Note: Descriptions are shown in the official language in which they were submitted.
25~3
.
PYRROLO[l,2-a]IMIDAZOLE AND IMIDAZO[l,2-alPYRIDINE
DERIVATIVES AND THEIR USE AS 5-LIPOXYGENASE PATHWAY
INHIBITORS
- CROSS REFERENCE TO RELATED APPLICATIONS
This is a continuation-in-part of Serial No.
15 092,258, filed September 2, 1988, which is a
continuation-in-part of Serial No. 856,928, filed April
28, 1986, now abandoned, which is a continuation-in-part
of Serial No. 808,407, filed December 12, 1985, which is
abandoned.
BACKGROUND OF THE INVENTION
This invention relates to novel compounds, pharma-
ceutical compositions and methods of inhibiting the
5-lipoxygenase pathway of arachidonic acid metabolism in
an animal in need thereof which comprises administering to
~ 25 such animal an effective, 5-lipoxygenase pathway inhibiting
: amount of a pyridyl and phenyl substituted pyrrolo-
tl,2-a]imidazole, or pyridyl and phenyl substituted
: imidazo[l,2-a]pyridine, or a pharmaceutically acceptable
salt thereof.
Davidson et al., U. S. Patent 4,507,481, issued
March 26, 1985, disclose compounds of the formula:
a
2~l3
-- 2 --
1 wherein:
X is ~ or S(O)n;
n is 0, 1 or 2;
Rl is H, lower alkyl, phenyl, benzyl or
benzyl substituted with lower alkylamino,
lower alkylamino, nitro, halo, hydroxy or
lower alkoxy-;
R2 is H or XRl;
A is C~2 or CH2CH3;
R3 and R4 are independently selected
from A, lower alkyl, aryl, aryl substituted
with lower alkyl, amino, lower alkylamino,
nitro, lower alkoxy, hydroxy or halogen;
provided that at least one of R3 and R4 is
aryl or substituted aryl; and
R5 and R6 are each H or join to form a
double bond at the 2,3-position.
Davidson et al. also disclose that such comounds are
immunostimulants or immunosuppresants based on (a) their
inhibiting or stimulating activity in a chemotaxis assay
which measures the ability of a drug substance to influence
the movement of murine macrophages responding to comple-
ment; (b) their immunosuppressing or activating activity
in the Kennedy plaque assay in which an animal's humoral
S immune system is depressed artificially with 6-mercapto-
purine. Neither the chemotaxis assay nor the Kennedy
plaque assay is of any known utility for detecting or
suggesting compounds which are inhibitors of the
5-lipoxygenase pathway. Davidson et al~ alsc disclose
that such compounds have antiinflammatory activity as
determined by the carrageenan-induced paw edema assay in
rats. As stated above, such assay has no known utility in
detecting or suggesting compounds which are inhibitors of
the 5-lipoxygenase pathway. Davidson et al. also disclose
that such compounds have antiviral activity in mice with
hepatitis; but such activity is of no known utility in
2il;~
1 detecting or suggesting compounds which are inhibitors of
the S-lipoxygenase pathway.
SUMMARY OF THE INVENTION
This invention relates to a compound of.the
formula (I)
~2 ~3
,a
. ~
~ t
FORMULA (I)
wherein
. 1) One of R or Rl must be alkyl substituted
pyridyl and the other is selected frQm:
(a) monosubstituted phenyl wherein said
substituent is selected from H, halo, hydroxy
Cl 3 alkoxy, Cl 3 alkylthio, Cl 4 alkyl,
Cl 3 alkylsulfinyl, Cl 3 alkylsulfonyl,
Cl_3 alkylamino, Cl 3 dialkylamino, CF3,
N-(Cl_3 alkyl)-N-(cl-3alkanamido)~
N-pyrrolidino, N-piperidino, prop-2-ene-1-oxy or
2,2,2-trihaloethoxy;
(b) disubstituted phenyl wherein said
substituents are the same and are selected from
halo, Cl_3 alkoxy, Cl_3 alkylamino, Cl_3
dialkylamino, N-pyrrolidino, N-piperidino,
2,2,2-trihaloethoxy, prop-2-ene-1-oxy, or
hydroxy, or the disubstituents together form
methylene dioxy group;
. ~ ,
2il~
_ 4 --
1 (c) disubstituted phenyl wherein said
substituents are not the same and are
independently selected from halo, Cl 3
alkylamino, nitro, N-(Cl 3alkyl)-N-(C1 3
alkanamido, Cl 3 dialkylamino, amino,
~-pyrrolidino or N-piperidino;
(d) disubstituted phenyl wherein one of said
substituents must be Cl 3 alkoxy, hydroxy,
2,2,2-trihaloethoxy or prop-2-ene-1-oxy and the
other substituent is independently selected from
halo, Cl_3 alkylamino, N-(Cl_3alkyl)-
N-Cl 3alkanamido), Cl 3dialkylamino, amino,
N-pyrrolidino or N-piperidino; or
(e) disubstituted phenyl wherein one
substituent is selected from Cl_3 alkylthio,
Cl 3 alkylsulfinyl, and Cl 3 alkylsulfonyl
and the other is selected from C2 3 alkoxy,
nitro, halo, amino, Cl 3 aIkylamino, or Cl 3
dialkylamino; or
2) One of R or Rl is 2-pyridyl or 3-pyridyl and
the other is selected from:
(a) monosubstituted phenyl wherein said
substituent is selected from Cl 3 alkylthio,
Cl 3 alkylsulfinyl, Cl 3 alkylsulfonyl,
Cl_3alkoxy or hydroxy; or
(b) disubstituted phenyl wherein one
: substituent is selected from Cl 3 alkylthio,
Cl 3 alkylsulfinyl, or Cl 3 alkylsulfonyl and
the other is selected from Cl_3 alkoxy, nitro,
halo, amino, Cl 3 alkylamino, or Cl_3
dialkylamino, or
3) R is 4-pyridyl and Rl is selected from:
(a) monosubstituted phenyl wherein said
substituent is selected from Cl 3 alkylthio,
- 5
1. Cl 3 alkylsulfinyl, Cl 3 alkylsulfonyl or
hydroxy; or
(b) disubstituted phenyl wherein one
substituent is selected from Cl 3 alkylthio,
Cl 3 alkylsulfinyl, or Cl 3 alkylsulfonyl and
the other is selected from C2 3 alkoxy, nitro,
halo, amino, Cl 3 alkylamino, or Cl 3
dialkylamino; or
4) Rl is 4-pyridyl and ~ selected from:
(a) monosubstituted phenyl wherein said
substituent is selected from Cl 3 alkylthio,
Cl 3 alkylsulfinyl, Cl 3 alkylsulfonyl,
hydroxy or C2 3 alkoxy, or branched or
unbranched C2 5 alkenylthio or C2 5
alkenylsulfinyl; or
(b) disubstituted phenyl wherein one
substituent is selected from Cl_3 alkylthio,
Cl 3 alkylsulfinyl, or Cl 3 alkylsulfonyl and
the other is selected from C2 3 alkoxy, nitro,
halo, amino, C} 3 alkylamino, or Cl 3
dialkylamino, or branched or unbranched C2 5
alkenylthio or C2 5 alkenylsulfinyl; or
5) One of R or R is pyridyl or alkyl
substituted pyridyl and the other is
(a) monosubstituted phenyl wherein said
substituent is from alkenylthio, alkenylsulfinyl,
thiol tHS-], acylthio tAC(O)S-], dithioacyl
tAC(S)S-], thiocarbamyl [AAlNC(O)S-],
dithiocarbamyl [AAlNC(S)S-],
alkylcarbonylalkylthio CAC(O)CH2S-],
carbalkoxyalkylthio tBOC(O)CH2S-],
alkoxycarbonylthio [BOC(O)S-],
alkoxythionothio~BOC(S)S-], phenylthio,
alkoxyalkylthio[BOC~2S-~, alkoxyalkyl-
.sulfinyltBOCH2S(O)], alkylthioalkylthio
[BSCH2S-], disulfide ~BlSS-], or
2~ 2.~
-- 6 --
1 acyloxyalkylthio tAC(O)OCH2S-] wherein the
- CH2 is optionally substituted with Cl_4alkyl,
and A and A are hydrogen, Cl galkyl or
phenyl, B is Cl galkyl or phenyl, and Bl is
Cl g alkyl, aryl, heteroaryl, or a Formula (I~
compound linked through the thio group on the
phenyl ring of R or Rl;
b) disubstituted phenyl wherein the
substitutents are the same and are selected from
Cl 3 alkylthio, Cl 3 alkylsulfinyl, Cl 3
alkylsulfonyl, alkenylthio, alkenylsulfinyl,
thiol [HS-], acylthio tAC(O)S-], dithioacyl
[AC(S)S-], thiocarbamyl [AAlNC(O)S-],
dithiocarbamyl tAAlNC(S)S-],
alkylcarbonylalkylthio tAC(O)CH2S-],
carbalkoxyalkylthio [BOC(O)CH2S-],
alkoxycarbonylthio tBOC(O)S-],
alkoxythionothio[BOC(S)S-], phenylthio,
alkox~alkylthiotBOCH2S-], alkoxyalkyl-
sulfinyltBOCH2S(O)], alkylthioalkylthio
[BSCH2S-], disulfide tBlSS-], or
acyloxyalkylthio tAC(O)OCH2S-] wherein the
CH2 is optionally substituted with Cl 4alkyl,
and A and Al are hydrogen, Cl galkyl or
phenyl, B is Cl galkyl or phenyl, and Bl is
Cl g alkyl, aryl, heteroaryl, or a Formula (I)
compound linked through the thio group on the
phenyl ring of R or Rl: or
(c) disubstituted phenyl wherein one
substituent is seleated rom C2_3 alkoxy,
nitro, halo, amino, Cl 3 alkylamino, Cl 3
dialkylamino and the other is selected from
alkenylthio, alkenylsulfinyl, thiol tHS-],
acylthio tAC(O)S-], dithioacyl tAC~S)S-],
thiocarb~myl tAAlNC(O)S-], dithiocarbamyl
- 7 -
1 ~AAlNC(S)S-], alkylcarbonylalkylthio
tAc(o)cH2s-]~ carbalkoxyalkylthio
~BOC(o)CH2S-], alkoxycarbonylthio tBOC(O)S-],
alkoxythionothio[30C(S)S-], phenylthio,
alkoxyalkylthio~BOCH2S-], alkoxyalkyl-
sulfinyl~BOCH2S(O)], alkylthioalkylthio
~BSCH2S-], disulfide ~BlSS-], or
acyloxyalkylthio ~AC(O)OCH2S-] wherein the
CH2 is optionally substituted with Cl 4alXyl,
and A and A are hydrogen, Cl galkyl or
phenyl, B is Cl galkyl or phenyl, and Bl is
Cl_g alkyl, aryl, heteroaryl, or a Formula (I)
compound linked through the thio group on the
phenyl ring of R or Rl; or
6) One of Rl or R is pyridyl or alkyl
substituted pyridyl and the other is selected
from monosubstituted phenyl wherein said
substituent is
~S~(C~2~n~5
wherein Rl is pyridyl or alkyl substituted
pyridyl and R2, R3, R , R , R , R ,
: R~ and R9 are defined as in formula (I);
and R2 R3 R4 R5, R6, R7, R8 and R9 are
H, or one or two of R , R , R , R , R , R ,
R7, R8 and R9 are independently selected from H or
Cl 2 alkyl; and n is O or l;
35 or a pharmaceuticaily acceptable salt thereof.
~ ' .
.5l~
- 8 -
1 The term N-(Cl 3 alkyl)-N-(Cl 3 alkanamido)
is used herein at all occurrances to mean one of the
following:
O O
Cl 2 alkyl-CN - or HCN -
~1 3 alkyl Cl 3 alkyl
The term aryl or heteroaryl is used herein at all
occurences to mean aromatic ring(s) or ring systems from 5
10 to 16 carbon atoms, which may include bi- or tri-cyclic
systems and may include, but are not limited to heteroatoms
selected from O, N, or S. Representative examples include,
but are not limited to, phenyl, napthyl, pyridyl, thiazinyl,
and furanyl.
This invention also relates to a pharmaceutical
composition comprising a pharmaceutically acceptable carrier
or diluent and an effective, non-toxic 5-lipoxygenase
pathway inhibiting amount of a compound of the formula (I)
as defined above, or a pharmaceutically acceptable salt
20 thereof~
This invention also relates to a method of~treating
a 5-lipoxygenase pathway mediated disease in an animal in
need thereof which comprises administering to such animal an
effective, non-toxic 5-lipoxygenase pathway inhibiting
2; amount of a compound of Formula (I) as defined above, or a
pharmaceutically acceptable salt thereof.
This invention also relates to intermediate
compoullds used in the preparation of a compound of
Formula (I) having the following structural formula (J):
~i~~2
~ ~R
FORMULA (J)
Z~ r~
wherein
n is 0 or 1;
R2 R3 R4 R5, R6, R7, R8
5 and R9 are H, or one or two of R2, R3, R4, R5,
R6, R7, R8 and R9 are independently selected from
H or Cl 2 alkyl;
Rlo is Cl_4 alkyl;
and Xl is selected from
(a) phenyl or monosubstituted phenyl wherein
said substituent is selected from H, fluoro,
chloro, Cl_3 alkoxy, Cl_4 alkyl, Cl_3
alkylthio, alkenylthio, phenylthio,
alkoxyalkylthio [BOCH2S-], alkoxyalkylsulfinyl
lS ~BOCH2S(O)], alkylthioalkylthio [BSCH2S-],
C1 3 dialkylamino, CF3, Cl 3 alkylamino,
N-pyrrolidino, N-piperidino, prop-2-ene-1-oxy or
2,2,2-trihaloethoxy, wherein the CH2 is
optionally substituted with Cl 4alkyl, and B is
Cl_galkyl or phenyl,;
(b) disubstituted phenyl wherein said
substituents are the same and a~e selected from
fluoro, chloro, Cl_3 alkoxy, Cl_3 y
amino, N-pyrrolidino, N-piperidino, 2,2,2-
trihaloethoxy, prop-2-ene-1-oxy, Cl 3alkylthio,
alkenylthio, phenylthio, alkoxyalkylthio
~BOCH2S-], alkylthioalkylthio [BSCH2S-],
wherein the CH2 is optionally substituted with
Cl_4alkyl, B is Cl galkyl or phenyl, or the
disubstituents together ~orm a methylene dioxy
group:
(c) disubstituted phenyl wherein said
s-bstituents are not the same and are
independently selected from fluoro, chloro,
3s Cl 3 alkylamino, Cl 3 dialkylamino,
N~pyrrolidino, or N-piperidino;
-- 10 --
.
1 (d) disubstituted phenyl wherein one of said
substituents must be Cl 3 alkoxy,
2,2,2-trihaloethoxy or prop-2-ene-1-oxy and the
other substituent is independently selected from
S fluoro, chloro, Cl 3 alkylamino, Cl 3
dialkylamino, N-pyrrolidino or N-piperidino;
(e) disubstituted phenyl wherein one
substituent is selected from C2 3alkoxy, nitro,
halo, N-(Cl 3alkanamido), di~Cl_3alkyl)amino,
or Cl 3 alkylamino and the other is selected
from alkenylthio, phenylthio, alko~yalkylthio
[BOCH2S-], alkylthioalkylthio tBSCH2S-],
wherein the CH2 is optionally substituted with
Cl 4alkyl, and B is Cl galkyl or phenyl; or
lS (f) pyridyl or alkyl substituted pyridyl.
This inventibn also relates to intermediate
compounds used in the preparation of a compound of Formula
(I) having the followinq structural Formula (L):
~ R9
: 25 ~ a6
EoRMU~A
wherein:
n i8 0 or 1,
R , R3, R4, R5, R6 R7 R8 R~
are all H, or one or two of R2, R3, R4,
RS R6 R7 R8 and R9 are
independently selected from H or Cl 2 alkyl;
one of yl or y2 is independently selected
35. from 4-tl,2-dihydro-2-(C1 4-alkyl]pyridyl
substituted with N-(Cl 8 alkanoyl~, N-(Cl 8
2~
1 alkoxycarbonyl), N-(benzoyl), N-(phenoxy-
carbonyl), N-(phenylacetyl), or N-(benzyloxy-
carbonyl);
and the other is selected from
(a) monosubstituted phenyl wherein said
substituent is selected from H, halo, Cl 3
alkoxy, Cl 3 alkylthio, alkenylthio,
phenylthio, alkoxyalkylthio ~BOCH2S-],
alkoxyalkylsulfinyl tBOCH2S(O)],
alkylthioalkylthio ~BSCH2S-], wherein the
C~2 is optionally substituted with Cl 4alkyl,
and B is Cl galkyl or phenyl, Cl 4 alkyl,
N-(Cl_3 alkyl)-N-(Cl_3 alkanamido), Cl 3
dialkylamino, CF3, N-pyrrolidino, N-piperidino,
prop-2-ene-1-oxy or 2,2,2-trihaloethoxy;
(b? disubstituted phenyl wherein said
substitutents are the same and are selected from
halo~ Cl_3 alkoxy, Cl 3 dialkylamino,
Cl 3alkylthio, N-pyrrolidino, N-piperidino,
. 2,2,2-trihaloethoxy, prop-2-ene-1-oxy,
alkenylthio, phenylthio, alkoxyalkylthio
[BOCH2S-], alkylthioalkylthio [BSCH2S-],
wherein the CH2 is optionally substituted with
Ci 4alkyl, and B is Cl 9alkyl or phenyl, or
: 25 the disubstituents together form a methylene
dioxy group;
(c) disubstituted phenyl wherein said
substituents are not the same and are
independently selected from halo, N-tCl 3
alkyl)-N-(Cl_3 alkanamido),
Cl 3 dialkylamino, N-pyrrolidino, or
N-piperidino; or
(d) disubsti.uted ~henyl wherein one of
said substituents must be Cl 3 alkoxy,
Cl 3 alkylthio, 2,2,2-trihaloethoxy or
prop-2-ene-1-oxy and the other substituent is
independently selected from halo, Cl 3
2~
_ 12 -
1 alkylamino, N-(Cl 3 alkyl)-N-~Cl 3
alkanamido), Cl 3dialkylamino, N-pyrrolidino,
or N-piperidino;
(e) disubstituted phenyl wherein one substituent
is selected from C2 3alkoxy, nitro, halo,
N-~Cl 3alkanamido), di(Cl 3alkyl)amino, or
Cl 3 alkylamino and the other is selected from
alkenylthio, phenylthio, alkoxyalkylthio
tBOCH2S-], alkylthioalkylthio [~SCH2S-~,
wherein the CH2 is optionally substituted with
Cl 4alkyl, and B is Cl galkyl or phenyl;
or a salt thereof.
~ETAILED DESCRIPTION OF THE INVENTION
This invention relates to compounds of Formula
(I) as described above, pharmaceutical compositions
comprising a pharmaceutically acceptable carrier or
diluent and a compound of Formula (I), methods of treating
5-lipoxygenase pathway mediated diseases comprising
20administration of a compound of Formula (I) or a
pharmaceutical composition containing a compound of
Formula ~I). This invention also relates to compounds of
Formula (J) and (L) as described above.
All of the compounds of Formula (I) are useful in
25 inhibiting the 5-lipoxygenase pathway of arachidonic acid
metabolism in an animal in need thereof.
The compounds of Formula (I) can be prepared
according to the following synthetic route:
z~
~9 ) ca~'9
F08~ ~) . FOEI~ t8 )
N ~ ~ X ~ R3
F~
$~ ~c~ FORM~SI.A (EI)
FO~MIJLA ( E )
FO~A ~ F ~ ~ ~R
Br FORMU~A ( ~)
o~ 6 / y2
~ 9
FO~M~) FORMULA (L )
2~J~b~ ~ S ~
1 All the compounds of Formula (E), Formula (F),
Formula (G), Formula (~), Formula (J) and Formula ~L) are
useful as intermediates in the preparation of compounds of
Formula (I). All of the necessary compounds of Formula
5 (A), Formula (B), Formula (C) and Formula (D) can be
obtained from commercial sources or are preparable by
conventional techniques such as those set out herein.
The compounds of Formula (E) have the following
structure
~1~
J
FORMULA (E)
wherein
n is 0 or 1;
R2 R3 R4 R5, R6, R7, R8
and R9 are H, or one or two of R2, R3, R4, R5,
R6 R7 R8 and R9 are
independently selected from H or Cl 2 alkyl;
X is selected from:
(a) pyridyl;
(b) monosubstit~ted phenyl, wherein said
substituent is seleated from halo, Cl 3 alkoxy,
amino, hydroxy, Cl 3 alkylthio, alkenylthio,
phenylthio, alkoxyalkylthio ~BOCH2S-],
alkoxyalkylsulfinyl ~BOCH2S(O)],
alkylthioalkylthio [BSCH2S-], wherein the
CH2 is optionally subs~ tuted with Cl 4alkyl,
and B is Cl galkyl or phenyl, Cl 4 alkyl,
Cl 3 alkylamino, Cl 3 dialkylamino, CF3,
N-(Cl 3 alkanamido), N-(Cl 3 alkyl)-~-(Cl 3
Z~ Z~
1 alkanamido), N-pyrrolidino, N-piperidino,
prop-2-ene-1-oxy or 2,2,2-trihaloethoxy;
(c) disubstituted phenyl wherein said
substituents are the same and are selected from
halo, Cl_3 alkoxy, Cl_3 alkylthio,
alkenylthio, phenylthio, alkoxyalkylthio
tBOCH2S-], alkylthioalkylthio tBSCH2S-],
wherein the CH2 is optionally substituted with
Cl 4alkyl, and B is Cl galkyl or phenyl,
Cl 3 alkylamino, Cl 3 dialkylamino, amino,
N-pyrrolidino, N-piperidino, 2,2,2-trihaloethoxy,
prop-2-ene-l-osy, hydroxy, or the disu~stituents
together form a methylene diosy group;
(d) disubstituted phenyl wherein said
substituents are not the same and are
independently selected from halo, Cl 3
alkylamino, nitro, N-(Cl 3 alkanamido),
N-(Cl_3 alkyl)-N-(Cl 3 alkanamido), Cl 3
dialkylamino, amino, N-pyrrolidino, or
N-piperidino; or
(e) disubstituted phenyl wherein one of said
substituents must be Cl 3 alkoxy, hydroxy,
Cl 3 alkylthio, 2,2,2-trihaloetho~y or
prop-2-ene-1-osy and the other substituent is
independently selected from halo, Cl 3
alkylamino, nitro, N-(Cl 3 alkyl)-N-~Cl 3
alkanamido), Cl 3 dialkylamino, amino,
N-pyrrolidino, or N-piperidino;
(f) disubstituted phenyl wherein one
substituent is selected from C2 3alkoxy, nitro,
halo, N-(Cl 3alkanamido), di(Cl 3alkyl)amino,
or Cl 3 alkylamino and the other is selected
from alkenylthio, phenylthio, alkoxyalkylthio
tBOCH2S-], alkylthioalkylthio tBSCH2S-],
wherein the CH2 is optionally substituted with
Cl 4alkyl, and B is Cl galkyl or phenyl;
2~,5 ~r5~
- 16 -
1 provided that when n is 1, and R2, R3,
R4, R5, R6, R7, R8 and R9 are H, X is other
than 2,4-dimethoxyphenyl or 4-aminophenyl;
or a salt thereof.
A further intermediate compound used in the
preparation of a compound of Formula (I) is a compound of
the formula:
~2
S~ a3
~ '`p,9
~7
~ 6
FORMULA (F)
wherein:
n is 0 or 1,
R , R3, R4, R5, R6 R7 R8 R9
are all H, or one or two of R2, R3, R4,
RS R6 R7 R8 and R9 are
independently selected from H or Cl 2 alkyl;
x2 is 4-(1,4-dihydro)pyridyl substituted
with N-(Cl 8 alkanoyl), N-(Cl_8 y
carbonyl), N-(benzoyl), N-(phenoxycarbonyl),
N-(phenylacetyl), or N-(benzyloxycarbonyl);
xl is selected from
(a) monosubstituted phenyl wherein said
substituent is selected from H, halo, Cl 3
alkoxy, hydroxy, Cl_3 alkylthio, alkenylthio,
phenylthio, alkoxyalkylthio [BOCH2S-],
alkoxyalkylsulfinyl ~BOCH2S(O)],
alkylthioalkylthio [BSCH2S-], wherein the
CH2 is optionally substituted with Cl 4alkyl,
3s and B is ~1 galkyl or phenyl, Cl 4 alkyl,
N-(Cl 3 alkyl)-N-(Cl 3 alkanamido), Cl 3
2~
- 17 -
1 dialkylamino, CF3, N-pyrrolidino, N-piperidino,
prop-2-ene-1-oxy or 2,2,2-trihaloethoxy;
(b) disubstituted phenyl wherein said
substitutents are the same and are selected from
halo~ Cl_3 alkoxy~ Cl_3 dialkylamino~ Cl 3
alkylthio, alkenylthio, phenylthio,
alko~yalkylthio [BOCH2S-], alkoxyalkylsulfinyl
[BOCH2S(O)], alkylthioalkylthio tBSCH2S-],
wherein the CH2 is optionally substituted with
Cl 4alkyl, and B is Cl galkyl or phenyl,
N-pyrrolidino, N-piperidino, 2,2,2-trihaloethoxy,
or prop-2-ene-1-oxy, or the disubstituents
together form a methylene dioxy group;
(c) disubstituted phenyl wherein said
substituents are not the same and are
independently selected from halo, nitro, hydroxy,
N-(Cl_3 alkyl)-N-(Cl 3 alkanamido),
Cl 3 dialkylamino, N-pyrrolidino, or
N-piperidino; or
(d) disubstituted phenyl wherein one of
said substituents must be Cl 3 alko~y, hydrosy,
Cl 3 alkylthio, 2,2,2-trihaloethoxy or
prop-2-ene-1-osy and the other substituent is
: independently selected from halo, Cl 3
alkylamino, nitro, N-(Ci 3 alkyl)-N-(Cl 3
alkanamido), Cl 3dialkylamino, amino,
N-pyrrolidino, or N-piperidino;
(e) disubstituted phenyl wherein one
substituent is selected from C2 3alko~y, nitro,
halo, N-(Cl 3alkanamido), di(Cl 3alkyl)amino,
or Cl 3 alkylamino and the other is selected
from alkenylthio, phenylthio, alkoxyalkylthio
IBOCH2S-], alkylthioalkylthio tBscH2s-]~
wherein the CH2 is optionally substituted with
Cl 4alkyl, and B is Cl galkyl or phenyl;
or a salt thereof.
2.5~
- 18 -
1 A further intermediate compound used in the
preparation of a compound of Formula (I) is a compound of
the formula:
S SL ~ 8
~" a~
FORMULA ~G)
wherein:
n is 0 or 1,
R2 R3 R4, R5, R6, R7, R8
and R9 are all H, or one or two of R2, R3,
R , R5, R6, R7, R8 and-R9 are
independently selected from H or Cl 2 alkyl; and
xl is selected from
(a) monosubstituted phenyl wherein said
substituent is selected from H, fluoro, chloro,
Cl 3 alkoxy, C~_4 alkyl, Cl_3 dialkyl-
amino, CF3, Cl 3 alkylamino,
N-pyrrolidino, N-piperidino, prop-2-ene-1-oxy
or 2,2,2-tri-haloethoxy, Cl 3 alkylthio,
alkenylthio, phenylthio, alkoxyalkylthio
tBOCH2S-], alkoxyalkylsulfinyl
tBOCH2S(O)], alkylthioalkylthio
tBSCH2S-], wherein the CH2 is optionally
substituted with Cl_4alkyl, and B is
Cl galkyl or phenyl;
(b) disubstituted phenyl wherein said
substituents are the same and are selected
from fluoro, chloro, Cl 3 alkoxy, Cl 3
dialkylamino, N-pyrrolidino, N-piperidino,
- 2,2,2-trihaloethoxy, prop-2-ene-1-oxy, Cl 3
alkylthio, alkenylthio, phenylthio,
2')~
-- 19 --
1 alkoxyalkylthio tBOCH~S-~,
alkoxyalXylsulfinyl tBOCH2S(O)],
alkylthioalkylthio tBSCH2S-~, wherein the
CH2 is optionally substituted with
Cl 4alkyl, and B is Cl galkyl or phenyl,
or the disubstituents together form a
methylene dioxy group;
(c) disubstituted phenyl wherein said
substituents are not the same and are
independently selected from fluoro, chloro,
Cl 3 alkylamino, Cl 3 dialkylamino,
N-pyrrolidino, or N-piperidino; or
(d) disubstituted phenyl wherein one of
said substituents must be Cl 3 alkoxy,
2,2,2-trihaloethoxy or prop-2-ene-1-oxy and
the other substituent is independently
selected from fluoro, chloro, Cl 3 alkyl-
amino, Cl 3 dialkylamino, ~-pyrrolidino, or
N-piperidino; or
(e) disubstituted phe~yl wherein one
substituent is selected from C2 3alkoxy,
nitro, halo, N-(Cl 3alkanamido),
di(Cl 3alkyl)amino, or Cl 3dialkylamino
and the other is selected from alkenylthio,
phenylthio, alkoxyalkylthio tBocH2s-]~
alkylthioalkylthio tBSCH2S-], wherein the
CH2 is optionally substituted with
Cl 4alkyl, and B is Cl_galkyl or phenyl;
or a salt thereof.
A fu~ther intermediate compound used in the
preparation of a compound of Formula (I) is a compound of
the formula:
~ ~ ~
o ~N~ (C~ g
~6 , .
,
FORMULA (H)
2i~ .5t~
- 20 -
1 wherein:
n is 0 or l;
R2 R3 R4 R5, R6, R7, R8,
and R9 are H, or one or two of R2, R3,
R4 R5 R6 R7, R8 and R9 are
independently selected from H or Cl 2 alkyl;
X is selected from:
(a) pyridyl;
(b) monosubstituted phenyl, wherein said
substituent is selected from H, halo, Cl 3
alkoxy, Cl 3 alkylthio, alkenylthio,
phenylthio, alkoxyalkylthio ~BOCH2S-],
alkoxyalkylsulfinyl [BOCH2S(O)],
alkylthioalkylthio ~BSCH2S-], wherein the
lS CH2 is optionally substituted with
Cl 4alkyl, and B is Cl galkyl or phenyl,
Cl 4 alkyl, N-(Cl 3 alkanamido), Cl_3
dialkylamino, CF3, N-pyrrolidino, or
.N-piperidino;
(c) disubstituted phenyl wherein said
substituents are the same and are select.ed
from halo, Ci_3 alkoxy, Cl_3 alkylthio~
alkenylthio, phenylthio, alkoxyalkylthio
tBoCH2S-], alkoxyalkylsulfinyl
[BOCH2S(O)], alkylthioalkylthio
[BSCH2S-], wherein the CH2 is optionally
substituted with Cl 4alkyl, and B is
Cl galkyl or phenyl, N-(Cl_3 alkanamido),
Cl_3 dialkylamino, N-pyrrolidino, or
N-p.iperidino, or the disubstituents together
form a methylene-dioxy group:
(d) disubstituted phenyl wherein said
substituents are not the same and are
independently selected from halo, nitro,
N-(Cl_3 alkanamido), Cl_3 alkoxy, Cl_3
dialkylamino, N-pyrrolidino, or N-piperidino;
or
Z~ 5~
- 21 -
1 (e) disubstituted phenyl wherein one of
said substituents must be Cl 3 alkoxy,
Cl 3alkylthio, hydroxy, 2,2,2-trihaloethoxy
or prop-2-ene-1-oxy and the other substituent
is independently selected from halo, nitro,
N-(Cl_3 alkyl)-N-(Cl_3 alkanamido), Cl 3
dialkylamino, N-pyrrolidino or N-piperidino;or
(f) disubstituted phenyl wherein one
substituent is selected from C2 3alkoxy,
nitro, halo, N-(Cl 3alkanamido),
di(Cl 3alkyl)amino, or Cl 3 alkylamino and
the other is selected from alkenylthio,
phenylthio, alkoxyalkylthio tBOCH2S-],
alkylthioalkylthio tBSCH2S-], wherein the
CH2 is optionally substituted with
Cl 4alkyl, and B is Cl galkyl or phenyl;
or a salt thereof.
. Compounds of Formula (B), wherein n, R2, R3,
20 R4, R5, R6, R7, R8 and R9 are as defi~ed
above, can be prepared by 0-alkylation of the
corresponding 2-piperidone or 2-pyrrolidone of Formula
(A), wherein n, R2, R3 R4 R5 R6 R7 8
and R9 are as defined above, with an alkylating agent,
25 such as dimethylsulfate, according to the method of Wick
et al., Helv. Chim Acta, 54, 513 (1971). The necessary
compounds of Formula (A) are commercially available or are
prepared by known techniques. Compounds of Formula (C)
wherein n, R2, R3, R4 R5 R6 R7 R8
30 R9 are as defined above, can be prepared by treatment of
the corresponding compound of Formula (B) with ammonia or
an ammonium salt, such as ammonium chloride, in absolute
ethanol according to the method of Etienne et al., Compt.
~n~ 2, 2660 (1964). Compounds of Formula (C) wherein
35 n is 0 or 1 and R2; R3, R4 R5 R6 R7 R8
and R are H are preferably prepared as described by the
2~-5
- 22 -
1 method of Moriconia and Cevasco, J. Orq. Chem., 33, 2109
(1968) as their hydrohalide salts and liberated to the
bases with concentrated aqueous NaOH or preferably with
one molar equivalent of sodium methoxide in an alcoholic
5 solvent. Compounds of Formula (D), wherein ~ is Br and
X is as defined above, are commercially available or are
prepared by treatment of the correspondingly substituted
acetophenone in CH2C12, CHC13, acetic acid or 48%
hydrobromic acid with one equivalent of bromine [See,
Langley~ Or~. SYn. Coll., 1, 127 (1944); Cowper et al.,
Orq. SYn. Coll., 2, 480 (1943); and Lorenzin, et al., J.
Orq. Chem., 32, 4008 (1967)], or alternatively, by
reaction in chloroform-ethyl acetate with a suspension of
copper (II) bromide by the method of King and Ostrum, J.
5orq~ Chem., 29, 3459 (1964).
The necessary acetophenones are commercially
available or preparable by known techniques.
Alternatively the Formula (D) compounds, wherein X3 is
chloro and X is (a) 4-monosubstituted phenyl where the
20 substituent is selected from H, halo, C1 4 alkyl,
Cl 3 alkoxy, or (b) 3,4-disubstituted phenyl wherein the
substituents are the same and are selected from C1 3
alkoxy, or methylenedioxy, or where the substituents are
independently selected from halo or Cl 3 alkoxy, can be
25 prepared by acylating the corresponding mono- or
disubstituted benzene by Friedel Crafts reaction with
2-chloroacetyl-chloride and AlC13, by the method of
Joshi et al., J. HeterocYclic Chem., 16, 1141 (1979).
Compounds of Formula (E) serve as intermediates
30 in the preparation of the compounds of Formula (I).
Preferably, compounds of Formula (E) are prepared from
their corresponding compound of Formula (H). Com-
pounds of Formula tH) ser-!e as intermediates in the
preparation of compounds of Formula (E). Compounds of
35 Formula (H)~are prepared by treatment of a solution of a
substituted Formula (D) compound, such as a 2-haloaceto-
phenone, or a 2-bromoacetyl-2, 3 or 4-pyridine, which are
2;,~
- 23 -
1 described by Taurins et al., J. HeterocYclic Chem., 7,
1137 (1970), in a neutral, preferably nonpolar solvent
with one molar equivalent of the corresponding Formula (C)
compound, maintaining the temperature at or below 25C.
5 The resulting Formula (H) hydrohalide salts are converted
to Formula (E) compounds by refluxing in water.
Alternatively, compounds of Formula (E) are prepared by
treatment of a solution of the 2-iminopyrrolidine or
2-iminopiperidine with a substituted 2-bromoacetophenone
lOOf Formula (D), either in a polar organic solvent, such as
DMF or ethanol, or in a nonpolar chlorinated hydrocarbon,
followed by removing all or most of the solvent and
refluxing the residue in aqueous solution. Compounds of
Formula (E) wherein X is a pyridyl optionally substituted
lsby a Cl_4 alkyl group are prepared by treatment of a
mixture of a bromoacetylpyridine and 2-iminopyrrolidine or
their hydrohalide salts in a polar aprotic solvent, such
as dimethylformamide, with 2 to S equivalents of a base,
such as a metal carbonate salt.
Compounds of Formula (I) where R is phenyl or
substituted phenyl, and Rl is 4-pyridyl are preferably
prepared in two steps by a modification of the method of
Lantos et al., European Patent Application No. 203,787
published March 12, 1986. In the first step, the
25 coEresponding compound of Formula (E) is treated,
preferably at 20-25C, with pyridine and an acyl halide,
an aroylhalide, an arylalkyl haloformate ester, or an
alkyl haloformate ester, such as acetyl bromide,
benzoylchloride, benzyl chloroformate, or preferably ethyl
30 chloroformate, in a solvent in which the reactants are
soluble and inert to form the compound of Formula (F).
Alternatively the acyl pyridinium salt can be preformed
and added to the solution of the Formula (E) compound.
Compounds of Formula (F) serve as intermediates in the
35 preparation of the compounds of Formula (I). In the
second step, the Formula ~F) compound, a 1,4-
dihydropyridine product, is deacylated and aromatized with
- Z~10~
- 24 -
1 sulfur in refluxing decalin, tetralin, P-cymene or xylene,
or preferably with potassium tert.-butoxide in
tert.-butanol with 2 gas at reflux for 15 minutes to
the afford the corresponding compound of Formula (I).
Compounds of Formula (I) wherein R or Rl is
alkyl substituted pyridyl can be prepared by a similar
process from compounds of Formula (L). The Formula (L)
compound is deacylated and aromatized with sulfur in
decalin, tetralin, p-cymene or xylene or with potassium
10tert-butoxide in tert.-butanol with oxygen gas at reflux
for 15 minutes to afford the corresponding Formula (I)
compound. The compounds of Formula (I) may now be
optionally reduced, hydrolyzed, oxidized, demethylated, or
acylated to produce other desired Formula (I) compounds
lSproduced by this synthetic route. Compounds of Formula
(L) are prepared by treatment of the Formula (I) compound
with an acyl halide, aroylhalide, arylalkyl haloformate
ester or an alkyl haloformate ester and a Cl 4 alkyl
Grignard reagent using the process of Comins, D.L., and
20Abdullah, A.H., J. Orq. Chem., ~ol. 47, p. 4315 (1982).
The same Formula (E) compounds used to prepare-
the 4-pyridyl Formula (I) compounds are employed to
prepare the 2-pyridyl and 3-pyridyl Formula (I) compounds.
Treatment of the Formula (E) compounds with bromine by the
25 procedure of Kano, Yakuqaku Zasshi, 92, 51 (1972), results
in 3-bromination to afford the 3-bromo-2-(substituted
phenyl)-6,7-dihydro-(5H)-pyrrolo(1,2-a)imidazoles and
3-bromo-2-(substituted phenyl)-5,6,7,8-tetrahydro-imidazo-
(1,2-a)pyridines compounds of Formula (G). The compounds
30 of Formula (G) serve as intermediates in the preparation
of compounds of Formula (I). Formula (E) or Formula (G)
compounds are treated with n-butyl }ithium (n-BuLi) in
tetrahydrofuran to afford their 3-lithio derivat.~es by
metalla~ion or halogen-metal interchange respectively.
3s Transmetallation of the 3-lithio compounds with Mg8r2 or
ZnC12 to the corresponding magnesium or zinc compounds,
2~
- 25 -
1 according to the method of ~egishi et al., J. Orq. Chem.,
42, 1821, (1977), permits aryl coupling to a 2-, 3- or
4-bromopyridine, 2-, 3- or 4-iodopyridine, or 2-,3-, or 4-
trifluro methyl sulfonyl oxy-pyridine or otherwise called
5 the trifilate esters of 2-,3-, or 4- hydroxy pyridines,in
the presence of PdC12~1,4-bis(diphenylphosphino)-butane)
catalyst, a bidentate Pd (II) catalyst, using the method
of Kumada et al., Tetrahedron Letters, 22, 5319 (1981).
Alternatively the Formula (G) compounds may be coupled to
10the 2 or 3-metalated pyridine employing this bidentate Pd
(II) catalyst, or the corresponding Ni(II) C12
(1,2-bis(diphenylphosphino) ethane catalyst tsee, Pridgen,
J. Orq. Chem., 47, 4319 (1982)]. By either of these
routes, Formula (I) compounds are obtained where Rl is
152-pyridyl or 3-pyridyl. Yet another preparation for
Formula (I) compounds is treating the Formula (G)
compounds with an alkyllithium reagent to afford the
3-lithio derivative as noted above, transmetallate with
magnesium bromide to form the Grignard reagent and add a
20 catalytic amount of a cuprous(I3 halide, such as
cuprous(I) iodide, in the presence of a solution of an
N-acyl pyridinium salt, followed by deacylation and
oxidation. The final compounds produced by these coupling
reaction(s) may then be optionally acylated, oxidized,
25 reduced, demethylated, and hydrolyzed to produced other
desired compoudns of Formula (I) compounds.
The compounds of Formula (I) can also be prepared
from Formula (E) by preparation of the trialkyltin
derivative of Formula (E), designated as Formula (J). The
30 compound of Formula (J) is prepared by treatment of the
3-lithio derivative of Formula (E) with trialkyltin
chloride. The Formula (J) compound is reacted with a
mixture of an aryl or heteroaryl halide, preferably
iodide, or triflate, and tetrakis(triphenylphosphine)-
35 palladium in a mix~ure of THF (tetrahydrofuran~ and HMPA(hexamethylphosphoramide) to yield a compound of Formula
2~
- 26 -
l(I). The compounds of Formula (I) wherein either of R and
Rl are 2-pyridyl, 3-pyridyl or wherein R is 2-pyridyl,
3-pyridyl or 4-pyridyl are preferably made by this route.
The compounds of Formula (I) wherein either or both of R
5 and Rl are alkyl substituted pyridyl are also prepared
by this route. Alternatively, compounds of Formula (I)
may be prepared by the analogous reaction of an aryl or
heteroaryl trialkyltin compound with a mixture of a
Formula (G) compound and tetrakis-(triphenylphosphine)-
lOpalladium under similar conditions. The reactionconditions for Formula (G), and (J) compounds require that
the substituent amino and sulfur substituted compounds,
for example, be in their lowest oxidation state, as well
as protected, i.e. N-(Cl 3 alkyl)-N-(Cl 3alkanamido),
15etc., hence the final products of these reactions are all
optionally subject to additional oxidation/acylation, etc.
procedures.
Regioisomers of Formula (I) compounds where Rl
is substituted phenyl, or 2,3 or 4-pyridyl and R is 2, 3,
20and 4-pyridyl are obtained from compounds of Formula (E)
where X is 2,3, or 4-pyridyl. Compounds of Formula (E)
where X is 2, 3 or 4-pyridyl are prepared by treàtment of
a 2, 3, or 4-bromoacetylpyridine hydrobromide salt of
Formula (D), wherein R is 2, 3 or 4-pyridyl [prepared as
2s described by Taurins et al., J. Het Chem., 7, 1137 (1970)]
with 2-3 equivalents of the 2-iminopyrrolidine or
2-iminopiperidine by the procedure used to prepare the
other compounds of Formula (E) described above. 3-
Bromination, by the procedure of Kano cited above, affords
30 the corresponding Formula (G) compounds. Metallation of
the Formula (E) compounds with n-BuLi or halogen-metal
interchange of the Formula (G) compounds with n-BuLi,
followed by transmetallation with MgBr2 and coupling to
the substituted halobenzene, preferably iodobenzene, or
35 2,3, or 4-halopyridine, preferably where halo is iodo, in
the presence of the bidentate phosphine-palladium or
Z~ Z~
- 27 -
nickel complex as described above affords the desired
regioisomers of Formula (I). Alternatively the metallated
pyridine or substituted benzene may be coupled to the
Formula (G) compounds employing the catalysts as described
5 above.
Alternately the compounds of Formula (I) wherein
R or Rl is a mono or di-substituted phenyl having at
least one fluoro substituent can be converted to the
corresponding Formula (I) compounds having an alkylthio
losubstituted phenyl group or a phenylthio substituted
phenyl group. The fluoro substituted phenyl compound of
Formula (I) is treated with 1.2 equivalents of the sodium
salt of the alkylmercaptan or arylmercaptan in an aprotic
polar solvent, preferably dimethylformamide.
Compounds of Formula (I) where R or Rl is a
mono- or di-substituted phenyl having at least one Cl 3
alkylsulfinyl, Cl 3alkylsulfonyl, acyloxyalkylsulfinyl,
or Cl 3alkenylsulfinyl substituent are prepared by
treatment of one or more equivalents of the corresponding
20 compound of Formula (I) where R or Rl are Cl 3
alkylthiophenyl, Cl 3alkylsulfinylphenyl, acyloxy-
alkylthiophenyl or alkenylthiophenyl with one or more
equivalents of an oxidizing agent (such as
3-chloroperbenzoic acid in an inert solvent or sodi~m
25 periodate in a polar solvent such as aqueous methanol
containing a mineral acid such as hydrochloric acid) per
mercapto function, in an inert solvent. Compounds of
Formula (I) wherein R or Rl are Cl 3 alkylsulfonyl
substituted phenyl are prepared by treatment o~ one
30 equivalent of the corresponding Cl 3 sulfinyl Formula
(I) compound with 2/3 equivalent of KMnO4 per sulfinyl
function in aqueous acid solution by the method of
Chatterway e~ al., ~. Chem. Soc. 1352 (1930~, or
alternatively with one equivalent of a peracid.
Acetophenones substituted with a mono- or di-
substituted phenyl having at least one N-(Cl 3alkanamido)
Zi~ 5f~
- 28 -
lor N-(C1_3 alkyl)-N-(Cl 3 alkanamido), and in some
cases the Formula (E), and Formula (I) compounds, are
prepared by acylation of the corresponding amino and
N-(Cl 3 alkylamino) compounds with the alkanoic acid
5 anhydride or chloride in pyridine. Another alternative
preparation of the N-(Cl 3 alkyl)-N-(Cl 3 alkanamido)
phenyl substituted Formula (E) and Formula (I) compounds is
the alkylation of the corresponding N-(Cl 3 alkan-
amido) substituted compounds with sodium hydride and a
10Cl_3 alkyl bromide or iodide in dimethylformamide.
Formula (E) and Formula (I) compounds containing a
mono- or di-substituted phenyl having at least one amino
substituent are prepared either by hydrolysis of the
corresponding N-(Cl 3 alkanamido) compounds in refluxing
156 N mineral acid or by catalytic reduction of the
correspondlng nitro compounds.
Formula (E), Formula (G), and Formula (I)
compounds containing a mono- or di-substituted phenyl
having at least one N-(Cl 3 alkylamino) substituent are
20preferably prepared by acid cat'alyzed hydrolysis of the
corresponding N-(Cl 3 alkyl)-N-(Cl 3 alkanamido)
compounds of Formula (E), Formula (G) and Formula (I),
respectively, prepared as described above for the
aminophenyl substituted 'compounds, or alternatively, either
25by (a) reduction of the corresponding N-(Cl 3 alkanamido)
compounds with borane or borane dimethylsulfide complex in
THF by the method of Brown, "Organic Synthesis via
Boranes", John Wiley and Sons, (1975), or (b) by cleavage
of the corresponding N,N-(di Cl 3 alkylamino)phenyl
30 substituted Formula (E) and Formula (I) compounds with
cyanogen bromide in the Von Braun reaction ~see, Hageman
Org. Reactions, Vol. 7, 198 (1953)].
Fo mula (E) and Formula (I) compounds containing a
mono- or di- substituted phenyl having at least one N,N-
35 (di Cl 3 alkylamino) substituent are alternativelyprepared either by reduction of the corresponding
Z~ 51~
- 29 -
1 ~-(Cl_3 alkyl)-N-(Cl_3 alkanamido) compounds of Formula
(E) and Formula (I) with borane as described above for the
N-(Cl 3 alkylamino) substituted compounds, or by
displacement of the bromide by a N,N-dialkylamine in the
5 corresponding 4-bromo-3-nitrophenyl Formula (E) and Formula
(I) compounds by heating at 140C with the ~,N-dialkylamine
and potassium carbonate in an inert solvent.
Formula (E) and Formula (I) compounds containing a
mono- or di-substituted phenyl having at least one
loN-pyrrolidino and N-piperidino substituent are
alternatively prepared by cyclodialkylation of the
corresponding aminophenyl compounds with dibromobutane or
dibromopentane and anhydrous potassium carbonate in an
inert solvent such as dimethylformamide.
lS Compounds of Formula (E) where X is mono- or di-
substituted phenyl having at least one 2,2,2-
trihaloethoxy or prop-2-ene-1-oxy substituent are
prepared by alkylation of the appropriate phenols of
Formula (E) with trifluoromethylsulfonic acid
20 2,2,2-trifluoroethyl ester or allyl bromide respectively as
described by Bender et al., J. Med. Chem., 28, 1169 (1985),
for preparation of compounds No. 23 and 33 described
therein. Appropriately substituted mono and dihydroxy
phenyl compounds or disubstitued phenyl compounds wherein
25 one substituent is hydroxy of Formula (E) and Formula (I)
are obtained by treatment of their respective
correspondingly substituted methoxy derivatives with HBr in
acetic acid, or preferably with BBr3 in CH2C12 by the
method described by Bender et al., J. Med. Chem., _ , 1169
30 (1985),for the preparation of compound No. 14 described
therein.
Compounds of Formula (I) where R is Cl 3alkoxy
mono- or di- substituted phenyl a;e pre ared by alkyl.tion
of the appropriately substituted hydroxyphenyl compounds
35 with the corresponding Cl 3 alkylhalide in the presence
of a strong base such as sodium hydride ln an aprotic
organic solvent such as dimethylformamide.
21~ 51~
- 30 -
1 Compounds of Formula (I) wherein R or Rl is
phenyl substituted with an acyloxyalkylthio group wherein
the alkyl is optionally substituted with Cl 4alkyl are
prepared by treating a compound of Formula (I) wherein R
5 is phenyl substituted with at least one alkylsulfinyl group
with an alkanoic acid anhydride. Hydrolysis of the
resulting acyloxyalkylthio compounds yields compounds of
Formula (I) wherein one of Rl or R is phenyl substituted
with a sulfhydryl function. The sulfhydryl substituted
lOcompounds can be treated with an alkanoic acid anhydride
or an alkylthiono acid chloride in pyridine to prepare
compounds of Formula (I) wherein one of Rl or R is phenyl
substituted with one or more acylthio or dithioacyl groups.
Alternatively the sulfhydryl substituted compounds can be
15treated with an amine, or a hindered amine, such as
di~Cl 3alkyl)amine under appropriate conditions to
prepare compounds of Formula (I).
Compounds of Formula (I) wherein one of Rl or R
is phenyl substituted with at least one thiocarbamyl or
20dithiocarbamyl group are prepared by treating the
sulfhydryl-containing compound prepared as above with a
carbamyl halide or thiocarbamyl halide in the presence of a
base such as pyridine to yield the desired compounds. The
two hydrogen atoms on the respective nitrogen atom in the
25caEbamyl halides or thiocarbamyl halide derivatives may be
replaced independently by alkyl, alkenyl, alkynyl, aryl or
heteroaryl derivative, which may in turn be optionally
substituted.
Compounds of Formula (I) wherein Rl or R is
30 phenyl substituted with an alkenylthio group wherein one
carbon atom separates the sulfur from the carbon bearing
the double bond can be prepared by alkylating a compound of
Formula (I) wherei~ one of Rl or R is phenyl substituted
with at least one sulfhydryl group with an appropriately
35 substituted alkenylhalide, such as allylbromide.
Zil;(~(?2~
- 31 -
.
1 Compounds of Formula (I) wherein Rl or R is
phenyl substituted with an alkylcarbonylalkylthio or
carbalkoxyalkylthio group are prepared by treatment of the
corresponding sulfhydryl substituted compounds with an
5 alkylcarbonylalkylhalide, such as bromoacetone, or with a
carbalkoxyalkylhalide, such as ethylbromoacetate.
Compounds of Formula (I) wherein R or Rl is
phenyl substituted with an alkenylthio group wherein the
sulfur is attached to the carbon bearing the double bond
lOare prepared from the corresponding compounds wherein the
phenyl is substituted with a mercapto group. The mercapto
- substituted compound is converted to a metal salt in a
polar solvent with a strong base such as a metal hydride, a
metal alkoxide or lithium diethylamide. The metal
15mercaptide salt is treated with trialkylsilyl-
methylchloride to afford an intermediate compound of
Formula (I) wherein R or Rl is phenyl substituted with at
least one trialkylsilylmethylsulfide group. This
intermediate in an aprotic solvent such as tetrahydrofuran
20 is treated at reduced temperature with a lithiating reagent
such as lithium diethylamide followed by treatment with an
appropriate aliphatic aldehyde or ketonè to prepare the
compounds of Formula (I) wherein R or Rl is phenyl
substituted with one or more alkenylthio groups.
Compounds of Formula (I) wherein R or Rl is
phenyl substituted with an alkoxycarbonylthio are prepared
by reacting a metal mercaptide salt prepared as described
above, with an appropriate alkyl or aryl chloroformate.
The metal mercaptide salt is formed from a compound of
30 Formula (I) wherein one of R or Rl is phenyl substituted
with a sulfhydryl function prepared as previously
described. Compoundc of Formula (I) wherein R or Rl is
phenyl substit.uted with one or more alkoxythionothio groups
are prepared by reacting the metal mercaptide with the
35 appropriate alkyl or aryl halothionoformate.
Zl~ Sf~
- 32 -
1 Compounds of Formula (I) wherein R or Rl is
alkoxyalkylthio are prepared by reacting the metal
mercaptide salt, prepared as described above, with an
approprate halomethyl ether. Oxidation of the resulting
5 alkoxyalkylthio compounds by reacting with a suitable
oxidizing agent such as chloroperbenzoic acid yields the
compounds of Formula (I) wherein R or Rl is phenyl
substituted with an alkoxyalkylsulfinyl.
Compounds of Formula (I) wherein R or Rl is
10phenyl substituted with an alkylthioalkylthio group are
prepared by reacting the analogous sulfhydryl compound,
prepared as described above, with the appropriate carbonyl
component, such as formaldehyde, acetone, or acetaldehyde,
using either mineral or Lewis acid catalysis conditions to
lSyield the symmetrical dithioketal. The intermediate
hydroxylalkylthio derivative reacts with another sulhydryl
containing compound under the acid catalysis conditions to
yield what is essentially a "bis" type compound, differing
only by thç alkyl chain insertion, i.e. [Formula
20~ S-CRRl-S-Formula (I)]. The substitution of the alkyl,
R,or Rl, is determined by the reactive carbonyl
functional group; wherein R or Rl may be Cl g alkyl,
aryl or heteroaryl, all optionally substituted. The
nonsymmetrical thioketals can be prepared by the reaction
250f the metal mercaptan salt, prepared as described above,
with a halomethyl thioether to yield compounds of Formula
(I) wherein one of ~ or Rl is phenyl substituted with one
or more alkylthioalkylthio groups. The metal salt reacts
with an independent and varying alkyl chain length
30 halomethyl~CRRl]thioalkyl~aryl/heteroaryl] compound to
yield the "non-bis" type compounds, tFormula
(I)-S-CRRl-S-R2], wherein R and Rl are as defined
above for the "bis" compounds, and R2 is a Cl g alkyl,
aryl or heteroaryl group which may be optionally
3s substituted.
21~ f ~ r5
-- 33 --
1 Compounds of Formula (I) wherein R or Rl is
phenyl substituted with a substituted disulfide group, a
"bis" type structure, are prepared by mild air oxidation of
the compounds of Formula (I) wherein R or Rl is phenyl
5 substituted with a sulfhydryl group, prepared as described
above, i.e. ~Formula (I)-S-S-Formula (I)]. The
nonsymmetrical disulfide compound, wherein only one
component is a compound of Formula (I), and the other half
of the disulfide link is an alkyl, aryl or heteroaryl
derivative, may be prepared by reaction o~ a sulfhydryl
compound of Formula (I), with the appropriate sulfenyl
halide, in an ethereal solvent to afford compounds of
Formula (I) wherein one of R or Rl is phenyl substituted
with one or more ~alky}]- dithio groups, i.e. ~Formula
15 (I)-S-S-R2], wherein R-R2 are as defined in the above
paragraph. The contemplated sulfenyl halide derivatives of
alkyl, aryl, or heteroaryl groups may be optionally
susbtituted.
The disulfide compound(s) may also be prepared
20 from the corresponding alkyl sulfoxide compounds, such as
methylsulfinyl, propylsulfinyl, iso-propylsulfinyl, wherein
the alkyl can be a straight chain or branched derivative
having from 1 to 9 carbon atoms, in a solvent, preferably a
chlorinated one such as chloroethylene, methylene chloride
25 or.chloroform, to which is added a carboxcylic acid
anhydride, such as trifluroacetic anhydride, or acetic
anhydride. The Pummerer rearrangement reaction may require
some heating prior to addition of an alkali metal
hydroxide, such as sodium hydroxide. I~ acetic anhydride
30 is used than heating is also likely to be needed during the
hydroxide treatment, before addition of iodine solid
(I2), which then affords the symmetrical disulf~de
compound as is noted above Mixtures of the sulfoxide
compounds may be present in the solution to yield
"symmetrical" compounds but with varying substituent groups
on the pyrrolo/ pyridyl-imidizole ring system.
2`il(~(~2~5~
- 34 -
1 Pharmaceutically acceptable salts and their
. preparation are well known to.those skilled in pharmaceu-
ticals. Pharmaceutically acceptable salts of the compounds
of Formula (I) which are useful in the present invention
5 include, but are not limited to, maleate, fumarate,
lactate, oxalate, methanesulfonate, ethane-sulfonate,
benzenesulfonate, tartrate, citrate, hydrochloride,
hydrobromide, sulfate and phosphate salts. Preferred
pharmaceutically acceptable salts of the compounds of
Formula (I) include hydrochloride and hydro-
bromide salts, and such salts can be prepared by known
techniques such as the method of Bender et al., U.S. Patent
4,175,127, the disclosure of which is hereby incorporated
by reference.
lS It has now been discovered that the compounds of
Formula (I) are useful for treating disease states
mediated by the 5-lipoxygenase pathway of arachidonic acid
metabolism in an animal, including mammals, in need
thereof. The discovery that the compounds of Formula (I)
20are inhibitors of the 5-lipoxygenase pathway is based on
the effects of the compounds of Formula (I) on tissue
inflammation in vivo and on the production of
5-lipoxygenase products by inflammatory cells in vitro in
assays,some of which are described hereinafter. In
25 summary, such assays reveal that the compounds of Formula
(I) display anti-inflammatory activity in arachidonic
acid-induced inflammation in the mouse ear mode.l. The
cyclooxygenase inhibitor, indomethacin, did not reduce
inflammation in these assays. The 5-lipoxygenase pathway
30 inhibitory action of the compounds of Formula t$) was
confirmed by showing that they impaired the production of
5-lipoxygenase products such as leukotriene B4 (di-HETE)
and 5-HETE production by RBL-l cells.
The pathophysiological role of arachidonic acid
35 metabolites has been the focus of recent intensive studies.
In addition to the well-described phlogistic activity
Z~5~
- 35 -
1 (i.e. general inflammatory activity) of prostaglandins,
the more recent description of similar activity for
eicosanoids has broadened the interest in these products
as mediators of inflammation [See, O'Flaherty, Lab.
5 Invest., 47, 314-329 (1982)]. The reported discovery of
potent chemotactic and algesic activity for LTB4 [see,
Smith, Gen. Pharmacol., 12, 211-216 (1981) and Levine et
al., Science, 22s, 743-745 (1984)], together with known
LTC4 and LTD4-mediated increase in capillary
lopermeability ~see, Simmons et al., Biochem. Pharmacol.,
32, 1353-1359 (1983), Veno et al., Prostaqlandins, 21,
637-647 (1981), and Camp et al., Br. J. Pharmacol., 80,
497-502 (1983)], has led to their consideration as targets
for pharmacological intervention in both the fluid and
15 cellular phases of inflammatory diseases.
The pharmacology of several inflammatory model
systems has attested to the effectiveness of cortico-
steroids in reducing the cellular infiltration. These
results, and the observation that corticosteroids inhibit
20 the generation of both cyclooxygenase and lipoxygenase
products, suggest that such dual inhibitors may effectively
reduce both the fluid and cellular phases of the inflam-
matory response since selective cyclooxygenase inhibitors
do not reliably inhibit cell influx into inflammatory
25 sites tSee, Vinegar et al., Fed. Proc., 35, 2447-2456
(1976), Higgs et al., Brit. Bull., 39, 265-270 (1983), and
Higgs et al., Prostaqlandins, Leukotrienes and Medicine,
13, 89-92 (l984)l~ The observations outlined above
cogently argue that a dual inhibitor of arachidonic acid
30 metabolism would be a more effective antiinflammatory
agent than an inhibitor of cyclooxygenase only. Under
optimal conditions, it is likely that an agent with
preferentia~ lipoxygenase inhibitory activity would not
share the ulcerogenic liability of cyclooxygenase
35 inhibitors or the toxicity of corticosteroids. This may
suggest that the compounds of the present invention could
21~ Z~R
- 36 -
1 be useful in treating diseases where it is beneficial to
limit ulcerogenic activity or steroidal side effects such
as osteoarthritis. [See Palmoski et al., "Benoxaprofen
Stimulates Proteoglycan Synthesis in Normal Canine Knee
5 Cartiledge in Vitro," Arthritis and Rheumatism 26, 771-774
(1983) and Rainsford, K.D., Aqents and Actions 21, 316-319
(1987).]
Recent clinical data also support the enthusiasm
for inhibitors of the S-lipoxygenase pathway in a variety
lOof inflammatory diseases in which granulocyte and/or
monocyte infiltration is prominent. The reported
demonstration of elevated levels of LTB4 in rheumatoid
arthritic joint fluid ~See, Davidson et al., Ann. Rheum.
Dis., 42, 677-679 (1983)] also suggests a contributing
15role for arachidonic acid metabolites in rheumatoid
arthritis. The recently reported preliminary observation
of efficacy, including remission, reported with
sulfasalazine treatment of rheumatoid arthritic patients
tSee Neumann et al., Brit. Med. J., 287, 1099-1102 (1983)]
20illustrates the utility of inhibitors of the 5-lipoxy-
genase pathway in rheumatoid arthritis.
Sulfasalazine, which is used for treatment of
ulcerative colitis, has been reported to inhibit L~B4
and 5-~ETE production in vitro [See, Stenson et al., J.
25 Clin. Invest., 69, 494-497 (1982)]. This observation,
coupled with the fact that it has been reported that
inflamed gastrointestinal mucosa from inflammatory bowel
disease patients showed increased production of LTB4
[See, Sharon et al., Gastroenterol., 84, 1306 (1983)],
30 suggests that sulfasalazine can be effective by virtue of
inhibition of production of chemotactic eicosanoids (such
as the 5-lipoxygenase pathway product known as LTB4).
The observations serve to underscore utility of inhibitors
of the 5-lipoxygenase pathway in inflammatorY bowel
35 disease.
2';, ~ S?~
- 37 -
1Another area of utility for an inhibitor of the
5-lipoxygenase pathway is in the treatment of psoriasis.
It was demonstrated that involved psoriatic skin had
elevated levels of LTB4 ~See, Brain et al., Lancet, 19,
5 February 19, 1983]. The promising effect of benoxaprofen
on psoriasis [See, Allen et al., Brit. J. Dermatol., los,
126-129 (1983)], a compound with in vitro lipoxygenase
inhibitory activity on psoriasis, lends support to the
concept that inhibitors of the 5-lipoxygenase pathway can
be useful in the treatment of psoriasis.
Lipoxygenase products have been identified in
exudate fluids from gouty patients. This disorder is
characterized by massive neutrophil infiltration during
the acute inflammatory phases of the disease. Since a
major 5-lipoxygenase product, LTB4, is produced by
neutrophils, it follows that inhibition of the synthesis
of LTB4 can block an amplification mechanism in gout.
Another area in which inhibitors of the 5-lipoxy-
genase product can have utility is in mYocardial
20 infarction. Studies in dogs with the dual inhibitor,
BW755-C, demonstrated that the area of infarction following
coronary occlusion was reduced, and such reduction was
attributed to inhibition of leukocyte infiltration into
the ischaemic tissue tSee, Mullane et al., J. Pharmacol.
25 Exp. TheraP., 228, 510-S22 (1984)].
Yet another area of utility for inhibitors of the
5-lipoxygenase pathway is in the area of prevention of
reiection of orqan transPlants~ ~See, e.g., Foegh et al.,
Adv. Prostaqlandin, Thromboxane, and Leukotriene ~esearch,
30 13, 209-217 (1983).~
Yet another utility for inhibitors of the
5-lipoxygenase.pathway is in the treatment of tissue
trauma. ~See, e.g., Denzlinger et ~1. Science, 2~0 (4723~,
330-332 (1985)].
35Purthermore, another area of utility for inhib-
itors of the 5-lipoxygenase pathway is in t.he treatment of
211~C~Z5~
- 38 -
inflammatorY reaction in the central nervous sYstem,
including multiple sclerosis. [See, e.g., Mackay et al.,
Clin. Exp. Immunoloqy, 15, 471-482 (1973)].
Additionally, another area of utility for
inhibitors of the 5-lipoxygenase pathway is in the
treatment of asthma. [See, e.g., Ford-Hutchinson, J.
AllerqY Clin. Immunol., 74, 437-440 (1984)].
Another area of utility for inhibitors of the
5-lipoxygenase pathway is in the treatment of vasculitis,
glomerulonephritis, and immune complex disease. [See
Kadison et al., "Vasculitis: Mechanism of Vessel Damage"
in Inflammation: Basic Principles and Clinical
Correlates, 703-718, Ed. Gallin et al., Raven Press, N.~.,
N.Y. (1988).]
Another area of utility for inhibitors of the
5-lipoxygenase pathway is in the treatment of dermatitis.
tSee Pye et al., "Systemic Therapy" in Textbook of
DermatoloqY, Vol. III, 2501-2528, Ed. Rook et al.,
Blackwell Scientific Publications, Oxford, England (1986).]
Another area of utility for inhibitors of the
5-lipoxygenase pathway is in the treatment of
atherosclerosis. Recent studies have shown that
inhibition of oxidative modification of low density
lipoprotein slows progression of atherosclerosis, and that
inhibitors of lipoxygenase effectively inhibit
cell-induced oxidative modification. ~See Carew et al.,
Proc Natl. Acad Sci. USA, 84, 7725-7729, November 1987;
-
and Steinberg, D., Cholesterol and Cardiovascular Disease,76, 3, 508-514(1987).l An additional area of utility for inhibitors of
the 5-lipoxygenase pathway is in the optical area, in
particular general inflammation of the corneal anterior
and posterior segments due to disease or surgery such as
in post surgical inflammation, uveitis, and allergic
conjuntivitis. [See Rao N. et al. Arch. Ophathmal. 105
(3) 413-419 (1987); Chiou, L. and Chiou, G. J. Ocular
X'll~C~X~
_ 39 _
1 Pharmacol. I, 383-390 (1985): Bazan H., J. Ocular Pharma.
4, 43-49 (19~8); and Verbey N.L. et al., Current EYe
Research 7, 361-368 (1988).]
The pharmaceutically effective compounds of this
5 invention are administered in conventional dosage forms
prepared by combining a compound of Formula (I) ("active
ingredient") in an amount sufficient to produce 5-lipoxy-
genase pathway inhibiting activity with standard pharma-
ceutical carriers according to conventional procedures.
These procedures may involve mixing, granulating and
compressing or dissolving the ingredients as appropriate
to the desired preparation.
The pharmaceutical carrier employed may be, for
example, either a solid or liquid. Exemplary of solid
15carriers are lactose, terra alba, sucrose, talc, gelatin,
agar, pectin, acacia, magnesium stearate, stearic acid and
the like. Exemplary of liquid carriers are syrup, peanut
oil, olive oil, water and the like. Similarly, the carrier
or diluent may include time delay material well known to
20 the art, such as glyceryl monostearate or glyceryl
distearate alone or with a wax.
A wide variety of pharmaceutical forms can be
employed. Thus, if a solid carrier is used, the
preparation can be tableted, placed in a hard gelatin
25 ca~sule in powder or pellet form or in the form of a
troche or lozenge. The amount of solid carrier will vary
widely but preferably will be from about 25 mg. to about
1 g. When a liquid carrier is used, the preparation will
be in the form of a syrup, emulsion, soft gelatin capsule,
30 sterile injectable liquid such as an ampule or nonaqueous
liquid suspension.
To obtain a stable water soluble dose form, a
pharmaceutically acceptable salt of a compound of Formu_a
(I) is dissolve~ in an aqueous solution of an organic or
35 inorganic acid, such as a 0.3 M solution of succinic acid
or, preferably, citric acid.
2`~
- 40 -
1 Preferably, each parenteral dosage unit will
contain the active ingredient ~i.e., the compound of
Formula (I)] in an amount of from about 50 mg. to about
500 mg. Preferably, each oral dosage will contain the
active ingredient in an amount of from about 100 mg to
about 1000 mg.
The compounds of Formula (I) may also be admin-
istered topically to a mammal in need of the inhibition of
the 5-lipoxygenase pathway of arachidonic acid metabolism.
10 Thus, the compounds of Formula (I) may be administered
topically in the treatment or prophylaxis of inflammation
in an animal, including man and other mamm~ls, and may be
used in the relief or prophylaxis of 5-lipoxygenase pathway
mediated diseases such as rheumatoid arthritis, rheumatoid
15 spondylitis, osteoarthritis, gouty arthritis and other
arthritic conditions, inflamed joints, eczema, psoriasis
or other inflammatory skin conditions such as sunburn;
inflammatory eye conditions including conjunctivitis;
pyresis, pain and other conditions associated with
20 inflammation.
The amount of a compound of Formula (I) (herein-
after referred to as the active ingredient) required for
therapeutic effect on topical administration will, of
course, vary with the compound chosen, the nature and
25 sqverity of the inflammatory condition and the animal
undergoing treatment, and is ultimately at the discretion
of the physician. A suitable anti-inflammatory dose of an
active ingredient is 1.5 ~g to 500 mg of base for topical
administration, the most preferred dosage being 1 ~g to
1000 ~g, for example 5 to 25 ~g administered two or
three times daily.
By topical administration is meant non-systemic
administration and includes the -pplication of a compound
of Formula (I) externally to the epidermis, to the buccal
cavity and instil~ation of such a compound into the ear,
eye and nose, and where the compound does not significantly
Z~f~
- 41 -
l enter the blood stream. By systemic administration is
meant oral, intravenous, intraperitoneal and intramuscular
administration.
While it is possible for an active ingredient to
5 be administered alone as the raw chemical, it is prefera-
ble to present it as a pharmaceutical formulation. The
active ingredient may comprise, for topical administration,
from 0.001% to 10% w/w, e.g. from 1% to 2% by weight of
the formulation although it may comprise as much as lO~
lO w/w but preferably not in excess of 5~ w/w and more
preferably from 0.1% to 1% w/w of the formulation.
The topical formulations of the present invention,
both for veterinary and for human medical use, comprise an
active ingredient together with one or more acceptable
15 carrier(s) ~herefor and optionally any other therapeutic
ingredient(s). The carrier(s) must be 'acceptable' in the
sense of being compatible with the other ingredients of
the formulation and not deleterious to the recipient
thereof.
Formulations suitable for topical administration
include liquid or semi-liquid preparations suitable for
penetration through the skin to the site of inflammation
such as: liniments, lotions, creams, ointments or pastes,
and drops suitable for administration to the eye, ear or
25 nose.
Drops according to the present invention may
comprise sterile aqueous or oily solutions or suspensions
and may be prepared by dissolving the active ingredient in
a suitable aqueous solution of a bactericidal and/or
30 fungicidal agent and/or any other suitable preservative,
and preferably including a surface active agent. The
resulting solution may then be clarified by filtration,
transferred ~o a ~uitable container which is then sealed
and sterilized by autoclaving or maintaining at 98-100C.
35 for half an hour. Alternatively, the solution may be
sterilized by filtration and transferred to the container
2lJlt~
- 42 -
1 by an aseptic technique. Examples of bactericidal and
fungicidal agents suitable for inclusion in the drops are
phenylmercuric nitrate or acetate (0.002%), benzalkonium
chloride (0.01%) and chlorhexidine acetate (0.01%). Suita-
5 ble solvents for the preparation of an oily solutioninclude glycerol, diluted alcohol and propylene glycol.
Lotions according to the present invention
include those suitable for application to the skin or
eye. An eye lotion may comprise a sterile aqueous solution
10 optionally containing a bactericide and may be prepared by
methods similar to those for the preparation of drops.
Lotions or liniments for application to the skin may also
include an agent to hasten drying and to cool the skin,
such as an alcohol or acetone, and/or a moisturizer such
15 as glycerol or an oil such as castor oil or arachis oil.
Creams, ointments or pastes according to the
present invention are semi-solid formulations of the active
ingredient for external application. They may be made by
mixing the active ingredient in finely-divided or powdered
20 form, alone or in solution or suspensiori in an aqueous or
non-aqueous fluid, with t~e aid of suitable machinery,
with a greasy or non-greasy basis. The basis may comprise
hydrocarbons such as hard, soft or liquid paraffin,
glycerol, beeswax, a metallic soap; a mucilage; an oil of
25 natural origin such as almond, corn, arachis, castor or
olive oil; wool fat or its derivatives, or a fatty acid
such as steric or oleic acid together with an alcohol such
as prolylene glycol or macrogols. The formulation may
incorporate any suitable surface active agent such as an
30 anionic, cationic or non-ionic sulfactant such as sorbitan
esters or polyoxyethylene derivatives thereof~ Suspending
agents such as natural gums, cellulose derivatives or
inorganic materials such as silicaceous silicas, nd otL~r
ingredients such as lanolin, may also be included.
The compounds of Formula (I) may also be
administered by inhalation. By "inhalation" is meant
21`b~ 5
- 43 -
1 intranasal and oral inhalation administration.
Appropriate dosage forms for such administration, such as
an aerosol formulation or a metered dose inhaler, may be
prepared by conventional techniques. The preferred daily
5 dosage amount of a compound of Formula (I) administered by
inhalation is from about 10 mg to about 100 mg per day.
This invention also relates to a method of treat-
ing a disease state which is mediated by the 5-lipoxygenase
pathway in an animal in need thereof, including humans and
other mammals, which comprises administering to such animal
an effective, 5-lipoxygenase pathway inhibiting amount of
a Formula (I) compound. By the term "treating" is meant
either prophylactic or therapeutic therapy. By the term
"mediated" is meant caused by or exacerbated by. Such
15Formula (I) compound can be administered to such animal in
a conventional dosage form prepared by combining the
Formula (I~ compound with a conventional pharmaceutically
acceptable carrier or diluent according to known tech-
niques. It will be recognized by one of skill in the art
20 that the form and character of the pharmaceutically
acceptable carrier or diluent is dictated by the amount of
active ingredient with which it is to be combined, the
route of administration and other well-known variables.
The Formula (I) compound is administered to an animal in
25 need of inhibition of the 5-lipoxygenase pathway in an
amount sufficient to inhibit the 5-lipoxygenase pathway.
The route of administration may be oral, parenteral, by
inhalation or topical. The term parenteral as used herein
includes intravenous, intramuscular, subcutaneous, intra-
30 rectal, intravaginal or intraperitoneal administration.The subcutaneous and intramuscular forms of parenteral
administration are generally preferred. The daily
parenteral dosage regimen will preferably be from about sO
mg to about 1000 mg per day. The daily oral dosage
35 regimen will preferably be from about 150 mg to about 2000
mg per day. It will be recognized by one of skill in the
2'1~ Z~;~
- 44 -
1 art that the optimal quantity and spacing of individual
dosages of the Formula (I) compound will be determined by
the nature and extent of the condition being treated, the
form, route and site of administration, and the particular
animal being treated, and that such optimums can be
determined by conventional techniques. It will also be
appreciated by one of skill in the art that the optimal
course of treatment, i.e., the number of doses of the
Formula (I) compound given per day for a defined number of
10 days, can be ascertained by those skilled in the art using
conventional course of treatment determination tests.
In the tests used to determine activity as
S-lipoxYgenase pathway inhibitors, male Balb/c mice (20-28
g), were used. All mice were obtained from Charles River
15 Breeding Laboratories, Kingston, N.Y. Within a single
experiment, mice were age matched.
Reagents were.employed as follows:
Compounds of Formula (I) were each used as the
free base. The compounds were dissolved in acid saline.
20 Compounds were administered by lavage at the indicated
dose in a final volume of 10 ml/kg.
For in vitro experiments, compounds wer`e dissolved
at appropriate concentrations in ethanol (final cnncentra-
tion 1.0%) and then diluted to final concentrations using
25 the buffers indicated in the text.
Arachidonic Acid-Induced Mouse Ear Inflammation
Arachidonic acid in acetone (2 mg/20 ~1) was
applied to the inner surface of the left ear. The
thickness of both ears was then measured with a dial
micrometer one hour after treatment, and the data were
expressed as the change in thickness (10 3 cm) between
treated and untreated ears.
Test compounds were given orally in acid/salin~
at the times indicated in the text prior to the topical
application of arachidonic acid.
AssaY of 5-LipoxYqenase Activities
- 45 -
1 The 5-lipoxygenase (5LO) was isolated from
extracts of RBL-l cells. These cells were obtained from
the American Type Culture Collection (#CRL 1378) and were
grown at 37 with 5% CO2 in spinner culture using Eagles
5 essential medium (MEM) supplemented medium with 10% heat
inactivated fetal calf serum. The cells were collected
from culture by centrifugation at 2,000xg for 20 minutes
and then washed twice with 50mM sodium phosphate (pH 7.0)
that contained lmM EDTA and 0.1% gelatin. After this
wash, the cells were resuspended in fresh phosphate buffer
to achieve a concentration of 5X107 cells/ml. This
suspension was disrupted by nitrogen cavitation using the
Parr bomb at 750psi for 10 minutes. The broken cells were
then centrifuged at lO,OOOxg for 20 minutes. The
15 supernatant was collected and centrifuged at 100,000 xg
for 60 minutes. This supernatant was collected and stored
at -70C until assayed.
The inhibition of 5-lipoxygenase activity was
measured by one of two assays, the radiotracer extent
20 assay either measured after 90 seconds at 20C or measured
according to the method of G. K. Hogaboom et al.,-
Molecular Pharmacol. 30, 510-519 (1986)-or the continuous
2 consumption assay. The results from either assay are
comparable if not identical. All compounds were dissolved
25 in ethanol with the final concentration of ethanol being
1% in the assay.
The radiotracer extent assay examined the
5-lipoxygenase products [transLTB4 (DI-HETE), SHETE and
5HPETE] produced after a 90 second incubation at 20C.
30 Aliquots (40~L) of the supernatant were preincubated
with the inhibitor or vehicle for 10 minutes in 25mM
BisTris buffer (pH 7.0) that also contained lmM EDTA. lmM
ATP, 50mM NaCl, 5% e_hylen^ gylcol and lC0 ~g/ml of
sonicated phosphatidylcholine (total volume 0.238 ml).
35 The 5-lipoxygenase reaction was initiated by the addition
of CaC12 (2mM) and l-C14-arachidonic acid (25~M;
2'~
- 46 -
1 100,000dpm))(final volume 0.25ml). After 90 seconds, the
reaction was terminated by the addition of two volumes
(0.5ml) of ice chilled acetone. The sample was allowed to
deproteinize on ice for 10 minutes prior to centrifuging
5 at 1,000 xg for 10 minutes. The deproteinized
supernatants were dried under argon and then redissolved
in 200 ~L of ethanol. These samples were then
analyzed.by reverse phase HPLC as described by G.K.
Hogaboom et al., Molecular Pharmacol. 30: 510-519 (1986),
10 herein incorporated by reference. The compound-mediated
inhibition of S-lipoxygenase activity is described as the
concentration of compound causing a 50% inhibition of
product synthesis.
The second assay for assessing inhibition of the
15 5-lipoxygenase activity was a continuous assay which
monitored the consumption of 2 as the reaction
progressed. The 5-lipoxygenase enzyme (200~L) was
preincubated with the inhibitor or its vehicle in 25mM
BisTris buffer (pH 7.0) that contained lmM EDTA, lmM ATP,
20 5mM NaCl and 5% ethylene glycol for 2 minutes at 20C
(total volume 2.99 ml). Arachidonic acid (10~M) and
CaC12 ~2mM) were added to start the reaction, and the
decrease in 2 concentration followed with time using a
Clark-type electrode and the Yellow Spring 2 monitor
25 (type 53)(Yellow Springs, OH). The optimum velocity was
calculated from the progress curves. The compound-
mediated inhibition of 5-lipoxygenase activity is
described as the concentration of compound causing a 50%
inhibition of optimum velocity for the vehicle-treated
30 sample.
LTC-~ Production from ~uman Monoc~tes in vitro
Human monocytes were prepared from leukosource
packs supplied by t~e American Red Cross; The leukosource
packs were fractionated by a two-step procedure described
35 by F. Colatta et al., J. Immunol. 132, 936 (1984), herein
incorporated by reference, that uses sedimentation on
- 47 -
1 Ficoll followed by sedimentation on Percoll. The monocyte
fraction that results from this technique was composed of
80-90% monocytes with the remainder being neutrophils and
lymphocytes.
The monocytes (1.5x106) were placed into
polypropylene tubes and used as a suspended culture. The
assay buffer consisted of RPMI 1640 buffer, ~Moore, G. E.
et al., JAMA, 199, 519 (1967) herein incorporated by
referenceJ 1% human A~3 serum, 2mM glutamine, 25 mM HEPES
t4-(2-hydroxyethyl)-1-piperazine-ethanesulfonic acid], and
lmM CaC12 (total volume 0.45ml). Compounds (O.OSml)
were added in 10% ethanol solution, and the cells were
preincubated for 45-60 minutes at 37C with constant
agitation. A23187 calcium ionophore (2~M) was used to
15 stimulate the cells. After an additional 15 minutes, the
buffer was collected by centrifugation (6QO xg for 15
minutes) and stored at -70C until assayed. LTC4
production was measured by radioimmunassay which was
performed using a New England Nuclear Leukotriene
20 C-4(3H) RIA Kit according to the manufacturer's (New
England Nucelar, Boston Massachusetts) instructions. The
compound-mediated inhibition of LTC4 is described as the
concentration of compound causing a 50~ inhibition of
LTC4 proauction.
25 Inhibition of the Eicosanoid Production Following Calcium
Ionophore (60~M) Stimulation in Human Whole Blood
The eicosanoids, which include the 5-lipoxygenase
products LTB4, transLTB4, 20-hydroxyLTB4, S-HETE,
and the 12-lipoxygenase product are extracted from the
30 whole blood following A23187 calcium ionophore
stimulation. The extracts are separated by reverse phase
high pressure liquid chromatography and quantified by
absorbance methods.
Venous human blood is collected into
35 polypropylene tubes containing 1% heparin. The blood is
then aliquoted into 4.5 ml volumes and preincubated at
2il~ 25~
- 48 -
1 37C for 10 minutes in polypropylene tubes (15 ml sizej.
Compound or carrier ~50 ~L dimethylsulfoxide) is added 5
minutes prior to stimulation. Calcium ionophore (0.5ml)
is added, and the blood incubated for 10 minutes.
5 Prostaglandin B2(1 nmole) is added, and the blood
extracted as described below.
The samples are centrifuged at lOOOxg for 15
minutes at 5C. The plasma is collected, and one volume
of methanol is added to the plasma. This suspension is
10 then centrifuged at lOOOxg for ten minutes at 5C. The
supernatant is collected and diluted with 1.5 volumes of
chilled aqueous 1% formic acid: 1% triethylamine. This
mixture is loaded onto a preconditioned J.T. Baker C18 SPE
cartridge (Phillipsburg, NJ) at a flow rate of 1-2
15 ml/minute. (The cartridge is preconditioned according to
manufacture's recommendations.) The absorbed sample is
washed in the following order with three (3) ml each of
(i) aqueous 1% formic acid: 1% triethylamine; (ii)
petroleum ether; and (iii) 20% acetonitrile: 1%
20 triethylamine-
The eicosanoids are eluted in 3ml of 70%
acetonitrile: 1% triethylamine. The solvent is removed
under vacuum. The sample is resuspended in 200uL of 50%
methanol buffered with ammonium acetate.
The sample (175 ~1) is loaded into a WATERS
(Milford, MA) RCM NOVA PAK C18 (lOOx8mm) column with the
starting mobile phase of 90% A (A = 10% acetonitrile
buffered with 30mM ammonium acetate to pH6.8) and 10% B
(B - 90% acetonitrile buffered with 30mM ammonium acetate
30 to pH6.8). The flow rate for the separation is
2.5ml/minute. At one minute the %B is increased to 27% in
a step fashion. By 12 minutes the %B has increased in a
concave hyperbolic functi~ (curve 9) t~ 40% and increases
in a linear manner to 60% by 22 minutes. Under these
35 developing conditiQns, the retention times for the
eicosanoids are: 20-hydroxyLTB4, 4.6 minutes;
58
_ ~,9 _
.
1 thromboxane B2, 6.5 minutes; transLTB4, 10 minutes;
LTB4, lO. 5 minutes; 12-HETE, 10. 4 minutes; 5-HETE, 21
minutes. The HPLC system consisted of WATERS 510 pumps,
840 controller, WISP injector and 990 detector.
The eicosanoids in the samples are verified by
their retention times and their W absorbance spectra.
The peaks are quantified with reference to the internal
standard and their absorbance response at their maximum
absorbance wavelength.
10 The Effect of Compounds of Formula (I) on Arachidonic
Acid-induced Inflammation
Elucidation of the antiinflammatory activity of
the compounds of Formula (I) was achieved in a model of
arachidonic acid-induced edema in mice. The mouse ear
15 edematous response to arachidonic acid has been shown to
be sensitive to agents that inhibit both lipoxygenase- and
cyclooxygenase-generated mediators or that selectively
inhibit lipoxygenase, but not cyclooxygenase, enzyme
activity tSee, Young et al., J. Invest. Dermatol., 82,
20 367-371 (1984)]. Compounds of Formula (I) produced marked
inhibition of the edematous response normally seen 1 hour
after the application of 2 mg of arachidonic acid to the
ear (Table I~. The cyclooxygenase inhibitors,
indomethacin (10 mg/kg, p.o.), ibuprofen (250 mg/kg, p.o.)
25 and naproxen (100 mg/kg, p.o.) do not exhibit detectable
antiinflammatory activity in this assay.
These findings indicate that compounds of Formula
(I) are potent inhibitors of both the cellular and edema-
tous responses of inflammation in mice. These inflammatory
30 responses were also inhibited by agents that inhibit
lipoxygenase activity but not by selective cyclooxygenase
inhibitors.
The Effect of ComPounds of Formula (I) on Arachidor.ic Acid
Metabolism
Experiments using a soluble extract preparation
of RBL-l cells containing only lipoxygenase activity
Zllti(?~5~
- 50 -
1 confirmed the inhibitory effects of compounds of Formula
(I) on LTB4 (DI-HETE) production (Table II).
Indomethacin at concentrations up to 10 4M was
inactive. The data presented in Table II indicate that
5 compounds of Formula (I) are inhibitors of the
5-lipoxygenase pathway as confirmed by their ability to
inhibit DI-HETE, a S-lipoxygenase pathway product. The
data presented in Table III indicate that compounds of
Formula (I) are inhibitors of the 5-lipoxygenase pathway
as confirmed by their ability to inhibit the total 5-HETE
and DI-HETE, 5-lipoxygenase pathway products. The data in
Table IIIA indicates that compounds of Formula (I) are
inhibitors of the S-lipoxygenase pathway as confirmed by
measurement of oxygen consumption by the 5-lipoxygenase
15 enzyme.
LTC4 Inhibition AssaY
As shown in Table IV, compounds of Formula (I)
were e~ficacious in inhibiting LTC4 production, a
5-lipoxygenase pathway product, by human monocytes. These
20 data confirm the ability of compounds of Formula (I) to
inhibit the 5-lipoxygenase pathway.
Inhibition of E~lcosanoid Production
As shown in Table V, compounds of Formula (I)
were effective in inhibiting the production of various
25 S-lipoxygenase pathway products in human blood. This data
demonstrates that the compounds of Formula (I) inhibit the
5-lipoxygenase pathway. The inhibition of thromboxane
B2 demonstrates that the compounds inhibit the
cyclooxygenase pathway and are therefore dual inhibitors.
21~ S~ -
-- 51 --
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e c ~ ~ N
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g ~ o ~ 2
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-- 53 --
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o ~, " ~~ ~ E '~I ~ ' ' C
25 ~ i
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El E.E. E ~ E.~ ~ Z
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2i-3(~C~2~
-- 54 --
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-- 56 --
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U
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ca -- S S S :~ -- S T T E
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o ~ ~ ~ ~ ~ ~ C .. .. e
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-- 57 --
o . ~o
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I I I I I
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er
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Zl~t~
59 --
'
TA8I.E V~
A~
S-LO Inh~it~cn CNS P~450 Inhlbi- AAEE~MOUSE
r-l~tlv- to ~CIIVlty tl~ ' ED~o
Ca~pount C (Log 0) IC~o~l~M mg/k9 tPo~
A. Nf~ ~lpop~.
~N~
~ ~ ~ . 2 7
~
N~
B. ~N~
~ \ 0~8 . 5.0 14
S~o . . ~1.20
N~
C. ~
~C~N ~2.1~) 21.4 28
~0
IN3
~C~ ~2.611) 2 0
~-S
6J~
q sign in~icates presence and m~n~ sign absence.
** ~ot active-
- 60
TAOLE VII
CN~ Tox1c1tY 1n Mice
/
' ~ R j~3
~ ~ ~8
~ 9
~X~
~,
Oose One~ 24 ~
~9~ n ~ ~ ~ ma~kq DO t5~1C ~5~LCS
1~ 0 50 4-pyrldyl4-methoxyphenyl 200 - -
2 0 S 4-pyr1dyl4-fluorophenyl 200 - -
3 0 C 4-pyr1dyl4-fluorophenyl 200 + +
4 0 C 4-pyr1dyl 4-nethoxyphenyl - ISO + +
l C 4-pyr1dyl 4-methoxyphenyl 200 +
6 0 C 4-pyridyl 4-~l-ethoxy)phenyl 200 + +
7 0 C 4-pyr1dyl 4-methylthiophenyl 200 ~ +
8 0 C 4-pyridyl 4-Tethylsulfinylphenyl 200
9 0 C 4-pyr1dyl 4-methylsulfonylphenyt 200
lO O C 4-pyr1dyl 4-ethYlthioPhenyl 200
ll O C 4-pyr1dyl 4-ethylsulf1nylphenyl 300
12 0 C 4-pyridyl 4-acetoxymethylthiophenyl 200
13 0 C H 4-pyridyl 200
14 0 C 4-Tethylthiophenyl 4-pyrtdyl 200 + +
lS O C 4-methyl5ulfinylphenyl 4-pyridyl 200
16 0 C 4-~2~nethyl)pyr1dyl 4-methylth10phenyl 200
17 0 C 4-~2-methyl)pyrldyl 4-methylsulf1nylphenyl 200 _ _
18 0 C 4-~2-methyl)pyrldyl 4wnethoxyphenyl 200
3 0
M1nus s1gn 1nd1cates absenee and plus Sisn presence of convulsions
at one hour and death at 24 hours.
This compound l~tabolt~es to the corresPonding sulfide which causes convulsions
R , R , R , R , R , R , R and R each is hydrogen for comPounds
3 5 numbered to 18 above.
5~t~
-- 61 --
Table VIII
P-450 Inh~ oQ
~ ~ .
x~~a7
R4 / R5
No . ~ Bl B ~sol
S 4-pyrtdyl 4-methoxyphenyl 12.5
0 2 S0 4-pyrldyl 4-methoxyphenyl >lO0
3 S02 4-pyr1dyl 4~nethoxyphenyl 26.2
4 S 4-pyridyl 4-fluorophenyl 0.9
C 4-pyr1dyl 4-methoxyphenyl 21.4
6 S 4-fluorophenyl 4-pyr1dyl 0.5
7 C 4-pyr1dyl 4-~l-ethoxy)phenyl 8.4
8 C 4-pyr1dyl 4-(l-propoxy)phenyl 62.7
9 C 4-pyr1dyl 4-(2-propoxy)phenyl 2.5
lo C 4-N-methylpyr1dyl 4-methoxyphenyl 108
ll C 4^pyrldyl 4-methylth10phenyl 43.7
12 C 4-pyridyl 4-methYlsul fi nyl phenyl 866
13 C 4-pyr1dyl 4-methylsulfonylphenyl >loo
14 C 4-pyrtdyl 4-ethylth10phenyl 28.1
lS C 4-pyr1dyl 4-ethylsulf1nylphenyl >lO0
16 C 2-pyr1dyl 4-methoxyphonyl >tO0
17 C 3-pyr1dyl 4-methoxyphenyl >lO0
18 C H 4-pyr1dyl 80.1
19 C 4-methylthiophenyl 4-pyridyl 5.2
C 4-methylsulf1nylphenyl 4-pyridyl 13.7
3 5 C 4-(2-methyl )pyridyl 4-methylthiophenyl 57.5
22 C 4-(2-methyl)pyridyl 4-methylsulflnylphenyl >lO00
23 C 4-(2-methyl )pyridyl 4-methoxyphenyl 56.6
R2, R3, R4, R5, R6, R7. R8, and R9 each ~s hydrogen and n is 0
for comPounds numbered l to 23 above.
.
. ~ ~
%~5`~
- 62 -
1 It has now been found that the compounds of the
present invention have superior properties over previously
known compounds as summarized by the data in Table VI.
Compound A, 5-(4-pyridyl)-6-(4-fluorophenyl)-2,3-
5 dihydroimidazo[2,1-b]thiazole, and compound B,
5-(4-pyridyl)-6-(4-fluorophenyl)-2,3-dihydroimidazo
[2,1-b]thiazole oxide, are representative of compounds
taught in U.S. Patent 4,175,127 issued November 20, 1979~
Compound C,2-(4-methoxyphenyl)-3-(4-pyridyl)-6,7 dihydro-
~SH]-pyrrolotl,2-a]imidazole is specifically taught in
U.S. Patent 4,719,218 issuing from the parent case of the
present application. Compound D, 2-(4-methylthiophenyl)-
3-(4-pyridyl)-6,7-dihydro-t5H]-pyrrolotl,2-a]imidazole and
compound E, 2-(4-methylsulfinylphenyl)-3-(4-pyridyl)-
15 6,7-dihydro-t5H]-pyrrolo~1,2-a]imidazole are
representative of the present invention.
Structural modifications described in this
application have reduced the severity, when compared to
prior art compounds, of two undesirable side effects: 1)
20 CNS toxicity; and 2) inhibition of cytochrome P-450
dependent enzyme activities, which is a deficiency that
could result in clinically relevant drug interactions.
More specifically, the elimination of the sulfur on the
bicyclic fused ring nucleus of the compounds and
25 rep}acement of the fluorine with a methoxy group reduced
inhibition of cytochrome P-450 dependent enzymes, but did
not eliminate the presence of adverse central nervous
system (CNS) activity~ This is shown by a comparison of
the data in Table VI for compound C with A. It was
30 believed that the CNS effects were related to the ability
of a compound to penetrate the CNS and hence to
lipophilicity. Compounds A and C are both highly
lipophilic and demonstrat^1 similar CNS effects. The log
D shown on Table VI is a measure of lipophilicity
35 determined via high pressure liquid chromatography.
t(~
_
1 However, it was found that introduction of polarity into
the phenyl ring, pyridyl ring, or bicyclic fused ring
reduced 5-lipoxygenase inhibition activity. A comparison
of compounds D and E in Table VI demonstrate this effect
5 for introduction of polarity into the phenyl ring and
comparison of compounds A and B demonstrates this effect
for the bicyclic fused ring.
A comparison of compounds A and B demonstrated a
reduction in the undesirable CNS activity. A similar
ect is shown comparing claimed compounds D and E.
Incorporation of polarity into A yielded compound B, and
reduced CNS toxicity. Incorporation of polarity into
compound D yielded compound E, and reduced CNS toxicity.
Further compound E is metabolized in vivo to compound D.
Therefore, conversion of a polar but inactive prodrug (E)
in vivo to its metabolite (D) reduces CNS toxicity. In
addition compound D has less CNS toxicity than prior art
compound A. Thus the claimed compounds D and E have
reduced inhibition of cytochrome P-450 dependent enzymes
20 and reduced adverse CNS activity. This conclusion is
further supported by the following data.
LOG D Determination
The procedure used to determine the log D's
25 listed on Table VI was as follows. A 20 ~1 sample was
injected into a Shandon Hypersil O~S, 5~ (100 mm x 4.6
mm ID) column and was eluted using a mobile phase of 65:35
MeOH:H2O (The aqueous portion was .Cl M in KH2PO4
and adjusted to pH 7.4 with KOH after mixing the MeOH), at
30 a flow rate of 2 ml per minute. Eluting peaks were
detected by W absorbance at 222 nm. All samples were
made up at 0.1 mg/ml. (Retentions were identical at 0.01
mg/ml.)
- 64 -
1 The data was analyzed by determining the
regression line corresponding to the log k' vs. literature
log P of the reference standards. (See Unger, S.H. et al.,
J. Pharm. Sci., 67, 1364 (1978). The log P (log D) was
5 then determined for the test sample from its log k' on
this line. Reproduciblity was usually better than 0.5%.
The reference standards and their literature log
P's included NaNO2, 0.0; acetanalide, 1.16;
acetophenone, 1.66; anisole, 2.08; chlorobenzene, 2.84;
benzophenone, 3.18; anthracene, 4.45; and
pentachlorobenzene, 5.12.
CNS Activity
Effects on the central nervous system (CNS) of
the claimed and prior art compounds was demonstrated in
cynomolgus monkeys.
Oral administration of 90 mg/kg/day of compound A
on Table VI, 5-(4-pyridyl)-6-(4-fluorophenyl)-2,3-dihydro
imidazot2,1-b]thiazole to two cynomolgus monkeys (1
female, 1 male) for two consecutive days induced body
20 tremors in both monkeys and severe, recurrent convulsions
in the male animal. Administration of 30 mg/kg/day of
compound A on Table VI to two cynomolgus monkeys (1
female, 1 male) for S or 6 consecutive days was associated
with emesis and gastric ulceration in both monkeys but
25 with no evidence of convulsions or body tremors. Monkeys,
when administered a second dose of 90 mg~kg of compound A
died with convulsions within 1 to S hours after dosing.
A single oral dose of 90 mg/kg of compound C in
Table VI, 2-(4-methoxyphenyl)-3-(4-pyridyl)-6,7-dihydro-
30 [SH]-pyrrolo[1,2-a]imidazole to 1 female and 1 male monkey
resulted in death of both animals. The male became
sedated, lost consciousness and died within l.S hours of
dosing; the female demonstrated both decre~sed mc~or
activity and convulsions prior to death within 3.5 hours
35 of dosing. A single oral dose of 60 mg/kg to two
¢ fi~rj~
- 65 -
1 additional monkeys resulted in sedation, loss of
consciousness and death of one (male) within 1 hour of
dosing. Additional monkeys tolerated repeated doses of 45
mg/kg or 30 mg/kg and one animal tolerated an escalating
5 dose schedule of 30-90-120 mg/kg.
Two monkeys (1 female, 1 male) were gavaged with
90 mg/kg of compound E, 2-(4-methylsulfinylphenyl)-3-
(4-pyridyl)-6,7-dihydro-[5H]-pyrrolo[1,2-a]imidazole, and
clinical effects were not observed. Additional monkeys
were orally administered 200, 400 or 800 mg/kg of compound
E to probe the limiting dose and toxic effect(s). Both
monkeys receiving 800 mg/kg died, the female within 2
hours of dosing and the male between 12-24 hours of
dosing. Convulsions in these animals were not observed.
The two monkeys administered 400 mg~kg were
repeatedly administered this dose for 7 consecutive days;
each animal experienced emesis within 1 to 5 hours of
dosing after the 1st, 3rd and 4th doses, whereas only the
female experienced emesis after the 5th, 6th and 7th
20 doses. A complete necropsy, serum clinical chemistry,
hematology and histological examination was completed on
both monkeys. Evidence of drug related change was not
observed. Emesis was the only observation in monkeys
administered 400 mg/kg/day of compound E for 7 consecutive
25 days.
In summary, compounds A and C each caused
conwlsions and death after either two or one doses
respectively of 90 mg/kg, while compound E at that dosage
caused no observable clinical effects. Compound E
30 administered at 400 mg/kg/day for seven days caused only
emesis. Thus compound E does not have the adverse CNS
effects demonstrated by the prior art compounds A and C.
3~3
- 66 -
1 Effects on the central nervous system of the
claimed and prior art compounds was also demonstrated in
mice as shown by the data in Table VII. For compounds 1
to 5, representative of previously known compounds,
5 convulsions occurred in mice at one hour and death at
24 hours after administration of 3 of 5 compounds. For
compounds 6 to 18 representing the present invention,
convulsions occurred at one hour upon administration of
only 3 of 13 compounds and death occurred at 24 hours for
104 Of 13 compounds. This data indicates a general
improvement in reducing C~S activity for compounds of the
present invention.
CYtochrome P-450 Inhibition
The inhibitory effect of se~eral compounds on
hepatic cytochrome P-450 dependent mixed function oxidase
actiYity was evaluated in vitro in rat microsomes using
the prototypical substrate, ethoxycoumarin, as follows.
Animals: Male Sprague-Dawley rats, 9-10 weeks of age and
20 weighing 300-340 g, were dosed daily with Na-phenobarbital
for three days, i.p. (1 ml/kg in ultrapure H2O), at 80
mg/kg/day. The animals were ~illed by cervical
dislocation 24 hours after the last dose and pooled
hepatic microsomes were prepared by differential
25 centrifugation. Microsomes were stored at -80C.
In vitro enzvme studies: The possible inhibitory effects
of several compounds listed on Table VIII on hepatic
cytochrome P-450 dependent mixed function oxidase activity
30 were assessed using ethoxycoumarin-O-deethylase (ECOD)
activity. The deethylation of the substrate,
7-ethoxycoumarin, is detected by measuring the
fluorescence of 7-hydroxycoumarin according to the method
of Lee N.H. et al., Toxicoloqist, 5, 164 (1985).
35 Microsomal incubations consisting of 15 ~1 pooled
t~ ~3
- 67 -
1 Na-phenobarbital-induced microsomes (approx. 0.3 mg/ml
microsomal protein) and 875 ~1 reaction mixture of 0.45
mM 7-ethoxycoumarin, 5 mM glucose-6-phosphate, 0.5
units/ml glucose-6-phosphate dehydrogenase and 5 mM
5 MgC12 in 0.1 M N-2-hydroxyethylpiperazine-N -2-
ethanesulfonic acid,, pH 7.8 were prepared. Varying
concentrations of the test compounds, dissolved in a small
amount of dimethyl sulfoxide ~10 ~1), were added
directly to the incubations. Solvent controls were
10 incubated in the presence of dimethyl sulfoxide. After a
two minute preincubation at 37C, the deethylation
reaction was initiated by adding 100 ~1 0.74 mM
B-nicotinamide-adenine dinucleotide phosphate/0.74 mM
B-nicotinamide-adenine dinucleotide. The reaction was
15 stopped after incubating for 10 minutes at 37C by adding
2.5 ml basic MeOH, pH 9Ø The samples were spun at 2500
revolutions per minute for 15 minutes. Two mls of the
supernatent was transferred into disposable fluorescence
cuvets and the fluorescence of each sample was measured at
20 the excitation wavelength 390 nm and emission wavelength
454 nm! The PROBIT procedure was used to calculate IC50
values according to the SAS Institute Inc., SAS User's
guide: Statistics, 1982 Edition, Cary NC: SAS Institute
Inc. 1982, 287 pp.
The results are summarized in Table VIII and
demonstrate that compounds of the claimed invention have
reduced inhibition of P-450 enzyme compared to previously
known compounds. Compounds 1 to 6 represent previously
known compounds. The IC50, which is the concentration
30 at which S0% of the enzyme activity is inhibited, was less
than 30 ~M for each of these compounds except compound
2. Compounds 7 to 23 represent the. claimed invention.
The major~.y of these co~pounds have an IC50 above 30
~M. Compounds of the claimed invention, because of the
35 reduced inhibition-of cytochrome P-450 dependent enzymes,
2~ 5;~
- 68 -
1 would be expected to have significantly less clinicallyrelevant drug interactions than prior art compounds.
The following examples are to be construed as
merely illustrative and not a limitation of the scope of
5 the present invention in any way.
Temperature is in degrees Centigrade (C).
EXAMP~E 1
2-(4-FluoroPhenyl)-6~7-dihydro-(5H)-pyrrolo~l~2-a]imidazole
(Formula (E) ComPound)
Method A.
A stirred solution of l5g (87 mmoles) of 2-chloro-
4-fluoroacetophenone in 75ml of SD 30 alcohol was treated
at 25 C with 10.65g (104 mmoles) of 2-iminopyrrolidine,
lS resulting in an exothermic temperature rise to 40C.
After stirring for one hour (hr), approximately 75ml of
ethyl acetate was added, and the mixture was extracted
with dilute HCl to dissolve the precipitate. The aqueous
acidic extract was separated from the organic phase,
20 adjusted to a pH between 4 and 5, and heated on a steam
bath for 24 hrs. The solution was adjusted to pH 2,
extracted with ether, brought to pH 8, and extracted with
methylene ch}oride. The basic organic phase was chromato-
graphed on silica, eluting with 4% methanol in methylene
25 chloride. The residue obtained on concentration of the
pooled fractions was recrystallized from CC14, melting
point (mp) 137.5-139C.
Method B.
(a) 1-(4-FluoroPhenYl)-2-(2-iminoPYrrolidin
yl)-ethanone hYdrocholoride (Formula (H)
comPound
A stirred solution of 37.3g (216 mmoles) of
2-chloro~ 4-fluorophenyl)-ethanone (prepared as
described by Joshi et al., J. HeterocYclic Chem. 16, 1141
35 (1979)) in 70 ml o chloroform chilled in a methanol-ice
bath between 15-18C, was treated with a solution of 20g
.
2~ r ~
- 69 -
1 (238 mmoles) of 2-imino-pyrrolidine in S0 ml of
chloroform at such a rate as to maintain the temperature
of the reaction mixture. After an additional 2 hours, the
mixture was triturated with 300 ml Et2O, filtered, and
5 the crystals were washed with ether and recrystallized
from alcohol to give white needles of the named Formula
(H) compound, mp 207-208C.
Anal. Calcd. for C12H14Cl F N20:C, 56.15; H, 5.50;
N, 10.91. Found: C, 56.14; H, 5.50; N, 10.90.0 (b) 2-(4-Fluorophen~1)-6,7-dihYdro-(5H)-pYrrolo
~1,2-a]imidazole (Formula (E) ComPound)
An aqueous solution of 31g (0.12 mole) of the
named Formula (H) compound of Method B, part a above, was
heated in 300 ml of water on a steam bath for 8 hours.
15 The solution was adjusted to pH 6.5, and the resulting
precipitate was filtered, dried under vacuum and
recrystallized from CC14 to give the named Formula (E)
compound, mp 137.5-139C.
Anal. Calcd. for C12HllFN2: C, 71.27; H, 5.48, N, 13.85.
20 Found: C, 71.00; H, 5.61; N, 13.73.
EXAMPLE 2
2-(4-FluorophenYl)-3-(4-pyridyl)-6~7-dihydro-[5H]-pyrrolo
~1,2-a]imidazole
A stirred solution of 13.1g (0.065 mole) of 2-(4-
fluorophenyl)-6,7-dihydro-[5H]-pyrrolo~1,2-a]imidazole,
prepared as described in Example 1, and 51.4g (0.6S mole)
of dry pyridine in 17ml of dry methylene chloride at
22-25C was treated over 1.5 hours (hr) with 35.~g (0.325
3~ mmole) of ethyl chloroformate. The solution was stirred
at 25C overnight, and the treatment with pyridine and
ethyl chloroformate repeated as before, followed by a 24
hr period of stirring. ~fter _ more treatments as
described above, the solvent was removed in vacuo. The
35 residue was dissolved in 5% aqueous NaHCO3 and extracted
into methylene chloride. The organic phase was washed
with 5%
Z~
- 70 -
1 aqueous NaHCO3 and dried over anhydrous K2CO3. The
volatile solvents were removed in vacuo and the residue
extracted into methylene chloride. The organic phase was
extracted repeatedly with 0.2M HCl until traces of starting
5 material were removed, then washed with 5% Na2CO3
-solution, dried over K2CO3 (anhydrous), and striped in
vacuo. The residue was crystallized from toluene-hexane
to give the compound of Formula (F) known as 3-(N-ethoxy-
carbonyl-1,4-dihydro-4-pyridyl)-2-(4-fluoro-phenyl)-6,7-
10 dihydrot5H]-pyrrolo(1,2-a]imidazole, m.p. 146-147C.
Method A. 0.5g (1.4 mmoles) of the Formula (F)
product described in Example 2 was heated with stirring in
5ml of decalin under argon. Upon reaching a temperature
of 80C, 0.06g (1.8 mmoles) of sulfur was added and the
15 mixture heated to 1~5C until starting material was con-
sumed. The cooled mixture was filtered and the solid
washed with petroleum ether and dissolved in chloroform-
ethyl acetate (1:1). This solution was decolorized with
- Darco, and chromatographed on silica. Elution with 20%
20 methanol in chloroform-ethyl acetate (1:1) afforded a
fraction which was concentrated in vacuo, and recrystal-
lized from carbon tetrachloride to give the desired
Example II title product, mp 163-164.5C.
Method B. 15.0g (42.4 mmoles) of a Formula (F)
25 c~mpound, i.e., 3-(N-ethoxycarbonyl-1,4-dihydro-4-pyridyl)-
2-(4-fluorophenyl)-6,7-dihydrot5H)-pyrrolo~1,2-a~imidazole,
prepared as described above, was added to a stirred
solution of 28.6g (255 mmoles) of potassium tert.-butoxide
dissolved in tert.-butanol ~2S0 ml) into which 2 was
30 being bubbled. The solution was heated to reflux for 15
minutes, and the solvent then removed in vacuo. The solid
product was extracted into methylene chloride, washed with
water and then extra~ted into aque~us 3~ HCl. This aqueous
acidic phase was made basic with cold 10% aqueous sodium
35 hydroxide and extracted with methylene chloride. The
resulting organic phase was dried over anhydrous K2CO3
.
;2''lJ ~ ,58
- 71
1 and the solvent was removed in vacuo. Two recrystalliza-
tions from toluene gave the Example II title product, mp
165-166C. Anal. Calcd. for C17H14FN3:C, 73.10; H,
5.05; N, 15.04. Found: C, 73.31; H, 5.11; M, 15.08.
EXAMPLE 3
2-(4-Methylthiophen~rl)-3-(4-pyridYl)-6,7-dihYdro-[5H]-
pYrrolotl,2-a]imidazole
A stirred solution of 5.5 g (19.7 mmoles) of
10 2-(4-fluorophenyl)-3-(4-pyridyl)-6,7-dihydro-[5H]-
pyrrolo[l,2]imidazole, prepared as described in Example 2
in 75 ml of dry (sieve) dimethylformamide was treated with
1.65 g (23~6 mmoles) of sodium thiomethylate under argon
atmosphere. The reaction mixture was heated overnight at
lS 75C followed by an additional 2 hours at 95C, poured
into cold water and extracted twice with ethyl acetate.
The organic phase was washed three times with water, dried
over anhydrous potassium carbonate, and stripped in
vacuo. The residue was recrystallized twice from ethyl
20 acetate to afford the titled compound, mp 171-172C.
Anal- Calcd- for C18H17N3S C, 3 ;
13.67; S, 10.43. Found: C, 69.93; H, 5.40; N, 13.76; S,
10.75.
In an analagous manner to the process of Example 3,
25 2-(4-propylthiophenyl)-3-(4-pyridyl)-6,7-dihydro-
~5H]-pyrrolo ~1,2-a] imidazole was prepared.
mp 92 -93 C.
Analysis Calcd. for C20H21N3S: C, 71.61; H, 6.31;
N, 12.53; S, 9.56. Found: C, 71.69; H, 6.41; N, 12.82;
30 S, 9,44,
NMR (CDC13) ~: 8.55 (m, 2H), 7.45-7.15 (m, 6H),
4.04 (t, 2H), 2.96 (t, 2H), 2.90 (t, 2H), 2.65
(quintet, 2H), 1.66 (sextet, 2H), 1.00 (t, 3H'.
Mass Spec (DCl/NH3) 336 (m + 1)
5~
- 72 -
1 EXAMPLE 4
2-(4-MethYlsulfinYlphenyl)-3-(4-pyridYl~-6,7-dihYdro-
~SH]-pyrrolo[1,2-a]imidazole.
To a stirred solution of S.0 g (16.3 mmoles) of
2-(4-methylthiophenyl)-3-(4-pyridyl)-6,7-dihydro-[SH]-
pyrrolo[l,2-a]imidazole of Example 3 dissolved in 75 ml of
chloroform, chilled in an ice bath, was added dropwise a
solution of 3.30 g (16.3 mmoles) of 85% 3-chloroperbenzoic
acid in chloroform. After stirring at 25C overnigh~, the
10 reaction mixture was washed with 5% sodium carbonate,
dried over anhydrous potassium carbonate, and stripped in
vacuo. The residue was flash chromatographed on silica
eluting with S to 10% methanol in methylene chloride:
2-propanol (9:1). The solvent was removed in vacuo and
15 the residue recrystallized from ethyl acetate to give the
desired titled compound, mp 163.5-165.5C. lH NMR (360
MHz, CDC13) ~ 8.62 (2H,d), 7.68 (2H,d), 7.57 (2H,d),
7.25 (2H,d), 4.05 (2H,t), 3.02 (2H,t), 2.72 (s)
superimposed upon 2.69 (m) (5H total). Mass Spec. (CI)
20 (M+H) 324 (MW = 323).
-- In an alternate procedure to that of Example 4,
2-(4-propylsulfinylphenyl)-3-(4-pyridyl)-6,7-dihydro-[5H]
pyrrolo~l,2-a]imidazole was prepared. The sulfide product
25 (1.4 g) 2-(4-propylthiophenyl)-3-(4-pyridyl)-6,7-dihydro-
[SH]-pyrrolo ~1,2-a] imidazole prepared as described in
Example 3 above was dissolved in 2s ml of acetic acid and
added to a solution containing 1.35 g of potassium sulfate
(K2S2O8) in 30 ml of water. The reaction was stirred
30 ovérnight at room temperature and worked up by diluting
with methylene chloride neutralizing with potassium
carbonate. The residue was columned on silica gel to
afford the product and then further puri~`ied by
recrystalization from ether/methylene chloride: m.p.
114-116C; mass spec (DCI/NH3) 352(M+1), 336. Analysis
Calcd- for C2_H21N3SO: C, 68.35~ H, 6.02; N, 11.96;
S, 9.12. Found: C, 68.17; H, 6.14; N, 11.97; S, 9.05.
~i3~ P~.5
-- 73 --
1 EXAMPLE s
2-~4-Methylsulfonylphenyl)-3-~4-pyridyl)-6 . 7-dihYdro- ~ 5H ] -
pYrrolo[1,2-a]imidazole.
A stirred solution of 0.64 g (1.98 mmoles) of
5 2-(4-methylsulfinylphenyl)-3-(4-pyridyl)-6,7-dihydro-[SH]-
pyrrolotl,2-a]imidazole of Example 4 in water was treated
dropwise over 45 minutes with an aqueous solution of 0.209
g ~1.32 mmoles) of potassium permanganate. After stirring
overnight, the suspension was extracted with methylene
10 chloride. The organic phase was dried over anhydrous
potassium carbonate and stripped in vacuo. The residue
flash chromatographed in silica eluting with 2 to 4%
methanol in chloroform. The solvent was removed in vacuo
and the residue recrystallized from ethyl acetate to
15 afford the desired titled compound, mp 222.5-224C. 1H
NMR (250 MHz, CDC13) ~ 8.62 (2H,d), 7.85 (2H,d), 7.72
(2H,d), 7.26 (2H,d), 4.05 (2H,t), 3.05(s) superimposed
upon 3.03(t) (5H total), 2.70 (2H,q).
- EXAMPLE 6
2-(4-MethoxYphenYl)-6~7-dihvdro-~5H]-pYrrolo-~1,2-a]
imidazol-3-Yl-tri-n-butYltin
a) 2-(4-MethoxYphenyl)-6,7-dih~dro-[5H]-PYrrolo
tl,2-a]imidazole (Formula (E) ComPound).
To a solution of 6.8 g (29.7 mmoles) of 2-
bromo-4'-methoxyacetophenone in 50 ml of CHC13 was added
a solution of 5 g (59.4 mmoles) of 2-iminopyrrolidine in
30 ml of CHC13 with chilling. After 4 hours of stirring
at 25C, the solvent was removed in vacuo. ~he residue
30 was dissolved in water, the pH adjusted to 2.5 and the
solution heated on a steam bath under argon atmosphere for
8 hours. The cooled solution was adjusted to pH 6. The
resulting precipitate was filtered, washed with water and
dried in vacuo to afford the titled compound, mp
35 116-117.5C.
;~ Jl~ r ~5~
- 74 -
1 b) 2-(4-Methoxyphenyl)-6~7-dihydro-[sH]
pYrrolo[l,2-a]imidazol-3-Yl-tri-n-butYltin
To an ice-cold (0C) solution of [16.8 g,
0.078 mol] 2-(4-methoxyphenyl)-6,7-dihydro-[5H]-
S pyrrolo[l,2-a]imidazole in 200 ml of dry tetrahydrofuran
under argon was added dropwise over 20 minutes 35 mL
[0.0858 mol] of a 2.5M solution of n-butyl lithium in
hexane. Once the addition was complete, the deep-red
solution was stirred in the cold for five minutes and then
10 a solution of the tributyltin chloride [26.~ g, 0.0975
mol] in 50 ml of dry tetrahydrofuran was added over 20
min. The reaction mixture was stirred at ice-bath
temperatures for 1.5 hours and then saturated ammonium
chloride was added. The layers were shaken together and
15 separated and the organic extract was washed an additional
time with saturated ammonium chloride and then dried with
anhydrous potassium carbonate. The solvent was removed
in vacuo to give 50g of a crude oil, which was taken up
twice in cold hexane, filtering off the unreacted
20 2-(4-methoxy-phenyl)-6,7-dihydro-[5H]-pyrrolo[1,2-a]-
imidazole each time. The product was purified on a column
of silica, eluting with 1:1 ethyl acetate~hexane in the
presence of 1% diethylamine, to give 19.2 g (49% of a
yellow oil.
25 Anal. Calcd for C25H40Sn N20:
C, S9.66, H, 8.01; N, 5.57. Found: C,59.32; H, 8.01,
N,5.41.
EXAM?LE 7
30 2-(4-MethoxYPhenYl)-3-(2-Pyridyl)-6~7-dihydro-~5H]-pyrr
[1,2-a]imidazole
A solution of 2-bromopyridine (0.948 g, 0.006
mol) in 2 ml of hexamethylphosphoramide and 10 mL of dry
tetrahydrofuran was deoxygenated with argon for 30 minutes
35 in the dark. To this solution was added 70 mg of tetrakis
(triphenylphosphine)palladium; the reaction was heated to
P ~51~
- 75 -
1 50C for 15 minutes and then it was allowed to return to
room temperature. The Formula (J) tin-intermediate
prepared as in Example 6 (lg, 0.002 mol) in 10 ml of dry
tetrahydrofuran was then added dropwise. The reaction
5 mixture was heated to reflux for 24 hours and then
worked-up by adding ethyl acetate and twice shaking the
organic extract with 10% potassium fluoride solution,
washing with water twice and then drying with saturated
sodium chloride solution and anhydrous magnesium sulfate.
10 The organic extract was concentrated in vacuo to give an
oil which was purified by flash chromatography in silica,
- eluting with 20-50% isopropanol in hexane. The resulting
solid was recrystallized from ethyl acetate, mp.
142.5-145C;
15 NMR (CDC13)~: 8.55 (d, lH), 7.45 (d, 2H),
7.4-6.9 (m, 3H), 6.8 (d, 2H),
4.25 (t, 2H), 3.8(s, 3H)
2.9 (t, 2H), 2.6 (m, 2H)
Mass Spec. (CI)(M+H) 292 (MW=291).
EXAMPLE 8
2-(4-MethoxYPhenyl)-3-(3-pyridyl)-6,7-dihYdro-
~5H¦-pyrrolo~1,2-a]imidazole
The reaction was carried out as described in
25 Example 7 for 2-bromopyridine. Commercially-available
3-bromo-pyridine was used in synthesis of the above-named
compound. The molar amounts were also the same. The
crude product was purified by flash chromatography on
silica, eluting with 20-30% isopropanol in hexane. The
30 product was recrystallized from ethyl acetate.
mp. 164-~65C.
NMR (CDC13)~: 8.6 (m 2H), 7.65 (m, lH),
;.45 (d, 2H), 7.3 (m, lH),
6.8 (d, 2H), 4.0 (t, 2H),
3.8 (s, 3H), 3.0 (t, 2H),
2.65 (m, 2H)
Mass Spec (CI)(M + H)+ = 292 (MW=291).
5~
- 76 -
1 EXAMP~E 9
2-(4-MethoxYphenyl)-3-(2,6-dimethYl-4-pYridYl)-6,7-
dihYdro-tsH]-pyrrolotl~2-a] imidazole
The 4-bromo-2,6-lutidine used in the palladium
catalyzed coupling reaction was synthesized from
commercially-available 2,6-lutidine N-oxide as described
in the literature tJ.O.C., 27, 1665 (1962), R. F. Evans
and H.C. Brown]. The coupling reaction was carried out as
described previously in Example 7.
The product was purified by flash chromatography,
on silica, eluting with 20-50% isopropanol in hexane.
mp. 178-179C.
NMR(CDC13)~: 7.4 (d, 2H), 7.2(s,2H)
6.8 (d, 2H), 4.2 (t, 2H),
3.8 (s, 3H), 2.9 (s, 2H)
2.65 (m, 2H), 2.55 (s, 6H)
In another process described by Stille et al. in
J.A.C.S., 109, p. 5478-5486 (1987) the titled compound was
20 also prepared.
To a solution of 2,6-dimethyl-4-(trifluoromethyl-
sulfonyloxy)pyridine tl mmol, prepared from the known
2,6-dimethyl-4-hydroxypyridine by treatment of the
hydroxypyridine with sodium hydride in DMF containing
25 N-phenyltrifluoromethanesulfonimide followed by
purification using silica gel chromatography\
NMR(CDC13)~: 2.59 (s, 6H), 6.91 (s, 2~)] in 5 mL of
dioxane was added 2-(4-methoxyphenyl)-6,7-dihydro-[5H]-
pyrrolotl,2-a]imidazol-3-yl-tri-n-butyltin (1 mmol), LiCl
(3 mmol), Pd(PPh3)4(0.2 mmol), and a few crystals of
~,6-di-t-butyl-4-methylphenol. The resulting mixture was
stirred and heated at reflux under an argon atmosphere for
sev~ral hours, then cooled to room temperature. Following
workup the residue was columned on silica gel to afford
the product which ~as further purified by
recrystalization; m.p. 178-179C, ~MR(CDC13)~: 7.47
,5~
- 77 -
1 (d,2H), 6.95 (s, 2H), 6.85 (d, 2H), 4.00 (t, 2H), 3.82 (s,
3H), 2.99 (t, 2H), 2.65 (m, 2H), 2.50 (s, 6H).
Analysis Calcd. for C20H21N3O: C, 75.21; H, 6.63;
N, 13.16. Found: C, 74.84; H, 6.74; N, 13.06
EXAMPLE 10
2-(4-HYdroxyphenYl)-3-(4-pYridyl)-6,7-dihydro-[5H]-pyrrolo
tl,2-aJimidazole dihYdrobromide
a. 2-(4-MethoxYphenYl~-6,7-dihydro-~SH]-~yrrolo
[1,2-a]imidazole (Formula (E) ComPound).
To a solution of 6.8 g (29.7 mmoles) of
2-bromo-4'-methoxyacetophenone in 50 ml of CHC13 was
added a solution of 5 g (59.4 mmoles) of
lS 2-iminopyrrolidine in 30 ml of CHC13 with chilling.
After 4 hours of stirring at 25C, the solvent was removed
in vacuo. The residue was dissolved in water, the pH
adjusted to 2.5 and the solution heated on a steam bath
under argon atmosphere for 8 hours. The cooled solution
20 was adjusted to pH 6. The resulting precipitate was
filtered, washed with water and dried in vacuo to afford
the titled compound, mp 116-117.C.
b. 3-(N-EthYloxYcarbonY1-l,4-dihYdro-4-pyridyl)-
2-(4-methoxYPhenYl)-6,7-dihydro-~5H]-Pyrrolo~l~2-a]imidazole
A stirred solution of 2.8 g (13.1 mmoles) of
2-(4-methoxyphenyl)-6,7-dihydro-~SH]-pyrrolo~1,2-a]
imidazole, prepared as described above, and 6.2 g (78.4
mmoles) of dry pyridine in 30 ml of dry CH2C12 was
treated dropwise over 1 hour at S C under argon
30 atmosphere with 4.25 g (30.2 mmoles) of ethyl
chloroformate. After stirring for 1 hour an additional
3.1 g (39.2 mmoles) of pyridine was added, followed by
2.15 g (19.8 mmoles) of ethyl chloroformate added over 2
hours. The mixture was stirred overnight at 25 C, then
35 poured into ice water made alkaline with Na2CO3 and
extracted with CH2C12. The organic phase was
- 78 -
1 sequentially washed with 0.2 N HCl, water, and aqueous
K2CO3 solution, dried over Na2SO4 and stripped in
vacuo to afford the titled compound as an amber resin.
TLC (Alumina; CHC13) of extracte~ product shows mixture
containing a major slower moving product spot (Rf 0.35)
and a minor starting material spot (Rf 0.46); NMR
indicates a mixture of 61% 3-(~-ethoxycarbonyl-1,4-dihydro-
4-pyridyl)-2-(4-methoxyphenyl)-6,7-dihydro[5H]-pyrrolo-
10 tl,2-a]imidazole Formula (F)* intermediate, 12%
2-(4-methoxyphenyl)-3-(4-pyridyl)-6,7-dihydro[5H]-pyrrolo-
[1,2-a]imidazole spontaneously oxidized Formula (I)
product, and 27% 2-(4-methoxyphenyl)-6,7-dihydro-tSH]-
pyrrolo[l,2]a]imidazole Formula (E) starting material:
15 (9OMHz, CDC13) d 8.62 (d, 0.23H), 7.67 (d) and 7.42 (d)
superimposed upon 7.8-7.15 (m, 2.33H), 7.15-6.8 (m,
- 3.33H), 4.85 (d-d, 1.2H)*, 4.64 (p, 0.63H)*, 4.27 (q,
1.3H)*, 3.93 (t) superimposed upon 3.8 (s, 4.5H), 3.0-2.3
(m, 4.0H), 1.32 (t, 1.86H)*.
*Those signals indicated with an asterisk above represent
exclusively the following Formula (F) protons: C3-H and
C5-H protons on dihydropyridine ring, C4-H proton on
dihydropyridine ring, CH20 protons on ethoxycarbonyl
25 function, and CH3 protons of ethoxycarbonyl function,
respectively.
c. 2-(4-MethoxYPhenY1)-3-(4-pYridyl)-6~7-dihydr
~5H]-Pyrrolotl,2-a]imidazole ~Formula (I) ComPound)
4.1 g (11.2 mmole) of the compound described in
30 Part b) above was heated with stirring in 25 ml of decalin
under argon. Upon reaching 85C, the solid was dissolved,
and 0.468 g (14.6 mmoles) of sulfur was added. The
mixture was :~ated to 165C and another 0.235 g (7;3
mmoles) of sulfur was added. After another 45 minutes,
35 the starting material was consumed, and the cooled
reaction mixture was diluted with 25 ml of petroleum ether
- 79 -
1 and filtered. The filtered solid was washed with
additional petroleum ether, dissolved in CHC13-EtOAc and
chromatographed on silica. The material eluting with 8 to
25% methanol in CHC13-EtOAc (1:1) was concentrated in
5 vacuo and recrystallized from toluene-cyclohexane to give
the desired product, mp 157.5-158.5C; Anal. Calcd. for
C18H17N3O:C, 74.20; H, 5.88; N, 14.42. Found: C,
74.09; H, 5.88; N, 14.45.
d. 2-(4-HYdroxYphenYl)-3-(4-pYridyl)-6~7-dihydr
10 [5HJ-pyrrolo[1,2-a]imidazole dihYdrobromide.
A stirred solution of 3g (10.3 mmoles) of
2-(4-methoxyphenyl)-3-(4-pyridyl)-6,7-dihydro-~5H]-pyrrolo
~1,2-a]imidazole of Part c) above in 150 ml of dry
methylene chloride was treated dropwise at -80C with a
15 solution of 17.7 g (30.9 mmoles) of boron tribromide in
methylene chloride and allowed to warm to room temperature
overnight. The reaction mixture was chilled in an ice
bath, 5 to 10 ml of water added, and the solvent removed
in vacuo. The residue was recrystallized from hot water
20 containing 0.5 ml. of 48% hydrobromic acid and dried in
vacuo to afford the titled compound as bright yellow
crystals, mp 257-258C. Anal. Calçd. for
C17H15N3O.2HBr.l/3H2O: C, 45.87; H, 4.00; N,
9.44. Found: C,45.66; H, 3.69; N,9.67.
EXAMPLE 11
2-(4-Ethox~,rPhenyl)-3-(4-pyridyl)-6,7-dihYdro-~5H]-pYrrolo
[1,2-a]imidazole.
A stirred solution of 1.2 g (2.7 mmoles) of 2-(4-
30 hydroxyphenyl)-3-(4-pyridyl)-6,7-d-ihydro-~SH]-pyrrolo~1,2-
a]imidazole dihydrobromide of Example 10 in 25 ml of dry
dimethylformamide cooled in an ice b.ath was treated with
360 mg (9.0 mmoles) of 60% sodium hydride dispGrsion and
allowed to warm to room temperature. A solution of 420 mg
35 (2.7 mmoles) of ethyl iodide in 2 ml of dimethylformamide
was added dropwise, and after 2 hours an additional 105 mg
X~'J~ 5,~
. - 80 -
1 (0.67 mmole) of ethyl iodide was added followed by another
90 mg (2.25 mmoles) of 60% sodium hydride suspension.
After stirring overnight, the mixture was poured into 10
volumes of ice water and extracted three times with ethyl
acetate. The organic phase was washed with water, dried
over anhydrous potassium carbonate and concentrated in
vacuo. The residue was flash chromatographed on silica
and the fractions eluting with 4 to 6% methanol in
chloroform were combined, concentrated in vacuo, and
10 recrystallized from ethyl acetate to afford the titled
compound, mp 133-135C. Anal. Calcd. for ClgHlgN3O:
C, 74.73, H, 6.27: ~, 13.76. Found: C, 74.23; H, 6.01;
N, 13.74.
EXAMPLE 12
2-(4-(l-PropoxY)PhenYl)-3-(4-~yridvl)-6~7-dihydro-[5H]
pyrrolotl,2-a]imidazole.
A stirred solution of 1.2 g (2.7 mmoles) of 2-(4-
hydroxyphenyl)-3-(4-pyridyl)-6,7-dihydro-[5H]-pyrrolotl,2-
20 a]imidazole dihydrobromide of Example 10 in 20 ml of dry
dimethylformamide cooled in an ice bath was treated with
360 mg (9.0 mmoles) of 60% sodium hydride dispersion and
allowed to warm to room temperature. 450 mg (2.7 mmoles)
of powdered potassium iodide was added, followed by
25 d~opwise addition of a solution of 332 mg (2.7 mmoles) of
l-propyl bromide in 2 ml of dimethylformamide. After 2
hours an additional 83 mg (0.67 mmole) of l-propyl bromide
was added followed by another 90 mg (2.25 mmoles) of 60~
sodium hydride suspension, and the mixture heated to 65C
30 for 2.5 hours. After ætirring overnight, the mixture was
poured into 10 volumes of ice water and extracted three
times with ethyl acetate. The organic phase was washed
with water, dried over anhyarous ~assium carbonate and
concentrated ~n vacuo. The residue was flash
chromatographed on.silica and the fractions eluting with 3
to 6% methanol in chloroform were combined, concentrated
- 81 -
1 in vacuo, and recrystallized from ethyl acetate to afford
the titled compound, mp 148.5-150C. Anal. Calcd. for
C20H21N3O: C, 75.21; H, 6.63; N, 13.16. Found: C,
74.95; H, 6.59; N, 13.17.
EXAMPLE 13
2-(4-(2-Propoxy)phenYl)-3-(4-PyridYl)-6,7-d hYdro-[5H]-
pYrrolo[1,2-a]imidazole.
A stirred solution of o.so g (2.0 mmoles) of
10 2-(4-hydroxyphenyl)-3-(4-pyridyl)-6,7-dihydro-[5H]-
pyrrolo~l,2-a]imidazole dihydrobromide of Example 10 in 20
ml of dry dimethylformamide cooled in an ice bath was
treated with 267 mg (6.67 mmoles) of 60% sodium hydride
dispersion and allowed to warm to room temperature. A
15 solution of 374 mg. (2.22 mmoles) of 2-propyl iodide in 2
ml of dimethylformamide was added dropwise and the
reaction mixture heated at 100C for 4 hours. Another 35
mg (0.88 mmole) of 60% sodium hydride suspension was added
at room temperature, followed by 113 mg (0.67 mmole) of
20 2-propyl iodide and the mixture heated at 100C for an
additional 3 hours. After stirring overnight, the mixture
was poured into 10 volumes of ice water and extracted
three times with ethyl acetate. The organic phase was
washed with water, dried over anhydrous potassium
25 carbonate and concentrated in vacuo. The residue was
flash chromatographed on silica and the fraction eluting
with 2% methanol in chloroform, concentrated in vacuo, and
recrystallized from ethyl acetate to afford the titled
compound, mp 148-150C. Anal. Calcd. for C20H21N3O:
30 C, 75.21; H, 6.63; N, 13.16. Found: C, 75.38; H, 6.58;
N, 13.26.
3~2,5~
- 82 -
1 EXAMPLE 14
2-(4-Ethylthiophenyl)-3-(4-pyridyl)-6,7-dihydro-[5H]-
EYrrolo[l~2-a]imidazole
Sodium hydride (60%) (0.75 g, 19 mmol) was added
5 to a solution of ethanethiol (2.1 ml, 1.7 g, 28 mmol) in
N,N-dimethylformamide (15 ml) at 0C under an argon
atmosphere. After stirring for 0.5 hours, 2-(4-fluoro-
phenyl)-3-(4-pyridyl)-6,7-dihydro-t5H]-pyrrolo[1,2-a~-
imidazole (3.5 g, 12.5 mmol) of Example 2 was added and
10 the resulting solution heated to 95 C for 6 hours. The
cooled reaction mixture was evaporated under reduced
pressure and the residue partitioned between lN aqueous
sodium hydroxide and dichloromethane. The organic layer
was washed successively with water and brine, dried
15 (magnesium sulfate) and concentrated. The residue was
chromatographed on silica gel eluting with 25:1
chloroform/methanol. Fractions containing product were
combined, the solvent evaporated and the residue
recrystallized from ethyl acetate to afford the titled
20 compound; mp. 124-125 C. Anal. Calcd. for
ClgHlgN3S: C,70.99; H, 5.96; N, 13.08; S, 9.97:
Found: C, 70.99; H, 5.92; N, 13.07; S, 9.81.
EXAMPLE 15
25 2-(4-Ethylsulfinylphenyl)-3-(4-pyridyl)-6,7-dihydro-tSH]-
pyrrolotl,2-a]imidazole
The title comopund was prepared from
6,7-dihydro-2-(4-ethylthiophenyl)-3-(4-pyridyl)-[5H]-
pyrrolotl,2-a]imidazole of Example 14 by the procedure
30 described in Example 4. mp. 108-110. 1 H NMR (250
MHz, CDCL3)~ 8.61 (2H, d), 7~6S (2H, d), 7.53 (2H, d),
7.24 (2H, d), 4.05 (2H, t), 3.02 (2H, t), 2.86 (2H, m),
2.69 (2H, m), 1.23 (3H, t).
~J'!.`~
- 83 -
1 EXAMPLE 16
2-(4-Mercaptophenyl)-3-(4-pyridyl)-6,7-dihydro-[5H]-
~yrrolo-[1,2-a]imidazole
To 5 g (15.5 mmole) of 2-(4-methylsulfinyl-
S phenyl)-3-(4-pyridyl)-6,7-dihydro-[5H]-pyrrolo~1,2-a]-
imidazole prepared as in Example 4 dissolved in 100 ml
methylene chloride and cooled to 0 was added 9.7 g (46.4
mmole, 6.5 ml) of trifluoroacetic anhydride in 25 ml of
methylene chloride. The mixture was heated to reflux for
10 1 hour. The reaction mixture was stripped on the rotovap,
then treated with water, and extracted with methylene
chloride. The extract was washed with 3N NaHCO3 and
saturated NaCl and treated with Na2SO4, then stripped
to leave 5.1 g of crude product. This material was
15 dissolved in anhydrous methanol (50 ml) and treated with a
2s% solution of NaOCH3/MeOH (5 ml, 23 mmole). This
mixture was stirred at room temperature for 3 hours, then
poured onto ice water and neutralized with 3N NaHCO3.
After removing most of the methanol on the rotovap, the
20 residue was partitioned between methylene chloride and
water. The organic layer was washed with water and
saturated NaCl, treated with Na2SO4 and stripped. The
residue was flash chromatographed on a silica gel column
using a gradient of 1 to 5% MeOH in methylene chloride to
25 give 3.1 g (10.5 mmole) of the titled compound.
EXAMPLE 17
2-(4-Trimethylacetylthiophenyl)-3-(4-pyridyl)-
6,7-dihYdro-~5H]-Pvrrolo~l,2-a]imidazole
To 1.0 g (3.4 mmole) of 2-(4-mercaptophenyl)-
3-(4-pyridyl)-6,7-dihydro-~5H]-pyrrolo~1,2-a] imidazole
prepared as in Example 16 in 50 ml methylene chloride at
0C was alded a solution of 0.3 g (3.7 mmole, 0.?6 ml)
trimethylacetyl chloride in 10 ml CH2C12 over a period
35 of 10 minutes. The reaction was allowed to come to room
temperature and was stirred for 30 minutes. The mixture
- 8~ -
1 was then diluted with methylene chloride and washed with
3N NaHCO3, saturated NaCl, treated with Na2SO4,
stripped, then flash chromatographed on silica with
methylene chloride containing 1% to 5~ MeOH. The isolated
5 material was recrystallized from ethyl acetate to give
0.43 g of the titled compound. 33.5% yield, mp 216-217.5
C. C22H23N3OS, Calculated, C: 70.00, H: 6.14, N:
11.13; Found, C: 70.01, H: 6.20, N: 10.99.
EXAMPLE 18
2-(4-Acetylthiophenyl)-3-(4-pyridyl)-6,7-dihydro-[5H]-
pYrrO10 r 1,2-a~imidazole
To 1.0 g (3.4 mmole) of 2-(4-mercaptophenyl)-
3-(4-pyridyl)-6,7-dihydro-[5H]-pyrrolo~1,2-a] imidazole
15 prepared as in Example 16 in 50 ml methylene chloride at
0C was added a solution of 0.3 g (3.7 mmole, 0.26 ml)
acetyl chloride in 10 ml CH2C12 over a period of 10
minutes. The reaction was allowed to come to room
temperature and was stirred for 30 minutes. The mixture
20 was then diluted with methylene chloride and washed with
3N NaHCO3, saturated NaCl, treated with Na2SO4,
stripped, then flash chromatographed on silica with
methylene chloride containing 1% to S~ MeOH. The isolated
material was recrystallized twice from ethyl acetate to
25 give 0.20 g of the titled compound. 17.6% yield, mp
152-154C. ClgH17N3OS, Calculated, C: 68.03, H:
5.11, N: 12.53; Found, C: 68.25, H: 5.40, N: 12.14.
EXAMPLE 130 2-(4-PYridYl)-6,7-dihydro-[5H]-pyrrolo[1,2-a]imidazole
A stirred suspension of 10g (35.6 mmoles) of
4-(bromoacetyl)-pyridine hydrobromide and 12.9 g (107
mmoles) of 2-imino-pyrrolidine hydrochloride in 100 ml of
dry dimethylformamide was treated with 18.9 g (178 mmoles)
35 of anhydrous sodium carbonate. This suspension was heated
at 80C overnight in an oil bath. The solvent was removed
- 8S -
1 in vacuo, the residue dissolved in water and extracted
with chloroform. The organic layer was washed three times
with water, dried over anhydrous potassium carbonate and
stripped in vacuo. The residue was chromatographed on
silica and eluted with lQ-lS~ methanol in methylene
chloride acetone (85:15). This fraction was stripped in
vacuo and the solid residue recrystallized twice from
ethyl acetate to afford the desired titled compound, mp
140-141C, lHNMR (250 MHz, CDC13) ~ 8.62 (2H,d),
10 7.60(2H,d), 7.34(1H,s), 4.04(2H,t), 2.95 (2H,t),
2.64(2H,q).
EXAMPLE 20
2-~4-(2-Methyl-propenylthio)phenyl]-3-(4-pyridyl)-6,7-
15 dihYdro-[5H]-pYrrolo~1,2-a]imidazole.
A solution of 5g (17 mmoles) of 2-(4-mercapto-
phenyl)-3-(4-pyridyl)-6,7-dihydro-~SH]-pyrrolo[1,2-a]-
imidazole in dry tetrahydrofuran is treated at -20OC with
a solution of 17 mmoles of lithium diethylamide from 6.8
20 ml of 2.5M n-butyl lithium. After warming, a solution of
1.57g (17 mmoles) of trimethylsilylmethylchloride in
tetrahydrofuran is added dropwise. When the reaction is
complete, the mixture is immersed in an ice bath and a
second solution (17 mmoles) of lithium diethylamide is
25 added. After stirring for lS minutes, a solution of 0.99
g (17 mmoles) of acetone in tetrahydrofuran is added, and
the mixture is stirred lS minutes at 0 and lS minutes at
25C. The mixture is poured into water, extracted with
methylene chloride, and the organic layer dried, and
30 chromatographed on silica to afford the desired titled
compound.
z~
~ 86 -
1 EXAMPLE 21
3-(4-Methylsulfinylphenyl)-2-(4-pyridyl)-6,7-dihydro-[5H]-
Pyrrolotl~2-a]imidazole
a) 2-(4-PYridYl)-6,7-dihydro-t5H]-PYrrrolotl,2-a]imidazol-
3-yl-tri-n-butvltin (Formula (J) ComPound).
To a cold (-5 to 0C) solution of 0.5 g (2.7
mmol) of 2-(4-pyridyl)-6,7-dihydro-[5H]-pyrrolo-
tl,2-a]-imidazole prepared as in Example 19, in 20 ml
of dry tetrahydrofuran under argon was added 1.08 ml
(2.7 mmol) of a 2.5M solution of n-butyllithium in
hexane dropwise over 20 minutes. The reaction
mixture was stirred for 1.5 hours and then a solution
of 1.0 g (3.07 mmol) of tri-n-butyltin chloride in 2
ml of dry tetrahydrofuran was added dropwise. The
reaction mixture was then treated with a saturated
aq~eous solution of ammonium chloride. The organic
layer was extracted a second time with saturated
ammonium chloride solution and then dried over
~nhydrous potassium carbonate. The solvent was
removed in vacuo and the residue extracted twice with
hexane. The extract was concentrated and purified by
chromatography on silica eluting with 5-8% methanol
in hexane-ethyl acetate (1:1) containing 1% diethyl
amine to afford the titled compound as an oil,
1HNMR(250MHz, CDC13) ~: 8.52 (2H,d), 7.47
(2H,d), 3.97 (2H,t), 2.95 (2H,t), 2.64(2H,g), 1.42
(6H,m), 1.27 (6H,m), 1.08 (6H,m), 0.84(6H,t).
b) 3-(4-MethYlthioPhenYl)-2-(4-PYridYl)-6,7-dihYdro-~5H]-
p~Yrrolo~1,2-a]imidazole.
A solution of 2.69 g ~10.9 mmol) of l-methyl-
thio-4-iodobenzene in 6.8 ml of hexamethyl-
phosphoramide ~nd 68 ml of dry tetrahydrofuran was
purged by bubbling argon through for 15 minutes and
then treated with 240 mg of tetrakis(triphenyl-
phosphine)palladium. The mixture was heated at 50C
- 87 -
1 for 15 minutes and then treated dropwise with a
solution of 1.7 g (3.57 mmol) of compound a) above
in 15 ml of dry tetrahydrofuran. The mixture was
refluxed in an 80C oil bath overnight, then cooled,
ethyl acetate added, and washed twice with 10%
aqueous sodium fluoride solution, three times with
water, and extracted into cold 3~ HCL. The aqueous
phase was washed twice with methylene chloride, made
alkaline with 10% sodium hydroxide, and the product
extracted into methylene chloride and dried over
anhydrous potassium carbonate. The crude product was
purified by flash chromatography on silica eluting
with 2-3% methanol in a solution of 66% methylene
chloride and 33% acetone containing 2% water. The
lS residue was recrystallized from ethanol-ethyl acetate
and dried in vacuo to give the titled compound as
yellow crystals, mp 174-175.5C.
c) 3-~4-MethYlsulfinylphenyl)-2-(4-pyridyl)-6,7-dihydro-
~5H]-pyrrolo~1,2-a]imidazole.
A solution of 0.345 g (1.12 mmol) of compound b)
above, in S ml of water containing 0.75 ml of 3 N
hydrochloric acid was treated dropwise at 5C over
1.5 hours with a solution of 0.267 g (1.24 mmol) of
sodium periodate in S ml of water. The reaction
mixture was left at this temperature overnight, then
warmed to 20C, extracted twice with methylene
chloride, brought to pH 4 and extracted 4 times with
methylene chloride, then brought to pH 10 with
30 aqueous sodium carbonate, and extracted into
methylene chloride. The organic phase was dried over
anhydrous potassium carbonate and concentrated in
vacuo. The residue was di~ssolved in hot ethyl
acetate, crystallized and dried in vacuo to give the
titled compound, mp 179.5-181.5C.
2~ 5?~
- 88 -
1 EXAMPTE 22
2-(4-Methylsulfinylphenyl)-3-~4-(2-methyl)-
pyridyl]-6,7-dihydro-~5H]-pyrrolo~1,2-]imidazole
a) 2-(4-Fluorophenyl)-3-[4-(1-acetyl-2-methYl-
1,2-dihYdro-~eyridvl)]-6,7-dihydro-[SH]-
Pyrrolo[l~2~a]imidazole~
To a solution of 3.3g (11.9 mmole) of
2-(4-fluorophenyl)-3-(4-pyridyl)-6,7-dihydro-[5H~-
pyrrolo-[1,2,a]imidazole in dry tetrahydrofuran at
-20C was added l.a4 g (23.8 mmole) of acetyl
chloride. The reaction was stirred at -20C for 10
minutes and then 8.81 ml of 2.7M methylmagnesium
bromide (20 mmol) was added. The reaction was
stirred an additional 15 minutes and then warmed to
room temperature for 30 minutes. The reaction was
quenched with aqueous NH4Cl, adjusted to pH 7.5
with bicarbonate, and extracted repeatedly with
methylene chloride. The combined organic extracts
were dried over sodium sulfate, filtered, and
concentrated in vacuo to afford the crude
dihydropyridine.
H NMR 250MHz (CDC13) ~: 7.58 (2H, d-d), 7.00
(2H, t), 6.48 (lH, d), 5.68 (lH, d), 5.32 (lH, P),
5.18 (lH, d), 3.96 (2H, q), 2.95 (2~, t), 2.60 (2H,
p), 2.20 (3H, s), 1.22 (3H, d). NMR indicates 2.5~
starting material based upon an ~-pyridyl proton at
8.57.
b) 2-(4-Fluorophenyl)-3-~4-(2-methyl)pyridyl~-6,7-dihydro-
[SH~-Pyrrolo~l~2~a]imidazole~
The crude dihydropyridine was aromatized by
heat.ng at 190C for 1 hour in a solution composed of
150 ml decalin, 15 ml diglyme, and 1.0 g (31 mmol) of
sublimed sulfur. The reaction was filtered, diluted
with petroleum.ether, and chilled. The resulting
solid was collected and purified by ~lash
Z~ 2,5~
- 89 -
1 chromatography on silica gel eluting with methylene
chloride containing o.-1.5~ methanol and crystallized
from ethyl acetate to afford 2.84g ~82% yield)
2-(4-fluorophenyl)3-[4-(2-methyl)pyridyl]6,7-dihydro-
~5H]-pyrrolo~1,2,a]imidazole.
lH NMR 250Mhz (CDC13) ~: 8.46 (lH, d), 7.48 (2H,
d-d), 7.10 (lH, s), 7.01 (lH,d), 6.98 (2H, t), 4.05
(2H, t), 3.00 (2H, t), 2.65 (2H, p), 2.55
(3H, s).
Mass Spec (CI), m/e 294 (M + H)+.
c) 2-(4-Methylthiophenyl)-3-[4-(2-methyl)pyridyl]-6,7-
dihYdro-[5H]-pYrrolo[l,2,a]imidazole.
A stirring solution of 3.0 g (10.2 mmol) of
compound (b) above and 0.87 (11.8 mmol) of sodium
thiomethoxide in 40 ml of dry dimethylformamide was
heated under an argon atmosphere overnight at 120C.
The reaction was poured into cold water and extracted
twice with ethyl acetate. The organic phase was
filtered, washed three times witX water, dried over
anhydrous potassium carbonate, and stripped in vacuo.
The residue was recrystallized from ethyl acetate to
afford 1.1 g (34% yield) of the titled compound. mp.
131-i32C. NMR 250MHz (CDC13)~: 8.5 (d, lH), 7.45
(d, 2H), 7.lS (d, 2H), 7.14-7.1 (m, 2H), 4.01 (t, 2H),
3.0 (t, 2H), 2.62 (m, 2H), 2.51 (s, 3H), 2.47 (s,
3H). mp 131-132C.
Mass Spec (CI), m/e 322 (M + H)+.
d) 2-(4-Methylsulfinylphenyl)-3-~4-(2-methyl)pyridyl]-6,7-
dihYdro-[5H]-~Yrrolo~1,2,a~imidazole.
A solution of 200 mg (0.62 mmol) of compound c)
above dissolved in 1.5 ml of water containing 1 ml of
1.2 N HCl wa~ treated dropwise at 5C over 1.5 hours
with a solution of 119 mg (0.56 mmol) of sodium
~i ) l b ~;~,5~
- 90 -
1 periodate in 1.5 ml of water. The reaction mixture
was treated as in Example 21 (c) to yield 179 mg (87%
yield) of the titled compound.
mp 128-131C. NMR 250MHz (CDC13)~: 8.5(d, lH),
7.7~d, 2H), 7.55(d, 2H), 7.15-7.05(m, 2H), 4.05(t,
2H), 3.05(t, 2H), 2.75(s, 3H), 2.68(m, 2H).
Anal. Calcd. for ClgHlgN3S-O.5H20-0.25
EtOAc : C, 65.19; H, 6.02; N, 11.40. Found- C,
65.00; N, 11.23; H, 5.71.
Mass Spec (CI), m/e 338 (M + H)+.
In an analogous manner to the process of Example
22(a`) and (b) 2-(4-methoxyphenyl)-3-~4-(2-methyl)pyridyl]-
15 6~7-dihydro-tsH]-pyrrolotl~2-a]-imidazole in 40~ yield was
prepared after flash chromatography on silica elution
with methylene chloride in 0.-1.5% methanol, and
crystallization from ethyl acetate. mp 158-160C from
ETOAc.
20 Anal. Calcd. for Clg Hlg N30-1/4 H20: C, 73.64;
H, 6.34; N, 13.56. Found: C, 73.76; H, 6.28; N, 13.52.
Ma-ss Spec (CI), m/e 306 (M + H)+.
lH NMR 250 MHz (CDC13) ~: 8.44 (d, lH), 7.45 (d,
2H), 7.}3 (s, lH), 7.07 (d, lH), 6.83 (d, 2H), 4.05 (t,
25 2H), 3.82 (s, 3H), 3.00 (t, 2H), 2.67 (p, 2H), 2.52 ~s,
3H).
The 2-(4-methoxyphenyl)-3-~4-(2-methyl-1,2-dihydro-
pyridyl)~6,7-dihydro-~5H]-pyrrolo ~1,2-]imidazole
intermediate of the above example was purified by flash
30 chromatography in methylene chloride containg 0.5~
methanol, yielding the following data: lH ~MR 250MHz
~CDC13) ~: 7.57 (d, 2H), 6.88 (d, 2H), 6.47 (d, lH),
5.68 (d, lH), 5.4 - 5.25 (m, 1-2H), 5 20 (d, lH), 3.94 (q,
2H), 3.82 (s, 3H), 2.92 (t, 2H), 2.60 ~p, 2H), 2.20 (s,
35 3H), 1.22 (d, 3H).-
~c~ ) r C~!~Z,51~
-- 91 --
1 EXAMPLE 23
2-(4-Carbethoxymethylthiophenyl)-3-(4-pyridyl)-6,7-dihydro-
[5H]-PYrrolo~l,2-a]imidazole
To 1.0 gm (3.4 mmole) of 2-(4-mercaptophenyl)-3-
(4-pyridyl)-6,7-dihydro-~5H]-pyrrolo[1,2-a]imidazole in 50
ml methylene chloride at 0 was added a solution of 0.63 g
(3.7 mmole, 0.43 ml) ethyl bromoacetate in 10 ml
CH2C12 over a period of 10 minutes. The reaction was
allowed to come to room temperature and was stirred for 30
10 minutes. The mixture was then diluted with methylene
chloride and washed with 3N NaHCO3, saturated NaCl,
, treated with Na2SO4, stripped, then flash
chromatographed on silica with methylene chloride
containing 1% to 5% MeOH. The isolated material was
15 recrystallized from ethyl acetate to gi~e 0.35g of the
titled product. 27.2% yield, mp 102-103C. Analyzed for
C21H21N3O2S, Calculated, C: 66.47, H:5.58, N:
11.07; Found, C: 66.39, H: 5.62, N: 10.97.
EXAMPLE 24
2-(4-Acetoxymethylthiophenyl)-3-(4-pyridyl)-6,7-dihydro-
t5H]-Pyrrolotl,2-a]imidazole
To 1 g (3.1 mmole) of 2-(4-methylsulfinylphenyl)-
3-(4-pyridyl)-6,7-dihydro-[5H]-pyrrolo[1,2-a]imidazole was
25 added 25 ml acetic anhydride. The mixture was heated to
reflux for 1 hour. The reaction mixture was stripped on
the rotovap, then treated with water, and extracted with
methylene chloride. The extract was washed with 3N
NaHCO3 and saturated NaCl and treated with Na2SO4,
30 then stripped to leave 1.1 g of crude product. This crude
material was then flash chromatographed on a silica gel
column using a gradient of 1 to 5~ MeOH in methylene
chloride to give after recrystallization from EtO~c 0.80 g
(2.2 mmole) of the titled product. 71% yield, mp
125.5-126.5C. Analyzed for C20HlgN302S~
Calculated, C: 65.73, H:5.24, N: 11.50; ~ound, C: 66.03,
H: 5.26, N: 11.30.
,5~
- 92 -
1 EX~MPLE 2s
2-(4-Methylsulfinylphenyl)-3-[4-(2,6-dimethyl)pyridyl]-6,7-
dihYdro-t5H]-pYrrolotl~2-a]imidazole
a) 2-(4-Fluorophenyl)-6,7-dihydro-[5H]-
Pvrrolotl,2-a]imidazole-3-Yl-tri-n-but~ltin
To a -78C solution of 2-(4-fluorophenyl)-6,7-
dihydro-t5H]-pyrrolotl,2-a]imidazole (2.0g, 0.010 mole) in
60ml of tetrahydrofuran (THF) is added 4.Oml of 2.5M
n-butyllithium. The solution is warmed to -30C for 20
10 minutes and then tributyltin chloride (3.3g, 0.01 mole) in
THF is added. The reaction is allowed to warm gradually
to 20C and then is quenched with saturated ammonium
chloride. Further workup and purification on silica as
described in Example 6b yields the titled compound.
b) 2-(4-Fluorophenyl)-3-t4-(2,6-dimethyl)pyridyl]-
6,7-dihYdro-[5H]-pYrrolo[l~2-a]imidazole
The 2-(4-fluorophenyl)-6,7-dihydro-[SH]-
pyrrolotl,2-a]imidazole-3-yl-tri-n-butyltin is coupled
with 4-bromo-2,6-lutidine prepared as in Example 9 using
20 the coupling procedure described in Example 7. The
product is purified by flash chromatography on silica.
c) 2-(4-Thiomethylphenyl)-3-t4-(2,6-dimethyl)-
E~ridYl]-6,7-dihYdro-[SH]-~Yrrolotl,2-a]imidazole
A stirring solution of 2-(4-fluorophenyl)-3-t4-
25 (2~6-dimethyl)pyridyl~-6~7-dihydro-tsH]-pyrroloEl~2-a]-
imidazole (0.55g) and sodium thiomethylate (0.16g) in 7 ml
of dry DMF is heated under an argon atmosphere overnight
at l2aoc or greater. Then reaction is poured into cold
water and extracted twice with ethyl acetate~ The
30 combined organic layer is washed with water, dried over
potassium carbonate, and stripped in vacuo. Column
chromatography on silica yields the titled compound.
2~, 4~t~
- 93 -
1 d) 2-(4-Methylsulfinylphenyl)-3-[4-(2,6-dimethyl)-
pYridyl]-6,7-dihydro-~sH]-pyrrolo~l~2-a]imidazole
A solution of the above thiomethyl compound is
oxidized using the procedure described in Example 22(d).
Column chromatography on silica gives the titled
methylsulfinyl compound.
EXAMPLE 26
2-(4-Ethoxycarbonylthiophenyl)-3-(4-pyridyl)-6,7-dihydro-
E 5H]-Pyrrolo(1,2-a]imidazole
To an ice-bath cooled solution containing 1.0 g
3.4mmole) of 2-(4-mercaptophenyl)-3-(4-pyridyl)-6,7-
dihydro-~5H]-pyrrolo~1,2-a]imidazole prepared as in
Example 16 and 0.5ml (3.6mmole) of triethylamine in lOml
lS of methylene chloride is added 0.33ml (3.5mmole) of ethyl
chloroformaté. The reaction is allowed to warm to room
temperature and stirred for several hours. Workup and
chromatography in a manner analogous to that outlined in
Example 18 affords the desired titled compound.
EXAMPLE 27
2-(4-Phenoxythiocarbonylthiophenyl)-3-(4-pyridyl)-6,7-
dihYdro-t5H]-Pyrrolo~l~2-a]imidazole
To an ice-bath cooled solution containing l.o g
25 (3.4mmole) of 2-(4-mercaptophenyl~-3-(4-pyridyl)-6,7-
dihydro-t5H]-pyrrolo[1,2-a]imidazole prepared as in
Example 16 and 0.5 ml (3.6 mmole) of triethylamine in 10
ml of diglyme is added 0.48 ml (3.5mmole) of phenyl
chlorothionoformate. The reaction is allowed to warm to
30 room temperature and heated at 40 to 120C for several
hours. Workup and chromatography in a manner analogous to
that outlined in Example 18 affords the desired titled
com~ound.
s~
- 94 -
1 EXAMPLE 28
2[4-(2-OxobutYl)thiophenyl]-3-(4-p~ridvl)-6,7-dihydro-[SH]-
_yrrolo[1,2-a]imidazole
To an ice-bath cooled solution containing 1.0 g
(3.4mmole) of 2-(4-mercaptophenyl)-3-(4-pyridyl)-6,7-
dihydro-~5H]-pyrrolo~1,2-a]imidazole prepared as in
Example 16 and 0.5 ml (3.6 mmole) of triethylamine in 10
ml of methylene chloride is added 0.36 ml (3.5mmole) of
l-bromo-2-butanone. The reaction is allowed to warm to
10 room temperature and stirred at room temperature for
several hours. Workup and chromatography in a manner
analogous to that outlined in Example 18 affords the
desired titled compound.
,
EXAMPLE 29
2-(4-Metho~ynethylthiophenyl]-3-(4-pyridyl)-6,7-dihydro-
~5H~-PYrrolotl,2-a]imidazole
To an ice-bath cooled solution containing 1.0 g
(3.4mmole) of 2-(4-mercaptophenyl)-3-(4-pyridyl)-6,7-
20 dihydro-t5H]-pyrrolo~1,2-a]imidazole prepared as in
Example 16 and 0.5 ml (3.6 mmole) of triethylamine in lOml
of methylene chloride is added 0.27 ml ~3.5 mmole) of
bromomethyl methyl ether. The reaction is allowed to warm
to room temperature and stirred at room temperature for
25 several hours. Workup and chromatography in a manner
analogous to that outlined in example 18 affords the
desired titled compound.
EXAMPLE 30
30 2,2-Propan-diyl-bis[2-(4-thiophenyl)-3-(4-pyridyl)-6,7-
dihYdro-[5H]-P~rrolo[l~2-a]imidazole
To an ice-bath cooled solution containing 1.0 g
(3.4 mmole) of 2-(4-mercaptophenyl)-3-(4-pyridyl)-6,7-
dihydro-[SH]-pyrrolo[1,2-a]imidazole prepared as in
35 Example 16 and 0.12 ml (1.7 mmole) of acetone in S ml of
methylene chloride is added 0.10 ml of boron trifluoride
J ~ 51~
_ 95 _
1 etherate. After 4 hours at 0C the reaction is diluted
with methylene chloride and worked up as outlined in
Example 18. Purification by chromatography on silica
affords the desired dithioketal.
EXAMPLE 31
2-(4-Mercaptophenyl)-3-(4-pyridyl)-6,7-dihydro-[SH]-
Eyrrolo~l,2-a]imidazole disulfide.
2.0 (6.8 mmole) of 2-(4-mercaptophenyl)-3-
10 (4-pyridyl)-6,7-dihydro-t5H]-pyrrolo~1,2-a]imidazole
prepared as in Example 16 is dissolved in a solution
containing 4 parts ethanol and 1 part concentrated aqueous
ammonia and allowed to air oxidize in an open flash at
20-40C for 1 to 4 days. The solvent is stripped in -~acuo
15 and the product is purified by chromatography on silica to
yield the desired disulfide.
In an alternate procedure to that described in
Example 31, the title compound is prepared by adding to a
stirred, ice-cooled solution containing l.Og of the
2Q sulfoxide, 2-(4-methylsulfinylphenyl)-3-(4-pyridyl)-6,7-
dihydro-t5H]-pyrrolotl,2-a]imidazole in 7 ml of
chloroethylene, 1.27 ml of trifluroacetic anhydride. The
solution was allowed to warm and stirred at room
temperature for about 2 hours at which point lOml of
25 ethanol and 3ml of a 10% sodium hydroxide solution was
added. Fifteen minutes later I2 (800mg) was added.
After about an additional 1 hour of stirEing the reaction
mixture was diluted with methylene chloride, washed with a
10% sodium hydroxide solution, and dried over potass1um
30 carbonate. Flash chromatography on silica afforded 935 mg
of product which was recrystallized to yield 530mg of a
yellow solid.
M.P., 230 C., decomp.
Mass Spec. (DC}3/NH3) 585(M+1), 294; ~MR(C~C13) ~:
35 8.7 (m,4H), 7.5-7.2 (m,12H~, 3.9 (t,6H), 2.95 (t, 6H),
,5~
- 96 -
1 2.63 (m, 4H). Analysis Calcd. for C34H28S6S2: C,
69.84; H, 4.83; N, 14.37; S, 10.97. Found: C, 68.34; H,
4.88; N, 13.63; S, 10.49.
EXAMPLE 32
2-(4-Ethyldithiophenyl)-3-(4-pyridyl)-6,7-dihydro-~5H]-
Pyrrolo[l~2-a~imidazole~
Ethanesulfenyl chloride (Q.33 g) is added
dropwise to an ice-bath cooled solution containing 1.0 g
10 (3-4 mmole) of 2-(4-mercaptophenyl)-3-(4-pyridyl)-
6,7-dihydro-~5H]-pyrrolo~1,2-a]imidazole prepared as in
Example 16 in tetrahydrofuran. The mixture is allowed to
warm to room temperature. Workup yields the crude
disulfide which is purified by chromatography on silica.
EXAMPLE 33
2-(4-N-Phenylaminocarbonylthiophenyl)-3-(4-pyridyl)-6,7-
dihYdro-t5H]-Pyrrolo~l~2-a]imidazole
Phenyl isocyanate (0.38ml, 3.Smmole) is added
20 dropwise to a stirring ice-bath cooled solution containing
1.0 g (3.4 mmole) of 2-(4-mercaptophenyl)-3-(4-pyridyl)-
6,7-dihydro[SH]-pyrrolotl,2-a]imidazole prepared as in
Example 16 in tetrahydrofuran. The mixture is allowed to
warm to room temperature. Workup yields the crude titled
25 compound which is purified by chromatography on silica.
EXAMPLE 34
2-(4-~-Phenyldithiocarbamoylphenyl)-3-(4-pyridyl)-
6,7-dihYdro-~5H]-Pyrrolo~l~2--a]imidazole
Phe~yl isothiocyanate (0.42 ml, 3.5 mmole) is
added dropwise to a stirring ice-bath cooled solution
containing 1.0 g (3.4 mmole) of 2-(4-mercaptophenyl)-
3-(4-pyridyl)-~,7-dih~dro-~5H]-pyrr~1O~1,2-a]imidazole
prepared as in Example 16 in tetrahydrofuran. The mixture
is allowed to warm.to room temperature and stirred for
several hours. Workup yieldæ the crude titled compound
which is purified by chromatography on silica.
~:~`5`~C~
- 97 -
1 EXAMPLE 35
2-(4-Dithiocarbamoylphenyl)-3-(4-pyridyl)-6,7-dihydro-[5H]-
pYrr-olo[l~2-a]imidazole
Thiocarbamoyl chloride (336 mg, 3.5mmole) is
added dropwise to a stirring ice-bath cooled solution
containing 1.0 g (3.4 mmole) of 2-(4-mercaptophenyl)-3-(4-
pyridyl)-6,7-dihydro-[5H]-pyrrolo[1,2-a]imidazole prepared
as in Example 16 in tetrahydrofuran. The mixture is
allowed to warm to room temperature and stirred for
10 several hours. Workup yields the crude titled compound
which is purified by chromatography on silica.
EXAMPLE 36
2-(4-N,N-Dimethylaminocarbonylthiophenyl)-3-(4-pyridyl)-6,7-
15 dihYdro-[5H]-PYrrolotl,2-a]imidazole
N,N-Dimethylcarbamoyl chloride (375 mg, 3.5
mmole) is added dropwise to a stirring -20C solution
containing 1.0 g (3.4 mmole) of 2-(4-mercaptophenyl)-3-(4-
pyridyl)-6,7-dihydro-t5H]-pyrrolo[1,2-a]imidazole prepared
20 as in Example 16 in tetrahydrofuran. The mixture is
allowed to warm to room temperature. Workup yields the
crude thiocarbamate which is purified by chromatography on
silica.
EXAMPLE 37
2-(4-Dithiobenzoylphenyl)-3-(4-pyridyl)-6,7-dihydro-~5H]-
EYrrlo[1,2-a]imidazole
Thiobenzoyl chloride (546 mg, 3.5 mmole) is added
dropwise to a stirring ice-bath cooled solution containing
30 1.0 g (3.4 mmole) of 2-~4-mercaptophenyl)-3-(4-pyridyl)-
6,7-dihydro-~5H]-pyrrolo~1,2-a]imidazole prepared as in
Example 16 in tetrahydrofuran. The mixture is allowed to
warm to room temperature and stirred for several hours
Workup yields the crude titled compound which is purified
35 by chromatography ~n silica.
5~
- 98 -
1 EXAMPLE 38
2-(4-Methylsulfinylphenyl)-3-(4-pyridyl)-s,6,7,8-tetrahydro-
imidazo[l~2-a]Pyridine
a) 1-(4-Fluorophenyl)-2-(2-iminopiperidinYl)-
ethan-l-one
A solution of 15.3g (0.071 mole) of 25% sodium
methoxide in methanol is added to a solution of 10g (0.074
mole) of 2-iminopiperidine hydrochloride in 50 ml of dry
methanol with stirring under argon in an ice bath. The
10 solvent is removed in vacuo and the residue taken up in 50
ml of chloroform and filtered under argon. This solution
is added dropwise to a stirred solution of 12.82 g (0.074
mole) of 2-chloro 1-(4-fluorophenyl)ethanone in 130 ml of
chloroform at 15C. After 6 hours at room temperature the
15 solvent is concentrated in vacuo, a minimum amount of
methylene chloride is added to dissolve the residue, and
ether added to afford a heavy oil. The supernatant is
discarded and the oil dried in vacuo to give the titled
Formula (H) compound.
b) 2-(4-FluoroPhenyl)-5,6,7,8-tetrahYdro-
imidazo~l,2-a]Pvridine.
The Formula (H) compound prepared as described
in a) above is dissolved in a minimum volume of hot water
and is refluxed under argon for 24 hours. On cooling in
25 an ice bath, a precipaitate is formed. The supernatant is
decanted, the precipitate treated with 10% aqueous NaOH
solution and extracted into methylene chloride. The
organic phase is dried over anhydrous potassium carbonate
and concentrated in vacuo. The residue is purified by
30 chromatography on silica to afford the titled Formula (E)
compound.
~i3 ~ ,5~
_ 99 _
c) 3-(~1-EthYloxYcarbonYl-1,4-dihYdro-4
pyridyl)-2-(4-fluorophenYl)-5~6~7~8
tetrahYdroimidazo[1,2-a]Pyridine
A stirred solution of lOg (0.046 mole) of the
5 Formula (E) compound prepared as described in b) above,
dried in vacuo, in 20 ml of dry methylene chloride and
181.9g (2.3 moles) of dry pyridine is treated over 2 hours
with 25 g (0.23 mole) of ethylchloroformate maintaining
the temperature below 25C. Every 48 hours another 25 g
10 of ethylchloroformate is added for a total of 125 g (1.15
moles). The solvent is removed in vacuo, poured into cold
5% NaHCO3 solution and extracted into methylene
chloride. The organic phase is dried over anhydrous
K2CO3 and all volatile solvents removed in vacuo. The
15 ~esidue is dissolved in methylene chloride extracted
repeatedlY with 0.2M HCl until starting material removed,
then washed with 5% NaHCO3 solution. The organic phase
is dried over anhydrous K2CO3, and concentrated in
vacuo to afford the titled Formula (F) compound.
d) 2-(4-FluoroPhenyl)-3-(4-PYridYl)-5,6,7,8-
tetrahYdroimidazo[1,2-a]Pyridine
15g (0.041 mole) of the Formula (F) co~pound prepared as
described in c) above is added to a stirred solution o~
13.8 g (0.123 mole) of potassium tert-butoxide in 125 ml
25 of. dry (sieve) tert-butanol into which 2 is bubbled.
The solution is heated to reflux under argon until all the
starting material is consumed, and the solvent is then
removed 1n vacuo. The product is isolated as described in
Example 2, Method B above, purified by flash chromato-
30 graphy on silca and dried in vacuo to afford the titledFormula (I) compound.
(e) 2-(4-MethylthioPhenYl)-3-~4-PYridvl)-
5,6,7,8-tetrahYdroimidazotl,2-a]PYridine
A stirred solution of sg (0.017 mole) of the
35 compound prepared in d) above in S0 ml of dry (sieve)
dimethylformamide is treated with 1.47g (0.021 mole) of
Z11~2,~
-- 100 --
1 sodium thiomethylate at 95C overnight. The titled
product is isolated as described in Example 22c.
(f) 2-(4-MethylsulfinylphenYl)-3-(4-pyridYl)-
5,6,7,8-tetrahydroimidazo~1,2-a]pyridine
A stirred solution of 2g (6.2 mmoles) of the
compound prepared in e) above dissolved in 20 ml of water
containing 4.1 ml of 3~ hydrochloric acid is treated with
a solution of 1.5 g (6.9 mmoles) of sodium periodate
dropwise at 5C over 1.5 hours in 20 ml of water. This
10 reaction mixture is treated as in Example 21(c) to afford
the titled compound.
EXAMPLE 39
3-(4-Pyridyl)-2-(4-methoxyphenyl)-s~6~7~8-tetrahydroimidazo
15 [1,2-a] Pyridine
a) 2-(4-methoxYPhenyl)-5,6,7,8-tetrahYdroimidazo-
[1,2,-a] PYridine
A solution of 15.3g (0.071 mole) of 25% (by weight)
20 sodium methoxide in absolute methanol was added to a
stirred solution of 10g (0.074 mole) of 2-iminopiperidine
hydrochloride in 40 ml of chloroform. This solution was
added dropwise under argon to a stirred solution of 17.4g
(0.074 mole) of 2-bromo-4'-methoxyacetophenone in 150ml of
25 dry chloroform at 15C. After addition, the solution
was stirred for 4 hours at ambient temperature and then
concentrated in vacuo. The resin was dissolved in a
minimal amount of methylene chloride and ether was added
to afford a heavy oily layer. The supernatant was
decanted and the the oil layer dried of solvent in vacuo
to afford the compound. This residue was dissolved in a
minimal amount of hot water and the stirred solution
heated on a steam bath under argon for 15 hours. On
cooling, a precipitate formed which was filtered, made
alkaline with aqueous sodium hydroxide and extracted into
ethyl acetate. The organic layer was dried over potassium
3~.~C~ .5~
-- 101 --
1 carbonate, filtered and concentrated in vacuo. The solid
was triturated with hexane and air dried to give the
titled product, mp 124-126C.
b) 3-~-ethoxvcarbonYl-l~4-dihydro-4-pyridyl)-2
(4-methoxYphenvl)-5,6,7,8-tetrahYdroimidazo tl,2-a]
PYridine
To a stirred solution of 2.7g (li.8mmoles) of
2-(4-methoxyphenyl)-5,6,7,8-tetrahydroimidazo ~1,2-a]
10 pyridine, as prepared in part (a) above, was added 16.84 g
(213 mmoles) of dry pyridine in 30ml of dry methylene
chloride over argon, and was treated dropwise over two
hours at ambient temperature in a water bath with 7.7 g
(71 mmoles) of ethyl chloroformate. After 48 hours,
15 another 3.84 g (35.4 mmoles) of ethyl chloroformate was
added over 2 hours. The mixture was stirred overnight,
poured into ice water, made alkaline and extracted into
methylene chloride. The organic phase was se~uentially
washed with 0.2~ hydrochloric acid, water and aqueous
20 potassium carbonate solution, dried over sodium sulfate
and stripped in vacuo to afford the titled compound as a
resin. TLC (Alumina; CH2C12) of extracted product
shows a single elongated spot (Rf 0.55), while starting
material gives a faster moving single elongated spot (Rf
25 0..64); NMR indicates sample is a mixture containing 42
mole percent residual pyridine as well as the desired
titled Formula (F) intermediate: (9OMHz, CDC13) ~:
d 8.6 (broad d 0.84H), 7.7-6.65 ~m, 8.7H), 4.82 (broad d)*
superimposed upon 4.78 (broad s, 2.9H)*, (s, 7H), 2.85
30 (broad t, 1.85H)*, 1.86 (broad q 4.5H)*, 1.29 (q, 3.1H)*.
~ The signals indicated with an asterisk above represent
exc~usively the Formula (F) protons.
Z i ) ~
-- 102 --
c) 3-(4-Pyridyl-2-(4-methoxyphenyl)-
5,6,7,8-tetrahYdroimidazo [1,2-a] pyridine
2.7g (7.1mmoles) of the compound prepared in part (b)
above was heated with stirring in 25 ml of decaline under
5 argon. Upon reaching 100C, the solid dissolved, and
.34 g(l0.7 mmoles) of sulfur was added. The mixture was
heated to 160C for 30 minutes and another 0.34g of
sulfur was added. After another 45 minutes, the reaction
mixture was cooled, diluted with 25ml of petroleum ether
10 and extracted with acetonitrile. The acetonitrile phase
was separated, and concentrated in vacuo to a resin. The
resin, dissolved in methylene chloride, was extracted with
3N hydrochloric acid. The aqueous acidic layer was made
treated with 5% sodium carbonate solution and extracted
15 with chloroform. The chloroform layer was dried over
anhydrous potassium carbonate, concentrated in vacuo, and
chromatographed on silica, eluting with çhloroform: ethyl
acetate (1:2), containing 2% methanol. Evaporation of
the solvent gave an oil which was crystallized from
20 toluene-hexane to give the titled product, mp 136.5-138
C .
Analyzed for C19 Hlg N3 O, Calculated, 74.73, H:
6.27, N:13.76; Found, C: 75.04, H: 6.43, N: 13.95.
Mass Spec (CI), m/e 305, (M + H)+.
EXAMPLE 40 -- CAPSULE COMPOSITION
A pharamceutical composition of this invention in the
form of a capsule is prepared by filling a standard
two-piece hard gelatin capsule with 50 mg. of a compound
30 of Formula (I), in powdered form, 110 mg. of lactose, 32
mg. of talc and 8 mg. of magnesium stearate.
EX~MPLE 41 -- INJECTA~LE PARENTERAL COMPOSITION
A pharmaceutical composition of this invention in
35 a form suitable for administration by injection is
prepared by stirring 1.5~6 by weight of a compound of
~ q~ 258
- 103 -
1 Formula (I) in 10% by volume propylene glycol and water.
-The solution is sterilized by filtration!
EXAMPLE 42 - OI~TMENT COMPOSITION
5 Compound of Formula (I) 1.0 g
White soft paraffin to 100.0 g
The compound of Formula (I) i5 dispersed in a
small volume of the vehicle and this dispersion is
gradually incorporated into the bulk to produce a smooth,
10 homogeneous product which is filled into collapsible metal
tubes.
EXAMPLE 43 - TOPICAL CREAM COMPOSITION
Compound of Formula (I) 1.0 g
15 Polawax GP 200 20.0 g
Lanolin Anhydrous 2.0 g
White Beeswax 2.5 g
Methyl hydroxybenzoate 0.1 g
Distilled Water to 100.0 g
20The polawax, beeswax and lanolin are heated
together at 60C and added to a solution of methyl
hydroxybenzoate. Homogenization is achieved using high
speed stirring and the temperature is allowed to fall to
50C. The compound of Formula (I) is added and dispersed
25 t~roughout, and the composition is allowed to cool with
slow speed stirring.
EXAMPLE 44 - TOPICAL LOTION COMPOSITION
Compound of Formula (I) 1.O g
30 Sorbitan Monolaurate 0.6 g
Polysorbate 20 0.6 g
Cetostearyl Alcohol 1.2 g
Glycsrin 6 0 g
Methyl Hydroxybenzoate 0.2 g
35 Purified Water B.P. to 100.00 ml
2,~
- 104 -
1 The methyl hydroxybenzoate and glycerin are
dissolved in 70 ml of the water at 75. The sorbitan
monolaurate, polysorbate 20 and cetostearyl alcohol are
melted together at 75C and added to the aqueous
solution. The resulting emulsion is homogenized, allowedto cool with continuous stirring and the compound of
Formula (I) is added as a suspension in the remaining
water. The whole suspension is stirred until homogenized.
EXAMPLE 45 - EYE DROP COMPOSITION
Compound of Formula (I) 0.5 g
Methyl Hydroxybenzoate 0.01 g
Propyl Hydroxybenzoate 0.04 g
Purified Water B.P. to 100.00 ml
The methyl and propyl hydroxybenzoates are
dissolved in 70 ml purified water at 75C and the
resultin.g solution is allowed to cool. The compound of
Formula (I) is then added, and the solution is made up to
100 ml with purified water. The solution is sterilized by
20 filtration through a membrane filter (0.22 mu m pore size)
and packed aseptically into suitable sterile containers.
EXAMPLE 46 - COMPOSITION FOR ADMINISTRATION BY INHALATION
For an aerosol container with a capacity of 15-20
25 ml: Mix 10 mg of a compound of Formula (I) with 0.1-0.2%
of a iubricating agent, such as Span 85 or oleic acid, and
disperse such mixture in a propellant (c.a.), such as
freon, preferably a combination of freon 114 and freon 12,
and put into an appropriate aerosol container adapted for
either intranasal or oral inhalation administration.
EXAMPLE 47 - COMPOSITION FOR ADMINISTRATION BY INHALATION
For an aerosol container with a capacity of
15-20 ml: Dissolve 10 mg of a compound of Formula (I) in
ethanol (6-8 ml),.add 0.1-0.2% of a lubricating agent,
such as Span 85 or oleic acid, and disperse such in a
,
~ p~s~
- 105 -
1 propellant (c.a.), such as freon, preferably a combintion
of freon 144 and freon 12, and put into an appropriate
aerosol container adapted for either intranasal or oral
inhalation administration.
s
