CA1255666A - Phenethanolamine compounds - Google Patents

Abstract

A B S T R A C T

PHENETHANOLAMINE COMPOUNDS

The invention provides compounds of the general formula (I) (I) wherein Ar represents a phenyl group optionally substituted by one or more substituents selected from halogen atoms, or C1-6 alkyl, -(CH2)qR, [where R is hydroxy, C1-6 alkoxy, -NR3R4 (where R3 and R4 each represents a hydrogen atom, or a C1-4 alkyl group, or -NR3R4 forms a saturated heterocyclic amino group which has 5-7 ring members and optionally contains in the ring one or more atoms selected from -0-or -S- or a group -NH or -N(CH3)-), -NR5COR6 (where R5 represents a hydrogen atom or a C1-4 alkyl group, and R6 represents a hydrogen atom or a C1-4 alkyl, C1-4 alkoxy, phenyl or -NR3R4 group), -NR5SO2R7 (where R7 represents a C1-4 alkyl, phenyl or -NR3R4 group), -COR8 (where R8 represents hydroxy, C1-4 alkoxy or -NR3R4), -SR9 (where R9 is a hydrogen atom, or a C1-4 alkyl or phenyl group), -SOR9, SO2R9, or -CN, and q represents an integer from 0 to 3], -O(CH2)rR10 [where R10 represents a hydroxy or C1-4 alkoxy group and r is an integer 2 or 3], or -NO2 groups or an alkylenedioxy group of formula -O(CH2)pO-, where p represents an integer 1 or 2;
R1 and R2 each represent a hydrogen atom or a C1-3 alkyl group with the proviso that the sum total of carbon atoms in R1 and R2 is not more than 4;
X represents a C1-7 alkylene, C2-7 alkenylene or C2-7 alkynylene chain and Y represents a bond, or a C1-6 alkylene, C2-6 alkenylene or C2-6 alkynylene chain with the provisos that the sum total of carbon atoms in X and Y is 2-10 and when X
represents C1-7 alkylene, Y represents C2-6 alkenylene or C2-6 alkynylene;
and physiologically acceptable salts and solvates thereof.
The compounds of formula (I) have a selective stimulant action at .beta.2-adrenoreceptors and are useful, in particular in the treatment of diseases associated with reversible airways abstruction such as asthma and chronic bronchitis

Description

- ~ZS~6~i PHENETIIANOLAMINE COMPOUNDS

1 This invention relates to phenethanolamine compounds having a stimulant action at ~2-adrenoreceptors, to processes for their preparation, -to pharmaceutical compositions containing them and to their use in medicine.
Thus the present invention provides cornpounds oF the general formula (I) HOCH~2 ~ _~ Rl H0~ CI-ICH2NHIXCH20CH2YAr (I) ~ -~ OH R

wherein Ar represents a phenyl group optionally substituted by one or more substltuents selected from halogen atoms, or Cl_6alkyl~ ~(CH2)qR~ [where R is hydroxy, C1_6 alkoxy, -NR3R4 (where R3 and R4 each represents a hydrogen atom, or a Cl_4 alkyl group, or -NR3R'I forms a saturated heterocyclic amino group which has 5-7 ring members and optionally contains in the ring one or more atoms selected from -û- or -5- or a group -Nll- or -N(CH3)-), -NR5CoR6 (where R5 represents a hydrogen atom or a Cl-,~ alkyl group, and R6 represents a hydrogen atom or a Cl_4 alkyl, Cl_4 alkoxy, phenyl or -NR3R4 group), -NR5502R7 (where R7 represents a Cl_4 alkyl, phenyl or -NR3R4 group), -CoR3 (where R8 represents hydroxy, Cl_4 alkoxy or -NR3R4), -SR9 (where R9 is a hydrogen atom, or a Cl_4 alkyl or phenyl group), -SûR9, 502R9, or -CN, and q represents an integer From 0 to 3], ~0(CH2)rR1 [where Rl represents a hydroxy or Cl_4 alkoxy group and r is an integer 2 or 3], or -N02 S~6~

1 groups or an all<ylenedioxy group of forrnula -O(CH2)pn-, where p represents an integer 1 or 2;
Rl and R2 each represents a hydrogen atom or a Cl-3 alkyl group with the proviso that the sum total of carbon atoms in Rl and R2 is not more than 4;
X represents a Cl~7 alkylene, C2-7 all<enylene or C2-7 alkynylene chain and Y represents a bond, or a Cl_6 alkylene, C2_6 all<enylene or C2_6 alkynylene chain with the provisos that the sum total of carbon atoms in X and Y is 2-10 and when X
represents Cl_7 alkylene, Y represents C2-6 alkenylene or C2-6 alkynylene; and physiologically acceptable salts and solvates (e.g. hydrates) thereof.
It will be appreciated that the compounds of general formula (I) possess one or two asymmetric carbon atoms, namely the carbon atom of the -ICH- group and, when Rl and 0~1 R2 are different groups, the carbon atom to which these are attached.
The compounds according to the invention thus include all enantiomers, diastereoisomers and mixtures thereof, including racemates. Compounds in which the carbon atom in the -Cl-l- group is in the R configuration 0~1 are preferred.
In the definition of general formula (I), the term alkenylene includes both cis and trans structures.
In the general formula (I), the chain X may for example contain 2 to 7 carbon atoms and may be for example -(CH2)2-~ -(Cl-l2)3-~ -(Cll2)~ (CH2)5-' CH2C~
(CH2)2cH=cll-~ -(Cl-l2)2C-C-, -C~l=CHCH2-, -CH=CH(CH2)2_ or -CH2C-CCH2-. The chain Y may be for example -CH2-, -(CH2)2-~ -(Cll2)3-~ -(CH2)4-~ -(CH2)s-~ -(Cli2)6-, -CH=CH-, -C_C-, -CH2CII=CH-, or -Cll2C--C-.
In general, the total number of carbon atoms in the chains X and Y is preferably ~L to 10 inclusive and may be 66~;i 1 for example 5, 6, 7~or ~. Compounds wherein the surn total of carbon atoms in the chains X and Y is 5, 6 or 7 are particularly preferred.
In the compounds of formula (I) Rl and R2, for example, may each be methyl, ethyl, propyl or isopropyl groups except that if one Of Rl and R2 is a propyl or isopropyl group, the other is a hydrogen atom or a methyl group. Thus for example Rl may be a hydrogen atom or a methyl, ethyl or propyl group. R2, for example, may be a hydrogen atom or a methyl group.
Rl and R2 are each preferably a hydrogen atom or a methyl group.
A preferred group of compounds is that wherein Rl and R2 are both hydrogen atoms, or Rl is a hydrogen atom and R2 is a Cl_3 alkyl group, particularly a methyl group, or Rl is a methyl group and R2 is a methyl group.
~hen -NR3R4 in compounds of formula (I) represents a saturated heterocyclic amino group, this may have 5, 6 or 7 ring members and optionally contain in the ring a heteroatom selected from -0-, or -S-, or a group -Nl-l- or -N(CH3)-~ Examples of sucll -NR3RIi groups are pyrrolidino, piperidino, hexamethylenimino, piperazino, N-methylpiperazino, rnorpholino, homornorpholino or thiamorpholino.
The group Ar may be for example a phenyl group.
Alternatively Ar may be a substituted phenyl group and may for example contain one 7 two or three substituents, which may be present at the 2-, 3-, 4-, 5- or 6-positions on the phenyl rinq.
Examples of the substituents which may be present on the phenyl group represented by Ar include chlorine,`
bromine, iodine, fluorine, methyl, ethyl, ~(CH2)qR
[where R is hydroxy, methoxy, ethoxy, amino, methylamino, ethylamino, dimethylamino, diethylamillo, morpllolino, piperidino, piperazino, N-methylpiperazino, -NHCHû, NHCOR6 (where R6 is Cl_4 alkyl, e.g. methyl, ethyl, isopropyl or ~1;25~

1 n-butyl, Cl_" all<oxy, e.g. methoxy, ethoxy, isopropoxy, or n-butoxy, phenyl, amino or N,N-dimethylamino), -N(CH3)COCH3, -NR5502R7, where R5 represents a hydrogen atom or a methyl group and R7 represents methyl, ethyl, isopropyl, n-butyl or phenyl, -NHS02NH2, -N11502N(CH3)2, -COOH, -COOCH3, -CONH2, -CON(CH3)2, -CONR3R4 (where NR3R4 is piperidinot morpholino, pipera~ino or N-methyl-piperazino) -SR9 (where R9 is methyl, ethyl or phenyl) -SOCH3, -SO2CH3, or CN and q is zero, l, 2 or 3], -N02,

2 2 ~ O(CH2)30H, -O(CH2)20CH3, or -O(CH2)20CH CH .
Particular examples of a monosubstituted phenyl group represented by Ar include phenyl substituted by the group ~(CH2)qR where R is Cl_6alkoxy and q is an integer l, 2 or 3, or R is -NR3R~, -Nsso2R7~ -CoR3, -SR9 or O(CH2)rRl [where q, R3, R4, R5, R7, R8, R9, r and RlO
are as defined for formula (I)]. In particular, the group Ar may be phenyl substituted by -OH, -CH20i1, -(CH2)20H, (C'1 ) OH CH OC113, -NH(C~3), -N(C~-13)2, N~1C 2 3 morpholino, pyrrolldino, piperidino, -CH2N(CH3)2, -CH2-piperidino, -N11502CH3, -NHS02(CH2)2CH3, NHS02(CH2)3C1-13~ -N~1502-ph~nyl, -NHSû2N(CH3)2, -C02H, -C02C~13~ -C02C~`12C~13~ -Co2(c~l2)2c~l3~ -CONH2, -CON(C~13)2, -SCH3, -SC112C1-13, -S-phenyl, or -O(CH2)2ûC1-13.
Particular examples of a trisubstituted phenyl group represented by Ar include phenyl substituted by an amino and two methy] groups, (for example 3,5-dimethyl-4-amino-phenyl), an amino group and two chlorine atoms, (for example 3,5-dichloro-4-aminophenyl), or three methoxy groups, (for example 3,4,5-trimethoxyphenyl). Particular examples of a disubstituted phenyl group represented by Ar include phenyl substituted by two hydroxyl groups,~(for example 3,5-dihydroxyphenyl,) or a hydroxyl and methoxy group, (for example 3-methoxy-4-hydroxyphenyl,).
In general, when the substituent on the phenyl group represented by Ar is one of the groups ~(CH2)qR~ where R
is -NR3R4, -NR5CoR6, -NR5502R7, -COR8, -SR9, -SOR9, -S02R9 3LZ5~6 l or -CN and q is an integer l, 2 or 3, any additional substituent present on the phenyl group is desirably one which is different from those substituents.
In one aspect the invention provides compounds of formula (I) in which Ar represents a phenyl group optionally substituted by one or two substituents selected from halogen atoms7 Cl_3 alkyl or Cl_3 all<oxy groups, or by an all<ylenedioxy group of formula -O(CI-l2)pO- where p is 1 or 2, and X, y, Rl and R2 are as defined for formula (I).
Particularly important compounds of the invention are:-- (Z)-N-[4-[3-[[6-[[2-Hydroxy-2-[4-hydroxy-3-(hydroxy-methyl)phenyl]ethyl]amino]hexyl]oxy]-l-propenyl]phenyl]
methanesulphonamide;
4-Hydroxy-al-[[[6-[[3-[4-[(l-methylpiperazine-4-yl)methyl]
phenyl]-2-propynyl]oxy]hexyl]amino]methyl-1,3-benzenedi-methanol;
N-[4-[3-[[6-[[2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phen-yl]ethyl]amino]hexyl]oxy]-l-propynyl]phenyl]acetamide;
4-Hydroxy-al-[[[6-[4-[(4-hydroxy-3-methoxyphenyl)-3E-but-enyl]oxy]hexyl]amino]methyl]-1,3-benzenedimethanol;
(_)-N-[4-[3[[6-[[2-llydroxy-2-[4-hydroxy-3~(hydroxymethyl) phenyl]ethyl]amino]hexyl]oxy]-l-propenyl]phenyl]acetamide;
4-Hydroxy-al-[[[6-(4-phenylbutoxy)-3,Z-hexerlyl]amino]
methyl]-1,3-benzenedimethanol;
4-Hydroxy-al-[[[l-methyl-6-[(4-phenyl-3,Z-butenyl)oxy]
hexyl]amino]methyl]-1,3-benzenedimethanol;
and the physiologically acceptable salts and solvates thereof.
Suitable physiologically acceptahle salts of the compounds of general formula (I) include acid addition salts derived from inorganic and organic acids, such as hydrochlorides, hydrobromides, sulphates, phosphates, rnaleates, tartrates, citrates, benzoates, 4-methoxy-benzoates, 2- or 4-hydroxybenzoates, 4-chlorobenzoates, p-toluenesulphonates, methanesulphonates, ascorbates, salicylates, acetates, fumarates, succinates, lactates, ~L~2S5~6~

1 glutarates, gluconates, tricarballylates, hydroxy-naphthalenecarboxylates e.g. l-hydroxy- or 3-hydroxy-2-naphthalenecarboxylates, or oleates. The compounds may also form salts with suitable bases. Examples of such salts are all<ali metal (e.g. sodium and potassium), and alkaline earth metal (e.g. calcium or rnagnesiurn) salts.
The compounds according to the invention have a selective stimulant action at ~2-adrenoreceptors, which furthermore ia of a particularly advantageous profile.
The stimulant action was demonstrated in the isolated trachea of the guinea-pig, where compounds were ahown to cause relaxation of PGF2a-induced contractions.
Compounds according to the invention have shown a particularly long duration of action in this test.
The cornpounds according to the invention may be used in the treatment of diseases associated with reversible airways obstruction such as asthma and chronic bronchitis.
The compounds according to the invention may also be used For the treatment of premature labour, depression and congestive heart failure, and are also indicated as useful for the treatment of inflammatory and allergic sl<in diseasea, glaucoma, ancl in the treatment of conditions in which there is an advantage in lowering gaatric acidity, particularly in gastric and peptic ulceration.
The invention accordingly further provides compounds of formula (I) and their physiologically acceptable salts and solvates for use in the therapy or prophylaxis of diseases associated with reversible airways obstruction in -human or animal subjects.
The compounds according to the invention may be formulated for administration in any convenient way. The invention therefore includes within its scope pharmaceutical compositions comprising at least one compound of formula (I) or a physiologically acceptable salt or aolvate thereof formulated for use in human or ~2~

1 veterinary medicine. Such compositions may be presented for use with physiologically acceptable carriers or excipients, optionally with supplementary medicinal agents.
Ihe compounds may be formulated in a form suitable for administration by inhalation or insufflation, or for oral, buccal, parenteral, topical ~lncluding nasal) or rectal administration. Administration by ir,halation or insufflation is preferred.
For administration by inhalation the compounds according to the invention are conveniently delivered in the form of an aerosol spray presentation frorn pressurised packs9 with the use of a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane1 dichloro-tetrafluoroethane, carbon dioxide or other suitable gas, or from a nebuliser. In the case of a pressurised aerosol the dosage unit may be determined by providing a valve to deliver a metered amount.
~lternatively, for sdministration 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 compouncl 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 pacl<s from which the powder may be administered with the aid of an inhaler or insufflator.
For buccal administration the composition may take the form of tablets, drops or lozenges formulated in conventional manner.
The compounds of the invention may be forrnulated for parenteral administration. Formulations for injections 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 ~Z~Sf~6~

1 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 pharrnaceutical composition may take the form Or 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 aclministration, 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 n.0005mg to lOOmg, which may be conveniently administered in one or 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 hy inhalation is û.0005mg to lOmg, for oral administration is 0.02mg to lOOmg, and for parenteral administration is O.OOlmg to 2mg.
The compounds according to the invention may be prepared by a number of processes, as described in the following wherein X, Y, Ar, Rl and R2 are as defined for general formula (I) unless otherwise specified. It will be appreciated that certain of the reactions described below are capable of affecting other groups in the ` - ~ZSS66~;

l starting mflterial which are desired in the end product.
Care must therefore be taken in accordance with conventionfll practice, to use reagents and/or reaction conditions under which such groups remain substantially inert. In the general processes described below the final step in the reaction may be the removal of a protecting group. Suitable protecting groups and their removal are described in general process (3) below.
According to one general process (l), a compound of gsneral formula (I) may be obtained by reaction of a compound of general formula (II):
R120C~2 R 0~ -Z (II) (wherein Z reoresents a group -CH-/CH2 or -ICIlCH2L, R12 and 0 ~1 R13 ls eflch a hydrogen atom or a protecting group, and L
represents a leaving group, for example a halogen atom such as chlorine, bromine or iodine, or a hydrocarbyl-sulphonyloxy group such as methanesulphonyloxy or p-toluenesulphonyloxy) with an amine of general formula (III) H2NICXC~l20C~l2YAr (III) followed by removal of any protecting groups where present, as described hereinafter.
The reaction may be effected in the presence of a suitable solvent for example an alcohol, such as ethanol, a halogenated hydrocarbon e.g. chloroform, a substituted amide e.g. dimethylformamide or an ether such as - \ o \
5~66 1 tetrahydrofuran or dioxan at a temperature from ambient to the reflux, optionally in the presence of a base such as an organic amine e.g. diisopropylethylamine or an inorganic base such as sodium carbonate.
In another general process (2), a compound of general formula (I) may be prepared by alkylation. Conventional alkylation procedures may be used.
Thus, for example, in one process (a), a compound of general formula (I) in which Rl is a hydrogen atom may be prepared by alkylation of an amine of general formula (IV) Rl20CH2 o _~
R l 30~ CI-IC5,-1 2NR l 4R l 5 ( IV ) =o OH

(wherein Rl2, Rl3 and Rl4 is each a hydrogen atom or a protecting group and R15 is a hydrogen atom) followed by removal of any protecting group where present.
The alkylation (a) mr~y be effected using an alkylating agent of general formula (V):

LCII-IXC~l20CIl2YAr (V) (wherein L is as previously defined).
The alkylation is preferably effected in the presence of H suitable acid scavenger, for example, inorganic hases such as sodium or potassium carbonate, organic bases such as triethylasnine, diisopropylethylamine or pyridine, or all<ylene 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 or dioxan, a ketone e.g. butanone or methyl isobutyl ketone, a substituted amide e.g. dimethylformamide or a chlorinated \
~S~6~6 1 hydrocarbon e.g. chloroform at a temperature between ambient and the reflux temperature of the solvent.
According to another example (b) of an all<ylation process, a compound of general formula (I) in which Rl represents a hydrogen atom may be prepared by alkylation of an amine of general formula (IV) with a compound of general formula (VI):

R2COXCH20CH2YAr (VI) in the presence of a reducing agent, followed when necessary by removal of any protecting groups.
Suitable reducing agents include a hydride such as a metal hydride such as sodium borohydride, sodium cyanoborohydride or lithium alulninium hydride. Suitable solvents for the reaction with 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 tert-butyl methyl ether, or tetrahydrofuran.
When a compound of formula (IV) where Rl4 and Rl5 are each hydrogen atorns is used~ the intermediate imine of formula (VII) may be formed:
R12oc\2 \ _ / 1 l2N=CIXCil2ûCil2yAr (VII) (wherein Rl2 and R13 are as defined for formula (II)).
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).

~2~ 6 l In another general process (3), a compound of general formula (I) may be obtained by deprotection of a protected intermediate of general formula (VIII):
R120CH~2 ~ R1 Rl30~ CHCH 2NRl4~XCII20CH2`~Ar (VIII) O _- OH R

(wherein R12, Rl3 and Rl4 are as previously defined except that at least one of Rl2, Rl3 and Rl4 is a protecting group).
The protecting group may be any conventional protecting group, for example as described in "Protective Groups in Organic Chemistry", Ed. J.F.W. McOmie ~Plenum Press, 1973). Thus R12 and/or R13 for example may each be tetrahydropyranyl, and R14 may be an acyl group such as trichloroacetyl or trifluoroacetyl.
The deprotection to yield a compound of general formula (I) may be effected using conventional techniques.
Thus for example, when R12 and/or R13 is a tetrahydro-pyranyl this may be cleavecl by hydrolysis under acidicconditions. Acyl groups represented by Rl4 mfly be removed by hydrolysis, for example with a base such as sodium hydroxide, or a group such as trichloroacetyl may be removed by reduction with, for example, zinc and acetic acid.
In a particular embodiment of the deprotection process (3), Rl20CI-I2- and Rl30- may together represent a protecting group R16 OCH2- (wherein R16 and Rl7, which R ~ O-may be the same or different, each represents a hydrogenatom or an alkyl or aryl group). The protecting group may be cleaved using for example hydrochloric acid in a solvent such as water or an alcohol such as ethanol at normal or elevated temperatures.

~z5S6~, 1 In another general process (4), a compound of general formula (I) may be prepared by reduction. Thus, for example, a compound of general formula (I) may be prepared by reducing an intermediate of general formula (IX):

O--.
Rl30-o /~7--Xl-X2-X3~CH20CH2Y~Ar (IX) [wherein Rl3 is 8S defined for general formula (II) and at lesst one of Xl, X2, X3, and X4 represents a reducible group and the other(s) take the appropriate meaning as follows, which is xl is -CH(OH)-, x2 is -CH2NRl4, X3 is -CRlR2X, X4 is -CH20Rl2 and Y and Ar are as defined for formula (I)] followed where necessary by removal of any protecting groups.
Suitable reducible groups include those wherein xl is a group -C=O, x2 is an imine (-CH=N-) group or a group -CONH-, X3 is a group -COX-, or -X2-X3- is a group -CH2N-CR2X, and X4 is a group -Co2Rl3 (wherein Rl3 represents a hydrogen atom, or an all<yl, aryl or aralkyl group) or -CHO.
The rer~uction may be effected using reducing agents conveniently employed for the reduction of carboxylic acids, aldehydes, esters, I<etones, imines, and amides.
Thus, for example, when xl in general formula (IX) represents a -C=O group this may be reduced to a -CH(OH)-~5 group using a hydride such as a metal hydride for example lithium aluminium hydride, sodium bis(2-methoxyethoxy) aluminium hydride, sodium borohydride or aluminium hydride. The reaction may be effected in a solvent, where appropriflte an alcohol e.g. methanol or ethanol, or an ether such as tetrahydrofuran, or a halogenated hydrocarbon such as dichloromethane.

\~
~ss6~

1 When x2 in general forrnula (IX) represents the group -C~-l=N-, or -X2-X3- represents -CH2N=CR2X this may be reduced to a -CH2NH- or -Cl-l2NHCIIR2X- group using a reducing agent and conditions as just described for the S reduction of xl when this represents a -C=O group.
When x2 or X3 in general formula (IX) represents a -CONH- or -COX- group this may be reduced to a group -CH2NH- or -CH2X- respectively using a hydride such as a complex metal hydride for example lithium aluminium hydride or sodium bis(2-methoxyethoxy)aluminium hydride in a solvent such as an ether, e.g. tetrahydrofuran or diethyl ether.
When X4 represents a group -Co2Rl3 or -Cl-lO this may be reduced to a group -CH20H using a hydride such as a complex metal hydride for example lithium aluminium hydride, sodium bis(2-methoxyethoxy)aluminiurn hydride, sodium borohydride, diisobutylaluminium hydride or lithium triethylborohydride in a solvent such as an ether, e.g.
tetrahydrofuran or diethyl ether, or a halogenated hydrocarbon 0.9. dichloromethane at a temperature from 0C to the reflux.
In the reduction processes just described, the groups X4 and Rl30 in a compound of formula (IX) may together conveniently represent a group R ~ Cll2-. After the Rl reduction is complete, cleavage of this group using e.g. a dilute acid in a solvent such as water at normal temperature yielcls a compound of formula (I).
In another process, a compound of formula (I) in which Y is a C2_6 alkynylene chain irl which the acetylene group is adjacent to the group Ar may be prepared by reaction of an intermediate of formula (X) ~I n c \ 2~
H0 -o\ /~ ICllCll2NRl4¢XCH20CH2YlC_CH (X) ~_o OH R2 (where yl is a bond or a Cl-4 alkylene group and preferably or-e of Rl and/or R2 is a hydrogen atom) with an aryl halide Ar llal (where llal i5 a halogen atom, for example an iodine atom) followed where necessary by removal of any protecting group. The reaction is performed in the presence of a metal catalyst (e.g.
copper) and ~n organometallic reagent such as bis(triphenylphosphino) palladium (Il) chloride and a base such as an organic amine e.g. diethylamine diisopropyl-ethylamine.
Intermediates of formula (X) may be prepared by reaction of a bromol<etone of formula (XI) ~IOC~2 H0~ COCII2Br (XI) wlth an amine Rl4HNC(Rl~(R2)XCH20CH2YlC-CI-I in the presence oF a base such as sodium carbonate and a solvent such as ethyl acetate, followed by reduction using a reducing agent such as sodium borohydride in a solvent such as ethanol. The intermediate amines used in this process may be prepared by reaction of a bromide HC_CYlCH20CH2XC(Rl)(R2)Br with an amine Rl4NH2. The bromides may be prepared by all<ylation of an appropriate alcohol HC-CYlCH20H with a disubstituted alkane BrCH2XC(Rl)(R2)Br in the presence of a base such as sodium hydroxide and a phase transfer catalyst such as tetrabutylamnonium bisulphate. The starting materials for ~2~ 6 l this reaction are either known or may be prepared by rnethods analogous to those used for the preparation of the l<nown compounds.
It is also possible to prepare a compound of general formula (I) by a process comprising interconversion of another compound of general formula (I)~
For example, a compound of formula (I) in which X
and/or Y is an alkenylene chain may be prepared by reduction of a corresponding compound in which X and/or Y
is an alkynylene chain. The reduction may be effected 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 a low temperature e.g. 0C.
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 iso-propanol.
Physiologically acceptable salts may also be prepared from other salts, including other physiologically 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.

~Z5~666 1 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 frorn which the 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 crystallisa-tion.
Racemates of diastereoisomers may be obtained by conventional methods of separation e.g. fractional crystallisation isomers of cornpounds of formula (I).
The intermediate compounds used in the above general processes are either known compounds or they may be prepared by methods analogous to those used for the preparation of the l<nown compounds. Suitable methods for preparing the intermediate compounds are described in U.l<.
Patent Specification No. 214n~00A and in the examples included hereinafter \~

S~6 The following examples illustrate the invention.
Temperatures are in C. 'Dried' refers to drying using magnesium sulphate except where otherwise stated. Thin layer chromatography (t.l.c.) was carried out over SiO2.
The following flbbreviations are used: DMF dimethylformamide;
THF - tetrahydrofuran; EA - ethyl acetate; ER - diethyl ether;
[C] - column chromatography on silica (Merck 9385); [FCS] - flash column chromatography on silica (Merck 9385) Intermediate 1 referred to below is al-(aminomethyl)-4-hydroxy-1,3-~0 benzenedimethanol.
In_ermediate 2 (E)-4-[3-Methoxy-4-(methoxymethoxy)phenyl]-3-buten-1-ol n-Butyllithium (1.6M in hexane, 25mQ) was added dropwise to a stirred suspension of (3-hydroxypropyl)triphenylphosphonium bromide (8.039) in dry THF (50mQ) cooled to 0 under nitrogen. The resulting blood-red solution was stirred at 0 for lOmin and then 3-methoxy-4-(methoxymethoxy)-benzaldehyde (3.609) in dry THF (lOmQ) was added dropwise over 5min. The mixture was allowed to warm to room temperature, stirred for 4h water (lOmQ) was added and the majority of the solve~t was removed in vacuo at - -4û. A solution of the residual oil in ER (20ûmQ) was washed with water (150mQ), dried, treated with charcoal, concentrated and purified by [FCS]
eluting with EA/hexane (1:1) to give the title compound (1.559).
T.l.c. (EA-Hexane 1:1) Rf 0.30.
Intermediate 3 1-[4-[(6-Bromohexyl)oxy]butyl]-3-methoxy-4-(methoxymethoxy)benzene A solution of Intermediate 6b (2.059) in absolute ethanol (30mQ) was hydrogenated over a pre-reduced 10~ PdO on carbon catalyst (0.29, 50O
paste in water) until the uptake of hydrogen (130mQ) ceased. The catalyst was removed by filtration ~ yflo) and the solvent removed in vacuo at 40 to afford the title compound (2.059). T.l.c. (EA-Hexane 1:2~ Rf 0.64.
Intermediate 4 6-[(Tetrahydro-2H-pyran-2-yl)oxy]-1-hexanol * Trademark ~5~6 1 Hexane-1,6-diol (70.9g)~was melted in a water bath at ca. 60, the melt cooled to 45 and dihydropyran (16.829) quicl<ly added followed by lON hydrochloric acid (O.lmQ). The mixture was stirred and cold water added to maintain a reaction temperature of approximately 50. When the exotherm had subsided, the mixture was stirred at room temperature for 0.5h, then diluted with water (500mQ) and extracted with ER (2x250mQ).
The ER solution was washed with water (3x50ûmQ), dried and concentrated to yield an oil which was purified by [FCS] elution with EA/hexane (1:1) affording the title compound (19.69). T.l.c. (EA/hexane 1:1) Rf 0.40.
Intermediate 5 6-[(2-Propynyl)oxy]-l-hexanol A mixture nf Intermediate 4 (18.69), propargyl bromide (80o in toluene; 14.~89) 40O w/v aqueous sodium hydroxide solution (200mQ) and tetrabutylammonium bisulphate (3.349) was stirred at room temperature for 5h, diluted with water (500mQ) and extracted with ER (2x250mR). The ER
solution was dried and concentrated to yield an oil which was taken up in a mixture of methanol (lOOmQ) and 2N hydrochloric acid. After stirring for 2h the methanol was removed in vacuo at 40, the residual aqueous phase diluted with brine (lOOmQ), extracted with ER (2x75mQ), dried, concentrated, and purified by [FCS] elution with 25~ EA/cyclohexane yielding the title compound (8.69) T.l.c. (EA:I-lexane 1:4) Rf 0.16.
Intermediate 6 a) l-Bromo-6-[(2-propynyl)oxy]hexane A mixture of propargyl alcohol (5.69), 1,6-dibromohexane (73.29), tetrabutylammoniumbisulphate (0.59), and aqueous sodium hydroxide (50 w/v, 25ml was stirred at room temperature for 20h, diluted with water (50ml), and extracted with ER (2 x lOOml). The dried extract was evaporated and the residue was purified by [C] eluted with cyclohexane followed by cyclohexane - ER (19:1) to give the title compound as a colourless oil (15.09) T.l.c. (cyclohexane - ER 9:1) Rf 0.4.
The following compounds were prepared in a similar manner:
b) [(E)-1-[4-[(6-Brornohexyl)oxy]-l-butenyl]-3-methoxy-4-(methoxymethoxy) benzene, (1.559) from Intermediate 2 (1.49) and 1,6-dibromohexane (6.139).
Purification by [FCS] eluting with 5o EA/hexane increasing to 20o. T.l.c.
(25~ EA-cyclohexane) Rf 0.5.

~5S~

1 c) (E/Z)-5~[4-[(6-Bromohexyl)oxy]-3-butenyl]-1,3-benzodioxolane (E:Z =

3:2) (0.929) from 1,6-dibromohexane (2.79) and (E/Z)-4-[1,3-benzordioxol-5-yl]-3-butenol, (E:Z = 3:2) (0.2g; see U.K.Patent Specification No. 2140800A). Purification by [FCS] eluting ~lith cyclohexane then cyclohexane-ER (9:1).
T.l.c. (Cyclohexane-EA 4:1) Rf 0.5.
d) [4 -Propynyloxy)butyl]benzene, (18.39) from propargyl alcohol (109) and (4-bromobutyl)benzene (389). Purification by [C] eluting with cyclohexane-ER (19:1). T.l.c. (Cyclohexane-ER 19:1) Rf 0.2.
e) [4-(3-Butynyloxy)butyl]benzene, (9.5q) from (4-bromobutyl)benzene (159) and 3-butyn-1-ol (59)~ T.l.c. (Cyclohexane;ER 9:1) Rf 0.45.
f) [4-[(2-Propynyl)oxy]-l,Z-buteny-]benzene~ (4.89) from

4-phenyl-3,Z-buten~ l-ol (59) and propargyl bromide (4.059). Purification by [C] eluting with cyclohexane-ER (9:1). T.l.c. (Cyclohexane-ER 9:1) Rf 0.45.
Intermediate 7 N-(4-Iodophenyl)methanesulphonamide Methanesulphonyl chloride (11.439) was added dropwise over 10 min to a stirred solution ofr 4-iodoaniline (21.99) in pyridine (150ml) cooled to -15 under nitrogen. During the addition, the trmperature was not allowed to rise above -10. The mixture was allowed to warm up to room temperature, stirred for 0.5h and the solvent removed in vacuo at 45 to give a red oil which was triturated with a mixture of EA (300ml) and 2N
hydrochloric acid. The organic phase was washed with further 2N HCl (150ml), dried, treated with charcoal and concentrated to yield the crude product as a pale yellow powder. Recrystallisation from EA/hexane yielded the title compound as a highly crystalline cream solid (25.09) m.p.
135-136.5.
Intermediate 8 N-[4-[3-[(6-Hydroxyhexyl)oxy]-l-propynyl]phenyl]methanesulphonamide Copper (I) iodide (43mg) was added to a solution of Intermediate 7 (13.379) Intermediate 5 (7.029) and bis(triphenylphosphine)palladium (II) chloride (316mg) in diethylamine (275ml), and the mixture stirred at room temperature under nitrogen for 22h. The solvent was evaporated in vacuo at 35, the residual brown oil taken up in EA (250ml) and the solution washed with 2N hydrochloric acid (2 x 200ml). The acid phase was extracted with ~ZS5~
l further EA (50ml), the~combined organics dried and evaporated onto 'flash' silica (~lercl< 9385; 759). The impregnated silica was applied to [FC5]
eluting with EA/hexane (4:1) to give the title compound as a fawn solid (13.69). Recrystallisation from EA/hexane yielded a fawn crystalline powder tll-2g) m.p. 83-~4.5.
Intermediate 9 (Z)-N-[4-[3-[(6-Hydroxy _ yl)oxy]-1-propenyl]phenyl]methanesulphon-amide A solution of Interrnediate B (ll.Og) in pyridine (250rnR) was hydrogenated at atmospheric pressure and room temperature over a pre-reduced Lindlar catalyst (3.5g) in pyridine (50mQ) until the uptake of hydrogen ceased.
The catalyst was removed by filtration through 'hyflo', the pad washed with ethanol (50mQ) and the solvents evaporated in vacuo at 50. A
solution of the residual brown oil in EA (300mQ), was washed with 2N
hydrochloric acid (2x250mQ), dried and treated with activated charcoal.
Concentration afforded the title compound (10.7~) m.p. 65-67.
Intermediate 10 (Z)-N-[4-[3-[(6-Bromohexyl)oxy]-l-propenyl]phenyl]methanesulphonamide Triphenylphosphine (8.819) in dichloromethane (50ml) was added dropwise over 5 min to a stirred solution of carbon tetrabromide (11.149) and Intermediate 9 (10.09) in dichloromethane (lûOml) cooled to 0 under nitrogen. When the addition was complete the mixture was stirred at room temperature for 3h, the solution evaporated onto silica (Merck 9385; 509) and the impregnated material subjected to [FCS] eluting with EA/hexane (1:3) to give the title compound as a colourless crystalline powder 9.19, m.p. 78-81.
Intermediate 11 1-(4-Iodobenzoyl)-4-methylpiperazine 4-Iodobenzoyl chloride (10.09) was added portionwise to N-methylpiperazine (3.89) in triethylamine (40ml) under nitrogen at room temperature. The resulting suspension was stirred at room temperature for 2h, triethylamine was removed under reduced pressure, and the residue was psrtitioned between aqueous sodium bicarbonate (lM; 50ml) and EA (2 x lOOml). The dried (Na250") organic phase was evaporated and the residue was triturated with ER (2 x 25ml) to give the title compound as a beige solid (4.79).

l~S~
1 Intermediate 12 _ 1-[(4-Iodophenyl)methyl]-4-methylpiperazine Diborane in Tl-IF (lM; 50ml) was added during 5 min to Intermediate 11 (5.09) in TI~F (lOOml) under nitrogen. The solution was refluxed for 3h, cooled, and treated cautiously with hydrochloric acid (2M; 50ml). The mixture was refluxed for 15 min and Tl-lF was removed under reduced pressure. The residue was basified with aqueous sodiurn hydroxide (2M) and extracted with EA (2 x 20ml). The dried (Na2504) extract was evaporated and the residue was purified by [C] eluted with ER followed by EA to give the title compound as a cream solid (2.89).
Intermediate 13 4-Hydroxy-~1-[[[6-[(2-propynyl)oxy]hexyl]amino]methyl]-1,3-benzenedi-m anol Intermediate 6 (6.09) was added dropwise to a solution of Intermediate 1 (5.09) and N,N-diisopropylethylamirle (7.09) in DMF (lOOml) at 75. The solution was heated at 75-80 for 2h and DMF was evaporated under reduced pressure. The residue was partitioned between EA (2 x 200ml) and aqueous sodium bicarbonate (lM; 50ml). The dried organic phase was filtered and evaporated, and the residue was purified by [C~ eluting with EA-methanol-triethylamine (90:10:1) to give a yellow gum. Trituration oF
the gum with ER (2 x 25ml) gave the title compound (1.159) m.p. 66-68.
Intermediate 14 (E)-4-[4-[(6-Bromohex-yl)oxy]-l-butenyl]-2-methoxyphenol A solution of Intermediate 3 (4.509) and 4-toloenesulphonic acid (2.349) in a mixture of THF (80mQ) and water (lOmQ) was heated under reflux for 2.5h and then the solvent evaporated in vacuo at 4n to yield a viscous oil. This was tal<en up in EA (lOOmQ) and the solution wahsed with 8o sodium bicarbonate solution (2x75mQ), dried, concentrated and purified by [FCS] eluting with 25~ EA-hexane to qive the title compound (3.609).
T.l.c. (EA-cyclohexane 1:3) Rf 0.44.
Intermediate 15 Z55~66 1 a) 5-(4-Phenylbutoxy)-3~pentyn-l-ol Intermediate 6d (6.ng) was added to a stirred suspension of lithamide [from lithium (0.2259)] in liquid ammonia (30mQ) at -78. Dimethyl-sulphoxide (20mR) was added and ammonia was evaporated on a water bath at 50. The resulting solution at 15 was treated with ethylene oxide (1.55) at -60 and the mixture was stirred at room temperature for 2h. Water (50mQ) was added and the emulsion was extracted with ER (5x80mQ), dried, evaporated and purified by [C] eluting witll cyclohexane-ER 7:3 to give the title compound (4.2g). T.l.c. (Cyclohexane-ER 3:1) Rf 0.15.
The following compound was prepared in a similar manner:~

b) [4 [(6-Chloro-2-hexynyl)oxy] l~Z butenyl]benzene, (3.59) from Intermediate 6f (4.89). Distillation in place of [C] gave the title compound. T.l.c. (Cyclohexane-ER 9:1) Rf 0.4.

Intermediates 16-18 were prepared in a similar manner to Intermediate lû:-Intermediate 16 [4-[(5-Bromo-2-pentynyl)oxy]butyl]benze-eJ (4.05g) from Intermediate 15 (4g). Purification by [C] eluting with cyclohexane-ER 19:1.
T.l.c. (Cyclohexane-ER 9:1) Rf 0.4.
Intermediate 17 -[4-[(6-Bromo-3-hexynyl)oxy]butyl]benzene, (4.29) from Intermediate 23 (3.89). Purification by [C] eluting with cyclohexane-ER (4:1).
T.l.c. (Cyclohexane-ER 9:1) Rf 0.4.
Intermediate 18 [4-[[(4-Bromo-2-butynyl)oxy]butyl]benzene, (8.2g) frorn Intermediate 21 (8g). Purification by [C] eluting with cyclohexane-ER (9:1).
T.l.c. (Cyclohexane-ER 9:1) Rf 0.4.
Intermediate 19 [4-[(6-Iodo-2-hexynyl)oxy]-l,Z-butenyl]benzene ~ mixture of Intermediate 15 (3.0g) sodium iodide (5.25g) and butanone (15mQ) was refluxed for 18h. ER (150mQ) was added and the suspension was filtered and evaporated to give the title compound (3.99).
T.l.c. (Cyclohexane-ER 9:1) Rf 0.4.
Intermediate 20 ~4 1 7-(4-Phenylbutoxy)-5-heptyn-2-one A mixture of Intermediate 18 (4.09) acetylacetone (1.549) potassium carbonate (1.939) and ethanol (25m~) was refluxed for 16h, filtered and evaporated. The residue was treated with ER (50m~), filtered, evaporated, and purified by [C] eluting with cyclohexane-ER (17:3) then distillation to give the title compound (1.59). T.l.c. (Cyclohexane-ER 3:1) Rf 0.35.
Intermediate 21 4-(4-Phenylbutoxy)-2-butyn-l-ol n-Butyllithium in hexane (1.6M; 31.5ml) was added dropwise to Intermediate 6d (9,09) in THF (50ml) at -78 under nitrogenO THe solution was stirred at -78 for 20 min and paraformaldehyde (1.59) was added. THe suspension was allowed to warm to room temperature and was stirred for lh. The resulting solution was treated with saturated aqueous ammonium chloride (150ml) and extracted with ER (2 x 200ml). The dried extrac-t was evaporated and the residue was purified by [C] eluting with cyclohexane -ER (3:1) to give the title compound as a colourless oil (8.49).
T.l.c. (Cyclohexane - ER 3:1) Rf 0.15.
Intermediate 22 .
[7-(4-Phenyl-3-butynyl)oxy]-2-heptanone Interrnediate 21 (20.169) in ER (lOOml) was added to a stirred mixture of magnesium turnings (1.79) and iodine (one small crystal) under nitrogen with stirring at a rate which maintained a gentle reflux. The cooled mixture was aclded to acetic anhydride (14ml) in ER (30ml) at -65 to -60 under nitrogen with mechanical stirring over 1.25h. The mixture was stirred at -65 for 1.5h, allowed to warm to -10, and treated with aqueous saturated ammonium chloride (lOOml), followed by ER (lOOml). The aqueous layer was separated, and the ER layer washed with aqueous lM
sodium hydroxide (200rnl). The combined aqueous layers were extracated with ER (200ml)s and the organic extract combined with the above ER layer. The dried (Na250~) ER solution was evaporated and purified by [FCS] eluting with cyclohexane - ER (98:2 - 85:15) to give an oil which was heated at 185 in vacuo (0.4 Torr) for lh. The residual oil was further purified by [FCS] eluting with ER-cyclohexane (1:3) to give the title compound as a colourless oil (3.289).
Intermediate 23 6-(4-Phenylbutoxy)-3-hexyn-1-ol 1 8romoethane (3.829) in ~I-IF (20ml) was added dropwise to magnesium (û.85g) under nitrogen at a rate to maintain gentle reflux. Interrnediate 6e (7.0~) in Tl-IF (lOml) was added dropwise to the cloudy solution and the mixture was heated at 50-60 for lh. [thy]ene oxide (3.529) was added to the solution at n and the mixture was stirred at 0 for lOmin, at roorn temperature for lh, and at reflux for 3h, treated with saturated aqueous ammonium chloride (lOOml) and extracted with ER (2 x lOOml). The dried extract was evaporated and at the residue was purified by [C] eluting with cyclohexane-ER (20:7) to give a colourless oil (4.89). Distillation gave the title compound as a colourless oil (4.09) b.p. 165-170/0.3mm. Hg T.l.c. (Cyclohexane - ER 1:1) Rf 0.35.
Intermediate 24 [3-[(6-Bromohexyl)oxy]-l-propynyl]benzene A mixture of 3-phenyl-2-propyn-1-ol (3.09), 1,6-dibromohexane (13.49) aqueous sodium hydroxide (50O w/w, l5ml) and tetrabutylammonium bisulphate (0.59) was stirred at room temperature for 18h, diluted with water (30ml), and extracted with ER (2 x 5ûml). The dried extract was evaporated and the residue was purified by [C] eluting with cyclohexane followed by cyclohexane-ER (19:1) to give the title compound as a colourless oil (5~19). T.l.c. (Cyclohexane - ER 9:1) Rf 0.2.
ExamplE~, 1 (Z)-N-[4-[3-[[6-[[2-1lydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl amino]hexyl]oxy]-l-propenyl]phenyl]methanesulphonamide Intermediate 10 was added portionwise over 5 min to a stirred solution of Intermediate 1 (1.109) and N,N-diisopropylethylalnine (1.559) in DMF (20ml) at 80 for 2h and the snlvent removed in vacuo at 60. The residual oil was dissolved in methanol (20ml) and evaporated onto silica (Merck 9385);
159), then subjected to [FCS] eluting with toluene/ethanol/methanol/0.88NI-13 (39:10:7:1) providing the title compound as an oil which solidified on trituration with dry ER (1.059) m.p.
113-116. T.l.c. (Toluene/ethanol/0.88 NH3 39:10:1) Rf 0.11.
Example 2 a) 4-llydroxy-al-[[[6-[[3-[4-[(1-methylpiperazine-4-yl)methyl]phenyl]-2-propynl]oxy]hexyl]amin_]methyl]-1,3-benzenedimethanol A mixture of Intermediate 13 (0.69), Intermediate 12 (0.639), bis(tri-phenylphosphino)palladium (II) chloride (0.029), cuprous iodide (0.0039) 5S~i6 1 and diethylamine (lOml) was stirred at roorn ternperature for 16h and evaporated. The residue was partitioned between aqueous sodiurn bicarbonate (lM; 201) and EA (2 x 50ml). The dried (Na250LI) extract was evaporated and the redsidue was purified by [C] eluting with EA-methanoltriethylamine 90:10:1 to give the ti le compound (0.39). T.l.c. EA-methanol-NH3 8n lo Rf 0.1.
The following compound was prepared in a similar manner:-b) N-[4 [3-[[6-[[2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl~
amino]hexyl]oxy]-l-propynyl]phenyl]acetamide, from Intermediate 13 (1.5g) and N-4-iodophenylacetamide (1.229). Purification by [FCS] eluting with EA-methanool-triethylamine (90:10:1) then trituration with ER gave the title compound (1.109).
Analysis Found C,66.2;H,7.55;N,6Ø
C26N3L~N205 H20 requires C,66.1;H,7.7;N,5.95o T.l.c. (EA-methanol-triethylamine 90:10:1) Rf 0.1.
Example 3 4-Hydroxy-al-[[[6-[4-[(4-hydroxy-3-methoxyphenyl)-3E-butenyl]oxy]hexyl]-amino]methyl]-1,3-benzenedimethanol A mixture of Interrnediate 1 (371mg), Intermediate 14 (482mg), and N,N-di-~0 isopropylethylt1mine (218mg) was stirred and heated at 75-80 in dry DMF
(5ml) under N2 for 2.5h. The mixture was poured into water (25ml), extracted with EA (2 x 25ml) and the organic phase washed wth 0.5N HCl (2 x 20rnl). The aqueous phase was adjusted to pl-l8 with 8o NaHCO3 solution, extracted with EA (2 x 25ml), and the organic phase dried (Na250L,), concentrated and purified by [FCS] (triethylamine deactivated silica) eluting with rnethanol-EA (1:6) to give the title compound (0.149) m.p.
48-53 (softens ca. 43). T.l.c. (Toluene-ethanol-0.88NH3 39:10:1) RfO.18.
Example 4 a) (Z)-N-[4-[3-[[6-[[2-llydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]-ethyl]amino]hexyl]oxy]-l-propenyl]phenyl]acetamide The compound of Example 2b (3509) in pyridine (lOml) was hydrogenated over pre-reduced Lindlars catalyst (lOOmg) for ~Lh. The reaction mixture was filtered (hyflo) and the filtrate was evaporated to leave a gum which was 1 triturated with ER to give the title compound (127rng) m.p. 105-lOB0.
T.l.c. (EA-methanol-triethylamine 90:10:1) Rf 0.08.
The following compounds were prepared in a similar manner:-b) 4-~lydroxy-al[[[6-(4-phenylbutoxy)-3,Z-hexenyl]aminc]methyl]-1,3-benzenedimethanol, (0.319) from the compound of Example 5c (0.49~.
Purification by [C] eluting with EA-methanol triethylamine (92:8:1) then trituration with ER (lOml). m.p. 94-95.
T.l.c~ (EA-methanol-N~l3 9:1:0.1) RF 0.2.
c) 4-Hydroxy-al-[[[l-methyl-6-[(4-ehyenyl-3,Zbutenyl)oxy]hexyl]amino]
methyl]-lt3-benzenedimethanol, (q.619) from the compound of Exalnple 6a (O.Bg). m.p. 71-74. T.l.c. triethylamine deactivated Si02 (EA-methanol 19:1) Rf 0.13.
Example 5 _ _ _ a) 4-Hydroxy-al-[[[6-[(3-phenyl-2-propynyl)oxy]hexyl]amino]methyl]-1,3-benzenedi~r!ethanol Intermediate 24 (3.559) was fldded dropwise to a solution of Intermediate (2.59) and N,N-diisopropylethylamine (2.69) in DMF (50ml) at 70. The solution was heated at 70-75 for 2h and evaporated. The residue was purified by [C] eluting with EA-methanol-triethylamine (92:8:1) to give a yellow oil. Trituration of the oil with ER (50ml) gave the title compound as a cream solid (0.779) m.p. 6~-70.
T.l.c. (EA-methanol-NH3 9:1:0.1) Rf 0.2.
The following compo-lnds were prepared in a similar manner:-b) 4-Hydroxy-al-[[[5-(4-phenylbutoxy)-3-p_ntynyl]arnino]methyl]-1,3-benzenedimethanol, from Intermediate 1 and Interrnediate 16. Purification by [C] eluting with EA-methanol-triethylamine (90:2n:1). m.p. 93-94.
c) 4-Hydroxy-al-[[[(6-(4-phenylbutoxy)-3-hexynyl]amino]methyl]-1,3-benzenedimethanol, from Intermediate 1 and Intermediate 17. Purification by [C] eluting with EA-Inet!-anol-triethylalnine (93:7:1). m.p. 60-61.
Example 6 a) 4-(llydroxy-al-[[[1-methyl-6-[(4-phenyl-3-b~!tynyl)oxy]hexyl]amino]-methyl]-1,3-benzenedimethanol Sodium cyanoborohydride (0.759) was added to Interrmediate 1 (2.269), Intermediate 22 (3.199) and acetic acid (0.7ml) in methanol (40ml) at room temperature with stirring and the mixture stirred overnight under nitrogen. The mixture was evaporated, the residue treated with aqueous saturated sodium bicarbonate (lOOml) and extracted with EA (3 x 120ml).
The combined dried (Na25O4), organic extracts were evaporated and the -` ~255~;6S~

1 residual oil was purified by [FCS] eluting with EA-methanol-triethylamine (94:5 1) to give the title compound as a white solid (1.569) m.p. 95-97.
b) 4-Hydroxy-al-[[[l-methyl-6-(4-phenylbutoxy)-4-hexynyl]amino]methyl]-1,3-benzenedimethanol, (0.679) from Intermediate 1 (0.739) and Intermediate 20 (19). Purification by [C] eluting with EA-methanol-triethylamine (9:1:0.1). m.p. 57-59.
T~l~co (EA-methanol-NI-13 9:1:0.1) Rf 0.2.
c) 4-~lydroxy-al-[[[6-[(4-phenyl-31Z-butenyl)oxy]-4-hexynyl]amino]methyl]
-1,3- benzenedimethanol, (0.399) from Intermediate 1 (19) and Interrnediate 19 (1.949). m.p. 72-74. T.l.c. (EA-methanol-NH3 9:1:0.1) Rf 0.2.
Example 7 _ (E/Z)-t~l-[[[6-[[4-(1,3-Benzodioxol-5-yl)-3-butenyl]oxy]hexyl]amino]
methyl]-4-hydroxy-1,3-ben~ nedimethanol A mixture of Intermediate 1 (0.79) DMF (lOml), N,N-diisopropylethylamine (0.69) and Intermediate 6c (0.99) was heated at 75 for 2h. The mixture was diluted with water (lOOml), acidified to pl~3 with 2M hydrochloric acid, basified to pl-l~ with solitl potassium bicarhonate and extracted with EA (2 x 50ml). The extracts were waslled with water (25ml), brine (25ml), dried (Na2SO4) and evaporated in vacuo to give an oil (19) which was purified by [FCS] on triethylalnine-deactivated silica using EA-methanol-triethylamine (~5:15:1) as the eluant to give the title saliqenin as a viscous oil which on cooling gave a waxy solid (0.439), m.p. 6~-72.
T.l.c. triethylamine decativated SiO2 (EA methanol-triethylamine S5:15:1) Rf 0.31.
The following are examples of suitable formulations of compounds of the invention. The term "active ingredient" is used herein to represent a compound of the invention.

Tablets These may be prepared by the normal methods such as wet granulation or direct compression.

A. Direct Compression mg/tablet ~9 Z5~f~66 1 Active ingredient ~ 2.0 Microcrystalline Cellulose USP196.5 Magnesium Stearate BP 1.5 Compression weight 2ûû.0 The active ingredient is seived through a suitable seive and blended with lactose, starch and pregelatinised maize starch. Suitable volumes of purified water are added and the powders are granulated. After drying, the granules are screened and blended with the magnesium stearate. The granules are then compressed into tablets using 7mrn diameter punches.
Tablets of other strengths may be prepared by altering the ratio of active ingredient to lactose or the compression weight and using punches to suit.

C. For buccal administration mq/tablet Active ingredient 2.0 Lactose BP 94.8 Sucrose BP 86.7 mqttable-t Hydroxypropylmethylcellulose 15.0 MagnesiuM Stearate BP 1.5 Compression weight 2ûû.0 The active ingredient is seived through a suitable seive and blended with the lactose, s-lcrose and hydroxypropylmethylcellulose. Suitable volumes of purified water are added and the powders are granulated. After drying, the granules are screened and blended with the magnesium stearate.
The granules are then compressed into tablets using suitable punches.
The tablets may be film coated with suitable film forming materials, such as hydroxylpropyl methylcellulose, using standard techniques.
Alternatively the tablets may be sugar coated.

Capsules mg!capsule Active ingredient 2.0 ~2~6~

1 *Starch 1500 97 0 Magnesium Stearate BP 1.0 Fill weight 100.0 * A forrn of directly compressible starch.
The active ingredient is seived and blended with the excipients. The mix is filled into size No. 2 hard gelatin capsules using suitable machinery. Other doses may be prepared by altering the fill wright and if necessary changing the capsule size to suit.

Syrup This may be either a sucrose or sucrose free presentation.

A. Sucrose Syrup mg/5ml does Active ingredient 2.0 Sucrose BP 2750.0 Glycerine BP 500.0 Buffer Flavour ) as required Colour Preservative) Purified Water BP to 5.0ml The active ingredient, buffer, flavour, colour and preservative are dissolved in some of the water and the glycerine is added. The remainder of the water is heated to dissolve the sucrose and is then cooled. The two solutions are combined, adjusted to volume and mixed. The syrup produced is clarified by filtration.

B. Sucrose-Free mg/5ml dose Active ingredient 2.0mg Hydroxypropyl methylcellulose USP

3 \
`"` ~2~666 1 (viscosity type 40bo) 22.5mg Buffer Flavour Colour ) 8S required Preservative) Sweetener Purified Water BP to 5.0ml The hydroxypropyl methylcellulose is dispersed in hot water, cooled and then mixed with an aqueous solution containing the active ingredient and the other components of the formulation. The resultant solution is-adjusted to volume and mixed. The syrup is clarified by filtration.

Metered Dose Presurised Aerosoi A. Suspension Aerosol mq/metered_dose Per can Active ingredient micronised 0.100 26.40mg Oleic Acid BP 0.1002.64mg Trichlorofluoromethane BP 23.64 5.679 Dichlorodifluoromethane BP 61.25 14.709 The active ingredient is micronised in,a fluid energy mill -to a fine particle size range. The Oleic Acid is mixed with the Trichlorofluoromethane at a temperature of 10~15C and the micronised drug is mixed into the solution with fl high shear mixer. The suspension is metered into aluminium aerosol cans and suitable metering valves, delivering n5mg of suspension are crimped onto the cans and the Dichlorodifluoromethane is pressure filled into the cans through the valves.

~z~

/ B. Solution Aerosol mq/metered dose Per can Active ingredient 0.05513.20mg Ethanol BP 11.100 2.669 Dichlorotetrafluoroethane BP 25.160 6.049 Dichlorodifluoromethane BP 37.740 9.069 Oleic acid BP, or a suitable surfactant e.g. Span 85 (sorbitan trioleate) may also be included.
The'active ingredient is dissolved in the ethanol together with the o oleic acid or surfactant if used. The alcoholic solution is metered into a suitable aerosol containers followed by the tr~chlorofluoromethane.
Suitable metering valves are crimped onto the containers and dichlorodifluoromethane is pressure filled into them through the valves.

Suppositiories g Active ingredient 2.Omg *Witepsol H15 to 1.09 * A proprietary grade of Adeps So`lidus-Ph. Eur.~~ -' '' A suspension of the active ingredient in molten Witepso~ is prepared and filled, using suitable machinery, into 19 size suppository moulds.

Ini~ction for Intravenous Administration mg/ml Active ingredient 0.5mg Sodium Chloride BP as required Water for Injection'BP to l.Oml ~

2 ~ Sodium chloride may be added to adjust'the tonicity of the solution and the pH may be adjusted, using acid or'alkali, to that of optimum stability and/or to facilitate solution of the active ingredient.
Alternatively suitable buffer salts may be used.
+ Trademark ~`~' `- 3 ~ ~ Z~5~6 1 The solution is prepared, clarified and filled into appropriate size ampoules sealed by fusion of the glass. The injection is sterilised by heating in an autoclave using one of the acceptable cycles. Alternatively the solution may be sterilised by filtration and filled into sterile ampoules under aseptic conditions. The solution may be packed under an inert atmosphere of nitrogen or other suitable gas.

Inhalation Cartridges mq/cartridqe Active ingredient micronised 0.200 Lactose BP to 25.0 The active ingredient is micronised in a fluid energy mill to a fine particle size range prior to blending with normal tabletting grade lactose in a high energy mixer. The powder blend is filled into No. 3 hard gelatin capsules on a suitable encapsulating machine. The contents of the cartridges are administered using a powder inhaler such as the Glaxo Rotahaler.

Claims (18)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows.

1. A process for the production of compounds of the general formula (I) (I) wherein Ar represents a phenyl group optionally substituted by one or more substituents selected from halogen atoms, or C1-6 alkyl, -(CH2)qR, [where R is hydroxy, C1-6 alkoxy, -NR3R4 (where R3 and R4 each represents a hydrogen atom, or a C1-4 alkyl group, or -NR3R4 forms a saturated heterocyclic amino group which has 5-7 ring members and optionally contains in the ring one or more atoms selected from -O-or -S- or a group -NH- or -N(CH3)-), -NR5COR6 (where R5 represents a hydrogen atom or a C1-4 alkyl group, and R6 represents a hydrogen atom or a C1-4 alkyl, C1-4 alkoxy, phenyl or -NR3R4 group), -NR5SO2R7 (where R7 represents a C1-4 alkyl, phenyl or -NR3R4 group), -COR8 (where R8 represents hydroxy, C1-4 alkoxy or -NR3R4), -SR9 (where R9 is a hydrogen atom, or a C1-4 alkyl or phenyl group), -SOR9, SO2R9, or -CN, and q represents an integer from 0 to 3], -O(CH2)rR10 [where R10 represents a hydroxy or C1-4 alkoxy group and r is an integer 2 or 3], or -NO2 groups or an alkylenedioxy group of formula -O(CH2)pO-, where p represents an integer 1 or 2;
R1 and R2 each represent a hydrogen atom or a C1-3 alkyl group with the proviso that the sum total of carbon atoms in R1 and R2 is not more than 4;
X represents a C1-7 alkylene, C2-7 alkenylene or C2-7 alkynylene chain and Y represents a bond, or a C1-6 alkylene, C2-6 alkenylene or C2-6 alkynylene chain with the provisos that the sum total of carbon atoms in X and Y is 2-10 and when X
represents C1-7 alkylene, Y represents C2-6 alkenylene or C2-6 alkynylene;
and physiologically acceptable salts and solvates thereof which comprises:
(1) reacting a compound of general formula (II) (II) (wherein Z represents a group , R12 and R13 are each hydrogen or a protecting group, and L is a leaving group) with an amine of general formula (III) (III) followed, if necessary, by removal of any protecting groups present; or (2a) for the preparation of a compound of formula (I) in which R1 is a hydrogen atom, alkylating an amine of general formula (IV) (IV) (wherein R12, R13 and R14 are each a hydrogen atom or a protecting group and R15 is a hydrogen atom) with an alkylating agent of general formula (V) (V) (wherein L is a leaving group) followed, if necessary, by removal of any protecting group present; or (2b) for the preparation of a compound of formula (I) in which R1 is a hydrogen atom, alkylating an amine of general formula (IV) in which R12, R13 and R14 are each a hydrogen atom or a protecting group and R15 is a hydrogen atom, with a compound of general formula (VI) R2COXCH2OCH2YAr (VI) in the presence of a reducing agent followed, if necessary, by removal of any protecting groups present; or (3) deprotection of protected intermediate of general formula (VIII) (VIII) (wherein R12, R13 and R14 are each a hydrogen atom or a protecting group, except that at least one of R12, R13 and R14 is a protecting group; or (4) reducing an intermediate of general formula (IX) (IX) in which R13 is a hydrogen atom or a protecting group, X1 is -CH(OH)- or a group convertible thereto by reduction, X2 is -CH2NR14 or a group convertible thereto by reduction, X3 is -CR1R2X or a group convertible thereto by reduction, X4 is -CH2OR12 or a group convertible thereto by reduction, at least one of X1, X2, X3, X4 representing a reducible group followed, if necessary, by removal of any protecting groups present;
(5) for the preparation of a compound of formula (I) in which Y is a C2-6 alkynylene chain in which the acetylene group is adjacent to the group Ar, reacting an intermediate of formula (X) (X) (in which Y1 is a bond or a C1-4 alkylene group) with an aryl halide ArHal (where Hal is a halogen atom) followed, if necessary, by removal of any protecting groups present;
(6) for the preparation of a compound of formula (I) in which X and/or Y is an aklenylene chain, reducing the correspond-ing compound in which X and/or Y is an alkynylene chain; and if desired, converting the resulting compound of general formula (I) or a salt thereof into a physiologically acceptable salt or solvate thereof.

2. A process as claimed in claim 1, for the production of compounds in which the chain X contains 2 to 7 carbon atoms.

3. A process as claimed in claim 2, for the production of compounds in which the total number of carbon atoms in the chains X and Y is 4 to 10 inclusive.

4. A process as claimed in claim 1, for the production of compounds in which the chain X is -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -CH2C?C-, -(CH2)2CH=CH-, -(CH2)2C?C-, -CH=CHCH2, -CH=CH(CH2)2- or -CH2C?CCH2- and the chain Y is -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, (Ch2)5-, (CH2)6, -CH=CH-, -C?C-, -CH2CH=CH- or -CH2C?C-, with the proviso that at least one of the chains X and Y is an alkenylene or alkynylene group.

5. A process as claimed in claim 1 for the production of compounds in which R1 and R2 are both hydrogen atoms, R1 is a hydrogen atom and R2 is a C1-3 alkyl group or R1 and R2 are both methyl groups.

6. A process as claimed in claim 1, for the production of compounds in which the phenyl group represented by Ar is unsubstituted or contains one, two or three substituents selected from chlorine, bromine, iodine, fluorine, methyl, ethyl, -(CH2)qR [where R is hydroxy, methoxy, ethoxy, amino, methylamino, ethylamino, dimethylamino, diethylamino, morpholino, piperidino, piperazino, N-methylpiperazino, -NHCHO, -NHCOR6 (where R6 is C1-4 alkyl, C1-4 alkoxy, phenyl, amino or N,N-dimethylamino), -N(CH3)COCH3, -NR5SO2R7, where R5 represents a hydrogen atom or a methyl group and R7 represents methyl, ethyl, isopropyl, n-butyl or phenyl, -NHSO2NH2, -NHSO2N(CH3)2, -COOH, -COOCH3, -CONH2, -CON(CH3)2, -CONR3R4 (where NR3R4 is piperidino, morpholino, piperazino or N-methylpiperazino), -SR9 (where R9 is methyl, ethyl or phenyl), -SOCH3, -SO2CH3, or CN and q is zero, 1, 2 or 3], -NO2, -O(CH2)2OH, -O(CH2)3OH, -O(CH2)2OCH3, or -O(CH2)2OCH2CH3.

7. A process as claimed in claim 1, for the production of compounds in which Ar is a phenyl group monosubstituted by the group -(CH2)qR where R is C1-6 alkoxy and q is an integer 1, 2 or 3, or R is -NR3R4, -NR5SO2R7, -COR8, -SR9 or O(CH2)rR10.

8. A process as claimed in claim 7, for the production of compounds in which Ar is a phenyl group monosubstituted by -OH, -CH2OH, -(CH2)2OH, -(CH2)3OH, -CH2OCH3, -NH(CH3), -N(CH3)2, -NHCH2CH3, morpholino, pyrrolidino, piperidino, -CH2N(CH3)2, -CH2- piperidino, -NHSO2CH3, -NHSO2(CH2)2CH3, -NHSO2(CH2)3CH3, -NHSO2-phenyl, -NHSO2N(CH3)2, -CO2H, -CO2CH3, -CO2CH2CH3, -CO2(CH2)2CH3, -CONH2, -CON(CH3)2, -SCH3, -SCH2CH3, -S-phenyl, or -O(CH2)2OCH3.

9. A process as claimed in claim 1, for the production of a compound which is:-(Z)-N-[4-[3-[[6-[[2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl) phenyl]ethyl]amino]hexyl]oxy]-l-propenyl]phenyl]methanesul-phonamide;
4-Hydroxy-.alpha.1-[[[6-[[3-[4-[(l-methylpiperazine-4-yl)methyl]
phenyl]-2-propynl]oxy]hexyl]amino]methyl]-1,3-benzenedimeth-anol;
N-[4-[3-[[6-[[2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]
ethyl]amino]hexyl]oxy]-l-propynyl]phenyl]acetamide;
4-Hydroxy-.alpha.1-[[[6-[4-[(4-hydroxy-3-methoxyphenyl-3E butenyl]
oxy]hexyl]amino]methyl]-1,3-benzenedimethanol;
(Z)-N-[4-[3[[6-[[2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl) phenyl]ethyl]amino]hexyl]oxy]-l-propenyl]phenyl]acetamide;
4-Hydroxy-.alpha.1-[[[6-(4-phenylbutoxy)-3,z-hexenyl]amino]methyl]
1,3-benzenedimethanol;
4-Hydorxy-.alpha.1-[[[l-methyl-6-[(4-phenyl-3,Z-butenyl)oxy]hexyl]
amino]methyl]-1,3-benzenedimethanol;
or a physiologically acceptable salt or solvate thereof.

10. A compound of the general formula (I) as defined in claim 1 and physiologically acceptable salts and solvates thereof.

11. Compounds of the general formula (I) as defined in claim 1 wherein the chain X contains 2 to 7 carbon atoms, and physiologically acceptable salts and solvates thereof.

12. Compounds of the general formula (I) as defined in claim 1 in which the total number of carbon atoms in the chains X and Y is 4 to 10 inclusive, and physiologically acceptable salts and solvates thereof.

13. Compounds of the general formula (I) as defined in claim 1 wherein X and Y are defined in claim 4, and physiologically acceptable salts and solvates thereof.

14. Compounds of the general formula (I) as defined in claim 1 wherein R1 and R2 are defined in claim 5, and physiologically acceptable salts and solvates thereof.

15. Compounds of the general formula (I) as defined in claim 1 wherein the phenyl group is defined in claim 6, and physiologically acceptable salts and solvates thereof.

16. Compounds of the general formula (I) as defined in claim 1 wherein Ar is defined in claim 7, and physiologically acceptable salts and solvates thereof.

17. Compounds of the general formula (I) as defined in claim 1 wherein Ar is defined in claim 8, and physiologically acceptable salts and solvates thereof.

18. A compound selected from the group of compounds consisting of:
(Z)-N-[4-[3-[[6-[[2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl) phenyl]ethyl]amino]hexyl]oxy]-1-propenyl]phenyl]methanesulphonamide;
4-Hydroxy-.alpha.1-[[[6-[[3-[4-[(1-methylpiperazine-4-yl)methyl]phenyl]-2-propynl]oxy]hexyl]amino]methyl]-1,3-benzenedimethanol;
N-[4-[3-[[6-[[2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl) phenyl]ethyl]amino]hexyl]oxy]-l-

Claim 18 continued ...

propynyl]phenyl]acetamide;
4-Hydroxy-.alpha.1-[[[6-[4-[(4-hydroxy-3-methoxyphenyl-3E-butenyl] oxy]hexyl]amino]methyl]-1,3-benzenedimethanol;
(Z)-N-[4-[3[[6-[[2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl) phenyl]ethyl]amino]hexyl]oxy]-l-propenyl]phenyl]acetamide;
4-Hydroxy-.alpha.1-[[[6-(4-phenylbutoxy)-3,Z-hexenyl]amino]methyl] -1,3-benzenedimethanol;
4-Hydroxy-.alpha.1-[[[l-methyl-6-[(4-phenyl-3,Z-butenyl)oxy]hexyl] amino]methyl]-1,3-benzenedimethanol;
or a physiologically acceptable salt or solvates thereof.