JP5688367B2 - 新規なウレアおよびチオウレア誘導体 - Google Patents
新規なウレアおよびチオウレア誘導体 Download PDFInfo
- Publication number
- JP5688367B2 JP5688367B2 JP2011524406A JP2011524406A JP5688367B2 JP 5688367 B2 JP5688367 B2 JP 5688367B2 JP 2011524406 A JP2011524406 A JP 2011524406A JP 2011524406 A JP2011524406 A JP 2011524406A JP 5688367 B2 JP5688367 B2 JP 5688367B2
- Authority
- JP
- Japan
- Prior art keywords
- compound
- optionally substituted
- sulfonamide
- amino
- pyridin
- 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 - Fee Related
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- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 title description 32
- 239000004202 carbamide Substances 0.000 title description 12
- 150000003585 thioureas Chemical class 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims description 181
- -1 1,2,4-triazin-3-yl Chemical group 0.000 claims description 83
- 125000001072 heteroaryl group Chemical group 0.000 claims description 37
- 125000000623 heterocyclic group Chemical group 0.000 claims description 34
- 108010064862 Nicotinamide phosphoribosyltransferase Proteins 0.000 claims description 26
- 102000015532 Nicotinamide phosphoribosyltransferase Human genes 0.000 claims description 26
- 150000003839 salts Chemical class 0.000 claims description 21
- 229910052739 hydrogen Inorganic materials 0.000 claims description 19
- 239000001257 hydrogen Substances 0.000 claims description 19
- 239000003814 drug Substances 0.000 claims description 17
- 125000003118 aryl group Chemical group 0.000 claims description 16
- 125000006652 (C3-C12) cycloalkyl group Chemical group 0.000 claims description 13
- 150000002431 hydrogen Chemical class 0.000 claims description 13
- 125000003107 substituted aryl group Chemical group 0.000 claims description 12
- 102000004190 Enzymes Human genes 0.000 claims description 9
- 108090000790 Enzymes Proteins 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 206010028980 Neoplasm Diseases 0.000 claims description 6
- 230000000694 effects Effects 0.000 claims description 6
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 5
- 201000011510 cancer Diseases 0.000 claims description 5
- 241000124008 Mammalia Species 0.000 claims description 4
- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 claims description 3
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- 206010033128 Ovarian cancer Diseases 0.000 claims description 2
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 2
- 230000002401 inhibitory effect Effects 0.000 claims description 2
- 125000004498 isoxazol-4-yl group Chemical group O1N=CC(=C1)* 0.000 claims description 2
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims 1
- 238000000034 method Methods 0.000 description 127
- 239000007858 starting material Substances 0.000 description 105
- 238000005160 1H NMR spectroscopy Methods 0.000 description 101
- 239000000203 mixture Substances 0.000 description 49
- HDOUGSFASVGDCS-UHFFFAOYSA-N pyridin-3-ylmethanamine Chemical compound NCC1=CC=CN=C1 HDOUGSFASVGDCS-UHFFFAOYSA-N 0.000 description 47
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 37
- 150000001412 amines Chemical class 0.000 description 37
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 36
- NUKYPUAOHBNCPY-UHFFFAOYSA-N 4-aminopyridine Chemical compound NC1=CC=NC=C1 NUKYPUAOHBNCPY-UHFFFAOYSA-N 0.000 description 28
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 27
- 125000000062 cyclohexylmethoxy group Chemical group [H]C([H])(O*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 24
- 125000000586 2-(4-morpholinyl)ethoxy group Chemical group [H]C([H])(O*)C([H])([H])N1C([H])([H])C([H])([H])OC([H])([H])C1([H])[H] 0.000 description 23
- 238000006243 chemical reaction Methods 0.000 description 22
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 19
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 19
- BAWFJGJZGIEFAR-NNYOXOHSSA-N NAD zwitterion Chemical compound NC(=O)C1=CC=C[N+]([C@H]2[C@@H]([C@H](O)[C@@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 BAWFJGJZGIEFAR-NNYOXOHSSA-N 0.000 description 17
- 235000001968 nicotinic acid Nutrition 0.000 description 17
- 239000011664 nicotinic acid Substances 0.000 description 17
- 229960003512 nicotinic acid Drugs 0.000 description 17
- 235000005152 nicotinamide Nutrition 0.000 description 16
- 239000011570 nicotinamide Substances 0.000 description 16
- 229960003966 nicotinamide Drugs 0.000 description 16
- 229960004979 fampridine Drugs 0.000 description 15
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 14
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 14
- 229950006238 nadide Drugs 0.000 description 14
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 14
- 125000006619 (C1-C6) dialkylamino group Chemical group 0.000 description 13
- 238000010511 deprotection reaction Methods 0.000 description 13
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 13
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 235000013877 carbamide Nutrition 0.000 description 12
- 210000004027 cell Anatomy 0.000 description 12
- 201000010099 disease Diseases 0.000 description 12
- 229910052736 halogen Inorganic materials 0.000 description 12
- 150000002367 halogens Chemical class 0.000 description 12
- 239000008194 pharmaceutical composition Substances 0.000 description 12
- 125000001424 substituent group Chemical group 0.000 description 12
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 12
- 238000009472 formulation Methods 0.000 description 11
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 11
- 125000006239 protecting group Chemical group 0.000 description 11
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 10
- 239000002253 acid Substances 0.000 description 10
- 238000013270 controlled release Methods 0.000 description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 10
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 9
- 239000002585 base Chemical class 0.000 description 9
- 238000004587 chromatography analysis Methods 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N dichloromethane Natural products ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- NAHHNSMHYCLMON-UHFFFAOYSA-N 2-pyridin-3-ylethanamine Chemical compound NCCC1=CC=CN=C1 NAHHNSMHYCLMON-UHFFFAOYSA-N 0.000 description 8
- JQAMGGDAKUKZQF-UHFFFAOYSA-N 6-amino-n-(cyclohexylmethoxy)hexane-1-sulfonamide Chemical compound NCCCCCCS(=O)(=O)NOCC1CCCCC1 JQAMGGDAKUKZQF-UHFFFAOYSA-N 0.000 description 8
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 8
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 8
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 8
- 229940079593 drug Drugs 0.000 description 8
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 8
- 239000003112 inhibitor Substances 0.000 description 8
- 230000005764 inhibitory process Effects 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 7
- OIBQJAGXPSRAEX-UHFFFAOYSA-N 3-(5-aminopentyl)-1-(2-morpholin-4-ylethoxy)-1-propan-2-ylurea;dihydrochloride Chemical compound Cl.Cl.NCCCCCNC(=O)N(C(C)C)OCCN1CCOCC1 OIBQJAGXPSRAEX-UHFFFAOYSA-N 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 229910021529 ammonia Inorganic materials 0.000 description 7
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 6
- 125000004845 (C1-C6) alkylsulfonylamino group Chemical group 0.000 description 6
- PFKFTWBEEFSNDU-UHFFFAOYSA-N 1,1'-Carbonyldiimidazole Substances C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 6
- 125000003320 C2-C6 alkenyloxy group Chemical group 0.000 description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 125000000217 alkyl group Chemical group 0.000 description 6
- 230000037396 body weight Effects 0.000 description 6
- 125000004432 carbon atom Chemical group C* 0.000 description 6
- IKYOVSVBLHGFMA-UHFFFAOYSA-N dipyridin-2-yloxymethanethione Chemical compound C=1C=CC=NC=1OC(=S)OC1=CC=CC=N1 IKYOVSVBLHGFMA-UHFFFAOYSA-N 0.000 description 6
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 6
- 239000002609 medium Substances 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 description 5
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 description 5
- 229930024421 Adenine Natural products 0.000 description 5
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- 229960000643 adenine Drugs 0.000 description 5
- 125000003545 alkoxy group Chemical group 0.000 description 5
- 229940024606 amino acid Drugs 0.000 description 5
- 235000001014 amino acid Nutrition 0.000 description 5
- 150000001413 amino acids Chemical class 0.000 description 5
- 125000004429 atom Chemical group 0.000 description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 125000004122 cyclic group Chemical group 0.000 description 5
- 239000002552 dosage form Substances 0.000 description 5
- 235000019439 ethyl acetate Nutrition 0.000 description 5
- 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 description 5
- 125000005842 heteroatom Chemical group 0.000 description 5
- 150000002540 isothiocyanates Chemical class 0.000 description 5
- 125000000468 ketone group Chemical group 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 5
- YBSLUBPQYDULIZ-UHFFFAOYSA-N oxalic acid;urea Chemical compound NC(N)=O.OC(=O)C(O)=O YBSLUBPQYDULIZ-UHFFFAOYSA-N 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 5
- NXLNNXIXOYSCMB-UHFFFAOYSA-N (4-nitrophenyl) carbonochloridate Chemical compound [O-][N+](=O)C1=CC=C(OC(Cl)=O)C=C1 NXLNNXIXOYSCMB-UHFFFAOYSA-N 0.000 description 4
- 125000004738 (C1-C6) alkyl sulfinyl group Chemical group 0.000 description 4
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 description 4
- CIISBYKBBMFLEZ-UHFFFAOYSA-N 1,2-oxazolidine Chemical compound C1CNOC1 CIISBYKBBMFLEZ-UHFFFAOYSA-N 0.000 description 4
- QVOJLJVGIWTIDR-UHFFFAOYSA-N 6-morpholin-4-ylsulfonylhexan-1-amine Chemical compound NCCCCCCS(=O)(=O)N1CCOCC1 QVOJLJVGIWTIDR-UHFFFAOYSA-N 0.000 description 4
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- WFBHRSAKANVBKH-UHFFFAOYSA-N N-hydroxyguanidine Chemical compound NC(=N)NO WFBHRSAKANVBKH-UHFFFAOYSA-N 0.000 description 4
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 4
- 125000003342 alkenyl group Chemical group 0.000 description 4
- 230000029936 alkylation Effects 0.000 description 4
- 238000005804 alkylation reaction Methods 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 125000004104 aryloxy group Chemical group 0.000 description 4
- ZSIQJIWKELUFRJ-UHFFFAOYSA-N azepane Chemical compound C1CCCNCC1 ZSIQJIWKELUFRJ-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 125000002837 carbocyclic group Chemical group 0.000 description 4
- 229940125904 compound 1 Drugs 0.000 description 4
- 239000000839 emulsion Substances 0.000 description 4
- AEDIXYWIVPYNBI-UHFFFAOYSA-N heptanamide Chemical compound CCCCCCC(N)=O AEDIXYWIVPYNBI-UHFFFAOYSA-N 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 235000006408 oxalic acid Nutrition 0.000 description 4
- 125000004043 oxo group Chemical group O=* 0.000 description 4
- PWHUPFOHNXWYSH-UHFFFAOYSA-N pyridin-3-ylmethylurea Chemical compound NC(=O)NCC1=CC=CN=C1 PWHUPFOHNXWYSH-UHFFFAOYSA-N 0.000 description 4
- 229910052717 sulfur Inorganic materials 0.000 description 4
- DKYBVKMIZODYKL-UHFFFAOYSA-N 1,3-diazinane Chemical compound C1CNCNC1 DKYBVKMIZODYKL-UHFFFAOYSA-N 0.000 description 3
- 125000004777 2-fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 description 3
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 3
- PQGCEDQWHSBAJP-TXICZTDVSA-N 5-O-phosphono-alpha-D-ribofuranosyl diphosphate Chemical compound O[C@H]1[C@@H](O)[C@@H](O[P@](O)(=O)OP(O)(O)=O)O[C@@H]1COP(O)(O)=O PQGCEDQWHSBAJP-TXICZTDVSA-N 0.000 description 3
- LRLHZELSGKXAHP-UHFFFAOYSA-N 6-amino-n-(cyclohexylmethoxy)-n-(2-fluoroethyl)hexane-1-sulfonamide Chemical compound NCCCCCCS(=O)(=O)N(CCF)OCC1CCCCC1 LRLHZELSGKXAHP-UHFFFAOYSA-N 0.000 description 3
- OQJOKLWDWRBFBF-UHFFFAOYSA-N 6-amino-n-(cyclohexylmethoxy)-n-[2-[2-(2-methoxyethoxy)ethoxy]ethyl]hexane-1-sulfonamide Chemical compound COCCOCCOCCN(S(=O)(=O)CCCCCCN)OCC1CCCCC1 OQJOKLWDWRBFBF-UHFFFAOYSA-N 0.000 description 3
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- WRYCSMQKUKOKBP-UHFFFAOYSA-N Imidazolidine Chemical compound C1CNCN1 WRYCSMQKUKOKBP-UHFFFAOYSA-N 0.000 description 3
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 3
- 102000003993 Phosphatidylinositol 3-kinases Human genes 0.000 description 3
- 108090000430 Phosphatidylinositol 3-kinases Proteins 0.000 description 3
- 229940100389 Sulfonylurea Drugs 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 125000001769 aryl amino group Chemical group 0.000 description 3
- 125000005129 aryl carbonyl group Chemical group 0.000 description 3
- 125000004657 aryl sulfonyl amino group Chemical group 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 150000001805 chlorine compounds Chemical class 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 229940125782 compound 2 Drugs 0.000 description 3
- 229940126214 compound 3 Drugs 0.000 description 3
- HTFFABIIOAKIBH-UHFFFAOYSA-N diazinane Chemical compound C1CCNNC1 HTFFABIIOAKIBH-UHFFFAOYSA-N 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- 150000002085 enols Chemical class 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 125000002541 furyl group Chemical group 0.000 description 3
- 125000005241 heteroarylamino group Chemical group 0.000 description 3
- 125000005223 heteroarylcarbonyl group Chemical group 0.000 description 3
- 125000005419 heteroarylsulfonylamino group Chemical group 0.000 description 3
- 150000003840 hydrochlorides Chemical class 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 125000002883 imidazolyl group Chemical group 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 125000005956 isoquinolyl group Chemical group 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 229940101270 nicotinamide adenine dinucleotide (nad) Drugs 0.000 description 3
- OZQGLZFAWYKKLQ-UHFFFAOYSA-N oxazinane Chemical compound C1CCONC1 OZQGLZFAWYKKLQ-UHFFFAOYSA-N 0.000 description 3
- 125000004430 oxygen atom Chemical group O* 0.000 description 3
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 3
- 238000007911 parenteral administration Methods 0.000 description 3
- 230000037361 pathway Effects 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 239000002243 precursor Substances 0.000 description 3
- 239000000651 prodrug Substances 0.000 description 3
- 229940002612 prodrug Drugs 0.000 description 3
- 125000004076 pyridyl group Chemical group 0.000 description 3
- 125000000714 pyrimidinyl group Chemical group 0.000 description 3
- 125000000168 pyrrolyl group Chemical group 0.000 description 3
- GJAWHXHKYYXBSV-UHFFFAOYSA-N quinolinic acid Chemical compound OC(=O)C1=CC=CN=C1C(O)=O GJAWHXHKYYXBSV-UHFFFAOYSA-N 0.000 description 3
- 125000005493 quinolyl group Chemical group 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- JUJBNYBVVQSIOU-UHFFFAOYSA-M sodium;4-[2-(4-iodophenyl)-3-(4-nitrophenyl)tetrazol-2-ium-5-yl]benzene-1,3-disulfonate Chemical compound [Na+].C1=CC([N+](=O)[O-])=CC=C1N1[N+](C=2C=CC(I)=CC=2)=NC(C=2C(=CC(=CC=2)S([O-])(=O)=O)S([O-])(=O)=O)=N1 JUJBNYBVVQSIOU-UHFFFAOYSA-M 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
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Description
本発明は、特に、ニコチンアミドホスホリボシルトランスフェラーゼ(NAMPRT)酵素の阻害に有用である、個々のウレアおよびチオウレア誘導体に関する。
Xは=O、=S、=NH、=NOHおよび=NO−Meより選択され;
Aは−C(=O)−、−S(=O)2−、−C(=S)−および−P(=O)(R5)−より選択され、ここでR5はC1−6−アルキル、C1−6−アルコキシおよびヒドロキシより選択され;
Bは単結合、−(CH2)3−6−、−O−、および−O−(CH2)2−5−より選択され;
Dは単結合、−O−、−CR7R8−および−NR9より選択され、ここでR7、R8およびR9は、独立して、水素、所望により置換されていてもよいC1−12−アルキル、所望により置換されていてもよいC1−12−アルケニル、所望により置換されていてもよいアリール、所望により置換されていてもよいヘテロシクリル、および所望により置換されていてもよいヘテロアリールより選択され;
mは0−12の整数であり、nは0−12の整数であり、ここでm+nの合計は1−20であり;
pは0−4の整数であり;
R1は所望により置換されていてもよいヘテロアリールより選択され;
R2は水素、所望により置換されていてもよいC1−12−アルキル、所望により置換されていてもよいC3−12−シクロアルキル、−[CH2CH2O]1−10−(所望により置換されていてもよいC1−6−アルキル)、所望により置換されていてもよいC1−12−アルケニル、所望により置換されていてもよいアリール、所望により置換されていてもよいヘテロシクリル、および所望により置換されていてもよいヘテロアリールより選択され;およびR3は所望により置換されていてもよいC1−12−アルキル、所望により置換されていてもよいC3−12−シクロアルキル、−[CH2CH2O]1−10−(所望により置換されていてもよいC1−6−アルキル)、所望により置換されていてもよいC1−12−アルケニル、所望により置換されていてもよいアリール、所望により置換されていてもよいヘテロシクリル、および所望により置換されていてもよいヘテロアリールより選択されるか;またはR2およびR3は介在する原子(すなわち、−N−B−)と一緒になって所望により置換されていてもよいN−含有のヘテロ環またはヘテロ芳香族環を形成し;
R4およびR4*の各々は、独立して、水素、所望により置換されていてもよいC1−12−アルキルおよび所望により置換されていてもよいC1−12−アルケニルより選択される;
ただし、pが0の場合、R1は所望により置換されていてもよいチアゾール−2−イル以外の基であり;および
該化合物はフェニル−NH−C(=O)−(CH2)5−NH−C(=S)−NH−(4−ピリジル)以外の化合物である]
で示される化合物またはその医薬上許容される塩およびプロドラッグに関する。
Xが=Oであり、Aが−SO2−である場合、Bは−O−または−(CH2)3−6−もしくは−O−(CH2)2−5−であり;および
Xが=Oであり、Aが−C(=O)−であって、p=0である場合、Bは−O−または−(CH2)3−6−もしくは−O−(CH2)2−5−であり;および
Xが=Oであり、Aが−C(=O)−であって、p=0である場合、R1は
Xが=Oであり、Aが−C(=O)−であって、p=1−4である場合、R1は
以外の基であり;および
Xが=Sであり、Aが−C(=O)−であって、p=1−4である場合、R3はベンジルまたは
以外の基である。
本願明細書において、「C1−12−アルキル」および「C1−6−アルキル」なる語は、各々、1ないし12個および1ないし6個の炭素原子を有する直鎖、環状または分枝炭化水素基を意図するものであり、例えば、メチル、エチル、プロピル、イソ−プロピル、シクロプロピル、ブチル、イソ−ブチル、tert−ブチル、シクロブチル、ペンチル、シクロペンチル、ヘキシルまたはシクロヘキシルである。
一の主たる実施態様において、Xは=Oおよび=Sより選択される。
Xは=Oおよび=Sより選択され;
Aは−C(=O)−および−S(=O)2−より選択され;
Bは−O−であり;
Dは単結合、−O−および−NR9より選択され;
mは2−8の整数であり、nは0であり;
pは0−2の整数であり;
R2は水素、所望により置換されていてもよいC3−12−シクロアルキル、−[CH2CH2O]1−10−(所望により置換されていてもよいC1−6−アルキル)、−(CH2)0−2−(所望により置換されていてもよいアリール)、−(CH2)0−2−(所望により置換されていてもよいヘテロアリール)および−(CH2)0−2−(所望により置換されていてもよいヘテロシクリル)より選択され;
R3は所望により置換されていてもよいC3−12−シクロアルキル、−[CH2CH2O]1−10−(所望により置換されていてもよいC1−6−アルキル)、所望により置換されていてもよいC1−12−アルケニル、所望により置換されていてもよいアリール、所望により置換されていてもよいヘテロシクリル、および所望により置換されていてもよいヘテロアリールより選択され;
R4は水素、所望により置換されていてもよいC3−12−シクロアルキル、−(CH2)0−2−(所望により置換されていてもよいアリール)、−(CH2)0−2−(所望により置換されていてもよいヘテロアリール)および−(CH2)0−2−(所望により置換されていてもよいヘテロシクリル)より選択され;および
R4*は水素である。
Xは=Oおよび=Sより選択され;
Aは−C(=O)−および−S(=O)2−より選択され;
Bは−(CH2)3−6−および−O−(CH2)2−5−より、好ましくは−(CH2)3−4−および−O−(CH2)1−3−より選択され;
Dは単結合、−O−および−NR9より選択され;
mは2−8の整数であり、nは0であり;
pは0−2の整数であり;
R2は水素、所望により置換されていてもよいC3−12−シクロアルキル、−[CH2CH2O]1−10−(所望により置換されていてもよいC1−6−アルキル)、−(CH2)0−2−(所望により置換されていてもよいアリール)、−(CH2)0−2−(所望により置換されていてもよいヘテロアリール)および−(CH2)0−2−(所望により置換されていてもよいヘテロシクリル)より選択され;
R3は所望により置換されていてもよいC3−12−シクロアルキル、−[CH2CH2O]1−10−(所望により置換されていてもよいC1−6−アルキル)、所望により置換されていてもよいC1−12−アルケニル、所望により置換されていてもよいアリール、所望により置換されていてもよいヘテロシクリルおよび所望により置換されていてもよいヘテロアリールより選択され;
R4は水素、所望により置換されていてもよいC3−12−シクロアルキル、−(CH2)0−2−(所望により置換されていてもよいアリール)、−(CH2)0−2−(所望により置換されていてもよいヘテロアリール)および−(CH2)0−2−(所望により置換されていてもよいヘテロシクリル)より選択され;および
R4*は水素である。
本発明の化合物は、後記する方法を、有機合成有機化学の分野にて公知の方法または当業者により認識されるその変法と一緒に用いて合成することができる。好ましい方法は、限定されるものではないが、後記する方法を包含する。
別法として、一般式(Ib)のチオウレアをメチル化し、その後で、各々、O−メトキシヒドロキシルアミン、ヒドロキシルアミンまたは保護ヒドロキシルアミン、あるいはアンモニアまたはアンモニア均等物と反応させてもよい。保護ヒドロキシルアミンまたはアンモニア均等物が用いられるならば、脱保護工程が必要である。
本発明の化合物は、NAMPRTの阻害を介してNADをダウンレギュレートするのに特に有用であり、したがってNF−κBの活性化が関係している疾患を治療するのに特に有用であると考えられる。かかる方法は、炎症および組織修復障害;特に関節リウマチ、炎症性腸疾患、喘息およびCPOD(慢性閉塞性肺疾患)、骨関節炎、骨粗しょう症および線維症;乾癬、アトピー性皮膚炎および紫外線誘発の皮膚損傷を含む皮膚病;自己免疫疾患、例えば、全身性エリトマトーデス、多発性硬化症、乾癬性関節炎、強直性脊椎炎、組織および臓器拒絶反応、アルツハイマー病、発作、アテローム性動脈硬化症、再狭窄、糖尿病、糸球体腎炎、癌(特に、乳癌、前立腺癌、肺癌、結腸癌、頸癌、卵巣癌、皮膚癌、CNS、膀胱癌、膵臓癌、白血病、リンパ腫またはホジキン病より選択される)、悪液質、感染および後天性免疫不全症候群(AIDS)を含む特定のウイルス感染に伴う炎症、成人呼吸窮迫症候群、運動失調性毛細血管拡張症を含む種々の疾患の治療に有用である。
一般式(I)の化合物は、所望の投与形路に適するように、適宜、医薬組成物に処方される。
一の実施態様において、医薬組成物は単位剤形である。かかる実施態様において、各単位剤形は、典型的には、0.1−500mg、例えば0.1−200mg、例えば0.1−100mgの化合物を含む。
一般的操作、調製例および実施例
核磁気共鳴 1H NMRスペクトル(300MHz)および13C NMR(75.6)では、特記しない限り、テトラメチルシラン(δ=0.0)またはクロロホルム(δ=7.25)または重水素クロロホルム(δ=76.81、13C NMRの場合)標準に対する重水素クロロホルム溶液についての化学シフト値(δ)(ppm)を引用する。規定のマルチプレット(ダブレット(d)、トリプレット(t)、ダブレットダブレット(dd)、ダブレットトリプレット(dt)、カルテット(q))または規定されていないマルチプレット(m)の値は、範囲が引用されていない場合には、略中点で示される。(bs)はブロードシングレットを示す。
CDI 1,1’−カルボニルジイミダゾール
DCCI ジシクロヘキシルカルボジイミド
DCM ジクロロメタン
DCE 1,2−ジクロロエタン
DIEA ジイソプロピルエチルアミン
DMF N,N−ジメチルホルムアミド
DMAP N,N−ジメチルアミノピリジン
DPT ジ(2−ピリジル)チオノカルボナート
EDC N−(ジメチルアミノプロピル)−N−エチルカルボジイミド塩酸塩
EtOAc 酢酸エチル
HATU O−(7−アザベンゾトリアゾール−1−イル)−N,N,N',N'−テトラメチルウロニウム・ヘキサフルオロホスフェート
HOBt 1−ヒドロキシベンゾトリアゾール
MS 質量スペクトル
NMM N−メチルモルホリン
NMR 核磁気共鳴
rt 室温
THF テトラヒドロフラン
TLC 薄層クロマトグラフィー
MS[M+H]+=476.3;[M−H]−=574.3.3;[M−H+HCOOH]−=520.5
MS[M+H]+=430.2;[M−H]−=528.3
1H−NMR(CD3OD):8.47(m,2H)、7.36(m,2H)、4.39(s,2H)、3.75(d,2H)、3.16(m,4H)、1.9−1.15(m,17H)、1.00(m,2H)
1H−NMR(200MHz)(DMSO−d6):10.99(bs,1H)、9.21(t,1H)、8.44(d,2H)、7.88(d,2H)、4.11(t,2H)、3.74−3.60(m,4H)、3.58−3.39(m,3H)、3.42(t,2H)、2.90(t,2H)、2.83−2.67(m,4H)、1.96−1.65(m,5H)、1.90−1.65(13H)
1H−NMR(CD3OD):δ 8.79(bs,1H)、8.48(m,1H)、7.01(m,1H)、4.10(m,1H)、4.08(t,2H)、3.71(m,6H)、2.67(t,2H)、2.56(m,4H)、2.51(t,2H)、1.95−1.05(m,18H)
1H−NMR(200MHz)(DMSO−d6):δ 14.36(bs,1H)、10.85(bs,1H)、8.51(d,2H)、7.84(d,2H)、7.22(bs,1H)、4.03(t,2H)、3.02−3.44(m,6H)、1.90−1.54(m,6H)、1.54−1.21(m,6H)
1H−NMR(200MHz)(DMSO−d6):10.25−9.50(bs,1H)、8.36 bs,2H)、7.56(bs,2H)、7.23−6.78(m,1H)、4.40−3.92(m,6H)、3.40−3.70(m,3H)、3.35−2.97(m,4H)、2.80−2.59(m,4H)、2.00−1.64(m,5H)、1.64−0.91(m,13H)
1H−NMR(CD3OD):δ 8.50(d,1H)、8.43(dd,1H)、7.80(dt,1H)、7.41(m,1H)、4.37(s,2H)、4.14(bs,1H)、4.08(t,2H)、3.72(m,4H)、3.15(t,2H)、2.68(t,2H)、2.56(m,4H)、2.49(t,2H)、1.95−1.1(18H)
1H−NMR(CD3OD):δ 8.47(m,2H)、7.36(m,H)、4.379(s,2H)、4.14(bs,1H)、4.08(t,2H)、3.72(m,4H)、3.16(t,2H)、2.67(t,2H)、2.56(m,4H)、2.50(t,2H)、1.95−1.05(18H)
1H−NMR(DMSO−d6):δ 11.12(bs,1H)、10.96(t,1H)、9.97(bs,1H)、9.08(d,1H)、8.72(d,1H)、3.65(m,4H)、3.12(m,2H)、1.65(m,10H)、1.41(m,4H)、1.16(m,3H)、0.90(m,2H)
1H−NMR(CD3OD):δ 8.98(d,2H)、8.63(d,2H)、4.14(bs,1H)、3.76(t,2)、3.72(m,4H)、2.68(t,2H)、2.57(m,4H)、2.51(m,2H)、1.9−1.25(m,17H)、1.20(m,1H)
13C−NMR(CD3OD):δ 160.99、148.94、148.38、137.47、125.26、83.80、73.00、71.59、71.42、71.38、68.74、59.14、53.53、46.11、42.18、40.92、38.37、31.04、29.29、27.56、27.39、26.88、23.53
1H−NMR(CD3OD):δ 8.49(bs,1H)、8.43(d,1H)、7.79(dt,1H)、7.41(m,1H)、4.37(s,2H)、3.75(d,2H)、3.16(m,4H)、1.85−1.1(m,17)、1.00(m,2H)
1H−NMR(CD3OD):δ 8.52(bs,1H)、8.43(d,1H)、7.85(m,1H)、7.42(m,1H)、4.82(s,2H)、4.13(bs,1H)、4.08(t,2H)、3.72(m,4H)、3.46(m,2H)、2.68(m,2H)、2.56(m,4H)、2.49(t,2H)、1.95−1.1(m,18H)
1H−NMR(DMSO−d6):δ 9.96(s,1H)、8.67(bs,1H)、7.74(bs,1H)、3.66(d,2H)、3.42(m,2H)、3.11(m,2H)、2.21(s,3H)、2.06(s,3H)、1.80−0.8(m,19)
1H−NMR(DMSO−d6):δ 8.65(bs,1H)、7.73(bs,1H)、4.03(bs,1H)、3.95(t,2H)、3.57(m,4H)、3.40(m,2H)、2.53(m,2H)、2.43(m,4H)、2.39(t,2H)、2.21(s,3H)、2.05(s,3H)、1.8−1.1(m,18H)
1H−NMR(400MHz)(DMSO−d6):δ 8.75−8.67(m,2H)、8.27(m,1H)、7.88(m,1H)、6.59(bs,1H)、6.22(bs,1H)、4.34(s,2H)、4.03(t,2H)、3.27(m,2H)、3.18(m,2H)、2.98(t,2H)、1.79(m,2H)、1.69(m,2H)、1.61(m,2H)、1.44−1.31(m,4H)、1.20−1.31(m,2H)
1H−NMR(CD3OD):δ 8.38(d,1H)、8.24(m,1H)、8.19(d,1H)、3.74(m,4H)、3.20(m,2H)、1.9−1.4(m,13)、1.26(m,4H)、0.99(m,2H)
1H−NMR(CD3OD):δ 8.42(d,1H)、8.40(dd,1H)、7.75(dt,1H)、7.39(m,1H)、4.15(bs,1H)、4.08(t,2H)、3.72(m,4H)、3.39(t,2H)、3.10(t,2H)、2.83(t,2H)、2.67(m,2H)、2.56(m,4H)、2.49(t,2H)、1.95−1.05(m,18H)
1H−NMR(CD3OD):δ 8.44(m,2H)、7.33(m,2H)、4.15(bs,1H)、4.08(t,2H)、3.72(m,4H)、3.42(t,2H)、3.10(t,2H)、2.85(t,2H)、2.67(m,2H)、2.56(m,4H)、2.49(t,2H)、1.95−1.25(m,17H)、1.10(m,1H)
1H−NMR(CD3OD):δ 8.49(d,1H)、8.43(dd,1H)、7.79(dt,1H)、7.41(m,1H)、4.37(s,2H)、4.18(t,2H)、3.98(m,1H)、3.71(m,4H)、3.22(m,2H)、3.16(t,2H)、2.66(m,2H)、2.55(m,4H)、1.87(m,2H)、1.51(m,4H)、1.41(m,2H)、1.29(d,6H)
1H−NMR(CD3OD):δ 8.50(d,1H)、8.43(dd,1H)、7.79(dt,1H)、7.42(m,1H)、6.98(t,1H)、4.37(s,2H)、3.97(m,2H)、3.55(m,2H)、3.16(m,4H)、1.73(m,4H)、1.53(m,4H)、1.37(m,2H)
1H−NMR(CD3OD):δ 8.28(m,2H)、7.47(m,2H)、3.96(t,2H)、3.55(t,2H)、3.22(m,4H)、1.72(m,4H)、1.57(m,4H)、(m,2H)
1H−NMR(CD3OD):δ 8.50(d,1H)、8.43(dd,1H)、7.79(dt,1H)、7.42(m,1H)、4.37(s,2H)、3.71(m,4H)、3.52(m,1H)、3.24(m,2H),3.15(t,2H)、3.02(m,2H)、2.49(m,4H)、2.40(t,2H)、1.9−1.25(m,19H)、1.18(m,1H)
1H−NMR(CD3OD):δ 8.28(m,2H)、7.46(m,2H)、3.70(m,4H)、3.51(m,1H)、3.23(m,4H)、3.03(m,2H)、2.47(m,4H)、2.37(t,2H)、1.82(m,8H)、1.7−1.25(m,11H)、1.17(m,1H)
1H−NMR(CD3OD):δ 8.38(d,1H)、8.23(dd,1H)、8.20(d,1H)、4.14(bs,1H)、4.07(t,2H)、3.71(m,6H)、2.67(t,2H)、2.55(m,4H)、2.51(t,2H)、1.9−1.25(m,17H)、1.20(m,1H)
1H−NMR(CD3OD):δ 8.53(d,1H)、8.44(dd,1H)、7.85(dt,1H)、7.42(m,1H)、4.82(s,2H)、3.87(d,2H)、3.72(t,2H)、3.66(m,6H)、3.6−3.4(m,6H)、3.37(s,3H)、3.18(m,2H)、1.87(m,2H)、1.85−1.15(m,15H)、1.05(m,2H)
1H−NMR(CD3OD):δ 8.28(m,2H)、7.46(m,2H)、3.87(d,2H)、3.72(t,2H),)、3.66(m,6H)、3.55(m,2H)、3.44(t,2H)、3.37(s,3H)、3.21(m,4H)、1.89(m,2H)、1.8−1.1(m,15H)、1.04(m,2H)
1H−NMR(CD3OD):δ 8.28(m,2H)、7.46(m,2H)、3.89(d,2H)、3.71(m,4H)、3.42(t,2H)、3.22(m,4H)、2.67(t,2H)、2.53(m,4H)、1.95−1.15(m,17)、1.05(m,2H)
1H−NMR(CD3OD):δ 8.49(d,1H)、8.43(dd,1H)、7.79(dt,1H)、7.41(m,1H)、4.37(s,2H)、3.90(d,2H)、3.71(m,4H)、3.42(t,2H)、3.16(m,4H)、2.68(t,2H)、2.54(m,4H)、1.87(m,2H)、1.83−1.58(m,6H)、1.52(m,4H)、1.39(m,2H)、1.26(m,3H)、1.06(m,2H)
1H−NMR(CD3OD):δ 8.42(d,1H)、8.40(dd,1H)、7.75(dt,1H)、7.39(m,1H)、3.90(d,2H)、3.71(m,4H)、3.39(m,4H)、3.19(m,2H)、3.11(t,2H)、2.84(t,2H)、2.68(t,2H)、2.53(m,4H)、1.87(m,2H)、1.85−1.1(m,15H)、1.05(m,2H)
1H−NMR(CD3OD):δ 8.41(m,2H)、7.75(m,1H)、7.39(m,1H)、3.75(d,2H)、3.39(t,2H)、3.18(m,2H)、3.10(t,2H)、2.84(t,2H)、1.85−1.1(m,17H)、1.0(m,2H)
1H−NMR(CD3OD):δ 8.28(m,2H)、7.46(m,2H)、4.16(m,2H)、3.70(m,4H)、3.56(m,1H)、3.24(m,4H)、2.64(t,2H)、2.54(m,4H)、2.00−1.05(m,16H)
1H−NMR(CD3OD):δ 8.28(m,2H)、7.46(m,2H)、4.16(m,2H)、3.71(m,4H)、3.58(m,1H)、3.19(m,4H)、2.65(t,2H)、2.55(m,4H)、2.00−1.05(m,20H)
1H−NMR(CDCl3):δ 9.55(bs,1H)、9.04(t,1H)、8.75(m,1H)、8.42(d,1H)、7.76(s,1H)、6.89(m,1H)、3.79(d,2H)、3.38(m,2H)、3.20(m,2H)、1.83(m,2H)、1.75−1.05(m,15H)、0.93(m,2H)
1H−NMR(CD3OD):δ 8.49(d,1H)、8.43(dd,1H)、7.79(dt,1H)、7.41(m,1H)、4.37(s,2H)、3.98(t,2H)、3.82(m,1H)、3.76(m,4H)、3.22(t,2H)、3.14(t,2H)、2.83(t,2H)、2.77(m,4H)、1.9−1.45(m,11)、1.36(m,4H)、1.15(m,1H)
1H−NMR(CD3OD):δ 8.42(d,1H)、8.40(dd,1H)、7.76(dt,1H)、7.40(m,1H)、3.96(t,2H)、3.85(m,1H)、3.74(m,4H)、3.39(t,2H)、3.23(t,2H)、3.10(t,2H)、2.84(t,2H)、2.62(t,2H)、2.58(m,4H)、1.9−1.05(m,16)
1H−NMR(CD3OD):δ 8.73(bs,1H)、8.43(d,1H)、7.30(m,1H)、4.30(m,1H)、4.08(m,2H)、3.71(m,6H)、2.67(t,2H)、2.56(m,4H)、2.50(t,2H)、1.95−0.75(m,18H)
1H−NMR(CD3OD):δ 8.48(dd,1H)、7.78(dt,1H)、7.35(d,1H)、7.28(m,1H)、3.90(d,2H)、3.71(m,4H)、3.49(t,2H)、3.42(t,2H)、3.19(m,2H)、3.11(t,2H)、2.96(t,2H)、2.68(t,2H)、2.53(m,4H)、1.95−1.1(m,17)、1.05(m,2H)
1H−NMR(CD3OD):δ 8.48(dd,1H)、7.78(dt,1H)、7.35(d,1H)、7.28(m,1H)、4.15(m,1H)、4.08(t,2H)、3.72(m,4H)、3.49(t,2H)、3.10(t,2H)、2.96(t,2H)、2.67(t,2H)、2.56(m,4H)、2.49(m,2H)、1.95−1.05(m,18H)
1H−NMR(CD3OD):δ 8.49(d,1H)、8.43(dd,1H)、7.80(dt,1H)、7.42(m,1H)、4.37(s,2H)、4.16(t,2H)、3.71(m,4H)、3.59(m,1H)、3.19(m,4H)、2.65(t,2H)、2.55(m,4H)、1.90(m,6H)、1.75−1.25(m,9)、1.19(m,1H)
1H−NMR(CD3OD):δ 8.49(d,1H)、8.43(dd,1H)、7.80(dt,1H)、7.42(m,1H)、4.37(s,2H)、4.16(t,2H)、3.71(m,4H)、3.58(m,1H)、3.17(m,4H)、2.65(t,2H)、2.55(m,4H)、2.0−1.1(m,20H)
1H−NMR(CD3OD):δ 8.49(d,1H)、8.43(dd,1H)、7.79(dt,1H)、7.41(m,1H)、4.37(s,2H)、4.22(m,1H)、3.99(t,2H)、3.72(m,4H)、3.22(t,2H)、3.13(t,2H)、2.63(t,2H)、2.58(m,4H)、1.52(m,4)、1.38(m,2H)、1.18(d,6H)
1H−NMR(CD3OD):δ 8.41(m,2H)、7.77(dt,1H)、7.40(m,1H)、4.25(m,1H)、3.98(t,2H)、3.74(m,4H)、3.39(t,2H)、3.23(t,2H)、3.10(t,2H)、2.83(t,2H)、2.63(t,2H)、2.57(m,4H)、1.53(m,4)、1.36(m,2H)、1.17(d,6H)
1H−NMR(CD3OD):δ 8.29(m,2H)、7.46(m,2H)、4.25(m,1H)、3.97(t,2H)、3.73(m,4H)、3.24(m,4H)、2.60(t,2H)、2.55(m,4H)、1.60(m,4)、1.42(m,2H)、1.16(d,6H)
1H−NMR(CD3OD):δ 8.49(d,1H)、8.43(dd,1H)、7.79(dt,1H)、7.41(m,1H)、4.37(s,2H)、4.22(m,1H)、3.99(t,2H)、3.72(m,4H)、3.22(t,2H)、3.13(t,2H)、2.63(t,2H)、2.58(m,4H)、1.52(m,4H)、1.38(m,2H)、1.18(d,6H)
1H−NMR(CD3OD):δ 8.41(m,2H)、7.75(dt,1H)、7.40(m,1H)、3.99(m,1H)、3.70(m,4H)、3.39(t,2H)、3.21(t,2H)、3.10(t,2H)、3.02(m,2H)、2.84(t,2H)、2.47(m,4H)、2.39(t,2H)、1.82(m,4H)、1.47(m,4H)、1.37(m,2H)、1.25(d,6H)
1H−NMR(CD3OD):δ 8.28(m,2H)、7.46(m,2H)、3.99(m,1H)、3.71(m,4H)、3.22(m,4H)、3.02(m,2H)、2.47(m,4H)、2.39(t,2H)、1.82(m,4H)、1.49(m,6H)、1.25(d,6H)
1H−NMR(CD3OD):δ 8.49(d,1H)、8.43(dd,1H)、7.79(dt,1H)、7.42(m,1H)、4.37(s,2H)、4.07(m,1H)、3.70(m,4H)、3.17(m,4H)、3.03(m,2H)、2.48(m,4H)、2.39(t,2H)、1.95−1.30(m,18H)
1H−NMR(CD3OD):δ 8.49(d,1H)、8.43(dd,1H)、7.79(dt,1H)、7.41(m,1H)、4.37(s,2H)、3.75(d,2H)、3.17(m,4H)、1.75(m,8H)、1.51(m,4H)、1.26(m,3H)、0.99(m,2H)
1H−NMR(CD3OD):δ 8.49(d,1H)、8.43(dd,1H)、7.79(dt,1H)、7.41(m,1H)、4.37(s,2H)、4.10(t,2H)、3.36(t,2H)、3.19(m,4H)、1.87(m,4H)、1.71(m,2H)、1.51(m,4H)
1H−NMR(CD3OD):δ 8.49(d,1H)、8.43(dd,1H)、7.79(dt,1H)、7.41(m,1H)、4.37(s,2H)、3.75(d,2H)、3.16(m,4H)、1.76(m,8H)、1.6−1.1(m,11H)、0.99(m,2H)
1H−NMR(CD3OD):δ 8.49(d,1H)、8.43(dd,1H)、7.79(dt,1H)、7.41(m,1H)、4.37(s,2H)、4.11(t,2H)、3.36(t,2H)、3.17(m,4H)、1.86(m,4H)、1.71(m,2H)、1.49(m,4H)、1.37(m,4H)
1H−NMR(CD3OD):δ 8.48(d,1H)、7.82(t,1H)、7.42(d,1H)、7.30(m,1H)、4.44(s,2H)、4.17(m,1H)、4.10(t,2H)、3.73(m,4H)、3.16(t,2H)、2.8−2.4(m,8H)、1.9−1.25(m,17H)、1.21(m,1H)
1H−NMR(CD3OD):δ 8.49(d,1H)、8.43(dd,1H)、7.79(dt,1H)、7.41(m,1H)、4.37(s,2H)、4.20(bs,2H)、4.04(m,1H)、3.70(t,4H)、3.21(bs,2H)、3.16(t,2H)、2.65(t,2H)、2.54(t,4H)、2.0−1.3(m,16H)
1H−NMR(CD3OD):δ 8.49(d,1H)、8.43(dd,1H)、7.79(dt,1H)、7.42(m,1H)、4.37(s,2H)、3.71(m,4H)、3.65(m,1H)、3.23(m,2H)、3.15(t,2H)、3.01(m,2H)、2.47(m,4H)、2.38(t,4H)、2.0−1.3(m,22H)
MS[M+H]+=540.3;[M−H+HCOOH]−=584.5
1H−NMR(CD3OD):8.49(d,1H)、8.43(dd,1H)、7.79(dt,1H)、7.42(m,1H)、4.37(s,2H)、4.24(m,1H)、4.20(m,2H)、3.71(t,4H)、3.15(t,2H)、3.07(t,2H)、2.70(t,2H)、2.57(t,4H)、2.41(m,2H)、2.15(m,2H)、1.84(m,2H)、1.74(m,2H)、1.50(m,4H)、1.39(m,2H)
1H−NMR(CD3OD):δ 8.49(d,1H)、8.43(dd,1H)、7.79(dt,1H)、7.42(m,1H)、4.37(s,2H)、4.21(m,1H)、3.71(m,4H)、3.29(m,2H)、3.15(t,2H)、2.97(m,2H)、2.48(m,4H)、2.41(t,2H)、2.21(m,4H)、1.74(m,6H)、1.43(m,6H)
1H−NMR(CD3OD):δ 8.49(d,1H)、8.43(dd,1H)、7.79(dt,1H)、7.42(m,1H)、4.37(s,2H)、3.51(m,1H)、3.17(m,4H)、3.02(m,2H)、2.35(t,2H)、2.26(s,6H)、1.9−1.25(m,19H)、1.18(m,1H)
1H−NMR(CD3OD):δ 8.59(d,1H)、8.30(d,1H)、8.04(bd,1H)、7.42(m,1H)、4.15(m,1H)、4.10(t,2H)、3.73(m,4H)、3.60(m,2H)、2.8−2.4(m,8H)、1.9−1.25(m,17H)、1.20(m,1H)
1H−NMR(CD3OD):δ 8.49(d,1H)、8.43(dd,1H)、7.79(dt,1H)、7.42(m,1H)、4.37(s,2H)、3.70(m,4H)、3.51(m,1H)、3.34(t,2H)、3.14(m,4H)、2.54(m,6H)、1.9−1.25(m,17H)、1.18(m,1H)
1H−NMR(CD3OD):δ 8.35(m,2H)、7.74(m,2H)、4.07(m,1H)、3.70(m,4H)、3.62(t,2H)、3.18(m,2H)、3.05(m,2H)、2.47(m,4H)、2.38(t,2H)、1.95−1.35(m,18H)
1H−NMR(CD3OD):δ 8.55(d,1H)、8.14(dd,1H)、7.96(dt,1H)、7.35(m,1H)、4.15(m,1H)、4.09(t,2H)、3.72(t,4H)、3.23(t,2H)、2.67(t,2H)、2.56(t,4H)、2.51(t,2H)、1.9−1.1(m,18H)
1H−NMR(CD3OD):δ 8.28(m,2H)、7.46(m,2H)、4.07(m,1H)、3.70(m,4H)、3.23(t,2H)、3.18(m,2H)、3.04(m,2H)、2.47(m,4H)、2.38(t,2H)、1.95−1.15(m,18H)
1H−NMR(CD3OD):δ 8.49(d,1H)、8.43(dd,1H)、7.79(dt,1H)、7.41(m,1H)、4.37(s,2H)、3.99(m,2H)、3.14(t,2H)、2.97(m,1H)、1.89(m,2H)、1.8−1.05(m,21H)
1H−NMR(DMSO−d6):δ 8.45(d,1H)、8.42(dd,1H)、7.63(dt,1H)、7.33(m,1H)、7.17(m,4H)、6.37(t,1H)、5.98(t,1H)、4.39(s,2H)、4.19(d,2H)、3.47(t,2H)、3.09(m,2H)、2.97(m,2H)、2.87(t,2H)、1.64(m,2H)、1.34(m,4H)、1.25(m,2H)
1H−NMR(CD3OD):δ 8.49(d,1H)、8.43(dd,1H)、7.79(dt,1H)、7.41(m,1H)、4.37(s,2H)、4.07(m,1H)、3.70(m,4H)、3.17(m,4H)、3.03(m,2H)、2.47(m,4H)、2.38(t,2H)、1.95−1.40(m,16H)
1H−NMR(CD3OD):δ 8.49(d,1H)、8.43(dd,1H)、7.79(dt,1H)、7.41(m,1H)、4.37(s,2H)、4.21(m,1H)、3.71(t,4H)、3.29(m,2H)、3.15(t,2H)、2.97(m,2H)、2.48(t,4H)、2.41(t,2H)、2.20(m,4H)、1.9−1.35(m,10H)
1H−NMR(CD3OD):δ 8.49(d,1H)、8.43(dd,1H)、7.79(dt,1H)、7.42(m,1H)、4.37(s,2H)、4.25(m,1H)、4.20(m,2H)、3.72(t,4H)、3.16(t,2H)、3.07(t,2H)、2.70(t,2H)、2.57(t,4H)、2.41(m,2H)、2.15(m,2H)、2.87(m,2H)、1.75(m,2H)、1.52(m,4H)
1H−NMR(CD3OD):δ 8.49(d,1H)、8.43(dd,1H)、7.79(dt,1H)、7.41(m,1H)、4.37(s,2H)、4.10(m,2H)、3.97(t,2H)、3.37(m,2H)、3.15(t,2H)、1.95−1.25(m,17H)
1H−NMR(CD3OD):δ 8.49(d,1H)、8.43(dd,1H)、7.79(dt,1H)、7.41(m,1H)、4.37(s,2H)、3.64(m,4H)、3.32(m,2H)、3.26(t,2H)、3.15(t,2H)、3.04(m,2H)、2.14(s,3H)、1.79(m,2H)、1.89(m,4H)、1.39(m,2H)
1H−NMR(CD3OD):δ 8.49(d,1H)、8.43(dd,1H)、7.80(dt,1H)、7.42(m,1H)、4.37(s,2H)、4.20(bs,2H)、4.04(m,1H)、3.70(t,4H)、3.17(m,4H)、2.65(t,2H)、2.54(t,4H)、2.0−1.45(m,14H)
1H−NMR(400MHz、DMSO−d6):δ 8.46(d,1H)、8.43(dd,1H)、7.63(dt,1H)、7.33(m,1H)、6.36(t,1H)、5.99(t,1H)、4.21(d,2H)、4.09(t,2H)、3.69−3.61(m,4H)、3.50(m,1H)、3.22(t,2H)、2.99(m,2H)、2.88−2.78(m,2H)、2.76−2.64(m,4H)、1.92−1.81(m,2H)、1.80−1.65(m,4H)、1.63−1.32(m,7H)、1.32−1.19(m,4H)、1.16−1.00(m,1H)
1H−NMR(CD3OD):δ 8.48(d,1H)、8.42(dd,1H)、7.78(dt,1H)、7.41(m,1H)、7.33(m,2H)、7.25(m,2H)、7.12(m,1H)、4.36(s,2H)、3.08(m,4H)、1.77(m,2H)、1.5−1.2(m,6H)
1H−NMR(CD3OD):δ 8.49(d,1H)、8.42(dd,1H)、7.79(dt,1H)、7.40(m,6H)、4.94(s,2H)、4.36(s,2H)、3.15(m,4H)、2.92(s,3H)、1.86(m,2H)、1.49(m,4H)、1.37(m,2H)
1H−NMR(CD3OD):δ 8.49(d,1H)、8.42(dd,1H)、7.79(dt,1H)、7.40(m,6H)、5.06(s,2H)、4.36(s,2H)、3.68(m,4H)、3.40(t,2H)、3.22(t,2H)、3.14(t,2H)、2.53(t,2H)、2.46(t,4H)、1.88(m,2H)、1.51(m,4H)、1.39(m,2H)
1H−NMR(CD3OD):δ 8.49(d,1H)、8.42(dd,1H)、7.78(dt,1H)、7.42(m,5H)、4.36(s,2H)、3.32(s,3H)、3.11(m,4H)、1.76(m,2H)、1.46(m,4H)、1.35(m,2H)
1H−NMR(CD3OD):δ 8.49(d,1H)、8.42(dd,1H)、7.77(m,1H)、7.44(m,5H)、4.36(s,2H)、3.85(m,2H)、3.63(m,4H)、3.14(m,4H)、2.44(m,6H)、1.79(m,2H)、1.47(m,4H)、1.36(m,2H)
1H−NMR(400MHz、DMSO−d6):δ 10.16(bs,1H)、8.53(bs,1H)、8.38(d,2H)、7.67(d,2H)、3.70(bs,4H)、3.51−3.36(m,3H)、3.13(t,2H)、3.02(t,2H)、2.85(bs,4H)、2.73(t,2H)、1.86−1.20(m,19H)、1.15−1.00(m,1H)
1H−NMR(400MHz、DMSO−d6):δ 10.29(bs,1H)、8.63(bs,1H)、8.41(d,2H)、7.75−7.70(m,2H)、4.12(t,2H)、3.94(m,1H)、3.66−3.60(m,4H)、3.48(m,2H)、3.19(t,2H)、2.78(t,2H)、2.65(bs,4H)、1.91−1.80(m,2H)、1.80−1.68(m,4H)、1.68−1.61(m,2H)、1.57(m,2H)、1.52−1.40(m,4H)、1.40−1.29(m,2H)
1H−NMR(400MHz、DMSO−d6):δ 10.52(bs,1H)、8.81(bs,1H)、8.44−8.38(m,2H)、7.76(d,2H)、4.13(t,2H)、3.94(m,1H)、3.66−3.60(m,4H)、3.49(m,2H)、3.21(t,2H)、2.80(t,2H)、2.71−2.62(m,4H)、1.92−1.69(m,6H)、1.69−1.55(m,4H)、1.55−1.40(m,4H)
1H−NMR(400MHz、CDCl3):δ 8.37(d,2H)、7.46(s,1H)、7.34(d,2H)、5.33(t,1H)、4.19(bs,2H)、4.01(m,1H)、3.71(t,4H)、3.28(m,2H)、3.09(bs,2H)、2.63(t,2H)、2.52(t,4H)、1.99−1.63(m,8H)、1.63−1.46(m,6H)
1H−NMR(400MHz、DMSO−d6):δ 10.32(bs,1H)、8.65(bs,1H)、8.41(d,2H)、7.77−7.72(m,2H)、3.81−4.05(m,4H)、3.47(m,2H)、3.29−3.19(m,2H)、1.82−1.43(m,10H)、1.43−1.27(m,4H)、1.22(t,3H)
1H−NMR(400MHz、DMSO−d6):δ 9.76(bs,1H)、8.36(d,2H)、7.57(d,2H)、6.93(t,1H)、4.04−3.88(m,2H)、3.88−3.81(m,2H)、3.29−3.16(m,2H)、3.09(m,2H)、1.81−1.16(m,14H)、1.21(t,3H)
1H−NMR(CD3OD):δ 8.35(m,2H)、7.72(m,2H)、4.62(dt,2H)、3.88(d,2H)、3.60(m,3H)、3.51(t,1H)、3.21(m,2H)、1.91(m,2H)、1.8−1.1(m,15H)、1.05(m,2H)
1H−NMR(CD3OD):δ 8.27(m,2H)、7.46(m,2H)、4.61(dt,2H)、3.88(d,2H)、3.55(dt,2H)、3.21(m,4H)、1.89(m,2H)、1.8−1.1(m,15H)、1.03(m,2H)
1H−NMR(CD3OD):δ 8.49(d,1H)、8.42(dd,1H)、7.79(dt,1H)、7.42(m,1H)、4.62(dt,2H)、4.37(s,2H)、3.88(d,2H)、3.55(dt,2H)、3.17(m,4H)、1.95−1.05(m,19H)
1H−NMR(400MHz、CDCl3):δ 8.38(m,2H)、7.34(m,2H)、7.24(s,1H)、5.11(t,1H)、4.19(bs,2H)、4.01(m,1H)、3.71(t,4H)、3.28(m,2H)、3.09(bs,2H)、2.62(t,2H)、2.51(t,4H)、1.96−1.66(m,8H)、1.60−1.46(m,6H)、1.39(m,2H)
1H−NMR(CD3OD):δ 8.49(d,1H)、8.43(dd,1H)、7.79(dt,1H)、7.42(m,1H)、4.37(s,2H)、4.06(m,1H)、3.70(t,4H)、3.19(m,4H)、3.06(m,2H)、2.47(t,4H)、2.38(t,2H)、2.0−1.5(m,14H)
1H−NMR(CD3OD):δ 8.49(d,1H)、8.43(dd,1H)、7.79(dt,1H)、7.41(m,1H)、4.37(s,2H)、4.19(m,1H)、3.71(t,4H)、3.28(m,2H)、3.18(m,2H)、3.00(m,2H)、2.48(t,4H)、2.40(t,2H)、2.19(m,4H)、1.9−1.5(m,8H)
1H−NMR(CD3OD):δ 8.37(m,2H)、7.73(m,2H)、4.08(m,1H)、3.70(m,6H)、3.17(m,4H)、2.47(t,4H)、2.39(t,2H)、2.0−1.5(m,14H)
1H−NMR(CD3OD):δ 8.36(m,2H)、7.72(m,2H)、4.21(m,1H)、3.70(m,6H)、3.30(t,2H)、3.08(m,2H)、2.48(t,4H)、2.40(t,2H)、2.20(m,4H)、1.82(m,6H)、1.66(m,2H)
1H−NMR(CD3OD):δ 8.43(d,1H)、8.40(dd,1H)、7.75(dt,1H)、7.40(m,1H)、4.07(m,1H)、3.69(m,4H)、3.39(t,2H)、3.17(m,4H)、3.06(m,2H)、2.84(t,2H)、2.46(t,4H)、2.38(t,2H)、2.0−1.5(m,14H)
1H−NMR(CD3OD):δ 8.43(d,1H)、8.40(dd,1H)、7.76(dt,1H)、7.40(m,1H)、4.21(m,1H)、3.70(m,4H)、3.40(t,2H)、3.30(t,2H)、3.14(t,2H)、3.00(m,2H)、2.84(t,2H)、2.47(t,4H)、2.41(t,2H)、2.21(m,4H)、1.9−1.5(m,8H)
1H−NMR(CD3OD):δ 8.49(d,1H)、8.43(dd,1H)、7.79(dt,1H)、7.40(m,1H)、4.37(s,2H)、3.73(t,4H)、3.25(t,4H)、3.15(t,2H)、3.03(m,2H)、1.80(m,2H)、1.55−1.25(m,6H)
1H−NMR(CD3OD):δ 8.49(d,1H)、8.43(dd,1H)、7.79(dt,1H)、7.42(m,1H)、4.37(s,2H)、3.37(m,4H)、3.15(t,4H)、3.03(m,2H)、1.76(m,6H)、1.66(m,4H)、1.6−1.25(m,6H)
1H−NMR(CD3OD):δ 8.49(d,1H)、8.43(dd,1H)、7.79(dt,1H)、7.42(m,1H)、4.37(s,2H)、3.34(m,4H)、3.15(t,4H)、3.06(m,2H)、1.95(m,4H)、1.79(m,2H)、1.6−1.25(m,6H)
1H−NMR(CD3OD):δ 8.35(m,2H)、7.73(m,2H)、3.62(t,2H)、3.24(m,4H)、3.01(m,2H)、1.82(m,2H)、1.8−1.35(m,12H)
1H−NMR(CD3OD):δ 8.35(m,2H)、7.72(m,2H)、4.11(t,2H)、3.62(t,2H)、3.37(t,2H)、3.22(m,2H)、1.88(m,4H)、1.71(m,4H)、1.52(m,4H)
A2780細胞を、100μlの培地中、3x103個の細胞/ウェルで96−ウェルに播種し、8ウェルを対照だけの培地で空のままとした。
%活性=[(Sc−B)/(So−B)]x100
ここで、Scは試験化合物の存在下で測定されたシグナルを意味し、Soは化合物の不在下で検出されたシグナルを意味し、Bは培地だけを含むブランクウェルにて測定されたバックグラウンドシグナルを意味する。GraphPad Prismを用いてデータを解析した。
Claims (10)
- 式(I)
[式中
Xは=Oおよび=Sより選択され;
Aは−C(=O)−および−S(=O)2 −より選択され;
Bは、−O−、−(CH2)3−6−、および−O−(CH2)2−5−より選択され;
Dは単結合、−O−および−NR9より選択され、ここでR 9は、独立して、水素、置換されていてもよいC1−12−アルキル、置換されていてもよいC1−12−アルケニル、置換されていてもよいアリール、置換されていてもよいヘテロシクリル、および置換されていてもよいヘテロアリールより選択され;
mは2−8の整数であり、nは0であり;
pは0−2の整数であり;
R1は置換されていてもよいヘテロアリールより選択され;
R2は水素、置換されていてもよいC3−12−シクロアルキル、−[CH2CH2O]1−10−(置換されていてもよいC1−6−アルキル)、−(CH 2 ) 0−2 −(置換されていてもよいアリール)、−(CH 2 ) 0−2 −(置換されていてもよいヘテロアリール)および−(CH 2 ) 0−2 −(置換されていてもよいヘテロシクリル)より選択され;
R3は、置換されていてもよいC3−12−シクロアルキル、−[CH2CH2O]1−10−(置換されていてもよいC1−6−アルキル)、置換されていてもよいC 2−12−アルケニル、置換されていてもよいアリール、置換されていてもよいヘテロシクリル、および置換されていてもよいヘテロアリールより選択され;
R 4 は、水素、置換されていてもよいC 3−12 −シクロアルキル、−(CH 2 ) 0−2 −(置換されていてもよいアリール)、−(CH 2 ) 0−2 −(置換されていてもよいヘテロアリール)および−(CH 2 ) 0−2 −(置換されていてもよいヘテロシクリル)より選択され;および
R 4* は水素である;
ただし、pが0の場合、R1は置換されていてもよいチアゾール−2−イル以外の基である]
で示される化合物またはその医薬上許容される塩。 - Bが−O−である、請求項1記載の化合物。
- Dが単結合である、請求項1または2に記載の化合物。
- R1が置換されていてもよいピリジン−4−イル、置換されていてもよいピリミジン−4−イル、置換されていてもよい1,2,4−トリアジン−3−イル、置換されていてもよいイソキサゾール−4−イル、置換されていてもよいピラジン−2−イル、および置換されていてもよいピコリルより選択される、請求項1−3のいずれか一項に記載の化合物。
- 請求項1−5のいずれか一項に記載の化合物を含む、医薬。
- 癌の治療用の医薬として用いるための、請求項6記載の医薬。
- 癌が、卵巣癌である、請求項7記載の医薬。
- 哺乳動物におけるニコチンアミドホスホリボシルトランスフェラーゼ(NAMPRT)の酵素活性を阻害するための、請求項6記載の医薬。
- 化合物がDNA損傷物質と組み合わせて投与される、請求項9記載の医薬。
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US20060258562A1 (en) * | 2000-07-31 | 2006-11-16 | Healor Ltd. | Methods and pharmaceutical compositions for healing wounds |
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NZ600583A (en) * | 2009-02-24 | 2013-08-30 | Healor Ltd | Visfatin therapeutic agents for the treatment of acne and other conditions |
JP2012533530A (ja) | 2009-07-17 | 2012-12-27 | トポターゲット・アクティーゼルスカブ | ニコチンアミドホスホリボシルトランスフェラーゼ阻害剤による癌治療の副作用の重症度を低下させるためのニコチン酸またはその前駆体もしくはプロドラッグ投与の有効性を予測するための方法 |
US8912184B1 (en) | 2010-03-01 | 2014-12-16 | Alzheimer's Institute Of America, Inc. | Therapeutic and diagnostic methods |
KR20130044382A (ko) * | 2010-03-01 | 2013-05-02 | 마이렉시스 인코포레이티드 | 화합물 및 그의 치료 용도 |
GB201006961D0 (en) * | 2010-04-27 | 2010-06-09 | Babraham Inst | NMN modulator |
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JP2012500831A (ja) | 2012-01-12 |
CA2735373A1 (en) | 2010-03-04 |
WO2010023307A1 (en) | 2010-03-04 |
MX2011002240A (es) | 2011-04-05 |
AU2009286604A1 (en) | 2010-03-04 |
US8871747B2 (en) | 2014-10-28 |
US20120010172A1 (en) | 2012-01-12 |
AU2009286604B2 (en) | 2015-05-28 |
CN102186822A (zh) | 2011-09-14 |
US20140357599A1 (en) | 2014-12-04 |
EP2342181A1 (en) | 2011-07-13 |
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