ZA200406507B - Fused pyridazine derivative compounds and drugs containing the compounds as the active ingredient. - Google Patents
Fused pyridazine derivative compounds and drugs containing the compounds as the active ingredient. Download PDFInfo
- Publication number
- ZA200406507B ZA200406507B ZA200406507A ZA200406507A ZA200406507B ZA 200406507 B ZA200406507 B ZA 200406507B ZA 200406507 A ZA200406507 A ZA 200406507A ZA 200406507 A ZA200406507 A ZA 200406507A ZA 200406507 B ZA200406507 B ZA 200406507B
- Authority
- ZA
- South Africa
- Prior art keywords
- alkyl
- hydrogen atom
- pharmaceutically acceptable
- acceptable salt
- alkylene
- Prior art date
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- -1 pyridazine derivative compounds Chemical class 0.000 title claims description 48
- 150000001875 compounds Chemical class 0.000 title claims description 47
- 239000004480 active ingredient Substances 0.000 title claims description 9
- 229940079593 drug Drugs 0.000 title claims description 8
- 239000003814 drug Substances 0.000 title claims description 8
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 73
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 41
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 40
- 229920006395 saturated elastomer Polymers 0.000 claims description 35
- 150000003839 salts Chemical class 0.000 claims description 30
- 125000003545 alkoxy group Chemical group 0.000 claims description 27
- 125000002947 alkylene group Chemical group 0.000 claims description 25
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 21
- 229910052757 nitrogen Inorganic materials 0.000 claims description 20
- 229910052760 oxygen Inorganic materials 0.000 claims description 20
- 239000001301 oxygen Substances 0.000 claims description 20
- 125000004434 sulfur atom Chemical group 0.000 claims description 20
- 125000005842 heteroatom Chemical group 0.000 claims description 19
- 125000005843 halogen group Chemical group 0.000 claims description 18
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 17
- 229920000776 Poly(Adenosine diphosphate-ribose) polymerase Polymers 0.000 claims description 14
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 14
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 claims description 13
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 13
- 125000002252 acyl group Chemical group 0.000 claims description 11
- 239000000203 mixture Substances 0.000 claims description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 9
- 125000004649 C2-C8 alkynyl group Chemical group 0.000 claims description 8
- 208000023589 ischemic disease Diseases 0.000 claims description 8
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 208000004454 Hyperalgesia Diseases 0.000 claims description 5
- 208000035154 Hyperesthesia Diseases 0.000 claims description 5
- 206010012601 diabetes mellitus Diseases 0.000 claims description 5
- 229960003444 immunosuppressant agent Drugs 0.000 claims description 5
- 230000001861 immunosuppressant effect Effects 0.000 claims description 5
- 239000003018 immunosuppressive agent Substances 0.000 claims description 5
- 208000027866 inflammatory disease Diseases 0.000 claims description 5
- 230000035939 shock Effects 0.000 claims description 5
- CUDDJOKEASSPCM-UHFFFAOYSA-N 4-(4-bromophenyl)-5,6,7,8-tetrahydro-2h-phthalazin-1-one Chemical compound C1=CC(Br)=CC=C1C1=NNC(=O)C2=C1CCCC2 CUDDJOKEASSPCM-UHFFFAOYSA-N 0.000 claims description 4
- HGXKVNRBKJMVLX-UHFFFAOYSA-N 4-phenyl-5,6,7,8-tetrahydro-2h-phthalazin-1-one Chemical compound C1=2CCCCC=2C(=O)NN=C1C1=CC=CC=C1 HGXKVNRBKJMVLX-UHFFFAOYSA-N 0.000 claims description 4
- 208000002249 Diabetes Complications Diseases 0.000 claims description 4
- 206010012655 Diabetic complications Diseases 0.000 claims description 4
- 208000010412 Glaucoma Diseases 0.000 claims description 4
- 206010019196 Head injury Diseases 0.000 claims description 4
- 208000001647 Renal Insufficiency Diseases 0.000 claims description 4
- 125000004450 alkenylene group Chemical group 0.000 claims description 4
- 206010008118 cerebral infarction Diseases 0.000 claims description 4
- 208000026106 cerebrovascular disease Diseases 0.000 claims description 4
- 239000003112 inhibitor Substances 0.000 claims description 4
- 201000006370 kidney failure Diseases 0.000 claims description 4
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 4
- 230000002265 prevention Effects 0.000 claims description 4
- 208000020431 spinal cord injury Diseases 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 3
- NAFRJSXRUUAWKI-UHFFFAOYSA-N 4-(4-chlorophenyl)-5,6,7,8-tetrahydro-2h-phthalazin-1-one Chemical compound C1=CC(Cl)=CC=C1C1=NNC(=O)C2=C1CCCC2 NAFRJSXRUUAWKI-UHFFFAOYSA-N 0.000 claims description 3
- LYSYBTOKVNYKME-UHFFFAOYSA-N 4-(4-methylphenyl)-5,6,7,8-tetrahydro-2h-phthalazin-1-one Chemical compound C1=CC(C)=CC=C1C1=NNC(=O)C2=C1CCCC2 LYSYBTOKVNYKME-UHFFFAOYSA-N 0.000 claims description 3
- VLHRCDZMDBOSMW-UHFFFAOYSA-N 4-(pyridin-4-ylmethyl)-5,6,7,8-tetrahydro-2h-phthalazin-1-one Chemical compound C1=2CCCCC=2C(=O)NN=C1CC1=CC=NC=C1 VLHRCDZMDBOSMW-UHFFFAOYSA-N 0.000 claims description 3
- 102000012338 Poly(ADP-ribose) Polymerases Human genes 0.000 claims description 3
- 108010061844 Poly(ADP-ribose) Polymerases Proteins 0.000 claims description 3
- 125000003302 alkenyloxy group Chemical group 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 125000004414 alkyl thio group Chemical group 0.000 claims description 3
- 125000005133 alkynyloxy group Chemical group 0.000 claims description 3
- 230000000798 anti-retroviral effect Effects 0.000 claims description 3
- 238000011319 anticancer therapy Methods 0.000 claims description 3
- VDEXQBMICBAUDA-UHFFFAOYSA-N ethyl 2-(4-oxo-5,6,7,8-tetrahydro-3h-phthalazin-1-yl)acetate Chemical compound C1CCCC2=C1C(=O)NN=C2CC(=O)OCC VDEXQBMICBAUDA-UHFFFAOYSA-N 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- YPVZTHKKFYLGOU-UHFFFAOYSA-N tert-butyl 2-(4-oxo-5,6,7,8-tetrahydro-3h-phthalazin-1-yl)acetate Chemical compound C1CCCC2=C1C(=O)NN=C2CC(=O)OC(C)(C)C YPVZTHKKFYLGOU-UHFFFAOYSA-N 0.000 claims description 3
- 125000004953 trihalomethyl group Chemical group 0.000 claims description 3
- SXTXREBNFQTGFW-UHFFFAOYSA-N 4-(3,4-dimethoxyphenyl)-5,6,7,8-tetrahydro-2h-phthalazin-1-one Chemical compound C1=C(OC)C(OC)=CC=C1C1=NNC(=O)C2=C1CCCC2 SXTXREBNFQTGFW-UHFFFAOYSA-N 0.000 claims description 2
- MGODEOQJXGJNKA-UHFFFAOYSA-N 4-(3-chloro-4-methoxyphenyl)-4a,5,8,8a-tetrahydro-2h-phthalazin-1-one Chemical compound C1=C(Cl)C(OC)=CC=C1C1=NNC(=O)C2C1CC=CC2 MGODEOQJXGJNKA-UHFFFAOYSA-N 0.000 claims description 2
- RTZMRASBASLJBV-UHFFFAOYSA-N 4-(4-fluorophenyl)-5,6,7,8-tetrahydro-2h-phthalazin-1-one Chemical compound C1=CC(F)=CC=C1C1=NNC(=O)C2=C1CCCC2 RTZMRASBASLJBV-UHFFFAOYSA-N 0.000 claims description 2
- PYKHMQHXJSYCDG-UHFFFAOYSA-N 4-phenyl-6,7,8,8a-tetrahydro-2h-pyrrolo[1,2-d][1,2,4]triazin-1-one Chemical compound N12CCCC2C(=O)NN=C1C1=CC=CC=C1 PYKHMQHXJSYCDG-UHFFFAOYSA-N 0.000 claims description 2
- IRPJYXBDZBGNEK-UHFFFAOYSA-N 7-hydroxy-4-phenyl-6,7,8,8a-tetrahydro-2h-pyrrolo[1,2-d][1,2,4]triazin-1-one Chemical compound C1C(O)CC(C(NN=2)=O)N1C=2C1=CC=CC=C1 IRPJYXBDZBGNEK-UHFFFAOYSA-N 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 125000004429 atom Chemical group 0.000 claims description 2
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 claims description 2
- 125000004951 trihalomethoxy group Chemical group 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims 6
- 230000004770 neurodegeneration Effects 0.000 claims 3
- 230000003449 preventive effect Effects 0.000 claims 2
- 229940123066 Polymerase inhibitor Drugs 0.000 claims 1
- 239000002547 new drug Substances 0.000 claims 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 37
- 229910052739 hydrogen Inorganic materials 0.000 description 14
- 101710179684 Poly [ADP-ribose] polymerase Proteins 0.000 description 11
- 102100023712 Poly [ADP-ribose] polymerase 1 Human genes 0.000 description 11
- 239000001257 hydrogen Substances 0.000 description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 8
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 6
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 6
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 6
- 229910052717 sulfur Inorganic materials 0.000 description 6
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 5
- 239000012453 solvate Substances 0.000 description 5
- CIISBYKBBMFLEZ-UHFFFAOYSA-N 1,2-oxazolidine Chemical compound C1CNOC1 CIISBYKBBMFLEZ-UHFFFAOYSA-N 0.000 description 4
- CZSRXHJVZUBEGW-UHFFFAOYSA-N 1,2-thiazolidine Chemical compound C1CNSC1 CZSRXHJVZUBEGW-UHFFFAOYSA-N 0.000 description 4
- OGYGFUAIIOPWQD-UHFFFAOYSA-N 1,3-thiazolidine Chemical compound C1CSCN1 OGYGFUAIIOPWQD-UHFFFAOYSA-N 0.000 description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
- WYNCHZVNFNFDNH-UHFFFAOYSA-N Oxazolidine Chemical compound C1COCN1 WYNCHZVNFNFDNH-UHFFFAOYSA-N 0.000 description 4
- 239000012661 PARP inhibitor Substances 0.000 description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
- 229940121906 Poly ADP ribose polymerase inhibitor Drugs 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- YPWFISCTZQNZAU-UHFFFAOYSA-N Thiane Chemical compound C1CCSCC1 YPWFISCTZQNZAU-UHFFFAOYSA-N 0.000 description 4
- MGNZXYYWBUKAII-UHFFFAOYSA-N cyclohexa-1,3-diene Chemical compound C1CC=CC=C1 MGNZXYYWBUKAII-UHFFFAOYSA-N 0.000 description 4
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cyclohexene Chemical compound C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 description 4
- LPIQUOYDBNQMRZ-UHFFFAOYSA-N cyclopentene Chemical compound C1CC=CC1 LPIQUOYDBNQMRZ-UHFFFAOYSA-N 0.000 description 4
- 101150114348 cycs gene Proteins 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- DTHHUAXKOMWYBI-UHFFFAOYSA-N oxadiazolidine Chemical compound C1CONN1 DTHHUAXKOMWYBI-UHFFFAOYSA-N 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- RLTPJVKHGBFGQA-UHFFFAOYSA-N thiadiazolidine Chemical compound C1CSNN1 RLTPJVKHGBFGQA-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 3
- 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 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- XSCHRSMBECNVNS-UHFFFAOYSA-N benzopyrazine Natural products N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 description 3
- 230000030833 cell death Effects 0.000 description 3
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 3
- 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 3
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 3
- 229950006238 nadide Drugs 0.000 description 3
- RRKODOZNUZCUBN-CCAGOZQPSA-N (1z,3z)-cycloocta-1,3-diene Chemical compound C1CC\C=C/C=C\C1 RRKODOZNUZCUBN-CCAGOZQPSA-N 0.000 description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 2
- UWYZHKAOTLEWKK-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline Chemical compound C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 description 2
- OQJVXNHMUWQQEW-UHFFFAOYSA-N 1,2,3,4-tetrahydropyrazine Chemical compound C1CNC=CN1 OQJVXNHMUWQQEW-UHFFFAOYSA-N 0.000 description 2
- JQIZHNLEFQMDCQ-UHFFFAOYSA-N 1,2,3,4-tetrahydropyridazine Chemical compound C1CC=CNN1 JQIZHNLEFQMDCQ-UHFFFAOYSA-N 0.000 description 2
- OTPDWCMLUKMQNO-UHFFFAOYSA-N 1,2,3,4-tetrahydropyrimidine Chemical compound C1NCC=CN1 OTPDWCMLUKMQNO-UHFFFAOYSA-N 0.000 description 2
- LBUJPTNKIBCYBY-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoline Chemical compound C1=CC=C2CCCNC2=C1 LBUJPTNKIBCYBY-UHFFFAOYSA-N 0.000 description 2
- UUZJJNBYJDFQHL-UHFFFAOYSA-N 1,2,3-triazolidine Chemical compound C1CNNN1 UUZJJNBYJDFQHL-UHFFFAOYSA-N 0.000 description 2
- AGSHYIAAUGKFEA-UHFFFAOYSA-N 1,2,5-oxadiazolidine Chemical compound C1CNON1 AGSHYIAAUGKFEA-UHFFFAOYSA-N 0.000 description 2
- QYMGRIFMUQCAJW-UHFFFAOYSA-N 1,2-dihydropyrazine Chemical compound C1NC=CN=C1 QYMGRIFMUQCAJW-UHFFFAOYSA-N 0.000 description 2
- BKWQKVJYXODDAC-UHFFFAOYSA-N 1,2-dihydropyridazine Chemical compound N1NC=CC=C1 BKWQKVJYXODDAC-UHFFFAOYSA-N 0.000 description 2
- WCFAPJDPAPDDAQ-UHFFFAOYSA-N 1,2-dihydropyrimidine Chemical compound C1NC=CC=N1 WCFAPJDPAPDDAQ-UHFFFAOYSA-N 0.000 description 2
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- GWYPDXLJACEENP-UHFFFAOYSA-N 1,3-cycloheptadiene Chemical compound C1CC=CC=CC1 GWYPDXLJACEENP-UHFFFAOYSA-N 0.000 description 2
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 description 2
- IMLSAISZLJGWPP-UHFFFAOYSA-N 1,3-dithiolane Chemical compound C1CSCS1 IMLSAISZLJGWPP-UHFFFAOYSA-N 0.000 description 2
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical compound C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-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
- SCEIUGQQBYRBPP-UHFFFAOYSA-N 2,3,4,5-tetrahydro-1h-azepine Chemical compound C1CCC=CNC1 SCEIUGQQBYRBPP-UHFFFAOYSA-N 0.000 description 2
- YYVKQFQZKSLYFN-UHFFFAOYSA-N 2,3,4,5-tetrahydro-1h-diazepine Chemical compound C1CNNC=CC1 YYVKQFQZKSLYFN-UHFFFAOYSA-N 0.000 description 2
- GLCYMVDVOVIDBB-UHFFFAOYSA-N 2,3,4,5-tetrahydrooxadiazepine Chemical compound C1CC=CONN1 GLCYMVDVOVIDBB-UHFFFAOYSA-N 0.000 description 2
- ABQOPHYTASMWLA-UHFFFAOYSA-N 2,3,4,5-tetrahydrooxazepine Chemical compound C1CNOC=CC1 ABQOPHYTASMWLA-UHFFFAOYSA-N 0.000 description 2
- SOHIYESEPVZKHS-UHFFFAOYSA-N 2,3,4,5-tetrahydrooxepine Chemical compound C1CCC=COC1 SOHIYESEPVZKHS-UHFFFAOYSA-N 0.000 description 2
- WHUAPUGLAGYTQS-UHFFFAOYSA-N 2,3,4,5-tetrahydrothiadiazepine Chemical compound C1CC=CSNN1 WHUAPUGLAGYTQS-UHFFFAOYSA-N 0.000 description 2
- IFPKIMVCYSSDDJ-UHFFFAOYSA-N 2,3,4,5-tetrahydrothiazepine Chemical compound C1CNSC=CC1 IFPKIMVCYSSDDJ-UHFFFAOYSA-N 0.000 description 2
- VRKPANGTGANDRQ-UHFFFAOYSA-N 2,3,4,5-tetrahydrothiepine Chemical compound C1CCC=CSC1 VRKPANGTGANDRQ-UHFFFAOYSA-N 0.000 description 2
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- YTQQIHUQLOZOJI-UHFFFAOYSA-N 2,3-dihydro-1,2-thiazole Chemical compound C1NSC=C1 YTQQIHUQLOZOJI-UHFFFAOYSA-N 0.000 description 2
- ZABMHLDQFJHDSC-UHFFFAOYSA-N 2,3-dihydro-1,3-oxazole Chemical compound C1NC=CO1 ZABMHLDQFJHDSC-UHFFFAOYSA-N 0.000 description 2
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- HBEDSQVIWPRPAY-UHFFFAOYSA-N 2,3-dihydrobenzofuran Chemical compound C1=CC=C2OCCC2=C1 HBEDSQVIWPRPAY-UHFFFAOYSA-N 0.000 description 2
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- PZJFUNZDCRKXPZ-UHFFFAOYSA-N 2,5-dihydro-1h-tetrazole Chemical compound C1NNN=N1 PZJFUNZDCRKXPZ-UHFFFAOYSA-N 0.000 description 2
- JECYNCQXXKQDJN-UHFFFAOYSA-N 2-(2-methylhexan-2-yloxymethyl)oxirane Chemical compound CCCCC(C)(C)OCC1CO1 JECYNCQXXKQDJN-UHFFFAOYSA-N 0.000 description 2
- VSWICNJIUPRZIK-UHFFFAOYSA-N 2-piperideine Chemical compound C1CNC=CC1 VSWICNJIUPRZIK-UHFFFAOYSA-N 0.000 description 2
- RSEBUVRVKCANEP-UHFFFAOYSA-N 2-pyrroline Chemical compound C1CC=CN1 RSEBUVRVKCANEP-UHFFFAOYSA-N 0.000 description 2
- BOLMDIXLULGTBD-UHFFFAOYSA-N 3,4-dihydro-2h-oxazine Chemical compound C1CC=CON1 BOLMDIXLULGTBD-UHFFFAOYSA-N 0.000 description 2
- NWWJFMCCTZLKNT-UHFFFAOYSA-N 3,4-dihydro-2h-thiazine Chemical compound C1CC=CSN1 NWWJFMCCTZLKNT-UHFFFAOYSA-N 0.000 description 2
- ATVJJNGVPSKBGO-UHFFFAOYSA-N 3,4-dihydro-2h-thiopyran Chemical compound C1CSC=CC1 ATVJJNGVPSKBGO-UHFFFAOYSA-N 0.000 description 2
- XBACROZWIIGGQJ-UHFFFAOYSA-N 4-phenyl-2,6,8,8a-tetrahydro-[1,3]thiazolo[3,4-d][1,2,4]triazin-1-one Chemical compound N12CSCC2C(=O)NN=C1C1=CC=CC=C1 XBACROZWIIGGQJ-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
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical compound C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 description 2
- PMPVIKIVABFJJI-UHFFFAOYSA-N Cyclobutane Chemical compound C1CCC1 PMPVIKIVABFJJI-UHFFFAOYSA-N 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
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- BXVYJQULAWJPSR-UHFFFAOYSA-N thiadiazepine Chemical compound S1C=CC=CN=N1 BXVYJQULAWJPSR-UHFFFAOYSA-N 0.000 description 1
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 1
- NYERMPLPURRVGM-UHFFFAOYSA-N thiazepine Chemical compound S1C=CC=CC=N1 NYERMPLPURRVGM-UHFFFAOYSA-N 0.000 description 1
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Description
y 4 | : ® @
FUSED PYRIDAZINE DERIVATIVE COMPOUNDS AND
DRUGS CONTAINING THESE COMPOUNDS AS THE ACTIVE INGREDIENT
The present invention relates to fused pyridazine derivative compounds.
More particularly, the present invention relates to (1) pyridazine derivative compounds represented by formula (I) (RY) ay m yon he
A
(wherein all symbols have the same meanings as described below), or pharmaceutically acceptable salts thereof, 2) a process for preparing thereof, and 3) an agent comprising the same as an active ingredient.
Poly(ADP-ribose)polymerase (abbreviated as PARP hereinafter), which is a nuclear enzyme activated by DNA strand breaks, plays a role in the transfer reaction of
ADP-ribose moiety from nicotinamide adenine dinucleotide (abbreviated as NAD"
Lereinafer) *c varicus proteins such as histones, DNA-polymerases and DNA- topoisomerases, erc.
DNA strand breaks caused by Peroxynitrite (ONOO") and oxygen radicals lead to overactivation of PARP (PARP is activated up to 100 times when Zn finger domain of PARP binds to DNA with nicks.). It is thought that overactivation of PARP causes depletion of NAD”, which is essential for electron transport system, and consequently depletion of ATP, leading to energy failure, ultimately resulting in cell death. (The suicide hypothesis of PARP activation : Free Radic. Biol Med. 21, 855 (1996) ; TIPS., 19, 287 (1998)). Therefore, it is considered that PARP inhibitor is useful as inhibitor of cell death.
Since caspase-3, which is one of interleukin-13-converting enzyme family, specifically cleaves PARP as the substrate (Cell., 81, 801 (1995)), it is suggested PARP is associated with apoptosis.
® @
It is reported that 3-aminobenzamide and nicotinamide generally known as inhibitors of PARP are useful for inhibition of cell death and improvement of diseases on various models of ischemic diseases (cerebral, myocardial, intestinal, skeletal muscular or retinal ischemia etc.), inflammatory diseases (arthritis, inflammatory bowel disease or multiple sclerosis efc.), diabetes, shock, extrapyramidal disease (7IPS., 19, 287 (1998) ; Eur. J. Pharmacol. 350, 1 (1998)) and hyperalgesia (Pain, 72, 355 (1997)) in vitro, in vivo and in PARP knockout mouse. And it is reported that PARP inhibitor is useful as an antiretroviral drug such as an anti HIV drug (Biochem. Biophys.
Res.Commum., 180, 504 (1991)), a sensitizer of anticancer therapy (Radiat. Res., 126, 367 (1991) ; Br J. Cancer., 72, 849 (1995)) or an immunosuppressant (Int. J.
Immunopharmac., 17, 265 (1995)).
PARP inhibitor is useful for prevention and/or treatment of various diseases, for example, ischemic diseases (cerebral infarction, myocardial infarction, reperfusion injury or postoperative injury efc.), inflammatory diseases (inflammatory bowel disease, multiple sclerosis, arthritis or lung injury efc.), neurodegenerative disorders (extrapyramidal disease, Parkinson's disease, Alzheimer’s disease, muscular dystrophy or lumbar spinal canal stenosis etc.), glaucoma, diabetes, diabetic complication, shock, head trauma, spinal cord injury, renal failure, hyperalgesia or blood flow obstruction etc.
And it is useful as an antiretroviral drug such as an anti HIV drug, a sensitizer of anticancer therapy or an immunosuppressant.
As PARP inhibitor, for example, in the specification of W000/44726, it is described that 2H-phthalazin-1-one derivatives represented by formula (A) 0
NH
_N (A)
Gr
JR
NO
(wherein R'* is (i) C1-4 alkyl substituted by hydroxy or amino, or
Gi) —AA—p2A_p3A in which A'* is -NR3*#C(O)- etc. wherein R** is hydrogen or C1-4 alkyl efc., A* is C1- 8 alkylene erc., A** is (i) hydrogen, (ii) -NR'4R™ or (iii) Cyc** etc. wherein R'7* is ®
®
C hydrogen, (ii) C1-8 alkyl etc., and R'®* is (i) hydrogen or (ii) C1-8 alkyl etc., Cyc™ is 3-10 membered mono- or bi-heterocyclic ring containing 1-4 of nitrogen atoms, 1-2 of oxygen atoms and/or one sulfur atom , R* is hydrogen or halogen erc. Necessary parts were extracted from the description of groups.) have PARP inhibitory activity.
In the specification of DE3302021, it is described that compounds represented by formula (B) 0)
R18
NH
RBZ (B) 3B
H a H H R ©
Sm Chae
Oo (wherein RP is hydrogen or C1-3 alkyl, R?® is hydrogen, R'® and RZ, taken together, are C1-4 alkylene, R®® is hydrogen or methyl, nB is 0-3, R*® is 1-pyrrolyl. Necessary parts were extracted from the description of groups.) have inhibitory activity of platelet aggregation.
In the specification of WQ98/31674, it is described that compounds represented by formula (C)
Oo
RAC ~~ RC
N
R3¢ = N (9)
R2C
RIC
(wherein RC is C1-4 alkoxy etc., R* is C1-8 alkoxy efc., RC and R*C is hydrogen or
R3C and R*C, taken together, are bond, RC is hydrogen etc. Necessary parts were extracted from the description of groups.) have phosphodiesterase inhibitory activity.
In Journal of Medicinal Chemistry., 44(16), 2511-2522 and 2523-2535 (2001), it is described that 4-(3-chloro-4-methoxyphenyl)-4a,5,8,8a-~ tetrahydrophthalazin-1(2H)-one (CAS Registry No. 244077-36-9) and 4-(3,4-
® ® dimethoxyphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one (CAS Registry No. 358368- 98-6) have phosphodiesterase inhibitory activity.
In Tetrahedron., 39(20), 3419-27 (1983), 4-phenyl-6,7,8,82- tetrahydropyrrolo[1,2-d][1,2,4]triazin-1(2H)-one (CAS Registry No. 89311-30-8) is described as synthetic intermediate.
In Synthesis., 240-242 (1995), 4-phenyl-5,6,7,8-tetrahydrophthalazin-1(2H)- one (CAS Registry No. 154810-22-7), 4-(4-methylphenyl)-5,6,7,8- tetrahydrophthalazin-1(2H)-one (CAS Registry No. 154810-23-8), 4-(4-fluorophenyl)- 5,6,7,8-tetrahydrophthalazin-1(2H)-one (CAS Registry No. 154810-24-9), 4-(4- chlorophenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one (CAS Registry No. 154810-25- 0), and 4-(4-bromophenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one (CAS Registry No. 154810-26-1) are described as synthetic intermediate.
In Bioorganic and Medicinal Chemistry., 6, 349-454 (1998), 7-hydroxy-4- phenyl-6,7,8,8a-tetrahydropyrrolo[ 1,2-d][1,2,4]triazin-1(2H)-one (CAS Registry No. 206126-90-1) and 4-phenyl-8,8a-dihydro[1,3]thiazolo[3,4-d][1,2,4]triazin-1(2H)-one (CAS Registry No. 206126-96-7) are described as synthetic intermediate.
In Journal of Medicinal Chemistry., 43(12), 2310-2323 (2000), 4-(pyridin- 4-ylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one (CAS Registry No. 212142-89-7) is described as synthetic intermediate.
In the specification of FR2647676, 4-t-butoxycarbonylmethyl-5,6,7,8- tetrahydrophthalazin-1(2H)-one (CAS Registry No. 134972-12-6) and 4- ethoxycarbonylmethyl-5,6,7,8-tetrahydrophthalazin-1(2H)-one (CAS Registry No. 134973-24-3) are described as synthetic intermediate.
In order to find a compound having poly(ADP-ribose)polymerase activity, the present inventors have conducted intensive studies and found, as a result, that the objects can be accomplished by the pyridazine derivative represented by formula D, and thus the present invention has been accomplished.
The present invention relates to (DH a fused pyridazine derivative compound represented by formula (I) 0 (R") Gry m yon ® he
A
_ ® wherein R! is (1) a hydrogen atom, (2) C1-8 alkyl, (3) C1-8 alkoxy, (4) hydroxy, (5) halogen atom, (6) nitro, (7) NR’R?, (8) C2-8 acyl, (9) C1-8 alkoxy substituted by phenyl or (10) C2-8 acyl substituted by NR’R?,
R?* and R? are each independently (1) a hydrogen atom or (2) C1-8 alkyl,
X and Y are each independently (1)C,(2)CHor 3) N, == ds (1) a single bond or (2) a double bond,
G4
Z
Y~ is (1) partially or fully saturated C3-10 mono-carbocyclic aryl or (2) partially or fully saturated 3-10 membered mono-hetero aryl containing 1 to 4 hetero atom(s) selected from oxygen, nitrogen and sulfur atoms,
Ais (1) A, (2) A%, 3) A’, (4) A' or (5) A’,
Alis re Tu
A'is —pg'pg?-E—F*,
LN
Alis —G'—Cyecl—G>
NZ
Atis 3
Ais Gor
D! is (1) -NR°C(0)-, (2) -NR°C(S)-, (3) -NR°SO;-, (4) -CH,-NR°-, (5) -CH;-0-, (6) -OC(O)-, (7) -CH,-NRSC(O)-, (8) -NR*C(O)NR’-, (9) -NR®C(0)O0-, (10) -NR°C(S)NR’-, (11) -
NR- or (12) -NR°C(=NR’)-,
R® and R” are each independently (1) a hydrogen atom, (2) C1-8 alkyl, (3) phenyl or (4) C1-8 alkyl substituted by phenyl,
. ®
D? is (1) C1-8 alkylene, (2) C2-8 alkenylene, (3) Cyc2, (4) -(Cl1-4 alkylene)-O-(C1-4 alkylene)-, (5) -(C1-4 alkylene)-S-(C1-4 alkylene)-, (6) -(C1-4 alkylene)-NR®-(C1-4 alkylene)-, (7) -(Cyc2)-(C1-8 alkylene)-, (8) -(C1-8 alkylene)-(Cyc2)- or (9) -(C1-4 alkylene)-(Cyc2)-(C1-4 alkylene)-,
Ris (1) a hydrogen atom, (2) C1-8 alkyl, (3) C1-8 alkoxycarbonyl, (4) phenyl or (5) C1-8 alkyl substituted by phenyl,
D’ is (1) a hydrogen atom, (2) -NR’R', (3) Cyc3, (4) -OR", (5) COOR", (6) CONR*R™, (7) cyano, (8) a halogen atom, (9) -C(=CR*)NR'*R'’ or (10) -NR'*C(=NR'*)NR?’R%,
R’ and R" are each independently (1) a hydrogen atom, (2) C1-8 alkyl, (3) C2-8 alkenyl, (4) C2-8 alkynyl, (5) Cyc3, (6)
C1-8 alkoxy, (7) C2-8 alkenyloxy, (8) C2-8 alkynyloxy or (9) C1-8 alkyl substituted by
Cyc3, C1-8 alkoxy, C1-8 alkylthio, cyano, hydroxy or 1 to 3 halogen atom(s),
R'® and R' are each independently (1) a hydrogen atom, (2) C1-8 alkyl, (3) C2-8 alkenyl, (4) C2-8 alkynyl, (5) C1-8 alkoxycarbonyl, (6) C2-8 acyl, (7) C3-8 cycloalkyl, (8) C1-8 alkoxycarbonyl substituted by Cyc4 or 1 to 3 halogen atom(s), or (9) C1-8 alkyl substituted by C1-8 alkoxy,
R' and R'? are each independently (1) a hydrogen atom or (2) C1-8 alkyl,
RY R'® RY R' RY R? and R* are each independently (1) a hydrogen atom, (2) C1-8 alkyl, (3) C1-8 alkoxycarbonyl, (4) pheny! or (5) C1-8 aiky. suostituted by pioenys,
R*is (1) a hydrogen atom, (2) C1-8 alkyl, (3) C1-8 alkoxy, (4) hydroxy, (5) halogen atom, (6) nitro or (7) NR*?RZ,
R* and R® are each independently (1) a hydrogen atom or (2) C1-8 alkyl,
E'is C1-4 alkylene,
EZ is (1) -C(O)NR*-, (2) -NR*C(0)-, (3) -NR*-, (4) -C(0)O- or (5) -S-,
R* is (1) a hydrogen atom, (2) C1-8 alkyl or (3) C1-8 alkyl substituted by phenyl,
E? is (1) a bond or (2) C1-8 alkylene,
® ®
E'is (1) C1-8 alkyl, (2) C2-8 alkenyl, (3) C2-8 alkynyl, (4) Cyc5, (5) NRPR*, (6) ORY, (7)
SR*, (8) COORY, (9) C1-8 alkyl substituted by two of OR®, (10) C1-8 alkyl substituted by 1 to 3 halogen atom(s), (11) cyano or (12) C2-8 acyl,
R* is (1) a hydrogen atom, (2) C1-8 alkyl, (3) C2-8 alkenyl, (4) C2-8 alkynyl, (5) Cyc5 or (6)
C1-8 alkyl substituted by Cyc5 or OR%,
R® is (1) a hydrogen atom, (2) C1-8 alkyl, (3) C1-8 alkoxycarbonyl, (4) phenyl or (5) C1-8 alkyl substituted by phenyl,
RY is (1) a hydrogen atom, (2) C1-8 alkyl, (3) CycS or (4) C1-8 alkyl substituted by Cyc5,
R* is (1) a hydrogen atom or (2) C1-8 alkyl,
G' is C1-8 alkylene,
Cycl is (1) partially or fully saturated C3-10 mono- or bi-carbocyclic aryl, or (2) partially or fully saturated 3-10 membered mono- or bi-hetero aryl containing 1 to 4 hetero atom(s) selected from oxygen, nitrogen and sulfur atoms,
Gis (1) a hydrogen atom, (2) C1-8 alkyl, (3) C1-8 alkoxycarbonyl, (4) C2-8 acyl, (5) Cyc6, (6) C1-8 alkyl or C2-8 alkenyl substituted by 1 to 2 substituent(s) selected from Cyc, hydroxy and C1-8 alkoxy, (7) C1-8 alkoxycarbonyl substituted by Cyc6, (8) -C(O)-
Cyc§, (8) nitro, (18) NRYR¥, (11) Ci-8 alkoxy or (12) Ci-8 alkyl substituted oy
NRYR*,
R* and R*? are each dependently (1) a hydrogen atom or (2) C1-8 alkyl,
R’ is (1) a hydrogen atom, (2) C1-8 alkyl, (3) C1-8 alkoxy, (4) hydroxy, (5) nitro, (6) NR*R*, (7) C1-8 alkyl substituted by NR*R*, (8) NHSO,0H, (9) amidino, (10) cyano, (11) a halogen atom, (12) Cyc8 or (13) C1-8 alkyl substituted by Cyc8,
R? and R* are each independently : (1) a hydrogen atom or (2) C1-8 alkyl,
Cyc2, Cyc3, Cyc4, CycS5, Cyc6 and Cyc8 are each independently
® ¢)) partially or fully saturated C3-10 mono- or bi-carbocyclic aryl, or (2) partially or fully saturated 3-10 membered mono- or bi-hetero aryl containing 1 to 4 hetero atom(s) selected from oxygen, nitrogen and sulfur atoms,
Cyc7 1s (1) partially or fully saturated C3-10 mono- or bi-carbocyclic aryl, or (2) partially or fully saturated 3-10 membered mono- or bi-hetero aryl containing 1 to 4 hetero atom(s) selected from oxygen, nitrogen and sulfur atoms, with proviso that Cyc7 is not benzene,
Cyc2, Cyc3, Cyc4, CycS, Cyc6 and Cyc8 are optionally substituted by 1 to 3 substituent(s) selected from (1) C1-8 alkyl, (2) C2-8 alkenyl, (3) C1-8 alkoxy, (4) halogen atom, (5) trihalomethyl, (6) trihalomethoxy, (7) C1-8 alkoxycarbonyl, (8) oxo, (9) C1-8 alkyl substituted by C1-8 alkoxy or phenyl, (10) hydroxy and (11) NR*R¥, m and n are each independently 1 or 2, wherein 6) when A is A! or A? then
G4
Z I isnot
Y<
CoC a e CO (ii) when A is A® and ~~ (= is CX or @¢ , then
Y<
Rig not hydroxy or CI1-R alkoxy, (iii) when Ais A’, then ~~ (23% is not
Y< < , ug , 4 or CC , and (iv) following compounds of (1) to (13) are excepted; (1) 4-(3-chloro-4-methoxyphenyl)-4a,5,8,8a-tetrahydrophthalazin-1(2H)- one, (2) 4-(3,4-dimethoxyphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, (3) 4-phenyl-6,7,8,8a-tetrahydropyrrolo[1,2-d][1,2,4]triazin-1(2H)-one, (4) 4-phenyl-5,6,7,8-tetrahydrophthalazin-1(2H)-one, (5) 4-(4-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, (6) 4-(4-fluoropheny!)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, (7) 4-(4-chlorophenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, -8-
I
® ® (8) 4-(4-bromophenyl)-5, 6,7,8-tetrahydrophthalazin-1(2H)-one, (9) 7-hydroxy-4-phenyl-6,7,8,8a-tetrahydropyrrolo] 1,2-d][1,2,4]triazin- 1(2H)-one, (10) 4-phenyl-8,8a-dihydro[ 1,3 ]thiazolo[3,4-d][1,2,4]triazin-1(2H)-one, (11) 4-(pyridin-4-ylmethyl)-5,6,7,8-tetrahydrophthalazin- 1(2H)-one, (12) 4-t-butoxycarbonylmethyl-5,6,7, 8-tetrahydrophthalazin-1(2H)-one, (13) 4-ethoxycarbonylmethyl-5,6,7, 8-tetrahydrophthalazin-1(2H)-one, or a pharmaceutically acceptable salt thereof, 2) a process for preparing thereof, and 3) an agent comprising the same as an active ingredient.
In the specification, C1-8 alkyl means methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl or isomeric groups thereof.
In the specification, C2-8 alkenyl means ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl or isomeric groups thereof.
In the specification, C2-8 alkynyl means ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl or isomeric groups thereof.
In the specification, C1-8 alkoxy means methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy or isomeric groups thereof.
In the specification, C2-8 alkenyloxy means ethenyloxy, propenyloxy, butenyloxy, pentenyloxy, hexenyloxy, heptenyloxy, octenyloxy or isomeric groups thereof.
In the specification, C2-8 alkynyloxy means ethynyioxy, propynyloxy, butynyioxXy, pentynyicxy, LexynylSxy, Lestymyloxy, cotynyloxy or isomeric groups thereof.
In the specification, C1-8 alkylthio means methylthio, ethylthio, propylthio, butylthio, pentylthio, hexyithio, heptylthio, octylthio or isomeric groups thereof.
In the specification, Cl1-4 alkylene means methylene, ethylene, trimethylene, tetramethylene or isomeric groups thereof.
In the specification, CI1-8 alkylene means methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene or isomeric groups thereof.
In the specification, C2-8 alkenylene means ethenylene, propenylene, butenylene, pentenylene, hexenylene, heptenylene, octenylene or isomeric groups thereof.
_ ®
In the specification, C1-8 alkoxycarbonyl means methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, heptyloxycarbonyl, octyloxycarbonyl or isomeric groups thereof.
In the specification, trihalomethyl is methyl substituted by three halogen atoms.
In the specification, trihalomethoxyl is methoxyl substituted by three halogen atoms.
In the specification, C2-8 acyl means ethanoyl (acethyl), propanoyl (propionyl), butanoyl (butyryl), pentanoyl (valeryl), hexanoyl, heptanoyl, octanoyl or isomeric groups thereof.
In the specification, C3-8 cycloalkyl means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl.
In the specification, halogen means chlorine, bromine, fluorine or iodine.
In the specification, partially or fully saturated C3-10 mono-carbocyclic aryl represented by ~~ @
Y< is cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclooctene, cyclononene, cyclodecene, cyclohexadiene, cycloheptadiene, cyclooctadiene efc.
In the specification, partially or fully saturated 3-10 membered mono-hetero aryl containing : tC 4 heterc atom(s; selected fom oxygen, nitrogen znd sulfur atoms represented by re &@
Y< means aziridine, azetidine, pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine, piperazine, dihydropyrimidine, tetrahydropyrimidine, ~perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, ~~ perhydropyridazine, ~~ dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine, tetrahydrodiazepine, perhydrodiazepine, oxirane, oxetane, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrooxepine,
® tetrahydrooxepine, perhydrooxepine, ~~ thiirane, thietane, dihydrothiophene, tetrahydrothiophene, dihydrothiaine (dihydrothiopyran), tetrahydrothiaine (tetrahydrothiopyran), ~~ dihydrothiepine, tetrahydrothiepine, ~~ perhydrothiepine, dihydrooxazole, tetrahydrooxazole (oxazolidine), dihydroisoxazole, tetrahydroisoxazole (isoxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole, tetrahydroisothiazole (isothiazolidine), dihydrofurazan, tetrahydrofurazan, dihydrooxadiazole, tetrahydrooxadiazole (oxadiazolidine), dihydrooxazine, tetrahydrooxazine, dihydrooxadiazine, tetrahydrooxadiazine, ~~ dihydrooxazepine, tetrahydrooxazepine, perhydrooxazepine, dihydrooxadiazepine, tetrahydrooxadiazepine, perhydrooxadiazepine, dihydrothiadiazole, tetrahydrothiadiazole ~(thiadiazolidine), dihydrothiazine, tetrahydrothiazine, dihydrothiadiazine, tetrahydrothiadiazine, dihydrothiazepine, tetrahydrothiazepine, perhydrothiazepine, dihydrothiadiazepine, tetrahydrothiadiazepine, perhydrothiadiazepine, morpholine, thiomorpholine, oxathiane, dioxolane, dioxane, dithiolane, dithiane ef.
In the specification, among partially or fully saturated 3-10 membered mono- or bi-hetero aryl containing 1 to 4 hetero atoms selected from oxygen, nitrogen or sulfur atom represented by Cycl, Cyc2, Cyc3, Cyc4, Cyc, Cyc6, Cyc7 and Cyc8, 3- membered mono- or bi-hetero aryl containing 1 to 4 hetero atoms selected from oxygen, nitrogen or sulfur atom means, for example, pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepine, thiophene, thiaine, thiepine, oxazole, isoxazole, thiazole, isothiazole, furazan, oxadiazole, oxazine, oxadiazine, oxazepine, oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine, thiadiazepine, indole, isoindole, indolizine, benzorturan, isobenzofuran, oenzothicphens, Ischemzcothiophene, dithianaphthalene, indazole, quinoline, isoquinoline, quinolizine, purine, phthalazine, pteridine, naphthyridine, quinoxaline, quinazoline, cinnoline, benzoxazole, benzothiazole, benzimidazole, chromene, benzofurazan, benzothiadiazole, benzotriazole efc.
Also, partially or fully saturated 3-10 membered mono- or bi-hetero aryl containing 1-4 hetero atoms selected from oxygen, nitrogen or sulfur atom, means aziridine, azetidine, pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine, piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, ~dihydropyridazine, tetrahydropyridazine, ~~ perhydropyridazine, dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine, tetrahydrodiazepine, perhydrodiazepine, oxirane, oxetane, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrooxepine,
® ® tetrahydrooxepine, ~~ perhydrooxepine, thiirane, thietane, dihydrothiophene, tetrahydrothiophene, dihydrothiaine (dihydrothiopyran), tetrahydrothiaine (tetrahydrothiopyran), dihydrothiepine, tetrahydrothiepine, perhydrothiepine, dihydrooxazole, tetrahydrooxazole (oxazolidine), dihydroisoxazole, tetrahydroisoxazole (isoxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole, tetrahydroisothiazole (isothiazolidine), dihydrofurazan, tetrahydrofurazan, dihydrooxadiazole, tetrahydrooxadiazole (oxadiazolidine), dihydrooxazine, tetrahydrooxazine, dihydrooxadiazine, tetrahydrooxadiazine, dihydrooxazepine, tetrahydrooxazepine, perhydrooxazepine, dihydrooxadiazepine, tetrahydrooxadiazepine, perhydrooxadiazepine, dihydrothiadiazole, tetrahydrothiadiazole (thiadiazolidine), dihydrothiazine, tetrahydrothiazine, dihydrothiadiazine, tetrahydrothiadiazine, dihydrothiazepine, tetrahydrothiazepine, perhydrothiazepine, dihydrothiadiazepine, tetrahydrothiadiazepine, perhydrothiadiazepine, morpholine, thiomorpholine, oxathiane, indoline, isoindoline, dihydrobenzofuran, perhydrobenzofuran, dihydroisobenzofuran, perhydroisobenzofuran, dihydrobenzothiophene, perhydrobenzothiophene, dihydroisobenzothiophene, perhydroisobenzothiophene, dihydroindazole, perhydroindazole, dihydroquinoline, tetrahydroquinoline, perhydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline, perhydroisoquinoline, dihydrophthalazine, tetrahydrophthalazine, perhydrophthalazine, dihydronaphthyridine, tetrahydronaphthyridine, perhydronaphthyridine, dihydroquinoxaline, tetrahydroquinoxaline, perhydroquinoxaline, dihydroquinazoline, tetrahydroquinazoline, perhydroquinazoline, ~~ dihydrocinnoline, tetrahydrocinnoline, perhydrocinnoline, benzoxathiane, dihydrobenzoxazine, dihydrobenzothiazine, pyrazinomorpholine, dihydrobenzoxazo.e, pernydrobenzoxazale, dihydrobenzotiiazcls, perhydrobenzothiazole, dihydrobenzimidazole, perhydrobenzimidazole, dioxolane, dioxane, dithiolane, dithiane, dioxaindan, benzodioxane, chroman, benzodithiolane, benzodithiane efc.
The above hetero ring includes N-oxide which is the compound where nitrogen is oxidized.
In the specification, partially or fully saturated C3-10 mono- or bi- carbocyclic aryl represented by Cycl, Cyc2, Cyc3, Cyc4, CycS, Cyc6, Cyc and Cyc8 is cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclooctene, cyclononene, cyclodecene, cyclopentadiene, cyclohexadiene, cycloheptadiene, cyclooctadiene, benzene, pentalene, azulene, perhydroazulene,
. perhydropentalene, indene, perhydroindene, indan, naphthalene, teterahydronaphthalene or perhydronaphthalene etc.
Unless otherwise specified, all isomers are included in the present invention.
For example, alkyl, alkenyl, alkynyl, alkylene and alkoxy group includes straight or branched ones. In addition, isomers on double bond, ring, fused ring (E-, Z-, cis-, trans-isomer), isomers generated from asymmetric carbon atom(s) (R-, S-, a-, B-1somer, enantiomer, diastereomer), optically active isomers (D-, L-, d-, l-isomer), polar compounds generated by chromatographic separation (more polar compound, less polar compound), equilibrium compounds, mixtures thereof at voluntary ratios and racemic mixtures are also included in the present invention.
According to the present invention, unless otherwise indicated and as is apparent for those skilled in the art, symbol a indicates that it is bound to the opposite side of the sheet (namely o-configuration), symbol eg indicates that it is bound to the front side of the sheet (namely B-configuration), symbol +7 indicates that it is ot-, B- or a mixture thereof, and symbol ~~ indicates that it is a mixture of o-configuration and B-configuration.
The compound of the present invention can be converted into a pharmaceutically acceptable salt by known methods.
The pharmaceutically acceptable salt is preferably water-soluble.
The pharmaceutically acceptable salt means, for example, salts of alkali metals (potassium, sodium, lithium, efc.), salts of alkaline earth metals (calcium, magnesium, efc.), ammonium salts (tetramethylammonium, tetrabutylammmonium, etc), salts cof crgenic amines (triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris(hydroxymethyl)methylamine, lysine, arginine, N-methyl-D- glucamine, efc.), acid-addition salts (inorganic acid salts (hydrochloride, hydrobromate, hydroiodate, sulfate, phosphate, nitrate, efc.), organic acid salts (acetate, trifluoroacetate, lactate, tartrate, oxalate, fumarate, maleate, benzoate, citrate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, isethionate, glucuronate, gluconate, etc.), efc.
Furthermore, solvates or solvates of the above alkai (earth) metals, ammmonium, organic amines and acid-addition salts of the compound of the present invention are included in the pharmaceutically acceptable salt of the present invention.
The solvate is preferably nontoxic and water-soluble. Appropriate solvate means, for example, solvates such as water, an alcohol solvent (ethanol eic.), etc.
In the specification, xX
Yo is preferably partially or fully saturated C3-7 mono-carbocyelic aryl, or partially or fully saturated 3-7 membered mono-hetero aryl containing 1 to 2 hetero atom(s) selected from oxygen, nitrogen and sulfur atom. Moreover, partially or fully saturated C3-7 mono-carbocyclic aryl, or partially or fully saturated 3-7 membered mono-hetero aryl is preferably following compounds;
Partially or fully saturated 3-7 membered mono-hetero aryl containing 1 to 2 hetero atom(s) selected from oxygen, nitrogen and sulfur atoms is preferably following compounds; aL OX. CX. Cr GX
N ’ N 1 ’ SZ ’ N ! ~ ~ H
H
: H N <
OCC fy LK
HN CX "ON NS
H aA Od dit Sd
NN ! SNS ’ S Nu ’ EAN ' SNS
YY
Ae
In the specification, A is preferably Al, A%or AC.
In the specification, D! is preferably -NR®C(O)-, -NR°C(S)-, -NR®SO,- or -
CH,-NR®-, and more preferably -NREC(0)-.
In the specification, D? is preferably C1-8 alkylene, C2-8 alkenylene, -(C1-4 alkylene)-O-(C1-4 alkylene)-, -(C1-4 alkylene)-S-(C1-4 alkylene)-, -(C1-4 alkylene)-
NR®-(C1-4 alkylene)- or -(C1-8 alkylene)-(Cyc2)-, and more preferably C1-8 alkylene.
In the specification, D’ is preferably NR°R' or Cyc3.
In the specification, E! is preferably C1-4 alkylene.
In the specification, E? is preferably -C(O)NR**., NR*C(0)-, -NR*- or -S-
In the specification, E’ is preferably bond or C1-8 alkylene.
In the specification, E* is preferably CycS or NR¥R%.
In the specification, Cycl is preferably partially or fully saturated 3-10 membered mono-hetero aryl containing 1 to 2 hetero atom(s) selected from oxygen, nitrogen and sulfur atom.
In the specification, when A is A’ or A, at least one of X and Y is preferably
N.
In the specification, when A is Alor AY xX
Z 1 is preferably
Y
N
HN
OC. WX "OC OX
H
$Y SN
LUNG or LUNG
Amcrg the compounds of the present invention represented by formula (I), preferred compounds are compounds represented by formula (I-A-1) (0)
NH
1
Rm = (I-A-1) a © N12 3 (R)y— —7D—D"—D
A
(wherein all symbols have the same meanings as described above.), compounds represented by formula (I-A-2)
0)
Ryt m
Sy (1-A-2)
H
4 > 1 2 3 (R TC —D*—D
AN
(wherein all symbols have the same meanings as described above), compounds represented by formula (I-B-1)
Oo
NH
(RY) ! 1-B-1 ~N (1- = ) g'—e?—e’—E* (wherein all symbols have the same meanings as described above), compounds represented by formula (I-B-2) 0) 1 Ie NH
Rr 1k 1-8-2)
NT
H “ ~ -
E'—E*—E>—E* (wherein all symbols have the same meanings as described above.), compounds represented by formula (I-C-1) (0
NH
1 (R CL (1-C-1) ~N
® (wherein all symbols have the same meanings as described above.), and compounds represented by formula (I-C-2) oO me I I-C-2
N ~N (-c-2)
N
H ee (wherein all symbols have the same meanings as described above.).
Concrete compounds of the present invention include compounds shown in
Tables 1 to 90, compounds described in Examples, and pharmaceutically acceptable salts thereof.
In each Table, Me represents methyl group, Et represents ethyl group, Pr represents propyl group, i-Pr represents isopropyl group, Bu represents butyl group, c-
Pr represents cyclopropyl group, c¢-Bu represents cyclobutyl group, c-Pen represents cyclopentyl group, c-Hex represents cyclohexyl group, Ph represents phenyl group, Bn represents benzyl group, and other symbols have the same meanings as described above.
table 1 0 [ _N 1-A-1-1 0 ( ) nN" D2—p?
H
No 020° | No .0%D° [No .0%D°
H
1 Me 11 {CHz);-NH, 21 ~_N_=°H 2 Er 12 ACHAeNH, | 22 Ney 3 Bu 13 (CHz)s-NH, 23 uN cH 4 -CHyCl 14 -CHp)sNHMe | 24 Ney § ACHeOH | 15 -(CHJeNHMe | 25 N° ,CH
Me cH 6 «CH,),-OH 16 -CH,-NMe; 26 SNF
Me Me 7 ACHJsCOM | 47 -CHeNMe, | 27 JX No Son
Me 8 -(CHy);COMe | 18 {CHsNMe; | 28 ~~~N~Fpe
H
NH | o } - - -C- N Me lo yy, | 19 ACHIeNHoPr | 29 ~~ ~~
NH Me ~~NENH, 20 -CH,-NH-c-Bu 30 SONS Me
H Me ‘Me H table 2 0]
On _N
I-A-1-1 o (1-A-1-1)
N~ DD?
H
H
S CH
31 No Me | 49 MONTY 2 | 51 ») ne . H Me ~~ N
Me
CH NN
32 YTTNTETE | 42 SAN Fe 52 OO
H Me ~~ So « 33 ~~ N Ag, | 43 Nc | 53 li )OMe
CH H NON
N 2 N 3wCTNT | 44 Nyy, | 54 ome
H Me )-OMe
N_& 45 55 N = ~ OH, 46 Th, 56 ae 37 NO ~eCH2 47 NY NH, 57 'S
H Me | FF A Ne
Me a | SN
N NTN
38 ONT Ne 48 A 58 gp. ~~ Or ~~ 39 N“Sen | 49 Lh, 59 fone = NOON OMe 40 ~S NH, so 60 NY table 3
Oo
CA
~N (I-A-1-1) 0)
N~ DZD?
H
OMe NNN ~O~n 81 61 iJ 4 LO Olowe
SNCN ro ~ Orn 0 stone | 1 NY | mS
Me Me
SON OMe 0s 84 Sen 64 1’ Me IY 74 fing \_)-OMe
OMe
So OMe 65 oh) 75 ude Lo | 88 NY
Me Me
SSN On Sen 66 me Me Dome 76 {8 86 Ome f ~Oo~n ~Se~p
CENOUS ERR D |e Oo
O S o TN mm ~ Oo ~ 69 J 79 N™_ ome win
SCN ~0~n OMe 70 wie J | J table 4 0 $s ~N 1-A-1-2 0 { )
N~SD2—D? a H
COZ EC LR
1 Me 11 ACHsNH, | 21 NCH 2 Pr 12 ACHaeNH, | 22 77 NTNcn 3 Bu 13 <CHlsNH, | 23 _N_zCH 4 -CHyCl 14 ACHseNHMe | 24 Nc
Me ~(CH;);-OH 15 -(CH;)4-NHMe 25 ___N _=CH
Me cH 6 -(CH2)4-OH 16 -CH2-NMe; 26 SON
Me Me 7 ACHJsCOM | 17 ACHaeNMe, | 27 | KN cH
Me 8 -(CH;)3-CO.Me 18 -(CH3)4-NMe, 28 SOS N Me
H
NH | | H
N:P | 49 HCHy)4-NH-c-Pr | 29 ~~ Noa Me
NH, Me
NH Me ~~pt 20 CHyNH<cBu | 30 “KN Me
N" "NH
H 2 Me Me H table 5
Oo
Ou ~.N
I-A-1-2 o ( )
N~ DPD? ci H
No 02D) [No tp’ [No ptt
H s CH 31 Nox Me | 41 OY NTF™2 | 59 1) nee Ne H Me ~
Me 392 SNe 42 “SNF 52 SONY
H Me s . 33 ~~NoAgy, 43 ~~ ~ TN cH 53 Ou 2a OMe
CH H NN
34 me NTE 44 Ney, 54 Nome
H Me [OMe
Neh 45 55 N = ~O~nH, 46 Wh, 56 de OMe 27 On y~CHe 47 YT XYTNH; 57 m : H Me | 0 pC | NNN
Me ~~~ 38 SON 48 I 58 OU
Oo ~~ 39 Me SCH 49 Li, 59 oh Ae
S oM 40 ~~ SNH, 50 OO 60 ~NY {<]
table 6 0) [a : _N (I-A-1-2) (0)
NS DZD? ci H
OMe ~~ ~O0.~ 61 NY N
J 71 LO 81 Come
NSN ae) ~ On 62 oe 72 ~~ NA 82 2
Oo 63 iL 73 NSN gz “ON fing OMe LO Lo 64 SSN OMe 74 9 ~Se~n
Me Me TY fing 84 L)-ONe
OMe - YY TNT ~~ So OMe 85 N_~ 75 Me Mm 85 NY
Wr hg ES ~ 66 Me M 76 YSN 86 e Me ome 1 Come : ~Oc~n NSS 7 kJ | 7 SILL “ &8 SN 78 Oy 88 ~ENY 69 J 79 ~O~"NN on ag LJ-oue
N Ne OMe 0 wie LJ | 80 NY table 7 0
Oh _N
I-A-1-3 o ( )
N~ DZD?
CF, H ho oo [Ne ood [Ne vier 1 Me 11 -CHaeNH, | 21 CH 2 Pr 12 HCHpeNH, | 22 7 NTNen 3 Bu 13 -CHlsNH, | 23 _N_zCH 4 -CHyC 14 ACHeNHMe | 24 7 Ncy § -(CH)sOH | 15 {CHaeNHWe | 25 N° CH
Me _cH 6 -(CH2);-OH 16 -CHz-NMe; 26 ~~ ~Z
Me Me 7 ACHJyCOM | 17 {CHisNMe, | 27 I~ Neu
Me 8 -(CH2)s-COMe | 18 -(CH3)4-NMe, 28 SNe 9 NH | 19 (CH NH-CPY | 29 He ~~ 0H, 2)4 ~
NH Me ~~N*NH, 20 -CHp-NH-c-Bu 30 SON Me
H me Me H table 8
Oo
Pi ~N 1-A-1-3 o ( )
Ag
CF, H
No oi0 [No oiD* [No 0D
H
S_~ CH, 31 Noa Me | 44 "NTF 51 nde Me H Me nh
SSA | 40 Os S| sa SN
H Me ~~ ~N Me 0
H Me S_~ ~ 33 ~~ Nihgy, 43 ~~ Nc 53 ou 0 OMe
CH H SN
N 2 N 3am Ne | 44 ~Ne~ww, | 4 LD-0me
H Me OM ~S~Noben, | 45 “Cha 55 SAT :
Me Me Me Me
N
37 “ONC | gy SYSYTNH: | 57 mM
H Me | i SZ | NN ST
Me 38 NON Me 48 NL | 8 39 Me CH 49 Lo, 59 cf Loe
N om 40 “SNH, so 1) 60 ~Y }
table 9 0)
Bhi ~.N (1-A-1-3) 0
N° D?—D?
CF; H
No 0%* | No nD? | No pAD® 61 OMe 74 NNT 81 ONY
NNN —~o Ouny 62 Dome 72 ~~ NU/ 82 $ 63 TL 73 SSN 33 NON tig OMe oO (_O
Me Me Y 74 add 84 ome e 65 ro 75 SENN 35 ~ Son OMe
I Me M L o iM ig eMe LO US
YON [0] Sen 66 Ne Me 76 ~0~n 86
Dove a lowe jer JD | TT yer Ol
NN lo) 69 iJ 79 “ON on ve Or €
Oo OMe © wie J | wo Y table 10 0 [NH _N (I-A-1-4)
N—D?—D3
H
No op [Ne op [Ne oo 1 Me 11 (CHasNH, | 21 CH 2 Pr 12 -(CH2)4-NH; 22 SNe 3 Bu 13 (CHsNH; | 23 NCH 4 CHpCl 14 -(CHpjsNHMe | 24 ~~ NSSeu
Me
ACHps-OH | 15 -(CHp)eNHMe | 25 _ __ N° 2CH
Me cH 6 -(CHy),-OH 16 -CH,-NMe; 26 SNF
Me Me
NS
7 ACHsCOM | 17 ACHayNMe, | 27 LJ ~ Me “CH
Me 8 +{CHy)3-CO,Me | 18 -(CHp)s;-NMe, 28 ~~~N~ Me
H
NH - -NH-c- N Me
E A, | 19 CHINE | 28 ~~ te
NH Me ~~nNH, | 20 CHANHeBu | 30 SA N~Fwe
H Me me H -27-
A table 11 (0) $s ~.N (1-A-1-4)
N—D?—D?
H
No oid [Ne orp [Ne 00
H Ss CH 31 SN Me 4“ NT 2 | 5 li)
Me Me Me
Me ~~ 32 SNS: 42 NSN ve 52
H Me S S 33 ~o~N_Acy, 43 ~~ ~NcH 53 Ril
CH, H SNOSNCN
H Me [OMe
N_A 45 55 N i hg CH, “Uh 0, fing - ~~ O~NH, 46 Uh, 56 mde L>-OMe 0) CH 37 ~ NY 2 47 Oye 57 uD
Me NN 3s SON te a TN se 0 o S 39 TN NcH | 49 Sn, 59 oh Hone “ OMe 40 ~S<~NH, 50 ~~ 60 YY table 12
Oo
Ph ~N (I-A-1-4)
N—D*—D°
H
No oot [No php’ | No ohp® on on | wn
J 0 OMe
NNN ro ~O~N 62 oe 72 ~~ NU 82 O
SNOT o g NN SAUNT 63 I fag PS. 73 Lo 83 LO 64 we NY 74 Pi 84 SSNS ome e Me Me Me
OMe
S_~ OMe 65 J 75 I 85 \ me’ Me ) ~ J “STN Ou ~S-~n 66 Me Me one 76 NA 86 Doe ~ Orrin - SSeS 67 oN | 77 L) | 8:
NSN ~Cr ~S nN 68 QO | | ee Lo 69 iJ 79 ONY om wn ore 70 we 80 OY table 13 0
Oh _N (I-A-1-5)
N—D2—D? ct H
No wip [Ne oot [No op 1 Me 11 -(CHy)3-NH, 21 N _4CH 2 Pr 12 -CHeNH, | 22 7 NTNcy 3 Bu 13 ~(CH,)s-NH, 23 uN ACH 4 -CH,-Cl 14 -(CHy)3-NHMe | 24 NINH § ACHJsOH | 15 -(CHpeNHMe | 25 N° CH
Me _cH 6 -(CHy)4OH 16 -CH;-NMe, 26 ~S~NA
Me Me 7 CHsCOM | 17 {CHaaNMe, | 27 JS Me SCH
Me 8 -(CH2sCOMe | 18 -ACHysNMez | 28 “~~~ Me
H
NH | CH,)s-NH-c-P | n Me ! 9 ~~ANH, | 19 -(CHp)s-NH<c-Pr | 29 ~~ ,
NH Me ~~N*’NH, 20 -CHyNH-c-Bu | 30 SKN ve
H Me me H table 14 0)
CA
~.N (I-A-1-5)
N—D?*—D’® ci H
CE CT
H S_~ CH, .) 31 Nox Me | 41 NTF 51 NK ude Me H Me
Me ~~ 32 SNH 42 SAN we 52 >
H Me ~Sone OMe
CH H SNSNN
34 me Te Pl o44 ~No~NH, 54 LD-owe
H Me [OMe
N 55 N i, g AcH, | 45 “Che ing
N
= ~O~NH, 46 Uh, 56 De ~O.~ CH, x NH, wey we Cw 0
Me NNN o S 39 ~ Ncw 49 Sh 59 eh Kos
S ~~ OMe table 15 0) [A ~.N (1-A-1-5)
N—p?*—p? ci H
OMe SUNT ~0.~N 61 J 0 81 Olome 62 Te 72 ~~ NU 82 J fing OMe Lo LO 64 hl Oa 74 (5 | aa SN om
Me M (o} ene mde °
OMe
S OM
65 J 75 wee ob 85 Ny :
Me Me
SN “Oo ~Se~n « we” ye | 78 wo |e TT, ra ~~ Con oS nN 7 Ad | T Dw 2
ANPEPN 0) | Ss 6 N ON ASNT 8 QO | 0 | 8 Lo 69 iJ ~0n 0 70 wn VO) 80 ~ NY table 16 0)
Oh _N (1-A-1-6)
N—D?*—D?
CF, H 1 Me 11 ACHdeNH, | 21 _N_zCH 2 Pr 12 ACHAeNH, | 22 TN Nc 3 Bu 13 ACHeNH, | 23 _N_=CH 4 -CHyCl 14 {CHasNHMe | 24 TN Seu
CHJwOH | 15 -<CHaeNHMe | 25 NZ CH
Me _cH 6 -(CH,)4,-OH 16 -CH,-NMe, 26 SNF
Me Me 7 ACHpsCOM | 17 «(CHsNMex | 27 dn Me SCH
Me 8 -(CHp)sCOMe | 18 -(CH)sNMe; | 28 ~~ Me
H
NH | CHj)s-NH-c-P | N Me 9 ~~ANH, . 19 - 204" -c-Pr 29 NNN .
NH Me ~~n"NH, | 20 -CHyNH-c-Bu | 30 NONN TE Me
H Me Me H table 17 0)
Pi ~N (I-A-1-6)
N—D*—D*
CF; vo wr wow [le oo
H
S_~ CH, 31 Nox Me | gq NY 51 Ww
Me We Ve H Me ~
Me
H Me S ~ 33 ~~ Nhe, 43 ~ Neu 53 _l1OMe
CH H NSN
N 2 N 34 MeN Te 44 ~Ne~py, 54 \_>-oMe
H Me [_)-OMe
N_A, 55 N ® Totem | 45 Cw ig a= On ~eCH2 47 NYT NH, R7 m - i H Me | - Z ’ NN NS
Me NSN 38 SON We 48 $Y; 58 1
NON
39 Me SCH 49 Lh, 59 of ne
S ~N OMe 40 ~S<nH, so 60 NY table 18 0
Ph ~N (1-A-1-6) ~] x N—D2—D?3 cr, H
No 00’ | Ne ofp! | No oR0® 61 hi J m © od Cone
SN ro ~Oc~n 62 Tone 72 ~NJ 82 $ ~N oO 0 NTN NON 63 I fing oe 73 (_O 83 LO 64 RA 74 HS 84 SNS ome
Me Me me Me
OMe . YY SENN ~S_~ OMe 65 N_ 75 mem S| 85 N™Y
Ag ° ~
SSN On ~S nN 66 Mme Me Toe 76 NA 86 Olowe 7 J | 7 Oo Oo
NNN ~O~n ~SeNy 68 |e 0 | 88 . 69 J 79 ON oy wT L-ove 0] OM 70 wie YD | so CTY table 19 0)
Cy _N (I-A-1-7)
N
No oo [Ne oo [Ne om 1 Me 11 -CHeNH, | 21 __N_zCH he Ve a 2 Pr 12 ACHpuNHp | 22 Neh 3 Bu 13 ACHJsNHz | 23 _N_zCH 4 CHC 14 {CHe-NHMe | 24 7 NScn
ACH)yOH | 15 ACHeNHWe | 25 N° CH
Me cH 6 -(CH3)4-OH 16 -CH,-NMe, 26 SONA
Vie Me ~ 7 ACHsCOM | 17 HCHaaNVe, | 27 J Ne SoH
Me 8 wren 18 -(CH;)4-NMe, 28 ~~ NE Me
H
9 ~~ 19 “Chigjgminn-C-r’ 25 STR
NH, | | Me
NH Me ~~N2NH 20 -CH,-NH-c-Bu 30 SON We
H me ‘we H table 20
Oo
Ps ~N (I-A-1-7)
N
CE CZ
H s. CH 31 SeoNosMe | ogg OYTNTETE 8 ND
Me Me Me
Me
SSN CH, S NTN 32 NY. 42 ~ Ne 52 LD
H Me S ~ 3B Ng, | BT Ne | 53 NOME
CH H NN
N 2 N
BE me NY. 4 ~Ne~yy, 54 "ome
H Me (-ome
Noten, | 45 55 N wd ve i “The mde
NNT
36 ~~O~"NH, 46 Uh, 56 ydfe L)-OMe
Opp CHz NH; 37 NYS a UJ 57 kJ wie SNA 8 ome | #0 CF [sw TTD ~~ Oc~n~a 39 Ne <CH 49 Ln, 59 oh oe = OMe 40 ~So NH, 50 ~~ 60 SY
Claims (30)
1. A fused pyridazine derivative compound represented by formula (I) 0) rR’ z ny (Rm a 0) A wherein R! is (1) a hydrogen atom, (2) C1-8 alkyl, (3) C1-8 alkoxy, (4) hydroxy, (5) halogen atom, (6) nitro, (7) NR’R?, (8) C2-8 acyl, (9) C1-8 alkoxy substituted by phenyl or (10) C2-8 acyl substituted by NR’R?, R? and R? are each independently (1) a hydrogen atom or (2) C1-8 alkyl, X and Y are each independently (DC, (2)CHor 3) N, T===T is (1) a single bond or (2) a double bond, xX” Y~ is (1) partially or fully saturated C3-10 mono-carbocyclic aryl or (2) partially or fully saturated 3-10 membered mono-hetero aryl containing 1 to 4 hetero atom(s) selected from oxygen, nitrogen and sulfur atoms, Ais (1) AL, (2) AZ (3) A, (4) A* or (5) A’, 1: 4 Z
2 A'is (R oe —p
3, A’is —E'—E2—E*—FE4, Adis a {eyer)
4. ~ 5 Alls oR In’
® ®
Ais Gro
D!is (1) -NR®C(0)-, (2) -NRSC(S)-, (3) -NR®SO,-, (4) -CH,-NR®-, (5) -CH,-0-, (6) -OC(O)-, (7) -CH2-NR®C(0)-, (8) -NRC(O)NR’-, (9) -NR°C(0)O-, (10) -NR*C(S)NR-, (11) - NR®- or (12) -NR°C(=NR")-,
R® and R” are each independently (1) a hydrogen atom, (2) C1-8 alkyl, (3) phenyl or (4) C1-8 alkyl substituted by phenyl,
D? is (1) C1-8 alkylene, (2) C2-8 alkenylene, (3) Cyc2, (4) ~(Cl-4 alkylene)-O-(C1-4 alkylene)-, (5) -(C1-4 alkylene)-S-(C1-4 alkylene)-, (6) -(C1-4 alkylene)-NR®-(C1-4 alkylene)-, (7) -(Cyc2)-(C1-8 alkylene)-, (8) -(C1-8 alkylene)-(Cyc2)- or (9) -(C1-4 alkylene)-(Cyc2)-(C1-4 alkylene)-,
R%is (1) a hydrogen atom, (2) C1-8 alkyl, (3) C1-8 alkoxycarbonyl, (4) phenyl or (5) C1-8 alkyl! substituted by phenyl,
D’ is (1) a hydrogen atom, (2) -NR’R™, (3) Cyc3, (4) -OR", (5) COOR", (6) CONR"R", (7) cyano, (8) a halogen atom, (9) -C(=CR*)NRR"” or (10) -NR'*C(=NR*)NR*’R*,
R® and R" are each independently (1) & hydrogen atom, 12) C1-8 2lkyl, (2) C2-8 alkenyl, (4) C2-2 allymy! (5) Cyl, (6) C1-8 alkoxy, (7) C2-8 alkenyloxy, (8) C2-8 alkynyloxy or (9) C1-8 alkyl substituted by Cyc3, C1-8 alkoxy, C1-8 alkylthio, cyano, hydroxy or 1 to 3 halogen atom(s),
R' and R'* are each independently (1) a hydrogen atom, (2) C1-8 alkyl, (3) C2-8 alkenyl, (4) C2-8 alkynyl, (5) C1-8 alkoxycarbonyl, (6) C2-8 acyl, (7) C3-8 cycloalkyl, (8) C1-8 alkoxycarbonyl substituted by Cyc4 or 1 to 3 halogen atom(s), or (9) C1-8 alkyl substituted by C1-8 alkoxy,
RY and R"? are each independently (1) a hydrogen atom or (2) C1-8 alkyl,
RY R' RY R!® RY R? and R* are each independently (1) a hydrogen atom, (2) C1-8 alkyl, (3) C1-8 alkoxycarbonyl, (4) phenyl or (5) C1-8 alkyl substituted by phenyl,
R*is
® ®
(1) a hydrogen atom, (2) C1-8 alkyl, (3) C1-8 alkoxy, (4) hydroxy, (5) halogen atom, (6) nitro or (7) NR*?R?,
R* and R® are each independently (1) a hydrogen atom or (2) C1-8 alkyl,
E'is C1-4 alkylene,
E*is (1) -C(O)NR**-, (2) -NR**C(0)-, (3) -NR**-, (4) -C(0)O- or (5) -S-,
R** is (1) a hydrogen atom, (2) C1-8 alkyl or (3) C1-8 alkyl substituted by phenyl,
E’ is (1) abond or (2) C1-8 alkylene,
E'is (1) C1-8 alkyl, (2) C2-8 alkenyl, (3) C2-8 alkynyl, (4) Cyc5, (5) NR¥R*, (6) ORY, (7) SR”, (8) COORY, (9) C1-8 alkyl substituted by two of OR®, (10) C1-8 alkyl substituted by 1 to 3 halogen atom(s), (11) cyano or (12) C2-8 acyl,
R* is (1) a hydrogen atom, (2) C1-8 alkyl, (3) C2-8 alkenyl, (4) C2-8 alkynyl, (5) Cyc5 or (6) C1-8 alkyl substituted by Cyc5 or OR%,
R* is (1) a hydrogen atom, (2) C1-8 alkyl, (3) C1-8 alkoxycarbonyl, (4) phenyl or (5) C1-8 alkyl substituted by phenyl,
RY is (1) ahydrogen atom, (2) C1-8 alkyl, (3) Cyc5 or (4) C1-8 alkyl substituted by Cycs5,
R* is (1) a hydrogen atom or (2) C1-8 alkyl,
G' is C1-8 alkylene,
Cycl is (1) partially or fully saturated C3-10 mono- or bi-carbocyclic aryl, or (2) partially or fully saturated 3-10 membered mono- or bi-hetero aryl containing 1 to 4 hetero atom(s) selected from oxygen, nitrogen and sulfur atoms,
Gis (1) a hydrogen atom, (2) CI1-8 alkyl, (3) C1-8 alkoxycarbonyl, (4) C2-8 acyl, (5) Cyc6, (6) C1-8 alkyl or C2-8 alkenyl substituted by 1 to 2 substituent(s) selected from Cyc, hydroxy and C1-8 alkoxy, (7) C1-8 alkoxycarbonyl substituted by Cyc6, (8) -C(O)- Cyc6, (9) nitro, (10) NR*R* (11) C1-8 alkoxy or (12) C1-8 alkyl substituted by NRYR*
_ R*! and R*? are each dependently (1) a hydrogen atom or (2) C1-8 alkyl, R’is (1) a hydrogen atom, (2) C1-8 alkyl, (3) C1-8 alkoxy, (4) hydroxy, (5) nitro, (6) NR¥R*, (7) C1-8 alkyl substituted by NR*R*’, (8) NHSO,0H, (9) amidino, (10) cyano, (11) a halogen atom, (12) Cyc8 or (13) C1-8 alkyl substituted by Cyc8, R* and R* are each independently (1) a hydrogen atom or (2) C1-8 alkyl, Cyc2, Cyc3, Cyc4, CycS5, Cyc6 and Cyc8 are each independently (1) partially or fully saturated C3-10 mono- or bi-carbocyclic aryl, or (2) partially or fully saturated 3-10 membered mono- or bi-hetero aryl containing 1 to 4 hetero atom(s) selected from oxygen, nitrogen and sulfur atoms, Cyc7 is (1) partially or fully saturated C3-10 mono- or bi-carbocyclic aryl, or (2) partially or fully saturated 3-10 membered mono- or bi-hetero aryl containing 1 to 4 hetero atom(s) selected from oxygen, nitrogen and sulfur atoms, with proviso that Cyc7 is not benzene, Cyc2, Cyc3, Cyc4, Cyc5, Cyc6 and Cyc8 are optionally substituted by 1 to 3 substituent(s) selected from (1) C1-8 alkyl, (2) C2-8 alkenyl, (3) C1-8 alkoxy, (4) halogen atom, (5) trihalomethyl, (6) trihalomethoxy, (7) C1-8 alkoxycarbonyl, (8) oxo, (9) C1-8 alkyl substituted by C1-8 alkoxy or phenyl, (10) hydroxy and (11) NR*R*; m and n are each independently 1 or 2, wherein 0) when A is A’ or A? then G4 Z I isnot Y< Col Low CO (ii) when A is A* and ~~ (2% is XC or CX , then Y< R® is not hydroxy or C1-8 alkoxy, (ii) when A is A’, then pe (=X is not Yu Cw om
® ® (iv) following compounds of (1) to (13) are excepted, (1) 4-(3-chloro-4-methoxyphenyl)-4a,5,8, 8a-tetrahydrophthalazin-1(2H)-one, 2) 4-(3,4-dimethoxyphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 3) 4-phenyl-6,7,8,8a-tetrahydropyrrolo[1,2-d][1,2,4]triazin-1(2H)-one, 4) 4-phenyl-5,6,7,8-tetrahydrophthalazin-1(2H)-one, (5) 4-(4-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 6) 4-(4-fluorophenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, ©) 4-(4-chlorophenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, ®) 4-(4-bromophenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 9) 7-hydroxy-4-phenyl-6,7,8,8a-tetrahydropyrrolo[1,2-d][1,2,4]triazin-1(2H)- one, (10) 4-phenyl-8,8a-dihydro[1,3 Jthiazolo[3,4-d][1,2,4]triazin-1(2H)-one, (11) 4-(pyridin-4-ylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, (12) 4-t-butoxycarbonylmethyl-5,6,7,8-tetrahydrophthalazin-1(2H)-one, (13) 4-ethoxycarbonylmethyl-5,6,7,8-tetrahydrophthalazin-1(2H)-one, or a pharmaceutically acceptable salt thereof.
2. The compound represented by formula (I) according to claim 1, wherein 7 © ~ is partially or fully saturated C3-7 mono-carbocyclic aryl and A is Al, or a pharmaceutically acceptable salt thereof.
3. The compound represented by formula (I) according to claim 1, wherein - Gc ~ is partially or fully saturated C3-7 mono-carbocyclic aryl and A is A’ or a pharmaceutically acceptable salt thereof.
4. The compound represented by formula (I) according to claim 1, wherein - Gc ~ is partially or fully saturated C3-7 mono-carbocyclic aryl and A is A’ or a pharmaceutically acceptable salt thereof.
5. The compound represented by formula (I) according to claim 1, wherein xX Zz i Y< is partially or fully saturated C3-7 mono-carbeeyclic aryl and A is A® or A’, or a pharmaceutically acceptable salt thereof.
6. The compound represented by formula (I) according to claim 1, wherein X~ ZL Y< is partially or fully saturated 3-7 membered mono-hetero ary! containing 1 to 2 hetero atom(s) selected from oxygen, nitrogen and sulfur atoms and A is Al, or a pharmaceutically acceptable salt thereof.
7. The compound represented by formula (I) according to claim 1, wherein xX Z i Y< is partially or fully saturated 3-7 membered mono-hetero aryl containing 1 to 2 hetero atom(s) selected from oxygen, nitrogen and sulfur atoms and A is A% or a pharmaceutically acceptable salt thereof.
8. The compound represented by formula (I) according to claim 1, wherein “X 7 Z 1 Y< is partially or fully saturated 3-7 membered mono-hetero aryl containing 1 to 2 hetero atom(s) selected from oxygen, nitrogen and sulfur atoms and A is A? or a pharmaceutically acceptable salt thereof.
9. The compound represented by formula (I) according to claim 1, wherein xX Z 1 Y< is partially or fully saturated 3-7 membered mono-hetero aryl containing 1 to 2 hetero atom(s) selected from oxygen, nitrogen and sulfur atoms and A is A* or A’, or a pharmaceutically acceptable salt thereof.
10. The compound represented by formula (I) according to claim 1, wherein
PCT/JP03/01694 @ X~ Y~ is .
11. A poly(ADP-ribose)polymerase inhibitor comprising, as an active ingredient, the compound represented by formula (I) according tc claim 1 or a pharmaceutically acceptable salt thereof, :
12. A preventive and/or treatment agent for ischemic diseases, inflammatory diseases, neurodegenerative diseases, glaucoma, diabetes, diabetic complication, shock, head trauma, spinal cord injury, renal failure or hyperalgesia comprising, as an active ingredient, the compound represented by formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof. :
13. An antiretroviral drug comprising, as an active ingredient, the compound represented ‘by formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof. . )
14. A sensitizer of anticancer therapy comprising, as an active ingredient, the compound represented by formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof.
15. An immunosuppressant comprising, as an active ingredient, the compound represented by formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof.
16. The preventive and/or treatment agent according to claim 12, wherein the ischemic disease is cerebral infarction. -
17. The compound or the pharmaceutically acceptable salt according to claim 1, which is described in any one of Example 1 to 62.
18. Use of the compound represented by formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof in the manufacture of a preparation for preventing or treating ischemic diseases, inflammatory diseases, neurodegenerative diseases, glaucoma, diabetes, diabetic complication, shock, head trauma, spinal cord injury, renal failure or hyperalgesia. -280 - AMENDED SHEET
PCT/JP03/01694 ® 19. Use according to claim 18, wherein the ischemic disease is cerebral infarction.
20. A substance or composition for use in a method for preventing or treating ischemic diseases, inflammatory diseases, neurodegenerative diseases, glaucoma, diabetes, diabetic complication, shock, head trauma, spinal cord injury, renal failure or hyperalgesia, said substance or composition comprising the compound represented by formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, and said method comprising said substance or composition.
21. A substance or composition for use in a method of prevention or treatment according to claim 20, wherein the ischemic disease is cerebral infarction.
22. A compound according to any one of claims 1 to 10, substantially as herein described and illustrated.
23. An inhibitor according to claim 11, substantially as herein described and illustrated.
24. An agent according to claim 12, substantially as herein described and illustrated. ©
25. A drug according to claim 13, substantially as herein described and illustrated.
26. A sensitizer according to claim 14, substantially as herein described and illustrated.
27. An immunosuppressant according to claim 15, substantially as herein described and illustrated.
28. Use according to claim 18 or claim 19, substantially as herein described and illustrated. -281 - AMENDED SHEET
PCT/JP03/01694 ® 29. A substance or composition for use in a method of treatment or prevention according to claim 20 or claim 21, substantially as herein described and illustrated.
30. A new compound, a new inhibitor, a new agent, a new drug, a new sensitizer, a new immunosuppressant, a new use of a compound according to claim 1 or a pharmaceutically acceptable salt thereof, or a substance or composition for a new use in a method of prevention or treatment, substantially as herein described. \ -282 - AMENDED SHEET
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2002042259 | 2002-02-19 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ZA200406507B true ZA200406507B (en) | 2005-02-21 |
Family
ID=34685725
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ZA200406507A ZA200406507B (en) | 2002-02-19 | 2004-08-16 | Fused pyridazine derivative compounds and drugs containing the compounds as the active ingredient. |
Country Status (3)
| Country | Link |
|---|---|
| CN (1) | CN101284819A (en) |
| ES (1) | ES2362406T3 (en) |
| ZA (1) | ZA200406507B (en) |
-
2003
- 2003-02-18 ES ES03705265T patent/ES2362406T3/en not_active Expired - Lifetime
- 2003-02-18 CN CNA2007101537273A patent/CN101284819A/en active Pending
-
2004
- 2004-08-16 ZA ZA200406507A patent/ZA200406507B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| ES2362406T3 (en) | 2011-07-04 |
| CN101284819A (en) | 2008-10-15 |
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