JPH02134382A - Bisbenzylisoquinoline derivative - Google Patents
Bisbenzylisoquinoline derivativeInfo
- Publication number
- JPH02134382A JPH02134382A JP28579088A JP28579088A JPH02134382A JP H02134382 A JPH02134382 A JP H02134382A JP 28579088 A JP28579088 A JP 28579088A JP 28579088 A JP28579088 A JP 28579088A JP H02134382 A JPH02134382 A JP H02134382A
- Authority
- JP
- Japan
- Prior art keywords
- compound
- formula
- group
- bisbenzylisoquinoline
- compound expressed
- 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
- BJWWOUUGCAPHOV-UHFFFAOYSA-N 1,3-dibenzylisoquinoline Chemical class C=1C2=CC=CC=C2C(CC=2C=CC=CC=2)=NC=1CC1=CC=CC=C1 BJWWOUUGCAPHOV-UHFFFAOYSA-N 0.000 title claims description 7
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims abstract description 3
- 239000002253 acid Substances 0.000 claims description 6
- 239000004480 active ingredient Substances 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 23
- 239000002904 solvent Substances 0.000 abstract description 6
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 abstract description 4
- 229910000104 sodium hydride Inorganic materials 0.000 abstract description 4
- 239000012312 sodium hydride Substances 0.000 abstract description 4
- 125000000217 alkyl group Chemical group 0.000 abstract description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 abstract description 2
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 abstract description 2
- 239000011261 inert gas Substances 0.000 abstract description 2
- 125000003545 alkoxy group Chemical group 0.000 abstract 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 abstract 1
- 239000003795 chemical substances by application Substances 0.000 abstract 1
- 125000000062 cyclohexylmethoxy group Chemical group [H]C([H])(O*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 abstract 1
- 229910052736 halogen Inorganic materials 0.000 abstract 1
- 150000002367 halogens Chemical class 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- YJRWQNIRFXVBRB-WDYNHAJCSA-N homoaromoline Chemical compound C1C(C=C2)=CC=C2OC(=C2)C(OC)=CC=C2C[C@H](C2=C3)N(C)CCC2=CC(OC)=C3OC2=C(O)C(OC)=CC3=C2[C@H]1N(C)CC3 YJRWQNIRFXVBRB-WDYNHAJCSA-N 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- YJRWQNIRFXVBRB-UHFFFAOYSA-N Cycleapeltine Natural products C1C(C=C2)=CC=C2OC(=C2)C(OC)=CC=C2CC(C2=C3)N(C)CCC2=CC(OC)=C3OC2=C(O)C(OC)=CC3=C2C1N(C)CC3 YJRWQNIRFXVBRB-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 239000000843 powder Substances 0.000 description 5
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 229940125782 compound 2 Drugs 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 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 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 229940125904 compound 1 Drugs 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- WVTKBKWTSCPRNU-KYJUHHDHSA-N (+)-Tetrandrine Chemical compound C([C@H]1C=2C=C(C(=CC=2CCN1C)OC)O1)C(C=C2)=CC=C2OC(=C2)C(OC)=CC=C2C[C@@H]2N(C)CCC3=CC(OC)=C(OC)C1=C23 WVTKBKWTSCPRNU-KYJUHHDHSA-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
- 241000196324 Embryophyta Species 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- ATHHXGZTWNVVOU-UHFFFAOYSA-N N-methylformamide Chemical compound CNC=O ATHHXGZTWNVVOU-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 2
- 239000008116 calcium stearate Substances 0.000 description 2
- 235000013539 calcium stearate Nutrition 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 241000219071 Malvaceae Species 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 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
- YKTSYUJCYHOUJP-UHFFFAOYSA-N [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] Chemical compound [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] YKTSYUJCYHOUJP-UHFFFAOYSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 125000004429 atom Chemical group 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
- UUWSLBWDFJMSFP-UHFFFAOYSA-N bromomethylcyclohexane Chemical compound BrCC1CCCCC1 UUWSLBWDFJMSFP-UHFFFAOYSA-N 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 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
- 201000011510 cancer Diseases 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 210000004748 cultured cell Anatomy 0.000 description 1
- 230000001085 cytostatic effect Effects 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- -1 for example Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 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
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- WVTKBKWTSCPRNU-UHFFFAOYSA-N rac-Tetrandrin Natural products O1C(C(=CC=2CCN3C)OC)=CC=2C3CC(C=C2)=CC=C2OC(=C2)C(OC)=CC=C2CC2N(C)CCC3=CC(OC)=C(OC)C1=C23 WVTKBKWTSCPRNU-UHFFFAOYSA-N 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
本発明は新規なビスベンジルイソキノリン誘導体及びそ
れを有効成分とする抗がん剤に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel bisbenzylisoquinoline derivative and an anticancer agent containing the same as an active ingredient.
つづらふじ科その他の植物に含有されるビスベンジルイ
ソキノリン系アルカロイド、例えばテトランドリン、セ
ファランチｙ等に抗がん作用のあることは知られている
（ Ｃｈｅｍ、 Ｐｈａｒｍ。It is known that bisbenzylisoquinoline alkaloids, such as tetrandrine and cephalanthyl, contained in plants of the family Tiliaceae and other plants, have anticancer effects (Chem, Pharm).
Ｂｕｌｌ、第２４巻２４１６〜２４２０頁１９７６年参
照）。本発明者らは、ベンゼン環に水酸基ヲ有スるビス
ベンジルイソキノリン系アルカロイド例えばホモアロモ
リン及びファンキノリンの水酸基にアルキル基を導入し
て各種誘導体を合成し、それら化合物について薬理作用
を検討した。その結果、ある種のビスベンジルイソキノ
リン誘導体が優れたかん細胞増殖抑制作用を示すことを
見出した。Bull, Vol. 24, pp. 2416-2420, 1976). The present inventors synthesized various derivatives by introducing an alkyl group into the hydroxyl group of bisbenzylisoquinoline alkaloids having a hydroxyl group on the benzene ring, such as homoaromoline and fanquinoline, and investigated the pharmacological effects of these compounds. As a result, we found that certain bisbenzylisoquinoline derivatives exhibit excellent cell growth inhibiting activity.
本発明はこの知見に基くもので、一般式式Ｉの化合物は
、一般式
（式中Ｒｔ ハＣ，〜Ｃ１゜−アルコキシ基、シクロヘ
キシルメチルオキシ基又はベンジルオキシ基、Ｒ２及び
Ｒ８は一方が水素原子、他方がメトキシ基を示す）で表
わされるビスベンジルイソキノリン誘導体又はその酸付
加塩である。The present invention is based on this knowledge, and the compound of the general formula I has the following general formula: one atom and the other represents a methoxy group) or an acid addition salt thereof.
式■の化合物は文献未載の新規化合物であって、例えば
下記のものがあげられる。７−〇−ペンジルホモアロモ
リン（化合物１ ）、 ７ 。The compound of formula (1) is a new compound that has not been described in any literature, and includes, for example, the following compounds. 7-0-penzyl homoaromoline (compound 1), 7.
−ｎ−テカニルホモアロモリン（化合物２）、７−０−
ｎ−へキシルホモアロモリン（化合物６）、７−０−
シクロヘキシルメチルファンキノリン（化合物４）、７
−０− ｎ−オクチルファンキノリン（化合物５ ）、
７−０−ｎ−ブチルファンキノリン（化合物６）など
。-n-tecanyl homoaromoline (compound 2), 7-0-
n-hexyl homoaromoline (compound 6), 7-0-
Cyclohexylmethylphanquinoline (compound 4), 7
-0-n-octylphanquinoline (compound 5),
7-0-n-butylfanquinoline (compound 6) and the like.
（式中Ｒ２及びＲ１は前記の意味を有する）で表わされ
る化合物を一般式
（式中ＲはＣ１〜Ｃｌ０−アルキル基、シクロヘキシル
メチル基又はベンジル基、Ｚはハロゲン原子を示す）で
表わされる化合物と反応させることにより得られる。A compound represented by the general formula (wherein R2 and R1 have the above-mentioned meanings) (wherein R is a C1-Cl0-alkyl group, a cyclohexylmethyl group, or a benzyl group, and Z represents a halogen atom) Obtained by reacting with
式１１の化合物としては、ホモアロモリン（Ｒ２＝ Ｈ
、Ｒ３＝ ０ＣＨ８）、ファンキノリン（Ｒｔ ＝ ０
ＣＨ５、Ｒ，＝Ｈ）等があげられる。式■の化合物には
ＳＳ体、ＳＲ体、Ｒ８体及びＲＲ体の４種の立体異性体
が存在するが、これらの異性体を用いてもよい。The compound of formula 11 includes homoaromoline (R2=H
, R3=0CH8), fanquinoline (Rt=0
CH5, R, =H), etc. The compound of formula (1) has four stereoisomers: SS form, SR form, R8 form and RR form, and these isomers may also be used.
式■の化合物の置換基Ｚのだめのハロゲン原子としては
、例えば塩素原子、沃素原子、臭素原子があげられる。Examples of the halogen atom in the substituent Z of the compound of formula (2) include a chlorine atom, an iodine atom, and a bromine atom.
置換基ＨのためのＣ８〜Ｃｌ０−アルキル基としては例
えばプロピル基、ブチル基、ペンチル基、ヘキシル基、
ヘプチル基、オクチル基、ノニル基、デカニル基があげ
られる。Examples of the C8-Cl0-alkyl group for the substituent H include propyl group, butyl group, pentyl group, hexyl group,
Examples include heptyl group, octyl group, nonyl group, and decanyl group.
直鎖状のアルキル基が好ましい。Straight chain alkyl groups are preferred.
式■と弐■の化合物の反応は溶媒中、反応剤の存在下に
行うことが好ましい。溶媒としては例えばンメチルホル
ムアミド、テトラヒドロフラン、ジエチルエーテルなど
のエーテル類、反応剤としては例えば水素化ナトリウム
が用いられる。The reaction of the compounds of formulas (1) and (2) is preferably carried out in a solvent in the presence of a reactant. As the solvent, for example, ethers such as methylformamide, tetrahydrofuran and diethyl ether are used, and as the reactant, for example, sodium hydride is used.
本反応は不活性ガス例えばアルゴンガス、窒素ガス中で
行うことが好ましい。This reaction is preferably carried out in an inert gas such as argon gas or nitrogen gas.
弐■の化合物は常法により酸付加塩に導（ことができる
。酸としては生理的に無害な酸、例えば塩酸、硫酸、硝
酸、燐酸等の無機酸、酢酸。The compound 2) can be converted into an acid addition salt by a conventional method. Examples of acids include physiologically harmless acids, such as inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid, and acetic acid.
フマル酸、りんご酸、（えん酸、こはく酸等が好ましい
。Fumaric acid, malic acid, (citric acid, succinic acid, etc.) are preferred.
式Ｉの化合物は優れたかん細胞増殖抑制作用を示す。し
たがって本発明はさらに式Ｉの化合物を有効成分とする
抗がん剤である。The compounds of formula I exhibit excellent cytostatic activity. Accordingly, the present invention further provides an anticancer agent containing a compound of formula I as an active ingredient.
式Ｉの化合物は抗がん剤としてそのまま用いてもよいが
１通常は賦形剤、結合剤、滑沢剤、溶剤、安定化剤等を
添加し、錠剤、散剤、顆粒剤、カプセル剤、注射剤等に
製剤化して用いられる。賦形剤としては例えば殿粉、乳
糖、メチルセルロース、結晶セルロース、合成珪酸アル
ミニウム等、結合剤としては例えばヒドロキシプロピル
セルロース、ポリビニルピロリドン等、滑沢剤としては
例えばタルク、ステアリン酸マグネシウム、ステアリン
酸カルシウム等があげられる。The compound of formula I may be used as it is as an anticancer agent, but usually excipients, binders, lubricants, solvents, stabilizers, etc. are added to form tablets, powders, granules, capsules, etc. It is used in formulations such as injections. Excipients include starch, lactose, methylcellulose, crystalline cellulose, synthetic aluminum silicate, etc. Binders include hydroxypropyl cellulose, polyvinylpyrrolidone, etc. Lubricants include talc, magnesium stearate, calcium stearate, etc. can give.
本発明の薬剤の投与量は、経口投与の場合は１日当り有
効成分として１０〜１０００ｍ９好ましくは６０〜６０
０■である。In the case of oral administration, the dosage of the drug of the present invention is 10 to 1000 m9 as the active ingredient per day, preferably 60 to 60 m9.
It is 0■.
製造例１
ホモアロモリン５９２ｒｎ９（１ミリモル）を無水ジメ
チルホルムアミド５ ｍｌに溶解した溶液に水素化ナト
リウム（６０％）４４■（１，１ミリモル）を加え５、
アルゴン気流中ベンジルクロライド１４０ｒｎ９（１，
１ミリモル）を加える。室温に一夜放置したのちエーテ
ルで抽出、乾燥後溶媒を留去する。残留物にヘキサンを
加えて戸数すると、融点６２〜６５℃の無孔状粉末とし
て化合物１が得られる。Production Example 1 To a solution of homoaromoline 592rn9 (1 mmol) dissolved in 5 ml of anhydrous dimethylformamide, add 44 μm (1.1 mmol) of sodium hydride (60%).
Benzyl chloride 140rn9 (1,
1 mmol). After standing at room temperature overnight, the mixture was extracted with ether, dried, and the solvent was distilled off. When hexane is added to the residue, Compound 1 is obtained as a non-porous powder with a melting point of 62-65°C.
同様にして化合物２及び３が得られる。Compounds 2 and 3 are obtained in the same manner.
化合物２：融点７２〜７４℃、無孔状粉末〃 ３： 〃
６０〜６４℃、 〃製造例２
ファンキノリン５９２ｍ９Ｃ１ミリモル）を無水ジメチ
ルホルムアミド５ ｍｌに溶解した溶液に水素化ナトリ
ウム（６０％）４４ｒｎ９（１，１ミリモル）ヲ加工、
アルゴン気流中シクロヘキシルメチルブロマイド１９５
■（１，１ミリモル）を加える。室温に一夜放置したの
ちエーテルで抽出、乾燥後溶媒を留去する。残留物にヘ
キサンを加えて戸数すると、融点８１〜８３℃の無孔状
粉末として化合物４が得られる。Compound 2: Melting point 72-74°C, non-porous powder 3: 〃
60-64°C, [Production Example 2] Sodium hydride (60%) 44rn9 (1.1 mmol) was processed into a solution of fanquinoline 592m9C1 mmol) dissolved in 5 ml of anhydrous dimethylformamide.
Cyclohexyl methyl bromide 195 in argon stream
■ Add (1.1 mmol). After standing at room temperature overnight, the mixture was extracted with ether, dried, and the solvent was distilled off. When hexane is added to the residue and mixed, Compound 4 is obtained as a non-porous powder with a melting point of 81-83°C.
同様にして化合物５．６が得られる。Compound 5.6 is obtained in the same manner.
化合物５：＠点７７〜７９℃、無孔状粉末／／ ６：
ｕ ９１〜９３℃、 〃実験例
ヒト大腸がん由来培養細胞株ＰＲＭＩ４７８８細胞を用
い、山崎らのｄｙｅ−ｕｐｔａｋｅ法（Ｊｐｎ、 Ｊ。Compound 5: @ point 77-79°C, non-porous powder // 6:
u 91-93°C, Experimental Example Using human colon cancer-derived cultured cell line PRMI4788 cells, the dye-uptake method of Yamazaki et al. (Jpn, J.
Ｍａｄ、 Ｓｃｉ、 Ｂ１１１．第３９巻１０５〜１１
８頁１９８６年参照）によって被験物質のかん細胞増殖
抑制の程度を測定した。Mad, Sci, B111. Volume 39, 105-11
8, 1986), the degree of inhibition of canal cell proliferation by the test substance was measured.
がん細胞の増殖を５０％抑制する被験物質の濃度（ＩＣ
５゜）を下記表に示す。The concentration of the test substance that inhibits the proliferation of cancer cells by 50% (IC
5°) are shown in the table below.
製剤例１
化合物１の５００■、乳糖３．０ 、ｐ 、とぅもろこ
ｔ、殿粉１．２８．＠、ヒドロキシプロピルセルロース
２００ｍ９及びステアリン酸マグネシウム２０１ｎ９を
よく混合し、造粒したのち打錠して１錠当り１００ｒｎ
９の錠剤とする。Formulation Example 1 Compound 1 500, lactose 3.0, p, corn t, starch 1.28. @, 200 m9 of hydroxypropyl cellulose and 201 n9 of magnesium stearate were mixed well, granulated, and then tableted to yield 100 rn/tablet.
9 tablets.
製剤例２
化合物２の５００■、乳糖２．５ 、＠ 、ばれいしょ
殿粉１．７５ ｇ、結晶セルロース２４０ｒｎ９及びス
テアリン酸カルシウム１０ｍ９をよく混合し、この混合
物をカプセルに充填して１力プセル中有効成分１０ｍ９
を含有するカプセル剤とする。Formulation Example 2 500g of Compound 2, 2.5g of lactose, 1.75g of potato starch, 240rn9 of crystalline cellulose, and 10m9 of calcium stearate are thoroughly mixed, and this mixture is filled into capsules to contain the active ingredients in a capsule. 10m9
A capsule containing the following.
製剤例３
化合物６の塩酸塩５００ ｍ９及びＤ−マンニトール１
．０ｇを注射用蒸留水に溶解して全量１゜Ｑ ａｔとす
る。この溶液を０．２μのメンブレンフィルターで濾過
し、２ｍｌのアンプルに分注し、溶封したのち加熱滅菌
して注射剤とする。Formulation Example 3 Compound 6 hydrochloride 500 m9 and D-mannitol 1
．． Dissolve 0g in distilled water for injection to make a total volume of 1°Qat. This solution is filtered through a 0.2 μm membrane filter, dispensed into 2 ml ampoules, melt-sealed, and heat sterilized to obtain an injection.
Claims (1)
クロヘキシルメチルオキシ基又はベンジルオキシ基、Ｒ
＿２及びＲ＿３は一方が水素原子、他方がメトキシ基を
示す）で表わされるビスベンジルイソキノリン誘導体又
はその酸付加塩。 ２、第１請求項に記載のビスベンジルイソキノリン誘導
体又はその酸付加塩を有効成分とする抗がん剤。[Claims] 1. General formula ▲ Numerical formula, chemical formula, table, etc. ▼
A bisbenzylisoquinoline derivative or an acid addition salt thereof, represented by _2 and R_3, one of which is a hydrogen atom and the other a methoxy group. 2. An anticancer agent containing the bisbenzylisoquinoline derivative or its acid addition salt according to claim 1 as an active ingredient.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP28579088A JPH02134382A (en) | 1988-11-14 | 1988-11-14 | Bisbenzylisoquinoline derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP28579088A JPH02134382A (en) | 1988-11-14 | 1988-11-14 | Bisbenzylisoquinoline derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH02134382A true JPH02134382A (en) | 1990-05-23 |
Family
ID=17696105
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP28579088A Pending JPH02134382A (en) | 1988-11-14 | 1988-11-14 | Bisbenzylisoquinoline derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH02134382A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013107428A1 (en) * | 2012-01-21 | 2013-07-25 | 杭州本生药业有限公司 | 7-substituted hanfangichin b derivative, and preparation method and use thereof |
| CN104039794A (en) * | 2012-01-21 | 2014-09-10 | 杭州本生药业有限公司 | 7-substituted hanfangichin B derivative, and preparation method and use thereof |
| JP2014524449A (en) * | 2011-08-19 | 2014-09-22 | ハンジョウ ベンシェン ファーマシューティカル シーオー．， エルティーディー． | 5-substituted tetrandrine derivatives, their preparation and their use |
-
1988
- 1988-11-14 JP JP28579088A patent/JPH02134382A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2014524449A (en) * | 2011-08-19 | 2014-09-22 | ハンジョウ ベンシェン ファーマシューティカル シーオー．， エルティーディー． | 5-substituted tetrandrine derivatives, their preparation and their use |
| WO2013107428A1 (en) * | 2012-01-21 | 2013-07-25 | 杭州本生药业有限公司 | 7-substituted hanfangichin b derivative, and preparation method and use thereof |
| CN104039794A (en) * | 2012-01-21 | 2014-09-10 | 杭州本生药业有限公司 | 7-substituted hanfangichin B derivative, and preparation method and use thereof |
| JP2015504075A (en) * | 2012-01-21 | 2015-02-05 | ハンジョウ ベンシェン ファーマシューティカル シーオー．， エルティーディー．Ｈａｎｇｚｈｏｕ Ｂｅｎｓｈｅｎｇ Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ｃｏ．， Ｌｔｄ． | 7-Substituted Hanfungitin B Derivatives, Preparation Method and Use |
| US9328122B2 (en) | 2012-01-21 | 2016-05-03 | Hangzhou Bensheng Pharmaceuticals Co., Ltd. | 7-substituted Hanfangichin B derivative, and preparation method and use thereof |
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