WO1993021198A1 - Novel sialylsteroid - Google Patents

Novel sialylsteroid Download PDF

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Publication number
WO1993021198A1
WO1993021198A1 PCT/JP1993/000466 JP9300466W WO9321198A1 WO 1993021198 A1 WO1993021198 A1 WO 1993021198A1 JP 9300466 W JP9300466 W JP 9300466W WO 9321198 A1 WO9321198 A1 WO 9321198A1
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Prior art keywords
steroid
sialyl
formula
represented
neuac
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PCT/JP1993/000466
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French (fr)
Japanese (ja)
Inventor
Masaaki Numata
Takayuki Ishii
Mamoru Sugimoto
Kei Sugai
Naokazu Sugiyama
Tomoya Ogawa
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Mect Corporation
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Publication of WO1993021198A1 publication Critical patent/WO1993021198A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/20—Carbocyclic rings
    • C07H15/207—Cyclohexane rings not substituted by nitrogen atoms, e.g. kasugamycins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C401/00—Irradiation products of cholesterol or its derivatives; Vitamin D derivatives, 9,10-seco cyclopenta[a]phenanthrene or analogues obtained by chemical preparation without irradiation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J17/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, having an oxygen-containing hetero ring not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C07J17/005—Glycosides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/005—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of only two carbon atoms, e.g. pregnane derivatives

Definitions

  • the present invention relates to novel sialyl steroids. (: Background technology 3
  • Steroids are widely used in clinical practice because they are effective in a wide range of diseases and have a strong effect, but their use is also severely restricted. Thus, there is a demand for the development of a steroid derivative which retains the above-mentioned effects as a medicament and has no or reduced side effects.
  • sialic acid naturally exists in a free state, but most of it is bound to mucopolysaccharides, glycoproteins, glycopeptides, and glycolipid molecules.
  • the present inventors have previously found that the side effects of steroids can be reduced by binding cyanorelic acid to certain steroids.
  • An object of the present invention is to provide a novel steroid derivative having no side effects or reduced side effects while retaining the action and effect as a medicine.
  • the present invention provides a novel sialyl steroid represented by the following general formula (I) or (II) or a salt thereof.
  • R 2 is a hydrogen atom or an acetyl group
  • R 3 is a hydrogen atom or a lower alkyl group.
  • Steroid components I ⁇ of the invention cortisone, dexamethasone and vitamin D 3.
  • Cortisone is a type of adrenocortical hormone extracted from the adrenal cortex and having a carbohydrate metabolism-promoting action. It is used as an anti-inflammatory agent for rheumatoid arthritis and other inflammations, and as an anti-allergic agent.
  • Dexamethasone is also a type of synthetic adrenocortical hormone-used as an anti-inflammatory agent for improving adrenocortical dysfunction, rheumatoid arthritis and other inflammations, and as an anti-allergic agent.
  • the vitamin D are known several vitamin to D 5, important is vitamin D 2 ⁇ beauty vitamin D 3. Vitamin D promotes absorption of calcium from the intestine and regulates the amount of calcium in the blood. The lack causes growth impairment and causes useless diseases. These cause excessive disorder when large amounts of t and slip are used.
  • the sialyl steroid of the present invention is obtained by condensing a sialic acid hydride represented by the following formula (VI) with a steroid represented by the following formula ( ⁇ ), (IV) or (V) in the presence of a catalyst: Can be easily produced by deprotection.
  • a sialic acid hydride represented by the following formula (VI) with a steroid represented by the following formula ( ⁇ ), (IV) or (V) in the presence of a catalyst:
  • a catalyst can be easily produced by deprotection.
  • the salt of the sialyl steroid of the present invention include an alkali metal salt such as a sodium salt and a potassium salt, an ammonium salt and the like.
  • R 2 is an acetyl group
  • R 3 is a lower alkyl group, for example, a methyl group
  • X is a halogen atom, for example, a chlorine atom or a bromine atom.
  • the solvent for the condensation reaction CH 2 C1 2, THF, CH 3 CN, CHC1 3 , and examples of the catalyst HgBr 2 -Hg (CN) 2, AgOTf, Ag 2 C0 3 , or the like can be used.
  • This reaction sufficiently proceeds at a temperature of 20 ° C. to 30 ° C. for 10 minutes to 24 hours.
  • the sialyl steroids of the present invention retain the original medicinal properties of the steroids, do not cause or reduce side effects even when used for a long period of time, and have improved solubility in water.
  • Vitamin D 3 combined with cyanoleic acid has a longer blood half-life. -
  • the compound (52.31) (62.7 ⁇ 11101) was dissolved in methanol 21111, 1N sodium methoxide 301 was added, and the mixture was stirred at 0 ° C for 18 hours and then distilled under reduced pressure.
  • the residue was dissolved in methanol (2 ml) and water (lml) and stirred at 20 ° C for 18 hours. After evaporating the reaction mixture under reduced pressure, the residue was purified by Sephadex LH-20 (eluted with methanol) to give compound 5 (formula 5).
  • R 1 is a cortisone residue represented by the formula (III), R 2 is a hydrogen atom, and R 3 is sodium.
  • R 1 is a cortisone residue represented by the formula (III), R 2 is a hydrogen atom, and R 3 is sodium.
  • Compound 6 33.6 mg (83%)
  • Activated molecular sieve 4 Vitamin D 3 (5 g) 20 5 mg (0.7 84 strokes ol), Hg (CN) 2 2 1 2mg (0.8 2 ⁇ ol), HgBr 2 9 6 mg (0.2 6 negation ol), black hole Holm 2 ml was added, black one 1 0 ° C Methyl 2,4-, 8,9-tetra-10-acetyl-N-acetylacetylneuraminate (Compound 2) dissolved in 2 ml of mouth form 2 O Omg (0.392 mmol) ) was added and the mixture was stirred as it was for 40 hours. The reaction solution was distilled off after filtration through Celite.
  • Hartley male guinea pigs were purchased from SLC and preliminarily reared for one week before use in experiments. The animals were kept in an animal room at 23 ⁇ 1 ° C and a humidity of 55 ⁇ 5%, and were allowed free access to solid feed (RG-RO; oriental yeast) and water.
  • Sensitization was performed by intravenously administering anti-ovalbumin (2.5 ml) of anti-ovalbumin to about 250 g of guinea pig. 30 minutes later, 0.025m and 0.05 Omg
  • the ovalbumin solution containing 0.05 ml was intradermally administered to the abdomen, which had been shaved the day before, at two sites at a total of four sites to induce a reaction.
  • the area of bleeding at each stimulation site 2 hours after the antigen administration was measured and used as an index of the degree of reaction.
  • Drugs were administered intravenously or subcutaneously 1, 2, 4 and 6 hours before antigen administration, respectively.
  • Sialyldexamethasone (alpha form) (Compound 13) Intravenous administration at 40, 76, 59, and 53% at 1, 2, 4, and 6 hours before administration, ie, the strongest at 2 hours before administration 4 hours before subcutaneous administration of dexamethasone (20, 30, 60, 63, and 57% inhibition at 1, 2, 4, & hour pre-dose, respectively).
  • Sialyl degisamethasone (yS form) (compound 14) was inhibited by 22, 39, 41 and 36% by intravenous administration for 1, 2, 4, and 6 hours before.
  • Intravenous administration of dexane reduced approximately 32% 1 hour before administration, but 2 & 4, 25 and 23% after 2, 4 and 6 hours.
  • Dexamethasone showed the greatest inhibitory effect 4 hours before administration, whereas other dexamethasone derivatives showed the strongest inhibition 1 or 2 hours before administration.
  • Dexane is an aqueous solution containing dexamethasone sodium metasulfobenzoate, and can be applied to a wide range of diseases in the venous thigh as well as dexamethasone.
  • the efficacy in the alsus reaction was considerably weaker than that of dexamethasone (approximately 1/2 of dexamethasone).
  • sialyldexamethasone (body) had an inhibitory effect of dexamethasone 2 hours before administration. The effect was similar to that of the administration 4 hours before, indicating that the effect was stronger than that of dexane.
  • sialyl dexamethasone was a useful compound having a stronger effect than other aqueous dexamethasone derivatives, although it did not enhance the efficacy of dexamethasone.
  • Test Example 2 Power lagenin foot edema (anti-inflammatory)
  • Rats weighing 100-120 g were used as 6 rats per group. Under ether anesthesia, 8 ml of air was injected subcutaneously into the back of the rat, and the next day, 4 ml of 2% sulphuramen was injected as an inflammation substance.
  • the test drug was administered intravenously on days 5, 6, and 7 after infusion of Keragenin. On the 8th day, the animals were exsanguinated and killed, and the granulation was carefully peeled off, the amount of the exudate of the contents and the weight of the granuloma were measured, and the inhibition rate with respect to the physiological saline administration group was calculated.
  • Sialyl dexamethasone (compound 13) was about 1-5 to 1-3 of dexamethasone phosphate.
  • An antiserum containing anti-ovalbumin IgE antibody was passively sensitized by intradermally administering 0.1 ml of the antiserum to the back of a rat shaved the day before. 48 hours after the sensitization, an antigen (ovalbumin, 25 mg / kg) and Evans blue (12.5 mg / kg) were intravenously administered (5 ml / kg) to induce a PCA reaction. After blood release 30 minutes later, the skin was peeled off and the area of the reaction site inside was measured. The test drug was administered 3 hours before the antigen challenge.
  • Sialyl dexamethasone (Compound 13) was about 1/10 the potency of dexamethasone phosphate and about 3 times as potent as dexamethasone metasulfobenzoate.
  • Test Example 5 Forssman reaction (airway resistance method) (Type II allergic method) In order to compare the efficacy of dexamethasone derivatives against type II allergic method, the effect on the Forssman reaction (airway resistance method) was examined.
  • Guinea pigs were anesthetized with pentobarbital, and a trachea was inserted with a Y-shaped force neurator, and artificial respiration was performed 70 times a minute. Air supply amount of one time 3. 5 ⁇ 4. 5 ⁇ 1, the feed pressure was 1 0 cm H 2 0. Power collaterals Nyure leads to the aquarium, 1 0 captured cm H 2 0 in the excess air come out out Winning connection as flow rate through the news one Motakogurafu (pneumotachograph), was converted to a flow rate by using the integrator. Forssman antiserum was diluted 5-fold with physiological Ti, and 0.1 ml / 100 g body weight was injected intravenously to elicit a reaction. The test drug was administered intravenously 1 hour before the administration of Forssman antiserum.
  • the rats were sensitized by intravenously administering 2.5 ml Zkg of anti-ovalbumin / heron serum to molmolts weighing about 250 g. Thirty minutes later, 0.0250 ml of an ovalbumin solution containing 0.025 mg and 0.05 Omg was applied to the abdomen, which had been shaved the day before, at two sites each, for a total of four sites. The administration elicited a response. The area of redness at each stimulation site 2 hours after antigen administration was measured and used as an index of the degree of reaction. The test drug was administered intravenously 3 hours before the antigen administration.
  • Sialyldexamethasone (Compound 13) "was about 10 times as potent as dexamethasone phosphate and dexamethasone metasulfobenzoate.
  • Test Example 7 Passive Alsus Reaction (Rat) (Type III Allergic I)
  • Sialyldexamethasone (compound 13) was about 13 more potent than dexamethasone phosphate.
  • Test Example 8 Delayed Contact Skin Reaction (Type IV Allergy) (Cellular Immunity)
  • Sialyldexamethasone (compound 13) showed an inhibitory effect (about 22%) from lingZkg, whereas dexamethasone phosphate had no effect at lmgZkg. At 1 Omg / kg, both drugs showed almost the same inhibitory effect (about 50%).
  • Test Example 9 Immunosuppressive action (humoral immunosuppressive action)
  • mice Seven-week-old DBA / 2 mice were immunized intravenously with 0.2 ml of 10% shedding red blood cells (SRBC).
  • SRBC shedding red blood cells
  • the spleen was excised, used as a single cell suspension, and adjusted to 2.5 ⁇ 10 6 cells / ml.
  • 0.8 m of the cell suspension was added to a test tube, 50% of SRBC was added to 0.1 ml, and 0.1 ml of dried complement was mixed and injected into the Cunningham chamber. After 1 hour incubator base over preparative 37 ° C, it was calculated PFC number ⁇ BiSo PFC number of splenocytes Number 1 0 6 per count the hemolytic plaque (plaque).
  • test drug was administered subcutaneously for 4 days from the day of immunization.
  • Dexamethasone phosphate and dexamethasone metasulfobenzoate inhibited humoral immunity at 0.01 mg / g
  • sialyl dexamethasone (Compound 13) exhibited an inhibitory effect at 1 mgZkg. (It is thought that the effect of suppressing humoral immunity related to infectious disease induction is weak.)
  • Test Example 10 Simple acute toxicity test
  • a simple acute toxicity test was performed to compare the acute toxicity of dexamethasone derivatives.
  • One dose of a drug dissolved in physiological water was administered once from the vein of a male mouse, and on the first day, body weight was measured and symptoms were observed daily, and survival was determined 72 hours after administration. In addition, in surviving animals, body weight measurement and symptom observation were performed until one week after the bowing of the animals.
  • Dexamethasone phosphate was 180 mg / kgv and dexamethasone methazozobenzoate died 100% at 800 mgZkg, respectively.
  • sialyldexamethasone (compound 13) died in one subject after administration of 40 mg OmgZkg, and the animals immediately after administration had stopped exercising, but recovered several minutes later, and recovered 300 mgXkg. There was no effect at 100 mg / kg.

Abstract

Sialic acid derivatives of cortison, dexamethasone and vitamin D3 represented by general formula (I), wherein R1 represents a steroid residue selectd from among cortisone, dexamethasone and vitamin D¿3; R?2 represents hydrogen or acetyl; and R3 represents hydrogen or lower alkyl. These derivatives not only retain the drug effects inherent in the steroids, but also exhibit no or little side effects even after being used for long and have an improved solubility in water. Further, the sialylated vitamin D¿3? has a long half-life period in blood.

Description

明細書 新規シァリルステロイド 隱分野〕  Description New cyaryl steroids
本発明は新規なシァリルステロイドに関する。 (：背景技術 3  The present invention relates to novel sialyl steroids. (: Background technology 3
ステロイドは非常に広範な疾患に効果があり、 また作用も強いことから、 臨床 で幅広く用いられているが、 副作用も強く使用が制限されている。 そこで、 上記 医薬としての作用効果を保持するとともに、 副作用のない又は軽減されたステロ ィド誘導体の開発が望まれている。  Steroids are widely used in clinical practice because they are effective in a wide range of diseases and have a strong effect, but their use is also severely restricted. Thus, there is a demand for the development of a steroid derivative which retains the above-mentioned effects as a medicament and has no or reduced side effects.
一方、 シアル酸は天然に遊離状態でも存在するが、 大部分はムコ多糖、 糖蛋白 質、 糖ペプチド、 糖脂質分子中に結合して存在している。 、  On the other hand, sialic acid naturally exists in a free state, but most of it is bound to mucopolysaccharides, glycoproteins, glycopeptides, and glycolipid molecules. ,
本発明者らはこれまでにある種のステロイドにシァノレ酸を結合させることによ りステロイドの副作用を軽減できることを見出している。  The present inventors have previously found that the side effects of steroids can be reduced by binding cyanorelic acid to certain steroids.
本発明の目的は、 医薬としての作用効果を保持するとともに、 副作用のない又 は軽減された新規なステロイド誘導体を提供することである。  An object of the present invention is to provide a novel steroid derivative having no side effects or reduced side effects while retaining the action and effect as a medicine.
〔発明の開示〕 [Disclosure of the Invention]
本発明は、 下記の一般式 （I ) 又は （I I) で表される新規シァリルステロイド 又はその塩を提供するものである。  The present invention provides a novel sialyl steroid represented by the following general formula (I) or (II) or a salt thereof.
( I )
Figure imgf000003_0001
Figure imgf000004_0001
式中 は下記の式（ΙΠ)、 （IV)又は （V)で表されるステロイド残基であ り、 R2 は水素原子又はァセチル基であり、 R3 は水素原子又は低級アルキル基 あ 。 (I)
Figure imgf000003_0001
Figure imgf000004_0001
In the formula, a steroid residue represented by the following formula (ΙΠ), (IV) or (V), R 2 is a hydrogen atom or an acetyl group, and R 3 is a hydrogen atom or a lower alkyl group.
Figure imgf000004_0002
Figure imgf000004_0002
(IV) (IV)
Figure imgf000004_0003
Figure imgf000005_0001
以下、 本発明を詳細に説明する。
Figure imgf000004_0003
Figure imgf000005_0001
Hereinafter, the present invention will be described in detail.
本発明のィ匕合物のステロイド成分は、 コルチゾン、 デキサメタゾン及びビタミ ン D 3 である。 コルチゾンは副腎皮質から抽出された糖質代謝促進作用を有する 副腎皮質ホルモンの一種であり、 リユーマチ性関節炎その他の炎症に抗炎症剤と して、 また抗アレルギー剤として使用されている。 デキサメタゾンも合成副腎皮 質ホルモンの一種であり-、 副腎皮質機能不全の改善、 リューマチ性関節炎その他 の炎症に抗炎症剤として、 また抗アレルギー剤として使用されている。 ビタミン Dとしてはビタミン 〜D 5 など数種が知られ、 重要なものはビタミン D 2 及 びビタミン D3 である。 ビタミン Dは腸からのカルシウムの吸収を促進し、 血液 中のカルシウム量を調節する。 その欠如は成長障害を起こし佝僂病の原因となる。 これらは t、ずれも大量に用いると過剰症障害を起こす。 Steroid components I匕合of the invention, cortisone, dexamethasone and vitamin D 3. Cortisone is a type of adrenocortical hormone extracted from the adrenal cortex and having a carbohydrate metabolism-promoting action. It is used as an anti-inflammatory agent for rheumatoid arthritis and other inflammations, and as an anti-allergic agent. Dexamethasone is also a type of synthetic adrenocortical hormone-used as an anti-inflammatory agent for improving adrenocortical dysfunction, rheumatoid arthritis and other inflammations, and as an anti-allergic agent. The vitamin D are known several vitamin to D 5, important is vitamin D 2及beauty vitamin D 3. Vitamin D promotes absorption of calcium from the intestine and regulates the amount of calcium in the blood. The lack causes growth impairment and causes useless diseases. These cause excessive disorder when large amounts of t and slip are used.
本発明のシァリルステロイドは、 下記の式 （VI) で表されるシアル酸ハラィド と下記の式 （ΙΙΓ ) 、 (IV )又は （V )で表されるステロイドを触媒存在下で縮 合させ、 により脱保護することにより容易に製造することができる。 本発明 のシァリルステロイドの塩としては、 ナトリウム塩、 カリウム塩等のアルカリ金 属塩、 アンモニゥム塩等が挙げられる。 The sialyl steroid of the present invention is obtained by condensing a sialic acid hydride represented by the following formula (VI) with a steroid represented by the following formula (ΙΙΓ), (IV) or (V) in the presence of a catalyst: Can be easily produced by deprotection. Examples of the salt of the sialyl steroid of the present invention include an alkali metal salt such as a sodium salt and a potassium salt, an ammonium salt and the like.
Figure imgf000006_0001
Figure imgf000006_0001
Figure imgf000006_0002
Figure imgf000007_0001
式 （VI) 中、 R2 はァセチル基であり、 R3 は低級アルキル基、 例えば、 メチ ル基であり、 Xはハロゲン原子、 例えば、 塩素原子、 臭素原子である。
Figure imgf000006_0002
Figure imgf000007_0001
In the formula (VI), R 2 is an acetyl group, R 3 is a lower alkyl group, for example, a methyl group, and X is a halogen atom, for example, a chlorine atom or a bromine atom.
縮合反応の溶媒としては CH2C12 、 THF、 CH3CN、 CHC13 等が、 触媒としては HgBr2-Hg(CN)2 、 AgOTf 、 Ag2C03等が使用できる。 この反応は温度一 2 0 °C〜3 0 °C、 1 0分〜 2 4時間で十分に進行する。 The solvent for the condensation reaction CH 2 C1 2, THF, CH 3 CN, CHC1 3 , and examples of the catalyst HgBr 2 -Hg (CN) 2, AgOTf, Ag 2 C0 3 , or the like can be used. This reaction sufficiently proceeds at a temperature of 20 ° C. to 30 ° C. for 10 minutes to 24 hours.
脱保護の際の溶媒としては MeOH-水、 MeOH等が、 触媒としては、 NaOH、 NaOCH3 K0H、 U0H、 K2C03 等が使用できる。 この反応は 0 °C〜3 0 °C、 3 0分〜 2 4時 間で十分に進行する。 Solvent The MeOH- water during deprotection, MeOH, and examples of the catalyst, NaOH, NaOCH 3 K0H, U0H , K 2 C0 3 , or the like can be used. This reaction proceeds sufficiently at 0 ° C. to 30 ° C. for 30 minutes to 24 hours.
〔産 ^ の利用可能性〕 [Availability of production ^]
本発明のシァリルステロイドノは、 ステロイド本来の薬効を保持するとともに、 長期間使用しても副作用を併発することがなく又は副作用が軽減され、 水に対す る溶解性も向上する。 またビタミン D 3 にシァノレ酸を結合させたものは、 血中半 減期が長くなる。 - The sialyl steroids of the present invention retain the original medicinal properties of the steroids, do not cause or reduce side effects even when used for a long period of time, and have improved solubility in water. Vitamin D 3 combined with cyanoleic acid has a longer blood half-life. -
〔発明を実施するための最良の形態〕 [Best mode for carrying out the invention]
以下、 実施例及び試験例により本発明を更に詳細に説明する。  Hereinafter, the present invention will be described in more detail with reference to Examples and Test Examples.
実施例 1 Example 1
活性ィ匕したモレキュラーシーブ 4 A1. 5 gにコルチゾン (化合物 1 ；式 (ΙΙΓ )) 2 12mg (0.59腿 ol) 、 Hg(CN)2 1 0 6mg (0.4 lmol)、 HgBr2 48mg (0. 1 3画 ol)、 CH2CI2 2mlを加え、 一 10 °Cでジクロロメタン 1mlに溶解した I一 クロ口一 4， 7, 8， 9—テトラ一ひ一ァセチルー N—ァセチルノイラミン酸メ チル (化合物 2 ；式 (VI)において R 2 がァセチル であり、 R3 がメチル基であ り Xがクロゾレである化合物) （CI体） 1 0 Om (0.20腿 ol) を 2回加え、 その まま 40時間攪捽した。反応液をセライト濾過後留去した。残渣をシリカゲル力 ラムクロマトグラフィー （60 g、 トノレェン：エタノール = 1 ： 2、 クロ口ホゾレ 、ム：メタノール =9 : 1) で精製した。ィ匕合物 3 (式 （I) において R1が式 (III)で表されるコルチゾン残基であり、 R2 がァセチル基であり、 R3 がメチ ル基である化合物） 及び化合物 4 (式 （II) において R1 が式 （III)で表される コルチゾン残基であり、 R2がァセチル基であり、 R3 がメチル基である化合物） か'得られた。 Activated molecular sieve 4 A1.5 g in cortisone (Compound 1; Formula (ΙΙΓ)) 2 12 mg (0.59 t ol), Hg (CN) 2 106 mg (0.4 lmol), HgBr 2 48 mg (0.13 ol), and CH2CI2 2 ml were added and dissolved in dichloromethane 1 ml at 110 ° C. 4,7,8,9-tetra-acetyl-N-methylacetylneuraminate (Compound 2; in formula (VI), R 2 is acetyl, R 3 is a methyl group, and (CI compound) (CI compound) 10 Om (0.20 tmol) was added twice, and the mixture was stirred for 40 hours. The reaction solution was distilled off after filtration through Celite. The residue was purified by silica gel column chromatography (60 g, Tonolene: ethanol = 1: 2, black sizzle, methanol: methanol = 9: 1). And compound 4 (compound of formula (I) wherein R 1 is a cortisone residue represented by formula (III), R 2 is an acetyl group, and R 3 is a methyl group) In the formula (II), R 1 is a cortisone residue represented by the formula (III), R 2 is an acetyl group, and R 3 is a methyl group.
化合物 3 ： 74.4mg (23%)  Compound 3: 74.4 mg (23%)
R f =0.05 (トルエン：メタノ一ル =9 ： 1)  R f = 0.05 (toluene: methanol = 9: 1)
rH-NMR (500 MHz, TMS, CDCI3)SH ； 0.623(s, 3H, CH3) 、 1.398(s, 3H, CH3) 、 1.871(s, 3H, Ac)、 2.047(s, 6H, 2Ac) 、 2.159(s, 3H， Ac)、 2.833(dd, 1H， J=4.4, 12.5Hz, H-3eq. (NeuAc)) . 3.677(dd, 1H， J=2.2, 10.6Hz, H-6) 、 3.800(s, 3H, 0CH3)、 4.031[q, IH, J=10.3Hz, H-5(NeuAc)]、 4.055[dd， IH, J= 5.5， 12.5Hz, H-9(NeuAc)l. 4.186(d, IH, J=19.4Hz, H-21)、 .265[dd, IH, J= 2.6， 12.5Hz， H-9' (NeuAc)]. 4.917圆， 1H， J=4.8, 10.6, 12.1Hz, H-4(NeuA c)] 、 5.097[d, IH, J=10.3Hz, NH(NeuAc)]、 5.318[dd, 1H， J=2.6, 9.9Hz， H- 7(NeuAc)] 、 5.369(d, 1H， J=19.4Hz, H-21)、 5.487[ddd， IH, J=2.6, 5.5, 9.5 Hz, H-8(NeuAc)] 、 5.727(s, IH, H-4) 。 rH-NMR (500 MHz, TMS , CDCI 3) S H; 0.623 (s, 3H, CH 3), 1.398 (s, 3H, CH 3), 1.871 (s, 3H, Ac), 2.047 (s, 6H, 2Ac), 2.159 (s, 3H, Ac), 2.833 (dd, 1H, J = 4.4, 12.5Hz, H-3eq. (NeuAc)). 3.677 (dd, 1H, J = 2.2, 10.6Hz, H-6 ), 3.800 (s, 3H, 0CH 3), 4.031 [q, IH, J = 10.3Hz, H-5 (NeuAc)], 4.055 [dd, IH, J = 5.5, 12.5Hz, H-9 (NeuAc) l. 4.186 (d, IH, J = 19.4Hz, H-21), .265 [dd, IH, J = 2.6, 12.5Hz, H-9 '(NeuAc)]. 4.917 圆, 1H, J = 4.8, 10.6, 12.1Hz, H-4 (NeuA c)], 5.097 [d, IH, J = 10.3Hz, NH (NeuAc)], 5.318 [dd, 1H, J = 2.6, 9.9Hz, H-7 (NeuAc) ], 5.369 (d, 1H, J = 19.4Hz, H-21), 5.487 [ddd, IH, J = 2.6, 5.5, 9.5 Hz, H-8 (NeuAc)], 5.727 (s, IH, H-4 ).
C41H55N017として C 41 H 55 N0 17
理論値 C ; 59.05, H； 6.65, N； 1.68  Theoretical C; 59.05, H; 6.65, N; 1.68
実測値 C ; 58.88, H； 6.60, N； 1.59  Found C; 58.88, H; 6.60, N; 1.59
化合物 4 ： 64 Omg (20 %  Compound 4: 64 Omg (20%
； Rf=0.0 & (トルエン：メタノール =9 : 1)  Rf = 0.0 & (toluene: methanol = 9: 1)
一 NMR (500 MHz, TMS,
Figure imgf000008_0001
； 0.641(s, 3H, CH3) 、 1. 12(s, 3H， CH3)、 1.899(s, 3H, Ac)、 2.016(s, 3H， Ac). 2.028(s, 3H， Ac). 2.041(s, 3H, Ac)、 2.152(s, 3H， Ac)、 2.522[dd, 1H, J=5.1, 13.2Hz, H-3eq(NeuAc)), 3.832 (s, 3H, 0CH3) 、 4.119[q, 1H, J=10.3Hz, H-5(NeuAc)]ヽ 4.434(d, 1H， J=18.3H z， H-21)、.4.565[dd， 1H， J=l.8, 10.6Hz, H-9(NeuAc)]、 4.874(d, 1H， J=18.7H z， H- 21)、 5.128[m, 1H， H-8(NeuAc)]、 5.149[dd, 1H， J=2.2, 11.0Hz, H-9' (NeuAc)]、 5.360[t, 1H， J=l.8Hz, H-7(NeuAc)] 、 5.391(m, 1H, H-4(NeuAc)]、 5.733(s, 1H, H-3) 。 NMR (500 MHz, TMS,
Figure imgf000008_0001
0.641 (s, 3H, CH 3 ), 1.12 (s, 3H, CH 3 ), 1.899 (s, 3H, Ac), 2.016 (s, 3H, Ac). 2.028 (s, 3H, Ac). 2.041 (s, 3H, Ac), 2.152 (s, 3H, Ac), 2.522 [dd, 1H, J = 5.1 , 13.2Hz, H-3eq (NeuAc)), 3.832 (s, 3H, 0CH 3), 4.119 [q, 1H, J = 10.3Hz, H-5 (NeuAc)]ヽ4.434 (d, 1H, J = 18.3Hz, H-21), .4.565 [dd, 1H, J = 1.8, 10.6Hz, H-9 (NeuAc)], 4.874 (d, 1H, J = 18.7H z, H-21), 5.128 [m, 1H, H-8 (NeuAc)], 5.149 [dd, 1H, J = 2.2, 11.0Hz, H-9 '(NeuAc)], 5.360 [t, 1H, J = l.8Hz, H-7 (NeuAc)], 5.391 (m, 1H, H-4 (NeuAc)], 5.733 (s, 1H, H-3).
C41H55N017として C 41 H 55 N0 17
理論値 C ； 59.05, H； 6.65, N； 1.68  Theoretic C; 59.05, H; 6.65, N; 1.68
実測値 C； 59.10， H； 6.75， N； 1.68  Found C; 59.10, H; 6.75, N; 1.68
ィ匕合物 3 52. 31¾ (62.7 ^11101)をメタノール21111に溶かし、 1 Nナトリウ ムメトキシド 3 0 1を加え、 0°Cで 1 8時間攪捽した後減圧留去した。 残渣 をメタノール 2 mlと水 lmlに溶かし、 2 0°Cで 1 8時間攪拌した。 反応液を減圧 留去後セフアデックス LH— 2 0 (メタノール溶出） で精製し、 化合物 5 (式 The compound (52.31) (62.7 ^ 11101) was dissolved in methanol 21111, 1N sodium methoxide 301 was added, and the mixture was stirred at 0 ° C for 18 hours and then distilled under reduced pressure. The residue was dissolved in methanol (2 ml) and water (lml) and stirred at 20 ° C for 18 hours. After evaporating the reaction mixture under reduced pressure, the residue was purified by Sephadex LH-20 (eluted with methanol) to give compound 5 (formula 5).
(I) において R1 が式 （III)で表されるコルチゾン残基であり、 R2 が水素原 子であり、 R3 がナトリウムである化合物） を得た。 In (I), R 1 is a cortisone residue represented by the formula (III), R 2 is a hydrogen atom, and R 3 is sodium.
化合物 5 ： 35. 7mg (8 5%) Compound 5: 35.7 mg (85%)
R f =0.2 6 (酢酸ェチル：エタノール：水 =5 : 2 : 1)  R f = 0.26 (ethyl acetate: ethanol: water = 5: 2: 1)
'H-NMR (500 MHz, TMS, CD30D)5H ; 0.615(s, 3H， CH3) 、 1.423(s, 3H， CH3)、 1.736[t, 1H， J=12.5Hz， H-3ax(NeuAc)]、 2.003(s, 3H, NAc) 、 2.839[dd, 1H， J=4.0, 12.5Hz, H-3eq(NeuAc)], 3.518[dd, 1H， J=l.8, 9.2Hz, H-6(NeuAc)]、 3.568[m, 1H, H-8(NeuAc)〗、 3.649 [m, 1H, H-4(NeuAc)]、 4.512(d, 1H， J=18.3H z， H- 21)、 4.755(d, 1H, J=18.3Hz, H—21)、 5.711(s, 1H， H—4) 。 'H-NMR (500 MHz, TMS, CD 3 0D) 5 H; 0.615 (s, 3H, CH 3), 1.423 (s, 3H, CH 3), 1.736 [t, 1H, J = 12.5Hz, H- 3ax (NeuAc)], 2.003 (s, 3H, NAc), 2.839 [dd, 1H, J = 4.0, 12.5Hz, H-3eq (NeuAc)], 3.518 [dd, 1H, J = l.8, 9.2Hz , H-6 (NeuAc)], 3.568 [m, 1H, H-8 (NeuAc)〗, 3.649 [m, 1H, H-4 (NeuAc)], 4.512 (d, 1H, J = 18.3Hz, H -21), 4.755 (d, 1H, J = 18.3Hz, H-21), 5.711 (s, 1H, H-4).
化合物 4 50. lmg (74.3 ^mol)をメタノール 2mlに溶かし、 1 Nナトリウ ムメトキシド 3 0 ;z 1を加え、 20°Cで 1 8時間攪拌した後、 減圧留去した。残 渣をメタノール 2mlと水 lmlに溶かし、 20°Cで 1 8時間攪拌した。 反応液を減 圧留去後セフアデックス LH— 20 (メタノール溶出） で精製し、 ィ匕合物 6 (式 Compound 4 (50.lmg, 74.3 ^ mol) was dissolved in methanol (2 ml), 1N sodium methoxide 30; z1 was added, the mixture was stirred at 20 ° C for 18 hours, and then distilled under reduced pressure. The residue was dissolved in methanol (2 ml) and water (lml) and stirred at 20 ° C for 18 hours. After depressurizingly distilling the reaction mixture, the reaction mixture was purified by Sephadex LH-20 (eluted with methanol) to obtain a compound 6 (formula
(II) において R1 が式 （III)で表されるコルチゾン残基であり、 R2 が水素原 子であり、 R3 力ナトリウムである化合物） を得た。 化合物 6 ： 33.6mg (83%) In (II), R 1 is a cortisone residue represented by the formula (III), R 2 is a hydrogen atom, and R 3 is sodium. Compound 6: 33.6 mg (83%)
R f =0.22 酸ェチル：エタノール：水 =5 : 2 : 1)  R f = 0.22 Ethyl acid: ethanol: water = 5: 2: 1)
1H— NMR (500 MHz, TMS, CD30D) 5H ； 0.623(s, 3H， CH3) 、 1. 22(s, 3H， CH3)、 1.663[dd, 1H， J-11.4, 12.8Hz， H-3ax(NeuAc)] 、 L978(s, 3H， NAc) 、 2. 12[dd, IH, J=5.1, 12.8Hz， H- 3eq(NeuAc)]、 3.616[dd, IE J=5.9, 11.4Hz, H-9(NeuAc)] 、 3.682[td, 1H， J=2.9, 9.2Hz, H-8(NeuAc)] 、 3.714[dd, 1H， J= 1.1， 10.6Hz, H-7(NeuAc)]、 3.798[dd, 1H， J=2.6, 11.氣 H-9' (NeuAc)]、 3.958[t, IH, J=L0.3Hz, H- 5(NeuAc)]、 4.104[dt, IH, J=4.8, 10.3Hz, H-4 (NeuAc)lv 4.280(d, 1H， J=18.3Hz, H— 21)、 4.648(d, 1H， J=18.3Hz, H-21)、 5.709(s, IH, H-4) 0 実施例 2 一 1H- NMR (500 MHz, TMS, CD 3 0D) 5 H; 0.623 (s, 3H, CH 3), 1. 22 (s, 3H, CH 3), 1.663 [dd, 1H, J-11.4, 12.8Hz , H-3ax (NeuAc)], L978 (s, 3H, NAc), 2.12 [dd, IH, J = 5.1, 12.8Hz, H-3eq (NeuAc)], 3.616 [dd, IE J = 5.9, 11.4Hz, H-9 (NeuAc)], 3.682 [td, 1H, J = 2.9, 9.2Hz, H-8 (NeuAc)], 3.714 [dd, 1H, J = 1.1, 10.6Hz, H-7 (NeuAc) )], 3.798 [dd, 1H, J = 2.6, 11.ki H-9 '(NeuAc)], 3.958 [t, IH, J = L0.3Hz, H-5 (NeuAc)], 4.104 [dt, IH , J = 4.8, 10.3Hz, H-4 (NeuAc) lv 4.280 (d, 1H, J = 18.3Hz, H-21), 4.648 (d, 1H, J = 18.3Hz, H-21), 5.709 (s , IH, H-4) 0 Example 2
活性化したモレキュラーシーブ 3 A 2 gとモレキュラーシーブ 4 A 1 gにデキ サメタゾン （化合物 1 0 ) 9 5 Omg (2.42画 ol) 、 Hg(CN)2 48 Omg (1.3 醒 ol) 、 HgBr2上 0 & g (4.1匪 ol) 、 ァセトニ卜リル 8mlを加え、 一 1 0¾で クロ口ホルム 2ndに溶かした 2—クロロー 4, 7, 8, 9—テトラー 0—ァセチ ルー N—ァセチルノイラミン酸メチル（化合物 2) (C1体） 3.7 03 g (7.26 πιοΐ) を加え、 20 で 1 8時間攪拌した。反応液にテトラヒドロフラン 5 mlを 加え、 &時間攪拌した。反応液をセライト濾過後減圧留去し、残渣をシリカゲル カラムクロマトグラフィー （20 0 g、 トルエン：酢酸ェチル =1 ： 2、 次いで クロロホノレム：メタノール =9 : 1) 鐃いて、 ローバーカラム （登録商標) （ク ロロホルム：メタノール =20 : 1) て 製した。ィ匕合物 11 (式（I) におい て R1 が式 (IV) で表されるデキサメタゾン残基であり、 R2がァセチル基であ り、 R3 がメチル基である化合物） 及び化合物 12 (式 （II) において が式 (IV) で表されるデキサメタゾン残基であり、 R2 がァセチル基であり、 R3 が メチル基である化合物） 力得られたひ Activated molecular sieves 3 A 2 g molecular sieve 4 A 1 g to dexamethasone (Compound 1 0) 9 5 Omg (2.42 strokes ol), Hg (CN) 2 48 Omg (1.3 s Awakening ol), HgBr 2 on 0 & g (4.1 bandol ol) and 8 ml of acetonitrile, and add 10 ml of 2-chloro-4,7,8,9-tetra-0-acetyl-N-methyl acetylneuraminate (Compound 2) (C1 form) 3.703 g (7.26 πιοΐ) was added, and the mixture was stirred at 20 for 18 hours. 5 ml of tetrahydrofuran was added to the reaction solution, and the mixture was stirred for & hour. The reaction mixture was filtered through celite and evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (200 g, toluene: ethyl acetate = 1: 2, then chlorophonolem: methanol = 9: 1). Chloroform: methanol = 20: 1). Compound 12 (compound of formula (I) in which R 1 is a dexamethasone residue represented by formula (IV), R 2 is an acetyl group, and R 3 is a methyl group) and compound 12 (In the formula (II), is a dexamethasone residue represented by the formula (IV), R 2 is an acetyl group, and R 3 is a methyl group.)
化合物 1 1 ： 1. 0 3 5 mg (49.4 %) Compound 11: 1.035 mg (49.4%)
R f =0.5 15 (クロ口ホルム：メタノール =15 ： 1)  R f = 0.5 15 (form: methanol = 15: 1)
iH— NMR(500 MHz, TMS,
Figure imgf000010_0001
CH3)、 1.014 (s， 3H, CH3)、 1.538(s, 3H， CH3) 、 1.878、 2.030 . 2.045、 2.148 、 2.159 (4s, 15H, 4Ac)、 2.795[dd, 1H， J=4.4， 12.5Hz, H-3eq(NeuAc)]、 3.788(s, 3H, 0CH3)、 4.022[dd, IH, J=6.2, 12.5Hz, H-9(NeuAc)]、 4.043[q, IH, J=10.6Hz, H-5(NeuAc)] 、 4.262[dd, 1H， J=2.9, 12.5Hz, H- 9' (NeuAc)]、 4.278(d, 1H， J =18.7Hz, H - 21)、 4.920[ddd, 1H， J=4.8, 10.6, 12.1Hz, H-4(NeuAc)] 、 5.111 (d, 1H， J=18.7Hz, H-21)、 5.173(d, 1H， J=10.3Hz, NH)、 5.286[dd， 1H， J=2.2, 9.5Hz， H-7(NeuAc)]、 5.475[ddd, 1H， J=2.9, 6.2， 9.5Hz, H-8(NeuAc)〗、 6.107 (s, IH, H-4). 6.325(dd， 1H， J=l.8, 10.3Hz, H-l) 、 7.218(d, 1H， J=10.3Hz, H-2) 、 iH—NMR (500 MHz, TMS,
Figure imgf000010_0001
CH 3 ), 1.014 (s, 3H, CH 3) , 1.538 (s, 3H, CH 3), 1.878, 2.030. 2.045, 2.148, 2.159 (4s, 15H, 4Ac), 2.795 [dd, 1H, J = 4.4, 12.5Hz, H -3eq (NeuAc)], 3.788 ( s, 3H, 0CH 3), 4.022 [dd, IH, J = 6.2, 12.5Hz, H-9 (NeuAc)], 4.043 [q, IH, J = 10.6Hz, H -5 (NeuAc)], 4.262 [dd, 1H, J = 2.9, 12.5Hz, H-9 '(NeuAc)], 4.278 (d, 1H, J = 18.7Hz, H-21), 4.920 [ddd, 1H , J = 4.8, 10.6, 12.1Hz, H-4 (NeuAc)], 5.111 (d, 1H, J = 18.7Hz, H-21), 5.173 (d, 1H, J = 10.3Hz, NH), 5.286 [ dd, 1H, J = 2.2, 9.5Hz, H-7 (NeuAc)], 5.475 [ddd, 1H, J = 2.9, 6.2, 9.5Hz, H-8 (NeuAc)〗, 6.107 (s, IH, H- 4). 6.325 (dd, 1H, J = l.8, 10.3Hz, Hl), 7.218 (d, 1H, J = 10.3Hz, H-2),
C42H56NlFl017 として As C42H 56 NlFl0 1 7
理論値 C； 58.26， H； 6.52, N； 1.62  Theory C; 58.26, H; 6.52, N; 1.62
実測値 C； 58.31, H； 6.55， N； 1.59  Found C; 58.31, H; 6.55, N; 1.59
化合物 1 2 ： 0.347 g ( 16. 6 %) Compound 12: 0.347 g (16.6%)
R f =0.54 5 (クロ口ホルム ： メタノール- 1 5 : 1)  R f = 0.54 5 (cloth form: methanol-15: 1)
lH— NMR(500 MHz, TMS, CDC") ； 0.855(d, 3H, J=7.3Hz, CH3)、 1.028 (s， 3H, CH3)、 1.547(s， 3H， CH3) 、 1.896、 1.997 、 2.030、 2.047、 2.155 (5s, 15H, 5Ac)、 2.556[dd， 1H， J=4.8, 12.8Hz, H_3eq(NeuAc)]、 3.821(s, 3H， 0CH3)、 4.098[q, IH, J=10.3Hz, H-5(NeuAc)]、 4.498(d, 1H， J=17.6Hz, H - 21)、 4.807(d, 1H， J=17.6Hz, H-21)、 5.241[dt, 1H， J=2.6, 7.3Hz, H-8(NeuAc)] 、 5.399[dt, IH, J=4.8, 11.0Hz, H—4(NeuAc)]、 5. 20(d, 1H， J=10.3Hz, NH)、 6.114(s, 1H， H-4)、 6.333(dd, 1H， J=l.8, 9.9Hz， H-l). 7.218(d, 1H， J=9.9
Figure imgf000011_0001
lH- NMR (500 MHz, TMS, CDC "); 0.855 (d, 3H, J = 7.3Hz, CH 3), 1.028 (s, 3H, CH 3), 1.547 (s, 3H, CH 3), 1.896, 1.997, 2.030, 2.047, 2.155 ( 5s, 15H, 5Ac), 2.556 [dd, 1H, J = 4.8, 12.8Hz, H_3eq (NeuAc)], 3.821 (s, 3H, 0CH 3), 4.098 [q, IH, J = 10.3Hz, H-5 (NeuAc)], 4.498 (d, 1H, J = 17.6Hz, H-21), 4.807 (d, 1H, J = 17.6Hz, H-21), 5.241 [dt, 1H , J = 2.6, 7.3Hz, H-8 (NeuAc)], 5.399 [dt, IH, J = 4.8, 11.0Hz, H-4 (NeuAc)], 5.20 (d, 1H, J = 10.3Hz, NH), 6.114 (s, 1H, H-4), 6.333 (dd, 1H, J = 1.8, 9.9 Hz, Hl). 7.218 (d, 1H, J = 9.9)
Figure imgf000011_0001
C42H56NiFi0,7 として C 4 2H 56 NiFi0,7
理論値 C； 58.26, H； 6.52， N； 1.62  Theory C; 58.26, H; 6.52, N; 1.62
実測値 C； 58.04, H； 6.75, N； 1.60  Found C; 58.04, H; 6.75, N; 1.60
化合物 1 1 9 89mg (1. 1 4 2腿 ol) をメタノール 1 5 mlに溶かし、 1 Nナ トリウムメトキシド 50 0 1を加え、 2 0 °Cで 6時間攪拌した。 反応液を減圧 留去後、 残渣をメタノール 1 0ml、 水 3mlに溶解し、 2 0°Cで 1 8時間攪拌した c 反応液を減圧留去し、 残渣をセフアデックス LH— 2 0 (メタノール溶出） で精 製し、ィ匕合物 13 (式 （I) において R1 が式 (IV) で表されるデキサメタゾン 残基であり、 R2 が水素原子であり、 R3 がナトリウムである化合物） を得た。 化合物 13 ： 749mg (9 Z%) 89 mg (1.142) of compound 111 was dissolved in 15 ml of methanol, 500 N of 1 N sodium methoxide was added, and the mixture was stirred at 20 ° C for 6 hours. The reaction mixture was evaporated under reduced pressure, the residue methanol 1 0 ml, dissolved in water 3 ml, and c reaction solution was stirred for 1 8 hours at 2 0 ° C was removed in vacuo and the residue Sephadex LH-2 0 (methanol elution ) To obtain a compound 13 (a compound of the formula (I) wherein R 1 is a dexamethasone residue represented by the formula (IV), R 2 is a hydrogen atom, and R 3 is sodium). . Compound 13: 749 mg (9 Z%)
R.f =0.459 (ブタノール：エタノール：水 = 2 : 1 : 1)  R.f = 0.459 (butanol: ethanol: water = 2: 1: 1)
^-NMRCSOO NEz, TMS， CD30D) SH ； 0.841(d, 3H， J=7.0Hz, CH3)、 1.007 (s， 3H，CH3) 、 1.584(s, 3H, GH3) 、 L721[t, 1H， J=12.1Hz, H-3ax(NeuAc)]. 2.013(s, 3H, NAc) 、 2.870[dd, 1H， J=2.9, II.7Hz, H— 3eq(NeuAc)]、 3.900[m, IH, H-8(NeuAc)] 、 4.602(d, IH, J=18.3Hz, 11-21)、 .675(d, 1H， J=18.3Hz, H 一 21)、 6.070(s, IH, H- 4) 、 6.284(dd, IH, J=l.8, l(L3Hz， H-1) 、 7.408(d, IH, ^ -NMRCSOO NEz, TMS, CD 3 0D) S H; 0.841 (d, 3H, J = 7.0Hz, CH 3), 1.007 (s, 3H, CH 3), 1.584 (s, 3H, GH 3), L721 [t, 1H, J = 12.1Hz, H-3ax (NeuAc)]. 2.013 (s, 3H, NAc), 2.870 [dd, 1H, J = 2.9, II.7Hz, H-3eq (NeuAc)], 3.900 [m, IH, H-8 (NeuAc)], 4.602 (d, IH, J = 18.3Hz, 11-21), .675 (d, 1H, J = 18.3Hz, H-21), 6.070 (s, IH, H-4), 6.284 (dd, IH, J = l.8, l (L3Hz, H-1), 7.408 (d, IH,
J=10.3Hz， H-2) 。 J = 10.3Hz, H-2).
化合物 12 3 07mg (0.3 5 5腿 ol) をメタノール 1 0mlに溶解し、 1 Nナ トリウムメトキシド 20 0 / を加え、 2 0°Cで&時間攪拌した。 反応液を減圧 留去後、残渣をメタノール 10ml、水 lmlに溶解し、 20°Cで 1 8時間攙捽した。 反応液を减圧留去し、 残渣をセフアデツクス LH— 20 (メタノール^出） で精 製し、化合物 14 (式 （II) において R1 が式（IV) で表されるデキサメタゾン 残基であり、 R2が水素原子であり、 R3 がナトリウムである化合物） を得た。 化 14 ： 17 9mg (71%) Compound 13007 mg (0.355 mol) was dissolved in methanol (10 ml), 1N sodium methoxide (200 /) was added, and the mixture was stirred at 20 ° C for & hour. After evaporating the reaction solution under reduced pressure, the residue was dissolved in 10 ml of methanol and 1 ml of water, and the solution was heated at 20 ° C for 18 hours. The reaction solution was distilled off under reduced pressure, and the residue was purified with Sephadex LH-20 (methanol). Compound 14 (in formula (II), R 1 is a dexamethasone residue represented by formula (IV), A compound wherein R 2 is a hydrogen atom and R 3 is sodium). Chemical formula 14: 17 9 mg (71%)
R f =0.459 (ブ夕ノール：エタノール： 7j =2 ： 1 ： 1)  R f = 0.459 (butanol: ethanol: 7j = 2: 1: 1)
一匪 R(500 MHz, TMS, CD30D)dH ； 0.826(d, 3H， J=7.3Hz, CH3)、 1.001 (s， 3H， CH3)、 l:587(s， 3H， CH3)、 1.978(s, 3H, ΝΑο)Γ2.449[dd, 1H， J=5.1, 12.8Hz, H-3ea(NeuAc)] 、 3.399 [d， IH, H=9.5Hz, H-6(NeuAc)] 、 3.644[dd, IH, J=5.5, 11.4Hz, H-9(NeuAc)]、 3.708[d， IH, L4Hz, H-7(NeuAc)]、 3.789[dd, IH, 'J=2.9, 11.4Hz, Η-θ' (NeuAc)]、 3.945 [t, 1H， J=10.3Hz, H-5(NeuAc)]、 111[dt, IH, J=5.1, 9.9Hz, H-4(NeuAc)]. 4237[m, 1H， H-8(NeuAc)] 4.295 [d, 1H， J=18.3Hz, H-21)、 4.612(d, IH, J=18.3Hz, H-21) 6.069(s, 1H， H-4)、 291(dd, 1H， J=1.8, 9.9Hz， H-1). 7. 19(d, 1H， J=10.3Hz, H-2)。 実施例 3 Ichi匪R (500 MHz, TMS, CD 3 0D) d H; 0.826 (d, 3H, J = 7.3Hz, CH 3), 1.001 (s, 3H, CH 3), l: 587 (s, 3H, CH 3 ), 1.978 (s, 3H, ΝΑο) Γ2.449 [dd, 1H, J = 5.1, 12.8Hz, H-3ea (NeuAc)], 3.399 [d, IH, H = 9.5Hz, H-6 (NeuAc )], 3.644 [dd, IH, J = 5.5, 11.4Hz, H-9 (NeuAc)], 3.708 [d, IH, L4Hz, H-7 (NeuAc)], 3.789 [dd, IH, 'J = 2.9 , 11.4Hz, Η-θ '(NeuAc)], 3.945 [t, 1H, J = 10.3Hz, H-5 (NeuAc)], 111 [dt, IH, J = 5.1, 9.9Hz, H-4 (NeuAc) )]. 4237 [m, 1H, H-8 (NeuAc)] 4.295 [d, 1H, J = 18.3Hz, H-21), 4.612 (d, IH, J = 18.3Hz, H-21) 6.069 (s , 1H, H-4), 291 (dd, 1H, J = 1.8, 9.9Hz, H-1). 7.19 (d, 1H, J = 10.3Hz, H-2). Example 3
活性化したモレキュラーシーブ 4 Al.5 gにビタミン D3(ィ匕合物 20) 30 1 mg (0.7 84画 ol) 、 Hg(CN)2 2 1 2mg (0.8 2誦 ol) 、 HgBr2 9 6 mg (0.2 6 匪 ol) 、 クロ口ホルム 2 mlを加え、 一 1 0°Cでクロ口ホルム 2 mlに溶解した 2— クロ口一 4， 7, 8， 9—テトラ一 0—ァセチル一 N—ァセチルノイラミン酸メ チル （化合物 2) (C1体） 2 0 Omg (0.3 9 2mmol) を加え、 そのまま 4 0時間 攪拌した。 反応液をセライト濾過後留去した。 残渣をシリカゲルカラムクロマト グラフィー （6 0 g、 エーテル：エタノール = 24 : 1、 次いで 300 g、 トル ェン：メタノール = 1 0 : 1) で精製した。 化合物 2 1 (式 （I) において R1 が式 （V) で表されるビタミン D3 残基であり、 R2 がァセチル基であり、 R3 がメチル基である化合物） 及び化合物 2 2 (式 (II) において が式 （V) で 表されるビタミン D3 残基であり、 R2 がァセチル基であり、 R3 がメチル基で ある化合物） が得られた。 Activated molecular sieve 4 Vitamin D 3 (5 g) 20 5 mg (0.7 84 strokes ol), Hg (CN) 2 2 1 2mg (0.8 2誦ol), HgBr 2 9 6 mg (0.2 6 negation ol), black hole Holm 2 ml was added, black one 1 0 ° C Methyl 2,4-, 8,9-tetra-10-acetyl-N-acetylacetylneuraminate (Compound 2) dissolved in 2 ml of mouth form 2 O Omg (0.392 mmol) ) Was added and the mixture was stirred as it was for 40 hours. The reaction solution was distilled off after filtration through Celite. The residue was purified by silica gel column chromatography (60 g, ether: ethanol = 24: 1, then 300 g, toluene: methanol = 10: 1). Compound 21 (a compound of the formula (I) wherein R 1 is a vitamin D 3 residue represented by the formula (V), R 2 is an acetyl group, and R 3 is a methyl group) and compound 22 ( In the formula (II), is a compound in which is a vitamin D 3 residue represented by the formula (V), R 2 is an acetyl group, and R 3 is a methyl group.
化合物 2 1 ： 4 7mg (1 4%) Compound 21: 47 mg (14%)
R f =0. 2 3 (トルエン：メタノール = 1 0 : 1)  R f = 0.23 (toluene: methanol = 10: 1)
— NMR(500 MHz, TMS, CDC13)(5H ; 0.556(S， 3H， CH3) 、 0.864 、 0.868 (2d, 6H， J=6.6Hz, 2CH3) 、 0.919(d， 3H, J=6.6Hz, CH3)、 1.888、 2.019、 2.027、 2.132 、 2.156(5s, 15H, 5Ac) 、 2.572[dd, 1H， J=4.3, 12.8Hz, H-3eq(NeuAc)]、 3.787(s, 3H， 0CH3)、 4.169(dd, 1H， J=5.5, 12.1Hz, H-9(NeuAc)]、 4.337[dd, 1H， J=2.6, 12.5Hz, H- 9' (NeuAc)]、 4.794[d, 1H, J=2.6Hz, C=Ciffl_) 、 4.867 [m, 1H， H - 4(NeuAc)] 、 5.008(bs， 1H， C=C )^ 5.117(d, 1H, J=9.9Hz, NH)、 5.326(dd, 1H, J=1.5, 7.7Hz, H-7(NeuAc)] 、 5.383[ddd, 1H， J=2.9, 5.9, 7.7 Hz, H-8(NeuAc)]、 6.036(d, 1H， J=ll.7Hz, H-6又は H-7)、 6.231(d, 1H， J=11.4 Hz, H-6又は H-7) 。 - NMR (500 MHz, TMS, CDC1 3) (5H; 0.556 (S, 3H, CH 3), 0.864, 0.868 (2d, 6H, J = 6.6Hz, 2CH 3), 0.919 (d, 3H, J = 6.6 Hz, CH 3 ), 1.888, 2.019, 2.027, 2.132, 2.156 (5s, 15H, 5Ac), 2.572 [dd, 1H, J = 4.3, 12.8Hz, H-3eq (NeuAc)], 3.787 (s, 3H, 0CH 3 ), 4.169 (dd, 1H, J = 5.5, 12.1Hz, H-9 (NeuAc)], 4.337 [dd, 1H, J = 2.6, 12.5Hz, H-9 '(NeuAc)], 4.794 [d , 1H, J = 2.6Hz, C = Ciffl_), 4.867 [m, 1H, H-4 (NeuAc)], 5.008 (bs, 1H, C = C) ^ 5.117 (d, 1H, J = 9.9Hz, NH ), 5.326 (dd, 1H, J = 1.5, 7.7Hz, H-7 (NeuAc)], 5.383 [ddd, 1H, J = 2.9, 5.9, 7.7Hz, H-8 (NeuAc)], 6.036 (d, 1H, J = ll.7Hz, H-6 or H-7), 6.231 (d, 1H, J = 11.4Hz, H-6 or H-7).
化合物 2 2 ： 4.5ing (1.3%) Compound 22: 4.5ing (1.3%)
Rf =0.24 (トルエン：メタノール = 1 0 ： 1)  Rf = 0.24 (toluene: methanol = 10: 1)
'Η - NMR (500 MHz, TMS, CDC13)<5H ； 0.552(s, 3H, CH3)、 0.863 、 0.868 (2d, 6H, J=6.6Hz, 2CH3) 、 0.917(d, 3H, J=6.2Hz, CH3)、 1.874、 1.995、 2.013、 2.075 、 2.134(5s, 15H， 5Ac) 、 2.541[dd, 1H， J=4.8, 13.1Hz, H-3eq(NeuAc)]、 3.837(s, 3H， 0CH3)、 4.812、 5.043(2bs, 2H, C=国、 5.133[m, 1H, H-8(NeuAc)]. 5.260[ni, 1H, H-4(NeuAc)] 5.992(d, 1H, J=11.4Hz, H-6又は H- 7)、 6.100(d， 1 H, J=li.0Hz, H-6又は H- 7)。 'Η - NMR (500 MHz, TMS, CDC1 3) <5H; 0.552 (s, 3H, CH 3), 0.863, 0.868 (2d, 6H, J = 6.6Hz, 2CH 3), 0.917 (d, 3H, J = 6.2Hz, CH 3), 1.874 , 1.995, 2.013, 2.075, 2.134 (5s, 15H, 5Ac), 2.541 [dd, 1H, J = 4.8, 13.1Hz, H-3eq (NeuAc)], 3.837 (s, 3H, 0CH 3 ), 4.812, 5.043 (2bs, 2H, C = country, 5.133 [m, 1H, H-8 (NeuAc)]. 5.260 [ni, 1H, H-4 (NeuAc)] 5.992 (d, 1H , J = 11.4Hz, H-6 or H-7), 6.100 (d, 1 H, J = li.0Hz, H-6 or H-7).
化合物 2 1 1 8mg (20. 9 ^moi)をメタノール 2mlに溶かし、 1 Nナトリウ ムメトキシド 3 0 1を加え、 0 °Cで 20時間攪拌した。反応液を減圧留去し た。残渣をメタノール 2mし 水 lmlに溶かし、 20°Cで 20時間攪拌した後、 減 圧留去し、残渣をセフアデックス LH— 20 (メタノール溶出） で精製し、 化合 物 23 (式 （I) において が式 (V) で表されるビタミン D3残基であり、 R2 が水素原子であり、 R3 がナトリウムである化合物） を得た。 Compound 211 mg (20.9 ^ moi) was dissolved in methanol 2 ml, 1N sodium methoxide 301 was added, and the mixture was stirred at 0 ° C for 20 hours. The reaction solution was distilled off under reduced pressure. The residue was dissolved in 2 ml of methanol, dissolved in 1 ml of water, stirred at 20 ° C for 20 hours, depressurized and distilled off, and the residue was purified with Sephadex LH-20 (eluted with methanol) to give Compound 23 (formula (I) Is a vitamin D 3 residue represented by the formula (V), R 2 is a hydrogen atom, and R 3 is sodium.
化合物 2 3 ： 14.7mg (10 0 %) Compound 23: 14.7 mg (100%)
R f =0.462 (醉酸ェチル：エタノール： 7j =5 : 2 : 1)  R f = 0.462 (Ethyl sulphate: ethanol: 7j = 5: 2: 1)
XH-NMR (500 MHz, TMS, CD30D)5H ; 0.554(s， 3H, CH3- 18)、 0.877 、 0.880(2d, 6H, CH3-26及び 27) 、 0.941(d, 3H, CH3-21)、 1.541[t, 1H, J=12.1H z， H-3ax(NeuAc)]v 2.014(s, 3H, NAc) 、 2.83載 1H, J=4. , 12. lHz, H-3eq (NeuAc)]、 3.692[dd, 1H， J=4.8， II.氣 H-9(NeuAc)]、 3.831[dd, 1H, J=2.6, 11.4Hz, H-9 ' (NeuAc)]、 3.916[m， IH, H-8(NeuAc)]、 4.154(m, 1H, H-3) 、 4.689 、 4.974(2bs, 2H, 2H—19)、 5.998(d, 1H, J=li.0Hz, H-6又は H-7)、 6.213 (d, 1H， J=11.4Hz, H-6又は H— 7)。 実施例 4 XH-NMR (500 MHz, TMS , CD 3 0D) 5 H; 0.554 (s, 3H, CH 3 - 18), 0.877, 0.880 (2d, 6H, CH 3 -26 and 27), 0.941 (d, 3H , CH 3 -21), 1.541 [t, 1H, J = 12.1Hz, H-3ax (NeuAc)] v 2.014 (s, 3H, NAc), 2.83 1H, J = 4., 12.lHz, H- 3eq (NeuAc)], 3.692 [dd, 1H, J = 4.8, II. Ki H-9 (NeuAc)], 3.831 [dd, 1H, J = 2.6, 11.4Hz, H-9 '(NeuAc)], 3.916 [m, IH, H-8 (NeuAc)], 4.154 (m, 1H, H-3), 4.689, 4.974 (2bs, 2H, 2H-19), 5.998 (d, 1H, J = li.0Hz, H -6 or H-7), 6.213 (d, 1H, J = 11.4Hz, H-6 or H-7). Example 4
デキサメタゾン （化合物 1 0) 7.0 0 gをテトラヒドロフラン 1 3 0mlに溶解 し、 モレキュラーシーブ 4A 7 g及び 2—クロ口一 4, 7, 8， 9ーテトラ一 0—ァセチルー N—ァセチルノイラミン酸メチル（化合物 2 ) (C1 体） 11.0 8 gを加えた後、 一40° でアルゴン気流下テトラヒドロフランに溶解したシノレバ 一トリフレート 5.5 5 gを加えた。徐々に温度を室温まで戻しながら 1.5時間攪 捽した後、 更に化合物 2を 4.63 g加えて室温で一晩攪拌した。反応液をろ過し、 ろ液の溶媒を減圧留去後、 残渣を酢酸ェチル 200mlに溶解し、 飽和:^ 7j T¾fe 净後、無水硫酸マグネシウムで乾燥し溶媒を減圧留去した。得られた残渣をシリ 力ゲルカラムクロマトグラフィー （クロ口ホルム：メタノール = 2 0 ： 1) にて 分離精製し、 化合物 1 1の白色粉末 9.26 g (収率 52 %) を得た。 また、 原 料化合物 1.0を L 72 g (24.6%) 回収した。化合物 1 1は更に酢酸ェチルに て再結晶し無色結晶 5. 8 9 gを得た。 7.0 g of dexamethasone (compound 10) was dissolved in 130 ml of tetrahydrofuran, and 7 g of molecular sieve 4A and 4,7,8,9-tetra-1 0-acetyl-N-acetylneuraminate methyl Compound 2) (C1 form) 11.08 g was added, and 5.55 g of sinoleva monotriflate dissolved in tetrahydrofuran was added at 140 ° C under an argon stream. After stirring for 1.5 hours while gradually returning the temperature to room temperature, 4.63 g of Compound 2 was further added, followed by stirring at room temperature overnight. The reaction solution was filtered, and the solvent in the filtrate was distilled off under reduced pressure. The residue was dissolved in 200 ml of ethyl acetate. After saturation: ^ 7jT, the solution was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (form: methanol = 20: 1) to obtain 9.26 g (yield: 52%) of compound 11 as a white powder. In addition, 72 g (24.6%) of the raw material compound 1.0 was recovered. Compound 11 is further converted to ethyl acetate. The crystals were recrystallized to give 5.89 g of colorless crystals.
〔化合物 1 1 (結晶） の物性値〕  [Physical properties of compound 11 (crystal)]
分子量 8 6 5. 9 0  Molecular weight 8 6 5.90
融点 1 5 6 °C  Melting point 1 56 ° C
化合物 1 1 2.9 8 gをメタノール 2 Omlに溶解し、 0°Cで 1 Nナトリウムメ トキシド 0.7 mlを加えた後、 室温で 2時間攪拌した。 反応液の溶媒を減圧留去後、 残渣に水 1 0ml及び、 1 Nナトリウムメ トキシド 3.4mlを加え室温で 3 0分間攪 拌した。 反応液をセフアデックス LH— 2 0にのせメタノールで溶出し、 得られ た画分の溶媒を減圧留去し、 ィ匕合物 1 3の白色粉末 2.3 0 g (収率 94.7 %) を 得た。 化合物 1 3は更にメ夕ノールにて再結晶し無色結晶 1.20 gを得た。  The compound (11.2.98 g) was dissolved in methanol (2 Oml), and 1N sodium methoxide (0.7 ml) was added at 0 ° C, followed by stirring at room temperature for 2 hours. After evaporating the solvent of the reaction solution under reduced pressure, 10 ml of water and 3.4 ml of 1N sodium methoxide were added to the residue, followed by stirring at room temperature for 30 minutes. The reaction solution was placed on Sephadex LH-20 and eluted with methanol, and the solvent of the obtained fraction was distilled off under reduced pressure to obtain 2.30 g (yield 94.7%) of a white powder of the compound 13. . Compound 13 was further recrystallized from methanol to give 1.20 g of colorless crystals.
〔化合物 1 3 (結晶） の物性値〕  [Physical properties of compound 13 (crystal)]
分子量 7 05.7 1  Molecular weight 7 05.7 1
融点 2 1 4°C (分解）  Melting point 2 14 ° C (decomposition)
【試験例】 [Test example]
次に本発明の化合物 1 3 (シァリルデキサメタゾン） の各種薬理試験の方法及 び結果について説明する。  Next, methods and results of various pharmacological tests of compound 13 (sialyldexamethasone) of the present invention will be described.
試験例 1 アルザス反応に対する作用 Test Example 1 Effect on Alsace reaction
実験材料および方法  Experimental materials and methods
1 ) 実験動物  1) Laboratory animals
ハートレイ系雄性モルモットは SLCより購入し、 1週間予備飼育した後、 実 験に用いた。 なお、 動物は 23± 1°C、 湿度 5 5 ±5%の動物室で飼育し、 固形 飼料 （RG— RO；オリエンタル酵母） と水は自由摂取させた。  Hartley male guinea pigs were purchased from SLC and preliminarily reared for one week before use in experiments. The animals were kept in an animal room at 23 ± 1 ° C and a humidity of 55 ± 5%, and were allowed free access to solid feed (RG-RO; oriental yeast) and water.
2 ) 使用薬物  2) Drugs used
シァリルデキサメタゾン (化合物 1 3及び 1 4)、 デキサメタゾン (和光純薬） 、 デキサン （メタスルホ安息香酸デキサメタゾンナトリウム；富士製薬工業） 3) 実験方法  Sialyldexamethasone (compounds 13 and 14), dexamethasone (Wako Pure Chemical Industries), dexane (dexamethasone sodium metasulfobenzoate; Fuji Pharma Co., Ltd.) 3) Experimental method
25 0 g前後のモルモッ 卜に、 抗ォバルブミンゥサギ血清 2.5ml ¼を静脈内 に投与することにより感作した。 その 3 0分後に、 0.0 2 5mおよび 0.0 5 Omg を含むォバルブミン溶液 0. 0 5 mlを前日剪毛しておいた腹部に各 2力所ずつ計 4 力所皮内投与し反応を惹起した。抗原投与し 2時間後の各刺激部位における出血 の面積を測定し反応の程度の指標とした。薬物は抗原投与の 1， 2 , 4， 6時間 前にそれぞれ静脈内投与あるいは皮下投与した。 Sensitization was performed by intravenously administering anti-ovalbumin (2.5 ml) of anti-ovalbumin to about 250 g of guinea pig. 30 minutes later, 0.025m and 0.05 Omg The ovalbumin solution containing 0.05 ml was intradermally administered to the abdomen, which had been shaved the day before, at two sites at a total of four sites to induce a reaction. The area of bleeding at each stimulation site 2 hours after the antigen administration was measured and used as an index of the degree of reaction. Drugs were administered intravenously or subcutaneously 1, 2, 4 and 6 hours before antigen administration, respectively.
4 ) 実験結果  4) Experimental results
シァリルデキサメタゾン （α体） （化合物 1 3 ) 静脈内投与は 1， 2 , 4 , 6 時間前投与でそれぞれ 4 0、 7 6、 5 9及び 5 3 %、 すなわち、 2時間前投与で 最も強く抑制し、 デキサメタゾン ( 1， 2， 4 , &時間前投与でそれぞれ 2 0、 3 0、 6 3及び 5 7 %抑制） の 4時間前皮下投与と同程度であった。  Sialyldexamethasone (alpha form) (Compound 13) Intravenous administration at 40, 76, 59, and 53% at 1, 2, 4, and 6 hours before administration, ie, the strongest at 2 hours before administration 4 hours before subcutaneous administration of dexamethasone (20, 30, 60, 63, and 57% inhibition at 1, 2, 4, & hour pre-dose, respectively).
シァリルデギサメタゾン （yS体） （化合物 1 4 ) は 1、 2、 4、 6時間前静脈 内投与で 2 2、 3 9、 4 1及び 3 6 %抑制した。  Sialyl degisamethasone (yS form) (compound 14) was inhibited by 22, 39, 41 and 36% by intravenous administration for 1, 2, 4, and 6 hours before.
デキサン静脈内投与は 1時間前投与で約 3 2 %抑制したが、 2、 4、 6時間前 投与での抑制は 2 &、 2 5及び 2 3 %であった。  Intravenous administration of dexane reduced approximately 32% 1 hour before administration, but 2 & 4, 25 and 23% after 2, 4 and 6 hours.
デキサメタゾンが 4時間前投与で最大の抑制効果を示.したのに対し、 他のデキ サメタゾン誘導体は 1、 2時間前投与で最も強く抑制した。  Dexamethasone showed the greatest inhibitory effect 4 hours before administration, whereas other dexamethasone derivatives showed the strongest inhibition 1 or 2 hours before administration.
5 ) 考察  5) Discussion
デキサンはメタスルホ安息香酸デキサメタゾンナトリゥムを含有する水性 ¾ 液であり、 静脈腿でデキサメタゾンと同様広範な疾患に一適応できる。 しかし、 ァルサス反応における効力はデキサメタゾンと比べかなり弱いものであった （デ キサメタゾンの約 1 / 2 ) o これに対し、 シァリルデキサメタゾン （ 体） は 2 時間前投与での抑制効果がデキ^タゾンの 4時間前投与の效果と同程度であり、 デキサンよりも効力が強いことが示された。  Dexane is an aqueous solution containing dexamethasone sodium metasulfobenzoate, and can be applied to a wide range of diseases in the venous thigh as well as dexamethasone. However, the efficacy in the alsus reaction was considerably weaker than that of dexamethasone (approximately 1/2 of dexamethasone). In contrast, sialyldexamethasone (body) had an inhibitory effect of dexamethasone 2 hours before administration. The effect was similar to that of the administration 4 hours before, indicating that the effect was stronger than that of dexane.
このように、 シァリルデキサメ夕ゾンはデキサメ夕ゾンの効力を増強はしなか つたものの、他の水性デキサメタゾン誘導体よりも強い効果を有する有用な化合 物であることがわかった。 試験例 2 力ラゲニン足踱浮腫（抗炎症）  Thus, it was found that sialyl dexamethasone was a useful compound having a stronger effect than other aqueous dexamethasone derivatives, although it did not enhance the efficacy of dexamethasone. Test Example 2 Power lagenin foot edema (anti-inflammatory)
デ サメタゾン及びデキサメタゾン誘導体の抗炎症作用の効力比較をするため に代表的な炎症モデルである力ラゲニン足躕浮腫に対する作用を検討した。  In order to compare the efficacy of the anti-inflammatory effect of desamethasone and a dexamethasone derivative, the effect of a representative inflammation model on the force-lagenin foot edema was examined.
I 4 体重 2 0 0 g前後のラットを用い、 左皿足の容積を測定した後、 起炎物質と して 1 %ス一力ラゲニン溶液 0 . l mlを左後肢足跛に皮下投与して浮腫を惹起し た。 6時間後の足の容積を測定し、 浮腫率を算出し、 生理食塩水投与群に対する 抑制率を算出した。 被験薬は起炎物質投与と同時に皮下又は静脈内投与した。 シァリルデキサメタゾン （化合物 1 3 ) はリン酸デキサメ夕ゾンの約 1 / 1 0、 メ夕スルホ安息香酸デキサメタゾンの約 1 / 3の効力であつた。 I 4 Using a rat weighing about 200 g, measure the volume of the left paw, and subcutaneously administer 0.1 ml of a 1% sulphurous lagenin solution as a proinflammatory substance to the left hind paw to cause edema. Evoked. Six hours later, the paw volume was measured, the edema rate was calculated, and the inhibition rate for the saline administration group was calculated. The test drug was administered subcutaneously or intravenously at the same time as the administration of the inflammatory substance. Sialyl dexamethasone (compound 13) was about 1/10 the potency of dexamethasone phosphate and about 1/3 that of dexamethasone benzoate.
、 試験例 3 力ラゲニン肉芽腫 （抗炎症） , Test Example 3 Power lagenin granuloma (anti-inflammatory)
デキサメ夕ゾン誘導体の抗炎症作用の効力比較をするために肉芽腫形成に対す る作用を検討した。  In order to compare the efficacy of the dexamethasone derivative to the anti-inflammatory effect, the effect on granuloma formation was examined.
体重 1 0 0〜1 2 0 gのラットを 1群 6匹として使用した。 エーテル麻酔下に ラットの背部皮下に 8 mlの空気を注入し、 翌日起炎物質として 2 %ス一力ラゲ二 ン 4 mlを注入した。 被験薬は力ラゲニン注入後 5、 6、 7日に静脈内投与した。 8日目に放血致死させ肉芽囊を注意深く剥離し、 内容物の浸出液量及び肉芽腫の 重量を測定し、 生理食塩水投与群に対する抑制率を算出した。  Rats weighing 100-120 g were used as 6 rats per group. Under ether anesthesia, 8 ml of air was injected subcutaneously into the back of the rat, and the next day, 4 ml of 2% sulphuragegen was injected as an inflammation substance. The test drug was administered intravenously on days 5, 6, and 7 after infusion of Keragenin. On the 8th day, the animals were exsanguinated and killed, and the granulation was carefully peeled off, the amount of the exudate of the contents and the weight of the granuloma were measured, and the inhibition rate with respect to the physiological saline administration group was calculated.
シァリルデキサメ夕ゾン （化合物 1 3 ) はリン酸デキサメ夕ゾンの 1ノ 5〜 1 ノ 3程度の効力であった。 試験例 4 P C A反応 （同種 P C A反応） ( I型ァレルギ一）  Sialyl dexamethasone (compound 13) was about 1-5 to 1-3 of dexamethasone phosphate. Test Example 4 PCA reaction (same type PCA reaction) (Type I allergic)
デキサメタゾン誘導体の I型ァレルギ一に対する効力比較をするために典型的 な I型ァレルギ一のモデルである P C A反応に対する作用を検討した。  In order to compare the efficacy of the dexamethasone derivative against type I allergy, the effect on the PCA reaction, which is a typical model of type I allergy, was examined.
抗ォバルブミン I g E抗体を含む抗血清を前日剪毛しておいたラット背部に 0. l ml皮内投与して受動的に感作した。 感作 4 8時間後に抗原 （ォバルブミン、 2 5 mg/kg) 及びエバンスブルー （1 2 . 5 mg/kg) を静脈内投与 ( 5 ml/kg) し、 P C A反応を惹起させた。 3 0分後に放血後、 皮膚を剥離して内部の反応部 位の面積を測定した。被験薬は抗原チャレンジ 3時間前に投与した。  An antiserum containing anti-ovalbumin IgE antibody was passively sensitized by intradermally administering 0.1 ml of the antiserum to the back of a rat shaved the day before. 48 hours after the sensitization, an antigen (ovalbumin, 25 mg / kg) and Evans blue (12.5 mg / kg) were intravenously administered (5 ml / kg) to induce a PCA reaction. After blood release 30 minutes later, the skin was peeled off and the area of the reaction site inside was measured. The test drug was administered 3 hours before the antigen challenge.
シァリルデキサメ夕ゾン （化合物 1 3 ) はリン酸デキサメタゾンの約 1 / 1 0、 メタスルホ安息香酸デキサメ夕ゾンの約 3倍の効力であった。 試験例 5 フォルスマン （Forssman) 反応 （気道抵抗法） （Π型ァレルギ一） デキサメタゾン誘導体の II型ァレルギ一に対する効力比較をするためにフオル スマン反応 （気道抵抗法） に対する作用を検討した。 Sialyl dexamethasone (Compound 13) was about 1/10 the potency of dexamethasone phosphate and about 3 times as potent as dexamethasone metasulfobenzoate. Test Example 5 Forssman reaction (airway resistance method) (Type II allergic method) In order to compare the efficacy of dexamethasone derivatives against type II allergic method, the effect on the Forssman reaction (airway resistance method) was examined.
モルモットをペントバルビタールで麻酔し、 気管に Y字型力ニューレを揷入し て 1分間に 7 0回の頻度で人工呼吸を行つた。 1回の送気量は 3. 5〜4. 5 ιπ1、 送 気圧は 1 0 cm H20とした。 力ニューレの側枝は水槽に導き、 1 0 cm H20に打ち勝 つて出てくる余剰空気をニュ一モタコグラフ （pneumotachograph) を介して流速 としてとらえ、 インテグレータを用いて流量に換算した。 フォルスマン抗血清は 生理 Tiで 5倍希釈し、 体重 1 0 0 g当たり 0 . 1 mlを静脈内に注射して反応 を惹起した。被験薬はフォルスマン抗血清投与 1時間前に静脈内投与した。 Guinea pigs were anesthetized with pentobarbital, and a trachea was inserted with a Y-shaped force neurator, and artificial respiration was performed 70 times a minute. Air supply amount of one time 3. 5~4. 5 ιπ1, the feed pressure was 1 0 cm H 2 0. Power collaterals Nyure leads to the aquarium, 1 0 captured cm H 2 0 in the excess air come out out Winning connexion as flow rate through the news one Motakogurafu (pneumotachograph), was converted to a flow rate by using the integrator. Forssman antiserum was diluted 5-fold with physiological Ti, and 0.1 ml / 100 g body weight was injected intravenously to elicit a reaction. The test drug was administered intravenously 1 hour before the administration of Forssman antiserum.
シァリルデキサメタゾン （化合物 1 3 ) 及びリン酸デキサメタゾンともに I mg /kgでフォルスマン反応を抑制した。 試験例 6 受身ァルサス反応 （モルモット）  Both sialyl dexamethasone (compound 13) and dexamethasone phosphate suppressed the Forssman reaction at Img / kg. Test Example 6 Passive Alsus Reaction (guinea pig)
デキサメタゾン誘導体の III型アレルギーに対する効力比較をするために典型 的な III型ァレルギ一のモデルであるアルザス反応に対する作用を検討した。 体重 2 5 0 g前後のモルモルツトに、 抗ォバルブミンゥサギ血清 2. 5 mlZkgを 静脈内に投与することにより感作した。 その 3 0分後に、 0. 0 2 5 mg及び 0. 0 5 O mgを含むォバルブミン溶液 0. 0 5 0 mlを前日剪毛しておいた腹部に各 2力所ず つ計 4力所皮内投与し反応を惹起した。抗原投与 2時間後の各刺激部位における 発赤面積を測定し反応の程度の指標とした。被験薬は抗原投与 3時間前に静脈内 投与した。  In order to compare the efficacy of dexamethasone derivatives against type III allergy, the effect on the Alsace reaction, which is a typical model of type III allergy, was examined. The rats were sensitized by intravenously administering 2.5 ml Zkg of anti-ovalbumin / heron serum to molmolts weighing about 250 g. Thirty minutes later, 0.0250 ml of an ovalbumin solution containing 0.025 mg and 0.05 Omg was applied to the abdomen, which had been shaved the day before, at two sites each, for a total of four sites. The administration elicited a response. The area of redness at each stimulation site 2 hours after antigen administration was measured and used as an index of the degree of reaction. The test drug was administered intravenously 3 hours before the antigen administration.
シァリルデキサメタゾン （化合物 1 3 )"はリン酸デキサメタゾン、 メタスルホ 安息香酸デキサメ夕ゾンの約 1 0倍の効力であつた。 試験例 7 受身ァルサス反応（ラット） （III型ァレルギ一）  Sialyldexamethasone (Compound 13) "was about 10 times as potent as dexamethasone phosphate and dexamethasone metasulfobenzoate. Test Example 7 Passive Alsus Reaction (Rat) (Type III Allergic I)
デキサメタゾン誘導体の III型アレルギーに対する効力比較をするために典型 的な III型アレルギーのモデルであるァノレサス反応に対する作用を検討した。 体重 1 5.0 g前後のラッ卜に抗ォバルブミンゥサギ血清 0. 5 mlZ l 5 0 gを静 脈内に投与することにより感作した。 その 3 0分後に、 ォバルブミン溶液 0.025mg/0.1mlを左側足躕皮下に注射してアルザス反応を惹起させた。 抗原 投与後 2〜 5時間後の足の容積を測定し、 生理食塩水投与群に対する抑制率を算 出した。 被験薬は静脈内投与した。 In order to compare the efficacy of dexamethasone derivatives against type III allergy, the effect on the anoresus reaction, which is a typical model for type III allergy, was examined. 0.5 ml Zl 50 g of anti-ovalbumin and heron serum was added to a rat weighing about 15.0 g. It was sensitized by intravenous administration. Thirty minutes later, 0.025 mg / 0.1 ml of ovalbumin solution was injected subcutaneously into the left foot to induce an Alsace reaction. The volume of the paw 2 to 5 hours after the antigen administration was measured, and the inhibition rate with respect to the physiological saline administration group was calculated. The test drug was administered intravenously.
シァリルデキサメタゾン （化合物 13 ) はリン酸デキサメ夕ゾンの約 1 3の 効力であった。 試験例 8 遅延型接触性皮膚反応 （IV型アレルギー） （細胞性免疫）  Sialyldexamethasone (compound 13) was about 13 more potent than dexamethasone phosphate. Test Example 8 Delayed Contact Skin Reaction (Type IV Allergy) (Cellular Immunity)
デキサメタゾン誘導体の IV型アレルギーに対する効力比較をするために IV型ァ レルギ一のモデルである接触性皮膚炎に対する作用を検討した。  In order to compare the efficacy of dexamethasone derivatives against type IV allergy, the effect of dexamethasone on contact dermatitis, a model of type IV allergy, was examined.
I CR系雄性マウスを用い、 剪毛したマウスの腹部に、 7%塩ィ匕ピクリノレ.ァ セトン容液 0. 1mlを塗布し感作した。 6日後に右耳に 7%塩化ピクリル.ァセ トン容液 1 0 1を塗布し、 皮膚炎を惹起した。 反応惹起 24時間後に耳介の一 部をパンチしその重量を測定した。被験薬は抗原投与 1時間前に尾静脈内より投 与した。  Using an ICR male mouse, 0.1 ml of a 7% Shiridani picrinole.aceton solution was applied to the abdomen of the shaved mouse to sensitize the mouse. Six days later, a 7% picryl chloride acetate solution 101 was applied to the right ear to induce dermatitis. 24 hours after the induction of the reaction, a part of the pinna was punched and its weight was measured. The test drug was administered via the tail vein one hour before the antigen administration.
シァリルデキサメタゾン （化合物 13) は lingZkgから抑制効果 （約 22%) が認められたのに対し、 リン酸デキサメタゾンは lmgZkgでは効果は認められな かった。 1 Omg/kgでは両薬物ともほぼ同程度の抑制効果 （約 50%) が認めら れた。 試験例 9 免疫抑制作用 （液性免疫抑制作用）  Sialyldexamethasone (compound 13) showed an inhibitory effect (about 22%) from lingZkg, whereas dexamethasone phosphate had no effect at lmgZkg. At 1 Omg / kg, both drugs showed almost the same inhibitory effect (about 50%). Test Example 9 Immunosuppressive action (humoral immunosuppressive action)
デキサメタゾン誘導体の液性免疫に対する効力を比較するために P F C産生に 対する作用を検討した。  In order to compare the efficacy of the dexamethasone derivative on humoral immunity, the effect on PFC production was examined.
7週令の DBA/2マウスに 10%ヒッジ赤血球 (SRBC) 0.2mlを静脈内に投 与して免疫した。 免疫 4日後に脾臓を摘出し、 単細胞浮遊液とし、 2.5 X106 Cells/mlに調製した。試験管に細胞浮遊液 0.8mし 50%SRBC0. lmし 乾燥補体 0.1mlを混合し、 カニンガムチャンバ一に注入した。 37°Cで 1時間インキュべ ートした後、 溶血班 （プラーク） を数えて脾細胞数 1 06 個当たりの PFC数及 び総 PFC数を算出した。 被験薬は免疫日より 4日間、 皮下投与した。 リン酸デキサメタゾン及びメタスルホ安息香酸デキサメタゾンは 0. 0 1 mg/ g から液性免疫の抑制が認められたのに対し、 シァリルデキサメタゾン （化合物 1 3 ) は 1 mgZkgから抑制効果が認められた。 （感染症誘癸等に関与する液性免 疫抑制作用は弱いと考える） 試験例 1 0 簡易急性毒性試験 Seven-week-old DBA / 2 mice were immunized intravenously with 0.2 ml of 10% shedding red blood cells (SRBC). Four days after the immunization, the spleen was excised, used as a single cell suspension, and adjusted to 2.5 × 10 6 cells / ml. 0.8 m of the cell suspension was added to a test tube, 50% of SRBC was added to 0.1 ml, and 0.1 ml of dried complement was mixed and injected into the Cunningham chamber. After 1 hour incubator base over preparative 37 ° C, it was calculated PFC number及BiSo PFC number of splenocytes Number 1 0 6 per count the hemolytic plaque (plaque). The test drug was administered subcutaneously for 4 days from the day of immunization. Dexamethasone phosphate and dexamethasone metasulfobenzoate inhibited humoral immunity at 0.01 mg / g, whereas sialyl dexamethasone (Compound 13) exhibited an inhibitory effect at 1 mgZkg. (It is thought that the effect of suppressing humoral immunity related to infectious disease induction is weak.) Test Example 10 Simple acute toxicity test
デキサメタゾン誘導体の急性毒性を比較するために簡易急性毒性試験をした。 雄マウスの静脈より生理^水に溶解した薬物を 1回投与し、 これを第 1日目と して毎日体重測定及び症状観察を行い、 投与 7 2時間後に生死の判定を行った。 また、 生存して ヽる動物においては弓 Iき鐃き一週間後まで体重測定及び症状観察 を行った。  A simple acute toxicity test was performed to compare the acute toxicity of dexamethasone derivatives. One dose of a drug dissolved in physiological water was administered once from the vein of a male mouse, and on the first day, body weight was measured and symptoms were observed daily, and survival was determined 72 hours after administration. In addition, in surviving animals, body weight measurement and symptom observation were performed until one week after the bowing of the animals.
リン酸デキサメタゾンが 1 8 0 0 mg/kgv メタスゾ ホ安息香酸デキサメタゾン が 8 0 0 mgZkgでそれぞれ 1 0 0 %死亡した。一方シァリルデキサメタゾン （化 合物 1 3 ) は 4 0 ϋ O mgZkg投与で 1例死亡し、 投与直後の動物に運動停止が見 られたが数分後に回復し、 3 0 0 0 mgXkg. 2 0 0 0 mg/kg. 1 0 0 0 mgZkg投 与では全く影響を及ぼさなかった。 リン酸デキサメタゾン 1 2 0 0 mg/kg. 9 0 O mgZkg投与では投与直後の動物に運動停止、 眼瞼下垂か'見られ、 5時間後 の "^症状において運動性が低下していた。 メダスルホ安息香酸デキサメタゾン 4 0 O mgZkgにおいて投与 3 0分後に 2例痙攣を起した後死亡し、 3 0 O mg/kg で尾の壊死が見られた。 さらに体重はリン酸デキサメタゾン 1 2 0 O mgZkgで減 少したのに対しシァリルデキサメタゾン （化合物 1 3 ) 3 0 0 0 mg ¾では変化 はなかった。  Dexamethasone phosphate was 180 mg / kgv and dexamethasone methazozobenzoate died 100% at 800 mgZkg, respectively. On the other hand, sialyldexamethasone (compound 13) died in one subject after administration of 40 mg OmgZkg, and the animals immediately after administration had stopped exercising, but recovered several minutes later, and recovered 300 mgXkg. There was no effect at 100 mg / kg. After administration of dexamethasone phosphate at 1200 mg / kg. 90 OmgZkg, the animals immediately after administration showed cessation of movement, ptosis, and decreased motility in the "^ symptoms 5 hours later. Medasulfobenzoic acid Dexamethasone acid at 40 O mgZkg 30 minutes after administration, 2 patients died after convulsions, tail necrosis was observed at 30 Omg / kg, and body weight was reduced by dexamethasone phosphate at 120 OmgZkg. In contrast, there was no change with 3,000 mg of sialyldexamethasone (compound 13).

Claims

請求の範囲 The scope of the claims
1. 下記の一般式 （I)又は （II) で表されるシァリルステロイド又はその塩: 1. A sialyl steroid represented by the following general formula (I) or (II) or a salt thereof:
Figure imgf000021_0001
Figure imgf000021_0002
式中 R1 は下記の式 （111)、 (IV)又は （V) で表されるステロイド残基で あり、 R2 は氷素原子又はァセチノレ基であり、 R3 は 原子又は低級アルキ ル基である。
Figure imgf000021_0001
Figure imgf000021_0002
In the formula, R 1 is a steroid residue represented by the following formula (111), (IV) or (V), R 2 is a chromium atom or an acetylino group, and R 3 is an atom or a lower alkyl group. It is.
CH，一
Figure imgf000021_0003
Figure imgf000022_0001
CH, one
Figure imgf000021_0003
Figure imgf000022_0001
Figure imgf000022_0002
Figure imgf000022_0002
2. —般式 （I ) で表されるシァリルステロイドであって、 R1 力式 （III)で表 されるステロイド残基であり、 R2 がァセチノレ基であり、 R 3 がメチル基であ る請求項 1記載のシァリルステロィド又はその塩。 ― 2. —A sialyl steroid represented by the general formula (I), R 1 is a steroid residue represented by the formula (III), R 2 is an acetinol group, and R 3 is a methyl group. The sialyl steroid according to claim 1, or a salt thereof. ―
3. "^式 （II) で表されるシァリルステロイドであって、 R1 力式 （ΠΙ)で表 されるステロイド残基であり、 R2 がァセチル基であり、 R3 がメチル基であ る請求項 1記載のシァリルステロイド又はその塩。 3. "^ A sialyl steroid represented by the formula (II), R 1 is a steroid residue represented by the formula (ΠΙ), R 2 is an acetyl group, and R 3 is a methyl group. 2. The sialyl steroid according to claim 1, or a salt thereof.
4. 一般式 （I ) で表されるシァリルステロイドであって、 R 1 が式 （III)で表 されるステロイド残基であり、 R2 が水素原子であり、 R3 力ナトリウム原子 である請求項 1記載のシァリゾレステロイド又はその塩。 4. A sialyl steroid represented by the general formula (I), wherein R 1 is a steroid residue represented by the formula (III), R 2 is a hydrogen atom, and R 3 is a sodium atom. 2. The schizoresteroid according to claim 1, or a salt thereof.
5. —般式（II) で表されるシァリルステロイドであって、 R1 力式 （ΙΠ)で表 されるステロイド残基であり、 R2 が水素原子であり、 R3 がナトリウム原子 である請求項 1記載のシァリルステロィド又はその塩。 5. —Sialyl steroid represented by the general formula (II), R 1 is a steroid residue represented by the formula (ΙΠ), R 2 is a hydrogen atom, and R 3 is a sodium atom The sialyl steroid or a salt thereof according to claim 1, which is:
6. 一般式 ( I ) で表されるシァリルステロイドであって、 R 1 が式 （IV) で表 されるステロイド残基であり、 R2 がァセチル基であり、 R3 がメチル基であ る請求項 1記載のシァリルステロィド又はその塩。 6. A sialyl steroid represented by the general formula (I), wherein R 1 is a steroid residue represented by the formula (IV), R 2 is an acetyl group, and R 3 is a methyl group. The sialyl steroid according to claim 1, or a salt thereof.
7. 一般式 (II) で表されるシァリルステロイドであって、 R 1 が式 （IV) で表 されるステロイド残基であり、 R2 がァセチル基であり、 R3 がメチル基であ る請求項 1記載のシァリルステロィド又はその塩。 7. A sialyl steroid represented by the general formula (II), wherein R 1 is a steroid residue represented by the formula (IV), R 2 is an acetyl group, and R 3 is a methyl group. The sialyl steroid according to claim 1, or a salt thereof.
8. —般式 （I ) で表されるシァリルステロイドであって、 R 1 が式 （IV) で表 されるステロイド残基であり、 R2 が水素原子であり、 R3 がナトリウム原子 である請求項 1記載のシァリルステロイド又はその塩つ 8. A sialyl steroid represented by the general formula (I), wherein R 1 is a steroid residue represented by the formula (IV), R 2 is a hydrogen atom, and R 3 is a sodium atom. 2. The sialyl steroid according to claim 1, or a salt thereof.
9. 一般式 (II) で表されるシァリルステロイドであって、 R 1 が式 （IV) で表 されるステロイド残基であり、 R2 が水素原子であり、 R3 がナトリウム原子 である請求項 1記載のシァリルステロイド又はその塩。 9. A sialyl steroid represented by the general formula (II), wherein R 1 is a steroid residue represented by the formula (IV), R 2 is a hydrogen atom, and R 3 is a sodium atom 2. The sialyl steroid according to claim 1, or a salt thereof.
10. 一般式 （I ) で表されるシァリルステロイドであって、 R 1 が式 （V) で表 されるステロイド残基であり、 R2 がァセチル基であり、 R3 がメチル基であ る請求項 1記載のシァリルステロィド又はその塩。 10. A sialyl steroid represented by the general formula (I), wherein R 1 is a steroid residue represented by the formula (V), R 2 is an acetyl group, and R 3 is a methyl group. The sialyl steroid according to claim 1, or a salt thereof.
11. 一般式 （II) で表されるシァリルステロイドであって、 R 1 が式 （V) で表 されるステロイド残基であり、 R2 がァセチル基であり、 R3 カ チノレ基であ る請求項 1記載のシァリルステロイド又はその塩。 11. A sialyl steroid represented by the general formula (II), wherein R 1 is a steroid residue represented by the formula (V), R 2 is an acetyl group, and R 3 is a cation group. The sialyl steroid according to claim 1, or a salt thereof.
12. 一般式 （IJ で表されるシァリルステロイドであって、 R 1 が式 （V) で表 されるステロイド残基であり、 R2 が水素原子であり、 R3 がナートリウム原子 である請求項 1記載のシァリルステロィド又はその塩。 12. A compound of the formula (IJ, wherein R 1 is a steroid residue represented by the formula (V), R 2 is a hydrogen atom, and R 3 is a sodium atom. Item 6. The sialyl steroid or a salt thereof according to Item 1.
13. 一般式 (II) で表されるシァリルステロイドであって、 R 1 が式 （V) で表 されるステロイド残基であり、 R2 が水素原子であり、 R3 がナトリウム原子 である請求項 1記載のシァリルステロイド又はその塩。 13. A sialyl steroid represented by the general formula (II), wherein R 1 is a steroid residue represented by the formula (V), R 2 is a hydrogen atom, and R 3 is a sodium atom 2. The sialyl steroid according to claim 1, or a salt thereof.
PCT/JP1993/000466 1992-04-13 1993-04-13 Novel sialylsteroid WO1993021198A1 (en)

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JP4/92953 1992-04-13

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WO2001051057A2 (en) * 2000-01-14 2001-07-19 Strakan Limited Glycosides and orthoester glycosides of glucocorticoids and uses thereof
CN114891057A (en) * 2022-05-26 2022-08-12 沈阳药科大学 Sialic acid derivative modified compound and synthesis method and application thereof

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001051057A2 (en) * 2000-01-14 2001-07-19 Strakan Limited Glycosides and orthoester glycosides of glucocorticoids and uses thereof
WO2001051057A3 (en) * 2000-01-14 2002-03-21 Strakan Group Plc Glycosides and orthoester glycosides of glucocorticoids and uses thereof
CN114891057A (en) * 2022-05-26 2022-08-12 沈阳药科大学 Sialic acid derivative modified compound and synthesis method and application thereof
CN114891057B (en) * 2022-05-26 2023-10-17 沈阳药科大学 Sialic acid derivative modified compound and synthesis method and application thereof

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