WO1986006720A1 - Ascorbic acid derivatives, production thereof, and pharmaceutical preparation therefrom - Google Patents

Abstract

A pharmaceutical preparation comprising an ascorbic acid derivative or its homolog having the general formula (I) wherein R1 represents an organic residue having a molecular weight of from 15 to 700 and R2 represents a hydrogen atom or a hydroxyl group. This preparation can be used in preventing and improving functional disturbance in the cardiovascular system.

Description

 Book

 Ascorbic acid derivatives, their production and preparation

Technical field

 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.

Background art

 Diseases of the heart, which are common in adults, such as brain and kidney, are mainly caused by cell and tissue damage and death caused by ischemic conditions as underlying lesions. It is in. For example, ischemic heart disease, cerebral ischemic injury, ischemic renal injury, ischemic digestive dysfunction, etc., along with the development of highly civilized and aging societies, their morbidity has increased and the mortality rate in developed countries has increased. Has become the main cause.

 Recently, it has been revealed that reactive oxygen species or active organic radical species play a major role in the development of lesions in ischemic tissues (ie, decreased cell function; impairment, destruction, necrosis, etc.). I. Fridovich. Annual Review of Pharmacology and Toxicology 23, 2, 3 9 (1 9 8 3); J. M. Mc Cord, The New England Journal of Medicine

Medicine), 312, 1559 (19-8 δ); K. P. Burton, J. M.

cCord, and G. Ghai, American Journal of Physiology, 246, H776 (1994)]. Is an active oxygen species or active organic radical species in living super - Okisai door two on radical (OT), radical hydroxide (· 0 Eta), singlet oxygen 0 _2), peroxide radical (R 00 ·) such Are thinking. In particular, the generation of OT in vivo and subsequent events The relationship of reactive oxygen species to cell or tissue damage has significant implications. In particular, excessive generation of οΤ 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.

 It is known that the action of superoxide dismutase, which effectively or specifically eliminates 0, is effective in protecting or ameliorating tissue damage after ischemia reperfusion or ischemia Granger, G. Rutili, J ,, M. Mc Cord, Gastroentero Mouth-(Gastroenterology). 81, 22 (19981). Compounds such as ascorbic acid, α-tocoprolol, cystine and reduced glutathione have a scavenging effect on free radicals, and these compounds cause tissue damage that is expected to involve free radicals in certain disease states. It can be prevented [I. Fridorich, Science, 20ί, 875 (19778)].

 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 α-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:

[Wherein, R ¹ represents an organic residue having a molecular weight of 15 to 70.0, R ² represents hydrogen or a hydroxyl group, and R ³ represents hydrogen, an acyl group, a phosphono group, or a sulfo group. A circulatory dysfunction preventive / improving agent containing an ascorbic acid derivative represented by the formula

[Wherein, R ¹ is an organic residue having a molecular weight of 15 to 700, R ² is hydrogen or a hydroxyl group, and R ³ is hydrogen, an acyl group, a phosphono group, or a sulfo group. When R ² is a hydroxyl group and R ³ is hydrogen, R ¹ is an organic residue having a molecular weight of 72 to 700, 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 to 700, respectively. Ascorbic acid derivatives and homologues represented by

(3) —General formula ⁰ ο for x

 [ΠΙ]

R ⁴

[Wherein, 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, and R 2 represents two hydrogen, acetal residue or ketal residue. The groups are respectively shown. A compound represented by the general formula, which is subjected to a hydrolysis reaction or a reduction reaction after an acidic hydrolysis reaction.

 West

 -_—

 HO HO

 0, aj

HO 0-R ¹

[Wherein, R ¹ is as defined above. A method for producing ascorbic acid derivatives and homologues represented by

(4) General formula

H0,

 , 0

 , P0:

HO 0-R '

[Wherein, 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. D one

A general formula characterized by being subjected to a reaction or an acyl group removal reaction

[Wherein, R and R ² have the same meaning as described above. R ⁵ represents an acyl group, a phosphono group or a sulfo group. For the production of ascorbic acid conductors and homologues represented by:

(5) —General formula

 V

 One ί

 — 0,

 -0-i

 Ό ,.

 = 0

R ⁺ 0 0- ¹

[Wherein, R ¹ and R ⁺ have the same meaning as described above. R ⁶ represents an acetate residue, a ketal residue or 0 = S <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.

H0_

 H—I

 -Hi, [I c]

H0 in 0-R ¹ = formula, R ¹ has the same meaning as defined above. This is a method for producing an ascorbic acid derivative and a homologue represented by the following formula: In the above general formula, 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, η-propyl, isopropyl, η-butyl, isobutyl, η-pentyl, n-hexyl, η-heptyl, η-octyl, η-nonyl, η- Acetyl, η-pentesyl, η-dodecyl, η-tridecinole, η-tetradecyl, η-pentadecyl, η-hexadecyl, η-heptadecyl, η-heptadecyl, η-nonadecyl, η-eicosyl, η —Henikosyl, η- 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.

 Examples of the substituent of the alkyl group 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. Optionally substituted aminocarbonyl group, optionally substituted vinyl group, optionally substituted ethynyl group, optionally substituted cycloalkyl group An aryl group which may have a substituent, an aryl group which may have a substituent,

CH ₃ , —no people

 Group or

R ⁷

One CH

[Wherein, R ⁷ represents a methyl group, a methoxy group or two R ⁷ forming one CH = CH—CH = CH— group, and R ⁸ may have a substituent. A phenyl. Naphthyl and a phenyl. ].

 As the hydroxyl group which may have a substituent,

-0-R ⁹

Wherein R ⁹ represents hydrogen, C t- ₃ alkyl or phenyl. Wherein the amino group which may have a substituent is a group represented by the formula:

 D 10

 -n

: Where 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,

One C 0-0—R ¹²

[Wherein R ¹² represents hydrogen, CL-3 alkyl or phenyl). Is an aminocarbonyl group which may have a substituent,

-C 0-HR ¹³

In the two formulas, R ¹³ represents hydrogen, C-3 alkyl, phenyl or p-hydroxyphenyl. Is a vinyl group which may have the substituent,

 R

 One CH = C <

R ¹⁵

In the two formulas, and R ¹⁵ are the same or different and represent hydrogen, phenyl, ρ-methoxyphenyl, 3-pyridyl or 3,4-methylenedioxyphenyl. Is a ethynyl group which may have the substituent The expression

-C = C-R ¹⁶

[ ^Where R ^1S is hydrogen or C! Shows ₁₈ alkyls. ] And the groups represented by

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.

As good Ariru group optionally having said substituent, the formula -, t ⁹ ·

[Wherein, R ¹⁷ , R ¹⁸ and R ¹³ are the same or different and each represents hydrogen, alkyl of C 丄 -3, alkoxy of C, halogen, ethoxycarbonyldienyl, phenyl, carboquinol, carboxymethyl or Indicates lupoxyshetil. And a group represented by コ 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.

 Examples of the halogen include chlorine, bromine, fluorine, and iodine.

Specific examples of the hydroxyl group having the substituent include, for example, methoxy, ethoxy, propoxy, isopropoxy, and phenoquine. Specific examples of the amino group having the substituent include, for example, methylamino, dimethylamino, ethylamino, propylamino, isopropylamino, phenylamino, ρ-hydroxyphenylamino, and the like. Is mentioned. Specific examples of the carboxyl group having the substituent include, for example, methoxycarbonyl, ethoxycarbonyl, phenoxycarbonyl and the like. Specific examples of the aminocarbonyl group having the substituent include, for example, methylaminocarbonyl, dimethylaminocarbonyl, isopropylaminocarbonyl, phenylaminocarbonyl, ρ-hydroxyphenylaminocarbonyl and the like. . Specific examples of the 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. Specific examples of the ethynyl group having the substituent include, for example, methylethynyl, ethylethylinyl, _η -pentylethynyl and the like. Specific examples of the 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. Specific examples of the 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 -carboxyethyl) phenyl and the like. Specific examples of the heterocyclic group which may have a substituent include, for example, 2-, 3- or 4-pyridyl, 2- or 3-phenyl, morpholino, pyrrolidinyl, piperidinyl Dinyl, piperazinyl, 4-monophenylpiperazinyl, 4- (ρ-fluorophenyl) piperazinyl, 4-diphenylmethylpiperazinyl, 4- · (P-methoxyphenyl) piperazinyl and the like. , May have three substituents, such as, for example,

 Examples include alkyl, carboxyl, hydroxyl, phenyl, halogen, carboxymethyl, and benzoyl.

 In the above general formula, 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, η-heptyl, η-heptyl, n-nonyl, η-decyl, π- ゥ decyl, η-dodecyl, η-tridecyl, η-tetradecyl, η-ventadecyl , Η-Hexadecyl, η-Hetadecyl, η-Kutadecyl, η-No

o-5 Nadecyl, n-eicosyl, n-henechol, 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.

 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.

0 In the above general formula, 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,

HO

^R7

Wherein 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 optionally substituted 2 - Examples of the substituent of or three to thienyl詐酸, for example alkyl of C ₃ is like et be. 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! -3 alkoxy, Mechirenjiokishi and halogen. 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.

 Examples of the above C i -s lower alkyl include methyl, ethyl, η-propyl, isopropyl, η-butyl, isobutyl, n-pentyl, and η-hexyl.

Examples of the C i- ₃ alkyl include methyl, ethyl, η-propyl, and isopropyl.

Examples of the above C ₃ alkoxy include methoxy, ethoxy, n-propoxy, isopropoxy and the like.

Examples of the halogen include chlorine, bromine, iodine, and fluorine.

225 o 5 In the above general formula, 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. Examples of the group which can be removed by benzyl include benzyl, ρ-methoxybenzyl and the like.

 As the above acetal residue, for example, the formula

R ²¹ -CH <

[In the formula, R ²¹ represents d-3 alkyl, phenyl or p-methoxyphenyl. ;: The ketal residue includes, for example, 0 formula C <-

Wherein, 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.

When R ³ in the compound [I] or [Π] is a phosphono group or a sulfo group, a salt may be formed, and examples of the salt include a sodium salt and a potassium salt. .

In the compound [I], 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 [ΠΠ] 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 [位].

Further, a group capable of leaving the protective group R ^{4 at} the 3-position of the compound [ΕΙ] by a reduction reaction In the case of, after removing the acetal residue or the ketone residue at the 5th and 6th positions in the compound [ΒΠ] by acidic hydrolysis, the protective group at the 3rd position is then removed by catalytic reduction. Thus, compound [Ia] can be obtained.

Compound [Ib] in which R ³ is an acyl group in compound [I] is obtained by subjecting compound [I] in which R ³ is hydrogen to [ ]

[Wherein, RR ² and R ⁵ have the same meaning as in the previous ^. R ⁵ represents an acyl group. When a compound represented by the formula [1] is produced, 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. Can be produced. 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. , Ethanol, dioxan. Tetrahydrofuran, 1,2-dimethoxyethane, etc., or a hydrous organic solvent for about 1-2 hours at a temperature of about 10-80 ° C. Complete.

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.

In the acylation reaction of the method of the present invention, 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 [Ί] 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.

 In the acylation reaction, carboxylic acid chlorides or anhydrides (including mixed acid 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.

In the phosphorylation reaction of the method of the present invention, examples of the phosphating agent include 2-cyanoethyl phosphate-dicyclohexyl carpoimide, di-paranitrobenzylphosphoryl chloride, and dioxane diphosphite. , Dimorpholyl phosphate, pyrophosphoryl tetrachloride and the like. _Λ

In sulfation reaction of the present process, as the sulfating agent, ₍₃ S 0) sulfuric anhydride, pyridine sulfur trioxide (S 0 ₃ -〇 ₅ 11 ₅ 1 ^), sulfuric anhydride Jiokisan (30 ₃ -0

C ₊ H ₈ 0), dimethyl sulfate Holm § Mi de anhydride _{[S 0 3 - HC ON (} CH 3) 2], Sulfuric anhydride Toryechiruami down _{[S 0 3 - N (C} 2 H 5) 3] , and the like. Examples of the solvent used in the above-mentioned phosphorylation reaction and sulfation reaction include dioxane, dimethylformamide, chloroform, and methylene chloride. The reaction temperature is about −10 to 50 ° C. And the reaction time is about 1 to 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 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. -By the dehydration reaction, the general formula [VI]

In the formula, 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.

 In the method of the present invention, the compound used as a starting material can be produced, for example, by the following reaction steps.

[A], a compound [ΠΙ] in which X is an acetal or a ketal residue in the compound [ΠΙ], a compound [R in which the R ⁸ is an acetal or ketal residue in the compound [V] Production method:

fascorbic acid, d, β-ascorbic acid.

. ¹ Isoasukorubin acid

Acetalization,

 Ketalization

R ¹ — Z

R ^e ', r

R ⁺ -00-R ^{1 In the} above formula, X ′ and R ⁶ ′ represent an acetal or ketal residue ₍ When ascorbic acid is used as a raw material, first, ascorbic acid is acetalized or ketalized to produce compound [VI]. In this reaction, ascorbin is reacted with ketones or aldehydes such as aceton, benzaldehyde, cyclopentanone, and cyclohexanone. Examples of 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. Examples of the catalyst include acetyl chloride, sulfuric acid, toluene toluenesulfonic acid, hydrogen sulfonic acid, and the like. The response time is 4 to 24 hours.

Next, the compound [VI = is represented by the formula R ⁺ — where R ⁺ has the same meaning as described above.

Y represents a halogen (eg, chlorine, bromine). ] (Eg, chloromethyl methyl ether, benzyl chloride, benzyl chloride) with dimethylformamide, dimethylsulfoxide (.DMSO), hexamethylphosphoramide 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.

Then, 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). ] In a solvent alone or in a mixture of dimethylformamide, dimethylsulfoxide, hexamethylphosphoramide, tetrahydrofuran and the like, or an inorganic base (eg, sodium hydroxide). , 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 [化合物] obtained above to the same hydrolysis reaction as described above.

 [Β] and compound [ΙΤ '] in which X is two hydrogens in compound [ΠΙ] can also be produced by the following method.

r ascorbic acid,

 Isoascorbic acid

R ⁴ -Y

R ¹ — Z

HO HO

 V,. = 0 [Ι'Ί, ΓΧ]

R ⁺ - 0 0- ¹ In the above method, using the Asukorubin acid or Isoasukorubin acid as raw family, first 3-position hydroxyl group of the main Tokimechiruku σ Lai de usual manner Benjirubu port Mai de, trimethylsilylchloride Lai de, dimethyl By reacting with tert-butylsilyl chloride or the like, a 3-0-ether form [IX] is obtained, and the thus obtained compound [ら れ] is added to に ^ —Ζ [where RL and And z have the same meaning as described above. ] In a single or mixed solvent of dimethylformamide, dimethylsulfoxide, hexamethylphosphoramide, tetrahydrofuran, dioxane, etc., in an inorganic base (eg, carbonated sodium carbonate, sodium carbonate, etc.). 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.

[C], compound [V], wherein R ⁶ is 0 = S <group.

 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. 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 compounds [m] and [V] produced by the above method are useful, for example, as synthetic intermediates for producing the compound [I].

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, '', ト, ゥ heron, dog, monkey, human, etc.). Death, myocardial infarction, etc.), subarachnoid hemorrhage disorder, 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.

 Specific examples of the above-mentioned 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. And 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. When administered orally ^ to the above mammals, the dose is usually about Q.img / kg to 5 Omg / kg body weight, preferably as a single dose. Administer about Q.5 nig / kg to 2 Og / kg body weight about 1 to 3 times a day.

In the case of 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.

 When producing the above oral preparations, for example, tablets, binders (eg, hydr σ-xypropylcellulose, hydroxymethyl cellulose σ-pyrmethylcellulose, mac σ-gol, etc.), disintegrants (eg, starch, carboxy Methylcellulose power Runum, etc.), excipients (clear, lactose, starch, etc.), lubricants (eg, magnesium stearate, talc, etc.) can be added as appropriate.

In addition, when producing non-diabetic preparations such as injections, tonicity agents (such as grape, D-sorbitol, D-mannitol, sodium chloride, etc.), preservatives (eg, Benzyl alcohol, butanol and paraoxybenzoate

-.2 Methyl I55, propyl paraoxybenzoate, etc.), and buffering agents (eg, phosphate buffer, sodium formate buffer) can be added as appropriate.

 Also, the general formula

R ²⁰ - 0 0- ¹

[Wherein, RR ² and R ³ have the same meaning as described above. R ² ° is indicated by R ³ above.

10 has the same significance as the However, the file represented by R ³ and

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].

'= I can be carried out in the same manner as the acylation reaction leading to I.

 BEST MODE FOR CARRYING OUT THE INVENTION

 Hereinafter, the present invention will be more specifically described with reference to Experimental Examples, Reference Examples, and Examples.

20.

 Experimental example 1, antioxidant activity studied using stable radicals:

According to the method of M. S. Pruss [Nature 181, 1 pp. 119, 19 δ 8], the stable free radical α, diphenyl “/ 3_picrylhydrazyl ( The reduction activity of D Ρ Ρ Η) was examined and used as an indicator of antioxidant activity, ie, O.lmM DPPH ethanol solution 3 mU This test drug “that is, R ^{1 =} — (CH ₂ ) ₁₇ in compound [I] CH ₃ , R ² = OH, A compound with R ³ = H (also referred to as compound (111)) is added, and after 20 minutes, the absorbance is measured at a wavelength of 5 17 rnn using a spectrophotometer. did. The difference in absorbance from the solvent [dimethylformamide (DMF) 0.5% or less] control was defined as the reduction activity.

 The experimental results are as shown in FIG.

 In 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.

Experimental example 2: Inhibition of lipid peroxide production in rat brain homogenate:

 (i) Method

 Male SD rats (12 weeks old) were bled under vent barbital anesthesia and their tissues were removed. The brain tissue was homogenized in a phosphate buffer (PH7.4) and used as a 5% homogenate. The homogenate is 37. C. After incubating for 1 hour, the amount of lipid peroxide produced as described by Ohkawa et al. [Analytical Biochemistry, 95: 5151, 1979]. Was measured by the Ciobarbilic acid method.

 Test drug should be at final concentration before incubating in 5% homogenate.

It was added to be 10 to ¹⁵ M. The inhibitory action on lipid peroxide production was expressed as a% inhibition rate in comparison with the solvent (DMSO) added group.

(Π) The results are shown in Table 1.

The inhibitory activity of lipid peroxide formation varies with the chain length when the number (n) of the side chain methylene groups in the general formula [I] is changed from n = 7 to 21; n = 13 to 19 Of the compounds, the inhibition rate is more than 80%, much higher than that of vitamin E won. The compound (1-12) had higher activity than the compound having a methylene chain at position 3 with n = 17. In the same experimental system, vitamin C promoted lipid peroxide production more markedly.

table 1

 Inhibitory effect on lipid peroxide production in rat brain homogenate (TBA method)

 Compound [] Inhibition rate%

R ^ O HR ^ HR ¹ ^ ― CCH 2) 7 CH 3-6.6 3.0

R ^ O HR ^ HR ¹ --(CH ₂ ) ₉ CH ₃ 40.0 2 1.1

R ² = OH, R ³ = H, R ^L = — (C H2) il C H3 55.7-26.5

R ^ O HR ^ HR ¹ ^-(CH ₂ ) ₁₃ CH ₃ 93.i ± 5.3

 — (Then ri2) "CH3 100.0 ± 0

R ^ O HR ^ HR ^-(CH ₂ ) ₁₅ CH ₃ 78.5 ± 11.7

R ^ O HR ^ HR ¹ ^ — (C H2) 3: 7C H3 88.6 Sat 6.8

R ² = OH, R ³ = H, R ^l =-(CH ₂ ) ₁₃ CH ₃ 95.4 Sat 4.6

The concentration of 3-position compounds' 45.4 Saturday 8.7 having a group Vita Mi emissions C -71.6 ± 36.8 Vita Mi emissions E 44.9 ± 11.7 Note) Each compound in 1 0_ ⁵ M, each of the experimental examples number 3. The suppression rate was shown as the average value of soil standard error.

Note: Compound having a group at the 3-position

HO ^

 HO

 .-0, '

CH ₃ (CH ₂ ) ₁₇ 0 OH Experimental Example 3, Fe ³⁺ —two-mouth triacetate in rats

 (i) Method

 Male SLC-Wistar La Soto (4 weeks, 64-85 g) was used. Food and water were provided ad libitum and kept individually in metabolic cages. Body weight, urine volume, and urine protein (BI0-RAD method) were measured daily, and the presence or absence of urinary occult blood reaction (Rubstick paper method) was examined. On the last day, the kidneys were excised and weighed.

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.

(Π) Results.

 The results of the last day of the experiment are shown in Tables 2 and 3.

In the vehicle-administered group, renal damage due to Fe ³⁺ -NTA appeared, renal weight increased remarkably, and occult blood reaction appeared in urine in most cases. Urine volume and urine protein also increased significantly. In the compound (111) group, renal impairment was reduced.

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. Table 2

 - Five

Fe ³⁺ —Nitrilo triacetate (NTA) Effect on renal injury Body weight Renal volume Urinary occult blood group ω (mg) 'reaction

None. 2 118 51 0/2

Vehicle * ² 6 86.6 2 3.7 68.2 2.1 5/6 Compound (1 1 1 2) 6 95.5-3.0 56.5 ± 2.0 '^' 3/6 Vitamin C 6 89.2x4.1 64.5 ± 1.7 5 / 6 vitamin E 6 99.3 ± 2., 3 4/60 The dose of each drug was 3 Og / kg, orally

 n: Number of experimental examples

^^ NonerFe ^-Normal animals not receiving NTA. , ² Vehicle: Arabic gum suspension · · Table 3

Effect of Fe ³⁺ -Nitrilo triacetate (NTA) on renal damage Urine volume Urine protein

 Group n l / day (mg / aay)

 one 6 5.4 ± 1.2 3.0 ± i.1

 Vehicle 6 13.23: 2.0 15.1 ± 1.9

0 Compound (1 1 1 2) 6 7.4 ± 1.3 8.1 ± 2.1 <<

 Vitamin C 6. 10.3 ± 1.7 10.7 = 2.4

 Vitamin E 6 • 9.0 ± i.O 6.3 ± 1.4

 The dose of each drug is 3 Omg / kg, oral administration

 n: Number of experimental examples

N one: Fe ³⁺ — shows normal animals not receiving NTA ₍ Vehicle: Arabia gum suspension) Experimental Example 4, Coronary artery occlusion of rat heart-Inhibition of ventricular arrhythmia during reperfusion:

 (i) Method

 Male SD rats (9-13 weeks old, 250-37 Og) were used. Pentopalbital anesthesia, the chest was opened under artificial respiration, the left anterior descending coronary artery was ligated with a silk thread for 5 minutes, then the closure was released, and the blood was reperfused and observed for 10 minutes. Standard IV technique II lead electrocardiogram was recorded to investigate the occurrence of ventricular arrhythmia.

 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.

(Π)

 When the left anterior descending coronary artery is closed for 5 minutes and then reperfused; represented by sporadic extrasystoles (PVCs), ventricular tachycardia (VT) and ventricular fibrillation (VF) Ventricle ¾Arrhythmia occurs. νϊ and VF can be reversibly paroxysmal or sustained VF development can lead to death.

 In the vehicle-treated group (control), 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.

 In the 20 and 50 mg / kg groups of compound (111), the occurrence of arrhythmias was significantly significantly suppressed in a dose-dependent manner. If an arrhythmia occurred, its duration was shortened. Therefore, mortality from VF was also low. The incidence of single-shot PVCs was around 10 times / min in the Vehicle group, but significantly less in the compound (111) group.

On the other hand, oral administration of 50 mg / kg of vitamin C and vitamin E had no significant effect Table 4

 Effects of coronary occlusion-reperfusion on ventricular arrhythmias in rat hearts Ventricular fibrillation Ventricular tachycardia

 Group Frequency of occurrence Duration Frequency of occurrence Duration Extra-systolic mortality Control 7/8 (88) 83.9 ± 27.5 7/8 (88) 3 8 ± 15.0 10.8 ± 3.5 2/8 (25) Compound

 (1-12)

 50mg / kg 2/9 << (22) 1.2- 0.8 2/9. (22) 3.2 Sat 2.6 << 1.1 ± 0.3 ^ 0/9 (0) Control 16/18 (89) 74.2 ± 30.8 17/18 ( 94) 26.5 Sat 6.8 11.8 4.0 4.0 2/18 (11) Compound ''.

(1-12)

 20mg / kg 9/17 ^ (53) 3i.0 ± 28.2 ii / 1'7 (65) 10.2 ± 3.2 << 3.3 ± 0.8 << 1/17 (6) Control 17/18 (94) 74.1 ± 36.0 17/18 (94) 16.6 ± 4.4 7.3 ± .7 3/18 (17) Vita

Min C

 50mg / kg 6/6 (100) 9.7 Sat 2.5 6/6 (100) 19.0 3.0 3.0 ± 1.0 0/6 (0) Vita

 Min E

 50mg / kg 6/10 (60) 43.4 ± 36.0 7/10 (70) 22.3 Sat 9.7 7.0-4.1 1/10 (10) x: Ρ <0.05, ^ ':? <0.01, compared to control group 铰

 The frequency of ventricular fibrillation and ventricular tachycardia is the number of occurrences / number of experimental cases (%), and the duration is average ± S Ε Ε 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 (%).

 Experimental Example 5, Inhibition of ischemic seizures by bilateral common carotid artery ligation in SHR rats:

(i) Method Male SHR La Soto (22 weeks old, around 360 g) was used. A middle incision was made in the neck under light ether anesthesia, and the bilateral common carotid arteries were separated and ligated to cause cerebral ischemia. Thereafter, the patient was awakened from anesthesia and the behavior was observed for 4 hours.

 The drug was orally administered as a gum arabic suspension 60 minutes before bilateral carotid artery ligation. Table 5 shows the results.

 (ii) Results

 When the bilateral common carotid arteries were ligated and the brain was made ischemic, the vehicle group showed ischemic seizures, a pre-seizure spasm, about 1 δ0 minutes later, and the seizure was 180 minutes in about 90% of rats. Occurred within. However, 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%.

 Table 5-

'' Inhibition of ischemic seizures during bilateral carotid artery ligation in SHR rats.

 Ischemic seizures

 Group-n hours (min) Frequency of occurrence

 Vehicle 41 15JL Sat 4 36/41 (87.8%)

 Compound (1 1 1 2) 5 199 ± 13 << 1/5 * (20%)

 Compound (111): 10 Orag / kg p.o .; Vehicle: Arabic gum suspension

 ©: Within 1 80 min

 《· ： P <0.05

 Experimental example 6, acute toxicity in mice

 (i) Method

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. (Π) Results

 After oral administration of compound (1-12) at 300 and 1000 Og / kg, half of both groups showed sedation and ptosis, but both recovered within 3 hours . After 24 hours of observation, both groups did not die.

Reference example 1

(1) Dissolve L-ascorbic acid acetate (42 g Oigmoie) in a mixed solvent of dimethylformamide (100 ml) and hexamethylphosphoramide (100 ml), and add potassium carbonate (100 g). 32 g, 0.23 mole) was added and the mixture was ice-cooled. To this was dissolved methyl methyl ether (18 g, 0.22 mole) in tetrahydrofuran (25 ml), and the solution was added dropwise over 20 minutes. After stirring at room temperature for 2.5 hours, water (200 ml) was added, then 2N hydrochloric acid was added to adjust the pH to 5.0, and the mixture was extracted four times with ethyl acetate. The organic layer was washed with water, dried, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography, eluted with isopropyl ether-ethyl acetate (2 _: 1). After concentration, the residue was recrystallized from the same solvent system. 5, 6-0,0-Isopropylidene 3-0-methoxymethoxyscorbic acid (46 g) was obtained. mp 93 ~ 94.

Elemental analysis (for CnH ^ O?) ''

 Min Qi value: C, 50.84; H, 6.05%

 Calculated: C, 50.77; H.6.20 '

(2) Dissolve L-5, 6-0, diisopropylidene-3-0-methoxymethylascorbic acid (1.84 g, 7.1 mmole) in dimethyl sulfoxide (10 ml), and add octadecyl iodide (2.68 g). g) and potassium carbonate (l.Og) were added and reacted at 60 ° C for 6 hours. After the reaction, add water (50 ml) and extract the product with ethyl acetate. The organic layer was washed with water, dried and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with isopropyl ether. After concentration, the residue was recrystallized from isopropyl ether-ethyl acetate to give L_5,6- 0,0-Isopropylidene-3-0-Methoxymethyl-2-0-year-old kutadecylascorbic acid (ref. 111) (0.8 g) was obtained. Table 6 shows the physical properties.

 In the same manner as in Reference Example 1, the compounds shown in Table 6 [(Ref. 113)] were prepared from ((Ref. 113)).

Ten

) ^ ¾ 9

— t

 »O ε

) H0 (' Table 6 (continued)

 Bz: benzyl, Me: methyl, Ph: phenyl, iP r: isopropyl, Εt: ethyl

 Reference example 2

 (1) L-ascorbic acid acetonide (21.6 g, 0.1 mole) was dissolved in dimethylformamide (12 Oml) and cooled with ice. To this was added potassium carbonate (14 g, 0.1 ml), followed by addition of benzylbutamide (11.2 mD), and the mixture was stirred at room temperature for 20 hours. The mixture was neutralized with hydrochloric acid and extracted twice with ethyl acetate to adjust the pH to 5.0.The organic layer was washed with water, dried (magnesium sulfate) and concentrated under reduced pressure.The product was subjected to silica gel column chromatography. Elute with isopropyl ether-ethyl acetate (3: 1), concentrate, and recrystallize from isopropyl ether-ethyl ester. 1,5,6-0,0-isopropylidene-1-3-0-benzylas Corbic acid (13 g, 40%), mp 105-106 ° C was obtained.

(2) L-5, 6-0,0-isopropylidene-13-0-benzylascorbic acid (3.06 g, 0.01 mole) was added to dimethyl sulfoxide (20 mi) and tetrahydrofuran (15 ml). The mixture was dissolved in a mixed solvent, and carbonic acid lime (0.5 g, 0.0 U, 5 mole) was added. Next, ogutadecyl iodide (3.83 g) was added and the mixture was stirred at room temperature for 18 hours. After the reaction, water (100 mi) was added, and the mixture was extracted with ethyl acetate.

ο-, 5 The organic layer was washed with water, dried (magnesium sulfate) and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with isopropyl ether monoethyl acetate (10: 1). L-5, 6-0, 0-isopropylidene 3--0-benzyl-2-0- Octadecyl scorbic acid [compound (Ref. 2-7)] (3.8 g) was obtained. Table 7 shows the physical properties.

 In the same manner as in Reference Example 2, a compound (Ref 2-1) was prepared from the compounds (Ref 2-1) shown in Table 7. 0

0

(^^ 7ΟΑ Reference Example 3-

(1) L-5,6-0,0-Isopropylidene-3--1-benzyl-2-0-year-old cutadecylascorbic acid (3.8g) in tetrahydrofuran (40ml) and methanol (1 Oml) And 2N hydrochloric acid (2 O ml) was added thereto, followed by stirring at 50 ° C for 24 hours. After the reaction, the reaction mixture was concentrated under reduced pressure, and the product was extracted with ethyl acetate. The organic layer was washed with water, dried, concentrated under reduced pressure, and the residue was recrystallized from isopropyl ether-acetate to give 3-0-benzyl-2-0-tadecylascorbic acid [compound (Reference 3-7)] ( 2.6 g) were obtained. Table 8 shows the physical properties. '

(2) The compound obtained in Reference Example 2 was treated in the same manner as described above to prepare a compound (Reference 3-12)] from the compound (Reference 3-1). The results are shown in Table 8.

〇

Hyo

 ,, Hyo Hyo 0 κ Hyo

. (ϋ Example 1

 L-5, 6-0,0-Isopropylidene-1 3-0-Methoxymethyl_2-10-year-old cutadecylascorbic acid (i.2g) is treated with methanol (3 Oml) and tetrahydrofuran ( (1 Oml), mixed with 2N hydrochloric acid (1 Oml), and stirred at 50 ° C for 6 hours. The reaction solution was concentrated under reduced pressure, the product was extracted with ethyl acetate, the organic layer was washed with water, dried (magnesium sulfate), concentrated under reduced pressure, and the residue was recrystallized from isopropyl ether-ethyl ester to obtain 2-0- Octadecyl scorbic acid [compound (112)] (0.82 g) was obtained. Table 9 shows the physical properties.

Example 2

 3-0-Benzyl-2-0-octadecylascorbin (2.lg) is dissolved in ethyl acetate (25ml), 5% Pd-C (0.5g) is added, and catalytic reduction is performed at normal pressure. went. 'The catalyst was filtered, concentrated under reduced pressure, and the product was recrystallized from diisopropyl monoethyl acetate to give 2-0-octadecylascorbic acid [compound (1-2)] ( 1.5 g) were obtained. Table 9 shows the physical properties.

Example 3

Table 9 shows the compound (111) from the compound (111) prepared by the method according to Example 1 and Example 2.

Factory MM n

^ 9

be: o J

 tr3

Three

03

(

 CD

O

-) Hyo O COCH

 C

Three

3 3

Three

(^^ 9A Table 9 (continued)

 ! 7.38 (7H, m), 8.45 (2H, m) Compound (1-37) was obtained by subjecting the hydroquinone derivative obtained after performing the same method as in Example 2 to iron chloride oxidation. .

 Example 4

(1) Pyridin (1 mi) was added to a solution of 2-0-octadecyl-L-ascorbic acid (0.8 g, 2 mmole) in sulphate (2 Omi), and then benzoyl chloride [0.28 g, 2 mmoie) was added dropwise. The reaction solution was stirred for 1 hour, then acidified by adding 2N hydrochloric acid, and the organic layer was washed with water and dried (magnesium sulfate). After evaporating the solvent under reduced pressure, the product was recrystallized from isopropyl ether-ethyl acetate to obtain 3-0-benzoyl-1-0-year-old octadecyl-L-ascorbic acid (0.6 g. 49%). Was. mp.6 8—6 9. C. C ₃ H _{+ 80 ?} (F o nd: C, 69.94; H.8.98 Anal.Calcd: C, 69.89; H, 9.08) _o

(2) According to the above, benzoylation of 2-0-hexadecyl-L-ascorbic acid yields 3-0-benzoyl-2-0-hexadecyl-L-ascorbic acid, mp. 7 7-78 ° C was gotten. _{C 23 H + 4 0 7 (} . Found:.. C 69.21; Η, 8 · 82% Anal C alcd: C, 69 · 02; H, 8.79).

 Example δ

(1) 2-O-octadecyl-L-ascorbic acid (0.8g, 2iMiole) in a form-mouth solution of pyridine (iml) and 4,4-dimethylaminopyridine (0.1g) 1 was added, and then acetyl chloride (0.25 ml) was added dropwise at room temperature. After the reaction solution was stirred for 18 hours, the organic layer was washed with 2N hydrochloric acid, washed with water and dried. The solvent was distilled off under reduced pressure, and the product was recrystallized from isopropyl ether-ethyl acetate to obtain 61-acetyl-2-0-year-old octadecyl-L-ascorbic acid (0.6 g, 65%). mp. 1 17 — 1 18 ° C. _{C 2S H + 0 0 7 (} F OLind:.. C, 66.24; H, 9.95% Anai Calcd: C, 66.35; H, 9.85). (2) According to the above, 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:

Λ3 · shi / "two.

6— 0—Acetyl-2—Q—Pentadecyl-L-ascorbic acid, nip. 1 1 2-1 13 ° C ₃ C 23H40 O ₇ (Found: C, 64.59; H, 9.'48¾ ₀ Anal. Calcd: C , 64.46; H, 9.41).

5 6— 0—Benzoyl 2— 0—Pentadecyl-L-ascorbic acid,

'' mp. 1 3 9—140 ° C. _{C 23 H + 2 0 7 (} F OLind: C, 68.36; H, 8.78%.

 Anal. Calcd: C, 68.55; H, 8.63).

6—0—phenylacetyl—2—0—pentadecyl—L-ascorbic acid, mp. 126-127 ° C. _{C 23 H + 0 7 (F} oiind: C, 68.79; H, 8.99%).

 Anal. Calcd: C, 69.02; H, 8.79).

6- 0- Asechiru 2 0- to Kisadeshiru L Asukorubin acid, mp.1 1 4- 1 1 5 ° (: C 2 + H + 2 0 7 (F ound:.. C, 65.02; H, 9.64% A nalCalcd: C, 65.13; H, 9.56) ₀

6—0—nicotinol 2-—one-year-old kutadecyl-L-ascorbic acid hydrochloride, mp. _{C 3 + H + 8 N 0} 7 C 1 (F ound:.. C, 66.49; H.8.70; N, 2.20% Anal Calcd: C, 66.06; H, 7.83;, 2.27) 0 Example 6

Pyridine (1 ml) was added to a solution of 2-0-octadecyl-L-ascorbic acid (0.8 g, 2iole) in formaldehyde (20 ml), and then acetyl chloride (0.25 ml) was added dropwise at room temperature. After stirring the reaction solution for 1 hour, it was washed with 2N hydrochloric acid, and the organic layer was washed with water and dried. The solvent was distilled off under reduced pressure, and the product was recrystallized from isopropyl ether-ethyl acetate to obtain 3-0-acetyl-2-0-octadecyl-L-ascorbic acid (0.8 g, 87%). mp.7 8- 7 9 ° C, C 2 eH + 6 07 (Found:.. C, 66.07; H, 9.80% Anal Calcd: C, 66.35; H, 9.85).

 Example 7

 -To a solution of 2-0-octadecyl-L-ascorbic acid (0.8 g, 2 minole) and phenylisocyanic acid (0.24 g, 2 mmole) in chloroform (20 ml), add acetic acid (0.1 ml). Ripened at 60 ° C for hours. After the reaction, the product was washed with water, dried and concentrated to obtain the product. Recrystallization from ethyl isopropyl ether gave 6-0-phenylcarbamoyl-2-0-octadecyl-L-a-scorbic acid (0.75 g). π. ί 4 9— 15 0 ° (:.

C3iH _{+ 9} 0 ₇ (Fouiid: C, 68.14; HJ.08; Ν, 2.74%. Anal. Clcd: C, 67.98; H.9.02;, 2.56) ₀

 Example 8

1) Benzyl bromide (12 ml) was added dropwise to a solution of sodium D-isoascorbate (2 Og.O.lmole) in dimethylformamide (50 ml), and the mixture was heated at 50 ° C for 4 hours. Was done. Water (100 ml) was added to the reaction solution, and the product was oiled with ethyl acetate. After the organic layer was dried, concentrated and concentrated, the crude product was subjected to silica gel column chromatography and developed with ethyl acetate to give 2-0-benzyl-D-isoascorbic acid (10 g, 37%). Obtained. This benzyl form (10 g, 0.037 mole) was mixed with dimethyl sulfoxide (4 Old) and tetrahydro. It was dissolved in a mixed solvent of furan (1 Offll) and reacted with octadecyl iodide (14 g) in the presence of potassium carbonate (5 g) by heating at 50 ° C for 2 hours. After cooling, water

(10 Oral) was added and the product was extracted with isopropyl ether. The organic layer was washed with ice, dried and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, developed with isopropyl ether: ethyl acetate (1: 1), and the obtained crude crystal was purified with hexane: isopropyl ether Recrystallization from (1: 1) gave 2-0-year-old cactadecyl-13-0-benzyl-1-D-isoascorbic acid (5 g, 26%). mp. 6 2-6 3 _{C 3 1 H 50 0 6 (} F o Ji nd:. C, 72.02; H , 9.67% o Anal Calcd: C, 71.78; Η, 9 · 72).

2) A solution of 2-0-octadecyl-3-0-benzyl-D-isoascorbic acid (3 g, 5.7 oleole) obtained in the above reaction in ethanol (50 ml) was added in the presence of 5% Pd-carbon (Q .2g), and a hydrogenation reaction was carried out at normal pressure. i After 8 hours, the catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give 2-0-octadecyl D-isoas :? Rubic acid (2 g, 80%) was obtained. mp. 103-104 ° C. _{C 2 + H + + 0 8} (F oiind:.. C, 67.45; H, 10.46% Anal Calcd: C, 67.26; H, 10.35) o

Example 9

5.6-0,0-Isopropylidene-3-O-Methoxymethyl-1-20 One-year-old ctadecyl-1-L-ascorbic acid (5 g, 10 mmole) in tetrahydrofuran (20 ml) was added to i, 8 —Diazabicyclo [5,4,0] —7-Pendecene (3 ml) was added, and the mixture was heated with stirring at 50 ° C. for 2 hours. After cooling, ethyl acetate (4 Oml) was added, washed twice with 2N hydrochloric acid, washed with water, dried and concentrated under reduced pressure, and the residue was washed with ethanol (4 Oml) and 2N hydrochloric acid (2 Oml). The mixture was heated and stirred at 60 ° C for 6 hours in a mixed solvent of the above. After concentration of the reaction solution under pressure, the product was dissolved in ethyl acetate, washed with water, dried and concentrated. The crude product is recrystallized from isopropyl ether to give 2-0-octadecyl-5-dehydroxyascorbic acid (2 g, 51%) was obtained. mp.1 1 4—1 1 5 C. _{C 2 + H 42 0 5 (} F ound:.. C, 70.24; H, i0.42% Anai Calcd: C, 70.21; H, 10.31) o

5% Pd-carbon (0.2 g) was added to the ethanol solution (10 ml) of 2-0-octadecyl-5-dehydroxyascorbic acid (0.4 g, 1 mmole) obtained above. The mixture was stirred under a hydrogen atmosphere under normal pressure for 4 hours. After completion of the reaction, the catalyst was removed by filtration, and the filtrate was subjected to reduced pressure. The residue was recrystallized from isopropyl ether / hexane to obtain the desired d, i2-2-0-year-old cutadecyl-δ-doxyascorbic acid (0.2 g). mp.83—84 ° C. C2 ₊ H _{++ 5} (Foiind: C, 69.33; H, 10.47%. Anal. Calcd: C, 69.86; H, 10.75) _o Example 10

 Tablets are prepared by conventional means using the following ingredients.

1 ¹ = (〇 ^ 1 ₂ ) ₁₇ 〇11 ₃ ,

Compounds with R = OH, R ³ = H (l-12) · δ 0 mg corn · Starch 90 mg lactose 30 mg hydroxypropylcellulose L 2 5 mg magnesium ♦ Stearate 5jig

 '' Total 200 mg

 (Per tablet) Take 1 to 3 tablets per adult per day after meals (three times a day).

Example 1 1

 Tablets are prepared by conventional means using the following ingredients.

Compound Π ;! Nya! ^^^^: ^^! ^,

Compound with R ² = OH and R ³ = H (1-9) 60 mg Corn, starch 80 mg Lactose 30 mg

-I 55 Hydroxypropylcellulose L 2 5 mg Magnesium ♦ Stearate 5 jng Total 200 mg Take 1 to 3 capsules a day per adult 3 times a day after each meal).

 Industrial applicability

 Compound [I] has excellent circulatory dysfunction prevention / improvement activity, and thus can be used as a circulatory dysfunction prevention / amelioration agent.

Ten

20

Claims

The scope of the claims

 (1), general formula

R ³

H0 -0-R ¹

[Wherein, R ¹ represents an organic residue having a molecular weight of 15 to 700, R ² represents hydrogen or a hydroxyl group, and R ³ represents hydrogen, an acyl group, a phosphono group or a sulfo group. A preventive / improving agent for circulatory dysfunction, which comprises an ascorbic acid derivative represented by the formula:

(2), general formula

R ¹

[Wherein, R ¹ is an organic residue having a molecular weight of 15 or more to 700, R ² is hydrogen or a hydroxyl group, and R ³ (also hydrogen, an acyl group, a phosphono group or a sulfo group, ^{When 2} is a hydroxyl group and R ³ is hydrogen, RL represents 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.] An ascorbic acid derivative or homologue represented by the formula:

(3), general formula

H

 o ——-.,

 o

[Wherein, R ¹ represents an organic residue having a molecular weight of 15 or more to 700, R ⁺ represents a group capable of leaving by a hydrolysis or reduction reaction R, and X represents two hydrogens, an acetate residue or a ketal. Residues are indicated. Wherein the compound represented by the general formula is subjected to a hydrolysis reaction or a hydrolysis reaction followed by a reduction reaction.

In this formula, R ¹ has the same meaning as described above. A method for producing ascorbic acid derivatives and homologues represented by the formula:

(4), general formula

H0

R ²

[In the formula, R ¹ represents an organic residue having a molecular weight of 15 or more and 700, and R ² represents hydrogen or a hydroxyl group. Is subjected to an acylation reaction, and if necessary, an acyl group transfer reaction or an acylation reaction.

1255 General formula characterized by being subjected to a sil group removal reaction

R ¹

[Wherein, R ¹ and R ² have the same meaning as described above. R ⁵ represents an acyl group, a phosphono group or a sulfo group. The method for producing ascorbic acid derivatives and homologues represented by the formula:

 10. (5), General formula

R6

 , 0 ,,

R ⁴ — 0 0-R ¹

[Wherein, R ¹ represents an organic residue having a molecular weight of 15 to 70, R ⁺ represents a group capable of leaving by a hydrolysis reaction or a reduction reaction, and R ^s represents an acetal residue or a ketal residue. Or 0 = S <represents a group. Is subjected to a dehydration reaction, followed by a reduction reaction and, if necessary, a hydrolysis reaction.

20 General formula ''

R ¹

[Wherein, R ¹ has the same meaning as described above. A method for producing an ascorbic acid derivative and homologues represented by the formula: