Phenyl heterocycles as COX-2 inhibitors

• US 5,536,752 A
• Filed: 05/08/1995
• Issued: 07/16/1996
• Est. Priority Date: 06/24/1993
• Status: Expired due to Fees

• Current Assignee: Merck Frosst Canada & Company (Merck & Co., Inc.)
• Original Assignee: Merck Frosst Canada & Company (Merck & Co., Inc.)
• Inventors: Leger, Serge, Leblanc, Yves, Therien, Michel, Ducharme, Yves, Wang, Zhaoyin, Prasit, Petpiboon, Gauthier, Jacques Y.
• Primary Examiner(s): Ivy, C. Warren
• Assistant Examiner(s): OWENS, AMELIA A
• Application Number:
  US08/436,672
• Time in Patent Office: 435 Days
• Field of Search: 568/33, 564/88, 514/602, 514/678, 514/682
• US Class Current: 514/602
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/16 for influenza or rhinoviruses
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/04 Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• CPC Class Codes: C07C 2601/08 the ring being saturated
• CPC Class Codes: C07C 311/29 having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 311/46 Y being a hydrogen or a carbon atom
• CPC Class Codes: C07C 311/49 to nitrogen atoms
• CPC Class Codes: C07C 317/24 : having sulfone or sulfoxide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
• CPC Class Codes: C07D 275/02 : not condensed with other rings
• CPC Class Codes: C07D 277/26 : Radicals substituted by sulfur atoms
• CPC Class Codes: C07D 307/38 : with substituted hydrocarbon radicals attached to ring carbon atoms
• CPC Class Codes: C07D 307/58 : One oxygen atom, e.g. butenolide
• CPC Class Codes: C07D 333/18 : by sulfur atoms
• CPC Class Codes: C07D 333/38 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 405/04 : directly linked by a ring-member-to-ring-member bond

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 ##STR219## or a pharmaceutically acceptable salt thereof wherein:

X--Y--Z-- is selected from the group consisting of;

(a) --CH₂ CH₂ CH₂ --,

(b) --C(O)CH₂ CH₂ --, and

(c) --CH₂ CH₂ C(O)--,

wherein side b is a double bond, and sides a an c are single bonds;

R¹ is selected from the group consisting of

(a) S(O)₂ CH₃,

(b) S(O)₂ NH₂,

(c) S(O)₂ NHC(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) C₃, C₄, C₅, C₆, and C₇, cycloalkyl,

(b) mono-, di- or tri-substituted phenyl wherein the substituent is selected from the group consisting of

(1) hydrogen,

(2) halo,

(3) C_1-6 alkoxy,

(4) C_1-6 alkylthio,

(5) CN,

(6) CF₃,

(7) C_1-6 alkyl,

(8) N₃,

(9) --CO₂ H,

(10) --CO₂ --C_1-4 alkyl,

(11) --C(R⁵)(R⁶)--OH,

(12) --C(R⁵)(R⁶)--O--C_1-4 alkyl, and

(13) --C_1-6 alkyl-CO₂ --R⁵ ;

(c) 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) hydrogen,

(2) halo, including fluoro, chloro, bromo and iodo,

(3) C_1-6 alkyl,

(4) C_1-6 alkoxy,

(5) C_1-6 alkylthio,

(6) CN,

(7) CF₃,

(8) N₃,

(9) --C(R⁵)(R⁶)--OH, and

(10) --C(R⁵)(R⁶)--O--C_1-4 alkyl;

R⁵ and R⁶ are each independently selected from the group consisting of

(a) hydrogen, and

(b) C_1-6 alkyl,

or R⁵ and R⁶ or R⁷ and R⁸ together with the carbon to which they are attached form a monocyclic saturated carbon ring of 3, 4, 5, 6 or 7 atoms.

2. A compound according to claim 1 wherein X--Y--Z-- is selected from the group consisting of:

(a) --CH₂ CH₂ CH₂ --,

(b) --C(O)CH₂ CH₂ --, and

(c) --CH₂ CH₂ C(O)--.

3. A compound according to claim 2 wherein R² is selected from the group consisting 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) C_1-4 alkoxy,

(4) C_1-4 alkylthio,

(5) CN,

(6) CF₃,

(7) C_1-4 alkyl,

(8) N₃, and

(9) --C(R⁵)(R⁶)--OH;

R⁵ and R⁶, are each independently selected from the group consisting of

(a) hydrogen, and

(b) methyl or ethyl,

or R⁵ and R⁶ together with the carbon to which they are attached form a saturated carbon ring of 4, 5 or 6 atoms.

4. A compound according to claim 3 of the formulae ##STR220## wherein R¹ is selected from the group consisting of

(a) S(O)₂ CH₃,

(b) S(O)₂ NH₂,

(c) S(O)NHCH₃, and

(d) S(O)NHNH₂ ;

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 consisting of fluoro, chloro and bromo,

(3) C_1-3 alkoxy,

(4) C_1-3 alkylthio,

(5) CN, and

(6) C_1-3 alkyl.

5. A compound according to claim 4 wherein R¹ is selected from the group consisting of

(a) S(O)₂ CH₃,

(b) S(O)₂ NH₂,

(c) S(O)NHCH₃, and

(d) S(O)NHNH₂ ;

R² is

mono or di-substituted phenyl wherein the substitutents are selected from the group consisting of

(1) hydrogen,

(2) halo, selected from the group consisting of fluoro, chloro and bromo,

(3) methoxy, and

(4) methyl.

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

mono or di-substituted phenyl wherein the substitutents are selected from the group consisting of

(1) hydrogen,

(2) halo, selected from the group consisting of fluoro, chloro and bromo.

7. A compound according to claim 2 wherein R² is a mono- or di-substituted heteroaryl wherein heteroaryl is selected from the group consisting of

(1) furanyl,

(2) diazinyl, triazinyl, tetrazinyl,

(3) imidazolyl,

(4) isooxazolyl,

(5) isothiazolyl,

(6) oxadiazolyl,

(7) oxazolyl,

(8) pyrazolyl,

(9) pyrrolyl,

(10) thiadiazolyl,

(11) thiazolyl,

(12) thienyl,

(13) triazolyl, and

(14) tetrazolyl,

wherein the substitutents are selected from the group consisting of

(a) hydrogen,

(b) fluoro or chloro

(c) C_1-3 alkoxy,

(d) C_1-6 alkylthio,

(e) CN,

(5) CF₃,

(6) C_1-3 alkyl,

(7) --C(R⁵)(R⁶)--OH, and

(8) --C(R⁵)(R⁶)--O--C_1-4 alkyl.

13. A compound according to claim 1 which is 2-(4-Fluorophenyl)-3-(4-(methylsulfonyl)phenyl)-2-cyclopenten-1-one.

15. A pharmaceutical composition for treating an inflammatory disease susceptable to treatment with an non-steroidal antiinflammatory 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.

8. 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) 2-furanyl,

(2) 3-furanyl,

(3) 2-thienyl,

(4) 3-thienyl,

(5) 3-isoxazolyl,

(6) 4-isoxazolyl,

(7) 5-isoxazolyl,

(8) 3-isothiazolyl,

(9) 4-isothiazolyl,

(10) 5-isothiazolyl,

(11) 2-oxazolyl,

(12) 4-oxazolyl,

(13) 5-oxazolyl,

(14) 2-thiazolyl,

(15) 4-thiazolyl,

(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,

(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,

(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,

(38) 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.

9. A compound according to claim 8 wherein the heteroaryl is selected from the group consisting 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,

(14) 1,2,3-thiadiazol-5-yl,

(15) 1,2,4-thiadiazol-3-yl,

(16) 1,2,4-thiadiazol-5-yl,

(17) 1,3,4-thiadiazol-2-yl,

(18) 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.

10. A compound according to claim 9 wherein the heteroaryl is selected from the group consisting of

(1) 3-isothiazolyl,

(2) 4-isothiazolyl,

(3) 5-isothiazolyl,

(4) 2-oxazolyl,

(5) 4-oxazolyl,

(6) 5-oxazolyl,

(7) 2-thiazolyl,

(8) 4-thiazolyl,

(9) 5-thiazolyl,

(10) 1,2-diazinyl,

(11) 1,3-diazinyl, and

(12) 1,4-diazinyl,

wherein the substitutents are selected from the group consisting of

(1) hydrogen,

(2) fluoro or chloro,

(3) C_1-3 alkoxy,

(4) C_1-3 alkylthio,

(5) CN,

(6) C_1-3 alkyl, and

(7) --C(R⁵)(R⁶)--OH,

wherein R⁵ and R⁶ are each independently hydrogen, methyl or ethyl.

11. A compound according to claim 10 wherein R¹ is selected from the group consisting of

(a) S(O)₂ CH₃,

(b) S(O)₂ NH₂,

(c) S(O)NHCH₃, and

(d) S(O)NHNH₂.

12. A compound according to claim 11 wherein the hetereooaryl is selected from the group consisting of

(1) 3-isothiazolyl,

(2) 4-isothiazolyl,

(3) 5-isothiazolyl,

(4) 2-oxazolyl,

(5) 4-oxazolyl,

(6) 5-oxazolyl,

(7) 2-thiazolyl,

(8) 4-thiazolyl,

(9) 5-thiazolyl,

(10) 1,2-diazinyl,

(11) 1,3-diazinyl, and

(12) 1,4-diazinyl, and

wherein the substitutents are selected from the group consisting of

(1) hydrogen,

(2) fluoro or chloro,

(3) methoxy,

(4) methylthio,

(5) CF₃,

(6) methyl.

14. A compound which is ##STR221##