- ~ZS~6~i
PHENETIIANOLAMINE COMPOUNDS
1 This invention relates to phenethanolamine compounds
having a stimulant action at ~2-adrenoreceptors, to
processes for their preparation, -to pharmaceutical
compositions containing them and to their use in medicine.
Thus the present invention provides cornpounds oF the
general formula (I)
HOCH~2
~ _~ Rl
H0~ CI-ICH2NHIXCH20CH2YAr (I)
~ -~ OH R
wherein
Ar represents a phenyl group optionally substituted by one
or more substltuents selected from halogen atoms, or
Cl_6alkyl~ ~(CH2)qR~ [where R is hydroxy, C1_6 alkoxy,
-NR3R4 (where R3 and R4 each represents a hydrogen atom,
or a Cl_4 alkyl group, or -NR3R'I forms a saturated
heterocyclic amino group which has 5-7 ring members and
optionally contains in the ring one or more atoms selected
from -û- or -5- or a group -Nll- or -N(CH3)-), -NR5CoR6
(where R5 represents a hydrogen atom or a Cl-,~ alkyl
group, and R6 represents a hydrogen atom or a Cl_4 alkyl,
Cl_4 alkoxy,
phenyl or -NR3R4 group), -NR5502R7 (where R7 represents a
Cl_4 alkyl, phenyl or -NR3R4 group), -CoR3 (where R8
represents hydroxy, Cl_4 alkoxy or -NR3R4), -SR9 (where R9
is a hydrogen atom, or a Cl_4 alkyl or phenyl group),
-SûR9, 502R9, or -CN, and q represents an integer From 0
to 3], ~0(CH2)rR1 [where Rl represents a hydroxy or
Cl_4 alkoxy group and r is an integer 2 or 3], or -N02
S~6~
1 groups or an all<ylenedioxy group of forrnula -O(CH2)pn-,
where p represents an integer 1 or 2;
Rl and R2 each represents a hydrogen atom or a Cl-3 alkyl
group with the proviso that the sum total of carbon atoms
in Rl and R2 is not more than 4;
X represents a Cl~7 alkylene, C2-7 all<enylene or C2-7
alkynylene chain and
Y represents a bond, or a Cl_6 alkylene, C2_6 all<enylene
or C2_6 alkynylene chain with the provisos that the sum
total of carbon atoms in X and Y is 2-10 and when X
represents Cl_7 alkylene, Y represents C2-6 alkenylene or
C2-6 alkynylene; and physiologically acceptable salts and
solvates (e.g. hydrates) thereof.
It will be appreciated that the compounds of general
formula (I) possess one or two asymmetric carbon atoms,
namely the carbon atom of the -ICH- group and, when Rl and
0~1
R2 are different groups, the carbon atom to which these
are attached.
The compounds according to the invention thus include
all enantiomers, diastereoisomers and mixtures thereof,
including racemates. Compounds in which the carbon atom
in the -Cl-l- group is in the R configuration
0~1
are preferred.
In the definition of general formula (I), the term
alkenylene includes both cis and trans structures.
In the general formula (I), the chain X may for
example contain 2 to 7 carbon atoms and may be for example
-(CH2)2-~ -(Cl-l2)3-~ -(Cll2)~ (CH2)5-' CH2C~
(CH2)2cH=cll-~ -(Cl-l2)2C-C-, -C~l=CHCH2-, -CH=CH(CH2)2_ or
-CH2C-CCH2-. The chain Y may be for example -CH2-,
-(CH2)2-~ -(Cll2)3-~ -(CH2)4-~ -(CH2)s-~ -(Cli2)6-, -CH=CH-,
-C_C-, -CH2CII=CH-, or -Cll2C--C-.
In general, the total number of carbon atoms in the
chains X and Y is preferably ~L to 10 inclusive and may be
66~;i
1 for example 5, 6, 7~or ~. Compounds wherein the surn total
of carbon atoms in the chains X and Y is 5, 6 or 7 are
particularly preferred.
In the compounds of formula (I) Rl and R2, for
example, may each be methyl, ethyl, propyl or isopropyl
groups except that if one Of Rl and R2 is a propyl or
isopropyl group, the other is a hydrogen atom or a methyl
group. Thus for example Rl may be a hydrogen atom or a
methyl, ethyl or propyl group. R2, for example, may be a
hydrogen atom or a methyl group.
Rl and R2 are each preferably a hydrogen atom or a methyl
group.
A preferred group of compounds is that wherein Rl and
R2 are both hydrogen atoms, or Rl is a hydrogen atom and
R2 is a Cl_3 alkyl group, particularly a methyl group, or
Rl is a methyl group and R2 is a methyl group.
~hen -NR3R4 in compounds of formula (I) represents a
saturated heterocyclic amino group, this may have 5, 6 or
7 ring members and optionally contain in the ring a
heteroatom selected from -0-, or -S-, or a group -Nl-l- or
-N(CH3)-~ Examples of sucll -NR3RIi groups are pyrrolidino,
piperidino, hexamethylenimino, piperazino,
N-methylpiperazino, rnorpholino, homornorpholino or
thiamorpholino.
The group Ar may be for example a phenyl group.
Alternatively Ar may be a substituted phenyl group and may
for example contain one 7 two or three substituents, which
may be present at the 2-, 3-, 4-, 5- or 6-positions on the
phenyl rinq.
Examples of the substituents which may be present on
the phenyl group represented by Ar include chlorine,`
bromine, iodine, fluorine, methyl, ethyl, ~(CH2)qR
[where R is hydroxy, methoxy, ethoxy, amino, methylamino,
ethylamino, dimethylamino, diethylamillo, morpllolino,
piperidino, piperazino, N-methylpiperazino, -NHCHû, NHCOR6
(where R6 is Cl_4 alkyl, e.g. methyl, ethyl, isopropyl or
~1;25~
1 n-butyl, Cl_" all<oxy, e.g. methoxy, ethoxy, isopropoxy, or
n-butoxy, phenyl, amino or N,N-dimethylamino),
-N(CH3)COCH3, -NR5502R7, where R5 represents a hydrogen
atom or a methyl group and R7 represents methyl, ethyl,
isopropyl, n-butyl or phenyl, -NHS02NH2, -N11502N(CH3)2,
-COOH, -COOCH3, -CONH2, -CON(CH3)2, -CONR3R4 (where NR3R4
is piperidinot morpholino, pipera~ino or N-methyl-
piperazino) -SR9 (where R9 is methyl, ethyl or phenyl)
-SOCH3, -SO2CH3, or CN and q is zero, l, 2 or 3], -N02,
2 2 ~ O(CH2)30H, -O(CH2)20CH3, or -O(CH2)20CH CH .
Particular examples of a monosubstituted phenyl group
represented by Ar include phenyl substituted by the group
~(CH2)qR where R is Cl_6alkoxy and q is an integer l, 2
or 3, or R is -NR3R~, -Nsso2R7~ -CoR3, -SR9 or
O(CH2)rRl [where q, R3, R4, R5, R7, R8, R9, r and RlO
are as defined for formula (I)]. In particular, the group
Ar may be phenyl substituted by -OH, -CH20i1, -(CH2)20H,
(C'1 ) OH CH OC113, -NH(C~3), -N(C~-13)2, N~1C 2 3
morpholino, pyrrolldino, piperidino, -CH2N(CH3)2,
-CH2-piperidino, -N11502CH3, -NHS02(CH2)2CH3,
NHS02(CH2)3C1-13~ -N~1502-ph~nyl, -NHSû2N(CH3)2, -C02H,
-C02C~13~ -C02C~`12C~13~ -Co2(c~l2)2c~l3~ -CONH2, -CON(C~13)2,
-SCH3, -SC112C1-13, -S-phenyl, or -O(CH2)2ûC1-13.
Particular examples of a trisubstituted phenyl group
represented by Ar include phenyl substituted by an amino
and two methy] groups, (for example 3,5-dimethyl-4-amino-
phenyl), an amino group and two chlorine atoms, (for
example 3,5-dichloro-4-aminophenyl), or three methoxy
groups, (for example 3,4,5-trimethoxyphenyl). Particular
examples of a disubstituted phenyl group represented by Ar
include phenyl substituted by two hydroxyl groups,~(for
example 3,5-dihydroxyphenyl,) or a hydroxyl and methoxy
group, (for example 3-methoxy-4-hydroxyphenyl,).
In general, when the substituent on the phenyl group
represented by Ar is one of the groups ~(CH2)qR~ where R
is -NR3R4, -NR5CoR6, -NR5502R7, -COR8, -SR9, -SOR9, -S02R9
3LZ5~6
l or -CN and q is an integer l, 2 or 3, any additional
substituent present on the phenyl group is desirably one
which is different from those substituents.
In one aspect the invention provides compounds of
formula (I) in which Ar represents a phenyl group
optionally substituted by one or two substituents selected
from halogen atoms7 Cl_3 alkyl or Cl_3 all<oxy groups, or
by an all<ylenedioxy group of formula -O(CI-l2)pO- where p
is 1 or 2, and X, y, Rl and R2 are as defined for formula
(I).
Particularly important compounds of the invention are:-
- (Z)-N-[4-[3-[[6-[[2-Hydroxy-2-[4-hydroxy-3-(hydroxy-
methyl)phenyl]ethyl]amino]hexyl]oxy]-l-propenyl]phenyl]
methanesulphonamide;
4-Hydroxy-al-[[[6-[[3-[4-[(l-methylpiperazine-4-yl)methyl]
phenyl]-2-propynyl]oxy]hexyl]amino]methyl-1,3-benzenedi-
methanol;
N-[4-[3-[[6-[[2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phen-
yl]ethyl]amino]hexyl]oxy]-l-propynyl]phenyl]acetamide;
4-Hydroxy-al-[[[6-[4-[(4-hydroxy-3-methoxyphenyl)-3E-but-
enyl]oxy]hexyl]amino]methyl]-1,3-benzenedimethanol;
(_)-N-[4-[3[[6-[[2-llydroxy-2-[4-hydroxy-3~(hydroxymethyl)
phenyl]ethyl]amino]hexyl]oxy]-l-propenyl]phenyl]acetamide;
4-Hydroxy-al-[[[6-(4-phenylbutoxy)-3,Z-hexerlyl]amino]
methyl]-1,3-benzenedimethanol;
4-Hydroxy-al-[[[l-methyl-6-[(4-phenyl-3,Z-butenyl)oxy]
hexyl]amino]methyl]-1,3-benzenedimethanol;
and the physiologically acceptable salts and solvates
thereof.
Suitable physiologically acceptahle salts of the
compounds of general formula (I) include acid addition
salts derived from inorganic and organic acids, such as
hydrochlorides, hydrobromides, sulphates, phosphates,
rnaleates, tartrates, citrates, benzoates, 4-methoxy-
benzoates, 2- or 4-hydroxybenzoates, 4-chlorobenzoates,
p-toluenesulphonates, methanesulphonates, ascorbates,
salicylates, acetates, fumarates, succinates, lactates,
~L~2S5~6~
1 glutarates, gluconates, tricarballylates, hydroxy-
naphthalenecarboxylates e.g. l-hydroxy- or 3-hydroxy-2-
naphthalenecarboxylates, or oleates. The compounds may
also form salts with suitable bases. Examples of such
salts are all<ali metal (e.g. sodium and potassium), and
alkaline earth metal (e.g. calcium or rnagnesiurn) salts.
The compounds according to the invention have a
selective stimulant action at ~2-adrenoreceptors, which
furthermore ia of a particularly advantageous profile.
The stimulant action was demonstrated in the isolated
trachea of the guinea-pig, where compounds were ahown to
cause relaxation of PGF2a-induced contractions.
Compounds according to the invention have shown a
particularly long duration of action in this test.
The cornpounds according to the invention may be used
in the treatment of diseases associated with reversible
airways obstruction such as asthma and chronic
bronchitis.
The compounds according to the invention may also be
used For the treatment of premature labour, depression and
congestive heart failure, and are also indicated as useful
for the treatment of inflammatory and allergic sl<in
diseasea, glaucoma, ancl in the treatment of conditions in
which there is an advantage in lowering gaatric acidity,
particularly in gastric and peptic ulceration.
The invention accordingly further provides compounds
of formula (I) and their physiologically acceptable salts
and solvates for use in the therapy or prophylaxis of
diseases associated with reversible airways obstruction
in -human or animal subjects.
The compounds according to the invention may be
formulated for administration in any convenient way. The
invention therefore includes within its scope
pharmaceutical compositions comprising at least one
compound of formula (I) or a physiologically acceptable
salt or aolvate thereof formulated for use in human or
~2~
1 veterinary medicine. Such compositions may be presented
for use with physiologically acceptable carriers or
excipients, optionally with supplementary medicinal
agents.
Ihe compounds may be formulated in a form suitable
for administration by inhalation or insufflation, or for
oral, buccal, parenteral, topical ~lncluding nasal) or
rectal administration. Administration by ir,halation or
insufflation is preferred.
For administration by inhalation the compounds
according to the invention are conveniently delivered in
the form of an aerosol spray presentation frorn pressurised
packs9 with the use of a suitable propellant, such as
dichlorodifluoromethane, trichlorofluoromethane1 dichloro-
tetrafluoroethane, carbon dioxide or other suitable gas,
or from a nebuliser. In the case of a pressurised aerosol
the dosage unit may be determined by providing a valve to
deliver a metered amount.
~lternatively, for sdministration by inhalation or
insufflation, the compounds according to the invention may
take the forM of a dry powder composition, for example a
powder mix of the compouncl and a suitable powder base
such as lactose or starch. The powder composition may be
presented in unit dosage form in for example capsules or
cartridges of e.g. gelatin, or blister pacl<s from which
the powder may be administered with the aid of an inhaler
or insufflator.
For buccal administration the composition may take
the form of tablets, drops or lozenges formulated in
conventional manner.
The compounds of the invention may be forrnulated for
parenteral administration. Formulations for injections
may be presented in unit dosage form in ampoules, or in
multi-dose containers with an added preservative. The
compositions may take such forms as suspensions, solutions
or emulsions in oily or aqueous vehicles, and may contain
~Z~Sf~6~
1 formulatory agents such as suspending, stabilising and/or
dispersing agents. Alternatively, the active ingredient
may be in powder form for reconstitution with a suitable
vehicle, e.g. sterile pyrogen-free water, before use.
For topical administration the pharrnaceutical
composition may take the form Or ointments, lotions or
creams formulated in a conventional manner, with for
example an aqueous or oily base, generally with the
addition of suitable thickening agents and/or solvents.
For nasal application, the composition may take the form
of a spray, formulated for example as an aqueous solution
or suspension or as an aerosol with the use of a suitable
propellant.
The compounds of the invention may also be formulated
in rectal compositions such as suppositories or retention
enemas, e.g. containing conventional suppository bases
such as cocoa butter or other glyceride.
Where pharmaceutical compositions are described above
for oral, buccal, rectal or topical aclministration, these
may be presented in a conventional manner associated with
controlled release Forms.
A proposed daily dosage of active compound for the
treatment of man is n.0005mg to lOOmg, which may be
conveniently administered in one or two doses~ The
precise dose employed will of course depend on the age and
condition of the patient and on the route of
administration. Thus a suitable dose for administration
hy inhalation is û.0005mg to lOmg, for oral administration
is 0.02mg to lOOmg, and for parenteral administration is
O.OOlmg to 2mg.
The compounds according to the invention may be
prepared by a number of processes, as described in the
following wherein X, Y, Ar, Rl and R2 are as defined for
general formula (I) unless otherwise specified. It will
be appreciated that certain of the reactions described
below are capable of affecting other groups in the
` - ~ZSS66~;
l starting mflterial which are desired in the end product.
Care must therefore be taken in accordance with
conventionfll practice, to use reagents and/or reaction
conditions under which such groups remain substantially
inert. In the general processes described below the final
step in the reaction may be the removal of a protecting
group. Suitable protecting groups and their removal are
described in general process (3) below.
According to one general process (l), a compound of
gsneral formula (I) may be obtained by reaction of a
compound of general formula (II):
R120C~2
13 //
R 0~ -Z (II)
(wherein Z reoresents a group -CH-/CH2 or -ICIlCH2L, R12 and
0 ~1
R13 ls eflch a hydrogen atom or a protecting group, and L
represents a leaving group, for example a halogen atom
such as chlorine, bromine or iodine, or a hydrocarbyl-
sulphonyloxy group such as methanesulphonyloxy or
p-toluenesulphonyloxy) with an amine of general formula
(III)
IR 1
H2NICXC~l20C~l2YAr (III)
R2
followed by removal of any protecting groups where
present, as described hereinafter.
The reaction may be effected in the presence of a
suitable solvent for example an alcohol, such as ethanol,
a halogenated hydrocarbon e.g. chloroform, a substituted
amide e.g. dimethylformamide or an ether such as
- \ o
\
5~66
1 tetrahydrofuran or dioxan at a temperature from ambient to
the reflux, optionally in the presence of a base such as
an organic amine e.g. diisopropylethylamine or an
inorganic base such as sodium carbonate.
In another general process (2), a compound of general
formula (I) may be prepared by alkylation. Conventional
alkylation procedures may be used.
Thus, for example, in one process (a), a compound of
general formula (I) in which Rl is a hydrogen atom may be
prepared by alkylation of an amine of general formula
(IV)
Rl20CH2
o _~
R l 30~ CI-IC5,-1 2NR l 4R l 5 ( IV )
=o OH
(wherein Rl2, Rl3 and Rl4 is each a hydrogen atom or a
protecting group and R15 is a hydrogen atom) followed by
removal of any protecting group where present.
The alkylation (a) mr~y be effected using an
alkylating agent of general formula (V):
LCII-IXC~l20CIl2YAr (V)
R2
(wherein L is as previously defined).
The alkylation is preferably effected in the presence
of H suitable acid scavenger, for example, inorganic hases
such as sodium or potassium carbonate, organic bases such
as triethylasnine, diisopropylethylamine or pyridine, or
all<ylene oxides such as ethylene oxide or propylene oxide.
The reaction is conveniently effected in a solvent such as
acetonitrile or an ether e.g. tetrahydrofuran or dioxan, a
ketone e.g. butanone or methyl isobutyl ketone, a
substituted amide e.g. dimethylformamide or a chlorinated
\
~S~6~6
1 hydrocarbon e.g. chloroform at a temperature between
ambient and the reflux temperature of the solvent.
According to another example (b) of an all<ylation
process, a compound of general formula (I) in which Rl
represents a hydrogen atom may be prepared by alkylation
of an amine of general formula (IV) with a compound of
general formula (VI):
R2COXCH20CH2YAr (VI)
in the presence of a reducing agent, followed when
necessary by removal of any protecting groups.
Suitable reducing agents include a hydride such as
a metal hydride such as sodium borohydride, sodium
cyanoborohydride or lithium alulninium hydride. Suitable
solvents for the reaction with these reducing agents will
depend on the particular hydride used, but will include
alcohols such as methanol or ethanol, or ethers such as
diethyl ether or tert-butyl methyl ether, or
tetrahydrofuran.
When a compound of formula (IV) where Rl4 and Rl5 are
each hydrogen atorns is used~ the intermediate imine of
formula (VII) may be formed:
R12oc\2
\ _ / 1 l2N=CIXCil2ûCil2yAr (VII)
(wherein Rl2 and R13 are as defined for formula (II)).
Reduction of the imine using the conditions described
above, followed, where necessary, by removal of any
protecting groups, gives a compound of general formula
(I).
~2~ 6
l In another general process (3), a compound of general
formula (I) may be obtained by deprotection of a protected
intermediate of general formula (VIII):
R120CH~2
~ R1
Rl30~ CHCH 2NRl4~XCII20CH2`~Ar (VIII)
O _- OH R
(wherein R12, Rl3 and Rl4 are as previously defined except
that at least one of Rl2, Rl3 and Rl4 is a protecting
group).
The protecting group may be any conventional
protecting group, for example as described in "Protective
Groups in Organic Chemistry", Ed. J.F.W. McOmie ~Plenum
Press, 1973). Thus R12 and/or R13 for example may each be
tetrahydropyranyl, and R14 may be an acyl group such as
trichloroacetyl or trifluoroacetyl.
The deprotection to yield a compound of general
formula (I) may be effected using conventional techniques.
Thus for example, when R12 and/or R13 is a tetrahydro-
pyranyl this may be cleavecl by hydrolysis under acidicconditions. Acyl groups represented by Rl4 mfly be removed
by hydrolysis, for example with a base such as sodium
hydroxide, or a group such as trichloroacetyl may be
removed by reduction with, for example, zinc and acetic
acid.
In a particular embodiment of the deprotection
process (3), Rl20CI-I2- and Rl30- may together represent a
protecting group R16 OCH2- (wherein R16 and Rl7, which
R ~ O-
may be the same or different, each represents a hydrogenatom or an alkyl or aryl group). The protecting group may
be cleaved using for example hydrochloric acid in a
solvent such as water or an alcohol such as ethanol at
normal or elevated temperatures.
~z5S6~,
1 In another general process (4), a compound of general
formula (I) may be prepared by reduction. Thus, for
example, a compound of general formula (I) may be prepared
by reducing an intermediate of general formula (IX):
X4
O--.
Rl30-o /~7--Xl-X2-X3~CH20CH2Y~Ar (IX)
[wherein Rl3 is 8S defined for general formula (II) and at
lesst one of Xl, X2, X3, and X4 represents a reducible
group and the other(s) take the appropriate meaning as
follows, which is xl is -CH(OH)-, x2 is -CH2NRl4, X3 is
-CRlR2X, X4 is -CH20Rl2 and Y and Ar are as defined for
formula (I)] followed where necessary by removal of any
protecting groups.
Suitable reducible groups include those wherein xl is
a group -C=O, x2 is an imine (-CH=N-) group or a group
-CONH-, X3 is a group -COX-, or -X2-X3- is a group
-CH2N-CR2X, and X4 is a group -Co2Rl3 (wherein Rl3
represents a hydrogen atom, or an all<yl, aryl or aralkyl
group) or -CHO.
The rer~uction may be effected using reducing agents
conveniently employed for the reduction of carboxylic
acids, aldehydes, esters, I<etones, imines, and amides.
Thus, for example, when xl in general formula (IX)
represents a -C=O group this may be reduced to a -CH(OH)-
~5 group using a hydride such as a metal hydride for example
lithium aluminium hydride, sodium bis(2-methoxyethoxy)
aluminium hydride,
sodium borohydride or aluminium hydride. The reaction may
be effected in a solvent, where appropriflte an alcohol
e.g. methanol or ethanol, or an ether such as
tetrahydrofuran, or a halogenated hydrocarbon such as
dichloromethane.
\~
~ss6~
1 When x2 in general forrnula (IX) represents the group
-C~-l=N-, or -X2-X3- represents -CH2N=CR2X this may be
reduced to a -CH2NH- or -Cl-l2NHCIIR2X- group using a
reducing agent and conditions as just described for the
S reduction of xl when this represents a -C=O group.
When x2 or X3 in general formula (IX) represents a
-CONH- or -COX- group this may be reduced to a group
-CH2NH- or -CH2X- respectively using a hydride such as
a complex metal hydride for example lithium aluminium
hydride or sodium bis(2-methoxyethoxy)aluminium hydride in
a solvent such as an ether, e.g. tetrahydrofuran or
diethyl ether.
When X4 represents a group -Co2Rl3 or -Cl-lO this may
be reduced to a group -CH20H using a hydride such as
a complex metal hydride for example lithium aluminium
hydride, sodium bis(2-methoxyethoxy)aluminiurn hydride,
sodium borohydride, diisobutylaluminium hydride or lithium
triethylborohydride in a solvent such as an ether, e.g.
tetrahydrofuran or diethyl ether, or a halogenated
hydrocarbon 0.9. dichloromethane at a temperature from
0C to the reflux.
In the reduction processes just described, the groups
X4 and Rl30 in a compound of formula (IX) may together
conveniently represent a group R ~ Cll2-. After the
Rl
reduction is complete, cleavage of this group using e.g. a
dilute acid in a solvent such as water at normal
temperature yielcls a compound of formula (I).
In another process, a compound of formula (I) in
which Y is a C2_6 alkynylene chain irl which the acetylene
group is adjacent to the group Ar may be prepared by
reaction of an intermediate of formula (X)
~I n c \ 2~
H0 -o\ /~ ICllCll2NRl4¢XCH20CH2YlC_CH (X)
~_o OH R2
(where yl is a bond or a Cl-4 alkylene group and
preferably or-e of Rl and/or R2 is a hydrogen atom) with an
aryl halide Ar llal (where llal i5 a halogen atom, for
example an iodine atom) followed where necessary by
removal of any protecting group. The reaction is
performed in the presence of a metal catalyst (e.g.
copper) and ~n organometallic reagent such as
bis(triphenylphosphino) palladium (Il) chloride and a base
such as an organic amine e.g. diethylamine diisopropyl-
ethylamine.
Intermediates of formula (X) may be prepared by
reaction of a bromol<etone of formula (XI)
~IOC~2
H0~ COCII2Br (XI)
wlth an amine Rl4HNC(Rl~(R2)XCH20CH2YlC-CI-I in the presence
oF a base such as sodium carbonate and a solvent such as
ethyl acetate, followed by reduction using a reducing
agent such as sodium borohydride in a solvent such as
ethanol. The intermediate amines used in this process may
be prepared by reaction of a bromide
HC_CYlCH20CH2XC(Rl)(R2)Br with an amine Rl4NH2. The
bromides may be prepared by all<ylation of an appropriate
alcohol HC-CYlCH20H with a disubstituted alkane
BrCH2XC(Rl)(R2)Br in the presence of a base such as sodium
hydroxide and a phase transfer catalyst such as
tetrabutylamnonium bisulphate. The starting materials for
~2~ 6
l this reaction are either known or may be prepared by
rnethods analogous to those used for the preparation of the
l<nown compounds.
It is also possible to prepare a compound of general
formula (I) by a process comprising interconversion of
another compound of general formula (I)~
For example, a compound of formula (I) in which X
and/or Y is an alkenylene chain may be prepared by
reduction of a corresponding compound in which X and/or Y
is an alkynylene chain. The reduction may be effected
using, for example hydrogen and a lead-poisoned palladium
on calcium carbonate catalyst in a solvent such as
pyridine, or lithium aluminium hydride in a solvent such
as diethyl ether at a low temperature e.g. 0C.
In the general processes described above, the
compound of formula (I) obtained may be in the form of a
salt, conveniently in the form of a physiologically
acceptable salt. Where desired, such salts may be
converted to the corresponding free bases using
conventional methods.
Physiologically acceptable salts of the compounds of
general formula (I) may be prepared by reacting a compound
of general formula (I) with an appropriate acid or base in
the presence of a suitable solvent such as acetonitrile,
acetone, chloroform, ethyl acetate or an alcohol, e.g~
methanol, ethanol or iso-propanol.
Physiologically acceptable salts may also be prepared
from other salts, including other physiologically
acceptable salts, of the compounds of general formula (I),
using conventional methods.
When a specific enantiomer of a compound of general
formula (I) is required, this may be obtained by
resolution of a corresponding racemate of a compound of
general formula (I) using conventional methods.
~Z5~666
1 Thus, in one example an appropriate optically active
acid may be used to form salts with the racemate of a
compound of general Formula (I). The resulting mixture of
isomeric salts may be separated for example by fractional
crystallisation, into the diastereoisomeric salts frorn
which the required enantiomer of a compound of general
formula (I) may be isolated by conversion into the
required free base.
Alternatively, enantiomers of a compound of general
formula (I) may be synthesised From the appropriate
optically active intermediates using any of the general
processes described herein.
Specific diastereoisomers of a compound of formula
(I) may be obtained by conventional methods for example,
by synthesis from an appropriate asymmetric starting
material using any of the processes described herein, or
by conversion of a mixture of isomers of a compound of
general Formula (I) into appropriate diastereoisomeric
derivatives e.g. salts which then can be separated by
conventional means e.g. by fractional crystallisa-tion.
Racemates of diastereoisomers may be obtained by
conventional methods of separation e.g. fractional
crystallisation isomers of cornpounds of formula (I).
The intermediate compounds used in the above general
processes are either known compounds or they may be
prepared by methods analogous to those used for the
preparation of the l<nown compounds. Suitable methods for
preparing the intermediate compounds are described in U.l<.
Patent Specification No. 214n~00A and in the examples
included hereinafter
\~
S~6
The following examples illustrate the invention.
Temperatures are in C. 'Dried' refers to drying using magnesium sulphate
except where otherwise stated. Thin layer chromatography (t.l.c.) was
carried out over SiO2.
The following flbbreviations are used: DMF dimethylformamide;
THF - tetrahydrofuran; EA - ethyl acetate; ER - diethyl ether;
[C] - column chromatography on silica (Merck 9385); [FCS] - flash column
chromatography on silica (Merck 9385)
Intermediate 1 referred to below is al-(aminomethyl)-4-hydroxy-1,3-
~0 benzenedimethanol.
In_ermediate 2
(E)-4-[3-Methoxy-4-(methoxymethoxy)phenyl]-3-buten-1-ol
n-Butyllithium (1.6M in hexane, 25mQ) was added dropwise to a stirred
suspension of (3-hydroxypropyl)triphenylphosphonium bromide (8.039) in dry
THF (50mQ) cooled to 0 under nitrogen. The resulting blood-red solution
was stirred at 0 for lOmin and then 3-methoxy-4-(methoxymethoxy)-
benzaldehyde (3.609) in dry THF (lOmQ) was added dropwise over 5min. The
mixture was allowed to warm to room temperature, stirred for 4h water
(lOmQ) was added and the majority of the solve~t was removed in vacuo at - -
4û. A solution of the residual oil in ER (20ûmQ) was washed with water
(150mQ), dried, treated with charcoal, concentrated and purified by [FCS]
eluting with EA/hexane (1:1) to give the title compound (1.559).
T.l.c. (EA-Hexane 1:1) Rf 0.30.
Intermediate 3
1-[4-[(6-Bromohexyl)oxy]butyl]-3-methoxy-4-(methoxymethoxy)benzene
A solution of Intermediate 6b (2.059) in absolute ethanol (30mQ) was
hydrogenated over a pre-reduced 10~ PdO on carbon catalyst (0.29, 50O
paste in water) until the uptake of hydrogen (130mQ) ceased. The catalyst
was removed by filtration ~ yflo) and the solvent removed in vacuo at 40
to afford the title compound (2.059). T.l.c. (EA-Hexane 1:2~ Rf 0.64.
Intermediate 4
6-[(Tetrahydro-2H-pyran-2-yl)oxy]-1-hexanol
* Trademark
~5~6
1 Hexane-1,6-diol (70.9g)~was melted in a water bath at ca. 60, the
melt cooled to 45 and dihydropyran (16.829) quicl<ly added followed by
lON hydrochloric acid (O.lmQ). The mixture was stirred and cold water
added to maintain a reaction temperature of approximately 50. When the
exotherm had subsided, the mixture was stirred at room temperature for
0.5h, then diluted with water (500mQ) and extracted with ER (2x250mQ).
The ER solution was washed with water (3x50ûmQ), dried and concentrated to
yield an oil which was purified by [FCS] elution with EA/hexane (1:1)
affording the title compound (19.69). T.l.c. (EA/hexane 1:1) Rf 0.40.
Intermediate 5
6-[(2-Propynyl)oxy]-l-hexanol
A mixture nf Intermediate 4 (18.69), propargyl bromide (80o in
toluene; 14.~89) 40O w/v aqueous sodium hydroxide solution (200mQ) and
tetrabutylammonium bisulphate (3.349) was stirred at room temperature for
5h, diluted with water (500mQ) and extracted with ER (2x250mR). The ER
solution was dried and concentrated to yield an oil which was taken up in
a mixture of methanol (lOOmQ) and 2N hydrochloric acid. After stirring
for 2h the methanol was removed in vacuo at 40, the residual aqueous
phase diluted with brine (lOOmQ), extracted with ER (2x75mQ), dried,
concentrated, and purified by [FCS] elution with 25~ EA/cyclohexane
yielding the title compound (8.69) T.l.c. (EA:I-lexane 1:4) Rf 0.16.
Intermediate 6
a) l-Bromo-6-[(2-propynyl)oxy]hexane
A mixture of propargyl alcohol (5.69), 1,6-dibromohexane (73.29),
tetrabutylammoniumbisulphate (0.59), and aqueous sodium hydroxide (50
w/v, 25ml was stirred at room temperature for 20h, diluted with water
(50ml), and extracted with ER (2 x lOOml). The dried extract was
evaporated and the residue was purified by [C] eluted with cyclohexane
followed by cyclohexane - ER (19:1) to give the title compound as a
colourless oil (15.09) T.l.c. (cyclohexane - ER 9:1) Rf 0.4.
The following compounds were prepared in a similar manner:
b) [(E)-1-[4-[(6-Brornohexyl)oxy]-l-butenyl]-3-methoxy-4-(methoxymethoxy)
benzene, (1.559) from Intermediate 2 (1.49) and 1,6-dibromohexane (6.139).
Purification by [FCS] eluting with 5o EA/hexane increasing to 20o. T.l.c.
(25~ EA-cyclohexane) Rf 0.5.
~5S~
1 c) (E/Z)-5~[4-[(6-Bromohexyl)oxy]-3-butenyl]-1,3-benzodioxolane (E:Z =
3:2) (0.929) from 1,6-dibromohexane (2.79) and
(E/Z)-4-[1,3-benzordioxol-5-yl]-3-butenol, (E:Z = 3:2) (0.2g; see
U.K.Patent Specification No. 2140800A). Purification by [FCS] eluting
~lith cyclohexane then cyclohexane-ER (9:1).
T.l.c. (Cyclohexane-EA 4:1) Rf 0.5.
d) [4 -Propynyloxy)butyl]benzene, (18.39) from propargyl alcohol (109)
and (4-bromobutyl)benzene (389). Purification by [C] eluting with
cyclohexane-ER (19:1). T.l.c. (Cyclohexane-ER 19:1) Rf 0.2.
e) [4-(3-Butynyloxy)butyl]benzene, (9.5q) from (4-bromobutyl)benzene (159)
and 3-butyn-1-ol (59)~ T.l.c. (Cyclohexane;ER 9:1) Rf 0.45.
f) [4-[(2-Propynyl)oxy]-l,Z-buteny-]benzene~ (4.89) from
4-phenyl-3,Z-buten~ l-ol (59) and propargyl bromide (4.059). Purification
by [C] eluting with cyclohexane-ER (9:1). T.l.c. (Cyclohexane-ER 9:1) Rf
0.45.
Intermediate 7
N-(4-Iodophenyl)methanesulphonamide
Methanesulphonyl chloride (11.439) was added dropwise over 10 min to a
stirred solution ofr 4-iodoaniline (21.99) in pyridine (150ml) cooled to
-15 under nitrogen. During the addition, the trmperature was not allowed
to rise above -10. The mixture was allowed to warm up to room
temperature, stirred for 0.5h and the solvent removed in vacuo at 45 to
give a red oil which was triturated with a mixture of EA (300ml) and 2N
hydrochloric acid. The organic phase was washed with further 2N HCl
(150ml), dried, treated with charcoal and concentrated to yield the crude
product as a pale yellow powder. Recrystallisation from EA/hexane yielded
the title compound as a highly crystalline cream solid (25.09) m.p.
135-136.5.
Intermediate 8
N-[4-[3-[(6-Hydroxyhexyl)oxy]-l-propynyl]phenyl]methanesulphonamide
Copper (I) iodide (43mg) was added to a solution of Intermediate 7
(13.379) Intermediate 5 (7.029) and bis(triphenylphosphine)palladium (II)
chloride (316mg) in diethylamine (275ml), and the mixture stirred at room
temperature under nitrogen for 22h. The solvent was evaporated in vacuo at
35, the residual brown oil taken up in EA (250ml) and the solution washed
with 2N hydrochloric acid (2 x 200ml). The acid phase was extracted with
~ZS5~
l further EA (50ml), the~combined organics dried and evaporated onto 'flash'
silica (~lercl< 9385; 759). The impregnated silica was applied to [FC5]
eluting with EA/hexane (4:1) to give the title compound as a fawn solid
(13.69). Recrystallisation from EA/hexane yielded a fawn crystalline
powder tll-2g) m.p. 83-~4.5.
Intermediate 9
(Z)-N-[4-[3-[(6-Hydroxy _ yl)oxy]-1-propenyl]phenyl]methanesulphon-
amide
A solution of Interrnediate B (ll.Og) in pyridine (250rnR) was hydrogenated
at atmospheric pressure and room temperature over a pre-reduced Lindlar
catalyst (3.5g) in pyridine (50mQ) until the uptake of hydrogen ceased.
The catalyst was removed by filtration through 'hyflo', the pad washed
with ethanol (50mQ) and the solvents evaporated in vacuo at 50. A
solution of the residual brown oil in EA (300mQ), was washed with 2N
hydrochloric acid (2x250mQ), dried and treated with activated charcoal.
Concentration afforded the title compound (10.7~) m.p. 65-67.
Intermediate 10
(Z)-N-[4-[3-[(6-Bromohexyl)oxy]-l-propenyl]phenyl]methanesulphonamide
Triphenylphosphine (8.819) in dichloromethane (50ml) was added dropwise
over 5 min to a stirred solution of carbon tetrabromide (11.149) and
Intermediate 9 (10.09) in dichloromethane (lûOml) cooled to 0 under
nitrogen. When the addition was complete the mixture was stirred at room
temperature for 3h, the solution evaporated onto silica (Merck 9385; 509)
and the impregnated material subjected to [FCS] eluting with EA/hexane
(1:3) to give the title compound as a colourless crystalline powder 9.19,
m.p. 78-81.
Intermediate 11
1-(4-Iodobenzoyl)-4-methylpiperazine
4-Iodobenzoyl chloride (10.09) was added portionwise to N-methylpiperazine
(3.89) in triethylamine (40ml) under nitrogen at room temperature. The
resulting suspension was stirred at room temperature for 2h, triethylamine
was removed under reduced pressure, and the residue was psrtitioned
between aqueous sodium bicarbonate (lM; 50ml) and EA (2 x lOOml). The
dried (Na250") organic phase was evaporated and the residue was triturated
with ER (2 x 25ml) to give the title compound as a beige solid (4.79).
l~S~
1 Intermediate 12
_
1-[(4-Iodophenyl)methyl]-4-methylpiperazine
Diborane in Tl-IF (lM; 50ml) was added during 5 min to Intermediate 11
(5.09) in TI~F (lOOml) under nitrogen. The solution was refluxed for 3h,
cooled, and treated cautiously with hydrochloric acid (2M; 50ml). The
mixture was refluxed for 15 min and Tl-lF was removed under reduced
pressure. The residue was basified with aqueous sodiurn hydroxide (2M) and
extracted with EA (2 x 20ml). The dried (Na2504) extract was evaporated
and the residue was purified by [C] eluted with ER followed by EA to give
the title compound as a cream solid (2.89).
Intermediate 13
4-Hydroxy-~1-[[[6-[(2-propynyl)oxy]hexyl]amino]methyl]-1,3-benzenedi-
m anol
Intermediate 6 (6.09) was added dropwise to a solution of Intermediate 1
(5.09) and N,N-diisopropylethylamirle (7.09) in DMF (lOOml) at 75. The
solution was heated at 75-80 for 2h and DMF was evaporated under reduced
pressure. The residue was partitioned between EA (2 x 200ml) and aqueous
sodium bicarbonate (lM; 50ml). The dried organic phase was filtered and
evaporated, and the residue was purified by [C~ eluting with
EA-methanol-triethylamine (90:10:1) to give a yellow gum. Trituration oF
the gum with ER (2 x 25ml) gave the title compound (1.159) m.p. 66-68.
Intermediate 14
(E)-4-[4-[(6-Bromohex-yl)oxy]-l-butenyl]-2-methoxyphenol
A solution of Intermediate 3 (4.509) and 4-toloenesulphonic acid (2.349)
in a mixture of THF (80mQ) and water (lOmQ) was heated under reflux for
2.5h and then the solvent evaporated in vacuo at 4n to yield a viscous
oil. This was tal<en up in EA (lOOmQ) and the solution wahsed with 8o
sodium bicarbonate solution (2x75mQ), dried, concentrated and purified by
[FCS] eluting with 25~ EA-hexane to qive the title compound (3.609).
T.l.c. (EA-cyclohexane 1:3) Rf 0.44.
Intermediate 15
Z55~66
1 a) 5-(4-Phenylbutoxy)-3~pentyn-l-ol
Intermediate 6d (6.ng) was added to a stirred suspension of lithamide
[from lithium (0.2259)] in liquid ammonia (30mQ) at -78. Dimethyl-
sulphoxide (20mR) was added and ammonia was evaporated on a water bath at
50. The resulting solution at 15 was treated with ethylene oxide (1.55)
at -60 and the mixture was stirred at room temperature for 2h. Water
(50mQ) was added and the emulsion was extracted with ER (5x80mQ), dried,
evaporated and purified by [C] eluting witll cyclohexane-ER 7:3 to give the
title compound (4.2g). T.l.c. (Cyclohexane-ER 3:1) Rf 0.15.
The following compound was prepared in a similar manner:~
b) [4 [(6-Chloro-2-hexynyl)oxy] l~Z butenyl]benzene, (3.59) from
Intermediate 6f (4.89). Distillation in place of [C] gave the title
compound. T.l.c. (Cyclohexane-ER 9:1) Rf 0.4.
Intermediates 16-18 were prepared in a similar manner to Intermediate
lû:-
Intermediate 16
[4-[(5-Bromo-2-pentynyl)oxy]butyl]benze-eJ (4.05g) from Intermediate 15
(4g). Purification by [C] eluting with cyclohexane-ER 19:1.
T.l.c. (Cyclohexane-ER 9:1) Rf 0.4.
Intermediate 17
-
[4-[(6-Bromo-3-hexynyl)oxy]butyl]benzene, (4.29) from Intermediate 23
(3.89). Purification by [C] eluting with cyclohexane-ER (4:1).
T.l.c. (Cyclohexane-ER 9:1) Rf 0.4.
Intermediate 18
[4-[[(4-Bromo-2-butynyl)oxy]butyl]benzene, (8.2g) frorn Intermediate 21
(8g). Purification by [C] eluting with cyclohexane-ER (9:1).
T.l.c. (Cyclohexane-ER 9:1) Rf 0.4.
Intermediate 19
[4-[(6-Iodo-2-hexynyl)oxy]-l,Z-butenyl]benzene
~ mixture of Intermediate 15 (3.0g) sodium iodide (5.25g) and butanone
(15mQ) was refluxed for 18h. ER (150mQ) was added and the suspension was
filtered and evaporated to give the title compound (3.99).
T.l.c. (Cyclohexane-ER 9:1) Rf 0.4.
Intermediate 20
~4
5566
1 7-(4-Phenylbutoxy)-5-heptyn-2-one
A mixture of Intermediate 18 (4.09) acetylacetone (1.549) potassium
carbonate (1.939) and ethanol (25m~) was refluxed for 16h, filtered and
evaporated. The residue was treated with ER (50m~), filtered, evaporated,
and purified by [C] eluting with cyclohexane-ER (17:3) then distillation
to give the title compound (1.59). T.l.c. (Cyclohexane-ER 3:1) Rf 0.35.
Intermediate 21
4-(4-Phenylbutoxy)-2-butyn-l-ol
n-Butyllithium in hexane (1.6M; 31.5ml) was added dropwise to Intermediate
6d (9,09) in THF (50ml) at -78 under nitrogenO THe solution was stirred
at -78 for 20 min and paraformaldehyde (1.59) was added. THe suspension
was allowed to warm to room temperature and was stirred for lh. The
resulting solution was treated with saturated aqueous ammonium chloride
(150ml) and extracted with ER (2 x 200ml). The dried extrac-t was
evaporated and the residue was purified by [C] eluting with cyclohexane -
ER (3:1) to give the title compound as a colourless oil (8.49).
T.l.c. (Cyclohexane - ER 3:1) Rf 0.15.
Intermediate 22
.
[7-(4-Phenyl-3-butynyl)oxy]-2-heptanone
Interrnediate 21 (20.169) in ER (lOOml) was added to a stirred mixture of
magnesium turnings (1.79) and iodine (one small crystal) under nitrogen
with stirring at a rate which maintained a gentle reflux. The cooled
mixture was aclded to acetic anhydride (14ml) in ER (30ml) at -65 to -60
under nitrogen with mechanical stirring over 1.25h. The mixture was
stirred at -65 for 1.5h, allowed to warm to -10, and treated with
aqueous saturated ammonium chloride (lOOml), followed by ER (lOOml). The
aqueous layer was separated, and the ER layer washed with aqueous lM
sodium hydroxide (200rnl). The combined aqueous layers were extracated with
ER (200ml)s and the organic extract combined with the above ER layer. The
dried (Na250~) ER solution was evaporated and purified by [FCS] eluting
with cyclohexane - ER (98:2 - 85:15) to give an oil which was heated at
185 in vacuo (0.4 Torr) for lh. The residual oil was further purified by
[FCS] eluting with ER-cyclohexane (1:3) to give the title compound as a
colourless oil (3.289).
Intermediate 23
6-(4-Phenylbutoxy)-3-hexyn-1-ol
1 8romoethane (3.829) in ~I-IF (20ml) was added dropwise to magnesium (û.85g)
under nitrogen at a rate to maintain gentle reflux. Interrnediate 6e (7.0~)
in Tl-IF (lOml) was added dropwise to the cloudy solution and the mixture
was heated at 50-60 for lh. [thy]ene oxide (3.529) was added to the
solution at n and the mixture was stirred at 0 for lOmin, at roorn
temperature for lh, and at reflux for 3h, treated with saturated aqueous
ammonium chloride (lOOml) and extracted with ER (2 x lOOml). The dried
extract was evaporated and at the residue was purified by [C] eluting with
cyclohexane-ER (20:7) to give a colourless oil (4.89). Distillation gave
the title compound as a colourless oil (4.09) b.p. 165-170/0.3mm. Hg
T.l.c. (Cyclohexane - ER 1:1) Rf 0.35.
Intermediate 24
[3-[(6-Bromohexyl)oxy]-l-propynyl]benzene
A mixture of 3-phenyl-2-propyn-1-ol (3.09), 1,6-dibromohexane (13.49)
aqueous sodium hydroxide (50O w/w, l5ml) and tetrabutylammonium bisulphate
(0.59) was stirred at room temperature for 18h, diluted with water (30ml),
and extracted with ER (2 x 5ûml). The dried extract was evaporated and the
residue was purified by [C] eluting with cyclohexane followed by
cyclohexane-ER (19:1) to give the title compound as a colourless oil
(5~19). T.l.c. (Cyclohexane - ER 9:1) Rf 0.2.
ExamplE~, 1
(Z)-N-[4-[3-[[6-[[2-1lydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl
amino]hexyl]oxy]-l-propenyl]phenyl]methanesulphonamide
Intermediate 10 was added portionwise over 5 min to a stirred solution of
Intermediate 1 (1.109) and N,N-diisopropylethylalnine (1.559) in DMF (20ml)
at 80 for 2h and the snlvent removed in vacuo at 60. The residual oil
was dissolved in methanol (20ml) and evaporated onto silica (Merck 9385);
159), then subjected to [FCS] eluting with
toluene/ethanol/methanol/0.88NI-13 (39:10:7:1) providing the title compound
as an oil which solidified on trituration with dry ER (1.059) m.p.
113-116. T.l.c. (Toluene/ethanol/0.88 NH3 39:10:1) Rf 0.11.
Example 2
a) 4-llydroxy-al-[[[6-[[3-[4-[(1-methylpiperazine-4-yl)methyl]phenyl]-2-
propynl]oxy]hexyl]amin_]methyl]-1,3-benzenedimethanol
A mixture of Intermediate 13 (0.69), Intermediate 12 (0.639), bis(tri-
phenylphosphino)palladium (II) chloride (0.029), cuprous iodide (0.0039)
5S~i6
1 and diethylamine (lOml) was stirred at roorn ternperature for 16h and
evaporated. The residue was partitioned between aqueous sodiurn bicarbonate
(lM; 201) and EA (2 x 50ml). The dried (Na250LI) extract was evaporated and
the redsidue was purified by [C] eluting with EA-methanoltriethylamine
90:10:1 to give the ti le compound (0.39). T.l.c. EA-methanol-NH3 8n lo
Rf 0.1.
The following compound was prepared in a similar manner:-
b) N-[4 [3-[[6-[[2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl~
amino]hexyl]oxy]-l-propynyl]phenyl]acetamide, from Intermediate 13 (1.5g)
and N-4-iodophenylacetamide (1.229). Purification by [FCS] eluting with
EA-methanool-triethylamine (90:10:1) then trituration with ER gave the
title compound (1.109).
Analysis Found C,66.2;H,7.55;N,6Ø
C26N3L~N205 H20 requires C,66.1;H,7.7;N,5.95o
T.l.c. (EA-methanol-triethylamine 90:10:1) Rf 0.1.
Example 3
4-Hydroxy-al-[[[6-[4-[(4-hydroxy-3-methoxyphenyl)-3E-butenyl]oxy]hexyl]-
amino]methyl]-1,3-benzenedimethanol
A mixture of Interrnediate 1 (371mg), Intermediate 14 (482mg), and N,N-di-
~0 isopropylethylt1mine (218mg) was stirred and heated at 75-80 in dry DMF
(5ml) under N2 for 2.5h. The mixture was poured into water (25ml),
extracted with EA (2 x 25ml) and the organic phase washed wth 0.5N HCl
(2 x 20rnl). The aqueous phase was adjusted to pl-l8 with 8o NaHCO3 solution,
extracted with EA (2 x 25ml), and the organic phase dried (Na250L,),
concentrated and purified by [FCS] (triethylamine deactivated silica)
eluting with rnethanol-EA (1:6) to give the title compound (0.149) m.p.
48-53 (softens ca. 43). T.l.c. (Toluene-ethanol-0.88NH3 39:10:1)
RfO.18.
Example 4
a) (Z)-N-[4-[3-[[6-[[2-llydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]-
ethyl]amino]hexyl]oxy]-l-propenyl]phenyl]acetamide
The compound of Example 2b (3509) in pyridine (lOml) was hydrogenated over
pre-reduced Lindlars catalyst (lOOmg) for ~Lh. The reaction mixture was
filtered (hyflo) and the filtrate was evaporated to leave a gum which was
1 triturated with ER to give the title compound (127rng) m.p. 105-lOB0.
T.l.c. (EA-methanol-triethylamine 90:10:1) Rf 0.08.
The following compounds were prepared in a similar manner:-
b) 4-~lydroxy-al[[[6-(4-phenylbutoxy)-3,Z-hexenyl]aminc]methyl]-1,3-
benzenedimethanol, (0.319) from the compound of Example 5c (0.49~.
Purification by [C] eluting with EA-methanol triethylamine (92:8:1) then
trituration with ER (lOml). m.p. 94-95.
T.l.c~ (EA-methanol-N~l3 9:1:0.1) RF 0.2.
c) 4-Hydroxy-al-[[[l-methyl-6-[(4-ehyenyl-3,Zbutenyl)oxy]hexyl]amino]
methyl]-lt3-benzenedimethanol, (q.619) from the compound of Exalnple 6a
(O.Bg). m.p. 71-74. T.l.c. triethylamine deactivated Si02 (EA-methanol
19:1) Rf 0.13.
Example 5
_ _ _
a) 4-Hydroxy-al-[[[6-[(3-phenyl-2-propynyl)oxy]hexyl]amino]methyl]-1,3-
benzenedi~r!ethanol
Intermediate 24 (3.559) was fldded dropwise to a solution of Intermediate
(2.59) and N,N-diisopropylethylamine (2.69) in DMF (50ml) at 70. The
solution was heated at 70-75 for 2h and evaporated. The residue was
purified by [C] eluting with EA-methanol-triethylamine (92:8:1) to give a
yellow oil. Trituration of the oil with ER (50ml) gave the title compound
as a cream solid (0.779) m.p. 6~-70.
T.l.c. (EA-methanol-NH3 9:1:0.1) Rf 0.2.
The following compo-lnds were prepared in a similar manner:-
b) 4-Hydroxy-al-[[[5-(4-phenylbutoxy)-3-p_ntynyl]arnino]methyl]-1,3-
benzenedimethanol, from Intermediate 1 and Interrnediate 16. Purification
by [C] eluting with EA-methanol-triethylamine (90:2n:1). m.p. 93-94.
c) 4-Hydroxy-al-[[[(6-(4-phenylbutoxy)-3-hexynyl]amino]methyl]-1,3-
benzenedimethanol, from Intermediate 1 and Intermediate 17. Purification
by [C] eluting with EA-Inet!-anol-triethylalnine (93:7:1). m.p. 60-61.
Example 6
a) 4-(llydroxy-al-[[[1-methyl-6-[(4-phenyl-3-b~!tynyl)oxy]hexyl]amino]-
methyl]-1,3-benzenedimethanol
Sodium cyanoborohydride (0.759) was added to Interrmediate 1 (2.269),
Intermediate 22 (3.199) and acetic acid (0.7ml) in methanol (40ml) at room
temperature with stirring and the mixture stirred overnight under
nitrogen. The mixture was evaporated, the residue treated with aqueous
saturated sodium bicarbonate (lOOml) and extracted with EA (3 x 120ml).
The combined dried (Na25O4), organic extracts were evaporated and the
-` ~255~;6S~
1 residual oil was purified by [FCS] eluting with EA-methanol-triethylamine
(94:5 1) to give the title compound as a white solid (1.569) m.p. 95-97.
b) 4-Hydroxy-al-[[[l-methyl-6-(4-phenylbutoxy)-4-hexynyl]amino]methyl]-
1,3-benzenedimethanol, (0.679) from Intermediate 1 (0.739) and
Intermediate 20 (19). Purification by [C] eluting with
EA-methanol-triethylamine (9:1:0.1). m.p. 57-59.
T~l~co (EA-methanol-NI-13 9:1:0.1) Rf 0.2.
c) 4-~lydroxy-al-[[[6-[(4-phenyl-31Z-butenyl)oxy]-4-hexynyl]amino]methyl]
-1,3- benzenedimethanol, (0.399) from Intermediate 1 (19) and Interrnediate
19 (1.949). m.p. 72-74. T.l.c. (EA-methanol-NH3 9:1:0.1) Rf 0.2.
Example 7
_
(E/Z)-t~l-[[[6-[[4-(1,3-Benzodioxol-5-yl)-3-butenyl]oxy]hexyl]amino]
methyl]-4-hydroxy-1,3-ben~ nedimethanol
A mixture of Intermediate 1 (0.79) DMF (lOml), N,N-diisopropylethylamine
(0.69) and Intermediate 6c (0.99) was heated at 75 for 2h. The mixture
was diluted with water (lOOml), acidified to pl~3 with 2M hydrochloric
acid, basified to pl-l~ with solitl potassium bicarhonate and extracted with
EA (2 x 50ml). The extracts were waslled with water (25ml), brine (25ml),
dried (Na2SO4) and evaporated in vacuo to give an oil (19) which was
purified by [FCS] on triethylalnine-deactivated silica using
EA-methanol-triethylamine (~5:15:1) as the eluant to give the title
saliqenin as a viscous oil which on cooling gave a waxy solid (0.439),
m.p. 6~-72.
T.l.c. triethylamine decativated SiO2 (EA methanol-triethylamine S5:15:1)
Rf 0.31.
The following are examples of suitable formulations of compounds of
the invention. The term "active ingredient" is used herein to represent a
compound of the invention.
Tablets
These may be prepared by the normal methods such as wet granulation
or direct compression.
A. Direct Compression
mg/tablet
~9
Z5~f~66
1 Active ingredient ~ 2.0
Microcrystalline Cellulose USP196.5
Magnesium Stearate BP 1.5
Compression weight 2ûû.0
The active ingredient is seived through a suitable seive and blended
with lactose, starch and pregelatinised maize starch. Suitable volumes of
purified water are added and the powders are granulated. After drying, the
granules are screened and blended with the magnesium stearate. The
granules are then compressed into tablets using 7mrn diameter punches.
Tablets of other strengths may be prepared by altering the ratio of
active ingredient to lactose or the compression weight and using punches
to suit.
C. For buccal administration
mq/tablet
Active ingredient 2.0
Lactose BP 94.8
Sucrose BP 86.7
mqttable-t
Hydroxypropylmethylcellulose 15.0
MagnesiuM Stearate BP 1.5
Compression weight 2ûû.0
The active ingredient is seived through a suitable seive and blended
with the lactose, s-lcrose and hydroxypropylmethylcellulose. Suitable
volumes of purified water are added and the powders are granulated. After
drying, the granules are screened and blended with the magnesium stearate.
The granules are then compressed into tablets using suitable punches.
The tablets may be film coated with suitable film forming materials,
such as hydroxylpropyl methylcellulose, using standard techniques.
Alternatively the tablets may be sugar coated.
Capsules mg!capsule
Active ingredient 2.0
~2~6~
1 *Starch 1500 97 0
Magnesium Stearate BP 1.0
Fill weight 100.0
* A forrn of directly compressible starch.
The active ingredient is seived and blended with the excipients. The
mix is filled into size No. 2 hard gelatin capsules using suitable
machinery. Other doses may be prepared by altering the fill wright and if
necessary changing the capsule size to suit.
Syrup
This may be either a sucrose or sucrose free presentation.
A. Sucrose Syrup
mg/5ml does
Active ingredient 2.0
Sucrose BP 2750.0
Glycerine BP 500.0
Buffer
Flavour ) as required
Colour
Preservative)
Purified Water BP to 5.0ml
The active ingredient, buffer, flavour, colour and preservative are
dissolved in some of the water and the glycerine is added. The remainder
of the water is heated to dissolve the sucrose and is then cooled. The
two solutions are combined, adjusted to volume and mixed. The syrup
produced is clarified by filtration.
B. Sucrose-Free
mg/5ml dose
Active ingredient 2.0mg
Hydroxypropyl methylcellulose USP
3 \
`"` ~2~666
1 (viscosity type 40bo) 22.5mg
Buffer
Flavour
Colour ) 8S required
Preservative)
Sweetener
Purified Water BP to 5.0ml
The hydroxypropyl methylcellulose is dispersed in hot water, cooled
and then mixed with an aqueous solution containing the active ingredient
and the other components of the formulation. The resultant solution is-
adjusted to volume and mixed. The syrup is clarified by filtration.
Metered Dose Presurised Aerosoi
A. Suspension Aerosol
mq/metered_dose Per can
Active ingredient micronised 0.100 26.40mg
Oleic Acid BP 0.1002.64mg
Trichlorofluoromethane BP 23.64 5.679
Dichlorodifluoromethane BP 61.25 14.709
The active ingredient is micronised in,a fluid energy mill -to a fine
particle size range. The Oleic Acid is mixed with the
Trichlorofluoromethane at a temperature of 10~15C and the micronised drug
is mixed into the solution with fl high shear mixer. The suspension is
metered into aluminium aerosol cans and suitable metering valves,
delivering n5mg of suspension are crimped onto the cans and the
Dichlorodifluoromethane is pressure filled into the cans through the
valves.
~z~
/ B. Solution Aerosol
mq/metered dose Per can
Active ingredient 0.05513.20mg
Ethanol BP 11.100 2.669
Dichlorotetrafluoroethane BP 25.160 6.049
Dichlorodifluoromethane BP 37.740 9.069
Oleic acid BP, or a suitable surfactant e.g. Span 85 (sorbitan
trioleate) may also be included.
The'active ingredient is dissolved in the ethanol together with the
o oleic acid or surfactant if used. The alcoholic solution is metered into a
suitable aerosol containers followed by the tr~chlorofluoromethane.
Suitable metering valves are crimped onto the containers and
dichlorodifluoromethane is pressure filled into them through the valves.
Suppositiories
g Active ingredient 2.Omg
*Witepsol H15 to 1.09
* A proprietary grade of Adeps So`lidus-Ph. Eur.~~ -' ''
A suspension of the active ingredient in molten Witepso~ is prepared
and filled, using suitable machinery, into 19 size suppository moulds.
Ini~ction for Intravenous Administration
mg/ml
Active ingredient 0.5mg
Sodium Chloride BP as required
Water for Injection'BP to l.Oml ~
2 ~ Sodium chloride may be added to adjust'the tonicity of the solution
and the pH may be adjusted, using acid or'alkali, to that of optimum
stability and/or to facilitate solution of the active ingredient.
Alternatively suitable buffer salts may be used.
+ Trademark
~`~'
`- 3 ~ ~ Z~5~6
1 The solution is prepared, clarified and filled into appropriate size
ampoules sealed by fusion of the glass. The injection is sterilised by
heating in an autoclave using one of the acceptable cycles. Alternatively
the solution may be sterilised by filtration and filled into sterile
ampoules under aseptic conditions. The solution may be packed under an
inert atmosphere of nitrogen or other suitable gas.
Inhalation Cartridges
mq/cartridqe
Active ingredient micronised 0.200
Lactose BP to 25.0
The active ingredient is micronised in a fluid energy mill to a fine
particle size range prior to blending with normal tabletting grade lactose
in a high energy mixer. The powder blend is filled into No. 3 hard gelatin
capsules on a suitable encapsulating machine. The contents of the
cartridges are administered using a powder inhaler such as the Glaxo
Rotahaler.
