3,4-diaryl-2-hydroxy-2,5-dihydrofurans as prodrugs to COX-2 inhibitors

• US 5,698,584 A
• Filed: 10/25/1996
• Issued: 12/16/1997
• Est. Priority Date: 02/13/1996
• Status: Expired due to Fees

• Current Assignee: Merck Frosst Co. (Merck & Co., Inc.)
• Original Assignee: Merck Frosst Canada & Company (Merck & Co., Inc.)
• Inventors: Leger, Serge, Black, Cameron, Hughes, Gregory, Han, Yongxin, Wang, Zhaoyin, Hamel, Pierre, Prasit, Petpiboon
• Primary Examiner(s): DENTZ, BERNARD I
• Application Number:
  US08/738,143
• Time in Patent Office: 417 Days
• Field of Search: 549/476, 549/479, 549/480, 514/462, 514/471, 514/472, 514/473
• US Class Current: 514/462
• CPC Class Codes: C07C 317/22 with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
• CPC Class Codes: C07C 323/64 containing thio groups and sulfur atoms, not being part of thio groups, bound to the same carbon skeleton
• CPC Class Codes: C07D 213/34 to which a second hetero atom is attached
• CPC Class Codes: C07D 307/30 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 307/32 Oxygen atoms
• CPC Class Codes: C07D 307/58 One oxygen atom, e.g. butenolide
• CPC Class Codes: C07D 307/60 Two oxygen atoms, e.g. succinic anhydride
• CPC Class Codes: C07D 307/62 Three oxygen atoms, e.g. ascorbic acid
• CPC Class Codes: C07D 307/64 Sulfur atoms
• CPC Class Codes: C07D 307/66 Nitrogen atoms
• CPC Class Codes: C07D 307/68 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 307/94 spiro-condensed with carbocyclic rings or ring systems, e.g. griseofulvins
• CPC Class Codes: C07D 405/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07F 9/117 with cycloaliphatic alcohols

Abstract

The invention encompasses the novel compound of Formula I useful in the treatment of cyclooxygenase-2 mediated diseases. ##STR1## The invention also encompasses certain pharmaceutical compositions for treatment of cyclooxygenase-2 mediated diseases comprising compounds of Formula I.

Claims

1. A compound of Formula I ##STR65## or a pharmaceutically acceptable salt thereof wherein:

R¹ is selected from the group consisting of

(a) S(O)₂ CH₃,

(b) S(O)₂ NHR⁸,

(c) S(O)₂ NHC(O)CF₃,

(d) S(O)(NH)NH₂,

(e) S(O)(NH)NHC(O)CF₃,

(f) P(O)(CH₃)NH₂,

(g) P(O)(CH₃)₂, and

(h) C(S)NH₂ ;

R² is selected from the group consisting of

(a) NR¹⁰ R¹¹,

(b) SR¹¹,

(c) OR¹¹,

(d) R¹¹,

(e) C1-10alkenyl,

(f) C1-10alkynyl,

(g) unsubstituted, mono-, di-, tri- or tetra-substituted C₃ -C₁₀ cycloalkenyl wherein the substituents are independently selected from the group consisting of

(1) halo,

(2) C_1-6 alkoxy,

(3) C_1-6 alkylthio,

(4) CN,

(5) CF₃,

(6) C_1-10 alkyl,

(7) N₃,

(8) --CO₂ H,

(9) --CO₂ --C_1-10 alkyl,

(10) --C(R¹²)(R¹³)--OH,

(11) --C(R¹²)(R¹³)--O--C_1-4 alkyl,

(12) --C_1-10 alkyl-CO₂ --R¹² ;

(13) benzyloxy,

(14) --O--(C_1-10 alkyl)-CO₂ R¹², and

(15) --O--(C_1-10 alkyl)-NR¹² R¹³ ;

(h) a mono-, di-, tri- or tetra-substituted heterocycloalkyl group of 5, 6 or 7 members or a benzoheterocycle wherein said heterocycloalkyl or benzoheterocycle contains 1 or 2 heteroatoms selected from O, S, or N and optionally contains a carbonyl group or a sulfonyl group, and wherein said substituents are independently selected from the group consisting of

(1) halo,

(2) C_1-10 alkyl,

(3) C_1-10 alkoxy,

(4) C_1-10 alkylthio,

(5) CN,

(6) CF₃,

(7) N₃,

(8) --C(R¹²)(R¹³)--OH, and

(9) --C(R¹²)(R¹³)--O--C_1-10 alkyl;

(i) styryl or mono or di-substituted styryl wherein the substituent are independently selected from the group consisting of

(1) halo,

(2) C_1-6 alkoxy,

(3) C_1-6 alkylthio,

(4) CN,

(5) CF₃,

(6) C_1-10 alkyl,

(7) N₃,

(8) --CO₂ H,

(9) --CO₂ --C_1-10 alkyl,

(10) --C(R¹²)(R¹³)--OH,

(11) --C(R¹²)(R¹³)--O--C_1-4 alkyl,

(12) --C_1-10 alkyl-CO₂ --R¹² ;

(13) benzyloxy,

(14) --O--(C_1-10 alkyl)-CO₂ R¹², and

(15) --O--(C_1-10 alkyl)-NR¹² R¹³ ;

(j) phenylacetylene or mono- or di-substituted phenylacetylene wherein the substituents are independently selected from the group consisting of

(1) halo,

(2) C_1-6 alkoxy,

(3) C_1-6 alkylthio,

(4) CN,

(5) CF₃,

(6) C_1-10 alkyl,

(7) N₃,

(8) --CO₂ H,

(9) --CO₂ --C_1-10 alkyl,

(10) --C(R¹²)(R¹³)--OH,

(11) --C(R¹²)(R¹³)--O--C_1-4 alkyl,

(12) --C_1-10 alkyl-CO₂ --R¹²,

(13) benzyloxy,

(14) --O--(C_1-10 alkyl)-CO₂ R¹²,

(15) --O--(C_1-10 alkyl)-NR¹² R¹³,

(k) C_1-10 fluoroalkenyl, and

(l) mono- or di-substituted bicyclic heteroaryl of 8, 9 or 10 members, containing 2, 3, 4 or 5 heteroatoms, wherein at least one heteroatom resides on each ring of said bicyclic heteroaryl, said heteroatoms independently selected from O, S and N and said substituents are independently selected from the group consisting of

(1) hydrogen,

(2) halo,

(3) C_1-10 alkyl,

(4) C_1-10 alkoxy,

(5) C_1-6 alkylthio,

(6) CN,

(7) C_1-6 fluoroalkyl, including CF₃,

(8) N₃,

(9) --C(R⁵)(R⁶)--OH,

(10) --C(R⁵)(R⁶)--O--C_1-10 alkyl;

R³ is hydrogen, C_1-10 alkyl, CH₂ OR⁸, CN, CH₂ CN, or C_1-6 fluoroalkyl, F, CONR⁸₂, 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 independently selected from the group consisting of

(1) halo,

(2) C_1-10 alkyl,

(3) C_1-10 alkoxy,

(4) C_1-10 alkylthio,

(5) CN,

(6) CF₃,

(7) N₃,

(8) --C(R¹²)(R¹³)--OH, and

(9) --C(R¹²)(R¹³)--O--C_1-10 alkyl;

R⁴ is

(a) hydrogen,

(b) C_1-10 alkyl,

(c) C_1-10 alkoxy,

(d) C_1-10 alkylthio,

(e) --OH,

(f) --OCOR⁸,

(g) --SH,

(h) --SCOR⁸,

(i) --OCO₂ R⁹,

(j) --SCO₂ R⁹,

(k) OCONR⁸₂,

(l) SCONR⁸₂ ;

(m) C_3-10 cycloalkoxy, and

(n) C_3-10 cycloalkylthio,

or R³ and R⁴ together with the carbon to which they are attached form a monocyclic ring of 3, 4, 5, 6, or 7 members which ring optionally contains one or two heteroatoms selected from O, S or N;

R⁵ is selected from the group consisting of

(a) OR¹⁷,

(b) SR¹⁸,

(c) NR¹⁷ R¹⁸,

(d) NHS(O)₂ R¹⁸,

(e) S(O)R¹⁸,

(f) S(O)₂ R¹⁸,

(g) S(O)₂ NR¹⁷₂,

(h) OP(O)(OR¹⁶)₂ ;

each R⁸ is independently selected from the group consisting of

(a) hydrogen and

(b) R⁹ ;

each R⁹ is independently selected from the group consisting of

(a) C_1-10 alkyl,

(b) --C_1-10 alkyl-CO₂ H

(c) C_1-10 alkyl-NH₂

(d) phenyl or mono-, di- or tri-substituted phenyl wherein the substituents are independently selected from halo, C_1-10 alkyl, C_1-10 alkoxy, C_1-10 alkylthio, C_1-10 alklyCO₂ H, C_1-10 alkylNH₂, CN, CO₂ H and CF₃,

(e) benzyl or mono-, di- or tri-substituted benzyl wherein the substituents are independently selected from halo, C_1-10 alkyl, C_1-10 alkoxy, C_1-10 alkylthio, C_1-10 alkylCO₂ H, C_1-10 alkylNH₂, CN, CO₂ H and CF₃,

(f) C_3-10 cycloalkyl,

(g) C_1-10 alkanoyl, and

(h) benzoyl or mono-, di-, or trisubstituted benzoyl wherein the substituents are independently selected from halo, C_1-10 alkyl, C_1-10 alkoxy, C_1-10 alkylthio, C_1-10 alkylCO₂ H, --C_1-10 alkylNH₂, CN, CO₂ H and CF₃,

each R¹⁰ is independently selected from the group consisting of

(a) hydrogen and

(b) R¹¹ ;

R¹¹ is selected from the group consisting of

(a) C_1-10 alkyl,

(b) C_3-10 cycloalkyl,

(c) unsubstituted, mono-, di- or tri-substituted phenyl or naphthyl wherein the substituents are independently selected from the group consisting of

(1) halo,

(2) C_1-10 alkoxy,

(3) C_1-10 alkylthio,

(4) CN,

(5) CF₃,

(6) C_1-10 alkyl,

(7) N₃,

(8) --CO₂ H,

(9) --CO₂ --C_1-10 alkyl,

(10) --C(R¹²)(R¹³)--OH,

(11) --C(R¹²)(R¹³)--O--C_1-4 alkyl,

(12) --C_1-6 alkyl-CO₂ --R¹²,

(13) benzyloxy,

(14) --O--(C_1-10 alkyl)-CO₂ R¹², and

(15) --O--(C_1-10 alkyl)-NR¹² R¹³,

(d) unsubstituted, 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 said 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, and wherein said substituents are independently selected from the group consisting of

(1) halo,

(2) C_1-10 alkyl,

(3) C_1-10 alkoxy,

(4) C_1-10 alkylthio,

(5) CN,

(6) CF₃,

(7) N₃,

(8) --C(R¹²)(R¹³)--OH, and

(9) --C(R¹²)(R¹³)--O--C_1-10 alkyl;

(e) unsubstituted, mono- or di-substituted benzoheterocycle in which the benzoheterocycle is a 5, 6, or 7-membered ring which contains 1 or 2 heteroatoms independently selected from O, S, or N and optionally a carbonyl group or a sulfonyl group, wherein said substituents are selected from the group consisting of

(1) halo,

(2) C_1-10 alkyl,

(3) C_1-10 alkoxy,

(4) C_1-10 alkylthio,

(5) CN,

(6) CF₃,

(7) N₃,

(8) --C(R¹²)(R¹³)--OH, and

(9) --C(R¹²)(R¹³)--O--C_1-10 alkyl;

(f) unsubstituted, mono- or di-substituted benzocarbocycle in which the carbocycle is a 5, 6, or 7-membered ring which optionally contains a carbonyl group, wherein said substituents are independently selected from the group consisting of

(1) halo,

(2) C_1-10 alkyl,

(3) C_1-10 alkoxy,

(4) C_1-10 alkylthio,

(5) CN,

(6) CF₃,

(7) N₃,

(8) --C(R¹²)(R¹³)--OH, and

(9) --C(R¹²)(R¹³)--O--C_1-10 alkyl;

each R¹² or R¹³ is independently selected from the group consisting of

(a) hydrogen, and

(b) C_1-10 alkyl,

or R¹² and R¹³ together with the atom to which they are attached form a saturated monocyclic ring of 3, 4, 5, 6 or 7 atoms;

each R¹⁶ is independently selected from the group consisting of hydrogen, C_1-6 alkyl and unsubstituted or mono- or disubstituted benzyl, wherein the substituents are selected from halo, CN, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylthio or C_1-6 fluoroalkyl;

each R¹⁷ is independently selected from the group consisting of

(a) hydrogen and

(b) R¹⁸ ; and

each R¹⁸ is independently selected from the group consisting of

(a) C_1-10 alkyl,

(b) --C_1-10 alkyl-CO₂ H

(c) C_1-10 alkyl-NH₂

(d) phenyl or mono-, di- or tri-substituted phenyl wherein the substituents are independently selected from halo, C_1-10 alkyl, C_1-10 alkoxy, C_1-10 alkylthio, C_1-10 alklyCO₂ H, C_1-10 alkylNH₂, CN, CO₂ H and CF₃,

(e) benzyl or mono-, di- or tri-substituted benzyl wherein the substituents are independently selected from halo, C_1-10 alkyl, C_1-10 alkoxy, C_1-10 alkylthio, C_1-10 alkylCO₂ H, C_1-10 alkylNH₂, CN, CO₂ H and CF₃,

(f) C_3-10 cycloalkyl,

(g) H-(oxyethyl)n wherein n is 1 to 6,

(h) C_1-10 alkanoyl, and

(i) benzoyl or mono-, di-, or trisubstituted benzoyl wherein the substituents are independently selected from halo, C_1-10 alkyl, C_1-10 alkoxy, C_1-10 alkylthio, C_1-10 alkylCO₂ H, --C_1-10 alkylNH₂, CN, CO₂ H and CF₃.

2. A compound according to claim 1 wherein

R⁵ is selected from the group consisting of

(a) OR¹⁷,

(b) SR¹⁸, and

(c) NHS(O)₂ R¹⁸.

3. A compound according to claim 1 wherein:

R¹ is selected from the group consisting of

(a) S(O)₂ CH₃,

(b) S(O)₂ NHR⁸,

(c) S(O)₂ NHC(O)CF₃, and

(d) S(O)(NH)NH₂ ;

R² is selected from the group consisting of

(a) SR¹¹,

(b) OR¹¹,

(c) R¹¹,

(d) unsubstituted, mono-, di-, tri- or tetra-substituted C_3-6 cycloalkenyl wherein the substituents are independently selected from the group consisting of

(1) halo,

(2) C_1-6 alkoxy,

(3) C_1-6 alkylthio,

(4) CN,

(5) CF₃,

(6) C_1-10 alkyl,

(7) N₃,

(8) --CO₂ H,

(9) --CO₂ --C_1-6 alkyl,

(10) --C(R¹²)(R¹³)--OH,

(11) --C(R¹²)(R¹³)--O--C_1-4 alkyl,

(12) --C_1-6 alkyl-CO₂ --R¹² ;

(13) benzyloxy,

(14) --O--(C_1-10 alkyl)-CO₂ R¹², and

(15) --O--(C_1-10 alkyl)-NR¹² R¹³ ;

(e) a mono-, di-, tri- or tetra-substituted heterocycloalkyl group of 5, 6 or 7 members or a benzoheterocycle wherein said heterocycloalkyl or benzoheterocycle contains 1 or 2 heteroatoms selected from O, S, or N and optionally contains a carbonyl group or a sulfonyl group, and wherein said substituents are independently selected from the group consisting of

(1) halo,

(2) C_1-6 alkyl,

(3) C_1-6 alkoxy,

(4) C_1-6 alkylthio,

(5) CN,

(6) CF₃,

(7) N₃,

(8) --C(R¹²)(R¹³)--OH, and

(9) --C(R¹²)(R¹³)--O--C_1-6 alkyl;

(f) phenylacetylene or mono- or di-substituted phenylacetylene wherein the substituents are independently selected from the group consisting of

(1) halo,

(2) C_1-6 alkoxy,

(3) C_1-6 alkylthio,

(4) CN,

(5) CF₃,

(6) C_1-6 alkyl,

(7) N₃,

(8) --CO₂ H,

(9) --CO₂ --C_1-6 alkyl,

(10) --C(R¹²)(R¹³)--OH,

(11) --C(R¹²)(R¹³)--O--C_1-4 alkyl,

(12) --C_1-6 alkyl-CO₂ --R¹²,

(13) benzyloxy,

(14) --O--(C_1-6 alkyl)-CO₂ R¹²,

(15) --O--(C_1-6 alkyl)-NR¹² R¹³, and

R³ is hydrogen, C_1-10 alkyl, CH₂ OR⁸, CN, CH₂ CN, or C_1-6 fluoroalkyl, F, CONR⁸₂ ;

R⁴ is

(a) hydrogen,

(b) C_1-6 alkyl,

(c) C_1-6 alkoxy,

(d) C_1-6 alkylthio,

(e) --OH,

(f) --OCOR⁸,

(g) --SH,

or R³ and R⁴ together with the carbon to which they are attached form a monocyclic ring of 3, 4, 5, 6, or 7 members which ring optionally contains one or two heteroatoms selected from O, S or N;

R⁵ is selected from the group consisting of

(a) OR¹⁷,

(b) SR¹⁸, and

(c) NHS(O)₂ R¹⁸ ;

each R⁸ is independently selected from the group consisting of

(a) hydrogen and

(b) R⁹ ;

each R⁹ is independently selected from the group consisting of

(a) C_1-10 alkyl,

(b) --C_1-10 alkyl-CO₂ H

(c) C_1-10 alkyl-NH₂

(d) phenyl or mono-, di- or tri-substituted phenyl wherein the substituents are independently selected from halo, C_1-10 alkyl, C_1-10 alkoxy, C_1-10 alkylthio, C_1-10 alklyCO₂ H, C_1-10 alkylNH₂, CN, CO₂ H and CF₃,

(e) benzyl or mono-, di- or tri-substituted benzyl wherein the substituents are independently selected from halo, C_1-10 alkyl, C_1-10 alkoxy, C_1-10 alkylthio, C_1-10 alkylCO₂ H, C_1-10 alkylNH₂, CN, CO₂ H and CF₃,

(f) C_3-10 cycloalkyl,

(g) C₁ -C₁₀ alkanoyl, and

(h) benzoyl or mono-, di-, or trisubstituted benzoyl wherein the substituents are independently selected from halo, C_1-10 alkyl, C_1-10 alkoxy, C_1-10 alkylthio, C_1-10 alkylCO₂ H, --C_1-10 alkylNH₂, CN, CO₂ H and CF₃,

R¹¹ is selected from the group consisting of

(a) C_1-10 alkyl,

(b) C_3-10 cycloalkyl,

(c) unsubstituted, mono-, di- or tri-substituted phenyl or naphthyl wherein the substituents are independently selected from the group consisting of

(1) halo,

(2) C_1-6 alkoxy,

(3) C_1-6 alkylthio,

(4) CN,

(5) CF₃,

(6) C_1-6 alkyl,

(7) N₃,

(8) --CO₂ H,

(9) --CO₂ --C_1-6 alkyl,

(10) --C(R¹²)(R¹³)--OH,

(11) --C(R¹²)(R¹³)--O--C_1-4 alkyl,

(12) --C_1-6 alkyl-CO₂ --R¹²,

(13) benzyloxy,

(14) --O--(C_1-6 alkyl)-CO₂ R¹², and

(15) --O--(C_1-6 alkyl)-NR¹² R¹³,

(d) unsubstituted, 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 said 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, and wherein said substituents are independently selected from the group consisting of

(1) halo,

(2) C_1-6 alkyl,

(3) C_1-6 alkoxy,

(4) C_1-6 alkylthio,

(5) CN,

(6) CF₃,

(7) N₃,

(8) --C(R¹²)(R¹³)--OH, and

(9) --C(R¹²)(R¹³)--O--C_1-6 alkyl;

(e) unsubstituted, mono- or di-substituted benzoheterocycle in which the benzoheterocycle is a 5, 6, or 7-membered ring which contains 1 or 2 heteroatoms independently selected from O, S, or N and optionally a carbonyl group or a sulfonyl group, wherein said substituents are selected from the group consisting of

(1) halo,

(2) C_1-6 alkyl,

(3) C_1-6 alkoxy,

(4) C_1-6 alkylthio,

(5) CN,

(6) CF₃,

(7) N₃,

(8) --C(R¹²)(R¹³)--OH, and

(9) --C(R¹²)(R¹³)--O--C_1-10 alkyl;

(f) unsubstituted, mono- or di-substituted benzocarbocycle in which the carbocycle is a 5, 6, or 7-membered ring which optionally contains a carbonyl group, wherein said substituents are independently selected from the group consisting of

(1) halo,

(2) C_1-6 alkyl,

(3) C_1-6 alkoxy,

(4) C_1-6 alkylthio,

(5) CN,

(6) CF₃,

(7) N₃,

(8) --C(R¹²)(R¹³)--OH, and

(9) --C(R¹²)(R¹³)--O--C_1-10 alkyl;

each R¹² or R¹³ is independently selected from the group consisting of

(a) hydrogen, and

(b) C_1-6 alkyl,

each R¹⁷ is independently selected from the group consisting of

(a) hydrogen and

(b) R¹⁸ ; and

each R¹⁸ is independently selected from the group consisting of

(a) C_1-6 alkyl,

(b) --C_1-10 alkyl-CO₂ H

(c) C_1-6 alkanoyl, and

(d) H-(oxyethyl)n wherein n is 1 to 6.

4. A compound according to claim 3 wherein:

R¹ is selected from the group consisting of

(a) S(O)₂ CH₃, and

(b) S(O)₂ NHR⁸ ;

R² is selected from the group consisting of

(a) OR¹¹,

(b) R¹¹,

(c) a mono-, di-, tri- or tetra-substituted heterocycloalkyl group of 5, 6 or 7 members or a benzoheterocycle wherein said heterocycloalkyl or benzoheterocycle contains 1 or 2 heteroatoms selected from O, S, or N and optionally contains a carbonyl group or a sulfonyl group, and wherein said substituents are independently selected from the group consisting of

(1) halo,

(2) C_1-4 alkyl,

(3) C_1-4 alkoxy,

(4) C_1-4 alkylthio,

(5) CF₃, and

(6) --C(R¹²)(R¹³)--OH;

(d) phenylacetylene or mono- or di-substituted phenylacetylene wherein the substituents are independently selected from the group consisting of

(1) halo,

(2) C_1-4 alkyl,

(3) C_1-4 alkoxy,

(4) C_1-4 alkylthio,

(5) CF₃, and

(6) --C(R¹²)(R¹³)--OH;

R³ is hydrogen, C_1-4 alkyl, CH₂ OH, or C_1-6 fluoroalkyl, F, CONH₂ ;

R⁴ is

(a) hydrogen,

(b) C_1-4 alkyl,

(c) C_1-4 alkoxy,

(d) C_1-4 alkylthio,

(e) --OH,

or R³ and R⁴ together with the carbon to which they are attached form a monocyclic ring of 3, 4, 5, 6, or 7 members which ring optionally contains one or two heteroatoms selected from O, S or N;

R⁵ is selected from the group consisting of

(a) OR¹⁷, and

(b) SR¹⁸ ;

each R⁸ is independently selected from the group consisting of

(a) hydrogen and

(b) R⁹ ;

each R⁹ is independently selected from the group consisting of

(a) C_1-4 alkyl,

(b) --C_1-4 alkyl-CO₂ H

(c) phenyl or mono-, di- or tri-substituted phenyl wherein the substituents are independently selected from halo, C_1-4 alkyl, C_1-4 alkoxy, C_1-4 alkylthio, C_1-4 alklyCO₂ H, C_1-4 alkylNH₂, CN, CO₂ H and CF₃,

(f) C_3-6 cycloalkyl,

(g) C₁ -C₄ alkanoyl, and

(h) benzoyl or mono-, di-, or trisubstituted benzoyl wherein the substituents are independently selected from halo, C_1-4 alkyl, C_1-4 alkoxy, C_1-4 alkylthio, C_1-4 alkylCO₂ H, --C_1-4 alkylNH₂, CN, CO₂ H and CF₃,

R¹¹ is selected from the group consisting of

(a) unsubstituted, mono- or di-substituted phenyl wherein the substituents are independently selected from the group consisting of

(1) halo,

(2) C_1-4 alkoxy,

(3) C_1-4 alkylthio,

(5) CF₃,

(6) C_1-4 alkyl,

(7) --CO₂ H,

(8) --CO₂ --C_1-6 alkyl,

(9) --C(R¹²)(R¹³)--OH,

(d) unsubstituted, mono- or di-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 said 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, and wherein said substituents are independently selected from the group consisting of

(1) halo,

(2) C_1-4 alkoxy,

(3) C_1-4 alkylthio,

(4) CF₃,

(5) C_1-4 alkyl,

(6) --CO₂ H,

(7) --CO₂ --C_1-6 alkyl,

(8) --C(R¹²)(R¹³)--OH,

(e) unsubstituted, mono- or di-substituted benzoheterocycle in which the benzoheterocycle is a 5, 6, or 7-membered ring which contains 1 or 2 heteroatoms independently selected from O, S, or N and optionally a carbonyl group or a sulfonyl group, wherein said substituents are selected from the group consisting of

(1) halo,

(2) C_1-4 alkoxy,

(3) C_1-4 alkylthio,

(4) CF₃,

(5) C_1-4 alkyl,

(6) --CO₂ H,

(7) --CO₂ --C_1-6 alkyl,

(8) --C(R¹²)(R¹³)--OH,

(f) unsubstituted, mono- or di-substituted benzocarbocycle in which the carbocycle is a 5, 6, or 7-membered ring which optionally contains a carbonyl group, wherein said substituents are independently selected from the group consisting of

(1) halo,

(2) C_1-4 alkoxy,

(3) C_1-4 alkylthio,

(4) CF₃,

(5) C_1-4 alkyl,

(6) --CO₂ H,

(7) --CO₂ --C_1-6 alkyl,

(8) --C(R¹²)(R¹³)--OH,

each R¹² or R¹³ is independently selected from the group consisting of

(a) hydrogen, and

(b) C_1-6 alkyl,

each R¹⁷ is independently selected from the group consisting of

(a) hydrogen and

(b) R¹⁸ ; and

each R¹⁸ is independently selected from the group consisting of

(a) C_1-4 alkyl,

(b) --C_1-4 alkyl-CO₂ H

(c) C_1-6 alkanoyl, and

(d) H-(oxyethyl)n wherein n is 1 to 4.

5. A compound according to claim 4 wherein:

R¹ is selected from the group consisting of

(a) S(O)₂ CH₃, and

(b) S(O)₂ NH₂ ;

R² is selected from the group consisting of

(a) OR¹¹,

(b) R¹¹,

(c) a mono- or di-substituted heterocycloalkyl group of 5 or 6 members or a benzoheterocycle wherein said heterocycloalkyl or benzoheterocycle contains 1 or 2 heteroatoms selected from O, S, or N and optionally contains a carbonyl group or a sulfonyl group, and wherein said substituents are independently selected from the group consisting of

(1) halo,

(2) C_1-3 alkyl,

(3) C_1-3 alkoxy,

(4) C_1-3 alkylthio, and

(5) CF₃,

(d) phenylacetylene or mono- or di-substituted phenylacetylene wherein the substituents are independently selected from the group consisting of

(1) halo,

(2) C_1-3 alkyl,

(3) C_1-3 alkoxy,

(4) C_1-3 alkylthio, and

(5) CF₃,

R³ is hydrogen, C_1-4 alkyl, C_1-6 fluoroalkyl or F;

R⁴ is

(a) hydrogen,

(b) C_1-3 alkyl,

(c) C_1-3 alkoxy,

(d) C_1-3 alkylthio,

(e) --OH,

or R³ and R⁴ together with the carbon to which they are attached form a monocyclic ring of 3, 4, 5 or 6 members which ring optionally contains one or two heteroatoms selected from O, S or N;

R⁵ is selected from the group consisting of

(a) OR¹⁷, and

(b) SR¹⁸ ;

each R⁸ is independently selected from the group consisting of

(a) hydrogen and

(b) R⁹ ;

each R⁹ is independently selected from the group consisting of

(a) C_1-4 alkyl,

(b) --C_1-4 alkyl-CO₂ H

(f) C_3-6 cycloalkyl,

(g) C_1-3 alkanoyl, and

R¹¹ is selected from the group consisting of

(a) unsubstituted, mono- or di-substituted phenyl wherein the substituents are independently selected from the group consisting of

(1) F or Cl,

(2) C_1-4 alkoxy,

(3) C_1-4 alkylthio,

(5) CF₃,

(6) C_1-4 alkyl, and

(7) --CO₂ H,

(d) unsubstituted, mono- or di-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 said 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, and wherein said substituents are independently selected from the group consisting of

(1) F or Cl,

(2) C_1-4 alkoxy,

(3) C_1-4 alkylthio,

(5) CF₃,

(6) C_1-4 alkyl, and

(7) --CO₂ H,

(e) unsubstituted, mono- or di-substituted benzoheterocycle in which the benzoheterocycle is a 5 or 6-membered ring which contains 1 or 2 heteroatoms independently selected from O, S, or N and optionally a carbonyl group or a sulfonyl group, wherein said substituents are selected from the group consisting of

(1) F or Cl,

(2) C_1-4 alkoxy,

(3) C_1-4 alkylthio,

(5) CF₃,

(6) C_1-4 alkyl, and

(7) --CO₂ H,

(f) unsubstituted, mono- or di-substituted benzocarbocycle in which the carbocycle is a 5 or 6-membered ring which optionally contains a carbonyl group, wherein said substituents are independently selected from the group consisting of

(1) F or Cl,

(2) C_1-4 alkoxy,

(3) C_1-4 alkylthio,

(5) CF₃,

(6) C_1-4 alkyl, and

(7) --CO₂ H,

each R¹⁷ is independently selected from the group consisting of

(a) hydrogen and

(b) R¹⁸ ; and

each R¹⁸ is independently selected from the group consisting of

(a) C_1-4 alkyl,

(b) --C_1-4 alkyl-CO₂ H

(c) C_1-4 alkanoyl, and

(d) H-(oxyethyl)n wherein n is 1, 2, 3 or 4.

6. A compound according to claim 5 wherein:

R¹ is selected from the group consisting of

(a) S(O)₂ CH₃, and

(b) S(O)₂ NH₂ ;

R² is selected from the group consisting of

(a) OR¹¹,

(b) R¹¹,

(c) a mono- or di-substituted heterocycloalkyl group of 5 or 6 members wherein said heterocycloalkyl contains 1 or 2 heteroatoms which is N and optionally contains a carbonyl group, and wherein said substituents are independently selected from the group consisting of

(1) Cl or F,

(2) C_1-2 alkyl, and

(3) C_1-2 alkoxy,

(d) phenylacetylene or mono- or di-substituted phenylacetylene wherein the substituents are independently selected from the group consisting of

(1) Cl or F,

(2) C_1-2 alkyl, and

(3) C_1-2 alkoxy,

R³ is hydrogen, C_1-3 alkyl;

R⁴ is hydrogen, C_1-3 alkyl;

or R³ and R⁴ together with the carbon to which they are attached form a monocyclic ring of 3, 4, 5 or 6 carbon atoms;

R⁵ is selected from the group consisting of

(a) OR¹⁷, and

(b) SR¹⁸ ;

each R⁸ is independently selected from the group consisting of

(a) hydrogen and

(b) R⁹ ;

each R⁹ is independently selected from the group consisting of

(a) C_1-4 alkyl,

(b) --C_1-4 alkyl-CO₂ H

(f) C_3-6 cycloalkyl, and

(g) C_1-3 alkanoyl,

R¹¹ is selected from the group consisting of

(a) unsubstituted, mono- or di-substituted phenyl wherein the substituents are independently selected from the group consisting of

(1) F or Cl,

(2) C_1-4 alkoxy,

(3) C_1-4 alkylthio,

(5) CF₃,

(6) C_1-4 alkyl, and

(7) --CO₂ H,

(d) unsubstituted, mono- or di-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 said 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, and wherein said substituents are independently selected from the group consisting of

(1) F or Cl,

(2) C_1-4 alkoxy,

(3) C_1-4 alkylthio,

(5) CF₃,

(6) C_1-4 alkyl, and

(7) --CO₂ H,

(e) unsubstituted, mono- or di-substituted benzoheterocycle in which the benzoheterocycle is a 5 or 6-membered ring which contains 1 or 2 heteroatoms independently selected from O, S, or N and optionally a carbonyl group or a sulfonyl group, wherein said substituents are selected from the group consisting of

(1) F or Cl,

(2) C_1-4 alkoxy,

(3) C_1-4 alkylthio,

(5) CF₃,

(6) C_1-4 alkyl, and

(7) --CO₂ H,

(f) unsubstituted, mono- or di-substituted benzocarbocycle in which the carbocycle is a 5 or 6-membered ring which optionally contains a carbonyl group, wherein said substituents are independently selected from the group consisting of

(1) F or Cl,

(2) C_1-4 alkoxy,

(3) C_1-4 alkylthio,

(5) CF₃,

(6) C_1-4 alkyl, and

(7) --CO₂ H,

each R¹⁷ is independently selected from the group consisting of

(a) hydrogen and

(b) R¹⁸ ; and

each R¹⁸ is independently selected from the group consisting of

(a) C_1-4 alkyl,

(b) --C_1-4 alkyl-CO₂ H

(c) C_1-6 alkanoyl, and

(d) H-(oxyethyl)n wherein n is 1 to 4.

7. A compound according to claim 6 wherein:

R¹ is selected from the group consisting of

(a) S(O)₂ CH₃, and

(b) S(O)₂ NH₂ ;

R² is selected from the group consisting of

(a) OR¹¹,

(b) R¹¹,

(c) a mono- or di-substituted heterocycloalkyl group of 5 or 6 members wherein said heterocycloalkyl contains 1 or 2 heteroatoms which is N and optionally contains a carbonyl group, and wherein said substituents are independently selected from the group consisting of

(1) Cl or F,

(2) C_1-2 alkyl, and

(3) C_1-2 alkoxy;

R³ is hydrogen, methyl or ethyl;

R⁴ is hydrogen, methyl or ethyl;

R⁵ is OR¹⁷ ;

R¹¹ is selected from the group consisting of

(a) unsubstituted, mono- or di-substituted phenyl wherein the substituents are independently selected from the group consisting of

(1) F or Cl,

(2) C_1-4 alkoxy,

(3) C_1-4 alkylthio,

(5) CF₃,

(6) C_1-4 alkyl, and

(7) --CO₂ H,

(b) unsubstituted, mono- or di-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 said 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, and wherein said substituents are independently selected from the group consisting of

(1) F or Cl,

(2) C_1-4 alkoxy,

(3) C_1-4 alkylthio,

(5) CF₃,

(6) C_1-4 alkyl, and

(7) --CO₂ H,

each R¹⁷ is independently selected from the group consisting of

(a) hydrogen and

(b) R¹⁸ ; and

each R¹⁸ is independently selected from the group consisting of

(a) C_1-4 alkyl,

(b) --C_1-4 alkyl-CO₂ H

(c) C_1-6 alkanoyl, and

(d) H-(oxyethyl)n wherein n is 2, 3 or 4.

8. A compound according to claim 7 wherein:

R¹ is selected from the group consisting of

(a) S(O)₂ CH₃, and

(b) S(O)₂ NH₂ ;

R² is selected from the group consisting of

(a) OR¹¹,

(b) R¹¹,

(c) a mono- or di-substituted heterocycloalkyl group of 5 or 6 members wherein said heterocycloalkyl contains 1 or 2 heteroatoms which is N and optionally contains a carbonyl group, and wherein said substituents are independently selected from the group consisting of

(1) Cl or F,

(2) C_1-2 alkyl, and

(3) C_1-2 alkoxy;

R³ is hydrogen, methyl or ethyl;

R⁴ is hydrogen, methyl or ethyl;

R⁵ is OR¹⁷ ;

R¹¹ is selected from the group consisting of

(a) unsubstituted, mono- or di-substituted phenyl wherein the substituents are independently selected from the group consisting of

(1) F or Cl,

(2) C_1-4 alkoxy,

(3) C_1-4 alkylthio,

(5) CF₃,

(6) C_1-4 alkyl, and

(7) --CO₂ H,

(b) unsubstituted, mono- or di-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 said 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, and wherein said substituents are independently selected from the group consisting of

(1) F or Cl,

(2) C_1-4 alkoxy,

(3) C_1-4 alkylthio,

(5) CF₃,

(6) C_1-4 alkyl, and

(7) --CO₂ H,

each R¹⁷ is independently selected from the group consisting of

(a) hydrogen and

(b) R¹⁸ ; and

each R¹⁸ is independently selected from the group consisting of

(a) C_1-4 alkyl,

(b) --C_1-4 alkyl-CO₂ H

(c) C_1-6 alkanoyl, and

(d) H-(oxyethyl)n wherein n is 2, 3 or 4.

9. A compound according to claim 8 wherein:

R¹ is selected from the group consisting of

(a) S(O)₂ CH₃, and

(b) S(O)₂ NH₂ ;

R² is selected from the group consisting of

(a) OR¹¹,

(b) R¹¹,

R³ is hydrogen, methyl or ethyl;

R⁴ is hydrogen, methyl or ethyl;

R⁵ is OR¹⁷ ;

R¹¹ is an unsubstituted, mono- or di-substituted phenyl wherein the substituents are independently selected from the group consisting of

(1) F or Cl,

(2) C_1-4 alkoxy,

(3) C_1-4 alkylthio,

(5) CF₃,

(6) C_1-4 alkyl, and

(7) --CO₂ H,

each R¹⁷ is independently selected from the group consisting of

(a) hydrogen and

(b) R¹⁸ ; and

each R¹⁸ is independently selected from the group consisting of

(a) C_1-3 alkyl,

(b) --C_1-3 alkyl-CO₂ H

(c) C_1-3 alkanoyl, and

(d) H-(oxyethyl)n wherein n is 2 to 4.

10. A compound according to claim 8 wherein

R² is a mono- or di-substituted heteroaryl wherein heteroaryl is selected from the group consisting of

(1) furanyl,

(2) diazinyl,

(3) imidazolyl,

(4) isooxazolyl,

(5) isothiazolyl,

(6) oxadiazolyl,

(7) oxazolyl,

(8) pyrazolyl,

(9) pyridyl,

(10) pyrrolyl,

(11) tetrazinyl,

(12) tetrazolyl,

(13) thiadiazolyl,

(14) thiazolyl,

(15) thienyl,

(16) triazinyl, or

(17) triazolyl, and the substituents are selected from the group consisting of

(1) hydrogen,

(2) halo,

(3) C_1-4 alkyl,

(4) C_1-4 alkoxy,

(5) C_1-4 alkylthio,

(6) CN, and

(7) CF₃.

11. A compound according to claim 10 wherein

R² is a mono- or di-substituted heteroaryl wherein heteroaryl is selected from the group consisting of

(1) furanyl,

(2) diazinyl,

(3) imidazolyl,

(4) isooxazolyl,

(5) isothiazolyl,

(6) oxadiazolyl,

(7) oxazolyl,

(8) pyrazolyl,

(9) pyridyl,

(10) pyrrolyl,

(11) thiazolyl,

(12) thienyl, wherein the substituents are selected from the group consisting of

(1) hydrogen,

(2) halo,

(3) C_1-3 alkyl,

(4) C_1-3 alkoxy,

(7) CF₃.

12. A compound according to claim 11 wherein

R² is a mono- or di-substituted heteroaryl wherein heteroaryl is selected from the group consisting of

(1) furanyl,

(2) diazinyl,

(3) imidazolyl,

(4) oxadiazolyl,

(5) pyrazolyl,

(6) pyridyl,

(7) pyrrolyl,

(8) thiazolyl,

(9) thienyl, wherein the substituents are selected from the group consisting of

(1) hydrogen,

(2) halo,

(3) methyl,

(4) methoxy, and

(5) CF₃.

13. A compound according to claim 12 wherein

R² is a mono- or di-substituted heteroaryl wherein heteroaryl is selected from the group consisting of

(1) furanyl,

(2) diazinyl,

(3) imidazolyl,

(4) oxadiazolyl,

(5) pyrazolyl,

(6) pyridyl,

(7) thiazolyl,

(8) thienyl, wherein the substituents are selected from the group consisting of

(1) hydrogen,

(2) Cl or F,

(3) methyl,

(4) methoxy,

(5) CF3.

14. A compound according to claim 1 selected from the group consisting of

(a) 5,5-Dimethyl-3-(3-fluorophenyl)-2-hydroxy-4-(4-(methylsulfonyl)phenyl)-2,5-dihydrofuran,

(b) 3-(3,5-Difluorophenyl)-5,5-dimethyl-2-hydroxy-4-(4-(methylsulfonyl)phenyl)-2,5-dihydrofuran,

(c) 5,5-Dimethyl-3-(4-fluorophenyl)-2-hydroxy-4-(4-(methylsulfonyl)phenyl)-2,5-dihydrofuran,

(d) 5,5-Dimethyl-3-(4-fluorophenyl)-2-methoxy-4-(4-(methylsulfonyl)phenyl)-2,5-dihydrofuran,

(e) 5,5-Dimethyl-2-ethoxy-3-(3-fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2,5-dihydrofuran,

(f) 5,5-Dimethyl-3-(3-fluorophenyl)-2-isopropoxy-4-(4-(methylsulfonyl)phenyl)-2,5-dihydrofuran,

(g) 5,5-Dimethyl-3-(3-fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-methylthio-2,5-dihydrofuran,

(h) 5-Ethyl-3-(4-fluorophenyl)-2-hydroxy-5-methyl-4-(4-(methylsulfonyl)phenyl)-2,5-dihydrofuran,

(i) 5,5-Dimethyl-3-(3-fluorophenoxy)-2-hydroxy-4-(4-(methylsulfonyl)phenyl)-2,5-dihydrofuran,

(j) 5,5-Dimethyl-3-(3,4-difluorophenoxy)-2-hydroxy-4-(4-(methylsulfonyl)phenyl)-2,5-dihydrofuran,

(k) 3-(3,4-Difluorophenyl)-2-hydroxy-4-(4-(methylsulfonyl)phenyl)-2,5-dihydrofuran

(l) 2-Acetoxy-5,5-dimethyl-3-(3-fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2,5-dihydrofuran,

(m) Sodium(5,5-dimethyl-3-(3-fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2,5-dihydrofuran-2-yloxy) actetate,

(n) 3-isopropoxy-5,5-dimethyl-4-(4-methylsulfonylphenyl)-2,5-dihydrofuran-2-ol),

(o) 5,5-Dimethyl-4-(4-methylsulfonylphenyl)-3 phenyl-2,5-dihydrofuran-2-ol),

(p) 3-(3-Fluorophenyl)-5,5-dimethyl-4-(4-methylsulfonylphenyl)-2,5-dihydrofuran-2-ol),

(q) 3-(3,4-Difluorophenyl)-5,5-dimethyl-4-(4-methylsulfonylphenyl)-2,5-dihydrofuran-2-ol),

(r) 3-(1-Cyclopropylethoxy)-5,5-dimethyl-4-(4-methylsulfonylphenyl)-2,5-dihydrofuran-2-ol),

(s) 3-(Cyclopropylmethoxy)-5,5-dimethyl-4-(4-methylsulfonylphenyl)-2,5-dihydrofuran-2-ol), and

(t) 3-(3,4-Difluorophenoxy)-5-methyl-4-(4-methylsulfonylphenyl)-5-2,2,2-trifluoroethyl)-2,5-dihydrofuran-2-ol).

15. A pharmaceutical composition for treating an inflammatory disease susceptable to treatment with an non-steroidal anti-inflammatory agent comprising:

a non-toxic therapeutically effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier.

16. A pharmaceutical composition for treating cyclooxygenase mediated diseases advantageously treated by an active agent that selectively inhibits COX-2 in preference to COX-1 comprising:

a non-toxic therapeutically effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier.

17. A method of treating an inflammatory disease susceptable to treatment with an non-steroidal anti-inflammatory agent comprising:

administration to a patient in need of such treatment of a non-toxic therapeutically effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier.

18. A method of treating cyclooxygenase mediated diseases advantageously treated by an active agent that selectively inhibits COX-2 in preference to COX-1 comprising:

administration to a patient in need of such treatment of a non-toxic therapeutically effective amount of a compound according to claim 1.