Sulfonylphenylpyrazole compounds useful as COX-2 inhibitors

Details Sulfonylphenylpyrazole compounds useful as COX-2 inhibitors Sulfonylphenylpyrazole compounds useful as COX-2 inhibitors

2000-08-25

2002-10-29

Ford, John M. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S372000, C514S210030, C514S212010, C514S374000, C514S378000, C514S397000, C514S406000, C514S232500, C514S233200, C514S256000, C514S252010, C514S322000, C514S339000, C514S314000, C514S333000, C514S307000, C540S603000, C546S199000, C546S187000, C546S275700, C546S167000, C546S152000, C546S148000, C544S371000, C544S238000, C544S333000, C544S117000, C548S206000, C548S181000, C548S215000, C548S240000, C548S159000, C548S311700, C548S304400, C548S305100, C548S217000

Reexamination Certificate

active

06472416

ABSTRACT:

TECHNICAL FIELD
The present invention encompasses novel sulfonylphenylpyrazole 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 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 isoenzymes PGHS-1 and PGHS-2 are more commonly referred to as cyclooxygenase-1 or COX-1 and cyclooxygenase-2 or COX-2. These isozymes have been shown to have different gene regulation and represent distinctly different prostaglandin biosynthesis pathways.
The PGHS-1 or COX-1 pathway is expressed constitutively in most cell types. This is an important “housekeeping” enzyme in many tissues, including the gastrointestinal (GI) tract and the kidneys. 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 or COX-2 pathway involves an induction mechanism which has been linked to inflammation, mitogenesis and ovulation phenomena. COX-2 is the inducible isoform associated with inflammation.
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 sulfonylphenylpyrazole compounds which are selective inhibitors of cyclooxygenase-2 (COX-2).
The compounds of the present invention are selected from the group having the formulas I, II, and III, below
wherein
one of R
1
and R
2
is selected from the group consisting of:
 wherein
R
7
is selected from the group consisting of alkyl, amino, alkylamino, dialkylamino;
X
4
is selected from the group consisting of —SO
2
—, —SO(NR
8
)—;
R
8
is selected from the group consisting of hydrogen, alkyl, and cycloalkyl;
R
9
is selected from the group consisting of hydrogen and halogen; and
And the other of R
1
and R
2
is selected from the group consisting of 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
10
.
The Y group is selected from the group consisting of, —O—, —S—, —C(R
11
)(R
12
)—, C(O)NR
14
—, —C(O)—, —C(O)O—, —NH—, —NC(O)—, and —NR
13
—
R
10
is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxy, cycloalkyl, cycloalkenyl, amino, cyano, aryl, arylalkyl, heterocyclic, and heterocyclic (alkyl),
R
11
, R
12
, and R
13
are independently selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic (alkyl), and cyano; and
R
14
is selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic (alkyl), and cyano;
R
3
is selected from the group consisting of alkyl, substituted alkyl, alkenyl, alkynyl, aryl, aryl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, heterocyclic, arylcarbonylalkyl, cycloalkylcarbonylalkyl, heterocycliccarbonylalkyl, alkylcarbonylalkyl, aryl(substituted alkyl), and arylalkyl;
R
4
is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, aryl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, heterocyclic, aryl(substituted alkyl), and arylalkyl;
X
1
is selected from the group consisting of O, N(R
4
), wherein R
4
is as previously described, and S;
X
2
is selected from the group consisting of —O—(CH
2
)n-, —S—(CH
2
)
n
—, N(R
4
)—(CH
2
)
n
—, wherein n is 0 or 1 and R
4
is as previously described, —O—CH(R′)—, —S—CH(R′)—, and —N(R
4
)—CH(R′)—;
X
3
is absent, or is selected from the group consisting of —CH
2
—, and —C(R
15
)(R
16
)—, wherein R
15
and R
16
are independently selected from the group consisting of hydrogen and alkyl;
R
5
and R
6
are selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, aryl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, heterocyclic, aryl(substituted alkyl), and arylalkyl, or R
5
and R
6
are taken together with the atoms to which they are attached to form a 5 to 7 membered ring, optionally aromatic, and optionally containing one or two heteroatoms selected from O, N, and S, and optionally substituted with 1 to 2 groups selected from alkyl, hydroxy, halogen, oxo, haloalkyl, cyano and nitro;
the dashed bond represents an optional double bond;
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 sulfonylphenylpyrazole compounds which are cyclooxygenase (COX) inhibitors and are selective inhibitors of cyclooxygenase-2 (COX-2).
The compounds of the present invention are selected from the group having the formulas I, II, and III, below
wherein
one of R
1
and R
2
is selected from the group consisting of:
 wherein
R
7
is selected from the group consisting of alkyl, amino, alkylamino, dialkylamino;
X
4
is selected from the group consisting of —SO
2
—, —SO(NR
8
)—;
R
8
is selected from the group consisting of hydrogen, alkyl, and cycloalkyl;
R
9
is selected from the group consisting of hydrogen and halogen; and
And the other of R
1
and R
2
is selected from the group consisting of 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
10
.
The Y group is selected from the group consisting of, —O—, —S—, —C(R
11
)(R
12
)—, C(O)NR
14
—, —C(O)—, C(O)O—, —NH—, —NC(O)—, and —NR
13
—
R
10
is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxy, cycloalkyl, cycloalkenyl, amino, cyano, aryl, arylalkyl, heterocyclic, and heterocyclic (alkyl),
R
11
, R
12
, and R
13
are independently selected from the group. consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic (alkyl), and cyano; and
R

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