Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-05-24
2004-03-30
Rotman, Alan L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S327000, C514S328000, C514S329000, C514S330000, C514S345000, C514S346000, C514S348000, C514S350000, C514S354000, C514S423000, C546S219000, C546S221000, C546S222000, C546S223000, C546S224000, C546S225000, C546S226000, C546S242000, C546S244000, C546S245000, C546S290000, C546S292000, C546S297000, C546S298000, C546S299000, C548S531000, C548S536000, C548S565000
Reexamination Certificate
active
06713492
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a drug comprising a modified N-acyloxylated cycloalkyl compound as an effective ingredient and, more particularly, to a drug comprising an N-acyloxylated cycloalkyl compound which can scavenge in vivo active oxygen or free radicals and is useful as an agent for preventing or curing various diseases induced by in vivo active oxygen or free radicals and as a reagent for non-invasively acquiring biological images by a magnetic resonance method, typified by the ESR (Electron Spin Resonance) method, or for detecting in vivo active oxygen or free radicals in collected organisms.
BACKGROUND ART
Active oxygen is defined as one type of oxygen species with a short life which is very reactive and takes part in various types of in vivo oxidation reactions. The scope of active oxygen varies depending on the definition. In a narrow sense, active oxygen means a hydroxyl radical (.OH), superoxide (O
2
−
), singlet oxygen (
1
O
2
), and hydrogen peroxide (H
2
O
2
). In a broad sense, active oxygen includes a peroxy radical (LOO.) and alkoxy radical (LO.) which are derived from the reaction of the above active species and biological components such as unsaturated fatty acid L, and a hypochlorite ion (ClO
−
) formed from H
2
O
2
and Cl
−
by the reaction with myeloperoxidase and the like.
Radicals are defined as atoms or molecules which possess one or more unpaired electrons. A hydroxyl radical, superoxide, peroxy radical, and alkoxy radical are all radicals. Singlet oxygen and hydrogen peroxide are not radicals, but are formed from a radical reaction or cause other radical reactions.
In recent years, active oxygen and free radicals showing various in vivo bioactivity have attracted attention and have been studied in the field of biology, medicine, and pharmacology. The active oxygen or free radicals are generated in vivo due to ultraviolet rays, radiation, atmospheric pollution, oxygen, metal ions, ischemia-reperfusion, and the like. Active oxygen and free radicals thus generated cause various in vivo reactions such as peroxidization of lipids, denaturation of proteins, and decomposition of nucleic acids. Ischemic diseases, digestive diseases, cancer, cranial nervous diseases accompanied by nerve degeneration, inflammation, cataracts, and drug-induced organopathy are known as diseases accompanied by such phenomena. Noninvasive detection of such active oxygen and free radicals which relate to so many diseases may help in the investigation of the causes of a number of such diseases and provide useful medical information.
The following two methods are known as conventional methods for detecting free radicals. One of these is an indirect method consisting of adding a reagent to a reaction system and detecting the resulting changes in absorbance or emission of light by the reaction system. The other method is an electron spin resonance (ESR) method consisting of directly detecting unpaired electron of free radicals. Since the ESR method can measure both liquid and solid samples and even opaque or non-uniform samples, this method is very advantageous for detecting active oxygen in collected biological samples or in vivo.
The problem in detecting in vivo active oxygen or free radicals is that ESR cannot directly measure active oxygen or free radicals in a living body due to their short life. To solve this problem, a method of indirectly observing in vivo active oxygen or free radicals by administering a reagent to a living body and measuring the chemical changes in the reagent caused by active oxygen or free radicals using ESR has been employed. For this purpose, a spin trapping method has been developed with an objective of measuring active oxygen having unpaired electrons such as hydroxyl radicals. This method makes use of the capability of a trapping agent to rapidly react with free radicals having only a short life and produce a spin adduct which is stable, has a long life, and can be detected by ESR, as shown in the following formula. In a narrow sense, the spin trapping agent has been defined as a compound having a double bond in the scavenging site, such as 5,5-dimethyl-1-pyrroline-1-oxide (DMPO) shown below.
Specifically, measurement of short-life active oxygen becomes possible by adding a compound which can rapidly react with radicals and produces a spin adduct sufficiently stable for measuring ESR to the measuring system as a spin trapping agent, and measuring the stable spin adduct.
Therefore, the requirements to be satisfied by the compound used as a spin trapping agent include: (1) capability of rapidly reacting with active oxygen and free radicals, (2) being converted into sufficiently stable radicals, (3) being chemically stable when handled, and (4) being free from toxicity.
An attempt to directly detect or image in vivo active oxygen or free radicals by using the above spin trapping agent has been undertaken. However, large volume biological samples cannot be measured using conventional ESR devices which utilize microwaves of an X-band (about 9.5 GHz) due to high dielectric loss in water.
In recent years, ESR-CT utilizing low-frequency microwaves (300-2000 MHz) has been developed, making it possible to directly detect or image free radicals in a sample containing a large amount of water, particularly, free radicals in a living body.
The principle of a nuclear magnetic resonance (NMR) method was discovered in 1945. In 1973, Lauterbur first applied the NMR method to magnetic resonance imaging (MRI) which is an imaging device used in medicine. Since then, the NMR method has progressed remarkably and becomes one of the most universal diagnostic methods at present.
MRI first appeared as a diagnostic method using no contrast media. At present, contrast media are used to increase the detectability of a lesion site which is difficult to shade. Therefore, contrast media exhibiting superior detectability are demanded.
In recent years, the utility of nitroxide compounds as contrast media for MRI or ESR and the antioxidation effect thereof has attracted attention. For example, paramagnetic inorganic compounds such as gadolinium are administered as contrast media to contrast the lesion site in the MRI diagnosis used in medicine. However, because of toxicity of such inorganic compounds, nitroxide compounds have been considered as MRI contrast media which can be used instead of gadolinium. As ESR imaging has been developed and the utility thereof has attracted attention, the utility value of nitroxide compounds as imaging agents has increased. The possibility of utilization of nitroxide compounds as an active oxygen scavenging agent has also been suggested (see J. Biol. Chem. 263: 17921; 1998).
If information about active oxygen or free radicals in biological tissue can be acquired as biological images by the noninvasive magnetic resonance measuring method, this information can be used for studying pathology in which active oxygen and free radicals take part, such as ischemic diseases, digestive diseases, cancer, cranial nervous diseases accompanied by nerve degeneration, inflammation, cataracts, and drug-induced organopathy (hereinafter referred to “diseases related to active oxygen and the like”) and diagnosing these diseases.
In this situation, a report has been published describing the characteristics of some type of hydroxylamine derivative which can easily react with free radicals and active oxygen by oxidative stimulation (active oxygen, etc.) and be converted into a nitroxide compound having ESR signals (Biochem Biophys Res Commun 230, 54-57, 1997). The compound is not a spin trapping agent in the stringent sense because this is not a generally defined nitron or nitroso compound. However, inasmuch as the capability of scavenging spins as shown by the following formula, the compound has the same function as the spin trapping agent in a narrow sense.
In the above formula, A′ represents an alkylene group which may be substituted.
Although it has been known that super oxide in solutions or cells can be detected by measu
Aoyama Masaaki
Itoh Osamu
Obara Heitaro
Yokoyama Hidekatsu
Covington Raymond
Daiichi Radioisotope Laboratories, Ltd.
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
Rotman Alan L.
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