IE56814B1 - Mitomycin analogs - Google Patents
Mitomycin analogsInfo
- Publication number
- IE56814B1 IE56814B1 IE272/84A IE27284A IE56814B1 IE 56814 B1 IE56814 B1 IE 56814B1 IE 272/84 A IE272/84 A IE 272/84A IE 27284 A IE27284 A IE 27284A IE 56814 B1 IE56814 B1 IE 56814B1
- Authority
- IE
- Ireland
- Prior art keywords
- lower alkyl
- hydroxymethyl
- indole
- pyrrolo
- azirino
- Prior art date
Links
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical class C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 title abstract description 7
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 118
- -1 acetamino, acetyl Chemical class 0.000 claims abstract description 88
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 31
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 23
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims abstract description 22
- 125000003282 alkyl amino group Chemical group 0.000 claims abstract description 21
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 19
- 239000001257 hydrogen Substances 0.000 claims abstract description 19
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 19
- 241001465754 Metazoa Species 0.000 claims abstract description 16
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 16
- 125000002883 imidazolyl group Chemical group 0.000 claims abstract description 14
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims abstract description 12
- 125000001475 halogen functional group Chemical group 0.000 claims abstract description 9
- HSMPSHPWCOOUJH-UHFFFAOYSA-N anilinyl Chemical class [NH]C1=CC=CC=C1 HSMPSHPWCOOUJH-UHFFFAOYSA-N 0.000 claims abstract description 8
- 201000010099 disease Diseases 0.000 claims abstract description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 8
- 230000001613 neoplastic effect Effects 0.000 claims abstract description 8
- 125000001786 isothiazolyl group Chemical group 0.000 claims abstract description 7
- 125000004193 piperazinyl group Chemical group 0.000 claims abstract description 7
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 75
- 150000001875 compounds Chemical class 0.000 claims description 73
- QMRIWYCCTCNABA-UHFFFAOYSA-N indole-4,7-quinone Chemical compound O=C1C=CC(=O)C2=C1C=CN2 QMRIWYCCTCNABA-UHFFFAOYSA-N 0.000 claims description 64
- 238000000034 method Methods 0.000 claims description 46
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 claims description 17
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 9
- 239000000126 substance Substances 0.000 claims description 8
- OIYWKBOYJXEVBU-UHFFFAOYSA-N carbamic acid 1H-indole-4,7-dione Chemical compound C(N)(O)=O.N1C=CC=2C(C=CC(C12)=O)=O OIYWKBOYJXEVBU-UHFFFAOYSA-N 0.000 claims description 7
- 230000037396 body weight Effects 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical class NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 4
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims description 3
- 239000002671 adjuvant Substances 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 2
- 239000004202 carbamide Chemical class 0.000 claims description 2
- 235000013877 carbamide Nutrition 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 claims 2
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims 1
- 238000004458 analytical method Methods 0.000 description 32
- 238000002844 melting Methods 0.000 description 32
- 230000008018 melting Effects 0.000 description 32
- HYFMSAFINFJTFH-NGSRAFSJSA-N mitomycin A Chemical compound O=C1C(OC)=C(C)C(=O)C2=C1[C@@H](COC(N)=O)[C@]1(OC)N2C[C@@H]2N[C@@H]21 HYFMSAFINFJTFH-NGSRAFSJSA-N 0.000 description 32
- HYFMSAFINFJTFH-UHFFFAOYSA-N Mitomycin-A Natural products O=C1C(OC)=C(C)C(=O)C2=C1C(COC(N)=O)C1(OC)N2CC2NC21 HYFMSAFINFJTFH-UHFFFAOYSA-N 0.000 description 31
- 238000000354 decomposition reaction Methods 0.000 description 31
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 22
- 150000003254 radicals Chemical class 0.000 description 18
- 239000007787 solid Substances 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 11
- 229910000027 potassium carbonate Inorganic materials 0.000 description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 5
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 4
- 101150041968 CDC13 gene Proteins 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 125000003342 alkenyl group Chemical group 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 229930192392 Mitomycin Natural products 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 3
- 230000000118 anti-neoplastic effect Effects 0.000 description 3
- 230000003115 biocidal effect Effects 0.000 description 3
- 238000012216 screening Methods 0.000 description 3
- JJYPMNFTHPTTDI-UHFFFAOYSA-N 3-methylaniline Chemical compound CC1=CC=CC(N)=C1 JJYPMNFTHPTTDI-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- KHBQMWCZKVMBLN-UHFFFAOYSA-N Benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1 KHBQMWCZKVMBLN-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 125000000304 alkynyl group Chemical group 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 125000005518 carboxamido group Chemical group 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 125000004093 cyano group Chemical group *C#N 0.000 description 2
- 229960004857 mitomycin Drugs 0.000 description 2
- RZXMPPFPUUCRFN-UHFFFAOYSA-N p-toluidine Chemical compound CC1=CC=C(N)C=C1 RZXMPPFPUUCRFN-UHFFFAOYSA-N 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 229960001866 silicon dioxide Drugs 0.000 description 2
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical group [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 description 2
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 125000001544 thienyl group Chemical group 0.000 description 2
- DZGWFCGJZKJUFP-UHFFFAOYSA-N tyramine Chemical compound NCCC1=CC=C(O)C=C1 DZGWFCGJZKJUFP-UHFFFAOYSA-N 0.000 description 2
- PRZSMDYEVUSNJM-SLFFLAALSA-N (1r,4as,10ar)-1-(hydroxymethyl)-1,4a-dimethyl-7-propan-2-yl-3,4,10,10a-tetrahydro-2h-phenanthren-9-one Chemical compound OC[C@]1(C)CCC[C@]2(C)C3=CC=C(C(C)C)C=C3C(=O)C[C@H]21 PRZSMDYEVUSNJM-SLFFLAALSA-N 0.000 description 1
- ZRTGHKVPFXNDHE-UHFFFAOYSA-N (3-methyl-1,2-thiazol-5-yl)azanium;chloride Chemical compound [Cl-].CC=1C=C([NH3+])SN=1 ZRTGHKVPFXNDHE-UHFFFAOYSA-N 0.000 description 1
- GPRYKVSEZCQIHD-UHFFFAOYSA-N 1-(4-aminophenyl)ethanone Chemical compound CC(=O)C1=CC=C(N)C=C1 GPRYKVSEZCQIHD-UHFFFAOYSA-N 0.000 description 1
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- SNTWKPAKVQFCCF-UHFFFAOYSA-N 2,3-dihydro-1h-triazole Chemical compound N1NC=CN1 SNTWKPAKVQFCCF-UHFFFAOYSA-N 0.000 description 1
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 1
- SXAMGRAIZSSWIH-UHFFFAOYSA-N 2-[3-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-1,2,4-oxadiazol-5-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C1=NOC(=N1)CC(=O)N1CC2=C(CC1)NN=N2 SXAMGRAIZSSWIH-UHFFFAOYSA-N 0.000 description 1
- XXZCIYUJYUESMD-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-3-(morpholin-4-ylmethyl)pyrazol-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C=1C(=NN(C=1)CC(=O)N1CC2=C(CC1)NN=N2)CN1CCOCC1 XXZCIYUJYUESMD-UHFFFAOYSA-N 0.000 description 1
- FYELSNVLZVIGTI-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-5-ethylpyrazol-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C=1C=NN(C=1CC)CC(=O)N1CC2=C(CC1)NN=N2 FYELSNVLZVIGTI-UHFFFAOYSA-N 0.000 description 1
- YJLUBHOZZTYQIP-UHFFFAOYSA-N 2-[5-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-1,3,4-oxadiazol-2-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C1=NN=C(O1)CC(=O)N1CC2=C(CC1)NN=N2 YJLUBHOZZTYQIP-UHFFFAOYSA-N 0.000 description 1
- UHGULLIUJBCTEF-UHFFFAOYSA-N 2-aminobenzothiazole Chemical compound C1=CC=C2SC(N)=NC2=C1 UHGULLIUJBCTEF-UHFFFAOYSA-N 0.000 description 1
- XPQIPUZPSLAZDV-UHFFFAOYSA-N 2-pyridylethylamine Chemical compound NCCC1=CC=CC=N1 XPQIPUZPSLAZDV-UHFFFAOYSA-N 0.000 description 1
- LGDHZCLREKIGKJ-UHFFFAOYSA-N 3,4-dimethoxyaniline Chemical compound COC1=CC=C(N)C=C1OC LGDHZCLREKIGKJ-UHFFFAOYSA-N 0.000 description 1
- WNRGWPVJGDABME-UHFFFAOYSA-N 3,5-Dimethoxyaniline Chemical compound COC1=CC(N)=CC(OC)=C1 WNRGWPVJGDABME-UHFFFAOYSA-N 0.000 description 1
- YBAZINRZQSAIAY-UHFFFAOYSA-N 4-aminobenzonitrile Chemical compound NC1=CC=C(C#N)C=C1 YBAZINRZQSAIAY-UHFFFAOYSA-N 0.000 description 1
- OEQQFQXMCPMEIH-UHFFFAOYSA-N 4-chloro-1,3-benzothiazol-2-amine Chemical compound C1=CC=C2SC(N)=NC2=C1Cl OEQQFQXMCPMEIH-UHFFFAOYSA-N 0.000 description 1
- TYMLOMAKGOJONV-UHFFFAOYSA-N 4-nitroaniline Chemical compound NC1=CC=C([N+]([O-])=O)C=C1 TYMLOMAKGOJONV-UHFFFAOYSA-N 0.000 description 1
- CONKBQPVFMXDOV-QHCPKHFHSA-N 6-[(5S)-5-[[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]methyl]-2-oxo-1,3-oxazolidin-3-yl]-3H-1,3-benzoxazol-2-one Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C[C@H]1CN(C(O1)=O)C1=CC2=C(NC(O2)=O)C=C1 CONKBQPVFMXDOV-QHCPKHFHSA-N 0.000 description 1
- GPNAVOJCQIEKQF-UHFFFAOYSA-N 6-nitro-1,3-benzothiazol-2-amine Chemical compound C1=C([N+]([O-])=O)C=C2SC(N)=NC2=C1 GPNAVOJCQIEKQF-UHFFFAOYSA-N 0.000 description 1
- QLUFBCVWKTWKBF-UHFFFAOYSA-N 6-nitro-1,3-benzothiazole Chemical compound [O-][N+](=O)C1=CC=C2N=CSC2=C1 QLUFBCVWKTWKBF-UHFFFAOYSA-N 0.000 description 1
- 206010003445 Ascites Diseases 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 208000028018 Lymphocytic leukaemia Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical class [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical class [H]C([H])([H])C(*)=O 0.000 description 1
- 125000005036 alkoxyphenyl group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- LHIJANUOQQMGNT-UHFFFAOYSA-N aminoethylethanolamine Chemical compound NCCNCCO LHIJANUOQQMGNT-UHFFFAOYSA-N 0.000 description 1
- IMUDHTPIFIBORV-UHFFFAOYSA-N aminoethylpiperazine Chemical compound NCCN1CCNCC1 IMUDHTPIFIBORV-UHFFFAOYSA-N 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 229940034982 antineoplastic agent Drugs 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 125000005874 benzothiadiazolyl group Chemical group 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 125000004663 dialkyl amino group Chemical group 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 229960004931 histamine dihydrochloride Drugs 0.000 description 1
- PPZMYIBUHIPZOS-UHFFFAOYSA-N histamine dihydrochloride Chemical compound Cl.Cl.NCCC1=CN=CN1 PPZMYIBUHIPZOS-UHFFFAOYSA-N 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000012750 in vivo screening Methods 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 208000003747 lymphoid leukemia Diseases 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- ODHSPTHLPCXPTL-UHFFFAOYSA-N n'-(5-nitropyridin-2-yl)ethane-1,2-diamine Chemical compound NCCNC1=CC=C([N+]([O-])=O)C=N1 ODHSPTHLPCXPTL-UHFFFAOYSA-N 0.000 description 1
- KVKFRMCSXWQSNT-UHFFFAOYSA-N n,n'-dimethylethane-1,2-diamine Chemical compound CNCCNC KVKFRMCSXWQSNT-UHFFFAOYSA-N 0.000 description 1
- PEMGGJDINLGTON-UHFFFAOYSA-N n-(3-aminophenyl)acetamide Chemical compound CC(=O)NC1=CC=CC(N)=C1 PEMGGJDINLGTON-UHFFFAOYSA-N 0.000 description 1
- CHMBIJAOCISYEW-UHFFFAOYSA-N n-(4-aminophenyl)acetamide Chemical compound CC(=O)NC1=CC=C(N)C=C1 CHMBIJAOCISYEW-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 238000012746 preparative thin layer chromatography Methods 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- JHHZLHWJQPUNKB-UHFFFAOYSA-N pyrrolidin-3-ol Chemical compound OC1CCNC1 JHHZLHWJQPUNKB-UHFFFAOYSA-N 0.000 description 1
- 125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- FDDDEECHVMSUSB-UHFFFAOYSA-N sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 229960003732 tyramine Drugs 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
- C07D487/14—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
Mitomycin derivatives useful for treatment of neoplastic disease states in animals have the formula IIIa, wherein: Y is hydrogen or lower alkyl; and Z is an hydroxy substituted 1-pyrrolidinyl radical, or a lower alkyl substituted piperidyl radical, or a 1-piperazinyl radical or an acetamino, acetyl, carbamido, cyano, carboxy lower alkylamino, di-lower alkoxy, nitro, sulfamyl, or lower alkyl substituted anilino radical, or a radical of the formula, wherein R is hydrogen or lower alkyl and R<1> is a nitrogen containing heterocyclic radial selected from amino substituted triazolyl, lower alkyl substituted isothiazolyl, benzothiazolyl, and nitro and halo substituted derivatives of benzothiazolyl, or R<1> is a substituted lower alkyl radical selected from amino lower alkyl, lower alkylamino lower alkyl, hydroxy lower alkylamino lower alkyl, hydroxy lower alkoxy lower alkyl, imidazolyl lower alkyl, nitro substituted imidazolyl lower alkyl, mono- and di-hydroxy phenyl lower alkyl, nitro substituted pyridylamino lower alkyl, piperazinyl lower alkyl, and pyridyl ethyl.
Description
The present invention relates generally to antibiotic mitosane compounds and to their use in the treatment of neoplastic disease states in animals.
The disclosures of U.S. Letters Patent No. 5 4,268,676; co-pending U.S. Patent Application Serial No. 206,529 filed November 13, 1980; and Patent Specification No.5 may provide essential and nonessential material relating to the present invention.
Briefly summarized, said U.S. Patent No. 4,268,676 and cc-pending application Serial No. 206,529 set forth a statement of the background of the ongoing search in the art for new and useful compounds which are structurally related to the mitomycins, which possess antibiotic activity, which have low toxicity and which display a substantial degree of antitumor activity in animals. More particularly, they disclose new compounds of the formula I, wherein; Y is hydrogen or lower alkyl; and X is a thiazolamino radical, a furfurylamino radical or a radical of the formula, ** in which R, R and R* are the same or different and selected from the group consisting of hydrogen and 3 lower alkyl, and R is selected from the group consisting of lower alkenyl, halo-lower alkenyl, lower alkynyl, lower alkoxycarbonyl, thienyl, formamyl, tetrahydrofuryl and benzene sulfonamide.
Said U.S. patent and pending application also disclose novel methods for treatment of neoplastic disease states in animals, which methods comprise administering a therapeutically effective amount of a compound of the formula, Xa, wherein: Y is hydrogen or lower alkyl? and Z 15 is a thiazolamino radical, a furfurylamino radical, a cyclopropylamino radical, a pyridylamino radical, or a radical of the formula® 6 in which R , R , and R are the same or different and selected from the group consisting of hydrogen and lower alkyl, and R7 is selected from the group consisting of lower alkenyl, halo-lower alkenyl, lower alkynyl, lower alkoxycarbonyl, halo-lower alkyl, hydroxy-lower alkyl, pyridyl, thienyl, formamyl, tetrahydrofuryl, benzyl, and benzene sulfonamide.
Patent Specification No. 52 9^6 * also discloses compounds with a substantial degree of antitumor activity in animals of the following formula Ila, wherein: Y is hydrogen or lower alkyl; and Z is a lower alkoxy substituted quinolinylamino radical, a cyano substituted pyrazolylamino radical or a monoor di-lower alkyl substituted thiazolamino radical, or a nitrogen-containing heterocyclic radical selected from the group consisting of 1-pyrrolinyl, 1indolinyl, N-thiazolidinyl, N-morpholinyl, 1-piperazinyl, and N-thiomorpholinyl radicals, or a cyano, phenyl, carboxamido or lower alkoxycarbonyl substituted 1-aziridinyl radical, or a lower alkyl, formyl or acetyIphenyl substituted 1-piperazinyl radical, or an hydroxy or piperidyl substituted 1-piperidyl radical, or a lower alkoxy, amino or halo substituted pyridylamino radical, or a carboxamido, mercapto or methylenedioxy substituted anilino radical, or R I a radical of the formula, -N-R' wherein R is hydrogen or lower alkyl and R* is a nitrogen-containing heterocyclic radical selected from the group consisting of quinuclidinyl, pyrazolyl, 1-triazolyl, isoquinolinyl, indazolyl, benzoxazolyl, thiadiazolyl and benzothiadiazolyl, and lower alkyl and halo substituted derivatives thereof, or a butyrolactonyl radical, or an adamantyl radical, or a mono-lower alkoxy substituted phenyl radical, or a substituted lower alkyl radical selected from the group consisting of mercapto lower alkyl, carboxy lower alkyl, mono-, di- and tri-lower alkoxy lower alkyl, lower alkyl thio lower alkyl and lower alkoxyearbonyl substituted derivatives thereof, cyano lower alkyl, mono-, di- and tri-lower alkoxy phenyl lower alkyl, phenyl cyclo lower alkyl, 1-pyrrolidinyl lower alkyl, N-lower alkyl pyrrolidinyl lower alkyl, Nmorpholinyl lower alkyl, and lower dialkylamino lower alkyl.
Also pertinent to the background of the present invention are the following references; Cosulich, et al., U.S. Patent No. 3,332,944; Matsui, et al., U.S. Patent No. 3,410,867; Nakano, et al, U.S. Patent No. 4,231,936; Matsui, et al., U.S. Patent No. 3,429,894; Remers, U.S. Patent No. 4,268,676; Matsui, et al., U.S.
Patent No. 3,450,705; Matsui, et al., U.S. Patent No. 3,514,452; and Xmai, et al., Gann, 71, pp. 560-562 (1980).
According to the present invention, there are provided novel compounds of the formula, III, wherein: Y is hydrogen or lower alkyl? and X is an hydroxy substituted 1-pyrrolidinyl radical, or a lower alkyl substituted piperidyl radical, or an acetamino, acetyl, carbamide, cyano, carboxy lower alkylamino, di-lower alkoxy, nitro, or sulfamoyl substituted anilino radical, or R a radical of the formula, -N-R1 wherein R is hydrogen or lower alkyl and R1 is a nitrogen containing heterocyclic radical selected from amino substituted triazolyl, lower alkyl substituted isothiazolyl, benzothiazolyl, and nitro and halo substituted derivatives of benzothiazolyl, or R1 is a substituted lower alkyl radical selected from amino lower alkyl, lower alkylamino lower alkyl, hydroxy lower alkylamino lower alkyl, hydroxy lower alkoxy lower alkyl, imidazolyl lower alkyl, nitro substituted imidazolyl lower alkyl, ri mono- and di-hydroxy phenyl lower alkyl, nitro substituted pyridylamino lower alkyl, and piperazinyl lower alkyl.
Also provided according to the invention is a substance for use in the preparation of a medicament for treatment of a neoplastic disease state in an animal, said substance comprising a therapeutically effective amount of a compound of the formula, Ilia, is or or Ilia wherein: Y is hydrogen or lower alkyl; and Z an hydroxy substituted 1-pyrrolidinyl radical, a lower alkyl substituted piperidyl radical, acetyl, carbamido, an acetamino, cyano, carboxy lower alkylamino, dilower alkoxy, nitro, sulfamoyl, or lower alkyl substituted anilino radical, or R a radical of the formula® -N-R3, wherein R is hydrogen or lower alkyl and is a nitrogen containing heterocyclic radical selected from amino substituted triazolyl, lower alkyl substituted isothiazolyl, benzo25 thiazolyl, and nitro and halo substituted derivatives of benzothiazolyl, or R1 a substituted lower alkyl radical selected from amino lower alkyl, lower alkylamino lower alkyl, hydroxy lower alkylamino lower alkyl, hydroxy lower alkoxy lower alkyl, imidazolyl lower alkyl, nitro substituted imidazolyl lower alkyl, mono- and di-hydroxy phenyl lower alkyl, nitro substituted pyridylamino lower alkyl, piperazinyl lower alkyl, and 2-(pyridyl)ethyl.
Unless otherwise indicated, the term lower, applied to alkyl radicals shall designate such straight . or branched chain radicals as to include from one to six carbon atoms. By way of illustration, lower alkyl shall mean and include, for exanple, methyl, ethyl, propyl, butyl, pentyl and hexyl radicals as well as isopropyl radicals, and t-butyl radicals. Similarly, lower as applied to alkoxy shall designate a radical having one to six carbon atoms.
It will be apparent that the compounds of formula III are all comprehended by the specifications of formula Ilia. Put another way, all the novel antibiotic mitomycin derivatives of formula III are useful in practice of the novel antineoplastic therapeutic methods which involve administration of compounds of formula I IIa.
Mitomycin derivatives of the invention are prepared by the reaction of mitomycin A with the appropriately selected amine compounds. The N-alkylmitomycin (e.g., N-methylmitomycin) derivatives are similarly prepared by the reaction of a selected amine with Nalkylmitomycin A prepared from mitomycin C, e.g., according to the methods generally disclosed in Cheng, et al., J.Med.Chem., 20, No. 6, 767-770 (1977), The preparative reactions generally yield the desired product as a crystalline solid which is readily soluble b in alcohol.
Substances of the invention are used in a medicament for a method in which the administration of effective amounts of one or more < of the compounds of formula Ilia, as an active ingredient, together with desired pharmaceutically acceptable diluents, adjuvants and carriers, to an animal suffering from a neoplastic disease state is carried out. Unit dosage forms of oorapounds administered according to . the methods described above may range from 0.001 to 5.0 mg and preferably from 0.004 to 1.0 mg, of the compounds. Such unit dosage quantities may be given to provide a daily dosage of from O.l to 100 mg per kg, and preferably from 0.2 to 51.2 mg per kg, of body weight of the animal treated.
Parenteral administration, and especially intraperitoneal administration, is the preferred route for practice of the above methods.
Other aspects and advantages of the present invention will become apparent upon consideration of the following description.
The following Examples 1 through 32, describing preparation of certain presently preferred compounds according to the invention, are for illustrative purposes only and are not to be construed as limiting the invention. Unless otherwise indicated, all reactions were carried out at room temperature (20*C), without added heat.
Unless otherwise indicated, all thin layer chromatographic (TLC) procedures employed to check the progress of reactions involved the use of a pre-coated silicagel plate and a mixture of methanol and chloroform (2:8 by volume) as a developing solvent.
Example 1 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy5-methyl-6-(3-hydroxy-l-pyrrolidlnyl) -azirino[2 *, 31:3/4] pyrrolo[1,2-a]indole-4,7-dione carbamate A solution of mitomycin A (50 mg) in 6 ml of anhydrous methanol was treated with 3-pyrrolidinol (13 mg) under nitrogen at room temperature. VThen thinlayer chromatography on silica gel (2:8 methanolchloroform as solvent) showed that starting material no longer was present, the mixture was filtered and evaporated under reduced pressure. The residue was purified by preparative thin-layer chromatography using the same solvent system. This procedure gave 23 mg (40% yield) of the desired product having a melting point of 82®85°C (decomposition) and providing the following analysis: NMR (DMSO-d,, TS): '6' values in ppm. - o Absence of the 6-methoxy peak at 4.02 and the appearance of new peaks at 1.6-2.2 (m,2), 2.8-3.1 (broad s,5) and 4.0-4.3 (m,l).
Example 2 1,la,2,8,8a,8b-Hexahvdro-8-(hydroxymethyl)-8a-methoxy5-methy 1-6- (3-methyIpiperidyl) - aziHnofe\ 3':3,4JpyriOlo [1,2-a)indole-4,7-dione carbamate This compound was prepared by the procedure described in Example 1. From 70 mg of mitomycin A and 200 mg of 3-methyl pipeline was obtained 46 mg (55% yield) of the desired product having a melting point of 75®-88°C (decomposition) and providing the following analysis: NMR (CDClj, TS): f <51 values in ppm.
Absence of the 6-methoxy peak at 4.02 and the appearance of new peaks at 0.85 (d,3), 1.102.15 (m,5) and 2.15-3.32 (m,4).
Example 3 (Comparative) 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy5^methyl-6-(l-piperazinyiy-flizirinot^1,3^;3,4ipyrrolo-" [1,2-aJindole-4,7-dione carbamate This compound was prepared by the procedure described in Example 1. From 60 mg of mitomycin A and 30 mg of anhydrous piperazine was obtained 23 mg (34% yield) of the desired product having a melting point greater than 200°C (decomposition) and providing the following analysis: NMR (DMSO-d,, TS): *6' values in ppm.
Absence of the 6-methoxy peak at 4.02 and the appearance of new peaks at 1.9 (broad s,l) and 2.9 (s,8) .
Example 4 20 1,1a,2,8,8a,8b-ttexahydro-8-(hydroxymethyl)-8a-methoxy5-methyl-6-[4-(acetylamino)anilino]-azirinoT21,3':3,4] pyrrolo[1,2-afIndole-4,7-dione carbamate This compound was prepared by the procedure described in Example 1. From 100 mg of mitomycin A and excess 4-(acetylamino)aniline was obtained 102 mg (76% yield) of the desired product having a melting point of 143e-145eC (decomposition) and providing the following analysis: i 2 NMR (CDCI3, TS): 'δ* values in ppm.
Absence of the 6-methoxy peak at 4.02 and the appearance of new peaks at 2.1 (s,3), 7.4 (d,2), 7.6 (s,l) and 8.9-9.3 (s,l).
Example 5 1,la,2,8,8a,8b-Hexahvdro-8-(hydroxymethyl)-8a-methoxy5^methyl-6-[3-(acetylamino)aniflno]-azirino[2 *,31;3,4T pyrrolojl,2-a]indole^?, 7-dione carbamate This compound was prepared by the procedure described in Example 1, except that a small amount of solid potassium carbonate was added. From 70 mg of mitomycin A and 150 mg of 3-(acetylamino)aniline was obtained 67 mg (72% yield) of the desired product having a melting point of 140°-143°C (decomposition) and providing the following analysis: NMR (Acetone-dg, TS): ’δ1 values in ppm.
Absence of the 6-methoxy peak at 4.02 and the appearance of new peaks at 2.1 (s,3), 6.7-7.5 (m,4), 8.0 (broad s,l) and 9.3 (s,l), Example 6 1, la, 2,8,8a,8b-Hexahvdro-8-(hydroxymethyl)-8a-methoxyy-methyl-6-(4-acetylanilino)-azirino[21,31:3,4]pyrrolo [1,2-a]indoTe-4,7-dione carbamate This compound was prepared by the procedure described in Example 1, except that a small amount of solid potassium carbonate was added. From 70 mg of mitomycin A and 510 mg of 4-acetylaniline was obtained 25 mg (28% yield) of the desired product having a melting point of 103°-104eC (decomposition) and providing the following analysis: 3 NMR (CDCl^r TS): ’4' values in ppm.
Absence of the 6-methoxy peak at 4.02 and the appearance of new peaks at 2.1 (s,3), 6.6(d,2), 7.3 (d,2) and 7.0-7.3 (broad s,l).
Example 7 1,la,2,8,8a,8b-Hexahvdro-8-(hydroxytnethy 1)-8a-methoxy-5methyl-6~[4-(1-ureido)anllino]-azlrinot21,31: 3,4]pyrrolo [Ϊ,2-a]indole-4,7-dione carbamate This carbamido-substituted compound was prepared by the procedure described in Example 1. From 50 mg of mitomycin A and 227 mg of 4-(1-ureido)aniline was obtained 49 mg (67% yield) of the desired product having a melting point of 93®-95®C (decomposition) and providing the following analysis: NMR (CDClTS): ’o' values in ppm.
Absence of the 6-methoxy peak at 4.02 and the appearance of new peaks at 5.03 (s,2), 6.9 Example 8 20 1»la,2,8,8a,8b-Hexahydro-8-(hydroxytnethy 1) -8a-methoxy-5^ methyl-6-(4-cyanoaniiino)-azirino[21,3*:3,4]pyrrolofl,2-a] indole-4,7-dione^arbamate This compound was prepared by the procedure described in Example 1, except that a small amount of solid potassium carbonate was added. From 70 mg of mitomycin a and 472 mg of 4-aminobenzonitrile was obtained 23 mg (24% yield) of the desired product having a melting point of 124®-126®C (decomposition) and providing the following analysis: 4 NMR (CDCl^, TS): 'δ1 values in ppm.
Absence of the 6-methoxy peak at 4.02 and the appearance of new peaks at 6.6 (d,2), 7.4 (d,2) and 7.0-7.3 (broad s,l).
Example 9 1,la,2,8,8a,8b-Hexahvdro-8-(hydroxymethyl)-8a-methoxy-5methy1-6-(3-cyanoanilinoj-azlrino[21,31:3,4]pyrrolo[1,2-a] indole-4,7-dione carbamate This compound was prepared by the procedure described in Example 1, except that a small amount of solid potassium carbonate was added. From 71 mg of mitomycin A and 500 mg of 3-aminobensonitrile was obtained 30 mg (34% yield) of the desired product having a melting point of 97°-98°C (decomposition) and providing the following analysis: NMR (CDCl^, TS): '5* values in ppm.
Absence of the 6-methoxy peak at 4.02 and the appearance of new peaks at 7.2-7.8 (m,4).
Example 10 20 1*laf 2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5methyl-6-T4^(N-glycyl)anilino]-azirino[21,31:3,4)pyrrolo [1,2-a]xndole-4, T-3ione carbamate This compound was prepared by the procedure described in Example 1. From 50 mg of mitomycin A and 249 mg of 4-(N-glycyl)aniline was obtained 62 mg (90% yield) of the desired product having a melting point of 83®-85eC (decomposition) and providing the following analysis: NMR (DMSO-dg, TS): 'δ* values in ppm.
Absence of the 6-methoxy peak at 4.02 and the appearance of new peaks at 3.1 (s,2), 6.3-6.6 (broad s,2), 6.6-6.8 (broad s,2) and 6.6-7.1 (broad s,2).
Example 11 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5methvl-6-(3,4-dimethoxyanlllno)-azirino[21,31:3,4]pyrrolo Tl, 2-ίΐΤΐηάοΐ6-4,7-dione carbamate This compound was prepared by the procedure described in Example 1. From 50 mg of mitomycin A and 229 mg of 3,4-dimethoxyaniline was obtained 61 mg (91% yield) of the desired product having a melting point of 114°116 ®C (decomposition) and providing the following analysis: NMR (CDC13, TS): 'δ1 values in ppm.
Absence of the 6-methoxy peak at 4.02 and the appearance of new peaks at 3.8 (s,6), 6.3-6.9 (m,3) and 7.7 (s,l) .
Example 12 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5methyT-y- (3T5-dimethoxyaifiTino HazIrinoT21,3 r: 3,4ΓρντΓθ1ο (ΐ,2-a]indole-4,7-dione carbamate This compound was prepared by the procedure described in Example 1. - From 50 mg of mitomycin A and 229 mg of 3,5-dimethoxyaniline was obtained 60 mg (88% yield) of the desired product having a melting point of 98*-100*C (decomposition) and providing the following analysis: NMR (CDC13, TS): ’δ’ values in ppm.
Absence of the 6-methoxy peak at 4.02 and the 6 appearance of new peaks at 3.8 (s,6), 5.9-6.4 (broad s,3) and 7.6 (s,l).
Example 13 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5methyl-β- (4-nitgoaniiIno) -azirino_[21,31 ; 3,4] pyrrolo [1,2-a] indole-4,7-dione carbamate This compound was prepared by the procedure described in Example 1, except that a small amount of solid potassium carbonate was added. From 70 mg of mitomycin A and 276 mg of 4-nitroaniline was obtained 16 mg (9% yield) of the desired product having a melting point of 132°-134® C (decomposition) and providing the following analysis: NMR (Acetone-dg, TS): '6* values in ppm.
Absence of the 6-methoxy peak at 4.02 and the appearance of new peaks at 6.9-7.3 (d,2), 7.4-7.9 (d,2) and 7.9-8.4 (broad s,l).
Example 14 1,la,2,8,8 a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5methvl-6- {4-sul£amoy3.anilinoy-azirino [21, 3 *: 3,4) pyrrolo [1,2-a)indole-4,7-dione carbamate This compound was prepared by the procedure described in Example 1, except that a small amount of solid potassium carbonate was added. From 70 mg of mitomycin A and 688 mg of sulfanilamide was obtained 25 mg (26% yield) of the desired product having a melting point of 113e-115eC (decomposition) and providing the following analysis: NMR (CDCl^, TS): *6’ values in ppm.
Absence of the 6-methoxy peak at 4.02 and the appearance of new peaks at 7.0 (d,2), 7.5 (s,l) and 7.9 (d,2).
Example 15 1,1al2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5methyl-6-(4-methylanilino)-azirinof 21, 3^ :3,4)pyrroloI1, 2-a) indole-4,7-dione carbamate This compound was prepared by the procedure described in Example 1. From 60 mg of mitomycin A and excess 4-methylaniline was obtained 63 mg (86% yield) of the desired product having a melting point of 113®115°C (decomposition) and providing the following analysis: NMR (CDCl^, TS)s ·$' values in ppm.
Absence of the 6-methoxy peak at 4.02 and the appearance of new peaks at 2.3 (s,3), 6.5-7.3 (broad s,4) and 7.6 (broad s,l).
Example 16 1,la,2,8,8a,8b-Hexahvdro-8-(hydroxymethyl)-8a-methoxy-5methyl-6-(3-methyranilino)^azirinol21,31:3,4]pyrrolo[1,2-a] indole-4,7-dione calrbamate This compound was prepared by the procedure described in Example 1. From 70 mg of mitomycin A and 276 mg of 3-methylaniline was obtained 66 mg (78% yield) of the desired product having a melting point of 89°-91°C (decomposition) and providing the following analysis: NMR (CDCl^, TS): 'δ * values in ppm.
Absence of the 6-methoxy peak at 4.02 and the appearance of new peaks at 2.4 (s,3), 6.7-7.5 (m,4) and 7.8 (s,l).
Example 17 1,1a,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-m6thoxy°5methyl-6-[(5-amino-l,2,4°triazol-3-yl)amino]-azirino (21,31:3,4)pyrrolo fl,2-a)indole-4,7-dione^carbamate This compound was prepared by the procedure described in Example 1, except that a small amount of solid potassium carbonate was added. From 50 mg of mitomycin A and 30 mg of 3,5-diamino-l,2,4-triazole was obtained 13 mg (5.5% yield) of the desired product having a melting point of 117°-120®C (decomposition) and providing the following analysis: NMR (DMSO-dg, TS): *6 * values in ppm.
Absence of the 6-methoxy peak at 4.02 and the appearance of a new peak at 5.37 (s,3).
Example 18 1.,la,2,8,8a,8b7Hexahydro-8-(hydroxymethyl)-8a-methoxy-5niethyl-6- {(3-i^thylis0thi~azol-5-yl) amino] -azirino (2 1,31:3,4] pyrrolo[1,2-a]indole-4,7-dione carbamate This compound was prepared by the procedure described in Example 1, except that 0.5 ml of triethylamine was added. From 60 mg of mitomycin A and 30 mg of 5amino-3-methylisothiazole hydrochloride was obtained 4.5 mg (8.5% yield) of the desired product having a melting point of 87°-90eC (decomposition) and providing the following analysis: NMR (CDCl^r TS): ’6' values in ppm.
Absence of the 6-methoxy peak at 4.02 and the appearance of new peaks at 2.3 (s,3), 6.1 25 (s,l) and 6.4 (s,l).
Example 19 1,la,2,8,8a,8b-Hexahvdro-8-(hydroxymethyl)-8a-methoxy-5methy1-6-[(2-Fenzothiazoiyl) amino]-aziruno[ 2 *, 31: J, 4]pyrrolo Tl,2-a]indole-4,7-dione carbamate This compound was prepared by the procedure described in Example 1, except that a small amount of solid potassium carbonate was added. From 50 mg of mitomycin Ά and 25 mg of 2-aminobenzothiazole was obtained 12 mg (18% yield) of the desired product having a melting point of 82°-85’C [decomposition) and providing the following analysis: NMR (CDCl^, TS): '6' values in ppm.
Absence of the 6-methoxy peak at 4.02 and the appearance of new peaks at 7.1-8.0 (m,5).
Example 20 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)~8a-methoxy5-methyl-6-[(6-nitrobenzothiazol°2-yl)amino]-azirino [21,31;3,4) pyrrolo(1,2-a]indole-4,7-dione carbamate ‘ This compound was prepared by the procedure described in Example 1, except that a small amount of solid potassium carbonate was added. From 50 mg of mitomycin A and 30 mg of 2-amino-6-nitrobenzothiazole was obtained 20 mg (27% yield) of the desired product having a melting point of 869-89°C (decomposition) and providing the following analysis: NMR (DMSO-dg, TS): '6' values in ppm.
Absence of the 6-methoxy peak at 4.02 and the appearance of new peaks at 6.9-8.3 (m,4).
Example 21 1,1a,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5methvl-6-t(4-chlorobenzothiazol-2-yl)amino]-azirino [21 ® 3f 41 pyrroFo [37L2-a] indole-4,7/dione carbamate This compound was prepared by the procedure described in Example 1, except that a small amount of solid potassium carbonate was added. From 150 mg of mitomycin A and 27 mg of 2-amino-chlorobenzothiazole was obtained 30 mg (14% yield) of the desired product having a melting point of 89°-91°C (decomposition) and providing the following analysis: NMR (CDCl^, TS) s ’δ1 values in ppm.
Absence of the 6-methoxy peak at 4.02 and the appearance of new peaks at 7.1-8.0 (broad s,4) .
Example 22 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5methyl-6- [ (2-aminoethyi) amino] -azirino [ 21,311:3,4] pyrrolo [1,2-a]indole-4,7-dione carbamate This compound was prepared by the procedure described in Example 1, except that the solvent was dichloromethane. From 50 mg of mitomycin A and 10 mg of 1,2-diaminoethane was obtained 35 mg (65% yield) of the desired product having a melting point of 202®205®C (decomposition) and providing the following analysis: NMR (CDC13, TS) : ‘6 * values in ppm.
Absence of the 6-methoxy peak at 4.02 and the appearance of new peaks at 1.5 (broad s,2) and 3.5 (broad s,4).
Example 23 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5methvl-6-[methyl(2-methylaminoethyl)amino]-azlrino [2 *, 3^3,4] pyrrolo [ΪΤ2-a] indole-4*, 7-dione carbamate This compound was prepared by the procedure described in Example 1, except that a small amount of solid potassium carbonate was added. From 50 mg of mitomycin A and 25 mg of sym-dimethylethylenediamine was obtained 28 mg (50% yield) of the desired product having a melting point of 99-101°C (decomposition) and providing the following analysis: NMR (CDC13# TS)i *6’ values in ppm.
Absence of the 6-methoxy peak at 4.02 and the appearance of new peaks at 1.3 (s,l), 2.5 (s,6), and 2.7 (s,4).
Example 24 1,la,2,8,8a,8b-Hexahvdro-8-(hydroxymethyl)-8a-methoxy-5methyl-6-[2-(2-hydroxyethylamino)ethylamino]-azirino 12*,3' s3,4]pyrrolotlr2-a]indole-4,7-dione carbamate This compound was prepared by the procedure described in Example 1, except that the solvent was dichloromethane. From 50 mg of mitomycin A and 18 mg of 2-(2-aminoethylamino)ethanol was obtained 35 mg (58% yield) of the desired product having a melting point of 115°-118°C (decomposition) and providing the following analysis: NMR (CDCl^, TS): '6' values in ppm.
Absence of the 6-methoxy peak at 4.02 and the appearance of new peaks at 2.7 (broad s,7) and 3.7 (t,3).
Example 25 1, la, 2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxv-5methyl-6- [2- (2-hydroxyethqxyJethy^aminol-azirino [21/31;3,4] pyrrolo [1,2-a] indole-4,7-clione carbamate This compound was prepared by the procedure described in Example 1, except that the solvent was dichloromethane. From 60 mg of mitomycin A and 20 mg of 2-(2-arainoethoxy)ethanol was obtained 30 mg (42% yield) of the desired product having a melting point of 99°-102°C (decomposition) and providing the following analysis: NMR (CDCl^r TS): values in ppmAbsence of the 6-methoxy peak at 4.02 and the appearance of new peaks at 3.3-3.9 (broad s,9) and 6.4-6.8 (broad s,l).
Example 26 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5methyl-6- [ 2- 1 :TTU pyrrolo[1/2-a]indole-4T7-dione carbamate This compound was prepared by the procedure described in Example 1, except that 128 mg of sodium methoxide was added. From 70 mg of mitomycin A and 368 mg of histamine dihydrochloride was obtained 61 mg (71% yield) of the desired product having a melting point of 72°-73eC (decomposition) and providing the following analysis: NMR (DMSO-dg, TS): *6’ values in ppm.
Absence of the 6-methoxy peak at 4.02 and the appearance of new peaks at 3.0-3.27 (m,4), 7.5 (s,l), 8.0-8.7 (broad s,2) and 8.1 (s,l).
Example 27 1/la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy-5me thy1-6-ΐ(2-ni tro-1-imidaz oly 1)ethy1amino)-aziri no [2*,3f:3,4]pyrrolo[1,2-a]indole-4,7-dione carbamate This compound was prepared by the procedure described in Example 1. From 72 mg of mitomycin A and excess 1-(2-aminoethyl)-2-nitroimidasole was obtained 60 mg (70% yield) of the desired product having a melting point of 83®-85°C (decomposition) and providing the following analysis: NMR (CDCl^f TS): ’δ1 values in ppm.
Absence of the 6-methoxy peak at 4.02 and the appearance of new peaks at 3.4 (t,2), 4.6 (t,2), 7.3 (broad s,2) and 7.6 (s,l).
Example 28 1, la,2,8,8a,8b-Hexahvdro-8°(hydroxymethyl)-8a-methoxy-55 methvl-6-12- (4-hydroxyphenyij ethylamino] -azlrino[2 r,~3 Γ:~3,4 3 pyrrolo[1,2-a]indoie-4,7-dlone carbamate This compound was prepared by the procedure described in Example 1. From 130 mg of mitomycin A and 510 mg of tyramine was obtained 138 mg (81% yield) of 10 the desired product having a melting point of 120°125*C (decomposition) and providing the following analysis: NMR (CDClj, TS): '6' values in ppm.
Absence of the 6-methoxy peak at 4.02 and the appearance of new peaks at 2.6 (t,2), 2.8 (t,2), 6.7 (d,2), 7.0 (d,2) and 8.0 (s,l).
Example 29 1,1a ,.2,8,8a,8b-Hexahydro-8- (hydroxymethyl) -8a-methoxy-5methyl-6-[2- (3,4-dihydroxyphenyl)ethylamino) -azirfno 20 f2f, P :3,4]pyrrolo (T, 2-a]in^ole-4,7-dione carbamate This compound was prepared by the procedure described in Example 1, except that 138 mg of sodium methoxide was added. From 110 mg of mitomycin A and 660 mg of 3-hydroxytyramine hydrobromide was obtained 60 mg (40% yield) of the desired product decomposing without melting above 125°C and providing the following analysis: NMR (CDCl^, TS): *6 * values in ppm.
Absence of the 6-methoxy peak at 4.02 and the appearance of new peaks at 2.6 (t,2), 2.8 (t,2), 6-4-6.8 (m,3) and 8.3 (broad s,2).
Example 30 1,la,2,8,8a,8b-Hexahvdro-8-(hydroxymethyl)-8a^methoxy-5methyl-6-{2-[(5-nitro-2-pyridyl)amxnoTethylamino)-azirino [21,3':3,4]pyrroio[1,2-a]indole-4,7-dione carbamate This compound was prepared by the procedure described in Example 1, except that the solvent was dichlorornethane. From 50 mg of mitomycin A and 30 mg of 2-(2-aminoethylamino)-5-nitropyridine was obtained 40 mg (56% yield) of the desired product having a melting point of 76*-79°C (decomposition) and providing the following analysis: NMR (CDCl^, TS): *61 values in ppm.
Absence of the 6-methoxy peak at 4.02 and the appearance of new peaks at 3.3-4.0 (m,4), 6.2-6.7 (broad s,2), 8.1 (d,l), 8.2 (d,l) and 9.0 (s,l).
Example 31 1,la,2,8,8a,8b-Hexahvdro-8-(hydroxymethyl)-8a-methoxy-5methyl-6-[2-(1-piperazinyl)ethylamino]-azirino t21,33,4] pyrroloTi »2-a]indole-4,7-dione*carbamate This compound was prepared by the procedure described in Example 1, except that the solvent was dichlorornethane. From 50 mg of mitomycin A and 20 mg of N-(2-aminoethyl) piperazine was obtained 23 mg (36% yield) of the desired product having a melting point of 138®-141®C (decomposition) and providing the following analysis: NMR (CDCl^r TS): '6' values in ppm.
Absence of the 6-methoxy peak at 4.02 and the appearance of new peaks at 1.6-2.1 (broad s,l), 2.2-2.6 (broad s,8), 2.6-2.8 (broad s,4) and 6.9 (t,l) .
Example 32 1, la, 2,8,8a, 8b-Hexahvdro-8- (hydroxymethyl) -8a-methoxy-5methyl-6-[2-(2-pyridyl)ethylamino]-azirino(21,31:3,4] pyrrolo[1,2-a]indole-4,7-dione carbamate This compound was prepared by the procedure described in Example 1. From 70 mg of mitomycin A and 250 mg excess of 2-(2-aminoethyl)pyridine was obtained 51 mg (56% yield) of the desired product having a melting point of 64*-77°C (decomposition) and providing the following analysis: NMR (CDCl^, TS): '6' values in ppm.
Absence of the 6-methoxy peak at 4.02 and the appearance of new peaks at 2.8 (m,4), 7.0-7.8 (m,3) and 8.5 (d,l).
With specific reference to the compounds comprehended by formula Ilia, the above examples illustrate the following structural variations. 1. Compounds wherein Z is a hydroxy substituted 1-pyrrolidinyl radical represented by Example 1. 2. Compounds wherein Z is a lower alkyl substituted piperidyl radical represented by Example 2. 3. Compounds wherein z is an acetamino, acetyl, carbamido, cyano, carboxy lower alkylamino, di-lower alkoxy, nitro, sulfamyl or lower alkyl substituted anilino radical are represented, respectively, by Examples 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 and 16. 4. Compounds wherein Z is a radical of the formula R -i-R^ and wherein is a nitrogen containing heterocylic radical selected from amino substituted triasolyl, lower alkyl substituted isothiazolyl, benzothiazolyl and nitro and halo substituted derivatives of benzothiazolyl are represented, respectively, by Examples 17, 18, 19, 20 and 21.
. Compounds wherein Z is a radical of the formula R -N-R^ and wherein R^ is a substituted lower alkyl radical selected from amino lower alkyl, lower alkylamino lower alkyl, hydroxy lower alkylamino lower alkyl, hydroxy lower alkoxy lower alkyl, imidazolyl lower alkyl, nitro substituted imidazolyl lower alkyl, mono- and di-hydroxy phenyl lower alkyl, nitro substituted pyridylamino lower alkyl, piperazinyl lower alkyl and pyridyl ethyl are represented, respectively, by Examples 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 and 32.
While none of the foregoing Examples are illustrative of compounds wherein Y is other than hydrogen, compounds wherein ¥ is lower alkyl are nonetheless within the comprehension of the invention, reference being made to analogously substituted compounds of aforesaid U.S. Patent No. 4,268,676, co-pending patent application Serial No. 206,529 and Patent Specification No. 52956 Compounds according to the present invention are believed to possess anti-bacterial activity against gram-positive and gram-negative microorganisms in a manner similar to that observed for the naturally occurring mitomycins and are thus potentially useful as therapeutic agents in treating bacterial infections in humans and animals.
Usefulness of oanpounds of formula Ilia in the manufacture of medicaments for use in antlneoplastic therapeutic methods is demonstrated by the results of in vivo screening procedures wherein the compounds are administered in varying dosage amounts to mice in which a P388 leukemic condition is induced. The procedures were carried out according to Lymphocytic Leukemia P388 - Protocol 1.200", published in Cancer Chemotherapy Reports, Part 3, Vol. 3, No. 2, page 9 (September, 1972). Briefly put, the screening procedures involved administration of the test compound to CDF^ female mice previously infected with 10^ ascites cells implanted intraperitonealiy Test compounds were administered on the first day of testing only, and the animals were monitored for vitality, * inter alia> over a 35-day period.
Results of screening of compounds of Examples 1 through 32 are set forth in Table I below. Data given includes optimal dose (O.D."), i.e., that dosage in mg/kg of body weight of the animal at which the maximum therapeutic effects are consistently observed.
Also included is the median survival time (MST) expressed as the MST of the test animals compared to the MST of controls x 100 (% T/C). Within the context of the in vivo P388 procedure noted above, a % T/C value of 125 or greater indicates significant antineoplastic therapeutic activity. The lowest dose in mg/kg of body weight at which the 125% T/C value is obtained is known as the minimum effective dose (MED). These doses also are listed in Table I. It is worthy of note that the exceptionally high MST values obtained in the P388 screenings reported in Table I are also indicative of the absence of substantial toxicity of the compounds at the dosages indicated.
TABLE 1 Example NO. Optimal Dose mg/kg MST as % T/C MED 1 25.6 163 0.8 2 25.6 238 <0.2 3 12.8 200 0.2 4 25.6 >333 <0.2 5 25.6 231 0.2 6 6.4 167 0.4 7 25.6 194 1.6 8 3.2 150 0.8 9 12.8 172 <0.2 10 25.6 322 0.8 11 12.8 >333 0.2 12 6.4 161 0.4 13 3.2 172 >0.2 14 25.6 225 0.2 15 12.8 167 0.4 16 12.8 181 0.4 17 12.8 181 1.6 18 25.6 169 0.8 19 25.6 150 12.8 20 25.6 128 25.6 21 25.6 144 1.6 22 3.2 178 0.4 23 25.6 133 12.8 24 12.8 133 12.8 25 25.6 181 0.4 26 25.6 163 1.6 27 25.6 150 3.2 28 25.6 218 1.6 29 12.8 139 12.8 30 12.8 144 6.4 31 25.6 138 12.8 32 25.6 >375 0.2 Clearly among the most preferred compounds employed as antineoplastic agents according to the invention are those exhibiting more than twice the relative life-extending capacity generally characterized as evidencing significant therapeutic potential, i.e., those having an MST % T/C value greater than 2 x 125.
The class of such compounds is seen to include the compounds of Examples 4, 10, 11 and 32.
As may be noted from Table X, initial single dosages of as little as 0.2 mg/kg showed substantial long term antineoplastic activity. Accordingly, the methods of treatment may involve therapeutic administra tion of unit dosages of as little as 0.001 mg or as much as 5 mg, preferably from 0.004 mg to 10 mg, of the compounds as the active ingredient in a suitable pharmaceutical preparation. Such preparations may be administered in a daily regimen calling for from 0.1 mg to 100 mg per kg, preferably from about 0.2 to about 51.2 mg per kg, of the body weight of the animal suffering from neoplastic disease. It is preferred that the compounds be administered parenterally. Pharmaceutical compositions suitable for use in practice of methods of the invention may comprise simple water solutions of one or more of the compounds of formula Ilia, but may also include well known pharmaceutically acceptable diluents, adjuvants and/or carriers such as saline suitable for medicinal use.
Further aspects and advantages of the present invention are expected to occur to those skilled in the 30 art upon consideration of the foregoing description and consequently only such limitations as appear in the appended claims should be placed thereon.
Claims (11)
1. A compound of the formula. wherein: Y is hydrogen or lower alkyl; and X is an hydroxy substituted 1-pyrrolidinyl radical, or a lower alkyl substituted piperidyl radical, or an acetamino, acetyl, carbamide, cyano, carboxy lower alkylamino, di-lower alkoxy, nitro, or sulfamoyl substituted anilino radical, or R a radical of the formula, -Ij-R^ wherein R is hydrogen or lower alkyl and R 1 is a nitrogen containing heterocyclic radical selected from amino substituted triazolyl, lower alkyl substituted isothiazolyl, benzothiazolyl, and nitro and halo substituted derivatives of benzothiazolyl, or R 1 is a substituted lower alkyl radical selected from amino lower alkyl, lower alkylamino lower alkyl, hydroxy lower alkylamino lower alkyl, hydroxy lower alkoxy lower alkyl, imidazolyl lower alkyl, nitro substituted imidazolyl lower alkyl, mono- and di-hydroxy phenyl lower alkyl, nitro substituted pyridylamino lower alkyl, and piperazinyl lower alkyl.
2. A compound according to Claim 1 selected from: 1, la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-Same thoxy-5-me thy 1-6- (3-hydroxy-l-pyrrolidinyl) -azirino [2 1 ,3':3,4]pyrrolo(1,2-a]indole-4,7-dione carbamate; 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8amethoxy-5-methyl-6-(3-methylpiperidyl)-azirino[2' ,3' :3,4] pyrrolo[1,2-a]indole-4,7-dione carbamate ? 1,1a,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8amethoxy-5-methyl6-[4-(acetylamino)anilino]-azirino [2 1 ,3':3,4]pyrrolo(1,2-a]indole-4,7-dione carbamate; 1,1a,2,8,8a,8b-Hexahydro-8- (hydroxymethyl)-8amethoxy-5-methyl-6-[3-(acetylamino)anilino]-azirino [2 1 ,3':3,4]pyrrolo[1,2-a]indole-4,7-dione carbamate; 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8amethoxy-5-methyl-6-(4-acetylanilino)-azirino[2 1 ,3 1 :3,4] pyrrolo[1,2-aJ indole-4,7-dione carbamate; 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-Same thoxy-5-methyl-6- [4- (1-ureido)anilino]-azirino[2 1 ,3’:3,4] pyrrolo(1,2-a) indole-4,7-dione carbamate ? 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8amethoxy-5-methyl-6-(4-cyanoanilino)-azirino(2 1 ,3 1 :3,4] pyrrolo[1,2-a]indole-4,7-dione carbamate; 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8amethoxy-5-methyl-6-(3-cyanoanilino)-azirino[2’,3':3,4] pyrrolo[1,2-a)indole-4,7-dione carbamate; 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8amethoxy-5-methyl-6-[4-(N-glycyl)anilino]-azirino[2’, 3’:3,4] pyrrolo[1,2-a]indole-4,7-dione carbamate; 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8amethoxy-5-methyl-6-(3,4-dimethoxyanilino)-azirino[2 v ,3 f :3,4] pyrrolo[1,2-a]indole-4,7-dione carbamate; 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8amethoxy-5-methyl-6-(3,5-dimethoxyanilino)-azirino[2 1 ,3’:3,4] pyrrolo[1,2-a]indole-4,7-dione carbamate; 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8amethoxy-5-methyl-6-(4-nitroanilino)-azirino[2’,3’:3,4] pyrrolo[1,2-a]indole-4,7-dione carbamate; 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8amethoxy-5-methyl-6-(4-sulfamoylanilino)-azirino[2', 3';3,4] pyrrolo[1,2-a]indole-4,7-dione carbamate; 1,18,2,8,83,8b-Hexahydror8-(hydroxymethyl)-8amethoxy-5-methyl-6-[(5-amino-l,2,4-triazol-3-yl)amino]azirino[2',3’:3,4]pyrrolo[1,2-a]indole-4,7-dione carbamate; 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8amethoxy-5-methy1-6-[(3-methylisothiazol-5-yl)amino)-azirino [2 1 ,3':3,4]pyrrolo(1,2-a]indole-4,7-dione carbamate; 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8amethoxy-5-methyl-6-[(2-benzothiazolyl)amino]-azirino 12’,3 1 :3,4]pyrrolo[1,2-a]indole-4,7-dione carbamate; 1,1a,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a-methoxy5-methyl-6-[(6-nitrobenzothiazol-2-yl)amino)-azirino [2*,3’:3,4]pyrrolo[1,2-a]indole-4,7-dione carbamate; 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl) 8a-methoxy-5-methyl-6-[(4-chlorobenzothiazol-2-yl) amino]azirino[2 1 ,3 1 :3,4]pyrrolo [1,2-a]indole-4,7-dione carbamate; 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8amethoxy-5-methyl-6-[(2-aminoethyl)amino]-azirino[2',3',3,4] pyrrolo[1,2-a]indole-4,7-dione carbamate; 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8amethoxy-5-methyl-6-[methyl(2-methylaminoethyl)amino]-azirino [2',3':3,4]pyrrolo[l,2-a]indole-4,7-dione carbamate; 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-Same thoxy-5-methyl-6- [2- (2-hydroxyethylamino)ethylamino]azirino[2',3':3,4]pyrrolo[1,2-a]indole-4,7-dione carbamate? 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8amethoxy-5-methyl-6-[2-(2-hydroxyethoxy)ethylamino]-azirino [2',3*:3,4]pyrrolo[l,2-a]indole-4,7-dione carbamate; 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8amethoxy-5-methyl-6-[2-(4-imidazolyl)ethylamino]-azirino [2*,3’:3,4]pyrrolo[1,2-a]indole-4,7-dione carbamate; 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8amethoxy-5-methyl-6-[(2-nitro-l-imidazolyl)ethylamino]azirino[2 1 ,3 1 :3,4]pyrrolo[1,2-a]indole-4,7-dione carbamate; 1, la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8amethoxy-5-methyl-6-[2-(4-hydroxyphenyl)ethylamino]-azirino [2',3':3,4]pyrrolo[l,2-a]indole-4,7-dione carbamate; 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8a5 methoxy-5-methyl-6- [2-(3,4-dihydroxyphenyl)ethylamino]azirino[2',3':3,4]pyrrolo[1,2-a]indole-4,7-dione carbamate? 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8amethoxy-5-methyl-6-{2-[(5-nitro-2-pyridyl)amino]ethylamino} azirino[2',3':3,4]pyrrolo[1,2-a]indole-4,7-dione carbamate; 10 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8amethoxy-5-methyl-6-[2-(1-piperazinyl)ethylamino]-azirino [2*,3’:3,4]pyrrolo[1,2-a]indole-4,7-dione carbamate.
3. · A substance for use in the preparation of a 15 medicament for treatment of a neoplastic disease state in an animal, said substance comprising a therapeutically effective amount of a compound of the formula, wherein: Y is hydrogen or lower alkyl; and Z 20 is an hydroxy substituted 1-pyrrolidinyl radical, or a lower alkyl substituted piperidyl radical, or 2 5 an acetamino, acetyl, carbamido, cyano, carboxy lower alkylamino, dilower alkoxy, nitro, sulfamoyl, or lower alkyl substituted anilino radical, or 3^ R a radical of the formula, -N-R^ wherein R is hydrogen or lower alkyl and R 1 is a nitrogen containing heterocyclic radical selected from amino substituted triazolyl, lower alkyl substituted isothiazolyl, benzothiazolyl, and nitro and halo substituted derivatives of benzothia- * zolyl, or R 1 is a substituted lower alkyl radical selected from amino lower alkyl, lower * alkylamino lower alkyl, hydroxy lower alkylamino lower alkyl, hydroxy lower alkoxy lower alkyl, imidazolyl lower alkyl, nitro substituted imidazolyl lower alkyl, mono- and di-hydroxy phenyl lower alkyl, nitro substituted pvridylamino lower alkyl, piperazinyl lower alkyl, and 2-(pyridyl) ethyl.
4. A substance according to Claim. 3 wherein the compound is selected from: 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8amethoxy-5-methyl-6-(3-hydroxy-l-pyrrolidinyl)-azirino [2 1 ,3':3,4]pyrrolo(1,2-a)indole-4,7-dione carbamate; 1,la,2,8,8a,8b-Hexahydro-S-(hydroxymethyl)-8amethoxy-5-methyl-6-(3-methylpiperidyl)-azirino[2’,3’:3,4] pyrrolo[1,2-a]indole-4,7-dione carbamate? 1, la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8amethoxy-5-methyl-6-[4-(acetylamino)anilino]-azirino [2^3 1 :3,4]pyrrolo[ 1,2-a] indole-4,7-dione carbamate; 1,la,2,8,8a,3b-Hexahydro-8-(hydroxymethyl)-8amethoxy-5-methyl-6-[3-(acetylamino)anilino]-azirino [2^,3 1 :3,4]pyrrolo[1,2-a]indole-4,7-dione carbamate ? * 1, la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-3amethoxy-5-methyl-6-(4-acetylanilino)-azirino[2',3 1 :3,4] T pyrrolo[1,2-a]indole-4,7-dione carbamate; 1,1a,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8amethoxy-5-methyl-6-(4-(1-ureido)anilino]-azirino[2 1 ,3 1 :3,4) pyrrolo(1,2-a]indole-4,7-dione carbamate; 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8amethoxy-5-methyl-6- (4-cyanoanilino)-azirino[2 ^3^3,4] pyrrolo[1,2-a]indole-4,7-dione carbamate ? 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8amethoxy-5-methyl-6- (3-cyanoanilino) -azirino [2^3^3,4] pyrrolo[1,2-a]indole-4,7-dione carbamate; 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-eame thoxy -5-me thy 1-6- [4-(N-glycyl)anilino]-azirino[2 1 ,3 1 :3,4] pyrrolo[1,2-a]indole-4,7-dione carbamate? 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8amethoxy-5-methyl-6- (3,4-dimethoxyanilino)-azirino[2 1 ,3*:3,4] pyrrolo[1,2-a]indole-4,7-dione carbamate; 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8amethoxy-5-methyl-6-(3,5-dimethoxyanilino)-azirino[2 *,3 1 :3,4] pyrrolo[1,2-a]indole-4,7-dione carbamate ? 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8amethoxy-5-methyl-6- (4-nitroanilino)-azirino[2’,3’:3,4] pyrrolo[1,2-a]indole-4,7-dione carbamate; 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8amethoxy-5-methyl-6-(4-sulfamoyl anilino)-azirino(2’,3 * :3,4] pyrrolo[1,2-a]indole-4,7-dione carbamate; 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8amethoxy-5-methyl-6-(4-methylanilino)-azirino[2 1 ,3':3,4] pyrrolo[1,2-a]indole-4,7-dione carbamate; 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8amethoxy-5-methyl-6-(3-methylanilino)-azirinoI2 1 ,3':3,4] pyrrolo[1,2-a]indole-4,7-dione carbamate; 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl) -8amethoxy-5-methyl-6-[(5-amino-l,2,4-triazol-3-yl) amino]azirino[2',3 1 :3,4]pyrrolo[1,2-a]indole-4,7-dione carbamate; 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8amethoxy-5-methyl-6- [ (3-methylisothiazol-5-yl)amino]-azirino [2',3':3,4]pyrrolo(1,2-a]indole-4,7-dione carbamate? 1, la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)8a-methoxy-5-methyl-6-[(2-benzothiazolyl)amino]-azirino [2*,3’:3,4]pyrrolo[1,2-a]indole-4,7-dione carbamate? 1,la,2,8,8a,8b-Hexahyaro-8-(hydroxymethyl)-8amethoxy-5-methyl-6-I(6-nitrobenzothiazol-2-yl)amino]-azirino (2’,3’:3,4]pyrrolo[1,2-a]indole-4,7-dione carbamate? t 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8amethoxy-5-methyl-6-((4-chlorobenzothiazol-2-yl)amino]azirino[2*,3 1 :3,4]pyrrolo[1,2-a]indole-4,7-dione carbamate; ‘ 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8amethoxy-5-methyl-6-[(2-aminoethyl)amino]-azirino(2',3':3,4] pyrrolo[1,2-a]indole-4,7-dione carbamate; 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-Same thoxy-5-methyl-6- [methyl (2-methylaminoethyl) amino]-azirino [2 1 ,3’:3,4]pyrrolo[l,2-a]indole-4,7-dione carbamate? 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8amethoxy-5-methyl-6-(2-(2-hydroxyethylamino)ethylamino]azirino [2’,3 1 :3,4]pyrrolo[1,2-a]indole-4,7-dione carbamate; 1, la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8amethoxy-5-methy1-6-[2-(2-hydroxyethoxy)ethylamino]-azirino [2 1 ,3’:3,4]pyrrolo[1,2-a]indole-4,7-dione carbamate; 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8amethoxy-5-methy1-6-[2-(4-imidazolyl)ethylamino]-azirino [2’,3’:3,4]pyrrolo[1,2-a]indole-4,7-dione carbamate; 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8amethoxy-5-methyl-6-[(2-nitro-l-imidazolyl)ethylamino]azirino [2',3 β 23,4] pyrrolo [ 1,2-a] indole-4,7-dione carbamate; 1, la, 2,8,8a, 8b-Hexahydro-8- (hydroxymethyl) -Same thoxy-5-methyl-6- t2-(4-hydroxyphenyl)ethylamino]-azirino [2*,3':3,4]pyrrolo[1,2-a]indole-4,7-dione carbamate; 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-eame thoxy-5-me thy 1-6- [2-(3,4-dihydroxyphenyl)ethylamino]azirino[2',3':3,4]pyrrolo[1,2-a]indole-4,7-dione carbamate; » 1,la,2,8,8a,8b-Hexahydro-8-(hydroxymethyl)-8amethoxy-5-methyl-6-{2-[(5-nitro-2-pyridyl)amino]ethylamino)azirino[2',3 1 :3,4]pyrrolo[1,2-a]indole-4,7-dione carbamate ? 1,la,2,8,8a,8b-Hexahydro-8- (hydroxymethyl) -8amethoxy-5-methyl-6- [2- (2-pyridyl)ethylamino] -asirino [2' ,3' :3,4]pyrrolo[1,2-a]indole-4,7-dione carbamate. j 5. A substance according to claim 3 wherein the amount
5. Of the compound administered comprises a daily dose of from 0.2 mg to 51.2 mg per kg of the body weight of the animal.
6. A pharmaceutical composition for use in treatment of a neoplastic disease in an animal, said 10 composition comprising a pharmaceutically acceptable solvent, diluent, adjuvant or carrier and, as the active ingredient, from 0.001 to 5 mg of a compound of the formula 15 wherein: Y is hydrogen or lower alkyl; and Z is an hydroxy substituted 1-pyrrolidinyl radical, or a lower alkyl substituted piperidyl radical, 20 or an acetamino, acetyl, carbamido, cyano, carboxy lower alkylamino, di7 lower alkoxy, nitro, sulfamoyl, or lower alkyl substituted anilino radical, or R a radical of the formula, -N-R^ wherein R is hydrogen or lower alkyl and R 1 is a nitrogen containing heterocyclic radical selected from amino substituted triazolyl, lower alkyl substituted isothiazolyl, benzothiazolyl, and nitro, and halo substituted derivatives of benzothiazolyl, or r1 is a substituted lower alkyl radical selected from amino lower alkyl, lower alkylamino lower alkyl, hydroxy lower alkylamino lower alkyl, hydroxy lower alkoxy lower alkyl, imidazolyl lower alkyl, nitro substituted imidazolyl lower alkyl, mono- and di-hydroxy phenyl lower alkyl, nitro substituted pyridylamino lower alkyl, piperazinyl lower alkyl, and 2-(pyridyl)ethyl.
7. A compound of the formula (III) given and defined in Claim 1, which is any one of those specifically hereinbefore mentioned, other than those claimed in Claim 2.
8. A process for preparing a compound of the formula (III) given and defined in Claim 1, substantially as hereinbefore described vzith particular reference to the accompanying Examples.
9. A compound of the formula (III) given and defined in Claim 1, whenever prepared by a process claimed in Claim 8.
10. A substance according to Claim 3, substantially as hereinbefore described.
11. A pharmaceutical composition according to Claim 6, substantially as hereinbefore described.
Applications Claiming Priority (1)
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US46461283A | 1983-02-07 | 1983-02-07 |
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IE840272L IE840272L (en) | 1984-08-07 |
IE56814B1 true IE56814B1 (en) | 1991-12-18 |
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IE272/84A IE56814B1 (en) | 1983-02-07 | 1984-02-06 | Mitomycin analogs |
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JP (1) | JPS59152384A (en) |
KR (1) | KR900006854B1 (en) |
AT (1) | AT385509B (en) |
AU (1) | AU571193B2 (en) |
BE (1) | BE898856A (en) |
CA (1) | CA1252789A (en) |
CH (1) | CH658658A5 (en) |
DD (1) | DD233844A5 (en) |
DE (1) | DE3403922A1 (en) |
DK (1) | DK161890C (en) |
ES (1) | ES8607305A1 (en) |
FI (1) | FI80698C (en) |
FR (1) | FR2540500B1 (en) |
GB (1) | GB2134514B (en) |
GR (1) | GR81455B (en) |
HU (1) | HU190236B (en) |
IE (1) | IE56814B1 (en) |
IL (1) | IL70897A (en) |
IT (1) | IT1178855B (en) |
LU (1) | LU85199A1 (en) |
NL (1) | NL8400338A (en) |
NO (1) | NO161374C (en) |
NZ (1) | NZ206932A (en) |
OA (1) | OA07654A (en) |
PH (1) | PH20249A (en) |
PT (1) | PT78067B (en) |
SE (1) | SE461982B (en) |
YU (1) | YU44984B (en) |
ZA (1) | ZA84788B (en) |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
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US4487769A (en) * | 1982-06-04 | 1984-12-11 | Bristol-Myers Company | Amidines |
CA1282069C (en) * | 1985-09-12 | 1991-03-26 | Damon L. Meyer | Antibody complexes of hapten-modified diagnostic or therapeutic agents |
JPS63150282A (en) * | 1986-12-13 | 1988-06-22 | Kyowa Hakko Kogyo Co Ltd | Mitomycin derivative |
JPS63246379A (en) * | 1987-03-31 | 1988-10-13 | Kyowa Hakko Kogyo Co Ltd | 7-n,8-n-ethylenemitomycin 8-imines |
DE69127345D1 (en) * | 1990-11-13 | 1997-09-25 | Kyowa Hakko Kogyo Kk | Mitomycin derivatives |
Family Cites Families (7)
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US3332944A (en) * | 1964-11-02 | 1967-07-25 | American Cyanamid Co | Antibiotic derivatives of mitomycins a, b, c and porfiromycin |
JPS5439098A (en) * | 1977-08-31 | 1979-03-24 | Kyowa Hakko Kogyo Co Ltd | Mitomycin c derivatives |
US4268676A (en) * | 1979-12-05 | 1981-05-19 | University Patents, Inc. | Mitomycin analogs |
JPS5686184A (en) * | 1979-12-17 | 1981-07-13 | Kyowa Hakko Kogyo Co Ltd | Novel mitomycin c derivative |
NZ199617A (en) * | 1981-05-15 | 1985-08-30 | University Patents Inc | Azirino(2',3',:3,4)pyrrolo(1,2-a)indole-4,7-dione derivatives and pharmaceutical compositions |
US4487769A (en) * | 1982-06-04 | 1984-12-11 | Bristol-Myers Company | Amidines |
US4642352A (en) * | 1983-12-23 | 1987-02-10 | Bristol-Myers Company | Acylamino mitosanes |
-
1984
- 1984-01-25 NZ NZ206932A patent/NZ206932A/en unknown
- 1984-01-27 GB GB08402233A patent/GB2134514B/en not_active Expired
- 1984-02-02 ZA ZA84788A patent/ZA84788B/en unknown
- 1984-02-03 AU AU24073/84A patent/AU571193B2/en not_active Ceased
- 1984-02-03 NL NL8400338A patent/NL8400338A/en not_active Application Discontinuation
- 1984-02-04 DE DE19843403922 patent/DE3403922A1/en not_active Withdrawn
- 1984-02-06 DD DD84259885A patent/DD233844A5/en not_active IP Right Cessation
- 1984-02-06 GR GR73720A patent/GR81455B/el unknown
- 1984-02-06 NO NO840433A patent/NO161374C/en unknown
- 1984-02-06 HU HU84483A patent/HU190236B/en not_active IP Right Cessation
- 1984-02-06 DK DK052484A patent/DK161890C/en active
- 1984-02-06 ES ES529478A patent/ES8607305A1/en not_active Expired
- 1984-02-06 CH CH550/84A patent/CH658658A5/en not_active IP Right Cessation
- 1984-02-06 PT PT78067A patent/PT78067B/en not_active IP Right Cessation
- 1984-02-06 AT AT0037684A patent/AT385509B/en not_active IP Right Cessation
- 1984-02-06 IE IE272/84A patent/IE56814B1/en not_active IP Right Cessation
- 1984-02-06 CA CA000446811A patent/CA1252789A/en not_active Expired
- 1984-02-06 PH PH30204A patent/PH20249A/en unknown
- 1984-02-07 SE SE8400628A patent/SE461982B/en not_active IP Right Cessation
- 1984-02-07 FR FR8401845A patent/FR2540500B1/en not_active Expired
- 1984-02-07 IL IL70897A patent/IL70897A/en unknown
- 1984-02-07 JP JP59021505A patent/JPS59152384A/en active Pending
- 1984-02-07 FI FI840502A patent/FI80698C/en not_active IP Right Cessation
- 1984-02-07 OA OA58227A patent/OA07654A/en unknown
- 1984-02-07 BE BE0/212351A patent/BE898856A/en not_active IP Right Cessation
- 1984-02-07 KR KR1019840000574A patent/KR900006854B1/en not_active IP Right Cessation
- 1984-02-07 IT IT67113/84A patent/IT1178855B/en active
- 1984-02-07 YU YU217/84A patent/YU44984B/en unknown
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