Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-06-27
2002-10-15
Owens, Amelia (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S459000, C514S282000, C549S292000, C549S293000, C549S294000, C546S282100
Reexamination Certificate
active
06465509
ABSTRACT:
BACKGROUND OF THE INVENTION
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 (COX-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 (COX-2) has been cloned, sequenced and characterized initially from chicken, murine and human sources. This enzyme is distinct from the COX-1 which has been cloned, sequenced and characterized from various sources including the sheep, the mouse and man. The second form of cyclooxygenase, COX-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, COX-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, COX-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 COX-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.
Furthermore, such a compound will also inhibit prostanoid-induced smooth muscle contraction by preventing the synthesis of contractile prostanoids and hence may be of use in the treatment of dysmenorrhea, premature labour, asthma and eosinophil related disorders. It will also be of use in the treatment of Alzheimer's disease, for decreasing bone loss particularly in postmenopausal women (i.e. treatment of osteoporosis) and for the treatment of glaucoma.
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, and in an article in
Drug News and Perspectives,
Vol. 7, pp. 501-512, 1994.
SUMMARY OF THE INVENTION
The invention encompasses the novel compounds of Formula I, which are useful in the treatment of cyclooxygenase-2 mediated diseases:
or a pharmaceutically acceptable salt thereof wherein:
X is selected from the group consisting of:
(a) a bond,
(b) —(CH
2
)
m
—, wherein m=1 or 2,
(c) —C(O)—,
(d) —O—,
(e) —S—, and
(f) —N(R
5
)—;
R
1
is selected from the group consisting of:
(a) C
1-10
alkyl, optionally substituted with 1-3 substituents independently selected from the group consisting of:
(1) hydroxy,
(2) halo,
(3) C
1-10
alkoxy,
(4) C
1-10
alkylthio, and
(5) CN,
(b) phenyl or naphthyl, and
(c) heteroaryl, which is comprised of a monocyclic aromatic ring of 5 atoms having one hetero atom which is S, O or N, and optionally 1, 2, or 3 additional N atoms; or
a monocyclic ring of 6 atoms having one hetero atom which is N, and optionally 1, 2, or 3 additional N atoms,
wherein groups (b) and (c) above are each optionally substituted with 1-3 substituents independently selected from the group consisting of:
(1) halo,
(2) C
1-10
alkoxy,
(3) C
1-10
alkylthio,
(4) CN,
(5) C
1-10
alkyl, optionally substituted to its maximum with halo, and
(6) N
3
;
R
2
is selected from the group consisting of
(a) C
1-6
alkyl, optionally substituted to its maximum with halo,
(b) NH
2
, and
(c) NHC(O)C
1-10
alkyl, optionally substituted to its maximum with halo;
R
3
and R
4
are each independently selected from the group consisting of:
(a) hydrogen,
(b) halo, and
(c) C
1-6
alkyl, optionally substituted to its maximum with halo; and
R
5
is selected from the group consisting of:
(a) hydrogen and
(b) C
1-6
alkyl, optionally substituted to its maximum with halo.
The invention also encompasses certain pharmaceutical compositions comprising compounds of Formula I as well as methods of treating cyclooxygenase-2 mediated diseases comprising administering to a patient in need of such treatment a non-toxic therapeutically effective amount of a compound of Formula I.
DETAILED DESCRIPTION OF THE INVENTION
The invention encompasses the novel compounds of Formula I, which are useful in the treatment of cyclooxygenase-2 mediated diseases
or a pharmaceutically acceptable salt thereof wherein:
X is selected from the group consisting of:
(a) a bond,
(b) —(CH
2
)
m
—, wherein m=1 or 2,
(c) —C(O)—,
(d) —O—,
(e) —S—, and
(f) —N(R
5
)—;
R
1
is selected from the group consisting of:
(a) C
1-10
alkyl, optionally substituted with 1-3 substituents independently selected from the group consisting of:
(1) hydroxy,
(2) halo,
(3) C
1-10
alkoxy,
(4) C
1-10
alkylthio, and
(5) CN,
(b) phenyl or naphthyl, and
(c) heteroaryl, which is comprised of a monocyclic aromatic ring of 5 atoms having one hetero atom which is S, O or N, and optionally 1, 2, or 3 additional N atoms; or
a monocyclic ring of 6 atoms having one hetero atom which is N, and optionally 1, 2, or 3 additional N atoms,
wherein groups (b) and (c) above are each optionally substituted with 1-3 substituents independently selected from the group consisting of:
(1) halo,
(2) C
1-10
alkoxy,
(3) C
1-10
alkylthio,
(4) CN,
(5) C
1-10
alkyl, optionally substituted to its maximum with halo, and
(6) N
3
;
R
2
is selected from the group consisting of
(a) C
1-6
alkyl, optionally substituted to its maximum with halo,
(b) NH
2
, and
(c) NHC(O)C
1-10
alkyl, optionally substituted to its maximum with halo;
R
3
and R
4
are each independently selected from the group consisting of:
(a) hydrogen,
(b) halo, and
(c) C
1-6
alkyl, optionally substituted to its maximum with halo; and
R
5
is selected from the group consisting of:
(a) hydrogen and
(b) C
1-6
alkyl, optionally substituted to its maximum with halo.
An embodiment of the invention is that wherein X is a bond.
Another embodiment of the invention is that wherein X is —O—.
Another embodiment of the invention is that wherein X is —S—.
Another embodiment of the invention is that wherein R
2
is CH
3
.
Another embodiment of the invention is that wherein R
3
is hydrogen.
Another embodiment of the invention is that wherein m is 1.
Another embodiment of the invention encompasses compounds of Formula I wherein R
1
is phenyl, optionally substituted with 1-3 substituents independently selected from the group consisting of:
(1) halo,
(2) C
1-10
alkoxy,
(3) C
1-10
alkylthio,
(4) CN,
(5) C
1-10
alkyl, optionally substituted to its maximum with halo, and
(6) N
3
.
A class of this embodiment encompasses compounds wherein R
1
is as defined above and R
2
is CH
3
. Another class of this embodiment encompasses compounds wherein R
1
is as defined above and R
3
is H.
Another embodiment of the invention encompasses compounds of Formula I wherein R
1
is heteroaryl, which is comprised of a monocyclic aromatic ring of 5 atoms having one hetero atom which is S, O or N, and optionally 1, 2, or 3 additional N atoms; or a monocyclic ring of 6 atoms having one hetero atom which is N, and optionally 1, 2, or 3 additional N atoms, wherein heteroaryl is optionally substituted with 1-3 substituents independently selected from the group consisting of:
(1) halo,
(2) C
1-10
alkoxy,
(3) C
1-10
alkylthio,
(4) CN,
(5) C
1-10
alkyl, optionally substituted t
Lau Cheuk Kun
Li Chun-Sing
Prasit Petpiboon
Therien Michel
Merck Frosst Canada & Co.
Owens Amelia
Rose David L.
Yuro Baynard
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