CA2084290A1

CA2084290A1 - Inhibition of 5-lipoxygenase and cyclooxygenase pathway mediated diseases

Info

Publication number: CA2084290A1
Application number: CA002084290A
Authority: CA
Inventors: Jerry L. Adams; Paul E. Bender; Timothy F. Gallagher; John R. Heys; Carl Perchonock; Anthony J. Villani
Original assignee: Individual
Current assignee: SmithKline Beecham Corp
Priority date: 1990-06-12
Filing date: 1991-06-07
Publication date: 1991-12-13
Also published as: ZA914491B; IE911977A1; AU8205991A; PT97960A; NZ238485A; EP0533837A4; EP0533837A1; KR930700104A; JPH05508153A; WO1991019497A1

Abstract

A method of dual inhibition of 5-lipoxygenase pathway mediated diseases and cyclooxygenase pathway mediated diseases in a subject in need thereof which comprises administering to such subject an effective, non-toxic 5-lipoxygenase pathway inhibiting amount or an effective, non-toxic cyclooxygenase pathway inhibiting amount of a diaryl-substituted imidazole fused to a second unsaturated 5 or 6 membered heterocyclic ring containing a nitrogen bridgehead atom wherein said second 5 membered ring also contains a sulfur or oxygen atom or said 6 membered ring may also contain an additional nitrogen atom.

Description

. ~ WO 91/19497 ~ 0 ~ l~ 2 ~ ~ PCI'/llS91/04022 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.

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 =\
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

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:

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:

~ + 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) FORMULA (C) ~ /--\ ~ FORMULA (li) (R~0)3sn$~ Fomu~la (F) R~R3 FORMULA (lla) ~ N W ~, FORMULA (Il) $~Formula (G) 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.

7 -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.

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.

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.

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 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 ~

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-(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.

~(~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 -~(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.

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.

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.

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~

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 . .

.
, . .~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.

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.

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.

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.

, .. . ...

Claims

What is claimed is:

1. A method of treating an OPUFA mediated disease in a subject in need thereof which comprises administering to such subject an effective OPUFA inhibiting amount of a compound of the formula:
wherein:
W is -CR5=CR7-, -N=CR7-, -S- or -O-;
R2 R3, R5, and R7 are, independently, -H or C1-2 alkyl;
one of R1 and R0 is 4-pyridyl or C1-4alkyl-4-pyridyl, provided that when R1 is Cl 4 alkyl-4-pyridyl the alkyl substituent is locased at the 2-position of the pyridine ring, and the other of R1 and R0 is (a) phenyl or monosubstituted phenyl wherein said substituent is C1-4 alkyl, halo, hydroxy, C1-4 alkoxy, C1-3 alkylthio, C1-3 alkylsulfinyl, C2-5 1-alkenyl-1-thio, C2-5 1-alkenyl-1-sulfinyl, C3-5 2-alkenyl-1-thio, C3-5 2-alkenyl-1-sulfinyl, C1-3 alkylsulfonyl, C2-5 1-alkenyl-1-sulfonyl, C3-5 2-alkenyl-1-sulfonyl, C1-3 alkylamino, C1-3 dialkylamino. CF3, N-(C1-3alkanamido), N-(C1-3alkyl)-N-(C1-3alkanamido), N-pyrrolidino, N-piperidino, prop-2-ene-1-oxy or 2,2,2-trihaloethoxy, thiol, acylthio, dithio-acyl, thiocarbamyl, dithiocarbamyl, alkylcarbonylalkylthio, carbalkoxy-alkylthio, alkoxycarbonylthio, alkoxythionothio, phenylthio, phenyl-sulfinyl, alkoxyalkylthio, alkoxyalkylsulfinyl alkylthioalkylthio, Z, or acyloxyalkylthio;
(b) disubstituted phenyl wherein said subsdtutents are, independently, C1-3 alkylthio, C1-3 alkoxy, halo, C1-4alkyl, C1-3 alkylamino, N-(C1-3 alkyl)-N-(C1-3alkanamido, C1-3 dialkylamino, amino, N-pyrrolidino or N-piperidino;
(c) disubstituted phenyl wherein one of said substituents is C1-3 alkoxy, halo, CF3, C1-4 alkyl, and the other substituent is thiol, acylthio, dithioacyl, thiocarbamyl, dithiocarbamyl, alkylcarbonylalkylthio, carbalkoxyalkylthio, alkoxycarbonylthio, alkoxythionothio, phenylthio, alkoxyalkylthio, alkoxyalkylsulfinyl, alkylthioalkylthio, Z, or acyloxyalkylthio; or (d) disubstituted phenyl wherein one of said substituents is amino, C1-3 alkylamino or C1-3 dialkylamino; and the other substituent is C1-3 alkylsulfinyl, C2-5-1-alkenyl-1-thio, C2-5 1-alkenyl-1-sulfinyl, C3-5 2-alkenyl-1-thio, C3-5 2-alkenyl-1- sulfinyl, thiol, acylthio, dithioacyl, thiocarbamyl, dithiocarbamyl, alkylcarbonylalkylthio, carbalkoxyalkylthio, alkoxycarbonylthio, alkoxythionothio, phenylthio, phenylsulfinyl, alkoxyalkylthio, alkoxyalkylsulfinyl, alkylthioalkylthio, Z, or acyloxyalkylthio; or (e) disubstituted phenyl wherein said substituents are the same and are selected from halo, C1-3 alkoxy, C1-3 alkylamino, C1-3 dialkylamino, N-pyrrolidino, N-piperidino, 2,2,2-trihaloethoxy, prop-2-ene-1-oxy, or hydroxy, C1-3 alkylthio, C1-3 alkylsulfinyl, C1-3 alkyl-sulfonyl, C2-5 1-alkenyl-1-thio, C2-5-1-alkenyl-1-sulfinyl, C3-5 2-alkenyl-1-thio, C3-5 2-alkenyl-1-sulfinyl, thiol, acylthio, dithioacyl, thiocarbamyl, dithio-carbamyl, alkylcarbonylalkylthio, carbalkoxyalkylthio, alkoxycarbonylthio, alkoxythionothio, phenylthio, phenylsulfinyl, alkoxyalkylthio, alkoxyalkyl-sulfinyl, alkylthioalkylthio, Z, or acyloxyalkylthio; or wherein the substituents together form a methylene dioxy group;
(f) a moiety of one of the following formulae:
or wherein t is 0 or 1;
R4 and R6 are independently selected from hydrogen, C1-9 alkyl, aryl or heteroaryl;
Z is -S-(CR4R6)t-S-Z1;

Z1 is C1-9 alkyl, aryl or heteroaryl;
or a pharmaceutically acceptable salt thereof.

2. The method according to Claim 1 wherein W is -CR5=CR7-, -N=CR7-, -S- or -O-;
R2 and R3 are hydrogen, one of R1 and R0 is 4-pyridyl or C1-2 alkyl-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 R1 and R0 is (a) monosubstituted phenyl wherein said substituent is halo, C1-3 alkylamino, C1-3 dialkylamino, thiol, hydroxy, C1-3 alkoxy, C1-3 alkylthio, C1-3 alkylsulfinyl, acyloxyalkylthio, or acylthio;
(b) disubstituted phenyl wherein said substitutents are, independently, C1-3 alkylthio, C1-3 alkoxy, C1-3 alkylamino, C1-3 dialkylamino, N-pyrrolidino, or N-piperidino; or (c) disubstituted phenyl wherein one of said substituents is C1-3 alkylsulfinyl, acylthio, 1-acyloxy-1-alkylthio and the other is C1-3 alkoxy or halo; or (d) disubstituted phenyl wherein one of said substituents is C1-3 alkylamino, C1-3 dialkylamino and the other is selected from acylthio, alkylsulfinyl, phenylsulfinyl or acyloxyalkylthio; or (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 1-acyloxy-1-alkylthio or wherein the substituents together form a methylene dioxy group.

3. The method of Claim 2 wherein:
W is -CR5=CR7-, -N=CR7-, -S-, or -O-;
R2 and R3 are hydrogen, one of R1 and R0 is 4-pyridyl or C1-2 alkyl-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 R1 and R0 is (a) monosubstituted phenyl wherein said substituent is C1-3 alkoxy, C1-3 alkylthio, C1-3 alkylsulfinyl, acyloxyalkylthio, or acylthio;
(b) disubstituted phenyl wherein said substitutents are, independently, C1-3 alkylthio, C1-3 alkoxy, C1-3 alkylamino, or C1-3 dialkylamino; or (c) disubstituted phenyl wherein one of said substituents is C1-3 alkylsulfinyl, acylthio, 1-acyloxy-1-alkylthio and the other is C1-3 alkoxy or halo; or (d) disubstituted phenyl wherein one of said substituents is C1-3 alkylamino, C1-3 dialkylamino and the other is selected from acylthio, alkylsulfinyl, phenylsulfinyl or acyloxyalkylthio; or (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 1-acyloxy-1-alkylthio or wherein the substituents together form a methylene dioxy group.

4. The method according to Claim 2 which is 2-(4-methoxyphenyl)-3-(4-pyridyl)-imidazo-[1,2-a]-pyridine.

5. The method according to Claim 1 to 4 wherein the enzyme 5-lipoxygenase is inhibited.

6. The method of treatment according to Claim 5 wherein the OPUFA mediated disease is selected from arthritis, rheumatoid arthritis, osteoarthritis, allergic rhinitis, psoriasis, dermatitis, ischemic induced myocardial injury, reperfusion injury, gout, asthma, adult respiratory distress syndrome, atherosclcrosis, inflammatory bowel disease, stroke, spinal cord injury or traumatic brain injury.

7. A method of treating a cyclooxygenase pathway mediated disease in a subject in need thereof which comprises administering to such subject an effective, non-toxic cyclooxygenase pathway inhibiting amount of a compound of the formula:
FORMULA (I) W is -CR5=CR7-, -N=CR7-, -S- or -O-;
R2, R3, R5, and R7 are, independently, -H or C1-2 alkyl;
one of R1 and R0 is 4-pyridyl or C1-4 alkyl-4-pyridyl, provided that when R1 is C1-4 alkyl-4-pyridyl the alkyl substituent is located at the 2-position of the pyridine ring, and the other of R1 and R0 is (a) phenyl or monosubstituted phenyl wherein said substituent is C1-4 alkyl, halo, hydroxy, C1-4 alkoxy, C1-3 alkylthio, C1-3 alkylsulfinyl, C2-5 1-alkenyl-1-thio, C2-5 1-alkenyl-1-sulfinyl, C3-5 2-alkenyl-1-thio, C3-5 2-alkenyl-1-sulfinyl, C1-3 alkylsulfonyl, C2-5 1-alkenyl-1-sulfonyl, C3-5 2-alkenyl-1-sulfonyl, C1-3 alkylamino, C1-3 dialkylsmino, CF3, N-(C1-3alkanamido), N-(C1-3 alkyl)-N-(C1-3alkanamido), N-pyrrolidino, N-piperidino, prop-2-ene-1-oxy or 2,2,2-trihalcethoxy, thiol, acylthio, dithioacyl, thiocarbamyl, dithiocarbamyl, alkylcarbonylalkylthio, carbalkoxyalkylthio, alkoxycarbonylthio, alkoxythionothio, phenylthio, phenylsulfinyl, alkoxyalkylthio, alkoxyalkylsulfinyl alkylthioalkylthio, Z, or acyloxyalkylthio;
(b) disubstituted phenyl wherein said substitutents are, independently, C1-3 alkylthio, C1-3 alkoxy, halo, C1-4 alkyl, C1-3 alkylamino, N-(C1-3alkyl)-N-(C1-3 alkanamido, C1-3 dialkylamino. amino, N-pyrrolidino or N-piperidino;
(c) disubstituted phenyl wherein one of said substituents is C1-3 alkoxy, halo, CF3, C1-4 alkyl, and the other substituent is thiol, acylthio, dithioacyl, thiocarbamyl, dithiocarbamyl, alkylcarbonylalkylthio, carbalkoxyalkylthio, alkoxycarbonylthio, alkoxythionothio, phenylthio, alkoxyalkylthio, alkoxyalkylsulfinyl, alkylthioalkylthio, Z, or acyloxyalkylthio; or (d) disubstituted phenyl wherein one of said substituents is amino, C1-3 alkylamino or C1-3 dialkylamino; and the other substituent is C1-3 alkylsulfinyl, C2-5-1-alkenyl-1-thio, C2-5 1-alkenyl-1-sulfinyl, C3-5 2-alkenyl-1-thio, C3-5 2-alkenyl-1- sulfinyl, thiol, acylthio, dithioacyl, thiocarbamyl, dithiocarbamyl, alkylcarbonylalkylthio, carbalkoxy-alkylthio, alkoxycarbonylthio, alkoxythionothio, phenylthio, phenylsulfinyl, alkoxyalkylthio, alkoxyalkylsulfinyl, alkylthioalkylthio, Z, or acyloxyalkylthio; or (e) disubstituted phenyl wherein said substituents are the same and are selected from halo, C1-3 alkoxy, C1-3 alkylamino, C1-3 dialkylamino, N-pyrrolidino, N-piperidino, 2,2,2-trihaloethoxy, prop-2-ene-1-oxy, or hydroxy, C1-3 alkylthio, C1-3 alkylsulfinyl, C1-3 alkyl-sulfonyl, C2-5 1-alkenyl-1-thio, C2-5 -1-alkenyl-1-sulfinyl, C3-5 2-alkenyl-1-thio, C3-5 2-alkenyl-1-sulfinyl, thiol, acylthio, dithioacyl, thiocarbamyl, dithiocarbamyl, alkylcarbonylalkylthio, carbalkoxyalkylthio, alkoxycarbonylthio, alkoxythionothio, phenylthio, phenylsulfinyl, alkoxyalkylthio, alkoxyalkylsulfinyl, alkylthioalkylthio, Z, or acyloxyalkylthio; or wherein the substituents together form a methylene dioxy group;

(f) a moiety of one of the following formulae:
or wherein t is 0 or 1;
R4 and R6 are independently selected from hydrogen, C1-9 alkyl, aryl or heteroaryl;
Z is -S-(CR4R6)t-S-Z1;
Z1 is C1-9 alkyl, aryl or heteroaryl;
or a pharmaceutically acceptable salt thereof.

8. The method according to Claim 7 wherein the other of R1 and R0 is W is -CR5=CR7-, -N=CR7-, -S- or -O-;
R2 and R3 are hydrogen, one of R1 and R0 is 4-pyridyl or C1-2 alkyl-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 R1 and R0 is (a) monosubstituted phenyl wherein said substituent is halo, CF3, C1-3 alkylamino, C1-3 dialkylamino, thiol, hydroxy, C1-3 alkoxy, C1-3 alkylthio, C1-3 alkylsulfinyl, acyloxyalkylthio, or acylthio;
(b) disubstituted phenyl wherein said substitutents are, independently, C1-3 alkylthio, C1-3 alkoxy, C1-3 alkylamino, C1-3 dialkylamino, N-pyrrolidino,or N-piperidino; or (c) disubstituted phenyl wherein one of said substituents is C1-3 alkylsulfinyl, acylthio, 1-acyloxy-1-alkylthio and the other is C1-3 alkoxy or halo; or (d) disubstituted phenyl wherein one of said substituents is C1-3 alkylamino, C1-3 dialkylamino and the other is selected from acylthio, alkylsulfinyl, phenylsulfinyl or acyloxyalkylthio; or (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 1-acyloxy-1-alkylthio or wherein the substituents together form a methylene dioxy group.

9. The method of Claim 8 wherein:
W is -CR5=CR7-, -N=CR7-;
R2 and R3 are hydrogen, one of R1 and E~o is 4-pyridyl or Cl 2 alkyl-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 R1 and R0 is (a) monosubstituted phenyl wherein said substituent is C1-3 alkoxy, C1-3 alkylthio, C1-3 alkylsulfinyl, acyloxyalkylthio, or acylthio;
(b) disubstituted phenyl wherein said substitutents are, independently, C1-3 alkylthio, C1-3 alkoxy, C1-3 alkylamino, or C1-3 dialkylamino; or (c) disubstituted phenyl wherein one of said substituents is C1-3 alkylsulfinyl, acylthio, 1-acyloxy-1-alkylthio and the other is C1-3 alkoxy or halo; or (d) disubstituted phenyl wherein one of said substituents is C1-3 alkylamino, C1-3 dialkylamino and the other is selected from acylthio, alkylsulfinyl, phenylsulfinyl or acyloxyalkylthio; or (e) disubstituted phenyl wherein the substituents are the same and are C1-3 alkoxy, C1-2 alkylsulfinyl, C2-3 1-allcenyl-1-thio, 2-propenyl-1-thio or 1-acyloxy-1-alkylthio or wherein the substituents together form a methylene dioxy group.

10. The method according to Claim 9 which is 2-(4-methoxyphenyl)-3-(4-pyridyl)-imidazo [1,2-a]-pyridine.

11. The method according to Claim 7 wherein the cyclooxygenase disease state is pyresis, pain, osteoarthritis, rheumatoid arthritis, thrombosis, inflammation, uticaria or edema.

12. A method of treating an OPUFA mediated disease in a subject in need thereof which comprises administering to such subject an effective. OPUFA inhibiting amount of 2-(4-Methoxyphenyl)-3-(4-pyridyl)-7-oxo-5,6-dihydro-[7Hl-pyrrolo-[1,2-a]-imidazole;
5,6-dihydro-2-(4-Methoxyphenyl)-3-(4-pyridyl)-[7H]-pyrrolo-[1,2-a]-imidazole-7-ol; or 5,6-dihydro-7,7-difluoro-2-(4-Methoxyphenyl)-3-(4-pyridyl)-[7H]-pyrrolo-[ I ,2-a]-imidazole or a pharmaceutically acceptable salt thereof.

13. The method according to Claim 12 wherein the OPUFA mediated disease is selected from arthritis, rheumatoid arthritis, osteoarthritis, allergic rhinitis, psoriasis, dermatitis, ischemic induced myocardial injury, reperfusion injury, gout, asthma, adult respiratory distress syndrome, atherosclerosis, inflammatory bowel disease, stroke, spinal cord injury or traumatic brain injury.

14. The method according to Claim 13 wherein the enzyme 5-lipoxygenase is inhibited.

15. A method of treating a cycloxygenase pathway mediated disease in a subject in need thereof which comprises administering to such subject an effective cyclooxygenase inhibiting amount of 2-(4-Methoxyphenyl)-3-(4-pyridyl)-7-oxo-5,6-dihydro-[7Hl-pyrrolo-[1,2-a]-imidazole;
5,6-dihydro-2-(4-Methoxyphenyl)-3-(4-pyridyl)-[7H]-pyrrolo-[1,2-a]-imidazole-7-ol; or 5,6-dihydro-7,7-difluoro-2-(4-Methoxyphenyl)-3-(4-pyridyl)-[7Hl-pyrrolo-[1,2-a]-imidazole; or a pharmaceutically acceptable salt thereof.

16. A compound of the formula Formula (II) wherein W is -CR5=CR7-, -N=CR7-, -S- or-O-;
R2, R3, R5, and R7 are, independently, -H or C1-2 alkyl;
and one of T1 and T0 is 4-pyridyl or C1-4 alkyl-4-pyridyl, provided that when T1 is C1-4 alkyl-4-pyridyl the alkyl substituent is located at the 2-position of the pyridine ring, and the other of T1 and T0 is (a) monosubstituted phenyl wherein said substituent is hydroxy, C1-3 alkylsulfonyl, C2-5 1-alkenyl-1-sulfonyl, C3-5 2-alkenyl-1-sulfonyl C3-5 2-alkenyl-1-sulfonyl, C1-3 alkylamino, C1-3 dialkylamino, CF3, N-C1-3-alkanamido, N-(C1-3 alkyl)-N-(C1-3 alkanamido), N-pyrrolidino, N-piperidino, prop-2-ene-1-oxy, 2,2,2-trihaloethoxy, thiol, acylthio, dithioacyl, thiocarbamyl, dithiocarbamyl, alkylcarbonylalkylthio, carbalkoxyalkylthio, alkoxycarbonylthio, alkoxythionothio, phenylthio, alkoxyalkylthio, alkoxyalkylsulfinyl, alkylthioalkylthio, or Z; or (b) disubstituted phenyl wherein one of said substituents is amino, N-C1-3-alkanamido, N-(C1-3 alkyl)-N-(C1-3alkanamido), C1-3 alkylamino, C1-3 dialkylamino, N-pyrrolidino, or N-piperidino; and the other substituent is C1-3 alkylsulfinyl, C2-5-1-alkenyl-1-thio, C2-5 1-alkenyl-1-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 (c) disubstituted phenyl wherein said substituents are the same and are selected from halo, C1-3 alkoxy, C1-3 alkylamino, C1-3 dialkylamino, N-pyrrolidino, N-piperidino, 2,2,2-trihaloethoxy, prop-2-ene-1-oxy, hydroxy, thiol, acylthio, dithioacyl, thiocarbamyl, dithiocarbamyl, alkylcarbonylalkylthio, carbalkoxyalkylthio, alkoxycarbonylthio, alkoxythionothio, phenylthio, alkoxyalkylthio, alkoxyalkylsulfinyl, alkylthioalkylthio, or Z; or (d) disubstituted phenyl wherein said substituents are, independently C1-3 alkylamino, C1-3 dialkylamino, amino, N-(C1-3alkyl)-N-(C1-3 alkanamido, N-pyrrolidino or N-piperidino; or (e) a moiety of one of the following formulae:
or wherein t is 0 or 1;
R4 and R6 are independently selected from hydrogen, C1-9 alkyl, aryl or heteroaryl;

Z is -S-(CR4R6)t-S-Z1;
Z1 is C1-9 alkyl, aryl or heteroaryl;
or a pharmaceutically acceptable salt thereof.

17. A pharmaceutical composition according comprising a compound of Claim 16 and a pharmaceutically acceptable carrier or diluent.

18. A method of treating an OPUFA mediated disease, in a mammal in need thereof,which process comprises administering to said mammal an effective OPUFA inhibiting amount of a compound according to Claim 16..

19. The method according to Claim 18 wherein the enzyme 5-lipoxygenase is inhibited.

20. A pharmaceutical composition for use in medicine for treatment of an OPUFA or cyclooxygenase mediated disease state comprising a pharmaceutically acceptable carrier or diluent and a compound of Formula (III):
Formula (III) wherein W is -CR5=CR7-, -N=CR7-, -S- or -O-;
R2, R3, R5, and R7 are, independently, -H or C1-2 alkyl;
and one of S1 and S0 is 4-pyridyl or C1-4 alkyl-4-pyridyl, provided that when S1 is C1-4 alkyl-4-pyridyl the alkyl substituent is located at the 2-position of the pyridine ring, and the other of S1 and S0 is (a) monosubstituted phenyl wherein said substituent is H, C1-4 alkyl, halo, C1-2 alkoxy, C1-3 alkylthio, C1-3 alkylsulfinyl, C2-5 1-alkenyl-1-thio, C2-5 1-alkenyl-1-sulfinyl, C3-5 2-alkenyl-1-thio, C3-5 2-alkenyl-1-sulfinyl, or acyloxyalkylthio; or (b) disubstituted phenyl wherein said substitutents are, independently, C1-3 alkylthio, C1-3 alkoxy, halo, or C1-4 alkyl; or (c) disubstituted phenyl wherein one of said substituents is C1-3 alkoxy, halo, C1-4 alkyl; and the other is C1-3 alkylsulfinyl, C2-5 -1-alkenyl-1-thio, C2-5 1-alkenyl-1-sulfinyl, C3-5 2-alkenyl-1-thio, C3-5 2-alkenyl-1- sulfinyl, or acyloxyalkylthio: or (d) disubstituted phenyl wherein the substituents are the same and are C1-3 alkylsulinfyl, C2-5 1-alkenyl-1-thio, C2-5-1-alkenyl-1-sulfinyl, C3-5 2-alkenyl-1-thio, C3-5 2-alkenyl-1-sulfinyl, or acyloxyalkylthio; or wherein the substituents together form a methylene dioxy;
and the pharmaceutically acceptable salts thereof.

21. A pharmaceutical composition for use in treating an OPUFA mediated disease comprising a pharmaceutically acceptable carrier or diluent and a compound 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]-imidazole-7-ol; or 5,6-dihydro-7,7-difluoro-2-(4-Methoxyphenyl)-3-(4-pyridyl)-[7H]-pyrrolo-[1,2-a]-imidazole; or pharmaceutically acceptable salt thereof.

22. A process for oxidizing arylsulfides to arylsulfoxides wherein the aryl sulfide is a substituent group on a heteroaromatic nitrogen containing ring system, which process comprises treating said arylsulfide with sodium or potassium persulfate in aqeuous acetic acid to yield the corresponding aryl sulfoxide derivative; provided that the heteroaromatic ring is other than a 2-(C1-3 alkylsulfidephenyl)-3-(4-pyridyl)-6,7-dihydro-[5H]-pyrrolo-[2,1-a]imidazole ring system when the oxidant is potassium persulfate.

23. The process according to Claim 22 wherein the aryl sulfide is a phenylsulfide moiety.

24. The process according to Claim 23 wherein the aryl sulfide is an alkyl or aryl substituted sulfide.

25. The process according to Claim 24 wherein the alkyl substituted sulfide is methylthio or ethylthio.

26. The process according to Claim 25 wherein the oxidant is potassium persulfate.

27. The process according to Claim 26 wherein the oxidant is sodium persulfate.

28. The process according to Claim 26 or 27 wherein the reaction temperature is from about 0°C to about 60°C.

29. The process according to Claim 22 wherein an additional co-solvent, such as acetone or THF is used.

30. The process according to Claim 22 wherein the heteroaromatic nitrogen containing ring system is selected from pyrrole, pyrazole, imidazole, imidazolididine, pyrazolidine, pyrazoline, morpholine, pyridine, pyrazine, indolizine, indoline, purine, quinoline, isoquinoline, napthyridine, triazole, pyrimidine, piperidine, isoindole, 3H-indole, cinnoline, carbazole, phenanthradine. phenazine, isothiazole, imidazo[1,2-b]-[1,2,4]triazine, triazine, pyridazine,6,7-dihydro-[5H]-pyrrolo[2,1-a]imidazole, 2,3-dihydroimidazo[2,1-b]-thiazole, imidazo[2,1-b]thiazole; 2,3,4,5 tetrahydro-imidazo-[2,1-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.

31. The process according to Claim 22 wherein the oxidant is sodium persulfate and the heteroaromatic nitrogen containing ring, is 3-(4-pyridyl)-6,7-dihydro-[5H]pyrrolo-[2,1-a]imidazole ring and the aryl sulide is 2-methylthiophenyl or 2-propylthiophenyl.