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WO1986007592A1 - Derives d'acide ascorbique, leur procede de preparation, et preparations les contenant - Google Patents

Derives d'acide ascorbique, leur procede de preparation, et preparations les contenant Download PDF

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Publication number
WO1986007592A1
WO1986007592A1 PCT/JP1985/000340 JP8500340W WO8607592A1 WO 1986007592 A1 WO1986007592 A1 WO 1986007592A1 JP 8500340 W JP8500340 W JP 8500340W WO 8607592 A1 WO8607592 A1 WO 8607592A1
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WO
WIPO (PCT)
Prior art keywords
group
reaction
residue
ascorbic acid
acid
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/JP1985/000340
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English (en)
Japanese (ja)
Inventor
Shinji Terao
Minoru Hirata
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Takeda Pharmaceutical Co Ltd
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/JP1985/000340 priority patent/WO1986007592A1/fr
Priority to IL78739A priority patent/IL78739A/xx
Priority to AU57350/86A priority patent/AU599029B2/en
Priority to GR861228A priority patent/GR861228B/el
Priority to PH33764A priority patent/PH24833A/en
Priority to DK220786A priority patent/DK220786A/da
Priority to EP86106521A priority patent/EP0202589B1/fr
Priority to DE8686106521T priority patent/DE3669104D1/de
Priority to FI862029A priority patent/FI862029A7/fi
Priority to AT86106521T priority patent/ATE50494T1/de
Priority to PT82591A priority patent/PT82591B/pt
Priority to JP61111945A priority patent/JPH0739342B2/ja
Priority to CA000509360A priority patent/CA1293728C/fr
Priority to ES555014A priority patent/ES8801643A1/es
Priority to IE131386A priority patent/IE59143B1/en
Priority to NO861956A priority patent/NO172343C/no
Priority to HU862087A priority patent/HU197735B/hu
Priority to CN86103398A priority patent/CN1014409B/zh
Priority to KR1019860003855A priority patent/KR940000073B1/ko
Publication of WO1986007592A1 publication Critical patent/WO1986007592A1/fr
Anticipated expiration legal-status Critical
Priority to US07/245,943 priority patent/US4959362A/en
Ceased legal-status Critical Current

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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.
  • reactive oxygen species or active organic radical species in living organisms include superoxide ionone radical (OT), hydrazine hydroxide ( ⁇ 0 ⁇ ), singlet oxygen radical 0 2 ), and peroxide radical ( R 00 ⁇ ) is considered.
  • OT superoxide ionone radical
  • ⁇ 0 ⁇ hydrazine hydroxide
  • R 00 ⁇ peroxide radical
  • the generation of 0; in vivo and subsequent events The relationship of reactive oxygen species to cell or tissue damage has significant implications.
  • excessive production of oT is considered to be a significant factor as an essential factor of ischemia reperfusion at the site of ischemic lesion or tissue damage after ischemia.
  • Superoxide that effectively or specifically eliminates 0 to protect or ameliorate tissue damage after ischemia reperfusion or ischemia.
  • the effect of superoxide dismutase may be effective Known [D.N. Granger, G. Rutili, J .. Mc Cord, Gastroenterology, sigma- (Gastroenterology), ⁇ J_, 22 (1981)].
  • compounds such as ascorbic acid, ⁇ -tocopherol, cystine, and reduced daltathione have a scavenging effect on free radicals, and these compounds cause tissue damage that is expected to involve free radicals in certain disease states. Can be prevented [I. Fridor-ich, Science (Science), 210, ⁇ 875 (197.8)].
  • the present inventors have been based on basic research so far that active oxygen species and organic radicals play a very important role in biological tissue damage, and are more potent than the aforementioned free radical scavengers, We have been exploring new types of active oxygen species that are superior in terms of formulation and pharmaceuticals, as well as drugs for scavenging organic radicals.
  • 2-O-g-substituted ascorbic acid derivatives and their homologous derivatives are more powerful than reactive compounds such as ascorbic acid and tocoprole in in vitro experiments and in animal models of various diseases.
  • the present inventors have found that they show a radical elimination effect and suppress ischemic heart and cerebral dysfunction and renal dysfunction at a low dose. As a result of further study based on these findings, the present invention was completed.
  • the present invention provides: R 3 — 0, ⁇
  • HO '0-R' In the formula, is an organic residue having a molecular weight of i5 to 700, R 2 is hydrogen or a hydroxyl group, R 3 is hydrogen, an acyl group, a phosphono group which may be substituted Or a sulfo group. R 3 and the hydroxyl group of R 2 may form an acyl residue or a ketal residue.
  • a preventive / improving agent for circulatory dysfunction comprising an ascorbic acid derivative and a homolog or a salt thereof represented by the formula:
  • 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, or an optionally substituted
  • R 2 is a hydroxyl group and R 3 is hydrogen.
  • R 1 is an organic residue having a molecular weight of 72 or more and up to 700, when R 2 is hydrogen or a hydroxyl group and R 3 is an acyl group, a phosphono group or a sulfo group, and when R 2 is hydrogen and R 3 is hydrogen
  • R 1 represents an organic residue having a molecular weight of 15 or more and 700 or more, respectively.
  • R 3 and the hydroxyl group of R 2 may form an acetal residue or a ': methyl residue.
  • R 1 represents an organic residue having a molecular weight of 15 to 700
  • R + represents a group which can be removed by hydrolysis or reduction
  • X represents two hydrogens, an acetate residue or a ketal residue. The groups are indicated accordingly.
  • R 1 is as defined above.
  • R 5 represents a acyl group, a phosphono group or a sulfo group.
  • V 0-+ -0 0-R 1
  • R 1 and R + have the same meanings as described above.
  • a general formula characterized by subjecting a compound represented by: to a dehydration reaction Ct, and then to a reduction reaction and, if necessary, a hydrolysis reaction.
  • R 1 has the same meaning as described above. Ascorbic acid induced by i methods of producing conductors and homologs, and
  • R 1 has the same meaning as described above. Is to subject the ascorbic acid derivative and the homologue represented by the formula [1] to an acetalization or ketalization reaction.
  • examples of the organic residue represented by R 1 having a molecular weight of 15 to 700 include, for example, a straight-chain or branched 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, more preferably 9 to 22 carbon atoms. 20 are preferred.
  • Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl Isobutyl, n-pentyl, n-hexyl, n-heptyloctyl, n-nonyl, n-decyl, n-indecyl, n-dodecyl, n-tridecyl, n-tetra
  • Examples include decyl, n-pentadecyl, n-hexadecyl, n-heptadecyl, n-titadecyl, n-nonadecyl, ⁇ -eicosyl, ⁇ -henecosyl, and n-docosyl.
  • 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.
  • 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 carboxyl group which may have a substituent.
  • R 3 represents hydrogen, C t - 3 alkyl or phenyl.
  • the amino group which may have a substituent is a group represented by the formula: R 10
  • 11 1 ° Oyobi 11 11 show Do or different hydrogen, C alkyl,-phenyl or p- human Dorokishifuweniru respectively.
  • carboxyl group which may have a substituent is a group represented by the formula:
  • R 12 represents hydrogen, C i- 3 alkyl or phenyl.
  • the group represented by the formula (I) is an aminocarbonyl group which may have a substituent,
  • R 13 represents hydrogen. C alkyl, phenyl or P-hydroxyphenyl].
  • the vinyl represented by the formula (1) is a vinyl which may have a substituent
  • R 15 are the same or different and represent hydrogen, phenyl, ⁇ -methoxyphenyl, 3-pyridyl or 3,4-methylenedioxyphenyl.
  • the ethynyl group which may have a substituent is a group represented by the formula:
  • R 16 represents hydrogen or C alkyl.
  • C 3 - is preferably a s, and examples thereof, for example, cyclo-propyl, cyclobutyl, cyclopentyl, or ': click - to ⁇ Xyl and the like.
  • the cycloalkyl may have 1 to 3 substituents. Frequently, examples of the substituent include a carboxyl group, a hydroxyl group and an alkyl group.
  • R 1 7, R 1 8 and R 1 9 are the same or different and are hydrogen, C t one third ⁇ alkyl, C i - 3 of Arukokishino, androgenic, Etokinkarubo two Rueparu, Hue sulfonyl, carboxyl , Carboxymethyl or 1-carboxyethyl. Or naphthyl which may be substituted with 1 to 3 C i- 3 alkyl, C 3 alkoxynoperogen, carboxy or acetyl.
  • alkyl of S C examples include methyl, ethyl, 11-propyl, isopropyl, n-butyl, isobutyl, ⁇ -pentyl, n-hexyl and the like.
  • Examples of the above alkyl include methyl, ethyl, n-propyl, isopropyl and the like.
  • alkoxy of the above C examples include, for example, methoxy, ethoxyquin, ⁇ -propoxy, isopropoquine and the like.
  • halogen examples include chlorine, bromine, fluorine, and iodine.
  • hydroxyl group having a substituent examples include, for example, methoxy, ethoxy, propoquine, isopropoxy, phenoxy and the like.
  • amino group having the substituent examples include, for example, methylamino, dimethylamino, ethylamino, propylamino, isopropylamino, Phenylnamino. P-hydroxyphenylamino and the like.
  • carboxyl group having the substituent include, for example, methoxycarbonyl, ethoxycarbonyl, phenoxycarbonyl and the like.
  • aminocarbonyl group having the substituent examples include methylaminocarbonyl, dimethylaminocarbonyl.isopropylaminocarbonyl, phenylaminocarbonyl, ⁇ -hydroxyphenylaminocarbonyl, and the like.
  • vinyl group having the substituent include, for example, propynyl, butenyl, pentenyl, hexenyl, heptenyl, 1,1-diphenyl ethenyl, 1-phenyl-1- (3-pyridyl) ethenyl, 11-yl 1- (2-Chenyl) ethenyl.
  • ethynyl group having the substituent include, for example, methylethynyl, ethyl: tinyl, ⁇ -pentylethynyl and the like.
  • cycloalkyl group which may have a substituent include, for example, cyclopropyl.cyclopentyl, cyclohexyl, 1-carboxycyclopropyl, 2-carboxycyclopropyl, 1-carboxycyclopentyl, 1-carboxycyclopentyl, —Carboxycyclohexyl, 4-carboxycyclohexyl and the like.
  • the substituent may be, for example, alkyl, carboxyl, hydroxyl, phenolnoperogen, carboxymethyl, benzoyl and the like.
  • examples of the organic residue represented by R 1 having a molecular weight of 72 to 700 include, for example, a linear or branched alkyl group which may have a substituent. .
  • alkyl group in the linear or branched alkyl group which may have a substituent having a molecular weight of 72 to 700, an alkyl group having 6 to 22 carbon atoms is preferable, and 11 To 20 are preferred. Examples include ⁇ -hexyl, ⁇ -heptyl, n-octyl, n-nonyl, ⁇ -decyl, ⁇ -pin r-syl, ⁇ -totesyl, ⁇ -triancle, and ti-te trasizole.
  • N- ⁇ antadecyl N-hexadecyl, ⁇ -heptadecyl, ⁇ -heptadecyl, ⁇ -nonadecyl, ⁇ -eicosyl, ⁇ -henecosyl, and ⁇ _docosyl.
  • the number of methylene groups in the linear or branched alkyl group having a substituent having a molecular weight of 15 to 700 is preferably from 1 to 22.
  • the substituent in the linear or branched alkyl group which may have a substituent having a molecular weight of 72 to 700, the substituent having a molecular weight of 15 to 700 may be used.
  • Straight-chain or branched alkyl which may be substituted The same substituents as those in the group can be mentioned. : ',
  • the acyl group represented by R 3 and R 5 in the above general formula is a linear or branched fatty acid having 1 to 22 carbon atoms, optionally substituted benzoic acid, optionally substituted phenyl. Acid, optionally substituted phenyl acid, dicarboxylic acid, formula
  • R 7 and R 8 have the same meanings as described above, nu represents 1 or 2, and m 2 represents an integer of 2 to '8.) or a substituted or substituted carboxylic acid derived from a carboxylic acid. And an aminocarbonyl group which may be substituted.
  • fatty acid examples include formic acid, acetic acid, propionic acid, valeric acid, butyric acid, hexanoic acid, heptanoic acid, octanoic acid, nonanoic acid, decanoic acid, pendecanoic acid, dodecanoic acid, tridecanoic acid, tetradecanoic acid, and pentadecanoic acid.
  • Examples include xadenic acid, heptadecanoic acid, octadecanoic acid, nonadecanoic acid, eicoic acid, and isopionic acid.
  • substituent of the acid be said substituted, for example A kill of C, C 3 alkoxy, and the like Mechirenjioki Shino ⁇ androgenic. It may be the substituted - As the substituent or three to thienyl ⁇ , for example alkyl of C t one 3 like et be.
  • substituent of the optionally substituted phenylacetic acid include d-3 alkyl, C'3 alkoxy, methylenedioxy-xino, and logene.
  • the R 1 7 substituted optionally may be Fuweniru group, the substituent group a thienyl group or a naphthyl group, for example alkyl of C 3, C -!
  • substituent of the optionally substituted aminocarbonyl group include a lower alkyl group of C or a monophenyl group which may be mono- or di-substituted.
  • the lower C lower alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, and n-hexyl.
  • 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 malonic acid, succinic acid, glutaric acid, adipic acid and the like.
  • the C t - the lower alkyl of e for example methyl, Echiru, .eta. propyl, Isopuropiru, n- butyl, Isobuchiru, .eta. pentyl, etc. hexyl and the like to the n-.
  • alkyl of C examples include methyl, ethyl, ⁇ -propyl, isopropyl and the like.
  • Examples of the C alkoxy include methoxy, ethoxyquin, ⁇ -propoxy, isopropoxy and the like.
  • halogen examples include chlorine, bromine, iodine, and fluorine.
  • the substituent in the optionally substituted phosphono group represented by R 3 in the above general formula is preferably, for example, a mono-substituted one.
  • examples thereof include, for example, a group represented by the formula — (C ⁇ 2 ) ⁇ —R 2 + [
  • n represents an integer of 1 to 3
  • R 2 + represents an amino, dialkylamino, trialkylamino, or nitrogen-containing complex ring group. ].
  • Dialkylamino represented by the R 2 4 the alkyl in the trialkyl ⁇ Mino, for example methyl, Echiru, .eta. propyl, isopropyl are preferred.
  • the heterocyclic having a nitrogen represented by the R 24, for example 1 one pyridinium Jinio, 1, 3-Chiazorinio, piperazinyl, Piperi Gino, morpholino, and the like pin port Rijini is.
  • Examples of the group capable of leaving by the hydrolysis represented by R 4 in the above general formula include methoxymethyl, ethoxymethyl, benzyloxymethyl, 2-tetrahydroviranyl, trimethylsilyl, dimethyl tertiary butylsilyl, etc.
  • Examples of the obtained group include benzyl, ⁇ -methoxybenzyl, and the like.
  • acetal residue examples include, for example, a compound represented by the formula -R 21 -CH ⁇
  • R 21 represents alkyl, phenyl or p-methoxyphenyl of Ci-s.
  • the ketal residue is, for example, a compound represented by the formula: ⁇
  • R 22 and R 23 are the same or different, and hydrogen, Ct- 3 alkyl or R 22 and R 23 is — (CH 2 ) a— (where a represents 4 or 5) ) Is formed. ]
  • the group represented by] is mentioned.
  • alkyl of Ct-3 examples include methyl, ethyl, ⁇ -propyl, and isop ⁇ -pill.
  • the compound [I] or [ ⁇ ] when the compound [I] or [ ⁇ ] is a compound capable of forming a salt, the compound may form a salt.
  • the salt include sodium salt, potassium salt, ammonium salt, hydrochloride, sulfate and the like.
  • an inner salt may be formed.
  • the compound [Ia] in which R 2 is a hydroxyl group and R 3 is hydrogen is a group from which the protecting group R + in the compound [ ⁇ ] can be removed by a hydrolysis reaction.
  • the compound [la] is subjected 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 [ ⁇ ]. can do.
  • the protecting group R + at the 3-position of the compound [ ⁇ ] is a group that can be removed by a reduction reaction
  • the acetal residue or the ketol residue at the 5- or 6-position in the compound [dish] is subjected to acidic hydrolysis.
  • the protective group at the 3-position is then removed by subjecting it to a catalytic reduction reaction, whereby compound [Ia] can be obtained.
  • R 1 , !! 2 and R 5 have the same meaning as described above.
  • R 5 represents an acyl group.
  • the compound can be further produced by subjecting it to an acyl group transfer reaction.
  • Compound [ ⁇ c] in which R 2 and R 3 are hydrogen in compound [I] 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 performed, for example, by adding water or methanol in the presence of an acidic catalyst such as hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, toluene sulfonic acid, methanesulfonic acid, and camphorsulfonic acid.
  • Organic solvents such as ethanol, ethanol, dioxan, tetrahydrofuran and 1,2-dimethoxetane.
  • the reaction is completed in these aqueous organic solvents in a temperature range of about 10 to 80 for about 1 to 2 hours.
  • the catalytic reduction reaction in the above production process is performed, for example, in the presence of palladium, palladium carbon, platinum black, palladium chloride, platinum oxide, etc., in the presence of methanol, ethanol, ethyl acetate, acetic acid, dioxane, 1,2-dimethoxyethane, and the like. It can be carried out in any organic solvent at about 10 ° C. to 100 ° C. for about 4 to 10 hours.
  • the 3-position hydroxyl group is more reactive than the 6-position hydroxyl group, and the 3-position hydroxyl group is first acylated.
  • the 3-0-acyl derivative can be easily converted into a 6-0-acyl derivative [VI] by weak intramolecular rearrangement to a 6-position hydroxyl group under weak basic conditions depending on the kind of the acyl group.
  • 3-0-Acyl derivatives also exist as intermediates, but are susceptible to intramolecular rearrangement and hydrolysis, and are chemically unstable compounds. Therefore, the 6-0-acyl derivative can also be produced by intramolecular transfer of a 3-0-acyl derivative.
  • the intramolecular transfer reaction is carried out in the presence of a weak base [eg, pyridyl, sodium carbonate, buffer solution (pH about 7 to 8)] at a temperature range of about 20 to 100 ° C. Progress in 1-10 hours.
  • a weak base eg, pyridyl, sodium carbonate, buffer solution (pH about 7 to 8)
  • carboxylic acid chlorides or anhydrides are commonly used, using pyridin, triethylamine, carbonated lime, carbonated hooder, and the like. It is carried out in the presence of a base such as sodium bicarbonate in a temperature range of about 10 ° to 50 ° C. Reaction times are often within about l to i 0 hours.
  • the phosphating agent may be, for example, 2-cyanoethyl phosphite hexyl mouth hexyl carpomide, di-paranitrobenzylphosphoryl chloride, dioxane diphosphite, Dimorpholyl phosphate, pyrophosphoryl tetrachloride And the like.
  • Examples of the solvent used in the phosphorylation reaction and the hydrophobic oxidation reaction include dioxane, dimethylformamide, chloroform, and methylene chloride, and the reaction temperature is about 110 to 50. C, and the reaction time is about i-10 hours.
  • the obtained compound is converted into a salt form by a conventional method.
  • the removal of the 3-position acyl group can be carried out by adding sodium hydrogencarbonate or pyridine in an equal molar amount to methanol or ethanol, and hydrolyzing at room temperature.
  • the reaction time is about 1 to 6 hours.
  • the dehydration reaction in the above production process is, for example, 1,5-diazabicyclo [4,3,0] -5-nonene, 1,4-diazabic ⁇ ['2,2,2,2-octane, 1,8 —Diazabicyclo [5, 4.1-1-7- ⁇ ]
  • Organic solvents such as methylene chloride, chloroform, dioxane, tetrahydrofuran, and benzene in the presence of organic bases such as indecene, pyridine, and triethylamine.
  • R + — 0 0— R 1 [Wherein, R 1 and R 4 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 reaction for acetalizing or ketalizing the compound [Ia] to produce the compound [Id] is performed by adding a ketone or aldehyde such as acetone, benzaldehyde, cyclopentanone, or cyclohexanone to the starting material.
  • a ketone or aldehyde such as acetone, benzaldehyde, cyclopentanone, or cyclohexanone
  • As the reaction solvent toluene, tetrahydrofuran, chloroform, methyl ether, dichloromethane, dichloromethane, etc. are used.
  • the reaction is carried out at a temperature of about i5 ° C to 150 ° C in the presence of an acidic catalyst.
  • the catalyst examples include acetyl chloride, sulfuric acid, ⁇ -toluenesulfonic acid, camphor-sulfonic acid and the like.
  • the reaction time is about 1 to 24 hours.
  • the ascorbic acid derivative [I] thus produced is separated by a method known per se and purified by means of purification (eg, column chromatography using silica gel, polystyrene resin, activated carbon, reverse phase system, recrystallization, etc.). It can be collected.
  • the compound used as a raw material in the method of the present invention can be produced, for example, by the following reaction steps.
  • X ′ and R 6 represent an acetal or ketal residue
  • compound [W] is first produced by acetalizing or ketalizing ascorbic acid.
  • ascorbin is reacted with a ketone or aldehyde such as aceton, benzaldehyde, cyclopentanone, cyclohexanone, and the like.
  • a reaction solvent tetrahydrofuran, chloroform, dimethyl ether, dichloromethane, dichloroethane and the like are used.
  • the reaction is carried out at room temperature to 60 ° C. in the presence of an acidic catalyst.
  • the catalyst include acetyl chloride, sulfuric acid, toluene sulfonic acid, and camphorsulfonic acid.
  • the reaction time is between 4 and 24 hours.
  • Y represents a halogen (eg, chlorine, bromine).
  • halogen eg, chlorine, bromine
  • DMS 0 dimethylformamide, dimethyl sulfoxide
  • Inorganic bases such as potassium carbonate, sodium carbonate, sodium hydroxide, sodium hydroxide, sodium bicarbonate, either alone or in a mixed solvent of rumid tetrahydrofuran. Reacts in the presence of tritium or the like to produce compound [VI].
  • the reaction is carried out at a temperature of 0 ° C. to 40 ° C. (preferably 25 ° C.), and the reaction is completed in 1 to 18 hours.
  • the compound [VI] 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).
  • an inorganic base eg, sodium hydroxide.
  • To produce compound [ ⁇ ] or [V] by reacting in the presence of potassium, sodium carbonate, carbonated carbonate) for 1 to 18 hours at a temperature of 10 to 60.
  • the compound [ITH in which X is two hydrogens in the compound [ ⁇ ] can be produced by subjecting the compound [ ⁇ ] obtained above to the same hydrolysis reaction as described above.
  • the compound [ ⁇ in which X is two hydrogens in [ ⁇ ] can also be produced by the following method.
  • ascorbic acid or isoascorbic acid is used as a raw material.
  • the hydroxyl group at position 3 is first used according to a conventional method, such as methoxymethyl chloride, ethoxymethyl chloride, benzyl methyl chloride, benzylbutamide, trimethyllinyl chloride, and dimethyl. Reaction with tertiary butylsilyl chloride, etc. to give a 3-0-ether form [K], and then the compound thus obtained In [IX], RL—Z [wherein, R 1 and Z have the same meanings as described above.
  • the compound [X] can be produced by reacting for 1 to 20 hours in a temperature range of about 10 to 60 hours.
  • an inorganic base eg, potassium carbonate, sodium carbonate, etc.
  • the compound [X] can be produced by reacting for 1 to 20 hours in a temperature range of about 10 to 60 hours.
  • 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, methylene chloride, etc., for example, triethylamine, pyridine.
  • a solvent such as tetrahydrofuran, dimethylformamide, chloroform, methylene chloride, etc., for example, triethylamine, pyridine.
  • 1.8-diazabicyclo [, 5,4,0] -7-ndene The reaction is carried out in the presence of an organic base. The reaction is carried out at about 0 to 30 ° C for about 1 to 6 hours. ,
  • the compound [I] of the present invention or a salt thereof has an antioxidant effect in an in vitro experiment using a stable radical or a side homogenate, and ischemia-reperfusion model, rat ischemia brain model or oxygen in rat heart. In free rat-induced rat renal injury models, etc., it has the effect of preventing and improving dysfunction, respectively, and has extremely low toxicity and side effects. Therefore, the compound [I] of the present invention or a salt thereof is ischemic heart failure (arrhythmia, coronary artery spasm, heart disease) in mammals (eg, mouse, rat, rabbit, dog, monkey, human, etc.).
  • ischemic heart failure arrhythmia, coronary artery spasm, heart disease
  • 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 such as renal function improvers and agents for treating stress gastrointestinal ulcers.
  • the compound of the present invention has low toxicity (for example, no acute toxicity in mice was found to have been killed by oral administration of 100 mg / kg).
  • pharmaceutical compositions eg, tablets, capsules (including soft capsules, microcapsules), liquids, suppositories, injections] according to a method known per se. , Nasal drug] can be safely administered orally or parenterally.
  • the zero dose varies depending on the subject of administration, the route of administration, and the degree of symptoms.
  • O mg / kg body weight preferably about O.SmgZ kg 20 mg / kg body weight is administered about 1 to 3 times a day.
  • binders eg, hydroxypropylcellulose, hydroxymethylpropylmethylcellulose, mac-goal, etc.
  • disintegrants eg, starch, carboxymethylcellulose
  • excipients eg, lactose, starch, etc.
  • lubricants eg, magnesium stearate, talc, etc.
  • parenteral preparations such as injections
  • isotonic agents eg, grape ⁇ , D-sorbitol, D-mannitol, sodium chloride, etc.
  • preservatives eg, benzyl alcohol, kuguchiguchi
  • buffers eg, phosphate buffer, sodium acetate buffer, etc.
  • R 2 and R 3 have the same meaning as described above.
  • R 2 ° has the same meaning as that of the acyl represented by R 3 .
  • the symbols represented by ' may be the same or different.
  • Compound [XI] can be produced in the same manner as in the acylation reaction of compound [I] to acylate compound [] to give compound [lb].
  • FIG. 1 one shows the result of the test drug, one shows the result of vitamin E, and one shows the result of vitamin C.
  • the above test drug was reduced in a dose-dependent manner DPPH at a concentration of at least 1 0 one 5 M.
  • Vitamin C and vitamin E also had comparable activities.
  • Tissue was also prepared in phosphate buffer (PH7.4) and used as a 5% homogenate. After incubating the homogenate at 37 ° C for 1 hour, follow the procedure of Ohkawa et al. [Analytical Biochemistry, 95: 55-5,1977].
  • the production amount of oxidized lipid was measured by the Tiobarbituric acid method, and the test drug was added to a final concentration of 10 to 15 M before incubating in a 5% homogenate.
  • the inhibitory action on lipid peroxide production was expressed as a% inhibition rate in comparison with the solvent (DMSO) added group.
  • the results are shown in Table 1.
  • R 2 0 H
  • R 3 H
  • R 1 -(CH 2 ) 9 CH 3 40.0 Sat 1.1
  • the drug was administered once daily, but the drug or its vehicle (Aravia gum suspension) was orally administered; 4.0 to 60 minutes later, nitrilotriacetate (NTA) or Fe 3+ —NTA was administered. Administered intraperitoneally. Fe 3+ -NTA was administered in a 1: 4 (molar ratio) mixture, 5 mg / kg as Fe 3+ for 3 days, and then 10 mg / kg for 5 days.
  • the drugs examined were compound (111), vitamin C and vitamin E, and all were orally administered at 30 mgZkg.
  • Fe 3+ — indicates a normal animal not receiving NTA.
  • Vitamin C 6 10.3 ⁇ 1.7 10.7 ⁇ 2.4
  • Vitamin E 6 9.0 ⁇ 1.0 6.3 ⁇ 1.4
  • the dose of each drug is 3 OmgZkg, oral administration
  • the test drug was 3 O mg / kg approximately 90 minutes before coronary artery closure under anesthesia, 20 mg / kg (total 50 mg / kg) approximately 45 minutes before or approximately 90 and 45 minutes Prior to this, 1 Omg / kg (total amount of 2 OmgZkg) was administered as a gum arabic suspension. The results are shown in the total dose and are shown in Table 4.
  • the frequency of ventricular fibrillation and ventricular tachycardia is the number of occurrences, the number of experimental cases (%), and the duration is seconds, indicating the average soil SEM.
  • the extrasystole is the number of extrasystoles Zrnin, and the mortality is the number of deaths / "number of experimental cases (%).
  • the vehicle group showed a pre-convulsions, which is an ischemic attack, approximately 1 ⁇ 0 minutes later, and the attack was about 90% of the time.
  • mice Male Crj-ICR mice (4 weeks old, 2 126 g) were used. 6 animals per group The compound (111) was orally administered at 300 and 100 mg OkgZkg. After drug administration, each group was kept in a cage and observed for symptoms for 24 hours.
  • the drug was a gum arabic suspension and administered in a volume of Q.lnil / l Og. ( ⁇ ) Results
  • Table 9 shows the compound (113) from the compound (111) prepared by the method according to Example 1 and Example 2 described above.
  • the compound (113) was obtained by subjecting the obtained hydroquinone body to iron chloride oxidation after performing the same method as in Example 2.
  • This benzyl compound (10 g, 0, 037 moie) was dissolved in a mixed solvent of dimethyl sulfoxide (40 ml) and tetrahydrofuran (1 Otnl), and octadecyl iodide (5 g) was dissolved in the presence of potassium carbonate (5 g). The resultant was reacted with 14 g) under heating at 50 ° C for 2 hours. After cooling, water
  • Tablets are prepared by conventional means using the following ingredients.
  • Tablets are prepared by conventional means using the following ingredients.
  • ⁇ -Tosylic acid 50 mg was added to 2-0-octadecyl-L-ascorbic acid (0.8 g, 2 (MO1) in acetone solution (5 Oftg), and the mixture was stirred at room temperature for 6 hours. The residue was dissolved in ethyl acetate, washed with water, dried and concentrated under reduced pressure The crude crystals were recrystallized from diisopropyl ether (IPE). 2-0-year-old kuta decyl 5,6-0,0-isopropylidene-ascorbic acid (0.8 g, 91%) was obtained.
  • IPE diisopropyl ether
  • Compound [I: or a salt thereof has an excellent preventive / ameliorating effect on circulatory dysfunction, and thus can be used as a circulatory dysfunction preventive / ameliorating agent.

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Abstract

Des préparations médicinales contiennent des dérivés d'acide ascorbique représentés par la formule générale (I), dans laquelle R2 représente un résidu organique ayant un poids moléculaire compris entre 15 et 700 et R2 représente de l'hydrogène ou un groupe hydroxyle. Les homologues ou les sels de ces dérivés d'acide ascorbique peuvent être utilisés comme médicaments préventifs de troubles de la fonction circulatoire.
PCT/JP1985/000340 1983-12-19 1985-06-18 Derives d'acide ascorbique, leur procede de preparation, et preparations les contenant Ceased WO1986007592A1 (fr)

Priority Applications (21)

Application Number Priority Date Filing Date Title
ZA852614A ZA852614B (en) 1985-05-17 1985-04-09 Ascorbic acid ethers and their production
PCT/JP1985/000340 WO1986007592A1 (fr) 1985-06-18 1985-06-18 Derives d'acide ascorbique, leur procede de preparation, et preparations les contenant
IL78739A IL78739A (en) 1985-05-17 1986-05-09 Ascorbic acid derivatives and pharmaceutical compositions containing them
AU57350/86A AU599029B2 (en) 1985-05-17 1986-05-12 Ascorbic acid derivatives, production and use thereof
GR861228A GR861228B (en) 1985-05-17 1986-05-12 Ascorbic acid derivatives production and use therefor
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
EP86106521A EP0202589B1 (fr) 1985-05-17 1986-05-14 Composés pharmaceutiques qui contient des dérivés de l'acide ascorbique
DE8686106521T DE3669104D1 (de) 1985-05-17 1986-05-14 Pharmazeutische praeparate, die ascorbinsaeurederivate enthalten.
FI862029A FI862029A7 (fi) 1985-05-17 1986-05-14 Askorbiinihappojohdannaiset, niiden valmistus ja käyttö.
AT86106521T ATE50494T1 (de) 1985-05-17 1986-05-14 Pharmazeutische praeparate, die ascorbinsaeurederivate enthalten.
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
JP61111945A JPH0739342B2 (ja) 1985-05-17 1986-05-15 アスコルビン酸誘導体含有製剤
CA000509360A CA1293728C (fr) 1985-05-17 1986-05-16 Derives de l'acide ascorbique, production et utilisation
ES555014A ES8801643A1 (es) 1985-05-17 1986-05-16 Un metodo para producir nuevos derivados del acido ascorbico
IE131386A IE59143B1 (en) 1985-05-17 1986-05-16 Pharmaceutical compositions containing ascorbic acid derivatives
NO861956A NO172343C (no) 1985-05-17 1986-05-16 Analogifremgangsmaate for fremstilling av terapeutisk aktive askorbinsyrederivater
HU862087A HU197735B (en) 1985-05-17 1986-05-16 Process for producing ascorbinic acid derivatives and pharmaceutical compositions containing them
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/JP1985/000340 WO1986007592A1 (fr) 1985-06-18 1985-06-18 Derives d'acide ascorbique, leur procede de preparation, et preparations les contenant

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Citations (3)

* 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
JPS60130582A (ja) * 1983-12-19 1985-07-12 Takeda Chem Ind Ltd 食品用酸化防止剤，アスコルビン酸誘導体およびその製造法

Patent Citations (3)

* 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
JPS60130582A (ja) * 1983-12-19 1985-07-12 Takeda Chem Ind Ltd 食品用酸化防止剤，アスコルビン酸誘導体およびその製造法

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