WO2011052759A1 - Novel nitroxyl radical compound and process for production thereof - Google Patents

Novel nitroxyl radical compound and process for production thereof Download PDF

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WO2011052759A1
WO2011052759A1 PCT/JP2010/069385 JP2010069385W WO2011052759A1 WO 2011052759 A1 WO2011052759 A1 WO 2011052759A1 JP 2010069385 W JP2010069385 W JP 2010069385W WO 2011052759 A1 WO2011052759 A1 WO 2011052759A1
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内海英雄
酒井浄
山田健一
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国立大学法人九州大学
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/34—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/20—Spiro-condensed ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/20—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/20—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D495/20—Spiro-condensed systems

Definitions

  • the present invention relates to a 2,6-position substituted piperidine nitroxyl radical and a novel synthesis method thereof.
  • Nitroxyl radicals are known as relatively stable radicals, but they react sensitively to various active oxygen and redox substances, so that the effects of nitroxyl radicals on various diseases involving free radicals are reduced. Expected.
  • nitroxyl radicals have been reported to react with ascorbic acid, thiols (metal-catalyzed reactions), mitochondrial respiratory chain, NADPH, cytochrome P450, and the like in cells, inducing apoptosis and via cytochrome P450. It has been reported that production of H 2 O 2 and the like cause cytotoxicity.
  • nitroxyl radicals having a tetraethyl group have been reported to have a significantly reduced reactivity with ascorbic acid.
  • the conventional method has many reaction steps and is complicated, and therefore, there is a problem that the yield of 2,6-substituted nitroxy radical is very low.
  • development of a method for synthesizing a nitroxy radical in which various substituents are introduced into the 2,6-positions in a simple and high yield is desired.
  • the inventors have conducted various studies in order to solve the above problems, and as a result, have developed a simple and high-yield synthesis method for 2,6-position substituted piperidine-based nitroxyl radicals. Furthermore, when the effectiveness of the nitroxyl radical obtained by the production method was examined, it was revealed that it has a gastric mucosal damage suppressing effect and a blood pressure lowering effect in an adjuvant arthritis model rat.
  • a feature of the present invention is that a 2,6-substituted piperidine having an alkyl group such as a methyl group on a nitrogen atom is used.
  • 1,2,2,6,6-pentamethylpiperidin-4-one having a methyl group on nitrogen is used, it is remarkable compared to 2,2,6,6-tetramethylpiperidin-4-one An increase in yield and a reaction promoting effect were observed. Therefore, in this reaction, it is most important to use a piperidine compound in which an alkyl group such as a methyl group is substituted on nitrogen as a starting material.
  • Examples of the ketone used in the production method of the present application include cyclic / chain carbonyl compounds such as cyclohexanone, pyran ring, thiopyran ring, acetaminophen, and benzaldehyde.
  • Table 2 shows specific carbonyl compounds and corresponding products (piperidone).
  • the carbonyl compound having a cyclic structure and the linear carbonyl compound have different selectivity for the pyrrolidone product. That is, when a carbonyl compound having a ring structure is used as a raw material, a disubstituted product is obtained as a main product, whereas when a linear carbonyl compound is used as a raw material, a monosubstituted product is mainly used. Obtained as product. In the case of a carbonyl compound having a phenyl group, a mono-substituted product is selectively obtained. Furthermore, when 2-adamantanone is used as the carbonyl compound, both mono- and di-substituted products are obtained.
  • ammonium chloride is used as the base used in the production step of the piperidone derivative, but is not limited thereto.
  • the oxidation of piperidone derivatives to nitroxy radical derivatives generally uses a tungsten catalyst and hydrogen peroxide, but is not limited thereto.
  • MCPBA is used for oxidation to the 2,6-positioned adamantane-substituted nitroxyl radical.
  • the ESR parameter was calculated by dissolving the nitroxy radical derivative obtained by the production method of the present invention in 10 mM PB (pH 7.4) (50 ⁇ M) and measuring at room temperature. However, 12 contains 0.5% EtOH from the viewpoint of solubility. The results are shown in the table below.
  • the method is A compound represented by Formula 2,
  • R 5 to R 8 are independently a compound represented by Formula 2, which is C 1 -C 20 alkyl; A compound represented by Formula 3,
  • a compound produced by the above production method is provided.
  • the compound can be used for the treatment of gastric mucosal damage (gastric ulcer) or hypertension.
  • a pharmaceutical composition comprising the above compound and a pharmaceutically acceptable carrier.
  • a method for treating gastric mucosal damage comprising the step of administering the compound to a subject, and treating hypertension
  • a method comprising the step of administering the compound to a subject.
  • the compound is preferably administered in an amount of about 0.0001-4 g / day.
  • gastric mucosal damage when the compound is 18 mM, it can be administered at a dose of 90 ⁇ mol / kg.
  • FIG. 1 is a graph showing the evaluation of cytotoxicity of a nitroxyl radical compound according to an embodiment of the present invention.
  • FIG. 2 is a graph showing the effect of the nitroxyl radical compound according to one embodiment of the present invention on the gastric mucosa.
  • FIG. 3 is a graph showing the effect of a nitroxyl radical compound according to an embodiment of the present invention on blood pressure fluctuations.
  • Reagents were purchased from Sigma-Aldrich, Wako Pure Chemical Industries, Ltd. and used without purification.
  • the melting point was measured using a micro melting point measuring device MP-500P (Yanaco).
  • Mass spectrometry was measured with JMS-600H (JEOL), and 3-nitrobenzyl alcohol was used as a matrix.
  • the IR spectrum was measured by a solution method or a total reflection method using FT / IR-4200 (JASCO).
  • 1 H-NMR was measured using Unity INOVA 400 (Varian), and tetramethylsilane (TMS) was used as a standard substance.
  • the chemical shift ( ⁇ ) was based on TMS (0 ppm), and the coupling constant was expressed in Hz. Elemental analysis was requested from Kyushu University Faculty of Science, Central Elemental Analysis Laboratory.
  • Method B 1.69 g (10 mmol) of 1,2,2,6,6-pentamethylpiperidin-4-one (2) and 2.94 g (30 mmol) of cyclohexanone (a) were dissolved in 15 ml of DMSO, and 3.21 g (60 mmol) of NH 4 Cl. ) was added at room temperature. The solution was stirred at 60 ° C. for 5 hours. The reaction mixture was diluted by adding 40 mL of water and acidified with 7% aqueous hydrochloric acid. This was washed with ether and the aqueous layer was made alkaline with 10% K 2 CO 3 aqueous solution.
  • Methyl 3- (2,6,6-trimethyl-4-oxopiperidin-2-yl) propanoate (3g) According to Method B, cyclohexanone was changed to methyl levulinate (g). This compound has been obtained as a mixture with a disubstituted product and has not yet been isolated. The structure was identified by methyl 3- (2,6,6-trimethyl-4-oxoperidin-1-oxyl-2-yl) propanoate (4 g) obtained by oxidizing 3 g.
  • 2,2-dimethyl-6,6-dipropyl-4-oxo-piperidin-1-yl 1-oxyl (4) According to Method A, 2,2-dimethyl-6,6-dipropyliperidin-4-one (3) 59 mg (0.28 mmol) was used as a starting material. The reaction solution was stirred overnight at room temperature. Moreover, the progress of the reaction was confirmed by TLC, and H 2 O 2 and Na 2 WO 4 ⁇ 2H 2 O were appropriately added. After extraction, the product was purified by silica gel column chromatography (hexane, ethyl acetate) to obtain 38 mg (yield: 60%) of an orange oily substance.
  • 2,2-dibutyl-6,6-dimethyl-4-oxo-piperidin-1-yl 1-oxyl (6) According to Method A, 2,2-dibutyl-6,6-dimethylpiperidin-4-one (5) 100 mg (0.42 mmol) was used as a starting material. The reaction solution was stirred overnight at room temperature. Moreover, the progress of the reaction was confirmed by TLC, and H 2 O 2 and Na 2 WO 4 ⁇ 2H 2 O were appropriately added. After extraction, the product was purified by silica gel column chromatography (hexane, ethyl acetate) to obtain 53 mg (yield: 50%) of an orange oily substance.
  • 2-butyl-2,6,6-trimethyl-4-oxo-piperidin-1-yl 1-oxyl (8) According to Method A, 2-butyl-2,6,6-trimethylpiperidin-4-one (7) (199 mg, 1.01 mmol) was used as a starting material. The reaction solution was stirred overnight at room temperature. Moreover, the progress of the reaction was confirmed by TLC, and H 2 O 2 and Na 2 WO 4 ⁇ 2H 2 O were appropriately added. After extraction, the residue was purified by silica gel column chromatography (hexane / ethyl acetate, 95: 5) to obtain 68 mg (yield: 32%) of an orange oily substance.
  • 2,6-dibutyl-2,6-dimethyl-4-oxo-piperidin-1-yl-oxyl 10
  • 2,6-dibutyl-2,6-dimethylpiperidin-4-one 9 77 mg (0.32 mmol) was used as a starting material.
  • the reaction solution was stirred overnight at room temperature.
  • the progress of the reaction was confirmed by TLC, and H 2 O 2 and Na 2 WO 4 ⁇ 2H 2 O were appropriately added.
  • the product was purified by silica gel column chromatography (hexane, ethyl acetate) to obtain 25 mg (yield: 31%) of an orange oily substance.
  • 2,2,6-trimethyl-6-octyl-4-oxo-piperidin-1-yl 1-oxyl 12
  • 2,2,6-trimethyl-6-octipeliperidin-4-one (11) 100 mg (0.39 mmol) was used as a starting material.
  • the reaction solution was stirred overnight at room temperature.
  • the progress of the reaction was confirmed by TLC, and H 2 O 2 and Na 2 WO 4 ⁇ 2H 2 O were appropriately added.
  • the product was purified by silica gel column chromatography (hexane, ethyl acetate) to obtain 78 mg (yield: 74%) of an orange oily substance.
  • Cytotoxic nitroxyl radicals have been reported to react with ascorbic acid, thiols (metal-catalyzed reactions), mitochondrial respiratory chain, NADPH, cytochrome P450, etc. in cells, inducing apoptosis and via cytochrome P450 It has been reported that production of H 2 O 2 and the like cause cytotoxicity.
  • the present inventors have reported that the reactivity with the ascorbic acid of the nitroxyl radical having a tetraethyl group is significantly reduced. Therefore, the cytotoxicity of the synthesized nitroxyl radical compound was evaluated.
  • HUVEC human umbilical vein endothelial cells
  • a CO 2 incubator at 37 ° C. under 5% CO 2 using Brett Kit EGM as a medium.
  • HUVEC were subcultured at regular intervals to maintain a logarithmic growth phase, and the period between 2 and 5 passages was used for the experiment.
  • HUVEC 5000 cells / well
  • Mycobacterium tuberculosis H37 RA was ground in an agate mortar, and heavy minor oil was added dropwise thereto, and further ground to 10 mg / ml.
  • This tuberculosis-killed oil suspension was sonicated for 3 minutes and then taken into a 1 ml syringe, and 100 ⁇ L was administered into the left footpad of a 5-week-old DA rat under isoflurane anesthesia to induce adjuvant arthritis.
  • In the negative control group only heavy mineral oil was administered into the left footpad.
  • DA rats were fasted in the breeding cage on day 13 after administration of the adjuvant. However, drinking water was free drinking.
  • indomethacin (20 mg / kg) was orally administered to rats to create gastric ulcers.
  • the same amount of 5% NaHCO 3 was orally administered as a vehicle.
  • the nitroxyl radical compound was orally administered 5 minutes before administration of indomethacin.
  • Tempol (see FIG. 2), a known nitroxyl radical compound, shows an inhibitory action at a concentration of 900 ⁇ mol / kg, but the nitroxyl radical compound synthesized according to the present invention (compounds A and B in FIG. 2). ) was also shown to have significant inhibitory action on gastric mucosal damage at a concentration of up to 1/10 compared to Tempol, and it became clear that it showed an inhibitory effect at a lower concentration than known compounds .
  • TEMPO-based nitroxyl radical compounds such as Tempol, a blood pressure lowering action of nitroxyl radical, have a blood pressure lowering action and are widely used in hypertension research. Although the cause of the blood pressure lowering action has not yet been clarified, it is considered that it is due to the ability to scavenge active oxygen because it has a correlation with the SOD-like action. Therefore, we clarify the blood pressure lowering action of the newly synthesized nitroxyl radical compound.
  • FIG. 3 shows changes in blood pressure over time after administration of the nitroxyl radical compound.
  • the blood pressure lowering action exhibited by the newly developed nitroxyl radical compound (compound C) was significantly higher than that of Tempol, which is a known nitroxyl radical compound.
  • the duration of the blood pressure lowering action lasts for a long time when the novel nitroxyl compound (Compound C) is compared with Tempol.

Abstract

Disclosed are: a process for producing a novel nitroxyl radical; and the compound. The nitroxyl radical produced by the process has a therapeutic effect on gastric ulcer and hypertension.

Description

新規ニトロキシルラジカル化合物及びその製造方法Novel nitroxyl radical compound and method for producing the same
　本出願は、２００９年１０月２９日付出願の米国仮出願第６１／２５６，１８４号に対して優先権を主張するものであり、前記仮出願の開示内容はすべて、本願発明に組み込まれるものである。 This application claims priority to US Provisional Application No. 61 / 256,184, filed Oct. 29, 2009, the entire disclosure of which is incorporated herein. is there.
　本発明は、２，６位置換ピペリジン系ニトロキシルラジカル及びその新規合成法に関する。 The present invention relates to a 2,6-position substituted piperidine nitroxyl radical and a novel synthesis method thereof.
　ニトロキシルラジカルは、比較的安定なラジカルとして知られているが、種々の活性酸素や酸化還元物質に対して鋭敏に反応することから、フリーラジカルが関与する様々な疾患に対するニトロキシルラジカルの効果が期待されている。 Nitroxyl radicals are known as relatively stable radicals, but they react sensitively to various active oxygen and redox substances, so that the effects of nitroxyl radicals on various diseases involving free radicals are reduced. Expected.
　フリーラジカルが関与する疾患は、疾患の原因となるフリーラジカル種が異なるため、特定の疾患に特異的に働く有効なラジカル補足種が望まれている。これまでの研究により、ニトロキシルラジカルの基本骨格や側鎖の違いにより、その反応性が異なることが知られている（Ｆ．Ｖｉａｎｅｌｌｏ，ｅｔ　ａｌ．，Ｋｉｎｅｔｉｃｓ　ｏｆ　ｎｉｔｒｏｘｉｄｅ　ｓｐｉｎ　ｌａｂｅｌ　ｒｅｍｏｖａｌ　ｉｎ　ｂｉｏｌｏｇｉｃａｌ　ｓｙｓｔｅｍｓ：Ａｎ　ｉｎ　ｖｉｔｒｏ　ａｎｄ　ｉｎ　ｖｉｖｏ　ＥＳＲ　ｓｔｕｄｙ．Ｍａｇｎ　Ｒｅｓｏｎ　Ｉｍａｇ，　１９９５．１３（２）：２１９－２２６．；Ｗ．Ｒ．Ｃｏｕｅｔ，ｅｔ　ａｌ．，Ｉｎｆｌｕｅｎｃｅ　ｏｆ　ｃｈｅｍｉｃａｌ　ｓｔｒｕｃｔｕｒｅ　ｏｆ　ｎｉｔｒｏｘｙｌ　ｓｐｉｎ　ｌａｂｅｌｓ　ｏｎ　ｔｈｅｉｒ　ｒｅｄｕｃｔｉｏｎ　ｂｙ　ａｓｃｏｒｂｉｃ　ａｃｉｄ．　Ｔｅｔｒａｈｅｄｒｏｎ，　１９８５．４１（７）：１１６５－１１７２．；Ｋ．　Ｔａｋｅｓｈｉｔａ，　ｅｔ　ａｌ．，　Ｋｉｎｅｔｉｃ　ｓｔｕｄｙ　ｏｎ　ＥＳＲ　ｓｉｇｎａｌ　ｄｅｃａｙ　ｏｆ　ｎｉｔｒｏｘｙｌ　ｒａｄｉｃａｌｓ，ｐｏｔｅｎｔ　ｒｅｄｏｘ　ｐｒｏｂｅｓ　ｆｏｒ　ｉｎ　ｖｉｖｏ　ＥＳＲ　ｓｐｅｃｔｒｏｓｃｏｐｙ，ｃａｕｓｅｄ　ｂｙ　ｒｅａｃｔｉｖｅ　ｏｘｙｇｅｎ　ｓｐｅｃｉｅｓ．Ｂｉｏｃｈｉｍ　Ｂｉｏｐｈｙｓ　Ａｃｔａ，２００２．１５７３（２）：１５６－６４．）。例えば、ニトロキシルラジカルは、細胞内で、アスコルビン酸やチオール（金属が触媒する反応）、ミトコンドリア呼吸鎖、ＮＡＤＰＨ、シトクロムＰ４５０などと反応することが報告され、アポトーシスの誘発や、シトクロムＰ４５０を介したＨ２Ｏ２の産生などが細胞毒性の原因となっていると報告されている。一方、テトラエチル基を有するニトロキシルラジカルは、アスコルビン酸との反応性が顕著に低下していることが報告されている。 Diseases involving free radicals are different in free radical species that cause the disease, and therefore, effective radical scavenging species that specifically act on specific diseases are desired. It is known that the reactivity differs depending on the basic skeleton and side chain of the nitroxyl radical according to previous studies (F. Vianello, et al., Kinetics of nitroxide spin label removal in biological systems: An in vitro and in vivo ESR study.Magn Reson Imag, 1995.13 (2): 219-226 .; WR Couette, et al., Inflation of chemical structure of sci- tives in vitro. 1985.41 (7): 1165-1172; . Eshita, et al, Kinetic study on ESR signal decay of nitroxyl radicals, potent redox probes for in vivo ESR spectroscopy, caused by reactive oxygen species.Biochim Biophys Acta, 2002.1573 (2): 156-64).. For example, nitroxyl radicals have been reported to react with ascorbic acid, thiols (metal-catalyzed reactions), mitochondrial respiratory chain, NADPH, cytochrome P450, and the like in cells, inducing apoptosis and via cytochrome P450. It has been reported that production of H 2 O 2 and the like cause cytotoxicity. On the other hand, nitroxyl radicals having a tetraethyl group have been reported to have a significantly reduced reactivity with ascorbic acid.
　近年、イソインドリン骨格のニトロキシルラジカルのα位の置換基をエチル基にすることによって、ＴＥＭＰＯと比較して、ｐ－フェニレンジアミン（Ｎ．Ｋｏｃｈｅｒｇｉｎｓｋｙ　ａｎｄ　Ｈ．Ｍ．Ｓｗａｒｔｚ，Ｃｈｅｍｉｃａｌ　ｒｅａｃｔｉｖｉｔｙ　ｏｆ　ｎｉｔｒｏｘｉｄｅｓ，ｉｎ　Ｎｉｔｒｏｘｉｄｅ　Ｓｐｉｎ　Ｌａｂｅｌｓ：Ｒｅａｃｔｉｏｎｓ　ｉｎ　Ｂｉｏｌｏｇｙ　ａｎｄ　Ｃｈｅｍｉｓｔｒｙ，Ｎ．Ｋｏｃｈｅｒｇｉｎｓｋｙ　ａｎｄ　Ｈ．Ｍ．Ｓｗａｒｔｚ，Ｅｄｉｔｏｒｓ．１９９５，ＣＲＣ　Ｐｒｅｓｓ：　Ｂｏｃａ　Ｒａｔｏｎ．ｐ．２７－６６．）やアスコルビン酸（Ｌ．　Ｍａｒｘ，ｅｔ　ａｌ．，Ａ　ｃｏｍｐａｒａｔｉｖｅ　ｓｔｕｄｙ　ｏｆ　ｔｈｅ　ｒｅｄｕｃｔｉｏｎ　ｂｙ　ａｓｃｏｒｂａｔｅ　ｏｆ　１，１，３，３－ｔｅｔｒａｅｔｈｙｌｉｓｏｉｎｄｏｌｉｎ－２－ｙｌｏｘｙｌ　ａｎｄ　ｏｆ　１，１，３，３－ｔｅｔｒａｍｅｔｈｙｌｉｓｏｉｎｄｏｌｉｎ－２－ｙｌｏｘｙｌ．　Ｊ　Ｃｈｅｍ　Ｓｏｃ，　Ｐｅｒｋｉｎ　Ｔｒａｎｓ　１，２０００：１１８１．）による還元に対して抵抗性が増すことが報告されている。また、イミダゾール骨格のニトロキシルラジカルのα位の炭素をエチル基に置換したものが、アスコルビン酸に対して還元抵抗性を示すことが報告されている（Ａ．Ａ．Ｂｏｂｋｏ，ｅｔ　ａｌ．，Ｒｅｖｅｒｓｉｂｌｅ　ｒｅｄｕｃｔｉｏｎ　ｏｆ　ｎｉｔｒｏｘｉｄｅｓ　ｔｏ　ｈｙｄｒｏｘｙｌａｍｉｎｅｓ：ｒｏｌｅｓ　ｆｏｒ　ａｓｃｏｒｂａｔｅ　ａｎｄ　ｇｌｕｔａｔｈｉｏｎｅ．Ｆｒｅｅ　Ｒａｄｉｃ　Ｂｉｏｌ　Ｍｅｄ，２００７．４２（３）：４０４－１２．）。このように、ニトロキシルラジカルのα位の置換基を変えることによって、様々な物質に対する反応性を制御できると考えられる。 In recent years, p-phenylenediamine (N. Kocherginsky and HM Swartz, Chemical reactivity of nitroxides, in, compared with TEMPO by replacing the α-position substituent of the nitroxyl radical of the isoindoline skeleton with an ethyl group. Nitroxide Spin Labels: Reactions in Biology and Chemistry, N. Kocherginsky and HM Swartz, Editors. 1995, CRC Press: Boca Raton.p.27.66. competitive study of the reduction by as resistance to reduction by orbate of 1,1,3,3-tetraethylindolinin-2-yloxyl and of 1,1,3,3-tetramethylisoindolinin-2-yloxyl.J Chem Soc, Perkin Trans 1,2000: 1181.) It has been reported that it increases. In addition, it has been reported that a substance in which the carbon at the α-position of the nitroxyl radical of the imidazole skeleton is substituted with an ethyl group exhibits reduction resistance against ascorbic acid (AA Bobko, et al., Reverseable). reduction of nitroxides to hydroxylamines: roles for ascorbate and glutathione.Free Radic Biol Med, 2007.42 (3): 404-12.). Thus, it is thought that the reactivity with respect to various substances can be controlled by changing the substituent at the α-position of the nitroxyl radical.
　２，６位置換ニトロキシルラジカルの従来の合成法を下記に示す。 The conventional synthesis method of the 2,6-position substituted nitroxyl radical is shown below.
Figure JPOXMLDOC01-appb-C000009
Figure JPOXMLDOC01-appb-C000009
　図に示すように、従来法は、反応ステップが多く煩雑であり、そのため２，６位置換ニトロキシラジカルの収率が非常に低いという課題が挙げられる。この課題を解決するために、簡便かつ高収率で２，６位に様々な置換基を導入するニトロキシラジカルの合成法の開発が望まれている。 As shown in the figure, the conventional method has many reaction steps and is complicated, and therefore, there is a problem that the yield of 2,6-substituted nitroxy radical is very low. In order to solve this problem, development of a method for synthesizing a nitroxy radical in which various substituents are introduced into the 2,6-positions in a simple and high yield is desired.
　また、当該発明者により開発されたニトロキシラジカルの製造方法が、国際特許公開第ＷＯ２００８／０９３８８１号に開示されており、本特許出願は、この参照により本願明細書に組み込まれるものである。 Also, a method for producing a nitroxy radical developed by the inventor is disclosed in International Patent Publication No. WO2008 / 093881, and this patent application is incorporated herein by this reference.
　発明者らは、上記課題を解決するために、様々な検討を重ねた結果、２，６位置換ピペリジン系ニトロキシルラジカルの簡便且つ高収率合成方法を開発した。さらに、当該製造方法により得られたニトロキシルラジカルの有効性を検討したところ、アジュバンド関節炎モデルラットにおける胃粘膜損傷抑制効果、並びに血圧降下作用を有することが明らかとなった。 The inventors have conducted various studies in order to solve the above problems, and as a result, have developed a simple and high-yield synthesis method for 2,6-position substituted piperidine-based nitroxyl radicals. Furthermore, when the effectiveness of the nitroxyl radical obtained by the production method was examined, it was revealed that it has a gastric mucosal damage suppressing effect and a blood pressure lowering effect in an adjuvant arthritis model rat.
　当該発明方法によると、１，２，２，６，６－ペンタアルキルピペリジン－４－オンを出発原料として、アンモニウム塩の存在下、カルボニル化合物を反応させると、２及び６位が置換されたピペリドンが生成され、更に、この化合物を酸化することにより、２及び６位が置換されたニトロキシラジカルが得られる。 According to the method of the present invention, when 1,2,2,6,6-pentaalkylpiperidin-4-one is used as a starting material and a carbonyl compound is reacted in the presence of an ammonium salt, piperidone substituted at the 2- and 6-positions Further, by oxidizing this compound, a nitroxy radical substituted at the 2- and 6-positions can be obtained.
　本願発明の特徴としては、窒素原子上にメチル基などのアルキル基を有する、２，６置換ピペリジンを用いることである。窒素上にメチル基を有する１，２，２，６，６－ペンタメチルピペリジン－４－オンを用いた場合、２，２，６，６－テトラメチルピペリジン－４－オンと比べて、顕著な収率の上昇並びに反応促進効果が見られた。従って、当該反応は、窒素上にメチル基などのアルキル基が置換されているピペリジン化合物を出発物質として用いることが最も重要である。 A feature of the present invention is that a 2,6-substituted piperidine having an alkyl group such as a methyl group on a nitrogen atom is used. When 1,2,2,6,6-pentamethylpiperidin-4-one having a methyl group on nitrogen is used, it is remarkable compared to 2,2,6,6-tetramethylpiperidin-4-one An increase in yield and a reaction promoting effect were observed. Therefore, in this reaction, it is most important to use a piperidine compound in which an alkyl group such as a methyl group is substituted on nitrogen as a starting material.
Figure JPOXMLDOC01-appb-T000010
Figure JPOXMLDOC01-appb-T000010
　本願製造方法に使用される前記ケトンとしては、例えば、シクロヘキサノン、ピラン環、チオピラン環、アセトアミノフェンなどの環状・鎖状カルボニル化合物やベンズアルデヒドなどが用いられる。 Examples of the ketone used in the production method of the present application include cyclic / chain carbonyl compounds such as cyclohexanone, pyran ring, thiopyran ring, acetaminophen, and benzaldehyde.
　具体的なカルボニル化合物と対応する生成物（ピペリドン）を表２に示す。 Table 2 shows specific carbonyl compounds and corresponding products (piperidone).
Figure JPOXMLDOC01-appb-T000011
Figure JPOXMLDOC01-appb-T000011
Figure JPOXMLDOC01-appb-T000012
Figure JPOXMLDOC01-appb-T000012
　上記表から明らかなように、環状構造を有するカルボニル化合物と、直鎖状カルボニル化合物では、ピロリドン生成物に対して異なる選択性が見られる。つまり、環構造を有するカルボニル化合物を原料として用いた場合、二置換体が主生成物として得られるのに対して、直鎖状のカルボニル化合物を原料として用いた場合には、一置換体が主生成物として得られる。また、フェニル基をもつカルボニル化合物の場合では、一置換体が選択的に得られる。さらに、２－アダマンタノンをカルボニル化合物として用いた場合、一置換体と二置換体の両方が得られる。 As is apparent from the above table, the carbonyl compound having a cyclic structure and the linear carbonyl compound have different selectivity for the pyrrolidone product. That is, when a carbonyl compound having a ring structure is used as a raw material, a disubstituted product is obtained as a main product, whereas when a linear carbonyl compound is used as a raw material, a monosubstituted product is mainly used. Obtained as product. In the case of a carbonyl compound having a phenyl group, a mono-substituted product is selectively obtained. Furthermore, when 2-adamantanone is used as the carbonyl compound, both mono- and di-substituted products are obtained.
　上述したように、ケトンの立体構造により、ピぺリドン誘導体生成物に対する一置換体及び二置換体の選択性が異なること、並びに、ＮＨ４Ｃｌを１５ＮＨ４Ｃｌに変えてＴＥＭＰＯＮＥを出発物質に用いて当該発明を行うと、［１５Ｎ］ＴＥＭＰＯＮＥが得られることなどから、以下のスキームで示される反応機構が推測される。 As described above, the selectivity of mono- and di-substituents with respect to the piperidone derivative product varies depending on the steric structure of the ketone, and TEMPONE is changed from NH 4 Cl to 15 NH 4 Cl. When the invention is carried out using the above, the reaction mechanism shown in the following scheme is presumed because [ 15 N] TEMPONE is obtained.
Figure JPOXMLDOC01-appb-C000013
Figure JPOXMLDOC01-appb-C000013
　当該発明の製造方法において、ピぺリドン誘導体の生成工程において用いられる塩基は、塩化アンモニウムが使用されるが、これに限られるものではない。 In the production method of the present invention, ammonium chloride is used as the base used in the production step of the piperidone derivative, but is not limited thereto.
　また、塩化アンモニウムと共に、水酸化セシウム（ＣｓＯＨ）、又はベンジルトリメチルアンモニウムヒドロキシド（トリトンＢ）を用いた場合、収率の向上が見られる。 In addition, when cesium hydroxide (CsOH) or benzyltrimethylammonium hydroxide (Triton B) is used together with ammonium chloride, the yield is improved.
　ピぺリドン誘導体からニトロキシラジカル誘導体への酸化は、一般に、タングステン触媒と過酸化水素が用いられるが、これに限られるものではない。２，６位アダマンタン置換ニトロキシルラジカルへの酸化には、ＭＣＰＢＡが用いられる。 The oxidation of piperidone derivatives to nitroxy radical derivatives generally uses a tungsten catalyst and hydrogen peroxide, but is not limited thereto. MCPBA is used for oxidation to the 2,6-positioned adamantane-substituted nitroxyl radical.
　当該発明の製造方法により得られるニトロキシラジカル誘導体を、１０ｍＭ　ＰＢ（ｐＨ７．４）に溶解し（５０μＭ）、室温下測定することで、ＥＳＲパラメーターを算出した。ただし、溶解性の点から、１２は０．５％ＥｔＯＨを含む。結果を下記表に示した。 The ESR parameter was calculated by dissolving the nitroxy radical derivative obtained by the production method of the present invention in 10 mM PB (pH 7.4) (50 μM) and measuring at room temperature. However, 12 contains 0.5% EtOH from the viewpoint of solubility. The results are shown in the table below.
Figure JPOXMLDOC01-appb-T000014
Figure JPOXMLDOC01-appb-T000014
Figure JPOXMLDOC01-appb-T000015
Figure JPOXMLDOC01-appb-T000015
Figure JPOXMLDOC01-appb-T000016
Figure JPOXMLDOC01-appb-T000016
　本発明の一実施形態によると、当該発明は、化学式１で示されるニトロキシラジカル化合物の製造方法であって、
Figure JPOXMLDOC01-appb-C000017
 　式中、
　Ｒ１～Ｒ４は、独立して、Ｃ１～Ｃ１０のアルキルであるか、或いは、Ｒ１及びＲ２、又はＲ３及びＲ４が共に結合して、（ＣＨ２）ｎ、（ＣＨ２）ｎＯ（ＣＨ２）ｎ、（ＣＨ２）ｎＳＯ２（ＣＨ２）ｎ、（ＣＨ２）ｎＮＸ（ＣＨ２）ｎ、（ＣＨ２）ｎＣＹ（ＣＨ２）ｎ、
　Ｘは、ＣＨ３ＣＯ、ＣＦ３ＣＯ、又はＲ１ＣＯであり、
　Ｙは、酸素（＝Ｏ）、（ＯＣＨ２）ｎであり、
　ｎは２～４の整数であり、
　当該方法は、
　化学式２で示される化合物であって、
Figure JPOXMLDOC01-appb-C000018
 According to one embodiment of the present invention, the present invention is a method for producing a nitroxy radical compound represented by Formula 1,
Figure JPOXMLDOC01-appb-C000017
 Where
R 1 to R 4 are independently C 1 to C 10 alkyl, or R 1 and R 2 , or R 3 and R 4 are bonded together to form (CH 2 ) n , (CH 2) n O (CH 2) n, (CH 2) n SO 2 (CH 2) n, (CH 2) n NX (CH 2) n, (CH 2) n CY (CH 2) n,
X is CH 3 CO, CF 3 CO, or R 1 CO;
Y is oxygen (= O), a (OCH 2) n,
n is an integer from 2 to 4,
The method is
A compound represented by Formula 2,
Figure JPOXMLDOC01-appb-C000018
　式中、
　Ｒ５～Ｒ８は、独立して、Ｃ１～Ｃ２０のアルキルである、化学式２で示される化合物と、
　化学式３で示される化合物であって、
Figure JPOXMLDOC01-appb-C000019
 Where
R 5 to R 8 are independently a compound represented by Formula 2, which is C 1 -C 20 alkyl;
A compound represented by Formula 3,
Figure JPOXMLDOC01-appb-C000019
　式中、
　Ｒ１～Ｒ４は、独立して、Ｃ１～Ｃ１０のアルキル、Ｒ１及びＲ２、又はＲ３及びＲ４が共に結合して、（ＣＨ２）ｎ、（ＣＨ２）ｎＯ（ＣＨ２）ｎ、（ＣＨ２）ｎＳ（ＣＨ２）ｎ、（ＣＨ２）ｎＮＸ（ＣＨ２）ｎ、（ＣＨ２）ｎＣＹ（ＣＨ２）ｎ、
　Ｘは、ＣＨ３ＣＯ、ＣＦ３ＣＯ、又はＲ１ＣＯであり、
　Ｙは、酸素（＝Ｏ）、（ＯＣＨ２）ｎであり、
　ｎは２～４の整数である、化学式３で示される化合物と
　をアンモニウム塩の存在下にて反応させることにより、２，６置換－４－ピペリドン誘導体を生成させる工程と、
　前記２，６置換－４－ピペリドン誘導体を酸化させる工程と、
　を有する、前記ニトロキシラジカル化合物の製造方法が提供される。 Where
R 1 to R 4 are independently C 1 to C 10 alkyl, R 1 and R 2 , or R 3 and R 4 are bonded together to form (CH 2 ) n , (CH 2 ) n O ( CH 2) n, (CH 2 ) n S (CH 2) n, (CH 2) n NX (CH 2) n, (CH 2) n CY (CH 2) n,
X is CH 3 CO, CF 3 CO, or R 1 CO;
Y is oxygen (= O), a (OCH 2) n,
n is an integer of 2 to 4, and a compound represented by Chemical Formula 3 is reacted in the presence of an ammonium salt to produce a 2,6-substituted-4-piperidone derivative;
Oxidizing the 2,6-substituted-4-piperidone derivative;
A process for producing the nitroxy radical compound is provided.
　また、本発明に係る他の一実施形態によれば、上記製造方法によって製造された化合物が提供される。この場合、この化合物は、胃粘膜損傷（胃潰瘍）又は高血圧の治療に使用されることができる。 Also, according to another embodiment of the present invention, a compound produced by the above production method is provided. In this case, the compound can be used for the treatment of gastric mucosal damage (gastric ulcer) or hypertension.
　さらに、本発明に係る別の一実施形態によれば、上記化合物と薬学的に許容可能な担体とを有する医薬組成物が提供される。 Furthermore, according to another embodiment of the present invention, there is provided a pharmaceutical composition comprising the above compound and a pharmaceutically acceptable carrier.
　また、本発明に係る他の一実施形態によれば、胃粘膜損傷（胃潰瘍）を治療する方法であって、この方法は、上記化合物を対象に投与する工程を含むものである方法、並びに高血圧を治療する方法であって、この方法は、上記化合物を対象に投与する工程を含むものである方法が提供される。この場合、当該２つの方法において、前記化合物は、約０．０００１～４ｇ／日の量で投与されることが好ましい。さらに、胃粘膜損傷（胃潰瘍）を治療する際に、当該化合物が１８ｍＭである場合、９０μｍｏｌ／ｋｇの用量で投与されることができる。 In addition, according to another embodiment of the present invention, a method for treating gastric mucosal damage (gastric ulcer), the method comprising the step of administering the compound to a subject, and treating hypertension A method is provided comprising the step of administering the compound to a subject. In this case, in the two methods, the compound is preferably administered in an amount of about 0.0001-4 g / day. Further, in treating gastric mucosal damage (gastric ulcer), when the compound is 18 mM, it can be administered at a dose of 90 μmol / kg.
図１は、本発明の一実施形態に係るニトロキシルラジカル化合物の細胞毒性の評価を示すグラフである。FIG. 1 is a graph showing the evaluation of cytotoxicity of a nitroxyl radical compound according to an embodiment of the present invention. 図２は、本発明の一実施形態に係るニトロキシルラジカル化合物の胃粘膜に与える影響を示すグラフである。FIG. 2 is a graph showing the effect of the nitroxyl radical compound according to one embodiment of the present invention on the gastric mucosa. 図３は、本発明の一実施形態に係るニトロキシルラジカル化合物の血圧変動に及ぼす影響を示すグラフである。FIG. 3 is a graph showing the effect of a nitroxyl radical compound according to an embodiment of the present invention on blood pressure fluctuations.
　以下に、実施例を用いて本発明について説明するが、本発明は、これらに限定されるものではないことが理解される。 Hereinafter, the present invention will be described with reference to examples, but it is understood that the present invention is not limited thereto.
　試薬はＳｉｇｍａ－Ａｌｄｒｉｃｈ、和光純薬工業株式会社より購入し、精製せず用いた。融点は微量融点測定装置ＭＰ－５００Ｐ（Ｙａｎａｃｏ）を用いて測定した。質量分析はＪＭＳ－６００Ｈ（ＪＥＯＬ）にて測定し、３－ニトロベンジルアルコールをマトリックスとして用いた。ＩＲスペクトルはＦＴ／ＩＲ－４２００（ＪＡＳＣＯ）を用い、溶液法または全反射法にて測定した。１Ｈ－ＮＭＲはＵｎｉｔｙ　ＩＮＯＶＡ　４００（Ｖａｒｉａｎ）を用いて測定し、標準物質としてｔｅｔｒａｍｅｔｈｙｌｓｉｌａｎｅ（ＴＭＳ）を用いた。化学シフト（δ）はＴＭＳ（０ｐｐｍ）を基準とし、カップリング定数はＨｚ単位で示した。元素分析は九州大学理学部中央元素分析所に測定を依頼した。 Reagents were purchased from Sigma-Aldrich, Wako Pure Chemical Industries, Ltd. and used without purification. The melting point was measured using a micro melting point measuring device MP-500P (Yanaco). Mass spectrometry was measured with JMS-600H (JEOL), and 3-nitrobenzyl alcohol was used as a matrix. The IR spectrum was measured by a solution method or a total reflection method using FT / IR-4200 (JASCO). 1 H-NMR was measured using Unity INOVA 400 (Varian), and tetramethylsilane (TMS) was used as a standard substance. The chemical shift (δ) was based on TMS (0 ppm), and the coupling constant was expressed in Hz. Elemental analysis was requested from Kyushu University Faculty of Science, Central Elemental Analysis Laboratory.
　７－Ａｚａｄｉｓｐｉｒｏ［５．１．５．３］ｈｅｘａｄｅｃａｎ－１５－ｏｎｅ（３ａ）
　方法Ａ
　２，２，６，６－テトラメチルピペリジン－４－オン（１）１．５５ｇ（１０ｍｍｏｌ）とシクロヘキサノン（ａ）２．９４ｇ（３０ｍｍｏｌ）をＤＭＳＯ　１５ｍｌに溶解し、ＮＨ４Ｃｌ　３．２１ｇ（６０ｍｍｏｌ）を室温下で加えた。この溶液を６０℃で２０時間撹拌した。水を４０ｍＬ加え希釈し、７％塩酸水溶液で酸性にした。これを、エーテルで洗浄し、水層を１０％Ｋ２ＣＯ３水溶液でアルカリ性にした。さらに、これを酢酸エチルで抽出し、水洗を行い、有機層を硫酸ナトリウム乾燥し、溶媒を完全に留去した。その後、シリカゲルカラムクロマトグラフィー（ヘキサン、酢酸エチル）で精製し、再結晶を行い白色結晶３７６ｍｇ（収率：１６％）を得た。 7-Azadispiro [5.1.5.3] hexadecan-15-one (3a)
Method A
1.55 g (10 mmol) of 2,2,6,6-tetramethylpiperidin-4-one (1) and 2.94 g (30 mmol) of cyclohexanone (a) were dissolved in 15 ml of DMSO, and 3.21 g (60 mmol) of NH 4 Cl. ) Was added at room temperature. The solution was stirred at 60 ° C. for 20 hours. The reaction mixture was diluted by adding 40 mL of water and acidified with 7% aqueous hydrochloric acid. This was washed with ether and the aqueous layer was made alkaline with 10% K 2 CO 3 aqueous solution. Further, this was extracted with ethyl acetate, washed with water, the organic layer was dried over sodium sulfate, and the solvent was completely distilled off. Thereafter, the residue was purified by silica gel column chromatography (hexane, ethyl acetate) and recrystallized to obtain 376 mg (yield: 16%) of white crystals.
　方法Ｂ
　１，２，２，６，６－ペンタメチルピペリジン－４－オン（２）１．６９ｇ（１０ｍｍｏｌ）とシクロヘキサノン（ａ）２．９４ｇ（３０ｍｍｏｌ）をＤＭＳＯ１５ｍｌに溶解し、ＮＨ４Ｃｌ３．２１ｇ（６０ｍｍｏｌ）を室温下で加えた。この溶液を６０℃で５時間撹拌した。水を４０ｍＬ加え希釈し、７％塩酸水溶液で酸性にした。これを、エーテルで洗浄し、水層を１０％Ｋ２ＣＯ３水溶液でアルカリ性にした。さらに、これを酢酸エチルで抽出し、水洗を行い、有機層を硫酸ナトリウム乾燥し、溶媒を完全に留去した。その後、シリカゲルカラムクロマトグラフィー（ヘキサン、酢酸エチル）で精製し、再結晶を行い白色結晶７９９ｍｇ（収率：３４％）を得た。
ｍｐ：１０３℃（ｈｅｘａｎｅ－ＥｔＯＡｃ，ｌｉｔ．ｍｐ　１０１－１０３℃［１９］）；
ＭＳ（ＦＡＢ＋）：２３６．３（Ｍ＋＋１）；
νｍａｘ／ｃｍ－１：１６８９（Ｃ＝Ｏ）；
１Ｈ－ＮＭＲ（４００ＭＨｚ；ＣＤＣｌ３）δ（ｐｐｍ）：１．３６－１．４６（８Ｈ，ｍ），１．４７－１．５６（８Ｈ，ｍ），１．６８－１．７１（４Ｈ，ｍ），２．３１（４Ｈ，ｓ）；
Ｆｏｕｎｄ：Ｃ，７６．５１；Ｈ，１０．６８；Ｎ，５．９３％．Ｃａｌｃ．ｆｏｒＣ１５Ｈ２５ＮＯ：Ｃ，７６．５５；Ｈ，１０．７１；Ｎ，５．９５％． Method B
1.69 g (10 mmol) of 1,2,2,6,6-pentamethylpiperidin-4-one (2) and 2.94 g (30 mmol) of cyclohexanone (a) were dissolved in 15 ml of DMSO, and 3.21 g (60 mmol) of NH 4 Cl. ) Was added at room temperature. The solution was stirred at 60 ° C. for 5 hours. The reaction mixture was diluted by adding 40 mL of water and acidified with 7% aqueous hydrochloric acid. This was washed with ether and the aqueous layer was made alkaline with 10% K 2 CO 3 aqueous solution. Further, this was extracted with ethyl acetate, washed with water, the organic layer was dried over sodium sulfate, and the solvent was completely distilled off. Thereafter, the product was purified by silica gel column chromatography (hexane, ethyl acetate) and recrystallized to obtain 799 mg (yield: 34%) of white crystals.
mp: 103 ° C. (hexane-EtOAc, lit. mp 101-103 ° C. [19]);
MS (FAB + ): 236.3 (M ++ 1);
ν max / cm −1 : 1689 (C═O);
1 H-NMR (400 MHz; CDCl 3 ) δ (ppm): 1.36-1.46 (8H, m), 1.47-1.56 (8H, m), 1.68-1.71 (4H) , M), 2.31 (4H, s);
Found: C, 76.51; H, 10.68; N, 5.93%. Calc. forC 15 H 25 NO: C, 76.55; H, 10.71; N, 5.95%.
　７－Ａｚａ－３，１１－ｄｉｏｘａｄｉｓｐｉｒｏ［５．１．５．３］ｈｅｘａｄｅｃａｎ－１５－ｏｎｅ　（３ｂ）
　方法Ｂに従って、シクロヘキサノン（ａ）をテトラヒドロ－４Ｈ－ピラン－４－オン（ｂ）３．００ｇ（３０ｍｍｏｌ）に変えて行った。得られた結晶はＨｅｘａｎｅ－ＥｔＯＡｃから再結晶した。
収率：３２％；　
ｍｐ：１６７℃；
ＭＳ（ＦＡＢ＋）：２４０．１　（Ｍ＋＋１）；　
νｍａｘ／ｃｍ－１：１６９２（Ｃ＝Ｏ）；　
１Ｈ－ＮＭＲ（４００ＭＨｚ；ＣＤＣｌ３）δ（ｐｐｍ）：１．６４（８Ｈ，ｔ，Ｊ＝５．６Ｈｚ），２．４０（４Ｈ，ｓ），３．５４－３．６０（４Ｈ，ｍ），３．８１－３．８７（４Ｈ，ｍ）；
Ｆｏｕｎｄ：Ｃ，６５．１７；Ｈ，８．８５；Ｎ，５．８６％．Ｃａｌｃ．ｆｏｒ　Ｃ１３Ｈ２１ＮＯ３：Ｃ，６５．２５；Ｈ，８．８４；Ｎ，５．８５％． 7-Aza-3,11-dioxadaspiro [5.1.5.3] hexadecan-15-one (3b)
According to Method B, cyclohexanone (a) was changed to 3.00 g (30 mmol) of tetrahydro-4H-pyran-4-one (b). The obtained crystals were recrystallized from Hexane-EtOAc.
Yield: 32%;
mp: 167 ° C;
MS (FAB + ): 240.1 (M ++ 1);
ν max / cm −1 : 1692 (C═O);
1 H-NMR (400 MHz; CDCl 3 ) δ (ppm): 1.64 (8H, t, J = 5.6 Hz), 2.40 (4H, s), 3.54 to 3.60 (4H, m ), 3.81-3.87 (4H, m);
Found: C, 65.17; H, 8.85; N, 5.86%. Calc. for C 13 H 21 NO 3: C, 65.25; H, 8.84; N, 5.85%.
　７－Ａｚａ－３，１１－ｄｉｔｈｉａｄｉｓｐｉｒｏ［５．１．５．３］ｈｅｘａｄｅｃａｎ－１５－ｏｎｅ（３ｃ）
　方法Ｂに従ってシクロヘキサノン（ａ）をテトラヒドロ－４Ｈ－チオピラン－４－オン（ｃ）　３．４９ｇ（３０ｍｍｏｌ）に変えて行った。
収率：３０％；　
ｍｐ：１５５－１５７℃（ＥｔＯＡｃ）；
ＭＳ（ＦＡＢ＋）：２７２．２（Ｍ＋＋１）；　
νｍａｘ／ｃｍ－１：１６９７（Ｃ＝Ｏ）；　
１Ｈ－ＮＭＲ（４００ＭＨｚ；ＣＤＣｌ３）δ（ｐｐｍ）：０．８（１ｓ，ｂｒ　ｓ），１．７５－１．９０（８Ｈ，ｍ），２．２７（４Ｈ，ｓ），２．４３－２．５０（４Ｈ，ｍ），２．８８－２．９５（４Ｈ，ｍ）；　
Ｆｏｕｎｄ：Ｃ，５７．５４；Ｈ，７．７８；Ｎ，５．１１％．Ｃａｌｃ．ｆｏｒ　Ｃ１３Ｈ２１ＮＯＳ２：Ｃ，５７．５２；Ｈ，７．８０；Ｎ，５．１６％． 7-Aza-3,11-dithiadispiro [5.1.5.3] hexadecan-15-one (3c)
According to Method B, cyclohexanone (a) was changed to 3.49 g (30 mmol) of tetrahydro-4H-thiopyran-4-one (c).
Yield: 30%;
mp: 155-157 ° C. (EtOAc);
MS (FAB + ): 272.2 (M ++ 1);
ν max / cm −1 : 1697 (C═O);
1 H-NMR (400 MHz; CDCl 3 ) δ (ppm): 0.8 (1 s, br s), 1.75-1.90 (8 H, m), 2.27 (4 H, s), 2.43 -2.50 (4H, m), 2.88-2.95 (4H, m);
Found: C, 57.54; H, 7.78; N, 5.11%. Calc. for C 13 H 21 NOS 2: C, 57.52; H, 7.80; N, 5.16%.
　３，１１－Ｄｉａｃｅｔｙｌ－３，７，１１－ｔｒｉｔｈｉａｄｉｓｐｉｒｏ［５．１．５．３］ｈｅｘａｄｅｃａｎ－１５－ｏｎｅ　（３ｄ）
９－Ａｃｅｔｙｌ－２，２－ｄｉｍｅｔｈｙｌ－１，９－ｄｉａｚａｓｐｉｒｏ［５．５］ｕｎｄｅｃａｎ－４－ｏｎｅ（３ｄ’）
　方法Ｂと同様に１，２，２，６，６－ペンタメチルピペリジン－４－オン（２）０．８４５　ｇ　（５ｍｍｏｌ）、１－アセチル－４－ピペリドン（ｄ）２．１２ｇ（１５ｍｍｏｌ）、ＮＨ４Ｃｌ　１．６１ｇ（３０ｍｍｏｌ）、ＤＭＳＯ　１２ｍｌの混合物を５８～６２℃で８時間加熱撹拌する。水４０ｍＬで希釈し、７％塩酸水溶液で酸性にした後、エーテルで中性部分を抽出除去した。水層を１０％Ｋ２ＣＯ３水溶液でｐＨ　９～１０に調整し、クロロホルムで抽出し、硫酸ナトリウムで乾燥した。溶媒を減圧下、留去して得られた油状物質を、シリカゲルカラムクロマトグラフィー（１～５％ＭｅＯＨ／ＣＨＣｌ３）で精製し、ｈｅｘａｎｅ－ＥｔＯＡｃから再結晶を行い、３ｄ　３２８ｍｇ、３ｄ’５５６ｍｇを得た。
３ｄ；
収率：２１％；　
ｍｐ：１６４．２℃；
ＭＳ（ＦＡＢ＋）：３２２．３（Ｍ＋＋１）；　
νｍａｘ／ｃｍ－１：１６８７（Ｃ＝Ｏ），１６３４（Ｎ－Ａｃ）；　
１Ｈ－ＮＭＲ（４００ＭＨｚ；ＣＤＣｌ３）δ（ｐｐｍ）：１．５８－１．６６（８Ｈ，ｍ），２．０８（６Ｈ，ｓ），２．３８（４Ｈ，ｓ），３．３７－３．７１（８Ｈ，ｍ）；
Ｆｏｕｎｄ：Ｃ，６２．９２；Ｈ，８．６２；Ｎ，１２．１２％．Ｃａｌｃ．ｆｏｒ　Ｃ１７Ｈ２７Ｎ３Ｏ３：Ｃ，６３．５３；Ｈ，８．４７；Ｎ，１３．０７％．
３ｄ’；
収率：４７％；　
ｍｐ：８０．４℃（ｈｅｘａｎｅ－ＥｔＯＡｃ）；　
ＭＳ（ＦＡＢ＋）：２３９．２（Ｍ＋＋１）；
１Ｈ－ＮＭＲ（４００ＭＨｚ；ＣＤＣｌ３）δ（ｐｐｍ）：１．２１（６Ｈ，ｄ，Ｊ＝１３．６Ｈｚ），１．５０－１．６９（４Ｈ，ｍ），２．０５（３Ｈ，ｓ），２．２８（４Ｈ，ｄ，Ｊ＝９．２Ｈｚ），３．３４－３．７８（４Ｈ，ｍ）；
Ｆｏｕｎｄ：Ｃ，６４．８６；Ｈ，９．２８；Ｎ，１１．６７％．Ｃａｌｃ．ｆｏｒ　Ｃ１３Ｈ２２Ｎ２Ｏ２：Ｃ，６５．５１；Ｈ，９．３０；Ｎ，１１．７５％． 3,11-Diacetyl-3,7,11-trithiadispiro [5.1.5.3] hexadecan-15-one (3d)
9-Acetyl-2,2-dimethyl-1,9-diazaspiro [5.5] undecan-4-one (3d ′)
As in Method B, 1,2,2,6,6-pentamethylpiperidin-4-one (2) 0.845 g (5 mmol), 1-acetyl-4-piperidone (d) 2.12 g (15 mmol), A mixture of 1.61 g (30 mmol) of NH 4 Cl and 12 ml of DMSO is heated and stirred at 58 to 62 ° C. for 8 hours. After diluting with 40 mL of water and acidifying with 7% aqueous hydrochloric acid, the neutral part was extracted and removed with ether. The aqueous layer was adjusted to pH 9-10 with 10% K 2 CO 3 aqueous solution, extracted with chloroform, and dried over sodium sulfate. The oily substance obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (1-5% MeOH / CHCl 3 ) and recrystallized from hexane-EtOAc to obtain 3d 328 mg, 3d′556 mg. Obtained.
3d;
Yield: 21%;
mp: 164.2 ° C;
MS (FAB + ): 322.3 (M ++ 1);
ν max / cm −1 : 1687 (C═O), 1634 (N- Ac );
1 H-NMR (400 MHz; CDCl 3 ) δ (ppm): 1.58-1.66 (8H, m), 2.08 (6H, s), 2.38 (4H, s), 3.37- 3.71 (8H, m);
Found: C, 62.92; H, 8.62; N, 12.12%. Calc. for C 17 H 27 N 3 O 3: C, 63.53; H, 8.47; N, 13.07%.
3d ′;
Yield: 47%;
mp: 80.4 ° C. (hexane-EtOAc);
MS (FAB + ): 239.2 (M ++ 1);
1 H-NMR (400 MHz; CDCl 3 ) δ (ppm): 1.21 (6H, d, J = 13.6 Hz), 1.50-1.69 (4H, m), 2.05 (3H, s ), 2.28 (4H, d, J = 9.2 Hz), 3.34-3.78 (4H, m);
Found: C, 64.86; H, 9.28; N, 11.67%. Calc. for C 13 H 22 N 2 O 2: C, 65.51; H, 9.30; N, 11.75%.
　１，４，１４，１７－Ｔｅｔｒａｏｘａ－９－ａｚａｔｅｔｒａｓｐｉｒｏ［４．２．１．２．４．２．３．２］ｔｅｔｒａｃｏｓａｎ－２１－ｏｎｅ（３ｅ）
　方法Ｂに従ってシクロヘキサノン（ａ）を１，４－シクロヘキサンジオンモノエチレンアセタール（ｅ）４．６９ｇ（３０ｍｍｏｌ）に変えて行い、Ｈｅｘａｎｅ－ＥｔＯＡｃから再結晶を行い３ｅ　１．１２ｇを得た。
収率：３２％；
ｍｐ：１９０．６℃；
ＭＳ（ＦＡＢ＋）：３５２．４（Ｍ＋＋１）．
νｍａｘ／ｃｍ－１：１６９９（Ｃ＝Ｏ），１０８３（－Ｏ－ＣＨ２－ＣＨ２－Ｏ－）；
１Ｈ－ＮＭＲ（４００ＭＨｚ；ＣＤＣｌ３）δ（ｐｐｍ）：１．５６－１．７４（１２Ｈ，ｍ），１．８５－１．９２（４Ｈ，ｍ），２．３２（４Ｈ，ｓ），３．９３（８Ｈ，ｔ，Ｊ＝２．８Ｈｚ）；
Ｆｏｕｎｄ：Ｃ，６４．９５；Ｈ，８．３０；Ｎ，４．０５％．Ｃａｌｃ．ｆｏｒ　Ｃ１９Ｈ２９ＮＯ５：Ｃ，６４．９３；Ｈ，８．３２；Ｎ，３．９９％． 1,4,14,17-Tetraoxa-9-azetraspiro [4.2.1.2.4.2.3.2] tetracosan-21-one (3e)
According to Method B, cyclohexanone (a) was changed to 4.69 g (30 mmol) of 1,4-cyclohexanedione monoethylene acetal (e) and recrystallized from Hexane-EtOAc to obtain 3e 1.12 g.
Yield: 32%;
mp: 190.6 ° C;
MS (FAB <+> ): 352.4 (M ++ 1).
ν max / cm −1 : 1699 (C═O), 1083 (—O—CH 2 —CH 2 —O—);
1 H-NMR (400 MHz; CDCl 3 ) δ (ppm): 1.56-1.74 (12H, m), 1.85-1.92 (4H, m), 2.32 (4H, s), 3.93 (8H, t, J = 2.8 Hz);
Found: C, 64.95; H, 8.30; N, 4.05%. Calc. for C 19 H 29 NO 5: C, 64.93; H, 8.32; N, 3.99%.
　２，２，６－Ｔｒｉｍｅｔｈｙｌ－６－ｐｈｅｎｙｌｐｉｐｅｒｉｄｉｎ－４－ｏｎｅ　（３ｆ）
　方法Ｂに従ってシクロヘキサノン（ａ）をアセトフェノン（ｆ）　３．６０　ｇ　（３０　ｍｍｏｌ）に変えて行った。
収率：１６％；
ｍｐ：１０９．５℃（ＥｔＯＡｃ）；
ＭＳ（ＦＡＢ＋）：２１８．２（Ｍ＋＋１）．
１Ｈ－ＮＭＲ（４００ＭＨｚ；ＣＤＣｌ３）δ（ｐｐｍ）：１．２０（３Ｈ，ｓ），１．３１（３Ｈ，ｓ），２．２３－２．５０（４Ｈ，ｍ），２．３４（３Ｈ，ｓ），４．１７－４．２０（１Ｈ，ｍ），７．１１－７．３３（４Ｈ，ｍ）；
Ｆｏｕｎｄ：Ｃ，７７．９２；Ｈ，８．７８；Ｎ，６．４４％．Ｃａｌｃ．ｆｏｒ　Ｃ１９Ｈ２９ＮＯ５：Ｃ，７７．３８；Ｈ，８．８１；Ｎ，６．４５％． 2,2,6-Trimethyl-6-phenylpiperidin-4-one (3f)
According to Method B, cyclohexanone (a) was changed to 3.60 g (30 mmol) of acetophenone (f).
Yield: 16%;
mp: 109.5 ° C. (EtOAc);
MS (FAB <+> ): 218.2 (M ++ 1).
1 H-NMR (400 MHz; CDCl 3 ) δ (ppm): 1.20 (3H, s), 1.31 (3H, s), 2.23 to 2.50 (4H, m), 2.34 ( 3H, s), 4.17-4.20 (1H, m), 7.11-7.33 (4H, m);
Found: C, 77.92; H, 8.78; N, 6.44%. Calc. for C 19 H 29 NO 5: C, 77.38; H, 8.81; N, 6.45%.
　Ｍｅｔｈｙｌ　３－（２，６，６－ｔｒｉｍｅｔｈｙｌ－４－ｏｘｏｐｉｐｅｒｉｄｉｎ－２－ｙｌ）ｐｒｏｐａｎｏａｔｅ（３ｇ）
　方法Ｂに従ってシクロヘキサノンをレブリン酸メチル（ｇ）に変えて行った。この化合物は、二置換体との混合物が得られており、単離には至っていない。構造の同定は、３ｇを酸化して得られるＭｅｔｈｙｌ　３－（２，６，６－ｔｒｉｍｅｔｈｙｌ－４－ｏｘｏｐｉｐｅｒｉｄｉｎ－１－ｏｘｙｌ－２－ｙｌ）ｐｒｏｐａｎｏａｔｅ（４ｇ）で行った。 Methyl 3- (2,6,6-trimethyl-4-oxopiperidin-2-yl) propanoate (3g)
According to Method B, cyclohexanone was changed to methyl levulinate (g). This compound has been obtained as a mixture with a disubstituted product and has not yet been isolated. The structure was identified by methyl 3- (2,6,6-trimethyl-4-oxoperidin-1-oxyl-2-yl) propanoate (4 g) obtained by oxidizing 3 g.
　２，２－Ｄｉｍｅｔｈｙｌ－６－ｐ－ｔｏｌｙｌｐｉｐｅｒｉｄｉｎ－４－ｏｎｅ（３ｈ）
　方法Ｂに従ってシクロヘキサノン（ａ）をｐ－トルアルデヒド（ｈ）３．６０ｇ（３０ｍｍｏｌ）に変えて行った。
収率：１０％；
ｍｐ：１０９．５℃（ｈｅｘａｎｅ）；
ＭＳ（ＦＡＢ＋）：２１８．２（Ｍ＋＋１）；
νｍａｘ／ｃｍ－１：１６９３（Ｃ＝Ｏ）；
１Ｈ－ＮＭＲ（５００ＭＨｚ；ＣＤＣｌ３）δ（ｐｐｍ）：１．２０（３Ｈ，ｓ），１．３１（３Ｈ，ｓ），１．５３（１Ｈ，ｂｒｓ），２．２５－２．５０（４Ｈ，ｍ），２．３４（３Ｈ，ｓ），４．１８（１Ｈ，ｄｄ，Ｊ１＝１１．５Ｈｚ，Ｊ２＝３．５Ｈｚ），７．１６（２Ｈ，ｄ，Ｊ＝８．０Ｈｚ），７．２９（２Ｈ，ｄ，Ｊ＝８．０Ｈｚ）；
Ｆｏｕｎｄ：Ｃ，７７．５５；Ｈ，８．８２；Ｎ，６．５３％．Ｃａｌｃ．ｆｏｒ　Ｃ１４Ｈ１９ＮＯ：Ｃ，７７．３８；Ｈ，８．８１；Ｎ，６．４５％． 2,2-Dimethyl-6-p-tolypiperidin-4-one (3h)
According to Method B, cyclohexanone (a) was changed to 3.60 g (30 mmol) of p-tolualdehyde (h).
Yield: 10%;
mp: 109.5 ° C (hexane);
MS (FAB + ): 218.2 (M ++ 1);
ν max / cm −1 : 1693 (C═O);
1 H-NMR (500 MHz; CDCl 3 ) δ (ppm): 1.20 (3H, s), 1.31 (3H, s), 1.53 (1H, brs), 2.25 to 2.50 ( 4H, m), 2.34 (3H, s), 4.18 (1H, dd, J 1 = 11.5 Hz, J 2 = 3.5 Hz), 7.16 (2H, d, J = 8.0 Hz) ), 7.29 (2H, d, J = 8.0 Hz);
Found: C, 77.55; H, 8.82; N, 6.53%. Calc. for C 14 H 19 NO: C , 77.38; H, 8.81; N, 6.45%.
　３，１１－Ｔｒｉｆｌｕｏｒｏａｃｅｔｙｌ－３，７，１１－ｔｒｉｔｈｉａｄｉｓｐｉｒｏ［５．１．５．３］ｈｅｘａｄｅｃａｎ－１５－ｏｎｅ（３ｉ）
９－Ｔｒｉｆｌｕｏｒｏａｃｅｔｙｌ－２，２－ｄｉｍｅｔｈｙｌ－１，９－ｄｉａｚａｓｐｉｒｏ［５．５］ｕｎｄｅｃａｎ－４－ｏｎｅ（３ｉ’）
　方法Ｂに従ってシクロヘキサノン（ａ）を１－トリフルオロアセチル－４－ピペリドン（ｉ）５．８５ｇ（３０ｍｍｏｌ）に変えて行った。ＥｔＯＡｃで中性部分を抽出除去し、ｐＨ９～１０に調整後、ＣＨＣｌ３で抽出した。Ｈｅｘａｎｅ－ＥｔＯＡｃから再結晶し、３ｉ　１９２ｍｇ、３ｉ’１２６ｍｇを得た。
３ｉ；
収率：４％；　
ｍｐ：１７２．６－１７３．２℃；
ＭＳ（ＦＡＢ＋）：４３０．２（Ｍ＋＋１）；
νｍａｘ／ｃｍ－１：１６８８（－Ｎ－ＣＯ－ＣＦ３）；
１Ｈ－ＮＭＲ（４００ＭＨｚ；ＣＤＣｌ３）δ（ｐｐｍ）：１．６４－１．７７（８Ｈ，ｍ），２．４２（４Ｈ，ｓ），３．５７－３．８２（８Ｈ，ｍ）；
Ｆｏｕｎｄ：Ｃ，４７．６２；Ｈ，５．０１；Ｎ，９．７９％．Ｃａｌｃ．ｆｏｒ　Ｃ１７Ｈ２１Ｆ６Ｎ３Ｏ３：Ｃ，４７．５６；Ｈ，４．９３；Ｎ，９．７９％．
３ｉ’；
収率：４％；　
ｍｐ：８５．８－８６．４℃（ｈｅｘａｎｅ－ＥｔＯＡｃ）；
ＭＳ（ＦＡＢ＋）：２９３．１（Ｍ＋＋１）；
νｍａｘ／ｃｍ－１：１６９２（－Ｎ－ＣＯ－ＣＦ３）；
１Ｈ－ＮＭＲ（４００ＭＨｚ；ＣＤＣｌ３）δ（ｐｐｍ）：１．２３（３Ｈ，ｓ），１．２５（３Ｈ，ｓ），１．６２－１．８０（４Ｈ，ｍ），２．３０（２Ｈ，ｓ），２．３３（２Ｈ，ｓ），３．５４－３．９６（４Ｈ，ｍ），；
Ｆｏｕｎｄ：Ｃ，５３．３０；Ｈ，６．４４；Ｎ，９．５８％．Ｃａｌｃ．ｆｏｒ　Ｃ１３Ｈ１９Ｆ３Ｎ２Ｏ２：Ｃ，５３．４２；Ｈ，６．５５；Ｎ，９．５８％． 3,11-Trifluoroacetyl-3,7,11-trithiadispiro [5.1.5.3] hexadecan-15-one (3i)
9-Trifluoroacetyl-2,2-dimethyl-1,9-diazaspiro [5.5] undecan-4-one (3i ′)
According to Method B, cyclohexanone (a) was changed to 5.85 g (30 mmol) of 1-trifluoroacetyl-4-piperidone (i). The neutral part was removed by extraction with EtOAc, adjusted to pH 9-10, and extracted with CHCl 3 . Recrystallization from Hexane-EtOAc gave 3i 192 mg, 3i ′ 126 mg.
3i;
Yield: 4%;
mp: 172.6-173.2 ° C;
MS (FAB + ): 430.2 (M ++ 1);
ν max / cm −1 : 1688 ( —N—CO 2 —CF 3 );
1 H-NMR (400 MHz; CDCl 3 ) δ (ppm): 1.64-1.77 (8H, m), 2.42 (4H, s), 3.57-3.82 (8H, m);
Found: C, 47.62; H, 5.01; N, 9.79%. Calc. for C 17 H 21 F 6 N 3 O 3: C, 47.56; H, 4.93; N, 9.79%.
3i ';
Yield: 4%;
mp: 85.8-86.4 ° C (hexane-EtOAc);
MS (FAB + ): 293.1 (M ++ 1);
ν max / cm −1 : 1692 ( —N—CO 2 —CF 3 );
1 H-NMR (400 MHz; CDCl 3 ) δ (ppm): 1.23 (3H, s), 1.25 (3H, s), 1.62-1.80 (4H, m), 2.30 ( 2H, s), 2.33 (2H, s), 3.54-3.96 (4H, m),
Found: C, 53.30; H, 6.44; N, 9.58%. Calc. for C 13 H 19 F 3 N 2 O 2: C, 53.42; H, 6.55; N, 9.58%.
　方法Ｃ
　７－Ａｚａ－１５－ｏｘｏｄｉｓｐｉｒｏ［５．１．５．３］ｈｅｘａｄｅｃ－７－ｙｌ－７－ｏｘｙｌ（４ａ）
　７－Ａｚａｄｉｓｐｉｒｏ［５．１．５．３］ｈｅｘａｄｅｃａｎ－１５－ｏｎｅ（３ａ）２３５ｍｇ（０．９９ｍｍｏｌ）をエタノール１０ｍＬに溶解し、Ｎａ２ＷＯ４・２Ｈ２Ｏ　５０ｍｇ（０．１５ｍｍｏｌ）を加え、この溶液にＨ２Ｏ２（３０％）２ｍＬを徐々に加えた。これを室温下、２４時間撹拌した。その後、Ｋ２ＣＯ３を加えクエンチし、クロロホルムで抽出した。続いて、溶媒を完全に留去し、再結晶（ヘキサン）により精製し、微黄色鱗片状結晶２０８ｍｇ（収率：８３％）を得た。
ｍｐ：１１４．２°Ｃ（ｌｉｔ．ｍｐ　１１４－１１６°Ｃ）；
ＭＳ　（ＦＡＢ＋）：２５０．３（Ｍ＋）；　
νｍａｘ／ｃｍ－１：１７１７（Ｃ＝Ｏ）；　
Ｆｏｕｎｄ：Ｃ，７１．８６；Ｈ，９．６２；Ｎ，５．５７％．Ｃａｌｃ．ｆｏｒ　Ｃ１５Ｈ２４ＮＯ２：Ｃ，７１．９６；Ｈ，９．６６；Ｎ，５．５９％． Method C
7-Aza-15-oxodispiro [5.1.5.3] hexadec-7-yl-7-oxyl (4a)
235 mg (0.99 mmol) of 7-Azadispiro [5.1.5.3] hexadecan-15-one (3a) was dissolved in 10 mL of ethanol, and 50 mg (0.15 mmol) of Na 2 WO 4 · 2H 2 O was added, To this solution was slowly added 2 mL of H 2 O 2 (30%). This was stirred at room temperature for 24 hours. Then quenched added K 2 CO 3, and extracted with chloroform. Subsequently, the solvent was completely distilled off and purified by recrystallization (hexane) to obtain 208 mg (yield: 83%) of slightly yellow scale crystals.
mp: 114.2 ° C (lit. mp 114-116 ° C);
MS (FAB <+> ): 250.3 (M <+> );
ν max / cm −1 : 1717 (C═O);
Found: C, 71.86; H, 9.62; N, 5.57%. Calc. for C 15 H 24 NO 2: C, 71.96; H, 9.66; N, 5.59%.
　７－Ａｚａ－３，１１－ｄｉｏｘａ－１５－ｏｘｏｄｉｓｐｉｒｏ［５．１．５．３］ｈｅｘａｄｅｃ－７－ｙｌ－７－ｏｘｙｌ（４ｂ）
方法Ｃに従って７－Ａｚａ－３，１１－ｄｉｏｘａｄｉｓｐｉｒｏ［５．１．５．３］ｈｅｘａｄｅｃａｎ－１５－ｏｎｅ（３ｂ）１３０ｍｇ（０．５４ｍｍｏｌ）を原料として行った。ＥｔＯＡｃから再結晶し、４ｂ　１１０ｍｇ（０．４３ｍｍｏｌ）を得た。
収率：８０％；
ｍｐ：１４９．５°Ｃ；
ＭＳ（ＦＡＢ＋）：２５５．２（Ｍ＋＋２）；
νｍａｘ／ｃｍ－１：１７１７（Ｃ＝Ｏ）；　
Ｆｏｕｎｄ：Ｃ，６１．２３；Ｈ，７．９７；Ｎ，５．４０％．Ｃａｌｃ．ｆｏｒ　Ｃ１３Ｈ２０ＮＯ４：Ｃ，６１．４０；Ｈ，７．９３；Ｎ，５．５１％． 7-Aza-3,11-dioxa-15-oxodispiro [5.1.5.3] hexadec-7-yl-7-oxyl (4b)
According to Method C, 7-Aza-3,11-dioxadaspiro [5.1.5.3] hexadecan-15-one (3b) 130 mg (0.54 mmol) was used as a starting material. Recrystallization from EtOAc gave 4 mg 110 mg (0.43 mmol).
Yield: 80%;
mp: 149.5 ° C;
MS (FAB <+> ): 255.2 (M < + > + 2);
ν max / cm −1 : 1717 (C═O);
Found: C, 61.23; H, 7.97; N, 5.40%. Calc. for C 13 H 20 NO 4: C, 61.40; H, 7.93; N, 5.51%.
　７－Ａｚａ－３，１１－ｄｉｔｈｉａ－３，３，１１，１１，１５－ｐｅｎｔａｏｘｏｄｉｓｐｉｒｏ［５．１．５．３］ｈｅｘａｄｅｃ－７－ｙｌ－７－ｏｘｙｌ（４ｃ）
　７－Ａｚａ－３，１１－ｄｉｔｈｉａｄｉｓｐｉｒｏ［５．１．５．３］ｈｅｘａｄｅｃａｎ－１５－ｏｎｅ（３ｃ）２１０ｍｇ（０．７８ｍｍｏｌ）、Ｎａ２ＷＯ４・２Ｈ２Ｏ　１１８ｍｇ（０．３６ｍｍｏｌ）、ＭｅＯＨ　３ｍｌ、及び、Ｈ２Ｏ２（３０％）１ｍＬを混合し、室温で４８時間撹拌した。Ｋ２ＣＯ３を加え、ＣＨＣｌ３：ＭｅＯＨ＝３：１の混合溶媒で抽出し、溶媒を留去した。これを、水から再結晶し４ｃ　８０ｍｇ（０．２３ｍｍｏｌ）を得た。
収率：２９％；
ｍｐ：２１２．５－２１４．２°Ｃ；
ＭＳ（ＦＡＢ＋）：３５１．０（Ｍ＋＋１）；
νｍａｘ／ｃｍ－１：１７１２（Ｃ＝Ｏ），１２８７（ＳＯ２），１１２２（ＳＯ２）；
Ｆｏｕｎｄ：Ｃ，４４．３８；Ｈ，５．７９；Ｎ，３．９３％．Ｃａｌｃ．ｆｏｒ　Ｃ１３Ｈ２１ＮＯ５Ｓ２：Ｃ，４４．５６；Ｈ，５．７５；Ｎ，４．００％． 7-Aza-3,11-dithia-3,3,11,11,15-pentaoxodispiro [5.1.5.3] hexadec-7-yl-7-oxyl (4c)
7-Aza-3,11-dithiadispiro [5.1.5.3] hexadecan-15-one (3c) 210 mg (0.78 mmol), Na 2 WO 4 .2H 2 O 118 mg (0.36 mmol), MeOH 3 ml And 1 mL of H 2 O 2 (30%) were mixed and stirred at room temperature for 48 hours. K 2 CO 3 was added, extraction was performed with a mixed solvent of CHCl 3 : MeOH = 3: 1, and the solvent was distilled off. This was recrystallized from water to obtain 80 mg (0.23 mmol) of 4c.
Yield: 29%;
mp: 212.5-214.2 ° C;
MS (FAB <+> ): 351.0 (M ++ 1);
ν max / cm −1 : 1712 (C═O), 1287 (SO 2 ), 1122 (SO 2 );
Found: C, 44.38; H, 5.79; N, 3.93%. Calc. for C 13 H 21 NO 5 S 2: C, 44.56; H, 5.75; N, 4.00%.
　３，１１－Ｄｉａｃｅｔｙｌ－１５－ｏｘｏ－３，７，１１－ｔｒｉｔｈｉａｄｉｓｐｉｒｏ［５．１．５．３］ｈｅｘａｄｅｃ－７－ｙｌ－７－ｏｘｙｌ（４ｄ）
　方法Ｃに従って３，１１－Ｄｉａｃｅｔｙｌ－３，７，１１－ｔｒｉｔｈｉａｄｉｓｐｉｒｏ［５．１．５．３］ｈｅｘａｄｅｃａｎ－１５－ｏｎｅ（３ｄ）を原料として行った。
ｍｐ：１６２－１６３°Ｃ；
ＭＳ（ＦＡＢ＋）：３３７．３（Ｍ＋＋１）；
νｍａｘ／ｃｍ－１：１７２０（Ｃ＝Ｏ），１６３７（－Ｎ－ＣＯ－ＣＨ３）； 3,11-Diacetyl-15-oxo-3,7,11-trithiadispiro [5.1.5.3] hexadec-7-yl-7-oxyl (4d)
According to Method C, 3,11-Diacetyl-3,7,11-trithiadispiro [5.1.5.3] hexadecan-15-one (3d) was used as a starting material.
mp: 162-163 ° C;
MS (FAB + ): 337.3 (M ++ 1);
ν max / cm −1 : 1720 (C═O), 1637 ( —N—CO 2 —CH 3 );
　１，４，１４，１７－Ｔｅｔｒａｏｘａ－９－ａｚａ－２１－ｏｘｏｔｅｔｒａｓｐｉｒｏ［４．２．１．２．４．２．３．２］ｔｅｔｒａｃｏｓ－９－ｙｌ－９－ｏｘｙｌ（４ｅ）
　方法Ｃに従って１，４，１４，１７－Ｔｅｔｒａｏｘａ－９－ａｚａｔｅｔｒａｓｐｉｒｏ［４．２．１．２．４．２．３．２］ｔｅｔｒａｃｏｓａｎ－２１－ｏｎｅ（３ｅ）を原料として行った。
ｍｐ：１８３．２－１８４．２°Ｃ；
ＭＳ（ＦＡＢ＋）：３６７．３（Ｍ＋＋１）；
νｍａｘ／ｃｍ－１：１７１３（Ｃ＝Ｏ）；
Ｆｏｕｎｄ：Ｃ，６２．１８；Ｈ，７．３８；Ｎ，３．８８％．Ｃａｌｃ．ｆｏｒ　Ｃ１９Ｈ２８ＮＯ６：Ｃ，６２．２８；Ｈ，７．７０；Ｎ，３．８２％． 1,4,14,17-Tetraoxa-9-aza-21-oxotetraspiro [4.2.1.2.4.2.3.2.2] tetracos-9-yl-9-oxyl (4e)
According to Method C, 1,4,14,17-Tetraoxa-9-azetratraspiro [4.2.1.2.4.2.3.2.2] tetracosan-21-one (3e) was used as a starting material.
mp: 183.2-184.2 ° C;
MS (FAB + ): 367.3 (M ++ 1);
ν max / cm −1 : 1713 (C═O);
Found: C, 62.18; H, 7.38; N, 3.88%. Calc. for C 19 H 28 NO 6: C, 62.28; H, 7.70; N, 3.82%.
　７－Ａｚａ－３，１１，１５－ｔｒｉｏｘｏｄｉｓｐｉｒｏ［５．１．５．３］ｈｅｘａｄｅｃ－７－ｙｌ－７－ｏｘｙｌ（４ｅ’）
　１，４，１４，１７－Ｔｅｔｒａｏｘａ－９－ａｚａｔｅｔｒａｓｐｉｒｏ［４．２．１．２．４．２．３．２］ｔｅｔｒａｃｏｓａｎ－２１－ｏｎｅ（３ｅ）５３６ｍｇ（１．５３ｍｍｏｌ）を水２ｍＬと酢酸５ｍＬに溶解し、１０％ＨＣｌを滴下し、７０℃で撹拌した。この溶液を水で希釈し、ｐＨを７に調整し、酢酸エチルで抽出した。有機層を硫酸ナトリウムで乾燥し、溶媒を完全に留去した。その後、シリカゲルカラムクロマトグラフィーｈｅｘａｎｅ／ＥｔＯＡｃ，１：４）で分離精製し、再結晶（ヘキサン、酢酸エチル）により７－Ａｚａ－３，１１，１５－ｔｒｉｏｘｏｄｉｓｐｉｒｏ［５．１．５．３］ｈｅｘａｄｅｃａｎｅの白色個体３３０ｍｇ（１．２５ｍｍｏｌ）を得た。
収率：８２％
ｍｐ：９９．７℃；
ＭＳ（ＦＡＢ＋）：２６４．２（Ｍ＋＋１）；
νｍａｘ／ｃｍ－１：１７０５（Ｃ＝Ｏ）；　
１Ｈ－ＮＭＲ（４００ＭＨｚ；ＣＤＣｌ３）δ（ｐｐｍ）：１．２４（１Ｈ，ｂｒｓ），１．８７－２．０５（８Ｈ，ｍ），２．２９－２．６７（８Ｈ，ｍ），２．４９（４Ｈ，ｓ）；
Ｆｏｕｎｄ：Ｃ，７６．５１；Ｈ，１０．６８；Ｎ，５．９３％．Ｃａｌｃ．ｆｏｒ　Ｃ１５Ｈ２５ＮＯ：Ｃ，７６．５５；Ｈ，１０．７１；Ｎ，５．９５％．
　続いて、得られた７－Ａｚａ－３，１１，１５－ｔｒｉｏｘｏｄｉｓｐｉｒｏ［５．１．５．３］ｈｅｘａｄｅｃａｎｅ　２１５ｍｇ（０．８２ｍｍｏｌ）を方法Ｃに従って酸化し、４ｅ’１７０ｍｇ（０．６１ｍｍｏｌ）を得た。
収率：７５％
ｍｐ：１６１．５℃；
ＭＳ（ＦＡＢ＋）：２７９．３（Ｍ＋＋１）；
νｍａｘ／ｃｍ－１：１７０８（Ｃ＝Ｏ）；
Ｆｏｕｎｄ：Ｃ，６４．７１；Ｈ，７．２５；Ｎ，５．０６％．Ｃａｌｃ．ｆｏｒ　Ｃ１５Ｈ２０ＮＯ４：Ｃ，６４．７３；Ｈ，７．２４；Ｎ，５．０３％． 7-Aza-3,11,15-trioxodispiro [5.1.5.3] hexadec-7-yl-7-oxyl (4e ')
1,4,14,17-Tetraoxa-9-azetratraspiro [4.2.1.2.4.2.3.2.2] tetracosan-21-one (3e) (536 mg, 1.53 mmol) in water (2 mL) and acetic acid (5 mL) 10% HCl was added dropwise and stirred at 70 ° C. The solution was diluted with water, the pH was adjusted to 7, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and the solvent was completely distilled off. Thereafter, the product was separated and purified by silica gel column chromatography hexane / EtOAc, 1: 4), and recrystallized (hexane, ethyl acetate) from 7-Aza-3,11,15-trioxodispiro [5.1.5.3] hexadecane. 330 mg (1.25 mmol) of white solid was obtained.
Yield: 82%
mp: 99.7 ° C;
MS (FAB + ): 264.2 (M ++ 1);
ν max / cm −1 : 1705 (C═O);
1 H-NMR (400 MHz; CDCl 3 ) δ (ppm): 1.24 (1H, brs), 1.87-2.05 (8H, m), 2.29-2.67 (8H, m), 2.49 (4H, s);
Found: C, 76.51; H, 10.68; N, 5.93%. Calc. for C 15 H 25 NO: C , 76.55; H, 10.71; N, 5.95%.
Subsequently, 215 mg (0.82 mmol) of the obtained 7-Aza-3,11,15-trioxodispiro [5.1.5.3] hexadecane was oxidized according to Method C to obtain 4e′170 mg (0.61 mmol). It was.
Yield: 75%
mp: 161.5 ° C;
MS (FAB + ): 279.3 (M ++ 1);
ν max / cm −1 : 1708 (C═O);
Found: C, 64.71; H, 7.25; N, 5.06%. Calc. for C 15 H 20 NO 4: C, 64.73; H, 7.24; N, 5.03%.
　Ｍｅｔｈｙｌ　３－（２，６，６－ｔｒｉｍｅｔｈｙｌ－４－ｏｘｏｐｉｐｅｒｉｄｉｎ－１－ｏｘｙｌ－２－ｙｌ）ｐｒｏｐａｎｏａｔｅ（４ｇ）
　方法Ｃに従ってＭｅｔｈｙｌ　３－（２，６，６－ｔｒｉｍｅｔｈｙｌ－４－ｏｘｏｐｉｐｅｒｉｄｉｎ－２－ｙｌ）ｐｒｏｐａｎｏａｔｅ（３ｇ）と二置換体の混合物１４７ｍｇを原料として用い、赤色油状物質を得た３７ｍｇ（０．１５ｍｍｏｌ）。
ＭＳ（ＦＡＢ＋）：２４２．２（Ｍ＋）；
νｍａｘ／ｃｍ－１：１７２０（Ｃ＝Ｏ）；
Ｆｏｕｎｄ：Ｃ，５８．９３；Ｈ，８．２７；Ｎ，５．６５％．Ｃａｌｃ．ｆｏｒ　Ｃ１２Ｈ２０ＮＯ４：Ｃ，５９．４９；Ｈ，８．３２；Ｎ，５．７８％． Methyl 3- (2,6,6-trimethyl-4-oxopiperidin-1-oxyl-2-yl) propanoate (4g)
According to Method C, a mixture of 147 mg of methyl 3- (2,6,6-trimethyl-4-oxoperidin-2-yl) propanoate (3 g) and a disubstituted product was used as a raw material to obtain 37 mg (0.15 mmol) ).
MS (FAB <+> ): 242.2 (M <+> );
ν max / cm −1 : 1720 (C═O);
Found: C, 58.93; H, 8.27; N, 5.65%. Calc. for C 12 H 20 NO 4: C, 59.49; H, 8.32; N, 5.78%.
　３，１１－Ｔｒｉｆｌｕｏｒｏａｃｅｔｙｌ－３，７，１１－ｔｒｉｔｈｉａ－１５－ｏｘｏｄｉｓｐｉｒｏ［５．１．５．３］ｈｅｘａｄｅｃ－７－ｙｌ－７－ｏｘｙｌ（４ｉ）
　方法Ｃに従って３，１１－Ｔｒｉｆｌｕｏｒｏａｃｅｔｙｌ－３，７，１１－ｔｒｉｔｈｉａｄｉｓｐｉｒｏ［５．１．５．３］ｈｅｘａｄｅｃａｎ－１５－ｏｎｅ（３ｉ）１３０ｍｇ（０．３０ｍｍｏｌ）を原料として行い、４ｉ　５７ｍｇ（０．１３ｍｍｏｌ）を得た。
収率：４２％
ＭＳ（ＦＡＢ＋）：４４５．１（Ｍ＋＋１）；
Ｆｏｕｎｄ：Ｃ，４４．９０；Ｈ，４．４６；Ｎ，９．２５％．Ｃａｌｃ．ｆｏｒ　Ｃ１７Ｈ２０Ｆ６Ｎ３Ｏ４：Ｃ，４５．９５；Ｈ，４．５４；Ｎ，９．４６％． 3,11-Trifluoroacetyl-3,7,11-trithia-15-oxodispiro [5.1.5.3] hexadec-7-yl-7-oxyl (4i)
According to Method C, 3,11-Trifluoroacetyl-3,7,11-trithiadispiro [5.1.5.3] hexadecan-15-one (3i) 130 mg (0.30 mmol) was used as starting material, and 4i 57 mg (0.13 mmol) )
Yield: 42%
MS (FAB + ): 445.1 (M ++ 1);
Found: C, 44.90; H, 4.46; N, 9.25%. Calc. for C 17 H 20 F 6 N 3 O 4: C, 45.95; H, 4.54; N, 9.46%.
　７－［ １５ Ｎ］－Ａｚａ－１５－ｏｘｏｄｉｓｐｉｒｏ［５．１．５．３］ｈｅｘａｄｅｃ－７－ｙｌ－７－ｏｘｙｌ（５ａ）
　ＮＨ４Ｃｌを１５ＮＨ４Ｃｌに変えて、７－Ａｚａ－１５－ｏｘｏｄｉｓｐｉｒｏ［５．１．５．３］ｈｅｘａｄｅｃ－７－ｙｌ－７－ｏｘｙｌ（４ａ）と同様に行った。
ｍｐ：１１５．４－１１７．４℃（ｈｅｘａｎｅ）；
ＭＳ（ＦＡＢ＋）：２５１．３（Ｍ＋＋１）；
νｍａｘ／ｃｍ－１：１７１７（Ｃ＝Ｏ）；
Ｆｏｕｎｄ：Ｃ，７１．６７；Ｈ，９．７９；Ｎ，５．６７％．Ｃａｌｃ．ｆｏｒ　Ｃ１５Ｈ２４ １５ＮＯ２：Ｃ，７１．６８；Ｈ，９．６２；Ｎ，５．５７％． 7- [ 15 N] -Aza-15-oxodispiro [5.1.5.3] hexadec-7-yl-7-oxyl (5a)
NH 4 Cl was changed to 15 NH 4 Cl, and the same procedure as in 7-Aza-15-oxodispiro [5.1.5.3] hexadec-7-yl-7-oxyl (4a) was performed.
mp: 115.4-117.4 ° C. (hexane);
MS (FAB + ): 251.3 (M ++ 1);
ν max / cm −1 : 1717 (C═O);
Found: C, 71.67; H, 9.79; N, 5.67%. Calc. for C 15 H 24 15 NO 2 : C, 71.68; H, 9.62; N, 5.57%.
　７－［ １５ Ｎ］－Ａｚａ－３，１１－Ｄｉｏｘａ－１５－ｏｘｏｄｉｓｐｉｒｏ［５．１．５．３］ｈｅｘａｄｅｃ－７－ｙｌ－７－ｏｘｙｌ（５ｂ）
　ＮＨ４Ｃｌを１５ＮＨ４Ｃｌに変えて、７－Ａｚａ－３，１１－Ｄｉｏｘａ－１５－ｏｘｏｄｉｓｐｉｒｏ［５．１．５．３］ｈｅｘａｄｅｃ－７－ｙｌ－７－ｏｘｙｌ（４ｂ）と同様に行った。
ｍｐ：１７１．７－１７２．０℃（ＥｔＯＡｃ）；
ＭＳ（ＦＡＢ＋）：２５６．２３（Ｍ＋＋１）；
νｍａｘ／ｃｍ－１：１７１９（Ｃ＝Ｏ）；
Ｆｏｕｎｄ：Ｃ，６１．１８；Ｈ，７．９０；Ｎ，５．５２％．Ｃａｌｃ．ｆｏｒ　Ｃ１３Ｈ２０ １５ＮＯ４：Ｃ，６１．１６；Ｈ，７．９０；Ｎ，５．４８％． 7- [ 15 N] -Aza-3,11-Dioxa-15-oxodispiro [5.1.5.3] hexadec-7-yl-7-oxyl (5b)
Change in the same manner as 7-Aza-3,11-Dioxa-15-oxodispiro [5.1.5.3] hexadec-7-yl-7-oxyl (4b), changing NH 4 Cl to 15 NH 4 Cl. It was.
mp: 171.7-172.0 ° C. (EtOAc);
MS (FAB <+> ): 256.23 (M ++ 1);
ν max / cm −1 : 1719 (C═O);
Found: C, 61.18; H, 7.90; N, 5.52%. Calc. for C 13 H 20 15 NO 4 : C, 61.16; H, 7.90; N, 5.48%.
　７－［ １５ Ｎ］－Ａｚａ－３，１１，１５－ｔｒｉｏｘｏｄｉｓｐｉｒｏ［５．１．５．３］ｈｅｘａｄｅｃ－７－ｙｌ－７－ｏｘｙｌ（５ｃ）
　ＮＨ４Ｃｌを１５ＮＨ４Ｃｌに変えて、７－Ａｚａ－３，１１，１５－ｔｒｉｏｘｏｄｉｓｐｉｒｏ［５．１．５．３］ｈｅｘａｄｅｃ－７－ｙｌ－７－ｏｘｙｌ（４ｅ’）と同様に行った。
ｍｐ：１６５．８℃（Ｈｅｘａｎｅ－ＥｔＯＡｃ）；
ＭＳ（ＦＡＢ＋）：２８０．２２（Ｍ＋＋１）；
νｍａｘ／ｃｍ－１：１７０７（Ｃ＝Ｏ）；
Ｆｏｕｎｄ：Ｃ，６４．４７；Ｈ，７．２２；Ｎ，５．０１％．Ｃａｌｃ．ｆｏｒ　Ｃ１５Ｈ２０ １５ＮＯ４：Ｃ，６４．５０；Ｈ，７．２２；Ｎ，５．０１％． 7- [ 15 N] -Aza-3,11,15-trioxodispiro [5.1.5.3] hexadec-7-yl-7-oxyl (5c)
NH 4 Cl was changed to 15 NH 4 Cl, and the same procedure as 7-Aza-3,11,15-trioxodispiro [5.1.5.3] hexadec-7-yl-7-oxyl (4e ′) was performed. .
mp: 165.8 ° C. (Hexane-EtOAc);
MS (FAB + ): 280.22 (M ++ 1);
ν max / cm −1 : 1707 (C═O);
Found: C, 64.47; H, 7.22; N, 5.01%. Calc. for C 15 H 20 15 NO 4 : C, 64.50; H, 7.22; N, 5.01%.
　２，２－ｄｉｅｔｈｙｌ－６，６－ｄｉｍｅｔｈｙｌｐｉｐｅｒｉｄｉｎ－４－ｏｎｅ　（１）
　１，２，２，６，６－ペンタメチルピペリジン－４－オン１．６９ｇ（１０ｍｍｏｌ）と３－ペンタノン５．１６ｇ（６０ｍｍｏｌ）をＤＭＳＯ　２８ｍｌに溶解し、ＣｓＯＨ　１．５０ｇ（１０ｍｍｏｌ）、ＮＨ４Ｃｌ　３．２２ｇ（６０ｍｍｏｌ）を室温下で加えた。この溶液を８０℃で４時間攪拌した。水を適量加えて希釈し、７～８％塩酸水溶液で酸性にした。これを、エーテルで洗浄し、水層をＫ２ＣＯ３水溶液でアルカリ性にした。さらに、これを酢酸エチルで抽出し、有機層を硫酸ナトリウムで乾燥し、溶媒を完全に留去した。その後、シリカゲルカラムクロマトグラフィー（ヘキサン、酢酸エチル）で精製し、淡黄色油状物質２５ｍｇ（収率：１％）を得た。 2,2-diethyl-6,6-dimethylpiperidin-4-one (1)
1.69 g (10 mmol) of 1,2,2,6,6-pentamethylpiperidin-4-one and 5.16 g (60 mmol) of 3-pentanone were dissolved in 28 ml of DMSO, and 1.50 g (10 mmol) of CsOH, NH 4 Cl 3.22 g (60 mmol) was added at room temperature. The solution was stirred at 80 ° C. for 4 hours. An appropriate amount of water was added for dilution, and the solution was acidified with a 7-8% aqueous hydrochloric acid solution. This was washed with ether and the aqueous layer was made alkaline with aqueous K 2 CO 3 solution. Further, this was extracted with ethyl acetate, the organic layer was dried over sodium sulfate, and the solvent was completely distilled off. Thereafter, the residue was purified by silica gel column chromatography (hexane, ethyl acetate) to obtain 25 mg (yield: 1%) of a pale yellow oily substance.
　方法Ｂ
　２，２－ｄｉｍｅｔｈｙｌ－６，６－ｄｉｐｒｏｐｙｌｐｉｐｅｒｉｄｉｎ－４－ｏｎｅ　（３）
　１，２，２，６，６－ペンタメチルピペリジン－４－オン１．６９ｇ（１０ｍｍｏｌ）と４－ヘプタノン３．４３ｇ（３０ｍｍｏｌ）をＤＭＳＯ　１６ｍｌに溶解し、ＴｒｉｔｏｎＢ　２ｍｌ（４．４０ｍｍｏｌ）、ＮＨ４Ｃｌ　２．６８ｇ（５０ｍｍｏｌ）を室温下で加えた。この溶液を５０℃で４．５時間攪拌した。水を適量加えて希釈し、７～８％塩酸水溶液で酸性にした。これを、エーテルで洗浄し、水層をＫ２ＣＯ３水溶液でアルカリ性にした。さらに、これを酢酸エチルで抽出し、有機層を硫酸ナトリウムで乾燥し、溶媒を完全に留去した。その後、シリカゲルカラムクロマトグラフィー（ヘキサン、酢酸エチル）で精製し、得られた結晶をヘキサンから再結晶し、淡黄色針状結晶３６８ｍｇ（収率：１７％）を得た。ｍｐ：５３．４－５５．０℃；ＭＳ（ＦＡＢ＋）：２１２．２（Ｍ＋＋１）；ｖｍａｘ／ｃｍ－１：１６９０（Ｃ＝Ｏ）；１Ｈ－ＮＭＲ（３００ＭＨｚ；ＣＤＣｌ３）δ（ｐｐｍ）：０．８８（６Ｈ，ｔ，Ｊ＝７．０５Ｈｚ），１．２１（６Ｈ，ｓ），１．２６－１．４５（８Ｈ，ｍ），２．２３（２Ｈ，ｓ），２．２６（２Ｈ，ｓ）；Ｆｏｕｎｄ：Ｃ，７３．７４；Ｈ，１１．８８；Ｎ，６．６７％．Ｃａｌｃ．ｆｏｒ　Ｃ１３Ｈ２５ＮＯ：Ｃ，７３．８８；Ｈ，１１．９２；Ｎ，６．６３％． Method B
2,2-dimethyl-6,6-dipropyliperidin-4-one (3)
1.69 g (10 mmol) of 1,2,2,6,6-pentamethylpiperidin-4-one and 3.43 g (30 mmol) of 4-heptanone were dissolved in 16 ml of DMSO, 2 ml (4.40 mmol) of Triton B, NH 4 2.68 g (50 mmol) of Cl was added at room temperature. The solution was stirred at 50 ° C. for 4.5 hours. An appropriate amount of water was added for dilution, and the solution was acidified with a 7-8% aqueous hydrochloric acid solution. This was washed with ether and the aqueous layer was made alkaline with aqueous K 2 CO 3 solution. Further, this was extracted with ethyl acetate, the organic layer was dried over sodium sulfate, and the solvent was completely distilled off. Then, it refine | purified by silica gel column chromatography (hexane, ethyl acetate), and the obtained crystal was recrystallized from hexane to obtain 368 mg (yield: 17%) of pale yellow needle-like crystals. mp: 53.4-55.0 ° C .; MS (FAB + ): 212.2 (M + +1); v max / cm −1 : 1690 (C═O); 1 H-NMR (300 MHz; CDCl 3 ) δ (ppm): 0.88 (6H, t, J = 7.05 Hz), 1.21 (6H, s), 1.26-1.45 (8H, m), 2.23 (2H, s) 2.26 (2H, s); Found: C, 73.74; H, 11.88; N, 6.67%. Calc. for C 13 H 25 NO: C , 73.88; H, 11.92; N, 6.63%.
　２，２－ｄｉｍｅｔｈｙｌ－６，６－ｄｉｐｒｏｐｙｌ－４－ｏｘｏ－ｐｉｐｅｒｉｄｉｎ－１－ｙｌ　１－ｏｘｙｌ（４）
　方法Ａに従って、２，２－ｄｉｍｅｔｈｙｌ－６，６－ｄｉｐｒｏｐｙｌｐｉｐｅｒｉｄｉｎ－４－ｏｎｅ（３）５９ｍｇ（０．２８ｍｍｏｌ）を原料として行った。反応溶液は、室温で一晩攪拌した。また、反応の進行をＴＬＣで確認し、Ｈ２Ｏ２とＮａ２ＷＯ４・２Ｈ２Ｏを適宜追加した。抽出後、シリカゲルカラムクロマトグラフィー（ヘキサン、酢酸エチル）で精製し、橙色油状物質３８ｍｇ（収率：６０％）を得た。ＭＳ（ＦＡＢ＋）：２２６．３（Ｍ＋）；ｖｍａｘ／ｃｍ－１：１７２０（Ｃ＝Ｏ）；Ｆｏｕｎｄ：Ｃ，６８．９５；Ｈ，１０．７６；Ｎ，６．２８％．Ｃａｌｃ．ｆｏｒ　Ｃ１３Ｈ２４ＮＯ２：Ｃ，６８．９９；Ｈ，１０．６９；Ｎ，６．１９％． 2,2-dimethyl-6,6-dipropyl-4-oxo-piperidin-1-yl 1-oxyl (4)
According to Method A, 2,2-dimethyl-6,6-dipropyliperidin-4-one (3) 59 mg (0.28 mmol) was used as a starting material. The reaction solution was stirred overnight at room temperature. Moreover, the progress of the reaction was confirmed by TLC, and H 2 O 2 and Na 2 WO 4 · 2H 2 O were appropriately added. After extraction, the product was purified by silica gel column chromatography (hexane, ethyl acetate) to obtain 38 mg (yield: 60%) of an orange oily substance. MS (FAB + ): 226.3 (M + ); vmax / cm- 1 : 1720 (C = O); Found: C, 68.95; H, 10.76; N, 6.28%. Calc. for C 13 H 24 NO 2: C, 68.99; H, 10.69; N, 6.19%.
　２，２－ｄｉｂｕｔｙｌ－６，６－ｄｉｍｅｔｈｙｌｐｉｐｅｒｉｄｉｎ－４－ｏｎｅ　（５）
　方法Ｂに従って、４－ヘプタノンを５－デカノン４．２７ｇ（３０ｍｍｏｌ）に変えて行った。反応溶液は、６０℃の水浴中で４時間攪拌した。シリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル，８５：１５）で精製し、淡黄色油状物質１０６ｍｇ（収率：４％）を得た。ＭＳ（ＦＡＢ＋）：２４０．３（Ｍ＋＋１）；ｖｍａｘ／ｃｍ－１：１７０５（Ｃ＝Ｏ）；１Ｈ－ＮＭＲ（３００ＭＨｚ；ＣＤＣｌ３）δ（ｐｐｍ）：０．８９（６Ｈ，ｔ，Ｊ＝６．７Ｈｚ），１．２５（６Ｈ，ｓ），１．２４－１．５６（１２Ｈ，ｍ），２．２３（２Ｈ，ｓ），２．２６（２Ｈ，ｓ）；Ｆｏｕｎｄ：Ｃ，７４．８３；Ｈ，１１．９６；Ｎ，５．９７％．Ｃａｌｃ．ｆｏｒ　Ｃ１５Ｈ２９ＮＯ：Ｃ，７５．２６；Ｈ，１２．２１；Ｎ，５．８５％． 2,2-dibutyl-6,6-dimethylpiperidin-4-one (5)
According to Method B, 4-heptanone was changed to 4.27 g (30 mmol) of 5-decanone. The reaction solution was stirred in a 60 ° C. water bath for 4 hours. Purification by silica gel column chromatography (hexane / ethyl acetate, 85:15) gave 106 mg (yield: 4%) of a pale yellow oily substance. MS (FAB + ): 240.3 (M + +1); v max / cm −1 : 1705 (C═O); 1 H-NMR (300 MHz; CDCl 3 ) δ (ppm): 0.89 (6H, t, J = 6.7 Hz), 1.25 (6H, s), 1.24-1.56 (12H, m), 2.23 (2H, s), 2.26 (2H, s); : C, 74.83; H, 11.96; N, 5.97%. Calc. for C 15 H 29 NO: C , 75.26; H, 12.21; N, 5.85%.
　２，２－ｄｉｂｕｔｙｌ－６，６－ｄｉｍｅｔｈｙｌ－４－ｏｘｏ－ｐｉｐｅｒｉｄｉｎ－１－ｙｌ　１－ｏｘｙｌ（６）
　方法Ａに従って、２，２－ｄｉｂｕｔｙｌ－６，６－ｄｉｍｅｔｈｙｌｐｉｐｅｒｉｄｉｎ－４－ｏｎｅ（５）１００ｍｇ（０．４２ｍｍｏｌ）を原料として行った。反応溶液は、室温で一晩攪拌した。また、反応の進行をＴＬＣで確認し、Ｈ２Ｏ２とＮａ２ＷＯ４・２Ｈ２Ｏを適宜追加した。抽出後、シリカゲルカラムクロマトグラフィー（ヘキサン、酢酸エチル）で精製し、橙色油状物質５３ｍｇ（収率：５０％）を得た。ＭＳ（ＦＡＢ＋）：２５４．３（Ｍ＋）；ｖｍａｘ／ｃｍ－１：１７２０（Ｃ＝Ｏ）；Ｆｏｕｎｄ：Ｃ，７０．５５；Ｈ，１１．０５；Ｎ，５．２４％．Ｃａｌｃ．ｆｏｒ　Ｃ１５Ｈ２８ＮＯ２：Ｃ，７０．８２；Ｈ，１１．０９；Ｎ，５．５１％． 2,2-dibutyl-6,6-dimethyl-4-oxo-piperidin-1-yl 1-oxyl (6)
According to Method A, 2,2-dibutyl-6,6-dimethylpiperidin-4-one (5) 100 mg (0.42 mmol) was used as a starting material. The reaction solution was stirred overnight at room temperature. Moreover, the progress of the reaction was confirmed by TLC, and H 2 O 2 and Na 2 WO 4 · 2H 2 O were appropriately added. After extraction, the product was purified by silica gel column chromatography (hexane, ethyl acetate) to obtain 53 mg (yield: 50%) of an orange oily substance. MS (FAB + ): 254.3 (M + ); v max / cm −1 : 1720 (C═O); Found: C, 70.55; H, 11.05; N, 5.24%. Calc. for C 15 H 28 NO 2: C, 70.82; H, 11.09; N, 5.51%.
　２－ｂｕｔｙｌ－２，６，６－ｔｒｉｍｅｔｈｙｌｐｉｐｅｒｉｄｉｎ－４－ｏｎｅ　（７）
２，６－ｄｉｂｕｔｙｌ－２，６－ｄｉｍｅｔｈｙｌｐｉｐｅｒｉｄｉｎ－４－ｏｎｅ　（９）
　方法Ｂに従って、４－ヘプタノンを２－ヘキサノン３．００ｇ（３０ｍｍｏｌ）に変えて行った。反応溶液は、５０℃の水浴中で２．５時間攪拌した。抽出後、シリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル，９：１）で精製し、淡黄色油状物質（７）２３９ｍｇ（収率：１２％）と淡黄色油状物質（９）９８ｍｇ（収率：４％）を得た。（７）：ＭＳ（ＦＡＢ＋）：１９８．３（Ｍ＋＋１）；ｖｍａｘ／ｃｍ－１：１７０３（Ｃ＝Ｏ）；１Ｈ－ＮＭＲ（３００ＭＨｚ；ＣＤＣｌ３）δ（ｐｐｍ）：０．９０（３Ｈ，ｔ，Ｊ＝７．１Ｈｚ），１．１６（３Ｈ，ｓ），１．２３（６Ｈ，ｓ），１．２９－１．３３（６Ｈ，ｍ），２．２２－２．２６（４Ｈ，ｍ）；Ｆｏｕｎｄ：Ｃ，７２．８３；Ｈ，１１．６３；Ｎ，７．０２％．Ｃａｌｃ．ｆｏｒ　Ｃ１２Ｈ２３ＮＯ：Ｃ，７３．０４；Ｈ，１１．７５；Ｎ，７．１０％．（９）：ＭＳ（ＦＡＢ＋）：２４０．４（Ｍ＋＋１）；ｖｍａｘ／ｃｍ－１：１７０６（Ｃ＝Ｏ）；１Ｈ－ＮＭＲ（３００ＭＨｚ；ＣＤＣｌ３）δ（ｐｐｍ）：０．９１（６Ｈ，ｔ，Ｊ＝３．３Ｈｚ），１．１４（６Ｈ，ｓ），１．２８－１．４６（１２Ｈ，ｍ），２．１８－２．３１（４Ｈ，ｍ）；Ｆｏｕｎｄ：Ｃ，７５．１５；Ｈ，１２．１１；Ｎ，５．７５％．Ｃａｌｃ．ｆｏｒ　Ｃ１５Ｈ２９ＮＯ：Ｃ，７５．２６；Ｈ，１２．２１；Ｎ，５．８５％． 2-butyl-2,6,6-trimethylpiperidin-4-one (7)
2,6-dibutyl-2,6-dimethylpiperidin-4-one (9)
According to Method B, 4-heptanone was changed to 3.00 g (30 mmol) of 2-hexanone. The reaction solution was stirred in a 50 ° C. water bath for 2.5 hours. After extraction, the product was purified by silica gel column chromatography (hexane / ethyl acetate, 9: 1) to obtain 239 mg (yield: 12%) of a pale yellow oily substance (7) and 98 mg (yield: 4) of a pale yellow oily substance (9). %). (7): MS (FAB + ): 198.3 (M + +1); v max / cm −1 : 1703 (C═O); 1 H-NMR (300 MHz; CDCl 3 ) δ (ppm): 0. 90 (3H, t, J = 7.1 Hz), 1.16 (3H, s), 1.23 (6H, s), 1.29-1.33 (6H, m), 2.22-2. 26 (4H, m); Found: C, 72.83; H, 11.63; N, 7.02%. Calc. for C 12 H 23 NO: C , 73.04; H, 11.75; N, 7.10%. (9): MS (FAB + ): 240.4 (M + +1); v max / cm −1 : 1706 (C═O); 1 H-NMR (300 MHz; CDCl 3 ) δ (ppm): 0. 91 (6H, t, J = 3.3 Hz), 1.14 (6H, s), 1.28-1.46 (12H, m), 2.18-2.31 (4H, m); Found: C, 75.15; H, 12.11; N, 5.75%. Calc. for C 15 H 29 NO: C , 75.26; H, 12.21; N, 5.85%.
　２－ｂｕｔｙｌ－２，６，６－ｔｒｉｍｅｔｈｙｌ－４－ｏｘｏ－ｐｉｐｅｒｉｄｉｎ－１－ｙｌ　１－ｏｘｙｌ（８）
　方法Ａに従って、２－ｂｕｔｙｌ－２，６，６－ｔｒｉｍｅｔｈｙｌｐｉｐｅｒｉｄｉｎ－４－ｏｎｅ（７）１９９ｍｇ（１．０１ｍｍｏｌ）を原料として行った。反応溶液は、室温で一晩攪拌した。また、反応の進行をＴＬＣで確認し、Ｈ２Ｏ２とＮａ２ＷＯ４・２Ｈ２Ｏを適宜追加した。抽出後、シリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル，９５：５）で精製し、橙色油状物質６８ｍｇ（収率：３２％）を得た。ＭＳ（ＦＡＢ＋）：２１２．３（Ｍ＋）；ｖｍａｘ／ｃｍ－１：１７２０（Ｃ＝Ｏ）；Ｆｏｕｎｄ：Ｃ，６８．０１；Ｈ，１０．４４；Ｎ，６．５３％．Ｃａｌｃ．ｆｏｒ　Ｃ１２Ｈ２２ＮＯ２：Ｃ，６７．８９；Ｈ，１０．４４；Ｎ，６．６０％． 2-butyl-2,6,6-trimethyl-4-oxo-piperidin-1-yl 1-oxyl (8)
According to Method A, 2-butyl-2,6,6-trimethylpiperidin-4-one (7) (199 mg, 1.01 mmol) was used as a starting material. The reaction solution was stirred overnight at room temperature. Moreover, the progress of the reaction was confirmed by TLC, and H 2 O 2 and Na 2 WO 4 · 2H 2 O were appropriately added. After extraction, the residue was purified by silica gel column chromatography (hexane / ethyl acetate, 95: 5) to obtain 68 mg (yield: 32%) of an orange oily substance. MS (FAB +): 212.3 ( M +); v max / cm -1: 1720 (C = O); Found: C, 68.01; H, 10.44; N, 6.53%. Calc. for C 12 H 22 NO 2: C, 67.89; H, 10.44; N, 6.60%.
　２，６－ｄｉｂｕｔｙｌ－２，６－ｄｉｍｅｔｈｙｌ－４－ｏｘｏ－ｐｉｐｅｒｉｄｉｎ－１－ｙｌ－ｏｘｙｌ（１０）
　方法Ａに従って、２，６－ｄｉｂｕｔｙｌ－２，６－ｄｉｍｅｔｈｙｌｐｉｐｅｒｉｄｉｎ－４－ｏｎｅ（９）７７ｍｇ（０．３２ｍｍｏｌ）を原料として行った。反応溶液は、室温で一晩攪拌した。また、反応の進行をＴＬＣで確認し、Ｈ２Ｏ２とＮａ２ＷＯ４・２Ｈ２Ｏを適宜追加した。抽出後、シリカゲルカラムクロマトグラフィー（ヘキサン、酢酸エチル）で精製し、橙色油状物質２５ｍｇ（収率：３１％）を得た。ＭＳ（ＦＡＢ＋）：２５４．３（Ｍ＋）；ｖｍａｘ／ｃｍ－１：１７２０（Ｃ＝Ｏ）；Ｆｏｕｎｄ：Ｃ，７０．９４；Ｈ，１０．９８；Ｎ，５．１８％．Ｃａｌｃ．ｆｏｒ　Ｃ１５Ｈ２８ＮＯ２：Ｃ，７０．８２；Ｈ，１１．０９；Ｎ，５．５１％． 2,6-dibutyl-2,6-dimethyl-4-oxo-piperidin-1-yl-oxyl (10)
According to Method A, 2,6-dibutyl-2,6-dimethylpiperidin-4-one (9) 77 mg (0.32 mmol) was used as a starting material. The reaction solution was stirred overnight at room temperature. Moreover, the progress of the reaction was confirmed by TLC, and H 2 O 2 and Na 2 WO 4 · 2H 2 O were appropriately added. After extraction, the product was purified by silica gel column chromatography (hexane, ethyl acetate) to obtain 25 mg (yield: 31%) of an orange oily substance. MS (FAB + ): 254.3 (M + ); v max / cm −1 : 1720 (C═O); Found: C, 70.94; H, 10.98; N, 5.18%. Calc. for C 15 H 28 NO 2: C, 70.82; H, 11.09; N, 5.51%.
　２，２，６－ｔｒｉｍｅｔｈｙｌ－６－ｏｃｔｙｌｐｉｐｅｒｉｄｉｎ－４－ｏｎｅ　（１１）
　方法Ｂに従って、４－ヘプタノンを２－デカノン４．６９ｇ（３０ｍｍｏｌ）に変えて行った。反応溶液は、５０℃の水浴中で４時間攪拌した。抽出後、シリカゲルカラムクロマトグラフィー（ヘキサン、酢酸エチル）で精製し、淡黄色油状物質１３７ｍｇ（収率：５％）を得た。ＭＳ（ＦＡＢ＋）：２５４．３（Ｍ＋＋１）；ｖｍａｘ／ｃｍ－１：１７０８（Ｃ＝Ｏ）；１Ｈ－ＮＭＲ（３００ＭＨｚ；ＣＤＣｌ３）δ（ｐｐｍ）：０．８７（３Ｈ，ｔ，Ｊ＝５．７Ｈｚ），１．１６（３Ｈ，ｓ），１．２２（６Ｈ，ｓ），２．１６－２．２９（４Ｈ，ｍ）；Ｆｏｕｎｄ：Ｃ，７５．５７；Ｈ，１２．１５；Ｎ，５．０９％．Ｃａｌｃ．ｆｏｒ　Ｃ１６Ｈ３１ＮＯ：Ｃ，７５．８３；Ｈ，１２．３３；Ｎ，５．５３％． 2,2,6-trimethyl-6-octipeliperidin-4-one (11)
According to Method B, 4-heptanone was changed to 4.69 g (30 mmol) of 2-decanone. The reaction solution was stirred in a 50 ° C. water bath for 4 hours. After extraction, the product was purified by silica gel column chromatography (hexane, ethyl acetate) to obtain 137 mg (yield: 5%) of a pale yellow oily substance. MS (FAB + ): 254.3 (M + +1); v max / cm −1 : 1708 (C═O); 1 H-NMR (300 MHz; CDCl 3 ) δ (ppm): 0.87 (3H, t, J = 5.7 Hz), 1.16 (3H, s), 1.22 (6H, s), 2.16-2.29 (4H, m); Found: C, 75.57; H, 12.15; N, 5.09%. Calc. for C 16 H 31 NO: C, 75.83; H, 12.33; N, 5.53%.
　２，２，６－ｔｒｉｍｅｔｈｙｌ－６－ｏｃｔｙｌ－４－ｏｘｏ－ｐｉｐｅｒｉｄｉｎ－１－ｙｌ　１－ｏｘｙｌ（１２）
　方法Ａに従って、２，２，６－ｔｒｉｍｅｔｈｙｌ－６－ｏｃｔｙｌｐｉｐｅｒｉｄｉｎ－４－ｏｎｅ（１１）１００ｍｇ（０．３９ｍｍｏｌ）を原料として行った。反応溶液は、室温で一晩攪拌した。また、反応の進行をＴＬＣで確認し、Ｈ２Ｏ２とＮａ２ＷＯ４・２Ｈ２Ｏを適宜追加した。抽出後、シリカゲルカラムクロマトグラフィー（ヘキサン、酢酸エチル）で精製し、橙色油状物質７８ｍｇ（収率：７４％）を得た。ＭＳ（ＦＡＢ＋）：２６８．３（Ｍ＋）；ｖｍａｘ／ｃｍ－１：１７２１（Ｃ＝Ｏ）；Ｆｏｕｎｄ：Ｃ，７１．４５；Ｈ，１１．１３；Ｎ，５．１０％．Ｃａｌｃ．ｆｏｒ　Ｃ１６Ｈ３０ＮＯ２：Ｃ，７１．５９；Ｈ，１１．２７；Ｎ，５．２２％． 2,2,6-trimethyl-6-octyl-4-oxo-piperidin-1-yl 1-oxyl (12)
According to method A, 2,2,6-trimethyl-6-octipeliperidin-4-one (11) 100 mg (0.39 mmol) was used as a starting material. The reaction solution was stirred overnight at room temperature. Moreover, the progress of the reaction was confirmed by TLC, and H 2 O 2 and Na 2 WO 4 · 2H 2 O were appropriately added. After extraction, the product was purified by silica gel column chromatography (hexane, ethyl acetate) to obtain 78 mg (yield: 74%) of an orange oily substance. MS (FAB + ): 268.3 (M + ); v max / cm −1 : 1721 (C═O); Found: C, 71.45; H, 11.13; N, 5.10%. Calc. for C 16 H 30 NO 2: C, 71.59; H, 11.27; N, 5.22%.
　２，２－ｄｉｍｅｔｈｙｌ－６－ｓｐｉｒｏ－２’－ｔｒｉｃｙｃｌｏ［３．３．１．１ ３’，７’ ］ｄｅｃａｎｅｐｉｐｅｒｉｄｉｎｅ－４－ｏｎｅ（１３）
２，６－ｄｉｓｐｉｒｏ－２’，２’－ｄｉｔｒｉｃｙｃｌｏ［３．３．１．１ ３’，７’ ］ｄｅｃａｎｅｐｉｐｅｒｉｄｉｎｅ－４－ｏｎｅ（１６）
　方法Ｂに従って、４－ヘプタノンを２－アダマンタノン４．５１ｇ（３０ｍｍｏｌ）に変えて行った。反応条件はＴａｂｌｅに示した。抽出後、シリカゲルカラムクロマトグラフィー（ヘキサン、酢酸エチル）で精製し、得られた結晶をヘキサンからそれぞれ再結晶し、白色針状結晶（１３）と淡黄色鱗片状結晶（１６）を得た。（１３）：収率：（粗結晶）；ｍｐ：９２．５－９２．６℃；ＭＳ（ＦＡＢ＋）：２４８．３（Ｍ＋＋１）；ｖｍａｘ／ｃｍ－１：１６９９（Ｃ＝Ｏ）；１Ｈ－ＮＭＲ（３００ＭＨｚ；ＣＤＣｌ３）δ（ｐｐｍ）：１．２３（６Ｈ，ｓ），１．５０－１．９５（１４Ｈ，ｍ），２．２７（２Ｈ，ｓ），２．５３（２Ｈ，ｓ）；Ｆｏｕｎｄ：Ｃ，７７．６５；Ｈ，１０．１２；Ｎ，５．６０％．Ｃａｌｃ．ｆｏｒ　Ｃ１６Ｈ２５ＮＯ：Ｃ，７７．６８；Ｈ，１０．１９；Ｎ，５．６６％．（１６）：収率：０．６２％（２．５時間５０℃）（粗結晶）；ｍｐ：１３１．２－１３１．５℃；ＭＳ（ＦＡＢ＋）：３４０．４（Ｍ＋＋１）；ｖｍａｘ／ｃｍ－１：１７０９（Ｃ＝Ｏ）；１Ｈ－ＮＭＲ（４００ＭＨｚ；ＣＤＣｌ３）δ（ｐｐｍ）：１．２５（ｂｒｓ），１．５６－１．６９（ｍ），１．７９－１．９２（ｍ），２．３３（ｂｒｓ），２．３６（ｂｒｓ），２．６１（４Ｈ，ｓ）；Ｆｏｕｎｄ：Ｃ，８１．３０；Ｈ，９．７７；Ｎ，４．０７％．Ｃａｌｃ．ｆｏｒ　Ｃ２３Ｈ３３ＮＯ：Ｃ，８１．３７；Ｈ，９．８０；Ｎ，４．１３％． 2,2-dimethyl-6-spiro-2′-tricyclo [3.3.1.1 3 ′, 7 ′ ] decane piperidine-4-one (13)
2,6-dispiro-2 ′, 2′-dilyticcyclo [3.3.1.1 3 ′, 7 ′ ] decane piperidine-4-one (16)
According to Method B, 4-heptanone was changed to 4.51 g (30 mmol) of 2-adamantanone. The reaction conditions are shown in Table. After extraction, the product was purified by silica gel column chromatography (hexane, ethyl acetate), and the resulting crystals were recrystallized from hexane to obtain white needle crystals (13) and pale yellow scale crystals (16). (13): Yield: (crude crystals); mp: 92.5-92.6 ° C .; MS (FAB + ): 248.3 (M + +1); v max / cm −1 : 1699 (C═O 1 H-NMR (300 MHz; CDCl 3 ) δ (ppm): 1.23 (6H, s), 1.50-1.95 (14H, m), 2.27 (2H, s), 2. 53 (2H, s); Found: C, 77.65; H, 10.12; N, 5.60%. Calc. for C 16 H 25 NO: C, 77.68; H, 10.19; N, 5.66%. (16): Yield: 0.62% (2.5 hours at 50 ° C.) (crude crystals); mp: 131.2-131.5 ° C .; MS (FAB + ): 340.4 (M + +1); v max / cm −1 : 1709 (C═O); 1 H-NMR (400 MHz; CDCl 3 ) δ (ppm): 1.25 (brs), 1.56-1.69 (m), 1.79 -1.92 (m), 2.33 (brs), 2.36 (brs), 2.61 (4H, s); Found: C, 81.30; H, 9.77; N, 4.07 %. Calc. for C 23 H 33 NO: C , 81.37; H, 9.80; N, 4.13%.
　方法Ｃ
　２，２－ｄｉｍｅｔｈｙｌ－６－ｓｐｉｒｏ－２’－ｔｒｉｃｙｃｌｏ［３．３．１．１ ３’，７’ ］ｄｅｃａｎｅ－４－ｏｘｏ－ｐｉｐｅｒｉｄｉｎ－１－ｙｌ　１ｏｘｙｌ　（１４）
２，２－ｄｉｍｅｔｈｙｌ－６－ｓｐｉｒｏ－２’－ｔｒｉｃｙｃｌｏ［３．３．１．１３’，７’］ｄｅｃａｎｅｐｉｐｅｒｉｄｉｎｅ－４－ｏｎｅ（１３）４１０ｍｇ（１．６６ｍｍｏｌ）をクロロホルム３０ｍｌに溶解し、氷浴中で攪拌した。ＭＣＰＢＡ３７１ｍｇ（１．６６ｍｍｏｌ）を加え、１５分後に室温に戻し、さらに２時間攪拌を続けた。クロロホルムで抽出を行い、有機層を硫酸ナトリウムで乾燥し、溶媒を完全に留去した。その後、シリカゲルカラムクロマトグラフィー（ヘキサン、酢酸エチル）で精製し、得られた結晶をジイソプロピルエーテルから再結晶し、橙色鱗片状結晶１７２ｍｇ（収率：４０％）を得た。ｍｐ：１３４．７－１３５．３℃；ＭＳ（ＦＡＢ＋）：２６２．３（Ｍ＋）；ｖｍａｘ／ｃｍ－１：１７０９（Ｃ＝Ｏ）；Ｆｏｕｎｄ：Ｃ，７３．１３；Ｈ，９．１４；Ｎ，５．２９％．Ｃａｌｃ．ｆｏｒ　Ｃ１６Ｈ２４ＮＯ２：Ｃ，７３．２５；Ｈ，９．２２；Ｎ，５．３４％． Method C
2,2-dimethyl-6-spiro-2′-tricyclo [3.3.1.1 3 ′, 7 ′ ] decane-4-oxo-piperidin-1-yl 1oxyl (14)
2,2-dimethyl-6-spiro-2′-tricyclo [3.3.1.1 3 ′, 7 ′ ] decane piperidine-4-one (13) 410 mg (1.66 mmol) was dissolved in chloroform 30 ml, ice Stir in the bath. 371 mg (1.66 mmol) of MCPBA was added, and after 15 minutes, the temperature was returned to room temperature, and stirring was further continued for 2 hours. Extraction was performed with chloroform, the organic layer was dried over sodium sulfate, and the solvent was completely distilled off. Then, it refine | purified by silica gel column chromatography (hexane, ethyl acetate), and the obtained crystal | crystallization was recrystallized from diisopropyl ether, and 172 mg (yield: 40%) of the orange scale-like crystal | crystallization was obtained. mp: 134.7-135.3 ° C .; MS (FAB + ): 262.3 (M + ); v max / cm −1 : 1709 (C═O); Found: C, 73.13; H, 9 .14; N, 5.29%. Calc. for C 16 H 24 NO 2: C, 73.25; H, 9.22; N, 5.34%.
　２，２－ｄｉｍｅｔｈｙｌ－６－ｓｐｉｒｏ－２’－ｔｒｉｃｙｃｌｏ［３．３．１．１ ３’，７’ ］ｄｅｃａｎｅ　－４－ｈｙｄｒｏｘｙ－ｐｉｐｅｒｉｄｉｎ－１－ｙｌ　１ｏｘｙｌ　（１５）
２，２－ｄｉｍｅｔｈｙｌ－６－ｓｐｉｒｏ－２’－ｔｒｉｃｙｃｌｏ［３．３．１．１３’，７’］ｄｅｃａｎｅ－４－ｏｘｏ－ｐｉｐｅｒｉｄｉｎ－１－ｙｌ　１ｏｘｙｌ（１４）１８０ｍｇ（０．７３ｍｍｏｌ）をエタノール５ｍｌに溶解し、水浴中で攪拌した。ＮａＢＨ４３４ｍｇ（０．９１ｍｍｏｌ）を加え、室温に戻し、一晩攪拌を続けた。また、反応の進行をＴＬＣで確認し、ＮａＢＨ４を適宜追加した。これをクロロホルムで抽出し、有機層を硫酸ナトリウムで乾燥し、溶媒を完全に留去した。その後、シリカゲルカラムクロマトグラフィー（クロロホルム／メタノール，９９：１）で精製し、得られた結晶を酢酸エチルから再結晶し、赤紫色鱗片状結晶８９ｍｇ（収率：４６％）を得た。ｍｐ：１３２．０－１３３．６℃；ＭＳ（ＦＡＢ＋）：２６４．３（Ｍ＋）；ｖｍａｘ／ｃｍ－１：３４０７（ｂｒ，ＯＨ）；Ｆｏｕｎｄ：Ｃ，７２．５５；Ｈ，９．８９；Ｎ，５．３６％．Ｃａｌｃ．ｆｏｒ　Ｃ１６Ｈ２４ＮＯ２：Ｃ，７２．６９；Ｈ，９．９１；Ｎ，５．３０％． 2,2-dimethyl-6-spiro-2′-tricyclo [3.3.1.1 3 ′, 7 ′ ] decane-4-hydroxy-piperidin-1-yl 1oxyl (15)
2,2-dimethyl-6-spiro-2′-tricyclo [3.3.1.1 3 ′, 7 ′ ] decane-4-oxo-piperidin-1-yl 1oxyl (14) 180 mg (0.73 mmol) Dissolved in 5 ml of ethanol and stirred in a water bath. NaBH 4 34 mg (0.91 mmol) was added, the temperature was returned to room temperature, and stirring was continued overnight. Further, the progress of the reaction was confirmed by TLC, and NaBH 4 was appropriately added. This was extracted with chloroform, the organic layer was dried over sodium sulfate, and the solvent was completely distilled off. Thereafter, the product was purified by silica gel column chromatography (chloroform / methanol, 99: 1), and the obtained crystal was recrystallized from ethyl acetate to obtain 89 mg (yield: 46%) of reddish purple scaly crystals. mp: 132.0-133.6 ° C .; MS (FAB + ): 264.3 (M + ); v max / cm −1 : 3407 (br, OH); Found: C, 72.55; H, 9 .89; N, 5.36%. Calc. for C 16 H 24 NO 2: C, 72.69; H, 9.91; N, 5.30%.
２，６－ｄｉｓｐｉｒｏ－２’，２’－ｄｉｔｒｉｃｙｃｌｏ［３．３．１．１ ３’，７’ ］ｄｅｃａｎｅｐｉｐｅｒｉｄｉｎｅ－４－ｏｘｏ－ｐｉｐｅｒｉｄｉｎ－１－ｙｌ　１－ｏｘｙｌ（１７）
方法Ｃに従って、２，６－ｄｉｓｐｉｒｏ－２’，２’－ｄｉｔｒｉｃｙｃｌｏ［３．３．１．１３’，７’］ｄｅｃａｎｅｐｉｐｅｒｉｄｉｎｅ－４－ｏｎｅ（１６）１４９ｍｇ（０．４３９ｍｍｏｌ）を原料として行った。抽出後、シリカゲルカラムクロマトグラフィー（ヘキサン、酢酸エチル）で精製し、得られた結晶をヘキサンから再結晶し、紫色球状結晶１８ｍｇ（収率：１２％）を得た。ｍｐ：１５４．６－１６０．９℃；ＭＳ（ＦＡＢ＋）：３５４．３（Ｍ＋）；ｖｍａｘ／ｃｍ－１：１７０５（Ｃ＝Ｏ）；Ｆｏｕｎｄ：Ｃ，７７．６７；Ｈ，９．０３；Ｎ，３．７６％．Ｃａｌｃ．ｆｏｒ　Ｃ２３Ｈ３２ＮＯ２：Ｃ，７７．９２；Ｈ，９．１０；Ｎ，３．９５％． 2,6-dispiro-2 ′, 2′-dilyticcyclo [3.3.1.1 3 ′, 7 ′ ] decane piperidine-4-oxo-piperidin-1-yl 1-oxyl (17)
According to Method C, 149 mg (0.439 mmol) of 2,6-dispiro-2 ′, 2′-diisticcyclo [3.3.1.1 3 ′, 7 ′ ] decanepiperidine-4-one (16) was used as a starting material. . After extraction, the product was purified by silica gel column chromatography (hexane, ethyl acetate), and the obtained crystals were recrystallized from hexane to obtain 18 mg of purple spherical crystals (yield: 12%). mp: 154.6-160.9 ° C .; MS (FAB + ): 354.3 (M + ); v max / cm −1 : 1705 (C═O); Found: C, 77.67; H, 9 .03; N, 3.76%. Calc. for C 23 H 32 NO 2: C, 77.92; H, 9.10; N, 3.95%.
　細胞毒性
　ニトロキシルラジカルは、細胞内で、アスコルビン酸やチオール（金属が触媒する反応）、ミトコンドリア呼吸鎖、ＮＡＤＰＨ、シトクロムＰ４５０などと反応することが報告され、アポトーシスの誘発や、シトクロムＰ４５０を介したＨ２Ｏ２の産生などが細胞毒性の原因となっていると報告されている。一方、テトラエチル基を有するニトロキシルラジカルは、アスコルビン酸との反応性が顕著に低下していることを、本発明者らは報告している。そこで、合成したニトロキシルラジカル化合物の細胞毒性を評価した。 Cytotoxic nitroxyl radicals have been reported to react with ascorbic acid, thiols (metal-catalyzed reactions), mitochondrial respiratory chain, NADPH, cytochrome P450, etc. in cells, inducing apoptosis and via cytochrome P450 It has been reported that production of H 2 O 2 and the like cause cytotoxicity. On the other hand, the present inventors have reported that the reactivity with the ascorbic acid of the nitroxyl radical having a tetraethyl group is significantly reduced. Therefore, the cytotoxicity of the synthesized nitroxyl radical compound was evaluated.
　方法
　ＨＵＶＥＣ（ヒト臍帯静脈内皮細胞）はブレットキットＥＧＭを培地として用いて、３７℃、５％ＣＯ２下、ＣＯ２インキュベーターで培養した。また、ＨＵＶＥＣは対数増殖期を維持するために、一定の間隔で継代を行い、２～５代培養の間を実験に用いた。ＨＵＶＥＣ（５０００ｃｅｌｌｓ／ｗｅｌｌ）は、コラーゲンＩコートした透明平底プレートを用いて、各濃度のニトロキシルラジカルを添加後、２４時間インキュベートし、細胞生存率をＷＳＴ－１法により解析した。２４時間インキュベート後、ＷＳＴ－１試薬を各ウェル１０μｌずつ添加し、３時間インキュベート後、４５０ｎｍの吸光度をプレートリーダーにて測定した。ポジティブコントロールに２％Ｔｗｅｅｎ２０、ネガティブコントロールにＰＢＳを用い、データはコントロールに対する相対値（％）で表した。 Method HUVEC (human umbilical vein endothelial cells) were cultured in a CO 2 incubator at 37 ° C. under 5% CO 2 using Brett Kit EGM as a medium. In addition, HUVEC were subcultured at regular intervals to maintain a logarithmic growth phase, and the period between 2 and 5 passages was used for the experiment. HUVEC (5000 cells / well) was incubated for 24 hours after adding each concentration of nitroxyl radical using a collagen I-coated transparent flat bottom plate, and the cell viability was analyzed by the WST-1 method. After 24 hours of incubation, 10 μl of WST-1 reagent was added to each well, and after 3 hours of incubation, the absorbance at 450 nm was measured with a plate reader. 2% Tween 20 was used as a positive control, PBS was used as a negative control, and data was expressed as a relative value (%) to the control.
　結果
　ＨＵＶＥＣ細胞にニトロキシルラジカル化合物を添加し、２４時間後の細胞増殖能を測定した。その結果、Ｏｘｏ－ＴＥＭＰＯ、Ｔｅｍｐｏｌは、濃度依存的な細胞増殖能抑制効果を示した。一方、テトラエチル基を導入した化合物では、１ｍＭの濃度まで細胞増殖能抑制効果は認められず、脂溶性が高いにも関わらず低毒性であることが示された（図１を参照）。 Results A nitroxyl radical compound was added to HUVEC cells, and the cell growth ability after 24 hours was measured. As a result, Oxo-TEMPO and Tempol showed a concentration-dependent cell growth inhibitory effect. On the other hand, a compound having a tetraethyl group introduced showed no inhibitory effect on cell growth ability up to a concentration of 1 mM, indicating that it was low in toxicity despite its high fat solubility (see FIG. 1).
　胃潰瘍モデル動物を用いた薬効評価
　アジュバント関節炎ラットの作成
　ニトロキシルラジカルが、アジュバント関節炎ラット（ＡＡラット）におけるインドメタシン惹起胃潰瘍を抑制するか否か検討した。 Evaluation of drug efficacy using gastric ulcer model animals Creation of adjuvant arthritic rats It was investigated whether nitroxyl radical suppresses indomethacin-induced gastric ulcers in adjuvant arthritic rats (AA rats).
　方法
　結核死菌Ｍｙｃｏｂａｃｔｅｒｉｕｍ　ｔｕｂｅｒｃｕｌｏｓｉｓ　Ｈ３７　ＲＡを瑪瑙乳鉢中で磨砕し、この中にｈｅａｖｙ　ｍｉｎｅｒａｌ　ｏｉｌを滴下しつつ加え、さらに磨砕し１０ｍｇ／ｍｌとした。この結核死菌－ｏｉｌ懸濁液を３分間超音波処理後１ｍｌ容量のシリンジにとり、イソフルラン麻酔下、５週齢のＤＡラットの左足蹠皮内に１００μＬ投与し、アジュバント関節炎を惹起した。陰性対照群は、ｈｅａｖｙ　ｍｉｎｅｒａｌ　ｏｉｌのみを左足蹠皮内に投与した。 Method Mycobacterium tuberculosis H37 RA was ground in an agate mortar, and heavy minor oil was added dropwise thereto, and further ground to 10 mg / ml. This tuberculosis-killed oil suspension was sonicated for 3 minutes and then taken into a 1 ml syringe, and 100 μL was administered into the left footpad of a 5-week-old DA rat under isoflurane anesthesia to induce adjuvant arthritis. In the negative control group, only heavy mineral oil was administered into the left footpad.
　ＤＡラットは、アジュバント投与後１３日目に飼育ケージ内にて絶食させた。ただし、飲料水は自由飲水とした。絶食開始から２４時間後にインドメタシン（２０ｍｇ／ｋｇ）をラットに経口投与して胃潰瘍を作成した。コントロールでは、ｖｅｈｉｃｌｅとして５％ＮａＨＣＯ３を同量経口投与した。ニトロキシルラジカル化合物は、インドメタシン投与５分前に経口投与した。 DA rats were fasted in the breeding cage on day 13 after administration of the adjuvant. However, drinking water was free drinking. After 24 hours from the start of fasting, indomethacin (20 mg / kg) was orally administered to rats to create gastric ulcers. As a control, the same amount of 5% NaHCO 3 was orally administered as a vehicle. The nitroxyl radical compound was orally administered 5 minutes before administration of indomethacin.
　胃粘膜損傷面積計測
　インドメタシンによる胃潰瘍惹起４時間後、ラットを過麻酔下頚椎脱臼により処理し、直ちに胃を食道、小腸側をそれぞれ約１ｃｍずつ残して切断し摘出した。幽門部側を鉗子で固定し、１％ホルマリン溶液を１０ｍｌ注入後、噴門部側を鉗子で固定した。これを１０－２０分間浸し続けることにより胃壁を両側面から固定した。固定後、大湾部に沿って胃を切開し、胃腔内膜をデジタルカメラで撮影した。画像処理ソフトＩｍａｇｅ　Ｊを用いて胃底部粘膜に発生した損傷面積を計測した。 Measurement of gastric mucosal damage area 4 hours after induction of gastric ulcer by indomethacin, the rat was treated by cervical dislocation under overanaesthesia, and the stomach was immediately cut and excised leaving about 1 cm each of the esophagus and the small intestine. The pylorus part side was fixed with forceps, 10 ml of 1% formalin solution was injected, and the cardia part side was fixed with forceps. The stomach wall was fixed from both sides by continuing soaking for 10-20 minutes. After fixation, the stomach was incised along the Great Bay, and the gastric lumen was photographed with a digital camera. Using the image processing software Image J, the damaged area generated in the gastric floor mucosa was measured.
　結果
　インドメタシンによる胃潰瘍惹起の程度を、インドメタシンを経口投与したＡＡラットの胃底部粘膜損傷面積で評価した結果、ニトロキシルラジカル化合物を投与していないＡＡラットでは、損傷面積が高い値を示し、胃潰瘍を惹起していること、つまり胃底部粘膜に炎症が起きていることが確認された。一方、ニトロキシルラジカル化合物を投与したＡＡラットでは、ニトロキシルラジカル化合物を投与していないＡＡラットと比較して損傷面積が有為に減少していることが示され、ニトロキシルラジカル化合物が、胃潰瘍における粘膜損傷を有為に抑制していることを示した。 Results The degree of gastric ulcer induced by indomethacin was evaluated by the damage area of the gastric fundus mucosa of the AA rat to which indomethacin was orally administered. That is, i.e., inflammation of the gastric floor mucosa was confirmed. On the other hand, the AA rats administered with the nitroxyl radical compound showed a significantly reduced damage area compared to the AA rats not administered with the nitroxyl radical compound. It showed that mucosal damage was significantly suppressed.
　既知のニトロキシルラジカル化合物であるＴｅｍｐｏｌ（図２を参照）は、９００μｍｏｌ／ｋｇの濃度で抑制作用を示しているが、本発明に基づき合成されたニトロキシルラジカル化合物（図２における化合物Ａ及びＢ）は、Ｔｅｍｐｏｌと比較して最大１／１０の濃度で有為な胃粘膜損傷の抑制作用を有していることも示され、既知化合物より低濃度で抑制効果を示すことが明らかとなった。 Tempol (see FIG. 2), a known nitroxyl radical compound, shows an inhibitory action at a concentration of 900 μmol / kg, but the nitroxyl radical compound synthesized according to the present invention (compounds A and B in FIG. 2). ) Was also shown to have significant inhibitory action on gastric mucosal damage at a concentration of up to 1/10 compared to Tempol, and it became clear that it showed an inhibitory effect at a lower concentration than known compounds .
　ニトロキシルラジカルの血圧降下作用
　ＴｅｍｐｏｌなどＴＥＭＰＯ系ニトロキシルラジカル化合物は、血圧降下作用を有し、高血圧研究に広く用いられている。血圧降下作用の原因は未だ明らかにはなっていないが、ＳＯＤ様作用と相関があることから、活性酸素消去能によるものではないかと考察されている。そこで、今回新たに合成したニトロキシルラジカル化合物の血圧降下作用を明らかにする。 TEMPO-based nitroxyl radical compounds such as Tempol, a blood pressure lowering action of nitroxyl radical, have a blood pressure lowering action and are widely used in hypertension research. Although the cause of the blood pressure lowering action has not yet been clarified, it is considered that it is due to the ability to scavenge active oxygen because it has a correlation with the SOD-like action. Therefore, we clarify the blood pressure lowering action of the newly synthesized nitroxyl radical compound.
　方法
　日周リズムへの影響を避けるために、実験は全て９：００から１６：００の間に行った。自然発症高血圧モデルラット（ＳＨＲ；♂、２０８－３３０ｇ）は、イソフルランを用いて麻酔を施した。平均血圧（ＭＡＰ）は、大腿部の動脈にポリエチレンチューブ（ＰＥ－５０）をカニュレーション後、ｔｒａｎｓｄｕｃｅｒ（ＭＬＴ０６７０　ＢＰ　Ｔｒａｎｓｄｕｃｅｒ，ＡＤｉｎｓｔｒｕｍｅｎｔｓ，Ｓｙｄｎｅｙ，Ａｕｓｔｒａｌｉａ）とａｍｐｌｉｆｉｅｒ（ＭＬ１１７　ＢＰ　Ａｍｐ，ＡＤｉｎｓｔｒｕｍｅｎｔｓ，Ｓｙｄｎｅｙ，Ａｕｓｔｒａｌｉａ）にて計測した。ニトロキシルラジカル溶液（６０μｍｏｌ／ｋｇ）を１ｍｌ／ｍｉｎの速度で大腿静脈より投与し、投与後２０分間血圧と心拍数を測定した。 Method All experiments were performed between 9:00 and 16:00 in order to avoid effects on the diurnal rhythm. Spontaneously hypertensive model rats (SHR; ♂, 208-330 g) were anesthetized with isoflurane. Mean blood pressure (MAP) cannulated polyethylene tube (PE-50) in femoral artery, then transducer (MLT0670 BP Transducer, ADinstruments, Sydney, Australia) and amplifier (ML117 BP Amp, Australia) Measured at. Nitroxyl radical solution (60 μmol / kg) was administered from the femoral vein at a rate of 1 ml / min, and blood pressure and heart rate were measured for 20 minutes after administration.
　結果
　ニトロキシルラジカル化合物を投与後の経時的な血圧変化を図３に示す。今回新たに開発したニトロキシルラジカル化合物（化合物Ｃ）が示す血圧降下作用は、既知のニトロキシルラジカル化合物であるＴｅｍｐｏｌと比較して有為に高い作用を示した。また、血圧降下作用の持続時間は、新規ニトロキシル化合物（化合物Ｃ）は、Ｔｅｍｐｏｌと比較し長時間にわたって持続することも示された。 Results FIG. 3 shows changes in blood pressure over time after administration of the nitroxyl radical compound. The blood pressure lowering action exhibited by the newly developed nitroxyl radical compound (compound C) was significantly higher than that of Tempol, which is a known nitroxyl radical compound. Moreover, it was also shown that the duration of the blood pressure lowering action lasts for a long time when the novel nitroxyl compound (Compound C) is compared with Tempol.
　尚、上述の実施例は本発明の好適な実施の一例ではあるが、その範囲を限定するものではなく、本発明の要旨を逸脱しない範囲において種々変形実施可能である。 The above-described embodiment is an example of a preferred embodiment of the present invention, but the scope thereof is not limited, and various modifications can be made without departing from the gist of the present invention.
　下記に本願発明に係る参照文献を記載するが、これらは、この参照により本願明細書に完全に組み込まれるものである。
（参照文献）
（１）Ｂ．　Ｈａｌｌｉｗｅｌｌ，　Ｏｘｉｄａｔｉｖｅ　ｓｔｒｅｓｓ　ａｎｄ　ｃａｎｃｅｒ：　ｈａｖｅ　ｗｅ　ｍｏｖｅｄ　ｆｏｒｗａｒｄ？　Ｂｉｏｃｈｅｍ　Ｊ，　２００７．　４０１（１）：　１－１１．
（２）Ｔ．　Ｓａｎｏ，　ｅｔ　ａｌ．，　Ｏｘｉｄａｔｉｖｅ　ｓｔｒｅｓｓ　ｍｅａｓｕｒｅｍｅｎｔ　ｂｙ　ｉｎ　ｖｉｖｏ　ｅｌｅｃｔｒｏｎ　ｓｐｉｎ　ｒｅｓｏｎａｎｃｅ　ｓｐｅｃｔｒｏｓｃｏｐｙ　ｉｎ　ｒａｔｓ　ｗｉｔｈ　ｓｔｒｅｐｔｏｚｏｔｏｃｉｎ－ｉｎｄｕｃｅｄ　ｄｉａｂｅｔｅｓ．　Ｄｉａｂｅｔｏｌｏｇｉａ，　１９９８．　４１（１１）：　１３５５－６０．
（３）Ｍ．　Ｙａｍａｔｏ，　Ｔ．　Ｅｇａｓｈｉｒａ，　ａｎｄ　Ｈ．　Ｕｔｓｕｍｉ，　Ａｐｐｌｉｃａｔｉｏｎ　ｏｆ　ｉｎ　ｖｉｖｏ　ＥＳＲ　ｓｐｅｃｔｒｏｓｃｏｐｙ　ｔｏ　ｍｅａｓｕｒｅｍｅｎｔ　ｏｆ　ｃｅｒｅｂｒｏｖａｓｃｕｌａｒ　ＲＯＳ　ｇｅｎｅｒａｔｉｏｎ　ｉｎ　ｓｔｒｏｋｅ．　Ｆｒｅｅ　Ｒａｄｉｃ　Ｂｉｏｌ　Ｍｅｄ，　２００３．　３５（１２）：　１６１９－３１．

（４）Ｈ．Ｕｔｓｕｍｉ，　ｅｔ　ａｌ．，　Ｎｏｎｉｎｖａｓｉｖｅ　ｍａｐｐｉｎｇ　ｏｆ　ｒｅａｃｔｉｖｅ　ｏｘｙｇｅｎ　ｓｐｅｃｉｅｓ　ｂｙ　ｉｎ　ｖｉｖｏ　ｅｌｅｃｔｒｏｎ　ｓｐｉｎ　ｒｅｓｏｎａｎｃｅ　ｓｐｅｃｔｒｏｓｃｏｐｙ　ｉｎ　ｉｎｄｏｍｅｔｈａｃｉｎ－ｉｎｄｕｃｅｄ　ｇａｓｔｒｉｃ　ｕｌｃｅｒｓ　ｉｎ　ｒａｔｓ．　Ｊ　Ｐｈａｒｍａｃｏｌ　Ｅｘｐ　Ｔｈｅｒ，　２００６．　３１７（１）：　２２８－３５．
（５）Ｋ．　Ｙａｍａｄａ，　Ｉ．　Ｙａｍａｍｉｙａ，　ａｎｄ　Ｈ．　Ｕｔｓｕｍｉ，　Ｉｎ　ｖｉｖｏ　ｄｅｔｅｃｔｉｏｎ　ｏｆ　ｆｒｅｅ　ｒａｄｉｃａｌｓ　ｉｎｄｕｃｅｄ　ｂｙ　ｄｉｅｔｈｙｌｎｉｔｒｏｓａｍｉｎｅ　ｉｎ　ｒａｔ　ｌｉｖｅｒ　ｔｉｓｓｕｅ．　Ｆｒｅｅ　Ｒａｄｉｃ　Ｂｉｏｌ　Ｍｅｄ，　２００６．　４０（１１）：　２０４０－６．
（６）Ｈ．　Ｓａｎｏ，　ｅｔ　ａｌ．，　Ａ　ｎｅｗ　ｎｉｔｒｏｘｙｌ－ｐｒｏｂｅ　ｗｉｔｈ　ｈｉｇｈ　ｒｅｔｅｎｔｉｏｎ　ｉｎ　ｔｈｅ　ｂｒａｉｎ　ａｎｄ　ｉｔｓ　ａｐｐｌｉｃａｔｉｏｎ　ｆｏｒ　ｂｒａｉｎ　ｉｍａｇｉｎｇ．　Ｆｒｅｅ　Ｒａｄｉｃ　Ｂｉｏｌ　Ｍｅｄ，　２０００．　２８（６）：　９５９－６９．
（７）Ｔ．　Ｈｅｒｒｌｉｎｇ，　ｅｔ　ａｌ．，　ＵＶ－ｉｎｄｕｃｅｄ　ｆｒｅｅ　ｒａｄｉｃａｌｓ　ｉｎ　ｔｈｅ　ｓｋｉｎ　ｄｅｔｅｃｔｅｄ　ｂｙ　ＥＳＲ　ｓｐｅｃｔｒｏｓｃｏｐｙ　ａｎｄ　ｉｍａｇｉｎｇ　ｕｓｉｎｇ　ｎｉｔｒｏｘｉｄｅｓ．　Ｆｒｅｅ　Ｒａｄｉｃ　Ｂｉｏｌ　Ｍｅｄ，　２００３．　３５（１）：　５９－６７．
（８）Ｄ．Ｊ．　Ｌｕｒｉｅ，　ｅｔ　ａｌ．，　Ｐｒｏｔｏｎ－ｅｌｅｃｔｒｏｎ　ｄｏｕｂｌｅ　ｍａｇｎｅｔｉｃ　ｒｅｓｏｎａｎｃｅ　ｉｍａｇｉｎｇ　ｏｆ　ｆｒｅｅ　ｒａｄｉｃａｌ　ｓｏｌｕｔｉｏｎｓ．　Ｊ　Ｍａｇｎ　Ｒｅｓ，　１９８８．　７６：　３６６－３７０．
（９）Ｋ．　Ｙａｍａｄａ，　ｅｔ　ａｌ．，　Ｓｙｎｔｈｅｓｉｓ　ｏｆ　ｎｉｔｒｏｘｙｌ　ｒａｄｉｃａｌｓ　ｆｏｒ　Ｏｖｅｒｈａｕｓｅｒ－ｅｎｈａｎｃｅｄ　ｍａｇｎｅｔｉｃ　ｒｅｓｏｎａｎｃｅ　ｉｍａｇｉｎｇ．　Ａｒｃｈ　Ｐｈａｒｍ　（Ｗｅｉｎｈｅｉｍ），　２００８．　３４１（９）：　５４８－５３．
（１０）Ｍ．Ｃ．　Ｋｒｉｓｈｎａ，　ｅｔ　ａｌ．，　Ｏｖｅｒｈａｕｓｅｒ　ｅｎｈａｎｃｅｄ　ｍａｇｎｅｔｉｃ　ｒｅｓｏｎａｎｃｅ　ｉｍａｇｉｎｇ　ｆｏｒ　ｔｕｍｏｒ　ｏｘｉｍｅｔｒｙ：　ｃｏｒｅｇｉｓｔｒａｔｉｏｎ　ｏｆ　ｔｕｍｏｒ　ａｎａｔｏｍｙ　ａｎｄ　ｔｉｓｓｕｅ　ｏｘｙｇｅｎ　ｃｏｎｃｅｎｔｒａｔｉｏｎ．　Ｐｒｏｃ　Ｎａｔｌ　Ａｃａｄ　Ｓｃｉ　Ｕ　Ｓ　Ａ，　２００２．　９９（４）：　２２１６－２１．
（１１）Ｈ．　Ｕｔｓｕｍｉ，　ｅｔ　ａｌ．，　Ｓｉｍｕｌｔａｎｅｏｕｓ　ｍｏｌｅｃｕｌａｒ　ｉｍａｇｉｎｇ　ｏｆ　ｒｅｄｏｘ　ｒｅａｃｔｉｏｎｓ　ｍｏｎｉｔｏｒｅｄ　ｂｙ　Ｏｖｅｒｈａｕｓｅｒ－ｅｎｈａｎｃｅｄ　ＭＲＩ　ｗｉｔｈ　１４Ｎ－　ａｎｄ　１５Ｎ－ｌａｂｅｌｅｄ　ｎｉｔｒｏｘｙｌ　ｒａｄｉｃａｌｓ．　Ｐｒｏｃ　Ｎａｔｌ　Ａｃａｄ　Ｓｃｉ　Ｕ　Ｓ　Ａ，　２００６．　１０３（５）：　１４６３－８．
（１２）Ｊ．Ｍ．　Ｍｅｔｚ，　ｅｔ　ａｌ．，　Ａ　ｐｈａｓｅ　Ｉ　ｓｔｕｄｙ　ｏｆ　ｔｏｐｉｃａｌ　Ｔｅｍｐｏｌ　ｆｏｒ　ｔｈｅ　ｐｒｅｖｅｎｔｉｏｎ　ｏｆ　ａｌｏｐｅｃｉａ　ｉｎｄｕｃｅｄ　ｂｙ　ｗｈｏｌｅ　ｂｒａｉｎ　ｒａｄｉｏｔｈｅｒａｐｙ．　Ｃｌｉｎ　Ｃａｎｃｅｒ　Ｒｅｓ，　２００４．　１０（１９）：　６４１１－７．
（１３）Ｙ．　Ｍｉｕｒａ，　Ｎ．　Ｎａｋａｍｕｒａ，　ａｎｄ　Ｉ．　Ｔａｎｉｇｕｃｈｉ，　Ｌｏｗ－ｔｅｍｐｅｒａｔｕｒｅ　"ｌｉｖｉｎｇ"　ｒａｄｉｃａｌ　ｐｏｌｙｍｅｒｉｚａｔｉｏｎ　ｏｆ　ｓｔｙｒｅｎｅ　ｉｎ　ｔｈｅ　ｐｒｅｓｅｎｃｅ　ｏｆ　ｎｉｔｒｏｘｉｄｅｓ　ｗｉｔｈ　ｓｐｉｒｏ　ｓｔｒｕｃｔｕｒｅｓ．　Ｍａｃｒｏｍｏｌｅｃｕｌｅｓ，　２００１．　３４（３）：　４４７－４５５．
（１４）Ｃ．　Ｗｅｔｔｅｒ，　ｅｔ　ａｌ．，　Ｓｔｅｒｉｃ　ａｎｄ　ｅｌｅｃｔｒｏｎｉｃ　ｅｆｆｅｃｔｓ　ｉｎ　ｃｙｃｌｉｃ　ａｌｋｏｘｙａｍｉｎｅｓ－－ｓｙｎｔｈｅｓｉｓ　ａｎｄ　ａｐｐｌｉｃａｔｉｏｎｓ　ａｓ　ｒｅｇｕｌａｔｏｒｓ　ｆｏｒ　ｃｏｎｔｒｏｌｌｅｄ／ｌｉｖｉｎｇ　ｒａｄｉｃａｌ　ｐｏｌｙｍｅｒｉｚａｔｉｏｎ．　Ｃｈｅｍｉｓｔｒｙ，　２００４．　１０（５）：　１１５６－６６．
（１５）Ｍ．Ｊ．　Ａｒｏｎｅｙ，　ｅｔ　ａｌ．，　Ｍｏｌｅｃｕｌａｒ　Ｐｏｌａｒｉｓａｂｉｌｉｔｙ．　Ｔｈｅ　Ｍｏｌｅｃｕｌａｒ　Ｃｏｎｆｏｒｍａｔｉｏｎｓ　ｏｆ　Ｓｏｍｅ　Ｓｕｂｓｔｉｔｕｔｅｄ　４－　Ｐｉｐｅｒｉｄｏｎｅｓ　ａｓ　Ｓｏｌｕｔｅｓ．　Ｊ　Ｃｈｅｍ　Ｓｏｃ，　１９６６：　９８．
（１６）　Ｍ．　Ｃｙｇｌｅｒ，　ｅｔ　ａｌ．，　ＣＯＮＦＯＲＭＡＴＩＯＮ　ＯＦ　ＴＨＥ　ＰＩＰＥＲＩＤＩＮＥ　ＲＩＮＧ　Ｐａｒｔ　ＩＶ．　Ｉｎｖｅｓｔｉｇａｔｉｏｎｓ　ｏｆ　４－ｔｅｒｔ－ｂｕｔｙｌ－４－ｈｙｄｒｏｘｙ－２，２，６，６－ｔｅｔｒａｍｅｔｈｙｌｐｉｐｅｒｉｄｉｎｅ　ｄｅｒｉｖａｔｉｖｅｓ．　Ｊ　Ｍｏｌ　Ｓｔｒｕｃｔ，　１９８０．　６８：　１６１－１７１．
（１７）　Ｚ．　Ｍａ，　Ｑ．　Ｈｕａｎｇ，　ａｎｄ　Ｊ．Ｍ．　Ｂｏｂｂｉｔｔ，　Ｏｘｏａｍｍｏｎｉｕｍ　Ｓａｌｔｓ．　５．　Ａ　Ｎｅｗ　Ｓｙｎｔｈｅｓｉｓ　ｏｆ　Ｈｉｎｄｅｒｅｄ　Ｐｉｐｅｒｉｄｉｎｅｓ　Ｌｅａｄｉｎｇ　ｔｏ　Ｕｎｓｙｍｍｅｔｒｉｃａｌ　ＴＥＭＰＯ－Ｔｙｐｅ　Ｎｉｔｒｏｘｉｄｅｓ．　Ｓｙｎｔｈｅｓｉｓ　ａｎｄ　Ｅｎａｎｔｉｏｓｅｌｅｃｔｉｖｅ　Ｏｘｉｄａｔｉｏｎｓ　ｗｉｔｈ　Ｃｈｉｒａｌ　Ｎｉｔｒｏｘｉｄｅｓ　ａｎｄ　Ｃｈｉｒａｌ　Ｏｘｏａｍｍｏｎｉｕｍ　Ｓａｌｔｓ．　Ｊ　Ｏｒｇ　Ｃｈｅｍ，　１９９３．　５８：　４８３７－４３．
（１８）Ｊ．Ｅ．　Ｂａｋｅｒ，　ｅｔ　ａｌ．，　Ｓｐｉｎ　ｌａｂｅｌ　ｏｘｉｍｅｔｒｙ　ｔｏ　ａｓｓｅｓｓ　ｅｘｔｒａｃｅｌｌｕｌａｒ　ｏｘｙｇｅｎ　ｄｕｒｉｎｇ　ｍｙｏｃａｒｄｉａｌ　ｉｓｃｈｅｍｉａ．　Ｆｒｅｅ　Ｒａｄｉｃ　Ｂｉｏｌ　Ｍｅｄ，　１９９７．　２２（１－２）：　１０９－１５．
（１９）Ｈ．　Ｈｕ，　Ｇ．　Ｓｏｓｎｏｖｓｋｙ，　ａｎｄ　Ｈ．Ｍ．　Ｓｗａｒｔｚ，　Ｓｉｍｕｌｔａｎｅｏｕｓ　ｍｅａｓｕｒｅｍｅｎｔｓ　ｏｆ　ｔｈｅ　ｉｎｔｒａ－　ａｎｄ　ｅｘｔｒａ－ｃｅｌｌｕｌａｒ　ｏｘｙｇｅｎ　ｃｏｎｃｅｎｔｒａｔｉｏｎ　ｉｎ　ｖｉａｂｌｅ　ｃｅｌｌｓ．　Ｂｉｏｃｈｉｍ　Ｂｉｏｐｈｙｓ　Ａｃｔａ，　１９９２．　１１１２（２）：　１６１－６．
（２０）Ｊ．Ｂ．　Ｆｅｉｘ，　Ｊ．Ｊ．　Ｙｉｎ，　ａｎｄ　Ｊ．Ｓ．　Ｈｙｄｅ，　Ｉｎｔｅｒａｃｔｉｏｎｓ　ｏｆ　１４Ｎ：１５Ｎ　ｓｔｅａｒｉｃ　ａｃｉｄ　ｓｐｉｎ－ｌａｂｅｌ　ｐａｉｒｓ：　ｅｆｆｅｃｔｓ　ｏｆ　ｈｏｓｔ　ｌｉｐｉｄ　ａｌｋｙｌ　ｃｈａｉｎ　ｌｅｎｇｔｈ　ａｎｄ　ｕｎｓａｔｕｒａｔｉｏｎ．　Ｂｉｏｃｈｅｍｉｓｔｒｙ，　１９８７．　２６（１３）：　３８５０－５．
（２１）木下祐一，　生体内レドックスメカニズム解析に向けた新規スピンプローブ剤の開発．　修士論文，　２００７
（２２）Ｅ．　Ｓａｒｔｏｒｉ，　ｅｔ　ａｌ．，　Ａ　ｔｉｍｅ－ｒｅｓｏｌｖｅｄ　ｅｌｅｃｔｒｏｎ　ｐａｒａｍａｇｎｅｔｉｃ　ｒｅｓｏｎａｎｃｅ　ｉｎｖｅｓｔｉｇａｔｉｏｎ　ｏｆ　ｔｈｅ　ｓｐｉｎ　ｅｘｃｈａｎｇｅ　ａｎｄ　ｃｈｅｍｉｃａｌ　ｉｎｔｅｒａｃｔｉｏｎｓ　ｏｆ　ｒｅａｃｔｉｖｅ　ｆｒｅｅ　ｒａｄｉｃａｌｓ　ｗｉｔｈ　ｉｓｏｔｏｐｉｃａｌｌｙ　ｓｙｍｍｅｔｒｉｃ　（１４Ｎ－Ｘ－１４Ｎ）　ａｎｄ　ｉｓｏｔｏｐｉｃａｌｌｙ　ａｓｙｍｍｅｔｒｉｃ　（１４Ｎ－Ｘ－１５Ｎ）　ｎｉｔｒｏｘｙｌ　ｂｉｒａｄｉｃａｌｓ．　Ｊ　Ａｍ　Ｃｈｅｍ　Ｓｏｃ，　２００７．　１２９（２５）：　７７８５－９２．
（２３）Ｊ．Ｆ．Ｗ．　Ｋｅａｎａ，　Ｎｅｗｅｒ　Ａｓｐｅｃｔｓ　ｏｆ　ｔｈｅ　Ｓｙｎｔｈｅｓｉｓ　ａｎｄ　Ｃｈｅｍｉｓｔｒｙ　ｏｆ　Ｎｉｔｒｏｘｉｄｅ　Ｓｐｉｎ　Ｌａｂｅｌｓ．　Ｃｈｅｍ　Ｒｅｖ，　１９７８．　７８（１）：　３７．
（２４）大矢博昭、山内淳，　電子スピン共鳴，　講談社サイエンティフィク．　１９８９：　講談社．
（２５）Ｂ．Ｓ．　Ｗｉｎｋｌｅｒ，　Ｓ．Ｍ．　Ｏｒｓｅｌｌｉ，　ａｎｄ　Ｔ．Ｓ．　Ｒｅｘ，　Ｔｈｅ　ｒｅｄｏｘ　ｃｏｕｐｌｅ　ｂｅｔｗｅｅｎ　ｇｌｕｔａｔｈｉｏｎｅ　ａｎｄ　ａｓｃｏｒｂｉｃ　ａｃｉｄ：　ａ　ｃｈｅｍｉｃａｌ　ａｎｄ　ｐｈｙｓｉｏｌｏｇｉｃａｌ　ｐｅｒｓｐｅｃｔｉｖｅ．　Ｆｒｅｅ　Ｒａｄｉｃ　Ｂｉｏｌ　Ｍｅｄ，　１９９４．　１７（４）：　３３３－４９．
（２６）Ｓ．　Ｍｏｒｒｉｓ，　ｅｔ　ａｌ．，　Ｃｈｅｍｉｃａｌ　ａｎｄ　ｅｌｅｃｔｒｏｃｈｅｍｉｃａｌ　ｒｅｄｕｃｔｉｏｎ　ｒａｔｅｓ　ｏｆ　ｃｙｃｌｉｃ　ｎｉｔｒｏｘｉｄｅｓ　（ｎｉｔｒｏｘｙｌｓ）．　Ｊ　Ｐｈａｒｍ　Ｓｃｉ，　１９９１．　８０（２）：　１４９－５２．
（２７）Ｍ．　Ｓｈｉｂｕｙａ，　Ｍ．　Ｔｏｍｉｚａｗａ，　ａｎｄ　Ｙ．　Ｉｗａｂｕｃｈｉ，　ＴＥＭＰＯ／ＮａＩＯ４－ＳｉＯ２：　ａ　ｃａｔａｌｙｔｉｃ　ｏｘｉｄａｔｉｖｅ　ｒｅａｒｒａｎｇｅｍｅｎｔ　ｏｆ　ｔｅｒｔｉａｒｙ　ａｌｌｙｌｉｃ　ａｌｃｏｈｏｌｓ　ｔｏ　ｂｅｔａ－ｓｕｂｓｔｉｔｕｔｅｄ　ａｌｐｈａ，ｂｅｔａ－ｕｎｓａｔｕｒａｔｅｄ　ｋｅｔｏｎｅｓ．　Ｏｒｇ　Ｌｅｔｔ，　２００８．　１０（２１）：　４７１５－８．
（２８）Ｘ．　Ｗａｎｇ，　ｅｔ　ａｌ．，　ＴＥＭＰＯ／ＨＣｌ／ＮａＮＯ２　ｃａｔａｌｙｓｔ：　ａ　ｔｒａｎｓｉｔｉｏｎ－ｍｅｔａｌ－ｆｒｅｅ　ａｐｐｒｏａｃｈ　ｔｏ　ｅｆｆｉｃｉｅｎｔ　ａｅｒｏｂｉｃ　ｏｘｉｄａｔｉｏｎ　ｏｆ　ａｌｃｏｈｏｌｓ　ｔｏ　ａｌｄｅｈｙｄｅｓ　ａｎｄ　ｋｅｔｏｎｅｓ　ｕｎｄｅｒ　ｍｉｌｄ　ｃｏｎｄｉｔｉｏｎｓ．　Ｃｈｅｍｉｓｔｒｙ，　２００８．　１４（９）：　２６７９－８５．
（２９）Ｋ．　Ｎａｋａｈａｒａ，　ｅｔ　ａｌ．，　Ｒｅｃｈａｒｇｅａｂｌｅ　ｂａｔｔｅｒｉｅｓ　ｗｉｔｈ　ｏｒｇａｎｉｃ　ｒａｄｉｃａｌ　ｃａｔｈｏｄｅｓ．　Ｃｈｅｍ　Ｐｈｙｓ　Ｌｅｔｔ，　２００２．　３５９（５－６）：　３５１－３５４．
（３０）Ａ．　Ｄｈａｎａｓｅｋａｒａｎ，　ｅｔ　ａｌ．，　Ｍｉｔｏｃｈｏｎｄｒｉａ　ｓｕｐｅｒｏｘｉｄｅ　ｄｉｓｍｕｔａｓｅ　ｍｉｍｅｔｉｃ　ｉｎｈｉｂｉｔｓ　ｐｅｒｏｘｉｄｅ－ｉｎｄｕｃｅｄ　ｏｘｉｄａｔｉｖｅ　ｄａｍａｇｅ　ａｎｄ　ａｐｏｐｔｏｓｉｓ：　ｒｏｌｅ　ｏｆ　ｍｉｔｏｃｈｏｎｄｒｉａｌ　ｓｕｐｅｒｏｘｉｄｅ．　Ｆｒｅｅ　Ｒａｄｉｃ　Ｂｉｏｌ　Ｍｅｄ，　２００５．　３９（５）：　５６７－８３．
（３１）Ａ．Ａ．　Ｂｏｂｋｏ，　ｅｔ　ａｌ．，　１９Ｆ　ＮＭＲ　ｍｅａｓｕｒｅｍｅｎｔｓ　ｏｆ　ＮＯ　ｐｒｏｄｕｃｔｉｏｎ　ｉｎ　ｈｙｐｅｒｔｅｎｓｉｖｅ　ＩＳＩＡＨ　ａｎｄ　ＯＸＹＳ　ｒａｔｓ．　Ｂｉｏｃｈｅｍ　Ｂｉｏｐｈｙｓ　Ｒｅｓ　Ｃｏｍｍｕｎ，　２００５．　３３０（２）：　３６７－７０．
（３２）Ａ．　Ｍｏｄｉｃａ，　Ｄ．Ｊ．　Ｌｕｒｉｅ，　ａｎｄ　Ｍ．　Ａｌｅｃｃｉ，　Ｓｅｑｕｅｎｔｉａｌ，　ｃｏ－ｒｅｇｉｓｔｅｒｅｄ　ｆｌｕｏｒｉｎｅ　ａｎｄ　ｐｒｏｔｏｎ　ｆｉｅｌｄ－ｃｙｃｌｅｄ　Ｏｖｅｒｈａｕｓｅｒ　ｉｍａｇｉｎｇ　ａｔ　ａ　ｄｅｔｅｃｔｉｏｎ　ｆｉｅｌｄ　ｏｆ　５９　ｍＴ．　Ｐｈｙｓ　Ｍｅｄ　Ｂｉｏｌ，　２００６．　５１（３）：　Ｎ３９－４５．
（３３）Ｒ．　Ｍｕｒｕｇｅｓａｎ，　ｅｔ　ａｌ．，　Ｆｌｕｏｒｉｎｅ　ｅｌｅｃｔｒｏｎ　ｄｏｕｂｌｅ　ｒｅｓｏｎａｎｃｅ　ｉｍａｇｉｎｇ　ｆｏｒ　１９Ｆ　ＭＲＩ　ｉｎ　ｌｏｗ　ｍａｇｎｅｔｉｃ　ｆｉｅｌｄｓ．　Ｍａｇｎ　Ｒｅｓｏｎ　Ｍｅｄ，　２００２．　４８（３）：　５２３－９．
（３４）Ｃ．　Ｂｕｈｒｍｅｓｔｅｒ，　ｅｔ　ａｌ．，　Ｔｈｅ　Ｕｓｅ　ｏｆ　２，２，６，６－Ｔｅｔｒａｍｅｔｈｙｌｐｉｐｅｒｉｎｙｌ－Ｏｘｉｄｅｓ　ａｎｄ　Ｄｅｒｉｖａｔｉｖｅｓ　ｆｏｒ　Ｒｅｄｏｘ　Ｓｈｕｔｔｌｅ　Ａｄｄｉｔｉｖｅｓ　ｉｎ　Ｌｉ－Ｉｏｎ　Ｃｅｌｌｓ．　Ｊ　Ｅｌｅｃｔｒｏｃｈｅｍ　Ｓｏｃ，　２００６．　１５３（１０）：　Ａ１８００－Ａ１８０４． References relating to the present invention are set forth below and are fully incorporated herein by this reference.
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Claims (13)

  1. 　化学式１で示されるニトロキシラジカル化合物の製造方法であって、
    Figure JPOXMLDOC01-appb-C000001
     　式中、
    　Ｒ１～Ｒ４は、独立して、Ｃ１～Ｃ１０のアルキルであるか、或いは、Ｒ１及びＲ２、又はＲ３及びＲ４が共に結合して、（ＣＨ２）ｎ、（ＣＨ２）ｎＯ（ＣＨ２）ｎ、（ＣＨ２）ｎＳＯ２（ＣＨ２）ｎ、（ＣＨ２）ｎＮＸ（ＣＨ２）ｎ、（ＣＨ２）ｎＣＹ（ＣＨ２）ｎ、
    　Ｘは、ＣＨ３ＣＯ、ＣＦ３ＣＯ、又はＲ１ＣＯであり、
    　Ｙは、酸素（＝Ｏ）、（ＯＣＨ２）ｎであり、
    　ｎは２～４の整数であり、
    　当該方法は、
    　化学式２で示される化合物であって、
    Figure JPOXMLDOC01-appb-C000002
     　式中、
    　Ｒ５～Ｒ８は、独立して、Ｃ１～Ｃ２０のアルキルである、化学式２で示される化合物と、
    　化学式３で示される化合物であって、
    Figure JPOXMLDOC01-appb-C000003
     　式中、
    　Ｒ１～Ｒ４は、独立して、Ｃ１～Ｃ１０のアルキル、Ｒ１及びＲ２、又はＲ３及びＲ４が共に結合して、（ＣＨ２）ｎ、（ＣＨ２）ｎＯ（ＣＨ２）ｎ、（ＣＨ２）ｎＳ（ＣＨ２）ｎ、（ＣＨ２）ｎＮＸ（ＣＨ２）ｎ、（ＣＨ２）ｎＣＹ（ＣＨ２）ｎ、
    　Ｘは、ＣＨ３ＣＯ、ＣＦ３ＣＯ、又はＲ１ＣＯであり、
    　Ｙは、酸素（＝Ｏ）、（ＯＣＨ２）ｎであり、
    　ｎは２～４の整数である、化学式３で示される化合物と
    　をアンモニウム塩の存在下にて反応させることにより、２，６置換－４－ピペリドン誘導体を生成させる工程と、
    　前記２，６置換－４－ピペリドン誘導体を酸化させる工程と、
    　を有する、前記ニトロキシラジカル化合物の製造方法。     A method for producing a nitroxy radical compound represented by Chemical Formula 1,
    Figure JPOXMLDOC01-appb-C000001
     Where
    R 1 to R 4 are independently C 1 to C 10 alkyl, or R 1 and R 2 , or R 3 and R 4 are bonded together to form (CH 2 ) n , (CH 2) n O (CH 2) n, (CH 2) n SO 2 (CH 2) n, (CH 2) n NX (CH 2) n, (CH 2) n CY (CH 2) n,
    X is CH 3 CO, CF 3 CO, or R 1 CO;
    Y is oxygen (= O), a (OCH 2) n,
    n is an integer from 2 to 4,
    The method is
    A compound represented by Formula 2,
    Figure JPOXMLDOC01-appb-C000002
     Where
    R 5 to R 8 are independently a compound represented by Formula 2, which is C 1 -C 20 alkyl;
    A compound represented by Formula 3,
    Figure JPOXMLDOC01-appb-C000003
     Where
    R 1 to R 4 are independently C 1 to C 10 alkyl, R 1 and R 2 , or R 3 and R 4 are bonded together to form (CH 2 ) n , (CH 2 ) n O ( CH 2) n, (CH 2 ) n S (CH 2) n, (CH 2) n NX (CH 2) n, (CH 2) n CY (CH 2) n,
    X is CH 3 CO, CF 3 CO, or R 1 CO;
    Y is oxygen (= O), a (OCH 2) n,
    n is an integer of 2 to 4, and a compound represented by Chemical Formula 3 is reacted in the presence of an ammonium salt to produce a 2,6-substituted-4-piperidone derivative;
    Oxidizing the 2,6-substituted-4-piperidone derivative;
    A process for producing the nitroxy radical compound, comprising:
  2. 　請求項１記載の方法において、前記アンモニウム塩は、塩化アンモニウムである、方法。 2. The method of claim 1, wherein the ammonium salt is ammonium chloride.
  3. 　請求項１記載の方法において、前記２，６置換－４－ピペリドン誘導体を生成させる工程は、水酸化セシウムを含むものである、方法。 2. The method according to claim 1, wherein the step of producing the 2,6-substituted-4-piperidone derivative includes cesium hydroxide.
  4. 　請求項１記載の方法において、前記２，６置換－４－ピペリドン誘導体を生成させる工程は、ベンジルトリメチルアンモニウムヒドロキシド（トリトンＢ）を含むものである、方法。 2. The method according to claim 1, wherein the step of producing the 2,6-substituted-4-piperidone derivative comprises benzyltrimethylammonium hydroxide (Triton B).
  5. 　化学式２で示される化合物であって、
    Figure JPOXMLDOC01-appb-C000004
     　式中、
    　Ｒ５～Ｒ８は、Ｃ１～Ｃ２０のアルキルである、化学式２で示される化合物と、
    　化学式３で示される化合物であって、
    Figure JPOXMLDOC01-appb-C000005
     式中、
    　Ｒ９～Ｒ１０は、Ｃ１～Ｃ１０のアルキル、Ｒ９及びＲ１０が共に結合して、（ＣＨ２）ｎ、（ＣＨ２）ｎＯ（ＣＨ２）ｎ、（ＣＨ２）ｎＳ（ＣＨ２）ｎ、（ＣＨ２）ｎＮＸ（ＣＨ２）ｎ、（ＣＨ２）ｎＣＹ（ＣＨ２）ｎ、
    　Ｘは、ＣＨ３ＣＯ、ＣＦ３ＣＯ、又はＲ１ＣＯであり、
    　Ｙは、酸素（＝Ｏ）、（ＯＣＨ２）ｎであり、
    　ｎは２～４の整数である、化学式３で示される化合物と
    　をアンモニウム塩の存在下にて反応させることにより、２，６置換－４－ピペリドン誘導体を生成させる工程と、
    　前記２，６置換－４－ピペリドン誘導体を酸化させる工程と、
    　を含む方法により製造される、化学式１
    Figure JPOXMLDOC01-appb-C000006
     で示される化合物。     A compound represented by Formula 2,
    Figure JPOXMLDOC01-appb-C000004
     Where
    R 5 to R 8 are C 1 to C 20 alkyl, the compound represented by Formula 2,
    A compound represented by Formula 3,
    Figure JPOXMLDOC01-appb-C000005
     Where
    R 9 to R 10 are C 1 to C 10 alkyl, R 9 and R 10 are bonded together to form (CH 2 ) n , (CH 2 ) n O (CH 2 ) n , (CH 2 ) n S (CH 2 ) n , (CH 2 ) n NX (CH 2 ) n , (CH 2 ) n CY (CH 2 ) n ,
    X is CH 3 CO, CF 3 CO, or R 1 CO;
    Y is oxygen (= O), a (OCH 2) n,
    n is an integer of 2 to 4, and a compound represented by Chemical Formula 3 is reacted in the presence of an ammonium salt to produce a 2,6-substituted-4-piperidone derivative;
    Oxidizing the 2,6-substituted-4-piperidone derivative;
    Chemical formula 1 produced by a method comprising
    Figure JPOXMLDOC01-appb-C000006
     A compound represented by
  6. 　請求項５記載の化合物であって、この化合物は、以下の化学式、
    Figure JPOXMLDOC01-appb-C000007
    Figure JPOXMLDOC01-appb-C000008
     　で示されるニトロキシラジカル化合物。     6. The compound of claim 5, wherein the compound has the following chemical formula:
    Figure JPOXMLDOC01-appb-C000007
    Figure JPOXMLDOC01-appb-C000008
     A nitroxy radical compound represented by
  7. 　請求項５記載の化合物であって、この化合物は、胃粘膜損傷の治療に使用されるものである、化合物。 6. The compound according to claim 5, wherein the compound is used for treatment of gastric mucosal damage.
  8. 　請求項５記載の化合物であって、この化合物は、高血圧の治療に使用されるものである、化合物。 6. The compound according to claim 5, wherein the compound is used for the treatment of hypertension.
  9. 　請求項５記載の化合物と薬学的に許容可能な担体とを有する、医薬組成物。 A pharmaceutical composition comprising the compound according to claim 5 and a pharmaceutically acceptable carrier.
  10. 　胃粘膜損傷を治療する方法であって、この方法は、請求項５記載の化合物を対象に投与する工程を含むものである、方法。 A method for treating gastric mucosal damage, comprising the step of administering the compound of claim 5 to a subject.
  11. 　請求項１０記載の方法において、前記化合物は、約０．０００１～４ｇ／日の量で投与されるものである、方法。 11. The method of claim 10, wherein the compound is administered in an amount of about 0.0001-4 g / day.
  12. 　高血圧を治療する方法であって、この方法は、請求項５記載の化合物を対象に投与する工程を含むものである、方法。 A method for treating hypertension, the method comprising the step of administering the compound of claim 5 to a subject.
  13. 　請求項１２記載の方法において、前記化合物は、約０．０００１～４ｇ／日の量で投与されるものである、方法。 13. The method of claim 12, wherein the compound is administered in an amount of about 0.0001-4 g / day.
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2001026610A (en) * 1999-05-11 2001-01-30 Sankyo Co Ltd Preparation of polymer and polymerization mediator
JP2001081076A (en) * 1999-07-09 2001-03-27 Sankyo Co Ltd Polymerization mediator and production of polystyrene
WO2008093881A1 (en) * 2007-01-31 2008-08-07 Kyushu University, National University Corporation Method for synthesis of nitroxyl radical

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2001026610A (en) * 1999-05-11 2001-01-30 Sankyo Co Ltd Preparation of polymer and polymerization mediator
JP2001081076A (en) * 1999-07-09 2001-03-27 Sankyo Co Ltd Polymerization mediator and production of polystyrene
WO2008093881A1 (en) * 2007-01-31 2008-08-07 Kyushu University, National University Corporation Method for synthesis of nitroxyl radical

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