Diaryl-2-(5H)-furanones as Cox-2 inhibitors

Details Diaryl-2-(5H)-furanones as Cox-2 inhibitors Diaryl-2-(5H)-furanones as Cox-2 inhibitors

1997-06-12

2001-04-24

Higel, Floyd D. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C514S326000, C514S438000, C514S461000, C546S016000, C546S214000, C546S284400, C548S169000, C548S207000, C548S517000, C549S060000, C549S268000, C549S295000, C549S320000, C549S462000

Reexamination Certificate

active

06222048

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention relates to methods of treating cyclooxygenase mediated diseases and certain pharmaceutical compositions therefor.
Non-steroidal, antiinflammatory drugs exert most of their antiinflammatory, analgesic and antipyretic activity and inhibit hormone-induced uterine contractions and certain types of cancer growth through inhibition of prostaglandin G/H synthase, also known as cyclooxygenase. Initially, only one form of cyclooxygenase was known, this corresponding to cyclooxygenase-1 or the constitutive enzyme, as originally identified in bovine seminal vesicles. More recently the gene for a second inducible form of cyclooxygenase (cyclooxygenase-2) has been cloned, sequenced and characterized initially from chicken, murine and human sources. This enzyme is distinct from the cyclooxygenase-1 which has been cloned, sequenced and characterized from various sources including the sheep, the mouse and man. The second form of cyclooxygenase, cyclooxygenase-2, is rapidly and readily inducible by a number of agents including mitogens, endotoxin, hormones, cytokines and growth factors. As prostaglandins have both physiological and pathological roles, we have 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 gastrointestinal integrity and renal blood flow. In 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, hormones, growth factors, and cytokines. Thus, a selective inhibitor of cyclooxygenase-2 will have similar antiinflammatory, antipyretic and analgesic properties to a conventional non-steroidal antiinflammatory drug, 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. In 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 in aspirin-sensitive asthmatic subjects.
A brief description of the potential utilities of cyclooxygenase-2 inhibitors is given in an article by John Vane,
Nature,
Vol. 367, pp. 215-216, 1994 and in an article in
Drug News and Perspectives,
Vol. 7, pp. 501-512, 1994.
SUMMARY OF THE INVENTION
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.
The invention also encompasses certain pharmaceutical compositions for treatment of cyclooxygenase-2 mediated diseases comprising compounds of Formula I.
DETAILED DESCRIPTION OF THE INVENTION
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.
or a pharmaceutically acceptable salt thereof wherein:
Y is selected from the group consisting of
(a) C(R
10
)(R
11
),
(b) oxygen,
(c) sulfur,
R
1
is selected from the group consisting of
(a) S(O)
2
CH
3
,
(b) S(O)
2
NH
2
,
(c) S(O)
2
NHC(O)CF
3
,
(d) S(O)(NH)NH
2
,
(e) S(O)(NH)NHC(O)CF
3
,
(f) P(O)(CH
3
)NH
2
,
(g) P(O)(CH
3
)
2
,
R
2
is selected from the group consisting of
(a) C
1-6
alkyl,
(b) C
3-7
cycloalkyl,
(c) mono-, di- or tri-substituted phenyl or naphthyl 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) CF
3
,
(7) C
1-6
alkyl,
(8) N
3
,
(9) —CO
2
H,
(10) —CO
2
—C
1-4
alkyl,
(11) —C(R
5
)(R
6
)—OH,
(12) —C(R
5
)(R
6
)—O—C
1-4
alkyl, and
(13) —C
1-6
alkyl—CO
2
—R
5
;
(14) benzyloxy,
(15) —O—(C
1-6
alkyl)—CO
2
R
5
,
(16) —O—(C
1-6
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 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, 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) CF
3
,
(8) N
3
,
(9) —C(R
5
)(R
6
)—OH, and
(10) —C(R
5
)(R
6
)—O—C
1-4
alkyl;
(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; the 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) CF
3
,
(8) N
3
,
(9) —C(R
5
)(R
6
)—OH, and
(10) —C(R
5
)(R
6
)—O—C
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) 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) 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) CF
3
,
(8) N
3
,
(9) —C(R
5
)(R
6
)—OH, and
(10) —C(R
5
)(R
6
)—O—C
1-4
alkyl;
R
3
is C
1-7
alkyl, CH
2
OR
7
, CN, CH
2
CN, or C
1-6
fluoroalkyl, F, CONR
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, including fluoro, chloro, bromo and iodo,
(3) C
1-6
alkyl,
(4) C
1-6
alkoxy,
(5) C
1-6
alkylthio,
(6) CN,
(7) CF
3
,
(8) N
3
,
(9) —C(R
5
)(R
6
)—OH, and
(10) —C(R
5
)R
6
)—O—C
1-4
alkyl;
R
4
is
(a) mono- or di-substituted phenyl or mono- or di-substituted benzyl or mono or di-substituted heteroaryl or mono-or di-substituted heteroarylmethyl, 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) CF
3
,
(8) N
3
,
(9) —C(R
5
)(R
6
)—OH, and
(10) —C(R
5
)(R
6
)—O—C
1-4
alkyl, or
(b) C
1-7
alkyl, CH
2
OR
7
, CN, CH
2
CN, or C
1-6
fluoroalkyl, F or CONR
7
2
; or
R
3
and R
4
together with the carbon to which they are attached form a saturated monocyclic ring of 3, 4, 5, 6 or 7 atoms, optionally containing 1 or 2 heteroatoms chosen independently from O, S, N, and optionally hexa-substituted by R
12
and optionally containing a carbonyl or sulfonyl group,
each R
12
is independently selected from the group consisting of
(a) hydrogen,
(b) C
1-6
alkyl,
(c) phenyl or monosubstituted phenyl wherein the substituents may be halo, C
1-6
alkyl, C
1-6
alkoxy, C
1-6
alkylthio, CN, or CF
3
,
(d) benzyl or monosubstituted benzyl wherein the substituents may be halo, C
1-6
alkyl, C
1-6
alkoxy, C
1-6
alkylthio, CN, or CF
3
,
(e) —CO
2
-alkyl,
(f) halo;
R
5
, R
6
and R
7
are each independently selected from the group consisting of
(a) hydrogen, and
(b) C
1-6
alkyl,
or R
5
and R
6
together with the carbon to which they are attached form a saturated monocyclic carbon ring of 3, 4, 5, 6 or 7 atoms;
R
8
and R
9
are independently selected from the group consisting of:
(a) hydrogen,
(b) C
1-7
alkyl, or
R
8
and R
9
together form a double bonded O or S;
R
10
and R
11
are independently
(a)

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