner as a colorless oil. TLC _Rf 0.45 (ethyl acetate-hexane 1: 1 as eluent).

Intermediate 18

4- [4 - {[6 - {[2- {3 - {[(dimethylamino) sulfonyl} -aniino] -4- (phenylmethoxy) phenyl} -2-oxo-ethyl] -N- Preparation of (benzyl) amino} hexyl] oxy} -1-butynyl] -N, N-dipropylbenzamide

0.7 g of N'-5- [bromoacetyl-2- (phenylmethoxy) phenyl] N, N-dimethylsulfamide, 0.76 g of intermediate 14 and

A mixture of diisopropylethylamine (23 g) in dimethylformamide (10 ml) was stirred under nitrogen for 4 hours. The solvent was evaporated in vacuo and the residue was dissolved in ethyl acetate (100 mL) and washed with water (75 mL). The aqueous layer was re-extracted with ethyl acetate (2 x 50 mL) and the combined extracts were dried and evaporated in vacuo. The resulting yellow oil was purified by flash column chromatography eluting with 7: 1 toluene: ethyl acetate. 0.47 g of the desired product as a yellow oil, TLC _Rf 0.28 (toluene: ethyl acetate = 5: 1 as eluent).

Intermediate 19 (E) -N- [2-Hydroxy-5- {1-hydroxy-2 - [{6 - [{4- [3,5-bis (phenylmethoxy) phenyl] -3-butene}} Preparation of -oxyl] -hexyl} -amino] ethyl} phenyl] -methaneshthylfemamide

To a solution of 1.5 g of intermediate 21 and 0.57 g of diisopropylethylamine in 25 ml of dimethylformamide at 70 ° C under a nitrogen atmosphere with stirring was added 2.13 g of 3,5-bis (phenylmethoxy) -1- [ 4 - {(6-Bromo-hexyl) -oxy} -3-butenyl] -benzene is added dropwise. The solution was stirred at 70 ° C for 6 hours, diluted with water (100 mL), extracted with ethyl acetate (2 x 100 mL), washed with water (100 mL), dried and evaporated in vacuo. The resulting brown oil was purified by flash chromatography eluting with 9: 2 ethyl acetate: methanol. 0.79 g of the desired product as a brown oil, TLC _Rf 0.22 (toluene, ethanol, and 0.88 g / cm ³ density ammonia = 39: 10: 1 as eluent).

Intermediate 20

N- [5- {1-Hydroxy-2 - [{1,1-dimethyl-5- (4- {4- (4-morpholinyl) phenyl} butoxy] pentyl} anano] ethyl} Preparation of 2- (phenylmethoxy) phenyl] -methanesulfonamide 0.74 g of N- [5- (oxoacetyl) -2- (phenylmethoxy) phenyl] methanesulfonamide hydrate and 0.70 g of intermediate 13. A solution of 20 ml of benzene was refluxed with Dean-Stark for 0.5 hours until no further water collected, the solvent was removed in vacuo at 40 ° C and the residual oil was evaporated. Dissolve in methanol (ml) and stir at 0 ° C under nitrogen atmosphere, add 0.75 g of sodium borohydride in portions over 0.5 hour, stir at 0 ° C for 15 minutes and then at room temperature for 20 hours. The solution was acidified to pH 2 with 2N hydrochloric acid solution, the major methanol was evaporated in vacuo at 40 ° C and the resulting oil was treated with ethyl acetate (75 mL) and sodium bicarbonate solution (8%). The aqueous phase was extracted with additional 50 ml of ethyl acetate, and the combined organic phases were dried and concentrated. The product was purified by flash column chromatography eluting with 39: 10: 1 toluene / ethanol / 0.88 g / cm ³ ammonium hydroxide. Obtaining 0.75 g of the title compound as a pale brown viscous gum form, TLC R _f = 0.42 (toluene, ethanol, and 0.88 g / cm ³ density of ammonium hydroxide solution 39: 10: 1 a mixture of).

Intermediate 21

N- [5- (2-amino-l-hydroxyethyl) -2-hydroxyphenyl] methanesulfonamide

Intermediate 22

Preparation of N- (4-iodobenzoyl) piperidine

To a solution of piperidine (3.53 g) in triethylamine (40 mL) at 0 ° C was added portionwise 4-iodobenzoyl chloride (10.0 g), and the suspension was stirred at room temperature under nitrogen for 1 hour. The reaction mixture was poured into 2N aqueous hydrochloric acid (200 mL) and extracted with ethyl acetate (3 x 100 mL). The combined extracts were washed with 100 mL water, 100 mL 8% aqueous sodium bicarbonate, and 10 mL water, dried and concentrated. The resulting solid (10.25 g) was purified by flash column chromatography eluting with diethyl ether: hexane (1: 2 → 1: 1). Yield: 9.33 g of the title compound as a white solid, m.p. 126-127 ° C.

23. Intermediate

Preparation of N, N-Diethyl-4-iodo-phenylacetamide 10.62 g of 4-iodo-phenylacetyl chloride was added in portions at 0 ° C under nitrogen atmosphere to 3.0 g of diethylamine and 40 ml of triethylamine. mixture was washed with methylene chloride (5 mL) and the suspension was stirred at room temperature for 2 hours. Diethyl ether (150 mL) was added, filtered and the filtrate was concentrated. 7.94 g of a residue are obtained, which is purified by flash column chromatography eluting with 2: 1 diethyl ether / hexane. 4.72 g of the title compound as a yellow oil, TLC _Rf value of 0.31 (diethyl ether).

Intermediate 24

Preparation of J-Bram-6 - [(2-propynyl) oxy] hexane

5.6 g propargyl alcohol, 73.2 g 1,6-dibromohexane,

A mixture of 0.5 g of tetra (n-butyl) ammonium sulfate and 25 ml of 50% aqueous sodium hydroxide solution was stirred at room temperature for 20 hours, diluted with 50 ml of water and extracted twice with 100 ml of diethyl ether. The dried extract was evaporated and the residue was purified by flash column chromatography eluting with 19: 1 cyclohexane: diethyl ether. 15.0 g of the expected product are obtained in the form of a colorless oil

TLC Rf = 0.4 (9: 1 cyclohexane: diethyl ether).

Intermediate 25

Preparation of 2- [4 - {(6-bromo-hexyl) -oxy} -butyl] -N, N-diethyl-benzamide mg of copper (I) iodide, 3.04 g of 1-bromo-6 - [(3- butynyl) oxyhexane, 3.95 g of N, N-diethyl-2-iodobenzamide, 200 mg of bis (triphenylphosphine) palladium (n) chloride, 2.60 g of N, N-dicyclohexylamine and 20 ml the acetonitrile mixture was stirred at room temperature under nitrogen for 4.5 hours, diluted with 200 mL of water and filtered. The filtrate was evaporated in vacuo and the residue treated with activated charcoal in ethanol (100 mL) and the solvent evaporated in vacuo. The resulting oil (5.32 g) was hydrogenated over a palladium oxide catalyst (1.25 g, 50% in water, 1.25 g, 50% aqueous paste) in anhydrous ethanol (190 ml), filtered through a hyflo filter and evaporate in vacuo. The resulting oil was purified by flash column chromatography eluting with 2: 1 cyclohexane: ethyl acetate. 2.04 g of the desired product as a yellow oil, TLC R _f = 0.14 (toluene, ethanol, and 0.88 g / cm ³ density of ammonium hydroxide solution 40: 10: 1 as eluent).

Intermediate 26

Preparation of 4- [4 - {(5-bromopentyl) oxy} butyl] -N, N-diethylbenzamide

Proceeding as above, starting from 25 mg of copper (I) iodide, 6.06 N, N-diethyl-4-iodobenzamide, 4.38 g of intermediate 2, 250 mg of bis (triphenylphosphine) palladium II) chloride and 4.0 g of dicyclohexylamine were reacted in 30 ml of acetonitrile for 2 hours and then hydrogenated over 10% palladium on carbon in the form of a 50% paste. Purification was carried out on Merck 7734 silica gel and the product was eluted with hexane: diethyl ether 1: 1 and diethyl ether. 5.81 g of the desired product as a light brown oil, TLC _Rf 0.37 (diethyl ether);

Intermediate 27

Preparation of N- [4- {4 - [(6-Bromo-hexyl) -oxy] -butyl} -benzoyl] -piperidine

Starting as above, starting from 9.30 g of intermediate 22, 6.46 g of 1-bromo-6 - [(3-butynyl) oxyhexane, 5.90 g of Ν, Ν-dicyclohexylamine, 150 mg of bis (triphenylphosphine) palladium (II) chloride and 30 mg copper (I) iodide in 90 ml acetonitrile for 20 hours, followed by hydrogenation over 10% palladium on carbon and flash column purification eluting with diethyl ether / hexane (1: 1) to give the title compound. 7.55 g of product as a dark brown oil, vékonyrérteg chromatography _Rf 0.25 (ether-hexane 2: 1 as eluent).

Intermediate 28

Preparation of 4- [4 - {(6-Bromohexyl) oxy} butyl] -N, N-diethylphenylacetamide

4.65 g of intermediate 23, 3.22 g of 1-bromo-6 - [(3-butynyl) oxy] hexane, 2.94 g of Ν, Ν-dicyclohexylamine, 75 mg of bis (triphenylphosphine) Palladium (II) chloride and 15 mg of copper (I) iodide in 30 ml of acetonitrile were reacted as described for the preparation of intermediate 27, catalytically hydrogenated and purified by flash column chromatography to give 3.51 g of the title compound as a dark brown oil. chromatography R _f = 0.18 (ether-hexane 2: 1 as eluent).

Intermediate 29

Preparation of 3- [4 - {(6-Bromohexyl) oxy} butyl] -N, N-diethylbenzamide

8.49 g of N, N-diethyl-3-iodobenzamide, 6.99 g of 1-bromo-6 - [(3-butynyl) oxy] hexane, 350 mg of bis (triphenylphosphine) palladium (H) chloride, Copper (I) iodide (250 mg) and dicyclohexylamine (6.45 g) were stirred in acetonitrile (35 ml) at room temperature for 2 days, then the solvent was evaporated and the residue partitioned between water (100 ml) and ethyl acetate (100 ml). The phases are separated and the organic phase is treated with 5 g of activated carbon, dried and concentrated. To the resulting oil was added ethanol (100 mL) and the resulting fine precipitate was filtered off and the filtrate was hydrogenated over 10% palladium on carbon and purified by flash column chromatography eluting with diethyl ether / cyclohexane (1: 2). 5.91 g of the desired product as a brown oil, TLC R _f = 0.175 (hexane: diethyl ether 1: 1 as eluent).

Intermediate 30

Preparation of 4- [3 - {[6 - {(phenylmethyl) amino} hexyl] oxy} propyl]], Ν-dipropylbenzamide

6.62 g of intermediate 7, 4.40 g of intermediate 24, 4.0 g of dicyclohexylamine, 250 mg of bis (triphenylphosphine) palladium (II) chloride and 25 mg of copper (I) iodide in 40 ml The slurry in acetonitrile was treated as described for Intermediate 25, hydrogenated over 10% palladium on carbon as a catalyst and purified by flash column chromatography (hexane: diethyl ether 2: 1). The resulting orange oil (5.1 g) was added to benzylamine (15 mL) at 140 ° C under nitrogen. After 2 hours, the reaction mixture was added to a mixture of 200 ml of 2N hydrochloric acid and 100 ml of ice. The aqueous mixture was extracted with ethyl acetate (3 x 100 mL), and the combined organic layers were washed with 2N sodium bicarbonate, water, then brine, dried and concentrated. The resulting dark brown oil was purified by flash column chromatography eluting with 95: 5: 1 to 90: 10: 1 toluene, diethyl ether and triethylamine. 2.4 g of the title compound as a pale yellow oil, TLC _Rf

HU 206 869 B

0.36 (90: 10: 1 toluene: ethanol: triethylamine).

31. Intermediate

Preparation of N- [6- {2- [4- (N, N-Dimethylamino) phenyl] ethoxy} hexyl] benzylamine

73.84 g 1,6-dibromohexane, 10 g 4- (N, N-dimethylamino) phenylethanol, 200 ml 50% sodium hydroxide solution and 3.4 g tetra (n-butyl) The mixture was stirred vigorously at room temperature for 72 hours, diluted with water (500 mL) and extracted with diethyl ether (2 x 100 mL). The dried extract was evaporated to give a yellow oil which was purified by flash column chromatography eluting with hexane followed by 9: 1 hexane: ethyl acetate. 4- [2 - {(6-bromohexyl) oxy} ethyl] -N, N-dimethylaniline was obtained as a yellow oil. 15 g of the above aniline derivative are added to 45 ml of benzylamine under stirring at 140 ° C under nitrogen and the mixture is further stirred for 2 hours. The benzylamine was removed in vacuo at 90 ° C and the resulting solution was partitioned between 150 mL of sodium bicarbonate solution and 2 x 100 mL of ethyl acetate. The combined organic phases are dried and concentrated and the product is purified by flash column chromatography eluting with a gradient of 1: 1 diethyl ether / hexane. 11.1 g of the desired product as a yellow oil, TLC R _f = 0.62 (toluene, ethyl acetate, and 0.88 g / cm ³ density of ^{1 *} ammonium hydroxide 95: 4: 1 a mixture of).

Example 1 (a) N, N-Diethyl-4- [4 - {[6 - {[2-hydroxymethyl-2- {4-hydroxy-3 [(methylsulfonyl) amino] phenyl} ethyl] Preparation of -amino} -hexyl] oxy} butyl] benzamide benzoic acid salt

1.0 g of intermediate 6 in 2 ml of dimethylformamide

A mixture of intermediate 21 (1.2 g) and diisopropylethylamine (1.3 g) in dimethylformamide (20 ml) was added dropwise at 75 ° C. The solution was heated at 75-80 ° C for 90 minutes and then concentrated in vacuo. The residue was purified by flash column chromatography eluting with 80: 20: 1 toluene / ethyl acetate / 0.88 g / cm ³ ammonium hydroxide. A colorless gum was obtained which was treated with 10 ml of chloroform in a mixture of 0.3 g of benzoic acid and 5 ml of chloroform, and the chloroform was evaporated. The residue was triturated with diethyl ether (2 x 25 mL) to give 0.55 g of the title compound as a white solid, m.p. 90-92 ° C.

Elemental analysis results for C ₂ 9 H ₄₈ N ₃ O ₆ SxC ₇ H ₆ O ₂ :

Calculated: C, 62.8; H, 7.9; N, 6.1%; Found: C, 63.3; H, 7.55; N, 5.9.

In the same manner as described above, the following chemical compounds are also prepared.

(b) Propyl 4- [4 - {[5 - {[2-hydroxy-2- {4-hydroxy-3 [(methylsulfonyl) amino] phenyl} ethyl] amino} pentyl ] oxy} -l-butynyl] benzoate

Starting from 1.0 g of intermediate 21, 1.43 g

Intermediate 5 and 1.0 g of diisopropylethylamine were used, the reaction was carried out for 2 hours, and the benzoic acid treatment in chloroform was discontinued.

0.26 g of the expected product are obtained in the form of a white solid, m.p. 88-90 ° C.

Elemental analysis results for C ₂₈ H ₃₈ N ₂ O ₇ S:

Calculated: C, 61.5; H, 7.0; N, 5.1;

Found: C, 61.0; H, 7.0; N, 5.0.

(c) N- [2-Hydroxy-5- {1-hydroxy-2 - [{6- [4- (4-nitrophenyl) butoxy] hexyl} amino] ethyl} phenyl] methanesulfonamide

Starting material was 2.5 g of intermediate 21, 3.6 g of 1- [4 - {(6-bromohexyl) oxy} butyl] -4-nitrobenzene and

2.6 g of diisopropylethylamine were used, the reaction time was two hours, and benzoic acid treatment in chloroform was discontinued.

1.15 g of the expected product are obtained in the form of a beige solid, m.p. 77-80 ° C.

Elemental analysis results for C ₂₅ H ₃₇ N ₃ O ₇ S:

Calculated: C, 57.3; H, 7.1; N, 8.0; Found: C, 57.0; H, 7.1; N, 7.85.

Example 2 (a) (E) -N- [2-Hydroxy-5- {1-hydroxy-2 - [{6 - [{4- (4-fluorophenyl) -3-butemyl} oxy] - Preparation of hcxyl} -atnino] -ethyl} -phenyl] -methanesulfonamide hydrate

1.34 g of intermediate 21 and 0.57 g of diisopropylethylamine in 25 ml of dimethylformamide under a nitrogen atmosphere at 70 ° C with stirring

Intermediate 1 is added. The solution was stirred at 70 ° C for 5 hours, diluted with water (100 mL) and extracted with ethyl acetate (2 x 100 mL). The organic layer was washed with water (100 mL), dried and concentrated in vacuo. The resulting brown oil was purified by flash column chromatography eluting with 9: 1 ethyl acetate: methanol. The resulting brown foam was triturated with diethyl ether to give 0.47 g of the title product as a white solid, m.p. 79-80 ° C.

Elemental analysis results for C ₂₅ H ₃₅ N ₂ O ₅ Sx 5 H ₂ O:

date; C = 59.6%, H = 7.2%, N = 5.6%;

Found: C, 59.6; H, 7.15; N, 5.6.

The following compound is also prepared as described above.

(b) N- [2-Hydroxy-5- {1-hydroxy-2 - [{6- (4-phenylbutoxy) -3-heximyl} amino] ethyl} phenyl] methanesulfonamide hydrate

Intermediate 21 (0.8 g), [4 - {(6-bromo-3-hexynyl) oxy} butyl] benzene (1 g) and diisopropylethylamine (0.45 g) were used as starting material and the reaction time was 2 hours.

159 mg of the title product as a yellow foam, TLC _Rf 0.22 (toluene, ethyl acetate, and 0.88 g / cm ³ density of ammonium hydroxide solution 39: 10: 1 as eluent).

Elemental analysis results for C ₂₅ H ₃₄ N ₂ Oy <0.5 H ₂ O:

Calculated: C, 62.1; 11, 7.3; N, 5.8.

Found: C, 61.6; H, 7.3; N, 5.7.

HU 206 869 B

Example 3 (a) Propyl 4- [4 - {[5 - {[2-hydroxy-2- {4-hydroxy-3 [(methylsulfonyl) amino] phenyl} ethyl] amino} - Preparation of pentyl] oxy} butyl] benzoate

A solution of 0.2 g of the product of Example 1 (b) in 20 ml of ethanol is hydrogenated over 0.05 g of 10% palladium-on-carbon and filtered through a hyflo filter and evaporated. The residue was triturated with diethyl ether (20 mL). 0.19 g of the expected product is obtained in the form of an off-white solid, m.p. 74-76 ° C.

Elemental analysis results for C _{2 g} H _{4 2} N ₂ O 7 S:

Calculated: C, 61.1; H, 7.7; N, 5.1; Found: C, 60.6; H, 7.4; N, 5.0%.

The following compounds are prepared in a similar manner.

(b) N- [2-Hydroxy-5- {! -hydroxy-2 - [{6- [4- (3,5-dihydroxy-phenyl) -butoxy] -hexyl} -amino} -ethyl} -phenyl] -ethanesulfonamide hydride

Starting material was 0.5 g of Intermediate 19 and 40 mg of 5% palladium on carbon palladium on carbon and 30 mg of 5% palladium on carbon.

0.27 g of the expected product are obtained in the form of a beige solid, m.p. 73-74 ° C.

Elemental analysis results based on the formula ^ · 25 ^ 38Ν2θ7 ^ ^χ Η ₂ Ο:

Calculated: C, 56.8; H, 7.6; N, 5.3; found: C = 56.3%, H = 7.6%, N = 5.2%, (c) N- [4- {4 - [[6 - [[2-Hydroxy-2- [3- [ (aminocarbonyl) amino} -4-hydroxyphenyl] ethyl} amino] hexyl} oxy] butyl} phenyl] butanesulfonamide hydrate Starting material: 0.8 g of intermediate 15 and 200 g of the precursor. mg of 10% palladium on carbon and 200 mg of 5% platinum on carbon are used.

Gave 0.45 g of the title compound as a beige foam, TLC _Rf 0.16 (Toluene: ethanol: 0.88 g / cm ³ density of ammonium hydroxide solution 39: 10: 1 as eluent).

Elemental Analysis for C29H ₄₆ N ₂ O ₄ O6SxH Calc'd:

Calculated: C, 58.4; H, 8.1; N, 9.4;

Found: C, 58.3; H, 7.75; N, 8.9.

(d) N- [5- {2 - [{6- [4- (4-Aminophenyl) butoxy] hexyl} amino] -1-hydroxyethyl} -2-hydroxyphenyl] -ethanesulfonamide; hydrate

0.5 g of the compound prepared in Example 1 (c) are used as starting material and the reduction is carried out over 0.1 g of 10% palladium on carbon and 0.1 g of 5% platinum on 5% metal.

0.3 g of the expected product are obtained in the form of a beige solid, m.p. 57-60 ° C.

Elemental analysis results for C _{2 5} H ₃₉ N ₃ O ₅ SxH ₂ O:

Calculated: C, 58.7; H, 8.0; N, 8.2;

Found: C, 58.3; H, 7.5; N, 8.0.

Example 4

N- [2-Hydroxy-5- {l-hydroxy-2 - [{5- [4- {4- (3-methoxypropyl) phenyl} butoxy] pentyl} amino] ethyl} phenyl] formamide Preparation of Benzoic Acid Salt Hydrate A solution of 0.85 g of intermediate 17 in palladium oxide catalyst containing 0.5 g of 10% metal and 0.25 g of 5% metal platinum oxide catalyst in anhydrous ethanol was prepared. hydrogenation. The mixture was filtered through a hyflo filter and the solvent removed. The resulting oil was purified by flash column chromatography eluting with 39: 10: 1 toluene / ethanol / 0.88 g / cm ³ ammonium hydroxide. 0.2 g of the expected product are obtained in the form of the free base as a viscous, colorless oil. The product was dissolved in methanol (5 mL), benzoic acid (50 mg) was added and the solvent was evaporated. The resulting viscous oil was triturated with diethyl ether to give 0.16 g of the title compound as a white powder, m.p. 88-91 ° C.

Elemental analysis for C _{2 »4} H 2 N ₂ O ₅ xC7H ₆ O ₂ x 0.5 H ₂ O: Calcd: C = 68.04%, H 7.99%, N = 4.53%;

Found: C, 68.21; H, 7.75; N, 4.54.

Example 5

N- [2-Hydroxy-5- {l-hydroxy-2 - [{6- [4- (4-hydroxy-3-methoxyphenyl) butoxy] hexyl} amino] ethyl} phenyl] methanesulfonamide, preparation of hydrate

A solution of intermediate (16) (0.36 g) in anhydrous ethanol (20 mL) was hydrogenated over 40 mL of 10% palladium on carbon and 40 mg of 5% platinum on carbon in 5 mL of ethanol. The mixture was filtered through a hyflo filter and evaporated. The resulting brown oil was purified by flash column chromatography eluting with 39: 10: 1 toluene / ethanol / 0.88 g / cm ³ ammonium hydroxide. The resulting brown oil was triturated with diethyl ether 40 mg of the title product as a brown foam, TLC _Rf 0.23 (Toluene: ethanol: 0.88 g / cm ³ density of ammonium hydroxide solution 39: 10: 1).

Elemental analysis results for C ₂₆ H ₄₀ N ₂ O ₇ Sx0.5 H ₂ O:

Calculated: C, 58.5; H, 7.7; N, 5.25;

found; C = 58.4%, H = 7.85%, N = 4.9%.

Example 6

N - [{4- [4 - {[6 - {[2-Hydroxy-2- {4-íiidroxi-3 - [(methylsulfonyl) amino] phenyl} ethyl] amino} hexyl] oxy} butyl] phenyl} methyl] pentanamide benzoate salt

A solution of 0.9 g of N- [5- (bromoacetyl) -2- (phenylmethoxy) phenyl] methanesulfonamide, 1.0 g of intermediate 11 and 0.65 g of diisopropylethylamine in 15 ml of tetrahydrofuran was added at room temperature. Leave to stand for 20 hours, filter and evaporate. The residue was purified by flash column chromatography eluting with diethyl ether. The resulting yellow oil was treated with 0.3 g of 10% palladium on carbon in 40 mL of ethanol.

Hydrogenation was carried out over catalyst B and 0.2 g of 5% metal-based platinum on carbon, filtered and evaporated. The residue was purified by flash column chromatography eluting with 80: 20: 1 toluene / ethanol / 0.88 g / cm ³ ammonium hydroxide. 0.2 g of a colorless gum are obtained, which is dissolved in 15 ml of chloroform, treated with 0.7 g of benzoic acid and evaporated. The residue was triturated with diethyl ether (15 mL) to give 0.2 g of the title compound as a white solid, m.p. 88-89 ° C.

Analysis calculated for C _3i vascular ₄ H 9 N ₃ O ₆ SXC ₇ H ₈ O ₂ Calc'd;

Calculated: C, 63.1; H, 7.8; N, 5.8;

Found: C, 63.0; H, 7.7; N, 5.8.

Example 7

4- [4 - {[6 - {[2- {3 - {[(Dimethylamino) -sztdfonil} -amino] -4-hydroxyphenyl} -2-hydroxy-ethyl] amino} hexyl] oxy } -butyl] -N, N-dipropylbenzamide (E) -2-fumarate salt hydrate (1: 1)

A solution of Intermediate 18 (0.43 g) in anhydrous ethanol (30 ml) was hydrogenated in a predetermined mixture of 100 mg of 5% metal platinum oxide catalyst and 100 mg of 10% palladium on carbon in 10 ml of anhydrous ethanol. The mixture was filtered through a hyflo filter and evaporated in vacuo. 0.27 g of a yellow oil are obtained. The oil was purified by flash column chromatography eluting with 39: 10: 1 toluene / ethyl alcohol / 0.88 g / cm ³ ammonium hydroxide. 200 mg of a yellow oil are obtained, which is dissolved in 2 ml of methanol and treated with 40 mg of fumaric acid. The solution was concentrated in vacuo and the residue was triturated with diethyl ether. 0.2 g of the desired product as cream colored foam, TLC _Rf 0.21 (Toluene: ethanol: 0.88 g / cm ³ density of ammonium hydroxide solution 39: 10: 1 as eluent).

Elemental Analysis for: C ₃₃ H ₅₄ N ₄ O ₆ S x C ₄ H ₂ Ox0.2 H ₂ O Calculated: C, 58.9; H, 7.8; N, 7.4;

Found: C, 58.6; H, 8.0; N, 6.9.

Example 8

N- [2-Hydroxy-5- {1-hydroxy-2 - [{1,1-dinethyl] -5- {4- {4- (4-morpholinyl) phenyl} butoxy} pentyl} amino] -ethyl} phenyl] -ethanesulfonamide

A solution of Intermediate 20 (0.65 g) in anhydrous ethanol (25 mL) was hydrogenated at room temperature under atmospheric pressure over a palladium oxide catalyst (10% metal, 0.5% pre-reduced in 50% aqueous paste). The catalyst was removed by filtration through a hyflo filter. The product was purified by flash column chromatography eluting with 39: 10: 1 toluene / ethanol / 0.88 g / cm ³ ammonium hydroxide. 128 mg of the title compound are obtained as a tan powder, m.p. 165-167 ° C.

Elemental analysis results for C ₃₀ H ₄₇ N ₃ O ₆ S:

Calculated: C, 62.36; H, 8.20; N, 7.27; Found: C, 62.22; H, 8.37; N, 6.99.

Example 9

N- {2-Hydroxy-5- {1-hydroxy-2 - [{1-methyl-6- [2- {4- (methylthio) phenyl} ethoxy] hexyl} amino] ethyl} - phenyl] methanesulfonamide

A solution of intermediate 21 (0.62 g), 7- [2- (4- (methylthio) phenyl) ethoxy] -2-heptanone (0.7 g) and acetic acid (0.18 g) in methanol (15 mL) was added. was treated with sodium cyanoborohydride under a nitrogen atmosphere and allowed to stand at room temperature for 18 hours in the presence of 4 A molecular sieve. After adding 50 ml of a 1M aqueous sodium bicarbonate solution, the mixture was extracted with ethyl acetate (2 x 100 ml). The extract was dried and evaporated and the residue was purified by flash column chromatography eluting with 80: 20: 1 toluene: ethanol: 0.88 g / cm ³ ammonium hydroxide. The resulting semi-solid residue was triturated with diethyl ether (50 mL). 0.45 g of the expected product is obtained in the form of a white solid, m.p. 133-138 ° C.

Elemental analysis results for C ₂₅ H ₃₈ N ₂ O ₅ S ₂ :

Calculated: C, 58.8; H, 7.5; N, 5.5; Found: C, 58.8; H, 7.6; N, 5.3.

Example 10

N, N-dipropyl-4- [3 - {[6 - {[2-hydroxy-2- {4-hydroxy-3- [(methylsulfonyl szidfoml) amino] phenyl} ethyl] amino} -kexi. l-oxy} propyl] benzamide benzoate salt hydrate

1.93 g of N- [5- (bromoacetyl) -2- (phenylmethoxy) phenyl] methanesulfonamide, 2.10 g of intermediate 30 and 0.68 g of diisopropylethylamine are prepared in 45 ml of dichloromethane. solution was stirred under a nitrogen atmosphere for 24 hours. The mixture was diluted with water (150 mL) and extracted with diethyl ether (200 mL). The organic layer was washed with brine (50 mL), dried and concentrated in vacuo. 3.57 g of a yellow oil are obtained, which is dissolved in 170 ml of anhydrous ethanol and 1.0 g of 10% palladium-on-carbon catalyst and

Hydrogenated platinum oxide catalyst (1.2 g, 5%) in a mixture of dry ethanol (20 mL), filtered through a hyflo filter and evaporated in vacuo. The resulting oil was purified by flash column chromatography eluting with a 40:20: 1 mixture of toluene, ethanol and 0.88 g / cm ³ ammonium hydroxide. The resulting oil was triturated with ether to give the title compound in 1.40 g of the free base form of the titled compound as a white foam, TLC _Rf value of 0.16 (Toluene: ethanol: 0.88 g / cm ³ density ammonium hydroxide 40: 10: 1 solution). A portion of the product (0.60 g) was dissolved in methanol (10 mL) and treated with benzoic acid (0.14 g). 0.54 g of the expected product is obtained in the form of a white solid, m.p. 100.5-101.5 ° C.

I

HU 206 869 B

Elemental Analysis for C3, H4oN O ₇ H ₆ SXC _fi O ₇ x H ₇ O: Calcd: C = 62.3%, H 7.8%, N 5.7%;

Found: C, 62.2; H, 7.8; N, 5.7.

Example 11

N- [5- {2-Hydroxy-I-hydroxy-2 - [{6- {2- [4- (dimethylamino) phenyl} ethoxy-hexyl} -amino] ethyl} phenyl] methanesulfonamide hydrate Prepared from 10 g of N- [5- (bromoacetyl) -2- (phenylethoxy) phenyl] methanesulfonamide, 3.54 g of intermediate 31 and 2.1 g of diisopropylethylamine. except that 1.5 g of a 10% palladium on carbon catalyst and 1.5 g of a 5% palladium on carbon catalyst are used as the hydrogenation catalyst and toluene, ethanol and 0.88 eluent are used as eluents for the flash column purification. 80: 20: 1 ammonium hydroxide solution (g / cm ^{3) was} used and benzoic acid treatment was omitted.

450 mg of the title compound are obtained as a light brown solid, m.p. 45-50 ° C.

Elemental analysis for C 5 H _{3 2} 9 N ₃ O ₅ Sx0,7 _H2O Calc'd:

Calculated: C, 59.31; H, 8.04; N, 8.29;

S = 6.33%;

Found: C, 59.27; H, 8.05; N, 8.18.

Example 12

N, N-Diethyl-4- [4 - {[5 - {[2-hydroxy-2- {4-hydroxy-3- [(Mette-sulfonyl) amino] phenyl} -ethylthio] amino} pentyl] Preparation of oxy} butyl] benzimidate benzoate salt hydrate

Starting from 2.5 g of intermediate 21, 0.89 g of diisopropylethylamine and 2.7 g of intermediate 26, the title compound was prepared according to the procedure of Example 1 (a), and the reaction time was 4-4 hours. Flash column chromatography was eluted first with a mixture of toluene, ethanol and 0.88 g / cm ³ ammonium hydroxide (78: 20: 2, then 73: 25: 2) using methanol as the solvent for the benzoic acid treatment. the amount of benzoic acid was 0.45 g.

1.35 g of the desired product as a solid, mp 92-105 ° C, TLC R _f = 0.19 (toluene: ethanol 0,88g / cm ³ density of ammonium hydroxide solution 38: 10: 2 a mixture of).

Elemental analysis calculated for CΗ HΗΝΗΝΝ, ΟΟχΟ, δΟ C ₇ H ₆ O ₂ x 0.5 H ₂ O: C, 61.98; H, 7.64; N, 6. 27%;

Found: C, 61.88; H, 7.58; N, 5.99.

Example 13

N- [2-Hydroxy-5- {1-hydroxy-2 - [{6- [4- {4- (1-piperidinylcarbonyl) phenyl} butoxy] hexyl] amino] - Preparation of ethyl} -phenyl] -methanesulfonylidene hydrobrominide hydrate

Starting from 1.0 g of Intermediate 21, 1.15 g of Intermediate 27 and 0.38 g of diisopropylethylamine, the title compound was prepared according to Example 1 (a) and the reaction time was 4 hours. Flash column chromatography eluted with 80: 20: 2 toluene / ethanol / 0.88 g / cm ³ ammonium hydroxide to give a foam (0.28 g) in methanol (2 mL, 0.4 mL, 1 M). of methanolic hydrogen bromide. The solution was concentrated and the residue was triturated with diethyl ether.

0.22 g of the title product compound as a yellow foam, TLC _Rf 0.16 (Toluene: ethanol: 0.88 g / cm ³ density of ammonium hydroxide solution 80: 20: 2 eluent).

Elemental analysis for C ₃₁ H ₄₇ N ₃ O ₆ SxHBrx, 1.5 H ₂ O: Calcd: C = 53.4%, H 7.2%,

N = 6.0%, S = 4.6%, Br = 11.5%; Found: C, 53.3; H, 7.0;

N = 5.7%, S = 4.6%, Br = 12.0%.

Example 14

N, N-diethyl-2- [4 - {[6 - {[2-hydroxy-2- {4-hydroxy-3- [(meti.l-sulfonyl) -amino] phenyl} ethyl] amino} - hexyl] oxy} butyl] benzamide acetate salt hydrate

Starting from 1.70 g of Intermediate 21, 1.9 g of Intermediate 25 and 0.66 g of diisopropylethylamine, the title compound is obtained according to the procedure of Example 1 (a) using a reaction time of 3 hours. The solvent was then distilled off in vacuo, and the residue was dissolved in methanol (30 mL) and pre-adsorbed on silica gel flash column chromatography. Elution is carried out with a 40: 10: 1 mixture of toluene, ethanol and 0.88 g / cm ³ ammonium hydroxide solution. 0.56 g of a foam is obtained which is dissolved in 10 ml of methanol and treated with 0.06 ml of glacial acetic acid. 0.40 g of the expected product is obtained in the form of a brownish-yellow foam, TLC ₍ 0.09 g, 40: 10: 1, toluene / ethanol / 0.88 g / cm ³ ).

Analysis calculated for C ₃₀ H ₄₇ N ₃ O ₆ S x C ₂ H ₄ O ₂ x H ₂ O: C, 58.6; H, 8.1; N, 6.4;

Found: C, 58.5; H, 7.5; N, 6.0.

Example 15

N, N-Diethyl-4- [4 - {[6 - {[2-hydroxy-2- {4-hydroxy-3 [(methylsulfonyl) amino] phenyl] ethyl] amino Preparation of} -hexyloxy} -butyl] -phenylacetaind-benzoate salt hydrate

Starting from 2.0 g of Intermediate 21, 2.29 g of Intermediate 28 and 0.76 g of diisopropylethylamine, the title compound was prepared according to the procedure of Example 1 (a) and the reaction time was 3 hours. The foam (0.7 g) obtained by flash column chromatography was partitioned between ethyl acetate (50 mL) and 8% aqueous sodium bicarbonate solution (50 mL) and the dried organic layer was concentrated. The resulting 0.20 g of foam was treated with 80 ml of benzoic acid in chloroform.

114 mg of the title compound are obtained in the form of a cream-colored solid, m.p. 114-116 ° C.

Elemental analysis results for C ₃ i H ₄₉ N ₃ O ₆ Sxl, 25 C ₇ H ₆ O ₂ x H ₂ O:

EN 206 869 B calculated: C = 62.6%, H = 7.7%,

N = 5.5%, S = 4.2%; Found: C, 62.7; H, 7.7;

N = 5.5%, S = 4.4%.

Example 16

N, N-Diethyl-3- [4 - {[6 - {[2-hydroxy-2- {4-hydroxy-3- [(methylsulfonyl) amino] phenyl} ethyl] amino} hexyl] Preparation of oxy} butyl] benzamide

Starting from 3.0 g of Intermediate 29, 2.9 g of Intermediate 21 and 3.6 g of diisopropylethylamine, the title compound was prepared according to Example 1 (a) at a reaction temperature of 100 ° C. Flash column chromatography eluted with toluene, ethanol and 0.88 g / cm ³ ammonium hydroxide solution 80: 20: 2 and toluene, methanol and 0.88 g / cm ³ ammonium hydroxide solution 50:50 : Gradient elution from 2: 1 mixtures.

1.2 g of the title compound as a sticky pink foam, TLC _Rf 0.1 (toluene, ethanol, and 0.88 g / cm ³ density of ammonium hydroxide solution 80: 20: 2) Optical rotation: .

Claims (7)

PATENT CLAIMS A process for the preparation of aminophenol derivatives of the formula: wherein: X is C 1-7 alkylene or C 2-7 alkynylene, Y is (C 1 -C 6) -alkylene, (C 2 -C 6) -alkenylene or (C 2 -C 6) -alkynylene and The total number of carbon atoms in groups X and Y is 5, 6 or 7; R ¹ and R ² are hydrogen or methyl; Q is formyl, acetyl, carbamoyl, (dimethylamino) sulfonyl or methylsulfonyl; and Ar is a phenyl group having an amino, dimethylamino, nitro, morpholino group, - (CH ₂ ) _q NHCOR ⁶ - in the formula ^R6 is C1-4 alkyl and q is 1-4 -, -NH-SO ₂ R ⁷ - in the formula R ⁷ is C 1 -C 4 alkyl, -COR ⁸ - in the formula R ⁸ is C 1 -C 4 alkoxy or NR ³ R ^{4 in} the latter formula R ³ and R ⁴ are C 1-4 alkyl or together with the nitrogen to which they are attached form a piperidine ring, -CH ₂ CONR ³ R ⁴ - in the formula R ³ and R ⁴ are C 1-4 alkyl, -SR ⁹ R ⁹ is C 1 -C 4 alkyl, or - (CH ² f R ¹⁰ ) wherein r is 3 and R '0 is C 1 -C 4 alkoxy - substituted; or Ar is 3,5-dihydroxyphenyl or 3-methoxy-4-hydroxyphenyl; or when X is an alkynylene group and / or Y is an alkenylene or alkynylene group, Ar may also be optionally substituted with a fluorine atom, and pharmaceutically acceptable salts and hydrates thereof, characterized in that: a) preparation of a compound of formula (I) wherein R ¹ is hydrogen, an amine (II) of the formula: - wherein ^R17 is hydrogen, and Q is as defined above - with an alkylating agent of formula (III): - wherein L is a leaving and Ar, R ² , X and Y are as defined herein; obsession b) for the preparation of compounds of formula I wherein R ¹ is hydrogen, an amine of formula II wherein Q is as defined above and R ¹⁷ is hydrogen or a hydrogen atom which can be substituted under the reaction conditions is a compound of formula IV alkylating with a compound in the presence of a reducing agent; obsession c) a protected intermediate of formula VI: wherein R ¹ , R ² , Ar, X, Y and Q are as defined in the present specification and R ¹⁵ and R ¹⁶ are each independently hydrogen or a protecting group, provided that at least one of them represents a protecting group - removing the protecting group (s); obsession d) an intermediate of formula VII: wherein: R ¹⁵ is hydrogen or protecting group, X ¹ is -CH (OH) or a group which can be converted to it by reduction, X ² is -CH ₂ NR ¹⁶ - wherein R ¹⁶ is hydrogen or protecting group - or a group which can be converted to it by reduction, X ³ is a -CR * R ² group X or a group which can be converted by reduction, wherein R ² and X are as defined herein, Q, Y and Ar are as defined herein, and at least one of X ¹ , X ² and X ³ represents a reducible group and / or Y and / or Ar contains a reducible group - reducing and optionally removing any protecting groups present and optionally converting the resulting compound of formula (I) or a salt thereof into a pharmaceutically acceptable salt and optionally isolating it in the form of a hydrate. A process for the preparation of a compound of formula (I) according to claim 1 wherein Y is a C 1-3 alkylene group, wherein the appropriately substituted starting materials are used. 3. The method of claim 1 or 2 for preparing a compound (I) of formula wherein R ¹ and R ² is hydrogen, characterized in that the (substituted starting compounds are used appropriately. HU 206 869 B 4. A process for the preparation of compounds of formula I according to any one of claims 1 to 3, wherein Q is a methanesulfonyl group, wherein the appropriately substituted starting compounds are used. 5. A process for the preparation of a compound of formula (I) according to any one of claims 1 to 3 wherein Ar is phenyl substituted with diethylaminocarbonyl, wherein the appropriately substituted starting materials are used. The process according to claim 1, which is N, N-diethyl-4- [4 {[6 - {[2-hydroxy-2- {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl} ethyl]. ] -amino} -hexyl] -oxy} -butyl] -benzamide and pharmaceutically acceptable salts and hydrates thereof, wherein the appropriately substituted starting materials are used. 7. A process for the preparation of a pharmaceutical composition, characterized in that a compound of formula (I), wherein X, Y, R ¹ , R ² , Q and Ar are as defined in claim ¹ , is prepared by any one of the methods according to claim ¹ , or a pharmaceutically acceptable salt or hydrate thereof;