JPH0455191B2 - - Google Patents
Info
- Publication number
- JPH0455191B2 JPH0455191B2 JP1440484A JP1440484A JPH0455191B2 JP H0455191 B2 JPH0455191 B2 JP H0455191B2 JP 1440484 A JP1440484 A JP 1440484A JP 1440484 A JP1440484 A JP 1440484A JP H0455191 B2 JPH0455191 B2 JP H0455191B2
- Authority
- JP
- Japan
- Prior art keywords
- dione
- dithiol
- ylidene
- general formula
- group
- 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.)
- Expired
Links
- -1 Dithiol-2-ylidene Chemical class 0.000 claims description 20
- 150000001875 compounds Chemical class 0.000 claims description 16
- 239000003814 drug Substances 0.000 claims description 7
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 6
- 208000019423 liver disease Diseases 0.000 claims description 6
- 125000003258 trimethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])[*:1] 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- IBNLVXNNYIGLLB-UHFFFAOYSA-N 4-propan-2-ylcyclohexane-1,3-dione Chemical compound CC(C)C1CCC(=O)CC1=O IBNLVXNNYIGLLB-UHFFFAOYSA-N 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- LOGSONSNCYTHPS-UHFFFAOYSA-N cyclopentane-1,3-dione Chemical compound O=C1CCC(=O)C1 LOGSONSNCYTHPS-UHFFFAOYSA-N 0.000 claims description 3
- BADXJIPKFRBFOT-UHFFFAOYSA-N dimedone Chemical compound CC1(C)CC(=O)CC(=O)C1 BADXJIPKFRBFOT-UHFFFAOYSA-N 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 229940124597 therapeutic agent Drugs 0.000 claims description 3
- BXDJIVKCVVTETR-UHFFFAOYSA-N 4-methylcyclohexane-1,3-dione Chemical compound CC1CCC(=O)CC1=O BXDJIVKCVVTETR-UHFFFAOYSA-N 0.000 claims description 2
- 125000000129 anionic group Chemical group 0.000 claims description 2
- HJSLFCCWAKVHIW-UHFFFAOYSA-N cyclohexane-1,3-dione Chemical compound O=C1CCCC(=O)C1 HJSLFCCWAKVHIW-UHFFFAOYSA-N 0.000 claims description 2
- 239000002904 solvent Substances 0.000 description 9
- 206010067125 Liver injury Diseases 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 231100000234 hepatic damage Toxicity 0.000 description 7
- 230000008818 liver damage Effects 0.000 description 7
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 6
- 239000013078 crystal Substances 0.000 description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- IRKODEMCSCXDOI-UHFFFAOYSA-M 1,3-dithiol-2-ylidene(methyl)sulfanium;perchlorate Chemical compound [O-]Cl(=O)(=O)=O.CSC=1SC=C[S+]=1 IRKODEMCSCXDOI-UHFFFAOYSA-M 0.000 description 3
- RFLIZWSLNXFRIC-UHFFFAOYSA-N 2-(1,3-dithiol-2-ylidene)-5,5-dimethylcyclohexane-1,3-dione Chemical compound O=C1CC(C)(C)CC(=O)C1=C1SC=CS1 RFLIZWSLNXFRIC-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 102100036475 Alanine aminotransferase 1 Human genes 0.000 description 3
- 108010082126 Alanine transaminase Proteins 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 230000001771 impaired effect Effects 0.000 description 3
- 210000004185 liver Anatomy 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- WPHAFPAFYDFOJR-UHFFFAOYSA-N 2-(1,3-dithiol-2-ylidene)-4-methylcyclohexane-1,3-dione Chemical compound O=C1C(C)CCC(=O)C1=C1SC=CS1 WPHAFPAFYDFOJR-UHFFFAOYSA-N 0.000 description 2
- VIOPPSBIJRKGEG-UHFFFAOYSA-N 2-(1,3-dithiol-2-ylidene)-4-propan-2-ylcyclohexane-1,3-dione Chemical compound O=C1C(C(C)C)CCC(=O)C1=C1SC=CS1 VIOPPSBIJRKGEG-UHFFFAOYSA-N 0.000 description 2
- YYYUZRHTQUIZIM-UHFFFAOYSA-N 2-(1,3-dithiol-2-ylidene)cyclohexane-1,3-dione Chemical compound O=C1CCCC(=O)C1=C1SC=CS1 YYYUZRHTQUIZIM-UHFFFAOYSA-N 0.000 description 2
- XJGAZCWXULIQTB-UHFFFAOYSA-N 2-(1,3-dithiol-2-ylidene)cyclopentane-1,3-dione Chemical compound O=C1CCC(=O)C1=C1SC=CS1 XJGAZCWXULIQTB-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 125000003710 aryl alkyl group Chemical group 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- WYKJWNVWJOKVQP-UHFFFAOYSA-N 1,3-dithiole-2-thione Chemical compound S=C1SC=CS1 WYKJWNVWJOKVQP-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- SURCGQGDUADKBL-UHFFFAOYSA-N 2-(2-hydroxyethylamino)-5-nitrobenzo[de]isoquinoline-1,3-dione Chemical compound [O-][N+](=O)C1=CC(C(N(NCCO)C2=O)=O)=C3C2=CC=CC3=C1 SURCGQGDUADKBL-UHFFFAOYSA-N 0.000 description 1
- PLGPBTCNKJQJHQ-UHFFFAOYSA-N 4,4-dimethylcyclohexane-1,3-dione Chemical compound CC1(C)CCC(=O)CC1=O PLGPBTCNKJQJHQ-UHFFFAOYSA-N 0.000 description 1
- TWQLMCLEFOMAGX-UHFFFAOYSA-N 4-ethyl-5-methylcyclohexane-1,3-dione Chemical compound CCC1C(C)CC(=O)CC1=O TWQLMCLEFOMAGX-UHFFFAOYSA-N 0.000 description 1
- IDESFDLCRXUSGK-UHFFFAOYSA-N 4-ethylcyclohexane-1,3-dione Chemical compound CCC1CCC(=O)CC1=O IDESFDLCRXUSGK-UHFFFAOYSA-N 0.000 description 1
- RRPRDBWLNNQNDM-UHFFFAOYSA-N 5,5-dibenzylcyclohexane-1,3-dione Chemical compound C1C(=O)CC(=O)CC1(CC=1C=CC=CC=1)CC1=CC=CC=C1 RRPRDBWLNNQNDM-UHFFFAOYSA-N 0.000 description 1
- VUUNCMULTZRHHS-UHFFFAOYSA-N 5,5-diethylcyclohexane-1,3-dione Chemical compound CCC1(CC)CC(=O)CC(=O)C1 VUUNCMULTZRHHS-UHFFFAOYSA-N 0.000 description 1
- QPDAUGDDIALNNE-UHFFFAOYSA-N 5,5-dimethyl-4-phenylcyclohexane-1,3-dione Chemical compound CC1(C)CC(=O)CC(=O)C1C1=CC=CC=C1 QPDAUGDDIALNNE-UHFFFAOYSA-N 0.000 description 1
- IYUHIAGDLSLWOQ-UHFFFAOYSA-N 5-methyl-5-phenylcyclohexane-1,3-dione Chemical compound C=1C=CC=CC=1C1(C)CC(=O)CC(=O)C1 IYUHIAGDLSLWOQ-UHFFFAOYSA-N 0.000 description 1
- DMIIMPQQPXUKOO-UHFFFAOYSA-N 5-methylcyclohexane-1,3-dione Chemical compound CC1CC(=O)CC(=O)C1 DMIIMPQQPXUKOO-UHFFFAOYSA-N 0.000 description 1
- UPPYKNLSSLIIAZ-UHFFFAOYSA-N 5-phenylcyclohexane-1,3-dione Chemical compound C1C(=O)CC(=O)CC1C1=CC=CC=C1 UPPYKNLSSLIIAZ-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 230000002152 alkylating effect Effects 0.000 description 1
- SLUNEGLMXGHOLY-UHFFFAOYSA-N benzene;hexane Chemical compound CCCCCC.C1=CC=CC=C1 SLUNEGLMXGHOLY-UHFFFAOYSA-N 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 229940073608 benzyl chloride Drugs 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- GHAFORRTMVIXHS-UHFFFAOYSA-L bromosulfophthalein sodium Chemical compound [Na+].[Na+].C1=C(S([O-])(=O)=O)C(O)=CC=C1C1(C=2C=C(C(O)=CC=2)S([O-])(=O)=O)C(C(Br)=C(Br)C(Br)=C2Br)=C2C(=O)O1 GHAFORRTMVIXHS-UHFFFAOYSA-L 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000002026 chloroform extract Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 231100000753 hepatic injury Toxicity 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000000644 isotonic solution Substances 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000004923 naphthylmethyl group Chemical group C1(=CC=CC2=CC=CC=C12)C* 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Inorganic materials [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 1
- 229940021222 peritoneal dialysis isotonic solution Drugs 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000011282 treatment Methods 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
Description
本発明は新規な１，３−ジチオール−２−イリ
デン誘導体に関するものである。
さらに詳細には、本発明は肝障害抑制作用を有
する一般式〔〕
〔式中Ｚは置換もしくは未置換のエチレン基また
はトリメチレン基を示す〕で表わされる１，３−
ジチオール−２−イリデン誘導体、その製法およ
びそれを含有する医薬に関するものである。
本発明者らは、肝臓に疾患を持つ患者が多い反
面、有効な肝臓疾患治療剤のない現状に鑑み、新
規な肝臓疾患用剤を開発すべく、種々の化合物を
合成し、その肝障害抑制効果を調べた。
その結果、本発明化合物は四塩化炭素で誘発さ
れた被験動物肝障害モデルにおいて、血清中
GPT（グルタミツク−ピルビツクトランスアミナ
ーゼ）活性および血清中BSP（スルホブロムフタ
レイン ソデイウム テトラヒドレート）残量の
上昇を著しく抑制し、顕著な肝障害抑制効果をも
たらすことが判明した。また、肝臓の肉眼的観察
所見も、本発明化合物の顕著な肝障害抑制効果を
示すものであつた。
このように本発明化合物は、著しい肝障害抑制
効果を有し、各種肝臓疾患に対する予防および治
療剤として有用である。
本発明化合物は一般式〔〕
〔式中Ｚは置換もしくは未置換のエチレン基また
はトリメチレン基を示す〕で表わされる１，３−
ジチオール−２−イリデン誘導体である。一般式
〔〕中Ｚは置換されていてもよいエチレン基ま
たはトリメチレン基を示し、そ置換基としては例
えば低級アルキル基，アラルキル基およびアリー
ル基などが挙げられる。ここに低級アルキル基と
はメチル基，エチル基，プロピル基，イソプロピ
ル基，ブチル基，イソブチル基，tert−ブチル
基，ペンチル基，ヘキシル基などを、アラルキル
基とはベンジル基，ナフチルメチル基などを、ア
リール基とはフエニル基，ナフチル基などを意味
する。
本発明化合物の代表的なものを列挙すると次の
とおりである。
(1) ２−（１，３−ジチオール−２−イリデン）
シクロペンタン−１，３−ジオン
(2) ２−（１，３−ジチオール−２−イリデン）−
４，４−ジエチルシクロペンタン−１，３−ジ
オン
(3) ２−（１，３−ジチオール−２−イリデン）
シクロヘキサン−１，３−ジオン
(4) ２−（１，３−ジチオール−２−イリデン）−
４−メチルシクロヘキサン−１，３−ジオン
(5) ２−（１，３−ジチオール−２−イリデン）−
４−エチルシクロヘキサン−１，３−ジオン
(6) ２−（１，３−ジチオール−２−イリデン）−
４−イソプロピルシクロヘキサン−１，３−ジ
オン
(7) ２−（１，３−ジチオール−２−イリデン）−
５−メチルシクロヘキサン−１，３−ジオン
(8) ２−（１，３−ジチオール−２−イリデン）−
５−フエニルシクロヘキサン−１，３−ジオン
(9) ２−（１，３−ジチオール−２−イリデン）−
４，４−ジメチルシクロヘキサン−１，３−ジ
オン
(10) ２−（１，３−ジチオール−２−イリデン）−
５，５−ジメチルシクロヘキサン−１，３−ジ
オン
(11) ２−（１，３−ジチオール−２−イリデン）−
５，５−ジベンジルシクロヘキサン−１，３−
ジオン
(12) ２−（１，３−ジチオール−２−イリデン）−
４−エチル−５−メチルシクロヘキサン−１，
３−ジオン
(13) ２−（１，３−ジチオール−２−イリデン）−
５−メチル−５−フエニルシクロヘキサン−
１，３−ジオン
(14) ２−（１，３−ジチオール−２−イリデン）−
５，５−ジエチルシクロヘキサン−１，３−ジ
オン
(15) ２−（１，３−ジチオール−２−イリデン）−
５，５−ジメチル−４−フエニルシクロヘキサ
ン−１，３−ジオン
但し、本発明はこれら代表例に限定されるもの
ではない。
本発明化合物〔〕は一般式〔〕
〔式中Ｚは前記の意味を有する〕で表わされるβ
−ジケトン類を塩基の存在下に一般式〔〕
〔式中Ｒは低級アルキル基またはベンジル基、Ｘ
はアニオン残基を示す〕で表わされるジチオリウ
ム塩と反応させることにより製造することができ
る。
一般式〔〕で表わされるβ−ジケトン類とし
ては、例えばシクロペンタン−１，３−ジオン，
４，４−ジエチルシクロペンタン−１，３−ジオ
ン，４−エチルシクロヘキサン−１，３−ジオ
ン，４−イソプロピルシクロヘキサン−１，３−
ジオン，５−メチルシクロヘキサン−１，３−ジ
オン，５−フエニルシクロヘキサン−１，３−ジ
オン，４，４−ジメチルシクロヘキサン−１，３
−ジオン，５，５−ジメチルシクロヘキサン−
１，３−ジオン，５，５−ジベンジルシクロヘキ
サン−１，３−ジオン，４−エチル−５−メチル
シクロヘキサン−１，３−ジオン，５−メチル−
５−フエニルシクロヘキサン−１，３−ジオン，
５，５−ジエチルシクロヘキサン−１，３−ジオ
ン，５，５−ジメチル−４−フエニルシクロヘキ
サン−１，３−ジオンなどを挙げることができ
る。
また一般式〔〕で表わされるジチオリウム塩
は、１，３−ジチオール−２−チオンをジメチル
硫酸，ヨウ化メチル、ヨウ化エチルなどでアルキ
ル化するか、または塩化ベンジルなどでベンジル
化することにより合成することができる。
本発明の実施に際し、一般式〔〕で表わされ
るβ−ジケトン類と一般式〔〕で表わされるジ
チオリウム塩との反応は、適当な溶媒を使用して
行うことが望ましい。当該溶媒としては反応に関
与しない溶媒が好ましく、例えばテトラヒドロフ
ラン，ジオキサン，アルコール類，酢酸，ジメチ
ルスルホキサイド，ジメチルホルムアミドなどを
挙げることができる。また、これらの溶媒は二種
以上を混合して使用することもできる。
本発明の実施に使用できる塩基としては、例え
ば金属ナトリウム，水素化ナトリウム，ナトリウ
ムメトキサイド，水酸化ナトリウム，水酸化カリ
ウムなどが挙げられる。反応は通常０℃〜溶媒の
沸点までの温度範囲で行なわれるが、反応速度を
コントロールするためにこれ以上あるいはこれ以
下の温度で行なうこともできる。
反応終了後、常法例えば反応物から適当な溶媒
で目的物を抽出し、溶媒を除去すれば目的物が得
られる。また、必要に応じて再結晶法あるいはカ
ラムクロマト法などにより、目的物を分離・精製
することもできる。
本発明化合物を肝臓疾患治療剤として使用する
場合、その投与量は、患者の体重、年令、性別、
投与方法、体調、病状などにより異なるが、通常
経口投与の場合は、体重１Kg当り１日に0.1〜2.5
mg、非経口投与の場合は、体重１Kg当り１日に
0.01〜100mgである。
本発明の化合物を製剤化するためには、製剤の
技術における通常の方法で錠剤，顆粒剤，散剤，
懸濁剤，カプセル剤，注射液，等張液などの剤形
とする。
経口用固形製剤を製造する場合は主薬に賦形
剤、さらに必要に応じて縮合剤，崩壊剤，滑沢
剤，着色剤，矯味矯臭剤を加えた後、常法により
錠剤，被覆錠剤，顆粒剤，散剤，カプセル剤とす
る。
注射剤を調整する場合には、主薬に必要により
PH調整剤，緩衝剤，懸濁剤，溶解補助剤，安定化
剤，等張化剤，保存剤などを添加し、常法によ
り、皮下、筋肉内、静脈内用注射剤とする。
以下に薬理試験例を挙げ本発明化合物の肝障害
抑制効果を示す。
薬理試験例
供試薬剤（実施例１の化合物）をオリーブ油に
懸濁して、マウス（23±２ｇ）に経口投与し、薬
剤の投与６時間後に四塩化炭素を投与した。四塩
化炭素の投与24時間後にBSP75mg／Kgを尾静脈
内へ投与し、その30分後に心採血を行ない、血清
中のGPT活性（Reitman−Frankel）およびBSP
残量を測定した。また採血直後の肝障害を肉眼的
に観察し、下記の様な評価法により判定を行つ
た。
０……正常な肝臓
２……わずかに障害を認めたもの
４……明かに障害を認めたもの
６……著しい障害
供試薬剤は下表に示されるように、各測定項目
のいずれにおいても著しい肝障害抑制効果を示し
た。
The present invention relates to novel 1,3-dithiol-2-ylidene derivatives. More specifically, the present invention provides the general formula [] 1,3- represented by [wherein Z represents a substituted or unsubstituted ethylene group or trimethylene group]
This invention relates to dithiol-2-ylidene derivatives, their production methods, and pharmaceuticals containing them. Although there are many patients with liver diseases, there are currently no effective treatments for liver diseases.In order to develop new drugs for liver diseases, the present inventors synthesized various compounds to suppress liver damage. We investigated the effects. As a result, the compound of the present invention was found to be effective in serum levels in a carbon tetrachloride-induced liver injury model in test animals.
It was found that the increase in GPT (glutamic-pyruvic transaminase) activity and the residual amount of BSP (sulfobromophthalein sodium tetrahydrate) in serum was significantly suppressed, resulting in a significant liver damage suppressing effect. Macroscopic observation of the liver also showed that the compound of the present invention had a remarkable effect of suppressing liver damage. As described above, the compound of the present invention has a remarkable effect of inhibiting liver damage and is useful as a prophylactic and therapeutic agent for various liver diseases. The compound of the present invention has the general formula [] 1,3- represented by [wherein Z represents a substituted or unsubstituted ethylene group or trimethylene group]
It is a dithiol-2-ylidene derivative. In the general formula [], Z represents an optionally substituted ethylene group or trimethylene group, and examples of the substituent include a lower alkyl group, an aralkyl group, and an aryl group. Here, lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, etc., and aralkyl includes benzyl, naphthylmethyl, etc. , aryl group means phenyl group, naphthyl group, etc. Representative compounds of the present invention are listed below. (1) 2-(1,3-dithiol-2-ylidene)
Cyclopentane-1,3-dione(2) 2-(1,3-dithiol-2-ylidene)-
4,4-diethylcyclopentane-1,3-dione (3) 2-(1,3-dithiol-2-ylidene)
Cyclohexane-1,3-dione (4) 2-(1,3-dithiol-2-ylidene)-
4-Methylcyclohexane-1,3-dione (5) 2-(1,3-dithiol-2-ylidene)-
4-Ethylcyclohexane-1,3-dione (6) 2-(1,3-dithiol-2-ylidene)-
4-isopropylcyclohexane-1,3-dione (7) 2-(1,3-dithiol-2-ylidene)-
5-Methylcyclohexane-1,3-dione (8) 2-(1,3-dithiol-2-ylidene)-
5-phenylcyclohexane-1,3-dione (9) 2-(1,3-dithiol-2-ylidene)-
4,4-dimethylcyclohexane-1,3-dione(10) 2-(1,3-dithiol-2-ylidene)-
5,5-dimethylcyclohexane-1,3-dione (11) 2-(1,3-dithiol-2-ylidene)-
5,5-dibenzylcyclohexane-1,3-
Dione(12) 2-(1,3-dithiol-2-ylidene)-
4-ethyl-5-methylcyclohexane-1,
3-Dione(13) 2-(1,3-dithiol-2-ylidene)-
5-Methyl-5-phenylcyclohexane-
1,3-dione(14) 2-(1,3-dithiol-2-ylidene)-
5,5-diethylcyclohexane-1,3-dione (15) 2-(1,3-dithiol-2-ylidene)-
5,5-dimethyl-4-phenylcyclohexane-1,3-dione However, the present invention is not limited to these representative examples. The compound of the present invention [] has the general formula [] β represented by [in the formula, Z has the above meaning]
- Diketones are prepared with the general formula [] in the presence of a base. [In the formula, R is a lower alkyl group or a benzyl group,
represents an anionic residue] by reacting with a dithiolium salt represented by: Examples of β-diketones represented by the general formula [] include cyclopentane-1,3-dione,
4,4-diethylcyclopentane-1,3-dione, 4-ethylcyclohexane-1,3-dione, 4-isopropylcyclohexane-1,3-
dione, 5-methylcyclohexane-1,3-dione, 5-phenylcyclohexane-1,3-dione, 4,4-dimethylcyclohexane-1,3
-Dione, 5,5-dimethylcyclohexane-
1,3-dione, 5,5-dibenzylcyclohexane-1,3-dione, 4-ethyl-5-methylcyclohexane-1,3-dione, 5-methyl-
5-phenylcyclohexane-1,3-dione,
Examples include 5,5-diethylcyclohexane-1,3-dione and 5,5-dimethyl-4-phenylcyclohexane-1,3-dione. Dithiolium salts represented by the general formula [] can be synthesized by alkylating 1,3-dithiol-2-thione with dimethyl sulfate, methyl iodide, ethyl iodide, etc., or by benzylating it with benzyl chloride, etc. can do. In carrying out the present invention, the reaction between the β-diketones represented by the general formula [] and the dithiolium salt represented by the general formula [] is preferably carried out using an appropriate solvent. The solvent is preferably a solvent that does not participate in the reaction, such as tetrahydrofuran, dioxane, alcohols, acetic acid, dimethyl sulfoxide, dimethylformamide, and the like. Moreover, these solvents can also be used in combination of two or more types. Bases that can be used in the practice of the present invention include, for example, sodium metal, sodium hydride, sodium methoxide, sodium hydroxide, potassium hydroxide, and the like. The reaction is usually carried out at a temperature ranging from 0°C to the boiling point of the solvent, but it can also be carried out at a temperature higher or lower than this in order to control the reaction rate. After completion of the reaction, the target product can be obtained by a conventional method, for example, by extracting the target product from the reactants with a suitable solvent and removing the solvent. Furthermore, the target product can also be separated and purified by recrystallization, column chromatography, or the like, if necessary. When the compound of the present invention is used as a therapeutic agent for liver disease, the dosage should be determined based on the patient's weight, age, sex,
It varies depending on the administration method, physical condition, medical condition, etc., but in the case of oral administration, the dose is usually 0.1 to 2.5 per kg of body weight per day.
mg per kg body weight per day for parenteral administration
It is 0.01-100mg. To formulate the compounds of the present invention, tablets, granules, powders,
Dosage forms include suspensions, capsules, injections, and isotonic solutions. When manufacturing oral solid preparations, excipients are added to the active ingredient, and if necessary, condensing agents, disintegrants, lubricants, coloring agents, and flavoring agents are added, and then tablets, coated tablets, and granules are prepared using conventional methods. In the form of tablets, powders, and capsules. When preparing injections, add the main drug as necessary.
Add PH adjusting agents, buffering agents, suspending agents, solubilizing agents, stabilizers, isotonic agents, preservatives, etc., and prepare subcutaneous, intramuscular, or intravenous injections using conventional methods. Pharmacological test examples are given below to demonstrate the liver damage suppressing effects of the compounds of the present invention. Pharmacological Test Example A test drug (compound of Example 1) was suspended in olive oil and orally administered to mice (23±2 g), and carbon tetrachloride was administered 6 hours after administration of the drug. 24 hours after administration of carbon tetrachloride, 75 mg/Kg of BSP was administered into the tail vein, and 30 minutes later, cardiac blood was collected, and serum GPT activity (Reitman-Frankel) and BSP were measured.
The remaining amount was measured. In addition, liver damage was visually observed immediately after blood collection, and judgment was made using the following evaluation method. 0...Normal liver 2...Slightly impaired liver 4...Obviously impaired 6...Severely impaired It showed a remarkable effect on suppressing liver damage.
【表】
以下に実施例を挙げて説明する。
実施例 １
乾燥テトラヒドロフラン20mlに60％油性水素化
ナトリウム0.4ｇを懸濁し、氷冷下に５，５−ジ
メチルシクロヘキサン−１，３−ジオン1.4ｇを
徐々に加える。水素ガスの発生が終つてから、２
−メチルチオ−１，３−ジチオリウム パークロ
レート2.5ｇを加え１時間加熱還流する。ついで
反応液から溶媒を減圧留去し、残留物に氷水を加
えたのち、目的物をクロロホルム抽出する。クロ
ロホルム抽出液を減圧濃縮し、残留物をベンゼン
−ｎ−ヘキサンより再結晶すると２−（１，３−
ジチオール−２−イリデン）−５，５−ジメチル
シクロヘキサン−１，３−ジオン2.0ｇ（収率83
％）がm.p201℃の結晶として得られる。
IRνKBr naxcm-1：2950，1585，1380，1338，1280，
715
NMR（CDCI3）δ：1.07（6H，ｓ），2.53（4H，
ｓ），7.46（2H，ｓ）
実施例 ２
シクロヘキサン−１，３−ジオン１，１ｇ，２
−メチルチオ−１，３−ジチオリウム パークロ
レート2.5ｇを用い、実施例１と同様に処理し、
ベンゼンより再結晶すると２−（１，３−ジチオ
ール−２−イリデン）シクロヘキサン−１，３−
ジオン１，７ｇ（収率82％）がm.p.225〜６℃の
結晶として得られる。
IRνKBr naxcm-1：3100，1590，1380，1262，190
NMR（CDCI3）δ：2.01（2H，ｔ），2.67（4H，
ｔ），7.42（2H，ｓ）
実施例 ３
４−メチルシクロヘキサン−１，３−ジオン
1.3ｇ，２−メチルチオ−１，３−ジチオリウム
パークロレート2.5ｇを用い、実施例１と同様
に処理し、アセトンより再結晶すると２−（１，
３−ジチオール−２−イリデン）−４−メチルシ
クロヘキサン−１，３−ジオン1.6ｇ（収率69％）
がm.p.147〜８℃の結晶として得られる。
IRνKBr naxcm-1：3050，1590，1380，1270，1225，
720
NMR（CDCI3）δ：1.32（3H，ｄ），1.70〜2.90
（5H，ｍ），7.44（2H，ｓ）
実施例 ４
４−イソプロピルシクロヘキサン−１，３−ジ
オン1.5ｇ，２−メチルチオ−１，３−ジチオリ
ウム パークロレート2.5ｇを用い、実施例１と
同様に処理し、酢酸エチル−ジエチルエーテルよ
り再結晶すると２−（１，３−ジチオール−２−
イリデン）−４−イソプロピルシクロヘキサン−
１，３−ジオン2.1ｇ（収率85％）がm.p.115〜７
℃の結晶として得られる。
IRνKBr naxcm-1：2950，1592，1380，1278，1275，
700
NMR（CDCI3）δ：0.90（3H，ｄ），1.21（3H，
ｄ），1.70〜3.02（6H，ｍ），7.45（2H，ｓ）
実施例 ５
シクロペンタン−１，３−ジオン1.0ｇ，２−
メチルチオ−１，３−ジチオリウム パークロレ
ート2.5ｇを用い、実施例１と同様に処理し、シ
リカゲルカラムクロマトにより精製すると２−
（１，３−ジチオール−２−イリデン）シクロペ
ンタン−１，３−ジオン0.2ｇ（収率10％）がm.
p.205〜７℃の結晶として得られる。
IRνKBr naxcm-1：2920，1610，1430，1410，1300，
1250
NMR（CDCI3）δ：7.90（2H，ｓ），2.70（4H，
ｓ）[Table] Examples will be given and explained below. Example 1 0.4 g of 60% oily sodium hydride is suspended in 20 ml of dry tetrahydrofuran, and 1.4 g of 5,5-dimethylcyclohexane-1,3-dione is gradually added under ice cooling. After the generation of hydrogen gas has finished, 2
Add 2.5 g of -methylthio-1,3-dithiolium perchlorate and heat under reflux for 1 hour. Then, the solvent was distilled off from the reaction solution under reduced pressure, ice water was added to the residue, and the target product was extracted with chloroform. The chloroform extract was concentrated under reduced pressure, and the residue was recrystallized from benzene-n-hexane to give 2-(1,3-
dithiol-2-ylidene)-5,5-dimethylcyclohexane-1,3-dione 2.0 g (yield 83
%) is obtained as crystals with m.p 201°C. IRν KBr nax cm -1 : 2950, 1585, 1380, 1338, 1280,
715 NMR (CDCI 3 ) δ: 1.07 (6H, s), 2.53 (4H,
s), 7.46 (2H, s) Example 2 Cyclohexane-1,3-dione 1,1g,2
- Treated in the same manner as in Example 1 using 2.5 g of methylthio-1,3-dithiolium perchlorate,
Recrystallization from benzene yields 2-(1,3-dithiol-2-ylidene)cyclohexane-1,3-
1.7 g (82% yield) of the dione are obtained as crystals with a mp of 225-6°C. IRν KBr nax cm -1 : 3100, 1590, 1380, 1262, 190 NMR (CDCI 3 ) δ: 2.01 (2H, t), 2.67 (4H,
t), 7.42 (2H, s) Example 3 4-Methylcyclohexane-1,3-dione
2-(1,
1.6 g (yield 69%) of 3-dithiol-2-ylidene)-4-methylcyclohexane-1,3-dione
is obtained as crystals with a temperature of mp 147-8°C. IRν KBr nax cm -1 : 3050, 1590, 1380, 1270, 1225,
720 NMR ( CDCI3 ) δ: 1.32 (3H, d), 1.70-2.90
(5H, m), 7.44 (2H, s) Example 4 Same as Example 1 using 1.5 g of 4-isopropylcyclohexane-1,3-dione and 2.5 g of 2-methylthio-1,3-dithiolium perchlorate. 2-(1,3-dithiol-2-
ylidene)-4-isopropylcyclohexane-
2.1g of 1,3-dione (yield 85%) has mp115~7
Obtained as crystals at °C. IRν KBr nax cm -1 : 2950, 1592, 1380, 1278, 1275,
700 NMR (CDCI 3 ) δ: 0.90 (3H, d), 1.21 (3H,
d), 1.70-3.02 (6H, m), 7.45 (2H, s) Example 5 Cyclopentane-1,3-dione 1.0g, 2-
2.5 g of methylthio-1,3-dithiolium perchlorate was treated in the same manner as in Example 1, and purified by silica gel column chromatography.
(1,3-dithiol-2-ylidene)cyclopentane-1,3-dione 0.2 g (yield 10%) m.
Obtained as crystals at p.205-7°C. IRν KBr nax cm -1 : 2920, 1610, 1430, 1410, 1300,
1250 NMR (CDCI 3 ) δ: 7.90 (2H, s), 2.70 (4H,
s)
Claims (1)
はトリメチレン基を示す〕で表わされる１，３−
ジチオール−２−イリデン誘導体。 ２ ２−（１，３−ジチオール−２−イリデン）
シクロペンタン−１，３−ジオンである特許請求
の範囲第１項記載の化合物。 ３ ２−（１，３−ジチオール−２−イリデン）
シクロヘキサン−１，３−ジオンである特許請求
の範囲第１項記載の化合物。 ４ ２−（１，３−ジチオール−２−イリデン）−
４−メチルシクロヘキサン−１，３−ジオンであ
る特許請求の範囲第１項記載の化合物。 ５ ２−（１，３−ジチオール−２−イリデン）−
４−イソプロピルシクロヘキサン−１，３−ジオ
ンである特許請求の範囲第１項記載の化合物。 ６ ２−（１，３−ジチオール−２−イリデン）−
５，５−ジメチルシクロヘキサン−１，３−ジオ
ンである特許請求の範囲第１項記載の化合物。 ７ 一般式〔〕 〔式中Ｚは置換もしくは未置換のエチレン基また
はトリメチレン基を示す〕で表わされるβ−ジケ
トン類を塩基の存在下に一般式〔〕 〔式中Ｒは低級アルキル基またはベンジル基，Ｘ
はアニオン残基を示す〕で表わされるジチオリウ
ム塩と反応させることを特徴とする一般式〔〕 〔式中Ｚは前記の意味を有する〕で表わされる
１，３−ジチオール−２−イリデン誘導体の製
法。 ８ 一般式〔〕 〔式中Ｚは置換もしくは未置換のエチレン基また
はトリメチレン基を示す〕で表わされる１，３−
ジチオール−２−イリデン誘導体を含有する肝臓
疾患治療剤。[Claims] 1 General formula [I] 1,3- represented by [wherein Z represents a substituted or unsubstituted ethylene group or trimethylene group]
Dithiol-2-ylidene derivative. 2 2-(1,3-dithiol-2-ylidene)
The compound according to claim 1, which is cyclopentane-1,3-dione. 3 2-(1,3-dithiol-2-ylidene)
The compound according to claim 1, which is cyclohexane-1,3-dione. 4 2-(1,3-dithiol-2-ylidene)-
The compound according to claim 1, which is 4-methylcyclohexane-1,3-dione. 5 2-(1,3-dithiol-2-ylidene)-
The compound according to claim 1, which is 4-isopropylcyclohexane-1,3-dione. 6 2-(1,3-dithiol-2-ylidene)-
The compound according to claim 1, which is 5,5-dimethylcyclohexane-1,3-dione. 7 General formula [] [In the formula, Z represents a substituted or unsubstituted ethylene group or trimethylene group] β-diketones represented by the general formula [] [In the formula, R is a lower alkyl group or a benzyl group,
represents an anionic residue] General formula characterized by reaction with a dithiolium salt represented by [] A method for producing a 1,3-dithiol-2-ylidene derivative represented by [wherein Z has the above-mentioned meaning]. 8 General formula [] 1,3- represented by [wherein Z represents a substituted or unsubstituted ethylene group or trimethylene group]
A therapeutic agent for liver diseases containing a dithiol-2-ylidene derivative.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1440484A JPS60161980A (en) | 1984-01-31 | 1984-01-31 | 1,3-dithiol-2-ylidene derivative |
| CN 85105298 CN85105298A (en) | 1984-01-31 | 1985-07-10 | 1, the preparation method of 3-dithiole-2-ylidene derivatives |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1440484A JPS60161980A (en) | 1984-01-31 | 1984-01-31 | 1,3-dithiol-2-ylidene derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS60161980A JPS60161980A (en) | 1985-08-23 |
| JPH0455191B2 true JPH0455191B2 (en) | 1992-09-02 |
Family
ID=11860105
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP1440484A Granted JPS60161980A (en) | 1984-01-31 | 1984-01-31 | 1,3-dithiol-2-ylidene derivative |
Country Status (2)
| Country | Link |
|---|---|
| JP (1) | JPS60161980A (en) |
| CN (1) | CN85105298A (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4863925A (en) * | 1986-09-24 | 1989-09-05 | Nihon Nohyaku Co., Ltd. | Cyclohexanedione derivative for hepatic disorders and a process for producing the same |
| AT389310B (en) * | 1988-03-09 | 1989-11-27 | Nihon Nohyaku Co Ltd | Cyclohexanedione derivative and process for its preparation |
-
1984
- 1984-01-31 JP JP1440484A patent/JPS60161980A/en active Granted
-
1985
- 1985-07-10 CN CN 85105298 patent/CN85105298A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| CN85105298A (en) | 1987-01-28 |
| JPS60161980A (en) | 1985-08-23 |
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