Note: Descriptions are shown in the official language in which they were submitted.
. ~ WO 91/19497 ~ 0 ~ l~ 2 ~ ~ PCI'/llS91/04022
1 0 - 1-
1 5
INHIBITION OF 5-LIPOXYGENASE AND CYCLOOXYGENASE PATHWAY MEDIATED
FEL~) OF THE lNVENTION
2 0 This invention relates to a method of treating 5-lipoxygenase and
cyclooxygenase pathway mediated diseases.
BACKGROUND OF THE lNVE~TION
The metabolism of arachidonic acid occurs by many pathways. One route
~; of metabolism is via the cyclooxygenase (CO) mediated pathway which produces PGH2
2 5 which is in turn metabolized to the prostanoids (PGE2, TXA2~ and prostacyclin). These
pr~ducts are produced by various cells including polymorphonuclear leukocvtes, mast cells
and monocytes. Another route is by the lipoxygenase mediated pathway which oxidizes
arachidonic acid initially to 5-hydroperoxy-eicosatetraenoic acid (5-HPETE) which is
further metabolized to LTA4, the precursor to the peptidoleukotrienes (LTC4, LTD4, and
3 0 LTE4) and LTB4. Additionally 5-HPETE is converted to 5-hydroxyeicosatetraenoic acid
(5-HE'rE).
Lipoxygenases are classified according to the position in the arachidonic
acid which is oxygenated. Platelets metabolize arachidonic acid to 12-HETE, while
polymorphonuclear leukocytes (PMNs) contain 5 and 15 lipoxygenases. It is known that
3 5 12-HETE and 5,12-di~TE are chemotactic for human neutrophils and eosinophils, and
may augment the inflammation process. 5-HPETE is known to be a precursor to the
peptidylleukotrienes, formerly known as slow reacting substance of anaphylaxis (SRS-A)
and LTB4. The SRS family of molecules, such as leukotrienes C4 and D4 have been
;`
,
~ . . .
. ,
.. . .
,. :
" ~
WO 91tl9497 ~ 0 ~ ~ 2 ~ 2 - PCl/US91/04022 ~.
shown to be potent bronchoconstrictors. LTB4 has been shown to be a potent chemotatic
for PMNs. The products of the 5-lipoxygenase pathway are believed to play an important
role in initiating and maintaining the inflamrnatory response of asthma, allergy, arthritis,
psoriasis, and inflammatory bowel disease. It is believed that blockage of this enzyme will
5 interrupt the valious p~thways involved in these disease states and as such inhibitors
should be useful in treating a varienJ of inflammatorJ diseases, such as those inumerated
above. The absence of selective inhibitors of lipoxygenase, as opposed to cyclooxygenase,
which are active in vivo has pre~ented adequa~e investigation of the role of leukotrienes in
inflarnrnation.
1 0 The arac'lidonic acid oxyg~nated prcducts, as noted above, have been
identified as mediators of various inflammator/ conditions. The various inflam-mator,v
disease states caused by these r~.edia ~rs ~n~ ~any cther c~.di~ions, as discussed herein,
are all conditions in which an oxy~enated polyunsaturated fatty acid metabolite inhibitor,
such as a 5-lipoxyg~.lse (~-LC) inhibi;o., ~Nould be ind cated.
1 5 The arachidonic acid oxygenated products, as no~ed above, have been
idendfied as mediators of various inflammatory conditions. Such inflammatory conditions
are rheumatoid arthritis, bronchial inflarnmation, inflarnmatory bo~el disease, asthma,
cardiovasular disorders, glaucoma, emphysema, acute respiratory distress syndrome,
lupus, gout, psoriasis, pyresis, pain and other allergic oriented disorders such as allergic
2 0 rhinits, food allergies, and udcaria. These disease states and addidonal condididons such
as blood platelet aggregation, and notably conditions resulting from thrombosis, including
~otal or partial thrombosis, coronary thrombosis, phlebids and phlebothrombosis (also
associated with inflammation), are all conditions in which a dual inhibitor of both CO and
5-LO would be indicated.
2 5 There remains a need for treatrnen~, in this field, for compounds which are
effecdve inhibitors of the products formed by oxygenation of poly-unsaturated fatty acids,
such as arachidonic acid. By inhibition of the oxygenated polyunsaturated fatty acids
(hereinafter OPUFA), such as by inhibiting the enzymes 5-lipoxygenase (5-LO) andcyclooxgenase (CO) the formation of various leukotrienes and prostaglandins will be
3 0 prevented.
" .
SU~IARY OF l'HF. rNVE~llON
This invention relates to a method of ~reating an OPIJFA mediated disease in a
subject in need thereof which comprises administering to such subject an effective OPU~:A
3 5 inhibiting amount of a compound of the folmula
. wo gl/~9497 -3 - 2 ~ g /? ) ~ J~ PCI/US91/04022
~3
1 $y
R
FOR'/nJLA (I)
whereln:
W is -CRs=CR7-, -N=CR7-, -S- or -O-;
R2 R3, Rs, and R7 are, independently, -H or C1 2 alkyl,
one of R1 and ~o is 1-pyridyl or Cl 4 alkyl-4-pvridyl, provided that when Rl
is Cl 4 alkyl-4-pyridyl the aLkyl substituent is lccated at the 2-position of the pyridine ring,
and the other of R1 and Ro is
(a) phenyl or monosubstituted phenyl wherein said substituent is C1 4
1 0 allcyl, halo, hydroxy, Cl ~ allcoxy, Cl 3 alkylthio, Cl 3 aLkylsulfinyl, C2
5 l-aLcenyl-l-L'nio, C2 5 i-aLcenyl-l-sulFlnyl, Cl 3 aLkylsulronyl, C2 51-
alkenyl-1-sulfonyl, C3 5 2-alkenyl-1-sulfonyl, C3 5 2-alkenyl-1-sulfonyl,
Cl 3 alkylarnino, Cl 3 dialkylarnino, CF3, N-(Cl 3 alkan-arnido), N-(C1
3 alkyl)-N-(C1 3alkanarnido), N-pyrrolidino, N-piperidino, prop-2-ene-1-
1 5 oxy, 2,2,2-trihaloethoxy, thiol, acylthio, dithioacyl, thiocarbamyl, dithio-
carbamyl, aL~cylcarbonylalkylthio, carbalkoxyalkylthio, alkoxycarbonylthio,
alkoxythionothio, phenylthio, phenylsulfinyl, alkoxyalkylthio, alkoxyalkyl-
sulfinyl, alkylthioalkylthio, Z, or acyloxyalkylthio;
(b) disubsdtuted phenyl wherein said subsdtutents are, independently,
2 0 C1 3 al}cylthio, Cl 3 allcoxy, halo, C1 4 alkyl, C1 3 alkylarnino, N-(Cl.
3alkyl)-N-(Cl 3 alkanamido, C1.3 dialkylarnino, amino, N-pyrrolidino or
N-piperidino;
(c) disubstituted phenyl wherein one of said substituens is C1 3
alkoxy, halo, Cl 4 alkyl or CF3, and the other substituent is thiol,
2 5 alkylsulfinyl, acylthio, dithioacyl, thiocarbamyl, dithiocarbamyl, alkylcarbonylalkylthio, carbalkoxyalkylthio, alkoxycarbonylthio,
alkoxythionothio, phenylthio, phenylsulfinyl, alkoxyalkylthio,
a1koxyalkylsulfinyl, alkylthioalkylthio, Z, or acyloxyalkylthio; or
(d) disubstituted phenyl wherein one of said substituents is amino,
3 0 Cl 3 alkylamino or Cl 3 dialkylamino; and the other substituent is C1 3
alkylsul~myl, C2 s -I-alkenyl-l-thio, C2 5 1-alkenyl-1-sulfinyl, C3 5 2-
alkenyl-l-thio, C3 5 2-alkenyl-1- sulfinyl, thiol, acylthio, dithioacyl,
thiocarbamyl, dithiocarbamyl, alkylcarbonylalkylthio. carbalkoxyalkylthio,
alkoxycarbonylthio, alkoxythionothio, phenylthio, phenylsulfinyl,
: ; . , '
. .
WO 91/19497 ~ ~ 4 2 ~ ~ pcr/us91/o4o22 ~-
., ,
- alkoxyalkylthio, alkoxyalkyl~ lfinyl, alkylthioalkylthio, Z, or
acyloxyalkylthio; or
(e) disubstituted phenyl lerein said substituents are the same and are
selected from halo, C1 3 alk~ y, C1 3 alkylamino, Cl 3 dialkylamino, N-
pyrrolidino, N-piperidino, 2, 2-trihaloethoxy, prop-2-ene-1-oxy,
hydroxy, C1 3 alkylthio, C1 alkylsulfinyl, C1 3 alkyl-sulfonyl, C2 5 1-
alkenyl-1-thio, C2 5 -1-alker. I-1-sulfinyl, C3 5 2-alkenyl-1-thio, C3 5 2-
alkenyl-1-sulfinyl, thiol, acyl io, dithioacyl, thiocarbamyl, dithio-
carbamyl, alkylcarbonylalkyl io, carbaLkoxy-alkylthio, alkoxycarbonyl-
1 0 thio, alkoxythionothio, phem :hio, phenylsulfinyl, alkoxyal}cylthio,
alkoxyalkylsulfinyl, alkylthi~ Ikylthio, ~, or acyloxyalkylthio; or wherein
the substituents together forrr I methylene dioxy group;
(f) a moiety of one of the )llowing formulae:
~3
, R1~ ~
~S--(CR,,R6~;--S~N or
Rl~iR3
~S--(CR~R~ I--S~
R
whereintisOorl;
E~4 and R6 are independently elected from hydrogen, Cl g alkyl, aryl or
heteroaryl;
2 0 Z is -S-(CR4R6),-S ZI;
Zl is Cl g alkyl, aryl or hete ~aryl;
or a pharmaceutically acccptable salt thercof
Another aspect of this inventior elates to a method of treating a
cyclooxygenase pathway mediated disease i 1 subject in need thereof which comprises
2 5 administering to such subject an effective, n ~-toxic cyclooxygenase pathway inhibiting
` amount of a compound of Formula (I).
.
';
~ :.
, ,
; ~- WO 91/19497 5 Pcr/uS9l/04022
Another aspect of this invention relates to the novel compounds of Formula
(II) and a pharmaceutical composidon comprising a pharrnaceutically acceptable carrier or
diluent and an effective amount of a compound of Formula (II).
Another aspect of this invention relates to a method of treadng an OPUFA
5 mediated disease in a subject in need thereof which comprises administering to such subject
an effective, OPUFA inhibiting amount of a compound of Fotmula (II), The cornpounds
of Formula (II) are also effective cyclooxygenase inhibitors and therefor useful in the
treatment of CO mediated disease states as well.
Another aspect of this invention relates to a method of treating an OPUFA
1 0 mediated disease in a subject in need thereof which comprises adrninistering to such subject
an effective, OPUFA inhibiting amount of a compound of Formula (m). The compounds
of Formula (m) are also effective cyclooxygenase inhibitors and therefor useful in the
treatment of CO mediated disease states as well.
1 5 DETAn FD DESCRlPTION OF THE INVEI`~ llON
This invention relates to a method of using the compounds of Formula (I), as
described above, for OPUFA mediated diseases comprising administration of an effective
amount of a compound of Formula (I) to a mammal, including humans, in need thereof.
Preferably the enyme 5-lipoxygenase is inhibited. The invendon furtherrelates to a
2 0 method of treadng a cyclooxygenase pathway mediated disease? which process comprises
administratdon of an cffective amount of a compound of Fonnula ~I) to a mamrnal,including humans, in need thereof.
This invendon also relates to the novd compounds of Formula (~1), described
below and pharmaceutical compositions comprising a compound of Formula (II) and a
2 5 pharmaceudcally acceptable calTier or diluent. This inventdon also relates to a method of
using the compounds of Formula (II) for treadng OPUFA mediated disease, preferably by
inhibition of the 5-lipoxygenase enzyme in a mammal, including humans, in need thereof. .
This invention also relates to a method of treating a cyclooxygenase pathway mediated
~ disease comprising administration of an effective amount of cyclooxygenase pathway
3 0 inhibiting amount of a compound of Formula (II) to a mammal, including humans, in need
of such inhibition.
The compounds of Formula (Il) are encompassed within the genus of the
compounds of Formula (I) and are represented by the structure:
. ~
, ~, . .
WO 91/19497 2 ~ ~ 4 2 ~ 6 - PCr/US91/04022~
j~3
~N~
Formula (Il)
wherein
W is -CRs=CR7-, -N=C~7-, -S- or -0-,
S R2, R3, Rs, and ~7 are, independently, -~I or Cl 2 alkyl;
and one of Tl and To is 4-pyridyl or Cl 4 alkyl-4-pyridyl, provided that when
Tl is Cl 4 aLkyl-4-pyridyl ~he aLc~l substituent is located at the 2-position of the pyridine
ring, and the other of T1 and To is
(a) monosubstituted pheny! wherein sa~d substituent is hydroxy,
` 10 C1 3 aLkylsulfonyl~ C~ 5 1-aL~enyl-1-sul.~onyl, C, 5 2-aLkenyl-l-sulfonyl,
C3 5 2-a}cemJI-1-sulronyl, C~ 3 a!kylamijlo, Cl 3 diaLkylarnino, CF3, N-C
3 -alkanamido, N-(Cl 3 alkyl)-N-(Cl 3 alkanamido), N-pyrrolidino, N-
piperidino, prop-2-ene-1-oxy, 2,2,2-trihaloethoxy, thiol, acylthio, dithioacyl,
thiocarbamyl, dithiocarbarnyl, alkylcarbonylalkylthio, carbalkoxyalkylthio,
;~ 1 5 alkoxycarbonylthio, alkoxythionothio, phenylthio, alkoxyalkylthio,
alkoxyalkylsulfinyl, alkylthioalkylthio, or Z; or
(b) disubstitutcd phcnyl wherein one of said substituents is arnino, N-
Cl 3 -alkanamido, N-(Cl 3 alkyl)-N-(Cl 3alkanarnido), Cl 3 alkylarnino,
Cl 3 dialkylamino, N-pyrrolidino, or N-piperidino; and the other substituent
2 0 is Cl 3 alkylsulfinyl, C2 5 -1-alkenyl-l-thio, C2 S l-alkenyl-l-sulfinyl, C3
~;~, 5 2-alkenyl-1-thio, C3 5 2-alkenyl-1- sulfinyl, thiol, acylthio, dithioacyl,
thiocarbamyl, dithiocarbamyl, alkylcarbonylalkylthio, carbalkoxyalkylthio,
alkoxycarbonylthio, alkoxythionothio, phenylthio, alkoxyalkylthio,
alkoxyalkylsulfinyl, alkylthioalkylthio, Z, or acyloxyalkylthio; or
~ 2 5 (c) disubstituted phenyl wherein said substituents are the same and are
selected from halo, Cl 3 alkoxy, Cl 3 alkylarnino, Cl 3 dialkylamino, N-
pyrrolidino, N-piperidino, 2,2,2-trihaloethoxy, prop-2-ene~1-oxy, hydroxy,
thiol, acylthio, dithioacyl, thiocarbarnyl, dithiocarbarnyl,
alkylcarbonylalkylthio, carbalkoxyalkylthio, alkoxycarbonylthio,
3 0 alkoxythionothio, phenylthio, alkoxyalkylthio, alkoxyalkylsulfinyl,
alkylthioalkylthio, or Z; or
~; (d) disubstituted phenyl wherein said substituents nre, indepenàently
.. Cl 3 alkylamino, Cl 3 dialkylarm~no~ amino, N-(Cl 3alkyl)-N-(Cl 3
alkanarnido, N-pyrrolidino or N-piperidino; or
.
: .. ,
wo 91/19497 7 PCr/US91/04022
- (e) a moiety of one of the following formulae:
j~3
DV
S--(CR4R6j,--S~/
OR R R
~3
~S--(C~ s)l S ~
wherein t is 0 or l;
R4 and R6 are independently selected from hydrogen, Cl 9 alkyl, aryl or
heteroaryl;
Z is -S-(CR4R6)rS-Zl;
Zl is Cl 9 aL~yl, aryl or heteroaryl;
l 0 ar a pharmaceutically acceptable salt thereof.
.
One aspect of this invention is use in medicine of the compounds of Formula
(III), which are also encompassed within the genus of the compounds of Formula tI). The
compounds of Formula (III) are useful as OPUFA inhibitors and in the treatment of CO
. 1 5 mediated diseases, preferably by inhibition of the ~-LO and CO enzymes respectively. The
` compounds of Formula (III) are represented by the structure:
R~ R~ 3
I \
Sl~ ~
: sr Forrnula (III)
2 0 wherein
W is -CR~=CR7-~ -N=CR7-, -S- or -O-;
R ~ R3, Rs, and R7 are, independently, -H or Cl ~ alkyl;
.,
;~ ,. :
'` :.
wo 9l/ls4s7 ~ a ~ 8 - PCT/US91/04022
and one of S 1 is 4-pyridyl or Cl 4 alkyl-4-pyridyl, provided that when S 1 or So is Cl 4
alkyl-4-pyridyl the alkyl substituent is located at the 2-posidon of the pyridine ring, and the
other of S 1 and So is
(a) monosubstituted phenyl wherein said substituent is -H, Cl 4 alkyl,
S halo, Cl 2 alkoxy, Cl 3 alkylthio, Cl 3 alkylsulfinyl, C2 5 1-alkenyl-1-thio, C2.s
1-alkenyl-1-sulfinyl, C3 5 2-alkenyl-1-thio, C3-s 2-alkenyl-1-sulfinyl, or
acyloxyalkylthio; or
(b) disubstituted phenyl wherein said substitutents are, independently, Cl 3
alkylthio, C1 3 alkoxy, halo, or C1 4 alkyl; or
1 0 (c~ disubstituted phenyl wherein one of said substi~uents is C1 3 alkoxy,
halo, Cl 4 allcyl; and the other is Cl 3 alkylsulfinyl, C2 5 -1-aLcenyl-l-thio, C~
1-alkenyl-1-sulfinyl, C3 5 2-alkenyl-1-thio, C3 5 2-alkenyl-1- sulfinyl, or
acyloxyalkylthio: or
(d) disubstituted phenyl wherein the substi~uents are the s~me and are C1 3
allcylsulinfyl, C2 ~1-aLkenyl-1-thio, C2 s-l-aLkenyl-1-sulfinyl, C3 5 ~-aLke:lyl-1-
thio, C3 5 2-alkenyl-1-sulfinyl, or acyloxyalkylthio; or wherein the substi~uents
together form a methylene dioxy;
and the pharmaceutically acceptable salts thereof.
~; Another aspect of the presen~ invendon is a pharmaceudcal composition comprising
2 0 a pharmaceudcally acceptable ca~ier or diluent and a compound of Forrnula (III) for use in
treadng an OPUFA or CO pathway mediated disease state.
,~,
Another aspect of the present invention is a method of treating an OPUl:A mediated
disease state, in a mammal, including humans, in need of such treatment by administering
2 5 an effective amount of a compound or pharmaceutically acceptable salt thereof selected
from
2-(4-Methoxyphenyl)-3-(4-pyridyl)-7-oxo-5,6-dihydro-[7H] -pyrrolo-
[ 1 ,2-a]-imidazole;
5,6-dihydro-2-(4-Methoxyphenyl)-3-(4-pyridyl)-[7H]-pyrrolo-[1 ,2-a]-
3 0 imidazole-7-ol; or
5,6-dihydro-7,7-difluoro-2-(4-Methoxyphenyl)-3-(4-pyridyl)-[7H]-pyr,rolo-
[1,2-a]-imidazole.
Preferaby the enzyme 5-1ipoxygenase is inhibited.
3 5 Another aspect of the present invention is a method of treating a CO pathway
mediated disease state, in a mammal, including humans, in need of such treatment, which
process comprises administering, an effective amoun~ of a compound or pharmaceutically
acceptable salt thereof, selected from
, :
,. WO91/19497 ~ Pcr/US91/04022
2-(4-Methoxyphenyl)-3-(4-pyridyl)-7-oxo-5,6-dihydro-[7H]-pyrrolo-[1 ,2-a~-
imidazole;
5,6-dihydro-2-(4-Methoxyphenyl)-3-(4-pyridyl)-[7H]-pyrrolo-[ I ,2-a~-imidazole-7-
ol; or
5,6-dihydro-7,7-difluoro-2-(4-Methoxyphenyl)-3-(4-pyridyl)-[7H]-pyTrolo-
[ 1 ,2-a] -imidazole.
Yet another aspect of the present invention is a pharmaceutical composition
comprising a pharmaceutically acceptable carrier or diluent and a compound or
1 0 pharmaceutically acceptable salt thereof, selecud from 2-(~Methoxyphenyl)-3-(4-pyridyl)-
7-oxo-5,6-dihydro-[7H]-pyrrolo-~1,2-a]-imidazole; S,6-dihydro-2-(4 Methoxyphenyl)-3-
(4-pyridyl)-[7H]-pyrrolo-[1 ,~-a]-imida~ole-7-ol; or 5,6-dihydro-7,7-difluoro-2-(4-
Methoxyphenyl)-3-(4-pyridyl)-[7H]-pyrrolo-[ I ,2-a]-imidazole, for use in treating a CO or
OPUFA pathway mediated disease.
Preferred OPUFA mediated disease states inhibited in the processes of the
present invention, include, but are not limited to, arthritis, rheumatoid arthritis,
osteoarthritis, allergic rhinitis, psoriasis, derrnatitis, ischemic induced myocardial injury
reperfusion injury, gout, asthma, adult respiratory distress syndrome, atherosclerosis,
2 0 inflammatory bowel disease, slroke, spinal coTd injury and traumadc brain injury.
: Preferred Cyclooxygenase mediated disease states inhibited in the processes of
the present invention, include, but are not limited to, pyresis, pain, osteoarthritis,
rheumatoid arthritis, thrombosis, inflamrnation, uticaria or edema.
2 5 The compounds of Formula (III) are described in a U.S. patent application by
Bender ~., U.S.S.N. 07/365,349, filed June 13, 1989, and in Bender ~L. PCT
US90/03367, filed contemporaneously herewith, the entire disclosures all of which are
hereby incorporated by reference. It has now been found that the compounds of Formula
(III~ possess the ability to inhibit both the 5-lipoxygenase and cyclooxygenase enzymes
3 0 thereby making them useful for treating either a 5-LO or CO pathway mediated disease stare
in a mammal in need thereof.
A prefemd embodiment of this invention for the compounds of Forrnula (I) is
where W is -CR5=CR7- or -N=CR7.
Preferred compounds of Formula (I) include those wherein:
3 5 W is -CRs=CR7-, -N=CR7-, -S- or -O-;
R2 and R3 are hydrogen,
: . :
WO 91/19497 2 ~ ~ 4 2 9 ~ o - PCr/US91/04022~
one of Rl and Ro is 4-pyridyl or C1 2 alkyl4-pyridyl, provided that when R1
is Cl 2 alkyl-4-pyridyl the alkyl substituent is located at the 2-position of the pyridine ring,
and the other of Rl and Ro is
(a) monosubstituted phenyl wherein said substituent is halo,
Cl 3 allcylamino, C1.3 dialkylamino, thiol, hydroxy, Cl.3 alkoxy, Cl.3
aLcylthio, Cl 3 alkylsulfinyl, acyloxyalkylLhio, or acylthio;
(b) disubstituted phenyl wherein said substitutents are, independently,
Cl 3 aLcylthio, Cl 3 alkoxy, Cl.3 alkylamino, Cl.3 dialkylamino, N-
pyrrolidino,orN-piperidino; or
l 0 (c) disubstituted phenyl wherein one oî said substituents is Cl 3
alkylsulfinyl, acylthio, 1-acyloxy-1-alkylthio and the other is Cl 3 alkoxy or
halo; or
(d) disubs;ituted phenyl wherein one of said substituents is C1.3
aLkylal-nino, Cl.3 diaLcyl~mino and ;he other is selected from acylthio,
1 5 alkylsulfinyl, phenylsulIinyl or acyloxyallcyl hio; o}
(e) disubstituted phenyl wherein the substituents are the same and are
C1.3 alkoxy, C1 2 alkylsulfinyl, C2 3 1-alkenyl-1-thio, 2-propenyl-1-thio or
~. l-acyloxy-1-alkylthio or wherein the substituents together form a methylene
; dioxy group.
` More preferred are the compounds of Formula (I) wherein:
W is -CRs=CR7-, -N=CR7-, -S- or -O-;
R2 and R3 are hydrogen,
one of ~1 and Ro is 4-pyridyl or C1 2 alkyl~-pyridyl, provided that
.. 2 5 when Rl is C1 2 alkyl-~pyridyl the alkyl substituen~ is located at the 2-
position of the pyridine ring, and the other of R1 and Ro is
(a) monosubstituted phenyl wherein said substituent is C1.3 alkylthio,
Cl 3 alkylsulfinyl, acyloxyalkylthio, or acylthio;
. (b) disubstituted phenyl wherein said substdtutents are, independently,
3 0 C1 3 alkylthio, C1.3 alkoxy, C1.3 alkylamino, or C1.3 dialkylamino; or
(c) disubstituted phenyl wherein one of said subsdtuents is Cl 3
alkylsulfinyl, acylthio, 1-acyloxy-1-alkylthio and the other is Cl 3 alkoxy or
halo; or
(d) disubsdtuted phenyl wherein one of said substituents is Cl 3
3 5 alkylamino, Cl.3 dialkylarnino and the other is selec~ed from acylthio,
alkylsulfinyl, phenylsulfinyl or acylo~;yalkylthio: or
(e) disubstituted phenyl wherei:l ~he subs~ituen~s are the same and are
Cl.3 alkoxy, Cl 2 alkylsulfinyl, C~ 3 1-alkenyl-l-thio, 2-propenyl-1-thio or
WO 91~19497 ~ PCr/US91/04022
1-acyloxy-1-aL~cylthio or wherein the substituents together form a methylenc
dioxy group.
The most preferred compound of Formula (I) is 2-(4-Methoxyphenyl)-3-(4-
S pyTidyl)-imidazo[1,2-a]-pyridine.
Other preferred compounds are:
2-(4-methoxyphenyl)-3-(4-(2-me~hyl)pyridyl)imidazo[1 ,2-a]pyridine;
2-(4-fluorophenyl)-3-(4-pyridyl)imidazo[ 1 ,2-a]pyridine;
1 0 2-(4-methylthiophenyl)-3-(~-pyridyl)imidazo[ 1 ,2-a]pyridine;
2-(4-methylsulfiny!phenyl)-3-(4-pvridvl)imidazo[ 1 ,2-a]pyridine;
2-(4-din-.ethyl-allcyl~m~inopher.yl)-3-(~-pyr.dyl)imid3zo[ 1 ,2-a]pyri.dine;
2-(4-methyl-aminophenyl)-3-(4-pyr.dyl)i!nida_o[ 1 ,2-a]pyridine;
2-(4-N-piperidinophenyl)-~-( '-pyridyl)imida7o[1,2-a]p~T.dine;
1 5 2-(4-acetoxymelhylthiophenyl)-3-(4-pyridyl)imidazo[1,2-ajpyridine;
2-(4-(2-acetylthio)phenyl)-3-(4-pyridyl)imidazo[1,2-a]pyridine;
2-(4-(2-acetylthio)phenyl)-3-(4-(2-methyl)pyridyl)imidazo[ 1 ,2-a]pyridine;
2-(~pyridyl)-3-(4-methylsulfinyl)phenyl)imidazo[ 1,2-a]pyridine;
2-(4-pyridyl)-3-(4-methylthiophenyl)imidazo[1,2-a]pyridine;
2 0 2-(4-pyridyl)-3-(4-methylsulfinyl)phenyl)imidazo[1,2-a]pyndine;
6-(4-methylthiophenyl)-5-(4-pyridyl)imidazo[2,1 -b]oxazole;
6-(4-acetylthiophenyl)-5-(4-pyridyl)imidazo[2,1 -~]oxazole;
6-(4-methylsulfinylphenyl)-S-(4-pyridyl)imidazo[2,1-b]oxazole;
7-(4-fluosophenyl)-6-(4-pyridyl)imid zo[l,2-a]pyrimidine;
2 S 7-(4-methylthiophenyl)-6-(4-pyridyl)imidazo[1,2-a]pyrimidine;
7-(4-methylsulfinylphenyl)-6-(4-pyridyl~imidazo[1,2-a]pyrimidine;
6-(4-methylthiophenyl)-S-(4-pysidyl)-imidazo[2, 1 -b]thiazole;
6-(4-methylsulfinylphenyl)-S-(4-[2-methyl]-pyridyl)-imidazo[2,1 -b]thiazole;
6-t4-fluorophenyl)-3-(4-pyridyl)- imidazo[2,1-b]thiazole;
3 0 6-(4-N-pyITolidinophenyl)-3-(4-pyridyl)-imidazo[2,1-b]thiazole;
6-(4-methoxyphenyl)-S-(4-(2-methyl)pyridyl)-imidazo[2,1-b]thiazole;
6-(4-acetylthiophenyl)-S-(4-(2-methyl)py~idyl)-imldazo[2,1-b]thiazole;
S-(4-acetylthiophenyl)-S-(4-pyridyl)-imidazo[2,1-b]thiazole;
S-(4-methylsulfinylphenyl)-6-(4-(2-methyl)pyridyl)-imidazo[2,1-b]thiazole; or
3 5 6-(4- dimethylalkylaminophenyl)-5-(4-(2-methyl)pyridyl)-imidazo[2,1-b]thiazole;
or a phasmaceu~ically acceptable salt of any one of the above compounds.
,
.
.. ` '' . ' .
2 0 ~
WO91/19497 -12 - PCl/US91/04022
A preferred embodiment of this invention for the compounds of Formula (II)
is where W is -CRs=CR7- or -N=CR7.
A preferred emodiment of the present invention are the compounds of Fonnula
(II) wherein:
W is -CRs=CR7-, -N=CR7-, -S- or -O-;
R2 and R3 are hydrogen,
one of Rl and Ro is 4-pyridyl or Cl 2 aL~cyl-4-pyridyl, provided that when R1
is C1 2 alkyl-4-pyridyl the alkyl substituent is located at the 2-position of the pyridine ring,
and the other of R I and Ro is
1 0 (a) monosubstituted phenyl wherein said substituent is Cl.3 alkylamino.
Cl 3 dialkylarnino, thiol, hydroxy, or acylthio;
(b) disubstituted phenyl wherein said substitutents are, independentl-,
Cl 3 alkylarnino, Cl 3 diallcylamino, N-pyrrolidino, or N-piperidino; or
(c) disubstituted phenyl wherein one of said substituen~s is C1 3
- 1 5 acylthio and the other is C1 3 alkoxy or halo; or
(d) disubstituted phenyl wherein one of said substituents is Cl 3
alkylarnino, Cl 3 dialkylamino and the other is selected from acylthio, alkylsulfinyl,
phenylsulfinyl or acyloxyallcylthio.
2 0 More preferred compounds of Formula (II) are those where
W is -CRs=CR7-, -N=CR7-;
where one of R1 and Ro is
~, (a) monosubstituted phenyl wherein said substituent is Cl 3
dialkylamino or acylthio;
2 5 (b) disubstituted phenyl wherein said substitutents are, independently,
C1.3 alkylarnino, or C1.3 dialkylamino, N-pyrrolidino, or N-piperidino; or
(c) disubstitu~ed phenyl wherein one of said substituents is acylthio and
the other is C1 3 alkoxy or halo; or
(d) disubstituted phenyl wherein one of said substituents is C~ 3
3 0 alkylamino, C1.3 dialkylarnino and the other is selected from acylthio,
alkylsulfinyl, phenylsulfinyl or acyloxyalkylthio.
It should be noted that the compounds of Formula (I), (II) or (III) where Rl or
Ro may be a Cl 3 alkylsulfinyl, C2 5 l-alkenyl-1-sulfinyl, C2 5 -2 alkenyl-l-sulfinyl,
3 5 alkoxyalkylsulfinyl, and phenylsulfinyl moietv, are prodrugs which are reductively
converted in vivo to the corresponding alkylthio or alkenylthio form.
By the term "halo" as used herein is meant all halogens, i.e., chloro, fluoro,
bromo and iodo, preferably fluorine.
91/1949~ -13 - PCI/US91/04022
By the term "aryl" as used herein is mean~ phenyl, or naphthyl, which are both
optionally substituted with halogen, Cl.3 aL~coxy, Cl.3 alkylthio or Cl 1 alkyl.By the term "heteroaryl" as used herein is meant a 5-10 membered aromatic
ring system in which one or more rings contain one or more heteroatoms selected from the
5 group consisting of N, O or S; such as, but not limited, to quinoline, isoquinoline,
pyridine, pyrimidine, oxazole, thiazole, thiadiazole, triazole, imidazole; all of which may be
optionally substituted by one or more of halogen, Cl.3 allcoxy, Cl.3 alkylthio or Cl~ alkyl
moieties.
By the term "OPUFA mediated disease or disease state" is meant any
1 0 disease state which is mediated (or modulated) by oxidation of polyunsaturated fatty acids.
specifically the arachidonic acid metabolic pathway. The oxidation of arachidonic acid by
such enz,vmes as the lipoxygenase enzymes or cyclooxgenase enzyme is specifically
targeted by the present invention. Such enzymes include, but are not limited to, 5-LO, 12-
LO, 15-LO, and CO; which produce the following mediators, including but not limited to,
1 ~ PGE2, LTB4, LTC4, LTD4, prostaglandins, thromboxane, and prostocyclin.
By the term "OPUFA interfering amount" is meant an effective amount of a
compound of Formula (I) which shows a reduction of the in vivQ levels of an oxgyenated
arachidonic acid metabolite.
By the term "sulfinyl" as used herein is meant the oxide of the corresponding
2 0 sulfide. By the term "thio" as used herein is meant d e sulfide. For further clarification,
the following table oudines the structural attachment of the atoms of the Rl and Ro
substituents of the compounds of Fonnula (I):
Table 1
BlQ~Btl Structural Attachment
2 5 C1 3alkylsulfinyl [AS(O)-]
C~ 5 l-alkenyl-l-thio [AAlC=CHS-~ .
C2 5 l-alkenyl-l-sulfinyl [AAlC=CHS(O)-]
C3 5 2-alkenyl-1-thio [ACH=CAlCH2S-]
C3 5 2-alkenyl-1-sulfinyl [ACH=CA1CH2S(O)-]
3 0 l-acyloxy-l-alkylthio [AC(O)OCH(Al)S-]
acylthio [DC(O)S-]
dithioacyl [DC(S)S-]
thiocarbamyl [DDlNC(O)S-]
dithiocarbamyl [DDlNC(S)S-]
3 5 alkylcarbonylalkylthio [DC(O)cH2s-]
carbalkoxyalkylthio [BOC(O)CH~S-~
alkoxycarbonylthio [BOC(O)S-]
alkoxythionothio [BOC(S)S-]
..
.
.
.
Wo 91~19497 2 0 ~ ~ 2 ~ 14 - PC~/US91/04022 ,~"~
allcoxyalkylthio [BocH2s-]
alkoxyalkylsulfinyl [BOCH2S(O)]
alkylthioalkylthio [BSCH2S-]
disulfide [Z] [-S-S-Zl]
NOTE: A and Al are hydrogen or aLkyl; and D and D1 are hydrogen, Cl~g alkyl, or
phenyl; B is Cl 9 alkyl or aryl; and Zl is aryl, heteroaryl or Cl g alkyl. The
hydrogen atoms in the CH2 ~roups described in Table I are, independently,
optionally substituted by a Cl 1 aLkyl moiety.
1 0
Another as~ect of the present invention is the novel oxidation of an aryl
sulfide, in pardclllar al!~yl thio arvl function, such as a methylthiophenyl group, to the
correspondin, sulfoxide wherein the aryl sulfide is substituted on a heteroaromatic nitrogen
containing ring system. such 2S imida~ole, triazole, pyrimidine, pyridine, 6,7-dihydro-
1 5 [5H]-pyrrolo[2,1-a]imidazole, 2,3-dihydroimidazo[2,1-b]-a'liazoie, irnidazo[2,1-
i b]thiazole, imidazo[2,1-b]oxazole, imidazo[1,2-a]pyridine, 5,6,7,8-tetrahydroimidazo[1,2-
a]pyridine, or a imidazo[1,2-a]pyrimidine ring system. The process occurs in high yield
with minimal forrnation of the sulfone byproducts~ This process oxidizes the sulfide in
higher yidds than do altcmative methods, such as m-chloroperbenzoic acid. This process
2 0 also utilizcs ~he inexpensive and readily available reagents, potassium or sodium persulfate.
This process also does not utilize toxic metal, thus providing advantages in purification of
the reaction product and disposal of wastes.
Sodium and potassium persulfate are salts of peroxysulfuric acid. Other more
commonly used peroxyacids, such as m-chloroperbenzoic acid, are well-known to oxidize
2 5 amines and pyridines to their N-oxides. It would be the expectation, that persulfuric acid
or its salts would exhibit similiar reactivity and hence make them useless for the oxidation
of compounds such as those disclosed herein, as they contain several nitrogen atoms.
- Furtherrnore, sodium and potassium persulfate have been known for some dme to oxidize
aniline derivatdves to aniline-o-sulfates ( the Boyland Sims oxidation, disclosed in Boyland
3 0 et al., J~ ~Soc. 3623 (1953), and in 3erhman et al, J. Org~ Chem. 43, 4551 tl978))
and to act as a c~oxidant in the oxidation of a wide variety of alkylarnine to aldehydes or
ketones (see Bacc,n et al., J. Chem Soc. 'C), 1384 (1966). Srinivasan et al., Indian J.
., 268, p. 193 (1987) describes th` xidalion of a number of sulfide compounds
which have other functionalities such as methoxy, nitro, acetyl, and chloro groups but none
3 5 contain an amine nit~ogen, such as the compounds of this invendon. The present
invention has found that the persulfate reagents no~ only work on the compounds of
Formula (I), tII) and (III) disclosed herein, but ~ill also work ~ell on their interrnediates
WOgl/19497 -15 ~ PCr/US91/û4022
and other ring systems which contain a heterocyclic nitrogen atom, such as pyridine,
imidazole, or other tertiary amine moieties.
Prefered aryl sulfides are the phenylsulfide derivadves. Further preferred are
the alkyl substituted alkyl sulfide derivatives, such as methyl or ethyl thio. Hetero-aromatic
5 and non-aromatic nitrogçn containing ring system on which the aryl sulfide moiety is
found, includes but is not limited to pyrrcle, pyr~ole, imidazole, imidazolididine,
pyrazolidine, pyrazoline, morpholine, pyridine, pyrazine, indolizine, indoline, purine,
quinoline, isoquinoline, napthyridine, triazole. pyrimidine, piperidine, isoindole,3H-
indole, ciMoline, carbazole, phenanthradine, phenazine, isothiazole, imidazo[1,2-
1 0 b]~l ,2,4]triazine, triazine, pyrsdazine, ~,7-dihydro-[5H]-pyrrolo-[2,1 -a]imidazole, 2,3-
dihydroirnidazo[2,1 -b] -thiazole- 1 -oxide or 1,1 -dioxide, imidazo-[2,1 -b]thiazole; 2,3,4,5
tetrahydro-imidazo[2,1-b]thiazole-1-oxide or 1.1-dioxide. imidazo[2,1-b]oxazole,imidazo[1,2-a]pyridine, 5,6,7,3-tetr3hydroimidazo-[1,~-a]pyridine, or a imidazo-[1,2-a]pyrimidine rin~, system. The aryl sulfide groups in ;he case of multiple ring systems
1 5 may be attached to either ring, saturaled or unsaturaled.
Preferrably the nitrogen heterocyclic ring system is irnidazole, pyrole, 2,3-
dihydroimidazo[2,1 -b]-thiazole, imidazo[2,1 -b] thiazole- 1 -oxide or 1,1 -dioxide,
imidazo[1,2-a]pyridine, 6,7-dihydro-[5H]-pyrrolo[2,1-a]imidazole or imidazole. The
particulars of the oxidation are further dcscribed herein in the synthetic chemistry section.
2 0 More preferably is the oxidation of 2-(4-Methylthiophenyl)-3-(4-pyridyl)-6,7-
dihydrolSHlpyrrololl,2-a]imidazole to the corresponding methylsulfonyl derivative Most
preferred is the use of the oxidant sodium persulfate.
The preparation of 2-(4-Methoxyphenyl)-3-(4-pyridyl)-7-oxo-5,6-dihydro-
[7H]-pyrrolo[1,2-a]imidazole; 5,6-dihydro-2-(4-Methoxyphenyl)-3-(4-pyridyl)-[7H]-
2 5 pyrrolo[1,2-a]imidazole-7-ol; and 5,6-dihydro-7,7-difluoro-2-(4-Methoxyphenyl)-3-(4-
pyridyl)-[7'Hl-pyTrolo~1,2-a]imidazole is disclosed in Gallagher et al., Tetrahedron Letters,
Vol. ~0, No. 48, pp.6599-6602 (1989) the entire disclosure of which is hereby
incorporated by reference. Preparation of the pharrnaceutically acceptable salts of these
three compounds can be prepared by known techniques such as the method of Bender et
3 0 al., U.S. Patent 4,175,127, issued November 20, 1979, the disclosure of which is hereby
incoTporated by reference.
I'he preparation of all compo~ nds of Formula (III) and the pharrnaceutically
acceptable salts thereof ,which are also encompassed within the Formula (I) genus
described herein, when W is -CRs=CR7-, -N=CR7-, -S- or-O-; and R2, R3, Rs, and R7
3 5 are independently H or Cl 2 alkyl are prepared as described in U.S. patent application by
Bender et al., U.S.S.N. 071365,349, filed June 13, 1989, and in Bender et ah, PCI
US/90/03367, filed 3une 12, 1990 the entire disclosures ~11 of which are hereby
incorporated by reference.
', :
wo 91/19497 2 0 ~ '~ 2 ~ u -16 - PCI/US91/04022
The preparadon of all compounds of Formula (TI) and pharrnaceutically acceptablesalts thereof may be prepared by one skilled in the art using analogous methods readily
available and adaptable to the ring systems described U.S. patent application by Bender
ak, U.S.S.N. 07/365,349, filed June 13, 1989, and in Bender ~}L, PCT Serial PCT
US/90/03367, filed June 12, 1990. Said analogous methods for synthesis of the particul~
substituent groups of Formula (II) are disclosed in Bender et al., U.S. Patent Number
4,175,127, issued November 20, 1979, Bender et al., U.S. Patent Application Serial
Number 07/106,199 filed on July 10, 1987 or Bender ~, U.S. Patent Number
4,803,279, issued February 9, 1989, and in Adarns et al., U.S. Patent 4,719,218, issued
1 0 01/12/88 the entire disclosures of all of which are hereby incorporated by reference.
The preparation of all the remaining compounds of Formula (II) can be
carried out by one of skill in th~o art according to the procedures outlined in the E~amples,
infra.
All the compounds of For nula (C), Formula (D), Forrnula (E), Formul~
1 5 (F), Formula (G) and Formula (H) are useful as intermediates in the preparation of the
compounds of Formula (II). The preparation of all the compounds of Formula (C),
Formula (D), Forrnula (E), Formula (F), Forrnula (G) and Formula (H) can be carried out
by one of skill in the art according to the procedures outlined in the Exarnples, infra.
Pharmaceutically acceptable salts and their preparation are well known to
2 0 those skilled in pharmaceuticals. Pharmaceudcally acceptable salts of the compounds of
Formula (I) or Formula (II) which are useful in the present invention 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) or
2 5 Formula (II) include hydrochloride and hydrobromide salts, and such salts can be prepared
by known techniques such as the method of Bender et al., U.S. Patent 4,175,127, issued
November 20, 1979.
The compounds of the present invention may contain 1 or more asymmetric
carbon atoms and may exist in racemic and optically active forms. All of these compounds
3 0 are contemplated to be within the scope of the present invention.
.~ The compounds of intermediate Formula (C) are represented by the structure:
R~3
I_
~W
X N
FORMIJLA (C)
or a pharmaceutically acceptable salt thereof,
2 ~
. ~ Wo91/19497 -17 - PCr/US91/04022
wheresn:
W is -CRs=CR7-, -N=CR7-, -S- or -0-;.
R2, R3, Rs and R7 are, independently H or C1.2 alkyl;
X is a) 4-pyridyl or mono-C1 4alkyl-substituted pyridyl; or
b) monosubstituted phenyl wherein said substituent is selected from
halo, Cl 3 alkoxy, hydroxy, Cl 3 alkylthio, Cl 4 alkyl, alkenylthio,
phenylthio, alkoxyalkylthio, alkylthioalkylthio, Cl 3 aLkylamino,
alkylcarbonylalkylthio, carbalkoxyalkylthio, Cl 3 dialkylamino, CF3, N-
(C1 3 alkyl)-N-(C1 3 alkanarnido), N-pyrrolidino, N-piperidino, prop-2-
; I O ene-l-oxyor2,2,2-trihaloethoxy;
(c) disubstituted phenyl wherein said substituents are the same and
arc selected from halo, C1 3 alkoxy, C1 3 alkylthio, C1 3 alkylamino, Cl
3 dialkylamino, N-pyrrolidino, N-piperidino, 2,2,2-trihaloethoxy, prop-2-
ene-l-oxy, or hydroxy;
1 ~ (d) disubstituted phenyl wherein said substituents are not the same
and are independently selec~ed from halo, Cl 3 alkylarnino, nitro, N-(Cl 3
alkyl)-N-(Cl 3 alkanamido), Cl 3 dialkylamino, N-pyrrolidino, or N-
piperidino; or
(e) disubsdtuted phenyl wherein one of said substituents must be C
2 0 3 alkoxy, hydroxy, Cl 3 alkylthio, 2,2,2-trihaloethoxy or prop-2-ene-I-
oxy and the other substituent is independently selected from halo, Cl 3
alkylamino, nitro, N-(Cl 3 alkyl)-N-(Cl 3 aL~canamido), Cl 3
dialkylarnino, N-pyrrolidino, or N-piperidino;
The Intennediate compounds of Forrnula (D) are represented by the strucnrre:
~ 25
. R2 R3
.. ~
N W
Y'~
. y~ .
FORMULA (D),
or a pharmaceutically acceptable salt thereof,
: wherein:
3 0 W is -CRs=CR7-, -N=CR7-, -S- or -0-;
R2, R3, Rs and R7 are, independently, -H or Cl 2 alkyl;
Y1 is 4-(1,4-dihydro)pyridyl substituted with N-(C1 8 alkanoyl), N-(Cl 8
alkoxycarbonyl), N-benzoyl, N-phenoxycarbonyl, N-phenylacetyl, or N-benzyloxy-
carbonyl;
.
, - .:... , . ~ ,
WO 91/1~497 ~ 2 ~ 8 - PCI/US91/04022 ,~
Yo is (a) monosubstituted phenyl wherein said substituent is C1~3
alkylthio, Cl 3 alkoxy, halo, Cl 4 alkyl, hydroxy, alkenylthio, phenythio,
alkoxyalkylthio, alkylthioalkylthio, alkylc~rbonylalkyl hio, carbalkoxy-
alkylthio, Cl 3 dialkylarnino, CF3, N-(Cl.3 alkyl)-N-(Cl 3 alkanamido),
N-pyrrolidino, N-piperidino, prop-2-ene-1-oxy, or 2,2,2-trihaloethoxy;
(b) disubstituted phenyl wherein said s~lbstituents are the same and
are selected from halo, C1 3 aLkoxy, Cl 3 allcylthio, alkenylthio,
phenylthio, alkoxyalkylthio, alkylthioaLkylthio, Cl 3 dialkylamino, N-
pyrrolidino, N-piperidino, 2,2,2-trihaloethoxy, prop-2-ene-1-oxy, or
1 0 hydro:~y; or wherein the substitutents together form a methylene dioxy
group; or
(c) disubs~irute~ phenyl wherein said substitu~ents are~ independentlv,
Cl 3 alkylthio, Cl 3 al!coxy, halo, C1 1 alkyl, N-(CI 3 alkyl)-N-(Cl 3
alkanamido), Cl 3 diaLkyl2m.ino, N-p~Omolidino, or ~i-?iper.dino; or
1 5 (d) disubstir~t~d phenyl wher in orle of said subs;iluents mus; be Cl
. 3 alkoxy, hydroxy, Cl 3 alkylthio, 2,2,_-trihaloethoxy orprop-2-ene-1-oxy
and the other substituent is independently selected from halo, N-(Cl 3
alkyl)-N-(CI 3 alkanamido), Cl 3 dialkylaIruno, N-pyrrolidino or N-
piperidino; or
2 0 (e) disubstituted phenyl wherein one of said substituents must be
. Cl 3 alkoxy, halo, Cl 3 dialkylamino, and the other is selccted from
alkenylthio, phenylthio, allcoxyal`kylthio, or alkylthioalkylthio,
The intermediate compounds of Formula (E) are represented by the structure:
~3
~ N ~W
.. y--N
2 5 Zl~
FORMULA tE),
whereln:
W is -CRs=CR7-, -N=CR7-, -S- or -O-;
R ~, R3, R5 and R7 are, independently~ -H or C1 2 alkyl;
3 0 one of Zl and Zo is 4-(1,2-dihydro-'~-alkyl)pyridyl subs~ituted with N-(CI-8
alkanoyl), N-(C1-8 alkoxycarbonyl), N-benzoyl, N-phenoxycarbonyl, N-phenylacetyl, or
N-benzyloxycarbonyl; and the other of Zl and Zo is
ta) monosubstituted phenyl wherein said subs;ituent is selected from
Cl 3 alkoxy, halo, Cl 4 .qlkyl, C1 3 alkylthio, alkenylthio, phenylthio,
' ' ' ` '
,
'~
2 0 ~ .1 r~ ('; ~J
~, WO 91/19497 -19 - PCr/US91/04022
alkoxyalkylthio, alkylthioalkylthio, N-(Cl 3 alkyl)-N-(Cl 3 aLl~anamido),
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 independently
selected from Cl.3 alkylthio, Cl 3 alkoxy, halo, C1.4 alkyl, N-(C1 3
alkyl)-N-(Cl 3 alkanamido),CI 3 diaLkylamino, N-pyrrolidino, or N-
piperidino;
(c) disubstituted phenyl wherein said substitutents are the same and are
selected from halo, Cl 3 alkoxy, Cl 3 diaLkylamino, Cl 3alkylthio, N-
1 0 pyrrolidino, N-piperidino, 2,~,2-trihaloethoxy,or prop-2-ene-1-oxy,
alkenylthio, phenylthio, alkoxyaLkylthio, or alkylthioa1'cylthio; or wherein
the substitutents together forrn a methylene dioxy group;
(d) disubstituted phenyl wherein one of said substituents must be C1 3
alkoxy, C1 3 alkylthio, 2,2,2-tnhaloethoxv orprop-2-ene-1-oxy and the
1 5 other substituent is indepe:lde~ v ~elor~._d fr-~m ha!o, N-(Cl 3 aLlcyl)-N-
(C1 3 alkanamido), C1 3 dialkylarnino, N-pyrrolidino, or N-piperidino;
(e) disubstituted phenyl wherein one of said substituents must be C1 3
alkoxy, halo, or C1 3 di-alkylamino, and the other substituent is selected
from alkenylthio, phenylthio, alkoxyaLkylthio, or alkylthioalkylthio;
2 0 or a pharmaceutically acceptable salt thereof.
The intermediate compounds of Forrnula (P) are represented by the stlucture:
.. R2 R3
'' ' ` /==1\
(R1O)3sn
.`. X2
FORMIJLA (F)
2 5 wherein:
: W is -CRs=CR7-, -N=CR7-, -S- or -O-;
R2, R3, Rs and R7 are, independently, -H or C1 2 alkyl;
` Rlo is Cl 4 alk,,l; and
X2 is 4-pyridyl or mono-Cl 4alkyl-substituted pyridvl;or
3 0 (a) monosubstituted phenyl wherein said substituent is selected from
fluoro, chloro, Cl 3 alkoxy, Cl 4 alkyl, Cl 3 alkylthio, alkenythio,
phenylthio, alkoxyalkyllhio, alkyllhioalkylthio, Cl 3 dialkylamino, CF3,
C1 3 alkylamino, N-pyrrolidino, N-piperidino, prop-2-ene- 1-oxy or 2~2~ 7-
trihaloethoxy;
.
:..................................... , :: , . .
. . .
: . , .. : ,.
2 ~ 2 ~ 'J
WO 91/19497 -20 - PCr/US91/04022 ,~,_
(b) disubsdtuted phenyl wherein said substitucnts arc the same and are
selected from fluoro, chloro, Cl 3 alkoxy, C1 3 dialkylamino, N-
pyrrolidino, N-piperidino, 2,2,2-trihaloethoxy, prop-2-ene-l~oxy,
alkenythio, phenylthio, alkoxyalkylthio, alkylthioalkylthio;
(c) disubstituted phenyl wherein said substituents are independently
select~d 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 C1 3
alkoxy, 2,2,2-trihaloethoxy or prop-2-ene-1-oxy and the other substituent is
1 0 independently selected from fluoro, chloro, C1 3 alkylamino, C1 3
dialkylamino, N-pyrrolidino or N-piperidino; or
e) disubstituted phenyl wherein one of said substituents must be Cl 3
alkoxy, fluoro, chloro, Cl 3 alkylamino, or Cl 3 dialkylamino, and the
other is selected from alkenythio, phenylthio, alkoxyalkylthio, or
1 5 alkylthioalkylthio.
The interrnediate compounds of Forrnula (G) are represented by the structure:
~3
N W
.` '~
.. V~
FORMIJLA (G),
or a pharmaceutically acccptable salt thereof,
. 2 0 wherein:
W is -CRs=CR7-, N=CR7-, -S- or -O-;
R2, R3, Rs and R7 are, independently, -H or C1 2 alkyl; and
one of V1 or Vo is 4-pyridyl or Cl 4alkyl-4-pyridyl, provided that when Vl is
Cl 4alkyl-4-pyridyl the alkyl substitutent is located at the 2-position of the pyridine ring,
2 5 and the other of Vl and Vo is selected from:
(a) monosubstituted phenyl wherein said substituent is mercapto; or
(b) disubstituted phenyl wherein one of said substituents must be
mercapto and the other is selected from mercapto, C1 3 alkoxy, halo, nitro,
Cl 4 alkyl, 2,2,2-trihaloe~hoxy, prop-2-ene-1-oxy, C1 3 alkanamido, N-Cl 3
3 0 -alkyl-CI.3alkanamido, Cl 3 dialkylamino, N-pyrrolidino or N-piperidino;
The intennediate compounds of Forrnula (H) are represented by the structure:
.
~ Q ~ ~ ~ 9 ~
~ WO 91/19497 -21 - PCl/US91/04022
73
=\
N
X1'
FORMULA (H)
wherein:
W is -CRs=CR7-, -N=CR7-, -S- or-O-;
R2, R3, Rs and R7 are, independently, -H or Cl 2 alkyl; and
xl is selected from
(a) monosubstituted phenyl wherein said substituent is selected
from fluoro, chloro, Cl 3 alkoxy, C1 4 alkyl, Cl 3 dialkylamino,
CF3, Cl 3 alkylamino, N-pyrrolidino, N-piperidino, prop-2-ene-1-
1 0 oxy, 2,2,~-trihaloeth.oxy, Cl 3 alkylthio, alkenylthio, phenylthio,
alkoxyalkylthio, or alkyl-~ioalkylthio;
(b) disubstituted phenyl wherein said substituents are the sarne
and are selected from fluoro, chloro, Cl 3 alkoxy, C1 3 dialkylamino,
N-pyrrolidino, N-piperidino, 2,2,2-trihaloethoxy, prop-2-ene-1-oxy,
1 5 Cl 3 alkylthio, alkenylthio, phenylthio, alkoxyalkylthio, or
alkylthioalkylthio;
(c) disubstituted phenyl wherein said substituents are
independently selected from fluoro, chloro, Cl 3 alkylthio, Cl 3
alkylamino, C1 3 dialkylamino, N-pyrrolidino, orN-piperidino; or
. 2 0 (d) disubstituted phenyl wherein one of said substituents must be
C1 3 alkoxy, 2,2,2-trihaloethoxy or prop-2-ene-1-oxy and the other
substituent is independently selected from fluoro, chloro, Cl 3
alkylamino, Cl 3 dialkylamino, N-pyrrolidino, or N-piperidino;
(e) disubstituted phenyl wherein one of said substituents must be
2 5 Cl 3 alkoxy, fluoro, chloro or C1.3 dialkylamino; and the othersubsdtuent is independently selected from alkenylthio, Cl.3 alkylthio,
phenylthio, alkoxyalkylthio, or alkylthioalkylthio;
or a salt thereof.
Additional intermediate compounds which are also useful in the process of this
3 0 invention to make the compounds of Formula (II) are compounds of Fonnulas (IIa) and
(lIb) as described below. Additionally, as more elaborately described herein, while all of
the compounds of Formula (II) are useful in the method of the subject invention, some of
the compounds of Formula (II) are also useful as intermediates in the preparation of other
compounds of Formula (II).
;
.
W O 91/19497 ~ 0 8 !~ 2 ~ 22 - PC~r/US91/04022
As used herein in the Synthesis Examples, thc term "Formula (A)" rcfcrs to a
compound of the formula:
X~O
FORMULA (A)
wherein:
X is chosen from a "roup consistinD of mono or disubstituted phenyl as
defined in Forrnula (C), 4-pyridyl and mono-C1 4alky!-substituted-~-pyridyl; and X1 is a halogen such as Cl or Br.
1 0 As used herein in the Syn~hesis Examples, the term "Formula (B)" refers to a
compound of the formula:
N~,~W
NH2
FORMULA (B)
1 5 wherein:
W is -CRs=CR7-, -N=CR7-, -S- or -O-; and
R2, R3, Rs and R7 are. independently, -H or C1 2 alkyl.
The compounds of Formula (IIa) are represented by the stIucutre:
7,~3
N~ 3
R1~N//-
R~
Forrnula (lIa)
wherein:
W3 is -CRsaCR7-, -N=CR7-, -S- or -O-;
R2, R3, Rs, and R7 are, independently, -H or C1 2 alkyl;
2 5 and one of Rl and Ro is 4-pyridyl or Cl 4 alkyl-4-pyridyl. and the other of
R1 and Ro is
(a) monosubstituted phenyl Y. herein said substituent is C1 3
alkylsulfinyl;
.,.. , . . ~ . .
,
WO 91/19497 -23 2 i3 ~ 3 PC~/US91/04022
(b) disubstituted phenyl wherein one of said substituents is C 1.3
alkylsulfinyl; and the other is selected from Cl.3 alkylsulfinyl, Cl A, alkyl,
nitro, N-Cl.3 -alkanarnido, N-(CI.3 alkyl)-N-(Cl 3alkanamido), Cl.3
dialkylamino, N-pyr;olidino,N-piperidino, halo, Cl.3 alkoxy, 2,2,2-
trihaloethoxy, orprop-2-ene-1-oxy.
As used herein in the Synthesis Examples, the ,errn "Formula (Ilb)" refers to a
compound of the formula:
R2 R3
Ror
FORMULA (IIb)
wherein:
W2 is -CR ~=CR7-, -N=CR7-, -S- or -O-;
-R3, Rs, R7 and Rg are, independently, H or Cl 2 alkyl;
One of Rl or Ro is 4 pyridyl and tne other is selected from:
l 5 (a) phenyl or monosubstituted phenyl wherein said substituent is
; selected from Cl 3 alkylthio, Cl 3 alkoxy, halo, Cl 4 alkyl, alkenylthio,
phenylthio, alkoxyalkylthio, alkylthioalkylthio, N-(Cl 3 alkyl)-N-(Cl 3
alkanamido),Cl 3 dialkylamino, CF3, N-pyrrolidino, N-piperidino, prop-2-
ene-l-oxy, 2,2,2-trihaloethoxy, alkylcarbonylaL~cylthio, carbalkoxyaIkylthio,
2 0 phenylthio, alkoxyalkylthio, or alkylthioalkylthio; or
(b) disubstituted phenyl wherein said substitutents are
independently selected from N-tCl 3 alkyl)-N-(C1 3 alkanamido), Cl 3
dialkylamino, N-pyrrolidino, or N-piperidino;
(c) disubstituted phenyl wherein said subsdtutents are the same
2 5 and are selected from halo, Cl 3 alk-oxy, C1 3 dialkylarnino, C1 3 alkylthio,
N-pylTolidino, N-piperidino, 2,2,2-trihaloethoxy, prop-2-ene-1-oxy,
hydroxy, alkylcarbonylalkylthio, carbalkoxyalkylthio, phenylthio,
aLcoxyalkylthio, or alkylthioalkylthio;
(d) disubstituted phenyl wherein one of said substituents is Cl 3
3 0 alkylthio, N-(Cl 3 alkyl)-N-(Cl 3 aLkanamido), C1 3 dialkylamino, N-
pyrrolidino, or N-piperidino; and the other subsdtuent is selected from C2 5-
l-alkenyl-l-thio,C3.s-2-alkenyl-1-~hio,phenylthio. alkylc rbonylalkylthio,
carbalkoxyalkylthio, alkoxyalX~ rro, or ~LkylthioaLkylthio;
or a salt thereof.
.
; '
~ : ,' '' . ,
,
wo 91/19497 2 0 ~ ~ 2 ~ 24 - Pcr/ussl/o4o22
The compounds of Formula (II) can be preparcd according to the following
Scheme 1:
SCHEME 1
~ + N~W ~.~W
:~ NH N
FORMULA (A) 2 FoRMuLA (B) XFORMULA (C)
~3
FORMULA (C) :-- ~N~W ~ FOhMULA (Il)
~--N Formula (D)
RI~R3
FORMULA (llb) -- ~ /=\ - ~ FORMULA (Il)
~Fotmula (E)
R2 R3
FORMULA (C) ~ /--\ ~ FORMULA (li)
(R~0)3sn$~ Fomu~la (F)
X2
R~R3
FORMULA (lla) ~ N W ~, FORMULA (Il)
$~Formula (G)
V2
FOAMULA(C) --~ FORMULA(H~ ~ FORMULA(II)
~: `' ' ' : , ,
:, ~ . : ; j , : , ,
.' . , : '' ~:
'' ` ' ' ' ..
WO 91/19497 -25 - 2 ~ g ~ PCI /US91/04022
All the necessary l-aryl-2-halo-ethanone Formula (A) compounds wherein X
is a halogen such as Cl or Br and X is chosen from a group consisting of mono ordisubstituted phenyl, 4-pyridyl, and alkyl-substituted 4-pyridyl, are known in the art or are
prepared by treatment of the correspondingly substituted l-phenylethanones or 1-(4-
S pyridyl)ethanones (which are comrnercially available or known in the art) with oneequivalent of halogen, preferably bromine, in acetic acid, 48% hydrobromic acid, or a
halocarbon solvent such as chloroform. See, e.g., Langley, rg. Svn. Coll., 1. 127
tl944) and Taurins et al., J. ~leterocvclic Chem., 1. 1137 (1970). Alternatively, the mono
and disubstituted 1-phenyl-2-chloro-ethanone Formula (A) compounds can be prepared by
1 0 Friedel CraFts acylation of the corresponding mono or disubstituted benzenes with 2-
chloroacetyl chloride and aluminum chloride by the method of Joshi et al., J. E~eterocvclic
Chem., 16, 1141 (1979). By these methods, Formula (A) compounds are prepared
wherein X is ~-pyridyl, mono-C1 4alkyl-substituted pyridyl, monosubstituted phenyl (as
defined in Fo muia (C); or disubs~i~uted phenyl (as defined in Formula (C)).
1 5 Compounds of Formula (C) as defined above are prepared from the following
classes of Formula (B) compounds wherein R2, R3, Rs, or R7 are hydrogen or are one or
more C1 2 alkyl groups; i.e.,: -
1. 2-amino-(1,3)-oxazole (W= O);
2. 2-amino-(1,3)-thiazole (W= S);
2 0 3. 2-arninopyridine (W= -(C-Rs)=(C-R7)-),; and
4. 2-arninopyrimidine (W= -(N=CR7)-)
The necessary Pormula (B) compounds are comrnercially available or are known in the art
and can be readily prepared by one of skill in the art.
The Forrnula (B) compound is reacted with a l-aryl-2-halo-ethanone Forrnula
2 5 (A) compound to afford the Formula (C) compound by alkyladon followed by
cyclodehydration. In this way, the following classes of Formula (C) compounds are
prepared:
1. imidazo[2,1-b]oxazole (W= O);
2. irnidazo[2,1-b]thiazole (W= S);
3 0 3. imidazo[l,2-alpyridine (W=-(C-Rs)=(C-R7)-);
4. imidazo~l,2-a]pyrimidine (W= -(N=CR7)-)
The reaction to form the Formula (C) compounds is performed in a nonpolar
solvent such as chloroforrn or toluene, or in a polar nonprodc solvent such as
dimethylforrnamide or acetonitrille. AU~ylation is facilitated by the presence of one to four
3 5 equivalents of a base such as powdered sodium ca~rbonate or triethylamine, and
cyclodehydration is facilitated by heating (between ambient temperature and reflux) or
removing the solvent and refluxing the residue in w aler or dilute aqueous acid.
WO gl/19497 ~ 3 ~ PCT/US91/~4022,
Compounds of Formula (C) may be treated with an alkyllithium compound
to yield the corresponding lithium reagent by metallation. The lithium interrnediate may
then be treated with an excess of magnesium halide or zinc halide etherate to yield the
corresponding organometallic reagent by transmetallation To this or~anometallic reagent a
5 4-bromo,4-iodopyridine or the triflate ester of a 4-hydroxy pyndine (a 4-trifluoromethyl-
sulfonyloxypyTidine)is added in the presence of a palladiurn (O) catalyst, such as
tetrakis(triphenyl-phosphine)-palladium, with hexamethyl-phosphoramide; or with a
palladium (II) catalyst, such as PdCl~(l,~bis(diphenylphosphino)-butane) catalyst,
optionally, in the presence of lithium chloride and a base,such as triethylamine, to yield the
1 0 corresponding Formula (II) compounds. [See Xum2da er al., T~trahPdron Letters, ~,
5319 (1981).]
Compounds of Forrnula (F) as defi l.- 7 a~o~:e ~- n..-r~..edi~tes tO the
corresponding Formula (II) compounds ~nd ~re prepærPd by me~ql!a~ion of th.e appropriale
Formula (C) compounds, where X is 4-pyri~,i or n~.ono21~yl-s~ss~ir~te; ~-pyridyl, wi~h a
1 5 lithiating agent (such as s-butyllithium or n-butyllithium) in an e~.ere31 solverlt (such as
tetrahydrofuran), followed by treatment with a tnalkyltin halide. These Formula (F)
compounds are employed to prepare the Formula (Il) compounds where R~ is 4-pyridyl or
monoalkyl-substituted 4-pyridyl, i.e., one mole equivalent of the Forrnula (F) compound is
added to an excess of a solution of a mono- or di-substituted phenyl bromide, triflate, or
2 0 preferably the iodide, in an inert solvent (such as tetrahydrofuran) preferably containing
lO~o hexamethyl-phosphoramide(HMPA) and 1 to 10 mole percent of a palladium (0)
catalyst (such as tetrakis(triphenylphosphine)-palladium) by the method described in
Adams ~aL. U.S. Patent 4,719,218, issued 01112/88 and in Adams et al., U.S. Patent
Application Serial Number 07/255,816, filed Oc~ober 11, 1988 now U.S. Patent Number
2 ~ 5,002,942, issued March 26, 1991, or by using a palladium (II) catalyst in the presence of
lithium chloride and an added base such as triethylamine. Triflate precursors are prepared
from the corresponding substituted phenols by treatrnent with trifluorosulfonic anhydride in
the presence of a base such as pyridine or triethylamine.
The compounds of Formula tII) wherein either R and Ro are a 4-alkyl
3 0 substituted pyridyl are also prepared by this route. Alternatively, compounds of Formula
(II) rnay be prepared by the analogous reaction of an aryl or heteroaryl trialkyltin compound
with a mixture of a Formula (H) compound and letrakis-(triphenylphosphine)-palladium
under similar condidons. The re lction conditions for Formula (F), and (H) compounds
require that the substituent amino and sulfur substituted compounds, for example, be non-
3 5 oxidized, or protected, i.e. N-(CI 3 alkyl)-N-(C1 3alkanamido!~ etc., hence the final
products of these reactions are all optionally subjec~ to additionai oxid~tion/acylation, etc.
procedures. For use herein, when a compound of Formula (C) contains X as a phenyl
WO 91/19497 -27 - 2 ~ J ~pCr/US91/04022
(mono- or di- substiuted), the phenyl must be subsdtuted with other than hydroxy,
bromine, or iodine to yield a compound of Formula (~).
The compounds of Forrnula (C) may also be treated with an excess of
bromine to yield a bromo derivative, (a compound of Forrnula (H)) wherein the subs~ituent
5 group on the phenyl of a Formula tC) compound is substituted with other than an iodine,
bromine, hydrogen, hydroxy or nitro substituent group, and is added to a pyridine boronic
acid [B(OH)2 -4-pyridyl ] with a palladium catalyst such as Pd(Ph2P(CH2)4- PPh2)C12 or
Pd(PPh3)4 in the presence of about three equivalenls of scdium 'oicarbonate for about 12
hours under reflux conditions with a Dl~/E (dimethyl ethane)/~I2 in a 3: l ratio. The
1 0 pyridine-4-boronic acid is prepared from ~brotr.cpyridine by reation with n-butyllithium,
trapping of the anion with triethyl borate and acid hy~irolysis of the boronate ester. rne
method is similiar to that of Fischer and Haviniga, Rec. Trav. Chim. Davs Bas, 84, 439
(1965). Additional references for coupling of bromopyridines with boronic acids are
Sniec!cus,Y., Tetrahedron Lett., 29, 2135 (198~) and Te.as~..ri~, M., Ch~m. Ph~;m.
1 5 Bull., 11, 4755 (1985).
The brominated Formula (C) compound (Formula (H) compound) can also,
following halogen-metal exchange with n-BuLi and transmetallation with MgBr2, becoupled to a subsdtutcd halobenzene, preferably an iodide in the presence of bidentate
palladium (II) catalyst or a Ni(Il)C12 (1,2-bi-diphenyl-phosphino)ethane) catalyst to yield
2 0 thc desircd regioisomer of the compounds of Formula (II). [See, Pridgen, J. Org. Chem.,
47, 4319 (1982)].
The magnesium or zinc derivative of a Formula (C) compound, however
derivcd, when X is other than a 4-mono Cl 1 aL~cylpyridyl or 4-pyridyl may also be
coupled to a subsituted 4-halopyridine in the presence of the noted palladium (lI) or Ni (II)
2 5 catalyst to yield the final desired compounds of Formula (II).
Compounds of Formula (II) 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
ç~" European Patent Application No. 203,787 published March 12, 1986, the disclosure
of which is herein incorporated by reference.
3 0 Compounds of Formula (D), as defined above, are N-(substituted carbonyl)-
1,4-dihydropyridines. The Ponnula (D) compounds are prepared by treatment of thectnsesponding Formula (C) compounds of classes 1, 2,3,and 4 described above, with a
substituted carbonyl pyridinium salt by the method of Bender Ç~L, U.S. Paten~
4,803,279, issued February 9, 1989; Adams et al., U.S. Paten~ 4,719,218, issued
3 5 01/12/88 and in Adams ~L, U.S. Patent Number 5,002,942, issued March 26, 1991.
The pyridinium salt may be either prefortned or preferably prepared in situ by addition of
the substituted carbonyl halide (such as an acyl halide, an ~royl halide, an arylalk~ l
haloformate ester, or preferably an alkyl haloformate ester, such as acetyl bromide,
.
...
.
20~ll2~
WO 91t19497 -28 - PCI/US9l/04022 " _
benzoylchloride, benzyl chloroformate, or preferably ethyl chlorofortnatc) to a solution of
the Formula (C) compound in pyridine or in an inert solvent such as me~hylene chloride to
which pyridine has been added.
Compounds of Formula (E), as defined above, serve as intermediates in the
5 preparation of Formula (II) compounds where one of Ro or Rl in the product Forrnula (II)
compound is mono-alkyl substi~uted pyridyl. Compounds of Formula (E) are N-
(substituted carbonyl)~-(1,2-dihydro-2-alkyl)pyridines and are prepared by the method of
Comins et al., J. Or~,. Chem., 47, 4315 (1982), i.e., by treatment of an appropriate
- Formula (IIb) compound in a dry ethereal solvent such as tetrahydrofuran at reduced
1 0 temperature (telow CC) with a substituted carbonyl halide (such as an acyl halide, an
aroyl halide, an arvlalkyl haloformate ester, or preferably an alkyl haloforrnate ester),
followed bv t-eatment with ~n allcyl grignard reagent.
Compounds of Formula (D) and Formula (E) serve as intermediates in the
preparat;.on OI the com~ounds of Forrr.ula (Il) and are converted into compounds of
1 5 Formula (Ii) by deacylation and oxidation with a mild oxidizing agent by the methods
described in Bender et al., U.S. Patent No. 4,803,279; Adams et al., U.S. Patent4,719,218, issued 01/12/~8 and in Adams et al., U.S. Patent Number 5,002,942, issued
March 26, 1991. Exemplary oxidation systems are sulfur in a refluxing inert solvent, or -
solvent mixture (such as decalin, decalin and diglyme, p-cymene, xylene, mesitylene), or
2 0 preferably with potassium tert.-butoxide in ~.-butanol with 2 gas at reflux for lS
minutes to the afford the corres-ponding compound of Fo~nula (II). The compounds of
Formula (II) rnay now be optionally reduced, hydrolyzed, oxidized, demethylated, or
acylated to produce other desired Formula (Il) compounds produced by this synthetic
route.
2 5 Regioisomers of Formula (II) compounds where Rl is substituted phenyl,
or 4-pyridyl and Ro is 4-pyridyl are obtained from compounds of Formula (C) whe~e X is
. 4-pyridyl. Compounds of Formula (C) where X is 4-pyridyl or 2-aL~cyl-4-pyridyl are
prepared by treatment of an alkyl substituted or unsubstituted 4-bromoacetylpyridine
hydrobromide salt of Formula (A), wherein R is 4-pyridyl or 2-alkyl-4-pyridyl [prepared
3 0 as described by Taurins et al., J. Het Chem., l,1137 (1970)] with 2-3 equivalents of the 2-
aminopyrrole or 2-aminopyridine by the procedure used to prepare the other compounds of
Formula (C) described above. Bromination, by the procedure of Kano cited above, affords
the corresponding Formula (H) compounds, as previously described. Metallation of Ihe
Formula (C) compounds with n-BuLi or halogen-metal interchange of the Formula (H)
3 5 compounds with n-BuLi, followed by transmetallation with MgBr2 and coupling to the
substituted halobenzene, preferably iodobenzene. or 4-halopyridine, preferably where halo
is iodo, in the presence of the bidentate phosphine palladium or nickel complex as
described above affords the desired regioisomers of Forrnula (II). Alternatively the
WO 91/19497 2 :~ 3 i~ } Pcr~US91,04022
mctallated pyndine or substituted benzene may be coupled to the Formula tH) compounds
employing the catalysts as described above.
Compounds of Formula (II) where one of R1 or Ro is mono or disubstituted
phenyl possessing a 4-halogen substituent (preferably fluoride) can be converted to the 4-
S alkylthio Formula (II) compound by displacement of the halide ion with approximatetly 1,2
equivalents of the sodium salt of the metal alkyl-mercaptide salt (such as sodium
thioethoxide), or arylmercaptan, in a polar nonprotic solvent (such as dimethyl-formamide)
heated to between 70 and 150C.
Compounds of Formula (G) possessing one or more mercapto functionalities
1 0 are prepared via Pummerer Rea~Tangement on the corresponding alkylsulfinyl-substituted
compounds of Formula (IIa). Pummerer Rearrangement of the corresponding compounds
of Formula (IIa) is accomp!ished by the method described in Adatns et al., U.S. Patent
Number 5,0Q2,94~, issued March 26, 1991 by refluxing with an alkanoic acid anhydride.
The compounds of Form.ula (C) may also be used to make the analagous compounds of
1 5 Forrnula (G) containing a hydrogen in the Vl position. Such use of the Formula (C)
compounds wherein the allcylthio group is oxidized to an alkylsulfinyl function and then
reacted in the similiar manner as the Formula (IIa) compounds described herein to yield the
corresponding mercapto substituted Formula (C) compounds, which may in turn be used to
prepare the various other Formula (C) compounds, such as alkoxyalkylthio, alkenylthio,
2 0 alkylthioallcylthio, alkylcarbonylalkylthio, or carbaLlcoxyalkylthio funcdons.
The Formula (G) compounds where one of V 1 or Vo is a mono or di-
substituted phenyl having at least one mercapto substdtuent are obtained by hydrolysis of
the Formula (II) acyloxyalkylthio products or preferably by treatment of a Formula (IIa)
compound with trifluoroacetic anhydride followed by basic solvolysis with a base such as
2 5 sodium methoxide in methanol, similar to the method of R. N. Young et al., Tetrahedron
Letters, 25, 1753 (1984).
Forrnula (G) compounds serve as intermediates for the synthesis of Formula
(II) compounds where one of Rl or Ro of the Forrnula (II) compound is mono or
disubsdtuted phenyl having at least one 2-alkenyl-1-thio function. A solution of the
3 0 Formula tG) intermediate in a polar solvent such as dimethylformamide is treated with a
base, preferably a metal hydride such as sodium hydride, and the sodium mercaptide salt
formed is treated with a l-nalo-2-alkene such as allyl bromide and heated from 25 to 80C
to give the Formula (II) compounds where one of Rl or Ro is a disubstituted phenyl
having at least one 2-alkenyl- l-thio substituent.
3 5 The Formula (G) compounds described above also serve as intermediates for
the synthesis of Formula (II) compounds in which one of Rl or Ro is a di-substituted
phenyl having at least one 1 -alkenyl- 1 -thio function. Treatment of the Formula (G)
compound in a nonprotic solvent such as tetrahydrofuran with a strong base such as lithium
.. .
.:
WO 91/19497 2 ~ ~ l' 2 , i~ -30 - PCI /~IS91/04022
diethylamide at low temperature (-78 to -20C) generates the lithium mercaptide salt. This
salt is alkylated at 0C with a trimethylsilyl-methylating agent (such as trimethylsilylmethyl
halide, triflate, or acetate) to forrn the trimethylsilylmethylthio substituent. The latter is
deprotonated with addition of another molar equivalent of lithium die~hyl~rnide and treated
S with an aldehyde or ketone to give the Formula (II) compound where Vo or V I is a di-
substituted phenyl having at least one 1-alkenyl-1-thio substituent.
Compounds of Formula (II) where one of R I or Ro is mono or
disubstituted phenyl possessing a 4-halogen substituen~ (prererably fluoride) can ~e
convented to the 4-alkylthio Forrnula (~) compound by displacemen~ of the halide ion with
1 0 a metal alkyl-mercaptide salt (such as sodium thioethoxide) in a ~olar nonprotic solvent
(such as dimethylformamide) heated to between 70 and l~GC.
The Formula (G) compounds may be obtained by trea;mer.t of a Formul2
(~I) or (Ill) compounds containing a halophenyl function, prefer~bly a fluoro orbromophenyl, having at least one halo substituent on the ~he ny ! -. ~.g, in dimethyl su!fox~de
1 5 (DMSO~ with NaSH(sodium bisuifide). An al~ernati~e reacvon .o ,i~ld a Fo~nula (")
compound containing a substituted phenyl wherein one of the substituents is a mercapto
function, or a Forrnula tG) compound is to treat a halophenyl derivative of Formula (II), or
(C) with the sodium salt of an allcylmercaptan with catalytic amount of a palladium (O)
compound, such as tetrakis(triphenylphosphine)-palladium in a solvent, such as DMSQ
2 0 Compounds of Formula (I) or (II) wherein R or Rl is a mono- or di-substituted phenyl having u least one Cl 3alkylsulfinyl, Cl 3alkylsulfonyl, or C1 3
alkenylsulfinyl, or compounds of Formula (II) wherein R or Rl is a di-substituted phenyl
having at least one Cl 3allcylsulfinyl, Cl 3alkylsulfonyl, or Cl 3alkenylsulfinyl; or R or R
is a mono- or di-substituted phenyl having at least one alkoxyalkylsulf~yl or phenyl-
2 5 sulfinyl substituent are prepared by treatment of one or more equivalents of the
corresponding compound of Forrnula's (I), (II) or (III) wherein R or Rl are Cl 3alkylthiophenyl, Cl.3 alkylsulfinylphenyl, acyloxyalkylthiophenyl, alkoxyalkylthio,
phenylthio, or alkenylthiophenyl with one or more equivalents of an oxidizing agent (such
as 3 chloroperbenzoic acid in an inert solvent or sodium or potassium persulfate in an
3 0 aqueous organic acid, such as acetic acid, or sodium periodate in peroxide, a polar solvent
such as aqueous methanol containing a mineral acid such as hydrochloric acid), aqueous
acetic acid, per mercapto function, in an inert solvent. Compounds of Formula (II)
- wherein R or Rl are Cl 3 alkyl-sulfonyl, alkenyl-sulfonyl or alkenyl-sulfinyl substituted
phenyl are prepared by treatment of one equivalent of the colTesponding Cl 3 sulfinyl
. 3 5 Formula (Il) compound with 2/3 equivalent of K~SnO4 per sulfinyl function in aqueous
acid solution by the method of Chatterway et al., J. Chem. Soc. 135~ 30), or
alternatively with one equivalent of a peracid.
wo 91/19497 -31 - ~ ~ 3 ~ J PCr/US91/04022
Compounds of Formula (Il) possessing an alkylsulfinyl, 1-alkenyl-1~
sulfinyl, or 2-alkenyl-1-sulfinyl mono or disubstituted phenyl ring, or those compounds of
Formula (II) prepared by oxidation of the corresponding compounds of Formula (lla)
(possessing, respectively, an alkylthio, 1 -alkenyl- l-thio or 2-alkenyl- 1 -thio mono or
5 disubstituted phenyl ring by employing one equivalent of oxidizing agent per sulfide in the
molecule can be produced by use of an oxidizing agent as well. rne oxidizing agent may
be an organic peracid (such as 3-chloroperoxybenzoic) added dropwise to a solution of the
Formula (II) compound in a halocarbon (such as methylene chioridej at ice bath
temperature, or an inorganic agent (such as sodium periodale, sodiurn persulfate,
1 0 potassium persulfate, or hydrogen peroxide) in aqeuous acetic acid~ or acetic acid, added
dropwise to a solution of the Formula (Il) compound in water containing 2 equivalents of
an inorganic acid (such as hydrochloric acid).
Applicant's have found as one aspec. of this in~.-ention the use of the
oxidizing agents, scdium persulfate and potassium persulfaL fGr prcd~cing a-yl sulfoxides
1 5 from arylsulfides on ni~rogen containing heterocyciic ring systems. i his is a prccess
which comprises treating said aryl sulfide with sodium or potassium persulfate in aqeuous
acetic acid yielding the corresponding arylsulfoxide. As noted previously, Srinivasan et
al., Indian J. Chem., 268, p. 193 (1987) describes the oxidation of a number of sulfide
compounds which have other functionalities such as methoxy, nitro, acetyl, and chloro
2 0 groups but none contain an arnine nitrogen such as the compounds of this invendon. It is
in fact the oxidation of such moiedes while attached to such hetero nitrogen ring systems
that is unusual as the expectation that the nitrogen would themselves be oxidized.
Applicants show herein that thc arylsulfides, particularly the aL~cylthiophenyl moieties can
safely be oxidized to the corresponding sulfones in the presence of a hetero-nitrogen
2 5 containing ring system.
The reaction temperatures may be quiu varied and ranger from about 0 C to
about 100 C. Preferably the temperature range is from about 0 C to about 60 C. The
reaction time may be from minutes to days, and an additional co-solvent may also be used.
Such co-solvents include, but are not limited to, THF (tetrahydrofuran) and acetone. The
3 0 method of mixing need not be in a drop vise fashion as indicated above for other oxiziding
agents.
Prefered aryl sulfides are the phenylsulfide derivatives. Further preferred are
the alkyl substituted alkyl sulfide derivatives, such as methyl or ethyl thio. Hetero-aromatic
and non-aromatic nitrogen containing ring system on which the aryl sulfide moiety is
3 5 found, includes but is not limited to, imidazole, triazole, pyrrole, pyrimidine, pyridine,
6,7-dihydro-[5H]-pyrrolo[2, 1 -a]imidazole, pyrrolo[2, 1 -a]imidazole: ',3-
dihydroimidazo[2,1-b]-thiazole, imidazo~2.1-b]~hi~zole--oxide or l,1-dioxide; 2,3,4,5,
tetrahydro-imidazo[2,1-b]thiazole-1-oxide or l,l-dioxide, imidazo[2,1-b]oxazole,
WO 9Itt9497 h ~ 2 ~ ~ -32 - pcr/us91/o4o22
imidazo[ 1 ,2-a]pyridine, 5,6,7,8-tetrahydroimidazo [ 1 ,2-a]pyridine; 1 ,4-dihydroypyridinyl;
1,2,5,6-tetrahydropyridininyl, or a imidazo-[1,2-a]pyrimidine ring systems, The aryl
sulfide in the case of multiple ring systems may be attached to either ring,
Preferrably the nitrogen heterocyclic ring system is 2,3-
5 dihydroimidazo[2,1-b]-thiazole, imidazo[2,1-b]thiazole-1-oxide or l,l-dioxide,imidazo[1,2-a]pyridine, 6,7-dihydro-[SH]-pyrrolo[2,1-a~imidazole or imidazole,
Acetophenones substituted with a mono- or di-substituted phenyl having at
least one N-(Cl 3alXanarnido)or N-(C1 3 alkyl)-N-(Cl 3 alkanamido), and in some cases
the Formula (C), and Formula (Il) compounds, are prepared by acylation of the
1 0 corresponding arnino and N-(Cl 3 alkylamino) compounds with the alkanoic acid
anhydride or chloride in pyridine. Another alternative preparation of the N-(C1 3 aLl~yl)-N-
(C1 3 alkanamido) phenyl subs,itute,d Formula (C) and Formula (II) compounds is the
alkylation of the cor; sponding N-(Cl 3 alkanamido) substituted compounds with sodium
hydride and a C1 3 al~yl bromide or iodide in dimethylformarnide
1 5 Formula (C) and Formula (II) compounds containing a mono- or di-
substituted phenyl having at least one amino substituent are prepared either by hydrolysis
of the corresponding N-(C1 3 alkanamido) compounds in refluxing 6 N mineral acid or by
catalytic reducdon of thc corresponding nitro compounds.
Formula (C) and Forrnula (II) compounds containing a mono- or di-
2 0 substituted phenyl having at least one N-(Cl 3 alkylamino) substituent are preferably
preparcd by acid catalyzed hydrolysis of the corresponding N-(Cl.3 alkyl)-N-(Cl 3
alkanarnido) compounds of Formula (C) and Formula (II), respcctivcly, prepared as
described above for the aminophenyl substituted compounds, or alternatively, either by (a)
reduction of the corresponding N-(C1.3 allcanarnido) compounds with borane or borane
2 5 dimethylsulfide complex in l~HF by the method of Brown, "Or~anic Svnthesis via
Boranes", John Wiley and Sons, (1975), or (b) by cleavage of the corresponding N,N-(di
Cl.3 alkylamino)phenyl subsdtuted Formula (C) and Forrnula (II) compounds with
cyanogen bromide in the Von Braun reacdon ~see, Hageman Org. Reacdons, Vol. 7, 198
(1953)],
3 0 Formula (C) and Forrnula (II) compounds containing a mono- or di-
subsdtuted phenyl having at least one N,N-(di Cl.3 alkylamino) subsdtuent are
alternatively prepared either by reduction of the corresponding N-(Cl 3 alkyl)-N-(CI 3
alkanamido) compounds of Formula (C) and Forrnula (Il) with borane as described above
for the N-(Cl 3 alkylamino) substituted compounds, or by displacement of the bromide by
3 5 a N,N-dialkylamine in the corresponding 4-bromo-3-nitrophenyl Formula (C) and Formula
(II) compounds by heating at 140C with the N,N-dialkylamine and potassium carbonate in
an inert solvent.
WO 91/1~497 3~ 2 ~ ~ ~, J J PCI'/US91/04022
Formula (C) and Formula (Il) compounds containing a rnono- or di-
substituted phenyl having at least one N-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
5 solvent such as dimethylformamide.
Compounds of Formula (C) 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 (C) with trifluoromethylsulfonic acid
2,2,2-t~iIluoroethyl ester or allyl bromide respectively as described by Bender et al., L
1 0 Med. Chem., 2~,1169 (1985), for preparation of compounds No. 23 and 33 described
therein. Appropriately substituted mono and dihydroxy phenyl compounds or disubstitued
phenyl compounds wherein one substituent is hydroxy of Formula (C) and Formula (II)
are obtained by tre~tment of their respective correspondingly substituted methoxy
derivatives with HBr in acetic acid, or preferably with BBr3 in CH2Cl2 by the method
1 5 described by Bender et al., J. ~,Ied. Chem., 2~, 1169 (1985), for ;he preparation of
compound No. 14 described therein.
Compounds of Formula (II) or Formula (C) where R is Cl 3alkoxy mono-
or di- substituted phenyl are prepared by alkyladon of the appropriately substituted
hydroxyphenyl compounds with the corresponding Cl 3 alkylhalide in the presence of a
2 0 strong base such as sodium hydride in an aprotic organic solvent such as
dimethylformamide.
Compounds of Formula (I~) wherein R or Rl is phenyl di-substituted with
an acyloxyaLlcylthio group wherein the alkyl is optionally substdtuted with
Cl 4alkyl are prepared by treating a compound of Formula (IIa) wherein Rl is phenyl
2 5 substituted with at least one allcylsulfinyl group with an alkanoic acid anhydride.
Hydrolysis of the resuldng acyloxyalkylthio compounds yields compounds of Formula (G)
wherein one of Rl or R is phenyl substituted with a sulfhydryl funcdon. The sulfhydryl
substituted compounds can be treated with an alkanoic acid anhydride or an alkylthiono
' acid chloride in pyridine or a hindered amine, such as di(C1 3alkyl)amine under
3 0 appropriate conditions, to prepare compounds of Forrnula (G) wherein one of Rl or R is
phenyl subsdtuted with one or more acylthio or dithioacyl groups.
Compounds of Formula (rI) wherein one of R1 or R is phenyl s~bsdtuted
with at least one thiocarbamyl or dithiocarbamyl group are prepared by treating the
sulfhydryl-containing Formula (G) compound, prepared as above,with a carbamyl halide
3 5 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 carbamyl
halides or thiocarbamyl halide derivatives may be replaced independently by alkyl, alkenyl,
alkynyl, aryl or heteroaryl derivative, which may in turn be optionally substituted.
WO 91/19497 -34 - P-,~/US91/04022, ~
,
Compounds of Formula (Il) whcrein Rl or R is phenyl disubsdtuted with
an alkenylthio group wherein one saturated carbon atom separates the sulfur from the
carbon bearing the double bond can be prepared by alkylating a compound of Formula (G)
(or Forrnula (C) wherein one of Rl or Ro may be a phenyl substituted with al least one
5 sulfhydryl group),with an appropriately substituted alkenylhalide, such as allylbromide.
Compounds of Formula (n) or Formula (C), whe,ein RI or R is phenyl
substituted with an alkylcarbonylalkylthio or carbalkoxyallcylthio group are prepared by
treatment of the corresponding sulfhydryl substituted compounds with an
alkylcarbonylalkylhalide, such as bromoacetone, or with a carbalkoxyalkylhalide, such as
1 0 ethylbromoacetate.
Compounds of Forrnula (II) wne.ein Ro or Ri is phenyl substituted with an
alkenylthio group wherein the sulfur is attached to the carcon bea.ing the double bond are
prepared from the corresponding compounds of Forrnu!a (G) or (C), 2S defined above,
wherein the phenyl is substituted with a mercapto grup. The ~r.e ~a?to s~..bstituted
1 5 compound is converted to a metal sal~ in a poiar solven~ wilh a s~og `oase juch as a m.er~l
hydride, a metal alkoxide or lithium diethylarnide. The metal mercaptide salt is treated with
trialkylsilylmethylchloride in an aprotic solvent such as tetrahydrofuran is treated at reduced
temperature with a lithiating reagent such as lithium diethylamide followed by treatment
with an appropriate aliphatic aldehyde or ketone to prepare the compounds of Formula (II)
2 0 and Formula (C),wherein R, Rl or X, is phenyl substituted with one or more alkenylthio
groups.
Compounds of Forrnula (II) 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 forrned
2 5 from a compound of Formula (G) wherein one of R or R1 is phenyl substituted with a
sulfhydryl function prepared as previously described. Compounds of Formula (II)
wherein R or R1 is phenyl substituted with one or more alkoxythionothio groups are
prepared by reacting the metal mercaptide with the appropriate alkyl or aryl
halothionoformate .
3 0 Compounds of Formula (II) wherein R or Rl is alkoxyalkylthio are
prepared by rcacting the metal mercaptide salt of Formula (G) or Formula (C), prepared as
described abo~e, with an appropriate halomethyl cther. Oxidation of the resulting
alkoxyalkylthio compounds by reacting with a suitable oxidizing agen~ such as
chloroperbenzoic acid yields the compounds of Formula (II) wherein R or Rl is phenyl
3 5 subsdtuted with an alkoxyalkylsulfinyl.
Compounds of Formula (TI) w herein R or Rl is phenyl substituted with a
substituted disulfide group are prep~red by mild air o:cidation of ~he compounds of Forrnula
(II) wherein R or Rl is phenyl substituted with a sulfhydryl group, prepared as described
wo 91/19497 ~ ~ 8 i1 2 ~ ~ pC~/US91/04022
above. The nonsyrnmetrical disulflde (Z) wherein Z is -S-S-ZI and Zl is phenyl or Cl.g
alkyl, the compound may be prepared by reaction of the sulfhydryl compound with the
appropriate sulfenyl halide in an ethereal solvent to afford compounds of Forrnula (II)
wherein one of R or R1 is phenyl substituted with one or more alkyl-dithio or aryl-dithio
groups The method of Mukaiyama et al, Tetrahedron Letters, 56:5907-08 ( 1968) allows
for use of the desired aryl-SH or alkyl-SH reagent ~eated ~i~h diethylazcclicarbo;~ylate in
1:1 equivalence at room tempertaure in a solvent, yielding an adduct which is then treated
with 1:1 ratio of the desired mercaptan of Forrnula (Ci). This process will also yield the
disulfide dimer of the compounds of Formula (II). Preferably the disulfide linkage is on
1 0 the Ro position of the compounds of Formulas (I) and (II).
Compounds of Formula (II) and rormula (C), wherein R, Rl or X, is
phenyl substituted with an alkylthioalkvlthio ~roup are pre?ared by reacting the analogous
sulfhydryl compound, prepared as described a~ove. with the appropriate carbonyl
component, such as formaldehyde, acetone, or aceta!dehYd-. using eithe- mineral or Lewis
1 5 acid catalysis conditions to yield the symIr.ehical dihlio~;etal. rn~ in~e~me,diate
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 the alkyl chain insertion, i.e. [Forrnula (II)-S-CRRl-S-Forrnula (II)]. The substitution
of the aLkyl, R,or Rl, is deterrnined by the reactive carbonyl functional group, wherein R
2 0 or R1 trlay be Cl g alkyl, aryl or heteroaryl, all optionally substituted. The
nonsymrnetncal thioketals can be prepared by the reaction of the metal mercaptan salt,
prepared as described above, with a halomethyl thioether to yield compounds of Formula
(II) wherein one of R or Rl is phenyl substituted with one or more alkylthioalkylthio
groups. The met~l salt reacts with an independent and varyin" alkyl chain length2 5 halomethyl-[CRR1]-thioalkyl[aryVheteroaryl] compound to yield the "non-bis" type
compounds, [Formula (I)-S-CRRl-S-R2], wherein R and Rl are as defined above for the
"bis" compounds, and R2 i$ a C1 9 alkyl, aryl or heteroaryl group which may be
optionally substituted. A mixture of Ro and Rl linkages is contemplated, as part of the
present invention, hoever, preferably the linkage is on both Ro positions of the compounds
3 0 of Formula tI) or (II).
An alternate method of preparation of the nonsyrnmetrical disulfide
compound, wherein only one componen~ is a compound of Formula (lI), and the other half
of the disulfide link is an alkyl, aryl or heteroaryl derivative, may be prepared by reaction
of a sulfhydryl compound of Forrnula (II), with the appropriale sulfenyl halide, in an
3 5 ethereal solvent to afford compounds of Formula (II) wherein one of R or Rl is phenyl
substituted with one or more ~alkyl]- dithio roups, i.e. ~Formula (II)-S-S-R2], wherein
R-R2 are as defined in the above paragraph. The contemplated sulfenyl h31ide derivatives
of alkyl, aryl, or heteroaryl groups may be optionally substituted.
2 ~3 '~ Y ~
W O 91/19497 -36 - PC~r/US91/04022 ,~.
The disulfide compound(s) may also be prcpared from shc corresponding
alkyl sulfoxide compounds, such as methylsulfinyl, propylsulfinyl, iso-propylsulfinyl,
wherein the alkyl can be a straight chain or branched derivativc having from 1 to 9 carbon
atoms, in a solvent, preferably a chlorinated one such as chloroethylene, methylene
5 chloride 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. If ace2ic anhydride is used than heating is also likely to be needed during the
hydroxide treatment, before addition of iodine solid (12), which then affords the
1 0 symmetlical disulfide compound as is noted above Mixtures of the sulfoxide compounds
may be present in the solution to yield "symmetrical" compounds but with varyingsubstituent groups on the di-heteroaryl-imid2zole ring system of the present invention.
This invention also relates to the use of a pharmaceutical composition
comprising an effective, non-toxic amount of a compound of Formula (L9) and a
l 5 pharmaceutically acceptable carrier or diluent in the methods disclosed herein.
Pharmaceutically acceptable salts and their preparation are well known to those
skilled in pharrnaceuticals. Pharmaceutically acceptable salts of the compounds of Formula
(I) which are useful in the present invention include, but are not limited to, maleate,
fumarate, lactate, oxalate, methancsulfonate, ethane-sulfonate, benzenesulfonate, tartrate,
2 0 citrate, hyd~chloride, hydrobromide, sulfate and phosphate salts. Preferred
pharmaceutically acceptable salts of the compounds of Formula (I) include hydrochloride
and hydro-brornide 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.
METHOD OF TREATMENT
It has now been discovered that the compounds of Formula tI) 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
3 0 compounds of Formula (I) are inhibitors of the 5-lipoxygenase pathway is based on the
effects of the compounds of Forrnula (I) on the production of 5 1ipoxygenase products in
blood ex vivo and on the 5-lipoxygenase in vitro assays, some of which are described
hereinafter. The 5-lipoxygenase pathway inhibitory action of the compounds of Formula
(I) was confirmed by showing that they impaired the production of 5-lipoxygenase3 5 products such as leukotriene B4 production by RBL-I cell supernants.
The pathophysiological role of arachidonic acid metabolites has been the
focus of recent intensive studies. In addition ~o the well-described phlogistic activity (i.e.
general inflammatory activity) of prostaglandins. the more recen~ description of sirnilar
WO91/]9497 ~37 - 20~ j PCI`/US91/04022
activity for eicosanoids has broadened the interest in these products as mcdiators of
inflammation ~See, O'Flaherty, Lab. Tnvest., 47, 314-329 (1982)]. The reportcd
discovery of potent chemotactic and algesic activity for LTB4 [see, Smith, ~L
Pharrnacol,12, 211-216 (1981) and Levine et al., Science, ~,743-745 (1984)],
S together vith known LTC4 and LTD4-mediated increase in capillary permeability [see,
Simmons et al., Biochem. Pharmacol., 32, 1353-1359 (1983), Vane et al., Prosta~lanAins,
21, 637-647 (1981), and Carnp et al., Br. J. Pharmacol., ~Q, 497-502 (1983)], has led to
their consideration as targets for pharmacological intervention in both the fluid and cellular
phases of inflammatory diseases.
1 0 The pharmacology of several inflamrnatory model systems has attested to
the effectiveness of corticosteroids in reducing the cellular infiltration. These results, and
the observation that corticosteroids inhibit the generation of both cyclooxygenase and
lipoxygenase products, suggest that such dual inhibitors may effectively reduce both the
fluid and cellular phases of the inflarnma~ory response since selective cyclooxygenase
1 5 inhibitors do not reiiably inhibit cell influx into inflarnmatory sites [See, Vinegar et al.,
Fed. Proc., 35, 2447-2456 (1976), Higgs et al., Brit. Bull., 39, 265-270 (1983), and
Higgs et al., Prostavlandins. Leukotrienes and Medicine, 13, 89-92 (1984)]. Under
opdmal conditions, it is likely that an agent with preferentdal lipoxygenase inhibitory
activity would not share the ulcerogenic liability of cyclooxygenase inhibitors or the toxicity
2 0 of corticosteroids. This may suggest that the compounds of the present invention could be
useful in treadng diseases where it is beneficial to limit ulcerogenic acdvi~y or steroidal side
effects such as osteoarthritis. lSee Palmoski et al., "Benoxaprofen Stimulates
- Proteoglycan Synthesis in Normal Canine Knee Cartiledge in Vitro," Arthrids and
; Rheumatism 26,771-774 (1983) and Rainsford, K.D., Agents and Actions 21, 316-319
2 5 (1987).]
Clinical data supports the enthusiasm for inhibitors of the 5-lipoxygenase
pathway in a variety of inflamrnatory diseases in which granulocyte and/or monocyte
infiltration is prorninent. The reported demonstration of elevated levels of LTB4 in
rheumatoid arthritic joint fluid [See, Davidson et al., Ann. Rheum. Dis~, 42, 677-679
- 3 0 (1983)] also suggests a contributing role for arachidonic acid metabolius in rheumatoid
arthrids. Sulfasalazine, which is used for treatment of ulceradve colitis, has been reported
to inhibit LTB4 and 5-HETE production in vi~ro [See, Stenson et al., J~ Clin~ Invest~, 69,
494-497 (1982)]~ The recently reported preliminary observation of efficacy, including
remission, reported with sulfasalazine treatment of rheumatoid arthritic padents [See
3 ~ Neumann et ah, Brit. Med. J., 287,1099-1102 (1983)] illustrates the utility of inhibitors
of the S-lipoxygenase pathway in rheumatoid arthntis.
Additionally it has been repor~ed Iha~ inflarned gastrointestinal mucosa from
inflammatory bowel disease patients showed increased production of LTB4 [See, Sharon et
WO 91/19497 2 0 g ~ 38 - Pcr/US9l/04022
al., Gastroenterol., 84, 1306 (1983)], which suggests that sulfasalazinc can bc cffcctive by
virtue of inhibition of producdon of chemotactic eicosanoids (such as the S-lipoxygen~se
pathway product known as LTB4). The observations serve to underscore utility of
inhibitors of the 5-lipoxygenase pathway in inflammatorv bowel 5iise~se.
Another area of utility for an inhibitor of the 5-lipoxygen~se pathway is in
the treatment of psoriasis. It was dernonstraled that invol~/ed psoriatic skin had ele~/ated
levels of LTB4 [See, Brain et al., Lancet, 19, February 19, 1983]. The promising effect of
- benoxaprofen on psoriasis [See, Allen e~ al., Bnt J 13elmatol., 109, 126-1~9 (1983)], a
compound with in vitro lipoxygenase inhibitory activity lends support to the concept that
1 0 inhibitors of the S-lipoxygenase pathway c n ~e uset^ul in the ~eatment of ~soriasis.
Lipoxygenase products have '~een identiIled in exudate fluids from gouty
patients. This disorder is charac~eri~ed bv massive neutropnil infiitration during the acute
inflammatory phases of the disease. Since a major 5-lipoxygen~se prcduct, LTB4, is
produced by neutrophils, i~ follows that inhibition cf the syn~esis of LTB ~ may bloclc an
1 5 amplification mechanismin out.
Another area in which inhibitors of the 5-lipoxygenase product can have
utility is in mvocardial infarction. Studies in dogs with the dual inhibitor, BW755-C,
demonstrated that the area of infarction following coronary occlusion was r~duced, and
such reduction was attributed to inhibition of leukocyte infiltration into the ischaemic tissue
2 0 [See, Mullane et al., J. Pharmacol. Ex~. Therap., ~, 510-522 (1984)].
Yet another area of utility for inhibitors of the S-lipoxygenase pathway is in
the area of prevention of rejection of organ transplants. ~See, e.g., Foegh et al., Adv.
~QS~jn. Thromboxane. and Leukotriene Research, 13,209-217 (1983).]
Yet another utility for inhibitors of the 5-lipoxygenase pathway is in the
2 5 treatrnent of ~ssue ~rauma. [See, e.g., Denzlinger e~ al. Science, ~30 (47~3), 330-332
(1985)].
Furthermore, another area of utility for inhibitors of the 5-lipoxygenase
pathway is in the treatment of in~ ~Q~en~al nervoy~,
including multiple sclerosis. [See, e.g., Mackay et al., Clin Ex~ Immunologv,15, 471-
3 0 482 (1973)].
Another area of utility for inhibitors of the 5-lipoxygenase pathway is in the
treatment of asthma. [See, e.g., Ford-Hutchinson, J. Allergy Clin. Irnmur~, 74, 437-
440 (1984)]. Additionally another utility for inhibi~ors of the S-lipoxygense pa~hway is in
the treatment of Adult Respitory Distress Syndrome~ [See, e~g~, Pacitti et~ al~, Circ. Shock
3 5 , ~, 155-168 (1987)]. Yet another utility for inhibitors of the 5-lipoxygenase pathway is
in the treament of allergic rhinitis~
Another area of utility for inhibitors of the S-lipoxygenase pathway is in the
treatrnent of vasculitis, glomerulonephritis, and iminune complex disease. [See Kadison e~
WO 91/19497 ~ ~,l r~ /~ 3 9 J3 Pcr/US9l/04022
al., "Vasculitis: Mechanism of Vessel Damage" in
Clinical Correlates, 703-718, Ed. Gallin et al., Raven Press, N.Y., N.Y. (1988),]
Another area of utility for inhibitors of the 5-lipoxygenase pathway is in the
treatment of dermatitis. [See Pye et al., "Systemic Therapy" in Textbook of DermatologY,
s Vol. m, 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
treatrnent of atherosclerosis. Recent studies have shown that inhibition of o~idative
modification of low density lipoprotein slows progression of atherosclerosis, and that
1 0 inhibitors of lipoxygenase effectively inhibit cell-induced oxidati~e modification. [See
Carew et al., Proc. Natl. Acad. Sci. USA, 84, 7725-7729, Novem'oer 1987; and
Steinberg, D., Cholesterol and Cardiovascular Disease 76, 3. ~08-514 (1987).]
An additional area of utility for inhibitors of the ~-lipoxygenase pathway is
in the optical area, in particular general inf.amma;ion of the comeal anter;or and poster;or
1 5 segrnents due to disease or surgery such as in post surgicai in~larnmation, uvei~is, and
allergic conjuntivitis. [See Rao N. et al. Arch. Ophathmal. 105 (3) 413-419 (1987);
Chiou, L. and Chiou, G. J. Ocular Pharmacol. 1, 383-390 (1985); Bazan H., J. Ocular
~L 4. 43-49 (1988); and Ver~ey N.L. et al., Current Eve Research 7, 361-368
(1988).]
2 0 Yet anotha area in which inhibitors of lipid peroxidation involved in the
OPU~:A mediated can have utility is tha~ generally refered as degenerative neurological
disorders, such as Parkinson's disease. Another area is that of traumatic or ischemic
injuries, such as stroke, brain or spinal cord injuries and inflammatory disease of the brain
and spinal column. More specicially preferred disease states are the mycardial induced
2 5 ischemic injuries and/or reperfusion injuries. [See, Braughler et al., Jour. Biol. Chem.,
Vol. 262, No. 22, pplO438-40 (1987), see also Xu et al., J. Neurochemistrv, 55, 907-91
(1990); Asano et al., Molecula~ and Chemical Neuropatholo~v. 10:101-133 (1989) and
Bracken e~ al., NE. J. Med., 322:140~-1411 tl990)]
3 0 It has also been discovered that the compounds of Formula (I) are useful for
treating disease states mediated by the cyclooxygenase pathway of arachodonic acid in an
animal, including mammals, in need thereof. The discovery that the compound of Formula
(T) are inhibitors of cyclooxygenase products is based upon the effects of the compounds of
Formula (I) on the production of the PGE2 products, and the human monocyte data, the
3 5 assays of which are described herein.
FORMULATION OF PHARMACEUTICAL COMPOSITIO~S
wo 91/19497 2 a ~ ~ 2 ~ ~ 40 PCr/US91/04022 ~.
This invention also relates to a pharmaceudcal composition comprising an
effecti~ e, non-toxic amount of a Formula (I), Formula (II) or (III) compound or salt
thereof. and a pharmaceutically acceptable carrier or diluent for use in the methods
described herein. The compounds of Formula (1), Formula (1:1) or (III) are administered in
S conventional dos~ge forms prepared by combining a compound of Formula (I), Formula
(II) or (III) in an amount sufficient to produce an OPUFA inhibi~ing, 5-LO inhibiting or CO
inhibiting activity with standard pharmaceutical carriers according to conventional
procedures. The compounds of Formula (I), Formula (II), or Forrnulas (III) may also be
adrninisted in conventional dosages in combination with a known, second therapeutically
1 0 active compound, such as an antihistarnine, anti-bacterial or anti-fungal agent. These
procedures mav involve mixing, granulating and compressing or dissolving the ingredients
as appropr;ate to the desired preparation.
This in~ention relates to a pharmaceutical composition comprising an effective
arnounr of a compoundor a pharmaceutically acceptable salt thereof of 2-(4-
Methoxyphenyl)-3-(4-pyridyl)-7-oxo-5,6-dihydro-[7H]-pyrrolo[1 ,2-a]imidazole; 5,6-
Dihydro-2-(4-Methoxyphenyl)-3-(4-pylidyl)-[7H]-pyrrolo[1,2-a]imidazole-7-ol; or 5,6-
Dihydro-7,7-difluor~2-(4-Methoxyphenyl)-3-(4-pyridyl)-[7H]-pyrrolo[1 ,2-a]-imidazole
and a pharmaceutically acceptable carrier or diluent tor treating an OPI~;A, specifically a 5-
LO, or CO pathway mediated disease state. These compounds are administered in
2 0 conventional doseage fonns prepared by combining them in an amount sufficient to
produce OPUPA, 5-LO inhibiting or CO inhibiting activity with standard pharmaceutical
camers according to conventional procedures.
The pharmaceutical carrier employed may be, for example, either a solid or
liquid. Exemplary of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar,
2 5 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 the art, such as glyceryl monostearate or glyceryl
distearate alone or with a wax.
A wide variety of pharmaceutical forrns can be employed. Thus, if a solid
3 0 carrier is used, the preparation can be tableted, placed in a hard gelatin capsule in powder or
pellet form or in the form of a troche or lozenge. The amount of solid carrier will vary
widel~ but preferably will be from about 25 mg. to about l g. When a liquid carrier is
used, ~he preparation will be in the form of a syrup, emulsion, soft gelatin capsule, sterile
injectable liquid such as an ampule or nonaqueous liquid suspension.
3 5 To obtain a stable water soluble dose form of an insoluble Formula (I) or
Formula (II) compound, a pharmaceutically accep~able salt of the Formula (I) or Forrnula
(II) cornpound is dissolved in an aqueous solution of an organic or inorganic acid, such as
a 0.3 ~vl solution of succinic acid or, preferably, cilric acid.
'
~ 8 ~
. WO 91/19497 -41 - PCr/US91/04022
Preferably, each parenteral dosage unit will contain the activc ingrcdient [i.c.,
the compound of Forrnula (I) or (II)] 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.
S The compounds of Formula (I) or (II) may also be administered topically,
Thus, the compounds of Formula (I) or Forrnula (Il) may be adnunistered lopically in the
treatment or prophylaxis of inflammation in an animal, including man and other
mammals,and may be used in the relief or prophylaxis of 5-lipoxygenase pathway mediated
diseases such as rheumatoid arthritis, rheumatoid spondylitis,osteoarthritis, gouty arthritis
1 0 and other arthritic cor.ditions, inflamed joints, eczema, psoriasis or other inflammatory skin
conditions such as sunburn; inflammatory eye conditions including conjunctivitis; pyresis,
pain and other conditions associa~ed with inflammalion.
The amount of a compound of Formula (I) or Formula (II) required for
therapeutic effec~ on topical administration will, of course, vary with the compound
1 5 chosen, the nature and severity of the inflamma~ory 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 mg to 500 mg of base for topical administration, the
most preferred dosage being 1 mg to 1000 mg, for example 5 to 250 mg administered two
or threc times daily.
2 0 By topical administration is meant non-systemic administration and includes
the applicadon of a compound of Formula (I) or (II) externally to the epidermis, to the
buccal cavity and insdlladon of such a compound into tlle ear, eye and nose, and where the
compound does not significantly enter the blood stream. By systemic administration is
meant oral, intravenous, intraperitoneal and intramuscular administradon.
2 5 While it iS possible for an active ingredient to be administered alone as the raw
chemical, it is preferable to present it as a pharmaceutical formularion. 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 forrnulation although it may comprise as much as 10% w/w but
preferably not in excess of 5% w/w and more preferably from 0.1% to 1% w/w of the
3 0 formulation.
The topical formuladons of the present invention ,both for veterninary and
human medical use, comprise an active ingredient together with one or more acceptable
carrier(s) therefor 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
3 5 and not deleterious to the recipient thereof.
Forrnulations suitable for topical adrninistration include liquid or semi-liquidpreparations suitable for penetration through the skin to the site of inflammation such as
.
wosl/l9497 208 ~2 ~ 2 - PCl/US91/04022 ~,r
liniments, lotions, crearns, ointments or pastes, and drops suitablc for administration to the
eye, ear or 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
S suiuble aqueous solution of a bactericidal and/or fung~cidal agent and/or any other suitable
preservative, and preferably including a surface acti~/e a ,ent. The resulting solution may
then be clarified by filtration, transferred to a suitabie cont~iner which is then sealed and
sterilized by autoclaving or maintaining at 98-lCOC. for half an hour. Alternatively, the
solution may be sterilized by filtration and transferred to ~he container by an aseptic
1 0 technique. Examples of bactericidal and fungicidal agents sui~able for inclusion in the
drops are phenylmercuric nitrate or acetate (0.û02%), benzalkonium chnloride (0.01%~ and
chlorhexidine aceute (0.01%). Suitable solvents for ~he ?reparation of an oilv solution
include glycerol, diluted alcohol and propylene glycol.
Lotions according to the present invention i~.c!ude those sui;able for
1 5 application to the skin or eye. An eye lo~ion may compris~ a sierile aqueous solu~ion
optionally containing a bactericide and may be prepared by methods sirnilar 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 as glycerol or an oil such as castor oil or arachis oil.
2 0 Creams, ointments or pastes according to the present invention are semi-solid
formulations of the active ingredient for external application. They rnay be made by mixing
the active ingredient in finely-divided or powdered form, alone or in solution or suspension
in an aqueous or non-aqueous fluid, with the aid of suiuble machinery, with a greasy or
non-greasy basis. The basis may comprise hydrocarbons such as hard, soft or liquid
2 5 paraffin, glycerol, beeswax, a metallic soap; a mucilage; an oil of natural origin such as -
almond, corn, arachis, castor or olive oil; wool fat or its derivadves, or a fatty acid such as
steric or oleic acid together with an alcohol such as prolylene ,lycol or macrogols. The
forcnulation may incorporate any suitable surfæe active agent such as an anionic, cationic
or non-ionic sulfactant such as sorbitan esters or polyoxyethylene derivatives thereof~
3 0 Suspending agents such as natural gums, cellulose derivadves or inorganic materials such
as silicaceous silicas, and other ingredients such as lanolin, may also be included.
The compounds of Formula (I) or (II) may also be administered by inhalation~
By "inhalation" is meant intranasal and oral inhalation adminis~ation. Appropriate dosage
forms for such administration, such as an aerosol formulation or a metered dose inhaler,
3 5 may be prepared by conventional techniques. The daily dosage amount of a compound of
Formula (I) or (n) administered by inhalation is from about .lmg to ~bout 100 mg,~;g
preferably about I mg to about 10 mglkg per day.
,. , ........ , ~ ,. . . .
WO 9l/19497 43 ~ ~ ~31~ 2 ~ ~ PCr/US91/040~2
A compound of Formula tl) or (II) or a pharmaceutically acccptable salt
thereof can be adtninistered to such human in a conventional dosage form prepared by
combining a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof,
with a conventional pharmaceutically acceptable carrier or diluent according to known
S techniques, such as those described above as well as those described in Adams et al., U,S.
Patent Number 5,002,942, issued March 26, 1~91. It will be r cognized by one of skill in
the art that the form and character of the pharrnaceutically acceptable carrier or diluent is
dictated by the amount of active ingredient with which ie is to be combined, the route of
administration and other well-known variables.
1 0 The route of administration may be oral, pulmon~T~y, parenteral, buccal, intra-
articular ,nasal or topical. The term parenteral as used herein includes intravenous,
intrarnuscular, subcutaneous intranasal, intrarectah intravagin21 or intraperitoneal
administration. The subcutaneous and intramuscular forrns of parenteral administration are
generally preferred. The daily oral dosage re~.men will p.efe~bly be from about 5 lo about
1 5 100 mg/kilograrn of total body weight. The d~ily paren;erul dosage .-egim~en will preferably
be from about 2 to about 80 mg per kilograrn (lcg) of total body weight, most preferably
from about 3 to about 60 mg/kg. The daily topical dosage regimen will preferably be from
about 2 mg to about 10 mg per site of administration. It will be recognized by one of skill
in the art that the optimal quantity and spacing of individual dosages of a compound of
2 0 Formula (I) or (Il) or pharmaceutically accep~able salts thereof will be determined by the
nature and extent of the condition being treated, the form, route and site of administration,
and the particular patient being treated, and that such optimums can be determine~d by
conventional techniques.
It wiD also be appreciated by one of skill in the art that the optimal quantity and
2 5 spacing of individual dosages of the Forrnula (I) or (II~ compound will be deterrnined by
the nature and extent of the condition being treated, the form, route and site of
administration, and the particular animal being ~reated, and that such optimums can be
determined by conventional techniques. It will also be apprecia~ed by one of skill in the art
that the optimal course of treatment, i.e., the number of doses of a compound of Formula
3 0 (I) or (11) or a phamnaceutically acceptable salt thereof given per day for a defined number
of days, can be ascertained by those skilled in the art using conventional course of
treatmen: determination tests.
The route of adrninistration for the compounds an their pharmaceutically
acceptable salts of 2~ Methoxyphenyl)-3-( '-p~Tidyl)-7-oxo-5,6-dihydro-[7H]-
3 5 pyrrolo[1,2-a]imidazole; 5,6- Dihydro-2-t4-l~lethoxyphenyl)-3-t4-pyridyl)-[7H]-
pyrrolo[l,2-a]imidazole-7-ol; or 5,6-Dihydro-7.7-difluoro-2-~ l-Methoxyphenyl)-3-(4-
pyridyl)-[7H]-pyrrolo[1,2-a]-imidazole ma~ be bv oral, pulmonary, p;lren~eral, buccal,
intra-articular ,nasal or topical means as defined herein. The subcutaneous and
,
W O 91/~9497 ~ ~ 8 l~ 2 ~! ~ 44 PC~r/US91/04022
intramuscular forms of parenteral adrninistration are generally preferred. The daily oral
dosage regimen will preferably be from about 1 to about 100 mg/kilogram of total body
weight dependent upon the route of administration, preferably from about 2mg to about
80mg/kg per day. It will be recognized by one of skill in the art that the optimal quantity
5 and spacing of individual dosages of one of these three compounds or pharmaceutically
acceptable salts thereof will be determined by the nature and extent of the condition being
treated, the form, route and site of administration, and the particular patient being treated,
and that such opdmums can ~e determined by convendonal techniques.
1 0 EXAMPI,ES
Without further elaboratdon. it is believed that one skilled in the art can, using
the preceding desc iption, utilize the present invention to its fullest extent. The following
Examples are, therefore, to ~e construed as merely illus~ative and not a limitation of the
scope of th., presen; invenr.on in any W2~'.
1 ~
P~ARMAOEU'llCAL COMPOSTION EXAMPLES
EXAMPLE A - CAPSULE COMPOSlTlON
A pharmaceutical composiion of this invention in the form of a capsule is
2 0 prepared by filling a standa-d two-piece hard gela~in capsule with 50 mg. of a compound of
Formula (I), in powdered form, 110 mg. of lac~ose, 32 mg. of talc and 8 mg. of
magnesium stearase.
EXAMPLE B - l~JECTABLE PARENTERAL COMPOSlllON
2 5 A pharmaceutical composition of this invention in a form suitable for
administration by injection is prepared by stirring 1.5% by weight of a compound of
Formula (I) in 10% by volume propylene glycol and water. The solution is sterilized by
filtration.
EXAMPLE C - O~MENT COMPOSITlON
Compound of Fo.-mula (I) 1.0 g
White soft paraffin to 100.0 g
The compound of Formula ~1) is dispersed in a small volume of the vehicle
3 5 and this dispersion is gradually incorporated into the bulk to produce a smooth,
homogeneous prc,duct which is filled into collapsible meIal tubes.
EXAMPLE D - TOPICAL CREAM CO~lPOSmON
WO 91/19497 45 2 ~ PCr/US91/04022
Compound of Formula (1) 1.0 g
Carbowax 200 20.0 g
Lanolin Anhydrous 2.0 g
White Beeswax 2.5 g
5 Methyl hydroxybenzoa~e 0.1 g
Distilled Water to lC0.0 g
The carbowax, 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 ~emperature is allowed to fall to 50C. The compound of Forrnula (I) is
1 0 added and dispersed throughout, and the composition is allowed to cool with slow speed
, stlmnD.
EXAMPLE E - T(~PICAL LOTION COMPOSmON
Compound of Forrnula (I) 1.0 g
1 5 Sorbitan Monolaurate 0.6 g
Polysorbate ~0 0.6 g
Cetostearyl Alcohol 1.2 g
Glycerin 6.0 g
Methyl Hydroxybenzoate 0.2 g
2 0 Purified Water B.P. to 100.00 ml
Thc methyl hydroxybenzoate and glycerin are dissolved in 70 ml of the water
at 75C. Thc sorbitan monolaurate, polysorbate 20 and cetostearyl alcohol are melted
together at 75C and added to the aqueous solutdon. The resuldng emulsion is
homogenized, allowed to cool with condnuous stirring and the compound of Formula tI) is
` 2 5 added as a suspension in the remaining water. The whole suspension is stirred until
homogenized.
EXAMPLE F - EYE DROP COMPOSl llO~'
Compound of Formula (I) 0.5 g
3 0 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 resulting solution is allowed ~o cool. The compound of Formula (I) is then
3 5 added, and the solution is made up to 100 ml with purified water. The solution is sterilized
by filtration through a membrane filter (0.~' mm pore size) and packed aseptically into
suitable sterile containers.
W O gl/19497 ~ 2 9 iJ -46 - PC~r/US91/04022 ,
E~;~MPI,E G - COMPOSITlON FOR ADMINISTRATION BY INHAI~
For an aerosol container with a capacity of 15-20
ml: Mix 10 mg of a compound of Formula (I) with 0.1-0.2% of a lubricating 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 adap~ed for either intranasal or oral inhalation adminis~iioll.
E AMPI E H - COMPO$1T10N FOR ADMINISTRATION BY ~ALATION
For an aerosol container with a capacity of 15-20 ml: Dissolve 10 mg of a
1 0 compound of Formula (I) in ethanol (6-8 ml), add 0.1-0.2~c of a lubricating agent, such 25
Span 85 or oleic acid, and disperse such in a propellan~ (c.a.), such as freon, preferably a
combintion of freon 144 and freon 1~, and put into an a?propriate aerosoi container
adapted for either intranasal or oral inhalation administration.
1 5 UTILlTY EXAlvlPLES
In the tests used to determine activity as 5-lipoxygenase pathway inhibitors,
male Balb/c mice (20-~8 g), were used. All mice were obtained from Charles RiverBreeding Laboratories, Kingston, N.Y. Within a single experiment, rnice were agematched.
2 0 Reagents were employed as follows:
Compounds of Formula (I) were used as the free base. The compounds
were dissolved in acid saline. Compounds were administered by lavage at the indicated
dose in a final volume of 10 mVkg.
For in vitro experiments, compounds were dissolved at appropriate
2 5 concentrations in ethanol (final concentration 1.0%) and then diluted to final concentrations
using the buffers indicated in the text.
Arachidonic Acid-lnduced Mouse Ear Inflammadon
Arachidonic acid in acetone (2 mg~20 ml) was applied to the inner surface of
the left ear. The thickness of both ears was then measured with a dial micrometer one hour
3 0 aftcr treatment, and the data were expressed as the change in thickness (10~3 cm) between
treated and untreated ears.
Test compounds were given crally in acid/saline at the times indicated in the
text prior to the topical application of arachidonic acid.
Assav of 5-Lipoxvgenase Acdvities
3 5 The 5-lipoxygenase (S-LO) 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% C2 in spinner culture using Eagles essential medium (ME~I~
supplemented medium with 10% heat inactivated fetal calf serum. The cells were collected
~ ~ WO 91/19497 47 2 0 ~ 3 Pc~/us91/o4o22
from culture by centrifugadon at 2,000xg for 20 minutes and then washcd twicc with
50rnM sodium phosphate (pH 7.0) that contained ImM EDTA and 0.1 % gelatin, After this
wash, the cells were resuspended in fresh phosphate buffer to achieve a concentradon of
5X107 cells/ml. This suspension was disrupted by nitrogen cavita~ion using the Parr bomb
at 750psi for 10 rninutes. The broken cells were then centrifuged at lO,OO~xg for 20
minutes. The supernatant was collected and centrifuged at lOO,COO 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 assay either measured after SO seconds at 20C or measured
1 0 according to the method of G. K. Hogaboom et al., Moleclllar Ph~macol. 30, S 10-S 19
(1986) or the continuous 2 consumption assay. The resu!ts from either assay arecomparable if not identical. All compounds w~re dissolved in ethanol with the final
concentration of ethanol being 1 % in the assay.
The radiotracer extent assay examined the 5-!ipox~venase pr~ducts
1 5 [transLTB4 (DI-H~TE), 5HETE and 5HPETE] producod ~-r ~ co second incubation at
20C. Aliquots (40mL) of the supernatant were preincubated with the inhibitor or vehicle
for 10 minutes in 25mM BisTris buffer (pH 7.0) that also contained lrnM EDTA. lrnM
ATP, SOmM NaCl, 5% ethylene gylcol and 100 mglml of sonicated phosphatidylcholine
(total volume 0.238 ml). The 5-lipoxygenase reaction was initiated by the addition of
2 0 CaC12 (2mM) and 1-C14-arachidonic acid (25mM; lOO,OOOdpm))(final volume 0.25ml).
After 90 seconds, the reaction was terminated by the addition of two volumes (O.Sml) of
ice chilled acetone. The sample was allowed to deproteinize on ice for 10 minutes prior to
centrifuging at 1,000 xg for 10 minutes. The deproteinized supernatants were dried under
argon and then redissolved in 200 mL of ethanol. These samples were then analyzed by
2 5 reverse phase HPLC as described by G.K. Hogaboom et al., Molecular Pharmacol. 30:
510-519 (1986), herdn incorporated by reference. The compound-mediated inhibition of
5-lipoxygenase activity is described as the concentration of compound causing a 50%
inhibition of product synthesis.
The second assay for assessing inhibition of the S-lipoxygenase activity was
3 0 a continuous assay which monitored the consumption Of 2 as the reaction progressed.
The 5-1ipoxygenase enzyme (200mL) was preincubated with the inhibitor or its vehicle in
25mM BisTris buffer (pH 7.0) that contained Im~M EDTA, lmM ATP, 5mM NaCI and 5%
ethylene glycol for 2 minutes at 20~C (total volume 2.99 ml). Arachidonic acid (lOmM)
and CaC12 (2mM) were added to start the reaction. and Ihe decrease in 2 concen~ration
3 5 followed with time using a Clark-type electrode and the Yellow Spring 0~ monitor (type
53)(Yellow Springs, OH). The optimum veloci~ was calculated from ~he progress curves.
;. The compound mediated inhibition of S-lipoxygenase activitv is described as the
~.
.
WO gl/19497 2 ~ 8 !~ 2 9 3 -48 - PCI /US91/04022
- concentration of compound causing a 50% inhibition of optimum velocity for thc vehiclc-
treated sample.
LTC-4 / PGE~ Production from Hllman Monocvtes in vitro
a) Cell Preparation: Human monocytes were prepared from leukosource packs
supplied by the American Red Cross (Philadelphia,Pa). The leukosource packs werefractionated by a two-step procedure described by F. Colatta et al., J. Immunol. 132, 936
(1984), herein incorporated by reference, that uses sequential sedimentation on Ficoll
followed by sedimentation on Percoll. The monocyte fraction that results from this
1 0 technique was composed of greater than 85% monocytes (with the remainder being
neutrophils and Iymphocytes). The monocytes (1.5 X 106) were placed into
polyprop . le~e tubes and used as a suspended culture. The assay buffer consisted of RPMI
1640 buffer, ~Mcore, G. E. et al., JAMA, 199, 519 (1967) herein incorporated by
reference~ l~c human A3 se-um, 2mM glutamine, 1C0 U/ml Pericillin/Streptomycin, 25
1 5 mM HEPES [~(2-hydroxyethyl)-1-piperazine-e~hanesulfonic acid], and lmM CaC12.
b) LTC4/PGE2 Production: Monocytes (0.9mUtube) were dispensed into 12 X 75
mm polypropylene tubes (as a suspended culture). Compounds (lOOul of a 10X stock of
the compound of interest) dissolved in the assay media was added per tube (performed in
duplicte). The cells were incubated for about 45 minutes at about 7C with constant
2 0 aBtation in a humidified incubator. A23187 calcium ionophore (2uM final concentration)
used to sdmulate the cdls, was added and the monocytes were incubated an addidonal 15
minutes. Supematants were then collected from each tube, clarified by centrifugation,
dividcd into two aliguots and stored at -70C until assayed.
c) Radio-immunoassay: Supematants were assayed for LTC4 production and
2 5 PCiE2 by radioimmunassay; which was performed using a New England Nuclear
Leukotriene [3H]-LTC4 and [125Il-PGE2 RIA Kit according to the manufacturer's (New
England Nucelar, Boston Massachusetts) instructions. The compound-mediated inhibition
of LTC4 is described as the concentradon of compound causing a 50% inhibition of LTC4
production.
; WO 91/19497 9 2 0 ~ PCr/US91/04022
TABLE I
ANllD~FLAMMATORY ACTlVlTY OF FORMULA (I)
.,
PERCENT ~BITION OFARACHrDONIC ACID-INDUCEDMOUSE EAR
S ~_ (SOm~/lcg~.o.)
COMPOUND NUMBERk..... 1....... 65.0
a Mouse ear edema was measured as described in Griswold et al., Inflammation, 11(2),
1 0 189-199 (1987), the disclosure of which is hereby incorporated by reference.b compound no. 1 is 2-(4-methoxyphenyl)-3-(4-pyridyl)-imidazo-[1,2-a]-pyridine.
;
TABLE n - 5-LO DATA:
COMPOUND NUMBERb .... 1 ...... .16.0
COMPOUND NUMBERC .... 2....... 36.0
COMPOUND NUMBER~ .... 3....... greater than 100
COMPOUND NUMBERe .... 4....... greater than 100
.~ .
2 0 c compound no. 2 is 5,6-Dihydro 7,7-difluoro-2-(4-Methoxyphenyl)-3-(4-pyridyl)-t7H]-
pylTolo[1,2-a]-imidazole.
d compound no. 3 is 2-(4-Methoxyphenyl)-3-(4-pyridyl)-7-oxo-5,~dihydro [7H]-
pyrrolo[l,2-a]imidazole.
e compound no. 4 is 5,6-Dihydro-2-(4-Methoxyphenyl)-3-(4-pyridyl)-[7H]-pyrrolo[1,2-
2 5 `a]imidazole-7-ol.
TABLE m - LTC4 DATA:
COMPOUND NUMBER~..... 1....... .12Ø
. COMPOUND NUMBER .... 2....... .15.0
~' 30 COMPOUND NuMBERd , 3 ,, ..... ,, 33 0
COMPOUND NUMBERe .... 4....... .18.0
TABLE 1~ - PGE~TA
- 3 5 COMPOUND NUMBER k ... 1....... Ø4
. ' ,~' ' . :
WO 91/19497 2 ~ g ~ 2 ~ ~ 50 Pcr/US91/04022 ~-s
REST~TS
Based upon the data shown herein the compounds of Forrnula (I) show
inhibition of both 5-LO and CO activity and the 7-substituted difluroro, 7-oxo and 7-
hydroxy derivatives of a pyrrolo[2, l -a]irr~dazole, and therefore are expected to be useful in
5 the treatrnent of OPUFA, specifically mediated by inhibi~on of the 5-LO and CO mediated
enzymes.
SYNT~TIC EXAMPLES
~Y~MP~E 1
2-(4-Mercaptophenvl)-3-(4-pvridvl)imidazor 1 .2-ai ,pvridine
Formula (G! Compound
The title compound is prep~red by treatinV ~ methylsulfinylphenyl)-3-(4-
pyridyl)imidazo[1,~-a]-pyr.dine, prepared as descli~ed in ~ ~mole 15, of ~3ender et ~1.,
1 5 U.S. Aplication Serial Number 07/3O5,349, ~lled June 1~, lS~9.
A solution of 5.17 g (15.5 mmoles) of 2-(4-methylsulfinylphenyl)-3-(4-
pyridyl)imidazo[l,2-a~pyridine in methylene chloride is cooled to 0C is treated with 9.7 g
(46.4 mmoles, 6.5 ml) of trifluoroacetic anhydride in methylene chloride. The mixture is
heated to reflux for 1 hour and stripped in vacuo. The residue is treatcd with water and
2 0 extracted into methylene chloride. The organic phase is washed with aqueous sodium
bicarbonate, saturated brine, dried over anhydrous sodium sulfate and stripped in vacuo. A
solution of this residue in anhydrous methanol is neutralized with 5 ml (23 mmoles) of a
25% soludon of sodium methoxide in methanol and sdrred at room temperature for 3hours. This solution is then poured into ice-water, treated with 3N sodium bicarbonate
2 5 solution, and concentrated in vacuo to remove most of Ihe me2hanol. This mixture is then
extracted into methylene chloride, and the organic phase is washed wilh water, saturated
brine, dried over anhydrous sodium sulfate and stripped in vacuo The residue is
chromatographed on silica to afford the title compound.
3 ~CAMPLE 2
2-(4-Ethoxvcarbonvlthiophenyl)-3-(4-pvridvl~-imidazo~ 1 .2-alpvridine
To an ice bath cooled solution containing 1.03 g, (3.4mmole) of 2-(4-
mercaptophenyl)-3 (4 pyridyl) imidazo~ 1,2-a]pyridine prepared as in Example 1 above,
and 0.5ml (3.6mmole) of triethylamine in 10rnl of methylene chloride is added 0.33ml
3 5 (35mmole) of ethyl chloroformate~ The reaction is allowed to warm to room temperature
and stirred for several hours. The mixture is then diluted with methylene chloride and
washed with 3N NaHCO3, saturated NaCI, ~eated with Na~SO~, stripped, then fl~sh
: ,
`. . ' ' :.
O 91/19497 -5 1 - ~ B ~ 3~ PCr/US91/04022
chromatographed on silica with methylene chloride containing MeOH to give the desired
titled compound.
~AIvlPLE 3
2-(4-Phenoxvthiocarbonvlthiophenvl)-3-(4-pvT~dvl)-imidazo~1.2-alpvridine
To an ice-bath cooled soludon containing 1.03 g (3.4mmole) of 2-(4-
mercaptophenyl)-3-(4-pyridyl)-imidazo[1,2-a]pyridine prepared as in Example 1 above,
and 0.5 ml (3.o mmole) of triethylan~ine in 10 ml of diglyme is addsd 0.48 ml (3.5mmole)
of phenyl chlorothionoformate. The reaction is allowed to warm to room temperature and
1 0 heated at 40 to 120C for several hours. Wor.lcup ~I-d chrcmato, aphy in a manner
analogous to thal outlined in Example 2 affords ~,e des:,. ed d~led compound.
~YA~iPLE 4
2~4-(2-Oxobutvl)thiophenvll-3-(4-pvridvl)-imidazol 1~2-alpvriaine
1 5 To an ice-bath cooled solution containing 1.0 3g (3.4tnmole) of 2-(4-
mercaptophenyl)-3-(~pyridyl)-imidazo[1,2-a]pyridine prepared as in Example 1 above,
and 0.5 ml (3.6 mmole) of triethylamine in 10 ml of methylene chloride is added 0.36 rnl
(3.5mmole) of 1-bromo-2-butanone. The reaction is allowed to warm to room temperature
and stirred at room tcmperature for several hours. Worlcup and chromatography in a
2 0 manner analogous to that outlined in Example 2 affords the desired titled compound.
EXAMPLE5
2-(4-Methoxvmethvlth~henvll-3-(4-pvlidvl)-imidazorl .2-alpvridine
To an ice-bath cooled soludon containing 1.03 g (3.4mmole) of 2-(4-
. 2 5 mercaptophenyl)-3-(4-pyridyl)-imidazo[ 1 ,2-a]pyridine prepared as in Example 1 above,
;` 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 reacdon is allowed to warm to room
; temperature and sdrred at room temperature for several hours~ Workup and
chromatography in a manner analogous to that outlined in Example 2 affords the desired
30 ` titledcompound.
~; EXAMPLE 6
~` 2.~ aAn-divl-bisr2-(4-thiophenvl)-3-(4-pvridvl)-imidazo~ l .2-alpvridine
To an ice-ba~h cooled soludon conuining 1.03 g (3.4 mmole) of 2-(4-
3 5 mercaptophenyl)-3-t4-pyridyl)-imidazo[1,2-a]pyridine prepared as in Example 1 and 0.12
ml (1~7 mmole) of acetone in 5 rnl of methylene chloride is added 0.10 ml of boron
trifluoride etherate~ After 4 hours at 0C ~he reaction is diluted with methylene chloride and
wo 9l/19497 2 ~ 52 - PCr/US9l/04022 ~-,
worked up as outlined in Example 2. Purification by chromatography on silica affords the
desired dithioketal.
EXAMPLE 7
2-(4-Mercaptophenvl)-3-(4-pvridv~)-imidazo[1.2-a~pyridjne d~lfide
2.06g. (6.8 mmole) of 2-(4-mercaptophenyl)-3-(4-pyridyl)-imidazo[1,2-
a]pyridine prepared as in Example 1 above, is dissolved in a solution containing 4 parts
ethanol and 1 part concentrated aqueous ammonia and allowed to air oxidize in an open
flaslc at 20-40C for 1 to 4 days. The solvent is stripped in vacuo and the product is
1 0 purified bv chromatography on silica to yield the desired disulfide.
In an alternate procedure to that described in above 2-(4-Mercaptophenyl)-3-
(4-pyridyl)-imidazo~1,2-a]pyridine is prepared in situ by adding to a stirred, ice-cooled
solution containing 1.03g of the sulfoxide, 2-(4-methylsulfinylphenyl)-3-(4-pyridyl)-
imidazo[1,2-a]pyridine in 7 ml of chloroethylene, 1.27 ml of trifluroacetic anhydride. The
1 5 solution is allowed to warm and stirred at room temperature for about 2 hours at which
point lOml of ethanol and 3ml of a 10% sodium hydroxide solution is added. Fifteen
rninutes later I2 (800mg) is added. After about an addiùonal 1 hour of stirIing the reaction
mixture is diluted with methylene chloride, washed with a 10% sodium hydroxide solution,
and dried over potassium carbonate. Flash chromatography on silica affords the desired
2 0 title compound.
EXAMPLE 8
2-(4-Ethvldithiophenvl)-3-(4-pvridvl~-irnidazorl .2-alpvridine
Ethanesulfenyl chloride (0~33 g) is added dropwise to an ice-bath cooled
2 5 solution containing 1.03 g (3.4 mmole) of 2-(4-mercaptophenyl)-3-(4-pyridyl)
imidazo[1,2-a]pyridine prepared as in Example 1 above, in tetrahydrofuran. The mixture is
allowed to warm to room temperature. Workup yields the crude disulfide which is purified
by chromatography on silica
3 0 EXAMPLE 9
2-(4-N-Phenvlaminocarbonylthiophenvl)-3-(4-pvridvl)-imidazorl ~2-alpvridine
Phenyl isocyanate (0.38ml, 3.5mmole) is added dropwise to a stirring ice-
bath cooled solution containing 1~03 g (3.4 mmole~ of 2-(4-mercaptophenyl)-3-(4-pyridyl)-
imidazo~1,2-a]pyridine prepared as in Example 1 above, in tetrahydrofuran. The mixture is
3 5 allowed to warm to room temperature. Workup yields the crude titled compound which is
purified by chrornatography on silica.
:
. .: . :.
,:
9 ~
WO 91/19497 53 PCI/US91/04022
EXAk~LE 10
2-(4-N-Phenyldithiocarbamovlphenvl)-3-(4-~vridvl)-imidazo~ 1.2-alpvridine
Phenyl isothiocyanate (0.42 ml, 3.5 mmole) is added dropwise to a stirring
ice-bath cooled solution containing 1.03 g (3.4 mmole) of 2-(4-mercaptophenyl)-3-(4-
S pyridyl)-imidazo[1,2-a]pyridine prepared as in Examplel 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 by chromatography on silica.
EXAMPLE I I
1 0 2-(4-Dithiccarbamovlphenvl~-3-(4-pvridvl)-imidazofl.2-alpvridine
Thiocarbamoyl chloride (336 mg, 3.5mmole) is added dropwise to a stirring
ice-bath ccoled solution containing 1.03 g (3.4 mmole) of 2-(4-mercaptophenyl)--3-(4-
pyridyl)-imidazo[1,2-a]pyridine prepared as in Example 1 above, in tetrahydrofuran. The
mixture is allowed to warm to rcom temperature and stirred for several hours. Workup
1 5 yields the crude titled compound which is purified by chromatography on silica.
EXA~LE 12
2-(4-N.N-l:)imethvlaminocarbonvlthiophenvl)--3-(4-~vridvl)-imidazorl.2-alpvridine
N,N-Dimethylcarbamoyl chloride (375 mg, 3.5 mmole) is added dropwise
2 0 to a stirring -20C solution containing 1.03g (3.4 mmole) of 2-(4-mercaptophenyl)-3-(4-
pyridyl)-imidazo[1,2-a]pyridine prepared as in Example 1 above, in tetrahydrofuran. The
mixture is allowed to warm to room temperature. Workup yields the crude thiocarbamate
which is purified by chromatography on silica.
2 5 EXAMPLE 13
2-(4-Dithiobenzovlphenvl)-3-(4-pvridvl)-imidazor 1.2-alpvridine
Thiobenzoyl chloride (546 mg, 3.5 mmole) is added dropwise to a stirring
ice-bath cooled soludon containing 1.03g (3.4 mmole) of 2-(4-mercaptophenyl)-3-(4-
pyridyl)-imidazo[1,2-a]pyridine prepared as in Example 1 above in tetrahydrofuran. The
3 0 mixture is allowed to warm to room temperature and stirred for several hours. Workup
yields the crude titled compound which is purified by chromatography on silica.
EXAMPLE 14
~(~Methvlsul~lnvlphenvl)-5-(4-~Tidvl)imldazo~2.1 -blthiazole.
3 ~ Formu!a (T~ Compound
The title compound is prepared b- treating 6-(4-methylthiophenyl)-5-(4-
pyridyl)imidazo~2,1-b]thiazole, as described in Example 20 of Bender et al., U.S.
Application Serial Number 07/365,349, filed June 13, 1989.
.. . . - .
, . . .
wo 91/19497 ~ 2 ~ ~ Pcr~ussl/o4o22 i -
EXAMPLE 15
~(4-Methvlsulfinvlphenvl)-5-(4-pvridvl)imidazo~2.1 bloxazQI~,
Formula (I) Compound
The title compound is prepared by treadng 6-(4-methylthiophenyl)-5-(4-
pyridyl)-imidazo[2,1-b]oxazole,as descri~ed in Example 23, Bender et al., U.S.
Application Serial Number 07/365,349, filed June 13, 1989.
EXAMPLE 16
1 0 2-(~Mlethvlslllfinvl~henvl)-3-(d-~vndvl~imidazorl.~-alDvrin~idine
Formula (n Cornpound
Tne ti~le compound is prepared by trea~ing 2-(4-methyl~iophenyl)-3-(4-
pyridyl)-imidazo[1,2-a]-py~imidine, as described in Exal-nple 26, Bender et al., U.S.
Application Serial Num~er 07/36~,3~9, nied iune 13, 1933.
1 5
EXAMPLE 17
2-(4-Methoxvphenyl)-3-(4-pvridvl)imidazor 1.2-alpvndine.
Formula (I) Compound
a) 2-(4^Methox~henvl)imidazorl.2-alpvridine
2 0 A chloroform solution of 7.3 g (32 mmoles) of 1-(4methoxyphenyl)-2-
bromo-ethan-1-one and 3.0 g (32 mmoles) of 2-aminopyridine was stirred for 5 hours and
a precipitate was obtained on chilling. This pxcipitate was washed with cold carbon
tetrachloride and recrystallized from ethyl acetate to afford the title compound, melting point
(mp) 135-137C, Calcd for C14H12N20; C: 74.98; H: 5.39, N: 12.~9, Found, C: 74.64,
2 5 H: 5.35, N: 12.63.
b) 2-(~Methoxyphenvl)-3-(1 -ethoxvcarbonvl- I .~dihvdropvridvl)imidazor 1.2-
alpvndine
A soludon of 1.5 g (6.69 mmoles) of 2-(4-methoxyphenyl)irnidazo~1,2-
a]pyridine, prepared as described in Example lOa, of Bender et al., U.S. Aplication Serial
3 0 Number 07/365,349, filed June 13, 1989, whose disclosure is incorporated by reference
herein, is dissolved in 20 ml of dry methylene chloride containing 5.29 g (66.9 mmoles) of
pyridine was treated with 3.63 g (33.4 mmoles) of ~ithyl chloroformate over one hour.
After 72 hours, the mixture was poured into 0.3 N HCl at 0C and extracted into methylene
chlolide. The organic phase was washed with 0.3 N HCl, water and then dried over3 5 anhydrous sodium sulfate. The solvent was stripped in vacuo to give the title compound as
a tan powder, IH-NMR (250 MHz, CDC13) o ~.17 (d,1 H), 7 60 (d,1 H), 7.50 (d,2 H),
7.12 (d-d,l H), 7.0 (br s,2 H), 6.9~ (d.2 H). 6 76 (t.l H), 5.02 (p.1 H), 4.79 (br s,2 H),
4.32 (q,2 H), 3.76 ts,3 H), 1.30 (t,3 H).
:;
WO 91/19497 55 2 Q ~ ~ r~ ~ ~ PCI/US91/04022
c)- 2-(4-Methoxvphenvl)-3-(4-pvrid!tl)imidazorl.2-alpvridine
A mixture of 1.2 g (3.20 mrnoles) of 2-(4-methoxy-phenyl)-3-(1-
ethoxycarbonyl-1,4-dihydropyridyl)-imidazo[1,2-a~pyridine, prepared as described in
Example lOb, of Bender ~al . U.S. Aplication Serial Number 07/365,349, filed June 13,
1989, in 10 ml of decalin was heated at 185 to 190C under argon with 0.154 g (4.8
mmoles) of sublimed sulfur for 1.5 hours. The cooled reaction mixture was extracted with
3N HCI and the aqueous layer washed with methylene chloride, made alkaline with 5%
sodium carbonale solution and e:c~ac~ed with methylene chloride. The basic organic phase
was dried over anhydrous potassium car~onate and stripped in vacuo. The residue was
1 0 chromatographed on silica :lnd eluted ~ith 1 to ~% of methanol in chloroforrn~ethyl acetate
(1:1). Recrys.allization two ti~es from ethyl acetate,tether and once from ethylacetate/hexane gave th~ ~itle comFound, ~p 1'7.5~ .5C, C lCd for C1gH1sN3O; C:
75.73, H: 5.02, ~: 13.34; found C: 75.96, ~: 5.05, N: 1~.C0.
1 5 EXAMPLE 18
2-(4-Methvlsul~lnvlphenvl)-3-(4-pvridvl)imidazo~ 1.2-alpvridine
To a stirred solution of 5.0 g (16.3 mrnoles) of 2-(4-methylthiophenyl)-3-
;~ (~pyridyl)imidazo[1,2-a~pyridine prepared as described in Example 12, of Bender et al.,
U.S. Application Serial Number 07/365,349, filed June 13, 1989 dissolved in 75 ml of
2 0 chloroform, chilled in an icc bath, is added dropwise a solution of 3.30 g (16.3 mmoles) of
85% 3-chloroperbenzoic acid in chloroform. After stirring at 25C overnight, the reaction
mixture is washed with 5% sodium carbonate, dried over anhydrous potassium carbonate,
and stripped in vacuo. The residue is flash chromatographed on silica eluting with
methanol in methylen? chloride: 2-propanol (9: 1). The solvent is removed i~ Yacuo and the
2 5 residue recrystallized from ethyl acetate to give the desired titled compound.
In an alternate procedure to that above, 2-(4-propylsulfinylphenyl)-3-(4-
pyridyl)imidazo[l,2-a]pyridine is prepared. The sulfide product (1.4 g) 2-(4-
propylthiophenyl)-3-(4-pyridyl)imidazo[1,2-a]p,vridine is prepared, in an analogous
3 0 method to that described above, and is dissolved in 25 rnl of acedc acid and added to a
solution containing 1.35 g of potassium persulfate (K2S2Og) in 30 ml of water. The
reactdon is stirred overnight at room temperature and worked up by dilutiug with methylene
chloride neutralizing with potassium carbona~e. The residue is colurnned on silica gel to
afford the product.
Example 19
2-(~Methvlsulfoxvphenvl)-3-bromo-6~7-dihvdro~lp~,rrolo~ -alimidazole
wo 91/19497 2 0 ~ ~ 2 ~ ~ -56 - Pcr/us9l/o4o22 ~
A 375 mg (1.21 mmol) portion of [formula 1, R, = methylthio, R2 = bromo] 2-(4-
Methylthiophenyl)-3-bromo-6,7-dihydro[5H~pylTolo[1,2-a]irnidazole was dissolved in 4
mL of glacial acetic acid. A 347 m~ (1.45 mmol) portion of sodium persulfate wasdissolved in 2 mL of water The two solutions were combined, and the resulting mixture
5 was stirred at room temperature for 20 h, Saturated aqueous NaHCO3 solution was added,
followed by sufflcient solid NaHCO3 to rnake the m~xture basic The mixture was then
ex~acted with three portions of EtOAc, The combined extracts were dried over MgSO4,
filtered, and the filtrate was evaporated ~n vacuo to give 372 mg of white crystalline solid.
This matenal was recrystallized from EtOAc to give 265 mg (67% yield) of 2-(4-
1 0 Methylsulfinylphenyl)-3-bromo-6,7-dihydro[5H]pyrrolo[1,2-a]irnidazole [formula 1 (Rl =
methylsulfoxy, R2 = bromo] as white blades, mp 181-2~C. FT-IR (KBr, cm~ 3100-
2800 (C-H), 1630 (C=N + C=C), 1085 + 1049 (S=O), 846 (C-H) IH MMR (CDCI3):
8 13 (2H, d, J = 8.43), 7.67 (2H, dd, J = 6.82~ 1.4), 4.01 (2H, t, J = 7.12), 3.02 (2H, t,
J = 7.6), 2.75 (3H, s), 2.66 (2H, quint, J = 7.35). '3C NMR (CDCI3): 154.32, 143.63,
l 5 140.50, 136.61, 126.79, 123.65, 95.37, 44.76, 43.95, 25.25, 24.30. CI-MS (NH3):
328 (lS), 327 (89), 326 (19), 325, ((M + H)+, 100), 311 (40), 309 (41), 247 (34), 231
(20). Elemental analysis: Calc'd for C,3H,3BrNO2S, C 48.01, H 4.03, N, 8.61; found, C
48.16, H, 4.03, N 8.77.
R2 N~
. ,
~ `N
R~
EXAMPLE 20
2-t4-Methvlsulfox~henvl~-6.7-dihvdrorSHlpv~olo~ 1.2-alimidazole
A 32 mg (0.139 mmol) portion of 2-(4-Methylthiophenyl)-6,7-dihydro-
2 S [SH]pyrrolo[1,2-a]imidazole (formula 1, Rl = methylthio. R2 = H), was dissolved in 0.5
mL of glacial acetic acid, and combined with a solution of 40 mg (0.167 mmol) of sodium
persulfate in 0.3 mL water. The resulting mixture was stirred at room temperature for 3 h,
then worked up as in Example 1, giving 39 mg of product as a brown oil. This wasseparP.ted on a preparative TLC plate developed twice in 1 :9 (v/v) ethanol:methyh,ne
3 0 chloride to give 12.5 mg (36% yield) of 1 (Rl = methylsulfinyl, R2= H) as a clear glass~
FT-IR (film): 3100-2800 (C-H), 1598 + 1545 (C=C), 1385 (C-N or C-H), 1088 + 1043(S=O) 953 (=C-H), 840 (C-H), 752 (C-S)~ 'H NMR (CDCl3): 7.89 (2H, d, J = 8~5),
7~63 (2H, d, J = 8~5), 7~27 (lH, s), 4~04 (2H. t~ J = 7~1), 2.95 (2H, t, 7.5), 2.74 (3H~
` s), 2~64 (2H, quint, J = 7~3)~ "C NMR (CDCl3) 155.41, 144.97, 142.92, 137.86,
3 S 125.27, 123.98, lll.S2, 44.93, 43.91, 26.09, 21.14. DCI-MS (CH4): 249 (12), 248
. .
.
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. .~WO 91/19497 2 0 ~ ~ 2 ~ ') pC~/US91/04022
(15), 247 ((M + H)+, 100), 231 (4), 230 (4), 184 (2). HRMS (CI- CH.~): required for
C,3Hl4N2OS, 247.0913 for (M + H); found, 247.0909.
EXAMPLE 21
2-(~Methvlsulfinvlphenvl)-3-(4-pvridvl)-6.7-dihvdrorSHlpvrrolor 1.2-alimidazole
To a solution of 154 mg (0.5 mmol) of 2-(4-Methylthiophenyl)-3-(4-pyridyl)-6,7-
dihydro[5Hlpyrrolo[1,2-a]imidazole in 2 mL of glacial acetic acid was added dropwise an
aqueous solution of potassium persulfate (135 mg, O.S mmol in 3.5 mL) at room
temperature. The reaction mixture was stirred for 22 h, producing a clear yellow solution.
1 0 The pH of the solution was adjusted to 8-9 by the addition of solid potassium carbonate,
and then ex~acted four times with 20 mL of methylene chloride. The combined extracts
were washed successively with 25 mL water, 25 mL of saturated aqueous sodium chloride
soludon, tnen dried over magnesium sulfate. ll~e drying agent was removed by filtlation,
and the filtrate was evaporated in vacuo. The resulting oil solidified on standing at room
1 5 temperature, then was slurried in ethyl acetate and the solvent filtered off, giving 108 mg
(67% yield) of 2-(4-Methylsulfoxyphenyl)-3-(4-pyridyl)-6,7-dihydro[SH]pyrrolo[1,2-
a]imidazole. TLC analysis tAnaltech SiO2, 95:5 methylene chloride:methanol) showed the
absence of any sulfone derivative, and the presence of a single spot comigrating with the
, methylsulfoxy derivadve.
`~ 20
~XAMPLE 22
2-(4-Methvlsulfoxv~henvl)-3-(4-pvridvl)-6.7-dihvdrorSHlpvrrolorl.2-alimidazole
To a solution of 154 mg (O.S mmol) of 2-(4-Methylthiophenyl)-3-(4-pyridyl)-6,7-
dihydro~5Hlpyrrolo~1,2-a]imidazole in 2 mL of glacial acetic acid was added dropwise an
2 S aqueous solu~ion of sodium persulfate (143 mg, 0.6 mmol in 1 mL) at room temperature.
The reaction mixture was stirred for 28 h. A 50 rnL portion of water added, the pH was
adjusted to 8-9 by the addition of solid potassium carbonate, and then the mixture was
extracted three times with 20 mL of methylene chloride. The combined extracts were
washed successively with 25 mL water, 25 mL of saturated aqueous sodium chloride3 0 solution, then dried over magnesium sulfate. The drying agent was removed by filtration,
and the filtrate was evaporated in vacuo. After drying for 18 h at 56C/35 rnm of Hg, the
solid weighed 153.6 mg for a chemical yield of 95%. The chemical purity was determined
by HPLC to be 92%. No sulfone derivative was detected by HPLC.
3 5 EXAMPLE 23
2-(4-propvlsulfinvlphenvl)-3-~4 pvridvl)-6~7-dihvdro-rSHlpvrrolorl.2-alimidazoleThe sulfide (1.4 g) 2-(4-propylthiophen~.1)-3-(4-pyridyl)-6,7-dihydro- [5H]-
pyrrolo [1,2-a] irnidazole was prepared as descnbed in Example 3 of US Patenl No.
:,
WO 91/19497 2 0 ~ 4 2 J~ i~ 58 PCr/US91/04022
Adams et al., U.S. Patent 4,719,218, issued 01/12/88, and see Exarnple 18 of this
application as well, and was dissolved in 25 ml of acetic acid and added to a solulion
containing 1.35 g of potassium persulfate (K2S2Og) in 30 ml of water. The renction was
stirred overnight at room temperature and worked up by diluting with methylene chloride
5 neutralizing with potassium carbonate. The residue W'lS columned on silica gel to afford
the product and then further purified bv z~cryst~liz2tiGn r.rom e~he.r/methylene chlor.de:
m.p. 114-116C; mass spec (DCI/NH3) 352(M+1), 336. Analysis Calcd. for
C20~I21N3SO: C, 68.35; H, 6.02; N, 11.96; S, 9.12. Found: C, 63.17; H, 6.14; N,
11.97; S, 9.05.
1 0
The above description fully discloses t~.e inven~ion including prefe~ed
embodiments thereof. Mcdific~.ions and im~prove~,len.â of -~e em~dirnents sl}ecifically
disclosed herein ale within Lhe scope of ~.he following c!~irr.s Wi~hout f~- her ela~oration,
it is believed that one sXilled in ~le ar. carl, using the preceding descr.ption, utilize the
1 5 present invention to its fullest extent. rnerefore the Exarnples herein are to be construed as
merely illustrative and not a limitation of the scope of the present invention in any way.
The embodiments of the invention in which an exclusive property or privilege is claimed
are defined as follows.
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