WO1995015967A1 - Compose nitro - Google Patents

Compose nitro Download PDF

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Publication number
WO1995015967A1
WO1995015967A1 PCT/JP1994/002048 JP9402048W WO9515967A1 WO 1995015967 A1 WO1995015967 A1 WO 1995015967A1 JP 9402048 W JP9402048 W JP 9402048W WO 9515967 A1 WO9515967 A1 WO 9515967A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
ethyl
mixture
phosphonate
added
Prior art date
Application number
PCT/JP1994/002048
Other languages
English (en)
French (fr)
Japanese (ja)
Inventor
Hiroshi Koga
Haruhiko Sato
Tadakatsu Takahashi
Original Assignee
Chugai Seiyaku Kabushiki Kaisha
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Chugai Seiyaku Kabushiki Kaisha filed Critical Chugai Seiyaku Kabushiki Kaisha
Priority to AU11212/95A priority Critical patent/AU1121295A/en
Publication of WO1995015967A1 publication Critical patent/WO1995015967A1/ja

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
    • C07F9/6552—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a six-membered ring
    • C07F9/65522—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a six-membered ring condensed with carbocyclic rings or carbocyclic ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/40—Esters thereof
    • C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4015—Esters of acyclic unsaturated acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/44—Amides thereof
    • C07F9/4403—Amides thereof the acid moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4411—Amides of acyclic unsaturated acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6536—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and sulfur atoms with or without oxygen atoms, as the only ring hetero atoms
    • C07F9/6539—Five-membered rings

Definitions

  • the present invention relates to nitro compounds, and more particularly, to novel compounds having a vasodilatory effect.
  • Nitrite and nitrate are widely used for drug treatment of angina.
  • NO donors The major pharmacological effect of these drugs, known as NO donors, is the dilation of large coronary arteries, the mechanism of which is the generation of nitric oxide (NO) in vivo and the subsequent increase in cGMP levels, resulting in vasorelaxation. It exerts its action.
  • NO nitric oxide
  • NO d 0 n 0 r such as nitrites and nitrates have been used as sublingual tablets basically because their effects are transient.
  • improved preparations such as sustained-release preparations, liniments, and patches have been developed to maintain their effects, but if the blood concentration is to be maintained at a constant level for a long period of time, the vascular smoothness consumed when NO is generated
  • the problem is that cysteine in muscle is withered and resistance develops.
  • the present inventors considered that, as a direct NO donor, a tolerance based on continuous injection of the above-mentioned long-acting improved preparations such as nitrites and nitrates was developed by generation of NO accompanied by cysteine consumption in vascular smooth muscle.
  • a tolerance based on continuous injection of the above-mentioned long-acting improved preparations such as nitrites and nitrates was developed by generation of NO accompanied by cysteine consumption in vascular smooth muscle.
  • FK 409 chemical structural characteristics of FK 409 that acts
  • the present inventors have found that the compound to achieve the first object achieves the present invention. That is, the present invention provides the following general formula (I)
  • R 2 represent a hydrogen atom or an optionally substituted lower alkyl group or an optionally substituted t, aromatic hydrocarbon group
  • R 3 represents a hydrogen atom or a lower alkyl group which may have a substituent or an aromatic hydrocarbon group which may have a substituent;
  • R 4 represents a hydrogen atom or a lower alkyl group
  • R 5 represents a hydrogen atom or an optionally substituted t, lower alkyl group or an optionally substituted acyl group
  • R 6 and R 7 represent a hydroxyl group or an alkoxy group or an amino group which may have a substituent
  • a lower alkyl group which may have a substituent an aromatic hydrocarbon group which may have a substituent, an acyl group which may have a substituent,
  • Substituents of an amino group which may have a substituent and an alkylene group which may have a substituent together include a methyl group, a dimethyl group, an ethyl group, a getyl group and an n- propyl group.
  • Lower alkyl groups such as i-propyl group, n-butyl group, i-butyl group, s-butyl group, t-butyl group, etc., acetyl groups such as acetyl group, propionyl group, and bivaloyl group; methoxy groups; And alkoxy groups such as propoxy group and i-propoxy group, acetylthio group, benzoylthio group, mercapto group such as 3,5-di-tert-butyl-4-hydroxyhydroxythio group, and 6-hydroxyquinone.
  • the lower alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms, for example, a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group. Group, s-butyl group, t-butyl group, etc.
  • the aromatic hydrocarbon group include a phenyl group and a naphthyl group.
  • the alkylene group represents an alkylene group having 2 to 7 carbon atoms.
  • the acyl group refers to a formyl group, an acetyl group, a propionyl group, a petyryl group, a bivaloyl group and the like.
  • the alkoxy group represents a methoxy group, an ethoxy group, a propoxy group, an i-propoxy group, a phenoxy group and the like.
  • the compound of the present invention is a novel compound which is not described in any literature, and can be produced, for example, as follows.
  • nitrous oxide can be usually produced by reacting nitrous acid or a salt thereof with an acid.
  • Preferred examples of nitrites include alkali metal salts such as sodium salt and potassium salt, and alkaline earth metal salts such as calcium salt.
  • inorganic acids such as acetic acid or, preferably c
  • the reaction includes organic acids, water or methanol, ethanol, alcohol Ya Te and propanol,
  • the reaction is carried out in a solvent such as trahydrofuran, dioxane, methylene chloride or a mixture thereof, and the temperature is preferably carried out under mild conditions such as cooling, room temperature, or heating. . W09S / 15967
  • the compound represented by the general formula (I) is represented by the general formula (nr):
  • alkylating agent examples include alkoxy carbonyl alkyl halides such as diazo methane trimethylsilyl diazomethane such as diazomethane and diazoethane, tertiary butoxycarbonylmethyl bromide and methoxycarbonyl methyl chloride, and carboxy.
  • carboxyalkyl killer compounds such as quinmethyl bromide and carboxymethyl chloride.
  • acylating agent examples include the following (1) to (4).
  • Acid anhydrides such as acetic anhydride and propionic anhydride
  • acetyl halides such as acetyl chloride, propionyl chloride, and bivaloyl chloride
  • This reaction can be carried out in a solvent such as methanol, ethanol, etc., tetrahydrofuran, N, N-dimethylformamide, water, etc., or a mixture thereof in the presence or absence of a base.
  • a base such as methanol, ethanol, etc., tetrahydrofuran, N, N-dimethylformamide, water, etc., or a mixture thereof in the presence or absence of a base.
  • the base to be used include inorganic bases such as potassium carbonate, sodium carbonate, potassium hydroxide and sodium hydroxide, and organic bases such as sodium hydride, sodium alkoxide, potassium alkoxide, alkyllithium, pyridine, and triethylamine. Is mentioned.
  • the compound (I) of the present invention can be obtained by applying the specific production method described in Examples.
  • Ethyl (dimethylamide) [(E, E) -3-ethyl-1,3-pentagenyl] phosphate 160018 and a 10% aqueous methanol solution (4 ml) were mixed with 0.2 ml of concentrated hydrochloric acid under ice-cooling. A mixture of 19 Omg of sodium nitrite and lm 1 of a 10% aqueous methanol solution was added, and the mixture was stirred at room temperature for 30 minutes. Water was added and extracted with ethyl acetate. The organic layer is washed with water and dried, and the solvent is distilled off.
  • Jetyl [(E) — 3-ethyl-1-hydroxyminnow 4-nitro-2-pentenyl] phosphonate 350 mg, 6-hydroxy-1,2,5,7.8-tetramethylchroman 1-2-capillonic acid 290 mg
  • To a mixture of 10 ml of toluene and 2 ml of methylene chloride were added 240 mg of N, N'-dicyclohexylcarbodiimide and 40 mg of 4-dimethylaminopyridine, and the mixture was stirred at room temperature for 24 hours.
  • test compound the compound of the present invention obtained in the examples was used.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
PCT/JP1994/002048 1993-12-07 1994-12-06 Compose nitro WO1995015967A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU11212/95A AU1121295A (en) 1993-12-07 1994-12-06 Nitro compound

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP5/343784 1993-12-07
JP34378493 1993-12-07

Publications (1)

Publication Number Publication Date
WO1995015967A1 true WO1995015967A1 (fr) 1995-06-15

Family

ID=18364218

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1994/002048 WO1995015967A1 (fr) 1993-12-07 1994-12-06 Compose nitro

Country Status (3)

Country Link
AU (1) AU1121295A (enrdf_load_stackoverflow)
TW (1) TW278077B (enrdf_load_stackoverflow)
WO (1) WO1995015967A1 (enrdf_load_stackoverflow)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH01113398A (ja) * 1987-10-28 1989-05-02 Nissan Chem Ind Ltd 光学活性なジヒドロピリジン−５−ホスホン酸エステル
JPH04128265A (ja) * 1990-09-20 1992-04-28 Kirin Brewery Co Ltd Ｋｒｎ２３９１酸付加塩およびその用途

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH01113398A (ja) * 1987-10-28 1989-05-02 Nissan Chem Ind Ltd 光学活性なジヒドロピリジン−５−ホスホン酸エステル
JPH04128265A (ja) * 1990-09-20 1992-04-28 Kirin Brewery Co Ltd Ｋｒｎ２３９１酸付加塩およびその用途

Also Published As

Publication number Publication date
TW278077B (enrdf_load_stackoverflow) 1996-06-11
AU1121295A (en) 1995-06-27

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