Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1997-06-09
1999-03-23
Richter, Johann
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514405, 540557, 546 82, 5483595, A61K 31415, C07D23154
Patent
active
058860169
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT U.S. 95/11403 filed on Sep. 15, 1995.
FIELD OF THE INVENTION
This invention is in the field of antiinflammatory pharmaceutical agents and specifically relates to compounds, compositions and methods for treating inflammation and inflammation-associated disorders, such as arthritis.
BACKGROUND OF THE INVENTION
Prostaglandins play a major role in the inflammation process and the inhibition of prostaglandin production, especially production of PGG.sub.2, PGH.sub.2 and PGE.sub.2, has been a common target of antiinflammatory drug discovery. However, common non-steroidal antiinflammatory drugs (NSAIDs) that are active in reducing the prostaglandin-induced pain and swelling associated with the inflammation process are also active in affecting other prostaglandin-regulated processes not associated with the inflammation process. Thus, use of high doses of most common NSAIDs can produce severe side effects, including life threatening ulcers, that limit their therapeutic potential. An alternative to NSAIDs is the use of corticosteroids, which have even more drastic side effects, especially when long term therapy is involved.
Previous NSAIDs have been found to prevent the production of prostaglandins by inhibiting enzymes in the human arachidonic acid/prostaglandin pathway, including the enzyme cyclooxygenase (COX). The recent discovery of an inducible enzyme associated with inflammation (named "cyclooxygenase-2 (COX-2)" or "prostaglandin G/H synthase II") provides a viable target of inhibition which more effectively reduces inflammation and produces fewer and less drastic side effects.
The novel compounds described herein are such safe and also effective antiinflammatory agents. The invention compounds are found to show usefulness in vivo as antiinflammatory agents with minimal side effects. The compounds described herein preferably selectively inhibit cyclooxygenase-2 over cyclooxygenase-1.
Substituted pyrazoles having antiinflammatory activity are described in copending applications 08/160,594 and 08/160,553.
U.S. Pat. No. 3,940,418 to R. Hamilton describes tricyclic
U.S. Pat. No. 4,803,193 to Kanda et al, describes as heat sensitive recording matertials.
V. Colota et al (J.Med.Chem., 33, 2646 (1991)) describe tricyclic
U.S. Pat. Nos. 4,816,467 and 5,206,258 to Doria et al describe -oxo-propanamides as immunomodulators. G. Doria et al (Farmaco, 46, 843 (1991)) also describe the immunomodulating activity of pyrazolylpropanamides, and specifically ethyl xylate. British patent 2,227,741 describes related application No. 347,773 similarly describes such fused pyrazole compounds, and specifically yrazole-3-propanamide. U.S. Pat. No. 5,260,328 to Doria et al describes oxo-propanamides for the treatment of rheumatoid arthritis.
U.S. Pat. No. 4,678,499 to Pasteris et al describes 1-aryl-indenopyrazol-4-one-5-sulfonamides as having herbicidal activity. Specifically, 1-phenylindenopyrazol-4-one-5-sulfonamide and described.
The invention's benzopyranopyrazolyl derivatives are found to show usefulness in vivo as antiinflammatory agents with minimal side effects.
DESCRIPTION OF THE INVENTION
A class of compounds useful in treating inflammation-related disorders is defined by Formula I: ##STR2## wherein A is --(CH.sub.2).sub.m --X--(CH.sub.2).sub.n --; wherein X is selected from S(O).sub.p, O and NR.sup.3 ; formyl, alkoxycarbonyl, carboxyl, carboxylalkyl, alkoxycarbonylalkyl, amidino, cyanoamidino, aminocarbonyi, alkoxy, alkoxyalkyl, aminocarbonylalkyl, N-alkylaminocarbonyl, N-arylaminocarbonyl, N,N-dialkylaminocarbonyl, N-alkyl-N-arylaminocarbonyl, alkylcarbonyl, alkylcarbonylalkyl, hydroxyalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylthioalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, N-alkylaminosulfonyl, N-arylaminosulfonyl, arylsulfonyl, N,N-dialkylaminosulfonyl, N-alkyl-N-arylaminosulfonyl and heterocyclic; optionally substituted at a substitutable position with one or more radicals selected from alkylsulfonyl, aminosulfonyl, halo, alkyl, alkoxy, hydroxyl and haloalkyl; alkylt
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Bertenshaw Stephen R
Graneto Matthew J
Rogier, Jr. Donald J
Talley John J
Bulock Joseph W.
G.D. Searle & Co.
Richter Johann
Sackey Ebenezer
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