JPH0193589A - 4'-o-demethyl-1-epipodophylotoxin derivative - Google Patents
4'-o-demethyl-1-epipodophylotoxin derivativeInfo
- Publication number
- JPH0193589A JPH0193589A JP11599787A JP11599787A JPH0193589A JP H0193589 A JPH0193589 A JP H0193589A JP 11599787 A JP11599787 A JP 11599787A JP 11599787 A JP11599787 A JP 11599787A JP H0193589 A JPH0193589 A JP H0193589A
- Authority
- JP
- Japan
- Prior art keywords
- formulas
- demethyl
- general formula
- group
- tables
- 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.)
- Granted
Links
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 8
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 6
- 125000006239 protecting group Chemical group 0.000 claims description 14
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 8
- 125000003277 amino group Chemical group 0.000 claims description 7
- 239000002786 epipodophyllotoxin derivative Substances 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 4
- YJGVMLPVUAXIQN-UHFFFAOYSA-N epipodophyllotoxin Natural products COC1=C(OC)C(OC)=CC(C2C3=CC=4OCOC=4C=C3C(O)C3C2C(OC3)=O)=C1 YJGVMLPVUAXIQN-UHFFFAOYSA-N 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims 10
- 229910052757 nitrogen Inorganic materials 0.000 claims 1
- 125000004433 nitrogen atom Chemical group N* 0.000 claims 1
- YJGVMLPVUAXIQN-XVVDYKMHSA-N podophyllotoxin Chemical compound COC1=C(OC)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@H](O)[C@@H]3[C@@H]2C(OC3)=O)=C1 YJGVMLPVUAXIQN-XVVDYKMHSA-N 0.000 claims 1
- 229960001237 podophyllotoxin Drugs 0.000 claims 1
- YVCVYCSAAZQOJI-UHFFFAOYSA-N podophyllotoxin Natural products COC1=C(O)C(OC)=CC(C2C3=CC=4OCOC=4C=C3C(O)C3C2C(OC3)=O)=C1 YVCVYCSAAZQOJI-UHFFFAOYSA-N 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 24
- 238000006243 chemical reaction Methods 0.000 abstract description 9
- 239000012442 inert solvent Substances 0.000 abstract description 6
- 239000002841 Lewis acid Substances 0.000 abstract description 4
- 150000007517 lewis acids Chemical class 0.000 abstract description 4
- 239000002246 antineoplastic agent Substances 0.000 abstract description 2
- 238000010511 deprotection reaction Methods 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 51
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 13
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- 239000002904 solvent Substances 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- 230000001093 anti-cancer Effects 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- -1 glucose glycoside Chemical class 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- 125000004432 carbon atom Chemical group C* 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
- 238000007796 conventional method Methods 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 3
- 230000004083 survival effect Effects 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- YJGVMLPVUAXIQN-LGWHJFRWSA-N (5s,5ar,8ar,9r)-5-hydroxy-9-(3,4,5-trimethoxyphenyl)-5a,6,8a,9-tetrahydro-5h-[2]benzofuro[5,6-f][1,3]benzodioxol-8-one Chemical compound COC1=C(OC)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O)[C@@H]3[C@@H]2C(OC3)=O)=C1 YJGVMLPVUAXIQN-LGWHJFRWSA-N 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 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
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- SAGINAGERRNGGV-UHFFFAOYSA-N benzyl n-(2-hydroxyethyl)carbamate Chemical compound OCCNC(=O)OCC1=CC=CC=C1 SAGINAGERRNGGV-UHFFFAOYSA-N 0.000 description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 238000010531 catalytic reduction reaction Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- XBRDBODLCHKXHI-UHFFFAOYSA-N epolamine Chemical compound OCCN1CCCC1 XBRDBODLCHKXHI-UHFFFAOYSA-N 0.000 description 2
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 2
- 229960005420 etoposide Drugs 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- 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
- 208000007093 Leukemia L1210 Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- MKYBYDHXWVHEJW-UHFFFAOYSA-N N-[1-oxo-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propan-2-yl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(C(C)NC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 MKYBYDHXWVHEJW-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 125000002668 chloroacetyl group Chemical group ClCC(=O)* 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- YDVNLQGCLLPHAH-UHFFFAOYSA-N dichloromethane;hydrate Chemical compound O.ClCCl YDVNLQGCLLPHAH-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229930182470 glycoside Natural products 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000006902 nitrogenation reaction Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000000384 rearing effect Effects 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Abstract
Description
【発明の詳細な説明】
〔産業上の利用分野〕
本発明の４′−〇−デメチルー１−エピポドフィロトキ
シン誘導体は抗癌活性を有し、抗癌剤として有用なもの
である。DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The 4'-0-demethyl-1-epipodophyllotoxin derivative of the present invention has anticancer activity and is useful as an anticancer agent.
４′−〇−デメチルー１＝エピポドフィロトキシンが抗
癌活性を有することは公知である（例えば特公昭４６−
６９１０など）。またその誘導体であるエトポシド（Ｅ
ｔｏｐｏｓｉｄｅ ）が優れた抗癌活性を有することは
公知であり（例えば特公昭４５−３８２５８，０８Ｐ３
１３３５１など）、現在すでに医薬として販売されてい
る。It is known that 4'-〇-demethyl-1=epipodophyllotoxin has anticancer activity (for example, Japanese Patent Publication No. 1973-
6910 etc.). In addition, its derivative etoposide (E
toposide) is known to have excellent anticancer activity (for example, Japanese Patent Publication No. 45-38258, 08 P3).
13351, etc.), which are already on sale as medicines.
エトポシド（Ｅｔｏｐｏｓｉｄｅ ）は４′−〇−デメ
チルー１−エピポドフィロトキシンのグルコース配糖体
であり、優れた抗癌活性を示すが原料の糖自体非常に高
価である上、保護基の導入など、合成に非常に多くの工
程を要する。Etoposide is a glucose glycoside of 4'-〇-demethyl-1-epipodophyllotoxin and exhibits excellent anticancer activity, but the raw sugar itself is very expensive and requires the introduction of protective groups. , requires a large number of steps to synthesize.
また、水に対する溶解度が極めて小さ（、注射および経
口投与において極めて苦労しているのが現状である。In addition, it has extremely low solubility in water (currently, it is extremely difficult to administer by injection or oral administration).
本発明者らは、上記問題点を解決すべ（、種々研究の結
果、下記一般式〔Ｉ〕で表わされる４′−ｏ −デメチ
ル−１−エピポドフィロトキシン誘導体およびその塩が
優れた抗腫瘍活性を示しかつ水に対する溶解度もよいこ
とを見い出し、本発明を完成した。また糖を含まないの
で保護基の導入などの工程がほとんどなく、極めて安価
に製造できる。In order to solve the above problems, the present inventors have found that the 4'-o-demethyl-1-epipodophyllotoxin derivative represented by the following general formula [I] and its salts have excellent anti-inflammatory properties. The present invention was completed by discovering that it exhibits tumor activity and good solubility in water.Also, since it does not contain sugar, there are almost no steps such as introduction of protective groups, and it can be produced at an extremely low cost.
即ち、本発明は
（１１下記一般式〔Ｉ〕
〔式中、Ｒはアルキレン基、田およびＲ２はそれぞれ水
素原子、低級アルキル基、フエニされる４′−〇−デメ
チルー１−エピポドフィロトキシン誘導体もしくはその
薬理学的に許容される塩および
（２）下記一般式（ＩＩ）
（式中、Ｙは水素原子またはヒドロキシ基の保護基を示
す。）で表わされる４′−〇−デメチルー１−エピポド
フィロトキシンもしくは七〇〇−保護体に下記一般式〔
■〕
〔式中、Ｒはアルキレン基、Ｒ３およびＲ４はそれぞれ
水素原子、低級アルキル基、フェニル置換アルキル基ま
たはアミン基の保護基も反応させ、保護基がある場合に
は次で保護基を除去することを特徴とする一般式〔Ｉ〕
で表わされる４’−ｏ−デメチル−１−エピポドフィロ
トキシン誘導体もしくはその薬理学的に許容される塩の
製造法に関するものである。That is, the present invention provides (11) the following general formula [I] [wherein R is an alkylene group, R and R2 are each a hydrogen atom or a lower alkyl group, and 4'-〇-demethyl-1-epipodophyllotoxin A derivative or a pharmacologically acceptable salt thereof and (2) 4'-〇-demethyl-1- represented by the following general formula (II) (wherein, Y represents a hydrogen atom or a hydroxy group-protecting group) The following general formula for epipodophyllotoxin or 700-protected form [
[In the formula, R is an alkylene group, and R3 and R4 are each hydrogen atom, a lower alkyl group, a phenyl-substituted alkyl group, or a protecting group for an amine group. If there is a protecting group, the protecting group is removed by the following steps. General formula [I] characterized by
The present invention relates to a method for producing a 4'-o-demethyl-1-epipodophyllotoxin derivative or a pharmacologically acceptable salt thereof.
一般式（１）における凡のアルキレン基トシては例えば
、炭素数１〜１０のアルキレン基があげられ、より具体
的にはメチレン基、エチレン基、プロピレン基およびブ
チレン基などである。Examples of the alkylene group in general formula (1) include alkylene groups having 1 to 10 carbon atoms, and more specifically, methylene groups, ethylene groups, propylene groups, and butylene groups.
本発明における低級アルキル基としては炭素数１〜４の
低級アルキル基が好ましく、メチル基、エチル基、プロ
ピル基などをあげることができる。The lower alkyl group in the present invention is preferably a lower alkyl group having 1 to 4 carbon atoms, such as a methyl group, an ethyl group, a propyl group, and the like.
また本発明におけるフェニル置換アルキル基としては、
例えばフェニル置換の炭素数１ないし４のアルキル基、
より具体的にはベンジル基、フェニルエチル基などがあ
げられる。Furthermore, the phenyl-substituted alkyl group in the present invention includes:
For example, a phenyl-substituted alkyl group having 1 to 4 carbon atoms,
More specific examples include benzyl group and phenylethyl group.
−＝］なとの基があげられる。An example is the group -=].
一般式［１）の化合物の代表的化合物を下表に示す。な
お表においてはｒ４／−０−デメチル−１−エピポドフ
ィロトキシン」の語をｒＤＥＭＥＰＪなる略号で示す。Representative compounds of the general formula [1] are shown in the table below. In the table, the term "r4/-0-demethyl-1-epipodophyllotoxin" is indicated by the abbreviation rDEMEPJ.
一般式（Ｉｔ）の４′−〇−デメチルー１−エピポドフ
ィロトキシンもしくはその保護体と一般式（０１）で表
わされるアルコールの反応は通常不活性溶媒中で、好ま
しくはルイス酸の存在下で行われる。The reaction between 4'-〇-demethyl-1-epipodophyllotoxin of general formula (It) or its protected form and the alcohol represented by general formula (01) is usually carried out in an inert solvent, preferably in the presence of a Lewis acid. It will be held in
本発明で使用される溶媒は、不活性なものなら何でも良
く通常、ジクロロメタン、クロロホルム１．２−ジクロ
ロメタンなどが使用される。使用される一般式〔ｌ）で
表わされるアルコールの量は、一般式〔ｎ〕で表わされ
る４′−〇−デメチルー１−エピポドフィロトキシンも
しくはその〇−保護体１モルに対し通常０．５〜５モル
の割合で使用される。また、使用されるルイス酸は主と
して三弗化ホウ素エチルエーテルであり、その量は一般
式Ｅｌｌ）で表わされる４′−〇−デメチルー１−エピ
ポドフィロトキシンもしくはその〇−保護体とアルコー
ルの合計１モルに対し通常０．５〜３モルの割合で使用
される。反応温度は通常−ｉ ｏ ｏ ’ｃ〜１００℃
好ましくは一８０°Ｃ〜室温より好ましくは一３０℃〜
０℃で行われる。The solvent used in the present invention may be any inert solvent, and dichloromethane, chloroform-1,2-dichloromethane, etc. are usually used. The amount of the alcohol represented by the general formula [l] to be used is usually 0.000 to 1 mole of 4'-〇-demethyl-1-epipodophyllotoxin or its 〇-protected product represented by the general formula [n]. It is used in a proportion of 5 to 5 moles. The Lewis acid used is mainly boron trifluoride ethyl ether, and the amount of the Lewis acid is a combination of 4'-〇-demethyl-1-epipodophyllotoxin or its 〇-protected form represented by the general formula Ell) and alcohol. It is usually used in a proportion of 0.5 to 3 moles per 1 mole of the total. The reaction temperature is usually -i o o'c ~ 100°C
Preferably from -80°C to room temperature, more preferably from -30°C
Performed at 0°C.
一般式（Ｉｆ）における〇−保護基としては一般に使用
されるものが使用でき、例えばアセチル基、クロロアセ
チル基、ベンジルオキシカルボニル基などが使用できる
。これらの保護基の除去は常法により、例えば、加水分
解、接触還元などの方法で行われる。As the 0-protecting group in the general formula (If), commonly used groups can be used, such as an acetyl group, a chloroacetyl group, a benzyloxycarbonyl group, and the like. Removal of these protecting groups is carried out by conventional methods such as hydrolysis and catalytic reduction.
また一般式（Ｍｌ）におけるアミン基の保護基としては
、一般に使用されるアミノ基の保護基が使用でき、アセ
チル基、ベンジル基、ベンジルオキシカルボニル基など
があげられる。Further, as the protecting group for the amine group in the general formula (Ml), commonly used protecting groups for the amino group can be used, such as an acetyl group, a benzyl group, a benzyloxycarbonyl group, and the like.
これらの保護基の除去は不活性溶媒中で、例えば−１０
０℃〜溶媒の沸点で行うことができる。保護基の除去が
加水分解であるときは、酸またはアルカリの存在下で行
われ、接触還元の場合には常法、即ち、Ｐｄ黒、Ｐｔな
との存在下で行うことができる。Removal of these protecting groups is carried out in an inert solvent, e.g.
It can be carried out at 0°C to the boiling point of the solvent. When the protecting group is removed by hydrolysis, it is carried out in the presence of an acid or an alkali, and in the case of catalytic reduction, it can be carried out by a conventional method, ie, in the presence of Pd black, Pt, etc.
また一般式〔ｌ〕のＲｔが水素原子、低級アルキル基、
またはフェニル置換アルキル基を示し、Ｒ２カ低級アル
キル基またはフェニル置換アルキル基を示す化合物は１
次の方法によっても得ることができる。Further, Rt in the general formula [l] is a hydrogen atom, a lower alkyl group,
or a phenyl-substituted alkyl group, and the compound in which R2 represents a lower alkyl group or a phenyl-substituted alkyl group is 1
It can also be obtained by the following method.
即ち、下記一般式（ＩＶ）
〔式中、ＲおよびＹは前記と同じ意味を示し、 Ｒｓは
アミン基、モノ低級アルキルアミノ基、モノ（フェニル
置換アルキル）アミノ基またはモノＮ−保護アミノ基を
示す。〕で表わされる４′−〇−デメチルー１−エピポ
ドフィロトキシン誘導体もしくはその〇−保護体に下記
一般式ＣＶＩ
Ｒ，−ＣＨｏ
（式中、鳥は水素原子、低級アルキル基、フェニル基、
フェニル置換アルキル基ヲ示ｊ。）で表わされるアルデ
ヒドを不活性溶媒中で反応させ、生成したシックの塩基
を、金属水素錯化合物、例えばシアン化水素化ホウ素ナ
トリウムなどで還元し、保護基のある場合には次いで保
護基を除去することにより得ることができる。この化合
物は次の一般式（ＶＩ〕で示される。That is, the following general formula (IV) [wherein R and Y have the same meanings as above, Rs represents an amine group, a mono-lower alkylamino group, a mono (phenyl-substituted alkyl) amino group or a mono N-protected amino group] show. ] to the 4'-〇-demethyl-1-epipodophyllotoxin derivative or its 〇-protected derivative represented by the following general formula CVI R, -CHO (wherein, bird is a hydrogen atom, a lower alkyl group, a phenyl group,
Indicates a phenyl-substituted alkyl group. ) is reacted in an inert solvent, the Schick's base produced is reduced with a metal hydrogen complex compound, such as sodium cyanoborohydride, and if there is a protecting group, then the protecting group is removed. It can be obtained by This compound is represented by the following general formula (VI).
（式中、ＲおよびＲ６は前記と同じ意味を示す。Ｒ７は
水素原子、低級アルキル基、フェニル置換アルキル基を
示す。）
金属水素錯化合物として、主として、シアン化水素化ホ
ウ素ナトリウム、水素化ホウ素亜鉛などの水素化ホウ素
化合物が使用される。(In the formula, R and R6 have the same meanings as above. R7 represents a hydrogen atom, a lower alkyl group, or a phenyl-substituted alkyl group.) Examples of metal hydrogen complex compounds include mainly sodium cyanoborohydride, zinc borohydride, etc. of borohydride compounds are used.
またその使用量は、一般式［Ｉ％’）で表わされる４′
−〇−デメチルー１−エピポドフィロトキシンもしくは
その〇−保護体１モルに対し、通常１〜５等量が使用さ
れる。The amount used is 4' expressed by the general formula [I%')
It is usually used in an amount of 1 to 5 equivalents per mole of -〇-demethyl-1-epipodophyllotoxin or its 〇-protected form.
反応温度は通常Ｏ℃〜３０℃で行われる。The reaction temperature is usually 0°C to 30°C.
溶媒は、不活性なものなら何でもよく、通常、アセトニ
トリル、メタノール、ジクロロメタン等が使用される。Any inert solvent may be used, and acetonitrile, methanol, dichloromethane, etc. are usually used.
使用されるアルデヒドの量は一般式（ＩＶ”ｌｌで表わ
される４′−ｏ−デメチル−１−エピポドフィロトキシ
ン誘導体もしくはその〇−保護体１モルに対し、通常０
．５〜５モルの割合で使用され一般式［ＩＶ）のＲ５が
アミン基の場合０．５〜１．５モル程度用いる時は主と
してモノアルキル化が生じ、１．５モル以上使用する場
合には主としてジアルキル化が生じる。The amount of aldehyde used is usually 0 to 1 mole of the 4'-o-demethyl-1-epipodophyllotoxin derivative or its 〇-protected product represented by the general formula (IV''ll).
．． When used in a proportion of 5 to 5 moles and R5 in general formula [IV] is an amine group, monoalkylation mainly occurs when about 0.5 to 1.5 moles are used, and when 1.5 moles or more is used, Primarily dialkylation occurs.
本発明の化合物は常法により酸と塩を形成することもで
き、それらの塩としては例えば塩酸、硫酸、リン酸、酢
酸、クエン酸などの無機酸または有機酸との塩があげら
れる。The compound of the present invention can also form a salt with an acid by a conventional method, and examples of such salts include salts with inorganic or organic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, and citric acid.
（１）本発明の化合物ＮｌＸ１ （１−ｏ −（２−ジ
メチルアミノエチル） −ＤＥＭＥＰ）の塩酸塩の水に
対する溶解性は２ ｍｇ／ｍｌ （３０℃）以上であっ
た。(1) The solubility of the hydrochloride of the compound NlX1 (1-o-(2-dimethylaminoethyl)-DEMEP) of the present invention in water was 2 mg/ml (30°C) or more.
（２）本発明化合物の抗腫瘍作用を次のようにして調べ
た。(2) The antitumor effect of the compound of the present invention was investigated as follows.
マウス白血病Ｌ１２１０細胞１０５個をマウスの腹腔内
に接種し、２４時間後より１日１回９日間連続で、本発
明の化合物を生理食塩水に懸濁させ、腹腔内に投与した
。３０日間飼育観察して次式により延命率を求めた。105 murine leukemia L1210 cells were intraperitoneally inoculated into mice, and 24 hours later, the compound of the present invention was suspended in physiological saline and administered intraperitoneally once a day for 9 consecutive days. After rearing and observing the animals for 30 days, the survival rate was calculated using the following formula.
なお対照群には生理食塩水のみを投与した。Note that only physiological saline was administered to the control group.
この対照群の平均生存日数は８．６〜１０日であった。The average survival time of this control group was 8.6-10 days.
その結果、化合物ｒｌ！１１（１−ｏ−（２−ジチルア
ミノエチル）−ＤＥＭＥＰ）を１．２５ｍｇ／ｋｇ／日
投与したとき、その延命率は２７０以上であった。As a result, the compound rl! When 1.25 mg/kg/day of 11(1-o-(2-ditylaminoethyl)-DEMEP) was administered, the survival rate was 270 or more.
この結果から明らかなように本発明化合物は非常に優れ
た抗腫瘍効果を示す。As is clear from these results, the compound of the present invention exhibits very excellent antitumor effects.
次に本発明化合物の合成法を実施例により具体的に示す
。Next, the method for synthesizing the compounds of the present invention will be specifically illustrated with reference to Examples.
実施例１゜
１− ｏ −（２−アミノエチル）−４′−〇−デメチ
ルー１−エピポドフィロトキシンの（化合物Ｎ１４）の
製造法
４’ −ｏ −ベンジルオキシカルボニル−４′−〇−
デメチルー１−エピポドフィロトキシン（−般式１：Ｉ
Ｉ〕Ｙ＝ＣＯＯＣＨｚＰｈ ）３２０■、Ｎ−ベンジル
オキシカルボニルエタノールアミン〔一般式％式％
水ジクロロメタンｇ ｍｌに溶解し一１０℃に冷却する
。三弗化ホウ素エチルエーテル２００μｌを滴下し、１
時間−１０℃で攪拌した後、ピリジン２００μ！を滴下
し、反応液を水洗後、有機層を無水硫酸す） ＩＪウム
で乾燥した。溶媒を減圧濃縮して得られた粗生成物を酢
酸エチル−メタノールの１対１混合液３０ｍ１に・溶解
し１０％パラジウム／炭素４０■を加えて、室温、常圧
下水素ガスで１時間還元した。触媒を口去した後溶媒を
減圧濃縮して得られた粗生成物をシリカゲルカラムクロ
マトグラフィー（展開溶媒メタノール／クロロホルム＝
１／４）により単離することにより１９１■（７２％）
の一般式〔Ｉ〕（ａｔ ＝几２＝Ｈ）の化合物が得られ
た。Example 1 1- Method for producing 1-o-(2-aminoethyl)-4'-〇-demethyl-1-epipodophyllotoxin (compound N14) 4'-o-benzyloxycarbonyl-4'-〇-
Demethyl-1-epipodophyllotoxin (- general formula 1: I
I]Y=COOCHzPh) 320 µ, N-benzyloxycarbonylethanolamine [General formula % Formula % Dissolved in water dichloromethane g ml and cooled to -10°C. Drop 200 μl of boron trifluoride ethyl ether and
After stirring for an hour at -10°C, 200μ of pyridine! After washing the reaction solution with water, the organic layer was dried with anhydrous sulfuric acid and IJum. The crude product obtained by concentrating the solvent under reduced pressure was dissolved in 30 ml of a 1:1 mixture of ethyl acetate and methanol, 40 μl of 10% palladium/carbon was added, and the mixture was reduced with hydrogen gas at room temperature and normal pressure for 1 hour. . After removing the catalyst, the solvent was concentrated under reduced pressure and the resulting crude product was subjected to silica gel column chromatography (developing solvent: methanol/chloroform =
191■ (72%) by isolation by 1/4)
A compound of the general formula [I] (at=几2=H) was obtained.
ｍｐ １８１〜４℃（メタノニルから再結晶）〔α〕も
”＝−４６°（Ｃ：０．４メタノール）Ｍ、Ｓ、 （
ＦＡＢ−ＭＳ ） ４４４ （Ｍ＋Ｈ）実施例２゜
１− ｏ −（２−ジメチルアミノエチル）−４′−〇
−デメチルー１−エピポドフィロトキシン（化合物隔１
）の製造法
実施例１で得られた１ −ｏ −（２−アミノエチル）
−４′−〇−デメチルー１−エピポドフィロトキシン（
一般式［１）Ｒ１＝几２＝Ｈ）８８■をメタノール３
ｍｌに溶解し、室温で３７％ホルマリン水溶液（一般式
（Ｖ） Ｒｓ ＝Ｈ） ０．０５ ｍｌを加えた後、シ
アン化水素化ホウ素ナトリウム３０■を徐々に加え、３
０分間攪拌した。反応終了後ジクロロメタン１０ｍｔを
加え水洗後、有機層を無水硫酸ナトリウムで乾燥した。mp 181~4℃ (recrystallized from methanol) [α] = -46° (C: 0.4 methanol) M, S, (
FAB-MS) 444 (M+H) Example 2゜1-o-(2-dimethylaminoethyl)-4'-〇-demethyl-1-epipodophyllotoxin (compound interval 1
) 1-o-(2-aminoethyl) obtained in Example 1
-4'-〇-demethyl-1-epipodophyllotoxin (
General formula [1) R1=几2=H)88■ methanol 3
After adding 0.05 ml of 37% formalin aqueous solution (general formula (V) Rs = H) at room temperature, 30 μl of sodium cyanoborohydride was gradually added.
Stirred for 0 minutes. After the reaction was completed, 10 mt of dichloromethane was added, and after washing with water, the organic layer was dried over anhydrous sodium sulfate.
溶媒を減圧濃縮して得られた粗生成物をシリカゲル薄層
クロマトグラフィー（メタノール／クロロホルム＝ １
／３ ）で分離し、８５■（９０％）の一般式（１）
（Ｒ，＝Ｒ２＝ＣＨ，）の化合物が得られた。The crude product obtained by concentrating the solvent under reduced pressure was subjected to silica gel thin layer chromatography (methanol/chloroform = 1
/3), and the general formula (1) of 85■ (90%)
A compound (R,=R2=CH,) was obtained.
ｍｐ：１９５〜７°Ｃ（メタノールから再結晶）〔α兄
２ ＝−５７°（ｃ：ｏ、ｓ メタノール）Ｍ、Ｓ、
（ＦＡＲ−ＭＳ ） ４７２ （Ｍ十Ｈ）実施例３
゜
１−ｏ−（２−ピロリジノエチル）−４′−〇−テメチ
ルー１−エピポドフィロトキシン（化合物遅７）の製造
法
１−（２−ヒドロキシエチル）ピロリジン（一般式〔厘
〕−Ｎり化が−０）３５■を無水ジクロロメタンｌ ｍ
ｌに溶解し、−１５℃に冷却した後、三弗化ホウ素エチ
ルエーテル１１０μｌを滴下し１０分間攪拌した。この
溶液中に４′−〇−ベンジルオキシカルボニルー４’
−ｏ−デメチル−１−エピポドフィロトキシン１０８■
を無水ジクロロメタンｌ ｍｌに溶解した溶液を１５分
を要して滴下し、−１０℃〜−１５℃でさらに３０分間
攪拌した後、ピリジン１００μｌを滴下した。mp: 195 ~ 7 ° C (recrystallized from methanol) [α brother 2 = -57 ° (c: o, s methanol) M, S,
(FAR-MS) 472 (M1H) Example 3
゜Production method of 1-o-(2-pyrrolidinoethyl)-4'-〇-temethyl-1-epipodophyllotoxin (compound 7) 1-(2-hydroxyethyl)pyrrolidine (general formula [厘]- Nitrogenation is -0) 35■ in anhydrous dichloromethane l m
After cooling to -15°C, 110 μl of boron trifluoride ethyl ether was added dropwise and stirred for 10 minutes. In this solution, 4'-〇-benzyloxycarbonyl-4'
-o-demethyl-1-epipodophyllotoxin 108■
A solution prepared by dissolving .
反応液を水洗後、有機層を無水硫酸ナトリウムで乾燥し
た。溶媒を減圧濃縮して得られた粗生成物を酢酸エチル
ーメ′タノールの１対１混合液１０ｍｔに溶解し、１０
％パラジウム／炭素１５■を加えて室温、常圧下、水素
ガスで１時間還元した。触媒を口去した後溶媒を減圧濃
縮して得られた粗生成物をシリカゲル薄層クロマトグラ
フィー（展開溶媒メタノール／クロロホルム＝１／３）
で分離することにより８１■（８１％）の一般式［，１
］ ＜−Ｎ＜’：’、が−Ｎコ）の化合物が得られた。After washing the reaction solution with water, the organic layer was dried over anhydrous sodium sulfate. The crude product obtained by concentrating the solvent under reduced pressure was dissolved in 10 mt of a 1:1 mixture of ethyl acetate and methanol.
% palladium/carbon was added and the mixture was reduced with hydrogen gas at room temperature and normal pressure for 1 hour. After removing the catalyst, the solvent was concentrated under reduced pressure, and the resulting crude product was subjected to silica gel thin layer chromatography (developing solvent: methanol/chloroform = 1/3).
By separating 81■ (81%) general formula [,1
]<-N<':', a compound with -N co) was obtained.
ｍｐ ２２７〜８℃（メタノールから再結晶）〔α〕晶
３ ＝−４８°（ｃ：ｏ、ｓ メタノール）Ｍ、Ｓ、
（ＦＡＢ−ＭＳ ） ４９８ （Ｍ＋Ｈ）実施例４゜
ｌ −ｏ −（２−ジエチルアミンエチル）−４′−□
−７’メチル−１−エピポドフィロトキシン（化合物
Ｎ１１６）の製造法
実施例３において１−（２−ヒドロキシエチル）−ピロ
リジンの代りに２−ジエチルアミンエタノール一般式（
ＩＩ：］ （Ｒ３＝ ＦＬａ ＝ Ｃ２Ｈ３） ３５■
を用いて同様に反応、後処理を行ったところ、ｓ ｏｎ
ｖ（ｓ ｏ％）の一般弐ｍ（Ｒ，−几２ ＝ Ｃ２Ｒ５
）の化合物が得られた。mp 227-8°C (recrystallized from methanol) [α] Crystal 3 = -48° (c:o,s methanol) M, S,
(FAB-MS) 498 (M+H) Example 4゜l -o -(2-diethylamineethyl)-4'-□
-7'Methyl-1-epipodophyllotoxin (Compound N116) Production Method In Example 3, 2-diethylamineethanol general formula (
II: ] (R3= FLa = C2H3) 35■
When the reaction and post-treatment were carried out in the same manner using s on
General 2m(R, -几2 = C2R5) of v(so%)
) was obtained.
ｍｐ ： １９６〜８°Ｃ（メタノールから再結晶）〔
α〕晶’＝−７３° （ｃ：ｏ、ｓ、 クロロホルム
）Ｍ、Ｓ、 （ＦＡＢ−ＭＳ ） ５００ （Ｍ十Ｈ
）実施例５゜
１− ｏ −（２−モルホリノエチル） −４’ −。mp: 196-8°C (recrystallized from methanol) [
α] Crystal'=-73° (c: o, s, chloroform) M, S, (FAB-MS) 500 (M
) Example 5゜1-o-(2-morpholinoethyl)-4'-.
−デメチル−１−エピポドフィロトキシン（化合物遅２
）の製造法
実施例３において１−（２−ヒドロキシエチル）−ピロ
リジンの代りにＮ−２−ヒドロキシｍｐ：２２０〜４℃
（メタノールから再結晶）〔α〕晶’＝−７３° （Ｃ
：０．６． クロロホルム）Ｍ、Ｓ、 （ＦＡＢ−Ｍ
Ｓ ） ５１４ （Ｍ＋Ｈ）実施例６゜
１−ｏ−（２−ベンジルアミノエチル）−４′−〇−デ
メチルー１−エピポドフィロトキシン（化合物遅３）の
製造法
実施例１においてＮ−ベンジルオキシカルボニルエタノ
ールアミンの代りにＮ−ベンジル−Ｎ−ベンジルオキシ
カルボニルエタノールアミン（一般式ＣＭｌ ］ Ｒ３
”’ ＣＨ２Ｐｈ 、 Ｒ４”” Ｃｏ□ＣＨ２Ｐｈ）
２０５■を用いて同様に反応、後処理を行ったところ２
２４ｍｇ（７０％）の一般式ＣＤ （Ｒ＋ ＝Ｈ，Ｒ２
＝ＣＨ２Ｐｈ）の化合物が得られた。-demethyl-1-epipodophyllotoxin (compound slow 2
) in Example 3, N-2-hydroxy mp: 220-4°C instead of 1-(2-hydroxyethyl)-pyrrolidine
(Recrystallized from methanol) [α] crystal' = -73° (C
:0.6. Chloroform) M, S, (FAB-M
S) 514 (M+H) Example 6゜Production method for 1-o-(2-benzylaminoethyl)-4'-〇-demethyl-1-epipodophyllotoxin (compound 3) In Example 1, N-benzyl N-benzyl-N-benzyloxycarbonylethanolamine (general formula CMl) instead of oxycarbonylethanolamine R3
"' CH2Ph , R4"" Co□CH2Ph)
When the reaction and post-treatment were carried out in the same manner using 205■, 2
24 mg (70%) of the general formula CD (R+ = H, R2
=CH2Ph) was obtained.
ｍｐ：１４６〜８℃（メタノールから再結晶）〔α〕晶
’＝−５１° （Ｃ：０．５ クロロホルム）Ｍ、Ｓ
、 （ＦＡＢ−ＭＳ ） ５３４ （Ｍ＋Ｈ）実施例７
゜
１−ｏ−（２−メチルアミノエチル）−４′−〇−デメ
チルー１−エピポドフィロトキシン（化合物崗５）の製
造法
実施例１において（一部省略）の代りにＮ −ベンジル
オキシカルボニル−Ｎ−メチルエタノールアミン（一般
式［１１１） Ｒ３＝Ｃ）−１３，Ｒ４＝Ｃ０２Ｃ）−
Ｉ２Ｐｈ）１５０■’￥用いてＮ−ベンジルオキシカル
ボニルエタノールアミン２００■（７３％）の一般式（
ＩＩＩ） （Ｒ＋””Ｈ，Ｒ２＝ＣＨ３）の化合物が得
られた。mp: 146-8°C (recrystallized from methanol) [α] crystal' = -51° (C: 0.5 chloroform) M, S
, (FAB-MS) 534 (M+H) Example 7
゜Method for producing 1-o-(2-methylaminoethyl)-4'-〇-demethyl-1-epipodophyllotoxin (compound 5) In Example 1, N-benzyloxy was used instead of (partially omitted). Carbonyl-N-methylethanolamine (general formula [111) R3=C)-13, R4=C02C)-
General formula of N-benzyloxycarbonylethanolamine 200■ (73%) using
III) The compound (R+""H, R2=CH3) was obtained.
ｍｐ：１８２° （エタノールから再結晶）〔α〕る３
＝−６０° （Ｃ：０．５ メタノール）Ｍ、Ｓ、
（ＦＡＢ−ＭＳ ） ４５８ （Ｍ＋Ｈ）特許出願人
財団法人 微生物化学研究会手続補正書
昭和６３年２月１日mp: 182° (recrystallized from ethanol) [α]ru 3
=-60° (C: 0.5 methanol) M, S,
(FAB-MS) 458 (M+H) Patent applicant
Microbial Chemistry Research Association Procedural Amendments February 1, 1986
Claims (2)
ぞれ水素原子、低級アルキル基、フェニル置換アルキル
基もしくは両者が結合して窒素原子とともに▲数式、化
学式、表等があります▼（ｎは２−６の整 数を示す。）または▲数式、化学式、表等があります▼
、▲数式、化学式、表等があります▼を示す。〕で表わ
される４′−ｏ−デメチル−１−エピポドフィロトキシ
ン誘導体もしくはその薬理学的に許容される塩、(1) The following general formula [I] ▲ Numerical formulas, chemical formulas, tables, etc. Along with the nitrogen atom, there are ▲mathematical formulas, chemical formulas, tables, etc.▼(n indicates an integer from 2 to 6) or ▲numerical formulas, chemical formulas, tables, etc.▼
, ▲There are mathematical formulas, chemical formulas, tables, etc.▼. ] 4'-o-demethyl-1-epipodophyllotoxin derivative or a pharmacologically acceptable salt thereof,
す。）で表わされる４′−ｏ−デメチル−１−エピポド
フィロトキシンもしくはそのｏ−保護法に下記一般式〔
III〕 ▲数式、化学式、表等があります▼ 〔式中、Ｒはアルキレン基、Ｒ＿３およびＲ＿４はそれ
ぞれ水素原子、低級アルキル基、フエニル置換アルキル
基またはアミノ基の保護基もしくは両者が結合して▲数
式、化学式、表等があります▼は▲数式、化学式、表等
があります▼ （ｎは２〜６の整数を示す）または▲数式、化学式、表
等があります▼、▲数式、化学式、表等があります▼を
示す。〕で表わされるアルコールを反応させ、保護基が
ある場合には次で保護基を除去することを特徴とする一
般式〔 I 〕で表わされる４′−ｏ−デメチル−１−エ
ピポドフィロトキシン誘導体もしくはその薬理学的に許
容される塩の製造法。(2) The following general formula [II] ▲ Numerical formulas, chemical formulas, tables, etc. are available▼ (In the formula, Y represents a hydrogen atom or a protecting group for a hydroxy group.) 4'-o-demethyl-1-epi The following general formula for podophyllotoxin or its o-protection method [
III] ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R is an alkylene group, and R_3 and R_4 are each a hydrogen atom, a lower alkyl group, a phenyl-substituted alkyl group, a protecting group for an amino group, or both are bonded ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ is ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (n indicates an integer from 2 to 6) or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ Mathematical formulas, chemical formulas, tables, etc. There is ▼. 4'-o-demethyl-1-epipodophyllotoxin represented by the general formula [I], which is obtained by reacting an alcohol represented by A method for producing a derivative or a pharmacologically acceptable salt thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP11599787A JPH07116197B2 (en) | 1987-05-14 | 1987-05-14 | 4'-0-demethyl-1-epipodophyllotoxin derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP11599787A JPH07116197B2 (en) | 1987-05-14 | 1987-05-14 | 4'-0-demethyl-1-epipodophyllotoxin derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH0193589A true JPH0193589A (en) | 1989-04-12 |
| JPH07116197B2 JPH07116197B2 (en) | 1995-12-13 |
Family
ID=14676294
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP11599787A Expired - Lifetime JPH07116197B2 (en) | 1987-05-14 | 1987-05-14 | 4'-0-demethyl-1-epipodophyllotoxin derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH07116197B2 (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1990009788A1 (en) * | 1989-02-23 | 1990-09-07 | The University Of North Carolina At Chapel Hill | Etoposide analogues |
| US5024269A (en) * | 1989-08-24 | 1991-06-18 | Zexel Corporation | Laminated heat exchanger |
| US5338867A (en) * | 1992-04-24 | 1994-08-16 | Genelabs Technologies, Inc. | Preparation of 4β- amino podophyllotoxin compounds |
| US5541223A (en) * | 1989-02-23 | 1996-07-30 | Yale University | 4β-amino podophyllotoxin analog compounds and methods |
-
1987
- 1987-05-14 JP JP11599787A patent/JPH07116197B2/en not_active Expired - Lifetime
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1990009788A1 (en) * | 1989-02-23 | 1990-09-07 | The University Of North Carolina At Chapel Hill | Etoposide analogues |
| EP0461141A1 (en) * | 1989-02-23 | 1991-12-18 | University Of North Carolina At Chapel Hill | Etoposide analogues |
| US5541223A (en) * | 1989-02-23 | 1996-07-30 | Yale University | 4β-amino podophyllotoxin analog compounds and methods |
| EP0461141B1 (en) * | 1989-02-23 | 1999-11-03 | University Of North Carolina At Chapel Hill | Etoposide analogues |
| US5024269A (en) * | 1989-08-24 | 1991-06-18 | Zexel Corporation | Laminated heat exchanger |
| US5338867A (en) * | 1992-04-24 | 1994-08-16 | Genelabs Technologies, Inc. | Preparation of 4β- amino podophyllotoxin compounds |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH07116197B2 (en) | 1995-12-13 |
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