US 5,691,374 AGranted

Diaryl-5-oxygenated-2-(5H) -furanones as COX-2 inhibitors

AssigneeMerck Frosst Canada, Inc.

InventorsCameron Black, Erich Grimm, Zhaoyin Wang, Serge Leger

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Abstract

The invention encompasses the novel compound of Formula I as well as a method of treating cyclooxygenase-2 mediated diseases comprising administration to a patient in need of such treatment of a non-toxic therapeutically effective amount of a compound of Formula I. ##STR1## The invention also encompasses certain pharmaceutical compositions for treatment of cyclooxygenase-2 mediated diseases comprising compounds of Formula I.

Claims18

Dependent claims

A compound of formula Ib ##STR40## or a pharmaceutically acceptable salt thereof wherein:

R.sup.1 is selected from the group consisting of
(a) S(O).sub.2 CH.sub.3,
(b) S(O).sub.2 NH.sub.2,
(c) S(O).sub.2 NHC(O)CF.sub.3,
(d) S(O)(NH)NH.sub.2,
(e) S(O)(NH)NHC(O)CF.sub.3,
R.sup.2 is selected from the group consisting of
(a) C.sub.3-6 cycloalkyl,
(b) mono- or di- substituted C.sub.3 -C.sub.6 cycloalkenyl wherein the substituent is selected from the group consisting of
(1) halo,
(2) C.sub.1-4 alkoxy,
(3) C.sub.1-4 alkylthio,
(4) CN,
(5) CF.sub.3,
(6) C.sub.1-6 alkyl,
(7) N.sub.3,
(8) --CO.sub.2 H,
(9) --CO.sub.2 -C.sub.1-6 alkyl,
(10) --C(R.sup.5)(R.sup.6)-OH,
(11) --C(R.sup.5)(R.sup.6)-O-C.sub.1-4 alkyl,
(c) unsubstituted or mono-, di- or tri-substituted phenyl or naphthyl wherein the substituent is selected from the group consisting of
(1) halo,
(2) C.sub.1-4 alkoxy,
(3) C.sub.1-4 alkylthio,
(4) CN,
(5) CF.sub.3,
(6) C.sub.1-6 alkyl,
(7) N.sub.3,
(8) --CO.sub.2 H,
(9) --CO.sub.2 -C.sub.1-4 alkyl,
(10) --C(R.sup.5)(R.sup.6)-OH,
(11) --C(R.sup.5)(R.sup.6)-O-C.sub.1-4 alkyl, and
(12) --C.sub.1-4 alkyl-CO.sub.2 -R.sup.5 ;
(13) --O--(C.sub.1-4 alkyl)-CO.sub.2 R.sup.5,
(d) unsubstituted or mono-, di- or tri-substituted heteroaryl wherein the heteroaryl is a monocyclic aromatic ring of 5 atoms, said ring having one hetero atom which is S, O, or N, and optionally 1, 2, or 3 additional 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 or 3 additional N atoms, said substituents are selected from the group consisting of
(1) halo,
(2) C.sub.1-4 alkyl,
(3) C.sub.1-4 alkoxy,
(4) C.sub.1-4 alkylthio,
(5) CN,
(6) CF.sub.3,
(7) N.sub.3,
(8) --C(R.sup.5)(R.sup.6)-OH, and
(9) --C(R.sup.5)(R.sup.6)-O-C.sub.1-4 alkyl;
(e) an unsubstituted or a mono- or di-substituted benzoheterocycle in which the heterocycle is a 5, 6, or 7-membered ring which may contain 1 or 2 heteroatoms chosen independently from O, S, or N and which may contain a carbonyl group or a sulfonyl group;
the said substituents are selected from the group consisting of
(1) halo,
(2) C.sub.1-4 alkyl,
(3) C.sub.1-4 alkoxy,
(4) C.sub.1-4 alkylthio,
(5) CN,
(6) CF.sub.3,
(7) N.sub.3,
(8) --C(R.sup.5)(R.sup.6)-OH, and
(9) --C(R.sup.5)(R.sup.6)-O-C.sub.1-4 alkyl;
(f) a heterocycloalkyl group of 5, 6 or 7 members which contains 1 or 2 heteroatoms chosen from O, S, or N and optionally contains a carbonyl group or a sulfonyl group
(g) an unsubstituted or a mono- or di-substituted benzocarbocycle in which the carbocycle is a 5, 6, or 7-membered ring which optionally contains a carbonyl group, the said substituents are selected from the group consisting of
(1) halo,
(2) C.sub.1-4 alkyl,
(3) C.sub.1-4 alkoxy,
(4) C.sub.1-4 alkylthio,
(5) CN,
(6) CF.sub.3,
(7) N.sub.3,
(8) --C(R.sup.5)(R.sup.6)-OH, and
(9) --C(R.sup.5)(R.sup.6)-O-C.sub.1-4 alkyl;
R.sup.3 is hydrogen, C.sub.1-4 alkyl, CH.sub.2 OR.sup.7, CN, CH.sub.2 CN, or C.sub.1-4 fluoroalkyl, F, CONR.sup.7.sub.2, unsubstituted or mono- or di-substituted phenyl, unsubstituted or mono or di-substituted benzyl, unsubstituted or mono- or di-substituted heteroaryl, unsubstituted or mono or di-substituted heteroarylmethyl, wherein the substituents are selected from the group consisting of
(1) halo,
(2) C.sub.1-4 alkyl,
(3) C.sub.1-4 alkoxy,
(4) C.sub.1-4 alkylthio,
(5) CN,
(6) CF.sub.3,
(7) N.sub.3,
(8)--C(R.sup.5)(R.sup.6)-OH, and
(9) --C(R.sup.5)(R.sup.6)-O-C.sub.1-4 alkyl;
R.sup.4 is
(a) C.sub.1-4 alkoxy,
(b) C.sub.1-4 alkylthio,
(c) --OH,
(d) --OCOR.sup.7,
(e) --SH,
(f) --SCOR.sup.7,
(g) --OCO.sub.2 R.sup.8,
(h) --SCO.sub.2 R.sup.8,
(i) OCONR.sup.7.sub.2, and
(j) SCONR.sup.7.sub.2 ;
each R.sup.5 or R.sup.6 is independently selected from the group consisting of
(a) hydrogen, and
(b) C.sub.1-4 alkyl,
each R.sup.7 is independently selected from the group consisting of
(a) hydrogen and
(b) R.sup.8 ;
each R.sup.8 is independently selected from the group consisting of
(a) C.sub.1-6 alkyl,
(b) phenyl or monosubstituted phenyl wherein the substituents may be halo, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkylthio, CN, or CF.sub.3,
(c) benzyl or monosubstituted benzyl wherein the substituents may be halo, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkylthio, CN, or CF.sub.3.

96 more elements

A compound selected from the group consisting of

(1) 5-Hydroxy-4-(4-(methylsulfonyl)phenyl)-3-phenyl-2-(SH)-furanone,
(2) 5-Hydroxy-3-(3,4-difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furan one,
(3) 5-Hydroxy-5-methyl-4-(4-(methylsulfonyl)phenyl)-3-phenyl-2-(5H)-furanone,
(4) 3-(4-Fluorophenyl)-5-hydroxy-5-methyl-4-(4-(methylsulfonyl)phenyl)-2-(5H)- furanone,
(5) 3-(4-Chlorophenyl)-5-hydroxy-5-methyl-4-(4-(methylsulfonyl)phenyl) -2- (5H)-furanone,
(6) 3-(3,4-Difluorophenyl)-5-hydroxy-5-methyl-4-(4-(methylsulfonyl)phenyl) -2- (5H) -furanone,
(7) 3-(3-Fluorophenyl)-5-hydroxy-5-methyl-4-(4-(methylsulfonyl)phenyl)-2- (5H)-furanone,
(8) 3-(3,5-Difluorophenyl)-5-hydroxy-5-methyl-4-(4-(methylsulfonyl)phenyl) -2- (5H)-furanone,
(9) 5-Methoxy-5-methyl-4-(4-(methylsulfonyl)phenyl)-3-phenyl-2-(5H)-furanone,
(10) 3-(4-Chlorophenyl)-5-methoxy-5-methyl-4-(4-(methylsulfonyl)phenyl)-2-(5H)- furanone,
(11) 3-(3,4-Difluorophenyl)-5-methoxy-5-methyl-4-(4-(methylsulfonyl) phenyl) -2- (5H) -furanone,
(12) 3-(3-Fluorophenyl)-5-methoxy-5-methyl-4-(4-(methylsulfonyl)phenyl)-2-(5H)- furanone,
(13) 3-(3,5-Difluorophenyl)-5-methoxy-5-methyl-4-(4-(methylsulfonyl)phenyl)-2-( 5H)-furanone,
(14) 3-(4-Fluorophenyl)-5-methoxy-5-methyl-4-(4-(methylsulfonyl) phenyl)-2-(5H)-furanone,
(15) 5-Ethoxy-3-(4-fluorophenyl)-5-methyl-4-(4-(methylsulfonyl)phenyl)-2-( 5H)-furanone,
(16) 3-(4-Fluorophenyl)-5-methyl-4-(4-(methylsulfonyl)phenyl)-5-propoxy-2-(SH)- furanone, (18) 5-Methyl- 5 -methylthio-4-(4-
(17) 3 -(4-Fluorophenyl)-5-isopropoxy-5-methyl-4- (4-(methylsulfonyl)phenyl)-2-(5H)-furanone,
(18) 5-Methyl-5-methylthio-3-(4-(methylsulfonyl)phenyl)-3 -phenyl-2-(5H)-furanone,
(19) 5-Ethylthio-5-methyl-4-(4-(methylsulfonyl)phenyl)-3-phenyl-2-(SH)-furanone
(20) 5-Ethyl-5-hydroxy-4-(4-(methylsulfonyl)phenyl)-3-phenyl-2- (5H)-furanone,
(21) 5-Ethyl-3-(3-fluorophenyl)-5-hydroxy-4-(4-(methylsulfonyl)phenyl)-2-( 5H)-furanone,
(22) Acetic acid, 3-(4-(methylsulfonyl)phenyl)-5-methyl-5-oxo-4-phenyl-2,5-dihydrofuran-2-yl ester, and
(23) 5-Hydroxy-5-methyl-4-((4-methylsulfonyl)phenyl)-3-(2-naphthyl)-2-(5H)-fura none.

20 more elements

Dependencies are inferred from the claim text.

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Abstract

A compound of formula Ib ##STR40## or a pharmaceutically acceptable salt thereof wherein:

R.sup.1 is selected from the group consisting of
(a) S(O).sub.2 CH.sub.3,
(b) S(O).sub.2 NH.sub.2,
(c) S(O).sub.2 NHC(O)CF.sub.3,
(d) S(O)(NH)NH.sub.2,
(e) S(O)(NH)NHC(O)CF.sub.3,
R.sup.2 is selected from the group consisting of
(a) C.sub.3-6 cycloalkyl,
(b) mono- or di- substituted C.sub.3 -C.sub.6 cycloalkenyl wherein the substituent is selected from the group consisting of
(1) halo,
(2) C.sub.1-4 alkoxy,
(3) C.sub.1-4 alkylthio,
(4) CN,
(5) CF.sub.3,
(6) C.sub.1-6 alkyl,
(7) N.sub.3,
(8) --CO.sub.2 H,
(9) --CO.sub.2 -C.sub.1-6 alkyl,
(10) --C(R.sup.5)(R.sup.6)-OH,
(11) --C(R.sup.5)(R.sup.6)-O-C.sub.1-4 alkyl,
(c) unsubstituted or mono-, di- or tri-substituted phenyl or naphthyl wherein the substituent is selected from the group consisting of
(1) halo,
(2) C.sub.1-4 alkoxy,
(3) C.sub.1-4 alkylthio,
(4) CN,
(5) CF.sub.3,
(6) C.sub.1-6 alkyl,
(7) N.sub.3,
(8) --CO.sub.2 H,
(9) --CO.sub.2 -C.sub.1-4 alkyl,
(10) --C(R.sup.5)(R.sup.6)-OH,
(11) --C(R.sup.5)(R.sup.6)-O-C.sub.1-4 alkyl, and
(12) --C.sub.1-4 alkyl-CO.sub.2 -R.sup.5 ;
(13) --O--(C.sub.1-4 alkyl)-CO.sub.2 R.sup.5,
(d) unsubstituted or mono-, di- or tri-substituted heteroaryl wherein the heteroaryl is a monocyclic aromatic ring of 5 atoms, said ring having one hetero atom which is S, O, or N, and optionally 1, 2, or 3 additional 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 or 3 additional N atoms, said substituents are selected from the group consisting of
(1) halo,
(2) C.sub.1-4 alkyl,
(3) C.sub.1-4 alkoxy,
(4) C.sub.1-4 alkylthio,
(5) CN,
(6) CF.sub.3,
(7) N.sub.3,
(8) --C(R.sup.5)(R.sup.6)-OH, and
(9) --C(R.sup.5)(R.sup.6)-O-C.sub.1-4 alkyl;
(e) an unsubstituted or a mono- or di-substituted benzoheterocycle in which the heterocycle is a 5, 6, or 7-membered ring which may contain 1 or 2 heteroatoms chosen independently from O, S, or N and which may contain a carbonyl group or a sulfonyl group;
the said substituents are selected from the group consisting of
(1) halo,
(2) C.sub.1-4 alkyl,
(3) C.sub.1-4 alkoxy,
(4) C.sub.1-4 alkylthio,
(5) CN,
(6) CF.sub.3,
(7) N.sub.3,
(8) --C(R.sup.5)(R.sup.6)-OH, and
(9) --C(R.sup.5)(R.sup.6)-O-C.sub.1-4 alkyl;
(f) a heterocycloalkyl group of 5, 6 or 7 members which contains 1 or 2 heteroatoms chosen from O, S, or N and optionally contains a carbonyl group or a sulfonyl group
(g) an unsubstituted or a mono- or di-substituted benzocarbocycle in which the carbocycle is a 5, 6, or 7-membered ring which optionally contains a carbonyl group, the said substituents are selected from the group consisting of
(1) halo,
(2) C.sub.1-4 alkyl,
(3) C.sub.1-4 alkoxy,
(4) C.sub.1-4 alkylthio,
(5) CN,
(6) CF.sub.3,
(7) N.sub.3,
(8) --C(R.sup.5)(R.sup.6)-OH, and
(9) --C(R.sup.5)(R.sup.6)-O-C.sub.1-4 alkyl;
R.sup.3 is hydrogen, C.sub.1-4 alkyl, CH.sub.2 OR.sup.7, CN, CH.sub.2 CN, or C.sub.1-4 fluoroalkyl, F, CONR.sup.7.sub.2, unsubstituted or mono- or di-substituted phenyl, unsubstituted or mono or di-substituted benzyl, unsubstituted or mono- or di-substituted heteroaryl, unsubstituted or mono or di-substituted heteroarylmethyl, wherein the substituents are selected from the group consisting of
(1) halo,
(2) C.sub.1-4 alkyl,
(3) C.sub.1-4 alkoxy,
(4) C.sub.1-4 alkylthio,
(5) CN,
(6) CF.sub.3,
(7) N.sub.3,
(8)--C(R.sup.5)(R.sup.6)-OH, and
(9) --C(R.sup.5)(R.sup.6)-O-C.sub.1-4 alkyl;
R.sup.4 is
(a) C.sub.1-4 alkoxy,
(b) C.sub.1-4 alkylthio,
(c) --OH,
(d) --OCOR.sup.7,
(e) --SH,
(f) --SCOR.sup.7,
(g) --OCO.sub.2 R.sup.8,
(h) --SCO.sub.2 R.sup.8,
(i) OCONR.sup.7.sub.2, and
(j) SCONR.sup.7.sub.2 ;
each R.sup.5 or R.sup.6 is independently selected from the group consisting of
(a) hydrogen, and
(b) C.sub.1-4 alkyl,
each R.sup.7 is independently selected from the group consisting of
(a) hydrogen and
(b) R.sup.8 ;
each R.sup.8 is independently selected from the group consisting of
(a) C.sub.1-6 alkyl,
(b) phenyl or monosubstituted phenyl wherein the substituents may be halo, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkylthio, CN, or CF.sub.3,
(c) benzyl or monosubstituted benzyl wherein the substituents may be halo, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkylthio, CN, or CF.sub.3.

96 more elements