WO1986006720A1 - Derives d'acide ascorbique, production desdits derives et preparation pharmaceutique pouvant en resulter - Google Patents

Derives d'acide ascorbique, production desdits derives et preparation pharmaceutique pouvant en resulter Download PDF

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Publication number
WO1986006720A1
WO1986006720A1 PCT/JP1985/000272 JP8500272W WO8606720A1 WO 1986006720 A1 WO1986006720 A1 WO 1986006720A1 JP 8500272 W JP8500272 W JP 8500272W WO 8606720 A1 WO8606720 A1 WO 8606720A1
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WIPO (PCT)
Prior art keywords
group
reaction
compound
acid
hydrogen
Prior art date
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PCT/JP1985/000272
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English (en)
Japanese (ja)
Inventor
Shinji Terao
Minoru Hirata
Original Assignee
Takeda Chemical Industries, Ltd.
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
Priority to ZA852614A priority Critical patent/ZA852614B/xx
Application filed by Takeda Chemical Industries, Ltd. filed Critical Takeda Chemical Industries, Ltd.
Priority to PCT/JP1985/000272 priority patent/WO1986006720A1/fr
Priority to ZA863421A priority patent/ZA863421B/xx
Priority to IL78739A priority patent/IL78739A/xx
Priority to GR861228A priority patent/GR861228B/el
Priority to AU57350/86A priority patent/AU599029B2/en
Priority to PH33764A priority patent/PH24833A/en
Priority to DK220786A priority patent/DK220786A/da
Priority to FI862029A priority patent/FI862029A/fi
Priority to AT86106521T priority patent/ATE50494T1/de
Priority to EP86106521A priority patent/EP0202589B1/fr
Priority to DE8686106521T priority patent/DE3669104D1/de
Priority to JP61111945A priority patent/JPH0739342B2/ja
Priority to PT82591A priority patent/PT82591B/pt
Priority to CA000509360A priority patent/CA1293728C/fr
Priority to IE131386A priority patent/IE59143B1/en
Priority to HU862087A priority patent/HU197735B/hu
Priority to ES555014A priority patent/ES8801643A1/es
Priority to NO861956A priority patent/NO172343C/no
Priority to CN86103398A priority patent/CN1014409B/zh
Priority to KR1019860003855A priority patent/KR940000073B1/ko
Publication of WO1986006720A1 publication Critical patent/WO1986006720A1/fr
Priority to US07/245,943 priority patent/US4959362A/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three 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
    • C07D307/62—Three oxygen atoms, e.g. ascorbic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to an ascorbic acid derivative useful as an agent for preventing and improving circulatory dysfunction, a method for producing the same, and a preparation.
  • ischemic heart disease cerebral ischemic injury, ischemic renal injury, ischemic digestive dysfunction, etc.
  • ischemic heart disease cerebral ischemic injury, ischemic renal injury, ischemic digestive dysfunction, etc.
  • their morbidity has increased and the mortality rate in developed countries has increased. Has become the main cause.
  • the present inventors have been based on basic research to date that active oxygen species and organic radicals play a very important role in biological tissue damage, and are more potent than the above-mentioned free radical scavengers, We have been exploring new types of reactive oxygen species that are excellent in terms of both pharmaceutical and pharmaceutical properties, as well as drugs for eliminating organic radicals. As a result, 2-0-substituted ascorbic acid derivatives and their homologous derivatives are stronger in reactive oxygen species and organic radicals than in ascorbic acid and ⁇ -tocopherol in in vitro experiments and various animal models of disease. The present inventors have found that a low dose suppresses ischemic heart and cerebral dysfunction and renal dysfunction, and further studies based on these findings have completed the present invention.
  • the present invention provides:
  • R 1 represents an organic residue having a molecular weight of 15 to 70.0
  • R 2 represents hydrogen or a hydroxyl group
  • R 3 represents hydrogen, an acyl group, a phosphono group, or a sulfo group.
  • R 1 is an organic residue having a molecular weight of 15 to 700
  • R 2 is hydrogen or a hydroxyl group
  • R 3 is hydrogen, an acyl group, a phosphono group, or a sulfo group.
  • R 1 is an organic residue having a molecular weight of 72 to 700
  • R 2 is hydrogen or a hydroxyl group
  • R 3 is an acyl group, a phosphono group or a sulfo group.
  • R 1 represents an organic residue having a molecular weight of 15 to 700, respectively.
  • R 1 represents an organic residue having a molecular weight of 15 to 700
  • R + represents S which can be removed by hydrolysis or reduction
  • R 2 represents two hydrogen, acetal residue or ketal residue. The groups are respectively shown.
  • R 1 is as defined above.
  • R 1 and R 2 are as defined above.
  • the ascorbic acid derivatives and homologues represented by the formula [1] are subjected to an acylation reaction, a phosphorylation reaction or a sulfation reaction.
  • R 5 represents an acyl group, a phosphono group or a sulfo group.
  • a general formula characterized by subjecting a compound represented by ['] to a dehydration reaction, followed by a reduction reaction and, if necessary, a hydrolysis reaction.
  • R 1 has the same meaning as defined above.
  • examples of the organic residue represented by R 1 having a molecular weight of 15 to 700 include, for example, a linear or technical alkyl group which may have a substituent.
  • the alkyl group in the linear or branched alkyl group which may have a substituent having a molecular weight of 15 to 700 is preferably an alkyl group having 1 to 22 carbon atoms, and more preferably 9 to 22 carbon atoms. 20 are preferred.
  • Examples include methyl, ethyl, ⁇ -propyl, isopropyl, ⁇ -butyl, isobutyl, ⁇ -pentyl, n-hexyl, ⁇ -heptyl, ⁇ -octyl, ⁇ -nonyl, ⁇ - Acetyl, ⁇ -pentesyl, ⁇ -dodecyl, ⁇ -tridecinole, ⁇ -tetradecyl, ⁇ -pentadecyl, ⁇ -hexadecyl, ⁇ -heptadecyl, ⁇ -heptadecyl, ⁇ -nonadecyl, ⁇ -eicosyl, ⁇ —Henikosyl, ⁇ - Docosyl, etc.
  • the number of methylene groups in the above-mentioned unsubstituted linear or branched alkyl group having a substituent having a molecular weight of 15 to 00 is preferably from 1 to 22.
  • substituent of the alkyl group examples include a hydroxyl group which may have a substituent, an amino group which may have a substituent, a carboxyl group which may have a substituent, and a substituent.
  • a phenyl Naphthyl and a phenyl. ].
  • R 9 represents hydrogen, C t- 3 alkyl or phenyl.
  • the amino group which may have a substituent is a group represented by the formula:
  • R L. And R 11 are the same or different and represent hydrogen, C 3 alkyl, phenyl or P-hydroxyphenyl, respectively. Is a carboxyl group which may have a substituent,
  • R 12 represents hydrogen, CL-3 alkyl or phenyl). Is an aminocarbonyl group which may have a substituent,
  • R 13 represents hydrogen, C-3 alkyl, phenyl or p-hydroxyphenyl. Is a vinyl group which may have the substituent,
  • R 15 are the same or different and represent hydrogen, phenyl, ⁇ -methoxyphenyl, 3-pyridyl or 3,4-methylenedioxyphenyl. Is a ethynyl group which may have the substituent.
  • the cycloalkyl Le group in good consequent opening alkyl group optionally having said substituent, C 3 - is preferably a e, and examples thereof, for example, click port propyl, consequent opening butyl, consequent opening pentyl or consequent Mouth hexyl and the like.
  • the cycloalkyl may have one to three substituents, and examples of the substituent include carboxyl, hydroxyl, and CL- 6 alkyl.
  • R 17 , R 18 and R 13 are the same or different and each represents hydrogen, alkyl of C ⁇ -3, alkoxy of C, halogen, ethoxycarbonyldienyl, phenyl, carboquinol, carboxymethyl or Indicates lupoxyshetil. And a group represented by ⁇ or a naphthyl which may be substituted with 1 to 3 alkyl of C, alkoxino, logen, carboxy or acetyl of C.
  • Examples of the above t-e alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, dibutyl, n-pentyl, n-hexyl and the like.
  • the alkyl of said C 3, such as methyl, Echiru, .eta. propyl, isopropyl an 'etc. can be mentioned.
  • Examples of the Ci- 3 alkoxy include methoxy, ethoxyquin, n-propoxy and isopropoquine.
  • halogen examples include chlorine, bromine, fluorine, and iodine.
  • hydroxyl group having the substituent examples include, for example, methoxy, ethoxy, propoxy, isopropoxy, and phenoquine.
  • amino group having the substituent examples include, for example, methylamino, dimethylamino, ethylamino, propylamino, isopropylamino, phenylamino, ⁇ -hydroxyphenylamino, and the like. Is mentioned.
  • Specific examples of the carboxyl group having the substituent include, for example, methoxycarbonyl, ethoxycarbonyl, phenoxycarbonyl and the like.
  • aminocarbonyl group having the substituent examples include, for example, methylaminocarbonyl, dimethylaminocarbonyl, isopropylaminocarbonyl, phenylaminocarbonyl, ⁇ -hydroxyphenylaminocarbonyl and the like.
  • vinyl group having the substituent include, for example, propynyl, butenyl, pentenyl, hexenyl, heptenyl, 1,1-diphenyl-2-ethenyl, 1-phenyl-1- (3-pyridyl) ethenyl , 1-phenyl- 1- (2-phenyl) ethenyl and the like.
  • ethynyl group having the substituent include, for example, methylethynyl, ethylethylinyl, ⁇ -pentylethynyl and the like.
  • cycloalkyl group which may have a substituent include, for example, cyclopropyl, cyclopentyl, cyclohexyl, 1-carboxycyclopropyl, 2-carboxycyclopropyl, 1-carboxycyclopentyl, 1-carboxy Cyclohexyl, 4-carboxycyclohexyl and the like.
  • aryl group which may have a substituent include, for example, phenyl, 1- or 2-naphthyl, 2-, 3- Or 4 monomethylphenyl, 2 —, 3 — or 4 — dimethoxyphenyl, 2 —, 3 — or 4 monomethoxyphenyl, 2 —, 3 — or 4 monohalogenophenyl (however, the halogen atom is chlorine , Bromine, and fluorine atoms.), 2,3-Methylenedioxyphenyl, 3,4-dimethylphenyl, 3,4-dimethoxyphenyl, 4- (ethoxycarborylethenyl) phenyl, 4-isopropyl Phenyl, 4—methoxycarbonylphenyl, 3,4,5-trimethylphenyl, 3,4,5—trimethoxyphenyl, 4-biphenyl, 4-monocarboxyphenyl, 4-carboxymethylphenyl, 4- (1 -carboxyethy
  • Examples include alkyl, carboxyl, hydroxyl, phenyl, halogen, carboxymethyl, and benzoyl.
  • examples of the organic residue having a molecular weight of 72 or more and 700 or less include, for example, a linear or branched alkyl group which may have a substituent S. .
  • the alkyl group in the linear or branched alkyl group which may have a substituent having a molecular weight of 72 to 700 is preferably an alkyl group having 6 to 22 carbon atoms, and more preferably i 1 To 20 are preferred. Examples are n-hexyl, ⁇ -heptyl, ⁇ -heptyl, n-nonyl, ⁇ -decyl, ⁇ - ⁇ decyl, ⁇ -dodecyl, ⁇ -tridecyl, ⁇ -tetradecyl, ⁇ -ventadecyl , ⁇ -Hexadecyl, ⁇ -Hetadecyl, ⁇ -Kutadecyl, ⁇ -No
  • the number of methylene groups in the linear or branched alkyl group having a substituent having a molecular weight of from 15 to 700 is preferably from 1 to 22.
  • Examples of the substituent in the linear or branched alkyl group which may have a substituent having a molecular weight of 72 to 700 include the substituents having a molecular weight of 15 to 700. And the same substituents as those in the alkyl group of the straight chain or branched chain which may be substituted.
  • the acyl groups represented by R 3 and R 5 are a linear or branched fatty acid having 1 to 22 carbon atoms, an optionally substituted benzoic acid, an optionally substituted phenyl acetate. , Optionally substituted phenylacetic acid, dicarboxylic acid,
  • R 7 and R 8 are as defined above, nu is 1 or 2, and m 2 is an integer of 2 to 80. And an aminocarbonyl group.
  • Examples of the lipoacid include formic acid, acetic acid, propionic acid, valeric acid, butyric acid, hexanoic acid, heptanoic acid, octanoic acid, nonanoic acid, decanoic acid, undecanoic acid, dodecanoic acid, tridecanoic acid, tetradecanoic acid, Examples include pentadecanoic acid, hexadenic acid, heptadecanoic acid, octadecanoic acid, nonadecanoic acid, eicoic acid, and isopropionic acid.
  • a substituent of the benzoic acid which may be substituted examples include alkyl, CL- 3 alkoxy, methylenedioxy, halogen and the like.
  • the substituent of the the optionally substituted off X sulfonyl acetate also example CL - 3 alkyl, alkoxy CL -3, Mechirenjiokishi, and etc. halogen.
  • the R 1 7 substituted optionally may be Fuweniru group, the substituent group a thienyl group or a naphthyl group, for example C i-3 alkyl, C!
  • Examples of the substituent of the optionally substituted aminocarbonyl group include a mono- or di-substituted Ci-s lower alkyl group or a monophenyl group.
  • Examples of the lower C lower alkyl include-methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, n-hexyl and the like.
  • Examples of the substituent include phenyl, naphthyl, pyridyl, imidazolyl and the like.
  • Examples of the acyl group derived from a dicarboxylic acid include monoesters.
  • Examples of the dicarboxylic acid include, for example, malonic acid, succinic acid, glutaric acid, adipic acid and the like.
  • C i -s lower alkyl examples include methyl, ethyl, ⁇ -propyl, isopropyl, ⁇ -butyl, isobutyl, n-pentyl, and ⁇ -hexyl.
  • Examples of the C i- 3 alkyl include methyl, ethyl, ⁇ -propyl, and isopropyl.
  • Examples of the above C 3 alkoxy include methoxy, ethoxy, n-propoxy, isopropoxy and the like.
  • halogen examples include chlorine, bromine, iodine, and fluorine.
  • groups which can be eliminated by the hydrolysis represented by R + include, for example, methoxymethyl, benzyloxymethyl, 2-tetrahydropyranyl, trimethylnyl, dimethyl tertiary butylsilyl and the like.
  • groups which can be removed by benzyl include benzyl, ⁇ -methoxybenzyl and the like.
  • R 21 represents d-3 alkyl, phenyl or p-methoxyphenyl. ;:
  • the ketal residue includes, for example, 0 formula C ⁇ -
  • R 22 and R 2 are the same also is properly different, hydrogen, and alkyl Le or R 22 and R 23 are in one (CH 2) a- (wherein a C L, a is 4 or 5 shown ) Is formed. ]
  • the group represented by] is mentioned.
  • the alkyl of said C 3 such as methyl, Echiru, .eta. propyl, and isopropyl.
  • a salt may be formed, and examples of the salt include a sodium salt and a potassium salt.
  • the compound [Ia] in which R 2 is a hydroxyl group and R 3 is hydrogen is the compound [la] when the protecting group R + in the compound [ ⁇ ] is a group which can be eliminated by a hydrolysis reaction. ] To an acidic hydrolysis reaction to simultaneously remove the acetal or ketal residue at positions 5 and 6 and the protecting group at position 3 in compound [ ⁇ ].
  • R 5 represents an acyl group.
  • the compound can be further produced by subjecting it to an acyl group transfer reaction.
  • Compound [Ic] in which R 2 and R 3 are hydrogen in compound [ ⁇ ] is obtained by subjecting compound [V] to a dehydration reaction under basic conditions, followed by a catalytic reduction reaction and, if necessary, an acidic hydrolysis reaction.
  • the acidic hydrolysis reaction in the above production process is carried out, for example, by adding water or methanol in the presence of an acidic catalyst such as hydrochloric acid, sulfuric acid, phosphoric acid, diacid, di-toluenesulfonic acid, methanesulfonic acid, and camphorsulfonic acid.
  • an acidic catalyst such as hydrochloric acid, sulfuric acid, phosphoric acid, diacid, di-toluenesulfonic acid, methanesulfonic acid, and camphorsulfonic acid.
  • the catalytic reduction reaction in the above production process is carried out, for example, in the presence of palladium, palladium carbon, platinum black, palladium chloride, platinum oxide, etc., with methanol, It can be carried out in an organic solvent such as ethanol, ethyl acetate, diacid, dioxane, 1,2-dimethoxetane at about 10 ° C. to 100 ° C. for about 4 to 10 hours.
  • an organic solvent such as ethanol, ethyl acetate, diacid, dioxane, 1,2-dimethoxetane at about 10 ° C. to 100 ° C. for about 4 to 10 hours.
  • the enolic hydroxyl group at the 3-position has a higher reactivity than the hydroxyl group at the 6-position, and the hydroxyl group at the 3-position is first acylated.
  • 3 _ 0 Ashiru derivatives weakly basic conditions depending on the kind of Ashiru group: or readily rearranges intramolecularly to the 6-hydroxyl group of 6-O-Ashiru derivative 1 can Rukoto changed to [pi.
  • the 3-0-acyl derivative [ ⁇ ] also exists as an intermediate, is susceptible to intramolecular rearrangement and hydrolysis, and is a chemically unstable compound. Therefore, the 6-0-acyl derivative can also be produced by subjecting the 3-0-acyl derivative to intramolecular transfer.
  • the intramolecular transfer reaction is carried out in the presence of a weak base [eg, pyridyl, sodium carbonate, buffer solution (about 7 to 8)] in a temperature range of about 20 to 100, and in about 1 to 10 hours. proceed.
  • carboxylic acid chlorides or anhydrides are widely used by using a generally known method, and pyridine, triethylamine, carbonated lime, sodium carbonate, and the like are commonly used. Approximately -10 in the presence of bases such as sodium bicarbonate. It is performed in a temperature range of ⁇ 50 ° C. Reaction times are often within about 1 to 10 hours.
  • examples of the phosphating agent include 2-cyanoethyl phosphate-dicyclohexyl carpoimide, di-paranitrobenzylphosphoryl chloride, and dioxane diphosphite. , Dimorpholyl phosphate, pyrophosphoryl tetrachloride and the like. ⁇
  • the removal of the 3-position acyl group can be carried out by adding sodium hydrogencarbonate or pyridine in an equimolar amount to methanol, ethanol or an aqueous solvent thereof and hydrolyzing at room temperature.
  • the reaction time is about 1 to 6 hours.
  • the dehydration reaction in the above-mentioned production process includes, for example, 1,5-diazabicyclo [4: 3,0] -5-nonene, 1,4 diazabicyclo [2,2,2] octane, 1,8 diaza, cyclo [5,4] , 0] —about 30 to 80% in an organic solvent such as methylene chloride, chloroform, dioxane, tetrahydrofuran, and benzene in the presence of an organic base such as 7-indene, pyridine, and triethylamine. It can be performed in a temperature range of ° C for about 1 to 1 hour.
  • an organic solvent such as methylene chloride, chloroform, dioxane, tetrahydrofuran, and benzene
  • an organic base such as 7-indene, pyridine, and triethylamine. It can be performed in a temperature range of ° C for about 1 to 1 hour.
  • R 1 and R * are as defined above. Is obtained. .
  • Compound [Ic] can be produced by subjecting compound ["VI" to a reduction reaction and, if necessary, a hydrolysis reaction.
  • the hydrolysis reaction can be performed in the same manner as those described above.
  • the ascorbic acid derivative [I] thus produced can be obtained by a simple separation / purification means known per se ( ⁇ , silica gel, polystyrene resin, column chromatography using activated carbon, reversed phase system, recrystallization, etc.). It can be collected separately.
  • the compound used as a starting material can be produced, for example, by the following reaction steps.
  • X ′ and R 6 ′ represent an acetal or ketal residue
  • ascorbic acid is acetalized or ketalized to produce compound [VI].
  • ascorbin is reacted with ketones or aldehydes such as aceton, benzaldehyde, cyclopentanone, and cyclohexanone.
  • the reaction solvent include tetrahydrofuran.chloroform, diethyl ether, dichloromethane, and dichloroethane.
  • the reaction is carried out at room temperature to 60 and in the presence of an acidic catalyst.
  • the catalyst include acetyl chloride, sulfuric acid, toluene toluenesulfonic acid, hydrogen sulfonic acid, and the like.
  • the response time is 4 to 24 hours.
  • Y represents a halogen (eg, chlorine, bromine).
  • halogen eg, chlorine, bromine
  • ] Eg, chloromethyl methyl ether, benzyl chloride, benzyl chloride
  • Inorganic bases' such as potassium carbonate, sodium carbonate, sodium hydroxide, sodium hydroxide, sodium hydroxide, etc. Reacts in the presence to produce compound. The reaction is carried out at a temperature of 0 to 40 (preferably 25), and the reaction is completed in 1 to 18 hours.
  • the compound [W] thus obtained has the formula R 1 —Z wherein R 1 has the same meaning as described above.
  • Z represents a halogen (eg, chlorine, bromine).
  • Potassium hydroxide, sodium carbonate and carbonated carbonate for 1 to 18 hours at a temperature of 10 to 60 hours.
  • the compound or [V can be produced by anti-IS with C.
  • Compound [n] in which x is two hydrogens in compound [m] can be produced by subjecting compound [ ⁇ ] obtained above to the same hydrolysis reaction as described above.
  • V,. 0 [ ⁇ ' ⁇ , ⁇ ]
  • the compound [X] can be produced by reacting in the presence of the compound for about 1 to 20 hours in a temperature range of about 10 to 60 ° C.
  • the above compound can be obtained by reacting compound [X] with thionyl chloride.
  • the reaction is carried out in a solvent such as tetrahydrofuran, dimethylformamide, chloroform, or methylene chloride, for example, triethylamine, pyridine, 1,8-diazabicyclo [5,4,0] -7-indene.
  • a solvent such as tetrahydrofuran, dimethylformamide, chloroform, or methylene chloride, for example, triethylamine, pyridine, 1,8-diazabicyclo [5,4,0] -7-indene.
  • the reaction is performed in the presence of an organic salt group.
  • the reaction is carried out at about 0 to 30 ° C for about i to 6 hours.
  • the compound of the present invention [I] has an antioxidant effect in an in vitro experiment using a stable radical or brain protein, and has a blood-reperfusion model in rat heart or rat ischemia-cerebral model. Alternatively, it has an effect of preventing and improving dysfunction in rat renal injury models caused by oxygen free radicals, and has extremely low toxicity and side effects. Therefore, the compound of the present invention [ ⁇ ] can be used for ischemic heart failure (arrhythmia, coronary artery spasm, heart tissue dysfunction) in mammals (eg, mouse, '', ⁇ , ⁇ heron, dog, monkey, human, etc.).
  • ischemic heart failure arrhythmia, coronary artery spasm, heart tissue dysfunction
  • ischemic brain tissue disorder clear, cerebral infarction, blur, senile dementia, etc.
  • ischemic renal disorder ischemic gastrointestinal disorder (eg, gastrointestinal tract disorder) Ulcers, etc.) It can be used as a preventive / ameliorating agent for circulatory dysfunction because it has therapeutic and preventive / improving effects on various disorders such as.
  • agents for preventing and improving circulatory dysfunction include, for example, antiarrhythmic agents, antimyocardial infarction agents, anticerebral infarction, blurring, senile dementia preventive agents, and improved treatment after subarachnoid hemorrhage.
  • circulatory system improvers, renal function improvers, and agents for treating stress-induced gastrointestinal ulcers include, for example, antiarrhythmic agents, antimyocardial infarction agents, anticerebral infarction, blurring, senile dementia preventive agents, and improved treatment after subarachnoid hemorrhage.
  • circulatory system improvers renal function improvers, and agents for treating stress-induced gastrointestinal ulcers.
  • the compound of the present invention has low toxicity (for example, no acute toxicity in mice was found to be killed by oral administration of 100 mg / kg in mice).
  • the compound of the present invention is a known pharmacologically acceptable carrier. , Excipients, diluents, etc., and according to a method known per se, a pharmaceutical composition [eg, tablets, capsules (including soft capsules, microcapsules), liquids, suppositories, injections, nasal tablets, Can be safely administered orally or nonradially.
  • the dosage varies depending on the administration target, administration route, symptoms, and the like.
  • the dose is usually about Q.img / kg to 5 Omg / kg body weight, preferably as a single dose.
  • parenteral administration for example, about 5 mg to iOmg / kg as a suppository may be administered once or twice daily. As an injection, it is preferable to give 0 to about 5 g / kg once or twice a day.
  • binders eg, hydr ⁇ -xypropylcellulose, hydroxymethyl cellulose ⁇ -pyrmethylcellulose, mac ⁇ -gol, etc.
  • disintegrants eg, starch, carboxy Methylcellulose power Runum, etc.
  • excipients clear, lactose, starch, etc.
  • lubricants eg, magnesium stearate, talc, etc.
  • tonicity agents such as grape, D-sorbitol, D-mannitol, sodium chloride, etc.
  • preservatives eg, Benzyl alcohol, butanol and paraoxybenzoate
  • buffering agents eg, phosphate buffer, sodium formate buffer
  • phosphate buffer sodium formate buffer
  • the acyl represented by R 2 ° may be the same or different. Has the same pharmacological action as the above compound [E], and has low toxicity. Therefore, compound [XI] can be used for the same administration as the compound, for the prevention and treatment of similar diseases, and with the same dosage, administration route and dosage form.
  • Compound [XI] is prepared by acylating compound [I] and compound [] y].
  • FIG. 1 -Hin- shows the results of the self-tested drug, 11-1 shows the results of vitamin E, and _ ⁇ 1 shows the results of vitamin C, respectively.
  • the above test drug was reduced in a dose-dependent manner DP PH at a concentration of at least 1 0_ 5 M.
  • Vitamin C and vitamin E also had comparable activities.
  • Test drug should be at final concentration before incubating in 5% homogenate.
  • vitamin C promoted lipid peroxide production more markedly.
  • Drug was administered once a day, the drug or its Vehicle a (gum arabic suspension) was orally administered, after 4 0-6 0 min two Toriro triacetate - the NT A - DOO (NT A) or Fe 3 + Administered intraperitoneally.
  • a mixed solution of Fe 3 + —NTA at a ratio of 1: 4 (mol ratio) was administered at 5 mg / kg as Fe 3+ for 3 days, followed by 10 mg Zkg for 5 days.
  • the drugs examined were compound (1-12 '). Vitamin C and Vitamin E, both of which were orally administered at 30 rag / kg.
  • Kidney weight was significantly lower than in the Vehicle group, urine volume and urinary protein excretion were significantly suppressed, and urinary occult blood reactions were observed in only half of the patients.
  • Vitamin E performed similarly, but the majority of patients showed a half-reaction of occult blood.
  • Vitamin C did not show any significant renal damage-reducing effect.
  • the dose of each drug is 3 Omg / kg, oral administration
  • the test drug was 3 OmgZkg approximately 90 minutes before coronary artery closure under anesthesia, 2 Omg / kg (total 50 mg / kg) approximately 45 minutes before, or 1 dose approximately 90 and 45 minutes before, respectively.
  • OmgZkg (total 20 mgZkg) was administered as a gum arabic suspension. The results are shown in the total dose and are shown in Table 4.
  • VF ventricular fibrillation
  • VF and V were found in more than 90% of animals, and their durations were about 80 and 20 to 30 seconds, respectively, and 10 to 25% of animals. Died of persistent VF.
  • the frequency of ventricular fibrillation and ventricular tachycardia is the number of occurrences / number of experimental cases (%), and the duration is average ⁇ S ⁇ ⁇ in seconds.
  • the extrasystole was expressed as the number of extrasystoles / min, and the mortality was expressed as the number of deaths Z in the number of experimental cases (%).
  • the drug was orally administered as a gum arabic suspension 60 minutes before bilateral carotid artery ligation.
  • Table 5 shows the results.
  • the vehicle group showed ischemic seizures, a pre-seizure spasm, about 1 ⁇ 0 minutes later, and the seizure was 180 minutes in about 90% of rats. Occurred within.
  • the compound (1-12) orally administered at a dose of 100 mg / kg significantly delayed the onset of seizures by about 40 minutes. The rate of seizures within 180 minutes was significantly reduced to 20%.
  • mice Male Crj-ICR mice (4 weeks old, 21-6 g) were used.
  • the compound (111) was administered at 300 and 1000 mg / kg in a group of 6 animals. After drug administration, each group was kept in a cage and observed for 24 hours.
  • the drug was a gum arabic suspension and administered in a volume of Q.lml / l Og. ( ⁇ ) Results
  • Table 9 shows the compound (111) from the compound (111) prepared by the method according to Example 1 and Example 2.
  • 2-0-pentadecyl-L-ascorbic acid, 2-0-hexadecyl-L-ascorbic acid and 2-0-year-old octadecyl-L-ascorbic acid are acetylated, benzoylated, and phenylacetylated. And nicotinoylation reaction, respectively, to produce the following compounds:
  • Tablets are prepared by conventional means using the following ingredients.
  • Tablets are prepared by conventional means using the following ingredients.
  • Compound [I] has excellent circulatory dysfunction prevention / improvement activity, and thus can be used as a circulatory dysfunction prevention / amelioration agent.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Préparation pharmaceutique comprenant un dérivé d'acide ascorbique ou son homologue et possédant la formule générale (I) oú R1 représente un résidu organique d'un poids moléculaire de 15 à 700 et R2 représente un atome d'hydrogène ou un groupe hydroxyle. Ladite préparation peut être utilisée pour prévenir et soigner des troubles fonctionnels du système cardio-vasculaire.
PCT/JP1985/000272 1983-12-19 1985-05-17 Derives d'acide ascorbique, production desdits derives et preparation pharmaceutique pouvant en resulter WO1986006720A1 (fr)

Priority Applications (22)

Application Number Priority Date Filing Date Title
ZA852614A ZA852614B (en) 1985-05-17 1985-04-09 Ascorbic acid ethers and their production
PCT/JP1985/000272 WO1986006720A1 (fr) 1985-05-17 1985-05-17 Derives d'acide ascorbique, production desdits derives et preparation pharmaceutique pouvant en resulter
ZA863421A ZA863421B (en) 1985-05-17 1986-05-07 Ascorbic acid derivatives,production and use thereof
IL78739A IL78739A (en) 1985-05-17 1986-05-09 Ascorbic acid derivatives and pharmaceutical compositions containing them
GR861228A GR861228B (en) 1985-05-17 1986-05-12 Ascorbic acid derivatives production and use therefor
AU57350/86A AU599029B2 (en) 1985-05-17 1986-05-12 Ascorbic acid derivatives, production and use thereof
PH33764A PH24833A (en) 1985-05-17 1986-05-13 Ascorbic acid derivatives and pharmaceutical composition thereof
DK220786A DK220786A (da) 1985-05-17 1986-05-13 Ascorbinsyrederivater og fremstilling og anvendelse deraf
DE8686106521T DE3669104D1 (de) 1985-05-17 1986-05-14 Pharmazeutische praeparate, die ascorbinsaeurederivate enthalten.
AT86106521T ATE50494T1 (de) 1985-05-17 1986-05-14 Pharmazeutische praeparate, die ascorbinsaeurederivate enthalten.
EP86106521A EP0202589B1 (fr) 1985-05-17 1986-05-14 Composés pharmaceutiques qui contient des dérivés de l'acide ascorbique
FI862029A FI862029A (fi) 1985-05-17 1986-05-14 Askorbinsyraderivat, deras framstaellning och anvaendning.
JP61111945A JPH0739342B2 (ja) 1985-05-17 1986-05-15 アスコルビン酸誘導体含有製剤
PT82591A PT82591B (pt) 1985-05-17 1986-05-15 Processo para a preparacao de derivados do acido ascorbico e de composicoes farmaceuticas que os contem
IE131386A IE59143B1 (en) 1985-05-17 1986-05-16 Pharmaceutical compositions containing ascorbic acid derivatives
CA000509360A CA1293728C (fr) 1985-05-17 1986-05-16 Derives de l'acide ascorbique, production et utilisation
HU862087A HU197735B (en) 1985-05-17 1986-05-16 Process for producing ascorbinic acid derivatives and pharmaceutical compositions containing them
ES555014A ES8801643A1 (es) 1985-05-17 1986-05-16 Un metodo para producir nuevos derivados del acido ascorbico
NO861956A NO172343C (no) 1985-05-17 1986-05-16 Analogifremgangsmaate for fremstilling av terapeutisk aktive askorbinsyrederivater
CN86103398A CN1014409B (zh) 1985-05-17 1986-05-17 生产抗坏血酸衍生物的方法
KR1019860003855A KR940000073B1 (ko) 1985-05-17 1986-05-17 아스코르브산 유도체의 제조방법
US07/245,943 US4959362A (en) 1983-12-19 1988-09-19 Pharmaceutical compositions containing certain ascorbic acid derivatives useful in the prophylaxis and treatment of disorders of the circulatory system

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/JP1985/000272 WO1986006720A1 (fr) 1985-05-17 1985-05-17 Derives d'acide ascorbique, production desdits derives et preparation pharmaceutique pouvant en resulter

Publications (1)

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WO1986006720A1 true WO1986006720A1 (fr) 1986-11-20

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Country Link
DK (1) DK220786A (fr)
WO (1) WO1986006720A1 (fr)
ZA (1) ZA863421B (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5857373A (ja) * 1981-10-01 1983-04-05 Sunstar Inc Ｌ−アスコルビン酸誘導体の製法
JPS58131978A (ja) * 1982-01-15 1983-08-06 イ−ライ・リリ−・アンド・カンパニ− アスコルビン酸エ−テルおよび関連化合物

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5857373A (ja) * 1981-10-01 1983-04-05 Sunstar Inc Ｌ−アスコルビン酸誘導体の製法
JPS58131978A (ja) * 1982-01-15 1983-08-06 イ−ライ・リリ−・アンド・カンパニ− アスコルビン酸エ−テルおよび関連化合物

Also Published As

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ZA863421B (en) 1988-01-27
DK220786A (da) 1986-11-18
DK220786D0 (da) 1986-05-13

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