JPS63170383A - Alicyclic dicarboximide compound - Google Patents
Alicyclic dicarboximide compoundInfo
- Publication number
- JPS63170383A JPS63170383A JP62043732A JP4373287A JPS63170383A JP S63170383 A JPS63170383 A JP S63170383A JP 62043732 A JP62043732 A JP 62043732A JP 4373287 A JP4373287 A JP 4373287A JP S63170383 A JPS63170383 A JP S63170383A
- Authority
- JP
- Japan
- Prior art keywords
- liver
- dicarboximide
- hept
- ene
- compound
- 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
- -1 Alicyclic dicarboximide compound Chemical class 0.000 title claims description 14
- 239000000126 substance Substances 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 21
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 abstract description 12
- 208000019423 liver disease Diseases 0.000 abstract description 8
- 238000002360 preparation method Methods 0.000 abstract description 5
- 239000002904 solvent Substances 0.000 abstract description 5
- 230000018044 dehydration Effects 0.000 abstract description 4
- 238000006297 dehydration reaction Methods 0.000 abstract description 4
- 210000004185 liver Anatomy 0.000 abstract description 4
- 206010019728 Hepatitis alcoholic Diseases 0.000 abstract description 3
- 208000002353 alcoholic hepatitis Diseases 0.000 abstract description 3
- 231100000331 toxic Toxicity 0.000 abstract description 3
- 230000002588 toxic effect Effects 0.000 abstract description 3
- 230000001587 cholestatic effect Effects 0.000 abstract description 2
- QZVQQUVWFIZUBQ-UHFFFAOYSA-N 3-fluoroaniline Chemical compound NC1=CC=CC(F)=C1 QZVQQUVWFIZUBQ-UHFFFAOYSA-N 0.000 abstract 1
- 241000045500 Diseae Species 0.000 abstract 1
- 238000006482 condensation reaction Methods 0.000 abstract 1
- 238000010438 heat treatment Methods 0.000 abstract 1
- 230000002439 hemostatic effect Effects 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 238000012360 testing method Methods 0.000 description 10
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 6
- 230000037396 body weight Effects 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
- 229920002261 Corn starch Polymers 0.000 description 5
- 239000008120 corn starch Substances 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- JFUOAGBSDGCVES-UHFFFAOYSA-N 3-but-2-enyl-4-methylpyrrolidine-2,5-dione Chemical compound CC=CCC1C(C)C(=O)NC1=O JFUOAGBSDGCVES-UHFFFAOYSA-N 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- 206010067125 Liver injury Diseases 0.000 description 4
- 239000001768 carboxy methyl cellulose Substances 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 239000008187 granular material Substances 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 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 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 229920002678 cellulose Polymers 0.000 description 3
- 239000001913 cellulose Substances 0.000 description 3
- 235000010980 cellulose Nutrition 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 229940125904 compound 1 Drugs 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000000796 flavoring agent Substances 0.000 description 3
- 235000013355 food flavoring agent Nutrition 0.000 description 3
- 231100000234 hepatic damage Toxicity 0.000 description 3
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 3
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 230000008818 liver damage Effects 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 239000011812 mixed powder Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 208000030090 Acute Disease Diseases 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 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
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 208000004930 Fatty Liver Diseases 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 206010019708 Hepatic steatosis Diseases 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 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
- 241000700159 Rattus Species 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 2
- 229940105329 carboxymethylcellulose Drugs 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 208000019425 cirrhosis of liver Diseases 0.000 description 2
- 239000003086 colorant Substances 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 208000010706 fatty liver disease Diseases 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 230000003908 liver function Effects 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 231100000240 steatosis hepatitis Toxicity 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 238000005550 wet granulation Methods 0.000 description 2
- MUTGBJKUEZFXGO-OLQVQODUSA-N (3as,7ar)-3a,4,5,6,7,7a-hexahydro-2-benzofuran-1,3-dione Chemical compound C1CCC[C@@H]2C(=O)OC(=O)[C@@H]21 MUTGBJKUEZFXGO-OLQVQODUSA-N 0.000 description 1
- KMOUUZVZFBCRAM-OLQVQODUSA-N (3as,7ar)-3a,4,7,7a-tetrahydro-2-benzofuran-1,3-dione Chemical compound C1C=CC[C@@H]2C(=O)OC(=O)[C@@H]21 KMOUUZVZFBCRAM-OLQVQODUSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- FTZQXOJYPFINKJ-UHFFFAOYSA-N 2-fluoroaniline Chemical compound NC1=CC=CC=C1F FTZQXOJYPFINKJ-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 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
- 206010002091 Anaesthesia Diseases 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
- 206010010904 Convulsion Diseases 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
- WLLGXSLBOPFWQV-UHFFFAOYSA-N MGK 264 Chemical compound C1=CC2CC1C1C2C(=O)N(CC(CC)CCCC)C1=O WLLGXSLBOPFWQV-UHFFFAOYSA-N 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 238000000692 Student's t-test Methods 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 231100000215 acute (single dose) toxicity testing Toxicity 0.000 description 1
- 231100000460 acute oral toxicity Toxicity 0.000 description 1
- 238000011047 acute toxicity test Methods 0.000 description 1
- 125000002723 alicyclic group Chemical group 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 150000001448 anilines Chemical class 0.000 description 1
- 125000003118 aryl group Chemical group 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
- 210000000941 bile Anatomy 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000000872 buffer 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
- 229920003123 carboxymethyl cellulose sodium Polymers 0.000 description 1
- 229940063834 carboxymethylcellulose sodium Drugs 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 230000007882 cirrhosis Effects 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000036461 convulsion Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000003001 depressive effect Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- 230000001037 epileptic effect Effects 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000000417 fungicide Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 244000144993 groups of animals Species 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 230000005976 liver dysfunction Effects 0.000 description 1
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
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- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
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Abstract
Description
【発明の詳細な説明】
（産業上の利用分野）
本発明は新規な脂環式ジカルボン酸イミド化合物に関す
る。DETAILED DESCRIPTION OF THE INVENTION (Industrial Field of Application) The present invention relates to a novel alicyclic dicarboxylic acid imide compound.
（従来の技術）
ヘキサヒドロ無水フタル酸、テトラヒドロ無水フタル酸
などの脂環式ジカルボン酸無水物と種々のアニリン類と
を脱水縮合して得られる脂環式ジカルボン酸イミド化合
物は、従来がら多数知られている（たとえば、特公昭４
７−１９１９６号、特開昭５９−２３１０５７号など）
。しかし、既知の脂環式ジカルボン酸イミド化合物の用
途は農業用殺菌剤やてんかんなどの痙撃を伴う疾患の治
療剤に限られていた。(Prior Art) A large number of alicyclic dicarboxylic acid imide compounds obtained by dehydration condensation of alicyclic dicarboxylic anhydrides such as hexahydrophthalic anhydride and tetrahydrophthalic anhydride with various anilines have been known for a long time. (For example,
7-19196, JP-A-59-231057, etc.)
. However, the uses of known alicyclic dicarboxylic acid imide compounds have been limited to agricultural fungicides and therapeutic agents for diseases accompanied by convulsions such as epilepsy.
（発明が解決しようとする問題点）
本発明者らは、かかる脂環式ジカルボン酸イミド化合物
の類縁体について鋭意検討を行なった結果、後記一般式
（１）で表わされる文献未記載の新規化合物が実験的に
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り顕著な肝機能の低下抑制
あるいは改善効果をもたらすことを見い出し、本発明を
完成するに到りた。(Problems to be Solved by the Invention) As a result of intensive studies on analogs of such alicyclic dicarboxylic acid imide compounds, the present inventors discovered a novel compound represented by the general formula (1) below, which has not been described in any literature. The present invention has been completed based on the discovery that when administered orally to test animals with liver damage, which is an experimentally created disease model, it brings about a remarkable effect of suppressing or improving the decline in liver function. It was.
（問題点を解決するための手段９
かくして本発明により
一般式（Ｉ）
（式中、ｎは１〜５の整数を示す。）
で表わされる脂環式ジカルボン酸イミド化合物が提供さ
れる。(Means for Solving Problems 9) Thus, the present invention provides an alicyclic dicarboxylic acid imide compound represented by the general formula (I) (wherein n represents an integer of 1 to 5).
一般式（Ｉ）で表わされる化合物は、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０
すなわち、
一般式
（式中、ｎは前記と同義である。）で表わされる化合物
と、
一般式
で表わされる化合物とを脱水縮合させて、目的の一般式
（Ｉ）で表わされる化合物を得ることができるＯ
本反応においては溶媒を使用する方が好ましく、好適な
溶媒としては、酢酸、プロピオン酸等の低級脂肪酸を挙
げることができる。また溶媒としてベンゼン、トルエン
等の芳香族液状化合物、クロロホルム、クロルベンゼン
等のハロゲン化炭化水素、アセトン、メチルエチルケト
ン等のケトン類を使用して本反応を行なった場合には、
反応生成物はモノアミドの形で得られるので、加熱処理
あるいｔｉｐ−）ルエンスルホン酸、硫酸、塩酸等の酸
性触媒、酢酸ンーダ、トリエチルアミン等の塩基性触媒
もしくは無水酢酸、チオニルクロライド等の脱水触媒を
用いてイミド化することにより目的の一般式（Ｉ）で表
わされる化合物を得ることができる。The compound represented by the general formula (I) can be produced by various methods, and an example of a commonly used method is as follows. (n has the same meaning as above) and the compound represented by the general formula can be subjected to dehydration condensation to obtain the target compound represented by the general formula (I). In this reaction, a solvent is used. It is preferable to use , and suitable solvents include lower fatty acids such as acetic acid and propionic acid. In addition, when this reaction is carried out using an aromatic liquid compound such as benzene or toluene, a halogenated hydrocarbon such as chloroform or chlorobenzene, or a ketone such as acetone or methyl ethyl ketone as a solvent,
Since the reaction product is obtained in the form of a monoamide, it may be heated or treated with an acidic catalyst such as toluenesulfonic acid, sulfuric acid, or hydrochloric acid, a basic catalyst such as acetic acid, triethylamine, or a dehydration catalyst such as acetic anhydride or thionyl chloride. The target compound represented by general formula (I) can be obtained by imidization using.
本反応は通常２０〜２５０℃、好ましくは５０〜１５０
℃で行なわれ、反応時間は通常１０分〜２０時間、好ま
しくは３０分〜５時間である０以下に一般式（Ｉ）で表
わされる化合物の代表例を示す。This reaction is usually carried out at 20 to 250°C, preferably 50 to 150°C.
The reaction time is usually 10 minutes to 20 hours, preferably 30 minutes to 5 hours.Representative examples of compounds represented by formula (I) are shown below.
Ｎ−（２−フルオロフェニル）−７−オキサビシクロ［
２，２，１］ヘプト−５−エン−２，３−ジカルボキシ
イミド、
Ｎ−（５−フルオロフェニル）−７−オキサビシクロ［
２，２，１］ヘプト−５−エン−２，３−ジカルボキシ
イミド、
Ｎ−（４−フルオロフェニル）−７−オキサビシクロ［
２，２，１］ヘプト−５−エン−２４３−ジカルボキシ
イミド、
Ｎ〜（２，４−ジフルオロフェニル）−７−オキサビン
クロ［２，２，１］ヘプト−５−エン−２，３−ジカル
ボキシイミド、
Ｎ −（３，５〜ジフルオロフエニル）−７−オキサビ
シクロ［２，２ｉ］ヘプト−５−エン−２，３−ジカル
ボキシイミド、
Ｎ−（２，５−ジフルオロフェニル）−７−オキサビシ
クロ［２，２，１］へブドー５−工ン−２，３−ジカル
ボキシイミド、
Ｎ−（２，６−ジフルオロフェニル）−７−オキサビシ
クロ（２１１）ヘプト−５−エン−２，３−ジカルボキ
シイミド、
Ｎ−（２，４，ロートリフルオロフェニル）−７−オキ
サビシクロ（２，２，１）ヘプト−５−エン−２，３−
ジカルボキシイミド、
Ｎ −（２，３，５，６−テトラフルオロフエニル）−
７−オキサビシクロ（２，２，１）ヘプト−５−エン−
２，３−ジカルボキシイミド、
Ｎ−（２，３，４，５，６−ペンタフルオロフェニル）
−７−オキサビシクロ（２，２，１）ヘプト−５−エン
−２，３−ジカルボキシイミド、
などが挙げられる。N-(2-fluorophenyl)-7-oxabicyclo[
2,2,1]hept-5-ene-2,3-dicarboximide, N-(5-fluorophenyl)-7-oxabicyclo[
2,2,1]hept-5-ene-2,3-dicarboximide, N-(4-fluorophenyl)-7-oxabicyclo[
2,2,1]hept-5-ene-243-dicarboximide, N~(2,4-difluorophenyl)-7-oxabinclo[2,2,1]hept-5-ene-2,3-di Carboximide, N-(3,5-difluorophenyl)-7-oxabicyclo[2,2i]hept-5-ene-2,3-dicarboximide, N-(2,5-difluorophenyl)-7 -Oxabicyclo[2,2,1]hept-5-ene-2,3-dicarboximide, N-(2,6-difluorophenyl)-7-oxabicyclo(211)hept-5-ene-2 ,3-dicarboximide, N-(2,4,rotrifluorophenyl)-7-oxabicyclo(2,2,1)hept-5-ene-2,3-
Dicarboximide, N-(2,3,5,6-tetrafluorophenyl)-
7-Oxabicyclo(2,2,1)hept-5-ene-
2,3-dicarboximide, N-(2,3,4,5,6-pentafluorophenyl)
-7-oxabicyclo(2,2,1)hept-5-ene-2,3-dicarboximide, and the like.
上記一般式（Ｉ）で表わされる化合物は、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ＬＤ５．値は３０００ ｗｌｋｙ体
重より低毒なレベルにある。The compound represented by the above general formula (I) has extremely low toxicity to humans and mammals, and generally has an acute oral toxicity of LD5 to mice (male). The value is at a less toxic level than 3000 wlky body weight.
上記一般式（Ｉ）で表わされる化合物は、四塩化炭素投
与により実験的につくられた病態そ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す。When the compound represented by the above general formula (I) is orally administered to test animals with liver damage experimentally created by administration of carbon tetrachloride, it causes a marked decrease in liver function. It has a suppressive or ameliorating effect.
急性もしくは慢性の肝臓疾患、たとえば脂肪肝。Acute or chronic liver disease, such as fatty liver.
アルコール性肝炎、中癲性肝障害、欝血肝、胆汁欝滞性
肝障害または肝硬変などを治療するには、一般式（Ｉ）
で表わされる化合物を成人に対して経口投与で１〜３０
ｒｎ９／ｋｆ体重／日を１日に１〜６回に分けて投与
する。この投与量は患者の年齢１体重、症状により適宜
増減することができる。To treat alcoholic hepatitis, epileptic liver disorder, congested liver, cholestatic liver disorder or cirrhosis, use the general formula (I)
Oral administration of the compound represented by 1 to 30 to adults.
Administer rn9/kf body weight/day in 1 to 6 divided doses per day. This dosage can be adjusted as appropriate depending on the age, weight, and symptoms of the patient.
一般式（Ｉ）で表わされる化合物は、常法により常用の
担体や稀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用液体製剤として使用
に供することができる。The compound represented by general formula (I) can be prepared by dispersing it in a commonly used carrier or diluent by a conventional method to form solid preparations for oral administration such as tablets, granules, powders, capsules, liquid preparations, suspensions, etc. It can be used as a liquid preparation for oral administration such as a tablet or an emulsion.
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、ヒドロキシグロビ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、この他必要に応じて界面活性剤９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, binders such as hydroxypropyl cellulose, hydroxyglobil methyl cellulose, carboxymethyl cellulose, polyvinyl alcohol, gelatin, gum arabic, wetting agents such as glycerin, ethylene glycol, There are disintegrants such as corn 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 9 Coloring agents, flavoring agents, etc. can be used.
経口投与用液体製剤の調製に使用できる稀釈剤としては
、水、エタノール、グリセリン、プロピレングリコール
、ポリエチレンクリコール、ｇ天。Diluents that can be used to prepare liquid formulations for oral administration include water, ethanol, glycerin, propylene glycol, polyethylene glycol, and gelatin.
トラガントなどがあり、必要に応じて溶解補助剤。Tragacanth, etc., and solubilizing agents as needed.
緩衝剤、保存剤、香料９着色剤、呈味剤などを使用する
ことができる。Buffers, preservatives, flavoring agents, coloring agents, flavoring agents, etc. can be used.
（発明の効果）
一般式（Ｉ）で表わされる化合物は、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、うつ補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。(Effects of the Invention) The compound represented by the general formula (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 damage,
It is effective in the treatment of congestive liver, bile, depressive complement liver dysfunction, and liver cirrhosis, which is the final stage thereof, and can be used as a therapeutic agent for these liver diseases.
（実施例）
以下、一般式（Ｉ）で表わされる化合物の実施例および
試験例を挙けて本発明を具体的に説明する。(Examples) Hereinafter, the present invention will be specifically explained with reference to Examples and Test Examples of the compound represented by the general formula (I).
実施例１
Ｎ−（３−フルオロフェニル）−７−オキサビシクロ［
２，２，１］ヘプト−５−エン−２，３−ジカルボキシ
イミドの合成
３．６−ニンドオキソー１．２．３．６−テトラハイド
ロ無水フタル酸８．０ｙと６−フルオロアニリン５５１
を５０１ｎｌ！の酢酸中、４時間還流下に反応させた。Example 1 N-(3-fluorophenyl)-7-oxabicyclo[
Synthesis of 2,2,1]hept-5-ene-2,3-dicarboximide 3.6-nindooxo 1.2.3.6-tetrahydrophthalic anhydride 8.0y and 6-fluoroaniline 551
501nl! of acetic acid under reflux for 4 hours.
冷却後注水し、析出した粗結晶を戸数した。After cooling, water was added and the precipitated coarse crystals were collected.
次いでエタノールより再結晶を行ない、目的物（以下、
化合物１と称するＯ ）７．２９を得た。Next, recrystallization is performed from ethanol to obtain the target product (hereinafter referred to as
O 2 ) 7.29, designated as compound 1, was obtained.
収率５８％、 ｍ、ｐ、１３ ＆５〜１６９５℃実施例
２〜１０
実施例１に準じて下記構造式で示される化合物２〜１０
を得た。これを第１表に示す。Yield 58%, m, p, 13 & 5-1695°C Examples 2-10 Compounds 2-10 shown by the following structural formula according to Example 1
I got it. This is shown in Table 1.
第１表 第 １ 表 （つづき） 製剤例１ 化合物４ ６００７．結晶セルロース１２Ｃ１’。Table 1 Table 1 (continued) Formulation example 1 Compound 4 6007. Crystalline cellulose 12C1'.
とうもろこしでんぷん１２６２を混合して均一な混合粉
体トし、ヒドロキシプロピルセルロース４５２を結合剤
として湿式造粒法により顆粒を調製した。Corn starch 1262 was mixed into a uniform mixed powder, and granules were prepared by wet granulation using hydroxypropyl cellulose 452 as a binder.
これにステアリン酸マグネシウム９？を混合した後打錠
し、直径９１１ｍ 、重量３００ダの錠剤へ０００個を
得た。Magnesium stearate 9 in this? The mixture was mixed and then tableted to obtain 000 tablets with a diameter of 911 m and a weight of 300 Da.
製剤例２ 化合物１ ６００！、結晶セルロース１ｓｏｒ。Formulation example 2 Compound 1 600! , crystalline cellulose 1 sor.
とうもろこしでんぷん１４０５’、ステアリン酸マグネ
シウム１０２を均一に混合した。Corn starch 1405' and magnesium stearate 102 were mixed uniformly.
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３．０００個を得た。This mixed powder was filled into No. 1 hard capsules at a rate of 300 square centimeters per capsule to obtain 3,000 capsules.
製剤例３ 化合物７ ２００９．マンニトール３００Ｆ。Formulation example 3 Compound 7 2009. Mannitol 300F.
とうもろこしでんぷん４５０７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５０５’を結合
剤として湿式造粒法により顆粒を調製し、顆粒剤１．
Ｏｏ ｏ個を得た。Corn starch 4507 was mixed to obtain a uniform mixed powder, and granules were prepared by wet granulation using hydroxypropyl cellulose 505' as a binder to obtain granules 1.
I got Oo o pieces.
製剤例４
化合物８ ２００ｒ、乳糖８００２を均一に混合して散
剤を調製し、これを１０００１１９ずつ分包して散剤１
． ＯＯＯ包を得た。Formulation Example 4 Compound 8 200r and lactose 8002 were mixed uniformly to prepare a powder, which was divided into 1000119 portions to form powder 1.
．． I got OOO packets.
試験例す
る作用
ウィスター系雄性ラット（生後７週齢９体重約１８０ｆ
）６匹を一群とし、水および飼料を自由に摂取させて試
験に供した。Test Example Effect Wistar male rats (7 weeks old, 9 weight, approximately 180 f)
) A group of 6 animals was used for the test with free access to water and feed.
実施例１〜１０で得た一般式（Ｉ）で表わされる化合物
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■／ｒｎ！！の被験薬を調製し
た。The compounds represented by the general formula (I) obtained in Examples 1 to 10 were suspended in a 0.2% sodium carboxymethyl cellulose aqueous solution to a concentration of 10 μ/rn! ! The test drug was prepared.
各被験薬５ｍｌ／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係四塩化炭素オリーブ油溶液
１０ｍｊ／’ｊ’体重を同様に経口投与し、た。5 ml/kg body weight of each test drug was orally administered to animals in separate groups, and 30 minutes later, 10 mj/'j' body weight of a 5% carbon tetrachloride olive oil solution was orally administered in the same manner.
四塩化炭素投与２４時間後Ｋ、エーテル麻酔下この動物
から採血を行ない、日立１ｎｓ−ｓｏ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。24 hours after administration of carbon tetrachloride, blood was collected from the animal under ether anesthesia and rate assayed by enzymatic method using a Hitachi 1ns-so type autoanalyzer to determine serum GPT.
The value was measured.
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５ ｒｒｔｌ／に７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。As a control, a 0.2% sodium carboxymethylcellulose aqueous solution (5 rrtl/kg) was orally administered to animals in separate groups at a dose of 7 body weight, and treated as described above, and serum GPT values were measured.
その結果を第２表に示す。The results are shown in Table 2.
第 ２ 表
四塩化炭素投与による急性肝障害ラットに対する作用（
註）
ｍｅａｎ −１−８，Ｅ。Table 2 Effects of carbon tetrachloride administration on rats with acute liver damage (
Note) mean -1-8,E.
有意差は四塩化炭素投与群に対するｔ検定＊傘：ｐ〈α
０１． ＊傘車： ｐ＜０．００１試験例２
急性毒性
ＩＣＲ系雄性マウス（体重約２５９）１０匹を一群とし
て試験に供した。Significant differences are determined by t-test for the carbon tetrachloride administration group *Umbrella: p〈α
01. *Umbrella car: p<0.001 Test Example 2 A group of 10 acutely toxic ICR male mice (body weight approximately 259) was subjected to the test.
化合物１および化合物４をそれぞｔ″ＬＱ、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
穐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Ｏ
その後１４日間観察を行ない、ＬＤ５．値を求めた０
その結果を第３表に示す。Compound 1 and Compound 4 were each suspended in a 2% carboxymethyl cellulose sodium aqueous solution at t''LQ to prepare test drugs at each concentration, and these were orally administered once to separate groups of animals in a geometric series. The administered O was then observed for 14 days, and the LD5. value was determined. The results are shown in Table 3.
第 ３ 表 急性毒性試験Table 3 acute toxicity test
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP62043732A JPS63170383A (en) | 1987-02-26 | 1987-02-26 | Alicyclic dicarboximide compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP62043732A JPS63170383A (en) | 1987-02-26 | 1987-02-26 | Alicyclic dicarboximide compound |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP61202819 Division | 1986-08-29 | 1986-08-29 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPS63170383A true JPS63170383A (en) | 1988-07-14 |
Family
ID=12671954
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP62043732A Pending JPS63170383A (en) | 1987-02-26 | 1987-02-26 | Alicyclic dicarboximide compound |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS63170383A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000004023A1 (en) * | 1998-07-14 | 2000-01-27 | The University Of Newcastle Research Associates Limited | Anhydride modified cantharidin analogues useful in the treatment of cancer |
| EP1458723A1 (en) * | 2001-12-19 | 2004-09-22 | Bristols-Myers Squibb Company | Fused heterocyclic succinimidecompounds and analogs thereof, modulators of nuclear hormone receptor function |
| JP2009517389A (en) * | 2005-11-28 | 2009-04-30 | モーメンティブ・パフォーマンス・マテリアルズ・インク | Method for preparing unsaturated imidoalkoxysilane |
-
1987
- 1987-02-26 JP JP62043732A patent/JPS63170383A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000004023A1 (en) * | 1998-07-14 | 2000-01-27 | The University Of Newcastle Research Associates Limited | Anhydride modified cantharidin analogues useful in the treatment of cancer |
| EP1458723A1 (en) * | 2001-12-19 | 2004-09-22 | Bristols-Myers Squibb Company | Fused heterocyclic succinimidecompounds and analogs thereof, modulators of nuclear hormone receptor function |
| EP1458723A4 (en) * | 2001-12-19 | 2005-12-21 | Bristol Myers Squibb Co | Fused heterocyclic succinimidecompounds and analogs thereof, modulators of nuclear hormone receptor function |
| JP2009517389A (en) * | 2005-11-28 | 2009-04-30 | モーメンティブ・パフォーマンス・マテリアルズ・インク | Method for preparing unsaturated imidoalkoxysilane |
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