NL8502012A - AMINOPHENOL COMPOUNDS. - Google Patents

Description

»*«.

VO 7298

Aminophenol compounds.

The invention relates to aminophenol derivatives having a stimulatory effect on β-3-adrenoceptors, to methods for their preparation, to pharmaceutical preparations containing them, and to their use in medicine.

Aminophenol derivatives with a sulfonamido or ureldo substituent in the phenol ring have previously been described as bronchodilators that stimulate 8-adrenoreceptors.

British patent 993,584 describes compounds of the general structural formula 16 of the formula sheet.

10 wherein R * represents lower alkyl, phenyl or toluyl; X represents, inter alia, hydroxy; Z represents -CH (OH) - among others; 2 3 R and R each represent hydrogen and 4 R represents hydrogen, lower alkyl or aralkyl or aryloxyalkyl, wherein the aryl ring may be substituted if desired with hydroxy, methoxy or methylenedioxy.

British patent 1,286,225 describes compounds of the general structural formula 17 of the formula sheet.

wherein R represents hydrogen, alkyl, phenyl, dimethylaminoethyl or dimethyl aminopropyl; 2 3 R and R each represent, inter alia, hydrogen and 4 R represents a C 1 -alkyl, C-cycloalkyl, C-cycloalkylmethyl 3-5 O 3 3e or the group of formula 18.

wherein: 5 6 25 R and R each represent hydrogen, hydroxy or methoxy.

We have now found a new group of aminophenol derivatives, which differ structurally from those described in British Pat. Nos. 993,584 and 1,286,225, and which have a desirable and useful scope.

The invention therefore provides compounds of the general formula (1).

wherein m is an integer from 2 - 8 and n is an integer from 1 - 7 where the sum of m + n equals 4 - 12; Ar represents a phenyl group, optionally substituted with one or more substituents selected from halogen atoms, C 1-6 alkyl or <3 kn ~ * * υ ·. -jc 1 * - i -2-C, c alkoxy groups or an alkylenedioxy group of the formula 1-6 -O (CH) 0-, 2 p wherein p is 1 or 2; 1 2 5 R and R each represent a hydrogen atom or a C 1 -alkyl group provided that 1 2 1 - the sum of the carbon atoms in R and R does not exceed 4; Q represents an R ^ CO, R ^ NHCO, R ^ R ^ NSO or R ^ SO group where 3 4 2 2 R and R each represent a hydrogen atom or a C ^ ^ alkyl group and R ^ a ^ alkyl group , and physiologically acceptable salts and solvent compounds (eg hydrates) thereof.

It is clear that the compounds of the general formula (1) have one or two asymmetric carbon atoms, namely the carbon 1 2

atom of the -CH- group and, when R and R are different groups, 15 OH

the carbon atom to which they are attached.

The compounds of the invention therefore include all enantiomers, diastereoisomers and mixtures thereof, including racemates. Compounds, in which the carbon atom in the CH group is the 20 OH

R configuration is preferred.

According to an aspect of the invention, there are provided compounds of the formula (1) wherein: 1 2 m, n, R and R are as defined above.

Ar represents a phenyl group, optionally substituted with 1 or 2 substituents selected from halogen atoms, C 1-6 alkyl or C 1-6 alkoxy groups, or an alkylenedioxy group of the formula -O (CH) 0-2 p wherein: 30 p 1 or 2 is and 3 3 5 3 4

Q represents the group R CO-, R NHCO- or R SO -, in which R and R.

15 as defined in formula (1) and R represents a C 1-6 alkyl group.

In the general formula (1), the chain- (CH2) m - e.g. 35 - (CH2) 2-, - (CH2) 3-, - (CH2) 4 -, - (CH2) 5-, - (CH2) ) 6- or - (CH ^? - and the chain - (C ^ n "can be, for example - (CH ^ -, - (CH ^ -, - (CH2) 4-, - (CH2) 5 or - (CH2) ) g-.

H 'S Λ ’· · ·' '~ JS -i» «...

* * -3-

Preferably, the total number of carbon atoms in the chains is - (CH-) m- and - (CH_) n - 6 to 12 and may be, for example, 7, 8, 9 or 10.

6 *

Compounds in which the sum m + n equals 7.8 or 9 are particularly preferred.

The preferred compounds of general formula (1) are those wherein m = 2 or 3 and n is 6, or m is 4 and n is 3, 4 or 5, or m is 5 and n is 2, Is 3 or 4. Most preferably m 5 and n 4.

1 2

For example, in the compounds of formula (1), R and R can each be methyl, ethyl, propyl or isopropyl groups, except that if 1 2 is one of the groups R or R, a propyl or isopropyl group, the other a hydrogen atom or a methyl group. Thus, R * can be, for example, a 2 hydrogen atom or a methyl, ethyl or propyl group. R 1 can be, for example, a hydrogen atom or a methyl group. R and R are each preferably a hydrogen atom or a methyl group.

A preferred group of compounds is the group 12 wherein R and R are both hydrogen atoms, or R is a hydrogen atom 2 and R is a C, alkyl group, especially a methyl group.

3 4

In the group Q, R and R can each be, for example, a hydrogen atom 20 or a methyl, ethyl, propyl or isopropyl group and R1 can be, for example, a methyl, ethyl, propyl, isopropyl or butyl group. Preferably, R 4 represents hydrogen or methyl, R represents hydrogen or methyl and R 5 represents alkyl. Preferred meanings for the group Q are HCO-, 1 J J 5 5 CH 2 CO-, NH 2 CO-, (CH 2) 2 NSO 2 ~, and R SO 2 ~, wherein R is alkyl, more in particular methyl or n- propyl. A preferred group of compounds is the group, wherein Q represents HCO-, NH2CO- or, more preferably, CH2 SC1-.

Examples of substituents which may be present on the phenyl group indicated by Ar include, if desired, bromine, iodine or, in particular, chlorine or fluorine atoms, or an alleyl group (eg methyl or ethyl), or an alkoxy group (eg methoxy) or ethoxy). The phenyl group an denoted by Ar contain, for example, 1 or 2 substituents, which may be present at the 2-, 3-, 4-, 5- or 6-position on the phenyl ring. Ar is preferably a phenyl group, if desired, substituted with a substituent, especially a methyl group or a fluorine atom. More preferably, Ar means an unsubstituted phenyl group.

8502012 ♦ #% -4-

A preferred group of compounds are the compounds of formula, (1a) wherein: m is an integer from 2-5; n an integer from 2-6, 5 and the sum m + n equals 7, 8, or 9; R 1 represents hydrogen and 2 R represents a hydrogen or a methyl group;

Ar represents a phenyl group, optionally substituted with a methyl group or a fluorine atom; and Q represents HCO-, CH 2 CO-, NH 2 CO-, (C 2 NSC 2 - or R 2 SO 2), wherein R 2 is alkyl, and physiologically acceptable salts and solvent compounds thereof.

A particularly preferred group of compounds of formula (1a) is the group wherein m is 5 and n is 4.

Another particularly preferred group of compounds of formula (1a) is the group wherein Q R is SC 1 - and R is a methyl group.

In a further particularly preferred group of compounds of formula (1a), Ar is a fluorine-substituted phenyl group, or more preferably, an unsubstituted phenyl group.

Particularly important compounds of 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, 8502012 * -5- 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, 5 N- [2-hydroxy-5- [1-hydroxy- 2 - [[6- [4- {4-methylphenyl) butoxy] hexyl] amino] ethyl] phenyl] methanesulfonamide, and the physiologically acceptable salts and solvent compounds thereof.

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

The compounds according to the invention have a selective, stimulating effect on S-adreno receptors, which in addition has a particularly favorable character. The stimulatory effect was demonstrated in the isolated guinea pig trachea, where the compounds were found to cause relaxation of PGF-induced contractions. The compounds according to the invention were found to have a particularly long duration of action in this test.

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

The compounds of the invention can also be used for the treatment of premature labor, depression and congestive heart failure, and are also indicated for the treatment of inflammatory and allergic skin diseases, glaucoma and for the treatment of conditions in which it is beneficial to reduce the acidity of the gastric juice, especially in case of inflammation of the gastrointestinal tract.

8502012 u t> -6-

Accordingly, the invention further provides compounds of formula (1) and their physiologically acceptable salts and solvent compounds for use in the treatment or prevention of diseases associated with reversible airway obstruction in humans and animals.

The compounds of the invention can be brought into a dosage form in any suitable manner. The invention therefore also relates to pharmaceutical preparations containing at least one compound of formula (1) or a physiologically acceptable salt or a compound with solvent thereof, formulated for use in human or animal medicine.

Such formulations may be presented for use with physiologically acceptable carriers or excipients, if desired with further drugs.

The compounds can be brought into a form suitable for administration by inhalation or insufflation or for oral, buccal, parenteral, topical (including nasal) and / or rectal administration. Administration by inhalation or insufflation is preferred.

For inhalation administration, the compounds of the invention are conveniently administered in the form of an aerosol spray administration from pressurized packages, using a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas, or from an atomizer. In the case of a pressurized aerosol, the dosage unit can be determined by providing a tap for dispensing a measured amount.

Alternatively, for administration by inhalation or blowing, the compounds of the invention may be in the form of a dry powder mixture, for example, a powder mixture of the compound and a.

Suitable powder base, such as lactose or starch. The powder mixture can be administered in unit dose form in, for example, capsules or cartridges of, for example, gelatin, or blister packs, from which the powder can be administered by means of an inhaler or blower.

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

8502012 -7- * t,

For buccal administration, the composition may be in the form of conventionally prepared tablets, drops, or cough tablets.

The compounds of the invention can be molded for parenteral administration. Preparations for injections can be in unit dose form in ampoules or multi-dose containers with added preservative. The mixtures can be brought in such a form as suspensions, solutions or emulsions in oil or aqueous carriers and can contain preparation agents, such as suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient may be in powder form to be combined with a suitable carrier before use, such as, for example, sterile pyrogen-free water.

For topical administration, the pharmaceutical composition may be in the form of ointments, lotions or creams, which are formulated in a conventional manner, eg, with an aqueous or oily base, generally by the addition of suitable thickeners and / or solvents. For nasal administration, the composition may be in the form of a spray, for example, in the form of an aqueous solution or suspension or as an aerosol, using an appropriate propellant.

The compounds of the invention may also be in the form of rectal compositions, such as suppositories or retention clisms, which contain, for example, a conventional suppository base, such as cocoa butter or other glycerides.

Where above pharmaceutical compositions are described for oral, buccal, rectal or topical administration, they may be administered in a conventional manner, in conjunction with sustained release forms.

A proposed daily dose of active compound for the treatment of man is 0.005-100 mg, which can be easily administered in 1 or 2 doses. The precise dose used will, of course, depend on the age and condition of the patient and on the route of administration. Thus, a suitable dose for administration by inhalation is 0.005 - 20 mg, for oral administration 0.02 - 100 mg, and for parenteral administration is 0.01 - 2 mg for administration by injection and 0.01 - 25 mg for administration by infusion.

8502012 ύ · -8-

The compounds of the invention can be prepared by a number of methods as described below, wherein Q, m, n, Ar, 1 2 R and R have the meaning defined for the general formula (1) unless otherwise stated. It will be understood that certain reactions described below may affect other groups in the starting material which are desired in the final product; this mainly relates to the reduction processes described, in particular where a hydride is used as a reducing agent and final products are desired, 3 in which Q represents the group R CO- and where hydrogen and a metal catalyst are used in the preparation of intermediates, containing an ethylene or ethyne bond. Therefore, in accordance with conventional practice, care should be taken to use reagents that do not affect such groups, or run the reaction as part of a chain that avoids their use when such groups are present in the starting material. In the general methods described below, the last step in the reaction may be the removal of a protecting group. Suitable protected groups and their removal are described in the general procedure (2) below.

According to a general method (1), a compound of the general formula (1) can be prepared by alkylation. Conventional alkylation methods can be used.

For example, in one process (a), a compound of the general formula (1), wherein R 1 is a hydrogen atom, can be prepared by alkylation of an amine of the general formula (2) wherein each of 6 7 of the groups R and R a hydrogen atom or a protecting group 8 and R is a hydrogen atom, followed by removal of any protecting group present.

The alkylation (a) can be carried out using an alkylating agent of the general formula (3) in which 30 L represents 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 scavenger, for example inorganic bases such as sodium or potassium carbonate, organic bases such as triethylamine, diisopropylethylamine or pyridine, or alkylene oxides or propylene oxides.

The reaction is easily carried out in a solvent, such as 8502012 -9 - acetonitrile or an ether, for example tetrahydrofuran or dioxane, a ketone, for example butanone or methyl isobutyl ketone, a substituted amide, for example dimethylformamide or a chlorinated cooking hydrogen, for example chloroform. temperature between ambient temperature 5 and the reflux temperature of the solvent.

According to another example (b) of an alkylation process, a compound of the general formula (1), wherein R * represents a hydrogen atom, can be prepared by alkylation of an amine of the general formula (4): R 7 and R 7 mean above, g R represents a hydrogen atom or a group convertible therein under the reaction conditions and represents X 1 -CH (OH) - or jc = 0, with a compound of the general formula (5): 15 in the presence of a reducing agent, if necessary followed by removal of any protecting groups.

g

Examples of suitable R groups that can be converted to a hydrogen atom are arylmethyl groups, such as benzyl, α-methyl-benzyl and benzylhydryl groups.

Suitable reducing agents include hydrogen in the presence of a catalyst such as platinum, platinum oxide, palladium, palladium oxide, Raney nickel or rhodium, on a support, such as carbon, using Vein an alcohol, for example ethanol, or an ester, for example ethyl acetate, or an ether, for example tetrahydrofuran or water, as a reaction solvent, or a mixture of solvents, for example a mixture of two or more of the above-described solvents at normal or elevated temperature and pressure, for example at 20-100 ° C and at 1- 10 atmosphere.

7 8

Alternatively, when one or both groups R and R are hydrogen atoms, the reducing agent may be a hydride such as diborane or a metal hydride such as sodium borohydride, sodium cyanoborohydride or lithium aluminum hydride. Suitable solvents for the reaction with these reducing agents will depend on the hydride used, but will include alcohols, such as methanol or ethanol, or ethers such as diethyl ether or t-butyl methyl ether, or tetrahydrofuran.

When a compound of the formula (2) is used, wherein 7 8 R and R are each hydrogen atoms, the imine of the formula (6} can be formed as 8502012 -10-g intermediate wherein R has the meaning as defined for formula ( 2).

Reduction of the imine using the conditions described above, if necessary followed by removal of any protecting groups, gives a compound of the general formula (1)

When it is desired to use a protected intermediate of the general formula (2) or (4), it is especially easy to use hydrogen and a catalyst, as described above, with protecting groups R and R which are below these reducing conditions can be converted to a hydrogen atom, avoiding the need for a separate deblocking step. Suitable protecting groups of this kind include arylmethyl groups such as benzyl, benzhydryl and α-methylbenzyl.

In another general method (2), a product of the general formula (1) can be obtained by deprotecting a protected 6 7 intermediate of the general formula (7) (wherein R and R have the meaning previously stated, except that at least one of groups 6 7 R and R is a protecting group).

The protecting group can be any conventional protecting group, for example as described in "Protective Groups in Organic Chemistry", 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 tetrahydro-pyranyl. Examples of suitable amino protecting groups represented by R are aralkyl groups, such as benzyl, ot-methylbenzyl, diphenylmethyl or triphenylmethyl and acyl groups, such as trichloroacetyl or trifluoroacetyl.

The deblocking to provide a compound of the general formula (1) can be done using conventional techniques. For example, when R and / or R is an aralkyl group, these can be cleaved off by hydrogenolysis in the presence of a metal catalyst g (e.g. palladium on carbon). When R is tetrahydropyranyl, it can be cleaved by hydrolysis under acidic conditions.

Acyl groups represented by R can be removed by hydrolysis, for example with a base such as sodium hydroxide, or a group such as trichloroacetyl can be removed by reduction with, for example, 8502012 7-11 zinc and acetic acid. However, the choice of the acyl group R and the method of its removal will depend on the nature of the group Q.

In another general method (3), a compound of the general formula (1) can be prepared by reduction. For example, a compound of the general formula (1) can be prepared by reducing an intermediate of the general formula (8) (where R has the meaning defined for the general formula (2) and at least 12 3 4 one of the groups X, X, X and X represents a reducible group and the others have the following suitable meaning, wherein X * is equal 2 7 3 1 2 4 10 to -CH (OE) -, X to -CH NR, x on -CR R (CHJ, -enX on -CH „) 2 2 mi z η – 1 if necessary followed by removal of any protecting groups).

Suitable reducible groups include the groups wherein X1 is a ^ 2 / C = O group, x a -CH ^ NY group (wherein Y represents a group convertible to hydrogen by catalytic hydrogenation, eg an arylmethyl group such as benzyl, benzhydryl or α-methylbenzyl), or a 3 imine group (-CH = N-) or a group -CONH-, X a group -CO (CH 2) or a 1 2 5 5 ^ group -CR RX - where X is a C alkenylene or C 1 -alkynylene, or 2 3 2 4 -X -X - a -CH 2 N = CR (CH_) group, or X being a C, alkenylene or 2 2 m-1 2-b 20 C is alkynylene. In one convenient side of the reduction process, R may be a hydrogen-convertible group under the reducing conditions used and may be, for example, an arylmethyl group such as benzyl, benzhydryl or α-methylbenzyl.

The reduction can be carried out with the aid of reducing agents with which ketones, imides, amides, protected amides, olefins and alkynes can be easily reduced. For example, when X * in the general formula (8) represents a C = O group, it can be reduced to a -CH (OH) group using hydrogen in the presence of a catalyst, as described above for the process (1 ) part 30 (b). Alternatively, the reducing agent may be, for example, a hydride such as diborane or a metal hydride such as lithium aluminum hydride, sodium bis (2-methoxyethoxy) aluminum hydride, sodium borohydride or aluminum hydride. The reaction can be performed in a solvent, where appropriate, an alcohol, for example, methanol or ethanol, or an ether, such as tetrahydrofuran, or a halogenated hydrocarbon, such as dichloromethane.

8502012 2 * 4 -12-

When X in the general formula (8) represents a -CH NY group 2 3 2 1 or the group -CH = N-, or X -X CH „N = CR (CEL). 2 ml can be re-duoated to a -CE ^ NH- or -CH ^ NHCHR2 (CH ^) ^ ^ group using hydrogen in the presence of a catalyst, as described above for method (1), part (b). Alternatively, 2 2 3 2 when X or -X -X is the group -CH = N- or -CH „N = CR (CEL) -, it can be 2 ^ 2 m — 1 to a -CHnNH- or CH NHCHR (CHJ group to be reduced with be-222 m-1 with the aid of a reducing agent and under conditions as before

1 N

for the reduction of X when it represents a) c = 0 group.

• 2 3 10 When X or X in the general formula (8) represents a -CONH or CO (CH 2) m 2 group, it can be reduced to a -CH 1 -NH- or a -CH 2 (CH.) group using a hydride such as diborane or 2 ml of a complex metal hydride such as lithium aluminum hydride or sodium bis (2-methoxyethoxy) aluminum hydride in a solvent such as an ether, for example tetrahydrofuran or diethyl ether.

3 12 5

When X in the general formula (8) represents a -CR RX group 1 2, it can be reduced to a -CR R (CH ^^^ group using hydrogen in the presence of a catalyst, as described above for the method (1) part (b).

4 When X is a C 1 -alkenyl or C -alkynyl group, this 2-o 2—0 can be reduced to - (CHJ - by hydrogen and a 2 ½ -1 catalyst, as just described. this aspect of the reduction process include suitable starting materials of the formula (8) compounds, wherein CR RX and / or X each contain one -C = C or -C = C bond When both contain unsaturated bonds, they are the same or different.

Examples of the reduction process are, in particular, the examples, wherein a compound of the general formula (1), wherein - (represents CHJ, (CHJ_-), is prepared from a corresponding compound-2 m 2, wherein - (CHJ - -CH = CH (CHJ -, -C = C (CHJ -, - (CHJ represents "CH = CHCH - 2 m 22 22 22 2 or - (CH2) 2C = CCH2").

In the following examples, a compound of the general formula (1), wherein - represents ((CH.) - - (CH.) - or - (CH.) - can be prepared 2 n 2 4 2 2 by reduction of a corresponding compound of the formula 35 (1), wherein - (CHJ - -CH „CH = CH-CH -, -OLC = CCH -, -CH„ OLCH = CH-, 2 n 2 2 22 22 -CH2CH2C = C-, -CH2CH = CH or -CH2C = C-.

8502012 «« -13-

In the general method described above, the compound of formula (1) can be obtained in the form of a salt, preferably in the form of a physiologically acceptable salt. If desired, such salts can be converted into their corresponding free acids by conventional methods.

Physiologically acceptable salts of the compounds of the general formula (1) can be prepared by reacting a compound of the general formula (1) with a suitable acid or base in the presence of a suitable solvent, such as acetonitrile, acetone, chloroform, ethyl acetate or an alcohol, for example methanol, ethanol or isopropanol.

Physiologically acceptable salts can also be prepared from other salts, including other physiologically acceptable salts of the compounds of the general formula (1) using conventional methods.

When a specific enantiomer of a compound of the general formula (1) is desired, it can be obtained by dissolving a corresponding racemate of a compound of the general formula (1) using conventional methods.

For example, in an example, a suitable optically active acid can be used to form salts with the racemate of a compound of the general formula (1). The resulting mixture of isomeric salts can be separated, for example, by fractional crystallization into the diastereomeric salts, from which the desired enantiomer of a compound of the general formula (1) can be isolated by conversion to the desired free base.

Alternatively, enantiomers of a compound of the general formula (1) can be synthesized from the appropriate optically active intermediates using any of the general methods described herein.

Specific diastereomers of a compound of formula (1) can be obtained by conventional methods, for example, by synthesis from a suitable asymmetric starting material by any of the methods described herein, or by conversion of a. Mixture of isomers of a compound of the general formula (1) in suitable diastereomeric derivatives, for example salts, which can then be separated by customary means, for example, fractionated 85 0 2 0 1 2 -14 crystallization.

Suitable methods for the preparation of the intermediates used in the above general processes are described below 1 2 6 7 8 1 2. In the following, Ar, R, R, R, R, R, Q, X, X, 3 4 5 5 X, X, X, Y and L are defined as above unless otherwise stated. "Hal" represents a halogen atom. Where an intermediate with a protected hydroxyl and / or amino group is desired, it can be obtained by conventional protection methods, such as described, for example, by McOmie (see Method (2) above).

Intermediates of the general formula (8) for use in the general method (3) can be prepared by a number of methods.

For example, intermediates of the general formula (8) in which X * is a ^ C = O group can be prepared from a haloketone of the formula (9) by reaction with an amine of the general formula (10) wherein 7 R is a hydrogen atom or a group which can be converted therein by catalytic hydrogenation.

The reaction can be carried out in a cold or warm 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 (2) and (9) are known products or can be prepared according to the methods described by Kaiser et al. In J. Med. Chem., 1974, 17, 49 and Larsen et al. In J. Med, Chem., 1967,. 10, 462.

Intermediates of the general formula (8), wherein X 1 is a C = O group, can be reduced to the corresponding intermediate, wherein X is a -CH (OH) group, for example, using a metal- hydride, such as sodium borohydride in a solvent, for example ethanol.

Imino ketones of the general formula (8), i.e., where 2 X is a -CH = N group, can be obtained from a phenylglyoxal-35 derivative of the formula (11) by the reaction with an amine of the formula 10 wherein Y represents a hydrogen atom, in a solvent, such as benzene, tetrahydrofuran, or an alcohol, e.g., ethanol, at temperatures of at most reflux temperature. The phenylglyoxal derivatives of the formula (11) can be obtained from a haloketone of the formula (9) by the action of a dialkyl sulfoxide such as dimethyl sulfoxide.

Intermediates of the general formula (8), which is a -CO (CH-) - group, can be prepared by acylation of an amine cm -1 of the formula (12) using an ester or an activated derivative of a acid of the formula (13).

Suitable activated derivatives include the acid chloride, anhydride or imidazolide. The reaction can, if desired, be carried out in a solvent, such as tetrahydrofuran, benzene or chloroform, if desired in the presence of a base, such as pyridine or triethylamine. The acids (13) can be used directly when a coupling agent such as dicyclohexylcarbodiimide is added.

Acids of the formula (13) can be obtained by treating an alcohol of the general formula (14) with a suitable oxidizing agent, for example pyridinium dichromate in a solvent such as dimethylformamide.

2 3 2

Intermediates of the formula (8), wherein -X -X - -CH 1 N 2 CR

(CH-) - can be obtained by reaction of an amine

2 m- X

of the formula (12), wherein R is a hydrogen atom, with a compound of the formula (5) in a solvent, such as acetonitrile.

2

Intermediates of the formula (8) wherein X is -CONH- can be prepared by reacting an amine of the formula (10) wherein 7 R is hydrogen with an acid of the formula (15) in the presence of a coupling agent, such as dicyclohexylcarbodiimide. The acids of formula (15) can be prepared according to methods analogous to conventional methods of preparing α-keto and α-hydroxycarbon-30 acids.

3

Intermediates of the formula (8), wherein X is 12 5 4 CR RX and / or X is C-alkenylene or C-alkynylene, may be prepared 2-0 2-b by methods analogous to the methods described herein for the preparation of the compounds of formula (1).

Intermediates of formulas (3), (5), (10) and (14) can be prepared as described in British Patent Specification 2,140,800A or by methods analogous to those described therein.

8502012 -16-

The following examples illustrate the invention. Temperatures are in degrees Celsius. "Dry" refers to drying using magnesium sulfate unless otherwise noted. Thin layer chromatography was performed on SiO 2. Column chromatography and flash column chromatography were both performed on silica (Merck 9385).

Intermediate 1.

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

A solution of 0.53 g of N- [5-bromoacetyl) -2- (phenylmethoxy) phenyl] formamide, 0.68 g of N [6- (3-phenylpropoxy) hexyl] benzenemethanamine hydrobromide (compound A) and 0, 65 g of Ν, Ν-diisopropylethylamine in 10 ml of dichloromethane were kept at 23 ° C for 18 hours. The mixture was diluted with 20 ml of water, extracted with 30 ml of diethyl ether and the organic phase was washed with 20 ml of water, 20 ml of brine, dried and evaporated to an oil. Purification by flash column chromatography by eluting with diethyl ether cyclohexane (3: 2) gave the product as a pale yellow oil (0.72 g). Thin layer chromatography (diethyl ether cyclohexane 3: 2) gave an R 2 value of 0.28.

The following were prepared in the same way: 20 Intermediate 2.

1.01 g of N- [2- (phenylmethoxy) -5 - [[(phenylmethyl) [6- (3-phenylpropoxy) hexyl] amino] acetyl] phenyl] urea was obtained from 0.8 g of N- [5- ( bromoacetyl) -2- (phenylmethoxy) phenyl] urea and 0.91 g of compound A. Purification was by thin layer chromatography on triethylamine-deactivated silica (ethyl acetate-cyclohexane 4: 1).

Intermediate 3.

0.5 g of N- [2- (phenylmethoxy) -5 - [[(phenylmethyl) [6- (3-phenylpropoxy) hexyl] -amino) acetyl] phenyl] methanesulfonamide was obtained from 0.45 g of N- [5- bromoacetyl) -2- (phenylmethoxy) phenyl] methanesulfonamide and 0.46 g of compound A. Purification was by thin layer chromatography (cyclohexane diethyl ether 3: 2) to give an R 2 value of 0.36.

Intermediate 4.

N- [5- [1-hydroxy-2 - [[6- (4-phenylbutoxy) hexyl] phenylmethyl) amino] ethyl] -2- (phenylmethoxy) phenyl] methanesulfonamide. 35 To a nitrogen stirred solution of 1, 9 g of N- [5-bromoacetyl) -2- (phenylmethoxy) phenyl] methanesulfonamide and 1.62 g of N- [6- (4-phenylbutoxy) hexyl] benzenemethamide in 100 ml of tetrahydrofuran became 1.23 g Ν, Ν- diisopropylethylamine was added and the mixture was stirred for sn 'r'; ai 'Ij': · - * -17- Stirred under nitrogen at room temperature for 40 hours. The solution was diluted with 50 ml diethyl ether, filtered and evaporated in vacuo to a brown oil (4.2 g), which was dissolved in 50 ml methanol and treated with 0.74 g sodium borohydride. The mixture was stirred under nitrogen for 1 hour, diluted with 150 ml water and extracted with 2 x 150 ml diethyl ether. The organic phase was washed twice with 100 ml of water #, dried and evaporated in vacuo to a brown oil. Purification by flash column chromatography using cyclohexane-ethyl acetate (2: 1) as eluent gave 1.92 g of the title compound as a yellow oil. Thin-10 layer chromatography (cyclohexane-ethyl acetate 2: 1) gave an R 2 value of 0.23. Elemental analysis (%):

Found: C 69.8; H 7.8; N 4.2;

Calculated for C39H5N205S ° '75 H2 °: C 70 '° m> H 7'7? N 4'2 *

Intermediate 5.

15 (5- [1-hydroxy-2 - [[6- (4-phenylbutoxy) hexyl] (phenylmethyl) amino] ethyl] -2- (phenylmethoxy) phenyl] urea ._________

A solution stirred under nitrogen of 2 g of N - {(5-bromoacetyl-2- (phenylmethoxy) phenyl] urea and 1.87 g of N- [6- (4-phenylbutoxy) hexyl] benzene-methanamine in 100 ml of tetrahydrofuran with 1.42 g N, N-20 diisopropylethylamine The mixture was stirred at room temperature under nitrogen for 19 hours, diluted with 50 ml diethyl ether, filtered and the filtrate evaporated in vacuo. A solution of 4.4 g of the orange obtained oil in 100 ml of methanol was treated with 1.2 g of sodium borohydride and stirred under nitrogen for 19 hours The mixture was diluted with 200 ml of water, extracted twice with 150 ml of diethyl ether and the organic phase was washed with 100 ml of water , dried and evaporated in vacuo to an orange oil Purification by flash column chromatography using ethyl acetate-cyclohexane (2: 1) as eluent gave 1.72 g of the title compound as a yellow oil Thin layer chromatography (ethyl acetate-methanol 3: 1) gave an R ^ value of 0.7).

Product 6.

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

100 ml of a solution (1.6 M) of n-butyl lithium in hexane was added dropwise to a stirred suspension of 32.1 g of 35 (3-hydroxypropyl) triphenylphosphonium bromide in 200 ml of dry tetrahydrofuran cooled to 0 ° C under nitrogen. A solution of 9.93 g of 4-fluoro-850201? Benzaldehyde in 100 ml of dry tetrahydrofuran was added dropwise and the mixture was stirred at 0 ° C for 30 minutes and at room temperature for an additional 1.5 hours. The mixture was diluted gently with 25 ml of water, the solvent was evaporated in vacuo at 40 ° C and the residue partitioned between 200 ml of ethyl acetate and 200 ml of water. The aqueous phase was extracted again with 200 ml of ethyl acetate, the organic phases were combined, dried and evaporated in vacuo to a brown oil. Purification by flash column chromatography using cyclohexane diethyl ether (1: 1) as eluent gave 6.33 g of the title compound as a colorless oil. Thin layer chromatography (cyclohexane-diethyl ether 1: 1) gave an R 1 value of 0.13.

Intermediate 7.

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

The mixture of 5.73 g of intermediate 6, 25.2 g of 1,6-dibromohexane, 1.5 g of tetrabutyl ammonium bisulfate and 45 ml of 40% sodium hydroxide solution was stirred for 18 hours, diluted with 200 ml of water and extracted with 2 x 150 ml ethyl acetate. The organic phase was washed with 100 ml of water and 100 ml of brine, dried and evaporated in vacuo to a yellow oil. Purification by flash column chromatography with cyclohexane-ethyl acetate (10: 0-9: 1) as eluent gave 8.49 g of a yellow oil. Thin layer chromatography (cyclohexane-ethyl acetate 9: 1) gave an R 2 value of 0.34.

Intermediate 8.

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

1.34 g of intermediate 7 was added to a stirred solution of 1.50 g of [5 - [(2-amino-1-nydroxyethyl)] - 2-hydroxyphenyl] methanesulfonamide and 0.57 g of Ν-diisopropylethylamine in 25 ml dimethylformamide 30 at 70 ° C under nitrogen. The solution was kept at 70 ° C for 5 hours

stirred, diluted with 100 ml of water and extracted with 2 x 100 ml of ethyl acetate. The organic phase was washed with water, dried over Na 2 SO 4 and evaporated in vacuo to a brown oil which was purified by flash column chromatography on triethylamine inactivated silica (Merck 9385, 100 g) with ethyl acetate-methanol (9: 1) as an eluent to give 0.5 g of brown foam. Trituration with diethyl ether gave 0.47 g of the title compound as a white solid, mp 79 DEG-80 DEG (with decomposition).

8502012 • * -19-

Intermediate 9.

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

2.8 g of propanesulfonyl chloride was added to a stirred solution of 3.95 g of 1- [3-amino-4- (phenylmethoxy) phenyl] ethanone and 3.58 g of triethylamine in 80 ml of dry dichloromethane at 0 ° C. The solution was stirred at 0 ° C for 2 hours, diluted with 200 ml diethyl ether, washed successively with 100 ml 2N hydrochloric acid and 100 ml 8% sodium bicarbonate solution, dried and evaporated in vacuo to a buttery solid. This was slurried in cyclohexane to give a solid, which was stirred in 100 ml of 1N sodium hydroxide solution and filtered. The filtrate was acidified with 2N hydrochloric acid and extracted with 2 x 150ml ethyl acetate. The combined dried organic extracts were evaporated in vacuo to a buttery solid, which was recrystallized from ethyl acetate to 3.40 g of a white solid, mp 130-130.5 ° C.

Intermediate 10.

N-C 5-bromoacetyl-2- (phenylmethoxy) phenyl] propanesulfonamide.

A solution of 1.52 g of bromine in 25 ml of chloroform was added dropwise over 1.5 hours to a stirred solution of 3 g of intermediate 9 in 25 ml of chloroform at room temperature. The solution was washed with 30 ml of water, 30 ml of 8% sodium bicarbonate solution, dried over Na2 SO4 and evaporated in vacuo to a product which was recrystallized from ethyl acetate to yield 2.75 g of the title compound as a light orange solid with mp 99.5-25 100.5 ° C.

Intermediate 11.

N- [2- (phenylmethoxy) -5- [2 - [[6- (3-phenylpropoxy) hexyl] (phenylmethyl) amino] -1-oxoethyl] phenyl] propanesulfonamide. 0.55 g of intermediate 10, 0.5 g of N- [6- (3-phenylpropoxy) hexyl] benzene-30 methanamine and 0.22 g of Ν, Ν-diisopropylethylamine in 10 ml of dimethylformamide were stirred together under nitrogen for 2.5 hours. The solution was diluted with 50 ml of water, extracted with 2 x 50 ml of ethyl acetate and the organic phase was washed with 30 ml of 2N hydrochloric acid, 30 ml of 8% sodium bicarbonate solution and then dried over Na 2 SO 4. Evaporation in vacuo gave a yellow oil, which was purified by flash column chromatography using toluene ethyl acetate (9: 1) as eluent to yield 0.77 g of the title compound as a colorless oil. Thin layer chromatography (toluene ethyl acetate 9: 1) gave a value of 0.15.

3 5 0?, C 1 2 -20-

Intermediate 12.

1- [4- [6-bromhexyl) oxy] butyl] -4-methylbenzene.

A mixture of 6.5 g of 4-methylbenzene butanol, 24.4 g of 1,6-dibromo-hexane, 25 ml of a 50% aqueous sodium hydroxide solution and 0.5 g of tetrabutyl ammonium bisulfate was stirred at room temperature for 20 hours, diluted with 50 ml of water and extracted with 2 x 100 ml of diethyl ether. The dried extract was evaporated and the residue was purified by chromatography using cyclohexane as the eluent followed by cyclohexane diethyl ether (93: 7) to give 9.8 g of the title compound 10 as a colorless oil. Thin layer chromatography (cyclohexane diethyl ether 9: 1) gave an R 2 value of 0.5.

Intermediate 13.

N- [6- [4- (4-methylphenyl) butoxy] hexyl] benzenemethanamine hydrochloride.

5.0 g of intermediate 12 was added dropwise at 25 ° C to 25 ml of benzylamine. The solution was heated to 110-120 ° C for 2 hours, cooled, poured into 250 ml 2N hydrochloric acid, filtered to give 5.3 g of the title compound as a white solid, mp 119-121 ° C.

Intermediate 14.

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

0.95 g of sodium were dissolved in 9.47 g of warm 1,3-propanediol and then 10 g of (6-bromhexyl) benzene were added dropwise. The mixture was stirred at 100 ° C for 3 hours under nitrogen, poured into 200 ml of water and 30 ml of 2N hydrochloric acid and extracted with 2 x 150 ml of diethyl ether, dried and evaporated in vacuo to a yellow oil. Purification by flash column chromatography using cyclohexane diethyl ether (3: 1-0: 1) as eluent gave 5.46 g of the title compound as a colorless oil. Thin layer chromatography (cyclohexane-ethyl ether 3: 1) gave an R 2 value of 0.08.

30 Intermediate 15.

C 6- (3-bromopropoxy) hexyl benzene.

7.50 g of triphenylphosphine in 50 ml of dry dichloromethane were added dropwise over a 10 minute period to a stirred solution of 5.2 g of intermediate 14 and 9.49 g of carbon tetrabromide in 90 ml of dry dichloromethane at 0 ° C under nitrogen. The solution was stirred at room temperature for 2 hours, absorbed on 40 g of silica and purified by flash column chromatography. Elution with cyclohexane diethyl ether (8: 1) gave a colorless oil, which was distilled and 8502012

. V

-21- yielded 6.58 g of the title compound as a colorless oil. Thin layer chromatography (diethyl ether) gave an R ^ value of 0.63.

Intermediate 16.

N, N-dimethyl-N '- [5- [2 - [[6- (4-phenylbutoxy) hexyl] (phenylmethyl) amino] -1-5 oxoethyl] -2- (phenylmethoxy) phenyl] sulfamide. 8 g of N- [5-bromoacetyl-2- (phenylmethoxy) phenyl] -N, N-dimethylsulfamide, 0.64 g of N- [6- (4-phenylbutoxy) hexyl] benzenemethanamine and 0.27 g of Ν, Ν diisopropylethylamine was stirred in 10 ml of dimethylformamide under nitrogen at room temperature for 4.5 hours. The solvent was evaporated in vacuo and the residue was dissolved in 100 ml of ethyl acetate and washed with 75 ml of water. The aqueous phase was extracted again with 2 x 50 ml ethyl acetate and the combined organic phases were dried and evaporated in vacuo to a yellow oil. Purification by flash column chromatography with toluene ethyl acetate (10: 1) as eluent gave 0.66 g of the title compound as yellow oil. Thin layer chromatography (toluene ethyl acetate 5: 1) gave an R 1 value of 0.35. Intermediate 17.

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

4.0 g of [4 - [(5-bromopentyl) oxy] butyl] benzene was added dropwise to 20 ml of benzylaraine at 110 ° C. The solution was heated at 110-120 ° C for 90 minutes and cooled. 125 ml of 2N hydrochloric acid was added and the mixture was extracted with 2 x 100 ml of ethyl acetate. The organic extract was washed with 100 ml of aqueous sodium carbonate solution and 100 ml of brine, dried and evaporated.

The residue was distilled to give 3.3 g of the title compound as a colorless oil with a boiling point of 190-195 ° C / 0.1 mm Hg. Thin layer chromatography (cyclohexane diethyl ether 1: 1) gave an R 2 value of 0.25. Example I.

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

A solution of 0.25 g of intermediate 1 in 20 ml of ethanol was hydrogenated at room temperature and atmospheric pressure over 0.15 g of 10% palladium on carbon and 0.15 g of 10% platinum on carbon as catalysts. The mixture was filtered through "hyflo" and evaporated in vacuo. The residue was triturated with diethyl ether and cooled to give 0.092 g of the product as a white solid, mp 85 DEG-86 DEG (with decomposition).

8 5 ö 2 C 12 * * -22-

Thin layer chromatography on triethylamine deactivated silica (ethyl acetate methanol 7: 3) gave a value of 0.68.

In the same way were prepared:

Example II.

5 0.26 g of N- [2-hydroxy-5- [1-hydroxy-2 - [[6- (3-phenylpropoxy) hexyl] amino] ethyl] phenyl] urea mp 78-80 ° C from 0 .6 g of intermediate 2. Thin layer chromatography on triethylamine deactivated silica (ethyl acetate-methanol 7: 3) gave an R 2 value of 0.62.

Example III.

0.13 g N- [2-hydroxy-5- [1-hydroxy-2 - [[6- (3-phenylpropoxy) hexyl] amino] ethyl] phenyl] methanesulfonamide, m.p. 130-134 ° C (decomposed) ) was obtained from 0.3 g of intermediate 3. Thin layer chromatography on triethylamine inactivated silica (ethylamine-methanol 7: 3) gave an R 2 value of 0.62.

£

Example IV.

N- [2-hydroxy-5- [1-hydroxy-2 - [[6- (4-phenylbutoxy) hexyl] amino] ethyl] phenyl] methanesulfonamide. 0.98 g of intermediate 4 in 20 ml of absolute ethanol was hydrogenated. Deposited over 50 mg of 10% palladium on carbon and 50 mg of 5% platinum on carbon as catalysts. The mixture was filtered through "hyflo" and evaporated in vacuo. The residual brown oil (0.72 g) hardened on trituration with diethyl ether to give 0.34 g of the title compound, mp 88-91 ° C.

25 Elemental analysis (%):

Found: C 61.8; H 7.7; N 5.55

Calculated for C 25 H 33 N 2 O 5 OS · H 2 H 2: C H 8.0; N 5.8.

Example V.

N- [2-hydroxy-5- [1-hydroxy-2 - [[6- (4-phenylbutoxy) hexyl] amino] ethyl] phenyl] 30 urea.

A solution of 0.7 g of intermediate 5 in 15 ml of ethanol was hydrogenated over 50 mg of 10% palladium on carbon and 50 mg of platinum on carbon as a catalyst. The mixture was filtered through "hyflo" and evaporated in vacuo to a yellow oil, which was triturated with diethyl ether to give 0.32 g of an off-white solid, mp 87-89 ° C. Thin layer chromatography (ethyl acetate-methanol 1: 1) gave an R value of 0.18. r 85 02 0 1 2, * -23-

Example VI.

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

A solution of 0.70 g of [7- [2-phenylethoxy] heptan-2-one and 1.54 g of 5 N- [5- [2- [bis (phenylmethyl) amino] -1-oxoethyl] -2- ( phenylmethoxy) phenyl] methanesulfonamide in 50 ml absolute ethanol was hydrogenated over a mixture of 250 mg pre-reduced 5% platinum on carbon and 250 mg 10% palladium on carbon as catalysts in 25 ml ethanol. The mixture was filtered through "hyflo" and evaporated in vacuo 10 to 1.3 g of a white solid. Purification by flash column chromatography on triethylamine inactivated silica (Merck 9385, 50 g) with ethyl acetate-methanol (9: 2) as eluent followed by trituration with diethyl ether gave 0.88 g of the title compound, m.p. 122. 5-123.5 ° C.

15 Elemental analysis (%):

Found: C 60.3; H 7.7; N 5.9

Calculated for c H _N_O_S 0.75 H.0: C 60.3; H 7.9; N 5.9.

24 36 2 5 2

Example VII.

N- [2-hydroxy-5- [1-hydroxy-2 - [[6- [4- (4-fluorophenyl) butoxy] hexyl] amino] 20 ethyl] phenyl] methanesulfonamide.

A solution of 0.25 g of intermediate 8 in 10 ml of absolute ethanol was hydrogenated over a pre-reduced mixture of 40 mg of 10% palladium on carbon and 40 mg of 5% platinum on carbon as catalysts in 5 ml of ethanol. The mixture was filtered through "hyflo" and evaporated in vacuo to a brown oil which, on trituration with diethyl ether, gave 0.15 g of the title compound as an off-white solid, mp 84-85 ° C (decomposition) .

Elemental analysis (%):

Found: C 56.5; H 7.4; N 5.4 Calculated for C 4 H 4 FN 3 S 3 H C 5 56.4 H 7.8; N 5.3.

Example VIII.

N- [2-hydroxy-5- [1-hydroxy-2 - [[6- (3-phenylpropoxy) hexyl] amino] ethyl] phenyl] propanesulfonamide. 0.65 g of a solution of intermediate 11 in 40 ml absolute ethanol was hydrogenated over a mixture of 150% previously reduced 10% palladium on carbon and 150 mg 5% platinum on carbon as catalysts in 10 ml ethanol. The mixture was filtered through a "hyflo" and evaporated in vacuo to a yellow oil which was fine at fine f * * 7 Λ 4 Λ v ν 'c. j; Rubbing with diethyl ether gave 170 mg of the title compound as a white solid, m.p. 82-83.5 * (decomposed). Elemental analysis (%):

Found: C 62.3; H 7.9; N 5.5 5 Calculated for C0 H ΛΝ „0 S.0.5 HO: c 62.2; H 8.2; N 5.6.

2b 4U 2d 2

Example IX.

N- [2-Hydroxy-5- [1-hydroxy-2 - [[3- [6-phenylhexyl) oxy] propyl] amino] ethyl] phenyl] methanesulfonamide benzoate (salt). 0.69 g of intermediate 15 in 2 ml of dimethylformamide were added dropwise to a solution of 0.85 g of N- [5 - [(2-amino-1-hydroxy-ethyl)] -2-hydroxyphenyl] methanesulfonamide and 0.33 g of N, N- diisopropylethyl amine in 20 ml dimethylformamide at 80 ° C under nitrogen. The mixture was stirred at 80 ° C for 3 hours and evaporated in vacuo. The residual oil was dissolved in 50 ml of ethyl acetate and washed with 100 ml of water. The aqueous phase was extracted again with 75 ml of ethyl acetate, the combined organic phases were dried over Na 2 SO 4 and evaporated in vacuo to an oil. Purification by flash column chromatography with toluene-ethanol-0.88 wt% ammonia solution (39: 10: 1) gave a brown oil, which was dissolved in 10 ml of methanol and 20 with 0.08 g of benzoic acid was treated. The solvent was evaporated in vacuo and the residue triturated with diethyl ether to give 140 mg of the title compound as an ivory solid, mp 133-133.5 ° C.

Elemental Analysis (%): Found: C, 62.79; H 7.27; N 4.77

Calculated for C 18 H 18 OcS. C H. CL 0.5 H 4 O: C 62.50; H 7.28; N 4.70.

24 3b 2 b 762 2

Example X.

N- [2-hydroxy-5- [1-hydroxy-2- [[5- (4-phenylbutoxy) pentyl] amino] ethyl] phenyl] acetamide. A solution of 1.00 g of N- [5 Bromoacetyl-2- (phenylmethoxy) phenyl] acetamide, 0.9 g of intermediate 17 and 0.46 g of N, N-diisopropylethylamine in 50 ml of dimethylformamide were stirred under nitrogen for 6 hours.

The solution was diluted with 50 ml of water and extracted with 2 x 100 ml of ethyl acetate and washed with 50 ml of 2N hydrochloric acid, 50 ml of 2N sodium-35 carbonate, dried over Na 2 SO 4 and evaporated in vacuo to a yellow oil which crystallized at stand. The resulting buttery solid (1.67 g) was dissolved in 90 ml of ethanol and hydrogenated over a mixture of 300 mg of pre-reduced 10% palladium oxide on carbon 3 5 f! 9 fi 1 o '! · V v fc. V I 4 i. 25 and 300 mg of 5% platinum oxide on carbon as catalysts in 25 ml of ethanol. The mixture was filtered through "hyflo" and evaporated in vacuo to an oil which gave a brown foam on trituration with diethyl ether. Purification by flash column chromatography with toluene ethanol-5 0.88% by weight ammonia solution (39: 10: 1) as eluent gave an oil which, on trituration with diethyl ether, gave 0.31 g of the title compound as a brown foam .

Thin layer chromatography (toluene-ethanol-0.88 wt% ammonia solution 39: 10: 1) gave an R 2 value of 0.26.

10 Elemental analysis (%):

Found: C 68.66; H 8.53; N 6.39

Calcd for C 7 H N O 0.5 H 0 C 68.62; H 8.52; N 6.40.

25 36 2 4 2

Example XI.

N '- [2-hydroxy-5- [1-hydroxy-2 - [[6- (4-phenylbutoxy) hexyl] amino] ethyl] phenyl] -15 Ν, Ν-dimethylsulfamide.

A solution of 0.61 g of intermediate 16 in 30 ml of absolute ethanol was hydrogenated over a mixture of 150 mg of pre-reduced 5% platinum oxide on carbon and 150 mg of 10% palladium oxide on carbon as catalysts in 10 ml ethanol. The mixture was filtered through "hyflo" and evaporated in vacuo to an oil. Purification by flash column chromatography with toluene ethanol-0.88 wt.

% ammonia solution (39: 10: 1) as the eluent gave a brown oil which, when triturated with diethyl ether, gave 0.20 g of a buttery solid, m.p. 75-77 ° C.

Elemental analysis (%):

Found: C 60.96; H 8.12; N 8.16

Calcd for 3 ° 35: C 61.51; H 8.14; N 8.28.

Example XII.

N- [2-hydroxy-3- [1-hydroxy-2 - [[6- [4- (4-methylphenyl) butoxy] hexyl] amino] ethyl 1 phenyl] methanesulfonamide.

A solution of 1.0 g of N- [5-bromoacetyl) -2-phenylmethoxy) phenyl] methanesulfonamide, 0.9 g of the amine, obtained by basicizing intermediate 13 and 0.4 g of Ν-diisopropylethylamine in 20 ml of tetra-35 hydrofuran was left at room temperature for 18 hours, filtered and evaporated. The residue was purified by column chromatography with cyclohexane diethyl ether (1: 1) as eluent to 1.0 g of a yellow oil. The oil was hydrogenated in 50 ml ethanol and 30 ml tetrahydrofuran 8502012 4-26 over 0.4 g 10% palladium on carbon and 0.3 g 5% platinum on carbon as catalyst for 5 hours, filtered and evaporated. The residue was purified by column chromatography with toluene-ethanol-0.88 wt.% Ammonia solution (80: 20: 1) as eluent 5 to give a yellow oil, which was triturated with 40 ml diethyl ether and 0.2 g of the title compound gave a yellow solid with a melting point of 65-67 ° C. Thin layer chromatography (toluene-ethanol-0.88% by weight ammonia solution 80: 20: 1) gave an R 2 value of 0.2.

Example XIII.

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

A solution of 4.0 g of N- [2-hydroxy-5- [1-hydroxy-2 - [[6-4-phenylbutoxy) hexyl] amino] ethyl] phenyl] methanesulfonamide in 50 ml chloroform was treated with 0.8 g acetic acid and the chloroform was evaporated. The residue was triturated with 50 ml of diethyl ether, and a yellow solid remained, which was recrystallized from ethyl acetate-methanol to give 3.7 g of the title compound as a white solid, mp 121-123 ° C.

Elemental Analysis (%): 20 Found: C 59.3; H 7.9 r N 5.1

Calculated for C25H38N2C> 5S.C2H4O2.0.5H2O: C 59.2; H 7.85; N 5.1.

The following are examples of suitable preparations of the compounds of the invention. The term "active ingredient" used herein represents a compound of the invention and may be, for example, the compound of Example IV.

Tablets: These can be prepared by the normal method, such as wet grinding or direct pressing.

TABLE A.

A. Direct pressing mg / tablet

Active ingredient 2.0 35 Microcrystalline cellulose USP 196.5

Magnesium stearate BP 1.5

Press weight 200.0 8502012 -27-, fr

The active ingredient is sieved through a suitable screen, mixed with excipients and pressed using 7 mm diameter punches.

Other strength tablets can be prepared by changing the ratio of the active ingredient to the microcrystalline cellulose or the press weight and using appropriate punches. # TABLE B.

B. Wet grinding.

mg / tablet 10 Active ingredient 2.0

Lactose BP 151.5

Starch BP 30.0

Pregelatinized corn starch BP 15.0

Magnesium stearate BP 1.5 15 Press weight 200.0

The active ingredient is sieved through a suitable sieve and mixed with lactose, starch and pregelatinized corn starch. Appropriate volumes of pure water are added and the powders are ground.

After drying, the granules are sieved and mixed with the magnesium stearate. The granules are then pressed into tablets using 7 mm diameter punches.

Different strength tablets can be prepared by changing the ratio of the active ingredient to the lactose or using the press weight and appropriate punches.

25 TABLE C.

C. For buccal administration.

mg / tablet

Active ingredient 2.0

Lactose BP 94.8 30 Sucrose BP 86.7

Hydroxypropylmethylcellulose 15.0

Magnesium stearate BP 1.5

Press weight 200.0

The active ingredient is sieved through a suitable sieve and mixed with the lactose, sucrose and hydroxypropylmethylcellulose. Appropriate volumes of pure water are added and the powders are ground.

After drying, the granules are sieved and mixed with magnesium stearate. The granules are then pressed into tablets using suitable punches.

3502012 -28-

The tablets can be coated with suitable film-forming materials, such as hydroxypropylmethylcellulose, using standard techniques. Alternatively, the tablets can be coated with sugar.

5 TABLE D.

Capsules mg / capsule

Active ingredient 2.0

Starch 1500 97.0 10 Magnesium stearate BP 1.0

Fill weight 100.0 x) A form of directly compressible starch.

The active ingredient is sieved and mixed with the excipients. The mixture is placed in hard gelatin capsules of size No. 2 using suitable equipment. Other doses can be prepared by changing the fill weight and, if necessary, the capsule size.

Syrup.

It can contain sucrose! or sucrose-free formulation.

20 TABLE E.

A. Sucrose syrup.

mg / 5 ml dose

Active ingredient 2.0

Sucrose BP 2750.0 25 Glycerin BP 500.0

Buffer)

Flavoring) as required

Pigment )

Preservative) 30 Pure water BP ad 5.0 ml

The active ingredient, buffer, flavor, colorant and preservative are dissolved in a little of the water and the glycerine is added. The remaining water is heated to dissolve the sucrose and then cooled. The two solutions are combined, brought to the correct volume and mixed. The syrup formed is clarified by filtration.

8502012 -29- TABLE F.

B. Sucrose-free syrup.

mg / 5 ml dose

Active ingredient 2.0

Hydroxypropylmethylcellulose USP

(viscosity type 4000) * 22.5

Buffer)

Flavoring)

Colorant) as required 10 Preservative)

Sweetener)

Pure water BP ad 5.0 ral

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

Pressurized aerosol with metered dose.

20 TABLE G.

A. Suspension aerosol.

mg / metered dose per can

Active ingredient (crushed) 0.100 26.40 mg

Oleic acid BP 0.100 2.64 mg 25 Trichlorofluoromethane BP 23.64 5.67 g

Dichlorofluoromethane BP 61.25 14.70

The active ingredient is reduced to a fine particle size in a liquid mill. The oleic acid is mixed with the trichlorofluoromethane at a temperature of 10-15 ° C and the comminuted drug is mixed with a high shear mixer in the solution. The suspension is placed in aliquots into aluminum aerosol cans and suitable metering valves, which deliver 85 mg of suspension, are placed on the cans and the dichlorodifluoromethane 35 is pressurized into the cans.

85 02 0 12 -30- TABLE Η.

B. Solution aerosol ♦ ml / measured dose per can

Active ingredient 0.055 13.20 mg 5 Ethanol BP 11,100 2.66 g

Dichlorotetrafluoroethane BP 25.160 6.04 g

Dichlorodifluoromethane BP 37.740 9.06 g

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

10

The active ingredient is dissolved in the ethanol along with the oleic acid or surfactant, if used.

The alcoholic solution is metered into suitable aerosol containers, followed by the trichlorofluoromethane. Appropriate dosing taps are placed on the containers and the dichlorodifluoromethane is pressurized through the taps.

Suppositories.

TABLE I.

20 Active ingredient 2.0 mg ^ Witepsol H 15 ad 1.0 g 5t) a branded item from Adeps Solidus Ph. EUR.

A suspension of the active ingredient is prepared in melted Witepsol and put into 1 g suppository forms using suitable equipment.

Injection for intravenous administration.

TABLE J.

30 mg / ml

Active ingredient 0.5 mg

Sodium chloride BP as needed

Water for injections BP ad 2.0 ml 35 Sodium chloride can be added to control the osmotic pressure of the solution and the pH can be adjusted by acid or base to the pH of the optimum stability and / or optimal stability. 2 0 1 2 * -31- solubility of the active ingredient. Alternatively, suitable buffer salts can be used.

The solution is prepared, clarified and placed in suitable sized ampoules which are closed by fusion.

The injection is sterilized by autoclaving by one of the acceptable procedures. Alternatively, the solution * can be sterilized by filtration and filled into sterile ampoules under aseptic conditions. The solution can be packaged under an inert atmosphere of nitrogen or other suitable gas.

10

Inhalation cartridges.

TABLE K.

mg / cartridge

Crushed active ingredient 0.200 15 Lactose BP ad 25.0

The active ingredient is comminuted in a liquid mill to a fine particle size before mixing with normal tableting grade lactose in a high shear mixer. The powder mixture is placed into size No. 3 hard gelatin capsules in a suitable encapsulating machine. The contents of the cartridges are administered using a powder inhaler such as Glaxo's "Rotahaler".

8502012

Claims (16)

Compounds of the general formula (1) according to the formula sheet, wherein: m is an integer from 2 to 8 and n is an integer from 1 to 7, the sum of m + n being 4 to 12; Compounds according to claim 1, wherein the total number of carbon atoms in the chains is - (CH_) - and - (CH_) - 7-10. 2 m 2 n 2 P wherein 10 p is 1 or 2; 1 2 R and R each represent a hydrogen atom or a C 1 alkyl group, 1 2 wherein the sum of the carbon atoms in R and R does not exceed 4; 3 3 3 4 5 Q represents an R CO, R NHC0, RR NSO or R S0 4 group, where 3 4 11 15. and R each represent a hydrogen atom or a C 5 alkyl group and 5 1 - 3 R represents an alkyl group; and physiologically acceptable salts and solvent compounds thereof. Compounds according to claim 2, wherein m is 2 or 3 and n is 6, or m 4 and n is 3, 4 or 5, or m 5 and n is 2, 3 or. 4. Compounds according to claim 3, wherein m is 5 and n 4. 1 2 5. Compounds according to claims 1-4, wherein R and R independently represent a hydrogen atom or a methyl group. Ar represents a phenyl group optionally substituted with one or more substituents selected from halogen atoms, alkyl or alkoxy groups or an alkylenedioxy group of the formula -O (CH-) O-, Compounds according to claim 5, wherein R * is a hydrogen atom 2 and R is a hydrogen atom or a methyl group. Compounds according to one or more of claims 1 to 6, wherein Q is HC0-, CH ^ CO-, NH2CO-, (CH ^ ^ NS ^ - or R ^ SO ^ -, wherein R ^ ^ alkyl 30 is 5 5 Compounds according to claim 7, wherein Q is R SO 2 -, wherein R is methyl. 8502012 -33- Compounds according to one or more of claims 1-8, wherein Ar is an unsubstituted phenyl group or a phenyl group substituted with one substituent, which is a methyl group or a fluorine atom. 10. Compounds of the general formula (1a) according to the formula sheet, wherein m is an integer from 2-5, n is an integer from 2-6 and the sum of m + n is 7, 8 or 9; R * represents hydrogen and 10. a hydrogen atom or a methyl group; Ar represents a phenyl group, optionally substituted with a methyl group or a fluorine atom and Q represents an HCO-, CH 3 CO 3, NH 2 O-, (CEL 1 NSO 2 or R 5 SC> 2), wherein R 1 is a C 1-3 alkyl; 15 and physiologically acceptable salts and solvent compounds thereof. Compounds of the general formula (1a) according to claim 10, wherein m is 5 and n 4, Q CH 2 SO 2 - and Ar is a phenyl group or a phenyl group substituted with a fluorine atom. 12. The compound: N- [2-hydroxy-5- [1-hydroxy-2 [[6- (4-phenylbutoxy) hexyl] amino] ethyl] phenyl] methanesulfonamide and physiologically acceptable salts and solvent compounds thereof. 13. The connections: 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] ethylphenyl] 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] 35 urea? S 5 0 2 0 11 -34- 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; 5 and physiologically acceptable salts and solvent compounds thereof. 1 2 Compounds according to claim 1, wherein n, n, R and R are as defined in claim 1, Ar represents a phenyl group, optionally substituted with 1 or 2 substituents selected from halogen atoms,? -Alkyl- or? -alkoxy groups, or an alkylenedioxy group of the formula -O (CH-) O-2 p where p is 1 or 2, and 15. represents the group R ^ CO-, R ^ NHCO-, or R ^ SO - wherein R ^ and R ^ 5 2 are defined in claim 1 and R is alkyl. Process for the preparation of compounds according to claims 1 to 14, or a physiologically acceptable salt or compound with solvent thereof, characterized in that the following preparation steps are carried out: (1a) for the preparation of a compound with the formula (1) wherein R is a hydrogen atom, alkylation of an amine of the general formula (2) according to the formula sheet wherein each of the 6 groups R and R is a hydrogen atom or a protecting group and 3 R is a hydrogen atom, with a alkylating agent of the general formula (3) according to the formula sheet wherein L represents a leaving group, if necessary followed by the removal of any protective group present or (1b) for the preparation of a compound of the formula (1), wherein R * is a hydrogen atom, alkylation of an amine of the general formula (4) according to the formula sheet wherein each of the 6 7 groups R and R is a hydrogen atom or a protecting group, 8 R is a hydrogen atom or a group which can be converted therein under the reaction conditions, and represents X 1 - CH (OH) - or C 1 = 0, according to the formula sheet with a compound of the general formula ( 5) in the presence of a reducing agent, if necessary followed by removal of 8502012, · -35- any protecting group present or (2) deblocking of a protected intermediate of the general formula (7) according to the formula sheet in which each of the groups R and R is a hydrogen atom or a protecting group, except that at least one of the groups R and R is a protecting group, or (3) reduction of an intermediate of the general formula (8) according to g is the formula sheet in which R is a hydrogen atom or a protecting group, X * -CH (OH) - or a group which is by reduction therein to convert 2 7, X is -C1 / NR or a group which is by reduction therein '3 ^ 12 10 can be converted, X -CR R (CH2is or a gr oep, which can be converted by reduction therein and X4 - (CH-). or a group convertible by η η-1 reduction therein, wherein at least one of the growth pins X, X, X and X represents a reducible group, if necessary followed by removal of any present, protecting group and, if desired, conversion of the obtained compound of the general formula (1) or a salt thereof into a physiologically acceptable salt or solvent compound thereof. A pharmaceutical composition, comprising at least one compound of the general formula (1) according to any one of claims 1 to 14, 20 or a physiologically acceptable salt or solvent compound thereof, together with a physiologically acceptable carrier or excipient. 8 ΐ) 0>; 0 1 2