JPH01290669A - Novel lignane compound - Google Patents
Novel lignane compoundInfo
- Publication number
- JPH01290669A JPH01290669A JP63112325A JP11232588A JPH01290669A JP H01290669 A JPH01290669 A JP H01290669A JP 63112325 A JP63112325 A JP 63112325A JP 11232588 A JP11232588 A JP 11232588A JP H01290669 A JPH01290669 A JP H01290669A
- Authority
- JP
- Japan
- Prior art keywords
- compound
- liver
- formula
- tetramethoxy
- cyclooctadiene
- 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
- 150000001875 compounds Chemical class 0.000 title abstract description 27
- -1 Lignan compounds Chemical class 0.000 claims abstract description 11
- 229930013686 lignan Natural products 0.000 claims abstract description 11
- 235000009408 lignans Nutrition 0.000 claims abstract description 11
- 208000019423 liver disease Diseases 0.000 claims abstract description 6
- 239000003814 drug Substances 0.000 claims description 8
- 239000000126 substance Substances 0.000 claims description 3
- 229940124597 therapeutic agent Drugs 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 abstract description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 abstract description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 abstract description 5
- RRKODOZNUZCUBN-CCAGOZQPSA-N (1z,3z)-cycloocta-1,3-diene Chemical compound C1CC\C=C/C=C\C1 RRKODOZNUZCUBN-CCAGOZQPSA-N 0.000 abstract description 4
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 abstract description 4
- 238000002360 preparation method Methods 0.000 abstract description 4
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 abstract description 3
- 235000019253 formic acid Nutrition 0.000 abstract description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 abstract description 3
- 208000030090 Acute Disease Diseases 0.000 abstract description 2
- 208000004930 Fatty Liver Diseases 0.000 abstract description 2
- 206010019708 Hepatic steatosis Diseases 0.000 abstract description 2
- 206010019728 Hepatitis alcoholic Diseases 0.000 abstract description 2
- 230000001154 acute effect Effects 0.000 abstract description 2
- 208000002353 alcoholic hepatitis Diseases 0.000 abstract description 2
- 208000019425 cirrhosis of liver Diseases 0.000 abstract description 2
- 208000010706 fatty liver disease Diseases 0.000 abstract description 2
- 210000004185 liver Anatomy 0.000 abstract description 2
- 231100000240 steatosis hepatitis Toxicity 0.000 abstract description 2
- 206010019663 Hepatic failure Diseases 0.000 abstract 2
- 208000007903 liver failure Diseases 0.000 abstract 2
- 231100000835 liver failure Toxicity 0.000 abstract 2
- 210000000941 bile Anatomy 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 231100000614 poison Toxicity 0.000 abstract 1
- 239000002574 poison Substances 0.000 abstract 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 abstract 1
- 238000012360 testing method Methods 0.000 description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 12
- 230000037396 body weight Effects 0.000 description 10
- 241001465754 Metazoa Species 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 239000001768 carboxy methyl cellulose Substances 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 239000008187 granular material Substances 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
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- 210000002966 serum Anatomy 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 229920002261 Corn starch Polymers 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 239000008120 corn starch Substances 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 4
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 206010067125 Liver injury Diseases 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
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- 239000000796 flavoring agent Substances 0.000 description 3
- 235000013355 food flavoring agent Nutrition 0.000 description 3
- 244000144993 groups of animals Species 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 239000011812 mixed powder Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- MSWZFWKMSRAUBD-GASJEMHNSA-N 2-amino-2-deoxy-D-galactopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@H](O)[C@@H]1O MSWZFWKMSRAUBD-GASJEMHNSA-N 0.000 description 2
- 206010002091 Anaesthesia Diseases 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 238000000692 Student's t-test Methods 0.000 description 2
- 230000037005 anaesthesia Effects 0.000 description 2
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 239000003086 colorant Substances 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 238000006911 enzymatic reaction Methods 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 150000005692 lignans Chemical class 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 239000004006 olive oil Substances 0.000 description 2
- 235000008390 olive oil Nutrition 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000012353 t test Methods 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 244000215068 Acacia senegal Species 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 240000006079 Schisandra chinensis Species 0.000 description 1
- 235000008422 Schisandra chinensis Nutrition 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 231100000460 acute oral toxicity Toxicity 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 230000001587 cholestatic effect Effects 0.000 description 1
- 230000007882 cirrhosis Effects 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000000498 cooling water Substances 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000008717 functional decline Effects 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 231100000234 hepatic damage Toxicity 0.000 description 1
- 231100000304 hepatotoxicity Toxicity 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000008818 liver damage Effects 0.000 description 1
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】 に見上９１用分野 本発明は新規なリグナン化合物に関する。[Detailed description of the invention] 91 field for viewing The present invention relates to novel lignan compounds.
ｋ米り且１
全合成あるいは五味子類から抽出することにより得られ
るリグナン類は、従来からいくつか知られている〈アメ
リカ特許明細書第４００３９１６号、特開昭５５−２２
６１２）。Some lignans obtained by total synthesis or extraction from Schisandra have been known (U.S. Pat.
612).
光１−が一解遇↓丈ｊ−尤ｊ（１１
本発明の目的は、肝疾患治療に有効なリグナン化合物を
提供すやことにあるゆ
！１ま皐東ｔ（な竺力千我
本発明者らは、リグナン類の類縁体について鋭意検討を
行なった結果、優れた効果のある新規リグナン化合物を
見出し本発明を完成した。The object of the present invention is to provide a lignan compound that is effective for the treatment of liver diseases. As a result of intensive studies on analogs of lignans, they discovered a new lignan compound with excellent effects and completed the present invention.
本発明は、下記式Ｉ で表わされるリグナン化合物及び 式Ｉ で表わされるリグナン化合物である。The present invention provides the following formula I A lignan compound represented by and Formula I It is a lignan compound represented by
本発明に係わる式■及び式■の化合物は、種々の方法に
よって製造することが可能であるが、その中で通常用い
られる方法の一例を示せば次の如くである。The compounds of formula (1) and formula (2) according to the present invention can be produced by various methods, and an example of a commonly used method is as follows.
すなわち、公知物質である６５．７５−ジメチル−７−
ヒドロキシ−８−才キソー２．３−メチレンジオキシ−
１，１０，１１，１２−テトラメトキシ−［Ｓコージベ
ンゾ［ａ、ｅコシクロオクタジエンと塩酸ヒドロキシア
ミンとをピリジン無水物中で反応させて、式！の化合物
（以下化合物Ｉと称する。）を得ることができる。この
反応は通常２０〜２５０℃、好ましくは５０〜１５０℃
で行なわれ、反応時間は通常２〜６時間である。また、
化合物■と硫酸・蟻酸とを反応させて式Ｉの化合物（以
下化合物■と称する。）を得ることができる。この反応
は通常２０〜１００’Ｃ，好ましくは３０〜５０℃で行
なわれ、反応時間は通常２〜６時間である。That is, the known substance 65.75-dimethyl-7-
Hydroxy-8-year-old xo-2,3-methylenedioxy-
1,10,11,12-tetramethoxy-[S-codibenzo[a,e-cocyclooctadiene and hydroxyamine hydrochloride are reacted in pyridine anhydride to form the formula! (hereinafter referred to as compound I) can be obtained. This reaction is usually carried out at 20-250°C, preferably at 50-150°C.
The reaction time is usually 2 to 6 hours. Also,
A compound of formula I (hereinafter referred to as compound (2)) can be obtained by reacting compound (1) with sulfuric acid/formic acid. This reaction is usually carried out at 20 to 100'C, preferably 30 to 50C, and the reaction time is usually 2 to 6 hours.
λ里立友１
本発明に係わる化合物Ｉ及び化合物Ｉは、四塩化炭素投
与により実験的につくられた病態モデルの肝障害をもっ
た被験動物に対して経口的に投与することによって顕著
な肝機能の低下抑制あるいは改善効果をもたらした。λri Tatsutomo 1 Compound I and Compound I according to the present invention can be administered orally to test animals with liver damage in a pathological model created experimentally by administration of carbon tetrachloride. It has the effect of suppressing or improving functional decline.
また、ヒトや哺乳動物に対する毒性が極めて低く、一般
にマウス（雄性）に対する急性経口毒性ＬＤｓｓ値は３
０００＋ｖ ／ｋｇ体重より低毒なレベルにあった。In addition, the toxicity to humans and mammals is extremely low, and the acute oral toxicity LDss value for mice (male) is generally 3.
The toxicity level was lower than 000+v/kg body weight.
化合物Ｉ及び化合物Ｉは、種々の原因によって生ずるヒ
トや哺乳動物の急性もしくは慢性の肝臓疾患、たとえば
脂肪肝、アルコール性肝炎、中毒性肝障害、うっ血肝、
胆汁うっ滞性肝障害あるいはそれらの終末像である肝硬
変などの治療に効果があり、これらの肝疾患の治療剤と
して使用することができる。Compound I and Compound I can be used to treat acute or chronic liver diseases in humans and mammals caused by various causes, such as fatty liver, alcoholic hepatitis, toxic liver disease, congestive liver,
It is effective in the treatment of cholestatic liver disorders and the terminal stage thereof, cirrhosis, and can be used as a therapeutic agent for these liver diseases.
このためには、化合物！及び化合物■を成人に対して経
口投与で１〜３０■／ｋｇ体重７日を１日１〜３回に分
けて投与する。この投与量は患者の年齢、体重、症状に
より適宜増減することができる。 化合物■及び化合物
■は、常法により常用の担体や希釈剤に分散して調製す
ることにより、錠剤、顆粒剤、散剤、カプセル剤などの
経口投与用固体製剤や液剤、懸濁剤、乳剤などの経口投
与液体製剤として使用に供することができる。For this, compounds! and Compound (2) are orally administered to adults at 1 to 30 ■/kg body weight for 7 days in 1 to 3 divided doses a day. This dosage can be adjusted as appropriate depending on the age, weight, and symptoms of the patient. Compound ■ and Compound ■ can be prepared by dispersing them in commonly used carriers and diluents in a conventional manner to form solid preparations for oral administration such as tablets, granules, powders, capsules, solutions, suspensions, emulsions, etc. It can be used as an orally administered liquid preparation.
経口投与用固体製剤の調製に使用できる担体としては、
乳糖、ブドウ糖、結晶セルロース、マンニトール、コー
ンスターチ、砂糖などの賦形剤、ヒドロキシプロピルセ
ルロース、ヒドロキシプロピルメチルセルロース、カル
ボキシメチルセルロース、ポリビニルアルコール、ゼラ
チン、アラビヤゴムなどの結合剤、グリセリン、エチレ
ングリコールなどの湿潤剤、とうもろこしでんぷん、ば
れいしょでんぷん、カルボキシメチルセルロースカルシ
ウム、低置換度ヒドロキシプロピルセルロースなどの崩
壊剤、ステアリン酸カルシウム、ステアリン酸マグネシ
ウム、タルク、ポリエチレングリコール、硬化油などの
滑沢剤があり、この他 ２必要に応じて界面活性剤、
着色剤、矯味剤などを使用することができる。Carriers that can be used to prepare solid preparations for oral administration include:
Excipients such as lactose, glucose, crystalline cellulose, mannitol, corn starch, sugar, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, binders such as polyvinyl alcohol, gelatin, gum arabic, wetting agents such as glycerin, ethylene glycol, corn There are disintegrants such as starch, potato starch, calcium carboxymethyl cellulose, and low-substituted hydroxypropyl cellulose, and lubricants such as calcium stearate, magnesium stearate, talc, polyethylene glycol, and hydrogenated oil. activator,
Coloring agents, flavoring agents, etc. can be used.
経口投与用液剤の調製に使用できる希釈剤としては、水
、エタノール、グリセリン、プロピレングリコール、ポ
リエチレングリコール、寒天、トラガントなどがあり、
必要に応じて溶解補助剤、緩衝剤、保存剤、香料、着色
剤、呈味剤などを使用することができる。Diluents that can be used to prepare solutions for oral administration include water, ethanol, glycerin, propylene glycol, polyethylene glycol, agar, and tragacanth.
A solubilizing agent, a buffering agent, a preservative, a flavoring agent, a coloring agent, a flavoring agent, etc. can be used as necessary.
支凰遭
以下、実施例により化合物■及び化合物■の製造方法、
試験例により化合物Ｉ及び化合物Ｉの効果を詳細に説明
する。Below, according to Examples, compound ■ and method for producing compound ■,
Compound I and the effects of Compound I will be explained in detail using test examples.
実施例１
７ｇの６５．７５−ジメチル−７−ヒドロキシ−８−才
キソー２．３−メチレンジオキシ−１，１０，１１，１
２−テトラメトキシ−［Ｓ］−ジベンゾ［ａ、ｅ］シク
ロオクタジエンと１４ｇの塩酸ヒドロキシルアミンを７
０ｍ１ｌのピリジン無水物中４時間還流した０反応液を
冷却後水を加え、ジクロルメタンで抽出した０次いで、
ジクロルメタン層を１０％塩酸及び水つ
で洗浄した後、無水硫酸ナトリ、ムで乾燥した。溶媒を
留去後、残渣をアセトンにより再結晶を行ない標記の化
合物Ｉを６．５７ｇ得た。Example 1 7g of 65.75-dimethyl-7-hydroxy-8-year-old xo-2,3-methylenedioxy-1,10,11,1
2-Tetramethoxy-[S]-dibenzo[a,e]cyclooctadiene and 14 g of hydroxylamine hydrochloride were added to 7
The reaction solution was refluxed for 4 hours in 0 ml of anhydrous pyridine, and after cooling, water was added and extracted with dichloromethane.
The dichloromethane layer was washed with 10% hydrochloric acid and water, and then dried over anhydrous sodium sulfate. After distilling off the solvent, the residue was recrystallized with acetone to obtain 6.57 g of the title compound I.
ｍ、ｐ、 ２５２〜２５４℃
実施例２
実施例１で得られた２、５ｇの６５．７５−ジメチル−
７−ヒドロキシ−８−ヒドロキシイミノ−２，３−メチ
レンジオキシ−１，１０，１１，１２−テトラメトキシ
−［Ｓ］−ジベンゾ［ａ、Ｃ］シクロオクタジエンと２
５ｍ１の１規定硫酸・蟻酸を室温で４時間攪拌した１次
いで、反応液を冷却水１００ｍ１ｌと混合し、ジクロル
メタンで抽出した。更に、ジクロルメタン層を水で洗浄
した後、無水硫酸ナトリウムで乾燥した。溶媒を留去後
、残渣を分取シリカゲル薄層クロマトグラフィーくシリ
カゲル−ＧＦｚｓａ−ＪＲ開溶媒；ヘキサン：酢酸エチ
ル−７：３）を行ないアセトンで溶出後、溶媒を留去し
、標記の化合物Ｉを１．６ｇ得た。m, p, 252-254°C Example 2 2.5 g of 65.75-dimethyl- obtained in Example 1
7-hydroxy-8-hydroxyimino-2,3-methylenedioxy-1,10,11,12-tetramethoxy-[S]-dibenzo[a,C]cyclooctadiene and 2
5 ml of 1N sulfuric acid/formic acid was stirred at room temperature for 4 hours.Then, the reaction solution was mixed with 100 ml of cooling water and extracted with dichloromethane. Further, the dichloromethane layer was washed with water and then dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was subjected to preparative silica gel thin layer chromatography using silica gel-GFzsa-JR (opening solvent: hexane:ethyl acetate - 7:3) and eluting with acetone, and the solvent was evaporated to obtain the title compound I. 1.6g of was obtained.
ｍ、ｐ、 ９６〜９７℃
実施例３［錠剤の製造］
化合物ｌを６００組結晶セルロース１２０ｇ及びとうも
ろこしでんぷん１２６ｇを混合して均一な混合粉体とし
、ヒドロキシプロピルセロース４５ｇを結合剤として湿
式造粒法により顆粒を調製した。これにステアリン酸マ
グネシウム９ｇを混合した後打錠（７、直径ｇｍｍ、重
量３００■の錠剤３０００個を得た。m, p, 96-97°C Example 3 [Manufacture of tablets] Compound 1 was mixed with 120 g of 600-set crystalline cellulose and 126 g of corn starch to form a uniform mixed powder, and wet-processed using 45 g of hydroxypropylcellose as a binder. Granules were prepared by the granule method. This was mixed with 9 g of magnesium stearate and then tableted (3,000 tablets with a diameter of 7 gmm and a weight of 300 square meters were obtained).
実施例４［カプセル剤の製造コ
化合物Ｉを６００ｇ、結晶セルロース１５０ｇ、とうも
ろこしでんぷん１４０ｇ及びステアリン酸マグネシウム
１０ｇを均一に混合した。この混合粉体を１カプセル当
り３００■ずつ１号硬カプセルに充填し、カプセル３０
００個を得た。Example 4 [Production of Capsules] 600 g of Compound I, 150 g of crystalline cellulose, 140 g of corn starch and 10 g of magnesium stearate were uniformly mixed. This mixed powder was filled into No. 1 hard capsules at a rate of 300 μ per capsule.
Obtained 00 pieces.
実施例５［顆粒剤の製造］
化合物■を６００ｇ、マンニトール３００ｇ及びとうも
ろこしでんぷん４５軸を混合して均一な混合粉体とし、
ヒドロキシプロピルセルロース５０ｇを結合剤として湿
式造粒法により顆粒を調製し、顆粒剤１０００個を得た
。Example 5 [Manufacture of granules] 600 g of compound (1), 300 g of mannitol and 45 corn starch were mixed to form a uniform mixed powder,
Granules were prepared by wet granulation using 50 g of hydroxypropyl cellulose as a binder to obtain 1000 granules.
実施例６［散剤の製造］
化合物■を２００ｇ及び乳糖８００ｇを均一に混合して
散剤を調製１２、これを１０００Ｔｌｔずつ分包して散
剤１０００包を得た。Example 6 [Manufacture of powder] 200 g of compound (1) and 800 g of lactose were uniformly mixed to prepare powder 12. This was divided into 1000 Tlt portions to obtain 1000 packages of powder.
試験例１
［四塩化炭素投与による急性肝障害ラットに対する作用
コ
ウィスター系雄性ラット（生後７週齢、体重約１８０ｇ
＞６匹を一群とし、水及び飼料を自由に摂取きせて試験
に供した。実施例１及び２で得た化合物１及び■を０．
２％カルボキシメチルセルロース・ナトリウム水溶液に
懸濁して濃度１０＋ｗ／ｍＩｌの被験薬を調製した。各
被験薬５ｍＱ／ｋｇ体重をそれぞれ別個の群の動物に経
口投与し、３０分後に５％四塩化次素オリーブ油溶液１
０ｍ１ｌ／ｋｇ体重を同様に経口投与した。四塩化炭素
投与２４時間後に、エーテル麻酔下この動物から採血を
行ない、日立７１５ｏ型オートアナライザーを用いて酵
素法でシー１ヘアツセイし、血清のＧＰＴ値を測定した
。対照として０．２％カルボキシメチルセルロース・ナ
トリウム水溶液５ｒｒｄｌ／ｋｇ体重を別個の群の動物
に経口投与し、以下前記の処理に準じて処理し、血清の
ＧＰＴ値を測定した。Test Example 1 [Effect on rats with acute liver damage due to administration of carbon tetrachloride] Cowistar male rats (7 weeks old, weight approximately 180 g)
Groups of >6 animals were given free access to water and feed for testing. Compounds 1 and 2 obtained in Examples 1 and 2 were mixed with 0.
The test drug was prepared by suspending it in a 2% sodium carboxymethylcellulose aqueous solution at a concentration of 10+w/ml. 5 mQ/kg body weight of each test drug was orally administered to separate groups of animals, and 30 minutes later, 5% hypotetrachloride olive oil solution 1
Similarly, 0 ml/kg body weight was orally administered. Twenty-four hours after the administration of carbon tetrachloride, blood was collected from the animal under ether anesthesia, and blood was assayed using an enzymatic method using a Hitachi 715o autoanalyzer to measure the serum GPT value. As a control, 5 rrdl/kg body weight of a 0.2% sodium carboxymethylcellulose aqueous solution was orally administered to a separate group of animals, which were then treated in the same manner as described above, and serum GPT values were measured.
血清ＧＰＴ値増加抑制率は下記式より算出した。The rate of inhibition of increase in serum GPT value was calculated using the following formula.
血清ＧＰＴ値増加抑制率−
第１表
（注）
平均値上標準誤差
有意差は四塩化炭素投与群に対するｔ検定傘”：Ｐ＜０
．０１． 本傘本： Ｐ ＜０．００１試験例２
［Ｄ−ガラクトサミン投与による急性肝障害ラットに対
する作用コ
ウィスター系雄性ラット（生後７週齢、体重的１８０ｇ
） ６匹を一群とし、水及び飼料を自由に摂取させて試
験に供した。実施例１及び２で得た化合物Ｉ及びπを０
．２％カルボキシメチルセルロース・ナトリウム水溶液
に懸濁して濃度１０■／ｍｌの被験薬を調製した。各被
験薬５ｍＱ／ｋｇ体重をそれぞれ別個の群の動物に経口
投与し、３０分後に５％四塩化炭素オリーブ油溶液１０
ｍＱ／ｋｇ体重を同様に経口投与した。Ｄ−ガラクトサ
ミン投与２４時間後に、エーテル麻酔下この動物から採
血を行ない、日立７１５０型オートアナライザーを用い
て酵素法でレートアッセイし、血清のＧＰＴ値を測定し
た。対照として０．２％カルボキシメチルセルロ−スト
リウム水溶液５ｍｌ／ｋｇ体重を別個の群の動物に経口
投与し、以下前記の処理に準じて処理し、血清のＧＰＴ
値を測定した．その結果を第２表に示（注）
平均値上標準誤差
有意差は四塩化炭素投与群に対するｔ検定率＊：ｐ＜０
．０１． 本本本． ｐ ＜０．００１試験例３
［急性毒性コ
ＩＣＲ系雄性マウス（体重２５ｇ）１０匹を一群として
試験に供した．化合物Ｉ及び■をそれぞれ０．２％カル
ボキシメチルセルロース・ナトリウム水溶液に懸濁して
各種濃度の被験薬を調製し、これをそれぞれ別個の群の
動物に等比級数的に１回経口投与した。その後１４日間
観察を行ない、ＬＤｓｓ値を求めた。その結果を第３表
に示す。Suppression rate of increase in serum GPT value - Table 1 (Note) Significant difference in standard error above mean value is t-test umbrella for carbon tetrachloride administration group": P < 0
．． 01. Main book: P <0.001 Test Example 2 [Effect of D-galactosamine administration on rats with acute liver damage] Cowister male rats (7 weeks old, weight 180 g)
) A group of 6 animals was used for the test with free access to water and feed. Compounds I and π obtained in Examples 1 and 2 were
．． The test drug was prepared by suspending it in a 2% sodium carboxymethylcellulose aqueous solution at a concentration of 10 ml/ml. 5 mQ/kg body weight of each test drug was orally administered to separate groups of animals, and 30 minutes later, 10 mQ/kg body weight of each test drug was administered in 5% carbon tetrachloride olive oil solution.
mQ/kg body weight was similarly administered orally. Twenty-four hours after the administration of D-galactosamine, blood was collected from the animal under ether anesthesia, and the rate assay was performed by an enzymatic method using a Hitachi 7150 autoanalyzer to measure the GPT value of the serum. As a control, 5 ml/kg body weight of a 0.2% carboxymethylcellulostrium aqueous solution was orally administered to a separate group of animals, which were then treated in the same manner as described above.
The value was measured. The results are shown in Table 2 (Note) The significant difference in the standard error of the mean is the t-test rate for the carbon tetrachloride administration group*: p<0
．． 01. This book this book. p <0.001 Test Example 3
[10 acutely toxic ICR male mice (body weight 25 g) were used as a group for the test. Test drugs at various concentrations were prepared by suspending each of Compounds I and (1) in a 0.2% sodium carboxymethyl cellulose aqueous solution, and these were orally administered once to separate groups of animals in a geometric series. Thereafter, observation was performed for 14 days, and the LDss value was determined. The results are shown in Table 3.
第３表 特許出願人 チュングオ イーシュエ クウーシュエユアン ヤ才 ウー イエンヂウスウオ 大正製薬株式会社Table 3 Patent applicant Chunguo Yixue Kwushueyuan Yasai Wu Taisho Pharmaceutical Co., Ltd.
Claims (3)
物を有効成分とする肝疾患治療剤(3) A therapeutic agent for liver disease containing the lignan compound according to claim 1 or 2 as an active ingredient
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63112325A JPH01290669A (en) | 1988-05-09 | 1988-05-09 | Novel lignane compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63112325A JPH01290669A (en) | 1988-05-09 | 1988-05-09 | Novel lignane compound |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH01290669A true JPH01290669A (en) | 1989-11-22 |
Family
ID=14583851
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP63112325A Pending JPH01290669A (en) | 1988-05-09 | 1988-05-09 | Novel lignane compound |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH01290669A (en) |
-
1988
- 1988-05-09 JP JP63112325A patent/JPH01290669A/en active Pending
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