WO1992003419A1 - Isocarbostiryl compounds and antitumor use thereof - Google Patents
Isocarbostiryl compounds and antitumor use thereof Download PDFInfo
- Publication number
- WO1992003419A1 WO1992003419A1 PCT/CA1991/000302 CA9100302W WO9203419A1 WO 1992003419 A1 WO1992003419 A1 WO 1992003419A1 CA 9100302 W CA9100302 W CA 9100302W WO 9203419 A1 WO9203419 A1 WO 9203419A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- alkyl
- triazol
- substituted
- alkoxy
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims description 55
- 230000000259 anti-tumor effect Effects 0.000 title claims description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 25
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 23
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 10
- 201000009030 Carcinoma Diseases 0.000 claims abstract description 4
- 208000032839 leukemia Diseases 0.000 claims abstract description 3
- -1 triazol-5-yl Chemical group 0.000 claims description 56
- 125000003545 alkoxy group Chemical group 0.000 claims description 20
- 125000001424 substituent group Chemical group 0.000 claims description 18
- 229910052736 halogen Inorganic materials 0.000 claims description 17
- 150000002367 halogens Chemical class 0.000 claims description 17
- 238000000034 method Methods 0.000 claims description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 14
- 239000001257 hydrogen Substances 0.000 claims description 13
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 7
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 6
- 125000005599 alkyl carboxylate group Chemical group 0.000 claims description 6
- 125000002947 alkylene group Chemical group 0.000 claims description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 4
- 125000002252 acyl group Chemical group 0.000 claims description 4
- 229910052783 alkali metal Inorganic materials 0.000 claims description 4
- 150000001340 alkali metals Chemical class 0.000 claims description 4
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 230000020477 pH reduction Effects 0.000 claims description 4
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 3
- 125000000389 2-pyrrolyl group Chemical group [H]N1C([*])=C([H])C([H])=C1[H] 0.000 claims description 3
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 3
- 125000001397 3-pyrrolyl group Chemical group [H]N1C([H])=C([*])C([H])=C1[H] 0.000 claims description 3
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims description 3
- 150000004703 alkoxides Chemical class 0.000 claims description 3
- 125000002962 imidazol-1-yl group Chemical group [*]N1C([H])=NC([H])=C1[H] 0.000 claims description 3
- 125000003037 imidazol-2-yl group Chemical group [H]N1C([*])=NC([H])=C1[H] 0.000 claims description 3
- 125000002140 imidazol-4-yl group Chemical group [H]N1C([H])=NC([*])=C1[H] 0.000 claims description 3
- 125000000336 imidazol-5-yl group Chemical group [H]N1C([H])=NC([H])=C1[*] 0.000 claims description 3
- 125000004287 oxazol-2-yl group Chemical group [H]C1=C([H])N=C(*)O1 0.000 claims description 3
- 125000003145 oxazol-4-yl group Chemical group O1C=NC(=C1)* 0.000 claims description 3
- 125000004304 oxazol-5-yl group Chemical group O1C=NC=C1* 0.000 claims description 3
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 claims description 3
- 125000004495 thiazol-4-yl group Chemical group S1C=NC(=C1)* 0.000 claims description 3
- 125000004496 thiazol-5-yl group Chemical group S1C=NC=C1* 0.000 claims description 3
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
- 206010006187 Breast cancer Diseases 0.000 claims description 2
- 208000026310 Breast neoplasm Diseases 0.000 claims description 2
- 201000008275 breast carcinoma Diseases 0.000 claims description 2
- PLFUTTWSGLAZEX-UHFFFAOYSA-N diethyl 5-acetyl-1-methyl-6-oxo-2-phenylpyridine-3,4-dicarboxylate Chemical compound C(C)(=O)C=1C(N(C(=C(C1C(=O)OCC)C(=O)OCC)C1=CC=CC=C1)C)=O PLFUTTWSGLAZEX-UHFFFAOYSA-N 0.000 claims description 2
- VSBUAMHAZCTEAH-UHFFFAOYSA-N diethyl 5-acetyl-2-ethyl-1-methyl-6-oxopyridine-3,4-dicarboxylate Chemical compound C(C)(=O)C=1C(N(C(=C(C1C(=O)OCC)C(=O)OCC)CC)C)=O VSBUAMHAZCTEAH-UHFFFAOYSA-N 0.000 claims description 2
- JBAJEZZNIFOLBT-UHFFFAOYSA-N ethyl 5-acetyl-4-(2-ethoxy-2-oxoethyl)-2-(furan-2-yl)-6-oxo-1h-pyridine-3-carboxylate Chemical compound N1C(=O)C(C(C)=O)=C(CC(=O)OCC)C(C(=O)OCC)=C1C1=CC=CO1 JBAJEZZNIFOLBT-UHFFFAOYSA-N 0.000 claims description 2
- 206010017758 gastric cancer Diseases 0.000 claims description 2
- 208000010749 gastric carcinoma Diseases 0.000 claims description 2
- 201000000498 stomach carcinoma Diseases 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 7
- 125000006528 (C2-C6) alkyl group Chemical group 0.000 claims 3
- 125000002541 furyl group Chemical group 0.000 claims 3
- 239000008194 pharmaceutical composition Substances 0.000 claims 3
- 229910003827 NRaRb Inorganic materials 0.000 claims 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims 2
- 150000002431 hydrogen Chemical class 0.000 claims 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 2
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 claims 2
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 2
- 125000004076 pyridyl group Chemical group 0.000 claims 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims 2
- 239000002253 acid Substances 0.000 claims 1
- 208000003362 bronchogenic carcinoma Diseases 0.000 claims 1
- 239000007795 chemical reaction product Substances 0.000 claims 1
- UDEDHCMSFDGCTE-UHFFFAOYSA-N ethyl 5-acetyl-2-(4-bromophenyl)-4-(2-ethoxy-2-oxoethyl)-6-oxo-1h-pyridine-3-carboxylate Chemical compound N1C(=O)C(C(C)=O)=C(CC(=O)OCC)C(C(=O)OCC)=C1C1=CC=C(Br)C=C1 UDEDHCMSFDGCTE-UHFFFAOYSA-N 0.000 claims 1
- 229910052500 inorganic mineral Inorganic materials 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 239000011707 mineral Substances 0.000 claims 1
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 claims 1
- 230000003013 cytotoxicity Effects 0.000 abstract description 5
- 231100000135 cytotoxicity Toxicity 0.000 abstract description 5
- 210000004881 tumor cell Anatomy 0.000 abstract description 3
- 201000011510 cancer Diseases 0.000 abstract 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 33
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- 239000000243 solution Substances 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 9
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 9
- 210000004027 cell Anatomy 0.000 description 8
- 238000004458 analytical method Methods 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 229910001868 water Inorganic materials 0.000 description 6
- 0 *C(c(c1c2)cc(O)c2O)=C(*)[N+](*)C1=O Chemical compound *C(c(c1c2)cc(O)c2O)=C(*)[N+](*)C1=O 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- UFTHEDBYLPFRDP-UHFFFAOYSA-N 5,6-dihydro-2h-oxazine Chemical class C1CC=CNO1 UFTHEDBYLPFRDP-UHFFFAOYSA-N 0.000 description 2
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 2
- SXRSQZLOMIGNAQ-UHFFFAOYSA-N Glutaraldehyde Chemical compound O=CCCCC=O SXRSQZLOMIGNAQ-UHFFFAOYSA-N 0.000 description 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 244000309466 calf Species 0.000 description 2
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 239000007758 minimum essential medium Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 description 1
- RNJOKCPFLQMDEC-UHFFFAOYSA-N 4(R),8-dimethyl-trans-2-nonenoyl-CoA Chemical class COC(=O)CC(=O)CC(=O)OC RNJOKCPFLQMDEC-UHFFFAOYSA-N 0.000 description 1
- LLKFNPUXQZHIAE-UHFFFAOYSA-N 5-(3-aminopropyl)-8-bromo-3-methyl-2h-pyrazolo[4,3-c]quinolin-4-one Chemical compound O=C1N(CCCN)C2=CC=C(Br)C=C2C2=C1C(C)=NN2 LLKFNPUXQZHIAE-UHFFFAOYSA-N 0.000 description 1
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 1
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 1
- SVDDCUCZQIKJCP-XCFKWOOQSA-N CC(/C=C(/C)\OC(C)=N)=O Chemical compound CC(/C=C(/C)\OC(C)=N)=O SVDDCUCZQIKJCP-XCFKWOOQSA-N 0.000 description 1
- 239000006145 Eagle's minimal essential medium Substances 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical group [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- GCPWJFKTWGFEHH-UHFFFAOYSA-N acetoacetamide Chemical compound CC(=O)CC(N)=O GCPWJFKTWGFEHH-UHFFFAOYSA-N 0.000 description 1
- 229940009456 adriamycin Drugs 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 230000003444 anaesthetic effect Effects 0.000 description 1
- 230000003266 anti-allergic effect Effects 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- ZSANYRMTSBBUCA-UHFFFAOYSA-N diethyl 3-oxopentanedioate Chemical compound CCOC(=O)CC(=O)CC(=O)OCC ZSANYRMTSBBUCA-UHFFFAOYSA-N 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- HHFAWKCIHAUFRX-UHFFFAOYSA-N ethoxide Chemical compound CC[O-] HHFAWKCIHAUFRX-UHFFFAOYSA-N 0.000 description 1
- XQXHPKYNZKTFTG-UHFFFAOYSA-N ethyl 5-acetyl-2,4-bis(2-ethoxy-2-oxoethyl)-6-oxo-1h-pyridine-3-carboxylate Chemical compound CCOC(=O)CC=1NC(=O)C(C(C)=O)=C(CC(=O)OCC)C=1C(=O)OCC XQXHPKYNZKTFTG-UHFFFAOYSA-N 0.000 description 1
- UNHZSJYQNJKDLW-UHFFFAOYSA-N ethyl 5-acetyl-2-benzyl-4-(2-ethoxy-2-oxoethyl)-6-oxo-1h-pyridine-3-carboxylate Chemical compound N1C(=O)C(C(C)=O)=C(CC(=O)OCC)C(C(=O)OCC)=C1CC1=CC=CC=C1 UNHZSJYQNJKDLW-UHFFFAOYSA-N 0.000 description 1
- SGBHDHYCWSFBIW-UHFFFAOYSA-N ethyl 5-acetyl-4-(2-ethoxy-2-oxoethyl)-2-(2-fluorophenyl)-6-oxo-1h-pyridine-3-carboxylate Chemical compound N1C(=O)C(C(C)=O)=C(CC(=O)OCC)C(C(=O)OCC)=C1C1=CC=CC=C1F SGBHDHYCWSFBIW-UHFFFAOYSA-N 0.000 description 1
- AJFHHZDZVXIPGO-UHFFFAOYSA-N ethyl 5-acetyl-4-(2-ethoxy-2-oxoethyl)-2-(4-fluorophenyl)-6-oxo-1h-pyridine-3-carboxylate Chemical compound N1C(=O)C(C(C)=O)=C(CC(=O)OCC)C(C(=O)OCC)=C1C1=CC=C(F)C=C1 AJFHHZDZVXIPGO-UHFFFAOYSA-N 0.000 description 1
- XSBWXZCHUOUKET-UHFFFAOYSA-N ethyl 5-acetyl-4-(2-ethoxy-2-oxoethyl)-6-oxo-2-pyridin-3-yl-1h-pyridine-3-carboxylate Chemical compound N1C(=O)C(C(C)=O)=C(CC(=O)OCC)C(C(=O)OCC)=C1C1=CC=CN=C1 XSBWXZCHUOUKET-UHFFFAOYSA-N 0.000 description 1
- 229940093499 ethyl acetate Drugs 0.000 description 1
- 235000019439 ethyl acetate Nutrition 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 239000003589 local anesthetic agent Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- GXHFUVWIGNLZSC-UHFFFAOYSA-N meldrum's acid Chemical compound CC1(C)OC(=O)CC(=O)O1 GXHFUVWIGNLZSC-UHFFFAOYSA-N 0.000 description 1
- NBTOZLQBSIZIKS-UHFFFAOYSA-N methoxide Chemical compound [O-]C NBTOZLQBSIZIKS-UHFFFAOYSA-N 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 229940056360 penicillin g Drugs 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/80—Acids; Esters in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
- C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
Definitions
- the present invention relates to novel alkyl 3- substituted-6,8-dihydroxy-l(2H)-oxoisoquinoline-4-carboxylates.
- the invention further relates to the process for the preparation and to the cytotoxicity and anti-tumor use of such compounds.
- R is C 1 _ 7 alkyl; unsubstituted phenyl or a phenyl substituted by different electron donating or electron attracting groups at different positions; an optionally substituted 5-or 6-membered ring azine, preferably pyridine or pyrimidine; or a C- ⁇ g alkylene, substituted terminally with optionally substituted phenyl, azinyl, or C- j ⁇ alkyl carboxylate; R 2 is hydrogen or a C 1-Q alkyl chain;
- R 3 , R 4 , R 5 and R 6 independently are hydrogen, hydroxy, C x _ 6 alkoxy, or halogen.
- the physiologically acceptable compounds of formula I possess pharmacological properties exhibiting cytotoxicity, in particular, against a wide variety of tumor cell lines.
- the compounds of the- present invention may be utilized as active compounds in medicaments, being formulated with one or more pharmaceutically acceptable carriers.
- R ⁇ is an alkylene moiety substituted terminally with optionally substituted phenyl, azinyl or alkyl carboxylate, it is preferably of the formula -R 8 -R 9 , wherein R 8 is C 1-6 alkylene and R g is phenyl, which is unsubstituted or is substituted by different electron donating or electron attracting groups at different positions, azinyl, or C- ⁇ ⁇ alkyl carboxylate.
- R ⁇ or R 9 are substituted phenyl
- the phenyl ring is preferably substituted by one or two substituents, which are preferably in the m- or p- positions, and are C- ⁇ C ⁇ alkyl, C- L *- ⁇ alkoxy, or halogen, preferably fluorine.
- R or R 9 are azinyl or azole, they are a 5- or 6- membered ring azole or azine.
- Suitable 5 membered azole rings include 2-thienyl, 3- thienyl, 2-furyl, 3-furyl, pyrrol-2-yl, pyrrol-3-yl, 3- isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 3-isothiazolyl, 4- isothiazolyl, 5-isothiazolyl, 3-pyrazolyl, 4-pyrazolyl, 5- pyrazolyl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, imidazol-1-yl, imidazol-2-yl, imidazol-4-yl; imidazol-5-yl, l,2,3-triazol-4-yl, triazol-5-yl, triazol-1-yl, l,2,4-triazol-2-yl,
- Suitable 6 membered azinyl rings include 2-pyridyl, 4- pyridyl (unsubstituted or substituted with one or two electron donating moieties such as C j -C ⁇ j alkoxy, halogen or ⁇ -0 4 alkyl; or electron withdrawing substituents such as C 2 -C 6 acyl, 0 -0 4 alkoxy carbonyl, and nitro) , 2-pyrimidyl, 4-pyrimidyl, 5- pyrimidyl (unsubstituted or substituted by one or two electron donating moieties such as - ⁇ -C ⁇ alkoxy, halogen or 0 ⁇ 0 4 alkyl; or electron withdrawing substituents such as C 2 -C 6 acyl, ⁇ -0 4 alkoxy carbonyl, and nitro, at positions other than the point of attachment), l,2,4-triazine-3-yl, -5-yl, and -6-yl (unsubsti
- the compounds of formula I are preferably prepared by treating an appropriately substituted pyridine derivative of formula II
- R an ⁇ R 2 are defined above and R 7 is 0 -0 4 alkyl, with an alkali metal 0 -0 4 alkoxide in ethanol at a temperature of 5° to 95°C, preferably at room temperature, followed by acidification to a pH of less than 6.0, preferably 2.0 to 6.0, more preferably about 5.0.
- Compounds of formula II may suitably be prepared by treating an appropriately substituted 4-oxo-l,3-oxazine derivative of formula III with a suitably substituted 1,3- acetonedicarboxylate of formula IV in the presence of a base, for example, potassium t-butoxide, in an aprotic solvent, for example, tetrahydrofurane, at a temperature of 5° to 95°C, preferably at room temperature.
- a base for example, potassium t-butoxide
- an aprotic solvent for example, tetrahydrofurane
- the 4-oxo-l, 3-oxazine derivatives of formula II may suitably be prepared according to the conventional procedure of reacting an appropriately substituted amide with meldrum's acid followed by catalytic cyclization of the acetoacetamide intermediate preferably at room temperature.
- SUBSTITUTE SHEET reactions of a compound of formula II with sodium ethoxide and the reaction of a compound of formula III with a compound of formula IV may involve varying reaction times (suitably 2 to 24 hours or more) but preferably if at room temperature or below will involve a time of at least 12 hours to ensure complete reaction.
- the alkali metal 0 -0 4 alkoxide is a methoxide or an ethoxide.
- the alkali metal preferably is potassium or sodium.
- the compounds of the present invention can be used to treat leukemia, such as acute lymphoblastic leukemia, as well as solid tumors, such as breast carcinoma, gynecologic carcinoma, bronchagenic carcinoma, and gastric carcinoma in mammals, including man.
- solid tumors that may be treated by compounds of the present invention are e.g., tumors of the lung, breast, ovary and colon.
- the compounds may be administered to the patient, generally a human patient, by any convenient method, but i.v. injection is preferred, suitably at a dosage level of 50 to 80 mg/m 2 , preferably 60 to 75 mg/m .
- Selected compounds of this invention were tested for cytotoxicity and other potential pharmacological activity in accordance with known techniques.
- Example 9 3-Acetyl-5-ethoxycarbonyl-4-ethoxycarbonyl methyl-6- phenyl-2(lH-pyridone) .
- KB cells were cultivated in Eagles minimum essential medium supplemented with 10% calf serum and incubated at 37°C in a humidified 5% C0 2 atmosphere to prepare a cell stock.
- SUBSTITUTE SH ⁇ ET ISA/EP Cells were counted using a neubauer hemocytomer and seeded in 96 well plates at 100 ⁇ l of 3 X 10 3 cells per ml and cultured for 1 day. Test compounds were diluted and 100 ⁇ l of the solution was added in triplicate wells to give five final concentrations of 10, 5, 1, 0.5 and 0.1 ⁇ ml "1 . Control wells were identical except that test compound was absent. These were cultured " for three days. Then the cells were fixed with addition of 20 ⁇ l of 25% glutaraldehyde for 15 minutes, washed with water and dried. Then the cells were stained with 100 ⁇ l of 0.05% crystal violet for 15 minutes, washed with water and dried.
- Example l was reacted with potassium t-butoxide as in Example l to produce a compound of the formula.
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Abstract
Alkyl 3-substituted-6,8-dihydroxy-1(2H)-oxoisoquinoline-4-carboxylates, such as ethyl 6,8-dihydroxy-3-phenyl-1(2H)-oxoisoquinoline-4-carboxylate, exhibit cytotoxicity against a wide variety of tumor cell lines, and can thus be used to treat cancer such as leukemias and carcinomas.
Description
ISOCARBOSTIRYL COMPOUNDS AND ANTITUMOR USE THEREOF
BACKGROUND OF THE INVENTION:
The present invention relates to novel alkyl 3- substituted-6,8-dihydroxy-l(2H)-oxoisoquinoline-4-carboxylates. The invention further relates to the process for the preparation and to the cytotoxicity and anti-tumor use of such compounds.
3-carboxy-2,4-dialkyl-l(2H)-oxoisoquinolines have been reported to possess local anesthetic activity, and 4-formyl-2- substituted-l(2H)-oxoquinolines have also been reported to possess anti-allergic activity. Note, for instance, Farmaco. Ed. Sci., 39(3), 229045 [CA. 100(23), 185342n] , and Chem. Pharm. Bull., 31(4), 1277-82 [C . 99(17), 139728f] . SUMMARY OF THE INVENTION:
In accordance with the present invention, there are provided compounds having the formula:
R3, R4, R5 and R6 independently are hydrogen, hydroxy, Cx_6 alkoxy, or halogen.
Advantageously, the physiologically acceptable compounds of formula I possess pharmacological properties exhibiting cytotoxicity, in particular, against a wide variety of tumor cell lines.
Thus, the compounds of the- present invention may be utilized as active compounds in medicaments, being formulated with one or more pharmaceutically acceptable carriers. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS: When Rλ is an alkylene moiety substituted terminally with optionally substituted phenyl, azinyl or alkyl carboxylate, it is preferably of the formula -R8-R9, wherein R8 is C1-6 alkylene and Rg is phenyl, which is unsubstituted or is substituted by different electron donating or electron attracting groups at different positions, azinyl, or C-^ ^ alkyl carboxylate.
When Rλ or R9 are substituted phenyl, the phenyl ring is preferably substituted by one or two substituents, which are preferably in the m- or p- positions, and are C-^C^ alkyl, C-L*-^ alkoxy, or halogen, preferably fluorine. When R or R9 are azinyl or azole, they are a 5- or 6- membered ring azole or azine.
Suitable 5 membered azole rings include 2-thienyl, 3- thienyl, 2-furyl, 3-furyl, pyrrol-2-yl, pyrrol-3-yl, 3- isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 3-isothiazolyl, 4- isothiazolyl, 5-isothiazolyl, 3-pyrazolyl, 4-pyrazolyl, 5- pyrazolyl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, imidazol-1-yl, imidazol-2-yl, imidazol-4-yl; imidazol-5-yl, l,2,3-triazol-4-yl, triazol-5-yl, triazol-1-yl, l,2,4-triazol-2-yl, triazol-5-yl, and triazol-4- yl.
Suitable 6 membered azinyl rings include 2-pyridyl, 4- pyridyl (unsubstituted or substituted with one or two electron donating moieties such as Cj-C^j alkoxy, halogen or ^-04 alkyl; or electron withdrawing substituents such as C2-C6 acyl, 0 -04 alkoxy carbonyl, and nitro) , 2-pyrimidyl, 4-pyrimidyl, 5- pyrimidyl (unsubstituted or substituted by one or two electron donating moieties such as -^-C^ alkoxy, halogen or 0^04 alkyl; or electron withdrawing substituents such as C2-C6 acyl, ^-04 alkoxy carbonyl, and nitro, at positions other than the point of attachment), l,2,4-triazine-3-yl, -5-yl, and -6-yl (unsubstituted or substituted by one or two electron donating moieties such as _ -C^ alkoxy, C - 4 alkyl or halogen or electron withdrawing substituents such as C2-C6 acyl, C1-C4
SUBSTITUTE SHEET
alkoxy carbonyl, and nitro, at positions other than the point of attachment) .
The compounds of formula I are preferably prepared by treating an appropriately substituted pyridine derivative of formula II
wherein R an~ R 2 are defined above and R7 is 0 -04 alkyl, with an alkali metal 0 -04 alkoxide in ethanol at a temperature of 5° to 95°C, preferably at room temperature, followed by acidification to a pH of less than 6.0, preferably 2.0 to 6.0, more preferably about 5.0.
Compounds of formula II may suitably be prepared by treating an appropriately substituted 4-oxo-l,3-oxazine derivative of formula III with a suitably substituted 1,3- acetonedicarboxylate of formula IV in the presence of a base, for example, potassium t-butoxide, in an aprotic solvent, for example, tetrahydrofurane, at a temperature of 5° to 95°C, preferably at room temperature.
The 4-oxo-l, 3-oxazine derivatives of formula II may suitably be prepared according to the conventional procedure of reacting an appropriately substituted amide with meldrum's acid followed by catalytic cyclization of the acetoacetamide intermediate preferably at room temperature.
While the reactions described above will proceed very well at room temperature (which is preferred) , the reactions may be conducted at a temperature within the range of 5 - 95°C The
SUBSTITUTE SHEET
reactions of a compound of formula II with sodium ethoxide and the reaction of a compound of formula III with a compound of formula IV may involve varying reaction times (suitably 2 to 24 hours or more) but preferably if at room temperature or below will involve a time of at least 12 hours to ensure complete reaction.
Preferably the alkali metal 0 -04 alkoxide is a methoxide or an ethoxide. The alkali metal preferably is potassium or sodium. The compounds of the present invention can be used to treat leukemia, such as acute lymphoblastic leukemia, as well as solid tumors, such as breast carcinoma, gynecologic carcinoma, bronchagenic carcinoma, and gastric carcinoma in mammals, including man. Among other solid tumors that may be treated by compounds of the present invention are e.g., tumors of the lung, breast, ovary and colon. The compounds may be administered to the patient, generally a human patient, by any convenient method, but i.v. injection is preferred, suitably at a dosage level of 50 to 80 mg/m2, preferably 60 to 75 mg/m . Selected compounds of this invention were tested for cytotoxicity and other potential pharmacological activity in accordance with known techniques.
More particularly, Ethyl 6,8-dihydroxy-3-phenyl-l(2H)- oxoisoqύinoline-4-carboxylate, Ethyl 6,8-dihydroxy-3-ethyl- l(2H)-oxoisoquinoline-4-carboxylate, Ethyl 6,8-dihydroxy-3- phenylmethyl-l(2H)-oxoisoquinoline-4-carboxylate, Ethyl 6,8- dihydroxy-3-(2-pyridyl)-l(2H)-oxoisoquinoline-4-carboxylate, and Ethyl 6,8-dihydroxy-3-(4-fluorophenyl) -l(2H) - oxoisoquinoline-4-carboxylate demonstrated remarkable cytotoxicity against KB tumor lines.
Example 1 Ethyl 6,8-dihydroxy-3-phenyl-l(2H)-oxoisoquinoline-4- carboxylate.
3-Acetyl-5-ethoxycarbonyl-4-ethoxy carbonyl methyl-6- phenyl-2(lH)-pyridone (3.713 g. 10 mmol) was added to a solution of metallic sodium (0.250 g; 11 g atom) in ethanol (15 ml) . The solution was stirred at room temperature over night. The mixture was poured into water (160 ml) and
SUBSTITUTE SHEET
acidified with 10% hydrochloric acid, followed by concentration under reduced pressure. The residue was purified by recrystallization from ethylacetate to obtain colorless prisms of the title compounds, mp 280 - 282°C, yield 96%.
NMR (CDC13 + DMSO -d6, 300 MHZ): 0.94 (3H,6, J = 2 Hz); 6.70 (1H, d, J = 2 Hz); 7.53 (5H, s) ; 10.30-12.30 (2H, br, exchangeable- with D20) ; 13.20 (1H, s) (Exchangeable with D20) .
Analysis found: 0,66.68; H; 4.64; N, 4.38
Required C18H 5NOs
C, 66.46; H, 4.65; N, 4.31
IR (KBr) : 1690 cm-1
Schematic for Example 1
1. EϊO
Employing the procedure of Example 1 and starting with the appropriately • 6-substituted-3-acetyl-5-ethoxycarbσnyl-4- ethoxycarbonyl methyl-2(lH)-pyridone derivative, the following compounds were prepared.
Example 2
Ethyl 6,8-dihydroxy-3-ethyl-l(2H)-oxoisoquinoline-4- carboxylate, yield 94% mp 245 - 246 βC (AcOET) .
NMR (CDCI3 + DMSO - d6) 1.30 (3H, t, J = 7 Hz) ; 1.42 (3H, t, J = 7 HZ); 2.67 (2H, q, J = 7 Hz); 4.43 (2H, q, J = 7 Hz); 6.35 (1H, d, J = 2 Hz); 6.63 (1H, d, J = 2 Hz); 9.60 - 10.50 (1H, br, exchangeable with D20) ; 11.20 - 12.00 (1H, br, exchangeable with D20) ; 12.60 - 13.60 (1H, br, exchangeable with D20) . IR (KBr) : 1700 cm -1
Analysis found: C, 60. 53 ; H, 5.48 ; N, 4 . 98 Required: Cl4H15N05
C, 60. 65 ; H, 5. 45 ; N, 5 . 05 Example 3 Ethyl 6 , 8-dihydroxy-3-benzyl-l (2H) -oxoisoquinoline-4 - carboxylate
SUBSTITUTE SHEET A/EP
Yield: 87%; mp: 238 - 239°C (MeOH)
NMR (CDC13 + DMSO - d6): 1.30 (3H, t, J *= 7 Hz); 4.03 (2H, s); 4.34 (2H, q, J = 7 Hz); 6.33 (IH, d, J - 2 Hz); 6.58 (IH, d, J = 2 Hz); 7.30 (5H, s); 10.17 (IH, br, exchangeable with D20) ; 13.03 (IH, br, exchangeable with D20) . IR (KBr).: 1690 cm-1
Analysis" found: C, 67.43; H, 5.20; N, 4.09 Required: C19H27N05
C, 67.25; H, 5.05; N, 4.13 Example 4
Ethyl 6 , 8 -dihydroxy-3 - (p-f luorophenyl ) - l ( 2H ) - oxoisoquinoline-4 -carboxylate
Yield: 90%; mp: 303 - 307°C (AcOEt)
NMR (CDCI3 + DMSO - d6) : 0.93 (3H, t, J = 7 Hz) ; 4.03 (2H, q, J = 7 Hz); 6.35 (IH, d, J = 2 Hz); 6.63 (IH, d, J = 2 Hz);
7.03 - 7.63 (4H, ) ; 10.10 - 12.10 (IH, br, exchangeable with
D20) ; 11.60 (IH, br, exchangeable with D20) ; 13.07 (IH, s, exchangeable with D20)
Hi-Ms m/e observed: 343.0861 Required C18H24N05F: 343.0856
Example 5 Ethyl 6,8-dihydroxy-3-(p-bromophenyl)-l(2H)- oxoisoquinoline-4-carboxylate
Yield: 77%; p: 314 - 317°C (AcOET) NMR (CDCI3, DMSO - d6) : 0.93 (3H, t, J = 7 Hz); 4.05 (2H, q, J = 7 Hz); 6.37 (IH, d, J = 2 Hz); 6.65 (IH, d, J = 2 Hz); 7.33 - 7.77 (4H, m) , 10.25 (IH, s, exchangeable with D20) ; 11.50 - 12.10 (IH, br, exchangeable with D20) . IR (KBr) : 1690 cm"1 Example 6
Ethyl 6,8-dihydroxy-3-(2-Furyl)-1(2H)-oxoisoquinoline-4- carboxylate
Yield: 76%; mp: 274 - 276°c (AcOET)
NMR (CDCI3 + DMSO - d6) : 1.27 (3H, t, J = 7 Hz); 4.37 (2H, q, J = 7 Hz); 6.38 (IH, d, J = 2 Hz); 6.50 (IH, d, J = 2 Hz);
6.57 - 6.67 (IH, m) ; 7.18 - 7.29 (IH, m) ; 7.62 - 7.70 (IH, ) ;
10.23 (IH, s, exchangeable with D20) ; 10.30 - 10.80 (IH, br, exchangeable with D20) ; 13.03 (IH, s, exchangeable with D20) .
SUBSTITUTE SHEET ISA/EP
IR (KBr) : 1685 cm"1
Hi - Ms m/e observed: 315.0741
Required C16H13N06: 315.0743
Example 7 Ethyl 6,8-dihydroxy-3-(2-pyridyl)-l(2H)-oxoisoquinoline-4- carboxylate *
Yield: 91%; mp: 245 - 246°C (AcOET)
NMR (CDC13 + DMSO - d6): 1.03 (3H, t, J = 7 Hz) ; 4.14 (2H, q, J = 7 HZ); 6.42 (IH, d, J = 2 Hz) ; 6.72 (2H, d, J = 2 Hz) ; 7.33 - 8.12 (3H, m) ; 8.66 - 8.77 (IH, m) ; 10.33 (IH, s, exchangeable with D20) ; 11.30 - 12.00 (IH, br, exchangeable with D20) ; 13.07 (IH, s, exchangeable with D20) . IR (KBr) : 1685 cm Hi - Ms m/e observed: 326.0974 Required C17H14N205: 326.0903
Example 8 Ethyl 6,8-dihydroxy-3-ethoxycarbonylmethyl-l (2H) - oxoisoquinoline-4-carboxylate
Yield: 75%; mp: 210 - 212°C (AcOET) NMR (CDCI3 + DMSO - d6) : 1.26 (3H, t, J = 7 Hz) ; 1.37 (3H, t, J = 7 Hz); 3.77 (2H, s) ; 4.22 (2H, q, J = 7 Hz); 4.35 (2H, q, J = 7 Hz); 6.32 (IH, d, J = 2 Hz) ; 6.85 (IH, d, J = 2 Hz); 9.50 - 11.00 (IH, br exchangeable with D20) ; 11.53 - 11.94 (IH, br, exchangeable with D20) ; 12.67 - 13.29 (IH, br, exchangeable with D20) .
IR (KBr): 1725, 1705 cm"1
Hi - Ms m/e observed: 335.1091
Required C16H17N07: 335.1005
Example 9 3-Acetyl-5-ethoxycarbonyl-4-ethoxycarbonyl methyl-6- phenyl-2(lH-pyridone) .
A solution of potassium t-butoxide (1.1 g: 10 mmol) and diethyl 1,3-acetonedicarboxylate (2g, 10 mmol) in tetrahydrofuran (THF) (20 ml) was stirred at room temperature for 30 min. 2-Phenyl-6-methyl-l,3-oxazine-4-one (1.87 g, 10 mmol) was added to the solution, and the mixture was stirred at room temperature overnight followed by acidification with 10% HCl. The resulting solution was concentrated under reduced
SUBSTITUTE SHEET
pressure, and purified by recrystallization from methanol to colorless prisms of the titled compound, mp 182 - 183°C
Yield 90%
NMR (CDC13) 0.83 (3H, t, J = 7 Hz); 1.24 (3H, t, J = Hz); 2.36 (3H, s); 3.80 (2H, s) ; 3.94 (2H, q, J = 7 Hz); 4.13 (2H, q, J = 7 Hz);-7.44 (5H, s); 12.50 - 13.50 (IH, br, exchangeable with D20) .
Schematic for Example 9
By procedures similar to those used in Example 9 and startingwithappropriate2-substituted-6-methyl-l,3-oxazine-4- one the following compounds were prepared.
Example 10 3-Acetyl-5-ethoxycarbonyl-4-ethoxycarbonyl methyl-6-ethyl- 2(IH)-pyridone
Yield 83% mp 136°C (Et20)
NMR (CDCI3) 1.27 (3H, t, J = 7 Hz); 1.37 (6H, t, J = 7 Hz); 2.60 (3H, s) ; 2.78 (2H, q, J = 7 Hz); 3.83 (2H, s) ; 4.18 (2H, q, J = 7 Hz); 4.35 (2H, q, J = 7 Hz); 13.30 - 14.20 (IH, br, exchangeable with D20) .
IR (KBr) 1725, 1695 cm' -1
SUBSTITUTE SHEET ISA/EP
Example 11
3-Acetyl-5-ethoxycarbonyl-4-ethoxycarbonylmethyl-6-benzyl- 2(IH)-pyridone
Yield: 86%; mp: 162 - 163°C (MeOH) NMR (CDC13): 1.27 (6H, t, J = 7 Hz); 2.56 (3H, s) ; 3.83 (2H, s); 4.17 (2H, s) ; 4.20 (2H, q, J - 7 Hz); 4.32 (2H, q, J - 7 Hz), 7.30 (5H, s) ; 12.50 - 13.60 (IH, b, exchangeable with D20).
IR (KBr): 1715, 1695 cm"1 Example 12
3-Acetyl-5-ethoxycarbonyl-4-ethoxycarbonylmethyl-6-(p- fluorophenyl)-2 (IH)-pyridone
Yield: 86%; mp: 187 - 189°C (MeOH)
NMR (CDCI3) : 0.93 (3H, t, J = 7 Hz); 1.27 (3H, t, J - 7 Hz); 2.40 (3H, s) ; 3.88 (2H, s) ; 4.03 (2H, q, J = 7 Hz); 4.20 (2H, q, J = 7 Hz); 7.03 - 7.67 (4H, m) . IR (KBr): 1740, 1715, 1695 cm"1 Hi - Ms m/e observed: 389.1265 Required C20H20FNO6: 389.1875 Example 13
3-Acetyl-5-ethoxycarbonyl-4-ethoxycarbonylmethyl-6-(p- bromophenyl-2(IH)-pyridone
Yield: 83%; mp: 175 - 176 °C (MeOH)
NMR (CDCI3) : 0.93 (3H, t, J = 7 Hz); 1.27 (3H, t, J = 7 Hz); 2.40 (3H, s) ; 3.88 (2H, s) ; 4.03 (2H, q, J 7 Hz) ; 4.20 (2H, q, J = 7 HZ); 7.27 - 7.73 (4H, m) ; 12.30 - 13.60 (IH, br, exchangeable with D2θ)
IR (KBr): 1735, 1715, 1690 cm"1
Example 14 3-Acetyl-5-ethoxycarbonyl-4-ethoxycarbonylmethyl-6-(2- furyl)-2(IH)-pyridone
Yield: 85%; mp: 138 - 140°C (EtOH)
NMR (CDCI3) : 1.27 (6H, t, J = 7 Hz); 2.60 (3H, s) ; 3.83 (2H, s) ; 4.20 (2H, q, J = 7 Hz) ; 4.33 (2H, q, J = 7 Hz) ; 6.53 - 6.63 (IH, m) ; 7.40 - 7.60 (2H, m) ; 12.00 - 13.80 (IH, br, exchangeable with D20) .
IR (KBr): 1735, 1720, 1700 cm"1
Hi - Ms m/e observed: 361.1078
SUBSTITUTE SHEET ISA/EP
Required C28H19N07: 361.1761
Example 15 3-Acety1-5-ethoxycarbony1-4-ethoxycarbonylmethy1-6-(2- pyridyl)-2(IH)-pyridone Yield: 87%; mp: 175 - 176°C (MeOH)
NMR (CDC13): 1.02 (3H, t, J = 7 Hz) ; 1.27 (3H, t, J = 7 Hz); 2.53 (3H, S) ; 3.95 (2H, s) ; 4.i6 (2H, q, J = 7 Hz); 4.22 (2H, q, J = 7 Hz); 7.37 - 8.03 (3H, ) ; 8.70 - 8.83 (IH, m) ; 12.00 - 13.90 (IH, br, exchangeable with D20) . IR (KBr): 1735, 1715, 1685 cm"1
Example 16 3-Acetyl-4,6-diethoxycarbonylmethyl-5-ethoxycarbonyl-2- (1H)-pyridone
Yield: 72%; mp: 120 - 122°C (MeOH) NMR (CDCI3) : 1.27 (6H, t, J = 7 Hz) ; 1.35 (3H, t, J = 7 HZ); 2.58 (3H, s); 3.93 (4H, s) ; 4.15 (2H, q, J = 7 Hz) ; 4.18 (2H, q, J = 7 Hz); 4.27 (2H, q, J - 7 Hz); 13.00 - 14.50 (IH, br, exchangeable with D20) .
Hi - Ms m/e observed: 381.1370 Required C18H23N08: 381.1424
In Vitro KB Cell Cvtotoxic Assay The method employed in the assay was a modification of the crystal violet assay (Gillies et al. Anal. Biochem. , 159 , 109 (1986) . Materials:
- KB cells (ATCC CCL 17)
- Minimum Essential Medium, Eagles (Modified with Earles salt) supplemented with 10% calf serum, 100 IUml-1 penicillin G, 100 ugml"1 streptomycin. - Compounds dissolved in DMSO to 20 mgl"1 and further diluted in the 10% CS-MEM
- Crystal violet
- 25% glutaraldehyde
- deionized water Procedure:
KB cells were cultivated in Eagles minimum essential medium supplemented with 10% calf serum and incubated at 37°C in a humidified 5% C02 atmosphere to prepare a cell stock.
SUBSTITUTE SHΕET ISA/EP
Cells were counted using a neubauer hemocytomer and seeded in 96 well plates at 100 μl of 3 X 103 cells per ml and cultured for 1 day. Test compounds were diluted and 100 μl of the solution was added in triplicate wells to give five final concentrations of 10, 5, 1, 0.5 and 0.1 μml"1. Control wells were identical except that test compound was absent. These were cultured" for three days. Then the cells were fixed with addition of 20 μl of 25% glutaraldehyde for 15 minutes, washed with water and dried. Then the cells were stained with 100 μl of 0.05% crystal violet for 15 minutes, washed with water and dried. The wells were eluted with 100 μl of 0.05 M NaH2P04/ethanol (l:lv/v) and read at OD540 on a multiscan spectrophotometer. ED50 values were calculated using the formula -
% inhibition greater than 50% - 50%
% inhibition greater than 50% - % inhibition less than 50% to give the interpolative value between two dilutions.
The selected compounds of this invention were tested against KB tumor cell lines. The results are shown in the following Table.
TD50 OF ISOCARBOSTERYL DERIVATIVES
Compound # 1 2 4
7
Adriamycin 0.04
SUBSTITUTE SHEET
Example 17 An intermediate of the formula
was reacted with potassium t-butoxide as in Example 1 to produce a compound of the formula
Example 18 An intermediate of the formula
was reacted with potassium t-butoxide as in Example l to produce a compound of the formula.
SUBSTITUTE SHEET
Example 19 3-Acetyl-5-ethyoxycarbonyl-4-ethoxycarbonylmethyl-6-(3- pyridyl)-2(IH)-pyridone.
A solution of potassium t-butoxide (0.178 g, 1.59 mmol) and diethyl-l,3-acetonedicarboxylate (0.322 g, 1.59 mmol) in tetrahydrofuran (THF) (5ml) was stirred at room temperature for 30 min. 2-(3-pyridyl)-6-methyl-l,3-oxazin-4-one (0.300 g, 1.59 mmol) was added to the solution, and the mixture was stirred at room temperature overnight followed by acidification with 10% HCl. The resulting solution was concentrated under reduced pressure and purified by elution through a silica gel column using methanol-chloroform (1:10) as eluent to give colorless powder of the titled compound, mp 209 - 211°c Yield: 47% NMR (CDC13, 200 MHz): 0.89 (3H, t, J = 7Hz) ; 1.25 (3H, t, J = 7Hz) ; 2.39 (3H, s) ; 3.83 (2H, s) ; 3.97 (2H, q, J = 7Hz) ; 4.14 (2H, q, J = 7Hz) 7.31 - 7.37 (IH, m) ; 7.75 - 7.79 (IH, m) ; 8.53 - 8.64 (2H, m) ; 12.40 - 13.50 (IH, br, exchangeable with D20) . IR (KBr): 1735, 1715, 1685 cm"1
Analysis found: C, 61.36; H, 5.31; N, 7.47 Required: C19H20N2O6: C, 61.27; H, 5.42; N, 7.52
Example 20 3-Acetyl-5-ethoxycarbonyl-4-ethoxycarbonylmethyl-6-(2- fluorophenyl)-2(IH)-pyridone
By procedure similar to that used in Example 19 and starting with the appropriate 2-substituted-6-methyl-l,3- oxazine-4-one, the title compound was prepared.
SUBSTITUTE SHEET
Yield: 59%, mp 195 - 197°C
NMR (CDC13 200 MHz): 0.87 (3H, t, J = 7Hz) ; 1.25 (3H, t, J = 7Hz); 2.35 (3H, s) ; 3.91 (2H, s) ; 3.97 (2H, q, J = 7Hz) ; 4.15 (2H, q, J = 7HZ); 7.20 - 7.64 (4H, m) ; 12.2 - 13.7 (IH, br, exchangeable with D20)
IR (KBr): 1740, 1715, 1695 cm"1
Analysis found: C, 61.63; H, 5.31; N, 3.74.
Required: C2oH2oFN06: C, 61.68; H7 5.19; N, 3.60
Example 21 Ethyl-6,8-dihydroxy-3-(3-pyridyl)-1(2H)-oxoisoquinoline-4- carboxylate.
3-Acetyl-5-ethoxycarbonyl-4-ethoxycarbonylmethyl-6-(3- pyridyl)-2(IH)-pyridone (0.280 g, 0.754 mmol) was added to a solution of metallic sodium (0.019 g, 0.829 mmol) in ethanol (5 ml) . The solution was stirred at room temperature overnight. The mixture was poured into water (40 ml) and acidified with 10% hydrochloric acid, followed by concentration under reduced pressure. The residue was purified by elution through a silica gel column using methanol-chloroform (1:9) as eluent to give the titled compound as a fine colorless powder, m.p. 278 - 280°C
Yield: 61%
NMR (CDCI3 + DMSO - d5, 200 MHz): 0.93 (3H, t, J = 7Hz) ; 4.03 (2H, t, J = 7HZ) ; 6.43 (IH, d, J = 2Hz) ; 6.76 (IH, d, J = 2 Hz); 7.39 - 7.46 (IH, m) ; 7.79 - 7.85 (IH, m) ; 8.68 - 8.71 (2H, m) ; 9.90 - 10.00 (IH, br, exchangeable with D20) ; 11.40 - 11.60 (IH, br, exchangeable with D20) ; 12.89 - 12.95 (IH, br, exchangeable with D20) . IR: 1685 cm"1 Analysis found: C, 62.49; H, 4.19; N, 8.72.
Required: C17H14N205: C, 62.57; H, 4.33; N. 8.59
SUBSTITUTE SHEET
Example 22
Ethyl-6 ,8-dihydroxy-3-(2-fluorophenyl)-l(2H)- oxoisoquinoline-4-carboxylate.
By procedure used in Example 21 and starting with the appropriate 6-substituted-3-acetyl-5-ethoxycarbonyl-4- ethoxycarbonylmethyl-2(lH)-pyridone derivative, the title compound was prepared.
Yield: 64%, m.p. 279 - 281°C
NMR (CDC13 + DMSO - d6, 200 MHz): 0.89 (3H, t, J = 7Hz) ; 4.01 (2H, q, J -= 7HZ); 6.47 (IH, d, J = 2 Hz) ; 6.90 (IH, d, J = 2Hz); 7.13 - 7.3 (2H, m) ; 7.36 - 7.53 (2H, m) ; 9.50 - 9.90 (IH, br, exchangeable with D20) ; 10.10 - 11.10 (IH, br, exchangeable with D20) ; 12.60 - 12.70 (IH, br, exchangeable with D20) .
IR (KBr) : 1690 cm"1
Analysis found: C, 63 .10 ; N, 4. 19 ; N, 4.01
Required: C18H14N05F: C, 62.97 ; H, 4.12 ; N, 4.08
SUBSTITUTE SHEET ISA/EP
Claims
1. A compound of the formula
wherein.R2 is C^C, alkyl; phenyl which is unsubstituted or is substituted by at least one substituent which is selected from the group consisting of 0 -04 alkyl, ι- 4 alkoxy and halogen; an optionally substituted 5- or 6-membered ring azine selected
-NRaRb?
R4 and R6 are independently hydroxy, halogen, or C -C4 alkoxy;- C-i -Cg alkylene;
SUBSTITUTE SHEET 
JSA/EP R9 is phenyl which is unsubstituted or is substituted by at least one substituent selected from the group consisting of
C2-C4 alkyl, C2-C4 alkoxy and halogen, an optionally substituted
5- or 6-membered ring azole or azine, and C2-C4 alkyl carboxylate; and
Ra and Rjj are independently hydrogen or C2-C4 alkyl.
2. The compound of claim 1, wherein the electron donating moiety is selected from the group consisting of C2-C4 alkoxy, C^-C^ alkyl or halogen.
3. The compound of claim 1, wherein the electron withdrawing substituent is selected from the group consisting of C2-C6 acyl, C2-C alkoxy carbonyl, and nitro.
4. The compound of claim 1, wherein Rλ is hydrogen, methyl, ethyl, isopropyl, t-butyl, n-pentyl, n-hexyl or n- heptyl.
5. The compound of claim 4, wherein R2 is ethyl, R3 and R5 are both hydrogen atoms, and R4 and R6 are both hydroxyl groups.
6. The compound of claim 1, wherein R2 is phenyl which is unsubstituted or substituted by halogen or C -C3 alkoxy.
7. The compound of claim 1, wherein Rx is pyridyl or furyl.
8. The compound of claim 1, wherein R2 is benzyl or ethoxy carbonylmethyl.
9. The compound of claim 1, wherein said compound is selected from the group consisting of:
Ethyl 6,8-dihydroxy-3-phenyl-l(2H)-oxoisoquinoline-4- carboxylate;
Ethyl 6,8-dihydroxy-3-ethyl-l(2H)-oxoisoquinoline-4- carboxylate;
Ethyl 6,8-dihydroxy-3-benzyl-l(2H)-oxoisoquinoline-4- carboxylate;
Ethyl 6 , 8 -d ihydroxy- 3 - ( p- f luoropheny l ) - 1 ( 2 H ) - oxoisoquinoline-4-carboxylate ; Ethy l 6 , 8 - d i hydr o xy - 3 - ( p - br omoph e ny 1 ) - 1 ( 2 H ) - oxoisoquinoline-4-carboxylate;
Ethyl 6,8-dihydroxy-3-(2-furyl)-l(2H)-oxoisoquinoline-4- carboxylate;
SUBSTITUTE SHEET ISA/EP Ethyl 6,8-dihydroxy-3-(2-pyridyl)-1(2H)-oxoisoquinoline-4- carboxylate; and
Ethyl 6,8-dihydroxy-3-ethoxycarbonylmethyl-l-(2H)- oxoisoquinoline-4-carboxylate.
10. The compound of claim 1, wherein R2 is C2-C4 alkyl.
11. The compound of claim 1, wherein R9 is 2-pyridyl.
12. A" pharmaceutical composition for the treatment of tumors comprising an anti-tumor effective amount of the compound of claim 1, and a pharmaceutically acceptable carrier.
13. A pharmaceutical composition for the treatment of tumors comprising an anti-tumor effective amount of the compound of claim 10, and a pharmaceutically acceptable carrier.
14. A pharmaceutical composition for the treatment of tumors comprising an anti-tumor effective amount of the compound of claim 11, and a pharmaceutically acceptable carrier.
15. A method of treating leukemia or a solid tumor in a patient in need of such treatment, said method comprising administering to said patient an anti-tumor effective amount of a compound of claim 1.
16. The method of claim 13, wherein the solid tumor is breast carcinoma, gynecologic carcinoma, bronchogenic carcinoma or gastric carcinoma.
17. A compound of the formula
wherein R1 is C^G**, alkyl; phenyl which is unsubstituted or is substituted by at least one substituent which is selected from the group consisting of C2-C4 alkyl, C2-C4 alkoxy and halogen, an optionally substituted 5- or 6-membered ring azine selected from the group consisting of 2-thienyl, 3-thienyl, 2-furyl, 3-
SUBSTITUTE SHEET furyl, pyrrol-2-yl, pyrrol-3-yl, 3-isoxazolyl, 4-isoxazolyl, 5- isoxazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 3- pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, imidazol-5-yl, l,2,3-triazol-4-yl, triazol-5-yl, triazol-1-yl, 1,2,4-triazol- triazol-2-yl,-triazol-4-yl, triazol-5-yl, 2-pyridyl, 4-pyridyl unsubstituted or substituted with at least one electron donating moiety or electron withdrawing substituent, 1,2,4- triazine-3-yl, l,2,4-triazine-5-yl, l,2,4-triazine-6-yl, unsubstituted or substituted by at least one electron donating moiety or electron withdrawing substituent at a position other than the point of attachment, or -R8-R9; R2 is hydrogen or C-^Cg alkyl; R3 and R5 are independently hydrogen or an electron donating group which is C2-C6 alkyl, C2-C4 alkoxy or
- RaRb
R and R6 are independently hydroxy, halogen, or C2-C4 alkoxy; R7 is C2-C8 alkyl;
R8 is C2-C6 alkylene;
R9 is phenyl which is unsubstituted or is substituted by at least one substituent which is selected from the group consisting of C -C4 alkyl, C2-C4 alkoxy and halogen, an optionally substituted 5- or 6-membered ring azine, and C -C4 alkyl carboxylate; and
Ra and Rb are independently hydrogen or C2-C4 alkyl.
18. The compound of claim 17, wherein R is hydrogen, methyl, ethyl, isopropyl, t-butyl, n-pentyl, n-hexyl or n- heptyl.
19. The compound of claim 18, wherein R2 is ethyl.
20. The compound of claim 17, wherein is phenyϊ which is unsubstituted or substituted by halogen or 0 -03 alkoxy.
21. The compound of claim 13, wherein x is pyridyl or furyl.
22. The compound of claim 13, wherein Rλ is benzyl or ethoxy carbonylmethyl.
SUBSTITUTE SHEET
23. The compound of claim 13 , wherein said compound is selected from the group consisting of
3-Acetyl-5-ethoxycarbonyl-4-ethoxycarbonyl methyl-6- phenyl-2 (IH) -pyridone;
3-Acetyl-5-ethoxycarbonyl-4-ethoxycarbonyl methyl-6-ethyl- 2 (IH) -pyridone;
3 -Acety 1-5 -ethoxycarbony 1-4 -ethyoxycarbonylmethy 1-6- benzyl-2 (IH) -pyridone;
3-Acetyl-5-ethoxycarbonyl-4-ethyoxycarbonylmethyl-6- (p- f luorophenyl) -2 (IH) -pyridone;
3-Acetyl-5-ethoxycarbonyl-4-ethoxycarbonylmethyl-6- (p- bromo-phenyl) -2 (IH) -pyridone;
3-Acetyl-5-ethoxycarbonyl-4-ethoxycarbonylmethyl-6- (2- furyl) -2 (IH) -pyridone;
3-Acetyl-5-ethoxycarbonyl-4-ethoxycarbonylmethyl-6- (2- pyridyl) -2 ( IH) -pyridone ; and
3-Acetyl-4 , 6-diethoxycarbonylmethyl-5-ethoxycarbonyl-2- ( IH) -pyridone .
24. A method of making a compound of the formula:
wherein Rx is C2-C7 alkyl; phenyl which is unsubstituted or is substituted by at least one substituent selected from the group consisting of C2-C4 alkyl, C2-C4 alkoxy and halogen, an optionally substituted 5- or 6-membered ring azine selected from the group consisting of 2-thienyl, 3-thienyl, 2-furyl, 3- furyl, pyrrol-2-yl, pyrrol-3-yl, 3-isoxazolyl, 4-isoxazolyl, 5- isoxazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 3- pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, imidazol-5-yl, l,2,3-triazol-4-yl, triazol-5-yl, triazol-l-yl, 1,2,4-triazol-
SUBSTITUTE SHEET triazol-2-yl, triazol-5-yl, triazol-4-yl, l,2,4-triazine-3-yl, l,2,4-triazine-5-yl, l,2,4-triazine-6-yl, unsubstituted or substituted by at least one electron donating moiety or electron withdrawing substituent at a position other than the point of attachment, 2-pyridyl, 4-pyridyl, unsubstituted or substituted with at least one electron donating moiety or electron withdrawing substituent, and -R8-R9;
R2 is hydrogen or C -C8 alkyl;
R3 and R5 are independently hydrogen or an electron donating group which is C2-C6 alkyl, C2-C4 alkoxy or -NRaRb;
R4 and R6 are independently hydroxy, halogen, or -1- -4 alkoxy;
R8 is C2-C6 alkylene; and
R9 is phenyl which is unsubstituted or is substituted by at least one substituent which is selected from the group consisting of C2-C4 alkyl, C2-C4 alkoxy and halogen, an optionally substituted 5- or 6-membered ring azine and C2-C4 alkyl carboxylate;
Ra and Rb are independently hydrogen or C -C4 alkyl; said method comprising (i) reacting a compound of the formula
wherein Rχ and R2 are defined above and R7 is C2-C8 alkyl with an alkali metal C2-C4 alkoxide at a temperature of about 5 to 95°C and (ii) acidifying at a temperature of 5° to 95°C the resulting reaction product to a pH of less than 6.0.
25. The method of claim 24, wherein the pH is about 5.0.
26. The method of claim 24, wherein the acidification is by addition of a mineral acid.
27. The compound of claim 1 wherein R2 is a C2-C8 alkyl chain.
SUBSTITUTE SHEET
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US571,680 | 1984-01-18 | ||
| US57168090A | 1990-08-23 | 1990-08-23 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1992003419A1 true WO1992003419A1 (en) | 1992-03-05 |
Family
ID=24284626
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/CA1991/000302 WO1992003419A1 (en) | 1990-08-23 | 1991-08-22 | Isocarbostiryl compounds and antitumor use thereof |
Country Status (3)
| Country | Link |
|---|---|
| AU (1) | AU8328691A (en) |
| WO (1) | WO1992003419A1 (en) |
| ZA (1) | ZA916646B (en) |
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| US5776962A (en) * | 1994-08-03 | 1998-07-07 | Cell Pathways, Inc. | Lactone compounds for treating patient with precancerous lesions |
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| US5874440A (en) * | 1995-06-07 | 1999-02-23 | Cell Pathways, Inc. | Method of treating a patient having precancerous lesions with phenyl pyrimidinone derivatives |
| US5942520A (en) * | 1998-01-27 | 1999-08-24 | Cell Pathways, Inc. | Method for inhibiting neoplastic cells by exposure to substituted N-cycloalkylmethyl-1-H-pyrazolo (3,4-B) quinolone-4 amines |
| US5990117A (en) * | 1998-04-15 | 1999-11-23 | Cell Pathways, Inc. | Method for inhibiting neoplastic cells and related conditions by exposure to quinazoline derivatives |
| US6020379A (en) * | 1999-02-19 | 2000-02-01 | Cell Pathways, Inc. | Position 7 substituted indenyl-3-acetic acid derivatives and amides thereof for the treatment of neoplasia |
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| US6046206A (en) * | 1995-06-07 | 2000-04-04 | Cell Pathways, Inc. | Method of treating a patient having a precancerous lesions with amide quinazoline derivatives |
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| US6060477A (en) * | 1995-06-07 | 2000-05-09 | Cell Pathways, Inc. | Method of treating a patient having precancerous lesions with phenyl cycloamino pyrimidinone derivatives |
| US6077842A (en) * | 1998-11-24 | 2000-06-20 | Cell Pathways, Inc. | Method of inhibiting neoplastic cells with pyrazolopyridylpyridazinone derivatives |
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| US6133271A (en) * | 1998-11-19 | 2000-10-17 | Cell Pathways, Inc. | Method for inhibiting neoplastic cells and related conditions by exposure thienopyrimidine derivatives |
| US6156528A (en) * | 1997-05-30 | 2000-12-05 | Cell Pathways, Inc | Methods for using a phosphodiesterase in pharmaceutical screening to identify compounds for treatment of neoplasia |
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| US6180629B1 (en) | 1998-08-14 | 2001-01-30 | Cell Pathways, Inc. | [4,5]-Fused-1,3-disubstituted-1,2-diazine-6-one derivatives with nitrogen containing substitutents in position one for the treatment of neoplasia |
| US6187779B1 (en) | 1998-11-20 | 2001-02-13 | Cell Pathways, Inc. | Method for inhibiting neoplastic cells and related conditions by exposure to 2,8-disubstituted quinazoline derivatives |
| US6200980B1 (en) | 1995-06-07 | 2001-03-13 | Cell Pathways, Inc. | Method of treating a patient having precancerous lesions with phenyl purinone derivatives |
| US6200771B1 (en) | 1998-10-15 | 2001-03-13 | Cell Pathways, Inc. | Method of using a novel phosphodiesterase in pharmaceutical screeing to identify compounds for treatment of neoplasia |
| US6232312B1 (en) | 1995-06-07 | 2001-05-15 | Cell Pathways, Inc. | Method for treating patient having precancerous lesions with a combination of pyrimidopyrimidine derivatives and esters and amides of substituted indenyl acetic acides |
| US6262059B1 (en) | 1995-06-07 | 2001-07-17 | Cell Pathways, Inc. | Method of treating a patient having precancerous lesions with quinazoline derivatives |
| US6268372B1 (en) | 1998-09-11 | 2001-07-31 | Cell Pathways, Inc. | Method for inhibiting neoplastic cells and related conditions by exposure to 2,9-disubstituted purin-6-ones |
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| WO2015015420A1 (en) * | 2013-07-30 | 2015-02-05 | Narodowy Instytut Zdrowia Publicznego Państwowy Zakład Higieny | Novel derivatives of a 3,4-dihydroisoquinoline-3-carboxylic acid having anti-cancer properties, a method for their synthesis, pharmaceutical compositions comprising said derivatives, and their use |
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| WO2011107709A1 (en) * | 2010-03-01 | 2011-09-09 | Universite Joseph Fourier | Use of isoquinolones for preparing drugs, novel isoquinolones and method for synthesising same |
| JP2013521265A (en) * | 2010-03-01 | 2013-06-10 | ユニヴェルシテ ジョセフ フーリエ | Use of isoquinolones for drug manufacture, novel isoquinolones and methods for their synthesis |
| US8883763B2 (en) | 2010-03-01 | 2014-11-11 | Universite Joseph Fourier | Use of isoquinolones for preparing drugs, novel isoquinolones and method for synthesising same |
| EA032434B1 (en) * | 2010-03-01 | 2019-05-31 | Юниверсите Гренобль Альп | Use of isoquinolones for preparing drugs, isoquinolones and method for synthesising same |
| WO2015015420A1 (en) * | 2013-07-30 | 2015-02-05 | Narodowy Instytut Zdrowia Publicznego Państwowy Zakład Higieny | Novel derivatives of a 3,4-dihydroisoquinoline-3-carboxylic acid having anti-cancer properties, a method for their synthesis, pharmaceutical compositions comprising said derivatives, and their use |
Also Published As
| Publication number | Publication date |
|---|---|
| ZA916646B (en) | 1992-07-29 |
| AU8328691A (en) | 1992-03-17 |
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