JPH01197486A - Novel podophyllotoxin derivative, antitumor agent and intermediate - Google Patents
Novel podophyllotoxin derivative, antitumor agent and intermediateInfo
- Publication number
- JPH01197486A JPH01197486A JP2191588A JP2191588A JPH01197486A JP H01197486 A JPH01197486 A JP H01197486A JP 2191588 A JP2191588 A JP 2191588A JP 2191588 A JP2191588 A JP 2191588A JP H01197486 A JPH01197486 A JP H01197486A
- Authority
- JP
- Japan
- Prior art keywords
- compound
- formula
- antitumor agent
- demethylpodophyllotoxin
- synthesis
- 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
- 239000002246 antineoplastic agent Substances 0.000 title claims abstract description 7
- YJGVMLPVUAXIQN-XVVDYKMHSA-N podophyllotoxin Chemical class 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 title claims description 8
- 239000003600 podophyllotoxin derivative Substances 0.000 title claims description 7
- 239000000543 intermediate Substances 0.000 title description 3
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 claims abstract description 9
- SRBFZHDQGSBBOR-IOVATXLUSA-N D-xylopyranose Chemical group O[C@@H]1COC(O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-IOVATXLUSA-N 0.000 claims abstract description 8
- PYMYPHUHKUWMLA-UHFFFAOYSA-N arabinose Natural products OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 claims abstract description 8
- SHZGCJCMOBCMKK-UHFFFAOYSA-N D-mannomethylose Chemical group CC1OC(O)C(O)C(O)C1O SHZGCJCMOBCMKK-UHFFFAOYSA-N 0.000 claims abstract description 4
- SHZGCJCMOBCMKK-JFNONXLTSA-N L-rhamnopyranose Chemical group C[C@@H]1OC(O)[C@H](O)[C@H](O)[C@H]1O SHZGCJCMOBCMKK-JFNONXLTSA-N 0.000 claims abstract description 4
- PNNNRSAQSRJVSB-UHFFFAOYSA-N L-rhamnose Chemical group CC(O)C(O)C(O)C(O)C=O PNNNRSAQSRJVSB-UHFFFAOYSA-N 0.000 claims abstract description 4
- 125000000089 arabinosyl group Chemical group C1([C@@H](O)[C@H](O)[C@H](O)CO1)* 0.000 claims abstract description 4
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical group OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims abstract description 3
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical group OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims abstract description 3
- 239000008103 glucose Chemical group 0.000 claims abstract description 3
- 239000004480 active ingredient Substances 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 64
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 abstract description 33
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 abstract description 6
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 abstract description 4
- 239000007810 chemical reaction solvent Substances 0.000 abstract description 2
- 239000012024 dehydrating agents Substances 0.000 abstract description 2
- 239000000463 material Substances 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 238000003786 synthesis reaction Methods 0.000 description 14
- 230000015572 biosynthetic process Effects 0.000 description 13
- 239000002904 solvent Substances 0.000 description 13
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 230000000259 anti-tumor effect Effects 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 6
- 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 6
- 229960005420 etoposide Drugs 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 239000000203 mixture Substances 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 238000004809 thin layer chromatography Methods 0.000 description 4
- ALYNCZNDIQEVRV-UHFFFAOYSA-N 4-aminobenzoic acid Chemical compound NC1=CC=C(C(O)=O)C=C1 ALYNCZNDIQEVRV-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
- 206010028980 Neoplasm Diseases 0.000 description 3
- -1 azide compound Chemical class 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- FOVRGQUEGRCWPD-UHFFFAOYSA-N (5aR)-9t-beta-D-Glucopyranosyloxy-5t-(4-hydroxy-3,5-dimethoxy-phenyl)-(5ar,8at)-5,8,8a,9-tetrahydro-5aH-furo[3',4';6,7]naphtho[2,3-d][1,3]dioxol-6-on Natural products COC1=C(O)C(OC)=CC(C2C3=CC=4OCOC=4C=C3C(OC3C(C(O)C(O)C(CO)O3)O)C3C2C(OC3)=O)=C1 FOVRGQUEGRCWPD-UHFFFAOYSA-N 0.000 description 2
- YVCVYCSAAZQOJI-JHQYFNNDSA-N 4'-demethylepipodophyllotoxin Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O)[C@@H]3[C@@H]2C(OC3)=O)=C1 YVCVYCSAAZQOJI-JHQYFNNDSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 231100000111 LD50 Toxicity 0.000 description 2
- 208000007093 Leukemia L1210 Diseases 0.000 description 2
- 241001529936 Murinae Species 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 229960004050 aminobenzoic acid Drugs 0.000 description 2
- RWZYAGGXGHYGMB-UHFFFAOYSA-N anthranilic acid Chemical compound NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 description 2
- 229940045696 antineoplastic drug podophyllotoxin derivative Drugs 0.000 description 2
- 239000012752 auxiliary agent Substances 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 231100000053 low toxicity Toxicity 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- QBFXQJXHEPIJKW-UHFFFAOYSA-N silver azide Chemical compound [Ag+].[N-]=[N+]=[N-] QBFXQJXHEPIJKW-UHFFFAOYSA-N 0.000 description 2
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- 206010000830 Acute leukaemia Diseases 0.000 description 1
- 206010018612 Gonorrhoea Diseases 0.000 description 1
- SRBFZHDQGSBBOR-HWQSCIPKSA-N L-arabinopyranose Chemical compound O[C@H]1COC(O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-HWQSCIPKSA-N 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 206010041067 Small cell lung cancer Diseases 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000003438 effect on compound Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 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 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 208000001786 gonorrhea Diseases 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000009434 installation Methods 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 231100000636 lethal dose Toxicity 0.000 description 1
- 201000002364 leukopenia Diseases 0.000 description 1
- 231100001022 leukopenia Toxicity 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229960001237 podophyllotoxin Drugs 0.000 description 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 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- TZLVRPLSVNESQC-UHFFFAOYSA-N potassium azide Chemical compound [K+].[N-]=[N+]=[N-] TZLVRPLSVNESQC-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 229910001961 silver nitrate Inorganic materials 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
〔産業上の利用分野〕
本発明は抗腫瘍活性を有する新規ポドフィロトキシン誘
導体及びその中間体に関するものである。DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to novel podophyllotoxin derivatives having antitumor activity and intermediates thereof.
ポドフィロトキシンが抗腫瘍効果を有することは古（か
ら知られていたが、毒性が強いために人への適用は困難
であった。そこで毒性を軽減するために種々の半合成誘
導体が研究された結果、エトポシドおよびテニボシドが
開発された。It has been known for a long time that podophyllotoxin has antitumor effects, but its strong toxicity made it difficult to apply to humans.Therefore, various semi-synthetic derivatives were studied to reduce toxicity. As a result, etoposide and teniboside were developed.
エトポシドおよびテニボシドは種々の実験腫瘍に対し優
れた抗腫瘍効果を有し、エトポシドは小細胞肺癌、急性
白血病、悪性リンパ腫、皐丸腫瘍等に対する治療薬とし
て使用されているが、白血球減少等の副作用がかなりの
頻度で起こり治療上の問題点となっている。Etoposide and teniboside have excellent antitumor effects against various experimental tumors, and etoposide is used as a therapeutic agent for small cell lung cancer, acute leukemia, malignant lymphoma, and gonorrhea tumor, etc. However, it has side effects such as leukopenia. This occurs quite frequently and is a problem in treatment.
本発明者らはポドフィロトキシン誘導体を鋭意研究した
結果、弐（１）で示される新規ポドフィロトキシン誘導
体が優れた抗腫瘍効果を有し、かつエトポシドより低毒
性であることを見出し本発明を完成させた。As a result of intensive research into podophyllotoxin derivatives, the present inventors discovered that the new podophyllotoxin derivative represented by (2) (1) has excellent antitumor effects and is less toxic than etoposide. Completed the invention.
即ち、本発明は式（１１
（式中、Ｒはアラビノース、キシロース、ラムノース、
グルコース又ハ４．６−０−エチリテングルコビラノー
ス残基を示伊。）
で表わされる新規ポドフィロトキシン誘導体（以下、化
合物（１）と称する。）に関するものである。That is, the present invention relates to the formula (11 (wherein, R is arabinose, xylose, rhamnose,
Glucose or 4.6-0-ethylatene glucobylanose residues are shown. ) This relates to a novel podophyllotoxin derivative (hereinafter referred to as compound (1)) represented by:
更に本発明は、化合物（１）を有効成分とする抗腫瘍剤
及び中間体であるｐ−アミノ安息香酸−Ｎ −４，６−
０−エチリデン−Ｄ−グルコピラノシドに関する。Furthermore, the present invention provides an antitumor agent containing compound (1) as an active ingredient and an intermediate p-aminobenzoic acid-N-4,6-
0-ethylidene-D-glucopyranoside.
化合物（１）は、例えば下記に示す方法で製造すること
ができる。Compound (1) can be produced, for example, by the method shown below.
即ち、式（Ｉｔ）
で表わされる４β−アミノ−４′−デメチルポドフイロ
トキシンと式（Ｎ）
（式中、Ｒはアラビノース、キシロース、ラムノース、
クルコース又ハ４．６−０−ニーｙ−ＩＪ テングルコ
ビラノース残基を示す。）
で表わされる化合物を縮合することにより化合物（１）
を得ることができる。本発明化合物の合成原料である化
合物（ＩＩ）に後述の方法により得ることができる。That is, 4β-amino-4'-demethylpodophyllotoxin represented by formula (It) and formula (N) (wherein R is arabinose, xylose, rhamnose,
Cucrose or 4.6-0-Ny-IJ indicates a tenglucobilanose residue. ) By condensing the compound represented by
can be obtained. Compound (II), which is a raw material for the synthesis of the compound of the present invention, can be obtained by the method described below.
また化合物（１１１１は、例えばＪｏＭｅｄ、 Ｃｈｅ
ｍｏ、２６＊ ６２９＊１３２３（１９８３）に記載さ
れた方法に準じて、アミノ安息香酸と糖類を酢酸存在下
で縮合することにより得ら扛る。Also, the compound (1111 is available from JoMed, Che
It is obtained by condensing aminobenzoic acid and saccharide in the presence of acetic acid according to the method described in Mo., 26*629*1323 (1983).
化合物（Ｉｔ）と化合物（Ｉｆｆ）の縮合反応としては
、Ｎ、Ｎ’−ジシクロへキシルカルボジイミド、１−エ
チル−３−（３−ジメチルアミノプロピル）カルボジイ
ミド塩酸塩等の脱水剤の存在下で反応させる方法を挙げ
ることができ、化合物（ｍｌの使用量は化合物（Ｉｌｌ
に対して１〜５倍モルが好ましい。The condensation reaction between compound (It) and compound (Iff) is carried out in the presence of a dehydrating agent such as N,N'-dicyclohexylcarbodiimide or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride. The amount of compound (ml) used is the compound (Ill
It is preferably 1 to 5 times the amount by mole.
反応溶媒としては、メタノール、エタノール等のアルコ
ール類、ジクロロメタン、クロロホルム等のハロゲン化
アルキル類、テトラヒドロフラン、ジオキサン等のエー
テル類、アセトン等のケトン類、酢酸エチル等のエステ
ル類、ジメチルホルムアミド、ジメチルスルホキシド等
ヲ挙げることができる。Reaction solvents include alcohols such as methanol and ethanol, alkyl halides such as dichloromethane and chloroform, ethers such as tetrahydrofuran and dioxane, ketones such as acetone, esters such as ethyl acetate, dimethylformamide, dimethyl sulfoxide, etc. I can list wo.
反応温度は０〜５０℃が好ましい。The reaction temperature is preferably 0 to 50°C.
、 この様にして得られた化合物（１）は、後に示す試
験例かられかるように優れた抗腫瘍効果を有ししかも毒
性が低い化合物であり抗腫瘍剤として極めて有用である
。Compound (1) thus obtained is a compound that has excellent antitumor effects and low toxicity, as shown in the test examples shown later, and is extremely useful as an antitumor agent.
化合物＋１）を抗腫瘍剤として使用する場合の製剤化お
よ、び投与方法は従来公知の種々め方法が適用できる。When compound +1) is used as an antitumor agent, various conventionally known methods can be used for formulation and administration.
すなわち、投与方法としては注射、経口、直腸投与など
が可能である。製剤形態としては注射剤、粉末剤、顆粒
剤、錠剤、坐剤などの形態がとり得る。That is, possible administration methods include injection, oral administration, and rectal administration. The formulation may be in the form of injections, powders, granules, tablets, suppositories, etc.
製剤化の際には化合物（１）に悪影響を与えない限り、
医薬用に用いられる種々の補助剤、すなわち、担体やそ
の他の助剤、例えば安定剤、防腐剤、無痛化剤、乳化剤
等が必要に応じて使用されうる。When formulating, as long as it does not have an adverse effect on compound (1),
Various auxiliary agents used for pharmaceutical purposes, ie, carriers and other auxiliary agents, such as stabilizers, preservatives, soothing agents, emulsifiers, etc., may be used as necessary.
製剤において、化合物（１）の含量は製剤形態等により
広範囲に変えることが可能であり、一般には化合物（１
）を０．０１〜１００％（重量）、好ましくは０．１〜
７０％（重量）含有し、残りは通常医薬用に使用される
担体その他の補助剤からなる。In the formulation, the content of compound (1) can be varied widely depending on the formulation form, etc., and generally the content of compound (1)
) from 0.01 to 100% (by weight), preferably from 0.1 to 100% (by weight)
It contains 70% (by weight), and the rest consists of carriers and other adjuvants commonly used for pharmaceutical purposes.
化合物（１）の投与量は症状等により異なるが、成人１
人１日轟り０．０１〜８００■程度である。The dosage of compound (1) varies depending on symptoms, etc., but for adults 1
It is about 0.01-800cm per day for a person.
連設を必要とする場合には１日当りの使用量をおさえる
ことが好ましい。If continuous installation is required, it is preferable to limit the amount used per day.
化合物（ＩＩ）は、公知の４′−デメチルエピポドフィ
ロトキシンプロミド（Ｍ（特公昭４３−６４６９号参照
）を原料として、例えば次の反応経路を経て合成される
。Compound (II) is synthesized using the known 4'-demethylepipodophyllotoxin bromide (M (see Japanese Patent Publication No. 43-6469) as a raw material, for example, through the following reaction route.
（ｆＶ） （Ｖｌ）（ＩＩ）
（式中、Ｍはアルカリ金属または銀を示す。）即ち、化
合物■を式Ｍで表わ°される金属アジド化合物と反応さ
せることにより化合物師が得られる。本反応で使用する
式（９）で表わされる金属アジド化合物としては、例え
ばアジ化ナトリウム、アジ化カリウム、アジ化銀等が挙
げられ、その使用量は化合物■に対して１〜５倍モル使
用するのが好ましく、１．２〜３倍モルが特に好ましい
。使用する溶媒としては反応に悪影響を与えないもので
あれば特に限定されず、例えばアセトン、テトラヒドロ
フラン、酢酸エチル等が挙げられ、アセトンが更に好ま
しい、反応温度は０〜１００℃が好ましく、１０〜８０
℃が特に好ましい。(fV) (Vl) (II) (In the formula, M represents an alkali metal or silver.) That is, by reacting the compound (1) with a metal azide compound represented by the formula M, a compound is obtained. Examples of the metal azide compound represented by formula (9) used in this reaction include sodium azide, potassium azide, silver azide, etc., and the amount used is 1 to 5 times the molar amount of compound (■). It is preferable to do so, and 1.2 to 3 times the mole is particularly preferable. The solvent to be used is not particularly limited as long as it does not adversely affect the reaction, and examples thereof include acetone, tetrahydrofuran, ethyl acetate, etc., with acetone being more preferred.The reaction temperature is preferably 0 to 100 °C, and 10 to 80 °C.
C is particularly preferred.
次に化合物（Ｉｔ）は、化合物靜を酢酸エチル、アセト
ン、エタノール等の溶媒中、パラジウム−炭素等の触媒
存在下、室温で水素ガスにより還元して高収率で得るこ
とができる。Compound (It) can then be obtained in high yield by reducing the compound with hydrogen gas at room temperature in a solvent such as ethyl acetate, acetone, or ethanol in the presence of a catalyst such as palladium-carbon.
以下に本発明の実施例および試験例を挙げて具体的に説
明するが、本発明はこれら忙限定されるものではない。EXAMPLES The present invention will be specifically explained below with reference to Examples and Test Examples, but the present invention is not limited to these examples.
合成例１゜
４β−アジド−４′−デメチルポドフィロトキシン（化
合物（Ｍｌ））の合成
４′−デメチルエピポドフィロトキシンプロミド１０ｇ
をアセトン２００ｍ１中に加え、硝酸銀６８ｇおよびア
ジ化ナトリウム２．６ｇから調製したアジ化銀を加えて
１時間還流した後、不溶物を戸別した。炉液を溶媒留去
した後、残渣をシリカゲルカラムクロマトグラフィーに
て分離精製した。Synthesis Example 1 Synthesis of 4β-azido-4'-demethylpodophyllotoxin (compound (Ml)) 10 g of 4'-demethylepipodophyllotoxin bromide
was added to 200 ml of acetone, silver azide prepared from 68 g of silver nitrate and 2.6 g of sodium azide was added, and after refluxing for 1 hour, insoluble matter was removed. After distilling off the solvent from the furnace solution, the residue was separated and purified using silica gel column chromatography.
ベンゼン、／酢酸エチルー１９で溶出させて化合物（Ｖ
Ｄ５．４ｇを得た。Compound (V
5.4 g of D was obtained.
ｍ、ｐ、２１１〜２１２℃（分解）
ＩＲ（ＫＢｒ、Ｃｍ”−’）３４２５．２１００，１７
６５Ｍ５（ＦＡＢ） ４２５ （Ｍ ）、 ３８３Ｎ
ＭＲ（ＤＭＳＯ−ｄ６． ｐｐｍ） ８．３１ （ｓ、
、ＬＨ）、 ７．１（Ｓ、ＩＩ〜ｌ”）、６．６（ｓ
、ＩＨ）、６．１９（ｓ、２Ｈ）。m, p, 211-212°C (decomposition) IR (KBr, Cm''-') 3425.2100,17
65M5 (FAB) 425 (M), 383N
MR (DMSO-d6.ppm) 8.31 (s,
, LH), 7.1 (S, II~l''), 6.6 (s
, IH), 6.19(s, 2H).
６．０５（ｄ、２Ｈ）、５．１（ｄ、ＩＨ）、４．５４
（ｄ。6.05 (d, 2H), 5.1 (d, IH), 4.54
(d.
ｉＩ）、 ４．３８ （ｔ、 ＩＨ）、 ４．１２．（
ｔ、 ＩＩ（）。iI), 4.38 (t, IH), 4.12. (
t, II ().
３．６２（Ｓ、６Ｈ）、３．１６（ｄＸｄ、ＩＨ）、２
．９５（ｍ、ＬＨ）
合成例２゜
４β−アミノ−４−デメチルポドフィロトキシン（化合
物（■））の合成
化合物（２）３ｇを酢酸エチル２００ ｍｌに溶解し１
０％パラジウム−炭素０．５ｇを加えて室温で水素ガス
を吹込んだ。反応終了後、触媒を戸別し、炉液を溶媒留
去した後、残渣をメタノールから再結晶して化合物（Ｉ
Ｉ） ２．３ ｇを得た。3.62 (S, 6H), 3.16 (dXd, IH), 2
．． 95 (m, LH) Synthesis Example 2゜Synthesis of 4β-amino-4-demethylpodophyllotoxin (compound (■)) Dissolve 3 g of compound (2) in 200 ml of ethyl acetate and add 1
0.5 g of 0% palladium-carbon was added, and hydrogen gas was blown in at room temperature. After the reaction is completed, the catalyst is separated from each other, the solvent is distilled off from the furnace liquid, and the residue is recrystallized from methanol to obtain the compound (I
I) 2.3 g was obtained.
ｍ、ｐ、 ２２９〜２３０°Ｃ
ＩＲ（ＫＢｒ、 ｃｍ−”） ３４４０． ｌ ７５５
Ｍ５（ＦＡＢ） ３９９（Ｍ”）、３８３ＮＭＲ（Ｄ
ＭＳＯ−ｄ６． ｐｐｍ） ８．３ （ｓ、 ＩＨ）
、 ６．９９（ｓ、ＩＨ）、６．４４（ｓ、ＩＨ）、６
．２２（ｓ、２Ｈ）、５．９７（ｄ、２Ｈ）、４．４２
（ｄ、ＬＨ）。m, p, 229-230°C IR (KBr, cm-”) 3440. l 755
M5 (FAB) 399 (M”), 383NMR (D
MSO-d6. ppm) 8.3 (s, IH)
, 6.99 (s, IH), 6.44 (s, IH), 6
．． 22 (s, 2H), 5.97 (d, 2H), 4.42
(d, LH).
４．２５（ｍ、 ２Ｈ）、 ４．０４（ｄ、 Ｉｆ−Ｉ
）、 ３．６１（ｓ、６Ｈ）、３．３５（ｍ、３Ｈ）、
２．８（ｍ、ＬＨ）合成例３゜
ｐ−アミン安息香酸−Ｎ −４，６−０−エチリデンー
Ｄ−グルコピラノシド〔化合物（ｌａ））の合成
ｐ−アミノ安息香酸６．８５ ｇ、 ４．６−０−エチ
リデン−Ｄ−グルコビラノース１０．３ｇ、酢酸０、５
ｍｌを７５％エタノ−ｋ １２０ ｍｌ中、室温で２
０時間撹拌した。析出した結晶を濾過し、結晶を５０％
エタノールで洗浄後、エタノールから再結晶して化合物
（Ｉａ） ５．６ ｇを得た。4.25 (m, 2H), 4.04 (d, If-I
), 3.61 (s, 6H), 3.35 (m, 3H),
2.8 (m, LH) Synthesis Example 3 Synthesis of p-aminebenzoic acid-N-4,6-0-ethylidene-D-glucopyranoside [compound (la)] 6.85 g of p-aminobenzoic acid, 4. 6-0-ethylidene-D-glucobylanose 10.3g, acetic acid 0,5
ml in 120 ml of 75% ethanol at room temperature.
Stirred for 0 hours. Filter the precipitated crystals and remove 50% of the crystals.
After washing with ethanol, it was recrystallized from ethanol to obtain 5.6 g of compound (Ia).
ｍ、ｐ、１６８〜１７００Ｃ
ＩＲ（ＫＢｒ、ｃｍ”−’）３５３５．３３４０，１６
６０゜１６１５．１５４０．１０８０
合成例４゜
０−アミノ安息香酸−Ｎ−Ｌ−アラビノピラノシド〔化
合物（ｌｉｅ））の合成
アンスラニル酸６ｇ、Ｌ−アラビノース６．６ｇ、酢酸
Ｑ、 ５ ｍｌをメタノ−ｋ １２０ ｍｌ中で１時間
還流した。室温に放置後、析出した結晶を濾過し、水、
メタノールで洗浄して化合物（Ｍｅ）９．５ｇを得た。m, p, 168-1700C IR (KBr, cm"-') 3535.3340,16
60゜1615.1540.1080 Synthesis Example 4゜Synthesis of 0-aminobenzoic acid-N-L-arabinopyranoside [compound (lie)] 6 g of anthranilic acid, 6.6 g of L-arabinose, Q acetic acid, 5 ml was refluxed in 120 ml of methanol for 1 hour. After standing at room temperature, the precipitated crystals were filtered and mixed with water,
Washing with methanol gave 9.5 g of compound (Me).
ｍ、ｐ、 １６８〜１６９℃
ＩＲ（ＫＢｒ、ｃｍ−’） ３４５０．３３４５．
１６７０゜１５８３、 １５１０． １２３６
合成例５゜
下記の化合物を公知の方法、Ｊ−Ｍｅｄ、Ｃｈｅｍ、。m, p, 168-169°C IR (KBr, cm-') 3450.3345.
1670°1583, 1510. 1236 Synthesis Example 5 The following compound was prepared by a known method, J-Med, Chem.
２６．６２９．１３２３（１９８３）により合成した。26.629.1323 (1983).
ｐ−アミノ安息香酸−Ｄ−グルコピラノシド〔化合物（
Ｉｌｌｂ））
ｐ−アミノ安息香酸−Ｌ−ラムノピラノシド〔化合物（
Ｉｃ））
ｐ−アミノ安息香酸−Ｄ−キシロピラノシド〔化合物（
Ｉｌｌｄ））
実施例１゜
Ｎ −（ｐ −（４，６−０−エチリデン−Ｄ−グルコ
ピラノシル）アミノベンゾイル〕−４β−アミノー４′
−デメチルポドフィロトキシン〔化合物（ｌａ） ）の
合成
化合物（Ｉｌｌ ０．８ ｇをメタノール８０ｍ１に溶
解し化合物（ｆｆｌａ） ０．８ ｇおよび１−ニーｙ
−ルー ３− （３−ジメチルアミノゾロビル）カルボ
ジイミド塩醇塩０．８ｇを加えて室温で一晩撹拌した後
溶媒を留去した。残渣をシリカゲルカラムクロマトグラ
フィーにて精製し、クロロホルム／メタノール＝９３／
７溶出部をエタノールより再結晶して化合物（ｌａ）
０．２８ ｇを得た。p-aminobenzoic acid-D-glucopyranoside [compound (
Illb)) p-aminobenzoic acid-L-rhamnopyranoside [compound (
Ic)) p-aminobenzoic acid-D-xylopyranoside [compound (
Illd)) Example 1゜N-(p-(4,6-0-ethylidene-D-glucopyranosyl)aminobenzoyl]-4β-amino-4'
-Synthesis of Demethylpodophyllotoxin [Compound (la)] 0.8 g of the compound (Ill) was dissolved in 80 ml of methanol, and 0.8 g of the compound (ffla) and 1-niy
-Lu 3- (3-Dimethylaminozorobyl) 0.8 g of carbodiimide salt was added and the mixture was stirred overnight at room temperature, and then the solvent was distilled off. The residue was purified by silica gel column chromatography, and chloroform/methanol=93/
The eluted portion of 7 was recrystallized from ethanol to obtain compound (la).
0.28 g was obtained.
ＩＲ（ＫＢｒ、ｃｍ”） ３４２０．１７７２．１６
１０゜１５０２．１４８２
ＭＳ（ＦＡＢ）７０７（Ｍ＋Ｈ）、３８３，３０８ＮＭ
Ｒ（ＤＭＳＯｄｓ、ｐＩ）ｍ） ８．３３ （ｄ、 Ｉ
Ｈ）ｔ ８．２８（ｓ、ＩＨ）、７．７１（ｄ、２Ｈ
）、６．８２（ｄ、ＩＨ）、６．８０（ｓ、ＩＨ）、６
．７２（ｄ、２Ｈ）。IR (KBr, cm”) 3420.1772.16
10゜1502.1482 MS (FAB) 707 (M+H), 383,308NM
R(DMSOds, pI)m) 8.33 (d, I
H)t 8.28 (s, IH), 7.71 (d, 2H
), 6.82 (d, IH), 6.80 (s, IH), 6
．． 72(d, 2H).
６．５６（ｓ、ＩＨ）、６．２８（ｓ、２Ｈ）、５．９
９（ｄ、２Ｈ）、５．４２（ｍ、ＩＨ）、５．３２（ｂ
ｒ、ｓ。6.56 (s, IH), 6.28 (s, 2H), 5.9
9 (d, 2H), 5.42 (m, IH), 5.32 (b
r, s.
ＩＨ）、５．１９（ｂｒ、ｓ、ＩＨ）、４．７０（ｍ、
２Ｈ）。IH), 5.19 (br, s, IH), 4.70 (m,
2H).
４．５２（ｄ、ＩＨ）、４．３４（ｔ、ＩＨ）、３．９
６（ｍ、ＩＨ）、３．７０（ｍ、ＩＨ）、３．６５（ｓ
、６Ｈ）、 ３．５〜３．２ （ｍ、 ５Ｈ）、 ３．
１４ （ｍ、 ＩＨ）。4.52 (d, IH), 4.34 (t, IH), 3.9
6 (m, IH), 3.70 (m, IH), 3.65 (s
, 6H), 3.5-3.2 (m, 5H), 3.
14 (m, IH).
３．０２（ｍ、ＩＨ）、１．２４（ｄ、３Ｈ）実施例２
゜
Ｎ−（ｐ−（Ｄ−グルコピラノシル）アミノベンゾイル
〕−４β−アミノ−４′−デメチルポドフィロトキシン
〔化合物（ｌｂ） 、：Ｉの合成実施例Ｉにおいて、化
合物（ｌｌａ）の代りに化合物（Ｗｂ） １ ｇを用い
て同様に反応した後、溶媒を留去した。残渣をシリカゲ
ル薄層クロマトグラフィー（展開溶媒：酢酸エチル／メ
タノール＝４、 Ｒｆ＝０．１９ ）にて精製し化合物
（ｌｂ） ０．２５ ｇを得た。3.02 (m, IH), 1.24 (d, 3H) Example 2
゜N-(p-(D-glucopyranosyl)aminobenzoyl]-4β-amino-4'-demethylpodophyllotoxin [Compound (lb),: Synthesis of I In Example I, instead of Compound (lla) After reacting in the same manner using 1 g of compound (Wb), the solvent was distilled off.The residue was purified by silica gel thin layer chromatography (developing solvent: ethyl acetate/methanol = 4, Rf = 0.19) to obtain the compound (lb) 0.25 g was obtained.
ＩＲ（ＫＢｒ、ｃｍ”−’） ３３９０．１７７０．
１６０８゜１５０２．１４８２
ＭＳ（ＦＡＢ）６８１（Ｍ＋Ｈ）、５１９．３８３ＮＭ
Ｒ（ＤＭＳＯｄＬ ｐｐｍ） ８．３３ （ｄ、 ＩＨ
）、 ８．２９（ｓ、ＩＨ）、７．７２（ｄ、２Ｈ）、
６．８６（ｄ、ＩＨ）、 ６．８１ （ｓ、 ＩＨ）、
６．７０ （ｄ、 ２Ｈ）。IR (KBr, cm"-') 3390.1770.
1608°1502.1482 MS (FAB) 681 (M+H), 519.383NM
R (DMSOdL ppm) 8.33 (d, IH
), 8.29 (s, IH), 7.72 (d, 2H),
6.86 (d, IH), 6.81 (s, IH),
6.70 (d, 2H).
６．５６（ｓ、ＩＨ）、６．２８（ｓ、２Ｈ）、５．９
９（ｄ、 ２Ｈ）、 ５．４３（ｍ、 ＩＨ）、 ４．
９１ （ｄ、 ＩＨ）、４．５３（ｄ、ＩＨ）、４．３
８（ｍ、２Ｈ）。6.56 (s, IH), 6.28 (s, 2H), 5.9
9 (d, 2H), 5.43 (m, IH), 4.
91 (d, IH), 4.53 (d, IH), 4.3
8 (m, 2H).
３．７３ （ｍ、 ２Ｈ）、 ３．６５ （ｓ、 ６Ｈ
）、 ３．５〜３．０ （ｍ、 １０Ｈ）
実施例３゜
Ｎ−（ｐ−（Ｌ−ラムノピラノシル）アミンペンソイル
ツー４β−アミノ−４′−デメチルポドフィロトキシン
〔化合物（ｆｌｌｃ）］の合成実施例１において、化合
物（Ｉａ）の代りに化合物（Ｉｃ） １．６ ｇを用い
て同様に反応した後、溶媒を留去した。残渣をシリカゲ
ル薄層クロマトグラフィー（展開溶媒：クロロホルム／
メタノール＝ ９． Ｒｆ ＝ ０．１ ）にて精製し
化合物（Ｉｌｌｃ） ０．７４ｇを得た。3.73 (m, 2H), 3.65 (s, 6H
), 3.5-3.0 (m, 10H) Example 3゜N-(p-(L-rhamnopyranosyl)aminepensoyl-4β-amino-4'-demethylpodophyllotoxin [Compound (fllc) ] In Synthesis Example 1, 1.6 g of compound (Ic) was used in place of compound (Ia), and the solvent was distilled off.The residue was subjected to silica gel thin layer chromatography (developing solvent: chloroform). /
Methanol = 9. Rf = 0.1) to obtain 0.74 g of compound (Illc).
ＩＲ（ＫＢｒ、 ｃｍ””） ３３９０．１７７２．
１６０７゜１５０１．１４８０
ＭＳ（ＦＡＢ）６６５（Ｍ−＋−Ｈ）、５１９．３８３
ＮＭＲ（ＤＭＳＯ−ｄｓ、 ｐｐｍ） ８．３３ （
ｄ、 Ｌ Ｈ）、 ８．２９（ｓ、ＩＨ）、７．７１（
ｄ、２Ｈ）、６．８１（ｓ、１ｌ−１）、６．７７（ｄ
、２Ｈ）、６．５６（ｓ、ＩＨ）。IR (KBr, cm"") 3390.1772.
1607°1501.1480 MS (FAB) 665 (M-+-H), 519.383
NMR (DMSO-ds, ppm) 8.33 (
d, L H), 8.29 (s, IH), 7.71 (
d, 2H), 6.81 (s, 1l-1), 6.77 (d
, 2H), 6.56 (s, IH).
６．２８（ｓ、２Ｈ）、６．２５（ｄ、ＩＨ）、５．９
９（ｄ、２Ｈ）、５．４４（ｍ、ＩＨ）、４．９１（ｄ
、ＩＨ）、４．８３（ｍ、３Ｈ）、４．５２（ｄ、ＩＨ
）。6.28 (s, 2H), 6.25 (d, IH), 5.9
9 (d, 2H), 5.44 (m, IH), 4.91 (d
, IH), 4.83 (m, 3H), 4.52 (d, IH
).
４．３５ （ｍ、 ＩＨ）、 ３．７４ （ｍ、 ２Ｈ
）、 ３．６５（ｓ、６Ｈ）、３．４７（ｍ、２Ｈ）、
３．２２（ｍ、２Ｈ）、３．０２（ｍ、ＩＨ）、１．１
２（ｄ、３Ｈ）実施例４゜
Ｎ−（ｐ−（Ｄ−キシロピラノシル）アミノベンゾイル
〕−４β−アミノ−４′−デメチルポドフィロトキシン
〔化合物（Ｉｄ） ”Ｉの合成実施例１において、化合
物（Ｉｌａ）の代りに化合物（Ｉｄ） １．１ ｇを用
いて同様に反応した後、溶媒を留去した。残渣をシリカ
ゲル薄層クロマトグラフィー（展開溶媒：クロロホルム
／メタノール＝ ３． Ｒｆ＝０．３７ ）にて精製し
化合物（Ｉｄ）０．４１ｇを得た。4.35 (m, IH), 3.74 (m, 2H
), 3.65 (s, 6H), 3.47 (m, 2H),
3.22 (m, 2H), 3.02 (m, IH), 1.1
2(d,3H) Example 4゜N-(p-(D-xylopyranosyl)aminobenzoyl]-4β-amino-4'-demethylpodophyllotoxin [Synthesis of Compound (Id) "I" In Example 1 After reacting in the same manner using 1.1 g of compound (Id) instead of compound (Ila), the solvent was distilled off.The residue was subjected to silica gel thin layer chromatography (developing solvent: chloroform/methanol = 3. Rf = 0.37) to obtain 0.41 g of compound (Id).
ＩＲ（ＫＢｒ、ｃｍ−’） ３３６０．１７７５．１
６０５゜１５０２．１４８０
Ｍ５（ＦＡＢ） ６５１（Ｍ＋Ｈ）、５１９，３８３
ＮＭＲ（ＤＭＳＯｄ６．ｐｐｍ） ８．３２ （ｄ、
ｌ Ｈ）、 ８．１４（ｓ、ＩＨ）、７．７４（ｄ、２
Ｈ）、６．８４（ｓ、ＩＨ）、６．８０（ｄ、ＩＨ）、
６．６８（ｄ、２Ｈ）。IR (KBr, cm-') 3360.1775.1
605°1502.1480 M5 (FAB) 651 (M+H), 519,383
NMR (DMSOd6.ppm) 8.32 (d,
l H), 8.14 (s, IH), 7.74 (d, 2
H), 6.84 (s, IH), 6.80 (d, IH),
6.68 (d, 2H).
６．５６（ｓ、ＩＨ）、６．２８（ｓ、２Ｈ）、５．９
９（ｄ、 ２Ｈ）、 ５．４５（ｍ、 Ｉ
Ｈ）、 ４．５２（ｍ、 ２Ｈ）、４．３４（
ｍ、２Ｈ）、４．０８（ｍ、ＩＨ）。6.56 (s, IH), 6.28 (s, 2H), 5.9
9(d, 2H), 5.45(m, I
H), 4.52 (m, 2H), 4.34 (
m, 2H), 4.08 (m, IH).
３．８９（ｍ、ＩＨ）、３．７４（ｍ、２Ｈ）、３．６
５＜Ｓ９ ６Ｈ）、 ３．５〜３．２（ｍｌ’３Ｈ）
、 ３．０３（ｍ。3.89 (m, IH), 3.74 (m, 2H), 3.6
5<S9 6H), 3.5-3.2 (ml'3H)
, 3.03 (m.
ＩＨ）
実施例５゜
Ｎ−４ｏ−（Ｌ−アラビノピラノシル）アミノベンゾイ
ル〕−４β−アミノ−４′−デメチルポドフィロトキシ
ン〔化合物（Ｉｅ） ）の合成実施例１において、化合
物（Ｉａ）の代りに化合物（ｌｅ） ０．８ ｇを用い
て同様に反応した後、溶媒を留去した。残渣をシリカゲ
ル薄層クロマトグラフィー（展開溶媒：クロロホルム／
メタノール＝ ９． Ｒｆ ＝ ０．１７ ）にて精製
し化合物（１ｅ）０．２８ｇを得た。IH) Example 5 Synthesis of N-4o-(L-arabinopyranosyl)aminobenzoyl]-4β-amino-4'-demethylpodophyllotoxin [Compound (Ie)] In Example 1, the compound After reacting in the same manner using 0.8 g of compound (le) in place of (Ia), the solvent was distilled off. The residue was subjected to silica gel thin layer chromatography (developing solvent: chloroform/
Methanol = 9. Rf = 0.17) to obtain 0.28 g of compound (1e).
ＩＲ（ＫＢｒ、ｃｍ−１） ３４３０．１７７２．１
６３０゜１５０２、 １４８２
ＭＳ（ＦＡＢ）６５１（Ｍ＋Ｈ）、５１９．３８３ＮＭ
Ｒ（ＤＭＳＯ−ｄｓ、ｐｐｍ） ８．６６ （ｄ、 Ｉ
Ｈ）、 ８．４３（ｄ、ＩＨ）、８．２８（ｓ、ＩＨ
）、７．６６（ｄ、ＩＨ）、７．５２（ｔ、ＬＨ）、７
．１４（ｄ、ＩＨ）。IR (KBr, cm-1) 3430.1772.1
630°1502, 1482 MS (FAB) 651 (M+H), 519.383NM
R(DMSO-ds, ppm) 8.66 (d, I
H), 8.43 (d, IH), 8.28 (s, IH
), 7.66 (d, IH), 7.52 (t, LH), 7
．． 14(d, IH).
６．８４（Ｓ、ＩＨ）、６．７２（Ｌ、ＩＨ）、６．５
６（Ｓ、ＩＨ）、６．２７（ｓ、２Ｈ）、６．００（ｄ
、２Ｈ）、５．４３（ｍ、ＩＨ）、４．５６（ｂｒ、ｓ
、ＩＨ）。6.84 (S, IH), 6.72 (L, IH), 6.5
6 (S, IH), 6.27 (s, 2H), 6.00 (d
, 2H), 5.43 (m, IH), 4.56 (br, s
, IH).
４．５１（ｂｒ、ｓ、ＩＨ）、４．３７（ｍ、ＩＨ）、
３．７４（ｍ、ＩＨ）、３．６５（ｓ、６Ｈ）、３．５
〜３．２（ｍ。4.51 (br, s, IH), 4.37 (m, IH),
3.74 (m, IH), 3.65 (s, 6H), 3.5
~3.2 (m.
６Ｈ）、３．０１ （ｍ、ＩＨ）
試験例
生後６週齢の雌性ＣＤＦ、マウスの腹腔内にマウス白血
病Ｌ１２１０細胞ｌＸｌ０ 個を移植し、その翌日から
１日１回連日５日間種々の濃度（０，１％、０２％、０
．４％、０．８％、１．６％、３．２％）の薬剤を腹腔
内投与した。薬剤は３５％ジメチルスルホキシド−６５
％Ｔｗｅｅｎ ８０に溶解し、更に生理食塩水で１０倍
に稀釈して調製した。薬剤無処置群には溶媒（３，５％
ジメチルスルホキシド−６，５％Ｔｗｅｅｎ ８０−９
０％生理食塩水）のみを同様に投与した。腫瘍移植後６
０日間、動物の生死を観察し、薬剤処置群および薬剤無
処置群の平均生存日数から下記の式によりＴ／Ｃ（％）
を求め、また５０％致死量（ＬＤ５０ ）は定法により
算出した。6H), 3.01 (m, IH) Test Example 1X10 murine leukemia L1210 cells were intraperitoneally transplanted into 6-week-old female CDF mice, and from the next day onwards, they were injected once a day for 5 consecutive days at various concentrations ( 0.1%, 02%, 0
．． 4%, 0.8%, 1.6%, 3.2%) were administered intraperitoneally. The drug is 35% dimethyl sulfoxide-65
% Tween 80 and further diluted 10 times with physiological saline. The drug-free group received vehicle (3.5%
Dimethyl sulfoxide-6,5% Tween 80-9
0% physiological saline) alone was administered in the same manner. After tumor transplant 6
Observe whether the animals are alive or dead for 0 days, and calculate T/C (%) using the following formula from the average survival days of the drug-treated group and the drug-free group.
The 50% lethal dose (LD50) was calculated using a standard method.
本発明化合物および対照薬としてエトポシドの試験結果
を次表に示す。表中、ｍａｘ （Ｔ／Ｃ）は（Ｔ／Ｃ）
の最大値を示し、ＯｐＬ、 ｄｏｓｅはｍａｘ（Ｔ／Ｃ
）を示す投与量（最適投与量）を示す。The test results for the compound of the present invention and etoposide as a control drug are shown in the following table. In the table, max (T/C) is (T/C)
OpL, dose is max(T/C
) indicates the dose (optimal dose).
表 Ｌ１２１０に対する抗腫瘍効果および５０％致死量
表から明らかなように、本発明化合物はマウス白血病Ｌ
１２１０細胞を接種したマウスに対して顕著な延命効果
を有する。またＬＤｓｏ／ ａｐｔ。As is clear from Table 1, the antitumor effect and 50% lethal dose against L1210, the compound of the present invention is effective against murine leukemia L1210.
It has a remarkable survival effect on mice inoculated with 1210 cells. Also LDso/apt.
ｄｏｓｅの値がエトポシドのそれと比べて大きい。The dose value is larger than that of etoposide.
このことから最適投与量における毒性が低いことがわか
る。This indicates that toxicity is low at the optimum dose.
本発明化合物（１）は優れた抗腫瘍効果を有し、しかも
毒性が低いことから抗腫瘍剤として極めて有用である。The compound (1) of the present invention has excellent antitumor effects and low toxicity, making it extremely useful as an antitumor agent.
Claims (1)
ルコピラノース残基を示す。）で表わされるポドフィロ
トキシン誘導体。 ２ 第１項記載のポドフィロトキシン誘導体を有効成分
とする抗腫瘍剤。 ３ ｐ−アミノ安息香酸−Ｎ−４，６−Ｏ−エチリデン
−Ｄ−グルコピラノシド。[Claims] 1 Represented by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R represents arabinose, xylose, rhamnose, glucose or 4,6-O-ethylidene glucopyranose residue.) Podophyllotoxin derivative. 2. An antitumor agent containing the podophyllotoxin derivative according to item 1 as an active ingredient. 3 p-aminobenzoic acid-N-4,6-O-ethylidene-D-glucopyranoside.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2191588A JPH01197486A (en) | 1988-02-03 | 1988-02-03 | Novel podophyllotoxin derivative, antitumor agent and intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2191588A JPH01197486A (en) | 1988-02-03 | 1988-02-03 | Novel podophyllotoxin derivative, antitumor agent and intermediate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH01197486A true JPH01197486A (en) | 1989-08-09 |
Family
ID=12068380
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2191588A Pending JPH01197486A (en) | 1988-02-03 | 1988-02-03 | Novel podophyllotoxin derivative, antitumor agent and intermediate |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH01197486A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5541223A (en) * | 1989-02-23 | 1996-07-30 | Yale University | 4β-amino podophyllotoxin analog compounds and methods |
| FR2900154A1 (en) * | 2006-04-25 | 2007-10-26 | Inst Nat Sciences Appliq | New glycoconjugated gem-difluoride and their derivatives useful to treat cancer |
-
1988
- 1988-02-03 JP JP2191588A patent/JPH01197486A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5541223A (en) * | 1989-02-23 | 1996-07-30 | Yale University | 4β-amino podophyllotoxin analog compounds and methods |
| FR2900154A1 (en) * | 2006-04-25 | 2007-10-26 | Inst Nat Sciences Appliq | New glycoconjugated gem-difluoride and their derivatives useful to treat cancer |
| WO2007125194A1 (en) | 2006-04-25 | 2007-11-08 | Institut National Des Sciences Appliquees De Rouen (Insa) | New gem-difluoro c-glycoside compounds derived from podophyllotoxin, preparation and uses thereof |
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