WO1996033983A1 - Dibenzoxazepine n-oxide derivatives and drug containing the same as the active ingredient - Google Patents

Abstract

Dibenzoxazepine N-oxide derivatives represented by general formula (I), wherein R1 represents hydrogen, carboxy or lower alkoxycarbonyl; R2 represents lower alkyl or phenyl; and R3 and R4 represent each hydrogen, halogeno, amino, nitro, cyano, carboxy, lower alkoxycarbonyl, lower alkoxy, hydroxy, lower alkyl or phenyl; and a preventive or remedy for cerebral ischemia, cardiac diseases, digestive diseases, cancer, ageing or inflammation and a free-radical detector containing the same.

Description

 Dipenzoxazebin-1 N-oxide derivative and a medicinal vegetable containing it as an active ingredient

Technical field

 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. As 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. Background art

A free radical can be defined as an atom or molecule having one or more unpaired electrons. The discovery of a long stable unfavorable over La deer le-lived, M. G omberg in 1 9 0 0 years, capital re-off error two Rume Chirura di force Lumpur _{[(C, H «) 3} C · ] Begins to find.

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.

 — On the other hand, free radicals in vivo related to various diseases are less invasive than those outside the body! ! If they can be detected systematically, the causes of a number of diseases can be determined, and this will be useful information in medicine.

 Conventionally, 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. There is an ESR method that directly detects unpaired electrons in Cull.

 Of these, 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. Although it is extremely advantageous for the detection of chromosomes, free radicals in vivo are generally unstable and have a short lifetime, so it is difficult to directly measure them by the ESR method.

 Spin-trap methods have been developed to overcome the drawbacks of the ESR method. According to this method, as shown in the following formula, 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 ').

 R · + T → R T ·

(Free radical) (spin wrapping agent) (spin adduct) That is, it reacts quickly with free radical and is sufficiently stable for ESR measurement. Radiation can be measured by ESR method by adding a compound that generates spin-adduct into the measurement system as a spin-trapping agent. That is.

 Therefore, 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.

 Conventionally, 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-α-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].

 At present, prevention and treatment of adult diseases such as cerebral ischemia, heart disease, gastrointestinal disease, and cancer, prevention and treatment of inflammation, and prevention of aging are strongly demanded. There is a need to find a vegetative agent that effectively captures free radicals and to effectively prevent and cure the above diseases.

 In addition, as described above, if there is a compound that rapidly binds to free radicals in vivo and has sufficient stability, non-invasive! It can be used as a stain-trapping agent for the ESR method, which is an I-type measurement method, and it can be used for cancer screening from in vivo biological spectra and images of free radicals. It is useful for diagnosing pathological conditions involving in vivo free radicals, such as ischemia, inflammation, and the like, and the provision of such compounds is required. Disclosure of the invention

In order to solve the above-mentioned problems, 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.

 As a result, the dibenzoxazebine-1N-oxide derivative obtained by oxidizing the nitrogen atom of the oxazebine skeleton satisfies the above conditions, and is free radical carica. Used as a drug for the prevention and treatment of diseases such as cerebral ischemia, heart disease, gastrointestinal disease, cancer, aging, and inflammation, and as a diagnostic agent for spin traps, etc. They found that they could do this and completed the present invention.

 That is, the purpose of the present invention is to satisfy the following formula (I),

(In the formula, R, represents a hydrogen atom, a hydroxyl group or a lower alkoxycarbonyl group, R represents a lower alkyl group or a phenyl group, and 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. (Indicates a alkoxy group, a hydroxy group, a lower alkyl group or a phenyl group.)

Is to provide a dibenzoxazebine-1N-oxide derivative represented by the formula:

 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. . Brief description of the drawings

 Fig. 1 shows the results of 11-methyldibenzo [b, f] obtained in Example 1 as a sample.

[1, 4] oxazebin-1 10 — free radical with oxide It is a drawing showing a spin-duct ESR spectrum in the generator.

 FIG. 2 shows the results of the 11-ethyldibenzo [b, f] obtained in Example 2 as a sample.

 [1, 4] 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

, F] [1, 4] 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.

 [1, 4] 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. BEST MODE FOR CARRYING OUT THE INVENTION

In the dipenzoxazebinine 1-N-oxide derivative (I) of the present invention, 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.

That is, it is obtained by hydrogenating and then oxidizing the dipentoxoxazebin derivative represented by the formula (II) according to the following reaction formula.

 (ID (III)

(Wherein, R, R ₂ , R _s and R, have the above-mentioned meanings)

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. [See S. Murahashi, T. Shiota, Tetrahedron Letters, Vol. 28, No. 21, p2383-2386, 1987]! _β

 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.

When 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. After the reaction, for example, when 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. Even if 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.

Veil

Consolidation

(ID (wherein, R, R _a and R, have the above-mentioned meanings, X represents a halogen atom, and Y represents a leaving group) The 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. Examples of 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.

 In addition, 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.

 In the above reaction, when the substituent of each compound is changed by a transport reaction or dehydration reaction, or when it is a group that reacts with an acylating agent. However, this must be protected in accordance with ordinary law.

Then, 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

More specifically, 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 reasons why the compounds of the present invention bind to free radicals in vivo and have sufficient stability have not been elucidated for some reasons. It is speculated that, as represented by the formula, the double bond of the N atom of oxazepine and the oxide cooperate to capture free radical canole.

 (i) As described above, 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. In addition, a detection dish that is expected to be useful for imaging free radicals in vivo by the ESR method.

 In other words, 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.

Until now, ESR has been using X- and M-waves (about 9.5 GHz), but the dielectric loss due to water has been increasing. It was impossible to measure large and large-volume samples such as living bodies. However, recently, an ESR device using a microwave called L-node (1 GHz or less) has been developed, and free radicals in highly watery or biological samples have been developed. Non-invasive B measurements have become possible [see, for example, Pharmacia, 27, 7110-715 (1991)], which is extremely large, such as in humans. Open the possibility of measuring large volumes of biological samples I came.

 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. Hereinafter, the present invention will be described more specifically with reference to Examples, but the present invention is not limited to these Examples. Example 1

 Methyl dibenzo [b, f] [1, 4] Oxazebin-1 10 — Synthesis of oxide:

 (1) Synthesis of o-dinitrophenyl ether (2-dinitrophenylbenzene)

 Add 40 g (0.425 mol) of phenol to 20 g of potassium hydroxide

(0.356 mol) is melted while heating to 130 to 140 ° C, and the copper catalyst is removed after the temperature has dropped to 100 to 110 ° C. added. This solution is heated and transported at 150 to 160, and 0—two-croc benzene 19.7 g

 (0.125 mol), and after confirming that this temperature is maintained even after the heating is stopped, the remaining 0-two-clock vent benzene 19. 7 g were added. Thereafter, the heating current was applied for 30 minutes, and the reaction solution was added to ice water containing 12.5 g of sodium hydroxide.

The aqueous solution was extracted with ether, washed with water, and the solvent was distilled off. The residue was distilled under reduced pressure (142-144 * C / 2 mmHg) to give a brown liquid 39.06 g (MW.215, 0.182 mol, 72.7%). (2) Synthesis of o_aminodipheninoleether (2-aminophenyloxybenzen)

 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%).

(3) Synthesis of o-acetamidodiphenyl ether (2—acetamidophenyloxybenzene)

 To 4.26 g (19.5 mmol) of o-aminodiphenyl ether obtained in (2) above, 5 equivalents of 9.92 g (97. Mol), and several drops of concentrated sulfuric acid were added with stirring. After stirring for 30 minutes, the mixture was extracted with ether, washed with water, the solvent was distilled off, and the solid was recrystallized from toluene (4.2 lg, 18.5 milliliter, MW.227, 95.1%). (4) 1—Synthesis of 1-methyldibenzo [b, f] [1,4] oxazebin 6.5-g of θ-acetamidodiphenyl ether obtained in (3) above ( 28.7 milimol) to 58.6 g of polyphosphoric acid (MW.

(37.9.33, 143.8 millimoles) was added and the mixture was heated at 160 to 180 ° C. After heating for 4 hours, it was poured into a large amount of water in an ice bath, neutralized with lime carbonate, treated with activated carbon, and extracted with ether.

After washing with water, the solvent is distilled off, and the solid is recrystallized from ether-petroleum ether. (4.30 g, MW.209, 20.6 millimeters, 71.6%).

(5) 10, 11 1 — Synthesis of dihydro 1 1 -methyl dibenzo [b, f] [1,4] oxazebin

 4.30 g (20.6 mimol) of 11-methyldibenzo [b, f] [1,4] oxazebine obtained in (4) above was added to ethanol 20. Dissolve the solution in 5 ml, add 7 equivalents of 5.45 g of sodium borohydride (MW 0.37.83, 144 millimol) and stir at room temperature for 1 hour did. Add a large amount of water, extract with ether, wash with water, and evaporate the solvent. 3.86 g of oily crude 11-methyldibenzo [b, f] [1,4] oxazebin MW 21.1, 18.3 millimol, 88.9%).

 A mixture of ethyl hexyl monate (5: 1) was passed through silica gel column (Wakogel C—200, 75 to 150 / im) as the mobile phase, and then 10 11-Hydroxy 11-methyldibenzo [b, f] [1,4] oxazebin was obtained.

(6) 1 1 — Synthesis of methinoresinzo [b, f] [1, 4] oxazebin 10-oxide

Dissolve the 10-, 11-dihydro- 11-methyldibenzo [b, f] [1, 4,] oxazebin obtained in (5) above in methanol, and Air was expelled through a nitrogen stream. A catalytic amount of selenium dioxide (0.05 equivalent, MW.11.096) was added while shielding from light, and 3 equivalents of 30% hydrogen peroxide were added dropwise in an ice bath. . The temperature was returned to room temperature while stirring, and the mixture was stirred for 3 hours while being shielded from light. All subsequent operations were performed under light shielding and at room temperature or lower. The reaction mixture was added with sodium thiosulfate to eliminate excess hydrogen peroxide, and the reaction was stopped. <Concentration under reduced pressure, the aqueous layer was extracted with ether, and the solvent was distilled off. More refined did .

 Melting point: 58.5 to 60.5 ° C

Elemental analysis (C ^ HHNOZ * 0 as a ₂ H 2 O:. Was a form including the water because the hygroscopic there Ru):

 Calculated values: C73.48, H5.02, N6.12%

 Measured values: C73.63, H4.92, N6.22%

 Mass spectrum: 2 25 (M +) Example 2

 1 1-ethyldibenzo [b, f] [1,4] oxazebin-1 10 — Synthesis of oxide:

 (1) o-Synthesis of ethylaminodiphenylbenzene (2-ethylaminophenoxybenzen)

 o — To 1.7 g (9.11 mimol) of aminodiphenyl ether, add 0.5 ml of pyridin and 5 ml of benzene, cool in ice water and add propionyl chloride. 1.0 ml (d1.065, 1.02 g, about 92.52, 11.03 mmol) was added dropwise, and the temperature was gradually returned to room temperature. After cooling at room temperature for 3 hours, the mixture was reduced under reduced pressure *, added with water, neutralized with sodium bicarbonate, and extracted with ether. After the extract was washed with water, the solvent was distilled off to obtain 2.21 g (9.11 mmol, MW 241, 100%) of crude o-ethylamido diphenyl ether.

(2) Synthesis of 11-ethyldibenzo [b, f] [1,4] oxazebin ο-ethylaminodiphenyl ether 12.5.2 g (52.0 millimoles) 5 equivalents of Po Li Ri I acid 8 7 .8 g (.. MW 3 3 7 9 3, 0 2 6 molar) was added, 1 6 0 - heated in the range of 1 8 0 ^e C. After heating for 5 hours, pour a large amount of water in an ice bath, neutralize with potassium carbonate, and add activated charcoal to treat After that, the aqueous layer was extracted with ether. After washing with water, the solvent is distilled off, and the crude 11-ethyldibenzo [b, f] [1,4] oxazebin (9.62 g, MW22, 44.2 millimoles) , 85.1%).

NMR: CH _3; 1.29〗-30] _{-31ppm t; 3 Η, CH 2} ; 2.92 2.93 2.94 2.95ppm q; 2Η, Aromatic; 7.12 ~ 7.44ppm m; 8H, Solvent; CDC1 3

(3) Synthesis of 11-ethyldibenzo [b, f] [1,4] dihydroxazebin

 Dissolve 9.86 g (42.9 mimol) of 11-ethinoresibenzo [b, f] [1,4] oxazebin in 50 ml of anhydrous ether, and prepare 1.2 equivalents. 1.95 g of lithium aluminum hydride (MW 37.95, 51.5 millimoles) was added in an ice bath, and gradually heated to 40. For 24 hours. A large amount of water was added for ether extraction. The extract was washed with water, and the solvent was distilled off. The crude oily 11-ethyldibenzo [b, f] [1,4] dihydroxazebine 9.02 g (MW225, 40.1 mmol, 93.5%). This was purified using silica gel caram- ella (Wakogel C—200, 75-; 150 移動 m) using hexane: ethyl ethyl ester = 10: 1 as the mobile phase. Thus, 11-ethyldibenzo [b, f] [1,4] dihydroxazebin was obtained.

 NMR: CH 1.00 1.01 1.02ppm t; 3H, CH ,; 2.01 to 2.13ppu m; 2H,

 NH; 3.97ρρΒ broad s; 1H, CH; 4.31 4.32 4.33ppm t; 1H,

Aroma tic; 6.55 ~ 7.24 pm D; 8H

(4) Synthesis of 1 1-ethyldibenzo [b, f] [1,4] oxazebin-1 10—oxide

1 1—Ethyldibenzo [b, f] [1,4] Dissolve 1 g (4.44 millimoles) of dihydroxazebin in 30 ml of methanol and add Struggle The air was expelled through the stream. A catalytic amount of 25 mg of selenium dioxide (MW 110.96) was added, and 1.6 equivalents of 30% hydrogen peroxide (1.6 ml) were added dropwise in an ice bath while shielding light. The temperature was returned to room temperature while stirring was continued, and the reaction was continued for 4 hours while taking care not to exceed room temperature. The 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. . This was purified on silica gel caram (Wakoel C200, 75-: I50zm) using ethyl peroxylate as the mobile phase, and purified with 11-ethyldibenzo [b [f, [1,4] oxazebin-10-oxide: 200 mg (oil, MW 239, 0.84 millimol, 18.8%) was obtained.

_{NMR: CH 3; 1.35 1.37 1.38ppm} t; 3H, CH 2; 3.15 3.16 3.18 3.19ρρο q; 2Η, Aromatic; 7.19 ~ 8.02ppm m; 8H, Solvent; CD 3 0D implementation example 3

 1 1 1 n-Brobyl dibenzo [b, f] [1,4] oxazebin 1 10 — Synthesis of oxide:

 (1) Synthesis of o-Proviramide diphenyl ether (2-Bromidamide phenoxybenzen)

o — Amino dipheninole ether l.Og (5.41 milliliter), add 0.5 ml of viridine and 5 ml of benzene, cool in ice water and add butyric chloride. 0.7 ml of lil (d1.03, 691 mg, MW106.55, 6.49 millimol) was added dropwise, and the temperature was gradually returned to room temperature. After stirring at room temperature for 1 hour, the mixture was concentrated under reduced pressure, added with water, neutralized with sodium bicarbonate, and extracted with ether. After washing the extract with water, the solvent is distilled off, and the crude o-propylamide diphenyl 1.38 g of ether (5.41 millimol, MW 255, 100%) were obtained.

(2) Synthesis of 111-n-propyl dibenzo [b,: f] [1,4] oxazebin

 o — 96.2 g (37. 7 millimoles) of provinoremido dipheninooleatele with 6 equivalents of polyphosphoric acid 63.8 g (MW 33.7.93) , 189 mmol) and heated at 160-180 ° C. After heating for 6 hours, the mixture was poured into a large amount of water in an ice bath, neutralized with potassium carbonate, treated with activated carbon, and the aqueous layer was extracted with ether. After washing with water, the solvent is distilled off, and about 11 1-n_providipenyl [b, f] [1,4] oxazebin (7.61, MW237, 32.1 millimol, 85.1%).

NMR: CH ₃ ; 0.98 1.00 1.OO ppm t; 3H, CH ₂ ; 1.70 to 1.79 ppm m; 2H,

_{CH 2; 2.90 2.91 2.92ppm t;} 2H, Aromatic; 6.65 ~ 7.47ppm m; 8H, Solvent; CDC1 5

(3) Synthesis of 1 1 —n-Propyldibenzo [b, f] [1,4] dihydroπιoxaxebin

 1 1 1 n-Provir dibenzo [b, f] [1, 4] oxazebin

Dissolve 7.61 g (32.1 millimoles) in 50 ml of anhydrous ether,

Add 1.2 equivalents of 1.46 g of lithium aluminum hydride (MW 37.95, 38.5 mimol) in an ice bath and gradually add 40 ° C. The mixture was heated and stirred for 24 hours. Then, a large amount of water was added to carry out ether extraction, washed with water, and the solvent was distilled off to obtain an oily crude 111-n-propyldibenzo [b, f] [1,4] dihydro-CJoxazebi. 7.33 g (MW 239, 30.7 milliliter, 95.5%) were obtained. This is called silica gel (Wakogel C-200, 75). Purified using hexane: ethyl acetate = 10: 1 as the mobile phase to obtain 1 1-η-propyl dibenzo [b, f] [b, f] [1, 4] The dihydroxazebine was obtained.

NMR: CH ₃ ; 0.95 0.96 0.97 ppm t; 3H, CH ₂ ; 1.33 to 1.52 ppm m; 2H,

CH ₂ ; 1.97 to 2.07 ppm m; 2H, NH; 3.94 ppm broad s; 1H, CH; 4.43

4.44 4.45ppn t; 1 H, Aromatic; 6.53 ~ 7.24ppni m; 8H

(4) 1 1 1 n — Propinole dipenza [b, f] [1, 4]

 1 1 1 n — Propinoresipenzo [b, f] [1, 4] Dissolve 90 mg (3.85 mimol) of dihydroxazebine in 30 ml of methanol. However, the air was expelled through a sufficient nitrogen flow. A catalytic amount of 20 mg of selenium dioxide (MW 110.96) was added, and 3 equivalents of 1.4 ml of 30% hydrogen peroxide were added dropwise in an ice bath while shielding light. The temperature was returned to room temperature while surrounding the mixture, and the reaction was continued for 1 hour while being careful not to raise the temperature above room temperature. To the reaction mixture was added sodium sulfite heptahydrate (MW 25.15, 2.8 g / 15 ml aqueous solution) to stop the reaction, and the concentrated sugar was reduced to 3 O'C or less. did. The aqueous layer was extracted with methylene chloride and the solvent was distilled off to obtain crude 111-n-provirdibenzo [b, f] [1,4] oxazebin-110-oxide. This was purified by silica gel (Wakogel C—200, 75 to 150111) using ethyl acetate as a mobile phase, and purified by using 11-n-propyl dibenzo [ b, f] [1,4] o, xazebinine 10-Oxide 200 mg (oil-like, MW 253.3, 0.79 millimol, 20.5%) was obtained. .

 NMR: CH,; 1.03 1.04 1.05 ppm t; 3H, CH ,; 1.82 to 1.86 ppam; 2H,

CH ₂ ; 3.15ppm broad s; 1H, Aromatic; 7.18 ~ 8.01ppm n; 8H,

Solvent; CD ₃ 0D] Mass spectroscopy (Positive FAB method): 25 4 m / e (M + 1) Elemental analysis (C,, Η, as 0 ₂ N 1 / 4H ₂₀ ):

 Calculated value: C: 74.54%, H: 6.06%, Ν: 5.43%

 Actual measurement value: C: 74.37%, H: 6.07%, Ν: 5.33% Example 4

 111 Synthesis of phenyldibenzo [b, f] [1,4] oxazebin-110-oxide:

 (1) Synthesis of o-Penzol amide diphenyl ether (2—Penzol amide diphenyl benzene)

o — To 4.26 g (23.0 milimol) of aminodiphenyl ether, add 0.5 ml of viridine and 5 ml of benzene, and cool in ice water Then, 2.5 ml of benzyl chloride (d1.45, 3.56 g, MW 140.57, 25.3 millimol) was added dropwise, and the temperature was gradually raised to room temperature. I put it back. After stirring at room temperature for 1 hour, the mixture was concentrated under reduced pressure, water was added, and the mixture was neutralized with sodium bicarbonate and extracted with ether. The extract is washed with water, the solvent is distilled off, and the solid is recrystallized from toluene to obtain a θ-benzoylamide diphenyl ether 6.6.4 2 g (22 Millimol, MW 2887, 97.3%). (2) 1 1 Synthesis of 1-phenyldibenzo [b, f] [1,4] oxazebin ο—phenylamidodiphenylether 2.25 g (7 57.9 equivalents of polyphosphoric acid (MW 3 37.93, 38.9 millimoles), and heat with 180. Was. After heating for 2 hours, the mixture was poured into a large amount of water in an ice bath, neutralized with potassium carbonate, treated with activated carbon, and the aqueous layer was extracted with ether. After washing with water, the solvent is distilled off, and the crude oily 11-phenyldibenzo [b, f] [1,4] oxazebin (1.42 g, MW271, 5.24 MilliMonole, 67.3%).

NMR: Aromatic; 7.10 ~ 7.82ppm m ; 13H, So 1 vent; CDC1 3

(3) Synthesis of 1 1-phenyldibenzo [b, f] [1,4] dihydroxazebine

 11 Dissolve 1.03 g (3.80 milimonole) of monophenyldibenzo [b, f] [1,4] oxazebin in 10 ml of anhydrous ether, and prepare a solution of 1.2. An equivalent amount of lithium hydrogen hydride (173 mg, MW 37.95, 4.56 millimol) was added to an ice bath, and the mixture was gradually heated to 40. A large amount of water stirred for 24 hours was added, and ether was extracted. After washing with water, the solvent was distilled off, and the solvent was distilled off to form a diphenyl benzo [b, f] [1,4] diphenyl. There was obtained 3.86 g of doloxazebin (MW 271, 18.3 mirimone, 88.9%).

 NMR: NH; 4.81 ppm broad s; 1H, CH; 1.60 ppm s; 1H, Aromatic; 6.58 ~

 7.39ppm ni; 13H

(4) Synthesis of 11-phenyldibenzo [b, f] [1,4] oxazebin-10-oxide

 11 1-Diphenyldibenzo [b, f] [1,4] dihydroxazebin 300 mg (1.11 millimoles) in 15 ml of methanol Melted and expelled air through sufficient nitrogen flow. Add a catalytic amount of 1 O mg of selenium dioxide (MW 110.96) and add 3 equivalents of 30% hydrogen peroxide in an ice bath.

0.4 ml was added dropwise while shielding light. The temperature was returned to room temperature while continuing to stir, and the reaction was allowed to continue for 3 hours while taking care not to exceed the room temperature. The reaction was quenched by addition of sodium sulfite heptahydrate (MW25.2.15, 229 mg / 5 ml aqueous solution), and concentrated under reduced pressure at 30 ° C or lower. Then, the aqueous layer was extracted with methylene chloride and the solvent was distilled off to obtain crude 11-phenyldibenzo [b, f]. [1, 4] Oxazebin-1 10 — Oxide was obtained. This was purified by silica gel column (Wakogel C—200, 75-: L50〃m) using hexane: ethyl acetate = 1: 1 as the mobile phase. , 11-1-phenyldibenzo [b, f] [1, 4] oxazebin 10-oxide 150 mg (MW 2887, 0.52 mimol, 47 6%).

NMR: Aromatic; 7.10 ~ 8.04ppm n ; 13H, So lvent; CD 3 0D Ma scan scan Bae click preparative Honoré (Positive FAB method): 2 8 7 m / e (M + 1) Elemental analysis (C ,, H ₁₃ 0, N 1 / 6H, 0):

 Calculated values: C: 78.61%, H: 4.63%, N: 4.82%

 Actual measured value: C: 78.71%, H: 4.75%, N: 4.92%

 Melting point: 5 3 to 5 4 Example 5

 In Example 1 (1), o-chloronitrobenzen was replaced with 4-chloro-3-nitrobenzoic acid, and phenol was replaced with ο-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.

 • 1 1 1-methyl 1- 4-methoxydiphenyl [, f] [1, 4] oxazebin 1 8—potassium sulfonic acid-10—oxide

 · 1 1-Methyl 3-Methoxy dibenzo [b, f] [1, 4] Oxazebine 1 8-Potassium-10-Oxide

 -1 1-Methynolay 2-Methoxy benzo [b, f] [1,4] oxazebin 1 8-Potassium ruponate-10-Oxide

• 2, 4, 11 — Trimethylinobenzo [b, f] [1, 4] oxazebin 8 — Potassium sulfonic acid 10 — Oxide Example 6

In 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. A book having the substituents shown in the right side of Table 1 according to Example 1 except that acetic anhydride of Example 1 (3) is replaced with the acylating agent of Table 1 in place of (V). The invention compound (I) is obtained.

Starting compound Compound of the present invention (I)

Compound (V) Acylating agent R, R ₂ R ₄ o-methoxypheno-ft anhydride 8-C00C ₂ H ₅ CH ₃ H 4-OCH3

111_ methoxyphenol 8-C00C ₂ H ₆ CH ₃ 3- OCH ₃ H

D—Utoxyfuunol 8-COOC2H 5 CH ₃ 2-OCHj H

2 4 child, 'methyl phenol _{8-C00C 2 H 5 CH 3} 2-CH3 4-CH3 -onyl m- methoxy phenol 7 ° chloride _{Π 8-C00C 2 H 5 C} 2 H5 3-OCH3 H

0—Methoxyphenol Chloride Henzoyl 8-C00C ₂ H ₆ C Ηίί H 4-OCHj m—Methoxy phenol ¾ 8-COOCJH-CH ₅ 3-0 CH H p- ^ Toxiphenol 8-C00C ₂ H ₅ eHs 2-OCHj H

0_ Methoxy phenol m-methine W, sodium chloride 8-COOCjHs ID-CHaCeH * H 4-OCH3 m-methoxyphenol 8-C00C ₂ H ₅ ID-CHaC »H ₄ 3-0CH ₃ H

2,4 sheet "Metokishifueno - Le chloride 7 Y O D _{ft 8-C00C 2 H s C2H5} 2-0CH 3 4-0CH 3

2,4 sheet "Metokishifueno - Le chloride Nri * I le _{8-C00C 2 H 5 CeHs 2} -OCHj 4-OCH3 m- Kono - le anhydrous醉酸 _{8-C00C 2 H 5 CH 3} 3-CHj H m- Methylphenol Chloride chloride 8-C00C ₂ H ₆ C 2H5 3-CH3 H

. -Skin -ul 8-COOCH5 C: H _S H 4-CH, m-methyl chloro η-futhyryl chloride 8-COOC2H5 nC ₃ H ₇ 3-CH ₃ H

P-Methyl Phenol Chloride Hydrogen 8-C00C ₂ H ₅ CeHs 2-CH ₃ H m-Methyl Phenol 8-C00C ₂ H ₅ CeHs 3-CH ₃ H

0-Methyl fu -A 8-COOCH5 CeHs H 4-CH ₃

P tilf -ft m-methyl W-yl peridot 8-C00C ₂ H ₅ 111-CH3C 2- CH ₃ H Reference Example 1

 3 — acetylamino 4 1 (3 — methoxyphenoxy) Apply 8.3 g of ethyl monobenzoate to 15.4 g of oxine chloride and dry. After flowing for 3 hours in 50 ml of Tonolen, the mixture was cooled. The precipitated crystals are filtered and washed with ethyl acetate, and 11-methyl-13-methoxydibenzo [b, f] [1,4] oxazebin-18-caproluconic acid 8.2 g of ethyl hydrochloride were obtained. This was neutralized with ammonia water, extracted with ethyl acetate, the extract was reduced, ethanol was added to the residue, and the precipitated crystals were further treated with ethanol. Recrystallized to give colorless needle crystals of 11-methyl-3- (methoxydibenzo [b, f] [1,4] oxazebin-18-ethyl-ethyl proponate) 6.9 g ( Yield 88%).

 Elemental analysis (as σ,, Η,, Ν Ο *)

 Calculated value: C: 69.44%, H: 5.5%, N: 4.5%

 Measured value: C: 69.48%, H: 5.56%, N: 4.43%

 Melting point: 1 17-: L 18 'C Reference example 2

 11-Methyl-3-3-methoxydibenzo [b, f] [1,4] oxazebin-18 obtained in Reference Example 1 Ethyl carboxylate lg was added to methanol 10 ml , And 10 ml of 1N sodium hydroxide was added, and the mixture was passed for 1 hour. After cooling, the mixture was neutralized with dilute hydrochloric acid, and the precipitated crystals were collected by filtration and recrystallized from methanol to obtain 11-methyl-3--3-methoxydibenzo [, f] [1,4] 0.84 g (92% yield) of oxazebin-18-carponic acid was obtained.

Elemental analysis (as C,, Η _{Ι 3} Ν 0 <)

 Calculated values: C: 67.84%, H: 4.63%, N: 4.94%

 Measured value: C: 67.82%, H: 4.61%, N: 4.90%

Melting point: 2 4 7 (decomposition) Example Ί

 The 11-methyl-3—methoxydibenzo [b, f] [1,4] oxazebin-18-8-potassium ethyl obtained in Reference Example 1 was replaced with the methyl ester of Example 1 (5 ) And processed in the same manner as in (6) to obtain 11-methyl-3-methoxydibenzo [b, f] [1,4] oxazebin-18-ethonyluponate 1 0 — get the oxide. Example 8

 The 11-methyl-3—methoxydibenzo [b, f] [1,4] oxazebin obtained in Reference Example 2 and 8-calponic acid were combined with (5) and Example 5 in Example 1. And the same treatment as in (6) to obtain 11-methyl-3-methoxydibenzo [b, f] [1,4] oxazebin-18-caproluconic acid-10-oxoxy Get de. Example 9

 Free radical capture test:

 Using the Phenton reaction, which is known as a free radical generating system, the present compounds were examined for their ability to capture free radicals. That is, in a pentane reaction system using divalent iron ion and hydrogen peroxide, and using methanol as a solvent, the methanol radical is obtained as shown in the following equation. It is known that cal ('CH, OH) is formed [eg Tetrahedron Lett .. 7 7 5-7 7 8

(Refer to (1977)). However, this metabolic radical has a short life and cannot be directly measured by the ESR method.

F e ₂ + + H, 0 ² → F e ₅ ⁺ + 0 H "+ · Ο Η

C Η, 0 Η +-0 Η → C Η ₂₀ 0 Η + Η: 0 However, if a compound acting as a spin-trapping agent is present in the system, it will trap methanol radicals and form spin-ducts. Then, it becomes possible to measure by the ESR method.

 By utilizing this principle, it is determined whether or not the compound of the present invention has a spin trapping ability and, consequently, a radical scavenging ability, by performing a phenton reaction to generate a radical. As a source, X-NO, and ESR were used and investigated as follows.

 [Preparation of reagents]

 (1) Samples ①

 9.8 M hydrogen peroxide solution (commercially available 30% hydrogen peroxide solution is used)

 (2) Samples ②

 6.8 mM ferrous chloride solution (using 6.8 mg ferrous chloride tetrahydrate dissolved in 5 ml methanol)

 (3) Sample liquid

 11-Methyldibenzo [b, f] [1,4] oxazebin obtained in Example 1 10—The amount of oxamide of 38 mM was measured in methanol 5 Dissolve in aliquot ml and use as sample liquid a.

 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.

The amount of 11-phenyldibenzo [b, f] [1,4] oxazebin obtained in Example 4 was adjusted to 38 mM of 10-oxoxide in 5 ml of methanol. And dissolve it in Sample Solution d. [Measurement of ESR spectrum of sample]

 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.

 Add the sample (1) 101, the sample (yes b) 7401 and the sample (2) 250-1 to a glass tube and stir to obtain a reaction solution B.

 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).

 Add 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.

 The reaction solutions A, B, C and D were each absorbed into a separate flat cell (manufactured by Robotec), and the ESR spectrum was measured.

 [Measurement of control ESR spectrum]

 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.

 [Measurement conditions of ESR spectrum]

 ESR was measured under the following conditions.

 Measuring device: Electronic spinning device [JES-REIX (manufactured by Nihon Denshi)]

 External magnetic field 3 34.5 ± 5 mT

 Magnetic field change parent 1 0 0 kHz

 Magnetic field modulation width: 0.1 mT

 Time constant: 0.1 second

 Micro wave output: 5 mW

 Sweep time: 2 minutes

Measurement temperature: Room temperature [Result]

 The ESR spectra of Reaction Solutions A, B, C and D are shown in FIGS. 1, 2, 3 and 4. Figure 5 shows the ESR spectrum of the control solution. As is evident from the results, it was confirmed that the test compound of the present invention was prepared by using 11-methyldibenzo [b, f] [1,4] oxazebin-10-oxide,

1 1-Ethyl dipenza [b, f] [1,4] Oxazebin 1 0 — Oxide, 1 1 1 n — Propinoresinzo [b, f] [1,4] Oxazebin 10-Oxide and 11-phenyldibenzo [b, f] [1,4] Oxazebin 10-Oxide A signal was obtained, but no signal was obtained in the control.

From the above, it was confirmed that the compound of the present invention effectively captured free radicals (metanol radical, -CH ₂ OH). Industrial applicability

 The compound of the present invention captures free radicals in a living body, and the resulting spin-duct has sufficient stability.

 Further, since free radicals generated in the living body are considered to cause diseases such as cerebral ischemia, heart disease, digestive disease, cancer, aging, and inflammation, the compound of the present invention is used. Can be used as preventive and therapeutic agents for these diseases.

 In addition, by using the compound of the present invention, 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.

Claims

 The scope of the claims

1. The following equation (I),

(Wherein, R, is a hydrogen atom, a is force Rupoki Sill group or lower alk breath imposes Le Poni Le group, R, is shows the lower alkyl group or a full e alkenyl group, R ₃ Contact And R, respectively, are a hydrogen atom, a halogen atom, an amino group, a nitro group, a cyano group, a hydroxyl group, a lower alkoxycarbonyl group, (Indicates lower alkoxy group, hydroxy group, lower alkyl group or phenyl group.)

A dibenzoxazebine-1N-oxide derivative represented by the formula:

2. The following equation (II),

 (II)

(Wherein, R, R ₂ , R ₃ and R, have the meaning described above)

The following formula (I) is characterized in that the dibenzoxazebine derivative represented by R, N:

, 〇 ノ

 (i)

(Wherein, R, R ₂ , R ₃ and R <have the above-mentioned meanings)

A method for producing a dibenzoxazebine-1N-oxide derivative represented by the following formula (I)

(Wherein, R, R ₂ , R ₃ and R, have the meaning described above)

A pharmaceutical comprising, as an active ingredient, a dibenzoxazebine-1N-oxide derivative represented by the following formula:

4. The pharmaceutical according to claim 3, which is a free radical scavenger.

5. The medicament according to claim 3 or 4, which is an agent for preventing or treating cerebral ischemia, heart disease, gastrointestinal disease, cancer, aging or inflammation.

6. The medicament according to claim 3 or 4, which is an agent for detecting free radicals.