Prostaglandin endoperoxide H synthase biosynthesis inhibitors

Details Prostaglandin endoperoxide H synthase biosynthesis inhibitors Prostaglandin endoperoxide H synthase biosynthesis inhibitors

1999-10-27

2001-10-23

Bernhardt, Emily (Department: 1611)

Organic compounds -- part of the class 532-570 series

Organic compounds

Four or more ring nitrogens in the bicyclo ring system

C544S232000, C544S238000, C544S239000, C544S241000, C514S085000, C514S241000

Reexamination Certificate

active

06307047

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 compounds of the present invention have the formula I:
or a pharmaceutically acceptable salt, ester, or prodrug thereof, wherein
X is selected from the group consisting of O, S, —NR
4
, —NOR
a
, and —NNR
b
R
c
;
R
4
is selected from the group consisting of alkenyl, alkyl, aryl, arylalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclic, and heterocyclic alkyl;
R
a
, R
b
, and R
c
are independently selected from the group consisting of alkyl, aryl, arylalkyl, cycloalkyl, and cycloalkylalkyl;
R is selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxyiminoalkoxy, alkyl, alkylcarbonylalkyl, alkylsulfonylalkyl, alkynyl, aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylhaloalkyl, arylhydroxyalkyl, aryloxy, aryloxyhaloalkyl, aryloxyhydroxyalkyl, arylcarbonylalkyl, carboxyalkyl, cyanoalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylidenealkyl, haloalkenyl, haloalkoxyhydroxyalkyl, haloalkyl, haloalkynyl, heterocyclic, heterocyclic alkoxy, heterocyclic alkyl, heterocyclic oxy, hydroxyalkyl, hydroxyiminoalkoxy, —(CH
2
)
n
C(O)R
5
, —(CH
2
)
n
CH(OH)R
5
, —(CH
2
)
n
C(NOR
d
)R
5
, —(CH
2
)
n
CH(NOR
d
)R
5
, —(CH
2
)
n
CH(NR
d
R
e
)R
5
, —R
6
R
7
, —(CH
2
)
n
C≡CR
7
, —(CH
2
)
n
[CH(CX′
3
)]
m
(CH
2
)
p
R
7
, —(CH
2
)
n
(CX′
2
)
m
(CH
2
)
p
R
7
, and —(CH
2
)
n
(CHX′)
m
(CH
2
)
p
R
7
;
R
5
is selected from the group consisting of hydrogen, alkenyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkenyl, cycloalkyl, haloalkenyl, haloalkyl, haloalkynyl, heterocyclic, and heterocyclic alkyl;
R
6
is selected from the group consisting of alkenylene, alkylene, halo-substituted alkenylene, and halo-substituted alkylene;
R
7
is selected from the group consisting of hydrogen, alkenyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl, haloalkyl, heterocyclic, and heterocyclic alkyl;
R
d
and R
e
are independently selected from the group consisting of hydrogen, alkenyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkenyl, cycloalkyl, haloalkyl, heterocyclic, and heterocyclic alkyl;
X′ is halogen;
m is an integer from 0-5;
n is an integer from 0-10; and
p is an integer from 0-10; and
R
1
, R
2
, and R
3
are independently selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, alkoxyiminoalkoxy, alkoxyiminoalkyl, alkyl, alkynyl, alkylcarbonylalkoxy, alkylcarbonylamino, alkylcarbonylaminoalkyl, aminoalkoxy, aminoalkylcarbonyloxyalkoxy aminocarbonylalkyl, aryl, arylalkenyl, arylalkyl, arylalkynyl, carboxyalkylcarbonyloxyalkoxy, cyano, cycloalkenyl, cycloalkyl, cycloalkylidenealkyl, haloalkenyloxy, haloalkoxy, haloalkyl, halogen, heterocyclic, hydroxyalkoxy, hydroxyiminoalkoxy, hydroxyiminoalkyl, mercaptoalkoxy, nitro, phosphonatoalkoxy, Y, and W; provided that one of R
1
, R
2
, or R
3
must be W, and further provided that only one of R
1
, R
2
, or R
3
is W;
W is selected from the group consisting of
X
1
is selected from the group consisting of S(O)
2
, S(O)(NR
10
), S(O), Se(O)
2
, P(O)(OR
11
), and P(O)(NR
12
R
13
);
X
2
is selected from the group consisting of hydrogen, alkenyl, alkyl, alkynyl and halogen;
R
9
is selected from the group consisting of alkenyl, alkoxy, alkyl, alkylamino, alkylcarbonylamino, alkynyl, amino, cycloalkenyl, cycloalkyl, dialkylamino, —NHNH
2
, and —NCHN(R
10
)R
11
;
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 3-6 membered ring containing 1 or 2 heteroatoms selected from the group consisting of O, S, and NR
7
;
Y is selected from the group consisting of —OR
14
, —SR
14
, —C(R
16
)(R
17
)R
14
, —C(O)R
14
, —C(O)OR
14
, —N(R
16
)C(O)R
14
, —NC(R
16
)R
14
, and —N(R
16
)R
14
;
R
14
is selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, alkyl, alkylthioalkyl, alkynyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclic, heterocyclic alkyl, hydroxyalkyl, and NR
18
R
19
; and
R
16
, R
17
, R
18
, and R
19
are independently selected from the group consisting of hydrogen, alkenyl, alkoxy, alkyl, cycloalkenyl, cycloalkyl, aryl, arylalkyl, heterocyclic, and heterocyclic alkyl.
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.
In one embodiment, compounds of the present invention have formula I wherein,
R
2
is W;
X
1
is selected from S(O)
2
, S(O), Se(O)
2
, and S(O)(NR
10
);
R
9
is selected from alkenyl, alkoxy, alkyl, alkylamino, alkylcarbonylamino, alkynyl, amino, cycloalkenyl, cycloalkyl, and dialkylamino; and
X, X
2
, R, R
1
, R
3
, and R
10
are as defined in formula I.
In another embodiment, compounds of the present invention have formula I wherein,
R
2
is W;
W is
X
1
is selected from S(O)
2
, S(O), Se(O)
2
, and S(O)(NR
10
);
R
9
is selected from alkenyl, alkoxy, alkyl, alkylamino, alkylcarbonylamino, alkynyl, amino, cycloalkenyl, cycloalkyl, and dialkylamino; and
X, X
2
, R, R
1
, R
3
, and R
10
are as defined in formula I.
In another embodiment, compounds of the present invention have formula I wherein,
R
2
is W;
W is
X
2
is selected from hydrogen and halogen;
R is selected from hydrogen, alkenyl, alkyl, alkynyl, alkylcarbonylalkyl, alkylsulfonylalkyl, carboxyalkyl, cyanoalkyl, haloalkyl, hydroxyalkyl, cycloa

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