CA2364039A1 - Use of phenyl heterocycles in the relief or treatment of rheumatoid arthritis, osteoarthritis, fever, pain, headache or dysmenorrhea - Google Patents

Use of phenyl heterocycles in the relief or treatment of rheumatoid arthritis, osteoarthritis, fever, pain, headache or dysmenorrhea Download PDF

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CA2364039A1
CA2364039A1 CA002364039A CA2364039A CA2364039A1 CA 2364039 A1 CA2364039 A1 CA 2364039A1 CA 002364039 A CA002364039 A CA 002364039A CA 2364039 A CA2364039 A CA 2364039A CA 2364039 A1 CA2364039 A1 CA 2364039A1
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phenyl
furanone
methylsulfonyl
compound
fluorophenyl
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Petpiboon Prasit
Yves Ducharme
Yves Leblanc
Jacques Y. Gauthier
Zhaoyin Wang
Serge Leger
Michel Therien
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    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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    • C07C311/45—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups at least one of the singly-bound nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfonamides
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    • C07C311/49—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups having nitrogen atoms of sulfonamide groups further bound to another hetero atom to nitrogen atoms
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    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
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    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated

Abstract

The invention relates to use of compounds of formula (I):

(see formula I) in the relief or treatment of rheumatoid arthritis, osteoarthritis, fever, pain, headache or dysmenorrhea.

Description

WO 95!00501 PCTlCA94100318 -]-This Application is a Divisional of Canadian Patent Application Serial No: 2, 163, 888, filed June 9, 1994:
BACKGROUND OF THE INVENTION
This invention relates to compounds and pharmaceutical s compositions for the treatment of cyclooxygenase mediated diseases and methods of treatment thereof. -Non-steroidal, antiinflammatory drugs exert most of their antiinflammatory, analgesic and antipyretic activity and inhibit hormone-induced uterine contractions and certain types of cancer growth through 1 o inhibition of prostaglandin G/H synthase, also known as cyclooxygenase.
Up until recently, only one form of cyclooxygenase had been characterized, this corresponding to cyclooxygenase-1 or the constitutive enzyme, as originally identified in bovine seminal vesicles. Recently the gene for a second inducible form of cyclooxygenase (cyclooxygenase-2) 1 s has been cloned, sequenced and characterized from chicken, murine and human sources. This enzyme is distinct from the cyclooxygenase-1 which has now also been cloned, sequenced and characterized from sheep, murine and human sources. The second form of cyclooxygenase, cyclooxygenase-2, is rapidly and readily inducible by a number of agents including 2 o mitogens, endotoxin, hormones, cytokines and growth factors. As prostaglandins have both physiological and pathological roles, we have concluded that the constitutive enzyme, cyclooxygenase-1, is responsible, in large part, for endogenous basal release of prostaglandins and hence is important in their physiological functions such as the maintenance of 2s gastrointestinal integrity and renal blood flow. In contrast, we have concluded that the inducible form, cyclooxygenase-2, is mainly responsible for the pathological effects of prostaglandins where rapid induction of the enzyme would occur in response to such agents as inflammatory agents, hormones, growth factors, and cytokines. Thus, a selective inhibitor of 3 o cyclooxygenase-2 will have similar antiinflammatory, antipyretic and analgesic properties to a conventional non-steroidal antiinflammatory drug, WO 95!00501 PCTlCA94100318 and in addition would inhibit hormone-induced uterine contractions and have potential anti-cancer effects, but will have a diminished ability to induce some of the mechanism-based side effects. In particular, such a compound should have a reduced potential for gastrointestinal toxicity, a reduced potential for renal side effects, a reduced effect on bleeding times and possibly a lessened ability to induce asthma attacks in aspirin-sensitive asthmatic subjects.
SUMMARY OF THE INVENTION
The invention encompasses novel compounds of Formula I
1 o useful in the treatment of cyclooxygenase-2 mediated diseases.
R~
I \
R2 ~~~ Z
-Y
~e ~vention also encompasses certain pharmaceutical compositions and methods for treatment of cyclooxygenase-2 mediated diseases comprising the use of compounds of Formula I.

DETAILED DESCRIPTION OF THE INVENTION
The invention encompasses the novel compound of Formula I
useful in the treatment of cyclooxygenase-2 mediated diseases 10 ' R2 ~~~ cZ
-Y
I
or pharmaceutically acceptable salts thereof wherein:
X-Y Z-is selected from the group consisting of:
. (a) -CH2CH2CH2-, (b) -C(O)CH2CH2_, (c) -CH2CH2C(O)-, (d) -CRS(RS')-O-C(O)-, (e) -C(O)-O-CRS(R5~)-, (~ -CH2-NR3_CH2_, (g) -CRS(RS')-NR3-C(O)-, (h) _CR4=CR4'_S_, (i) -S-CR4=CR4~-, 2s C1) -S-N=CH-, (k) -CH=N-S-, (1) -N=CR4-O-, (m) -O-CR4=N-' (n) -N=CR4-NH-;
(o) -N=CR4-S-, and (p) -S-CR4=N-;
(9) -C(O)-NR3-CRS(RS')-(r) -R3N-CH=CH- provided Rlis not -S(O)2Me (s) -CH=CH-NR3- provided Rlis not -S(O)ZMe when side b is a double bond, and sides a an c are single bonds; and X-Y Z-is selected from the group consisting of:

(a) =CH-O-CH=, and (b) =CH-NR3-CH=

, (c) =N-S-CH=, (d) =CH-S-N=, to (e) =N-O-CH=, (f) =CH-O-N=, (g) =N-S-N=, (h) =N-O-N=, when sides a and c are double bonds and side b is a single bond;

1 s R 1 is selected from the group consisting of (a) S(O)2CH3~

(b) S(O)2~2, (c) S(O)~iC(O)CF3, (d) S(O)(NH)CH3, 20 S(O)(NH)NH2, (e) (f) S(O)(NH)NHC(O)CF3, (g) P(O)(CH3)OH, and .

(h) P(O)(CH3)N~-I2 , R2 is selec ted from the group consisting of 2 s (a) C 1-6alkyl, (b) C3, C4, C5, C6, and C7, cycloalkyl, (c) mono-, di- or tri-substituted phenyl or naphthyl wherein the substituent is selected from the group consisting of ( 1 ) hydrogen, -3 0 (2) halo, (3) C1_6alkoxy, -$-(4) Cl_6alkylthio, (5) CN, (6) CF3, (7 ) C 1-6alkyl, (8) N3~
s (9) _C02H~
(10) -COZ-Cl..4alkyl, (11 ) -C(R5)(R6)-OH, (12) -C(RS)(R6)-0-Cl-4alkyl, and ( 13 ) -C 1 _6alkyl-C02-R5;
i o (d) mono-, di- or tri-substituted heteroaryl wherein the heteroaryl is a monocyclic aromatic ring of 5 atoms, said ring having one hetero atom which is S, O, or N, and optionally 1, 2, or 3 additionally N atoms; or the heteroaryI is a monocyclic ring of 6 atoms, said ring i s having one hetero atom which is N, and optionally 1, 2, 3, or 4 additional N atoms; said substituents are selected from the group consisting of ( 1 ) hydrogen, (2) halo, including fluoro, chloro, bromo and iodo, (3) Cl-6alkyl, (4) C 1 _6alkoxy, ( 5 ) C 1-( alkylthi o, (6) CN, ) CF3 25 (8) N3~
(9) -C(RS)(R6)-OH, and (10) -C(RS)(R6)-0-C1_4alkyl;
(e) benzoheteroaryl which includes the benzo fused analogs of (d);
R3 is selected from the group consisting of a o (a) hydrogen, (b) CF3, (c) CN, (d) C I _6a1kY1, (e) hydroxyCl _6alkyl, -C(O)-Cl-6a~Yl~

(g) optionally substituted ( 1 ) -C I _5 alkyl-Q, (2) -Cl_3alkyl-O-CI_3alkyl-Q, (3) -CI_3alkyl-S-CI_3alkyl-Q, (4) -CI-5 alkyl-O-Q, or (5) -C I _5 alkyl-S-Q, 1 o wherein the substituent resides on the alkyl and the substituent is CI_3alkyl;

(h) -Q

R4 and R4~ are each independently selected from the group consisting of (a) hydrogen, i s (b) CF3, (c) CN, (d) CI_6alkyl, (e) . _Q~

(17 20 (g) _S_Q~ and (h) optionally substituted ( I ) -CI _5 alkyl-Q, (2) -O-C I _5 alkyl-Q, (3) -S-CI _5 alkyl-Q, 25 (4) _CI_3alkyl-O-C1_3alkyl-Q

(5) -CI_3alkyl-S-CI_3alkyl-Q, (6) -C I _5 alkyl-O-Q, (7) -CI_5 alkyl-S-Q, wherein the substituent resides on the alkyl and the substituent 3 o is C I _3alkyl, and w R5, RS', R6, R~ and Rg are each independently selected from the group consisting of (a) hydrogen, (b) C1_6alkYl, or RS and R6 or R~ and Rg together with the carbon to which they are attached form a saturated monocyclic carbon ring of 3, 4, 5, 6 or 7 atoms;
Q is C02H, C02-C~_4allcyl, tetrazolyl-5-yl, C(R~)(Rg)(OH), or C(R~)(R8)(O-C 1-4alkYl)~
~o provided that when X-Y-Z is -S-CR4= CR4', then R4 and R4' are other than CF3 .
In one aspect, within this embodiment are the compounds of formula I
is R~
2o R2 -Y
I
or pharmacetically acceptable salts thereof wherein:
X-Y-Z- is selected from the group consisting of -C(O)-O-CRS(RS')- when 2s side b is a double bond, and sides a and c are single bonds; and R 1 is selected from the group consisting of (a) S'(O)2CH3~
(b) S(O)2~TH2~
R2 is selected from the group consisting of 3 0 (a) C 1 _6alkyl, (b) C3, C4, C5, C(, and C~, cycloalkyl, WO 95!00501 PCT/CA94/00318 _$-(c) heteroaryl (d) benzoheteroaryl (e) mono- or di-substituted phenyl wherein the substituent is selected from the group consisting of ( 1 ) hydrogen, (2) halo, (3) Cl-6alkoxy, (4) C1-6alkylthio, (5) CN, (6) CF3, (7) C1_6alkyl, ($) N3~

(9) -C02H, (10) -C02-Cl~alkyl, (11 ) -C(RS)CR6)_OH, is (12) -C(RS)(R6)-O-C1_4alkyl, and ( 13 ) -C 1 _6alkyl-C02-RS;

R5, RS' and R6 are each independently selected from the group consisting of (a) hydrogen, (b) Cl_6alkyl, or R5 and R6 together with the carbon to which they are attached form a saturated monocyclic carbon ring of 3, 4, 5, 6 or 7 atoms.
2s One genus within the embodiment described above is the compound of formula I wherein X-Y-Z-is selected from the group consisting of:
(a) -CH2CH2CH2-, (b) -C(O)CH2CH2-, 3 0 (c) -CH2CH2C(O)-, (d) -CRS(R5~)-O-C(O)-, WO 95!00501 PCTICA94100318 (e) -C(O)-O-CRS(R~:')-, ,, (f) -CH2-NR3_CH2_, (g)~-CRS{R5~)-NR3-C(O)-, (h) -CR4=CR4'-S-, (i) -S-CR4=CR4'-, G) -S-N=CH-, (k) -CH=N-S-, (1) -N=CR4-O-, (m) -O-CR4=N-l o (n) -N-CR4-NH-, (o) -N=CR4-S-, and (p) -S-CR4=N-, (9) -C(O)-NR3-CR5(RS')-;
(r) -NR3-CH=CH- provided R1 is other than -S(O)2Me, (s) -CH=CH-NR3- provided R1 is other than -S(O)2Me.
Within this genus is the sub-genus of compounds of formula I
wherein R 1 is selected from the group consisting of .

(a) S(O)2CH3, (b) S(O)2~2 {c) S(O)S-IC{O)CF3, (d) S(O)NHCH3, (e) S(O)TII~-i2, and (f) S(O)NHNHC(O)CF3:

2s R2 is selected from the group consisting of (a) C1 alkyl, (b) C3, C~, C5, C6, and C~, cycloalkyl, " (c) mono- or di-substituted phenyl wherein the substituent is selected from the group consisting of . ( 1 ) hydrogen, (2) fluoro, chloro and bromo , , -IO-(3) C1_4alkoxy, (4) Cl~allcylthio, (5) CN, (6) CF3, (7) C1 _4alkyl, (8) N3~
(9) -C02H, (10) -C02-C1_3alkyl, (11 ) -C(RS)(R6}-OH, and (12) _C(RS)(R6)-O-C1-3a~yl~

l o (d) mono- or di-substituted heteroaryl selected from the group consi sting of ( 1 ) furanyl, (2) diazinyl, triazinyl and tetrazinyl, (3) imidazolyl, (4) isooxazolyl, (5) isothiazolyl, (6) oxadiazolyl, (7) oxazolyl, (8) pyrazolyl, (9) PYn'olyl, (10) thiadiazolyl, (11 ) thiazolyl, (12) thienyl, (13) triazolyl, and 2 5 ( 14) tetrazolyl, wherein sai d substituents are selected from the group consisting of (a) hydrogen, (b) fluoro, chloro, bromo, (c} Cl~alkoxy, (d) Cl~,alkylthio, (e) . CN, WO 95!00501 PCTICA94100318 (5) CF3, ..
(6) C1 ~q.alkyl, N3, (g) -C(RS)(R6)-OH, (9) -C(R~)(R6)-O-Cl _4alkyl.
s Within this sub-genus is the class of compounds of formula I
' wherein R2 is selected from the group consisting of (a) cyclohexyl, and l o (b) mono- or di-substituted phenyl, and wherein the substitutents are selected from the group consisting of ( 1 ) hydrogen, (2) halo, i s (3 ) C 1 _4alkoxy, (4) C1 ~alkylthio, (5) CN, . (6) CF3, (7) Cl~alkyl, 20 (g) N3~ ~d -C(RS)(R6)-OH~

R3 is selected from the group consisting of (a) hydrogen, (b) CF3, 2 s (c ) C 1-3 alkyl and hydroxyC 1 _3 alkyl, (d) ~CN, R4 and R4~ are each independently selected from the group consisting of (a) hydrogen, (b) CF3, 3 0 (c) CI _3alkyl, (d) CN, .

WO 95/00501 ~ PCT/CA94/00318 (e) chloro and fluoro; and R5, RS~, R6, are each independently selected from the group consisting of (a) hydrogen, (b) methyl or ethyl, or R~ and R6 together with the carbon to which they are attached form a saturated carbon ring of 4, 5 or 6 atoms, Within this class is the sub-class of compounds of formula I wherein . X-Y-Z-is selected from the group consisting of:
(a) -CH2-O-C(O)-, i o (b) -C(O)-O-CH2-, and (c) -CH2-NR3_C(p)-;
R 1 is selected from the group consisting of (a) S(O)2CH3, (b) S(O)2NH2~
i s (c) S(O)NHCH3, and (d) S(O)~2;
R2 is selected from the group consisting of mono or di-substituted phenyl wherein the substitutents are selected from the group consisting of 2 0 ( 1 ) hydrogen, (2) halo, selected from the group consisting of fluoro, chloro and bromo, (3) CI_3alkoxy, (4) C1_3allcylthio, 25 (5) CN, and ) C 1-3 alkyl;
R3 is selected from the group consisting of (a) hydrogen, (b) CF3, 30 (c) C1_3alkyl and hydroxyCl_3alkyl.

WO 95100501 PCTlCA94100318 Within this sub-class is the group of compounds of formula I
wherein X-Y-Z is selected from the group consisting of:
(a) -CH2-O-C(O)-, and (b) -C(O)-O-CH2-, and R 1 is selected from the group consisting of (a) S(O)2CH3~
(b) S(O)ZNH2, (c) S(O)NHCH3, and (d) S(O)~2 R2 is mono or di-substituted phenyl wherein the substitutents are selected from the group consisting of ( 1 ) hydrogen, (2) halo, selected from the group consisting of fluoro, i s chloro and bromo, (3) methoxy, and.
(4) methyl. .
This group may be more particularly defined as the 2o compounds of formula I wherein X-Y Z is selected from the group consisting of:
(a) -CHZ-O-C(O)-, and (b) -C(O)-O-CHZ-, and R 1 is selected from the group consisting of 2s (a) S(O)2CH3, and (b) S(O)2~2 R2 is - mono or di-substituted phenyl wherein the substitutents are selected from the group consisting of 3 0 ( 1 ) hydrogen, CA 02364039 2001-12-17 ~ "
(2} halo, selected from the group consisting of fluoro, chloro and bromo.
Within the sub-genus escribed above there is the class of compounds of formula I wherein s R2 is a mono- di-substituted heteroaryl wherein heteroaryl or is selected fro m the group consisting of ( 1 ) furanyl, (2) diazinyl, triazinyl, tetrazinyl, (3) imidazolyl, to isooxazolyl, (4) (5} isothiazolyl, (6) oxadiazolyl, (7) oxazolyl, (8) pyrazolyl, ~ s (9) PYrrolyl, ( 10) thiadiazolyl, ( 11 ) thiazolyl, ( I 2) thienyl, ( 13 ) triazolyl, and 2 0 tetrazolyl, ( 14) - wherein the substitutents are selected from the group consisting of (a) hydrogen, (b) fluoro or chloro, as (c) C1_3alkoxy, (d) CI _6alkylthio, (e) CN, (5) CF3, (6) C1 _3a1kY1, s o (~) -C(R5)(R6}-~H~

(8) -C(R5)(R6}-0-C1-4a1ky1.
Within this class there is the sub-class of compounds of s formula I wherein R2 is a mono- or di-substituted heteroaryl wherein heteroaryl is selected from the group consisting of ( 1 ) 2-furanyl, (2) 3-furanyl, (3) 2-thienyl, (4) 3-thienyl, (5) 3-isoxazolyl, ,. 10 (6) 4-isoxazolyl, (7) 5-isoxazolyl, (8) 3-isothiazolyl, (9) 4-isothiazolyl, (10) S-isothiazolyl, s (I 1 ) 2-oxazolyl, (12) 4-oxazolyl, (13) 5-oxazolyl, (14) 2-fhiazolyl, (15) 4-thiazolyl, 20 (16) 5-thiazolyl, (17) 1,2,3-thiadiazol-4-y1, (18) 1,2,3-thiadiazoI-5-yl, (19) 1,2,4-thiadiazol-3-yl, (20) 1,2,4-thiadiazol-5-yl, 2s (21) 1,3,4-thiadiazol-2-yl, (22) 1,2,5-thiadiazol-3-yl, (23) I,2,3-oxadiazol-4-y1, (24) 1,2,3-oxadiazol-5-yl, (25) 1,2,4-oxadiazol-3-yl, ,.
30 (26) 1,2,4-oxadiazol-5-yl, (27) 1,3,4-oxadiazol-2-yl, (28) 1,2,5-oXadiazol-3-yl, (29) pyrazol-4-yl, (30) pyrazol-5-yl, (31 ) 1,2,3-triadiazol-4-yl, (32) 1,2,3-triadiazol-5-yl, s (33 ) 1,2,4-triadiazol-3-yl, (34) 1,2,4-triadiazol-5-yl, (35) 1,2-diazinyl, (36) 1,3-diazinyl, (37) 1,4-diazinyl, to (3g) 1,2,3,4-tetrazin=5-yl, (39) 1,2,4,5-tetrazin-4-yl, (40) 1,3,4,5-tetrazin-2-yl,and (41 ) 1,2,3,5-tetrazin-4-yl.

i s Within this sub-class there is the group of compounds of formula I wherein the heteroaryl is selected from the group consisting of ( 1 ) 3-isoxazolyl, (2) 4-isoxazolyl, (3) 5-isoxazolyl, 20 (4) 3-isothiazolyl, (5) 4-isothiazolyl, (6) 5-isothiazolyl, (7) 2-oxazolyl, (8) 4-oxazolyl, 2s (9) 5-oxazolyl, (10) 2-thiazolyl, (11) 4-thiazolyl, (12) 5-thiazolyl, (13) 1,2,3-thiadiazol-4-yl, (14) 1,2,3-thiadiazol-5-yl, (15) 1,2,4-thiadiazol-3-yl, (16) 1,2,4-thiadiazol-5-yl, ( 17) 1,3,4-thiadiazol-2-yl, (18) I,2,5-thiadiazol-3-yl, (19) 1,2,3-oxadiazol-4-yl, (20) 1,2,3-oxadiazol-5-yl, (21) 1,2,4-oxadiazol-3-yl, (22) 1,2,4-oxadiazol-5-yl, (23) 1,3,4-oxadiazol-2-yl, (24) 1,2,5-oxadiazol-3-yl, (25) 1,2-diazinyl, (26) 1,3-diazinyl, and (27) 1,4-diazinyl.

These heteroaryls may be more particularly defined as being selected from the group consisting of 1 s ( 1 ) 3-isothiazolyl, (2) 4-isothiazolyl, (3) 5-isothiazolyl, (4) 2-oxazolyl, (5) 4-oxazolyl, (6) 5-oxazolyl, (7) 2-thiazolyl, (8) 4-thiazolyl, (9) 5-thiazolyl, (10) 1,2-diazinyl, 2 s ( 11 ) 1,3-diazinyl, and ( 12) 1,4-diazinyl, and wherein the substitutents are selected from the group consisting of - ( 1 ) hydrogen, (2) fluoro or chloro, 3 0 (3) CI _3alkoxy, (4) , C I _3 alkylthi o, (5) CN, (6)' ~ C 1-3alkyl, and ( ) .-c~s)(R6)-OH' wherein RS and R6 are each independently hydrogen, methyl or ethyl.
and may be further particularly Given these more particularly defined definitions of heteroaryl, the compounds of formula I includes the group wherein X-Y Z is selected from the group consisting of:
i o (a) -CH2-O-C(O)-, (b) -C(O)-O-CH2-, and (c) -CH2-NR3_C(O)_~

R1 is selected from the group consisting of (a) S(O)2CH3, i s (b) S(O)2NH2, (c) S(O)NHCH3, and (d) S(O)NHNH2, and R3 is selected from the group consisting of (a) hydrogen, 20 (b) CF3, (c) C1_3alkyl and hydroxyCl-3alkyl, (d) CN.

A second genus within the embodiment described above is the compounds of formula I wherein X-Y-Z-is selected from the group consisting of:
(a) =CH-O-CH=, and (b) =CH-NR3-CH=, 3 0 (c) =N-S-CH=, (d) =CH-S-N=, (e) =N-O-CH=, (fj =CH-O-N=, ' (g) =N-S-N=
(h) =N-O-N=.
s Within this genus is the sub-genus of compounds of formula I

wherein R 1 is selected from the group consisting of (a) S(O)2CH3, (b) S(O)2NH2, io (c) S(O)~C(O)CF3, .

(d) S(O)(NH)CH3, (e) S('0)(NH)NH2, and (f) S(O)(NH)NHC(O)CF3;

R2 is selec ted from the group consisting of i s (a) C 1 ~a~yl, (b) C3, C4, C5, C6, and C~, cycloalkyl, (c) mono- or di-substituted phenyl wherein the substituent is selected from the group consisting of ( 1 ) hydrogen, 20 (2) fluoro, chloro, and bromo, (3) Cl~alkoxy, (4) Cl~alkylthio, (5) CN, (6) CF3, 2s (~) Cl~,alkyl, N3~

(9) -C02H, - ( 10) -C02-C 1 _3 alkyl, (10) -C(RS)(R6)-OH~ and 30 (11) -C(RS)(R6)-O-C1-3alkyl~

(d) mono- or di-substituted heleroaryl selected from the group consisting of ( 1 ) furanyl, (2) diazinyl, triazinyl and tetrazinyl, (3) imidazolyl, (4) isooxazolyl, (5) isothiazolyl, (6) oxadiazolyl, (7) oxazolyl, (8) pyrazolyl, .

i o (9) PYn'olyl, . .-(10) thiadiazolyl, (11 ) thiazolyl, (12) thienyl, (13) triazolyl, and i5 (14) tetrazolyl, wherein sai d substituents are selected from the group consisting of (a) hydrogen, (b) fluoro, chloro, bromo, (c) Cl~alkoxy, 20 (d) Cl~allcylthio, (e) CN, (5) CF3, (6) Cl~alkyl, N3, 2s (g) _C(RS)(R6)-pH;

-C(RS)(R6)-~-C1-4alkyl.

For purposes of this specification the heretoaryls of this sub-genus may be more particularly described in any of the manners described 3 o above.

' CA 02364039 2001-12-17 Within this sub-genus there, is the class of compounds of formula I wherein . , .
RZ is selected from the group .consisting of (a) cyclohexyl, and - .
(b) mono or di substituted phenyl, and s wherein the substitutents are selected from the group consisting of ( 1 ) hydrogen, (2) halo, (3) C1-4alkoxy, i o (4) C 1 ~allcylthio, (5) CN, (6) CF3, (7 ) C 1-4alkyl.
(g) N3, and i s (9) -C(RS)(R6)-OH;
R3 is selected from the group consisting of (a) hydrogen, (b) CF3, (c) C1_3alkyl and hydroxyCl-3alkyl, ao (d) R5, RS~, R6, ire each independently selected from the group consisting of (a) hydrogen, (b) methyl or ethyl, or RS and R6 together with the carbon to which they are attached 2s form a saturated carbon ring of 4, 5 or 6 atoms.
Within this class there is the sub-class of compounds of - formula I wherein X Y-Z-is selected from the group consisting of:
,, 3 0 (a) =CH-O-CH=
(b) =N-S-N=, (c) -N_O_N=
R 1 is selected from the group consisting of (a) . S(4)2CH3~ ~d (b) S(~)2~2 R2 is selected from the group consisting of mono- or di-substituted phenyl wherein the substitutents are selected from the group consisting of ( I ) hydrogen, (2) halo, selected from the group consisting of fluoro, chloro and bromo, i o (3 ) C I _3alkoxy, (4) C1 _3alkylthio, (5) CF3, (6) C1 _3alkyl;
R3 is selected from the group consisting of i s (a) hydrogen, (b) CF3 (c) CI _3alkyl and hydroxyCl _3alkyl, RS and R6 are each selected from the group consisting of (a) hydrogen, 20 (b) methyl or ethyl, or R5, R5~ and R6 together with the carbon to which they are attached form a saturated carbon ring of 5, 6 or 7 atoms.
For purposes of this specification alkyl is defined to include 2s linear, branched, and cyclic structures, with CI_6alkyl including including methyl, ethyl, propyl, 2-propyl, s- and t-butyl, butyl, pentyl, hexyl, 1,1-dimethylethyl, cyclopropyl, cyclobutyl, cyclopentyI and cyclohexyl.
Similarly, CI_6alkoxy is intended to include alkoxy groups of from 1 to 6 carbon atoms of a straight, branched, or cyclic configuration.. Examples of 3 0 lower alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy, and the like. Likewise, CI_6allcylthio is WO 95100501 PCTlCA94100318 intended to include allcylthio groups of from 1 to 6 carbon atoms of a straight, branched or cyclic configuration. .Examples of lower alkylthio groups include methylthio, propylthio; isopropylthio, cycloheptylthio, etc.
By way of illustration, the propylthio group signifies -SCH2CH2CH3.
Heteroaryl includes furan, thiophene, pyrrole, isoxazole, isothiazole, pyrazole, oxazole, thiazole, imidazole, 1,2,3-oxadiazole, 1,2,3-thiadiazole, 1,2,3-triazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,3,4-triazole, 1,2,5-oxadiazole, 1,2,5-thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,4,5-tetrazine, and the like.
i o Benzoheteroaryl includes the above heteroaryl rings to which it is possible to fuse a benzene ring.
Exemplifying the invention are:
(a) 3-(4-{Aminosulfonyl)phenyl)-2-{4-fluorophenyl)-5-(2-hydroxy-2-propyl)thiophene, i s (b) 3-(4-(Aminosulfonyl)phenyl)-2-(4-fluorophenyl)thiophene, (c) 3-(4-(Aminosulfonyl)phenyl)-2-(4-fluorophenyl)-5-(2-propyl)thiophene, (d) 3-(4-(Aminosulfonyl)phenyl)-2-cyclohexylthiophene, (e) 5-(4-Carboxyphenyl)-4-(4-20 (methylsulfonyl)phenyl)thiophene-2-carboxylic acid, (f) 4-(4-Fluorophenyl)-2-methyl-5-(4-(methylsulfonyl)phenyl)thiazole, (g) 2-(4-Fluorophenyl)-3-(4-(methylsulfonyl)phenyl)-2-cyclopenten-1-one 2s (h) 4-(4-(Methylsulfonyl)phenyl)-5-(4-fluorophenyl)-isothiazole, (i) 3-(4-Fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(SH)-furanone, (j) 3-(4-Fluorophenyl)-4-(4-(aminosulfonyl)phenyl)-2-(SH)-3 0 ~r~one, (k) 3-(4-Fluorophenyl)-4-(4-(methylsulfonyl)phenyl)furan, WO 95!00501 PCT/CA941003I8 -~ (1) 5,5-Diiriethyl-3-(4-fluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(51~-furanone, ~(In) 2-(4-(Aminosulfonyl)phenyl)-3-(4-fluorophenyl)thiophene, and (n) 3-(4-(Trifluoroacetylaminosulfonyl)phenyl)-2-(4-s fluorophenyl)thiophene, (o) 3-(3-FluorophenyI)-4-(4-(methylsulfonyl)phenyl)-2-(SH)-furanone, (p) 5,5-Dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(SIB-furanone, (q) 5,5-Dimethyl-3-(3-chlorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(SH)-furanone, (r) 3-(3,4-Difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(SH)-furanone, (s) 3-(3,4-Dichlorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-1 s (SH)-furanone, (t) 5,5-Dimethyl-3-(3,4-difluorophenyl)-4-(4-methyl su if onyl )phenyl)-2-(SH)-furan one, (u) 5,5-Dimethyl-3-(3,4-dichlorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(SH)-furanone, (v) 5,5-Dimethyl-3-(4-chlorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(SH)-furanone, (w) 3-(2-Naphyhyl)-4-(4-(methylsulfonyl)phenyl)-2-(SH)-furanone, (x) 5,5-Dimethyl-3-(2-naphyhyl)-4-(4-2 s (methylsulfonyl)phenyl)-2-(SH)-furanone, (y) 3-phenyl-4-(4-(methylsulfonyl)phenyl)-2-(SH)-furanone.
Further illustrating the invention are (a) 3-(3,4-Difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(SH)-furanone, and (b) 3-phenyl=4-(4-(methylsulfonyl)phenyl)-2-(SH)-furanone, or a pharmaceutically acceptable salt thereof.
Some~of the~coInpounds described herein contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers. The present invention is meant to comprehend such possible diastereomers as well as their racemic and resolved, enantiomerically pure forms and pharmaceutically acceptable salts thereof.
Some of the compounds described herein contain olefinic double bonds, and unless'specified otherwise, are meant to include both E
1 o and Z geometric isomers.
In a second embodiment, the invention encompasses pharmaceutical compositions for inhibiting cyclooxygenase and for treating cyclooxygenase mediated diseases as disclosed herein comprising a pharmaceutically acceptable carrier and a non-toxic therapeutically 1 s effective amount of compound of formula I as described above.
. Within this embodiment the invention encompasses pharmaceutical compositions for inhibiting cyclooxygenase-2 and for treating cyclooxygenase-2 mediated diseases as disclosed herein comprising a pharmaceutically acceptable carrier and a non-toxic therapeutically 2o effective amount of compound of formula I as described above.
In a third embodiment, the invention encompasses a method of inhibiting cyclooxygenase and treating cyclooxygenase mediated diseases, advantageously treated by an active agent that selectively inhibits COX-2 in preference to COX-1 as disclosed herein comprising:
2s a~~istration to a patient in need of such treatment of a non-toxic therapeutically effective amount of a compound of Formula I as disclosed herein.
For purposes of this specification a compound is said to selectively inhibit COX-2 in preference to COX-1 if the ratio of the IC50 3 o concentration for COX-1 inhibition to COX-2 inhibition is 100 or greater.

The pharmaceutical compositions of the present invention comprise a compound of Formula I as an active ingredient or a pharmaceutically acceptable salt, thereof, and may 'also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients. The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, 1 o potassium, and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N~ -dibenzylethylenediamine, 1 s diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, 2 o tripropylamine, tromethamine, and the like.
It will be understood that in the discussion of methods of treatment which follows, references to the compounds of Formula I are meant to also include the pharmaceutically acceptable salts.
The Compound of Formula I is useful for the relief of pain, 2s fever and inflammation of a variety of conditions including rheumatic fever, symptoms associated with influenza or other viral infections, common cold, Iow back and neck pain, dysmenorrhea, headache, toothache, sprains and strains, myositis, neuralgia, synovitis, arthritis, including rheumatoid arthritis degenerative joint diseases (osteoarthritis), gout and s o ankylosing spondylitis, bursitis, burns, injuries, following surgical and dental procedures. In addition, such a compound may inhibit cellular neoplastic transformations and ~metastic tumor growth and hence can be used in the treatment of cancer. Compounds of formula I may also be ' useful for the =treatment of dementia including pre-senile and senile dementia, and in particular, dementia associated with Alzheimer Disease (ie Alzheimer's dementia).
Compounds of formula I will also inhibit prostanoid-induced smooth muscle contraction by preventing the synthesis of contractile prostanoids and hence may be of use in the treatment of dysmenorrhea, premature labor and asthma.
By virtue of its high cyclooxygenase-2 (COX-2) activity and~or its selectivity for cyclooxygenase-2 over cyclooxygenase-1 (COX-1 ) as defined above, compounds of formula I will prove useful as an alternative to conventional non-steroidal antiinflammatory drugs (NSAID'S) particularly where such non-steroidal antiinflammatory drugs may be contra-indicated such as in patients with peptic ulcers, gastritis, 15 regional enteritis, ulcerative colitis, diverticulitis or with a recurrent history of gastrointestinal lesions; GI bleeding, coagulation disorders including anemia such as hypoprothrombinemia, haemophilia or other bleeding problems (including those relating to reduced or impaired platelet function); kidney disease (eg impaired renal function); those prior to 2o surgery or taking anticoagulants; and those susceptible to NSAID induced asthma.
Similarly, compounds of formula I, will be useful as a partial or complete substitute for conventional NSAII7'S in preparations wherein they are presently co-administered with other agents or ingredients. Thus 2s ~ her aspects, the invention encompasses pharmaceutical compositions for treating cyclooxygenase-2 mediated diseases as defined above comprising a non-toxic therapeutically effective amount of the compound - of Formula I as defined above and one or more ingredients such as another pain reliever including acetominophen or phenacetin; a potentiator 3 o including caffeine; an H2-antagonist, aluminum or magnesium hydroxide, simethicone, a decongestant including phenylepht-ine, WO 95/00501 PCT/CA94I0031$
phenylpropanolamine, pseudophedrine, oxymetazoline, ephinephrine, naphazoline, xylometazoline, propylhexedrine, or levo-desoxyephedrine;
an antiitussive including codeine, hydrocodone, caramiphen, carbetapentane, or dextramethorphan; a diuretic; a sedating or non-sedating antihistamine. In addition the invention encompasses a method of treating s cyclooxygenase mediated diseases comprising: administration to a patient in need of such treatment a non-toxic therapeutically effect amount of the compound of Formula I, optionally co-administered with one or more of such ingredients as listed immediately above.
i o Compounds of the present invention are inhibitors of cyclooxygenase-2 and are thereby useful in the treatment of cyclooxygenase-2 mediated diseases as enumerated above. This activity is illustrated by their ability to selectively inhibit cyclooxygenase-2 over cyclooxygenase-1. Accordingly, in one assay, the ability of the compounds 15 of this invention to treat cyclooxygenase mediated diseases can be demonstrated by measuring the amount of prostaglandin E2 (PGE2) synthesized in the presence of arachidonic acid, cyclooxygenase-1 or cyclooxygenase-2 and a compound of formula I. The IC50 values represent the concentration of inhibitor required to return PGE2 synthesis 2 o to 50 % of that obtained as compared to the uninhibited control.
Illustrating this aspect, we have found that the Compounds of the Examples are more than 100 times more effective in inhibiting COX-2 than they are at inhibiting COX-1. In addition they all have a COX-2 IC50 of 1 nM to 1 p,M. By way of comparison, Ibuprofen has an IC50 for COX-2 of 1 p.M, 2 s ~d ~domethacin has an IC50 for COX-2 of approximately 100 nM.
For the treatment of any of these cyclooxygenase mediated diseases, compounds of formula I may be administered orally, topically, parenterally, by inhalation spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, s o adjuvants and vehicles. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection WO 95/00501 ~ PCT/CA94100318 or infusion techniques. In addition to the treatment of warm-blooded animals such as mice, rats, horses, cattle sheep, dogs, cats, etc., the ' compound of the invention is effective in the treatment of humans.
. , As indicated above, pharmaceutical compositions for treating cyclooxygenase-2 mediated diseases as defined may optionally include one or more ingredients as listed above.
The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
i o Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically 1 s elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharnlaceutically acceptable excipients which are suitable for the manufacture of tablets. These .excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and 2 o disintegrating agents, for example, corn starch, or alginic acid; binding . agents, for example starch, gelatin or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc. The tablets may be un~oated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby 2s provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the technique described in the U.S.
- ~ Patent 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for control release.
f 30 Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent; for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredients is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Such s excipients are suspending agents, for example sodium carboxymethyl cellulose, methylcellulose, hydroxy-propylmethycelIulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for 1 o example polyoxyethylene stearate, .or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene-oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters 1 s derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.
2 o Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, 2s ~d flavoring agents may be added to provide a palatable oral preparation.
These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active 3 o ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above.
Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
. The pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said 1 o partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavouring agents.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such 1 s formulations may also contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the lalown art using those suitable dispersing or wetting agents and suspending agents which have been 2o mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed 2s oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
Compounds of formula I may also be administered in the form . 3 0 of a suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-WO 95100501 ~ PCT/CA94/00318 irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.
For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing the compound of Formula I are employed.
(For purposes of this application, topical application shall include mouth washes and gargles.) Dosage levels of the order of from about 0.01 mg to about 140 mg/kg of body weight per day are useful in the treatment of the above-indicated conditions, or alternatively about 0.5 mg to about 7 g per patient per day. For example, inflammation may be effectively treated by the administration of from about 0.01 to 50 mg of the compound per kilogram of body weight per day, or alternatively about 0.5 mg to about 3.5 g per patient per day, preferably 2.5 mg to 1 g per patient per day.
The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example; a formulation intended for the oral administration of humans may contain from 0.5 mg to 5 g of active agent compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition. Dosage unit forms will generally contain between from about 1 mg to about S00 mg of an active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg.
It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
Methods of S, the is WO 95!00501 PCTlCA94l00318 The compounds of the present invention can be prepared according to the following methods.
Method A:
The ~i-chlorovinylaldehyde III can be obtained from the ketone II and the Vilsmeier reagent (DMF-POC13) using the general method described by Weissenfels (Z. Chem. 1966, 6, 471 ). The thiophene compound IV is obtained from III using the general method described by Weissenfels (Z. Chem., 1973, 13, 57). The thiol compound V can be obtained after oxidation of compound IV (Ra = -SMe) with one equivalent i o of m-CPBA followed by treatment of the resulting sulfoxide with TFAA at reflux. The sulfonamide group (VI) can then be formed by the method of Kharash (J. Amer. Chem. Soc. 1951, 73, 3240). The hydrolysis of compound VI and decarboxylation with Cu bronze in quinoline provides compound VII. Compound VII (R4 = H) can be treated with halogenating 1 s agent such as bromine in acetic acid to allow the preparation of the 5-bromothiophene (VII, R4 = Br). When it is desired to have a nitrile group at C-5, this can be accomplished from VI via amide formation using the Weinreb methodology (Tetrahedron Letters, 1977, 4171) followed by dehydration with TFAA. The CF3 group can be introduced at C-5 of VII
2o via the method of Girard (J. Org. Chem. 1983, 48, 3220).
The introduction of an alkyl group at C-S can be achieved via a Friedel-Crafts reaction on VII (R4 = H) and an acyl chloride, Cl-CO-lower alkyl and a catalyst such as TiCl4, followed by reduction. For R4=Me, this can be achieved from the ester (R4=C02Me) via a DIBAL-H
2s reduction followed by deoxygenation using the method of Lau (J. Org.
Chem. 1986, 51, 3038). Tertiary alcohols (R4= - C(CH3)20H) can be obtained from VI and MeMgBr. These tertiary alcohols can also be deoxygenated using the method of Lau. Similarly, the thiophene IX can be prepared from ketone VIII.
METHOD A
Ra Ra O

O R2 1,2-dichloroethane CI R2 II Ra= SMe or -S02Me III
Ra /
when Ra=S02Me 1 o O and R2 =PhC02Me HS ~ R2 OMe S R HO-Py/Et3N IV ( R4=-C02Me) Ra=S02Me R2 =PhC02H

when Ra is SMe R =C02H
1. m-CPBA/CHZC12 H2N,S,,O
2. TFAA O, - /
2o HS /
1.C12/HOAc 2. NH3 R2 S~
R2 S~ R4 VI (R4=C02Me) 2s V ( R4=-C02Me) HZN,S ~
O' 1.H0-VI
2. Cu/quinoline R4 VII ( R4=H) METHOD A CONT'D
VII ~~ R4= Br VII R4 = C~-Csalkyl R4 = CF3 1.amidation VI -- VI R4=CN
2. TFAA
to MeMgBr VI (R4 = -C(CH3)20H) VI
a R2 O ~ --w -'- R1 ~ ' S~ R
R2 . IX
Vlll Method B:
2 ° Ketone X can be converted to the thiophene compound XI
using general methods already described in Method A. The thiophene XII
can be prepared by metallation of XI with n-BuLi, quenching with methyl phosphonic dichloride and addition of water or ammonia (X' = OH or NH2). Similarly, the other regioisomer XN can be prepared from ketone 2 5 X~I.
Br Br /
2 R2 ~ ~ 4 s p R S R
X XI
1.n-BuLi f~

2. Me(CI)2P0 . X
to \
3. H20 or NH3 S
xll x' = off or NH2 Br R2 l O \ . -~ .-.~. X / \ ~S~ Ra R2 HsC, W--XIII O XIV
X' = OH or NH2 2 s Method C:
Bromination of ketone II gives the a-bromoketone XV which is then converted to the thiazole XVI after treatment with a thioamide.
Similarly, ketone VIII can be converted to thiazole XVII.

W095100501 PCTlCA94/00318 METHOD C
S

O R Ra~ NH2 I i Br? . ----_ Br / Ra Ra / XV
m ~
\
s R2~~- 4 N R
XVI
Ra ~ /
Ra' _ NH2 N
VIII

S
XVII
Method D:
2 s Ketone XV can be converted to the imidazole compound XVIII after treatment with formamide using the preparation of Brederick et al, Chem. Ber. 1953, p. 88.
METHOD D
O Ra R4' _ NH2 ~ N
XV R
NH
XVIII
Method E:
Pyrole compound XX can be obtained from diketone XIX
1 o using the general procedures of Friedman et al, J. Org. Chem. 1965, 30, p.
854, K. Dimroth et al, Ber. 1956, 56, 2602, K.Dimroth et al, Ann. 1961, 634, 102. The free NH of the pyroIe can be acyl.ated with CI-CO-lower alkyl in the presence of a base such as Et3N. Also alkylated products can be prepared using alkyl halides as reagents with a base such as NaH.
METHOD E
O I~/~Ie0~0 O
( ~ MeO~N~MeO
R~ \ O
XIX NaH/DMF O°C to r.t ~N H2 H~ ~ RZ
180° C .~.
3o Ra XX
r Method F:
The compounds of type XXV can be prepared from readily available 4-substituted phenylacetyl chlorides XXIa. Reaction of di(3-butenyl)cadmium with a 4-substituted phenylacetyl chloride provides ketone XXI. Ozonolysis of XXI affords keto aldehyde XXIb which is cyclized by base to give cyclopentenone XXII. Addition of arylmagnesium bromide or aryllithium to XXII gives allylic alcohol XXIV. Oxidation of XXN with ~pyridinium chlorochromate affords the desired 2,3-disubstituted cyclopentenone XXV. For preparation of compound XXV
(Rl=S02Me), 4-methylthiophenyllithium is used followed by oxidation i o with the magesium salt of monoperoxyphthalic acid (MMPP) or m-chloroperoxybenzoic acid (mCPBA) to introduce the required methylsulfonyl group in XXV.
~s WO 95!00501 ~ PCTlCA94l00318 - 40 _ .
METHOD F
OII R2 ~~~d ~ R2 Ci s XXta XXI
R
i O
M

O~ O R2 NaOMe R ~ XXIII
XXIb XXII
/ \
PCC w HO,,, _---R2 ~ R2 ~
O
XXIV XXV
Method G:
The sequence of Method G is the same as in Method F except R 1 containing acid chloride is used as starting material. RZ is introduced at a later stage via a carbonyl addition reaction, followed by PCC oxidation.
METHOD G
/ Ri O / Ri O
//\/~ d \ \
s CI
Ri R' 1. O3 '~ 2 --HO
2. NaOMe ~~ R2 O
is R' P-~ R2 O
~CVI
2s Method H:
The 4,5-disubstituted isothiazoles and isothiazol-3(2H)-one-1,1-dioxides can be prepared by the general method described by B.
Schulze et al, Helvetica Chimica Acta, 1991, 74, 1059. Thus, aldehyde IIZ
(Ra=S02Me) or XXVB is treated with excess NH4SCN in refluxing 3 o acetone to provide the corresponding 4,5-disubstituted isothiazoles XXX
and XXVIII, oxidation of which with hydrogen peroxide yields XXXI and XXIX.
METHOD H
MeO2S ~ S02Me Vlll w ~ CI I , NH4SCN H202, AcOH
(Ra = S02Me) R2 CHO '' R2 / S
-N
XXVI I XXVI I i S02Me Me02S
O w ~ CHO NH4SCN
,,I
R2 / S~ O R~CI
NH
O III (Ra = S02Me), XXIX
S02Me S02Me i H202, AcOH
R2 / ~ R2 / O
S-N O:.S.-NH
O
XXX
XXXI
ethod I:
3 o An appropriately substituted aryl bromomethyl ketone is reacted with an appropriately substituted aryl acetic acid in a solvent such WO 95100501 PCTlCA94100318 as acetonitrile in the presence of a base such as triethylamine and then treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) to afford either the lactone x;XXIII or XXXV.
METHOD I
R~
R' /
R2~C02H

Base Br O O
O
II XXXIII
R' O
R2~Br' Base R2 / O
H02C p XXX I V XXXV
R2 is a mono- or disubstituted phenyl or 2 s a mono- or disubstituted heteroaryl Method J:
Either of the lactones x;XXIII or XXXV in a solvent such as THF is reacted with a reducing agent such as diisobutyl aluminium hydride or lithium borohydride at -78°C, to yield the furan XXXVI.
METHOD J
R' XXX I I I ~ \
1. DIBAL-H
XXXV ~' 2. H+
R2 w O
XXXV I
1 o Method K:
The preparation of lactams XXXVII and XXXIX can be achieved by the same reaction as described in Method I, except an appropriate amide XXXVIII is used.

METHOD K
R~ R~
\ ~ R2~CONHR3 r Base Br O R2 /
io . NR3 XXXI I O
XXXVI I
R' Rt O \
/ I R2~ Br \ Base 2o CONHR3 NR3 XXXVI I I XXXIX
Method L:
Methyl 2-hydroxy isobutyrate is silylated with TMSCI to give the TMS ether XLI, which is treated with 4-methylthiophenyllithium to provide ketone XLII. Desilylation followed by acylation yields keto-ester XLN, which can be cyclized to lactone XLV by base catalysis. Oxidation of XLV with MMPP or mCPBA affords the desired product XLVI.

METHOD L
SMe OH
OTMS
OMe TMSCI OMe Li O imidazole O
XL XLI
1o OTMS / SMe OH SMe N-Bu4NF
i~ ~ w XLII XLIII
F
O
F
CI
O O / SMe Pyridine, DMAP
O
XLIV
F F
DBU (ol XLV SMe XLVI 5U2Me METHOD M
SMe Aq. base org. solvent OH ~ I SMe Phase O transfer O
XLViI catalyst XLIII
i o An alternative preparation of the hydroxy ketone XLIII is the oxidation of the known (J. Org. Chem. 1991 56, 5955-8; Sulfur Lett. 1991, 12, 123-32) ketone XLVII. A mixture of XLVII, aqueous base, such as NaOH, organic solvents such as carbon tetrachloride/toluene and a phase transfer catalyst such as ALIQUAT 336 is stirred in air at room i s temperature to provide XLIII. Compound XLIII is also described in U.S.
4,321,118 and Org. Coat. 1986, 6, 175-95.
Method N
R' CO, Hz0 O
~ R ~ \ ~ G'-Rz ~ .~- \
solvent, catalyst O
'F
XLVIII , XXXIII X:XXV
By reacting a~n acetylene XLVIIZ with carbon monoxide and water in the presence of suitable catalysts, a mixture of compound x;~~XIII
s o and its isomer x:XXV is obtained. The isomers are separable by standard procedures in the art such as chromatography or crystallization. Examples of useful catalysts and conditions are PdCl2 in aqueous HCI and EtOH, . WO 95100501 PCTlCA94/00318 heated at 50-150°C and 50-150 atmospheres of pressure, or Rh4 (CO)12 (or Rh6(CO) 16) in aqueous THF (or acetone, acetonitrile, benzene, toluene, EtOH, MeOH) containing a trialkylamine, at 50-150°C and 20-300 atmospheres pressure. See Takahashi et al., Organomettallics 1991,10, 2493-2498; and Tsuji et. al., J. Am. Chem. Soc. 1966, 88, 1289-1292.
Method O
/ SMe 1o O ",~- M ~ ~ SMe l.c~xcx=cl.Br,I) \
a ~. rMSCI O
aol~ent M = Li. Mg TMSO LI
XLIX L
SMe SMe Pd(OAc)2/Cu(OAc)Z, O~ \ ~ IZ, pyridine V
or PhIO~rMSNj, n-Bu~NF 0 l .
O
LII LIII
SMe / I S(O)2Me (HO)~BR LN \ io) \_ V ~.. ~ R = alkyl. aryl Pd°
O R O R
LV L~
1, 4-Addition to XLIX of 4-methylthiophenyl organometallic reagents L in the presence of copper salts and the trapping of the resultant enolate with trialkyl silyl chloride such as TMSCI or TIPSCI provide the 3 o ketene acetal LI. The ketene acetal can then be oxidized to the substituted butenolide LII by the method of Ito using catalytic amounts of Pd2(OAC)2 and Cu(OAc)2 and 02 in MeOH or by the method of Magnus using WO 95100501 ~ PCTICA94/00318 and Cu(OAc)2 and 02 in MeOH or by the method of Magnus using PhIO/TMSN3 and Bu4NF. Introduction of the iodine can be accomplished by treating LII with I2 in the presence of pyridine to afford LITI.
Palladium catalyzed Susuki or Stille coupling of LIII with the appropriate aryl or alkyl partner such as the boronic acid LIV provides the butenolide LV. The sulfide can be oxidized to a sulfone by various oxidizing agents such as peracetic acid, MPPM, MMPP or H202 to give the desired compound LVI. See Y. Ito et. al., J. Am. Chem. Soc. 1979,101, 494;
and P. Magnus et. al., Tet. Lett.1992, 2933.
to Accordingly, in a further aspect the invention is directed to a process of making a compound of formula XXXIII
R~

O

O

XXX I I I
comprising:

(al) reacting in an organic solvent a compound of formula XXXII' R' . /

~O

XXXI I' 1 o with a bromine reagent to yield a compound of formula XXXII
R' /

) Br O

XXXI I
For purposes of this specification the organic solvent shall be defined to include, but not be limited to methylene chloride, chloroform, carbontetrachloride and acetic acid. Similarly, the bromine reagent shall be defined to include, but not be limited to bromine, pyridinium perbromide hydrobromide, CuBr~,, and N-bromosuccinimide.
2s (a2) reacting in a non-aqueous polar solvent a compound of formula XXXII
with a compound of formula R2~ COZH
3 o in the presence of a base to produce a compound of formula A

R' O il R2 O
A
(a3) treating in a non-aqueous polar solvent a compound of formula A with 1 o strong base to yield a compound of formula XXXIII.
For purposes of this specification the non-aqueous polar solvent shall be defined to include, but not be limited to, acetonitrile propionitrile, acetone, 2-butanone and tetrahydrofuran. Similarly, the base 15 is defined to include, but not be limited to a tri-C1-3alkylamine such as tri-ethylamine. Moreover, the strong base is defined to include, but not be limited to, an amidine, a guanidine, lithium diisopropylamide and potassium bis-(trimethylsilyl) amide.
2o In an alternative, the invention is directed to a process of making a compound of formula XXXIII
R' O

O

3 o XXXI I 1 comprising:
(bl) reacting an acteylene compound of the formula XLVIII
'R ~ \ C-C-RZ
XLVIII
with carbon monoxide and water in the presence of a suitable catalyst to 1 o yield a compound of formula XXXIII and XXXV.

R, is xxxv For purposes of this specification suitable catalysts include, but 2 o ~.e not limited to Ru4(CO) t 2, Co2(CO)g or PdCI
2 in aqueous THF or acetone, acetonitrile, benzene, toluene, methyl alcohol or ethyl alcohol.
In a second alternative, the invention is directed to a process of making a compound of formula XXXIQ

J

O

O

XXXI I I
1 o comprising:
(cl) reacting a compound of formula LIII

i O

LIII
with a reagent of the formula (HO)2BR2 ~ an aqueous solvent such as benzene, toluene, THF, MeOH, DME or EtOH and in the presence of a suitable palladium catalyst to yield a compound of formula LV, and . WO 95100501 PCTlCA94100318 O

O

LV
i o (c2) oxidizing the compound of formula LV to yield a compound of formula XXXIII.
For purposes of this specification, the catalyst is defined to include, but not be limited to palladium catalysts. Similarly, the solvent is i s intended to include, but not be limited to benzene, toluene, THF, MeOH, DME or EtOH.
In all of the process alternatives, RI and R2 are as defined above for the portion of Detailed Description and Claims directed to the 2o compounds of formula I.
Representative Compounds Tables I and II illustrate compounds of formula I.

WO 95100501 PCTlCA94/00318 - s$ -Table I
r Example Method nO2NH2 F
c02NH2 to F

Me ~ ~ ~ 3 A
SJ' Me ~ F
~ S02NH2 ~ ~ A
S-~02Me F .
3o N ~ 6 C
' ~Me'~S
S02Me Table I (continued) r Example Method s . 7 F
SOzMe r to S02Me r S02Me r ~ 1p Table I (continued) Example Method S02Me S02Me r "02NHC(O)CF3 . 14 A
F

CA 02364039 2001-12-17 , WO 95100501 PCTlCA94100318 Table I (continued) Example Method S02Me r to 16 I
S02Me 1~ I
S02Me 2o 18 1 S02Me F
SOZMe Table I (continued) Example Method S02Me ~I

l0 S02Me '7Me S02Me S02Me S02Me WO 95/00501 PCTlCA94100318 Table I tcontinuedl r Example' Method s S02Me I

S02Me I
1s SOZMe r S02Me ( S02Me WO 95!00501 PCTICA94/00318 Table I (continued) Example Method S02Me I
l0 31 I
S02Me is 302Me S02Me r I

S02Me WO 95!00501 PCTICA94100318 Table I (continued) F3 Example Method S02Me io I

~~2Me '7Me 'I

S02Me w2Me r S02Me . WO 95/00501 . PCT/CA94100318 Table I (continued) Me Example Method S02Me l0 41 I
S02Me C

S02Me , ' 4e ;r 43 t S02Me r r~r S02Me WO 95!00501 PCTICA94/00318 Table I (continued) r Exam le P Method s r 45 t S02Me ~I
to ~ 46 I
S02Me "r 1s S02Me 3r 48 t S02Me ~02Me Table I fcontinuedl Example Method s 50 t ~02Me I

Zs 7Me ~I

a ~~2NH2 Table I ~continuedl Example Method F
N,S I w S02Me 10 "O2Me 56 L+M
CI
~ 5 "'~2Me 57 L+M
~02Me 58 L+M
F
_ F

. WO 95/00501 PCT/CA94100318 Table I (continued) Example Method S02Me g L+M
' O ~ ~ CI
O v _CI
to "02Me 60 L + M
is - CI

WO 95!00501 ~ PCT/CA94100318 Table II
s r Me ~OzNH2 F

to -S
OH
15 ~02NH2 FsC FsC
2o F S02NH2 ~D2NH2 2s OMe OMe Table II (continued) r Me Me to r~~2NH2 r F

F

~'O2NH2 "OZNH2 OMe OMe Table II (continued) OH
n n w~
~12 ~J2NH2 OH
io OH "~ '~H2 ~J2NH2 ~~ yH2 C02H

OH

Met ~02NH2 ~J2NH2 Table II f continued) ''~zNH2 Me ~J2NH2 to f~r1 AIIJ
nn vy Met OH
OH
°~zNH2 n WO 95!00501 PCTICA94100318 Table II f continued) C

to "'~2N H2 "02NH2 C C
.
CI
n r~2Me Table II (continued "02NH2 Hn Hn to ~02NH2 F
C

"02NH2 ~02NH2 F F

WO 95/00501 PCT/CA.94/00318 Table II (continutedl ... r S02NH2 S02Me to "02Me ~O2NH2 HM Hf~
F
"02NH2 ~,02NH2 C C
CI Br ~02NH2 C
_ Br - , WO 95IOOSOI - PCT/CA94I00318 Table II lcontinued) ~02NH2 ~02NH2 F
F F
r "02NH2 S02NH2 Me F F
r r r 3o SOZNH2 S02NH2 Table I1 (concluded) r. n n , y "02NH2 2 ., 02N H2 ~02Me "02N H2 - F - CI -- CI
2Q S02Me SOzNH2 S02Me -..

Table II (conclu~dedl . .
"02NH2 "02Me ~02NH2 Me Me - F - CI - CI
to ~'02Me S02Me S02NH2 Me Me F _ _ 2 o S02Me S02NH2 S02Me CI
S02Me S02NH2 S02NH:
CI
CI CI

CA 02364039 2001-12-17 , WO 95!00501 PCTlCA94100318 _7g_ Table II (concluded) S02NH2 S02Me S02NH2 Me Me F F CI
to S02Me "02Me ~02NH2 Me Me CI CI
CI CI C
2o S02Me S02NH2 SOzMe F F OMe S02Me 02NH2 S02Me OMe CI CI

' CA 02364039 2001-12-17 Table II (concluded) ~02NH2 c02Me S02NH2 Me Me Me F F OMe F F
to S02Me ~~2Me "02NH2 Me Me OMe OMe OMe 2 o S02Me S02N H2 S02Me C
Me Me me S02Me S02NH2 SOzMe Me Me Me WO 95100501 PCTlCA94/00318 -80_ AssaYs-for Determining Biological Activity The compound of Formula I can be tested using the following assays to determine their cyclooxygenase-2 inhibiting activity.
Inhibition of CXclooxXQenase Activity Compounds were tested as inhibitors of cyclooxygenase activity in whole cell and microsomal cyclooxygenase assays. Both of these assays measured prostaglandin E2 (PGEZ) synthesis in response to arachidonic acid, using a radioimmunoassay. Cells used for whole cell 1 o assays, and from which microsoriles were prepared for microsomal assays, were human osteosarcoma 143 cells (which specifically express cyclooxygenase-2) and human U-937 cells (which specifically express cyclooxygenase-1 ). In these assays, 100% activity is defined as the difference between prostaglandin E2 synthesis in the absence and presence 1 s of arachidonate addition. ICSO values represent the concentration of putative inhibitor required to return PGE2 synthesis to 50% of that obtained as compared to the uninhibited control. Representative results are shown in Table III.
2o Representative Rat Paw Edema Assay - Protocol Male Sprague-Dawley rats (150-200g) were fasted overnight and were given po either vehicle (5% tween 80 or 1 % methocel) or a test compound at 9 - IO am. One hr later, a line was drawn using a permanent 2 s marker at the level above the ankle in one hind paw to define the area of the paw to be monitored. The paw volume (Vph) was measured using a plethysmometer (Ugo-Basile, Italy) based on the principle of water displacement. The animals were then injected subplantarly with 50 ul of a 1 % carrageenan solution in saline (FMC Corp, Maine) into the paw using 3 o an insulin syringe with a 25-gauge needle (i.e. 500 ug carrageenan per paw). Three hr later, the paw volume (V3h) was measured and the increases in paw volume yV3h - VOh) were calculated. The animals were euthanized by C02 aphyxiation and the absence or presence of stomach , lesions scored. Stomach scores were expressed as the sum of total lesions in mm. Paw edema data were corrtpared with the vehicle-control group and percent inhibition calculated taking the values in the control group as 100%. Since a maximum of 60 - 70% inhibition (paw edema) was obtained with standard NSAIDs, ED3p values were used for comparison. All treatment groups were coded to eliminate observer bias. With this protocol, the ED3p for Indomethacin is 1.0 mg/kg. Representative results are shown in Table IV.
~o is _g2_ TABLE III*
Whole Cells Microsomes Example Conc. COX-2 COX-1 Conc. COX-2 COX-1 s (nM) % inhib. % inhib. (nM) % inhib. % inhib.

3 10 ' 42 10 33 19 io 3 100 100 100 76 12 is 8 10 4I

100 95 100 71 12 .

13 '10 41 10 52 7 as 14 1000 101 1000 69 0 Example Conc. COX-2 COX-1 Conc, COX-2 COX-1 (nM) ~ % ~inhib.% inhib. (nM) % inhib. % inhib.
~

s 15 160 95 l0 17 40 41 is 19 160 59 2s 24 160 78 . 26 80 27 .

so 27 20 38 Example Conc. COX-2 COX-1 Conc. COX-2 COX-1 (nM) % inhib.% inhib. (nM) % inhib. % inhib.

28 ~ 20 48 s 29 20 78 io 32 5 43 .

is 34 10 30 Zo 35 160 83 Zs 37 10 53 WO 95/00501 PCTlCA94100318 Example Conc. COX-2 COX-1 Conc. COX-2 COX-1 (nM) % inhib. % inhib. (nM) % inhib. % inhib.

s 40 40 72 l0 42 160 44 43 40 l0I

is 44 160 106 as 47 160 101 WO 95!00501 PCT/CA94/00318 Example Conc. COX-2. COX-1 Conc. COX-2 COX-1 (nM) % inhib.% inhib. (nM) % inhib. % inhib.
io 53 40 96 is 55 10 48 * In the whole cell assay Ibuprofen has an IC50 for COX-1 of 1000 nM, and an IC50 for COX-2 of 3000 nM. Similarly, Indomethacin has an IC50 for COX-1 of 100 nM, and an IC50 for COX-2 of 10 nM.

WO 95/00501 pCTICA94100318 _ $"j TABLE IV
T
ED30f m~/kg,~ STRUCTURE
3.00 , S02Me S /
io F
1s >10.00 , S02Me w S
F

_ gg _ 1.40 /. S02NH2 S

F

to 2.80 , S02Me (in l lo methocel) 0.72 O

O ~

F

0.43 , S02Me F

3.00 j ~S02NH2 HO S
F
>3.00 / S02NH2 3.00 \
s /
F
1.10 / S02Me \
N
S /
F

<0.30 , F
s S

0.42 , S02Me is i O
F
0.034 / S02NH2 O
I ,, O
F

2.03 , S02Me \I
O
s O .
\ I
F F
to 1.49 , S02Me \ I
F
15 ~ /
F
2 0 0.35 , S02Me \
O
I
25 ~ I
F
F

0.33 / S02Me O (:
s Br io 0.90 , S02Me O
/
is O
ci 20 0.3g , S02Me O
O

WO 95!00501 PCTICA94/00318 O~gg , S02Me \
O
O
Br \
CI
to 0.47 , S02Me O
I

F \
CI
20 0.71 , S02Me \
O
I
CI

WO 95100501 PCTlCA94100318 ~l,pp / S02Me o I
Br i F
to 1.85 / S02Me O I
15 ~ /
O
CI
CI
20 0.22 / S02Me 0.23 o I
CI
o /
CI

0.43 . / S02Me O
CI
0 /~
\
F
to 2.17 / S02Me O
O

2o SO Me 0.81 / I 2 \
O
F
O
. OMe 0.6.8 , S02Me \
CI
s i O \
OMe to 0.16 , S02Me \ \
1.00 , S02Me O
O
SMe WO 95/00501 PCTlCA94100318 _97_ ~,. :0.,33 / S02Me o ~ ,_ O \
F
0.46 / S02Me O
O /

Br 0.76 ~. S02Me O
Br O \
Br WO 95100501 PCT/CA94l00318 0.48 / ~ - ~S02NH2 \
O I
s I
O
F
F
to 0.46 / S02NH2 o I
O \
CI
CI
0.26 , S02Me O I
O
CI
F

WO 95!00501 PCT/CA941003I8 0.55 / S02Me O
s f /
O
Br F
to 0.25 / S02Me O

O \
CI
0.1-.3 / S02Me O
O

WO 95100501 PCTlCA94100318 0.10 , S02Me I /
F
F
to 0.13 , S02Me O
/
CI
CI
0.07 / S02Me 2s I ~-CI

WO 95!00501 ~ PCT/CA94100318 The invention will now be illustrated by the following non-limiting examples in which, unless stated otherwise: . . , (i) all operations were carried out at room or ambient temperature, that is, at a temperature in the range 18-25°C;
evaporation of solvent was carried out using a rotary evaporator under reduced pressure (600-4000 pascals: 4.5-30 mm. Hg) with a bath temperature of up to 60°C;
the course of reactions was followed by thin layer chromatography (TLC) and reaction times are given for illustration only; melting points are uncorrected and 'd' indicates decomposition; the melting points given are 1 o those obtained for the materials prepared as described; polymorphism may result in isolation of materials with different melting points in some preparations; the structure and purity of all final products were assured by at least one of the following techniques: TLC, mass spectrometry, nuclear magnetic resonance (NMR) spectrometry or microanalytical data; yields i 5 are given for illustration only; when given, NMR data is in the form of delta (8) values for major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as internal standard, determined .
at 300 MHz or 400 MHz using the indicated solvent; conventional abbreviations used for signal shape are: s. singlet; d. doublet; t. triplet;
m.
2o multiplet; br. broad; etc.: in addition "Ar" signifies an aromatic signal;
chemical symbols have their usual meanings; the following abbreviations have also been used v (volume), w (weight), b.p. (boiling point), m.p.
(melting point), L (liter(s)), mL (milliliters), g (gram(s)), mg (milligrams(s)), mol (moles), mmol (millimoles), eq (equivalent(s)).
The following abbreviations have the indicated meanings:
Ac - acetyl Bn - benzyl DBU - 1,8-diazabicyclo[5.4.0]undec-7-ene 3 o DIBAL - diisobutylaluminum hydride DMAP . - . 4-(dimethylamino)pyridine DMF - N,N-dimethylformamide Et3N - - triethylamine LDA - lithium diisopropylamide m-CPBA - metachloroperbenzoic acid MMPP - monoperoxyphtalic acid s MPPM - monoperoxyphthalic acid, magnesium salt Ms - methanesulfonyl = mesyl = S02Me Ms0 ~ - methanesulfonate = mesylate NSAID - ' non-steroidal anti-inflammatory drug i o OXONE~ = 2KHS05KHSOq.K2S04 PCC - pyridinium chlorochromate PDC - pyridinium dichromate Ph - phenyl Phe - benzenediyl 1 s pye - pyridinediyl r.t. - room temperature ~

rac. - racemic SAM - aminosulfonyl or sulfonamide or 20 TBAF - tetra-n-butylammonium fluoride Th - 2- or 3-thienyl TFAA - trifluoroacetic acid anhydride THF - tetrahydrofuran Thi - thiophenediyl 2 s TLC - thin layer chromatography TMS-CN - trimethylsilyl cyanide Tz - 1 H (or 2H)-tetrazol-5-yl C3H5 - allyl 3o Alk, l Group Abbreviations Me - methyl Et - ethyl n-Pr - normal propyl i-Pr - isopropyl n-Bu - normal butyl i-Bu - isobutyl s-Bu - secondary butyl t-Bu - tertiary butyl c-Pr - cyclopropyl c-Bu - cyclobutyl c-Pen - cyclopentyl 1 o c-Hex - cyclohexyl EXAMPLE ~I' 3-(4-Aminosulfonyl)phenyl)-2-(4-fluorophenyl)-5-(2-hydroxy-2-prop llv thiophene .
to 1: 1-(4-Fluorophenyll-2-(4-~methylthio~phenyl~ethanone To 4-fluorobenzaldehyde (5.40 g) in 1,2-dichloroethane (43.50 mL) were added TMS-CN (4.32 g) and ZnI2 (44 mg). After 0.5 h at r.t., the solvent was removed in vacuo. To the resulting TMS
cyanohydrin (9.20 g) in THF (42.0 mL) at -78°C was added dropwise a to solution of LDA 0.51M in THF (88.9 mL). After a period of 0.5 h, a THF
solution (30.0 mL) of 4-(chloromethyl)thioanisole (9.93 g) was added dropwise over 0.5 h. After 18 h at +5°C, the resulting mixture was treated with TBAF (57.5 mL) followed by a 25%, aqueous solution of NH40Ac (100 mL) and extracted with EtOAc (2 x 150 mL). After 1 s evaporation, a 10:1 mixture of Et20 and hexane (200 mL) was added to the crude ketone. After stirring for 10 h and filtration, the title product was obtained as a solid by filtration (2.40 g).
1H NMR (CD3COCD3): b 2.45 (3H, s), 4.34 (2H, s), 7.19-7.29 (6H, m), 8.14 (2H, q).
Step Z: Cis,traps-3-chloro-3-(4-fluorophenyl)-2-(4-(methylthio)-phen~propenal To a solution of 1-{4-fluorophenyl)-2-(4-(methylthio)phenyl ethanone (2.50 g) in 1,2-dichloroethane (27.0 mL) were introduced the 2s Vilsmeier reagent (Aldrich catalog, 1992-1993) 3.3M (11.6 mL) and DMAP (1.17 g): After a period of 4 h at 80°C, the reaction mixture was extracted with EtOAc and 25% aqueous solution of NH40Ac. After evaporation in vacuo and drying for a few hours, the title product was used as such for the next step.
1H NMR (CD3COCD3): 8 2.40 and 2.48 (3H, Zs), 6.90-7.80 (8H, m), 9.55 (1H, s).

Step 3: 5-(4-Fluorophenyl)=4-(4-(methylthio)phenyl)thiophene-2-carboxXlic acid methyl ester To a solution of cis,trans 3-chloro-3-(4-fluorophenyl)-2-(4 (methylthio)phenyl)propenal (3.00 g) in pyridine (12.0 mL) were added s methyl thioglycolate (1.16 mL) and Et3N (4.09 mL). The resulting mixture was then heated at 80°C for 2 h. After extraction with EtOAc and washing v~iith 3N HCI, the title product was purified by flash chromatography (30% EtOAc in hexane) (2.00 g).
1H NMR (CD3COCD3): 8 2.48 (3H, s), 3.88 (3H, s), 7.11 (2H, t), 7.21 i o (4H, s), 7.37 (2H, q), 7.80 (1 H; s).
Step,_4: 5-(4-Fluorophenyl)-4-(4-(methylsulfinyl)phenyl)thiophene-2-carboxylic acid methyl ester To a solution of 5-(4-fluorophenyl)-4-(4-(methylthio)phenyl)-i s thiophene-2-carboxylic acid methyl ester (5.60 g) in CH2CI2 (84.0 mL) at 0°C was added portionwise m-CPBA 50 to 60% (5.39 g). After TLC
showed completion (50% EtOAc in hexane), the reaction mixture was extracted with saturated NaHC03, dried over Na2S04, filtered and evaporated to dryness to provide the title compound as a white foam (5.00 2o g)_ 1H NMR (CD3COCD3}: 8 2.75 (3H, s), 3.92 (3H, s), 7.I5 (2H, t), 7.40 (2H, q), 7.52 (2H, d), 7.66 (2H, d), 7.90 (1 H, s).
to 5: 4-(4-(Aminosulfonyl)phenyl)-5-(4-fluorophenyl)thiophene-2-2s carboxylic acid methyl ester 5-(4-Fluorophenyl)-4-(4-(methylsulfinyl)phenyl)thiophene-2-carboxylic acid methyl ester (0.500 g) was dissolved in TFAA (10.0 mL) and refluxed for 0.5 h. The solvent was then removed in vacuo and the resulting residue was co-evaporated 10 times with a Et3N-MeOH solution 30 (1:1) (100.0 mL) to provide a viscous oil after pumping for a few hours.
The oil was dissolved in HOAc (10.0 mL) and treated at +10°C with Cl2 in WO 95100501 ~ PCT/CA94/00318 HOAc (1.9M) (3.5 mL). After 20 min., the solvent was removed under reduced pressure and after pumping, THF (20.0 mL) was added to the resulting mass of product. After bubbling NH3 through for a few minutes at 0°C, the reaction mixture was stirred for 0.5 h at r.t. After extraction with EtOAc - 25% NH40Ac solution and flash chromatography (30 to 40% EtOAc in hexane), the title product was obtained as a white solid (0.210 g).
1 H NMR (CD3COCD3): 8 3,90 (3H, s), 6.55 (2H, bs), 7.13 (2H, t), 7.40 (2H, q), 7.46 (2H, d), 7.83 (2H, d), 7.90 (1H, s).
1 o to 6: 3-(4-Aminosulfonyl)phenyl)-2-(4-fluorophenyl)-5-(2-h droxy-2-propvl)thiophene To 4-(4-aminosulfonyl)phenyl)-5-(4-fluorophenyl)thiophene-2-carboxylic acid methyl ester (0.460 g) in THF (5.70. mL) at 0°C was added MeMgBr (1.4M) in toluene-THF solution (5.00 mL). The mixture i s was then stirred at r.t. for a few hours. The reaction was quenched by the addition of 25% NH40Ac solution, extracted with.EtOAc and dried over with Na2S04. The title compound was purified by flash chromatography (40 to 50% EtOAc in hexane) (0.300 g).
IH NMR (CD3COCD3): 8 1.65 (6H, s), 4.52 (IH, s), 6.55 (2H, bs), 7.09 20 (3H, m), 7.34 (2H, dd), 7.30 (2H, m), 7.43 (2H, d), 7.82 (2H, d). Anal.
calcd. for ClgHIgFN03S2; C, 58.31; H, 4.60; N, 3.58. Found: C, 57.94;
H, 4.66; N, 3.44 3-(4-(Aminosulfonvl)phenyl)-2-(4-fluorophenyllthiophene Step 4-(4-(Aminosulfonyl)phenyl)-5-(4-fluorophenyl)thiophene-2-carboxvlic acid s o To a solution of 4-(4-(aminosulfonyl)phenyl)-5-(4-fluoro-phenyI)thiophene-2-carboxylic acid methyl ester (Example 1, Step 5) (0.210 g) in THF (2.0 mL) were added MeOH ( 1.0 mL), NaOH 1 N ( 1.0 mL) and a few drops of NaOH ION. The resulting mixture was heated at 45°C for 2 h and the reaction was then partitioned between EtOAc and (3N) to provide the title product as a white solid (0.200 g).
1H NMR (CD3COCD3) 8 6.60 (2H, s), 7.15 (2H, t), 7.35 (2H, q), 7.45 (2H, d), 7.82 (2H, d), 7.87 (1H, s).
Ste~2: 3-(4-(AminosulfonYl_lphenyll-2-l4-fluorophen l~phene To a solution of 3-(4-(aminosulfonyl)phenyl)-2-(4-fluorophenyl)thiophene-2-carboxylic acid (0.280 g) in quinoline (4.0 mL) to was added Cu bronze (0.300 g): After 0.5 h at 180°C under nitrogen, the reaction mixture was extracted with EtOAc and HCl 3N, dried over Na2S04 and purified by flash chromatography (30% EtOAc in hexane) to give the title compound as a white solid (0.180 g).
1H NMR (CD3COCD3): 8 6.60 (2H, bs), 7.15 (2H, t), 7.29 (1H, d), 7.35 15 (2H, q), 7.45 (2H, d), 7.60 (1H, d), 7.83 (2H, d).
Anal. calcd for C16H12FNO2S2~
C, 57.65; H, 3.60; N, 4.20.
Found: C, 57.62; H, 3.59; N, 4.15.

3-(4-(Aminosulfon~phenyll-2-(4-fluorophenvl~~-5-(2-prop~llthio hene 2s 1H ~ (CD3COCD3) 81.40 (6H, d), 3.25 (1H, septuplet), 6.58 (2H, bs), 7.05 (IH, s), 7.15 (2H, t), 7.32 (2H, dd), 7.46 (2H, d), 7.80 (2H, d).
Anal. calcd. for CI9HIgFN02S2.
C, 60.80; H, 4.80; N, 3.73.
3 o Found: C, 60.59; H, 4.45; N, 3.60.

WO 95100501 PCTlCA94100318 3-~4-(Aminosulfonyllphenvll-2-cvclohex, l~thiophene IH NMR (CD3)2)CO) 8 1.24-1.40 (3H, m), 1.40-1.56 (2H, m), 1.65-1.85 s (3H, m), 1.90-2.0 (2H, m), 3.18 ( 1 H, m), 6.58 (2H, bs), 7.05 ( 1 H, d), 7.37 (1H, d), 7.58 (2H, d), 7.97 (2H, d).

5-(4-Carboxyphenyl}-4-(4-(methylsulfonyl)phenyl)thiophene-2-carboxylic acid to l: 4-(2-(4-Methylthiophenyl)-1-oxo-ethyl)benzoic acid methyl ester is To methyl 4-formylbenzoate (10.30 g) in I,2-dichloroethane at r.t. were added TMS-CN (6.58 mL) and ZnI2 (2.00 g), after 0.5 h at r.t., the solvent was removed in vacuo. To the resulting TMS cyanohyrin (5.00 g) in THF (22.0 mL) at -78°C was added dropwise a solution of LDA
0.87 M in THF (26.2 mL). After a period of 0.5 h, a THF solution (10.0 2 o mL) of 4-(chloromethyl)thioanisole was added dropwise over 0.5 h. The temperature was then brought slowly to -20°C then to 5°C for 2 h and TBAF 1 M in THF (50.0 mL) was added. After the addition of 25 %
aqueous solution of NH40Ac, the reaction mixture was extracted with EtOAc, dried over NAS04, evaporated in vacuo and purified by flash 2s chromatography (20 to 30% EtOAc in hexane) to afford the title compound as a white solid (7.00 g).
Step 2: 4-(1-Oxo-2-(4-(methylsulfonyl)phenyl)ethyl) benzoic acid methyl ester 3o To 7.10 g of 4-(2-(4-methylthiophenyl)-1-oxo-ethyl)benzoic acid methyl ester in MeOH (100 mL) was added oXOne (21.0 g) in H20 (20.0 mL) at 0°C. After a few hours at r.t., the reaction mixture was extracted with EtOAc and H20 to afford after flash chromatography (50 to ..
100% EtOAc in hexane), the title product as a white solid (3.20 g).
1H NMR (CD3COCD3) 8 3.10 (3H, s), 3.95 (3H, s), 4.65 (2H, s), 7.60 (2H, d), 7.96 (2H, d), 8.20 (4H, q).
Step 3: Cis,trans 4-(1-Chloro-3-oxo-2-{4-(methylsulfonyl)phenyl)-1-propenyl)benzoic acid methyl ester To a solution of 4-(1-oxo-2-{(4-methylsulfonyl)phenyl)ethyl) benzoic acid (1.70 g) in 1,2-dichloroethane (15.0 mL) were added the i o Vilsmeier reagent 3.3 M (6.2 mL) and DMAP (0.624 g). The resulting mixture was heated at 80°C for 4 h. The reaction mixture was then extracted with 25 % aqueous solution of NH40Ac and EtOAc. After drying over Na2S04 and evaporation the title compound was obtained as an oil and used as such for the next step.
~s Step 4: 5-(4-(Methoxycarbonyl)phenyl)-4-(4-(methylsulfonyl)-phenvllthiophene-2-carboxylic acid methyl ester Prepared from 4-(1-chloro-3-oxo-2-(4-methylsulfonyl)-phenyl)-1-propenyl)benzoic acid methyl ester as for Example 1, Step 3.
20 1H NMR (CD3COCD3) 8 3.13 (3H, s), 3.85 and 3.92 (6H, 2s), 7.50 (2H, d), 7.55 (2H, d), 7.90 (2H, d), 7.92 (1H, s), 7.92 (2H, d).
Std 5-(4-{Carboxyphenyl)-4-(4-(methyl)sulfonyl)phenyl)-thiophene-2-carboxylic acid 2s Prepared from 5-(4-(methoxycarbonyl)phenyl)-4-(4-(methyl)sulfonyl)phenyl) thiophene-2-carboxylic acid methyl ester as for Example 2, Step I.
- IH NMR (CD3COCD3) 8 3.15 (3H, s), 7.50 (2H, d), 7.62 (2H, d), 7.95 (2H; d), 7.98 (1H, s), 8.05 (2H, d).
Anal calcd. for C19HI4O6S2~0.1 H20:
_.
., C, 56.46; H, 3.51.
Found: C, 56.18; H, 3.5I.

s 4-(4-Fluorophenyl)-2-methyl-5-(4-(methylsulfonyl)phenyl)thiazole Step l: 1-(4-Fluorophenvl)-2-(4-(methylsulfonvl)nhenvl)ethanone To 1-(4-Fluorophenyl)-2-(4-(methylthio)phenyl)ethanone of Example l, Step 1 (17.9 g) in a solution of CH2C12-MeOH (272.0 mL/27.0 i o mL) at 0°C was added MPPM (28:0 g). The cooling bath was then removed and the reaction mixture stirred at r.t. for 1 h. At 0°C, additional MPPM (28.0 g) was added and the reaction mixture kept for I.5 h at r.t.
The insoluble material was filtered followed by evaporation of the solvents, the residue was then extracted with CH2C12-NaHC03. After evaporation 1 s in vacuo, the resulting solid was washed with ether-hexane (1:1 ) and filtered to provide the title compound 16.8 g.
1H NMR (CD3COCD3) 8 3.13 (3H, s), 3.58 (2H, s), 7.29 (2H, t), 7.55 (2H, d), 7.88 (2H, d), 8.20 (2H, dd).
2o St, ep 2: 2-Bromo-1-(4-fluorophenyl)-2-(4-(methylsulfonyl)phenyl)-ethanone To 1-(4-Fluorophenyl)-2-(4-(methylsulfonyl)phenyl)ethanone (1.00 g) in CH2C12 containing CHC13 (1.0 mL) and CC14 (1.0 mL) was added bromine (0.614 g). After shining light for 1 h, the reaction was 2s quenched with Na2S204, extracted with CH2C12, dried over Na2S04 and evaporated to yield the title compound which was used as such for the next step (I.10 g).
1H NMR (CD3COCD3) b 3.10 (3H, s), 7.05 (1H, s), 7.30 (2H, t), 7.87 (2H, d), 7.95 (2H, d), 8.25 (2H, dd).

Std 3: 4-(4-Fluorophenyl)-2-methyl-5-(4-(methylsulfonyl)phenyl)-thiazole ~~
To 2-bromo-I-(4-fluorophenyl)-2-(4-(methylsulfonyl)phenyl)-ethanone ( 1.10 g) in ethanol (15.0 mL) were added thioacetamide (0.266 g) and pyridine (0.300 mL). After refluxing for 2 h, the reaction mixture was extracted with EtOAc, 25% NH40Ac and purified by flash chromatography (50% EtOAc in hexane then 90% Et20 in hexane) to yield the title compound (0.320 g).
1H NMR (CD3COCD3) S 2.72 (3H, s), 3.15 (3H, s), 7.09 (2H, t), 7.52 (2H, dd), 7.60 (2H, d), 7.92 (2H, d).
to Anal. calcd. for C17H14FN02S2:
C, 58,78; H, 4.03; N, 4.03.
Found: C, 58.71, H, 4.17; N, 3.85.

2-(4-FluorophenXll-3-(4-(meth Isy ulfon ~~llphenvll-2-c~clopenten-1-one Step 1: 1-(4-Fluorophenyll-5-hexen-2-one To a suspension of 14.6 g (80 mmol) of CdCl2 in 200 mL of 2o ewer cooled to 0°C was added I15 mL of 1.3 M solution of 3-butene-1-magnesium bromide dropwise. The mixture was refluxed for 1 h and ether was then removed by distillation. Benzene (S00 mL) was introduced, followed by a solution of 17.5 g (100 mmol) 4-fluorophenylacetyl chloride. After refluxing for 1 h, the reaction mixture was quenched with 200 mL of saturated aqueous NH4CI, SO mL of 1 N HCI, and extracted with 200 mL of 1:1 hexane/EtOAC. The organic phase was dried over MgS04 and concentrated. The residue was purified by flash chromatography eluted with 4:1 hexane/EtOAc to give 15 g of the title product.
1H ~ (CDC13) S 2.40 (2H, t), 2.53 (2H, t), 3.63 (2H, s), 4.90-4.98 (2H, m), 5.67-5.78 (1H, m), 6.98 (2H, t), 7.13 (2H, m).

Step 2: 1-(4-Fluorophenyll-5-oxo-2=pentanone A solution of 14 g of 1-(4-fluorophenyl)-5-hexen-2-one in 200 mL of -3:1 CH2Cl2/MeOH was cooled to -78°C and treated with excess ozone. The resulting mixture was treated with 15 g of triphenylphosphine s and stirred at room temperature for 1 h. The reaction mixture was concentrated and flash chromatographed with 3:1 hexane/EtOAc to give 8 g of the title ketoaldehyde.
1 H NMR (CDCl3) 8 2..72 (4H, s), 3.71 (2H, s), 6.99 (2H, t), 7.14 (2H, m), 9.73 (1H, s).
io Step 3: 2-(4-Fluorophen~l-2-cyclopenten-I-one A solution of 8 g of 1-(4-fluorophenyl)-5-oxo-2-pentanone in 300 mL of MeOH was treated with 2 g of NaOMe. The mixture was stin;ed for 2 h and then quenched with 5 mL of HOAc. The solvent was 1 s evaporated and the residue purified by flash chromatography, eluting with 3:1 hexane/EtOAc to give 7 g of the title product.
1H NMR (CDCl3) 8 2.57 (2H, m), 2.68 (2H, m), 7.04 (2H, J=8.8 Hz, t), 7.67 (2H, J=8.8, 5.5 Hz, dd), 7.77 ( 1 H, m).
2 o Step 4: 1-(4-(Methylthio)phenyl)-2-(4-fluorophenyl)-2-cyclo-penten-1-of To a solution of 3.86 g (19 mmol) of 4-bromothioanisole in 90 mL of Et20 cooled at -78°C, was added 22 mL of 1.7 M solution of t-BuLi in pentane (38 mmol) dropwise. The reaction mixture was stirred for 15 2s m~ at -78°C and a solution of 2.23 g of 2-(4-Fluorophenyl)-2-cyclopenten-1-one in 10 mL of Et20 was added. After stirring for 15 min at -78°C, the reaction mixture was warmed to 0°C, and quenched with 50 mL of sat.
NH4Cl. The product was extracted with 100 mL EtOAc, dried over Na2S04, and purified by flash chromatography, eluted with 4:1 3 o hexane/EtOAc to give 3.4 g of the desired product.

1H NMR (CDC13) b 2.12 (1H, s), 2.34 (2H, m), 2.44 (3H, s), 2.45-2.52 (1H, m), 2.56-2.65 (1H, m), 6.37 (1H, m), 6.84 (2H, J=8.7 Hz, t), 7.17 (2H, J=8.3 Hz, d), 7.24-7.33 (4H, m).
Step 5: 2-(4-Fluorophenyl)-3-(4-(methylthio)phenyl)-2-cyclo-'s penten-1-one To a suspension of PCC (4.5 g, 20.9 mmol) and 10 g of anhydrous 4th molecular sieves in 150 mL of CH2Cl2 was added a solution of 2.2 g (7.3 mmoI) of 1-(4-(methylthio)phenyl)-2-(4-fluorophenyl)-2-cyclopenten-1-of in 20 mL CH2CI2. The mixture was stirred for 1 h at r.t.
to and then diluted with 300 mL of Et20. After filtration and concentration, the residue was flash chromatographed with 2:1 hexane/EtOAc to give 1.5 g of the title product.
1H NMR (CDC13) 8 2.45 (3H, s), 2.68 (2H, m), 3.00 (2H, m), 7.02 (2H, J=8.6 Hz, t), 7.11 (2H, J=8.6 Hz, d), 7.15-7.23 (4H, m).
is Step 6: 2-{4-Fluorophenyl)-3-(4-{methylsulfonyl)phenyl)-2-cvclonenten-1-one To a solution of 50 mg (0.17 mmol) of 2-(4-Fluorophenyl)-3-(4-methylthio)phenyl)-2-cyclopenten-1-one in 8 mL of 10:1 CH2C12/MeOH
20 was added 124 mg (0.2 mmol) of MPPM. The reaction mixture was stirred at room temperature for 2 h and then diluted with 10 mL of I :1 hexane/EtOAc. After filtration and concentration, the residue was purified by flash chromatography eluted with 2:1 EtOAc/hexane to give 45 mg of the title product.
2s 1H NMR (acetone-d6) 8 2.67 (2H, m), 3.14 (3H, s), 3.16 (2H, m), 7.05-7.10 (2H, m), 7.20-7.25 (2H, m), 7.63 (2H, d), 7.93 (2H, d).

3 0 4_(4-(Methylsulfonvl)phenyl)-5-(4-fluorophenyI~isothiazole To a solution of 338 mg (1 mmol) of cis,trans 3-chloro-3-(4-fluorophenyl)-2-(4-(methylsulfonyl)phenyl)propenal in 5 mL of acetone was added 230 mg (3 mmol) of NH4SCN. The reaction mixture was refluxed for 3 h, and then quenched with 20 mL of saturated NaHC03.
The product was extracted with 100 mL of EtOAc, dried over Na2S04, s concentrated and purified by flash chromatography eluted with 3:2 hexane/EtOAc to give 250 mg of the title product.
1H NMR (CDCl3) S 8.57 (1H, s), 7.93 (3H, d), 7.50 (2H, d), 7.30 (2H, t), 7.08 (2H, t).
to EXAMPLE 9 3-f4-FIuoTOphenvll-4-(4-(methylsulfonvll,~ henyll-2-(SHl-furanone St, ep 1: 2-Bromo-1-!4-(methvlsulfonyll~henyllethanone z s A solution of 197 g of 4-(Methylthio)acetophenone (ref:
JACS, 1952, 74, p. 5475) in 700 mL of MeOH and 3500mL of CH2C12 was added 881 g of MMPP over a period of 30 min. After 3 h at room temperature the reaction mixture was filtered and the filtrate was washed with 2 L of saturated aqueous solution of NaHC03 and 1 L of brine. The 2 o aqueous phase was further extracted with 2 L of CH2Cl2. The combined extracts was dried over Na2S 04 concentrated to give 240 g of 4-(methylsulfonyl)acetophenone as a white solid.
To a cooled (-5 °C) solution of 174 g of 4-(methylsulfonyl)acetophenone in 2.5 L of CHC13 was added 20 mg of 2s AIC13, followed by a solution of 40 mL of Br2 in 300 mL CHC13. The reaction mixture was then treated with 1.5 L of water and the CHC13 was separated. The aqueous layer was extracted with 1 L of EtOAc. The combined extracts was dried over Na2S04 and concentrated. The crude product~was recystalized from 50/50 EtOAc/hexane to give 210 g of 2-ao bromo-1-t4-~ et ylsulfonyl)phenvllethanone as a white solid.

St,_ en 2:
. To the product of Step 1 (216 mg) dissolved in acetonitrile (4 mL) was added Et3N (0.26 mL), followed by 4-fluorophenylacetic acid (102 mg). After 1.5.h at room temperature 0.23 mL of DBU was added.
The reaction mixture was stirred for another 45 min and then treated with 5 mL of 1N HCI. The product was extracted with EtOAc, dried over Na2S04 and concentrated. The residue was purified by flash chromatography (40% EtOAc in hexane) to yield 150 mg of the title compound as a solid.
1H NMR (CD3COCD3) 8 3.15 (3H, s), 5.36 (3H, s), 7.18 (2H, J=8.9 Hz, t}, l 0 7.46 (2H, m), 7.7 (2H, J=8.65 Hz, d), 7.97 (2H, J=8.68, d).

3-(4-Fluorophenvll-4-(4-(aminosulfonyl~phen"yll-2-(2H)-furanone 1H NMR (CD3COCD3) 8 5.34 (2H, s), 6.67 (2H, bd), 7.18 (2H, m), 7.46 (2H, m), 7.61 (2H, m), 7.90 (2H, m).
M.P. 187-188 °C (d).
2o EXAMPLE 11 3-(4-Fluorophenyll-4-(4-(meth lsulfon ~~Ilphenvllfuran to 1:
Using the product of Example 10, (0.2 g) in THF (5 mL) and toluene (3 mL) was added slowly at -78°C a solution of DIBAL (0.72 mL, 1M in toluene). After 15 min, the solution was warrned up to 0°C for another.l5 min. This mixture was then poured into a chilled aqueous solution of sodium potassium tamate and EtOAc. The organic layer was 3 o stirred for 0.5 h with a few crystals of camphor sulfonic acid. This WO 95100501 ~ PCTICA94100318 solution was then concentrated and purified by flash chromatography to yield the title compound.
1H NMR (CDCl3) _ 3.1 (3H, s), 7.02 (2H, J=8.9, t), 7.18 (2H, m), 7.4 (2H, J=8.8 Hz, d), 7.58 ( 1 H, s), 7.68 ( 1 H, s), 7.85 (2H, J=8.8 Hz, d) 5,5-Dimethyl-3-(4-fluorophenyl)-4-(4-methylsulfonylphenyl)-2-(SH)-furanone to Step 1: Methyl 2-trimethylsilvloxvisobut~rrate To a solution of I.2 mL (10.4 mmol) of methyl 2-hydroxy-isobutyrate in 50 mL of CH2Cl2 were added 1.2 g (17.6 mmol) of imidazole and 2.I mL (16.6 mmol) of TMSCI. The mixture was stirred at r.t. for 1.5 h and quenched with 20 mL of H20. The organic layer was i 5 dried over MgS04, concentrated and passed through a short plug of silica gel eluted with 9:1 hexane/EtOAc. Evaporation of solvent afforded 1.27 g of the title compound as a colorless oil.
IH NMR (CD3COCD3) 8 0.08 (9H, s), 1.38 (6H, s), 3.67 (3H, s).
2o Step 2: ?-TrimethXlsilylox,~r-4'-~methylthiolisobutyrophenone A solution of 204 mg (1.0 mmol) of 4-bromothioanisole in 2.5 mL of THF was cooled to -78°C and treated with 0.42 mL of 2.5 M n-BuLi solution in hexane. After stirring at -78°C for 1 h, a solution of 380 mg (2.0 mmol) of methyl 2-trimethylsilyloxyisobutyrate in 2 mL of THF was 2s added. The mixture was stirred at -78°C for 2 h and then quenched with NH40Ac buffer. The product was extracted with EtOAc, dried over MgS04 and concentrated. The residue was purified by flash chromatography, eluting with 19:1 hexane/EtOAc to give 95 mg of the title product.
so 1H NMR (CD3COCD3) 8 0.05 (9H, s), 1.52 (6H, s), 2.53 (3H, s), 7.33 (2H, d), 8.12 (2H, d).

S. tep 3: 2-Hvdroxy-4'-(methyl~hio)isobutyro henone To a solution of 40 mg ('0.14 mmol) of 2-trimethylsilyloxy-4'-(methylthio)isobutyrophenone in 2 mL THF was added 0.2 mL of 1 M n-Bu4NF in THF. The resulting mixture was stirred for 30 min and then quenched with 10 mL of NH40Ac buffer. The product was extracted with EtOAc, dried over MgS04 and concentrated. The residue was purified by flash chromatography, eluting with 4:1 hexane/EtOAc to give 25 mg of the title product.
1H NMR (CD3COCD3) 8 1.50 (6H, s), 2.54 (3H, s), 4.68 (1H, s), 7.30 i o (2H, d), 8.15 (2H, d).
Step 4: 2-(4-Fluorophenvlacetoxy)-4'-(methvIthio)isobutvrophenone To a solution of 72 mg (0.34 mmol) 2-hydroxy-4'-(methylthio)isobutyrophenone in 1.7 mL of CH2CI2 were added 0.2 mL of i s pyridine and 140 mg (0.81 mmol) of 4-fluorophenylacetyl chloride. The mixture was stirred at room temperature overnight and then quenched with NH40Ac buffer. The product was extracted with EtOAc, dried over MgS04 and concentrated. The crude product was purified by flash chromatography eluting with 8:1 hexane/EtOAc to give 95 mg of the title 2o product.
1H NMR (CD3COCD3) 8 1.62 (3H, s), 1.67 (3H, s), 2.48 (3H, s), 3.79 (2H, s), 7.0-7.3 (6H, m), 7.78 (2H, d).
to : 5,5-Dimethyl-3-(4-fluorophenyl-4-(4-methylthiophenyl)-2-25 (SH)-furanone To a solution of 95 mg of 2-(4-fluorophenylacetoxy)-4'-(methylthio)-isobutyrophenone in 4 mL of CH2C12 was added 0.2 mL of 1,8-diazabicyclo(5.4.0)undec-7-ene. The mixture was stirred for 4 h and diluted with NH40Ac buffer. The product was extracted with EtOAc, 3 o dried over MgS04 and concentrated. The residue was purified by flash chromatography, eluting with 20:1 toluene/EtOAc to give 75 mg of the title product.
1H NMR (CD3COCD3) 8 1.58 (6H, s), 2.50 (3H, s), 7.03 (2H, dd), 7.25-7.35 (4H, m), 7.41 (2H, dd).
Step 6: 5,5-Dimethyl-3-(4-fluorophenyl)-4-(4-methylsulfonylphenyI)-2-(SH)-furanone To a solution of 81 mg of 5,5-dimethyl-3-(4-fluorophenyl)-4-(4-methyl-thiophenyl)-2-oxo-2H-dihydrofuran in 1.8 mL of CH2CI2 and 0.2 mL of MeOH was added 250 mg of MPPM. The reaction mixture was 1 o stirred at room temperature for 1 h and then quenched with aqueous NaHC03. The product was extracted with EtOAc, dried over MgS04 and concentrated. The crude product was purified by flash chromatography eluting with 1:1 hexane/EtOAc to give 73 mg of the title product.
1 H NMR (CD3COCD3) 8 1.62 (6H, s), 3.15 (3H, s), 7.02 (2H, dd), 7.40 i s (2H, dd), 7.65 (2H, d), 8.03 (2H, d).

2-ll4-aminosulfonyllphenv~-3-(4-fluoro hen, llthiophene 1H NMR (CD3COCD3) S 6.60 (2H, bs), 7.12 (2H, t), 7.25 (1H, d), 7.35 (2H, m), 7.45 (2H, d), 7.65 (1 H, d), 7.85 (2H, d).
Analysis calculated for C16H12f''NS202 2 s C, 57.65; H, 3.60; N, 4.20 Found: C, 57.55; H, 3.79; N, 4.03 3 0 3_(4-(Trifluoroacetvlaminosulfonvllphenyll-2-(4-fluoronhenyllthiophene 1H NMR (300 MHz, CD3COCD3) 8 7.15 (2H, t), 7.30 (3H, m), 7.45 (2H, d), 7.65 ( 1 H, d), 7.95 (2H, d).

3-12.4-Difluorophenvl)-4-(4-(methxlsulfonyl)phen~)-2-(51~-furanone _ Analysis calculated for C1~H12F204S
C, 58.28; H, 3.45; S, 9.15 1 o Found: C, 58.27; H, 3.50; S, 9.27 3-(3,4-Difluorophenyl)-4-(4-(methylsulfonyl~phenvI)-2-(SF~-furanone i 5 To a solution of 3,4-difluorophenylacetic acid (ALDRICH
CHIMICAL) (10 g) and 2-bromo-1-(4-(methylsulfonyl)phenyl)ethanone Example 9, Step 1 ) ( 17.3 g) in acetonitrile (200 mL) at room temperature was added slowly triethylamine (20.2 mL). After I h at room temperature, the mixture was cooled in an ice bath and treated with 17.4 2o mL of DBU. After 2 h at 0°C, the mixture was treated with 200 mL of HCl and the product was extracted with EtOAc, dried over Na2S04 and concentrated. The residue was applied on top of a silica gel plug (sintered glass funnel) eluted with 75% EtOAc/hexane, giving after evaporation of the solvent and swish in ethyl acetate, 10 g of the title compound.
Analysis calculated for C1~H12F204S
C, 58.28; H, 3.45; S~, 9.15 Found: C, 58.02; H, 3.51; S, 9.35 a o EXAMPLE 17 3_-(2 6-Difluorophenyll-4-(4-(meth ls~ ulfonyl)phenyl)-2-(SHl-furanone Analysis calculated for C1~H12F204S
C, 58.28; H, 3.45; S, 9.15 Found: C, 58.18; H, 3.50; S, 9.44 s 3-(2 5-Difluoro~h~ )-4-(4-(methvlsulfonvl)phenyl)-2-(S~II-furanone to Analysis calculated for C1~H12F2C)4S
C,58.28;H,3.45;S,9.15 Found: C, 58.89; H, 3.51; S, 9.11 3-~,3 5-Difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(SHl-furanone Analysis calculated for C1~H12F204S
C, 58.28; H, 3.45; S, 9.15 2o Found: C, 58.27; H, 3.62; S, 9.32 3-(4-Bromopheny~l)-4-(4-(methylsulfonyl)phenyl)-2-(SHl-furanone Analysis calculated for C1~H13Br04S
C, 51.94; H, 3.33; S, 8.16 Found: C, 51.76; H, 3.42; S, 8.21 a o EXAMPLE 21 3-(4-Chloronhenvl)-4-(4-(methylsulfonyl)phenyl)-2-(SHl-furanone 1 H NMR (300 MHz, CDC13) .8 7.93 (2H, d), 7.49 (2H, d), 7.35 (4H, m), 5.16 (2H, s), 3.06 (3H, s) 3-(4-MethoxXphenyll-4-(4-(methyl ulfon~rl)T enyl)-2-(SHl-furanone Analysis calculated for CigH1605S
to C, 62.78 H, 4.68; S, 9.31 Found: C, 62.75; H, 4.72; S, 9.39 3-(Phenyl)-4-(4-(meth 1 ulfonyl)phenyl)-2-(SHl-furanone To a solution of phenylacetic acid (27.4 g, 201 mmol) and 2-bromo-1-(4-(methylsulfonyl)phenyl)ethanone (Example 9, Step 1 ) (60 g, 216 mmol, 1.075 eq.) in acetonitrile (630 mL) at 25°C was added slowly triethyIamine (30.8 mL, 1.1 eq.). The mixture was stirred for 20 min. at 2o room temperature and then cooled in an ice bath. DBU (60.1 mL, 3 eq.) was slowly added. After stirring for 20 min. in the ice bath, the reaction was complete and the mixture was acidified with 1N HCI (color changes from dark brown to yellow). Then 2.4 L of ice and water were added, stirred for a few minutes, then the precipitate was filtered and rinsed with 2s water (giving 64 g of crude wet product). The solid was dissolved in 750 mL of dichloromethane (dried over MgS04, filtered) and 300 g of silica gel was added. The solvent was evaporated to near dryness (silica gel a bit ' sticky) and the residue was applied on top of a silica gel plug (sintered glass funnel) eluted with 10% EtOAc/CH2C12, giving after evaporation of the 3 o solvent and swish in ethyl acetate, 36.6 g (58%) of the title compound.

Analysis calculated for C1~H1404S
C, 64.95; H, 4.49; S, 10.20 Found: C, 64.63; H, 4.65; S, 10.44 s 3-(2-Chlorophen, I~4-(methylsulfonvl)phenyl)-2-(S~-furanone Analysis calculated for C1~H13C104S
C, 58.54; H, 3.76; S, 9.19 1 o Found: C, 58.59; H, 3.80; S, 9.37 3-(2-Bromo-4-fluorophenyl)-4-(4-~methylsulfonyl)phenyl)-2-(SH')-15 ~ranone Analysis calculated for C1~H12BrF04S
C, 49.75; H, 2.93 Found: C, 49.75; H, 3. 01 3-(2-Bromo-4-Chlorophenyl)-4-(4-(methylsulfonvl)phenyl)-2-(SI~-furanone 1H NMR (300 MHz, acetone-d6) 8 7.95 (2H, d), 7.85 (1H, d), 7.63 (2H, dd), 7.55 ( 1 H, dd), 7.45 ( 1 H, d), 5.50 (2H, s), 3.15 (3H, s) WO 95100501 . PCT/CA94/00318 3-(4-Chloro-2-fluorophenyl)-4-(4-(meth~sulfonyl)phenyll-2-(SH)-furanone 1H NMR (300 MHz, acetone-d6) 8 8.0 (2H, d), 7.70 (2H, d), 7.50-7.30 (3H, m), 5.35 (2h, s), 3.15 (3H, s) s 3-(3-Bromo-4-fluorophenyl)-4-(4-(meth ls~nvl)phenyl)-2-(SH~-furanone ~o Analysis calculated for C1~H12BrF04S
C, 49.75; H, 2.93 Found: C, 49.44; H, 2.98 1 s EXAMPLE 29 3-(3-Chlorophenyl)-4-(4-(meth lsy ulfonvllphenvl)-2-(SH)-furanone Analysis calculated for C 1 ~H 13C104S
C, 58.54; H, 3.76 2o Found: C, 58.29; H, 3.76 3-(2-Chloro-4-fluorophenvl)-4-(4-(meth, lsulfon~phenyl)-2-lSH)-25 ranone Analysis calculated for C1~H12C1F04S
' C, 55.67; H, 3.30 Found: C, 55.67; H, 3.26 WO 95!00501 PCTICA94100318 3-12.4-Dichloro~henvll-4-(4-(methylsulfonyl_lphenyl)-2-(SHl-furanone Analysis calculated for C 1 ~H 12C1204S
C, 53.28; H, 3.16; S, 8.37 , Found: C, 52.89; H, 3.23; S, 8.58 l0 3-(3.4-Dichlorophenyl)-4-(4-(methylsulfonyl~phenyl'~-2-(SH)-furanone Analysis calculated for C1~H12C1204S
C, 53.28; H, 3.16; S, 8.37 Found: C, 53.07; H, 3.32; S, 8.51 3- 2.6-Dichlorophenyl)-4-(4-(methylsulfonvl)phen"yl)-2-(SH)-furanone ~~ysis calculated for C1~H12C1204S
C, 53.28; H, 3.16; S, 8.37 Found: C, 52.99; H, 3.22; S, 8.54 3-(3-Chloro-4-fluoronhenvl)-4-(4-(methvlsulfonyl)phenvl)-2-(SHl-furanone .
1H NMR (300 MHz, acetone-d6) d 8.0 (2H, d), 7.70 (2H, d), 7.60 (1H, d), 3 0 7.25-7.40 (2H, m), S.3S (2H, s), 3.1 S (3H, s) WO 95/00501 PCTlCA94100318 3-(4-Trifluorometh,~phenvl)-4-(4-(methvlsulfonyl)phenyl)-2-(SHl-furanone s 1H ~R (CD3COCD3) 8 8.10 (2H, d), 7.82-7.93 (4H, m), 7.75 (2H, d), 5.55 (2H, s), 3.30 (3H, s) io 3-(3-Fluoro-4-methoxyphenyl)-4-(4-(meth lsulfonvl)phenvl)-2-(SHl-furanone Analysis calculated for C1gH15F05S
C, 59.66; H, 4.17 i s Found: C, 59.92; H, 4.37 3-(3-Chloro-4-methoxyphenvl)-4-(4-(methvlsulfon~phenvl)-2-(SH)-20 ~ranone Analysis calculated for CigH15C105S
C, 57.07; H, 3.99 Found: C, 57.29; H, 4.15 ' ~3-Bromo-4-methox,Yphenyl)-4-(4-(meth lsulfon 1)~Dhenyl)-2-(SH)-furanone Analysis calculated for C1gH15Br05S

C, 51.08; H, 3.57 Found: C, 51.38; H, 3.62 ~ ~ .

s 3-(2-FluorophenXl)-4-(4-(methylsulfon~phenyl)-2-(SHl-furanone Analysis 'calculated for C1~H13F04S
C, 61.44; H, 3.94 Found: C, 61.13; H, 3.85 la 3-(4-Meth, lv thiophen~l)-4-(4-~methylsulfonvl)phenyl)-2-(SI-~-furanone i s 1 H NMR (300 MHz, acetone-d6) d 8.0 (2H, d), 7.70 (2H, d), 7.35 (2H, d), 7.25 (2H, d), 5.35 (2H, s), 3.15 (3H, s), 2.55 (3H, s) 20 3_(3-Fluorophenyll-4.-(4-(methvlsulfonvl)phe~nvl,)-2-(SHl-furanone iH NMR (300 MHz, CDC13) d 7.93 (2H, d), 7.49 (2H, d), 7.35 (1H, m), 7.12 (3H, m), 5.18 (2H, s), 3.06 (3H, s) 2 s EXAMPLE 42 3-(2-Chloro-6-fluorophenvl)-4-f4-(methvlsulfo~~phen'rl)-2-(SH)-ranone 3 0 1H NMR (300 MHz, acetone-d6), d 8.0 (2H, d), 7.70 (2H, d), 7.55-7.65 (1H, m), 7.40 (1H, d), 7.30 (1H, m), 5.60 (2H, s), 3.15 (3H, s) 3 (3-Bromo-4-methyly=henvll-4-(4-(methvlsulfonvllohenvll-2-(SF~-fur_ anOne Analysis calculated for C1gH15Br04S
C, 53.08; H, 3.71 Found: C, 53.06; H, 3.83 i o EXAMPLE 44 3 (4-Bromo-2-fluoro~henvll-4-(4-(methvIsulfon ~~ll,phenvll-2-(SHl-furanone is Analysis calculated for C1~H12BrF04S
C, 49.65; H, 2.94 Found: C, 49.76; H, 3.00 3-(3 4-Dibromo~henyll-4-(4-(methylsulfonyllphenyl~-2-ISHI-furanone 1H NMR (300 MHz, acetone-d6) 8 8.0 (2H, d), 7.80 (1H, d), 7.75 (3H, m), 7.25 (1H, d), 5.35 (2H, s), 3.15 (sH, s) 3-(4-Chloro-3-fluoronhenyll-4-(4-(methylsulfon,~phenyl)-2-(SHl-ran a Analysis calculated for C1~H12C1F04S

C, 55.67; H, 3.30 Found: C, 55.45; H, 3.30 3 (4-Bromo-3-fluorophenyll-4-(4-(methylsulfonvllphenyll-2-(SHl-furanone y Analysis calculated for C1~H12BrF04S
C, 49.66; H, 2.94; S, 7.80 1 o Found: C, 49.79; H, 3.01; S, 7.51 3-(4-Bromo-2-chloro~henvl)-4-(4-(methylsulfonvl)phenvl)-2-(SH)-ranone Analysis calculated for C1~H12BrC104S
C, 47.74; H, 2.83; S, 7.50 Found: C, 47.92; H, 2.84; S, 7.42 3 ('2 Na~l; t~hvll-4-(4-(methylsulfonvl)phenvll-2-(SHE-furanone A~lysis calculated for CZ1H1604S
C, 69.22; H, 4.43 Found: C, 69.22; H, 4.46 3 (7-Ouinolinyl)-4-(4-(methxlsulfonyllphenyl)-2-(SHl-furanone WO 95!00501 PCTlCA94/00318 Analysis calculated for CZpH15NO4S
C, 65.74; H, 4.14; N, 3.83 Found: C, 65.34; H, 4.40; N, 3.80 M.S. (DCI, CH4) calculated for M+, 365 s Found for M++1, 366 3-(3.4-Dichlorophenyl?-4-(4-(aminosulfon~phenyll-2-(2Hl-furanone to 1H NMR (400 MHz, CD3COCD3) 8 7.92 (2H, dd), 7,64 (3H, dm), 7.60 (1H, dd), 7.32 (1H, dd), 6.70 (1H, bs), 5.38 (2H, s) is 3-(3.4-Difluorophenyll-4-(4-(aminosulfon~)phenyl!-2-(ZH~-furanone 1H NMR (400 MHz, CD3COCD3) 8 7.92 (2H, dd), 7,64 (2H, dd), 7.30-7.45 (2H, m), 7.22 (1H, m), 6.68 (2H, bs), 5.37 (2H, s) 3-(3-Chloro-4-methoxyphenyll-4-(4-(aminosulfon~~phenyl)-2-(2Hl-furanone Analysis calculated for CI~HI4C1NOSS
C, 53.76; H, 3.72, N, 3.69 Found: C, 53.32; H, 3.84, N, 3.59 M.S. (DCI, CH4) calculated for M+, 379 ~ Found for M++1, 380 3~3-Bromo-4-methoxyphenyll-4-(4-(aminosulfonyl_lphenvll-2-(21-~-furanone Analysis calculated for C1~H14BrNOSS
C, 48.13; H, 3.33, N, 3.30 Found: C, 48.26; H, 3.40, N, 3.28 i o M,S. (DCI, CH4) calculated for M+, 423 Found for M++1, 424 3-(phenyll-4-l4-(methvlsulfonYl_lphenyll-2-(51~-furanone Into a 20 ml glass ampule are added 1 g of 2-(4-(methylsulfonyl)phenyl)phenylacetylene, 20 mg of Rh4(CO) 1 Z, 1.5 g of Et3N, 10 ml of THF, 1 ml of water under nitrogen atmosphere, and the ampule is placed in a 100-ml stainless steel autoclave. The reaction system 2o is flushed three times with CO then charged at room temperature to a initial CO pressure of 100 atm. The reaction is carried at 100 °C for 5 h.
The solution is then diluted with 50 ml of benzene and washed with brine, 1N HCI. The benzene solution is dried over Na2S04, and concentrated.
The crude products are separated by column chromatography on silica gel 2 s eluted with 2:1 EtOAc/hexane to give the title compound and its regioisomer.

3 0 3_(phenvll-4-(4-(meth, ls~ ulfon~,~henvl~-2-~;~F~-furanone Step 1: 2-trimethylsilyloxy-4-(4-(meth 11~ thio~henyl~-3.4-dihvdrofuran To a solution of 3.86 g (19 mmol) of 4-bromothioanisole in 90 mL of Et20 cooled at -78°C, is added 22 mL of 1.7 M solution of t-BuLi in pentane (38 mmol) dropwise. The reaction mixture is stirred for 15 min at -78°C and 3.8 g of CuI is added and the reaction mixture is allowed to warm to -40 °C over a period of 30 min. A solution of I.7 g of 2(SH)-s furanone in 10 ml of THF is added. After stirring for 1 h, 2 ml of freshly distilled TMSCI is added dropwise. The reaction mixture is then treated with 2 ml of Et3N and 50 ml of sat. NaHC03, and extracted with 100 ml of ether. The ether layer is dried over Na2S04 and concentrated to the crude title compound which is used for the next step without further purification.
to St, ep 2: 4-(4-(methvlthio)phenyll-2-(SHl-furanone To a solution of 4 g of Pd(OAc)2 in 100 ml of acetonitrile is added dropwise the crude product from Step 1 (5 g) under nitrogen at room 1 s temperature. After 10 h at room temperature, the mixture is condensed under reduced pressure and the residue is purified by flash chromatography on silica gel eluted with 2:1 hexane/EtOAc to give the title . compound.
2o Ste ~ : 3-iodo-4-(4-(methvlthiolphenyll-2-(Sly-furanone To a solution of 3 g of the product of Step 2 in 30 ml of pyridine is added 8.7 g of I2. The mixture is stirred for 24 h and then diluted with 200 ml of ether, washed with 100 ml of 5N HCl and 50 ml of 2s 5N Na2S203. The ether layer is dried over Na2S04 and concentrated to give the title compound.
Step 4: 3-(Phenvll-4-(4-(methylthiolphenyll-2-(SH)-furanone 3o A mixture of 4 g of the product of Step 3, 3.7 g of PhB(OH)2, 0.4 g of Ph3As, 0.4 g of PdCl2(PhCN)2 in 100~m1 of benzene and 15 ml of WO 95!00501 PCTICA94/00318 2N NaOH is refluxed for 6 h. Ether(200 ml) is then added and the mixture is washed with 100 ml of saturated NaHC03. The organic layer is dried over MgS04 and concentrated. The residue is purified by flash chromatography on silica gel eluted with 4:1 hexane/EtOAc to give the title compound.
Step 5: 3-(Phenyl!-4-(4-(methylsulfon~~phenyl)-2-(SHl-furanone To a solution of 3 g of the product of Step 4 in 80 mL of 10:1 CH2C12/MeOH is added 5.5 g of MPPM. The reaction mixture is stirred at 1 o room temperature for 2 h and then diluted with 100 mL of 1:1 hexane/EtOAc. After filtration and concentration, the residue is purified by flash chromatography eluted with 2:1 EtOAc/hexane to give the title product.'

Claims (21)

1. A compound formula (I):

wherein:
R1 is selected from the group consisting of (a) S(O)2CH3 and (b) S(O)2NH2; and R2 is unsubstituted, mono- or di-substituted phenyl wherein the substituents are selected from the group consisting of halo, methoxy and methyl, said halo being selected from the group consisting of fluoro, chloro and bromo, for use in the relief or treatment of rheumatoid arthritis, osteoarthritis, fever, pain, headache or dysmenorrhea.
2. A compound according to claim 1, wherein R2 is unsubstituted, mono- or di-substituted phenyl wherein the substituents are selected from the group consisting of fluoro, chloro and bromo.
3. A compound according to claim 1, selected from (1) 2-(4-Fluorophenyl)-4-(4-(methylsulfonyl)-phenyl)-2-(5H)-furanone, (2) 3-(4-Fluorophenyl)-4-(4-(aminosulfonyl)-phenyl)-2-(5H)-furanone, (4) 3-(2,4-Difluorophenyl)-4-(4-(methylsulfonyl) phenyl)-2-(5H)-furanone, (5) 3-(3,4-Difluorophenyl)-4-(4-(methylsulfonyl) phenyl)-2-(5H)-furanone, (6) 3-(2,6-Difluorophenyl)-4-(4-(methylsulfonyl) phenyl)-2-(5H)-furanone, (7) 3-(2,5-Difluorophenyl)-4-(4-(methylsulfonyl) phenyl)-2-(5H)-furanone, (8) 3-(3,5-Difluorophenyl)-4-(4-(methylsulfonyl) phenyl)-2-(5H)-furanone, (9) 3-(4-Bromophenyl)-4-(4-(methylsulfonyl)-phenyl)-2-(5H)-furanone, (10) 3-(4-Chlorophenyl)-4-(4-(methylsulfonyl)-phenyl)-2-(5H)-furanone, (11) 3-(4-Methoxyphenyl)-4-(4-(methylsulfonyl) phenyl)-2-(5H)-furanone, (12) 3-(Phenyl)-4-(4-(methylsulfonyl)-phenyl)-2-(5H)-furanone, (13) 3-(2-Chlorophenyl)-4-(4-(methylsulfonyl)-phenyl)-2-(5H)-furanone, (14) 3-(2-Bromo-4-fluorophenyl)-4-(4-(methyl-sulfonyl)phenyl)-2-(5H) furanone, (15) 3-(2-Bromo-4-chlorophenyl)-4-(4-(methyl-sulfonyl)phenyl)-2-(5H)-furanone, (16) 3-(4-Chloro-2-fluorophenyl)-4-(4-(methyl-sulfonyl)phenyl)-2-(5H)-furanone, (17) 3-(3-Bromo-4-fluorophenyl)-4-(4-(methyl-sulfonyl)phenyl)-2-(5H)-furanone, (18) 3-(3-Chlorophenyl)-4-(4-methylsulfonyl)-phenyl-2-(5H)-furanone, (19) 3-(2-Chloro-4-fluorophenyl)-4-(4-(methyl sulfonyl)phenyl)-2-(5H)-furanone, (20) 3-(2,4-Dichlorophenyl)-4-(4-(methylsulfonyl) phenyl)-2-(5H)-furanone, (21) 3-(3,4-Dichlorophenyl)-4-(4-(methylsulfonyl) phenyl)-2-(5H)-furanone, (22) 3-(2,6-Dichlorophenyl)-4-(4-(methylsulfonyl) phenyl)-2-(5H)-furanone, (23) 3-(3-Chloro-4-fluorophenyl)-4-(4-methyl-sulphonyl)phenyl)-2-(5H)-furanone, (25) 3-(3-Fluoro-4-methoxyphenyl)-4-(4-(methyl-sulfonyl)phenyl)-2-(5H)-furanone, (26) 3-(3-Chloro-4-methoxyphenyl)-4-(4-(methyl-sulfonyl)phenyl)-2-(5H)-furanone, (27) 3-(3-Fluoro-4-methoxyphenyl)-4-(4-(methyl-sulfonyl)phenyl)-2-(5H)-furanone, (28) 3-(2-Fluorophenyl)-4-(4-methylsulfonyl)-phenyl)-2-(5H)-furanone, (30) 3-(3-Fluorophenyl)-4-(4-(methylsulfonyl)-phenyl)-2-(5H)-furanone, (31) 3-(2-Chloro-6-fluorophenyl)-4-(4-(methyl-sulfonyl)phenyl)-2-(5H)-furanone, (32) 3-(3-Bromo-4-methylphenyl)-4-(4-(methyl-sulfonyl)phenyl)-2-(5H)-furanone, (33) 3-(4-Bromo-2-fluorophenyl)-4-(4-(methyl-sulfonyl)phenyl)-2-(5H)-furanone, (34) 3-(3,4-Dibromophenyl)-4-(4-(methylsulfonyl) phenyl)-2-(5H)-furanone, (35) 3-(4-Chloro-3-fluorophenyl)-4-(4-(methyl-sulfonyl)phenyl)-2-(5H)-furanone, (36) 3-(4-Bromo-3-fluorophenyl)-4-(4-(methyl-sulfonyl)phenyl)-2-(5H)-furanone, (37) 3-(4-Bromo-2-chlorophenyl)-4-(4-(methyl-sulfonyl)phenyl)-2-(5H)-furanone, (40) 3-(3,4-Dichlorophenyl)-4-(4-(aminosulfonyl)-phenyl-2-(2H)-furanone, (41) 3-(3,4-Difluorophenyl)-4-(4-(aminosulfonyl)-phenyl)-2-(2H)-furanone, (42) 3-(3-Chloro-4-methoxyphenyl)-4-(4-(amino-sulfonyl)phenyl)-2-(2H)-furanone, and (43) 3-(3-Bromo-4-methoxyphenyl)-4-(4-(amino-sulfonyl)phenyl)-2-(2H)-furanone.
4. 3-(3,4-Difluorophenyl)-4-(4-(methylsulfonyl) phenyl)-2-(5H)-furanone, for use in the relief or treatment of rheumatoid arthritis, osteoarthritis, fever, pain, headache or dysmenorrhea.
5. 3-Phenyl-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone, for use in the relief or treatment of rheumatoid arthritis, osteoarthritis, fever, pain, headache or dysmenorrhea.
6. A pharmaceutical composition for relief or treatment of rheumatoid arthritis, osteoarthritis, fever, pain, headache or dysmenorrhea, comprising:
a non-toxic therapeutically effective amount of a compound according to claim 1, 2, 3, 4 or 5, in association with a carrier.
7. A compound of formula (I), as defined in claim 1, 2 or 3, for use in relief or treatment of rheumatoid arthritis.
8. The compound of claim 4, for use in relief or treatment of rheumatoid arthritis.
9. The compound of claim 5, for use in relief or treatment of rheumatoid arthritis.
10. Use of a compound of formula (I), as defined in claim 1, 2 or 3; in the manufacture of a medicament for the for use in the relief or treatment of rheumatoid arthritis, osteoarthritis, fever, pain, headache or dysmenorrhea.
11. Use of the compound of claim 4, in the manufacture of a medicament for the for use in the relief or treatment of rheumatoid arthritis, osteoarthritis, fever, pain, headache or dysmenorrhea.
12. Use of the compound of claim 5, in the manufacture of a medicament for the for use in the relief or treatment of rheumatoid arthritis, osteoarthritis, fever, pain, headache or dysmenorrhea..
13. A pharmaceutical composition for use in the relief or treatment of rheumatoid arthritis, osteoarthritis, fever, pain, headache or dysmenorrhea, comprising an acceptable anti-inflammatory amount of a compound of formula (I), as defined in claim 1, 2 or 3, in association with a pharmaceutically acceptable carrier.
14. A pharmaceutical composition for use in the relief or treatment of rheumatoid arthritis, osteoarthritis, fever, pain, headache or dysmenorrhea, comprising an acceptable therapeutically effective amount of the compound of claim 4, in association with a pharmaceutically acceptable carrier.
15. A pharmaceutical composition for use in the relief or treatment of rheumatoid arthritis, osteoarthritis, fever, pain, headache or dysmenorrhea, comprising an acceptable therapeutically effective amount of the compound of claim 5, in association with a pharmaceutically acceptable carrier.
16. Use of a compound of formula (I), as defined in claim 1, 2 or 3, in the relief or treatment of rheumatoid arthritis, osteoarthritis, fever, pain, headache or dysmenorrhea.
17. Use of the compound of claim 4, in the relief or treatment of rheumatoid arthritis, osteoarthritis, fever, pain, headache or dysmenorrhea.
18. Use of the compound of claim 5, in the relief or treatment of rheumatoid arthritis, osteoarthritis, fever, pain, headache or dysmenorrhea.
19. An antirheumatoid arthritis, pharmaceutical composition comprising an acceptable therapeutically effective amount of a compound of formula (I), as defined in claim 1, 2 or 3, in association with a pharmaceutically acceptable carrier.
20. An antirheumatoid arthritis, pharmaceutical composition comprising an acceptable therapeutically effective amount of the compound of claim 4, in association with a pharmaceutically acceptable carrier.
21. An antirheumatoid arthritis, pharmaceutical composition comprising an acceptable therapeutically effective amount of the compound of claim 5, in association with a pharmaceutically acceptable carrier.
CA002364039A 1993-06-24 1994-06-09 Use of phenyl heterocycles in the relief or treatment of rheumatoid arthritis, osteoarthritis, fever, pain, headache or dysmenorrhea Abandoned CA2364039A1 (en)

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CA002364039A Abandoned CA2364039A1 (en) 1993-06-24 1994-06-09 Use of phenyl heterocycles in the relief or treatment of rheumatoid arthritis, osteoarthritis, fever, pain, headache or dysmenorrhea
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