Patent EA-000795-B1 (EA)
Title: (methylsulfonyl)phenyl-2-(5h)-furanones as cycloovygenase-2 inhibitors
Inventor: BELLEY MICHEL
IPC: C07D405/12
Filed: 1996-10-09
Abstract: oxy)-4-(4-methylsulfonyl)phenyl-5H-furan-2-one, an1. A compound of Formula I   or a pharmaceutically acceptable salt thereof wherein: X is selected fro claim 1,5,6, 7, 21, 23 or 24 wherein R<16> and R CO, (d) O, (e) S, and (f) N(R<15>) with the proviso that when R<3> and R<4> are other than (1) botherein R<1> is SO2CH3. 35. A pharmaceutically acceptable salt of a compound of formula (I), as defineform a saturated monocyclic carbon ring of 3,4,5,613, 14, 15, 16, 21, 22, 23, 24, 25, 26, 27, 28, 29, 32, 22 or 34.  36. A compound of formula (I), orof (a) C(R<11>)(R<12>),  (b) CO, (c) O, and (d) S; R<1> is selected from the group consisting of  (a12, 13, 14, 15, 16, 21, 22, 23, 24, 25, 26, 27, 28, 29, 32, 22 or 34, for use in treating an inflammatory disease. 37. A compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined in claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 the substituents are selected from the group consisting of (1) hydrogen, (2) halo, (3) C1-C10 a1koxy, (4) C1-C10 alkylthio, (5) CN, (6) C1-C6 fluoroalkyl, (7) C1-C10 alkyl, (8) N3, (9) -CO2H, (10) -Cereof, as defined in claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,21,22,23,24,25,26, CO2-R<5>, (14) benzyloxy, (15) -O-( C1-C6 alkyl)-Cament for the treatment of inflammatory disease. 3no- , di- or tri-substituted heteroaryl wherein th comprising an acceptable, anti-inflammatory amount of a compound of formula (I), as defined in claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 1oms; or the heteroaryl is a monocyclic ring of 6 aor 34, in association with a pharmaceutically acceptable carrier. 40. A compound according to claim 1, which is 5,5-dimethyl-4-(4- methylsulfonylphenyl-3-(2-propoxy)-5H-furan-2-one. 41. A compound according to claim 1, which is pharmaceutically accep CN, (7) CF3, (8) N3, (9) -C(R<5>)(R<6>)-OH,  (10) -C(R<5>)(R<6>)-O- C1-C10 alkyl, and (11) C1-C6 fluoroalkyl; (d) a mono- or di- substituted benzohetan inflammatory disease. 43. A compound according membered ring which may contain 1 or 2 heteroatomsygenase mediated diseases. 44. A compound accordiny contain a carbonyl group or a sulfonyl group; wherein the substituents are selected from the groupy disease. 45. An anti-inflammatory pharmaceuticalalkyl, (4) C1-C10 alkoxy, (5) C1-C10 alkylthio, (6matory amount of a compound of formula (I), as defined in claim 29, 40 or 41 in association with a puoroalkyl; (e) a heterocycloalkyl group of 5, 6 or 7 members which contains 1 or 2 heteroatoms chosen from 0, S, or N and optionally contains a carbonyl group or a sulfonyl group, (f) a mono- or di- substituted benzocarbocycle in which the carbocycle is a 5, 6, or 7-membered ring which optionally contains a carbonyl group, wherein the substituents are selected from the group consisting of (1) hydrogen, (2) halo, (3) C1-C10 alkyl, (4) C1-C10 alkoxy, (5) C1-C10 alkylthio, (6) CN, (7) CF3, (8) N3, (9) -C(R<5>)(R<6>)-OH, (10) -C(R<5>)(R<6>)-O- C1-C10 alkyl, and (11) C1-C6 fluoroalkyl; (g) a mono- or di-substituted bicyclic heteroaryl of 8, 9, or 10 members, containing 2 to 5 heteroatoms chosen independently from O, S or N, and in which each ring contains at least one heteroatom, wherein the substituents are selected from the group consisting of (1) hydrogen, (2) halo, (3) C1-C10 alkyl, (4) C1-C10 alkoxy, (5) C1-C10 alkylthio, (6) CN, (7) CF3, (8) N3, (9) -C(R<5>)(R<6>)-OH, (10) -C(R<5>)(R<6>)-O- C1-C10 alkyl, and (11) C1-C6 fluoroalkyl; R<3> is hydrogen, C1-C10 alkyl, CH2OR<7>, CN, CH2CN, C1-C6 fluoroalkyl, F, CON(R<7>)2, mono- or di-substituted phenyl, mono or di-substituted benzyl, mono- or di-substituted heteroaryl, mono or di-substituted heteroarylmethyl, wherein the substituents are selected from the group consisting of (1) hydrogen, (2) halo, (3) C1-C6 alkyl, (4) C1-C6 alkoxy, (5) C1-C6 alkylthio, (6) CN, (7) CF3, (8) N3, (9) -C(R<5>)(R<6>)-OH, (10) -C(R<5>)(R<6>)-O- C1-C4 alkyl, and (11) C1-C6 fluoroalkyl; R<4> is (a) hydrogen (b) C1-C10 alkyl, (c) C1-C10 alkoxy, (d) C1-C10 alkylthio,  (e) -OH, (f) -OCOR<7>,  (g) -SH, (h) -SCOR<7>,  (i) -OCO2R<8>,  (j) -SCO2R<8>,  (k) OCON(R<7>)2,  (1) SCON(R<7>)2, and (m) C1-C6 fluoroalkyl; or R<3> andR<4> together with the carbon to which they are attached form a saturated monocyclic carbon ring of 3, 4, 5, 6 or 7 atoms; R<5> and <6> are each independently selected from the group consisting of: (a) hydrogen, and (b) C1-C10 alkyl, or R5 and R<6> together with the atom to which they are attached form a saturated monocyclic ring of 3, 4, 5, 6 or 7 atoms; each R<7> is independently selected from the group consisting of: (a) hydrogen, (b) C1-C6 alkyl, (c) phenyl or monosubstituted phenyl wherein the substituents may be halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, CN, or CF3, and (d) benzyl or monosubstituted benzyl wherein the substituents may be halo, C1-C6 alkyl, alkoxy, C1-C6 alkylthio, CN, or CF3, or two R<7> groups taken together with the nitrogen to which they are attached form a saturated monocyclic ring of 5, 6 or 7 atoms, optionally containing an additional O, S or NR<5>; each R<8> is independently selected from the group consisting of: (a) C1-C6 alkyl,  (b) phenyl or monosubstituted phenyl wherein the substituents may be halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, CN, or CF3, and (c) benzyl or monosubstituted benzyl wherein the substituents may be halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, CN, or CF3; R<9> and R<10> are independently selected from the group consisting of: (a) hydrogen, and (b) C1-C7 alkyl, or  R<9> and R<10> together with the carbon atom to which they are attached form a carbonyl or thiocarbonyl group; R<11> and R<12> are independently (a) hydrogen, (b) mono- or di-substituted phenyl or mono- or di-substituted benzyl or mono- or di-substituted heteroaryl or mono- or di substituted heteroarylmethyl, wherein the substituents are selected from the group consisting of (1) hydrogen,  (2) fluoro, chloro, bromo and iodo, (3) C1-C6 alkyl, (4) C1-C6 alkoxy,  (5) C1-C6 alkylthio, (6) CN, (7) CF3, (8) N3, (9) -C(R<13>)(R<14>)-OH,  (10) -C(R<13>)(R<14>)-O-C(R<13>)(R<14>)-O C1-C4 alkyl, and (11) C1-C6  fluoroalkyl, or (c) C1-C7 alkyl, CH2OR<7>, CN, CH2CN, C1-C6 fluoroalkyl, CON(R<7>)2, F, or OR<7>; or R<11> and R<12> together with the carbon to which they are attached form a saturated monocyclic carbon ring of 3, 4, 5, 6 or 7 atoms; R<13> and R<14> are independently selected from the group consisting of: (a) hydrogen, (b) C1-C7 alkyl, or  R<13> and R<14> together with the carbon to which they are attached form a carbonyl, -C(=S)-, or a saturated monocyclic carbon ring of 3, 4, 5, 6, or 7 atoms. R<15> is selected from the group consisting of: (a) hydrogen, (b) C1-C10 alkyl,  (c) mono-, di- or tri-substituted phenyl or naphthyl wherein the substituents are selected from the group consisting of: (1) hydrogen, (2) halo, (3) C1-C10 alkoxy, (4) C1-C10 alkylthio, (5) CN, (6) C1-C6 fluoroalkyl, (7) C1-C10 alkyl, (8) N3,  (9) -CO2H, (10) -CO2- C1-C10 alkyl, (11) -C(R<5>)(R<6>)-OH, (12) -C(R<5> )(R<6>)-O- C1-C4 alkyl, and (13) - C1-C6 alkyl-CO2-R<5>; (14) benzyloxy, (15) -O-( C1-C6 alkyl)-CO2R<5>, and (16) -O-( C1-C6 alkyl)-NR<5>R<6>, (d) mono- , di- or tri-substituted heteroaryl wherein the heteroaryl is a monocyclic aromatic ring of 5 atoms, said ring having one hetero atom which is S, O, or N, and optionally 1, 2, or 3 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, wherein the substituents are selected from the group consisting of: (1) hydrogen, (2) halo, (3) C1-C10 alkyl, (4) C1-C10 alkoxy,  (S) C1-C10 alkylthio,  (6) CN, (7) CF3, (8) N3, (9) -C(R<5>)(R<6>)-OH, (10) -C(R<5>)(R<6>)-O,- C1-C10 alkyl, and (11) C1-C6 fluoroalkyl; (e) 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; wherein the substituents are selected from the group consisting of: (1) hydrogen,  (2) halo, (3) C1-C10 alkyl,  (4) C1-C10 alkoxy, (5) C1-C10 alkylthio, (6) CN, (7) CF3, (8) N3, (9) -C(R<5>)(R<6>)-OH, (10) -C(R<5>)(R<6>)-O-C1-C10 alkyl, and (11) C1-C 6 fluoroalkyl;  (f) a heterocycloalkyl group of 5, 6 or 7 members which contains 1 or 2 heteroatoms chosen from 0, S, or N and optionally contains a carbonyl group or a sulfonyl group, (g) a mono- or di- substituted benzocarbocycle in which the carbocycle is a 5, 6, or 7-membered ring which optionally contains a carbonyl group, wherein the substituents are selected from the group consisting of: (1) hydrogen,  (2) halo, (3) C1-C10 alkyl,  (4) C1-C10 alkoxy, (5) C1-C10 alkylthio, (6) CN, (7) CF3, (8) N3, (9) -C(R<5>)(R<6>)-OH, (10) -C(R<5>)(R<6>)-O-C1-C4 alkyl, and (11) C1-C 6 fluoroalkyl;  R<16> and R<17> are independently selected from the group consisting of: (a) hydrogen, (b) C1-C10 alkyl,  (c) C1-C10 alkanoic acid, (d) C1-C10 alkylamine,  (e) phenyl or monosubstituted phenyl wherein the substituents are halo, C1-C10 alkyl, C1-C10 alkoxy, C1-C10 alkylthio, C1-C10 alkanoic acid, C1-C10 alkylamine, CN, CO2H or CF3, and (f) benzyl or monosubstituted benzyl wherein the substituents are halo, C1-C10 alkyl, C1-C10, C1-C10 alkylthio, C1-C10 alkanoic acid, C1-C10 alkylamine, CN, CO2H or CF3, or R<16> and R<17> together with the nitrogen to which they are attached form a saturated monocyclic ring of 5, 6 or 7 atoms, optionally containing an additional O, S or NR<5>. 2. A compound according to claim 1 wherein R<9> and R<10> together with carbon atom to which they are attached form a carbonyl. 3. A compound according to claim 2 wherein X is selected from the group consisting of: (a) CH2, and (b) O, Y is selected from the group consisting of: (a) CH2, and (b) O,  R<1> is selected from the group consisting of: (a) SO2CH3, (b) SO2NR<16>R,<17> and (c) S(O)(NH)NH2; R<2> is selected from the group c