Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
1999-07-16
2001-03-06
Killos, Paul J. (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S645000, C564S265000, C564S300000
Reexamination Certificate
active
06197826
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to novel &agr;-(2-hydroxyphenyl) 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) typically prevent the production of prostaglandins by inhibiting enzymes in the human arachidonic acid/prostaglandin pathway, including the enzyme cycloxygenase (COX). The enzyme COX is 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 &agr;-(2-hydroxyphenyl) 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 alkyl, alkenyl, alkoxy, acylamino, amino, substituted amino, aryl, cycloalkyl, halogen, nitro and —C═N(O)—R
5
, wherein R
5
is alkyl, substituted alkyl or cycloalkyl;
R
2
is selected from the group consisting of hydrogen, alkyl, alkenyl, alkoxy, acylamino, amino, substituted amino, aryl, cycloalkyl, halogen and nitro; or R
1
and R
2
can be joined together to form an alkylenedioxy group;
R
3
is selected from the group consisting of hydrogen, alkyl and aryl; and
R
4
is selected from the group consisting of alkyl, substituted alkyl and cycloalkyl; and pharmaceutically acceptable salts thereof.
Preferably, R
1
is selected from the group consisting of alkoxy, alkyl, halogen, nitro and —CH═N(O)—R
5
, wherein R
5
is alkyl, substituted alkyl or cycloalkyl. More preferably, R
1
is alkyl. Examples of preferred R
1
groups include, but are not limited to, tert-butyl, bromo, fluoro, chloro, methyl, methoxy, nitro and [(tert-butyl)oxidoimino]methyl. A particularly preferred R
1
group is tert-butyl.
R
2
is preferably selected from the group consisting of alkoxy, alkyl and halogen. More preferably, R
2
is alkyl. Examples of preferred R
2
groups include, but are not limited to, hydrogen, tert-butyl, bromo, chloro, methoxy and methyl. A particularly preferred R
2
group is tert-butyl.
When R
1
and R
2
are attached to adjacent carbon atoms, R
1
and R
2
are also preferably joined together to form an alkylenedioxy group having 1 to about 6 carbon atoms, more preferably 1 or 2 carbon atoms. Particularly preferred alkylenedioxy groups include methylenedioxy and ethylenedioxy.
R
3
is preferably 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 having 3 to about 8 carbon atoms and cycloalkyl having 3 to about 8 carbon atoms. 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 n-propyl, isopropyl, n-butyl, tert-butyl and cyclohexyl.
R
5
is preferably selected from the group consisting of alkyl having 3 to about 8 carbon atoms and cycloalkyl having 3 to about 8 carbon atoms. More preferably, R
5
is alkyl having 3 to 6 carbon atoms or cycloalkyl having 5 to 6 carbon atoms. Particularly preferred R
5
groups include n-propyl, isopropyl, n-butyl, tert-butyl and cyclohexyl.
In a preferred embodiment, this invention is directed to a compound of formula II:
wherein
R
6
is selected from the group consisting of alkyl and cycloalkyl;
R
7
is selected from the group consisting of alkyl and cycloalkyl; and
R
8
is selected from the group consisting of alkyl, substituted alkyl and cycloalkyl; and pharmaceutically acceptable salts thereof.
Preferably, R
6
and R
7
are the same or different and each is independently selected from an alkyl group having from 1 to about 6 carbon atoms. More preferably, R
6
and R
7
are independently selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. Still more preferably, R
6
and R
7
are both tert-butyl.
R
8
is preferably selected from the group consisting of alkyl having 3 to about 8 carbon atoms and cycloalkyl having 3 to about 8 carbon atoms. More preferably, R
8
is alkyl having 3 to 6 carbon atoms or cycloalkyl having 5 to 6 carbon atoms. Particularly preferred R
8
groups include n-propyl, isopropyl, n-butyl, tert-butyl and cyclohexyl.
Particularly preferred &agr;-(2-hydroxyphenyl) nitrone compounds include those having the formula shown in Table I.
TABLE I
No.
R
a
R
b
R
c
R
d
R
e
1
—H
—H
—Cl
—H
—C(CH
3
)
3
2
—C(CH
3
)
3
—H
—C(CH
3
)
3
—H
—C(CH
3
)
3
3
—Br
—H
—Br
—H
—C(CH
3
)
3
4
—F
—H
—H
—H
—C(CH
3
)
3
5
—CH═N(O)—C(CH
3
)
3
—H
—CH
3
—H
—C(CH
3
)
3
6
—CH
3
—H
—H
—H
—C(CH
3
)
3
7
—CH═N(O)—C(CH
3
)
3
—H
—Cl
—H
—C(CH
3
)
3
8
—H
—H
—OCH
3
—H
—C(CH
3
)
3
9
—H
—H
—NO
2
—H
—C(CH
3
)
3
10
—OCH
2
CH
3
—H
—H
—H
—C(CH
3
)
3
11
—H
—OCH
3
—H
—H
—C(CH
3
)
3
12
—H
—N(CH
2
CH
3
)
2
—H
—H
—C(CH
3
)
3
13
—Cl
—H
—Cl
—H
—C(CH
3
)
3
14
—H
—H
—Br
—H
—C(CH
3
)
3
15
—H
—OCH
3
—H
—OCH
3
—C(CH
3
)
3
16
—H
—H
—OCF
3
—H
—C(CH
3
)
3
17
—I
—H
—I
—H
—C(CH
3
)
3
18
—H
—OCH
3
—H
—H
—C(CH
3
)
3
Accordingly, in another of its composition aspects, this invention is directed to each of the individual compounds:
&agr;-(5-chloro-2-hydroxyphenyl)-N-tert-butylnitrone
&agr;-(3,5-di-tert-butyl-2-hydroxyphenyl)-N-tert-butylnitrone
&agr;-(3,5-dibromo-2-hydroxyphenyl)-N-tert-butylnitrone
&agr;-(3-fluoro-2-hydroxyphenyl)-N-tert--butylnitrone
&agr;-{3-[(tert-butyl)oxidoimino]methyl-2-hydroxy-5-methylphenyl)}-N-tert-butylnitrone
&agr;-(2-hydroxy-3-methylphenyl)-N-tert-butylnitrone
&agr;-{3-[(tert-butyl)oxidoimino]methyl-5-chloro-2-hydroxyphenyl)}-N-tert-butylnitrone
&agr;-(2-hydroxy-5-methoxyphenyl)-N-tert-butylnitrone
&agr;-(2-hydroxy-5-nitrophenyl)-N-tert-butylnitrone
&agr;-(3-ethoxy-2-hydroxyphenyl)-N-tert-butylnitrone
&agr;-(2-hydroxy-4-methoxyphenyl)-N-tert-butylnitrone
&agr;-(4-N,N-diethylamino-2-hydroxyphenyl)-N-tert-butylnitrone
&agr;-(3,5-dichloro-2-hydroxyphenyl)-N-tert-butylnitrone
&agr;-(4,6-dimethoxy-2-hydroxyphenyl)
Carney John M.
Waterbury L. David
Wilcox Allan L.
Burns Doane , Swecker, Mathis LLP
Centaur Pharmaceuticals, Inc.
Killos Paul J.
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