CA1296335C - Dichloroaniline derivatives - Google Patents

Abstract

ABSTRACT
DICHLOROANILINE DERIVATIVES

The invention provides compounds of the general formula (I) ( I ) wherein X represents a bond, C1-6 alkylene, C2-6 alkenylene or C2-6 alkynylene chain and Y represents a bond, or a C1-4 alkylene, C2-4 alkenylene or C2-4 alkynylene chain with the proviso that the sum total of carbon atoms in X and Y is not more than 8;
Ar represents a phenyl group substituted by one or more substituents selected from nitro, -(CH2)qR [where R is C1-3 alkoxy, -NR3R4 (where R3 and R4 each represent 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 or -NR3R4 group), and q represents an integer from 1 to 3], -(CH2)rR7 [where R7 represents -NR5SO2R8 (where R8 epresents a C1-4 alkyl, phenyl or -NR3R4 group) -NR5COCH2N(R5)2 (where each of the groups R5 represents a hydrogen atom or a C1-4 alkyl group), -COR9 (where R represents hydroxy, C1-4 alkoxy or NR3R4), -SR10 (where R10 is a hydrogen atom, or a C1-4 alkyl group optionally substituted by hydroxy, C1-4 alkoxy or NR3R4), -SOR10, -SO2R10, -CN or -NR11R12 (where R11 and R12 represent a hydrogen atom or a C1-4 alkyl group, at least one of which is C2-4 alkyl substituted by a hydroxy, C1-4 alkoxy or NR3R4 group), and r represents an integer from 0 to 3], -O(CH2)qCOR9 (where q and R9 are as defined above), or -O(CH2)tR13 [where R13 represents hydroxy, NR3R4, NR11R12 or a C1-4alkoxy group optionally substituted by hydroxy, C1-4 alkoxy or NR3R4, and t is an integer 2 or 3].
R1 and R2 each represents 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;
and physiologically acceptable salts and solvates (e.g. hydrates) thereof.
The compounds have a stimulant action at .beta.2-adreno-receptors and may be used in the treatment of diseases associated with reversible airways obstruction such as asthma and chronic bronchitis.

Description

DICIILOROANILINE DERIVATIVES

This invention relates to dichloroaniline derivatives having a stimulant action at ~2-adrenoreceptors, to processes for their preparation, to pharmaceutical compositions containing them and to their use in medicine.
Dihaloaniline derivatives have previously been described as bronchodilators having stimulant activity at ~-adrenoreceptors.
Thus British Patent Specification No. 1178191 describes compounds of the general structure Hal ~ _ a IR 4 5 'r /~--ClH-CINR R
H2N ~ ~0 Rl R3 Hal in which the substituents Hal represent bromine or chlorine atoms; Rl represents hydroqen or hydroxyl; R2 and R3 each represent hydrogen or Cl- 4 alkyl; and R4 and Rs each represent hydrogen, Cl_6 alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, dialkylaminoalkyl, cycloalkyl, phenyl, benzyl or adamantyl, or NR4Rs forms a heterocylic ring optionally substituted by Cl_3 alkyl groups.
We have now found a novel group of dichloroaniline derivatives, which differ structurally from those described in British Patent Specification No. 1178191, and ~5 which have a desirable and useful profile of activity.
Thus the present invention provides compounds of the general formula (I) C
//~ Rl ;\ / ~HCH2NHlxcH20cH2yAr (I) wherein .

3~

X represents a bond, Cl_6 alkylene, C2_6 alkenylene or C2_6 all<ynylene chain and Y represents a bond, or a Cl_4 alkylene, C2_4 alkenylene or C2_4 alkynylene chain with the proviso that the sum total of carbon atoms in X and Y is not more than ~;
Ar represents a phenyl group substituted by one or more substituents selected from nitro, -(CH2)qR [where R is Cl-3 alkoxy, -NR3R4 (where R3 and R4 each represent a hydrogen atom, or a Cl_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 -û- or -S- or a group -NH- or -N(CH3)-), -NR5CoR6 (where R5 represents a hydrogen atom or a Cl_4 alkyl group, and R6 represents a hydrogen atom or a Cl_4 alkyl, Cl_4 alkoxy or -NR3R4 group), and q represents an integer from 1 to 3], -(CH2)rR7 [where R7 represents -NR 5so 2R8 (where R8 represents a Cl-4 alkyl, phenyl or -NR3R4 group), -NR5CoCH2N(R 5) 2 (where each of the groups R5 represents a hydrogen atom or a Cl-4alkYl group), -COR9 (where R9 represents hydroxy, Cl_4 alkoxy or NR3R4), -SRl (where.Rl is a hydrogen atom, or a Cl_4 alkyl group optionally substituted by hydroxy, Cl-4 alkoxy NR3R4) SORlo SO Rl -CN, or -NRllRl2 (where Rll and Rl2 represent a hydrogen atom or a Cl-4 alkyl group, at least one of which is c2_4alkyl substituted by a hydroxy, Cl-4 alkoxy or NR3R4 group), and r represents an integer from O to 3], ~O(CH2)qCOR9 (where q and R9 are as defined above), or -o(cH2)tRl3 [where Rl3 represents hydroxy, NR3R4, NRllRl2 or a Cl-4 alkoxy group optionally substituted by hydroxy, Cl-4 alkoxy or NR3R4, and t is an integer 2 or 3].
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;
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, ~63~

namely the carbon atorn of the -CH- group and, when Rl and OIJ
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 -CH- group is in the R configuration are preferred.
ûH
In the definition of general formula (I), the term alkenylene includes both cis and trans structures.
According to one aspect, the invention provides compounds of formula (I) in which Rl, R2, X, Y and Ar are as defined for formula (I) and R7~ represents -NR5502R8, -CûR9, -SRl, -SûRl, -Sû2Rl, -CN or -NRllRl2.
In the general formula (I), the chain X nay be for example a bond, -CH2 , -(CH2)2-~ -(CH2)3-~ -(CH2)4-~
-(CH2)5-~ -(CH2)6-~ -CH2c-c-~ -(CH2)2CH=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-, -CH=CH-, -C-C-, CH2CH=CH-, or -CH2C--C-.
Preferably the total number of carbon atoms in the chains X and Y is 4 to 8 inclusive. Compounds wherein the sum total of carbon atoms in the chains X and Y is 4, 5, 6 or 7 are particularly preferred.
ûne preferred group of compounds of formula (I) is that in which X represents a Cl-6 alkylene chain and Y
represents a Cl_4 alkylene chain. Particular compounds of this type are those wherein X represents -(CH2)3- or -(CH2)4- and Y is -CH2-, -(CH2)2- or -(CH2)3-.
In the compounds of formula (I) Rl and R2 may each be, for example, 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 may be, for example, a hydrogen atom nr a metllyL group. Rl and R2 are each preferably a hyclrogen atom or a rnethyl group A preferred group of compounds are those 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.
When -NR3R4 in compounds of formula (I) represents a saturated heterocyclic amino group, this may have 57 6 or 7 ring members and optionally contains in the ring a heteroatom selected from -0- or -S-, or a group -NH- or -N(CH3)-. Examples of such -NR3R4 groups are pyrrolidino, piperidino, hexamethyleneimino, piperazino, N-methylpiperazino, morpholino, homomorpholino or thiamorpholino.
Ar may be for example a phenyl group substituted by ~(CH2)qR [where R represents Cl_3 alkoxy e.g. methoxy, diCl_4alkylamino e.g. dimethylamino, morpholino, piperidino, piperazino, N-methylpiperazino, -NHCOR6 (where R6 is Cl_4 alkyl e.g. methyl), and q is 1 or 2], ~(CH2)rR7 [where R7 represents -NR5502R3 (where R5 represents hydrogen or methyl, and R8 represents Cl-4 alkyl e.g. methyl), -NHCoCH2N(R5)2 (where both groups R5 represent Cl_4 alkyl e.g. methyl), -CoR9 (where R9 represents Cl_4 alkoxy e.g. ethoxy, amino, dicl-4alkylamino e.g. dimethylamino, morpholino, piperidino, piperazino or N-methylpiperazino), -NRllRl2 (where one or both of Rll and Rl2 represents a C2_4 alkyl e.g. ethyl group substituted by a hydroxy or diCl_4alky]amino e.9. dimethylamino group, and the other represents a hydrogen atom), and r is zero or 1], -OCH2CORg (where R9 is diCl_4alkylamino e.g.
dimethylamino), or -o(CH2)2Rl3 (where Rl3 is diCl_4alkylamino e.g. dimethylamino).

33~
A preferred grnup nf compourlds according to the invention are those o~ the formula (la) Cl o //
H2N - ~ ~9 - ICHCH2NHCH2XCH20CH2YAr (Ia) /- OH
Cl wherein X represents a C3_4 alkylene chain and Y
represents a Cl_3 alkylene chain with the proviso that the total number of carbon atoms in X and Y is 5 or 6; and Ar represents a phenyl group substituted by a group selected from Cl-4 alkoxymethyl (e.g. methoxymethyl), morpholinomethyl, diCl_4alkylaminoCl_2alkyl (e.g.
dimethylaminoethyl), -CH2NHCoR5 (where R6 is Cl-4 alkyl e.g. methyl), -NR5502R8 (where R5 is hydrogen or methyl and R8 is Cl-4 alkyl e.g. methyl), -NHCoCH2N(R5)2 (where both groups R5 represent Cl_4 alkyl e.g. methyl), -COR9 (where R9 is hydroxy, Cl-4 alkoxy e.g. ethoxy, amino, diCl_4alkylamino e.g. dimethylamino, or morpholino), -CH2COR9 (where R9 is amino or diCl_4alkylamino e.g.
dimethylamino), -NRllR12 (where Rll and Rl2 both represent hydroxy C2_4 alkyl e.g. hydroxyethyl), diCl_4alky]amino-ethylamino (e.g. dimethylaminoethylamino), -OCH2COR9 (where R9 is diCl_4alkylamino e.g. dimethylamino) or -o(CH2)2Rl3 (where Rl3 is diCl 4alkylamino e.g. dimethyl-amino); and physiologically acceptable salts and solvates thereof.
Particularly preferred compounds of formula (Ia) are those in which X and Y are as defined for formula (Ia);
and Ar represents a phenyl group substituted by a group selected from -CH2NHCOR6 (where R6 is methyl), -NHS02R8 (where R8 is methyl), -COR9 (where R9 is hydroxy, ethoxy, amino or morpholino), or -CH2COR9 (where R9 is amino or ;

, .

33~5 dimcthylamino), aod physiologically acceptable salts and solvates thereof.
Particularly important compounds of the invention are:
4-[3-~[6-[[2-(4-amino-3,5-dichlorophenyl)-2-hydroxy-ethyl]amino]hexyl]oxy]propyl]benzamide;ethyl 4-[3-[[6-[[(4 amino-3,5-dichlorophenyl)-2-hydroxy-ethyl]amino]hexyl]oxy]propyl]benzoate;
N-[[3-[3-[[6-[[2-(4-amino-3,5-dichlorophenyl)-2-hydroxy-ethyl]amino]hexyl]oxy]propyl]phenyl]methyl]acetamide;
4-[4-[5-[[2-(4-amino-3,5-dichlorophenyl)-2-hydroxyethyl]-amino]pentyloxy]butyl]-N~N-dimethylbenzene acetamide;
4-[3-[[6-[[2-(4-amino-3,5-dichlorophenyl)-2-hydroxyethyl]
amino]hexyl]oxy]propyl]benzoic acid;
4-t4-[3-[[6-[[2-(4-amino-3,5-dichlorophenyl)-2-hydroxy-ethyl]amino]hexyl]oxy]propyl]benzoyl]morpholine;
N-[4-[3-[[6-[[2~(4-amino-3,5-dichlorophenyl)-2-hydroxy-ethyl]amino]hexyl]oxy]ethyl]phenyl]methanesulphonamide;
4-[3-[[6-[[2-(4-amino-3,5-dichlorophenyl)-2-hydroxy-ethyl]amino]hexyl]oxy]propyl]benzeneacetamide;
and the physiologically acceptable salts and solvates thereof.
Suitable physiologically acceptable salts of the compounds of general formula (l) include acid addition salts derived from inorganic and organic acids, such as hydrochlorides, hydrobromides, sulphates, phosphates, maleates, tartrates, citrates, benzoates, 4-methoxy-benzoates, 2- or 4-hydroxybenzoates, 4-chlorobenzoates, p-toluenesulphonates, methanesuIphonates, sulphamates, ascorbates, salicylates, acetates, fumarates, succinates, lactates, 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 alkali metal (e.g. sodium and :

~3~5 potassium), and all<al~r)e earth metal ~r-.g ralciurrl or magnesium) salts.
The compounds according to the invention have a stimulant action at ~2-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 PGF2a-induced contractions. Compounds according to the invention have shown a particularly long duration of action in this test.
The compounds 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 are also indicated as useful for the treatment of inflammatory and allergic skin diseases, congestive heart failure, depression, premature labour, glaucoma, and in the treatment of conditions in which there is an advantage in lowering gastric 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 suojects.
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 solvate thereof formulated for use in human or veterinary medicine. Such compositions may be presented for use with physiologically acceptable carriers or excipients, optionally with supplementary medicinal agents.

~2~
The compounds may be formulate-J in a form suitable for administratlon by inhalation or insuff]ation, or for oral, buccal, parenteral, topical (including nasal) or rectal administration. Administration by inhalation 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 from pressurised packs, with the use of a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, 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.
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 conventional manner.
The compounds of the invention may be formulated for parenteral administration by bolus injection or continuous infusion. Formulations 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 forlns as susper1sior1s, soLutior1s or emlJIsions in oily or aqueous vehLcles, and may contair1 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 ointrnents, 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 tha 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 O.OO5mg to 100mg, 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 by inhalation is O.ûO5mg to 20mg, for oral administration is 0.02mg to 100mg, and for parenteral administration is 0.01mg to 2mg for administration by bolus injection and 0.01mg to 25mg for administration by infusion.
The compounds according to the invention may be prepared by a number of processes, as described in the following. In the following description of processes for - - 1 (.) -l~q~33~
preparing compounds of formula (I) and interme(Jiates which may be used in the preparation thereof, X, Y, Ar, Rl and R2 are as defined for general formula (I) unless otherwise specified. In addition, any substituent in the group Ar may be a precursor substituent which is convertible into the required substituent by conventional methods It will be appreciated that certain of the reactions described below are capable of affecting other groups in the starting material which are desired in the end product, this applies especially in the reduction processes described, particularly where hydrogen and a catalyst are used and when an ethylene or acetylene linkage is required in the compound of the invention.
Care must therefore be taken in accordance with conventional practice, either to use reagents which will not affect such groups, or to perform the reaction as part of a sequence which avoids their use when such groups are present in the starting material.
In the preparation of both intermediates and end-products the final step in the reaction may be the removal of a protecting group. Conventional protecting groups may be used, as described for example in "Protective Groups in Organic Chemistry", Ed. J. F. W.
Mcûmie (Plenum Press, 1973). Thus hydroxyl groups may for example be protected by aralkyl groups such as benzyl, diphenylmethyl or triphenylmethyl, or as tetrahydropyranyl derivatives. Suitable amino protecting groups include aralkyl groups such as benzyl, a-methylbenzyl, diphenylmethyl or triphenylmethyl, and acyl groups such as acetyl, trichloroacetyl or trifluoroacetyl.
Conventional methods of deprotection may be used.
Thus for example aralkyl 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 hydrolysls with an acid such as a : . :

lZ~3~5 mineral acid e.g. hydrochloric acid, or a base such as sodium hydroxide or potassium carbonate, or a group such as trichloroacetyl may be removed by reduction with, for example, zinc and acetic acid.
In one general process (1), a compound of general formula (I) may be prepared by alkylation. Conventional alkylation procedures rnay 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 (II) C\

H2N ~ CIHcH2NRl4Rl5 (II) ~ OH
Cl (wherein Rl4 is a hydrogen atom or a protecting group and R15 is a hydroge~n atom) followed by removal of any protecting group where present.
The alkylation~(a) may be effected using an alkylating agent of general formula (III):
`~ : :: : : : :
~LCHXCH20CH2YAr~
R2 ~
~ ~ :
`
(wherein L is a leaving group~, for example a ~halogen atom :
such as~chlorine, bromin~e~or iodine, or~a ~ ;
hydrocarbylsulph~ony;loxy group s~uch as msthanesuiphony10xy or p-toluenesulphony~loxy).
~ ; The~a1ky1~st1on~is~preferably~sFfected in~ the presence :
I of~a suitab~le~acid~ scavenger,~for example, inorganic bases such~as sodium or~patassiurn car~bo~nà~te, organic bases such ~as~tr1ethy1~smi~ns,~diisopr~opy~lethylamine~or pyridine, or 35 ~ a~lky~I~ene~oxid s~such~ as~et~hylene oxide or propylene oxide.

.. . .

: .

.:

The reaction is converlierltly effected in a soLvent sucll as acetonitrile or an ether e.g. tetrallydrofurcll-l or di(3xarl, a ketone e.g. butanone or metllyL isobutyl ketone, a substituted amide e.g. dimethylformarnide or a chlorinated S 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 Rl represents a hydrogen atom may be prepared by alkylation of an amine of general formula (II), as previously defined except that Rl5 is a hydrogen atom or a group convertible thereto under the reaction conditions, with a compound of general formula (IV):

R2COXCH2ûCH2YAr (IV) in the presence of a reducing agent, followed when necessary by removal of any protecting groups.
Examples of suitable Rls 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 2û to 10ûC and from 1 to 10 atmospheres.
Alternatively when one or both of Rl4 and Rls are hydrogen atoms, the reducing agent may be a hydride such as diborane or a metal hydride such as sodium borohydride, sodium cyanoborohydride or lithium alurninium hydride.
Suitable solvents for the reaction with these reducing `` 12~363~

agents will depend on the particular hydride used, hut 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 (II) where Rl4 and Rl5 are each hydrogen atoms is used, the interrnediate imine of formula (V) may be formed:
Cl . _ --H2N ~ - CIHCH2N=ClXCH2ûCH2YAr (V) OH R
Cl 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).
Where it is desired to use a protected intermediate of general formula (II) it is particularly canvenient to use hydrogen and a catalyst as described above with protecting group Rl4 which is capable of being converted to a hydrogen atom~under these reducing conditions,~thus avoiding the need for a separate deprotection step.
! Suitable protecting groups;of this type include arylmethyl groups such as benzyl, bénzhydr;yl and a-methylbenzyl.
In another general process (2), a compound of general formula (I) may be prepared by reduction. Thus, for example, a compound of gen;eral formula (I) may be prepared by reducing an intermediate of general formula (VI):
~ ~ -Cl ~ ~

; X4 ~ Xl-X2-X3-CH2bCH2Y-Ar (VI) ; . , ~' ~; ' 63~
wherein at least one of X4, Xl, X2, X3 and Y represents a reducible group and/or Ar contains a reducible group and the other(s) take the appropriate meaning as follows, which is X4 is -NH2, xl is -CH(OH)-, X2 is -CH2NRl4-(wherein Rl4 is a hydrogen atom or a protecting group), X3is -CRlR2X, and Ar and Y are as defined in formula (I), followed where necessary by removal of any protecting groups.
Suitable reducible groups include those wherein X4 is -N02, Xl is a group >C=O, X2 is a group -CH2NY'- (wherein Y' represents a group convertible to hydrogen by catalytic hydrogenation, for example an arylmethyl group such as benzyl, benzhydryl or a-methylbenzyl), or an imine (-CH=N-) group or a group -CONH-, X3 is a group -COX- or a group CRlR2X (where X is C2_6 alkenylene or C2_6 alkynylenej, or -X2-X3- is a group -CH2N=CR2X-, Y is C2_4 alkenylene or alkynylene, and Ar is a phenyl group substituted by a group containing an amide linkage such as ~(CH2)q_lCONR3R4 or -NHCoRl7 (where -NHCoRl7 is reducible to the group NHRl2).
The reduction may be effected using reducing agents conveniently employed for the reduction of ketones, imines, amides, protected amines, alkenes, alkynes and nitro groups. Thus, for example, when X4 in general formula (VI) represents a~nitro~ group, this may be reduced to an amino group~using hydrogen in the presence of a catalyst as previously described for process (1) part (b).
When Xl in general formula (VI) represents a >C=O
group ~this may be reduced~to a~-CH(OH)- group using hydrogen~in the~presence o;f a catalyst as previously;
described for process (1)~ part ~(b).~ Alternatively, the reducing agent~ may~be, for example, a hydride such as diborane or~a~me~tal hydride such~as lithium aluminium hydride, sodium bis(2-methoxyethoxy) aluminium hydride, sodium~borohydride or aluminium hydride. The reaction may be~effec~ted~in~a solvent, wh;ere~appropriate an alcohol ~:

.
.

e.g. methanol or ethanol, o~ an ether sucll as tetrahydrofuran, or a halogenated hydrocarborl such as dichloromethane.
When x2 in general formula (VI) represents a -CH2NY'-group or the group -CH-N-, or -X2-X3- represents -CH2N=CR2X- this may be reduced to a -CH2NH- or -CH2NHCHR2X- group using hydrogen in the presence of a metal catalyst as previously described for process (1) part (b). Alternatively, when x2 or -X2-X3- is the group -CH=N- or -CH2N=CR2X- this may be reduced to a -CH2NH- or -CH2NHCHR2X- group using a reducing agent and conditions as just described for the reduction of Xl when this represents a >C=O group.
When x2 or X3 in general formula (VI) represents a -CONH- or -COX- group, or Ar is phenyl substituted by a gruop containing an amide linkage such as ~(CH2)q_lCONR3R4 or -NHCOR 17 (where R17 is as defined previously), this may be reduced to a group -CH 2NH- or -CH2X-, or to phenyl suhstituted by the group ~(CH2)qNR3R4 or -NHR12, respectively, using a hydride such as diborane or a complex metal hydride such as lithium aluminium hydride or sodium bis(2-methoxyethoxyjaluminium hydride in a solvent such as an ether,~e.g. tetrahydrofuran or diethyl ether.
When X3 represents a group CRlR2X where X is C2_6 slkenylene or C2_6 alkynylene, or Y represents C2_4 alkenylene or C2 4 alkynylene, this may be reduced to C2 6 alkylene or C2_4 alkylene respectively using hydrogen in the presence of a catalyst as previously described for process (1) part (b). Alternatively, when X is C2 6 slkynylene or Y is C2-4 al~kynylene;thls may be~reduced to C2 6 alkenylene or C2_4 alkenylene respec~tively using for example hydrogen and a le~ad-poisoned palladium on calcium carbonate catalyst in a so~lvent such as pyridine, or 3S lithium aluminium~hydride in a solvent such as diethyl ether~at~a low~t~emperature~e.g. 0C.

,~ ~ - ~ . '. : :
: ' ; ' .
:

In a fu~ther general process (3), a compolJnd of general formula (I) may be prepared by deprotection of a protected intermediate of formula (VII) Cl Rl6HN ~ CIHCH2NRl4~XCH2ûCH2YAr (VII) . OH R2 Cl where Rl4 and Rl6 each represent a hydrogen atom or a protecting group, and/or any hydroxy and/or amino substituent in the group Ar is protected, with the proviso that at least one of Rl4 and/or Rl6 represents a protecting group and/or Ar contains a protecting group.
Suitable protecting groups and their methods of removal are as described previously. Thus, for example, Rl4 may represent an aralkyl group e.g. benzyl, which may be removed by hydrogenolysis in the presence of a metal catalyst (e.g. palladium on charcoal), and/or Rl6 may represent an acyl group which may be removed by boiling with a dilute mineral acid (e.g. hydrochloric acid).
Compounds of formula~(I) may also be prepared by a process comprising interconversion of one compound of general formula (I) to another.
; 25 Thus for~example a compound of formula (I) in which Ar represents a phenyl group substituted by the group -(CH2)rCOR9 where R9 is~hydroxy may be prepared by hydrolysis of the corresponding compound of formula (I) in which R9 represents Cl_4~alkoxy. The hydrolysis may for `30 example be carried~out~ un~der basic condit~iona using e.g.
sodium hydroxide.
In the general~prDcesses~des~crlbed above,~the compound of~formula (I)~;obtained may be in the form of a salt~, convenlentl~y~in the~form~of a physiologically acceptable sal~t~. Wh~ere~desired, such~ealts may be :` ~
.

- ]7 -- ".

converted to the correspondillg free acids usinc conventional methods.
Physiologically acceptable salts of the compounds of general formula (I) may be prepared by reacting a cornpound 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 enantlomer 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 the required enantiomer Df a compound of general formula (I) may be isolated by conversion into the required free~ba~se. ~ ~
Alt~ernatively, 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 appropriat;e~asymmetric starting material using an~y~of the~proces~ses des~cribed herein, or ;
by conversion of~a~mixture of isomers of a compound of general~ f~ormula~(;l) into a~ppropriate diastereoisomeric derivatives e~.~g.~salts~whi~ch~then can be separated by ~ co~nvention~al~means e.g~.~ by~ fractlonal crystallisation.

, ~ ~
:: :: : . ~ :

' ~ - 18 -~6~5 Intermediate compounds of general formula (VI) for use in general process (2) may be prepared by a number oF
processes, analogous to those described in UK Patent Specification No. 2165542A.
Thus for example intermediates of general formula (VI) in which xl is a group /C=O may be prepared from a haloketone of formula (VIII) Cl \

H2N ~ CûCH2Hal (VIII) Cl by reaction with an amine of general formula (IX) Rl Y'NHCIXCH20CH2YAr (IX) (wherein Y' is hydrogen or a group convertible thereto by catalytic hydrogenation). The reaction may be effected in a cold or hot solvent, for example tetrahydrofuran, tert-butyl methyl ether, dioxan, chloroform, dimethylformamide, acetonitrile or a ketone such as butanone or methyllsob~utyl~ketone, or an ester,~ for example ethyl acetate, pr~eferably in the presence of a base such as diisoprop~ylethylamine, sodium-carb~onate or other acid scavenger such as propy~lene~oxide.
Interme;diates~ of general formu~la (VI) ln which Xl is a group )C=O may~be reduced to ~the corresponding `30 intermedlate in~which~XI is~a~group -CH(OH)~ uslng for example a metal hydride~such~as~s~odium borohydride~in a~
solvent~e.g. e~thanol.
Interm~edia~tes of~formulae~ , ;(IV), (VIII~
nd ~ n-~ o~p-un~ o- ~y b~ pr-p ~e~ oy :
:

:

33~

methods analogous to those described for the preparation of known compounds.
Suitable methods for preparing intermediates of formulae (III), (IV) and (IX) are described in UK Patent Specifications Nos. 2140800A, 2159151A, 2165542A and in the exemplification included hereinafter.

:
:
: ~ :

: .

: .
~, :
: : ' :

-- 20 ~
3~

The following examples illustrate tl~e inventiorl. Ternperatures are in C. 'Dried' refers to drying using magnesium sulphate or sodium sulphate except where otherwise stated. Thin layer chrornatography (t.l.c.) was carried out over 8in2, and flash column chromatography (FCC) was carried out on silica (Merck 9385) using, unless otherwise stated, one of the following solvent systems: A-toluene:ethanol:0.88 ammonia; B-toluene:ethanol:triethylarnine; C-ethyl acetate:hexane:
triethylamine; D-ethylacetate:methanol:triethylamine;
E-cyclohexane:ethyl acetate:triethylamine. The following abbreviations are used: THF - tetrahydrofuran; DMF-dimethylformarnide;
BTPC-bis(triphenylphosphine)palladium (II) chloride; DEA-N,N-diisopropylethylamine.

Intermediate 1 is 1-(4-amino-3,5-dichlorophenyl)-2-bromoethanone.

Intermediate 2 (Z)-N-[4-[3-[[6-[(Phenylmethyl)amino]hexyl]oxy]-l-propenyl]phenyl]-methanesulphonamide, hydrochloride (Z)-N-[4-[3-[(6-Bromohexyl)oxy]-I-propenyl]phenyl]methanesulphonamide (2.09) was added to benzylamine (6ml) at 125, under nitrogen. The reaction mixture was stirred~at 125 for 3h, cooled to room temperature and added to 2N hydrochloric acid (50ml) and water (20ml).
The resultant white solid was collected by filtration, washed in turn with 2N hydrochloric acid, water and ether then dried in vacuo at 50 to give the title compound as a whlte powder (1.09) m.p. 133-134.

Intermediate 3 ~ ~
(Z)-N-[4-[3-[[6-[[2-(4-Amino-3,5-dichlorophenyl)-2-hydroxyethyl]-(phenylmethyl)amino]hexyl]oxy]-l-propenyl]phenyl]methanesulphonamide A suspension of Intermediate l (520mg),~Intermediate 2 (850mg) and DEA
(SOOmg) ln THF (25ml) was stlrred at room temperature overnight. After filtration, the filtrate was concentrated to an oil which was dissolved~ln methanol~(20ml) cooled in an ice-bath snd treated with sodium borohydride (250mg). The pale yellow solution was stirred at room temperature overnight, the methanol was evaporated and the resldue partitioned~between watsr (25ml) and ethyl acetate (25ml). The `

`

3~;
organic phase was washed with water and brine, dried ancl concer,trated to a red oil which was purified by FCC eluting with System E (75:25:1) to give the title compound as a colourless oil (540mg). T.l.c.
(System E 75:25:1) Rf 0.09.

Intermediate 4 4-Iodo-N~N-dimethylbenzeneethanamine~ hydrochloride 4-Bromo-N,N-dimethylbenzeneethanamine, hydrochloride (0.659) was partitioned between ethyl acetate (10mQ) and 8o sodium bicarbonate (10mQ). The aqueous layer was extracted with ethyl acetate (10mQ), and the combined organic extracts were dried and concentrated to give the free base (û.57g). n-8utyl lithium (1.6M in hexane, 1.72mQ) was added to a solution of the free base (0.579) in THF (10mQ) at -78, and the mixture was stirred under nitrogen for 30 min. A solution of iodine (0.639) in THF (10mQ) was added dropwise and after 10 min the reaction was quenched by addition of saturated ammonium chloride (10mQ). The THF was evaporated and the aqueous residue was extracted with ethyl acetate (2x15mQ). The organic extracts were washed with 10,o sodium thiosulphate (15mQ) and brine (15mQ), dried and concentrated to yield a brown oil. The oil in ether (10mQ) and dichloromethane (2mQ) was treated with ethereal hydrogen chloride and the resultant precipitate was collected by filtration and dried to give the title compound as a white solid (0.549).
Analysis Found: C,38.77; H,4.87; N,4.39; Cl,11.36; I,40.67.
CloHl4IN.HCl requires C,38,55; H,4.85; N,4.5; Cl,11.38; I,40.73o.

Intermedlate 5 N-(4-Iodophenyl)-N-methylmethanesulphonamide A mixture of N-(4-iodophenyi)methanesulphonamide (4.39), 50O aqueous sodium~hydroxide (25m~), iodomethane (5mQ), dichloromethane (1OmQ) and tetrabutylammonium bisulphate (0.59) was stirred vigorously for 2h.
Water (50mQ) was added and the mixture was extracted with ether (3x50m~). The organic extracts were washed with water and brine, dried and concentrated to a solid which was triturated with hexane to give the tltle come~ as white crystals (4.19) m.p. 106-107.
: ~ :
: ~ :::::

:
::

, 11 Z~
Intermediate 6 2-(4-Iodophenoxy)-N,N-dimethylacetamide Dimethylamine (33~O w/w in IMS, 5.B5mQ) was added dropwise to a suspension of [(4-iodophenoxy)acetyl chloride (9.499) in triethylamine (50mQ) at 0 under nitrogen. The suspension was stirred for 2h at 0 and partitioned between ethyl acetate (300rnQ) and 8~o aqueous sodium bicarbonate (3ûOmQ). The organic layer was dried and the solvent was evaporated to leave an oil which was purified by FCC eluting with diethyl ether to give the title compound as a white solid (3.969), lO m.p. 63-65.

Intermediate 7 4-Iodo-N,N-dimeth lbenzeneacetamide 4-Iodophenylacetyl chloride (5.159) was added portionwise to 15 dimethylamine (0.909) in triethylamine (25mQ) at 0. The suspension was stirred at 0 for 2h and chloroform (100mQ) was added. The organic phase was washed with 8~o aqueous sodium bicarbonate (50mQ), dried and concentrated to give a red solid (5.09) which was purified by FCC eluting with ether followed by ethyl acetate to give the title 20 compound as a yellow solid (2.589) m.p. 75-77.

Intermediate 8 N-Dimethyl 4-[4-[5-[(phenylmethyl)amino]pentyloxy]butyl]benzene-acetamide 25 Intermediate 16 (1.609) was added dropwise to benzylamine (3.5mQ) at 120 under nitrogen. The solution was stirred for 3h at 120 and poured into 0.8N aqueous hydrochloric acid (65mQ). The aqueous mixture was extracted with ethyl acetate (3x30mQ) and the combined extracts were washed with 8,6 aqueous sodium bicarbonate (50mQ) and 30 brine (50mQ), dried and concentrated to give an oil (0.569). The combined aqueous phases weré re-extracted with ethyl acetate (2x50mQ), dried and concentrated to give an oil (0.92g). The two oils were combined and purified by FCC eluting with ethyl acetate-triethylamine (100:1) to~give the title compound as~a pale yellow oil (1.009), 35 t.l.c.~(Ethyl acetate-trlethylam1ne 100:1) RF 0.1.
~; ~ ~: : : : :

: ~ :

i3~
Intermediate 9 N-[[3-[3-[[6-[(Phenylmethyl)amino]hexyl]oxy]-1-propyny~]pherlyl]-methyl]acetamide A suspension of N-[(3-iodophenyl)methyl]acetamide (3.919), N-[6-[(2-propynyl)oxy]hexyl]benzenemethanamine (3.48g), BTPC (100mg) and copper iodide (60mg) in diethylamine (75m~) was stirred at room temperature under nitrogen for 20h. The reaction mixture was poured into diethyl ether (100m~) and filtered. The filtrate was concentrated to give an oil (6.629) which was purified by FCC eluting with System D (100:0:1~100:10:1) to give the title compound as a red oil (4.609), t.l.c. (Ethyl acetate-triethylamine 100:1) Rf 0.12.

Intermediates 10-13 were prepared in a similar manner:

Intermediate 10 N,N-Dimethyl-4-[3-[[6-[(phenylmethyl)amino]hexyl~oxy]-1-propynyl]benzamide From 4-iodo-N,N-dimethylbenzamide (2.59) and N-[6-[(2-propynyl)oxy]-hexyl]benzenemethanamine (2.239). FCC purification eluting with ethyl ~O acetate-triethylamine (100:1) gave the title compound as an orange oil (2.969), t.l.c. (Ethyl acetate + few drops triethylamine) Rf 0.15.

Intermediate ll N,N-Dimethyl-2-[4-[3-[[6-[(phenylmethyl)amino]hexyl]oxy]-1-propynyl]-phenoxy] acetamide From Intermediate 6 (3.919) and N-[6-[(2-propynyl)oxy]hexyl]-benzenemethanamine (3.149). FCC purification eluting with System C
(83:17:1) gave a product (3.879) which was re-columned as previously but using ethyl acetate-triethylamine (100:1) as the eluant to give the title compound as an orange oll (1.449), t.l.c. (Ethyl acetate few drops triethylamine) Rf 0.3.

Intermediate 12 N-Methyl-N-[4-[3-[[6-[(phenylmethyljamino]hexyl]oxy]-1-propynyl]
phenyI] methanesulphonamide From Intermedlate 5 (1.89) and N-[6-[(2-propynyl)oxy]hexyl]-:

. ~ -.

~9~33~i benzenemetl~anamil1e (1.593, except that triethylamine/THF (1:1, 50m~)) was used instead of diethylamine. FCC purification eluting with Systern B (95:5:1) gave the title compound as an orange oil (2.09), t.l.c.
(System B 95:5:1) Rf 0.13.

Intermediate 13 4-[3-[[6-[[2-(4-Amino-3,5-dichlorophenyl)-2-hydroxyethyl](phenyl-methyl)aminoJhexyl]oxy]-l-propynyl)benzamide From Intermediate 24 (550mg) and 4-iodobenzamide (250mg), except that diethylamine/THF (4:1, 10ml) was used instead of diethylamine, and addition of the reaction mixture to ether followed by filtration was omitted. FCC purification of the concentrated reaction mixture eluting with System B (90:10:1) gave the title compound as a pale yellow oil (540mg), t.l.c.~System B 90:10:1) Rf 0.35.
Intermediate 14 N-[4-[3-[[6-[[2-(4-Amino-3,5-dichlorophenyl)-2-hydroxyethyl](phenyl-methyl)amino]hexyl]oxy]-l-propynyl]phenyl]-2-(dimethylamino) acetamide A suspension of Intermediate 24 (1.09), 2-(dimethylamino)-N-(4-iodophenyl)acetamide (68ûmg), dicyclohexylamine (450mg), BTPC (50mg) and copper (I) iodide (10mg) in acetonitrile (15ml) was stirred under nitrogven for 3hr. Ether (25ml) was added, the precipitate was removed by filtration, the solvent was evaporated and the residue purified by FCC eluting with System C (50:50:1) to give the title compound as a yellow oil (800mg~, t.l.c. (System A 80:20:2) Rf 0.53.

Intermediate 15 4-[4-[3-[[6-[(Phenylmethyl)amlno]hexyl~oxy]-1-propynyl]benzoyl]-morpholine ~ ~
4-(4-Iodobenzoyl)morpholine (4.09) and N-[6-[~(2-propynyl)oxy]-hexyl]benzenemethanamine (3.099) were reacted according to the method~
of Intermediate 14.~FCC~pùrification ~eluting with~ethyl acetats-triethylamins (100:1) gave ths title compound as a yellow oil (2.219), t.l.c. (Ethyl acetate-~triethylamine 100:1) Rf 0.2.

.~
. - .
: :` :
`
:

: ' : ', ,: ' ,' . , .~ : - ' .

lntermediate 16 4-[4-[(5-Bromopentyl)oxy]butyl]-N,N-dirnethylbenzeneacetamide A mixture of Intermediate 7 (2.509), 1-bromo-5-(3-butynyloxy)pentane (1.909), dicyclohexylamine (1.739), BTPC (50mg) and copper iodide (10mg) was stirred in acetonitrile (30mQ) under nitrogen for 2h.
Ether (80mQ) was added, the mixture was filtered, the filtrate was concentrated and the residue was refluxed in ethanol (100mQ) with charcoal and filtered (hyflo). The solution was hydrogenated over 10o palladium on charcoal (50O paste in water; 1.09) for 48h, filtered (hyflo) and concentrated to give a residue which was purified by FCC
eluting with ether-ethyl acetate (100:0)80:20) to give the title compound as a yellow oil (1.629), t.l.c. (Ether) Rf 0.12.

Intermediate 17 (Z)-N-[t3-[3-[[6-[[2-(4-Amino-3~5-dichlorophenyl)-2-hydroxyethyl]-(phenylmethyl)amino]hexyl]oxy]-1-propenyl]phenyl]methyl]acetamide A solution of Intermediate l (1.449), Intermediate 9 (2.09) and DEA
(66ûmg) in THF (20mQ) was left to stand for 20h at room temperature under nitrogen. The precipitate was removed by filtration and the filtrate was concentrated to give an oil which was dissolved in methanol (20mQ) cooled in an ice-bath, and treated portionwise with sodium borohydride (750mg). The reaction rnixture was stirred at room temperature under nitrogen for 2h and concentrated to give an oil to which water (100mQ) was added. The mixture was extracted with ethyl acetate (3x50mQ? and the combined extracts were washed with water (50mQ) and brine (50mQ), dried and concentrated to give an oil which was purified by FCC eluting with~5y~stem B (95:5:1) to give the title compound as a yellow oil (1.519), t.l.~c. (System B 95:5:1) Rf 0.13.

Intermediates 18-24 were prepared in a similar manner:
:
Intermediate 18 ~
4-t4-[5-[[2-(4-Amino-3,5-dichlorophenyl)-2-hydroxyethyl](phenyl-methyl)amino]pentyloxy]butyl]-N,N- methylbenzenea etamide From Intermedlate i;(690mgj~and Intermediate 8 (1.019). The sodium borohydride/methanol reaction was continued for 24h. fCC purification :: ~ ~ : : : :

.. . .
, ' . , . ~ ;, ~ , .
, , ' . :

~63~35 eluting with System C (50:50:1) gave the title compound as a yellow ~ oil (1.129), t.l.c. (Ethyl acetate-hexane (1:1) ~ few drops triethylamine) Rf û.1.

Intermediate 19 (Z?-2-[4-[3-[[6-[[2-(4-Amino-3,5-dichlorophenyl)-2-hydroxyethyl]-(phenylmethyl)amino]hexyl]oxy]-1-propenyl]phenoxy]-N~N-dimeth~
acetamide From Intermediate l (951mg) and Intermediate ll (1.429). FCC
purification eluting with System B (97:3:1) gave the title compound as a yellow oil (1.119), t.l.c. (System B 95:5:1) Rf 0.31.

Intermediate 20 N-[4-[2-[[6-[[2-(4-Amino-3~5-dichlorophenyl)-2-hydroxyethyl](phen methyl)amino]hexyl]oxy]ethyl]phenyl]methanesulphonamide From Intermediate l (0.79) and N-[4-[2-[[6-[(phenylmethyl)amino]-hexyl]oxy]ethyl3phenyl]methanesulphonamide (19). FCC purification eluting with System B (98:2:1) gave the title compound as a yellow oil (1.29), t.l.c. (System A 80:20:1) Rf û.47.

Intermediate 21 N-[4-[3-[[6-[[2-(4-Amino-3,5-dichlorophenyl)-2-hydroxyethyl](phenyl-methyl)amino] hexyl]oxy]-1-propynyl]phenyl]-N-methylmethane-sulphonamide From Intermediate l (660mg) and Intermediate 12 (1.09). The sodium borohydride/methanol reaction was continued for 18h. FCC purification eluting with System C (33:66:1~50:50:1) gave the title compound as a pale yellow oil (320mg), t.l.c. (hexane-ether-triethylamine 50:50:1) Rf 0.04.

Intermediate 22 (Z)-4-[3-[[6-[[2-(4-Amino~ -dich~lorophenyl)-2-hydroxyethyl](phenyl-methyl)amino]hexyl]oxy]-1-propeny ]-N,N-_imethylbenzamide From Intermediate l (1.09) and Intermediate 10 (1.399). FCC
purification eluting with System B (97:3:1) gave the title compound as a yellow oil (0.939); t.l.c. (System B 95:5:1) Rf 0.3.

::
.

`
:`

, , Intermediate 23 4-[4-[3-[[6-[[2~(4-Amino-3,5-dichlorophenyl)-2-hydroxyethyl~(phenyl-methyl)amino] hexyl]oxy]-1-propynyl]benzoyl]morpholine From Intermediate l (1.09) and Intermediate 15 (1.539). The sodium borohydride/methanol reaction was continued for 60h. FCC purification eluting with System B (97:3:1) gave the title compound as an orange oil (1.549), t.l.c. (System B 95:5:1) Rf 0.25.

Intermediate 24 4-Amino-3,5-dichloro-a-[[(phenylmethyl)[6-[(2-propynyl)oxy]hexyl]
amino]methyl]benzenemethanol From Intermediate l (1.09) and N-[6-[(2-propynyl)oxy]hexyl]benzene-methanamine (870mg), carrying out the first stage of the reaction for only 25 min. FCC purification eluting with System C (20:80:1) gave the title~compound as a colourless oil (1.279), t.l.c. (System C 20:80:1) Rf 0.33.

Intermediate 25 N,N-Bis[2-phenylmethoxy)ethyl]-4-iodobenzeneamine A mixture of 2,2'-(4-iodophenylimino)bis-ethanol (29), benzyl bromide (2.39), tetra-n-butylammonium bisulphate (0.49) and 50O sodium hydroxide (20ml) was stirred vigorously for 5h. The mixture was diluted with water (20ml), extracted with ethyl acetate (2x20ml) and the combined extracts were washed consecutively with water (5ûml) and brine (50ml), dried and evaporated. Purification by FCC eluting with hexane-ether (19~:1)9:1) gave the title compound as a pale yellow oil (2.19)j t.I.c. (hexane-ether l:l) Rf 0.7.

Intermediate 26 ~
4-Amino-3,5-dichloro-a-~[[6-[[3-[4-bis[2-(phenylmethoxy)ethyl]amino]-phenyl]-2ipropynyl]oxy]hexyl](phenylmethyl)amino]methyl]benzene-methanol ~ ; ~
A solution of Intermediate 24 (1.9g)j Intermediate 25 (1.759), BTPC
(90mg)~and~copper (I) iodlde (9mg) in~diethylamine/tetrahydrofuran (4:1~ 30ml)~was stlrred at~room temperature under nitrogen for 2 days.

, : :
: ~ ~

, - . : . : , .
~ ' '. : , - :: , ~ ' : , . : , : , , .

.

~ 8~,33~

The solvent was evapo~ated and the residue was purified by FCC eluting with System C (20:8û:1-~30:70:1) to give the title compound as an orange oil (1.759), t.l.c. (System C 20:80:1) Rf 0.17.

Intermediate 27 4-Amino-3,5-dichloro-a-Ct6-[[3-[4-[2-(dimethylamino)ethoxy]phenyl]-2-propynyl)oxy]hexyl](phenylmethyl)amino]methyl]ben~enemethanol A solution of 2-(4-iodophenoxy)-N,N-dirnethylethanamine' (1.579), Intermediate 24 (2.949), BTPC (100mg) and copper iodide (10mg) in diethylamine (30ml) and acetonitrile (10ml) was stirred at room temperature under nitrogen for 16h. The solvent was evaporated and the residue was purified by FCC eluting with System B (95:5:1) to give the title compound as a red oil (3.579), t.l.c. (System B 95:5:1) Rf 0.26.
Example l 4-[3-[[6-[[2-(4-Amino-3,5-dichlorophenyl)-2-hydroxyethyl]amino]hexyl]-oxy]propyl]ben~am de Intermediate 13 (1.39) was hydrogenated over 10o palladium oxide on carbon~(50O aqueous paste, 280mg) in ethanol (15m~) containing hydrochloric acid (conc. HCl/EtOH, 1:9 v/v, 2m~). The catalyst was removed by filtration through hyflo, the solvent was evaporated and the residue was partitioned between 8o sodium bicarbonate (25m~) and ethyl acetate (25m~)~ The aqueous layer was re-extracted with ethyl acetate (25m~) and the combined organic extracts were washed with 8n sodium bicarbonate and brine, dried and concentrated to a semi-solid which ~was triturated with ether/ethyl acetate (~4:1) to give the title compound as an off-white sol1d (240mg, 22o) m.p. 91-94, t.l.c.
(System A 80:20:2) Rf 0.25.
~ ~
Examples 2-9 were prepared ln~-a similar manner:
~: : : : ` :
' Example 2 ;N-[4-~3-[~6-[[2-(4-Amlno-3,5-dlchlorophenyl)-2-hydroxyethyl]amino]-35 ; hexyl]oxy]propyl]phenyl]methanesulphonamide From Intermediate ~3 ~(500mg). Evaporation of the ethyl acetate extracts ~ gave~an~o~il whloh- was~purifled~by~FCC~eluting with System B (95:5:1) ., ~ . .

~ ~6;~35 followed by trituration with dry ether tù give the title compound as a white powder (10ûmg) m.p. 62 64.
Analaysis Found: C,54.82;H,7.26;N,7 36 C24H35Cl2N304S-0-35C4l~l00 rquires C,54.63jH,6.95;N,7.52,o Example 3 Ethyl 4-[3-[[6-[[(4-amino-3,5-dichlorophenyl)-2-hydroxyethyl]amino-hexyl]oxy]propyl]benzoate From ethyl 4-[3-[[6-[[(4-amino-3,5-dichlorophenyl)-2-hydroxyethyl]-(phenylmethyl)amino]hexyl]oxy]l-propynyl]benzoate (SOOmg), using pre-reduced 10~o palladium on charcoal (50O paste in water, 60mg) as the catalyst for hydrogenation. The residue obtained by evaporation of the ethyl acetate extract was purified by FCC eluting with System C
(50:50:1) to give the title compound as a white solid (97mg) m.p.
66-68. T.l.c. (System C 50:50:1) Rf 0.05.

Example 4 N-[4-[3-[[6-[[2-(4-Amino-3,5-dichlorophenyl)-2-hydroxyethyl]amino]-hexyl]oxy]propyl]phenyl]-2-(dimethylamino)acetamidej (E)-butenedioate (salt) (1:1) From Intermediate 14 (750mg), using conc. HCl/EtOH, 1:9 v/v, 2.2ml.
The yellow oil (520mg) obtained after concentration of the ethyl acetate extracts was dissolved in methanol (5ml) and treated with a solution of fumaric acid (120mg) in methanol (2ml), the methanol was evaporated and the residue was triturated with ether to give a yellow solid (610mg) which was recrystallised from isopropanol (15ml) to give the title compound as a white solid (~100mg) m.p. 106-110. -Analysis Found: ~ C,56.32; H,6.97; N,7.94; Cl,11.32.
C27H40Cl2N403.C4H404 requires C,56.79; H,6.76; N,8.55; Cl, 10.82o.
Example 5 4-[3-[[6-[[2-(4-Amino-3,5-dichlorophenyl)-2-hydroxyethyl]amino]-hexyl]oxy]propyl]-N,N-dlmethylbenzamide,~(E)-butenedioate (salt)~

From Intermediate 2Z (0.~82g)~using pre-reduced 10~o p~alladlum on charcoal~(50O~ aqueous paste~, 100mg) as the catalyst;for hydrogenation.

~ , . ' "
- .' . ': . .

~ 30 -~96335 Evaporation o~ the Ethyl Aceta-te oxtrac-ts gav~ an oil which was purified by FCC eluting with System B (95:5:1) to giYe an oil. The oil (0.429) in methanol (2m~) was treated with (E)-butenedioic acid (47.6rng) in methanol (2mQ) and the solution was concentrated The residue was triturated with diethyl ether to give the title compound as a white solid (0.479) m.p. 107-109.
Analyais Found: C,59.0jH,7.2jN,7.2;Cl,12.6.
C26H37Cl2N303 0-5C4H44 requires C~55.2;H~6.9;N~7.4;cl~12.5oo.

Example 6 4-[4-[3-~[6-[[2-(4-Amino-3,5-dichlorophenyl)-2-hydroxyethyl]amino]-hexyl]oxy]-propyl]benzoyl]morpholine From Intermediate 23 (0.709) using pre-reduced 10o palladium on charcoal (50O aqueous paste, 8Qmg) at the catalyst for hydrogenation.
E~aporation of the ethyl acetate extract gave an oil which was purified by FCC eluting with System B (95:5:1) to give the title compound as a yelIow oil (391ms). A solution of the title compound (390mg) in methanol (2ml) was treated with (E)-butenedioic acid (41.1mg) in methanol (2ml), anc the solvent was evaporated to give an oil which, on trituration with diethyl ether, gave the (E)-butenedioate salt (2:1) of the title compound as a white solid (40mg), m.p. 114-116.
Analysis Found: C,58.7;H,6.0;N,6.7;Cl,11.9.
(C28H39Cl2N304)2.C4H404 requir~s C~59.0;H~6.8;N~6.9;Cl~11.6n Example 7 N-[[3-[3-[[6-[[2-(4-Amino-3,5-cl_hlorophenyl)-2-hydroxyethyl]amino]-hexyl]oxy~ propyl]phenyl]methyl]acetamide From Intermediate 17 (1.409) u~;ing pre-reduced 10o palladium on ~30 charcoal (50O aqueous paste, 170mg) as the catalyst for hydrogenation.
The solid obtained from the ethyl acetate extracts was triturated with diethyI ether to give the t _ e compound as a white solid (0.76q) m.p.
91-94;, t.l.c. (System A 80:20:2) Rf 0.45.
Analysls Found:~ C,60.7;H,7.5;N,7.9;Cl,13.9.
C26H37Cl2N303 requires C~61.2;H~7.3;N~8.2;Cl~13.9o.

. ~

~ ~ .
~' :
::

... , . , ~ -- : ~
'` : '; .. " , ' ', ' . ~ .

Example 8 2-[4-[3-[[6-[[2-(4-Amino-3,5-dichlorophenyl)-2-hydroxyethyl]arnino~-hexyl]oxy] propyl]phenoxy], N,N-dimethylacetamide (E)-butenedioate (salt) (2:1) From Intermediate 19 (0.999) using pre-reduced 10~o palladium on charcoal (50O aqueous paste, 115mg) as the catalyst for hydrogenation.
Concentration of the ethyl acetate extract gave an oil. The oil (0.7ûg) in methanol (2mQ) was treated with (E)-butenedloic acid (75.5mg) in methanol (2m~) and the solution was concentrated. The residue was triturated with diethyl ether to give the title compound as a buff solid (0.639), m.p. 116-118, t.l.c. (System B 95:5:1) Rf 0.17.

Example 9 N-[4-[3-[[6-[[2-(4-Amino-3~5-dichlorophenyl)-2-hydroxyethyl]amino]
hexyl]oxy]propyl]phenyl]-N-methylmethanesulphonamide hydrochloride From Intermediate 21 (250mg) using pre-reduced 10o palladium oxide on carbon (50O aqueous paste, 50mg) as the catalyst for hydrogenation.
Concentration of the ethyl acetate extract gave an oil which was purified by FCC eluting with System B (99:1:1~95:5:1) to give a yellow oil (130mg). The oil in ether (5m~) was treated with ethereal hydrogen chloride and the resultant oil was triturated with dry ether to give the title compound as a yellow solid (9Omg), t.l.c. (System a 95:5:1) Rf 0.56.
Analysis Found: C,51.14;H,7.02;N,6.87;Cl,17.82;5,5.00.
C~sH37Cl2N3045.HCl requires C~51.50;H~6.57;N~7.21;Cl~18.24;5~5.50o.

Example 10 4-Amino-3,5-dichloro-a-[~[6=[3-[4-[2-(dimethylamino)ethyl]phenyl]-propoxy]hexyl]amino]methyl]benzenemethanol~
A solution of Intermediate 4 as its~free base (1.549) Intermediate 24 (2.949), BTPC (100mg) and copper (I) iodide~(10mg) in diethylamine (30m~j and acetonitrile (10m~ was stirred under nitrogen for 18h.
The solution was concentrated in vacuo to give a brown oil which was purified by FCC eluting with~System B (95:5:1) to give a yellow oil (2.49). The oil (2.39) was hydrogenated over 10' palladium oxide on :

: ~
~ , 33'-~
~2 -carbon (50O aqueous paste, 500mq) in ethanol (20mR) containing hydrochloric acid (conc. HCl/EtOH; 1:9 v/v, 6.9mQ). The catalyst was removed by filtration through hyflo, the ethanol was evaporated and the residue was partitioned between 8o sodium bicarbonate (2ûmQ) and ethyl acetate (20mR). The aqueous layer was re-extracted with ethyl acetate (20mR) and the combined organic extracts were washed with sodium bicarbonate (2ûmQ) and brine (20mR), dried and concentrated to give a yellow oil. The oil was purified by FCC eluting with System B
(98:2:1) to give a pale yellow oil (1.29) which was triturated with hexane to give the title compound as a white solid (1.19) m.p.
41.5-43.5.
Analysis Found: C,63.23jH,8.37;N,8.10;Cl,13.69.
C27H40Cl2N3û2 requires C,63.64;H~7.91;N,8.25;Cl~13.92o.

Example ll 4-[4-[5-[[2-(4-Amino-3,5-dichlorophenyl)-2-hydroxyethyl]-amino]-pentyloxy]butyl]-N,N-dimethylbenzeneacetamide Intermediate 18 (1.ûûg) in ethanol (2ûmR) containing hydrochloric acid ; (conc. HCl/EtOH, 1:9 v/v, 1.48mR) was hydrogenated over pre-reduced 10o palladium on charcoal (150mg, 50O paste in water). The reaction mixture was filtered (hyflo) and the filtrate was concentrated. The residue was partitioned between ethyl acetate (1ûOm~) and 8~o aqueous sodium bicarbonate (2x50mR). The dried organic layer was concentrated and the residual oil was purified by FCC eluting with System D
(100:0:1~90:10:1) to give the title compound as a yellow oil (0.699).
The title compound (469mg) in methanol (2ml) was treated~with (E)-butenedioic acid (51.9mg) in methanol (2ml). The solution was concentrated to give an oil whlch was triturated with diethyl ether to give the (E)-butenedioate salt (2:1) of the title compound (407mg), m.p. 107-110.
Analysis Found: C,59.9;H,7.4;N,7.0;Cl,12.0 C27H39Cl2N303Ø5C4H404 requires C,59.8;H,7.1;N,7.2iCl,12.2 Exam le 12 ~ ~
P
-~ 35 N-[4-[3-[[6-[[2-(4-Amino-3,5-dichlorophenyl)-2-hydroxyethyl]amino]-hexyl]oxy]ethyl]phenyl-]methanesulphonamide Intermediate 20 (1.29) was hydrogenated as~in Example 11, :`

::

using pre-reduced 10~o palladium oxide on carhon ~50O aqueous paste, 150mg) as the catalyst. Evaporation of the ethyl acetate extract gave a yellow oil which was purified by FCC eluting with System B (92:8:1) to give a pale yellow oil which when triturated with ether gave the title compound as a white solid (445mg), m.p. 62-65.
Analysis Found: C,52.94; H,6.40; N,7.79; C1,13.96; 5,6.17.
C23H33Cl2N3U45 requires C,53.28; H,6.42; N,8.10; Cl,13.68; S~6.18o.

Example 13 4-t3-[[6-5[2-(4-Amino-3,5-dichlorophenyl)-2-hydroxyethyl]amino]hexyl]
ox ]pro l]benzeneacetamide Y PY
4-[3-[(6-Bromohexyl)oxy]propyl]benzeneacetamide (950mg) was added to a stirred solution of 4-amino-~-(aminomethyl)-3,5-dichloro-benzenemethanol (9ûOmg) and DEA (650mg) in DMF (1Om~) at 100 under nitrogen. After 1h the solvent was evaporated and the residue was partitioned between 8~o sodium bicarbonate (2ûmQ) and ethyl acetate (20mQ). The organic layer was washed with water and brine, dried and concentrated in vacuo to give a yellow solid which was triturated with ether to give the title compound as an off-white powder (510mg) m.p.104-106.
Analysis Found: ; C,60.58;H,7.35jN,8.11;Cl,13.83 C2sH35Cl2N303 requlres C,60.4a;H,7.11;N~û.46;Cl,14.28o Example 14 4-Amino-3,5-dichloro-a-[[[6-[3-[4-(methoxymethyl)phenyl]propoxy]
hexyl]amino~methyl]benzenemethanol, (E)-butenedioate (2:1) (salt) 1-~3-[(6-Bromohexyl)oxy]propyl]-4-(methoxymethyl)benzene (1.09) and 4-amino-a-(aminomethyl)-3~,5-dichlorobenzenemethanol (1.09) were reacted according to the method of Example 13. Concentration of the ethyl acetate extract gave an oil which was purified by FCC eluting with System B (90:10:1) to give a yellow oil (620mg). The oil in isopropanol (5mQ)~ was treated with a hot solution of fumaric acid (20mg) in isopropanol (2m~) and~after~1h ths two phase system was stirred vigorously to leave a pale yellow precipitate which was collected by filtratlon and~drled ln vacuo to give the title compound ~: ~

: ~ ~

, ~2~
as a pale yellow powder (550mg) m.p. 110-112, t.l.c. (System A
80:20:2) Rf 0.43.
Analysis Found: C,59.3~jH.6.87;N,4.8a;Cl,13.31.
C25H36Cl2N203Ø5C4H404 requires C~59~89;H~7~07;N~5~17;Cl~13 09o Example 15 4-[3-[[6-[[2-(4-Amino-3,5-dichlorophenyl)-2-hydroxyethyl]amino]hexyl]-oxy]propyl]benzoic acid The product according to Example 3 (600mg) in ethanol (8ml) was lO treated with 2N sodium hydroxide (4ml) and stirred at reflux for lh.
The ethanol was evaporated, water (20ml) was added to the residue and the mixture was neutralised using 2N hydrochloric acid. Ethyl acetate (25ml) was added and the two phase mixture was vigorously stirred for lûmin. The resulting precipitate was collected by filtration, washed 15 with ethyl acetate and dried to give a cream solid (450mg), which was triturated with warm methanol (10ml) and filtered to give the title compound as a white powder (290mg) m.p. 190-191.
Analysis Found: C,59.22,H6.82;N,5.62;Cl,14.40.
C24H32Cl2N204 requires C,59.63;H6.67;N,5.79,Cl,14.67o.
Example 1 6 4-Amino-3,5-dichloro--[[[6-[3-[4-[(4-morpholinyl)methyl]phenyl]
propoxy]hexyl]amino]methyl]benzenemethanol The product according to Example 6 (0.679) in benzene~(10mR) was added 25 dropwise to lithium aluminium hydride (300mg) in dry diethyl ether (15mR) at room temperature under nitrogen. The suspension was stirred for 18h at room temperature ~and treatment with water (0.3mR), 2N
aqueous sodium hydroxide (0.6mR) and water (0.6mR) gave a precipitate which was filtered off (hyflo). The filtrate was concentrated to give 30 an oil which was purified by FCC eluting with System B (95:5:1) to give the title compound as a white solid (318mg) m.p. 57-59 , t.l.c.
(System B 95:5:1) Rf 0.22.

' ;~ ~

:: : ::: `: :

3~ 3~
Example 17 4-Amino-3,5-dichloro-~-[[[6-[3-[-4[[2-(dirnethylamino)ethyl]amino]
phenyl]propoxy]hexyl]amino]methyl]benzenernethanol-(E)-butenedioate (2:3) (salt) The product according to Example 4 as its free base (440mg) was treated with lithium aluminium hydride (420mg) following the method of Example 16. After 7 days, water (1mQ), 2N aqueous sodium hydroxide (2m~) and water (1mQ) were added successively, the precipitate being removed by filtration through hyflo and the ether was evaporated to leave a brown oil. A solution of the oil (320mg) and fumaric acid (7amg) in methanol (3m~) was concentrated to an oil which was triturated with ether to give the title compound as a brown solid (230mg), m.p. 41-45.
Analysis Found: C,56.59;H,7.35;N,7.30;C1,9.61.
C27H42Cl2N402.1.5C4H404 requires C~56.66;H~6.91;N~8.01;Cl~10.13o.

Examples 18 and 19 were prepared according to the method of Example Example 18 4-Amino-3,5-dichloro-~-[[[6-[3-[4-[bis(2-hydroxyethyl)amino]-phenyl)propoxy]hexyl]amino]methyl]benzenemethanol :
` From Intermediate 26 (402mg), using conc. HCl/EtOH 1:9 v/v, O.9ml.
Evaporation of the ethyl acetate extracts gave a brown oil which was ~5 purified by FCC eluting with System B (95:5:1~80:20:1) to give the title compound as a pale yellow oil (85mg), t.l.c. (System A 80:20:2) Rf 0.33. o (CDCl3) 1.2-1.63 and 1.84 (-CH2-); 3.4 (-OCH-2); 3.54 and 3.81, 8H, (-CH2CH20H)2; 6.62 and 7.04, 4H, (CH of phenyl ring); 7.17, 2H, (CH of dichloroaniline ring).

Example 19 ~ ~
4-Amino-3,5-dichloro-a-[[[6-[3-[4-[2-(dimethylamino)ethoxy]phenyl]-propoxy)hexyl]amino]met~y~_benzenemethanol From Intermediate 27 (3.42g), using pre-reduced 10~ palladium on ~charcoal (50O paste in water, 750mg) as the catalyst for hydrogenatlon, in ethanol (30ml) containing hydrochloric acid (conc.

: ~ :

:

~L2~
-~G-HCl/EtOH 1:9 v/v, 10.1ml). The oil obtained by evapo~ation of the ethyl acetate extracts was purified hy fCC eluting ~Jith System A
(80:20:2) followed by further FCC chromatography of the impure fractions eluting with System B (95:5:1). The combined oils obtained (493mg) in methanol (5ml) were treated with (E)-butenedioic acid (109mg) in methanol (5ml). The solution was concentrated and the residual foam was triturated with diethyl ether to give the title compound as a pale yellow foarn (0.361g), t.l.c. (System A 80:20:2) Rf 0.5.
Analysis Found C,56.1;H,7.2;N,6.2;Cl,11.0 C27H4lCl2N303.1.25C4H404Ø8H20 requires C~56.0;H~7.0;N~6.1;C1~10.3,o The following are examples of suitable formulation of compounds of the invention. The term 'active ingredient' is used herein to represent a compound of the invention.
: :
Tablets (Direct~Compression) mg/tablet Active ingredient 2.0 Microcrystalline Cellulose USP 196.5 Magneslum~Stearate BP ~ ~ 1.5 ~ Compresslon~weight 200.0 The active~ingredient is ~ieved~through a suitable sieve,~blended with the excipients and compressed~using 7mm diameter punches.
Tablets of other;strengths~may be prepared by altering the ratio of actlve~ingredient to mlcrocryst~alline cellulose or the compression weight and `using punches to~suit. ~
30~ The tablets~may be film coated with suitable film forming ~materlal~s,~such as hydroxypropylmethylcellulose,~ uslng~standard techniques.~Alter~natively~the~tablets~may be sugar~coated.

: ~

j 3~;i Syrup (Sucrose-free) mg/5ml dose Active ingredient 2.0mg Hydroxypropyl methylcellulose USP
(viscosity type 4000) 22.5mg Buffer Flavour Colour ) as 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 ! 15 solution is adj~usted to volume and rnixed. The syrup is clarified by filtration.

Metered Dose Pressurised Aerosol A. Suspension AerosoI
mg/metered dose Per can Active ingredient micronised 0.100 26.4ûmg Oleic~Acid BP ~ ; 0.100 2.64mg Trichlorofluoromethane;BP ~23.64 ~ ; 5.679 Dichlorodifluoromethane BP~ 61.25 14.70g ~ ~
The active~ingredient is~;;rnicronised in a fluid energy mill to a fine partlcle size~range.~ The~oleic~acid is mixed with the trichlorofluoromethane at a~temperat~ur~e~of~10-15C~and~the micronised ~ drug~is~mlxed lnto the;solution~wlth~a high shear mixer. The - suspension is~metered into~aluminium aerosol~cans and suitable metering~valves~dèlivering~85mg~of suspens~ion are~crimped onto the~
` ~cans and~the~d~ichlorodifluoromet~hane is~press~ure~filled into the cans~
through~the~valves.

.

- ` ` ~: ; , . :
::
': ' ` ~` - 38 -B. Solution Aerosol mg/metered dose Per can Active ingredient 0.055 13.20rng Ethanol BP 11.100 2.669 Dichlorotetrafluoroethane BP 25.160 6.049 Dichlorodifluoromethane BP 37.740 9.06g 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 oleic acid or surfactant if used. The alcoholic solution is metered into suitable aerosol containers followed by the dichlorotetrafluoroethane. Suitable metering valves are crimped onto the containers and dichlorodifluoromethane is pressure filled into them through the valves.

In ection for Intravenous Administration mg/ml Active ingredient 0.5mg Sodiurn Chloride BP as required Water For Injection;8P to 1.ûml 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 stabillty and/or faoilitate solution of the active ingredient.
Alternatively suitable buffer salts may be used.
The solution is prepared, clarified and filled into appropriate size ampoules sealed by fusion of the gIass. The injection is sterilised by heating in an autoclave using ane 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.
~

: ~ :
:

. ,: . : ~ : , ,.
, ' ~

, .
. ~ , -3~
Inhalation Cartridges mg/cartridge 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 (17)

1. A process for the preparation of compounds of the general formula (I) (I) wherein X represents a bond, or a C1-6 alkylene, C2-6 alkenylene or C2-6 alkynylene chain and Y represents a bond, or a C1-4 alkylene, C2-4 alkenylene or C2-4 alkynylene chain with the proviso that the sum total of carbon atoms in X and Y is not more than 8;
Ar represents a phenyl group substituted by one or more substltuents selected from nltro, -(CH2)qR [where R is C1-3 alkoxy, -NR3R4 (where R3 and R4 each represent a hydrogen atom,for: 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 or -NR3R4 group), and q represents an integer from to 3], -(CH2)rR7 [where R7 represents -NR5SO2R8 (where R8 represents a C1-4 alkyl, phenyl or -NR3R4 group), -NR5COCH2N(R5)2 (where each of the groups R5 represents a hydrogen a tom or a C1-4 alkyl group), -COR9 (where R9 represents hydroxy, C1-4 alkoxy or NR3R4), -SR10 (where R10 is a hydrogen atom, or a C1-4 alkyl group optionally substituted by hydroxy, C1-4 alkoxy or NR3R4), -SOR10, SO2R10, -CN or -NR11R12 (where R11 and R12 represent a hydrogen atom or a C1-4 alkyl group, at least one of which is C2-4 alkyl substituted by a hydroxy, C1-4 alkoxy or NR3R4 group), and r represents an integer from 0 to 3], -O(CH2)qCOR9 (where q and R9 are as defined above), or -O(CH2)tR13 twhere R13 represents hydroxy, NR3R4, NR11R12 or a C1-4 alkoxy group optionally substituted by hydroxy, C1-4 alkoxy or NR3R4, and t is an integer 2 or 3]; and R1 and R2 each represents 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;
and physiologically acceptable salts and solvates thereof, which comprises:
(1a) for the preparation of a compound of formula (I) in which R1 is a hydrogen atom, alkylating an amine of general formula (II) (II) (wherein R14 is a hydrogen atom or a protecting group and R15 is a hydrogen atom) with an alkylating agent of formula (III) (III) (wherein L is a leaving group and R2, X, Y and Ar are as defined above) followed, if necessary, by removal of any protecting group present; or (1b) for the preparation of a compound of formula (I) in which R1 is a hydrogen atom, alkylating an amine of general formula (II) as defined above except that R15 is a hydrogen atom or a group convertible thereto under the reaction conditlons, with a compound of general formula (IV) R2COXCH2OCH2YAr (IV) (wherein R2, X, Y and Ar are as defined above) in the presence of a reducing agent followed, if necessary, by removal of any protecting groups present;
or (2) reducing an intermediate of general formula (VI) (VI) wherein X1 is -CH(OH)- or a group convertible thereto by reduction, X2 is -CH2NR14 - (wherein R14 is a hydrogen atom or a protecting group) or a group convertible thereto by reduction;
X3 is -CR1R2X- or a group convertible thereto by reduction (wherein R1 and R2 are as defined above);
X4 is -NH2 or a group convertible thereto by reduction;
and Y and Ar are as defined above or are groups convertible thereto by reduction; at least one of X1, X2, X3 and X4 representing a reducible group and/or Y representing a reducible group and/or Ar containing a reducible group, followed, if necessary, by removal of any protecting group present; or (3) deprotecting a protected intermediate of general formula (VII) (VII) wherein R1, R2, X, Y and Ar are as defined above R14 and R16 each represent a hydrogen atom or a protecting group and/or any hydroxy and/or amino substituent in the group Ar is protected, with the proviso that at least one of R14 and R16 represents a protecting group or Ar contains a protecting group;
or (4) for the preparation of a compound of formula (I) in which Ar represents a phenyl group substituted by the group -(CH2)rCOR9 where r is as defined above and R9 is hydroxy, hydrolysing the corresponding compound of formula (I) in which R9 represents C1-4 alkoxy;
and if desired, converting the resulting compound of general formula (I) or a salt thereof into a physiologically acceptable salt of solvate thereof.

2. A process as claimed in claim 1 for the production of compounds in which the sum total of carbon atoms in the chains -X- and -Y- is 4, 5, 6 or 7,

3. A process as claimed in claim 1 or 2 for the production of compounds in which X represents -(CH2)3-or -(CH2)4-, and Y represents -CH2-, -(CH2)2- or -(CH2)3-.

4. A process as claimed in claim 1 or 2 for the production of compounds in which R1 and R2 are both hydrogen atoms or R1 is a hydrogen atom and R2 is a C1-3 alkyl group.

5. A process as claimed in claim 1 or 2 for the production of compounds in which Ar represents a phenyl group substituted by -(CH2)qR [where R represents C1-3 alkoxy, diC1-4alkylamino, morpholino, piperidino, piperazino, N-methylpiperazino, -NHCOR6 (where R6 is C1-4 alkyl), and q is 1 or 2], -(CH2)rR7 (where R7 represents -NR5SO2R8 (where R5 represents hydrogen or methyl, and R8 represents C1-4 alkyl -NHCOCH2N(R5)2 (where both groups R5 represent C1-4 alkyl), -COR9 (where R9 represents C1-4 alkoxy, amino diC1-4alkylamino, morpholino, piperidino, piperazino or N-methylpiperazino), -NR11R12 (where one or both of R11 and R12 represents a C2-4 alkyl group substituted by a hydroxy or diC1-4 alkylamino group and the other represents a hydrogen atom), and r is zero or 1], -OCH2COR9 (where R9 is diC1-4alkylamlno), or -O(CH2)2R13 (where R13 is diC1-4 alkylamino).

6. A process as claimed in claim 1 for the production of compounds of the general formula (1a):

(1a) wherein X represents a C3-4 alkylene chain and Y represents a C1-3 alkylene chain, with the proviso that the total number of carbon atoms in X and Y is 5 or 6; and Ar represents a phenyl group substituted by a group selected from C1-4 alkoxymethyl morpholinomethyl, diC1-4alkylaminoC1-2alkyl, -CH2NHCOR6 (where R6 is C1-4 alkyl), NR5SO2R8 (where R5 is hydrogen or methyl, and R8 is C1-4 alkyl), -NHCOCH2N(R5)2 (where both groups R5 represent C1-4 alkyl) -COR9 (where R9 is hydroxy, C1-4 alkoxy, amino diC1-4alkylamino, or morpholino), -CH2COR9 (where R9 is amino or diC1-4 alkylamino), -NR11R12 (where R11 and R12 both represent hydroxy,hydroxy C2-4 alkyl), diC1-4alkylaminoethylamino, -OCH2COR9 (where R9 is diC1-4 alkylamino); or -O(CH2)2R13 where R13 is diC1-4alkylamino; and physiologically acceptable salts and solvates thereof.

7. A process as claimed in claim 6 for the production of compounds in which Ar represents a phenyl group substituted by a group selected from -CH2NHCOR6 (where R6 is methyl) -NHSO2R8 (where R8 is methyl), -COR9 (where R9 is hydroxy, ethoxy, amino or morpholino, or -CH2COR9 (where R9 is amino or dimethylamino).

8. A process as claimed in claim 1 for the production of a compound selected from:
4-[3-[[6-[[2-(4-amino-3,5-dichlorophenyl)-2-hydroxy-ethyl]amino]hexyl]oxy]propyl]benzamide;
ethyl:4-[3-[[6-[[(4-amino-3,5-dichlorophenyl)-2-hydroxy-ethyl]amino]hexyl]oxy]propyl]benzoate;
N-[[3-[3-[[6-[[2-(4-amino-3,5-dichlorophenyl)-2-hydroxy-ethyl]amino]hexyl]oxy]propyl]phenyl]methyl]acetamide;

4-[4-[5-[[2-(4-amino-3,5-dichlorophenyl)-2-hydroxyethyl]-amino]pentyloxy]butyl]-N,N-dimethylbenzene-acetamide;
4-[3-[[6-[[2-(4-amino-3,5-dichlorophenyl)-2-hydroxyethyl]-amino]hexyl]oxy]propyl]benzoic acid;
4-[4-[3-[[6-[[2-(4-amino-3,5-dichlorophenyl)-2-hydroxy-ethyl]amino]hexyl]oxy]propyl]benzoyl]morpholine;
N-[4-[3-[[6-[[2-(4-amino-3,5-dichlorophenyl)-2-hydroxy-ethyl]amino]hexyl]oxy]ethyl]phenyl]methanesulphonamide;
4-[3-[[6-[[2-(4-amino-3,5-dichlorophenyl)-2-hydroxy-ethyl]amino]hexyl]oxy]propyl]benzeneacetamide;
and physiologically acceptable salts and solvates thereof.

9. Compound of the general formula (I) (I) wherein X represents a bond, or a C1-6 alkylene, C2-6 alkenylene or C2-6 alkynylene chain and Y represents a bond, or a C1-4 alkylene, C2-4 alkenylene or C2-4 alkynylene chain with the proviso that the sum total of carbon atoms in X and Y is not more than 8;
Ar represents a phenyl group substituted by one or more substituents selected from nitro, -(CH2)qR [where R is C1-3 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 or -NR3R4 group), and q represents an integer from 1 to 3], -(CH2)rR7 [where R7 represents -NR5SO2R8 (where R8 repre5ents a C1-4 alkyl, phenyl or NR3R4 group), -NR5COCH2N(R5)2 (where each of the groups R5 represents a hydrogen atom or a C1-4 alkyl group), -COR9 represents hydroxy, C1-4 alkoxy or NR R4), -SR10 (where R10 is a hydrogen atom, or a C1-4 alkyl group optionally substituted by hydroxy, C1-4 alkoxy or NR3R4), -SOR10, -SO2R10, -CN, or -NR11R12 (where R11 and R12 represent a hydrogen atom or a C1-4 alkyl group, at least one of which is C2-4 alkyl substituted by a hydroxy, C1-4 alkoxy or NR3R4 group), and r represents an integer from 0 to 3], -O(CH2)qCOR9 (where q and R9 are as defined above), or -O(CH2)tR13 [where R13 represents hydroxy, NR3R4, NR11R12 or a C1-4 alkoxy group optionally substituted by hydroxy, C1-4 alkoxy or NR3R4, and t is an integer 2 or 3]; and R1 and R2 each represents 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;
and physiologically acceptable salts and solvates thereof.

10. Compounds as claimed in claim 9 in which the sum total of carbon atoms in the chains -X- and -Y- is 4, 5, 6 or 7.

11. Compounds as claimed in claim 9 in which X
represents -(CH2)3- or -(CH2)4-, and Y represents -CH2-, -(CH2)2- or -(CH2)3-.

12. Compounds as claimed in any of claims 9, 10 or 11 in which R1 and R2 are both hydrogen atoms or R1 is a hydrogen atom and R2 is a C1-3 alkyl group.

13. Compounds as claimed in any cf claims 9, 10 or 11 in which Ar represents a phenyl group substituted by -(CH2)qR [where R represents C1-3 alkoxy, diC1-4alkyl-amino, morpholino, piperidino, piperazino, N-methyl-piperazino, -NHCOR6 (where R6 is C1-4 alkyl), and q is 1 or 2], -(CH2)rR7 [where R7 represents -NR5SO2R8 (where R5 represents hydrogen or methyl, and R8 represents C1-4 alkyl), -NHCOCH2N(R5)2 (where both groups R5 represent C1-4 alkyl), -COR9 (where R9 represents C1-4 alkoxy, amino diC1-4-alkylamino), morpholino, peperidino, piperazino or N-methyl-piperazino), -NR11R12 (where one or both of R11 and R12 presents a C2-4 alkyl group substituted by a hydroxy or diC1-4alkylamino group and the other represents a hydrogen atom), and r is zero or 1], -OCH2COR9 (where R9 is diC1-4alkylamino), or -O(CH2)2R13 (where R13 is diC1-4-alkylamino).

14. Compounds of the general formula (1a) (1a) wherein X represents a C3-4 alkylene chain and Y represents a C1-3 alkylene chain, with the proviso that the total number of carbon atoms in X and Y is 5 or 6; and Ar represents a phenyl group substituted by a group selected from C1-4 alkoxymethyl, morpholinomethyl, diC1-4-alkylaminoC1-2alkyl, -CH2NHCOR6 (where R6 is C1-4 alkyl), NR5SO2R8 (where R5 is hydrogen or methyl, and R8 is C1-4 alkyl), NHCOCH2N(R5)2 (where both groups R5 represent C1-4 alkyl), -COR9 (where R9 is hydroxy, C1-4 alkoxy, amino, diC1-4alkylamino, or morpholino), -CH2COR9 (where R9 is amino or diC1-4alkylamino), -NR11R12 (where R11 and R12 both represent hydroxy C2-4 alkyl), diC1-4alkylaminoethylamino, -OCH2COR (where R is diCl 4alkylamino); or -O(CH2)2R13 where R13 is diC1-4alkylamino; and physiologically acceptable salts and solvtes thereof.

15. Compounds as claimed in claim 14 in which Ar represents a phenyl group substituted by a group selected from -CH2NHCOR6 (where R6 is methyl) -NHSO2R8 (where R8 is methyl), -COR9 (where R9 is hydroxy, ethoxy, amino or morpholino),or -CH2COR9 (where R9 is amino or dimethylamino).

16. The compounds:
4-[3-[[6-[[2-(4-amino-3,5-dichlorophenyl)-2-hydroxy-ethyl]amino]hexyl]oxy]propyl]benzamide;
ethyl 4-[3-[[6-[[(4-amino-3,5-dichlorophenyl)-2-hydroxy-ethyl]amino]hexyl]oxy]propyl]benzoate;
N-[[3-[3-[[6-[[2-(4-amino-3,5-dichlorophenyl)-2-hydroxy-ethyl]amino]hexyl]oxy]propyl]phenyl]methyl]acetamide;
4-[4-[5-[[2-(4-amino-3,5-dichlorophenyl)-2-hydroxyethyl]-amino]pentyloxy]butyl]-N,N-dimethylbenzene-acetamide;
4-[3-[[6-[[2-(4-amino-3,5-dichlorophenyl)-2-hydroxyethyl]-amino]hexyl]oxy]propyl]benzoic acid;
4-[4-[3-[[6-[[2-(4-amino-3,5-dichlorophenyl)-2-hydroxy-ethyl]amino]hexyl]oxy]propyl]benzoyl]morpholine;
N-[4-[3-[[6-[[2-(4-amino-3,5-dichlorophenyl)-2-hydroxy-ethyl]amino]hexyl]oxy]ethyl]phenyl]methanesulphonamide;
4-[3-[[6 [[2-(4-amino-3,5-dichlorophenyl)-2-hydroxy-ethyl]amino]hexyl]oxy]propyl]benzeneacetamide;
and phsiologically acceptable salts and solvates thereof.

17. A pharamceutical composition comprising at least one compound of general formula (I) as defined in any of claims 9, 10 or 11 or a physiologically acceptable salt or solvate thereof, together with a physiologically acceptable carrier or excipient.