Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-09-14
2002-04-09
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S183000, C514S241000, C514S242000, C514S252040, C514S255050, C514S256000, C514S333000, C514S340000, C514S382000, C514S438000, C544S179000, C544S180000, C544S182000, C544S238000, C544S333000, C544S405000, C546S268400, C546S269100, C546S280400, C546S281400, C548S252000, C549S059000, C549S077000, C549S078000, C549S079000
Reexamination Certificate
active
06369084
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to compounds and methods for treating prostaglandin mediated diseases, and certain pharmaceutical compositions thereof. The compounds of the invention are structurally different from NSAIDs and opiates, and are antagonists of the pain and inflammatory effects of E-type prostaglandins.
Two review articles describe the characterization and therapeutic relevance of the prostanoid receptors as well as the most commonly used selective agonists and antagonists:
Eicosanoids: From Biotechnology to Therapeutic Applications,
Folco, Samuelsson, Maclouf, and Velo eds, Plenum Press, New York, 1996, chap. 14, 137-154 and Journal of Lipid Mediators and Cell Signalling, 1996, 14, 83-87. An article from
The British Journal of Pharmacology
(1994, 112, 735-740) suggests that Prostaglandin E
2
(PGE
2
) exerts allodynia through the EP
1
receptor subtype and hyperalgesia through EP
2
and EP
3
receptors in the mouse spinal cord.
Thus, selective prostaglandin ligands, agonists or antagonists, depending on which prostaglandin E receptor subtype is being considered, have anti-inflammatory, antipyretic and analgesic properties similar to a conventional non-steroidal anti-inflammatory drug, and in addition, inhibit hormone-induced uterine contractions and have anti-cancer effects. These compounds have a diminished ability to induce some of the mechanism-based side effects of NSAIDs which are indiscriminate cyclooxygenase inhibitors. In particular, the compounds have a reduced potential for gastrointestinal toxicity, a reduced potential for renal side effects, a reduced effect on bleeding times and a lessened ability to induce asthma attacks in aspirin-sensitive asthmatic subjects.
In The American Physiological Society (1994, 267, R289-R-294), studies suggest that PGE2-induced hyperthermia in the rat is mediated predominantly through the EP1 receptor. World patent applications WO 96/06822 (Mar. 7, 1996), WO 96/11902 (Apr. 25, 1996) and EP 752421-A1 (Jan. 8, 1997) disclose compounds as being useful in the treatment of prostaglandin mediated diseases.
SUMMARY OF THE INVENTION
The present invention relates to compounds represented by formula A
as well as pharmaceutically acceptable salts, hydrates and esters thereof, wherein:
y and z are independently 0-2, such that y+z=2;
R
a
is selected from the group consisting of:
1) heteroaryl, wherein heteroaryl is selected from the group consisting of:
a) furyl,
b) diazinyl, triazinyl or tetrazinyl,
c) imidazolyl,
d) isoxazolyl,
e) isothiazolyl,
f) oxadiazolyl,
g) oxazolyl,
h) pyrazolyl,
i) pyrrolyl,
j) thiadiazolyl,
k) thiazolyl
l) thienyl
m) triazolyl and
n) tetrazolyl,
said heteroaryl group being optionally substituted with one to three substituents selected from R
11
and C
1-4
alkyl,
2) —COR
6
,
3) —NR
7
R
8
,
4) —SO
2
R
9
,
5) hydroxy,
6) C
1-6
alkoxy, optionally substituted with one to three substituents selected from R
11
, and
7) C
1-6
alkyl, C
2-6
alkenyl or C
3-6
cycloalkyl, optionally substituted with one to three substituents selected from R
11
, and further substituted with 1-3 substituents selected from the group consisting of:
(a) —COR
6
(b) —NR
7
R
8
,
(c) —SO
2
R
9
,
(d) hydroxy,
(e) C
1-6
alkoxy or haloC
1-6
alkoxy, and
(f) heteroaryl,
such that R
a
is positioned on the phenyl ring to which it is bonded in a 1,3 or 1,4 relationship relative to the thienyl group represented in formula A;
each R
1
, R
2
, R
3
, R
4
and R
5
are independently selected from the group consisting of:
1) hydrogen,
2) halogen,
3) C
1-6
alkyl,
4) C
1-6
alkoxy,
5) C
1-6
alkylthio,
6) nitro,
7) carboxy and
8) CN, wherein items (3)-(5) above are optionally substituted with one or more substituents independently selected from R
11
;
R
6
is selected from the group consisting of hydrogen, hydroxy, C
1-6
alkyl, C
1-6
alkoxy and NR
7
R
8
, wherein C
1-6
alkyl or C
1-6
alkoxy are optionally substituted with one or more substituents independently selected from R
11
;
R
7
and R
8
are independently selected from the group consisting of:
(1) hydrogen,
(2) hydroxy,
(3) SO
2
R
9
(4) C
1-6
alkyl,
(5) C
1-6
alkoxy,
(6) phenyl,
(7) naphthyl,
(8) furyl,
(9) thienyl and
(10) pyridyl, wherein items (4)-(5) above are optionally substituted with one or more substituents independently selected from R
11
, and items (6)-(10) above are optionally substituted with one or more substituents independently selected from R
11
or C
1-4
alkyl,
R
9
is selected from the group consisting of
(1) hydroxy,
(2) N(R
10
)
2
,
(3) C
1-6
alkyl, optionally substituted with one or more substituents independently selected from R
11
,
(4) phenyl,
(5) naphthyl,
(6) furyl,
(7) thienyl and
(8) pyridyl, wherein items (4)-(8) above are optionally substituted with one or more substituents independently selected from R
11
or C
1-4
alkyl;
R
10
is hydrogen or C
1-6
alkyl; and
R
11
is the group consisting of halogen, hydroxy, C
1-3
alkoxy, nitro, N(R
10
)
2
and pyridyl.
The invention also encompasses pharmaceutical compositions and methods for treatment of prostaclandin mediated diseases.
DETAILED DESCRIPTION OF THE INVENTION
In one aspect of the invention, the invention encompasses compounds represented by formula A:
as well as pharmaceutically acceptable salts, hydrates and esters thereof, wherein:
y and z are independently 0-2, such that y+z=2;
R
a
is selected from the group consisting of:
1) heteroaryl, wherein heteroaryl is selected from the group consisting of:
a) furyl,
b) diazinyl, triazinyl or tetrazinyl,
c) imidazolyl,
d) isoxazolyl,
e) isothiazolyl,
f) oxadiazolyl,
g) oxazolyl,
h) pyrazolyl,
i) pyrrolyl,
j) thiadiazolyl,
k) thiazolyl
l) thienyl
m) triazolyl and
n) tetrazolyl,
said heteroaryl group being optionally substituted with one to three substituents selected from R
11
and C
1-4
alkyl,
2) —COR
6
,
3) —NR
7
R
8
,
4) —SO
2
R
9
,
5) hydroxy,
6) C
1-6
alkoxy, optionally substituted with 1-3 substituents selected from R
11
, and
7) C
1-6
alkyl, C
2-6
alkenyl or C
3-6
cycloalkyl, optionally substituted with 1-3 substituents selected from R
11
, and further substituted with 1-3 substituents selected from the group consisting of:
(a) —COR
6
(b) —NR
7
R
8
,
(c) —SO
2
R
9
,
(d) hydroxy,
(e) C
1-6
alkoxy or haloC
1-6
alkoxy, and
(f) heteroaryl,
such that R
a
is positioned on the phenyl ring to which it is bonded in a 1,3 or 1,4 relationship relative to the thienyl group represented in formula A;
R
1
, R
2
, R
3
, R
4
and R
5
are independently selected from the group consisting of:
1) hydrogen,
2) halogen,
3) C
1-6
alkyl,
4) C
1-6
alkoxy,
5) C
1-6
alkylthio,
6) nitro,
7) carboxy and
8) CN, wherein items (3)-(5) above are optionally substituted with one or more substituents independently selected from R
11
;
R
6
is selected from the group consisting of hydrogen, hydroxy, C
1-6
alkyl, C
1-6
alkoxy and NR
7
R
8
, wherein C
1-6
alkyl or C
1-6
alkoxy are optionally substituted with one or more substituents independently selected from R
11
;
R
7
and R
8
are independently selected from the group consisting of:
(1) hydrogen,
(2) hydroxy,
(3) SO
2
R
9
(4) C
1-6
alkyl,
(5) C
1-6
alkoxy,
(6) phenyl,
(7) naphthyl,
(8) furyl,
(9) thienyl and
(10) pyridyl, wherein items (4)-(5) above are optionally substituted with one or more substituents independently selected from R
11
, and items (6)-(10) above are optionally substituted with one or more substituents independently selected from R
11
or C
1-4
alkyl,
R
9
is selected from the group consisting of
(1) hydroxy,
(2) N(R
10
)
2
,
(3) C
1-6
alkyl, optionally substituted with one or more substituents independently selected from R
11
,
(4) phenyl,
(5) naphthyl,
(6) furyl,
(7) thienyl and
(8) pyridyl, wherein items (4)-(8) above are optionally substituted with one or more substituents independently selected from R
11
or C
1-4
alkyl;
R
10
is hydrogen or C
1-6
alkyl; and
R
11
is the group consisting of halogen, hydroxy, C
1-3
alkoxy, nitro, N(R
10
)
2
and pyridyl.
An embodiment of the invention that is of particular interest relates to compounds of formula A wherein R
a
is selected from
Labelle Marc
Lacombe Patrick
Ruel Rejean
Billups Richard C.
Merck Frosst Canada & Co.
Rao Deepak R.
Raymond Richard L.
Rose David L.
LandOfFree
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