JPH01117885A - Novel podophyllotoxin derivative and production thereof - Google Patents
Novel podophyllotoxin derivative and production thereofInfo
- Publication number
- JPH01117885A JPH01117885A JP27521387A JP27521387A JPH01117885A JP H01117885 A JPH01117885 A JP H01117885A JP 27521387 A JP27521387 A JP 27521387A JP 27521387 A JP27521387 A JP 27521387A JP H01117885 A JPH01117885 A JP H01117885A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- group
- compound
- cyclic amino
- formulas
- 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
- 238000004519 manufacturing process Methods 0.000 title claims description 8
- 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 description 5
- 239000003600 podophyllotoxin derivative Substances 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 65
- 125000003282 alkyl amino group Chemical group 0.000 claims abstract description 12
- 125000005843 halogen group Chemical group 0.000 claims abstract description 12
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 7
- 150000003839 salts Chemical class 0.000 claims abstract description 6
- 239000012433 hydrogen halide Substances 0.000 claims abstract description 3
- 229910000039 hydrogen halide Inorganic materials 0.000 claims abstract description 3
- 125000003277 amino group Chemical group 0.000 claims description 18
- 125000004122 cyclic group Chemical group 0.000 claims description 18
- 125000001424 substituent group Chemical group 0.000 claims description 12
- 125000001931 aliphatic group Chemical group 0.000 claims description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 11
- 239000000126 substance Substances 0.000 claims description 10
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
- 229920006395 saturated elastomer Polymers 0.000 claims description 7
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 5
- 239000003054 catalyst Substances 0.000 claims description 3
- 238000000034 method Methods 0.000 claims description 3
- 239000007800 oxidant agent Substances 0.000 claims description 3
- 239000003638 chemical reducing agent Substances 0.000 claims description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims 1
- 125000000217 alkyl group Chemical group 0.000 abstract description 5
- 231100000053 low toxicity Toxicity 0.000 abstract description 4
- 239000003795 chemical substances by application Substances 0.000 abstract description 3
- 229910052736 halogen Inorganic materials 0.000 abstract 4
- 150000002367 halogens Chemical class 0.000 abstract 2
- 150000001338 aliphatic hydrocarbons Chemical group 0.000 abstract 1
- 230000003327 cancerostatic effect Effects 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- 239000002904 solvent Substances 0.000 description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 230000004083 survival effect Effects 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- -1 ethoxy, propoxy, tertiary butoxy Chemical group 0.000 description 6
- 238000002844 melting Methods 0.000 description 6
- 230000008018 melting Effects 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- 241000699670 Mus sp. Species 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 230000001093 anti-cancer Effects 0.000 description 4
- 230000000259 anti-tumor effect Effects 0.000 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 description 4
- 238000003818 flash chromatography Methods 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 229940126062 Compound A Drugs 0.000 description 3
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 229960001237 podophyllotoxin Drugs 0.000 description 3
- 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 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 230000018044 dehydration Effects 0.000 description 2
- 238000006297 dehydration reaction Methods 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 2
- 239000012285 osmium tetroxide Substances 0.000 description 2
- 229910000489 osmium tetroxide Inorganic materials 0.000 description 2
- 125000003386 piperidinyl group Chemical group 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 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 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- ZQXCQTAELHSNAT-UHFFFAOYSA-N 1-chloro-3-nitro-5-(trifluoromethyl)benzene Chemical compound [O-][N+](=O)C1=CC(Cl)=CC(C(F)(F)F)=C1 ZQXCQTAELHSNAT-UHFFFAOYSA-N 0.000 description 1
- NHBKXEKEPDILRR-UHFFFAOYSA-N 2,3-bis(butanoylsulfanyl)propyl butanoate Chemical compound CCCC(=O)OCC(SC(=O)CCC)CSC(=O)CCC NHBKXEKEPDILRR-UHFFFAOYSA-N 0.000 description 1
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 1
- WFCSWCVEJLETKA-UHFFFAOYSA-N 2-piperazin-1-ylethanol Chemical compound OCCN1CCNCC1 WFCSWCVEJLETKA-UHFFFAOYSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- XWNSFEAWWGGSKJ-UHFFFAOYSA-N 4-acetyl-4-methylheptanedinitrile Chemical compound N#CCCC(C)(C(=O)C)CCC#N XWNSFEAWWGGSKJ-UHFFFAOYSA-N 0.000 description 1
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- 241000133570 Berberidaceae Species 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 239000004153 Potassium bromate Substances 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- MOQOOKGPCBQMCY-UHFFFAOYSA-N acetic acid;hexane Chemical compound CC(O)=O.CCCCCC MOQOOKGPCBQMCY-UHFFFAOYSA-N 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- JNGZXGGOCLZBFB-IVCQMTBJSA-N compound E Chemical compound N([C@@H](C)C(=O)N[C@@H]1C(N(C)C2=CC=CC=C2C(C=2C=CC=CC=2)=N1)=O)C(=O)CC1=CC(F)=CC(F)=C1 JNGZXGGOCLZBFB-IVCQMTBJSA-N 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000004663 dialkyl amino group Chemical group 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- UREBWPXBXRYXRJ-UHFFFAOYSA-N ethyl acetate;methanol Chemical compound OC.CCOC(C)=O UREBWPXBXRYXRJ-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- AHWALFGBDFAJAI-UHFFFAOYSA-N phenyl carbonochloridate Chemical compound ClC(=O)OC1=CC=CC=C1 AHWALFGBDFAJAI-UHFFFAOYSA-N 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- DJEHXEMURTVAOE-UHFFFAOYSA-M potassium bisulfite Chemical compound [K+].OS([O-])=O DJEHXEMURTVAOE-UHFFFAOYSA-M 0.000 description 1
- 229940099427 potassium bisulfite Drugs 0.000 description 1
- 229940094037 potassium bromate Drugs 0.000 description 1
- 235000019396 potassium bromate Nutrition 0.000 description 1
- 235000010259 potassium hydrogen sulphite Nutrition 0.000 description 1
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 229940079827 sodium hydrogen sulfite Drugs 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 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
- 238000002054 transplantation Methods 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］
本願発明は式ＣＩ）
（式中、Ｒ，、Ｒ，及びＲ８は独立に低級アルコキシ基
を、×はハロゲン原子又は水素原子を、Ｙはハロゲン原
子、水酸基又は−〇−Ｃｏ−Ｒ，を、Ｒ４は環状アミノ
基、アルキルアミノ基又は飽和もしくは不飽和の脂肪族
炭化水素残基を意味し、前記環状アミノ基は、ヒドロキ
シルアルキル基、環状アミノ基又は１．３−ベンゾオキ
ソラニルアルキル基を置換基として有してもよく、前記
アルキルアミノ基は環状アミノ基を置換基として有して
もよく、又前記脂肪族炭化水素残基は１つ以上の水酸基
を置換基として有してもよい、但し、Ｙが水酸基でＸが
水素原子である組合せを除く、）で表わされる化合物及
びその塩並びに式（’Ｉ）の化合物の製造法に関する６
式（１）の化合物は優れた抗癌作用を示し医薬として有
用である。Detailed Description of the Invention [Industrial Application Field] The present invention relates to formula CI) (wherein R, R, and R8 independently represent a lower alkoxy group, a halogen atom, a hydroxyl group, or -〇-Co-R, R4 means a cyclic amino group, an alkylamino group, or a saturated or unsaturated aliphatic hydrocarbon residue, and the cyclic amino group is a hydroxylalkyl group, a cyclic The alkylamino group may have an amino group or a 1,3-benzoxolanylalkyl group as a substituent, the alkylamino group may have a cyclic amino group as a substituent, and the aliphatic hydrocarbon residue may have a cyclic amino group as a substituent. A method for producing a compound and a salt thereof, which may have one or more hydroxyl groups as a substituent (excluding combinations in which Y is a hydroxyl group and X is a hydrogen atom), and a compound of formula ('I) 6 regarding
The compound of formula (1) exhibits excellent anticancer activity and is useful as a medicine.
［従来の技術］
ポドフィロトキシンはヒマラヤ原産のメギ科植物Ｐｏｄ
ｏｐｈｙｌｌｕｍ ｐｅｌｔａｔｕｍの根茎より抽出さ
れた物質であって、以下の化学構造式で表わされるもの
である。[Conventional technology] Podophyllotoxin is derived from Pod, a plant of the barberry family native to the Himalayas.
It is a substance extracted from the rhizome of Ophyllum peltatum and is represented by the chemical structural formula below.
該物質は抗癌作用を示すが毒性が強く医薬として実用化
されるには至りていない。Although this substance exhibits anticancer effects, it is highly toxic and has not been put to practical use as a medicine.
［発明が解決しようとする問題点］
本発明者等は抗癌作廟に優れ毒性の少ない新規なポドフ
ィロトキシンの誘導体を見い出すべくａ意検討した結果
６本発明を完成した。[Problems to be Solved by the Invention] The present inventors conducted a study to find a novel podophyllotoxin derivative with excellent anticancer properties and low toxicity, and as a result, the present invention was completed.
［発明の構成］
本発明は式（１）の化合物及びその塩並びに式（Ｉ）の
化合物の製造法に関する。[Structure of the Invention] The present invention relates to a compound of formula (1), a salt thereof, and a method for producing the compound of formula (I).
式（りにおいて、低級アルコキシ基としンツトキシ、エ
トキシ、プロポキシ、第三級ブトキシ等をあげることが
できる。ハロゲン原子としてはフッ素、塩素、真素、ヨ
ウ素等をあげることができる。環状アミノ基としてはピ
ロリジニル、ピペリジニル、ピペリジニル、ホモピペラ
ジニル、モルホリニル等をあげることができる。アルキ
ルアミノ基とはモノアルキルアミノ基文はジアルキルア
ミノ基を意味し、該ジアルキルアミノ基におけるアルキ
ル基は同−又は異なりていてもよく、更に該アルキルア
ミノ基におけるアルキル基としては一般に炭素数１〜６
の直鎖又は分岐状のものが適当である。ヒドロキシアル
キル基とは水酸基がアルキル基のいずれかの炭素に置換
したものであって、その具体例としては２−ヒドロキシ
エチル等をあげることができる。飽和又は不飽和の脂肪
族炭化水素残基については直鎖状又は分校状のものがあ
げられ、その総炭素数は一般に３０以下が適当であり、
これらは１つ以上の水酸基を有してもよい、該水酸基の
数は、一般に偶数が適当である。そして上記不飽和の脂
肪族炭化水素残基については三重結合及び／又は二重結
合を１つ以上有するものを意味する。In the formula (2), lower alkoxy groups include nitoxy, ethoxy, propoxy, tertiary butoxy, etc. Halogen atoms include fluorine, chlorine, true, iodine, etc. Cyclic amino groups include Examples include pyrrolidinyl, piperidinyl, piperidinyl, homopiperazinyl, morpholinyl, etc. An alkylamino group means a monoalkylamino group, and the alkyl groups in the dialkylamino group may be the same or different; Furthermore, the alkyl group in the alkylamino group generally has 1 to 6 carbon atoms.
Straight chain or branched ones are suitable. A hydroxyalkyl group is one in which a hydroxyl group is substituted on any carbon of an alkyl group, and specific examples thereof include 2-hydroxyethyl. The saturated or unsaturated aliphatic hydrocarbon residues may be linear or branched, and the total number of carbon atoms is generally 30 or less.
These may have one or more hydroxyl groups, and the number of hydroxyl groups is generally an even number. The unsaturated aliphatic hydrocarbon residue mentioned above means one having one or more triple bonds and/or double bonds.
式（１）の化合物において好ましい化合物としてはＸが
水素原子でＹがハロゲン原子である化合物又はＸが水素
原子で１４が不飽和の脂肪族炭化水素残基である化合物
をあげることができる。Preferred compounds of formula (1) include compounds where X is a hydrogen atom and Y is a halogen atom, or compounds where X is a hydrogen atom and 14 is an unsaturated aliphatic hydrocarbon residue.
式（Ｉ）の化合物については、その基本骨格及び置換基
について種々の異性体が存在し、それらの異性体及びそ
の混合物も本発明に含まれる。そして、式（りの化合物
の基本骨格の真性体については光学異性体があげられ、
中でも以下の式で表わされる異性体を好ましいものとし
てあげることができる。Regarding the compound of formula (I), various isomers exist regarding its basic skeleton and substituents, and these isomers and mixtures thereof are also included in the present invention. As for the intrinsic form of the basic skeleton of the compound of formula (R), there are optical isomers,
Among these, isomers represented by the following formulas are preferred.
（式中、Ｒ＋、 Ｒｘ、 Ｒｓ、 Ｘ及びＹは前記に同
じであり♂蝋はα又はβ結合を意味する。）
式（夏）の化合物の塩としては、Ｒ４が環状アミノ基又
はアルキルアミノ基セある場合、それと塩酸、硫酸、マ
レイン酸、酒石酸等の無機酸又は有機酸との酸付加塩を
あげることができる。(In formula, R+, Rx, Rs, When the base is present, acid addition salts of the base with inorganic or organic acids such as hydrochloric acid, sulfuric acid, maleic acid, tartaric acid, etc. can be mentioned.
次に式（Ｉ）の化合物の製造法を説明する。Next, a method for producing the compound of formula (I) will be explained.
式（Ｉ）の化合物の製造法は置換基の種類によって具な
り、以下にそれらの製造法を示す。The method for producing the compound of formula (I) depends on the type of substituent, and these production methods are shown below.
ａ）
（式中、Ｒ，、Ｒ，、Ｒ，及びＸは前記に同じであり、
Ｘ。a) (wherein R,, R,, R, and X are the same as above,
X.
はハロゲン原子を、Ｒ，及びＲ６は独立に低級アルキル
基を意味する０式（Ｉｌａ）の化合物をジクロロメタン
等の溶媒中−７８℃程度の低温下でハロゲン化水素又は
式（ｍ）の化合物と、好ましくは式（ｎｇの化合物と反
応させることにより式（Ｉａ）の化合物を製造すること
ができる。represents a halogen atom, and R and R6 independently represent a lower alkyl group. A compound of formula (Ila) is treated with hydrogen halide or a compound of formula (m) at a low temperature of about -78°C in a solvent such as dichloromethane. , preferably with a compound of formula (ng).
ｂ）
（式中、Ｒｔ、Ｒｓ、Ｒｓ及びＸは前記に同じであり、
Ｒ１はアリール基を、Ｒ４１は環状アミノ基又はアルキ
ルアミノ基を意味し、前記環状アミノ基はヒドロキシル
アルキル基、環状アミノ基又は１．３−ベンゾオキソラ
ニルアルキル基を置換基として有してもよく、又、前記
アルキルアミノ基は環状アミノ基を置換基として有して
もよい、）
式（ｎｂ）の化合物をジクロロメタン等の溶媒中室温下
で式（ｒＶ）の化合物と反応させることにより式（Ｉｂ
）の化合物を製造することができる。得られる式（Ｉｂ
）、の化合物を通常の方法で酸と処理することにより式
（Ｉｂ）の化合物の塩とすることができる。b) (wherein Rt, Rs, Rs and X are the same as above,
R1 represents an aryl group, R41 represents a cyclic amino group or an alkylamino group, and the cyclic amino group may have a hydroxylalkyl group, a cyclic amino group, or a 1,3-benzoxolanylalkyl group as a substituent. Alternatively, the alkylamino group may have a cyclic amino group as a substituent.) By reacting a compound of formula (nb) with a compound of formula (rV) in a solvent such as dichloromethane at room temperature, (Ib
) can be produced. The resulting formula (Ib
), can be treated with an acid in a conventional manner to form a salt of the compound of formula (Ib).
Ｃ）
（式中１．Ｒ＋、Ｒｔ、、Ｒ３及びＸは前記に同じであ
り、Ｒ４２は不飽和又は飽和の脂肪族炭化水素残基を意
味する。）
式（ｒｌａ）の化合物をジクロロメタン等の溶媒中ジシ
クロヘキシルカルボジイミド等の脱水縮合剤及びジメチ
ルアミノピリジン等の塩基性触媒の存在下式（ｖ）の化
合物と室温で反応させることにより式（Ｉｃ）の化合物
を製造することができる。C) (In the formula, 1. R+, Rt, , R3 and X are the same as above, and R42 means an unsaturated or saturated aliphatic hydrocarbon residue.) The compound of formula (Ic) can be produced by reacting with the compound of formula (v) at room temperature in the presence of a dehydration condensation agent such as dicyclohexylcarbodiimide and a basic catalyst such as dimethylaminopyridine in a solvent.
脱水縮合剤は式（ＩＩ （Ｌ）の化合物１当量に対し通
常１当量使用され、又塩基性触媒は通常触媒量使用され
る。The dehydration condensation agent is usually used in an amount of 1 equivalent per equivalent of the compound of formula (II (L)), and the basic catalyst is usually used in a catalytic amount.
ｄ）
（式中、Ｒ１，Ｒ１及びＲｓは前記に同じであり、１１
４３は１つ以上の水酸基を有する飽和又は不飽和の脂肪
族炭化水素残基を意味する。）
式（ＩＣ）の化合物をピリジン等の塩基性溶媒中四酸化
オスミウム等のグリコール形成酸化剤と室温で反応させ
次いで反応液を亜硫酸水素カリウム等の還元剤及び含水
ピリジン等の塩基性溶媒と水の混合物と処理することに
より式（Ｉｄ）の化合物を製造することができる。上記
グリコール形成酸化剤は式（ＩＣ）の化合物１当量に対
し通常１当量使用される。d) (wherein R1, R1 and Rs are the same as above, and 11
43 means a saturated or unsaturated aliphatic hydrocarbon residue having one or more hydroxyl groups. ) A compound of formula (IC) is reacted with a glycol-forming oxidizing agent such as osmium tetroxide in a basic solvent such as pyridine at room temperature, and the reaction solution is then reacted with a reducing agent such as potassium bisulfite and a basic solvent such as hydrated pyridine and water. A compound of formula (Id) can be prepared by treatment with a mixture of The above glycol-forming oxidizing agent is generally used in an amount of 1 equivalent per equivalent of the compound of formula (IC).
又、式（Ｉｌａ）の化合物においてＸがハロゲン原°子
である化合物は本発明化合物の一部賃であり、以下に示
す方法、により製造することができる。Further, the compound of formula (Ila) in which X is a halogen atom is a part of the compound of the present invention, and can be produced by the method shown below.
（式中、Ｒ，、Ｒ，、及びＲ３は前記に同じでありｘ２
はハロゲン原子を示す、）
即ち式（Ｖｌ）の化合物をクロロホルム等の溶媒中、硫
酸等の酸の存在下ハロゲン酸カリウム及びハロゲン化カ
リウムを室温で反応させることにより式（ｔｔａ’）の
化合物を製造することができる。(In the formula, R, , R, and R3 are the same as above, and x2
represents a halogen atom) That is, the compound of formula (tta') is prepared by reacting the compound of formula (Vl) with potassium halide and potassium halide in a solvent such as chloroform in the presence of an acid such as sulfuric acid at room temperature. can be manufactured.
次に式（Ｉｌｂ）の原料化合物の製造法を説明する。Next, a method for producing the raw material compound of formula (Ilb) will be explained.
ＣＩ−ＧＯＯＲ？
（Ｖ［Ｉ）
（ＩＩＱ） −−ｍ−→ （Ｉｌｂ）（式
中、Ｒ２は前記に同じ）
即ち、式（ＩＩωの化合物をジクロロメタン等の溶媒中
ピリジンの存在下式（ＶＩＩ）の化合物と室温てもよい
フェニル、ナフチル、ビフェニル等をあげることができ
る。CI-GOOR? (V[I) (IIQ) --m-→ (Ilb) (wherein R2 is the same as above) That is, a compound of formula (IIω) is combined with a compound of formula (VII) in the presence of pyridine in a solvent such as dichloromethane. Examples include phenyl, naphthyl, biphenyl, etc., which can be used at room temperature.
［発明の効果］
式（１）の化合物は優れた抗癌作用及び低い毒性を示す
ものである。従って、式（！）の化合物は抗癌剤として
優れたものである。[Effects of the Invention] The compound of formula (1) exhibits excellent anticancer activity and low toxicity. Therefore, the compound of formula (!) is an excellent anticancer agent.
以下、本発明を更に参考例、実施例及び試験例により説
明するが、本発明はこれ、らに限定されるものではない
。Hereinafter, the present invention will be further explained by reference examples, examples, and test examples, but the present invention is not limited thereto.
参考例１
ピリジン０６４ｍ１及びフェニルクロロホルメート１ｍ
＋１をジクロロメタン２４ｍ１とポドフィロトキシン（
以下化合物Ａ ） ４９６．８ｍｇの混合物に加えた。Reference example 1 064ml of pyridine and 1m of phenylchloroformate
+1 to 24ml of dichloromethane and podophyllotoxin (
The following compound A) was added to the mixture of 496.8 mg.
混合物を０℃で攪拌し、次いで室温で３０分間攪拌した
０反応液を飽和食塩水セ洗浄し、乾燥後溶媒を減圧下で
留去した。残漬をシリカゲルカラム（ヘキサン−酢酸エ
チル（１： １）で展開）で精製し、標記式で表わされ
る化合物（以下、化合物Ｂ）を針状晶として得た。融点
１８５．５〜１８６．５℃ＩＮＭＲ（４００ＭＨ２）：
δ２．９．３（ＩＨ，Ｔｗｏ ｄｏｕｂｌ＠ｔｓ
、Ｊ−１）Ｉり 、３．０５ （ＩＨ，ｍ） 、２．７
５ （ＩｉＨ、Ｓ） 、２．８５ （３Ｈ，ｓ、） 。The mixture was stirred at 0° C. and then stirred at room temperature for 30 minutes. The reaction solution was washed with saturated brine, dried, and the solvent was distilled off under reduced pressure. The residue was purified with a silica gel column (developed with hexane-ethyl acetate (1:1)) to obtain a compound represented by the title formula (hereinafter referred to as compound B) as needle-shaped crystals. Melting point 185.5-186.5℃INMR (400MH2):
δ2.9.3(IH, Two double@ts
, J-1) Iri, 3.05 (IH, m), 2.7
5 (IiH,S), 2.85 (3H,s,).
４．２５ （ＩＨ，ｔ、Ｊ−２１１ｚ） 、４．５ （
ＩＨｘ、ｑ、Ｊ−１，５Ｈｚ ） 、４．６５ （ＩＨ
、ｄ、Ｊ−ＩＨｚ） 、５．８５ （ＩＨ、ｄ 、Ｊ−
２Ｈｚ） 、５．９９−６．０４ （２Ｈ、ｃｌｏｓｌ
ｙ ５ｐａｃｅｄ、 ｃｏｕｐｌｅｄ、ｔｗｏ
５ｐｉｎ ｄｏｕｂｌｅｔ、Ｊ＝０．５Ｈｚ６．４
（２Ｈ，ｓ）、６．５５ （ＩＨ，ｓ）、７．９１１
（１Ｍ、ｓ）、７．２（３Ｈ，ｍ）。4.25 (IH, t, J-211z), 4.5 (
IHx, q, J-1,5Hz), 4.65 (IH
, d, J-IHz), 5.85 (IH, d, J-
2Hz), 5.99-6.04 (2H, closl
y 5paced, coupled, two
5pin double, J=0.5Hz6.4
(2H,s), 6.55 (IH,s), 7.911
(1M, s), 7.2 (3H, m).
７．３（ＩＨ，■）、７．４５（２Ｈ，■）；ＩＲ：１
７７０，１７４０，１５９０；参考例２
エピポドフィロトキシン（以下、化合物Ｃ）を参考例１
と同様に反応させて標記式で表わされる化合物（以下、
化合物Ｄ）を白色粉末として得た。融点９８℃
’ＨＭＮＲ（２００ＭＨｚ） ：δ３．１［Ｈ，ｍ）、
３．３，３．４（ＩＨ，Ｔｏｗｄｏｕｂｌｅｔｓ、Ｊ＝
ＨＩｘ）、３．７５ （６Ｈ，ｓ）、３．８２ （３Ｈ
，ｓ）、４．２（ＩＨ，ｑ、Ｊ−ＩＨｚ）、 ４．４
５（１８，ｔ、Ｊ−ＩＨｚ）、４．７（ＩＨ，ｄ。7.3 (IH, ■), 7.45 (2H, ■); IR: 1
770, 1740, 1590; Reference Example 2 Epipodophyllotoxin (hereinafter, compound C) was added to Reference Example 1
A compound represented by the title formula (hereinafter referred to as
Compound D) was obtained as a white powder. Melting point 98℃ 'HMNR (200MHz): δ3.1 [H, m),
3.3, 3.4 (IH, Towdoublets, J=
HIx), 3.75 (6H,s), 3.82 (3H
, s), 4.2 (IH, q, J-IHz), 4.4
5 (18, t, J-IHz), 4.7 (IH, d.
Ｊ−０，５Ｈｚ）、５．９９−６（２）１．ｃｌｏｓｌ
ｙ ５ｐａｃｅｄ、ｃｏｕｐｌｅｄ、ｔｗ。J-0,5Hz), 5.99-6(2)1. closl
y 5paced, coupled, tw.
５ｐｉｎ ｄｏｕｂｌｅｔ、 Ｊ＝０．５Ｈｚ）、
８．０８（１）１．ｄ、Ｊ−０，５Ｈｘ）。5pin double, J=0.5Hz),
8.08(1)1. d, J-0,5Hx).
６ （２Ｈ，ｓ） 、６゜６ （ＩＨ，Ｓ）、７．０８
（１８，■）７．２（２Ｈ，ｍ）、７３（１）１．ｍ）
、７．４（２Ｈ，ｍ）；ＩＲ：１７７０，１７４０．１
５９０ Ｃａ１−’；実施例１
化合物Ｂ ５３４ｍｇをジクロロメタン４ｍｌに溶解さ
せ、ピペラジンエタノール２■■ｇｕｍ温下で添加した
０反応を室温で２４時間行なった０反応液を飽和食塩水
で洗浄し、乾燥後減圧下で留去した。6 (2H, s), 6°6 (IH, S), 7.08
(18, ■) 7.2 (2H, m), 73 (1) 1. m)
, 7.4 (2H, m); IR: 1770, 1740.1
590 Ca1-'; Example 1 534 mg of compound B was dissolved in 4 ml of dichloromethane, and 2 g of piperazine ethanol was added under temperature. The 0 reaction was carried out at room temperature for 24 hours. The 0 reaction solution was washed with saturated saline and dried. It was then distilled off under reduced pressure.
残漬をシリカゲルのフラッシュカラムクロマトグラフィ
ー（酢酸エチル−メタノール（１： １）で展開）で精
製し、標記式で表わされる化合物を白色粉末として得た
。融点１０８℃
”ＮＭＲ（４００ＭＨｚ）： δ２．５５ （４Ｈ，
ｍ）、２．６５ （２Ｈ，ｔ、Ｊ−ＩＨｚ） 、２．８
５ （ＩＨ，ｍ） 、２．９５，２．９９ （ＩＨ，Ｔ
ｗｏ ｄｏｕｂｌｅｔｓ、Ｊ−ＩＨり 、 ３．５５
（４Ｈ，ｍ） 、３．７ （２Ｈ，ｔ、Ｊ−ＩＨり 、
３．７５ （６Ｈ，ｓ）３．１１ （３Ｈ，ｓ）、４．
２５（ＩＨ，ｔ、Ｊ−２Ｈり、４．４５（ＩＨ，ｐ、Ｊ
−ｔ、５ｏｚ） 、 ４．６ （ＩＨ，ｄ、Ｊ−ＩＨｚ
） 、５．８ （１）１．ｄ、Ｊ−２） 、５．９２−
６．０（２Ｈ，ｃｌｏｓｌｙ ５ｐａｃｅｄ、ｄｏｕ
ｂｌｅ ５ｐｉｎ ｄｕｂｌｅｔ、Ｊ＝ｏ、５ｕｚ
） 、 ６．４ （２Ｈ，ｓ） 、ｅ、ｓｓ （ＩＨ
，ｓ） 、８．２ （１１！、ｓ） ：ＩＲ：３４００
，１７７０．１７７１０．１６９０．１６００ Ｃ１１
−’；実施例８
化合物ＡＯ，Ｓｍｍｏｌ 、オレイン酸０．５ｍｍｏｌ
、ジシクロへキシルカルボジイミド０．５ａ＋ｍｏｌ
及び触媒量のジメチルアミノピリジンをジクロロメタン
に加え、混合物を室温で３時間攪拌した。不溶物を濾去
し、濾液を減圧留去した。残漬をシリカゲルのフラシツ
ェカラムクロマトグラフィ−（ヘキサン−酢酸エステル
（１：０．５）で展開）で精製し標記式で表わされる化
合物（以下、化合物Ｆ）を油状物として得た。The residue was purified by flash column chromatography on silica gel (developed with ethyl acetate-methanol (1:1)) to obtain a compound represented by the title formula as a white powder. Melting point: 108℃ NMR (400MHz): δ2.55 (4H,
m), 2.65 (2H, t, J-IHz), 2.8
5 (IH, m), 2.95, 2.99 (IH, T
wo doublets, J-IHri, 3.55
(4H, m), 3.7 (2H, t, J-IHri,
3.75 (6H, s) 3.11 (3H, s), 4.
25 (IH, t, J-2H, 4.45 (IH, p, J
-t, 5oz), 4.6 (IH, d, J-IHz
), 5.8 (1)1. d, J-2), 5.92-
6.0 (2H, closely 5 paced, dou
ble 5pin doublet, J=o, 5uz
) , 6.4 (2H,s) ,e,ss (IH
,s) ,8.2 (11!,s) :IR:3400
,1770.17710.1690.1600 C11
-'; Example 8 Compound AO, Smmol, oleic acid 0.5 mmol
, dicyclohexylcarbodiimide 0.5a+mol
and a catalytic amount of dimethylaminopyridine were added to dichloromethane and the mixture was stirred at room temperature for 3 hours. Insoluble materials were removed by filtration, and the filtrate was distilled off under reduced pressure. The residue was purified by Fraschice column chromatography on silica gel (developed with hexane-acetic acid ester (1:0.5)) to obtain a compound represented by the title formula (hereinafter referred to as compound F) as an oil.
’ＨＭＮＲ（４００ＭＨｚ） ： ６０．９ （３Ｈ，
ｔ、Ｊ−１，５Ｈｚ） １．３ （２０Ｈ。'HMNR (400MHz): 60.9 (3H,
t, J-1,5Hz) 1.3 (20H.
ｂｒｏａｄ ｓｌｎｇｌ＊ｔ）、１．７（２Ｈ，ｍ）
、２（４Ｈ，ｓ）、 ２．４５（２Ｈ，ｓ）２．８５
（ＩＨ，ｍ） 、２．９．３（ｌＨ，Ｔｗｏ ｄｏｕ
ｂｌｅｔｓ、Ｊ＝ＩＨｚ） 。broad slngl*t), 1.7 (2H, m)
, 2(4H,s), 2.45(2H,s)2.85
(IH, m) , 2.9.3 (lH, Two dou
bullets, J=IHz).
３．７８（１！Ｈ，ｓ） 、３．８２（３Ｈ，ｓ） 、
４．２（１Ｍ、ｔ、Ｊ＝２Ｈｚ）４．３５（ＬＨ，Ｑ
、Ｊ−１，７５Ｈｚ） 、４．６２ （ＩＨ，ｄ 、Ｊ
−ＩＨ２） 、５．３５ （２８，ｍ）５．８８（ＬＨ
，ｄｊ−２Ｈｘ）、５．９８−１１．０２（２Ｈ，ｃｌ
ｏｓｌｙ ５ｐａｃ＠ｄｃｏｕｐｌ＠ｄ、ｔｗｏ ５ｐ
ｌｎ ｄｏｕｂｌｅｔ、Ｊ＝０．５Ｈｚ）、８．４（２
Ｈ，ｓ）８．５５ （ＩＨ，ｓ） 、６．７５ （１８
，ｓ） ；ＩＲ：１７７０．１７２０．１５１１０；実
施例１９
化合物Ｅ ０．３５ｍｍｏｌ及びピリジン２ｎ＋１の混
合物に四酸化オスミウム０．３５ｍｍｏｌを室温で加え
、４時間攪拌した０反応液に亜硫酸水素ナトリウム１５
７．５” ｇｓ水２．２Ｂ＋＊ｌ、とリジン１．７５
ｍｌを加えオレンジ色が発色した後ジクロロメタンで抽
出した。抽出液を乾燥後減圧留去し、残漬をシリカゲル
のフラッシュカラムクロマトグラフィーで精製し、標記
式で表わされる化合物を白色粉末として得た。3.78 (1!H,s), 3.82 (3H,s),
4.2 (1M, t, J = 2Hz) 4.35 (LH, Q
, J-1,75Hz), 4.62 (IH,d, J
-IH2), 5.35 (28, m) 5.88 (LH
, dj-2Hx), 5.98-11.02 (2H, cl
osly 5pac@dcoupl@d, two 5p
ln doublet, J=0.5Hz), 8.4(2
H, s) 8.55 (IH, s), 6.75 (18
,s);IR:1770.1720.15110;Example 19 0.35 mmol of osmium tetroxide was added to a mixture of 0.35 mmol of compound E and 2n+1 pyridine at room temperature, and 15 sodium hydrogen sulfite was added to the reaction solution, which was stirred for 4 hours.
7.5” gs water 2.2B+*l, and lysine 1.75
ml was added and an orange color developed, followed by extraction with dichloromethane. The extract was dried and then evaporated under reduced pressure, and the residue was purified by flash column chromatography on silica gel to obtain a compound represented by the title formula as a white powder.
融点４３℃
’）ＩＭＮＲ（４００ＭＨｚ） ：δ０．９ （３Ｈ，
ｔ、Ｊ−１１Ｚ） 、１．３ （２０Ｈ。Melting point 43℃') IMNR (400MHz): δ0.9 (3H,
t, J-11Z), 1.3 (20H.
ｂｒ６ａｄ ｓｉｎｇｌｅｔ） 、１．４２（４Ｈ，＋
ａ） 、１．６８（２Ｈ４） 、２．４５（２Ｈ，ｍ）
、２．１１５ （１１（、ｍ） 、２．９．２Ｊ５
（ＬＨ，Ｔｗｏ ｄｏｕｂｌ＠ｔｓ。br6ad singlet) , 1.42 (4H, +
a) , 1.68 (2H4) , 2.45 (2H, m)
, 2.115 (11(, m) , 2.9.2J5
(LH, Two double@ts.
Ｊ−ＩＨｚ） 、３．８ （２Ｈ，ｆｆ１ｌ 、３．７
５ （ＳＨ，ｇ） 、３．８５ （３Ｈ，ｓ） 、４．
２（ＩＨ，ｔ、Ｊ＝２Ｈｚ） 、４．３５ （ＩＨ，ｑ
、Ｊ−１，５８り 、４．６２ （ｌＨ，ｄ。J-IHz), 3.8 (2H, ff1l, 3.7
5 (SH, g), 3.85 (3H, s), 4.
2 (IH, t, J=2Hz), 4.35 (IH, q
, J-1,58ri, 4.62 (lH,d.
Ｊ＝ＩＨｚ） 、 ５．９ （１）１ 、ｄ 、Ｊ−２
）１ｚ） 、 ５．９８−６．０３ （２１）１ 、
ｃｌｏｓ １ｙｓｐａｃｅｄ、ｃｏｕｐｌｅｄ ｔｗｏ
５ｐｌｎ ｄｏｕｂｌｅｔ、Ｊ−０，５）１ｚ）、６
．４（２Ｈ，Ｓ） 、６．５５ （ＬＨ，Ｓ） 、６．
７８（ＩＨ，ｓ） 。J=IHz), 5.9 (1)1, d, J-2
)1z), 5.98-6.03 (21)1,
clos 1yspaced, coupled two
5pln doublet, J-0,5)1z),6
．． 4 (2H, S), 6.55 (LH, S), 6.
78 (IH, s).
ＩＲ：３４Ｇ０，１７７０．１７２０．１５８０ ’ｃ
Ｉ１１−’Ｈ実施例２６
化合物Ａ ２０７薦ｇをジクロロメタン２ｍｌに溶解し
、これを攪拌しながらシタチルアミノ三フッ化イオウ０
．０８１ ｍｌを一７８℃で添加した０反応を室温で１
時間行なった０反応液を洗浄し、乾燥後溶媒を減圧で留
去した。残渣をシリカゲルのフラッシュカラムクロマト
グラフィー（ヘキサン−酢酸エチルで展開）で精製し標
記式で表わされる化合物を白色粉末として得た。融点１
０２℃’ＨＭＮＩ）（４００ＭＨｚ）：δ２．９ （Ｉ
Ｈ，ｓ）、３．２５，３．３５ （ＩＨ，Ｔｗ。IR:34G0,1770.1720.1580'c
I11-'H Example 26 207 g of Compound A was dissolved in 2 ml of dichloromethane, and while stirring, sulfur cytacylamino trifluoride was added.
．． 0.081 ml was added at -78°C for 1 reaction at room temperature.
The reaction mixture was washed for 1 hour, and after drying, the solvent was distilled off under reduced pressure. The residue was purified by flash column chromatography on silica gel (developed with hexane-ethyl acetate) to obtain a compound represented by the title formula as a white powder. Melting point 1
02℃'HMNI) (400MHz): δ2.9 (I
H, s), 3.25, 3.35 (IH, Tw.
ｄｏｕｂｌａｔｓ、Ｊ−ＩＨｚ） 、３．７５（６Ｈ，
ｓ） 、３．８２（３Ｈ，ｓ） 、４．３５（ｌＨ，ｑ
、Ｊ−ＩＳｌｌｚ）、４．ｔＳ （ＩＨ，ｔ、Ｊ−１，
７５Ｈｚ）、４．６５ （ｌ）Ｉ。doublets, J-IHz), 3.75 (6H,
s) , 3.82 (3H, s) , 4.35 (lH, q
, J-ISllz), 4. tS (IH, t, J-1,
75Hz), 4.65 (l)I.
ｏｖｅｒｌａｐｐｌｎｇ ｄｏｕｂｌｅｔｓ、Ｊ＝ＩＨ
ｚ）、５．Ｓ、５．６５（ＩＨ，ｄ。overlapplng doublets, J=IH
z), 5. S, 5.65 (IH, d.
Ｊ−０，７５Ｈｚ）、５．！１３−６．０（２Ｈ，Ｃｌ
０８ｌｙ ５ｐａｃｅｄ、ｃｏｕｐｌｅｄ。J-0,75Hz), 5. ! 13-6.0(2H,Cl
08ly 5paced, coupled.
ｔｗｏ ５ｐｉｎ ｄｏｕｂｌｅｔ、ＪｍＯ，５Ｈ
ｚ）、８．２５（２Ｈ，ｓ）、８．６（ＩＨ。two 5pin doublet, JmO, 5H
z), 8.25 (2H, s), 8.6 (IH.
Ｓ） 、８．９５ （ＩＨ，ｄ、Ｊ−０，５Ｈｚ） ；
ＩＲ：１７７０．−ＩＳ８０ ｃｍ−鳳；実施例２フ
化合物Ａ Ｏ，！ｖｓｏｌ、臭素酸カリウム１■ｍｏｌ
、臭化化カリウムｌｔａｍｏｌ ｓ Ｉ Ｎ硫酸０．７
５ｍ１及びクロロホルム５■ｌの混合物を室温で２４時
間攪拌した０反応液を通常の方法で後処理し、残渣をシ
リカゲルのフラッシュカラムクロマトグラフィーで精製
し標記式で表わされる化合物を白色粉末として得た。融
点２１２℃
’ＨＭＮＲ（４００ＭＨり：δ３．４５ （ＩＨ，丁ｗ
ｏ ｄｏｕｂｌ＠ｔｓ、Ｊ−ＩＳＨｚ）、３．８５
（１１（、ｍ）、３．９ （６Ｍ、ｓ）、３．９２ （
３８，ｓ）、４．２５（１）１ 、 ｔ、Ｊ”２Ｈｚ）
、 ４．６５ （ＩＨ，Ｑ、Ｊ−１，７５Ｈｚ） 、
５．５２ （ＩＨ，ｄ。S), 8.95 (IH, d, J-0,5Hz);
IR:1770. -IS80 cm-Feng; Example 2 Compound A O,! vsol, potassium bromate 1 mol
, potassium bromide ltamol s I N sulfuric acid 0.7
A mixture of 5 ml and 5 ml of chloroform was stirred at room temperature for 24 hours. The reaction solution was post-treated in a conventional manner, and the residue was purified by silica gel flash column chromatography to obtain the compound represented by the title formula as a white powder. . Melting point: 212°C 'HMNR (400MH): δ3.45 (IH,
o double@ts, J-ISHHz), 3.85
(11 (, m), 3.9 (6M, s), 3.92 (
38,s), 4.25(1)1,t,J”2Hz)
, 4.65 (IH, Q, J-1, 75Hz) ,
5.52 (IH, d.
Ｊ−１，５１（χ）、８．０４−１ｉ、０Ｂ（２１（、
ｃｌｏｓｌｙ ５ｐａｃｅｄ、ｃｏｕｐｌ＠ｄ。J-1,51(χ), 8.04-1i, 0B(21(,
closely 5paced, couple@d.
ｔｗｏ ５ｐｉｎ ｄｏｕｂｌａｔ、ＪｍＯ，５Ｈ
ｚ）、ｆｌ、２（ＩＨ，Ｓ）、６．５８（ＩＨ。two 5pin doublet, JmO, 5H
z), fl, 2 (IH, S), 6.58 (IH.
ｓ）、７．５（ＩＬｓ）；
ＩＲ：３４０Ｇ、１７８０．１１１７０，１６０ＧＣＩ
−’；試験例
本発明化合物の抗腫瘍活性は下記の方法により実施した
。s), 7.5 (ILs); IR: 340G, 1780.11170, 160GCI
-'; Test Example The antitumor activity of the compound of the present invention was tested by the following method.
ＣＤＦ、 （ＢＡＬＢ／ｃ ｘ ＤＢ＾／２）マウス腹
腔内にＰ−３８８マウス白血病細胞（以下Ｐ−３１１１
１細胞と略す）１０”個を移植した。 ゛
水に溶解あるいはＴｗｅａｎ ［１０に懸濁した本発明
化合物をＰ−３８８細胞移植後１日及び５８目に１２．
５〜ＩＯＱ、 ｓｇ／ｋｇの用量にマウス腹腔内に注射
した。CDF, (BALB/c x DB^/2) P-388 mouse leukemia cells (hereinafter P-3111) intraperitoneally
The compound of the present invention dissolved in water or suspended in Tween [10] was transplanted on day 1 and 58 after transplantation of P-388 cells.
Mice were injected intraperitoneally at a dose of 5 to IOQ, sg/kg.
その後本発明化合物被投与マウス（以下投与群と略す、
各群６匹）及び溶媒被投与マウス（以下対照群と略す、
各群１０匹）の生死を観察し、その平均生存日数を求め
、対照群の平均生存日数に対する投与群の平均生存日数
の比（％）を算出した。Thereafter, mice were administered the compound of the present invention (hereinafter referred to as administration group).
6 mice in each group) and vehicle-treated mice (hereinafter referred to as control group)
The survival of 10 animals in each group was observed, and the average number of days of survival was determined, and the ratio (%) of the average number of days of survival of the treated group to the average number of days of survival of the control group was calculated.
その値を本発明化合物の抗腫瘍活性とした。The value was defined as the antitumor activity of the compound of the present invention.
尚、対照群の平均生存日数は約１０日であった。The average survival time of the control group was about 10 days.
結果を表１に示した。The results are shown in Table 1.
表１
＊投与群平均生存日数／対照群平均生存日数中中投与し
たマウス６匹中３匹以上が投与化合物の毒性の為死亡
上表から明らかなように対照化合物であるポドフィロト
キシンを投与した群ではｓ ｏ ｍｇ／ｋｇ以上の投与
量では毒性が強く現われた。Table 1 *Average survival days of the administration group/average survival days of the control group More than 3 out of 6 treated mice died due to the toxicity of the administered compound.As is clear from the above table, the control compound podophyllotoxin was administered. In the group treated, toxicity appeared strongly at doses higher than s o mg/kg.
これに対して、本発明化合物では５０ ｍｇ／ｋｇ以上
の投与量でも毒性を表わさず、かつ優れた抗腫瘍効果を
示した。従って、本発明化合物が抗腫瘍活性に優れ、か
つ毒性も低いことが確認された。In contrast, the compound of the present invention exhibited no toxicity even at doses of 50 mg/kg or more and exhibited excellent antitumor effects. Therefore, it was confirmed that the compound of the present invention has excellent antitumor activity and low toxicity.
Claims (1)
級アルコキシ基を、Ｘはハロゲン原子又は水素原子を、
Ｙはハロゲン原子、水酸基又は−Ｏ−ＣＯ−Ｒ＿４を、
Ｒ＿４は環状アミノ基、アルキルアミノ基又は飽和もし
くは不飽和の脂肪族炭化水素残基を意味し、前記環状ア
ミノ基はヒドロキシルアルキル基、環状アミノ基又は１
，３−ベンゾオキソラニルアルキル基を置換基として有
してもよく、前記アルキルアミノ基は環状アミノ基を置
換基として有してもよく、又前記脂肪族炭化水素残基は
１つ以上の水酸基を置換基として有してもよい。但しＹ
が水酸基でＸが水素原子である組合せを除く。）で表わ
される化合物及びその塩 ２）式 ▲数式、化学式、表等があります▼ （式中、Ｒ＿１、Ｒ＿２及びＲ＿３はそれぞれ独立に低
級アルコキシ基を、Ｘはハロゲン原子又は水素原子を示
す。）で表わされる化合物をハロゲン化水素又は式 ▲数式、化学式、表等があります▼ （式中、Ｘ＿１はハロゲン原子を、Ｒ＿５及びＲ＿６は
独立に低級アルキル基を意味する）で表わされる化合物
と反応させることを特徴とする式 ▲数式、化学式、表等があります▼ （式中、Ｒ＿１、Ｒ＿２、Ｒ＿３、Ｘ及びＸ＿１は前記
に同じ）で表わされる化合物の製造法 ３）式 ▲数式、化学式、表等があります▼ （式中、Ｘはハロゲン原子又は水素原子を、Ｒ＿１、Ｒ
＿２及びＲ＿３はそれぞれ独立に低級アルコキシ基を、
Ｒ＿７はアルール基を意味する。）で表わされる化合物
を式 ＨＲ＿４＿１ （式中、Ｒ＿４＿１は環状アミノ基又はアルキルアミノ
基を意味し、前記環状アミノ基はヒドロキシルアルキル
基、環状アミノ基又は１，３−ベンゾオキソラニルアル
キル基を置換基として有してもよく、又前記アルキルア
ミノ基は環状アミノ基を置換基として有してもよい。）
で表わされる化合物と反応させることを特徴とする式 ▲数式、化学式、表等があります▼ （式中、Ｒ＿１、Ｒ＿２、Ｒ＿３、Ｘ及びＲ＿４＿１は
前記に同じ）で表わされる化合物の製造法 ４）式 ▲数式、化学式、表等があります▼ （式中Ｒ＿１、Ｒ＿２、及びＲ＿３はそれぞれ独立に低
級アルコキシ基を、Ｘはハロゲン原子又は水素原子を意
味する。）で表わされる化合物を脱水縮合剤及び塩基性
触媒の存在下式 Ｒ＿４＿２ＣＯＯＨ （式中、Ｒ＿４＿２は飽和又は不飽和の脂肪族炭化水素
残基を意味する。）で表わされる化合物と反応させ所望
により生成物をグリコール形成酸化剤と反応させ、次い
で、還元剤と処理することを特徴とする式 ▲数式、化学式、表等があります▼ （式中、Ｒ＿１、Ｒ＿２、Ｒ＿３及びＸは前記に同じで
あり、Ｒ＿４＿３は置換基として１つ以上の水酸基を有
することもある飽和もしくは不飽和の脂肪族炭化水素残
基を意味する。）で表わされる化合物の製造法。[Claims] 1) Formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R_1, R_2 and R_3 each independently represent a lower alkoxy group, X represents a halogen atom or a hydrogen atom,
Y is a halogen atom, a hydroxyl group, or -O-CO-R_4,
R_4 means a cyclic amino group, an alkylamino group, or a saturated or unsaturated aliphatic hydrocarbon residue, and the cyclic amino group is a hydroxylalkyl group, a cyclic amino group, or 1
, 3-benzoxolanylalkyl group as a substituent, the alkylamino group may have a cyclic amino group as a substituent, and the aliphatic hydrocarbon residue may have one or more It may have a hydroxyl group as a substituent. However, Y
Excludes combinations where is a hydroxyl group and X is a hydrogen atom. ) and their salts 2) Formula ▲ Numerical formulas, chemical formulas, tables, etc. are available▼ (In the formula, R_1, R_2 and R_3 each independently represent a lower alkoxy group, and X represents a halogen atom or a hydrogen atom.) A compound represented by is reacted with hydrogen halide or a compound represented by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. There are formulas ▲ mathematical formulas, chemical formulas, tables, etc. ▼ (in the formula, R_1, R_2, R_3, etc.▼ (In the formula, X is a halogen atom or a hydrogen atom, R_1, R
_2 and R_3 each independently represent a lower alkoxy group,
R_7 means an allyl group. ) is a compound represented by the formula HR_4_1 (wherein R_4_1 means a cyclic amino group or an alkylamino group, and the cyclic amino group is substituted with a hydroxylalkyl group, a cyclic amino group, or a 1,3-benzoxolanylalkyl group). (The alkylamino group may have a cyclic amino group as a substituent.)
Method for producing a compound represented by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (wherein R_1, R_2, R_3, X and R_4_1 are the same as above) 4) A compound represented by the formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R_1, R_2, and R_3 each independently represent a lower alkoxy group, and reacting with a compound of the formula R_4_2COOH in the presence of a basic catalyst, where R_4_2 means a saturated or unsaturated aliphatic hydrocarbon residue, and optionally reacting the product with a glycol-forming oxidizing agent; Next, there are formulas ▲ mathematical formulas, chemical formulas, tables, etc. that are characterized by treatment with a reducing agent ▼ (wherein R_1, R_2, R_3 and A process for producing a compound represented by (representing a saturated or unsaturated aliphatic hydrocarbon residue that may have a hydroxyl group).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP27521387A JPH01117885A (en) | 1987-10-30 | 1987-10-30 | Novel podophyllotoxin derivative and production thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP27521387A JPH01117885A (en) | 1987-10-30 | 1987-10-30 | Novel podophyllotoxin derivative and production thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH01117885A true JPH01117885A (en) | 1989-05-10 |
Family
ID=17552274
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP27521387A Pending JPH01117885A (en) | 1987-10-30 | 1987-10-30 | Novel podophyllotoxin derivative and production thereof |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH01117885A (en) |
Cited By (8)
| 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 |
| US5541223A (en) * | 1989-02-23 | 1996-07-30 | Yale University | 4β-amino podophyllotoxin analog compounds and methods |
| CN1035821C (en) * | 1991-01-25 | 1997-09-10 | 大鹏药品工业株式会社 | 4-deoxy-4-epipodophyllotoxin derivatives or pharmaceutically acceptable salt thereof |
| FR2810321A1 (en) * | 2000-06-20 | 2001-12-21 | Adir | Podophyllotoxin carbamate and thiocarbamate derivatives have improved anticancer activity |
| EP1643987A4 (en) * | 2003-07-01 | 2008-07-09 | California Pacific Med Center | Podophyllotoxin derivatives |
| US10087194B2 (en) | 2015-10-27 | 2018-10-02 | California Pacific Medical Center | Podophyllotoxin derivatives and their use |
| JP2019048851A (en) * | 2008-05-23 | 2019-03-28 | ザ ユニヴァーシティ オブ ブリティッシュ コロンビア | Modified Drugs for Use in Liposomal Nanoparticles |
| US11186594B2 (en) | 2015-10-27 | 2021-11-30 | California Pacific Medical Center | Podophyllotoxin derivatives and their use |
-
1987
- 1987-10-30 JP JP27521387A patent/JPH01117885A/en active Pending
Cited By (14)
| 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 |
| CN1035821C (en) * | 1991-01-25 | 1997-09-10 | 大鹏药品工业株式会社 | 4-deoxy-4-epipodophyllotoxin derivatives or pharmaceutically acceptable salt thereof |
| CN1046521C (en) * | 1991-01-25 | 1999-11-17 | 大鹏药品工业株式会社 | Preparation of derivative of 4-deoxcide-4-surface-podocyllin poison |
| FR2810321A1 (en) * | 2000-06-20 | 2001-12-21 | Adir | Podophyllotoxin carbamate and thiocarbamate derivatives have improved anticancer activity |
| WO2001098307A1 (en) * | 2000-06-20 | 2001-12-27 | Les Laboratoires Servier | Carbamate and thiocarbamate podophyllotoxin derivatives, preparation method and pharmaceutical compositions containing them |
| US6878746B2 (en) | 2000-06-20 | 2005-04-12 | Les Laboratoires Servier | Carbamate and thiocarbamate podophyllotoxin derivatives, preparation method and pharmaceutical compositions containing them |
| EP1643987A4 (en) * | 2003-07-01 | 2008-07-09 | California Pacific Med Center | Podophyllotoxin derivatives |
| US8158809B2 (en) | 2003-07-01 | 2012-04-17 | Sutter West Bay Hospitals | Podophyllotoxin derivatives |
| JP2019048851A (en) * | 2008-05-23 | 2019-03-28 | ザ ユニヴァーシティ オブ ブリティッシュ コロンビア | Modified Drugs for Use in Liposomal Nanoparticles |
| US10087194B2 (en) | 2015-10-27 | 2018-10-02 | California Pacific Medical Center | Podophyllotoxin derivatives and their use |
| US11186594B2 (en) | 2015-10-27 | 2021-11-30 | California Pacific Medical Center | Podophyllotoxin derivatives and their use |
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