WO1996033983A1 - Derives n-oxyde de dibenzoxazepine et medicament les contenant en tant que principe actif - Google Patents

Derives n-oxyde de dibenzoxazepine et medicament les contenant en tant que principe actif Download PDF

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Publication number
WO1996033983A1
WO1996033983A1 PCT/JP1996/001137 JP9601137W WO9633983A1 WO 1996033983 A1 WO1996033983 A1 WO 1996033983A1 JP 9601137 W JP9601137 W JP 9601137W WO 9633983 A1 WO9633983 A1 WO 9633983A1
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WO
WIPO (PCT)
Prior art keywords
group
oxazebin
oxide
compound
dibenzoxazebine
Prior art date
Application number
PCT/JP1996/001137
Other languages
English (en)
Japanese (ja)
Inventor
Heitaro Obara
Takashi Igarashi
Kazuhisa Sakurai
Tetsuo Oi
Original Assignee
Daiichi Radioisotope Laboratories, Ltd.
Yamagata Technopolis Foundation
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., Yamagata Technopolis Foundation filed Critical Daiichi Radioisotope Laboratories, Ltd.
Publication of WO1996033983A1 publication Critical patent/WO1996033983A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D267/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D267/02—Seven-membered rings
    • C07D267/08—Seven-membered rings having the hetero atoms in positions 1 and 4
    • C07D267/12—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D267/16—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with two six-membered rings
    • C07D267/20—[b, f]-condensed

Definitions

  • the present invention relates to a novel oxazebin-1N-oxide derivative, and more particularly, to a method capable of capturing a free radical in a living body.
  • a preventive and therapeutic agent for various diseases caused by zical, or detection for obtaining biological images by magnetic resonance method such as ESR (Electron Spin Resonance) The present invention relates to an oxazebin-1N-oxide derivative which is also useful as a vegetable.
  • a free radical can be defined as an atom or molecule having one or more unpaired electrons.
  • Radicals are generally unstable, but some are relatively stable.
  • the lifetime of benzyl radicals in the gas phase is 10 — 5 to 10--seconds, Simple methyl radicals, hydroxy radicals, etc. in the atmospheric pressure gas phase are 1 o- s to i 0-'seconds.
  • Free radicals are also produced in vivo, and are generally referred to as in vivo free radicals, and have recently been noted in the fields of biology, medicine and vegetation. Is underway.
  • causes of the production of free radicals in the body include ultraviolet light, radiation, air pollution, oxygen, lipid peroxidation, metal ions, and ischemia-reperfusion.
  • the resulting free radicals in the body cause various in vivo reactions, such as peroxidation of lipids, denaturation of proteins, and degradation of nucleic acids, resulting in brain reactions. It is thought to cause diseases such as ischemia, heart disease, gastrointestinal disease, cancer, aging, and inflammation.
  • methods for detecting free radicals include an indirect method and a free radical method in which a reaction reagent is added to the reaction system and the resulting change in absorbance or luminescence of the reaction system is detected.
  • ESR method that directly detects unpaired electrons in Cull.
  • the sample by the ESR method can be measured as a solution or a solid, and it can be measured as an opaque or heterogeneous sample.
  • free radicals in vivo are generally unstable and have a short lifetime, so it is difficult to directly measure them by the ESR method.
  • the trapping agent (T) reacts quickly with short-lived free radicals (R.) and can be detected by ESR. It utilizes stable, long-lived spin-ducts (RT ').
  • the compound used as a spin-trapping agent should react with the above-mentioned (1) promptly with free radical, and (2) be sufficiently stable In addition to the production of biomass, it is necessary to satisfy conditions such as (3) that it is chemically stable in terms of handling and (2) that it has low toxicity. Had been.
  • the trapping agent which has been mainly used for the study of free radicals in vivo is a cyclic two-to-one DMP 0 (5,5- Dimethyl-l-pyrroline-1-oxide), linear PBN (N-tert-But 1- ⁇ -phenylnitrone), and nitroso ), It could not be said that it satisfies the above conditions at all. (For example, Fanore Macia, 28, 13 4 7 to 13 5 2 (1992) See].
  • the present inventors have proposed a free radical in vivo.
  • a rapid search was conducted for compounds that rapidly bind to the compound, are stable, and are still guaranteed to be safe for living organisms.
  • the dibenzoxazebine-1N-oxide derivative obtained by oxidizing the nitrogen atom of the oxazebine skeleton satisfies the above conditions, and is free radical carica.
  • R represents a hydrogen atom, a hydroxyl group or a lower alkoxycarbonyl group
  • R represents a lower alkyl group or a phenyl group
  • R 3 represents And R «represent a hydrogen atom, a halogen atom, an amino group, a nitro group, a cyano group, a canolepoxyl group, a lower alkoxycarbonyl group, and a lower alcohol, respectively.
  • Another object of the present invention is to provide a method for producing the compound (I) and a medical vegetable containing the compound (I) as an active ingredient, such as a free radical scavenger.
  • Fig. 1 shows the results of 11-methyldibenzo [b, f] obtained in Example 1 as a sample.
  • FIG. 2 shows the results of the 11-ethyldibenzo [b, f] obtained in Example 2 as a sample.
  • Oxazepine 11 A drawing showing spinad ESR spectrum in a free radical generating system in which an oxide is present.
  • Figure 3 shows the results obtained by using the sample obtained in Example 3 as 1 1 1 n-propyldibenzo [b
  • Oxazebin-1 10 A drawing showing a spin-adduct ESR spectrum in a free-radical generation system in which an oxide exists. .
  • Figure 4 shows the 11-phenyldibenzo [b, f] obtained in Example 4 as a sample.
  • Oxazebin 10 A drawing showing spin-adduct ESR spectrum in a free radical generating system in which oxide is present.
  • FIG. 5 is a drawing showing ESR spectrum in a free radical generating system in which the compound of the present invention does not exist.
  • R is preferably a hydrogen atom or a hydroxyl group. It is. Further, as a preferable example of R, a methyl group can be mentioned. Further, a preferable combination of R 3 and R 4 includes a combination in which R, is hydrogen at the 2-position and R, is a methoxy group at the 4-position.
  • the dibenzoxazebine-1N-oxide derivative (I) of the present invention can be produced, for example, as follows.
  • This reaction is carried out by dissolving a dibenzoxazebin derivative ((), preferably in a solvent such as methanol, and then reacting a solution of sodium borohydride.
  • the double bond is hydrogenated with a reducing agent to give compound (III), which is then catalyzed using selenium dioxide and oxidized with hydrogen peroxide or the like.
  • the hydrogenation reaction may be performed at a temperature of about 0 to 30 ° C for about 0.5 to 24 hours, and the oxidation reaction may be performed at a temperature of about 0 to 30 ° C. It should be about 3 to 24 hours.
  • the S-substituent of the dibenzoxazebin derivative (II) is a group that can be changed by hydrogenation or oxidation, it is protected by a conventional method.
  • the substituent of compound (II) is a carboxy group, for example, this group may be replaced with a known protective capacity such as an alkoxyl propyl group. It may be a ropoxyl group.
  • a part of the dibenzoxazebine derivative (II), which is a starting material for the above reaction, is disclosed in, for example, Japanese Patent Application Laid-Open No. Sho 56-166180.
  • the compound is a compound that is not known, for example, according to the following reaction formula, the halogenated nitrobenzene derivative (IV) and the phenol derivative (V) may be used. It is a compound that can be easily synthesized from these compounds.
  • reaction between compound (IV) and compound (V) is carried out by reacting compound (IV) with a strong alkali to form its phenoxylate, which is then reacted with xylene or the like. This is done by heating in a solvent.
  • strong alkalis that can be used to make the amide compound (IV) a phenoxylate include potassium hydroxide, sodium hydroxide, and the like. It is.
  • the source of compound (VI) may be obtained by using a hydrogenation catalyst such as palladium monocarbon or a first tin chloride in ethanol.
  • the acylation of the compound (VII) is also carried out according to a conventional method by using an acylating agent such as acylated alcohol.
  • the compound of formula (VIII) can be prepared in a solvent such as xylene, benzene, toluene, or the like, in a solvent such as oxine chloride, polyphosphoric acid, phosphorus pentoxide, and zinc chloride. It may be heated in the presence of a dehydrating agent such as.
  • the dipenzoxazebin-N-oxide derivative (I) having a desired substituent is converted into the phenol derivative (V) by the group R of the compound (I).
  • a and a compound having a substituent corresponding to R are selected, and the compound (VII) obtained by passing through a nitro group is converted into an acyl group. It can be obtained by selecting the one corresponding to the base R, based on the acylating agent which is to be converted.
  • the dipenzoxazebin-1N-oxide derivative (I) obtained as described above is further purified as necessary, and then formulated into a pharmaceutical preparation according to a conventional method. It can be used as
  • it can be used as a free radical scavenger by oral or parenteral administration, and it can be used for cerebral ischemia, heart disease, gastrointestinal disease, Prevention of diseases such as cancer, aging, and inflammation. It can be used as a diagnostic agent such as a wrap.
  • the compound of the present invention binds to free radicals in vivo as described above, and stably retains the same. Therefore, an agent for preventing or treating a disease caused by these compounds.
  • a detection dish that is expected to be useful for imaging free radicals in vivo by the ESR method.
  • the ESR method is one of the magnetic co-methods, which targets unpaired electrons of atoms and molecules, but free radicals such as active oxygen and transition elements are unpaired electrons. All are subject to ESR measurement. Recently, as the relationship between active oxygen and physiological functions has been revealed, ESR has been actively used for identification of active oxygen and analysis of its oxidative reactions.
  • the compound of the present invention non-invasively measures the free radical of the human body as a detection dish in the ESR method using the ESR device B for the human body, etc. -It is expected that useful information on diseases or symptoms caused by radicals can be provided.
  • the present invention will be described more specifically with reference to Examples, but the present invention is not limited to these Examples.
  • the first tin chloride (170 g) was dissolved in ethanol (140 ml), and concentrated sulfuric acid (140 ml) in ethanol solution (210 ml) was added thereto. Further, 34.06 g (0.158 mol) of o-dinitrophenyl ether obtained in (1) was added dropwise at a temperature of 30 or less, and the mixture was stirred at room temperature for 3 hours. Let me do it. After distilling off ethanol, water was added and hydrochloric acid was further distilled off under reduced pressure. Until the aqueous solution becomes basic, sodium hydroxide was added, and this was extracted with ether, washed with water, and the solvent was distilled off to obtain 25.07 g (MW.185) of white crystals. , 0.136 mol, 85.5%).
  • reaction was quenched by adding sodium sulfite heptahydrate (MW 25.15, 3.0 g / 15 ml aqueous solution) and concentrated under reduced pressure at 3 O'C or less.
  • the aqueous layer was extracted with methylene chloride and the solvent was distilled off to obtain crude 11-ethyldibenzo [b, f] [1,4] oxazebin-10-oxide. .
  • Example 1 o-chloronitrobenzen was replaced with 4-chloro-3-nitrobenzoic acid, and phenol was replaced with ⁇ -methoxypheno.
  • Example 1 except that m-methoxyphenol, p-methoxyphenol and 2,4—dimethylphenol are used instead. The following compound is obtained according to the procedure.
  • Example 1 (1) o-chloronitrobenzen was added to ethyl 41-chloro-1-3-diethyl benzoate, and phenol was added to the compound shown in Table 1.
  • the invention compound (I) is obtained.
  • -Skin -ul 8-COOCH5 C H S H 4-CH, m-methyl chloro ⁇ -futhyryl chloride 8-COOC2H5 nC 3 H 7 3-CH 3 H
  • Example 2 The amount of 38 mM of 11-ethyldibenzo [b, f] [1,4] oxazebin-10-oxide obtained in Example 2 was added to 5 ml of methanol. Dissolve and use as sample liquid b.
  • the amount of 11-n—provirdipenza [b, f] [1,4] oxazebine-1 10—oxoxide obtained in Example 3 which is 38 mM of oxide is determined by the amount of methanol. Dissolve the sample solution in 5 ml, and use this solution as sample solution c.
  • Reagent (1) 101, sample solution (a) 7401 and sample (2) 2501 are added to a glass tube in this order, and stirred to obtain reaction solution A.
  • Samples (1) 100 (1), sample liquid c 7400 (1) and reagent (2) 501 are added to a glass tube in this order, and the mixture is stirred to obtain a reaction mixture (C).
  • reaction solution D reagent 1 10 ⁇ 1, sample solution d 7400 ⁇ 1 and reagent 2 2501 to the glass tube in this order, and stir the mixture to obtain reaction solution D.
  • reaction solutions A, B, C and D were each absorbed into a separate flat cell (manufactured by Robotec), and the ESR spectrum was measured.
  • Samples (1) 100-1 and reagents 2 250 // 1 were added to a glass tube in this order, and stirred to obtain a control solution. This solution was absorbed in a flat cell (made by Lapotek), and the ESR spectrum was measured.
  • ESR was measured under the following conditions.
  • Measuring device Electronic spinning device [JES-REIX (manufactured by Nihon Denshi)]
  • the compound of the present invention captures free radicals in a living body, and the resulting spin-duct has sufficient stability.
  • the compound of the present invention is used. Can be used as preventive and therapeutic agents for these diseases.
  • free radicals in vivo are not invaded! It can be imaged by the ESR method, which is an I-type measurement method, and can be used for in vivo analysis of cancer, ischemia, inflammation, etc. based on in vivo spectra and images of free radicals in vivo. It can be used for diagnosis of pathological conditions involving free radicals, and medically useful information can be obtained.
  • ESR method is an I-type measurement method

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

On décrit des dérivés N-oxyde de dibenzoxazépine représentés par la formule générale (I) dans laquelle R1 représente hydrogène, carboxy ou alcoxycarbonyle inférieur; R2 représente alkyle inférieur ou phényle; et R3 et R4 représentent chacun hydrogène, halogéno, amino, nitro, cyano, carboxy, alcoxycarbonyle inférieur, alcoxy inférieur, hydroxy, alkyle inférieur ou phényle. On décrit également un médicament préventif ou curatif, destiné à l'ischémie cérébrale, aux maladies cardio-vasculaires, aux maladies digestives, au cancer, au vieillissement ou à l'inflammation, ainsi qu'un détecteur de radicaux libres, contenant ces dérivés.
PCT/JP1996/001137 1995-04-25 1996-04-25 Derives n-oxyde de dibenzoxazepine et medicament les contenant en tant que principe actif WO1996033983A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP7/123046 1995-04-25
JP12304695 1995-04-25

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WO1996033983A1 true WO1996033983A1 (fr) 1996-10-31

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TWI427070B (zh) * 2006-10-28 2014-02-21 Methylgene Inc 組蛋白去乙醯酶抑制劑

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS56166180A (en) * 1980-05-28 1981-12-21 Chugai Pharmaceut Co Ltd Dibenzoxazepine derivative and its preparation
JPH07101947A (ja) * 1992-06-20 1995-04-18 Cassella Ag フエニル−１，２，５−オキサジアゾール−カルボンアミド−２−オキシド

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS56166180A (en) * 1980-05-28 1981-12-21 Chugai Pharmaceut Co Ltd Dibenzoxazepine derivative and its preparation
JPH07101947A (ja) * 1992-06-20 1995-04-18 Cassella Ag フエニル−１，２，５−オキサジアゾール−カルボンアミド−２−オキシド

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
TETRAHEDRON LETTERS, Vol. 28, No. 21, (1987), S. MURAHASHI et al., "Selenium Dioxide Catalyzed Oxidation of Secondary Amines with Hydrogen Peroxide", pages 2383-2386. *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TWI427070B (zh) * 2006-10-28 2014-02-21 Methylgene Inc 組蛋白去乙醯酶抑制劑
US9193749B2 (en) 2006-10-28 2015-11-24 Forum Pharmaceuticals, Inc. Dibenzo[b,f][1,4]oxazepin-11-yl-N-hydroxybenzamides as HDAC inhibitors

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