Diaryl bicyclic heterocycles as inhibitors of cyclooxygenase-2

Details Diaryl bicyclic heterocycles as inhibitors of cyclooxygenase-2 Diaryl bicyclic heterocycles as inhibitors of cyclooxygenase-2

1997-02-25

2001-12-11

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...

C514S469000, C544S238000, C544S376000, C548S125000, C548S127000, C548S128000, C548S131000, C548S134000, C548S136000, C548S143000, C548S159000, C548S235000, C548S247000, C549S006000, C549S220000, C549S051000, C549S057000, C549S058000, C549S469000

Reexamination Certificate

active

06329421

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 utility of cyclooxygenase-2 inhibitors is given in an article by John Vane,
Nature
, Vol. 367, pp. 215-216, 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.
and pharmaceutically acceptable salts thereof wherein:
—A═B—C═D— is selected from the group consisting of:
(a) —CH═CH—CH═CH—,
(b) —CH
2
—CH
2
—CH
2
—C(O)—, —CH
2
—CH
2
—C(O)—CH
2
—, —CH
2
—C(O)—CH
2
—CH
2
, —C(O)—CH
2
—CH
2
—CH
2
,
(c) —CH
2
—CH
2
—C(O)—, —CH
2
—C(O)—CH
2
—, —C(O)—CH
2
—CH
2
—
(d) —CH
2
—CH
2
—O—C(O)—, CH
2
—O—C(O)—CH
2
—, —O—C(O)—CH
2
—CH
2
—,
(e) —CH
2
—CH
2
—C(O)—O—, —CH
2
—C(O)—OCH
2
—, —C(O)—O—CH
2
—CH
2
—,
(f) —C(R
7
)
2
—O—C(O)—, —C(O)—O—C(R
7
)
2
—, —O—C(O)—C(R
7
)
2
—, —C(R
7
)
2
—C(O)—O—,
(g) —N═CH—CH—═CH—,
(h) —CH═N—CH═CH—,
(i) —CH═CH—N═CH—,
(j) —CH═CH—CH═N—,
(k) —N═CH—CH═N—,
(l) —N═CH—N═CH—,
(m) —CH═N—CH═N—,
(n) —S—CH═N—,
(o) —S—N═CH—,
(p) —N═N—NH—,
(q) —CH═N—S—,
(r) —N═CH—S—,
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
NHCOCF
3
,
(d) S(O)(NH)CH
3
,
(e) S(O)(NH)NH
2
,
(f) S(O)(NH)NHCOCF
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
3-7
, cycloalkyl,
(c) mono- or di-substituted phenyl or naphthyl wherein the substituent is selected from the group consisting of
(1) hydrogen,
(2) halo, including F, Cl, Br, I,
(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
8
;
(d) 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 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
and R
4
are the substituents residing on any position of —A═B—C═D— and are selected independently from the group consisting of:
(a) hydrogen,
(b) CF
3
,
(c) CN,
(d) C
1-6
alkyl,
(e) —Q
1
wherein Q
1
is Q
2
, CO
2
H, C(R
5
)(R
6
)OH,
(f) —O—Q
2
,
(g) —S—Q
2
, and
(h) optionally substituted
(1) —C
1-5
alkyl-Q
1
,
(2) —O—C
1-5
alkyl-Q
1
,
(3) —S—C
1-5
alkyl-Q
1
,
(4) —C
1-3
alkyl-O—C
1-3
alkyl-Q
1
,
(5) —C
1-3
alkyl-S—C
1-3
alkyl-Q
1
,
(6) —C
1-5
alkyl-O—Q
2
,
(7) —C
1-5
alkyl-S—Q
2
,
wherein the substituent resides on the alkyl chain and the substituent is C
1-3
alkyl, and Q
1
is Q
2
, CO
2
H, C(R
5
)(R
6
)OH Q
2
is CO
2
—C
1-4
alkyl, tetrazolyl-5-yl, or C(R
5
)(R
6
)O—C
1-4
alkyl; R
5
, R
6
and R
7
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, or two R
7
groups on the same carbon form a saturated monocyclic carbon ring of 3, 4, 5, 6 or 7 atoms;
R
8
is hydrogen or C
1-6
alkyl.
R
9
is hydrogen, C
1-6
alkyl or aryl.
X is O, S, NR
9
, CO, C(R
9
)
2
, C(R
9
)(OH), —C(R
9
)═C(R
9
)—; —C(R
9
)═N—;
—N═C(R
9
)—.
Exemplifying the invention are:
(a) 3-(4-(Methylsulfonyl)phenyl)-2-phenylbenzo[b]furan
(b) 3-(4-(Methylsulfonyl)phenyl)-2-phenylbenzo[b]-thiophene
(c) 3-(4-(Methylsulfonyl)phenyl)-2-phenyl-inden-1-one
(d) 2-(4-Fluorophenyl)-3-(4-(methylsulfonyl)-phenyl)indole
(e) 3-(4-Fluorophenyl)-2-(4-(methylsulfonyl)phenyl)indole
(f) 2-(4-Fluorophenyl)-3-(4-(methylsulfonyl)phenyl)-4H-thieno[2,3-c]furan-6-one
(g) 2-(3,4-Difluorophenyl)-3-(4-(methylsulfonyl)-phenyl)4H-thieno[2,3-c]furan-6-one
(h) 2-(4-Fluorophenyl)-3-(4-(aminosulfonyl)phenyl)-4H-thieno[2,3-c]furan-6-one
(i) 2-(3,4-Difluorophenyl)-3-(4-(aminosulfonyl)phenyl)-4H-thieno[2,3-c]furan-6-one
(j) 2-Phenyl-3-(4-(methylsulfonyl)phenyl)4,7-dihydro-thieno[2,3-c]pyran-5-one
The following abbreviations have the indicated meanings:
Ac=acetyl
C.I.=chemical ionization
DBU=1,8-diazabicyclo[5.4.0]undec-7-ene
DMF=N,N-dimethylformamide
DMSO=dimethyl sulfoxide
DMAP=4-dimethylaminopyridine
MMPP=monoperoxyphthalic acid??
MMPP=magnesium monoperoxyphthalate
MPPM=monoperoxyphthalic acid, magnesium salt hexahydrate
NBS=N-bromosuccinimide
NSAID=non-steroidal anti-inflammatory drug
PCC=Pyridinium chlorochromate
PDC=pyridinium dichromate
Ph=phenyl
PPA=polyphosphor

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