Note: Descriptions are shown in the official language in which they were submitted.
7~
-- 1 --
4-11666
Novel mercaptoimldazole_derivatives
The present invention relates to a process for the
manufacture of novel substituted 2-mercaptoimidazoles of
the formula
Rl ~ N ~
~ ~ S(O)n-R4 (I)
/ N
R2 R
in which at least one of the radicals Rl and R2 denotes a
pyridyl radical,-which may be N-oxidised, or a thienyl
radical and the other one denotes a phenyl radical which is
unsubstituted or substituted by halogen, ~3 is hydrogen or
lower alkyl, n is 0, 1 or 2 and R4 denotes a lower alkyl
radieal which is unsubstituted or substituted , in a
po~ltlon hlgher than the a-pos~tion, by hydroxy radical,
and lower alkoxy or lower alkylthlo, and of their pharma~
ceutically usable salts, in particular pharmaceutically
usable acld addition salts.
In this specification "lower" organic radicals and
compounds are to be understood as meanin~ those which
contain not more than 7 and in particular not more than
4 carbon atoms. Thienyl is for example 2-thienyl,and
pyridyl is for example 2-, 3- or 4-pyridyl.
I
2 - -3L lL~
Lower alkyl radicals which are substituted, in a
position higher than the 2-position, by hydroxyl, lower
alkoxy or lower alkylthio are hydroxy-lower alkyl, lower-
alkoxy-lower alkyl or lower alkylthio-lower alkyl radicals.
Hydroxy-lower alkyl is mono- or di-
hydroxy-lower alkyl, has in particular 2 to 4 C atoms and
is, for example, 2-hydroxyethyl, 2- ox 3-hydroxypropyl or
2,3-dihydroxypropyl.
Lower alkoxy-lower alkyl has 1 to 4
C atoms in each alkyl moiety and is, for example, 2-methoxy-
ethyl, 2-ethoxyethyl or 2- or 3-methoxypropyl.
Lower alkylthio-lower alkyl has 1 to
7 C atoms and is, for example, 2-methylthioethyl.
Lower alkyl has 1 to 7 C a-toms and is,
for example, methyl, ethyl, propyl, isopropyl or n-, iso-,
sec.- or tert.-butyl or, less preferentially, one of the
isomeric pentyl, hexyl or heptyl groups.
Lower alkoxy has 1 to 7 C atoms and
is, for example, methoxy, ethoxy, propoxy, isopropoxy or
n-, sec.-, iso- or tert.-butoxy or, less preferentially,
one of the isomeric pentyloxy, hexyloxy or heptyloxy ~roups.
Halogen is preferably halogen with an atomic number
of not more than 35, such as fluorine, chlorine or bromine.
Salts of compounds of the formula I are in parti-
cular pharmaceutically usable acid addition salts with
strong acids, such as a mineral acid, for example salts
with hydrogen halide acids, in particularhydrochloric acid
or hydrobromic acid, i.e. hydrohalides, in particular hydro-
chlorides and hydrobromides, or sulfuric acid salts, i.e.
bisulfates and sulfates.
The in~ention relates in particular to substituted
2-mercaptoimidazoles of the formula I in which R , R2, R3
s
.~
7~
-- 3 --
and R4 have the meanings lndicated hereinbefore under
formula I and n denotes 0, and pharmaceutically usable
salts, in particular pharmaceu~ically usable acid addition
salts, thereof, processes for their preparation, pharma-
ceutical preparations containing these compounds or
pharmaceutically usable acid addition.salts thereof, and
the use of the compounds defined abova.
The compou~ds of the fonmula I have valuable
pharmacological properties. In particular, they have
a pronounced anti-inflammatory, anti-nociceptive and~or
anti-thrombotic activity as well as an inhibitory action
on the prostaglandin synthesis. Thus, they prove to have
an excellent effect in rats in the kaolin paw oedema test
according to Helv. Phydiol. Acta 25, 156 (1967) in the
dosage range of about 15 to lS0 mg/kg, and also in the
Carrageneen paw oedema test according to Di Pasquale et al.,
Agents and Actions 5, 256 (1975) in the dosage range of
about 20 to 200 mg/kg, when administered perorally, in a
single dose, additionally also in the adjuvaus-arthritis
o the rat on four single doses of about lO to 60 mg/kg p.o.
and in mice in the writhing syndrome induced ~y phenyl-p-
benzoquinone, according to J. Pharmacol. exp. Therap.
125, 237 (l9S9), in the dosage range of about 30 to 300
mg/kg p.o. and in the emboly of the rabbit lung which
had been in~uced by dosage of arachidonates in a dosis
range of about 0,1 to 3 mg/ky p.o..
Furthermore, in ths concentration range of about
10 to 30 ml/l, they inhibit in ~itro the prostaglandin
sy~thesis from arachidonic acid, demonstrated in the test
arrangement-according to Prostaglandins 7, 123 (1974).
The compouL~ds of the formula I are therefore out-
standingly suitable as active ingredients in pharmaceu-
tical preparations ~or the treatment of inflammatory dis-
eases, in particular chronic inflammation of the rheumat
~.
. .
3.~ Z
4 -
ic type, such as chronic arthritis.
The invention relates primarily to compounds of the
formula I, wherein one of the radicals Rl or R2 is pyridyl
and the other is phenyl which may be substituted halogen
having an atomic number of not more than 35, such as chlori-
ne, but is preferably unsubstituted, R3 is hydrogen or
lower alkyl having 1 to 4 C atoms, such as methyl, n is O
and R4 is lower alkyl having 1 to 4 C atoms, such as methyl,
ethyl, propyl, isopropyl or butyl, hydroxy-lower alkyl which
has 1 to 4 C atoms and carries the hydroxyl group in a
position higher than the a-position, such as 2-hydroxy-ethyl,
or lower alkoxy- or lower alkylthio lower alkyl which has
1 to 4 C atoms in each alkyl moiety and carries the alkoxy
or alkylthio group in a position higher than the a-position,
s~ch as 2-methoxyethyl or 2-methylthioethyl, and their acid
addition salts.
The invention relates in particular to compounds of
the formula I in which one of the radicals R1 and R2 is un-
substituted pyridyl, such as 3-pyridyl, or thienyl, such as
2-thienyl, and the other is unsubstituted phenyl or phenyl
substituted by halogen having an atomic number of not more
than 35, such as chlorine and in particular fluorine, R3 is
hydrogen or, less preferentially, lower alkyl having 1 to 4
C atoms, such as methyl, n is 0, 1 or 2 and R4 is lower
alkyl having 1 to 4 C atoms, such as ethyl,and their salts.
The invention relates especially to compounds of the
formula I in which one of the radicals Rl and R~ is unsub-
stituted pyridyl, such as 3-pyridyl, and the other is un-
substituted phenyl or, less preferentially,phenyl substi-
tuted by halogen, for example chlorine or bromine, R3 is
hydrogen or lower alkyl having 1 to 4 C atoms, for example
methyl or ethyl, n is O and R4 is lower alkyl
having 1 to 4 C atoms, for example methyl or ethyl, or
hydroxy-lower alkyl which has 2 to 4 C atoms and carries
the hydroxyl group in a position higher than the a-positio~
( )7~;~
~ for example 2-.hydroxyethyl, and their acid addition
salts.
The invention relates very particularly to compounds
of the formula I in which one of the radicals Rl and R2 is
pyridyl, such as 3-pyridyl, and the other is phenyl, R3 is
hydrogen, n is O and R4 is lower alkyl having 1 to
4 C atoms, such as ethyl, and their acid addition
salts.
The invention relates specifically to the compounds
of the formula I named in the examples,and their acid
addition salts.
The compounds of the formula I and their salts can
be prepared by methods known per se, for example by reac-
ting compounds of the formulae
\ / ~
X (II) and Y - R4 (III),
2 ~R
in which either X denotes mercapto which can be in the form
of a salt, Y denotes reactively esterified hydroxyl, Rl, R2
. ; and R3 have the meanings given hereinbefore and R~ denotes
lower alkyl or lower alkyl substituted by lower alkoxy and/
~ or lower alkylthio or, when Rl denotes 3-pyridyl, R2 denotes
unsubstituted phenyl and R3 denotes hydrogen, represents
2-hydroxyethyl, or X denotes a halogen atom or a sulphonyl
group, Y denotes mercapto which can be in a salt form and
Rl, R2, R3 and R4 have the meanings given hereinbefore,
~. ~
Z
-- 6 --
or one of the radicals X and Y is a group of the formula
-S(O) -Yl, in which Yl denotes a halogen atom or, if n is 0,
and etherified mercapto group or, if n is 1 or 2, an e-theri-
fied hydroxyl group, and the other is a metal radical Y2,
with one another, or reacting a compound o the formula II
in which X is a mercapto group with a lower alkene or an
epoxy-lower alkane, which is unsubstituted or substituted as
indicated, or reacting a compound of the formula II, in which
X is a sulphinic or sulphonic acid group in the form of a
salt, with a compound of the formula III in which Y is a
halogen atom and, when required, converting, as specified in
claim 1, a resulting compound to another compound of the
formula I and/or converting a resulting free compound to an
acid addition salt or converting a resulting acid addition
salt to the free compound or to another salt.
Mercapto or sulphinic acid groups in the form of a salt
are, for example, in the form of an alkali metal salt or
ammonium salt, for example mercapto or sulphinic acid groups
in the form of the sodium, potassium or ammonium salt.
Reactively esterified hydroxyl groups are, for example,
halogen atoms, reactively esterified hydroxyl groups Y
furthermore hydroxyl groups esterified with sulphuric acid,
i.e. groups of the formula -O-S02-OR4, or hydroxyl groups
esterified with an organic sulphonic acid, for example, with
methane-, ethane-, benzene-, p-bromobenzene- or p-toluene-
sulphonic acid.
Halogen atoms X, Y and Yl are, for example, chlorine,
bromine or iodine.
Sulphonyl groups are sulphonyl groups derived from
organic sulphonic acids, for example, methanesulphonyl,
ethanesulphonyl, benzenesulphonyl, p-bromobenzenesulphonyl
or p-toluenesulphonyl.
:.`
,
7~
Esterified mercapto groups Y1 in groups X of the
formula -S(0)~-Yl in which n is 0 are, for example,
l-R3-4-Rl-S-R2-im~dazol-2-yl-thio radical~ and in gro~ps
Y of the formula S(O~n-Yl in which n is 0 are, for example,
those of the formula -SR4. Etherified hydroxyl is, for
example, hydroxyl etherified with an aromatic aclohol,
such as a substituted or unsubstituted phenol, ~n groups
of the formula -S(O)n~Yl in which n is 1, and also lower
alkoxy. Metal ra~icals Y2 are, for example, those
of the formulae -M , -MII/2 or -M I-Hal, in which M is an
alkali metal atom, for example lithium or sodium, and MII
is an alkaline earth metal atom, f~r example magnesium,
cadmium or zinc.
The reaction c~n be carrled out in a conventional
manner, especially in the manner known from the literature
~or analogous reaction~, if necessary in the presence of
a catalytic agent, and in the case of the reaction o~
mercapto compounds of the formula II with alkenes or
phenylalken~s, for ex2mple in the presence o~ acid agents,
such as Lewis acid~, for example of iron-II salts or
boron trifluoride, or.of peroxides,for ex~mpleof di tert.-
butyl peroxlde, or under the action of W light, for
example with a wavelength of about 200 to 350 um.
When carrying out the said reactions, the reaction is in
each case.preferably carried out in a sol~ent, and whe~
compounds o~ the formulae II and III in which one of the
radicals X and Y is a metal radical and ~e other is a
group o~ the formula -S(O)~-Yl are used as the starting
materials, and also in the case of the reaction of mer-
capto compounds of the formula II with alke~es or phenyl-
alXenes of the formula III, is carried out, for example,
i~ ether7 tetrahydrofuran or dioxan, or in the case of
,~ .
., . ., ~
~8(~
-- 8 --
the reaction of mercaptans or mercaptides or sulphinic acid
salts of the formula II with reactive esters, for example
halides, of the formula III is carried out, for example,
in an alcohol, for example in methanol, ethanol, ethylene
glycol or ethylene glycol monomethyl ether, the reactions
in each case advantageously being carriedout under an
inert gas atmosphere, for example under nitrogen, and if
necessary at elevated temperature, for example at the boil.
A preferred embodiment of the above process compri-
ses, for example, reacting a 2-mercapto- or 2-sulpho-
imidazole derivative of the formula II, which can be in the
form of one of the said salts, in a lower alkanol, for
example in methanol or ethanol, with a hydrochloric acid,
hydrobromic acid, hydriodic acid or sulphuricacid ester
of the formula II.
In another preferred embodiment, for example, a
compound o~ the formula II in which X is a metal radical
Y2, preferably lithium, and R3 preferably differs from
hydrogen, is reacted, for example in an open-chain or
cyclic aliphatic ether, for example in diethyl ether,
tert-butyl methyl ether, tetrahydrofuran or dioxan, with
a compound o~ the formula III in which Y is a group of the
formula -S-S-R4 or halogen-S-R4.
Some of the starting materials are known. Novel
starting materials can be prepared by methods known per se.
The compounds of the formula II in which X is mer-
capto, which have been cited as starting materials, i.e.
l-R3-4-Rl-5-R2-2-mercapto-imidazoles and 1-R3-4 -Rl-5-R2-
imidazoline-thiones, in which Rl, R2 and R3 are as defined
initially under the formula I, can be prepared, for
example, by subjecting a compound of the formula
~ . /
'! (IV)
~.3.~ R2 X2
A ~ 7 ~ ~
in which Xl is a group of the formula -NH-C(--S)-NHR3 and
X2 is hydroxyl, or X2 is a group of the formula
-NR~-C(=S)~NH2 and Xl is hydroxyl, or a tautomer thereof,
which can be in a ketalised form, to intramolecular
cyclisation
Tautomers of compounds of the formula IV are pre-
ferably the ketones tautomeric to the enols which have
the formula IVo These enols can be ketalised with lower
alkanols or lower alkanediols, for example with methanol,
ethanol ? ethylene glycol or 1,3-propylene glycol.
The intramolecular cyclisation can be carried ou-t
in a con~entional manner, especially in the manner des-
cribed in the literature for analogous reactions, for
example in a solvent, such-as water or an alcohol, for
example in water, ethanol, butanol, ethylene glycol or
ethylene glycol monomethyl ether, if necessary in the
presence of an acid condensing agent, such as a mineral
acid, for example hydrochloric acid, and/or at elevated
temperature, for example at the boil.
The starting materials of the for~ula IV, in turn,
can be obtained by methods known per se and are advan-
tageously prepared in situ and cyclised without isolation.
For this purpose, the starting material used is prefer-
ably a compound of the formula Rl-C0-CH(NHR3)-R2 (IVa) or
an acid addition salt thereof and this is reacted with
thiocyanic acid or a metal thiocyanate. A compound of
the formula IV is formed as an intermediate and this
cyclises according to the invention. A particularly
advantageous reaction is that of a hydrohalide,for exam~le
the hydrochloride, of a compound of the formula IVa with
an alkali metal thiocyanate or ammonium thiocyanate,suchas
withsodium thiocyanate or potassium thiocyanate, in aqueous
solution, if necessary with warming to 60 to 100C.
A variant of this process comprises reacting a
compound of the formula Rl-CH(NH2)~CO-R2 (IVb), or an
acid addition salt thereof, with an isothiocyanate of the
formula R3-N=C=S (IVc), in an analogous manner.
, .
r ç~ 7~1~
l~ -3 ~ ~
The starting materials of the formula IV can also
be prepared by reacting a compound of -the formula
Ro~CO~CHOH~Ro (IVd), or a compound of the formula
R0-CO-CH(halogen)-Rl (IVf) obtainable by a-halogenation,
for example with bromine in acetic acid, of a compound of
the formula Ro~CO~CH2~Ro (IVe), in which formulae one of
the groups Ro is the radical Rl and the other is the
radical R2, in a conventional manner with a thiourea
compound of the formula R3NH-CS-NH2 (IVg) or a compound
which produces the latter in situ, for example a R3-
ammonium thiocyanate. At elevated temperatures, for
example at 100-250, the compound of the formula IV which
is first formed cyclises in the manner according to the
invention. If Rl and R2 are different and R~ is not
hydrogen, it is possible, depending on the reactivities of
the individual component of the formula IVc and/or on the
reaction conditions, to obtain both or only one of the
possible isomers, i.e. a l-R3-4-Rl-5-R2-2(3H)-imidazoline-
2-thione and/or a 1-R3-4-R2-5-Rl-2(3H)-imidazoline-2-
thione, and these isomers can, if necessary, be separated
in a conventional manner, for example by fractional
crystallisation or by chromatography.
The starting materials of the formula IVa, in turn,
can be prepared in a manner known per se, for example by
con~rerting a compound of the formula Rl-C0-CH2-R2 to the
oxime, converting the oxime with toluenesulfonyl chloride
in pyridine to the oxime-ester, subjecting the latter to
the Neber's oxime/amine-ketone rearrangement and, if
desired, introducing a radical R3 into the resulting com-
pound of the formula Rl-CO-CH(NH2)-R2, for p
reaction with a lower alkyl bromide or lower alkyl iodide
Starting materials of the formula IVb can be pre-
pared in an analogous manner, using a compound of the
formula Rl-CH2-C0-R2 as the starting material.
Starting materials of the formula IVd in which R
and R2 are identical radicals Ro can also be prepared by
autocondensation of an aldehyde of the formula Ro~CH0
(IVh), for example effected with potassium cyanide in
ethanol/water or tetrabutyl-ammonium cyanide in water.
The compounds of the formula II in which X is mer-
capto can also be obtained by heating a corresponding
imidazole derivative of the formula
X ~
R2
R3
which is unsubstituted in the 2-position, in tetramethylene
sulfone with sulfur to about 150-250C, for example to
about 200C.
Starting materials of the formula II in which X
is a metal radical Y2 are preferably prepared in situ, for
example by reacting a compound of the formula V with a
metal-organic compound of the formula R-Y2 (VI), in which
R is an aliphatic radical, preferably lower alkyl, for
example with butyl-lithium or methyl- or butyl-magnesium
bromide, Compounds of the formula II in which Y2 is
a Zn-halogen or Cd-halogen group can then be obtained from
the magnesium-organic compounds thus obtainable, by re-
action with zinc chloride or cadmium dichloride.
The starting materials of the formula V can, in
turn, be prepared by heating a compound of the formula
R0-C0-CH(halogen)-R0 (IVf), in which one of the radicals
Ro is a group Rl and the other is a group R2, with form-
amide, preferably at the boil. The compounds of the
formula IVf can, in turn, be obtained by reacting a com-
pound of the formula Rl-CH=0 or R2-CH=0 (Va) in the pres-
ence of a di-lower alkylamine hydrochloride, for example
dimethylamine hydrochloride, with an alkali metal cyanide,
treating the resulting 2-Rl- or 2-R2-di-lower alkylamino-
acetonitrile (Vb) in dimethylformamide with sodium hydride
and then with a compound of the formula R2- or Rl-CX2-
halogen (Vc), hydrolysing the condensation product by
- 12 -
heating for several hours in a mixture of concentrated
hydrochloric acid and chloroform and halogenating the re-
sulting compound of the formula Ro~CO~CH2-Ro (IVe), for
example by means of bromine in acetic acid or copper-II
bromide in ethyl acetate.
Starting materials of the formula II in which X is
a free or esterified sulfo group or a sulfo group in the
form of an anhydride, such as sulfo, lower alkoxy- or
phenoxy-sul~onyl or a sulfonyloxysulfonyl group, can be
obtained, for example, by oxidising the mercapto group in
a compound of the formula II in which X is mercapto to the
sulfo group and, if desired, halogenating this, for ex-
ample with phosphorus pentachloride, and converting the
halogenosulfonyl group to esterified sulfo with an alcohol,
for example a lower alkanol or phenol, or to an anhydride
in the conventional manner, for example by reaction with
a sul~onic acid salt. Sul~inic acid esters of the
formula II can also be prepared analogously, the oxida-
tion of the mercap~an being stopped at the sulfinic acid
stage. Compounds of the formula II in which X is a
group -S-S-R4 can be obtained by mild oxidation of mer
captans of the formula II, for example by means of iron-
III chloride or atmospheric oxygen.
The compounds of the formula I in which n is O
can also be prepared by reacting a compound of the formula
R
o\ ~o
!
R / \X
in which one of the radicals Ro is a group Rl and the other
is a group R2 and X5 is a reactive esterified hydroxyl
group, it being possible for a compound of the formula VI
in which Rl and/or R2 is a hasic group also to be in the
form of an acid addition salt, with a compound of the
formula
EIN
~C-SR4 (VIa)
R -HN
separating a mix~ure of isomers,
C ,g
3.~ '71~
- 13 -
which may be obtained, andJ if desired, converting the
resulting compound to another compound of the formula I
and/or converting a resulting free compound to a salt or
converting a resulting salt to the free compound or to
another salt.
The reaction is carried out in a conventional
manner, preferably by liberating the N-R3-S-R4-isothio-
urea, and if necessary the compound of the formula VII,
_ situ from a salt, of a compound oE Lormula VIa,such as an
alkosulfate or halide, for example bromide or chloride,
and a compound of the formula VI which may be in the form
of a salt, for example by the action of a base, such as
an alkali metal hydroxide or alkali metal carbonate, for
example sodium hydroxide or carbonate or potassium
hydroxide or carbonate, or a nitrogen base, for example
ammonia, a tri-lower alkylamine, such as triethylamine or
N,N-diisopropylethylamine, or pyridine, 3 equivalents of
base being required if the starting materials of the
formula VI are in the form of a salt~and otherwise
2 e~uivalents of base bein~ required, the reaction ad-
vantageously being carried out in a solvent, such as a
lower alkanol, for example in methanol, ethanol, butanol
or amyl alcohol, if necessary at elevated temperature,
for example at the boil
The starting materials of the formula VI can be
prepared by methods known per se, for example by reacting
a compo~nd of the formula Rl-CH=O or R2-CH-O (Va) in the
presence of a di-lower alkylamine hydrochloride, for
example dimethylamine hydrochloride, with an alkali metal
cyanide, treating the resulting 2-Rl- or 2-R2-di-lower
alkylaminoacetoni~rile (Vb) in dimethylformamide with
sodium hydride and then with a compound of the formula
R2- or Rl-CH2 halogen (Vc), hydrolysing the condensation
product by heating for several hours in a mixture of con-
centrated hydrochloric acid and chloroform and halogena-
ting the resulting compound of the formula Ro~CO~CH2~Ro
(IVe), for example by means of bromine in acetic acid or
~,,,, ~
~8(i~1~
-- 14 --
copper-II bromide in ethyl acetate.
The compounds of the formula I in which R3 is
hydrogen can also be prepared by rearranging a compound
of the formula
X6\~/N
S-R4 (VII)
N
. .
in which X6 is mercapto or lower alkylthiol which is un-
substi-tuted or substituted by phenyl, which, in *urn, can
be substituted as indicated for Rl and R27 for example
methylthio or benzylthio.
The rearrangement can be effected in a convention-
al manner, if necessary in the presence of a ca+alyst,
such as a Lewis acid, for example aluminium trichloride,
and advantageously in a sol~ent, for example in benzene,
toluene, N,N-dimethylaniline, anisole, tetralin, chloro-
benzene, pyridine or decalin.
The starting materials of the formula VII can be
prepared in a manner known per se, for example by first
reacting a compound of the formula Vc R1CO-CO-R2 (VIIa)
with thiourea9 con~erting the resulting S-Rl-5-R2-2-
thiohydantoin with phosphorus pentasulfide to the corres-
ponding 5-Rl-5-R2-di-thiohydantoin and ~urther reacting
the latter with a lower alkyl halide, which can be sub-
stituted as indicated for X6.
In resulting compounds of the formula I it is
possible, within the scope of the given definition, to
introduce, convert or detach substituents.
Thus, for example, an organic radical R3 can be
introduced in place of a hydrogen atom R3 by reaction with
an agen~ which introduces theradical R3~ Such agents are,
for example 9 reactive esters, such as hydrogen halide acid
es~ers, for example hydrochloric, hydrobromic or hydriodic
acid esters 9 organic sulfonic acid esters, ~or example
~; ~ ,.;
2, ~ .
~ ~ ~t)7~
. ~
methane-, ethane-, benzene-, p-bromobenzene- or p-toluene-
sulfonic acid esters, or sulfuric acid esters of corres-
ponding alcohols R30H. The reaction with these agents
is carried out in a conventional manner, for example i~
the presence of a basic condensing agent, such as an
alkali metal hydroxide or alkali metal carbonate, for
example sodium hydroxide or potassium hydroxide or sodium
carbonate or potassium carbonate, an alcoholate, for
example an alkali metal lower alkanolate, such as sodium
methanolate, and also sodium hydride~ ad~antageously in
an inert solvent, for example in dimethylformamide or N-
methylpyrrolidone.
Furthermore, in compounds of the formula I, it is
possible to carry out N-oxida'ion on radicals -S(O)n-R4
in which n is 0 to the corresponding sulfinyl or sulfonyl
radicals in which n is 1 or 2, of radicals -S(O)n-R4 in
which n is 1 to the corresponding sulfonyl radicals in
n is 2 and/or of heteroaryl radicals Rl and/or R2
which have at least one free ring nitrogen atom ~ N, such
as pyridyl radicals. The oxidation is preferably
effected by the action of a suitable oxidis.ing agent,
advantageously in a solvent which is inert towards this
agent, if necessary with cooling or warming, for example
in the temperature range of about -30 to +100C, pre-
ferably at about 0 to 60C, in a closed vessel and/or
under an inert gas, such as nitrogen. Suitable
oxidising agents are, for example, peroxy compounds, such
.as hydrogen peroxide, organic hydroperoxides, for example
tert.-butyl hydroperoxide, organic per-acids, such as
aromatic or aliphatic percarboxylic acids, for example
m~chloroperoxybenzoic acid, peroxyacetic acid or permono-
phthalic acid, oxidising heavy metal compounds, such as
chromium-VI compounds or manganese-IV or manganese-VII
compounds, for example chromium trioxide, chromic acid,
manganese dioxide or potassium permanganate, oxidising
inorganic oxyacids,-such as oxyacids of nitrogen, of halo-
gens or of chalcogens, or the anhydrides or salts there-
;.~.
t)'7~j~
, ~
of, for example nitric acid, dinitrogen tetroxide, sele-
nium dioxide or sodium metaperiodate, and also ozone
Suitable solvents are, for example, halogenated hydro-
carbons, such as halogenoal~anes, for example carbon
tetra~.hloride, chloroform or methylene chloride, or
carboxylic acids, such as alkanoic acids, for example
acetic acid, or the anhydrides thereof~
In a pre~erred embodiment of this oxidation pro-
cess, it is possible, for example, to oxidise thioethers
of the formula I in which n is O and/or one of the radi-
cals Rl and/or R2 has an unsubstituted ring nitrogen atom
~ N by reaction with an organic per-acid, for example with
m-chloroperbenzoic acid, in a halogenoalkane, for example
in chloroform, to the corresponding sulfinyl or sulfonyl
compounds in which n is 1 or 2, and, if desired, at the
nitrogen atom ~N.
In another preferred embodiment, thioethers of the
formula I in which n is O can be selectively oxidised by
-treatment with sodium metaperiodate, preferably in a
halogenoalkane, ~or example in carbon tetrachloride or
chloroform, to the corresponding sulfoxides in which n is
1, or the latter can be oxidised with hydrogen peroxide
in acetic acid to sulfones in which n is 2.
Conversely, in compounds of the ~ormula I in
which n is 1 or 2 and/or heteroaryl radicals Rl and/or R2
are N-oxidised, it is possible to reduce the group
S(O)-R4 or -S(0)2-R4 to the corresponding group S(O)o-R4
and/or to reduce N-oxidised ring nitrogen ~ N-O to ~ N.
The reduction is effected by treatment with customary
reducing agents, for example with nascent or catalytically
activated hydrogen, such as iron or zinc and acid, such
as hydrochloric acid, or with hydrogen in the presence of
Raney nickel, advantageously in an inert solvent, such as
a lower alkanol, or with light metal hydrides or di-light
metal hydrides, for example with alkali metal aluminium
hydrides or alkali metal borohydrides, for example with
sodium borohydride or lithium aluminium hydride, advan-
, ,
~ ~()'7
B _~07
tageously in an inert solvent, such as an ether, forexample diethyl ether or tetrahydrofuran, or, for
selective reduction of ~N-O groups, with a phosphorus-
III compound, such as a phospine, for example triphenyl-
phosphine or tri-n-butylphosphine, or a phosphorous acid
ester, such as a tri-lower alkyl phosphiteg for example
with trimethyl phosphite or triethyl phosphite
Furthermore, it is possible, if desired, to
introduce additional C substituents into the radicals
Rl and R2 and also into aryl, aryloxy and arylthio groups
as constituents of R4. Thus, halogenation can be
carried out in a conventional manner, for example by re-
action with chlorine or bromine in the presence of iron
or by means of N-chlorosuccinimide. Furthermore,
alkylation can be carried out in a conventional manner,
~or example by reaction with an alkyl halide, alkanol or
alkene in the presence of aluminium trichloride.
Furthermore, nitration can be carried out in a convention-
al manner, for example by means of nitric acid/sulfuric
acid.
Furthermore, nitro groups can be reduced to amino
in a conventional manner, such as with nascent hydrogen
for example with iron/hydrochloric acid.
Amino groups can also be substituted in a con-
ventional manner, for example alkylated by reaction with
an alkylating agent, such as one of those mentioned, in
the presence of a basic condensing agent.
Furthermore, resulting free compounds can be con-
verted to acid addition salts in a manner known per se,
for example by reacting a solution of the free compound in
a suitable solvent or solvent mixture with one of the
abovementioned acids or with a solution thereof, or with
a suitable anion exchange resin.
Resulting acid addition salts can be converted to
the free compounds in a manner known per se, for example
by treatment with a base, such as an alkali metal hydrox-
ide, a metal carbonate or bicarbonate or ammonia, or
with a suitable anion exchange resin
Resulting acid addition salts can be converted to
other acid addition salts in a manner known per se, for
example by treatment with an anion exchange resin or by
treating a salt of an inorganic acid with a suitable metal
salt, such as a sodium, barium or silver sal-t, of an acid
in a suitable solvent, in which an inorganic salt which
forms is insoluble and thus precipitates out of the re-
action mixture.
The compounds, and their salts, can also be
obtained in the form of the hydrates or can incorporate
the solvent used for crystallisation.
Beoause of the close relationship between the
novel compounds in the free form and in the form of their
salts, what is stated in this specification in respect of
the free compounds or the salts thereof also applies by
analogy to the corresponding salts and free compounds.
The invention also relates to those embodiments
of the process in which a compound obtainable as an
intermediate at any process stage is used as the starting
material and the missing process steps are carried out,
or in which a starting material is formed under the re-
action conditions or is used in the form of a derivative
thereof, if desired in the form of a salt.
The starting materials used in the process of the
present invention are preferably those which result in
the compounds described initially as being particularly
valuable.
The pharmaceutical preparations according to the
invention, which contain compounds of the formula I or
II or pharmaceutically usable salts thereof, are those
which are intended for enteral, such as oral or rectal,
and parenteral administration and for topical application
to warm~-blooded animals and which contain the pharmaco-
logical active ingredient on its own or together with a
pharmaceutically usable carrier. The dosage of the
acti~e ingredient depends on the species of warm-blooded
/q
animal, the age and the individual condition and also on
the mode of administration. In the normal case, an
approximate daily dose of about 30-300 mg, advantageously
divided into several equal partial doses, is to be esti-
mated for a warm-blooded animal weighing about 75 kg, in
the case of oral administration.
The novel pharmaceutical preparations contain,
for example, from about 10% to about 80%, and preferably
from about 20% to about 60%, of the active ingredient.
Pharmaceutical preparations according to the invention
for enteral and parenteral administration are, for example,
those in the form of dosage units, such as sugar-coated
tablets, tablets, capsules or suppositories, as well as
ampoules. These are prepared in a manner known per
se, for example by conventional mixing, granulating,
sugar-coating, dissolving or lyophilising methods.
Thus, pharmaceutical preparations for oral use can be ob-
tained by combining the active ingredient with solid
carriers, granulating a resulting mixture if desired and
processing the mixture or granules, if desired or if nec-
essary after adding suitable adjuncts, to tablets or
sugar-coated tablet cores.
Suitable carriers are, in particular fillers,
such as sugars, for example lactose, sucrose, mannitol
or sorbitol, cellulose preparations and/or calcium phos-
phates, for example tricalcium phosphate or calcium
hydrogen phosphate, and also binders, such as starch
pastes~using, for example, maize, wheat, rice or potato
starch, gelatin, tragacanth, methylcellulose and/or poly-
vinylpyrrolidone, and/or, if desired, disintegrators,
such as the above starches, and also carboxymethyl starch,
crosslinked polyvinylpyrrolidone, agar or alginic acid or
a salt thereof, such as sodium alginate. Adjuncts
are in particu~ar glidants and lubricants, for example
silicic acid, talc, stearic acid or salts thereof, such
as magnesium stearate or calcium stearate, and/or poly-
ethylene glycol. Sugar-coated tablet cores are pro-
I E~ ,,,~o
vided with suitable coatings which can be resistant to
gastric juices, using, inter alia, concentrated sugar
solùtions which may contain gum arabic, talc, polyvinyl-
pyrrolidone, polyethylene glycol and/or titanium dioxide,
shellack in suitable organic solvents or solvent mixtures,
or, for the preparation of coatings resistant to gastric
juices, solutions of suitable cellulose preparations,
such as acetylcellulose phthalate or hydroxypropylmethyl-
cellulose phthalate.Dyesorpigments canbe addedto~he tablets
or the coatings of sugar-coated tablets~ for example to
identify or indicate different doses of active ingredient
Further pharmaceutical preparations for oral ad-
ministration are dry-filled capsules made of gelatin and
also soft, sealed capsules made of gelatin and a
plasticiser, such as glycerol or sorbitol. The dry-
filled capsules can contain the active ingredient in the
form of granules, for example in admixture with fillers,
such as lactose, binders, such as starches, and/or lubri-
cants, such as talc or magnesium stearate, and, if desired,
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 can also be added.
Pharmaceutical preparations for rectal admini-
stra-tion are, for example, suppositories, which consist
of a combination of an active ingredient with a supposi-
tory base. Examples of suitable suppository bases are
natural or synthetic triglycerides, paraffinhydrocarbons,
polyethylene glycols or high alkanols. Gelatin
rectal capsules, which contain a combination of the active
ingredient with a base, can also be used; base materials
are, for example, liquid triglycerides, polyethylene
glycols or paraffinhydrocarbons.
Preparations suitable for parenteral admini-
stration are, in particular, aqueous solutions of an
active ingredient in a water-soluble form, for example of
a water-soluble salt, and also suspensions of the active
ingredient, such as corresponding oily injection suspen-
sions7 for which suitable lipophilic solvents or vehicl0s,
such as fatty oils, for example sesame oil, or synthetic
fatty acid esters, for example ethyl oleate or tri-
glycerides, are used, or aqueous injection suspensions
which contain substances which increase the viscosity,
for example sodium carboxymethylcellulose, sorbi-tol and/or
dextran, and can also contain stabilisers.
Pharmaceutical preparations for topical applica-
tion are, in particular, creams, ointments, pastes, foams~
tinctures and solutions, which contain Prom about 0.5 to
about 20% of the active ingredient.
Creams are oil-in-water emulsions which contain
more than 50% of water Substances used as the
oleaginous base are, in particular, fatty alcohols, for
example lauryl alcohol, cetyl alcohol or stearyl alcohol,
fatty acids, for example palmitic acid or stearic acid,
liquid to solid waxes, for example isopropyl myristate,
wool wax or beeswax, and/or hydrocarbons, for example
petroleum jelly (petrolatum) or paraffin oil. Suit-
able emulsifiers are surface-active substances with
primarily hydrophilic properties, such as corresponding
non-ionic emulsifiers, for example fatty acid esters of
polyalcohols or ethylene oxide adducts thereof, such as
polyglycerol fatty acid esters or polyoxyethylene sorbitan
fatty acid esters (Tweens), and also polyoxyethylene
fatty alcohol ethers or fatty acid esters, or correspond-
ing ionic emulsifiers, such as alkali metal salts of
fatty alcohol sulfates, for example sodium lauryl-sulfate,
sodium cetyl-sulfate or sodium stearyl-sulfate, which are
customarily used in the presence of fatty alcohols, for
example cetyl alcohol or stearyl alcohol. Additives
to the aqueous phase are, inter alia, agents which re-
duce the extent to which the creams dry out, for example
polyalcohols, such as glycerol sorbitol, propylene
glycol and/or polyethylene glycols, and also preservatives,
perfumes and the like.
7~l~
Ointments are water-in-oil emulsions which con-
tain up to 70%, but preferably from about 20% to about 50/0,
of water or aqueous phases. The oleaginous phase
comprises, in particular, hydrocarbons, for example
petroleum jelly, paraffin oil and/or hard paraffins,
which preferably contain hydroxy compounds suitable for
improving the water-binding capacity, such as fatty alco-
hols or esters thereof, for example cetyl alcohol or wool
wax alcohols, or wool wax. Emulsifiers are corres-
ponding lipophilic substances, such as sorbitan fatty
acid esters (Spans), for example sorbitan oleate and/or
sorbitan isostearate. Additives to the aqueous phase
are, inter alia, humectants; such as polyalcohols, for
example glycerol, propylene glycol, sorbitol and/or
polyethylene glycol, and preservatives, perfumes and the
like.
Greasy ointments are anhydrous and contain, as
the base, in particular hydrocarbons, for example paraffin,
petroleum jelly and/or liquid paraffins, and also natural
or partially synthetic fat? for example coconut fatty acid
triglyceride, or preferably hardened oils, for example
hydrogenated groundnut oil or castor oil, and also fatty
acid partial esters of glycerol, for example glycerol
mono- and di-stearate, and, for example, the fatty alco-
hols, emulsifiers and/or additives for increasing the
absorption of water, which ha~e been mentioned in connect-
ion with the ointments.
Pastes are creams and ointments containing
secretion-absorbing powder constituents, such as metal
oxides, for example titanium oxide or zinc oxide, and
talc and/or aluminium silicates, the purpose of which is
to bind the moisture or secretion present.
Foams are administered from pressurised dis-
pensers and are liquid oil-in-water emulsions in aerosol
form, with halogena-ted hydrocarbons, such as chlorofluoro-
lower alkanes, ~or example dichlorodifluoromethane and
dichlorotetrafluoroethane, being used as propellants.
Substances used as the oleaginous phase are, inter alia,
hydrocarbons, for example paraffin oil, fatty alcohols,
for example cet~l alcohol, fatty acid esters, for example
isopropyl myristate, and/or other waxes. The emulsi-
fiers used are, inter alia, mixtures of those which have
primarily hydrophilic properties9 such as polyoxyethylene
sorbitan fatty acid esters (Tweens) and those which have
primarily lipophilic properties, such as sorbitan fatty
acid esters (Spans). In addition, the conventional
additives, such as preservatives and the like, are used.
Tinctures and solutions in most cases have an
a~ueous-ethanolic base, to which the following substances
are added9 inter alia: polyalcohols, for example
glycerol, glycols and/or polyethylene glycol, as humec-
tants for reducing evaporation, and fat-restoring sub-
stances, such as fatty acid esters with lower polyethy-
lene glycols, i.e. lipophilic substances which are soluble
in the aqueous mixture, as a replacement for fatty sub-
stances which are removed from the skin with the ethanol,
and, if necessary, other adjuncts and additives.
The pharmaceutical preparations for topical use
are prepared in a manner known per se, for example by
dissolving or suspending the active ingredien-t in the
base or in a part thereof, if necessary. When pro-
cessing the active ingredient in the form of a solution,
it is usually dissolved in one of the two phases before
emulsifying, and when processing the acti~e ingredient in
the form of a suspension, it is mixed with a part of the
base after emulsifying and then added to the remainder of
the formulation.
The present invention also relates to the use of
the compounds of the formulae I and II, and of the salts
of such compounds with salt-forming properties, prefer-
ably for the treatment of inflammations, in particular of
inflammatory chronic diseases of the rheumatic type,
particularly chronic arthritis.
The following examples illustrate the present
7~
invention without in any way restricting the scope thereo~.
Temperatures are in degrees Centigrade.
0.8 g of sodium is dissolved in 200 ml o~ ethanol.
8 g of 2-mercapto-4(5)-phenyl-5(4)-(3-pyridyl)-imidazole
are added to the solution and the mixture is heated under
reflux. After a clear solution has formed, 2.3 ml of
2-chloroethanol are added dropwise and the reaction mix-
ture is heated under reflux for 16 hours. The solvent
is evaporated off in vacuo and the residue is partitioned
between water and ethyl acetate. The organic phases
are washed with water and saturated sodium chloride solu-
tion, dried over sodium sulfate and evaporated.
Crystalline 2-(2-hydroxyethylthio)-5(4)-phenyl-4(5)-(3-
pyridyl)-imidazole is obtained as the residue and after
recrystallisation from ethyl acetate/petroleum ether this
melts at 128-130C.
The starting material can be prepared, for example,
as follows.
10.8 g of benzyl ~-pyridyl ketone are stirred to-
gether with 40 ml of pyridine and a solution of 8 g of
hydroxylamine hydrochloride in 15 ml of pyridine for 6
hours at 100. The reaction mixture is poured onto
ice/water and the resulting mixture is stirred for a
further 15 minutes. The crystals which have precipi-
tated are filtered off with suction, washed with water
and dried under a high vacuum. Benzyl 3-pyridyl
ketone oxime with a melting point of 122-126 is obtained.
A solution of 7.7 g of p-toluenesulfonyl chloride
in 15 ml of pyridine is added dropwise in the course of 5
minutes to a solution, which is stirred at -10, of 8.5 g
of benzyl ~-pyridyl ketone oxime in 20 ml of pyridine.
The reaction mixture is placed in a refrigerator for 24
hours and then poured onto ice/water. After some
stirring and grinding, the oil which has separated out
solidifies to crystals. These are filtered off with
suction, washed with water and dried under a high vacuum.
Benzyl 3-pyridyl ketone oxime p-toluenesulfonate is ob-
tained and this is employed in the next stage without
further puri~ication.
11.6 g of crude benzyl 3-pyridyl ketone oxime
p-toluenesulfonate are suspended in 90 ml of absolute etha-
~ol. A solution o~ 3.7 g of potassium tert.-butylate in
30 ml of absolute ethanol are then added dropwise at 0,
with stirring. The reaction mixture is stirred at 0 for
2 hours. me suspension is filtered with suction and the
filtrate~ which contains the desired a-amino-benzyl 3-pyri-
dyl ketone, is immediately reacted further in the nex~ s~e.
3.6 g of sodium thiocyanate are dissolved in
60 ml of ethanol and 4.5 ml of concentrated hydrochloric
acid are added to the solution. m e suspension is fil-
tered with suction and the filtrate is heated, together
with the alcoholic solution o~ a-amino-benzyl 3-pyridyl
ketone, for 18 hours under reflux. After cooling,
crude 2-mercapto-4(5)-phe~yl-5(4)-(3-pyridyl)-imidazole
can be filtered off, with suction, from the reaction
mixture. me ~iltrate contains further product.
The crude product is recrystallised from dimethylform-
amide/water and then melts at 290-300.
5 g of 2-mercapto-4(5)-phenyl-5(4)-(3-pyridyl)-
imidazole are dissolved in 50 ml of methanol and 10 ml of
2 N sodium hydroxide solution. 2.85 g of methyliodide
are added dropwise, the mixture is stirred for 2 hours at
room temperature, 50 ml of water are added, the resulting
mixture is filtered with suction and the residue is washed
with water. m is yields crude 2-methylthio-4(5)-phe-
nyl-5(4)-(3-pyridyl)-imidazole3 which when recrystallised
from a mixture of isopropanol and petroleum ether
(8:5 parts b~ volume~ melts at 193-194.
8 g of 2-mercapto-4(5)-phenyl-5(4)-(3 pyridyl)-
imidazole are dissolved in 40 ml of methanol and 16 ml of
2 N sodium hydroxide solution. 4.55 g o~ meth~l
iodide are added dropwise to the solution The mix-
ture is stirred ~or a further 2 hours at room temperature.
40 ml o~ water are added, the resulting mixtureis filtered
withsuction and the residue is washed with water- A mix-
ture of l-methyl-2-methylthio-4-phenyl-5-(3-pyridyl)-
imidazole and 1-methyl-2-methylthio-5-phenyl-4-(3-pyridyl)-
imidazole is obtained. This mixture can be separated
into the components by chromatography. Thus, on a
silica gel column, first one component with a melting
point o~ 141-143 is eluted with chloroform and then the
other component with a melting point of 125-127 is
eluted with chloroform/ethyl acetate (8:2 parts by volume).
~a~
The ~ollowing compounds can also be prepared in a
manner analogous to that described in ~ : ~(2-
hydroxyethylthio)-l-methyl-4-phenyl-5-(3-pyridyl)-imid-
azole, 2-~2-hydroxyethylthio)-1-methyl-5-phenyl-4-(3-
pyridyl)-imidazole, 2-(2-methoxyethylthio)-4(5)-phenyl-
5(4)-(3-pyridyl)-imidazole, 2-(2-methoxyethylthio)-1
methyl-4-phenyl-5-(3-pyridyl)-imidazole, 2-(2-methoxy-
ethylthio)-l-methyl-5-phenyl-4-(3-pyridyl)-imidazole, 2-
(2-methylthioethylthio)-4(5)-phenyl-5(4)-(3-pyridyl)-
imidazole, l-methyl-2-(2-methylthioethylthio)-4-phenyl-5-
(3-pyridyl)-imidazole, 1-methyl-2-(2-methylthioethylthio)-
5-phenyl-4-(3 pyridyl)-imidazole, 2-ethylthio-4(5)~phenyl-
5(4)-(3-pyridyl)-imidazole, 2-propylthio-4(5)-phe~yl-5(4)-
(3-pyridyl)-imidazole, 2-isopropyl-4(5)-phenyl-5(4)-(3-
pyridyl)-îmidazole, 2-methylthio-4,5-bis-(2-thienyl)-
imidazole and 2-ethylthio-4,5-bis-(2-thienyl)-imidazole.
In a manner analogous to that described in Example
2, the ~ollowing compounds can be prepared using, in each
case, 7.6 g of 2-mercapto-4(5)-phenyl-5(4)-(3-pyridyl)-
imidazole as the starting material: 2-ethylthio-4(5)-
phenyl-5(4)-(3-pyridyl)-imidazole,-melting point 196-198
(~rom isopropanol/petroleum ether), 2-propylthio-4(5)-
phenyl-5(4)-(3-pyridyl)-imidazole, melting point 143-144
.
~?~ .
(~rom isopropanol/petroleum ether) and 2-isopropylthio-
4(5)-phenyl-5(4)-(3-pyridyl)-imidazole, melting point
182-184 (from isopropanol/petroleum ether),
A solution of 6.~ g of 85~ m-chloroperbenzoic acid
in 70 ml of chloro~orm is added dropwise to a suspension
of 8 g o~ Z-methylthio-4(5)-phenyl-5(4~-(3-pyridyl~-
imidazole in 400 ml of chloroform, with stirring. The
resulting solution i~ le~t to stand o~ernlght and is then
washed successively with sodium bicarbonate solution and
water, dried over sodium sulfate and evaporated to dryness.
The re~idue is twice recrystallised from isopropanol/
petroleum ether. 2-Methanesulfinyl-4(5)-phenyl-5~4)-
(3-pyridyl)-imidazole with a melting point of 166-169
is obtained,
Using 2-ethylthio-4(5)-phenyl-5(4~-(3-pyridyl)-
imidazole as the startiIlg material, 2-ethanesulfin~l-
4~$)~phenyl-5(4)-(3-pyridyl)-imidazole with a melting
point of 162-164 is obtained in an analogous manner.
8 ml of acetic acid and 0.38 ml of 30% hydrogen
peroxide are added to 1,0 g of 2 ethanesulfinyl-4(5)-
phenyl-5(4)-(3-pyridyl)-imidazole and the mixture is
stirred overnight at 70. It is allowed to cool,
neutralised with sodium hydroxide solution and filtered
with suction. This yields 2-ethanesulfonyl-4(5)-
phenyl-5(4)-[3 (l-oxidopyridinio)]-imidazole, which melts
at 208-210.
2.86 g of -bromobenzyl 3-pyridyl ketone hydro-
bromide and 1 g of-S-methylisothiuronium bromide are sus-
pended in 30 ml of acetonitrile, ~.1 g of N,N-dilsopropyl-
ethylamine are added and the mixture is stirred o~ernight.
The reddish orange suspension is ~iltered and the fil-
trate is evaporated under reduced pressure, The
residue i~ taken up in chloroform, the chloroform solu-
tion is dried over sodlum sulfate and evaporated and the
r ;~ ;7 ~ ~
g_
residue is recrystallised from chloroform/petroleum
ether. 2-Methylthio-4(5)-phenyl-5(4)-(3-pyridyl)-
imidazole with a melting point of 193-194 is obtained.
The starting material can be prepared, for
example, as follows:
A solution of 17 g of bromine in 150 ml of acetic
acid is added dropwise to 20 g of benzyl 3-pyridyl ketone
in 200 ml of acetic acid and the mixture is stirred over-
night. The a-bromobenzyl 3-pyridyl ketone hydrobro-
mide which has precipitated is filtered off and can be used
without further purification.
~.
The following compounds can also be prepared in a
manner analogous to that described in ~ -
2-ethylthio-4(5)-(p-fluorophenyl)-5(4)-(2-thienyl)-imi-
dazole, 2-methylthio-4(5)-(p-fluorophenyl)-5(4)-(2-
thienyl)-imidazole and 2-propylthio-4(5)-(p~fluorophenyl)-
5(4)-(2-thienyl)-imidazole.
~æ~ .
Tablets containing 25 mg of active ~ngredient, for
example 2-methylthio~4(5)-phenyl-5(4)_(3-pyridyl)-imida-
zole, can be prepared as follows:
Constituents (for 1,000 tablets):
Active ingredient 25.0 g
Lactose 100.7 g
Wheat starch 7.5 g
Polyethylene glycol 6000 5.0 g
Talc 5 o g
Magnesium stearate 1.8 g
D`emineralised water q.s.
Pre~
.
A11 the solid ingredients are first forced through
; a sieve of 0.6 mm mesh width. The active ingredient,
the lactose, the talc, the magnesium stearate and half the
starch are then mixed. The other half of the starch
is suspended in 40 ml of water and this suspension is
added to a boiling solution of the polyethylene glycol in
)7~
100 ml of water. The resulting starch paste is addedto the bulk of the constituents and the mixture is granu-
lated, with the addition of water if necessary. The
granules are dried overnight at 35, forced through a
sieve of 1.2 mm mesh width and compressed to tablets which
are conca~e on both sides and about 5 mm in diameter.
Tablets containing, in each case, 25 mg of one of
the other compounds of the formula I named in Examples 1
to 4 can also be prepared in an analogous manner
Tablets, for chewing, containing 30 mg of active
ingredient, ~or example 2-methylthio-4(5)-phenyl-5(4)-(3
pyridyl)-imidazoline, can be prepared, for examile, as
foll~ws:
~E~ (for 1,000 tablets):
Active ingredient 30 0 g
Manni-tol 267.0 g
Lactose 179.5 g
Talc 20 0 g
Glycine 12 5 g
Stearic acid 10.0 g
Saccharine 1,0 g
5% gelatin solution q.s.
Preparation-
All the solid ingredients are first forced through
a sieve of 0 25 mm mesh width. The mannitol and the
lactose are mixed and granulated with the addition of
gelatin solution and the granules are forced through a
sieve of 2 mm mesh width, dried at 50 and again forced
through a sieve of 1.7 mm mesh width. The active
ingredient, the glycine and the saccharine are mixed
carefully, the mannitol, the lactose granules, the stearic
acid and the talc are now added and the whole is mixed
thoroughly and compressed to tablets which are concave on
both sides, have a diameter of about 10 mm and have a
breaking notch on the top.
Tablets for chewing containing, in each case,
7~;~
7~ 30
~ ,~
30 mg of one of the other compounds of the formula I
named in Examples l to 4 can also be prepared in an
analogous manner.
Tablets containing lO0 mg of active ingredient,
for example 2-methylthio-4(5)-phenyl-5(4)-(3-pyridyl)-
imidazole, can be prepared as follows:
(for 1,000 tablets):
Active ingredient lO0.0 g
Lactose 248.5 g
Maize starch 17.5 g
Polyethylene glycol 6000 5.0 g
Talc 15.0 g
Magnesium stearate 4.o g
Demineralised water q.s.
The solid ingredients are first forced through asieve of 0.6 mm mesh width. The active ingredient,
the lactose, the talc, the magnesium stearate and half
the starch are then intimately mixed. The other
half of the starch is suspended in 65 ml of water and this
suspension is added to a boiling solution of the poly-
ethylene glycol in 260 ml of water. The resulting
paste is added to the pulverulent substances and the
whole is mixed and granulated, if necessary with the
addition of water. The granules are dried overnight
at 35, forced through a sieve of 1.2 mm mesh width and
compressed to tablets which are concave on both sides9
are about 10 mm in diameter and have a breaking notch on
the top
Tablets containing 100 mg of another compound of
the formula I according to Example 1 can also be prepared
in an analogous manner.
~}
Tablets containing, in each case, 25 or lO0 mg of
a compound according to one o~ Examples 5 to 8, and
tablets for chewing containing 30 mg o~ a compound accor-
3 ~
ding to one of Examples 5 to 8, can also be prepared in a manneranalogous to that described in Examples 10 to 12.
xample 14
In an analogous manner as described in Example 6
2-ethanesulphinyl-4(5)-(4-fluorophenyl)-5(4)-(2-thienyl)-imidazole,
2-ethanesulphonyl-4(5)-(4-fluorophenyl)-5(4)-(2-thienyl)-imidazole
and 2-ethan sulphonyl-4(5)-phenyl-5(4)-(3-pyridyl)imidazole can
also be manufactured.
