Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-04-28
2001-04-03
Higel, Floyd D. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S117000, C548S127000
Reexamination Certificate
active
06211210
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to methods of treating cyclooxygenase mediated diseases and certain pharmaceutical compositions therefor.
Non-steroidal, anti-inflammatory drugs exert most of their anti- inflammatory, 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 anti-inflammatory, antipyretic and analgesic properties to a conventional non-steroidal anti-inflammatory 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 COX-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
A compound represented by formula I:
or a pharmaceutically acceptable salt or hydrate thereof
wherein:
R
1
is selected from the group consisting of:
(a) S(O)
2
CH
3
,
(b) S(O)
2
NHR
4
,
(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
and R
3
are each independently selected from the group consisting of:
(a) hydrogen,
(b) halo,
(c) C
1-6
alkoxy,
(d) C
1-6
alkylthio,
(e) CN,
(f) C
1-3
fluoroalkyl,
(g) C
1-6
alkyl,
(h) N
3
,
(i) —CO
2
H,
(j) —CO
2
—C
1-4
alkyl,
(k) —C(R
5
)(R
6
)—OH,
(l) —C(R
5
)(R
6
)—O—C
1-4
alkyl, and
(m) —C
1-6
alkyl-CO
2
—R
7
;
R
4
is selected from the group consisting of H, C
1-6
alkyl, phenyl and benzyl, and R
5
, R
6
and R
7
are each independently selected from the group consisting of:
(a) hydrogen, and
(b) C
1-6
alkyl.
Pharmaceutical compositions and methods of treatment are also included.
DETAILED DESCRIPTION OF THE INVENTION
The invention encompasses compounds represented by formula I:
as well as pharmaceutically acceptable salts and hydrates thereof
wherein:
R
1
is selected from the group consisting of:
(a) S(O)
2
CH
3
,
(b) S(O)
2
NHR
4
,
(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
and R
3
are each independently selected from the group consisting of:
(a) hydrogen,
(b) halo,
(c) C
1-6
alkoxy,
(d) C
1-6
alkylthio,
(e) CN,
(f) C
1-3
fluoroalkyl,
(g) C
1-6
alkyl,
(h) N
3
,
(i) —CO
2
H,
(j) —CO
2
—C
1-4
alkyl,
(k) —C(R
5
)(R
6
)—OH,
(l) —C(R
5
)(R
6
)—O—C
1-4
alkyl, and
(m) —C
1-6
alkyl-CO
2
—R
7
;
R
4
is selected from the group consisting of H, C
1-6
alkyl, phenyl and benzyl, and R
5
, R
6
and R
7
are each independently selected from the group consisting of:
(a) hydrogen, and
(b) C
1-6
alkyl.
As appreciated by those of skill in the art formula I includes, compounds of formulas IA and IB.
Within the embodiment described above, there is a genus of compounds of formula I wherein
R
1
is selected from the group consisting of:
(a) S(O)
2
CH
3
,
(b) S(O)
2
NHR
4
,
(c) S(O)
2
NHCOCF
3
,
(d) S(O)(NH)CH
3
,
(e) S(O)(NH)NH
2
,
(f) S(O)(NH)NHCOCF
3
,
R
2
and R
3
are each independently selected from the group consisting of:
(a) hydrogen,
(b) halo,
(c) C
1-4
alkoxy,
(d) C
1-4
alkylthio,
(e) CN,
(f) C
1-3
fluoroalkyl,
(g) C
1-4
alkyl,
(h) —C(R
5
)(R
6
)—OH,
(i) —C(R
5
)(R
6
)—O—C
1-4
alkyl, and
(j) —C
1-4
alkyl-CO
2
—R
7
;
R
4
is selected from the group consisting of hydrogen, C
1-4
alkyl, phenyl and benzyl, and
R
5
, R
6
and R
7
are each independently selected from the group consisting of:
(a) hydrogen, and
(b) C
1-4
alkyl.
Within this genus there is a class of compounds wherein:
R
1
is selected from the group consisting of:
(a) S(O)
2
CH
3
,
(b) S(O)
2
NHR
4
,
(c) S(O)
2
NHCOCF
3
,
(d) S(O)(NH)CH
3
,
R
2
and R
3
are each independently selected from the group consisting of:
(a) hydrogen,
(b) halo,
(c) C
1-3
alkoxy,
(d) C
1-3
alkylthio,
(e) CN,
(f) C
1-3
fluoroalkyl,
(g) C
1-3
alkyl,
(h) —C(R
5
)(R
6
)—OH,
(i) —C(R
5
)(R
6
)—O—C
1-3
alkyl, and
R
4
is selected from the group consisting of hydrogen, C
1-3
alkyl, phenyl and benzyl;
R
5
and R
6
are each independently selected from the group consisting of:
(a) hydrogen, and
(b) C
1-3
alkyl.
Within this class there is a sub-class of compounds of Formula Ia
Within this sub-class there is a group of compounds wherein:
R
1
is selected from the group consisting of:
(a) S(O)
2
CH
3
,
(b) S(O)
2
NHR
4
,
(c) S(O)(NH)CH
3
,
(d) S(O)(NH)NH
2
,
R
2
and R
3
are each independently selected from the group consisting of:
(a) hydrogen,
(b) halo,
(c) C
1-3
alkoxy,
(d) C
1-3
alkylthio,
(e) CN,
(f) C
1-3
fluoroalkyl,
(g) C
1-3
alkyl,
(h) —C(R
5
)(R
6
)—O—C
1-4
alkyl, and
R
4
is selected from the group consisting of hydrogen, C
1-4
alkyl, phenyl and benzyl;
R
5
and R
6
are each independently selected from the group consisting of:
(a) hydrogen, and
(b) C
1-3
alkyl.
Within this group there is a sub-group of compounds wherein:
R
1
is selected from the group consisting of:
(a) S(O)
2
CH
3
,
(b) S(O)
2
NHR
4
,
(c) S(O)(NH)CH
3
,
R
2
and R
3
are each independently selected from the group consisting of:
(a) hydrogen,
(b) halo,
(c) C
1-3
alkoxy,
(d) C
1-3
alkylthio,
(e) CN,
(f) C
1-2
fluoroalkyl,
(g) C
1-3
alkyl,
R
4
is selected from the group consisting of hydrogen, C
1-3
alkyl, phenyl and benzyl;
R
5
and R
6
are each independently selected from the group consisting of:
(a) hydrogen, and
(b) C
1-3
alkyl.
Within this sub-group are the compounds wherein
R
1
is selected from the group consisting of:
(a) S(O)
2
CH
3
,
(b) S(O)
2
NH
2
,
R
2
and R
3
are each independently selected from the group consisting of:
(a) hydrogen,
(b) halo,
(c) C
1-2
alkoxy,
(d) C
1-2
alkylthio,
(e) CN,
(f) C
1-2
fluoroalkyl, and
(g) methyl and ethyl.
The invention is illustrated by the compounds of the examples as disclosed herein as well as the compounds of Tables I, II and if.
Alkyl is defined to include linear, branched, and cyclic structures, of the indicated number of carbon atoms, including, but not restricted to, methyl, ethyl, propyl, 2-propyl, n-, i-, s- and t-butyl, pentyl, hexyl, 1,1-dimethylethyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
Alkoxy is intended to include alkoxy groups of the indicated number of carbon atoms of a straight, branched, or cyclic configuration. Examples of lower alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy, and the like.
Black Cameron
Gauthier Jacques Yves
Lau Cheuk Kun
Li Chun-Sing
Therien Michel
Billups Richard C.
Higel Floyd D.
Merck Frosst Canada & Co.
Rose David L.
Sackey Ebenezer
LandOfFree
Diphenyl-1,2,3-thiadiazol-3-oxides, compositions and methods... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Diphenyl-1,2,3-thiadiazol-3-oxides, compositions and methods..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Diphenyl-1,2,3-thiadiazol-3-oxides, compositions and methods... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2507587