JPH0193529A - Remedy of sialosylcholesterol for demyelinating disease - Google Patents
Remedy of sialosylcholesterol for demyelinating diseaseInfo
- Publication number
- JPH0193529A JPH0193529A JP25119887A JP25119887A JPH0193529A JP H0193529 A JPH0193529 A JP H0193529A JP 25119887 A JP25119887 A JP 25119887A JP 25119887 A JP25119887 A JP 25119887A JP H0193529 A JPH0193529 A JP H0193529A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- compound
- compound shown
- sialosylcholesterol
- demyelinating diseases
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 208000016192 Demyelinating disease Diseases 0.000 title claims abstract description 14
- 239000003814 drug Substances 0.000 claims description 8
- 238000011282 treatment Methods 0.000 claims description 6
- 229940124597 therapeutic agent Drugs 0.000 claims description 5
- 229940079593 drug Drugs 0.000 claims description 3
- 238000010253 intravenous injection Methods 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- 239000003889 eye drop Substances 0.000 claims description 2
- 229940012356 eye drops Drugs 0.000 claims description 2
- 238000010255 intramuscular injection Methods 0.000 claims description 2
- 239000007927 intramuscular injection Substances 0.000 claims description 2
- 239000007923 nasal drop Substances 0.000 claims description 2
- 229940100662 nasal drops Drugs 0.000 claims description 2
- 238000010254 subcutaneous injection Methods 0.000 claims description 2
- 239000007929 subcutaneous injection Substances 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 abstract description 30
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 abstract description 6
- 239000011734 sodium Substances 0.000 abstract description 6
- 229910052708 sodium Inorganic materials 0.000 abstract description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 abstract description 3
- 235000012000 cholesterol Nutrition 0.000 abstract description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 abstract description 2
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 2
- 239000001257 hydrogen Substances 0.000 abstract description 2
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 abstract description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract 1
- 238000006945 Knorr synthesis reaction Methods 0.000 abstract 1
- NASRDENTZCCAPN-UHFFFAOYSA-N OC([Na])=O Chemical compound OC([Na])=O NASRDENTZCCAPN-UHFFFAOYSA-N 0.000 abstract 1
- 239000003054 catalyst Substances 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 238000002360 preparation method Methods 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000000243 solution Substances 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 5
- 239000011347 resin Substances 0.000 description 5
- 229920005989 resin Polymers 0.000 description 5
- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 201000002491 encephalomyelitis Diseases 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- 241000700199 Cavia porcellus Species 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 231100000215 acute (single dose) toxicity testing Toxicity 0.000 description 2
- 238000011047 acute toxicity test Methods 0.000 description 2
- 230000000172 allergic effect Effects 0.000 description 2
- 208000010668 atopic eczema Diseases 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- DTGDZMYNKLTSKC-HKQCOZBKSA-N cholest-5-ene Chemical compound C1C=C2CCCC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 DTGDZMYNKLTSKC-HKQCOZBKSA-N 0.000 description 2
- DTGDZMYNKLTSKC-UHFFFAOYSA-N cholest-5-ene Natural products C1C=C2CCCCC2(C)C2C1C1CCC(C(C)CCCC(C)C)C1(C)CC2 DTGDZMYNKLTSKC-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000000921 elemental analysis Methods 0.000 description 2
- 238000000434 field desorption mass spectrometry Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 201000006417 multiple sclerosis Diseases 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000007127 saponification reaction Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 208000032116 Autoimmune Experimental Encephalomyelitis Diseases 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 229930186217 Glycolipid Natural products 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010021639 Incontinence Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 238000006994 Koenigs-Knorr glycosidation reaction Methods 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 208000003926 Myelitis Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 206010033799 Paralysis Diseases 0.000 description 1
- 101710093543 Probable non-specific lipid-transfer protein Proteins 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- SQVRNKJHWKZAKO-UHFFFAOYSA-N beta-N-Acetyl-D-neuraminic acid Natural products CC(=O)NC1C(O)CC(O)(C(O)=O)OC1C(O)C(O)CO SQVRNKJHWKZAKO-UHFFFAOYSA-N 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 239000007809 chemical reaction catalyst Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 210000003414 extremity Anatomy 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 108091008039 hormone receptors Proteins 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 210000003141 lower extremity Anatomy 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 229920001542 oligosaccharide Polymers 0.000 description 1
- 150000002482 oligosaccharides Chemical class 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- SQVRNKJHWKZAKO-OQPLDHBCSA-N sialic acid Chemical compound CC(=O)N[C@@H]1[C@@H](O)C[C@@](O)(C(O)=O)OC1[C@H](O)[C@H](O)CO SQVRNKJHWKZAKO-OQPLDHBCSA-N 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 201000008827 tuberculosis Diseases 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
〔産業上の利用分野〕
本発明は、神経を侵す難病の１つで、世界的に最も関心
をもたれている、脱髄性疾患の治療に有用な薬剤として
のシアロシルコレステロールに関する。[Detailed Description of the Invention] [Industrial Application Field] The present invention provides sialolysis as a drug useful for the treatment of demyelinating disease, which is one of the incurable diseases that affect the nerves and is of greatest interest worldwide. Concerning sylcholesterol.
多発性硬化症をはじめとする脱髄性疾患は、難治のもの
が多く、免疫療法等の治療法も未だ研究段階で、早急に
治療薬の開発が望まれている。Many demyelinating diseases, including multiple sclerosis, are difficult to treat, and treatments such as immunotherapy are still in the research stage, and there is an urgent need for the development of therapeutic drugs.
脱髄性疾患のモデルには、実験的アレルギー性脳を髄炎
（ＥＡＥ）がある。これは、中枢神経系組織を抗原とし
て中枢神経系に特異的に引き起こされる自己免疫性疾患
であり、重要な疾患モデルとして近年注目を集めている
。A model for demyelinating disease is experimental allergic encephalomyelitis (EAE). This is an autoimmune disease that is specifically caused in the central nervous system using central nervous system tissue as an antigen, and has recently attracted attention as an important disease model.
このようなＥＡＥ過程の制御機構ならびに関与因子の解
明は、多発性硬化症を含め自己アレルギーを基盤とし、
今日深刻な社会問題となっているアレルギー性脱髄性疾
患の治療につながるといえる。Elucidation of the control mechanism and factors involved in the EAE process is based on self-allergy, including multiple sclerosis, and
This can be said to lead to the treatment of allergic demyelinating diseases, which are a serious social problem today.
ところで、シアル酸は、動物或いは細菌の細胞表面にシ
アロ複合体く糖蛋白、糖脂質、オリゴ糖、多糖類等〉と
共に特異的な活性分子として存在し、近年免疫、癌、炎
症、ウィルス感染、細胞分化、ホルモン受容体等に関与
する物質として、医学的且つ薬理学的に注目されつつあ
るが、シアロシルコレステロールが脱髄性疾患治療とし
ての有用性を有することについては現在まで知られてい
なかった。By the way, sialic acid exists as a specific active molecule along with sialocomplexes, glycoproteins, glycolipids, oligosaccharides, polysaccharides, etc., on the cell surface of animals or bacteria, and has recently been used in immunology, cancer, inflammation, viral infections, etc. Sialosylcholesterol is attracting medical and pharmacological attention as a substance involved in cell differentiation, hormone receptors, etc., but until now it has not been known that sialosylcholesterol is useful as a treatment for demyelinating diseases. Ta.
従って、本発明は、脱髄性疾患の治療に有用なシアロシ
ルコレステロールをナトリウム塩にすることにより、水
溶性を増大させ、医薬品としての用途を拡大した、脱髄
性疾患の治療に有用なシアロシルコレステロールを提供
することを目的とするものである。Therefore, the present invention provides a sodium salt of sialosylcholesterol, which is useful in the treatment of demyelinating diseases, to increase its water solubility and expand its use as a pharmaceutical. The purpose is to provide sylcholesterol.
本発明は、シアロシルコレステロールについて、ＥＡＥ
を発症させたモルモットを用いて、その活性を試験した
ところ、延命効果を有するとの新たな知見に基づくもの
である。The present invention relates to sialosylcholesterol, EAE
This is based on the new finding that it has a life-prolonging effect when its activity was tested using guinea pigs that had developed the disease.
すなわち、本化合物は一般式（Ｉ）：
で表わされるシアロシルコレステロールを含有すること
を特徴とする脱髄性疾患治療剤を提供するものである。That is, the present compound provides a therapeutic agent for demyelinating diseases characterized by containing sialosylcholesterol represented by the general formula (I).
以下、本発明について詳細に説明する。The present invention will be explained in detail below.
本発明において、一般式（Ｉ）または（ＩＩ）で表わさ
れるシアロシルコレステロールの製造は一般に以下のよ
うにして行なわれる。In the present invention, sialosylcholesterol represented by general formula (I) or (II) is generally produced as follows.
式（■）：
で表わされる化合物（ＩＩＩ）をケーニッヒス・クノル
（Ｋｏｅｎ １ｇ５−にｎｏｒｒ）反応用触媒の存在下
にコレステロールと常圧で約２０〜２５℃の温度で、約
２〜７日反応させる。その際、コレステロールは、化合
物（■）１モルに対して約２〜５倍モル用いる。得られ
た反応生成物はカラムクロマトグラフイーなどの常法に
より、単離精製される（特開昭６１−２４３０９６号参
照）。Compound (III) represented by formula (■): is mixed with cholesterol in the presence of a Koenigs-Knorr reaction catalyst at normal pressure at a temperature of about 20 to 25°C for about 2 to 7 days. Make it react. At that time, cholesterol is used in a molar amount approximately 2 to 5 times per mole of compound (■). The obtained reaction product is isolated and purified by a conventional method such as column chromatography (see JP-A-61-243096).
尚、上記化合物（ＩＩＩ）は容易に入手可能な公知化合
物である。Incidentally, the above compound (III) is a known compound that is easily available.
更に、上記生成物を加水分解し、メトキシカルボニル基
をカルボキシルナトリウム基に、アセチル基を水素に変
換し、化合物（Ｉ） （α体）、化合物（■）（β体）
を得る。この工程について、以下に実施例で示す。Furthermore, the above product is hydrolyzed to convert the methoxycarbonyl group into a sodium carboxyl group and the acetyl group into hydrogen, resulting in compound (I) (α form) and compound (■) (β form).
get. This process will be shown in Examples below.
製造例１
３β−旦−（４′−アセタミド−２’、４’−ジデオキ
シ−３’、６’、７’、８’ −テトラ−０−アセチル
−１′−メトキシカルボニル−Ｄ−グリセロ−α−Ｄ−
ガラクトー１′−オクトピラノシル）コレスト−５−エ
ン（化合’ＪｉｌｌＪ （ＩＶ） ’）の５０ｍｇを、
メタノールの１００ｍｊ’に溶かして撹拌しながら２Ｎ
水酸化ナトリウム水溶液の２０ｒｒｆ！弱を滴下して約
０．２Ｎ水酸化ナトリウム／メタノール溶液とし、室温
で一晩撹拌することによりけん化を行なった。Production Example 1 3β-Dan-(4'-acetamide-2', 4'-dideoxy-3', 6', 7', 8'-tetra-0-acetyl-1'-methoxycarbonyl-D-glycero-α -D-
50 mg of galacto-1'-octopyranosyl)cholest-5-ene (compound 'JillJ (IV)'),
Dissolve in 100mj' of methanol and add 2N while stirring.
20rrf of sodium hydroxide aqueous solution! A weak solution was added dropwise to make an approximately 0.2N sodium hydroxide/methanol solution, and saponification was performed by stirring overnight at room temperature.
引き続き、撹拌しながらダウエックス（Ｄｏｗｅｘ）５
０ Ｗ （Ｈ” ） ｒｅｓｉｎを加えていき、溶液の
ｐ）Ｉを酸性（約ｐＨ４）に調整した後、その樹脂を除
き、減圧下乾燥し３β−０−（４’−アセタミド−２’
、４’−ジデオキシ−１′−力ルボキシーＤ−グリセロ
−α−Ｄ−ガラクト−１′−オクトピラノシル）コレス
ト−５−エンとして、白色粉末として得、次にこれらを
それぞれ０．０２Ｎ水酸化ナトリウム水溶液に溶かし、
ダイヤイオン（Ｄｉａｉｏｎ））ＩＰ２０樹脂カラムに
通して吸着させ、水洗後、７５％メタノール水にて溶出
し、メタノールを留去後、凍結乾燥して、ナトリウム３
β−〇−（４′−アセタミド−２’、４’ −ジデオキ
シ−１′−力ルボキシーＤ−グリセロ−α−Ｄ−ガラク
ト−１′−オクトピラノシル）コレスト−５−エナート
（化合物（Ｉ））を白色粉末として得た（３７ｍｇ、９
１％）。Continue to add Dowex 5 while stirring.
After adding 0 W (H") resin and adjusting the p)I of the solution to acidic (about pH 4), the resin was removed and dried under reduced pressure to obtain 3β-0-(4'-acetamide-2'
. Dissolve in
It was adsorbed through a Diaion (Diaion) IP20 resin column, washed with water, eluted with 75% methanol, and after distilling off the methanol, it was lyophilized and sodium 3
β-〇-(4'-acetamido-2',4'-dideoxy-1'-hydroxy-D-glycero-α-D-galacto-1'-octopyranosyl)cholesto-5-enate (compound (I)) Obtained as a white powder (37 mg, 9
1%).
製造例２
化合物（ｒＶ）の５０■を、メタノール１００ｒｄに溶
かして、２Ｎ−水酸化ナトリウム水溶液の２０−を加え
て、室温で一晩撹拌することにより、けん化を行ない、
引き続き、ダウエックス（Ｏｏｗｅｘ）５０ＷＸ８ （
Ｈ” ”）樹脂を加えて撹拌し、溶液のｐＨを７〜８と
した後、吸引ろ過、メタノールで洗浄することにより、
その樹脂を除き、ろ液および洗浄液をまとめて減圧下、
メタノールを留去、析出してきた白色不溶物はろ過後、
ろ液を凍結乾燥することにより、化合物（Ｉ）を白色粉
末として得た（３９ｍｇ、９６％）。Production Example 2 Saponification was carried out by dissolving 50 ml of compound (rV) in 100 ml of methanol, adding 20 ml of 2N aqueous sodium hydroxide solution, and stirring overnight at room temperature.
Continuing, Oowex 50WX8 (
H"") resin was added and stirred to bring the pH of the solution to 7 to 8, followed by suction filtration and washing with methanol.
After removing the resin, the filtrate and washing solution were combined under reduced pressure.
After distilling off methanol and filtering the precipitated white insoluble matter,
Compound (I) was obtained as a white powder by freeze-drying the filtrate (39 mg, 96%).
〔化合物（１）の物理化学的性状〕
ＦＤ−ＭＳ （ｍ／ｚ） ；７２２（Ｍ＋Ｎａ）、７
００（Ｍ＋１）。[Physicochemical properties of compound (1)] FD-MS (m/z); 722 (M+Na), 7
00(M+1).
３８６、３３６．３１４゜
元素分析（％）ＣｓｓＨｓｚＯｓＮＮａ ・２Ｈ２０計
算値：Ｃ，６１，９６； Ｈ，８，４２； Ｎ、 １．
９０゜実測値 Ｃ，６１，９２； Ｈ，８，７１、Ｎ、
２．０４゜〔α］” ：＋２．２° （Ｃ，１，０
メタノール）Ｉ Ｒｖ”’ ａｍ−’ ： ３２５０．
２９４０．１６０５゜’Ｈ−ＮＭＲ（４ＱＯＭＨｚ、
ｉｎ ＣＤ、００） δ Ｈ：０．７０４（
３Ｈ，ｓ、１８−Ｍｅ） ０．９９２（３Ｈ，ｓ、１
９−Ｍｅ）０、９３６ （３Ｈ，ｄ、 Ｊ＝６．５Ｈｚ
、 ２１−！Ｊｅ）０、８７０．０． ［５（３ＨＸ
２． ｄ、 Ｊ＝１．７）１ｚ、 ２６．２７−Ｍｅ）
２、０１０ （３ｔｌ、 ｓ、 ＮＡｃ）２、８３９（
ＩＨ，ｄｄ、 Ｊ＝４．２．１２．０Ｈｚ、 ２’ −
Ｈｅｑ）５、３３２ （ＬＨ，ｄ、 Ｊ＝５．５Ｈｚ、
６−Ｈ）１３ＣＮＭＲ（１００ＭＨｚ、 ｌｎ Ｃ
ＤａＯＤ） δＣ：１７５．９１（ＮＡｃ） １７
５．２６ （１’ −ＣＯＯＮａ）１４２．８７（Ｃ−
５） １２２．５９（Ｃ−９） １０２．５７（Ｃ
−１’）７０．５０（Ｃ−３） ４１．００（Ｃ−
２）製造例３
３β−０−（４’−アセタミド−２’、４’ −ジデオ
キシ−３’ ６’ ？’ ８’ −テトラ−ｐ−
アセチル−１′−メ°トキシカルボニルーＤ−グリセロ
−β−Ｄ−ガラクトー１′−オクトピラノシル）コレス
ト−５−エン（化合物（Ｖ））を化合物（■）゛の代わ
りに用いる他は製造例１と同様に操作し、ナトリウム３
β−０−（４’−アセタミド−２′。386, 336.314° Elemental analysis (%) CssHszOsNNa ・2H20 calculated value: C, 61,96; H, 8,42; N, 1.
90° actual measurement value C, 61, 92; H, 8, 71, N,
2.04゜〔α]”: +2.2° (C, 1, 0
methanol) I Rv"'am-': 3250.
2940.1605°'H-NMR (4QOMHz,
in CD, 00) δ H: 0.704 (
3H,s,18-Me) 0.992(3H,s,1
9-Me) 0,936 (3H, d, J=6.5Hz
, 21-! Je) 0, 870.0. [5(3HX
2. d, J=1.7)1z, 26.27-Me)
2,010 (3tl, s, NAc)2,839(
IH, dd, J=4.2.12.0Hz, 2'-
Heq) 5,332 (LH, d, J=5.5Hz,
6-H) 13CNMR (100MHz, lnC
DaOD) δC: 175.91 (NAc) 17
5.26 (1'-COONa)142.87(C-
5) 122.59 (C-9) 102.57 (C
-1') 70.50 (C-3) 41.00 (C-
2) Production Example 3 3β-0-(4'-acetamide-2',4'-dideoxy-3'6'?'8'-tetra-p-
Production Example 1 except that acetyl-1'-methoxycarbonyl-D-glycero-β-D-galacto-1'-octopyranosyl)cholest-5-ene (compound (V)) was used instead of compound (■). Proceed in the same manner as sodium 3
β-0-(4'-acetamide-2'.
４′−ジデオキシ−１′−力ルボキシー〇−グリセロ−
β−Ｄ−ガラクト−１′−オクトピラノシル〉コレスト
−５−エナート（化合物（■））を得た（３６ｍｇ、８
８％）。4'-dideoxy-1'-hydroxy-glycero-
β-D-galacto-1'-octopyranosyl>cholesto-5-enate (compound (■)) was obtained (36 mg, 8
8%).
製造例４
化合物（ｒＶ）の代わりに化合物（Ｖ）を用いる他は実
施例２と同様に操作し、化合物（Ｉ［）を得た（４０ｍ
ｇ、９８％）。Production Example 4 Compound (I[) was obtained (40m
g, 98%).
ＦＤ−ＭＳ （ｍ／ｚ） ；７２２（Ｍ＋Ｎａ＞、７
００（Ｍ＋１）。FD-MS (m/z); 722 (M+Na>, 7
00(M+1).
３８６゜
元素分析（％）Ｃ３−Ｈ６２０９ＮＮａ−Ｈ２０計算値
：Ｃ，６３，５２； Ｈ，８，９１； Ｎ、 １．９５
゜実測値 Ｃ，６３，８１； Ｈ，９，２５、Ｎ、 ２
．１３゜〔α］２４ニー１０．６’ （Ｃ，１，０メ
タノール）Ｉ ＲＬＪＫＢ” ｃｍ−’ ： ３２７０
．２９５０．１６０８゜’Ｈ−ＮＭＲ（４００ＭＨｚ、
ｉｎ ＣＤ３０Ｄ） δＨ：０、７００ （３Ｈ
，ｓ、 １８−Ｍｅ） ０．９９１ （３）１． ｓ
、 １９−Ｍｅ）０、９２８ （３Ｈ，ｄ、 Ｊ＝６．
５Ｈｚ、 ２１−Ｍｅ）０、８６１．０．８８０ （３
ＨＸ ２． ｄ、 Ｊ＝１．５）１ｚ、 ２６．２７−
Ｍｅ）１、９７２ （３）１． ｓ、 ＮＡｃ）２、４
８２ （ＩＨ，ｄｄ、 Ｊ：４．５．１３．０）Ｉｚ、
２’ −Ｈｅｑ）５、２８２ （ＬＨ，ｄ、 Ｊ＝５
．３Ｈｚ、 ６−Ｈ）１３Ｃ−ＮＭＲ（１００ＭＨｚ、
ｉｎ ＣＤ３０Ｄ） δＣ：１７６．９５（Ｎ
Ａｃ） １７４．５１ （１’ −ＣＯＯＮａ）１
４３．０８（Ｃ−５） １２２．４６（Ｃ−６）
１０１．３７（Ｃ−１’＞７２．３７（Ｃ−３）
４３．８２（Ｃ−２’）化合物（Ｉ）、（ＩＩ）はとも
に脱髄性疾患に治療剤として有効であるが、化合物（Ｉ
）のα体はとくに好ましい。386° Elemental analysis (%) C3-H6209NNa-H20 calculated value: C, 63,52; H, 8,91; N, 1.95
゜Actual measurement value C, 63, 81; H, 9, 25, N, 2
．． 13゜[α]24knee 10.6' (C, 1,0 methanol) I RLJKB"cm-': 3270
．． 2950.1608°'H-NMR (400MHz,
in CD30D) δH:0, 700 (3H
, s, 18-Me) 0.991 (3)1. s
, 19-Me) 0,928 (3H,d, J=6.
5Hz, 21-Me) 0, 861.0.880 (3
HX2. d, J=1.5)1z, 26.27-
Me) 1, 972 (3) 1. s, NAc)2,4
82 (IH, dd, J:4.5.13.0)Iz,
2'-Heq) 5, 282 (LH, d, J=5
．． 3Hz, 6-H) 13C-NMR (100MHz,
in CD30D) δC: 176.95 (N
Ac) 174.51 (1'-COONa)1
43.08 (C-5) 122.46 (C-6)
101.37 (C-1'>72.37 (C-3)
43.82(C-2') Both compounds (I) and (II) are effective as therapeutic agents for demyelinating diseases, but compound (I) and (II) are both effective as therapeutic agents for demyelinating diseases.
) is particularly preferred.
本発明化合物の投与方法は経口、非経口とも可能である
が、点眼剤、点鼻剤、吸入剤、内服剤、筋肉注射、皮下
注射、静脈注射が好ましい。投与量は疾患の程度と患者
の体重に依存するが、０．００１〜１０ｍｇが好ましい
。The compound of the present invention can be administered either orally or parenterally, but eye drops, nasal drops, inhalants, internal administration, intramuscular injection, subcutaneous injection, and intravenous injection are preferred. The dosage depends on the severity of the disease and the weight of the patient, but is preferably between 0.001 and 10 mg.
以下、本発明の薬剤につき実施例に示す。本発明はこれ
らに限定されるものではない。The drugs of the present invention will be shown in Examples below. The present invention is not limited to these.
（実施例）
Ｈａｒｔｌｅｙ系雄性モルモット（３００〜３５０ｇ、
常盤実験動物研究所）の後肢定速皮下に３００μｇのウ
シミニリン塩基性タンパク （ＭＢＰ。(Example) Hartley male guinea pig (300-350g,
300 μg of bovine miniphosphorus basic protein (MBP) was administered subcutaneously to the hind limbs of animals (Tokiwa Experimental Animal Research Institute) at a constant rate.
Ｓｉｇｍａ）を含むフロイント完全アジュバント（１ｍ
ｌ中１ ｍｇの青山Ｂ株結核死菌を含む）をモルモット
１匹当り０．１ ｍｉ２無麻酔下で注射した。Complete Freund's adjuvant (1 m
0.1 mi2 of Aoyama B strain (containing 1 mg of killed tuberculosis bacteria per 1 ml) was injected into each guinea pig under anesthesia.
以後、体重の増減、前後肢の麻痺、失禁の発現を経時的
に観察するとともに、本発明の化合物（α体）を６日目
〜１６日目の間毎日１日１回復内投与したものについて
もその経時的な変化を観察した。結果を、以下の表１に
示す。Thereafter, changes in body weight, paralysis of front and rear limbs, and onset of incontinence were observed over time, and the compound of the present invention (α-form) was administered once a day from day 6 to day 16. We also observed its changes over time. The results are shown in Table 1 below.
表−１より、本発明の化合物が実験的アレルギー性脳を
髄炎（ＥＡＥ）の治療に有効であることが分る。Table 1 shows that the compounds of the present invention are effective in treating experimental allergic brain myelitis (EAE).
（急性毒性試験）
急性毒性試験はｄｄｙ系雄性マウス４５週令に静脈内注
射を行なうことによって確認し、結果はＬ Ｄｓｏ ＝
９３ ｍｇ／ ｋｇ （化合物（Ｉ）） 、ＬＤＳＯ
＝２９１ ｍｇ／ｋｇ （化合物（■））であった。(Acute toxicity test) The acute toxicity test was confirmed by intravenous injection into ddy male mice at 45 weeks of age, and the results were L Dso =
93 mg/kg (compound (I)), LDSO
=291 mg/kg (compound (■)).
Claims (1)
を特徴とする脱髄性疾患治療剤。（２）脱髄性疾患治療
剤が点眼剤、点鼻剤、吸入剤、内服剤、静脈注射剤、筋
肉注射剤、皮下注射剤の形態にある、特許請求の範囲第
（１）項記載の脱髄性疾患治療剤。(1) General formula (I): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) or general formula (II): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) Contains sialosylcholesterol represented by A therapeutic agent for demyelinating diseases. (2) The therapeutic agent for demyelinating diseases is in the form of eye drops, nasal drops, inhalants, internal medicines, intravenous injections, intramuscular injections, and subcutaneous injections, according to claim (1). A treatment for demyelinating diseases.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP25119887A JPH0193529A (en) | 1987-10-05 | 1987-10-05 | Remedy of sialosylcholesterol for demyelinating disease |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP25119887A JPH0193529A (en) | 1987-10-05 | 1987-10-05 | Remedy of sialosylcholesterol for demyelinating disease |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH0193529A true JPH0193529A (en) | 1989-04-12 |
Family
ID=17219142
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP25119887A Pending JPH0193529A (en) | 1987-10-05 | 1987-10-05 | Remedy of sialosylcholesterol for demyelinating disease |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0193529A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6444649B1 (en) | 1998-04-10 | 2002-09-03 | Mitsubishi Chemical Corporation | Solid dispersion containing sialic acid derivative |
| EP2445291A2 (en) | 2004-07-28 | 2012-04-25 | NEC Corporation | Wireless transmission system and communications method |
| JP2014508807A (en) * | 2011-03-21 | 2014-04-10 | エンディース エルエルシー | 6-Substituted estradiol derivatives for use in remyelination of nerve axons |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS62209094A (en) * | 1986-03-10 | 1987-09-14 | Nippon Zoki Pharmaceut Co Ltd | Novel sialic acid derivative and production thereof |
-
1987
- 1987-10-05 JP JP25119887A patent/JPH0193529A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS62209094A (en) * | 1986-03-10 | 1987-09-14 | Nippon Zoki Pharmaceut Co Ltd | Novel sialic acid derivative and production thereof |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6444649B1 (en) | 1998-04-10 | 2002-09-03 | Mitsubishi Chemical Corporation | Solid dispersion containing sialic acid derivative |
| EP2445291A2 (en) | 2004-07-28 | 2012-04-25 | NEC Corporation | Wireless transmission system and communications method |
| JP2014508807A (en) * | 2011-03-21 | 2014-04-10 | エンディース エルエルシー | 6-Substituted estradiol derivatives for use in remyelination of nerve axons |
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