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WO1997024145A1 - Medicaments d'aide au diagnostic - Google Patents

Medicaments d'aide au diagnostic Download PDF

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Publication number
WO1997024145A1
WO1997024145A1 PCT/JP1996/003828 JP9603828W WO9724145A1 WO 1997024145 A1 WO1997024145 A1 WO 1997024145A1 JP 9603828 W JP9603828 W JP 9603828W WO 9724145 A1 WO9724145 A1 WO 9724145A1
Authority
WO
WIPO (PCT)
Prior art keywords
active oxygen
esr
carbon atoms
alkyl group
free radicals
Prior art date
Application number
PCT/JP1996/003828
Other languages
English (en)
Japanese (ja)
Inventor
Hideo Utsumi
Hiroaki Sano
Original Assignee
Daiichi Radioisotope Laboratories, Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Daiichi Radioisotope Laboratories, Ltd. filed Critical Daiichi Radioisotope Laboratories, Ltd.
Priority to AU12086/97A priority Critical patent/AU1208697A/en
Publication of WO1997024145A1 publication Critical patent/WO1997024145A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/20—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations containing free radicals, e.g. trityl radical for overhauser
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/46—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with hetero atoms directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/04—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members

Definitions

  • the present invention relates to a drug for detecting active oxygen and free radicals present in a living tissue, and more specifically, by obtaining information on active oxygen and free radicals in the brain, heart or other tissues as magnetic information.
  • the present invention relates to an agent for diagnosing a disease associated with active oxygen or free radicals, such as a tumor or an ischemic disease, and a method for detecting the disease using the same. Background technology
  • Reactive oxygen can be defined as oxygen species that are short-lived but highly reactive and participate in various in vivo oxidation reactions. The range varies depending on the definition, but in a narrow sense, the hydroxyl radical ( ⁇ ⁇ ⁇ ), superoxide ( ⁇ 2 —), singlet oxygen ('0 2 ), hydrogen peroxide (H in refers broad meaning to 2 O, pel O alkoxy radicals derived from the reaction between the active species and the biological component (such as unsaturated fatty acids L) (LOO ') and alkoxy radicals.
  • Active oxygen and radicals are generally unstable, and their lifetimes are Benzyl radical 1 0 5 to 1 0 4 seconds, simple Mechiruraji local atmospheric gas phase, such as human mud nitroxyl radical is 1 0 2 to 1 0 2 sec.
  • Reactive oxygen and free radicals in the living body generated by these factors cause various in vivo reactions such as peroxidation of lunar substances, denaturation of proteins, and decomposition of nucleic acids.
  • Known diseases associated with such phenomena include cerebral ischemia, heart disease, gastrointestinal diseases, cancer, aging, and inflammation.
  • active oxygen and free radicals in the living body are related to various diseases, so if they can be detected non-invasively from outside the body, the causes of various diseases can be investigated and useful medical information can be obtained. sell.
  • ESR Electron spin resonance 1 ectoron Spin Resonance
  • ESR devices that have been generally used so far use X-band (approximately 9.5 GHz) microwaves. Was impossible.
  • an ESR device using a low-frequency microwave called an L-band (390 to 155 ⁇ ⁇ ⁇ ⁇ Z ) (hereinafter referred to as “Shi-band £ 313 ⁇ 4 device”) has been developed. It is becoming possible to measure free radicals in large volume samples, especially biological samples, in vivo.
  • the principle of the ESR method is that a stable radical administered to a living body is usually acted on by an oxidoreductase in the living body or reacts with a reducing agent such as active radical oxygen ascorbic acid such as various radicals. Because of the loss of magnetism, this signal change is measured and analyzed to non-invasively image in vivo reactive oxygen and free radical reactions.
  • an ESR contrast agent a diagnostic agent containing a stable radical compound, which can be called an ESR contrast agent.
  • MRI was first introduced as a diagnostic method that does not require a contrast agent.However, to enhance the ability to detect lesions that are difficult to shade, the usefulness of the use of contrast agents is now recognized and generalized. ing. Accordingly, the emergence of a contrast agent with higher detectability has been desired.
  • contrast agents for MRI there are several types of contrast agents for MRI, including the nitroxide radical.
  • PCA 2,2,5,5-tetramethylpyrrolidine-11-oxy-13-carboxylic acid; 3-carboxyproxil
  • PCA 2,2,5,5-tetramethylpyrrolidine-11-oxy-13-carboxylic acid
  • 3-carboxyproxil 3-carboxyproxil
  • EEG electroencephalogram
  • MEG magnetoencephalogram
  • magnetoencephalography which measures changes in the magnetic field caused by biomagnetism, can accurately estimate the active site because the permeability of the magnetic field in living tissue is almost the same as in air and the magnetic field is not distorted. It is.
  • the magnetic field from the brain was extremely weak, one hundred millionth of the earth's magnetism, and its measurement required a highly sensitive magnetic sensor, which was difficult.
  • a magnetic fluxmeter using a superconducting quantum interference device (SQUID) was developed, and for the first time stable biomagnetic recording of the brain and other parts became possible.
  • SQUID superconducting quantum interference device
  • This diagnostic method is used to find the focus of epileptic seizures, and is becoming a useful test method for determining the application of surgical treatment for epilepsy. In the future, it is expected to be applied to the diagnosis of early symptoms of Alzheimer's disease.However, as mentioned above, the magnetic field from the brain is extremely weak. ing.
  • active oxygen-free radicals in living tissue can be obtained as a living body image by magnetic resonance, which is a noninvasive measurement method, cerebral ischemia and heart disease Research on conditions that are thought to involve free radicals such as active oxygen and free radicals such as disease, gastrointestinal diseases, cancer, aging, inflammation, and cataracts (hereinafter referred to as “reactive oxygen-related diseases”) Useful for diagnosing symptoms. Therefore, there is a need to provide a diagnostic agent capable of imaging various biological tissues, particularly brain tissues. Disclosure of the invention
  • the present inventors have searched for a stable radial compound that can be used to obtain information on active oxygen and free radicals in a living body as a biological image by magnetic resonance spectroscopy and magnetoencephalography. Ring N-oxyl compounds can easily detect active oxygen and free radicals, and can also image brain tissue that had been difficult to image conventionally.
  • the present inventors have found that the present invention is useful for obtaining a biological image by a magnetic resonance method or a magnetoencephalogram, and completed the present invention.
  • R represents an alkyl group having 1 to 4 carbon atoms
  • R 1 to R 5 each represent a hydrogen atom or an alkyl group having 1 to 4 carbon atoms.
  • FIG. 1 is a drawing showing a mouse brain band 1 ′: SR-CT image by 3-carboxy-proxil.
  • FIG. 2 is a drawing showing an L-band ESR-CT image of mouse brain by 3-carboxy-1-proxyl methyl ester.
  • FIG. 3 is a drawing showing an L-band ESR-CT image of mouse brain by 3-carboxy-proxylethyl ester.
  • FIG. 4 is a drawing showing an L-band ESR-CT image of mouse brain with 2-ethyl-2,5,5-trimethyloxazolidinoxyl.
  • the 5-membered ring N-oxyl compound that can be used in the present invention is a compound represented by the above formula (I) and a compound represented by the above formula (II).
  • the compound (I) is an ester of a pyrrolidineoxyl derivative having a carboxyl group and an alcohol, and is a known compound or a compound which can be easily produced according to a method for producing a known compound.
  • preferred compounds (I) include 3-carboxy-proxyl methyl ester and 3-carboxy proxy / reethyl ester.
  • the compound ( ⁇ ) can be produced, for example, by condensing an amino alcohol and a ketone.
  • Preferred examples of the compound include 2-ethyl-2,5,5-trimethyloxazolidinoxyl and the like. Are mentioned.
  • the compound is prepared by using a suitable pharmaceutically acceptable solvent such as physiological saline and isotonic phosphate. It may be dissolved in a buffer or the like, and if necessary, an optional component such as propylene glycol or benzyl alcohol may be added to form a formulation.
  • a suitable pharmaceutically acceptable solvent such as physiological saline and isotonic phosphate. It may be dissolved in a buffer or the like, and if necessary, an optional component such as propylene glycol or benzyl alcohol may be added to form a formulation.
  • Preferred dosage forms of the diagnostic agent of the present invention include injections, infusions, coatings, eye drops and the like.
  • the diagnostic agent of the present invention obtained as described above can be used as a diagnostic agent for related diseases such as active oxygen which detects the presence of active oxygen / free radicals by intravascular administration. It can be used for MRI imaging of diseases such as the heart, magnetoencephalography or ESR imaging.
  • the agent of the present invention can be administered to a normal experimental animal or a disease model experimental animal to detect and image an active oxygen-free radical generated from a tissue or an organ in a normal or diseased state from the outside. These results can be used as detection reagents for examining which diseases active oxygen and free radicals are involved in, and medically useful information can be obtained.
  • the collected biological sample is homogenized, an appropriate buffer solution and the agent of the present invention are added, and after reacting for an appropriate time, the ESR is measured to determine the amount of active oxygen and free radicals in the biological tissue. It can be used as a detection reagent whose presence or absence and amount can be measured.
  • the amount of the diagnostic agent of the present invention to be used varies depending on the purpose, the target organ, and the disease. In general, it may be administered in an amount of about 0.1 to 50 Omg Zkg.
  • reaction solution was cooled, washed three times with 50 ml of a saturated sodium bicarbonate solution and once with 50 ml of a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was distilled off.
  • mice use 36 mice (dd Y female) as 3 animals per group
  • a test sample was administered into the tail vein of a mouse under anesthesia under 7.5 ⁇ mo] and left for 3, 10 and 30 minutes. Then, blood was quickly removed and the brain was removed. Subsequently, 9 times as much phosphate buffer as the extracted brain and blood was added and homogenized. A portion of this homogenized sample is added, a potassium ferricyanide solution is added thereto to a final concentration of 5 mM, and the test sample, which has been converted to a hydroxylamine form with active oxygen in the living body, is reconverted into a double-mouthed oxide radical.
  • ESR One-electron oxidation
  • a sample for ESR was obtained. The concentration of the test sample after one-electron oxidation was measured by X-band ESR, and it was taken as the concentration in the biological sample.
  • test sample solution was prepared in the same amount as that administered to the mouse, treated under the same conditions as after adding a 9-fold amount of phosphate buffer, and the concentration of the test sample was measured by X-band ESR. The total dose was used.
  • Electron spin resonance device [JES-RE1X (H electron
  • the ratio of brain to blood is 0.157 after 10 minutes for 3-carboxy-proxil, whereas 0.836 to 1.779 for the other test compounds. It showed a high value. This indicates that the other three test compounds can cross the cerebral vascular barrier and migrate into the brain as compared to 3-carboxy-1-proxyl, which means that they can be used as a contrast agent in the brain. Was done.
  • Example 2
  • Example 1 Four kinds of the compounds of Example 1 were administered at 15 ⁇ mo 1 to the tail vein ⁇ ⁇ ⁇ of a mouse anesthetized with Nembutal (75 mg / kg, im), and the L-band ESR-CT image of the head cross section was measured under the following conditions did.
  • Measurement device electron spin resonance device [JES-RE3L (JEOL
  • FIG. 1 shows a mouse brain L-band ESR-CT image of 3-carboxy-proxil which is a comparison.
  • Ethyl 2,5,5 L-band ESR-CT images of each mouse brain of trimethyloxazolidinoxyl are shown in FIGS. 2, 3 and 4.
  • the five-membered ring N-oxyl compound which is an active ingredient of the diagnostic agent of the present invention, has a sufficient half-life and interacts with free radicals in the living body.
  • Reactive oxygen or other related diseases or symptoms that are useful for obtaining images and are thought to involve free radicals such as cerebral ischemia, heart disease, digestive disease, cancer, aging, inflammation, and cataract It can be used as a diagnostic agent.
  • a signal change in the living body of the compound is detected by ESR, NMR or the like, whereby the above-mentioned activity is obtained. Oxygen and related diseases can be detected and diagnosed.
  • 5-membered ring N-oxyl compounds cross the blood-brain barrier and interact with free radicals in the brain, making imaging of brain ischemia and brain tumors difficult with conventional magnetic resonance imaging. Is possible.
  • the diagnostic agent of the present invention can be used for MRI and magnetoencephalography, and can be used to measure extremely large volumes of biological samples such as human head. After the development of the R device, it is expected that non-invasive diagnosis of diseases or symptoms involving active oxygen and free radicals can be obtained by obtaining images of the distribution of free radicals in the brain by the ESR method.
  • the 5-membered N-oxyl compound is administered to normal experimental animals and disease model experimental animals, and can detect and image active oxygen and free radicals generated from tissues and organs under normal or diseased conditions. From these results, it can be used as a reagent for detecting which disease the active oxygen-free radical is involved in, and medically useful information can be obtained.
  • the signal intensity is measured by ESR to determine the activity in the biological tissue.
  • the presence or absence of oxygen and free radicals can be measured.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Radiology & Medical Imaging (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

Cette invention concerne des médicaments d'aide au diagnostic qui contiennent comme ingrédient actif des composés N-oxyle cycliques à 5 éléments représentés par la formule générale (I) ou par la formule générale (II) dans lesquelles R représente un alkyle C1-C4 et R1 et R2 représentent chacun l'hydrogène ou un alkyle C1-C4. En administrant ce type de médicament à un organisme vivant, il est possible de recueillir des informations sur l'oxygène actif ou les radicaux libres présents à l'intérieur des tissus dudit organisme vivant sous la forme d'images biologiques du type image de résonance du spin électrique (ESR), image de résonance magnétique nucléaire (RMN), magnétoencéphalogramme, etc. Ce médicament est donc utile en tant que médicament d'aide au diagnostic de maladies et de symptômes dans lesquels l'oxygène actif et des radicaux libres semblent intervenir, par exemple l'ischémie cérébrale, les maladies cardio-vasculaires, les maladies du système digestif, le cancer, le vieillissement, les inflammations et la cataracte. En administrant ces médicaments à des animaux de laboratoire sains ou malades, il est possible de détecter de manière externe et d'imager l'oxygène actif et les radicaux libres formés dans les tissus ou les organes à l'état normal ou en période de maladie. Sur la base de ces résultats, le médicament se révèle utile en tant que réactif de détection permettant d'étudier dans quelles maladies l'oxygène actif et les radicaux libres interviennent, ce qui fournit des informations médicales utiles. En outre, il est possible de déceler la présence d'oxygène actif ou de radicaux libres dans un tissu vivant et de quantifier cet oxygène actif ou ces radicaux libres en homogénéisant un échantillon prélevé sur un organisme vivant, en ajoutant à cet échantillon un tampon approprié et ledit médicament, en faisant réagir le mélange pendant un laps de temps approprié et en mesurant l'intensité des signaux par résonance du spin électronique. Ainsi, ces médicaments s'avèrent utiles en tant que réactifs, s'agissant de déceler l'oxygène actif dans des échantillons prélevés sur des organismes vivants.
PCT/JP1996/003828 1995-12-28 1996-12-26 Medicaments d'aide au diagnostic WO1997024145A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU12086/97A AU1208697A (en) 1995-12-28 1996-12-26 Diagnostic drugs

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JP7/352303 1995-12-28
JP35230395 1995-12-28

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999000365A1 (fr) * 1997-06-27 1999-01-07 Daiichi Radioisotope Laboratories, Ltd. Nouveaux composes nitroxyle, et medicaments et reactifs contenant ceux-ci en tant que principe actif
WO2003080566A3 (fr) * 2002-03-21 2003-12-11 Isis Innovation Inhibiteurs d'hydroxylase hif
JP2009504265A (ja) * 2005-08-11 2009-02-05 アメリカ合衆国 組織の酸化還元状態を決定するための方法
JP2018523657A (ja) * 2015-08-18 2018-08-23 ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア 画像化のためのニトロキシドを含むアミロイド結合剤およびその治療的使用

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3966409A (en) * 1973-11-30 1976-06-29 Ivan Hrvoic Nuclear magnetometers for earth's field measurements based on dynamic polarization of nuclei and free radical substance for use therein
JPS6094960A (ja) * 1983-08-03 1985-05-28 シエ−リング・アクチエンゲゼルシヤフト 新規ニトロキシル化合物、その製法およびこれを含有するｎｍｒ診断剤
JPH03506028A (ja) * 1988-07-19 1991-12-26 ハフスルンド・ニユコメド・イノベイシヨン・アクチエボラーグ 安定なフリーラジカル含有コントラスト媒体
WO1994002865A1 (fr) * 1992-07-23 1994-02-03 The United States Of America, Represented By The Secretary, Department Of Health And Human Services Detection de l'oxyde nitrique par resonance de spin electronique
US5431901A (en) * 1988-08-03 1995-07-11 Halpern; Howard J. Selective isotopic labeling of spin labels for electron spin resonance spectroscopy
JPH08298997A (ja) * 1995-05-10 1996-11-19 Doujin Kagaku Kenkyusho:Kk 酸化発色分析における還元物質の活性抑制方法
JPH0928396A (ja) * 1995-07-20 1997-02-04 Yamagata Pref Gov Technopolis Zaidan ペルオキシダーゼの測定方法

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3966409A (en) * 1973-11-30 1976-06-29 Ivan Hrvoic Nuclear magnetometers for earth's field measurements based on dynamic polarization of nuclei and free radical substance for use therein
JPS6094960A (ja) * 1983-08-03 1985-05-28 シエ−リング・アクチエンゲゼルシヤフト 新規ニトロキシル化合物、その製法およびこれを含有するｎｍｒ診断剤
JPH03506028A (ja) * 1988-07-19 1991-12-26 ハフスルンド・ニユコメド・イノベイシヨン・アクチエボラーグ 安定なフリーラジカル含有コントラスト媒体
US5431901A (en) * 1988-08-03 1995-07-11 Halpern; Howard J. Selective isotopic labeling of spin labels for electron spin resonance spectroscopy
WO1994002865A1 (fr) * 1992-07-23 1994-02-03 The United States Of America, Represented By The Secretary, Department Of Health And Human Services Detection de l'oxyde nitrique par resonance de spin electronique
JPH08298997A (ja) * 1995-05-10 1996-11-19 Doujin Kagaku Kenkyusho:Kk 酸化発色分析における還元物質の活性抑制方法
JPH0928396A (ja) * 1995-07-20 1997-02-04 Yamagata Pref Gov Technopolis Zaidan ペルオキシダーゼの測定方法

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
ACTA PHYSIOL. SCAND., 146(1), (1992), HARALDSSON G. et al., "ESR-measurement of Production of Oxygen Radicals in Vivo Before and After Renal Ischemia in the Rabbit", pages 99-105. *
ARCH. BIOCHEM. BIOPHYS., 215(2), (1982), ROSEN GERALD M. et al., "A Method for the Detection of Superoxide in Biological Systems", pages 367-78. *
INVEST. RADIOL., 19(6), (1984), GRIFFETH LANDIS K. et al., "Pharmacokinetics of Nitroxide NMR Contrast Agents", pages 553-62. *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999000365A1 (fr) * 1997-06-27 1999-01-07 Daiichi Radioisotope Laboratories, Ltd. Nouveaux composes nitroxyle, et medicaments et reactifs contenant ceux-ci en tant que principe actif
US6239145B1 (en) * 1997-06-27 2001-05-29 Daiitchi Radioisotope Laboratories, Ltd. Nitroxyl compounds and drugs and reagents containing the same as the active ingredient
WO2003080566A3 (fr) * 2002-03-21 2003-12-11 Isis Innovation Inhibiteurs d'hydroxylase hif
US7662854B2 (en) 2002-03-21 2010-02-16 Isis Innovation Limited HIF hydroxylase inhibitors
JP2009504265A (ja) * 2005-08-11 2009-02-05 アメリカ合衆国 組織の酸化還元状態を決定するための方法
EP1912561A4 (fr) * 2005-08-11 2010-12-22 Us Gov Health & Human Serv Procédé pour déterminer l'état redox d'un tissu
AU2006279951B2 (en) * 2005-08-11 2013-02-14 Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services Method for determining redox status of a tissue
JP2018523657A (ja) * 2015-08-18 2018-08-23 ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア 画像化のためのニトロキシドを含むアミロイド結合剤およびその治療的使用

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