JPH0324057A - Polyhydroxypiperidines and production thereof - Google Patents
Polyhydroxypiperidines and production thereofInfo
- Publication number
- JPH0324057A JPH0324057A JP1158162A JP15816289A JPH0324057A JP H0324057 A JPH0324057 A JP H0324057A JP 1158162 A JP1158162 A JP 1158162A JP 15816289 A JP15816289 A JP 15816289A JP H0324057 A JPH0324057 A JP H0324057A
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- JP
- Japan
- Prior art keywords
- formula
- group
- formulas
- derivative
- chemical
- 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
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 9
- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 claims abstract description 7
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims abstract description 7
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 6
- HMFHBZSHGGEWLO-SOOFDHNKSA-N D-ribofuranose Chemical class OC[C@H]1OC(O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-SOOFDHNKSA-N 0.000 claims abstract description 5
- 239000002841 Lewis acid Substances 0.000 claims abstract description 5
- 150000007517 lewis acids Chemical class 0.000 claims abstract description 5
- 238000010531 catalytic reduction reaction Methods 0.000 claims abstract description 4
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 3
- 125000004423 acyloxy group Chemical group 0.000 claims abstract 6
- 125000003545 alkoxy group Chemical group 0.000 claims abstract 2
- 230000002829 reductive effect Effects 0.000 claims description 14
- 239000000126 substance Substances 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- LXBIFEVIBLOUGU-UNTFVMJOSA-N (2s,3r,4r,5s)-2-(hydroxymethyl)piperidine-3,4,5-triol Chemical class OC[C@@H]1NC[C@H](O)[C@@H](O)[C@@H]1O LXBIFEVIBLOUGU-UNTFVMJOSA-N 0.000 claims description 2
- IVRMZWNICZWHMI-UHFFFAOYSA-N azide group Chemical group [N-]=[N+]=[N-] IVRMZWNICZWHMI-UHFFFAOYSA-N 0.000 claims description 2
- 238000010511 deprotection reaction Methods 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 abstract description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 abstract description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 abstract description 2
- 125000006239 protecting group Chemical group 0.000 abstract description 2
- 238000006798 ring closing metathesis reaction Methods 0.000 abstract description 2
- 229940122069 Glycosidase inhibitor Drugs 0.000 abstract 1
- 150000001540 azides Chemical group 0.000 abstract 1
- 230000008030 elimination Effects 0.000 abstract 1
- 238000003379 elimination reaction Methods 0.000 abstract 1
- 239000003316 glycosidase inhibitor Substances 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 238000006722 reduction reaction Methods 0.000 abstract 1
- 238000007142 ring opening reaction Methods 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 21
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 17
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 15
- 239000000047 product Substances 0.000 description 15
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- 238000005160 1H NMR spectroscopy Methods 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
- 102000004190 Enzymes Human genes 0.000 description 8
- 108090000790 Enzymes Proteins 0.000 description 8
- 230000002401 inhibitory effect Effects 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- 238000010898 silica gel chromatography Methods 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 238000000921 elemental analysis Methods 0.000 description 6
- -1 lithium aluminum hydride Chemical compound 0.000 description 6
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 6
- 235000019341 magnesium sulphate Nutrition 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 102000012086 alpha-L-Fucosidase Human genes 0.000 description 4
- 108010061314 alpha-L-Fucosidase Proteins 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 239000012280 lithium aluminium hydride Substances 0.000 description 4
- 239000000376 reactant Substances 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- GQXJZINGMGHWDU-SLPGGIOYSA-N (2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexanenitrile Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C#N GQXJZINGMGHWDU-SLPGGIOYSA-N 0.000 description 3
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 3
- 102000005744 Glycoside Hydrolases Human genes 0.000 description 3
- 108010031186 Glycoside Hydrolases Proteins 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 150000008065 acid anhydrides Chemical class 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 239000003638 chemical reducing agent Substances 0.000 description 3
- 229960002089 ferrous chloride Drugs 0.000 description 3
- NMCUIPGRVMDVDB-UHFFFAOYSA-L iron dichloride Chemical compound Cl[Fe]Cl NMCUIPGRVMDVDB-UHFFFAOYSA-L 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000006188 syrup Substances 0.000 description 3
- 235000020357 syrup Nutrition 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- LXBIFEVIBLOUGU-UHFFFAOYSA-N Deoxymannojirimycin Natural products OCC1NCC(O)C(O)C1O LXBIFEVIBLOUGU-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 102100024295 Maltase-glucoamylase Human genes 0.000 description 2
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 108010028144 alpha-Glucosidases Proteins 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- UHOVQNZJYSORNB-MZWXYZOWSA-N benzene-d6 Chemical compound [2H]C1=C([2H])C([2H])=C([2H])C([2H])=C1[2H] UHOVQNZJYSORNB-MZWXYZOWSA-N 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 150000001720 carbohydrates Chemical class 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- LXBIFEVIBLOUGU-JGWLITMVSA-N duvoglustat Chemical compound OC[C@H]1NC[C@H](O)[C@@H](O)[C@@H]1O LXBIFEVIBLOUGU-JGWLITMVSA-N 0.000 description 2
- 229930182470 glycoside Natural products 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 2
- 230000001766 physiological effect Effects 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 208000030507 AIDS Diseases 0.000 description 1
- 244000144725 Amygdalus communis Species 0.000 description 1
- 235000011437 Amygdalus communis Nutrition 0.000 description 1
- 229910015900 BF3 Inorganic materials 0.000 description 1
- 101150041968 CDC13 gene Proteins 0.000 description 1
- 101100274581 Caenorhabditis elegans chc-1 gene Proteins 0.000 description 1
- 244000045232 Canavalia ensiformis Species 0.000 description 1
- 235000010520 Canavalia ensiformis Nutrition 0.000 description 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- 241000725303 Human immunodeficiency virus Species 0.000 description 1
- 208000007976 Ketosis Diseases 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 235000014680 Saccharomyces cerevisiae Nutrition 0.000 description 1
- 241000533293 Sesbania emerus Species 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- PPWHTZKZQNXVAE-UHFFFAOYSA-N Tetracaine hydrochloride Chemical compound Cl.CCCCNC1=CC=C(C(=O)OCCN(C)C)C=C1 PPWHTZKZQNXVAE-UHFFFAOYSA-N 0.000 description 1
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- TUCNEACPLKLKNU-UHFFFAOYSA-N acetyl Chemical compound C[C]=O TUCNEACPLKLKNU-UHFFFAOYSA-N 0.000 description 1
- 235000020224 almond Nutrition 0.000 description 1
- 102000005840 alpha-Galactosidase Human genes 0.000 description 1
- 108010030291 alpha-Galactosidase Proteins 0.000 description 1
- 102000019199 alpha-Mannosidase Human genes 0.000 description 1
- 108010012864 alpha-Mannosidase Proteins 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 150000008209 arabinosides Chemical class 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- 102000005936 beta-Galactosidase Human genes 0.000 description 1
- 108010005774 beta-Galactosidase Proteins 0.000 description 1
- 102000006995 beta-Glucosidase Human genes 0.000 description 1
- 108010047754 beta-Glucosidase Proteins 0.000 description 1
- YSXKPIUOCJLQIE-UHFFFAOYSA-N biperiden Chemical group C1C(C=C2)CC2C1C(C=1C=CC=CC=1)(O)CCN1CCCCC1 YSXKPIUOCJLQIE-UHFFFAOYSA-N 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000004891 communication Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 235000008504 concentrate Nutrition 0.000 description 1
- 210000004748 cultured cell Anatomy 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 239000004210 ether based solvent Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229930182830 galactose Natural products 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- LTYRAPJYLUPLCI-UHFFFAOYSA-N glycolonitrile Chemical class OCC#N LTYRAPJYLUPLCI-UHFFFAOYSA-N 0.000 description 1
- 150000002338 glycosides Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- VKYKSIONXSXAKP-UHFFFAOYSA-N hexamethylenetetramine Chemical compound C1N(C2)CN3CN1CN2C3 VKYKSIONXSXAKP-UHFFFAOYSA-N 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000005650 intramolecular substitution reaction Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 150000002584 ketoses Chemical class 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- LXBIFEVIBLOUGU-DPYQTVNSSA-N migalastat Chemical compound OC[C@H]1NC[C@H](O)[C@@H](O)[C@H]1O LXBIFEVIBLOUGU-DPYQTVNSSA-N 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 1
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- CIJQGPVMMRXSQW-UHFFFAOYSA-M sodium;2-aminoacetic acid;hydroxide Chemical compound O.[Na+].NCC([O-])=O CIJQGPVMMRXSQW-UHFFFAOYSA-M 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- VIGBIBDAVDHOTP-UHFFFAOYSA-M sodium;ethanol;acetate Chemical class [Na+].CCO.CC([O-])=O VIGBIBDAVDHOTP-UHFFFAOYSA-M 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- FXUAIOOAOAVCGD-FKSUSPILSA-N swainsonine Chemical compound C1CC[C@H](O)[C@H]2[C@H](O)[C@H](O)CN21 FXUAIOOAOAVCGD-FKSUSPILSA-N 0.000 description 1
- 229960005566 swainsonine Drugs 0.000 description 1
- FXUAIOOAOAVCGD-UHFFFAOYSA-N swainsonine Natural products C1CCC(O)C2C(O)C(O)CN21 FXUAIOOAOAVCGD-UHFFFAOYSA-N 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 210000001550 testis Anatomy 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
- 125000005147 toluenesulfonyl group Chemical group C=1(C(=CC=CC1)S(=O)(=O)*)C 0.000 description 1
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 1
- PQDJYEQOELDLCP-UHFFFAOYSA-N trimethylsilane Chemical compound C[SiH](C)C PQDJYEQOELDLCP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Hydrogenated Pyridines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
[産業上の利用分野]
本発明は、ポリヒドロキシビベリジン類およびその製造
法に関するものであり、更に詳しくは、グリコシダーゼ
阻害作用を有するポリヒドロキシビベリジン類およびそ
の製造法に関するものである。DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to polyhydroxybiveridines and a method for producing the same, and more specifically to polyhydroxybiveridines having glycosidase inhibitory activity and their production method. It concerns the manufacturing method.
[従来の技術]
現在、糖の環内に窒素原子(N)を有する疑似糖類タイ
ブの酵素阻害剤(ポリヒドロキシビペリジン類)として
は、デオキシノジリマイシン,デオキシマンノノジリマ
イシン,カスタノスベルミン.スエインソニン等が知ら
れている。特に、カスタノスベルミンは培養細胞におい
て、エイズ・ウイルスの複製を阻害することが報告され
、スエインソニンはメラノーマ・ガン細胞が肺組織に侵
入する能力を低下させることが報告されている[フェロ
ーズ(L,E.Fe 1 1ows),ケミストリー
イン プリテン (9).842(1987)]。[Prior Art] Currently, enzyme inhibitors of the pseudosaccharide type (polyhydroxybiperidines) having a nitrogen atom (N) in the sugar ring include deoxynojirimycin, deoxymannonojirimycin, and castanosuber. Min. Swainsonine etc. are known. In particular, castanosvermine has been reported to inhibit the replication of the AIDS virus in cultured cells, and sweinsonine has been reported to reduce the ability of melanoma cancer cells to invade lung tissue [Fellers (L , E. Fe 1 1ows), Chemistry
In Preten (9). 842 (1987)].
これらの生理活性は、その構造が本来の基質の構造に類
似している為に、酵素作用が阻害され、必要な糖鎖が合
成されないことによ7るものである。These physiological activities are due to the fact that their structure is similar to that of the original substrate, so the enzymatic action is inhibited and the necessary sugar chains are not synthesized7.
この様に、その環内に窒素原子を含む疑似糖類には新し
い生理活性が期待されており、具体的には糖尿病.ガン
の転移,エイズなどの治療が検討されている。In this way, pseudosaccharides containing a nitrogen atom in their rings are expected to have new physiological activities, specifically for diabetes. It is being considered as a treatment for cancer metastasis, AIDS, etc.
ポリヒドロキシビペリジン類を糖類から合成する際の最
大の問題点は、ビペリジン環の形或にあるが、従来の方
法は次の三種に大別される。The biggest problem when synthesizing polyhydroxybiperidines from saccharides lies in the shape of the biperidine ring, and conventional methods can be broadly classified into the following three types.
I)アミノ基による分子内置換反応又はオキシランのr
5A′R反応を利用する方法
ともに、グルコースから誘導される1−アミノー5−0
−メシルーD−アルトリトール誘導体及び2−アミノー
6−0− トシルーD−マンノフラノシド誘導体の閉環
反応で、それぞれ、デオキシーL−フコノジリマイシン
、デオキシマンノノジリマイシンが合成されている[フ
リh (G.W.J.F lee t),ケミカルコミ
ュニケーション,841.(1985);ケミストリー
レター,1051 (1986)]。I) Intramolecular substitution reaction with amino group or r of oxirane
Both methods using 5A'R reaction and 1-amino-5-0 derived from glucose
Deoxy-L-fuconojirimycin and deoxymannonojirimycin have been synthesized by ring-closing reactions of -mesyl-D-altritol derivatives and 2-amino-6-0-tosyl-D-mannofuranoside derivatives [Furih (G. W.J.Fleet), Chemical Communication, 841. (1985); Chemistry Letters, 1051 (1986)].
2)分子内の還元的アミノ化による方法1−アミノー5
−ケトース又は5−アミノーアルドース誘導体の還元的
閉環がある。前者の方法でD−グルコースからデオキシ
ノジリマイシンが合成されている[キナースト(G.K
inast),アンゲバンテ ヘミーl 93,799
(1981)]。2) Method 1-Amino-5 by intramolecular reductive amination
- reductive ring closure of ketose or 5-aminoaldose derivatives. Deoxynojirimycin has been synthesized from D-glucose by the former method [Kinast (G.K.
inast), Angewante Hemyl 93,799
(1981)].
3)分子内アミノマーキュレーションを利用する方6−
プロモヘキソビラノシドから1−ペンジルアミノ−5−
ヘキセニトール誘導体とし、それをアミノマーキュレー
シジンにより閉環する。3) Those who use intramolecular amino merculation 6-
Promohexobiranoside to 1-pendylamino-5-
A hexenitol derivative is prepared, which is ring-closed with aminomercuricidin.
ガラクトースからデオキシガラクトノジリマイシンが合
威されている[ベルノータス(R.C.Bernota
s), カーボハイドレート●リサーチ,167,3
05 (1987)]。Deoxygalactonojirimycin has been synthesized from galactose [R.C.
s), Carbohydrate Research, 167, 3
05 (1987)].
[発明が解決しようとする課8]
本発明の目的は、酵素阻害活性を有する新規ポリヒドロ
キシピベリジン類、及び従来法よりも簡便なその製造法
を提供することにある。[Problem to be Solved by the Invention 8] An object of the present invention is to provide novel polyhydroxypiveridines having enzyme inhibitory activity and a method for producing the same that is simpler than conventional methods.
[課題を解決するための手段]
本発明者らは上記課題に関し鋭意検討した結果、本発明
に到達した。[Means for Solving the Problems] The present inventors have made extensive studies regarding the above problems, and as a result, have arrived at the present invention.
即ち本発明は、
下記一般式(1)
聞 H2
(式中、R は水素又はメチル基、RR は1
2I 3
いずれか一方が水素で他方は水酸基を示す)で表される
ポリヒドロキシピペリジン類
及び
下記一般式(n)
トリメチルシラン(以下、TMSCNとする)と反応さ
せ、開環、増炭させて、下記一般式(m)(式中、R
ないしR9は上記と同じ)で表され4
る鎖状措造物とした後、トリメチルシリル(以下、TM
Sとする)基を適当な脱離基に変換し、更に、シアノ基
を還元して閉環させて、下記一般式(IV)XはH.C
H OCH 又はClを示す)を、3′
3′
−X(式中、Xは上記と同じ)又はアジド基を示す)で
表されるリボフラノシド誘導体又はアラビノフラノシド
誘導体をルイス酸の存在下にシアノ(R4ないしR9は
上記と同じ)で表される1,5−ジデオキシ−1,5−
イミノーL一タリトール誘導体又は1.5−ジデオキシ
ー1,5−イミノーL−イジトール誘導体とし、ひき続
いて接触還元で脱保護することを特徴とする請求項(1
)記載のポリヒドロキシピペリジン類の製造法である。That is, the present invention has the following general formula (1): H2 (wherein, R is hydrogen or a methyl group, and RR is 1
2I 3 One of which is hydrogen and the other is a hydroxyl group) is reacted with polyhydroxypiperidines represented by the following general formula (n) trimethylsilane (hereinafter referred to as TMSCN) to open the ring and increase carbon, The following general formula (m) (wherein, R
4 to R9 are the same as above), and then trimethylsilyl (hereinafter, TM
The following general formula (IV) C
H OCH or Cl), 3'
A ribofuranoside derivative or an arabinofuranoside derivative represented by 3' -X (wherein X is the same as above) or an azide group is treated with cyano (R4 to R9 are the same as above) in the presence of a Lewis acid. 1,5-dideoxy-1,5-
Claim 1 characterized in that it is an imino-L monotalitol derivative or a 1,5-dideoxy-1,5-imino-L-iditol derivative, and is subsequently deprotected by catalytic reduction.
) is a method for producing polyhydroxypiperidines described in .
本発明を以下詳細に説明する。The present invention will be explained in detail below.
本発明による一般式(1)の新規化合物ポリヒドロキシ
ビペリジン類は、その式に示すように、糖の環内に窒素
原子を有する疑似糖類タイプの構造を持つ化合物である
。このように各種グリコシダーゼの基質となるグリコシ
ドの構造に類似しているため、それら酵素の阻害作用を
有している。The novel compound polyhydroxybiperidine of the general formula (1) according to the present invention is a compound having a pseudosaccharide type structure having a nitrogen atom in the sugar ring, as shown in the formula. Because it has a similar structure to glycosides that are substrates for various glycosidases, it has an inhibitory effect on these enzymes.
このポリヒドロキシビペリジン類(1)は、本発明方法
で製造することができる。This polyhydroxybiperidine (1) can be produced by the method of the present invention.
製造にあたっては、まず、一般式(n)で表されるリボ
フラノシド誘導体又はアラビノフラノシド誘導体をルイ
ス酸の存在下、TMSCNと反応させ、シアノ基とTM
S基とを同時に導入し、単一の立体配置を持つ鎖状グリ
コニトリル誘導体(I[[)とする。For production, first, a ribofuranoside derivative or an arabinofuranoside derivative represented by general formula (n) is reacted with TMSCN in the presence of a Lewis acid to form a cyano group and TM
A chain glyconitrile derivative (I[[) is obtained by simultaneously introducing an S group and a single steric configuration.
このときTMSCNの使用量は特に限定されないが、好
ましくは一般式(■)1当量に対し、TMSCNを過剰
に、さらに好ましくは約5当量を使用する。At this time, the amount of TMSCN used is not particularly limited, but TMSCN is preferably used in excess, more preferably about 5 equivalents, relative to 1 equivalent of general formula (■).
ルイス酸としては、ボロントリフルオリドエーテラート
,塩化第二錫などを例示することができる。その使用量
は特に限定されないが、触媒量あればよく、好ましくは
一般式(■)1当量に対して0.1当量が使用される。Examples of Lewis acids include boron trifluoride etherate and stannic chloride. The amount used is not particularly limited, but a catalytic amount is sufficient, and preferably 0.1 equivalent is used per equivalent of general formula (■).
反応は無溶媒、室温で行うのが好ましい。反応温度は、
特に限定されないが、一般には0℃ないし30℃程度で
行われる。The reaction is preferably carried out without a solvent at room temperature. The reaction temperature is
Although not particularly limited, it is generally carried out at about 0°C to 30°C.
反応時間は、反応条件により変り得るが、0℃程度で反
応を行った場合は、0.5〜2時間程度である。The reaction time may vary depending on the reaction conditions, but when the reaction is carried out at about 0°C, it is about 0.5 to 2 hours.
以上のようにして得られた一般式(III)で表される
TMS基をもつ鎖状構造物は、その反応途中で自然にT
MS基が脱離し、遊離のOH基を持つものが得られる。The chain structure having a TMS group represented by the general formula (III) obtained as described above spontaneously undergoes TMS during the reaction.
The MS group is eliminated and a product with a free OH group is obtained.
しかし、TMS基が導入されたままの形のものも残存す
るため、まずTMS基を除去する処理を行うのが好まし
い。例えば塩化メチレン中、塩化第一鉄を作用させれば
よい。こうして、すべてのTMS基を除去した後、次段
階の反応に進むのが好ましい。However, since some products remain with the TMS group introduced, it is preferable to first perform a treatment to remove the TMS group. For example, ferrous chloride may be used in methylene chloride. It is preferable to proceed to the next step of the reaction after all TMS groups have been removed in this way.
次いで、塩基の存在下、有機溶媒中ないしは無溶媒下に
適当な酸無水物又は酸クロリドを作用させて脱離基を導
入する。脱離基としてはメタンスルホニル基(図中Ms
と略す),ベンゼンスルホニル基,トルエンスルホニル
基,トリフルオロメタンスルホニル基などが例示され、
それらを含む酸無水物又は酸クロリドを使用すればよい
。使用する酸無水物又は酸クロリドの量は、特に限定は
ないが、鎖状構造物に対して好ましくは等量以上、さら
に好ましくは約10当量である。塩基としては、トリエ
チルアミン,ビリジンなどが例示される。Next, a leaving group is introduced by reacting with a suitable acid anhydride or acid chloride in the presence of a base in an organic solvent or in the absence of a solvent. The leaving group is a methanesulfonyl group (Ms in the figure).
), benzenesulfonyl group, toluenesulfonyl group, trifluoromethanesulfonyl group, etc.
An acid anhydride or acid chloride containing them may be used. The amount of acid anhydride or acid chloride to be used is not particularly limited, but is preferably at least equivalent to the chain structure, more preferably about 10 equivalents. Examples of the base include triethylamine and pyridine.
溶媒量は特に限定されないが、一般には1ミリモル当た
り1〜10mlで行われる。反応温度は特に限定されな
いが、一般には室温付近で行われる。反応時間は、数時
間以上であれば特に限定されないが、通常20時間前後
である。The amount of solvent is not particularly limited, but is generally 1 to 10 ml per mmol. Although the reaction temperature is not particularly limited, it is generally carried out around room temperature. The reaction time is not particularly limited as long as it is several hours or more, but is usually around 20 hours.
次いで、脱離基を導入した鎖状構造物のシアノ基を還元
剤を用いて還元し、アミノ体に導く。還元剤としては、
水素化リチウムアルミニウム,ラネーニッケルなどが例
示されるが好ましくは水素化リチウムアルミニウムが使
用される。溶媒はテトラヒドロフランなどエーテル系の
溶媒が使用されるが通常はジエチルエーテルが使用され
る。反応時間には特に限定はないが、一夜行えば十分で
ある。反応温度は室温以下であれば特に限定されないが
、好ましくは−30℃である。Next, the cyano group of the chain structure into which the leaving group has been introduced is reduced using a reducing agent to lead to an amino form. As a reducing agent,
Examples include lithium aluminum hydride and Raney nickel, but lithium aluminum hydride is preferably used. Ether solvents such as tetrahydrofuran are used as the solvent, but diethyl ether is usually used. There is no particular limitation on the reaction time, but one night is sufficient. The reaction temperature is not particularly limited as long as it is below room temperature, but is preferably -30°C.
生成したアミノ体は、単離・精製することなく次段階の
反応に進み、脱離基の脱離と同時に閉環させることがで
きる;この脱離・閉環は、例えば飽和酢酸ナトリウム/
エタノール溶媒中で加熱還流することにより得られる。The generated amino compound can proceed to the next step of the reaction without isolation or purification, and can be ring-closed at the same time as the leaving group is removed;
Obtained by heating under reflux in an ethanol solvent.
最後に、保護基を脱保護し、目的とする一般式(1)の
ポリヒドロキシピペラジン類が得られる。Finally, the protecting group is deprotected to obtain the desired polyhydroxypiperazines of general formula (1).
脱保護の方法としては、例えば塩酸塩の形にした後、接
触還元を実施すればよい。還元剤としては、パラジウム
炭素.水酸化パラジウムなどが例示されるが、好ましく
はパラジウム炭素が使用される。As a method for deprotection, for example, after converting into a hydrochloride form, catalytic reduction may be performed. Palladium on carbon is used as a reducing agent. Examples include palladium hydroxide, but palladium on carbon is preferably used.
反応溶媒としては、酢酸,酢酸添加メタノール,メタノ
ール.エタノールなどが例示されるが、好ましくはエタ
ノールが使用される。反応時間は条件により異なるが通
常5〜10時間である。As a reaction solvent, acetic acid, methanol with acetic acid added, methanol. Examples include ethanol, but ethanol is preferably used. The reaction time varies depending on the conditions, but is usually 5 to 10 hours.
[実施例] 以下、本発明を実施例で更に詳しく説明する。[Example] Hereinafter, the present invention will be explained in more detail with reference to Examples.
しかし、本発明はこれら実施例のみに限定されるもので
はない。However, the present invention is not limited to these examples.
(大施例1)
2−0−ベンジル−3.4.6−1りーO−アセチルー
5−0− トリメチルシリルーD−アロノニトリルの合
成
ベンジル−2.3.5−トリ一〇−アセチルーβ−D−
リボフラノシド500mg (1.3mmol)にTM
SCN13.5当量とB F 3 ’OEt O.
1当量を加え、室温で2時間反応2
させた。反応液を飽和重留水溶液中にあけ、二一テル抽
出した。有機層を飽和食塩水で洗った後、硫酸ナトリウ
ムで乾燥した後、減圧濃縮した。シリカゲル力ラムクロ
マトグラフィー(ヘキサン:酢酸エチル−4:1)で分
離・精製し、目的物を78,2%の収率で得た。(Major Example 1) Synthesis of 2-0-benzyl-3.4.6-1-O-acetyl-5-0-trimethylsilyl-D-alononitrile Benzyl-2.3.5-tri-10-acetyl-β-D −
TM to ribofuranoside 500mg (1.3mmol)
13.5 equivalents of SCN and BF3'OEtO.
1 equivalent was added and the reaction was allowed to proceed at room temperature for 2 hours. The reaction solution was poured into a saturated heavy distilled aqueous solution and extracted with 21 terres. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The product was separated and purified by silica gel column chromatography (hexane:ethyl acetate-4:1) to obtain the desired product in a yield of 78.2%.
[α]D−+60.2”
1H−NMR (C6D6)
67. 04 (s, Ph),5.63 (t
,H−3.J3. 4”3.6).5.54 (t,H
−4.J, 5=3.6).4.62 (d,H−2
.J2, 3−3.6).4 . 2 9 , 4
. 5 8 ( A B q ,C H 2 )
,4. 10〜3. 90 (m,H−5,H−
6a,H−6b).
1.84, 1. 69. 1. 67 (
s,OAc),元素分折:計算値C−56.75,H−
6.71,N−3. 01
実測値C−56.53,H−6.71.N−3.01
これを用いて、対応するポリヒドロキシピベリジン類を
製造できる。また本実施例における反応物及び生成物の
構造を第1図に示す。[α]D-+60.2" 1H-NMR (C6D6) 67.04 (s, Ph), 5.63 (t
, H-3. J3. 4”3.6).5.54 (t,H
-4. J, 5=3.6). 4.62 (d, H-2
.. J2, 3-3.6). 4. 2 9 , 4
.. 5 8 (ABq, CH2)
,4. 10-3. 90 (m, H-5, H-
6a, H-6b). 1.84, 1. 69. 1. 67 (
s, OAc), elemental analysis: calculated value C-56.75, H-
6.71, N-3. 01 Actual measurement value C-56.53, H-6.71. N-3.01 This can be used to produce the corresponding polyhydroxypiveridines. Furthermore, the structures of the reactants and products in this example are shown in FIG.
(実施例2)
2,3,4.6−テトラー0−ペンジルーD−アロノニ
トリルの合或
ベンジル−2.3.5−}り一〇一ベンジルーβ−D−
リボフラノシド3g (6mmo 1),TMSCN3
.8ml (30mmo l),ボロントリフルオリ
ドエーテラート70μl (0. 6mmo 1)
を混合し、室温で30分間反応させた。(Example 2) Combination of 2,3,4,6-tetra0-penzyl-D-alononitrile or benzyl-2.3.5-}-101benzyl-β-D-
Ribofuranoside 3g (6mmo 1), TMSCN3
.. 8ml (30mmol), boron trifluoride etherate 70μl (0.6mmol 1)
were mixed and allowed to react at room temperature for 30 minutes.
生成物をシリカゲルクロマトグラフィーで分離・精製し
、三つの成分を得た。即ち、2.3.4.6−テトラー
0−ベンジルー5−0−トリメチルシリルーD−アロノ
ニトリルを0.93g (25%) 、2,3,4.6
−テトラー0−ベンジルーD−アロノニトリルを1.6
8g (52%)、そして2.3.5−トリ一〇−ベン
ジルーβ−D一リボフラノシルシアニドを0.4g (
19%)の収量で得た。The product was separated and purified by silica gel chromatography to obtain three components. That is, 0.93 g (25%) of 2,3,4,6-tetra-0-benzyl-5-0-trimethylsilyl-D-alononitrile, 2,3,4.6
-Tetler 0-benzyl-D-alononitrile 1.6
8 g (52%), and 0.4 g (
19%) yield.
2.3,4.6〜テトラー0−ベンジルー5一〇−トリ
メチルシリルーD−アロノニトリル’H−NMR (C
DC1 3)
63.36 (dd,H−6a).
3. 46 (dd, H−6b),3. 7
0 (t, H−4).4. 04 (m,
H−3, H−5).4. 56, 4.
80 (ABq, Bn).4. 60. 4
. 84 (ABq, Bn),4. 40
(s, Bn). 4. 60 (s, B
n),7. 26−7. 30 (Ph).”C
−NMR (CDCl 3)
6 138.212, 137.728,135
.87, 116.89,79.649.
78.673,78. 43,
77. 013,?5.599. 73,9
4,73,792. 73.257.72.
62, 71. 839.70.
716.
元素分析二計算値C−72.92,H−7.06,N−
2.30
測定値C−73.08.H−7.01,N−2. 4
6.
2.3,4.6−テトラー0−ベンジルーD−アロノニ
トリル゜
[α] −+59.6°(8−1.71 CHCI
3)D
1H−NMR (CDCI3)
62.45 (d,H−2).
3.48 (d,2H,H−6a,6b),3.70
(dd,H−3).
4.10 (dd,H−4).
〜3.94 (m,H−5).
4.41 (s,2H,Bn).
4.46, 4.64 (ABq,Bn).4.5
8, 4.82 (ABq,Bn).4.64,
4.86 (ABq,Bn),7.26 (s,P
h)
”C−NMR (CDC1 3)
6137.77, 137.53,137.38
, 135.681,117.135,
78.77,78.62, 78.43,
77.02, 75.60,
74. 19, 73. 79.73.
307, 72.573,70.866,
70.132,69. 793.
元素分析:計算値C−75.95,H−6.56,N−
2.61
測定値C−75.76,H−6.39.N−2. 4
0.
2,3.5−1り−0−ベンジルーβ一D−リボフラノ
シルシアニド
[α] D− +1 7.1@(c−1.3 CHC
l 3)IH−NMR(CDCl 3)
64. 44−4. 60
(3XCH Bn及びH−1),
2
4.0 (dd,H−2.J1, 2−4.2,J2,
3−5),
4.28 (t,H−3,J3, 4−5).4.
24 (m, H−4).3. 50 (dd
d,H−5a, 5b)13C−NMR (CDC1
3)
6 137. 77, 137.
33,136.75 (芳香族 CH),
127. 72−128. 60
( m +芳香族 CM),
117.67(CN). 83.16,81.
07, 77. 70,73.
65, 73. 11,72.
67, 69. 45,68
. 96.
(実施例3)
2,3,4.6−テトラーO−ベンジルーD−アロノニ
トリルの合成
実施例2で合成した2,3.4.6−テトラーO−ベン
ジルー5−0− }リメチルシリルーD−アロノニトリ
ル0.9g (1.5mmo l)を塩化メチレン5m
lに溶解し、0.1gの塩化第一鉄を加えて室温で30
分間攪拌した。得られた反応混合物を、シリカゲルカラ
ムクロマトグラフイ(ヘキサン:酢酸エチル−2:1)
で分離・精製して目的物を0.71g (1.3mmo
l)得た。2.3,4.6~Tetler 0-benzyl-510-trimethylsilyl-D-alononitrile'H-NMR (C
DC1 3) 63.36 (dd, H-6a). 3. 46 (dd, H-6b), 3. 7
0 (t, H-4). 4. 04 (m,
H-3, H-5). 4. 56, 4.
80 (ABq, Bn). 4. 60. 4
.. 84 (ABq, Bn), 4. 40
(s, Bn). 4. 60 (s, B
n), 7. 26-7. 30 (Ph). "C.
-NMR (CDCl3) 6 138.212, 137.728,135
.. 87, 116.89, 79.649.
78.673,78. 43,
77. 013,? 5.599. 73,9
4,73,792. 73.257.72.
62, 71. 839.70.
716. Elemental analysis two calculated values C-72.92, H-7.06, N-
2.30 Measured value C-73.08. H-7.01, N-2. 4
6. 2.3,4.6-tetra 0-benzyl-D-alononitrile゜[α] −+59.6°(8-1.71 CHCI
3) D 1H-NMR (CDCI3) 62.45 (d,H-2). 3.48 (d, 2H, H-6a, 6b), 3.70
(dd, H-3). 4.10 (dd, H-4). ~3.94 (m, H-5). 4.41 (s, 2H, Bn). 4.46, 4.64 (ABq, Bn). 4.5
8, 4.82 (ABq, Bn). 4.64,
4.86 (ABq, Bn), 7.26 (s, P
h) "C-NMR (CDC1 3) 6137.77, 137.53, 137.38
, 135.681, 117.135,
78.77, 78.62, 78.43, 77.02, 75.60, 74. 19, 73. 79.73.
307, 72.573, 70.866,
70.132,69. 793. Elemental analysis: Calculated values C-75.95, H-6.56, N-
2.61 Measured values C-75.76, H-6.39. N-2. 4
0. 2,3.5-1-0-benzyl-β-D-ribofuranosyl cyanide [α] D- +1 7.1@(c-1.3 CHC
l3) IH-NMR (CDCl3) 64. 44-4. 60 (3XCH Bn and H-1), 2 4.0 (dd, H-2.J1, 2-4.2, J2,
3-5), 4.28 (t, H-3, J3, 4-5). 4.
24 (m, H-4). 3. 50 (dd
d, H-5a, 5b) 13C-NMR (CDC1
3) 6 137. 77, 137.
33,136.75 (aromatic CH), 127. 72-128. 60 (m + aromatic CM), 117.67 (CN). 83.16,81.
07, 77. 70, 73.
65, 73. 11,72.
67, 69. 45,68
.. 96. (Example 3) Synthesis of 2,3,4.6-tetra-O-benzyl-D-alononitrile 2,3,4.6-tetra-O-benzyl-5-0-}limethylsilyl-D-alononitrile synthesized in Example 2 .9g (1.5mmol) in 5m methylene chloride
Add 0.1 g of ferrous chloride and stir at room temperature for 30 min.
Stir for a minute. The resulting reaction mixture was subjected to silica gel column chromatography (hexane:ethyl acetate-2:1).
Separate and refine the target product to 0.71g (1.3mmo
l) Obtained.
(実施例4)
2,3.4.6−テトラーO−ベンジルー5−0一メタ
ンスルホニルーD−アロノニトリルの合成実施例2及び
3で得られた2,3,4.6−テトラーO−ベンジルー
D−アロノニトリル3.35g (6.2mmo 1)
を20mlのピリジンに溶かし、メタンスルホニルクロ
リド5ml(62mmo l)を加え室温で一昼夜攪拌
した。(Example 4) Synthesis of 2,3.4.6-tetra O-benzyl-5-0-methanesulfonyl-D-alononitrile 2,3,4.6-tetra O-benzyl obtained in Examples 2 and 3 D-Arononitrile 3.35g (6.2mmo 1)
was dissolved in 20 ml of pyridine, 5 ml (62 mmol) of methanesulfonyl chloride was added, and the mixture was stirred at room temperature overnight.
反応液を、氷冷した飽和重曹水に入れ、30分間攪拌し
た。沈殿物をセライト濾過し、濾液をクロロホルムで3
回抽出した。硫酸マグネシウムで乾燥した後、減圧濃縮
し、シリカゲルクロマトグラフィー(ヘキサン:酢酸エ
チル−4:1)により分離・精製し、目的物を黄色いシ
ラップとして3.6g (96.8%)得た。The reaction solution was poured into ice-cooled saturated sodium bicarbonate solution and stirred for 30 minutes. The precipitate was filtered through Celite, and the filtrate was diluted with chloroform for 3
Extracted twice. After drying over magnesium sulfate, the residue was concentrated under reduced pressure, and separated and purified by silica gel chromatography (hexane:ethyl acetate-4:1) to obtain 3.6 g (96.8%) of the desired product as a yellow syrup.
1H−NMR (CDC1 3)
64.55 (d,H−2,J 1. 2−3.82
).3.97 (dd,H−3.J2,3−6.72)
3. 89 (dd. H−4. J
簡3. 05)3. 4
5. 07 (ddd, H−5,J, 5−7
.33,3.36).
3、 6 7 (d d, H−6 a,J,
5−11.2),
3. 58 (dd, H−6b),2. 9
3 (s, Ms),
4.71, 4.68, 4.63,
4. 39 (CH Bn)2
13C−NMR(CDCl3)
δ 80.665, 78.03,77.
72, 70. 87,74. 1
0, 74. 25,73. 77,
73. 73,69. 73,
42. 489,112.34,
131.41,130.96, 130.7
4,129. 69
元素分析:計算値C−68.30,H−6.01N−2
. 28
測定値C−68.99,H−6.29,N−2. 2
3
(実施例5)
2,3,4.6−テトラ,一〇−ベンジルー1.5一ジ
デオキシー1,5−イミノーL一タリトールの合成
実施例4で得られた2,3.4.6−テトラー0−ベン
ジルー5−0−メタンスルホニル−D−アロノニトリル
280mg (0.45mmo !)を8mlのエーテ
ルに溶かし、これを水素化リチウムアルミニウム28m
g (0.74mmo l)の5mlエーテルの懸濁液
に−78℃で滴下した。1H-NMR (CDC1 3) 64.55 (d, H-2, J 1. 2-3.82
). 3.97 (dd, H-3.J2, 3-6.72)
3. 89 (dd. H-4. J
Simple 3. 05)3. 4 5. 07 (ddd, H-5, J, 5-7
.. 33, 3.36). 3, 6 7 (dd, H-6 a, J,
5-11.2), 3. 58 (dd, H-6b), 2. 9
3 (s, Ms), 4.71, 4.68, 4.63,
4. 39 (CH Bn)2 13C-NMR (CDCl3) δ 80.665, 78.03, 77.
72, 70. 87,74. 1
0, 74. 25,73. 77,
73. 73,69. 73,
42. 489,112.34,
131.41, 130.96, 130.7
4,129. 69 Elemental analysis: Calculated value C-68.30, H-6.01N-2
.. 28 Measured values C-68.99, H-6.29, N-2. 2
3 (Example 5) Synthesis of 2,3,4.6-tetra,10-benzyl-1,5-dideoxy-1,5-imino-L-talitol 2,3.4.6-obtained in Example 4 280 mg (0.45 mmo!) of Tetra 0-benzy-5-0-methanesulfonyl-D-alononitrile was dissolved in 8 ml of ether, and this was dissolved in 28 m of lithium aluminum hydride.
g (0.74 mmol) in 5 ml ether at -78°C.
徐々に−30℃まで温度を上げ、そのまま20時間攪拌
した。反応終了後、0.1mlの水を加え、セライトで
濾過し、硫酸マグネシウムで乾燥し、飽和酢酸ナトリウ
ムエタノール溶液に溶かし、6時間加熱還流した。減圧
濃縮し、クロロホルムに溶かして水で3回洗った。硫酸
マグネシウムで乾燥し、減圧濃縮の後、シリカゲルカラ
ムクロマトグラフィー(クロロホルム:アセトン−8=
1)で精製し110mgの目的物を得た(46%)。The temperature was gradually raised to -30°C, and the mixture was stirred for 20 hours. After the reaction was completed, 0.1 ml of water was added, filtered through Celite, dried over magnesium sulfate, dissolved in saturated sodium acetate ethanol solution, and heated under reflux for 6 hours. It was concentrated under reduced pressure, dissolved in chloroform, and washed three times with water. After drying with magnesium sulfate and concentration under reduced pressure, silica gel column chromatography (chloroform:acetone-8=
Purification was performed in step 1) to obtain 110 mg of the target product (46%).
この化合物はアセチル化して構造確認を行った。This compound was acetylated to confirm its structure.
[α] = 1 3. 5@(c −1.5
CHC 1 3)D
IH−NMR (CDCl3)
6 2. 88 (dd, H−1、J1,
1b−12.0.
J1, 2−12.0),
3. 25 (ddd, H−1b,Jエb,
2−5.0.J1, 3−2.1).4. 72
(dd, H−2).4.09 (dd,H
3= J 3,4−2.2) ,3. 38 (
dd, H−4. J −6. 0
).4. 5
4. 19 (ddd, H−5.J5, 6
a−11.0.J5, 6,−2.1)3。 89
(dd. H−6a,J6a,6,−11.0).
4. 00 (H−6b).
2.1 0 (S,CH3CO) ,
4.35−4.85 (q.CH2)
13C−NMR(CDCl3)
δ 34.701, 75.161.76.8
68, 56,908,67.158.
71,011.71.159. 73.20
9.74.283, 21.91B,138.
96, 138.19.137.598,
170.767元素分折:計算値C−76.43,
H−6.95,N−2. 48
測定値C−76.21,H−6.99,N−2.41
(実施fIJ6)
1.5−イミノーL一タリトール塩酸塩の合成実施例5
で得られた2.3.4.6−テトラーO−ベンジル−1
.5−ジデオキシー1.5−イミノーL一タリトール3
60mg (6.69mmol)を6mlのエタノール
に溶かし、4M塩化水素のメタノール溶液3mlを加え
減圧濃縮した。15mlのエタノールに溶かし、10%
パラジウム活性炭150mgを加え、約8時間攪拌しな
がら水素ガスを通じた。反応終了後、セライトで濾過し
、減圧濃縮した。残渣をクロロホルム:エタノール:水
−1:4:2でショート力ラムクロマトグラフィーを行
った後、濃縮し、20m】の水に溶かして活性炭300
mgを加えた。活性炭を濾別して、エタノールで数回共
沸させながら濃縮を行い目的物を塩酸塩として得た(収
量=97mg,70%)。[α] = 1 3. 5@(c -1.5
CHC 1 3) D IH-NMR (CDCl3) 6 2. 88 (dd, H-1, J1,
1b-12.0. J1, 2-12.0), 3. 25 (ddd, H-1b, Jeb,
2-5.0. J1, 3-2.1). 4. 72
(dd, H-2). 4.09 (dd, H
3=J3,4-2.2),3. 38 (
dd, H-4. J-6. 0
). 4. 5 4. 19 (ddd, H-5.J5, 6
a-11.0. J5, 6, -2.1)3. 89
(dd. H-6a, J6a, 6, -11.0). 4. 00 (H-6b). 2.1 0 (S, CH3CO), 4.35-4.85 (q.CH2) 13C-NMR (CDCl3) δ 34.701, 75.161.76.8
68, 56,908, 67.158.
71,011.71.159. 73.20
9.74.283, 21.91B, 138.
96, 138.19.137.598,
170.767 elemental analysis: calculated value C-76.43,
H-6.95, N-2. 48 Measured values C-76.21, H-6.99, N-2.41 (Implementation fIJ6) Synthesis Example 5 of 1.5-Iminol-L monotalitol hydrochloride
2.3.4.6-tetra O-benzyl-1 obtained in
.. 5-dideoxy-1,5-imino L-talitol 3
60 mg (6.69 mmol) was dissolved in 6 ml of ethanol, 3 ml of a 4M methanol solution of hydrogen chloride was added, and the mixture was concentrated under reduced pressure. Dissolve in 15ml ethanol, 10%
150 mg of palladium activated carbon was added, and hydrogen gas was passed through the mixture while stirring for about 8 hours. After the reaction was completed, it was filtered through Celite and concentrated under reduced pressure. The residue was subjected to short force chromatography using chloroform:ethanol:water (1:4:2), concentrated, dissolved in 20 m of water and purified with activated carbon 300 m
mg was added. Activated carbon was filtered off, and the mixture was concentrated while azeotropically distilled with ethanol several times to obtain the desired product as a hydrochloride (yield: 97 mg, 70%).
3. 21 (t, IH, H−2,J,
3−3.4),
3. 6 Cb d, I H. H−3,J 3.
4−0) ,3.52 (s,IH,H−4,J,,
5=O).2. 77 (t, IH, H
−5,J5,6a−7.02),
3. 24 (d,2H,H−6a,6b)13C
−NMR(CDCl 3)
δ49. 585, 6,1..628,
67. 821, 68.406.68.
844. 60. 361以上実施
例2〜6の各反応における反応物及び生成物の構造を第
2図に示す。3. 21 (t, IH, H-2, J,
3-3.4), 3. 6 Cb d, I H. H-3, J 3.
4-0) ,3.52 (s,IH,H-4,J,,
5=O). 2. 77 (t, IH, H
-5, J5, 6a-7.02), 3. 24 (d, 2H, H-6a, 6b) 13C
-NMR (CDCl3) δ49. 585, 6, 1. .. 628,
67. 821, 68.406.68.
844. 60. 361 The structures of the reactants and products in each reaction of Examples 2 to 6 are shown in FIG.
’H−NMR (D20)
6 2. 63 (d. IH, H−1,J
1, 15−14).
2. 89 (dd, IH, H−1b,’
1 b,2=3− 4),
(実施例7)
3,4.6−トリ一〇−ベンジル−5−0− トリメチ
ルシリルー2−0−メチルーD−グルコノニトリルの合
成
メチル−2.3.5−トリ一〇−ベンジルーβ一〇一ア
ラビノフラノシド630mg (1.4mmol).T
MSCN O.96ml (7.2mmo 1),
ボロントリフルオリドエーテラート1 7.8u 1
(0.14mmo 1)を混合し、室温で2時間反応
させた。生或物をシリカゲルカラムクロマトグラフィー
で分離●精製し、次の三或分をそれぞれシラップとして
得た。即ち、3.4.6−トリ一〇−ベンジル−5−0
−トリメチルシリルー2−0−メチルーD−グルコノニ
トリルを110mg(15%) 、3,4.6−トリ一
〇一ベンジルー2−0−メチルーD−グルコノニトリル
を90mg (14%’) 、2,3.5−トリ一〇−
ベンジルーβ(α)−D−アラビノフラノシルシアニド
を100mg (23%)を得た。'H-NMR (D20) 6 2. 63 (d. IH, H-1, J
1, 15-14). 2. 89 (dd, IH, H-1b,'
1b,2=3-4), (Example 7) Synthesis of 3,4.6-tri10-benzyl-5-0-trimethylsilyl-2-0-methyl-D-glucononitrile Methyl-2.3 .5-tri-10-benzyl-β-101 arabinofuranoside 630 mg (1.4 mmol). T
MSCN O. 96ml (7.2mmo 1),
Boron trifluoride etherate 1 7.8u 1
(0.14 mmol 1) and reacted at room temperature for 2 hours. The raw material was separated and purified by silica gel column chromatography, and the next three portions were obtained as syrup. That is, 3.4.6-tri-10-benzyl-5-0
110 mg (15%) of -trimethylsilyl-2-0-methyl-D-glucononitrile, 90 mg (14%') of 3,4.6-tri101benzyl-2-0-methyl-D-glucononitrile, 2 ,3.5-tri-10-
100 mg (23%) of benzyl-β(α)-D-arabinofuranosyl cyanide was obtained.
3,4.6−}りーO−ベンジル−5−0−トリメチル
シリルー2−0−メチル一〇一グルコノニトリル
IH−NMR (CDC1 3)
60.12 (s,TMS).
3. 43 (s, −OMe),3. 69
(dd, H−6a,J−4. 5, 9.
9),
3. 47 (dd, H−6b,J−4.
8. 9. 9),
3. 84−4. 05
( m + II−3 + K−4 + H−5
) +4. 26 (d, H−2. J
−4. 5).4. 45 (s, CH
Bn).2
4. 63 (s, CH Bn).2
4. 70 (s, CH Bn),2
7. 25 (s, Ph)
3,4.6−}りーO−ベンジル−2−0−メチル一〇
一グルコノニトリル
[α] o − + 3 0 ’ ( c − 0
. 8 8 , C H C l 3 )IH−N
MR (CDC1 3)
6 7. 3 (15H),
4. 7.
4. 56 (CH Bn).2
4. 5 (CH Bn).2
4.3 (d,IH,H−2,72. 3−6).4
.04 (dd.IH,H−3,J3. 4−3)3.
84 (dd.IH,H 4,J4.5■8)3.
9−4. 0 (IH),3. 6 (d,
2H, H−6a, 6b),3. 5
(s, 3H, Me)13C−NMR(CDCl
3)
δ 79. 06, 72. 2
3,70. 72, 69. 94
(CH).78. 04, 75
. 26,74.28, 73.50 (
CH2),58. 52, 116.
79 (CN).140, 31,
137.68 (芳香族)
元素分析二計算値C−72.89,H−6.72,N−
3. 04
測定値C−72.29,H−6.59.N−2. 9
4.
2,3.5−トリ一〇一ベンジルーβ(α)D−アラビ
ノフラノシルシアニド
’H−NMR (CDCl3)
64.68 (d,H−1,J t, 2−2.1)
.4.03 (dd,H−2,J −4.5),
2,3
4.20−4.40 (m,H−3,H−4),3.5
2 (d,H−5a,5b,
”H−NMR (CDC1 3)
δ 86.629, 83.73.353,
72.
72.038, 70.
69.109, 116,
1 37。 727, 137,136. 4
07
5 5 6,
3 77,
3 78,
589 (CN),
1 89.
(実施例8)
3,4.6−トリ一〇−ベンジル−2−0−メチル一〇
一グルコノニトリルの合成
実施例7で得られた3,4.6−}りーO−べンジルー
2−0−メチル−5−0−トリメチルシリルーD−グル
コノニトリル0.7g (1.2mmol)を塩化メチ
レン5mlに溶解し、0.1gの塩化第一鉄を加えて室
温で30分間攪拌した。得られた反応混合物を、シリカ
ゲル力ラムクロマトグラフィー(ヘキサン:酢酸エチル
−2=1)で分離・精製して目的物を0.59g(1.
0mmo I)得た。3,4.6-}-O-benzyl-5-0-trimethylsilyl-2-0-methyl-101 glucononitrile IH-NMR (CDC1 3) 60.12 (s, TMS). 3. 43 (s, -OMe), 3. 69
(dd, H-6a, J-4. 5, 9.
9), 3. 47 (dd, H-6b, J-4.
8. 9. 9), 3. 84-4. 05 (m + II-3 + K-4 + H-5
) +4. 26 (d, H-2. J
-4. 5). 4. 45 (s, CH
Bn). 2 4. 63 (s, CH Bn). 2 4. 70 (s, CH Bn), 2 7. 25 (s, Ph) 3,4.6-}-O-benzyl-2-0-methyl 101 glucononitrile [α] o − + 3 0′ (c − 0
.. 8 8 , C H C l 3 ) IH-N
MR (CDC1 3) 6 7. 3 (15H), 4. 7. 4. 56 (CH Bn). 2 4. 5 (CH Bn). 2 4.3 (d, IH, H-2, 72. 3-6). 4
.. 04 (dd. IH, H-3, J3. 4-3) 3.
84 (dd.IH,H 4,J4.5■8)3.
9-4. 0 (IH), 3. 6 (d,
2H, H-6a, 6b), 3. 5
(s, 3H, Me) 13C-NMR (CDCl
3) δ 79. 06, 72. 2
3,70. 72, 69. 94
(CH). 78. 04, 75
.. 26, 74.28, 73.50 (
CH2), 58. 52, 116.
79 (CN). 140, 31, 137.68 (Aromatic) Elemental analysis two calculated values C-72.89, H-6.72, N-
3. 04 Measured value C-72.29, H-6.59. N-2. 9
4. 2,3.5-tri-101benzyl-β(α)D-arabinofuranosylcyanide'H-NMR (CDCl3) 64.68 (d,H-1,J t, 2-2.1)
.. 4.03 (dd, H-2, J-4.5),
2,3 4.20-4.40 (m, H-3, H-4), 3.5
2 (d, H-5a, 5b, “H-NMR (CDC1 3) δ 86.629, 83.73.353,
72. 72.038, 70. 69.109, 116, 1 37. 727, 137, 136. 4
07 5 5 6, 3 77, 3 78, 589 (CN), 1 89. (Example 8) Synthesis of 3,4.6-tri10-benzyl-2-0-methyl101 glucononitrile 3,4.6-}-O-benzyl-2 obtained in Example 7 0.7 g (1.2 mmol) of -0-methyl-5-0-trimethylsilyl-D-glucononitrile was dissolved in 5 ml of methylene chloride, 0.1 g of ferrous chloride was added, and the mixture was stirred at room temperature for 30 minutes. The resulting reaction mixture was separated and purified by silica gel column chromatography (hexane:ethyl acetate-2=1) to obtain 0.59 g (1.
0 mmol I) was obtained.
(実施例9)
3,4.6−1り−O−ベンジル−5−0−メタンスル
ホニル−2一〇−メチルーD−グルコノニトリルの合成
実施例7及び8で得られた3,4.6−トリ一〇−ベン
ジル−2−0−メチルーD−グルコノニトリル180m
g (0.39mmo l)を3mlのビリジンに溶か
し、水冷下にメタンスルホニルクロリドlml (1
3mmol)を加えた。一夜攪拌後、反応液を氷冷した
飽和重曹水に注ぎ、7時間攪拌後、クロロホルムで3回
抽出した。硫酸マグネシウムで乾燥後、減圧濃縮し、シ
リカゲルショート力ラム(ヘキサン:酢酸エチル−4:
1)で精製し、目的物をシラップとして1 60mg(
74%)得た。(Example 9) Synthesis of 3,4.6-1-O-benzyl-5-0-methanesulfonyl-210-methyl-D-glucononitrile 3,4.6-1 obtained in Examples 7 and 8. 6-Tri10-benzyl-2-0-methyl-D-glucononitrile 180m
Dissolve g (0.39 mmol) in 3 ml of pyridine, and add 1 ml of methanesulfonyl chloride (1 ml) under water cooling.
3 mmol) was added. After stirring overnight, the reaction solution was poured into ice-cooled saturated sodium bicarbonate solution, stirred for 7 hours, and extracted three times with chloroform. After drying with magnesium sulfate, it was concentrated under reduced pressure, and filtrated with silica gel short column (hexane:ethyl acetate-4:
Purify in step 1) and use the target product as syrup to produce 160 mg (
74%).
1H−NMR(CDC1 3)
6 7. 3 (15H),
4. 9 (m, IH, H−5).4,7
, 4.68, 4.24(each
s,2H,CH2).
3. 7−4. 24 (m. 5H,H−2
+ 3+ 4+ 6a, 6b),3. 4
4 (s, 3H. Me).2. 96
(s, 3H, Me)(実施例10)
3.4.6−トリ一〇−ベンジル−2−0−メチル−1
.5−ジデオキシー1.5−イミノーL一イジトールの
合戊
実施例9で得られた3.4.6−トリーO−ベンジルー
5一〇−メタンスルホニル−2−0−メチルーD−グル
コノニトリル160mg (0.3mmo 1)を7.
5mlのエーテルに溶かし、水素化リチウムアルミニウ
ム17mg (0.45mmo1)の3mlエーテル懸
濁液に水冷下に滴下した。40分後、0. 1 m
lの水を加え、セライトで濾過した。硫酸マグネシウム
で乾燥し、減圧濃縮の後、酢酸ナトリウムの飽和エタノ
ール溶液に溶かし、一夜加熱還流し減圧濃縮した。クロ
ロホルムに溶かし、水で洗った。硫酸マグネシウムで乾
燥し、減圧濃縮を行い、シリカゲルカラムクロマトグラ
フィ−(クロロホルム:アセトン繻8:1)で精製し、
目的物を26mg (20%)得た。1H-NMR (CDC1 3) 6 7. 3 (15H), 4. 9 (m, IH, H-5). 4,7
, 4.68, 4.24(each
s, 2H, CH2). 3. 7-4. 24 (m. 5H, H-2
+ 3+ 4+ 6a, 6b), 3. 4
4 (s, 3H. Me). 2. 96
(s, 3H, Me) (Example 10) 3.4.6-tri10-benzyl-2-0-methyl-1
.. Synthesis of 5-dideoxy-1,5-imino-L-iditol 160 mg of 3.4.6-tri-O-benzy-510-methanesulfonyl-2-0-methyl-D-glucononitrile obtained in Example 9 ( 0.3 mmo 1) to 7.
The mixture was dissolved in 5 ml of ether and added dropwise to a suspension of 17 mg (0.45 mmol) of lithium aluminum hydride in 3 ml of ether while cooling with water. After 40 minutes, 0. 1 m
1 of water was added and filtered through Celite. After drying over magnesium sulfate and concentration under reduced pressure, the mixture was dissolved in a saturated ethanol solution of sodium acetate, heated under reflux overnight, and concentrated under reduced pressure. Dissolved in chloroform and washed with water. Dry with magnesium sulfate, concentrate under reduced pressure, and purify with silica gel column chromatography (chloroform:acetone 8:1).
26 mg (20%) of the desired product was obtained.
1H−NMR (CDCl 3)
62. 83 (dd. H−1g,J1,
、5−13.J1, 2−6.4),3. 00
(dd, H−1b,Jエb, 2−3.83)
3.21 (dt,H−2,J, 3−6.20)3
.57 (t,H−3,J, 4−6.20),3.3
9 (dd,H−4,J, 5−3.40)3.34
(ddd,H−5,J,6a−8.85,J, 6
,−5.45)3. 64 (t, H−6a,
J −9. 2)5, 6 b
3. 51 (dd, H−6b),4.64.
4.56. 4.52 (CH2)13C−
NMR(CDC13)
δ79.066, 77.047,76.67
2, 73.794,73.353,
72.57,67.594, 57.737
,54.663, 43.827これを実施例
6と同様にして脱保護し、2−0−メチル−1,5−イ
ミノーL−イジトール塩酸塩が得られた。1H-NMR (CDCl3) 62. 83 (dd. H-1g, J1,
, 5-13. J1, 2-6.4), 3. 00
(dd, H-1b, Jeb, 2-3.83) 3.21 (dt, H-2, J, 3-6.20) 3
.. 57 (t, H-3, J, 4-6.20), 3.3
9 (dd, H-4, J, 5-3.40) 3.34
(ddd, H-5, J, 6a-8.85, J, 6
, -5.45)3. 64 (t, H-6a,
J-9. 2) 5, 6 b 3. 51 (dd, H-6b), 4.64.
4.56. 4.52 (CH2)13C-
NMR (CDC13) δ79.066, 77.047, 76.67
2, 73.794, 73.353,
72.57, 67.594, 57.737
, 54.663, 43.827 This was deprotected in the same manner as in Example 6 to obtain 2-0-methyl-1,5-imino-L-iditol hydrochloride.
以上実施例7〜10の各反応における反応物及び生成物
の構造を第3図に示す。The structures of the reactants and products in each reaction of Examples 7 to 10 are shown in FIG. 3.
(実施例11)
酵素阻害活性
この様にして合戊した1,5−イミノーL一タリトール
に対して酵素阻害活性実験を実施した。(Example 11) Enzyme inhibitory activity An enzyme inhibitory activity experiment was conducted on the 1,5-imino-L monotalitol thus synthesized.
基質は、各酵素に対応するp(0)一ニトロフエニルグ
リコシドを用い、基質溶液(2〜4mM)200μ1、
阻害剤(l,5−イミノーL一タリー2−6
トール)溶液(1.6X10 〜10 M)20
0μ1を加え、これに各酵素溶液(1μg/m 1 〜
7ug/m l)2001t Iを加えて反応を開始し
た。25℃でインキコベートし、一定時間後にlmlの
0.05Mグリシンー水酸化ナトリウム緩衝液(PH1
0.1)を加え、加水分解により生じたp(0)一二ト
ロフェノールのアルカリ性における発色を、4 0 0
n mにおける吸光度で7lνj定することにより反
応速度を求めた。Dixon−plotにより、阻害定
数Kiを決定した。As a substrate, p(0)-nitrophenyl glycoside corresponding to each enzyme was used, and 200 μl of a substrate solution (2-4 mM) was used.
Inhibitor (l,5-imino-L-tally 2-6 toll) solution (1.6X10~10 M) 20
Add 0 μl of each enzyme solution (1 μg/m 1 to
7ug/ml)2001tI was added to start the reaction. Incubate at 25°C, and after a certain period of time add 1ml of 0.05M glycine-sodium hydroxide buffer (PH1
0.1), and the color development of p(0) ditrophenol produced by hydrolysis in alkalinity was
The reaction rate was determined by determining the absorbance at nm as 7lνj. Inhibition constant Ki was determined by Dixon-plot.
使用した酵素(由来)は次のものである。即ち、■α−
グルコシダーゼ(ビール酵母)
■β−グルコシダーゼ(アーモンド)
■α−ガラクトシダーゼ(コーヒーマメ)■β−ガラク
トシダーゼ(クロカビ)
■α−マンノシダーゼ(タチナタマメ)■α−フコシダ
ーゼ(牛の副精巣)
■α−フコシダーゼ(牛の腎臓)
などである。The enzymes (origins) used are as follows. That is, ■α−
Glucosidase (brewer's yeast) ■β-glucosidase (almond) ■α-galactosidase (coffee bean) ■β-galactosidase (black mold) ■α-mannosidase (jack bean) ■α-fucosidase (cow accessory testis) ■α-fucosidase (cow kidneys), etc.
この様にして求めた阻害活性を以下の表に示す。The inhibitory activities determined in this way are shown in the table below.
酵素 50%阻害(M)[K.]1
■α−グルコシダーゼ 3X10−3■β−グルコシ
ダーゼ Nl
■α−ガラクトシダーゼ Nl
■β−ガラクトシダーゼ Nl
■α−マンノシダーゼ Nl
■α−フコシダーゼ 2.7X10−5−5
[1.IXIO ]
■α−フコシダーゼ 8.OX10 ’−6
[7X10 ]
− 3
NI:阻害活性無し(>5xlO )[発明の効果
]
以上の説明から明らかなように、本発明のポリヒド口キ
シビペリジン類はα−グルコシダーゼ,α−フコシダー
ゼなどに対するグリコシダーゼ阻害活性が認められた。Enzyme 50% inhibition (M) [K. [1. IXIO] ■α-fucosidase 8. OX10'-6 [7X10]-3 NI: No inhibitory activity (>5xlO) [Effects of the invention] As is clear from the above explanation, the polyhydro-oxybiperidines of the present invention are effective against glycosidases such as α-glucosidase and α-fucosidase. Inhibitory activity was observed.
本発明のポリヒド口キシビペリジン類はりボフラノシド
誘導体またはアラビノシド誘導体をTMSCNで開環後
、シアノ基を還元してアミノ基とし、閉環させるという
本発明方法により簡単に製造することができた。The polyhydroxybiperidines of the present invention could be easily produced by the method of the present invention, in which a bofuranoside derivative or an arabinoside derivative is ring-opened with TMSCN, the cyano group is reduced to an amino group, and the ring is closed.
第1図は実施例1の、第2図は実施例2〜6の、第3図
は実施例7〜10の各反応における反応物及び生成物の
構造を示す図である。FIG. 1 is a diagram showing the structures of reactants and products in each reaction of Example 1, FIG. 2 is of Examples 2 to 6, and FIG. 3 is of Examples 7 to 10.
Claims (2)
いずれか一方が水素で他方は水酸基を示す)で表される
ポリヒドロキシピペリジン類。(1) The following general formula (I) ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) Polyhydroxypiperidines represented.
ルコキシ基又は▲数式、化学式、表等があります▼(式
中 XはH、CH_3、OCH_3、又はClを示す)を、
R_6、R_7はいずれか一方が水素で他方がアシルオ
キシ基又は▲数式、化学式、表等があります▼(式中、
X は上記と同じ)を、R_8はアシルオキシ基又は▲数式
、化学式、表等があります▼(式中、Xは上記と同じ) を、R_9はアシルオキシ基、▲数式、化学式、表等が
あります▼ −X(式中、Xは上記と同じ)又はアジド基を示す)で
表されるリボフラノシド誘導体又はアラビノフラノシド
誘導体をルイス酸の存在下にシアノトリメチルシランと
反応させ、開環、増炭させて、下記一般式(III) ▲数式、化学式、表等があります▼(III) (式中、R_4ないしR_9は上記と同じ)で表される
鎖状構造物とした後、トリメチルシリル基を適当な脱離
基に変換し、更に、シアノ基を還元して閉環させて、下
記一般式(IV) ▲数式、化学式、表等があります▼(IV) (R_4ないしR_9は上記と同じ)で表される1,5
−ジデオキシ−1,5−イミノ−L−タリトール誘導体
又は1,5−ジデオキシ−1,5−イミノ−L−イジト
ール誘導体とし、ひき続いて接触還元で脱保護すること
を特徴とする請求項(1)記載のポリヒドロキシピペリ
ジン類の製造法。(2) General formula (II) below ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) (In the formula, one of R_4 and R_5 is hydrogen and the other is an alkoxy group, or ▲There are mathematical formulas, chemical formulas, tables, etc.) (in the formula, X represents H, CH_3, OCH_3, or Cl),
Either one of R_6 and R_7 is hydrogen and the other is an acyloxy group, or there are numerical formulas, chemical formulas, tables, etc.▼ (in the formula,
X is the same as above), R_8 is an acyloxy group or ▲ there is a mathematical formula, chemical formula, table, etc. ▼ (in the formula, X is the same as above), R_9 is an acyloxy group, ▲ there is a mathematical formula, chemical formula, table, etc. ▼ A ribofuranoside derivative or arabinofuranoside derivative represented by -X (wherein X is the same as above) or an azide group is reacted with cyanotrimethylsilane in the presence of a Lewis acid to open the ring and increase the carbon content. After forming a chain structure represented by the following general formula (III) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (III) (in the formula, R_4 to R_9 are the same as above), a trimethylsilyl group is added to an appropriate It is converted into a leaving group, and then the cyano group is reduced and ring-closed, resulting in the following general formula (IV) ▲ Numerical formula, chemical formula, table, etc. ▼ (IV) (R_4 to R_9 are the same as above) 1,5
-dideoxy-1,5-imino-L-talitol derivative or 1,5-dideoxy-1,5-imino-L-iditol derivative, followed by deprotection by catalytic reduction (claim 1) ) The method for producing polyhydroxypiperidines described in .
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP1158162A JPH0324057A (en) | 1989-06-22 | 1989-06-22 | Polyhydroxypiperidines and production thereof |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP1158162A JPH0324057A (en) | 1989-06-22 | 1989-06-22 | Polyhydroxypiperidines and production thereof |
Publications (1)
Publication Number | Publication Date |
---|---|
JPH0324057A true JPH0324057A (en) | 1991-02-01 |
Family
ID=15665624
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP1158162A Pending JPH0324057A (en) | 1989-06-22 | 1989-06-22 | Polyhydroxypiperidines and production thereof |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPH0324057A (en) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7985760B2 (en) | 2002-07-17 | 2011-07-26 | Actelion Pharmaceuticals Ltd. | Piperidinetriol derivatives as inhibitors of glycosyceramid synthase |
US8022219B2 (en) | 2003-06-13 | 2011-09-20 | Actelion Pharmaceuticals Ltd. | 2-hydroxymethy1-3,4,5-trihydroxy-1-(4-pentyloxybenzyl) piperidine as glucosylceramide synthase (Gcs) inhibitor |
US8071780B2 (en) | 2003-06-13 | 2011-12-06 | Actelion Pharmaceuticals Ltd. | 2-Hydroxymethyl-3,4,5-trihydroxy-1-benzilpiperidine derivatives as inhibitors of glucosylceramide |
US8729099B2 (en) | 2001-01-12 | 2014-05-20 | Actelion Pharmaceuticals Ltd. | Pharmaceutically active piperidine derivatives |
-
1989
- 1989-06-22 JP JP1158162A patent/JPH0324057A/en active Pending
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8729099B2 (en) | 2001-01-12 | 2014-05-20 | Actelion Pharmaceuticals Ltd. | Pharmaceutically active piperidine derivatives |
US9199935B2 (en) | 2001-01-12 | 2015-12-01 | Acetelion Pharmaceuticals Ltd. | Pharmaceutically active piperidine derivatives |
US7985760B2 (en) | 2002-07-17 | 2011-07-26 | Actelion Pharmaceuticals Ltd. | Piperidinetriol derivatives as inhibitors of glycosyceramid synthase |
US8022219B2 (en) | 2003-06-13 | 2011-09-20 | Actelion Pharmaceuticals Ltd. | 2-hydroxymethy1-3,4,5-trihydroxy-1-(4-pentyloxybenzyl) piperidine as glucosylceramide synthase (Gcs) inhibitor |
US8071780B2 (en) | 2003-06-13 | 2011-12-06 | Actelion Pharmaceuticals Ltd. | 2-Hydroxymethyl-3,4,5-trihydroxy-1-benzilpiperidine derivatives as inhibitors of glucosylceramide |
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