WO1986007592A1 - Ascorbic acid derivatives, process for their preparation, and preparations containing same - Google Patents

Abstract

Medical preparations containing ascorbic acid derivatives represented by the general formula (I) wherein R1 represents an organic residue having a molecular weight of 15 to 700, and R2 represents hydrogen or a hydroxy group, homologues or salts thereof can be used as drugs for prophylaxis of circulatory function diseases.

Description

 Specification

 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, brain, kidney, etc., which are common in adults, are mainly caused by cell and tissue damage and death caused by ischemic conditions as basic lesions. It is in. For example, ischemic heart disease, armpit ischemic injury, ischemic renal injury, ischemic gastrointestinal ulcers, etc., along with the development of highly civilized and aging societies, their morbidity increases and deaths in developed countries. The rate is becoming a major factor.

 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, loss of fine function, disability, destruction, necrosis, etc.) [ Review of Pharmacology and Toxicology 2 _3, 23 9 C 19 8 3); J. cC I. F ridovich, Any ♦ Review of Pharmacology and Toxicology ord, The 'New England. Journal' ob ♦ Med Mew England Journal of

Medicine) .3_J_2_, 15 9 (1 9 8 5); K.P.Brton, J..

McCord, and G. Ghai, American Journal of Ph. I. 246. H76 (1984)]. Examples of reactive oxygen species or active organic radical species in living organisms include superoxide ionone radical (OT), hydrazine hydroxide (· 0Η), singlet oxygen radical 0 ₂ ), and peroxide radical ( R 00 ♦) is considered. In particular, the generation of 0; in vivo and subsequent events The relationship of reactive oxygen species to cell or tissue damage has significant implications. In particular, 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)]. In addition, compounds such as ascorbic acid, α-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. As a result, 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, β

R ² —: 5

 0, I]

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:

 (2) —general formula

R ³ — 0—

R ² —

 Hi.

 = 0

H0 0-R ^!

: Wherein 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

20 When it is a hono group or a sulfo group, 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 When 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. : Ascorbic acid derivatives and homologues or salts thereof represented by (3) —General formula

¹

¹

[Wherein, 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, and X represents two hydrogens, an acetate residue or a ketal residue. The groups are indicated accordingly. A compound represented by the general formula, which is subjected to a hydrolysis reaction or a reduction reaction after an acidic hydrolysis reaction.

H0

 HO ~ i 0

HO 0-R '

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

(4) General formula

H0

R ² H

 '0,

 ■. = 0

HO 0 -R ^{1 wherein} R ¹ and R ² are as defined above. Reaction, phosphorylation or sulfation of ascorbic acid derivatives and homologues When the acylation reaction is carried out in the reaction, if necessary, it may be subjected to an acyl group transfer reaction or an acyl group removal reaction.

HO 0-R ¹

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

(5) —General formula

0-

0 _{"Λ ·,.}

V = 0-+ -0 0-R ¹

Wherein R ¹ and R ⁺ have the same meanings as described above. The acetal residue represents a ketal residue or 0 = S group. 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.

H0―

 H

 0.-

-0

HO 0-R ¹

[Wherein, R ¹ has the same meaning as described above. Ascorbic acid induced by i methods of producing conductors and homologs, and

 (6) —general formula

H0,

 H0H

 , 0-, [I a]

 0

HO 0-R ¹

In the formula, 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.

General formula of 10 徵

X no Shaku 8

 H, 0 [I d

HO 0-R ^1- [wherein, X represents an acetal residue or a -ketal residue. R ¹ has the same meaning as described above. ₂₎ is a process for producing ascorbic acid derivatives and homologues

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 straight-chain or branched alkyl group which may have a substituent.

イソブチル， n—ペンチル， n—へキシル， n—へプチ 一ォクチル， n—ノ ニル， n—デシ レ， n—ゥンデシル， n— ドデシル， n— トリデシル， n—テトラ デシル， n—ペンタデシル， n—へキサデシル， n—へプタデシル， n—才クタ デシル， n—ノナデシル， η—エイ コシル， η—へネィコシル， n— ドコシルな どが挙げられる。 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, η-eicosyl, η-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.

 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 carboxyl group which may have a substituent. An aminocarbonyl group which may have a group, a vinyl group which may have a substituent, an ethynyl group which may have a substituent, and a cycloalkyl which may have a substituent Groups, aryl groups which may have a substituent, aryl groups which may have a substituent,

OH

 R

[In the formula, R ⁷ represents a methyl group, a methoxy group or two R ⁷ to form one CH—CH—CH = CH— group, and R ⁸ may have a substituent. These represent phenyl, naphthyl, chenyl, and pyridyl groups, respectively. ].

 As the hydroxyl group which may have a substituent,

-0-R ⁹

[In the formula, R ³ represents hydrogen, C _t - ₃ alkyl or phenyl. Wherein the amino group which may have a substituent is a group represented by the formula: R ¹⁰

-N < _{R ll}

Wherein, 11 ¹ ° Oyobi 11 ¹¹ show Do or different hydrogen, C alkyl,-phenyl or p- human Dorokishifuweniru respectively. Wherein the carboxyl group which may have a substituent is a group represented by the formula:

One CO— 0— R ¹²

[Wherein, 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,

-CO -NH-R ¹³

[Wherein, R ¹³ represents hydrogen. C alkyl, phenyl or P-hydroxyphenyl]. Wherein the vinyl represented by the formula (1) is a vinyl which may have a substituent,

R ^14-

-C H = C <

R ¹³

[Wherein, and R ¹⁵ are the same or different and represent hydrogen, phenyl, ρ-methoxyphenyl, 3-pyridyl or 3,4-methylenedioxyphenyl. Wherein the ethynyl group which may have a substituent is a group represented by the formula:

-C≡C-R ¹⁶

Wherein R ¹⁶ represents hydrogen or C alkyl. ] And the groups represented by The cycloalkyl Le group in good consequent opening alkyl group optionally having said substituent, C ₃ - is preferably a _s, and examples thereof, for example, cyclo-propyl, cyclobutyl, cyclopentyl, or ': click - to σ 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.

Examples of the aryl group which may have a substituent include:

 R 1 9

Wherein, 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 Rueteniru, 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.

 Examples of the alkyl of S C include methyl, ethyl, 11-propyl, isopropyl, n-butyl, isobutyl, η-pentyl, n-hexyl and the like.

 Examples of the above alkyl include methyl, ethyl, n-propyl, isopropyl and the like.

 Examples of the alkoxy of the above C include, for example, methoxy, ethoxyquin, η-propoxy, isopropoquine and the like.

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

(F three

Specific examples of the hydroxyl group having a substituent include, for example, methoxy, ethoxy, propoquine, isopropoxy, phenoxy and the like. Specific examples of the amino group having the substituent include, for example, methylamino, dimethylamino, ethylamino, propylamino, isopropylamino, Phenylnamino. P-hydroxyphenylamino and the like. 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 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 ethenyl, 1-phenyl-1- (3-pyridyl) ethenyl, 11-yl 1- (2-Chenyl) ethenyl. Specific examples of the ethynyl group having the substituent include, for example, methylethynyl, ethyl: tinyl, 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-carboxycyclopentyl, —Carboxycyclohexyl, 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 —Phenylmethoxyphenyl, 2 —, 3 — or 4 Monomonomethoxyphenyl, 2 —, 3 — or 4 — Monohalogenophenyl (however, halogen atoms represent chlorine, bromine and fluorine atoms), 2, 3 — Methylenedioxyphenyl, 3,4-dimethylphenyl, 3,4-dimethoxyphenyl, 4- (ethoxycarbonylylphenyl) phenyl, 4-isopropylisopropyl, 4-methoxycarbonylphenyl, 3,4 , 5 — Trimethylphenyl. 3, 4, 5 — Trimethoxyphenyl, 4 — Biphenyl, 4-Carboxyphenyl, 4-Carboxymethylphenyl, 4 1- (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, Piperazinyl, 4-phenylbiperazinyl, 4- (p-fluorophenyl) piperazinyl, 4-diphenylmethylpiperazinyl, 4- (p-methoxyphenyl) piperazinyl, etc., which have 1 to 3 substituents The substituent may be, for example, alkyl, carboxyl, hydroxyl, phenolnoperogen, carboxymethyl, benzoyl and the like.

In the above general formula, 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. .

 As the 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 η-hexyl, η-heptyl, n-octyl, n-nonyl, η-decyl, η-pin r-syl, η-totesyl, η-triancle, and ti-te trasizole. , N- ぺ antadecyl, n-hexadecyl, η-heptadecyl, η-heptadecyl, η-nonadecyl, η-eicosyl, η-henecosyl, and η_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.

As 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

(Wherein, 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.

Examples of the fatty acid 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. Is a substituent of the acid be said substituted, for example A kill of C, C ₃ alkoxy, and the like Mechirenjioki Shinoヽandrogenic. It may be the substituted - As the substituent or three to thienyl詐酸, for example alkyl of C _t one ₃ like et be. Examples of the 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 -! 3 alkoxy, and the like methylenedioxy O carboxymethyl Nono androgenic. Said substituted Examples of the 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. Examples of the lower C lower alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, and n-hexyl. 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 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-.

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

 Examples of the C alkoxy include methoxy, ethoxyquin, η-propoxy, isopropoxy and the like.

 Examples of the halogen 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 — (CΗ ₂ ) η—R ^{2 +} [ In the formula, n represents an integer of 1 to 3, and 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, ρ-methoxybenzyl, and the like.

Examples of the acetal residue include, for example, a compound represented by the formula -R ²¹ -CH <

[In the formula, R ²¹ represents alkyl, phenyl or p-methoxyphenyl of Ci-s. The ketal residue is, for example, a compound represented by the formula: <

[In 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.

 Examples of the alkyl of Ct-3 include methyl, ethyl, η-propyl, and isop σ-pill.

 When the compound [I] or [Π] is a compound capable of forming a salt, the compound may form a salt. Examples of the salt include sodium salt, potassium salt, ammonium salt, hydrochloride, sulfate and the like. Can be Further, an inner salt may be formed.

In the compound [I], 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 [ΠΠ] can be removed by a hydrolysis reaction. In this case, 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 [ΠΙ]. can do.

In addition, when the protecting group R ^{+ at} the 3-position of the compound [基] 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. After removal by the reaction, the protective group at the 3-position is then removed by subjecting it to a catalytic reduction reaction, whereby compound [Ia] can be obtained.

Compound [Ib] in which R ³ is an acyl group in compound [I] is obtained by subjecting compound [IV] in which R ³ is hydrogen in compound [I] to an acylation reaction. _-Or the general formula _ -—

¹

¹

[Wherein, R ¹ , !! ² and R ⁵ have the same meaning as described above. 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 [〖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. Can be produced. 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. Alternatively, 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.

 In the acylation reaction of the method of the present invention, 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.

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

In the phosphorylation reaction of the method of the present invention, 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.

In sulfation reaction of the present process, as the sulfating agent, ₍₃ S 0) sulfuric anhydride, sulfuric anhydride pyridinium Jin _{(S 0 3 - C 5 H} 5 N), Jiokisan sulfuric anhydride (S 0 ₃ 0 C ₊ H ₈ 0), dimethyl sulfate Holm § Mi de anhydride _{[S 0 3 - HC ON (} CH 3) 2], sulfuric triethylamine down anhydride _{[S 0 3 - N (C} 2 H 5) 3] , 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. 'I' The dehydration reaction in the above production process is, for example, 1,5-diazabicyclo [4,3,0] -5-nonene, 1,4-diazabic σ ['2,2,2,2-octane, 1,8 —Diazabicyclo [5, 4.1-1-7- ゥ] Organic solvents such as methylene chloride, chloroform, dioxane, tetrahydrofuran, and benzene in the presence of organic bases such as indecene, pyridine, and triethylamine. About 30 to 80 in the middle. It can be performed in the temperature range of C in about 1 to 4 hours.

 By the dehydration reaction, the general formula [NO]

H0 [VI]

 \ /

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 reduction reaction and

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. React. 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. Examples of the catalyst include acetyl chloride, sulfuric acid, ρ-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.

[Α], Compound [DI], wherein X is an acetal or ketal residue Compound [V], wherein R ⁶ is an acetal residue or a ketal residue [V -2. I 5

 R

 fascorbic acid, di2-ascorbic acid

^L isoascorbin triacid C &

 R

 ο レ 、，. · 」

 O Settlement,

 Ketalization

R

R¹ 1 -

R ¹ 1-

_

 R Y

Ko

 .0,

 = 0

R ⁺ -0 OH

R ¹ — Z

20

'' 8

 [v, [nr]

In the above formula, X ′ and R ⁶ represent an acetal or ketal residue ₍ When ascorbic acid is used as a raw material, compound [W] is first produced by acetalizing or ketalizing ascorbic acid. In this reaction, ascorbin is reacted with a ketone or aldehyde such as aceton, benzaldehyde, cyclopentanone, cyclohexanone, and the like. As 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. Examples of the catalyst include acetyl chloride, sulfuric acid, toluene sulfonic acid, and camphorsulfonic acid. The reaction time is between 4 and 24 hours.

Next, the compound [VE] has the formula R ⁴ — Υ [wherein, R ⁺ has the same meaning as described above.

Y represents a halogen (eg, chlorine, bromine). (E.g., chloromethyl methyl ether, chloromethyl ethyl ether, benzyl chloride, benzyl bromide) with dimethylformamide, dimethyl sulfoxide (DMS 0), 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.

Then, 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). ] In a single or mixed solvent of dimethylformamide, dimethylsulfoxide, hexamethylphosphoramide, tetrahydrofuran, etc., or an inorganic base (eg, sodium hydroxide. To produce compound [ΠΤ] 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. Can be. The compound [ITH in which X is two hydrogens in the compound [ΠΠ] can be produced by subjecting the compound [ΠΓ] obtained above to the same hydrolysis reaction as described above.

 Η

[B], the compound [ΕΤΊ in which X is two hydrogens in [、] can also be produced by the following method.

Η0 ~ I

 Η0

 fascorbic acid,

 Isoascorbic acid

R ⁺ -Y

R ¹ — Z:

: ΠΙ ', ΓΧ]

In the above method, ascorbic acid or isoascorbic acid is used as a raw material. First, 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. In the presence of an inorganic base (eg, potassium carbonate, sodium carbonate, etc.) in a solvent alone or in a mixture of dimethylformamide, dimethylsulfoxide, hexanemethylphosphoramide, tetrahydrofuran, dioxane and the like. The compound [X] can be produced by reacting for 1 to 20 hours in a temperature range of about 10 to 60 hours.

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

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.). Tissue death, myocardial infarction, etc.), subarachnoid hemorrhage disorder, ischemic brain tissue disorder (eg, cerebral infarction, blur, senile dementia, etc.), ischemic renal disorder, ischemic gastrointestinal tract disorder It can be used as a preventive and ameliorating agent for circulatory dysfunction because it has therapeutic and preventive / improving effects on various disorders such as harm (eg, gastrointestinal ulcers).

 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. 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). And 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.

When administered parenterally, for example, about 5 mg to 10 mg / kg of compound [I] as a suppository may be administered once or twice a day. As an injection, it is desirable to give about 0.1 mg / kg of Compound [I] once or twice a day. '

When producing the above oral preparations, for example, tablets, binders (eg, hydroxypropylcellulose, hydroxymethylpropylmethylcellulose, mac-goal, etc.), disintegrants (eg, starch, carboxymethylcellulose) Oral sucrose, excipients (eg, lactose, starch, etc.), lubricants (eg, magnesium stearate, talc, etc.) can be added as appropriate. In addition, when preparing parenteral preparations such as injections, use isotonic agents (eg, grape 耱, D-sorbitol, D-mannitol, sodium chloride, etc.), preservatives (eg, benzyl alcohol, kuguchiguchi) Butanol, methyl para-oxybenzoate, propyl para-oxybenzoate, etc.) and buffers (eg, phosphate buffer, sodium acetate buffer, etc.) can be appropriately compounded.

 Also, the general formula

R¹ [XI]

R ¹

[Wherein, RR 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 . However, the symbol represented by 'R ³ and R ² . The symbols represented by 'may be the same or different. Has the same pharmacological action as the above compound [I], and has low toxicity. Therefore, compound [XI] can be used for the same administration as compound [I], for the prevention and treatment of similar diseases, and with the same dosage, administration route and dosage form.

 Compound [XI] can be produced in the same manner as in the acylation reaction of compound [I] to acylate compound [] to give compound [lb].

BEST MODE FOR CARRYING OUT THE INVENTION

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

Experimental example 1, antioxidant activity studied using stable radicals:

The method of M.S. Pruss [Science free radicals a, a- a The reduction activity of 3-picrylhydrazyl (DPPH) was examined and used as an indicator of antioxidant activity. That, O.lmM DPPH ethanol solution 3 ml the test drug [i.e., R ^{1 =} in the compound _{[I] -. (CH 2} ) 17 CH 3, R 2 = OH, R 3 = H , compound (Compound :)] was added, and after 20 minutes, the absorbance was measured at a wavelength of 517 ntn using a spectrophotometer. 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, 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.

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

(i) Method

Male SD rats (12-week-old) were exsanguinated under pentobarbital anesthesia, and the brain tissue was removed.脑 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. The inhibitory activity of lipid peroxide formation is related to the chain length when the number (n) of side chain methylene groups in general formula [I] is changed from n = 7 to 21. -19 compounds were higher, with an inhibition of over 80%, much higher than vitamin E. The compound (1-12) had higher activity than the compound having a methylene chain at position 3 with n = l7. 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 [I]% inhibition

R ^ OH.R ^ H.R ^ ― C H 2) 7 C H 3 -6.6 Sat 3.0

R ² = 0 H, R ³ = H, R ¹ =-(CH ₂ ) ₉ CH ₃ 40.0 Sat 1.1

R = OH, R ³ = H, R ¹ = — CC H 2) ll C H3 55.7 ± 26.5

R ² = OH, R ³ = H, R ^l =-(CH ₂ ) _l3 CH ₃ 93.1 Sat 5.3

^{R = OH, R 3 = H} , R '= one (G H2) 13. H 3 95.4 ± 4.6

-(CH ₂ ) ₂₁ CH ₃ 38.1 ± 16.6

Compounds having a 3-position ^based-: 45.4 E 8.7 vitamin C -71.6 concentration of ± 36.8 Vita Mi emissions Ε .9 ± ll.'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 CH ₃

Experimental Example 3, Improvement effect of Fe ³⁺ —tri-triacetate renal injury in Lasothotium:

 (ί) Method

 Male SLC-Wistar rats (4 weeks old, 64-85 g) were 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 (Labastic paper method) was examined. On the last day, the kidneys were excised and weighed.

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.

(ϋ) Results

 The results on 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, kidney weight increased markedly, 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 reduced to half of the patients. It was just seen. Vitamin E performed similarly, but the majority with ^

Two

 Five

 Was. Vitamin C did not significantly reduce renal damage <Table 2

Fe ³⁺ —Nitrilo triacetate (NTA) Effect on renal injury Body ¾ Urinary occult blood

5? N (g) (fflg) l P U

None * ¹ 2 118 51 0/2

Vehicle * ² 6 86.6 ± 3.'7 68.2 ± 2.i 5/6 Compound (1-1 2) 6 95.5 ± 3.0 56.5 ± 2.0 <<<< 3/6 Vitamin C 6 89.2 ± 4.1 64.5 ± 1 7 5/6

10 Vitamin E 6 99.3 ± 2.3 54.3 ± 2.74 / 6 The dose of each drug is 3 OmgZkg. Oral administration

 I Number of experimental cases

None: Fe ³⁺ — indicates a normal animal not receiving NTA.

• ² Vehicle: Arabic rubber suspension

 L5

Fe ³⁺ —tri-oral triacetate (NTA) Effect on renal impairment Urine volume Urine protein

 Group n (mg / day)

 None 6 5.4 ± 1.2 3.0 ± 1.1

 20 Vehicle 6 13.2 ± 2.0 15.1 ± 1.9

 Compound (1 1 1 2) 6 7.4 ± 1.38.1 ± 2. '

 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

 η: Number of experimental examples

None: indicates a normal animal to which Fe ³⁺ -NTA has not been administered. Vehicle: Arabic gum suspension

Experimental Example 4, Coronary artery occlusion in rat heart-Reperfusion Inhibition of ventricular arrhythmia during the above:

 (i) Method

 Male SD rats and soto (9 to 13 weeks old, 250 to 370 g) were used. Pentovalbital anesthesia, thoracotomy was performed under artificial respiration, the anterior descending branch of the left coronary artery was ligated with silk for 5 minutes, then closed, reperfused and observed for 10 minutes. Standard fourth technique lead H electrocardiogram was recorded to investigate the occurrence of ventricular arrhythmias.

 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.

(Π) Results

 When the left anterior descending branch of the left coronary artery is closed for 5 minutes and then reperfused, it is seen as a solitary contraction. Ventricular arrhythmias occur. VT and VF are recurrent in paroxysm or sustained VF development leads to death.

 In the vehicle-treated group (control), animals with VF and V of 90% or more were observed, and their holding time was 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 the compound (111), the occurrence of arrhythmia was significantly significantly suppressed in a dose-dependent manner. If an arrhythmia occurred, its duration was shortened. Therefore, mortality from VF was also low. In addition, the occurrence of solitary FVCs was around 10 times in the Vehicle group, but significantly less in the compound (1-12) administration group.

On the other hand, oral administration of 50 ing / kg of vitamin C and vitamin E showed a significant No effect was observed

 Table 4

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

 Group Frequency of occurrence Frequency of occurrence Duration Premature contraction Mortality Control 7/8 (88) 83.9 ± 27.5 7/8 (88) 31.8 ± 15.0 10.8 ± 3.5 2/8 (25) Compound

 (1-12)

 50mg / kg 2/9 <<-(22) 1.2 Sat 0.8 << 2/9 << (22) 3.2 ± 2.6 << 1.1 ± G .3 << 0/9 (0) Control 16/18 (89) 74.2 ± 30.8 17/18 (94) 26.5 Sat 6.8 11.8 ± 4.0 2/18 (11) Compound

(1-12)

 20mg / kg 9/17 << (53) 31.0 ± 28.2 11/17 (65) 10.2 ± 3.2 << 3.3 ± 0.8 << 18 7 (6) Control 17 8 8 (94) 74.1 ± 36.0 17/18 '' (94) 16.6 Sat 4.4 7.3 ± 1.7 3/18 (17) Vita

Min C

 50mg / kg 6/6 (100) 9.7 ± 2.5 6/6 (100) 19.0 ° 3.0 5.1 ± 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): P <0.05, ^{s: s:} -: P <0.01, relative to control group

 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 (%).

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

--1255 (i) method

 Male SHR rats (22 weeks old, around 36 Og) were used. Under light anesthesia with ether, a middle incision was made in the neck, the bilateral common carotid arteries were separated and ligated. After cerebral ischemia was caused, the patient was awakened from anesthesia and the behavior was observed for 4 hours.

 Drugs were administered orally as gum arabic suspension 60 minutes before bilateral common carotid artery ligation. Table 5 shows the results.

 (ϋ) Results

 When the bilateral common carotid arteries were ligated and the brain was ischemic, the vehicle group showed a pre-convulsions, which is an ischemic attack, approximately 1 δ 0 minutes later, and the attack was about 90% of the time.

It occurred within 180 minutes in 10 minutes. However, the oral administration of compound (1-12) at 10 Omg / kg significantly delayed the onset of seizures by about 40 minutes. The incidence of seizures within L80 minutes was significantly reduced to 20%.

 Table 5 '

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

 Ischemic seizures

 Group n hours (min) Frequency of occurrence

 Vehicle 41 151 Sat 4 36/41 (87.8%)

 Compound (1 1 1 2) δ 199 ± 13 '= * 1 / (20%)

 20 Compounds (1-1 2): 〖0 0 mg / kg p.o. Vehicle: ARABIA rubber suspension

 @: Within 180 min

 《': P <0.05

 Experimental example 6, acute toxicity in mice

 (i) Method

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. (Π) Results

 When compound (111) was orally administered at 300 and 1000 mg / kg, in both groups, half of the subjects showed sedation and ptosis, but all recovered within 3 hours did. There were no deaths in either group with a 24-hour observation period.

 Reference example 1

(1) Dissolve L-ascorbic acid acetonide (42 g, 0.19 mole) in a mixed solvent of dimethylformamide (100 nU) and hexamethylphosphoramide (100 ml), and add potassium carbonate. (32 g, 0.23, mole) was added and the mixture was ice-cooled. To this, methyl methyl ether (18 g, 0.22 mole) was dissolved 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 is washed with water, dried, concentrated under reduced pressure, and the residue is subjected to silica gel column chromatography, eluted with isopropyl ether and ethyl acetate (2 _: 1). After condensing, the residue is recrystallized from the same solvent system. L-5, 6-0,0-Isopropylidene-3-0-methoxymethoxyscorbic acid (46 g) was obtained. i p. 93-94.

 Elemental analysis (for C H ^ O?)

 Analysis value: C, 50.84; H.6.05%

 Calculated: C .50.77; H.6.20

(2) L-5, 6-0,0-isopropylidene-3-0-methoxymethyla. Scorbic acid (1.84 g, 7.1 mmole) is dissolved in dimethyl sulfoxide (1 Oml), and octadecyl iodide ( 2.68g) and carbon dioxide rim (l.Og) and add 60 ° C Reacted for 6 hours. After the reaction, water (50 ml) was added, and the product was extracted 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, and concentrated. When recrystallized from isopropyl ether-ethyl acetate, L-5,6-0,0-isopropylidene-3-0-methoxymethyl-2-0-octadecylascorbic acid (ref. 1.1) 8g) was obtained. The physical properties are shown in Table 6, and in the same manner as in Reference Example 1, the compounds shown in Table 6 [(Reference 111) to (Reference 113)] were prepared.

e oH 0 " / S8dfl3 / d-Z698 OM /

CD

Table 6 (continued)

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

 Reference example 2

 (L) L-ascorbic acid acetate (2, 0.1 (11016) was dissolved in dimethylformamide (12 Oml) and cooled on ice, and potassium carbonate (ί4 g, 0.1 Lml) was added thereto. Then, benzylbutamide (11: 2 ml) was added, and the mixture was stirred at room temperature for 20 hours and 5. The reaction solution and water (100 ml) were neutralized with 2N hydrochloric acid, and p was added.

 H was set to 5.0, and extraction was carried out twice with ethyl acetate. The organic layer was washed with water, dried (magnesium sulfate) and concentrated under reduced pressure. The product was applied to silica gel column chromatography, eluted with isopropyl ether monoethyl acetate (3: 1), concentrated, and recrystallized from isopropyl ether monoethyl acetate to give L-5,06-0,0- Isopropylidene-1-3-0-benzylascorbic acid (13 g, 40%), mp 105-106 was obtained.

(2) L-5, 6-0,0-isopropylidene-1-3-0-benzylascorbic acid (3.06g, 0.01mole) was added to dimethyl sulfoxide (20ml) and tetrahydro sigma furan (1 5 ml) and dissolved in a mixed solvent, and lithium carbonate (1.5 g, 0.0115 mole) was added. Then, octadecyl iodide (3.83 g) was added, and the mixture was stirred at room temperature for 18 hours. After the reaction, water (100 ml) was added, and the mixture was extracted with ethyl acetate. 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 and ethyl acetate (10: 1). L-5,6-0,0-isopropylidene 3--0-benzyl-2-0 —3.8 g of kutadecylascorbic acid [compound (Ref. 2-17)] was obtained. Table 7 shows the physical properties.

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

i / sdfJc S / d O-I Z6S / 9M8

 00 ΐ 0 〇

〇H〇〇W- 〇 M0 Y Reference example 3 ''

 (1) L-5,6-0, diisopropylidene-3-0-benzyl-12-0-octadecylascorbic acid (3.8 g) was added to tetrahydrofuran (40 ml) and methanol. (2 O ml), and the mixture was stirred 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 is washed with water, dried and concentrated under reduced pressure, and the residue is recrystallized from isopropyl ether-acetate ether to give 3-0—benzyl 2-

The physical properties of _c obtained 0-octadecylascorbic acid [compound (Ref. 3-7)] (2.6 g) are shown in Table 8.

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

0 κ

CD CD CD a tl C〇 〇

CD CD CD

3 3 3 3 3), 〇 H H

Say 3-3 3

 Says 3

3 a-yo H 〇

 3 3), Hyo, H 2Hyo 0 ,,,) yo H Hd,), Hyo OHyo 〇 H

 c.

(^ § 8ϋ- Example 1

 L-5,6-0,0-isopropylidene-1-3-0-methoxymethyl-2-0-octadecylascorbic acid (1.2 g) in methanol (30 ml) and tetrahydrofuran (10 ml) ), Mixed with 2N hydrochloric acid (1 Oml) and stirred at 50 ° C for 6 hours. The reaction mixture 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. — 0-year-old Kutadecylascorbic acid [Compound (1-2)] (0.82 g) was obtained. Table 9 shows the physical properties.

Example 2

 3-0-benzyl 2- 0-octadecyl ascorbin (2. lg) dissolved in ethyl acetate (25 ml), 5% Pd-C (0.5 g) is added, and catalytic reduction at normal pressure Was done. The catalyst was filtered, then concentrated under reduced pressure, and the product was recrystallized from acetic acid with 1 g of isopropyl ether to give 2-0-octadecyl assuric acid [compound (1-2)] (1.5 g) was obtained. Table 9 shows the physical properties.

Example 3

Table 9 shows the compound (113) from the compound (111) prepared by the method according to Example 1 and Example 2 described above.

^ Factory

(^^ 9o, 0 £) Dimensions / df / l -_ Z6 0/98 OMS) ^ or C-

Table 9 (continued)

 Five

1

(^ 9A Table 9 (continued)

Five

 The compound (113) was obtained by subjecting the obtained hydroquinone body to iron chloride oxidation after performing the same method as in Example 2.

 Example 4

(1) To a solution of 2-0-octadecyl-diascorbic acid (0.8 g, 2 mmoie) in formaldehyde (2 Oml) was added pyridine (i ml), and then at room temperature, benzoyl chloride (i. 0.28 g, 2 mmoLe) was added dropwise. The reaction solution was stirred for 1 hour, then acidified with 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-octadecyl-L-ascorbic acid (0.6 g, 49%). . mp. 6 8-6 9 ° C. _{C 3 H + 8 0 7 (} F ound:.. C, 69.94; H, 8.98% Anal Calcd: C, 69.89; H, 9.08).

(2) According to the above, benzoylation of 2-0-hexadecyl-L-ascorbic acid yields 3-0-benzoylyl 2-0-hexadecyl-L-ascorbic acid, mp. 77-78. C was obtained. _{C 23 H + + 0 7 (} F o nd:.. C, 69.21; H, 8.82% Anal C alcd: C, 69.02; H, 8.79).

 Example δ

(1) 2 _ 0-year-old cactadecyl-L-ascorbic acid (0.8 g, 2 band oie) in a porcine form solution, pyridine (iml) and 4,4-dimethylaminopyridine (O.ig) In addition, acetate 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 monoethyl acetate to obtain 61-acetyl-12-0-octadecyl-L-ascorbic acid (0.6 g, 65%). mp. 1 1 7— 1 1 8 C ₂₈ H _4. 0 ₇ (F ound: C, 66.24; H,

9.95% o Anal. Calcd: C, 66.35; H.9.85).

 (2) According to the above, 2-0-pentadecyl-L-ascorbic acid, 2-0-hexadecyl-L-ascorbic acid 2-0-year-old octadecyl-L-ascorbic acid, acetylation, benzoylation, phenylacetylation, Nicotinylation and succinylation reactions were carried out, respectively, to produce the following compounds.

... (I) 6- 0- Asechiru 2 0- pentadecyl one L- Asukorubin acid, mp 1 1 2- 1 1 3 ° (: C 23 H + 0 7 (F ound: C, 64.59; H, 9.48 %.

Anal. Calcd: C. 64.46; Η, 9.41).

(ii) 6-0-Benzoyl-2-0-pentadecyl-L-ascorbic acid, mp.139-140. C. _{C 28 H + 2 0 7 (} F ound:. C, 68.36; H, 8.78¾ 0 Anal Calcd: C, 68.55; H, 8.63).

(m) 6- 0- off We sulfonyl § cetyl-2-0- pentadecyl one L- Asuko Rubin acid, mp 1 2 6- 1 2 7 ° (:.. C 23 H "0 7 (F ound: C, 68.79;

H, 8.99%). Anal. Calcd: C, 69.02; H, 8.79). -

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

(v) 6—0—nicotinol 2—0—octadecyl-L-ascorbine hydrochloride., mp. 14 2—14 3 ° (: C ₃₄ H _{+ 8} N 0 ₇ C 1 (Found:

C, 66.49; H. 8.70; N, 2.20%. Anal. Calcd: C, 66.06; H.7.83; N'2.27).

 (vi) 6-0- (3-Carboxypropionyl) -1- 2—0—Tetradecyl—L-ascorbic acid

 mp. 1 5 5-1 5 6. (:

(vii) 6 — 0— (3-carboxypropionyl) -1- 2—tetradecyl

— L-ascorbic acid

 mp. 1 5 6 — 1 5 7 ° (:.

(via) 6-0-(3 -carboxypropionyl) -1- 2 -pate tradyl-L-ascorbic acid

 mp. 1 5 5 — 1 5 6 ° (:.

Example 6

To a solution of 2-p-octadecyl-L-ascorbic acid (0.8 g, 2 oie) in chloroform (20 ml) was added pyridine (1 ml), and then acetyl chloride (0. The reaction solution was stirred for 1 hour, washed with 2N hydrochloric acid, the organic layer was washed with water and dried, the solvent was distilled off under pressure, and the product was recrystallized from isopropyl ether monoethyl acetate. . 3 - 0 Asechiru 2 -〇 one year old Kutade sill - L-Asukorubin acid (0.8g, 8 7%) was obtained mp.7 8- 7 9 ° C, C 26 Η + 8 0 7 (Found: C H, 9.80% Anal. Calcd: C, 66.35; H, 9.85).

Example 7

2-0 One year old Kutadecyl-L-ascorbic acid (0.8 g, 2 oleoresin) and phenylisosanoic acid (0.24 g, 2 mmoie) in a solution of crocodile form (20 ml) in trichlorochloroacetic acid (O.LnU) was added and heated at 60 ° C. for 1 hour. After the reaction, the product was washed with water, dried and concentrated to obtain a product. Recrystallization from isopropyl ether-ethyl ester gave 6-0-phenylcarbamoyl-12-0-octadecyl-L-ascorbic acid (0.75 g). mp. 1 4 9 — 1 5 0 C 3iH _{+ 8} NQ vCFound: C, 68.14; 'H, 9.08; N', 2.74%. Anal. Calcd

: C, 67.98; H, 9.02; N, 2.56).

Example 8

 1) Benzyl bromide (12 ml) was added dropwise to a solution of sodium D-isoascorbate (20 g Olmole) in dimethylformamide (50 ml), and the mixture was ripened at 50 ° C for 4 hours. Was done. Water (10 Oml) was added to the reaction solution, and the product was extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated. The crude product was subjected to silica gel column chromatography and developed with ethyl acetate, and 2-0-benzyl D-isoas, corbic acid (10 g, 37 %). 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

(-100 ml) was added, and the product was extracted with isopropyl ether. The organic layer was washed with water, 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 袓 crystal was purified with hexane: isopropyl ether (1: 1). Recrystallization from 1) yielded 2-0-cytadecyl-3-0-benzyl-1-D-isoascorbic acid (5 g, 26%). mp. 62-63 ° C; C _{3 L} H ₅₀ 〇 s (F ound:. C, 72.02; H, 9.67% Anal, Calcd: C, 71.78; H, 9.72). '

2) 2--0-tacutadecyl-3-0-benzyl-D obtained by the above reaction

A solution of isoscorbic acid (3 g, 5.7 oleole) in ethanol (50 ml) was subjected to a hydrogenation reaction in the presence of 5% Pd-carbon (0.2 g) at normal pressure. After 18 hours, the catalyst was filtered, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give 2-0-octadecyl-D-isoascorbic acid (2 g, 80%). mp. 103-104 ° C. C ₂₊ H ₊ 0 _S (Found: C, 67.45; H, 10.46%. Anal. Calcd: C, 67.26; H, 10.35) _o Example 9

 5.6—0,0—Isopropylidene 3-0—Methoxymethyl 1—2—0—Octadecyl—L-ascorbic acid (5 g, 10 mmole) in tetrahydrofuran (20 ml) in 1,8-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, add ethyl acetate (4 O ml), wash with 2N hydrochloric acid twice, then wash with water, dry and concentrate under reduced pressure, and then mix the residue with ethanol (4 Oml) and 2N hydrochloric acid (2 Oml). The mixture was heated and stirred in a solvent at 60 ° C for 6 hours. After the reaction solution was concentrated under reduced pressure, the product was dissolved in ethyl acetate, washed with water, dried and concentrated. The crude product was recrystallized from isopropyl ether to give 2-0-octadecyl-5-dehydroxyascorbic acid.

(2 g, 51%) was obtained. mp.1 14—1 15 ° C. _{C 2 + H + 2 0 5} (F ound:. C, 70.24; H, 10.42 Anal Calcd: C, 70.21; H, 10.31) o

A 5% Pd-carbon (0.2 g) was added to a ethanol solution (10 ml) of peta2, O-titadecyl-5-dehydroxascorbic acid (0.4 g, 1 mmole) obtained above. Was added and the mixture was stirred under a hydrogen atmosphere under normal pressure for 4 hours. After completion of the reaction, the catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from isopropyl ether-hexane to give the desired d-2-0-octadecyl-5-doxyascorbic acid (0.2 g). mp.8 3—84 ° C. C _{2 +} H ₊₊ O ₅ (Found:

C, 69.33; Η, ΙΟ.47 Anal.Calcd: C, 69.86; H, 10.75) _o Example 10

 Tablets are prepared by conventional means using the following ingredients.

In compound [I;], R ^{1 =} (CH ₂ ) ₁₇ CH ₃ ,

Compound with R ² = OH and R ³ = H (1-12) 50 mg Corn 'starch 90 mg Lactose 30 mg Hydroxypropylcellulose L 2 5 mg Magnesium stearate 5 mg Total 200 mg '(per tablet) For adults, take 1 to 3 mg / day after meals (three times a day).

Example 1 1

 Tablets are prepared by conventional means using the following ingredients.

In compound [I], R ^{1 =} (CH ₂ ) ₁₊ CH ₃ ,

Compound where R ² = OH, R ³ = H (1-9) 60 rag Corn, starch 80 mg Lactose oo 30 mg Hydroxypropylcellulose L 2 5 mg Magnesium stearate 5 mg

 If 200 mg per adult, take 1-3 tablets daily after meals (three times daily).

Example 1 2

 (1) ρ-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.

 mp. 81-82 ° C.

(2) 2-0-Dodecyl-L-ascorbic acid and 2-0-hexadecyl-l-ascorbic acid were subjected to the same reaction as above to give the following compounds, respectively. (i) 2-Pedodecyl 5.6-0,0-Isopropylidene L-ascorbic acid

 mp. 8 3-8 4. C.

(ii) 2-0-hexadecyl-1,5,6-0,0-isopropylidene-ciscorbic acid

 mp. 85-86 ° C.

Example 13

 (1) 2-0-Hexadecyl-L-ascorbic acid (0.8 g, 2 mmoi) and silk mouth hexanone (0.3 g) were added to a toluene solution (50¾2) of toluene-tosyl (50 mg). The resulting water was separated while perfusing over time. After cooling, the reaction solution was washed with saturated aqueous sodium hydrogen carbonate, dried, and concentrated under reduced pressure. The crude crystal was recrystallized from IPE to obtain 2-0-hexadecyl-5,6-0,0-cyclohexylidene-L-ascorbic acid (0.6 g, 84%).

 mp. 8 0— 8 1

(2) 2-0-Dodecyl-ascorbic acid was subjected to the same reaction as above to give the following compound.

 (i) 2— 0— dodecyl-5, & — 0,0—isopropylidene L—ascorbic acid

 mp. 85-86 ° C.

Industrial applicability

 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.

Claims

The scope of the claims  (1), general formula

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 which may be substituted. Each represents a sulfo group. R ³ and the hydroxyl group of R ² may form an acetal residue or a ketal residue. ] A preventive / improving agent for circulatory dysfunction, comprising an ascorbic acid derivative represented by the formula: ' (2), General 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, an optionally substituted 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 When it is a sulfo group or when R ² is hydrogen and R ³ is hydrogen, R ¹ represents an organic residue having a molecular weight of 15 to 700. The hydroxyl group of R ³ and R ² is an acetal residue or ketal residue Ascorbic acid derivatives and homologues or salts thereof.  (3), general formula X

R ¹ [Wherein, R ¹ represents an organic residue having a molecular weight of 15 or more to 700, R ⁺ represents a group which can be removed by hydrolysis or reduction reaction, and X represents two hydrogens, an acetal residue or a ketal. Residues are indicated. Or a reduction reaction after the hydrolysis reaction of the compound represented by formula (I). It has significance. Ascorbic acid induction method represented by].  '

o 5 i [In the formula, R ¹ represents an organic residue having a molecular weight of 15 to 700, and R ² represents hydrogen or a hydroxyl group. A general formula characterized by subjecting an ascorbic acid derivative or a homologue represented by the formula [1] to an acylation reaction and, if necessary, to an acyl group transfer reaction or an acyl group removal reaction.

R] 0 wherein R and R ² are as defined 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:  (5), general formula

R ⁺ -0 0-R ¹ [Wherein, R ¹ represents an organic residue having a molecular weight of 15 to 70, R ⁴ represents a group capable of leaving by a hydrolysis reaction or a reduction reaction, and R ⁸ represents an acetal residue or a ketal residue. Or 0 = S <represents a group. A general formula characterized by subjecting the compound represented by the formula [1] to a dehydration reaction, followed by a reduction reaction and, if necessary, a hydrolysis reaction.

[Wherein, R ¹ has the same meaning as described above. A method for producing an ascorbic acid derivative and homologues represented by the formula: (6), general formula HO ^  HO -H  .-0, HO 0— R ¹ [Wherein, R ¹ represents an organic residue having a molecular weight of 15 or more and 700 or more. A general formula characterized by subjecting an ascorbic acid derivative and a homologue represented by the formula [1] to a tartarization or ketalization reaction

.0, HO 0-R ¹ [Wherein, X represents an acetal residue or a ketal residue. R ¹ has the same meaning as described above. The method for producing ascorbic acid derivatives and homologues represented by the formula: