Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-06-16
2002-04-23
Powers, Fiona T. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S403000, C546S275400, C548S364400, C548S364700, C548S365700, C548S379100, C548S379700
Reexamination Certificate
active
06376519
ABSTRACT:
FIELD OF THE INVENTION
The invention relates generally to anti-inflammatory drugs, and more particularly to novel compounds which inhibit the activity of cyclooxygenase-2.
BACKGROUND OF THE INVENTION
The metabolites of arachidonic acid, such as prostaglandins, lipoxygenases and thromboxane products are produced in a wide variety of tissues and play a key role in several biological responses. Prostaglandins mediate both beneficial and undesirable biological reactions. The production of prostaglandins induces pain, swelling, heat and redness which are characteristic features of inflammation. The chronic inflammation associated with prostaglandin production leads to the breakdown of the injured tissue and angiogenesis. In pathologic chronic inflammation, normal tissues can be destroyed and the new blood vessel formation can support growth of abnormal tissue. Prostaglandins are also important for normal physiological processes in different organs. In the stomach, prostaglandins protect mucosa from acid. They also regulate blood flow and salt-water balance in the kidney. Prostaglandins are also important in platelets aggregation and participate in memory and other cognitive functions.
Prostaglandins are produced from cell membrane phospholipids by a cascade of enzymes. The enzymatic activities involve release of arachidonic acid from the cell membrane by phospholipase A
2
, followed by the conversion of arachidonic acid to a common prostaglandin precursor, PGH
2
, by cyclooxygenase (also called prostaglandin H synthase). PGH
2
is finally converted to various types of prostaglandins (PGE
1
, PGE
2
, PGI
2
or prostacyclin, PGF
2&agr;
and thromboxane) by cell-specific synthases.
Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) block the formation of prostaglandins by inhibiting cyclooxygenase activity. They have analgesic, antipyretic and anti-inflammatory activities. However, chronic treatment with the available NSAIDs often leads to disruption of beneficial prostaglandin-mediated processes. The side effects associated with constant usage of NSAIDs include gastrointestinal (GI) irritation and formation of life-threatening GI ulcers.
A dramatic advance in the field of inflammation research came with discovery of multiple enzymes for each step of the prostaglandin synthase cascade. The research suggested that in some situations, such as inflammation, cyclooxygenase was inducible. The cyclooxygenase known at the time, cyclooxygenase-1 (COX-1), was clearly non-inducible or modulated by glucocorticoids. A second, inducible form of cyclooxygenase known as cyclooxygenase-2 (COX-2) was subsequently identified and cloned by several groups of investigators. COX-1 is the constitutive cyclooxygenase isoform and is mainly responsible for the synthesis of cytoprotective prostaglandins in the GI tract and the synthesis of thromboxane which triggers platelet aggregation in blood platelets. COX-2 is inducible and short lived except in the case of certain tumors where it is constitutively activated. COX-2 expression is stimulated in response to endotoxins, cytokines, hormones, growth factors and mitogens. These observations suggest that COX-1 and COX-2 serve different physiological and pathophysiological functions. Indeed, it has been suggested that COX-1 is responsible for endogenous basal release of prostaglanclins and hence is important to the physiological functions of prostaglandins such as GI integrity and renal blood flow. On the other hand, it has been suggested that COX-2 is mainly responsible for the pathological effects of prostaglandins, where induction of the enzyme occurs in response to inflammatory agents, hormones, growth factors and cytokines. See, U.S. Pat. No. 5,604,253, incorporated herein by reference, for a discussion of the advantages of selective COX-2 inhibition. Principally, a selective COX-2 inhibitor is expected to possess similar anti-inflammatory, antipyretic and analgesic properties to a conventional NSAID but with reduced potential for gastrointestinal toxicity, and a reduced potential for renal side effects.
The differential tissue distribution of COX-1 and COX-2 provides an approach to develop selective inhibitors for COX-2 with reduced effect on COX-1, thereby preventing gastric side effects.
A number of selective COX-2 inhibitors have been reported. These include diaryl heterocyclics (Penning etal.,
J. Med. Chem
, 40,1347-1365 (1997); acetoxyphenyl alkyl sulfides (Kalgutkar et al.,
J. Med. Chem
, 41, 4800-4818 (1998); methane sulfonanilides (Li et al.,
J. Med. Chem
, 38, 4897-4905 (1995); and tricyclic inhibitor classes (Wilkerson et al.,
J. Med. Chem
., 38, 3895-3901 (1995). U.S. Pat. No. 5,604,253 discloses N-benzylindol-3-yl propanoic acid derivatives as cyclooxygenase inhibitors.
What is needed are additional COX-2 inhibitors, particularly compounds which selectively inhibit the cyclooxygenase activity of COX-2 over COX-1.
SUMMARY OF THE INVENTION
It is an object of the invention to provide compounds and pharmaceutical compositions thereof for inhibiting the biological activity of COX-2, in particular the cyclooxygenase activity of COX-2.
It is an object of the invention to provide for methods of treating disease conditions which are associated with undesired prostaglandin production and/or secretion.
It is an object of the invention to provide for the treatment of cyclooxygenase-mediated disorders.
It is an object of the invention to provide compounds which selectively inhibit COX-2 over COX-1.
It is an object of the invention to provide methods for synthesizing compounds of the invention and intermediates thereof.
These and other objects of the invention shall become apparent from the following disclosure.
Compounds of formula I, and pharmaceutically acceptable salts thereof, are provided
wherein:
X is selected from the group consisting of C
1
-C
6
trihalomethyl, preferably trifluoromethyl; C
1
-C
6
alkyl; and an optionally substituted or di-substituted phenyl group of formula II:
wherein:
R
3
and R
4
are independently selected from the group consisting of hydrogen, halogen, preferably chlorine, fluorine and bromine; hydroxyl; nitro; C
1
-C
6
alkyl, preferably C
1
-C
3
alkyl; C
1
-C
6
alkoxy, preferably C
1
-C
3
alkoxy; carboxy; C
1
-C
6
trihaloalkyl, preferably trihalomethyl, most preferably trifluoromethyl; and cyano;
Z is selected from the group consisting of substituted and unsubstituted aryl.
The carbon chains in the alkyl and alkoxy groups which may occur in the compounds of the invention may be straight or branched. The expression “C
1
-C
6
alkyl” thus extends to alkyl groups containing one, two, three, four, five or six carbons. The expression “C
1
-C
6
alkoxyl” thus extends to alkoxy groups containing one, two, three, four, five or six carbons.
The term “aryl”, alone or in combination, means a carbocyclic aromatic system containing one, two or three rings wherein such rings may be attached together in a pendent manner or may be fused. The term “aryl” is intended to include not only aromatic systems containing only carbon ring atoms but also systems containing one or more non-carbon atoms as ring atoms. Such systems may be known as “heteroaryl” systems. The term “aryl” is thus deemed to include “heteroaryl”.
Preferred aryl groups Z include phenyl and heteroaryl, which may be substituted or unsubstituted. By “substituted” is meant any level of substitution, although mon- di- and tri-substitution are preferred. The substituents are independently selected. The substituents are preferably selected from the group consisting of halogen, particularly chlorine, fluorine and bromine; hydroxyl; nitro; C
1
-C
6
alkyl, preferably C
1
-C
3
alkyl, most preferably methyl; C
1
-C
6
alkoxy, preferably C
1
-C
3
alkoxy, most preferably methoxy; carboxy; C
1
-C
6
trihaloalkyl, preferably trihalomethyl, most preferably trifluoromethyl; and cyano. Although mono-, di- and tri-substitution is preferred, full substitution, particularly when the aryl group is phenyl, is possible. According to one preferred embodiment, Z is phenyl, and is
Reddy E. Premkumar
Reddy M. V. Ramana
Drinker Biddle & Reath LLP
Powers Fiona T.
Temple University-of the Commonwealth of Higher Education
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