Pyrazole derivatives as anti-inflammatory/analgesic agents

Details Pyrazole derivatives as anti-inflammatory/analgesic agents Pyrazole derivatives as anti-inflammatory/analgesic agents

2001-04-02

2003-03-25

Fan, Jane (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C546S275700

Reexamination Certificate

active

06538009

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention relates to tricyclic pyrazole derivatives, methods of treatment and pharmaceutical compositions for the treatment of cyclooxygenase mediated diseases. The compounds of this invention inhibit the biosynthesis of prostaglandins by intervention of the action of the enzyme cyclooxygenase on arachidonic acid, and are therefore useful in the treatment or alleviation of inflammation, other inflammation associated disorders, such as arthritis, neurodegeneration and colon cancer, in mammals, preferably humans, dogs, cats, horses or livestock.
Nonsteroidal anti-inflammatory drugs (NSAID's) are widely used in treating pain and the signs and symptoms of arthritis because of their analgesic and anti-inflammatory activity. It is accepted that common NSAID's work by blocking the activity of cyclooxygenase (COX), also known as prostaglandin G/H synthase (PGHS), the enzyme that converts arachidonic acid into prostanoids. Prostaglandins, especially prostaglandin E
2
(PGE
2
), which is the predominant eicosanoid detected in inflammation conditions, are mediators of pain, fever and other symptoms associated with inflammation. Inhibition of the biosynthesis of prostaglandins has been a therapeutic target of anti-inflammatory drug discovery. The therapeutic use of conventional NSAID's is, however, limited due to drug associated side effects, including life threatening ulceration and renal toxicity. An alternative to NSAID's is the use of corticosteroids; however, long term therapy can also result in severe side effects.
The use of NSAID's in dogs and cats has been more limited than that in humans, e.g., only three such NSAID's have been approved by the Food and Drug Administration, Committee on Veterinary Medicine (FDA/CVM), for use in dogs in the United States, i.e., ETOGESIC® (etodolac), ARQUEL® (meclofenamic acid) and RIMADYL® (carprofen). Consequently, there is less experience and knowledge in veterinary medicine about safety and efficacy issues surrounding the use of NSAID's in dogs. In veterinary medicine, for example, the most common indication for NSAID's is the treatment of degenerative joint disease (DJD), which in dogs often results from a variety of developmental diseases, e.g., hip dysplasia and osteochondrosis, as well as from traumatic injuries to joints. In addition to the treatment of chronic pain and inflammation, NSAID's are also useful in dogs for treating post-surgical acute pain, as well as for treating clinical signs associated with osteoarthritis.
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, J. A.; Appleton, I.; Tomlinson, A.; Bishop-Bailey, D.; Croxtoll, J.; Willoughby, D. A.
Proc. Nat. Acad. Sci. USA,
1994, 91, 2046). COX-1 is thought 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. A pathological role for prostaglandins has been implicated in a number of human disease states including rheumatoid arthritis and osteoarthritis, pyrexia, asthma, bone resorption, cardiovascular diseases, dysmenorrhea, premature labor, nephritis, nephrosis, atherosclerosis, hypotension, shock, pain, cancer, and Alzheimer disease. It is believed that compounds that selectively inhibit the biosynthesis of prostaglandins by intervention of the induction phase of the inducible enzyme COX-2 and/or by intervention of the activity of the enzyme COX-2 on arachidonic acid would provide alternate therapy to the use of NSAID's or corticosteroids in that such compounds would exert anti-inflammatory effects without the adverse side effects associated with COX-1 inhibition.
A variety of sulfonylbenzene compounds which inhibit COX are referred to in patent publications (U.S. Pat. Nos. 5,466,823, 5,565,482, 5,670,532 and 5,886,016; PCT publications WO 97/16435, WO 97/14691, WO 96/19469, WO 96/36623, WO 96/03392, WO 96/03387, WO 97/727181, WO 96/936617, WO 96/19469, WO 96/08482, WO 95/00501, WO 95/15315, WO 95/15316, WO 95/15317, WO 95/15318, WO 97/13755, WO 97/11704, and WO 96/09293 and European Patent publication EP 0799523, EP 418845 and EP 554829). Each of the foregoing applications is incorporated herein by reference in its entirety.
SUMMARY OF THE INVENTION
The present invention relates to compounds of the formula
wherein the dashed line represents optional double bonds (which can be between any of the carbon atoms of the ring except that such bonds cannot be cumulative);
n is an integer from zero to four;
p is an integer from one to two;
X is >CR
7
or —N—;
Y is >CR
8
or —N—;
Z is >CHR
9
, —O—, —S—, >SO, >SO
2
, and >NR
10
;
W is >CR
5
R
6
;
R
1
is —CF
3
or —CHF
2
;
R
2
is (C
1
-C
6
)alkyl;
R
3
is hydrogen, halo, (C
1
-C
6
)alkyl, (C
2
-C
6
)alkenyl, (C
2
-C
6
)alkynyl, (C
1
-C
6
)alkoxy, —OCF
3
, (C
1
-C
6
)alkylcarbonyl, formyl, formamidyl, cyano, (C
1
-C
6
)alkoxycarbonyl, aminocarbonyl, N-(C
1
-C
6
)alkylaminocarbonyl or N,N-[(C
1
-C
6
)alkyl]
2
aminocarbonyl;
wherein said R
3
(C
1
-C
6
)alkyl may optionally be substituted with one to three substituents independently selected from halo, (C
1
-C
6
)alkoxy, cyano, (C
1
-C
6
)alkoxycarbonyl, aminocarbonyl, N-(C
1
-C
6
)alkylaminocarbonyl and N,N-[(C
1
-C
6
)alkyl]
2
aminocarbonyl;
R
4
is hydrogen; halo; hydroxy; (C
1
-C
6
)alkyl or (C
1
-C
6
)alkoxy optionally substituted with one to three halogen atoms;
wherein said R
4
(C
1
-C
6
)alkyl group may optionally be substituted with one to three substituents independently selected from halo, hydroxy, (C
1
-C
6
)alkoxy and cyano;
R
5
is hydrogen, halo, (C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy, (C
1
-C
6
)alkylcarbonyl, (C
1
-C
6
)alkoxycarbonyl or aminocarbonyl;
wherein said R
5
(C
1
-C
6
)alkyl group may optionally be substituted with one to three substituents independently selected from halo, hydroxy, (C
1
-C
6
)alkoxy and cyano;
R
6
is hydrogen, halo, (C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy, (C
1
-C
6
)alkylcarbonyl, (C
1
-C
6
)alkoxycarbonyl or aminocarbonyl;
R
7
is hydrogen, halo, hydroxy, (C
1
-C
6
)alkyl or (C
1
-C
6
)alkoxy optionally substituted with one to three halogen atoms;
wherein said R
7
(C
1
-C
6
)alkyl group may optionally be substituted with one to three substituents independently selected from halo, hydroxy, (C
1
-C
6
)alkoxy and cyano;
R
8
is hydrogen, halo, hydroxy, (C
1
-C
6
)alkyl or (C
1
-C
6
)alkoxy optionally substituted with one to three halogen atoms;
wherein said R
8
(C
1
-C
6
)alkyl group may optionally be substituted with one to three substituents independently selected from halo, hydroxy, (C
1
-C
6
)alkoxy and cyano;
R
9
is hydrogen, halo, hydroxy, (C
1
-C
6
)alkyl or (C
1
-C
6
)alkoxy optionally substituted with one to three halogen atoms;
wherein said R
9
(C
1
-C
6
)alkyl group may optionally be substituted with one to three substituents independently selected from halo, hydroxy, (C
1
-C
6
)alkoxy and cyano;
R
10
is hydrogen, (C
1
-C
6
)alkyl, (C
1
-C
6
)alkylcarbonyl or aminocarbonyl;
wherein said R
10
(C
1
-C
6
)alkyl group may optionally be substituted with one to three substituents independently selected from halo, hydroxy, (C
1
-C
6
)alkoxy and cyano;
with the proviso that at least one of X or Y is —N—;
and the pharmaceutically acceptable salts of such compounds.
The present invention also relates to the pharmaceutically acceptable acid addition salts of compounds of the formula I. The acids which are used to prepare the pharmaceutically acceptable acid addition salts of the aforementioned base compounds of this invention are those which form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succi

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