Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – N-c doai
Reexamination Certificate
2002-07-15
2004-05-04
Rotman, Alan L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
N-c doai
C514S440000, C514S278000, C514S415000, C514S603000, C560S022000, C560S023000, C560S136000, C564S266000, C564S265000
Reexamination Certificate
active
06730700
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to novel 3,4,5-trisubstituted aryl nitrone compounds and their use as therapeutic agents for the treatment of inflammation-related conditions in mammals, such as arthritis, and as analytical reagents for detecting free radicals.
2. State of the Art
Arthritis and related inflammatory disease conditions occur in more than 100 different forms, including rheumatoid arthritis (RA), osteoarthritis (OA), ankylosing spondylitis and systemic lupus erythematosus (SLE). Most forms of arthritis are characterized by some type of chronic inflammation. For example, RA typically involves chronic inflammation of the lining of the joints and/or the internal organs. Such chronic inflammation generally causes pain and swelling in the joints of those afflicted and may result in damage to cartilage, bone, tendons, ligaments and the like, ultimately leading to deformity and disability.
Prostaglandins have long been known to be involved in the inflammation process. Accordingly, a number of inhibitors of prostaglandin synthesis have been developed for the treatment of arthritis and related inflammatory disease conditions. Such non-steroidal antiinflammatory drugs (NSAIDS), such as aspirin, ibuprofen, naproxen and indomethacin, typically prevent the production of prostaglandins by inhibiting enzymes in the arachidonic acid/prostaglandin pathway, including the enzyme cycloxygenase (COX). The enzyme COX catalyzes the conversion of arachidonic acid to prostaglandin H2, the first step in the biosynthesis of prostaglandins such as prostacyclin and thromboxanes. The enzyme COX is now known to exist in two forms. COX-1 is a constitutive form of the enzyme found in most tissues and organs. Among other properties, COX-1 produces relatively small amounts of prostoglandins necessary for maintaining the integrity of the gastrointestinal tract. COX-2, on the other hand, is an inducible form of the enzyme associated with the increased production of prostoglandins during inflammatory conditions. Since many NSAIDS inhibit both forms of COX, they interfere with prostaglandin-regulated processes not associated with the inflammation process. As a result, many NSAIDS cause severe side effects, such as stomach ulcers and renal damage, which limit their effectiveness as therapeutics.
Accordingly, a need exists for novel classes of therapeutic compounds which effectively treat arthritis and other inflammation-related conditions without producing undesired side effects.
SUMMARY OF THE INVENTION
This invention provides novel 3,4,5-trisubstituted aryl nitrone compounds which are useful as therapeutics for reducing inflammation in mammals. In particular, the compounds of this invention are useful for treating arthritis and other inflammation-related conditions.
Accordingly, in one of its composition aspects, this invention is directed to compounds of formula I:
wherein
R
1
is selected from the group consisting of:
each R
2
is independently selected from a group of the formula:
R
3
is selected from the group consisting of hydrogen, alkyl, cycloalkyl and aryl;
R
4
is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl and substituted cycloalkenyl;
R
5
is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl and substituted cycloalkenyl;
R
6
and R
7
are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl and substituted cycloalkenyl; or R
6
and R
7
can be joined to form an alkylene or substituted alkylene group having from 2 to 10 carbon atoms;
R
8
is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl and substituted cycloalkenyl;
R
9
is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl and substituted cycloalkenyl; or R
8
and R
9
can be joined to form an alkylene or substituted alkylene group having from 2 to 10 carbon atoms;
R
10
is selected from the group consisting of hydrogen, lower alkyl and lower cycloalkyl; or R
1
and R
10
can be joined to form an alkylene, substituted alkylene, —C(O)— —S(O)— or —S(O)
2
— group;
R
11
and R
12
are independently selected from the group consisting of lower alkyl and lower cycloalkyl; or R
11
and R
12
can be joined to form an alkylene group having from 2 to 10 carbon atoms;
X is oxygen, sulfur, —S(O)— or —S(O)
2
—; and
W is oxygen or sulfur; and pharmaceutically-acceptable salts thereof.
Preferably, R
3
is hydrogen or lower alkyl. More preferably, R
3
is hydrogen or alkyl having 1 to 4 carbon atoms, more preferably 1 or 2 carbon atoms. Still more preferably, R
3
is hydrogen.
R
4
is preferably selected from the group consisting of alkyl, substituted alkyl and cycloalkyl. More preferably, R
4
is alkyl having 3 to 6 carbon atoms or cycloalkyl having 5 to 6 carbon atoms. Particularly preferred R
4
groups include methyl, n-propyl, isopropyl, 1-hydroxy-2-methylprop-2-yl, n-butyl, tert-butyl, 3-thiomethylpropyl, 3-(thiomethoxy)but-1-yl, cyclohexyl, 4-trifluoromethybenzyl and 3,4,5-trimethoxybenzyl.
R
5
is preferably selected from the group consisting of alkyl and cycloalkyl. More preferably, R
5
is lower alkyl. Particularly preferred R
5
groups include methyl, ethyl, n-propyl, isopropyl and n-butyl.
R
6
is preferably selected from the group consisting of alkyl and alkoxycarbonylalkyl (i.e., ROC(O)-alkyl-, where R is alkyl or cycloalkyl). Particularly preferred R
6
groups include ethyl, n-propyl, isopropyl, n-butyl, ethoxycarbonylmethyl and 2-(ethoxycarbonyl)ethyl. R
7
is preferably hydrogen.
Preferably, R
8
is alkyl or alkoxyalkyl (i.e., RO-alkyl-, where R is alkyl). Particularly preferred R
8
groups include methyl and methoxyethyl. R
9
is preferably hydrogen. Preferably, X is oxygen.
Preferably, R
10
, R
11
and R
12
are independently lower alkyl. More preferably, R
10
, R
11
and R
12
are methyl.
W is preferably oxygen.
In a preferred embodiment, this invention is directed to a compound of formula II.
wherein
R
13
is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl and substituted cycloalkyl;
R
14
is selected from the group consisting of alkyl, substituted akyl, cycloalkyl and substituted cycloalkyl; and pharmaceutically-acceptable salts thereof.
Preferably, R
13
is lower alkyl.
R
14
is preferably selected from the group consisting of alkyl, substituted alkyl and cycloalkyl. More preferably, R
14
is alkyl having 3 to 6 carbon atoms or cycloalkyl having 5 to 6 carbon atoms. Particularly preferred R
14
groups include methyl, n-propyl, isopropyl, 1-hydroxy-2-methylprop-2-yl, n-butyl, tert-butyl, 3-thiomethylpropyl, 3-(thiomethoxy)but-1-yl, cyclohexyl, 4-trifluoromethybenzyl and 3,4,5-trimethoxybenzyl.
In another preferred embodiment, this invention is directed to a compound of formula III:
wherein
R
15
and R
16
are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl; or R
15
and R
16
can be joined to form an alkylene or substituted alkylene group having from 2 to 10 carbon atoms;
R
17
is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl and substituted cycloalkyl; and pharmaceutically-acceptable salts thereof.
R
15
is preferably selected from the group consisting of alkyl and alkoxycarbonylalkyl (i.e., ROC(O)-alkyl-, where R is alkyl or cycloalkyl). Particularly preferred R
15
groups include ethyl, n-propyl, isopropyl, n-butyl, ethoxycarbonymethyl and 2-(ethoxycarbonyl)ethyl. R
16
is preferably hydrogen.
R
17
is preferabl
Carney John M.
Danielzadeh Albert
Mavandadi Farah
Waterbury L. David
Wilcox Allan L.
Renovis, Inc.
Reyes Hector M
Rotman Alan L.
LandOfFree
3,4,5,-trisubstituted aryl nitrone compounds and... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with 3,4,5,-trisubstituted aryl nitrone compounds and..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and 3,4,5,-trisubstituted aryl nitrone compounds and... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3260736