5-heterocyclo-pyrazoles

Details 5-heterocyclo-pyrazoles 5-heterocyclo-pyrazoles

2002-11-01

2003-09-30

Ramsuer, Robert W. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S326000, C546S211000, C540S575000, C540S603000

Reexamination Certificate

active

06627626

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention relates to 5-heterocyclo-pyrazoles, methods of treatment and pharmaceutical compositions for the treatment of cyclooxygenase mediated diseases, such as arthritis, neurodegeneration and colon cancer, in mammals, preferably humans, dogs, cats or livestock.
Sulfonyl pyrazoles are useful in the treatment of cyclooxygenase (COX) mediated diseases, such as arthritis, neurodegeneration and colon cancer, in mammals, preferably humans, dogs, cats or livestock. Two forms of COX are now known, a constitutive isoform (COX-1) and an inducible isoform (COX-2) of which expression is upregulated at sites of inflammation (Vane, J. R.; Mitchell, et. al.,
Proc. Natl. Acad. Sci. USA
, 1994, 91, 2046). COX-1 appears to play a physiological role and to be responsible for gastrointestinal and renal protection. On the other hand, COX-2 appears to play a pathological role and is believed to be the predominant isoform present in inflammation conditions. The therapeutic use of conventional COX inhibitors are limited due to drug associated side effects, including life threatening ulceration and renal toxicity. Compounds that selectively inhibit COX-2 would exert anti-inflammatory effects without the adverse side effects associated with COX-1 inhibition. Preferred compounds of the invention are selective COX-2 inhibitors.
A variety of sulfonylpyrazoles that inhibit COX have been described in patent publications WO 97/11704, WO 01/40216, EP 1104758, EP 1104759, and EP 1104760; U.S. Non-Provisional Patent Application No. 09/798,752, filed Mar. 2, 2001; and U.S. Non-Provisional Patent Application No. 09/824,550, filed 2 Apr. 2, 2001.
Filed simultaneously with the present application on Nov. 2, 2001, are U.S. Provisional Applications entitled “
Hydrazinyl and Nitrogen Oxide Pyrazoles”; “Heterocyclo
-
Alkylsulfonyl Pyrazoles
”; “5-
Heteroatom-Substituted Pyrazoles
”; and “5-(
Alkylidene
-
Cycloalkyl
)- and 5-(
Alkylidene
-
Heterocycl
)-
Pyrazoles
”, which refer to certain pyrazole COX-2 inhibitors. The aforesaid applications are herein incorporated in their entireties by reference.
SUMMARY OF THE INVENTION
The present invention relates to compounds of the formula I:
or the pharmaceutically acceptable salts thereof;
wherein m is 0, 1 or 3;
n is 1, 2, or 3;
wherein ring W is connected to the pyrazole ring through a nitrogen atom and is a radical selected from the group consisting of:
a) a saturated, partially saturated or aromatic (3- to 7-membered)-heterocyclyl ring optionally containing one to four ring heteroatoms independently selected from the groups consisting of —N═, —NH—, —O—, and —S—;
b) a saturated, partially saturated or aromatic (3- to 7-membered)-heterocyclyl ring optionally containing one to four ring heteroatoms independently selected from the groups consisting of —N═, —NH—, —O—, and —S—; wherein said saturated, partially saturated or aromatic (3- to 7-membered)-heterocyclyl is fused to a a saturated, partially saturated or aromatic (3- to 7-membered)-carbocyclic ring; and
c) a saturated, partially saturated or aromatic (3- to 7-membered)-heterocyclyl ring optionally containing one to four ring heteroatoms independently selected from the groups consisting of —N═, —NH—, —O—, and —S—; wherein said saturated, partially saturated or aromatic (3- to 7-membered)-heterocyclyl is fused to a saturated, partially saturated or aromatic (3- to 7-membered)-heterocyclyl containing one to two ring heteroatoms independently selected from the group consisting of —N═, —NH—, —S— and —O—;
R
1
is a radical selected from the group consisting of H, —NO
2
, —CN, (C
1
-C
6
)alkyl, (C
1
-C
6
)alkyl-SO
2
—, (C
6
-C
10
)aryl-SO
2
—, H—(C═O)—, (C
1
-C
6
)alkyl-(C═O)—, (C
1
-C
6
)alkyl-O—(C═O)—, (C
1
-C
9
)heteroaryl-(C═O)—, (C
1
-C
9
)heterocyclyl-(C═O)—, H
2
N—(C═O)—, (C
1
-C
6
)alkyl-NH—(C═O)—, [(C
1
-C
6
)alkyl]
2
-N—(C═O)—, [(C
6
-C
10
)aryl]-NH—(C═O)—, [(C
1
-C
6
)alkyl]-[((C
6
-C
10
)aryl)-N]—(C═O)—, HO—NH—(C═O)—, and (C
1
-C
6
)alkyl-O—NH—(C═O)—;
R
2
is a radical selected from the group consisting of H, —NO
2
, —CN, (C
2
-C
6
)alkenyl, (C
2
-C
6
)alkynyl, (C
3
-C
7
)cycloalkyl, (C
6
-C
10
)aryl, (C
1
-C
9
)heteroaryl, (C
1
-C
9
)heterocyclyl, (C
1
-C
6
)alkyl-O—, (C
3
-C
7
)cycloalkyl-O—, (C
6
-C
10
)aryl-O—, (C
1
-C
9
)heteroaryl-O—, (C
1
-C
9
)heterocyclyl-O—, H—(C═O)—, (C
1
-C
6
)alkyl-(C═O)—, (C
3
-C
7
)cycloalkyl-(C═O)—, (C
6
-C
10
)aryl-(C═O)—, (C
1
-C
9
)heteroaryl-(C═O)—, (C
1
-C
9
)heterocyclyl-(C═O)—, (C
1
-C
6
)alkyl-O—(C═O)—, (C
3
-C
7
)cycloalkyl-O—(C═O)—, (C
6
-C
10
)aryl-O—(C═O)—, (C
1
-C
9
)heteroaryl-O—(C═O)—, (C
1
-C
9
)heterocyclyl-O—(C═O)—, (C
1
-C
6
)alkyl-(C═O)—O—, (C
3
-C
7
)cycloalkyl-(C═O)—O—, (C
6
-C
10
)aryl-(C═O)—O—, (C
1
-C
9
)heteroaryl-(C═O)—O—, (C
1
-C
9
)heterocyclyl-(C═O)—O—, (C
1
-C
6
)alkyl-(C═O)—NH—, (C
3
-C
7
)cycloalkyl-(C═O)—NH—, (C
6
-C
10
)aryl-(C═O)—NH—, (C
1
-C
9
)heteroaryl-(C═O)—NH—, (C
1
-C
9
)heterocyclyl-(C═O)—NH—, (C
1
-C
6
)alkyl-O—(C═O)—NH—, (C
1
-C
6
)alkyl-NH, [(C
1
-C
6
)alkyl]
2
-N—, (C
3
-C
7
)cycloalkyl-NH—, [(C
3
-C
7
)cycloalkyl]
2
-N—, [(C
6
-C
10
)aryl]-NH—, [(C
6
-C
10
)aryl]
2
-N—, [(C
1
-C
6
)alkyl]-[((C
6
-C
10
)aryl)-N]-, [(C
1
-C
9
)heteroaryl]-NH—, [(C
1
-C
9
)heteroaryl]
2
-N—, [(C
1
-C
9
)heterocyclyl]—NH—, [(C
1
-C
9
)heterocyclyl]
2
-N—, H
2
N—(C═O)—, HO—NH—(C═O)—, (C
1
-C
6
)alkyl-O—NH—(C═O)—, [(C
1
-C
6
)alkyl]-NH—(C═O)—, [(C
1
-C
6
)alkyl]
2
-N—(C═O)—, [(C
3
-C
7
)cycloalkyl]-NH—(C═O)—, [(C
3
-C
7
)cycloalkyl]
2
-N—(C═O)—, [(C
6
-C
10
)aryl]-NH—(C═O)—, [(C
6
-C
10
)aryl]
2
-N—(C═O)—, [(C
1
-C
6
)alkyl]-[((C
6
-C
10
)aryl)-N]-(C═O)—, [(C
1
-C
9
)heteroaryl]-NH—(C═O)—, [(C
1
-C
9
)heteroaryl]
2
-N—(C═O)—, [(C
1
-C
9
)heterocyclyl]-NH—(C═O)—, (C
1
-C
6
)alkyl-S— and (C
1
-C
6
)alkyl optionally substituted by one —OH group or by one to four fluoro substituents;
Each R
3
is a radical independently selected from the group consisting of H, halo, —OH, —CN, —NO
2
, (C
2
-C
6
)alkenyl, (C
2
-C
6
)alkynyl, (C
3
-C
7
)cycloalkyl, (C
6
-C
10
)aryl, (C
2
-C
9
heterocyclyl, (C
1
-C
6
)alkyl-O—, H—(C═O)—, (C
1
-C
6
)alkyl-(C═O)—, HO—(C═O)—, (C
1
-C
6
)alkyl-O—(C═O)—, —NH
2
, (C
1
-C
6
)alkyl-NH—, [(C
1
-C
6
)alkyl]
2
-N—, (C
3
-C
7
)cycloalkyl-NH—, (C
6
-C
10
)aryl-NH—, [(C
1
-C
6
)alkyl][((C
6
-C
10
)aryl)-N]—, (C
1
-C
9
)heteroaryl-NH—, H
2
N—(C═O)—, [(C
1
-C
6
)alkyl]-NH—(C═O)—, [(C
1
-C
6
)alkyl]
2
-N—(C═O)—, [(C
6
-C
10
)aryl]-NH—(C═O)—, [(C
1
-C
6
)alkyl]-[((C
6
-C
10
)aryl)-N]—(C═O)—, (C
1
-C
6
)alkyl-O—NH—(C═O)—, (C
1
-C
6
)alkyl-(C═O)—HN—, (C
1
-C
6
)alkyl-(C═O)-[(C
1
-C
6
)alkyl-N]—, —SH, (C
1
-C
6
)alkyl-S—, (C
1
-C
6
)alkyl-(S═O)—, (C
1
-C
6
)alkyl-SO
2
—, and (C
1
-C
6
)alkyl optionally substituted with one to four fluoro substituents;
R
4
is an (C
1
-C
6
)alkyl radical, wherein said (C
1
-C
6
)alkyl radical may optionally be substituted by one to four fluoro substituents;
R
5
is a radical selected from the group consisting of H, halo, —OH, (C
1
-C
8
)alkyl-O—, (C
2
-C
6
)alkenyl, (C
2
-C
6
)alkynyl, (C
3
-C
7
)cycloalkyl, —CN, H—(C═O)—, (C
1
-C
6
)alkyl-(C═O)—, (C
1
-C
6
)alkyl-(C═O)—O—, HO—(C═O)—, (C
1
-C
6
)alkyl-O—(C═O)—, (C
1
-C
6
)alkyl-NH—, [(C
1
-C
6
)alkyl]
2
-N—, (C
3
-C
7
)cycloalkyl-NH—, (C
6
-C
10
)aryl-NH—, [(C
1
-C
6
)alkyl]-[((C
6
-C
10
)aryl)-N]—, (C
1
-C
9
)heteroaryl-NH—, H
2
N—(C═O)—, (C
1
-C
6
)alkyl-NH—(C═O)—, [(C
1
-C
6
)alkyl]
2
-N—(C═O)—, (C
6
-C

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