Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-12-17
2002-04-23
Owens, Amelia (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S231500, C514S254100
Reexamination Certificate
active
06376540
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to novel furan nitrone compounds and their use as free radical trapping agents and therapeutic agents. More particularly, this invention concerns furan nitrone compounds and their use as analytical reagents for detecting free radicals and as therapeutics for treating various medical dysfunctions and diseases.
2. State of the Art
Nitrones, such as &agr;-phenyl-N-ter-butylnitrone (PBN) and 5,5-dimethyl-1-pyrroline-N-oxide (DMPO), are known to be useful as analytical reagents for detecting free radicals. Such compounds function as “spin traps” by reacting with unstable free radicals to form relatively stable free radical spin adducts which are observable by electron spin resonance (ESR) spectroscopy. Thus, spin trapping allows previously unobservable free radicals to be identified and studied using ESR and related techniques.
The use of nitrones as spin traps for studying unstable free radicals has been applied to biological systems. In this regard, PBN, DMPO and related compounds have been used to identify superoxide (O
2
−
.) and hydroxyl radicals (HO.) in biological systems. Additionally, such nitrones have been used to study lipid peroxidation and other free radical-induced biological processes.
More recently, nitrone compounds, such as PBN and derivatives thereof, have been reported as therapeutics for the treatment of a wide variety of disease conditions arising from or characterized by free radical-induced oxidative damage. Such disease conditions include, for example, disorders of the central nervous system (CNS) and the peripheral nervous system, such as stroke, Parkinsonism, traumatic nerve damage and the like, and disorders of the peripheral organs, such as atherosclerosis, cardiac infarction, ulcerative colitis and the like. Nitrones have also been reported to treat certain inflammatory conditions, such as arthritis.
Although various nitrone compounds have been previously reported to be useful as analytical reagents or therapeutic agents, a need exists for novel nitrone spin traps having improved effectiveness ip these applications. For example, when using nitrones as therapeutic agents for treating acute conditions, such as stroke, cardiac infarction or the like, it is particularly desirable to be able to administer the nitrone spin trap at high doses, especially to the localized area immediately surrounding the acute incident, to minimize the amount of free radical-induced oxidative damage that occurs. Thus, nitrone compounds used to treat acute conditions should be non-toxic or have very low toxicity.
Additionally, when studying free radicals in biological systems or when treating various disease conditions caused by free radicals, it is important that the nitrone spin trap have sufficient solubility at the biological site where the free radicals are generated so that the radicals are trapped by the nitrone before they are quenched or cause oxidative damage by their surroundings. Thus, it would be particularly desirable to be able to readily optimize the solubility of nitrone compounds for a particular biological environment ranging in nature, for example, from aqueous to lipophilic.
Accordingly, a need exists for new classes of effective nitrone spin traps having improved properties such as low toxicity and increased solubility in a wide range of biological systems.
SUMMARY OF THE INVENTION
This invention provides novel furan nitrone compounds which are effective free radical spin traps and, accordingly, are useful as analytical reagents for detecting free radicals. Additionally, the furan nitrones of this invention have been found to be useful as therapeutics for treating various medical dysfunctions and diseases. In this regard, the furan nitrone compounds have surprisingly low toxicity even at relatively high dosage levels. Structurally, the furan nitrones of this invention are particularly useful as analytical reagents and/or therapeutics since one or more sulfur-derived functional groups are attached to the furan ring thereby allowing the lipophilicity of the compounds to be readily varied. This permits the compounds to be used in a wide variety of biological environments and/or optimized for a particular analytical or therapeutic use.
Accordingly, in one of its composition aspects, this invention is directed to compounds of formula I:
wherein
each R
1
is independently selected from the group consisting of hydrogen, alky, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkoxy, alkcycloalkyl, cycloalkyl, cycloalkenyl and halo;
R
2
is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cycloalkenyl;
R
3
is selected from the group consisting of alky, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cycloalkenyl;
each X is independently selected from the group consisting of —SO
3
Y, —S(O)R
4
, —SO
2
R
5
and —SO
2
NR
6
R
7
;
wherein Y is hydrogen or a pharmaceutically acceptable cation;
R
4
is selected from the group consisting of alky, substituted alky, alkenyl, alkynyl, alkyl, aryl, alkcycloalkyl, cycloalkyl and cycloalkenyl;
R
5
is selected from the group consisting of alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cycloalkenyl;
R
6
and R
7
are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cycloalkenyl; or R
6
and R
7
together with the nitrogen atom to which they are attached can form a heterocyclic ring containing from 2 to 8 carbon atoms and optionally from 1 to 3 additional heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur;
m is an integer from 1 to 3; and n is an integer from 0 to 2, provided that m+n=3; or pharmaceutically acceptable salts thereof.
Preferably, in the compounds of formula I above, R
1
is selected from the group consisting of hydrogen and alkyl. More preferably, R
1
is hydrogen.
R
2
is preferably selected from the group consisting of hydrogen, alkyl and aryl. More preferably, R
2
is hydrogen or alkyl. Still more preferably, R
2
is hydrogen.
Preferably, R
3
is selected from the group consisting of alkyl, alkaryl, aryl and cycloalkyl. More preferably, R
3
is alkyl or cycloalkyl. Still more preferably, R
3
is cycloalkyl. Especially preferred R
3
groups are cyclohexyl and isopropyl.
R
4
is preferably selected from the group consisting of alkyl, alkaryl, aryl and cycloalkyl. More preferably, R
4
is alky, aryl or cycloalkyl. Still more preferably, R
4
is alkyl.
Preferably, R
5
is selected from the group consisting of alkyl, alkaryl, aryl and cycloalkyl. More preferably, R
5
is alkyl, aryl or cycloalkyl. Still more preferably, R
5
is alkyl.
X is preferably —SO
3
Y, —SO
2
R
5
or —SO
2
NR
6
R
7
, wherein R
5
is alkyl, cycloalkyl or aryl and R
6
and R
7
are independently selected from the group consisting of hydrogen, alkyl and cycloalkyl. Alternatively, R
6
and R
7
are preferably joined together with the nitrogen atom to which they are attached to form a heterocyclic ring having 4 to 6 carbon atoms. More preferably, when X is —SO
2
NR
5
R
6
, R
5
is hydrogen and R
6
is selected from the group consisting of hydrogen, alkyl and cycloalkyl.
Preferably, m in formula I above is 1 or 2. More preferably, m is 1.
In another of its composition aspects, this invention is directed to a compound of formula II:
wherein R
2
, R
3
, X and m are as defined above, including the above defined preferred embodiments; or pharmaceutically acceptable its thereof.
In still another of its composition aspects, this invention is directed to a compound of formula III:
wherein
R
8
is selected from the group consisting of alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cycloalkenyl; and
Y selected from the group consisting of hydrogen and a pharmaceutically acceptable cation.
Preferably, in formula III above, R
8
is
Kelleher Judith A.
Maples Kirk R.
Waterbury Lowell David
Wilcox Allan L.
Xu Hong
Burns Doane , Swecker, Mathis LLP
Centaur Pharmaceuticals, Inc.
Owens Amelia
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