JP2729803B2 - Mannobiose derivatives - Google Patents
Mannobiose derivativesInfo
- Publication number
- JP2729803B2 JP2729803B2 JP63081036A JP8103688A JP2729803B2 JP 2729803 B2 JP2729803 B2 JP 2729803B2 JP 63081036 A JP63081036 A JP 63081036A JP 8103688 A JP8103688 A JP 8103688A JP 2729803 B2 JP2729803 B2 JP 2729803B2
- Authority
- JP
- Japan
- Prior art keywords
- mannobiose
- liposome
- mannopyranosyl
- compound
- group
- 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.)
- Expired - Lifetime
Links
- 150000002698 mannobioses Chemical class 0.000 title claims description 17
- 150000001875 compounds Chemical class 0.000 claims description 42
- 125000002252 acyl group Chemical group 0.000 claims description 8
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 87
- 239000002502 liposome Substances 0.000 description 66
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 44
- -1 tridecanoyl Chemical group 0.000 description 31
- 150000001408 amides Chemical class 0.000 description 27
- 238000006243 chemical reaction Methods 0.000 description 26
- 239000000725 suspension Substances 0.000 description 23
- DKXNBNKWCZZMJT-UHFFFAOYSA-N O4-alpha-D-Mannopyranosyl-D-mannose Natural products O=CC(O)C(O)C(C(O)CO)OC1OC(CO)C(O)C(O)C1O DKXNBNKWCZZMJT-UHFFFAOYSA-N 0.000 description 22
- GUBGYTABKSRVRQ-PZPXDAEZSA-N 4β-mannobiose 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-PZPXDAEZSA-N 0.000 description 21
- 238000005160 1H NMR spectroscopy Methods 0.000 description 20
- 238000000921 elemental analysis Methods 0.000 description 20
- VKOBVWXKNCXXDE-UHFFFAOYSA-N icosanoic acid Chemical compound CCCCCCCCCCCCCCCCCCCC(O)=O VKOBVWXKNCXXDE-UHFFFAOYSA-N 0.000 description 19
- 210000004185 liver Anatomy 0.000 description 18
- 239000000203 mixture Substances 0.000 description 18
- 239000000243 solution Substances 0.000 description 17
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 16
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 16
- 150000002632 lipids Chemical class 0.000 description 16
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 15
- 239000012528 membrane Substances 0.000 description 13
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical group C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 12
- 238000002360 preparation method Methods 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- 229920001202 Inulin Polymers 0.000 description 11
- 229940029339 inulin Drugs 0.000 description 11
- 239000002953 phosphate buffered saline Substances 0.000 description 11
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 description 10
- 210000001865 kupffer cell Anatomy 0.000 description 10
- 210000002540 macrophage Anatomy 0.000 description 10
- 125000000317 mannobiose group Chemical group 0.000 description 10
- 239000000126 substance Substances 0.000 description 10
- 238000012360 testing method Methods 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 150000002148 esters Chemical class 0.000 description 9
- 238000000034 method Methods 0.000 description 9
- 229940126062 Compound A Drugs 0.000 description 7
- 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 7
- 241000700159 Rattus Species 0.000 description 7
- 125000001124 arachidoyl group Chemical group O=C([*])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])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 7
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 7
- JYJIGFIDKWBXDU-MNNPPOADSA-N inulin Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)OC[C@]1(OC[C@]2(OC[C@]3(OC[C@]4(OC[C@]5(OC[C@]6(OC[C@]7(OC[C@]8(OC[C@]9(OC[C@]%10(OC[C@]%11(OC[C@]%12(OC[C@]%13(OC[C@]%14(OC[C@]%15(OC[C@]%16(OC[C@]%17(OC[C@]%18(OC[C@]%19(OC[C@]%20(OC[C@]%21(OC[C@]%22(OC[C@]%23(OC[C@]%24(OC[C@]%25(OC[C@]%26(OC[C@]%27(OC[C@]%28(OC[C@]%29(OC[C@]%30(OC[C@]%31(OC[C@]%32(OC[C@]%33(OC[C@]%34(OC[C@]%35(OC[C@]%36(O[C@@H]%37[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O%37)O)[C@H]([C@H](O)[C@@H](CO)O%36)O)[C@H]([C@H](O)[C@@H](CO)O%35)O)[C@H]([C@H](O)[C@@H](CO)O%34)O)[C@H]([C@H](O)[C@@H](CO)O%33)O)[C@H]([C@H](O)[C@@H](CO)O%32)O)[C@H]([C@H](O)[C@@H](CO)O%31)O)[C@H]([C@H](O)[C@@H](CO)O%30)O)[C@H]([C@H](O)[C@@H](CO)O%29)O)[C@H]([C@H](O)[C@@H](CO)O%28)O)[C@H]([C@H](O)[C@@H](CO)O%27)O)[C@H]([C@H](O)[C@@H](CO)O%26)O)[C@H]([C@H](O)[C@@H](CO)O%25)O)[C@H]([C@H](O)[C@@H](CO)O%24)O)[C@H]([C@H](O)[C@@H](CO)O%23)O)[C@H]([C@H](O)[C@@H](CO)O%22)O)[C@H]([C@H](O)[C@@H](CO)O%21)O)[C@H]([C@H](O)[C@@H](CO)O%20)O)[C@H]([C@H](O)[C@@H](CO)O%19)O)[C@H]([C@H](O)[C@@H](CO)O%18)O)[C@H]([C@H](O)[C@@H](CO)O%17)O)[C@H]([C@H](O)[C@@H](CO)O%16)O)[C@H]([C@H](O)[C@@H](CO)O%15)O)[C@H]([C@H](O)[C@@H](CO)O%14)O)[C@H]([C@H](O)[C@@H](CO)O%13)O)[C@H]([C@H](O)[C@@H](CO)O%12)O)[C@H]([C@H](O)[C@@H](CO)O%11)O)[C@H]([C@H](O)[C@@H](CO)O%10)O)[C@H]([C@H](O)[C@@H](CO)O9)O)[C@H]([C@H](O)[C@@H](CO)O8)O)[C@H]([C@H](O)[C@@H](CO)O7)O)[C@H]([C@H](O)[C@@H](CO)O6)O)[C@H]([C@H](O)[C@@H](CO)O5)O)[C@H]([C@H](O)[C@@H](CO)O4)O)[C@H]([C@H](O)[C@@H](CO)O3)O)[C@H]([C@H](O)[C@@H](CO)O2)O)[C@@H](O)[C@H](O)[C@@H](CO)O1 JYJIGFIDKWBXDU-MNNPPOADSA-N 0.000 description 7
- 238000010898 silica gel chromatography Methods 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 235000012000 cholesterol Nutrition 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- 229920000057 Mannan Polymers 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 230000037396 body weight Effects 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 239000000194 fatty acid Substances 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- YXIWHUQXZSMYRE-UHFFFAOYSA-N 1,3-benzothiazole-2-thiol Chemical compound C1=CC=C2SC(S)=NC2=C1 YXIWHUQXZSMYRE-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 125000004442 acylamino group Chemical group 0.000 description 4
- 125000003277 amino group Chemical group 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- RNPXCFINMKSQPQ-UHFFFAOYSA-N dicetyl hydrogen phosphate Chemical compound CCCCCCCCCCCCCCCCOP(O)(=O)OCCCCCCCCCCCCCCCC RNPXCFINMKSQPQ-UHFFFAOYSA-N 0.000 description 4
- 229940093541 dicetylphosphate Drugs 0.000 description 4
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 4
- 239000005457 ice water Substances 0.000 description 4
- 210000003141 lower extremity Anatomy 0.000 description 4
- GUBGYTABKSRVRQ-KWCWEWCRSA-N mannobiose Chemical compound 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-KWCWEWCRSA-N 0.000 description 4
- 125000000311 mannosyl group Chemical group C1([C@@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 4
- 239000012046 mixed solvent Substances 0.000 description 4
- 125000001419 myristoyl group Chemical group O=C([*])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])C([H])([H])[H] 0.000 description 4
- 210000000056 organ Anatomy 0.000 description 4
- 210000004738 parenchymal cell Anatomy 0.000 description 4
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 230000000717 retained effect Effects 0.000 description 4
- 230000008685 targeting Effects 0.000 description 4
- 230000010415 tropism Effects 0.000 description 4
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 3
- TWJNQYPJQDRXPH-UHFFFAOYSA-N 2-cyanobenzohydrazide Chemical compound NNC(=O)C1=CC=CC=C1C#N TWJNQYPJQDRXPH-UHFFFAOYSA-N 0.000 description 3
- 235000021360 Myristic acid Nutrition 0.000 description 3
- TUNFSRHWOTWDNC-UHFFFAOYSA-N Myristic acid Natural products CCCCCCCCCCCCCC(O)=O TUNFSRHWOTWDNC-UHFFFAOYSA-N 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000003125 aqueous solvent Substances 0.000 description 3
- 235000014113 dietary fatty acids Nutrition 0.000 description 3
- CITHEXJVPOWHKC-UHFFFAOYSA-N dimyristoyl phosphatidylcholine Chemical compound CCCCCCCCCCCCCC(=O)OCC(COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCC CITHEXJVPOWHKC-UHFFFAOYSA-N 0.000 description 3
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 3
- 238000009826 distribution Methods 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 210000002969 egg yolk Anatomy 0.000 description 3
- 229930195729 fatty acid Natural products 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- LPWCRLGKYWVLHQ-UHFFFAOYSA-N tetradecanoyl chloride Chemical compound CCCCCCCCCCCCCC(Cl)=O LPWCRLGKYWVLHQ-UHFFFAOYSA-N 0.000 description 3
- 210000003462 vein Anatomy 0.000 description 3
- IRFSXVIRXMYULF-UHFFFAOYSA-N 1,2-dihydroquinoline Chemical compound C1=CC=C2C=CCNC2=C1 IRFSXVIRXMYULF-UHFFFAOYSA-N 0.000 description 2
- OCVLSHAVSIYKLI-UHFFFAOYSA-N 3h-1,3-thiazole-2-thione Chemical compound SC1=NC=CS1 OCVLSHAVSIYKLI-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
- BTJIUGUIPKRLHP-UHFFFAOYSA-N 4-nitrophenol Chemical compound OC1=CC=C([N+]([O-])=O)C=C1 BTJIUGUIPKRLHP-UHFFFAOYSA-N 0.000 description 2
- 239000005725 8-Hydroxyquinoline Substances 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- 102000002322 Egg Proteins Human genes 0.000 description 2
- 108010000912 Egg Proteins Proteins 0.000 description 2
- JZNWSCPGTDBMEW-UHFFFAOYSA-N Glycerophosphorylethanolamin Natural products NCCOP(O)(=O)OCC(O)CO JZNWSCPGTDBMEW-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 102000004856 Lectins Human genes 0.000 description 2
- 108090001090 Lectins Proteins 0.000 description 2
- 235000021314 Palmitic acid Nutrition 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 238000004220 aggregation Methods 0.000 description 2
- 230000002776 aggregation Effects 0.000 description 2
- HIWPGCMGAMJNRG-VXSGSMIHSA-N alpha-D-Manp-(1->2)-D-Manp Chemical compound O[C@H]1[C@H](O)[C@@H](CO)OC(O)[C@H]1O[C@@H]1[C@@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HIWPGCMGAMJNRG-VXSGSMIHSA-N 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 125000001246 bromo group Chemical group Br* 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- OAIVIYSBZFEOIU-UHFFFAOYSA-N chloroform;propan-2-one Chemical compound CC(C)=O.ClC(Cl)Cl OAIVIYSBZFEOIU-UHFFFAOYSA-N 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 229910001873 dinitrogen Inorganic materials 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 235000013345 egg yolk Nutrition 0.000 description 2
- 238000006911 enzymatic reaction Methods 0.000 description 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- BXZBGYJQEFZICM-UHFFFAOYSA-N icosanoyl chloride Chemical compound CCCCCCCCCCCCCCCCCCCC(Cl)=O BXZBGYJQEFZICM-UHFFFAOYSA-N 0.000 description 2
- 238000010253 intravenous injection Methods 0.000 description 2
- 125000000400 lauroyl group Chemical group O=C([*])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 2
- 239000002523 lectin Substances 0.000 description 2
- 150000002704 mannoses Chemical class 0.000 description 2
- 239000003550 marker Substances 0.000 description 2
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 2
- 229960003540 oxyquinoline Drugs 0.000 description 2
- 125000001312 palmitoyl group Chemical group O=C([*])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])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 150000008104 phosphatidylethanolamines Chemical class 0.000 description 2
- 229920000515 polycarbonate Polymers 0.000 description 2
- 239000004417 polycarbonate Substances 0.000 description 2
- 239000011148 porous material Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- MCJGNVYPOGVAJF-UHFFFAOYSA-N quinolin-8-ol Chemical compound C1=CN=C2C(O)=CC=CC2=C1 MCJGNVYPOGVAJF-UHFFFAOYSA-N 0.000 description 2
- 150000003248 quinolines Chemical group 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 125000003696 stearoyl group Chemical group O=C([*])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])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
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- 239000002798 polar solvent Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
- 229910000105 potassium hydride Inorganic materials 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000003132 pyranosyl group Chemical group 0.000 description 1
- JFTFKVQLCMVNFC-UHFFFAOYSA-N quinolin-8-yl icosanoate Chemical compound C1=CN=C2C(OC(=O)CCCCCCCCCCCCCCCCCCC)=CC=CC2=C1 JFTFKVQLCMVNFC-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 150000004671 saturated fatty acids Chemical class 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 210000004989 spleen cell Anatomy 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 150000003432 sterols Chemical class 0.000 description 1
- 235000003702 sterols Nutrition 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000004149 thio group Chemical group *S* 0.000 description 1
- 229960000984 tocofersolan Drugs 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 150000004670 unsaturated fatty acids Chemical class 0.000 description 1
- 235000021122 unsaturated fatty acids Nutrition 0.000 description 1
- 239000011800 void material Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000002076 α-tocopherol Substances 0.000 description 1
- 235000004835 α-tocopherol Nutrition 0.000 description 1
Landscapes
- Saccharide Compounds (AREA)
- Medicinal Preparation (AREA)
Description
【発明の詳細な説明】 〔産業上の利用分野〕 本発明は、、特に肝クッパー細胞に代表されるマクロ
ファージ系細胞に対し特異的親和性を有する製剤、例え
ばリポソームの構成成分として有用な一般式（Ｉ） （式中R1〜R5は−OH、-OR6、-NHR6（R6はアシル基を示
す。）又は以下の式（ａ）、（ｂ）、（ｃ）、（ｄ）も
しくは（ｅ）示される基である。DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a preparation having specific affinity for macrophage cells represented by liver Kupffer cells, for example, a general formula useful as a component of liposomes. (I) (Wherein R 1 to R 5 are —OH, —OR 6 , —NHR 6 (R 6 represents an acyl group) or the following formulas (a), (b), (c), (d) or ( e) groups shown.
但し、R1〜R5の１つは-OR6又は-NHR6であり、残りの４
つの基のうちの１つが上記式（ａ）〜（ｅ）で示される
基のいずれかであり、その他の３つの基は−OHであ
る。〕で表わされるマンノビオース誘導体に関するもの
である。 However, one of R 1 to R 5 is -OR 6 or -NHR 6 and the remaining 4
One of the groups is any of the groups represented by the above formulas (a) to (e), and the other three groups are -OH. And a mannobiose derivative represented by the formula:
薬学及び医学分野において、臓器あるいは細胞指向型
製剤が注目されており、例えば薬剤をリポソームに含有
させて投与することにより、薬物を所望臓器あるいは細
胞に選択的に運搬させようとする技術に関していくつか
の提案が行われている。In the field of pharmacy and medicine, organ or cell-directed preparations have attracted attention. For example, there are several techniques for selectively transporting a drug to a desired organ or cell by administering a drug contained in liposomes. Proposals have been made.
これらのうち、肝クッパー細胞のようなマクロファー
ジ系細胞への標的化を目的としたリポソームの製剤研究
としては、例えば“Szoka"等の報告バイオケミカル・ア
ンド・バイオフィジカル・リサーチ・コミュニケーショ
ンズ〔Biochem.Biophys.Res.Comm.,110、140-146（198
3）〕がある。この先行技術においては、指向性を生じ
させるためにリポソーム脂質膜に含有させる物質として
ジマンノシルグリセリドの脂肪酸のジエステルが用いら
れているが、この物質はルテウス（Luteus）球菌から単
離された天然物質であり工業的生産が困難である。ま
た、合成物質をリポソーム脂質膜修飾物質として用い
て、同様に肝クッパー細胞に代表されるマクロファージ
系細胞に標的化させる研究としては、Bachhawat等の報
告バイオキミカ・バイオフィジカ・アクタ〔Biochim.Bi
ophys.Acta,632、562-572（1980）〕やShen等の報告バ
イオキミカ・バイオフィジカ・アクタ〔Biochim.Biophy
s.Acta,674、19-29（1981）〕などがある。ここで前者
においては、ｐ−ニトロフェニル−Ｄ−マンノシドを還
元したｐ−アミノフェニル−Ｄ−マンノシドと、天然リ
ン脂質の中では純品として得るには非常に高価なホスフ
ァチジルエタノールアミンとを、グルタールアルデヒド
でカップリングさせた、いわゆる３種類の化合物からな
る縮合物を用いている。また後者においては、コレステ
ロールの３位水酸基にヘキシル基-(CH2)6-を結合し、更
にチオ基−Ｓ−を介してＤ−マンノースの１位と結合さ
せた化合物を用いている。従って、前者、後者ともに化
合物としては複雑な構造を有し、原価や合成方法などの
工業的生産性の面、あるいは生体に投与した後の安全性
の面などから必ずしも有益な方法とは言い難い。Among these, as a formulation study of liposomes for the purpose of targeting to macrophage cells such as liver Kupffer cells, for example, reports on biochemical and biophysical research communications [Biochem. Biophys. .Res.Comm., 110 , 140-146 (198
3)]. In this prior art, a diester of a fatty acid of dimannosylglyceride is used as a substance contained in a liposome lipid membrane to generate directivity, and this substance is a natural substance isolated from Luteus cocci. And industrial production is difficult. In addition, as a study of using a synthetic substance as a liposome lipid membrane modifying substance and targeting macrophage cells also represented by liver Kupffer cells, Bachhawat et al. Reported Biochimica Biophysica Acta (Biochim.
ophys. Acta, 632 , 562-572 (1980)] and Shen et al.'s report on Biochimica Biophysica Acta [Biochim. Biophy
s. Acta, 674 , 19-29 (1981)]. Here, in the former, p-aminophenyl-D-mannoside obtained by reducing p-nitrophenyl-D-mannoside and phosphatidylethanolamine, which is extremely expensive to obtain as a pure product among natural phospholipids, are obtained by glutalysis. A condensate composed of so-called three types of compounds coupled with taraldehyde is used. In the latter, a compound in which a hexyl group — (CH 2 ) 6 — is bonded to the hydroxyl group at the 3-position of cholesterol, and further bonded to the 1-position of D-mannose via a thio group —S— is used. Therefore, both the former and the latter have a complex structure as a compound, and are not necessarily useful methods in terms of industrial productivity such as cost and synthesis method, or safety after administration to a living body. .
従って、上記の如く、肝クッパー細胞に代表されるマ
クロファージ系細胞への標的化を目的としたリポソーム
製剤の研究は行われてきてはいるが、その標的化の効率
や工業的生産性などを考えた場合、必ずしもその目的が
達成されたとは言い難い現状にある。Therefore, as described above, although liposome preparations for the purpose of targeting to macrophage cells typified by liver Kupffer cells have been studied, the efficiency of targeting and industrial productivity should be considered. In such a case, it is difficult to say that the purpose has been achieved.
本発明は、より効率的なマクロファージ系細胞への特
異的指向性をリポソームに付与でき、かつ工業的に再現
性よく大量生産可能な新規物質を提供することを目的と
する。An object of the present invention is to provide a novel substance that can impart more efficient specificity to macrophage cells to liposomes and that can be industrially reproducibly mass-produced.
本発明者等は、満足し得る特異的臓器指向性を有する
リポソームの配合成分を開発すべく研究を行った結果、
上記一般式〔Ｉ〕で表わされるマンノビオース誘導体を
リポソームの膜中に含有させると上記問題点が有効に解
決できるとの知見に基づいてなされたものである。The present inventors have conducted research to develop liposome components having satisfactory specific organ tropism.
The present invention has been made based on the finding that the above problem can be effectively solved when the mannobiose derivative represented by the above general formula [I] is contained in a liposome membrane.
本発明は上記一般式〔Ｉ〕で表わされるマンノビオー
ス誘導体を提供する。The present invention provides a mannobiose derivative represented by the above general formula [I].
式〔Ｉ〕における式（ａ）〜（ｅ）で示される基のう
ち、式（ａ）で示される基が好ましく、中でもR3、R4又
はR6が該基である化合物が好ましい。尚、上記式中は
α又はβ結合を示す。Among the groups represented by the formulas (a) to (e) in the formula [I], a group represented by the formula (a) is preferable, and a compound in which R 3 , R 4 or R 6 is the group is particularly preferable. In the above formula, α or β bond is shown.
上記式中、アシル基としては、炭素数12〜30のものを
好適に使用することができ、その例としてはドデカノイ
ル、トリデカノイル、テトラデカノイル、ペンタデカノ
イル、ヘキサデカノイル、ヘプタデカノイル、オクタデ
カノイル、ノナデカノイル、エイコサノイル、ヘニコサ
ノイル、ドコサノイル、トリコサノイル、テトラコサノ
イル、ヘキサコサノイル、トリアコンタノイル、９−ヘ
キサデセノイル、９−オクタデセノイル、9,12−オクタ
デカジエノイル、9,12,15−オクタデカトリエノイル、1
1−エイコセノイル、11,14−エイコサジエノイル、11,1
4,17−エイコサトリエノイル、4,8,12,16−エイコサテ
トラエノイル、13−ドコセノイル、4,8,12,15,19−ドコ
サペンタエノイル、15−テトラコセノイル、２−デカニ
ルヘキサデカノイル、２−テトラデシル−ヘキサデカノ
イル、２−テトラデシルヘキサデセノイル、２−テトラ
デセニルヘキサデカノイルなどの直鎖もしくは分枝状の
飽和もしくは不飽和脂肪酸由来のアシル基があげられ
る。このうち、エイコサノイルが好ましい。In the above formula, as the acyl group, those having 12 to 30 carbon atoms can be suitably used, and examples thereof include dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, and octadecanoyl. , Nonadecanoyl, eicosanoyl, henicosanoyl, docosanoyl, tricosanoyl, tetracosanoyl, hexacosanoyl, triacontanoyl, 9-hexadecenoyl, 9-octadecenoyl, 9,12-octadecadienoyl, 9,12,15-octadecatrienoyl, 1
1-eicosenoyl, 11,14-eicosadienoyl, 11,1
4,17-eicosatrienoyl, 4,8,12,16-eicosatetraenoyl, 13-docosenoyl, 4,8,12,15,19-docosapentaenoyl, 15-tetracosenoyl, 2-decanylhexadeca Examples thereof include acyl groups derived from a linear or branched saturated or unsaturated fatty acid such as noyl, 2-tetradecyl-hexadecanoyl, 2-tetradecylhexadecenoyl, and 2-tetradecenylhexadecanoyl. Of these, eicosanoyl is preferred.
又、式〔Ｉ〕において-NHR6及び-OR6が結合する位置
については特に限定されないが、一般にはR1が-NHR6又
は-OR6であることが望ましい。Further, the position where -NHR 6 and -OR 6 bind in the formula [I] is not particularly limited, but it is generally desirable that R 1 is -NHR 6 or -OR 6 .
次に式〔Ｉ〕で表わされるマンノビオース誘導体（以
下、本発明化合物という。）の製造法について説明す
る。Next, a method for producing the mannobiose derivative represented by the formula [I] (hereinafter, referred to as the compound of the present invention) will be described.
本発明化合物においてはR1〜R5の１つが-OR6を示す化
合物とR1〜R5の１つが-NHR6を示す化合物とで製造法が
異なる。以下、それぞれの製造法について詳述する。In the present invention compounds one of manufacturing methods with a compound showing a -NHR 6 compounds with R 1 to R 5 one of R 1 to R 5 showing a -OR 6 is different. Hereinafter, each manufacturing method will be described in detail.
１） R1〜R5の１つが-OR6を示す場合 本発明化合物の原料化合物について、酵母由来のα−
1,6−マンノビオース、コンニャク由来のβ−1,4−マン
ノビオース、茸の一種から得られるα−1,3−マンノビ
オース等のマンノースが２つ結合したマンノピラノシル
マンノピラノースなどのマンノビオースをあげることが
できる。これらのマンノビオースにR6COX（式中Ｘはハ
ロゲン原子を意味する）又は(R6CO)2Oを水系又は非水系
溶媒中で反応させることにより目的物を製造することが
できる。1) When one of R 1 to R 5 represents —OR 6 For the starting compound of the compound of the present invention, yeast-derived α-
Mannobiose such as mannopyranosyl mannopyranose to which two mannoses such as 1,6-mannobiose, β-1,4-mannobiose derived from konjac, and α-1,3-mannobiose obtained from one type of mushroom are combined. be able to. The desired product can be produced by reacting these mannobioses with R 6 COX (where X represents a halogen atom) or (R 6 CO) 2 O in an aqueous or non-aqueous solvent.
上記反応を水系溶媒下で行う場合には、マンノビオー
スの約20〜90％水溶液のpHを水酸化ナトリウム、水酸化
カリウム等のアルカリで約9.0に保ちながら、これにR6C
OX又は(R6CO)2Oを反応させればよい。R6COX又は(R6CO)2
Oはマンノビオースに対し通常0.1〜１倍モル使用され
る。反応は通常０〜60℃好ましくは40〜50℃で約１〜５
時間行なわれる。When the above reaction is carried out in an aqueous solvent, while maintaining the pH of an aqueous solution of about 20 to 90% of mannobiose at about 9.0 with an alkali such as sodium hydroxide or potassium hydroxide, R 6 C
OX or (R 6 CO) 2 O may be reacted. R 6 COX or (R 6 CO) 2
O is usually used in an amount of 0.1 to 1 mol per 1 mol of mannobiose. The reaction is usually carried out at 0 to 60 ° C, preferably at 40 to 50 ° C for about 1 to 5
Done for hours.
又、上記反応を非水系溶媒下で行う場合には、アセト
ン、ジオキサン、クロルベンゼン、トルエン、酢酸エチ
ル、塩化メチン等の溶媒とヘキサメチルホスフォリック
トリアミド（以下、HMPAと称す）、ジメチルスルホキシ
ド等の溶媒との混合溶媒中塩基の存在下、マンノビオー
スにR6COX又は(R6CO)2Oを反応させればよい。上記混合
溶媒の組合せについてはトルエン及びHMPAの組合せを好
ましいものとしてあげることができる。塩基としては、
ピリジン、４−ジメチルアミノピリジン、トリエチルア
ミン等の有機塩基、水酸化ナトリウム、水酸化カリウ
ム、炭酸ナトリウム、炭酸カリウム、炭酸水素ナトリウ
ム等の無機塩基、好ましくはピリジンをあげることがで
きる。R6COX又は(R6CO)2Oはマンノビオースに対して、
通常0.2〜4.0倍モル、好ましくは1.0〜2.0倍モル使用さ
れる。又塩基は通常R6COX又は(R6CO)2Oに対し等モル以
上使用される。When the above reaction is carried out in a non-aqueous solvent, a solvent such as acetone, dioxane, chlorobenzene, toluene, ethyl acetate, methine chloride and the like, hexamethylphosphoric triamide (hereinafter referred to as HMPA), dimethyl sulfoxide Mannobiose may be reacted with R 6 COX or (R 6 CO) 2 O in the presence of a base in a mixed solvent with such a solvent. Regarding the combination of the above-mentioned mixed solvents, a combination of toluene and HMPA is preferable. As the base,
Organic bases such as pyridine, 4-dimethylaminopyridine, triethylamine and the like; inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and sodium hydrogencarbonate, preferably pyridine can be mentioned. R 6 COX or (R 6 CO) 2 O for mannobiose,
Usually, it is used in a molar amount of 0.2 to 4.0 times, preferably 1.0 to 2.0 times. The base is usually used in an equimolar amount or more based on R 6 COX or (R 6 CO) 2 O.
反応は通常60〜100℃、好ましくは70〜90℃で２〜６
時間行なわれる。The reaction is usually carried out at 60 to 100 ° C, preferably 70 to 90 ° C for 2 to 6 hours.
Done for hours.
得られたマンノビオースのモノ脂肪酸エステルにおい
て、脂肪酸エステルの置換位置が異なるものが複数存在
する場合には、これを分離することなくそのまま用いて
も良いし、更にカラムクロマトグラフィーなどの分離手
段によって単一成分の脂肪酸モノエステルに分離するこ
ともできる。In the case of the obtained mono-fatty acid ester of mannobiose, when there are a plurality of mono-fatty acid esters having different substitution positions of the fatty acid ester, they may be used as they are without being separated, or may be used alone by a separation means such as column chromatography. It can also be separated into fatty acid monoesters as components.
またマンノビオースの還元性末端側マンノースの１位
水酸基に選択的にアシル基をエステル結合させるには、
Roulleau等（テトラヘドロン・レターズ、24、719-722
（1983）〕の方法を使用すればよい。即ち、塩基の存在
下で、マンノビオース（但しα−Ｄ−マンノピラノシル
−α−Ｄ−マンノピラノサイド、α−Ｄ−マンノピラノ
シル−β−Ｄ−マンノピラノサイドを除く）に、所望の
R6COOHとチアゾリジン−チオンとの反応によるアミド体
又は該R6COOHとｐ−ニトロフェノール、メルカプトベン
ゾチアゾール、８−ヒドロキシキノリン等との反応によ
るエステル体等の反応性アシル化剤、例えばＮ−エイコ
サノイル−チアゾリジンチオン、エイコサン酸−ｐ−ニ
トロフェニル、エイコサン酸−メルカプトベンゾチアゾ
イル、８−エイコサノイル−オキシキノリン等を反応さ
せる事により還元性末端側のマンノースの１位水酸基に
アシル基が結合したマンノビオースのモノ脂肪酸エステ
ルを製造することができる。Further, in order to selectively ester bond an acyl group to the hydroxyl group at the 1-position of the reducing terminal mannose of mannobiose,
Roulleau et al. (Tetrahedron Letters, 24 , 719-722
(1983)]. In other words, in the presence of a base, mannobiose (excluding α-D-mannopyranosyl-α-D-mannopyranoside, α-D-mannopyranosyl-β-D-mannopyranoside) is converted into a desired compound.
Reactive acylating agents such as amides by the reaction of R 6 COOH with thiazolidine-thione or esters by the reaction of R 6 COOH with p-nitrophenol, mercaptobenzothiazole, 8-hydroxyquinoline, etc. Mannobiose in which an acyl group is bonded to the 1-position hydroxyl group of mannose on the reducing terminal side by reacting eicosanoyl-thiazolidinethione, p-nitrophenyl eicosanoate, mercaptobenzothiazoyl eicosanoate, 8-eicosanoyl-oxyquinoline, or the like. Can be produced.
本反応に用いられる塩基としては、水素化カリウム、
水素化ナトリウム好ましくは、水素化ナトリウムがあげ
られ、その量としては例えば使用するアシル化剤の0.8
〜1.2倍モル量が好ましく例示できる。反応溶媒として
は、通常、ピリジン、メチルピロリドン、ジメチルスル
ホキシド、ヘキサメチルフォスフォリックトリアミド等
が好ましく例示できる。その使用量に特別な制約はない
が、例えばマンノビオースに対して、約５〜約50倍量の
如き使用量を例示することができる。又、使用するアシ
ル化剤の量も適宜選択できるが、例えばマンノビオース
に対して0.1〜1.0倍モル、好ましくは0.2〜0.5倍モルの
使用量を例示することができる。反応は通常アシル化剤
がR6COOHとチアゾリジンチオンの反応によるアミド体、
メルカプトベンゾチアゾール、又は８−ヒドロキシキノ
リン等の反応によるエステル体の場合、例えば10°〜60
℃、好ましくは20〜40℃の如き反応温度、又アシル化剤
がR6COOHとｐ−ニトロフェノールのエステル体の場合、
例えば40°〜95℃、好ましくは60°〜80℃の如き反応温
度で約１〜約５時間行なわれる。As the base used in this reaction, potassium hydride,
Sodium hydride, preferably, sodium hydride, the amount of which is, for example, 0.8% of the acylating agent used
A preferred molar amount is 1.2 to 1.2 times. Preferred examples of the reaction solvent include pyridine, methylpyrrolidone, dimethylsulfoxide, and hexamethylphosphoric triamide. There is no particular limitation on the amount of use, but for example, an amount of use such as about 5 to about 50 times the amount of mannobiose can be exemplified. In addition, the amount of the acylating agent to be used can be appropriately selected, and for example, the used amount is 0.1 to 1.0 times mol, preferably 0.2 to 0.5 times mol based on mannobiose. In the reaction, the acylating agent is usually an amide form by the reaction of R 6 COOH and thiazolidinethione,
In the case of an ester by a reaction such as mercaptobenzothiazole or 8-hydroxyquinoline, for example, 10 ° to 60 °
C., preferably a reaction temperature such as 20 to 40 ° C., and when the acylating agent is an ester of R 6 COOH and p-nitrophenol,
The reaction is performed at a reaction temperature of, for example, 40 ° to 95 ° C., preferably 60 ° to 80 ° C. for about 1 to about 5 hours.
２） R1〜R5の１つが-NHR6の場合 即ち、上記のマンノビオースを原料とし、これにベン
ジリデン基、アセチル基等の保護基を適宜組合せてマン
ノビオースの水酸基を保護し、ついで公知の方法に従い
マンノビオースの目的水酸基位置にアミノ基を導入す
る。得られた化合物を適当な有機溶媒中、活性エステル
法即ち縮合試薬の存在下R6COOHと反応させることにより
上記アミノ基にアシル基を結合することができる。溶媒
としては、テトラヒドロフラン、ジメチルホルムアミ
ド、ジクロロメタン、酢酸エチル、メタノール、エタノ
ール、ベンゼン、これらの適当な混合溶媒などをあげる
ことができる。その使用量には特別な制約はないが、例
えば原料化合物に対して約10〜約100重量体の如き使用
量を例示することができる。縮合試薬の例としては、た
とえば、N,N′−ジシクロヘキシルカルボジイミド（DC
C）、Ｎ−エチル−５−フェニルイソオキサゾリウム−
３′−スルホナート、ジフェニルケテン−ｐ−トリルイ
ミン、１−エトキシカルボニル−２−エトキシ−1,2−
ジヒドロキノリン（EEDQ）、Ｎ−イソブチルオキシカル
ボニル−２−イソ−ブチルオキシ−1,2−ジヒドロキノ
リン（IIDQ）、ジエチルフォスフォロシアニイデイト
（DEPC）などを例示することができる。その使用量は適
宜に選択変更できるが、例えば、原料化合物１モルに対
して約１〜約３モルの如き使用量を例示することができ
る。またR6COOHの原料化合物に対する使用量としては、
原料化合物１モルに対して約１〜３モル程度の使用量を
例示することができる。反応は通常−10〜50℃、好まし
くは０〜30℃で約２〜72時間行なわれる。2) When one of R 1 to R 5 is —NHR 6 That is, the above-mentioned mannobiose is used as a raw material, and a protecting group such as a benzylidene group or an acetyl group is appropriately combined with the mannobiose to protect the hydroxyl group of the mannobiose. In accordance with the above, an amino group is introduced into a target hydroxyl group position of mannobiose. An acyl group can be bound to the amino group by reacting the obtained compound with R 6 COOH in a suitable organic solvent in the presence of a condensing reagent by the active ester method. Examples of the solvent include tetrahydrofuran, dimethylformamide, dichloromethane, ethyl acetate, methanol, ethanol, benzene, and a suitable mixed solvent thereof. There is no particular limitation on the amount used, and examples thereof include an amount used such as about 10 to about 100 parts by weight based on the starting compound. Examples of the condensing reagent include, for example, N, N'-dicyclohexylcarbodiimide (DC
C), N-ethyl-5-phenylisoxazolium-
3'-sulfonate, diphenylketene-p-tolylimine, 1-ethoxycarbonyl-2-ethoxy-1,2-
Examples thereof include dihydroquinoline (EEDQ), N-isobutyloxycarbonyl-2-iso-butyloxy-1,2-dihydroquinoline (IIDQ), and diethylphosphorocyanide (DEPC). The amount of use can be appropriately selected and changed, and for example, the amount of use can be exemplified from about 1 to about 3 mol per 1 mol of the starting compound. The amount of R 6 COOH used for the starting compound is
An amount of about 1 to 3 mol can be exemplified with respect to 1 mol of the starting compound. The reaction is carried out usually at -10 to 50C, preferably at 0 to 30C for about 2 to 72 hours.
得られた化合物をメタノール、エタノール等の極性溶
媒、メタノールとクロロホルム等の混合溶媒中ナトリウ
ムメチラート等のナトリウムアルコキシド、アンモニ
ア、トリエチルアミン等のアルカリで処理することによ
り目的とする化合物を製造することができる。反応は通
常約０〜40℃で約１〜10時間行なわれる。The target compound can be produced by treating the obtained compound with a polar solvent such as methanol and ethanol, a sodium alkoxide such as sodium methylate in a mixed solvent such as methanol and chloroform, and an alkali such as ammonia and triethylamine. . The reaction is usually performed at about 0 to 40 ° C for about 1 to 10 hours.
反応終了後、必要に応じて、溶媒除去、結晶化、カラ
ムクロマトグラフィー等のそれ自体公知の分離精製手段
を利用して目的化合物を分離、精製することができる。After completion of the reaction, the target compound can be separated and purified, if necessary, using a known separation and purification means such as solvent removal, crystallization, and column chromatography.
また、マンノビオースの還元性末端側マンノースの１
位水酸基がアシルアミノ基に置換した化合物を製造する
には以下のようにすればよい。即ち、マンノビオースの
水酸基をアセチル基で保護したのち、還元性末端側マン
ノースの１位アセチルオキシル基をブロム原子に置換さ
せる。次いでアジド塩と反応させて該ブロム基をアジド
基に置換し、更に還元することにより還元性末端側マン
ノースの１位水酸基がアミノ基に置換したマンノビオー
スモノアミンを得ることができる。該アミノ基に上記活
性エステル法を用いてアシル基を結合させ、次いで目的
位置以外の水酸基をナトリウムメトキシド等のアルカリ
を用いて脱保護することにより目的とするマンノビオー
スの還元性末端側マンノースの１位水酸基がアシルアミ
ノ基に置換したマンノビオースのモノ脂肪酸アミドを製
造することができる。In addition, one of the reducing end mannoses of mannobiose
The production of a compound in which a hydroxyl group is substituted by an acylamino group may be carried out as follows. That is, after protecting the hydroxyl group of mannobiose with an acetyl group, the acetyloxyl group at the 1-position of the reducing terminal mannose is replaced with a bromo atom. Subsequently, the bromo group is substituted with an azide group by reacting with an azide salt, and further reduced to obtain mannobiose monoamine in which the hydroxyl group at the 1-position of reducing mannose is substituted with an amino group. An acyl group is bonded to the amino group using the above-mentioned active ester method, and then a hydroxyl group at a position other than the target position is deprotected using an alkali such as sodium methoxide to thereby reduce the number of the reducing end mannose of mannobiose. Mannobiose monofatty acid amides in which the hydroxyl group is substituted with an acylamino group can be produced.
更に、マンノビオースの還元性末端側もしくは非還元
性末端側マンノースの２位水酸基がアシルアミノ基に置
換した化合物は以下のようにすればよい。即ち、マンノ
サミンとマンノースを公知の縮合反応を用いて縮合さ
せ、次いで得られたマンノピラノシル−マンノサミン、
又は２−デオキシ−２−アミノ−マンノピラノシル−マ
ンノピラノースを上記活性エステル法を用いてR6COOHと
反応させることにより、マンノビオースの還元性末端側
もしくは非還元性末端側マンノースの２位水酸基がアシ
ルアミノ基に置換した化合物を製造することができる。Further, the compound in which the hydroxyl group at the 2-position of the reducing terminal side or non-reducing terminal side mannose of mannobiose is substituted with an acylamino group may be as follows. That is, mannosamine and mannose are condensed using a known condensation reaction, and then the obtained mannopyranosyl-mannosamine,
Alternatively, by reacting 2-deoxy-2-amino-mannopyranosyl-mannopyranose with R 6 COOH using the above-mentioned active ester method, the 2-position hydroxyl group of mannose at the reducing terminal side or non-reducing terminal side of mannobiose is acylamino. Compounds substituted with groups can be prepared.
次に本発明化合物を膜中に含有するリポソームの製造
法を説明する。Next, a method for producing a liposome containing the compound of the present invention in a membrane will be described.
ホスファチジルコリン、スフィンゴミエリン、ホスフ
ァチジルエタノールアミン等のリン脂質、糖脂質並びに
ジアルキル型合成界面活性剤等の膜成分物質を用いて公
知の方法〔アニュアル、レビュー、オブ、バイオフィジ
ックス、アンド、バイオエンジニアリング、９、467-50
8（1980）〕に従いリポソームの水分散液を調製する。
かかるリポソームは膜安定化剤としてコレステロール、
コレスタノール等のステロール類、ジアルキルホスフェ
ート、ジアシルホスファチジン酸、ステアリルアミン等
の荷電物質及びα−トコフェロール等の酸化防止剤等を
含んでいても良い。調製したリポソームの水分散液に式
〔Ｉ〕の化合物の水溶液を加え一定時間放置、好ましく
は膜の相転移温度以上もしくは40℃以上に加温し次いで
放冷することにより目的とするリポソームを製造するこ
とができる。又、式〔Ｉ〕の化合物をあらかじめ混合
し、これを公知のリポソームの製造法に従って処理する
ことによっても目的のリポソームを製造することができ
る。Phosphatidylcholine, sphingomyelin, phosphatidylethanolamine and other phospholipids, glycolipids and known methods using membrane components such as dialkyl-type synthetic surfactants [annual, review, ob, biophysics, and, bioengineering, 9 , 467-50
8 (1980)] to prepare an aqueous dispersion of liposomes.
Such liposomes are cholesterol as membrane stabilizers,
It may contain sterols such as cholestanol, charged substances such as dialkyl phosphate, diacylphosphatidic acid, and stearylamine, and antioxidants such as α-tocopherol. An aqueous solution of the compound of formula [I] is added to the prepared aqueous dispersion of liposomes, and the mixture is allowed to stand for a certain period of time, preferably heated to a temperature equal to or higher than the phase transition temperature of the membrane or 40 ° C., and then allowed to cool to produce the desired liposome. can do. Alternatively, the desired liposome can be produced by previously mixing the compound of the formula [I] and treating the mixture according to a known method for producing liposomes.
上記のようにして製造されるリポソームが前記マクロ
ファージ系細胞への指向性を有するには通常その調整工
程において本発明の化合物の全脂質膜成分に対する割合
を約1/40モル比以上にすることが望ましい。In order for the liposome produced as described above to have directivity to the macrophage cell, the ratio of the compound of the present invention to the total lipid membrane component is usually about 1/40 or more in the adjusting step. desirable.
本発明化合物を膜中に含有するリポソームは肝クッパ
ー細胞、マクロファージ、単球、脾細胞、リンパ球、肺
胞マクロファージ等のマクロファージ系細胞特に肝クッ
パー細胞に対して特異的指向性を有する。従って本発明
化合物はリポソームの構成成分として重要な化合物であ
る。Liposomes containing the compound of the present invention in the membrane have specific tropism for macrophage cells such as liver Kupffer cells, macrophages, monocytes, spleen cells, lymphocytes, and alveolar macrophages, particularly liver Kupffer cells. Therefore, the compound of the present invention is an important compound as a component of the liposome.
又、従来の技術において、前記マクロファージ系細胞
への指向性を有する製剤はリポソームのみであったが、
本発明化合物はリポソームのみならずミセル、マイクロ
エマルジョンにも前記指向性を付与することができる。Further, in the prior art, the preparation having a tropism for the macrophage cells was only liposomes,
The compound of the present invention can impart the directivity not only to liposomes but also to micelles and microemulsions.
次に実施例により本発明を説明するが、本発明はこれ
らに限定されるものではない。Next, the present invention will be described with reference to examples, but the present invention is not limited to these examples.
実施例１ ２−Ｏ−α−Ｄ−マンノピラノシル−Ｄ−マンノピラ
ノース400mgを水1mlに溶解し、これに10％苛性ソーダ水
溶液を加えpH＝9.0に調整した。次に10％苛性ソーダ水
溶液で反応pHを9.0に保ちながら、別にアラキジン酸と
塩化チオニルより調製したアラキジン酸クロライド277m
gを50℃で徐々に加え、同温で１時間撹拌した。Example 1 400 mg of 2-O-α-D-mannopyranosyl-D-mannopyranose was dissolved in 1 ml of water, and a 10% aqueous sodium hydroxide solution was added thereto to adjust the pH to 9.0. Next, while maintaining the reaction pH at 9.0 with a 10% aqueous solution of sodium hydroxide, 277 m of arachidic acid chloride separately prepared from arachidic acid and thionyl chloride.
g was gradually added at 50 ° C., and the mixture was stirred at the same temperature for 1 hour.
反応終了後、生成した沈殿を濾取し、メタノールより
再結晶した。得られた結晶化物をシリカゲルクロマトグ
ラフィー〔溶媒系；クロロホルム／メタノール＝30/1〜
5/1〕で２回精製して２−Ｏ−α−Ｄ−マンノピラノシ
ル−Ｄ−マンノピラノースのモノエイコ酸エステルの複
数成分混合物を得た。After completion of the reaction, the resulting precipitate was collected by filtration and recrystallized from methanol. The obtained crystallized product is subjected to silica gel chromatography [solvent system: chloroform / methanol = 30 / 1-
5/1] twice to obtain a mixture of plural components of monoeicoic acid ester of 2-O-α-D-mannopyranosyl-D-mannopyranose.
収 量;50mg TLC;Rf値0.5以下（複数成分） （CHCl3/MeOH＝2/1） 元素分析値；C32H60O12（分子量636.49）として 計算値（％）,C 60.38, H 9.43, O 30.15, 実験値（％）,C 60.75, H10.05, O 29.20 IR（KBr）;2845、2910、1465（CH）、1730（−CO-O−）1 H-NMR（90MHz,CDCl3/TMS）；δ 0.7〜1.40 （39H,Eicosanoyl）、2.8〜4.0（21H,Mannobiose ring
protons） 実施例２ ４−Ｏ−β−Ｄ−マンノピラノシル−Ｄ−マンノピラ
ノース400mgをヘキサメチルフォスフォリックトリアミ
ド（HMPA）8mlに溶解し、これにピリジン8mlを加えた。
別にアラキジン酸と塩化チオニルより調製したアラキジ
ン酸クロライド730mgをトルエン1.5mlに溶解し上記反応
液に30℃以下で加えた後、80〜85℃で約４時間撹拌下反
応させた。Yield: 50 mg TLC; Rf value 0.5 or less (multiple components) (CHCl 3 / MeOH = 2/1) Elemental analysis value: Calculated value (%) as C 32 H 60 O 12 (molecular weight 636.49), C 60.38, H 9.43 , O 30.15, experimental value (%), C 60.75, H10.05, O 29.20 IR (KBr); 2845, 2910, 1465 (CH), 1730 (-CO-O-) 1 H-NMR (90 MHz, CDCl 3 / TMS); δ 0.7-1.40 (39H, Eicosanoyl), 2.8-4.0 (21H, Mannobiose ring
Example 2 400 mg of 4-O-β-D-mannopyranosyl-D-mannopyranose was dissolved in 8 ml of hexamethylphosphoric triamide (HMPA), and 8 ml of pyridine was added thereto.
Separately, 730 mg of arachidic acid chloride prepared from arachidic acid and thionyl chloride was dissolved in 1.5 ml of toluene, added to the above reaction solution at 30 ° C. or lower, and then reacted at 80 to 85 ° C. with stirring for about 4 hours.
反応終了後、反応液を減圧濃縮した後、シラップをシ
リカゲルクロマトグラフィー〔溶媒系；クロロホルム／
アセトン＝30/1〜5/1〕で２回精製し、４−Ｏ−β−Ｄ
−マンノピラノシル−Ｄ−マンノピラノースのモノエイ
コサン酸エステルの４成分混合物を得た。After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the syrup was subjected to silica gel chromatography [solvent system: chloroform /
Acetone = 30/1 to 5/1] and purified twice to give 4-O-β-D
A quaternary mixture of monoeicosanoates of -mannopyranosyl-D-mannopyranose was obtained.
収 量;447mg TLC;Rf値0.5以下（４成分混合物） （CHCl3/MeOH＝2/1） IR（KBr）;2845、2910、1465（CH）、1730（−CO-O−） 元素分析値；C32H60O12（分子量636.49）として 計算値（％） C 60.38, H 9.43, O 30.15, 実験値（％） C 60.50, H 9.94, O 29.561 H-NMR（90MHz,CDCl3/TMS）；δ 0.7〜1.40 （39H,Eicosanoyl）、2.8〜4.0（21H,Mannobiose ring
protons） 実施例３ 実施例２で得た４成分混合物300mgをシリカゲルクロ
マトグラフィー〔溶媒系；クロロホルム／メタノール10
/1〜7/1〕で分画し、クロロホルム／メタノール（1/
1）、エーテルで粉末化してC6′位の水酸基にエイコサ
ン酸がモノエステル結合した４−Ｏ−（６−Ｏ−エイコ
サノイル−β−Ｄ−マンノピラノシル）−Ｄ−マンノピ
ラノースを得た。Yield: 447 mg TLC; Rf value 0.5 or less (4-component mixture) (CHCl 3 / MeOH = 2/1) IR (KBr); 2845, 2910, 1465 (CH), 1730 (-CO-O-) Elemental analysis Calculated value (%) as C 32 H 60 O 12 (molecular weight 636.49) C 60.38, H 9.43, O 30.15, experimental value (%) C 60.50, H 9.94, O 29.56 1 H-NMR (90 MHz, CDCl 3 / TMS ); Δ 0.7-1.40 (39H, Eicosanoyl), 2.8-4.0 (21H, Mannobiose ring
Example 3 300 mg of the four-component mixture obtained in Example 2 was subjected to silica gel chromatography [solvent system: chloroform / methanol 10
/ 1 to 7/1], and chloroform / methanol (1/1 to 7/1)
1) Powdered with ether to obtain 4-O- (6-O-eicosanoyl-β-D-mannopyranosyl) -D-mannopyranose in which eicosanoic acid was monoester-bonded to the hydroxyl group at the C 6 '-position.
収 量;126mg 分解点;152〜158℃ TLC;Rf＝0.50（CHCl3/MeOH＝2/1） IR（KBr）;2845、2910、1465（CH）、1730（−CO-O−） 元素分析値；C32H60O12（分子量636.49）として 計算値（％） C 60.38, H 9.43, O 30.15, 実験値（％） C 60.28, H 9.82, O 29.901 H-NMR（90MHz,DMSO-d6/TMS）δ 0.7〜1.40（39H,Eicos
anoyl）、2.8〜4.0（21H,Mannobiose ring protons）13 C-NMR（90MHz,DMSO-d6/TMS）δ 173.0、100.9、100.
8、938、77.9、74.2、73.2、71.0、70.6、70.4、69.0、
66.9、63.7、60.6 実施例４ 実施例３の４−Ｏ−（６−O-eicosanoyl-β−D-manno
pyranosyl）−D-mannopyranoseを溶出したカラムを、更
にクロロホルム／メタノール5/1〜1/1の溶媒で溶出する
ことによって、C6、C3′又はC2位の水酸基にエイコサン
酸がモノエステル結合した６−Ｏ−エイコサノイル−４
−Ｏ−β−１−マンノピラノシル−Ｄ−マンノピラノー
ス、４−Ｏ−（３−Ｏ−エイコサノイル−β−Ｄ−マン
ノピラノシル）−Ｄ−マンノピラノース及び２−Ｏ−エ
イコサノイル−４−Ｏ−β−Ｄ−マンノピラノシル−Ｄ
−マンノピラノースの３成分混合物を得た。Yield: 126 mg Decomposition point: 152-158 ° C TLC; Rf = 0.50 (CHCl 3 / MeOH = 2/1) IR (KBr); 2845, 2910, 1465 (CH), 1730 (-CO-O-) Elemental analysis Value; calculated as C 32 H 60 O 12 (molecular weight 636.49) (%) C 60.38, H 9.43, O 30.15, experimental value (%) C 60.28, H 9.82, O 29.90 1 H-NMR (90 MHz, DMSO-d 6 / TMS) δ 0.7-1.40 (39H, Eicos
anoyl), 2.8-4.0 (21H, Mannobiose ring protons) 13 C-NMR (90 MHz, DMSO-d 6 / TMS) δ 173.0, 100.9, 100.
8, 938, 77.9, 74.2, 73.2, 71.0, 70.6, 70.4, 69.0,
66.9, 63.7, 60.6 Example 4 4-O- (6-O-eicosanoyl-β-D-manno of Example 3)
The column eluted with pyranosyl) -D-mannopyranose was further eluted with a solvent of chloroform / methanol 5/1 to 1/1, whereby eicosanoic acid was bonded to the hydroxyl group at C 6 , C 3 ′ or C 2 at the monoester bond. 6-O-eicosanoyl-4
-O-β-1-mannopyranosyl-D-mannopyranose, 4-O- (3-O-eicosanoyl-β-D-mannopyranosyl) -D-mannopyranose and 2-O-eicosanoyl-4-O-β -D-mannopyranosyl-D
-A ternary mixture of mannopyranose was obtained.
収 量;108mg 分解点;148〜152℃ TLC;Rf＝0.12（３成分）（CHCl3/MeOH＝2/1） IR（KBr）;2845、2910、1465（CH）、1730（−CO-O−） 元素分析値；C32H60O12（分子量636.49）として 計算値（％） C 60.38, H 9.43, O 30.15, 実験値（％） C 60.67, H 9.73, O 29.601 H-NMR（90MHz,DMSO-d6/TMS）δ 0.7〜1.4（39H,Eicosa
noyl）、2.8〜4.0（21H,Mannobiose ring protons）13 C-NMR（90MHz,DMSO-d6/TMS）δ 173.0、172.9、172.
8、103.1、102.6、96.4、81.4、79.1、77.4、74.3、73.
6、73.3、71.1、70.7、70.5、70.3、69.1、67.5、67.
0、65.1、63.9、63.7、61.1、61.0 実施例５ ４−Ｏ−β−Ｄ−マンノピラノシル−Ｄ−マンノピラ
ノース300mgをHMPA 6mlに溶解し、これにピリジン6mlを
加えた。別にミリスチン酸と塩化チオニルより調製した
ミリスチン酸クロライド365mgをトルエン1mlに溶解し、
上記反応液に30℃以下で加えた後80〜85℃で４時間、撹
拌下反応させた。反応終了後、反応液を減圧濃縮し、得
られたシラップをシリカゲルクロマトグラフィー〔溶媒
系；クロロホルム／メタノール＝30/1〜5/1〕で２回精
製し、４−Ｏ−β−Ｄ−マンノピラノシル−Ｄ−マンノ
ピラノースのモノミリスチン酸エステルの複数成分混合
物を得た。Yield; 108 mg Decomposition point; 148-152 ° C TLC; Rf = 0.12 (3 components) (CHCl 3 / MeOH = 2/1) IR (KBr); 2845, 2910, 1465 (CH), 1730 (-CO-O −) Elemental analysis; calculated as C 32 H 60 O 12 (molecular weight 636.49) (%) C 60.38, H 9.43, O 30.15, experimental (%) C 60.67, H 9.73, O 29.60 1 H-NMR (90 MHz , DMSO-d 6 / TMS) δ 0.7 ~ 1.4 (39H, Eicosa
noyl), 2.8-4.0 (21H, Mannobiose ring protons) 13 C-NMR (90 MHz, DMSO-d 6 / TMS) δ 173.0, 172.9, 172.
8, 103.1, 102.6, 96.4, 81.4, 79.1, 77.4, 74.3, 73.
6, 73.3, 71.1, 70.7, 70.5, 70.3, 69.1, 67.5, 67.
0, 65.1, 63.9, 63.7, 61.1, 61.0 Example 5 300 mg of 4-O-β-D-mannopyranosyl-D-mannopyranose was dissolved in 6 ml of HMPA, and 6 ml of pyridine was added thereto. Separately, dissolve 365 mg of myristic acid chloride prepared from myristic acid and thionyl chloride in 1 ml of toluene,
The reaction solution was added at a temperature of 30 ° C. or lower and reacted at 80 to 85 ° C. for 4 hours with stirring. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the resulting syrup was purified twice by silica gel chromatography [solvent system: chloroform / methanol = 30/1 to 5/1] to obtain 4-O-β-D-mannopyranosyl. A multi-component mixture of monomyristate of -D-mannopyranose was obtained.
収 量;237mg TLC;Rf値0.48以下（複数成分） （CHCl3/MeOH＝2/1） IR（KBr）;2845、2910、1465（CH）、1730（−CO-O−） 元素分析値；C26H48O12（分子量552.43）として 計算値（％） C 56.52, H 8.69, O 34.73, 実験値（％） C 56.74, H 9.97, O 33.291 H-NMR（90MHz,CDCl3/TMS）δ、0.7〜1.40（27H,Myrist
oyl）、2.8〜4.0（Mannobiose ring protons） 実施例６ 実施例５で得た複数成分のマンノビオースモノミリス
チン酸エステル150mgをシリカゲルクロマトグラフィー
〔溶媒系：クロロホルム／メタノール＝5/1〜3/1〕で更
に２回分画し、C6位の水酸基にミリスチン酸がエステル
結合した６−Ｏ−ミリストイル−４−Ｏ−β−Ｄ−マン
ノピラノシル−Ｄ−マンノピラノースを得た。Yield: 237 mg TLC; Rf value 0.48 or less (multiple components) (CHCl 3 / MeOH = 2/1) IR (KBr); 2845, 2910, 1465 (CH), 1730 (-CO-O-) Elemental analysis; Calculated value (%) as C 26 H 48 O 12 (molecular weight 552.43) C 56.52, H 8.69, O 34.73, experimental value (%) C 56.74, H 9.97, O 33.29 1 H-NMR (90 MHz, CDCl 3 / TMS) δ, 0.7-1.40 (27H, Myrist
oyl), 2.8-4.0 (Mannobiose ring protons) Example 6 Silica gel chromatography of 150 mg of a plurality of components of mannobiose monomyristate obtained in Example 5 [solvent system: chloroform / methanol = 5 / 1-3 / 1] ] To give 6-O-myristoyl-4-O-β-D-mannopyranosyl-D-mannopyranose in which myristic acid is ester-bonded to the hydroxyl group at the C 6 position.
収 量;32mg TLC;Rf値0.15（CHCl3/MeOH＝2/1） IR（KBr）;2845、2910、1465（CH）、1730（−CO-O−） 元素分析値；C26H48O12（分子量552.43）として 計算値（％） C 56.52, H 8.69, O 34.73, 実験値（％） C 56.22, H 9.01, O 34.771 H-NMR（90MHz,CDCl3/TMS）δ、0.7〜1.40（27H,Myrist
oyl）、2.8〜4.0（Mannobiose ring protons）13 C-NMR（90MHz,DMSO-d6/TMS）δ 173.1 100.9、95.8、
92.4、77.7、77.4、73.6、70.7、70.6、70.1、69.1、6
7.0、63.5、61.4 実施例７ ミリスチン酸クロライド365mgをステアリン酸クロラ
イド449mgに変更した以外は実施例５と同様に操作して
４−Ｏ−β−Ｄ−マンノピラノシル−Ｄ−マンノピラノ
ースのモノステアリン酸エステルの複数成分混合物を得
た。Yield; 32 mg TLC; Rf value 0.15 (CHCl 3 / MeOH = 2/1) IR (KBr); 2845, 2910, 1465 (CH), 1730 (—CO—O—) Elemental analysis; C 26 H 48 O Calculated value (%) as 12 (molecular weight 552.43) C 56.52, H 8.69, O 34.73, experimental value (%) C 56.22, H 9.01, O 34.77 1 H-NMR (90 MHz, CDCl 3 / TMS) δ, 0.7 to 1.40 (27H, Myrist
oyl), 2.8-4.0 (Mannobiose ring protons) 13 C-NMR (90 MHz, DMSO-d 6 / TMS) δ 173.1 100.9, 95.8,
92.4, 77.7, 77.4, 73.6, 70.7, 70.6, 70.1, 69.1, 6
7.0, 63.5, 61.4 Example 7 Mono-stearic acid of 4-O-β-D-mannopyranosyl-D-mannopyranose was operated in the same manner as in Example 5, except that 365 mg of myristic acid chloride was changed to 449 mg of stearic acid chloride. A multi-component mixture of esters was obtained.
収 量;267mg TLC;Rf値0.51以下（複数成分） （CHCl3/MeOH＝2/1） IR（KBr）;2845、2910、1465（CH）、1730（−CO-O−） 元素分析値；C30H56O12（分子量608.47）として 計算値（％） C 59.21, H 9.20, O 31.53, 実験値（％） C 59.11, H 9.11, O 31.781 H-NMR（90MHz,CDCl3/TMS）δ、0.7〜1.4（35H,Stearoy
l）、2.8〜4.0（Mannobiose ring protons） 実施例８ ミリスチン酸クロライド365mgをベヘイン酸クロライ
ド530mgに変更した以外は実施例５と同様に操作して４
−Ｏ−β−Ｄ−マンノピラノシル−Ｄ−マンノピラノー
スのモノベヘイン酸エステルの複数成分混合物を得た。Yield: 267 mg TLC; Rf value 0.51 or less (multiple components) (CHCl 3 / MeOH = 2/1) IR (KBr); 2845, 2910, 1465 (CH), 1730 (-CO-O-) Elemental analysis; Calculated value (%) as C 30 H 56 O 12 (molecular weight 608.47) C 59.21, H 9.20, O 31.53, experimental value (%) C 59.11, H 9.11, O 31.78 1 H-NMR (90 MHz, CDCl 3 / TMS) δ, 0.7-1.4 (35H, Stearoy
l), 2.8-4.0 (Mannobiose ring protons) Example 8 The procedure of Example 5 was repeated except that 365 mg of myristic acid chloride was changed to 530 mg of beheic acid chloride.
A multicomponent mixture of mono-beheic acid esters of -O- [beta] -D-mannopyranosyl-D-mannopyranose was obtained.
収 量;262mg TLC;Rf値0.51以下（複数成分） （CHCl3/MeOH＝2/1） IR（KBr）;2845、2910、1465（CH）、1730（−CO-O−） 元素分析値；C34H64O12（分子量664.51）として 計算値（％） C 61.45, H 9.63, O 28.88, 実験値（％） C 61.30, H 9.99, O 28.711 H-NMR（90MHz,CDCl3/TMS）δ、0.7〜1.41（43H,Beheno
yl）、2.8〜4.0（Mannobiose ring protons） 参考例１ ４−Ｏ−（2,3,4,6−テトラ−Ｏ−アセチル−β−Ｄ−
マンノピラノシル）−2,3,6−トリ−Ｏ−アセチル−Ｄ
−マンノピラノシルアミン （以下化合物Ａ） ４−Ｏ−β−Ｄ−マンノピラノシル−Ｄ−マンノピラ
ノース2gにピリジン16ml、無水酢酸10mlを加え、室温で
一夜撹拌した。生成物を常法で処理して白色粉末状の４
−Ｏ−（2,3,4,6−テトラ−Ｏ−アセチル−β−Ｄ−マ
ンノピラノシル）−1,2,3,6−テトラ−Ｏ−アセチル−
Ｄ−マンノピラノース3.98gを得た。これをジクロルメ
タン20mlに溶解し、氷冷下、臭化水素飽和酢酸溶液20ml
（30％、w/v）を加え、０℃で15時間撹拌した。反応液
を氷水中に注ぎ、クロロホルムで抽出し、氷水、氷冷炭
酸水素ナトリウム水の順に洗浄し、乾燥（無水硫酸マグ
ネシウム）後、濃縮し、４−Ｏ−（2,3,4,6−テトラ−
Ｏ−アセチル−β−Ｄ−マンノピラノシル）−2,3,6−
トリ−Ｏ−アセチル−Ｄ−マンノピラノシルブロミド3.
97gを得た。得られた化合物3.97gをジメチルホルムアミ
ド80mlに溶解し、アジ化ナトリウム8.0gを加えて一夜撹
拌した。反応混合物を氷水へ注ぎ、クロロホルムで抽出
し、氷水、５％塩酸水、氷冷炭酸水素ナトリウム水で洗
浄後、乾燥し、未精製の４−Ｏ−（2,3,4,6−テトラ−
Ｏ−アセチル−β−Ｄ−マンノピラノシル）−2,3,6−
トリ−Ｏ−アセチル−Ｄ−マンノピラノシルアジド3.84
gを得た。これをシリカゲルクロマトグラフィー〔溶媒
系：クロロホルム−アセトン（30:1）〕で精製し、４−
Ｏ−（2,3,4,6−テトラ−Ｏ−アセチル−β−Ｄ−マン
ノピラノシル）−2,3,6−トリ−Ｏ−アセチル−Ｄ−マ
ンノピラノシルアジド2.98gを得た。このアジド2.88gを
メタノール140mlに溶解し、二酸化白金300mg存在下、2.
0時間接触還元した後、触媒をセライドで濾取し、濾液
を濃縮して、非晶質の表題化合物A2.57gを得た。Yield: 262 mg TLC; Rf value 0.51 or less (multiple components) (CHCl 3 / MeOH = 2/1) IR (KBr); 2845, 2910, 1465 (CH), 1730 (-CO-O-) Elemental analysis; Calculated value (%) as C 34 H 64 O 12 (molecular weight 664.51) C 61.45, H 9.63, O 28.88, experimental value (%) C 61.30, H 9.99, O 28.71 1 H-NMR (90 MHz, CDCl 3 / TMS) δ, 0.7 to 1.41 (43H, Beheno
yl), 2.8-4.0 (Mannobiose ring protons) Reference Example 1 4-O- (2,3,4,6-tetra-O-acetyl-β-D-
Mannopyranosyl) -2,3,6-tri-O-acetyl-D
-Mannopyranosylamine (hereinafter referred to as compound A) 16 ml of pyridine and 10 ml of acetic anhydride were added to 2 g of 4-O-β-D-mannopyranosyl-D-mannopyranose, and the mixture was stirred at room temperature overnight. The product is processed in the usual manner to give a white powder 4
-O- (2,3,4,6-tetra-O-acetyl-β-D-mannopyranosyl) -1,2,3,6-tetra-O-acetyl-
3.98 g of D-mannopyranose was obtained. This was dissolved in dichloromethane (20 ml), and under ice cooling, hydrogen bromide saturated acetic acid solution (20 ml)
(30%, w / v) and stirred at 0 ° C. for 15 hours. The reaction solution was poured into ice water, extracted with chloroform, washed with ice water and ice-cold aqueous sodium hydrogen carbonate in that order, dried (anhydrous magnesium sulfate), and concentrated to give 4-O- (2,3,4,6- Tetra-
O-acetyl-β-D-mannopyranosyl) -2,3,6-
Tri-O-acetyl-D-mannopyranosyl bromide 3.
97 g were obtained. 3.97 g of the obtained compound was dissolved in 80 ml of dimethylformamide, 8.0 g of sodium azide was added, and the mixture was stirred overnight. The reaction mixture was poured into ice water, extracted with chloroform, washed with ice water, 5% aqueous hydrochloric acid, and ice-cold aqueous sodium bicarbonate, dried, and purified to give crude 4-O- (2,3,4,6-tetra-
O-acetyl-β-D-mannopyranosyl) -2,3,6-
Tri-O-acetyl-D-mannopyranosyl azide 3.84
g was obtained. This was purified by silica gel chromatography [solvent system: chloroform-acetone (30: 1)] to give 4-
2.98 g of O- (2,3,4,6-tetra-O-acetyl-β-D-mannopyranosyl) -2,3,6-tri-O-acetyl-D-mannopyranosyl azide were obtained. 2.88 g of this azide was dissolved in 140 ml of methanol, and 2.
After catalytic reduction for 0 hours, the catalyst was filtered off through celite, and the filtrate was concentrated to obtain 2.57 g of the amorphous title compound A.
TLC;Rf値＝0.3（クロロホルム：エタノール＝19:1） 参考例２ Ｎ−エイコサノイル−４−Ｏ−（2,3,4,6−テトラ−Ｏ
−アセチル−β−Ｄ−マンノピラノシル）−2,3,6−ト
リ−Ｏ−アセチル−Ｄ−マンノピラノシルアミン 参考例１で得た化合物A580mgをエタノール25mlに溶解
し、これにベンゼン30mlに溶解したアラキジン酸627mg
を加えた後、Ｎ−エトキシカルボニル−２−エトキシ−
1,2−ジヒドロキノリン（EEDQ）494mgを加え室温で48時
間撹拌した。反応液を冷却し、析出した未反応のアラキ
ジン酸を濾取した後、濾液を濃縮した。得られた残渣を
シリカゲルクロマトグラフィー〔溶媒系；クロロホルム
−アセトン（30:1）〕で精製すると白色粉末状の標記物
質が得られた。TLC; Rf value = 0.3 (chloroform: ethanol = 19: 1) Reference Example 2 N-eicosanoyl-4-O- (2,3,4,6-tetra-O
-Acetyl-β-D-mannopyranosyl) -2,3,6-tri-O-acetyl-D-mannopyranosylamine 580 mg of the compound A obtained in Reference Example 1 was dissolved in 25 ml of ethanol, and then dissolved in 30 ml of benzene. Arachidic acid 627mg
After addition of N-ethoxycarbonyl-2-ethoxy-
494 mg of 1,2-dihydroquinoline (EEDQ) was added, and the mixture was stirred at room temperature for 48 hours. The reaction solution was cooled, and unreacted arachidic acid precipitated was collected by filtration, and the filtrate was concentrated. The obtained residue was purified by silica gel chromatography [solvent system: chloroform-acetone (30: 1)] to give the title substance as a white powder.
TLC;Rf値＝0.45（クロロホルム：アセトン＝6:1）1 H-NMR（90MHz,CDCl3/TMS）；δ、0.80〜1.60（39H,Eic
osanoyl）1.97〜2.20（21H,all S,OAc ×７）6.22（d,1
H,JNH,1＝9Hz,NH） IR（KBr）;3300（NH）、1750（OAc） 1660（アミドＩ）
1540（アミドII） 元素分析値；C46H75O18N（分子量930.10）として 計算値 ; C 59.40, H 8.13, N 1.51％ 実験値 ; C 59.60, H 8.25, N 1.39％ 実施例９ Ｎ−エイコサノイル−４−Ｏ−β−Ｄ−マンノピラノシ
ル−β−Ｄ−マンノピラノシルアミン 参考例２で得た化合物550mgをクロロホルム40ml、メ
タノール80mlに溶解しナトリウムメチラート40mgを加
え、室温で６時間撹拌した。生じた析出物を濾取した
後、これをメタノール、エーテルで充分洗浄し表題化合
物を得た。TLC; Rf value = 0.45 (chloroform: acetone = 6: 1) 1 H-NMR (90 MHz, CDCl 3 / TMS); δ, 0.80 to 1.60 (39H, Eic
osanoyl) 1.97-2.20 (21H, all S, OAc × 7) 6.22 (d, 1
H, J NH, 1 = 9 Hz, NH) IR (KBr); 3300 (NH), 1750 (OAc) 1660 (amide I)
1540 (amide II) Elemental analysis; calculated as C 46 H 75 O 18 N (molecular weight 930.10); C 59.40, H 8.13, N 1.51% experimental; C 59.60, H 8.25, N 1.39% Example 9 N− Eicosanoyl-4-O-β-D-mannopyranosyl-β-D-mannopyranosylamine 550 mg of the compound obtained in Reference Example 2 was dissolved in chloroform 40 ml and methanol 80 ml, and sodium methylate 40 mg was added, followed by stirring at room temperature for 6 hours. did. The resulting precipitate was collected by filtration and sufficiently washed with methanol and ether to obtain the title compound.
収量;240mg mp;194〜200℃1 H-NMR（90MHz,DMSO-d6/TMS）；δ,0.80〜1.50（39H,Ei
cosanoyl）4.60（d,1H,JNH,1＝10Hz,NH） IR（KBr）;3400〜3300（OH,NH）、1650（アミドＩ） 15
30（アミドII） 元素分析値；C32H61O11N（分子量635.83）として 計算値 ; C 60.45, H 9.67, N 2.20％ 実験値 ; C 60.25, H 9.57, N 2.15％ 参考例３ Ｎ−ラウロイル−４−Ｏ−（2,3,4,6−テトラ−Ｏ−ア
セチル−β−Ｄ−マンノピラノシル）−2,3,6−トリ−
Ｏ−アセチル−Ｄ−マンノピラノシルアミン 化合物A390mgを参考例２のアラキジン酸627mgをラウ
リル酸270mgに変更した以外は参考例２と同様に操作し
て表題化合物を得た。Yield; 240 mg mp; 194 to 200 ° C 1 H-NMR (90 MHz, DMSO-d 6 / TMS); δ, 0.80 to 1.50 (39H, Ei
cosanoyl) 4.60 (d, 1H, J NH, 1 = 10 Hz, NH) IR (KBr); 3400-3300 (OH, NH), 1650 (amide I) 15
30 (amide II) elemental analysis; calculated as C 32 H 61 O 11 N (molecular weight 635.83); C 60.45, H 9.67, N 2.20% experimental; C 60.25, H 9.57, N 2.15% Reference Example 3 N- Lauroyl-4-O- (2,3,4,6-tetra-O-acetyl-β-D-mannopyranosyl) -2,3,6-tri-
O-acetyl-D-mannopyranosylamine The title compound was obtained in the same manner as in Reference Example 2 except that 390 mg of compound A in Example 2 was replaced with 270 mg of lauric acid in Reference Example 2.
収量;465mg TLC;Rf値＝0.44（クロロホルム：アセトン＝6:1）1 H-NMR（90MHz,CDCl3/TMS）；δ,0.80〜1.60（23H,Laur
oyl）1.97〜2.21（21H,all S,OAc ×７） 6.22（d,1H,J
NH,1＝9Hz,NH） IR（KBr）;3300（NH）、1750（OAc） 1660（アミドＩ）
1540（アミドII） 元素分析値；C38H59O18N（分子量817.87）として 計算値 ; C 55.81, H 7.27, N 1.71％ 実験値 ; C 55.60, H 7.38, N 1.58％ 実施例10 Ｎ−ラウロイル−４−Ｏ−β−Ｄ−マンノピラノシル−
Ｄ−マンノピラノシルアミン 参考例３で得た化合物360mgを無水メタノール25mlに
溶解し、ナトリウムメチラート25mgを加え実施例９と同
様に操作して表題化合物を得た。Yield; 465 mg TLC; Rf value = 0.44 (chloroform: acetone = 6: 1) 1 H-NMR (90 MHz, CDCl 3 / TMS); δ, 0.80 to 1.60 (23H, Laur
oyl) 1.97 to 2.21 (21H, all S, OAc × 7) 6.22 (d, 1H, J
NH, 1 = 9 Hz, NH) IR (KBr); 3300 (NH), 1750 (OAc) 1660 (amide I)
1540 (amide II) Elemental analysis; calculated as C 38 H 59 O 18 N (molecular weight 817.87); C 55.81, H 7.27, N 1.71% experimental; C 55.60, H 7.38, N 1.58% Example 10 N− Lauroyl-4-O-β-D-mannopyranosyl-
D-Mannopyranosylamine 360 mg of the compound obtained in Reference Example 3 was dissolved in 25 ml of anhydrous methanol, and 25 mg of sodium methylate was added thereto.
収量;158mg1 H-NMR（90MHz,DMSO-d6/TMS）；δ,0.80〜1.50（23H,La
uroyl）4.60（d,1H,JNH,1＝10Hz,NH） IR（KBr）;3400〜3300（OH,NH）、1650（アミドＩ） 15
30（アミドII） 元素分析値；C24H45O11N（分子量523.61）として 計算値 ; C 55.05, H 8.66, N 2.68として 実験値 ; C 54.82, H 8.72, N 2.67 参考例４ Ｎ−ミリストイル−４−Ｏ−（2,3,4,6−テトラ−Ｏ−
アセチル−β−Ｄ−マンノピラノシル）−2,3,6−トリ
−Ｏ−アセチル−Ｄ−マンノピラノシルアミン 化合物A390mgを参考例２のアラキジン酸627mgをミリ
スチン酸315mgに変更した以外は参考例２と同様に操作
して表題化合物を得た。Yield: 158 mg 1 H-NMR (90 MHz, DMSO-d 6 / TMS); δ, 0.80 to 1.50 (23H, La
uroyl) 4.60 (d, 1H, J NH, 1 = 10 Hz, NH) IR (KBr); 3400-3300 (OH, NH), 1650 (amide I) 15
30 (amide II) elemental analysis; calculated as C 24 H 45 O 11 N (molecular weight 523.61); experimental as C 55.05, H 8.66, N 2.68; C 54.82, H 8.72, N 2.67 Reference Example 4 N-myristoyl -4-O- (2,3,4,6-tetra-O-
Acetyl-β-D-mannopyranosyl) -2,3,6-tri-O-acetyl-D-mannopyranosylamine Reference example 2 except that 390 mg of compound A was changed to 315 mg of arachidic acid in Reference example 2 and 315 mg of myristic acid. The title compound was obtained in the same manner as in.
収量;458mg TLC;Rf値＝0.43（クロロホルム：アセトン＝6:1）1 H-NMR（90MHz,CDCl3/TMS）；δ,0.80〜1.60（27H,Myri
stoyl）1.97〜2.22（21H,all S,OAc ×７）6.22（d,1H,
JNH,1＝9Hz,NH） IR（KBr）;3300（NH）、1750（OAc） 1665（アミドＩ）
1540（アミドII） 元素分析値；C40H63O18N（分子量845.93）として 計算値 ; C 56.79, H 7.51, N 1.66％ 実験値 ; C 56.38, H 7.71, N 1.58％ 実施例11 Ｎ−ミリストイル−４−Ｏ−β−Ｄ−マンノピラノシル
−Ｄ−マンノピラノシルアミン 参考例４で得た化合物360mgを無水メタノール25mlに
溶解し、ナトリウムメチラート25mgを加え実施例９と同
様に操作して表題化合物を得た。Yield; 458 mg TLC; Rf value: 0.43 (chloroform: acetone = 6: 1) 1 H-NMR (90 MHz, CDCl 3 / TMS); δ, 0.80 to 1.60 (27H, Myri
stoyl) 1.97 to 2.22 (21H, all S, OAc × 7) 6.22 (d, 1H,
J NH, 1 = 9 Hz, NH) IR (KBr); 3300 (NH), 1750 (OAc) 1665 (amide I)
1540 (amide II) elemental analysis; calculated as C 40 H 63 O 18 N (molecular weight 845.93); C 56.79, H 7.51, N 1.66% experimental; C 56.38, H 7.71, N 1.58% Example 11 N− Myristoyl-4-O-β-D-mannopyranosyl-D-mannopyranosylamine 360 mg of the compound obtained in Reference Example 4 was dissolved in 25 ml of anhydrous methanol, and 25 mg of sodium methylate was added. The title compound was obtained.
収量;175mg1 H-NMR（90MHz,DMSO-d6/TMS）；δ,0.80〜1.50（27H,My
ristoyl）4.60（d,1H,JNH,1＝10Hz,NH） IR（KBr）;3400〜3300（OH,NH）、1650（アミドＩ） 15
30（アミドII） 元素分析値；C26H49O11N（分子量551.67）として 計算値 ; C 56.61, H 8.95, N 2.54 実験値 ; C 56.88, H 8.77, N 2.48 参考例５ Ｎ−パルミトイル−４−Ｏ−（2,3,4,6−テトラ−Ｏ−
アセチル−β−Ｄ−マンノピラノシル）−2,3,6−トリ
−Ｏ−アセチル−Ｄ−マンノピラノシルアミン 化合物A390mgを参考例２のアラキジン酸627mgをパル
ミチン酸346mgに変更した以外は参考例２と同様に操作
して表題化合物を得た。Yield; 175 mg 1 H-NMR (90 MHz, DMSO-d 6 / TMS); δ, 0.80 to 1.50 (27H, My
ristoyl) 4.60 (d, 1H, J NH, 1 = 10 Hz, NH) IR (KBr); 3400-3300 (OH, NH), 1650 (amide I) 15
30 (amide II) elemental analysis; calculated as C 26 H 49 O 11 N (molecular weight 551.67); C 56.61, H 8.95, N 2.54 experimental; C 56.88, H 8.77, N 2.48 Reference Example 5 N-palmitoyl- 4-O- (2,3,4,6-tetra-O-
Acetyl-β-D-mannopyranosyl) -2,3,6-tri-O-acetyl-D-mannopyranosylamine Reference example 2 except that 390 mg of compound A was changed to 346 mg of arachidic acid in Reference example 2 and 346 mg of palmitic acid. The title compound was obtained in the same manner as in.
収量;480mg TLC;Rf値＝0.45（クロロホルム：アセトン＝6:1）1 H-NMR（90MHz,CDCl3/TMS）；δ,0.80〜1.60（31H,Palm
itoyl）1.97〜2.22（21H,all S,OAc ×７）6.22（d,1H,
JNH,1＝9Hz,NH） IR（KBr）;3300（NH）、1750（OAc） 1660（アミドＩ）
1540（アミドII） 元素分析値；C42H67O18N（分子量873.98）として 計算値 ; C 57.72, H 7.73, N 1.60％ 実験値 ; C 57.82, H 7.32, N 1.68％ 実施例12 Ｎ−パルミトイル−４−Ｏ−（β−Ｄ−マンノピラノシ
ル）−Ｄ−マンノピラノシルアミン 参考例５で得た化合物360mgを無水メタノール25mlに
溶解し、ナトリウムメチラート25mgを加え実施例９と同
様に操作して表題化合物を得た。Yield; 480 mg TLC; Rf value: 0.45 (chloroform: acetone = 6: 1) 1 H-NMR (90 MHz, CDCl 3 / TMS); δ, 0.80 to 1.60 (31H, Palm
itoyl) 1.97 to 2.22 (21H, all S, OAc × 7) 6.22 (d, 1H,
J NH, 1 = 9Hz, NH) IR (KBr); 3300 (NH), 1750 (OAc) 1660 (amide I)
1540 (amide II) elemental analysis; calculated as C 42 H 67 O 18 N (molecular weight 873.98); C 57.72, H 7.73, N 1.60% experimental; C 57.82, H 7.32, N 1.68% Example 12 N− Palmitoyl-4-O- (β-D-mannopyranosyl) -D-mannopyranosylamine 360 mg of the compound obtained in Reference Example 5 was dissolved in 25 ml of anhydrous methanol, and 25 mg of sodium methylate was added thereto. To give the title compound.
収量;160mg1 H-NMR（90MHz,DMSO-d6/TMS）；δ,0.80〜1.52（31H,Pa
lmitoyl）4.60（d,1H,JNH,1＝10Hz,NH） IR（KBr）;3400〜3300（OH,NH）、1650（アミドＩ） 15
30（アミドII） 元素分析値；C28H53O11N（分子量579.72）として 計算値 ; C 58.01, H 9.21, N 2.42％ 実験値 ; C 58.18, H 9.50, N 2.32％ 参考例６ Ｎ−ステアロイル−４−Ｏ−（2,3,4,6−テトラ−Ｏ−
アセチル−β−Ｄ−マンノピラノシル）−2,3,6−トリ
−Ｏ−アセチル−Ｄ−マンノピラノシルアミン 化合物A390mgを参考例２のアラキジン酸627mgをパル
ミチン酸383mgに変更した以外は参考例２と同様に操作
して表題化合物を得た。Yield; 160 mg 1 H-NMR (90 MHz, DMSO-d 6 / TMS); δ, 0.80 to 1.52 (31 H, Pa
lmitoyl) 4.60 (d, 1H, J NH, 1 = 10 Hz, NH) IR (KBr); 3400-3300 (OH, NH), 1650 (amide I) 15
30 (amide II) elemental analysis; calculated as C 28 H 53 O 11 N (molecular weight 579.72); C 58.01, H 9.21, N 2.42% experimental; C 58.18, H 9.50, N 2.32% Reference Example 6 N- Stearoyl-4-O- (2,3,4,6-tetra-O-
Reference Example 2 Acetyl-β-D-mannopyranosyl) -2,3,6-tri-O-acetyl-D-mannopyranosylamine Reference Example 2 except that 390 mg of compound A was changed from 627 mg of arachidic acid to 383 mg of palmitic acid in Reference Example 2. The title compound was obtained in the same manner as in.
収量;472mg TLC;Rf値＝0.45（クロロホルム：アセトン＝6:1）1 H-NMR（90MHz,CDCl3/TMS）；δ,0.80〜1.60（35H,Stea
royl）1.97〜2.22（21H,all S,OAc ×７）6.22（d,1H,J
NH,1＝9Hz,NH） IR（KBr）;3300（NH）、1750（OAc） 1660（アミドＩ）
1540（アミドII） 元素分析値；C44H71O18N（分子量902.04）として 計算値 ; C 58.59, H 7.93, N 1.55％ 実験値 ; C 58.63, H 8.02, N 1.70％ 実施例13 Ｎ−ステアロイル−４−Ｏ−β−Ｄ−マンノピラノシル
−Ｄ−マンノピラノシルアミン 参考例６で得た化合物360mgを無水メタノール25mlに
溶解し、ナトリウムメチラート25mgを加え実施例９と同
様に操作して表題化合物を得た。Yield: 472 mg TLC; Rf value: 0.45 (chloroform: acetone = 6: 1) 1 H-NMR (90 MHz, CDCl 3 / TMS); δ, 0.80 to 1.60 (35H, Stea
royl) 1.97 to 2.22 (21H, all S, OAc × 7) 6.22 (d, 1H, J
NH, 1 = 9 Hz, NH) IR (KBr); 3300 (NH), 1750 (OAc) 1660 (amide I)
1540 (amide II) elemental analysis; calculated as C 44 H 71 O 18 N (molecular weight 902.04); C 58.59, H 7.93, N 1.55% experimental; C 58.63, H 8.02, N 1.70% Example 13 N- Stearoyl-4-O-β-D-mannopyranosyl-D-mannopyranosylamine 360 mg of the compound obtained in Reference Example 6 was dissolved in 25 ml of anhydrous methanol, and 25 mg of sodium methylate was added thereto. The title compound was obtained.
収量;192mg1 H-NMR（90MHz,DMSO-d6/TMS）；δ,0.80〜1.50（35H,St
earoyl）4.60（d,1H,JNH,1＝10Hz,NH） IR（KBr）;3400〜3300（OH,NH）、1650（アミドＩ） 15
30（アミドII） 元素分析値；C30H57O11N（分子量607.78）として 計算値 ; C 59.29, H 9.45, N 2.30％ 実験値 ; C 59.42, H 9.58, N 2.58％ 参考例７ Ｎ−オレイル−３−Ｏ−（2,3,4,6−テトラ−Ｏ−ベン
ゾイル−α−Ｄ−マンノピラノシル）−2,4,6−トリ−
Ｏ−ベンゾイル−１−デオキシ−１−Ｎ−オレオイル−
Ｄ−マンノピラノシルアミン ３−Ｏ−α−Ｄ−マンノピラノシル−Ｄ−マンノピラ
ノース500mgを参考例１の無水酢酸10mlを塩化ベンゾイ
ル3.2mlに変更した以外は参考例１と同様に操作して３
−Ｏ−（2,3,4,6−テトラ−Ｏ−ベンゾイル−α−Ｄ−
マンノピラノシル）−2,4,6−トリ−Ｏ−ベンゾイル−
Ｄ−マンノピラノシルアミン410mgを得た。Yield: 192 mg 1 H-NMR (90 MHz, DMSO-d 6 / TMS); δ, 0.80 to 1.50 (35 H, St
earoyl) 4.60 (d, 1H, J NH, 1 = 10 Hz, NH) IR (KBr); 3400-3300 (OH, NH), 1650 (amide I) 15
30 (amide II) elemental analysis; calculated as C 30 H 57 O 11 N (molecular weight 607.78); C 59.29, H 9.45, N 2.30% experimental; C 59.42, H 9.58, N 2.58% Reference Example 7 N− Oleyl-3-O- (2,3,4,6-tetra-O-benzoyl-α-D-mannopyranosyl) -2,4,6-tri-
O-benzoyl-1-deoxy-1-N-oleoyl-
D-mannopyranosylamine 3-O-α-D-mannopyranosyl-D-mannopyranose 500 mg was used in the same manner as in Reference Example 1 except that 10 ml of acetic anhydride in Reference Example 1 was changed to 3.2 ml of benzoyl chloride. 3
-O- (2,3,4,6-tetra-O-benzoyl-α-D-
Mannopyranosyl) -2,4,6-tri-O-benzoyl-
410 mg of D-mannopyranosylamine were obtained.
次にこのアミン410mgを参考例２のアラキギン酸627mg
をオレイン酸403mgに変更した以外は参考例２と同様に
操作して表題化合物を得た。Next, 410 mg of this amine was added to 627 mg of arachigic acid in Reference Example 2.
Was changed to 403 mg of oleic acid, and the title compound was obtained in the same manner as in Reference Example 2.
収量;380mg TLC;Rf値＝0.43（クロロホルム：アセトン＝6:1）1 H-NMR（90MHz,CDCl3/TMS）；δ,0.80〜1.60（33H,Oleo
yl）6.22（d,1H,JNH,1＝9Hz,NH） 7.2〜8.3（35H,Bz×７） IR（KBr）;3300（NH）、1750（OBz） 1660（アミドＩ）
1540（アミドII） 元素分析値；C81H89O18N（分子量1364.59）として 計算値 ; C 71.30, H 6.57, N 1.03％ 実験値 ; C 71.12, H 6.87, N 0.98％ 実施例14 Ｎ−オレイル−３−Ｏ−α−Ｄ−マンノピラノシル−Ｄ
−マンノピラノシルアミン 参考例７で得た化合物360mgを無水メタノール25mlに
溶解し、ナトリウムメチラート25mgを加え実施例９と同
様に操作して表題化合物を得た。Yield; 380 mg TLC; Rf value: 0.43 (chloroform: acetone = 6: 1) 1 H-NMR (90 MHz, CDCl 3 / TMS); δ, 0.80 to 1.60 (33H, Oleo
yl) 6.22 (d, 1H, J NH, 1 = 9 Hz, NH) 7.2 to 8.3 (35H, Bz x 7) IR (KBr); 3300 (NH), 1750 (OBz) 1660 (amide I)
1540 (amide II) Elemental analysis; calculated as C 81 H 89 O 18 N (molecular weight 1364.59); C 71.30, H 6.57, N 1.03% experimental; C 71.12, H 6.87, N 0.98% Example 14 N− Oleyl-3-O-α-D-mannopyranosyl-D
-Mannopyranosylamine The compound (360 mg) obtained in Reference Example 7 was dissolved in anhydrous methanol (25 mL), and sodium methylate (25 mg) was added.
収量;102mg1 H-NMR（90MHz,DMSO-d6/TMS）；δ,0.80〜1.50（33H,Ol
eoyl）4.60（d,1H,JNH,1＝10Hz,NH） IR（KBr）;3400〜3300（OH,NH）、1650（アミドＩ） 15
35（アミドII） 元素分析値；C30H55O11N（分子量605.76）として 計算値 ; C 59.48, H 9.15, N 2.31％ 実験値 ; C 59.62, H 9.43, N 2.22％ 参考例８ （１）リポソームＩ（本発明物質含有）の調製 卵黄ホスファチジルコリン8.8μmol、コレステロール
5.6μmol、ジセチルホスフェート0.8μmol、以下に示す
本発明のマンノビオース誘導体0.8μmol又は1.6μmolを
試験管中でクロロホルム；メタノール混液（容積比2:
1）に加温して溶かした。次に窒素ガス気流中で有機溶
媒を除去して試験管のガラス壁にlipid filmを生成させ
た。ここにリン酸緩衝化生理食塩水（pH7.4、以下PBSと
略す）を3.2ml加えて振盪し、更に軽く超音波処理して
リポソームの懸濁液を調製した。これを40〜45℃に加温
し、次いで0.2μｍの孔径を有するポリカーボネート製
メンブランフィルターに通過させ、粒径0.2μｍ以下の
リポソームの懸濁液を調製した。次にこの1mlをゲル濾
過クロマトグラフィー〔カラム:Sepharose CL-4B、1.5c
mφ×15cm、溶出液:PBS（pH7.4）〕にかけて更にリポソ
ーム分画としてvoid volumeに溶出する画分6.5mlを得
た。このリポソーム分画につき、卵黄ホスファチジルコ
リンのコリン基をマーカーとして酵素法により定量し、
全脂質として0.5μmol/mlとなるようにPBS（pH7.4）に
より希釈した。得られたリポソームと使用したマンノビ
オース誘導体との対応を以下に示す。Yield; 102 mg 1 H-NMR (90 MHz, DMSO-d 6 / TMS); δ, 0.80-1.50 (33H, Ol
eoyl) 4.60 (d, 1H, J NH, 1 = 10 Hz, NH) IR (KBr); 3400-3300 (OH, NH), 1650 (amide I) 15
35 (amide II) elemental analysis; calculated as C 30 H 55 O 11 N (molecular weight 605.76); C 59.48, H 9.15, N 2.31% experimental; C 59.62, H 9.43, N 2.22% Reference Example 8 (1 ) Preparation of liposome I (containing the substance of the present invention) Egg yolk phosphatidylcholine 8.8 μmol, cholesterol
5.6 μmol, dicetyl phosphate 0.8 μmol, and 0.8 μmol or 1.6 μmol of the following mannobiose derivative of the present invention in a test tube were mixed with chloroform and methanol (volume ratio 2:
Heated to 1) and melted. Next, the organic solvent was removed in a stream of nitrogen gas to form a lipid film on the glass wall of the test tube. 3.2 ml of phosphate buffered saline (pH 7.4, hereinafter abbreviated as PBS) was added thereto, shaken, and further slightly sonicated to prepare a liposome suspension. This was heated to 40 to 45 ° C., and then passed through a polycarbonate membrane filter having a pore size of 0.2 μm to prepare a suspension of liposomes having a particle size of 0.2 μm or less. Next, 1 ml of this was subjected to gel filtration chromatography (column: Sepharose CL-4B, 1.5c
mφ × 15 cm, eluent: PBS (pH 7.4)] to obtain 6.5 ml of a fraction eluted in a void volume as a liposome fraction. The liposome fraction was quantified by an enzymatic method using the choline group of yolk phosphatidylcholine as a marker,
It was diluted with PBS (pH 7.4) so that the total lipid was 0.5 μmol / ml. The correspondence between the obtained liposome and the used mannobiose derivative is shown below.
（２）リポソームII（対照）の調製 卵黄ホスファチジルコリン8.8μmol、コレステロール
5.6μmol、ジセチルホスフェート0.8μmolをクロロホル
ム；メタノール混液に溶かすこと、及びlipid filmに加
えるPBS（pH7.4）量が2.88mlであること以外は上記
（１）と同様に処理し、リポソーム懸濁液1mlからゲル
濾過により6.2mlのリポソーム画分を得たのち、希釈し
て全脂質として0.5μmol/mlとなるようにした。 (2) Preparation of liposome II (control) Egg yolk phosphatidylcholine 8.8 μmol, cholesterol
5.6 μmol and 0.8 μmol of dicetyl phosphate are dissolved in a mixture of chloroform and methanol, and the same treatment as in (1) is performed except that the amount of PBS (pH 7.4) added to the lipid film is 2.88 ml, and the liposome suspension is performed. A 6.2 ml liposome fraction was obtained from 1 ml of the solution by gel filtration, and then diluted to a total lipid of 0.5 μmol / ml.
（３）リポソームIII（本発明物質含有）の調製 Ｌ−α−ジミリストイルホスファチジルコリン72.4μ
mol、コレステロール72.4μmol、ジセチルホスフェート
7.2μmol、以下に示す本発明のマンノビオース誘導体８
又は16μmolを試験管中でクロロホルム：メタノール混
液（容積比2:1）に加温して溶かした。次に窒素ガス気
流中で有機溶媒を除去して試験管のガラス壁にlipid fi
lmを生成させた。ここに3H−イヌリン240μCiを含有す
る1mMイヌリンのPBS（pH7.4）溶液6mlを加えて振盪し、
更に軽く超音波処理してリポソームの懸濁液を調製し
た。これを40〜45℃に加温し、次いで0.2μｍの孔径を
有するポリカーボネート製メンブランフィルターに通過
させ、粒径0.2μｍ以下のリポソームの懸濁液を調製し
た。次にこれを超遠心分離（15万×ｇ、１時間、２回）
し、上澄みを除去することによりリポソームに保持され
なかったイヌリンを除去し、PBS（pH7.4）を加え、全量
5.3mlのリポソームの懸濁液を得た。Ｌ−α−ジミリス
トイルホスファチジルコリンのコリン基をマーカーとし
て酵素法により定量したところ得られた懸濁液は0.5ml
あたり全脂質として10μmolの脂質を有していた。得ら
れたリポソーム、使用したマンノビオース誘導体及び放
射活性との対応を以下に示す。(3) Preparation of liposome III (containing the substance of the present invention) L-α-dimyristoyl phosphatidylcholine 72.4 μm
mol, cholesterol 72.4 μmol, dicetyl phosphate
7.2 μmol, mannobiose derivative 8 of the present invention shown below
Alternatively, 16 μmol was heated and dissolved in a chloroform: methanol mixed solution (volume ratio: 2: 1) in a test tube. Next, the organic solvent was removed in a stream of nitrogen gas, and the lipid fi
lm was generated. 6 ml of 1 mM inulin in PBS (pH 7.4) containing 240 μCi of 3 H-inulin was added thereto, and the mixture was shaken.
Further, the suspension was slightly sonicated to prepare a liposome suspension. This was heated to 40 to 45 ° C., and then passed through a polycarbonate membrane filter having a pore size of 0.2 μm to prepare a suspension of liposomes having a particle size of 0.2 μm or less. Next, this is ultracentrifuged (150,000 xg, 1 hour, 2 times)
Then, the inulin not retained by the liposome was removed by removing the supernatant, and PBS (pH 7.4) was added.
5.3 ml of liposome suspension was obtained. L-α-dimyristoylphosphatidylcholine was quantified by enzymatic method using the choline group as a marker, and the obtained suspension was 0.5 ml.
Per total lipid as 10 μmol lipid. The correspondence between the obtained liposome, the used mannobiose derivative and the radioactivity is shown below.
（４）リポソームIV（対照）の調製 Ｌ−α−ジミリストイルホスファチジルコリン76.2μ
mol、コレステロール76.2μmol、ジセチルホスフェート
7.6μmolをクロロホルムに溶かす以外は上記（３）と同
様に処理し、全量5.0mlのリポソームの懸濁液を得た。
得られた懸濁液は0.5mlあたり全脂質として10μmolの脂
質を有し、又1.29μCiのイヌリンをリポソームに保持し
ていた。 (4) Preparation of liposome IV (control) L-α-dimyristoyl phosphatidylcholine 76.2μ
mol, cholesterol 76.2 μmol, dicetyl phosphate
Except for dissolving 7.6 μmol in chloroform, the same treatment as in (3) above was performed to obtain a 5.0 ml total liposome suspension.
The obtained suspension had 10 μmol of lipid as a total lipid per 0.5 ml, and retained 1.29 μCi of inulin in the liposome.
（５）1H−イヌリン溶液（対照）の調製 前述の3H−イヌリン240μCiを含有する1mMイヌリンの
PBS（pH7.4）溶液6mlをPBS（pH7.4）にて20倍に希釈
し、全量0.5mlあたり１μCiのイヌリンを含有する溶液
を調製した。(5) Preparation of 1 H-inulin solution (control) 1 mM inulin containing 240 μCi of 3 H-inulin described above was prepared.
6 ml of a PBS (pH 7.4) solution was diluted 20-fold with PBS (pH 7.4) to prepare a solution containing 1 μCi of inulin per 0.5 ml of the total amount.
（６）リポソームＶ（対照）の調製 上記（４）と全く同一処方で同様に処理し、全量5.3m
lのリポソームの懸濁液を得た。得られた懸濁液は0.5ml
あたり全脂質として10μmolの脂質を有し、又1.08μCi
のイヌリンをリポソーム内に保持していた。(6) Preparation of liposome V (control) The same treatment as in (4) above was performed in the same manner, and the total amount was 5.3 m.
A suspension of 1 liposome was obtained. 0.5 ml of the resulting suspension
Has 10μmol of lipid per total lipid and 1.08μCi
Of inulin was retained in the liposome.
（７）リポソームVI（本発明物質含有）の調製 上記（３）のリポソームIII-2又はIII-4と全く同一処
方で同様に処理し、全量4.8mlのリポソームの懸濁液を
得た。得られた懸濁液はそれぞれ0.5mlあたり全脂質と
して10μmolの脂質を有し、又0.83若しくは0.91μCiの
イヌリンをリポソーム内に保持していた。(7) Preparation of liposome VI (containing the substance of the present invention) The liposome III-2 or III-4 of the above (3) was treated in the same manner as described above to obtain a liposome suspension in a total amount of 4.8 ml. Each of the obtained suspensions contained 10 μmol of lipid as total lipid per 0.5 ml, and retained 0.83 or 0.91 μCi of inulin in the liposome.
試験１ Ｄ−マンノースに糖特異性を有するレクチン（ソラマ
メ（Vicia fava）由来、シグマ社製）を200μg/ml含むP
BS（pH7.4）溶液を調製した。次に上記（１）〔No.I−
１〜Ｉ−５〕又は（２）で得たリポソームの懸濁液とレ
クチン溶液とを1:1の比率で混合し、軽く振盪して分光
光度計測定用のセルに各々分注後、波長450nmにおける
吸光度を経時的に測定（30分間）した。Test 1 P containing 200 μg / ml of a lectin having sugar specificity to D-mannose (Vicia fava, Sigma)
A BS (pH 7.4) solution was prepared. Next, the above (1) [No.
1 to I-5] or the liposome suspension obtained in (2) and the lectin solution are mixed at a ratio of 1: 1. The mixture is gently shaken and dispensed into cells for spectrophotometer measurement. Absorbance at 450 nm was measured over time (30 minutes).
上記（１）の本発明のマンノビオース誘導体を処方し
たリポソームの懸濁液では、経時的に吸光度が増加する
ことによりリポソームの凝集が認められ、その程度はＩ
−１≦Ｉ−２＜Ｉ−３＝Ｉ−４＜Ｉ−５であった。これ
に対して上記（２）の対照のリポソームでは特に凝集性
は認められなかった。In the liposome suspension formulated with the mannobiose derivative of the present invention (1), liposome aggregation is observed due to an increase in absorbance over time.
−1 ≦ I−2 <I−3 = I−4 <I−5. On the other hand, the control liposome of the above (2) did not show any particular aggregation.
以上のことから上記（１）のリポソームでは本発明の
マンノビオース誘導体がリポソーム膜に組みこまれ、マ
ンノース残基がリポソーム膜表面に露出していることが
確認された。From the above, it was confirmed that in the liposome (1), the mannobiose derivative of the present invention was incorporated into the liposome membrane, and mannose residues were exposed on the liposome membrane surface.
試験２ 上記（３）〔No.III-1〜III-4〕もしくは（４）で得
たリポソームの懸濁液又は（５）で得た3H−イヌリン溶
液を、それぞれSD系雄性ラット（体重140〜160g）の後
肢静脈内に体重100gあたり0.5ml注入した。30分後頚動
脈放血して開腹し、肝、肺、腎及び脾臓を摘出した。こ
れらの臓器の一部又は全部をとり、リン酸緩衝化生理食
塩水中でホモジェナイズした。次いで液体シンチレーシ
ョン法により放射活性を測定し、投与量に対する回収率
（％）を求めた。又、血清中の放射活性回収率はラット
の全血液を体重の6.5％、血清量を全血液の50％とみつ
もって計算した。結果を表−１に示す。尚、表中の値は
平均値±標準誤差であり、（ ）内はラット数を示す。
これらの値は静脈注射後30分の値である。Test 2 The suspension of the liposome obtained in the above (3) [No. III-1 to III-4] or (4) or the 3 H-inulin solution obtained in the above (5) was used for each of SD male rats (body weight). (140-160 g) 0.5 ml per 100 g body weight was injected into the hind limb vein. Thirty minutes later, the carotid artery was exsanguinated and the abdomen was opened, and the liver, lung, kidney and spleen were removed. Some or all of these organs were taken and homogenized in phosphate buffered saline. Next, the radioactivity was measured by the liquid scintillation method, and the recovery (%) with respect to the dose was determined. The recovery of radioactivity in serum was calculated by assuming that rat whole blood was 6.5% of body weight and serum amount was 50% of whole blood. The results are shown in Table 1. The values in the table are the mean ± standard error, and the numbers in parentheses indicate the number of rats.
These values are 30 minutes after intravenous injection.
表−１より明らかなように、本発明のマンノビオース
誘導体を含有するリポソームの肝への分布は、対照のリ
ポソームIVに比べ有意に大きく、又添加量を増すほど肝
への指向性が増大することが確認された。As is clear from Table 1, the distribution of the liposome containing the mannobiose derivative of the present invention to the liver was significantly larger than that of the control liposome IV, and the directivity to the liver increased as the amount of addition increased. Was confirmed.
試験３ 上記No.III-2もしくはNo.III-4のリポソーム懸濁液又
は（６）で得たリポソームの懸濁液を用いて、末端にＤ
−マンノースを有し、肝クッパー細胞指向性を有するマ
ンナンによる阻害効果をみた。即ち試験２と同一の条件
でラットにリポソーム懸濁液を投与する１分前に、マン
ナンのリン酸緩衝化生理食塩水を後肢静脈内（リポソー
ム注入側と反対側の後肢）に前投与し、以後試験２と同
様の操作を行った。マンナンの投与量はラット体重100g
あたり13.3mgとした。結果、つまりマンナンによる肝へ
の分布阻害効果を表−２に示す。ここで表中の値は、平
均値±標準誤差、（ ）内はラット数であり、これら
は、静脈注後30分の値である。 Test 3 Using the liposome suspension of No. III-2 or No. III-4 or the liposome suspension obtained in (6), add D
-The inhibitory effect of mannan having mannose and having the tropism of liver Kupffer cells was observed. That is, one minute before the administration of the liposome suspension to the rat under the same conditions as in Test 2, a mannan phosphate-buffered saline was pre-administered into the hind limb vein (the hind limb opposite to the liposome injection side) Thereafter, the same operation as in Test 2 was performed. The dose of mannan is 100g for rat body weight
13.3 mg per 1 mg. The results, that is, the distribution inhibition effect on liver by mannan are shown in Table-2. Here, the values in the table are average value ± standard error, and the numbers in parentheses are the numbers of rats. These values are 30 minutes after intravenous injection.
表−２より明らかなように、本発明のマンノビオース
誘導体を含有するリポソームの肝臓への分布は有意に抑
制された。これに対して対照のリポソーム（リポソーム
Ｖ）では、マンナンによる影響は受けなかった。As is clear from Table 2, the distribution of the liposome containing the mannobiose derivative of the present invention to the liver was significantly suppressed. In contrast, the control liposome (liposome V) was not affected by mannan.
以上のことから本発明のマンノビオース誘導体を含有
するリポソームは、優れた肝フッパー細胞への指向性を
有することが確認された。From the above, it was confirmed that the liposome containing the mannobiose derivative of the present invention has excellent directivity to hepatic hupper cells.
試験４ 上記（７）で得たリポソームの懸濁液をSD系雄性ラッ
ト（体重140-160g）の後肢静脈内に体重100gあたり0.5m
l注入した。30分後ネンブタールを腹腔内に投与し開腹
してすぐに、Berry-Friend及びSeglenの潅流法に従い肝
臓を前潅流用緩衝液、コラゲナーゼ溶液及び細胞洗浄用
ハンクス液にて潅流し、遊離肝細胞懸濁液を調製した。
これを冷却遠心分離し、肝実質細胞画分と、肝クッパー
細胞に富む非実質細胞画分とを得た。 Test 4 The suspension of the liposome obtained in the above (7) was injected into the hind limb vein of a male SD rat (140-160 g in weight) at 0.5 m / 100 g in body weight
l injected. Thirty minutes later, Nembutal was intraperitoneally administered, and immediately after laparotomy, the liver was perfused with a preperfusion buffer, collagenase solution and cell washing Hanks' solution according to the perfusion method of Berry-Friend and Seglen, and free hepatocyte suspension was performed. A suspension was prepared.
This was cooled and centrifuged to obtain a liver parenchymal cell fraction and a non-parenchymal cell fraction rich in liver Kupffer cells.
両画分の放射活性を測ったところ、95％以上の放射活
性が肝クッパー細胞に富む非実質細胞画分から回収さ
れ、肝実質細胞画分からはほとんど回収されなかった。When the radioactivity of both fractions was measured, 95% or more of the radioactivity was recovered from the non-parenchymal cell fraction rich in liver Kupffer cells, and hardly recovered from the liver parenchymal cell fraction.
以上の試験から、本発明のマンノビオース誘導体は肝
クッパー細胞に代表されるマクロファージ系細胞に対し
て特異的親和性を有する製剤、たとえばリポソームの構
成成分として有用であることが確認された。From the above test, it was confirmed that the mannobiose derivative of the present invention was useful as a preparation having a specific affinity for macrophage cells represented by liver Kupffer cells, for example, a component of liposomes.
フロントページの続き (72)発明者 広田 貞雄 東京都江戸川区北葛西１丁目16番13号 第一製薬中央研究所内 (72)発明者 菊池 寛 東京都江戸川区北葛西１丁目16番13号 第一製薬中央研究所内Continuation of the front page (72) Inventor Sadao Hirota 1-16-13 Kita-Kasai, Edogawa-ku, Tokyo Inside the Daiichi Pharmaceutical Research Laboratory (72) Inventor Hiroshi Kikuchi 1-1-16-13 Kita-Kasai, Edogawa-ku, Tokyo 1st Pharmaceutical Central Research Laboratory
Claims (4)
0のアシル基を示す。）又は以下の式（ａ）、（ｂ）、
（ｃ）、（ｄ）もしくは（ｅ）で示される基である。 但し、R1〜R5の１つは-OR6又は-NHR6であり、残りの４
つの基のうちの１つが上記式（ａ）〜（ｅ）で示される
基のいずれかであり、その他の３つの基は−OHであ
る。〕で表わされるマンノビオース誘導体。1. A compound of the general formula [I]: (Wherein, R 1 to R 5 are —OH, —OR 6 , and —NHR 6 (R 6 is a group having 12 to 3 carbon atoms.
Represents an acyl group of 0. ) Or the following formulas (a), (b),
It is a group represented by (c), (d) or (e). However, one of R 1 to R 5 is -OR 6 or -NHR 6 and the remaining 4
One of the groups is any of the groups represented by the above formulas (a) to (e), and the other three groups are -OH. ] The mannobiose derivative represented by these.
R2、R3及びR5の１つが-NHR6又は-OR6であり、他の３つ
の基が−OHである特許請求の範囲第１項記載の誘導体。Wherein a group R 4 is of formula (a), R 1,
One is a -NHR 6 or -OR 6, derivatives of claim 1 wherein the appended claims other three groups are -OH R 2, R 3, and R 5.
の１つが-NHR6又は-OR6であり、他の３つの基が−OHで
ある特許請求の範囲第１項記載の誘導体。(3) R 1 is a group represented by formula (d), and R 2 to R 5
One is a -NHR 6 or -OR 6, derivatives of claim 1 wherein the appended claims other three groups are -OH of.
R6又は-NHR6でありR2、R3及びR5が−OHである特許請求
の範囲第１項記載の誘導体。4. R 4 is a group represented by the formula (a), and R 1 is —O
The derivative according to claim 1, wherein R 6 or —NHR 6 and R 2 , R 3 and R 5 are —OH.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63081036A JP2729803B2 (en) | 1987-04-03 | 1988-04-01 | Mannobiose derivatives |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP62-82736 | 1987-04-03 | ||
| JP8273687 | 1987-04-03 | ||
| JP63081036A JP2729803B2 (en) | 1987-04-03 | 1988-04-01 | Mannobiose derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH01104088A JPH01104088A (en) | 1989-04-21 |
| JP2729803B2 true JP2729803B2 (en) | 1998-03-18 |
Family
ID=26422076
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP63081036A Expired - Lifetime JP2729803B2 (en) | 1987-04-03 | 1988-04-01 | Mannobiose derivatives |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2729803B2 (en) |
-
1988
- 1988-04-01 JP JP63081036A patent/JP2729803B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| JPH01104088A (en) | 1989-04-21 |
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