Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1998-08-20
2003-02-25
Bernhardt, Emily (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S085000, C544S232000, C544S238000, C544S239000, C544S240000, C544S241000
Reexamination Certificate
active
06525053
ABSTRACT:
TECHNICAL FIELD
The present invention encompasses novel pyridazinone compounds useful in the treatment of cyclooxygenase-2 mediated diseases. More particularly, this invention concerns a method of inhibiting prostaglandin biosynthesis, particularly the induced prostaglandin endoperoxide H synthase (PGHS-2, cyclooxygenase-2, COX-2) protein.
BACKGROUND OF THE INVENTION
The prostaglandins are extremely potent substances which produce a wide variety of biological effects, often in the nanomolar to picomolar concentration range. The discovery of two forms of prostaglandin endoperoxide H synthase, isoenzymes PGHS-1 and PGHS-2, that catalyze the oxidation of arachidonic acid leading to prostaglandin biosynthesis has resulted in renewed research to delineate the role of these two isozymes in physiology and pathophysiology. These isozymes have been shown to have different gene regulation and represent distinctly different prostaglandin biosynthesis pathways. The PGHS-1 pathway is expressed constitutively in most cell types. It responds to produce prostaglandins that regulate acute events in vascular homeostasis and also has a role in maintaining normal stomach and renal function. The PGHS-2 pathway involves an induction mechanism which has been linked to inflammation, mitogenesis and ovulation phenomena.
Prostaglandin inhibitors provide therapy for pain, fever, and inflammation, and are useful therapies, for example in the treatment of rheumatoid arthritis and osteoarthritis. The non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, naproxen and fenamates inhibit both isozymes. Inhibition of the constitutive enzyme PGHS-1 results in gastrointestinal side effects including ulcers and bleeding and incidence of renal problems with chronic therapy. Inhibitors of the induced isozyme PGHS-2 may provide anti-inflammatory activity without the side effects of PGHS-1 inhibitors.
The problem of side-effects associated with NSAID administration has never completely been solved in the past. Enteric coated tablets and co-administration with misoprostol, a prostaglandin derivative, have been tried in an attempt to minimize stomach toxicity. It would be advantageous to provide compounds which are selective inhibitors of the induced isozyme PGHS-2.
The present invention discloses novel compounds which are selective inhibitors of PGHS-2.
SUMMARY OF THE INVENTION
The present invention discloses pyridazinone compounds which are selective inhibitors of cyclooxygenase-2 (COX-2). The the compounds of the present invention have the formula I:
where
X is selected from the group consisting of O, S, NR
4
, N—OR
a
, and N—NR
b
R
c
, wherein R
4
is selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, heterocyclic, heterocyclic (alkyl), and arylalkyl; and R
a
, R
b
, and R
c
are independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl, and arylalkyl;
R is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkylcarbonylalkyl, alkylsulfonylalkyl, alkylsulfonylarylalkyl, alkoxy, alkoxyalkyl, carboxy, carboxyalkyl, cyanoalkyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, arylcarbonylalkyl, heterocyclic, heterocyclic (alkyl), heterocyclic (alkoxy), heterocyclic (oxy), —C(O)R
5
, —(CH
2
)
n
C(O)R
5
, —R
6
—R
7
, —(CH
2
)
n
CH(OH)R
5
, —(CH
2
)
n
CH(OR
d
)R
5
, —(CH
2
)
n
C(NOR
d
)R
5
, —(CH
2
)
n
C(NR
d
)R
5
, —(CH
2
)
n
CH(NOR
d
)R
5
, —(CH
2
)
n
CH(NR
d
R
e
)R
5
, —(CH
2
)
n
C≡C—R
7
, —(CH
2
)
n
[CH(CX′
3
)]
m
—(CH
2
)
n
—CX′
3
, —(CH
2
)
n
(C X′
2
)
m
—(CH
2
)
n
—CX′
3
, —(CH
2
)
n
[CH(CX′
3
)]
m
—(CH
2
)
n
—R
8
, —(CH
2
)
n
(C X′
2
)
m
—(CH
2
)
n
R
8
, —(CH
2
)
n
(CHX′)
m
—(CH
2
)
n
—CX′
3
, —(CH
2
)
n
(CHX′)
m
—(CH
2
)
n
—R
8
, and —(CH
2
)
n
—R
20
,
wherein R
5
is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclic, and heterocyclic (alkyl);
wherein R
6
is alkylene or alkenylene;
R
7
and R
8
are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heterocyclic, and heterocyclic (alkyl);
R
20
is selected from the group consisting of alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, heterocyclic, and heterocyclic (alkyl);
R
d
and R
e
are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heterocyclic, and heterocyclic (alkyl);
X′ is halogen;
n is from 0 to about 10, and m is 0 to about 5; at least one of R
1
, R
2
and R
3
is a group, substituted with a substituent having a group —X
1
—R
9
, having the formula:
where X
1
is selected from the group consisting of —SO
2
—, —SO(NR
10
)—, —PO(OR
11
)—, and —PO(NR
12
R
13
)—,
R
9
is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, —NHNH
2
, alkylamino, dialkylamino, alkoxy, thiol, alkylthiol, and protecting groups,
X
2
is selected from the group consisting of hydrogen or halogen;
R
10
, R
11
, R
12
, and R
13
are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl, or R
12
and R
13
can be taken together, with the nitrogen to which they are attached, to form a heterocyclic ring having from 3 to 6 atoms.
The remaining two of the groups of R
1
, R
2
, and R
3
, are independently selected from the group consisting of hydrogen, hydroxy, hydroxyalkyl, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, amido, amidoalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, amino, aminocarbonyl, aminocarbonylalkyl, alkylamino, dialkylamino, arylamino, arylalkylamino, diarylamino, aryl, heterocyclic, heterocyclic (alkyl), cyano, nitro, and —Y—R
14
, wherein Y is selected from the group consisting of, —O—, —S—, —C(R
16
) (R
17
)—,
C(O)NR
21
—, —C(O)—, —C(O)O—, —NH—, —NC(O)—, and —NR
19
—. R
14
is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxy, cycloalkyl, cycloalkenyl, amino, cyano, aryl, arylalkyl, heterocyclic, and heterocyclic (alkyl),
R
16
, R
17
, and R
19
are independently selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic (alkyl), or cyano; and
R
21
is selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic (alkyl), or cyano; or a pharmaceutically acceptable salt, ester, or prodrug thereof.
DETAILED DESCRIPTION OF THE INVENTION
All patents, patent applications, and literature references cited in the specification are hereby incorporated by reference in their entirety. In the case of inconsistencies, the present disclosure, including definitions, will prevail.
The present invention discloses pyridazinone compounds which are cyclooxygenase (COX) inhibitors and are selective inhibitors of cyclooxygenase-2 (COX-2). COX-2 is the inducible isoform associated with inflammation, as opposed to the constitutive isoform, cyclooxygenase-1 (COX-1) which is an important “housekeeping” enzyme in many tissues, including the gastrointestinal (GI) tract and the kidneys.
In one embodiment, the compounds of the present invention have the formula I:
where
X is selected from the group consisting of O, S, NR
4
, N—OR
a
, and N—NR
b
R
c
, wherein R
4
is selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, heterocyclic, heterocyclic (alkyl), and arylalkyl; and R
a
, R
b
, and R
c
are independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl, and arylalkyl;
R is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl
Abbott Laboratories
Bernhardt Emily
Chen Portia
Ward Michael J.
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