JP3073309B2 - Sialic acid-bound 5-deazaflavin compounds - Google Patents
Sialic acid-bound 5-deazaflavin compoundsInfo
- Publication number
- JP3073309B2 JP3073309B2 JP04102150A JP10215092A JP3073309B2 JP 3073309 B2 JP3073309 B2 JP 3073309B2 JP 04102150 A JP04102150 A JP 04102150A JP 10215092 A JP10215092 A JP 10215092A JP 3073309 B2 JP3073309 B2 JP 3073309B2
- Authority
- JP
- Japan
- Prior art keywords
- group
- phenyl
- substituted
- hydrogen atom
- atom
- 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
- SQVRNKJHWKZAKO-UHFFFAOYSA-N beta-N-Acetyl-D-neuraminic acid Natural products CC(=O)NC1C(O)CC(O)(C(O)=O)OC1C(O)C(O)CO SQVRNKJHWKZAKO-UHFFFAOYSA-N 0.000 title claims description 35
- SQVRNKJHWKZAKO-OQPLDHBCSA-N sialic acid Chemical compound CC(=O)N[C@@H]1[C@@H](O)C[C@@](O)(C(O)=O)OC1[C@H](O)[C@H](O)CO SQVRNKJHWKZAKO-OQPLDHBCSA-N 0.000 title claims description 32
- KWHWFTSHDPJOTG-UHFFFAOYSA-N Deazaflavin Chemical class C1=CC=C2C=C(C(=O)NC(=O)N3)C3=NC2=C1 KWHWFTSHDPJOTG-UHFFFAOYSA-N 0.000 title description 25
- 150000001875 compounds Chemical class 0.000 claims description 47
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 14
- 125000000217 alkyl group Chemical group 0.000 claims description 13
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 13
- -1 5-deazaflavin compound Chemical class 0.000 claims description 12
- 125000003282 alkyl amino group Chemical group 0.000 claims description 12
- 125000003545 alkoxy group Chemical group 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 7
- 125000003047 N-acetyl group Chemical group 0.000 claims description 6
- 125000005843 halogen group Chemical group 0.000 claims description 4
- BUGBHKTXTAQXES-UHFFFAOYSA-N Selenium Chemical group [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 claims description 3
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 3
- 229910052711 selenium Inorganic materials 0.000 claims description 3
- 229910052717 sulfur Inorganic materials 0.000 claims description 3
- 125000004434 sulfur atom Chemical group 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 125000000350 glycoloyl group Chemical group O=C([*])C([H])([H])O[H] 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 2
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 claims 1
- 125000001302 tertiary amino group Chemical group 0.000 claims 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 35
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- 238000006243 chemical reaction Methods 0.000 description 21
- 210000004027 cell Anatomy 0.000 description 18
- 239000000543 intermediate Substances 0.000 description 17
- 239000000203 mixture Substances 0.000 description 16
- 239000000243 solution Substances 0.000 description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 13
- 125000005233 alkylalcohol group Chemical group 0.000 description 13
- 238000004519 manufacturing process Methods 0.000 description 12
- 230000002829 reductive effect Effects 0.000 description 12
- 238000000034 method Methods 0.000 description 11
- 239000000126 substance Substances 0.000 description 11
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 9
- 210000004369 blood Anatomy 0.000 description 9
- 239000008280 blood Substances 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 230000008569 process Effects 0.000 description 8
- 125000005629 sialic acid group Chemical group 0.000 description 8
- 238000010898 silica gel chromatography Methods 0.000 description 8
- SQVRNKJHWKZAKO-PFQGKNLYSA-N N-acetyl-beta-neuraminic acid Chemical compound CC(=O)N[C@@H]1[C@@H](O)C[C@@](O)(C(O)=O)O[C@H]1[C@H](O)[C@H](O)CO SQVRNKJHWKZAKO-PFQGKNLYSA-N 0.000 description 7
- 230000001093 anti-cancer Effects 0.000 description 7
- 239000003054 catalyst Substances 0.000 description 7
- 239000002994 raw material Substances 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 206010028980 Neoplasm Diseases 0.000 description 6
- 201000011510 cancer Diseases 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- XKWQUTFERHHKNT-UHFFFAOYSA-N 6-anilino-1h-pyrimidine-2,4-dione Chemical class N1C(=O)NC(=O)C=C1NC1=CC=CC=C1 XKWQUTFERHHKNT-UHFFFAOYSA-N 0.000 description 5
- FDJKUWYYUZCUJX-UHFFFAOYSA-N N-glycolyl-beta-neuraminic acid Natural products OCC(O)C(O)C1OC(O)(C(O)=O)CC(O)C1NC(=O)CO FDJKUWYYUZCUJX-UHFFFAOYSA-N 0.000 description 5
- 230000008878 coupling Effects 0.000 description 5
- 238000010168 coupling process Methods 0.000 description 5
- 238000005859 coupling reaction Methods 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 229910052736 halogen Inorganic materials 0.000 description 5
- 150000002367 halogens Chemical class 0.000 description 5
- 239000002808 molecular sieve Substances 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 5
- XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical compound [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 4
- FDJKUWYYUZCUJX-AJKRCSPLSA-N N-glycoloyl-beta-neuraminic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@@H]1O[C@](O)(C(O)=O)C[C@H](O)[C@H]1NC(=O)CO FDJKUWYYUZCUJX-AJKRCSPLSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 4
- 238000000921 elemental analysis Methods 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 150000003141 primary amines Chemical class 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- QRUBYZBWAOOHSV-UHFFFAOYSA-M silver trifluoromethanesulfonate Chemical compound [Ag+].[O-]S(=O)(=O)C(F)(F)F QRUBYZBWAOOHSV-UHFFFAOYSA-M 0.000 description 4
- 159000000000 sodium salts Chemical class 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- 231100000419 toxicity Toxicity 0.000 description 4
- 230000001988 toxicity Effects 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 102000005348 Neuraminidase Human genes 0.000 description 3
- 108010006232 Neuraminidase Proteins 0.000 description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 230000036436 anti-hiv Effects 0.000 description 3
- 239000002246 antineoplastic agent Substances 0.000 description 3
- WDODWFPDZYSKIA-UHFFFAOYSA-N benzeneselenol Chemical class [SeH]C1=CC=CC=C1 WDODWFPDZYSKIA-UHFFFAOYSA-N 0.000 description 3
- 150000001720 carbohydrates Chemical class 0.000 description 3
- 229940125904 compound 1 Drugs 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 150000004702 methyl esters Chemical class 0.000 description 3
- 238000006386 neutralization reaction Methods 0.000 description 3
- 230000035790 physiological processes and functions Effects 0.000 description 3
- 229920000137 polyphosphoric acid Polymers 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical class SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 3
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 2
- LDLCZOVUSADOIV-UHFFFAOYSA-N 2-bromoethanol Chemical compound OCCBr LDLCZOVUSADOIV-UHFFFAOYSA-N 0.000 description 2
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 2
- PKUFNWPSFCOSLU-UHFFFAOYSA-N 6-chloro-1h-pyrimidine-2,4-dione Chemical compound ClC1=CC(=O)NC(=O)N1 PKUFNWPSFCOSLU-UHFFFAOYSA-N 0.000 description 2
- 241000283690 Bos taurus Species 0.000 description 2
- OJRUSAPKCPIVBY-KQYNXXCUSA-N C1=NC2=C(N=C(N=C2N1[C@H]3[C@@H]([C@@H]([C@H](O3)COP(=O)(CP(=O)(O)O)O)O)O)I)N Chemical compound C1=NC2=C(N=C(N=C2N1[C@H]3[C@@H]([C@@H]([C@H](O3)COP(=O)(CP(=O)(O)O)O)O)O)I)N OJRUSAPKCPIVBY-KQYNXXCUSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- 238000006994 Koenigs-Knorr glycosidation reaction Methods 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- AUNGANRZJHBGPY-SCRDCRAPSA-N Riboflavin Chemical compound OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-SCRDCRAPSA-N 0.000 description 2
- 241000700605 Viruses Species 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 230000000840 anti-viral effect Effects 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 235000014633 carbohydrates Nutrition 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229940125758 compound 15 Drugs 0.000 description 2
- 210000000448 cultured tumor cell Anatomy 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- VWWQXMAJTJZDQX-UYBVJOGSSA-N flavin adenine dinucleotide Chemical compound C1=NC2=C(N)N=CN=C2N1[C@@H]([C@H](O)[C@@H]1O)O[C@@H]1CO[P@](O)(=O)O[P@@](O)(=O)OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C2=NC(=O)NC(=O)C2=NC2=C1C=C(C)C(C)=C2 VWWQXMAJTJZDQX-UYBVJOGSSA-N 0.000 description 2
- 235000019162 flavin adenine dinucleotide Nutrition 0.000 description 2
- 239000011714 flavin adenine dinucleotide Substances 0.000 description 2
- 229940093632 flavin-adenine dinucleotide Drugs 0.000 description 2
- 150000002211 flavins Chemical class 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 210000004698 lymphocyte Anatomy 0.000 description 2
- 230000000873 masking effect Effects 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- ZXSQEZNORDWBGZ-UHFFFAOYSA-N 1,3-dihydropyrrolo[2,3-b]pyridin-2-one Chemical compound C1=CN=C2NC(=O)CC2=C1 ZXSQEZNORDWBGZ-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- QPOZFEXNJRQCQO-UHFFFAOYSA-N 2-(3,5-diphenyl-1h-tetrazol-2-yl)-4,4-dimethyl-5h-1,3-thiazole;hydrobromide Chemical compound [Br-].CC1(C)CSC(N2N([NH2+]C(=N2)C=2C=CC=CC=2)C=2C=CC=CC=2)=N1 QPOZFEXNJRQCQO-UHFFFAOYSA-N 0.000 description 1
- NDOPHXWIAZIXPR-UHFFFAOYSA-N 2-bromobenzaldehyde Chemical compound BrC1=CC=CC=C1C=O NDOPHXWIAZIXPR-UHFFFAOYSA-N 0.000 description 1
- ZFTBZKVVGZNMJR-UHFFFAOYSA-N 5-chlorouracil Chemical compound ClC1=CNC(=O)NC1=O ZFTBZKVVGZNMJR-UHFFFAOYSA-N 0.000 description 1
- MCWKRGUQAARPCJ-UHFFFAOYSA-N 6-(dodecylamino)-1h-pyrimidine-2,4-dione Chemical compound CCCCCCCCCCCCNC1=CC(O)=NC(O)=N1 MCWKRGUQAARPCJ-UHFFFAOYSA-N 0.000 description 1
- KDKKBSLUGDVIQM-UHFFFAOYSA-N 6-bromo-6-nitrocyclohexa-2,4-diene-1-carbaldehyde Chemical compound [O-][N+](=O)C1(Br)C=CC=CC1C=O KDKKBSLUGDVIQM-UHFFFAOYSA-N 0.000 description 1
- VLATWUZGXHPDLF-UHFFFAOYSA-N 6-phenoxy-1h-pyrimidine-2,4-dione Chemical compound N1C(=O)NC(=O)C=C1OC1=CC=CC=C1 VLATWUZGXHPDLF-UHFFFAOYSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- FNOJACZRUTWPCV-UHFFFAOYSA-N CC(C)(C)C(C=C1)=CC=C1C(C(N1)=O)=CNC1=[Se] Chemical compound CC(C)(C)C(C=C1)=CC=C1C(C(N1)=O)=CNC1=[Se] FNOJACZRUTWPCV-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- AUNGANRZJHBGPY-UHFFFAOYSA-N D-Lyxoflavin Natural products OCC(O)C(O)C(O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-UHFFFAOYSA-N 0.000 description 1
- 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 1
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 229930186217 Glycolipid Natural products 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 241000725303 Human immunodeficiency virus Species 0.000 description 1
- 238000012404 In vitro experiment Methods 0.000 description 1
- 102000004856 Lectins Human genes 0.000 description 1
- 108090001090 Lectins Proteins 0.000 description 1
- 102000048245 N-acetylneuraminate lyases Human genes 0.000 description 1
- 108700023220 N-acetylneuraminate lyases Proteins 0.000 description 1
- SUHQNCLNRUAGOO-UHFFFAOYSA-N N-glycoloyl-neuraminic acid Natural products OCC(O)C(O)C(O)C(NC(=O)CO)C(O)CC(=O)C(O)=O SUHQNCLNRUAGOO-UHFFFAOYSA-N 0.000 description 1
- FDJKUWYYUZCUJX-PGIATKPXSA-N N-glycoloylneuraminic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@@H]1OC(O)(C(O)=O)C[C@H](O)[C@H]1NC(=O)CO FDJKUWYYUZCUJX-PGIATKPXSA-N 0.000 description 1
- FDJKUWYYUZCUJX-KVNVFURPSA-N N-glycolylneuraminic acid Chemical compound OC[C@H](O)[C@H](O)[C@@H]1O[C@](O)(C(O)=O)C[C@H](O)[C@H]1NC(=O)CO FDJKUWYYUZCUJX-KVNVFURPSA-N 0.000 description 1
- 229930182473 O-glycoside Natural products 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- LCTONWCANYUPML-UHFFFAOYSA-M Pyruvate Chemical compound CC(=O)C([O-])=O LCTONWCANYUPML-UHFFFAOYSA-M 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- 241000277331 Salmonidae Species 0.000 description 1
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 102000018265 Virus Receptors Human genes 0.000 description 1
- 108010066342 Virus Receptors Proteins 0.000 description 1
- 229930003270 Vitamin B Natural products 0.000 description 1
- ABRVLXLNVJHDRQ-UHFFFAOYSA-N [2-pyridin-3-yl-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound FC(C1=CC(=CC(=N1)C=1C=NC=CC=1)CN)(F)F ABRVLXLNVJHDRQ-UHFFFAOYSA-N 0.000 description 1
- PWZXVVUVIMDWDA-UHFFFAOYSA-N [Na].C(C)(C)(C)C1=CC=C(C=C1)[SeH] Chemical compound [Na].C(C)(C)(C)C1=CC=C(C=C1)[SeH] PWZXVVUVIMDWDA-UHFFFAOYSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000340 anti-metabolite Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 229940100197 antimetabolite Drugs 0.000 description 1
- 239000002256 antimetabolite Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000003327 cancerostatic effect Effects 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 238000010531 catalytic reduction reaction Methods 0.000 description 1
- 239000003729 cation exchange resin Substances 0.000 description 1
- 230000032677 cell aging Effects 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- QQVDYSUDFZZPSU-UHFFFAOYSA-M chloromethylidene(dimethyl)azanium;chloride Chemical compound [Cl-].C[N+](C)=CCl QQVDYSUDFZZPSU-UHFFFAOYSA-M 0.000 description 1
- 239000005515 coenzyme Substances 0.000 description 1
- 210000003022 colostrum Anatomy 0.000 description 1
- 235000021277 colostrum Nutrition 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000006356 dehydrogenation reaction Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 1
- 235000013601 eggs Nutrition 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 1
- 125000004072 flavinyl group Chemical group 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 229930182470 glycoside Natural products 0.000 description 1
- 230000009422 growth inhibiting effect Effects 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 229940125697 hormonal agent Drugs 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 238000009863 impact test Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- BQINXKOTJQCISL-GRCPKETISA-N keto-neuraminic acid Chemical compound OC(=O)C(=O)C[C@H](O)[C@@H](N)[C@@H](O)[C@H](O)[C@H](O)CO BQINXKOTJQCISL-GRCPKETISA-N 0.000 description 1
- 239000002523 lectin Substances 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 150000002730 mercury Chemical class 0.000 description 1
- CERZMXAJYMMUDR-UHFFFAOYSA-N neuraminic acid Natural products NC1C(O)CC(O)(C(O)=O)OC1C(O)C(O)CO CERZMXAJYMMUDR-UHFFFAOYSA-N 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 150000002989 phenols Chemical group 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000027756 respiratory electron transport chain Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 239000002151 riboflavin Substances 0.000 description 1
- 235000019192 riboflavin Nutrition 0.000 description 1
- 229960002477 riboflavin Drugs 0.000 description 1
- 102220240796 rs553605556 Human genes 0.000 description 1
- 150000003378 silver Chemical class 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- NBYLLBXLDOPANK-UHFFFAOYSA-M silver 2-carboxyphenolate hydrate Chemical compound C1=CC=C(C(=C1)C(=O)O)[O-].O.[Ag+] NBYLLBXLDOPANK-UHFFFAOYSA-M 0.000 description 1
- LKZMBDSASOBTPN-UHFFFAOYSA-L silver carbonate Substances [Ag].[O-]C([O-])=O LKZMBDSASOBTPN-UHFFFAOYSA-L 0.000 description 1
- 229910001958 silver carbonate Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 150000003498 tellurium compounds Chemical class 0.000 description 1
- 229940035893 uracil Drugs 0.000 description 1
- 235000019156 vitamin B Nutrition 0.000 description 1
- 239000011720 vitamin B Substances 0.000 description 1
Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Saccharide Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
【０００１】[0001]
【産業上の利用分野】本発明は、制癌あるいは抗ウィル
ス活性を有する5-デアザフラビン類と、シアル酸類がＯ
−グリコシド結合した、新規な化合物に関する。This invention relates to 5-deazaflavins having anticancer or antiviral activity and sialic acids containing O
It relates to novel compounds which are glycosidic.
【０００２】[0002]
【従来の技術と問題点】制癌作用を持つ化合物としては
現在までに、多くの物質が開発されている。例えば、代
謝拮抗剤、抗生物質、放射性元素、ホルモン剤、アルキ
ル化剤など様々な構造を持つ化合物が提案されている。
また、昨今では、ＡＩＤＳを引き起こすＨＩＶウィルス
に対する有効な治療薬の開発も急務とされ、ＡＺＴなど
数種の化合物が提案され、それなりの効果をあげてい
る。しかしながら、これらの化合物は、癌細胞あるいは
ウィルス感染細胞に対し有効にダメージを与えるもの
の、正常細胞にも多かれ少なかれ、損傷を与えてしまう
ため、毒性、副作用が強いという欠点を有している。こ
のため、毒性の低い制癌剤の開発がこの分野で強く望ま
れている。2. Description of the Related Art Many compounds having a carcinostatic action have been developed so far. For example, compounds having various structures such as antimetabolites, antibiotics, radioactive elements, hormonal agents, and alkylating agents have been proposed.
In recent years, it has been urgently required to develop an effective therapeutic agent for the HIV virus that causes AIDS, and several types of compounds such as AZT have been proposed, and their effects have been improved. However, these compounds, while effectively damaging cancer cells or virus-infected cells, more or less damage normal cells, and thus have the drawback of having high toxicity and side effects. For this reason, the development of anti-cancer drugs having low toxicity is strongly desired in this field.
【０００３】ところで、フラビン化合物は、ビタミンＢ
2 として知られるリボフラビンやフラビンアデニンジヌ
クレオチド（ＦＡＤ）等に含まれ、生体内で補酵素とし
て、基質の脱水素、電子伝達などの重要な機能を担って
いる。このフラビン誘導体と細胞の老化や癌との関わり
が近年注目を浴びており、制癌作用を持つ化合物も提案
されている。この制癌作用を更に増強する目的で、フラ
ビンの５位の窒素原子を炭素原子で置き換えた5-デアザ
フラビン誘導体を合成する試みもなされており、そのう
ちいくつかのものは、強い制癌活性、並びに抗ＨＩＶ活
性を有することが報告されている。しかしながら、これ
らの物質においても、生体適合性に問題があり、治療薬
として用いた場合には正常細胞への毒性、副作用が懸念
される。By the way, flavin compounds are vitamin B
It is contained in riboflavin and flavin adenine dinucleotide (FAD) known as No. 2 and plays an important role as a coenzyme in vivo, such as dehydrogenation of substrates and electron transfer. The relationship between this flavin derivative and cell aging and cancer has attracted attention in recent years, and compounds having an anticancer effect have also been proposed. In order to further enhance this anti-cancer effect, attempts have been made to synthesize 5-deazaflavin derivatives in which the nitrogen atom at the 5-position of flavin has been replaced with a carbon atom, some of which have strong anti-cancer activity, and It is reported to have anti-HIV activity. However, these substances also have a problem in biocompatibility, and when used as a therapeutic agent, there is a concern about toxicity to normal cells and side effects.
【０００４】[0004]
【問題を解決する手段】本発明者は、かかる状況に鑑
み、制癌活性あるいは抗ＨＩＶウィルス活性を持つ5-デ
アザフラビン誘導体で、アルキルアルコール基を持つ化
合物とシアル酸がＯ−グリコシド結合した化合物を設計
した。シアル酸は、糖蛋白質や糖脂質で知られる複合糖
質の糖鎖の末端に含まれる酸性糖で、その多彩な生理機
能のため、近年益々その重要性を増してきている。シア
ル酸の骨格は、5-Ｎ−アセチル、または5-Ｎ−グリコリ
ルノイラミン酸であって、この他に、水酸基の幾つかが
Ｏ−アセチル化されたものも存在し、現在、シアル酸と
は、これら誘導体の総称と理解されている。この他に、
近年サケ科の授精卵から発見された、ノイラミン酸の、
５位のアミノ基が水酸基に変換された化合物（ＫＤＮ）
は、シアリダーゼによる加水分解を受けづらいという性
質があるが、これもシアル酸類の一種とみなされること
がある。In view of such circumstances, the present inventor has proposed a 5-deazaflavin derivative having an anticancer activity or an anti-HIV virus activity, which comprises a compound having an alkyl alcohol group and a sialic acid having an O-glycoside bond. Designed. Sialic acid is an acidic sugar contained in the terminal of the sugar chain of complex carbohydrates known as glycoproteins and glycolipids, and its importance has been increasing in recent years due to its various physiological functions. The backbone of sialic acid is 5-N-acetyl or 5-N-glycolylneuraminic acid, and some of the hydroxyl groups are also O-acetylated. Is understood as a generic term for these derivatives. In addition,
Of neuraminic acid that was recently discovered from salmonid fertilized eggs,
Compound in which the 5-position amino group has been converted to a hydroxyl group (KDN)
Has a property that it is not easily hydrolyzed by sialidase, but this is also sometimes regarded as a kind of sialic acids.
【０００５】シアル酸の多彩な機能には、例えば、糖鎖
を持つ化合物（複合糖質）の血中半減期の制御が挙げら
れる。すなわち、複合糖質の糖鎖にシアル酸が結合する
ことにより、その化合物の血中半減期が飛躍的に延長さ
れ、また、逆にシアル酸が糖鎖から切り出されると、そ
の化合物は速やかに血中から排除される。この性質が、
シアル酸を含む複合糖質を細胞表面にもつ細胞（例えば
リンパ球や赤血球など）の半減期をも制御していると考
えられている。また、シアル酸は、多彩なマスキング効
果も有する。すなわち、化合物にシアル酸が付与される
ことで、その物質はリンパ球や種々のレクチン等からマ
スクされて異物として認識され難くなり、結果的に、抗
原性や、毒性が回避されるのである。この他にも、シア
ル酸には、ウィルスのレセプター活性や、タンパク質へ
の、プロテアーゼ抵抗性の付与等まだまだ多くの生理機
能がある。[0005] Various functions of sialic acid include, for example, control of blood half-life of a compound having a sugar chain (glycoconjugate). That is, the binding of sialic acid to the sugar chain of glycoconjugates significantly increases the blood half-life of the compound, and conversely, when the sialic acid is cleaved from the sugar chain, the compound is rapidly released. It is eliminated from the blood. This property is
It is thought that the compound also controls the half-life of cells having complex carbohydrates containing sialic acid on the cell surface (eg, lymphocytes and erythrocytes). Sialic acid also has various masking effects. That is, when sialic acid is imparted to a compound, the substance is masked by lymphocytes, various lectins, and the like, making it difficult to be recognized as a foreign substance. As a result, antigenicity and toxicity are avoided. In addition, sialic acid has many other physiological functions such as virus receptor activity and protease resistance to proteins.
【０００６】以上述べたようなシアル酸の生理機能を考
慮すると、本発明者が設計した化合物は、5-デアザフラ
ビンのみの化合物に比べて以下の点で、優れている。 5-デアザフラビン類の親水性が高まる。シアル酸は
糖質の特徴として多くの水酸基をもつ他、有機酸として
はかなり強いカルボン酸（ｐＫａ＝２．７）も有するの
で、親水性が向上する。 血中半減期が向上する。前述のように、シアル酸が
導入されることで血中半減期が向上するので、１回の投
与量が非常に少なくでき、血中に長期間滞留するため、
正常でない細胞すなわち癌細胞や感染細胞にのみ選択毒
性が期待できる。そのうえ、前述のマスキング効果によ
り、抗原性や異物反応がマスクされ、副作用が抑えられ
る。 さらに、5-デアザフラビンに長鎖アルキル基な
どの非極性基を導入しておけば、シアル酸と5-デアザフ
ラビン残基が表面に露出したリポソームを作成すること
が出来、この形で投与することで更に有効な治療が行え
る。In view of the physiological function of sialic acid as described above, the compound designed by the present inventors is superior to the compound containing only 5-deazaflavin in the following points. Increases the hydrophilicity of 5-deazaflavins. Sialic acid has many hydroxyl groups as a characteristic of saccharides, and also has a carboxylic acid (pKa = 2.7) which is quite strong as an organic acid, so that hydrophilicity is improved. Blood half-life is improved. As described above, the introduction of sialic acid improves the half-life in the blood, so that a single dose can be extremely small and stay in the blood for a long time.
Selective toxicity can be expected only for abnormal cells, that is, cancer cells and infected cells. In addition, the masking effect described above masks antigenicity and foreign substance reactions, and suppresses side effects. Furthermore, if non-polar groups such as long-chain alkyl groups are introduced into 5-deazaflavin, liposomes in which sialic acid and 5-deazaflavin residues are exposed on the surface can be prepared. More effective treatment can be performed.
【０００７】以上の設計図に基づき、鋭意研究を重ねた
結果、すでに報告のある、制癌活性または抗ＨＩＶウィ
ルス活性を有する5-デアザフラビン類の骨格に、アルキ
ルアルコール基を導入した化合物の合成を行い、既知の
方法によってシアル酸の水酸基をアセチル基で保護し、
さらに還元末端をハロゲンで活性化して調製した化合物
とカップリングを行うことによって、効率よく目的の化
合物を合成できることを見いだして、本発明を完成し
た。As a result of intensive studies based on the above design drawings, the synthesis of a compound in which an alkyl alcohol group has been introduced into the backbone of 5-deazaflavins having anticancer activity or anti-HIV virus activity has been reported as a result of extensive studies. Performed, protecting the hydroxyl group of sialic acid with an acetyl group by a known method,
Furthermore, they have found that the desired compound can be efficiently synthesized by coupling with a compound prepared by activating the reducing end with halogen, and completed the present invention.
【０００８】すなわち本発明は一般式ＩまたはIIで表さ
れる新規なシアル酸結合5-デアザフラビン系化合物に関
わる。That is, the present invention relates to a novel sialic acid-binding 5-deazaflavin compound represented by the general formula I or II.
【０００９】[0009]
【化６】 Embedded image
【化７】 Embedded image
【００１０】式中Ｒは、Ｎ−アセチル（ＣＨ3 ＣＯＮＨ
- 、ＡｃＮとも表記する）基、Ｎ−グリコリル（ＨＯＣ
Ｈ2 ＣＯＮＨ- 、ＧｃＮとも表記する）基、または水酸
基を表し、ｄＦｌは、下記一般式、III 、IV、またはＶ
で表される5-デアザフラビン化合物である。すなわち、
本発明の化合物は、制癌作用あるいは抗ウィルス作用を
有する5-デアザフラビン類とシアル酸とが、α- あるい
はβ- Ｏ-グリコシド結合した化合物であり、また、逆
に5-デアザフラビン側からみると、5-デアザフラビンの
基本骨格を形成するピリミジン環、ピリジン環、及びベ
ンゼン環のいずれかにシアル酸が結合した化合物であ
る。In the formula, R is N-acetyl (CH 3 CONH
-, AcN), N-glycolyl (HOC)
H 2 CONH-, also referred GcN) represents a group or a hydroxyl group,, DFL is represented by the following formula, III, IV or V,
Is a 5-deazaflavin compound represented by That is,
The compound of the present invention is a compound in which 5-deazaflavins having anticancer action or antiviral action and sialic acid are α- or β-O-glycosidically linked, and conversely, when viewed from the 5-deazaflavin side. Is a compound in which sialic acid is bonded to any of a pyrimidine ring, a pyridine ring, and a benzene ring which form the basic skeleton of 5-deazaflavin.
【００１１】[0011]
【化８】 Embedded image
【化９】 Embedded image
【化１０】 Embedded image
【００１２】式中Ｒ1 は、水素原子、アルキル基、ハロ
ゲン置換アルキル基、フェニル置換アルキル基またはフ
ェニル基を表す。このうち、フェニル置換アルキル基と
は、例えば、ベンジル基などを指す。Ｒ2 は、水素原
子、アルキルアミノ基、フェニル置換アルキルアミノ
基、ヒドロキシ置換アルキルアミノ基、ハロゲン置換ア
ルキル基、アルコキシ基、ピリジル基、フェニル基、ハ
ロゲン原子もしくはトリフルオロメチル基、ニトロ基、
低級アルコキシ基のうちの一つで置換されたフェニル基
を表す。In the formula, R 1 represents a hydrogen atom, an alkyl group, a halogen-substituted alkyl group, a phenyl-substituted alkyl group or a phenyl group. Among them, the phenyl-substituted alkyl group refers to, for example, a benzyl group. R2 represents a hydrogen atom, an alkylamino group, a phenyl-substituted alkylamino group, a hydroxy-substituted alkylamino group, a halogen-substituted alkyl group, an alkoxy group, a pyridyl group, a phenyl group, a halogen atom or a trifluoromethyl group, a nitro group,
Represents a phenyl group substituted with one of the lower alkoxy groups.
【００１３】Ｒ3 は、水素原子、ニトロ基、シアノ基、
アルキル基、低級アルコキシ基、フェニル置換低級アル
コキシ基、低級アルキルアミノ基、フェニル置換低級ア
ルキルアミノ基または低級アルキルスルフォニル基を表
す。Ｙは、メチレン基またはアルキルアミノ基〔例えば
-ＮＨ-(ＣＨ2 ) n - や- Ｎ（ＣＨ3 ) -(ＣＨ2 ) n -]
などである。Ｘは、セレン原子、硫黄原子、酸素原子、
または基＝Ｎ−Ｒ4 を表す。ここで、Ｒ4 とは、アルキ
ル基、シクロアルキル基、フェニル置換低級アルキル
基、フェニル基、ハロゲン原子、もしくは低級アルコキ
シ基のうちの一つで置換されたフェニル基、低級アルキ
ルジ置換フェニル基、ナフチル基、低級アルキルジ置換
アミノナフチル基を表す。ここでＮは、２〜６の整数を
表す。 R 3 represents a hydrogen atom, a nitro group, a cyano group,
Represents an alkyl group, a lower alkoxy group, a phenyl-substituted lower alkoxy group, a lower alkylamino group, a phenyl-substituted lower alkylamino group or a lower alkylsulfonyl group. Y is a methylene group or an alkylamino group [for example,
-NH- (CH 2) n - or - N (CH 3) - ( CH 2) n -]
And so on. X is a selenium atom, a sulfur atom, an oxygen atom,
Or a group = N-R 4. Here, R 4 represents an alkyl group, a cycloalkyl group, a phenyl-substituted lower alkyl group, a phenyl group, a phenyl group substituted with one of a halogen atom or a lower alkoxy group, a lower alkyldi-substituted phenyl group, and a naphthyl. Represents a lower alkyldisubstituted aminonaphthyl group. Here, N is an integer of 2 to 6
Represent.
【００１４】一方、一般式Ｉ及びIIのシアル酸に関して
は、Ｒ0 がアセチル基のもの、（Ｎ−アセチルノイラミ
ン酸：ＮＡＮＡ）、グリコリル基のもの（Ｎ−グリコリ
ルノイラミン酸：ＮＧＮＡ）、水酸基のもの（ＫＤＮ）
を用いる。シアル酸の中ではＮＡＮＡが最も著名で、通
常はヒト正常細胞からはＮＡＮＡのみが検出される。し
かしながら、細胞が癌化するに伴ってＮＧＮＡを含む糖
鎖が検出されて来ることが知られている。この意味で、
ＮＧＮＡを含む化合物の合成は、癌細胞の糖鎖合成酵素
系を標的にできる可能性がある。また、ＫＤＮは、シア
ル酸のグリコシド結合を切断する酵素であるシアリダー
ゼに抵抗する物質として知られており、ＫＤＮを結合さ
せることで、ＮＡＮＡよりもさらに血中半減期が延びる
ことが考えられる。また、天然の糖鎖では、シアル酸は
すべてα- 結合体として見いだされ、シアリダーゼもα
- 結合体しか切断しないことが知られている。よって、
β- 結合体も血中半減期を延長するために有効であると
考えられる。On the other hand, as for the sialic acids of the general formulas I and II, R 0 has an acetyl group (N-acetylneuraminic acid: NANA), and R0 has a glycolyl group (N-glycolylneuraminic acid: NGNA). With hydroxyl groups (KDN)
Is used. NANA is the most prominent among sialic acids, and normally only NANA is detected from normal human cells. However, it is known that sugar chains containing NGNA are detected as cells become cancerous. In this sense,
The synthesis of compounds containing NGNA may be able to target the sugar chain synthase system of cancer cells. In addition, KDN is known as a substance that resists sialidase, which is an enzyme that cleaves glycoside bonds of sialic acid. By binding KDN, it is considered that the half-life in blood is further extended as compared with NANA. In natural sugar chains, all sialic acids are found as α-conjugates, and sialidase is also found in α-conjugates.
-It is known that only conjugates cleave. Therefore,
β-conjugates are also believed to be effective in extending blood half-life.
【００１５】一般式Ｉ及びIIで表される本発明化合物の
具体例を表１〜表４に示す。Specific examples of the compounds of the present invention represented by formulas I and II are shown in Tables 1 to 4.
【００１６】[0016]
【表１】 [Table 1]
【表２】 [Table 2]
【表３】 [Table 3]
【表４】 [Table 4]
【００１７】注）Ｒ3及びＹの置換基の前の数字は、各
置換基の5-デアザフラビン環上の位置をあらわす。例え
ば、6-ＮＯ2は、5-デアザフラビン環上の7位に置換され
ているニトロ基を表す。次に、本発明のシアル酸結合5-
デアザフラビン系化合物の合成方法について説明する。 （１）5-デアザフラビン類の合成。ア ルコール性水酸基を持った5-デアザフラビン化合物
は、特に制限されないが、例えば以下の製法のいずれか
で製造する事が出来る。製法に関してはこの他にも様々
な方法がある。Note: The numbers before the substituents R 3 and Y represent the position of each substituent on the 5-deazaflavin ring. For example, 6-NO 2 represents a nitro group substituted on the 7-position on the 5-Deazafurabin ring. Next, the sialic acid bond 5-
A method for synthesizing a deazaflavin compound will be described. (1) Synthesis of 5-deazaflavins. 5 Deazafurabin compounds having A alcohol hydroxyl group is not particularly limited, for example, can be produced by any of the following production method. There are various other manufacturing methods.
【００１８】製法Ａ 6-Ｎ- 置換- アミノウラシル(1) は、常法により6-クロ
ロウラシルと第一アミンとの縮合によって製造する。
(1) と適当なｏ- ハロゲノベンズアルデヒド(2) をジメ
チルホルムアミド(MF)中で3 〜24時間時間加熱還流す
る。反応液を必要ならば減圧濃縮し、析出した結晶ない
しは残渣を再結晶して、対応する、5-デアザフラビン誘
導体(1) を得る。この際、Ｒ1 または、Ｒ4 として、ア
ルキルアルコール (-(CH 2 )n -OH)基を持つ原料を用い
ると、それぞれ、3 位または10位にアルキルアルコール
基を有する5-デアザフラビンが合成できる。同様に、Ｒ
3 として、ｏ- 位、ｍ- 位、ｐ- 位にアルキルアルコー
ル基を持つｏ- ハロゲノベンズアルデヒド(2) を用いる
と、ｏ- 位では9 位、ｍ- 位では6位または8 位、ｐ-
位では7 位にアルキルアルコール基を持つ5-デアザフラ
ビンが合成できる。アルキルアルコールの水酸基を、例
えばベンジル（bzl)基やベンジルオキシカルボニル
（Ｚ）基で保護したまま合成を行い、接触還元などで保
護基を除去し、最後に過酸化水素や、ジエチルアゾジカ
ルボキシレート（ＤＡＤ）などで酸化を行って、目的物
を得る場合もある。Process A A 6-N-substituted-aminouracil (1) is prepared by a conventional method by condensation of 6-chlorouracil with a primary amine.
(1) and the appropriate o-halogenobenzaldehyde (2) are heated to reflux in dimethylformamide (MF) for 3-24 hours. The reaction solution is concentrated under reduced pressure if necessary, and the precipitated crystals or residue are recrystallized to obtain the corresponding 5-deazaflavin derivative (1). At this time, when a raw material having an alkyl alcohol (-(CH 2 ) n -OH) group is used as R 1 or R 4 , 5-deazaflavin having an alkyl alcohol group at the 3- or 10-position can be synthesized, respectively. . Similarly, R
When o-halogenobenzaldehyde (2) having an alkyl alcohol group at the o-, m-, and p-positions is used as 3, the o-position is 9-position, the m-position is 6- or 8-position, and p-
At the 7th position, 5-deazaflavin having an alkyl alcohol group at the 7th position can be synthesized. The synthesis is carried out while protecting the hydroxyl group of the alkyl alcohol with, for example, a benzyl (bzl) group or a benzyloxycarbonyl (Z) group. The protecting group is removed by catalytic reduction or the like. Finally, hydrogen peroxide or diethyl azodicarboxylate is used. In some cases, the target product is obtained by performing oxidation using (DAD) or the like.
【００１９】[0019]
【化１１】 Embedded image
【００２０】製法Ａ’ 製法Ａによって得られる3-無置換（Ｒ1 ＝Ｈ）の5-デア
ザフラビン及び、これと等モルの、Ｘ-(ＣＨ2 ) n ＯＨ
（Ｘ：ハロゲン）などの、ハロゲノアルキルアルコール
を、炭酸カリウム存在下ＤＭＦ中で加熱することで、3
位にアルキルアルコール基を有する5-デアザフラビン誘
導体が合成できる。Preparation A ′ 3-Desubstituted (R 1 ＨH) 5-deazaflavin obtained by Preparation A and an equimolar amount of X- (CH 2 ) n OH
By heating a halogenoalkyl alcohol such as (X: halogen) in DMF in the presence of potassium carbonate, 3
A 5-deazaflavin derivative having an alkyl alcohol group at the 2-position can be synthesized.
【００２１】製法Ｂ 製法Ａによって得られる、6、7、8、9 位のいずれかに脱離
基（例えば -ＯＣＨ3 、ハロゲンなど）を有する5-デア
ザフラビン及び、これと等モルの、アルキルアルコール
基を持つ強い求核剤、〔例えばヒドロキシアルキルアミ
ン（Ｈ2Ｎ-(ＣＨ2 ) n - ＯＨ）など〕を炭酸カリウム
存在下ＤＭＦ中で加熱することで、対応する位置にアル
キルアルコール基を有する5-デアザフラビン誘導体が合
成出来る。Process B 5-Deazaflavin having a leaving group (for example, -OCH 3 , halogen, etc.) at any of positions 6, 7, 8, and 9 obtained by Process A and an equimolar amount of an alkyl alcohol By heating a strong nucleophile having a group such as hydroxyalkylamine (H 2 N— (CH 2 ) n —OH) in DMF in the presence of potassium carbonate, the compound has an alkyl alcohol group at the corresponding position A 5-deazaflavin derivative can be synthesized.
【００２２】[0022]
【化１２】 Embedded image
【００２３】製法Ｃ 6-アニリノウラシル誘導体(6) とアルデヒド類(7) とを
溶融し、またはＤＭＦ中で長時間加熱還流して、対応す
る5-デアザフラビン誘導体(8) を得る。Ｒ1 、Ｒ3 、Ｒ
4 のうちどれかは、アルキルアルコール基を有するもの
とする。Process C The 6-anilinouracil derivative (6) and the aldehyde (7) are melted or heated and refluxed in DMF for a long time to obtain the corresponding 5-deazaflavin derivative (8). R 1 , R 3 , R
Any of 4 has an alkyl alcohol group.
【００２４】[0024]
【化１３】 Embedded image
【００２５】製法Ｄ テトラヒドロフラン（ＴＨＦ）あるいはＤＭＦ中で水素
化ナトリウム（ＮａＨ）によって置換チオフェノールあ
るいは置換セレノフェノール(9) をナトリウム塩にして
おき、3-Ｎ−置換-6- クロロウラシルを加えて加熱還流
することにより、6-アリールチオ（またはセレノ）ウラ
シル(10)を得る。次いで、(10)をビルスマイヤー試薬
（ＤＭＦ＋ＰＯＣｌ3 ) で処理し、対応する6-アリール
チオ（またはセレノ)-5-ホルミルウラシル(11)を得る。
(11)をポリリン酸（ＰＰＡ）中で加熱し、10- チア（ま
たはセレナ)-5-デアザフラビン類(12)を得る。Ｒ1 また
はＲ3 にアルキルアルコール基を持たせておくか、また
は、製法Ａ’や製法Ｃのようにあとからアルキルアルコ
ール基を導入しても良い。Preparation Method D A substituted thiophenol or substituted selenophenol (9) is converted to a sodium salt with sodium hydride (NaH) in tetrahydrofuran (THF) or DMF, and 3-N-substituted-6-chlorouracil is added. By heating to reflux, 6-arylthio (or seleno) uracil (10) is obtained. Then, (10) is treated with a Vilsmeier reagent (DMF + POCl 3 ) to give the corresponding 6-arylthio (or seleno) -5-formyluracil (11).
(11) is heated in polyphosphoric acid (PPA) to give 10-thia (or selena) -5-deazaflavins (12). R 1 or R 3 may have an alkyl alcohol group, or an alkyl alcohol group may be introduced later, as in Production Method A ′ or Production Method C.
【００２６】[0026]
【化１４】 Embedded image
【００２７】製法Ｄ’ 炭酸カリウムの存在下で置換フェノールを3-Ｎ−置換-6
- クロロウラシルと共に加熱還流して、6-フェノキシウ
ラシル(13)を得る。以後は製法Ｄと同様にして、10- オ
キサ-5- デアザフラビン類を得る。Process D 'The substituted phenol is substituted with 3-N-substituted-6 in the presence of potassium carbonate.
-Heat to reflux with chlorouracil to give 6-phenoxyuracil (13). Thereafter, in the same manner as in Production Method D, 10-oxa-5-deazaflavins are obtained.
【００２８】(2) シアル酸 原料のシアル酸に関しては、ＮＡＮＡは最近は大量に入
手可能である。ＮＧＮＡは、牛脳や牛初乳から生成でき
る。ＫＤＮは、マンノースとピルビン酸を基質として用
い、シアル酸アルドラーゼの逆反応によって合成するこ
とができる。 (3) 5-デアザフラビン類とシアル酸との反応 シアル酸は常法に従い、カルボン酸をメチルエステル
で、水酸基をアセチル基で保護し、還元末端をハロゲン
で活性化する。ここで、ハロゲンは、フッ素、塩素、臭
素のいずれかである。幾通りかの方法があるが、代表的
なものを製法Ｅに挙げる。こうして得られるシアル酸の
保護体を、以後アセチルハロゲノシアル酸と呼ぶ。(2) Sialic acid With respect to the raw material sialic acid, NANA has recently been available in large quantities. NGNA can be produced from bovine brain and bovine colostrum. KDN can be synthesized by a reverse reaction of sialic acid aldolase using mannose and pyruvate as substrates. (3) Reaction of 5-deazaflavins with sialic acid According to a conventional method, sialic acid protects a carboxylic acid with a methyl ester, protects a hydroxyl group with an acetyl group, and activates a reducing end with a halogen. Here, halogen is any of fluorine, chlorine, and bromine. Although there are several methods, a typical one is shown in Production Method E. The protected form of sialic acid thus obtained is hereinafter referred to as acetylhalogenosialic acid.
【００２９】[0029]
【化１５】 Embedded image
【００３０】5-デアザフラビンとシアル酸のカップリン
グは、通常行われるKoenigs-Knorr 反応によって行う。
すなわち、アセチルハロゲノシアル酸と5-デアザフラビ
ンの等モルを、有機溶媒に溶解あるいは懸濁し、適当量
のモレキュラーシーブズを加え、10〜15分間窒素置換を
行った後、1 〜3 倍量の触媒を加えて、遮光下10〜30時
間撹拌する。触媒等不溶部を濾別した後、溶媒を留去
し、シリカゲルカラムクロマトによって、原料、α- 結
合体、β- 結合体及び副生成物を分離する。有機溶媒と
しては特に限定されないが、たとえば、ＴＨＦやジオキ
サン、塩化メチレン、四塩化炭素、ＤＭＦ等が挙げられ
る。触媒も特に限定されないが、通常使用される銀塩や
水銀塩が有効である。一例を挙げると、炭酸銀、サリチ
ル酸銀、トリフルオロメチルスルフォン酸銀などであ
る。The coupling between 5-deazaflavin and sialic acid is carried out by the usual Koenigs-Knorr reaction.
That is, an equimolar amount of acetylhalogenosialic acid and 5-deazaflavin are dissolved or suspended in an organic solvent, an appropriate amount of molecular sieves is added, nitrogen replacement is performed for 10 to 15 minutes, and 1 to 3 times the amount of the catalyst is added. In addition, the mixture is stirred for 10 to 30 hours under light shielding. After filtering off the insoluble part of the catalyst and the like, the solvent is distilled off, and the raw material, α-conjugate, β-conjugate and by-products are separated by silica gel column chromatography. Although it does not specifically limit as an organic solvent, For example, THF, dioxane, methylene chloride, carbon tetrachloride, DMF, etc. are mentioned. Although the catalyst is not particularly limited, silver salts and mercury salts which are usually used are effective. Examples include silver carbonate, silver salicylate, and silver trifluoromethylsulfonate.
【００３１】Koenigs-Knorr 反応は、ＳＮ−１型反応で
あるため、原理的にα- 結合体とβ- 結合体が両方生成
する（化１６参照）。また、シアル酸の場合はこの他
に、Ｃ３位のプロトンがβ脱離して、二重結合を生じる
ものもある（ｅｎｅ体；化１６）。よって、反応後は、
原料、α- 結合体、β- 結合体とｅｎｅ体を分離する必
要があるが、本発明者は、シリカゲルカラムクロマトグ
ラフィーにおいて、適当な溶媒系を用いることで、これ
らが効率よく分離できることを見いだした。この溶媒系
は、例えば、クロロホルム／メタノール系や、ベンゼン
／ヘキサン系、トルエン／エタノール系等である。Since the Koenigs-Knorr reaction is an SN-1 type reaction, both α- and β-conjugates are generated in principle (see Chemical Formula 16). In addition, in the case of sialic acid, there is also a sialic acid in which the proton at the C3 position is β-eliminated to generate a double bond (ene form; Chemical formula 16). Therefore, after the reaction,
Although it is necessary to separate the raw material, α-conjugate, β-conjugate and ene form, the present inventor has found that these can be efficiently separated by using an appropriate solvent system in silica gel column chromatography. Was. The solvent system is, for example, a chloroform / methanol system, a benzene / hexane system, a toluene / ethanol system, or the like.
【００３２】[0032]
【化１６】 Embedded image
【００３３】5-デアザフラビンとのカップリング終了後
の、シアル酸の脱保護は、常法によって行う。すなわ
ち、保護体をメタノール／１Ｎ- ＮａＯＨ混液（3:1 か
ら10:1位）中室温で 2〜24時間撹拌し、陽イオン交換樹
脂で中和の後、溶媒を留去し、必要ならばシリカゲルカ
ラムクロマトグラフィー（例えばクロロホルム／メタノ
ール系などで溶出する）を実施した後結晶化を行う。化
合物によっては、結晶化しないものも多い。また、シア
ル酸のα- グリコシド結合は、酸性下で比較的不安定で
あるため、化合物の安定化のために、シアル酸残基のカ
ルボン酸をナトリウム塩のままで調製する事も多い。こ
の場合は非常に結晶化し難くなるので、純度を確認した
後凍結乾燥する。After completion of the coupling with 5-deazaflavin, sialic acid is deprotected by a conventional method. That is, the protected product is stirred at room temperature for 2 to 24 hours in a mixed solution of methanol / 1N-NaOH (3: 1 to 10: 1), neutralized with a cation exchange resin, and then the solvent is distilled off. After performing silica gel column chromatography (eluting with, for example, a chloroform / methanol system), crystallization is performed. Some compounds do not crystallize. Further, since the α-glycoside bond of sialic acid is relatively unstable under acidic conditions, the carboxylic acid of the sialic acid residue is often prepared as a sodium salt for stabilizing the compound. In this case, it is very difficult to crystallize, so freeze-drying is performed after confirming the purity.
【００３４】以下に実施例を挙げて、本発明を更に詳し
く説明する。もちろん本発明は以下の例で制限されるも
のではない。Hereinafter, the present invention will be described in more detail with reference to examples. Of course, the present invention is not limited by the following examples.
【００３５】[0035]
実施例１2−クロロ−4,7,8,9-テトラ- Ｏ- アセチル−Ｎ−アセ
チルノイラミン酸メチルエステル（アセチルクロロ−Ｎ
ＡＮＡ；製法Ｅ ） ＮＡＮＡ（0.1 mol)をピリジン／無水酢酸混合液（５：
１）中４℃で24時間撹拌して水酸基をアセチル化する。
反応液から溶媒を留去した後残渣をベンゼンに溶かし、
ジアゾメタンのジエチルエーテル溶液を適下し、カルボ
ン酸をメチルエステルにする。溶媒を留去した後、残渣
を塩化アセチルに溶解し４℃で24時間撹拌の後反応液を
減圧濃縮する。エーテル／ヘキサン／石油エーテル系で
再結晶を行い、アセチルクロロ−ＮＡＮＡを得た（収率
95％）。Example 1 2-chloro-4,7,8,9-tetra-O-acetyl-N-acetate
Cylneuraminic acid methyl ester (acetylchloro-N
ANA; Production method E ) NANA (0.1 mol) was mixed with a pyridine / acetic anhydride mixed solution (5:
1) Stir at 4 ° C. for 24 hours to acetylate the hydroxyl group.
After distilling off the solvent from the reaction solution, the residue was dissolved in benzene,
A solution of diazomethane in diethyl ether is dropped to convert the carboxylic acid to a methyl ester. After the solvent was distilled off, the residue was dissolved in acetyl chloride, and the mixture was stirred at 4 ° C. for 24 hours, and the reaction solution was concentrated under reduced pressure. Recrystallization was performed with an ether / hexane / petroleum ether system to obtain acetylchloro-NANA (yield).
95%).
【００３６】実施例２3-フェニル-10-(3- ヒドロキシプロピル-)-5- デアザフ
ラビン（製法Ａ ） 3-フェニル-6-(3-ヒドロキシプロピル-)アミノウラシル
(10 mmol) 及びo-ブロモベンズアルデヒド（11mmol）を
ＤＭＦ中100 ℃で20時間加熱した後反応液を減圧濃縮
し、析出した結晶をＤＭＦ中から再結晶して、3-フェニ
ル-10-(3-ヒドロキシプロピル-)-5- デアザフラビン
（中間体１）を得た（収率95％) 。Example 2 3-Phenyl-10- (3-hydroxypropyl-)-5-deazaf
Labin (Production A ) 3-phenyl-6- (3-hydroxypropyl-) aminouracil
After heating (10 mmol) and o-bromobenzaldehyde (11 mmol) in DMF at 100 ° C. for 20 hours, the reaction solution was concentrated under reduced pressure, and the precipitated crystals were recrystallized from DMF to give 3-phenyl-10- (3 -Hydroxypropyl-)-5-deazaflavin (intermediate 1) was obtained (yield 95%).
【００３７】実施例３3-フェニル-10-（3-Ｎ- アセチルノイラミニルプロピル
-)-5- デアザフラビン（化合物１ ） 中間体１（5 mmol）とアセチルクロロ−ＮＡＮＡ（5 mm
ol）を塩化メチレンに溶解し、モレキュラーシーブズを
加え、15分間窒素置換を行った後、トリフルオロメチル
スルフォン酸銀（6 mmol）を加えて、遮光下15時間撹拌
した。触媒等不溶部を濾別した後、溶媒を留去し、シリ
カゲルカラムクロマト（クロロホルム／メタノール系：
以後ＣＭ系と呼ぶ）によって、原料、α- 結合体、β-
結合体及びｅｎｅ体を分離した。このα- 及びβ- 結合
体をメタノール／１Ｎ- ＮａＯＨ系(5:1) 中室温で20時
間撹拌し、反応液をダウケミカル社製Ｄｏｗｅｘ５０
（Ｈ型）で中和した後減圧濃縮し、水／エーテル系から
再結晶して、化合物１を得た（以下α- 及びβ- 結合体
をそれぞれ１α、１βのように呼ぶ）。中間体１からの
化合物１の反応収率（１α＋１β）は７５％、α：β：
ｅｎｅ体の生成比は１：１．２：０．５であった。 融点 ： α体 276-282℃ β体 258-265℃ 元素分析値（％） ： Ｃ31Ｈ34Ｏ11Ｎ4 Ｃ Ｈ Ｎ 計 算 値 ５８．２９ ５．３７ ８．７８ 実 測 値 α体 ５８．３４ ５．３４ ８．７０ β体 ５８．２８ ５．３９ ８．７５Example 3 3-Phenyl-10- (3-N-acetylneuraminylpropyl
-)-5- Deazaflavin (compound 1 ) Intermediate 1 (5 mmol) and acetylchloro-NANA (5 mm)
ol) was dissolved in methylene chloride, molecular sieves were added, the mixture was purged with nitrogen for 15 minutes, silver trifluoromethylsulfonate (6 mmol) was added, and the mixture was stirred for 15 hours under light shielding. After filtering off the insoluble portion of the catalyst and the like, the solvent was distilled off, and silica gel column chromatography (chloroform / methanol:
The material, α-conjugate, β-
The conjugate and the ene form were separated. The α- and β-conjugates were stirred in a methanol / 1N-NaOH system (5: 1) at room temperature for 20 hours, and the reaction solution was added to Dowex 50 manufactured by Dow Chemical Company.
After neutralization with (H type), the mixture was concentrated under reduced pressure, and recrystallized from a water / ether system to obtain compound 1 (hereinafter, α- and β-conjugates are referred to as 1α and 1β, respectively). Reaction yield of compound 1 from intermediate 1 (1α + 1β) is 75%, α: β:
The generation ratio of the ene form was 1: 1.2: 0.5. Melting point: α-form 276-282 ° C β-form 258-265 ° C Elemental analysis value (%): C 31 H 34 O 11 N 4 CH N Calculated value 58.29 5.37 8.78 Observed value α-form 58 .34 5.34 8.70 β form 58.28 5.39 8.75
【００３８】実施例４3-（2-ヒドロキシエチル-)-6- ニトロ-10-ラウリル-5-
デアザフラビン（製法Ａ’ ） 6-ラウリルアミノウラシル(20 mmol) 及び2-ブロモ-2-
ニトロベンズアルデヒド（20 mol）をＤＭＦ中100 ℃で
18時間加熱した後反応液を減圧濃縮し、析出した結晶を
ＤＭＦ中から再結晶して、6-ニトロ-10-ラウリル-5- デ
アザフラビン（中間体２）を得た（収率93％）。中間体
２（10 mmol)及びエチレンブロモヒドリン（12 mmol)を
ＤＭＦに溶解し、炭酸カリウム（50 mmol)存在下100 ℃
で5 時間撹拌した後反応液を減圧濃縮し、析出した結晶
をＤＭＦから再結晶して3-(2- ヒドロキシエチル-)-6-
ニトロ-10-ラウリル-5- デアザフラビン（中間体３）を
得た（収率97％）。Example 4 3- (2-hydroxyethyl-)-6-nitro-10-lauryl-5-
Deazaflavin (Process A ' ) 6-laurylaminouracil (20 mmol) and 2-bromo-2-
Nitrobenzaldehyde (20 mol) in DMF at 100 ° C
After heating for 18 hours, the reaction solution was concentrated under reduced pressure, and the precipitated crystals were recrystallized from DMF to obtain 6-nitro-10-lauryl-5-deazaflavin (intermediate 2) (93% yield). Intermediate 2 (10 mmol) and ethylene bromohydrin (12 mmol) were dissolved in DMF, and the mixture was dissolved at 100 ° C. in the presence of potassium carbonate (50 mmol).
After stirring for 5 hours at room temperature, the reaction solution was concentrated under reduced pressure, and the precipitated crystals were recrystallized from DMF to give 3- (2-hydroxyethyl-)-6-
Nitro-10-lauryl-5-deazaflavin (intermediate 3) was obtained (yield 97%).
【００３９】実施例５3-（2-Ｎ−アセチルノイラミニルエチル-)-6- ニトロ-1
0-ラウリル-5- デアザフラビン（化合物８ ） 中間体３（5 mmol）とアセチルクロロ−ＮＡＮＡ（5 mm
ol）を塩化メチレンに溶解し、モレキュラーシーブズを
加え、15分間窒素置換を行った後、トリフルオロメチル
スルフォン酸銀（6 mmol）を加えて、遮光下15時間撹拌
した。触媒等不溶部を濾別した後、溶媒を留去し、シリ
カゲルカラムクロマト（ＣＭ系）によって、原料、α-
結合体、β- 結合体及びｅｎｅ体を分離した。このα-
及びβ- 結合体をメタノール／１Ｎ- ＮａＯＨ系(5:1)
中室温で20時間撹拌し、反応液をダウケミカル社製Ｄｏ
ｗｅｘ５０（Ｈ型）で中和した後減圧濃縮し、水／エー
テル系から再結晶して、化合物８α、８βを得た。中間
体３からの化合物８の反応収率（８α＋８β）は７６
％、α：β：ｅｎｅ体の生成比は１：１：０．３であっ
た。 融点 ： α体 276-282℃ β体 275-283℃ 元素分析値（％） ： Ｃ36Ｈ51Ｏ13Ｎ5 Ｃ Ｈ Ｎ 計 算 値 ５６．７４ ６．７５ ９．２０ 実 測 値 α体 ５６．５９ ６．６９ ９．２８ β体 ５６．６９ ６．７６ ９．２５Example 5 3- (2-N-acetylneuraminylethyl-)-6-nitro-1
0-Lauryl-5-deazaflavin (compound 8 ) Intermediate 3 (5 mmol) and acetylchloro-NANA (5 mm)
ol) was dissolved in methylene chloride, molecular sieves were added, the mixture was purged with nitrogen for 15 minutes, silver trifluoromethylsulfonate (6 mmol) was added, and the mixture was stirred for 15 hours under light shielding. After filtering off the insoluble portion of the catalyst and the like, the solvent was distilled off, and the raw material, α-form was purified by silica gel column chromatography (CM system).
The conjugate, β-conjugate and ene form were separated. This α-
And β-complex in methanol / 1N-NaOH system (5: 1)
The mixture was stirred at room temperature for 20 hours, and the reaction solution was converted to Dow Chemical Do.
After neutralization with wex50 (H type), the mixture was concentrated under reduced pressure, and recrystallized from a water / ether system to obtain compounds 8α and 8β. The reaction yield of compound 8 from intermediate 3 (8α + 8β) is 76
%, The production ratio of α: β: ene bodies was 1: 1: 0.3. Melting point: α form 276-282 ° C β form 275-283 ° C Elemental analysis value (%): C 36 H 51 O 13 N 5 CH N Calculated value 56.74 6.75 9.20 Actual measured value α form 56 .59 6.69 9.28 β form 56.69 6.76 9.25
【００４０】実施例６3-メチル-8-(2-ヒドロキシエチル）メチルアミノ-10-ラ
ウリル -5-デアザフラビン（製法Ｂ ） 製法Ａで合成した、3-メチル-8- フルオロ-10-ラウリル
-5- デアザフラビン（20mmol）及び、2-ヒドロキシメチ
ルアミン(12 mmol) をＤＭＦ中110 ℃で１時間加熱した
後反応液を減圧濃縮し、析出した結晶をＤＭＦから再結
晶して3-メチル-8-(2-ヒドロキシエチル）メチルアミノ
-10-ラウリル-5- デアザフラビン（中間体４）を得た
（97％）。Example 6 3-Methyl-8- (2-hydroxyethyl) methylamino-10-la
Uryl-5-deazaflavin (Process B ) 3-Methyl-8-fluoro-10-lauryl synthesized by Process A
-5-Deazaflavin (20 mmol) and 2-hydroxymethylamine (12 mmol) were heated in DMF at 110 ° C for 1 hour, the reaction solution was concentrated under reduced pressure, and the precipitated crystals were recrystallized from DMF to give 3-methyl- 8- (2-hydroxyethyl) methylamino
-10-Lauryl-5-deazaflavin (intermediate 4) was obtained (97%).
【００４１】実施例７3-メチル-8-(2-Ｎ−アセチルノイラミニルエチル）メチ
ルアミノ-10-ラウリル-5- デアザフラビン（化合物１
１ ） 中間体４（5 mmol）とアセチルクロロ−ＮＡＮＡ（5 mm
ol）を塩化メチレンに溶解し、モレキュラーシーブズを
加え、10分間窒素置換を行った後、トリフルオロメチル
スルフォン酸銀（6 mmol）を加えて、遮光下18時間撹拌
する。触媒等不溶部を濾別した後、溶媒を留去し、シリ
カゲルカラムクロマト（ＣＭ系）によって、原料、α-
結合体、β- 結合体及びｅｎｅ体を分離した。このα-
及びβ- 結合体をメタノール／１Ｎ- ＮａＯＨ系(5:1)
中室温で20時間撹拌し、反応液をダウケミカル社製Ｄｏ
ｗｅｘ５０（Ｈ型）で中和した後減圧濃縮し、水／エー
テル系から再結晶して、化合物１１を得た（以下α- 及
びβ- 結合体をそれぞれ１１α、１１βのように呼
ぶ）。中間体４からの化合物１１の反応収率（１１α＋
１１β）は７８％、α：β：ｅｎｅ体の生成比は1 : 1.
1 : 0.5 であった。 融点 ： α体 276-282℃ β体 235-240℃ 元素分析値（％） ： Ｃ38Ｈ57Ｏ11Ｎ5 Ｃ Ｈ Ｎ 計 算 値 ６０．０８ ７．５１ ９．２２ 実 測 値 α体 ６０．０３ ７．４９ ９．２１ β体 ５９．９９ ７．５５ ９．２３Embodiment 73-methyl-8- (2-N-acetylneuraminylethyl) methyl
Lumin-10-lauryl-5-deazaflavin (Compound 1
1 ) Intermediate 4 (5 mmol) and acetylchloro-NANA (5 mm
ol) in methylene chloride and remove molecular sieves.
After adding nitrogen for 10 minutes, add trifluoromethyl
Add silver sulfonate (6 mmol) and stir for 18 hours in the dark
I do. After filtering off insoluble parts such as catalysts, the solvent is distilled off,
Raw material, α-column by Kagel column chromatography (CM system)
The conjugate, β-conjugate and ene form were separated. This α-
And β-complex in methanol / 1N-NaOH system (5: 1)
The mixture was stirred at room temperature for 20 hours, and the reaction solution was converted to Dow Chemical Do.
Neutralized with Wex50 (H type) and concentrated under reduced pressure.
The compound was recrystallized from a tellurium compound to obtain compound 11 (hereinafter referred to as α-
And β-conjugates are referred to as 11α and 11β, respectively.
Bu). Reaction yield of compound 11 from intermediate 4 (11α +
11β) is 78%, and the production ratio of α: β: ene is 1: 1.
1: 0.5. Melting point: α-form 276-282 ℃ β-form 235-240 ℃ Elemental analysis value (%): C38H57O11NFive CH N calculated value 60.08 7.51 9.22 Actual value α-form 60.03 7.49 9.21 β-form 59.99 99.55 9.23
【００４２】実施例８3-(2- ヒドロキシエチル-)-7- t-ブチル-10-セレナ-5-
デアザフラビン（製法Ｄ ） ＴＨＦ中でp-第三ブチルセ
レノフェノールナトリウム塩（20 mmol)に6-クロロウラ
シル（22 mmol)を滴下し、28時間加熱還流後反応液を減
圧濃縮し、残渣を氷水に注入後酢酸エチルで抽出する。
シリカゲルカラムクロマト（ＣＭ系）を実施して、6-(p
-t- ブチルフェニルセレノウラシルを得た。次いで、こ
れをＤＭＦ／ＰＯＣｌ3 (5：１）中60℃で加熱し、残渣
を氷水に注入後酢酸エチルで抽出した。シリカゲルカラ
ムクロマト（ＣＭ系）を実施して、6-（4-t-ブチルセレ
ノ）-5- ホルミルウラシルを得た。これをポリ燐酸中 1
00℃で加熱して、3-（2-ヒドロキシエチル-)-7- t-ブチ
ル-10-セレナ-5- デアザフラビン（中間体５）を得た
（収率64％）。中間体５（10 mmol)及びエチレンブロモ
ヒドリン（12 mmol)をＤＭＦに溶解し、炭酸カリウム
（50 mmol)存在下100 ℃で5 時間撹拌した後反応液を減
圧濃縮し、析出した結晶をクロロホルムから再結晶して
3- (2-ヒドロキシエチル)-7-t- ブチル-10-ラウリル-5-
デアザフラビン（中間体６）を得た（収率94％）。Example 8 3- (2-hydroxyethyl-)-7-t-butyl-10-selena-5-
Deazaflavin (Preparation method D ) 6-Chlorouracil (22 mmol) was added dropwise to p-tert-butylselenophenol sodium salt (20 mmol) in THF, and the mixture was heated under reflux for 28 hours, concentrated under reduced pressure, and the residue was concentrated in ice water. After injection, extract with ethyl acetate.
After performing silica gel column chromatography (CM system), 6- (p
-t-Butylphenylselenouracil was obtained. It was then heated in DMF / POCl 3 (5: 1) at 60 ° C., the residue was poured into ice water and extracted with ethyl acetate. Silica gel column chromatography (CM system) was performed to obtain 6- (4-t-butylseleno) -5-formyluracil. This in polyphosphoric acid 1
Heating at 00 ° C. provided 3- (2-hydroxyethyl-)-7-t-butyl-10-selena-5-deazaflavin (intermediate 5) (yield 64%). Intermediate 5 (10 mmol) and ethylene bromohydrin (12 mmol) were dissolved in DMF, and the mixture was stirred at 100 ° C. for 5 hours in the presence of potassium carbonate (50 mmol), and the reaction solution was concentrated under reduced pressure. Recrystallize from
3- (2-hydroxyethyl) -7-t-butyl-10-lauryl-5-
Deazaflavin (intermediate 6) was obtained (94% yield).
【００４３】実施例９3- (2-Ｎ−アセチルノイラミニルエチル-)-7- t-ブチル
-10-セレナ-5- デアザフラビン（化合物１５ ） 中間体６（5 mmol）とアセチルクロロ−ＮＡＮＡ（5 mm
ol）を塩化メチレンに溶解し、モレキュラーシーブズを
加え、15分間窒素置換を行った後、トリフルオロメチル
スルフォン酸銀（6 mmol）を加えて、遮光下21時間撹拌
した。触媒等不溶部を濾別した後、溶媒を留去し、シリ
カゲルカラムクロマト（ＣＭ系）によって、原料、α-
結合体、β- 結合体及びｅｎｅ体を分離した。このα-
及びβ- 結合体をメタノール／１Ｎ- ＮａＯＨ系(5:1)
中室温で20時間撹拌し、反応液をダウケミカル社製Ｄｏ
ｗｅｘ５０（Ｈ型）で中和した後減圧濃縮し、水／エー
テル系から再結晶して、化合物１５α、１５βを得た。
中間体６からの化合物１５の反応収率（１５α＋１５
β）は７２％、α：β：ｅｎｅ体の生成比は１：１．
１：０．３であった。 融点 ： α体 246-259℃ β体 248-258℃ 元素分析値（％） ： Ｃ28Ｈ35Ｏ11Ｎ3 Ｓｅ Ｃ Ｈ Ｎ 計 算 値 ５０．３１ ５．２４ ６．２９ 実 測 値 α体 ５０．３９ ５．１９ ６．３１ β体 ５０．３３ ５．２０ ６．２７Example 9 3- (2-N-acetylneuraminylethyl-)-7-t-butyl
-10-Selena-5-deazaflavin (Compound 15 ) Intermediate 6 (5 mmol) and acetylchloro-NANA (5 mm)
ol) was dissolved in methylene chloride, molecular sieves were added, the atmosphere was replaced with nitrogen for 15 minutes, silver trifluoromethylsulfonate (6 mmol) was added, and the mixture was stirred under light shielding for 21 hours. After filtering off the insoluble portion of the catalyst and the like, the solvent was distilled off, and the raw material, α-form was purified by silica gel column chromatography (CM system).
The conjugate, β-conjugate and ene form were separated. This α-
And β-complex in methanol / 1N-NaOH system (5: 1)
The mixture was stirred at room temperature for 20 hours, and the reaction solution was converted to Dow Chemical Do.
After neutralization with Wex50 (H type), the mixture was concentrated under reduced pressure, and recrystallized from a water / ether system to obtain compounds 15α and 15β.
Reaction yield of compound 15 from intermediate 6 (15α + 15
β) is 72%, and the production ratio of α: β: ene is 1: 1.
1: 0.3. Melting point: α-form 246-259 ° C β-form 248-258 ° C Elemental analysis (%): C 28 H 35 O 11 N 3 Se CH N Calculated value 50.31 5.24 6.29 Actual value α-form 50.39 5.19 6.31 β-form 50.33 5.20 6.27
【００４４】前記表１〜表４に記載した本発明化合物
で、実施例２〜実施例９で触れなかった化合物について
も同様にして相当する出発物質から、それぞれの製法に
よって合成した。このようにして得られた本発明化合物
の物性を表５に示す。The compounds of the present invention described in Tables 1 to 4 and not mentioned in Examples 2 to 9 were synthesized in the same manner from the corresponding starting materials by the respective production methods. Table 5 shows the physical properties of the compound of the present invention thus obtained.
【００４５】[0045]
【表５】 [Table 5]
【００４６】注１）収率とは、原料の5-デアザフラビン
からのα体＋β体の収率である。 注２）Ｃ−５（δ値）とはＮＭＲ分析における5-デアザ
フラビン残基のの５位の炭素に結合しているプロトンの
δ値（重水中）を表す。 注３）Ｃ−３'(eq)(δ値）とはＮＭＲ分析におけるシア
ル酸残基のＣ−３’位のエクァトリアルプロトンのδ値
（重水中）を表す。同アクシャルのプロトンはアルキル
基と重なることが多く、同定不可能であった。 注４）表中ｄ）は分解点を表す。Note 1) The yield is the yield of α-form + β-form from the starting material 5-deazaflavin. Note 2) C-5 (δ value) indicates the δ value (in heavy water) of the proton bonded to the 5-position carbon of the 5-deazaflavin residue in NMR analysis. Note 3) C-3 ′ (eq) (δ value) refers to the δ value (in heavy water) of the equatorial proton at the C-3 ′ position of the sialic acid residue in NMR analysis. The proton of this axial often overlapped with the alkyl group and could not be identified. Note 4) d) in the table indicates the decomposition point.
【００４７】本発明の化合物は、種々の癌細胞に対して
抗腫瘍活性を示し、また、シアル酸が結合することで、
水に対する溶解度の上昇や、血中半減期の延長、毒性の
回避など生体適合性が増大しているので、結果として、
元々抗腫瘍活性を持つ5-デアザフラビンに比べて、更に
制癌剤としての有用性が上昇している。以下の実験結果
により、本発明の優れた点を説明する。The compounds of the present invention exhibit antitumor activity against various cancer cells, and bind to sialic acid,
Increased biocompatibility, such as increased solubility in water, increased blood half-life, and avoidance of toxicity,
Compared with 5-deazaflavin, which originally has antitumor activity, its usefulness as an anticancer agent has been further increased. The following experimental results explain the advantages of the present invention.
【００４８】実験１溶解度試験 本発明の化合物と、カップリング前の5-デアザフラビン
との、水に対する溶解度を比較した。結果を表６に示
す。なお、以下の実験では、シアル酸とカップリングす
る前の5-デアザフラビン化合物には、表１〜４に示した
化合物番号にセロをつけてあらわすことにする。たとえ
ば、前述の実施例の中間体１，３，４，６は、それぞれ
１−０，８−０，１１−０，１５−０とあらわす。化合
物１〜１５は、全てナトリウム塩とし、中性域での溶解
度を測定した。表６の結果から、本発明の化合物は、水
への溶解度が格段に上昇していることがわかる。以後の
実験では、本発明化合物はすべてナトリウム塩として使
用した。Experiment 1 Solubility Test The solubility of the compound of the present invention in water before coupling with 5-deazaflavin was compared. Table 6 shows the results. In the following experiments, 5-deazaflavin compounds before coupling with sialic acid are represented by adding cell numbers to the compound numbers shown in Tables 1-4. For example, Intermediates 1, 3, 4, and 6 in the above-described examples are represented as 1-0, 8-0, 11-0, and 15-0, respectively. Compounds 1 to 15 were all sodium salts, and the solubility in the neutral region was measured. From the results in Table 6, it can be seen that the compounds of the present invention have remarkably increased solubility in water. In the subsequent experiments, all the compounds of the present invention were used as sodium salts.
【００４９】[0049]
【表６】 [Table 6]
【００５０】実験２各種培養腫瘍細胞のin vitroでの増殖に及ぼす影響 被検化合物及び104 個のマウス白血病細胞（L 1210/C)
またはヒト口腔表皮癌細胞(KB)を含む培養液を96穴プレ
ートの各穴に 200μl になるように加え、5 ％ＣＯ2 −
95％空気下37℃で72時間培養した。培養後MTT[3-(4,4-
ジメチル- チアゾール-2- イル)-2,5-ジフェニルテトラ
ゾリウムブロマイド] 溶液(2mg/ml)を25μl ずつ各穴に
添加し、同条件下で更に４時間培養した。培養液を除去
した後、150 μl のＤＭＳＯを各穴に加えて形成したＭ
ＴＴ−フォルマザンを溶解し、マイクロプレートリーダ
ーによって 540nmにおける吸光度を測定し、細胞数の指
標とした。次式によって抑制率を算出し、50％制御する
被検化合物の濃度（ＩＣ50) を求めた。 得られたＩＣ50値（μｌ／ml) を表７にまとめた。The impact test compound on the growth of the in vitro experiments 2 various cultured tumor cells and 10 4 mouse leukemia cells (L 1210 / C)
Alternatively, a culture solution containing human oral epidermoid cancer cells (KB) is added to each well of a 96-well plate to a volume of 200 μl, and 5% CO 2 −
The cells were cultured at 37 ° C. in 95% air for 72 hours. After culture, MTT [3- (4,4-
Dimethyl-thiazol-2-yl) -2,5-diphenyltetrazolium bromide] solution (2 mg / ml) was added to each well in an amount of 25 μl, and the cells were further cultured under the same conditions for 4 hours. After removing the culture solution, 150 μl of DMSO was added to each well to form M
TT-formazan was dissolved, and the absorbance at 540 nm was measured using a microplate reader, and used as an index of cell number. The inhibition rate was calculated according to the following equation, and the concentration (IC 50 ) of the test compound that controlled 50% was determined. Table 7 summarizes the obtained IC 50 values (μl / ml).
【００５１】[0051]
【表７】 [Table 7]
【００５２】表７から明らかなように、本発明化合物
は、各種培養腫瘍細胞に対し、元来優れた増殖抑制作用
を持つ5-デアザフラビン化合物よりも更に優れた増殖抑
制効果を示し、制癌剤として非常に有用である。As is evident from Table 7, the compound of the present invention shows a much better growth inhibitory effect on various cultured tumor cells than a 5-deazaflavin compound which originally has an excellent growth inhibitory action, and is very useful as an anticancer agent. Useful for
───────────────────────────────────────────────────── フロントページの続き (58)調査した分野(Int.Cl.7，ＤＢ名) C07H 15/04,15/26 A61K 31/7072 A61P 35/00 ＣＡ（ＳＴＮ) ＲＥＧＩＳＴＲＹ（ＳＴＮ)──────────────────────────────────────────────────続 き Continued on the front page (58) Field surveyed (Int. Cl. 7 , DB name) C07H 15 / 04,15 / 26 A61K 31/7072 A61P 35/00 CA (STN) REGISTRY (STN)
Claims (5)
合5-デアザフラビン系化合物 【化１】 【化２】 （式中Ｒ0 は、Ｎ−アセチル（ＣＨ3 ＣＯＮＨ-)基、Ｎ
−グリコリル（ＨＯＣＨ2 ＣＯＮＨ-)基、または水酸基
を表し、ｄＦｌは、次の一般式、III 、IV、またはＶで
表される5-デアザフラビン化合物である。） 【化３】 【化４】 【化５】 （式中Ｒ1 は、水素原子、アルキル基、ハロゲン置換ア
ルキル基、フェニル置換アルキル基またはフェニル基を
表し、Ｒ2 は、水素原子、アルキルアミノ基、フェニル
置換アルキルアミノ基、ヒドロキシ置換アルキルアミノ
基、ハロゲン置換アルキル基、アルコキシ基、ピリジル
基、フェニル基、ハロゲン原子もしくはトリフルオロメ
チル基、ニトロ基、低級アルコキシ基のうちの一つで置
換されたフェニル基を表し、Ｒ3 は、水素原子、ニトロ
基、シアノ基、アルキル基、低級アルコキシ基、フェニ
ル置換低級アルコキシ基、低級アルキルアミノ基、フェ
ニル置換低級アルキルアミノ基または低級アルキルスル
フォニル基を表し、Ｙは、メチレン基またはアルキルア
ミノ基を表し、Ｘは、セレン原子、硫黄原子、酸素原
子、または基＝Ｎ−Ｒ4 を表す。ここで、Ｒ4 とは、ア
ルキル基、シクロアルキル基、フェニル置換低級アルキ
ル基、フェニル基、ハロゲン原子、もしくは低級アルコ
キシ基のうちの一つで置換されたフェニル基、低級アル
キルジ置換フェニル基、ナフチル基、低級アルキルジ置
換アミノナフチル基を表し、ｎは２〜６の整数を表
す。）1. A sialic acid-bound 5-deazaflavin compound represented by the general formula I or II: Embedded image (Where R 0 is an N-acetyl (CH 3 CONH—) group, N
Represents a glycolyl (HOCH 2 CONH—) group or a hydroxyl group, and dFl is a 5-deazaflavin compound represented by the following general formula, III, IV, or V. ) Embedded image Embedded image (Wherein R 1 represents a hydrogen atom, an alkyl group, a halogen-substituted alkyl group, a phenyl-substituted alkyl group or a phenyl group, and R 2 represents a hydrogen atom, an alkylamino group, a phenyl-substituted alkylamino group, a hydroxy-substituted alkylamino group Represents a phenyl group substituted by one of a halogen-substituted alkyl group, an alkoxy group, a pyridyl group, a phenyl group, a halogen atom or a trifluoromethyl group, a nitro group and a lower alkoxy group; R 3 represents a hydrogen atom; A nitro group, a cyano group, an alkyl group, a lower alkoxy group, a phenyl-substituted lower alkoxy group, a lower alkylamino group, a phenyl-substituted lower alkylamino group or a lower alkylsulfonyl group; Y represents a methylene group or an alkylamino group; X represents a selenium atom, a sulfur atom, an oxygen atom, or a group = NR Represents a 4. Here, the R 4, an alkyl group, a cycloalkyl group, a phenyl-substituted lower alkyl group, a phenyl group, one substituted phenyl group of the halogen atom or lower alkoxy group, a lower alkyl di-substituted Represents a phenyl group, a naphthyl group, or a lower alkyldisubstituted aminonaphthyl group, and n represents an integer of 2 to 6.)
チル基で且つ、ｄＦｌが一般式III で表される、特許請
求の範囲第１項に記載の化合物。（式中Ｒ1 はフェニル
基、Ｒ2 は水素原子を表し、Ｒ3 は水素原子、ニトロ基
または第３ブチル基を表す。）2. The compound according to claim 1, wherein in formulas I and II, R 0 is an N-acetyl group and dFl is represented by formula III. (In the formula, R 1 represents a phenyl group, R 2 represents a hydrogen atom, and R 3 represents a hydrogen atom, a nitro group or a tertiary butyl group.)
チル基で且つ、ｄＦｌが一般式IVで表される、特許請求
の範囲第１項に記載の化合物。（式中Ｒ2 は水素原子ま
たはトリフルオロメチルフェニル基を表し、Ｒ3 は水素
原子またはニトロ基を表し、Ｘは、基＝Ｎ−Ｒ4 を表
し、Ｒ4 はアルキル基を表す。）3. The compound according to claim 1, wherein in formulas I and II, R 0 is an N-acetyl group and dFl is represented by formula IV. (In the formula, R 2 represents a hydrogen atom or a trifluoromethylphenyl group, R 3 represents a hydrogen atom or a nitro group, X represents a group ＮN—R 4 , and R 4 represents an alkyl group.)
チル基で且つ、ｄＦｌが一般式Ｖで表される、特許請求
の範囲第１項に記載の化合物。（式中Ｒ1 はメチル基を
表し、Ｒ2 及びＲ3 は水素原子を表し、Ｘは、基＝Ｎ−
Ｒ4 を表し、Ｒ4 はアルキル基を表す。Ｙはメチレン
基、第２アミノ基または第３アミノ基を表す。）4. The compound according to claim 1, wherein in formulas I and II, R 0 is an N-acetyl group and dFl is represented by formula V. (Wherein R 1 represents a methyl group, R 2 and R 3 represent a hydrogen atom, and X represents a group = N-
Represents R 4, R 4 represents an alkyl group. Y represents a methylene group, a secondary amino group or a tertiary amino group. )
チル基で且つ、ｄＦｌが一般式III で表される、特許請
求の範囲第１項に記載の化合物。（式中Ｒ2 は水素原子
を表し、Ｒ3 は水素原子または第３ブチル基を表し、Ｘ
は、硫黄原子またはセレン原子を表す。）5. The compound according to claim 1, wherein in Formulas I and II, R 0 is an N-acetyl group and dFl is represented by Formula III. (Wherein R 2 represents a hydrogen atom, R 3 represents a hydrogen atom or a tertiary butyl group, and X
Represents a sulfur atom or a selenium atom. )
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP04102150A JP3073309B2 (en) | 1992-03-27 | 1992-03-27 | Sialic acid-bound 5-deazaflavin compounds |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP04102150A JP3073309B2 (en) | 1992-03-27 | 1992-03-27 | Sialic acid-bound 5-deazaflavin compounds |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH05271271A JPH05271271A (en) | 1993-10-19 |
| JP3073309B2 true JP3073309B2 (en) | 2000-08-07 |
Family
ID=14319712
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP04102150A Expired - Lifetime JP3073309B2 (en) | 1992-03-27 | 1992-03-27 | Sialic acid-bound 5-deazaflavin compounds |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP3073309B2 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019151516A1 (en) | 2018-02-05 | 2019-08-08 | テラ・ストーン株式会社 | Use of coenzyme factor for activation of atp production in cell |
| KR20200024283A (en) | 2018-02-05 | 2020-03-06 | 테라 스톤 가부시키가이샤 | Use of Coenzyme Factors to Activate ATP Production in Cells |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9321558D0 (en) * | 1993-10-19 | 1993-12-08 | Radopath Ltd | Anti-viral agents |
-
1992
- 1992-03-27 JP JP04102150A patent/JP3073309B2/en not_active Expired - Lifetime
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019151516A1 (en) | 2018-02-05 | 2019-08-08 | テラ・ストーン株式会社 | Use of coenzyme factor for activation of atp production in cell |
| KR20200024283A (en) | 2018-02-05 | 2020-03-06 | 테라 스톤 가부시키가이샤 | Use of Coenzyme Factors to Activate ATP Production in Cells |
| US11439644B2 (en) | 2018-02-05 | 2022-09-13 | Tera Stone Co., Ltd | Use of coenzyme factor for activation of ATP production in cell |
| KR20230003307A (en) | 2018-02-05 | 2023-01-05 | 테라 스톤 가부시키가이샤 | Use of coenzyme factor for activation of atp production in cell |
| KR20230004893A (en) | 2018-02-05 | 2023-01-06 | 테라 스톤 가부시키가이샤 | Use of coenzyme factor for activation of atp production in cell |
| KR20230004894A (en) | 2018-02-05 | 2023-01-06 | 테라 스톤 가부시키가이샤 | Use of coenzyme factor for activation of atp production in cell |
| EP4324528A2 (en) | 2018-02-05 | 2024-02-21 | Tera Stone Co., Ltd | Use of coenzyme factor for activation of atp production in cell |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH05271271A (en) | 1993-10-19 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU2016297155A1 (en) | Oligonucleotide compositions and methods thereof | |
| JPS6212795A (en) | Novel psolarene derivative | |
| CS270585B2 (en) | Method of 4-demethoxy-4-aminoanthracycline derivatives production | |
| CA2082528C (en) | Antitumor substance be-13793c derivatives | |
| DK163585B (en) | RETINOIDCARBOXYLSYRE-MONO AND -DISACCHARIDESTERE, THESE ESTERS FOR USE AS MEDICINES IN PARTICULAR FOR THE TREATMENT OF neoplasia ACNE OR PSORIASIS, METHOD FOR PREPARATION THEREOF, PHARMACEUTICAL PREPARATIONS CONTAINING THEM ESTERS AND USE OF Estonians FOR PRODUCTION OF A MEANS treatment of neoplasia, ACNE OR PSORIASIS | |
| WO1984000759A1 (en) | Desoxyuridine derivatives, processes for their preparation and their use as pharmaceuticals | |
| Lin et al. | Synthesis and antiviral activity of several 2, 5'-anhydro analogs of 3'-azido-3'-deoxythymidine (AZT), 3'-azido-2', 3'-dideoxyuridine (AZU), 3'-azido-2', 3'-dideoxy-5-halouridines, and 3'-deoxythymidine against human immunodeficiency virus (HIV-1) and Rauscher-Murine leukemia virus (R-MuLV) | |
| JP3073309B2 (en) | Sialic acid-bound 5-deazaflavin compounds | |
| KR20010012727A (en) | Novel Glycosylated Ginkgolide Derivatives, Their Application As Medicines and Pharmaceutical Compositions | |
| Xu et al. | Facile Approaches to 2-Deoxy-d-Glucose and 2-Deoxy-α-d-Glucopyranonucleosides from d-Glucal | |
| JP2806621B2 (en) | Novel anthracyclines and production method thereof | |
| JPH08506835A (en) | 3'-aziridino-anthracycline derivative | |
| RU2073681C1 (en) | Anthracycline glycoside and method of its synthesis | |
| JPH07316181A (en) | 2,3,4'-tris(acetyl)-4,6-ethylidene-beta-d-glucopyranoside, its production,and its use for producing 4'- demethylepipodophillotoxin.ethylidene-beta-d-glucopyranoside | |
| Rosowsky et al. | Synthesis and in vivo antitumor activity of potential 5-fluorouracil prodrugs | |
| JPH0560478B2 (en) | ||
| CA2292754C (en) | Process for the preparation of a deoxyuridine derivative | |
| ZA200402626B (en) | New hydroxyalkylindolocarbazole compounds, a process for their preparation and pharmaceutical compositions containing them | |
| EP0089678A1 (en) | Novel 2-beta-D-ribofuranosylselenazole-4-carboxamide compounds and methods for their production | |
| Cosford et al. | A short synthesis of 2′, 3′-didehydro-3′-deoxythymidine | |
| US4522815A (en) | Anthracycline glycosides | |
| US5034380A (en) | Alkoxymethylidene epipodophyllotoxin glucosides | |
| JPH06504550A (en) | Novel glucohydrolase inhibitors useful as antidiabetic agents | |
| WO2023058608A1 (en) | Glucose derivatives and anticancer agent using same | |
| JPH04500677A (en) | A special method for the synthesis of novel dithiocarbamate esters by replacing the hydroxylated sites of mono- or polyhydroxylated molecules, the products obtained by this method and their applications. |