AU2837001A - Acryloyl peptidic derivatives, process for their preparation and their use as antitumor agents - Google Patents
Acryloyl peptidic derivatives, process for their preparation and their use as antitumor agents Download PDFInfo
- Publication number
- AU2837001A AU2837001A AU28370/01A AU2837001A AU2837001A AU 2837001 A AU2837001 A AU 2837001A AU 28370/01 A AU28370/01 A AU 28370/01A AU 2837001 A AU2837001 A AU 2837001A AU 2837001 A AU2837001 A AU 2837001A
- Authority
- AU
- Australia
- Prior art keywords
- methyl
- amino
- pyrrol
- carbonyl
- pyrrole
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000000034 method Methods 0.000 title claims description 24
- 239000002246 antineoplastic agent Substances 0.000 title claims description 8
- 125000003647 acryloyl group Chemical group O=C([*])C([H])=C([H])[H] 0.000 title claims description 5
- 238000002360 preparation method Methods 0.000 title description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 354
- -1 hydroxy, methyl Chemical group 0.000 claims description 233
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 218
- 150000001875 compounds Chemical class 0.000 claims description 80
- 125000001397 3-pyrrolyl group Chemical group [H]N1C([H])=C([*])C([H])=C1[H] 0.000 claims description 41
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 30
- 229910052739 hydrogen Inorganic materials 0.000 claims description 26
- 239000001257 hydrogen Substances 0.000 claims description 26
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 20
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 16
- 150000003857 carboxamides Chemical class 0.000 claims description 16
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 15
- FLJBIGAZJFDVTC-UHFFFAOYSA-N 1-methylpyrrole-2-carboxamide Chemical compound CN1C=CC=C1C(N)=O FLJBIGAZJFDVTC-UHFFFAOYSA-N 0.000 claims description 13
- 150000002431 hydrogen Chemical class 0.000 claims description 10
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 9
- 125000000623 heterocyclic group Chemical group 0.000 claims description 8
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 claims description 7
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 6
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 6
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 239000000460 chlorine Substances 0.000 claims description 6
- 206010028980 Neoplasm Diseases 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 229940034982 antineoplastic agent Drugs 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- 238000002560 therapeutic procedure Methods 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 claims 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims 1
- 201000011510 cancer Diseases 0.000 claims 1
- 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 claims 1
- 239000003814 drug Substances 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 34
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 30
- 239000000243 solution Substances 0.000 description 29
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 28
- 239000002904 solvent Substances 0.000 description 19
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- UMLZCUKQMIDQJY-UHFFFAOYSA-N 1h-pyrrole-2-carboxamide;hydrochloride Chemical compound Cl.NC(=O)C1=CC=CN1 UMLZCUKQMIDQJY-UHFFFAOYSA-N 0.000 description 16
- 238000006243 chemical reaction Methods 0.000 description 14
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- 239000000203 mixture Substances 0.000 description 10
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- 239000007858 starting material Substances 0.000 description 9
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 9
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 8
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- 239000000843 powder Substances 0.000 description 7
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- 125000000389 2-pyrrolyl group Chemical group [H]N1C([*])=C([H])C([H])=C1[H] 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 5
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 5
- 238000003818 flash chromatography Methods 0.000 description 5
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Substances [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 5
- UPBAOYRENQEPJO-UHFFFAOYSA-N n-[5-[[5-[(3-amino-3-iminopropyl)carbamoyl]-1-methylpyrrol-3-yl]carbamoyl]-1-methylpyrrol-3-yl]-4-formamido-1-methylpyrrole-2-carboxamide Chemical compound CN1C=C(NC=O)C=C1C(=O)NC1=CN(C)C(C(=O)NC2=CN(C)C(C(=O)NCCC(N)=N)=C2)=C1 UPBAOYRENQEPJO-UHFFFAOYSA-N 0.000 description 5
- PFKFTWBEEFSNDU-UHFFFAOYSA-N 1,1'-Carbonyldiimidazole Substances C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 4
- AXVRBBFVTOPBOE-UHFFFAOYSA-N 1-aminopyrrole-2-carboxamide dihydrochloride Chemical compound Cl.Cl.NN1C(=CC=C1)C(=O)N AXVRBBFVTOPBOE-UHFFFAOYSA-N 0.000 description 4
- YYZVQYVIRZSNMJ-UHFFFAOYSA-N 1-methylpyrrole-2-carboxamide;hydrochloride Chemical compound Cl.CN1C=CC=C1C(N)=O YYZVQYVIRZSNMJ-UHFFFAOYSA-N 0.000 description 4
- WEJHQYYHCDJZQR-UHFFFAOYSA-N 1H-pyrrole-2-carboxamide dihydrochloride Chemical compound Cl.Cl.N1C(=CC=C1)C(=O)N WEJHQYYHCDJZQR-UHFFFAOYSA-N 0.000 description 4
- 229920002261 Corn starch Polymers 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 239000008120 corn starch Substances 0.000 description 4
- 235000019439 ethyl acetate Nutrition 0.000 description 4
- 125000001841 imino group Chemical group [H]N=* 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- 235000019198 oils Nutrition 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- GSMALGMHQITIKZ-UHFFFAOYSA-N Cl.[N+](=O)([O-])N1C(=CC=C1)C(=O)N Chemical compound Cl.[N+](=O)([O-])N1C(=CC=C1)C(=O)N GSMALGMHQITIKZ-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
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- 150000001412 amines Chemical class 0.000 description 3
- 125000003277 amino group Chemical group 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
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- 229940032147 starch Drugs 0.000 description 3
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- SXLTUPBFHKJHDE-UHFFFAOYSA-N 1-(2-aminoethyl)-2-methylguanidine;hydrochloride Chemical compound Cl.CN=C(N)NCCN SXLTUPBFHKJHDE-UHFFFAOYSA-N 0.000 description 2
- NVDATLDKVGDZJQ-UHFFFAOYSA-N 1-(3-aminopropyl)-2-methylguanidine;hydrochloride Chemical compound Cl.CN=C(N)NCCCN NVDATLDKVGDZJQ-UHFFFAOYSA-N 0.000 description 2
- HCNGGCURDWJVBE-UHFFFAOYSA-N 3-(benzimidazol-1-yl)propanenitrile Chemical compound C1=CC=C2N(CCC#N)C=NC2=C1 HCNGGCURDWJVBE-UHFFFAOYSA-N 0.000 description 2
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- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 2
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- LRSQDQTZXKVIOQ-UHFFFAOYSA-N N-[2-(4,5-dihydro-1H-imidazol-2-ylamino)propyl]-1-methyl-4-[(1-methyl-4-nitropyrrole-2-carbonyl)amino]pyrrole-2-carboxamide hydrochloride Chemical compound CC(CNC(=O)C1=CC(=CN1C)NC(=O)C2=CC(=CN2C)[N+](=O)[O-])NC3=NCCN3.Cl LRSQDQTZXKVIOQ-UHFFFAOYSA-N 0.000 description 1
- YGYUUKUQJHBYQF-UHFFFAOYSA-N N-[2-[(N,N'-dimethylcarbamimidoyl)amino]ethyl]-1-methyl-4-[[1-methyl-4-[(1-methyl-4-nitropyrrole-2-carbonyl)amino]pyrrole-2-carbonyl]amino]pyrrole-2-carboxamide Chemical compound CN1C(=CC(=C1)NC(=O)C=1N(C=C(C=1)[N+](=O)[O-])C)C(=O)NC1=CN(C(=C1)C(=O)NCCNC(=NC)NC)C YGYUUKUQJHBYQF-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
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- 235000002595 Solanum tuberosum Nutrition 0.000 description 1
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- 125000003368 amide group Chemical group 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- SJSWRKNSCWKNIR-UHFFFAOYSA-N azane;dihydrochloride Chemical compound N.Cl.Cl SJSWRKNSCWKNIR-UHFFFAOYSA-N 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
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- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Substances OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
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- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 229960004393 lidocaine hydrochloride Drugs 0.000 description 1
- YECIFGHRMFEPJK-UHFFFAOYSA-N lidocaine hydrochloride monohydrate Chemical compound O.[Cl-].CC[NH+](CC)CC(=O)NC1=C(C)C=CC=C1C YECIFGHRMFEPJK-UHFFFAOYSA-N 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 201000005296 lung carcinoma Diseases 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
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- AFVFQIVMOAPDHO-UHFFFAOYSA-N methanesulfonic acid Substances CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- SDDKIZNHOCEXTF-UHFFFAOYSA-N methyl carbamimidothioate Chemical compound CSC(N)=N SDDKIZNHOCEXTF-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- BXWQGXOBUMPZLC-UHFFFAOYSA-N methyl n,n'-dimethylcarbamimidothioate Chemical compound CNC(SC)=NC BXWQGXOBUMPZLC-UHFFFAOYSA-N 0.000 description 1
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- 238000002156 mixing Methods 0.000 description 1
- GRKXZGVDPSJTHW-UHFFFAOYSA-N n'-(1h-imidazol-2-yl)ethane-1,2-diamine;dihydrochloride Chemical compound Cl.Cl.NCCNC1=NC=CN1 GRKXZGVDPSJTHW-UHFFFAOYSA-N 0.000 description 1
- XQYFPFBSEAOCAQ-UHFFFAOYSA-N n'-(4,5-dihydro-1h-imidazol-2-yl)ethane-1,2-diamine Chemical compound NCCNC1=NCCN1 XQYFPFBSEAOCAQ-UHFFFAOYSA-N 0.000 description 1
- QCVAJJQYOLOTNF-UHFFFAOYSA-N n'-(4,5-dihydro-1h-imidazol-2-yl)propane-1,3-diamine;dihydrochloride Chemical compound Cl.Cl.NCCCNC1=NCCN1 QCVAJJQYOLOTNF-UHFFFAOYSA-N 0.000 description 1
- YNTOKMNHRPSGFU-UHFFFAOYSA-N n-Propyl carbamate Chemical compound CCCOC(N)=O YNTOKMNHRPSGFU-UHFFFAOYSA-N 0.000 description 1
- UZDCDEPVRHJLTA-UHFFFAOYSA-N n-[2-(4,5-dihydro-1h-imidazol-2-ylamino)propyl]-1-methyl-4-nitropyrrole-2-carboxamide;hydrochloride Chemical compound Cl.N=1CCNC=1NC(C)CNC(=O)C1=CC([N+]([O-])=O)=CN1C UZDCDEPVRHJLTA-UHFFFAOYSA-N 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000009826 neoplastic cell growth Effects 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 230000000174 oncolytic effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
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- 210000001672 ovary Anatomy 0.000 description 1
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- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229940068965 polysorbates Drugs 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 238000009495 sugar coating Methods 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- REXDCISUSLPKEC-UHFFFAOYSA-N tert-butyl N-[2-[[1-methyl-4-[[1-methyl-4-[(1-methyl-4-nitropyrrole-2-carbonyl)amino]pyrrole-2-carbonyl]amino]pyrrole-2-carbonyl]amino]propyl]carbamate Chemical compound CC(CNC(=O)OC(C)(C)C)NC(=O)c1cc(NC(=O)c2cc(NC(=O)c3cc(cn3C)[N+]([O-])=O)cn2C)cn1C REXDCISUSLPKEC-UHFFFAOYSA-N 0.000 description 1
- UYNSYFDLTSSUNI-UHFFFAOYSA-N tert-butyl n-(2-aminopropyl)carbamate Chemical compound CC(N)CNC(=O)OC(C)(C)C UYNSYFDLTSSUNI-UHFFFAOYSA-N 0.000 description 1
- UDWODNMLUJRTAV-UHFFFAOYSA-N tert-butyl n-[2-[(4-amino-1-methylpyrrole-2-carbonyl)amino]propyl]carbamate Chemical compound CC(C)(C)OC(=O)NCC(C)NC(=O)C1=CC(N)=CN1C UDWODNMLUJRTAV-UHFFFAOYSA-N 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 208000010570 urinary bladder carcinoma Diseases 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pyrrole Compounds (AREA)
- Hydrogenated Pyridines (AREA)
Description
WO 01/40181 PCT/EPOO/11714 ACRYLOYL PEPTIDIC DERIVATIVES, PROCESS FOR THEIR PREPARATION AND THEIR USE AS ANTITUMOR AGENTS. The present invention relates to new acryloyl peptidic 5 compounds, to a process for their preparation, to pharmaceutical compositions containing them and to their use in therapy, in particular as antitumor agents. Peptidic derivatives, for instance Distamycin A and analogous 10 thereof, are known in the art as antitumor agents. Distamycin A is an antibiotic substance with antiviral and oncolytic properties, having a polypyrrole framework (Nature 203, 1064 (1964); J. Med. Chem. 32, 774-778 (1989)). 15 The international patent application WO 97/43258, in the name of the applicant, discloses acryloyl distamycin derivatives wherein the amidino moiety is replaced by nitrogen-containing ending groups such as, for instance, cyanamidino, N methylamidino, ethylguanidino, amido, amidoximo, nitrile and 20 the like. Distamycin derivatives wherein at least one pyrrole ring of the aforementioned polypyrrole framework is replaced by an imidazole or pyrazole ring are also reported in the 25 literature. See, for a general reference, Anti-Cancer Drug Design 8, 173 192 (1993) ; J. Am. Chem. Soc. Vol. 114, 5911-5919 (1992); Anti-Cancer Drug Design 6, 501-517 (1991) ; patent applications EP-A-0246868 and WO 96/05196, both in the name 30 of the applicant. It has now been found that a new class of acryloyl peptidic derivatives, as defined hereinunder, is endowed with valuable biological properties. 35 Therefore, the present invention provides compounds which are acryloyl peptidic derivatives of formula WO 01/40181 PCT/EPOO/11714 -2 R1
R
3 > H N R2 H N N
CH
3 n wherein: n is 3 or 4; 5 m is 0, 1 or 2; X and Y are the same or different and are selected, independently for each heterocyclic ring, from N or CH; Ri and R 2 , the same or different, are selected from hydrogen, halogen or C 1
-C
4 alkyl; 10 R 3 is hydrogen or halogen; B is selected from the groups consisting of: ,4 O
NH
2
N-R
5 NH2 |1 NH NH-K\ NH x NH-C-NR 7
R
8 N-CN
N-R
6 N-NH 2 ' H H H N N N NH - NH and NH\ N N N wherein R 4 , R 5 , R, and R 8 are, independently from each other, hydrogen or C,-C 4 alkyl; R, is hydrogen, hydroxy or C 1
-C
4 15 alkyl; or a pharmaceutically acceptable salt thereof; provided that: i) X and Y are not both N atoms for the same heterocyclic ring; ii) when all of X and Y are CH groups and m is 0, then at 20 least one of R 4 , R, or R, is other than hydrogen; iii) when at least one of X and Y is other than CH, then at least one of R 4 and R 5 is other than hydrogen. The present invention includes within its scope also all 25 the possible isomers covered by the compounds of formula WO 01/40181 PCT/EPOO/11714 -3 (I), both separately and in admixture, as well as the metabolites and the pharmaceutically acceptable bio precursors (otherwise known as pro-drugs) of the compounds of formula (I). 5 In the present description, unless otherwise specified, the term alkyl includes straight or branched C,-C 4 alkyl groups such as, for instance, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl, methyl and 10 ethyl being preferred; the term halogen includes fluorine, chlorine, bromine and iodine, fluorine, chlorine or bromine being preferred. As above reported, X and Y are selected, independently for 15 each heterocyclic ring of the polyheterocyclic chain, between N and CH. This means that within the compounds of formula (I) and for different heterocyclic rings, X can be either N as well as CH; the same applies to Y provided that X and Y are not contemporaneously N for a single 20 heterocycle. Examples for the said heterocycles are pyrrole, pyrazole and imidazole. Pharmaceutically acceptable salts of the compounds of 25 formula (I) are those with pharmaceutically acceptable inorganic or organic acids such as, for instance, hydrochloric, hydrobromic, sulphuric, nitric, acetic, propionic, succinic, malonic, citric, tartaric, methanesulfonic and p-toluenesulfonic acid. 30 A preferred class of compounds, according to the present invention, is represented by the above formula (I) wherein
R
4 , R 5 , R, and R. are, independently from each other, hydrogen, methyl or ethyl and R, is hydrogen, hydroxy, 35 methyl or ethyl. Even more preferred, within this class, are the compounds WO 01/40181 PCT/EPOO/11714 -4 of formula (I) wherein n is 3 or 4; m is 0, 1 or 2; X and Y are CH; 5 R 1 and R 2 are hydrogen; R. is chlorine or bromine; B is selected from R4 H H N-R 0 NH 2 N N NH NH NR R NH NH \ NH N-R6 , , N-OH N and N wherein R 4 , RS, R, and R 8 are, independently from each 10 other, hydrogen or methyl and R, is hydrogen, hydroxy or methyl; provided that when m is 0, at least one of R 4 , R, or R. is other than hydrogen. Examples of specific compounds according to the present 15 invention, especially in the form of salts, preferably with hydrochloric acid, are the following: (1) N-(5-{[(5-{[(5-{[(2-{[amino(methylimino)methyl] amino}ethyl) amino] carbonyl} -1-methyl-1H-pyrrol-3 20 yl)amino]carbonyl)-1-methyl-lH-pyrrol-3 yl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)-4-[(2 bromoacryloyl)amino]-1-methyl-lH-pyrrole-2-carboxamide (2) N-(5-{[(5-{[(5-{[(2-{[amino(methylimino)methyl] amino}ethyl)amino]carbonyl}-1-methyl-lH-pyrrol-3 25 yl)amino]carbonyl)-l-methyl-lH-pyrrol-3 yl)amino]carbonyl}-1-methyl-lH-pyrrol-3-yl)-4-[(2 chloroacryloyl)amino]-1-methyl-lH-pyrrole-2 carboxamide (3) 4-[(2-bromoacryloyl)amino]-N-(5-{[(5-{[(5-{[(2 30 ([imino(methylamino)methyllamino}ethyl)amino]carbonyl} -1-methyl-lH-pyrrol-3-yl)amino]carbonyl}-1-methyl-lH pyrrol-3-yl)amino]carbonyl)-1-methyl-1H-pyrrol-3-yl) 1-methyl-lH-pyrrole-2-carboxamide (4) 4-[(2-chloroacryloyl)amino)-N-(5-{[(5-{[(5-{[(2- WO 01/40181 PCT/EPOO/11714 -5 {[imino(methylamino)methyl]amino}ethyl)aminolcarbonyl} -1-methyl-1H-pyrrol-3-yl)amino]carbonyl}-1-methyl-lH pyrrol-3-yl)amino]carbonyl}-1-methyl-lH-pyrrol-3-yl) 1-methyl-1H-pyrrole-2-carboxamide 5 (5) 4-[(2-bromoacryloyl)amino]-N-(5-{[(5-{[(5-{[(2 {[(dimethylamino) (imino)methyl]amino}ethyl)amino]carbo nyl}-1-methyl-lH-pyrrol-3-yl)amino]carbonyl}-1-methyl 1H-pyrrol-3-yl)aminolcarbonyl}-1-methyl-lH-pyrrol-3 yl)-1-methyl-lH-pyrrole-2-carboxamide 10 (6) 4-[(2-chloroacryloyl)amino]-N-(5-{[(5-{[(5-{[(2 {[(dimethylamino) (imino)methyllamino}ethyl)amino]carbo nyl}-1-methyl-lH-pyrrol-3-yl)amino]carbonyl}-1-methyl 1H-pyrrol-3-yl)amino]carbonyl}-1-methyl-1H-pyrrol-3 yl)-1-methyl-1H-pyrrole-2-carboxamide 15 (7) 4-[(2-bromoacryloyl)amino]-1-methyl-N-(l-methyl-5 {[(l-methyl-5-{[(l-methyl-5-{[(2-{[(methylamino) (methylimino)methyllamino}ethyl)amino]carbonyl}-lH pyrrol-3-yl)amino]carbonyl}-1H-pyrrol-3-yl)amino] carbonyl}-1H-pyrrol-3-yl)-lH-pyrrole-2-carboxamide 20 (8) 4-[(2-chloroacryloyl)amino]-1-methyl-N-(1-methyl-5 {[(l-methyl-5-{[(1-methyl-5-{[(2-{[(methylamino) (methylimino)methyl]amino}ethyl)amino]carbonyl}-lH pyrrol-3-yl)amino]carbonyl}-1H-pyrrol-3-yl)amino] carbonyl}-1H-pyrrol-3-yl)-lH-pyrrole-2-carboxamide 25 (9) N-{5-[({5-[({5-[({2-[(aminocarbonyl)amino]ethyl} amino)carbonyl]-1-methyl-1H-pyrrol-3 yl}amino)carbonyl]-1-methyl-1H-pyrrol-3 yl}amino)carbonyl]-1-methyl-lH-pyrrol-3-yl}-4-[(2 bromoacryloyl)amino]-l-methyl-lH-pyrrole-2-carboxamide 30 (10) N-{5-[({5-[({5-[({2-[(aminocarbonyl)aminolethyl) amino)carbonyl]-l-methyl-1H-pyrrol-3 yl}amino)carbonyl]-l-methyl-lH-pyrrol-3 yl}amino)carbonyl]-1-methyl-1H-pyrrol-3-yl}-4-[(2 chloroacryloyl)amino]-1-methyl-1H-pyrrole-2 35 carboxamide (11) 4-[(2-bromoacryloyl)amino]-1-methyl-N-(l-methyl-5 {[(l-methyl-5-{[(1-methyl-5-{[(2- WOO01/40181 PCTIEPOO/11714 -6 { [(methylamino) carbonyl] amino} ethyl) amino] carbonyl} lH-pyrrol-3-yl)amino] carbonyl}-lH-pyrrol-3 yl) amino] carbonyl} -lH-pyrrol-3-yl) -lH-pyrrole-2 carboxamide 5 (12) 4- [(2-chloroacryloyl)amino] -1-methyl-N- (l-methyl-5 [(l-methyl-5-{ [(l-methyl-5-{ (2 { [(methylamino) carbonyl] amino} ethyl) amino] carbonyl} iH-pyrrol-3-yl)amino] carbonyl}-1H-pyrrol-3 yl)aminolcarbonyl}-lH-pyrrol-3-yl) -lH-pyrrole-2 10 carboxamide (13) N-(5-{[(5-{[(5-{[(2-{[amino(hydroxyimilo)methyl] aminolethyl) amino] carbonyl} -i-methyl-1H-pyrrol-3 yl) amino] carbonyl }- 1-methyl -lH-pyrrol -3 yl) amino] carbonyl} -l-methyl-lH-pyrrol-3-yl) -4- [(2 15 bromoacryloyl) amino] -l-methyl-lH-pyrrole-2-carboxamide (14) N-(5-{[(5-{[(5-{[(2-{[amino(hydroxyimino)methyl] amino} ethyl) amino] carbonyl} -l-methyl-lH-pyrrol-3 yl)amino] carbonyl}-l-methyl-1H-pyrrol-3 yl)amino] carbonyl}-l-methyl-lH-pyrrol-3-yl) -4- [(2 20 chloroacryloyl)amino] -l-methyl-lH-pyrrole-2 carboxamide (15) 4-[(2-bromoacryloyl)amino]-N-[5-({[5-({L5-({[2-(4,5 dihydro-lH-imidazol-2-ylamino) ethyl] amino~carbonyl) -1 methyl-lH-pyrrol-3-yl] amino~carbonyl) -1-methyl-lH 25 pyrrol-3-yl] aminolcarbonyl) -1-methyl-lH-pyrrol-3-yl] 1-methyl -lH-pyrrole -2- carboxamide (16) 4-[(2-chloroacryloyl)amino]-N-[5-({[5-({[5-({[2-(4,5 dihydro-lH-imidazol-2-ylamino) ethyl] amino~carbonyl) -1 methyl-lH-pyrrol-3-yl] amino~carbonyl) -1-methyl-1H 30 pyrrol-3-yllaminolcarbonyl) -l-methyl-lH-pyrrol-3-yl] 1-methyl -lI-pyrrole -2- carboxamide (17) 4-[(2-bromoacryloyl)amino]-N-[5-({[5-({[5-({[2-(1H imidazol-2-ylamino) ethyl] amino~carbonyl) -l-methyl-lH pyrrol-3-yl] aminolcarbonyl) -1-methyl-lH-pyrrol-3 35 yl] aminolcarbonyl) -1-methyl-lH-pyrrol-3-yl] -i-methyl lH-pyrrole-2 -carboxamide (18) 4-[(2-chlorooacryloyl)amino]-N-[5-({[5-({[5-({[2-(lH- WO 01/40181 PCTIEPOO/11714 -7 imidazol-2-ylamino) ethyl] aminolcarbonyl) -1-methyl-iN pyrrol-3-yl] aminolcarbonyl) -l-methyl-lH-pyrrol-3 yl] aminolcarbonyl) -l-methyl-lH-pyrrol-3-yl] -1-methyl 1H-pyrrole-2 -carboxamide 5 (19) 4-1 (2-bromoacryloyl)amino] -i-methyl-N- [l-methyl-5 ({ [1-methyl-5- ({ [l-methyl-5- ({[2- (1,4,5,6-tetrahydro 2-pyrimidinylamino) ethyl] amino~carbonyl) -lH-pyrrol-3 yl] aminolcarbonyl) -lH-pyrrol-3-yl] aminolcarbonyl) -lH pyrrol-3-yl] -lH-pyrrole-2-carboxamide 10 (20) 4- [(2-chloroacryloyl)amino] -1-methyl-N- [l-methyl-5 ({ [l-methyl-5- ({[l-methyl-5- ({[2- (1,4,5,6-tetrahydro 2-pyrimidinylamino) ethyl] aminolcarbonyl) -lH-pyrrol-3 yl] amino~carbonyl) -lH-pyrrol-3-yl] aminolcarbonyl) -lH pyrrol-3-yl] -lH-pyrrole-2-carboxamide 15 (21) N-(5-{[(5-{[(5-{[(2{[amilo(imilo)methyl] aminolpropyl) amino] carbonyl} -l-methyl-lH-pyrrol-3 yl) amino] carbonyl} -l-methyl-lH-pyrrol-3 yl) amino] carbonyl} -l-methyl-lH-pyrrol-3-yl) -4- [(2 bromoacryloyl) amino] -l-methyl-lH-pyrrole-2-carboxamide 20 (22) N-(5-{[(5-{[(5-{[(2{[amino(imino)methyl] amino~propyl) amino] carbonyl} -l-methyl-lH-pyrrol-3 yl) amino] carbonyl} -l-methyl-1H-pyrrol-3 yl) amino] carbonyl} -l-methyl-lH-pyrrol-3-yl) -4- 1(2 chloroacryloyl) amino] -1-methyl-1H-pyrrole-2 25 carboxamide (23) 4- [(2-bromoacryloyl)amino] -1-methyl-N- (l-methyl-5 {[(l-methyl-5-{[(l-methyl-5-{[(2-[(methylamilo) (methylimino)methyl] aminolpropyl) amino] carbonyl} -1K pyrrol-3-yl) amino] carbonyl} -lH-pyrrol-3-yl) amino] 30 carbonyl} -lH-pyrrol-3-yl) -lH-pyrrole-2-carboxamide (24) 4- [(2-chloroacryloyl)amino] -1-methyl-N- (l-methyl-5 [(l-methyl-5-{ [(l-methyl-5-{ [(2-{ [(methylamino) (methylimino)methyl] aminolpropyl) amino] carbonyl} -lH pyrrol-3-yl) amino] carbonyl} -lH-pyrrol-3-yl) amino] 35 carbonyl} -lH-pyrrol-3-yl) -lH-pyrrole-2-carboxamide (25) N-{5-[({5-[({5-[({2-[(aminocarbonyl)aminolethyl} amino) carbonyl] -l-methyl-lH-pyrrol-3- WO 01/40181 PCT/EPOO/1 1714 -8 yllamino) carbonyl] -1-methyl-lH-pyrrol-3 yllamino)carbonyl]-l-methyl-lH-pyrrol-3-yl}-4-[(2 bromoacryloyl) amino] -1-methyl-lH-pyrrole-2-carboxamide (26) N-{5-[({5-[({5-1({2-[(aminocarbolyl)amfinolethyl} 5 amino) carbonyl] -1-methyl-lH-pyrrol-3 yllamino) carbonyl] -1-methyl-lH-pyrrol-3 yl~amino)carbonyl]-1-methyl-lH-pyrrol-3-yl}-4-[(2 chioroacryloyl) amino] -i-methyl-lH-pyrrole-2 carboxamide 10 (27) 4-[(2-bromoacryloyl)amino]-N-[5-({[5-({[5-({[2-(4,5 dihydro-lH-imidazol-2-ylamino) propyll amino) carbonyl) 1-methyl-lH-pyrrol-3-yllaminolcarbony-) -1-methyl-iN pyrrol-3-yll aminolcarbonyl) -l-methyl-1H-pyrrol-3-yl] 1-methyl- 1H-pyrrole-2 -carboxamide 15 (28) 4-[(2-chloroacryloyl)amino]-N-[5-({[5-({[5-({[2-(4,5 dihydro-lH-imidazol-2-ylamino) propyl] amino~carbonyl) l-methyl-lH-pyrrol-3-yl] amino) carbonyl) -l-methyl-lH pyrrol-3-yll aminolcarbonyl) -1-methyl-lH-pyrrol-3-yl] l-methyl-lH-pyrrole-2 -carboxamide 20 (29) 4- [(2-bromoacryloyl)amino] -1-methyl-N- [l-methyl-5 ({ [l-methyl-5- ({[1-methyl-5- ({ 12- (1,4,5, 6-tetrahydro 2-pyrimidinylamino) propyl] amino) carbonyl) -1H-pyrrol-3 yll aminolcarbonyl) -lH-pyrrol-3-yl] amino)carbonyl) -lH pyrrol-3-yl] -1N-pyrrole-2-carboxamide 25 (30) 4- [(2-chloroacryloyl)amino] -i-methyl-N- [1-methyl-5 ({ 11-methyl-5- ({[1-methyl-5- ({[2- (1,4,5,6-tetrahydro 2 -pyrimidinylamino) propyll amino) carbonyl) -1H-pyrrol-3 yl] aminolcarbonyl) -lH-pyrrol-3-yll aminolcarbonyl) -lH pyrrol-3-yl] -lH-pyrrole-2-carboxamide 30 (31) N-(5-{[(5-{[(2-{[amino(methylimino)methylI aminolethyl) amino] carbonyl) -1-methyl-lH-pyrrol-3 yl) amino] carbonyl}-1-methyl-lH-pyrrol-3-yl) -4- [(2 bromoacryloyl) amino] -l-methyl-lH-pyrrole-2-carboxamide (32) 4-11(2-bromoacryloyl)amino] -1-methyl-N- (l-methyl-5 35 { [(l-methyl-5-{ 11(2-{ (methylamino) (methylimino)methyl] aminolethyl) amino] carbonyl) -lH-pyrrol-3 yl)amino] carbonyl}-lH-pyrrol-3-yl) -lH-pyrrole-2- WO 01/40181 PCT/EPOO/11714 -9 carboxamide (33) 4-[(2-bromoacryloyl)amino]-1-methyl-N-(l-methyl-5 {[(1-methyl-5-{[(2-[(aminocarbonyl)amino] ethyl) amino] carbonyl} -1H-pyrrol-3-yl) amino] carbonyl} 5 1H-pyrrol-3-yl)-lH-pyrrole-2-carboxamide (34) 4-[(2-bromoacryloyl)amino]-N-[5-({[5-({[2-(4,5 dihydro-lH-imidazol-2-ylamino)ethyl]amino}carbonyl)-1 methyl-lH-pyrrol-3-yl]amino}carbonyl)-1-methyl-lH pyrrol-3-yl]-l-methyl-lH-pyrrole-2-carboxamide 10 (35) 4-[(2-bromoacryloyl)amino]-1-methyl-N-[l-methyl-5 ({[1-methyl-5-({[1-methyl-5-({[2-(1,4,5,6-tetrahydro 2-pyrimidinylamino)ethyl]amino}carbonyl)-1H-pyrrol-3 yl]amino}carbonyl)-lH-pyrrol-3-yl]amino}carbonyl)-lH pyrrol-3-yl]-lH-pyrrole-2-carboxamide 15 (36) N-(5-{[(5-{[(5-{[(2{[amino(imino)methyl] amino}butyl)amino]carbonyl}-1-methyl-1H-pyrrol-3 yl)amino]carbonyl)-1-methyl-lH-pyrrol-3 yl)amino]carbonyl}-l-methyl-lH-pyrrol-3-yl)-4-[(2 bromoacryloyl)amino]-1-methyl-lH-pyrrole-2-carboxamide 20 (37) N-(5-{[(5-{[(5-{[(2{[amino(imino)methyl] amino}butyl)amino]carbonyl)-l-methyl-1H-pyrrol-3 yl) amino] carbonyl} -l-methyl-lH-pyrrol-3 yl)amino]carbonyl}-l-methyl-lH-pyrrol-3-yl)-4-[(2 chloroacryloyl)amino]-l-methyl-lH-pyrrole-2 25 carboxamide. According to a further object of the present invention, the compounds of formula (I) can be prepared by a process which comprises reacting a compound of formula
H
2 N - xN N mB (II) 30 LH3CHO - n-p with a compound of formula WO 01/40181 PCT/EPOO/11714 - 10 R1 R 3 --NH R2 | Z 0 N ||
CH
3 p wherein n, m, X, Y, B, R 1 , R 2 , R 3 , X and Y are as defined above; p is 0 or 1 and Z is hydroxy or a suitable leaving group; and, if desired, 5 converting a compound of formula (I) into a pharmaceutically acceptable salt thereof. Within the above compounds of formula (III) , Z is hydroxy or a suitable leaving group for instance selected from chlorine, 2,4,5-trichlorophenoxy, pivaloyl, and the like. 10 The compounds of formula (II) may be prepared by converting a compound of formula T /Y XN\ N B (IV) _ CH 3 - n-p wherein X, Y, B, n, m and p are as defined above and T is 15 nitro or an amino group properly protected according to conventional techniques. As an example, the conversion of a compound of formula (IV) wherein T is nitro into a compound of formula (II) may be 20 carried out under hydrogen pressure in the presence of suitable hydrogenation catalysts, e.g. palladium on charcoal, into a suitable solvent such as dioxane, methanol, ethanol and mixtures thereof, at room temperature. 25 Likewise, the conversion of a compound of formula (IV) wherein T is a protected amino group into the free amino derivative of formula (II) may be carried out according to conventional deprotection techniques known in the art. See, WO 01/40181 PCT/EPOO/11714 - 11 for a general reference, J. Org. Chem. 43, 2285, 1978; J. Chem. Soc. Chem. Commun. 495, 1980. Examples of suitable amino protecting groups are, for instance, t-butyloxycarbonyl, triphenylmethyl or, more 5 preferably, carbobenzyloxy and formyl. In their tun, the compounds of formula (IV) wherein B is selected from R4
NH
2
N-R
5
NH
2
NH
2 NH -K, NH -K, NH -K, NH , N-CN ' N-R N-NH 2 ' N-OH H H H N N N NH-N\s NH -\ and NH \ N 'N N 10 can be prepared by reacting a compound of formula (V)
H
2 N
-
IY xN N B (V) _ 6H3 0 - n-p-1 with a compound of formula (VI): T T "(V I) xN Z 6H 3 0 wherein m, n, p, X, Y, T, B and Z are as defined above. 15 Instead, the compounds of formula (IV) wherein B is 0 ||
NH--C-NR
7
R
8 can be prepared by first reacting a compound of formula WO 01/40181 PCT/EPOO/11714 - 12 H 2 N
-
N N V (Vil) _ 6H 3 0 - n-p-i wherein X, Y, n, m and p are as defined above and V is a protected amino group, e.g. t-butoxycarbonyl-amino, with a compound of formula (VI) , by subsequently removing the 5 protecting group and by coupling the resultant compound with a suitable amine in presence of 1,1' carbonyldiimidazole (CDI). The compounds of formula (V) and (VII) can be prepared by 10 reacting a compound of formula
H
2 N N N mE (Vill) 6H 3 0 n-p-2 with a compound of formula T Y // z (VI) N 1 0
CH
3 wherein m, n, p, X, Y, T and Z are as defined above and E 15 is equal to B or V as defined within formulae (V) or (VII), respectively. The compounds of formula (VIII) can be prepared by reacting a compound of formula
H
2 N I/-Y xN N E (IX) 20
OH
3 0 - n-p-3 with a compound of formula WO 01/40181 PCT/IEPOO/11714 - 13 T T ' (V I) X' Z NY 6H 3 0 wherein m, n, p, X, Y, T, Z and E are as defined above. The compounds of formula (VIII) wherein n=4 and p=1 or n=3 5 and p=0 and those of formula (IX) wherein n=4 and p=0, all of which represented as compounds of formula
H
2N N N mE (X) CH30 can be obtained by reacting a compound of formula (VI) with a compound of formula (XI): E 10 whri HN m(XI) 10 wherein X, Y, m and E are as defined above. From the foregoing, it is clear to the skilled man that the compounds of formula (VIII) wherein n=3 and p=1 and those 15 of formula (IX) wherein n=3 and p=0, exactly correspond to the above compounds of formula (XI). The reaction between a compound of formula (II) and a compound of formula (III) or between a compound of formula 20 (V) , (VII) , (VIII) , (IX) and (XI) with a compound of formula (VI) , can all be carried out according to known methods, for instance as described in the aforementioned EP-A-246,868 and WO 96/05196. The compounds of formula (VI) are known or can be easily 25 prepared by known procedure as reported, for instance, in WO 96/05196; J.C.S. 1947-1032 and JACS £i2, 3495 (1940). The compounds of formula (XI) are known or can be easily WO 01/40181 PCT/EPO0/11714 - 14 prepared by known procedure such as, for instance, Synt. Comm. 28, 741, 1998; Synt. Comm. 20, 2559-2564, 3433-3437, 1990; J. Chem. Soc. Perkin Trans I, 173, 1990; J. Chem. Soc. 3127, 1963; J. Org. Chem. 275, 1963; J. Het. Chem. 5 2424, 1981; J. Org. Chem. 1157, 1959; J. Chem. Soc., 1629, 1958; J. Chem. Soc. 39, 1929. The compounds of formula (III) and (VI) are known or may be obtained by known methods (see, for a general reference, 10 Tetrahedron, 34, 2389, 1978; J. Org. Chem., 46, 3492, 1981; J. Org. Chem., 52, 3493, 1987; WO 96/05196 and WO 97/43258). The optional conversion of a compound of formula (I) into a 15 pharmaceutically acceptable salt, as well as the preparation of a free compound starting from a salt, may be carried out by known standard methods. Well known procedures such as, e.g., fractional crystallization or chromatography may also be followed for 20 separating a mixture of isomers of formula (I) into the single isomers. The compounds of formula (I) may be purified by conventional techniques such as, e.g., silica gel or alumina column chromatography, and/or by recrystallization 25 from an organic solvent such as, e.g., a lower aliphatic alcohol, e.g. methyl, ethyl or isopropyl alcohol, or dimethylformamide. The compounds of the invention show cytotoxic properties 30 towards tumor cells and are thus useful as antineoplastic agents, e.g. to inhibit the growth of various tumors such as, . for instance, carcinomas, e.g. mammary carcinoma, lung carcinoma, bladder carcinoma, colon carcinoma, ovary and endometrial tumors. Other neoplasias in which the compounds 35 of the invention could find application are, for instance, sarcomas, e.g. soft tissue and bone sarcomas, and the WO 01/40181 PCT/EPOO/11714 - 15 hematological malignancies such as, e.g., leukemias. The antitumor activity of the compounds of formula (I) was evaluated in vitro by cytotoxicity studies carried out on 5 murine L1210 leukemia cell. Cells were derived from in vivo tumors and established in cell culture. Cells were used until the tenth passage. Cytotoxicity was determined by counting surviving cells after 4 hours treatment and 48 hours growth in drug-free medium. 10 The percentage of cell growth in the treated cultures was compared with that of controls. Doses inhibiting 50% of the cellular growth in respect to controls, expressed as ID, 0 values, were calculated on dose-response curves. 15 The compounds of the invention can be administered by the usual routes, for example, parenterally, e.g. by intravenous injection or infusion, intramuscularly, subcutaneously, topically or orally. The dosage depends on the age, weight and conditions of the 20 patient and on the administration route. For example, a suitable dosage for administration to adult humans may range from about 0.05 to about 100 mg prn dse from 1 to 4 times a day. The pharmaceutical compositions object of the present 25 invention contain an effective amount of a compound of formula (I), as the active substance, in association with one or more pharmaceutically acceptable excipients. The pharmaceutical compositions of the invention are usually prepared following conventional methods and are administered 30 in a pharmaceutically suitable form. For instance, solutions for intravenous injection or infusion may contain sterile water as a carrier or, preferably, they may be in the form of sterile aqueous isotonic saline solutions. 35 Suspensions or solutions for intramuscular injections may contain, together with the active compound, a pharma ceutically acceptable carrier, e.g. sterile water, olive oil, WO 01/40181 PCT/EPOO/11714 - 16 ethyl oleate, glycols, e.g. propylene glycol and, if desired, a suitable amount of lidocaine hydrochloride. In the form for topical application, e.g. creams, lotions or pastes for use in dermatological treatment, the active 5 ingredient may be mixed with conventional oleaginous or emulsifying excipients. The solid oral forms, e.g. tablets and capsules, may contain, together with the active compound, diluents, e.g. lactose, dextrose, saccharose, cellulose, corn starch and potato 10 starch; lubricants, e.g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; binding agents, e.g. starches, arabic gums, gelatin, methylcellulose, carboxymethyl - cellulose, polyvinylpyrrolidone; disaggregating agents, e.g. a starch, 15 alginic acid, alginates, sodium starch glycolate; effervescing mixtures; dyestuffs; sweeteners; wetting agents, for instance, lecithin, polysorbates, laurylsulphates; and, in general, non-toxic and pharmacologically inactive substances used in pharmaceutical formulations. Said 20 pharmaceutical preparations may be manufactured in a known manner, for example by means of mixing, granulating, tabletting, sugar-coating, or film-coating processes. Furthermore, according to the present invention, there is provided a method of treating tumors in a patient in need of 25 it which comprises administering to the said patient a composition of the invention. The following examples are herewith intended to better illustrate the present invention without posing any 30 limitation to it. The abbreviations DMF, Et 2 0, EtOH, DCM, CDI, EtOAc and DMSO-d 6 stand for dimethylformamide, diethyl ether, ethanol, methylene chloride, 1,l'carbonyldiimidazole, ethyl acetate and deutero-dimethylsulfoxide, respectively. 35 Example 1 The intermediate N-(4.-dihydrn-lH-imidazol-2-yl)-l.2- WO 01/40181 PCT/EPOO/11714 - 17 pthan-diami np dihvdrnehlonridg To a solution of N-BOC ethylendiamine (1.6 g) in dry EtOH (20 ml), 2-methyltio-2-imidazoline hydroiodide (2.9 g), prepared as reported in Synth. Comm. 28, 741-746, 1998, was 5 added. The reaction mixture was refluxed for 8 h, the solvent evaporated under vacuum and the crude derivative dissolved in a solution of 5N HCl/MeOH (30 ml). The reaction solution was stirred at room temperature for 3 h, the solvent evaporated under vacuum and the crude product 10 washed with cool EtOH (15 ml) and then with Et-O (10 ml) , yielding the pure intermediate (1.2 g; y= 8 0%) as a yellow powder. m.p.(Et20) 135-138 OC PMR (DMSO-d) 6: 8.30 (bs, 3H), 8.22 (t, J=5.8 Hz, 1H), 15 3.87 (m, 4H), 3.36 (m, 4H). By analogous procedure and by using the opportune starting materials the following compounds can be obtained: N-(4,5-dihydro-lH-imidazol-2-yl)-1,3-propanediamine dihydrochloride; 20 N-(lH-imidazol-2-yl)-1,2-ethanediamine dihydrochloride; N-(lH-imidazol-2-yl)-1,2-propanediamine dihydrochloride; N- (2-aminoethyl) -N- (1,4,5, 6-tetrahydropyrimidin-2-yl) amine dihydrochloride; N- (3-aminopropyl) -N- (1,4,5, 6-tetrahydropyrimidin-2-yl) amine 25 dihydrochloride; The intyrmediatm To a solution of dimethylthiourea (4.17g) in dry EtOH (20 30 ml), iodomethane (2.8 ml) was added. The reaction was refluxed for 3 h, the solvent evaporated under vacuum, and the crude compound purified by precipitation EtOH/Et 2 O thus yielding the pure intermediate (9.8 g; y=98%) as a yellow powder. 35 The intermediatp N-(2-aminnethyl)-N' ,N' '-dimethyl guanidi n hydrohlnri de To a solution of N-BOC ethylendiamine (1.6 g) in dry EtOH (20 WO 01/40181 PCT/EPOO/11714 - 18 ml) { [(methylamino) (methylimino)methyl] sulfanyl}methane (3 g) was added. The reaction was refluxed for 8 h, the solvent evaporated under vacuum and the yellow crude oil dissolved in a solution of saturated hydrochloric acid in methanol. The 5 reaction solution was stirred at room temperature for 3 h, the solvent evaporated under vacuum yielding the crude intermediate as a yellow oil (1.2 g; y = 60%) PMR (DMSO-d,) 6: 8.18 (bs, 1H), 7.40 (bs, 1H), 3.40-3.20 (m, 4H) , 2.81 (m, 6H) . 10 By analogous procedure and by using the opportune starting materials the following compounds can be obtained: N- (2-aminoethyl) -N' -methylguanidine hydrochloride; N- (3-aminopropyl) -N' -methylguanidine hydrochloride; N- (2-aminoethyl) -N' '-methylguanidine hydrochloride; 15 N- (3-aminopropyl) -N' '-methylguanidine hydrochloride; N' - (2-aminoethyl) -N, N-dimethylguanidine hydrochloride; N' - (3-aminopropyl) -N, N-dimethylguanidine hydrochloride; The intermediate 20 N- (3-aminopropyl) guanijcinP dihydrnch1nri de To a solution of N-BOC-propylendiamine (1.5 g) in dry EtOH (25 ml), 2-methyl-2-thiopseudourea iodoidride (2.24 g) was added. The reaction was refluxed for 3 h, the solvent evaporated under vacuum, and the crude yellow oil dissolved 25 in a solution of 5N HCl/MeOH (30 ml) . The reaction solution was stirred at room temperature for 3 h, the solvent evaporated under vacuum and the residue was then treated with EtOH (15 ml) and with Et 2 O (10 ml) . The obtained emulsion was cooled and the solvent evaporated. The solid obtained after 30 cooling of the yellow oil was washed with Et 2 O yielding the intermediate as a white solid (1.15 g; y=70%). PMR (DMSO-d) 6: 8.24 (m, 6H) , 3.42 (m, 2H) , 2.86 (m, 2H), 1.91 (m, 2H). By analogous procedure and by using the opportune starting 35 material the following compound can be obtained: N- (4-aminobutyl)guanidine dihydrochloride WO 01/40181 PCT/EPOO/11714 - 19 Example 2 4-[F(2-bromn~acrylnyllaminnl -N-[r9-({[- (([-((r2-(4,59 dihydro-lH- imid a zol -2-ylaminc) Pthyl 1 aminn} rarbnnyl ) -1 mpthyl -1H-pyrrnl -- yl 1 aminn}carhnnyl ) -1 -methyl -1H-pyrrol -3 5 yl 1 am-inn)carhnnyl) -1-mthyl-1H-pyrrol -3-yl1 -1 -methyl -1H pyrrole -2-narhoxamide hydrochlnride (comp.15) Step I: The intermediatp N- [2- (4, -cdihydro-1H-imicdazol -2 yzlamino) ethyl 1 -1-mpthyl -4 -n i trn-1 H-p)yrrol e-2 10 narhnxamide hydrnnhlnridc9 To a solution of N-(4,5-dihydro-lH-imidazol-2-yl)-1,2 ethanediamine dihydrochloride(1.2 g), NaHCO, (1.5 g) in a mixture water/dioxane 1/1 (30 ml) a solution of 1-methyl-4 nitro-1H-pyrrole-2- carbonyl chloride, [prepared as reported 15 in WO 96/05196] (2 g) in dry dioxane(5 ml) was added dropwise at room temperature. The reaction was stirred for 1h, the solvent evaporated under vacuum and the crude residue purified by flash chromatography (methylene chloride/methanol:8/2) giving the intermediate (1.1 g, y= 20 60%) as a yellow powder. m.p. 168-170 *C PMR (DMSO-d,) 6: 8.46 (m,1H), 8.37 (t, J=5.8 Hz, 1H), 8.14 (d, J=1.7 Hz, 1H), 7.54 (d, J=1.7 Hz, 1H), 3.91 (s, 3H), 3.55 (m, 4H), 3.50 (m, 2H), 3.35 (m, 2H). 25 By analogous procedure and by using the opportune starting materials the following compounds can be obtained: N-[2-(4,5-dihydro-lH-imidazol-2-ylamino)propyl]-1-methyl-4 nitro-lH-pyrrole-2-carboxamide hydrochloride; N-(2-{[amino(imino)methyllamino}propyl)-1-methyl-4-nitro-lH 30 pyrrole-2-carboxamide hydrochloride m.p. 156-158 0 C PMR (DMSO-d) 6: 8.54 (t, J=7.2 Hz, 1H), 8.13 (m, 1H), 7.83 (m, 1H), 7.49 (m, 1H), 7.29 (bs, 4H), 3.91 (s, 3H), 3.38 (m, 2H) , 3.25 (m, 2H) , 1.74 (m, 2H) ; 35 N- (2-{ [amino(imino)methyl]amino}butyl) -1-methyl-4-nitro-lH pyrrole-2 -carboxamide hydrochloride; WO 01/40181 PCT/EP0O/11714 - 20 N-[5-({[2-(4,5-dihydro-lH-imidazol-2 ylamino) ethyl] amino}carbonyl) -l-methyl-lH-pyrrol-3-yl] -1 methyl-4-nitro-lH-pyrrole-2 -carboxamide hydrochloride m.p. 211-214 *C 5 PMR (DMSO-d,) 6: 10.36 (s, 1H), 8.49 (m, 2H), 8.41 (t, J=5.8 Hz, 1H), 8.23 (t, J=5.8 Hz, 1H), 8.17 (d, J=1.7 Hz, 1H), 7.63 (d, J=1.7 Hz, 1H), 7.24 (d, J=1.7 Hz, 1H), 6.94 (d, J=1.7 Hz, 1H), 4.14 (m, 2H), 3.95 (s, 3H), 3.81 (s, 3H), 3.58 (m, 2H), 3.60 (m, 4H); 10 N-[5-({[2-(4,5-dihydro-lH-imidazol-2 ylamino)propyl] amino)carbonyl) -l-methyl-1H-pyrrol-3-yl] -1 methyl-4-nitro-lH-pyrrole-2-carboxamide hydrochloride; N- (2-{ [amino(imino)methyl]amino}ethyl) -1-methyl-4-( [(1 methyl-4-nitro-lH-pyrrol-2-yl)carbonyl]amino}-lH-pyrrole-2 15 carboxamide hydrochloride m.p. 275-277 0 C PMR (DMSO-d,) 6: 10.30 (s, 1H), 8.21 (t, J=5.8 Hz, 1H), 8.19 (s, 1H), 7.69 (t, J=5.8 Hz, 1H), 7.60 (d, J=1.7 Hz, 1H), 7.22 (d, J=1.7 Hz, 1H), 7.21 (bs, 4H), 6.90 (d, J=1.7 20 Hz, 1H), 3.95 (s, 3H), 3.81 (s, 3H), 3.16 (m, 4H), 1.69 (m, 2H); N- [5- ({ [2- (4,5-dihydro-lH-imidazol-2 ylamino) ethyl] amino}carbonyl) -1-methyl-lH-pyrrol-3-yll -1 methyl-4-{ [(l-methyl-4-nitro-lH-pyrrol-2-yl)carbonyl]aamino} 25 1H-pyrrole-2-carboxamide hydrochloride m.p. 251-255 *C PMR (DMSO-d,) 6: 10.38 (s, 1H), 10.02 (s, 1H), 8.37 (m, 2H), 8.33 (t, J=5.8 Hz, 1H), 8.20 (t, J=5.8 Hz, 1H), 8.17 (d, J=1.7 Hz, 1H), 7.65 (d, J=1.7 Hz, 1H), 7.28 (d, J=1.7 30 Hz, 1H), 7.21 (d, J=1.7 Hz, 1H), 7.06 (d, J=1.7 Hz, 1H), 6.94 (d, J=1.7 Hz, 1H), 3.97 (m, 2H), 3.95 (s, 3H), 3.91 (s, 3H), 3.85 (s, 3H), 3.58 (m, 2H), 3.57 (m, 4H); N- [5- ({ [2- (4,5-dihydro-lH-imidazol-2 ylamino)propyl] amino)carbonyl) -l-methyl-1H-pyrrol-3-yll -1 35 methyl-4-{[(l-methyl-4-nitro-lH-pyrrol-2-yl)carbonyl]amino} 1H-pyrrole-2-carboxamide hydrochloride; WO 01/40181 PCT/EPOO/11714 - 21 N-(5-{[(2-{[amino(imino)methyllamino}propyl) amino]carbonyl)-1-methyl-1H-pyrrol-3-yl)-1-methyl-4-{[(1 methyl-4-nitro-1H-pyrrol-2-yl)carbonyl]amino}-1H-pyrrole-2 carboxamide hydrochloride 5 m.p. 278-281 *C PMR (DMSO-d,) 6: 10.12 (s, 1H), 9.99 (s, 1H), 8.21 (t, J=5.8 Hz, 1H), 8.19 (s, 1H), 7.69 (t, J=5.8 Hz, 1H), 7.60 (d, J=1.7 Hz, 1H), 7.22 (d, J=1.7 Hz, 1H), 7.21 (bs, 4H), 7.07 (m, 2H), 6.98 (d, J=1.7 Hz, 1H), 3.88 (s, 3H), 3.84 10 (s, 3H), 3.81 (s, 3H), 3.16 (m, 4H), 1.71 (m, 2H); N-(5-{[(2-{[amino(imino)methyllamino}butyl) amino]carbonyl}-l-methyl-1H-pyrrol-3-yl)-1-methyl-4-{[(1 methyl-4-nitro-lH-pyrrol-2-yl)carbonyl]amino)-lH-pyrrole-2 carboxamide hydrochloride; 15 N- (2-{ [amino (methylimino)methyl] amino}ethyl) -1-methyl-4 nitro-1H-pyrrole-2-carboxamide hydrochloride; N- (5-{ [(2-{ [amino(methylimino)methyllamino}ethyl) amino] carbonyl}-1-methyl-1H-pyrrol-3-yl) -1-methyl-4-nitro 1H-pyrrole-2-carboxamide hydrochloride; 20 N- (5-{ [(2-{ [amino (methylimino)methyl] amino}ethyl) amino] carbonyl}-1-methyl-1H-pyrrol-3-yl) -1-methyl-4-{ [(1 methyl-4-nitro-1H-pyrrol-2-yl)carbonyl]amino}-1H-pyrrole-2 carboxamide hydrochloride; N- (2- { [imino (methylamino)methyl] amino}ethyl) -1-methyl-4 25 nitro-lH-pyrrole-2-carboxamide hydrochloride; N- (5-{ [(2-{ [imino(methylamino)methyl]amino}ethyl) amino] carbonyl} -1-methyl-lH-pyrrol-3-yl) -1-methyl-4-nitro 1H-pyrrole-2-carboxamide hydrochloride; N-(5-{[(2-{[imino(methylamino)methyl]amino}ethyl) 30 amino] carbonyl}-l-methyl-lH-pyrrol-3-yl) -1-methyl-4-{ [(1 methyl-4-nitro-lH-pyrrol-2-yl)carbonyl]amino)-lH-pyrrole-2 carboxamide hydrochloride; N- (2- { [(dimethylamino) (imino) methyl] amino} ethyl) -1-methyl-4 nitro-lH-pyrrole-2-carboxamide hydrochloride; 35 N-(5-{[(2-{[(dimethylamino) (imino)methyl]amino}ethyl) amino] carbonyl}-1-methyl-lH-pyrrol-3-yl) -1-methyl-4-nitro 1H-pyrrole-2-carboxamide hydrochloride; WO 01/40181 PCT/EPOO/11714 - 22 N-(5-{[(2-{[(dimethylamino) (imino)methyllamino}ethyl) amino] carbonyl}-1-methyl-lH-pyrrol-3-yl) -l-methyl-4-{ [(1 methyl-4-nitro-1H-pyrrol-2-yl)carbonyl]amino}-lH-pyrrole-2 carboxamide hydrochloride; 5 1-methyl-N-(2-{[(methylamino) (methylimino)methyl]amino} ethyl)-4-nitro-1H-pyrrole-2-carboxamide hydrochloride m.p. 130-132 OC PMR (DMSO-d,) 6: 8.87 (t, J=5.8 Hz, 1H), 8.16 (s, 1H), 7.72 (m, 2H), 7.56 (m, 1H), 7.53 (d, J=1.7 Hz, 1H), 3.91 (s, 10 3H), 3.39 (m, 4H), 2.73 (m, 6H); 1-methyl-N- (2- { [(methylamino) (methylimino)methyl] amino} propyl)-4-nitro-1H-pyrrole-2-carboxamide hydrochloride; 1-methyl-N- (l-methyl-5-{ [(2-{ [(methylamino) (methylimino) methyl] amino}ethyl) amino] carbonyl} -1H-pyrrol -3 -yl) -4-nitro 15 1H-pyrrole-2 -carboxamide hydrochloride m.p. 178-181 *C PMR (DMSO-d) 6: 10.24 (s, 1H), 8.42 (t, J=5.8 Hz, 1H), 8.18 (s, 1H), 7.72 (m, 1H), 7.67 (m, 1H), 7.65 (m, 2H), 7.28 (d, J=1.7 Hz, 1H), 6.92 (d, J=1.7 Hz, 1H), 3.95 (s, 20 3H) , 3.85 (s, 3H) , 3.66 (m, 2H) , 3.39 (m, 2H), 2.73 (m, 6H); 1-methyl-N- (l-methyl-5- { [(2- { [(methylamino) (methylimino) methyl] amino}propyl) amino] carbonyl} -1H-pyrrol-3-yl) -4-nitro 1H-pyrrole-2-carboxamide hydrochloride; 25 1-methyl-N-(l-methyl-5-{[(2-{[(methylamino) (methylimino) methyl] amino}ethyl)amino] carbonyl}-lH-pyrrol-3-yl) -4-{ [(1 methyl-4-nitro-lH-pyrrol-2-yl)carbonyl]amino}-lH-pyrrole-2 carboxamide hydrochloride m.p. 211-214 OC 30 PMR (DMSO-d 6 ) 6: 10.15 (s, 1H), 9.99 (s, 1H), 8.31 (t, J=5.8 Hz, 1H), 8.18 (s, 1H), 7.72 (m, 2H), 7.57 (m, 1H), 7.26 (d, J=1.7 Hz, 1H), 7.23 (d, J=1.7 Hz, 1H), 7.11 (d, J=1.7 Hz, 1H), 7.05 (d, J=1.7 Hz, 1H), 6.92 (d, J=1.7 Hz, 1H), 3.89 (s, 3H), 3.84 (s, 3H), 3.80 (s, 3H), 3.54 (m, 35 2H), 3.39 (m, 2H), 2.76 (m, 6H); 1-methyl-N-(l-methyl-5-{[(2-{[(methylamino) (methylimino) WO 01/40181 PCT/EPOO/11714 - 23 methyl]amino}propyl)amino]carbonyl}-lH-pyrrol-3-yl)-4-{[(1 methyl-4-nitro-lH-pyrrol-2-yl)carbonyllamino}-1H-pyrrole-2 carboxamide hydrochloride; N-(2-{[amino(hydroxyimino)methyl]amino}ethyl)-1-methyl-4 5 nitro-lH-pyrrole-2-carboxamide; N-(5-{[(2-{[amino(hydroxyimino)methyl]amino}ethyl) amino] carbonyl}-1-methyl-1H-pyrrol-3-yl) -1-methyl-4-nitro 1H-pyrrole-2-carboxamide; N-(5-{[(2-{[amino(hydroxyimino)methyl]amino}ethyl) 10 amino]carbonyl}-1-methyl-lH-pyrrol-3-yl)-1-methyl-4-{[(1 methyl-4-nitro-lH-pyrrol-2-yl)carbonyl]amino}-lH-pyrrole-2 carboxamide; N-[2-(lH-imidazol-2-ylamino)ethyl]-l-methyl-4-nitro-lH pyrrole-2-carboxamide hydrochloride; 15 N- [5- ({ [2- (1H-imidazol-2-ylamino) ethyl] amino}carbonyl) -1 methyl-lH-pyrrol-3-yl] -1-methyl-4-nitro-1H-pyrrole-2 carboxamide hydrochloride; N-[5-({[2-(1H-imidazol-2-ylamino)ethyl]amino}carbonyl)-1 methyl-lH-pyrrol-3-yl]-1-methyl-4-{[(l-methyl-4-nitro-lH 20 pyrrol-2-yl)carbonyl]amino}-lH-pyrrole-2-carboxamide hydrochloride; 1-methyl-4-nitro-N-[2-(1,4,5,6-tetrahydro-2 pyrimidinylamino)ethyl]-lH-pyrrole-2-carboxamide hydrochloride; 25 1-methyl-N-[l-methyl-5-({[2-(1,4,5,6-tetrahydro-2 pyrimidinylamino)ethyl]amino}carbonyl)-lH-pyrrol-3-yl]-4 nitro-lH-pyrrole-2-carboxamide hydrochloride; 1-methyl-4-{[(l-methyl-4-nitro-lH-pyrrol-2 yl)carbonyl]amino}-N-[l-methyl-5-({[2-(1,4,5,6-tetrahydro-2 30 pyrimidinylamino)ethyl]amino}carbonyl)-lH-pyrrol-3-yl]-lH pyrrole-2-carboxamide hydrochloride; 1-methyl-4-nitro-N-[2-(1,4,5,6-tetrahydro-2 pyrimidinylamino)propyl]-lH-pyrrole-2-carboxamide hydrochloride; 35 1-methyl-N-[l-methyl-5-({[2-(1,4,5,6-tetrahydro-2 pyrimidinylamino)propyl]amino}carbonyl)-lH-pyrrol-3-yl]-4 nitro-lH-pyrrole-2-carboxamide hydrochloride; WO 01/40181 PCT/EPOO/11714 - 24 1-methyl-4-{ [(l-methyl-4-nitro-1H-pyrrol-2 yl)carbonyl]amino}-N-[l-methyl-5-({[2-(1,4,5,6-tetrahydro-2 pyrimidinylamino)propyl]amino}carbonyl)-lH-pyrrol-3-yl]-lH pyrrole-2-carboxamide hydrochloride; 5 Step II: The intermediate N-[2-(4,5c-dihydro-1H-imidazol--2 ylaminn)ethyl 1 -1 -mthyl -4 -amino-1H-pyrrnle-2 rarhnxamicdp dihydrochloride 1.25 g of intermediate (Step I) was dissolved in methanol 10 (100 ml), treated with 1N hydrochloric acid solution (2 ml) and reduced over Pd catalyst (10% on charcoal) under hydrogen atmosphere (60 psi) into a Parr apparatus. The solution obtained after filtration of the catalyst was evaporated in vacuum and the solid residue washed with dry 15 ethanol to yield 750 mg of the intermediate as a brown powder. PMR (DMSO-d,) 6: 10.05 (bs, 3H), 8.68 (bs, 2H), 8.46 (t, J=5.8 Hz, 1H), 8.37 (t, J=5.8 Hz, 1H), 8.14 (d, J=1.7 Hz, 1H), 7.54 (d, J=1.7 Hz, 1H), 3.89 (s, 3H), 3.46 (m, 4H), 20 3.50 (m, 2H) , 3.35 (m, 2H) . By analogous procedure and by using the opportune starting materials the following compounds can be obtained: N-[2-(4,5-dihydro-lH-imidazol-2-ylamino)propyl]-1-methyl-4 amino-lH-pyrrole-2-carboxamide dihydrochloride; 25 N- (2-{ [amino(imino)methyl] amino}propyl) -1-methyl-4-amino-lH pyrrole-2-carboxamide dihydrochloride PMR (DMSO-d,) 6: 10.33 (bs, 3H), 8.02 (t, J=5.8 Hz, 1H), 7.83 (m, 1H), 7.56 (m, 1H), 7.49 (bs, 4H), 7.22 (m, 1H), 3.77 (s, 3H), 3.36(m, 4H), 1.37 (m, 2H); 30 N- [2- (4,5-dihydro-lH-imidazol-2-ylamino)butyll -l-methyl-4 amino-lH-pyrrole-2-carboxamide dihydrochloride; N-[5-({[2-(4,5-dihydro-lH-imidazol-2 ylamino) ethyl] amino} carbonyl) -1-methyl-lH-pyrrol-3 -yl] -1 methyl-4-amino-lH-pyrrole-2-carboxamide dihydrochloride 35 PMR (DMSO-d,) 6: 10.36 (bs, 3H), 10.25 (s, 1H), 8.49 (m, 2H), 8.41 (t, J=5.8 Hz, 1H), 8.23 (t, J=5.8 Hz, 1H), 8.17 WO 01/40181 PCT/EPOO/11714 - 25 (d, J=1.7 Hz, 1H), 7.61 (d, J=1.7 Hz, 1H), 7.26 (d, J=1.7 Hz, 1H), 6.90 (d, J=1.7 Hz, 1H), 4.14 (m, 2H), 3.95 (s, 3H), 3.81 (s, 3H), 3.50(m, 2H), 3.52 (m, 4H); N-[5-({[2-(4,5-dihydro-1H-imidazol-2 5 ylamino)propyl]amino}carbonyl)-1-methyl-1H-pyrrol-3-yl]-1 methyl-4-amino-1H-pyrrole-2-carboxamide dihydrochloride; N-(2-{[amino(imino)methyl]amino}ethyl)-1-methyl-4-{[(1 methyl-4-amino-1H-pyrrol-2-yl)carbonyl]amino)-1H-pyrrole-2 carboxamide dihydrochloride 10 PMR (DMSO-d,) 6: 10.38 (bs, 3H), 10.30 (s, 1H), 8.21 (t, J=5.8 Hz, 1H), 7.69 (m, 1H), 7.68 (m, 1H), 7.55 (m, 1H), 7.20 (m, 1H), 7.14 (bs, 4H), 6.85 (m, 1H), 3.91 (s, 3H), 3.81 (s, 3H) , 3.03(m, 4H) , 1.45 (m, 2H); N-[5-({[2-(4,5-dihydro-1H-imidazol-2-ylamino)ethyl]amino} 15 carbonyl)-1-methyl-1H-pyrrol-3-yl]-1-methyl-4-{[(1-methyl-4 amino-1H-pyrrol-2-yl)carbonyl]amino}-1H-pyrrole-2-carboxamide dihydrochloride PMR (DMSO-d,) 6: 10.35 (bs, 3H), 10.32 (s, 1H), 10.02 (s, 1H), 8.37 (m, 2H), 8.33 (t, J=5.8 Hz, 1H), 8.20 (t, J=5.8 20 Hz, 1H), 8.17 (m, 1H), 7.65 (d, J=1.7 Hz, 1H), 7.28 (d, J=1.7 Hz, 1H), 7.21 (m, 1H), 7.06 (d, J=1.7 Hz, 1H), 6.94 (d, J=1.7 Hz, 1H), 3.97 (m, 2H), 3.95 (s, 3H), 3.91 (s, 3H), 3.87 (s, 3H), 3.45 (m, 2H), 3.52 (m, 4H); N-[5-({[2-(4, 5-dihydro-1H-imidazol-2 25 ylamino)propyl] amino}carbonyl) -1-methyl-1H-pyrrol-3-yl] -1 methyl-4-{ [(1-methyl-4-amino-1H-pyrrol-2-yl) carbonyl]amino} 1H-pyrrole-2-carboxamide dihydrochloride; N-(5-{ [(2-{ [amino(imino)methyl]amino}propyl) amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)-1-methyl-4-{[(1 30 methyl-4-amino-1H-pyrrol-2-yl) carbonyl] amino}-1H-pyrrole-2 carboxamide dihydrochloride PMR (DMSO-d,) 6: 10.20 (bs, 3H), 10.15 (s, 1H), 9.90 (s, 1H), 8.21 (t, J=5.8 Hz, 1H), 8.11 (m, 1H), 7.26 (m, 1H), 7.24 (bs, 4H), 7.22 (m, 1H), 7.11 (m, 1H), 7.08 (m, 1H), 35 7.05 (m, 2H), 6.99 (m, 1H), 3.89 (s, 3H), 3.84 (s, 3H), 3.81 (s, 3H), 3.36(m, 4H), 1.18 (m, 2H); WO 01/40181 PCT/EPOO/11714 - 26 N- (5-{ [(2-{ [amino(imino)methyl]amino}butyl) amino] carbonyl)-1-methyl-1H-pyrrol-3-yl) -1-methyl-4-{ [(1 methyl-4-amino-1H-pyrrol-2-yl)carbonyl]amino}-lH-pyrrole-2 carboxamide dihydrochloride; 5 N- (2- { [amino (methylimino)methyl] amino}ethyl) -1-methyl-4 amino-1H-pyrrole-2-carboxamide dihydrochloride; N-(5-{[(2-{[amino(methylimino)methyl]amino}ethyl) amino] carbonyl}-1-methyl-lH-pyrrol-3-yl) -1-methyl-4-amino 1H-pyrrole-2-carboxamide dihydrochloride; 10 N-(5-{[(2-{[amino(methylimino)methyl]amino}ethyl) amino] carbonyl)-1-methyl-lH-pyrrol-3-yl) -1-methyl-4-{ [(1 methyl-4-amino-lH-pyrrol-2-yl)carbonyl]amino}-lH-pyrrole-2 carboxamide dihydrochloride; N- (2- { [imino (methylamino)methyl] amino}ethyl) -1-methyl-4 15 amino-lH-pyrrole-2-carboxamide dihydrochloride; N- (5-{ [(2-{ [imino(methylamino)methyl]amino}ethyl) amino] carbonyl}-1-methyl-1H-pyrrol-3-yl) -1-methyl-4 -amino 1H-pyrrole-2-carboxamide dihydrochloride; N-(5-{[(2-{[imino(methylamino)methyl]amino}ethyl) 20 amino] carbonyl}-1-methyl-lH-pyrrol-3-yl) -1-methyl-4-{ [(1 methyl-4-amino-1H-pyrrol-2-yl) carbonyl] amino} -lH-pyrrole-2 carboxamide dihydrochloride; N- (2- { [(dimethylamino) (imino)methyl] amino}ethyl) -1-methyl-4 amino-lH-pyrrole-2-carboxamide dihydrochloride; 25 N-(5-{ [(2-{ [(dimethylamino) (imino)methyl]amino}ethyl) amino] carbonyl}-1-methyl-lH-pyrrol-3-yl) -1-methyl-4 -amino 1H-pyrrole-2-carboxamide dihydrochloride; N- (5-{ [(2-{ [(dimethylamino) (imino)methyl]amino}ethyl) amino] carbonyl} -1-methyl-lH-pyrrol-3-yl) -1-methyl-4- { [(1 30 methyl-4-amino-1H-pyrrol-2-yl)carbonyllamino}-1H-pyrrole-2 carboxamide dihydrochloride; 1-methyl-N-(2-{[(methylamino) (methylimino)methyllamino} ethyl) -4-amino-lH-pyrrole-2-carboxamide dihydrochloride PMR (DMSO-d,) 6: 10.03 (bs, 3H), 8.87 (t, J=5.8 Hz, 1H), 35 7.75 (m, 2H) , 7.66 (s, 1H) , 7.56 (m, 1H) , 7.53 (s, 1H), 3.85 (s, 3H), 3.28 (m, 4H), 2.66 (m, 6H); 1-methyl-N- (2- { [(methylamino) (methylimino)imethyl] amino) WO 01/40181 PCT/EP00/11714 - 27 propyl)-4-amino-1H-pyrrole-2-carboxamide dihydrochloride; 1-methyl-N- (l-methyl-5- { [(2- { [(methylamino) (methylimino) methyl] amino} ethyl) amino] carbonyl } -1H-pyrrol - 3 -yl) -4 - amino 1H-pyrrole-2-carboxamide dihydrochloride 5 PMR (DMSO-d) 6: 10.23 (bs, 3H), 10.17 (s, 1H), 8.36 (t, J=5.8 Hz, 1H), 7.82 (m, 1H), 7.72 (m, 1H), 7.68 (m, 1H), 7.54 (m, 2H), 7.22 (m, 1H), 6.94 (m, 1H), 3.97 (s, 3H), 3.78 (s, 3H), 3.44 (m, 2H), 3.27 (m, 2H), 2.58(m, 6H); 1-methyl-N-(l-methyl-5-{[(2-{[(methylamino) (methylimino) 10 methyl] amino}propyl) amino] carbonyl} -1H-pyrrol-3-yl) -4-amino 1H-pyrrole-2-carboxamide dihydrochloride; 1-methyl-N-(l-methyl-5-{[(2-{[(methylamino) (methylimino) methyl] amino}ethyl) amino] carbonyl} -lH-pyrrol-3-yl) -4- { [(1 methyl-4-amino-lH-pyrrol-2-yl) carbonyl] amino}-lH-pyrrole-2 15 carboxamide dihydrochloride PMR (DMSO-d,) 6: 10.22 (s, 1H), 10.15 (s, 1H), 10.01 (s, 1H), 8.28 (t, J=5.8 Hz, 1H), 7.78 (m, 2H), 7.57 (m, 1H), 7.46 (m, 1H), 7.26 (m, 1H), 7.21 (m, 1H), 7.02 (m, 1H) , 6.96 (m, 1H), 6.81 (m, 1H), 3.81 (s, 3H), 3.74 (s, 3H), 20 3.65 (s, 3H), 3.38 (m, 2H), 3.26 (m, 2H), 2.64 (m, 6H); 1-methyl-N- (l-methyl-5-{ [(2- { [(methylamino) (methylimino) methyl] amino}propyl) amino] carbonyl} -1H-pyrrol-3-yl) -4- { [(1 methyl-4-amino-lH-pyrrol-2-yl) carbonyl] amino} -lH-pyrrole-2 carboxamide dihydrochloride; 25 N- (2- { [amino (hydroxyimino)methyl] amino}ethyl) -1-methyl-4 amino-1H-pyrrole-2-carboxamide hydrochloride; N- (5- { [(2- { [amino (hydroxyimino)methyl] amino}ethyl) amino] carbonyl}~1-methyl-lH-pyrrol-3-yl) -1-methyl-4-amino 1H-pyrrole-2-carboxamide hydrochloride; 30 N- (5-{ [(2-{ [amino (hydroxyimino)methyl] amino}ethyl) amino]carbonyl}-l-methyl-lH-pyrrol-3-yl)-1-methyl-4-{[(1 methyl-4-amino-lH-pyrrol-2-yl) carbonyl] amino} -lH-pyrrole-2 carboxamide hydrochloride; N- [2- (lH-imidazol-2-ylamino) ethyl] -1-methyl-4-amino-lH 35 pyrrole-2-carboxamide dihydrochloride; N- [5- ({ [2- (1H-imidazol-2-ylamino)ethyl]aImino}carbonyl) -1 methyl-lH-pyrrol-3-yl] -1-methyl-4-amino-1H-pyrrole-2- WO 01/40181 PCT/EPOO/11714 - 28 carboxamide dihydrochloride; N- [5- ({ [2- (lH-imidazol-2-ylamino) ethyl] amino)carbonyl) -1 methyl-lH-pyrrol-3-yl]-1-methyl-4-{[(l-methyl-4-amino-lH pyrrol-2-yl) carbonyl] amino} -1H-pyrrole-2-carboxamide 5 dihydrochloride; 1-methyl-4-amino-N-[2-(1,4,5,6-tetrahydro-2 pyrimidinylamino)ethyl]-lH-pyrrole-2-carboxamide dihydrochloride; 1-methyl-N-[l-methyl-5-({[2-(1,4,5,6-tetrahydro-2 10 pyrimidinylamino) ethyl] amino}carbonyl) -lH-pyrrol-3 -yl] -4 amino-lH-pyrrole-2-carboxamide dihydrochloride; 1-methyl-4-{ [(l-methyl-4-amino-lH-pyrrol-2 yl)carbonyl]amino}-N-[l-methyl-5-({[2-(1,4,5,6-tetrahydro-2 pyrimidinylamino)ethyl]amino}carbonyl)-lH-pyrrol-3-yl]-lH 15 pyrrole-2-carboxamide dihydrochloride; 1-methyl-4-amino-N-[2-(1,4,5,6-tetrahydro-2 pyrimidinylamino) propyl] -lH-pyrrole-2-carboxamide dihydrochloride; 1-methyl-N-[l-methyl-5-({[2-(1,4,5,6-tetrahydro-2 20 pyrimidinylamino) propyl] amino}carbonyl) -lH-pyrrol-3 -yl] -4 amino-lH-pyrrole-2-carboxamide dihydrochloride; 1-methyl-4-{[(l-methyl-4-amino-lH-pyrrol-2 yl)carbonyl]amino}-N-[l-methyl-5-({ [2- (1,4,5,6-tetrahydro-2 pyrimidinylamino)propyl]amino}carbonyl)-1H-pyrrol-3-yl]-lH 25 pyrrole-2-carboxamide dihydrochloride. Step III Th title cmpnDun A solution of 4-[(2-bromoacryloyl)amino]-l-methyl-lH pyrrole-2-carbonyl chloride (175 mg), prepared as reported 30 in WO 97/43258, in dioxane (40 ml), was added dropwise at room temperature to a solution of the intermediate obtained from step II (205 mg) and NaHCO, (150 mg) in a mixture water/dioxane 2/1 (60 ml). The solution was stirred for 2 hours, the solvent was evaporated in vacuum and the crude 35 residue was purified by flash chromatography (methylene chloride/methanol:8/2) to give the title compound (175 mg; y = 60%)as a white solid.
WO 01/40181 PCT/EPOO/11714 - 29 FAB-MS: m/z 749(100, [M+H]*) PMR (DMSO-d,) 6: 10.30 (s, 1H), 9.95 (s, 1H), 9.92 (s, 1H), 9.90 (s, 1H), 8.24(m, 1H), 8.06 (bt, 1H), 7.23 (d, J=1.6 Hz, 1H), 7.22 (d, J=1.6 Hz, 1H), 7.21 (d, J=1.6 Hz, 1H) 5 7.16 (d, J=1.6 Hz, 1H), 7.06 (d, J=1.6 Hz, 1H), 7.05 (d, J=1.6 Hz, 1H), 7.03 (d, J=1.6 Hz, 1H), 6.95 (d, J=1.6 Hz, 1H), 6.68 (d, J=3.0 Hz, 1H), 6.21 (d, J=3.0 Hz, 1H), 3.84 (s, 3H), 3.83 (s, 3H), 3.80 (s, 3H), 3.77 (s, 3H), 3.58 (s, 4H), 3.40-3.20 (m, 4H). 10 By analogous procedure and by using the opportune starting materials the following compounds can be obtained: N-(5-{[(5-{[(5-{[(2-{[amino(methylimino)methyl] amino}ethyl)amino]carbonyl}-1-methyl-1H-pyrrol-3 yl)amino]carbonyl}-1-methyl-lH-pyrrol-3-yl)amino]carbonyl} 15 1-methyl-1H-pyrrol-3-yl)-4-[(2-bromoacryloyl)amino]-1 methyl-1H-pyrrole-2-carboxamide hydrochloride(comp.1); N-(5-{[(5-{[(5-{[(2-{[amino(methylimino)methyl] amino}ethyl)amino]carbonyl}-l-methyl-lH-pyrrol-3 yl)amino]carbonyl}-l-methyl-lH-pyrrol-3-yl)amino]carbonyl) 20 1-methyl-lH-pyrrol-3-yl)-4-[(2-chloroacryloyl)amino]-1 methyl-lH-pyrrole-2-carboxamide hydrochloride (comp.2); 4-[(2-bromoacryloyl)amino]-N-(5-{[(5-{[(5-{[(2 {[imino(methylamino)methyl]amino}ethyl)amino]carbonyl}-1 methyl-lH-pyrrol-3-yl)amino]carbonyl}-1-methyl-lH-pyrrol-3 25 yl)amino]carbonyl}-l-methyl-lH-pyrrol-3-yl)-1-methyl-lH pyrrole-2-carboxamide hydrochloride (comp.3); 4-[(2-chloroacryloyl)amino]-N-(5-{[(5-{[(5-{[(2 {[imino(methylamino)methyllamino}ethyl)amino]carbonyl}-1 methyl-lH-pyrrol-3-yl)amino]carbonyl}-1-methyl-lH-pyrrol-3 30 yl)amino]carbonyl}-1-methyl-lH-pyrrol-3-yl)-l-methyl-lH pyrrole-2-carboxamide hydrochloride (comp.4); 4-[(2-bromoacryloyl)amino]-N-(5-{[(5-{[(5-{[(2 {[(dimethylamino) (imino)methyl]amino}ethyl)amino]carbonyl} 1-methyl-1H-pyrrol-3-yl)amino]carbonyl}-1-methyl-lH-pyrrol 35 3-yl)amino]carbonyl}-l-methyl-lH-pyrrol-3-yl)-l-methyl-lH pyrrole-2-carboxamide hydrochloride (comp.5); WO 01/40181 PCT/EPOO/11714 - 30 4-[(2-chloroacryloyl)amino]-N-(5-{[(5-{[(5-{[(2 {[(dimethylamino) (imino)methyl]amino}ethyl)amino]carbonyl} 1-methyl-lH-pyrrol-3-yl)amino]carbonyl}-1-methyl-1H-pyrrol 3-yl)amino]carbonyl)-l-methyl-lH-pyrrol-3-yl)-1-methyl-1H 5 pyrrole-2-carboxamide hydrochloride (comp.6); 4-[(2-bromoacryloyl)amino]-1-methyl-N-(l-methyl-5-{[(1 methyl-5-{[(l-methyl-5-{[(2-{[(methylamino) (methylimino)methyl]amino}ethyl)amino]carbonyl)-lH-pyrrol 3-yl)amino]carbonyl}-1H-pyrrol-3-yl)amino] 10 carbonyl}-lH-pyrrol-3-yl)-lH-pyrrole-2-carboxamide hydrochloride (comp.7) FAB-MS: m/z 751(100, [M+H]*) PMR (DMSO-d,) 6: 10.28 (s, 1H), 9.94 (s, 1H), 9.91 (s, 1H), 9.90 (s, 1H), 8.16(bt, 1H), 7.52(bq, 2H), 7.43(bt, 1H), 15 7.22 (d, J=1.6 Hz, 1H), 7.21 (d, J=1.6 Hz, 1H), 7.20 (d, J=1.6 Hz, 1H) 7.18 (d, J=1.6 Hz, 1H), 7.06 (d, J=1.6 Hz, 1H), 7.05 (d, J=1.6 Hz, 1H), 7.03 (d, J=1.6 Hz, 1H), 6.93 (d, J=1.6 Hz, 1H), 6.67 (d, J=3.0 Hz, 1H), 6.21 (d, J=3.0 Hz, 1H), 3.84 (s, 3H), 3.83 (s, 3H), 3.80 (s, 3H), 3.78 (s, 20 3H), 3.40-3.20 (m, 4H), 2.73 (d, J=4.5Hz 6H); 4-[(2-chloroacryloyl)amino]-1-methyl-N-(l-methyl-5-{[(1 methyl-5-{[(l-methyl-5-{[(2-{[(methylamino) (methylimino)methyl]amino}ethyl)amino]carbonyl}-lH-pyrrol 3-yl)amino]carbonyl}-lH-pyrrol-3-yl)amino] 25 carbonyl}-1H-pyrrol-3-yl)-lH-pyrrole-2-carboxamide hydrochloride (comp.8); N-(5-{[(5-{[(5-{[(2-{[amino(hydroxyimino)methyl] amino}ethyl)amino]carbonyl}-1-methyl-lH-pyrrol-3 yl)amino]carbonyl)-l-methyl-lH-pyrrol-3-yl)amino]carbonyl} 30 1-methyl-lH-pyrrol-3-yl)-4-[(2-bromoacryloyl)amino]-1 methyl-lH-pyrrole-2-carboxamide (comp.13); N-(5-{[(5-{[(5-{[(2-{[amino(hydroxyimino)methyl] amino}ethyl)amino]carbonyl}-l-methyl-lH-pyrrol-3 yl)amino]carbonyl}-l-methyl-lH-pyrrol-3-yl)amino]carbonyl} 35 1-methyl-lH-pyrrol-3-yl)-4-[(2-chloroacryloyl)amino]-1 methyl-lH-pyrrole-2-carboxamide (comp.14); WO 01/40181 PCT/EPOO/11714 - 31 4-[(2-chloroacryloyl)amino]-N-[5-({[5-({[5-({[2-(4,5 dihydro-lH-imidazol-2-ylamino)ethyl]amino}carbonyl)-1 methyl-lH-pyrrol-3-yl]amino}carbonyl)-1-methyl-1H-pyrrol-3 yl]amino}carbonyl)-l-methyl-lH-pyrrol-3-yl]-l-methyl-lH 5 pyrrole-2-carboxamide hydrochloride (comp.16); 4-[(2-bromoacryloyl)amino]-N-[5-({[5-({ [5-({[2-(lH imidazol-2-ylamino)ethyl]amino}carbonyl)-1-methyl-lH pyrrol-3-yl]amino}carbonyl)-1-methyl-lH-pyrrol-3 yl]amino}carbonyl)-l-methyl-lH-pyrrol-3-yl]-l-methyl-lH 10 pyrrole-2-carboxamide hydrochloride Compp. 17); 4-[(2-chlorooacryloyl)amino]-N-[5-({[5-({[5-({[2-(lH imidazol-2-ylamino)ethyl]amino}carbonyl)-1-methyl-lH pyrrol-3-yl]amino}carbonyl)-1-methyl-lH-pyrrol-3 yl]amino}carbonyl)-1-methyl-lH-pyrrol-3-yl]-l-methyl-lH 15 pyrrole-2-carboxamide hydrochloride (comp.18); 4-[(2-bromoacryloyl)amino]-1-methyl-N-[l-methyl-5-({[1 methyl-5-({[1-methyl-5-({[2-(1,4,5,6-tetrahydro-2 pyrimidinylamino)ethyl]amino}carbonyl)-lH-pyrrol-3 yl]amino}carbonyl)-lH-pyrrol-3-yl]amino}carbonyl)-lH 20 pyrrol-3-yl]-lH-pyrrole-2-carboxamide hydrochloride (comp.19); 4-[(2-chloroacryloyl)amino]-1-methyl-N-[l-methyl-5-({[1 methyl-5-({[1-methyl-5-({[2-(1,4,5,6-tetrahydro-2 pyrimidinylamino)ethyl]amino}carbonyl)-1H-pyrrol-3 25 yl]amino}carbonyl)-lH-pyrrol-3-yl]amino}carbonyl)-lH pyrrol-3-yl]-lH-pyrrole-2-carboxamide hydrochloride (comp.20); N-(5-{[(5-{[(5-{[(2{[amino(imino)methyl] amino}propyl)amino]carbonyl}-1-methyl-lH-pyrrol-3 30 yl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)amino]carbonyl} 1-methyl-lH-pyrrol-3-yl)-4-[(2-bromoacryloyl)amino]-1 methyl-1H-pyrrole-2-carboxamide hydrochloride (comp.21) FAB-MS: m/z 749(100, [M+H]') PMR (DMSO-d,) 5: 10.30 (s, 1H), 9.95 (s, 1H), 9.92 (s, 1H), 35 9.90 (s, 1H), 8.24(m, 1H), 8.06 (bt, 1H), 7.23 (d, J=1.6 Hz, 1H), 7.22 (d, J=1.6 Hz, 1H), 7.21 (d, J=1.6 Hz, 1H) WO 01/40181 PCT/EPOO/11714 - 32 7.16 (d, J=1.6 Hz, 1H), 7.06 (d, J=1.6 Hz, 1H), 7.05 (d, J=1.6 Hz, 1H), 7.03 (d, J=1.6 Hz, 1H), 6.95 (d, J=1.6 Hz, 1H), 6.68 (d, J=3.0 Hz, 1H), 6.21 (d, J=3.0 Hz, 1H), 3.84 (s, 3H), 3.83 (s, 3H), 3.80 (s, 3H), 3.77 (s, 3H), 3.58 (s, 5 4H), 3.40-3.20 (m, 4H); N-(5-{[(5-{[(5-{[(2{[amino(imino)methyl] amino}propyl)amino]carbonyl}-1-methyl-lH-pyrrol-3 yl) amino] carbonyl} -l-methyl-lH-pyrrol-3-yl) amino] carbonyl) 1-methyl-lH-pyrrol-3-yl)-4-[(2-chloroacryloyl)amino]-1 10 methyl-1H-pyrrole-2-carboxamide hydrochloride (comp.22); 4-[(2-bromoacryloyl)amino]-i-methyl-N-(1-methyl-5-{[(1 methyl-5-{[(l-methyl-5-{[(2-{[(methylamino) (methylimino)methyl]amino}propyl)amino]carbonyl}-1H-pyrrol 3 -yl)amino]carbonyl}-1H-pyrrol-3-yl)amino] 15 carbonyl)-lH-pyrrol-3-yl)-lH-pyrrole-2-carboxamide hydrochloride (comp.23); 4-[(2-chloroacryloyl)amino]-i-methyl-N-(l-methyl-5-{[(1 methyl-5-{[(l-methyl-5-{[(2-{[(methylamino) (methylimino)methyl]amino}propyl)amino]carbonyl}-lH-pyrrol 20 3-yl)aminolcarbonyl}-lH-pyrrol-3-yl)amino] carbonyl}-lH-pyrrol-3-yl)-lH-pyrrole-2-carboxamide hydrochloride (comp.24); 4-[(2-bromoacryloyl)amino]-N-[5-({[5-({[5-({[2-(4,5 dihydro-lH-imidazol-2-ylamino)propyl]amino}carbonyl)-1 25 methyl-lH-pyrrol-3-yl]amino~carbonyl)-1-methyl-lH-pyrrol-3 yl]amino}carbonyl)-1-methyl-lH-pyrrol-3-yl]-l-methyl-lH pyrrole-2-carboxamide hydrochloride (comp.27); 4-[(2-chloroacryloyl)amino]-N-[5-({[5-({[5-({[2-(4,5 dihydro-1H-imidazol-2-ylamino)propyl]amino}carbonyl)-1 30 methyl-lH-pyrrol-3-yl]amino}carbonyl)-l-methyl-lH-pyrrol-3 yl]amino}carbonyl)-1-methyl-lH-pyrrol-3-yl]-l-methyl-lH pyrrole-2-carboxamide hydrochloride (comp.28); 4-[(2-bromoacryloyl)amino]-1-methyl-N-[l-methyl-5-({[1 methyl-5-({[1-methyl-5-({[2-(1,4,5,6-tetrahydro-2 35 pyrimidinylamino)propyl]amino}carbonyl)-lH-pyrrol-3 yl]amino}carbonyl)-1H-pyrrol-3-yl]amino}carbonyl)-lH- WO 01/40181 PCT/EPOO/1 1714 - 33 pyrrol-3-yl]-lH-pyrrole-2-carboxamide hydrochloride (comp.29); 4-[(2-chloroacryloyl)amino]-1-methyl-N-[l-methyl-5-({[1 methyl-5-({[1-methyl-5-({[2-(1,4,5,6-tetrahydro-2 5 pyrimidinylamino)propyl]amino}carbonyl)-1H-pyrrol-3 yl]amino}carbonyl)-lH-pyrrol-3-yl]amino}carbonyl)-lH pyrrol-3-yl]-lH-pyrrole-2-carboxamide hydrochloride (comp.30); N-(5-{[(5-{[(2-{[amino(methylimino)methyl] 10 amino}ethyl)amino]carbonyl)-1-methyl-lH-pyrrol-3 yl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)-4-[(2 bromoacryloyl)amino]-l-methyl-lH-pyrrole-2-carboxamide hydrochloride (comp.31); 4-[(2-bromoacryloyl)amino]-1-methyl-N-(l-methyl-5-{[(1 15 methyl-5-{[(2-{[(methylamino) (methylimino)methyl] amino}ethyl)amino]carbonyl)-1H-pyrrol-3-yl)amino]carbonyl) 1H-pyrrol-3-yl)-1H-pyrrole-2-carboxamide hydrochloride (comp.32); 4-[(2-bromoacryloyl)amino]-1-methyl-N-(l-methyl-5-{[(1 20 methyl-5-{[(2-[(aminocarbonyl)amino] ethyl)amino]carbonyl}-lH-pyrrol-3-yl)amino]carbonyl}-lH pyrrol-3-yl)-lH-pyrrole-2-carboxamide hydrochloride (comp.33); 4-[(2-bromoacryloyl)amino]-N-[5-({[5-({[2-(4,5-dihydro-lH 25 imidazol-2-ylamino)ethyl]amino}carbonyl)-1-methyl-lH pyrrol-3-yl]amino}carbonyl)-1-methyl-lH-pyrrol-3-yl]-1 methyl-lH-pyrrole-2-carboxamide hydrochloride (comp.34); 4-[(2-bromoacryloyl)amino]-1-methyl-N-[l-methyl-5-({[1 methyl-5-({[1-methyl-5-({[2-(1,4,5,6-tetrahydro-2 30 pyrimidinylamino)ethyl]amino}carbonyl)-lH-pyrrol-3 yl]amino}carbonyl)-lH-pyrrol-3-yl]amino}carbonyl)-1H pyrrol-3-yl]-lH-pyrrole-2-carboxamide hydrochloride (comp.35); N-(5-{[(5-{[(5-{[(2{[amino(imino)methyl] 35 amino}butyl)aminolcarbonyl}-l-methyl-lH-pyrrol-3 yl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)amino]carbonyl}- WO 01/40181 PCT/EPOO/11714 - 34 1-methyl-1H-pyrrol-3-yl)-4-[(2-bromoacryloyl)amino]-1 methyl-1H-pyrrole-2-carboxamide (comp.36) FAB-MS: m/z 752(80, [M+H]') PMR (DMSO-d6) d: 10.25 (s, 1H), 9.96 (s, 1H), 9.95 (s, 1H), 5 9.92 (s, 1H), 8.06 (bt, 1H), 7.22 (d, J=1.6 Hz, 1H), 7.21 (d, J=1.6 Hz, 1H), 7.20 (d, J=1.6 Hz, 1H) 7.18 (d, J=1.6 Hz, 1H), 7.07 (d, J=1.6 Hz, 1H) , 7.06 (d, J=1.6 Hz, 1H) , 7.03 (d, J=1.6 Hz, 1H), 6.93 (d, J=1.6 Hz, 1H), 6.68 (d, J=3.0 Hz, 1H), 6.21 (d, J=3.0 Hz, 1H), 3.84 (s, 3H), 3.83 10 (s, 3H), 3.80 (s, 3H), 3.77 (s, 3H), 3.58 (s, 4H), 3.19 3.21 (m, 2H);3.12-3.18 (m, 2H);1.42-1.50 (m, 4H); N-(5-{[(5-{[(5-{[(2{[amino(imino)methyl] amino}butyl)amino]carbonyl)-1-methyl-1H-pyrrol-3 yl)amino]carbonyl}-l-methyl-1H-pyrrol-3-yl)amino]carbonyl} 15 1-methyl-lH-pyrrol-3-yl)-4-[(2-chloroacryloyl)amino]-1 methyl-lH-pyrrole-2-carboxamide (comp.37). Example 3 N-- ({ - F ({- [({2- r(aminnca rhnnyll aminnlethyl)} 20 ami nnc) arbony-l 1 -1 -methyl - - 1H -pyrrol - 3 - yl }aminc) carhonyl 1 -1 -methyl -1-H-pyrrol -3 -yl } ami-nn) carhonyl l -1 -methyl 1H-pyrrol - 3 -yl }-4- F (2-hromnanryloyll aminnl -1 -methyl -1H pyrrol e-2-rarhoxamjide (comp.9) 25 Step I: The intermecdiate tert -hutyl 2- { F(1-methyl-4-ni trn 1 H-pyrrol - 2 -yl ) carhnyl 1 ami nn}ethylcarhamate To a solution of tert-butyl 2-aminoethylcarbamate (1.6 g) and triethylamine (1.5 ml) in dry dioxane (20 ml), a solution of 1-methyl-4-nitro-1H-pyrrole-2-carbonyl chloride (2 g) in dry 30 dioxane (10 ml) was added dropwise at room temperature. The reaction was stirred for 3h, the solvent allowed under vacuum and the crude residue purified by flash chromatography (methylene chloride/methanol:8/2) giving the intermediate (2.63 g, y= 81%) as a white powder. 35 m.p. 178-180 OC PMR (DMSO-d 6 ) 6: 8.38 (t, J=7.4 Hz, 1H), 8.12 (m, 1H), 7.39 WO 01/40181 PCT/EPOO/11714 - 35 (m, 1H), 6.90 (t, J=7.4 Hz, 1H), 3.89 (s, 3H), 3.23 (m, 2H), 3.07 (m, 2H), 1.36 (s, 9H). By analogous procedure and by using the opportune starting materials the following compounds can be obtained: 5 tert-butyl 2-{[(l-methyl-4-{[(1-methyl-4-nitro-lH-pyrrol-2 yl)carbonyl]amino}-1H-pyrrol-2-yl)carbonyl]amino} ethylcarbamate m.p. 211-214 *C PMR (DMSO-d,) 6: 10.24 (s, 1H), 8.18 (m, 1H), 8.03 (m, 1H), 10 7.59 (d, J=1.7HZ, 1H), 7.21 (d, J=1.7HZ, 1H), 6.86 (m, 2H), 3.95 (s, 3H) , 3.81 (s, 3H) , 3.19 (m, 2H) , 3.06 (m, 2H), 1.38 (s, 9H); tert-butyl 2-{[(l-methyl-4-{[(l-methyl-4-nitro-1H-pyrrol-2 yl)carbonyl]amino}-1H-pyrrol-2-yl)carbonyl]amino} 15 propylcarbamate; tert-butyl 2-{[(l-methyl-4-{[(l-methyl-4-{[(l-methyl-4 nitro-lH-pyrrol-2-yl)carbonyl]amino}-1H-pyrrol-2 yl)carbonyl]amino}-1H-pyrrol-2 yl)carbonyllamino}ethylcarbamate 20 m.p. 256-258 *C PMR (DMSO-d) 6: 10.30 (s, 1H) , 9.96 (s, 1H), 8.19 (m, 1H) 7.99 (m, 1H), 7.59 (m, 1H), 7.28 (d, J=1.7HZ, 1H), 7.20 (d, J=1.7HZ, 1H), 7.03 (d, J=1.7HZ, 1H), 6.87 (m, 2H), 3.96 (s, 3H), 3.90 (s, 3H), 3.80 (s, 3H), 3.22 (m, 2H), 3.04 (t, 25 J=5.6Hz,2H), 1.38 (s, 9H); tert-butyl 2-{[(1-methyl-4-{[(1-methyl-4-{[(1-methyl-4 nitro-1H-pyrrol-2-yl)carbonyl]amino}-1H-pyrrol-2 yl)carbonyl]amino}-1H-pyrrol-2 yl)carbonyl]amino}propylcarbamate; 30 Step II: The intermediate tert-hutyl 2-{ r(1-mpthyl-4-aminn 1iH-pyrrn1 -2-yl )'arhnnyl 1 aminn}ethyl na rhama t To a suspension of 10% Pd/C (100 mg) in a mixture of MeOH/H 2 0 1/1 (20 ml) at 0 OC, NaBH4 (684 mg) and 35 intermediate of step I (1.87 g) were added and stirred for 1h.
WO 01/40181 PCT/EPOO/11714 - 36 The catalyst was removed by filtration and the solvent allowed under vacuum. The residue dissolved in EtOAc (15 ml), washed with water (20 ml) then brine (40 ml) and finally dried over Na 2
SO
4 anhydrous. 5 The solvent was allowed under vacuum yielding the intermediate (1.44 g, y = 85%) as a yellow oil which is used without further purification in the next step. By analogous procedure and by using the opportune starting materials the following compounds can be obtained: 10 tert-butyl 2-{ [(l-methyl-4-amino-lH-pyrrol-2 yl) carbonyl] amino}propylcarbamate; tert-butyl 2-{[(l-methyl-4-{[(l-methyl-4-amino-lH-pyrrol-2 yl)carbonyl]amino}-lH-pyrrol-2-yl)carbonyl]amino) ethylcarbamate; 15 tert-butyl 2-{[(l-methyl-4-{[(-methyl-4-amino-lH-pyrrol-2 yl)carbonyllamino)-lH-pyrrol-2-yl)carbonyl]amino} propylcarbamate; tert-butyl 2-{[(l-methyl-4-{[(l-methyl-4-{[(l-methyl-4 amino-lH-pyrrol-2-yl)carbonyl]amino}-lH-pyrrol-2-yl) 20 carbonyllamino)-lH-pyrrol-2 yl)carbonyl]amino}ethylcarbamate; tert-butyl 2-{[(l-methyl-4-{[(1-methyl-4-{[(l-methyl-4 amino-lH-pyrrol-2-yl)carbonyllamino}-lH-pyrrol-2-yl) carbonyllamino}-1H-pyrrol-2 25 yl)carbonyllamino}propylcarbamate; N-{5-[({2-[(aminocarbonyl)amino]ethyl}amino)carbonyl]-1 methyl-lH-pyrrol-3-yl}-l-methyl-4-{[(l-methyl-4-amino-lH pyrrol-2-yl)carbonyl]amino}-lH-pyrrole-2-carboxamide. 30 Step III: The intermediate N-{r-r( {2 [ (ami nnrarhon1 ) ami-nn1 thyl }amino) carhnnyl 1 -1 methyl -1H-pyrrol -3-yl } -1 -methyl -4- { F (1 -methyl -4 nitro-1H-pyrrol -2-yl) carbonyl 1 aminn}-1H-pyrrole 2-ra rhoxami dp 35 A solution of the intermediate tert-butyl 2-{[(1-methyl-4 {[(l-methyl-4-{[(l-methyl-4-nitro-lH-pyrrol-2 yl)carbonyl]amino}-lH-pyrrol-2-yl)carbonyl]amino)-lH- WO 01/40181 PCT/EPOO/1 1714 - 37 pyrrol-2-yl) carbonyl] amino}ethylcarbamate (270 mg), in 5N HCl/methanol (20 ml) was stirred at room temperature for 2 h. The solvent was allowed under vacuum and the residue dissolved in DMF (5 ml) . To the DMF solution was cooled at 5 0 OC TEA (70 ml) and CDI (100 mg) were added. The reaction was stirred a room temperature for 3 h, the solvent allowed under vacuum, the solid residue dissolved in EtOAc (20 ml), and washed with H 2 0 (20 ml) . The separated organic phase was dried over Na 2
SO
4 anhydrous, the solvent evaporated in 10 vacuum and the solid residue dissolved in EtOH. The alcoholic solution was cooled at 0 IC and saturated with ammonia gas. The reaction solution was stirred for 3 h at room temperature, the solvent removed under vacuum and the crude residue purified by flash chromatography 15 (DCM/MeOH:8/2) to give the intermediate (200 mg, y = 80%) as a yellow solid. m.p. 256-258 OC PMR (DMSO-d) 6: 10.30 (s, 1H), 9.97 (s, 1H), 8.62 (m, 1H), 8.23(s, 1H), 8.19 (m, 1H), 7.66 (d, J=1.7 Hz, 1H), 7.59 (m, 20 1H), 7.25 (d, J=1.7 Hz, 1H), 7.21 (d, J=1.7 Hz, 1H), 7.07 (s, 2H), 6.87 (d, J=1.7 Hz, 1H), 3.96 (s, 3H), 3.86 (s, 3H), 3.80 (s, 3H), 3.35 (m, 4H). By analogous procedure and by using the opportune starting materials the following compounds can be obtained: 25 N-{5-[({2-[(aminocarbonyl)aminopropyl}amino)carbonyl]-1 methyl-lH-pyrrol-3-yl}-1-methyl-4-{[(1-methyl-4-nitro-lH pyrrol-2-yl)carbonyl]amino}-1H-pyrrole-2-carboxamide; N-{5-[({2-{[(methylamino)carbonyl]amino}ethylyl}amino) carbonyl]-1-methyl-lH-pyrrol-3-yl}-l-methyl-4-{[(1-methyl 30 4-nitro-1H-pyrrol-2-yl)carbonyllamino}-lH-pyrrole-2 carboxamide; N-{5-[({2-{[(methylamino)carbonyl]amino}propyl}amino) carbonyl]-1-methyl-lH-pyrrol-3-yl}-1-methyl-4-{[(1-methyl 4-nitro-lH-pyrrol-2-yl)carbonyljamino}-lH-pyrrole-2 35 carboxamide. Step IV: Thp title compnun WO 01/40181 PCT/EP00/11714 - 38 To a solution of the intermediate N-{5-[({2 [(aminocarbonyl)amino]ethyl}amino)carbonyll-l-methyl-1H pyrrol-3-yl}-1-methyl-4-{[(l-methyl-4-amino-lH-pyrrol-2 yl)carbonyl]amino}-lH-pyrrole-2-carboxamide (350 mg), 5 NaHCO, (412 mg) in a mixture water/dioxane 2/1 (80 ml) a solution of 4-[(2-bromoacryloyl)amino]-1-methyl-lH-pyrrole 2-carbonyl chloride prepared as reported in W097/43258 (287 mg) in dioxane (50 ml) was added dropwise at room temperature. The solution was stirred for 2 hours, the 10 solvent was evaporated in vacuum and the crude residue was purified by flash chromatography (DCM/MeOH:8/2) to give the title compound (435 mg; y = 60%)as a yellow powder. FAB-MS: m/z 725(80, [M+H]*) PMR (DMSO-d,) 6: 10.32 (s, 1H), 9.96 (s, 1H), 9.94 (s, 1H), 15 9.92 (s, 1H), 8.60 (m, 1H), 8.21(s, 1H), 8.17 (m, 2H), 7.66 (d, J=1.7 Hz, 1H), 7.59 (m, 2H) , 7.25 (d, J=1.7 Hz, 1H), 7.22 (m, 1H), 7.05 (s, 2H), 6.87 (d, J=1.7 Hz, 1H), 6.67 (d, J=3.0 Hz, 1H), 6.21 (d, J=3.0 Hz, 1H), 3.94 (s, 3H), 3.85 (s, 3H), 3.82 (s, 3H), 3.80 (s, 3H), 3.35 (m, 4H). 20 By analogous procedure and by using the opportune starting materials the following compounds can be obtained: N-{5-[({5-[({5-[({2-[(aminocarbonyl)amino]ethyl) amino)carbonyl]-1-methyl-lH-pyrrol-3-yl}amino)carbonyl]-1 methyl-lH-pyrrol-3-yl}amino)carbonyl]-l-methyl-lH-pyrrol-3 25 yl}-4-[(2-chloroacryloyl)amino]-l-methyl-lH-pyrrole-2 carboxamide (comp.10); 4-[(2-bromoacryloyl)amino]-1-methyl-N-(l-methyl-5-{[(1 methyl-5-{[(1-methyl-5-{[(2 {[(methylamino)carbonyl]amino}ethyl)amino]carbonyl}-1H 30 pyrrol-3-yl)amino]carbonyl}-lH-pyrrol-3-yl)amino]carbonyl} 1H-pyrrol-3-yl) -lH-pyrrole-2-carboxamide (comp.11); 4-[(2-chloroacryloyl)amino]-1-methyl-N-(l-methyl-5-{[(1 methyl-5-{[(l-methyl-5-{[(2-{[(methylamino)carbonyl] amino}ethyl)amino]carbonyl}-lH-pyrrol-3-yl)amino]carbonyl} 35 1H-pyrrol-3-yl)amino]carbonyl}-lH-pyrrol-3-yl)-1H-pyrrole 2-carboxamide (comp.12).
WO 01/40181 PCT/EPOO/11714 - 39 Example 4 Tablets each weighing 0.250 g and containing 50 mg of the active substance can be manufactured as follows: Composition for 10,000 tablets N-(5-{[(5-{[(5-{[(2{[amino(imino)methyl] Amino}propyl)amino]carbonyl}-1-methyl-1H-pyrrol-3 yl)amino]carbonyl}-1-methyl-lH-pyrrol-3 yl)amino]carbonyl}-1-methyl-lH-pyrrol-3-yl)-4-[(2- 500 g bromoacryloyl)amino]-1-methyl-lH-pyrrole-2-carboxamide hydrochloride (comp.21) Lactose 1,400 g Corn starch 500 g Talc powder 80 g Magnesium stearate 20 g 5 N-(5-{[(5-{[(5-{[(2{[amino(imino)methyl] amino}propyl)amino]carbonyl}-1-methyl-lH-pyrrol-3 yl)amino]carbonyl}-l-methyl-1H-pyrrol-3-yl)amino]carbonyl} 1-methyl-lH-pyrrol-3-yl)-4-[(2-bromoacryloyl)amino]-1 methyl-lH-pyrrole-2-carboxamide hydrochloride, lactose and 10 half of the corn starch were mixed; the mixture was then forced through a sieve of 0.5 mm mesh size. Corn starch (10 g) was suspended in warm water (90 ml) and the resulting paste was used to granulate the powder. The granulate was dried, comminuted on a sieve of 1.4 mm mesh 15 size, then the remaining quantity of starch, talc and magnesium stearate was added, carefully mixed and processed into tablets.
Claims (10)
1. A compound which is an acryloyl peptidic derivative of formula R1 R3 - H _ N R
2 -Y H 0 x' N B N m CH 3 5 wherein: n is 3 or 4; m is 0, 1 or 2; X and Y are the same or different and are selected, 10 independently for each heterocyclic ring, from N or CH; Ri and R 2 , the same or different, are selected from hydrogen, halogen or C 1 -C 4 alkyl; R 3 is hydrogen or halogen; B is selected from the groups consisting of: R0 NH 2 N-R 5 NH 2 II NH NH \ NH x NH-C-NR 7 R. N-CN N-R 6 ' N-NH 2 ' H H H N N N NH - NH and NH 15 N N N wherein R 4 , R 5 , R 7 and R. are, independently from each other, hydrogen or C 1 -C, alkyl; R, is hydrogen, hydroxy or C 1 -C, alkyl; or a pharmaceutically acceptable salt thereof; provided that: 20 i) X and Y are not both N atoms for the same heterocyclic ring; ii) when all of X and Y are CH groups and m is 0, then at least one of R 4 , R. or R 6 is other than hydrogen; iii) when at least one of X and Y is other than CH, then at 25 least one of R 4 and R 5 is other than hydrogen. WO 01/40181 PCT/EPOO/11714 - 41 2. A compound of formula (I) according to claim 1 wherein R 4 , R 5 , R 7 and R. are, independently from each other, hydrogen, methyl or ethyl and R, is hydrogen, hydroxy, methyl or ethyl. 5
3. A compound of formula (I) according to claim 1 wherein n is 3 or 4; m is 0, 1 or 2; X and Y are CH; 10 R 1 and R 2 are hydrogen; R, is chlorine or bromine; B is selected from 4 H H N-R 5 NH 2 N N NH ~ NH-C-NRR NH NH NH N-R 6 , , N-OH N and N wherein R 4 , R 5 , R 7 and R 8 are, independently from each 15 other, hydrogen or methyl and R, is hydrogen, hydroxy or methyl; provided that when m is 0, at least one of R 4 , R, or R6 is other than hydrogen.
4. A compound of formula (I) according to claim 1, and 20 the pharmaceutically acceptable salts, selected from the group consisting of: (1) N-(5-{[(5-{[(5-{[(2-{[amino(methylimino)methyl] amino}ethyl)amino]carbonyl}-l-methyl-lH-pyrrol-3 yl)aminolcarbonyl}-l-methyl-lH-pyrrol-3 25 yl)amino]carbonyl}-1-methyl-lH-pyrrol-3-yl)-4-[(2 bromoacryloyl)amino]-1-methyl-lH-pyrrole-2-carboxamide (2) N-(5-{[(5-{[(5-{[(2-{[amino(methylimino)methyl] amino}ethyl)amino]carbonyl}-l-methyl-lH-pyrrol-3 yl)amino]carbonyl}-1-methyl-lH-pyrrol-3 30 yl)amino]carbonyl}-l-methyl-lH-pyrrol-3-yl)-4-[(2 chloroacryloyl)amino]-1-methyl-lH-pyrrole-2 carboxamide (3) 4-[(2-bromoacryloyl)amino]-N-(5-{[(5-{[(5-{[(2 {[imino(methylamino)methyl]amino}ethyl)aminolcarbonyl} WO 01/40181 PCT/EPOO/11714 - 42 -1-methyl-lH-pyrrol-3-yl)amino]carbonyl}-1-methyl-1H pyrrol-3-yl)amino]carbonyl}-1-methyl-lH-pyrrol-3-yl) 1-methyl-1H-pyrrole-2-carboxamide (4) 4-[(2-chloroacryloyl)amino]-N-(5-{[(5-{[(5-{[(2 5 {[imino(methylamino)methyl]amino}ethyl)amino]carbonyl} -1-methyl-1H-pyrrol-3-yl)amino]carbonyl)-1-methyl-1H pyrrol-3-yl)amino]carbonyl}-1-methyl-lH-pyrrol-3-yl) 1-methyl-lH-pyrrole-2-carboxamide (5) 4-[(2-bromoacryloyl)amino]-N-(5-{[(5-{[(5-{[(2 10 {[(dimethylamino) (imino)methyl]amino}ethyl)amino]carbo nyl}-l-methyl-lH-pyrrol-3-yl)amino]carbonyl}-l-methyl 1H-pyrrol-3-yl)amino]carbonyl}-1-methyl-lH-pyrrol-3 yl)-l-methyl-lH-pyrrole-2-carboxamide (6) 4-[(2-chloroacryloyl)amino]-N-(5-{[(5-{[(5-{[(2 15 {[(dimethylamino) (imino)methyl]amino}ethyl)amino]carbo nyl}-1-methyl-1H-pyrrol-3-yl)amino]carbonyl}-1-methyl 1H-pyrrol-3-yl)amino]carbonyl}-1-methyl-lH-pyrrol-3 yl)-1-methyl-1H-pyrrole-2-carboxamide (7) 4-[(2-bromoacryloyl)amino]-1-methyl-N-(l-methyl-5 20 {[(l-methyl-5-{[(l-methyl-5-{[(2-{[(methylamino) (methylimino)methyl]amino}ethyl)amino]carbonyl}-lH pyrrol-3-yl)amino]carbonyl}-lH-pyrrol-3-yl)amino] carbonyl)-lH-pyrrol-3-yl)-lH-pyrrole-2-carboxamide (8) 4-[(2-chloroacryloyl)amino]-1-methyl-N-(l-methyl-5 25 {[(l-methyl-5-{[(1-methyl-5-{[(2-{[(methylamino) (methylimino)methyl]amino}ethyl)amino]carbonyl}-lH pyrrol-3-yl)amino]carbonyl}-lH-pyrrol-3-yl)amino] carbonyl}-lH-pyrrol-3-yl)-lH-pyrrole-2-carboxamide (9) N-{5-[({5-[({5-[({2-[(aminocarbonyl)aminolethyl} 30 amino)carbonyl]-l-methyl-lH-pyrrol-3 yl}amino)carbonyl]-1-methyl-lH-pyrrol-3 yl}amino)carbonyl)-1-methyl-lH-pyrrol-3-yl)-4-[(2 bromoacryloyl)amino]-1-methyl-lH-pyrrole-2-carboxamide (10) N-{5-[({5-[({5-[({2-[(aminocarbonyl)amino]ethyl} 35 amino)carbonyl]-l-methyl-lH-pyrrol-3 yl}amino)carbonyl]-1-methyl-lH-pyrrol-3 yllamino)carbonyl]-1-methyl-lH-pyrrol-3-yl}-4-[(2- WO 01/40181 PCT/EPOO/11714 - 43 chloroacryloyl)amino]-1-methyl-lH-pyrrole-2 carboxamide (11) 4-[(2-bromoacryloyl)aminol-l-methyl-N-(l-methyl-5 {[(l-methyl-5-{[(l-methyl-5-{[(2 5 {[(methylamino)carbonyl]amino}ethyl)amino]carbonyl} 1H-pyrrol-3-yl)amino]carbonyl}-lH-pyrrol-3 yl)amino]carbonyl}-lH-pyrrol-3-yl)-lH-pyrrole-2 carboxamide (12) 4-[(2-chloroacryloyl)amino]-1-methyl-N-(l-methyl-5 10 {[(1-methyl-5-{[(l-methyl-5-{[(2 {[(methylamino)carbonyl]amino}ethyl)amino]carbonyl} 1H-pyrrol-3-yl)amino]carbonyl}-lH-pyrrol-3 yl)amino]carbonyl}-lH-pyrrol-3-yl)-lH-pyrrole-2 carboxamide 15 (13) N-(5-{[(5-{[(5-{[(2-{[amino(hydroxyimino)methyl] amino}ethyl)amino]carbonyl}-1-methyl-lH-pyrrol-3 yl)amino]carbonyl)-l-methyl-1H-pyrrol-3 yl)amino]carbonyl}-l-methyl-lH-pyrrol-3-yl)-4-[(2 bromoacryloyl)amino]-1-methyl-lH-pyrrole-2-carboxamide 20 (14) N-(5-{[(5-{[(5-{[(2-{[amino(hydroxyimino)methyl] amino}ethyl)amino]carbonyl}-l-methyl-lH-pyrrol-3 yl)amino]carbonyl}-l-methyl-lH-pyrrol-3 yl)amino]carbonyl}-1-methyl-lH-pyrrol-3-yl)-4-[(2 chloroacryloyl)amino]-1-methyl-lH-pyrrole-2 25 carboxamide (15) 4-[(2-bromoacryloyl)amino]-N-[5-({[5-({[5-({[2-(4,5 dihydro-lH-imidazol-2-ylamino)ethyl]amino}carbonyl)-1 methyl-lH-pyrrol-3-yl]amino}carbonyl)-l-methyl-lH pyrrol-3-yl]amino}carbonyl)-1-methyl-lH-pyrrol-3-yl] 30 1-methyl-lH-pyrrole-2-carboxamide (16) 4-[(2-chloroacryloyl)amino)-N-[5-({[5-({[5-({[2-(4,5 dihydro-lH-imidazol-2-ylamino)ethyl]amino}carbonyl)-1 methyl-lH-pyrrol-3-yl]amino}carbonyl)-1-methyl-1H pyrrol-3-yl]amino}carbonyl)-1-methyl-lH-pyrrol-3-yl] 35 1-methyl-lH-pyrrole-2-carboxamide (17) 4-[(2-bromoacryloyl)amino]-N-[5-({[5-({[5-({[2-(lH imidazol-2-ylamino)ethyl]amino}carbonyl)-1-methyl-lH- WO 01/40181 PCT/EPOO/11714 - 44 pyrrol-3-yl] amino~carbonyl) -1-methyl-1H-pyrrol-3 yl] aminolcarbonyl) -l-methyl-1H-pyrrol-3-yl] -1-methyl 1H-pyrrole-2 -carboxamide (18) 4-[(2-chlorooacryloyl)amino]-N-[5-({[5-({[5-({[2-(lH 5 imidazol-2-ylamino)ethyllaminolcarbonyl) -1-methyl-1H pyrrol-3-yllamino~carbonyl) -1-methyl-lH-pyrrol-3 yl] aminolcarbonyl) -l-methyl-lH-pyrrol-3-y1] -1-methyl lH-pyrrole-2 -carboxamide (19) 4- [(2-bromoacryloyl)aminol -1-methyl-N- [1-methyl-5 10 ({[1-methyl-5-({[l-methyl-5-({[2-(l,4,5,6-tetrahydro 2-pyrimidinylamino) ethyl] amino~carbonyl) -lH-pyrrol-3 yl] aminolcarbonyl) -1H-pyrrol-3-yl] amino} carbonyl) -lH pyrrol-3-yl] -lH-pyrrole-2-carboxamide (20) 4- [(2-chloroacryloyl)amino] -1-methyl-N- [l-methyl-5 15 ({[l-methyl-5-({[1-methyl-5-({[2-(l,4,5,6-tetrahydro 2-pyrimidinylamino) ethyl] aminolcarbonyl) -lH-pyrrol-3 yl] aminolcarbonyl) -1H-pyrrol-3-yl] aminolcarbonyl) -1H pyrrol-3-yl] -1H-pyrrole-2-carboxamide (21) N-(5-{[(5-{[(5-{[(2{[amino(imino)methyl] 20 aminolpropyl) amino] carbonyl} -l-methyl-lH-pyrrol-3 yl) amino] carbonyl} -1-methyl-lH-pyrrol-3 yl)amino] carbonyl}-1-methyl-1H-pyrrol-3-y1) -4- [(2 bromoacryloyl) amino] -1-methyl-1H-pyrrole-2-carboxamide (22) N-(5-{[(5-{[(5-{[(2{[amino(imino)methylI 25 amino~propyl) amino] carbonyl} -1-methyl-1H-pyrrol-3 yl) amino] carbonyl} -1-methyl-1H-pyrrol-3 yl)aminolcarbonyl}-l-methyl-1H-pyrrol-3-yl)-4- [(2 chioroacryloyl) amino] -l-methylL-1H-pyrrole-2 carboxamide 30 (23) 4- [(2-bromoacryloyl)amino] -1-methyl-N- (l-methyl-5 { [(1-methyl-5-{ [(l-methyl-5-{ [(2-{ [(methylamino) (methylimino)methyl] amino~propyl) aminol carbonyl} -1H pyrrol -3 -y1)amino] carbonyl }- 1H-pyrrol -3 -yl) amino] carbonyl} -1H-pyrrol-3-yl) -1H-pyrrole-2-carboxamide 35 (24) 4-[(2-chloroacryloyl)amino] -1-methyl-N- (l-methyl-5 { [(l-methyl-5-{ [(1-methyl-5-{ [(2-{ [(methylamino) (methylimino)methyl] amino~propyl) amino] carbonyl} -lH- WO 01/40181 PCT/EPOO/1 1714 - 45 pyrrol -3 -yl) amino] carbonyl }- 1H-pyrrol -3 -yl) amino] carbonyl} -lH-pyrrol-3-yl) -1H-pyrrole-2-carboxamide (25) N-{5-[({5-[({5-[({2-[(aminocarbonyl)anino]ethyl} amino) carbonyl] -1-methyl-1H-pyrrol-3 5 yllamino) carbonyl] -1-methyl-1H-pyrrol-3 yllamino)carbonyl] -1-metbyl-1H-pyrrol-3-y1}-4- [(2 bromoacryloyl) amino] -1-methyl-1H-pyrrole-2-carboxamide (26) N-{5-[({5-[({5-[({2-[(aminocarbonyl)aminolethyl} amino) carbonyl] -1-methyl-1H-pyrrol-3 10 yl~amino) carbonyl] -1-methyl-1H-pyrrol-3 yllamino)carbonyl]-1-methyl-lH-pyrrol-3-yl}-4-[(2 chloroacryloyl) amino] -1-methyl-lH-pyrrole-2 carboxamide (27) 4-[(2-bromoacryloyl)amino]-N--[5-({[5-({E5-({[2-(4,5 15 dihydro-1H-imidazol-2-ylamino) propyl] amino~carbonyl) 1-methyl-1H-pyrrol-3-yl] amino~carbonyl) -1-methyl-1H pyrrol-3-yl] aminolcarbonyl) -l-methyl-1H-pyrrol-3-y1] 1-methyl - H-pyrrole- 2- carboxamide (28) 4-[(2-chloroacryloyl)amino]-N-[5-({[5-({[5-({[2-(4,5 20 dihydro-1H-imidazol-2-ylamino) propyl] amino~carbonyl) 1-methyl-1H-pyrrol-3-y1] amino~carbonyl) -1-methyl-lH pyrrol-3-yl] aminolcarbonyl) -1-methyl-1H-pyrrol-3-yl] 1-methyl - H-pyrrole- 2- carboxamide (29) 4- [(2-bromoacryloyl)amino] -1-methyl-N- [1-methyl-5 25 ({[l-methyl-5-({[1-methyl-5-({[2-(1,4,5,6-tetrahydro 2-pyrimidinylamino) propyl] amino~carbonyl) -1H-pyrrol-3 yl] aminolcarbonyl) -1H-pyrrol-3-yl] amino~carbonyl) -lH pyrrol -3 -yl] -lH-pyrrole- 2- carboxamide (30) 4- [(2-chloroacryloyl)amino] -1-methyl-N- [1-methyl-5 30 ({[1-methyl-5-({[1-methyl-5-({[2-(1,4,5,6-tetrahydro 2-pyrimidinylamino) propyl] amino~carbonyl) -1H-pyrrol-3 yl] amino~carbonyl) -1H-pyrrol-3-yl] amino~carbonyl) -1H pyrrol-3-yl] -lH-pyrrole-2-carboxamide (31) N-(5-{[(5-{[(2-{[amino(methylimino)methyl] 35 aminolethyl)amino] carbonyl}-1-methyl-1H-pyrrol-3 yl)aminolcarbonyl}-1-methyl-1H-pyrrol-3-yl)-4- [(2 bromoacryloyl) amino] -1-methyl-1H-pyrrole-2-carboxamide WO 01/40181 PCT/EPOO/11714 - 46 (32) 4-[(2-bromoacryloyl)amino]-1-methyl-N-(1-methyl-5 {[(1-methyl-5-{[(2-{[(methylamino) (methylimino)methyl] amino}ethyl)amino]carbonyl)-lH-pyrrol-3 yl)amino]carbonyl}-lH-pyrrol-3-yl)-lH-pyrrole-2 5 carboxamide (33) 4-[(2-bromoacryloyl)amino]-1-methyl-N-(1-methyl-5 {[(l-methyl-5-{[(2-[(aminocarbonyl)amino] ethyl)amino]carbonyl}-lH-pyrrol-3-yl)amino]carbonyl) 1H-pyrrol-3-yl)-lH-pyrrole-2-carboxamide 10 (34) 4-[(2-bromoacryloyl)aminol-N-[5-({[5-({[2-(4,5 dihydro-lH-imidazol-2-ylamino)ethyl]amino}carbonyl)-1 methyl-lH-pyrrol-3-yl]amino}carbonyl)-1-methyl-1H pyrrol-3-yl]-l-methyl-lH-pyrrole-2-carboxamide (35) 4-[(2-bromoacryloyl)amino]-1-methyl-N-[l-methyl-5 15 ({[1-methyl-5-({[1-methyl-5-({[2-(1,4,5,6-tetrahydro 2-pyrimidinylamino)ethyl]amino}carbonyl)-1H-pyrrol-3 yl]amino}carbonyl)-1H-pyrrol-3-yl]amino}carbonyl)-lH pyrrol-3-yl]-lH-pyrrole-2-carboxamide (36) N-(5-{[(5-{[(5-{[(2{[amino(imino)methyl] 20 amino}butyl)amino]carbonyl}-1-methyl-lH-pyrrol-3 yl)amino]carbonyl}-1-methyl-1H-pyrrol-3 yl)amino]carbonyl}-l-methyl-lH-pyrrol-3-yl)-4-[(2 bromoacryloyl)amino]-1-methyl-lH-pyrrole-2-carboxamide (37) N-(5-{[(5-{[(5-{[(2{[amino(imino)methyl 25 amino}butyl)amino]carbonyl}-1-methyl-lH-pyrrol-3 yl)amino]carbonyl}-l-methyl-1H-pyrrol-3 yl)amino]carbonyl}-l-methyl-lH-pyrrol-3-yl)-4-[(2 chloroacryloyl)amino]-1-methyl-lH-pyrrole-2 carboxamide. 30
5. A process for preparing a compound of formula (I), as defined in claim 1, which comprises reacting a compound of formula WO 01/40181 PCT/EPOO/11714 - 47 H 2 N xN N B (II) _ CH 3 O n-p with a compound of formula R R 3 2 -NH OH 0 _ H3 - p wherein n, m, X, Y, B, R 1 , R 2 , R 3 , X and Y are as defined 5 above; p is 0 or 1 and Z is hydroxy or a suitable leaving group; and, if desired, converting a compound of formula (I) into a pharmaceutically acceptable salt thereof.
6. A process according to claim 5 wherein Z is hydroxy or 10 a leaving group selected from chlorine, 2,4,5 trichlorophenoxy or pivaloyl.
7. A compound of formula (I) as defined in any one of claims from 1 to 3 for use in a method of treating the 15 human or animal body by therapy.
8. A compound of formula (I) according to claim 7 for use as an antineoplastic agent. 20
9. Use of a compound of formula (I) as defined in any one of claims from 1 to 3 in the manufacture of a medicament for use in the treatment of cancer.
10. A pharmaceutical composition which comprises an 25 effective amount of a compound of formula (I) as defined in any one of claims from 1 to 3 as an active principle, in association with one or more pharmaceutically acceptable carriers and/or diluents.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB9928703.9A GB9928703D0 (en) | 1999-12-03 | 1999-12-03 | Acryloyl peptidic derivatives,process for their preparation and their use as antitumour agents |
| GB9928703 | 1999-12-03 | ||
| PCT/EP2000/011714 WO2001040181A1 (en) | 1999-12-03 | 2000-11-23 | Acryloyl peptidic derivatives, process for their preparation and their use as antitumor agents |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU2837001A true AU2837001A (en) | 2001-06-12 |
| AU781657B2 AU781657B2 (en) | 2005-06-02 |
Family
ID=10865724
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU28370/01A Ceased AU781657B2 (en) | 1999-12-03 | 2000-11-23 | Acryloyl peptidic derivatives, process for their preparation and their use as antitumor agents |
Country Status (10)
| Country | Link |
|---|---|
| EP (1) | EP1242374A1 (en) |
| JP (1) | JP2003515586A (en) |
| KR (1) | KR20020084069A (en) |
| AU (1) | AU781657B2 (en) |
| BR (1) | BR0016115A (en) |
| CA (1) | CA2395094A1 (en) |
| GB (1) | GB9928703D0 (en) |
| NZ (1) | NZ519581A (en) |
| WO (1) | WO2001040181A1 (en) |
| ZA (1) | ZA200204722B (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB0011059D0 (en) * | 2000-05-08 | 2000-06-28 | Pharmacia & Upjohn Spa | Use of substituted acryloyl distamycin derivatives in the treatment of tumours associated with high levels of glutathione |
| GB0015447D0 (en) | 2000-06-23 | 2000-08-16 | Pharmacia & Upjohn Spa | Combined therapy against tumors comprising substituted acryloyl derivates and alkylating agents |
| GB0015446D0 (en) | 2000-06-23 | 2000-08-16 | Pharmacia & Upjohn Spa | Combined therapy against tumors comprising substituted acryloyl distamycin derivates,taxanes and/or antimetabolites |
| GB0016447D0 (en) | 2000-07-04 | 2000-08-23 | Pharmacia & Upjohn Spa | Process for preparing distamycin derivatives |
| US6576612B1 (en) | 2000-10-02 | 2003-06-10 | Pharmacia Italia S.P.A. | Antitumor therapy comprising distamycin derivatives |
| US6969592B2 (en) | 2001-09-26 | 2005-11-29 | Pharmacia Italia S.P.A. | Method for predicting the sensitivity to chemotherapy |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9416005D0 (en) * | 1994-08-08 | 1994-09-28 | Erba Carlo Spa | Peptidic compounds analogous to distamycin a and process for their preparation |
| GB9610079D0 (en) * | 1996-05-14 | 1996-07-17 | Pharmacia Spa | Distamycin deriratives process for preparing them and their use as antitumor and antiviral agents |
| GB9615692D0 (en) * | 1996-07-25 | 1996-09-04 | Pharmacia Spa | Acryloyl substituted distamycin derivatives, process for preparing them, and their use as antitumor and antiviral agents |
| GB9806689D0 (en) * | 1998-03-27 | 1998-05-27 | Pharmacia & Upjohn Spa | Acryloyl derivatives analogous to distamycin,process for preparing them,and their use as antitumour and antiviral agents |
-
1999
- 1999-12-03 GB GBGB9928703.9A patent/GB9928703D0/en not_active Ceased
-
2000
- 2000-11-23 BR BR0016115-2A patent/BR0016115A/en not_active IP Right Cessation
- 2000-11-23 AU AU28370/01A patent/AU781657B2/en not_active Ceased
- 2000-11-23 NZ NZ519581A patent/NZ519581A/en unknown
- 2000-11-23 JP JP2001541867A patent/JP2003515586A/en not_active Withdrawn
- 2000-11-23 EP EP00993255A patent/EP1242374A1/en not_active Withdrawn
- 2000-11-23 CA CA002395094A patent/CA2395094A1/en not_active Abandoned
- 2000-11-23 KR KR1020027007127A patent/KR20020084069A/en not_active Application Discontinuation
- 2000-11-23 WO PCT/EP2000/011714 patent/WO2001040181A1/en not_active Application Discontinuation
-
2002
- 2002-06-12 ZA ZA200204722A patent/ZA200204722B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| NZ519581A (en) | 2004-05-28 |
| BR0016115A (en) | 2002-08-20 |
| AU781657B2 (en) | 2005-06-02 |
| KR20020084069A (en) | 2002-11-04 |
| ZA200204722B (en) | 2004-02-03 |
| GB9928703D0 (en) | 2000-02-02 |
| EP1242374A1 (en) | 2002-09-25 |
| JP2003515586A (en) | 2003-05-07 |
| CA2395094A1 (en) | 2001-06-07 |
| WO2001040181A1 (en) | 2001-06-07 |
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