Note: Descriptions are shown in the official language in which they were submitted.
~04150;~
The present invention relates to new imidazo ~4,5-b~pyridines
having interesting physiological properties.
According to one feature of the present invention there are
providedcompounds of general formula:
R
~ i ~ R3 (I)
and isomers thereof of general formula:
R / Rl
5 ~ N ~ R (Ia)
wherein Rl represents an alkylamino, dialkylamino, hydroxy, allyloxy,
benzyloxy, alkylthio, alkylsulfinyl or alkylsulfonyl group, or an alkoxy
group optionally substituted by a halogen atom or by a hydroxy, alkoxy~
alkylthio~ alkylsulfinyl~ alkylsulfonyl~ alkylamino~ dialkylamino~
piperidino, morpholino, thiomorpholino, 4-alkylpiperazino, 4-phenyl-
piperazino, 4-methoxyphenylpiperazino, 4-phenylethylpiperazino, phenyl-
20 ethylamino, N-methyl-phenylethylamino or N-methyl-dimethoxy-phenylethyl-
amino group; ~
R2 represents a hydrogen or halogen atom or a hydroxy, methoxy, -
ethoxy, methyl, methylthio, methylsulfinyl or methylsulfonyl group;
R3 represents a hydrogen atom or a methoxy group; or two of
the groups Rl to R3 together represent a methylenedioxy group and the
remaining Rl, R2 or R3 group is as hereinbefore defined;
R4 represents a hydrogen atom~ an alkyl group optionally
substituted by a hydroxy, phenyl, dimethoxyphenyl, dialkylamino, piperidino,
morpholino, 4 methylpiperazino or 4-phenylpiperazino group, or a phenyl
.
1~)4150Z
group optionally substituted by a halogen atom or by one or two methoxy
groups, whereby each of the above mentioned alkyl or alkoxy groups contain
from 1 to 4 carbon atoms; and
R5 represents a hydrogen atom, a halogen atom or a lower alkyl
group and the corresponding imidazo ~4,5-b~ pyridine-~-oxides and isomers
thereof and acid addition salts thereof.
According to another feature of the invention, there is also
provided a process for the preparation of a compound of the general formula:
Rl
R5 - ~ R ~ 2 (I)
L-4
or an isomer thereof of the general formula: ~.
R5 ~ ~ ~ (Ia)
wherein R1 represents an alkylamino, dialkylamino, hydroxy, allyloxy,
benzyloxy, alkylthio, alkylsulfinyl or alkylsulfonyl group, or an alkoxy
group optionally substituted by a halogen atom or by a hydroxy, alkoxy,
alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, dialkylamino,
piperidino~ morpholino~ thiomorpholino~ 4-alkylpiperazino, 4-phenyl-
piperazino, 4-methoxyphenylpiperazino, 4-phenylethylpiperazino, phenyl- :
ethylamino, N-methyl-phenylethylamino or N-methyl-dimethoxy-phenylethyl-
amino group;
R2 represents a hydrogen or halogen atom or a hydroxy, methoxy,
ethoxy, methyl, methylthio, methylsulfinyl or methylsulfonyl group;
R3 represents a hydrogen atom or a methoxy group; or two of
the groups Rl to R3 together represent a methylenedioxy group and the
~ -3-
,~,
lU4150Z
remaining R1~ R2 or R3 group iS as hereinbefore defined;
R4 represents a hydrogen atom~ an alkyl group optionally
substituted by a hydroxy~ phenyl~ dimethoxyphenyl~ dialkylamino~ piperidino~
morpholino~ 4-methylpiperazino or 4-phenylpiperazino groUp~ or a phenyl
group optionally substituted by a halogen atom or by one or two methoxy
groups~ whereby each of the above mentioned alkyl or alkoxy groups contain
from 1 to 4 carbon atoms; and
R5 represents a hydrogen atom~ a halogen atom or a lower alkyl
group and the corresponding imidazo ~4~5b~pyridine-N-oxides and isomers
thereof and pharmaceutically acceptable acid addition salts thereof, which
comprises\either: -
(a) reacting a compound of the formula:
~H2 , .
5 ~ (II)
\Y ~ :
~ ,
-3a-
~ .
104~ S~;~
wherein R5 is as hereinbefore defined and Y represents a group of the formula
R4NH-, wherein R4 is as hereinbefore defined, with a compound of the formula
X ---~
3 (III)
wherein Rl, R2 and R3 are as hereinbefore defined and X represents a carboxyl,
thiocarboxyl or dithiocarboxyl group, or functional derivative thereof; or
(b) reacting a compound of the formula: -
~H2
R ~ 1 (IIa)
wherein R5 is as hereinbefore defined and Y represents a halogen atom, with
a compound of the formula~
1 ~ R2 (IIIa)
3 ~ -
wherein Rl, R2 and R3 are as hereinbefore defined and Xl represents an : .
appropriate -NR4 containing group which is derived from a carboxyl, thi-
carboxyl or dithiocarboxyl group; and when a pharmaceutically acceptable
acid addition salt is required converting a base of formula I obtained into
such a salt.
In general the compounds of general formula I and isomers thereof of
general formula Ia possess valuable physiological properties, in particular
an activity on the blood pressure and heart force, a positive isotropic effect,
an antiulcus activity, a platelet aggregation inhibiting effect and a prolong-
ing activity on the bleeding time. -
-3b-
104150Z
Preferred compounds according to the invention
by virtue of their particularly favourable physiological
properties are those(wherein Rl, R4 and R5 represent
hydrogen atoms and R2 and R3, which may be the same or
different, each represents a halogen atom or a methyl,
methoxy, ethoxy, alkylthio, alkylsulfinyl, dialkylamino- -
alkoxy, morpholinoalkoxy, thiomorpholinoalkoxy, 4-
methylpiperazinoalkoxy, 4-phenylpiperazinoalkoxy or
alkylsulfinylalkoxy group (wherein each alkyl group
contains from 1 to 3 carbon atoms and each alkoxy group :~contains 2 or 3 carbon atoms)and physiologically
compatible acid addition salts thereof. Particularly
preferred are the following compounds:-
2-(2,4-Dimethoxy-phenyl)-lH-imidazo~4,5-b]pyridine
and physiologically compatible acid addition salts thereof,
2-(2-Methoxy-4-methylmercapto-phenyl)-lH-imidazo-
[4,5-b] pyridine and physiologically compatible acid
addition salts thereof~
2-(2-Methoxy-4-methylsu~lnyl-phenyl)lH-imidazo
[4,5-b] pyridine and physiologically compatible acid
addition salts thereof,
2-(2-Methoxy-4-methyl-phenyl)-lH-imidazo[4,5-b]
pyridine and physiologically compatible acid addition
. ~. . .. . . . .
1041502
salts thereof,
2-(2-Methoxy-5-methylmercapto-phenyl)-lH-imidazo
[4,5-b] pyridine and physiologically compatible acid
addition salts thereof, and
2-(2-Ethoxy-4-methyl-phenyl)-lH-imidazo[4,5-b~
pyridine and physiologically compatible acid addition
salts thereof.
The new compounds of general formula I and isomers
thereof of general formula Ia as hereinbefore defined
may be prepared by either of the following processes,
which processes constitute further features of the
invention:- :
a) Reaction of a compound of formula
~ 2
5 ~ (II)
[wherein R5 is as hereinbefore defined and Y represents
a group of formula R4NH-(wherein R4 is as hereinbefore
defined)] with a compound of formula
-
2 (III)
3 ~
(wherein Rl to R3 are as hereinbefore defined and X :.
represents a carboxyl, thiocarboxyl or dithiocarboxyl
.
- ; : .
1~)4150Z
group) or a functional derivative thereof, for example
an acid halide, anhydride, ester or orthoester; and
b) Reaction of a compound of formula
R5 ~ 1 (II)
(wherein R5 is as hereinbefore defined and Y represents
a halogen-atom) with a compound of formula
Rl
2 (III) -
~wherein Rl to R3 are as hereinbefore defined and X
represents an appropriate -NR4 containing group (wherein
R4 is as hereinbefore defined) which is derived from a
carboxyl, thicarboxyl or dithiocarboxyl group, for example
a nitrile, amide, amido ester, imido thioester, imido ~ .
halide or amidine group],
In each case the reaction is preferably carried out
in the presence of a solvent, suitable solvents including
for example benzene, pyridine, glycol, toluene, acetone,
diethylene glycol and triethylamine. However the
reaction may also be performed in the absence of a solvent
104~S02
The reaction temperature used is determined by the
reactivity of the group X in the compound of formula
III used but generally the reaction is effected at
temperatures-from -20 to 250C. If desired the re-
action may be effected in the presence of an acidbinding agent, such as pyridine or triethylamine, or
in the presence of a catalytic quantity of an acid,
such as p-toluenesulfonic acid, or in the presence of
a dehydrating agent,such as phosphorus oxychloride or
thionyl chloride.
If for example a compound of formula III wherein X
represents a carboxyl or amide group is used the reaction ~ -
if conveniently carried out in the presence of phosphorus
oxychloride or thionyl chloride, if desired in the presence
of a tertiary organic base such as pyridine or triethyl-
amine, preferably at temperatures from -20C up to the
boiling point of the solvent used, e.g. at 120C.
If for example a compound of formula III wherein X
represents a nitrile group is used, the reaction is
conven~ently performed in the presence of a catalytic
quantity of an acid, such as p-toluenesulfonic acid,
preferably at temperatures from 120 to 180C, e.g. at
160C, optionally in the presence of a solvent. ~-
- 7 -
~ : ' : ' . ~ . -
'' :: ., ' : .
i~)4150Z
If for example a compound of formula III wherein X
represents a thioamide group is used, the reaction is
conveniently effected in the presence of a solvent, such
as glycol, and preferably at temperatures from 100 to
150C, e.g at 130C.
If a compound of formula II wherein Y represents a
halogen atom, e.g. a chlorine atom is used, the reaction
is preferably carried out via the corresponding amidine,
which is cyclized at elevated temperatures, e.g. at
temperatures from 100 to 200C, optionally without previous
isolation.
The compounds of general formula I and isomers thereof
of general formula Ia containing a reactive halogen atom
obtained according to the processes of the present invention
may, if desired, be subsequently converted into the
corresponding amino compounds with amines, and/or compounds
of general formula I and isomers thereof of general formula
Ia containing reactive hydrogen atoms, may if desired be
subsequently alkylated by means of an alkylating agent in
the presence of a base.
In addition a compound of formula I or an isomer
thereof of formula Ia may if desired be converted into the
104150Z
corresponding N-oxide, S-oxide or S,S-oxide compound by
means of an oxidizing agent. Finally a compound of
fo~mula I or an isomer thereof of formula Ia may if
desired be converted into an acid addition salt thereof,
S preferably into a physiologically compatible acid addition
salt. Suitable acids include for example hydrochloric
acid, hydrobromic acid, sulfuric acid, lactic acid, citric
acid, tartaric acid, maleic acid and fumaric acid.
m e starting compounds used for the processes
according to the invention are known from the literature,
or they may be prepared according to known processes (see
Examples).
As already mentioned above, the new compounds of
general fonmula I and isomers thereof of general fonmula
Ia in general show valuable pharmacological properties,
those which have been tested showing especially an activity
on the blood-pressure, a positive inotropic activity, an
~ - . . . ..
- antiulcus activity, a platlet aggregation inhibiting effect ~ -
and a prolonging activity on the bleeding time.
m e following compounds have been tested with respect -
to certain of their biological activities: ~-
A - 2-(2,4-Dimethoxy-phenyl)-lH-imidazo[4,5-b]pyridine
hydrochloride,
_ 9 _
-
~. ' :
- . : ,~ - -
.
1043 S0;~
B = 2-[2-(2-Methylsulfinyl-ethoxy)-4-methoxy-phenyl]-lH-
imidazo-[4,5-b]pyridine hydrochloride,
C = 2-(2-Methoxy-4-methylmercapto-phenyl)-lH-imidazo - -
[4,5-b]pyridine hydrochloride
D = 2-(2-Methoxy-4-methylsulfinyl-phenyl)-lH-imidazo
[4,5-b]pyridine hydrochloride,
E = 2-(2-Methoxy-5-methylmercapto-phenyl)-lH-imidazo
[4,5-b]pyridine hyrochloride
F - 2-(2-Methoxy-4-methyl-phenyl)-lH-imidazo~4,5-b]
pyridine hydrochloride
G = 2-(2-Ethoxy-4-methoxy-phenyl)-lH-imidazo~4,5-b]
pyridine hydrochloride,
H = 2-(2-Ethoxy-4-methyl-phenyl)-lH-imidazo[4,5-b]
pyridine hydrochloride,
I = 2-(2-Methoxy-4-chloro-phenyl)-lH-imidazo[4,5-b]
pyridine hydrochloride and
J ~ 2-[2-(2-Methylsulfinyl-ethoxy)-4-methylmercapto-
phenyl]-lH-imidazo~4,5-b]pyridine hydrochloride
1. Positive inotropic activity in the isolated auricle of
the guinea-PiR:
Isolated auricles of guinea-pigs were put into an organ bath
of 100 ml. The bath has been filled with a tyrode solution
- 10 -
1041SOZ
at a temperature of 30C. The tyrode solution was
infused with carbogen (95% of 2 and 5% of C02). The
spontaneous contractions of the auricles were registered
isometrically with a Statham-Force-transducer on a Grass-
polygraph. The auricles were charged with 1 g. Aftersufficient equilibrating time, the substances in question
were added to the organ bath. The concentration of the
substance in the bath was 1 x 10 5 g/ml in each case.
5 auricles were used for each solution.
The following Table gives the results:
Table I
Substance Increase of the contraction- ;-
amplitude in %
,
A 57.0
B 17.5
C 10.3
E 40.9
F 50.2
G 33.9
H 42.9
I 21.4
J 11.4
~ .
- 11 -
' ~ ' - ~ ' ., .' ''
. . - , '
., . . ., :
- ~ . .
:
,~ - . - . . .
1~4~502
2. Circulation exPerimentS on the narcotized cat:
Cat were narcotized with 30 mg/kg of pentobarbital-
sodium i.v. A plastic catheter was introduced into the
arteria femoralis and into the left ventricle of the
heart a steel catheter was introduced from the arteria
carotis. With Statham-pressure-transducers of the type
P23 AA and P23 Dc, the arterial blood-pressure and the
pressure in the left ventricle was registered continuously.
From the ventricle-pressure-curve, the contractility
parameters dp/dtmaX and VcE were continuously determined
by means of an analogous computer. The heart frequency
was ascertained from the ventricle-pressure-curve using
a tachograph. In addition, the EKG was registered in the
II derivation.
All registrations were effected on a Brush-direct-
writer. The substances were injected over a vena cannula
into the vena femoralis. At least three cats were used
for the test on each substance.
The following Table gives the results:
- 12 -
+~ ~041S02
O Cl ~ 11~ N CJ~ O O In O O u~ O O ~J N 01~
~ . ++ ' ' ++ ++ ' I ++ I
~ 0
~+~)~
+~ ~ h ;-
~g
0~ ~ . .V, . .,'
.)
0~ O-- ~ ~U~ ~ ~U~ ~ ~ U~U~ ~0
8 N ~ ~ N ;t U~ ~ U
+-'8++ ++ ++ ++ ++ ++ ++ ++ ++ ++ -:~
~ ~1
$~,
:: ~.
~--IU~ ~ O O ~ O O ~ O U~ O U~ O ~ O ~ U~ U~ O U~ ~
~
~o I I ++ ++ I ++ ++ + ++ 1 1. ++ ~. . ' .
~ . . :'
~.YU~O U~O U~O U~O U~O U~O U~O U~O U~O U~O
a ~-i " '; ' " ~ ' ' ' " '~
H¦ ~ ~ ~~,~ ~., 14 ~ ~ , ' ,
~1 ~
- 13 -
' '
.' ~ ~ '. .
1041S()2
None of the compounds showed any toxic side effects
using the doses applied.
According to yet a further feature of the present
invention there are provided pharmaceutical compositions
comprisingas active ingredient at least one compound of
formula I or isomer thereof of formula Ia or physologi-
cally compatible acid addition salt thereof in association
with a pharmaceutical carrier or excipient.
The compositions may for example be presented in a
form suitable for oral, rectal or parenteral administration.
Thus for example compositions for oral administration may
be solid or liquid and may take the form of tablets, coated
tablets or drops, such compositions comprising carriers or
excipients conventionally used in the pharmaceutical art.
For parenteral administration the carrier may be a
parenterally acceptable liquid, such as sterile water or
a parenterally acceptable oil, e.g. arachis oil, contained
in ampoules. For rectal administration compositions may
take the form of suppositories, the carrier comprising a
suppository base.
Advantageously the compositions may be formulated as
dosage units. Each dosage unit preferably contains from
35 to 200 mg, preferably from 50 to 100 mg, of active
ingredient.
1()41SO~
The following Examples serve to illustrate the
preparation of compounds according to the invention and
of pharmaceutical compositions containing the same.
- 15 -
.
1041S02
Example 1
2-(2,4-Dimethoxyphenvl)-lH-imidazo[4,5-b]pvridine
hydrochloride
54.5 g of 2,3-diaminopyridine and 91.1 g of 2,4-
dimethoxybenzoic acid were finely pulverized and added in
small amounts to 1500 ml of phosphorus oxychloride whilst
stirring. Afterwards, the mixture was refluxed for 2 hours,
and the phosphorus oxychloride was distilled off in vacuo.
The residue was triturated with 2000 ml of 2N hydrochloric
acid and the solid product obtained was suction filtered
and recrystallized from water.
Yield: 121 g (85% of theory), m.p.: 238C
Example 2
2-(2,4-Dimethoxvphenyl)-lH-imidazo[4,5-b]pvridine
hvdrochloride
360 mg of 2,4-dimethoxybenzoic acid were
dissolved in 2 ml of pyridine and a solution of 220 mg of
2,3-diaminopyridine in 2 ml of pyridine was added, where-
upon the corresponding salt precipitated out. Whilst
- 16 -
., .
,;
lOglSOZ .,
stirring and ice-cooling, 0.38 ml of phosphorus
oxychloride were added dropwise and the mixture was stirr-
ed for a further hour at 0C and 1 hour at room
temperature. Subsequently the excess of pyridine was
removed in vacuo and the residue was dissolved by adding
dilute hydrochloric acid. The mixture was neutralized
with sodium hydroxide solution and extracted with ethyl
acetate. The ethyl acetate layer was evaporated, the
residue was treated with a small quantity of 2N hydrochloric
acid, and the precipitate was suction filtered and recry-
stallized from water.
M.p.: 238 to 239C.
Example 3
2-(2,4-Dimethoxy-phenyl)-lH-imidazo[4,5-b]pyridine
hydrochloride
Prepared analogously to Example 2 from 2,3-
diaminopyridine, 2,4-dimethoxybenzoic acid and thionyl
chloride.
M.p.: 238 to 239C.
- 17 -
' ' - '''~ ~ ' ', , :
104~5UZ
Example 4
2-(2,4-Dimethoxy-phenyl)-lH-imidazo[4,5-b]pyridine
hydrochloride
900 mg of 2,4-dimethoxy-benzoic acid were converted
into the acid chloride by heating in a mixture of 3 ml of
benzene and 2 ml of thionyl chloride. Subsequently, the
mixture was evaporated in vacuo and the residue obtained
was taken up in 5 ml of benzene. This solution was
dropped into a solution of 550 mg of 2,3-diamino-pyridine
in 5 ml of pyridine whilst stirring. Afterwards, the
mixture was heated for a short time at 60C, then cooled
to room temperature, and 0.9 ml of phosphorus oxychloride
were added dropwise. After the mixture had been stirred
for a further 3 hours at room temperature, 2N hydrochloric
acid was added. The mixture was then neutrallized and
extracted with ethyl acetate. The ethyl acetate layers
were evaporated and a small quantity of 2N hydrochloric
acid was added to the residue. The crystals which
precipitated were suction filtered and recrystallized
- 18 -
- ~. . : . , -
10415t~;~
from water.
M.p.: 237 to 238C.
Example 5
2-(2,4-Dimethoxv-phenvl)-lH-imidazo[4,5-b~pyridine
hydrochloride
a) 2-Amino-3-(2,4-dimethoxybenzoyl-amino)-pyridine
hvdrochloride
530 mg of 2,4-dimethoxybenzoic acid were converted
into the acid chloride analogously to Example 4 and this
acid chloride was dissolved in 1 ml of benzene. The
solution obtained was added dropwise to a mixture of 440 mg
of 2,3-diamino-pyridine, 3 ml of pyridine and 2 ml of
triethylamine. After the whole mixture had been stirred
for a further 2 hours at room temperature, water was added, -
the mixture was neutralized with concentrated hydrochloric
acid and extracted with ethyl acetate. The ethyl acetate
was removed, the residue was treated with dilute hydro-
chloric acid, the precipitated crystals were suction
filtered and recrystallized from ethanol.
M.p.: 172 to 174C.
- 19 -
; , .- '' :.
. ~
~ 041502
b) 2,4-Dimethoxy-phenvl)-lH-imidazo[4,5-b]pyridine
hvdrochloride
155 mg of 2-amino-3-(2,4-dimethoxybenzoyl-amino)-
pyridine hydrochloride were dissolved in 2 ml of pyridine.
0.2 ml of phosphorus oxychloride were dropped in whilst
stirring at room temperature. After 2 hours the mixture
was poured into water and worked up analogously to
Example 4.
M.p.: 237 to 238C.
Example 6
2-(2,4-Dimethoxy-phenyl)-lH-imidazo~4,5-b]Pvridine
hydrochloride
155 mg of 2-amino-3-(2,4-dimethoxybenzoyl-amino)-
pyridine hydrochloride were heated for 5 minutes at 200 -
210C. The mixture was treated with a small quantity of
2N hydrochloric acid, and the precipitate was filtered
and recrystallized from water.
M.p.: 237 to 238C.
- 20 -
.
- - : . . ~ .': ' '
:
':
~041St~ ~
Example 7
2-(2 ,4-Dimethoxy-phenyl)-lH-imidazo[4,5-b]pyridine
hydrochloride
155 mg of 2-amino-3-(2,4-dimethoxybenzoyl-amino)-
pyridine hydrochloride were refluxed for 30 minutes in 2 ml
of glycol. The mixture was then diluted with water,
neutralized, extracted with ethyl acetate and processed
analogously to Example 4.
M.p.: 238 to 239C.
Example 8
2-(2,4-Dimethoxy-phenyl)-lH-imidazo[4,5-b]pyridine
hydrochloride
5.45 g of 2,3-diaminopyridine were added in small
amounts to 150 ml of phosphorus oxychloride whilst
stirring and 9.81 g of methyl 2,4-dimethoxybenzoate were
also added dropwise. The mixture was then heated at 120C,
After two hours the excess of phosphorus oxychloride was
evaporated in vacuo, the residue was digested with 2N
hydrochloric acid and the solid product obtained was
suction filtered and recrystallized from water.
M.p.: 238 to 239C.
- 21 -
- , ~
, '
1~)41SOZ
Example 9
2-(2,4-Dimethoxy-phenyl)-lH-imidazo[4,5-b]pyridine
hydrochloride
0.5 ml of morpholine were added whilst stirring to
470 mg of 2,4-dimethoxybenzoyl chloride in 6 ml of toluene.
After 20 minutes the toluene was ev~porated, the residue
was treated with dilute hydrochloric acid and this mixture
was extracted with ethyl acetate. After washing the
ethyl acetate layer with sodium bicarbonate solution and
evaporating off the solvent, crude 2,4-dimethoxybenzoyl-
morpholine was obtained as oil. This oil was dissolved
in S ml of pyridine, 250 mg of 2,3-diaminopyridine was
added and finally 1 ml of phosphorus oxychloride was added
dropwise whilst stirring and ice-cooling. After stirring
for 5 hours at 0C, ice-water was added, the mixture was
made alkaline with concentrated ammonia, heated for a
short time on the steam bath and extracted with ethyl
acetate. The ethyl acetate was removed, and the residue
obtained was treated with 2N hydrochloric acid, suction
- 22 -
',
; . .
~ 04~SOZ
filtered and recrystallized from water.
M.p.: 238C.
Example 10
2-(2,4-Dimethoxyphenyl)-lH-imidazo[4,5-b]pyridine
hvdrochloride
300 mg of 2,4-dimethoxybenzoyl-(4-chloro-anilide)
and 110 mg of 2,3-diaminopyridine were mixed and added in
small amounts to 3 ml of phosphorus oxychloride whilst
stirring. Afterwards the mixture was refluxed for 8 hous.Then
the phosphorus oxychloride was removed in vacuo, the
residue was triturated with 2N hydrochloric acid and the
solid product obtained was suction filtered and recrystal-
lized from water.
M.p.: 237 to 238C.
Example 11
2-(2,4-Dimethoxy-Phenyl)-lH-imidazo[4,5-b]pyridine
hydrochloride
600 mg of 2,4-dimethoxybenzoyl-(4-chloro-anilide)
in a mixture of 5 ml of benzene and 2 ml of thionyl
- 23 -
' - ' ' . ~ . :
- - ,.
1041~0Z
chloride were refluxed for 3 hours. After the mixture
had been evaporated the crude 2,4-dimethyl-N-(4-
chlorophenyl~-benzimidic acid chloride was obtained as
an oil. This oil was dissolved in 9 ml of toluene and
the solution was added to a solution of 200 mg of 2,3-di-
aminopyridine in 10 ml of isopropanol. The mixture was
heated for 10 minutes at 70C. The 2,4-dimethoxy-benzoic
acid-N-(4-chlorophenyl)-N'-(2-amino-3-pyridyl)-amidine
hydrochloride which formed was not isolated but was
dissolved in 20 ml of glycol after removing the iso-
propanol in vacuo. The glycol solution was refluxed
for 10 minutes. Subsequently water was added, the mixture
was made alkaline with concentrated ammonia, extracted
with ethyl acetate and worked up as described in Example 4.
M.p.: 237 ~o 238C.
Example 12
2-(2,4-Dimethoxy-phenyl)-lH-imidazo~4,5-b~pyridine hydro-
chloride
100 mg of 2,3-diaminopyridine, 200 mg of 2,4-
dimethoxybenzonitrile and 400 mg of p-toluenesulfonic acid ;
'~
- 24 -
. . - ~
~ 041S0;~
monohydrate were mixed together and heated for 3~ hours
at 160C The product was triturated with dilute
ammonia and ethyl acetate until the whole product had
dissolved. The aqueous layer wQs extracted with ethyl
acetate. After some time, when the combined ethyl
acetate layers had been extracted with a small quantity
of 2N hydrochloric acid, the product crystallized out from
the aqueous phase.
M.p.: 237 to 238C.
E~ample 13
2-(3,4,5-TrimethoxyPhenyl)-lH-imidazo[4,5-b]p~ridine
3.4 g of p-toluenesulfonic acid monohydrate and
15 ml of benzene were heated at 120C until all the benzene
had evaporated. Subsequently 1.1 g of 2,3-diaminopyridine
and 2 g of 3,4,5-trimethoxybenzoyl nitrile were added and
the mixture was heated for 2 hours at 150C. After
cooling, water was added, the mixture was extracted with
ethyl acetate, the ethyl acetate layers were washed with
dilute sodium hydroxide solution, evaporated and the
residue was recrystallized from isopropanol/petroleum
- 25 -
.
ether. 1041S02
M.p,: 226C.
Example 14
2-(3,4,5-Trimethoxy-phenyl)-lH-imidazo~4.5-b3pyridine
A mixture of 4.2 g of 3,4,5-trimethoxybenzoic acid
and 2.2 g of 2,3-diaminopyridine was refluxed for 2 hours
in 40 ml of phosphorus oxychloride. Subsequently the
excess of phosphorus oxychloride was distilled off,
water was added to the residue and the precipitated solid
product was suction filtered. The product was dissolved
in hot water, made alkaline with concentrated ammonia, and
the precipitate was suction filtered and recrystallized ~ --
from a small qusntity of isopropanol.
M.p.: 225 to 226C. ~ -
Example 15
2-(2,5-Dimethoxy-phenyl)-lH-imidazo[4,5-b]pvridine
a) 2,5-Dimethoxy-thiobenzoyl morPholide
A mixture of 10 g of 2,5-dimethoxybenzaldehyde, 10 g
of morpholine and 4 g of sulfur was heated st 130C for
3~ hours and subsequently dissolved in 300 ml of hot -~
ethanol. The product which precipitated out on cooling,
- 26 -
,
- : ' ' ""' - : ' ~' . -' '
- . - ~ ,
~ 04~502
was recrystallized from ethanol.
M.p,: 127C.
b) S-Methyl-2,5-dimethoxy-thiobenzoyl morpholide iodide
6 g of 2,5-dimethoxy-thiobenzoyl morpholide, 6.5 g
of methyl iodide and 30 ml of acetone were refluxed for
~ hours. Subse~uently the precipitated solid product was
suction filtered and washed with ether. The product
obtained was not purified further.
c? 2-(2,5-Dimethoxy-phenyl)-lH-imidazo[4,5-b]pyridine
2 g of S-methyl-2,5-dimethoxy-thiobenzoyl morpholide
iodide and 1.1 g of 2,3-diaminopyridine were heated in 30
ml of glycol for 40 minutes at 130C. Subsequently the
mixture was poured on ice-water, suction filtered and
recrystallized from ethanol/water.
M.p.: 23S~.
Example 16
2-(4-HYdroxy-phenYl)-lH-imidazo[4,5-b]p~ridine
a) 4-HYdroxy-thiobenzoYl morpholide
Prepared analogously to Example 15a from 12.2 g of
- 27 -
~' .....
.~ ,.. .
1041SQZ
4-hydroxy-benzaldehyde, 16 g of morpholine and 3,2 g of
sulfur.
M.p.: 205C
~) S-Methyl-4-hydroxy-thiobenzyl morpholide iodide
Prepared analogously to Example 15b from 14.4 g of
4-hydroxy-thiobenzyl morpholide and 2.1 g of methyl iodide
in 100 ml of acetone.
M.p.: 181C.
c? 2-(4-Hydroxy-phenyl~-lH-imidazo[4,5-b]pyridine
1.84 g of S-methyl-4-hydroxy-thiobenzyl morpholide
iodide were heated for 20 minutes at 130C with 1.1 g of
2,3-diaminopyridine in 30 ml of glycol. The product
precipitated whilst cooling and was dissolved in sodium
hydroxide solution and reprecipitated with an acid.
Analysis: Calculated: 65.87% C 5~13% H 16.46% N
Found: 65.90% C 5.16% H 16.47% N
- 28 -
- ~,, ~.. ..
. .
-
104~SOZ
Example 17
2-[4-Methoxy-2-(3-chloropropoxy)-phenyl]-lH-imidazo
[4,5-b~pyridine hydrochloride
a) 4-Methox~-2-(3-chloro-propoxy)-benzoyl morpholide -
21.9 g of 2-hydroxy-4-methoxy-benzoyl morpholide
were dissolved in 200 ml of dimethylformamide and 11.2 g
of potassium tert.-butoxide were added. After the whole
product had dissolved, 50 g of 1-chloro-3-bromopropane
were added and the mixture was heated for 2 hours at 130C.
Subsequently the mixture was evaporated in vacuo, the
residue was dissolved in ethyl acetate, and the solution
was washed with sodium hydroxide solution and water and
evaporated.
b) 2-[4-Methoxy-2-(3-chloropropoxy)-phenyl]-lH-imidazo
[4,5-b]Pvridine hydrochloride
20 g of 4-methoxy-2-(3-chloro-propoxy)-benzoyl -
morpholide, 7 g of 2,3-diamino-pyridine and 170 ml of
phosphorus oxychloride were refluxed for 2 hours. After
- 29 -
lO~lSOZ
evaporation of the phosphorus oxychloride, the residue was
mixed with water, neutralized with sodium hydroxide solution
and extracted with ethyl acetate. The hydrochloride was
precipitated with ethereal hydrochloric acid.
M.p.: 198C (decomp).
Example 18
2-[4-Methoxy-2-~2-chloroethoxy)-phenyl]-lH-imidazo
[4,5-b]pyridine hydrochloride
a) 4-Methoxy-2-(2-hydroxy-ethoxy)-benzoyl morpholide
23.7 g of 2-hydroxy-4-methoxy-benzoyl morpholide,
33.6 g of potassium tert.-butoxide and 37.4 g of ethylene
bromohydrin were heated in 100 ml of dimethylformamide for
6 hours at 120C. After evaporation in vacuo, the residue
was dissolved in chloroform and the solution was washed
with sodium hydroxide solution and water and evaporated.
b) 2-[4-Methoxy-2-(2-chloroethoxy)-phenyl]-lH-imidazo
L ,5-b]pyridine hvdrochloride
2.8 g of 4-methoxy-2-(2-hydroxy-ethoxy)-benzoyl
morpholide, 1.1 g of 2,3-diaminopyridine and 20 ml of
phosphorus oxychloride were refluxed for 2 hours. After
' :
- 30 -
.
, .
.
- ,. . . . .
1041S(~Z
evaporation w~ter was added, the mixture was neutralized,
extracted with ethyl acetate and the hydrochloride was
precipitated with ethereal hydrochloric acid from the
organic layer.
M.p.: 110C (decomp.).
ExamPle 19
2-[4-Methoxy-2-(3-chloropropoxy)-phenyl]-lH-imidazo
[4,5-b]pyridine hydrochloride
a) 4-Methoxy-2-(3-chloropropoxy)-benzoyl anilide -
2.5 g of 2-hydroxy-4-methoxy-benzoyl anilide, 5 ml
of l-chloro-3-bromopropane, 1.12 g of potassium tert.-
butoxide and 20 ml of dimethylformamide were heated for
2 hours at 130C. Subsequently the mixture was evaporated
in vacuo, water was added and the mixture was suction
filtered.
M.p.: 87 to 90C.
b) 2-[4-Methoxy-2-(3-chloropropoxy)-phenyl~-lH-imidazo
[4,5-b]pyridine hydrochloride
Prepared analogously to Example 17b from 4-methoxy-
- 31 -
1041SOZ
2-(3-chloropropoxy)-benzoyl anilide and 2,3-diamino-
pyridine.
M.p.: 198C.
Example 20
2-[4-Methoxy-2-(3-morpholino-propoxy)-phenyl]-lH-imidazo
[4,5-b]-pyridine
0.5 g of 2-[4-methoxy-2-(3-chloroproxy)-phenyl]-lH-
imidazo[4,5-b]-pyridine hydrochloride were refluxed for
4~ hours in 5 ml of morpholine. Water was then added,
the precipitate was suction filtered and recrystallized
from water.
M.p.: 108 to 110C.
Example 21
2-[4-Methoxy-2-(2-(4-phenyl-1-piperazinyl)-ethoxy)-
phenyl~-lH-imidazo[4,5-b]pvridine
Prepared from 1.7 g of 2-[4-methoxy-2-(2-chloro-
ethoxy)-phenyl]-lH-imidazo~4,5-b]pyridine and 3.2 g of 1-
phenylpiperazine by boiling for 8 hours in ethanol.
M.p.: 164 to 165~C (from isopropanol)
~ ~- . .. .
- 32 -
1~41502
Example 22
2-[4-Methoxy-2-(3-dimethylamino-propoxy)-phenyl]-lH-
imidazo[4,5-b~pyridine hydrochloride
1.8 g of 2-[4-methoxy-2-(3-chloropropoxy)-phenyl]-
lH-imidazo[4,5-b]-pyridine hydrochloride and 20 ml of
saturated dimethylamine solution in ethanoI were heated
for 8 hours in a closed vessel at 100C. Subsequently
the mixture was evaporated in vacuo and recrystallized
from isopropanol.
M.p.: 209 - 210C
Example 23
2-[4-Methoxy-2-(3-dimethylamino-propoxy)-phenyl]-lH-
imidazo-[4,5-b]pyridine dihydrochloride
1.64 g of 4-methoxy-2-(3-dimethylamino-propoxy)-
thiobenzoyl morpholide were dissolved in a mixture of 17 ml
of glacial acetic acid and 3 ml of acetic anhydride. 1 ml
of dimethyl sulfate was added and the mixture was heated
on the steam bath for 1 hour. Subsequently, the mixture
was evaporated in vacuo. The crude S-methyl-4-methoxy-
2-(3-dimethylamino-propoxy)-thiobenzoyl morpholide methyl
- 33 -
.. .. . -
, ,.
1041S02
sulfate obtained was dissolved in 13 ml of glycol 0.7 g
of 2,3-diaminopyridine was added and the mixture was
heated for 2 hours at 160C. Subsequently, the mixture
was poured into 50 ml of water, 5 ml of concentrated
ammonia were added and the mixture was extracted with
ethyl acetate. The ethyl acetate layers were evaporated,
the residue was dissolved in ethanol, ethereal hydrochloric
~acid was added and it was again evaporated. The residue
crystallized after trituration with toluene and a small
quantity of ethanol. The product was suction filtered
and recrystallized from isopropanol.
M.p.: of the dihydrochloride hydrate: 228 to 235C
(decomp.).
Example 24
2-(2,4-Dimethoxy-phenyl)-3-methyl-3H-imidazo[4,5-b]
pyridine _
800 mg of 2,4-dimethoxybenzoyl methylamide were
refluxed for 3 hours with 500 mg of 2-chloro-3-aminopyridine --
in 10 ml of phosphorus oxychloride. Subsequently, the
- 34 -
~, : . . .
1041S0;~
mixture was poured into water, neutralized with
concentrated ammonia and extracted with ethyl acetate.
After evaporation, the crude N-methyl-N'-(2-chloro-3-
pyridyl)-2,4-dimethoxy-benzamidine obtained was dissolved
in 10 ml of 10% glycolic sodium hydroxide solution and
heated for 4 hours at 180 to 190C. The mixture was
poured into water and extracted with ethyl acetate. The
compound obtained was purified by column chromatography
(silica gel, eluent CHC13: MeOH = 19 : 1).
M.p. of the hydrochloride: 196 to 197C
Example 25
2-(2,4-Dimethoxy-phenyl)-3-(4-chlorophenyl~-lH-imidazo
[4,5-b] pyridine
3 g of 2,4-dimethoxy-benzoyl (4-chloroanilide) and ;
1.3 g of 2-chloro-3-aminopyridine were refluxed for 2
hours in 16 ml of phosphorus oxychloride. Subsequently
the mixture was poured into water, neutralized with
concentrated ammonia and extracted with ethyl acetate. The
ethyl acetate layer was extracted with 3N hydrochloric acid.
- 35 -
1041SOZ
After neutralization of the aqueous layer, the mixture
was again extracted with ethyl acetate. The solid ¦~
product remaining after evaporation of the organic layer
was recrystallized from methanol.
M.p.: 176 to 178C.
Example 26
2-(2,4-Dimethoxy-phenyl)-lH-imidazo[4,5-b]pyridine
~y~ochloride
2.2 g of 2,3-diaminopyridine, 6.8 g of the imide
chloride of 2,4-dimethoxy-benzoyl morpholide and 12 ml of
triethylamine were heated for ~ hour at 120C in 10 ml of
diethyleneglycol dimethyl ether. After cooling, water
was added, the reaction mixture was extracted with chloro-
form and the chloroform layer was extracted with 2N
sodium hydroxide solution. The yellow hydrochloride -
which precipitated from the acidic solution was converted
into the base with ammonia, and was purified by column
chromatography. The hydrochloride was again precipitated
from acetone with ethereal hydrochloric acid.
M.p.: 237 to 238C.
- 36 -
. . . :
.. . .
' ' . ~ ~ '
lO~lS~Z
Example 27
2-(2~4-Dimethoxy~phenyl)-lH-imidazo[4,5-b~pyridine
hydrochloride
Prepared from 1. 1 g of 2,3-diaminopyridine and 3.5
of 2,4-dimethoxybenzoyl anhydride by hea~ing for 5 hours
at 180C The further processing was carried out as in
Example 26.
M.p.: 236 to 238C.
- 37 -
rA~
~0415~Z
Example 28
2-(2-Methoxyphenyl)-lH-imidazo[4,5-b]pyridine-hydrochloride
a) 2-Methoxy-thio-benzoic acid-morpholide
34 g of 2-methoxybenzaldehyde, 16 g of sulfur and 32,6 g of
morpholine were heated for 3 hours up to 120C. The reaction
mixture thus obtained was taken up in ethanol, filtered,
cooled and the precipitated yellow crystals were suction
filtered.
.. . . ..
Yield: 54,1 g (91 % of theory), m.p.: 80 to 82C. ~ ~ -
b) 2-Methoxy-thio-benzoic acid-morPholide-methoidide
47,4 g of 2-methoxy-benzoic acid-thiomorpholide were refluxed
for 1 hour in 150 ml of acetone with 25 ml of methyl iodide
and the precipitated yellow crystals were suction filtered
after cooling.
Yield: 64,4 g (85 % of theory), m.p.: 162 to 164C.
c) 2-(2-Methoxyphenyl)-lH-imidazo~4,5-b3pyridine ~ -
19 g of 2-methoxy-thio-benzoic acid-morpholide-methoidide and
8,7 g of 2,3-diaminopyridine were heated for 3 hours at 120C
in 70 ml of glycol. After cooling, water was added, the mix-
ture was made alkaline with ammonia and extracted with chloro-
form. The organic layer was washed with water and subsequent-
ly 2n hydrochloric acid was added. The precipitated product
was suction filtered, the base was set free with ammonia~
taken up in chloroform and purified over a silica gel column.
The colorless hydrochloride was obtained from acetone by
addition of ethereal hydrochloric acid.
M.p.: 233 to 234C.
-- 38 --
. . . :
.. . - ~ ,
~.~
1041SOZ
amplc ~9
2-(2-~lethoxyphctlyl)-3-methyl-3H-i-nli-dazo/4~5 ~ pyridin~ h~drocllloride
Prepared analogous to example 28 from 2-methylamino-3-amino-pyridine
and 2-methoxy-thio-benzoic acid-morpholide-methoiodide.
M.p.: 208 to 210 C.
Example 30
2-~2-(2-Methoxy-ethoxy)-phellyl7-lH-imidazo~ ,5-b7pyridine-hydro--
chloride
Prepared analogous to example 28 from 2-(2-methoxy-ethoxy)-thio-
benzoic acid-morpholide-methoiodide and 2,3-diaminopyridine.
M.p.: 170 to 172 C.
Example 31
2-(4-Methoxyphenyl)-lH-imidazo/4,5-b7pyridine-hydrochloride
prepared analogous to example 28 from 4~methoxy-thio-benzoic acid-
morpholide-methoiodide (m.p.: 142 to 144 C) and 2,3-diamino-pyridine.
M.p.: 243 to 245 C.
Example 32
2-(3-~lethoxy-4-hydroxy-phenyl)-111-imidazo~4~5-b7pyridine-hydro-
chloride
Prepared analogous to example 28 from 3-methoxy-4-hydroxy-thio-
benzoic acid-morpholide-methoiodide (m.p.: 178 to 180 C) and 2,3-
diaminopyridine.
M.p.: 251 to 254 C.
- 39 -
;r~
1041S0;~
Examplc 33
2~(2~3-dimctho~y-pheny~ H-imidazo/4~s-b7pyridine-hydroch]oridc
prepared analogous to example 28 from 2,3-dimethoxy-thio-benzoic
acid-morpholide-methoiodide (m.p.: 138 to 140 C) and 2,3-diamino-
pyridine .M.p.: 270 to 272 C.
Example 34
2-(2-Hydroxy-4-methoxy-phenyl)-~-imidazor4,5,-~ pyridine-hydro-
chloride
.
prepared analogous to example 28 from 2-hydroxy-4-methoxy-thio-
benzoic acid-morpholide-methoiodide (m.p.: 180 to 181C) and 2,3-
diPm;r opyridine.
M.p.: 190 to 192 C (decomp.).
N.p. of the free base: 292 to 293 C.
. .
le 35
2-(2,4-Dimethoxy-phenyl)-lH-im_dazo/4,5-b7pyridine-hydrochloride
Prepared analogo~s to example 28 from 2,4-dimethoxy-thio-benzoic
acid-morpholide-methoiodide (m.p.: 138 to 140 C (decomp.)) and 2,3-
diaminopyridine.
M.p.: 238 C (from methanol)
- 40 -
r~
.. ........ .
iO415U;~
E~ample ~6
2-(2~4-l~imethoxy-phellyl)-6-metllyl-lH-imidazo/4,5-b/pyridine-hydro-
chloride
Prepared allalogous to example 35 from 2,3-diamino-5-methyl-pyridine
and 2~4-dimethoxy-thio-benzoic acid-morpholide-methoiodide.
M.p.: 260 to 261 C.
Example 37
2-(2,4-Dimethoxy-phenyl)-7-methyl-lH-imidazo~ ,5-b7pyridine-hydro-
chloride
Prepared analogous to example 35 from 2,3-diamino-4-methyl-pyridine
2nd 2,4-dime~hoxy-thio-benzoic acid-morpholide-methoiodide.
.p.: 230 to 23]. C.
Example 38
2-(2~4-Dimethoxy-phenyl)-5-methyl-lH-imidazo~ ,5-b7pyridire-hydro-
chlori.de
Prepared analogous to example 35 from 2,3-diamino-6-methyl-pyridine
and 2~4-dimethoxj-th--o-benzoic acid-morpholide-methoiodide.
M.p.: 245 to 246 C.
Example 39
2-(2,4-Dimethoxy-ph~nyl)-6-chloro-lH-imi.dazo~4~5-b7pyridine-hydro-
chloride
_
Prepared analogous to example 35 from 2,3-diamino-5-chloro-pyridine
- 41 -
,~ .
.
,. . . . , , - - ; . . . : . .
104;1S(~Z
and 2,4-dimethox~-tllio-bcnzoic acid-morpholitle-methoiodidc.
M.p.: 253 to 255 C.
Example 40
2-(2-Ethoxy-4-methoxy-phenyl)-lH-imidazo/4~5-b7pyridine-hydrochloride
Prepared analogous to example 28 from 2-ethoxy-4-methoxy-thio-benzoic -
acid-morpholide-methoiodide (m.p.: 152 to 154C) and 2,3-diamino-
pyridine.
M.p.: 228 to 230 C.
Example 41
2-(2-Methoxy-4-ethoxy-phenyl)-lH-imidazo ~ ,5-b/pyridine-hydro-
chloride
Prepared analogous to example 28 from 2-methoxy-4-ethoxy-thio-
benzoic acid-morpholide-methoiodide and 2~3-diaminopyridine.
M.p.: 224 to 225 C (from methanol)
Example 42
2-(2~4-Diethoxy-phenyl)-lH-imidazo/4,5-b7pyridine-hydrochloride
Prepared analogous to example 28 from 2,4-diethoxy-thio-benzoic acid-
morpholide-methoiodide and 2,3-diaminopyridine.
M.p.: 224 to 226 C.
. . . ~ . .
r,~
''
~04~SI~
Example 43
2-/2-(2-Hydroxy-ethoxy)-4-methoxy-pheny~7~ imidazo/4,5-b/-
pyridine-hydroc2~.oride
-
prepared analogous to example 28 from 2-(2-hydroxy-ethoxy)-4-methoxy-
thio-benzoic acid-morpholide-methoiodide and 2,3-diaminopyridine.
M.p.: 237 to 239 C.
Example 44
2- ~ -(3-Hydroxy-propoxy)-4-methoxy-phenyl/-lH-imidazo~4,5-b/-
pyridine-hydrochloride
prepared analogous to example 28 from 2-l3-hydroxy-propoxy)-4-
methoxy-thio-benzoic acid-morpholide-methoiodide and 2,3-diamino-
pyridine.
N.p.: 170 C (whilst sirtering)
.
Example 45
2-/2-(2-Methoxy-ethoxy)-4-methoxy-pheny ~ -lH-imidazo/4,5-b7-
pyridine~hydrochloride
Prepared analogous to example 28 from 2-(2-methoxy-cthoxy)-4-methoxy-
thio-benzoic acid-morpholide-methoiodide and 2,3-diaminopyridine.
M.p.: 191 to 193 C.
Example 46
2-~ -Methoxy-4-(2-methylmercapto-ethoxy)-phenyl7-lH-imidazo-
/4,5-b7pyridine-hydrochloride
,~,~ , .
- - - , .. , . . .: : :
. . . ~ .
,: . ~. ~ - : - ,
1041S0;~
a) 4-(2-Methylmercapto-ethoxy)-2-hydroxy-benzaldehyde
12 g of 2,4-dihydroxy-benzaldehyde and 9,6 g of potassium-tert.-
butoxide were dissolved in 50 ml of ethyleneglycolmonomethylether,
9,6 g of methylmercaptoethylchloride were added and the reaction
mixture was stirred for 8 hours at 80C (bath temperature). After
removing the solvent, the residue was taken up in diluted sodium
hydroxide solution, the mixture was extracted twice with chloro-
form, the aqueous alkaline solution was separated, acidified and
extracted with chloroform. The organic phase was dried and eva-
porated. The residue was purified by column chromatography
(silica gel). The oil thus obtained was processed directly.
b) 4-(2-Methylmercapto-ethoxy)-2-methoxy-benzaldehyde ~
9,? g of 4-~2-methylmercapto-ethoxy)-2-hydroxy-benzaldehyde ~ -
were dissolved in ethanol together with 6,7 g of potassium-
tert.-butoxide, 4,3 ml of dimethyl-sulfate were added and the
mixture was refluxed for 3 hours. Then again 1 ml of dimethyl-
sulfate was added and the mixture was heated for a further
hour. After the ethanol had been distilled off, the residue
was taken up in water/chloroform and 2n sodium hydroxide solution
was added. The chloroform layer was separated, washed with water,
dried and evaporated.
M.p.: 99 to 100C (from cyclohexane)
c) 4-(2-Methylmercapto-ethoxy~-2-methoxy-thio-benzoic acid-morpholide
Prepared analogous to example 28a from 4-(2-methylmercapto-ethoxy)-
2-methoxy-benzaldehyde.
M.p.: 131 to 132C (from ethanol)
d) 2-~2-Methoxy-~ (2-methylmercapto-ethoxy)-phenyl]-lH-imidazo-[4,5-b]-
pyridine-hydrochloride
5,4 g of 4-(2-methylmercapto-ethoxy)-2-methoxy-thio-benzoic acid-
- 44 -
- . . :
104150Z.
morpholide were rcfluxcd for 1 1/2 hours togctllcr with
1~2 ml of mcthyliodidc in 50 ml of acetone. After coolinc, thc
solvent was removed and the obtained sirupy mcthoiodide was
heated Witll 3,6 g of 2,3-diaminopyridine in 20 ml of glycol
for 1 1/2 hours up to 120 C. The mixture was diluted with ~ater
and extracted with chloroform. Subsequently, 2n hydroch~oric acid
was added to the organic layer and the yellow precipitate was
suction filtered.
M.p.: 197 to 199 C (from methanol)
Example 47
2- ~ -Methoxy-4-(2-ethylmercapto-ethoxy)-phenyl/-lH-imidazo/4,5-b/-
pyridine-hydrochloride
prepared analogous to example ~6 from 4-(2-ethy~nercapto-ethox~)-2-
metho~-thio-benzoic acid-morpholide and 2,3-diaminopyridine. ~he
purification of the final product was effected by chromatography
oYer silica gel and the preclpitation of the hydrochloride was
effected by dissolving of the base in acetone and addition of
an excess of ethereal hydrochloric acid.
M.p.: 195 to 196C.
Example 48
2- ~ -Methoxy-4-(3-methylmercapto-propoxy)-phenyl/-1~-imidazo-
/4,5-b7pyridine-hydrochloridc
prepared analo~ous to example 46 from 4-(3-methyln~ercapto-propo~)-
2-methoxy-thio-bcn~ois acid~morpholide and 2~3-diaminopyridine.
M.p.: 189 to 191 C (decomp.).
. ~
'~''' ' ' ' .
- 45 -
. ~. , .
.
~04iSOZ
Examplc ~9
2-~2-Methoxy-~-(3-ethy]~ercapto-propox~)-phenyl/-lH-imida~o-
/4,5-b7pyridine-hydrochloride
Prepared analogous to example 46 from 4-(3-ethylmercapto-propoxy~
2-~ethoxy-thio-benzoic acid-morpholide and 2,3-diaminopyridine.
M.p.: 183 to 185 C (decomp.).
Example 50
2-~ -(2-Methylmercapto-ethoxy)-4-methoxy-phenyl/-lH-imida~o~ ,5-b7-
Eyridine-hydrochloride
Prep~red analogous to example 46 from 2-(2-methyl~ercapto-ethoxy)-
4-methoxy-thio-benzoic acid-morpholide and 2,3-diamino-pyridine.
M.p.: 204 to 206 C (decomp.).
Example 51
2- ~ -(2-Ethylmercapto-ethoxy)-4-methoxy-phenyl/-lH-imidazor4, 5-b7-
pyridine-hydrochloride
prepared analogous to example 46 from 2-(2-ethylmercapto-ethoxy)-4-
methoxy-thio-ben~oic acid-morpholide and 2,3-diaminopyridine.
M.p.: 193 to 195 C.
Example 52
2-/2-(3-llethylmercapto-propoxy)-4-methoxy-phenyl7-lH-imi.da~o-
r4,5-b7pyridine-hydrochloride
Prepared analogous to example 46 from 2-(3-methylmercapto-propoYy3-
4-methoxy-thio-ben~oic acid-morpholidc and 2,3-diaminopyridine.
M.p.: ]91 to 193 C.
, . .
rAl
- 46 -
, - '~ ' ~ , ; ' ;: '
10~150'~
E~ _ ~Ic 53
2-/2-(3-~thylmercapto-propoxy)-4-methox~-phenyl/-1ll-imidazo-
¦4,5-b/pyridine-h~drochloride
prepared analogous to example 46 from 2-(3-ethylmercapto-propo~y)-
4 methoxy-thio-benzoic acid-morpholide and 2,3-diaminopyridine.
M.p.: 187 to 189 C.
Example ~4
2-(2~3~4-Trimethoxy-phenyl)-lH-imidazo/4,5-b7-pyridine-hydro-
chloride
.
Prepared analo~ous to example 28 from 2,3,4-trimethoxy-thio-benzoic
acid-morpholide-methoiodide (m.p. 147 to 150 C) and 2~3-diamino-
pyridine.
M.p.: 231 to 233 C (decomp.).
Example 55
2-(2-Methoxy-3,4-mcthylenedioxy-phenyl)-lH-imidazo/4,5-b7pyridine-
hydrochloride
' - .
~repared analogous to example 28 from 2-methoxy-3, 4 methylenedioxy-
thio-benzoic acid-morpholide-methoiodide (m.p.: 109 to 111 C) ~nd
2,3-diaminopyridine.
M.p.: 266 to 268 C.
- 47 -
: , - . . . .
104iS02
Example 56
2-(2~4-Dimethoxy-3-hydroxy-phenyl)-lH-imidazo~4~5-b7pyridine-
hydrochloride
Prepared analogous to example 28 from 2,4-dimethoxy-3-hydro.Yy-thio-
ben~oic acid-morphol_de-methoiodide and 2,3-diaminopyridine.
M.p.: 115 to 118 C.
Example 57
2-(2-Methoxy-4-chloro-phenyl)-lH-imidazo/~ pyridine-hydro-
chloride
Prepared analogous to example 28 from 2-methoxy-4-chloro-thio-benzoic
acid-morpholide-methoiodide and 2,3-diaminopyridine.
M.p.: 302 to 305 C.
Example 58
2-(2-Methoxy-4-methyl-phenyl)-lH-imidazo/4,5-b7pyridine-hydro-
chloride
~. . .
Prepared analogous to example 28 from 2-methoxy-4-methyl-thio-ben70ic
acid-morpholide and 2,3-diaminopyridine.
M .p .: 256 C (decomp.).
Examplc 5
2-(2-Ethoxy-4-methyl-phenyl)-1~l-imidazo/4~5-b7pyridine-hydrocllloridc
Prepared analogous to example 28 from 2-ethoxy-4-mcthyl-thi.o-ben-oic
rA~
, - 48 -
- - .
. . - ~ . ~
lV41502
acid-morpholide-methoidide (m.p.: 142 to 144C) and 2,3-diamino-
pyridine.
M.p.: 224 to 225C (decomp.).
xample 60
2-(2-Methoxy-4-methylmercapto-phenyl)-lH-imidazo[4,5-b]pyridine-
hydrochloride
Prepared analogous to example 18b)from 2-methoxy-4-methylmercapto-
benzoic acid-morpholide (m.p.: 124 to 129C) and 2,3-diamino-pyri-
dine.
M.p.: 232 to 234C.
Example 61
2-(2-Methoxy-5-methylmercapto-phenyl)-lH-imidazo[4,5-b]pyridine-
hydrochloride
Prepared analogous to example 18b)from 2-methoxy-5-methyLmercapto-
benzoic acid-morpholide (m.p.: 106 to 108C) ard 2~3-diamino- --
pyridine.
M.p.: 247 to 248C.
Example 62
2-(2-Methoxy-4-ethylmercapto-phenyl)-lH-imidazo[4,5-b]pyridine-
hydrochloride
Prepared analogous to example 25 from 2-methoxy-4-ethylmercapto-
benzoic acid-morpholide and 2~3-diaminopyridine.
M.p.: 215 to 217C.
- 49 -
,
xample 63 ~04~502
2-(2-Methylmercapto-phenyl)-1H-imidazo[4,5-b]pyridine-hydrochloride
Prepared analogous to example 28 from 2-methylmercapto-thio-benzoic
acid-morpholide-methoiodide and 2~3-diaminopyridine.
M.p.: 185 to 187C.
xample 64
2-(2,4-Pismethylmercapto-phenyl-1H imidazo[4,5-b]pyridine-hydro-
chloride
Prepared analogous to example 28 from 2,4-bismethylmercapto-thio-
benzoic acid-morpholide-methoiodide and 2,3-diaminopyridine.
M.p.: 249 to 250C. `~
Example 65
2-[2-(2-Methylmercapto-ethoxy)-4-methylmercapto-phenyl]-lH-imidazo-
[4.5-b]pyridine-hydrochloride
Prepared analogous to example 28 from 2-(2-methylmercapto-ethoxy)-
4-methylmercapto-thio-benzoic acid-morpholide-methoiodide and 2,3-
diaminopyridine.
M.p.: 180`to 182C.
Example 66 -
2-~2-(2-Diethylamino-ethoxy)-4-methyl-phenyl]-1H-imidazo[4~5-b]-
pryidine-hydrochloride
Prepared analogous to example 28 from 2-(2-diethylamino-ethoxy)-4-
methyl-thio-benzoic acid-morpholide-methoiodide-hydrochloride and -
2,3-diaminopyridine.
M.p.: 221 to 223C.
- 50 -
`' ' ~ ~ .
.
.
r - ~
1041S0~
Example 67
2-(2-Allyloxr-4-methoxy-phenyl)-lH-imidazo[4,5-b]p~ridine ;
hydrochloride
16.5 g of 2-allyloxy-4-methoxy-benzoyl morpholide
and 7.1 g of 2,3-diaminopyridine were powdered and ~ -
intimately mixed and 30 ml of phosphorus oxychloride were
added dropwise whilst stirring. Subsequently, the
re~ction mixture was refluxed for 3 hours, the excess of
phosphorus oxychloride was removed and the residue was
decomposed with ice-water. The solu~ion, which had been
made alkaline with ammonia, was extracted with chloro~orm.
The organic solution was extracted with 2N hydrochloric
acid and the aqueous phase was made alkaline with c~mmonia
and extracted with chlorofonm. The chl~rofol~ ~olution
r
":IAl . .
1041S0;~
was dried, treated with charcoal/tonsil, filtered and
evaporated. The residue was dissolved in acetone and the
light yellow colored hydrochloride w~s precipitated with
ethereal hydrochloric acid.
M.p.: 189 to 191C.
Example 68
2-(2~4,5-Trimethoxy-phenyl)-lH-imidazo[4,5-b]pyridine
hydrochloride
a) 2-(2,4,5-Trimethoxy-phenyl)-1,3-dithiolanium-iodine
50 g of 1.2,4-trimethoxybenzene and 150 g of
2-methylmercapto-1,3-dithiolanium-methylsulfate were
stirred in 600 ml of glacial acetic acid for 4 hours at
70~C bath temperature. Subsequently, the solvent was
removet, the residue was dissolved in a mixture of
chloroform and water and an excess of potassium iodide
solution was added to the aqueous layer, whereby the
product precipitated as orange-colored crystals.
b) 2-(2,4,5-Trimethoxy-phenyl)-lH-imidazo[4,5-b]
pyridine hydrochloride
3.8 g of 2-(2,4,5-trimethoxy-phenyl)-1,3-dithiolanium
-iodide and 2.2 g of 2,3-diaminopyridine were heated for
.
Al~ 3;~ -- 5~--
~ ........
..... ~ .
1041S0~
10 minutes in 40 ml of glycol at 200C. After cooling
the mixture was extracted with ether and then with
chloroform. The chloroform layer was extracted with 2N
hydrochloric acid and the precipitated yellow hydrochloride
was suction filtered and recrystallized from glycol.
M.p.: 278 to 280C
Example 69
2-(2-,4,6-Trimethoxy-phenyl)-lH-imidazo[4,5-b]pyridine
hydrochloride
a) 2-(2~4,6-Trimethoxy-phenyl)-1,3-dithiolanium-iodide
33.6g of phloroglucinol-trimethyl ether and 105 g
of 2-methylmercapto-1,3-dithiolanium-methylsulfate were
held at 75C for 6 hours in 200 mI of glacial acetic acid
and the crystals which precipitated after standing over-
night were suction filtered, dissolved in w~ter and the
iodide thereof was precipitated with potassium iodide
solution.
M.p.: 153 to 154C.
5 3
rA~ ~
.
1041S02
b) 2-(2,4,6-Trimethoxy-phenyl)-lH-imidazo[4,5-b]
pyridine hydrochloride
4 g of 2-(2,4,6-trimethoxy-phenyl)-1,3-dithiolanium-
iodide, 2 2 g of 2,3-diaminopyridine and 5 g of lead acetate
were heated for 10 minutes in 75 ml of glycol. Subse-
quently the precipitated lead salt was filtered off, the
filtrate was diluted with water and the precipitated
product was suction filtered. After dissolving in
methanolic hydrochloric acid, the product was purified by
passage through a silica gel column (eluent: chloroform:
methanol s 9:1)
M.p.: 241 to 244C (from ethanol)
Example 70
2-(2,4-Dihydroxy-phenyl)-lH-imidazo[4,5-b]pyridine
hydrochloride
Prepared analogously to Example 69 from 3-hydroxy-
4-[1',3'-dithiacyclopentylidene-(2')]-cyclohexadiene-(2,5)-
one-(l) and 2,3-diaminopyridine.
M.p.: 298 to 301C.
. 5~G
r,A~
- ~ .
1041SUZ
Example 71
2-(4-Dimethylamino-Phenyl)-lH-imidazo[4,5-b]Pyridine
hydrochloride
Prepared analogously to Example 69 from 2(4-dimethyl-
amino-phenyl)-1,3-dithiolanium-iodide and 2,3-diamino-
pyridine in n-propanol.
M.p.: 337 to 339C.
ExamPle 72
2-(2-Methoxy-4-dimethylamino-phenyl)-lH-imidazo[4,5-b]
pyridine hydrochloride
a) 2-(2-Methoxy-4-dimethylamino-phenyl)-1,3-dithiolanium-
iodide
22.6 g of 3-dimethylamino-anisole, 43.2 g of 2-
methylmercapto-1,3-dithiolanium-methyl su~fate, 150 ml of
glacial acetic acid and 22.5 ml of pyridine were refluxed
for ~ hour. After cooling, the mixture was poured into
an aqueous potassium iodide solution, the precipitated
product wa8 suction filtered and dried.
M.p.: 189 to 195C (from dimethylformamide)
.. - , . .. ..
'A~ 55~
'~'.
., - - . , ~ . : .
.. . : ,. .
~4lSO'~
b) 2-(2-Methoxy-4-dimethylamino-phenyl)-lH-imidazo
[4,5-b~pyridine hydrochloride
Prepared analogously to Example 42 from 2-(2-methoxy-
4-dimethylamino-phenyl)-1,3-dithiolanium-iod~e and 2,3-
diaminopyridine.
M.p.: 258 to 260C (from methanol~
Example 73
2-(2-Methylsulfinvl-phenyl)-lH-imidazo[4,5-b]pyridine
hydrochloride
1.35 g of 2-(2-methylmercapto-phenyl)-lH-imidazo
[4,5-b]pyridine were dissolved in 20 ml of glacial acetic -~
acid and 0.64 8 of 30% hydrogen peroxide dissolved in 5 ml
of glacial acetic acid were added dropwise. After
standing overnight, the mixture was diluted with water,
neutralized with sodium bicarbonate and the precipitated
product was suction filtered and dried. By addition of
ethereal hydrochloric acid to a methanolic solution of the
product the colorless hydrochloride was obtained.
M.p.: 205 to 210C.
5~ . .
_ ,~ _
104150;~
Example 74
2-(2-Me ~ lsulfon~ phenyl)~ -imidazo~4,5-bJpyridine
hydrochloride
450 mg of 2-(2-methylmercapto-phenyl)-lH-imidazo
[4,5-b]pyridine hydrochloride and 370 mg of 300/D hydrogen
peroxide were heated for 3 hours at 70C in 20 ml of
glacial acetic acid. After evaporation and trituration
with petroleum ether, the desired product crystallized~
M.p.: 259 to 262C (from isopropanol)
Example 75
2- [2-(2-Methylsulfinyl-ethoxy)-phenyl]-lH-imidazo[~ ,s-b3
pyridine hydrvchloride
a) 2-[2-(2-Methylmercapto-ethoxy)-phenyl~-lH-imidazo
[~,5-b3pyridine hydrochloride
- 57 -
.
.. ~1 . .
- . , , ~ . .
~04~SOZ
Prepared aralogous to example 28 from 2-(2-methylmercapto-ethoxy)-
thio-benzoic acid-morpholide-methoiodide and 2,3-diaminopyridine.
M.p.: 138 to 140C.
b) 2-[2-(2-Nethylsulfinyl-ethoxy)-phenyl]-lH-imidazo[4,5-b]pyridine-
hydrochloride
4,3 g of 2-[2-(2-methylmercapto-ethoxy)-phenyl]-lH-imidazo-
[4,5-b]pyridine-hydrochloride and 1,5 g of 30 ~ hydrogen per-
oxide were stirred for 2 hours at room temperature in 100 ml
of glacial acetic acid. After standing over night, the mixture
was diluted with water, neutralized with bicarbonate and ex-
tracted with chloroform. The chloroform layer was evaporated,
the residue was taken up in acetone and the hydrochloride was
precipitated with methanolic hydrochloric acid.
.p.: 163 to 165C.
xample 76
2-[2-(2-Methylsulfinyl-ethoxy)-4-methoxy-phenyl]-lH-imidazo-
[4~5-b]~yridine-hydrochloride
Prepared analogous to example 75b from 2-~2-(2-methylmercapto-
ethoxy)-4-methoxy-phenyl]-lH-imidazo[4,5-b]pyridine-hydrochloride.
M.p.: 231 to 232C.
xample 77
2-[2-(2-Ethylsulfinyl-ethoxy)-4-methoxy-phenyl]-lH-imidazo[4,5-b]-
pYridine
Prepared analogous to example 75b from 2-[2-(2-ethylmercapto-ethoxy)-
~ methoxy-phenyl]-lH-imidazo~4,5-b3pyridine-hydrochloride.
M.p.: 188 to 189C.
1041~0Z
Example 78
2-[2-(3-Methylsulfinyl-propoxy~-4-methoxy~phenyl ~lH-
.
Prepared analogously to Example 75b from 2-[2-[2- -
(3-methylmercapto-prop~y~4-methoxy-pher,yl]-lH-imidazo
~4,5-b~pyridine hydrochloride
M.p.: 132 to 133C
Example 79
~ '' "'
L4 ~ 5-b ]Pyri dine
Prepared analogously to Example 75b from 2-~2-~3- .
ethylmercapto-propoxy)-4-methoxy-phenyl3-lH-imidazo[4,5-b3 : ;
pyridine hydrochloride. -;
p.: 126 to 127C.
- 59 - .
~, ..
~ r~
~ . . .
1~)41SO'~
Example 80
2-(2-Methoxy-4-methvlsulfinyl-phenyl)-lH-imidazo[4,5-b~
p~ridine hydrochloride
6.6 g of 2-(2-methoxy-4-methylmercapto-phenyl)-lH-
imidazo[4,5-b]-pyridine were dissolved in 100 ml of chloro-
form and a solution of 2.96 g of 3-chloro-perbenzoic acid
in 600 ml of chloroform was dropped in at -15 to -20C
during 5 hours. Subsequently, the mixture was extracted
with a dilute sodium carbonate solution and the chloroform
layer was dried and evaporated. The residue was purified
over a silica gel column (eluent: chloroform/methanol =
9:1) By addition of ethereal hydrochloric acid to a
methanolic solution of the base the yellow hydrochloride
was obtained.
M.p.: 154 to 155C.
ExamPle 81
2-(2-MethoxY-4-methYlsulfonYl-phenyl)-lH-imidazo[4~5-b~
pyridine hydrochloride
Prepared analogously to Example 74 from 2-(2-methoxy
-4-methylmercapto-phenyl)-lH-imidazo[4,5-b3pyridine
hydrochloride.
M.p.: 240 to 242~G.
r 60
pj~ _ ~ _
104150Z
Example 82
2-(2-Methoxy-4-ethylsulfinyl-phenyl)-lH-imidazo~4,5-b]
pyridine hydrochloride
Prepared analogously to Example 80 from 2-(2-
methoxy-4-ethylmerc~pto-phenyl)-lH-imidazo[4,5-b]pyridine
M.p.: 121 to 123C
Example 83
2-[2-(2-Methylsulfinyl-ethoxy)-4-methylmercapto-phenvl]-lH-
_idazo[4,5-b]pyridine
Prepared analogously to Example 80 from 2-[2-
methylmercapto-ethoxy)-4-methylmercapto-phenyl]-lH-imidazo
[4,5-b]pyridine and an equimolar quantity of 3-chloro-
perbenzoic acid.
M.p.: 191 to 192C (from acetone)
ExamPle 84
2-[2-(2-MethylsulfinYl-ethoxy)-4-methylsulfinYl-phenyl]-lM-
imidazo[4,5-b]pyridine
Prçpared analogously to Example 80 from 2-[2-(2-
methylsulfinyl-ethoxy)-4-methylmercapto-phenyl]-lH-imidazo
~4,5-b]pyridine and an equimolar quantity of 3-chloro-
perbenzoic acid.
M.p.: 190 to 191C.
104~50'~
Example 85
2-[2-(2-Methylsulfinyl-ethoxy)-4-methYl-phenyl]-lH-imidazo
[4,5-b~ pyridine hydrochloride
Prepared analogously to Example 75b from 2-~2-(2-
methylmercapto-ethoxy)-4-methyl-phenyl]-lH-imidazo[4,5-b]
pyridine hydrochloride.
M.p.: 191 to 192C (from acetone/ether).
Example 86
2-[2-(2-Methylsulfinyl-ethoxY)-4-chlorophen ~ H-imidazo
[4,5-b] yridine hydrochloride
Prepared analogously to Example 75b from 2-[2-(2-
methymercapto-ethoxy)-4-chloro-phenyl]-lH-imidazo[4,5-b]
pyridine hydrochloride.
M.p.: 221 to 222C (from acetone/ether).
Example 87
2-[2-Methoxy-4-(2-methYlsulfinyl-ethoxy)-phenyl]-lH-imidazo
[4,5-b]pyridine
Prepared analogously to Example 75 b from 2-[2-
methoxy-4-(2-methylmercapto-ethoxy)-phenyl]-lH-imidazo
[4,5-b]pyridine hydrochloride.
M.p.: 204 to 205C.
rA~ ~ ~
~041S0~
Example 88
2-[2-Methoxv-4-(2-ethylsulfinyl-ethoxy)-phenyl]-lH-imidazo
[4,5-b~ p~ridine
Prepared analogously to Example 75b from 2-~2-
methoxy-4-(2-ethyl-mercapto-ethoxy)-phenyl]-lH-imidazo
[4,5-b]pyridine hydrochloride.
M.p.: 217 to 219C
Example 89
2-[2-Methoxv-4-(3-methylsulfinvl-propoxv)-phenyl]-lH-
imidazo[4,5-b]pyridine
Prepared analogously to Example 75b from 2-[2-
methoxy-4-(3-methylmercapto-propoxy)-phenyl]-lH-imidazo
[4,5-b]pyridine hydrochloride.
M.p.: 179 to 180C.
Example 90
2-[2-MethoxY-4-(3-ethvlsulfinvl-propoxY~-phenyl]-lH-imidazo
[4,5-b] Pvridine hydrochloride
.
Prepared analogously to Example 75b from 2-[2- ~-
methoxy-4-(3-ethylmercapto-propoxy)-phenyl]-lH-imidazo
[4,5-b]pyridine hydrochloride
M.p.: 167 to 168C.
~3 , . .
--_&6~-- '
r~
104~50~
Example 91
2-(2-Methoxy-5-methylsulfinyl-phenyl)-lH-imidazo[4,5-b]
Pvridine
Prepared analogously to Example 80 from 2-(2-methoxy-
5-methylmercapto-phenyl)-lH-imidazo[4,5-b]pyridine
hydrochloride.
M.p.: 211 to 212C.
Example 92
2-(2-Methoxy-5-methylsulfonyl-phenyl)-lH-imidazo[4,5-b]
pyridine
Prepared analogously to Example 74 from 2-(2-
methoxy-5-methylmercapto-phenyl)-lH-imidazo[4,5-b]pyridine
hydrochloride
M.p.: 240 to 241C.
Example 93
2-(2,4-Dimethoxy-phenyl-lH-imidazo[4,5-b~Pvridine-oxide-(4)
1 g of 2-(2,4-dimethoxy-phenyl)-lH-imidazo[4,5-b]
pyridine and 1.35 g of 3-chloroperbenzoic acid were
stirred for 15 hours at 60C in 15 ml of glacial acetic
acid. Subsequently, the mixture was recrystallized from
6y
~ ~ .' . ' -
.
..
-
~041502
2N acetic acid by addition of charcoal. The further
purification was effected by boiling with acetone.
M.p.: 266 to 267C.
Example 94
2-(2,4-Dimethoxy-phenyl)-3-methyl-3H-imidazo[4~5-b~
Ey~idine hydrochloride
3.6 g of methyl iodide were added dropwise to a
solution of 3.5 g of 2-(2,4-dimethoxy-phenyl)-lH-imidazo
~4,5-b]pyridine hydrochloride and 27 g of potassium tert.-
butoxide in 40 ml of dimethylformamide. The mixture was
stirred for 2 hours at room temperature and then
evaporated. The residue was dissolved in chloroform4
water, the organic layer was separated, dried and evaporated.
The product was purified by column chromatography and
subsequently precipitated from the solution in acetone with
ethereal hydrochloric acid.
M.p.: 196 to 197C.
G~'
~ 'Al - ~
: . :
... , ' '
104~50'~
Example 95
2-(2-Hydroxy-phenyl)-3-methyl-3H-imidazo~ [4,5-b]pyridine
hydrochloride
Prepared analogously to Example 94 from 2-(2-
hydroxy-phenyl)-lH-imidazo[4,5-b]pyridine and methyl iodide.
M.p.: 215 to 216C.
Example 96
2-(2-Hvdroxy- 4-methoxy-phenyl)-3-(3-hydroxypropyl)-3H-
i.midazo~4,5-b~pvridine hvdrochloride
Prepared analogously to Example 94 from 2-(2-
hydroxy-4-methoxy-phenyl)-lH-imidazo[4,5-b~pyridine and
3-bromo-propanol.
l~.p.: 154 to 155C.
Example 97
2-(2,4-Dimethoxy-phenYl)-3-benzyl-3H-imidazo[4,5-b]pyridine
hydrochloride
Prepared analogously to Example 94 from 2-(2,4-
dimethoxy-phenyl)-lH-imidazo[4,5-b]pyridine and
benzyl bromide.
M.p.: 148 to 150C.
Example 98
2-(2-Dimethoxy-phenyl)-3-(2-diethYlaminoethyl)-3H-imidazo~
[4,5-b]pyridine dihYdrochloride
-. . .
;
-
. .
.
, ~ :
~04~50'~
Prepared analogously to Example 94 from 2-(2-
dimethoxy-phenyl)-lH-imidazo[4,5-b]pyridine and 2-
diethylamino-ethyl chloride at 80C.
M.p.: 185C.
Example 99
2-(2,4-Dimethoxy-phenyl)-3-(3-dimethylaminopropyl)-3H
imidazo~4,5-b]pyridine dihydrochloride
Prepared analogously to Example 94 from 2-(2,4-
dimethoxy-phenyl)-lH-imidazo t 4,5-b]pyridine and 3-
dimethylaminopropyl bromide at 70C.
M.p.: 190 to 192C (decomp.).
Example 100
2-(2-Methoxy-4-benzvloxy-phenyl)-lH-imidazot4,5-b]pyridine :
Prepared analogously to Example 10 from 2-methoxy-
4-benzyloxy-benzoyl morpholide and 2,3-diamino-pyridinç.
M.p. of the hydrochloride: 218 to 219C (decomp.).
Example 101
Prepared analogously to Example 10 from 2,4-dimethoxy-
benzoyl morpholide and 3-amino-2-butylamino-pyridine.
M.p. of the hydrochloride: 218 to 219C.
,
~1 - ~, '
rA~
., ,, ;
- : , -, ..... . -
: :.......... .
Example 102 1041S02
2-(2-Methoxv-4-hydroxy-phenyl)-lH-imidazo[4,5-b]pyridine
Prepared analogously to Example 10 from 2-
methoxy-4-hydroxy-benzoyl morpholide and 2,3-diamino-
pyridine.
M.p. of the hydrochloride: 230 to 231C.
Example 103
2-(2-Ethoxy-4-ethylmercapto-phenyl)-lH-imidazo~4,5-b~-
pyridine
Prepared analogously to Example 10 from 2-ethoxy-
4-ethylmercapto-benzoyl morpholide and 2,3-diamino-pyridine.
M.p. of the hydrochloride: 198 to 199C (decomp.).
ExamPle 104
2~4-Methoxy-2-(3-(4-methvl-l-piPerazinyl)-propoxy)-phenvl]
lH-imidazo[4,5-b]pyridine
Prepared analogously to Example 21 from 2-[4-methoxy-
2-(3-chloro-propoxy)-phenyl]-lH-imidazo[4,5-~] pyridine and
l-methylpiperazine.
M.p. of the trihydrochloride: 248C (decomp.)
Example 105
2-r4-MethoxY-2-(2-thiomorPholine-ethoxy)-phenyl]-lH- ,
imidazo~4,5-b]Pyridine
Prepared analogously to Ex~mple 21 from 2-[4-
methoxy-2-(2-chloro-ethoxy)-phenyl]-lH-imidazo[4,5-b]-
- ~1 ~~~
,
.. . . .. . .
104~50Z
-pyridine and thiomorpholine.
M.p.: 158 to 160C.
ExamPle 106
2-(2-Fluoro-4-methoxy-phenyl)-lH-imidazo~ 5-b~pYridine
Prepared analogously to Example 1 from 2-fluoro-
4-methoxy-benzoic acid and 2,3-diamino-pyridine.
M.p. of the hydro~hloride: 237 to 238C (decomp.).
Example 107
2-(4-Fluoro-2-methoxy-phenyl)-lH-imidazo[4.5-b]pyridine
Prepared analogously to Example 1 from 4-fluoro-
2-methoxy-benzoic acid and 2,3-diamino-pyridine.
M.p. of the hydrochloride: 235 to 236C (decomp.)
Example 108
2-(2-Hydroxy-4-methox~-phenyl)-3-phenyl-3H-imidazo-
r4,5-b]pyridine
4.9 g of 2-hydroxy-4-methoxy-benzanilide and 2.6 g
of 2-chloro-3-amino-pyridine were refluxed for 12 hours
in 50 ml of phosphorus oxychloride. After distilling
- 69 -
'. . . : ' ' ' ' - ' '
1041SOZ
off the excess of phosphorus oxychloride the residue was
boiled for 45 minutes with 2N hydrochloric acid,
neutralized with ammonia and the precipitated product
was recrystallized from isopropanol.
M.p.: 201C.
C Example ~
2-(2-Hvdroxy-4-methoxv-phenYl)-3-(2-methoxv-phenyl)-3H-
imidazo~4,5-b]pyridine
-
/~
Prepared analogously to Example ~Q from N-(2-
methoxy-phenyl)-2-hydroxy-4-methoxy-benzamide and 2-chloro-
3-amino-pyridine.
M.p.: 197C.
~Q
Example l~L
2-(2-Hydroxv-4-methoxy-phenvl)-3-(4-methoxv-phenvl)-
3H-imidazo~4,5~b]pvridine
/o&
Prepared analogously to Example ~9R from N-(4-
methoxy-phenyl)-2-hydroxy-4-methoxy-benzamide and 2-
chloro-3-amino-pyridine.
M.p.: 175C.
:':
Exam~le
2-(2-HvdroxY-4-methoxY-PhenYl)-3-(2-phenvlethvl)-3H
imidazo~4,5-b~pyridlne
/~&
Prepared analogously to ~xample ~Q from
5~1'. ~ ~ ....
. . -,
.. . . .
.. : . : . -
1041S02
N-(2-phenylethyl)-2-hydroxy-4-methoxy-benzamide and
2-chloro-3-amino-pyridine.
M.p.: 155C.
Example 112
2- ~ 4 Dimethoxy-phenyl)-3-phenyl-3H-imidazo[4,5-b]pyridine
Prepared from N-phenyl-N'-(2-chloro-3-pyridyl)-
2,4-dimethoxy-benzamidine by heating for 5 minutes with
sodium hydride in dimethylformamide at 120C.
M.p.: 138C (from cyclohexane/isopropanol = 9/1). -
ExamPle 113
2-(2,4 Dimethoxy-pheny1)-3-(2-methoxy-phenyl)-3H-imidazo-
[4,5-b]pyridine
Prepared analogously to Example 112 from N-(2-
methoxy-phenyl)-N~-(2-chloro-3-pyridyl)-2,4-dimethoxy-
benzamidine.
M.p.: 156C.
.
- : - - ~ , . : :
104~50Z
Y
Example r~
.
2-(2~4-Dimethoxy-phenyl)-3-(4-methoxy-phenyl)-3H-
imidazo[4,5-b~pyridine
~/~
Prepared analogously to Example ~ from
N-(4-methoxy-phenyl)-N'-(2-chloro-3-pyridyl)-2,4-
dimethoxy-benzamidine.
M.p.: 163C.
Example ~
2-(2,4-Dimet,hoxy-phenyl)-3-(3,4-dimethoxy-phenyl)-3H-
imidazo[4,5-b~pyridine
11~
Prepared analogously to Example ~4~from N-
(3,4-dimethoxy-phenyl)-N'-(2-chloro-3-pyridyl)-2,4-
dimethoxy-benzamidine.
M.p.: 190C.
I/6
Example ~9~
2-(3,4-Dimethoxy-phenyl)-3-(4-methoxy-phenyl)-3H-imidazo-
[4,5-b]pyridine
Prepared fron N-(4-methoxy-phenyl)-N'-(2-chloro-
3-pyridyl)-2,4-dimethoxy-benzamidine analogously to
Example ri~or by boiling in chlorobenzene.
M.p.: 181C.
Jl 1
2-(2,4-Dimethoxy-phenyl)-3-(3-morpholino-1-propYl)-3H-
imidazo~4,5-b]pYridine
72,
rAl - ~ - , , .
- . . ~ ~ . . ~
' " ~
1041S02
11~
Prepared analogously to Example ~ from
N-(3-morpholino-1-propyl)-N'~(2-chloro-3-pyridyl~-
2,4-dimethoxy-benzamidine.
M.p.: 207C.
Example ~
2-(2,6-~imethoxyphenyl)-lH-imidazo[4,5-b]pyridine
hvdrochloride
9.1 g of 2,6-dimethoxy-benzoic acid and 5.5 g of
2,3-diaminopyridine were refluxed for 3 hours in 100 ml
of phosphorus oxychloride. Subsequently the excess of
phosphorus oxychloride was distilled off and the
residue was carefully decomposed with ice-water. The
obt`ained solution was filtered, neutralized with
potassium carbonate and made alkaline with concentrated
ammonia. The suspension which formed was extracted
three times with chloroform. The chloroform layer was
dried over magnesium sulfate, filtered and the solvent
was removed. The remaining residue was dissolved in
50 ml of methanolic hydrochloric acid, subsequently
100 ml of isoprqpanol were added and the product was
kept in the deep freezer overnight. The precipitate
was suction filtered and washed with ether.
M.p.: 250 to 254C.
-- 76 -- '
rAl
1041S0~
Example
2-(2-Propoxy-4-methyl-phenyl)-lH-imidazo[4,5-b]pvridine
hydrochloride
1/~
Prepared analogously to Example ~Q from 2-
propoxy-4-methyl-benzoyl morpholide.
M.p.: 221 to 223~. (decomp.).
Example ~Y~L
2-(2-Butoxy-4-methyl-phenyl)-lH-imidazo[4,5-b]pyridine
hydrochloride
Prepared analogously to Example ~ from 2-butoxy-
4-methyl-benzoyl morpholide.
M.p.: 212 to 213C (decomp.).
/o~ I
Example ~X~
_ (4-Methylmercapto-phenyl)-lH-imidazo~4,5-b]pvridine
hydrochloride
Prepared analogously to Example ~Q from 4-mçthyl-
mercaptobenzoic acid.
M.p.: 230 to 232C.
Example k~
2-[2-(2-Methvlmercapto-ethoxY)-5-methylmercapto-phenyl]-
lH-imidazo r 4,5-b]pyridine hvdrochloride
50 g of S-methyl-~2-(2-methylmercapto-ethoxy)-5-
methylmercapto]-thiobenzoyl morpholide iodide (obtained ~ -
by reaction of [2-(2-methylmercapto-ethoxy)-5-methylmercapto]-
r~ _ ~
. : , .
104150Z
-thiobenzoyl morpholide with methyl iodide in methanol)
and 15 g of 2,3-diaminopyridine were heated for 3 hours
at 130C in 150 ml of glycol. After cooling, the mixture
was diluted with water and 30 ml of concentrated ammonia
were added. Subsequently, the mixture was extracted
with chloroform, the organic layer was washed with ~ater -
and 2N hydrochloric acid was added. The precipitate
was suction filtered and recrystallized from methanol.
M~p.: 190 to 191C.
l~ 3
E~ample ~i
2-(2-Methoxy-4-propylmercapto-phenyl)-lH-i~midazo~4,5-b~- ;
pyridine hydrochloride
Prepared analogously to Example ~ from 2-methoxy-
4-propylmercapto-benzoyl morpholide.
M.p.: 203 to 204C (decomp.).
Example ~
2-(2-Ethoxy-4-propvlmercapto-phenyl)-lH-imidazo~4,5-b]-
pyridine hydrochloride
Prepared analogously to Example ~Q from 2-ethoxy-
4-propylmercapto-benzoyl morpholide.
M.p.: 182 to 183C.
_ ~ _
. . .
. -
Example ~2 1041S02
2-(2-Methoxv-4-butylmercapto-phenyl)-lH-imidazo~4,5-b]-
pyridine hydrochloride
11~
Prepared analogously to Example r~Q from
2-methoxy-4-butylmercapto-benzoyl morpholide.
M.p.: 203 to 204C.
/~6
Example r~
2-(2-EthoxY-4-butylmercapto-phenyl)-H-imidazo[4,5-b~-
pyridine hydrochloride
Prepared analogously to Example ~ from 2-
ethoxy-4-butylmercaptobenzoyl morpholide.
M.p.: 207 to 208C.
Example ~9
2-(4-Methylsulfinyl-phenyl)-lH-imidazo[4,5-b]pyridine
5.9 g of 2-(4-methylmercapto-phenyl)-lH-imidazo-
[4,5-b]pyridine hydrochloride were dissolved in 100 ml
of glacial acetic acid and 2.4 g of 30% hydrogen
peroxide were added at 10C. Subsequently the mixture
was stirred for 3 hours, and then left to stand over-
night in the refrigerator and for 10 hours at laboratory
temperature. The mixture was made alkaline with ammonia
and was extracted several times with chloroform. The
starting material was separated by column chromatography.
The residue was suspended in acetone and the crystals -
: .
- ~6
Al ~ ,...... ..
~ ,.- . : , ,
1041S02
which formed were suction filtered.
M.p.: 240 to 242C.
Example 13~
2-(2-Ethoxy-5-methylsulfinyl-phenyl)-lH-imidazo[4,5-b]-
pyridine
/~1
Prepared analogously to Example ~22 from 2-(2-
ethoxy-5-methylmercapto-phenyl)-lH-imidazo[4,5-b]pyridine.
M.p.: 197 to 198C.
I~q
Example ~31
2-~2-(2-Methvlsulfinvl-ethoxy)-S-methylmercapto-phenyl]-
lH-imidazo[4,5-b]pyridine
Prepared analogously to Example ~ from 2-[2-(2-
methylmercapto-ethoxy)-5-methylmercapto-phenyl]-lH-
imidazo[4,5-b]pyridine hydrochloride.
M.p.: 189 to 190C.
I3 O
Example
2-(2-Ethoxy-4-ethylsulfinyl-phenyl)-lH-imidazo~4~5-b]
pyridine
Prepared analogously to Example 1~ from 2-(-2-
ethoxy-4-ethylmercapto-phenyl)-lH-imidazo[4,5-b]pyridine
hydrochloride.
M.p.: 166 to 167C.
~ .
_ ~ _
rA~
... .. .
-
~ 104~50Z
- ~ ~3,
Example 1~
2-t2-Methoxy-4-propylsulfinyl-phenyl)-lH-imidazor4,5-b]-
pyridine
td~
Prepared analogously to Example ~ from 2-(2- :~
methoxy-4-propylmercapto-phenyl)-lH-imidazo[4,5-b~-
pyridine hydrochloride,
M.p.: 182 to 183C.
Example
. 2-(2-Ethoxy-4-propvlsulfinyl-phenvl)-lH-imidazo[4,5-b~-
pyridine
~ 7
Prepared analogously to Ex~mple ~a from 2-(2-
ethoxy-4-propylmercapto-phenyl)-lH-imidazo~4,5-b~pyridine
hydrochloride.
M.p.: 182 to 183C (decomp.).
t3
Example rg~
2-(2-Ethoxy-4-butyl'sulfinyl-phenyl)-lH-imidazo[4,5-b~-
pyridine
1~1
Prepared analogously to Example r24~from 2-(2-
ethoxy-4-butylmercapto-phenyl)-lH-imidazo[4,5-b]pyridine
. hydrochloride.
..
: M.p.: 185 to 186C.
'Al ~
. . . .
. . .
- .
. ~ ............ . . -
. . . . .. . . .
041502
~ Example ~
~J
2-(4-Methylsulfonyl-phenyl)-lH-imidazoC4,5-b]pyridine
hydrochloride
6.95 g of 2-(4-methylmercapto-phenyl)-lH-
imidazo[4,5-b]pyridine hydrochloride were dissolved
in 100 ml of glacial acetic acid, 8.5 g of 30% hydrogen
peroxide were added and the mixture was left standing
for 4 days at room temperature. After purification
by passage through a silica gel column, the residue
was dissolved in acetone and the hydrochloride was
precipitated with methanolic hydrochloric acid.
M.p.: 286C.
/~
Example 137--
2-(2-Ethoxy-4-ethylsulfonyl-phenyl)-lH-imidazo~4,5-b]-
pvridine
400 mg of 2-(2-ethoxy-4-ethylmercapto-phenyl)-lH-
imidazo[4,5-b] pyridine hydrochloride were dissolved in
30 ml of glacial acetic acid together with 0.5 ml of 30%
hydrogen peroxide. The mixture was allowed to stand
overnight and was then heated for 1 hour at 90C.
After cooling, the mixture was diluted with water,
neutralized with bicarbonate, extracted with chloroform
and the organic layer was evaporated after drying. The
residue was purified by column chromatography.
M.p.: 207 to 208C (from acetone).
-- ~7
, rAl - ~ ~
:
~041S02
f~l f3G
Example ~9_
2-(2-Methoxy-4-propylsulfonyl-phenyl)-lH-imidazo[4,5-b~
pxridine
~3~
Prepared analogously to Example 137- from 2-(2-
methoxy-4-propylmercapto-phenyl)-lH-imidazo[4,5-b]-
pyridine.
M.p.: 219 to 220C.
/3'1
Example ~3a
2-(2-Ethoxy-4-butylsulfonyl-phenyl)-lH-imidazo[4,5-b]-
pyridine
Prepared analogously to Example r9~from 2-(2-
ethoxy-4-butylmercapto-phenyl)-lH-imidazo~4,5-b]pyridine.
M.p.: 156 to 157C.
Example
2-r2-Methoxy-4-(2-dimethYlamino-ethoxY)-Phenyl]-lH
imidazo~4,5-b]pyridine dihydrochloride
a) 2-[2-Methoxy-4-~2-chloroethoxy)-phenyl]-lH-imidazo-
[4,5-b~pvridine hydrochloride ~ --v
14 g of 2-methoxy-4-(2-hydroxyethoxy)-benzoyl
! morpholide were refluxed for l~ hours with 7.1 g of
2,3-diaminopyridine in 100 ml of phosphorus oxychloride. L
Subsequently the mixture w~s decomposed with ice-w~ter.
The gradually crystallizing prec~pitate was suction
_ ~- .
104150Z
filtered and washed with acetone.
M.p.: 266 to 268C (decomp.).
b) 2 g of 2-[2-methoxy-4-(2-chloroethoxy)-phenyl]-
lH-imidazo[4,5-b] pyridine hydrochloride were heated
in a closed vessel for 12 hours at 120C with 5 g of
dimethylamine in 100 ml of ethanol. After evaporation,
the residue was purified by column chromatography.
The hydrochloride was precipitated from acetone with
methanolic hydrochloric acid and subsequently recrystallized
from methanol.
M.p.: ~ 250C.
~ 3q
Example ~
2-[2-Methoxy-4-(3-dimeth~lamino-propoxy)-phenyl~-lH-
imidazo~4,5-b~pyridine dihydrochloride
Prepared analogously to Example 140 from 2-[2-
methoxy-4-(3-chloropropoxy)-phenyl]-lH-imidazo[4,5-b~-
pyridine hydrichloride.
M.p.: 238 to 242C.
; ' /Yo
Example ~aL
2-r2-Methoxy-4-(3-diethylamino-propoxy)-phenYl~-lH-
imidazo~4,5-b~ pyridine dihydrochloride
-
8/
'A~
104150Z
Prepared analogously to Example ~4Q from 2-~2-
methoxy-4-(3-chloropropoxy)-phenyl]-lH-imidazo[4,5-b]-
pyridine hydrochloride.
M.p.: 222 to 224C.
/'JI '
Example ~t~
2~2-Methoxy-4-(3-piperidino-propoxy)-phenyl]-lH-imidazo-
~4,5-b]pyridine dihydrochloride
/~q
Prepared analogously to Example ~4L from 2-[2-
methoxy-4-(3-chloropropoxy)-phenyl]-lH-imidazo-
~4,5-b]pyridine hydrochloride.
M.p.: 225 to 226C ~decomp.).
Example ~
2-[2-Methoxy-4-(3-(4-phenyl-piperazin-1-yl)-propoxy)- v
~envl]-lH-imidazor4,5-b]pyridine dihydrochloride -~
Prepared analogously to Example ~ from 2-[2-
methoxy-4-(3-chloro-propoxy)-phenyl]-lH-imidazo[4,5-b]- -
pyridine hydrochloride.
M.p.: 197 to 200C.
/~
ExamPle
2-r2-Methox~,r-4-(3-(4-(2-methoxvphenYl)-piperzin-l-Yl)- '~
hvdrate
g~2,
,
-
, .
1041502
Prepared analogously to Example 139 from 2-[2-
methoxy-4-(3-chloro-propoxy)-phenyl]-lH-imidazo[4,5-b]-
pyridine hydrochloride.
M.p.: Sintering from 180C.
Example 144
2-(2-Methoxy-4-morpholino-phenyl)-lH-imidazo[4,5-b]-
pyridine hydrochloride
a) 2-(2-Methoxy-4-morpholino-phenyl)-1 3-di~hiolanium-iodide
10.5 g of 3-morpholino-anisole and 15.7 g of 2-
methylmercapto-1,3-diethiolanium-methyl sulfate were boiled
~- in a mixture of 60 ml of glacial acetic acid and 8.3 ml
of pyridine for 1 hour. After cooling, the mixture was
poured into a saturated potassium iodide solution. The
red precipitate was suction filtered and washed with water.
The product was used without further purification.
- 83 -
. . .
~. '
lO~:~SO;~
b) 22 g of 2-(2-methoxy-4-morpholino-phenyl)-1,3-dithiol-
anium iodide,10.9 g of 2,3-diaminopyridine and 60 ml
of glycol were heated for 2 hours at 130C. After
cooling, water was added and the mixture was extracted
with chloroform. After evaporation, the residue was
purified by column chromatrography and the hydrochloride
was precipitated from acetone with ether/hydrochloride
acid.
M.p.: 207 to 209C (decomp.).
C Example ~ -v
2-~2-Methoxy-4-(4-methyl-piperazin-l-yl)-phenyl]-lH-
imidazo~4,5-b] pyridine dihydrochloride
~yy
- Prepared analogously to Example ~ from 3-(4-
- ~ methyl-piperazin-l-yl~-anisole.
M.p.: 279 to 282C.
~C
Example
2-~2-Methoxy-4-(4-ethyl-piperazin-l-yl)-phenvl~-lH
imidazo[4,5-b]pyridine dihydrochloride
Prepared analogously to Example ~4~from 3-(4-
ethyl-piperazin-l~yl)-anisole.
M.p.: 218 to 222C.
~4 :;
- ~1~ :
. ._ .. __ . .
.:
. .
,~, ~ ~1
`~ Example ~ 1041SOZ
2-~2-Methoxy-4-(4-propyl-piperazin-1-yl)-phenyl]-lH-
imidazo[4,5-b]pyridine dihydrochloride
/Y~
Prepared analogously to Example ffiL from
3-(4-propyl-piperazin-1-yl)-anisole.
M.p.: 256 to 258C.
Example ~il
2-[2-Ethoxy-4-(4-methyl-piperazin-1-yl)-phenyl~-lH-
imidazo[4,5-b]pyridine dihydrochloride
/~J'J
Prepared analogously to Example ~L from 3-(4-
methyl-piperazin-l-yl)-l-ethoxybenzene.
- M.p.: 269 to 271C.
)Y9
Example ~
2-(2-Ethoxy-4-(4-ethyl-piperazin-1-yl)-phenyl~-lH-
imidazo[4,5-b ~-pyridine dihydrochloride
lYS'
Prepared analogously to Example 14~-from
3-( 4-ethyl-piperazin-1-yl)-1-ethoxybenzene.
M.p.: 257 to 259C.
lSo
Example ~
2-[2-Methoxv- 4-( 4-phenyl-piperazin-1-vl)-phenvll-lH-
imidazo[4,5-b]pyridine dihvdrochloride
J~
Prepared analogously to Example 147 from 3-(4-
phenyl-p~perazin-l-yl~anisole.
M.p.: 217 to 219C.
~, .
rAl - ~~
'
104~50Z
C 151
Example ~4
2-[4-Methoxy-2-(2-morpholino-ethoxy)-phenyl]-lH
imidazo[4,5-b]pyridine
- Prepared from 6.3 g of 2-~4-methoxy-2-(2-chloro-
ethoxy)-phenyl]-lH-imidazo[4,5-b]pyridine by refIuxing
for 3 hours in 60 ml of morpholine, distilling off -~ ~ -
the excess of morpholine in vacuo and recrystallizing
the residue from isopropanol.
M.p.: 188 to 190C.
/,~ ,.
Example i~
2- r 4-Methoxy-2-(3-(4-phenyl-piperazin-1-yl)-propoxy)-
Phenyl~-lH-imidazo[4~5-b]pyridine
10 g of 2-[4-methoxy -2-(3-chloropropoxy)-phenyl]- ;
lH-imidazo[4,5-b]pyridine, 10.2 g of l-phenyl-piperazine
and 5 g of potassium carbonate were refluxed for 8
hours in 100 ml of ethanol. After distilling off the
ethanol in vacuo, the mixture was recrystallized from
ethanol/water 3:1.
M.p.: 162 to 163C.
IS3
Ex,amPle
2-~4-MethoxY-2-(3-(2-PhenYl-ethylamino)-propoxY)-phenyl]
lH-im~dazo~4,5-b~yridine dihvdrochloride
,' ~.r~l :. '' '
'
, : .
,
104150Z
- Prepared by heating 1.77 g of 2-[4-methoxy-
2-(3-chloropropoxy)-phenylJ-lH-imidazo[4,5-b]pyridine
in 10 ml of 2-phenyl-ethylamino for 1~ hours at 180C.
: The free base was converted into the dihydrochloride
with methanolic hydrochloric acid. Recrystallization
from isopropanol.
M.p.: 238C.
/54
Example ~L
2-[4.methox~-2-(3-(N-meth~l-N-2-phenvlethyl-amino)-
roPoxy)-Phenyl~-lH-imidazo[4,5-b]pyridine dihydrochloride
Prepared from 3.2 g of 2-[4-methoxy-2-(3-
chloropropoxy)-phenyl]-lH-imidazo[4,5-b]pyridine and
2.7 g of N-methyl-2-phenyl-ethylamine by heating for
6 hours in ethanol at 120C in a closed vessel. The
dihydrochloride was precipitated with ethereal hydrochloric
acid from an ethyl acetate solution of th~base, purified
by column, chromatography and recrystallized from isopropsnol.
M.p.: 212 to 215C.
Example ~
2-[4-Methoxy-2-(3-(N-methyl-N-(2-(3,4-dimethox~phe~yl)-
ethvl)-amino~-propoxy)-phenvl]-lH-imidazo~4,5-b]-
pyridine dihydrochloride
~7
~rp~ ~
. .
.~ -. .
1041S02
Prepared from 5.0 g of 2-[4-methoxy-2-(3-chloro-
propoxy)-phenyll-lH-imidazo[4,5-b]pyridine and 8.5 g of ~ v
N-[2-(3,4-dimethoxy-phenyl)-ethyl]-methylamine by
refluxing for 12 hours in ethylene glycol monomethyl
ether. Precipitation of the dihydrochloride from ethyl
acetate with ethereal hydrochloric acid.
M.p.: 169C.
Example ~
2-~4-Methoxv-2-(3-thiomorpholino-propoxy)-phenyl]-lH-
imidazoc4~5-b]pyridine
Pre~red analogously to Example 1,~ from 2-~4
methoxy-2-(3-chloropropoxy)-phenyl]-lH-imidazo[4,5-b]-
pyridine and thiomorpholine by heating for 30 hours.
Purification was by precipitation of the maleate from
ethyl acetate solution. The free base was obtained from
the maleate with 2N ammonia.
M.p.: 111C
Example
2-~4-Methoxv-2-(2-(4-methYl-PiPerazin- 1-Y1) -ethoxv)-
~he m ll-lH-imidazoc4,5-b~Pyridine
Prepared from 3.0 g of 2-~4-methoxy-2-(2-chloro-
etho~)-phenyl]-lH-imidazoC4,5-b]pyridine and 2.0 g
of N-methylpiperazine by refluxing for 40 hours in
': ,
~Ai~ g8 ~
.
. .
.
.
, . - . : : . :-`
. . . ~. i,., ,-:
.. .
104150Z
ethanol. After purification by column chromatography
, over silica gel, the product was recrystallized from
water.
-~ M.p.: 136 to 137C.
C /S~
Example ~L
2-~4-Methoxy-2-(3-(4-(2-phenylethyl)-piperazin-1-yl)-
propoxv)-phen,vl]-lH-imidazo~4,5-b]pyridine tri-
hydrochloride
lSy
Prepared analogously to Example ~5~ from 2-[4-
methoxy-2-(3-chloro-propoxy)-phenyl]-lH-imidazo[4,5-b~-
pyridine and 1-(2-phenyl-ethyl)-piperazine.
M.p.: 236 to 238C.
~5'q
Example K ~_
2-r4-Metho ~-2-(3-methylamino-propoxy)-phenvl]-lH-
imidazo[4,5-b]pyridine hydrochloride
/SY
Prepared analogously to Example ~i from 2-[4-
methoxy-2-(3-chloropropoxy)-phenyl]-lH-imidazo[4,5-b]-
pyridine and methylamine.
M.p.: 215C.
Example K3L
2-r4-Methoxy-2-(2-dimethylamino-ethoxy)-phenYl]-lH-
imidazo~4,5-b]pyridine dihydrochloride
~9
~ ,. . , . . , . . . . . .. .. _ .
-... . . . . :. ., - :.. ,-- .. : : :- . . .. . ..
- . .. . . . . ..
1041S02
t~ ~
Prepared analogously to Example 1,, from 2-[4-
methoxy-2-(2-chloro-ethoxy)-phenyl]-lH-imidazo[4,5-b]-
pyridine and dimethylamine.
M.p.: 240 to 242C.
Example K ~~
2-(2-MethYlamino-phenyl)-lH-imidazo[4,5-b]pyridine
1.77 g of N-methyl-isatinoyl anhydride and 1.09 g
of 2,3-diaminopyridine were melted and heated for 10
minutes at 180C. Recrystallization from ethyl acetate,
M.p.: 262 to 263C.
/6
Example ~6
2-(2,4-Dimethoxy-phenvl)-3-(2-phenvl-ethyl)-3H-imida
[4,5-b]p~ridine
0.17 g of 2-(2-hydroxy-4-methoxy-phenyl)-3-
(2-phenyl-ethyl)-3H-imidazo[4,5-b]pyridine were
dissolved in 7 ml of dimethylformamide. The mixture
was s~irred for 5 minutes with 0.02 g of sodium hydride
(80% suspension in oil) and reacted with 0.07 g of methyl
iodide under ice-cooling. After 4 hours, water was
.
adqed to the reaction mixture. The precipitated product
was dissolved in ethyl acetate, and the organic layer
was washed with 2N sodium hydroxide solution and water
9~
~rA~ , .. -
- - - " , ., , ~
- ~ . - - ~. 1 - - ,
. .
104150Z
and evaporated.
Recrystallization from ethanol/water.
M.p.: 157C.
~ 3
Example ~
2-(2,4-Dimethoxy-phenyl)-3-[2-(3,4-dimethoxv-phenyl)-
ethyl]-3H-imidazo~4,5-b]pyridine hydrochloride
Prepared analogously to Examp~e ~ from 3-amino-2-
[2-(3,4-dimethoxy-phenyl)-ethylamino]pyridine and 2,4-
dimethoxy-benzoic acid. The hydrochloride was
precipitated from ether.
M.p.: 195C.
~Y
Example ~t~c
2-(2-Fluoro-5-methvlmercapto-phenlrl)-lH-imidazo~4,5-b]-
E~ridine
/~
Prepared analogously to Example ~ from 2,3-
diaminopyridine and 2-fluoro-5-methylmercapto-benzoic acid.
M.p.: 195C.
/65'
Example ~
2-(2-Fluoro-5-methylsulfinyl-phenvl~-lH-imidazo~4,5-bl-
p~ridine
Prepared from 2-(2-fluoro-5-methylmercapto-phenyl)-
lH-imidazo~4,5-b]pyridi~e by oxidation with hydrogen
9~
` 'Al ~ :
,.
.
- .
- ~ . . . , . , , . ~ .
. ~ . . . .;
.-. - . ~- .- -, . . .
1041502
peroxide in glacial acetic acid at room temperature.
The purification was effected by column chromatography
on silica gel with chloroform/methanol 19:1 as eluent.
M.p.: 190 to 192C.
Example 1~2
2-(2-Fluoro-5-methylsulfonyl-phenyl)-lH-imidazo[4,5-b]-
pyridine
Prepared from 2-(2-fluoro-5-methylmercapto-phenyl)-
lH-imidazo[4,5-b]pyridine according to Example ~ , but
at 40C.
M.p.: 242C.
/C~
Example
2-(3,4-Dimethoxyphenyl)-3-(3-morpholino-propvl)-3H-imida
L4,5-b]pyridine dihydrochloride
a) N-(2-Chloro-3-PYridYl)-N'-(3-morpholinoPropyl)-3~4
dimethoxy-benzamidine
4.9 g of N-(3-morpholinopro w 1)-3,4-dimethoxy-
benzamide and 2.04 g of 2-chloro-3-aminopyridine were
refl,uxed for 2 hours in ~5 ml of phosphorus oxychloride.
A~ter distilling off the excess of phosphorus oxychloride,
the mixture was poured into water, The solution was made ~-
alkaline and extracted with ethyl acetate. After
9~
. ~rAl -~-
- . . . ..
.- . :
.
- .
-
~041502
evaporation of the residue, the product remained as
viscous oil.
b) 2-(3,4-Dimethoxyphenyl)-3-(3-morpholino-propyl)-3~-
imidazo[4,5-b ~ dine dihydrochloride
5.2 8 Of N-(2-chloro 3-pyridyl)-N'-(3-morpholino-
: propyl)-3,4-dimethoxy-benzamidine and 1.5 g of sodium
hydride (80% suspension in oil) were heated in 100 ml
of dimethylform.amide for 2 hours at 120C. The
dihydrochloride was precipitated from ether with
hydrochloric acid and recrystallized from ethanol/
cyclohexane.
C M-p-: 180C,
Example l~Y~_
2-(4-Methoxv-phenyl~-3-(3-morpholino-propoxy)-3H-imidazo-
.
: ~4,5-b~pyridine dihYdrochloride
/G ~
Prepared analogously to Ex~mple ~lQ fromN-(2-chloro-
3-pyridyl)-N'-(3-morpholino-prop.yl)-5-methoxy-benzamidine.
M.p.:.218C.
~q
Example
: - 2,(4-Methoxv-phenYl)-3-r3-(4-phenYl-piperazin-l-yl)-
propyl~-3H-imidazo[4,~-b~pyridine dihydrochloride hydrate . ~ .
. ~6 ~ :
Prepared an~logously to Example ~itt from N-(2-
chloro-3-pyridyl)-N'- r 3-( 4 phenyl-piperazin-1-yl~-
.
- . - . '
lSOZ
-pro W 1]-4-methoxy-benzamidine.
M.p.: 100C.
J1V
Example ~3L
2-(4-MetkoxY-phenvl)~3(2-morpholino-ethvl)-3H-imidazo-
~4,S-b~Pyrldlne hvdrochloride /6 1
- Prep~red analogously to Example ~ from N-(2-
cbloro-3-pyrldyl)-N'-(2-morpholino-ethyl)-4~methoxy-
benzamldlne.
M.p.: 149C.
ÉxamPle ~
2-(4-Methoxv-~henvl) 3-~3-(4-methyl-piPerazin-l-yl~-propyl]-
3H-imidazor4,5-blPYridine trihydrochloride
/6~
Prepared analogously to Example ~ from N-(2-
chloro-3-pyrldyl)-N'-~3-(4-methyl-pipeR~n-l-yl)-propyl]-
4-methoxy-benzamidlne.
M.p.: 2S7C
ample ~r
2~ MethoxY-phenYl)-3- ~ (4-methYl-piperazin-l-yl)-ethyl]-
3H-imidazo~4,5-b~Dvridine trlhYdrochloride
/G ~
Prepared analogou~ly to Example ~7erfrom N-(2-
chloro-3-pyrldyl)-N'-~-(4-methyl-piper~æin-1-yl)-ethyl~-
4-methoxy-benzamld~ne.
M,p.: 225C.
7~v
, . ............. .
.
. ' .
-
1041SOZ
Rxample 1732-~4-Methoxy-phenyl)-3-(3-dimethylamino-propyl)-3H-
imidazo[4,5-b]pyridine dihydrochloride
Prepared analogously to Example 167 from N-(2-
chloro-3-pyridyl3-N'-(3-dimethylamino-propyl)-4-methoxy-
benzamidine.
M.p.; 229C.
Example 174
2-(4 Methoxy-phenyl)-3-(3-piperidino-propyl~-3H-imidazo-C4~5-b]-
pyridine dihydrochloride
Prepared analogously to Example 167 from N-(2-
chloro-3-pyridyl)-N'/(3-piperidino-propyl)-4-methoxy-
benzamidine.
M.p.: 196C.
Example 175
2-(4-Methoxy-phenyl)-3-(4-morpholino-butyl)-3H-imidazo-
[4,5~1py~1dine dihydrochlo~ide hydrate
Prepared analogously to ~xample 167 from N-(2-
- - '
_ 95 -
.-, .. ~ .
, . .:. . . .. : -
- .. . ., . , -, , ~ . . .
-
104150Z
~: .
chloro-3-pyridyl)-N~-(4-morpholino-butyl)-4-methoxy-
benzamidine.
M.p.: 136C.
Example 176
2-(2-Fluoro-4-methylmercapto-phenyl)-lH-imidazo[4,5-b]-
Pyridine hydrochloride
Prepared analogously to ~xample 118 from 2-fluoro-
4-methyl-mercapto-benzoic acid and 2,3-diaminopyridine.
M.p.: 257C. `~
Example 177
-~luoro-4-methylsulfinyl-Phen,yl)-lH-imidazol!,4,5-b]-
pyridine
Prepared analogously to Example 165 from 2-(2- ~ ~
,.
, ~
,~ ,
: .
: . ' '
; `:
. i .
:' ' '
- 104150Z
fluoro-4-methyl-mercapto-phenyl)-lH-imidazo[4~5-b]-
pyridine. Crystallization by trituration in petroleum
ether.
M.p.: 219C.
Example 178
2-(4-Methylmercapto-phenyl)-3-(3-morpholino-propyl)-3H
imidazo[4,5-b]pyridine
Prepared analogously to Example 167 from
N-(2-chloro-3-pyridyl)-N'-(3-morpholino-propyl)-4 methyl-
mercapto-benzamidine. Recrystallized from ether/cyclohexane.
M.p.: 110C.
.
:~ .
- 97 -
:.
. . . :
~ 104150Z
2-[2-Propoxy-4-(4-methyl-piperazin-1-yl)-phenvl]-lH-
imidazo[4,5-blpyridine dihYdrochloride
Prepared analogously to Example ~ from 3-(4-
methyl-piperazin-l-yl)-l-propoxy-benzene.
M.p.: 237 to 238C.
/~
Example ~L
Tablets containing 100 mg of 2-(2,4-dimethoxy-phenYl)-
lH-imidazo[4,5-b]pyridine hydrochloride
~omposition:
1 tablet contains:
Active ingredient 100.0 mg
lactose 50.0 mg
polyvinyl pyrrolidone 5.0 mg
carboxymethylcellulose 19.0 mg
magnesium stearate 1.0 mg
175.0 mg
moist screening: 1.5 mm
Drying: in the circulating air
drier at 50C.
Dry screening: 1 mm
The dry granulate was admixed with the remaining
auxiliary products and pressed into tablets.
Weight of tablet: 17S mg
Punch: 8 mm 0
.. ~8
' ~ ~ ~
.
, .
^~ -
~ 04~S02
Example ~
Coated tablets containing 50 mg of 2-(2,4-dimethoxv-
phenyl)-lH-imidazo~4,5-b]pyridine hydrochloride
1 coated tablet core contains:
Active ingredient 50.0 mg
corn starch, dried 20.0 mg
soluble starch 2.0 mg
carboxymethylcellulose 7.0 mg
magnesium stearate 1.0 mg
80.0 mg
The active ingredient and corn starch were
homogeneously moistened with the aqueous solution of
the soluble starch.
Moist screening: 1.0 mm
Dry screening: 1.0 mm
Drying: at SO~C in the circulating air drier
The granulate and the remaining auxiliary products were
mixed and pressed to form coated tablet cores.
Weight of core: 80 mg
Punch: 6 mm, arched (5 mm)
The finished cores were covered with a coat
consisting essentially of sugas and talcum in conventional
manner. The finished coated tablets were polished with
~ .
. . --~2 --
'Al
1041~0'~
beeswax.
Weight of the coated tablet: 120 mg
Example ~
Suppositories containing 75 mg of 2-(2,4-dimethox -phenyl)- -
lH-imidazo[4,5-b]pyridine hydrochloride
1 suppository contains:
Active ingredient 75.0 mg
B - suppository mass ~.g. Witepsol~ Y
H 19 and Witepsol 45) 1 625.0 mg
1 700.0 mg
Method of preparation:
The suppository mass was melted. At 38C the
pulverized active ingredient was homogeneously dispersed
in the melt. The suppository mass was cooled to 35C
and poured into pre-cooled moulds. ~ -
Weight of suppository: 1.7 g
Example ~g~3
Ampoules containing 50 mg of 2-(2,4-dimethoxy-phenyl)-
- lH-imidazo~4,5-b]pyridine hydrochloride
1 ampoule contains:
Active ingredient 50.0 mg
sorbitol 250.0 mg
distilled water ad 5.0 ml
~r~ ~
4 ~Ra/e ~a~k
. - : '
- ' ' : - ~
.
~04i5S)Z
Method of preparation:
The active ingredient and the sorbitol were
dissolved in distilled water. The solution was made
up to the given volumn and filtered sterile.
Filling: into ampoul.es of 5 ml capacity
Sterilisation: 20 minutes at 120C.
Example ~
DroP solution containin~ 25 mg of 2-(2,4-dimethoxy-
enyl)-lH-imidazo[4,5-b~pyridine hydrochloride per 5 ml
Active ingredient 5.0 g
methyl p-hydroxybenzoate 0.035 g
propyl p-hydroxybenzoate 0.015 g
aniseed oil 0.05 g
menthol 0.06 g
sodium saccharine 1.0 g
glycerine 10.0 g
ethanol . 40.0 g
distilled water ad100.0 ml
Method of preparation:
.
The benzoic acid esters were dissolved in ethanol
and subsequently the aniseed oil and the menthol were
added. Active ingredient, glycerine and sodium
/0~
_ ~ _
io~
- saccharine were dissolved in water and added. The
solution was filtered pure.
.
' ' ~ '' '' ` '' ' "'" '. , ,
