Note: Descriptions are shown in the official language in which they were submitted.
~,~t~
4~1~722/+
Substituted imidazoles
The invention relates to ~ubstituted imidazoles of
the general formula
Ph - lH - N ~ N (I),
or salts thereof, in which Ph represents phenyl that is
unsubstituted or substituted by lower alkyl or by lower
alkoxy, and Rl and R2 each represents lower alkyl,
to their use, to processes for their manufacture and to
pharmaceutical preparations that contain a compound of
the formula I or a pharmaceutically acceptable salt
thereof.
Phenyl that is substituted by lower alkyl or by
lower alko~y has especially one or more, for example
. ~ C
- 2 -
two, also three, lower alkyl or lower alkoxy radicals
bonded especially in the ortho- and/or meta-position(s).
Hereinbefore and hereinafter, radicals or
compounds designated "lower" should preferably be
understood as meaning those containing up to and
including 7, especially up to and including 4, carhon
atoms.
The general terms used have the following
meanings:
Lower alkyl is, for example, methyl, ethyl, n-
propyl, isopropyl, n butyl, isobutyl, sec.-butyl or
tert.-butyl, and also includes corresponding pentyl,
hexyl or heptyl radicals.
Lower alkoxy is, for example, methoxy, ethoxy,
n-propoxy, isopropoxy, pentyloxy, isobutoxy or tert.-
butoxy.
Salts of compounds of the formula I are their acid
addition salts, preferably phar~aceutically acceptable
acid addition salts. These are formed, for example,
with strong inorganic acids, such as mineral acids, for
example sulphuric acid, a phosphoric acid or a hydro-
halic acid, with strong organic carboxylic acids, such
as lower alkanecarboxylic acids, for e~ample acetic
acid, optionally unsaturated dicarboxylic acids, for
example malonic, maleic or fumaric acid, or hydroxy-
carboxylic acids, for example tartaric or citric acid,
or with sulphonic acids, such as lower alkanesulphonic
acids or optionally substituted benzenesulphonic acids,
for example methane- or p-toluene-sulphonic acid.
Salts ~hat are unsuitable for pharmaceutical uses are
also included, since they can be used, for example, for
the isolation and purification of free compounds
according to the invention and their phar~aceutically
acceptable salts.
The compounds accordin~ to the invention have,
- 3 ~
for example, valuable pharmacological properties. In
particular, they are capable of selectively and rever-
sibly inhibiting the monoaminooxidase (MAo) of type A.
These properties can be demonstrated both in the rat
liver and in the rat brain where in each case the
breaking down of serotonin is selectively inhibited.
The determination of the MAO activity in the rat liver
or rat brain was carried out analogously to the method
of R~J o Wurtman et al., Biochem. Pharmacol. 1~,
1439 (1963), the inhibition of MAO being ascertained at
a dose upwards from approximately 1 mg/kg after peroral
administrativn of the active ingredient.
Accordingly, the compounds according to the
invention can be used for the prophylactic and thera-
peutic treatment of depressive conditions.
The invention therefore relates also to the
prophylactic and therapeutic treatment of the human and
animal body and to the use of the compounds according
to the invention for the treatment of depressive
conditions.
The invention relates, for example, to compounds
of the formula I, or their salts, in which Ph
represents phenyl that is unsubstituted or mono- or
poly-substituted, for example di-substituted, by lower
alkyl, especially ~ower alkyl having up to and
including 4 carbon atoms, and R1 and R2 each
represents lower alkyll especially lower alkyl having
up to and including 4 carbon atoms.
The invention relates, for example, to compounds
of the formula I, or their salts, in which Ph
represents phenyl that is mono- or poly-substituted,
for example di-substituted, by lower alkoxy, especially
lower alkoxy having up to and including 4 carbon atoms,
such as methoxy, and R1 and R2 each represents
lower alkyl~ especially lower alkyl having up to and
-- 4 --
including 4 carbon atoms, such as methyl.
The invention relates especially to compounds of
the formula I, or their salts, in whlch Ph represents
phenyl that is unsubstituted or mono-substituted in the
2- or 3-position by lower alkyl or lower alkoxy, each
having up to and including 4 carbon atoms, such as
methyl or methoxy, or di-substituted in the 2- and 6-
positions by lower alkyl having up to and including 4
carbon atoms, such as methyl, and Rl and R2 each
represents lower alkyl having up to and including 4
carbon atoms, such as methyl.
The invention relates especially to compounds of
the formula I~ or their salts, in which Ph represents
unsubstituted phenyl, and R1 and R2 each represents
lower alkyl having up to and including 4 carbon atoms,
such as methyl.
The invention relates specifically to the novel
compounds mentioned in the Examples and their salts.
The invention relates also to a process for the
manufacture of the compounds of the formula I and their
salts, characterised in that
a) a compound of the formula
Rl
I
Ph - CH - Xl (IIa),
in which X1 represents reactive esterified hydroxy,
is reacted with a compound of the formula
-- 5 ~ , t~
R2
I
Xz-N ~N (lIb),
in which X2 represents hydrogen or a metallic
radical, or
b) in a compound of the formula
Rl
I (III
Ph - CH - Het
in which Het represents a radical that can be
converted into 2-R2-imidazol-1-yl, Het is converted
into 2-R2-imidazol-1-yl, or
c) in a compound of the formula
Ph - A - N ~ (IV)
in which A represents a grouping that can he converted
into -CH(Rl)- and the radical R2' represents a
radical that can be converted into R2 or represents
- 6 - ~3~
R2, or in which A represents the grouping -CH(Rl)-
and R2' represents a radical that can be converted
into R2, A is converted into -CHlRl)- and/or R2
is converted into R2, or
d) a compound of the formula
R2
71~ l
Ph - C = N N A Q
_ .
in which A~ represents an anion of a protonic acid,
is reduced to the corresponding compound of the formula
1, or
e) a compound of the formula
I (VI)
Ph - CH - X3
in which X3 represents a group that can be converted
by cyclisation into 2-R2-imida201-l-yl, is cyclised,
or
f) a compound of the formula
., ~
~3~ 8
l4 i5
Ph - CH - N ~N (VI I a)
I I
is reacted with a compound of the formula R-X6
(VIIb) in which one of the radicals X4 and X6
represents reactive esterified hydroxy and the other
represents a metallie radical, X5 represents the
radical R2 and R represents the radical Rl, or
in which one of the radicals X5 and X6 represents
reaetive esterified hydroxy and the other represents a
metallic radical, X4 represents the radical R1 and
R represents the radical R2, or
g) for the manufaeture of compounds of the formula I
or their salts in which Ph represents phenyl
substituted by lower alkoxy~
in a eompound of the formula
Ph' - ~H - N ~N (VI I I )
I _!
in which Ph' represents a radical tnat can be converted
into Ph, Ph' is converted into Ph,
it being possible for the starting compounds listed in
variants a) to g) optionally to be in salt form, and,
t
-- 8 ~
if desired, a compound of the formula I obtainable
according to the invention is converted into a
different compound of the formula I, and/or, if
desired, a resulting salt is converted into the free
compound of the formula I or into a different salt,
and/or, if desired, a free compound of the formula I
obtainable according to the invention is converted into
a salt, and/or, if desired, a resulting isomeric
mixture is separated into the individual components.
The reactions described hereinbefore and
hereinafter in variants a) to g) are carried out in a
manner known ~r se, for example in the absence or,
customarily, in the presence of a suitable solvent or
diluent or a mixture thereof, the reactions being
carried out, as required, while cooling, at room
temperature or while heating, for example in a tempera-
ture range of from approximately -10 to approxi-
mately +250C, preferably from approximately 20 to
approximately 150C, and, if necessary, in a closed
vessel, under pressure, in an inert gas atmosphere
and/or under anhydrous conditions.
Some of the starting materials of the formulae IIa
and IIb, III, IV, V, VI, VIIa and VIIb and VIII, which
are listed hereinbefore and hereinafter and which were
developed for the manufacture of the compounds of the
formula I, are known or they can be manufactured
according to methods known per se, for example
analogously to the process variants described here-
inbefore and hereinafter.
Variant a):
Reactive esterified hydroxy represents especially
hydroxy esterified by a strong inorganic acid or
organic sulphonic acid, for example halogen, such as
chlorine, bromine or iodine, sulphonyloxy, such as
,~
_ 9 ~
hydroxysulphonyloxy, halosulphonyloxy, for exa~ple
fluorosulphonyloxy, optionally substltuted, for e~a~ple
halo-substituted, lower alkanesu]phonyloxy, for example
methane- or trifluoromethane-sulphonyloxy, cycloalkane-
sulphonyloxy, for example cyclohexanesulphonyloxy, or
optionally substituted, for example lower-alkyl- or
halo-substituted, benzenesulphonyloxy, for example ~-
bromophenyl- or p-toluene-sulphonyloxy.
A metallic radical is, for example, an alkali
metal radical, especially a lithium radical, and also a
copper(I) radical, or a lithium copper(I) radical
derived from lithium cuprates.
The reaction is carried out especially in the
presence of a condensation agent, such as a suitable
base.
As bases there come into consideration, for
example, alkali ~etal hydroxides, hydrides, amides,
alkoxides, carbonates, triphenylmethylides, di-lower
alkylamides, aminoalkylamides or lower alkylsilyl-
amides, naphthaleneamines, lower alkylamines, basic
heterocycles, ammonium hydroxide and carbocyclic
amines. There may be mentioned by way of example:
sodium hydroxide, hydride or amide, potassium tert.-
butoxide or carbonate, lithium triphenylmethyli~e or
diisopropylamide, potassium 3-(aminopropyl)-amide or
bis-(trimethylsilyl)-amide, dimethylaminonaphthalene,
di- or tri-ethylamine, pyridine, benzyltrimethyl-
ammonium hydroxide, 1,5-diazabicyclo[4.3.0]non-5-ene
(DBN) and 1,8-diazabicyslo[5.4.0]undec-7-ene (DBU).
If X2 represents hydrogen, the addition of a
further base is unnecessary if the compound of the
formula IIb acting as a base is used in excess. If
X2 represents a metallic radical, the reaction with
compounds of the formula IIb is advantageously effected
without the addition of bases.
~, ~
, .
- l o -
The reaction is preferably carried out with those
compounds of the formula IIb in which X2 represents
hydrogen.
Variant b)-
.
A radical Het that can be converted into 2-R2-
imidazol-l-yl can be, for example, 3-R2-pyrazol-1-yl.
The conversion thereof into 2-R2-imidazol-1-yl
can be effected, for example, by photoisomerisationr
for example by irradiation, such as with a high
pressure mercury lamp.
~ radical Het that can be converted into 2-R2-
imidazol-l-yl can also be 2-R2-imidazolin-1-yl,
especially 2-R2-imidazol-2-in-1-yl, which can be
converted into 2-R2-imidazol-~-yl, for example, by
dehydrogenation.
For the dehydrogenation there are used suitable
dehydrogenation agents, for example elements from the
sub-groups, preferably those of sub-group VIII of the
Periodic Table, for example pailadium, Raney nickel or
platinum, or corresponding noble metal derivatives, for
example platinum oxide or ruthenium triphenyl
phosphide chloride, it being possible for the agents to
be supported on suitable carriers, such as carbon.
Further preferred dehydrogenation agents are, for
example, quinones, such as ~-benzoquinones, for
example tetrachloro-~-benzoquinone or 2,3-dichloro-
5,6-dicyano-p-benzoquinone, and phenanthrene-9,10-
quinone. It is also possible to use N-
halosuccinimides, such as N-chlorosuccinimide,
manganese compounds, such as barium manganate or
manganese dioxide, and sulphur and selenium
derivatives, such as sulphur, selenium, selenium
dioxide or diphenylselenium bis-trifluoroacetate.
~ ~3~
Variant c):
~ structural element A that can be converted into
the grouping -CH(Rl)- represents, for example, the
g p ng C(R1 )(ZO)- in which Rl' represents
either the radical Rl having a radical Zl that can
be converted into hydrogen, and ZO represents
hydrogen, or Rl' represents Rl and ZO represents
a radical Zl that can be converted into hydrogen, or
in which Rl' and ZO together form lower
alkenylidene or a tautomeric form thereof. Likewise,
radicals R2' that can be converted into P~2 are
lower alkyl radicals substituted by a radical Zl that
can be converted into hydrogen.
Zl can be converted into hydrogen, for example,
by reduction and accordingly represents, for example,
hydroxy, etherified hydroxy, such as lower alkoxy,
halogen, sulphonyloxy, such as optionally substituted,
for example halo-substituted, lower alkanesulphonyloxy,
cyclo-lower alkanesulphonyloxy or optionally substi-
tuted, for example lower alkyl- or halo-substituted,
benzenesulphonyloxy, mercapto or etherified mercapto,
such as lower alkylthio.
The reductive conversion of A into the grouping
-CH~RI)- and/or of R2' into R2 is effected in a
manner known per se, for example with the aid of a
reducing agent, for example by hydrogenation in the
presence of a hydrogenation catalyst, by reduction with
a hydride transfer reagent cr by reduction with a
metallic reduction system comprising metal and a proton-
removing agent.
As hydrogenation catalysts there come into
consideration, for example, elements of sub-group VIII
of the Periodic Table of Elements, or derivatives
thereof, such as palladium, platinum, platinum oxide,
ruthenium, rhodium, tris-(triphenylphosphine)-
) ~
.
- 12 ~ 8
rhodium(I) halide, for example the chloride, or Raney
nickel; which are optionally supported on a carrier,
such as active carbon, an alkali metal carbonate or
sulphate or on a silica gel. As hydride transfer
reagents there come into consideration, for example,
suitable light metal hydrides, especially alkali metal
aluminium hydrides or borohydrides, such as lithium
aluminium hydride, lithi~m triethyl borohydride, sodium
borohydride, sodium cyanoborohydride, or tin hydrides,
such as triethyl- or tributyl-tin hydride, or diborane.
The metal component of the metallic reduction system
is, for example, a base metal, such as an alkali metal
or alkaline earth metal, for example lithium, sodium,
potassium, magnesium or calcium, or a transition metal,
for example zinc, tin, iron or titanium, whilst as
proton-removing agent there come into consideration,
for example, protonic acids, such as hydrochloric or
acetic acid, lower alkanols, such as ethanol, and/or
amines or ammonia. Such systems are, for example,
sodium/ammonia, zinc/hydrochloric or acetic acid, or
zinc/ethanol.
In preferred embodiments of this process, for
example, hydroxy or optionally etherified mercapto are
reduced by catalytic hydrogenation, for example in the
presence of Raney nickel, and halogen or sulphonyloxy
are reduced, for example, by hydride transfer reagents,
by tributyltin hydride, lithium aluminium hydride or
sodium cyanoborohydride or sodium/ammonia.
In addition, hydroxy can be replaced by hydrogen
by treatment with phosphorus (red) and hydrogen iodide
or iodine.
Preferably, radicals Zl that can be replaced by
hydrogen heing located in the benzylic position and are
replaced by hydrogen.
Zl can also represent carboxy. The decarboxy-
- 13 - ~ ~3~
lation of corresponding compounds of the formula IV can
customarily be carried out at elevated temperatures,
for example at a temperature upwards from approximately
50C, especially in a temperature range of from
approximately 100 to approximately 300C. The
decarboxylation can be assisted, for example, by the
presence of bases, such as high-boiling nitrogen bases,
for example, collidine, and/or in the presence of noble
metals, such as copper or copper bronze.
There are especially used as starting materials
those compounds of the formula IV that have only one
radical Zl that can be converted into hydrogen.
Variant d):
The reduction of the iminium salts of the formula
V to form the tertiary amines of the formula I is
effected, for example, with the aid of a reducing
agent, for example of the type listed in variant c).
Examples oE possible suitable methods of reduction are
catalytic hydrogenation, treatment with a hydride
transfer reagent, for example sodium borohydride, or
the use of the metallic reduction system zinc/hydro-
chloric acid.
It is also possible to use formic acid as reducing
agent.
Variant e):
A grouping X3 that can be converted by
cyclisation into 2-R2-imidazol-1-yl represents, for
example, the group of the formula
- N = CH - CH2 ~ NH - CO - R2 IVIa).
The cyclisation of the group VIa is effected, for
example, by customary treatment of corresponding
, .
.,
3~
compounds of the formula VII with an acidic agent,
especially a mineral acid anhydride, such as a
phosphorus oxyhalide, for example the oxychloride, or
phosphorus pentahalider for example the pentachloride.
The system trlphenylphosphine/hexachloroethane/tri-
ethylamine is especially suitable. The procedure is
especially carried out analogously to the method
described by W. Steglich et al., Liebigs ~nn. Chem.
1 _ , 1916-1927.
X3 can also represent a group oE the formula
12
~ C ~
IH -CHO (VIb)
in which the formyl group can also be in acetalised
form, for example in the form of formyl acetalised by
an alcohol, such as lower alkanol or lower alkanediol.
The cyclisation can be carried out, for example,
in the presence of an acidic agent, for example a
protonic acid, such as a mineral acid r for example a
hydrohalic, sulphuric or polyphosphoric acid, a
sulphonic acid, for example trifluoromethane- or p-
toluene-sulphonic acid, or a strong carboxylic acid,
for example an optionally substituted lower alkane-
carboxylic acid, for exa~ple glacial acetic acid or
trifluoroacetic acid. Also suitable are, for example,
the mineral acid anhydrides mentioned above.
Variant f):
Reactive esterified hy~roxy X4 or X5 or X6
has, for example, the meanin~ given for Xl in variant
a), whilst a metallic radical X4 or X5 or X6
~t
- 15 - ~2~3~
represents, for example, an alkali metal radical, such
as a lithium, sodium or potassium radical, a magnesium
halide radical, such as a magnesium bromide radical, a
copper radical, or a lithium copper radical derived
from lithium cuprates.
In a modiEication of the process, it is possible,
for example, to start from a compound of the formula
VIIa in which X4 and X5 each represents hydrogen
and to treat this compound with a strong base, such as
butyllithium, and to react the resulting compound of
the formula VIIa in which X4 and X5 each represents
a metallic radical, such as lithium, with at least two
moles of a compound of the formula VIIb. In this
operation there can first be obtained, ln situ, a
compound of the formula VIIa in which one of the
radicals X4 and X5 represents a metallic radical
and the other represents Rl or R2, respectively,
which compound then reacts further under the reaction
conditions directly to form the corresponding compound
of the formu~a I~
This reaction is advantageously initially carried
out at low temperatures, for example in a temperature
range of from ~78C to room temperature.
Variant g):
Ph' represents, for example, phenyl substituted by
hydroxy.
Such compounds of the formula VIII can be
converted into compounds of the formula I by etherifi-
cation with a lower alkylating agent. Lower alkylating
agents include, for example, lower alkanols or reactive
esters thereof, such as corresponding halo-derivatives,
such as chlorine, bromine or iodine derivatives,
sulphonyloxy derivatives, such as hydroxysulphonyloxy
derivatives, halosulphonyloxy derivatives, for example
- 16 - 123~82~
fluorosulphonyloxy derivatives, optionally substituted,
for example halo-substituted, lower alkanesulphonyloxy
derivatives, fo~ example methane- or trifluoromethane-
sulphonyloxy derivatives, cycloalkanesulphonyloxy
derivatives, for example cyclohexanesulphonyloxy
derivatives, or optionally substituted, for example
halo- or lower alkyl-substituted, benzenesulphonyloxy
derivatives, for example ~-bromophenyl- or p-toluene-
sulphonyloxy derivatives. There also come into
consideration as lower alkylating agents, for example,
di-lower alkyl sulphate, diazo-lower alkane, tri-lower
alkylsulphonium hydroxide, tri-lower alkylselenium
hydroxide, tri-lower alkyloxosulphonium hydroxide or
tri-lower alkylanilinium hydroxide, and also penta-
lower alkoxyphosphine.
When using reacti~e esters of lcwer alkanols or
di-lower alkyl sulphates as lower alkylating agents,
the ethe~ification is effected especially in the
presence of one of the bases mentioned above, whilst
the reaction with a diaza-lower alkane is optionally
carried out in the presence of a Lewis acid. Lewis
acids are, for example, halides of boron, aluminium,
tin(II), antimony(III), arsenic(III), silver(I),
zinc(II) and iron(III).
The etherification with the aid of a lower alkanol
is carried out, for example, in the presence of a
strong acid or, under anhydrous conditions, in the
presence of a dehydrating agent.
As strong acids there may be mentioned especially
strong protonic acids, for example mineral acids, such
as hydrohalic acids, sulphuric acid or a phosphoric
acid, strong carboxylic acids, such as an optionally
substituted, for example halo-substituted, lower alkane-
carboxylic acid or benzoic acid, for example glacial
acetic acid or trifluoroacetic acid, or sulphonic
- 17 -
acids, such as optionally substituted, for example
halo-substituted, lower alkanesulphonic acids, or
optionally substituted, for e~ample halo- or lower
alkyl-substituted, benzenesulphonic acids, for example
E~toluenesulphonic acid.
Suitable dehydrating agents are, for example,
carbodiimides, for example N,N'-di-lower alkyl or N,N'-
dicycloalkyl carbodiimides, such as N,N'-diethyl, N,N'-
diisopropyl or N,N'-dicyclohexyl carbodiimide,
advantageously with the addition of N-hydroxy-
succinimide or optionally substituted, for example
halo-, lower alkyl- or lower a~koxy substituted, 1-
hydroxybenzotriazole or N-hydroxy-5-norbornene-2,3-
dicarboxamide, N,N'-diimidazolecarbonyl, a suitable
phosphoryl or phosphine compound, for example diethyl-
phosphonyl cyanide, diphenylphosphonylazide or
triphenylphosphine disulphide, a 1-lower
alkyl-2-halopyridinium halide, for example
1-methyl-2-chloropyridinium iodide, a suitable
1,2-dihydroquinoline, for example N-ethoxycarbonyl-2-
ethoxy-1,2-dihydroquinoline, or 1,1'-(carbonyldioxy)-
dibenzotriazole.
Ph' also represents, for example, phenyl
containing a diazonium grouping -N2~A~ in which
A~ represents an anion of a strong protonic acid.
For the conversion of such compounds of the
formula VIII into corresponding compounds of the
formula I, the diazonium grouping -N2A~ is
substituted by lower alkoxy, especially by treatment
with a lower alkanol.
In an advantageous modification of this process
variant, the compounds of the formula VIII can be
formed _ situ and react further under the
.~
reaction conditions, without being isolated, to form
the compounds of the formula I. In this variant,
firstly a compound of the formula VIII in which Ph'
represents phenyl containing an amino group is used as
the starting material, and this compound is diazotised
with nitrites, such as alkali metal nitrites, or nitro-
lower alkanes in the presence of protonic aclds, for
example those of the type men~ioned above, and the com-
pounds of the formula VIII in which Ph'represents phenyl
containing a dia~onium grouping N~2A~, which compounds
are formed in situ, are reacted, without being
isolated, with a lower alkanol. Advantageously a
reaction temperature of from approximately -10 to
approximately +40C is selected for this reaction.
The invention relates especially to the
manufacturing processes described in the Examples.
A compound according to the invention can be
converted into a different compound according to the
invention by methods that are known ~ se.
Thus, for example, a lower alkyl radical can be
introduced into the phenyl ring Ph by alkylation, for
example, with a reactive ester of a lower alkanol in
the presence of a Lewis acid (Friedel Crafts
alkylation).
T~e manufacture of the starting materials
described in variants a) to g) is effected using
methods that are known per se.
Thus, for example, the starting material of the
formula III can be manufactured by reacting compounds
of the formula IIa with compounds of the formula
X2-Het (IIIa) analogously to the procedure described
in variant a).
In analogous manner, it is possible to obtain
starting compounds of the formulae IV, VIIa and VIII,
for example, by reacting compounds of the formulae
- 19 ~
Ph-A-Xl (IVa) and (IIb) [resulting in compounds of
the formula IV], or reacting compounds of the formulae
Ph-CH(X4)-Xl (VIIc) and
X2-N ~ N (VIId)
[resulting in compounds of the formula VIIa], or
reacting co~pounds of the formulae Ph'-CH(Rl)-Xl
(IIIa) and ~IIb) [resulting in compounds of the formula
VIII].
Compounds of the formula VI in which X3
represents a yrouping of the formula VIa can be
obtained, for example, by acid-catalysed reaction of
compounds of the formula
CH -C ~
~ \ H
NH-C-R2 (VIc)
with compounds of the formula
I (VId).
H2N - HC - Ph
- 20 ~
Compounds of the formllla VI in which X3 represents a
grouping of the formula VIb or VIb' can be ob-tained, for
example, by condensa-tion of compounds of -the formula
NH
~ (VIe)
R - C
X8
in which X8 represents a leaving group, such as lower
alkoxy or amino, and compounds of the formula
0~ 11
C - CH2 HN HC Ph ~VIf) or an acetale
H / thereof,
the secondary amino group r~a~ additionally contain an
acyl group, for example lower alkanoyl, such as acetyl.
A further variant for the manufacture of a compound of the
formula VI, in which X3 represents the grouping of the
formula VIb or VIb' respectively, consists in the reaction
of a compound of the formula VId with a compound of the
formula VIe and subsequent condensation of a compound ob-
tainable of the formula Ph-CH(Rl)-NH-C(R2)=NH (VIg) with a
monohalogeno-acetaldehyde or preferably an acetale thereof.
Likewise a compound of the formula Ph-CH(Rl)-N=C~R2)-X8
(VIh) may be reacted with an acetale of an aminoacetaldehyd.
A compound of the formula VI in which X3 represents the
grouping VIb or VIb' respectively may be preferably formed
in situ and is directly reacted, under the reaction condi-
tion, to the corresponding compound of the formula I.
Salts of compounds of the formula I can be
manufactured in a manner known ~ se. Thus, for
example, acid addition salts of compounds of the
formula I are obtained by treatment with an acid or a
- 20a -
suitable ion exchange reagent. Salts can be converted
in customary manner into the free compounds; acid
addition salts can be converted, for example, by
treatment with a suitable basic agent.
Depending upon the procedure and reaction
conditions used, the compounds according to the
invention having salt-forming, especially basic,
properties may be obtained in free form or in the form
of salts.
As a result of the close relationship between the
2 1 -- ~ r ~
novel compound in free form and in the orm of its
salts, hereinbefore and hereinafter the free compound
or its salts should be understood as meaning also the
corresponding salts or free compound, respectively,
where appropriate and expedient.
The novel compounds, including salts of salt-
forming compounds, can also be obtained in the form of
their hydrates or may include other solvents used for
crystallisation.
Depending upon the starting materials and
procedures chosen, the novel compounds may be obtained
in the form of one of the possible isomers or in the
form of mixtures thereof, for example, depending upon
the number of asymmetric carbon atoms, in the form of
pure optical isomers, such as antipodes, or in the form
of isomeric mixtures, such as racemates,
diastereoisomeric mixtures or racemic mixtures.
Resulting diastereoisomeric mixtures and racemic
mixtures can be separated into the pure isomers
diastereoisomers or racemates in known manner on the
basis of the physico-chemical differences between the
constituents, for example by fractional crystal-
lisationO
Resulting racemates can also be separated into the
optical antipodes according to known methods, for
example ky recrystallisation from an optically active
solvent, by chromatography over chiral adsorbents, with
the aid of suitable micro-organisms, by cleaving with
specificl immobilised enzymes, by means of the
formation of inclusion compounds, for example using
chiral crown ethers, in which case only one enantiomer
is complexed, or by conversion into diastereoisomeric
salts, for example by reaction of a basic end product
racemate with an optically active acid, such as a
carboxylic acid, for example tartaric or malic acid, or
- 22 -
a sulphonic acid, for example camphorsulphonic acid,
and separation of the diastereoisomeric mixture
obtained in this manner, for example on the basis of
their different solubilities, into the diastereo-
isomers, from which the desired enantiomer can be freed
by the action of suitable agents. Advantageously, the
more active enantiomer is isolated.
The invention also relates to those forms of the
process according to which a compound obtainable as
intermediate at any stage of the process is used as
starting material and the remaining steps are carried
out, or a starting material is used in the form of a
derivative or salt, and/or its racemates or antipodes
or, especially, is formed under the reaction
conditions.
In the process of the present invention it is
preferable to use those starting materials which result
in the compounds described at the beginning as being
especially valuable. The invention relates also to
novel starting materials, which were developed
especially for the manufacture of the compounds
according to the invention, to their use and to
processes for their manufacture, the variables Rl,
R2 and Ph having the meanings indicated for the
preferred groups of compounds of the formula I.
The invention relates also to the use of the
compounds of the formula or of pharmaceutically
acceptable salts of such compounds having salt-forming
properties, especially as active ingredients having
pharmacological, more especially antidepressive,
action. They can be used, preferably in the form of
pharmaceutically acceptable preparations, in a metl,od
for the prophylactic and/or therapeutic treatment of
the animal or human body, especially as anti-
depressants for the treatment of depression.
- 23 ~ c~
The invention relates a~so to pharmaceutical
preparations that contain as active ingredients the
compounds according to the invention or pharma-
ceutically acceptable salts thereof and to processes
for their ~anufacture.
The pharmaceutical preparations according to the
invention, whieh eontain the compounds according to the
invention or pharmaceutically acceptable salts thereof,
are for enteral, sueh as oral and rectal, and
parenteral administration to (a) warm-blooded
animal(s), the preparations eontaining the pharma-
eologieal aetive ingredient alone or together with a
pharmaceutically aceeptable carrier. The daily dose of
the aetive ingredient depends upon age and individual
eondition and upon the method of administration.
The aetive ingredients ean also be applied to the
skin with the aid of transdermal therapeutie systems
(TTS) which serve to provide a eontrolled pereutaneous
supply of active ingredient for systemic treatment, for
example in the form of an adhesive plaster of rounded
shape approximately from 2 to 50 cm2 in size. The
release of active ingredient can take plaee, for
example, over a period of from approximately 24 hours
to one week.
Such transdermal systems have a multi-layered
structure and eomprise, for example, from the outside
to the inside, an impermeable eover film, an aetive
ingredient reservoir, an adhesive or stieky layer and a
pull-off film to be removed before applieation. In the
ease of the eorresponding matrix or monolithie systems,
the aetive ingredient is distributed in a polymer
layer from whieh it is released by diffusion. It is
also possible to use membrane-controlled systems in
which a semipermeable or mieroporous control membrane
that determines the speed of diffusion is located
- 2~
between the active ing-edient reservoir and the skin.
As regards dosage, the amount of active ingredient
absorbed per time unit depends, for example, on the
size of the contact surface between the active
ingredient reservoir and the skin.
The novel pharmaceutical preparations contain, for
example, from approximately 10% to approximately ~0~,
preferably from approximately 20% to approximately 60~,
of active ingredient. Pharmaceutical preparations
according to the invention for enteral and parenteral
administration are, for example, those in dosage unit
forms, such as dragées, tablets, capsules or
suppositories, and also ampoules. They are
manufactured in a manner known per se, for example,
by means of conventional mixing, granulating,
confectioning, dissolving or lyophilising processes.
Thus, pharmaceutical preparations for oral use can be
obtained by combining the active ingredient with solid
carriers, optionally granulating a resulting mixture,
and processing the mixture or granulate, if desired or
necessary after the addition of suitable adjuncts, to
form tablets or dragée cores.
Suitable carriers are, especially, fillers, such
as sugars, for example lactose, saccharose, mannitol or
sorbitol, cellulose preparations and/or calcium
phosphates, for example tricalcium phosphate or calcium
hydrogen phosphate, also binders, such as starch pastes
using, for example, corn, wheat, rice or potato
starch, gelatine, tragacanth, methylcellulose and/or
polyvinylpyrrolidone, if desired, disintegrators, such
as the above-mentioned starches, also carboxymethyl
starch, cross-linked po]yvinylpyrrolidone, agar,
alginic acid or a salt thereof, such as sodium
alginate. Adjuncts are especially flow-regulating
agents and lubricants, for example silica, talc,
~ 25 - ~ ~3~
stearic acid or salts thereof, such as magnesium or
calcium stearate, and/or polyethylene glycol. Dragée
cores are provided with suitable coatings that may
be resistant to gastric juices r there being used~
inter alia, concentrated sugar solutions that may
contain gum arabie, tale, polyvinylpyrrolidone,
polyethylene glycol and/or titanium dioxide, or lacquer
solutions in suitable organic solvents or solvent
mixtures, or, for the manufacture of eoatings resistant
to gastric juices, solutions of suitable cellulose
preparations, sueh as acetylcellulose phthalate or
hydroxypropylmethylcellulose phthalate. Colourings or
pigments may be added to the tablets or dragée
coatings, for example for identification purposes or to
indicate different doses of active ingredient.
Further orally administrable pharmaceutical
preparations are dry-filled eapsules consisting of
gelatine, and also soft, sealed capsules eonsisting of
gelatine and a plasticiser, such as glycerine or
sorbitol. The dry-filled capsules may contain the
active ingredient in the form of a granulate, for
example in admixture with fillers, sueh as lactose,
binders, such as starches, and/or glidants, such as
talc or magnesium stearate, and optionally stabilisers.
In soft capsules, the active ingredient is preferably
dissolved or suspended in suitable liquids, such as
fatty oils, paraffin oil or liquid polyethylene
glycols, to which stabilisers may also be added.
There eome into consideration as reetally
administrable pharmaeeutieal preparations, for example,
suppositories that eonsist of a combination of the
aetive ingredient and a suppository base. Suitable as
suppository bases are, for example, natural or
synthetie triglycerides, paraffin hydroearbons, poly-
ethylene glycols or higher alkanols. It is also
~3~
possible to use gelatine rectal capsules that contain a
combination of the active ingredient and a base
material. Suitable base materials are, for example,
liquid triglycerides, polyethylene glycols or paraffin
hydrocarbons.
Suitable for parenteral administration are
especially aqueous solutions of an active ingredient in
water-soluble form, for example a water-soluble salt,
also suspensions of the active ingredient, such as
corresponding oily injection suspensionsl there being
used suitable lipophilic solvents or vehicles, such as
fatty oils, for example sesame oil, or synthetic fatty
acid esters, for example ethyl oleate, or tri-
glycerides, or aqueous injection suspensions that
contain viscosity-increasing substances, for example
sodium carboxymethylcellulose, sorbitol and/or dextran
and, optionally, also stabilisers.
The dosage of the active ingredient depends upon
the species of warm-blooded animal, age and individual
condition, and on the method of administration. In
normal cases, the estimated approximate daily dose for
a warm-blooded animal weighing approximately 75 kg is,
in the case of oral administration, from approximately
100 to approximately 500 mg, especially from 200 to
approximately 300 mg, advantageously in several equal
partial doses.
The following Examples illustrate the invention
described above but do not limit the scope thereof in
any way. Temperatures are given in degrees
Centigrade.
~3;~
- 27 -
Example 1
24.4 g (0.2 mol) of l-phenylethanol and 27.6 g
(0.2~ mol) of methanesulphoch]oride are dissolved in
250 ml of toluene and, while stirring at 10, a
solution of 28.2 g (0.28 mol) of triethylamine in 50 ml
of toluene is introduced dropwise over a period of 30
minutes. The reaction mixture is stirred for 12 hours
at room temperature and then the triethylamine hydro-
chloride that has formed is filtered off. The residue
is washed with toluene and the combined filtrates are
concentrated to dryness by evaporation under a
water-jet vacuum. While stirring at ~5, the
resulting oil is added dropwise in the course of 15
minutes to a solution of S0 g (0.6 mol) of 2-methyl-
imidazole and the mixture is kept at 100 for 6
hours. 200 ml of ether and 200 ml of water are added
to the reaction mixture and the organic phase is
separated off and washed three times with water.
The organic phases are extracted by shaking three times
using 100 ml of 2N hydrochloric acid each time, and the
aqueous acidic phases are rendered alkaline with
concentrated sodium hydroxide solution and again
extracted by shaking with ether. The organic phases
are dried over magnesium sulphate and the solvent is
removed under a water-jet vacuum. The oil that is
obtained as a crude product is distilled at 120
(13.3 Pa) under a high vacuum and, after recrystal-
lisation from cyclohexane, yields pure l-(l-phenyl-
ethyl)-2-methylimidazole which melts at 8~-85.
22.8 g (0.12 mol) of the resulting base are dissolved
in 100 ml of ethyl acetate and the solution is rendered
acidic (pH ~1) with alcoholic hydrochloric acid. ~fter
the addition of 25 ml of ether, the precipitate that
has formed is filtered off, washed with ether and dried
at 60 in vacuo. The resulting pure l-(l-phenyl-
- 28 ~
ethyl~-2-methylimidazole hydrochloride melts at
229-22g.5.
Example 2
In a manner analogous to that described in Example
1, oily 1-[1 (p-methylphenyl)-ethyl1-2-methyl-
imidazole is obtained from 40.86 g l0-3 mol~ of 1-
(~-methylphenyl)-ethanol and 73.9 g (0.9 mol~ of 2-
methylimidazole. The hydrochloride prepared therefrom
melts at 237-238.
Example 3
In a manner analogous to that described in Example
1, 21.3 g of oily 1-[1-(2,4-dimethylphenyl)-ethyl]-2-
methylimidazole are obtained as a crude product from
30.1 g (0.2 mol) of 1-(2,4-dimethylphenyl)-ethanol and
49.3 g (0.6 mol) of 2-methylimidazole. The hydro-
chloride prepared therefrom in analogous manner melts
at 238-239.
The 1~(2,4-dimethylphenyl)-ethanol required as
starting material is prepared as follows:
44.5 g (0.3 mol) of 2,4-dimethylacetophenone are
dissolved in 200 ml of isopropanol and, while stirring
at 60, an ice-cold solution of 5.7 g (0.15 mol) of
sodium borohydride in 50 ml of water is slowly added
dropwise thereto. The reaction mixture is heated at
reflux temperature for 4 hours, then cooled, and 200 ml
of 1 molar sodium dihydrogen phosphate solution are
added. The isopropanol is extensively remove~ under a
water-jet vacuum and the residue is extracted by
shaking with ether. The organic phases are washed with
brine and dried over magnesium sulphate and the solvent
is removed under a water-jet vacuum. The resulting
residue is distilled under a water-jet vacuum and
yields 1-(2,4-dimethylphenyl)-ethanol having a boiling
- 29 -
point (1866.5 Pa) of 120 [Ishizaka, Chem. Ber. 47,
2461, B.p.14 = 124-125].
_a~
In a manner analogous to that described in Example
1, oily 1-[1-(2-methylphenyl)-ethyl]-2-methylimidazole
is obtained as a crude product from 27.3 g (0.2 mol) of
1-[~2-methylphenyl)-ethyl]-ethanol and 49.3 g (0.6 mol)
of 2-methylimidazole. The hydrochloride melts at
237-238.
The 1-(2-methylphenyl)-ethanol required as
starting material is prepared analogously to Example 3
(V. Auwers et al. Chem. Ber. 58, 46, B.p.20 =
107-108).
Example 5
25 g (0O113 mol) of 1-(1-phenylethenyliden-1-yl)-
2-methylimidazole hydrochloride are added to 200 ml of
saturated potash solution and then extracted by shaking
three times using 100 ml of ether each time. The
organic extracts are dried over magnesium sulphate and
concentrated to dryness by evaporation in vacuo. The
resulting residue is dissolved in 500 ml of methanol
and, with the addition of 1 g of 5~ palladium-on-
carbon, hydrogenated at room temperature and normal
pressure. The catalyst is filtered off and washed with
methanol and the combined methanolic solutions are
concentrated to dryness by evaporation ln vacuo. The
resulting oily residue is crystallised from cyclohexane
and yields pure 1~ phenylethyl)-2-methyli~idazole
having a melting point of 84-85.
The starting material is obtained, for example, as
follows:
a) 130 g (0.68 mol) of ~-chlorophenylacetyl chloride
are added dropwise at 20-30 to 500 ml of ethanol and
_ 30 - ~ ~3~8~
the whole is stirred for 3 hours at 30-40. The
solvent is removed in vacuo and yields crude
2-chloro-2-phenylacetic acid ethyl ester. The result-
ing product (137 g) is dissolved in 2 litres of
toluene, and 170 g (2.07 mol) of 2-methylimidazole are
added to the solution. The reaction mixture is kept at
100 for 12 hours while stirring. The resulting
reaction mixture is extracted by shaking four times
using 500 ml of water each time and the aqueous phases
are then washed with a small ~uantity of toluene, and
the combined organic phases are dried over magnesiu~
sulphate. After removal of the solvent in vacuo,
crude, oily 2-phenyl-2-~2-methylimidazol-l-yl)-acetic
acid ethyl ester is obtained. The compound distils at
145 (26.6~ Pa). The pure hydrochloride melts at
157-159.
b) 1~2.9 g (0.5~5 mol) of 2-phenyl-2-(2-methy~-
imidazol-l-yl)-acetic acid ethyl estsr are dissolved in
1.5 litres of isopropanol and, while stirring at 5,
a solution of 23 g (0.6 mol) of sodium borohydride in
150 ml of water is added dropwise over a period of 30
minutes. The mixture is stirred without cooling for 6
hours, the temperature of the mixture reaching
45-50~. When cold, the mixture is rendered acidic
(pH = l-2) with a mixture of concentrated hydrochloric
acid and water (l:l) and the solvent is extensively
removed ln vacuo. ~aturated potash solution is added
to the residue at low temperature until an alkaline
reaction is obtained, and then the whole is extracted
by shaking three times using 300 ml of ether each
time. The combined organic phases are dried over
magnesium sulphate and the solvent is re-moved in
vacuo. The resulting oily residue is crystallised
from ether/cyclohexane and yields pure 2-phenyl-2-(2-
- 31
methvlimidazol-l-yl)-ethan-l-ol having a melting point
of 114-116.
105.3 g of the resulting base are dissolved in
300 ml of ethanol, and alcoholic hydrochloric acid is
added until an acidic reaction is obtained. ~fter the
addition of 200 ml of ethyl acetate and approximately
200 ml of ether, the product that has formed is
filtered off, washed with ethyl acetate and dried in
vacuo at 60. The pure 2-phenyl-2-(2-methyl-
imidazol-l-yl)-ethanol hydrochloride melts at
144-146.
115 g (0.481 mol) of 2-phenyl-2-(2-methyl-
imidazol-l-yl)-ethanol hydrochloride are dissolved in
1 litre of chloroform and boiled under reflux for 10
hours with 120 g (1 mol) of thionyl chloride. The
reaction mixture is concentrated to dryness by
evaporation in vacuo and the crude product is further
used directly. 120.4 g of the crude 1-[2-(1-chloro-2-
phenylethyl)]-2-methylimidazole hydrochloride are
dissolved in 1 litre of chloroform and stirred with
152 g (1.0 mol) of 1,8-diazabicyclo[5.4.0]undec-7-ene
for 12 hours at room temperature.
The reaction mixture is freed of solvent in
vacuo and 500 ml of cyclohexane and 500 ml of water
are added. The aqueous phase is separated off and the
organic phase is washed three times using 100 ml of
water each time. The organic phase is dried over
magnesium sulphate and the solvent is removed in
vacuo. The crude l-(l-phenylethenyliden-l-yl)-2-
methylimidazole is obtained in the form of an oil. The
base has a boiling point of ~.p. 130 (6.66 Pa).
82 g of the crude base are dissolved in 200 ml of ethyl
acetate, and approximately 7N alcoholic hvdrochloric
acid is added until an acidic reaction is obtained.
~fter the addition of 50 ml oE ether, the product that
- 32 -
has for~ed is filtered off, washed with ether and dried
in vacuo at 60. The pure 1~ phenylethenyliden-t-
yl) 2-methylimidazole hydrochloride melts at
258--260.
Example_6
8.6 g (0.05 mol) of 1-(1-phenylethyl)-imidazole
are dissolved in 80 ml of absolute tetrahydrofuran and,
at -70, 30 ml ~2 mol) of n-butyllithium solution in
hexane are added dropwise thereto. The mixture is
stirred for 30 minutes at -70, and then 7.1 g (0.05
mol) of methyl iodide in 20 ml of tetrahydrofuran are
added dropwise. The cooling means is removed and the
mixture is brought slowly to room temperature and then
left at this temperature for 2 hours. For working up,
25 ml of 2N sodium hydroxide solution are added and the
tetrahydrofuran is extensively removed in vacuo. The
residuQ is extracted by shaking with ether and the
organic phases are dried over magnesium sulphate and
the solvent is removed in vacuo. The resulting oily
residue is dissolved in ethyl acetate; ethereal hydro--
chloric acid is added until an acidic reaction is
obtained and the product that for~s is filtered off.
After recrystallisation from isopropanol/ether, the
pure 1-~1-phenylethyl)-2-methylimidazole hydrochloride
melts at 228-229.
Example 7
In a manner analogous to that described in Example
1, oily 1-[1-(3-methylphenyl)-ethyl]-2-methylimidazole
is obtained as a crude product from 13.6 g (0.1 mol) of
1-[1-(3-methylphenyl)-ethyl]-ethanol and 24.6 g (0O3
mol) of 2-methylimidazole. The hydrochloride melts at
228-230.
~3~
Example 8
In a manner analogous to that described in Example
1, crude 1-[1-(phenyl)-propyl]-2-methylimidazole is
obtained in the form of an oil from 13.6 g (0.1 mol) of
1-phenylpropan-1 -ol and 25 g (0.3 mol) of 2-methyl-
imidazole. The hydrochloride melts at 177-179.
Example 9
In a manner analogous to that described in Example
1, crude, oily 1-[1-(2-ethylphenyl~-ethyl]-2-methyl~
imidazole is obtained from 15.0 g (0.1 mol) of 1-(2-
ethylphenyl)-ethanol and 25 g (0.3 mol) of 2-methyl-
imidazole. The hydrochloride melts at 211-213.
Example 10
In a manner analogous to that described in Example
1, crystalline 1-[1-(2,6-dimethylphenyl)-ethyl]-2-
methylimidazole having a melting point of 100-1 03
is obtained from 15.0 g (0.1 mol) of 1-(2,6-dimethyl-
phenyl)-ethanol and 25 g (0.3 mol) of 2-methyl-
imidazole. The hydrochloride melts at 265-267.
Example 11
18.8 g (0.1 mol) of 1-[1 -(phenyl)-ethyl]-2-
methyl-4,5-dihydroirnidazole are dissolved in 4000 ml of
methylene chloride and, while stirring and with the
exclusion of moisture, 282 g (1.1 mol) of barium
manganate are added. The mixture is stirred under
reflux for 24 hours. 20 g of magnesium sulphate are
then added, the solid portions are filtered off and the
residue is washed with methy1 ene chloride. The organic
filtrates are concentrated to dryness by evaporation
ln vacuo and the resulting oil is dissolved in ethyl
acetate. After the addition of ethereal hydrochloric
acid until an acidic reaction is obtained, the
- 34 - ~ ~3~
hydrochloride that is formed is filtered off and
recrystallised from isopropanol/ether. The pure
l-[l-(phenyl)-ethyl]-2-methylimidazole hydrochloride
melts at 228-229.
The starting material is obtained as follows:
~) N-[l-(phenyl)-ethyl]-aminoethylamine
30 g (0.25 mol) of acetophenone are dissolved in
300 ml of methanol and, after the addition of 30 g
(0.5 mol) of ethylenediamine and l.0 g of platinum-on-
carbon, hydrogenated with hydrogen at 20 and normal
pressure over a period of 22 hours. The catalyst is
re-noved from the resulting solution by filtration, the
solvent is removed _ vacuo and the residue is
distilled under a water-jet vacuum. The N-[1-(phenyl)-
ethyl]-aminoethylamine, obtained in the form of an oil,
boils at 115-118 (1466.5 Pa).
b) 16.4 g (0.1 mol) of N-[l-(phenyl)-ethyl~-amino-
ethylamine are dissolved in 100 ml of ethanol and, at
0, 16.0 g (0.1 mol~ of acetamido acid ethyl ester
hydrochloride are introduced. The mixture is stirred
for 3 hours at ~ and the solvent is removed ln
vacuo. The resulting oil is extracted by shaking with
water and ether, and the ethereal extract is dried over
magnesium sulphate and the solvent is removed in
vacuo. The residue is dissolved in ethyl acetate, and
-
oxalic acid is added until an acidic reaction
is obtained. ~fter the addition of a little ether, the
product that has formed is filtered off and recrystal-
lised from isopropanol/ether. The pure l-[1-(phenyl)-
ethyl]-2-methyl-4,5-dihydroimidazole oxalate melts at
80-84.
For further reaction, 29 g of the oxalate are
converted into the free base with 1N potassiu~
35 ~ 3~
hydroxide solution and ether. The free base is
obtained which boils at 130 (1.33 Pa).
Example ! 2
5~0 g (0.0409 mol) of R-(+)-1-phenylethanol
([~122 = +39.5) and 5.2 g (0.055 mol) of methane-
sulphochloride are dissolved in 100 ml of ether and
cooled to 0, and at this temperature a solution
of 5.1 g (0.060 mol) of triethylamine in 50 ml of ether
is added drop~ise. The mixture is stirred for 1 hour
at 0 and the precipitate that has formed is filtered
off. The filtrate is concentrated by evaporation as
gently as possible under a water~jet vacuum, and the
residue is dissolved in 20 ml of toluene and, at 90,
added dropwise to a solution of 80 2 g (0.1 mol) of
2-methylimidazole. The mixture is heated at 90 for
1 hour. For working up, the mixture is dilute~ with
ether and with water and then extracted by shaking
three times with 50 ml of 2N hydrochloric acid. The
hydrochloric acid extracts are rendered alkaline with
concentrated sodium hydroxide solution and extracted
with ether. The resulting ethereal solutions are dried
over magnesium sulphate and concentrated to dryness.
The residue that remains is crystallised twice from
cyclohexane and yields pure laevorotatory 1~ phenyl-
ethyl)-2-methylimidazole havin~ a melting point of
113-1 15 [~ 2 = -15 + 1 . (Enantiomer purity
approximately 95% according to NMR.) The hydrochloride
melts at 243-244.
Example 13
In the same manner as that demonstrated in Example
11, dextrorotatory 1-[1-(phenyl)-ethyl]-2-methyl-
- 3~ 3~
imidazole ha~ing a ~elting point of 113-1 15
[~]20 = ~15 (+ 1) is obtained from 5O0 g of S(-)-1-
phenylethanol ([~12 = -41.3). The hydrochloride
melts at 243-244.
Example 14
In a manner analogous to that described in Example
1, 1-[1-~3-methoxyphenyl)-ethyl]-2-methylimidazole is
obtained in the form of an oil from 20.2 g (0.1 mol~ of
1-~3-methoxyphenyl)-ethanol and 25 g (0.3 mol~ of 2-
methylimidazole. The hydrochlcride melts at 197-
1 99o.
Example 15
6.0 g (0.0297 mol) of 1-[1-(2-hydroxyphenyl)-
ethyl]-2-methylimidazole and 25 ml of hexametapol are
suspended in 25 ml of tetrahydrofuran and, while
stirring at 20, 1.3 g (0.030 mol) ~f sodiu~
hydride suspension (55%) are added in portions. The
mixture is stirred for 2 hours at 20. ~ solution of
4.25 g (0.030 mol) of methyl iodide in 25 ml of
hexametapol is then added dropwise thereto and the
mixture is kept at 45 for 1 hour.
The reaction mixture is poured onto 200 ml of
ice-water and extracted by shaking with ~ethylene
chloride. The organic phases are separated off, w~shed
with water and dried over magnesium sulphate. After
removal of the solvent, crude 1-[1-(2-methoxypher1yl)-
ethyl]-2-methylimidazole is obtained in the orm of an
oil. The hydrochloride melts at 201-203.
The 1-[1~(2-methoxyphenyl)-ethyl]-2-methyl-
imidazole required as starting material can be obtained
as follows:
20.0 g (0.1 mol) of ~-methylene-1-(2-hydroxy-
benzyl)-2-methylimidazole are ~issolved in 500 ml of
-- 37 --
ethanol and, after the addition of 1 g of palladium-on-
carbon, hydrogenated at room temperature and norntal
pressure. The catalyst is then filtered off and the
solvent is extensively removed ln vacuo; fumaric acid
is added to the residue until a ~eakly acidic reaction
is obtained. After the addition of ethyl acetate, the
product that has formed is filtered off, recrystallised
from alcoholfethyl acetate and dried. The pure 1 [1-
(2-hydroxyphenyl)-ethyl]-2-methylimidazole melts at
148-1 50.
For further reaction, 10 g (0.03 mol) of the
fumarate are cleaved with 2N sodiu~ hydroxide solution
and ether to form the free base. The free base is
obtained which is reacted as described.
Example 16
In a manner analogous to that described in Example
1, a crude product is obtained from 18.2 g (0.1 mol) of
1-(2,3-dimethoxyphenyl)-ethanol and 25 g (0.3 mol) of
2-methylimidazole. The free base is chromatographed
over silica gel with methylene chloride/1-59~ methanol
and yields pure 1-11-(2,3-dimethoxyphenyl)-ethyl]-2-
methylimidazole having a melting point of 122-124.
The hydrochloride melts at 175-178.
Example 17
In a manner analogous to that described in Example
1, 7.9 g of pure 1-[1-(2,4,6-trimethylphenyl)-ethyl]-
2-methylimidazole having a melting point of 129-131
is obtained from 16.4 g (0.1 mol) of 1-(2,4,6-
trimethylphenyl)-ethanol and 25 g (0.3 mol) of 2-
methyl imidazole. The hydrochloride melts at 267
(decomposition) .
- 38 - ~3~
Example 18
In a manner analogous to that described in Exarnple
1 r from 9.1 g (0.05 mol) of 1-(2,6-dimethoxyphenyl)-
ethanol and 1 2.5 g (O.l5 mol) oE 2-methyli-nidazole
there are obtained 3.7 g of crude 1-[1-(2,6-dimethoxy-
phenyl)-ethyl]-2-methylimidazole which yields pure
hydrochloride having a melting point of 214-216.
The starting material can be prepared as follows:
16.6 g (0.1 mol) of 2,6-dimethoxybenzaldehyde are
dissolved in 200 ml of absolute tetrahydrofuran, and
60 ml of a 2.58 molar methylmagnesium iodide solution
in tetrahydrofuran are added dropwise thereto at 10.
The reaction mixture is kept at room temperature for 2
hours and then a solution of 30 g of ammonium chloride
in 200 ml of water is added. The resulting mixture is
extracted by shaking with ether, and the organic phases
are washed with brine and dried over magnesium
sulphate. After removal of the solvent, the residue is
crystallised from isopropyl ether/petroleum ether. The
resulting 1-t2,6-dimethoxyphenyl)-ethanol melts at
56-58.
Example 19
In a manner analogous to that described in Example
1, 1.95 g of oily 1-[1-(2,3-dimethylphenyl) -ethyl]-2-
methylimidazole are obtained from 3 g (0.02 mol) of
1-(2,3-dimethylphenyl)-ethanol and 4.92 g (0.06 mol) of
2-methylimidazole. The pure 1-[1-(2,3-dimethylphenyl)-
ethyl]-2-methylimidazole hydrochloride, which has a
melting point of 244-246, is prepared from 1.92 g of
the crude base with ethereal hydrochloric acid.
Example 20
9. 25 g (0.05 mol) of 1-phenylethyl bromide are
dissolved with 20. 5 g (0. 25 mol) of 2-methylimidazole
_ 39 _ ~ ~33~2~
in lO0 ml of toluene and, ~hile stirring, heated at
100 ~or ~ hours. The reaction mixture is coole~; 2N
hydrochloric acid is added until an acidic reaction is
obtained and the acidic aqueous phase is separated off.
The toluene solution is extracted by shaking three
times usin~ 50 ml of lN hydrochloric acid each ti~e and
the combined acidic aqueous phases are rendered
alkaline with concentrated sodium hydroxide solution.
The resulting mixture is extracted by shaking with
ether, and the ethereal solution is dried over
magnesium sulphate and the solvent is removed in
vacuo. The resulting residue is dissolved in ethyl
acetate, and ethereal hydrochloric acid is added until
an acidic reaction is obtained. ~fter a further
addition of ether, the product that has formed is
filtered off, washed with ether and recrystallised from
cyclohexane. The pure 1-(l-phenylethyl)-2-methyl-
imidazole melts at 84-85.
As described in Example 1, the hydrochloride is
prepared from the base. The pure l-(l-phenylethyl)-2-
methylimidazole hydrochloride melts at 229-229.5.
Example 21
10.9 g (0.1 mol) of acetiminomethyl ether hydro-
chloride are added to 23.02 g (0.11 mol) of N-(l-
phenylethyl)-2-aminoacetaldehyde dimethyl acetal and
the whole is dissolved in 200 ml of methanol and left
to stand for 4 days at room temperature. The reaction
mixture is freed of solvent in vacuo and the oily
residue is ~issolved in 250 ml of water and added to
500 ml of concentrated hydrochloric acid. The mixture
is concentrated to dryness by evaporation at tO0 and
the resulting residue is rendered alkaline with a
saturated potash solution. The resulting mixture is
extracted by shaking three times with 500 ml of ether
3~
- 40 -
and the ethereal phases are dried over magnesium
sulphate and the solvent is removed ~n vacuo. The
oily residue is distilled under a high vacuum (6.66
Pa), B.p. = 115-12Q. The resulting product is
dissolved in ethyl ~cetate, and ethereal hydrochloric
acid is added until an acidic reaction is obtained.
The product that forms is filtered off and recrystal-
lised from isopropanol/ether. The pure 1-(2-phenyl-
ethyl~-2-methylimidazole hydrochloride melts at
228-229.
The starting material can be obtained as follows:
a) 60.1 g (0.5 mol) of acetophenone are dissolved in
1000 ml of methanol with 56.78 g (0.54 mol) of 2-
aminoacetaldehyde dimethyl acetal and, after the
addition of 10 g of palladium-on-carbon, catalytically
hydrogenated at room temperature and normal pressure.
After the absorption of hydrogen is complete, the
catalyst is filtered off and the solvent is removed in
vacuo. The resulting residue is dîstilled under a
high vacuum at 60-65 (7.99 Pa) and yields pure
N-(l-phenylethyl)-2-aminoacetaldehyde dimethyl acetal.
b) 82 g (2 mol) of acetonitrile are dissolved in 65 g
(2 mol) of methanol and added to 500 ml of 4N ethereal
hydrochloric acid. The reaction mixture is left to
stand at room temperature and the product that is
formed is filtered off. The resulting product is
washed with ether and dried at room temperature ln
vacuo. The resulting acetiminomethyl ether hydro-
chloride melts at 97.
Example 22
9.1 g (0.05 mol) of 1-[2-methoxybenzyl]-imidazole
are dissolved in 90 ml of tetrahydrofuran and, at
- 4 1 - ~L~3;~
-78, 7. 1 9 (O. 11 mol, correspondin~ to 55.4 ml of
2 molar solution) of butyllithiu~ in 50 ml of
tetrahydroEuran are added dro~wise. The mixture is
stirred for 2 hours at -78 and then 17.0 g
(0.12 mol) of methyl iodide, dissolved in 20 ml of
tetrahydrofuran, are added dropwise. The reaction
mixture is heated to room temperature and stirred at
this temperature for 30 hours. 50 ml of w~ter are then
slowly added dropwise and the tetrahydrofuran is
extensively removed in vacuo.
After the addition of 2N sodium hydroxide solution
until a strongly alkaline reaction is obtained, the
residue is extracted by shaking with ether. The
organic phases are dried over magnesium sulphate and
the solvent is removed ln vacuo. The resulting oily
residue is dissolved in ethyl acetate, and ethereal
hydrochloric acid is added until an acidic reaction is
obtained. T~e product that is formed is filtered off
and recrystallised from isopropanol/ether. The pure
1-[1-(2-methoxyphenyl)-ethyl]-2-methylimidazole
hydrochloride melts at 201-203.
The starting material can be obtained as follows:
In a manner analogous to that described in Example
1, 9.78 g of pure, oily 2-methoxybenzylimidazole are
obtained from 13.8 9 (0.1 !nol) of 2-methoxybenzyl
alcohol and 34 g (0.5 mol) of imidazole. The resulting
product is distilled under a high vacuum at 120-130
(1.33 Pa).
Example 23
4.0 g (20 mmol) of 1-[1-(4-aminophenyl)-ethyl]-2-
methylimidazole are dissolved in 100 ml of Inethanol;
6 ml (60 mmol) of concentrated hydrochloric acid are
added and, at 0, 2.68 g (26 mmol) of tert.-butyl
nitrite are added dropwise. The mixture is stirred for
- 42 ~ ~ ~ 3 ;~
30 minutes at 0, then slowly heated to reflux over
the course of 1 hour and kept at this temperature for
30 minutes. The reaction mixture is concentrated under
a water-jet vacuum; 2N sodiun hydroxide solution is
added until an alkaline reaction is obtained and the
mixture is then diluted with brine and extracted by
shaking with ether. The ethereal extracts are dried
over magnesium sulphate, the solvent is removed in
vacuo, and alcoholic hydrochloric acid is added to the
residue until an acidic reaction is obtained. After
the addition of ethyl acetate, the product that has
formed is filtered off and dried. ~ter recrystal-
lisation from alcohol/ethyl acetate, the pure 1-[1-(4-
methoxyphenyl)-ethyl]-2-methylimidazole hydrochloride
is obtained having a melting point of 200-202.
The starting material can be obtained as follows:
16.5 g (0,,1 mol) of ~-nitroacetophenone are
dissolved in 160 ml OL Inethanol and, while cooling,
3.7 g (0.1 mol~ of sodium borohydri~e are slowly
introduced. When the addition is complete, the mixture
is slowly heated to 60 and is kept at this tempera-
ture until the evolution of gas has ceased. After
cooling, approximately 150 ml of 1 molar sodium
dihydrogen phosphate solution are added and the
methanol is extensively removed in vacuo. The
residuQ is extracted by shaking with ether and the
organic phases are dried over magnesium sulphate and
the solvent is removed in vacuo. The resulting
l-[~-nitrophenyl]-ethanol is further used in
the form of a crude oil.
Pure 1-[1-(4-nitrophenyl)-ethyl]--2-
methyliinidazole having a melting point of 78-79
(recrystallis~tion from diisopropyl ether/petroleum
ether) are obtained as described in Example 1 fro~ 16 g
(0.096 mol) of l-(p-nitrophenyl)-ethanol and 23.6 g
- ~3 ~ 3~
(0.29 mol) of 2 methylimidazole.
14.0 g (0.06 mol) of 1-[1-(4-nitrophenyl)-ethyl]-2-
methylimidazole are dissolved in 150 ml of ethanol; 2 g
of R~ney nickel are added and catalytic hydrogenation
is carried out with hydrogen at normal pressure and
20 over a period of 15 hours.
The catalyst is then filtered off, the solvent is
removed ln vacuo and the residue is crystallised from
ethyl acetate. The pure 1-[1-(4-aminophenyl)-ethyl~-2-
methylimidazole melts at 149-151. The dihydro-
chloride (from alcohol/ethyl acetate with alcoholic
hydrochloric acid) melts at 165-167.
Example 24
In a manner analogous to that described in E~ample
23, pure 1-[1-(2-methoxyphenyl)-ethyl]-2-methyl-
imidazole hydrochloride having a melting point of
201-203 can be obtained from 20.1 g (Oo1 mol) of
1-[1-(2-aminophenyl)-ethyl]-2-methylimidazole.
The dihydrochloride (from alcohol/ethyl acetate
with alcoholic hydrochloric acid) melts at lÇ5-167.
xample 25 Tablets containing 0.020 g of 1-(1-phenyl-
ethyl)-2-methylimidazole can be
manufactured, for example, as follows:
omposition (for 10,000 tablets):
active ingredient200.00 g
lactose 290.80 g
potato starch 274.70 g
stearic acid 10.00 g
talc 200.00 g
magnesium stearate 2.50 g
colloidal silica 32.00 g
ethanol q.s.
- 44 -
A mixture of the active ingredient, the lactose
and 194.70 g of potato starch is moistened with an
ethanolic solution of the stearic acid and granulated
through a sieve. After drying, the remaining potato
starch, the talc, the magnesiu~ stearate and the
colloidal silica are mixed in and the mixture is
compressed to form tablets which each weigh 0O1 g and,
if desired, can be provided with dividing notches for
more accurate adjustment of the dose.
xample 26 Capsules containing 0.025 g of 1~
phenylethyl~-2-methylimidazole can be
manufactured as follows:
Compositio_ (for 1,000 capsules):
active ingredient 25.00 g
lactose 249.00 g
gelatine 2.00 g
corn starch 10.00 g
talc 15.00 g
water q.s.
The active ingredient is mixed with the lactose
and the mixture is moistened uniformly with an aqueous
solution of the gelatine and then granulated through a
sieve of 1.2-1.5 mm mesh width. The granulate is mixed
with the dried corn starch and the talc, and 300 mg
portions are introduced into hard gelatine capsules
(size 1).
