3-phenyl-4-(4(methylsulfonyl)phenyl)-2-(5H)-furanone as a...

Details 3-phenyl-4-(4(methylsulfonyl)phenyl)-2-(5H)-furanone as a... 3-phenyl-4-(4(methylsulfonyl)phenyl)-2-(5H)-furanone as a...

1999-11-18

2001-05-29

Dentz, Bernard (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C549S323000

Reexamination Certificate

active

06239173

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention relates to compounds and pharmaceutical compositions for the treatment of cyclooxygenase mediated diseases and methods of treatment thereof.
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. Up until recently, only one form of cyclooxygenase had been characterized, this corresponding to cyclooxygenase-1 or the constitutive enzyme, as originally identified in bovine seminal vesicles. Recently the gene for a second inducible form of cyclooxygenase (cyclooxygenase-2) has been cloned, sequenced and characterized from chicken, murine and human sources. This enzyme is distinct from the cyclooxygenase-1 which has now also been cloned, sequenced and characterized from sheep, murine and human sources. 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.
SUMMARY OF THE INVENTION
The invention encompasses novel compounds of Formula I useful in the treatment of cyclooxygenase-2 mediated diseases.
The invention also encompasses certain pharmaceutical compositions and methods for treatment of cyclooxygenase-2 mediated diseases comprising the use of compounds of Formula I.
DETAILED DESCRIPTION OF THE INVENTION
The invention encompasses the novel compound of Formula I useful in the treatment of cyclooxygenase-2 mediated diseases
or pharmaceutically acceptable salts thereof wherein:
X—Y—Z-is selected from the group consisting of:
(a) —CH
2
CH
2
CH
2
—,
(b) —C(O)CH
2
CH
2
—,
(c) —CH
2
CH
2
C(O)—,
(d) —CR
5
(R
5′
)—O—C(O)—,
(e) —C(O)—O—CR
5
(R
5′
)—,
(f) —CH
2
—NR
3
—CH
2
—,
(g) —CR
5
(R
5′
)—NR
3
—C(O)—,
(h) —CR
4
═CR
4′
—S—,
(i) —S—CR
4
═CR
4′
—,
(j) —S—N═CH—,
(k) —CH═N—S—,
(l) —N═CR
4
—O—,
(m) —O—CR4═N—
(n) —N═CR
4
—NH—;
(o) —N═CR
4
—S—, and
(p) —S—CR
4
═N—;
(q) —C(O)—NR
3
—CR
5
(R
5′
)—;
(r) —R
3
N—CH═CH— provided R
1
is not —S(O)
2
Me
(s) —CH═CH—NR
3
— provided R
1
is not —S(O)
2
Me
when side b is a double bond, and sides a an c are single bonds; and
X—Y—Z-is selected from the group consisting of:
(a) ═CH—O—CH═, and
(b) ═CH—NR
3
—CH═,
(c) ═N—S—CH═,
(d) ═CH—S—N═,
(e) ═N—O—CH═,
(f) ═CH—O—N═,
(g) ═N—S—N═,
(h) ═N—O—N═,
when sides a and c are double bonds and side b is a single bond;
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)CH
3
,
(e) S(O)(NH)NH
2
,
(f) S(O)(NH)NHC(O)CF
3
,
(g) P(O)(CH
3
)OH, and
(h) P(O)(CH
3
)NH
2
,
R
2
is selected from the group consisting of
(a) C
1-6
alkyl,
(b) C
3
, C
4
, C
5
, C
6
, and C
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
;
(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) benzoheteroaryl which includes the benzo fused analogs of (d);
R
3
is selected from the group consisting of
(a) hydrogen,
(b) CF
3
,
(c) CN,
(d) C
1-6
alkyl,
(e) hydroxyC
1-6
alkyl,
(f) —C(O)—C
1-6
alkyl,
(g) optionally substituted
(1) —C
1-5
alkyl-Q,
(2) —C
1-3
alkyl-O—C
1-3
alkyl-Q,
(3) —C
1-3
alkyl-S—C
1-3
alkyl-Q,
(4) —C
1-5
alkyl-O—Q, or
(5) —C
1-5
alkyl-S—Q,
wherein the substituent resides on the alkyl and the substituent is C
1-3
alkyl;
(h) —Q
R
4
and R
4′
are each independently selected from the group consisting of
(a) hydrogen,
(b) CF
3
,
(c) CN,
(d) C
1-6
alkyl,
(e) —Q,
(f) —O—Q;
(g) —S—Q, and
(h) optionally substituted
(1) —C
1-5
alkyl-Q,
(2) —O—C
1-5
alkyl-Q,
(3) —S—C
1-5
alkyl-Q,
(4) —C
1-3
alkyl-O—C
1-3
alkyl-Q,
(5) —C
1-3
alkyl-S—C
1-3
alkyl-Q,
(6) —C
1-5
alkyl-O—Q,
(7) —C
1-5
alkyl-S—Q,
wherein the substituent resides on the alkyl and the substituent is C
1-3
alkyl, and
R
5
, R
5′
, R
6
, R
7
and R
8
are each independently selected from the group consisting of
(a) hydrogen,
(b) C
1-6
alkyl,
or R
5
and R
6
or R
7
and R
8
together with the carbon to which they are attached form a saturated monocyclic carbon ring of 3, 4, 5, 6 or 7 atoms;
Q is CO
2
H, CO
2
—C
1-4
alkyl, tetrazolyl-5-yl, C(R
7
)(R
8
)(OH), or
C(R
7
)(R
8
)(O—C
1-4
alkyl);
provided that when X—Y—Z is —S—CR
4
═CR
4′
, then R
4
and R
4′
are other than CF
3
.
One Class within this embodiment are the compounds of formula I
or pharmacetically acceptable salts thereof wherein: X—Y—Z— is selected from the group consisting of —C(O)—O—CR
5
(R
5′
)— when side b is a double bond, and sides a and c are single bonds; and
R
1
is selected from the group consisting of
(a) S(O)
2
CH
3
,
(b) S(O)
2
NH
2
,
R
2
is selected from the group consisting of
(a) C
1-6
alkyl,
(b) C
3
, C
4
, C
5
, C
6
, and C
7
, cycloalkyl,
(c) heteroaryl
(d) benzoheteroaryl
(e) mono- or di-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) 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
;
R
5
, R
5′
and R
6
are each independently selected from the group consisting of
(a) hydrogen,
(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.
For purposes of this specification alkyl is defined to include linear, branched, and cyclic structures, with C
1-6
alkyl including including methyl, ethyl, propyl, 2-propyl, s- and t-butyl, butyl, pentyl, hexyl, 1,1-dimethylethyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Similarly, C
1-6
alkoxy is intended to include alkoxy groups of from 1 to 6 carbon atoms of a strai

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