GB2230775A

GB2230775A - Phenethanolamine compounds

Info

Publication number: GB2230775A
Application number: GB8909274A
Authority: GB
Inventors: Lawrence Henry Charles Lunts; Brian David Judkins
Original assignee: Glaxo Group Ltd
Current assignee: Glaxo Group Ltd
Priority date: 1989-04-24
Filing date: 1989-04-24
Publication date: 1990-10-31
Also published as: GB8909274D0

Abstract

Compounds of the formula (I> <IMAGE> and physiologically acceptable salts and solvates thereof, wherein R<1> and R<2> represent a hydrogen or C1-3alkyl with the proviso that the sum total of carbon atoms in R<1> and R<2> is not more than 4; W represents a group <IMAGE> where Z represents a group R<3)<CH2)q where q is 0, 1 or 2 and R<3> is a group R<4>CONH-, R<4>NHCONH-, R<4>R<5>NSO2NH- or R<6>SO2NH or -OH; R<4> and R<5> represent hydrogen or a C1-3 alkyl; R<6> represents C1-3alkyl; R<7> is Cl or the group -CF3; X represents a bond or a C1-7alkylene, C2-7alkenylene or C2-7 alkynylene group and Y represents a bond or a C1-6 alkylene, C2-6alkenylene or C2-6alkynylene group with the proviso that the sum total of carbon atoms in X and Y is not more than 10; Q represents a saturated heterocyclic group which has 5 to 8 ring members and contains in the ring one or more atoms or groups selected from -O-, -S-, -NH- and -N(CH3)-, optionally substituted by a benzene ring fused to two adjacent carbon atoms, have stimulant action at 2-adrenoreceptors and may be used in the treatment of conditions associated with reversible airways obstruction, such as asthma and bronchitis, and in the treatment of inflammatory and allergic skin diseases, congestive heart failure, depression, premature labour, glaucoma and gastric and peptic ulceration.

Description

CHEMICAL COMPOUNDS This invention relates to phenethanolamine derivatives having a stimulant action at ss2-adrenoreceptors, to processes for their preparation, to pharmaceutical compositions containing them and to their use in medicine.

Thus the present invention provides compounds of general formula (I)

and physiologically acceptable salts and solvates thereof, wherein R1 and R2 each independently represent a hydrogen atom or a C1-3alkyl group with the proviso that the sum total of carbon atoms In R1 and R2 is not more than 4; W renresents a brown

or

where Z represents a group R3(CH2)q where q is O, 1 or 2 and R3 is a group R4CONH-, R4NHCONH-, R4R5NSO2NH- or R6SO2NH or -OH; R4 and R5 each represent a hydrogen atom or a C1-3alkyl group; R6 represents a C1-3alkyl group; R7 is a chlorine atom or the group -CF3;; X represents a bond or a C1-7alkylene, C2-7alkenylene or C2-7alkynylene group and Y represents a bond or a C1-6alkylene, C26alkenylene or C26alkynylene group kith the proviso that the sum total of carbon atoms in X and Y is not more than 10; Q represents a saturated heterocyclic group which has 5 to 8 ring members and contains in the. ring one or more atoms or groups selected from -0-, -5-, -NH- and -N(CH3)-, and which may be unsubstituted or substituted by a benzene ring fused to two adjacent carbon atoms.

The group Q may be attached to the rest of the molecule through any available position on the heterocyclic ring, including through a nitrogen atom.

It will be appreciated that the compounds of general formula (I) possess at least on asymmetric carbon atom. The compounds according to the invention thus include all enantiomers, diastereomers and mixtures thereof, including racemates. Compounds In which the carbon atom in the -CH(OH)- group is in the R configuration are preferred.

As used herein the term alkenylene includes both cis and trans structures.

Conveniently R1 and R2 each represent a hydrogen atom or a methyl group. In particular, R1 and R2 conveniently both represent hydrogen atoms.

In the definition of W in compounds of formula (I), Z may conveniently represent, for example HOCH2-, HCONH-, NH2CONH- or CH3S02NH-.

W may represent, for example

Conveniently, W represents a group

or

The chain X may be, for example -(CH2)2-, (CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -(CH2)2C=CH-, -(CH2)2C#C-, -CH=CHCH2-, -CH=CH(CH2)2- or -CH2C=CCH2.

The chain Y may be, for example, a bond, -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -CH2CH=CH- or CH2#C-.

Aptly the sum total of carbon atoms in chains X and Y is 4 to 9 inclusive.

The group Q may represent, for example

Conveniently Q represents

Preferred compounds according to the invention are those in which R1 and R2 each represent a hydrogen atom and W represents a group

or

Compounds according to the invention in which W represents a group

and Q represents a group

are preferred.

Compounds according to the invention in which R1 and R2 each represent a hydrogen atom and the sum total of carbon atoms in the chains X and Y is 4, 5, 6, 7, 8 or 9 are preferred.

Preferred compounds according to the invention include 4-Amino-3,5dIchloro-a-[[[6-[3-(2-tetrahydrofuranyl)propoxy] hexyl]amino]meth yl]benzenemethanol; 4-Amino-3,5-dichloro-α-[[[6-[2-(2-tetrahydrofuranyl)ethoxy] hexyl]amino]methyl]benzenemethanol; 4-Amino-3,5-dichloro-α-[[[6-[4-(4-morpholinyl)butoxy]hexyl] amino]methyl]benzenemethanol; 4-Amino-3,5-dichloro-a-FF[5-F2-(1,2,3,4-tetrahydroqulnollnyl) ethoxy]pentyl]amino]methyl]benzeneme-thanol; 4-Amino-3,5-dichloro-α-[[[6-[2-(1-piperidinyl)ethoxy]hexyl] amino]methyl]benzenemethanol; 4-AmIno-3, 5-dichloro-a-F [[6-[2-(2-tetrahydropyranyl )ethoxy] hexyl]amino]methyl]benzenemethanol; 4-Amino-3,5-dichloro-α-[[[6-[3-(2-tetrahydropyranyl)propoxy] hexyl]amino]methyl]benzenemethanol;; 4-Amino-3,5-dichloro-α-[[[6-[2-(1-methyl-2-piperldinyl)ethoxy] hexyl]amino]methyl]benzenemethanol; 4-Amino-3,5-dichloro-α-[[[6-[2-(2-piperidinyl)ethoxy]hexyl] amlno]methyl]benzenemethanol; 4-Amino-3,5-dichloro-α-[[[6-[4-(2-morpholinyl)butoxy]hexyl] amino]methyl]benzenemethanol; 4-Amino-3,5-dichloro-α-[[[[6-[4-(4-methyl-2-morpholinyl)butoxy] hexyl]amlno]methyl]benzenemethanol; 4-Amino-3, 5-dichloro-a-[[[6-F3-(4-tetrahydropyranyl)propoxy] hexyl]amino]methyl]benzenemethanol; 4-Hydroxy1 -[[[-6-F [6-(1-methyl-4-piperidinyl)hexyl]oxy] hexyl] aminoamethyl]-1,3-benzenedimethanol; and theIr physiologically acceptable salts and solvates.

Suitable physiologically acceptable salts of the compounds of general formula (I) include acid addition salts derived from inorganic and organic acids, such as hydrochlorides, hydrobromides, sulphates, phosphates, maleates, tartrates, citrates, benzoates, 4-methnxy-benzoates, 2- or 4-hydroxybenzoates, 4-chlorobenzonates, beozenesuiphonates, p-toluenesulphonates, naphthalenesulphonates, methanesulphonates, sulphamates, ascorbates, salicylates, acetates, dlphenylacetates, triphenylactates, adipates, fumarates, succinates, lactates, glutarates, gluconates, tricarballylates, hydroxynaphthalenecarboxylates e.g. l-hydroxy or 3-hydroxy-2naphthalenecarboxylates, or oleates.The compounds may also form salts with suitable bases where appropriate. Examples of such salts are alkali metal (e.g. sodium and potassium) and alkaline earth metal (e.g. calcium or magnesium) salts, and salts with organic bass (e.g.

triethylamine).

The compounds according to the invention have a stimulant action at p2-adrenoreceptors, which furthermore is of a particularly advantageous profile. The stimulant action was demonstrated In the Isolated trachea of the guinea-pig, where compounds were shown to cause relaxation of contractions induced by PGF2a or electrical stimulation. A prolonged duration of action has also been observed.

The compounds according to the invention may be used in the therapy or prophylaxis of conditions susceptible to amelioration by a compound possessing selective stimulant action at ss2-adrenoreceptors, particularly of diseases associated with reversible airways obstruction such as asthma and chronic bronchitis. Further examples of conditions which may be alleviated by administration of a compound possessing selective ss2-stimulant activity are inflammatory and allergic skin diseases, congestive heart failure, depression, premature labour, glaucoma and conditions in which there is an advantage in lowering gastric acidity, particularly in gastric and peptic ulceration.

The invention thus further provides compounds of formula (I) and their physiologcally acceptable salts for use as an active therapeutic agent in particular for the treatment of conditions subject to amelioration by a compound possessing selective stimulant action at P2-adrenoreceptors, for example diseases associated with reversible airways obstruction.

In a further or alternative aspect there is provided a method for the treatment of a disease associated with reversible airways obstruction in a mammal including man comprising administration of an effective amount of a compound of formula (I) or a physiologically acceptable salt thereof.

There is also provided in a further or alternative aspect use of a compound of formula (I) or a physiologically acceptable salt thereof for the manufacture of a medicament for the treatment of a condition which may be ameliorated by a compound having selective ss2-adrenoreceptor stimulant activity.

It will be appreciated by those skilled in the art that reference herein to treatment extends to prophylaxis as well as the treatment of established symptoms.

It is possible that a compound of the invention may be administered to a patient as the raw chemical, but it is preferable to present the active ingredient as a pharmaceutical formulation.

The invention accordingly provides a pharmaceutical formulation comprising a compound of formula (I) or a physiologically acceptable salt thereof together with one or more physiologically acceptable carriers and, optionally, other therapeutic andXor prophylactic ingredients. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterIous to the recipient thereof.

The compounds may be formulated in a form suitable for administration by inhalation or insufflation, or for oral, buccal, parenteral, topical (including nasal) or rectal administration.

Administration by inhalation o insufflation is preferred.

For administration by inhalation the compounds according to the invention are conveniently delivered in the form of an aerosol spray presentation from pressurised packs, with the use of a suitable propellant, such as dichlorodlfluoromethane, trichlorofluoromethane, dichlorotetraflurorethane, carbon dioxide or other suitable gas, or from a nebullser. In thr case of a pressurised aerosol the dosage unit may be determined by providing a valve to deliver a metered amount.

Alternatively, for administration by inhalation or insufflation, the compounds according to the invention may take the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base such as lactose or starch. The powder composition may be presented in unit dosage form in for example capsules or cartridges of e.g. gelatin, or blister packs from which the powder may be administered with the aid of an inhaler or insufflator.

For oral administration, the pharmaceutical composition may take the form of, for example, tablets, capsules, powders, solutions, syrups or suspensions prepared by conventional means with acceptable excipients.

For buccal administration the composition may take the form of tablets, drops or lozenges formulated in the conventional manner.

The compounds of the invention may be formulated for parenteral administration by bolus InjectIon or contInuous infusIon. Formulat.inn for injection may be presented in unit dosage form in ampoules, or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents. Alternatively, the active ingredient may be in powder form for reconstitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.

For topical administration the pharmaceutical composition may take the form of ointments, lotions or creams formulated in a conventional manner, with for example an aqueous or oily base, generally with the addition of suitable thickening agents and/or solvents. For nasal application, the composition may take the form of a spray, formulated for example as an aqueous solution or suspension or as an aerosol with the use of a suitable propellant.

The compounds of the invention may also be formulated in rectal compositions such as suppositories or retention enemas, e.g.

containing conventional suppository bases such as cocoa butter or other glyceride.

Where pharmaceutical compositions are described above for oral, buccal, rectal or topical administration, these may be presented in a conventional manner associated with controlled release forms.

A proposed daily dosage of active compound for the treatment of man is 0.005mg to lOOmg, which may be conveniently administered in one o two doses. The precise dose employed 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 O.005mg to 20mg, for oral administration is 0.02mg to lOOmg, and for parenteral administration is O.Olmg to 2mg for administration by bolus injection and O.Olmg to 25mg for administration by infusion.

The compounds according to the invention may be prepared by any process known in the art for the preparation of compounds of analogous structure. In the following description, R1, R2, X, Y, V; and 9 are as defined for general formula (I) unless otherwise specified.

In one general process (A), a compound of general formula (I) in which R1 is a hydrogen atom may be prepared by alkylation.

Conventional alkylation procedures may be used.

Thus, for example, in one alkylation process (a), a compound of general formula (I) in which R1 is a hydrogen atom may be prepared by alkylation of an amine of general formula (II)

(wherein R8 represents a hydrogen atom or a protecting group and R9 represents a hydrogen atom) followed by removal of any protecting groups where present.

The alkylation (a) may be effected using an alkylating agent of general formula (III)

(wherein L is a leaving group, for example a halogen atom such as chlorine, bromine or iodine, or a hydrocarbylsulphonyloxy group such as methanesulphonyloxy or p-toluenesulphonyloxy).

The alkylation is preferably effected in the presence of a suitable acid scavenger, for example inorganic bases such as sodium or potassium carbonate, organic bases such as triethylamine, dilsopropylethylamine or pyridine, or alkylene oxides such as ethylene oxide or propylene oxide. The reaction is conveniently effected in a solvent such as acetonitrile or an ether e.g. tetrahydrofuran, a ketone e.g. butanone, a substituted amide e.g. dimethylformamide or a chlorinated hydrocarbon e.g. chloroform, at a temperature between ambient and the reflux temperature of the solvent.

According to another example (b) of an alkylation process, a compound of general formula (I) in which R1 represents a hydrogen atom may be prepared by alkylation of an amine of general formula (II), as previously defined except that R9 is a hydrogen atom or a group convertible thereto under the reaction conditions, witch a compound of general formula (IV) : R2C0 XCH20CH2 Y-Q (Iv) in the presence of a reducing agent, followed when necesssry by removal of any protecting groups.

Examples of suitable R9 groups convertible into a hydrogen atom are arylmethyl groups such as benzyl, a-methylbenzyl and benzhydryl.

Suitable reducing agents include hydrogen in the presence of a catalyst such as platinum, platinum oxide, palladium, palladium oxide, Raney nickel or rhodium, on a support such as charcoal, using an alcohol, e.g. ethanol or methanol, or an ester, e.g. ethyl acetate, or an ether, e.g. tetrahydrofuran, or water, as reaction solvent, or a mixture of solvents, e.g. a mixture of two or more of those just described, at normal or elevated temperature and pressure, for example from 20 to 1000C and from 1 to 10 atmospheres.

Alternatively when one or both of R8 and R9 are hydrogen atoms, the reducing agent may be a hydride such as diborane or a metal hydride such as sodium borohydride, sodium cyanoborohydrd or lithium aluminium hydride. Suitable solvents for the reaction witch these reducing agents will depend on the particular hydride used, but will include alcohols such as methanol or ethanol, or ethers such as diethyl ether or tetrahydrofuran.

When a compound of formula (11) where R8 and R9 are each hydrogen atoms is used, the intermediate mine of formula (V) may be formed

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

In another general process (B) compounds of formula (I) may be prepared by reducing an intermediate of general formula (VI)

wherein at least one of X1, X2, X and Y represents a reducible group and the other(s) take the appropriate meaning as follows, which is X1 is -CH(OH)-, X2 is -CH2NR8- (where R8 represents a hydrogen atom or a protecting group), and X and Y are as defined in formula (I), followed where necessary by the removal of any protecting groups.

Suitable reducible groups .include those wherein X1 is a group > C=O, X2 is a group -CH2NR10 (wherein R10 represents a group convertible to hydrogen by catalytic hydrogenation, for example an arylmethyl group such as benzyl, benzhydryl or a-methylbenzyl), or -CONH-, X is an alkenylene or alkynylene group, Y is an alkenylene or alkynylene group.

The reduction may be effected using reducing agents conveniently employed for the reduction of ketones, amides, protected gamins, aikenes and alkynes.

Thus, for example, when X1 in general formula (II) represents a C:O group this may be reduced to a -CH(OH)- group using hydrogen in the presence of a catalyst such as platinum, platinum oxide, palladium palladium oxide, Raney nickel or rhodium, on a support such as charcoal, using an alcohol e.g. ethanol, an ester e.g. ethyl acetate, an ether e.g. tetrahydrofuran, or water, as reaction solvent, o a mixture of solvents, e.g. a mixture of two or more of those just described, at normal or elevated temperature and pressure, for example from 20 to 1000C and from 1 to 10 atmospheres. Alternatively, the reducing agent may be, for example, a hydride such a diborane or a metal hydride such as lithium aluminium hydride, sodium bis(2methoxyethoxy) aluminium hydride, sodium borohydride or aluminium hydride.The reaction may be effected in an appropriate solvent, such as an alcohol e.g. methanol or ethanol, or an ether such as tetrahydrofuran, or a halogenated hydrocarbon such as dichioromethane.

When X2 in general formula (VI) represents a -CH2NR10- group this may be reduced to a -CH2NH- group using hydrogen in the presence of a catalyst as described above.

When X2 In general formula (VI) represents a -CONH- group, this may be reduced to a group -CH2NH2- using a hydride such a diborane or a complex metal hydride such as lithium aluminium hydride in a solvent such as an ether e.g. tetrahydrofuran or diethyl ether.

When X and/or Y in general formula (VI) represents an alkenylene or alkynylene group, this may be reduced to an alkylene group using hydrogen in the presence of a catalyst as described above.

Alternatively, when X and/or Y represents an alkynylene group, this may be converted to an alkenylene group, using for example hydrogen and a lead-poisoned palladium on calcium carbonate catalyst in a solvent such as pyridine, or lithium aluminium hydride in a solvent such as diethyl ether at low temperature.

Where it is desired to use a protected intermedIate of general formula (VI) it is particularly convenient to use protecting groups which are capable of being removed under the reducing conditions, for example hydrogen and a catalyst, thus avoiding the need for a separate deprotection step. Suitable protecting groups of this type include arylmethyl groups such as benzyl, benzhydryl and a-methylbenzyl.

In the above reductIon process, and also in the preparation of intermediates, care must be taken to avoid the use of hydrogen and a catalyst when products are required in which X and/or Y represent aikenylene or alkynylene groups.

In a further process (C) compounds of formula (I) may be prepared by deprotecting an intermediate of general formula (VII)

wherein R8 is a protecting group and/or W and/or Q contains a protecting group.

The protecting group may be any conventional protecting group as described for example in "Protective Groups in Organic Synthesis", by Theodora Greene (John Wiley and Sons Inc, 1981). Thus, for example, hydroxyl groups may be protected by arylmethyl groups such as benzyl, dlphenylmethyl or triphenylmethyl, by acyl groups such a acetyl, or as tetrahydropyran yl derivatives. Examples of suitable amino protecting groups include arylmethyl groups such as beozyl, a-methylbenzyl, dlphenylmethyl or triphenylmethyl, and acyl groups such as acetyl, trichioroacetyl or trifluoroacetyl.

The deprotection to yield a compound of general formula (I) mey be effected using conventional techniques. Thus for example arylmethyl groups may be removed by hydrogenolysis in the presence of a metal catalyst (e.g. palladium on charcoal). Tetrahydropyranyl groups may be cleaved by hydrolysis under acidic conditions. Acyl groups may be removed by hydrolysis with an acid such as mineral acid e.g. hydrochloric acid, or a base such as sodium hydroxide or potassium carbonate, and a group such as trichloroacetyl may be removed by reduction with, for example, zinc and acetic acid.

Intermediates of formula (VI) for use in the reduction process (B) in which X1 is the group ) C:O may be prepared by reaction of a haloketone of formula (VII I) W-COCH2 Hal (VIII) (where Hal represents a halogen atom e.g. bromine) with an amine of formula (IX)

(where R8 is a hydrogen atom or a group convertible thereto by catalytic hydrogenation).

The reaction may be effected in a cold or hot solvent, for example tetrahydrofuran, dioxan, chloroform, dichloromethane, dimethylformamide, acetonitrile, a ketone such as butanone or an ester such as ethyl acetate, preferably in the presence of a base such as dilsopropylethylamine, sodium carbonate or other acid scavenger such as propylene oxide.

It is convenient not to purify the intermediates of formula (VI) formed by reaction of a haloketone of formula (VIII) with an amine of formula (IX), but to reduce the crude reaction product to give a compound of formula (I).

Gamines of formula (II) and haloketones of formula (VIII) are either known compounds or may be prepared by methods analogous to those described for the preparation of known compounds.

Suitable methods for preparing intermediates of formulae (III), (IV), (V) and (VI) are described in UK Patent Specification Nos.

2140800A, 2187734A and 2159151A and in the exemplification included hereinafter.

In the preparation of both intermediates and end-products the final step in the reaction may be the removal of a protecting gorup.

Conventional protecting groups may be usd as described for process (C), above.

In the general processes described above, the compound of formula (I) obtained may be in the form of a salt, conveniently in the form of a physiologically acceptable salt. Where desired, such salts may be converted to the corresponding free bases using conventional methods.

Physiologically acceptable salts of the compounds of general formula (I) may be prepared by reacting a compound of general formula (I) with an appropriate 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 may also be prepared from other salts, including other physiologcally acceptable salts, of the compounds of general formula (I), using conventional methods.

When a specific enantiomer of a compound of general formula (I) is required, this may be obtained by resolution of a corresponding racemate of a compound of general formula (I) using conventional methods.

Thus, in one example an appropriate optically active acid may be used to form salts with the racemate of a compound of general formula (I). The resulting mixture of isomeric salts may be separated for example by fractional crystallisation, into the diastereoisomeric salts from which th required enantiomer of a compound of general formula (I) may be isolated by conversion into the required free base.

Alternatively, enantiomers of a compound of general formula (I) may be synthesised from the appropriate optically active intermediates using any of the general processes described herein.

SpecifIc diastereoisomers of a compound of formula (I) may be obtained by conventional methods for example, by synthesis from an appropriate asymmetric starting material using any of the processes described herein, or by conversion of a mixture of isomers of a compound of general formula (I) into appropriate diastereoisomeric derivatives e.g. salts which then can be separated by conventional means e.g. by fractional crystallisation.

The following examples illustrate the invention. Temperatures are in OC. 'Dried' refers to drying using magnesium sulphate or sodium sulphate. Unless otherwise stated, thin layer chromatography (t.l.c.) was carried out on silica and flash column chromatography (FCC) on silica (Merck 9385).The following solvent systems may be used : System A - toluene:ethanol:0.88 ammonia; System B toluene:ethanol:O.88 ammonia; System C - hexane:ethyl acetate; System D- hexane:ethe.r. The following abbreviations are used : THF tetrahydrofuran, TAB - tetra-n-butylammonium hydrogen sulphate, LAH lIthIum aluminium hydride; DMF - dimethylformamide Example 1 4-Amino-3,5-dichloro-α;-[[[6-[3-(2-tetrahydrofuranyl)propoxy]hexyl] amino] methyl] benzenemethanol (a) 2-[3-[(6-Bromohexyl)oxy]propyl]tetrahydrofuran A solution of 2-[3-[(6-bromohexyl)oxy]propyl]furan (1.00g) in ethanol (lOml) was added to pre-hydrogenated rhodium on alumina (5, 0.159) in ethanol (20ml) and the mixture hydrogenated for 65h. The catalyst was removed by filtration and the filtrate concentrated to yield 1(a) (0.809), t.l.c. (System D, 1:1) Rf 0.37.

(b) N-[6-[3-(2-Tetrahydrofuranyl)propoxy]hexyl]benzenemethanamine l(a) (0.729) and benzylamine (5ml) were heated at 140 to 150 for 1 hour under nitrogen. The cooled solution was poured into 2M sodium carbonate solution (20ml) and extracted with ether (30ml). The organic extract was dried and evaporated. The residue was purified by FCC eluting with System A (39:10:1) to afford 1(b) (0.279), t.l.c.

(System A, 39:10:1) Rf 0.38.

(c) 4-Amino-3,5-dichloro-α-[(phenylmethyl)[6-[3-(2-tetrahydrofuranyl) propoxy]hexyl]amino]methyl]benzenemethanol A solution of 1-(4-amino-3,5-dichlorophenyl)-2-bromoethanone (189mg), 1(b) (212mg) and N,N-diisopropylethylamine (0.12ml) in THF (10ml) was allowed to stand under nitrogen at 220 for 5h and 5 for 3 days. The mixture was filtered and the filtrate evaporated to give an oil which was dissolved In methanol (lOml). Sodium borohydride (105mg) was added to the solution in portions over 10 minutes at 5 .

The solution was stirred at 5 for 1 hour, then evaporated. The residue was dissolved in ethyl acetate (25ml), washed with water (lOml), then brine (lOml), dried and evaporated. The residual oil was purified by FCC eluting with System C (2:1) to give 1(c) (250mg), t.l.c. (System C, 2:1) Rf 0.13.

(d) 4-Amino-3,5-dichloro-α-[[[6-[3-(2-tetrahydrofuranyl)propoxy] hexyl]amino]methyl]benzenemethanol A solution of 1(c)(225mg) in ethanol(5ml) and a solution of concentrated hydrochloric acid in ethanol (1:9, 0.43ml) were added to pre-reduced 10% palladium on charcoal. (50% aqueous paste, 50mg) in ethanol (lOml). The mixture was hydrogenated for 0.5h. The catalyst was removed by filtration and the filtrate evaporated. The residue was partitioned between 8% sodium bicarbonate solution (100ml) and ethyl acetate (8ûml). The organic phase was dried and evaporated to a gum which crystallised after 3 days.Trituration with hexane gave the title compound as an off-white solid (137mg) m.p. 56-62 C (mixture of diastereoisomers), t.l.c. (System A, 70:7:1) Rf 0.42.

Analysis found C,58.3; H,8.0; N,6.4; C1,16.1; C2lH34Cl2N203 requires C,58.2; H,7.9; N,6.5; Cl,16.4% Example 2 4-Amino-3,5-dichloro-α-5[[[6-[2-(2-tetrahydrofuranyl)ethoxy]hexyl] amino]methyl]benzenemethanol (a) 2-Tetrahydrofuranethanol, methanesulphonate Methanesulphonyl chloride (1.33ml) was added dropwise with ice cooling to a solution of 2-tetrahydrofuranethanol (1.829) and triethylamine (2.65ml) in dichloromethane (25ml).After 10 minutes the solution was stirred at 22 for 0.5h. Th solution was washed with 2M hydrochloric acid (25ml), 2M sodium carbonate solution (2 x 25ml), brine (10ml), then dried and evaporated to give 2(a) (2.709), t.l.c.

(ether) Rf 0.29.

(b) 6-[2-(2-Tetrahydrofuranyl)ethoxy]-1-hexanol 6-[(2-Tetrahydropyranyl)oxy]-l-hexanol (3.20g) in 1,2-dimethoxyethane (40ml) was treated with 80 sodium hydrjdo (525mg) and the mixture heated at reflux under nitrogen for 2 hours. A solution of 2(a) (2.689) In 1,2-dimethoxyethane (25ml) was added and the mixture stirred at reflux for 18 hours and allowed to stand for 36h. The mixture was evaporated. Water (60ml) was added and the solution extracted with ether (2 x lOOm 1). The ethereal extracts were dried and evaporated to an oil which was dissolved in methanol (70ml) and 2M hydrochloric acid (20ml) added. The solution was allowed to stand for 2 hours, then concentrated.The solution was basified to pH 12 with 2M sodium hydroxide solution, then extracted with dichloromethane (2 x 70ml). The organic extracts were dried and evaporated. The residue was purified by FCC eluting w,th ether/methanol v99:1-95:5) to give 2(b) (1.339), t.l.c. (ether) Rf 0.24.

(c) 6-(2-(2-Tetrahydrofuranyl)ethoxy]-l-hexanol, methanesulphonate 2(c) was prepared from 2(b) (1.079) in a similar manner to 2(a) to give (1.439), t.l.c. (ether) Rf 0.35.

(d) N-E6-E2-(2-Tetrahydrofura yl)ethoxy]hexyl]benzenemethanamine To a solution of 2(c) (0.839) in benzylamine (2ml) was added 35% sodium hydroxide solution (0.65ml). The mixture was heated at 60-70 for 16 hours under nitrogen. The cooled mixture was diluted with water (15ml) and extracted with ether (40ml). The ethereal extract was dried and evaporated. A second reaction mixture was combined at this stage (from 0.709 2(c)). The residue was purified by FCC eluting with System A (39:10:1) to afford 2(d) (1.309), t.l.c. (System A, 39:10:1) Rf 0.50.

(e) 4-Amino-3,5-dichloro-α-[[(phenylmethyl)[6-2-(tetrahydrofuranyl) ethoxy]hexyl]amino]methyl]benzenemethanol From 1-(4-amino-3,5-dichlorophenyl)-2-bromoethanone (1.20g) and 2(d) (1.24g) by the method of l(c) to give 2(e) (1.769), t.l.c.

(ether) Rf 0.53.

(f) 4-Amino-3,5-dichloro-α-[[[6-[2-(2-tetrahydrofuranyl)ethoxy] hexyl]amino]methyl]benzenemethanol Hydrogenation of 2(e) (1.60g) under the conditions described for the preparation of 1(d) followed by purification by FCC eluting with System B (95:4:1) and trituration with hexane gave the title compound (612mg), m.p. 58 C.

Analysis Found C,57.3; H,7.8; N,6.6; C1,16.8; C20H32C12N203 requires C,57.3; H,7.7; N,6.7; Cl,16.9% Example 3 4-Amino-3,5-dichloro-α-[[[6-[4-(4-morpholinyl)butoxy]hexyl]amino] methyl]benzenemethanol (a) 4-[4-[(6-Bromohexyl)oxy]butyl]morpholine A mixture of 4-morpholinebutanol (2.0g), 1,6-dibromohexane (9.29), TAB (155mg) and aqueous sodium hydroxide (50% w/v, 6.2ml) was stirred at room temperature for 1.75h, diluted with water (25ml) and extracted with ether (2 x 25ml).. The dried extract was evaporated and purified by FCC eluting with hexane followed by ether to give 3(a) (1.79), t.l.c. (System A, 80:20:1) Rf 0.49.

(b) 4-Amino-3,5-dichloro-α-[[[6-[4-(4-morpholinyl)butoxy]hexyl]amino] methyl]benzenemethanol A solution of 4-amino-α-(aminomethyl)-3,5-dichlorobenzenemethanol (1.1g), 3(a) (1.1g) and N,N-diisopropylethylamine (1.0ml) in DMF (25ml) was stirred at 100 C for 2.5h. The solvent was evaporated and the residue purified by FCC eluting with System B (95:5:1) to give a brown oil (350mg) which was recrystallised from ethyl acetate/hexane to afford the title compound as a white solid (140mg), m.p. 67-70 .

Analysis found C,58.15; H,8.2; N,8.8; C1,14.6; C22H37Cl2N203.0.2C6H14 requires C,58.1; H,8.4; N,8.8; Cl.14.8% Example 4 4-Amino-3,5-dichloro-α-[[5-[2-(1,2,3,4-tetrahydroquinolinyl)]ethoxy] pentyl]amino]methyl]benzenemethanol, (E) butenedioate salt (2:1) (a) 2-[2-[(5-Bromopentyl)oxy]ethyl]-1,2,3,4-tetrahydroquinoline From 1,2,3,4-tetrahydro-2-quinolinethanol (1.6g) and 1,5 dibromopentane (6.249) by the method of 3(a) to give 4(a) (1.319), t.l.c. (ether) Rf 0.54.

(b) N-[5-[2-(1,2,3,4-Tetrahydroquinolinyl)ethoxy]pentyl]benzene- methanamine 4(a) (1.29) and benzylamine (2.369) were heated together at 1250 under nitrogen for 0.5h. Excess benzylamine was evaporated. The residue was diluted with water (50ml) and extracted wIth ethyl acetate (100ml). The organic extract was washed with 2M hydrochloric acid (lOOml), then 8% sodium bicarbonate solution (100ml), dried and evaporated. The aqueous phase was re-extracted with dlchloromethane (2 x 100ml). The extracts were washed with sodium bicarbonate solution, dried and evaporated. The aqueous phase was basified with sodium bicarbonate solution to pH 8 and extracted with dichloromethane (2 x 100ml). The extracts were dried and evaporated.The combined residues were purified by FCC eluting with System B (95:5:1) to give 4(b) (1.22g), t.l.c. (System B, 95:5:1) Rf 0.16.

(c) 4-Amino-3,5-dichloro-α-[[(phenylmethyl)[5-[2-(1,2,3,4-tetrahydro quinolinyl)]ethoxy]pentyl]amino]methyl]benzenemethanol From 1-(4-amino-3,5-dichlorophenyl)-2-bromoethanone (0.88g) and 4(b) (1.log) by a similar method to 1(c) to give 4(c) (0.859), t.l.c.

(cyclohexane/ethyl acetate/triethylamine 19:5:1) Rf 0.32.

(d) 4-Aminc-3 ,5-dichloro-a-[[5-[2-(l,2,3,4-tetrahydroquinolinyl)] ethoxy]pentyl]amino]methyl]benzenemethanol, (E) butenedioate salt (2:1) A solution of 4(c) (0.789) in ethanol (40ml) was hydrogenated over pre-reduced 10 palladium oxide on charcoal (50S aqueous paste, 400mg) In ethanol (lOml) to which a solution of concentrated hydrochloric acid In ethanol (1:9 concentrated hydrochloric acid:ethanol, 2.55ml) was added. The catalyst was removed by filtration and the filtrate evaporated. The residue was purified by FCC eluting with System B (95:5:1) to give an oil (0.579) which was dissolved in methanol (15ml) and treated with fumaric acid (0.079).

The solution was evaporated and the residue triturated with ether to give the titles compound as a white solid (0.529) m.p. 1280.

Analysis Found C,59.1; H,6.7; N,7.8; C24H33Cl2N3O2.O.5C4H4O4 requires C,59.5; H,6.7; N,8.0% Example 5 4-Amino-3,5-dichloro-α-[[[6-[2-(1-piperidinyl)ethoxy]hexyl]amino] methyl]benzenemethanol (E)-butenedioate salt (2:1) (a) 1-(2-F (6-Bromohexyl)oxy)ethyl)piperidine From l-pipsridinethanol (5.0g) and 1,6-dibromohexane (20ml) by the method of 3(a) to give 5(a) (3.9g), t.l.c. (System B, 90:10:1), Rf 0.25.

(b) 4-Amino-3,5-dichloro-α-[[[6-[2-(1-piperidinyl)ethoxy]hexyl] amino]methyl]benzenemethanol (E)-butenedioate salt (2:1) From 5(a) (2.09) and 4-amino-α-(aminomethyl)-3,5- dichlorobenzenemethanol (2.29) by the method of 3(b) to give a pale brown solid (1.459). A portion of this material (97mg) in methanol (10ml) was treated with fumaric acid (13mg) and the solvent evaporated. Trituration of the pale yellow oil under ether gave the title compound as a white solid (75mg) m.p. 140-2DC.

Analysis Found C,54.2; H,7.2; N,7.7; C1,12.8; C21H35C12N302 '0'8C4H404.0.5H20 requires C,54.4; H,7.4; N,7.9; C1,13.3% Example 6 4-Amino-3,5-dichloro-α[[[6-[2-(2-tetrahydropyranyl)ethoxy]hexyl] amino]methyl]benzenemethanol, (E)-butenedioate salt (2:1) (a) 2-Tetrahydropyranylethanol, methanesulphonate From 2-tetrahydropyranylethanol (1.079) by the method of 2(a) to give 6(a) (1.759), t.l.c. (ether) Rf 0.58.

(b) 6-[2-(2-Tetrahydropyranyl)ethoxy]-1-hexanol From 6(a) (1.75g) and 6-[(2-tetrahydropyranyl)oxy]hexanol (2.30g) by the method of 2(b) to give 6(b) (1.03g), t.l.c. (ether) Rf 0.35.

(c) 6-[2-(2-Tetrahydropyranyl)ethoxy]hexanol, methanesulphonate From 6(b) (950mg) by the method of 2(a) to give 6(c) (1.299), t.l.c. (ether) Rf 0.42.

(d) N-[6-[2-(2-Tetrahydropyranyl)ethoxy]hexyl]benzenemethanamine From 6(c) (1.29g) and benzylamine (3ml) by the method of 2(d) to give 6(d) (1.239), t.l.c. (System A, 39:10:1) Rf 0.37.

(e) 4-Amino-3,5-dichloro-α-[[(phenylmethyl)[6-[2-(2- tetrahydropyranyl)ethoxy]hexyl]amino]methyl]benzenemethanol From 1-(4-amino-3,5-dichlorophenyl)-2-bromoethanone (1.069) and 6(d) (1.189) by the method of l(c) to give 6(e) (1.439), t.l.c.

(hexane/ethyl acetate, 2:1) Rf 0.08.

(f) 4-Amino-3,5-dichlora-α-[[[6-[2-(2-tetrahydropyranyl)ethoxy] hexyl]amino]methyl]benzenemethanol,(E)-butenedioate salt (2:1) From 6(e) (1.32g) by the method of l(d) to give a gum (62Omg) which was dissolved in methanol (lOml) and treated with fumaric acid (84mg). The solvent was evaporated. Trituration with ether caused crystallisation affording the title compound (439mg) m.p. 1270.

Analysis Found C,56.1; H,7.5; N,5.6; C1,14.7; C21H33Cl2N203- C4H404 requires C,56.2; H,7.4; N,5.7; Cl,14.4% Example 7 4-Amino-3,5-dichloro-α-[[[6-[3-(2-tetrahydropyranyl)propoxy] hexyl]amino]methyl]benzenemethanol (a) 2-(3-[(6-Bromohexyl)oxy]propyl]tetrahydropyran From 2-tetrahydropyranpropanol (O.71g) and 1,6-dibromohexane (5ml) by the method of 3(a) to give 7(a) (1.19g), t.l.c. (hexane/ ether, 4:1) Rf 0.17.

(b) N-[6-t3-(2-Tetrahydropyranyl)propoxyghexyl]benzenemethanamine From 7(a) (1.189) and benzylamine (6ml) similarly to 1(b) heating at 1200 for 2 hours to give 7(b) (1.309), t.l.c. (System A, 39:10:1) Rf 0.56.

(c) 4-Amino-3,5-dichloro-α-[[(phenylmethyl)[6-[3-(2-tetrahydro pyranyl)propoxy]hexyl]amino]methyl]benzenemethanol From l-(4-amino-3,5-dichlorophenyl)-2-bromoethanone (1.08g) and 7(b) (1.299) by the method of 1(c) to give 7(c) (1.829), t.l.c.

Silica/triethylamine (hexane/ethyl acetate, 2:1) Rf 0.35.

(d) 4-Amino-3,5-dichloro-α-[[[6-[3-(2-tetrahydropyranyl)propoxy) hexyl]amino]methyl]benzenemethanol From 7(c) (1.789) by the method of l(d). The crude product was purified by FCC over silica doped with 5% triethylamlne/chloroform, eluting with toluene/ethanol (19:1 to 9:1) to give the title compound (1.03g) m.p. 51-53 .

Analysis Found C,59.3; H,8.2; N,5.9; C1,16.0; C22H36C12N203 requires C,59.1; H,8.1; N,6.3; Cl,15.9% Example 8 4-amino-3,5-dichloro-[[[6-(2-(1-methyl-2-piperidinyl)ethoxy]hexyl] amino]methyl]benzenemethanol, E-butenedioate salt (2:1) (a) 2-[[(6-Bromohexyl)oxy]ethyl]-1-methylpiperidine From l-methyl 2-p peridineethanol (1.49) and 1,6-d-bromohexane (7.19) by the method of 3(a) to afford 8(a) (1.09) t.l.c. (System B, 90:10:1) Rf 0.4.

(b) 4-Amino-3,5-dichloro-α-[[[6-[2-(1-methyl-2-piperidinyl)ethoxy] hexyl]amino]methyl]benzenemethanol E-butenedioate salt (2:1) From 4-amino-z-(aminomethyl)-3,5-dichlorobenzenemethanol (0.979) and 8(a) (0.909) by the method of 5(b) with subsequent salt formation using fumaric acid to give the title compound (320mg) as a yellow solid m.p. 74-76 .

Analysis Found C,53.8; N,7.4; N,7.6; C1,13.6; C22H37Cl2N3O2.O.5C4H4O4.1.5H2O requires C,54.2; H,8.0; N,7.9; Cl,13.3% Example 9 4-Amino-3,5-dichloro-α-[[[6-[2-(2-piperidinyl)ethoxy]hexyl]amino] methyl]benzenemethanol (E) butenedloate selt (1:1) (a) l-(Phenylmethyl)-2-piperidinethanol A solution of 2-piperidinethanol (29), triethylamine (2.16ml) and benzyl bromide (1.84ml) in THF (6Oml) was stirred at room temperature for 4 hours. The precipitated solid was removed by fIltration. The filtrate was concentrated and the residue purified by FCC eluting with System A (90:10:1) to give 9(a) (2.289), t.l.c. (System A, 90:10:1) Rf 0.30.

(b) 2-t2-C(6-Bromohexyl)oxygethyl]-l-(phenylmethyl)piperidine From 9(a) (2.259) and 1,6-dibromohexane (7.519) by the method of 3(a) to give 9(b) (2.39), t.l.c. (hexane/ether, 1:1) Rf 0.47.

(c) N-[6-[2-[1-(Phenylmethyl)-2-piperidinyl]ethoxy]hexyl] benzenemethanamine From 9(b) (2.39) and benzylamine (8.0ml) similarly to 1(b), heating at 1000 for 1.5 hours, to give 9(c) (1.89) t.l.c. (System B, 90:10:1) Rf 0.60.

(d) 4-Amino-3,5-dichloro-α-[[[6-[2-[1-(phenylmethyl)-2-piperidinyl] ethoxy]hexyl](phenylmethyl)amino]methyl)benzenemethanol From 1-(4-amino-3,5-dichlorophenyl)-2-bromoethanone (1.439) and 9(c) (1.759) by the method of 1(c) to give 9(d) (1.lg), ,t.l.c.

(System B, 95:5:1) Rf 0.29.

(e) 4-Amino-3,5-dichloro-α-[[[6-[2-(2-piperidinyl)ethoxy]hexyl]amino] methyl]benzenemethanol (E) butenedioate salt (1:1) From 9(d) (1.Og) by the method of 4(d) to give the title compound (182mg) as a yellow solid m.p. 58-600C.

Analysis Found C,53.7; H,7.4; N,7.2; Cl,12.3; C21H35Cl2N3O2.1.25C4H4O4.O.25H2O requires C,53.65; H,7.0; N,7.2; Cl,12.2% Example 10 4-Amino-3,5-dichloro-α-[[[6-[4-(2-morpholinyl)butoxy]hexyl]amino] methyl]benzenemethanol (E)-butenedioate salt (1:1) (a) 4-(Phenylmethyl)-2-morpholinecarboxaldehyde Dimethyl sulphoxIde (O.39ml) was added to a solution of oxalyl chloride (0.46ml) In dichloromethane (12ml) at -70' under nitrogen.

After 10 minutes a solution of 4-phenylmethyl)-2-morpholinemethanol (1.0g) in dlchloromethane (5ml) was added at -70 . The solution was stirred at 700 for 0.5 hours, treated with triethylamine (1.8ml) and allowed to warm to room temperature. 8% sodium bicarbonate solution (5ml) was added and the solution diluted with water (15ml). The organic layer was washed with water (25ml) dried and evaporated. The residue was purified by FCC eluting wrth ether/hexane (1:1) to give 10(a) (595mg) t.l.c. (ether) Rf 0.33.

(b) (E) and (Z) 4-[4-(Phenylmethyl)-2-morpholinyl-3-buten-1-ol A mixture of 10(a) (6.439), 3-hydroxypropyltriphenylphosphonium bromide (14.24g) and potassium carbonate (5.339) in dloxane (63ml) and water (0.45ml) was heated at reflux overnight. The cooled mixture was diluted with ether (250ml), filtered and the filtrate evaporated. The residue was partitioned between 2M hydrochloric acid (250ml) and ethyl acetate (250ml). The acidic layer was re-extracted with ethyl acetate (2 x 125ml). The acidic layer was brought to pH 9 by addition of anhydrous potassium carbonate and extracted with ethyl acetate (3 x 250ml). The combined extracts were dried and concentrated to give 10(b) (7.7g) t.l.c. (ether) Rf 0.22.

(c) (E) and (Z) 2-r4-[t6-Bromohexyl)oxy]-l-butenyl]-4-(phenylmethyl) morpholine From 10(b) (3.59) and 1,6-dibromohexane (6.5ml) by the method of 3(a) to give 10(c) (3.1g), t.l.c. (hexane/ether, 3:1) Rf 0.29.

(d) (E) and (Z) N-[6-[[4-[4-(Phenylmethyl)-2-morpholinyl]-3-butenyl] oxy]hexyl]benzenemethanamine From 10(c) (3.Og) and benzylamine (10ml) by the method of 1(b) to give 10(c) (2.49), t.l.c. (System B, 95:5;1) Rf 0.48.

(e) (E) and (Z) 4-Amino-3,5-dichloro-α-[[[6-[[4-[4-(phenylmethyl)-2- morpholinyl]-3-butenyl]oxy]hexyl](phenylmethyl)amino]methyl] benzenemethanol From 1-(4-amino-3,5-dichlorophenyl)-2-bromoethanone (1.69) and 10(d) t2.4g) by the method of 1(c) to give 10(e) (3.29), t.l.c.

(System A, 90:10:1) Rf 0.40.

(f) 4-Amino-3 ,5-dichloro-a-[[[6-[4-(2-morpholinyl) butoxy]hexyl] amino] methyl]benzenemethanol (E)-butenedioate salt (1:1) From lO(e) (3.19) by the method of 4(d) to give the title compound (840mg) as a yellow powder m.p. 69 Analysis Found C,52.8; H,6.7; N,6.6; Cl,11.5; C22H37Cl2N3O3.C4H4O4.O.75H2O requires C,52.75;H,7.2; N,7.1; Cl,12.O% Example 11 4-Amino-3,5-dichloro-α-[[[6-[4-(4-methyl-2-morpholinyl)butoxy]hexyl] amino]methyl]benzenemethanol (E)-butenedioate salt (1:1) (a) 2-Morpholinebutanol A solution of 10(b) t3.8g) in ethanol (lOOml) containing concentrated hydrochloric acid in ethanol (1:9, 14ml) was hydrogentaed over pre-reduced dry palladium oxIde on carbon catalyst (380mg) for 10 days. The catalyst was removed by filtration and the filtrate evaporated. The resultant oil was partitioned between 8 sodium bicarbonate solution(50ml) and ethyl acetate (50ml). The aqueous phase was re-extracted with ethyl acetate (50ml).The extracts were concentrated and the residue purified by FCC eluting with System A (80:20:1 to 60:40:1) to give ll(a) (1.559) t.l.c. (System A, 60:40:1) Rf 0.29.

(b) Methyl [2-(4-hydroxybutyl)-4-morpholinyl]formate Methyl chloroformate (1.8g) was added dropwise to a stirred solution of ll(a) (1.59) and triethylamine (2.62ml) in THF (50ml) under nitrogen and stirred at room temperature for 1 hour. The solvent was evaporated and the residue partitioned between water (50ml) and ethyl acetate (50ml). The aqueous phase was extracted wth ethyl acetate (2 x 50ml). The organic extracts were dried and concentrated to give ll(b) (1.869), t.l.c. (ether) Rf 0.25.

(c) 4-Methyl-2-morpholinebutanol A solution of 11(b) (1.8g) in ether (15ml) was added dropwise to a stirred suspension of LAH (0.68g) in ether (10ml) and stirred at room temperature overnight. The suspension was diluted with ether (50ml). The precipitate was removed by filtration and washed with ethanol (2 x 50ml). The filtrate and washings were concentrated to a colourless oil. The aqueous layer was concentrated, filtered and the filter-cake washed with ethanol (2 x 50ml). The filtrate and the oil were combined and concentrated to give a white solid which was purified by FCC eluting sequentially with System B (97.5:2.5:1 to 95:5:1) and System A (90:10:1) to give ll(c) (850mg), t.l.c. (System A, 90:10:1) Rf 0.18.

(d) 2-[4-[(6-Bromohexyl)oxy]butyl]-4-methylmorpholine From ll(c) (1.059) and 1,6-dibromohexane (2.8ml) by the method of 3(a) to give ll(d) (660mg) t.l.c. (System A, 90:10:1) Rf 0.41.

(e) N-[6-[4-(4-Methyl-2-morpholinyl)butoxy]hexyl]benzenemethanamine From ll(d) (650mg) and benzylamine (3ml) by the method of 1(b) to give llXe) (710mg), t.l.c. (System A, 90:10:1) Rf 0.26.

(f) 4-Amino-3,5-dichloro-α-[[[6-[4-(4-methyl-2-morpholinyl)butoxy] hexyl](phenylmethyl)amino]methyl]benzenemethanol From 1-(4-amino-3,5-dichlorophenyl)-2-bromoethanone (550mg) and ll(e) (700mg) by the method of l(c) to give ll(f) (500mg).

(g) 4-Amino-3,5-dichloro-α-[[[6-[4-(4-methyl-2-morpholinyl)butoxy] hexyl]amino]methyl]benzenemethanol (E )-butenedioate salt (1:1) From ll(f) (300mg) according to the method of 4(d) to give the title compound (184mg) m.p. 40 C.

Analysis Found C,54.0; H,7.4; N,6.7; C23H37Cl2N3O3.C4H4O4.O.75H2O requires C,53.7; H,7.1; N,7.0 Example 12 4-Amino-3,5-dichloro-α-[[[6-[3-(4-tetrahydropyranyl)propoxy]hexyl] amino] methyl] benzenemethanol (a) 3-(4-Tetrahydropyranylidene)propanol A solution of n-butyllithium in hexane (1.49M, 33ml) was added slowly to a suspension of 3-hydroxypropyltriphenyl phosphonium bromide (9.62g) in THF (lOOml) at O to 100 under nitrogen. After 0.5h a solution of tetrahydropyran-4-one (1.80g) in THF (30ml) was added dropwise. The mixture was stirred at 220 under nitrogen for 2 hours before water (50ml) was added.Brine (50ml) and ethyl acetate (200ml) were added and the organic phase was separated. The aqueous phase was re-extracted with ethyl acetate (150ml). The organic extracts were dried and concentrated. The residue was purified by FCC eluting with hexane/ether (2:1 to 1:1) followed by ether to give 12(a) (1.809), t.l.c. (ether) Rf 0.29.

(b) 4-E3-E(6-Bromohexyl)oxy]-l-propylidene]tetrahydropyran From 12(a) (l.û3g) and 1,6-dibromohexane (6ml) by the method of 3(a) to give 12(b) (1.68g) t.l.c. (hexane/ether, 2:1) Rf 0.46.

(c) N-[6-[3-(4-Tetrahydropyranylidene)propoxy]hexyl]benzene- methanamine From 12(b) (1.339) and benzylamine (lOml) by the method of l(b) to give 12(c) (1.249), t.l.c. (System A, 39:10:1) Rf 0.55.

(d) 4-Amino-3,5-dichloro-αa-[[(phenylmethyl)[6-[3-(4-tetrahydro- pyranylidene)propoxy]hexyl]amino]methyl]benzenemethanol From 1-(4-amino-3,5-dichlorophenyl)-2-bromoethanone (1.109) and 12(c) (1.22g) according to the method of l(c) to give 12(d) (1.189) t.l.c. (ether) Rf 0.5.

(e) 4-Amino-3,5-dichloro-α-[[[6-[3-(4-tetrahydropyranyl)propoxy] hexyl]amino]methyl]benzenemethanol From 12(d) (1.869) by the method of l(d) with subsequent salt formation using fumaric acid (145mg). The fumarate salt was recrystallised from isopropanol. A solution of the salt in methanol (2ml) was basified with 2M sodium carbonate solution (25ml) and extracted with ethyl acetate (lOOml).The extract was dried and evaporated to a gum which on trituration with hexane gave the title compound (781mg) as a colourless powder m.p. 53-59 Analysis Found C,59.6; H,8.4; N,6.0; Cl,15.1; C22H36C12N203.0.08C6H14 requires C,59.4; H,8.2; N,6.2;C1,15.6 Example 13 4-Hydroxy -α-[[[6-(1-methyl-4-piperidinyl)hexyl]oxy]hexyl]amino] methyl]-1 ,3-benzenedimethanol (a) Methyl 6-[1-(phenylmethyl)-4-piperidinylidene]hexanoate A solution of l-(phenylmethyl)-4-plperidinone (29) in THF (5ml) was added dropwise to an ice cooled solution of potassium twbutoxide (llg) and carboxypentyltriphenyl phosphonium bromide (22.49) in THF (80ml). After 2 hours methanol (15ml) was added dropwise. Solvent was evaporated and the residue dissolved in distilled water and basified to pH 12 by addition of 2M sodium hydroxide solution (5ml)..

The solution was washed with ether. The aqueous phase was concentrated. The residue was taken up in methanol (100ml) and sulphuric acid (4ml) added dropwise. After 15 hours the solvent was evaporated and the residue added to aqueous potassium carbonate solution (20g/looml), then extracted with ethyl acetate (3 x 70ml).

The organic extracts were washed with brine, dried and evaporated.

The residue was purified by FCC eluting with ether to give 13(a) (2.129), t.l.c. (ether) Rf 0.4.

(b) Methyl 4-piperidinehexanoate A solution of 13(a) (10.09) in ethanol (200ml) was hydrogenated over 10% palladium on charcoal catalyst (1.09). The catalyst was removed by filtration and the filtrate evaporated to give 13(b) (7.029) as a colourless oil, t.l.c. (System A, 80:20:1) Rf 0.1.

(c) Methyl 1-(methoxycarbonyl)-4-piperidinehexanoate Methyl chloroformate (3.429) was added to a stirred solution of 13(b) (7.09) and triethylamine (5.05ml) in THF (lOOml) under nitrogen.

The mixture was stirred at room temperature for 1 hour and the solvent evaporated. The residue was partitioned between ethyl acetate (lOOml) and water (lOOml) containing 2M hydrochloric acid (10ml). The organic phase was dried and evaporated to give 13(c) (7.89), t.l.c.

(ether/hexane, 1:1) Rf 0.3.

(d) l-Methyl-4-piperidinehexanol A solution of 13(c) (7.89) in THF (50ml) was added dropwise durIng 0.5 hours to a stirred suspension of LAH (2.29) in THF (lOOml) under nitrogen at 00. The mixture was stirred for 2 days at room temperature. The reaction was quenched by the addition of water (2.2ml), 2M sodium hydroxide solution (2.2ml) and water (6.5ml). The suspension was filtered and the filtrate evaporated to give 13(d) (5.649), t.l.c. (System A, 80:20:1), Rf 0.05.

(e) 4-[6-[(6-Bromohexyl)oxy]hexyl]-1-methylpiperidine From 13(d) (5.59) and 1,6-dibromohexane (12.8ml) by the method of 3(a) to give 13(e) (2.69) t.l.c. (System A, 80:20:1) Rf 0.55.

(f) N-[6-[[6-(1-Methyl-4-piperidinyl)hexyl]oxy]hexyl] benzenemethanamine From 13(e) (2.69) and benzylamine (8ml) by a similar method to 1(b), heating at 1000 for 2 hours, to give 13(f) (2.72g), t.l.c.

(System A, 90:10:1) Rf 0.15.

(9) 4-Hydroxy-α-[[[6-[[6-(1-methyl-4-piperidinyl)hexyl]oxy]hexyl] amino]methyl]-1,3-benzenedimethanol A solution of 2-bromo-1-[4-hydroxy-3-(hydroxymethyl)phenyl] ethanone (851mg), 13(f) (1.359) and N,N-diisopropylethylamine (0.73ml) in THF (30ml) was stirred at room temperature overnight. The solvent was evaporated and the residue dissolved in ethanol (200ml) and hydrogenated over pre-reduced 5S platinum oxide on carbon (500mg) and 10 palladium oxide on carbon (500mg) catalyst. The catalyst was removed by filtration and the filtrate evaporated. The residue was purified by FCC eluting with System A (90:10:1 to 70:30:1) to give the title compound (220mg) as a pale yellow solid m.p. 89'C.

Analysis Found C,68.7; H,10.4; N,6.05; C27H48N204.0.5H20 requires C,68.5; H,10.4; N,5.9%

Claims

CLAIMS: 1. Compounds of general formula (I)

wherein R1 and R2 each independently represents a hydrogen atom or a C1-3alkyl group with the proviso that the sum total of carbon atoms in R1 and R2 is not more than 4; W represents a group

where Z represents a group R3(CH2)q where q is 0, 1 or 2 and R3 is a qroJpR4CONH-, R4NHCONH-, R4R5NSO2NH- or R6S02NH or OH; R4 and R5 each representsahydrogen atom or a C1-3alkyl group; R6 represents a C1-3alkyl group; R7 is a chlorine atom or the group -CF3;; X represents a direct bond or a C 1-7 7alkylene, C2 7alkenylene or C2-7alkynylene group and Y represents a direct bond or a C1-6alkylene, C2-6alkenylene or C2-6alkynylene group with the proviso that the sum total of carbon atoms in X and Y is not more than 10; Q represents a saturated heterocyclic group which has 5 to 8 ring members and contains in the ring one or more atoms or groups selected from -0-, -5-, H- and -N(CH3)-, and which may be unsubstituted or substituted by a benzene ring fused to two adjacent carbon atoms, and physiologically acceptable salts and solvates thereof.
2. Compounds according to claim 1, wherein, in the general formula (I), R1 and R2 each represents a hydrogen atom and W represents a group

or
3. Compounds according to claim 1 or 2, wherein, in the general formula (I), W represents a group

and Q represents a group
4. Compounds according to claim 1, wherein, in the general formula (I), R1 and R2 each represents a hydrogen atom and the sum total of carbon atoms in the chains X and Y is 4, 5, 6, 7, 8 or 9.
5. Compounds according to Claim 1 selected from: 4-Amino-3,5-dichloro-[[[6-[3-(2-tetrahydrofuranyl)propoxy] hexyl3amino]methyl]ben2enemethanol; 4-Amino-3,5-dichloro-α-[[[6-[2-(2-tetrahydrofuranyl)ethoxy] hexyl]amino)methyl]benzenemethanol; 4-Amino-3,5-dichloro-α-[[[6-[4-(4-morpholinyl)butoxy]hexyl] amino]methyl]benzenemethanol; 4-Amino-3,5-dichloro- α-[[[5-[2-(1,2,3,4-tetrahydroquinolinyl) ethoxy]pentyl]amino]methyl]benzenemethanol; 4-Amino-3,5-dichloro-α-[[[6-[2-(1-piperidinyl)ethoxy]hexyl] amino]methyl]benzenemethanol; 4-Amino-3,5-dichloro-α-[[[6-[2-(2-tetrahydropyranyl)ethoxy] hexyl] amino]methyl]benzenemethanol; 4-Amino-3, 5-dichloro-a-[ F [6-[3-(2-tetrahydropyranyi)propoxy] hexyl]amino]methyl]benzenemethanol;; 4-Amino-3,5-dichloro-α-[[[6-[2-(1-methyl-2-piperidinyl)ethoxy) hexyl]amino]methyl]benzenemethanol; 4-Amino-3,5-dichloro-α-[[[6-[2-(2-piperidinyl)ethoxy]hexyl] amino]methyl)benzenemethanol; 4-Amino-3,5-dichloro-α-[[[6-(4-(2-morpholinyl)butoxy]hexyl] amino]methyl]benzenemethanol; 4-Amino-3,5-dichloro-[[[6-[4-(4-methyl-2-morpholinyl)butoxy] hexyl]amino]methyl]benzenemethanol; 4-Amino-3,5-dichloro-α-[[[6-[3-(4-tetrahydropyranyl)propoxy] hexyl3amino]methyl]benzenemethanol; 4-Hydroxy-α-[[[-6-[[6(1-methyl-4-piperidinyl)hexyl]oxy]hexyl] amino]methyl]-1,3-benzenedimethanol; and their physiologically acceptable salts and solvates.
6. A pharmaceutical composition comprising, as active ingredient, a compound of general formula (I) as defined in claim 1 or a physiologically acceptable salt thereof together with one or more physiologically acceptable carriers therefor.
7. A pharmaceutical composition according to claim 6, formulated for administration by inhalation or insufflation.
8. A pharmaceutical composition according to claim 7, formulated in unit dosage form containing 0.005 mg to 20 mg active ingredient.