WO2011052759A1 - Nouveau radical nitroxyle et procédé de production associé - Google Patents

Nouveau radical nitroxyle et procédé de production associé 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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compound
mmol
compound represented
substituted
formula
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PCT/JP2010/069385
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Japanese (ja)
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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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Priority to JP2011538512A priority Critical patent/JP5911131B2/ja
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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.

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Hydrogenated Pyridines (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Cardiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Other In-Based Heterocyclic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

La présente invention concerne : un procédé de production d'un nouveau radical nitroxyle ; et le composé. Le radical nitroxyle produit par le procédé a un effet thérapeutique sur l'ulcère gastrique et l'hypertension.
PCT/JP2010/069385 2009-10-29 2010-10-29 Nouveau radical nitroxyle et procédé de production associé WO2011052759A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2001026610A (ja) * 1999-05-11 2001-01-30 Sankyo Co Ltd ポリマー製造方法及び重合メディエイター
JP2001081076A (ja) * 1999-07-09 2001-03-27 Sankyo Co Ltd 重合メディエイター及びポリスチレン製造方法
WO2008093881A1 (fr) * 2007-01-31 2008-08-07 Kyushu University, National University Corporation Procédé pour la synthèse d'un radical nitroxyle

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2001026610A (ja) * 1999-05-11 2001-01-30 Sankyo Co Ltd ポリマー製造方法及び重合メディエイター
JP2001081076A (ja) * 1999-07-09 2001-03-27 Sankyo Co Ltd 重合メディエイター及びポリスチレン製造方法
WO2008093881A1 (fr) * 2007-01-31 2008-08-07 Kyushu University, National University Corporation Procédé pour la synthèse d'un radical nitroxyle

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