JP2013536171A - チューブリシン類似体 - Google Patents
チューブリシン類似体 Download PDFInfo
- Publication number
- JP2013536171A JP2013536171A JP2013520001A JP2013520001A JP2013536171A JP 2013536171 A JP2013536171 A JP 2013536171A JP 2013520001 A JP2013520001 A JP 2013520001A JP 2013520001 A JP2013520001 A JP 2013520001A JP 2013536171 A JP2013536171 A JP 2013536171A
- Authority
- JP
- Japan
- Prior art keywords
- substituted
- unsubstituted
- group
- tubulin
- alkyl
- 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.)
- Granted
Links
- 150000001875 compounds Chemical class 0.000 claims abstract description 38
- 102000004243 Tubulin Human genes 0.000 claims abstract description 33
- 108090000704 Tubulin Proteins 0.000 claims abstract description 33
- 238000006243 chemical reaction Methods 0.000 claims abstract description 9
- 239000002537 cosmetic Substances 0.000 claims abstract description 4
- 230000002062 proliferating effect Effects 0.000 claims abstract description 4
- 239000000203 mixture Substances 0.000 claims description 41
- 125000003118 aryl group Chemical group 0.000 claims description 29
- 125000000217 alkyl group Chemical group 0.000 claims description 26
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 23
- 125000001072 heteroaryl group Chemical group 0.000 claims description 13
- 125000005647 linker group Chemical group 0.000 claims description 13
- 230000015572 biosynthetic process Effects 0.000 claims description 12
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 12
- 125000004404 heteroalkyl group Chemical group 0.000 claims description 10
- 125000004434 sulfur atom Chemical group 0.000 claims description 10
- 125000003545 alkoxy group Chemical group 0.000 claims description 9
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 9
- 229920001223 polyethylene glycol Polymers 0.000 claims description 9
- 229910052717 sulfur Inorganic materials 0.000 claims description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- -1 polyguanidine Substances 0.000 claims description 7
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical group C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 6
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical group C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- 125000003386 piperidinyl group Chemical group 0.000 claims description 5
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 4
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical group C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 4
- 125000002252 acyl group Chemical group 0.000 claims description 4
- 125000003282 alkyl amino group Chemical group 0.000 claims description 4
- 125000000732 arylene group Chemical group 0.000 claims description 4
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 4
- 125000005265 dialkylamine group Chemical group 0.000 claims description 4
- 238000009472 formulation Methods 0.000 claims description 4
- 125000005549 heteroarylene group Chemical group 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- SFDJOSRHYKHMOK-UHFFFAOYSA-N nitramide Chemical compound N[N+]([O-])=O SFDJOSRHYKHMOK-UHFFFAOYSA-N 0.000 claims description 4
- 230000035515 penetration Effects 0.000 claims description 4
- 108090000790 Enzymes Proteins 0.000 claims description 3
- 102000004190 Enzymes Human genes 0.000 claims description 3
- 239000002202 Polyethylene glycol Substances 0.000 claims description 3
- 150000001720 carbohydrates Chemical class 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 3
- 239000000427 antigen Substances 0.000 claims description 2
- 102000036639 antigens Human genes 0.000 claims description 2
- 108091007433 antigens Proteins 0.000 claims description 2
- 238000001514 detection method Methods 0.000 claims description 2
- 239000005556 hormone Substances 0.000 claims description 2
- 229940088597 hormone Drugs 0.000 claims description 2
- 108091008039 hormone receptors Proteins 0.000 claims description 2
- 150000004677 hydrates Chemical class 0.000 claims description 2
- 239000003446 ligand Substances 0.000 claims description 2
- 239000002207 metabolite Substances 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 102000039446 nucleic acids Human genes 0.000 claims description 2
- 108020004707 nucleic acids Proteins 0.000 claims description 2
- 150000007523 nucleic acids Chemical class 0.000 claims description 2
- 229920000768 polyamine Polymers 0.000 claims description 2
- 229920000642 polymer Polymers 0.000 claims description 2
- 229940002612 prodrug Drugs 0.000 claims description 2
- 239000000651 prodrug Substances 0.000 claims description 2
- 102000004169 proteins and genes Human genes 0.000 claims description 2
- 108090000623 proteins and genes Proteins 0.000 claims description 2
- 108020003175 receptors Proteins 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 239000012453 solvate Substances 0.000 claims description 2
- 239000011782 vitamin Substances 0.000 claims description 2
- 229930003231 vitamin Natural products 0.000 claims description 2
- 229940088594 vitamin Drugs 0.000 claims description 2
- 235000013343 vitamin Nutrition 0.000 claims description 2
- 239000002671 adjuvant Substances 0.000 claims 1
- 239000003085 diluting agent Substances 0.000 claims 1
- 239000003814 drug Substances 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 150000003722 vitamin derivatives Chemical class 0.000 claims 1
- 230000001085 cytostatic effect Effects 0.000 abstract description 2
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
- 125000003142 tertiary amide group Chemical group 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 57
- 230000002829 reductive effect Effects 0.000 description 25
- 239000000243 solution Substances 0.000 description 17
- 239000011541 reaction mixture Substances 0.000 description 16
- 239000002904 solvent Substances 0.000 description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 125000004432 carbon atom Chemical group C* 0.000 description 12
- 238000000746 purification Methods 0.000 description 12
- 238000005160 1H NMR spectroscopy Methods 0.000 description 11
- 210000004027 cell Anatomy 0.000 description 11
- 238000000034 method Methods 0.000 description 11
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
- 230000001472 cytotoxic effect Effects 0.000 description 8
- 238000004007 reversed phase HPLC Methods 0.000 description 8
- 125000001424 substituent group Chemical group 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 125000002947 alkylene group Chemical group 0.000 description 7
- 238000003776 cleavage reaction Methods 0.000 description 7
- 238000003818 flash chromatography Methods 0.000 description 7
- 230000007017 scission Effects 0.000 description 7
- 125000000547 substituted alkyl group Chemical group 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 235000019439 ethyl acetate Nutrition 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- 125000003342 alkenyl group Chemical group 0.000 description 5
- 125000000304 alkynyl group Chemical group 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 150000004702 methyl esters Chemical class 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- 0 CN(CCCC1)[C@]1*=O Chemical compound CN(CCCC1)[C@]1*=O 0.000 description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
- 108010043958 Peptoids Proteins 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 4
- 239000013058 crude material Substances 0.000 description 4
- BQIVJVAZDJHDJF-LURJTMIESA-N ethyl (2s)-2-amino-3-methylbutanoate Chemical compound CCOC(=O)[C@@H](N)C(C)C BQIVJVAZDJHDJF-LURJTMIESA-N 0.000 description 4
- 150000002430 hydrocarbons Chemical group 0.000 description 4
- 125000000405 phenylalanyl group Chemical group 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- WDBQJSCPCGTAFG-QHCPKHFHSA-N 4,4-difluoro-N-[(1S)-3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-pyridin-3-ylpropyl]cyclohexane-1-carboxamide Chemical compound FC1(CCC(CC1)C(=O)N[C@@H](CCN1CCC(CC1)N1C(=NN=C1C)C(C)C)C=1C=NC=CC=1)F WDBQJSCPCGTAFG-QHCPKHFHSA-N 0.000 description 3
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 150000001241 acetals Chemical group 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 239000012267 brine Substances 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 3
- 125000005842 heteroatom Chemical group 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 238000006452 multicomponent reaction Methods 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 238000002965 ELISA Methods 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 2
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- 229930012538 Paclitaxel Natural products 0.000 description 2
- 229920002873 Polyethylenimine Polymers 0.000 description 2
- 230000021736 acetylation Effects 0.000 description 2
- 238000006640 acetylation reaction Methods 0.000 description 2
- 238000005903 acid hydrolysis reaction Methods 0.000 description 2
- 125000004450 alkenylene group Chemical group 0.000 description 2
- 125000004419 alkynylene group Chemical group 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 125000003710 aryl alkyl group Chemical group 0.000 description 2
- 238000007630 basic procedure Methods 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
- 125000002619 bicyclic group Chemical group 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 230000021615 conjugation Effects 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
- 231100000433 cytotoxic Toxicity 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical compound [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 2
- 239000012039 electrophile Substances 0.000 description 2
- 125000004185 ester group Chemical group 0.000 description 2
- 125000004494 ethyl ester group Chemical group 0.000 description 2
- 125000004438 haloalkoxy group Chemical group 0.000 description 2
- 125000001188 haloalkyl group Chemical group 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 229920001427 mPEG Polymers 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- VSDUZFOSJDMAFZ-VIFPVBQESA-N methyl L-phenylalaninate Chemical compound COC(=O)[C@@H](N)CC1=CC=CC=C1 VSDUZFOSJDMAFZ-VIFPVBQESA-N 0.000 description 2
- 125000002950 monocyclic group Chemical group 0.000 description 2
- FSBLVBBRXSCOKU-UHFFFAOYSA-N n-butyl isocyanide Chemical compound CCCC[N+]#[C-] FSBLVBBRXSCOKU-UHFFFAOYSA-N 0.000 description 2
- 238000005580 one pot reaction Methods 0.000 description 2
- 125000004043 oxo group Chemical group O=* 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 229960001592 paclitaxel Drugs 0.000 description 2
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 2
- 229920000223 polyglycerol Polymers 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 150000003333 secondary alcohols Chemical class 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 125000005017 substituted alkenyl group Chemical group 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 125000006168 tricyclic group Chemical group 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- NDVHTWXQGWVTDX-WDSKDSINSA-N (2s,3s)-2-amino-3-methylpentanoyl isocyanide Chemical compound CC[C@H](C)[C@H](N)C(=O)[N+]#[C-] NDVHTWXQGWVTDX-WDSKDSINSA-N 0.000 description 1
- DLKUYSQUHXBYPB-NSSHGSRYSA-N (2s,4r)-4-[[2-[(1r,3r)-1-acetyloxy-4-methyl-3-[3-methylbutanoyloxymethyl-[(2s,3s)-3-methyl-2-[[(2r)-1-methylpiperidine-2-carbonyl]amino]pentanoyl]amino]pentyl]-1,3-thiazole-4-carbonyl]amino]-2-methyl-5-(4-methylphenyl)pentanoic acid Chemical compound N([C@@H]([C@@H](C)CC)C(=O)N(COC(=O)CC(C)C)[C@H](C[C@@H](OC(C)=O)C=1SC=C(N=1)C(=O)N[C@H](C[C@H](C)C(O)=O)CC=1C=CC(C)=CC=1)C(C)C)C(=O)[C@H]1CCCCN1C DLKUYSQUHXBYPB-NSSHGSRYSA-N 0.000 description 1
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 description 1
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 description 1
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 1
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
- XBNGYFFABRKICK-UHFFFAOYSA-N 2,3,4,5,6-pentafluorophenol Chemical compound OC1=C(F)C(F)=C(F)C(F)=C1F XBNGYFFABRKICK-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- VHSHLMUCYSAUQU-UHFFFAOYSA-N 2-hydroxypropyl methacrylate Chemical compound CC(O)COC(=O)C(C)=C VHSHLMUCYSAUQU-UHFFFAOYSA-N 0.000 description 1
- MJZUMMKYWBNKIP-UHFFFAOYSA-N 2-isocyanopropane Chemical compound CC(C)[N+]#[C-] MJZUMMKYWBNKIP-UHFFFAOYSA-N 0.000 description 1
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 1
- 125000006088 2-oxoazepinyl group Chemical group 0.000 description 1
- 125000004638 2-oxopiperazinyl group Chemical group O=C1N(CCNC1)* 0.000 description 1
- XMTQQYYKAHVGBJ-UHFFFAOYSA-N 3-(3,4-DICHLOROPHENYL)-1,1-DIMETHYLUREA Chemical compound CN(C)C(=O)NC1=CC=C(Cl)C(Cl)=C1 XMTQQYYKAHVGBJ-UHFFFAOYSA-N 0.000 description 1
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- 125000005986 4-piperidonyl group Chemical group 0.000 description 1
- HJCMDXDYPOUFDY-WHFBIAKZSA-N Ala-Gln Chemical compound C[C@H](N)C(=O)N[C@H](C(O)=O)CCC(N)=O HJCMDXDYPOUFDY-WHFBIAKZSA-N 0.000 description 1
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical compound C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 101710112752 Cytotoxin Proteins 0.000 description 1
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- 108010016626 Dipeptides Proteins 0.000 description 1
- 229930182844 L-isoleucine Natural products 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 1
- LFZAGIJXANFPFN-UHFFFAOYSA-N N-[3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-thiophen-2-ylpropyl]acetamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CCC(C=1SC=CC=1)NC(C)=O)C LFZAGIJXANFPFN-UHFFFAOYSA-N 0.000 description 1
- 125000001429 N-terminal alpha-amino-acid group Chemical group 0.000 description 1
- 229910004013 NO 2 Inorganic materials 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 102100040423 Transcobalamin-2 Human genes 0.000 description 1
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 1
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 229960002648 alanylglutamine Drugs 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000002927 anti-mitotic effect Effects 0.000 description 1
- 239000012062 aqueous buffer Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 125000002785 azepinyl group Chemical group 0.000 description 1
- 125000002393 azetidinyl group Chemical group 0.000 description 1
- 125000005605 benzo group Chemical group 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 238000001516 cell proliferation assay Methods 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 231100000599 cytotoxic agent Toxicity 0.000 description 1
- 239000002619 cytotoxin Substances 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000012894 fetal calf serum Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 125000000524 functional group Chemical class 0.000 description 1
- 230000009036 growth inhibition Effects 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 150000002431 hydrogen Chemical group 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 125000002462 isocyano group Chemical group *[N+]#[C-] 0.000 description 1
- 229960000310 isoleucine Drugs 0.000 description 1
- 125000004628 isothiazolidinyl group Chemical group S1N(CCC1)* 0.000 description 1
- 125000003971 isoxazolinyl group Chemical group 0.000 description 1
- SWVMLNPDTIFDDY-FVGYRXGTSA-N methyl (2s)-2-amino-3-phenylpropanoate;hydrochloride Chemical compound Cl.COC(=O)[C@@H](N)CC1=CC=CC=C1 SWVMLNPDTIFDDY-FVGYRXGTSA-N 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 230000029115 microtubule polymerization Effects 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical class N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 1
- OKPYIWASQZGASP-UHFFFAOYSA-N n-(2-hydroxypropyl)-2-methylprop-2-enamide Chemical compound CC(O)CNC(=O)C(C)=C OKPYIWASQZGASP-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 125000000160 oxazolidinyl group Chemical group 0.000 description 1
- 125000003566 oxetanyl group Chemical group 0.000 description 1
- 238000007248 oxidative elimination reaction Methods 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- IZUPBVBPLAPZRR-UHFFFAOYSA-N pentachloro-phenol Natural products OC1=C(Cl)C(Cl)=C(Cl)C(Cl)=C1Cl IZUPBVBPLAPZRR-UHFFFAOYSA-N 0.000 description 1
- 238000005897 peptide coupling reaction Methods 0.000 description 1
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 description 1
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 238000006894 reductive elimination reaction Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 150000003511 tertiary amides Chemical group 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- AYEKOFBPNLCAJY-UHFFFAOYSA-O thiamine pyrophosphate Chemical compound CC1=C(CCOP(O)(=O)OP(O)(O)=O)SC=[N+]1CC1=CN=C(C)N=C1N AYEKOFBPNLCAJY-UHFFFAOYSA-O 0.000 description 1
- 125000006090 thiamorpholinyl sulfone group Chemical group 0.000 description 1
- 125000006089 thiamorpholinyl sulfoxide group Chemical group 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 238000006257 total synthesis reaction Methods 0.000 description 1
- 229930184737 tubulysin Natural products 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- C07K5/021—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)n-C(=0)-, n being 5 or 6; for n > 6, classification in C07K5/06 - C07K5/10, according to the moiety having normal peptide bonds
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- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
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- C07K5/06—Dipeptides
- C07K5/06139—Dipeptides with the first amino acid being heterocyclic
- C07K5/06173—Dipeptides with the first amino acid being heterocyclic and Glp-amino acid; Derivatives thereof
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Abstract
【選択図】なし
Description
Wは、OR13又はNR14R15から選択される基であり、
Xは、置換された5員又は6員の芳香環(アリーレン)又は芳香族複素環(ヘテロアリーレン)、好ましくはチアゾール又はオキサゾールであり、
YはH、−CH2−、NH、NMe、硫黄原子又は酸素原子、好ましくは酸素原子であり、
ZはOR16、NR17R18、又は
R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R13、R14、R15、R16、R17、R18、R20、R21、R23、R24及びR25は各々独立して、H、置換された又は非置換のアルキル、置換された又は非置換のシクロアルキル、置換された又は非置換のアリール、置換された又は非置換のヘテロアリール、置換された又は非置換のヘテロアルキルを表し、R1及びR3又はR1及びR2が結合して、窒素原子とともに5員ピロリジン環又は6員ピペリジン環を形成していてもよく、
R12はH、アシル基(C(O)R)、置換された又は非置換のアルキル、置換された又は非置換のシクロアルキル、置換された又は非置換のアリールであり、ここで、Rは置換された若しくは非置換のアルキル、置換された若しくは非置換のシクロアルキル、又は置換された若しくは非置換のアリールであり、
R19は2位及び/又は3位及び/又は4位、及び/又は5位、及び/又は6位で、又は任意の組合せで、H、ハロゲン、ニトロ、アミン、モノアルキルアミン又はジアルキルアミン基、ヒドロキシル、アルキルオキシ、置換された又は非置換のアルキル、置換された又は非置換のシクロアルキル、置換された又は非置換のアリール、置換された又は非置換のヘテロアリール、置換された又は非置換のヘテロアルキルを表し、
R22はOH、NH2、アルキルオキシ、アルキルアミノ若しくはジアルキルアミノ基、又はリンカーを表し、
Vは硫黄原子又は酸素原子、−CH2−、NH又はNH−アルキル基である)を提供する。
Xは、置換された5員又は6員の芳香環(アリーレン)又は芳香族複素環(ヘテロアリーレン)、好ましくはチアゾール又はオキサゾールであり、
YはH、−CH2−、NH、NMe、硫黄原子又は酸素原子、好ましくは酸素原子であり、
ZはOR16、NR17R18、又は
R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R17、R18、R20、R21、R23、R24及びR25は各々独立して、H、置換された又は非置換のアルキル、置換された又は非置換のシクロアルキル、置換された又は非置換のアリール、置換された又は非置換のヘテロアリール、置換された又は非置換のヘテロアルキルを表し、R1及びR3が結合して、窒素原子とともに5員ピロリジン環又は6員ピペリジン環を形成していてもよく、
R12はH、アシル基(C(O)R)、置換された又は非置換のアルキル、置換された又は非置換のシクロアルキル、置換された又は非置換のアリールであり、ここで、Rは置換された若しくは非置換のアルキル、置換された若しくは非置換のシクロアルキル、又は置換された若しくは非置換のアリールであり、
R14及びR16は置換された若しくは非置換のアルキル、置換された若しくは非置換のシクロアルキル、置換された若しくは非置換のアリール、置換された若しくは非置換のヘテロアリール、置換された若しくは非置換のヘテロアルキル、又は通常のO保護基であり、
R19は2位及び/又は3位及び/又は4位、及び/又は5位、及び/又は6位で、又は任意の組合せで、H、ハロゲン、ニトロ、アミン、モノアルキルアミン又はジアルキルアミン基、ヒドロキシル、アルキルオキシ、置換された又は非置換のアルキル、置換された又は非置換のシクロアルキル、置換された又は非置換のアリール、置換された又は非置換のヘテロアリール、置換された又は非置換のヘテロアルキルを表し、
R22はNH2、アルキルオキシ、アルキルアミノ若しくはジアルキルアミノ基、又はリンカーを表し、
Vは硫黄原子又は酸素原子、−CH2−、NH又はNH−アルキル基である)。
R’はH又はメチル基であり、
R14、R15及びZは上記のように定義され、Zがチューブフェニルアラニル(Tup)であることが最も好ましい)。
ヒト前立腺がん細胞株(PC−3)及びヒト結腸がん細胞株(HT−29)を、ドイツ微生物コレクション(German Collection of Microorganisms)から入手した。全ての細胞株を、それらのそれぞれの寄託者によって推奨される条件下で培養した。PC−3細胞株及びHT−29細胞株の両方に対する細胞毒性及びGI50の決定を、MTT細胞増殖アッセイ(D. A. Scudiero et al. Cancer. Res. 48, 4827-4833 (1988))を用いて行った。両方の細胞株を、10%のウシ胎仔血清、1%のL−アラニル−L−グルタミン(200mM)、1%のペニシリン/ストレプトマイシン及び1.6%のhepes(1M)を添加したRPMI 1640培地中で維持した。PC−3細胞株については1ウェル当たり500個の細胞、HT−29細胞株については1ウェル当たり1500個〜2000個の細胞を、96ウェル細胞培養プレート(TPP,Trasadingen,Switzerland)に一晩播種し、各々の阻害剤の段階希釈物に3日間曝露した。ホルマザン塩の形成を、酵素結合免疫吸着測定法(ELISA)リーダー(DYNEX technologiesのMRX TC II)を用いて490nmで測定した。各々の化合物から、4つの独立した反復試験区(replicates)を作製した。
Ugi−4CR反応の基本手順:
遊離アミン(0.24mmol、1当量)のMeOH溶液(3ml)に、カルボニル成分(0.24mmol、1当量)のMeOH懸濁液(3ml)を、シリンジポンプを用いて2時間かけてゆっくりと添加した。続いて、酸成分(0.6mmol、2.5当量)を添加し、反応混合物を10分間撹拌した後、イソシアニド成分(0.24mmol、1当量)のMeOH溶液(3ml)を、シリンジポンプを用いて3時間かけて添加した。反応混合物を更に6時間撹拌した後、溶媒を減圧下で除去した。フラッシュカラムクロマトグラフィーによって、式(IV)を有する化合物が得られた。
Mep−Ile−OH 1bの調製:
化合物2:
化合物3:
ジアステレオマー混合物4:
化合物5、化合物6及び化合物7のための基本手順:
化合物5:
化合物6:
ジアステレオマー混合物7:
チューブギA、チューブギB及びチューブギDのための基本手順:
チューブギA:
チューブギB:
チューブギD(ジアステレオマー混合物):
Claims (14)
- 以下の一般式(II)を有するチューブリシン化合物、並びにその薬学的に許容される塩、水和物、溶媒和物、プロドラッグ、代謝産物、立体異性体、立体異性体混合物及び多形体:
Wは、OR13又はNR14R15から選択される基であり、
Xは、置換された5員又は6員の芳香環(アリーレン)又は芳香族複素環(ヘテロアリーレン)であり、
YはH、−CH2−、NH、NMe、硫黄原子又は酸素原子であり、
ZはOR16、NR17R18、又は
R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R13、R14、R15、R16、R17、R18、R20、R21、R23、R24及びR25は各々独立して、H、置換された又は非置換のアルキル、置換された又は非置換のシクロアルキル、置換された又は非置換のアリール、置換された又は非置換のヘテロアリール、置換された又は非置換のヘテロアルキルを表し、R1及びR3又はR1及びR2が結合して、窒素原子とともに5員ピロリジン環又は6員ピペリジン環を形成していてもよく、
R12はH、アシル基(C(O)R)、置換された又は非置換のアルキル、置換された又は非置換のシクロアルキル、置換された又は非置換のアリールであり、ここで、Rは置換された若しくは非置換のアルキル、置換された若しくは非置換のシクロアルキル、又は置換された若しくは非置換のアリールであり、
R19は2位及び/又は3位及び/又は4位、及び/又は5位、及び/又は6位で、又は任意の組合せで、H、ハロゲン、ニトロ、アミン、モノアルキルアミン又はジアルキルアミン基、ヒドロキシル、アルキルオキシ、置換された又は非置換のアルキル、置換された又は非置換のシクロアルキル、置換された又は非置換のアリール、置換された又は非置換のヘテロアリール、置換された又は非置換のヘテロアルキルを表し、
R22はOH、NH2、アルキルオキシ、アルキルアミノ若しくはジアルキルアミノ基、又はリンカーを表し、
Vは硫黄原子又は酸素原子、−CH2−、NH又はNH−アルキル基である)。 - Yが酸素原子であり、Xはがチアゾール又はオキサゾールである、請求項1に記載のチューブリシン化合物。
- R1及びR3が結合してピペリジン部分を形成する、請求項1又は2に記載のチューブリシン化合物。
- Zがチューブフェニルアラニル(Tup)である、請求項1〜3のいずれか一項に記載のチューブリシン化合物。
- WがNR14R15である、請求項1〜4のいずれか一項に記載のチューブリシン化合物。
- 前記化合物が、
(i)標的指向送達のための生体分子、又は、
(ii)前記化合物の溶解性、浸透、検出、放出又は選択性を改善することができる分子部分、
にコンジュゲートする、請求項1〜7のいずれか一項に記載のチューブリシン化合物。 - 前記生体分子がペプチド、機能タンパク質、酵素、抗原、抗体、(オリゴ)糖、(多)糖、核酸、ホルモン若しくはホルモン受容体結合体、又はビタミンである、請求項8に記載のチューブリシン化合物。
- 前記分子部分がポリエチレングリコール、ポリアミン、ポリグアニジン、色素、受容体リガンド又はポリマーから選択される、請求項8に記載のチューブリシン化合物。
- 医薬用途、農業用途、バイオツール用途又は化粧用途のための請求項1〜10のいずれか一項に記載のチューブリシン化合物の使用。
- 1つ又は複数の請求項1〜10のいずれか一項に記載のチューブリシン化合物と、必要に応じて1つ又は複数の薬学的に許容される担体、アジュバント及び/又は希釈剤とを含む医薬製剤。
- 増殖性障害の治療に使用される、請求項1〜10のいずれか一項に記載のチューブリシン化合物。
- 下記に示されるように、一般式(IV)を有する化合物を第三級アミド結合の生成のためにウギ型反応によって生成する方法:
Xは、置換された5員又は6員の芳香環(アリーレン)又は芳香族複素環(ヘテロアリーレン)であり、
YはH、−CH2−、NH、NMe、硫黄原子又は酸素原子であり、
ZはOR16、NR17R18、又は
R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R17、R18、R20、R21、R23、R24及びR25は各々独立して、H、置換された又は非置換のアルキル、置換された又は非置換のシクロアルキル、置換された又は非置換のアリール、置換された又は非置換のヘテロアリール、置換された又は非置換のヘテロアルキルを表し、R1及びR3又はR1及びR2が結合して、窒素原子とともに5員ピロリジン環又は6員ピペリジン環を形成していてもよく、
R12はH、アシル基(C(O)R)、置換された又は非置換のアルキル、置換された又は非置換のシクロアルキル、置換された又は非置換のアリールであり、ここで、Rは置換された若しくは非置換のアルキル、置換された若しくは非置換のシクロアルキル、又は置換された若しくは非置換のアリールであり、
R14及びR16は置換された若しくは非置換のアルキル、置換された若しくは非置換のシクロアルキル、置換された若しくは非置換のアリール、置換された若しくは非置換のヘテロアリール、置換された若しくは非置換のヘテロアルキル、又は通常のO−保護基であり、
R19は2位及び/又は3位及び/又は4位、及び/又は5位、及び/又は6位で、又は任意の組合せで、H、ハロゲン、ニトロ、アミン、モノアルキルアミン又はジアルキルアミン基、ヒドロキシル、アルキルオキシ、置換された又は非置換のアルキル、置換された又は非置換のシクロアルキル、置換された又は非置換のアリール、置換された又は非置換のヘテロアリール、置換された又は非置換のヘテロアルキルを表し、
R22はNH2、アルキルオキシ、アルキルアミノ若しくはジアルキルアミノ基、又はリンカーを表し、
Vは硫黄原子又は酸素原子、−CH2−、NH又はNH−アルキル基である)。
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