JP2007528383A - ピロロベンゾジアゼピン - Google Patents
ピロロベンゾジアゼピン Download PDFInfo
- Publication number
- JP2007528383A JP2007528383A JP2007502398A JP2007502398A JP2007528383A JP 2007528383 A JP2007528383 A JP 2007528383A JP 2007502398 A JP2007502398 A JP 2007502398A JP 2007502398 A JP2007502398 A JP 2007502398A JP 2007528383 A JP2007528383 A JP 2007528383A
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- Prior art keywords
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- compound
- acid
- alkyl group
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- Prior art date
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- YUOCYTRGANSSRY-UHFFFAOYSA-N pyrrolo[2,3-i][1,2]benzodiazepine Chemical compound C1=CN=NC2=C3C=CN=C3C=CC2=C1 YUOCYTRGANSSRY-UHFFFAOYSA-N 0.000 title description 13
- 150000003839 salts Chemical class 0.000 claims abstract description 25
- 239000012453 solvate Substances 0.000 claims abstract description 23
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims abstract description 13
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims description 70
- -1 Teoc Chemical compound 0.000 claims description 55
- 238000000034 method Methods 0.000 claims description 24
- 238000011282 treatment Methods 0.000 claims description 17
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 15
- 208000015181 infectious disease Diseases 0.000 claims description 14
- 241000894006 Bacteria Species 0.000 claims description 13
- 201000010099 disease Diseases 0.000 claims description 13
- 108090000623 proteins and genes Proteins 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 7
- 230000002062 proliferating effect Effects 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 claims description 2
- LJCZNYWLQZZIOS-UHFFFAOYSA-N 2,2,2-trichlorethoxycarbonyl chloride Chemical compound ClC(=O)OCC(Cl)(Cl)Cl LJCZNYWLQZZIOS-UHFFFAOYSA-N 0.000 claims description 2
- GDIHDSKOVXEJQQ-UHFFFAOYSA-N NC(O)=O.NC(O)=O.NC(O)=O.N Chemical group NC(O)=O.NC(O)=O.NC(O)=O.N GDIHDSKOVXEJQQ-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 206010041925 Staphylococcal infections Diseases 0.000 claims 1
- 208000015688 methicillin-resistant staphylococcus aureus infectious disease Diseases 0.000 claims 1
- 230000002194 synthesizing effect Effects 0.000 claims 1
- 125000006701 (C1-C7) alkyl group Chemical group 0.000 description 69
- 125000003118 aryl group Chemical group 0.000 description 50
- 125000000623 heterocyclic group Chemical group 0.000 description 43
- 230000001580 bacterial effect Effects 0.000 description 24
- 125000006413 ring segment Chemical group 0.000 description 17
- 125000003277 amino group Chemical group 0.000 description 16
- 229910052739 hydrogen Inorganic materials 0.000 description 16
- 125000001424 substituent group Chemical group 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 15
- 239000003242 anti bacterial agent Substances 0.000 description 15
- 229940088710 antibiotic agent Drugs 0.000 description 15
- 125000000217 alkyl group Chemical group 0.000 description 13
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 13
- 239000000243 solution Substances 0.000 description 13
- 239000001257 hydrogen Substances 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 11
- 229940125904 compound 1 Drugs 0.000 description 11
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 11
- 239000011734 sodium Substances 0.000 description 11
- 210000004027 cell Anatomy 0.000 description 9
- 239000000523 sample Substances 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 239000002253 acid Substances 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical compound OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 238000010790 dilution Methods 0.000 description 6
- 239000012895 dilution Substances 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 230000012010 growth Effects 0.000 description 6
- 238000004809 thin layer chromatography Methods 0.000 description 6
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 5
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- 229930194542 Keto Natural products 0.000 description 5
- 125000004432 carbon atom Chemical group C* 0.000 description 5
- 150000001768 cations Chemical class 0.000 description 5
- 125000004122 cyclic group Chemical group 0.000 description 5
- 239000000539 dimer Substances 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 238000010265 fast atom bombardment Methods 0.000 description 5
- 238000003818 flash chromatography Methods 0.000 description 5
- 125000005842 heteroatom Chemical group 0.000 description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 5
- 125000000468 ketone group Chemical group 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 125000006239 protecting group Chemical group 0.000 description 5
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical compound C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 description 5
- VXGWBAFIEDRDFB-XEENAYFCSA-N (6as,8z)-7-[5-[[(6as,8z)-8-ethylidene-2-methoxy-11-oxo-7,9-dihydro-6ah-pyrrolo[2,1-c][1,4]benzodiazepin-7-yl]oxy]pentoxy]-8-ethylidene-2-methoxy-7,9-dihydro-6ah-pyrrolo[2,1-c][1,4]benzodiazepin-11-one Chemical compound C([C@H]12)=NC3=CC=C(OC)C=C3C(=O)N1C\C(=C\C)C2OCCCCCOC\1[C@@H]2C=NC3=CC=C(OC)C=C3C(=O)N2CC/1=C/C VXGWBAFIEDRDFB-XEENAYFCSA-N 0.000 description 4
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 241000790917 Dioxys <bee> Species 0.000 description 4
- 206010028980 Neoplasm Diseases 0.000 description 4
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 108010059993 Vancomycin Proteins 0.000 description 4
- 125000003342 alkenyl group Chemical group 0.000 description 4
- 125000000304 alkynyl group Chemical group 0.000 description 4
- 150000001409 amidines Chemical class 0.000 description 4
- 125000000129 anionic group Chemical group 0.000 description 4
- 230000000844 anti-bacterial effect Effects 0.000 description 4
- 238000003556 assay Methods 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 238000009826 distribution Methods 0.000 description 4
- 235000019439 ethyl acetate Nutrition 0.000 description 4
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 4
- 239000000499 gel Substances 0.000 description 4
- FVIZARNDLVOMSU-UHFFFAOYSA-N ginsenoside K Natural products C1CC(C2(CCC3C(C)(C)C(O)CCC3(C)C2CC2O)C)(C)C2C1C(C)(CCC=C(C)C)OC1OC(CO)C(O)C(O)C1O FVIZARNDLVOMSU-UHFFFAOYSA-N 0.000 description 4
- 150000002466 imines Chemical class 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- PQNFLJBBNBOBRQ-UHFFFAOYSA-N indane Chemical compound C1=CC=C2CCCC2=C1 PQNFLJBBNBOBRQ-UHFFFAOYSA-N 0.000 description 4
- 238000004949 mass spectrometry Methods 0.000 description 4
- XMYQHJDBLRZMLW-UHFFFAOYSA-N methanolamine Chemical compound NCO XMYQHJDBLRZMLW-UHFFFAOYSA-N 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 125000000449 nitro group Chemical class [O-][N+](*)=O 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 230000003287 optical effect Effects 0.000 description 4
- 230000003647 oxidation Effects 0.000 description 4
- 238000007254 oxidation reaction Methods 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 229960003165 vancomycin Drugs 0.000 description 4
- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 description 4
- MYPYJXKWCTUITO-LYRMYLQWSA-O vancomycin(1+) Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C([O-])=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)[NH2+]C)[C@H]1C[C@](C)([NH3+])[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-O 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 3
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 3
- 208000035473 Communicable disease Diseases 0.000 description 3
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 241000192125 Firmicutes Species 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- LFTLOKWAGJYHHR-UHFFFAOYSA-N N-methylmorpholine N-oxide Chemical compound CN1(=O)CCOCC1 LFTLOKWAGJYHHR-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 241000191967 Staphylococcus aureus Species 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 150000001241 acetals Chemical class 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 125000002252 acyl group Chemical group 0.000 description 3
- 125000003545 alkoxy group Chemical group 0.000 description 3
- 125000003368 amide group Chemical group 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 3
- 208000022362 bacterial infectious disease Diseases 0.000 description 3
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 3
- 150000001721 carbon Chemical group 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 125000002091 cationic group Chemical group 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
- 125000004093 cyano group Chemical group *C#N 0.000 description 3
- 125000000753 cycloalkyl group Chemical group 0.000 description 3
- 239000002274 desiccant Substances 0.000 description 3
- 150000002009 diols Chemical class 0.000 description 3
- 150000002085 enols Chemical class 0.000 description 3
- 125000004185 ester group Chemical group 0.000 description 3
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000011521 glass Substances 0.000 description 3
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 3
- 125000001072 heteroaryl group Chemical group 0.000 description 3
- DOUHZFSGSXMPIE-UHFFFAOYSA-N hydroxidooxidosulfur(.) Chemical compound [O]SO DOUHZFSGSXMPIE-UHFFFAOYSA-N 0.000 description 3
- 125000001841 imino group Chemical group [H]N=* 0.000 description 3
- 150000002576 ketones Chemical class 0.000 description 3
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methylcyclopentane Chemical compound CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 description 3
- 125000002950 monocyclic group Chemical group 0.000 description 3
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 3
- 239000012299 nitrogen atmosphere Substances 0.000 description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 235000019198 oils Nutrition 0.000 description 3
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 3
- 150000008300 phosphoramidites Chemical class 0.000 description 3
- XSCHRSMBECNVNS-UHFFFAOYSA-N quinoxaline Chemical compound N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- 150000003573 thiols Chemical class 0.000 description 3
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 description 2
- GHOKWGTUZJEAQD-ZETCQYMHSA-N (D)-(+)-Pantothenic acid Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-ZETCQYMHSA-N 0.000 description 2
- UQVNRKBFAXNOGA-OHLDGCSVSA-N (Z)-tomaymycin Chemical compound CO[C@H]1NC2=CC(O)=C(OC)C=C2C(=O)N2C\C(=C/C)C[C@@H]12 UQVNRKBFAXNOGA-OHLDGCSVSA-N 0.000 description 2
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical compound C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 description 2
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 2
- CTMHWPIWNRWQEG-UHFFFAOYSA-N 1-methylcyclohexene Chemical compound CC1=CCCCC1 CTMHWPIWNRWQEG-UHFFFAOYSA-N 0.000 description 2
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Chemical compound C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 2
- VEPOHXYIFQMVHW-XOZOLZJESA-N 2,3-dihydroxybutanedioic acid (2S,3S)-3,4-dimethyl-2-phenylmorpholine Chemical compound OC(C(O)C(O)=O)C(O)=O.C[C@H]1[C@@H](OCCN1C)c1ccccc1 VEPOHXYIFQMVHW-XOZOLZJESA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 2
- JZIBVTUXIVIFGC-UHFFFAOYSA-N 2H-pyrrole Chemical compound C1C=CC=N1 JZIBVTUXIVIFGC-UHFFFAOYSA-N 0.000 description 2
- JVQIKJMSUIMUDI-UHFFFAOYSA-N 3-pyrroline Chemical compound C1NCC=C1 JVQIKJMSUIMUDI-UHFFFAOYSA-N 0.000 description 2
- HVBSAKJJOYLTQU-UHFFFAOYSA-N 4-aminobenzenesulfonic acid Chemical compound NC1=CC=C(S(O)(=O)=O)C=C1 HVBSAKJJOYLTQU-UHFFFAOYSA-N 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- UJOBWOGCFQCDNV-UHFFFAOYSA-N 9H-carbazole Chemical compound C1=CC=C2C3=CC=CC=C3NC2=C1 UJOBWOGCFQCDNV-UHFFFAOYSA-N 0.000 description 2
- 229920001817 Agar Polymers 0.000 description 2
- 208000035143 Bacterial infection Diseases 0.000 description 2
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- 230000000970 DNA cross-linking effect Effects 0.000 description 2
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 2
- 235000009161 Espostoa lanata Nutrition 0.000 description 2
- 240000001624 Espostoa lanata Species 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- 206010061598 Immunodeficiency Diseases 0.000 description 2
- 241000186779 Listeria monocytogenes Species 0.000 description 2
- 229930184247 Mazethramycin Natural products 0.000 description 2
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- 125000000213 sulfino group Chemical group [H]OS(*)=O 0.000 description 1
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 1
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 description 1
- 125000000565 sulfonamide group Chemical group 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 125000001174 sulfone group Chemical group 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
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- 208000024891 symptom Diseases 0.000 description 1
- 229940020707 synercid Drugs 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
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- 235000015523 tannic acid Nutrition 0.000 description 1
- 229940033123 tannic acid Drugs 0.000 description 1
- 229920002258 tannic acid Polymers 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 125000003666 tauryl group Chemical group [H]N([H])C([H])([H])C([H])([H])S(*)(=O)=O 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 201000003120 testicular cancer Diseases 0.000 description 1
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 1
- IFLREYGFSNHWGE-UHFFFAOYSA-N tetracene Chemical compound C1=CC=CC2=CC3=CC4=CC=CC=C4C=C3C=C21 IFLREYGFSNHWGE-UHFFFAOYSA-N 0.000 description 1
- KHVCOYGKHDJPBZ-WDCZJNDASA-N tetrahydrooxazine Chemical compound OC[C@H]1ONC[C@@H](O)[C@@H]1O KHVCOYGKHDJPBZ-WDCZJNDASA-N 0.000 description 1
- OSBSFAARYOCBHB-UHFFFAOYSA-N tetrapropylammonium Chemical compound CCC[N+](CCC)(CCC)CCC OSBSFAARYOCBHB-UHFFFAOYSA-N 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- GVIJJXMXTUZIOD-UHFFFAOYSA-N thianthrene Chemical compound C1=CC=C2SC3=CC=CC=C3SC2=C1 GVIJJXMXTUZIOD-UHFFFAOYSA-N 0.000 description 1
- CBDKQYKMCICBOF-UHFFFAOYSA-N thiazoline Chemical compound C1CN=CS1 CBDKQYKMCICBOF-UHFFFAOYSA-N 0.000 description 1
- JWCVYQRPINPYQJ-UHFFFAOYSA-N thiepane Chemical compound C1CCCSCC1 JWCVYQRPINPYQJ-UHFFFAOYSA-N 0.000 description 1
- XSROQCDVUIHRSI-UHFFFAOYSA-N thietane Chemical compound C1CSC1 XSROQCDVUIHRSI-UHFFFAOYSA-N 0.000 description 1
- VOVUARRWDCVURC-UHFFFAOYSA-N thiirane Chemical compound C1CS1 VOVUARRWDCVURC-UHFFFAOYSA-N 0.000 description 1
- 125000005300 thiocarboxy group Chemical group C(=S)(O)* 0.000 description 1
- 150000003566 thiocarboxylic acids Chemical class 0.000 description 1
- 125000005031 thiocyano group Chemical group S(C#N)* 0.000 description 1
- BQAJJINKFRRSFO-UHFFFAOYSA-N thiolane Chemical compound C1CCSC1.C1CCSC1 BQAJJINKFRRSFO-UHFFFAOYSA-N 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- 125000005505 thiomorpholino group Chemical group 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 229940113082 thymine Drugs 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- 238000006257 total synthesis reaction Methods 0.000 description 1
- PMMYEEVYMWASQN-IMJSIDKUSA-N trans-4-Hydroxy-L-proline Natural products O[C@@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-IMJSIDKUSA-N 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 150000004684 trihydrates Chemical class 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 229940035893 uracil Drugs 0.000 description 1
- 210000000626 ureter Anatomy 0.000 description 1
- 210000003932 urinary bladder Anatomy 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 229940005605 valeric acid Drugs 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
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- 230000009385 viral infection Effects 0.000 description 1
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- NLIVDORGVGAOOJ-MAHBNPEESA-M xylene cyanol Chemical compound [Na+].C1=C(C)C(NCC)=CC=C1C(\C=1C(=CC(OS([O-])=O)=CC=1)OS([O-])=O)=C\1C=C(C)\C(=[NH+]/CC)\C=C/1 NLIVDORGVGAOOJ-MAHBNPEESA-M 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
Description
いくつかのピロロベンゾジアゼピン(PBD)はDNAの特定の配列を認識してこれに結合する能力を有する。好ましい配列はPuGPuである。最初のPBD抗腫瘍性抗生物質であるアンスラ
マイシン(anthramycin)は、1965年に発見された (Leimgruberら、J. Am. Chem. Soc., 87, 5793-5795 (1965); Leimgruberら、J. Am. Chem. Soc., 87, 5791-5793 (1965))。それ以来、数多くの天然のPBDが報告され、また、さまざまな類似体を合成するための10種以上の合成系路が開発されてきた(Thurstonら、Chem. Rev. 1994, 433-465 (1994))。ファミリーのメンバーには、アベイマイシン(abbeymycin) (Hochlowskiら、J. Antibiotics, 40, 145-148 (1987))、チカマイシン(chicamycin) (Konishiら、J. Antibiotics, 37, 200-206 (1984)), DC-81 (日本国特許58-180 487; Thurstonら、Chem. Brit., 26, 767-772 (1990); Boseら、Tetrahedron, 48, 751-758 (1992))、マゼスラマイシン(mazethramycin) (Kuminotoら、J. Antibiotics, 33, 665-667 (1980))、ネオスラマイシン(neothramycin) AおよびB (Takeuchiら、J. Antibiotics, 29, 93-96 (1976))、ポロスラマイシン(porothramycin) (Tsunakawaら、J. Antibiotics, 41, 1366-1373 (1988))、プロスラカルシン(prothracarcin) (Shimizuら、J. Antibiotics, 29, 2492-2503 (1982); LangleyおよびThurston, J. Org. Chem., 52, 91-97 (1987))、シバノマイシン(sibanomicin) (DC-102) (Haraら、J. Antibiotics, 41, 702-704 (1988); Itohら、J. Antibiotics, 41, 1281-1284 (1988))、シビロマイシン(sibiromycin) (Leberら、J. Am. Chem. Soc
., 110, 2992-2993 (1988))およびトママイシン(tomamycin) (Arimaら、J. Antibiotics, 25, 437-444 (1972))が含まれる。PBDは下記の一般構造:
感染性疾患は世界的に死亡および疾病の主要な原因となっている。ペニシリンおよび他の抗生物質の導入以後、我々の幅広い細菌感染を効果的に治療する能力は劇的に向上したが、感染性疾患を制圧し続けるための努力に対する重大な脅威として多剤耐性が出現した。
R10は、窒素保護基であり、R11はOHまたはO-R12のいずれかであり、ここで、R12は、酸素保護基であり、またはR10およびR11は一緒になってN10とC11の間に二重結合を形成し;
R10’およびR11’はそれぞれR10およびR11と同じ選択肢から選択される]
の化合物ならびにその塩および溶媒和物を含む。
酸素保護基は当業者に公知である。多くの好適な基がGreene, T.W.およびWuts, G.M., 「有機合成における保護基」(Protective Groups in Organic Synthesis)、第3版、John Wiley & Sons, Inc., 1999の23〜200ページに記載されており、この文献を参照により本明細書に組み入れる。
本明細書において「場合により置換された」という表現は、置換されていないまたは置換された親基を意味する。
飽和単環式炭化水素化合物:
シクロプロパン(C3)、シクロブタン(C4)、シクロペンタン(C5)、シクロヘキサン(C6)、シクロヘプタン(C7)、メチルシクロプロパン(C4)、ジメチルシクロプロパン(C5)、メチルシクロブタン(C5)、ジメチルシクロブタン(C6)、メチルシクロペンタン(C6)、ジメチルシクロペンタン(C7)、およびメチルシクロヘキサン(C7);
不飽和単環式炭化水素化合物:
シクロプロペン(C3)、シクロブテン(C4)、シクロペンテン(C5)、シクロヘキセン(C6)、メチルシクロプロペン(C4)、ジメチルシクロプロペン(C5)、メチルシクロブテン(C5)、ジメチルシクロブテン(C6)、メチルシクロペンテン(C6)、ジメチルシクロペンテン(C7)、およびメチルシクロヘキセン(C7);および
飽和多環式炭化水素化合物:
ノルカラン(C7)、ノルピナン(C7)、ノルボルナン(C7)。
N1:アジリジン(C3)、アゼチジン(C4)、ピロリジン(テトラヒドロピロール)(C5)、ピロリン(たとえば、3-ピロリン、2,5-ジヒドロピロール)(C5)、2H-ピロールまたは3H-ピロール(イソピロール、イソアゾール)(C5)、ピペリジン(C6)、ジヒドロピリジン(C6)、テトラヒドロピリジン(C6)、アゼピン(C7);
O1:オキシラン(C3)、オキセタン(C4)、オキソラン(テトラヒドロフラン)(C5)、オキソール(ジヒドロフラン)(C5)、オキサン(テトラヒドロピラン)(C6)、ジヒドロピラン(C6)、ピラン(C6)、オキセピン(C7);
S1:チイラン(C3)、チエタン(C4)、チオラン(テトラヒドロチオフェン)(C5)、チアン(テトラヒドロチオピラン)(C6)、チエパン(C7);
O2:ジオキソラン(C5)、ジオキサン(C6)、およびジオキセパン(C7);
O3:トリオキサン(C6);
N2:イミダゾリジン(C5)、ピラゾリジン(ジアゾリジン)(C5)、イミダゾリン(C5)、ピラゾリン(ジヒドロピラゾール)(C5)、ピペラジン(C6);
N1O1:テトラヒドロオキサゾール(C5)、ジヒドロオキサゾール(C5)、テトラヒドロイソキサゾール(C5)、ジヒドロイソキサゾール(C5)、モルホリン(C6)、テトラヒドロオキサジン(C6)、ジヒドロオキサジン(C6)、オキサジン(C6);
N1S1:チアゾリン(C5)、チアゾリジン(C5)、チオモルホリン(C6);
N2O1:オキサジアジン(C6);
O1S1:オキサチオール(C5)およびオキサチアン(チオキサン)(C6);および
N1O1S1:オキサチアジン(C6)。
N1:ピロール(アゾール)(C5)、ピリジン(アジン)(C6);
O1:フラン(オキソール)(C5);
S1:チオフェン(チオール)(C5);
N1O1:オキサゾール(C5)、イソキサゾール(C5)、イソキサジン(C6);
N2O1:オキサジアゾール(フラザン)(C5);
N3O1:オキサトリアゾール(C5);
N1S1:チアゾール(C5)、イソチアゾール(C5);
N2:イミダゾール(1,3-ジアゾール)(C5)、ピラゾール(1,2-ジアゾール)(C5)、ピリダジン(1,2-ジアジン)(C6)、ピリミジン(1,3-ジアジン)(C6)(たとえば、シトシン、チミン、ウラシル)、ピラジン(1,4-ジアジン)(C6);
N3:トリアゾール(C5)、トリアジン(C6);および
N4:テトラゾール(C5)。
ベンゾフラン(O1)、イソベンゾフラン(O1)、インドール(N1)、イソインドール(N1)、インドリジン(N1)、インドリン(N1)、イソインドリン(N1)、プリン(N4)(たとえば、アデニン、グアニン)、ベンズイミダゾール(N2)、インダゾール(N2)、ベンズオキサゾール(N1O1)、ベンズイソキサゾール(N1O1)、ベンゾジオキソール(O2)、ベンゾフラザン(N2O1)、ベンゾトリアゾール(N3)、ベンゾチオフラン(S1)、ベンゾチアゾール(N1S1)、ベンゾチアジアゾール(N2S)から誘導されるC9(2個の縮合環を含む);
クロメン(O1)、イソクロメン(O1)、クロマン(O1)、イソクロマン(O1)、ベンゾジオキサン(O2)、キノリン(N1)、イソキノリン(N1)、キノリジン(N1)、ベンズオキサジン(N1O1)、ベンゾジアジン(N2)、ピリドピリジン(N2)、キノキサリン(N2)、キナゾリン(N2)、シンノリン(N2)、フタラジン(N2)、ナフチリジン(N2)、プテリジン(N4)から誘導されるC10(2個の縮合環を含む);
ベンゾジアゼピン(N2)から誘導されるC11(2個の縮合環を含む);
カルバゾール(N1)、ジベンゾフラン(O1)、ジベンゾチオフェン(S1)、カルボリン(N2)、ペリミジン(N2)、ピリドインドール(N2)から誘導されるC13(3個の縮合環を含む);および、
アクリジン(N1)、キサンテン(O1)、チオキサンテン(S1)、オキサントレン(O2)、フェノキサチイン(O1S1)、フェナジン(N2)、フェノキサジン(N1O1)、フェノチアジン(N1S1)、チアントレン(S2)、フェナントリジン(N1)、フェナントロリン(N2)、フェナジン(N2)から誘導されるC14(3個の縮合環を含む)。
ハロ:-F、-Cl、-Br、およびI。
ヒドロキシ:-OH。
チオン(チオケトン):=S。
アシル(ケト):-C(=O)R [式中、Rはアシル置換基、たとえば、C1-7アルキル基(C1-7アルキルアシルまたはC1-7アルカノイルとも呼ぶ)、C3-20ヘテロシクリル基(C3-20ヘテロシクリルアシルとも呼ぶ)、またはC5-20アリール基(C5-20アリールアシルとも呼ぶ)、好ましくはC1-7アルキル基である]。アシル基の例には、これらに限定されないが、-C(=O)CH3(アセチル)、-C(=O)CH2CH3(プロピオニル)、-C(=O)C(CH3)3(t-ブチリル)、および-C(=O)Ph(ベンゾイル、フェノン)が含まれる。
チオカルボキシ(チオカルボン酸):-C(=S)SH。
チオロカルボキシ(チオロカルボン酸):-C(=O)SH。
チオノカルボキシ(チオノカルボン酸):-C(=S)OH。
イミド酸:-C(=NH)OH。
ヒドロキサム酸:-C(=NOH)OH。
グアニジノ:-NH-C(=NH)NH2。
ニトロソ:-NO。
アジド:-N3。
シアノ(ニトリル、カルボニトリル):-CN。
イソシアノ:-NC。
シアネート:-OCN。
イソシアネート:-NCO。
チオシアノ(チオシアネート):-SCN。
イソチオシアノ(イソチオシアネート):-NCS。
スルフヒドリル(チオール、メルカプト):-SH。
スルホン酸(スルホ):-S(=O)2OH、-SO3H。
ホスホ:-P(=O)2。
ホスホン酸(ホスホノ):-P(=O)(OH)2。
リン酸(ホスホノオキシ):-OP(=O)(OH)2。
亜リン酸:-OP(OH)2。
遺伝子に基づく病気には、好ましくは増殖性疾患が含まれ、また、アルツハイマー病および細菌、寄生虫およびウイルス感染も含まれる。遺伝子発現の調節により治療することができる状態はすべて本発明の化合物により治療することができる。
当業者は、候補の化合物がある特定の細胞型に対する増殖性の状態を治療することができるか否かを、容易に決定することができる。たとえば、特定の化合物が示す活性を定量するために便利に使用することができるアッセイが、下記の実施例に記載されている。
グラム陽性菌については上で論じた。メチシリン耐性黄色ブドウ球菌(MRSA)およびバンコマイシン耐性腸球菌(VRE)の治療が特に興味深いが、化膿連鎖球菌(Streptococcus pyogenes)、ストレプトコッカス・アガラクティエ(Streptococcus agalactiae)およびリステリア菌(Listeria monocytogenes)などの他のグラム陽性菌による感染症の治療もまた興味深い。
上記のように、本発明は式Iの化合物の治療の方法への使用を提供する。好ましくは、治療に使用するための式Iの化合物は、2個のN10-C11イミン結合を有するか、またはN10がin vivoで除去することができる窒素保護基(R10、R10’)により保護されており、C11の置換基(R11、R11’)がOHである。また、治療を必要とする被験体に治療上有効な量の式Iの化合物を、好ましくは本発明の第3の態様である医薬組成物の形で投与することを含む治療の方法が提供される。治療上有効な量という用語は、患者に利益を与えるのに十分な量である。上記の利益は、少なくとも1つの症状の少なくとも改善である。投与される実際の量、ならびに投与の速度および時間経過は治療されるものの性質および重篤度に依存する。治療の処方、たとえば投与量の決定は、医師の責任の範囲内である。
他に特定しない限り、上記化合物にはこれらの置換基の公知のイオン、塩、溶媒和物、および保護された形が含まれる。たとえば、カルボン酸(-COOH)と記載された場合、それらのアニオン(カルボキシレート)型(-COO-)、塩または溶媒和物、ならびに慣用の保護された形も含まれる。同様に、アミノ基という記載には、アミノ基のプロトン化型(-N+HR1R2)、塩または溶媒和物、たとえば塩酸塩、ならびにアミノ基の慣用の保護された形が含まれる。同様に、ヒドロキシル基という記載には、そのアニオン型(-O-)、塩または溶媒和物、ならびに慣用の保護された形も含まれる。
ある種の化合物は1個以上の特定の幾何異性体、光学異性体、鏡像異性体、ジアステレオマー、エピマー、アトロピック(atropic)異性体、立体異性体、互変異性体、配座異性体、またはアノマー型として存在し得る。上記の異性体には、これらに限定されないが、シスおよびトランス型;EおよびZ型;c、tおよびr型;endoおよびexo型、R、S、およびmeso型、;DおよびL型;dおよびl型;(+)および(-)型;ケト、エノール、およびエノレート型;synおよびanti型;シンクリナルおよびアンチクリナル型;αおよびβ型;アキシアルおよびエクアトリアル型;舟、いす、ねじれ、エンベロープ、および半いす型;およびそれらの組合せが含まれ、これ以後、集合的に「異性体」(または異性体型)と呼ぶ。
と表される。
これらの形は、PBDのカルビノールアミンおよびカルビノールアミンエーテル型と呼ぶことができる。これらの平衡のバランスは化合物がおかれた状態、および基そのものの性質に依存する。
式Iの化合物は、WO 00/12508に記載されたものと同様の2つの別経路により作ることができる。重要な段階はC2-exo二重結合の形成である。これは、WO 00/12508のスキーム8および9に記載された方法により進行する。
R10およびR11が一緒になってN10およびC11の間に二重結合を形成するのが好ましい。
反応の進行は、ガラスプレート上の蛍光指示薬を含むGF254シリカゲルを用いた薄層クロマトグラフィー(TLC)によりモニターした。TLCプレートの可視化は、他に記載されていない場合にはUV光およびI2蒸気によりおこなった。フラッシュクロマトグラフィーはシリカゲル(J.T Baker 30-60μmの14 cmカラム)を用いておこなった。反応溶媒の大部分は、以下の通りの乾燥剤を使用した後,窒素雰囲気下で蒸留することにより精製し、すぐに使用した。乾燥剤:CH2Cl2およびMeCN (CaH2)、テトラヒドロフランおよびトルエン(ベンゾフェノンケチルナトリウム)、およびMeOH(マグネシウム片および触媒のヨウ素)。抽出およびクロマトグラフィーの溶媒は、J.T Bakerより購入し、それ以上精製せずに使用した。すべての有機化学物質はAldrich Chemical Co.より購入した。乾燥剤および無機試薬はBDHより購入した。
1,1’-[(ペンタン-1,5-ジイル)ジオキシ]-ビス[(11aS,2Z)-7-メトキシ-2-メチリデン-1,2,3,11a-テトラヒドロ-5H-ピロロ[2,1-c][1,4]ベンゾジアゼピン-5-オン] (1)
カリウム-t-ブトキシドの無水THF溶液 (0.5M、21.0 mL、10.6 mmol)を、エチルトリフェニルホスホニウムブロミド(3.94 g, 10.6 mmol)の無水THF (16 mL)中の懸濁液に滴下した。得られた黄色のイリド懸濁液を2時間攪拌還流した後、10℃でビス-ケトン2 (WO 00/12508の化合物214)(2.09 g、2.04 mmol)のTHF (15 mL)溶液を加えた。反応混合物をさらに90分間撹拌還流した後、室温に冷却した。混合物をEtOAc (100 mL)と水(100 mL)により分配し、有機層を飽和塩化ナトリウム(100 mL)により洗浄し、MgSO4により乾燥した。過剰の溶媒を除去すると褐色のオイルが得られた。それをフラッシュカラムクロマトグラフィー(50:50 v/v EtOAc/40-60o石油エーテル)にかけ、オレフィン3を黄色のガラス状物質として得た。収量 = 577 mg (28%); [α]24 D = -26o (c = 0.453, CHCl3); 1H NMR (250 MHz, CDCl3) δ8.82 (bs, 2H), 7.81 (bs, 2H), 6.84 (s, 2H), 6.02-5.87 (m, 2H), 5.38-5.20 (m, 6H), 4.63-4.55 (m, 6H), 4.15-3.85 (m, 8H), 3.82-3.52 (m, 10H), 2.75-2.49 (m, 4H), 2.03-1.80 (m, 4H), 1.77-1.22 (m, 8H), 0.85 (s, 18H), 0.00 (s, 12H); 13C NMR (62.9 MHz, CDCl3) δ168.9, 153.5, 150.6, 143.9, 135.6, 132.6, 131.9, 118.0, 116.7, 115.4, 111.3, 105.4, 68.6, 65.7, 63.7, 56.6, 54.6, 33.4, 28.8, 25.8, 22.6, 18.1, 14.6, -5.58; MS (FAB) m/z (相対強度) 1072 ([M + Na + H]+., 65), 1049 ([M + H]+., 28), 992 (13), 809 (39), 509 (33), 469 (49), 318 (26), 268 (100); IR (溶媒なし) 3319 (br), 2952, 2930, 2858, 1732, 1600, 1524, 1470, 1407, 1360, 1331, 1258, 1202, 1115, 1052, 1027, 938, 837, 812, 666 cm-1; HRMS [M + Na]+. C55H84N4O12Si2Naに対する計算値 m/z 1071.5522, 測定値(FAB) m/z 1071.5468。
TBAFの溶液(THF中の1.0 M溶液3.00 mL、3.00 mmol)を、0℃(氷/アセトン)でTHF (30 mL)中のビスシリルエーテル3 (1.23 g, 1.21 mmol)に加えた。反応混合物を室温に温めて一晩撹拌し、翌日TLC (50:50 v/v EtOAc/40-60o石油エーテル)により出発物質が完全になくなっていることを確認した。飽和NH4Cl (150 mL)を加えて反応混合物をEtOAc (3×60 mL)により抽出し、飽和塩化ナトリウム(150 mL)により洗浄し、乾燥し(MgSO4)、濾過し、減圧蒸発させて黄色のオイルを得た。フラッシュクロマトグラフィー(97:3 v/v CHCl3/MeOH)により精製して純粋なアルコール4を白色の泡状物質として得た。収量=879 mg (91%); [α]23 D = -2o (c = 0.29, CHCl3); 1H NMR (250 MHz, CDCl3) δ 8.64 (bs, 2H), 7.58 (bs, 2H), 6.82 (bs, 2H), 6.04-5.88 (m, 2H), 5.41-5.21 (m, 6H), 4.71-4.56 (m, 6H), 4.12-3.60 (m, 20H), 2.72 (dd, 2H, J = 8.2, 15.1 Hz), 2.38 (d, 2H, J = 15.3 Hz), 2.00-1.89 (m, 4H), 1.75-1.50 (m, 8H); 13C NMR (62.9 MHz, CDCl3) δ 170.5, 153.7, 150.4, 144.5, 134.2, 132.6, 130.9, 118.0 (x 2), 116.2, 110.9, 106.0, 68.5, 65.7, 65.3, 59.4, 56.6, 51.0, 34.1, 28.6, 22.7, 14.6; MS (FAB) m/z (相対強度) 843 ([M + Na]+., 100), 821 ([M + H]+., 17), 694 (32), 509 (43), 469 (40), 421 (25), 336 (50), 307 (34); IR (CHCl3) 3355 (br), 3016, 2941, 2875, 1723, 1600, 1525, 1465, 1434, 1409, 1330, 1266, 1216, 1179, 1118, 1072, 1051, 1028, 995, 933, 872, 667 cm-1; HRMS [M + Na]+. C43H56N4O12Naに対する計算値 m/z 843.3792, 測定値(FAB) m/z 843.3823。
ジメチルスルホキシド(0.45 g, 0.41 mL, 5.80 mmol)の無水CH2Cl2 (8 mL)中の溶液を、塩化オキサリルの溶液(CH2Cl2中の2M溶液1.46 mL、2.92 mmol)に、−45℃、窒素雰囲気下で撹拌しながら15分間かけて滴下した。反応混合物を−45℃で35分間撹拌した後、同じ温度でCH2Cl2 (8 mL)中のジオール4 (0.85 g、1.04 mmol)を15分間かけて加えた。さらに45分後に、トリエチルアミン(0.83g, 1.14 mL, 8.20 mmol)のCH2Cl2 (8 mL)中の溶液を15分間かけて加えた。反応混合物を−45℃で30分間撹拌した後、45分間かけて室温に温めた。反応混合物をCH2Cl2により希釈し、1M HCl (3×50 mL)、食塩水(50 mL)により洗浄し、MgSO4により乾燥した。過剰な溶媒を除去して粗生成物を得た。これをフラッシュカラムクロマトグラフィー(99:1 v/v CHCl3/MeOH)により精製して、生成物を白色のガラス状物質として得た。収量=0.495 g (58%); [α]22 D = +168o (c = 0.28, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.23 (s, 2H), 6.66 (s, 2H), 5.90-5.70 (m, 2H), 5.59-5.40 (m, 4H), 5.16 (bs, 2H), 5.11 (bs, 2H), 4.66 (dd, 2H, J = 5.57, 13.59 Hz), 4.44 (d, 2H, J = 13.2 Hz), 4.29-4.07 (m, 6H), 4.01 (t, 4H, J = 6.5 Hz), 3.90 (s, 6H), 3.63-3.56 (m, 2H), 2.93-2.77 (m, 2H), 2.66 (d, 2H, J = 16.4 Hz), 1.97-1.86 (m, 4H), 1.68-1.61 (m, 8H); 13C NMR (62.9 MHz, CDCl3) δ 166.8, 155.9, 150.2, 148.8,, 133.0, 131.8, 128.4, 125.5, 119.6, 118.2, 113.9, 110.6, 85.9, 69.0, 66.8, 59.3, 56.1, 47.5, 34.8, 28.5, 22.4, 14.8; MS (FAB) m/z (相対強度) 839 ([M + Na]+., 100), 799 (10), 781 (14), 465 (14), 443 (16), 413 (37), 388 (19), 336 (25), 271 (25); IR (CHCl3) 3225 (br), 3011, 2938, 2860, 1704, 1605, 1515, 1469, 1436, 1410, 1307, 1284, 1215, 1129, 1077, 1018, 994, 959, 916, 872, 666, 637 cm-1; HRMS [M + Na]+. C43H52N4O12Naに対する計算値 m/z 839.3479、測定値(FAB) m/z 839.3497。
ビス-alloc-カルビノールアミン5 (200 mg, 0.25 mmol)、トリフェニルホスフィン(6.30 mg, 24.1μmol)およびピロリジン(33 mg, 40.1μL 0.48 mmol)のCH2Cl2 (13 mL)中の溶液を窒素雰囲気下で撹拌しながら、触媒量のテトラキス(トリフェニルホスフィン)パラジウム(14.4 mg, 12.5 μmol)を加えた。反応混合物を室温に温め、反応の進行をTLC (95:5 v/v CHCl3/MeOH)によりモニターした。2時間半後に、TLCにより、反応が終了してUV光により明るい蛍光を発するスポットができたことが判明した。溶媒を減圧蒸発させ、得られた残渣をフラッシュクロマトグラフィー(98:2 v/v CHCl3/MeOH)にかけ、目的のビスイミン分子1を淡橙色のガラス状物質として得た。これにCHCl3を加えて減圧蒸発させることを繰り返してイミン型を得た。収量=160 mg (定量的); [α]21 D = +937o (c = 0.641, CHCl3); 1H NMR (250 MHz, CDCl3) δ 7.67 (d, 2H, J = 4.5 Hz), 7.50 (s, 2H) 6.80 (s, 2H), 5.63-5.55 (m, 2H), 4.38-3.96 (m, 8H), 3.94 (s, 6H), 3.86-3.80 (m, 2H), 3.20-3.03 (m, 2H), 2.90 (d, 2H, J = 15.8 Hz), 2.00-1.91 (m, 4H), 1.76-1.68 (m, 8H); 13C NMR (62.9 MHz, CDCl3) δ 164.9, 163.0, 150.8, 147.8, 140.6, 132.9, 119.8, 119.3, 111.4, 110.3, 68.7, 56.1, 53.4, 48.3, 35.3, 28.6, 22.5, 14.9; MS (FAB) m/z (相対強度) 613 ([M + H]+., 52), 443 (26), 421 (22), 329 (100), 307 (71), 242 (35), 220 (38); IR (CHCl3) 3220 (br), 2940, 2859, 1697, 1602, 1560, 1508, 1458, 1432, 1382, 1341, 1263, 1217, 1132, 1098, 1065, 1007, 875, 666 cm-1; HRMS [M + H]+. C35H41N4O6に対する計算値 m/z 613.3026、測定値(FAB) m/z 613.3047。
PBDのE/Zエチリデン基のC1およびC3共鳴の13C NMRスペクトルにおいて観察される化学シフトの差異により、化合物1における幾何異性体のおよその比を決定することができる。これらの観察は、C2-エチリデン部分を有するPBD天然産物トマイマイシン(tomaymycin)およびプロスラカルシンの全合成に関して発表された研究に基づいている (Mori, M.ら、Tetrahedron, 42, 3793 (1986))。
K562アッセイ
K562ヒト慢性骨髄白血病細胞を、10%ウシ胎仔血清および2 mMグルタミンを補足したRPM1 1640培地中で、5% CO2を含む加湿した空気中、37℃で維持し、特定の用量の試験化合物を加えて37℃の暗所で1時間インキュベートした。遠心分離(5分間、300 g)によりインキュベーションを終了し、細胞を薬物を含まない培地により1回洗浄した。適当な薬物処理の後、細胞を96-ウェルマイクロタイタープレートに移した(ウェルあたり104細胞、サンプルあたり8ウェル)。次に、プレートを5% CO2を含む加湿した空気中、37℃の暗所に置いた。アッセイは、生存細胞の、黄色の可溶性テトラゾリウム塩、臭化3-(4,5-ジメチルチアゾール-2-イル)-2,5-ジフェニル-2H-テトラゾリウム(MTT, Aldrich-Sigma)を還元して不溶性の紫のホルマザンの沈殿を生成する能力に基づくものである。プレートを4日間インキュベートした後(対照の細胞数をおよそ10倍に増加させる)、20μLのMTT溶液(リン酸緩衝生理食塩水中、5 mg/mL)をそれぞれのウェルに加えてプレートをさらに5時間インキュベートした。次にプレートを300 gで5分間遠心分離し、ウェルあたり10〜20μLを残してピペットで細胞ペレットから培地の大部分を取り出した。それぞれのウェルにDMSO (200μL)を加えてサンプルを完全に混合するまで撹拌した。次に光学濃度をTitertek Multiscan ELISAプレートリーダーにより波長550 nmで測定し、用量-反応曲線を作成した。それぞれの曲線について、最終光学濃度を対照値の50%に減少させるのに必要な用量であるIC50値を読み取った。
試験化合物により誘導されるDNA架橋の程度を、Hartleyおよび共同研究者(Hartley, J. A.ら、Analytical Biochemistry, 193, 131-134 (1991))の電気泳動アッセイ法を用いて測定した。閉環puc18 DNAをHindIIIにより線状化した後、脱リン酸化して、[γ32P]-ATPおよびポリヌクレオチドキナーゼを用いて最終的に5’-単一末端標識をおこなった。30〜40 ngのDNAを含有する反応を、水性TEOA (25 mMトリエタノールアミン、1 mM EDTA、pH 7.2)緩衝液中、最終体積が50μLとなるようにして37℃でおこなった。同量の停止溶液(0.6 M NaOAc、20 mM EDTA、100μg/mL tRNA)を加えることにより反応を終了した後、EtOHにより沈殿させた。遠心分離の後、上清を捨て、ペレットを凍結乾燥した。サンプルを10μLの標準分離緩衝液(30% DMSO、1 mM EDTA、0.04%ブロモフェノールブルーおよび0.04%キシレンシアノール)中に再懸濁し、90℃で2.5分間加熱することにより変性した後、氷/水浴中に浸漬した。比較のために、対照の変性していないサンプルを10μLの非変性緩衝液(0.6%スクロース、0.04%ブロモフェノールブルー、水性TAE緩衝液[40 mM Tris、20 mM酢酸、2 mM EDTA、pH 8.1]中)中に再懸濁して直接ゲルに載せた。電気泳動はTAE緩衝液中の0.8%水中アガロースゲル(20×25×0.5 cm)を用いて40 Vで14〜16時間かけて実施した。ゲルを、BioRad 583ゲル乾燥機を用いて、Whatman 3MMおよびDE8I濾紙のそれぞれの1つの層の上で減圧下80℃で2時間乾燥した。Hyperfilm-MP film (Amersham plc, U.K.)を、スクリーンを用いて4時間またはスクリーンを用いずに一晩(より鮮明な像を得るために)のいずれかで乾燥したゲルに曝露した後、オートラジオグラフを得た。BioRad GS-670画像レーザーデンシトメーターを用いてフィルムのバンドを定量した。架橋したDNAの量(DSバンド単独の濃度)に対するそれぞれのレーンの総DNAの測定値(二本鎖[DS]および一本鎖[SS]のバンドの濃度の合計)により架橋のパーセンテージを計算した。決定された架橋DNAのパーセンテージレベルに対して薬物濃度をプロットすることにより用量反応曲線が得られ、その結果、50%架橋するのに必要な量であるXL50が決定された。
材料および方法
収集
化合物1を評価するためにDr P. Taylor, School of Pharmacy, London (UK)が保持しているMRSA収集を使用した。それは38の株を含み、最近の10年間に英国の病院における多くの大流行の原因となった、流行性EMRSA-15およびEMRSA-16などの多くの国際的な株を含む。これらの株の起源となった国を表2に示す。
英国臨床研究所規格委員会(National Committee for Clinical Laboratory Standards, UK) (NCCLS)の指針により与えられた方法に従ってブロスMICをおこなった。Muller Hinton Broth (MHB)中に懸濁された試験される化合物100μlを、所望の濃度で無菌の96ウェルマイクロタイタープレートに入れた。ウェルの1つの列には、対照として使用するために化合物を入れずに100μlのMHBのみを加えた。2mlのMHB中で一晩増殖させた細菌培養物を希釈し、それぞれのサンプルについて100μlをウェルに加えて最終細菌計数が5×105 CFU/ml、すなわち、ウェルあたり105 CFUとなるようにした。最終的にウェルあたり200μlの体積となった。最終細菌計数を計算する場合に、サンプルをウェルに加えた後に達成される細菌サンプルのlin2希釈を考慮しなければならない。粘着性のプラスチックシールを使用してマイクロタイタープレートを密閉した後、細菌サンプルが均等に懸濁するように静かに振盪した。プレートを37℃で一晩インキュベートした。細菌の目に見える増殖が存在しない最低の濃度をその特定の細菌株のMICと定義する。
これらはNCCLSの指針、第6版(1997年1月)に従って実施された。
50 mlのMHBを含有する250 mlのフラスコを滅菌した。1本を対照として取っておき、試験する化合物を、MIC×1、MIC×2およびMIC×4のように濃度を増加させて残りの3本に加えた。一晩培養した細菌を二倍に希釈した。50 mlの上記懸濁液をそれぞれのフラスコに加えて、その時間を時間0とした。それぞれのフラスコのサンプルをすぐに取り出してビジュー瓶に入れた。100μlのそれぞれのサンプルを900μlの無菌PBSに移した。必要ならばさらに10倍希釈をおこなった。それぞれの希釈の20μlの液滴をNAプレート上に載せ、37℃で一晩インキュベートした。フラスコは37℃の振盪器上においた。同じ作業を時間1、2、4、6および24時間に繰り返してプレートを一晩インキュベートした。
化合物1の抗菌活性を定量するために使用された細菌を、さまざまな抗生物質に対して試験して、それらの他の抗微生物薬に対する全般的な感受性を測定し、結果を下記の表4〜8に示す。
化合物1の殺菌および静菌活性を研究するためにMRSA株P1を選んだ。この特定の株のMIC値は試験された大部分の株について得られたMIC値を代表するものであった(0.015 mg/L)。
Claims (15)
- R10’およびR11’がそれぞれR10およびR11と同一である、請求項1に記載の化合物。
- 窒素保護基がカルバメート窒素保護基から選択される、請求項1〜3のいずれか1項に記載の化合物。
- 窒素保護基が、Alloc、Troc、Teoc、BOC、Doc、Hoc、TcBOC、Fmoc、1-Adocおよび2-Adocからなる群より選択される、請求項4に記載の化合物。
- R10およびR11が一緒になってN10とC11の間に二重結合を形成する、請求項1または請求項2に記載の化合物。
- 少なくとも50%がE-、E-またはZ-、Z-型のいずれかである、請求項1〜6のいずれか1項に記載の化合物。
- 請求項1〜7のいずれか1項に記載の化合物を合成する方法。
- 治療の方法に使用するための、請求項1〜7のいずれか1項に記載の化合物またはその製薬上許容される塩もしくは溶媒和物。
- 請求項1〜7のいずれか1項に記載の化合物またはその製薬上許容される塩もしくは溶媒和物、および製薬上許容される賦形剤を含む医薬組成物。
- 遺伝子に基づく病気を治療するための医薬品の製造への、請求項1〜7のいずれか1項に記載の化合物またはその製薬上許容される塩もしくは溶媒和物の使用。
- 遺伝子に基づく病気にかかった被験体に治療上有効な量の請求項1〜7のいずれか1項に記載の化合物またはその製薬上許容される塩もしくは溶媒和物を投与することを含む、遺伝子に基づく病気の治療方法。
- 遺伝子に基づく病気が増殖性疾患である、請求項11に記載の使用または請求項12に記載の方法。
- 遺伝子に基づく病気がグラム陽性菌の感染である、請求項11に記載の使用または請求項12に記載の方法。
- グラム陽性菌がMRSAおよびVREから選択される、請求項14に記載の使用または方法。
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GB0412409A GB0412409D0 (en) | 2004-06-03 | 2004-06-03 | Pyrrolobenzodiazepines |
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EP1723152A1 (en) | 2006-11-22 |
WO2005085260A1 (en) | 2005-09-15 |
EP1723152B1 (en) | 2015-02-11 |
US7528126B2 (en) | 2009-05-05 |
US20070185073A1 (en) | 2007-08-09 |
JP5166861B2 (ja) | 2013-03-21 |
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