NO852809L - PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE AMINOPHENOLD DERIVATIVES. - Google Patents

Description

This invention relates to a method for the production of aminophenol derivatives with a stimulating effect on 32-adrenoreceptors, which can be included in pharmaceutical preparations and thus have medical use.

Aminophenol derivatives with a sulfonamido or ureido substituent in the phenol ring have previously been described as bronchodilators with a stimulating effect on 3-adrenoreceptors.

Thus, British patent 993584 describes compounds of the general formula

where R<1> is lower alkyl, phenyl or tolyl; X means i.a.

2 3

hydroxy; Z means i.a. -CH(OH)-; each of R and R means i.a. hydrogen; and R<4> means hydrogen, lower alkyl, aralkyl or aryloxyalkyl, where the aryl ring may optionally be substituted with hydroxy, methoxy or methylenedioxy.

British patent 1286225 describes compounds of the general formula

where R 1 means hydrogen, C. t-alkyl, phenyl, dimethylaminoethyl

2 3

or dimethylaminopropyl; each of R and R i.a. means hydrogen; and R<4> means C 3-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkylmethyl or

the group

where each of R~* and R^ means hydrogen,

hydroxy or methoxy.

We have now found a new group of aminophenol derivatives which differ structurally from the compounds described in British Patent 993584 and 1286225 and which have a desirable and applicable action profile.

Through the present invention, a method for the preparation of compounds with the general formula (I) has thus been provided

where

m is an integer from 2 to 8 and

n is an integer from 1 to 7, it being assumed that the sum m+n is 4 to 12;

Ar means a phenyl group which is optionally substituted with one or more substituents selected from halogen atoms, C 1-6 alkyl or C 1-6 alkoxy groups, or an alkylenedioxy group of the formula -O(CH 9 ) 0-, where p means 1 or 2;

1 2 p

R and R each represent a hydrogen atom or a C 1 -alkyl group,

1 2, provided that the sum of the carbon atoms in R and R is not more than 4;

Q3 means an R<3>CO-, R<3>NHCO-, R3R4NS0z 9- or R<5>SO^„ group, where R 5 and R each means a hydrogen atom or a C 1-4 alkyl group and R means a 4-alkyl group; as well as physiologically acceptable salts and solvates (e.g. hydrates) thereof.

The compounds of formula (I) have one or two asymmetric carbon atoms, namely the carbon atom in the -CH group and, when R and

OH

R 2 constitutes different groups, the carbon atom to which these are attached.

The compounds produced according to the invention thus include all enantiomers, diastereoisomers and mixtures thereof, including also racemates. Compounds where the carbon atom in the -CH group has the R configuration are preferred.

OH

According to one aspect of the present invention, there is provided a method for the preparation of compounds of formula (I), where m, n, R 1 and R 2 are as previously indicated, Ar means a phenyl group which is optionally substituted with one or two substituents selected from halogen atoms, C 1-3 alkyl or C 1-3 alkoxy groups, or an alkylenedioxy group of formula -0(CH~) 0-, where p is 1 or 2, and Q means the group

3 3 P 5 3 4

R CO-, R NHCO- or R SO,-, where R and R are as indicated under formula (I), and R<5> denotes a C 1-3 alkyl group.

In the general formula (I), the chain ~(CH2^m~ can for example be -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2) g-or -(CH2)7~, and the chain~(CH2^n~for example be -(CH2)2~,

-(<CH>2)3-, -(CH2)4-, -(CH2)5- or -(CH2)g-.

The total number of carbon atoms in the chain -(CH„) and

J 2 m ^ -(CH 2 „) n- is preferably 6 to 12, e.g. 7, 8, 9 or 10. Compounds where the sum m+n is 7, 8 or 9 are particularly preferred.

Preferred compounds of the general formula (I) are furthermore compounds where m is 2 or 3 and n is 6, or where m is 4 and n is 3, 4 or 5, or where m is 5 and n is 2, 3 or 4 , especially compounds where m is 5 and n is 4.

1 2

In compounds of formula (I) R and R can be, for example, methyl, ethyl, propyl or isopropyl groups, except

1 2

from that when one of R and R is a propyl or isopropyl group, the other must be a hydrogen atom or a methyl group. For example, R 1 can be a hydrogen atom or a methyl, ethyl or propyl group. R<2> can for example be a hydrogen atom

1 2

or a methyl group. R and R are both preferably a hydrogen atom or a methyl group. 1 2 A preferred group is compounds where R and R are both hydrogen atoms or where R is a hydrogen atom and R 2 is a C 1 _- alkyl group, especially a methyl group.

In the group Q, R<3> and R 4 can for example be a hydrogen atom or a methyl, ethyl, propyl or isopropyl group and R^ can for example be a methyl, ethyl, propyl, isopropyl or

r>4 butyl group. Preferably, RJ stands for hydrogen or methyl, R for hydrogen or methyl and R<5> for C₁₀alkyl. Preferred values for the group Q are HCO-, CH3CO-, NH2CO-, (CH3)2NS02-, and R<5>SO2, where R5 is C1-6 alkyl, especially methyl or n-propyl. A preferred group is compounds where Q is the group HCO-, NH2CO- or, preferably, CH3SO2-.

Examples of possible substituents that may occur on the phenyl group Ar include bromine, iodine or, in particular, chlorine or fluorine atoms, or a C 1 -3 alkyl group (e.g. methyl or ethyl) or a C 1 -3 alkoxy group (e.g. methoxy or ethoxy). The phenyl group Ar can, for example, contain one or two substituents which can occur in the 2-, 3-, 4-, 5- or 6-positions on the phenyl ring. Ar is preferably a phenyl group which is optionally substituted with a substituent, in particular a methyl group or a fluorine atom. But preferably Ar constitutes an unsubstituted phenyl group.

A preferred group consists of compounds of formula

(Ia)

where

m is an integer from 2 to 5; n is an integer from 2 to 6 and the sum m+n is 7, 8 or 9;

1 2

R means hydrogen and R a hydrogen atom or a methyl group; Ar means a phenyl group optionally substituted with a methyl group or a fluorine atom; and Q beetr yCr jH_C3Oa-lk, yClH; 3CoOg -f, yNsHio2ClOog-i, sk (CHak3s)e2NpSt0ab2- le elsalelr ter R5oS0g 2~so, lvhvatoerr thereof.

A particularly preferred group of compounds with formula (Ia) consists of compounds where m is 5 and n is 4.

Another particularly preferred group of compounds with

5 5 formula (Ia) , is made up of compounds where Q is R SO 2 ~ and R is a methyl group.

In a further particularly preferred group of compounds of formula (Ia), Ar is a phenyl group which is substituted with a fluorine atom, or is preferably unsubstituted.

Particularly important compounds produced according to the invention are: N-[2-hydroxy-5-[1-hydroxy-2-[[6-(4-phenylbutoxy)hexyl]-amino]ethyl]phenyl]methanesulfonamide; N-[2-hydroxy-5-[1-hydroxy-2-[[6-[4-(4-fluorophenyl)butoxy]-hexyl]amino]ethyl]phenyl]methanesulfonamide; N-[2-hydroxy-5-[1-hydroxy-2-[[1-methyl-6-(2-phenylethoxy)-hexyl]amino]ethyl]phenyl]methanesulfonamide; N-[2-hydroxy-5-[1-hydroxy-2-[[6-(3-phenylpropoxy)hexyl]-amino]ethyl]phenyl]formamide; N-[2-hydroxy-5-[1-hydroxy-2-[[6-(4-phenylbutoxy)hexyl]amino]-ethyl]phenyl]urea; N-[2-hydroxy-5-[1-hydroxy-2-[[3-[(6-phenylhexyl)oxy]propyl]-amino]ethyl]phenyl]methanesulfonamide; N-[2-hydroxy-5-[1-hydroxy-2-[[6-(3-phenylpropoxy)hexyl]-amino]ethyl]phenyl]urea; N-[2-hydroxy-5-[1-hydroxy-2-[[6-(3-phenylpropoxy)hexyl]amino]ethyl]phenyl]methanesulfonamide; N-[2-hydroxy-5-[1-hydroxy-2-[[6-[4-(4-methylphenyl)butoxy]hexyl]amino]ethyl]phenyl]methanesulfonamide;

and the physiologically acceptable salts and solvates thereof.

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

The compounds produced according to the invention have a selective stimulating effect on 32~ac^renoresisPtors• This also has a particularly advantageous effect profile. The stimulatory effect has been demonstrated on isolated guinea pig trachea, where the compounds were shown to cause relaxation of PGF2-α-induced contractions. In this test, the compounds have been shown to have a particularly long-lasting effect.

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

The new compounds can also be used for the treatment of premature birth, depression and congestive heart failure, and may also appear useful in the treatment of inflammatory and allergic skin disorders and glaucoma, as well as in the treatment of conditions where lowering the acidity of the gastric juice is an advantage, especially in gastric and peptic ulceration.

The compounds of formula (I) and their physiologically acceptable salts and solvates can be used therapeutically or prophylactically against diseases associated with reversible airway obstructions in animals or humans.

The compounds produced according to the invention can be included in pharmaceutical preparations which can contain at least one compound of formula (I) or a physiologically acceptable salt or solvate thereof, in formulations intended for use in human or veterinary medicine. Such preparations may contain physiologically acceptable carriers or excipients, possibly containing additional active substances.

The compounds can be included in preparations in an administration form suitable for inhalation or inhalation, or for peroral, buccal, parenteral, local (including nasal) or rectal administration. Administration by inhalation or

blowing in is preferred.

By inhalation administration, the compounds can be easily administered

in the form of an aerosol spray from a spray can with a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or another suitable gas, or from a nebuliser. If an aerosol is used, the dose can be determined using a valve that emits a measured amount.

As an alternative to inhalation or inhalation administration, the compounds produced according to the invention can also take the form of a dry powder, for example a powder mixture of the active ingredient and a suitable powder base, e.g. lactose or starch. The powder preparation can be available in the form of unit doses such as capsules made of gelatin or "blister" packs from which the powder can be given by means of an inhalation or inhalation device.

For oral administration, the preparations can, for example, take the form of tablets, capsules, powders, solutions, syrups or suspensions prepared by conventional methods with acceptable excipients.

For buccal administration, the preparations can take the form of

tablets, drops or lozenges prepared in a conventional manner.

The compounds produced according to the invention can also be included in formulations for parenteral administration. Injection formulations can be available in unit doses in the form of ampoules or in vials with added preservative. The preparations may take the form of suspensions, solutions or emulsions in oily or aqueous carriers and may contain auxiliaries such as suspending, stabilizing and/or dispersing agents. As an alternative, the active ingredient can be in the form of a powder that is reconstituted with a suitable carrier, e.g. sterile, pyrogen-free water, before use.

For local administration, the preparations can take the form of

ointments, lotions or creams which are prepared in a conventional way, for example on a water or oil basis, and generally with the addition of an appropriate thickening agent and/or solvents. For nasal application, the preparations can be prepared in spray form, for example as an aqueous solution or suspension or as an aerosol together with a suitable propellant.

The compounds produced according to the invention can also be used rectally by preparing the preparations as suppositories or retention enemas, e.g. based on conventional suppository excipients such as cocoa butter or other glycerides.

The above-mentioned preparations for peroral, buccal, rectal or local administration can be conventionally incorporated into retard preparations.

A suggested daily dose for human medicine is 0.005-100 mg of active substance, which can be given in the form of one or two doses. The exact dose will of course depend on the patient's age and condition and on the method of administration. A suitable dosage for inhalation administration is 0.005-20 mg, for oral administration 0.02-100 mg, and for parenteral administration will amount to 0.01-2 mg by injection and 0.01-25 mg by infusion.

The compounds of formula (I) can be prepared according to a

series of methods, discussed in the following, where Q, m, n, Ar,

R 1 and R 2 are as defined for the general formula (I) unless otherwise stated. In this connection, it can be mentioned that some of the reactions described below can affect certain groups in the starting material that are desired in the final product. This applies in particular in the reduction processes described, especially when a reducing hydride is used and end products are required where Q constitutes the group R 3CO-, and when hydrogen and a metal catalyst are used for the production of intermediate products containing an ethylene or acetylene bond. It must therefore, in accordance with common practice, either use reagents that do not affect these groups, or ensure that the reaction follows a scheme where the use of the reagent is avoided when such groups occur in the starting material. In the general methods described below, the final step in the reaction can be carried out

in the removal of a protecting group. Appropriate protecting groups and their removal are described in the general process (2) below.

According to the general process (1), a compound of formula (I) can be prepared by alkylation. Here, conventional alkylation methods can be used.

In a method (a), a compound of formula (I), where R 1 is a hydrogen atom, can be prepared by alkylating an amine of the general formula (II)

(where each of R 6 and R 7 is a hydrogen atom or a protecting group and R g is a hydrogen atom), whereupon any protecting group present is removed. The alkylation (a) can be carried out with an alkylating agent having the general formula (III)

where L means a leaving group, for example a halogen atom such as chlorine, bromine or iodine, or a hydrocarbylsulfonyloxy group, such as methanesulfonyloxy or p-toluenesulfonyloxy.

The alkylation is preferably carried out in the presence of a suitable acid binding agent, for example inorganic bases such as sodium or potassium carbonate, organic bases such as triethylamine, diisopropylethylamine or pyridine, or alkylene oxides such as ethylene oxide or propylene oxide. The reaction is conveniently carried out in a solvent such as acetonitrile or an ether, e.g. tetrahydrofuran or dioxane, a ketone, e.g. butanone or methyl isobutyl ketone, a substituted amide, e.g. dimethylformamide or a chlorinated hydrocarbon, e.g. chloroform, in the range from room temperature to the boiling point of the solvent.

According to another example (b) of an alkylation process, a compound of the general formula (I), where R^ constitutes a hydrogen atom, can be prepared by alkylating an amine of the general formula (IV):

6 7 8 where R and R are as previously defined, R means a hydrogen atom or a group which can be converted into hydrogen under the reaction conditions, and X stands for -CH(OH)- or ^-C=0 with a compound of the general formula (V):

in the presence of a reducing agent, whereupon any protecting groups are removed.

Examples of suitable R g groups, which can be converted to hydrogen, are arylmethyl groups such as benzyl, α-methylbenzyl and benzhydryl.

Suitable reducing agents include hydrogen in the presence of a catalyst such as platinum, platinum oxide, palladium, palladium oxide, Raney nickel or rhodium, on a support such as e.g. activated carbon, where an alcohol is used as a solvent, e.g. ethanol, an ester, e.g. ethyl acetate, an ether, e.g. tetrahydrofuran, or water, optionally a mixture, e.g. a mixture of two or more of the aforementioned solvents, at normal or higher temperature and pressure conditions, for example 20-100°C and 1-10 atm.

When one or both of R 7 and R 8 are hydrogen atoms, the reducing agent may alternatively be a hydride, such as diborane, or a metal hydride, such as sodium borohydride, sodium cyanoborohydride or lithium aluminum hydride. Suitable solvents for the reaction with these reducing agents will depend on which hydride is used, but can be alcohols such as methanol or ethanol, ethers such as diethyl ether or tert-butyl methyl ether, or tetrahydrofuran.

When a compound of formula (II) is used, where R<7>

and R are both hydrogen atoms, the imine intermediate (VI) can

formed:

(where R<6> is as indicated for formula (II)).

Reduction of the imine under the conditions described above with possibly subsequent removal of protecting groups gives a compound of the general formula (I).

When it is desired to use a protected intermediate with formula (II) or (IV), it is particularly easy to use hydrogen and a catalyst as described above for

6 7

the protecting groups R and R , which can be converted to a hydrogen atom under these reducing conditions. In this way, the need for a separate step for removing the protecting groups is avoided. Suitable protecting groups of this type include arylmethyl groups such as benzyl, benzhydryl and α-methylbenzyl.

According to another general process (2), a compound of formula (I) can be obtained by deprotection of a protected intermediate of general formula (VII):

(where R 6 and R 7 are as previously indicated, except that at least one of R<6> and R 7 is a protecting group).

The protecting group can be any conventional protecting group, for example as described in "Protective Groups in Organic Chemistry", ed. J. F. W. McOmie (Plenum Press, 1973). Examples of suitable hydroxyl protecting groups represented by R are aralkyl groups such as benzyl, diphenylmethyl or triphenylmethyl and tetrahydropyranyl.

Examples of suitable amino protecting groups represented by

R 7 are aralkyl groups such as benzyl, α-methylbenzyl, diphenylmethyl or triphenylmethyl, and acyl groups such as trichloroacetyl or trifluoroacetyl.

The removal of the protecting group, which gives a compound of formula (I), can be carried out according to conventional techniques. When R 6 and/or R 7 is an aralkyl group, it can for example be split off by hydrogenolysis in the presence of a metal catalyst (eg palladium on charcoal). When R 1 is tetrahydropyranyl, it can be cleaved by hydrolysis under acidic conditions. Acyl groups represented by R 7 can be removed by hydrolysis, for example with a base such as sodium hydroxide, while a group such as trichloroacetyl can be removed by reduction, for example with zinc and acetic acid. However, the choice of acyl group R 7 and the method of removal depends on the nature of the group Q.

According to another general process (3), a compound of formula (I) can be prepared by reduction. Thus, for example, one can reduce an intermediate with formula (VIII):

(where R is as indicated for the general formula (II) and where 12 3 4

at least one of X , X , X and X form a reducible group and

1 2

the others have the following meanings: X is -CH(OH)-, X is -CH2NR7, X3 is -CR1 R2 (CH2) m_1 - and X4 is -(CH2) .j-, after which any protective groups are removed.

Suitable reducible groups include those where X is

2

^C=0, X is the group -CH2NY- (where Y means a group which can be converted to hydrogen by catalytic hydrogenation, for example an arylmethyl group such as benzyl, benzhydryl or α-methyl-

benzyl), or an imine (-CH=N-) group or a -CONH group,

X3 is -CO(CH2)m_1- or the group -CR<1>R<2>X<5->, where X<5>is ^ 2- l~ alkenylene or C9 7alkynylene, or -X<2->X <3> is a -CH2N=CR 2 (CH2)^ group, or X<4> is <C>2_6alkenylene or C2-6~alkynylene. In an appropriate embodiment of the reduction, the group R can be a group which can be converted to hydrogen under the reduction conditions used, such as e.g. an arylmethyl group such as benzyl, benzhydryl or α-methylbenzyl.

The reduction can be carried out with reducing agents that readily reduce ketones, imines, amides, protected amines, alkenes and alkynes. For example, when X<1> in the general formula (VIII) means a ^C=0 group, it can be reduced to a -CH (OH) group with hydrogen in the presence of one of the catalysts mentioned in connection with process (1) part (b). Alternatively, the reducing agent may be a hydride, such as diborane or a metal hydride such as lithium aluminum hydride, sodium bis(2-methoxyethoxy)aluminum hydride, sodium borohydride or aluminum hydride. The solvent for the reaction can be an alcohol, e.g. methanol or ethanol, an ether such as tetrahydrofuran, or a halogenated hydrocarbon such as dichloromethane.

When X 2 in formula (VIII) means a -CH 2 NY group or the group

-CH=N-, or X<2->X<3>means -CH^ 9N f~\ =CR2(CH £ „) XII I it can be reduced to a -CH2NH- or -CH2NHCHR (CH2)m-1 -group with hydrogen in the presence of one of the catalysts mentioned in connection with the process

2 2 3 (1) part (b). As an alternative when X or -X -X the group is e-ClHle=Nr - CHel2NlHeCr HR -C2 H(C2 0NH=2C)mR _2^(C-gHr 20. u) mpp-e 1 v, ekd ahn jedelp n arv edude serreeds uktsijl oenn sm-iCdHlez0NrH-and conditions just described for the reduction of X1 when it represents a ^C=0 group. 2 3

When X or X in formula (VIII) means a -CONH- or

-C0(CHo) .-group, it can be reduced to a -CH-NH- or

Zm-1 2 -CH2(CH2)^ group with a hydride, such as diborane, or a complex metal hydride, such as lithium aluminum hydride or sodium bis(2-methoxyethoxy)aluminum hydride, in e.g. tetrahydrofuran or diethyl ether as solvent.

When X 3 in formula (VIII) means a -CR 1R 2 X 5 group, it can be reduced to a -CR 1 R 2(CH 2 ) group with hydrogen in the presence of one of the previously described catalysts for process (1) , part (b) .

When X 4 is C2_6alkenyl or C2_6alkynyl, it can be reduced to -(CH2)n with hydrogen and one of the catalysts just mentioned. In this reduction process, suitable starting materials of formula (VIII), compounds where each of

12 5 4

CR R X and/or X contains a -C=C- or -C=C- bond. Both contain unsaturated bonds, these can be the same or different.

Special examples of the reduction process are such where

a compound of formula (I), where ~(CH2^m~ketYr ~^ Cii2^ 5~' is prepared from a corresponding compound, where -(^H2^m~ means -CH=CH(CH2)3~, -C <=>C(CH2)3~, -(CH2)2CH=CHCH2~ or

-(CH2)2C-CCH2~. In other examples, a compound of formula (I), where -(CH„) - means -(CH0).- or -(CH0),-, can be prepared

zn z 4 z j

by reduction of a corresponding compound of formula (I), where"(CH2)n- means -CH2CH=CH-CH2-, -CH2C<=>CCH2-, -CH2CH2CH=CH-,

-CH2CH2C=C-, -CH2CH=CH- or -CH2C=C-.

In the general methods described above, the compound (I) can be obtained in the form of a salt, preferably a physiologically acceptable salt. Such salts can optionally be converted into the corresponding free acids using conventional methods.

Physiologically acceptable salts of the compounds of formula (I) can be prepared by reacting a compound of formula (I) with a suitable acid or base in the presence of a suitable solvent, such as acetonitrile, acetone, chloroform, ethyl acetate or an alcohol , e.g. methanol, ethanol or isopropanol.

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

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

As an example, a suitable optically active acid can be used for

to form salts with the racemate of a compound of formula (I). The resulting mixture of isomeric salts can be resolved into the diastereoisomeric salts, for example by fractional crystallization, whereupon the desired enantiomer of a compound with

formula (I) is isolated by conversion to the desired free base.

Enantiomers of a compound of formula (I) can alternatively be synthesized from the correct optically active intermediates by means of one of the general methods described here.

Specific diastereoisomers of a compound of formula (I) can be obtained by conventional methods, such as by synthesis from a suitable asymmetric starting material using the methods described herein, or by converting a mixture of isomers of a compound of formula ( I) in suitable diastereoisomeric derivatives, e.g. salts, which can then be separated in a conventional way, e.g. by fractional crystallization.

Appropriate methods for producing the intermediate compounds used in the above-mentioned general methods are described below. In the following discussion

1 2 "7 1 2 A R

are Ar, R, R, R, R, R, Q, X, X, X, X, X, Y and L as defined above unless otherwise indicated. "Hal" stands for a halogen atom. When an intermediate with a protected hydroxyl and/or amino group is desired, it can be obtained by using conventional protection methods, such as e.g. described by McOmie (see process (2) above).

Intermediate products of formula (VIII) for use in the general method (3) can be prepared by a number of methods. Thus, for example, intermediates of formula (VIII), where X -] is the group ^C=0, can be prepared from a haloketone of formula (IX): by reaction with an amine of the general formula (X):

where R 7 is a hydrogen atom or a group that can be converted to hydrogen by catalytic hydrogenation.

The reaction can be carried out in a cold or hot solvent, for example tetrahydrofuran, tert-butyl methyl ether, dioxane, chloroform, dimethylformamide, acetonitrile or a ketone such as butanone or methyl isobutyl ketone, or an ester, for example ethyl acetate, preferably in the presence of a base such as diisopropylethylamine, sodium carbonate or another acid scavenger such as propylene oxide.

The intermediates of formula (II) and (IX) are compounds that are either known or can be prepared by methods described by Kaiser et al. in J. Med. Chem., 1974, 17, 49, and Larsen et al., in J. Med. Chem., 1967, W, 462.

1

Intermediates of formula (VIII), where X is the group ^C=0, can be reduced to the corresponding intermediate, where X is a -CH(OH) group, for example by using a metal hydride, such as sodium borohydride in e.g. . ethanol as solvent.

2

Imino ketones of formula (VIII), i.e. where X is a -CH=N group, can be obtained from a phenylglyoxal derivative of formula (XI):

by reaction with an amine of formula (X), where Y represents a hydrogen atom, in a solvent, such as benzene, tetrahydrofuran or an alcohol, e.g. ethanol, at temperatures up to the boiling point. Phenylglyoxal derivatives of formula (XI) can be obtained from a haloketone of formula (IX) by means of a dialkyl sulfoxide, such as dimethyl sulfoxide. Intermediates of formula (VIII), where X 3 is a -CO(CH2^m_i_ group, can be prepared by acylation of an amine of formula (XII):

by means of an ester or an activated derivative of an acid of formula (XIII) :

Suitable activated derivatives include the acid chloride, an anhydride or imidazolide. The reaction can optionally be carried out in solvents such as tetrahydrofuran, benzene or chloroform, optionally in the presence of a base such as pyridine or triethylamine. The acids (XIII) can be used directly if a coupling agent such as dicyclohexyl carbodidimide is added.

Acids of formula (XIII) can be obtained by treating an alcohol of formula (XIV):

with a suitable oxidizing agent, for example pyridinium dichromate in a solvent such as dimethylformamide. Intermediates of formula (VIII), where -X 2 -X<3->means -CH2N=CR 2(CH2)m_^/ can be obtained by reacting an amine (XII), where R7 is a hydrogen atom, with a compound ( V) in a solvent such as acetonitrile.

Intermediates of formula (VIII), where X 2 is -CONH-, can be obtained by reacting an amine of formula (X), where R 7 is hydrogen, with an acid of formula (XV)

in the presence of a coupling agent, such as dicyclohexylcarbodiimide. The acids of formula (XV) can be prepared analogously to conventional methods for the preparation of α-keto and α-hydroxy carboxylic acids. 3 12 5 Intermediates of formula (VIII), where X is -CR R X - and/or X<4> is C2_6alkenylene or C2_galkynylene, can be prepared analogously to the methods described here for the preparation of compounds of formula (I).

Intermediate products with formula (III), (V), (X) and (XIV) can be prepared as described in UK patent 2140800A or analogously to the methods described there.

The following examples further illustrate the invention. The temperatures are indicated in °C. By "dried" is meant drying using magnesium sulphate unless otherwise stated. Thin layer chromatography (TLC) was performed on SiO 2 -[C] column chromatography and [FCS] "flash" column chromatography was in both cases performed on silica gel (Merck 9385).

The following abbreviations are used: EA - ethyl acetate;

ER - diethyl ether; CX - cyclohexane; ME - methanol; THF - tetrahydrofuran; T - toluene; ET - ethanol; A - 0.88 ammonia solution; DMF - dimethylformamide.

Intermediate 1

N-[ 2-( phenylmethoxy)- 5-[[( phenylmethyl)[ 6-( 3- phenylpropoxy) hexyl]-amino] acetyl] phenyl] formamide

A solution of N-[5-(bromoacetyl)-2-(phenylmethoxy)phenyl]-formamide (0.53 g), N-[6-(3-phenylpropoxy)hexyl Jbenzenemethanamine hydrobromide (0.68 g) (Compound A ) and N,N-diisopropylethylamine (0.65 g) in dichloromethane (10 ml), was kept at 23° for 18 hours. The mixture was diluted with water (20 mL), extracted with ER

(30 ml) and the organic phase washed with water (20 ml), brine (20 ml), dried and evaporated to an oil. Purification using [FCS] eluting with ER-CX (3:2) gave the desired product as a yellow oil (0.72 g). TLC

(ER-CX 3:2) Rf 0.28.

In a similar way, it was produced:

Intermediate product 2

N-[ 2-( phenylmethoxy)- 5-[[( phenylmethyl)[ 6-( 3- phenylpropoxy)-hexyl] amino] acetyl] phenyl] urea (1.01 g)

TLC. Et 3 N-deactivated silica (EA-CX 4:1) from N-[5-(bromoacetyl)-2-(phenylmethoxy)phenyl]urea (0.8 g) and compound A (0.91 g).

Intermediate product 3

N-[ 2-( phenylmethoxy)- 5-[[( phenylmethyl)[ 6-( 3- phenylpropoxy)-hexyl] amino] acetyl] phenyl] methanesulfonamide (0.5 g)

TLC. (CX-ER 3:2) Rf 0.36 from N-[5-(bromoacetyl)-2-(phenylmethoxy)phenyl]methanesulfonamide (0.45 g) and compound A (0.46 g).

Intermediate product 4

N-[ 5-[ 1- hydroxy- 2-[[ 6-( 4- phenylbutoxy) hexyl]( phenylmethyl)-amino] ethyl]- 2-( phenylmethoxy) phenyl] methanesulfonamide

To a solution of N-[5-(bromoacetyl)-2-(phenylmethoxy)-phenyl]methanesulfonamide (1.9 g) and N-[6-(4-phenylbutoxy)hexyl]-benzenemethanamine (1.62 g) in N,N-diisopropylethylamine (1.23 g) was added to THF (100 ml) while stirring in a nitrogen atmosphere and the mixture was stirred under nitrogen at room temperature for 40 hours. The solution was diluted with ER (50 mL), filtered and evaporated in vacuo to a brown oil (4.2 g) which was dissolved in ME (50 mL) and treated with sodium borohydride (0.74 g). The mixture was stirred under nitrogen for 1 hour, diluted with water (150 mL) and extracted with ER (2 x 150 mL). The organic phase was washed with water (2 x 100 mL), dried and evaporated in vacuo to a brown oil. Purification by [FCS] eluting with CX-EA (2:1) gave the title compound as a yellow oil (1.92 g). TLC (CX-EA 2:1) Rf 0.23.

Calculated for C3gH5QN2O5S•0.75H2O: C, 70.0; H, 7.7; N, 4.2% Found: C, 69.8; H, 7.8; N, 4.2%

Intermediate 5

[ 5-[ 1- hydroxy- 2-[[ 6-( 4- phenylbutoxy) hexyl]( phenylmethyl) amino]-ethyl]- 2-( phenylmethoxy) phenyl] urea

A solution of N-[5-bromoacetyl)-2-(phenylmethoxy)phenyl]-urea (2 g) and N-[6-(4-phenylbutoxy)hexyl]benzenemethanamine

(1.87 g) in THF (100 mL) stirred under nitrogen was treated with N,N-diisopropylethylamine (1.42 g). The mixture was stirred at room temperature under nitrogen for 19 h, diluted with ER (50 mL) and filtered, whereupon the filtrate was evaporated under vacuum. A solution of the resulting orange oil (4.4 g)

in ME (100 mL) was treated with sodium borohydride (1.2 g) and stirred under nitrogen for 19 h. The mixture was diluted with water (200 ml), extracted with ER (2 x 150 ml) and the organic phase washed with water (100 ml), dried and evaporated in vacuo to an orange oil. Purification by [FCS] eluting with EA-CX (2:1) gave the title compound as a yellow oil (1.72 g). TLC (EA-ME 3:1) Rf 0.7.

Intermediate 6

( E )- 4-( 4- fluorophenyl)- 3- buten- 1-ol

n-Butyllithium (1.6M in hexane, 100 mL) was added dropwise to a stirred suspension of (3-hydroxypropyl)triphenylphosphonium bromide (32.1 g) in dry THF (200 mL), cooled to 0°C under nitrogen . A solution of 4-fluorobenzaldehyde (9.93 g) in dry THF (100 mL) was added dropwise and the mixture stirred under nitrogen at 0°C for 30 minutes and at room temperature for a further 1.5 hours. The mixture was diluted carefully with water (25 mL) and the solvent evaporated under vacuum at 40°, whereupon the residue was partitioned between EA (200 mL) and water (200 mL). The aqueous phase was re-extracted with EA (200 mL) and the organic phases combined, dried and evaporated in vacuo to a brown oil. Purification by [FCS] eluting with CX-ER (1:1) gave the title compound as a colorless oil (6.33 g).

TLC. (CX-ER 1:1) Rf 0.13.

Intermediate product 7

( E)- 1-[[ 4-( 6- bromohexyl) oxy]- 2- butenyl]- 4- fluorobenzene

A mixture of Intermediate 6 (5.73 g), 1,6-dibromohexane (25.2 g), tetrabutylammonium bisulfate (1.5 g) and 40% sodium hydroxide solution (45 ml) was stirred for 18 hours, diluted with water (200 mL) and extracted with EA (2 x 150 mL). The organic phase was washed with water (100 mL), brine

(100 mL), dried and evaporated in vacuo to a yellow oil. Purification by [FCS] eluting with CX-EA (10:0 —> 9:1) gave

a yellow oil (8.49 g). TLC. (CX-EA 9:1) Rf 0.34.

Intermediate 8

(E)- N-[ 2- hydroxy- 5-[ 1- hydroxy- 2-[[ 6-[[ 4-( 4- fluorophenyl)-3- butenyl] oxy] hexyl] amino] ethyl] phenyl] methanesulfonamide

Intermediate 7 (1.34 g) was added to a stirred solution of [5-[(2-amino-1-hydroxyethyl)]-2-hydroxyphenyl]methanesulfonamide (1.50 g) and N,N -diisopropylethylamine (0.57 g) in DMF

(25 ml) at 70° under nitrogen. The solution was stirred at 70° for 5 h, diluted with water (100 mL) and extracted with EA (2 x 100 mL). The organic phase was washed with water (100 mL), dried (Na 2 SO 4 ) and evaporated in vacuo to a brown oil, which was purified by [FCS] on triethylamine-deactivated silica (Merck 9385, 100 g) eluting with EA-ME (9:1), to give a brown foam (0.5 g). Trituration with ER gave the title compound as a white solid (0.47 g), m.p. 79-80° (decomp.).

Intermediate 9

N-[5-acetyl-2-(phenylmethoxy)phenyl]propanesulfonamide

Propanesulfonyl chloride (2.8 g) was added to a stirred solution of 1-[3-amino-4-(phenylmethoxy)phenyl]ethanone (3.95 g)

and triethylamine (3.58 g) in dry dichloromethane (80 mL) at 0°C. The solution was stirred at 0°C for 2 hours, diluted with ER

(200 mL), washed successively with 2N hydrochloric acid (100 mL) and 8% sodium bicarbonate solution (100 mL), dried and evaporated in vacuo to give a cream yellow solid. This was slurried in CX to give a solid which was stirred in 1N sodium hydroxide (100ml) and filtered off. The filtrate was acidified with 2N hydrochloric acid

and extracted with EA (2 x 150 ml). The combined dried organic extracts were evaporated in vacuo to a cream yellow solid which was recrystallized from EA to give a white solid (3.40 g), m.p. 130-130.5°.

Intermediate 10

N-[5-bromoacetyl-2-(phenylmethoxy)phenyl]propanesulfonamide

A solution of bromine (1.52 g) in chloroform (25 ml) was added dropwise over the course of 1.5 hours to a stirred solution of Intermediate 9 (3 g) in chloroform (25 ml) at room temperature. The solution was washed with water (30 mL), 8% sodium bicarbonate solution (30 mL), dried (Na 2 SO 4 ) and evaporated in vacuo to give product which was recrystallized from EA to give the title compound as a pale orange solid (2 .75 g), m.p. 99.5-100.5°.

Intermediate 11

N-[ 2-( phenylmethoxy)- 5-[ 2-[[ 6-( 3- phenylpropoxy) hexyl]( phenylmethyl) amino]- 1- oxoethyl] phenyl] propanesulfonamide

Intermediate 10 (0.65 g), N-[6-(3-phenylpropoxy)hexyl]-benzenemethanamine (0.5 g) and N,N-diisopropylethylamine (0.22 g) in DMF (10 mL) were stirred together under nitrogen for 2.5 h, the solution was diluted with water (50 mL), extracted with EA

(2 x 50 mL), after which the organic phase was washed with 2N hydrochloric acid (30 mL), 8% sodium bicarbonate solution (30 mL) and then dried (Na 2 SO 4 ). Evaporation under vacuum afforded a yellow oil which was purified by [FCS] eluting with T-EA (9:1) to give the title compound as a colorless oil (0.77 g).

TLC. (T-EA 9:1) Rf 0.15.

Intermediate 12

1-[ 4-[( 6- bromohexyl) oxy] butyl]- 4- methylbenzene

A mixture of 4-methylbenzenebutanol (6.5 g), 1,6-dibromohexane (24.4 g), aqueous sodium hydroxide (50% w/v; 25 mL) and tetrabutylammonium bisulfate (0.5 g) was stirred at room temperature for 20 hours, diluted with water (50 ml) and extracted with ER (2 x 100 ml). The dried extract was evaporated and the residue purified at [C] eluting with CX and then with CX-ER (93:7) to give the title compound as a colorless oil (9.8 g). TLC. (CX-ER 9:1) Rf 0.5.

Intermediate 13

N-[ 6-[ 4-( 4- methylphenyl) butoxy] hexylJbenzenemethanamine hydrochloride

Intermediate 12 (5.0 g) was added dropwise to benzylamine (25 mL) at 110°. The solution was heated to 110-120°

for 2 h, cooled, poured into hydrochloric acid (2M; 250 mL) and filtered to give the title compound as a white solid (5.3 g), m.p. 119-121°.

Intermediate 14

3-[(6-phenylhexyl)oxy]-1-propanol

Sodium (0.95 g) was dissolved in warm 1,3-propanediol

(9.47 g) and then added dropwise (6-bromohexyl)benzene (10 g). The mixture was stirred under nitrogen at 100° for 3 hours, poured into water (200 mL) and 2N hydrochloric acid (30 mL) and extracted with ER (2 x 150 mL), dried and evaporated in vacuo to a yellow oil. Purification by [FCS] while eluting with CX-ER (3:1 —> 0:1)

gave the title compound as a colorless oil (5.46 g). TLC.

(CX-ER 3:1) Rf 0.08.

Intermediate 15

[ 6-( 3- bromopropoxy) hexyl] benzene

Triphenylphosphine (7.50 g) in dry dichloromethane (50 ml) was added dropwise over 10 minutes to a stirred solution of Intermediate 14 (5.2 g) and carbon tetrabromide (9.49 g) in dry dichloromethane (90 ml ), kept at 0°C under nitrogen. The solution was stirred at room temperature for 2 h, adsorbed onto silica (40 g) and purified by [FCS]. Elution with CX-ER (8:1)

gave a colorless oil which was distilled to give the title compound as a colorless oil (6.58 g). TLC. (IS)

Rf 0.63.

Intermediate 16

N,N- dimethyl- N'-[ 5-[ 2-[[ 6-( 4- phenylbutoxy) hexyl]( phenylmethyl)-amino]- 1- oxoethyl]- 2-( phenylmethoxy) phenyl] sulfamide

N-[5-bromoacetyl-2-(phenylmethoxy)phenyl]-N,N<1->dimethylsulfamide (0.8 g), N-[6-(4-phenylbutoxy)hexyl]benzenemethanamine (0.64 g ) and N,N-diisopropylethylamine (0.27 g) in DMF (10 mL), were stirred at room temperature under nitrogen for 4.5 h. The solvent was evaporated under vacuum and the residue dissolved in EA (100 mL) and washed with water (75 mL). The aqueous phase was re-extracted with EA (2 x 50 mL) and the combined organic phases dried and evaporated in vacuo to a yellow oil. Purification by [FCS] eluting with T-EA (10:1) gave the title compound as a yellow oil (0.66 g). TLC. (T-EA 5:1) Rf 0.35.

Intermediate 17

N-[5-(4-phenylbutoxy)pentyl]benzenemethanamine

[4-[(5-bromopentyl)oxy]butyl]benzene (4.0 g) was added dropwise to benzylamine (20 mL) at 110°. The solution was heated to 110-120° for 90 minutes and cooled. Hydrochloric acid (2M;

125 mL) was added and the mixture extracted with EA (2 x 100 mL). The organic extract was washed with aqueous sodium carbonate (100 mL) and brine (100 mL), dried and evaporated. The residue was distilled to give the title compound as a colorless oil (3.3 g), b.p. 190-195°/0.1 mm Hg. TLC. (CX-ER 1:1) Rf 0.25.

Example 1

N-[ 2- hydroxy- 5-[ 1- hydroxy- 2-[[ 6-( 3- phenylpropoxy) hexyl]-amino] ethyl] phenyl] formamide

A solution of Intermediate 1 (0.25 g) in ethanol (20 ml) was hydrogenated at room temperature and atmospheric pressure over 10% palladium on charcoal (0.15 g) and 10% platinum on charcoal (0.15 g) as catalysts. The mixture was filtered through hyflo and evaporated under vacuum. The residue was triturated with ER and cooled to give the product as a white solid (0.092 g), m.p. 85-86°

(decomp.). TLC. Et 3 N deactivated silica (EA-ME 7:3) Rf 0.68.

In a similar way, it was produced:

Example 2

N-[ 2- hydroxy- 5-[ 1- hydroxy- 2-[[ 6-( 3- phenylpropoxy) hexyl]-amino] ethyl] phenyl] urea, m.p. 78-80°.

TLC. Et 3 N deactivated silica (EA-ME 7:3) Rf 0.62 (0.26 g) from Intermediate 2 (0.6 g).

Example 3

N-[ 2- hydroxy- 5-[ 1- hydroxy- 2-[[ 6-( 3- phenylpropoxy) hexyl] amino] ethyl] phenyl] methanesulfonamide, m.p. 130-134° (decomp.). TLC. Et 3 N deactivated silica (EA-ME 7:3) Rf 0.62 (0.13 g) from Intermediate 3 (0.3 g).

Example 4

N-[ 2- hydroxy- 5-[ 1- hydroxy- 2-[[ 6-( 4- phenylbutoxy) hexyl]-amino] ethyl] phenyl] methanesulfonamide

Intermediate 4 (0.98 g) in absolute ethanol (20 mL) was hydrogenated over 10% palladium on charcoal (50 mg) and 5% platinum on charcoal (50 mg) as catalysts. The mixture was filtered through hyflo and evaporated under vacuum. The remaining brown oil (0.72 g) solidified by trituration with ER. and gave the title compound (0.34 g), m.p. 89-91°.

Calculated for C^H^N^S • 0.25H 2 O: C, 62.1; H, 8.0; N, 5.8% Found: C, 61.8; H, 7.7; N, 5.55%

Example 5

N-[ 2- hydroxy- 5-[ 1- hydroxy- 2-[[ 6-( 4- phenylbutoxy) hexyl]-amino] ethyl1] phenyl] urea

A solution of Intermediate 5 (0.7 g) in ethanol (15 mL) was hydrogenated over 10% palladium on charcoal (50 mg) and 5% platinum on charcoal (50 mg) as catalysts. The mixture was filtered through hyflo and evaporated in vacuo to give a yellow oil which was triturated with ER to give a light gray solid (0.32 g), m.p. 87-89°.

TLC. (EA-ME 1:1) Rf 0.18.

Example 6

N-[ 2- hydroxy- 5-[ 1- hydroxy- 2-[[ 1- methyl- 6-( 2- phenylethoxy)-hexyl] amino] ethyl] phenyl] methanesulfonamide

A solution of [7-[2-phenylethoxy]heptan-2-one (0.70 g)

and N-[5-[2-[bis(phenylmethyl)amino]-1-oxoethyl]-2-(phenylmethoxy)phenyl]methanesulfonamide (1.54 g) in absolute ethanol (50 mL), was hydrogenated over a mixt. of pre-reduced 5% platinum on charcoal (250 mg) and 10% palladium on charcoal (250 mg) as catalysts in ethanol (25 ml). The mixture was filtered through hyflo and evaporated under vacuum to a white solid (1.3 g). Purification by [FCS] on triethylamine-deactivated silica (Merck 9385, 50 g) eluting with EA-ME (9:2) followed by trituration with ER afforded the title compound as a white solid (0.88 g). , m.p. 122.5-123.5°.

Calculated for C24H36<N>2<0>5S•0.75H20:C, 60.3; H, 7.9; N, 5.9% Found: C, 60.3; H, 7.7; N, 5.9%

Example 7

N-[ 2- hydroxy- 5-[ 1- hydroxy- 2-[[ 6-[ 4-( 4- fluorophenyl) butoxy]-hexyl] amino] ethyl] phenyl] methanesulfonamide

A solution of Intermediate 8 (0.25 g) in absolute ethanol (10 ml) was hydrogenated over a pre-reduced mixture of 10% palladium on charcoal (40 mg) and 5% platinum on charcoal (40 mg) as catalysts in ethanol (5 mL). The mixture was filtered through hyflo and evaporated in vacuo to give a brown oil, which on trituration with ER gave the title compound as an off-white solid (0.15 g), m.p. 84-85° (decomp.).

Calculated for C₂H₂FN₂S-2H₂O: C, 56.4; H, 7.8; N, 5.3% Found: C, 56.5; H, 7.4; N, 5.4%

Example 8

N-[ 2- hydroxy- 5-[ 1- hydroxy- 2-[[ 6-( 3- phenylpropoxy) hexyl]-amino] ethyl] phenyl] propanesulfonamide

A solution of Intermediate 11 (0.65 g) in absolute ethanol (40 mL) was hydrogenated over a pre-reduced mixture of 10% palladium on charcoal (150 mg) and 5% platinum on charcoal

(150 mg) as catalysts, in ethanol (10 ml). The mixture was filtered through hyflo and evaporated under vacuum to give a

yellow oil, which on trituration with ER gave the title compound as a white solid (170 mg), m.p. 82-83.5° (decomp.).

Calculated for C26<H>40<N>2°5S"0'5H2°: C'62.2; H'8.2; N'5.6% Found: C, 62.3; H, 7.9 ; N, 5.5%

Example 9

N-[ 2- hydroxy- 5-[ 1- hydroxy- 2-[[ 3-[( 6- phenylhexyl) oxy] propyl]-amino] ethyl] phenyl] methanesulfonamide- benzoate (salt)

Intermediate 15 (0.69 g) in DMF (2 mL) was added dropwise to a solution of N-[5-[(2-amino-1-hydroxyethyl)]-2-hydroxyphenyl]methanesulfonamide (0.85 g) and N,N-diisopropylethylamine (0.33 g) in DMF (20 mL) at 80°C under nitrogen. The mixture was stirred at 80° for 3 hours and then evaporated under vacuum. The remaining oil was dissolved in EA (50 mL) and washed with

water (100 ml). The aqueous phase was re-extracted with EA

(75 mL), the combined organic phases dried (Na 2 SO 4 ) and evaporated in vacuo to an oil. Purification by [FCS] eluting with T-ET-A (39:10:1) gave a brown oil which was dissolved in ME (10 mL) and treated with benzoic acid (0.08 g). The solvent was evaporated under vacuum and the residue triturated with ER

to give the title compound as an ivory solid (140 mg), m.p. 133-133.5°.

Calculated for C24H36N2°5S' C7H6°2"0' 5H2O: C'62'50; H'7'28'" N'4/70% Found: C, 62.79; H, 7.27; N, 4.77

Example 10

N-[ 2- hydroxy- 5-[ 1- hydroxy- 2-[[ 5-( 4- phenylbutoxy) pentyl]-amino] ethyl1] phenyl] acetamide

A solution of N-[5-bromoacetyl-2-(phenylmethoxy)phenyl]-acetamide (1.00 g), Intermediate 17 (0.9 g) and N,N-diisopropylethylamine (0.46 g) in DMF (50 ml) was stirred under nitrogen for 6 hours. The solution was diluted with water (50 mL) and extracted with EA (2 x 100 mL) and washed with 2N hydrochloric acid (50 mL),

2N sodium bicarbonate (50 mL), dried (Na 2 SO 4 ) and evaporated in vacuo to a yellow oil which crystallized on standing.

The resulting cream yellow solid (1.67 g) was dissolved in ethanol (90 mL) and hydrogenated over a mixture of pre-reduced 10% palladium oxide on charcoal (300 mg) and 5% platinum oxide on charcoal (300 mg) as catalysts in ethanol (25 ml). The mixture was filtered through hyflo and evaporated under vacuum to an oil which, when rubbed with ER, gave a brown foam. Purification by [FCS] eluting with T-ET-A (39:10:1) gave an oil which on trituration with ER gave the title compound as a brown foam (0.31 g). TLC (T-ET-A 39:10:1) Rf 0.26.

Calculated for C25H36N2°4 *0' 5H20: C'68'62'" H'8.52; N, 6.40% Found: C, 68.66; H, 8.53; N, 6.39

Example 11

N'-[ 2- hydroxy- 5-[ 1- hydroxy- 2-[[ 6-( 4- phenylbutoxy) hexyl]-aminojetyl] phenyl]- N, N- dimethyl sulfamide

A solution of Intermediate 16 (0.61 g) in absolute ethanol (30 mL) was hydrogenated over a mixture of pre-reduced 5% platinum oxide on charcoal (150 mg) and 10% palladium oxide on charcoal (150 mg) as catalysts in ethanol (10ml). The mixture was filtered through hyflo and evaporated under vacuum to an oil. Purification by [FCS] eluting with T-ET-A (39:10:1) gave a brown oil which on trituration with ER gave a cream solid (0.20 g), m.p. 75-77°.

Calculated for C^H^N^S: C, 61.51; H, 8.14; N, 8.28% Found: C, 60.96; H, 8.12; N, 8.16

Example 12

N-[ 2- hydroxy- 5-[ 1- hydroxy- 2-[[ 6-[ 4-( 4- methylphenyl) butoxy]-hexyl] amino] ethyl] phenyl] methanesulfonamide

A solution of N-[5-(bromoacetyl)-2-(phenylmethoxy)phenyl]-methanesulfonamide (1.0 g), the amine (0.9 g) obtained by alkalization of Intermediate 13, and N,N-diisopropylethylamine (0 .4 g) in THF (20 mL), was left at room temperature for 18 h, filtered and evaporated. The residue was purified at [C] eluting with CX-ER (1:1) to give a yellow oil (1.0 g). The oil in ethanol (50 mL) and THF (30 mL) was hydrogenated over 10% palladium on charcoal (0.4 g) and 5% platinum on charcoal (0.3 g) for 5 hours, filtered and evaporated. The residue was purified at [c] eluting with T-ET-A (80:20:1) to give a yellow gummy product which was triturated with ER

(40 ml), whereby the title compound was obtained as a yellow solid (0.2 g), m.p. 65-67°. TLC (T-ET-A 80:20:1) Rf 0.2.

Example 13

N-[ 2- hydroxy- 5-[ 1- hydroxy- 2-[[ 6-( 4- phenylbutoxy) hexyl]-amino] ethyl] phenylmethanesulfonamide- acetate salt

A solution of N-[2-hydroxy-5-[1-hydroxy-2-[[6-(4-phenylbutoxy)hexyl]amino]ethyl]phenyl]methanesulfonamide (4.0 g) in chloroform (50 mL), was treated with acetic acid (0.8 g), after which the chloroform was evaporated. The residue was triturated with ER (50 mL)

and left a yellow solid which was recrystallized from EA-ME to give the title compound as a white solid (3.7 g), m.p. 121-123°.

Calculated for C2"5H38N2°5S "C2H4°2'0' 5H20: C'59'2'* H'7'85'"N'5'1 % Found: C, 59.3; H, 7.9; N, 5.1

Claims (14)

1. Process for the preparation of compounds of the general formula (I) where m is an integer from 2 to 8 and n is an integer from 1 to 7, it being assumed that the sum m+n is 4 to 12; Ar means a phenyl group which is optionally substituted with one or more substituents selected from halogen atoms, C 1 -6 alkyl or C 1 -galkoxy groups, or an alkylenedioxy group of the formula -O(CH 9 ) 0 -, where p means 1 or 2; 1 2 p R and R each mean a hydrogen atom or a C 1-4 alkyl group, provided that the sum of the carbon atoms in R 1 and R 2 is not more than 4; Q means an R <3> C0 -, R <3> NHC0 -, R <3> R <4> NS09 - or R <5> S09 - group, where 3 4 R and R each represent a hydrogen atom or a C 5 alkyl group and R represents a C 4 alkyl group; as well as physiologically acceptable salts and solvates thereof, characterized by (1a) for the preparation of a compound of formula (I), where R is a hydrogen atom, alkylation of an amine of the general formula (II) (where each of R 6 and R<7> is a hydrogen atom or a protecting group and R g is a hydrogen atom), with an alkylating agent of the general formula (III) LCH(CH0) 0(CH„) Ar (III) , ~ 2 . m 2 . n R (where L means a leaving group), optionally followed by removal of the protecting group; or (1b) for the preparation of a compound of formula (I), where R 1 is a hydrogen atom, alkylation of an amine of the general formula (IV) (where each of R 6 and R 7 is a hydrogen atom or a protecting group, R gmeans a hydrogen atom or a group which can be converted to hydrogen under the reaction conditions, and X1 stands for -CH(OH)- or ^C=0), with a connection with the general formula (V) in the presence of a reducing agent, whereupon any protecting groups are removed; or (2) removal of the protecting group in a protected intermediate of formula (VII) (where each of R 6 and R 7 is a hydrogen atom or a protecting group, but at least one of them is a protecting group); or (3) reduction of an intermediate of formula (VIII) (wherein R is a hydrogen atom or a protecting group, X 1 is, or can be reduced to, a -CH(OH) group, 2 7 X is, or can be reduced to, a -CH-NR -group, 3 T 2 X is, or can be reduced to, a -CR R (CH2)m_1 group, and as mX i4nest r, one elalv is X k1 a, n X r2 e, dx u3 seorg es X 4 tilst, year a for-r (CeHn 9) rned1u-gserrubppar e, group) followed, if necessary, by the removal of any protective groups; whereupon the resulting compound of formula (I) or a salt thereof is optionally converted into a physiologically acceptable salt or solvate thereof. 2. Method according to claim 1, characterized in that compounds are produced where the total number of carbon atoms in the chains~ (<--H2 ^m~°^~ ^H2 ^n~ is 7 to 10. 3. Process according to claim 2, characterized in that compounds are prepared where m is 2 or 3 and n is 6, or where m is 4 and n is 3, 4 or 5, or where m is 5 and n is 2, 3 or 4. 4. Method according to claim 3, characterized in that compounds are prepared where m is 5 and n is 4. 5. Method according to claims 1-4, characterized 1 2 by making compounds where R and R independently of each other stand for a hydrogen atom or a methyl group. 6. Process according to claim 5, characterized in that compounds are prepared where R i is a hydrogen atom and R <2> is a hydrogen atom or a methyl group. 7. Method according to claims 1-6, characterized in that compounds are prepared where Q is HCO-, CH3 CO-, NH2 CO-, (CH3 )NS02 -, or R<5>SO2", where R5 is C3 alkyl. 8. Method according to claim 7, characterized in that compounds are prepared where Q is R^SO„-, where R 5 stands for methyl. 9. Method according to claims 1-8, characterized in that compounds are prepared where Ar is a phenyl group which is optionally substituted with a methyl group or a fluorine atom. 10. Method according to claim 1, characterized in that compounds with the general formula (Ia) are prepared where m is an integer from 2 to 5, n is an integer from 2 to 6 and the sum m+n is 7, 8 or 9; R 1 means hydrogen and R<2> means a hydrogen atom or a methyl group; Ar means a phenyl group optionally substituted with a methyl group or a fluorine atom; and Q R5 beer tyCr | HC3Oa-lk, yClH; 3Cog O-f, yNsHio2ClOog-i, sk (CHak3s)e2NptS0ab2~ le elsalelr ter R5So0g 2~so, lvhvatoerr thereof. 11. Process according to claim 10, characterized in that compounds of formula (Ia) are prepared where m is 5 and n is 4, Q is CH3 SO2~ and Ar is a phenyl group or a phenyl group substituted with a fluorine atom. 12. Method according to claim 1, characterized by the preparation of the compound: N-[2-hydroxy-5-[1-hydroxy-2[[6-(4-phenylbutoxy)hexyl]amino]-ethyl]phenyl]methanesulfonamide and physiologically acceptable salts and solvates thereof. 13. Method according to claim 1, characterized in that one of the following compounds is produced: N-[2-hydroxy-5-[1-hydroxy-2-[[6-[4-(4-fluorophenyl)butoxy]-hexyl]amino]ethyl]phenyl]methanesulfonamide; N-[2-hydroxy-5-[1-hydroxy-2-[[1-methyl-6-(2-phenylethoxy)-hexyl]amino]ethyl]phenyl]methanesulfonamide; N-[2-hydroxy-5-[1-hydroxy-2-[[6-(3-phenylpropoxy)hexyl]-amino]ethyl]phenyl]formamide; N-[2-hydroxy-5-[1-hydroxy-2-[[6-(4-phenylbutoxy)hexyl]amino]-ethyl]phenyl]urea; N-[2-hydroxy-5-[1-hydroxy-2-[[3-[(6-phenylhexyl)oxy]propyl]-amino]ethyl]phenyl]methanesulfonamide; N-[2-hydroxy-5-[1-hydroxy-2-[[6-(3-phenylpropoxy)hexyl]-amino]ethyl]phenyl]urea; N-[2-hydroxy-5-[1-hydroxy-2-[[6-(3-phenylpropoxy)hexyl]amino]ethyl]phenyl]methanesulfonamide; N-[2-hydroxy-5-[1-hydroxy-2-[[6-[4-(4-methylphenyl)butoxy]hexyl]amino]ethyl]phenyl]methanesulfonamide; and physiologically acceptable salts and solvates thereof. 14. Method according to claim 1, characterized 1 2 in that compounds are prepared where m, n, R and R are as stated in claim 1, Ar means a phenyl group which optionally has one or two substituents selected from halogen atoms, C 1 -3 alkyl or 4 alkoxy groups, or a alkylenedioxy group of formula -0(CH„) 0-, where p is 1 or 2, and where Q means 3 P 3 3 4 the group R CO-, R NHCO5 - or R S0z~-, where R and R are as indicated in claim 1 and R is C₁ alkyl.