Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-12-27
2001-05-29
Kight, John (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S245000, C546S184000
Reexamination Certificate
active
06239145
ABSTRACT:
This is a 373 of PCT/JP98/02868 filed Jun. 26, 1998.
1. Technical Field
The present invention relates to novel nitroxyl compounds and drugs or reagents containing the same. More particularly, the present invention relates to novel nitroxyl compounds which are hydrolyzed in vivo, drugs usable in treating ischemic diseases, digestive diseases, cancer, cranial nervous diseases accompanied by nerve degeneration, inflammation, cataracts, or drug-induced organopathy caused by active oxygen or free radicals present in tissues, and reagents usable in diagnosing diseases relating to active oxygen or free radicals such as tumors and ischemic diseases by acquiring information about active oxygen or free radicals in the brain, heart, or other tissues as magnetic information.
2. 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.
A hydroxyl radical, superoxide, peroxy radical, and alkoxy radical are all radicals. Radicals are defined as atoms or molecules which possess at least one unpaired electron. 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 biological activities have attracted attention and have been studied in the field of biology, medicine, and pharmacology. Active oxygen and free radicals are formed in vivo due to ultraviolet rays, radiation, atmospheric pollution, oxygen, metal ions, ischemia-reperfusion, and the like.
Active oxygen and free radicals thus formed cause various in vivo reactions, for example, hyperoxidization 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 in vivo free radicals which relate to so many diseases may help investigate the causes of a number of such diseases and provide useful medical information.
The following two methods have been known as a conventional method for detecting free radicals. One of them is an indirect method which comprises putting a reagent into a reaction system and detecting the resulting changes in absorbance or emission of light of the reaction system. Another method is an electron spin resonance (ESR) method which comprises directly detecting unpaired electrons of free radicals. The ESR method can measure both liquid samples and solid samples. Because even opaque or non-uniform samples can be measured by the ESR method, this method is very advantageous for detecting active oxygen in collected biological samples or in vivo.
However, a large amount biological samples could not be measured by conventional ESR devices utilizing microwaves of an X-band (about 9.5 GHz), which causes a great dielectric loss in water. In recent years, an ESR device utilizing low-frequency microwaves (300-2000 MHz) has been developed. This development enables the in vivo measurement of samples containing a large amount of water, in particular, free radicals in living body.
The principle of the biometry ESR method using nitroxyl compounds as a probe is as follows. Stable radicals administered in vivo are reduced by reaction with active oxygen or free radicals and lose paramagnetism. These signal changes are measured and analyzed to image active oxygen and in vivo free radicals non-invasively. Therefore, diagnostic reagents containing stable radical compounds as ESR contrast media are indispensable for performing the ESR method.
The principle of a nuclear magnetic resonance (NMR) method was discovered in 1945. Lauterbur first applied the NMR method to an imaging device for medicine (magnetic resonance imaging; MRI) in 1973. Since then, this diagnostic method has progressed remarkably and become one of the most universal diagnostic methods.
MRI first appeared as a diagnostic method using no contrast media. In order to increase detectability of a lesion site which is difficult to shade, utility of the contrast media has been recognized and contrast media are now generally used. Accompanied by this, contrast media exhibiting superior detectability have been demanded.
There are many nerve cells in the brain. Changes in electromotive force accompanied by activity of the nerve cells are widely used as an electronencephalogram (EEG; brain waves) Electric current, which flows in the nerves, caused by such an electromotive force forms magnetic fields in the circumference thereof. A record of the magnetic fields thus formed is referred to as a magnetoencephalogram (MEG). The strength and direction of the magnetic fields are determined depending on the position, strength, and direction of the electric current. Therefore, measurement of the brain magnetic fields is essentially equivalent to the measurement of electroencephalography. Electric conductivity of the living body is not constant and greatly varies depending on the tissue, bone, and the like. Moreover, only information of the electrical potential strength is obtained from the electronencephalogram. Because of this, it is difficult to precisely presume the active site.
A magnetoencephalogram measures changes of the magnetic fields caused by the magnetism of a living body. Because transmittance of the magnetic fields in the tissue is constant and almost equal to that in air, magnetic fields are not distorted, whereby the active site can be presumed precisely. However, the ratio of the magnetic field from the brain to geomagnetism is 1:100,000,000. Therefore, a magnetism sensor with high sensitivity is required and measurement is difficult. About 20 years ago, a fluxmeter using a superconducting quantum interference device (SQUID) was developed and enabled stable recording of the magnetism of a living body such as the brain for the first time. At present, medical instruments capable of non-invasively imaging the active site of the brain nerve cells from the outside have been developed.
This diagnostic method is used for discovering the focus of ictus epilepticus and has become an examination method useful for determining application of surgical treatment of epilepsy. This method is expected to be applied to the examination of initial symptoms of Alzheimer's disease in the future. However, since magnetic fields from the brain are extremely weak as described above, contrast media for magnetoencephalograms which compensate for the weak magnetic fields have been demanded.
If information about active oxygen and free radicals in tissue can be acquired as biological images by the non-invasive magnetic resonance measuring method, such information is useful 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 as “active oxygen related diseases”) and diagnosing these diseases and symptoms.
In recent years, utility of nitroxyl compounds as contrast media for MRI and ESR and the antioxidation effect thereof have attracted attention. For example, paramagnetic inorganic compounds such as gadolinium are administered as contrast media in the MRI diagnosis in medicine in order to make a contrast for the lesion site.
Igarashi Takashi
Naruse Masaichi
Oi Tetsuo
Sano Hiroaki
Utsumi Hideo
Daiitchi Radioisotope Laboratories, Ltd.
Kight John
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
Robinson Binta
LandOfFree
Nitroxyl compounds and drugs and reagents containing the... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Nitroxyl compounds and drugs and reagents containing the..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Nitroxyl compounds and drugs and reagents containing the... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2490056