PL141883B1 - Method of obtaining novel derivatives of phenylethanolamine - Google Patents

Description

The subject of the invention is a method for the preparation of new phenylethanolamine derivatives showing an action stimulating the adrenergic receptors. It is known that some phenylethanolamine derivatives exert an action stimulating or blocking α adrenergic receptors. For example, British Patent No. 1,200,886 describes a group of phenylethanolamine derivatives of the general formula I in which, inter alia, X is a hydroxyalkyl group, R | and J6 are hydrogen and R is a straight or branched CpCe alkyl, aralkyl or aryloxyalkyl group. One of the compounds of this group that has found clinical application is salbutanol- (© c -IH.t.butylaminomethyl) - -4-hydroxy-m-xylyl-oC1, cc'-diol, thus a compound of formula 1, in wherein X- is the group -CH 2 OH, R- | and Rg are hydrogen and R4 is tert-butyl. Currently, it is widely used in the treatment of diseases such as bronchial asthma and chronic bronchitis. The effectiveness of salbutamol is due to its type of action, especially its potency combined with a selective stimulating effect on f1 adrenergic receptors * All stimulants currently used in clinical practice # p receptors have a disadvantageous feature which is a relatively short duration of action when administered during inhalation. For this reason, a stimulant of β2 receptors and having a relatively long duration of action would be very valuable in the treatment of bronchial asthma and other diseases of this type. In the search for new stimulants and beneficial properties, a new group of derivatives has now been discovered. phenylethanolamines, differing in structure from the group of compounds described in British Patent No. 1,200,886. During the trials, the new compounds showed a strong selective action stimulating the adrenergic receptors fi2f and, moreover, were characterized by a very advantageous type of action. They showed a longer duration of action than the compounds known from British Patent Specification No. 1 200 886.2 141 883 By the method according to the invention, new phenylethanolamine derivatives of the general formula 2 are prepared, in which m is an integer 2-8, n is an integer 1-7f with the sum of m + n is 4-12, Ar is a phenyl group optionally substituted with one or two substituents such as halogen, G-C * alkyl or C 1 -C * alkoxy. or an alkylenedioxy group of the formula -o (ct) - where p is a number 1 or 2, R and R are one or different and represent a hydrogen atom or a C1-C alkyl group, the total number of atoms being the carbon in R and R, is at most 4, as well as their physiologically acceptable salts and solvates, e.g. The compounds of general formula II have one or two asymmetric carbon atoms, i.e., a carbon atom in the moiety -CH / OH / - and in case R and R are different, the carbon atom to which the two groups are attached. preparation of all enantiomers, diastereoisomers and mixtures thereof, including racemic mixtures. Compounds in which the carbon atom in the moiety -CH / OH / - is in the R configuration are preferred. In formula 2, the chain - (CH2 / m-) is e.g. - / CH2 / 5-, - / CHo / 2 -, - / CH0 / 5-, - / CHo / ^ - or - / CT ^ / y, and the string - / d ^ / ln means e.g. - / CH2 / 2-, - / Cl ^ /, -, - / Cl ^ / ^ -, - / CHo / e- or - / CH2 / g-. Preferably the number of carbon atoms in both chains - / CPU? - l ^ CHo / n "is 6-12, e.g. 7f 8, 9 or 10. Compounds in which the sum of mm is 7, 8 or 9 are particularly preferred. Compounds of general formula II in which m is 3 are preferred. in is 6 or m is 4 and n is 3, 4 or 5 »or m is 5 and n is 2, 3, 4 or 5f or m is 6 and n is 2 or 3. 1 2 R and R are e.g. a methyl group, ethyl, propyl or isopropyl, except that when one of R and R is propyl or isopropyl, the other is hydrogen or methyl. Thus, for example, R may represent a hydrogen atom, a methyl group, or a methyl group. Iowa, ethyl or propyl, for example, R is hydrogen and methyl. R and R are preferably hydrogen or methyl. A preferred group of compounds according to the invention are those compounds wherein R and R are hydrogen. Another group of preferred compounds is hydrogen and R is C. -C, alkyl, especially methyl. those in which R and R 2 represent methyl groups. The group of formula III in the compounds of general formula II is, for example, the group - (CH 2 O / CH 2 -, - / CH 2 O / CH 3 -) , - / CH ^ O / CH ^, - / CH ^ o / CH ^ -, - / CH / CH ^ / CT ^ / fi / Cl ^ / y, -CH / CH ^ / CH ^ O / O ^ / ^ -, - / CH / CH3 // CH2 / 50 / CH2 / 3-, - / CH / CH3 // CH2 / ^ / CH2 / Zf-, -C / CHy ^ / Ct ^ / ^ / CHo / o- or a moiety of the formula -CHR / CH2 / c-O / CH2 / 2, in which R is a methyl, ethyl or propyl group. Examples of substituents that may be present on the phenyl group marked with the symbol Ar are: bromine, iodine and in particular chlorine or fluorine, or a methyl, ethyl, methoxy or ethoxy group. In general, Ar, preferably represents an unsubstituted phenyl group. In compounds for another preferred reason, Ar represents a phenyl group substituted with one substituent, in particular a fluorine or chlorine atom, or also a methoxy or methyl group. Suitable physiologically acceptable salts of compounds of general formula II are addition salts with inorganic or organic acids, such as hydrochlorides, sulfates, phosphates, maleates, tartrates, citrates, benzoates, 4-methoxybenzoates, 2- or 4-hydroxybenzoates, 4-chlorobenzoates, p-toluenesulfonates, methanesulfonates, ascorbates, salicylates, acetates, fumarates, succinates, lactates , glutarates, gluconates, tricarballylates, hydroxy-naphthalene carboxylates, e.g. 1-hydroxy- or 3-hydroxy-2-naphthalene carboxylates or oleates. These compounds may also form salts with appropriate bases, e.g. alkali metal salts (such as sodium or potassium) and alkaline earth metals (such as calcium and magnesium). 141 883 3 A particularly important group of compounds that have shown a favorable long-term effect during tests, the state of These compounds are represented by formula II, in which R and R have the meanings given above, m is an integer of 3-6, n is an integer of 2-6, and Ar is a phenyl group or a phenyl group substituted with a methoxy group, or methyl, or more preferably fluorine, or chlorine, as well as their physiologically acceptable salts or solvates, wherein in each case the total number of carbon atoms in the chains - / cHa / - and * / CH ^ / n "is 7-10, especially 7 , 8 or 9-4O A preferred group of such compounds of formula II are those in which R and R are hydrogen. Another preferred group of compounds of formula II of this type are those in which R is hydrogen or methyl and R is methyl. Another group of compounds of formula II above are those in which R and R are atoms hydrogen and Ar represents a phenyl group or a phenyl group substituted with a methoxy group or, more preferably, with a fluorine or chlorine atom. A particularly preferred group of the above compounds of formula II are those compounds wherein R and R are hydrogen or methyl. m is the number 4 or 5, n is the number 2, 3 or 4, and Ar is a phenyl group or a phenyl group substituted with a chlorine or fluorine atom, or a methoxy or methyl group and their physiologically acceptable salts and solvates. Particularly important compounds are given below: 4 -hydroxy-oL (phe- (4-phenylbutoxy) hexylaminomethyl? 7-1? 3-benzenedimethanol and its physiologically acceptable salts, 4-hydroxy-ot (? - (3-phenylpropoxy) hexylaminomethyl? 7-1,3-benzenedimethanol and its physiol the organically acceptable salts, 4-hydroxy-6- (2-phenylethoxy) hexylaminomethyl 7-1,3-benzenedimethanol and its physiologically acceptable salts, 4-hydroxy-vol 5- (4-phenylbutoxy) pentylaminomethyl 7-1, 3-benzenedimethanol and its physiologically acceptable salts, 4-hydroxy-i-methyl-6- (2-phenylethoxy) hexylaminomethyl (-1,3-benzenedimethanol) and its physiologically acceptable salts, 4-hydroxyol) and -methyl-5- (3-phenylpropoxy) pentylaminomethyl-7-1,3-benzenedimethanol and its physiologically acceptable salts, 4-hydroxy-methyl-5- (4-phenylbutoxy) pentylaminomethyl-1,3-benzenedimethanol and its physiologically acceptable salts, 4-hydroxy-ok ^ 1-ethyl-6- (2-phenylethoxy) hexylaminomethyl q7-1,3-benzenedimethanol and its physiologically acceptable salts, cC- / i, 1-dimethyl-6- (2-phenylethoxy) hexylaminomethyl q7-4- hydroxy-1,3-benzenedimethanol and its physiologically acceptable salts, N - (6- (2- (4-fluorophenyl) ethoxy) -1-methylhexylaminomethyl-7-4-hydroxy-1,3-benzene dimethanol and its physiologically acceptable salts, 4-hydroxy-α-6- (3- (4-methoxyphenyl) -propoxB-7-1-methylhexylaminomethyl L -1,3-benzenedimethanol and its physiologically acceptable salts, 4-hydroxy-α) and -methyl-6- (4-phenylbutoxy) hexylaminomethyl / -1,3-benzenedimethanol and its physiologically acceptable salts, 4-hydroxy-methylphenyl / ethoxy-hexylaminomethyl | -1,3-benzenedimethanol and its physiologically acceptable salts, 3- (2- (3-chlorophenyl) ethoxy-7-hexylaminomethyl, J-4-hydroxy-1,3-benzenedimethanol and its physiologically acceptable salts, 4- hydroxy-d £ 6- / 2- / 4-methoxyphenyl / ethoxx7hexylaminomethylj -1,3-ben Benodimethanol and its physiologically acceptable salts, cL - £ 6- / 3- / 4-fluorophenyl / propoxy7hexylaminomethyl f -4-hydroxy-1,3 -benzene-di-methanol and its physiologically acceptable salts. 4 141 883 The preparation of the new phenylethanolamine derivatives is described in detail below. 1 2 The symbols mf nf Ar, R and R have the meanings given above, unless otherwise stated. The final step in the process may be to remove the protecting group. Suitable protecting groups and methods for their removal are described below. The inventive process for the preparation of the new phenylethanolamine derivatives of general formula II and their physiologically acceptable salts and solvates consists in reducing the optionally protected compound of general formula IV, wherein Ar is as defined above, R is a hydrogen atom or a protecting group such as an aralkyl or a tetrahydropyranyl group, at least one of X, X, T, x "and r is a reducing group and the remaining substituent or substituents are have the following meanings: X is a group of formula -CHPOR, wherein R5 is a hydrogen atom or a protecting group, such as an aralkyl or tetrahydropyranyl group, X is a group of formula -CH / oh / -, k is a group of formula -Ct4 NR, where R 5 represents a hydrogen atom or a protecting group such as an aralkyl or acyl group, X 5 represents a group of the formula -CR R / CH 8 / j, in which R, R 1 and m have the above-mentioned meaning, aa is a group of the formula "(CHp)" - in which n is as defined above, followed by removal of any protecting groups present and optionally converting the compound of formula II or its salt into its physiologically acceptable salt, or Solvate. Suitable reducible groups are those wherein X is -CO2R and wherein R is hydrogen or an alkyl, aryl or aralkyl group, or X is CHO, X is -C 0, X5 is a group of the formula -Cl, NY-, in which Y is a group which can be converted to a hydrogen atom by catalytic hydrogenation, for example, an arylmethyl group such as benzyl, benzhydryl or cC-methylbenzyl, or Yr is an imino group of the formula - CH = N- or a group of the formula -CONH-, X4 is a group of the formula -CO / Cl4 in which ra is as defined above or a group of the formula -CR RX in which X1 is a C1 -CU group alkenyl or C1 -Cyalkynyl or a -X5- is a group of the formula -CH8N-CR / C1-4) , ^! in which R and m are as defined above, X5 is a C1-C6 alkenyl or a C1-C6 alkynyl group. When the reduction process is conveniently carried out, R represents a group which can be converted into a hydrogen atom under the reducing conditions used, such as an arylmethyl group, e.g. benzyl, benzhydryl or 6-methylbenzyl. Reductions are carried out using reducing agents used to reduce acids. carboxylic acids, aldehydes, esters, ketones, imines, amides, ethylene derivatives, acetylene and protected amines. For example, when X in Formula 4 is a group of the formula -CO 3 R or -CHO, the group is reduced to a -CFUOH group with a hydride such as boroethane or a complex metal hydride such as lithium aluminum hydride. sodium bis (2-methoxyethoxy) aluminum hydride, sodium borohydride, diisobutylaluminum hydride or lithium triethyl boron hydride in a solvent such as an ether, for example tetrahydrofuran or ethyl ether, or a halogenated hydrocarbon, for example dichloromethane in 0 ° C to reflux temperature. When X in Formula 4 represents -C 0, the group can be reduced to -CH (OH) - by using hydrogen in the presence of a metal catalyst. Suitable reducing agents are hydrogen in the presence of a metal catalyst such as platinum, platinum oxide, palladium, Raney nickel or rhodium on a carrier such as carbon in the presence of an alcohol, e.g. ethanol or an ester, e.g. ethyl acetate or an ether, e.g. tetrahydrofuran or water used as a solvent or solvent mixture for the reaction. For example, mixtures of one or more ingredients can be used under normal or elevated temperature and pressure conditions, e.g. 20-100 C and 1013-10130 hFa. Optionally, the reducing agent can be, for example, a hydride such as a boroethane or a metal hydride such as lithium aluminum hydride, sodium bis (methoxyethoxy) aluminum hydride, sodium borohydride or aluminum hydride. The reactions are carried out in a solvent which is a suitable alcohol, for example methanol or ethanol, or an ether such as tetrahydrofuran, or a halogenated hydrocarbon such as dichloromethane.141 883 5 When a in formula 4 is CHgNY or -CH = N-, or if -3T-X ^ means a group of formula -O ^^ CR / -CH ^^^^ 9 then such groups are reduced to -CH2NH- or -CHgNHCHR / C ^ / m_a with the use of hydrogen in the presence of of a metal catalyst, as stated above. Optionally when X * or -) CX ^ is a group of formula -CH = N- or a group of formula -CHgNaCR / au / -1f, these groups are reduced to the system -Cl4NH- or CHgNHCHR / C ^ / ^ * using the same reducing agent and under the same conditions as given above for the reduction of X representing the group -C → O, When) r or Yr in formula 4 represent a group of formula -CONH- or -CO / CJ ^ / m * 9, these groups are reduced to -C1 ^ NH- or -GL ^ / c ^ / j ^ by using a hydride such as boroethane or a complex metal hydride such as hydride lithium aluminum or sodium bis (2-methoxyethoxy) aluminum hydride in a solvent such as Jalt ether, e.g. tetrahydrofuran or ethyl ether. • ZA p C When X in formula 4 represents a group of formula -CR RX, this group is reduced to the group -CR R / CH2A11-I using hydrogen in the presence of a catalyst, such as platinum or palladium on a support such as carbon, in a solvent such as an alkanol, e.g. ethanol or methanol, or an ester, e.g. ethyl acetate, or an ether, e.g. tetrahydrofuran, at normal or elevated temperature and pressure. When X is a C2-C8 alkenyl or a C1-C6 alkynyl group, the group is reduced to a ~ / ^ 2 ^ n ^ n ~ group by hydrogen and catalyst, as described above, In this case of the reduction process, the starting compounds of formula 4 are suitable, in which each of the groups CR R X5 and / or X * contains one bond ^ C- or -CaC- # If the unsaturation occur in both groupings, they can be the same or different. in which the group of the formula - (CHp) - is the group - (CHp / 5 "t) is prepared from the corresponding compound in which the group of the formula - / CH2 / m- is the group -CH-CH / / C ^ / lf -CsC / Cl ^ / * -, - / CHp / ^ CH-CHCF ^ "luD ~ t'CHg / '^^ CCtig-, a compound of formula 2, in which the group of formula - / CH ^ / n- is the group - / CJL, //, - or - / Ctu /, -, is prepared by reducing the corresponding compound of formula II, in which the group of formula - / CfrL '/ ^ - is the group -Cl ^ CH- CH-Cl2, -C2C2 CC2, -CHgCHgCH-CH-, -CH2Cn2C * C-9 -CHgCHaCH- or -CH2C »C-. In the above reduction processes, suitably the groups X and R in the compound of Formula 4 are including the group of formula 5 in which R 'and R are the same or different and represent a hydrogen atom or an alkyl or aryl group, Pd after the reduction is completed, these groups are cleaved using, for example, a dilute acid solution in a solvent such as water and at normal temperature to form the compound of formula II. When R, R or Fr is a protecting group, it can be any of the n This protecting group, e.g. as described in "Protective Groups in Organic Chemistryn, Ed, J, F, W, McOmie, Plenum Fress, 1973. Suitable protecting groups for hydroxyl are R and Rrf are aralkyl groups such as benzyl, diphenylmethyl or triphenylmethyl and tetrahydropyranyl. Suitable amino protecting groups, denoted by the symbol R, are aralkyl groups such as benzyl, o-methylbenzyl, diphenylmethyl, or triphenylmethyl, and acyl groups such as trichloroacetyl or trifluoroacetyl groups. to obtain compounds of the general formula II, for example, when R, R2 and / or Br represents an aralkyl group, I are cleaved by hydrogenolysis in the presence of a metal catalyst, e.g. palladium on carbon. When R and / or F? denotes a tetrahydropyranyl group, it can be cleaved by hydrolysis in an acidic environment, the acyl groups denoted as Br are removed by hydrolysis, e.g. with a base such as sodium hydroxide, and a group such as trichloroacetyl is removed by reduction using e.g. zinc and acid acetic acid. The compound of formula II obtained by the process of the invention may be in the form of a salt, conveniently a physiologically acceptable salt. Such salts can be converted into the corresponding free bases by known methods. Physiologically acceptable salts of compounds of formula 2 are prepared by reacting a compound of formula 2 with an appropriate acid or base in the presence of a suitable solvent such as acetonitrile, acetone, chloroform, ethyl acetate or alcohol, e.g. methanol, ethanol or isopropanol. Physiologically acceptable salts are also prepared from other salts, as well as from other physiologically acceptable salts of the compounds of formula II, by known methods. If it is desired to prepare a compound of formula II having one asymmetric carbon atom in the form of a specific enantiomer, the enantiomeric mixture of the corresponding compound of formula II is separated by conventional methods. For the preparation of the salt from the enantiomeric mixture of the compound of formula II, the appropriate optically active acid. The resulting mixture of isomeric salts is separated, for example by fractional crystallization, into diastereomeric salts from which the desired enantiomer of the compound of the general formula II is isolated, transforming it into a free base. The enantiomers of the compound of the general formula 2 having one asymmetric carbon atom, optionally can be prepared from the corresponding optically active intermediates by one of the general processes described above. If there are two asymmetric carbon atoms in a compound of formula II, its specific diastereoisomers or enantiomers are prepared from the corresponding asymmetric starting materials or the mixture is separated. of isomers by the above-described methods. In the following, suitable methods for the preparation of the starting compounds used are described below, and in the method according to the invention. The symbols Ar, m, n, R, R, Br9 R, Y, Z, X, X, XT, and X6 have the meanings given above, unless otherwise indicated. "Hal" means halogen. The desired protected hydroxy and / or amino intermediate compound is prepared using known methods for introducing protecting groups, e.g. as described by McOmie (see above). The starting materials of formula IV are prepared in a number of ways. For example, compounds of formula IV where X is -C * O are prepared from a halogen ketone of formula VI by reacting it with an amine of formula VII in wherein Y is hydrogen or a group convertible to hydrogen by catalytic hydrogenation. The reactions are carried out in a cold or hot solvent, e.g. tetrahydrofuran, methyl ether III. - n-butyl, dioxane, chloroform, dimethylformamide, acetonitrile or in a ketone such as butanone or methyl isobutyl ketone or in an ester such as ethyl acetate, preferably in the presence of a base such as diisopropylethylamine, sodium carbonate or other acid scavenger , e.g. propylene oxide. When the group of formula - / CHgj ^ mi / or "/ CH2 / n- present in the amine of formula 7 contains an unsaturation, this process can produce a compound of formula 4 in which X is -CR R X 5 and / or X represents a CU-Cr alkenyl group or a C8-C6 alkynyl group. Compounds of formula 4 where X is -C 10 are reduced to the corresponding intermediate where X is -CH / OH / - using e.g. a metal hydride such as sodium borohydride in a solvent e.g. ethanol The minoketones of formula 4, i.e. those compounds where k is -CH * N-, are prepared from a phenylglyoxal derivative of formula 8 by reacting it with an amine of formula 7t in which Y is hydrogen, in a solvent such as benzene, tetrahydrofuran or an alcohol, e.g. ethanol, in the temperature range up to reflux temperature. The phenylglyoxal derivatives of formula 8 are prepared from haloketones of formula 6 by treatment with a di-alkyl sulfoxide such as dimethyl sulfoxide. 141 883 7 Compounds of formula 4 where y? is a group of formula -CO / CHp / -, is prepared from an acylating amine of formula 9 using an ester or an active acid derivative of formula Ar (CHp) n / CH2 / mC00H. Suitable active derivatives are acid chloride, anhydride or imidazolide. The reactions are optionally performed in a solvent such as tetrahydrofuran, benzene or chloroform, and optionally in the presence of a base such as pyridine or triethylamine. If a coupler such as dicyclohexylcarbodiimide is added, the acid of formula Ar / c ^ / ^ / c ^ / ^ O ^ H can be used directly. Acids of formula Ar / CHg ^ O / o ^ / mCO ^ H are produced by for the alcohol of formula Ar (c6) o / CH2 / CP4OH with a suitable oxidizing agent, e.g. with pyridinium dichloromate in a solvent such as dimethylformamide. Compounds of formula IV in which -) TX - is a group of formula -C "N-CR / CL", - !, is prepared by the reaction of the amine of formula 9 in which R 2 is hydrogen, with a compound of the formula R CO (CTU) -O-Zc 2), Ar, in in a solvent such as acetonitrile Compounds of Formula 4 in which x is a group of Formula -CONH- are prepared by reacting an amine of Formula 7 with an acid of Formula 10 in the presence of a binder such as di-cyclohexylcarbodiimide. 7f wherein X is a group convertible to a hydrogen atom. * 12 P and R and R are hydrogen atoms, prepared by the reaction of a compound of formula I ^ R / CH / CH2 / - o / CH2 / nArt wherein L is a leaving group such as bromo or methanesulfonyloxy, and R is hydrogen, with an amine of formula YNH2. The reactions are carried out in the absence of a solvent or in a solvent such as a ketone, e.g. butanone or methyl isobutyl ketone, an ether, e.g. tetrahydrofuran, or a substituted amide, e.g. dimethylformamide, optionally in the presence of a base such as sodium carbonate or an organic amine, e.g. triethylamine or N, N-diisopropylethylamine, at a temperature from 0 ° C to the reflux temperature. If necessary, then reacted with hydrogen in the presence of a metal catalyst such as platinum in a solvent such as an alcohol, e.g. ethanol, to give a compound of the formula 7% wherein Y is hydrogen. Alternatively, amines of formula 7% in which 1 1 R is hydrogen are prepared by reductive alkylation of an amine of formula Y NHL in which Y is a group convertible to hydrogen using a compound of formula R CO / CF ^^ - O "," Ar, followed by the conversion of the Y group to a hydrogen atom as given above. The reactions are carried out with hydrogen, without solvent or in the presence of a solvent such as an alcohol, e.g. ethanol, using a metal catalyst such as such as platinum or palladium, or with a complex metal hydride such as sodium borohydride or sodium cyanoborohydride, in an alcohol, for example ethanol. Amines of Formula 7 in which R and R are both alkyl groups, The acid is converted from the acid of formula 11. The acid is converted, via its chloride or azide, in the Curtius reaction to the amine of formula 7, wherein X is hydrogen. During this reaction, thermal rearrangement of the azide to isocyanate occurs, which in turn is subjected to Aug hydrolysis by treatment with an inorganic base, e.g. aqueous sodium hydroxide solution, optionally in a solvent such as ethanol. 1 2 The acids of formula 11 are prepared by alkylating the acids of formula CHR R CO 2 H, via their derivatives, with an alkylating agent of formula Ar (CH 2 / nO 1 CH 2 / mHal) in a solvent such as an ether, e.g. tetrahydrofuran, at a low temperature from 0 ° C to room temperature. 1 2 Compounds of formula 9, 10, 11 and CHR R CO 2 H are either known compounds or are prepared by methods analogous to the methods of preparation of known compounds. Alcohols of formula Ar / CH2 / no / CH2 / mCH2OH are prepared from compounds of formula LR / CH2 / m0- - / CH2 / Ar, nP # by treatment with sodium acetate and then hydrolyzing the product, e.g. with sodium hydroxide. 8 141 883 Compounds of formula LR ICt ^ / ra0ICH2 / nAr are prepared by reaction of an alcohol of formula Ar / ctu / OH with a disubstituted alkane of formula LCt ^ / CF ^ / L, where L is as L, where L and L may be the same or different, optionally in the presence of a solvent like tetrahydrofuran or dimethylformamide, in up to boiling point. The reactions are carried out by first producing the alcohol anion of the formula Ar / CH2 / nOH by addition of e.g. sodium hydride or a strong base such as sodium hydroxide and an interfacial transfer catalyst e.g. tetrabutylammonium sulfate. Optionally, an addition of a solvent such as dichloromethane or tetrahydrofuran may be used. The reactions are carried out at room temperature or elevated temperature. The compounds of the formulas Ar / CH2 / nOH and LCt ^ / C ^^ L are either known compounds or can be prepared by methods analogous to the preparation of known compounds. Aldehydes of formula R CO / CR? (J) / CR '/ n & rfk "&lt; 0 &gt; R is a hydrogen atom, prepared by oxidizing an alcohol of formula Ar / Cl - (nO1CH2 /' Ct ^ OH) with an oxidizing agent such as chlorochromate in a solvent such as halogenated a hydrocarbon, e.g. dichloromethane. Ketones of the formula RCO / CH2 / fJOI'CH2 / "" Ar, where R is an alkyl group, are prepared by the reaction of a halogen derivative Grignard complex of the formula Ar / CHO / y, o / CHo / fllHal, with a C1-4alkyl halide of the formula RCOC1 or an anhydride of the formula (RCO2) in a solvent such as an ether, e.g. diethyl ether or tetrahydrofuran. Halides of the formula Ar (CH2) O (Cl4) Hal are prepared by an alkylation of an alcohol of formula Ar / CH2 / nOH with a disubstituted alkane of formula iyCHp / Hal as described above. Ar / CH2 / n0 / CH2 / mHal and / Cl2 / mHal aa either with known compounds, or they can be obtained by methods analogous to the method for producing known compounds. The compounds according to the invention show a selective stimulating effect on adrenergic receptors / 32 and, moreover, they have a favorable type of action. The stimulant effect is shown on the example of a guinea pig. In the course of the studies, it was found that the compounds according to the invention inhibit contractions of the isolated trachea caused by the action of PGF2 eC. Other studies have shown that, when administered by inhalation or orally, the compounds according to the invention inhibit the bronchoconstriction induced by the action of histamine in conscious pigs. marine. In both trials, these compounds showed an exceptionally long duration of activity. The selectivity of the action of the compounds according to the invention has been demonstrated in tests carried out on rats and guinea pigs. At the concentrations used, in the order that inhibit contractions of the isolated trachea caused by PGFpOC, these compounds had little or no effect on the isolated left atrium of a rat or a guinea pig (tissue containing adrenergic receptors (hp). " that the compounds of the invention inhibit the anaphylactic release of spasmodic factors and inflammatory factors from sensitized human tissues, e.g., lung specimens. The compounds of the invention are used in the treatment of diseases associated with reversible airway obstruction such as asthma and chronic bronchitis. The compounds according to the invention are further useful in the treatment of pre-term labor, depression and cardiovascular and right ventricular failure, as well as in the treatment of inflammatory and allergic skin diseases, psoriasis, progressive skin diseases, glaucoma and in the treatment of diseases in which k it is beneficial to lower acidity, especially in ulcerative diseases of the gastrointestinal tract and the digestive system. The stimulant effect of the compounds of the invention on the adrenergic receptors (} 0 was determined by examining the prepared sections of the guinea pig trachea. The thoracic sections of the trachea placed in a superfusion apparatus and a continuous flow of oxygenated Kreba saline containing indomethacin (2.4 x 10 "m) and atropine (4 x 10 m) at 37 ° C with a flow rate of 2 ml / min. Changes in tension in the sections were measured with an isometric strain gauge. x 10 m) to the superfusion fluid At the beginning of each trial, 2 dose-effect curves were determined for the isoprenaline used as a standard (1 x 10 -1 x 10 m), while in each case J was waited for the maximum relaxation before the next By increasing the dose, the tissue was allowed to receive this dose-effect curve for a sufficient period of time. until return to the initial state (15-30 min.). After this time, the concentration-effect curves were determined, first for isoprenaline, and then for the test compound. This was done in the following way: the compound was administered at a low concentration (isoprene 3 × 10 m × -1 test compound 1 × 10 m) until maximum response was achieved, infusions were then stopped and the tissue allowed to recover in a maximum of 30 min. After this time period, the above steps were repeated with gradually increasing concentrations of the agonist, thus obtaining complete concentration effect-effect curves. The power was determined by comparing the concentration effect curve thus obtained with the curve obtained previously for isoprenaline. Potency was expressed as the ratio of the concentrations producing the same effect (assuming the value determined for isoprenaline as 1), so the ratio (EC ^ test compound) / (EC5Q isoprenaline) was calculated. For each reaction, the duration of action was also measured, defined as the time period since stopping infusion until 50% of the previous state. Relationships between the magnitude of the response and the duration of the drug's action were plotted, and the time periods during which 50% of the maximum response was obtained were determined. In the test described above, the relationships of examples XXVII, XXXVII and XXXVIII showed a power of 2.7, 2.8 and 2.4, respectively isoprenaline. The table below shows the results of a comparative study with the compounds salbutamol and salmefamol known from British Patent Specification No. 1,200,886. These are compounds of formula 1, where X | represents the group -CH 2 OH, R 1 and 1 ^ are hydrogen and FU is -G (CE,) for salbutamol or -CH / CH CH / Ch /BiOCH * for salmefamol, R 1 being 1,4-phenylene. The new compound of Example XXVII has a similar structure. It differs from these known compounds by the R i moiety which is - (CJ ^ / g10 ^ / 4R1, wherein Ri is phenyl. The table shows that all 3 compounds are similar in potency to isoprenaline, but the compound of example XXVII has a longer duration of action and is therefore more favorable. T a b i Test compound j j Compound of example | and XXVII and 1 L j. J Salbutamol J and Salmefamol | e 1 a Mdc 2.7 2.0 2.7! Duration of action i (minutes) 30 3.7 7.3 I The ability of the compounds according to the invention to protect against histamine-induced bronchospasm was investigated on the example of conscious guinea pigs. The basic method is the observation that bronchospasm leads to a reduction in the volume of inhaled air, and therefore an increase in the rate of breathing. The guinea pigs were placed in a whole-body plethysmograph, that is, in a chamber divided by a collar into 2 parts - the first chamber containing the head and the second chamber containing the rest of the body, and the pressure aiances in the second chamber were tracked with a low transducer. - pressure, from which a continuous, linear record of the respiratory rate was obtained using a meter connected to the recording system. The first chamber was connected to a expansion chamber into which an aerosol containing histamine was injected from a fixed concentration solution (typically 10-1483 mg / L) for a predetermined period of time (typically 10-15 seconds). R) d the end of this period of time the aerosol flow was turned off, but the guinea pig was left in the chamber in an atmosphere containing the atomized histamine until its respiratory rate had increased by * C% or for 4 minutes, whichever period was time passed earlier * The intensity of bronchial contraction was expressed as the areas under the respiration rate curve. Histamine was given to guinea pigs periodically until their respiration rate was established, then they were dosed with the test compound in the form of an aerosol or orally, and the histamine-induced response was re-tested, first 30 minutes after test compound administration, and then periodically until 24 hours after administration of the test compound. The studies used a series of doses of the test compound and determined the dose at which maximum protection was achieved and the time (dc 24 hours) necessary for the histamine-induced response to return to the level established prior to administration of the test compound. Each dose of the test compound was administered to at least four animals. The present invention produces compounds of the general formula II and their physiologically acceptable salts and solvates, useful in the treatment and prevention of diseases associated with reversible respiratory obstruction in humans and animals. These compounds may be formulated as pharmaceuticals for use in the treatment and prevention of diseases associated with reversible airway obstruction in humans and animals. The compounds according to the invention may be formulated to be administered in any convenient manner, the pharmaceutical compositions containing at least one compound of the formula II or a salt or solvate thereof in a form suitable for use in medicine and veterinary medicine. Such agents may be prepared with the use of physiologically acceptable carriers and embellishments and possibly other auxiliary agents. These compounds may be formulated as agents suitable for administration by inhalation or insufflation, or for oral, oral, parenteral, topical (e.g. nasal) administration, or rectal. Preferably, the compounds are administered by inhalation or insufflation. When administered by inhalation, the compounds of the invention are conveniently administered as an aerosol in pressurized containers in the presence of a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrifluoromethane or other dioxide, a suitable gas, or placed in a nebulizer. Pressurized aerosol canisters may be equipped with a valve that facilitates the dosing of a specific amount of the drug. The compounds of the invention may be administered by inhalation or blowing in the form of a dry powder, e.g. a mixture of a powdered compound and a suitable base. such as lactose or starch. Powders can be prepared in the form of unit doses in capsules or tablets, e.g. gelatine ones, or in packages from which the powder is dosed with an inhaler or blowing device. For oral administration, pharmaceuticals in the form of tablets, capsules, powders, solutions, syrups are used. or suspensions prepared by known methods, with the addition of acceptable excipients. For oral administration, tablets, drops or lozenges formed by known methods are used. The compounds according to the invention may be formulated as parenteral administration. Unit doses for injection are prepared in the form of ampoules or multi-dose containers and a preservative, these may take the form of suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain auxiliary agents such as suspending, stabilizing and / or dispersing agents. . Alternatively, the active ingredient may be in the form of a powder, prepared for administration with the addition of a suitable carrier, for example, sterile water, just before use. 141 883 11 For topical administration, pharmaceutical agents are used in the form of ointments, lotions or creams prepared in a known manner, with the addition of e.g. , an aqueous or oily base, usually with the addition of suitable thickeners and / or solvents. The compositions for nasal administration are prepared in the form of a spray, which may be, for example, a solution or suspension in water, or in the form of an aerosol with a suitable propellant. For rectal administration, suppositories or enemas9 containing known ingredients such as cocoa butter or other glycerides. The above-mentioned pharmaceuticals for oral, oral, rectal or topical administration can be formulated in a known manner which permits the controlled release of the active ingredient. The daily dose of the active ingredient for human treatment is 0.0005-100 mg. conveniently administered as a single dose or as two doses. The exact dose depends, of course, on the age and condition of the patient and on the route of administration of the drug. Thus, for administration by inhalation, a suitable dose is 0.0005-10 mg, for oral administration 0.02-100 mg and for parenteral administration 0.001-2 mg. are illustrated by the following examples, with examples 1-25 dealing with the preparation of starting materials. Thin layer chromatography (T, 1, c) was performed on SiO 2 and the solutions were dried over magnesium sulfate, unless otherwise stated. Abbreviations used: DMF - dimethylformamide, THF - tetrahydrofuran, EA - ethyl acetate, ER - ethyl ether, CX - cyclohexane, HX - hexane, BR - brine; flash column chromatography (fcs) on silica gel, on silica gel deactivated triethylamine - (FCTE7, T, 1, c, EN - thin layer chromatography on deactivated silica triethylamine, chromatography eluents: ZV - CX-BR / 19: 1 /, / ~ C7- BR-CX-triethylamine / 60: 4o /, / q7 - CX-ER / 1: 4 /, / e7- CX-ER / 4: 1 /, Zq7- ER A7 - CX-ER (3: 1), M-EA-CH3OH-NH3 (9: 1: 0.1) (n7-EA-CH2OH) 9: 1). Example I, (4- (6-Bromohexyloxy) butylbenzene, NaH in oil dispersed form (46%, 6.5 g) was added portionwise to a solution of 4-phenylbutanol (15.0 g) and 1,6-bromohexane (48.8 g) in THF (200 ml) under an atmosphere of The resulting suspension was heated to reflux for 27 hours and treated with H 2 O (80 ml). The mixture was extracted with ER (2 x 200 ml), the extracts dried and evaporated to give an orange oil. The oil was purified on a column packed with nitrogen. silica (800 ml) ZV to give a yellow oil, from which the title compound was obtained by distillation in the a colorless oil (15f0 g) with a boiling point of 90-95 ° C - 13.3 Ra. Example II, 6- (4-Phenylbutoxy / hexanol-1), A mixture of the compound of example I (10 g), sodium acetate trihydrate (34 8 g) H 2 O (25 ml) and trioctylpropyl ammonium chloride (2 g) were stirred vigorously while heating on a steam bath for 2.5 hours. The mixture was cooled, 2M NaOH solution (50 ml) and ethanol (50 ml) were added and the mixture was stirred at reflux for 30 minutes. The mixture was diluted with BR (200 ml) and extracted with ER. The organic phase was washed with water (200 ml), the BR (200 ml) and dried and evaporated under reduced pressure to give the title alcohol as a yellow oil (7.16 g). , l, c. f (jf with Rf "0.73" Example III, NZ "6- (4-Phenylbutoxy) hexyl-7-benzenemethanamine, A solution of benzylamine (16.64 g) and the compound of example I (11.27 g) in THP (45 ml) was kept at room temperature for 4 days, diluted with ER (450 ml) and filtered, Erzesacz was evaporated to obtain a colorless oil, from which, after purification by the fFSc ("g7) method, the title compound (9.94 g) was obtained as a colorless oil. Analysis results: found: C 81.60 H 10.1 N 4.42; calculated for C 21 H 26 NO: C 81.35 H 9.80 N 4.15 #. Example IV, 1- / 4-Hydroxy- 3- (Hydroxymethyl) phenyl7-2- {(6- (4-phenylbutoxy) -hexyl) (phenylmethyl) aminoJ ethanone. 2-bromo-1- (2f-hydroxy-3- (hydroxymethyl) -phenyl) -ethanone solution ( 1 g) of the compound of example III (1.4 g) and N, N-diisopropylethylamine (0.8 g) in THF12 141 883 (10 ml) was kept at 23 ° C for 3 days. Then the mixture was diluted with ER ( 60 ml), washed with 6% NaHCO 3 solution (50 ml) and BR (50 ml), dried and evaporated under reduced pressure to give Oil. After purification by ZfSC / (40 g) Ctil, the title compound was obtained as a viscous yellow oil (1.68 g). T.l.c. (b7: Rf> 0.42, Example V. 2-Bromo-1- (2,2-dimethyl-1,3-benzodioxane-6-yl) -ethanone. To a solution of 2-bromo-1-A-hydroxy-3- (hydroxymethyl / phenyl-ethanone) (5 g) and toluene-sulfonic acid (0.5 g) in CH2 & 2 (10 ° C) t kept at 23 ° C, 2-methoxypropane (10 g) was added with stirring over 15 minutes. The mixture was stirred for 3 hours, filtered through a pad of deactivated triethylamine and evaporated to give an oil, ZFCT-purified (300 g). the title compound was obtained as an oil (4.8 g) which solidified on cooling. A small sample was recrystallized from a light fraction of crude oil (boiling point 60-8D ° C) to obtain white crystals with a melting point of 47-48 ° C. Example VI. 1- (2,2-Dimethyl-1,3-benzodioxan-6-yl) (2-f (6-) (4-phenylbutoxy) hexyl (phenylmethyl) amino (ethanone). A solution of the compound of example V (1t6 g), the compound of example III (2.1 g) and N, N-diisopropylethylamine (1.2 g) in THF (15 ml) was kept at 23 ° C for 2 days. . The mixture was diluted with EA (80 ml), washed with 8% NaHCO * solution (50 ml) and BR (50 ml), dried (Na2SO4) and evaporated under reduced pressure to give a yellow oil. After purification by method / fSc7 (150 g) / e7, the title compound was obtained as a pale yellow oil (2.2 g). T.l.c. [Hx Rf - 0.27. Example VII * 6- (4-phenylbutoxy) caproic acid. A mixture of Example II (4 g) and pyridinium dichloromate (21.04 g) in DMF (50 ml) was stirred at room temperature for 15 hours, diluted with water (300 ml) and extracted with ER (2 x 100 ml). The extract was washed with water (2 x 250 ml), dried, filtered through a bed of silica and evaporated under reduced pressure to give a colorless oil. Purification method / FSC7 (80 g) Ze7 gave the title compound as a colorless oil (0.85 g), T.l.c. / fe7: Rf «0.27. Example VIII. N- (2-Hydroxy-2- (4-hydroxy-3- (hydroxymethyl) phenyl-7-ethyl-7- ~ 1- (4-phenylbutoxy) caproic acid amide. EMF (0.003 ml) and thionyl chloride (0.51 ml) were added to a solution of the compound of example VII (0.89 g) in anhydrous CH 2 O 4 (17 ml). The solution thus obtained was stirred at room temperature for 2.5 hours and evaporated to dryness to give the acid chloride. • E-Aminomethyl-4-hydroxy-1,3-benzenedimethanol (0.934 g) in THF was treated with trimethylsilyl / ethyl acetate (3.57 ml). To the thus prepared suspension, tetrabutylammonium fluoride (0.9 ml) was added dropwise while stirring at 0 C. The resulting solution was stirred at reflux for 2 hours, then added to the above acid chloride solution in fflF (10 ml) under a nitrogen atmosphere. Then triethylamine (3.4 ml) was added and the mixture was stirred at reflux for 4 hours, allowed to stand overnight, added to 2N hydrochloric acid (30 ml) and stirred for 15 minutes. The product was extracted into EA (3 x 25 mL), the extracts washed with water (25 mL), 8% NaHCO solution, (25 mL), and BR (25 mL). Dried over Na2SO4. the organic layer was evaporated to dryness to give a brown oil. The oil was chromatographed on silica (Merck 7754, 40 g) / U7 to give a yellow oil. On drying, the oil solidified to give the title amide as a white solid (1.06 g), m.p. 96-97.5 ° C Example IX 6- (4-Phenylbutoxy) hexanamine. The compound of Example III (25 g) in anhydrous ethanol (250 ml) was hydrogenated with palladium on carbon (1 g) and platinum on carbon (1 g) as a catalyst. The reaction mixture was filtered through a Hyflo pad and evaporated under reduced pressure to give the title amine as a colorless oil (16.49 g). T.l.c. EN (CH30H): Rf = 0.3. Example X. Methyl 2-Hydroxy-5- (6- (4-phenylbutoxy) hexyliminoacetylbenzoate. A solution of the compound of Example IX (0.49 g) in methanol (5 ml) was added over 15 minutes to a stirred suspension of methyl 5- (dihydroxyacetyl) -2-hydroxybenzoate in methanol (10 ml) at 23 ° C. The whole was stirred for 10 minutes, evaporated in vacuo and the residue was purified by method (FCT $ 7 (40 g) / g7 to give the title imine as a dark orange oil (0.06 g). This imine is unstable and should be used immediately upon receipt, T.l.c. EN / * G7: Rf = 0.37 Example XI. A- 2-Propynyloxy / butylbenzene. A mixture of propargyl alcohol (10.0 g), A-bromobutyl / benzene (38.0 g), aq. NaOH (80 ml, 50 # w / v) and tetrabutylammonium bisulfate (1.0 g) was stirred vigorously for 3 days, water (100 ml) was added and extracted with ER (2 x 200 ml). The dried extracts were evaporated and the residue was purified on a silica-packed column (Merck 9385, 500 ml) f ^ J9 to give the title compound as a colorless oil (18.3 g). T.l.c. / a7: Rf = 0.2. Example XII. N- (6-Chloro-2-hexyloxy) butyl-7-benzene. The compound of Example 11 (15.0 g) was added dropwise to a suspension of lithium amide obtained from lithium (0.61 g) in liquid ammonia (50 ml) at -33 ° C. The mixture was stirred for 2 hours and bromochloropropane was added dropwise. (13.9 g) in the ER (10 ml). The suspension thus obtained was stirred at -33 ° C for 3 hours and the ammonia was allowed to evaporate overnight. Water (30 ml) was carefully quenched and extracted with ER (3 x 50 ml). The extract was dried and evaporated and the residue distilled to give the title compound as a colorless oil (12.9 g), bp 140-150 ° C 40 ftu T.l.c. fpj: Rfs 0.2. Example XIII. N- (6-Iodo-2-hexynyl) butyl) benzene. A mixture of Example 12 (12.0 g), sodium iodide (20.0 g) and butanone (30 ml) was refluxed for 6 hours and stirred at room temperature for 2 days, filtered and evaporated. Reliability was dissolved in the ER (50 ml) and washed with water (50 ml) followed by aqueous sodium thiosulfate solution (50 ml). The organic phase was dried and evaporated to give the title compound as a pale yellow oil (12.6 g). Example XIV. 4-Hydroxy - <** - (6-A-phenylbutoxy) -4-hexynyl-aminomethyl-7- -1,3-benzenedimethanol. To a solution of cL aminomethyl-4-hydroxy-1,3-benzenedimethanol (6.7 g) and IJ, N-diisopropylethylamine (3.9 g) in DMT (250 ml) was added dropwise at 7D ° C the compound of example XIII (8 , 66 g). It was heated at 70 ° C for 2 hours and the EMF was removed under reduced pressure. The residue was taken up in aqueous NaHCO solution (1 m, 200 ml) and extracted with EA (3 x 250 ml). The extract was dried and evaporated and the residue was purified on a silica column (Merck 9385, 250 ml) to give a yellow oil. On grinding this oil with the ER, the title compound was obtained in the form of a white solid (4.3 g), mp 89-90 ° C. T.l.c. fWi Rf = 0.2. Example XV. Methyl 2-Hydroxy-5- [(phenylmethyl) - "6- (3-phenylpropoxy) hexylarinoacetyl} -benzoate. A solution of N, N-diisopropylethylamine (9.93 g) in CH 2 O 3 (15 ml) was added to the solution of 5 methyl-bromoacetyl-2-hydroxybenzoate (10 g) and N- (6- (3-phenylpropoxy) hexylbenzenemethanamine borohydride (14.87 g) in CHpCl® (256 ml) at 16 ° C. The solution was stirred under nitrogen while 23 hours at 20 ° C, washed with water (5 x 100 ml), dried and filtered The solution of the title compound thus obtained was used without further purification Tlcc / ER /: Rf = 0.7. dimethyl-7- (2-phenylethoxy) enanthic To a solution of diisopropylamine (27.5 g) in THF (4D ml) was added dropwise at -78 ° C and under a nitrogen atmosphere n-butyllithium in HX (1.6 m, 172 ml) It was warmed to 0 ° C., stirred for 45 minutes, then isobutyric acid (12.0 g) was added dropwise. The resulting suspension was stirred at room temperature for 4 hours, then 2- (75-bromopentyloxy) was added dropwise. ethyl / b enzen (25.0 g). The mixture was stirred at reflux for 16 hours, carefully quenched with hydrochloric acid (2m, 350 ml) and extracted with ER (2 x 250 ml). The extract was dried and evaporated and the residue was purified on a silica packed column (Merck 9385, 300 ml) / W to give the title compound as a colorless oil (17.0 g). T.l.c. [1], Rf, 0.35.14 141 883 Example XVII, 1,1-Dimethyl-6- (2-phenylethoxy) -hexylcarbamic acid phenylmethyl ester. To a solution of the compound of example XVI (8.0 g) and triethylamine (3.03 g) in acetone (100 ml) and water (100 ml) was added at 0 ° C ethyl chloroformate (3.26 g) in acetone (10 ml). The mixture was stirred for 40 minutes at 0 ° C, then sodium azide (2.25 g) in water (25 ml) was added dropwise. The suspension thus formed was stirred while warming at room temperature for 30 minutes, diluted with water (200 ml) and extracted with toluene (2 x 200 ml). The extracts were dried over Na 2 CO 2, evaporated to half the volume, heated at 70-80 ° C. for 2 hours and the toluene was removed under reduced pressure. The resulting isocyanate was heated in benzyl alcohol (20 ml) at 80-83 ° C. for 60 hours and then the benzyl alcohol was heated under reduced pressure (13.3 bar). The residue was purified on a silica packed column (Merck 9385, 300 ml), eluting with CX-ER (17: 3) to give the title compound as a colorless oil (7.45 g). T.l.c. [1] and Rf = 0.25 * Example XVIII. 1,1-Dimethyl-6- (2-phenylethoxy) hexylamine. A solution of the compound of Example XVII (6.8 g) in ethanol (100 ml) was hydrogenated over 1096 palladium on carbon (0.5 g) for 40 minutes, filtered and evaporated to give the title compound as a colorless oil (4.3 g) «Example XIX. Methyl 5- (2-dimethylamine-1-hydroxyethyl) -2- (phenylmethoxy) benzoate. To a suspension of methyl 5- (bromoacetyl) -2- (phenylmethoxy) benzoate (105.8 g) in absolute ethanol (11) and THF (11) was added dimethylamine (3396 solution in ethanol, 156 ml) while stirring. ). The resulting solution was stirred while warming at room temperature for 2 hours, quenched with NaBH 3 (25 g) and stirred at room temperature overnight. The solvent was removed under reduced pressure and water (500 mL) was added to the residue. The mixture was extracted with EA (2 x 500 ml), the combined extracts were washed with water and BR, dried over Na 2 SO 4, and concentrated under reduced pressure. The product was purified twice by method (FSC) using EA-methanol-triethylamine (80: 20: 1) to give the title compound as a beige solid (59.8 g), m.p. 79-81 ° C. Example XX. Methyl 5- (2-dimethylamine-1-hydroxyethyl) -2- (phenylmethoxy) benzoate salt with (S- (R *, rV) -2,3-bis (4-methylbenzoyloxy7succinic acid) salt (1: 1). The compound of example XIX (50 g) in hot methanol (250 ml) was mixed with / - / - di-p-tolyltartaric acid monohydrate (60 g) in hot methanol (250 ml). The precipitate was filtered off and recrystallized three times from methanol (25 ml / g) to give the title compound in the form of white needles (16.4 g), m.p. 169-170 ° C, /? 7? 8.2 = -103. 3P (c * 0.51 in CH2OH). Example XXI. (R) -5- (2- (dimethylamine) -1-hydroxyethyl-7-2- (phenylmethoxy) - methyl benzoate. Example XX (16.4 g) was partitioned between EA (175 ml) and 6N ammonium hydroxide solution (8.4 ml) in water (175 ml). The organic layer was washed with 8% NaHCO, (2 x 100 mL), BR, dried over NH 2 SO 4, and concentrated under reduced pressure to give the title compound as a viscous oil (7.9 g). T.l.c. / EA-tphthal-triethylamine (80: 20: 1): Rf = 0.23. Example XXII. Iodide (n -fi-hydroxy-3- (methoxycarbonyl) -N, N, N-trimethyl-4- (phenylmethoxy) benzoethyl ammonium iodide. The compound of Example XXI (7.85 g) and methyl iodide (17.5 ml) in acetone (55 ml) were stirred under reflux for 3 hours under a nitrogen atmosphere. Acetone was removed under reduced pressure and CHd was added to the residue ( 100 ml). The resulting precipitate was filtered off and dried under reduced pressure (12.2 g). Failure to recrystallize from methanol gave the title compound as an off-white solid (4.5 g), mp 85-120 ° C. Z "<7 ° C, 2-32.2 ° (c-9.7 in DMSC). Example XXIII. (R) -5-1.2-epoxyethyl-2- (phenylmethoxy) benzoate. Warm mixture of the compound of the example XXII in dry acetonitrile (200 ml) was treated with tetramethylammonium fluoride solvated with two particles of methanol (5.5 g) and stirred under reflux, removing the distillate continuously for 2.5 hours. The reaction nine was filtered and the filtrate was concentrated under reduced pressure to a semi-solid form. Anhydrous ER (100 ml) was added and all filtered again. The filtrate was concentrated to an oil which was purified by the / FCS7 method using a mixture of CX-EA-Trigthylamine 80: 20: 1. to give the title compound in the form of a colorless oil (1.98 g) .0.0 ° C + 19.9 ° (c 0.86 in benzene) T.I.c. / CX-EA-triethylamine 80:20 : 1 /: Rf = 0.14. Cycle ad XXIV. / R / -5- E 1-Arroxy-2 / phenylmethyl // "6- (3-phenylpropoxy) -hexylamino-7ethyl J-2- (phenylmethoxy) methyl benzoate. The compound of Example XXIII (1.9 g) and N- (6- (3-phenylpropoxy) hexyl-benzenemethanamine hydrobromide free base (2.17 g) in methanol (50 ml) were stirred under reflux under nitrogen atmosphere. within 6 hours. The solvent was removed under reduced pressure and the residual oil was purified by the (FSC) method using CX-EA-triethylamine as eluent (75: 25: 1) to give the title compound as a pale yellow oil (2.1 g). J ^ 7 ^ 6 = -62.4 [deg.] (0 * 0.74). T.l.c. (cX-EA-triethyl amine 80: 20: 1): Rf = 0.12. Example XXV. (R) - (-) - 4- (Phenylmethoxy) - &lt; * 1-N {(phenylmethyl) (6- (3-phenylpropoxy) hexylaminomethyl 7 J -1,3-benzenedimethanol. To a suspension of LiAlH ^ (300 mg) in anhydrous THF (40 ml) was added the compound of Example XXIV (2.0 g) in anhydrous THF (40 ml) while stirring at room temperature under nitrogen. The reaction mixture was placed in an oily bath, heated to 80 ° C and stirred under reflux for 5 minutes. To cool down, the mixture was carefully quenched with water (40 ml) and ER (40 ml). The phases were separated and the aqueous phase was re-extracted with ER (50 ml). The combined organic layers were washed with water and BR, dried over Na 2 SO 4 and concentrated under reduced pressure. Purification by method (FSO) using a mixture of CX-EA-triethylamine (66: 33: 1) as eluent gave the title compound as a clear, colorless oil (1.70 g). (° 7) 64.6 ° (c-0.6) in CHCl 3). T.l.c. (cX-EA-triethylamine 66: 33: 1): Rf- 0.15. Example XXVI. 1-Hydroxy-oC {(6- (4-phenylbutoxy) hexyl) (phenylmethyl) aminomethyl -1,3-benzenedimethanol. A solution of the compound of Example III (51 g) and 4-bromoacetyl-2- (hydroxymethyl) phenol diacetate (obtained from 36.25 g of 4-acetyl-2 (hydroxymethyl) -phenol diacetate 7 in CHCCL (410 ml) was stirred under the reflux condenser for 24 hours, cooled, and concentrated under reduced pressure. The solid oil was dissolved in toluene (75 ml) and concentrated. The oil was dissolved in toluene (125 ml), washed with water (150 ml) and BR (50 ml). The aqueous solutions were extracted with toluene (30 ml) and the combined extracts washed with water (50 ml) and concentrated. The crude ketoamine diacetate was stirred in ethanol (155 ml) and 10N hydrochloric acid (48 ml) in water (58 ml) was added dropwise with stirring keeping the temperature below 20 ° C. The solution was allowed to stand at 0 ° C for two days and then treated with ethanol (180 ml) and NaOH (17.6 g) in water (18 ml), while keeping the temperature below 15 ° C. NaBH * (11.06 g) and NaOH (2.11 g) in water were added, and after 24 hours additional NaB% (9.5 g) was added over 48 hours. The mixture was neutralized with 2N sulfuric acid and concentrated to a paste which was partitioned with 2N Na 2 CO, (100 mL) and EA (200 mL). The organic layer was treated sequentially with 2N NapCO 3 (100 ml) and EA (200 ml). The faded organic extracts were washed, dried and evaporated. The crude triol was chromatographed on Sorbsil (700 g) / q7 to give the title compound (26.5 g), identified by NMR spectrum. Example XXVII. 4-Hydrokay-O ^ - (6- (4-phenylbutoxy) hexylaminomethyl-7-1,3-benzene dimethanol. A solution of the compound of example IV (0.4 g) in absolute ethanol (25 ml) was hydrogenated at 23 ° C and atmospheric pressure with 10% palladium on carbon (0.2 g) as a catalyst and 1096 platinum on carbon (0 2 g). The mixture was filtered through a Hyflo pad and evaporated to give an oil. After purification by method / FCT§7 (20 g) [\ Q, an oil was obtained, from which, after trituration with the ER, the title compound was obtained in the form of a white solid (0.21 g), mp 76.5-77.5 ° C. T.l.c. EN ftjj: Rf = 0.31. Example XXVIII. 2,2-Dimethyl-^ - (6- (4-phenylbutoxy) hexylaminomethyl Q7-4H- -1,3-benzenedioxynomethanol-6. A solution of the compound of example VI (1 g) in absolute ethanol (20 ml) was hydrogenated at 23 ° C and atmospheric pressure with 10% palladium on carbon (0.1 g) and 10% platinum on carbon as a catalyst. (0.1 g). The mixture was filtered through Hyflo and evaporated under reduced pressure to give an oil which slowly crystallized. The precipitate was suspended at EX, filtered and dried to give the title compound as white crystals (0.72 g), mp 68-70 ° C. T.l.c. EN (EA-MeOH 19: 1 /: Rf * 0.45. Example XXIX. 4-Hydroxy-O-F * 6- (4-phenylbutoxy) hexylaminomethyl 7-1,3-benzenedimethanol. 26 g) in anhydrous THF (15 ml) was added with stirring at 0 ° C and under a nitrogen atmosphere a solution of the compound of example VIII (0.3 g) in anhydrous THF (5 ml). The mixture was stirred at 23 ° C for 20 hours, diluted carefully with water (30 ml), acidified to pH = 5 with 2M hydrochloric acid, basified to pH <8 with NaHCO, and extracted with EA (3 x 50 ml). The organic layer was washed with BR (50 ml), dried over Na 2 SO 4 and evaporated to an oil which, after purification by FCT 7), gave another oil. R) Cold ER trituration gave the title compound as a white solid (0.064 g), m.p. 75 -76.5 ° C; the melting point of the mixture with the product of Example XXVII is 75-76 ° C. EN / n7: Rf ≤ 0.31, Example XXX. 4-Hydroxy - N - (6-) 4-phenylbutoxy / hexylaminomethyl-7-1,3-benzenedimene tanol. To a solution of methyl 5- (bromoacetyl) -2-hydroxybenzoate (1 g) and N, N-diisopropylethylamine (0.85 g) in 1HF (10 ml) was added, while stirring, at 0 ° C the solution of the compound of Example IX (0.91 g) in THF (10 ml). It was stirred at 0 ° C for 2 hours, diluted with ether (50 ml), washed with 0.5M hydrochloric acid (50 ml), 6% NaHCO * solution (50 ml), BR (50 ml), dried and evaporated. getting oil. R) purification method / FC§7 (60 g) of Eci7 gave the intermediate glycyl compound as an oil (0.6 g). A solution of this oil (0.6 g) in anhydrous THF (5 ml) was added while stirring to a suspension of LiAlHi (0.25 g) in dry THF (25 ml) under nitrogen atmosphere at 23 ° C. The mixture was stirred for 18 hours, diluted carefully with water (50 ml), acidified to pH 5 with 2M hydrochloric acid, made to pH 8 with NaHCO * and extracted with EA (2 x 100 ml). The dried extract was evaporated to an oil, from which, after purification by the FCTS7 method (20 g) fltf, another oil was obtained. Fb was rubbed with ER to obtain the title compound in the form of a white powder (0.12 g) at a temperature of 75-5-76.50C, the melting point of the mixture with the product of example XXVII is 75-76 ° CTlc EN Mx Rf = 0.31 Example XXXI. 4-Hydroxy- ° C- (6- (4-phenylbutoxy) hexylaminamethyl-7-1,3-benzenedimethanol. A solution of Example X (0.58 g) in dry THF (25 ml) was added to a suspension of LiAlHA (0.5 g) in anhydrous THF (25 ml) at 0 ° C and nitrogen atmosphere for 10 minutes with stirring. ml). The mixture was stirred at 23 ° C. for 18 hours, diluted carefully with water (50 ml), acidified to pH 5 with 2M hydrochloric acid, basified to pH = 8 by addition of NaHCO, and extracted with EA (3 x 50 ml). The BR extract (50 ml) was dried over Na 2 SO 4 and evaporated to give an oil which, after purification by (FCT) 7 / W, gave a pale yellow oil. By grinding with cold ER, the title compound was obtained in the form of a white solid (0.115 g) with a melting point of 76-77 ° C, the melting point of the mixture with the product of Example XXVII was 75.5-76.5 ° C T.l.c. EN f ^ Ji Rf = 0.31. Example XXXII. 4-Hydroxy - *! 1- (S- (4-phenylbutoxy) hexylaminomethyl 7-1 → 3-benzenedimethanol. A solution of the compound of example XXVIII (0.3 g) in methanol (2 ml) was diluted with 2M hydrochloric acid (2 ml) and kept at 23 ° C for 5 hours. EA (15 ml) was added and the mixture was washed with 8% NaHCO 3 (15 ml), Br (15 ml), dried and evaporated under reduced pressure to give a colorless oil. After trituration with the ER, the title compound was obtained as a white solid (0.23 g), m.p. 76-77 ° C; the melting point of the mixture with the product of Example XXVII is 75-5-77 ° C. T.l.c. EN Rf = 0.31.141 883 17 Example XXXIII, 4-Hydroxy-oc - / "6- (4-phenylbutoxy) hexylaminomethylq7-1,3-benzenedimethanol. Solution of the compound of Example XXVI (230 g) in ethanol (1f3 1) was reduced with hydrogen in the presence of 10% palladium on carbon as a catalyst (46.5% paste in H 2 O, Go g). After removal of the catalyst and solvent, ER (2 L) was added to the residue. The solution was decanted from a small amount of resinous, insoluble residue and left overnight. Drainage gave the title compound (147 g), m.p. 75-77 ° C. Example XXXIV. Hydrate 4-hydroxy-° - / 6- (4-phenylethoxy) hexylaminoraety-1q7-1, 3- benzenedimethanol A solution of Example XIV (30 mg) in EA (20 ml) was hydrogenated over palladium on carbon (10%, 20 mg) for 5 hours, filtered through a Hyflo pad and concentrated under reduced pressure to afford the title compound as pale yellow solid (27 mg). Tlc / EA-ethanol-NH, 10: 1: 1 /: Rf = 0.3 »Hplc: column: 5 µH ypersil 5 mm x 10 mm; / Lmax: 276 nm, flow rate: 2 ml / min; eluent: HX-EA-isopropanol-NH- 10: 1: 0.15; retention time: 11.5 min. Example XXXV. 4-Hydroxy-O- (6- (4-phenylbutoxy) hexylaminomethyl-7-1,3-benzene dimethanol. To a solution of the compound of example XXVII (2.50 g) in isopropanol (10 ml) was added a solution of 2-hydroxybenzoic acid (0.83 g) in warm isopropanol (10 ml). The mixture was allowed to stand overnight at room temperature, the product was isolated, washed with isopropanol (3 x 5 ml) and dried under vacuum at 6 ° C to give the title salt as a colorless solid, mp 134-135 ° C. by using the compound of Example XXVII, the following salts were prepared. 4-Hydroxy-α- (* 6- (4-phenylbutoxy) -hexylaminomethyl-7-1,3-benzenedimethanol 4-chlorobenzoate. A product was obtained with a melting point of 117-119 ° C, which, on partial solidification again, melted at 134 ° C. 4-Hydroxybenzoate 4-hydroxy-O- (6- (4-phenylbutoxy) hexylaminomethyl) 7-1,3-benzenedimethanol, m.p. 136-138 ° C. 4-hydroxy-oc 1-hydroxy-2-naphthalenecarboxylate - (6- (4-phenylbutoxy) hexylaminomethyl-7-1,3-benzenedimethanol, m.p. 137-138 ° C. 4-Hydroxy-O- (6- (4-phenylbutoxy) hexylamino-methyl 3-hydroxy-2-naphthalenecarboxylate. 7-1,3-benzenedimethanol, m.p. 135-137 ° C. Example XXXVI. 4-Hydroxy-Q &lt; - - {(phenylmethyl) - (6- (3-phenylpropoxy) hexylaminomethyl-7, -1,3-benzenedimethanol. The compound of Example XV was added over 15 minutes to a solution of sodium bis (2-methoxyethoxy) aluminum hydride (3.4M solution in toluene, 33 ml) in CHpClo (50 ml), maintaining a temperature of 4-18 ° C at nitrogen atmosphere. After 1.75 hours at 15 ° C, the whole was cooled to 5 ° C and water (10 ml) was added very carefully. The filtrate was evaporated under reduced pressure, the residue was taken up in EA (250 ml) and 2N hydrochloric acid (250 ml). The organic layer was washed sequentially with 2N Na 2 CO 4 (200 ml) and N 2 O (200 ml), dried and evaporated to give the title compound as an orange oil (15.8 g). T.l.c. / ER /: R £ = 0.3. Example XXXVII. 4-Hydroxy-oi - (- 6- (3-phenylpropoxy) hexylaminomethyl-7- -1,3-benzenedimethanol. The product of Example XXVI (19 g) in ethanol (150 ml) was hydrogenated over 10% palladium on carbon catalyst (5.2 g). After 2 hours 40 minutes, the mixture was filtered and the filtrate was evaporated under reduced pressure to give a pale yellow oil which, after crystallization from EA, gave the title compound as a white solid (10.1 g), m.p. 82-84 ° C. C. Analysis Results: Found: C 71.76 H 8.60, N 3.43; calcd for C H H H N NO C 71.78 H 8.79, N 3.49%. 18 141 883 Example XXXVIII. ° L -Zl, 1-Dimethyl-6- (2-phenylethoxy) hexylaminomethyl 7- -4-hydroxy-1,3-benzenedimethanol. A solution of methyl 5- (bromoacetyl) -2-hydroxybenzoate (2.2 g), example XVIII (2.0 g) and NfN-diisopropylethylamine (1.16 g) in EA (40 ml) was heated under reflux with a 3 hours, filtered and evaporated, the filtration was quenched with ER (50 ml), filtered and the filtrate was added dropwise to a suspension of LiAlH4 (1.6 g) in ER (100 ml) at 0 ° C. The mixture was stirred at room temperature for 2 hours. , carefully treated with water (10 ml), acidified to pH = 1 with 2M hydrochloric acid and basified to pH = 8 by the addition of solid KgCO. The resulting suspension was extracted with CHCOU (4 x 200 ml), the extracts dried and evaporated. in a column packed with silica (Merck 9385, 150 ml), obtaining the title compound in the form of a beige solid (0.3 g) with a melting point of 68-71 ° C CTlc Mx Rfs 0.2. Example XXXIX, (R / - / - / - 4-hydroxy-1-Z 6 - / - 3-phenylpropoxy) hexylaminoethyl-1q 7-1,3-benzenedimethanol. The compound of Example XXV (750 mg) was hydrogenated in absolute methanol (60 ml) in a feed reduced against 10% palladium oxide on carbon (50% paste, 150 mg), R 2 hours uptake of hydrogen (7D ml) was determined. The catalyst was filtered off through a layer of Hyflo and the filtrate was concentrated under reduced pressure. The crude product was purified by ZFCS7 method using EA-methanol-triethylamine 80: 20: 1 as the eluent to give the title compound as a very viscous oil (270 mg). Specific conductivity £? TJz} ** -25.7 ° (c 0.3 CHCU), Tlc (EA-methanol-triethylamine 80: 20: 1): Rf: 0.22. Analysis Results: Found: C 71.44, H 8.34, N 3.43; calculated for C, H, N, N, C 71.79, H 8.79, N 3.49. Patent Claims 1. Method for the preparation of new phenylethanolamine derivatives of the general formula 2, where m is an integer of 2-8, n is an integer 1-7, with the sum of m + n being 4-12, Ar is a phenyl group optionally substituted with one or two substituents such as a halogen atom, a C1-C * alkyl group or a C1 -C6-alkoxy group or alkylenedioxy of the formula -o / CHp / D0-, where p is 1 or 2, R and R are the same or different and represent a hydrogen atom or a C-C alkyl group, the total number of carbon atoms is 12 in R and R is at most 4, as well as their physiologically acceptable salts and solvates, characterized in that an optionally protected compound of general formula IV is reduced, in which Ar is as defined above, R is hydrogen or a protecting group such as an aralkyl or tetrahydropyranyl group, at least one of X, X, and, XiX is a reducible group and the other substituent or substituents have the following meanings X is a group of formula -CH90R where R is hydrogen or a protecting group such as an aralkyl or tetrahydropyranyl group, X is a group of formula -CH / OH / - a is a group of the formula -CHoNR, in which R is a hydrogen atom or a protecting group such as an aralkyl or acyl group, Y / is a group of the formula -CR R / CH2 / m_i, in which R, R and m are as defined above, and X represents a group of formula - / CHp / nl * in which n is as defined above, followed by removal of any protecting groups present and optionally converting the resulting compound of formula 2 or a salt thereof into a physiologically acceptable salt or solvate. 2. A process according to claim 1, characterized in that a compound of formula IV containing one bond -C · C- or -C = C- in the group X of formula -CR RX 1 is reduced with the aid of hydrogen in the presence of a catalyst and / or group X, where group V? and X 1 are reduced to -GR 2 (GH 8) - and / or - (CH 2) 1.141 883 19, respectively. 2. A method according to claim 1, characterized in that for the preparation of compounds of formula 2, wherein R and R represent a hydrogen atom or a C1-C 1-6 alkyl group, m is an integer 3-6, n is a number 2-6 , where the sum of ra is 7-10, Ar is a phenyl group, optionally substituted with a methyl or methoxy group, or with a fluorine or chlorine atom, the compound of formula IV is reduced in which R is a hydrogen atom or a protecting group , at least one of X, X, JTf, "X" and 2 represents a reducing group and the remaining substituent or substituents have the appropriate meaning, i.e. X represents a group of formula -CH 2 OR in which Vc is hydrogen or a protecting group, X is a group of the formula -CH (OH), a is a group of the formula -CHUNR, in which R 2 is a hydrogen atom or a protecting group, X 1 is a group of the formula CR R (CH 2) m-1 'in which R, R and m are as defined above, and a is a group of formula ~ / ®h / n-A9 in which n is as defined above. th. 4. The process of claim 1, wherein in the preparation of 4-hydroxy- (phe- (4-phenylbutoxy) -hexylaminomethyl-7-1,3-benzenedimethanol or a physiologically acceptable salt thereof, 1-A-hydroxy-3-) is reduced. 1-Hydroxymethyl (phenyl) -2-J (6- - (4-phenylbutoxy) hexyl (phenylmethyl) amino-ethanone) and the protecting group is removed and the resulting compound is optionally salified. 5. The method according to p. 4. A process as claimed in claim 1, characterized in that in the preparation of 4-hydroxy-ac- (6- (4-phenylbutoxy) hexylaminomethyl7-1,3-benzenedimethanol 1-hydroxy-2-naphthalenoxacarboxylate, the 4-hydroxy-α - / 6- (4-phenylbutoxy) -hexylaminomethyl-7-1,3-benzenedimethanol reacts with 1-hydroxy-2-naphthalenecarboxylic acid. 141 883 HO - \ J OH R1 iflzórl H0CH2, Fj? 1 HO -O? CHCH? CfCH → mO- fcH ^ -Ar OH R2 Formula z -C (CHirrf) (CH ^ n "n Formula3 r40 - ^ 3" X1 X2-X3-CHPCH ^ <4-Ar Formula4 R ^ / OCHg "tfX tfO ^ COCH ^ Y ^ H ? (CH2) has ^^ xv. Xv.Yizór? Rt) H ^ cXH0 Rt ^ J- ^ CHgNHR3 R ^ 0

Claims (5)

Claims 1. A process for the preparation of new phenylethanolamine derivatives of the general formula 2, in which m is an integer of 2-8, n is an integer of 1-7, the sum of m + n being 4-12, Ar is a phenyl group, optionally substituted with one or two substituents, such as a halogen atom, a C1-C * alkyl group or a C1-C6-alkoxy group or an alkylenedioxy group of the formula -o / CHp / D0- in which p is a number 1 or 2, R and R, are the same or different and represent a hydrogen atom or a C.-C, alkyl group where the total number of 12 carbon atoms in R and R is at most 4, as well as their physiologically acceptable salts and solvates, characterized in that an optionally protected compound of formula IV is reduced in which Ar is as defined above, R is a hydrogen atom or a protecting group such as an aralkyl or tetrahydropyranyl group, at least one of X, X, and XiX is a group that undergoes reduction, and the remainder Each substituent or substituents have the following meanings: X is a group of formula -CH90R in which R is hydrogen or a protecting group such as an aralkyl or tetrahydropyranyl group, X is a group of formula -CH / OH / - and is a group of of the formula -CHoNR, in which R is a hydrogen atom or a protecting group such as an aralkyl or acyl group, Y / is a group of the formula -CR R / CH2 / m, in which R, R and m are as defined above, and X is a group of formula - / CHp / nl * wherein n is as defined above, followed by removal of any protecting groups present and optionally converting the resulting compound of formula 2 or a salt thereof into a physiologically acceptable salt or solvate thereof. 2. A process according to claim 1, characterized in that a compound of formula IV containing one bond -C · C- or -C = C- in the group X of formula -CR RX 1 is reduced with the aid of hydrogen in the presence of a catalyst and / or group X, where group V? and X.sub.2 are reduced to -GR.sub.2 (GH.sub.8) - and / or - (CH.sub.2) 1.141 883 19 3. The method according to p. 2. A method according to claim 1, characterized in that for the preparation of compounds of formula 2, wherein R and R represent a hydrogen atom or a C1-C 1-6 alkyl group, m is an integer 3-6, n is a number 2-6 , where the sum of ra is 7-10, Ar is a phenyl group, optionally substituted with a methyl or methoxy group, or with a fluorine or chlorine atom, the compound of formula IV is reduced in which R is a hydrogen atom or a protecting group , at least one of X, X, JTf, "X" and 2 represents a reducing group and the remaining substituent or substituents have the appropriate meaning, i.e. X represents a group of formula -CH 2 OR in which Vc is hydrogen or a protecting group, X is a group of the formula -CH (OH), a is a group of the formula -CHUNR, in which R 2 is a hydrogen atom or a protecting group, X 1 is a group of the formula CR R (CH 2) m-1 'in which R, R and m are as defined above and aa is a group of the formula ~ / ®h / n-A9 in which n is as defined above. 4. The method according to p. 4. The process of claim 1, wherein in the preparation of 4-hydroxy- (phe- (4-phenylbutoxy) -hexylaminomethyl-7-1,3-benzenedimethanol or a physiologically acceptable salt thereof, 1-A-hydroxy-3-) is reduced. 1-Hydroxymethyl (phenyl) -2-J (6- - (4-phenylbutoxy) hexyl (phenylmethyl) amino-ethanone) and the protecting group is removed and the resulting compound is optionally salified. 5. The method according to p. 4. A process as claimed in claim 1, characterized in that in the preparation of 4-hydroxy-ac- (6- (4-phenylbutoxy) hexylaminomethyl7-1,3-benzenedimethanol 1-hydroxy-2-naphthalenoxacarboxylate, the (4-phenylbutoxy) -hexylaminomethyl-7-1,3-benzenedimethanol reacts with 1-hydroxy-2-naphthalenecarboxylic acid. 141 883 HO - \ J OH R1 iflzórl H0CH2, Fj? 1 HO -O? CHCH → CfCH → mO- fcH ^ -Ar OH R2 Formula z -C (CHirrf) (CH ^ n "n Formula3 r40 - ^ 3" X1 X2-X3-CHPCH ^ <4-Ar Formula4 R ^ / OCHg "tfX tfO ^ COCH ^ Y ^ H ? (CH2) has ^^ xv. Xv. Yizór? Rt) H ^ cXH0 Rt ^ J- ^ CHgNHR3 R ^ 0