Organic compounds -- part of the class 532-570 series – Organic compounds – Sulfur containing
Reexamination Certificate
2001-01-30
2004-01-13
Barts, Samuel (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Sulfur containing
C564S307000
Reexamination Certificate
active
06677488
ABSTRACT:
FIELD OF THE INVENTION
This invention is in the field of anti-inflammatory 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
2
, PGH
2
and PGE
2
, has been a common target of anti-inflammatory drug discovery. However, common non-steroidal anti-inflammatory 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.
Substituted biphenyl compounds have been reported as components in photographic materials. U.S. Pat. No. 5,238,790, to Shimura et al., describes the use of biphenyl compounds as dispersion agents in photographic materials. U.S. Pat. No. 5,294,530, to Seto et al., describes photographic materials containing biphenyl compounds as anti-fading agents.
U.S. Pat. No. 4,990,647, to Himmler et al., describes a method for the preparation of unsymmetric biaryl compounds.
Substituted biphenyl compounds have been reported as having activity as angiotensin II antagonists. Heterocyclo-substituted biphenyl compounds are described by D. Kim, et al. [
Bioorg. Med. Chem. Lett.,
4, 41-44 (1994)]. U.S. Pat. No. 5,254,546, to Ardecky et al., describes tetrazole substituted biphenyl compounds. U.S. Pat. No. 5,240,928, to Allen et al., describes aminosulfonyl-substituted biphenyl compounds.
Recently, a terphenyl compound has been described as an anti-inflammatory agent [R. Copeland et al., Med. Chem. Res., 5, 384-393 (1995)].
DESCRIPTION OF THE INVENTION
A class of compounds useful in treating inflammation-related disorders is defined by Formula I:
wherein A is selected from aryl and heteroaryl, wherein A is optionally substituted with one or more radicals selected from alkyl, halo, alkoxy, alkylthio, cyano, haloalkyl, amino, alkylamino, carboxyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl, hydroxyl and mercapto; wherein each of R
1
through R
4
is independently selected from hydrido, halo, and alkoxy; and wherein each of R
5
through R
9
is independently selected from hydrido, alkyl, halo, alkoxy, alkylthio, cyano, haloalkyl, amino, alkylamino, haloalkoxy, hydroxyalkyl, alkoxyalkyl, hydroxyl, mercapto, aminosulfonyl and alkylsulfonyl; or a pharmaceutically-acceptable salt thereof.
Compounds of Formula I would be useful for, but not limited to, the treatment of inflammation in a subject, and for treatment of other inflammation-associated disorders, such as, as an analgesic in the treatment of pain and headaches, or as an antipyretic for the treatment of fever. For example, compounds of the invention would be useful to treat arthritis, including but not limited to rheumatoid arthritis, spondyloarthopathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus and juvenile arthritis. Such compounds of the invention would be useful in the treatment of asthma, bronchitis, menstrual cramps, tendinitis, bursitis, and skin-related conditions such as psoriasis, eczema, burns and dermatitis. Compounds of the invention also would be useful to treat gastrointestinal conditions such as inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome and ulcerative colitis and for the prevention or treatment of cancer, such as colorectal cancer. Compounds of the invention would be useful in treating inflammation in such diseases as vascular diseases, migraine headaches, periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease, sclerodoma, rheumatic fever, type I diabetes, myasthenia gravis, multiple sclerosis, sarcoidosis, nephrotic syndrome, Behcet's syndrome, polymyositis, gingivitis, hypersensitivity, swelling occurring after injury, myocardial ischemia, and the like. The compounds would also be useful in the treatment of ophthalmic diseases such as retinitis, retinopathies, uveitis, conjunctivitis, and of acute injury to the eye tissue. The compounds would also be useful in the treatment of pulmonary inflammation, such as that associated with viral infections and cystic fibrosis. The compounds would also be useful for the treatment of certain central nervous system disorders such as Alzheimer's disease and dementia. The compounds of the invention are useful as anti-inflammatory agents, such as for the treatment of arthritis, with the additional benefit of having significantly less harmful side effects. These compounds would also be useful in the treatment of allergic rhinitis, respiratory distress syndrome, endotoxin shock syndrome, atherosclerosis and central nervous system damage resulting from stroke, ischemia and trauma.
Besides being useful for human treatment, these compounds are also useful for veterinary treatment of mammals, including companion animals and farm animals, such as, but not limited to, horses, dogs, cats, sheep and pigs.
The present compounds may also be used in co-therapies, partially or completely, in place of other conventional anti-inflammatories, such as together with steroids, NSAIDs, 5-lipoxygenase inhibitors, LTB
4
antagonists and LTA
4
hydrolase inhibitors.
Suitable LTB
4
inhibitors include, among others, ebselen, Bayer Bay-x-1005, Ciba Geigy compound CGS-25019C, Leo Denmark compound ETH-615, Lilly compound LY-293111, Ono compound ONO-4057, Terumo compound TMK-688, Lilly compounds LY-213024, 264086 and 292728, ONO compound ONO-LB457, Searle compound SC-53228, calcitrol, Lilly compounds LY-210073, LY223982, LY233469, and LY255283, ONO compound ONO-LB-448, Searle compounds SC-41930, SC-50605 and SC-51146, and SK&F compound SKF-104493. Preferably, the LTB
4
inhibitors are selected from ebselen, Bayer Bay-x-1005, Ciba Geigy compound CGS-25019C, Leo Denmark compound ETH-615, Lilly compound LY-293111, Ono compound ONO-4057, and Terumo compound TMK-688.
Suitable 5-LO inhibitors include, among others, masoprocol, tenidap, zileuton, pranlukast, tepoxalin, rilopirox, flezelastine hydrochloride, enazadrem phosphate, and bunaprolast.
The present invention preferably includes compounds which selectively inhibit cyclooxygenase-2 over cyclooxygenase-l. Preferably, the compounds have a cyclooxygenase-2 IC
50
of less than about 0.2 &mgr;m, and also have a selectivity ratio of cyclooxygenase-2 inhibition over cyclooxygenase-l inhibition of at least 50, and more preferably of at least 100. Even more preferably, the compounds have a cyclooxygenase-1 IC
50
of greater than about 1 &mgr;M, and more preferably of greater than 10 &mgr;M. Such preferred selectivity may indicate an ability to reduce the incidence of common NSAID-induced side effects.
A preferred class of compounds consists of those compounds of Formula I wherein A is selected from phenyl, naphthyl, 5-membered heteroaryl and 6-membered heteroaryl, wherein A is optionally substituted with one or more radicals selected from lower alkyl, halo, lower alkoxy, lower alkylthio, cyano, lower haloalkyl, amino, lower alkylamino, lower dialkylamino, lower haloalkoxy, lower hydroxyalkyl, lower alkoxyalkyl, hydroxyl and mercapto; wherein each
Li James J
Norton Monica B
Reitz David B
Barts Samuel
G.D. Searle & Co.
McDonnell & Boehnen Hulbert & Berghoff
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