IMIDAZO[1,2-A]PYRIDINES

IMIDAZO[1,2-A]PYRIDINES

English Abstract

A B S T R A C T
The invention relates to imidazo[1,2-a]pyridines of the
general formula
<IMG>
(wherein the substituents R2,R3,R4 and R5 are as defined
in the specification) and includes 2,3-dihydro-9 5,6,7,8-
tetrahydro-, 2,3,5,6,7,8-hexahydro-analogues and salts of
such compounds. The invention also relates to processes
for preparing such compounds and to pharmaceutical compo-
sitions containing them. The compounds are antisecretory
and cytoprotective agents and are particularly useful in
the treatment of ulcer diseases.

Claims

The embodiments of the invention in which an exclusive
property or privilege is claimed are defined as follows:
1. Imidazo [1,2-a] pyridines of the general formula
<IMG> I
wherein
R2 is hydrogen, loweralkyl or hydroxyloweralkyl;
R5 is hydrogen, halogen or loweralkyl;
and either
R3 is loweralkyl, -CH2CN, hydroxyloweralkyl, -NO,
-CH2NC, <IMG> or, provided R2 is not hydrogen,
also hydrogen and
R4, being attached to any of the positions 5-, 6- or
7- of the nucleus, represents one of the groupings
-O-R8-Ar, -NH-R8-Ar, -R8-Ar, -CH=CH-Ar,
-CH=CH-CH2-Ar or -O-CH2-CH=CH2 ; or
R3 is as defined above and
R4, being attached to the 8-position of the nucleus,
represents any one of the groupings:
-CH=CH-Ar, -CH=CH-CH2-Ar or -O-CH2-CH=CH2; or
R3 is -NO, -CH2NC or <IMG> and

- 51 -
R4, being attached to the 8-position of the nucleus,
represents -O-R8-Ar, -NH-R8-Ar or -R8-Ar;
whereby, in the above definitions, R6 and R7 are inde-
pendently selected from hydrogen or loweralkyl;
R8 is a straight- or branched- chain loweralkylene
group and
Ar represents thienyl, furanyl, pyridyl, phenyl or
phenyl substituted by one or more substituents
selected from halogen and lower alkyl;
the 2,3-dihydro; 5,6,7,8-tetrahydro and 2,3,5,6,7,8-
hexahydro derivatives thereof and the pharmaceutically
acceptable salts of such compounds.
2. Compounds of Formula I as defined in claim 1
R2 represents -CH3 or -CH2CH3;
R5 represents hydrogen or -CH3;
R3 represents -NH2, -NHC2H5, -CH2CN or -CH3 and
R4, being attached to the 5-, 6- or 7- position of
the nucleus, represents -O-R8-Ar, -NH-R8-Ar,
-R8-Ar, -CH=CH-Ar or -CH=CH-CH2-Ar with R8 being methylene,
ethylene or propylene and Ar being phenyl,
o-fluorophenyl, p-fluorophenyl, p-chlorophenyl,
thienyl or furanyl.
51

- 52 -
3. Compounds of Formula I as defined in claim 1, wherein
R2 and R5 are as defined in claim 2; R4, being
attached to the 8-position of the nucleus, is as
defined in claim 2 and R3 represents -NH2 or -NHC2H5.
4. Compounds of Formula I as defined in claim 1 wherein
R2 and R5 are as defined in claim 2, R3 is -CH2CN or
-CH3 and R4, being attached to the 8-position of the
nucleus, is -CH=CH-Ar or -CH=CH-CH2-Ar, with Ar being
as defined in claim 2.
5. Compounds of the formula
<IMG>
IA
wherein R3 is -NH2;
R4 is -CH2-CH2-Ar or -CH2-CH2-CH2-Ar and
R5 is hydrogen or methyl, whereby
Ar is phenyl or 3-thienyl.
6. Compounds of Formula IA set forth in claim 5, wherein
R3 is -NH2, -CH2CN or -CH3
R4 is -CH=CH-Ar or -CH=CH-CH2-Ar and
R5 is hydrogen or methyl, whereby
Ar is phenyl or 3-thienyl.
52

- 53 -
7. Compound according to claim 5, being 3-amino-2-methyl-
8-(2-phenylethyl)-imidazo [1,2-a] pyridine.
8. Compounds according to claim 6, being 2,3-dimethyl-
8-(2-phenyl-ethenyl)-imidazo [1,2-a] pyridine
and
3-cyanomethyl-2-methyl-8-[E-1-(3-phenyl-propen-1-yl)]-
imidazo [1,2-a] pyridine.
9. Pharmaceutical compositions comprising a compound as
defined in any one of claims 1 and 2.
10. Process for the preparation of compounds as defined in
any one of claims 1 and 2 characterized in that either
A: a compound of the general formula
<IMG> II
is reacted with a compound of the general formula
<IMG> III
53

- 54 -
whereby, in the formulae, R2, R3, R4 and R5 are as
defined in claim 1, except that any free amino or
hydroxy groups present in R2 or R3 may be protected
by a protecting group which is subsequently removed,
and Z" represents a good leaving group; or,
B: for preparation of compounds wherein R4 is -O-R8-Ar,
-O-CH2-CH=CH2, -NH-R8-Ar, -R8-Ar, with R8 and Ar
being as defined in claim 1, a compound of the general
formula
<IMG>
IV
is reacted with a compound of the general formula
V
whereby in the above formulae R2, R3 and R5 are as
defined in claim 1, Hal represents Br, Cl or J,
Z represents halogen, OH, or NH2 and
Z' represents -R8-Ar or -CH2-CH=CH2.
54

-55-
C: for the preparation of compounds wherein R4 represents
-CH=CH-Ar or -CH=CH-CH2-Ar, a compound of Formula IV
wherein R2, R3 and R5 are as defined in claim 1 and Z
represents CHO is subjected to a Wittig reaction with
the appropriate Wittig reagent; or
D: for the preparation of compounds of Formula I wherein
R4 represents -CH=CH-Ar, reacting a compound of Formula
IV wherein R2, R3, and R5 are as defined in claim 1
and Z represents a phosphinylmethyl group, with a
compound of formula Ar-CHO whereby Ar is as defined
above; or
E: for the preparation of a compound of Formula I wherein
R2, R4 and R5 are as defined in claim 1 and R3
represents CH2CN, reacting a compound of Formula I
wherein R3 is a group -CH2X, X being a good leaving
group, with a metal cyanide; or
F: for the preparation of compounds of Formula I wherein
R2,R3,R4 and R5 are as defined in claim 1, except that
at least one of R2 and R3 must be hydroxyloweralkyl,
reducing a compound of Formula I wherein R2 and/or
R3 is a group -(R')nCOOR, R' being a lower alkylene
group having 1 to 5 carbon atoms, n being zero or
one and R being a hydrocarbon group; or

- 56 -
G: for the preparation of compounds of Formula I wherein
R2, R4 and R5 are as defined in claim 1 and R3 is
-NO, subjecting a compound of Formula I wherein R3 is
hydrogen to a nitrosation, in the 3-position, or
H: for the preparation of compounds of Formula I wherein
R3 is -NH2 and R2, R4 and R5 are as defined in
claim 1, reducing a compound of Formula I wherein R3
is -NO or NO2; or
I: for the preparation of compounds of Formula I wherein
R2, R4 and R5 are as defined in claim 1 and R3 is
-NR6R7 with R6 and/or R7 being loweralkyl, subjecting
a compound of Formula I wherein R3 is -NH2 to an
alkylation; or
J: for the preparation of a compound of Formula I wherein
R2, R4 and R5 are as defined in claim 1 and R3 is
-CH2NC, subjecting a compound wherein R3 is
a group <IMG> to a reaction with PCl3 in the
presence of an amine;
that a so-obtained compound of Formula I, if desired, is
reduced to the corresponding 2,3-dihydro-, 5,6,7,8-
tetrahydro- or 2,3,5,6,7,8-hexahydro derivative;
and that a compound obtained according to any one of the
processes described above, if desired, is transformed into
a salt.
56

- 57 -
11. Process according to claim 11, characterized in that
in process
A: Z" represents halogen, tosyl or mesyl and the
reaction is carried out by heating the reactants
together in an inert solvent;
B: when Z represents halogen, a copper catalyst is
used;
C: the Wittig reagent used is of the formula
<IMG>
with Ar being as defined in claim 1, R being a
hydrocarbon group;
E: X represents halogen, alkoxy, aryloxy, mesyl,
tosyl, a quaternary group, preferably
?(CH3)3 J? , or a quaternary group wherein the
quaternary ion is a non-nucleophilic counter ion
selected from BF? , PF? , CF3SO? , and FSO?
and the metal cyanide is an alkali metal cyanide;
F: the reduction is carried out by means of lithium
aluminium hydride;
G: the nitrosation is carried out by means of a
nitrite, preferably sodium nitrite, in the presence
of concentrated HCl;
57

- 58 -
H: the reduction is carried out by means of zinc
powder in acetic acid.
58

Description

1ZL~I957
NOVEL IMIDAZO [1,2-a] PYRIDINES
This invention relates to novel imidazo [1,2-a~ pyridinesg :
: to processes for their preparation, to pharmaceutical ~ :
compositions containing such compounds and to methods for
preparing such compositions. The compounds are parti-
cularly useful for treating peptic ulcer disease.
:~,
.. .
.
~:

~;2489S'~
The imidazo [1,2-a] pyridines of this invention include
compounds of the general formula
"
~ wherein
R2 represents hydrogen, loweralkyl or hydroxyloweralkyl;
R5 represents hydrogen, halogen or loweralkyl;
and either
R3 is loweralkyl, -CH2CN, hydroxyloweralkyl, -NO, -CH2NC
/R6
or -N \ or, provided R2 is not hydrogen, ~ :
R7
~: ~ 10 also hydrogen and
: R4 being attached to any of positions 5,:6 or 7 of the
: nucleus, represents any of the groupings
-O-R8-Ar, -NH-R~-Ar,-R8-Ar, -CH=CH-Ar, -CH=CH-CH2-Ar
or -O-CH2-CH=CH2; or
.
15 R3 is as defined above and ~ ~
:

5~
R4, being attached to the 8-position of the nucleus,
represents any of the groupings:
-CH=CH-Ar, -CH=CH-CH2-Ar or -0-CH2-CH=CH2; nr
/R6
R3 is -N0, -CH2NC or -N and
. R7
5 R4, being attached to the 8-position of the nucleus,
represents -0-R8-Ar, -NH-R8-Ar or -R8-Ar;
whereby in the above definitions, R6 and R7 are indepen-
dently selected from hydrogen or loweralkyl;
R8 is a straight- or branched- chain loweralkylene
group; and
Ar represents thienyl, furanyl, pyridyl, phenyl or phenyl
substituted by one or more substituents selected
from halogen and loweralkyl;
the 2,3-dihydro; 5,6,7,8-tetrahydro and 2,3 7 5,6,~,
8-hexahydro derivatives thereof and the pharmaceutically
acceptable salts of such compounds. ;
As used herein, the term "halogen" includes fluoro, chloro,
bromo and iodo, with fluoro and chloro being preferred;
the term "lower" includes straight and branched chain
hydrocarbon groups having up to six carbon atoms such as
methyl, ethyl, propyl, butyl, t-butyl, isopropyl,
neopentyl, dimethylbutyl etc, whereby methyl and ethyl
are preferred. Equally the loweralkylene groups represented
by R8 are such having 1 to 6 carbon atoms with ethylene, :
methylene and pro;?ylene being prefeFred.
::
"' ' .

5'7
The term "pyridyl" includes the 2-, 3- and 4-isomers and
the terms "thienyl" and "furanyl" include the 2- and
3-isomers.
In those instances where R5 is other than hydrogen, such
substituent may be at any of the positions 5-, 6-, 7- or
8- of the imidazo [192-a] pyridine nucleus which is not
occupied by the group R4. The preferred position for
the R4-group is the 8-position in the nucleus.
I One preferred group of compounds are those wherein
R2 represents -CH3 or -C2H
R5 is hydrogen or -CH3;
3 2' -NHC2H5~ -CH2CN or -CH and
R4,being attached to any of positions 5~ 6 or 7,
is either -O-R8-Ar, -NH-R8-Ar, -R8-Ar,-CH=CH-Ar
or -CH=CH-CH2-Ar, with R8 being ethylene, methylene or
propylene and Ar being phenyl, o-fluorophenyl,
p-fluorophenyl, p-chlorophenyl, thienyl or furanyl.
II Another preferred group of compounds are those wherein
R2, R4 and R5 are as defined above under I, whereby,
however, R4 is attached to the 8-position of the
nucleus; and R3 represents -NH2 or -NHC~H5.
III A further group of interest consists of compounds
wherein R2 and R5 are as defined above under group
I; R3 is -CH2CN or -CH3 and R4,being attached to
the 8-position of the nucleus, is -CH=CH-Ar or
-CH=CH-CH2-Ar, with Ar being as defined under I above.
, ~ .
, ~
.~

lZ4~ 5~
IV A most preferred group of compounds consists of
such having the general formula
R ~ - CH3 IA
R4
. ~
wherein R5 is hydrogen or methyl and eithen
R3 is -NH2 and
R4 iS -CH2-CH2-Ar or -CH -CH -CH -Ar;~
or ;~
R3 is -NH2,~-CH2CN~or -CH3 and
R4 is -CH=CH-Ar~o-~-C~H=CH-CH2-~A-
whereby Ar repre~sents phenyl or~3-thienyl.
~ ,

~Z'~i3957
The compounds of this invention may be obtained by pro-
cesses generally known for the preparation of compounds
having a similar structure. The basic step consists in
formation of the (substituted) imidazo [l,Z-a] pyridine
nucleus. Thus, the basic process comprises the following
reaction:
R5
. ~ ~,
A: ~ ~H2 ~ R2 ~ C - CH R3
II III
In the above formulae II and III, R2, R3, R4 and R5 are
as defined hereinabove, and Z" represents a good leaving
group, preferably a reactive inorganic or organic ester
group, such as halogen, tosyl, mesyl etc. Any free amino-
or hydroxy groups present in~ R2 and R3, may advantageously
be protected by a protecting group, which is subsequentiy
removed. The reaction is preferably carried out by heat-
ing the reactants together (e.g. at reflux temperature)in an inert solvent.
:
If in the above reaction a compound of Formula III wherein
R2 and R3 are both hydrogen and Z" is chlorine is used
(chloracetaldehydej, then R2 and R3 in the final compound~
are both hydrogen.
~ : :
'`' : : ~ : ~ ~
.:
, ~

lZ~5'7
These compounds are intermediates useful in the preparation
- of compounds falling within the scope of this invention~
e.g. as used in Step (ii) of process E hereinbelow:
If a compound of Formula III wherein R2 is methyl, R3 is
hydrogen and Z" is chlorine (chloracetone) is used, then
a compound wherein R2 is methyl and R3 is hydrogen is
obtained.
For preparing compounds wherein R4 represents -0-R8-Ar,
-0-CH2-CH=CH2, -NH-R8-Ar, or -R8-Ar, the following
process may be used
+ Hal - Z' > I
IV V
In the above Formula IV and V Hal represents Br, Cl or
J; Z represents halogen (Cl, Br, J), 0~ or NH2,
R2, R3 and R5 are as above defined and Z' represents
either -R8-Ar or -CH2-CH=CH2 with R8 and Ar being as
defined above.
The reactants are heated together under standard reaction
conditions known from the preparation of similar compounds,
e.g. in an inert solvent in the presence of a base. When
Z represents halogen, a copper catalyst is preferably used.
... :
.. ~
.
: `
~,

1248g~'~
When Z represents OH, or NH2 the reaction may be carried
out with or without such copper catalyst.
The starting compound of Formula IV may be obtained accord-
ing to process A above, i.e. by reacting a compound of
Formula II (wherein R4 is replaced by Z~with a compound of
Formula III.
C: Compounds of Formula I wherein R4 represents
-CH=CH-Ar or -CH=CH-CH2-Ar are preferably prepared
from a compound of Formula IV wherein Z represents a
CHO- group through a Wittig reaction or a modification
thereof. Again the starting compounds of Formula IV
needed for this process may be prepared according to
process A above. The Wittig reagents to be used are
preferably well-known dialkylphosphonates. Thus by
using a diethylbenzylphosphonate in the above reaction
a compound wherein R4 is phenylethenyl is obtained.
D: Alternatively the compounds of this invention wherein
R4 represents -CH=CH-Ar may be obtained by reacting
a compound of Formula IV wherein Z represents a
::
phosphinylmethyl group [e.g. -CH2-P(OC2H5)2]
with a compound Ar-CHO. The starting phosphonate
o~ Formula IV may be prepared as exemplified below:
A compound of Formula IV wherein ~ represents -CHO
(prepared by using process A above) is reduced (e.g.
with NaBH4) to the corresponding hydroxymethyl compound.
- ~ ,
~: ' ' ~-
-

lZ4~9~7
Chlorination thereof, e.g. with SOC12, replaces the
OH group by Cl and reaction of the resulting compound
wherein Z is -CH2Cl with P(OC2H5)3 provides the
desired starting compound.
For preparing compounds of Formula I wherein R3 represents
the group CH2CN, the following process may be applied:
E: A compound of general Formula I wherein R2, R4 and R5
- are as defined for Formula I but wherein R3 is replaced
by a group CH2XI(wherein X represents a good leaving
group), is reacted with a metal cyanide to yield the
desired product. Preferred leaving groups are
halogen, alkoxy? aryloxy, mesyl, tosyl, quaternary
groups such as N(CH3)3.J and quaternary groups
wherein the quaternary ion is a non-nucleophilic
~3 9
counter ion such as BF4 ~ pF6 ~ CF3S03 , FS03
etc. Additionally one may carry out the displace-
ment reaction in the presence of a~crown ether. The~
preferred metal cyanides are alkali metal cyanides.
The reaction is carried out under standard conditions,~
e.g. by heating the reactants in an inert solvent,
preferably dimethylformamide. When the quarternary
anion is a non-nucleophllic counter ion, the~reaction
may also be carried out in an aqueous solvent.
The starting compounds of this process may be obtain~
ed by standard procedures, e.g. as illustrated~below
for the quaternary 1odide salt~
:: : ~

12~~95'7
- 10 -
(i) A compound of Formula II is reacted with a
compound of Formula III wherein R3 is hydrogen
according to process A above.
(ii) The compound resulting from step (i), which
is a compound of Formula I wherein R3 is
hydrogen, is further reacted with dimethyl-
amine hydrochloride and paraformaldehyde by
heating the reactants in methanol at reflux
temperature.
(iii) The compound of step (ii) a compound of Formula
I wherein R3 represents -CH2N(CH3)2 is reacted
with CH3J to yield the desired methiodide.
Starting compounds wherein X represents halogen may be
obtained from the corresponding compound wherein X is
hydroxy through chlorination, e.g. by treatment with
phosphorylchloride.
:
F: Compounds wherein R2 and/or R3 represent an hydroxy-
: ~ loweralkyl group may be prepared by reducing a
compound of Formula I wherein R2 and/or R3 is . . : ~ ::
the group -(R )n COOR
(R' being a loweralkylene g.roup with:l t..o 5 carbon. atoms,
R being a hydrocarbon group and n being zero or one).:
Thus, reduction of a compound of Formula I wherein R
is replaced by -CODC2H5, e.g. by using lithium~alumin-
ium hydride in tetrahydrofuran, yields the correspond-
ing compound of:Formula I wherein R3 is -CH20H.
-
,,
.~ .
: -
;:

57
The starting compound (i.e. a compound wherein R2
and/or R3 is -(R')nCOOR may be prepared according to
process A above by using a compound of Formula III
providing the desired carboxylic acid ester group in
the 2- or 3- position.
As is obvious to any one skilled in the art, numerous
standard reactions may be used for introducing a
specific R2 and/or R3 group into the molecule or for
substituting one type of R2 and/or R3 by another.
G: Compounds wherein R3 represents -N0 may be prepared
by nitrousation of a compound of Formula I wherein
R3 is hydrogen. The reaction is carried out under
standard conditions, e.g. by reaction with a nitrite
(sodium nitriteJ in the presence of HCl.
H: Compounds of Formula I obtained according to process
G above may be used for the preparation of compounds
wherein R3 represents -NH2 in that the nitroso compound
is subjected to a standard reduction procedure, e.g. by
means of zinc powde`r in acetic acid. St:arting compounds
having N02 instead of N0 may likewise be reduced. ;
I: The compounds wherein R3 represents -N < 6 , with
R7
R6 and/or R7 being loweralkyl, are preferably prepared
by simple alkylation of compounds of Formula I wherein
R3 is an amino group.
~,,
.
,
.

~ 7
J: Compounds of Formula I wherein R3 represents isocyano-
methyl may be prepared by reacting a compound of Formula
I wherein R3 is CH2NHCH with POCl3 in the presence of
an amine. The starting compound may be obtained by
subjecting a compound wherein R3 is -CH20H to the
following sequence of reaction steps:
CHzOH MsCl~ ~ l >
O O
HC-oEt> ll CH2NHCH
~ (Ms is mesyl and Et ethyl).
R2
The 2,3-dihydro, 5,6,7,8-tetrahydro and 2,3,5,6,7,8-
hexahydro derivatives may be prepared~by standard reduc-
tion proceudres, e.g. by means of Hz in the presence of
a palladium catalyst.
It is also obvious to anyone skilled in the art that the
sequence of certain reactions may;be altered. Thus, for
example, one may, in accordance with process (A) above
first prepare a compound of the formula
:~
z
- : :
make the above described rearrangements within the
groups R2 and R3 and then complete the molecule by
carrying out process (B) above.
:
:
.

~L;Z4~9$'~
- 13 -
EXAMPLE I
8-Benzyloxy-2-methyl-3-nitroso imidazo_[l,2-a~eyridine
STEP A: Preparation of 2-amino-3-benzyloxypyridine.
In a 12 liter 3-neck round bottom flask equipped with a
mechanical stirrer and thermometer there were placed 2.5
liters of 40% sodium hydroxide solution, 26.5 9 of Adogen
464 (Reg. Trademark) and 2.5 liters of dichloromethane.
To this vigorously stirred mixture was added 5509 of
2-amino-3-hydroxypyridine. The temperature was 38C.
The brown orange mixture was cooled to 25C, and 677.5 9
of benzylchloride was added in one portion ~and the
mixture was allowed to separate into 2 phases. The lower
aqueous phase was separated a-nd diluted with 1 liter of ~
ice:water. This solution ~as then extracted with dichloro-
methane (3 x 15 liters). The combined dichloromethaneextracts were added to the original dichloromethane phase,
washed with 1 liter of saturated sodium chloride solution
and dried over potassium carbonate. The dichloromethane
extract was filtered and concentrated on the rotary eva-
porator to an orange solid. This solid was dissolved in~1 liter of boiling absolute ethanol, and the solution
was filtered. The filtrate was chilled, and the crystals
that formed were filtered, washed with 500 ml of ethanol
~; at -10C, and dried at 50C.; in a vacuum oven, to give
the desired product.
::
::
: : : :
.
: ~:.,' : : : ~ , :

1248~
- 14 -
STEP B: Preearation of 8-benzyloxy-2-methyl-imidazo
[1,2-a]~yridine
Into a 12 liter 3-necked flask equipped with a mechanical
stirrer and condenser, were placed 750 9 of 2-amino-3-
benzyloxy-pyridine (obtained according to Step A), 6.7S
liters of absolute ethanol ~one may also use methanol 3
liters) and 360 ml of chloroacetone. The solution was
heated under reflux for 4 hours.
An additional 180 ml of chloroacetone was added and the
dark solution was heated under reflux for 18 hours.
The solvent was evaporated off and the residual dark oil was
dissolved in 7 liters of water. me resulting solution was
made strongly basic with 15% sodium hydroxide and the basified
solution was extracted with several portions (4 x 1.5 liters)
of dichl~romethane. Ihe extracts were combined and washed
with brine and the washed extracts evaporated down to a dark
gum which was boiled witn 7 liters of diisopropyl ether. The
solution was decanted from insolubl2 material through a glass
wool plu~, and the filtrate was chilled. The resulting crys-
tals were filtered and washed with cold diisopropyl ether.Recrystallization provided the pure product of this example
(m.p. 93 - 95C.).
STEP C: Pre~aration of title comeound
To a stirred mixture of 10.0 9 (42.2 mmol) of 8-benzyloxy-
2-methyl-imidazo ~1,2-a] pyridine, 150 ml of water and
150 ml of chlorofurm is added cautiously (EXOTHERM)
179.5 ml (2.15 moles) of concentrated hydrochloric acid
and the resultant mixture is heated to an internal temp-
erature of approximately 55C. To this stirred and
heated mixture is added at a rate of approximately
-~ 7ml/minute a solution of 151 9 (2.11 moles) sodium nitr;te
:
'` ~ ' ' ''"
-: ',

12'~ 5~î
- 14a -
(97%) in 600 ml of water to produce a vigorous, but manage-
able, reflux. When the addition is complete, the reaction
mixture is allowed to cool to room temperature. The
lower (CHC13) layer is drawn off and the aqueous layer
extracted with three - 150 ml portions of chloroform.
The combined chloroform extracts are washed with two -
450 ml volumes of 2.4 M sodium carbonate solution, then
with a single 500 ml portion of saturated aqueous sodium
chloride. The extracts are concentrated in vacuo (rotary
- :

1;Z4139S'7
- 15 -
evaporator, 45C.) to less than one-half the original
volume, dried over anhydrous sodium sulfate and evaporated
to a viscous oil. Chromatography of the oil on silica
gel, eluting with chloroform/ethyl acetate (1/1~ yields
the title compound as a given crystalline solid,
mp 147.5 - 149~5~C. (dec).
EXAMPLE II
3-Amino-8-benz~loxy-2-methyl-imidazo [1,2-a] eyridine
A. phosehate
To a stirred mixture of 3.2 9 (12 mmol) of 8-benzyloxy-
2-methyl-3-nitroso-im!idazo [1,2-a3 pyridine in 24 ml of
glacial acetic acid and 33.5 ml of water is added portion-
wise 3.23 9 (49.5 mmol) of zinc powder over a two hour
period. When addition is complete, the reaction mixture
is stirred at room temperature for 30 minutes. The
mixture is filtered through Celite, and the filtratè
diluted with 75 ml each of ether and methylene chloride
and washed with a solution of 250 ml of 1.7 ~ sodium
hydroxide. The resultant emulsion is filtered through
Celite and the Celite pad washed thoroughly with 250 ml
of hot chloroform.
The layers of the filtrate are separated and the aqueous
phase extracted with the chloroform used to wash the
Celite pad. The combined organic extracts are washed
with two-125 ml portions of water and one-150 ml Yolume~
of saturated aqueous sodium chloride and then concentrated
under reduced pre'ssure to a volume of app~roximately lOO~ml.
The concentrate is dried over anhydrous sodium sulfate and
-;~ the solvent remo~ed under reduced pressure (rotary
,: : ~
-
- : . ' , ~ : : .

lZ'~ 5'~
16 -
evaporator, 40C.) to give a slightly tacky brown powder
that is triturated in ether (75 ml) - methylene chloride
(1 ml) to yield the free base of the title compound as
a light brown powder, mp 126 - 131.5C. (dec).
B.
850 mg (3.37 mmol) of the free base is dissolved in approx-
imately 40 ml of dry acetonitrile. To the stirred
solution is added 8 ml of an acetonitrile solution contain-
ing 3.4 mmol of phosphoric acid. A precipitate forms and
the mixture is diluted with 70 ml of ether and filtered.
The solid is triturated in 60 ml of fresh ether and filter-
ed to give the crude phosphate salt which upon recrystal-
lization from methanol - ethyl acetate yields the title
phosphate salt containing 1.3 moles of water of crystal-
lization, mp 214 - 214.5~C. (dec). ~;
:
EXAMPLE III
5-Benzyloxy-2,3-dimethylimidazo El,2-a3 eyridine
Sodium hydride (50% in oil, 4.8 g) is added to a solution
of benzyl alcohol (6.48 9) in dimethylformamide (200 ml).
5-chloro-2,3-dimethylimidazo [1,2-a] pyridine hydrobromide
(10.5 9) is added and the mixture is stirred at room
temperature for two hours.
;
The solvent is removed in vacuo and the residue is parti-
tioned between water (500 ml) and ether (400 ml). T~ie
ether layer is separated, dried over anhydrous sodium
sulfate and concentrated in vacuo to yield a yellow oil
which is chromatographed on silica gel (300 9) using ether
as an eluanl;. After an initial fore-run of a yellow oil,
:
'
- .
... ' ' '
: ' ~ . :
:
.
~ .

- 12~9X~
17 -
the product is obtained which crystallizes from l-chloro-
butane-hexane mixture.
Similarly, the use of benzylamine in place of benzyl
alcohol gives 5-benzylamino-2,3-dimethylimidazo [1,2-a]
pyridine.
EXAMPLE IV
7-Benzyloxy-3-cyanomethyl-2-methyl-imidazo [1,2-a]
~yridine
STEP A: Preparation of 3-chloro-4-oxopentanonitrile.
Into a l-neck, 3-1 round bottom flask there were placed
1 1 diethylether (Et20) and 100 g 4-oxopentanonitrile.
The magnetically stirred solution was cooled to 0 - 5C.,
one drop HCl/Et20 added, and 185 ml 97% of S02C12
previously chilled to 5 - 10C. was added all at once. 15 The ice bath was removed, and the pale greenish-yellow
solution was warmed to 20- 1C. over 5 min. by d hot
water bath. ~he temperature was maintained at 20- 1C.
by a cold water bath for 2~ hours. The pale yellow
solution was evaporated on a rotary evaporator in a 30C.
20 water bath at 80 mm vacuumj and carefully watched. Near `~
the end of solvent removal, the instant the near-colourless
residue began to turn orange, the flask was removed
:
:: : :
.,~i : :
.
,
'
.

~29~ 57
- 18 -
quickly and diluted with 1 1 cold Et 0. One ml SO C12
2 2
was added and stirred 15 min., and the orangish solution
was diluted with 1 1 cold Et20.
THe ether solution was washed with 1 1 cold saturated
NaHC03-solution which was in turn extracted with 2 x 1/2 1
cold CH2C12. The CH2C12 was evaporated, the residue
dissolved in 200 ml Et20, and added to the bicarbonate-
washed ether solution. The ether was extracted by
2 x 1 1 cold lODlo NaHS03-solution and discarded. The bisul-
- 10 fite solution was cooled in an ice bath and 25% NaOH was
added slowly to attain pH 7 (ca. 100 ml), 100 9 NaHC03
was added to saturate the solution, and it was extracted
with 5 x 1 1 CH2C12; 25 9 K2C03 was added followed by
extraction with 1 1 CH2C12, and this was repeated with
another 25 9 K2C03 - 1 1 CH2C12. The combined extracts
were dried over MgS04, and evaporated to leave a brown-
orange oil, estimated from pmr to contain 3-Cl isomer,
5-Cl lsomer, some unknown compounds and CH2C12.
Distillation of this oil through a jacketed 15-cm Vigreux
column at 0.3 mmHg gave 3-chloro-4-oxopentanonitrile
(b.p. 83 - 93C.)
'
STEP B: Preparation of title compound.
A solution of 2-amino-4-phenylmethoxypyridine (1.45 9),
; triethylamine (0.73 9) and 3-chloro-4-oxopentanonitrile
(0.95 9) in methanol (40 ml) is heated under re~lux for~
three hours. After one hour, additional 3-chloro-4-oxo-
pentanonitrile (0.5 9) and triethylamine (0.36 9) is
added. The solvent is removed in vacuo, and the residue
is partitioned between methylene chloride (50 ml~ and 2%
:: . :
. ' :, ; ' ':, : : :
' ,. , .'` ' ~ -

~Z~8~S~;'
, g
sodium hydroxide (50 ml). The methylene chloride layer is
removed and concentrated in vacuo to give 1.5 9 of crude
product.
A solution of crude product (1.1 9) and 0.6 ml pyridine
in 20 ml p-dioxane is cooled in an ice bath and treated
with 0.6 ml trifluoroacetic anhydride in 2 ml p-dioxane.
After removal of the ice bath, the reaction is stirred
for one hour, diluted with water (300 ml) and treated with
saturated sodium bicarbonate to pH 7-8. Filtration gives
lo 0.8 9 of a solid which is chromatographed on silica gel
(125 9) using 3% methanol in methylene chloride to give
the product which crystallizes from ethyl acetate.
Similarly, the use of 2-amino-4-benzylaminopyridine in
the above procedure yields 7-benzylamino-3-cyanomethyl-
2-methyl-imidazo [1,2-a] pyridine.
EXAMPLE V
8-Allyloxy-3-cyanomet~hyl-2-methyl-imidazo [1,2-a]
;eYr-dine
A.
20 8-Benzyloxy-3-cyanomethy1-2-methyl-imidazo [1,2-a~-
pyridine (40 9, 0.14 mol), 1,4-cyclohexadiene (50 9,
0.62 mol), dimethylformamide (600 ml) an~d palladium black
(2 9) are stirred together and heated. At 45C., sudden
exotherm occurs and the temperature rises rapidly to~
75 - 80C. Heating is discontinued and the mixture stir-
red for 1 hour. The catalyst is removed~by filtrat;o`n
and the cyclohexadiene removed in vacuo. The dimethyl-
formamide is removed in vacuo (0.1 mm) at 55C. to af;for~d~
: ~ : : : :
,
.: :
: . '

1~89S7
- 20 -
3-cyanomethyl-2-methyl-8-hydroxy imidazo [1,2-a] pyridine
(27 9, 0.14 mol).
B.
3-cyanomethyl-2-methyl-8-hydroxy imidazo [1,2-a] pyridine
(60.5 g, 0.32 mol) and dry dimethylformamide (1600 ml)
are stirred together and sodium hydride (15.4 9, 0.32 mol,
50% in oil) added during 15 minutes. The mixture is
stirred 1.5 hours after the addition of sodium hydride.
Allyl bromide (38.7 9, 0.32 mol) is added dropwise during
1 hour. After the addition of allyl bromide, the reaction
is stirred for an additional 1 hour. The dimethylformamide
is removed in vacuo. The residue partitioned between
water (1 liter) and chloroform (3 liters), the organic
layer separated, washed with water (1 liter) dried over
anhydrous magnesium sulfate and the solvent removed in
vacuo. Residual dimethylformamide is removed in vacuo
(0.1 mm). The residual oil is dissolved in chloroform
(300 ml) and filtered througha sllica gel~ plug (100 9,
tlc grade 60H) to remove coloured materials. This process
yields 29.2 g of an oil~
C. : : ,:
Treatment of the oil~ produced in Step B with ethereal
hydrogen chloride gives 8-allyloxy-3-cyanomethyl-2-methyl-
imidazo [1,2-a] pyridine (29.9 9, 0.11 mol.) mp 1~77 - 179C.
as the hydrochloride hemihydrate
; ;~
~: .
:~
: .. ~ :...... .
- ..

12~S~7
EXAMPLE VI
3-Cyanomethyl-2-meth~1-7-(2-ehenylethyl)-imidazo
__ _______ ________ _______ ___ ____ ____ __ __
[1,2 a] eyridine
STEP A: Preparation of 3-Dimethylaminomethyl-2-methyl-
7-(2-phenylethyl)-imidazo [1,2-a] pyridine.
Into a one-liter flask there was placed 2-methyl-7-(2-
phenylethyl)-imidazo [1,2-a] pyridine (112 9) dimethylamine
hydrochloride, paraformaldehyde (15.23 9) and methanol
(450 ml) and the mixture was refluxed with stirr;ng for
1.5 hours. Thereafter the mixture was boiled, open to
the air, for 3/4 hours. After cooling to room temperature
and treatment with concentrated hydrochloric acid (45 ml)
the mixture was stirred for 18 hours, filtered and the
thick white solid mass formed was washed with methanol
and 200 ml of anhydrous ether and dried.
:
STEP B: Preparation of 3-dimethylaminomethyl-2-methyl~
7-(2-phenylethyl)-imidazo ~1,2-a] pyridine
methiodide.
3-Di~ethylaminomethyl-2-methyl-7-(2-phenylethyl)-imidazo-
[1,2-a] pyridine hydrochloride (1.325 9) was dissolved
in 4.5 liters of hot water. The solution was made strongly
basic with 50% NaOH-solution. The chilled mixture was
extracted with dichloromethane (3 x 1.5 liters) and the
combined extracts were washed with brine (1.5 liters).
The dichloromethane extract was concentrated on a rotary
evaporator. The residual oil was dissolved in 2.5 liters ~;
of ethanol. With stirring the solution was cooled and
methyl iodide (232 ml) was added drop~iisè over a period
of 1.5 hours. The mixture was~allowed to warm to room

~2(~95'~
- 22 -
temperature overnight under continued stirring. The
white precipitate was collected after about 18 hours of
stirring, washed with 1.5 liters of ethanol and 3 liters
of ether. The resulting product is ready for use in
Step C below.
STEP C: Preparation of title compound.
A mixture of the methiodide of Step A (1,552 9) and sodium
- cyanide (310 9) in 8.4 liters of dimehtylformamide was
stirred and heated in a steam bath for one hour.
The dark brown reaction mixture was poured into 30 liters
of ice water and the mixture was stirred for one hour.
The brown solid product was collected, washed with cold
water and allowed to air dry. This material was dissolved
in 3.8 liters of hot methanol and treated with hydrogen
chloride gas until strongly acidic. The mixture was
cooled and the product collected. After washing with
methanol, acetronitrile and finally with ether the title -
product as the hydrochloride salt was obtained.
The salt was re-suspended in water and made strongly alka-
line with 10% sodium hydroxide. The product was extracted
with dichloromethane (3 x 2.5 liters) and the combined
extracts concentrated on a rotary evaporator. The residue
was dissolved in 3.6 liters of hot acetonitrile, and the
resulting solution filtered through a glass wool plug and
the filtrate was refrigerated overnight. The desired
product was then washed with cold acetonitrile (mp 118C.).
:
:
.. i :
-
.
.
.

~Z'~8~57
- 23 -
EXAMPLE VII
3-Amino-2-methyl-8-(trans-2-phenylethenyl)-imidazo
____ _____________________________ _______ _______
[1,2-a] eyridine hydrochloride
A. 2-Methyl-8-Formylimidazo [1,2-a] pyridine
. .
A mixture of 2-aminonicotinaldehyde (92.8g, 0.76mol) and
bromoacetone (114.59, 0.84mol) in dimethoxyethane (980ml)
is stirred for 2 hours at room temperature and then heated
at 65 with stirring for 14 hours. The solid which sepa-
rates is isolated by filtration, dissolved in 800ml
absolute ethanol and heated under reflux for 6 hours.
The ethanol solvent is removed under reduced pressure and
the residue treated with 138ml 6 N hydrochloric acid in
750ml water for 0.5 hour. The acidic aqueous layer is
washed with ether (2 x 300ml) and basified with cooling
15 (78ml 50% sodium hydroxide and 259 sodium bicarbonate).
The aqueous layer is extracted with~dichloromethane. The
extracts are combined and dried over anhyd~rous sodium
sulfate. Following~fil;tration, the solvent is removed~
under reduced pressure to afford 2-methy;1-8-formyl-
20 imidazo [1,2-a] pyridine, mp 136 - 139.5C. ;
B. 2-Methyl-8-hydroxymethylimidazo [1,2-a] pyridine
To a stirred suspension of 56.89 (û~.36mo~1) 2-methyl-8-
formylimidazo C1,2-a] pyridine in 400ml isopropanol at O
is added in portlons ûg (0.21mol) sodium~borohydride.
The reaction mlxtu~re ;s stirrbed at room temperature~for~ an~
additional 2 hours. The excess~sodium~bor~ohydride is
decomposed by the addition of distilled~water and the
; solution concentrated under reduced pressu~re at SûC.
: ,

~2~ S~7
- 24 -
The residue is dissolved in water and extracted with chloro-
form. The chloroform extracts are combined and dried over
anhydrous sodium sulfate. Following filtration, the
chloroform is removed under reduced pressure to give
2-methyl-8-hydroxymethylimidazo [1,2-a] pyridine.
C. 2-Methyl-8-chloromethylimidazo [1,2-a] pyridine
2-Methyl-8-hydroxymethylimidazo [1,2-a] pyridine 21.49
(0.13mol) is dissolved in 400ml dichloromethane. To the
solution at 0 C. is added dropwise with stirring l9ml
of thionyl chloride. The reaction mixture is stirred for
one hour and the dichloromethane is removed under reduced
pressure. The residue is dissolved in distilled water,
neutralized at 0C. with ammonium hydroxide and extracted
with dichloromethane. The extracts are combined and dried
over anhydrous sodium sulfate. Following filtration, the
dichloromethane is removed under reduced pressure to give ;
2-methyl-8-chloromethylimidazo [1,2-a] pyridine,
mp. 110 - 112C.
D. Diethyl (2-methyl-8-imidazo [1,2-a] pyridylmethyl)
20phosphonate
2-Methyl-8-chloromethylimidazo [1,2-a] pyridine 37.79
n. 21mol) and 9lml triethylphosphite are heated together~
at 145 - 150C. for 2 hours. Upon cooling, the residue is
triturated with petrQleum ether and dissolved in ether.
Insolubles are removed by filtration and the ether is
; evaporated under reduced pressure. The oil obtained is
~; dissolved in dichloromethane and dried~over anhydrous
sodium sulfate. Following filtration, the dichloromethane
. ~. :
~: :
:
.; : ' ~ ;
::

~4895~
- 25 -
is removed under reduced pressure to give diethyl (2-
methyl-8-imidazo [1,2-a] pyridylmethyl) phosphonate as an
o i 1 .
E. 2-Methyl-8-(2-phenylethenyl)-imidazo [1,2-a] pyridine
A solution of 48.59 (0.17mol) diethyl (2-methyl-8-imidazo-
[1,2-a] pyridylmethyl) phosphonate and 19.4ml benzaldehyde
in 400ml dimethoxyethane is added dropwise to a stirred
- suspension of sodium hydride (11.69, 0.48mol~ in dimethoxy-
ethane at 0C.
After stirring overnight, the dimethoxyethane is removed
under reduced pressure. The residue is dissolved in water
and extracted with dichloromethane. The dichloromethane
extracts are combined and dried over anhydrous sodium
sulfate. Following filtration, the dichloromethane is
removed under red~uced pressure. Re-crystallization from~
ethyl acetate gives 2-methyl-8-(2-phenylethenyl) imidazo-
[1,2-a] pyridine, mp 101~- 105C. -
~ F. 3-Nitroso-2-methyl-a-(2-phenylethenyl)-imidazo-
; [1,2-a] pyridine
:
To a solution of 5.0g~(0.02mol) 2-methyl-8-(2-phenyl-
ethenyl)-imidazo [1,2-a] pyridine dissolved in 40ml acetic ~;~
acid and lOOml water at 5C. is added in portions over 10
minutes, 2.79 (0.04mol) sodlum nitrite. The mixture is ;~
stirred at 0C. for 20 minutes and at room temperature for
2 hours. Additional water (50ml) is added, the solid is
isolated by filtration and washed thoroughly with distille~d
water (4 x 500ml);.

~2~ 57
- 26 -
Re-crystallization from ethyl acetate gives 3-nitroso-2-
methyl-8-(2-phenylethenyl)-imidazo [1,2-a] pyridine,
mp 158 - 160C.
G. 3-Amino-2-methyl-8-(2-phenylethenyl)-imidazo [1,2-a]
pyridine
.
To a stirred mixture of 3.09 (O.Olmol) 3-nitroso-2-methyl-
8-(2-phenylethenyl)-imidazo [1,2-a] pyridine in 50ml of
- glacial acetic acid and 50ml of water at 0C. is added in
portions 3.0g (0.046mol) zinc. When the addition is
complete the mixture is stirred at 0C. for 1 hour. The
mixture is filtered through celite; the filtrate is diluted
with water and dichloromethane and basified at 10C. with
80ml of 5N sodium hydroxide. The resultant emulsion is
filtered through a pad of celite and the celite pad is
washed thoroughly with hot chloroform. The layers of the
filtrate are separated and the aqueous phase is extracted
with chloroform. The organic layer is washed with water
and brine and dried over anhydrous sodium sulfate.
Following filtration, the chloroforrn is remvoed under
reduced pressure to give 3-amino-2-methyl~~-(phenylethenyl)-
imidazo [1,2-a] pyridine. 1.09 (0.004mol) of the free base
is dissolved in ethyl acetate and treated with 2ml of 3.4M
etheneal hydrogen-chl~oride. Re-crystallization of the
solid from methanol/ethyl acetate gives, 3-amino-2-methyl-
8-(trans-2-phenylethenyl)-imidazo [1,2-a] pyridine
hydrochloride, mp 241 - 250C. (dec.)
`` : . :
.

~2(~39S7
EXAMPLE VIII
2-Meth~1-3-isocyanomethyl-8-ehenylmeth
_ _
im_dazo_[1,2-a]_eyr_d_ne
2-Methyl-3-formylaminomethyl-8-phenylmethoxyimidazo- -
5 [1,2-a] pyridine lOOmg (0.29mmol) is added to 6ml dichloro-
methane containing 0.6ml diisopropyl ethylamine and O.lml
phosphorous oxychloride. The mixture is stirred for 2 hours
and diluted with water. The dichloromethane layer is
separated, washed with saturated sodium bicarbonate, brine
and dried over anhydrous magnesium sulfate.
Following filtration the dichloromethane is removed under
reduced pressure to give 2-methyl-3-isocyanomethyl-8-
phenylmethoxyimidazo [1,2-a] pyridine, m.p.
EXAMPLE IX
trans-2,3-Dimethyl-8-~2-phenylethenyl)-
_ _ _ _ _ _ ~
imidazo [1,2 a] eyridine h~ydrochloride
A. 2,3-Dimethyl-8-formylimidazo [1,2-a] pyridine
A solution of 2079 (1.7mol) 2-aminonicotlnaldehyde and
3009 (2.Omol) 3-bromo-2-butanone in 150ml dichloromethane
is heated on a steam bath allowing the solvent to distill
and the mixture is maintained at 100 - 105C. for 2 hours.
The reaction mixture is dissolved in dilute hydrochloric
acid and extracted with ether~ The aqueous layer is
neutralized with 20% sodium hydroxide~ The solid precipi-
;;~ 25 tate is ;solated by ~iltration and re-crystallized from
~:
'
. .
:.

12489~'7
- 28 -
ethyl acetate to give 2,3-dimethyl-8-formylimidazo-
[1,2-a] pyridine, mp 145 - 148C.
B. trans-2,3 dimethyl-8-(2-phenylethenyl)- ~ '
imidazo [1,2-a] pyridine hydrochloride
A stirred solution of 1169 (0.51mol) diethylbenzylphospho-
nate in ~OOml dimethylformamide is treated with-28g
(0.052mol) sodium methoxide.
2,3-Dimethyl-8-formylimidazo [1,2-a] pyridine (809, 0.46mol)
is added in portic~ns over 35 minutes while maintaining the
temperature between 30 - 35C. After stirring at room
temperature 2.5 hours, the solvent is removed under reduced
pressure and the residue portioned between 300ml dichloro-
methane and 500ml water.
The dichloromethane layer is separated and the solvent is
removed under reduced pressure. The solid is triturated
with ether (3 x lOOml) and insolubles are removed from
the ether solutions by filtration. The ether filtrates are
combined and treated with ethereal hydrogen chloride~
Re-crystallization of the solid from water gives trans-2,3-
dimethyl-8-(2-phenylethenyl)-imidazo [1,2-a] pyridine,
mp. 240 - 255C.
~: :
: :: ~ ,
. .... , .. ~ ... . : , :
.. . .
.
,... ~ :

~129~S7
- 29 -
According to the processes outlined above, using the
appropriate starting compounds, the following compounds
may be obtained.
1. 2,3-Dimethyl-8-[1-E-(3-phenylpropenyl)]-imidazo,i
- 5 [1,2-a] pyridine;
~m.p. of hydrochloride salt: 201 - 204C., dec.).
2. 2,3-Dimethyl-8-[(2-phenyl~ethenyl]-imidazo [1,2-a]
pyridine;
~ (m.p. of hydrochloride methanolate (~HCl^CH30H) :
243 - 255C.)
3. 3-Cyanomethyl-2-methyl-8-[E-(2-phenyl-1-ethenyl)]-
imidazo [1,2-a] pyridine;
, .
m.p. 133 - 136C.
4. 3-Cyanomethyl-2-methyl-8-~E-1-(3-phenyl-propen-1-
yl)]-imidazo [1,2-a] pyridine;
m.p. 143 - 145.5C.
5. 3-Cyanomethyl-2-methyl-6-(2-phenylethyl)-imidazo
[1,2-a] pyridine;
m.p. 139 - 141C.
6. 3-Amino-8-benzyloxy-2-ethyl-imidazo [1,2-a] pyridine;
m.p. 109 - 110C.
~:
7. 3-Amino-8-benzyloxy-2,7-dimethyl-imidazo [1,2-a]-
pyridine;
m.p. of the hydrochloride monohydrate : 181 - 183C.
' " ~., ' ~ .
- ,
~ "'... :
" ~
. .

~Z489S'7
-
- 30 -
8. 3-Amino-2-methyl-8-(2-phenylethyl)-imidazo [1,2-a]
pyridine
m.p. of the hydrochloride including 1 mole methanol
and 1/4 mol. H20 : 74.5C.
9. 3~-Amino-2-methyl-8-(3-thienylmethoxy)-imidazo ~1,2-a]
pyridine;
m.p. of hydrochloride: 187C. (dec.)
10. 3-Dimethylamino-2-methyl-8-phenylmethoxy-imidazo-
[1,2-a] pyridine;
m.p. of hydrochloride: 187C. (dec.) ~
11. 3-Amino-8-benzyloxy-2,6-dimethyl-imidazo [1,2-a]
pyridine;
m.p. 141 - 142C.
.i . ~
12. 8-Benzyloxy-3-ethylamino-2-methyl-imidazo [1,2-a]
pyridine;
m.p. of hydrochloride: 191C. (dec.)
13. 3-Amino-2-methyl-8-[(3-thienylmethyl)-amino]-imidazD
[1,2-a] pyridine;
m.p. 161 - 163C. (dec.)
20 14. 3-Amino-2-methyl-8-[Z-(2-phenylethenyl)~-imidazo
[1,2-a] pyridine;~
m.p. of the 1/3 hydrate: 116 - 125C.
15. 3-Amino-8-(4-chlorophenylmetho~xy)-2-methyl-imidazo
[1,2-a] pyridine;
m.p. of the 1/4 hydrate: 156 - 158C. (dec.
`
: `~j ` : ~
:
:~ :
;
,. .
:: . .
.: ~ ' :~

~2~89S7
- 31 -
16. 3-Amino-2-methyl-7-(2-phenylethyl)-imidazo [1,2-a]
pyridine;
m.p. 143 - 144C.
17. 3-Amin~-2-methyl-8-(2-thilenylmethoxy)-imidazo [1,2-a]
pyridine;
m.p. of 2/3-hydrate: 1~7 - 149C.
18. Trans-3-Amino-2,6-dimethyl-8- 2-phenylethenyl-imidazo
rl 2-a] pyridine;
m.p. of hydrochloride: 273 - 275C.
19. 3-Amino-8~(2-fluorophenylmethoxy)-2-methyl-imidazo
[1,2-a] pyridine;
m.p. of the 1/4 hydrate: 151 - 152.5C.
, . ;.
20. 3-Amino-8-(4-fluorophenylmethoxy)-2-methyl-imidazo
[1,2-a] pyridine;
m.p. of 1/4 hydrate: 165 - 156C.
21. 3-Amino-8-benzylamino-2-methyl-imidazo [1~2-a]
pyridine;
m.p. 145 - 155c. (dec.)
20 22. 3-Amino-2-methyl-8-(2-phenylethenyl)-imidazo
[1,2-a] pyridine;
m.p. of hydrochloride with 2/3 mol. H20 :
Decomposition at 241 - 250C.
:
23. 3-Amino-2-methyl-6-(2-phenylethyl)-imidazo ~1,2-a]
pyridine;
m.p. 120-122C.
:: : : ~
:
::
.. . , . . ~ .....
.
- -
...... .

lZ4~3~5'~
- 32 -
24. 3-Amino-2-methyl-8-[E-1-(3- phenylpropen-l-yl~]-
imidazo [1,2-a] pyridine;
m.p. of hydrochloride: 222 - 224C. (dec.)
25. 3-Ethy~amino-2-methyl-8-(2-phenylethyl)-im;dazo
[1,2-a] pyridine;
m.p. 145 - 147C. (dec.)
26. 3-Amino-2,7-dimethyl-8-(2-phenylethyl)-imidazo
[1,2-a] pyridine;
m.p.
27. 8-Benzyloxy-3-isocyanomethyl-2-methyl-imidazo
[1,2-a] pyridine;
m.p.
Other typical compounds of this invention are listed in
the Tables I to V below.
: ~ .
: ' :
-

~L24~5'7
- 33 -
TABLE I
Compounds of formul a
j~N J NO
~N ~ CH
R4 3
COMPOUND NO . R4 R5 m . p . C .
.
28. (8)-0-CH2 ~3 H
29. (8)-CH=CH--~3 H (dark green solid)
30. (8)-CH2-CH2 ~3 H 131.5 - 132.5 (dec.)
31, (6)-CH2-CH2 ~ H 114 - 115 (dec.)
32. (8)-0-CH2~ H 147.5 - 148.5 ~dec.) ~
33 (8~-0-CH2~ (7)-CH3 118 - 120 ~ ~ ;
34 (8)-0-CH2~3 ~ H 120 - 122
~: 35. (7)-CH2-CH2 ~3 H 116 ~ 118 (dec.)~ ~ :~
: ~ 36. (8)-CH=CH--~ H 158 - 160
~ ~O)~O-~ 133 - 34 (de-
~ ' :
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~LZ~9S~7
- 34 -
T A B L E I I
Compounds of formul a
R4~ ~ H 2 C N
COMPOUND NO . R4 ~ m. p . C .
3 8 . ( 8 ) -CH=CH--~ 134 - 136
39. (5)-CH2-CH2 ~ 118 - 119
40, ( 7 ) -CH2-CH2--~ 1 l 8 :
L~ (B)-O-C 2-C~=CHz ~
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~2~3957
- 35 -
_BLE I I I
Compounds of formula
/ ) ~ ~ H3
. COMPOUND NO. R4 R5 m.p.C.
42. (8)-CH=CH ~ (6)-CH3 149 - 150
43. cis (8)-CH=CH ~ H 174 - 177
43A. trans ~8 )-CH=CH~3 H 240 - 255
44. (7)-CH2-CH2~ H 88 - 93 .
45. ( ) H2 CH2 ~ H 105 - 107 .
46. (5)-CH2-CH2 ~ H 101 - 103
1047 . ( 5)-0-CH2 ~ H 110
48. ( 6)-CHz ~ ;3 H
.~ ~

124895'7
- 36 -
TABLE IV
Compounds of formula
R S - _~
COMPOUND NO. R4 R5 m.p.C.
49. (8)-CH=CH ~ (6)-CH3 93 ~ 94
50 . Ci 5 (8)-CH=CH ~ H solid)
51. trans(8)-CH=CH ~ H 100 - 102
52. (6~-CH2-CH2 ~ H 104 - 105
53. (5)-CH2-CH2- ~ H 86 - 88
54. (8)-CH=CH-~CH2 ~ H 73.5 - 78
(s)-0-CH2- ~ H (HCl-salt)
136.5 - 138.5 ;~
56. (6)-~-CH2 ~ H 228 230 ~ ~
57. (7) 2 CH2 ~ H (~HCl~l/4 H20) ~ ;
~ 92 - 122 ;
: :.
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lZ489S`-~
TABLE V
Compounds of formula
~'1`' I NHR6
~NJ R2
R4
COMPOU:D R2 - ~ R4 R5 R6 m.p.C.
58. CH3 (8)-0-CH2 ~ H H H~O)
214-215.5 dec.
59 CH3 (8)-0-CH2 ~ H CH3 (-HC1~0.25 H20)
193.5 - 194
60. C(CH3~3 (8)-0-CHz ~ H 173 - 175
61. CH3 (8)-0-CH2-CH2- ~ H H (~HCl~l/4 H20)
~; ~ ~ ~ ~ 138~- 140 dec.~ ;
62. CH3 l5)'CH2 CH2 ~ H H ~ 236 238
63. CH3 (8)-CH2 CH2 ~ (6)-CH3 H (~HCl)
15 ~64. ~ CH3 ¦ (8~-U ~H2- 9; ¦(6~ 9 ¦ 15/ l58
65. CH2~CH2 CH2 ~H3 (8)-~ CH ~ ~ H 115 -~117
66. ~ (8)-0 ~H2 ~ ~ H H ~ 6
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L~ ~89
- 38 -
TABL E V ( c ont i nued )
COIIPOUND ~ R4 R5 R5 m. p. C .
67 . CH2 CH2 CH3 (8 ) -0-CH2~ H H 88 - 89
. ~ 68. C~13 (8)-o-CH2~3 H H 120 - 121 (dec. )
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- 39 -
The term "pharmaceutically acceptable salts" of this
invention include salts wherein the acidic hydrogen forms
an acid addition salt with an am-ine. (e.g. the phosphate
salt of 3-amino-2-methyl-8-phenylmethoxyimidazo [1,2-a]-
pyridine).
Suitable acids for the pharmaceutically acceptable acidaddition salts include hydrochloric, sulfuric, phosphoric,
nitric, acetic, propionic, maleic, ascorbic, citric and
the like.
The acid addition salts are prepared via procedures well
known in the art.
The compounds of this invention are useful in the treatment
of peptic ulcers, having characteristics which enable the
compounds to relieve the symptoms of peptic ulcer disease
(including stress ulceration) and promote healing of
gastric and/or duodenal ulcers. The anti-ulcer activity
of tne compounds of Formula I is identified by tests
which measure their gastric antisecretory activity in the
rat and dog and by tests which measure their cytoprotec-
20 tive effect (sometimes also referred to in the art as ~;
mucoprotective effect) in rats. The compounds are useful
as conjunctive therapeutic agents for co-administration
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~2~8~5~
- 40 -
with such anti-inflammatory/analgesic agents as aspirin,
indomethacin, phenylbutazones, ibuprofen, naproxen,
tolmetin and other agents having the untoward side effect
of contributing to damage to the gastrointestinal tract.
The compounds of this invention, in order to be evaluated
for their applied use characteristics undergo testing
procedures according to standard biological procedures
wherein the compounds are evaluated both on an absolute
basis and on a comparative basis with compounds known to
possess the characteristics useful for the treatment and/or
prevention of peptic ulcer disease, duodenal ulcer disease
and drug induced gastric ulceration. Such tests include
testing in dogs prepared under aseptic surgical conditions
with either Heidenhain gastric pouches or simple gastric
fistulas fitted to facilitate collection of gastric secre-
tions. The test compounds are administered in appropriate
and well defined and well-known vehicles for either
intravenous delivery or oral administration. The agonists
employed to stimulate gastric secretion include such
compounds as histamine, pentagastrin, and feeding in
dogs equipped with Heidenhain pouches, and insulin hypo~
glycemia ~in addition to histamine and pentagastrin) in
dogs with gastric fistulas.
: : ~ : ~;
Caesarean-derived Sprague-Dawley male rats are used for
gastric secretion with pyloric ligation techniques and
anti-ulcer studies~employing aspirin-;nduced ulceration.
From these and other tests, as well as by comparision with
known anti-ulcer agents the compounds of this invention
are found to be effective for the oral treatment of the
30 ulcerative disease states herein mentioned at doses of ~ ~
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- 41 -
about 0.5 to 50 mgm per kilogram of body weight per day,
preferably being administered in 3-4 divided doses per
day. In those instances wherein it is desired to admini-
ster the compounds of this invention via a parenteral
route (e.g. intravenously) the compounds are administered
at a dose range of about 0.01 to 10 mg/kg in single or
multiple daily doses. Of course, the dose will be regu-
lated by the attending diagnostician depending on factors
such as the degree and severity of the disease state and
age and general condition of the patient being treated.
The recommended dose range for the preferred compounds
of this invention is the oral dose of 75 to 1600 mg/day
in three to four divided doses to achieve relief of the
symptoms of peptic ulcer disease and promote the healing
of gastric and/or duodenal ulcers.
In their use in the treatment of peptic ulcer disease,
gastric and duodenal ulcers, and in the prevention and
treatment of drug-induced gastric ulceration, the compounds
are administered in unit dosage forms such as tablets,
capsules, pills, powders, granules, sterile parenteral
solutions or suspensions, suppositories and the like.
Such preparations are prepared according to standard
techniques well-known in the art. A few examples of
such pharmaceutical formulations are as follows.
Formulations
The following formulations are to exemplify some of the
dosage forms in which the anti-ulcer agents of this inven-
tion may be employed. In each, the active ingred;ent is
designated by the term "Drug" which is meant to indicate
one of the following compounds:
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~2~95'7
- 42 -
3-amino-2-methyl-8-~2-phenylethyl)-imidazo [1,2-a]-
pyridine;
2,3-dimethyl-8- (2 -phenylethenyl) -imidazo ~1,2-a]-
pyridine; and
3-cyanomethyl-2-methyl-8-[E-1-(3-phenyl- propen-1-yl)]-
imidazo [1,2-a] pyridine.
. It will be appreciated, however, that each of these com-
pounds may be replaced by equally effectiYe quantities
of other compounds defined by Formula I and their pharma-
ceutically acceptable salts.
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- 43 -
Formulation
Tablets
No. Ingredient mg/tab mg/tab
1 Drug 25.0 400
2 Lactose impalpable powder
USP 114 241.5
3 Corn starch USP 25.0 50.0
4 Corn starch as 5% paste
in distilled water 10.0 35.0
Corn starch USP 25.0 50.0
6 Magnesium stearate USP 1.00 3.50
200 780
Method of Manufacture
Mix items nos. 1, 2 and 3 in a suitable blender 5 to 15 ~ ~
15 minutes. Pass through a fine screen (~4~) if necessary. ;`
Re-blend for S to lO minutes and granulate with item no. 4.
Pass the damp granulated mass through a coarse sieve (~6)
using a suitable mill. Dry the damp granules at 40 to
50C. overnight. Mill the dried granules using no. 20
screen. Add item no. 5 and blend for 5 to 10 minutes.
Add item no. 6 and blend further for 3 to 5 minutes.
Compress the tablet mixture into appropr,ate size and
weight tablets with a suitable tabletting machine.
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- 44 -
Formulation 2
Capsules
_ . Ingredient mg/tab mg/tab
1 Drug 25.0 400
2 Lactose, impalpable
powder USP 144 191.5
3 Corn starch USP 30.0 105
4 Magnesium stearate USP 1.00 3.50
200 700
Method of Manufacture
:
Mix items nos. 1~ 2 and 3 in a suitable blender for 5 to
lO~minutes. Pass through a fine screen~ 40) if necessary.
Re-blend for 5 to 10 minutes, add item no. 4 and mix
further for i to 50 m;nutes. Using a~suitabl~e machine,
~ 15 encapsulate the mixture lnto a two-piece~hard gela~in
; ~ capsule of~appropr~la~te size.
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- 45 -
Formulation 3
-
Suspensions
Ingredients Formula A Formula B
(mg/ml) (mg/ml)
Drug 5.0 80.0
Sucrose 600.0 600.0
Benzyl alcohol 10.0 10.0
Methylcellulose (15 cps) 4.0 4.0
Polysorbte 80 5.0 5.0
10 Vanillin 0.2 0.2
Purified Water q.s. 1.0 ml 1.0 ml
Method of Manufacture
1. Charge approximately 40% of the final volume of puri-
fied water in a stainless steel tank. Heat to boil-
ing. Agitate using an appropriate stirrer~ Agitation
should continue throughout procedure.
2. Add sucrose until it is dissolved.
3. Slowly add methylcellulose until it is well dispersed.
; 4. Start cooling the mixture to room temperature.
5. Add polysorbate, benzyl alcohol and vanillin until all
ingredients are well dispersed. ~ ;~
6. Add the Drug until an uniform disper;sion is formed. ~ ;
.~ 7. This suspension~is then q.s. to final volume wlth
purified water dt 25C.
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- 46 -
Formulation 4
Parenterals
2-methyl-8-phenylmethoxyimidazo [1,2-a]
pyridine-3-acetonitrile
Injection mg/ml
Drug 25.00
Methylparaben 1.30
Propylparaben 0.20
Sodium bisulfite 3.20
Disodium edetate 0.20
Sodium sulfate 2.60
10 Water for injection q.s. ad 1.0 ml
Method for Manufacture
1. Dissolve parabens in a portion (approximately 85% of ::
the final volume) of the water for injection at
65 - 70C.
2. Cool to 25 - 35C. Charge and dissolve sodium bisul- :
fite, disodium edetate and sodium sulfate.
3. Charge and dissolve the Drug. : :
4. Bring the solution to the final volume by adding water
: for injection. ~: ~
~:
5. Filter the solution through 0.22 u membrane;and fill
into appropriate containersO
: 6. Terminally steriiize the units by autoclaving.
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- 47 -
Formulation 5
Injectable Suspension
mg/ml
Drug (Sterile) 50.0
Benzyl alcohol 9.0
Methylparaben 1.8
Propylparaben 0.2
Sodium carboxymethylcellulose 5.0
Polyethylene Glycol 4000 10.0
. Povidone 5.0
10 Sodium Citrate 15.0
Disodium edetate 0.1
Water for injection q.s
To make 1.0 ml
Parenterals
:: :
15 Method of Preparation
. . _ _ . . . _
1. Dissolve parabens in a portion of water for injection
at 65 - 70C.
: 2. Cool to 25 - 35C. Charge and dissolve benzyl alcohol,
sodium,citrate, disodium edetate, PEG 4aooj povidone
and sodium carboxymethylcellulose.
3. Filter the solution and sterilize by autoclaving :
4. Make a slurry of the sterile active and pass it through
a colloid mill.
: 5. Mix it well with solution from Step 3 and pass it ~ :~
through the
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~lZ'~ 5';'
- 48 -
6. Bring the suspension to the final volume/weight and
fill into sterile containers.
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~2~89~7
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Formulation _
Suppositories
A. Formula mg/supp
Drug 5.0
Cocoa butter - 1995.0
2.0 9.
Procedure
- 1. Melt cocoa butter to about 32 - 35C.
2. Blend Drug into cocoa butter until well dispersed.
3. Pour into teflon-coated mould and congeal in refrig-
erator. Keep in refrigerator for an appropriate
length of time.
4. Remove suppositories from mould.
~:
B. Formula mg/supp
Drug 100.0
PEG 1000 182~4.0
PEG 4000 ; 76
2.0 9.
Procedure
1. Melt PEG lOOO and PEG 4000 in one container to 50C.
2. Add Drug to the mi;xture. ~Blend until well dispersed.
3. Pour into mould and congeal in refrigerator. Keep inrefrigerator for~an appropriate length of time.
: : . ,
~ 4. Remove suppositories from mould.
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