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
:
-- 7 --
~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
~:
.
.
15 -
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.
,~ ~ - ~ . '. : :
: ' ; '
.
:
3S
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)
R 2
(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
:
:
:
-- 19 --
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.
: ~ :
: ~ :::::
:
::
,
- 22 -
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]-
:
. ~ -
.
- 24 -
~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.
. ~
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335
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,
:`
::
- 33 -
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.
'
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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
1-
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.
: ~
- 37 -
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.
.
- ` ` ~: ; , . :
::
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` ~` - 38 -
335
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.
~
: ~ :
:
. ,: . : ~ : ,
,.
,
' ~
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- 39 -
-
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.
'
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