JPH0426662A - Amino acid acyl derivative and preparation thereof - Google Patents
Amino acid acyl derivative and preparation thereofInfo
- Publication number
- JPH0426662A JPH0426662A JP2133264A JP13326490A JPH0426662A JP H0426662 A JPH0426662 A JP H0426662A JP 2133264 A JP2133264 A JP 2133264A JP 13326490 A JP13326490 A JP 13326490A JP H0426662 A JPH0426662 A JP H0426662A
- Authority
- JP
- Japan
- Prior art keywords
- group
- general formula
- formula
- amino acid
- compound
- 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
- 238000002360 preparation method Methods 0.000 title abstract description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 81
- -1 acyloxycarbonyl Chemical group 0.000 claims abstract description 31
- 125000003277 amino group Chemical group 0.000 claims abstract description 30
- 125000006239 protecting group Chemical group 0.000 claims abstract description 26
- 239000000126 substance Substances 0.000 claims abstract description 25
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims abstract description 19
- 230000002378 acidificating effect Effects 0.000 claims abstract description 15
- 229920006395 saturated elastomer Polymers 0.000 claims abstract description 15
- 125000004103 aminoalkyl group Chemical group 0.000 claims abstract description 14
- 150000004670 unsaturated fatty acids Chemical group 0.000 claims abstract description 13
- 239000002253 acid Substances 0.000 claims abstract description 12
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 12
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 6
- 238000000034 method Methods 0.000 claims description 28
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 19
- 150000003862 amino acid derivatives Chemical class 0.000 claims description 18
- 125000004432 carbon atom Chemical group C* 0.000 claims description 18
- 230000002829 reductive effect Effects 0.000 claims description 17
- 125000004473 dialkylaminocarbonyl group Chemical group 0.000 claims description 15
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 14
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 13
- 239000000194 fatty acid Substances 0.000 claims description 13
- 229930195729 fatty acid Natural products 0.000 claims description 13
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 13
- 150000003839 salts Chemical class 0.000 claims description 12
- 150000004671 saturated fatty acids Chemical class 0.000 claims description 12
- 238000004519 manufacturing process Methods 0.000 claims description 11
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
- 150000002367 halogens Chemical group 0.000 claims description 5
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 4
- 235000021122 unsaturated fatty acids Nutrition 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 125000004042 4-aminobutyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])N([H])[H] 0.000 claims 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims 1
- 229910052794 bromium Inorganic materials 0.000 claims 1
- 235000003441 saturated fatty acids Nutrition 0.000 claims 1
- 150000001413 amino acids Chemical class 0.000 abstract description 30
- 239000002502 liposome Substances 0.000 abstract description 20
- 239000000463 material Substances 0.000 abstract description 11
- 239000003093 cationic surfactant Substances 0.000 abstract description 10
- 239000012528 membrane Substances 0.000 abstract description 10
- 125000005843 halogen group Chemical group 0.000 abstract 1
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical group O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 abstract 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 20
- 239000002904 solvent Substances 0.000 description 11
- 150000004665 fatty acids Chemical class 0.000 description 10
- 239000004094 surface-active agent Substances 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 150000001408 amides Chemical class 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 9
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- 239000012043 crude product Substances 0.000 description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 150000002148 esters Chemical group 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 239000003054 catalyst Substances 0.000 description 5
- 238000010531 catalytic reduction reaction Methods 0.000 description 5
- 239000000470 constituent Substances 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- ZEMPKEQAKRGZGQ-AAKVHIHISA-N 2,3-bis[[(z)-12-hydroxyoctadec-9-enoyl]oxy]propyl (z)-12-hydroxyoctadec-9-enoate Chemical compound CCCCCCC(O)C\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/CC(O)CCCCCC)COC(=O)CCCCCCC\C=C/CC(O)CCCCCC ZEMPKEQAKRGZGQ-AAKVHIHISA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 4
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 4
- 239000004472 Lysine Substances 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 239000000654 additive Substances 0.000 description 4
- 229910052786 argon Inorganic materials 0.000 description 4
- 238000007796 conventional method Methods 0.000 description 4
- 239000007789 gas Substances 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 229910052763 palladium Inorganic materials 0.000 description 4
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- REYJJPSVUYRZGE-UHFFFAOYSA-N Octadecylamine Chemical compound CCCCCCCCCCCCCCCCCCN REYJJPSVUYRZGE-UHFFFAOYSA-N 0.000 description 3
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 3
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000000996 additive effect Effects 0.000 description 3
- 125000002091 cationic group Chemical group 0.000 description 3
- 239000003638 chemical reducing agent Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 230000032050 esterification Effects 0.000 description 3
- 238000005886 esterification reaction Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000012046 mixed solvent Substances 0.000 description 3
- 229930014626 natural product Natural products 0.000 description 3
- 229960003104 ornithine Drugs 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000006722 reduction reaction Methods 0.000 description 3
- 239000012279 sodium borohydride Substances 0.000 description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- BWZVCCNYKMEVEX-UHFFFAOYSA-N 2,4,6-Trimethylpyridine Chemical compound CC1=CC(C)=NC(C)=C1 BWZVCCNYKMEVEX-UHFFFAOYSA-N 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- IDCBOTIENDVCBQ-UHFFFAOYSA-N TEPP Chemical compound CCOP(=O)(OCC)OP(=O)(OCC)OCC IDCBOTIENDVCBQ-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 238000007112 amidation reaction Methods 0.000 description 2
- 239000003945 anionic surfactant Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound 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 2
- 239000010941 cobalt Substances 0.000 description 2
- 229910017052 cobalt Inorganic materials 0.000 description 2
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 2
- 238000006482 condensation reaction Methods 0.000 description 2
- 239000002537 cosmetic Substances 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 229910052697 platinum Inorganic materials 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- 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 1
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- 239000000232 Lipid Bilayer Substances 0.000 description 1
- 239000012448 Lithium borohydride Substances 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 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
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 125000004442 acylamino group Chemical group 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 150000004645 aluminates Chemical class 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 239000003876 biosurfactant Substances 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 150000001841 cholesterols Chemical class 0.000 description 1
- 239000013065 commercial product Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 235000008504 concentrate Nutrition 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 125000004989 dicarbonyl group Chemical group 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
- MKRTXPORKIRPDG-UHFFFAOYSA-N diphenylphosphoryl azide Chemical compound C=1C=CC=CC=1P(=O)(N=[N+]=[N-])C1=CC=CC=C1 MKRTXPORKIRPDG-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 150000002366 halogen compounds Chemical class 0.000 description 1
- ARBOVOVUTSQWSS-UHFFFAOYSA-N hexadecanoyl chloride Chemical compound CCCCCCCCCCCCCCCC(Cl)=O ARBOVOVUTSQWSS-UHFFFAOYSA-N 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 229910000040 hydrogen fluoride Inorganic materials 0.000 description 1
- 125000001165 hydrophobic group Chemical group 0.000 description 1
- LFKYBJLFJOOKAE-UHFFFAOYSA-N imidazol-2-ylidenemethanone Chemical compound O=C=C1N=CC=N1 LFKYBJLFJOOKAE-UHFFFAOYSA-N 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 229910052987 metal hydride Inorganic materials 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- CZWJWNQZTSMVAZ-ZDUSSCGKSA-N methyl (2s)-6-amino-2-(phenylmethoxycarbonylamino)hexanoate Chemical compound NCCCC[C@@H](C(=O)OC)NC(=O)OCC1=CC=CC=C1 CZWJWNQZTSMVAZ-ZDUSSCGKSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- PBMIETCUUSQZCG-UHFFFAOYSA-N n'-cyclohexylmethanediimine Chemical compound N=C=NC1CCCCC1 PBMIETCUUSQZCG-UHFFFAOYSA-N 0.000 description 1
- 229910000480 nickel oxide Inorganic materials 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- WTBAHSZERDXKKZ-UHFFFAOYSA-N octadecanoyl chloride Chemical compound CCCCCCCCCCCCCCCCCC(Cl)=O WTBAHSZERDXKKZ-UHFFFAOYSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000002902 organometallic compounds Chemical class 0.000 description 1
- GNRSAWUEBMWBQH-UHFFFAOYSA-N oxonickel Chemical compound [Ni]=O GNRSAWUEBMWBQH-UHFFFAOYSA-N 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- 238000010647 peptide synthesis reaction Methods 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- SSOLNOMRVKKSON-UHFFFAOYSA-N proguanil Chemical compound CC(C)\N=C(/N)N=C(N)NC1=CC=C(Cl)C=C1 SSOLNOMRVKKSON-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- UQDJGEHQDNVPGU-UHFFFAOYSA-N serine phosphoethanolamine Chemical compound [NH3+]CCOP([O-])(=O)OCC([NH3+])C([O-])=O UQDJGEHQDNVPGU-UHFFFAOYSA-N 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000005728 strengthening Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000013076 target substance Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 230000005944 tissue migration Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
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
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
【発明の詳細な説明】
(産業上の利用分野)
本発明は、アミノ酸アシル誘導体及びその製造法に関す
るものであり、更に詳しくは、安全性が高く、生分解性
の良いアミノ酸系カチオン性界面活性剤として有用な化
合物である、塩基性アミノ酸と呼吸脂肪酸からなる新規
なアミノ酸アシル誘導体及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 an amino acid acyl derivative and a method for producing the same. The present invention relates to a novel amino acid acyl derivative consisting of a basic amino acid and a respiratory fatty acid, which is a compound useful as a pharmaceutical agent, and a method for producing the same.
(従来の技術)
界面活性剤は、その1分子中に親水基と疎水基(親油基
)を併せもった両親媒性物質である。(Prior Art) A surfactant is an amphiphilic substance having both a hydrophilic group and a hydrophobic group (lipophilic group) in one molecule.
周知の如く、合成界面活性剤は多種多様な分野で広範に
利用されており、近年、バイオサーファクタント、すな
わち天然物及び天然物から誘導される天然系界面活性剤
が、従来の合成界面活性剤よりも安全性が高く、しかも
新しい機能、特性が期待されるとして注目を集めている
。As is well known, synthetic surfactants are widely used in a wide variety of fields, and in recent years, biosurfactants, that is, natural products and natural surfactants derived from natural products, have become more popular than conventional synthetic surfactants. It is attracting attention as it is highly safe and is expected to have new functions and characteristics.
アミノ酸系界面活性剤は、この天然系界面活性剤でもっ
とも代表的な界面活性剤であり、現在すでに香粧品分野
で数多く用いられており、その種類、用途ともにさらに
広がりを見せつつある。Amino acid surfactants are the most typical natural surfactants, and are already widely used in the cosmetics field, and their types and applications are expanding further.
しかしながら、従来のアミノ酸系界面活性剤のイオン性
は、そのほとんどがアニオン性、ノニオン性または両性
であり、カチオン性のものは補備かな例しか知られてい
ない。However, most of the ionic properties of conventional amino acid surfactants are anionic, nonionic, or amphoteric, and only a few examples of cationic surfactants are known.
高機能物質として、種々の特殊用途への利用が期待され
ているカチオン性のアミノ酸系界面活性剤については、
僅かな報告(特開昭51−5413号に示されているN
(2−長鎖アシル塩基性アミノ酸誘導体や、Noda
A、ら、Chem、 Phar−m、 Bul、1.
、19.196199 (1971)に示されるステロ
イド系のアミノ酸エステルの例等)があるに過ぎず、本
発明が対象とするような、そのカルボキシル基を低級ア
ルコール型やアミド型にした塩基性アミノ酸のN(2−
アミノ基を介して高級脂肪酸との酸アミド結合から成る
アミノ酸アシル系誘導体はほとんど見当たらない。Regarding cationic amino acid surfactants, which are expected to be used for various special purposes as highly functional substances,
A few reports (N shown in JP-A No. 51-5413)
(2-long chain acyl basic amino acid derivatives, Noda
A., et al., Chem, Phar-m, Bul, 1.
, 19.196199 (1971)), but there are only basic amino acid esters whose carboxyl group is in the lower alcohol type or amide type, which is the subject of the present invention. N(2-
Amino acid acyl derivatives consisting of an acid amide bond with a higher fatty acid via an amino group are rarely found.
他方、リポソーム(内殻に水相を有する脂質二分子膜小
胞)の膜材に用いられる正荷電物質(カチオン性界面活
性剤)としては、現在、合成界面活性剤であるステアリ
ルアミンだけが常用されているのが現状である。On the other hand, stearylamine, a synthetic surfactant, is currently the only positively charged substance (cationic surfactant) used in the membrane material of liposomes (lipid bilayer vesicles with an aqueous inner shell). The current situation is that
しかしながら、このステアリルアミンの毒性に関する報
告(例えば、Tyrell、 D、 A、ら、Bioc
himBjo h s、Acta、、457,259(
1976) ; Adams、D、A、ら;J、Ne
urol、 Sci、 、 31.173〜(1977
)等)もあり、ステアリルアミンを生体系に用いる場合
には、その安全件に十分留意する必要を生ずるという問
題がある。However, reports regarding the toxicity of stearylamine (e.g. Tyrell, D. A., et al., Bioc.
himBjo hs, Acta, 457,259 (
1976); Adams, D. A., et al.; J. Ne.
urol, Sci, 31.173~ (1977
), etc.), and when stearylamine is used in biological systems, there is a problem in that it is necessary to pay sufficient attention to safety issues.
したがって、このような問題を解決するためには、安全
性が高く、高機能を発現するリポソーム膜材用正荷電物
質としてのカチオン性界面活性剤が強(要望されている
のが現状である。Therefore, in order to solve such problems, there is currently a demand for strong cationic surfactants as positively charged substances for liposome membrane materials that are highly safe and exhibit high functionality.
(発明が解決しようとする課題)
本発明の目的は、安全性が高く、生分解性に優れ、高機
能で、特にリポソーム膜材用正荷電物質として有用なア
ミノ酸系カチオン性界面活性剤を提供し、かつ、これを
効率よく製造することができる方法を提供することにあ
る。(Problems to be Solved by the Invention) An object of the present invention is to provide an amino acid-based cationic surfactant that is highly safe, has excellent biodegradability, is highly functional, and is particularly useful as a positively charged substance for liposome membrane materials. The object of the present invention is to provide a method that can efficiently manufacture the same.
(課題を解決するための手段)
上記した目的を実現する本発明は、塩基性アミノ酸と高
級脂肪酸から成る新規なアミノ酸アシル系誘導体が前述
の要望を満足する化合物であること、及びこの化合物を
効率よ(製造する方法を見出したことに基づいて成され
たものであり、以下その要旨を詳細に説明する。(Means for Solving the Problems) The present invention achieves the above-mentioned objects by providing that a novel amino acid acyl derivative consisting of a basic amino acid and a higher fatty acid is a compound that satisfies the above-mentioned requirements, and that this compound can be efficiently produced. This was accomplished based on the discovery of a manufacturing method for this method, and its gist will be explained in detail below.
即ち本発明は、一般式[工] :
O
[式中、RICOは炭素数が14〜20の飽和または不
飽和脂肪酸残基、R2はヒドロキシメチル、アルキルオ
キシカルボニル、アミノカルボニル、または低級モノも
しくはジアルキルアミノカルボニル基を表す。R3は低
級アミノアルキル基を表す]で示される塩基性アミノ酸
アシル誘導体及びその酸付加塩、更には、これらの化合
物の製造方法をその特徴とするものである。That is, the present invention has the following formula: Represents an aminocarbonyl group. R3 represents a lower aminoalkyl group] Basic amino acid acyl derivatives and acid addition salts thereof, and methods for producing these compounds are featured.
また、一般式[■] :
O
[式中、
RICOは炭素数が14〜20の飽和または不飽和脂肪
酸残基、R2はヒドロキシメチル、アルキルオキシカル
ボニル、アミノカルボニル、または低級モノもしくはジ
アルキルアミノカルボニル基を表す。R4は低級アミノ
アルキル基の末端アミン基に酸性条件下もしくは還元的
に脱離可能な保護基が付いたものを表す]で示される塩
基性アミノ酸アシル誘導体、更には、これらの化合物の
製造方法をその特徴とするもので・ある。In addition, the general formula [■]: O [wherein RICO is a saturated or unsaturated fatty acid residue having 14 to 20 carbon atoms, R2 is hydroxymethyl, alkyloxycarbonyl, aminocarbonyl, or a lower mono- or dialkylaminocarbonyl group represents. R4 represents a lower aminoalkyl group with a protective group attached to the terminal amine group that can be removed under acidic conditions or reductively], as well as methods for producing these compounds. This is its characteristic.
上記一般式[I]で示される化合物は、具体的には塩基
性アミノ酸であるリジン、オルニチンのカルボキシル基
がその還元型であるヒドロキシメチル基、そのエステル
型であるt−ブトキシカルボニル基、もしくはそのアミ
ド型であるアミノカルボニル基、または炭素数が1〜6
の直鎖または分岐鎖アルキル基から・なるモノもしくは
ジカルボニル基に変換された化合物であり、そのNa−
アミン基と高級脂肪酸とが酸アミド結合している塩基性
アミノ酸アシル誘導体、またはその酸付加塩である。Specifically, the compound represented by the above general formula [I] is a basic amino acid such as lysine or ornithine whose carboxyl group is a hydroxymethyl group which is its reduced form, a t-butoxycarbonyl group which is its ester form, or a t-butoxycarbonyl group which is its ester form. Aminocarbonyl group that is amide type or has 1 to 6 carbon atoms
It is a compound that has been converted into a mono- or dicarbonyl group consisting of a linear or branched alkyl group, and its Na-
It is a basic amino acid acyl derivative in which an amine group and a higher fatty acid are bonded through an acid amide bond, or an acid addition salt thereof.
これらの化合物は、アミノ酸系カチオン性界面活性剤で
あり、天然物構成要素の再結合及び化学修飾して得られ
る新規な天然系界面活性剤と言える。These compounds are amino acid-based cationic surfactants, and can be said to be novel natural surfactants obtained by recombining and chemically modifying natural product constituents.
また一般式[IT]で示される化合物は、アミノ酸部分
の末端アミノ基に、アミノ基の保護基であるベンジルオ
キシカルボニル基、t−ブトキシカルボニル基が付いた
化合物であり、これらの保護基を常法により還元的もし
くは酸性条件下で脱離させることにより、上記一般式[
I]で示される化合物を得ることができる。In addition, the compound represented by the general formula [IT] is a compound in which a benzyloxycarbonyl group or a t-butoxycarbonyl group, which is a protecting group for the amino group, is attached to the terminal amino group of the amino acid moiety. The above general formula [
A compound represented by I] can be obtained.
一般式[I]及び[II]で示される化合物の構成部分
の一つである塩基性アミノ酸は、分子内にアミノ基とカ
ルボキシル基を各々1個づつ有する他に、アミノ基、グ
アニジノ基、イミダゾリル基等の塩基性置換基を1個以
上有する塩基性アミノ酸であればよく、例えば天然由来
のリジン、オルニチン、アルギニン、ヒスチジン等が挙
げられるが、この他にも安全性が高いものであれば同様
に使用できる。Basic amino acids, which are one of the constituent parts of the compounds represented by general formulas [I] and [II], have one amino group and one carboxyl group in the molecule, as well as an amino group, a guanidino group, and an imidazolyl group. Any basic amino acid having one or more basic substituents such as a group may be used, such as naturally occurring lysine, ornithine, arginine, histidine, etc., but other amino acids may also be used as long as they are highly safe. Can be used for
不斉炭素原子を有するアミノ酸には光学異性体が存在す
るが、特に安全性に問題がない限り、L体、D体、DL
体のいずれも使用しつる。Amino acids with asymmetric carbon atoms have optical isomers, but unless there is a particular safety problem, L-form, D-form, DL-form
Use any part of your body.
本発明で使用しつる塩基性アミノ酸の内、量産化が進み
、極めて安価に入手できるリジンは、特に原料アミノ酸
として最適なものの一つである。Among the basic amino acids used in the present invention, lysine, which has been mass-produced and is available at an extremely low cost, is one of the most suitable amino acids as a raw material amino acid.
また、一般式[I]及び[II]で示される化合物のも
う一方の構成成分の一つである高級脂肪酸は、その脂肪
酸残基の炭素数が14〜20個で飽和または不飽和であ
れば特に制限はないが、より生体適合性を高め、また保
存安定性向上のためには、飽和の脂肪残基であることが
好ましい。Further, higher fatty acids, which are one of the other constituent components of the compounds represented by general formulas [I] and [II], can be used if the fatty acid residue has 14 to 20 carbon atoms and is saturated or unsaturated. Although there are no particular limitations, saturated fatty residues are preferred in order to further enhance biocompatibility and improve storage stability.
一般式[I]及び[nlで示される化合物の製造方法は
、一般式[1[1]:
[式中、R2はヒドロキシメチル、アルキルオキシカル
ボニル、アミノカルボニル、または低級モノもしくはジ
アルキルアミノカルボニル基を表す。R4は低級アミノ
アルキル基の末端アミノ基に酸性条件下もしくは還元的
に脱離可能な保護基がついたものを表す]で示される化
合物と、
一般式[TV]
X CR1[IV]
[式中、Xはハロゲンを表し、RICOは炭素数が14
〜20の飽和または不飽和脂肪酸残基な表す]で示され
る高級脂肪酸ハロゲン化物とを縮合することによって、
−M式[11]で示される化合物を得ることができ、ま
た一般式[n]で示される化合物中のR4である低級ア
ミノ基の末端アミノ基についている保護基を脱離させる
ことによって、一般式[I]で示される化合物を製造す
ることができる。The method for producing compounds represented by general formulas [I] and [nl is as follows: represent. R4 represents a lower aminoalkyl group with a protective group attached to the terminal amino group that can be removed under acidic conditions or reductively] and a compound represented by the general formula [TV] , X represents halogen, and RICO has 14 carbon atoms.
By condensing with a higher fatty acid halide represented by ~20 saturated or unsaturated fatty acid residues,
-M The compound represented by the formula [11] can be obtained, and by removing the protecting group attached to the terminal amino group of the lower amino group that is R4 in the compound represented by the general formula [n], the general A compound represented by formula [I] can be produced.
一般式[rl’llで示される化合物は、具体的には、
塩基性アミノ酸であるリジン、オルニチンのカルボキシ
ル基が、その゛還元型であるヒドロキシメチル基、その
エステル型であるt−ブトキシカルボニル基、もしくは
そのアミド型であるアミノカルボニル基、または炭素数
が1〜6の直鎖または分岐鎖アルキル基からなるモノも
しくはジアルキルアミノカルボニル基に変換された化合
物であり、そのNa−アミン基は未置換でフリーである
が、その末端アミノ基には、保護基であるベンジルオキ
シカルボニル基、t−ブトキシカルボニル基が付いてい
る化合物である。Specifically, the compound represented by the general formula [rl'll is:
The carboxyl group of the basic amino acids lysine and ornithine is a hydroxymethyl group which is its reduced form, a t-butoxycarbonyl group which is its ester form, an aminocarbonyl group which is its amide form, or a carbon number of 1 to 1. It is a compound converted into a mono- or dialkylaminocarbonyl group consisting of a straight-chain or branched-chain alkyl group of 6, and its Na-amine group is unsubstituted and free, but its terminal amino group has a protective group. It is a compound with a benzyloxycarbonyl group or t-butoxycarbonyl group.
一般式[m]で示される化合物である塩基性アミノ酸誘
導体の内、R2部分がその還元型であるヒドロキシメチ
ル基に変換された化合物は、公知の方法(例えば、5h
unichi Yamadaら; Chem。Among the basic amino acid derivatives represented by the general formula [m], the compound in which the R2 moiety is converted to its reduced form, hydroxymethyl group, can be prepared by a known method (for example, 5h
unichi Yamada et al; Chem.
Pharm、 Bull、旦(9)、 1140〜11
45 (1963)や特開昭52−148036号等)
に準じて合成することができる。Pharm, Bull, Dan (9), 1140-11
45 (1963) and JP-A-52-148036, etc.)
It can be synthesized according to
即ち、まず、一般式[III ]で示される化合物の塩
基性アミノ酸誘導体の内、カルボキシル基部分がそのエ
ステル型になったアミノ酸誘導体またはその酸付加塩を
原料化合物として、これに−数的な還元方法、例えば適
当な溶媒中で、還元剤に接触させる等の方法を適用して
一般式[ITI]で示される化合物である塩基性アミノ
酸誘導体の内、カルボキシル基部分がその還元型である
ヒドロキシメチル基に置換された化合物を得ることがで
きる。That is, first, among the basic amino acid derivatives of the compound represented by the general formula [III], an amino acid derivative in which the carboxyl group moiety is in the ester form or an acid addition salt thereof is used as a raw material compound, and this is numerically reduced. Hydroxymethyl whose carboxyl group moiety is the reduced form of the basic amino acid derivative, which is a compound represented by the general formula [ITI], is obtained by applying a method such as contacting with a reducing agent in an appropriate solvent. Compounds substituted with groups can be obtained.
この場合の還元剤としては、例えば水素化硼素リチウム
、水素化硼素ナトリウム、水素化リチウムアルミニウム
等の水素化金属化合物、ナトリウム・ジヒドロ・ビス−
(2−メトキシエトキシ)アルミネート等の水素化有機
金属化合物またはジボランなどが挙げられるが、特にこ
れらに限定されない。また、これらの還元剤とともに添
加剤として、例えば塩化カルシウム等のハロゲン化合物
を併用できる。Examples of the reducing agent in this case include metal hydride compounds such as lithium borohydride, sodium borohydride, lithium aluminum hydride, sodium dihydro bis-
Examples include, but are not limited to, hydrogenated organometallic compounds such as (2-methoxyethoxy)aluminate, diborane, and the like. Further, a halogen compound such as calcium chloride can be used together with these reducing agents as an additive.
還元時の溶媒としては、例えば水素化硼素ナトリウムを
使用する場合は、アルコール類または含水アルコール類
などの溶媒が使用できるが、この他にも還元反応に影響
を与えない溶媒、例えばジオキサン、テトラハイドロフ
ラン、エチルエーテル、ジエチレングリコールジメチル
エーテル等のエーテル類またはベンゼン等の芳香族類な
ども使用しうる。またこれらの溶媒とともに添加剤とし
て、例えばジエチルアミン、ピリジン、アニリン、N−
メチルアミン、γ−コリジン等のアミン類を併用しても
よい。As a solvent during reduction, for example, when using sodium borohydride, solvents such as alcohols or hydrous alcohols can be used, but other solvents that do not affect the reduction reaction, such as dioxane and tetrahydrohydride, can also be used. Ethers such as furan, ethyl ether, diethylene glycol dimethyl ether, or aromatics such as benzene may also be used. In addition to these solvents, additives such as diethylamine, pyridine, aniline, N-
Amines such as methylamine and γ-collidine may be used in combination.
還元時の反応温度は、一般に室温でも進行するが、適宜
、冷却または加熱して反応を有利に進行させてもよい。The reaction temperature during reduction generally proceeds at room temperature, but the reaction may be appropriately cooled or heated to advantageously proceed.
一般式[III ]で示される化合物である塩基性アミ
ノ酸誘導体の内、R2部分がそのエステル型であるアル
キルオキシカルボニル基に変換された化合物は、前述の
ように、一般式[rlI]で示される化合物である塩基
性アミノ酸誘導体の内、R2部分がその還元型であるヒ
ドロキシメチル基に変換された化合物を合成するための
出発原料物質とする場合と同様にして製造できる。Among basic amino acid derivatives that are compounds represented by the general formula [III], compounds in which the R2 moiety is converted to an alkyloxycarbonyl group, which is the ester type thereof, are represented by the general formula [rlI], as described above. It can be produced in the same manner as when using it as a starting material for synthesizing a basic amino acid derivative compound in which the R2 moiety is converted to its reduced form, hydroxymethyl group.
一般式[m]で示される化合物の塩基性アミノ酸誘導体
の内、R2部分がエステル型であるアルキルオキシカル
ボニル基に変換された化合物は、一般式[■■′]で示
される化合物中のR2′であるカルボキシル基部分を前
述のようにして、常法によりエステル化することにより
製造でき、また、R2部分がそのアミド型であるアミノ
カルボニル基、または炭素数が1〜6個の直鎖または分
岐鎖アルキル基から成るモノもしくはジアルキルアミノ
カルボニル基に変換された化合物は、一般式[■II′
]で示される化合物のR2′であるカルボキシル基部分
を公知の方法により、酸アミド型に変換することにより
製造できる。Among the basic amino acid derivatives of the compound represented by the general formula [m], the compound in which the R2 moiety is converted to an ester-type alkyloxycarbonyl group is the R2' in the compound represented by the general formula [■■']. It can be produced by esterifying the carboxyl group moiety as described above by a conventional method, and the R2 moiety is an amide carbonyl group, or a linear or branched chain having 1 to 6 carbon atoms. A compound converted into a mono- or dialkylaminocarbonyl group consisting of a chain alkyl group has the general formula [■II'
It can be produced by converting the carboxyl group portion, which is R2', of the compound represented by the above into an acid amide type by a known method.
即ち、公知の方法としては、一般にペプチド結合反応に
用いられる活性エステル化法、混合酸無水物化法、アジ
ド法、酸塩化物法、対称無水物法及びカップリング試薬
等を用いる方法が挙げられる。That is, known methods include an active esterification method, a mixed acid anhydride method, an azide method, an acid chloride method, a symmetric anhydride method, and a method using a coupling reagent, which are generally used in peptide bonding reactions.
このカップリング試薬としては、例えばN。Examples of this coupling reagent include N.
N′−シクロへキシルカルボジイミド、カルボニルイミ
ダゾール、ジフェニルホスホリルアジド等、及びN、N
′−シクロへキシルカルボジイミドと添加剤とを用いる
方法等がある。この場合の添加剤としては、N−ヒドロ
キシスフシイミド、1−ヒドロキシベンゾトリアゾール
、N−ヒドロキシ−5−ノルボルネン−12,3−ジカ
ルボン酸イミド等が挙げられる。N'-cyclohexylcarbodiimide, carbonylimidazole, diphenylphosphoryl azide, etc., and N,N
There is a method using '-cyclohexylcarbodiimide and an additive. Examples of the additive in this case include N-hydroxysufushiimide, 1-hydroxybenzotriazole, N-hydroxy-5-norbornene-12,3-dicarboxylic acid imide, and the like.
一般式[IV]で示される化合物は、具体的には高級脂
肪酸の酸ハロゲン化物であり、公知の方法によって合成
しつるとともに、例えばパルチミン酸クロライド、ステ
アリン酸クロライド等の市販品として容易に入手しつる
。The compound represented by the general formula [IV] is specifically an acid halide of a higher fatty acid, which can be synthesized by a known method or easily obtained as a commercial product such as palmitic acid chloride or stearic acid chloride. Vine.
−M式[IV]で示される化合物中のXで表わされるハ
ロゲンは、特に限定しないが、一般に塩素が常用される
。-M The halogen represented by X in the compound represented by formula [IV] is not particularly limited, but chlorine is generally used.
一般式[IIT ]及び[IV ]で示される化合物を
縮合させることによって一般式[II ]で示される化
合物を得るためには、この両者を、常法により、適当な
溶媒中、塩基性条件下で、反応させることによることが
できる。In order to obtain the compound represented by the general formula [II] by condensing the compounds represented by the general formula [IIT] and [IV], both of them are combined in a suitable solvent under basic conditions by a conventional method. This can be done by reacting with
また、上述のように一般式[rlT]及び[lV]で示
される化合物を縮合させることによって、一般式[II
]で示される化合物を得る方法とは別に、一般式[II
I]で示される化合物と炭素数が14〜20の飽和また
は不飽和脂肪酸とを、塩基性条件下、縮合剤を用いて縮
合することによって得ることができる。Further, as mentioned above, by condensing the compounds represented by the general formulas [rlT] and [lV], the general formula [II
] Apart from the method for obtaining the compound represented by the general formula [II
It can be obtained by condensing the compound represented by I] with a saturated or unsaturated fatty acid having 14 to 20 carbon atoms using a condensing agent under basic conditions.
即ちこの場合、前記の一般式[ITI]で示される化合
物の塩基性アミノ酸誘導体の内、R2部分がそのアミド
型であるアミノカルボニル基、または炭素数が1〜6個
の直鎖または分岐鎖アルキル基からなるモノもしくはジ
アルキルアミノカルボニル基に変換された化合物を得る
ために、 M式[11T′]で示される化合物のR2′
であるカルボキシル基部分を酸アミド型に変換した場合
の前述の製造法及び諸条件が同様に適用できる。That is, in this case, among the basic amino acid derivatives of the compound represented by the general formula [ITI], an aminocarbonyl group in which the R2 moiety is an amide type thereof, or a linear or branched alkyl group having 1 to 6 carbon atoms. In order to obtain a compound converted into a mono- or dialkylaminocarbonyl group consisting of a group, R2' of a compound represented by M formula [11T']
The above-mentioned production method and conditions for converting the carboxyl group moiety into an acid amide type can be similarly applied.
以上のようにして、化合物[II]を得ることができる
が、この方法とは別に、一般式[II]で示される化合
物の内、R2部分のカルボキシル基が、そのエステル型
であるアルキルオキシカルボニル基、そのアミド型であ
るアミノカルボニル基、または炭素数が1〜6個の直鎖
または分岐鎖アルキル基から成るモノもしくはジアルキ
ルアミノカルボニル基に変換された化合物は、下記の方
法によっても製造しつる。Compound [II] can be obtained as described above, but apart from this method, in the compound represented by general formula [II], the carboxyl group of the R2 portion is alkyloxycarbonyl, which is the ester type thereof. A compound converted into a mono- or dialkylaminocarbonyl group consisting of a group, its amide type aminocarbonyl group, or a linear or branched alkyl group having 1 to 6 carbon atoms can also be produced by the following method. .
即ち、一般式[III′]
[式中、R2′はカルボキシル基を表す。R4は低級ア
ミノアルキルの末端アミノ基に酸性条件下もしくは還元
的に脱離可能な保護基が付いたものを表す]で示される
化合物と、一般式[IV ]で示される高級脂肪酸ハロ
ゲン化物とを縮合することによって、
一般式[■′]
R2′
H○
[式中、RICOは炭素数が14〜20の飽和または不
飽和脂肪酸残基、R2′はカルボキシル基を表す。R4
は低級アミノアルキル基の末端アミノ基に酸性条件下も
しくは還元的に脱離可能な保護基が付いたものを表す]
で示される化合物を得た後、この一般式[■′]中のR
2′のカルボキシル基をアルキルオキシカルボニル、ア
ミノカルボニル、または低級モノもしくはジアルキルア
ミノカルボニル基に変換し、一般式[n]で示される化
合物(但し、この場合、R2はアルキルオキジカルボニ
ル、アミノカルボニル、または低級モノもしくはジアル
キルアミノカルボニル基のみを表わす)を得ることがで
きる。That is, the general formula [III'] [wherein R2' represents a carboxyl group]. R4 represents a lower aminoalkyl with a protective group attached to the terminal amino group that can be removed under acidic conditions or reductively] and a higher fatty acid halide represented by the general formula [IV]. By condensation, the general formula [■'] R2' H○ [wherein RICO represents a saturated or unsaturated fatty acid residue having 14 to 20 carbon atoms, and R2' represents a carboxyl group. R4
represents a lower aminoalkyl group with a protective group attached to the terminal amino group that can be removed under acidic conditions or reductively]
After obtaining the compound represented by, R in this general formula [■']
2' carboxyl group is converted to alkyloxycarbonyl, aminocarbonyl, or lower mono- or dialkylaminocarbonyl group, and the compound is represented by the general formula [n] (However, in this case, R2 is alkyloxycarbonyl, aminocarbonyl, or representing only lower mono- or dialkylaminocarbonyl groups).
更に、この方法により得た一般式[nlで示される化合
物中のR4である低級アルキル基の末端アミノ基に付い
ている保護基を脱離させることによって、一般式[I]
で示される化合物(但し、この場合、R2はアルキルオ
キシカルボニル、アミノカルボニル、または低級モノも
しくはジアルキルアミノカルボニル基のみを表わす)を
得ることができる。Furthermore, by removing the protecting group attached to the terminal amino group of the lower alkyl group R4 in the compound of general formula [nl obtained by this method, general formula [I]
A compound represented by (in this case, R2 represents only an alkyloxycarbonyl, aminocarbonyl, or lower mono- or dialkylaminocarbonyl group) can be obtained.
即ち、具体的には、一般式[111′lで示される化合
物中のR4の末端アミノ基保護基塩基性アミノ酸のカル
ボキシル基は、未処理、未置換で、そのままフリーの状
態であることを表している。That is, specifically, the carboxyl group of the terminal amino group protecting group basic amino acid of R4 in the compound represented by the general formula [111'l is untreated, unsubstituted, and is in a free state as it is. ing.
この一般式[IH′]で示される化合物と一般式[IV
]で示される化合物を、上記と同様にして縮合反応さ
せ、一般式[TI′]で示される化合物をまず得た後に
、この化合物のカルボキシル基を、上記の一般式[I]
で表わされる化合物の場合と同様の方法でエステル化も
しくはアミド化することによって、一般式[ITJの化
合物(但し、この場合、R2はアルキルオキシカルボニ
ル、アミノカルボニル、または低級モノもしくはジアル
キルアミノカルボニル基のみを表わす)を製造しつる。The compound represented by the general formula [IH'] and the general formula [IV
] is subjected to a condensation reaction in the same manner as above to obtain a compound represented by the general formula [TI'], and then the carboxyl group of this compound is converted into the compound represented by the general formula [I]
By esterification or amidation in the same manner as in the case of the compound represented by ) is manufactured.
この場合の縮合反応、エステル化、アミド化反応及び精
製工程等の諸条件は、前述の一般式[TII]と[IT
Jで示される化合物の製造における諸条件が同様に適用
できる。In this case, the conditions for the condensation reaction, esterification, amidation reaction, purification step, etc. are based on the general formula [TII] and [IT
The conditions for the preparation of the compound represented by J are similarly applicable.
以上のようにして得られた一般式[■]で示される化合
物の末端アミノ基に付いている保護基であるベンジルオ
キシカルボニル基、またはt−ブトキシカルボニル基を
常法により還元的もしくは酸性条件下で脱離させること
により、一般式[nlで示される化合物を得ることがで
きる。The benzyloxycarbonyl group or t-butoxycarbonyl group, which is a protecting group attached to the terminal amino group of the compound represented by the general formula [■] obtained as above, is removed under reducing or acidic conditions by a conventional method. By eliminating with , a compound represented by the general formula [nl can be obtained.
保護基を脱離させる反応は、ペプチド合成における公知
の方法により行ない得る。The reaction for removing the protecting group can be carried out by a known method for peptide synthesis.
即ち、例えば、還元的に保護基を脱離させる方法として
は、接触還元法等が用いられる。That is, for example, as a method for reductively removing a protecting group, a catalytic reduction method or the like is used.
接触還元に用いられる触媒としては、例えば白金、酸化
白金等の白金触媒類、パラジウム、パラジウム−炭素等
のパラジウム触媒類、酸化ニッケル、ラネーニッケル等
の触媒類、またはラネーコバルト等のコバルト触媒類が
挙げられ、接触還元時の溶媒としては、通常、水、メタ
ノール、エタノール、プロパツール、N、N−ジメチル
ホルムアミド、酢酸、ギ酸等もしくはこれらの混合溶媒
等が挙げられる。Examples of catalysts used for catalytic reduction include platinum catalysts such as platinum and platinum oxide, palladium catalysts such as palladium and palladium-carbon, catalysts such as nickel oxide and Raney nickel, and cobalt catalysts such as Raney cobalt. The solvent used in the catalytic reduction usually includes water, methanol, ethanol, propatool, N,N-dimethylformamide, acetic acid, formic acid, or a mixed solvent thereof.
また、酸性条件下での脱保護法において用いられる酸と
しては、例えば、トリフルオロ酢酸、塩酸、ギ酸、フッ
化水素等が挙げられ、この場合の溶媒としては、例えば
、ジクロロメタン、クロロホルム、ジオキサン、テトラ
ヒドロフラン、酢酸等が挙げられるが、特にこれらに限
定されるものではない。In addition, examples of acids used in the deprotection method under acidic conditions include trifluoroacetic acid, hydrochloric acid, formic acid, hydrogen fluoride, etc., and examples of solvents in this case include dichloromethane, chloroform, dioxane, Examples include, but are not limited to, tetrahydrofuran and acetic acid.
以上のようにして得られた一般式[I]で示される化合
物の酸付加塩としては、例えばギ酸塩、酢酸塩、トリフ
ルオロ酢酸塩、マレイン酸塩、酒石酸塩、シュウ酸塩等
の有機酸付加塩、または塩酸塩、硫酸塩、臭化水素酸塩
、硝酸塩等の無機酸付加塩等が挙げられるが、特にこれ
らに限定されない。Examples of the acid addition salt of the compound represented by the general formula [I] obtained as above include organic acid salts such as formate, acetate, trifluoroacetate, maleate, tartrate, and oxalate. Examples include addition salts, and inorganic acid addition salts such as hydrochloride, sulfate, hydrobromide, and nitrate, but are not particularly limited thereto.
一般式[I]で示される化合物の酸付加塩は、必要に応
じ、適宜、その付加塩を常法により除去し、無塩型に戻
して使用しつる。The acid addition salt of the compound represented by the general formula [I] can be used by removing the addition salt by a conventional method and returning it to a salt-free form, if necessary.
この化合物は天然物構成要素であるアミノ酸と高級脂肪
酸類とを再結合及び化学修飾して得られた天然系アミノ
酸アシル誘導体であり、安全性が高く、生分解性に優れ
たアミノ酸系カチオン性界面活性剤と言える。This compound is a natural amino acid acyl derivative obtained by recombining and chemically modifying amino acids and higher fatty acids, which are natural constituents, and is an amino acid-based cationic interface with high safety and excellent biodegradability. It can be said to be an activator.
また、一般式[I]で示される化合物は、アミノ酸と脂
肪酸とが酸アミド結合しており、しかもアミノ酸のカル
ボキシル基部分が還元され、低級アルコール型になって
いるか、またはアミド化されアミド型になっているため
、安全で、かつ安定であるため、製剤化のための原料と
して配合する場合に有利である。In addition, the compound represented by the general formula [I] has an acid amide bond between an amino acid and a fatty acid, and the carboxyl group of the amino acid is reduced to a lower alcohol type, or amidated to an amide type. Therefore, it is safe and stable, so it is advantageous when used as a raw material for formulation.
多くの報告(例えば、特開昭58−134197号等)
にあるように、アミノ酸高級アルキルエステル塩やその
N−低級アルキル置換体は、エステル塩の共通の欠点と
してその構造中にエステル結合を有するために加水分解
性が大きく、製品中に安定に配合することが困難な場合
が多いとされる。Many reports (for example, JP-A-58-134197, etc.)
As shown in , amino acid higher alkyl ester salts and their N-lower alkyl substituted products have a common drawback of ester salts, as they have an ester bond in their structure, which makes them highly hydrolyzable, making it difficult to stably incorporate them into products. It is said that this is often difficult.
また、アミノ酸系誘導体をリポソーム形成材料として利
用する報告(例えば、特開昭63−2921号等)があ
るが、この報告では、N−高級アシルアミノ酸であるア
ミノ酸系アニオン性界面活性剤を、生体で分解しやすく
、毒性の低い、リポソーム形成能を持つ脂質として使用
している。Additionally, there are reports on the use of amino acid derivatives as liposome-forming materials (for example, JP-A No. 63-2921, etc.), but in this report, amino acid-based anionic surfactants, which are N-higher acylamino acids, are used as liposome-forming materials. It is used as a lipid that is easily degradable, has low toxicity, and has the ability to form liposomes.
さらにアミノ酸脂質誘導体でリポソームを修飾し、癌細
胞へターゲツティングを試みた報告(第7回生物薬剤学
研究会要旨集、p、49〜(1989)等)もあるが、
この報告では市販のアミノ酸系カチオン性界面活性剤で
あるNa−ココイル−アルギニンエチルエステル(CE
A)等を用いており、アミノ酸で膜修飾したリポソーム
の新たな特性についての研究に着手している。Furthermore, there are reports of attempts to target cancer cells by modifying liposomes with amino acid lipid derivatives (Proceedings of the 7th Biopharmaceutical Research Society, p. 49-(1989), etc.);
This report describes a commercially available amino acid-based cationic surfactant, Na-cocoyl-arginine ethyl ester (CE).
A), etc., and have begun research on new properties of liposomes whose membranes are modified with amino acids.
また更に、アミノ基を有するコレステロール誘導体によ
るリポソームの表面修飾に関する報告(例えば、K、R
,Patelら、Biochimica et Bio
hsica 〜」」ユ郵、 256−264 (1
985)等)があるが、本発明のようなアミノ酸アシル
系カチオン性誘導体に関する報告は見当たらない。Furthermore, there are reports on the surface modification of liposomes with cholesterol derivatives having amino groups (e.g., K, R
, Patel et al., Biochimica et Bio
hsica ~” Yu Post, 256-264 (1
985), etc.), but no reports regarding amino acid acyl-based cationic derivatives such as those of the present invention have been found.
ところでリポソームの構成部分は、−数的に大別して3
種類、即ち、基材となる各種リン脂質、膜強化物質とし
てのコレステロール、及び膜荷電物質として各種カチオ
ン性またはアニオン性界面活性剤により成り立っており
、またリポソームに荷電物質を添加し、表面荷電を付与
することによりリポソーム同士の凝集を防止し、ラメラ
層間の静電的反発力により内殻水相を広げ、水溶性封入
物質のリポソームへの封入保持量等を増加させると同時
に、使用される荷電物質の種類によって、生体内でのリ
ポソームの挙動(例えば組織移行性等)が大きく影響さ
れることが知られている。By the way, the constituent parts of liposomes can be roughly divided into 3 parts.
The liposomes are made up of various types of phospholipids as base materials, cholesterol as membrane-strengthening substances, and various cationic or anionic surfactants as membrane-charged substances, and charged substances are added to liposomes to increase surface charge. This prevents aggregation between liposomes, expands the inner aqueous phase due to electrostatic repulsion between the lamellar layers, and increases the amount of water-soluble encapsulated substances encapsulated in the liposomes. It is known that the behavior of liposomes in vivo (for example, tissue migration) is greatly influenced by the type of substance.
一方、本発明のアミノ酸アシル系カチオン性界面活性剤
は、これをリポソーム膜材として利用する場合には、そ
の化学構造上、正荷電物質であるとともに、リポソーム
を塩基性アミノ酸により表面修飾する特徴を有している
。On the other hand, when the amino acid acyl-based cationic surfactant of the present invention is used as a liposome membrane material, due to its chemical structure, it is a positively charged substance and also has the characteristic of surface-modifying liposomes with basic amino acids. have.
(発明の効果)
以上のような説明から明らかなように、本発明によれば
、新規な天然系アミノ酸誘導体として、(1)安全性が
高く、生分解性に優れ、アミノ酸と高級脂肪酸が酸アミ
ド結合し、しかもアミノ酸のカルボキシル基部分が還元
型もしくはアミド型になっているため、
(2)製品(製剤)中に安定に配合できる。(Effects of the Invention) As is clear from the above explanation, according to the present invention, as a novel natural amino acid derivative, (1) it is highly safe and has excellent biodegradability, and amino acids and higher fatty acids are Because it has an amide bond and the carboxyl group of the amino acid is in the reduced or amide form, (2) it can be stably incorporated into products (preparations).
またリポソーム膜材として利用する場合、(3)安全で
新規な膜荷電物質
として、また
(4)アミノ酸修飾リポソームのための膜物質として、
従来にない特性をリポソームに付与しつる等の利点が期
待できるアミノ酸系カチオン性界面活性剤を提供するこ
とができる。In addition, when used as a liposome membrane material, (3) as a safe and novel membrane charged substance, and (4) as a membrane material for amino acid-modified liposomes.
It is possible to provide an amino acid-based cationic surfactant that imparts unprecedented properties to liposomes and can be expected to have benefits such as stiffness.
従って、本発明の化合物は、安全性、生体適合性、生体
膜との種々の親和性を配慮しなければならない医用リポ
ソーム等の分野への利用に適したアミノ酸系誘導体であ
るとともに、生医学用材料、化粧品への応用等、また、
さらに生化学、医学、薬学、工学等など幅広い分野にお
ける利用が期待され、その工業的価値は大きい。Therefore, the compound of the present invention is an amino acid derivative suitable for use in fields such as medical liposomes, which require consideration of safety, biocompatibility, and various compatibility with biological membranes, and is also suitable for use in biomedical applications. Materials, cosmetic applications, etc.
Furthermore, it is expected to be used in a wide range of fields such as biochemistry, medicine, pharmacy, and engineering, and its industrial value is great.
(実施例)
次に実施例により、本発明をさらに詳細に説明するが、
これらに限定されるものではない。(Example) Next, the present invention will be explained in more detail with reference to Examples.
It is not limited to these.
参考例、 N E−アミン基保護リシノールの合成N8
−ベンジルオキシカルボニルリジンメチルエステル(シ
グマ社) 3.31g (10m moβ)をエタノー
ル100mJ2に溶かし、水冷下、エタノール20 m
flに懸濁させた。水素化硼素ナトリウム2.66g
(70m’moβ)を滴下した。滴下終了後、油浴中、
1日、還流した。反応液を濾過し、減圧下、溶媒留去し
、濃縮物をクロロホルムに再溶解し、水洗した。有機層
を無水硫酸マグネシウムで乾燥後、減圧下、溶媒留去し
、得られた粗生成物をアセトニトリル中で結晶化し、目
的物であるε
N −ペンジルオキシ力ルポニルリジノール2.05g
を得た(収率77%)。Reference example, Synthesis of N E-amine group protected ricinol N8
-Dissolve 3.31 g (10 m moβ) of benzyloxycarbonyl lysine methyl ester (Sigma) in 100 mJ2 of ethanol, and add 20 m of ethanol under cooling with water.
It was suspended in fl. Sodium borohydride 2.66g
(70 m'moβ) was added dropwise. After dripping, in an oil bath,
It was refluxed for 1 day. The reaction solution was filtered, the solvent was distilled off under reduced pressure, and the concentrate was redissolved in chloroform and washed with water. After drying the organic layer over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting crude product was crystallized in acetonitrile to yield 2.05 g of the target product, ε N -penzyloxytriponylridinol.
was obtained (yield 77%).
実施例l
N8−ベンジルオキシカルボニル−N(Z−バルミトイ
ルリシノールの合成
N8−ペンジルオキシ力ルポニルリジノール1.49g
(5,6mmon)をクロロホルム70 +++j2
に溶解し、撹拌下、塩化バルミトイル1.55g(5,
6mmoρ)と水酸化ナトリウム水溶液5.6n+j2
を3回に分けて加え、そのまま室温にて4時間撹拌した
。反応液を飽和食塩水と水で洗浄し、有機層を無水硫酸
マグネシウムで乾燥後、減圧濃縮乾固し、固形粗生成物
2.79g (収率98%)を得た。Example l Synthesis of N8-benzyloxycarbonyl-N(Z-balmitoyllisinol) 1.49 g of N8-benzyloxycarbonyl-N(Z-balmitoyllisinol)
(5,6 mmon) in chloroform70 +++j2
1.55 g of balmitoyl chloride (5,
6 mmoρ) and sodium hydroxide aqueous solution 5.6n+j2
was added in three portions, and the mixture was stirred at room temperature for 4 hours. The reaction solution was washed with saturated brine and water, and the organic layer was dried over anhydrous magnesium sulfate and then concentrated to dryness under reduced pressure to obtain 2.79 g (yield: 98%) of a solid crude product.
得られた粗生成物をメタノール−水混合溶媒中で結晶化
し、目的物であるN8−ベンジルオキカルボニル−N(
Z−バルミトイルリシノール1.75g(収率62%)
を得た。The obtained crude product was crystallized in a methanol-water mixed solvent to obtain the target product N8-benzyloxycarbonyl-N(
Z-balmitoyl ricinol 1.75 g (yield 62%)
I got it.
実施例2
N8−ベンジルオキシカルボニル、No−バルミトイル
リジン−tert−ブチルエステルの合成(I)
N8−ベンジルオキシカルボニルリジン−tertブチ
ルエステル(塩酸塩)(東京化成社)599mg (1
,60m moρ)とステアリン酸600mg (2,
1,1m moβ)をジクロロメタン20 mj2に溶
解させ、水冷撹拌下、トリエチルアミン540mj2
(3,9mmo℃)とN、N−ジクロロへキシルカルボ
ジイミド494mg (2,40m mof2.)を添
加し、そのまま水冷下、2時間撹拌した後、室温にて1
日撹拌した。反応液を濾過後、濾液を水洗した。有機層
を無水硫酸マグネシウムで乾燥後、減圧濃縮乾固し、得
られた残渣をシリカゲルカラムにかけ、n−ヘキサン酢
酸エチル(5:l)混合溶媒で順次溶出させた。得られ
た溶出分画を薄層クロマトグラフィー(以下、TLC略
す)を用いて目的分画を集め、減圧濃縮乾固後、固形物
392mg (収率40%)を得た。この固形物をn
−ヘキサン中で結晶化することにより目的物質であるN
8−ベンジルオキシオキシカルボニル、N(Z−バルミ
トイルリジン−tert−ブチルエステルを得た。Example 2 Synthesis of N8-benzyloxycarbonyl, No-valmitoyllysine-tert-butyl ester (I) N8-benzyloxycarbonyllysine-tert-butyl ester (hydrochloride) (Tokyo Kasei Co., Ltd.) 599 mg (1
, 60m moρ) and stearic acid 600mg (2,
1,1m moβ) was dissolved in 20 mj2 of dichloromethane, and while stirring under water cooling, 540 mj2 of triethylamine was added.
(3.9 mmo℃) and 494 mg (2.40 mmof2.) of N,N-dichlorohexylcarbodiimide were added, and the mixture was stirred for 2 hours under water cooling, and then stirred for 1 hour at room temperature.
Stir for days. After filtering the reaction solution, the filtrate was washed with water. After drying the organic layer over anhydrous magnesium sulfate, it was concentrated to dryness under reduced pressure, and the resulting residue was applied to a silica gel column and sequentially eluted with a mixed solvent of n-hexane and ethyl acetate (5:l). The obtained elution fractions were subjected to thin layer chromatography (hereinafter abbreviated as TLC) to collect the desired fractions, and after concentration under reduced pressure to dryness, 392 mg (yield: 40%) of a solid was obtained. This solid matter is n
- By crystallizing in hexane, the target substance N
8-benzyloxyoxycarbonyl, N(Z-balmitoyllysine-tert-butyl ester was obtained.
実施例3
N8−ベンジルオキシカルボニル、Na−バルミトイル
リジン−tert−ブチルエステルの合成(II)
N8−ベンジルオキシカルボニルリジン−tert−ブ
チルエステル1.074g (2,88m mog )
をクロロホルム40m (2に溶解させ、3mρの水に
溶解した炭酸水素ナトリウム750mg1:塩化バルミ
トイル821mg (2,98mmoff)を3回に
分けて添加し、室温にて5時間撹拌した。この反応液に
水20m j2を加え、有機層を抽出し、水40mj2
で水洗した。有機層を無水硫酸マグネシウムで乾燥後、
減圧下、溶媒留去し、得られた粗生成物をn−ヘキサン
中で結晶化し、目的物であるN8−ベンジルオキシカル
ボニル、No−バルミトイルリジン−tert−ブチル
エステル1.376 g (収率83%)を得た。Example 3 Synthesis of N8-benzyloxycarbonyl, Na-balmitoyllysine-tert-butyl ester (II) N8-benzyloxycarbonyllysine-tert-butyl ester 1.074 g (2,88 m mog)
was dissolved in 40 m of chloroform (2, and 750 mg of sodium bicarbonate dissolved in 3 mρ of water: 821 mg of balmitoyl chloride (2,98 mmoff) was added in three portions, and the mixture was stirred at room temperature for 5 hours. Add 20 mj2, extract the organic layer, and add 40 mj2 of water.
I washed it with water. After drying the organic layer with anhydrous magnesium sulfate,
The solvent was distilled off under reduced pressure, and the resulting crude product was crystallized in n-hexane to yield 1.376 g of the target product, N8-benzyloxycarbonyl, No-valmitoyllysine-tert-butyl ester. 83%).
実施例4
Na−バルミトイルリシノールの合成
20三角フラスコ(テトロン撹拌子入り)にアルゴンガ
スを充填させ、10%パラジウム活性炭(小島化学薬品
) 180mgをゆつ(り入れ、再びアルゴンガスを置
換しながらエタノール100mj2を注入し、撹拌下、
懸濁させた。この懸濁液にN8ベンジルオキシカルボニ
ル−N(1−バルミトイルリシノール1.744g (
3,46m moj2)を添加し、フラスコを接触還元
装置(スキータ・パール法改良型;石井商会製)に接続
し、室温にて5時間撹拌した。反応液にメタノールを加
え、濾過し、その濾液を減圧濃縮乾固し、粗生成物1.
249g (収率98%)を得た。この粗生成物をエタ
ノール中で結晶化し、目的物であるNa−バルミトイル
−リシノール1.185g (収率92%)を得た。Example 4 Synthesis of Na-balmitoyl ricinol A 20 Erlenmeyer flask (with a Tetron stirring bar) was filled with argon gas, 180 mg of 10% palladium activated carbon (Kojima Chemical Co., Ltd.) was poured into the flask, and the argon gas was replaced again. Inject 100 mj2 of ethanol while stirring,
suspended. This suspension was added to N8 benzyloxycarbonyl-N (1-balmitoyl ricinol 1.744 g (
The flask was connected to a catalytic reduction apparatus (Skeeter-Pearl improved type; manufactured by Ishii Shokai) and stirred at room temperature for 5 hours. Methanol was added to the reaction solution, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain crude product 1.
249 g (yield 98%) was obtained. This crude product was crystallized in ethanol to obtain 1.185 g (yield: 92%) of Na-valmitoyl-ricinol, the target product.
実施例5
No−バルミトイル−リジン−tert−ブチルエステ
ルの合成
実施例4と同様にして、20三角フラスコ(テトロン撹
拌子入り)にアルゴンガスな充填させ、10%パラジウ
ム活性炭(小島化学薬品) 120 mgをゆっくり入
れ、再びアルゴンガスを置換をしながらエタノール10
0mj2を注入し、撹拌下、懸濁させた。この懸濁液に
N8−ベンジルオキシカルボニル−N(Z−バルミトイ
ル−リジン−tert−ブチルエステル1.185g
(2,06m mof2.)を添加し、フラスコを接触
還元装置に接続し、室温にて5.5時間撹拌した。反応
液を濾過し、その濾液を減圧濃縮乾固し、粗生成物90
3mg (収率99%)を得た。この粗生成物をアセト
ニトリル−〇−ヘキサン中で結晶化し、目的物であるN
CE−バルミトイル−リジン−tert−ブチルエステ
ル181mgを得た。Example 5 Synthesis of No-valmitoyl-lysine-tert-butyl ester In the same manner as in Example 4, 20 Erlenmeyer flasks (with Tetron stirring bar) were filled with argon gas, and 120 mg of 10% palladium activated carbon (Kojima Chemical) was added. Slowly add 10% of ethanol while replacing the argon gas again.
0 mj2 was injected and suspended under stirring. To this suspension was added 1.185 g of N8-benzyloxycarbonyl-N (Z-balmitoyl-lysine-tert-butyl ester).
(2.06 mmof2.) was added, the flask was connected to a catalytic reduction apparatus, and the mixture was stirred at room temperature for 5.5 hours. The reaction solution was filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain a crude product of 90%
3 mg (yield 99%) was obtained. This crude product was crystallized in acetonitrile-〇-hexane, and the target product N
181 mg of CE-valmitoyl-lysine-tert-butyl ester was obtained.
以下に分析結果を示す。The analysis results are shown below.
+ II
(CH2)、4C:H1lCH20H
(CH2) 18CH3CH20H
(CH2)14CH3CH20H
(GHz) I 4C+(3Coot−Bu(CH2)
+6c:H3C00t−Bu(CH2)、4C88C
0NH2
(CH2)14c83 C0NEt 2化合物の物
理化学的データ
mp: (℃)
IR: (cm−’)
’H−NMR: (ppm )
(CH2)4NH2
(CH2)、Nl2
(CH2)3NH2
(CH2)4NH2
(CH2)4NH2
(CH2)4NH2
(CH2)、Nl2
No、 1
mp : 1]7 〜120
IR: 3300,1645,1550.147ON
MR(CD、OD): 0.97(3H,t)、1.1
7〜1.80(8H,m) 、1.30(24H,s
) 、2.20(2H,t) 。+ II (CH2), 4C:H1lCH20H (CH2) 18CH3CH20H (CH2)14CH3CH20H (GHz) I 4C+(3Coot-Bu(CH2)
+6c: H3C00t-Bu (CH2), 4C88C
Physicochemical data of 0NH2 (CH2)14c83 C0NEt 2 compound mp: (℃) IR: (cm-') 'H-NMR: (ppm) (CH2)4NH2 (CH2), Nl2 (CH2)3NH2 (CH2)4NH2 (CH2)4NH2 (CH2)4NH2 (CH2), Nl2 No, 1 mp: 1] 7 ~ 120 IR: 3300, 1645, 1550.147 ON
MR (CD, OD): 0.97 (3H, t), 1.1
7-1.80 (8H, m), 1.30 (24H, s
), 2.20(2H,t).
2.64(2H,t) 、3.47(2H,dd)
、3.74(IH,br)No、 2
mp : 120 〜123
IR: 3300,1645,1550.147ON
MR(CD30D): 0.90(3)(、t)、1.
20〜1.70(8H,m) 、 1.28 (28
H,s) 、 2.20 (2H,t) 。2.64 (2H, t), 3.47 (2H, dd)
, 3.74 (IH, br) No, 2 mp: 120 ~ 123 IR: 3300, 1645, 1550.147 ON
MR (CD30D): 0.90(3)(,t), 1.
20-1.70 (8H, m), 1.28 (28
H,s), 2.20 (2H,t).
2.72(2H,t) 、3.48(2H,dd)
、3.85(IH,br)No、 3
mp : 107〜110
IR: 3320,1640,1560.147ONM
R(CD30D) : 0.88(3H,t) 、1
.27(24H,s)。2.72 (2H, t), 3.48 (2H, dd)
, 3.85 (IH, br) No, 3 mp: 107-110 IR: 3320, 1640, 1560.147ONM
R(CD30D): 0.88(3H,t), 1
.. 27 (24H, s).
1.40〜1.77(6H,m) 、2.20(2H
,t) 、2.93(2H,t) 、3.50(2
H,dd) 、3.86(LH,br)No、 4
mp:43〜46
IR: 3330.1730.1645,1530.1
47ONMR(CDCLi): 0.87(3H,t)
、1.09〜1.88(8H,m) 、1.26(2
4H,s) 、1.46(9H,s)2.19(2H
,t)、2.70(3H,br)。1.40-1.77 (6H, m), 2.20 (2H
,t) ,2.93(2H,t) ,3.50(2
H, dd), 3.86 (LH, br) No, 4 mp: 43-46 IR: 3330.1730.1645, 1530.1
47ONMR (CDCLi): 0.87 (3H, t)
, 1.09-1.88 (8H, m), 1.26 (2
4H, s), 1.46 (9H, s) 2.19 (2H
, t), 2.70 (3H, br).
4.46(LH,br) 、6.11.(LH,br
)No、 5
mp:49〜52
IR: 3330,1730,1645,1530.
147ONMR(CDCl2): 0.85(3H,t
)、1.08〜1.90(8H,m) 、1.23(
28H,s) 、1.44(9H,s)2.18(2
H,t) 、2.66(2H,t) 。4.46 (LH, br), 6.11. (LH,br
) No, 5 mp: 49-52 IR: 3330, 1730, 1645, 1530.
147ONMR (CDCl2): 0.85 (3H, t
), 1.08-1.90 (8H, m), 1.23 (
28H,s), 1.44(9H,s) 2.18(2
H,t), 2.66(2H,t).
4.48(IH,br)、5.98(IH,br)No
、 6
mp : 133 〜135
IR:3390,3295,3320,1675,16
20,155ONMR(CD30D): 0.87(3
H,t)、1.18〜1.89(8H,m) 、 1
.26 (24H,s) 、 2.22 (2H,t
)2.63(2H,t) 、4.60(LH,dd)
47O
No、 7
mp:38〜40
IR: 3295,1635,1540.147ON
MR(CD(1,L3) : 0.85(3H,t)
、1.00〜1.79(8H,m) 、1.09(
3H,t) 、1.20(3H,t) 、1.22
(24H,s)、2.18(2H,t)、2.49(2
H,br)。4.48 (IH, br), 5.98 (IH, br) No.
, 6 mp: 133 ~ 135 IR: 3390, 3295, 3320, 1675, 16
20,155ONMR (CD30D): 0.87(3
H, t), 1.18-1.89 (8H, m), 1
.. 26 (24H, s), 2.22 (2H, t
) 2.63 (2H, t), 4.60 (LH, dd)
47O No, 7 mp: 38-40 IR: 3295, 1635, 1540.147ON
MR(CD(1,L3): 0.85(3H,t)
, 1.00-1.79 (8H, m) , 1.09 (
3H, t) , 1.20 (3H, t) , 1.22
(24H, s), 2.18 (2H, t), 2.49 (2
H, br).
2.70(2H,t) 、3.13〜3.58(4H
,m) 。2.70 (2H, t), 3.13-3.58 (4H
, m).
4.86(IH,br)、6.50(LH,br)N。4.86 (IH, br), 6.50 (LH, br)N.
(CH2)14CH3 (CH2) l 5CHa (CH2) 14cH3 (CH□)14CH3 (CH2) 14CH3 (CH2116cH3 (CH2) 、 4CI(。(CH2)14CH3 (CH2) l 5CHa (CH2) 14cH3 (CH□)14CH3 (CH2) 14CH3 (CH2116cH3 (CH2), 4CI(.
(CH2) l−CH5
CH,0H
CH20)I
H20H
H20H
COOt−Bu
COOt−Bu
0NH2
0NEt2
(CH2) 4NH−CBZ
(CH2)4NH−(:BZ
(CH2)4NH−BOC
(C:H,)、NH−CBZ
(CH2)4NH−CBZ
(CH2) 4NH−CBZ
(CH2) 4NH−CBZ
(CH2)、NH−CBZ
化合物の物理化学的データ
mp: (’C)
IR: (cm−’)
’H−NMR: (ppm、 CDCLa )No、
8
mp : 102.5 〜103.5IR:
3415,3325,1685,1615,1560,
1550,1470゜27O
MR
+ 0.86(3H,t) 、1.08〜1.70(
88,m) 、1.22(24H,s) 、 2.
17 (2H,t) 、 2.90 (LH,br)
3.1.9(2H,br) 、3.58(2H,br
) 。(CH2) l-CH5 CH,0H CH20)I H20H H20H COOt-Bu COOt-Bu 0NH2 0NEt2 (CH2) 4NH-CBZ (CH2)4NH-(:BZ (CH2)4NH-BOC (C:H,), NH -CBZ (CH2)4NH-CBZ (CH2) 4NH-CBZ (CH2) 4NH-CBZ (CH2), NH-CBZ Physical and chemical data of the compound mp: ('C) IR: (cm-') 'H-NMR : (ppm, CDCLa)No,
8mp: 102.5 ~ 103.5IR:
3415, 3325, 1685, 1615, 1560,
1550, 1470°27O MR + 0.86 (3H, t), 1.08~1.70 (
88, m), 1.22 (24H, s), 2.
17 (2H, t), 2.90 (LH, br)
3.1.9 (2H, br), 3.58 (2H, br
).
3.87(IH,br)、4.82(LH,br)。3.87 (IH, br), 4.82 (LH, br).
5.08(2H,s)、5.82(LH,br)、7.
34(5t(,5)No、 9
mp
IR
MR
: 106〜107
: 3410,3330,1685,1615,15
60,1470.1280+ 0.87(3H,t)
、1.08〜1.69(8H,m) 、1.23(
24H,s)、2.17(2H,t)、2.77(LH
,br)。5.08 (2H, s), 5.82 (LH, br), 7.
34(5t(,5)No, 9mp IR MR: 106-107: 3410,3330,1685,1615,15
60,1470.1280+ 0.87(3H,t)
, 1.08-1.69 (8H, m) , 1.23 (
24H,s), 2.17(2H,t), 2.77(LH
,br).
3.18 (2H,br) 、 3.58 (2H,
br) 、 3.87(IH,br) 、4.81
.(LH,br) 、5.08(:28.s) 。3.18 (2H, br), 3.58 (2H,
br), 3.87 (IH, br), 4.81
.. (LH, br), 5.08 (:28.s).
5.82(1)!、br) 、7.34(5H,5)
No、 1 0
:96.5〜97.5
3410.3360.16g5,1615,1560,
1540.1470MR
+ 0.86(3H,t) 、1.02〜1.70(
8H,m) 、1.23(24H,s) 、1.4
2(9H,s) 、2.18(2H,t) 。5.82(1)! ,br) ,7.34(5H,5)
No, 10:96.5~97.5 3410.3360.16g5,1615,1560,
1540.1470MR + 0.86(3H,t), 1.02~1.70(
8H, m), 1.23 (24H, s), 1.4
2(9H,s), 2.18(2H,t).
2.92〜3.28(3H,m) 、3.60(2t
(、br) 、3.89(18,br) 、4.5
8(LH,br) 、5.85(IH,br)No、
1. 1
87〜88
MR
3360,1,690,1640,1560,1540
,1470,1,275: 0.85(3H,t)
、1.23(24H,s) 、1.40〜1.80(
6H,m) 、2.82(IH,br) 、3.2
0(2H,br) 。2.92-3.28 (3H, m), 3.60 (2t
(, br) , 3.89 (18, br) , 4.5
8 (LH, br), 5.85 (IH, br) No,
1. 1 87-88 MR 3360, 1,690, 1640, 1560, 1540
, 1470, 1,275: 0.85 (3H, t)
, 1.23 (24H, s) , 1.40-1.80 (
6H, m), 2.82 (IH, br), 3.2
0(2H,br).
3.59(2H,br)、3.91(LH,br)、4
.97(LH,brl 、 5.07 (2H,s)
、 5.90 (LH,br) 。3.59 (2H, br), 3.91 (LH, br), 4
.. 97 (LH,brl, 5.07 (2H,s)
, 5.90 (LH,br).
7.32(5H,5)
No、 1 2
MR
二 68〜69
二 3340.1735.1685.1650.154
0.1265: 0.88(3H,t) 、1.11
〜1.92(8H,m) 、1.25(24H,sl
、1.45(9H,s) ;2.20(2H,t
) 。7.32 (5H, 5) No, 1 2 MR 2 68-69 2 3340.1735.1685.1650.154
0.1265: 0.88(3H,t), 1.11
~1.92 (8H, m), 1.25 (24H, sl
, 1.45 (9H, s); 2.20 (2H, t
).
3.18(2H,dd) 、4.48(LH,br)
、4.81(LH,br) 、5.08(2H,
s) 、6.01(IH,br) 。3.18 (2H, dd), 4.48 (LH, br)
, 4.81 (LH, br) , 5.08 (2H,
s), 6.01 (IH, br).
7、35 (5H,5)
No、 1 3
MR
ニア0.5〜71.5
: 3340.1735,1685,1650,154
0.1265+ 0.86(3H,t) 、1.1(
1〜1.88(8H,m) 、1.24(28H,s
) 、1.44(9t(、sl 、2.17(28
,t)3、16 (2H,dd) 、 4.46 (
IH,br) 、 4.79(IH,br) 、5
.07(2H,s) 、5.98(]、t(、br)
。7, 35 (5H, 5) No, 1 3 MR Near 0.5-71.5: 3340.1735, 1685, 1650, 154
0.1265+ 0.86(3H,t), 1.1(
1 to 1.88 (8H, m), 1.24 (28H, s
), 1.44(9t(,sl, 2.17(28
, t) 3, 16 (2H, dd) , 4.46 (
IH, br), 4.79 (IH, br), 5
.. 07(2H,s), 5.98(],t(,br)
.
7、34 (5H,s)
No、 1 4
= 167〜170
: 3390,3300,3200,1695,16
75,1,620,154OMR
1470,1275
+ 0.88(3H,t) 、1.01〜1.98(
8H,m) 、1.25(24H,s) 、 2.
21 (2H,t) 、 3.21 (2H,br)
4.42(LH,br) 、4.86(LH,br)
、5.09(2H,s) 、5゜30(LH,b
r)、6.17(2H,br)。7, 34 (5H, s) No, 1 4 = 167-170: 3390, 3300, 3200, 1695, 16
75,1,620,154OMR 1470,1275 + 0.88(3H,t), 1.01~1.98(
8H, m), 1.25 (24H, s), 2.
21 (2H, t), 3.21 (2H, br)
4.42 (LH, br), 4.86 (LH, br)
, 5.09 (2H, s) , 5゜30 (LH, b
r), 6.17 (2H, br).
7.34(5H5)
No、 1 5
mp:シロップ
IR: 3305.1725.1630.1535.1
455.126ONMR: 0.85(3)1.t)
、1.00〜1.96(8H,m) 、1.07(3H
,t) 、1.14(3H,t) 、1.21(24H
,sr) 。7.34 (5H5) No. 1 5 mp: Syrup IR: 3305.1725.1630.1535.1
455.126ONMR: 0.85(3)1. t)
, 1.00-1.96 (8H, m), 1.07 (3H
,t) ,1.14(3H,t) ,1.21(24H
, sr).
2.15(2H,t) 、3.07〜3.57(6H,
m) 。2.15 (2H, t), 3.07-3.57 (6H,
m).
Claims (1)
飽和脂肪酸残基、R2はヒドロキシメチル、アルキルオ
キシカルボニル、アミノカルボニル、または低級モノも
しくはジアルキルアミノカルボニル基を表す。R3は低
級アミノアルキル基を表す]で示される塩基性アミノ酸
アシル誘導体及びその酸付加塩。 ▲数式、化学式、表等があります▼[II] [式中、R1COは炭素数が14〜20の飽和または不
飽和脂肪酸残基、R2はヒドロキシメチル、アルキルオ
キシカルボニル、アミノカルボニル、または低級モノも
しくはジアルキルアミノカルボニル基を表す。R4は低
級アミノアルキル基の末端アミノ基に酸性条件下もしく
は還元的に脱離可能な保護基が付いたものを表す]で示
される塩基性アミノ酸アシル誘導体。 3、請求項1において、R2がヒドロキシメチル基、R
3が4−アミノブチル、または3−アミノプロピル基で
ある塩基性アミノ酸アシル誘導体及びその酸付加塩。 4、請求項1において、R2がt−ブトキシカルボニル
基、R3が4−アミノブチル、または3−アミノプロピ
ル基である塩基性アミノ酸アシル誘導体及びその酸付加
塩。 5、請求項1において、R2がアミノカルボニル基、ま
たは炭素数が1〜6の直鎖または分岐鎖からなるモノも
しくはジアルキルカルボニル基、R3が4−アミノブチ
ル、または3−アミノプロピル基である塩基性アミノ酸
アシル誘導体及びその酸付加塩。 6、請求項2において、R2がヒドロキシメチル基、R
4が4−アミノブチル、または3−アミノプロピル基の
末端アミノ基に酸性条件下もしくは還元的に脱離可能な
保護基が付いたものである塩基性アミノ酸アシル誘導体
。 7、請求項2において、R2がt−ブトキシカルボニル
基、R4が4−アミノブチル、または3−アミノプロピ
ル基の末端アミノ基に酸性条件下もしくは還元的に脱離
可能な保護基が付いたものである塩基性アミノ酸アシル
誘導体。 8、請求項2において、R2がアミノカルボニル基、ま
たは炭素数が1〜6の直鎖または分岐鎖アルキルからな
るモノもしくはジアルキルカルボニル基、R4が4−ア
ミノブチル、または3−アミノプロピル基の末端アミノ
基に還元的もしくは酸性条件下で脱離可能な保護基が付
いたものである塩基性アミノ酸アシル誘導体。 9、請求項2及び6乃至8のいずれかにおいて、R4で
ある低級アミノアルキル基の末端アミノ基の保護基がベ
ンジルオキシカルボニル基またはt−ブトキシカルボニ
ル基である塩基性アミノ酸アシル誘導体。 10、一般式[III]: ▲数式、化学式、表等があります▼[III] [式中、R2はヒドロキシメチル、アルキルオキシカル
ボニル、アミノカルボニル、または低級モノもしくはジ
アルキルアミノカルボニル基を表す。R4は低級アミノ
アルキル基の末端アミノ基に酸性条件下もしくは還元的
に脱離可能な保護基がついたものを表す]で示される化
合物と、 一般式[IV]: ▲数式、化学式、表等があります▼[IV] [式中、Xはハロゲンを表し、R1COは炭素数が14
〜20の飽和または不飽和脂肪酸残基を表す]で示され
る高級脂肪酸ハロゲン化物とを縮合することによって、 一般式[II]: ▲数式、化学式、表等があります▼[II] [式中、R1COは炭素数が14〜20の飽和または不
飽和脂肪酸残基、R2はヒドロキシメチル、アルキルオ
キシカルボニル、アミノカルボニル、または低級モノも
しくはジアルキルアミノカルボニル基を表す。R4は低
級アミノアルキル基の末端アミノ基に酸性条件下もしく
は還元的に脱離可能な保護基が付いたものを表す]で示
される化合物を製造することを特徴とする請求項2の化
合物の製造方法。 11、請求項10の方法で製造した一般式[II]で示さ
れる化合物中のR4である低級アルキル基の末端アミノ
基についている保護基を脱離させることを特徴とする、
下記一般式[ I ]:▲数式、化学式、表等があります
▼[ I ] [式中、R1COは炭素数が14〜20の飽和または不
飽和脂肪酸残基、R2はヒドロキシメチル、アルキルオ
キシカルボニル、アミノカルボニル、または低級モノも
しくはジアルキルアミノカルボニル基を表す。R3は低
級アミノアルキル基を表す]で示される化合物を製造す
ることを特徴とする請求項1の化合物の製造方法。 12、一般式[III]で示される化合物と、炭素数が1
4〜20の飽和または不飽和脂肪酸とを塩基性条件下、
縮合剤を用いて、縮合することによって、一般式[II]
で示される化合物を製造することを特徴とする請求項2
の化合物の製造方法。 13、請求項12の方法で製造した一般式[II]で示さ
れる化合物中のR4である低級アルキル基の末端アミノ
基に付いている保護基を脱離させることを特徴とする、
一般式[ I ]で示される請求項1の化合物の製造方法
。 14、一般式[III′] ▲数式、化学式、表等があります▼[III′] [式中、R2′はカルボキシル基、R4は低級アミノア
ルキル基の末端アミノ基に酸性条件下もしくは還元的に
脱離可能な保護基が付いたものを表わす]で示される化
合物と、 一般式[IV]: ▲数式、化学式、表等があります▼[IV] [式中、Xはハロゲンを表わし、R1COは炭素数が1
4〜20の飽和または不飽和脂肪酸残基を表わす]で示
される高級脂肪酸ハロゲン化物とを縮合することによっ
て、 一般式[II′] ▲数式、化学式、表等があります▼[II′] [式中、R1COは炭素数が14〜20の飽和または不
飽和脂肪酸残基、R4は低級アミノアルキルの末端アミ
ノ基に酸性条件下もしくは還元的に脱離可能な保護基が
付いたものを表わす]で示されるアミノ酸誘導体を得た
後、この一般式[II′]中のR2′のカルボキシル基を
アルキルオキシカルボニル、アミノカルボニル、または
低級モノもしくはジアルキルアミノカルボニル基に変換
して、一般式[II]で示される化合物(但し、この場合
、R2はアルキルオキシカルボニル、アミノカルボニル
、または低級モノもしくはジアルキルアミノカルボニル
基のみを表わす)を製造することを特徴とする請求項2
の化合物の製造方法。 15、請求項14の方法で製造した一般式[II]で示さ
れる化合物中のR4である低級アルキル基の末端アミノ
基に付いている保護基を脱離させることを特徴とする一
般式[ I ]の化合物(但し、この場合、R2はアルキ
ルオキシカルボニル、アミノカルボニル、または低級モ
ノもしくはジアルキルアミノカルボニル基のみを表わす
)で示される請求項1の化合物の製造方法。 16、請求項10または12において、一般式[IV]中
、Xのハロゲンが塩素もしくは臭素であることを特徴と
する製造方法。[Claims] 1. General formula [I]: ▲Mathematical formula, chemical formula, table, etc.▼[I] [In the formula, R1CO is a saturated or unsaturated fatty acid residue having 14 to 20 carbon atoms, and R2 is Represents hydroxymethyl, alkyloxycarbonyl, aminocarbonyl, or lower mono- or dialkylaminocarbonyl group. R3 represents a lower aminoalkyl group] Basic amino acid acyl derivatives and acid addition salts thereof. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [II] [In the formula, R1CO is a saturated or unsaturated fatty acid residue having 14 to 20 carbon atoms, and R2 is hydroxymethyl, alkyloxycarbonyl, aminocarbonyl, or lower mono- or Represents a dialkylaminocarbonyl group. R4 represents a lower aminoalkyl group with a protective group attached to the terminal amino group that can be removed under acidic conditions or reductively]. 3. In claim 1, R2 is a hydroxymethyl group, R
A basic amino acid acyl derivative in which 3 is a 4-aminobutyl or 3-aminopropyl group, and an acid addition salt thereof. 4. The basic amino acid acyl derivative and acid addition salt thereof according to claim 1, wherein R2 is a t-butoxycarbonyl group, and R3 is a 4-aminobutyl or 3-aminopropyl group. 5. The base according to claim 1, wherein R2 is an aminocarbonyl group, or a linear or branched mono- or dialkylcarbonyl group having 1 to 6 carbon atoms, and R3 is a 4-aminobutyl or 3-aminopropyl group. amino acid acyl derivatives and their acid addition salts. 6. In claim 2, R2 is a hydroxymethyl group, R
A basic amino acid acyl derivative in which 4 is 4-aminobutyl or a 3-aminopropyl group with a protecting group attached to the terminal amino group that can be removed under acidic conditions or reductively. 7. In claim 2, R2 is a t-butoxycarbonyl group, R4 is 4-aminobutyl, or a 3-aminopropyl group with a protecting group attached to the terminal amino group that can be removed under acidic conditions or reductively. A basic amino acid acyl derivative that is 8. In claim 2, R2 is an aminocarbonyl group, or a mono- or dialkylcarbonyl group consisting of a linear or branched alkyl group having 1 to 6 carbon atoms, and R4 is the terminal of a 4-aminobutyl or 3-aminopropyl group. A basic amino acid acyl derivative that has an amino group attached with a protecting group that can be removed under reductive or acidic conditions. 9. The basic amino acid acyl derivative according to any one of claims 2 and 6 to 8, wherein the protecting group for the terminal amino group of the lower aminoalkyl group represented by R4 is a benzyloxycarbonyl group or a t-butoxycarbonyl group. 10. General formula [III]: ▲Mathematical formulas, chemical formulas, tables, etc.▼[III] [In the formula, R2 represents hydroxymethyl, alkyloxycarbonyl, aminocarbonyl, or a lower mono- or dialkylaminocarbonyl group. R4 represents a lower aminoalkyl group with a protective group attached to the terminal amino group that can be removed under acidic conditions or reductively] and the general formula [IV]: ▲ Numerical formula, chemical formula, table, etc. ▼ [IV] [In the formula, X represents halogen, and R1CO has 14 carbon atoms.
~20 saturated or unsaturated fatty acid residues] is condensed with a higher fatty acid halide represented by General formula [II]: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [II] [In the formula, R1CO represents a saturated or unsaturated fatty acid residue having 14 to 20 carbon atoms, and R2 represents hydroxymethyl, alkyloxycarbonyl, aminocarbonyl, or a lower mono- or dialkylaminocarbonyl group. R4 represents a lower aminoalkyl group with a protective group attached to the terminal amino group that can be removed under acidic conditions or reductively. Method. 11, characterized by removing the protecting group attached to the terminal amino group of the lower alkyl group R4 in the compound represented by the general formula [II] produced by the method of claim 10,
The following general formula [I]: ▲Mathematical formulas, chemical formulas, tables, etc.▼[I] [In the formula, R1CO is a saturated or unsaturated fatty acid residue having 14 to 20 carbon atoms, R2 is hydroxymethyl, alkyloxycarbonyl, Represents aminocarbonyl or a lower mono- or dialkylaminocarbonyl group. 2. The method for producing a compound according to claim 1, characterized in that R3 represents a lower aminoalkyl group. 12. A compound represented by the general formula [III] and a compound having 1 carbon number
4 to 20 saturated or unsaturated fatty acids under basic conditions,
By condensing using a condensing agent, the general formula [II]
Claim 2 characterized in that the compound represented by is produced.
A method for producing a compound. 13, characterized by removing the protecting group attached to the terminal amino group of the lower alkyl group R4 in the compound represented by the general formula [II] produced by the method of claim 12,
A method for producing the compound according to claim 1 represented by the general formula [I]. 14. General formula [III'] ▲Mathematical formulas, chemical formulas, tables, etc.▼[III'] [In the formula, R2' is a carboxyl group, and R4 is a lower aminoalkyl group whose terminal amino group is attached under acidic conditions or reductively. Represents a compound with a removable protecting group] and the general formula [IV]: ▲There are mathematical formulas, chemical formulas, tables, etc.▼[IV] [In the formula, X represents a halogen, and R1CO is Number of carbons is 1
4 to 20 saturated or unsaturated fatty acid residues] is condensed with a higher fatty acid halide represented by the general formula [II'] ▲There are mathematical formulas, chemical formulas, tables, etc.▼[II'] [Formula where R1CO represents a saturated or unsaturated fatty acid residue having 14 to 20 carbon atoms, and R4 represents a lower aminoalkyl with a protective group attached to the terminal amino group that can be removed under acidic conditions or reductively. After obtaining the shown amino acid derivative, the carboxyl group of R2' in this general formula [II'] is converted to an alkyloxycarbonyl, aminocarbonyl, or lower mono- or dialkylaminocarbonyl group to obtain the general formula [II]. Claim 2, characterized in that the compound shown in FIG.
A method for producing a compound. 15. General formula [I] characterized by removing the protecting group attached to the terminal amino group of the lower alkyl group that is R4 in the compound represented by general formula [II] produced by the method of claim 14. ] (However, in this case, R2 represents only an alkyloxycarbonyl, aminocarbonyl, or lower mono- or dialkylaminocarbonyl group). 16. The manufacturing method according to claim 10 or 12, wherein the halogen of X in general formula [IV] is chlorine or bromine.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2133264A JPH0426662A (en) | 1990-05-23 | 1990-05-23 | Amino acid acyl derivative and preparation thereof |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2133264A JPH0426662A (en) | 1990-05-23 | 1990-05-23 | Amino acid acyl derivative and preparation thereof |
Publications (1)
Publication Number | Publication Date |
---|---|
JPH0426662A true JPH0426662A (en) | 1992-01-29 |
Family
ID=15100554
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2133264A Pending JPH0426662A (en) | 1990-05-23 | 1990-05-23 | Amino acid acyl derivative and preparation thereof |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPH0426662A (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1999033787A1 (en) * | 1997-12-26 | 1999-07-08 | Kureha Chemical Industry Co., Ltd. | Amino acid derivatives |
US7939505B2 (en) | 2007-05-04 | 2011-05-10 | Marina Biotech, Inc. | Amino acid lipids and uses thereof |
-
1990
- 1990-05-23 JP JP2133264A patent/JPH0426662A/en active Pending
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1999033787A1 (en) * | 1997-12-26 | 1999-07-08 | Kureha Chemical Industry Co., Ltd. | Amino acid derivatives |
US7939505B2 (en) | 2007-05-04 | 2011-05-10 | Marina Biotech, Inc. | Amino acid lipids and uses thereof |
US8501824B2 (en) | 2007-05-04 | 2013-08-06 | Marina Biotech, Inc. | Amino acid lipids and uses thereof |
US8877729B2 (en) | 2007-05-04 | 2014-11-04 | Marina Biotech, Inc. | Amino acid lipids and uses thereof |
US9339461B2 (en) | 2007-05-04 | 2016-05-17 | Marina Biotech, Inc. | Arginine-based lipids for delivery of therapeutics |
US9731016B2 (en) | 2007-05-04 | 2017-08-15 | Marina Biotech, Inc. | Tyrosine-based lipids for delivery of therapeutics |
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