CA2176973C - Phenyl heterocycles as cyclooxygenase-2 inhibitors - Google Patents

Phenyl heterocycles as cyclooxygenase-2 inhibitors Download PDF

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CA2176973C
CA2176973C CA002176973A CA2176973A CA2176973C CA 2176973 C CA2176973 C CA 2176973C CA 002176973 A CA002176973 A CA 002176973A CA 2176973 A CA2176973 A CA 2176973A CA 2176973 C CA2176973 C CA 2176973C
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phenyl
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furanone
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Yves Ducharme
Jacques Yves Gauthier
Petpiboon Prasit
Yves Leblanc
Zhaoyin Wang
Serge Leger
Michel Therien
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Merck Frosst Canada and Co
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    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated

Abstract

Compounds useful in the treatment of cyclooxygenase-2- mediated diseases are provided of formula (I):
or a pharmaceutically acceptable salt thereof wherein:
X-Y-Z- is selected from the group consisting of:
(a) -CR5(R5')-O-C(O)- and (b) -C(O)-O-CR5'(R5')-' R1 is selected from the group consisting of (a) S(O)2CH3, (b) S(O)2NH2, (c) S(O)2NHC(O)CF3, (d) S(O)(NH)CH3, (e) S(O)(NH)NH2, (f) S(O)(NH)NHC(O)CF3, (g) P(O)(CH3)OH, and (h) P(O)(CH3)NH2, R2 is selected from the group consisting of (a) C1-6 alkyl, (b) C3, C4, C5, C6 and C7, cycloalkyl, (c) unsubstituted, mono-, di- or tri-substituted phenyl wherein the substituent is selected from the group consisting of (1) halo, (2) C1-6 alkoxy, (3) C1-6 alkylthio, (4) CN, (5) CF3, (6) C1-6 alkyl, (7) N3, (8) -CO2H, (9) -CO2C1-4 alkyl, (10) -C(R5)(R6)-OH, (11) -C(R5)(R6)-O-C1-4 alkyl, and (12) -C1-6 alkyl-CO2-R5;
(d) unsubstituted, mono-, di- or tri-substituted heteroaryl wherein the heteroaryl is a mono-cyclic 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 heteroaryl is a monocyclic ring of 6 atoms, said ring having one hetero atom which is N, and optionally 1,2 3 or 4 additional N atoms; and the substituents are selected from the group consisting of (1) halo, including fluoro, chloro, bromo and iodo, (2) C1-6 alkyl, (3) C1-6 alkoxy, (4) C1-6 alkylthio, (5) CN, (6) CF3, (7) N3, (8) -C (R5) (R6) -OH, and (9) -C (R5) (R6) -O-C1-4 alkyl;
R5 and R6 are independently selected from:
a) hydrogen, b) C1-6alkyl, or c) R5 and R6 together with the carbon to which they are attached form a monoclyclic ring of 3, 4, 5, 6 or 7 atoms; and each R5' is the same and is C1-6alkyl.

Description

BACKGROUND OF TI-II: INVLNTION
This invention relates to compounds and pharmaceutical compositions for the treatment of cyclooxygenase mediated diseases and methods of treatment thereof.
This Application is a Divisional of Canadian Patent Application Serial No.: 2,163,888, filed ,tune 9, 1994.
Non-steroidal, antiinflammatory drugs exert most of their antiinflannnatory, 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) 15 has been cloned, seduenced and characterized from chicken, uurine and human sources. rlhis 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 leave 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. W 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, horniones, 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, 2 ~ 76973 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. W 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 tn aspirin-sensitive asthmatic subjects.
SUMMARY OF THE INVENTION
The invention encompasses novel compounds of Formula 1 to useful in the treatment of cyclooxygenase-2 mediated diseases.
R~
R2 ~~ Z
-Y
The invention also encompasses certain pharmaceutical compositions and methods for treatment of cyclooxygenase-2 mediated diseases comprising the use of compounds of Formula I.
More especially the invention is concerned with the follow-ing compounds of formila (I) 2a R~
R2 / ~ Z
X-Y
or a pharmaceutically acceptable salt thereof wherein:
X-Y-Z- is selected from the group consisting of:
(a) -CR5 ~ (R5 ~ ) -O-C (O) - and (b) -C (O) -O-CR5 ~ (R5 ~ ) -, R1 is selected from the group consisting of (a) S (O) 2CH3, (b) S (O) 2NH2 , (c) S (O) 2NHC (O) CF3, (d) S (O) (NH) CH3, (e) S (O) (NH)NH2, ( f ) S (O) (NH) NHC (O) CF3 , (g) P (O) (CH3 ) OH, and (h) P(O) (CH3)NH2, R2 is selected from the group consisting of (a) C1_6 alkyl, (b) C3, C4, C5, C6 and C~, cycloalkyl, (c) unsubstituted, mono-, di- or tri-substituted phenyl wherein the substituent is selected from the group consisting of (1) halo, (2) C1_6 alkoxy, (3) C1_6 alkylthio, (4) CN, (5) CF3, (6) C1_6 alkyl, -Zb- 2176973 (7) N3, (8) -C02H, (9) -C02C1_4 alkyl, (10) -C (R5) (R6) -OH, (11) -C (R5) (R6) -O-C1_4 alkyl, and (12) -C1_6 alkyl-C02-R5;

(d) unsubstituted, mono-, di- or tri-substituted heteroaryl wherein the heteroaryl is a mono-cyclic 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 heteroaryl is a monocyclic ring of 6 atoms, said ring having one hetero atom which is N, and optionally 1, 2 3 or 4 additional N atoms; and the sub-stituents are selected from the group con-sisting of (1) halo, including fluoro, chloro, bromo and iodo, (2) C1-6 alkyl, (3) C1_6 alkoxy, (4) C1_6 alkylthio, (5) CN, (6) CF3, (7) N3, (8) -C(RS) (R6)-OH, and (9) -C(RS)(R6)-0-Cl_4 alkyl;

R5 and are independently selected from:

a) hydrogen, b) C1_6alkyl, or c) RS and R6 together with the carbon to which they are attached form a monoclyclic ring of 3, 4, 5, 6 or 7 atoms; and each RS' is the same and is C1_6alkyl.

A' Y

;YI' ~ 1 l ~ 9 l 3 DETAILED DESCRIPTION OF TI-IIJ INVCN~hION
The invention encompasses the novel compound of Formula I
useful in the treatment of cyclooxygeoase-2 mediated diseases R ~'~' Z
-Y
I
or pharmaceutically acceptable salts thereof wherein:
X-Y-Z-is selected from the group consisting of:
(a) _CH2CHZCH2-, (b) -C(O)CHZCH2_, (c) -CH2CH2C(O)-, (d) -CRS(R5~)-O-C(O)-, (e) -C(O)-O-CRS(RS )-' (~ -CH2-NR3-CH2-, (g) -CRS(R5~)-NR3-C(O)-, (h) -CR4=CR4~-S-, (i) -S-CR4=CR4~-, (j) -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-;
(q) -C(O)-NR3-CRS(R5~)-;

~~ ~6g73 YY

(r) -R3N-CH=CH- provided Rlis not -S(O)2Me (s) -CH=CH-NR3- provided R1 is not -S(O)2Me 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-CI-I=, (c) =N-S-CI-I=, (d) =CI-I-S-N=, .

l o (e) =N-O-CI-I=, (fj =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;

l s R 1 is ted from the group consisting of selec (a) S(O)2CH3, (b) S(O)2NH2, (c) S(O)~C(O)CF3, (d) S(O)(NH)CH3, 20 (e) S(O)(NH)NH2, (f) S(O)(NH)NHC(O)CF3, (g) P(O)(CH3)OH, and (h) P(O)(CH3)NH2, -R2 is selected from the group consisting of 25 (a) CI _6alkyl, (b) C3, Cq., C5, C(, and C~, 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) CI-6alkoxy, . ,~Y~
_5_ (4) C 1 _~alkyltliio, (5) CN, (7) Cl_~alkyl, (8) N3~
(g) _C02H, (10) -C02-Cl-q.alkyl, (11) -C(RS)(R6)-OH, (12) -C(RS)(R6)-O-Cl_4alkyl, and (13) -Cl_6alkyl-C02-R5;
(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 l, 2, or 3 additionally N atoms; or the heteroaryl is a monocyclic ring of 6 atoms, said ring i5 having one hetero atom which is N, and optionally l, 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_~alkyl, (4) Cl_6alkoxy, (5) Cl-~alkylthio, _ (6) CN, 2s (8) N3~
(9) -C(RS)(R6)-OH, and (10) -C(RS)(R~)-O-Cl-4alkyl;
(e) benzoheteroaryl which includes the benzo fused analogs of (d);
R3 is selected from the group consisting of (a) hydrogen, (b) CF3, 8YI' -(7-(c) CN, (d) C 1 _6alkyl, (e) hydroxyCl_6alkyl, (f) -C(O)-C1_6alkyl, (g)~ optionally substituted ( 1 ) -C 1 _5 alkyl-Q, (2) -Cl_3alkyl-O-C1_3alkyl-Q, (3) -Cl_3alkyl-S-C1_3alkyl-Q, (4) -Cl_$ alkyl-O-Q, or (5) -C 1 _5 alkyl-S-Q, 1 o wherein the substituent resides on the alkyl and the substituent is Cl_3alkyl;

(h) -Q

R4 and R4~ are each independently selected from the group consisting of (a) hydrogen, 1 s (b) CF3 (c) CN, (d) C1_~alkyl, (e) -Q

(f) -O-Q;

20 (g) _S_Q~ and (h) optionally substituted ( 1 ) -C 1 _5 alkyl-Q, (2) -O-C1_5 alkyl-Q, (3) -S-Cl_5 alkyl-Q, 25 (4) _Cl_3a~y1_O_C1-3alkyl-Q

(5) -C1_3alkyl-S-C1_3alkyl-Q, (6) -C 1 _5 alkyl-O-Q, (7) -C1_5 alkyl-S-Q, wherein the substituent resides on the alkyl and the substituent 3o is C1_3alkyl, and R5, RS~, R6, R~ and Rg are each independently selected i~rom the group consisting of (a) hydrogen, (b) C I _6alkyl, or RS and R~ 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-C1_4alkyl, tetrazolyl-5-yl, C(R~)(R~)(OH), or C(R~)(Rg)(O-C 1 _4alkyl);
io provided that when X-Y-Z is -S-CR'I= CR4~, then R'1 and R'~~ are other than CF3 .
In one aspect, within this embodiment are the compounds of formula I

2o R2 ~~~ cZ
-Y
I
or pharmacetically acceptable salts thereof wherein:
X-Y-Z- is selected from the group consisting of -C(O)-O-CRS(R5~)- when 25 side b is a double bond, and sides a and c are single bonds; and R1 is selected from the group consisting of (a) S(O)2CH3, (b) S(O)~1H2, R2 is selected from the group consisting of 3 0 (a) CI _~alkyl, (b) C3, C4, C5, C(, and C~, cycloalkyl, I _ yh _g_ (c) heteroaryl (d) benzoheteroaryl (e) 1110110- or di-substituted phenyl wherein the substituent is . selected from the group consisting of ( 1 ) hydrogefl, (2) halo, (3 ) C 1 _~alkoxy, (4) CI _~alkylthio, (5) CN, (6) CF3, t o (7) C l _6alkyl, N3~
(9) -C02H, ( 10) -C02-C 1 _q.alkyl, (I I ) -C( 5)(R6)-OH
i s ( 12) -C(RS)(R6)-O-C I _4alkyl, and ( 13 ) -C 1 _6alkyl-C02-R5;
R5, R5~ and R~ are each independently selected from the group conslstmg of (a) hydrogen, 20 (b) C1-6alkyl, or RS 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.
25 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) -CH2CHZC(O)-, (d) -CR5(R5~)-O-C(O)-, ~ ls~l3 (e) -C(O)-O_CR5(R5,)_~
(f) -CI-I2-NR3-CI-I2-, (g) -CRS(R5~)-NR3-C(O)-, (h) -CR4=CR4~-S-, (i) -S-CR4=CR4 -, (j) -S-N=CI-I-, (k) -CH=N-S-, (1) -N=CR4-O-, (m) -O-CR4=N- -(n) -N-CR4-NH-, l o (o) -N=CR4-S-, and (P) -S-CR4=N-, (9) -C(O)-NR3-CR5(R5 )-;
(r) -NR3-CH=CH- provided R1 is other than -S(O)ZMe, (s) -CH=CH-NR3- provided R1 is other than -S(O)ZMe.
Within this genus is the sub-genus of compounds of formula I
wherein R1 is selected from the group consisting of (a) S(O)2CH3, (b) S(O)~H2 (c) S(O)ZNHC(O)CF3, (d) S(O)NI-ICH3, (e) S(O)NHNH2, and (f) S(O)NHNHC(O)CF3;

R2 is ted from the group consisting of selec (a) C 1 _4a1kY1, (b) C3, C4, C5, C6, and C'7, cycloalkyl, (c) mono- or di-substituted phenyl wherein the substituent is selected from the group consisting of 3 0 ( 1 ) hydrogen, (2) fluoro, chloro, and bromo, 1. ,YP

(3) C1_4alkoxy, (4) C1 _4alkylthio, (5) CN, (7) C 1 _4alkyl, (8) N3, .

(9) -C02H, ( 10) -C02-C 1 _3 alkyl, (11) -C(RS)(R6)-OH, and (12) -C(RS)(R6)-O-C1_3alkyl, to (d) mono- or di-substituted heteroaryl selected from the group consi sting of ( 1 ) furanyl, (2) diazinyl, triazinyl and tetrazinyl, (3) iinidazolyl, 1 s (4) isooxazolyl, (5) isothiazolyl, (6) oxadiazolyl, (7) oxazolyl, (8) pyrazolyl, 20 (9) pyrrolyl, (10) thiadiazolyl, ( 11 ) thiazolyl, ( 12) thienyl, ( 13 ) triazolyl, and 2 5 ( 14) tetrazolyl, wherein said substituents are selected from the group consisting of (a) hydrogen, (b) fluoro, chloro, bromo, (c) C 1 _4alkoxy, 3 0 (d) C 1 _4alkylthio, (e) CN, ~~T~913 RYY

(S) CF3, (G) C 1 _q.alkyl, N3~
(g) -C(RS)(RG)-~H, -C(RS)(RG)-~-C 1-4alkyl.
s Within this sub-genus is the class of compounds of fomnula I
wherein R2 is select ed from the group consisting of (a) cyclohexyl, and to (b) mono- or di-substituted phenyl, and wherein the substitutents are selected from the group consisting of ( 1 ) hydrogen, (2) halo, (3) Cl_q.alkoxy, (4) C1-4alkylthio, (S) CN, (G) CF3, (7) C 1 _4alkyl, 20 (g) N3, and -C(RS)(RG)-~I-I;

R3 is select ed from the group consisting of (a) hydrogen, (b) CF3, 25 (c) C1_3alkyl and hydroxyCl_3alkyl, (d) CN, R4 and R4~ are each independently selected from the group consisting of (a) hydrogen, (b) CF3, 30 (c) C1_3alkyl, (d) CN, ~ l 6 ~ 73 ~YY

(e) chloro and fluoxo; and R5, RS~, R6, are each independently selected from tlae group consisting of (a) hydrogen, (b) methyl or ethyl, or IZS and R6 together with the carbon to which they are attached form a saturated carbon rilig of 4, 5 or 6 atoms, Within this class is the sub-class of compounds of formula 1 wherein X-Y-Z-is selected from the group consisting of:
(a) -CH2-O-C(O)-, l o (b) -C(O)-O-CI I2-, and (c) -CI12-NR3-C(O)-;
R 1 is selected from the group consisting of (a) S(O)2CH3, (b) S(O)2~~12~
15 (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 ( 1 ) hydrogen, (2) halo, selected from the group COllslstlllg of fluoro, chloro and bromo, (3) Cl_3alkoxy, (4) Cl-3alkylthio, 2s (5) CN, and (6) C1_3alkyl;
R3 is selected from the group consisting of (a) hydrogen, (b) CF3, (c) Cl_3alkyl and hydroxyCl_3alkyl.

d 16913 .. FYI' Within this sub-class is the group of COII7pOUIlds Of formula I
wherein _ X-Y-Z-is selected from the group consisting of:
(a) -CI-I2-O-C(O)-, and (b) -C(O)-O-CH2-, and R1 is selected from the group COIISIStIIlg of (a) S(O)2CI_I3, (b) S(O)2NI-IZ>
(c) S(O)NHCI-I3, and (d) S(O)NHNI-I2;
1 o 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 COIlslstlllg of fluoro, 15 chloro and bromo, -(3) methoxy, and (4) methyl.

This group tnay be more particularly defined as the 20 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 I is selected from the group consisting of 2s (a) S(O)2CH3, and (b) S(O)ZNH2, R2 is mono or di-substituted phenyl wherein the substitutents are selected from the group consistiilg of 3 0 ( 1 ) hydrogen, ~11b973 (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 R2 is a mono- di-substituted heteroaryl wherein hete~oaryl or is selected fro m the group COllslstlllg of ( 1 ) furanyl, (2) diazinyl, triazinyl, tetrazinyl, (3) imidazolyl, l o (4) isooxazolyl, (5) isothiazolyl, (6) oxadiazolyl, _ (7) oxazolyl, (8) pyrazolyl, y5 (9) pyrrolyl, (10) thiadiazolyl, ( 11 ) thiazolyl, ( 12) thienyl, (13) triazolyl, and 20 (14) tetrazolyl, wherein the substitutents are selected from the group consisting of (a) hydrogen, (b) fluoro or chloro, (c) C1_3alkoxy, (d) CI-(alkylthio, (e) CN, (5) CF3, (6) C1_3alkyl, 30 (~) -C

(8) -C(RS)(R6)-~-Cl-4alkyl.

~ 176973 Within this class there is the sub-class of compounds of fornmla I wherein R2 is a mono- or di-substituted heteroaryl wherein heteroaryl is selected fro m the group consisting of ( 1 ) 2-furanyl, (2) 3-furanyl, (3) 2-thienyl, (4) 3-thienyl, (5) 3-isoxazolyl, io (6) 4-isoxazolyl, (7) 5-isoxazolyl, (8) 3-isothiazolyl, (9) 4-isothiazolyl, (10) 5-isothiazolyl, i 5 ( 11 ) 2-oxazolyl, (12) 4-oxazolyl, (13) 5-oxazolyl, (14) 2-thiazolyl, (15) 4-thiazolyl, 20 (16) 5-thiazolyl, (17) 1,2,3-thiadiazol-4-yl, (18) 1,2,3-thiadiazol-5-yl, (19) 1,2,4-thiadiazol-3-yl, (20) 1,2,4-thiadiazol-5-yl, 2 s (21 ) 1,3,4-thiadiazol-2-yl, (22) 1,2;5-thiadiazol-3-yl, (23) 1,2,3-oxadiazol-4-yl, (24) 1,2,3-oxadiazol-5-yl, (25) 1,2,4-oxadiazol-3-yl, 3 0 (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, (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.

Within this sub-class there is the group of compounds of formula I wherein the heteroaryl is selected from the group COilslstlllg of ( 1 ) 3-isoxazolyl, (2) 4-isoxazolyl, (3) 5-isoxazolyl, (4) 3-isothiazolyl, (5) 4-isothiazolyl, (6) 5-isothiazolyl, (7) 2-oxazolyl, (8) 4-oxazolyl, (9) 5-oxazolyl, (10) 2-thiazolyl, ( 11 ) 4-thiazolyl, (12) 5-thiazolyl, (13) 1,2,3-thiadiazol-4-yl, 3 0 ( 14) 1,2,3-thiadiazol-5-yl, (15) 1,2,4-thiadiazol-3-yl, ~,, ~6~13 (16) 1,2,4-thiadiazol-5-yl, ( 17) 1,3,4-thiadiazol-2-yl, (18) 1,2,5-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 15 ( 1 ) 3-isothiazolyl, (2) 4-isothiazolyl, (3) 5-isothiazolyl, (4) 2-oxazolyl, (5) 4-oxazolyl, 20 (6) 5-oxazolyl, (7) 2-thiazolyl, (8) 4-thiazolyl, (9) 5-thiazolyl, ( 10) 1,2-diazinyl, 25 (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, 30 (3) C1_3alkoxy, (4) C1_3alkylthio, 2 ~ l 6 9 73 1 iYP

(5) CN, (6) Cl-3alkyl, and (7) -C(RS)(R~)-OII, 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 COllslstlllg of:
l o (a) _CH2_O_C(O)-, (b) -C(O)-O-CH2-, and (c) -CI I2-NR3-C(O)-;
R1 is selected from the group consisting of (a) S(O)2CH3, i 5 (b) S(O)2NIj2, (c) S(O)NHCH3, and (d) S(O)NHNH2, and R3 is selected from the group consisting of (a) hydrogen, 20 (b) CF3, (c) CI-3alkyl and hydroxyCl-3alkyl, (d) CN.
A second genus within the embodiment described above is the 25 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 (~) =N-S-CH=, (d) =CH-S-N=, 19028Y1' (e) =N-O-CI-I=, (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)~1H2, to (c) S(O)~THC(O)CF3, (d) S(O)(NH)CI-I3, (e) S(O)(NH)NH2, and (f) S(O)(NH)NHC(O)CF3;
R2 is selected from the group consisting of i s (a) C 1-4alkyl, (b) C3, Cq., C5, CG, and C'7, 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_q.alkoxy, (4) C 1-4alkylthio, (5) CN, (G) CF3, 2 s (7) C l _4alkyl, N3~

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

_. -tYI' (d) mono- or di-substituted heteroaryl 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, to (9) pyrrolyl, (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) C 1 _4alkoxy, 2 0 (d) C 1-4alkylthio, (e) CN, (5) CF3, (6) C1-q.alkyl, N3~

25 (8) _C

(9) -C(RS)(R6)-0-Cl-4alkyl.

For purposes of this specification the heretomyls of this sub-genus may be more particularly described in any of the maumers described 3 o above.
Within this sub-genus there is the class of compounds of formula I wherein R2 is selected from the group COIlslstlllg of (a) cyclohexyl, and (b)' mono or di substituted phenyl, and wherein the substitutents are selected from 'the group consisting of ( 1 ) hydrogen, (2) halo, (3) CI-q.alkoxy, l o (q.) C 1 _q.alkylthio, (5) CN, (G) CF3, (7) Cl_4alkyl, (8) N3, and i s (~) _C(RS)(R6)_pI-I;
R3 is selected from the group consisting of (a) hydrogen, _ (b) CF3, (c) CI-3alkyl and hydroxyCl-3alkyl, 20 (d) CN;
R5, RS~, RG, are 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 25 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=;
R1 is selected from the group consisting of (a) S(O)2CH3, and (b) S(O)2NH2;
R2 is selected from the group consisting of mono- or di-substituted phenyl wherein the substitutents are selected from the group consisting of ( 1 ) hydrogen, (2) halo, selected from the group COIlslstlllg of fluoro, chloro and bromo, to (3) C1-3alkoxy, (4) Cl_3alkylthio, (5) CF3, (6) C1_3alkyl;
R3 is selected from the group consisting of (a) hydrogen, (b) CF3, (c) Cl-3alkyl and hydroxyCl_3alkyl, RS and R6 are each selected from the group consisting of (a) hydrogen, (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 linear, branched, and cyclic structures, with C1_6alkyl including including methyl, ethyl, propyl, 2-propyl, s- and t-butyl, butyl, pentyl, hexyl, 1,1-dimethylethyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
Similarly, C1_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, C1_6alkylthio is intended to include alkylthio groups of from I to 6 carbon atoms of a straight, branched or cyclic configuration. Examples of lower alkylthio groups include methylthio, propylthio, isopropylthio, cycloheptylthio, elc.
By way of illustration, the propylthio group signifies -SCI-I2CI-I2CI-I3.
Heteroaryl includes furan, thiophene, pyrrole, isoxazole, isothiazole, pyrazole, oxazole, thiazole, irnidazole, 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, a«d the like.
to 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, (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-(methylsulfonyl)phenyl)thiophene-2-carboxylic acid, (f) 4-(4-Fluorophenyl)-2-methyl-S-(4-(methylsulfonyl)phenyl)thiazole, (g) 2-(4-Fluorophenyl)-3-(4-(methylsulfonyl)phenyl)-2-cyclopenten-1-one (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 o furanone, (k) 3-(4-Fluorophenyl)-4-(4-(methylsulfonyl)phenyl)furan, ._ 2176913 ~2sYE~
(I) 5,5-Dimethyl-3-(4-fluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(SIf )-furanonc, (m) 2-(4-(Aminosulfonyl)phenyl)-3-(4-fluorophenyl)thiophene, and (n) 3-(4-(Trifluoroacetylaminosulfonyl)phenyl)-2-(4-fluorophenyl)thiophene, ' (o) 3-(3-Fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(SH)-furanone, (p) 5,5-Dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(511)-furanone, l o (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-methylsulfonyl)phenyl)-2-(SF~-furanone, (u) 5,5-Dimethyl-3-(3,4-dichlorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(SH)-furanone, 20 (v) 5,5-Dimethyl-3-(4-chlorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(Std-furanone, (w) 3-(2-Naphyhyl)-4-(4-(methylsulfonyl)phenyl)-2-(SH)-furanone, (x) 5,5-Dimethyl-3-(2-naphyhyl)-4-(4-2 5 (methylsulfonyl)phenyl)-2-(SH)-furanone, (y) 3-phenyl-4-(4-(methylsulfonyl)phenyl)-2-(Stl)-furanone.
Further illustrating the invention are (a) 3-(3,4-Difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-3 0 (SH)-furanone, and ~28Y1' (b) 3-phenyl-4-(4-(methylsulfonyl)phenyl)-2-(Sll)-furanone, or a pharmaceutically acceptable salt thereof.
Some of the compounds described herein contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers. T'he 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 L
and Z geometric isomers.
W 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 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 1 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:
administration 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.

'~~~ ~, 21 l 6 9 ? 3 The pharmaceutical compositions of tl~e 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, to 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,N- dibenzylethylenediarnine, 1 s diethylamiile, 2-diethylaminoethanol, 2-dimethylaminoetlianol, ethanolamine, ethylenediamule, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabarnine, isopropylamille, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, 2o 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, 25 fever and inflammation of a variety of conditions including rheumatic fever, symptoms associated with influenza or other viral infections, common cold, low back and neck pain, dysmenorrhea, headache, toothache, sprains and strains, myositis, neuralgia, synovitis, arthritis, including rheumatoid arthritis degenerative joint diseases (osteoanthritis), gout and 3 o ankylosing spondylitis, bursitis, burns, injuries, following surgical and dental procedures. In addition, such a compound may inhibit cellular ~..~ ~)28YI' _ ~ l 1973 neoplastic transformations and metastic tumor growth and hence can be used in the treatment of cancer. Compounds of formula 1 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 ~rostanoid-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 to 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, 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 NSAID'S in preparations wherein they are presently co-administered with other agents or ingredients. Thus in further 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 phenylephriile, 2t1~913 .~028YP

phenylpropanolatnine, pseudophedrine, OXymetaz01117C, ep11111ephl'llle, naphazoline, xylornetazoline, propylhexedrine, or levo-desoxyeplledrine;
an antiitussive including codeine, Inydrocodone, caramiphen, carbetapentane, or dextramethorphan; a diuretic; a sedating or non-sedating antihistamine. In addition the invention encompasses a method of treating cyclooxygenase mediated diseases comprising: administration to a patient in need of such treatment a non-toxic tllerapeulically ei~fect amount of tile compound of Formula I, optionally co-administered with one or more of such ingredients as listed immediately above.
1 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 i 5 of this invention to treat cyclooxygenase mediated diseases can be demonstrated by measuring the amount of prostaglandin IJ2 (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 ao 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 pM. By way of comparison, Ibuprofen has an 1C50 for COX-2 of 1 pM, 25 and Indomethacin 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, 3 o adjuvants and vehicles. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection ,,~gYI, 217 ~ 9 7 3 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 s 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.
1 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 i s elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharnmceutically 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 2o 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 uncoated or they may be coated by known techniques to delay disintegration and absorption -in the gastrointestinal tract and thereby 2 s 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.
3 o Formulations for oral use may also be presented as hard gelatin capsules wherein the active iligredient is mixed with an inert solid 2~~b973 a,,o2sY1' diluent, for example, calcium carbonate, calcium pi~c~spluale 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 tile active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Suclu excipients are suspending agents, for example sodium carboxymelhyl-cellulose, methylcellulose, hydroxy-propylmethycellulose, 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 polyoxyethyleue sorbitol monooleate, or condensation products of ethylene oxide with partial esters i5 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.
2o 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, 25 and 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 ?8YP

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 paraffui or mixtures of these. Suitable emulsifying agents may be naturally-occurring phosphatides, for example soy bean, lecithin, ~md esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said to 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 i 5 formulations may also contain a demulcent, a preservative and flavoring and coloring agents. The phaunaceutical compositions may be in the form of a sterile injectable adueous or oleagenous suspension. This suspension may be formulated according to the known 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 25 oils are conventionally employed as a solvent or suspending medium. ror 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-~i 1597:1 irritating excipient which is solid at ordinary temperatures but liduid 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 admiliistration. 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 SOO mg of an active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 ~ng, 800 mg, or 1000 mg.
It will be understood, however, that the specific dose level for amy 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 Synthesis i X6973 ?sYo The compounds of the present invention can he prepared according to the following methods.
Method A:
The (3-chlorovinylaldehyde Ill can be obtained From the ketone Il and the Vilsmeier reagent (DMF-POC13) using the general method described by Weissenfels (Z. Chem. 1966, 6, 471 ). ~hlne thiophene compound IV is obtained from III using the general method described by Weissenfels (Z. Chem., 1973, 13, 57). The thiol con upound V can be obtained after oxidation of compound IV (Ra = -SMe) with one eduivalent to of m-CPBA followed by treatment of the resulting sulfoxide with TFAA at reflux. The sulfonamide group (VI) can then be founed 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 = II) can be treated with halogenating i 5 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 nitrite group at C-5, this can be accomplished from VI via amide fomnation using the Weinreb methodology (Tetrahedron Letters, 1977, 4171 ) followed by dehydration with TFAA. The CF3 group can be introduced at C-5 of VII
2 o via the method of Girard (J. Org. Chem. 1983, 48, 3220).
The introduction of an alkyl group at C-5 can be achieved via a Friedel-Crafts reaction on VII (R4 = H) and an acyl chloride, C1-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-I-I
25 reduction followed by deoxygenation using the method of Lau (J. Org.
Chem. 1986, 51, 3038). Tertiary alcohols (R4= - C(CI-I3)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 VIIL.

2 ~ X6913 w ,28YP

METHOD A
Ra i Ra . O /

O R2 1,2-dichloroethane CI R2 II Ra=-SMe or -S02Me III
Ra /
when Ra=S02Me to O and RZ =PhC02Me HS R2 ~ ~ 4 OMe S R HO-Py/Et3N IV ( R4=-C02Me~
Ra=S02Me' RZ =PhC02H
when Ra is SMe R4 =C02H
1. m-CPBA/CH2C12 H2N,S,0 2. T FAA ,, /
O
2o HS /
1.C12/HOAc 2. NH3 R S~ R4 R S~ R4 VI (R4=C02Me) V ( R4=-C02Me) H2N,S ~
1.H0-VI
2. Cu/quinoline R2 S R4 VII ( R4=H) ~sYn METHOD A CONT'D
R4 + R4= Br VII ~ ~ -- VII R4 = C1-C6alkyl R4 = CFs 1.amidation VI VI R4=CN
2. TFAA
to MeMgBr VI ~ VI (R4 = -C(CH3)20H) Ra R2 O ~ ~ ~ --'~ ~ / ~ 4 R1 ~ ' S~ R

VIII
Method B:
2o 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, duenching with nlethy( phosphoric dichloride and addition of water or ammonia (X' = OH or NH2). Similarly, the other regioisomer XIV can be prepared from ketone XIII.

?1T6913 asYP

METHOD B
Br Br /
\ ~ \
., O R2 R2 , S R4 X XI
1. n-BuLi ,O
-- H 3C _ P /
2. Me(CI)2P0 X
to \
3. H20 or NH3 S
XII X' = OH or NH2 / Br O \ I , -., X _ S~ R4 R2 H3C, ~~
XIII O XIV
X' = OH or NH2 2 5 Method C:
Bromination of ketone II gives the a-bromoketone XV which is then converted to the thiazole XVI after treaW ent with a thioamide.
Similarly, ketone VIII can be converted to thiazole XVII.

2gYP 2176973 METHOD C
S

s I I B r? R~2 Br ( \
/ Ra Ra / XV
S
Rz ~N~-Ra ~ s xvl Ra S /
4/ \ \ ~-2o VIII Br2 R NH2 2 // N 4 R S~ R
XVI I
Method D:
2s 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.

.4 ~8YF' 217b 9 7 3 METHOD D
R /
. R4 NHz '~ N
XV -- Rz~ ~~ R4 ~V H
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 pyrole can be acylated with Cl-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 ~e0~0 O
R ~ ~'2 1 ~ ~ ~ MeO~N~ Me0 R
XIX NaH/DMF O°C to r.t ~NHz H ~ ~ ~Ral. Rz N
3o R3 XX

.~.,,BYf' 21 ~f~~73 Method F:
The compounds of type XXV can be prepared i~rom readily available 4-substituted phenylacetyl chlorides XXIa. Reaction of di(3-butenyl)cadmium with a 4-substituted phenylacetyl chloride provides ketone XXI. Ozonolysis of XXl 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 XXIV with pyridinium chlorochromate affords the desired 2,3-disubstituted cyclopentenone XXV. ror preparation of compound XXV
(RI=S02Me), 4-methylthiophenyllithium is used followed by oxidation to with the magesium salt of monoperoxyphthalic acid (MMI'P) or m-chloroperoxybenzoic acid (mCPBA) to introduce the reduired methylsulfonyl group in XXV.

?8YI' METHOD F
O

CI
XXIa XX I

i to w O

R2 NaOMe ~ XXiil --~.
XXIb XXI I

/ \
2o HO, PCC
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. R2 is introduced at a later stage via a carbonyl addition reaction, followed by PCC oxidation.

J~g'~'~ 21 ? 6 9 l 3 METHOD G
,O. / R~ O / R1 \ (~~d \ \
CI ' R' R1 to 1. 03 --~ R2M HO
2. NaOMe PCC
R
O
XXV I
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 III
(Ra=S02Me) or XXVII is treated with excess NH4SCN in reFluxing acetone to provide the corresponding 4,5-disubstituted isothiazoles XXX

21769,73 and XXVIII, oxidation of which with hydrogen peroxide yields XXXI and XXIX.
METHOD H
Me02S ~ S02Me VIII ~ I CI
---~ ~ NH4SCN H202, AcOH

(Ra = S02Me) R CHO R2 / S
-N
XXVII
XXVIII
to S02Me Me02S
I ~ w ~ CHO NH4SCN
O _ R2 / S! O R I CI
NH
O III (Ra = S02Me) XXIX
S02Me S02Me I\
i i H202, AcOH
Rz / ~ R2 / O
S-N O:S-NH
O
XXX
Method I:
XXXI
3 o An appropriately substituted aryl bromomethyl ketone is reacted with an appropriately substituted aryl acetic acid in a solvent such 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 XXXIII or XXXV.
METHOD I
, R1 R~
R2nC02H

1 o Base I
Br O O
O
XXXI I - XXXI I I

O \
R2~ Br Base R2 / O
2o H02C p XXXIV XXXV
R2 is a mono- or disubstituted phenyl or a mono- or disubstituted heteroaryl Method J:
Either of the lactones XXXIII or XXXV in a solvent such as THF is reacted with a reducing agent such as diisobutyl aluminium hydride 3 0 or lithium borohydride at -78°C, to yield the furan XXXVI.

'28YP

METHOD J
R' XXXIII
or 1. DIBAL-H
XXXV
2. H+
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. -is ~~ 16973 19028Yf' METHOD K

/ ~ ~ \
R2~CONHR3 /
Base Br O R2 /
to NR3 XXXI I O
XXXV I I

O I \
R2~ Br /
\ Base 2o CONHR3 NR3 XXXV I 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 lactose XLV by base catalysis. Oxidation of XLV with MMPP or mCPBA affords the desired product XLVI.

_. 2 ~ 16973 m28Y1' METHOD L
SMe .OH
OTMS
OMe TMSCI
OMe Li O imidazole O
XL XLI
1o OTMS / SMe OH SMe N-Bu4NF
~ ' w XLII XLIII
~5 F
/ \

\ / F
CI
O O / SMe Pyridine, DMAP / -O
XLIV
F
DBU
SMe XLV I 5U2Me XLV

mo~~Yl>

METHOD M
SMe Aq. base OH / SMe \ I org. solvent Phase O transfer O
catalyst XLV I I XL I I I
l 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, adueous 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 temperature to provide XLIII. Compound XLIII is also described in U.S.
4,321,118 and Org. Coat. 1986, C, 175-95.
Method N
, R

CO, tlz0 tR ~ ~ ~G'-R2 + \
solvent, catalyst O
/ R~

By reacting an acetylene XLVIII with carbon monoxide and water in the presence of suitable catalysts, a mixture of compound XXXIII
30, and its isomer XXXV 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 HCl and EtOI-I, ..~ 217~9~~
Iy028Y1' heated at 50-150°C and 50-150 atmospheres of pressure, or Rh4 (CO) 12 (or Rh((CO) I b) in adueous TI IF (or acetone, acetonitrile, benzene, toluene,.EtOH, MeOH) containing a trialkylamine, at 50-150°C and 20-300 atmospheres pressure. See Takahashi et al., Org~anoniettullics~ 1991, 10, 2493-2498; and Tsuji et. al., J. Am. Chej~a. Soc. 1966, 88, 1289-1292.
Method O
/ SMe l0 M ~ ~ SMe 1. cux(x-cl,ur,l) O ~ + 2. 'I'MSCI O
solvent p M=Li,Mg . TMSO LI
XLIX L
SMe SMe /
Pd(OAc)2/Cu(OAc)2, OZ ~ ~ Iz. PY~idiuc v or I'I>IO/l'MSN3, u-I3u4N1~ O
O
LlI - LIII
SMe / S(~)2Me /
(I10)Zl3R LIV ~ ~ [O[
O ~ . ~ O K ---- alkyl, aryl Pdo ~R O R
LV
LVI
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 >> z~ l69»

and Cu(OAc)2 and 02 in Me0I1 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 LIII.
Palladium catalyzed Susuki or Stifle coupling of LIlI wily 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, MMPI' or II202 to give the desired compound LVI. See Y. Ito et. al., J. A~ri. C~iem. 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

XXXIII
comprising:

> z~ 169~~
-SO-(al) reacting in an organic solvent a compound of formula XXXII' R' ' /

\

XXXI I' to with a bromide 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 W elude, 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, CuBr2, and N-bromosuccinimide.
(a2) reacting in a non-aqueous polar solv_ ent a compound of formula with a compound of formula R2~ C02H
3 o in the presence of a base to produce a compound of formula A

- sl -/
, O O II 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 founula 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 is defined to include, but not be limited to a tri-CI-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, tine invention is directed to a process of making a compound of formula XXXIII

~

/

O

O

XXXIII

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

w O
O
XXXV
For purposes of this specification suitable catalysis include, but 2 o al-e not limited to Ru4(CO) 12, Co2(CO)g or PdCl2 in aqueous THF or acetone, acetonitrile, benzene, toluene, methyl alcohol or ethyl alcohol.
In a second alternative, the ilivention is directed to a process of making a compound of formula XXXIII

2'76973 O

O

XXXIII
1 o comprising:
(cl) reacting a compound of formula Llll /

I /

O

LIII
with a reagent of the formula (HO)2BR2 in 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 ~1769?3 O

O

LV
l 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 intended to include, but not be limited to benzene, toluene, 1'HF, Me0lI, DME or EtOH.
In all of the process alternatives, R I and RZ are as defined above for the portion of Detailed Description and Claims directed to the 2 o compounds of formula I.
Representative Compounds Tables I and II illustrate compounds of formula 1.

ew ,28YP
~1 T6913 - $$ -fable I
Lxan~ple Method . , ~ SOZNH2 w I 1 A
/ \ ' S
OH I i F

/ \ v 2 A
S ~~~
F
~S02NH2 / \ 3 A
Me S I ~
Me / \ 4 A
S
S02Me / \ 5 A
H02C Sue' F
~ \ v \ 6 C
Me S
SO Me .::.,2gY,~ 2 ~ 7 6 9 7 3 -s~-Table I (continued) i F Cxample Method . O w ~ _ ~ ~~ 7 F
S02Me F

to S02Me 9 t S02Me r i 10 t Table I~continuec~
IJxatnple Method i I F , O , I ~ 11 J
SOZMe C

S02Me F

2o S

S02NHC(O)CF3 S
F

-sg-Table I continued) Lxample Method S02Me F
O
v ~F
to O \ I ~ 16 I
S02Me S02Me F i O ~ I~ F
O ~ ~ 18 I
~S02Me F

S02Me _~~gy,, 2116973 -s~-'liable I ('continued) example Method O
O ~ ~~ 20 I
i S02Me ~I

SOZMe 7Me S02Me i O
2o O ~ I ~ 23 I
S02Me S02Me .~-,Z~,.,~ 21 l 6 9 7 3 -~o-rI'able I continued) Br i F IJxanuple Method O
O ~ y 25 I
i S02Me _ _I
SOZMe r n S02Me r S02Me i O ~ CI
O \ ( w 29 I
S02Me 217b973 Table I ~~continued) CI i .F ~xacnple Method O
O \ ~ 3~ I;
S02Me I
to I

S02Me ';I

S02Me S02Me ,. F
O ~ I CI
O \ I ~ 34 t S02Me 2I l b973 8YI' . Table I~continue~
CF3 Lxample Method O w_ ~
O \ ~ 35 I' i S02Me '~Me to I

S02Me 7Me 'I

S02Me 7Me ;r S02Me F
O
O \ I ~ 39 I
S02Me . ,sYP 21 l 6 9 l 3 'fable I (continuecl~
SMe i Example Method O
~ 40 I.
O
S02Me S02Me S02Me '~e 3r SOzMe F ~ Br O
O \ \ 44 I
i ~S02Me ~.._... _.~....~

~ ~ 16913 1yU28YP

Table I continued) Br / example Method O \ I Br O ~ \ 45 I;
/
S02Me ~I

S02Me ~r S02Me CI , Br O \
O. ~ \ 48 I
v ~ S02Me / I \
~ \ /
O.. ~ I \ 49 I
/ S02Me 2i7b913 - b5 -rhahle I Lcontinueci~
~xaunple Method 5~ I ;
~02Me ~I
to I

7Me ;) '~Me r 54 i a 2116973 rI'able I (continued) Example Method F
\
i N.S
S02Me 10 ~ S02Me 56 L+M
O ~ I \ CI
O
15 "72Me 57 L+M
SOZMe L+M

O \ ~ \ F
O ~ F

Z l l b913 Table I (continued IJxample Method ~ S02Me , 5g L+M
p ~ ~ CI
O v _CI
to "02Me 60 L+M
- CI

sY>>

Table II
r Me "02NH2 SOzNH2 F
S02NHz to S
OH
"02NH2 FsC FsC
. F S02NH2 ,.02NHz -OMe OMe ~Y'' 21 l 6 9 l 3 Table II ~continued~
~Me r Me ~02NH2 r F

F

~02NH2 - ~02NH2 OMe OMe FYI' 217b973 Table Il~continueci~
OH
-, . , H

~JZNHZ
OH
OH ''~ ~IH2 ~J2NH2 ~~ NH2 C02H
C02H ,;OZN H2 i OH

Met 3 0 ~02N H2 ~J2N H2 OH

Table II continued) ~'~2NH2 Me ~J2NH2 F
to Me S
OH
OH
°~2NH2 ,y~2~Yh 2 I l b 9 7 3 Tahle II ~continued~
r C

to "~2NH2 "02NH2 C C
CI
S02Me 2 0 ~, HN
O v 'F

.BYY

Table II (continued "02NH2 Hf~ Hf~
to S02NHz F

HN ' O v _F
C
n~2NH2 nO2NH2 F F

8YI' Table II (continuted) _ r S02NH2 S02Me ~02Me ~02NH2 HN H~
F F
~02NH2 ~02NH2 C C
CI Br ~02NH2 C
Br '8YP

Table II (continued ''02NH2 , ~OzNH2 F
F F
1 0 r,l r "02NH2 S02NH2 Me F ~F
r r r 3o S02NH2 S02NH2 ~t?b973 mo2sYn Table II ~concluded~
c~ ~ n y ~~2NH2 2 S02Nk~2 OH
to ~ ~02NH2 ~72N H2 02Me CI '~ CI
2o S02Me S02NH2 S02Me ~ n m 1902a ~ ~
_ 77 _ Table II concluded r~'J2N H2 ''~2ME "~2N H2 Me M Me .. F . -- CI " CI
to n02Me . S02Me SOZNH2 M
Me 2o S02Me S02NH2 S02Me C
CI
SO Me S02NH2 S02NH2 z C
C
CI
CI

mono , a _ 78 _ Table II (concluded SO Me S02NH2 Me M Me F F CI
to S02Me ~02Me "02N H2 Me Me Me , CI CI
CI CI CI
2 o S02Me S02N H2 S02Me C ( _ C
OMe F F
S02Me S02N H2 S02Me 30.
OMe CI CI

~t ?u973 t X02« . ~~

Table II (concluded) ~02NH2 . 02Me Me F F
F OMe F
to ''~2N H2 SOZMe 02Me Me OMe -- OMe OMe 2 o S02Me S02N H2 S02Me C C C
Me Me Me S02Me S02N H2 S02Me Me Me Me zxYU

Assays for Determinin~~ical ActivitX
The compound of Formula I can be tested using the following assays to determine their cyclooxygenase-2 inhibiting activity.
Inhibition of Cyclooxygenase Activity Compounds were tested as inhibitors of cyclooxygenase activity in whole cell and rnicrosomal cyclooxygenase assays. Bot(i of these assays measured prostaglandin E2 (PGE2) synthesis in response to arachidonic acid, using a radi.oimmunoassay. Cells used for whole cell to assays, and from which microsomes were prepared for rnicrosomal 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 tl~e difference between prostaglandin E2 synthesis in the absence and presence 15 pf arachidonate addition. IC50 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 °~o methocel) or a test compound at 9 - 10 am. One hr later, a line was drawn using a penmnent 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 usiilg 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 19028Y1' - ~l -increases in paw volume (V3t, - Vpt,) were calculated. rhhe animals were euthanized by C02 aphyxiation and the absence or presence of stomach lesions scored. Stomach scores were expressed as the su~» o(' total lesions in mm. Paw edema data were compared with the vehicle-control group and percent inhibition calculated taking the values in th a 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.
to 211b913 19U28Y1' rI'AI3LE lIl'~
Whole Cells ~ Microsomes Example Conc. COX-2 COX-1 Conc. COX-2 COX-1 (nM) % inhib.% inhib. (nM) % inhib.% inhib.

to ao 12 100 54 2s 14 1000 101 1000 69 0 211b973 Example Conc. COX-2 COX-1 Conc. COX-2 COX-1 (nM) % inllib.% inhib. (nM) % inhib. % inhib.

15 ~ 80 7G

l0 17 40 41 i5 19 160 59 ,2sY~

Example Conc. COX-2 COX-1 Cooc. COX-2 COX-I
(nM) % irihib.% inhih. (nM) lo inhib.~o inliib.
io 32 5 43 is 34 10 30 2s 37 10 53 . . ~,Z8Y1~

example Conc. COX-2 COX-1 Conc. COX-2 COX-1 (nM) % inhib. ~o inhib. (nM) % inhib. ~o inhib.
40 ~ 10 43 l0 42 160 44 2s 47 160 101 z~ T~9~~
~8Y1' Example Conc. COX-2 COX-1 Conc. COX-2 COX-1 (nM) % inhib.% inhib. (nM) % inhib.% inhib.
51 ~ 20 95 l0 53 40 96 i5 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.

2~7697~

TABLE IV
ED30On~ STRUCTURE
3.00 / S02Me S
F
> 10.00 / S02Me w S
F

,2~,.~~ 21 l 6 9 l3 1.40 / S02NH2 S /

F

to 2.80 / S02Me (in 1 %

methocel) 0.72 O

/

F

2o S02Me 0.43 O

F

3.00 / S02NH2 \
HO S /
F
to >3.00 / S02NH2 3 .00 \
s /
F
1.10 / S02Me N
~S
F

2~Y1' <0.30 / F
p S, / ' to 0.42 / S02Me O
15 ~ /
. O
F
0.034 / I S02NH2 O
/
F

~~76913 2.03 / S02Me O
O
F F
to 1.49 / S02Me O F
/I

\ _ F
20 0.35 ~ / S02Me O
O
25 \
F
F

~sY~~

0.33 / S02Me O
O \ ' Br to 0.90 , I S02Me O
i \ _ CI
20 0.38 . / S02Me O
25 O \

_ .zgYF~ ~ ~ ~ 6 9 l 3 0.88 / S02Me O
Br \
CI
to 0.47 / S02Me O
I

F \
CI
20 0.71 / SOZMe \I
O
i O
25 \ _ CI

1.00 / S02Me O
Br -i O \
F
to 1.85 / S02Me O
i O
CI \
CI
0.22 , S02Me 0.23 O
CI
i /
O
\
CI

'.8YY 21 l 6 9 l 3 0.43 , S02Me O
CI
O ~ ' \
F
to 2.17 , S02Me O
i 2o SO Me 0.81 O
F
OMe :»lBYF' 0.68 / S02Me O
CI

O M e_ to 0.16 / S02Me O

1.00 / S02Me o ~ _ 25 ~ /

SMe ._ 2 ~ ~6~1 ~
._ ~28YI' 0.33 / S02Me ., O
p I /I
O \ _ F
0.46 ~ / S02Me i5 ~ /
O

Br 0.76 / SO~Me O
/ Br O
Br ._. ~ ~ ~ 6 913 1 ~028YI' 0.48 / S02NH2 O
I
. O
F
F
to 0.46 / S02NH2 O
CI
CI
0.26 / S02Me O
O
CI
F

In028YI' 0.55 / I S02Me O
O \
Br F
to 0.25 , I S02Me O
I
O \
CI
0.1-.3 / I S02Me O
O
\ \

217b913 19U28Y1' 0.10 / I S02Me O ~ , /
O
F
F
0.13 / S02Me O
~ /
O
CI
CI
0.07 / S02Me O
CI

_~cYP

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 to those obtained for the materials prepared as described; polymorphism may result in isolation of materials with different melting points in some preparations; the stmcture and purity of all final products were assured by at least one of the following technidues: 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 (c~) values for major diagnostic protons, given in ports 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; ete.: 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-(dimethylaznino)pyridine ~~~6913 DMF - N,N-dimethylformamide Et3N - triethylamine LDA - lithium diisopropylamide m-CPBA - ~ metachloroperbenzoic acid M1V1PI' - ~ monoperoxyphlalic acid MPPM - monoperoxyplUl~alic acid, m~ynesimn salt Ms - methanesulfonyl = mesyl'= S02Me Ms0 - melhanesulfonate = cnesylate NSAID - non-steroidal anti-inflammatory drug to OXONEO = 2KHS05KHSOq.K2S0~.

PCC - pyridinium chlorochromate PDC - pyridinium dichromate Ph - phenyl Phe - benzenediyl i 5 Pye - pyridinediyl r.t. - room temperature rac. - racemic SAM - aminosulfonyl or sulfona~j~id~: or 2o TBAF - t:etra-n-butylammonium fluoride ~I h - 2- or 3-thienyl TFAA - trifluoroacetic acid anhydride THF - tetrahydrofuran Thi - thiophenediyl 25 TLC - thin layer chromatography TMS-CN - trimethylsilyl cyanide 'rz - IH (or 2H)-tetrazol-5-yl C3H5 - allyl 3 o Alkyl Group Abbreviations Me - methyl ~1?6973 .28YP

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 1y028Y(' EXAMPhI? l 3-(4-Aminosulfonyl)phenyl)-2-(4-Fluorophenyl)-5-(2-hydroxy-2-pro~ 1)y t~110phene Step l: 1-(4-Fluorophenyl)-2- 4-(meth ltd llio)phenvl)etlanone To 4-fluorobenzaldehyde (5.40 g) in 1,2-dichloroethane (43.50 I11L) were added TMS-CN (4.32 g) and Znl2 (44 rng). After 0.5 h at r.t., the solvent was removed iv vacc~o. To the resulting TMS
cyanohydrin (9.20 g) in TI-IF (42.0 mL) at -78°C was added dropwise a to solution of LDA O.S1M in rhHF (88.9 mL). After a period of 0.5 h, a TIIh 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 15 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): ~ 2.45 (3H, s), 4.34 (2I-1, s), 7.19-7.29 (6I-I, m), 8.14 (2H, q).
Step 2: Cis,traps-3-chloro-3-(4-fluorophenyl)-2-(4-(methylthio)-phenyl~pro~enal 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 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, 2s), 6.90-7.80 (8H, m), 9.55 (1H, s).

~~76973 1y028YP

Step 3: 5-(4-Fluorophenyl)-4-(4-(methylthio)phenyl)thiophene-2-carboxylic 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 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 with 3N HCI, the title product was purified by flash chromatography (30% EtOAc in hexane) (2.00 g).
I H NMR (CD3COCD3): 8 2.48 (3II, s), 3.88 (3I-I, s), 7.11 (2I-I, 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 5 thiophene-2-carboxylic acid methyl ester (5.60 g) in CH2C12 (84.0 mL) at 0°C was added portionwise m-CPBA 50 to 60% (5.39 g). After TLC
showed completion (50% EtOAe 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), IIl NMR (CD3COCD3): b 2.75 (3II, s), 3.92 (3I-I, s), 7.15 (2I-I, t), 7.40 (2H, q), 7.52 (2H, d), 7.66 (2II, d), 7.90 (III, s).
Step 5: 4-(4-(Aminosulfonyl)phenyl)-5-(4-fluorophenyl)thiophene-2-2 5 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 vucuo 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 ..
u~o2sY~

HOAc (1.9M) (3.5 mL). After 20 min., the solvent was removed under reduced pressure and after pumping, rI HF (20.0 mL) was added to the resulting mass of product. After bubbling NI-I3 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).
1H NMR (CD3COCD3): ~ 3,90 (31I, s), 6.55 (2I-I, bs), 7.13 (2H, t), 7.40 (2H, q), 7.46 (2H, d), 7.83 (2I-I, d), 7.90 (III, s).
1 o Step 6: 3-(4-Aminosulfonyl)phenyl)-2-(4-fluorophenyl)-5-(2-h dy roxy-2-propyl)thioahene To 4-(4-aminosulfonyl)phenyl)-5-(4-fluorophenyl)thiophene-2-carboxylic acid methyl ester (0.460 g) in TI-IF (5.70 mL) at 0°C was added MeMgBr (1.4M) in toluene-THF solution (5.00 mL). The mixture 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).
1H NMR (CD3COCD3): ~ 1.65 (6I-I, s), 4.52 (1H, s), 6.55 (2I-I, bs), 7.09 (3H, m), 7.34 (2H, dd), 7.30 (2I-I, m), 7.43 (2I-I, d), 7.82 (2I-I, d). Anal.
calcd. for C19HI8FN03S2; C, 58.31; I-i, 4.60; N, 3.58. Found: C, 57.94;
H, 4.66; N, 3.44 3-(4-(Aminosulfonyl)phenyl)-2-(4-fluorophenyl)thiophene Step 1: 4-(4-(Aminosulfonyl)phenyl)-5-(4-fluorophenyl)thiophene-2-carboxylic acid 3 o To a solution of 4-(4-(aminosulfonyl)phenyl)-5-(4-fluoro-phenyl)thiophene-2-carboxylic acid methyl ester (Example 1, Step 5) l~. Y1' (0.210 g) in TI-IF (2.0 mL) were added MeOH ( 1.0 mL), NaOI-I 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 HCI
(3N) to provide the title product as a white solid (0.200 g).
1H NMR (CD3COCD3) ~ 6.60 (2H, s), 7.15 (2I-L, t), 7.35 (2I1, q), 7.45 (2I-I, d), 7.82 (2I-I, d), 7.87 (lI-I, s).
Step 2: 3-(4-(Aminosulfonyl)phenyl)-2-(4-fluorophen I)~, thiophene To a solution of 3-(4-(aminosulfonyl)phenyl)-2-(4-fluorophenyl)thiophene-2-carboxylic acid (0.280 g) in quinoline (4.0 mL) 1 o 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°Io EtOAc in hexane) to give the title compound as a white solid (0.180 g).
1 H NMR (CD3COCD3): b 6.60 (2H, bs), 7.15 (2H, t), 7.29 ( l I-I, d), 7.35 1 s (2H, q), 7.45 (2I-I, d), 7.60 ( 1 H, d), 7.83 (2I-I, d).
Anal. calcd for C16H12FN02S2;
C, 57.65; II, 3.60; N, 4.20.
Found: C, 57.62; H, 3.59; N, 4.15.

3-(4-(Aminosulfon. 1)~, phenXl)-2- 4-fluorophenvl)-5-(2-prop I)y thiophene 1H NMR (CD3COCD3) 8 1.40 (6H, d), 3.25 (1H, septuplet), 6.58 (2H, bs), 7.05 (1H, s), 7.15 (2H, t), 7.32 (2H, dd), 7.46 (2H, d), 7.80 (2H, d).
Anal. calcd. for C 19H 1 gFN02S2.
C, 60.80; H, 4.80; N, 3.73.
3 o Found: C, 60.59; H, 4.45; N, 3.60.

.r 2116973 I ~. YY

ExAMPLE 4 3-(4-(Aminosulfon,~phen, l~)-2-cyclohexylthiophene 1H NMR (CD3)2)CO) 8 1.24-1.40 (3H, m), 1.40-1.56 (2I-I, m), 1.65-1.85 (3H, m), 1.90-2.0 (2H, IIl), 3.18 ( l I i, m), 6.58 (2I-I, bs)', 7.05 ( 1I-I, d), 7.37 (1H, d), 7.58 (2I-I, d), 7.97 (2H, d).

i o 5-(4-Carboxyphenyl)-4-(4-(methylsulfonyl)phenyl)thiophene-2-carboxylic acid Step l: 4-(2-(4-Methylthiophenyl)-1-oxo-ethyl)benzoic acid methyl ester 1 s To methyl 4-formylbenzoate (10.30 g) in 1,2-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 cyanohyrill (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 'rHF solution (10.0 2o 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 1M 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 25 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 3 o To 7.10 g of 4-(2-(4-methylthiophenyl)-1-oxo-ethyl)benzoic acid methyl ester in MeOH (100 mL) was added ozone (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) ~ 3.10 (3I-I, s), 3.95 (3II, s), 4.65 (2I-I, 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-propen,~)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 to 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.
Step 4: 5-(4-(Methoxycarbonyl)phenyl)-4-(4-(methylsulfonyl) phen 1)~ thiophene-2-carboxylic acid meth, 1 Prepared from 4-(1-chloro-3-oxo-2-(4-methylsulfonyl)-phenyl)-1-propenyl)benzoie acid methyl ester as for Example l, Step 3.
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 (2I-I, d), 7.92 (1H, s), 7.92 (2II, d).
Step 5: 5-(4-(Carboxyphenyl)-4-(4-(methyl)sulfonyl)phenyl)-thiophene-2-carboxylic acid Prepared from 5-(4-(methoxycarbonyl)phenyl)-4-(4-(methyl)sulfonyl)phenyl) thiophene-2-carboxylic acid methyl ester as for Example 2, Step 1.
1H NMR (CD3COCD3) 8 3.15 (3H, s), 7.50 (2H, d), 7.62 (2H, d), 7.95 (2H, d), 7.98 (lI-I, s), 8.05 (2H, d).
Anal calcd. for C 19H 140652'0.1 H20:

-1to-C, 56.46; I-I, 3.51.
Found: C, _56.18; I-I, 3.51.
EXAMPLI3 6 _ 4~4-Fluorophen,L)-2-meth,~(4-(methylsulfon, 1)~,-pheiyl)thiazole St_ ep 1: 1-(4-Fluorophen,~)-2-(4-(methylsulfonyl)phenyl ethanone To 1-(4-Fluorophenyl)-2-(4-(methylthio)phenyl)ethanone of Example 1, Step 1 ( 17.9 g) in a solution of CI I2C12-MeOH (272.0 mL/27.0 i o mL) at 0°C was added MPPM (28.0 g). rl he 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 1.5 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 i,z vacuo, the resulting solid was washed with ether-hexane (1:1) and filtered to provide the title compound 16.8 g.
lI-I NMR (CD3COCD3) b 3.13 (3I-I, s), 3.58 (2II, s), 7.29 (2H, t), 7.55 (21-I, d), 7.88 (2I-I, d), 8.20 (2I-I, dd). -2o Step 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 quenched with Na2S204, extracted with CI-I2C12, dried over Na2S04 and evaporated to yield the title compound which was used as such for the next step (1.10 g).
1H NMR (CD3COCD3) 8 3.10 (3H, s), 7.05 (1H, s), 7.30 (2H, t), 7.87 (2H, d), 7.95 (2H, d), 8.25 (2H, dd).

19~~~YP

Step 3: 4-(4-Fluorophenyl)-2-methyl-5-(4-(methylsulfonyl)phenyl)-thiazole To 2-bromo-1-(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% NI-I40Ac and purified'by flash chromatography (50% EtQAc in hexane then 90% Et20 in hexane) to yield the title COIIIpOllIld (0.320 g).
1H NMR (CD3COCD3) 8 2.72 (3II, s), 3.15 (3H, s), 7.09 (2II, t), 7.52 (2II, dd), 7.60 (2H, d), 7.92 (2H, d).
1 o Anal. calcd. for C 17H 14FN02S2:
C, 58,78; H, 4.03; N, 4.03.
Found: C, 58.71, H, 4.17; N, 3.85.

2 ~4-Fluorophen~rl)-3-(~~methylsulfonyl)phenyj -~yclopenten-1-one Step l: 1-(4-Fluoro~hen~)-5-hexes-2-one To a suspension of 14.6 g (80 mmol) of CdCl2 in 200 mL of 2o ether cooled to 0°C was added 115 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 (500 mL) was introduced, followed by a solution of 17.5 g (100 nunol) 4-fluorophenylacetyl chloride. After refluxing for 1 h, the reaction mixture was quenched with 200 mL of saturated aqueous NH4C1, 50 mL of 1 N HC1, 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 NMR (CDC13) ~ 2.40 (2H, t), 2.53 (2H, t), 3.63 (2H, s), 4.90-4.98 (2H, nl), 5.67-5.78 (1H, m), 6.98 (2H, t), 7.13 (2I-I, m).

1 Y I' 2~7~973 Std I-(4-Fluorophen~)-_5-oxo-2-pentanone A solution of 14 g of 1-(4-fluorophenyl)-5-hexen-2-one in 200 mL of 3:1 CH2C12/MeOH was cooled to -78°C and treated with excess ozone. The resulting mixture was treated with 15 g of triphenylphosphine 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.
1H NMR (CDC13) 8 2.72 (4H, s), 3.71 (2II, s), 6.99 (2H, t), 7.14 (2H, m), 9.73 (1H, s).
Step 3: 2-(4-FluorophenyU-2-cyclopenten-1-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 stirred for 2 h and then quenched with 5 mL of I-IOAc. hhe solvent was i5 evaporated and the residue purified by flash chromatography, eluting with 3:1 hexane/EtOAc to give 7 g of the title product.
IH NMR (CDC13) ~ 2.57 (2H, m), 2.68 (2II, m), 7.04 (2I-I, J=8.8 Hz, t), 7.67 (2H, J=8.8, 5.5 Hz, dd), 7.77 ( l I-I, m).
2o 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-l3uLi in pentane (38 mmol) dropwise. The reaction mixture was soured for 15 25 min at -78°C and a solution of 2.23 g of 2-(4-Fluorophenyl)-2-cyclopenten-1-one in 10 IllL 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.
NH4C1. 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.

~l T6973 1H NMR (CDC13) ~ 2.12 (lI-I, s), 2.34 (2II, m), 2.44 (3I-I, s), 2.45-2.52 ( 1 H, m), 2.56-2.65 ( l I-I, m), 6.37 ( I H, m), 6.84 (2I-I, J=8.7 I-Iz, t), 7.17 (2H, J=8.3 Hz, d), 7.24-7.33 (4II, m).
St~e~ 5: 2-(4-Fluorophenyl)-3-(4-(methylthio)phenyl)-2-cyclo-penten-1-one To a suspension of PCC (4.5 g, 20.9 mmol) and 10 g of anhydrous 4A molecular sieves in 150 mL of CII2C12 was added a solution of 2.2 g (7.3 mmol) of 1-(4-(methylthio)phenyl)-2-(4-fluorophenyl)-2-cyclopenten-1-of in 20 mL CH2C12. The mixture was stirred for 1 h at r.t.
1 o 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.
1 H NMR (CDC13) b 2.45 (3I-I, s), 2.68 (2H, m), 3.00 (2I-I, m), 7.02 (2H, J=8.6 Hz, t), 7.11 (2H, J=8.6 Hz, d), 7.15-7.23 (4I-I, m).
Step 6: 2-(4-Fluorophenyl)-3-(4-(methylsulfonyl)phenyl)-2-cyclopenten-1.-one To a solution of 50 mg (0.17 mmol) of 2-(4-Fluorophenyl)-3-(4-unethylthio)phenyl)-2-cyclopenten-1-one in 8 mL of 10:1 CI-I2C12/Me01-1 was added 124 mg (0.2 mmol) of MPPM. rhhe reaction mixture was stirred at room temperature for 2 h and then diluted with 10 mL of 1:1 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.
2 5 1 H NMR (acetone-d6) 8 2.67 (2H, m), 3.14 (3I-I, s), 3.16 (21 I, m), 7.05-7.10 (2H, m), 7.20-7.25 (2H, m), 7.63 (2H, d), 7.93 (21I, d).

3 0 4_(4_(Methylsulfonyl)phenyl)-5-(4-fluorophen~)-isothiazole z ~ ~6v1~

'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 nunol) of NH4SCN. The reaction mixture was refluxed for 3 h, and then duenched with 20mL of saturated NaI-IC03.
The product was extracted with 100 mL of EtOAc, dried over Na2S04, concentrated and purified by flash chromatography elutcd with 3:2 hexane/EtOAc to give 250 mg of the title product.
1 H NMR (CDCl3) cS 8.57 ( 11-l, s), 7.93 (3I-l, d), 7.50 (2I-I, d), 7.30 (2I-l, t), 7.08 (2H, t).
1 o EXAMPLE 9 3-(4-Fluorophenyl)-4-(4-(methylsulfon~phen (~~SH)-furanone St-ep l: 2-Bromo-1-(4-(methylsulfon~phenyl)ethanone 15 A solution of 1.97 g of 4-(Methylthio)acetophenone (ref:
JACS, 1952, 74, p. 5475) in 700 mL of Me01-I and 3500mL of CI-1X12 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 Nal-IC03 and 1 L of brine. The 2o aqueous phase was further extracted with 2 L of CII2C12. 'hhe combined extracts was dried over Na2S04 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 CHCl3 was added 20 mg of 2s AlCl3, followed by a solution of 40 mL of Br2 in 300 mL CHCl3. 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 2-3 o bromo-1-(4-(methylsulfon~)phenyl)ethanone as a white solid.

1 i' Y P
~~1E913 Step 2:
To the product of Step 1 (216 nag) dissolved in acetonitrile (4 mL) was added Et3N (0.26 mL), followed by 4-fluorophenylacetic acid (102 Illg). After 1.5 h at room temperature 0.23 mL of DI3U was added.
The reaction mixture was stirred for another 45 min and then treated with s 5 mL, of,1N IICI. T'he product was extracted with EtO~Ac, dried over Na2SOq. 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) ~ 3.15 (3H, s), 5.36 (3I-I, s), 7.18 (2I-I, J=8.9 Hz, t), l0 7.4G (2H, m), 7.7 (2I-I, J=8.G5 Hz, d), 7.97 (2II, J=8.G8, d).

3-(4-Fluorophenyl)-4-(4-(aminosulfonyl~hen~l)-~2/~)-furanone 1H NMR (CD3COCD3) ~ 5.34 (2I-i, s), G.G7 (2H, bd), 7.18 (2I-I, m), 7.4G.
(2H, m), 7.G 1 (2H, m), 7.90 (2fI, m).
M.P. 187-188 °C (d).
2o EXAMPLE l l 3-(4-Fluorophenyl)-4-(4 ~methylsulfonyl)phenyl)furan St_epl:
2s Using the product of Example 10, (0.2 g) in THF (5 mL) and toluene (3 II1L) was added slowly at -78°C a solution of DIBAL (0.72 mL, 1M in toluene). After 15 min, the solution was warmed up to 0°C for another 15 min. This mixture was then poured into a chilled aqueous solution of sodium potassium tartrate and EtOAc. The organic layer was 3 o stirred for 0.5 h with a few crystals of camphor sulfonic acid. This ~~16~13 solution was then concentrated and purified by flash chromatography to yield the title compound.
1 H NMR (CDC13) _ 3.1 (3H, s), 7.02 (21-I, J=8.9, t), 7.18 (2H, Ill), 7.4 (21-I, J=8.8 Hz, d), 7.58 ( 1 H, s), 7.68 ( 1 H, s), 7.85 (2I-I, J=8.8 I-Iz, d) 5,5-Dimethyl-3-(4-fluorophenyl)-4-(4-methylsulfonylphenyl)-2-(Sll)-furanone io St_ ep 1: Meths 2-trimeth~lsil~ox isy obutyrate To a solution of 1.2 mL (10.4 mmol) of methyl 2-hydroxy-isobutyrate in 50 mL of CH2C12 were added 1.2 g (17.6 rnmol) of imidazole and 2.1 mL (16.6 mmol) of TMSC1. The mixture was stirred at r.t. for 1.5 h and quenched with 20 mL of H20. The organic layer was 15 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.
1H NMR (CD3COCD3) 8 0.08 (9H, s), 1.38 (6H, s), 3.67 (3I1, s).
2o SteR2: 2-Trimethylsilyloxy-4'-(methYlthio)isobutyrophenone 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 nunol) of methyl 2-trimethylsilyloxyisobutyrate in 2 mL of THF was 25 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.
30 1H NMR (CD3COCD3) 8 0.05 (9H, s), 1.52 (6I-I, s), 2.53 (3H, s), 7.33 (2H, d), 8.12 (2H, d).

Y'~ 2 ~ 7 6 9 l3 Step 3: 2-Hydroxy-4'-(methylthio)isobutyrophenone To a solution of 40 mg (0.14 mmol) of 2-trimethylsilyloxy-4'-(methylthio)isobutyrophenone in 2 mL TIIF 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 clwomatography, eluting with 4:1 hexane/EtOAc to give 25 mg of the title product.
1H NMR (CD3COCD3) ~ 1.50 (GH, s), 2.54 (3I-I, s), 4.G8 (lI-I, s), 7.30 l o (2H, d), 8.15 (2I-I, d).
Step 4: 2-(4-Fluorophenylacetoxy)-4'-(methylthio)isobutyro~~henone To a solution of 72 mg (0.34 11111101) 2-hydroxy-4'-(methylthio)isobutyrophenone in 1.7 mL of CI-I2C12 were added 0.2 mL of 15 pyridine and 140 mg (0.81 nunol) 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 rng of the title 2 o product.
1H NMR (CD3COCD3) 8 1.G2 (3H, s), 1.G7 (3I-I, s), 2.48 (3I-I, s), 3.79 (2H, s), 7.0-7.3 (GI-I, m), 7.78 (2H, d).
Step 5: 5,5-Dimethyl-3-(4-fluorophenyl-4-(4-methyltliiophenyl)-2 2s (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, 3o dried over MgS04 and concentrated. The residue was purified by flash %17613 1902.8Y1' chromatography, eluting with 20:1 toluene/EtOAc to give 75 mg of the title product.
1 H NMR (CD3COCD3) b 1.58 (6H, s), 2.50 (3I-I, s), 7.03 (21-I, dd), 7.25-7.35 (4I-I, m), 7.41 (2H, dd).
St-ep 6: 5,5-Dimethyl-3-(4-fluorophenyl)-4-(4-methylsulfonylphenyl)-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 CH2C12 and 0.2 mL of MeOI-I was added 250 mg of MPPM. The reaction mixture was 1 o stirred at room temperature for 1 h and then quenched with adueous 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.
1H NMR (CD3COCD3) h 1.62 (6H, s), 3.15 (3H, s), 7.02 (2H, dd), 7.40 15 (2H, dd), 7.65 (2I-I, d), 8.03 (2H, d).
EXAMPL>13 2-((4-aminosulfon~phenvl)-3-(4-fluorophenvl)thio~hene 1H NMR (CD3COCD3) ~ 6.60 (2I-I, bs), 7.12 (2I-I, t), 7.25 (lIl, d), 7.35 (2H, m), 7.45 (2H, d), 7.65 (lI-I, d), 7.85 (2H, d).
Analysis calculated for C16H12FNS202 C, 57.65; H, 3.60; N, 4.20 Found: C, 57.55; H, 3.79; N, 4.03 3-(4_(Trifluoroacetylaminosulfon~)phen l~)-2-(4-fluorophen l~hio~helle 19028Y1' 1H NMR (300 MHz, CD3COCD3) b 7.15 (2I-l, t), 7.30 (3I-l, m), 7.45 (2I-I, d), 7.65 ( 1 H, d), 7.95 (2H, d).

3-(2,4-Difluorophen 1~)-4-(4-(methylsulfonyl)phenyl)-2-(SH)-furanone Analysis calculated for C1~H12FZO4S
C, 58.28; H, 3.45; S, 9.15 1 o Found: C, _58.27; H, 3.50; S, 9.27 3-(3 4-Difluorophen lyy4-(4-(methylsulfoyrl)phenyl);2-(Sly-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 1 h at room temperature, the mixture was cooled in an ice bath and treated with 17.4 2 o 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°lo 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 3 o EXAMPLE 17 3-(2,6-Difluorophenyl)-4-(4-(methylsulfon~)Phenyl)-2-(.511;1-furanone Analysis calculated for C1~H12F2~4S
C, 58.28; H, 3.45; S, 9.15 Found: ' C, 58.18; H, 3.50; S, 9.44 3-(2,5-Difluorophen~)-4-(4-(methylsulfon~Phenyl -2-(.5H)-furanone to Analysis calculated for CI~I-1121;2045 C, 58.28; H, 3.45; S, 9.15 Found: C, 58.89; H, 3.51; S, 9.11 3-(3,5-Difluor-oPhenyl -~4-~methylsulfonyl)Phen, l~)-2-(SH~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-Bromophenyl)-4-(4-(methylsulfon"~1)Pheliyl~-2-~Sf~-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 3 o EXAMPLE 21 3-(4-Chlorophen ly )-4-(4-(methylsulfonyl~phenyl)-2-(SH)-furanone 1H NMR (300 MHz, CDC13) 8 7.93 (2H, d), 7.49 (2H, d), 7.35 (4I-I, m), 5.16 (2H, s), 3.06 (3H, s) -3-(4-Methoxvphenvl)-4-(4-(methxlsulfon~lphenyl)-2-(SH)-furanone Analysis calculated for CIgHI~OSS
to C, 62.78 II, 4.68; S, 9.31 Found: C, 62.75; H, 4.72; S, 9.39 i 5 3-(phenyl)-4-(4-(methylsulfon~~l)nhe~-2~SH)-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 triethylamine (30.8 lnL, 1.1 eq.). The mixture was stirred for 20 min. at 2o room temperature and then cooled ill 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 I-ICl (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 2 s 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.

Z ~ 16913 Analysis calculated for C1~H14~4S
C, 64.95; H, 4.49; S, 10.20 Found: , C, 64.63; H, 4.65; S, 10.44 ' 3-(2-Chlorophenyl)-4-(4-(methylsulfonyll_phen~)-2-ASH)-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-(methylsulfon~phen~l)-2-~SH)-furanone 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-(methylsulfon rLllPhenyl)-2-(Sl~-furanone 1H NMR (300 MHz, acetone-d6) ~ 7.95 (2H, d), 7.85 (1H, d), 7.63 (2H, dd), 7.55 (1H, dd), 7.45 (1H, d), 5.50 (2H, s), 3.15 (3H, s) 1 r".:8YP

3-(4-Chloro-2-fluorophenyl)-4-(4-(methylsulfon 1)~ 1~~51I~
furanone 1H NMR (300 MHz, acetone-d~) ~ 8.0 (2II, d), 7.70 (2I-I, d), 7.50-7.30 (3I-I, m), 5.35 ' (2h, s), 3. I 5 (3I-I, s) 3-(3-Bromo-4-fluorophen~)-4-~4-~methyl su lfon~)pheny I)-~ 5H)-furanone to Analysis calculated for C1~H12BrF04S
C, 49.75; H, 2.93 Found: C, 49.44; H, 2.98 i 5 EXAMPLE 29 3-(3-Chlorophenyl)-4-(4-(methylsulfonyl)~hen~)-2-(.SHE-furanone Analysis calculated for C1~H13C10qS
C, 58.54; H, 3.76 2o Found: C, 58.29; H, 3.76 3-(2-Chloro-4-fluorophenyl)-4-(4-(methvlsulfon~l~phenyl)-2-(SHE
25 furanone Analysis calculated for C1~H12C1F04S
C, 55.67; H, 3.30 Found: C, 55.67; H, 3.26 t> _dYP
~1 Tb9?3 3-(2,4-Dichlorophen~l)-4-(4-(methylsulfon~~henyl)-2-(511)-furanone Analysis' calculated for C1~H12C1204S
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-Dichlorophen ly )-4-(4-(methylsulfon 1)phen~l)-2-(5H)-furanone ~alysis calculated for C1~H12C1244S
C, 53.28; H, 3.16; S, 8.37 Found: C, 52.99; H, 3.22; S, 8.54 3-(3-Chloro-4-fluorophenyl)-4-(4-(meth ls~n 1)ahenyl)-2-(SH)-furanone 1H NMR (300 MHz, acetone-d6) d 8.0 (2H, d), 7.70 (2H, d), 7.60 ( 1 H, d), 3 0 7.25-7.40 (2H, m), 5.35 (2H, s), 3.15 (3H, s) ~y~2~Yl~ ? ~ l 6 9 7 3 3-(4-Trifluoromethylphenyl)-4-(4-(methylsulfon~lplaenyl)-2-( 5f-f)-furanone 1H NMR (CD3COCD3) 8 8.10 (2H, d), 7.82-7.93 (4H, m), 7.75 (2I-I, d), 5.55 (2H, s), 3.30 (3H, s) io 3_(3-Fluoro-4-methoxyphenyl)-4-(4-(methylsulfonyl)phenvl)-2~SH~-furanone Analysis calculated for CIgI-II5FO5S
C, 59.66; H, 4.17 Found: C, 59.92; H, 4.37 3-(3-Chloro-4-methoxvphenvl)-4-(4-(methylsulfonyl)Phenyl~-2-(SH~-2o furanone Analysis calculated for C 1 gH 15C105S
C, 57.07; H, 3.99 Found: C, 57.29; H, 4.15 3-(3-Bromo-4-methoxyphenyl)-4-(4-(methylsulfonyl)phenyl)-2-(SHE
furanone Analysis calculated for C1gH15Br05S

C, 51.08; H, 3.57 Found: C, 51.38; I-I, 3.62 3-(2-Fluorophenyl)-4-(4-(methylsulfonyl)phen~)-2-(SH)-furanone Analysis calculated for C1~H13F04S
C, 61.44; II, 3.94 Found: C, 61.13; H, 3.85 to 3-(4-Methylthiophen~)-4-(4-(methylsulfonvl)phenvl~2~5H)-furanone 15 1H 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 (3Id, s) 20 3_(3-Fluoroyhenyl)-4-(4-(methylsulfonyl)phenyl)-2-(SH)-furanone 1H 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) 3-(2-Chloro-6-fluorophenyl)-4-(4-(methylsulfon~~henyl)-2-(SH)-furanone 3 0 1H NMR (300 MHz, acetone-d6), d 8.0 (2H, d), 7.70 (2H, d), 7.55-7.65 ( 1 H, m), 7.40 ( 1 H, d), 7.30 ( 1 H, m), 5.60 (2H, s), 3.15 (3I I, s) JZgYP 21 l 6 9 7 3 3-(3-Bromo-4-meth~lphen~)-4-(4-(meth~lsulfooyl)phenyl)-2-ASH) furanone Analysis calculated for C 1 ~H 1 SBr04S
C, 53.08; H, 3.71 Found: C, 53.06; H, 3.83 1 o EXAMPLE 44 3-(4-Bromo-2-fluoro~henyl)-4-(4-(methylsulfon 1)phenyl)-2-(SH~-furanone i5 Analysis calculated for C1~H12BrFOq.S
C, 49.65; H, 2.94 Found: C, 49.76; H, 3.00 3-(3,4-Dibromophen l~)-4-(4-(methylsulfon~l~phenyl)-2-(SH)-furanone 1H NMR (300 MHz, acetone-d6) S 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-fluorophenyl)-4-(4-(methvlsulfon r~l)phenyl -2-(SHE
furanone Analysis calculated for C1~H12C1FOq.S

C, 55.67; II, 3.30 Found: C, 55.45; II, 3.30 s 3-(4-Bromo-3-fluorophenyl)-4-(4-(methylsulfonyl~hen~)-~5H)-furanone Analysis calculated for C1~H12BrF04S
C, 49.66; H, 2.94; S, 7.80 to Found: C, 49.79; II, 3.01; S, 7.51 _ 3-(4-Bromo-2-chlorophenvl)-4-(4-(methylsulfon~)phen~)-2-~SH)-is furanone 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-Naphthyl)-4-(4-(methylsulfon 1)y - phenyl)-2-(SH)-furanone 2 s ~alysis calculated for C21H 16045 C, 69.22; H, 4.43 Found: C, 69.22; H, 4.46 3-(7-Ouinolinyl)-4-(4-(methylsulfonYl~phen l~)-2-(~SH)-furanone Analysis calculated for C2pH 15NO4S
C, 65.74; I-I, 4.14; N, 3.83 Found: C, 65.34; H, 4.40; N, 3.80 M.S. (DCI, CH4) calculated for M+, 365 Found for M-~-+l, 366 3-f3 4-Dichlorophenyl)-4-(4-(aminosulfon~phen~)-2-(2H~-furanone to 1H NMR (400 MHz, CD3COCD3) 8 7.92 (2I-I, dd), 7,64 (3H, dlll), 7.60 ( 1 H, dd), 7.32 ( 1 H, dd), 6.70 ( 1 H, bs), 5.38 (2I I, s) 3-L3 4-Difluorophenyl~-4-(4-(aminosulfonyl)pheny-2-(2H)-furanone 1H NMR (400 MHz, CD3COCD3) b 7.92 (2H, dd), 7,64 (2I-I, dd), 7.30-7.45 (2H, m), 7.22 (1H, m), 6.68 (2H, bs), 5.37 (2I I, s) 3-(3-Chloro-4-methox~hen~)-4-(4-(aminosulfon~phenyl)-2-(2Hl-furanone Analysis calculated for C1~H14CINO5S
C, 53.76; H, 3.72, N, 3.69 Found: C, 53.32; H, 3.84, N, 3.59 M.S. (DCI, CHq.) calculated for M+, 379 3 o Found for M++1, 380 21 ?6913 3-~3-Bromo-4-methoxX,~henvl)-4-(4-(aminosulfon~phenyl~-2-(2H~-furanone Analysis calculated for Cl~Hlq.BrNOSS
C, 48.13; H, 3.33, N, 3.30 Found: C, 48.26; H, 3.40, N, 3.28 1 o M,S. (DCI, CI-I4) calculated for M+, 423 Found for M++1, 424 15 3_(phenX,l)-4-(4-(methylsulfonyl~phenyl~-2-(SH)-furanone Into a 20 ml glass ampule are added 1 g of 2-(4-(methylsulfonyl)phenyl)phenylacetylene, 20 mg of Rh4(CO)12, 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 Na2SOq, and concentrated.
The crude products are separated by column chromatography on silica gel 2s eluted with 2:1 EtOAc/hexane to give the title compound and its regioisomer.

30 3_(phenyl)-4-(4-(meth l~ulfon~phenvl)-2-(Slf)-furanone St, ep l: 2-trimeth~silyloxv-4-~'4-(meth 1tY hioOphen~,l-3,4-dihXdrofuran ... ~~~YI' 2~169?3 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 Cul is added and the reaction mixture is allowed to warm 'to -40 °C over a period of 30 chin. A solution of 1.7 g of 2(SII)-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. NaI-IC03, and extracted wilt 100 ml of ether. The ether layer is dried over Na2SOq. and concentrated to the crude title compound which is used for the next step without fuuther purification.
Step 2: 4-(4-(methylthio)phenyl)-2-(SH)-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 temperature. After 10 h a.t 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 Step 3: 3-iodo-4-(4-(meth, l~io~phen, I)-2- 511)-furanone To a solution of 3 g of the product of Step 2 in 30 ml of pyridine is added 8.7 g of 12. The mixture is stirred for 24 h and then diluted with 200 ml of ether, washed with 100 ml of SN I-ICl and 50 ml of SN Na2S203. The ether layer is dried over Na2S04 and concentrated to give the title compound.
St, ep 4: 3-~Phenyl)-4-(4-(meth, l~~henyl)-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 1111 of benzene and 15 ml of 19028Y1' ~~T~913 2N NaOH is refluxed for 6 h. Ether(200 ml) is then added and the mixture is washed with 100 ml of saturated NaI-IC03. The organic layer is dried over MgS04 and concentrated. The residue is purified by flash chromatography on silica gel eluted with 4:1 liexane/EIOAc to give the title compomid.
Step 5: 3-(Phenyl)-4-(4-(methylsulfon~l~phenyl~2-(SN)-furanone To a solution of 3 g of the product of Step 4 ill 80 mL of 10:1 CH2C12/MeOH is added 5.5 g of MPPM. The reactiomoixturc 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 CtOAc/hexane to give the title product.

Claims (21)

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof wherein:
R1 is selected from the group consisting of (a) S(O)2CH3, and (b) S(O)2NH2, R2 is selected from the group consisting of unsubstituted, mono- or di-substituted phenyl wherein the substituent is halo; and each R5' is the same and is C1-6 alkyl.
2. A compound of formula (I), as defined in claim 1, or a pharmaceutically acceptable salt thereof, wherein R2 is unsubstituted phenyl.
3. A compound of formula (I), as defined in claim 1, or a pharmaceutically acceptable salt thereof, wherein R2 is mono- or di-substituted phenyl, wherein the substituent is halo.
4. A compound of formula (I), as defined in claim 1, or a pharmaceutically acceptable salt thereof, wherein R2 is mono-substituted phenyl, wherein the substituent is halo.
5. A compound of formula (I), as defined in claim 1, or a pharmaceutically acceptable salt thereof, wherein R2 is di-substituted phenyl, wherein the substituent is halo.
6. A compound of formula (I), as defined in claim 3, 4 or 5, or a pharmaceutically acceptable salt thereof, wherein said halo is selected from the group consisting of fluoro, chloro and bromo.
7. A compound of formula (I), as defined in claim 1, 2, 3, 4, 5 or 6, or a pharmaceutically acceptable salt thereof, wherein each R5' is methyl or ethyl.
8. A compound of formula (I), according to claim 1, 2, 3, 4, 5 or 6, or a pharmaceutically acceptable salt thereof, wherein each R5' is C1-4 alkyl.
9. A compound of formula (I), according to claim 8, or a pharmaceutically acceptable salt thereof, wherein each R5' is methyl.
10. A compound of formula (I), according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein R1 is SO2CH3.
11. A compound selected from (1) 5,5-Dimethyl-3(4-fluorophenyl)-4-(4-methyl-sulfonyl)phenyl)-2-(5H)-furanone, (2) 5,5-Dimethyl-3-(3-fluorophenyl)-4-(4-methyl-sulfonyl)phenyl)-2-(5H)-furanone, (3) 5,5-Diethyl-3-(3-chlorophenyl)-4-(4-methyl-sulfonyl)phenyl)-2-(5H)-furanone, (4) 5,5-Dimethyl-3- (3,4-difluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone, (5) 5,5-Dimethyl-3-(3,4-dichlorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone, (6) 5,5-Dimethyl-3-(4-chlorophenyl)-4-(4-methyl-sulfonyl)phenyl)-2-(5H)-furanone, (7) 5,5-Dimethyl-3-(2-naphthyl)-4-(4-(methyl-sulfonyl)phenyl)-2-(5H)-furanone,
12. 5,5-Dimethyl-3-(3-fluorophenyl)-4-(4-methyl-sulfonyl)phenyl)-2-(5H)-furanone.
13. A pharmaceutical composition for treating an inflammatory disease susceptible to treatment with a non-steroidal anti-inflammatory agent comprising:
a non-toxic therapeutically effective amount of a compound or salt according to any one of claims 1 to 12, in association with a carrier.
14. A pharmaceutically acceptable salt of a compound of formula (I), as defined in any one of claims 1 to 10.
15. A compound of formula (I), as defined any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof for use in treatment of an inflammatory disease susceptible to treatment with a non-steroidal anti-inflammatory agent.
16. A compound of claim 11 or 12, for use in treatment of an inflammatory disease susceptible to treatment with a non-steroidal anti-inflammatory agent.
17. Use of a compound of formula (I), as defined in any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of an inflammatory disease susceptible to treatment with a non-steroidal anti-inflammatory agent.
18. Use of a compound or salt of claim 11 or 12, in the manufacture of a medicament for the treatment of an inflammatory disease susceptible to treatment with a non-steroidal anti-inflammatory agent.
19. A non-steroidal anti-inflammatory pharmaceutical composition comprising an acceptable anti-inflammatory amount of a compound of formula (I), as defined in any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier.
20. A non-steroidal anti-inflammatory pharmaceutical composition comprising an acceptable anti-inflammatory amount of a compound of claim 11 or 12, in association with a pharmaceutically acceptable carrier.
21. Use of a compound or salt of any one of claims 1 to 12, as a selective inhibitor of cyclooxygenase-2 relative to cyclooxygenase-1.
CA002176973A 1993-06-24 1994-06-09 Phenyl heterocycles as cyclooxygenase-2 inhibitors Expired - Fee Related CA2176973C (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
CA002176974A Expired - Fee Related CA2176974C (en) 1993-06-24 1994-06-09 Phenyl heterocycles as cyclooxygenase-2 inhibitors
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