JPH10310598A - Sterol compound - Google Patents
Sterol compoundInfo
- Publication number
- JPH10310598A JPH10310598A JP10057291A JP5729198A JPH10310598A JP H10310598 A JPH10310598 A JP H10310598A JP 10057291 A JP10057291 A JP 10057291A JP 5729198 A JP5729198 A JP 5729198A JP H10310598 A JPH10310598 A JP H10310598A
- Authority
- JP
- Japan
- Prior art keywords
- compound
- substance
- mixture
- nmr
- cdcl
- 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
- -1 Sterol compound Chemical class 0.000 title abstract description 10
- 229930182558 Sterol Natural products 0.000 title abstract description 8
- 235000003702 sterols Nutrition 0.000 title abstract description 8
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims abstract description 5
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 abstract description 161
- 238000000034 method Methods 0.000 abstract description 19
- 239000000126 substance Substances 0.000 abstract description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 abstract description 9
- 239000004593 Epoxy Substances 0.000 abstract description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 abstract description 6
- 239000003814 drug Substances 0.000 abstract description 5
- 238000001727 in vivo Methods 0.000 abstract description 4
- 239000002246 antineoplastic agent Substances 0.000 abstract description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 3
- 230000002194 synthesizing effect Effects 0.000 abstract description 3
- 230000005917 in vivo anti-tumor Effects 0.000 abstract description 2
- 239000007858 starting material Substances 0.000 abstract description 2
- 230000001590 oxidative effect Effects 0.000 abstract 2
- 238000010306 acid treatment Methods 0.000 abstract 1
- 230000000767 anti-ulcer Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 60
- 239000000203 mixture Substances 0.000 description 35
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 33
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 26
- 238000005160 1H NMR spectroscopy Methods 0.000 description 25
- 230000015572 biosynthetic process Effects 0.000 description 21
- 239000000243 solution Substances 0.000 description 21
- 238000003786 synthesis reaction Methods 0.000 description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 16
- 238000006243 chemical reaction Methods 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 10
- 239000012043 crude product Substances 0.000 description 10
- 238000001704 evaporation Methods 0.000 description 10
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 9
- 230000000259 anti-tumor effect Effects 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 238000010898 silica gel chromatography Methods 0.000 description 8
- 235000017557 sodium bicarbonate Nutrition 0.000 description 8
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 8
- 229940126062 Compound A Drugs 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 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 6
- 241000699670 Mus sp. Species 0.000 description 6
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- 239000011345 viscous material Substances 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 238000003818 flash chromatography Methods 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- POILWHVDKZOXJZ-ARJAWSKDSA-M (z)-4-oxopent-2-en-2-olate Chemical compound C\C([O-])=C\C(C)=O POILWHVDKZOXJZ-ARJAWSKDSA-M 0.000 description 3
- MYMSJFSOOQERIO-UHFFFAOYSA-N 1-bromodecane Chemical compound CCCCCCCCCCBr MYMSJFSOOQERIO-UHFFFAOYSA-N 0.000 description 3
- FRIBMENBGGCKPD-UHFFFAOYSA-N 3-(2,3-dimethoxyphenyl)prop-2-enal Chemical compound COC1=CC=CC(C=CC=O)=C1OC FRIBMENBGGCKPD-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- XHCLAFWTIXFWPH-UHFFFAOYSA-N [O-2].[O-2].[O-2].[O-2].[O-2].[V+5].[V+5] Chemical compound [O-2].[O-2].[O-2].[O-2].[O-2].[V+5].[V+5] XHCLAFWTIXFWPH-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 150000001336 alkenes Chemical class 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 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 3
- 208000032839 leukemia Diseases 0.000 description 3
- 239000012299 nitrogen atmosphere Substances 0.000 description 3
- 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 3
- 238000003756 stirring Methods 0.000 description 3
- 229910001935 vanadium oxide Inorganic materials 0.000 description 3
- IKPSIIAXIDAQLG-UHFFFAOYSA-N 1-bromoundecane Chemical compound CCCCCCCCCCCBr IKPSIIAXIDAQLG-UHFFFAOYSA-N 0.000 description 2
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 description 2
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- XJUZRXYOEPSWMB-UHFFFAOYSA-N Chloromethyl methyl ether Chemical compound COCCl XJUZRXYOEPSWMB-UHFFFAOYSA-N 0.000 description 2
- 239000007818 Grignard reagent Substances 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- WJGAPUXHSQQWQF-UHFFFAOYSA-N acetic acid;hydrochloride Chemical compound Cl.CC(O)=O WJGAPUXHSQQWQF-UHFFFAOYSA-N 0.000 description 2
- 229940061627 chloromethyl methyl ether Drugs 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 2
- 150000004795 grignard reagents Chemical class 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- LULAYUGMBFYYEX-UHFFFAOYSA-N metachloroperbenzoic acid Natural products OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- PBLNBZIONSLZBU-UHFFFAOYSA-N 1-bromododecane Chemical compound CCCCCCCCCCCCBr PBLNBZIONSLZBU-UHFFFAOYSA-N 0.000 description 1
- AYMUQTNXKPEMLM-UHFFFAOYSA-N 1-bromononane Chemical compound CCCCCCCCCBr AYMUQTNXKPEMLM-UHFFFAOYSA-N 0.000 description 1
- VMKOFRJSULQZRM-UHFFFAOYSA-N 1-bromooctane Chemical compound CCCCCCCCBr VMKOFRJSULQZRM-UHFFFAOYSA-N 0.000 description 1
- KOFZTCSTGIWCQG-UHFFFAOYSA-N 1-bromotetradecane Chemical compound CCCCCCCCCCCCCCBr KOFZTCSTGIWCQG-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
- 244000215068 Acacia senegal Species 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 206010003445 Ascites Diseases 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 239000012981 Hank's balanced salt solution Substances 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- AFCARXCZXQIEQB-UHFFFAOYSA-N N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CCNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 AFCARXCZXQIEQB-UHFFFAOYSA-N 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000006735 epoxidation reaction Methods 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 125000002889 tridecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
Landscapes
- Steroid Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【0001】[0001]
【発明の属する技術分野】本発明は、抗腫瘍作用を有
し、医薬として有用なステロール化合物に関する。TECHNICAL FIELD The present invention relates to a sterol compound having an antitumor effect and useful as a medicine.
【0002】[0002]
【従来の技術】本化合物と類似の構造を有する化合物と
しては、特開平5−4998号公報に記載のXestospong
ia属海綿から単離された化合物(以下、化合物Aと称す
る)が知られている。化合物Aは、優れた抗腫瘍作用を
有しており新規抗癌剤として期待される。しかしなが
ら、化合物Aは海洋天然物由来であることから資源確保
に問題があり大量安定供給は困難であった。また、化合
物Aの17位側鎖中には5個の不斉炭素が存在している
ため、その効率的な立体選択的合成は至難であった。BACKGROUND OF THE INVENTION As a compound having a structure similar to that of the present compound, Xestospong described in JP-A-5-4998 is disclosed.
A compound isolated from genus ia sponge (hereinafter, referred to as compound A) is known. Compound A has excellent antitumor activity and is expected as a novel anticancer agent. However, since compound A is derived from marine natural products, there is a problem in securing resources, and it has been difficult to provide a stable supply in large quantities. In addition, since five asymmetric carbons are present in the side chain at the 17-position of compound A, efficient stereoselective synthesis thereof was extremely difficult.
【0003】本発明者らは、この問題点を解決するた
め、化合物Aの17位側鎖を簡素化し、有機合成化学的
方法による供給を可能にした化合物群を発明した(特開
平7−224087号公報)。In order to solve this problem, the present inventors have invented a compound group in which the side chain at the 17-position of compound A is simplified and can be supplied by an organic synthetic chemical method (Japanese Patent Laid-Open No. 7-224087). No.).
【0004】[0004]
【発明が解決しようとする課題】本発明は、有機合成化
学的方法により合成でき、より優れた抗腫瘍作用を有す
るステロール化合物を提供することを目的とする。SUMMARY OF THE INVENTION An object of the present invention is to provide a sterol compound which can be synthesized by an organic synthetic chemical method and has a better antitumor effect.
【0005】[0005]
【課題を解決するための手段】本発明者らは、特開平7
−224087号公報記載の化合物群についてより詳細
に抗腫瘍作用を比較検討した。その結果、特開平7−2
24087号の特許請求の範囲に包含されるものの具体
的に記載がない化合物が、公知の化合物A及び特開平7
−224087号公報に具体的に記載された化合物を大
幅に上回る優れた抗腫瘍作用を示す化合物を見いだし、
本発明を完成させた。Means for Solving the Problems The present inventors disclosed in Japanese Patent Laid-Open No.
The antitumor effects of the compounds described in JP-A-224087 were compared and studied in more detail. As a result, JP-A-7-2
Compounds which are included in the claims of Japanese Patent No. 24087 but which are not specifically described are known compounds A and
A compound exhibiting an excellent antitumor effect, which is significantly greater than the compounds specifically described in JP-A-224087,
The present invention has been completed.
【0006】以下、本発明を説明する。Hereinafter, the present invention will be described.
【0007】本発明は、式[I]The present invention provides a compound of the formula [I]
【0008】[0008]
【化2】 Embedded image
【0009】(式中、Rはノニル基又はデシル基を示
す。)で表されるステロール化合物である。(Wherein R represents a nonyl group or a decyl group).
【0010】[0010]
【発明の実施の形態】本発明化合物は、文献(Che
m.Ber.,第100巻,第464頁,1967年)記
載のステロイド誘導体3β,12β−ジヒドロキシ−5
α−プレグナン−20−オン(1)を出発原料として用
い、下記のスキーム1及びスキーム2に示す製法にした
がって合成することができる。以下に本発明化合物の合
成法を概説する。BEST MODE FOR CARRYING OUT THE INVENTION The compound of the present invention is described in the literature (Che).
m. Ber., Vol. 100, p. 464, 1967).
Using α-pregnan-20-one (1) as a starting material, it can be synthesized according to the production methods shown in the following schemes 1 and 2. The synthesis method of the compound of the present invention will be outlined below.
【0011】[0011]
【化3】 Embedded image
【0012】[0012]
【化4】 Embedded image
【0013】化合物(1)にN,N−ジイソプロピルエ
チルアミンなどの塩基存在下、クロロメチルメチルエー
テルを反応させて3位及び12位の水酸基を保護した誘
導体(2)を得る。化合物(2)に1−ブロモデカン又
は1−ブロモウンデカンから調製したグリニヤール試薬
を作用させて20位アルコール体(3):低極性異性体
及び(4):高極性異性体を得る。引続き、化合物
(3)と化合物(4)の混合物をイソプロパノールなど
の低級アルコール中、濃塩酸、濃硫酸又はパラトルエン
スルホン酸などの酸と作用させて20,22−(E)−
オレフィン体(5)を主生成物として得る。化合物
(5)に触媒量の酸化バナジウムアセチルアセトナート
の存在下、及び炭酸水素ナトリウムなどの塩基の存在下
又は非存在下、tert−ブチルヒドロペルオキシド又
はクメンヒドロペルオキシドを作用させて、20,22
−β−エポキシ体(6):高極性異性体及び20,22
−α−エポキシ体(7):低極性異性体を約10:1〜
5:1の生成比で得る。化合物(6)と化合物(7)の
混合物をピリジンなどの溶媒中、4−ジメチルアミノピ
リジンなどの塩基存在下、無水酢酸と反応させて3β,
12β−ジアセトキシ体(8)及び(9)を得る。両化
合物をカラムクロマトグラフィーにて分離し、得られた
β−エポキシ体(8)を塩化水素などの酸を含有した、
酢酸エチルなどの有機溶媒中にて反応させ、3β,12
β−ジアセトキシアリルアルコール体(10)及び3
β,22α−ジアセトキシ体(11)の混合物を得る。
両化合物をカラムクロマトグラフィーにて分離し、得ら
れた化合物(10)を塩化水素などの酸を含有した、酢
酸エチルなどの有機溶媒中にて反応させ、化合物(1
0)及び化合物(11)の混合物を得る。両化合物をカ
ラムクロマトグラフィーにて分離し、得られた化合物
(10)に対して上記と同様の操作を繰り返して化合物
(11)を得る。化合物(11)に触媒量の酸化バナジ
ウムアセチルアセトナートの存在下、tert−ブチル
ヒドロペルオキシド又はクメンヒドロペルオキシドを作
用させて、20,21−エポキシ体(12)を得る。化
合物(12)をメタノールなどの低級アルコール中、炭
酸カリウムなどの塩基と反応させて本発明の化合物(1
3)を得る。The compound (1) is reacted with chloromethyl methyl ether in the presence of a base such as N, N-diisopropylethylamine to obtain a derivative (2) in which the hydroxyl groups at the 3- and 12-positions are protected. The compound (2) is reacted with a Grignard reagent prepared from 1-bromodecane or 1-bromoundecane to obtain the 20-position alcohol (3): a low-polar isomer and (4): a high-polar isomer. Subsequently, the mixture of compound (3) and compound (4) is reacted with an acid such as concentrated hydrochloric acid, concentrated sulfuric acid or paratoluenesulfonic acid in a lower alcohol such as isopropanol to give 20,22- (E)-.
The olefin (5) is obtained as the main product. Compound (5) is reacted with tert-butyl hydroperoxide or cumene hydroperoxide in the presence of a catalytic amount of vanadium oxide acetylacetonate and in the presence or absence of a base such as sodium bicarbonate to give 20,22.
-Β-epoxy compound (6): highly polar isomer and 20,22
-Α-epoxy compound (7): about 10: 1 to less polar isomer
Obtained at a production ratio of 5: 1. The mixture of compound (6) and compound (7) is reacted with acetic anhydride in a solvent such as pyridine in the presence of a base such as 4-dimethylaminopyridine to give 3β,
The 12β-diacetoxy compounds (8) and (9) are obtained. Both compounds were separated by column chromatography, and the resulting β-epoxy compound (8) contained an acid such as hydrogen chloride.
Reaction in an organic solvent such as ethyl acetate
β-diacetoxyallyl alcohols (10) and 3
A mixture of β, 22α-diacetoxy compound (11) is obtained.
Both compounds were separated by column chromatography, and the resulting compound (10) was reacted in an organic solvent containing an acid such as hydrogen chloride, such as ethyl acetate, to give the compound (1).
0) and a mixture of compound (11). Both compounds are separated by column chromatography, and the same operation as described above is repeated on the obtained compound (10) to obtain a compound (11). Compound (11) is reacted with tert-butyl hydroperoxide or cumene hydroperoxide in the presence of a catalytic amount of vanadium oxide acetylacetonate to obtain a 20,21-epoxy compound (12). Compound (12) is reacted with a base such as potassium carbonate in a lower alcohol such as methanol to give compound (1) of the present invention.
Obtain 3).
【0014】また、本発明の化合物(13)は以下の方
法によっても合成することができる。すなわち、化合物
(10)と化合物(11)の混合物をメタノールなどの
低級アルコール中、炭酸カリウムなどの塩基と反応させ
てトリオール体(14)を得る。引き続き、化合物(1
4)を炭酸水素ナトリウムなどの塩基の存在下又は非存
在下、メタクロロ過安息香酸にてエポキシ化し、本発明
の化合物(13)を得る。The compound (13) of the present invention can also be synthesized by the following method. That is, a mixture of the compound (10) and the compound (11) is reacted with a base such as potassium carbonate in a lower alcohol such as methanol to obtain a triol compound (14). Subsequently, compound (1)
Epoxidation of 4) with metachloroperbenzoic acid in the presence or absence of a base such as sodium bicarbonate gives compound (13) of the present invention.
【0015】本発明のステロール化合物を医薬品として
用いる場合、これを医薬組成物に通常使用される担体
(例えばタルク、アラビアゴム、ラクトース、ステアリ
ン酸マグネシウム、トウモロコシデンプン等)と混合
し、経口又は非経口投与の製剤とする。その投与剤形と
しては、錠剤、顆粒剤、散剤、カプセル剤、シロップ
剤、懸濁剤、注射剤が挙げられ、患者の症状、年齢及び
治療の目的に応じて適宜選択することができる。その投
与量は、成人を治療する場合で1〜500mgであり、
これを1日1回又は2〜3回に分けて投与する。この投
与量は、患者の年齢、体重及び症状によって適宜増減す
ることができる。When the sterol compound of the present invention is used as a pharmaceutical, it is mixed with a carrier usually used in a pharmaceutical composition (eg, talc, gum arabic, lactose, magnesium stearate, corn starch) and is orally or parenterally administered. Formulation for administration. Examples of the dosage form include tablets, granules, powders, capsules, syrups, suspensions and injections, which can be appropriately selected depending on the condition, age and purpose of treatment of the patient. The dose is 1 to 500 mg when treating an adult,
This is administered once or twice or three times a day. This dosage can be appropriately increased or decreased depending on the age, weight and condition of the patient.
【0016】[0016]
【発明の効果】本発明により、公知の化合物A及び特開
平7−224087号公報に具体的に記載された化合物
を大幅に上回る優れた抗腫瘍作用を有するステロール化
合物が、有機合成化学的方法により提供された。本発明
のステロール化合物は、特開平7−224087号の特
許請求の範囲に包含される化合物群の中でも顕著に優れ
たin vivo抗腫瘍作用を有しており、かつ有機合成化学
的方法により容易に供給できることから、抗腫瘍作用を
有する医薬として有用である。Industrial Applicability According to the present invention, a sterol compound having an excellent antitumor effect, which is far superior to the known compound A and the compounds specifically described in JP-A-7-224087, can be synthesized by an organic synthetic chemical method. sponsored. The sterol compound of the present invention has a remarkably excellent in vivo antitumor effect among the compound group encompassed in the claims of JP-A-7-224087, and is easily prepared by an organic synthetic chemical method. Since it can be supplied, it is useful as a drug having an antitumor effect.
【0017】[0017]
【実施例】以下に実施例を挙げて本発明をさらに詳細に
説明する。なお、実施例に記載する化合物番号はスキー
ム1及びスキーム2に示した化合物番号と対応してい
る。また、実施例に記載する化合物番号に付随するaは
スキーム1及びスキーム2に示した化合物のRがノニル
基(n−C9H19)の場合を示し、bはスキーム1及び
スキーム2に示した化合物のRがデシル基(n−C10H
21)の場合を示している。The present invention will be described in more detail with reference to the following examples. The compound numbers described in the examples correspond to the compound numbers shown in Scheme 1 and Scheme 2. In addition, a attached to the compound number described in the examples indicates a case where R of the compound shown in Scheme 1 and Scheme 2 is a nonyl group (n-C 9 H 19 ), and b is shown in Scheme 1 and Scheme 2. R of the compound obtained is a decyl group (nC 10 H
21 ).
【0018】実施例1(スキーム1及びスキーム2に示
した化合物のRがノニル基の場合)1)化合物(2)の
合成 化合物(1)7.0gをジクロロメタン70mlに溶解
し、クロロメチルメチルエーテル5.05g及びN,N−
ジイソプロピルエチルアミン8.10gを加え、7時間
還流した。放冷後、反応液に氷水を加えて酢酸エチルに
て抽出し、抽出液を水、飽和食塩水にて順次洗浄し、無
水硫酸マグネシウムにて乾燥した。溶媒を留去して得ら
れた粗生成物をシリカゲルカラムクロマトグラフィー
[ヘキサン:酢酸エチル=2:1(v/v)にて溶出]
に付し、当該化合物画分を得た。これをヘキサンより再
結晶し、無色プリズム晶(2)を6.7g得た。Example 1 (when R in the compounds shown in Schemes 1 and 2 is a nonyl group) 1) Synthesis of compound (2) 7.0 g of compound (1) was dissolved in 70 ml of dichloromethane, and chloromethyl methyl ether was dissolved. 5.05 g and N, N-
8.10 g of diisopropylethylamine was added, and the mixture was refluxed for 7 hours. After cooling, ice water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated saline, and dried over anhydrous magnesium sulfate. The crude product obtained by evaporating the solvent is purified by silica gel column chromatography [hexane: ethyl acetate = 2: 1 (v / v)].
And the compound fraction was obtained. This was recrystallized from hexane to obtain 6.7 g of colorless prism crystals (2).
【0019】mp:94〜95℃ Anal.Calcd for C25H42O5:C,71.05;
H,10.02 Found:C,71.25;H,10.10 IR(KBr)νcm-1:1701,1150,10421 H−NMR(200MHz,CDCl3)δppm:0.
74(3H,s),0.82(3H,s),2.19(3H,s),2.68(1H,t,J=8Hz),3.
34(3H,s),3.36(3H,s),3.34-3.43(1H,m),3.43-3.58(1H,
m),4.63-4.74(4H,m) FABMS(+KI) m/z:461(MK+)。Mp: 94-95 ° C. Anal. Calcd for C 25 H 42 O 5 : C, 71.05;
H, 10.02 Found: C, 71.25; H, 10.10 IR (KBr) νcm -1 : 1701,1150,1042 1 H-NMR (200 MHz, CDCl 3 ) δ ppm: 0.
74 (3H, s), 0.82 (3H, s), 2.19 (3H, s), 2.68 (1H, t, J = 8Hz), 3.
34 (3H, s), 3.36 (3H, s), 3.34-3.43 (1H, m), 3.43-3.58 (1H,
m), 4.63-4.74 (4H, m) FABMS (+ KI) m / z: 461 (MK + ).
【0020】2)化合物(3a)及び化合物(4a)の
合成 マグネシウム603mgにジエチルエーテル20ml及
び触媒量のヨウ素を加え、窒素雰囲気下、1−ブロモデ
カン4.71gのジエチルエーテル40ml溶液を室温
にて滴下し、1時間撹拌した。このグリニヤール試薬溶
液を0℃に冷却した後、化合物(2)3.00gのベン
ゼン15ml溶液を滴下し、0℃にて1時間撹拌した。
反応液を塩化アンモニウム水溶液に注ぎ、酢酸エチルに
て抽出した。抽出液を飽和食塩水にて洗浄し、無水硫酸
マグネシウムにて乾燥後、溶媒を減圧下留去して粗生成
物を得た。これをシリカゲルカラムクロマトグラフィー
[ヘキサン:酢酸エチル=3:1(V/V)にて溶出]
にて精製し、化合物(3a)と化合物(4a)の混合物
を4.05g得た。この混合物は分離することなく、次
の反応に用いた。この混合物の一部を上記と同様のシリ
カゲルカラムクロマトグラフィーにて分離し、先に溶出
する画分から無色粘性物質(3a)を得、引き続き後か
ら溶出する画分から無色粘性物質(4a)を得た。2) Synthesis of compound (3a) and compound (4a) To 603 mg of magnesium were added 20 ml of diethyl ether and a catalytic amount of iodine, and under nitrogen atmosphere, a solution of 4.71 g of 1-bromodecane in 40 ml of diethyl ether was added dropwise at room temperature. And stirred for 1 hour. After cooling the Grignard reagent solution to 0 ° C., a solution of 3.00 g of compound (2) in 15 ml of benzene was added dropwise, and the mixture was stirred at 0 ° C. for 1 hour.
The reaction solution was poured into an aqueous ammonium chloride solution and extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product. This is eluted with silica gel column chromatography [hexane: ethyl acetate = 3: 1 (V / V)].
Then, 4.05 g of a mixture of the compound (3a) and the compound (4a) was obtained. This mixture was used for the next reaction without separation. A part of this mixture was separated by the same silica gel column chromatography as above, and a colorless viscous substance (3a) was obtained from the fraction eluted earlier, and a colorless viscous substance (4a) was obtained from the fraction eluted later. .
【0021】化合物(3a) IR(neat)νcm-1:3431,2927,1467,1152,110
1,1050,10241 H−NMR(300MHz,CDCl3)δppm:0.
83(3H,s),0.86(3H,s),0.88(3H,t,J=6.5Hz),1.19(3H,s),
1.97-2.07(1H,m),3.32-3.40(1H,m),3.37(3H,s),3.41(3
H,s),3.42-3.56(1H,m),4.68(2H,s),4.70(1H,d,J=6.9H
z),4.84(1H,d,J=6.9Hz),5.18(1H,s) FABMS(+KI) m/z:603(MK+)。Compound (3a) IR (neat) νcm -1 : 3431,2927,1467,1152,110
1,1050,1024 1 H-NMR (300 MHz, CDCl 3 ) δ ppm: 0.
83 (3H, s), 0.86 (3H, s), 0.88 (3H, t, J = 6.5Hz), 1.19 (3H, s),
1.97-2.07 (1H, m), 3.32-3.40 (1H, m), 3.37 (3H, s), 3.41 (3
H, s), 3.42-3.56 (1H, m), 4.68 (2H, s), 4.70 (1H, d, J = 6.9H
z), 4.84 (1H, d, J = 6.9 Hz), 5.18 (1H, s) FABMS (+ KI) m / z: 603 (MK + ).
【0022】化合物(4a) IR(neat)νcm-1:3434,2927,1467,1151,110
2,1050,10241 H−NMR(300MHz,CDCl3)δppm:0.
83(3H,s),0.84(3H,s),0.88(3H,t,J=6.7Hz),1.05(3H,s),
1.97-2.07(1H,m),3.33-3.43(1H,m),3.37(3H,s),3.42(3
H,s),3.43-3.57(1H,m),4.68(2H,s),4.70(1H,d,J=6.7H
z),4.79(1H,s),4.83(1H,d,J=6.6Hz) FABMS(+KI) m/z:603(MK+)。Compound (4a) IR (neat) νcm -1 : 3434,2927,1467,1151,110
2,1050,1024 1 H-NMR (300 MHz, CDCl 3 ) δ ppm: 0.
83 (3H, s), 0.84 (3H, s), 0.88 (3H, t, J = 6.7Hz), 1.05 (3H, s),
1.97-2.07 (1H, m), 3.33-3.43 (1H, m), 3.37 (3H, s), 3.42 (3
H, s), 3.43-3.57 (1H, m), 4.68 (2H, s), 4.70 (1H, d, J = 6.7H
z), 4.79 (1H, s), 4.83 (1H, d, J = 6.6 Hz) FABMS (+ KI) m / z: 603 (MK + ).
【0023】3)化合物(5a)の合成 化合物(3a)と化合物(4a)の混合物4.05gを
イソプロパノール100mlに溶解し、濃塩酸2mlを
加えて6.5時間還流した。反応液を冷却後、溶媒を留
去して得られた残渣をシリカゲルカラムクロマトグラフ
ィー[ヘキサン:酢酸エチル=2:1(V/V)にて溶
出]にて精製し、無色アモルファス(5a)を2.40
g得た。3) Synthesis of compound (5a) 4.05 g of a mixture of compound (3a) and compound (4a) was dissolved in 100 ml of isopropanol, 2 ml of concentrated hydrochloric acid was added, and the mixture was refluxed for 6.5 hours. After cooling the reaction solution, the residue obtained by evaporating the solvent was purified by silica gel column chromatography [eluted with hexane: ethyl acetate = 2: 1 (V / V)] to give a colorless amorphous (5a). 2.40
g was obtained.
【0024】IR(KBr)νcm-1:3459,2925,285
3,1467,10421 H−NMR(300MHz,CDCl3)δppm:0.
74(3H,s),0.82(3H,s),0.88(3H,t,J=6.7Hz),2.28(1H,t,J
=9.6Hz),3.52-3.66(2H,m),5.49(1H,t,J=7.2Hz) FABMS(+KI) m/z:497(MK+)。IR (KBr) vcm -1 : 3459,2925,285
3,1467,1042 1 H-NMR (300 MHz, CDCl 3 ) δ ppm: 0.
74 (3H, s), 0.82 (3H, s), 0.88 (3H, t, J = 6.7Hz), 2.28 (1H, t, J
= 9.6Hz), 3.52-3.66 (2H, m), 5.49 (1H, t, J = 7.2Hz) FABMS (+ KI) m / z: 497 (MK + ).
【0025】4)化合物(6a)の合成 化合物(5a)2.40gをジクロロメタン90mlに
溶解し、炭酸水素ナトリウム1.32g及び酸化バナジ
ウムアセチルアセトナート138mgを加えて窒素雰囲
気下、0℃に冷却した。この溶液にtert−ブチルヒ
ドロペルオキシド(3.86Mジクロロメタン溶液)1
3.5mlを加え、0℃にて3.5時間撹拌した。反応液
に酢酸エチルを加え、飽和炭酸水素ナトリウム水溶液及
び飽和食塩水にて順次洗浄後、無水硫酸マグネシウムに
て乾燥した。溶媒を減圧下留去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[ヘキサン:酢酸
エチル=2:1〜3:2(V/V)にて溶出]にて精製
し、化合物(6a)と化合物(7a)の混合物[(6
a)が主生成物]を1.90g得た。この混合物は分離
することなく、次の反応に用いた。上記のクロマトグラ
フィーにて先に溶出する画分から化合物(7a)と化合
物(6a)の混合物が得られ、後から溶出する画分から
無色アモルファス(6a)が得られた。4) Synthesis of Compound (6a) 2.40 g of Compound (5a) was dissolved in 90 ml of dichloromethane, 1.32 g of sodium hydrogen carbonate and 138 mg of vanadium oxide acetylacetonate were added, and the mixture was cooled to 0 ° C. under a nitrogen atmosphere. . To this solution was added tert-butyl hydroperoxide (3.86 M dichloromethane solution) 1
3.5 ml was added, and the mixture was stirred at 0 ° C. for 3.5 hours. Ethyl acetate was added to the reaction solution, and the mixture was washed successively with a saturated aqueous solution of sodium hydrogen carbonate and a saturated saline solution, and then dried over anhydrous magnesium sulfate. The crude product obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography [eluted with hexane: ethyl acetate = 2: 1 to 3: 2 (V / V)] to obtain compound (6a). And a mixture of compound (7a) [(6
a) was the main product]. This mixture was used for the next reaction without separation. A mixture of compound (7a) and compound (6a) was obtained from the fraction eluted first by the above chromatography, and colorless amorphous (6a) was obtained from the fraction eluted later.
【0026】化合物(6a) IR(KBr)νcm-1:3400,2925,1467,10471 H−NMR(300MHz,CDCl3)δppm:0.
69(3H,s),0.80(3H,s),0.88(3H,t,J=6.7Hz),1.29(3H,s),
3.23(1H,dd,J=11.3 and 4.6Hz),3.29(1H,t,J=6.1Hz),4.
44(1H,s) FABMS(+KI) m/z:513(MK+)。Compound (6a) IR (KBr) νcm -1 : 3400,2925,1467,1047 1 H-NMR (300 MHz, CDCl 3 ) δ ppm: 0.
69 (3H, s), 0.80 (3H, s), 0.88 (3H, t, J = 6.7Hz), 1.29 (3H, s),
3.23 (1H, dd, J = 11.3 and 4.6Hz), 3.29 (1H, t, J = 6.1Hz), 4.
44 (1H, s) FABMS (+ KI) m / z: 513 (MK + ).
【0027】5)化合物(8a)の合成 化合物(6a)と化合物(7a)の混合物1.90gを
ピリジン20mlに溶解し、無水酢酸2.04g及び4
−ジメチルアミノピリジン244mgを加え、室温にて
14時間撹拌した。反応液に酢酸エチルを加え、希塩酸
及び飽和食塩水にて順次洗浄後、無水硫酸マグネシウム
にて乾燥した。溶媒を減圧下留去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[ヘキサン:酢
酸エチル=8:1(V/V)にて溶出]にて精製し、先
に溶出する画分から無色粘性物質(8a)を1.26g
得、引き続き化合物(9a)を含む画分を得た。5) Synthesis of compound (8a) 1.90 g of a mixture of compound (6a) and compound (7a) was dissolved in 20 ml of pyridine, and 2.04 g of acetic anhydride and 2.04 g of acetic anhydride were added.
-Dimethylaminopyridine (244 mg) was added, and the mixture was stirred at room temperature for 14 hours. Ethyl acetate was added to the reaction solution, which was washed sequentially with dilute hydrochloric acid and saturated saline, and then dried over anhydrous magnesium sulfate. The crude product obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography [eluted with hexane: ethyl acetate = 8: 1 (V / V)]. 1.26 g of substance (8a)
Subsequently, a fraction containing the compound (9a) was obtained.
【0028】化合物(8a) IR(neat)νcm-1:2926,2855,1739,1468,136
9,1245,10241 H−NMR(300MHz,CDCl3)δppm:0.
82(3H,s),0.86(3H,s),0.88(3H,t,J=6.5Hz),1.25(3H,s),
2.01(3H,s),2.05(3H,s),2.57(1H,dd,J=8.5 and2.4Hz),
4.61(1H,dd,J=11.1 and 4.8Hz),4.62-4.75(1H,m) LSIMS m/z:559(MH+)。Compound (8a) IR (neat) νcm -1 : 2926,2855,1739,1468,136
9,1245,1024 1 H-NMR (300 MHz, CDCl 3 ) δ ppm: 0.
82 (3H, s), 0.86 (3H, s), 0.88 (3H, t, J = 6.5Hz), 1.25 (3H, s),
2.01 (3H, s), 2.05 (3H, s), 2.57 (1H, dd, J = 8.5 and2.4Hz),
4.61 (1H, dd, J = 11.1 and 4.8 Hz), 4.62-4.75 (1H, m) LSIMS m / z: 559 (MH <+> ).
【0029】6)化合物(10a)及び化合物(11
a)の合成 化合物(8a)6.92gに0.01規定塩化水素酢酸エ
チル溶液500mlを加え、室温にて5時間撹拌した。
反応液に飽和炭酸水素ナトリウム水溶液を加え、飽和食
塩水にて洗浄後、無水硫酸マグネシウムにて乾燥した。
溶媒を減圧下留去して得られた粗生成物をシリカゲルフ
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=10:1〜4:1(V/V)にて順次溶出]にて
精製し、先に溶出する画分から無色粘性物質(11a)
を3.37g、後から溶出する画分から無色粘性物質
(10a)を3.14g得た。6) Compound (10a) and compound (11)
Synthesis of a) To 6.92 g of compound (8a) was added 500 ml of a 0.01 N hydrogen chloride acetate solution, and the mixture was stirred at room temperature for 5 hours.
A saturated aqueous solution of sodium hydrogencarbonate was added to the reaction solution, and the mixture was washed with saturated saline and dried over anhydrous magnesium sulfate.
The crude product obtained by evaporating the solvent under reduced pressure was purified by silica gel flash column chromatography [eluted sequentially with hexane: ethyl acetate = 10: 1 to 4: 1 (V / V)]. Colorless viscous substance (11a) from the eluted fraction
3.37 g, and 3.14 g of a colorless viscous substance (10a) were obtained from the fraction eluted later.
【0030】ここで得られた化合物(10a)3.14
gに0.01規定塩化水素酢酸エチル溶液200mlを
加え、室温にて4時間撹拌した。反応液に飽和炭酸水素
ナトリウム水溶液を加え、飽和食塩水にて洗浄後、無水
硫酸マグネシウムにて乾燥した。溶媒を減圧下留去して
得られた粗生成物をシリカゲル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=8:1〜5:1
(V/V)にて順次溶出]にて精製し、先に溶出する画
分から化合物(11a)を1.28g、後から溶出する
画分から化合物(10a)を1.40g得た。この化合
物(10a)1.40gを上記と同様に反応させ、化合
物(11a)(全収量5.55g)及び化合物(10
a)(収量644mg)を得た。Compound (10a) 3.14 obtained here
200 g of a 0.01 N hydrogen chloride acetate solution was added to the resulting mixture, and the mixture was stirred at room temperature for 4 hours. A saturated aqueous solution of sodium hydrogencarbonate was added to the reaction solution, and the mixture was washed with saturated saline and dried over anhydrous magnesium sulfate. The crude product obtained by evaporating the solvent under reduced pressure was subjected to silica gel flash column chromatography [hexane: ethyl acetate = 8: 1 to 5: 1].
(Eluted sequentially with (V / V)] to obtain 1.28 g of compound (11a) from the fraction eluted first, and 1.40 g of compound (10a) from the fraction eluted later. 1.40 g of this compound (10a) was reacted in the same manner as described above, to give compound (11a) (5.55 g in total yield) and compound (10a).
a) (yield 644 mg) was obtained.
【0031】化合物(10a) IR(neat)νcm-1:3469,2927,2845,1737,137
0,1247,10261 H−NMR(300MHz,CDCl3)δppm:0.
84(3H,s),0.88(3H,t,J=6.8Hz),0.91(3H,s),1.92(3H,s),
2.01(3H,s),2.33(1H,t,J=9.9Hz),3.84-3.91(1H,m),4.61
-4.74(2H,m),4.97(1H,s),5.02(1H,s) LSIMS m/z:597(MH+)。Compound (10a) IR (neat) νcm -1 : 3469,2927,2845,1737,137
0.1247,1026 1 H-NMR (300 MHz, CDCl 3 ) δ ppm: 0.
84 (3H, s), 0.88 (3H, t, J = 6.8Hz), 0.91 (3H, s), 1.92 (3H, s),
2.01 (3H, s), 2.33 (1H, t, J = 9.9Hz), 3.84-3.91 (1H, m), 4.61
-4.74 (2H, m), 4.97 (1H, s), 5.02 (1H, s) LSIMS m / z: 597 (MH + ).
【0032】化合物(11a) IR(neat)νcm-1:2928,1736,1243,10241 H−NMR(300MHz,CDCl3)δppm:0.
78(3H,s),0.84(3Hs),0.88(3H,t,J=6.7Hz),2.02(3H,s),
2.08(3H,s),2.21(1H,t,J=9.9Hz),3.49(1H,dd,J=11.0 an
d 4.9Hz),4.61-4.75(1H,m),5.18(1H,s),5.25(1H,s),5.2
7(1H,t,J=7.2Hz) LSIMS m/z:597(MH+)。Compound (11a) IR (neat) νcm -1 : 2928,1736,1243,1024 1 H-NMR (300 MHz, CDCl 3 ) δ ppm: 0.
78 (3H, s), 0.84 (3Hs), 0.88 (3H, t, J = 6.7Hz), 2.02 (3H, s),
2.08 (3H, s), 2.21 (1H, t, J = 9.9Hz), 3.49 (1H, dd, J = 11.0 an
d 4.9Hz), 4.61-4.75 (1H, m), 5.18 (1H, s), 5.25 (1H, s), 5.2
7 (1H, t, J = 7.2Hz) LSIMS m / z: 597 (MH + ).
【0033】7)化合物(12a)の合成 化合物(11a)5.55gをジクロロメタン200m
lに溶解し、窒素雰囲気下、0℃に冷却後、80%クメ
ンヒドロペルオキシド3.75gのジクロロメタン3m
l溶液を加えて0℃にて4.5時間撹拌した。反応液に
酢酸エチルを加え、飽和炭酸水素ナトリウム水溶液及び
飽和食塩水にて順次洗浄後、無水硫酸マグネシウムにて
乾燥した。溶媒を減圧下留去して得られた粗生成物をシ
リカゲル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=5:1〜4:1(V/V)にて溶出]
にて精製し、無色粘性物質(12a)を4.81g得
た。7) Synthesis of Compound (12a) 5.55 g of Compound (11a) was added to 200 m of dichloromethane.
After cooling to 0 ° C. under a nitrogen atmosphere, 3.75 g of 80% cumene hydroperoxide and 3 m of dichloromethane were added.
Then, the mixture was stirred at 0 ° C. for 4.5 hours. Ethyl acetate was added to the reaction solution, and the mixture was washed successively with a saturated aqueous solution of sodium hydrogen carbonate and a saturated saline solution, and then dried over anhydrous magnesium sulfate. The crude product obtained by evaporating the solvent under reduced pressure is flash column chromatography on silica gel [hexane: ethyl acetate = eluted with 5: 1 to 4: 1 (V / V)].
Then, 4.81 g of a colorless viscous substance (12a) was obtained.
【0034】IR(neat)νcm-1:3436,2927,28
54,1736,1241,10281 H−NMR(300MHz,CDCl3)δppm:0.
67(3H,s),0.82(3H,s),0.88(3H,t,J=6.7Hz),2.02(3H,s),
2.08(3H,s),2.73(1H,d,J=3.9Hz),3.07(1H,d,J=3.9Hz),
3.34(1H,dd,J=11.0 and 4.6Hz),4.18(1H,s),4.62-4.75
(1H,m),4.77(1H,t,J=6.7Hz) FABMS m/z:575(MH+)。IR (neat) vcm -1 : 3436,2927,28
54,1736,1241,1028 1 H-NMR (300 MHz, CDCl 3 ) δ ppm: 0.
67 (3H, s), 0.82 (3H, s), 0.88 (3H, t, J = 6.7Hz), 2.02 (3H, s),
2.08 (3H, s), 2.73 (1H, d, J = 3.9Hz), 3.07 (1H, d, J = 3.9Hz),
3.34 (1H, dd, J = 11.0 and 4.6Hz), 4.18 (1H, s), 4.62-4.75
(1H, m), 4.77 (1H, t, J = 6.7Hz) FABMS m / z: 575 (MH + ).
【0035】8)化合物(13a)の合成 化合物(12a)4.81gをメタノール150mlに
溶解し、無水炭酸カリウム3.47gを加え、室温にて
1時間撹拌した。反応液に酢酸エチルを加え、水及び飽
和食塩水にて順次洗浄後、無水硫酸マグネシウムにて乾
燥した。溶媒を減圧下留去して得られた粗生成物をシリ
カゲル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=1:1〜2:3(V/V)にて溶出]
にて精製し、当該化合物画分3.0gを得た。これをヘ
キサン−酢酸エチルにて再結晶し、無色粉末(13a)
を2.54g得た。8) Synthesis of compound (13a) 4.81 g of compound (12a) was dissolved in 150 ml of methanol, and 3.47 g of anhydrous potassium carbonate was added, followed by stirring at room temperature for 1 hour. Ethyl acetate was added to the reaction solution, washed sequentially with water and saturated saline, and dried over anhydrous magnesium sulfate. The crude product obtained by evaporating the solvent under reduced pressure is flash column chromatography on silica gel [hexane: ethyl acetate = 1: 1 to 2: 3 (V / V)].
And 3.0 g of the compound fraction was obtained. This was recrystallized from hexane-ethyl acetate to give a colorless powder (13a).
2.54 g was obtained.
【0036】mp:74〜77℃ Anal.Calcd for C31H54O4:C,75.87;
H,11.09 Found:C,75.57;H,11.29 IR(KBr)νcm-1:3401,2926,28531 H−NMR(300MHz,CDCl3)δppm:0.
69(3H,s),0.81(3H,s),0.88(3H,t,J=6.7Hz),2.86(1H,d,J
=4.0Hz),3.05(1H,d,J=4.0Hz),3.30-3.41(1H,m),3.37(1
H,dd,J=10.9 and 4.6Hz),3.52-3.66(1H,m),4.15(1H,br
s) LSIMS(+KI) m/z:529(MK+)。Mp: 74-77 ° C. Anal. Calcd for C 31 H 54 O 4 : C, 75.87;
H, 11.09 Found: C, 75.57; H, 11.29 IR (KBr) νcm -1 : 3401, 2926, 2853 1 H-NMR (300 MHz, CDCl 3 ) δ ppm: 0.
69 (3H, s), 0.81 (3H, s), 0.88 (3H, t, J = 6.7Hz), 2.86 (1H, d, J
= 4.0Hz), 3.05 (1H, d, J = 4.0Hz), 3.30-3.41 (1H, m), 3.37 (1H
H, dd, J = 10.9 and 4.6Hz), 3.52-3.66 (1H, m), 4.15 (1H, br
s) LSIMS (+ KI) m / z: 529 (MK + ).
【0037】以下に化合物(13a)の別途合成法を示
す。 9)化合物(14a)の合成 化合物(10a)と化合物(11a)の混合物1.02
gをメタノール70mlに溶解し、無水炭酸カリウム
1.26gを加え、室温にて5時間撹拌した。反応液を
減圧下留去して得られた残渣にクロロホルムを加え、飽
和食塩水にて洗浄後、無水硫酸マグネシウムにて乾燥し
た。溶媒を減圧下留去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[クロロホルム:酢酸エチ
ル=1:1(V/V)にて溶出]にて精製し、無色粉末
(14a)を758mg得た。The method for separately synthesizing the compound (13a) is shown below. 9) Synthesis of compound (14a) 1.02 mixture of compound (10a) and compound (11a)
g was dissolved in 70 ml of methanol, and 1.26 g of anhydrous potassium carbonate was added, followed by stirring at room temperature for 5 hours. The reaction solution was evaporated under reduced pressure, chloroform was added to the obtained residue, and the mixture was washed with saturated saline and dried over anhydrous magnesium sulfate. The crude product obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography [eluted with chloroform: ethyl acetate = 1: 1 (V / V)] to obtain 758 mg of a colorless powder (14a). Was.
【0038】mp:166〜168℃ IR(KBr)νcm-1:3306,2927,2854,1467,10221 H−NMR(300MHz,CDCl3)δppm:0.
74(3H,s),0.83(3H,s),0.88(3H,t,J=6.7Hz),2.32(1H,t,J
=9.9Hz),3.47(1H,dd,J=11.2 and 4.8Hz),3.51-3.67(1H,
m),4.13(1H,t,J=7.0Hz),4.93(1H,s),5.07(1H,s) LSIMS(+KI) m/z:513(MK+)。[0038] mp: 166~168 ℃ IR (KBr) νcm -1: 3306,2927,2854,1467,1022 1 H-NMR (300MHz, CDCl 3) δppm: 0.
74 (3H, s), 0.83 (3H, s), 0.88 (3H, t, J = 6.7Hz), 2.32 (1H, t, J
= 9.9Hz), 3.47 (1H, dd, J = 11.2 and 4.8Hz), 3.51-3.67 (1H,
m), 4.13 (1H, t, J = 7.0 Hz), 4.93 (1H, s), 5.07 (1H, s) LSIMS (+ KI) m / z: 513 (MK + ).
【0039】10)化合物(13a)の合成 化合物(14a)750mgをジクロロメタン100m
lに溶解し、70%メタクロロ過安息香酸599mgを
加え、室温にて19時間撹拌した。反応液に酢酸エチル
を加え、チオ硫酸ナトリウム水溶液、飽和炭酸水素ナト
リウム水溶液及び飽和食塩水にて順次洗浄後、無水硫酸
マグネシウムにて乾燥した。溶媒を減圧下留去して得ら
れた粗生成物をシリカゲルカラムクロマトグラフィー
[ヘキサン:酢酸エチル=1:2(V/V)にて溶出]
にて精製し、当該化合物画分750mgを得た。これを
ヘキサン−酢酸エチルにて再結晶し、無色粉末(13
a)を658mg得た。10) Synthesis of compound (13a) 750 mg of compound (14a) was added to 100 m of dichloromethane.
and 599 mg of 70% metachloroperbenzoic acid was added, followed by stirring at room temperature for 19 hours. Ethyl acetate was added to the reaction solution, and the mixture was washed sequentially with an aqueous sodium thiosulfate solution, a saturated aqueous sodium hydrogen carbonate solution and saturated saline, and then dried over anhydrous magnesium sulfate. The crude product obtained by evaporating the solvent under reduced pressure is purified by silica gel column chromatography [hexane: ethyl acetate = 1: 2 (V / V)].
And 750 mg of the compound fraction was obtained. This was recrystallized from hexane-ethyl acetate to give a colorless powder (13
658 mg of a) were obtained.
【0040】実施例2(スキーム1及びスキーム2に示
した化合物のRがデシル基の場合)11)化合物(3
b)及び化合物(4b)の合成 実施例1の2)に記載した方法に準拠し、1−ブロモデ
カンに代えて1−ブロモウンデカンを用いて反応を行
い、化合物(3b)及び化合物(4b)を得た。Example 2 (when R in the compounds shown in Schemes 1 and 2 is a decyl group) 11) Compound (3
b) and Synthesis of Compound (4b) According to the method described in 2) of Example 1, the reaction was carried out using 1-bromoundecane instead of 1-bromodecane to give compound (3b) and compound (4b). Obtained.
【0041】化合物(3b) Anal.Calcd for C36H66O5:C,74.69;
H,11.49 Found:C,74.68;H,11.54 IR(KBr)νcm-1:3431,2927,2853,1467,1382,1
152,1101,1050,10241 H−NMR(300MHz,CDCl3)δppm:0.
83(3H,s),0.86(3H,s),0.88(3H,t,J=6.6Hz),1.19(3H,s),
1.98-2.08(1H,m),3.33-3.39(1H,m),3.36(3H,s),3.41(3
H,s),3.43-3.58(1H,m),4.66(2H,s),4.70(1H,d,J=6.8H
z),4.84(1H,d,J=6.8Hz),5.17(1H,s,exchangeable) FABMS(+KI) m/z:617(MK+)。Compound (3b) Anal. Calcd for C 36 H 66 O 5 : C, 74.69;
H, 11.49 Found: C, 74.68; H, 11.54 IR (KBr) νcm -1 : 3431,2927,2853,1467,1382,1
152,1101,1050,1024 1 H-NMR (300 MHz, CDCl 3 ) δ ppm: 0.
83 (3H, s), 0.86 (3H, s), 0.88 (3H, t, J = 6.6Hz), 1.19 (3H, s),
1.98-2.08 (1H, m), 3.33-3.39 (1H, m), 3.36 (3H, s), 3.41 (3
H, s), 3.43-3.58 (1H, m), 4.66 (2H, s), 4.70 (1H, d, J = 6.8H
z), 4.84 (1H, d, J = 6.8 Hz), 5.17 (1H, s, exchangeable) FABMS (+ KI) m / z: 617 (MK + ).
【0042】化合物(4b) Anal.Calcd for C36H66O5:C,74.69;
H,11.49 Found:C,74.52;H,11.53 IR(neat)νcm-1:3435,2927,2853,1467,136
7,1151,1101,1050,10241H−NMR(300MHz,C
DCl3)δppm:0.83(3H,s),0.84(3H,s),0.88(3H,
t.J=6.7Hz),1.05(3H,s),3.32-3.42(1H,m),3.36(3H,s),
3.41(3H,s),4.68(2H,s),4.70(1H,d,J=6.8Hz),4.78(1H,
s,exchangeable),4.83(1H,d,J=6.8Hz) FABMS(+KI) m/z:617(MK+)。Compound (4b) Anal. Calcd for C 36 H 66 O 5 : C, 74.69;
H, 11.49 Found: C, 74.52; H, 11.53 IR (neat) vcm -1 : 3435,2927,2853,1467,136
7,1151,1101,1050,1024 1 H-NMR (300 MHz, C
DCl 3 ) δ ppm: 0.83 (3H, s), 0.84 (3H, s), 0.88 (3H,
tJ = 6.7Hz), 1.05 (3H, s), 3.32-3.42 (1H, m), 3.36 (3H, s),
3.41 (3H, s), 4.68 (2H, s), 4.70 (1H, d, J = 6.8Hz), 4.78 (1H,
s, exchangeable), 4.83 (1H, d, J = 6.8 Hz) FABMS (+ KI) m / z: 617 (MK + ).
【0043】12)化合物(5b)の合成 実施例1の3)に記載した方法に準拠し、化合物(3
b)と化合物(4b)の混合物から化合物(5b)を得
た。12) Synthesis of Compound (5b) Compound (3b) was prepared according to the method described in 3) of Example 1.
Compound (5b) was obtained from a mixture of b) and compound (4b).
【0044】mp:80〜83℃ IR(KBr)νcm-1:3446,2921,2851,1470,1449,1
381,1081,10451 H−NMR(300MHz,CDCl3)δppm:0.
74(3H,s),0.82(3H,s),0.88(3H,t,J=6.7Hz),1.67(3H,s),
2.27(1H,t,J=9.6Hz),3.52-3.66(2H,m),5.49(1H,t,J=6.9
Hz) FABMS m/z:471(MH+)。Mp: 80-83 ° C. IR (KBr) νcm −1 : 3446,2921,2851,1470,1449,1
381,1081,1045 1 H-NMR (300 MHz, CDCl 3 ) δ ppm: 0.
74 (3H, s), 0.82 (3H, s), 0.88 (3H, t, J = 6.7Hz), 1.67 (3H, s),
2.27 (1H, t, J = 9.6Hz), 3.52-3.66 (2H, m), 5.49 (1H, t, J = 6.9
Hz) FABMS m / z: 471 (MH <+> ).
【0045】13)化合物(6b)の合成 実施例1の4)に記載した方法に準拠し、化合物(5
b)から化合物(6b)を得た。13) Synthesis of Compound (6b) Compound (5b) was prepared according to the method described in 4) of Example 1.
Compound (6b) was obtained from b).
【0046】化合物(6b) IR(KBr)νcm-1:3401,2924,28541 H−NMR(300MHz,CDCl3)δppm:0.
69(3H,s),0.80(3H,s),1.29(3H,s),3.23(1H,dd,J=11.1 a
nd 4.5Hz),3.29(1H,t,J=6.0Hz),3.52-3.66(1H,m),4.43
(1H,s) LSIMS(+KI) m/z:527(MK+)。Compound (6b) IR (KBr) νcm -1 : 3401,2924,2854 1 H-NMR (300 MHz, CDCl 3 ) δppm: 0.
69 (3H, s), 0.80 (3H, s), 1.29 (3H, s), 3.23 (1H, dd, J = 11.1 a
nd 4.5Hz), 3.29 (1H, t, J = 6.0Hz), 3.52-3.66 (1H, m), 4.43
(1H, s) LSIMS (+ KI) m / z: 527 (MK + ).
【0047】14)化合物(8b)の合成 実施例1の5)に記載した方法に準拠し、化合物(6
b)と化合物(7b)の混合物から化合物(8b)を得
た。14) Synthesis of Compound (8b) Compound (6b) was prepared according to the method described in 5) of Example 1.
Compound (8b) was obtained from a mixture of b) and compound (7b).
【0048】化合物(8b) IR(neat)νcm-1:2926,2854,1737,12451 H−NMR(300MHz,CDCl3)δppm:0.
82(3H,s),0.86(3H,s),0.88(3H,t,J=6.7Hz),2.01(3H,s),
2.05(3H,s),2.57(1H,dd,J=8.7 and 2.4Hz),4.60(1H,dd,
J=11.0 and 4.9Hz),4.61-4.74(1H,m) FABMS(+KI) m/z:611(MK+)。Compound (8b) IR (neat) νcm -1 : 2926,2854,1737,1245 1 H-NMR (300 MHz, CDCl 3 ) δ ppm: 0.
82 (3H, s), 0.86 (3H, s), 0.88 (3H, t, J = 6.7Hz), 2.01 (3H, s),
2.05 (3H, s), 2.57 (1H, dd, J = 8.7 and 2.4Hz), 4.60 (1H, dd,
J = 11.0 and 4.9 Hz), 4.61-4.74 (1H, m) FABMS (+ KI) m / z: 611 (MK + ).
【0049】15)化合物(10b)及び化合物(11
b)の合成 実施例1の6)に記載した方法に準拠し、化合物(8
b)から化合物(10b)及び化合物(11b)を得
た。15) Compound (10b) and compound (11)
Synthesis of b) According to the method described in 6) of Example 1, compound (8)
Compound (10b) and compound (11b) were obtained from b).
【0050】化合物(10b) IR(neat)νcm-1:3479,2926,2854,1737,124
5,10271 H−NMR(300MHz,CDCl3)δppm:0.
84(3H,s),0.88(3H,t,J=6.7Hz),0.92(3H,s),1.92(3H,s),
2.01(3H,s),2.33(1H,dd,J=10.8 and 9.1Hz),3.85-3.93
(1H,m),4.62-4.75(2H,m),4.98(1H,s),5.02(1H,s) FABMS(+KI) m/z:611(MK+)。Compound (10b) IR (neat) νcm -1 : 3479,2926,2854,1737,124
5,1027 1 H-NMR (300 MHz, CDCl 3 ) δ ppm: 0.
84 (3H, s), 0.88 (3H, t, J = 6.7Hz), 0.92 (3H, s), 1.92 (3H, s),
2.01 (3H, s), 2.33 (1H, dd, J = 10.8 and 9.1Hz), 3.85-3.93
(1H, m), 4.62-4.75 (2H, m), 4.98 (1H, s), 5.02 (1H, s) FABMS (+ KI) m / z: 611 (MK + ).
【0051】化合物(11b) IR(neat)νcm-1:3543,2926,2854,1736,124
3,10241 H−NMR(300MHz,CDCl3)δppm:0.
78(3H,s),0.84(3H,s),0.88(3H,t,J=6.7Hz),2.02(3H,s),
2.08(3H,s),2.21(1H,t,J=9.9Hz),2.32(1H,d,J=2.8Hz),
3.44-3.53(1H,m),4.62-4.75(1H,m),5.18(1H,s),5.25(1
H,s),5.27(1H,t,J=7.2Hz) FABMS(+KI) m/z:611(MK+)。Compound (11b) IR (neat) νcm -1 : 3543,2926,2854,1736,124
3,1024 1 H-NMR (300 MHz, CDCl 3 ) δ ppm: 0.
78 (3H, s), 0.84 (3H, s), 0.88 (3H, t, J = 6.7Hz), 2.02 (3H, s),
2.08 (3H, s), 2.21 (1H, t, J = 9.9Hz), 2.32 (1H, d, J = 2.8Hz),
3.44-3.53 (1H, m), 4.62-4.75 (1H, m), 5.18 (1H, s), 5.25 (1H, m)
H, s), 5.27 (1H, t, J = 7.2 Hz) FABMS (+ KI) m / z: 611 (MK + ).
【0052】16)化合物(12b)の合成 実施例1の7)に記載した方法に準拠し、化合物(11
b)から化合物(12b)を得た。 IR(neat)νcm-1:3452,2926,2854,1735,124
1,10291 H−NMR(200MHz,CDCl3)δppm:0.
67(3H,s),0.82(3H,s),0.88(3H,t,J=6.5Hz),2.02(3H,s),
2.08(3H,s),2.73(1H,d,J=3.8Hz),3.07(1H,d,J=3.8Hz),
3.34(1H,dd,J=10.8 and 4.6Hz),4.18(1H,s),4.59-4.78
(1H,m),4.78(1H,t,J=6.6Hz) FABMS m/z:589(MH+)。16) Synthesis of compound (12b) Compound (11b) was prepared according to the method described in 7) of Example 1.
Compound (12b) was obtained from b). IR (neat) νcm -1 : 3452,2926,2854,1735,124
1,1029 1 H-NMR (200 MHz, CDCl 3 ) δ ppm: 0.
67 (3H, s), 0.82 (3H, s), 0.88 (3H, t, J = 6.5Hz), 2.02 (3H, s),
2.08 (3H, s), 2.73 (1H, d, J = 3.8Hz), 3.07 (1H, d, J = 3.8Hz),
3.34 (1H, dd, J = 10.8 and 4.6Hz), 4.18 (1H, s), 4.59-4.78
(1H, m), 4.78 (1H, t, J = 6.6Hz) FABMS m / z: 589 (MH + ).
【0053】17)化合物(13b)の合成 実施例1の8)に記載した方法に準拠し、化合物(12
b)から化合物(13b)を得た。 mp:70〜73℃ Anal.Calcd for C32H56O4:C,74.14;
H,11.18 Found:C,75.88;H,11.21 IR(KBr)νcm-1:3401,2926,28521 H−NMR(200MHz,CDCl3)δppm:0.
69(3H,s),0.80(3H,s),0.88(3H,t,J=6.5Hz),2.14(1H,t,J
=9.6Hz),2.25(1H,br s,exchangeable),2.86(1H,d,J=3.9
Hz),3.05(1H,d,J=3.9Hz),3.26-3.42(1H,m),3.37(1H,dd,
J=11.1 and 4.7Hz),3.49-3.72(1H,m),4.18(1H,br s,exc
hageable) FABMS(+KI) m/z:543(MK+)高分
解能FABMS(+KI) m/z:Calcd fo
r C32H56O4K:543.3816 Found:5
43.3813。17) Synthesis of Compound (13b) According to the method described in 8) of Example 1, compound (12b)
Compound (13b) was obtained from b). mp: 70-73 ° C Anal. Calcd for C 32 H 56 O 4 : C, 74.14;
H, 11.18 Found: C, 75.88 ; H, 11.21 IR (KBr) νcm -1: 3401,2926,2852 1 H-NMR (200MHz, CDCl 3) δppm: 0.
69 (3H, s), 0.80 (3H, s), 0.88 (3H, t, J = 6.5Hz), 2.14 (1H, t, J
= 9.6Hz), 2.25 (1H, brs, exchangeable), 2.86 (1H, d, J = 3.9
Hz), 3.05 (1H, d, J = 3.9Hz), 3.26-3.42 (1H, m), 3.37 (1H, dd,
J = 11.1 and 4.7Hz), 3.49-3.72 (1H, m), 4.18 (1H, br s, exc
hageable) FABMS (+ KI) m / z: 543 (MK + ) High-resolution FABMS (+ KI) m / z: Calcd fo
r C 32 H 56 O 4 K : 543.3816 Found: 5
43.3813.
【0054】以下に化合物(13b)の別途合成法を示
す。 18)化合物(14b)の合成 実施例1の9)に記載した方法に準拠し、化合物(10
b)と化合物(11b)の混合物から化合物(14b)
を得た。 IR(KBr)νcm-1:3401,2926,28541 H−NMR(300MHz,CDCl3)δppm:0.
74(3H,s),0.83(3H,s),0.88(3H,t,J=6.7Hz),2.32(1H,t,J
=10.1Hz),3.47(1H,dd,J=11.4 and 4.7Hz),3.52-3.66(1
H,m),4.13(1H,t,J=6.9Hz),4.93(1H,s),5.07(1H,s) FABMS(+KI) m/z:527(MK+)。Hereinafter, a separate synthesis method of compound (13b) will be described. 18) Synthesis of Compound (14b) Compound (10b) was prepared according to the method described in 9) of Example 1.
Compound (14b) from a mixture of Compound (11b) and Compound (11b)
I got IR (KBr) νcm −1 : 3401,2926,2854 1 H-NMR (300 MHz, CDCl 3 ) δppm: 0.
74 (3H, s), 0.83 (3H, s), 0.88 (3H, t, J = 6.7Hz), 2.32 (1H, t, J
= 10.1Hz), 3.47 (1H, dd, J = 11.4 and 4.7Hz), 3.52-3.66 (1
H, m), 4.13 (1H, t, J = 6.9 Hz), 4.93 (1H, s), 5.07 (1H, s) FABMS (+ KI) m / z: 527 (MK + ).
【0055】19)化合物(13b)の合成 実施例1の10)に記載した方法に準拠し、化合物(1
4b)から化合物(13b)を得た。19) Synthesis of Compound (13b) Compound (1b) was prepared according to the method described in 10) of Example 1.
Compound (13b) was obtained from 4b).
【0056】以下に試験例を挙げて本発明化合物の有用
性を示す。The usefulness of the compound of the present invention will be described below with reference to Test Examples.
【0057】試験例 In vivo L1210白血病に対する延命効果 1)試験方法 L1210白血病細胞1×105個をDBA/2系雌性
マウスに腹腔内移植し、7日目の腹水より腫瘍細胞を採
取した。生細胞5×105個/mlの細胞浮遊液(ハン
クス平衡塩類溶液に浮遊)を調製し、その0.2ml
(1×105個/匹)をCDF1系雌性マウス(7週齢)
に腹腔内移植した。細胞移植日をday0として細胞移
植翌日より5日間、0.5%アラビアゴム−生理食塩水
に懸濁した被検化合物を腹腔内投与した。効果はマウス
の生存日数中央値(Median Survival Time;MST)を
求め、T/C=(被検化合物投与群のMST)/(コン
トロール群のMST)×100(%)により判定した。Test Example In Vivo Life Prolonging Effect on L1210 Leukemia 1) Test Method 1 × 10 5 L1210 leukemia cells were implanted intraperitoneally into DBA / 2 female mice, and tumor cells were collected from the ascites on the 7th day. Prepare a cell suspension of 5 × 10 5 viable cells / ml (suspended in Hank's balanced salt solution), and prepare 0.2 ml of the suspension.
(1 × 10 5 / animal) was used for CDF 1 female mice (7 weeks old)
Was implanted intraperitoneally. The test compound suspended in 0.5% gum arabic-physiological saline was intraperitoneally administered for 5 days from the day following the cell transplantation, with the cell transplant day being day 0. The effect was determined by determining the median survival time (MST) of the mice and T / C = (MST of the test compound administration group) / (MST of the control group) × 100 (%).
【0058】2)試験結果 本発明の化合物(13a)及び化合物(13b)、公知
の化合物A及び特開平7−224087号公報に具体的
に記載された化合物(Rがイソブチル基;以下、化合物
B)並びに特開平7−224087号公報の特許請求の
範囲に含まれるが具体的に記載がない本発明化合物の周
辺化合物[Rがヘプチル基(n−C7H15)、オクチル
基(n−C8H17)、ウンデシル基(n−C11H23)及
びトリデシル基(n−C13H27)の化合物、以下それぞ
れ化合物C、化合物D、化合物E及び化合物Fとする]
のin vivo L1210白血病に対する延命効果(T/
C、day30まで観察)及びday30における生存
マウス数(1群は6匹)を表1に示した。2) Test Results Compounds (13a) and (13b) of the present invention, known compounds A and compounds specifically described in JP-A-7-224087 (R is an isobutyl group; hereinafter, compound B) ) And peripheral compounds of the compound of the present invention which are included in the claims of JP-A-7-224087 but not specifically described [R represents a heptyl group (n-C 7 H 15 ), an octyl group (n-C 8 H 17 ), a compound of an undecyl group (nC 11 H 23 ) and a tridecyl group (nC 13 H 27 ), hereinafter referred to as compound C, compound D, compound E and compound F, respectively.
Effect of in vivo on L1210 leukemia in vivo (T /
Table 1 shows the number of surviving mice at C (observed up to day 30) and day 30 (6 mice per group).
【0059】[0059]
【表1】 [Table 1]
【0060】本発明の化合物(13a)及び化合物(1
3b)は、他の化合物と比較して顕著な延命効果(T/
C及び生存マウス数)を示しているので、抗腫瘍作用を
有する医薬として有用である。Compound (13a) and compound (1) of the present invention
3b) has a remarkable life-prolonging effect (T /
C and the number of surviving mice) are useful as a drug having an antitumor effect.
【0061】参考例[化合物C、化合物D、化合物E及
び化合物Fの合成] 実施例1の方法に準拠し、実施例1の2)に記載した1
−ブロモデカンの代わりに1−ブロモオクタン、1−ブ
ロモノナン、1−ブロモドデカン及び1−ブロモテトラ
デカンを用いて同様に反応を行い、化合物C、化合物
D、化合物E及び化合物Fを合成した。Reference Example [Synthesis of Compound C, Compound D, Compound E and Compound F] The method described in Example 1-2) was carried out in accordance with the method of Example 1.
The same reaction was carried out using 1-bromooctane, 1-bromononane, 1-bromododecane and 1-bromotetradecane instead of -bromodecane, to synthesize Compound C, Compound D, Compound E and Compound F.
【0062】化合物C mp:140〜145℃ IR(KBr)νcm-1:3401,2927,28541 H−NMR(300MHz,CDCl3)δppm:0.
69(3H,s),0.81(3H,s),0.88(3H,t,J=6.8Hz),2.16(1H,dd,
J=10.9 and 9.2Hz),2.85(1H,d,J=3.9Hz),3.06(1H,d,J=
3.9Hz),3.28-3.42(2H,m),3.52-3.70(1H,m) FABMS(+KI) m/z:501(MK+)。Compound Cmp: 140-145 ° C. IR (KBr) νcm −1 : 3401, 2927, 2854 1 H-NMR (300 MHz, CDCl 3 ) δ ppm: 0.
69 (3H, s), 0.81 (3H, s), 0.88 (3H, t, J = 6.8Hz), 2.16 (1H, dd,
J = 10.9 and 9.2Hz), 2.85 (1H, d, J = 3.9Hz), 3.06 (1H, d, J =
3.9 Hz), 3.28-3.42 (2H, m), 3.52-3.70 (1H, m) FABMS (+ KI) m / z: 501 (MK + ).
【0063】化合物D mp:128〜131℃ Anal.Calcd for C30H52O4:C,75.58;
H,10.99 Found:C,75.40;H,11.05 IR(KBr)νcm-1:3401,2927,28531 H−NMR(300MHz,CDCl3)δppm:0.
69(3H,s),0.80(3H,s),0.88(3H,t,J=6.8Hz),2.14(1H,dd,
J=10.6 and 8.9Hz),2.86(1H,d,J=4.0Hz),3.05(1H,d,J=
4.0Hz),3.30-3.40(2H,m),3.52-3.65(1H,m) FABMS(+KI) m/z:515(MK+)。Compound Dmp: 128-131 ° C. Anal. Calcd for C 30 H 52 O 4 : C, 75.58;
H, 10.99 Found: C, 75.40; H, 11.05 IR (KBr) νcm -1 : 3401, 2927, 2853 1 H-NMR (300 MHz, CDCl 3 ) δ ppm: 0.
69 (3H, s), 0.80 (3H, s), 0.88 (3H, t, J = 6.8Hz), 2.14 (1H, dd,
J = 10.6 and 8.9Hz), 2.86 (1H, d, J = 4.0Hz), 3.05 (1H, d, J =
4.0 Hz), 3.30-3.40 (2H, m), 3.52-3.65 (1H, m) FABMS (+ KI) m / z: 515 (MK + ).
【0064】化合物E mp:97〜101℃ Anal.Calcd for C33H58O4:C,76.40;
H,11.27 Found:C,76.13;H,11.39 IR(KBr)νcm-1:3420,2925,28531 H−NMR(300MHz,CDCl3)δppm:0.
68(3H,s),0.80(3H,s),0.88(3H,t,J=6.7Hz),2.16(1H,t,J
=9.9Hz),2.84(1H,d,J=4.0Hz),3.05(1H,d,J=4.0Hz),3.27
-3.34(1H,m),3.37(1H,dd,J=11.0 and 4.6Hz),3.51-3.66
(1H,m) FABMS(+KI) m/z:557(MK+)。Compound Emp: 97-101 ° C. Anal. Calcd for C 33 H 58 O 4 : C, 76.40;
H, 11.27 Found: C, 76.13; H, 11.39 IR (KBr) νcm -1 : 3420, 2925, 2853 1 H-NMR (300 MHz, CDCl 3 ) δ ppm: 0.
68 (3H, s), 0.80 (3H, s), 0.88 (3H, t, J = 6.7Hz), 2.16 (1H, t, J
= 9.9Hz), 2.84 (1H, d, J = 4.0Hz), 3.05 (1H, d, J = 4.0Hz), 3.27
-3.34 (1H, m), 3.37 (1H, dd, J = 11.0 and 4.6Hz), 3.51-3.66
(1H, m) FABMS (+ KI) m / z: 557 (MK + ).
【0065】化合物F mp:84〜89℃ Anal.Calcd for C35H62O4:C,76.87;
H,11.43 Found:C,76.79;H,11.71 IR(KBr)νcm-1:3401,2924,28521 H−NMR(300MHz,CDCl3)δppm:0.
69(3H,s),0.80(3H,s),0.88(3H,t,J=6.7Hz),2.15(1H,dd,
J=10.8 and 9.0Hz),2.85(1H,d,J=4.0Hz),3.05(1H,d,J=
4.0Hz),3.28-3.35(1H,m),3.37(1H,dd,J=11.0 and 4.6H
z),3.51-3.67(1H,m) FABMS(+KI) m/z:585(MK+)。Compound Fmp: 84-89 ° C. Anal. Calcd for C 35 H 62 O 4 : C, 76.87;
H, 11.43 Found: C, 76.79 ; H, 11.71 IR (KBr) νcm -1: 3401,2924,2852 1 H-NMR (300MHz, CDCl 3) δppm: 0.
69 (3H, s), 0.80 (3H, s), 0.88 (3H, t, J = 6.7Hz), 2.15 (1H, dd,
J = 10.8 and 9.0Hz), 2.85 (1H, d, J = 4.0Hz), 3.05 (1H, d, J =
4.0Hz), 3.28-3.35 (1H, m), 3.37 (1H, dd, J = 11.0 and 4.6H
z), 3.51-3.67 (1H, m) FABMS (+ KI) m / z: 585 (MK + ).
Claims (1)
るステロール化合物。(1) Formula (1) (Wherein, R represents a nonyl group or a decyl group).
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP10057291A JPH10310598A (en) | 1997-03-12 | 1998-03-10 | Sterol compound |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP5721997 | 1997-03-12 | ||
JP9-57219 | 1997-03-12 | ||
JP10057291A JPH10310598A (en) | 1997-03-12 | 1998-03-10 | Sterol compound |
Publications (1)
Publication Number | Publication Date |
---|---|
JPH10310598A true JPH10310598A (en) | 1998-11-24 |
Family
ID=26398235
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP10057291A Pending JPH10310598A (en) | 1997-03-12 | 1998-03-10 | Sterol compound |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPH10310598A (en) |
-
1998
- 1998-03-10 JP JP10057291A patent/JPH10310598A/en active Pending
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US3822254A (en) | Synthesis of 25-hydroxycholesterol | |
Skrydstrup et al. | 1, 2‐cis‐C‐glycoside synthesis by samarium diiodide‐promoted radical cyclizations | |
JPH0261476B2 (en) | ||
Kraus et al. | Synthesis of 7, 7, 8-trideuteriated trichothecenes | |
BE1000407A4 (en) | Anthracycline glycosides antitumor activity, preparation, the intermediate compounds of that preparation, and composition and use of these substances. | |
JPH10310598A (en) | Sterol compound | |
JPH023797B2 (en) | ||
WO1998040399A1 (en) | Sterol compounds | |
WO1995016699A1 (en) | Steroid derivative | |
CN114230601B (en) | Preparation and application of chiral enol compound | |
JPS59181299A (en) | 20,23-dideoxy-20,23-bis-substituted amino-mycaminosyl relonolide | |
CN115894303B (en) | Preparation method of (3-amino bicyclo [1.1.1] pentane-1-yl) carbamic acid tert-butyl ester and intermediate thereof | |
EP0049144B1 (en) | 5-fluoro uracil derivatives | |
JPH0463056B2 (en) | ||
JPH10251294A (en) | Cis-sterol compound | |
CA2196102A1 (en) | Streptogramine derivatives, preparation of same and pharmaceutical compositions containing same | |
JPS5998091A (en) | Novel organosilicon compound, its preparation and antitumor agent containing said compound as active constituent | |
CN115141234A (en) | Synthesis process of clindamycin phosphate raw material medicine | |
JPH07224087A (en) | Steroid derivative | |
JPS6126555B2 (en) | ||
JPH01143853A (en) | 3-pyrrolin-2-one derivative | |
JPS6219598A (en) | 2,3,2'3'-tetra-o-alkyl-alpha,alpha-trehalose derivative | |
JPH0616667A (en) | New production of pyrazolo(1,5-a)pyridine derivative | |
JPH04244058A (en) | Vitamin a acid ester compound | |
EP0707011A1 (en) | Sterol compound |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
LAPS | Cancellation because of no payment of annual fees |