HRP20050115A2 - Combinations of drugs for the treatment of neoplasms - Google Patents

Info

Publication number

HRP20050115A2

HRP20050115A2 HR20050115A HRP20050115A HRP20050115A2 HR P20050115 A2 HRP20050115 A2 HR P20050115A2 HR 20050115 A HR20050115 A HR 20050115A HR P20050115 A HRP20050115 A HR P20050115A HR P20050115 A2 HRP20050115 A2 HR P20050115A2

Authority

HR

Croatia

Prior art keywords

bis

alkyl

furan

benzimidazolyl

independently

Prior art date

2002-07-11

Links

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• Global Dossier
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• 206010028980 Neoplasm Diseases 0.000 title claims description 120
• 238000011282 treatment Methods 0.000 title claims description 46
• 239000003814 drug Substances 0.000 title description 16
• 229940079593 drug Drugs 0.000 title description 14
• YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 158
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 113
• 150000001875 compounds Chemical class 0.000 claims description 100
• XDRYMKDFEDOLFX-UHFFFAOYSA-N pentamidine Chemical compound C1=CC(C(=N)N)=CC=C1OCCCCCOC1=CC=C(C(N)=N)C=C1 XDRYMKDFEDOLFX-UHFFFAOYSA-N 0.000 claims description 78
• 238000000034 method Methods 0.000 claims description 72
• ZPEIMTDSQAKGNT-UHFFFAOYSA-N chlorpromazine Chemical compound C1=C(Cl)C=C2N(CCCN(C)C)C3=CC=CC=C3SC2=C1 ZPEIMTDSQAKGNT-UHFFFAOYSA-N 0.000 claims description 66
• 125000003118 aryl group Chemical group 0.000 claims description 64
• 229960004448 pentamidine Drugs 0.000 claims description 57
• 125000003545 alkoxy group Chemical group 0.000 claims description 54
• 229960001076 chlorpromazine Drugs 0.000 claims description 53
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 49
• 208000035269 cancer or benign tumor Diseases 0.000 claims description 49
• 229910052799 carbon Inorganic materials 0.000 claims description 49
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 47
• 229910052736 halogen Inorganic materials 0.000 claims description 41
• 150000002367 halogens Chemical class 0.000 claims description 41
• 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 38
• 230000001028 anti-proliverative effect Effects 0.000 claims description 37
• 239000003795 chemical substances by application Substances 0.000 claims description 36
• -1 chlorphenerazine Chemical compound 0.000 claims description 36
• 201000011510 cancer Diseases 0.000 claims description 35
• 210000004027 cell Anatomy 0.000 claims description 34
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 33
• KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 32
• 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 29
• 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 28
• ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 claims description 24
• 125000004104 aryloxy group Chemical group 0.000 claims description 22
• 150000003839 salts Chemical class 0.000 claims description 20
• 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 17
• PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 claims description 16
• 239000003112 inhibitor Substances 0.000 claims description 16
• 229910052760 oxygen Inorganic materials 0.000 claims description 16
• 230000012010 growth Effects 0.000 claims description 15
• OFBQJSOFQDEBGM-UHFFFAOYSA-N n-pentane Natural products CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims description 13
• JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical compound O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 claims description 12
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 12
• 208000020816 lung neoplasm Diseases 0.000 claims description 12
• 239000001294 propane Substances 0.000 claims description 12
• 238000002560 therapeutic procedure Methods 0.000 claims description 11
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 10
• 238000011161 development Methods 0.000 claims description 10
• 229910052731 fluorine Inorganic materials 0.000 claims description 10
• 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 10
• MMURVNDSFNJHAM-OWOJBTEDSA-N 4-[(e)-2-(4-carbamimidoylphenyl)ethenyl]benzenecarboximidamide Chemical compound C1=CC(C(=N)N)=CC=C1\C=C\C1=CC=C(C(N)=N)C=C1 MMURVNDSFNJHAM-OWOJBTEDSA-N 0.000 claims description 9
• ZJHZBDRZEZEDGB-UHFFFAOYSA-N 4-[5-(4-carbamimidoylphenyl)furan-2-yl]benzenecarboximidamide Chemical compound C1=CC(C(=N)N)=CC=C1C1=CC=C(C=2C=CC(=CC=2)C(N)=N)O1 ZJHZBDRZEZEDGB-UHFFFAOYSA-N 0.000 claims description 9
• 229930012538 Paclitaxel Natural products 0.000 claims description 9
• RGCVKNLCSQQDEP-UHFFFAOYSA-N Perphenazine Chemical compound C1CN(CCO)CCN1CCCN1C2=CC(Cl)=CC=C2SC2=CC=CC=C21 RGCVKNLCSQQDEP-UHFFFAOYSA-N 0.000 claims description 9
• 125000003710 aryl alkyl group Chemical group 0.000 claims description 9
• 229910052794 bromium Inorganic materials 0.000 claims description 9
• 239000001273 butane Substances 0.000 claims description 9
• TUESWZZJYCLFNL-DAFODLJHSA-N chembl1301 Chemical compound C1=CC(C(=N)N)=CC=C1\C=C\C1=CC=C(C(N)=N)C=C1O TUESWZZJYCLFNL-DAFODLJHSA-N 0.000 claims description 9
• 229910052801 chlorine Inorganic materials 0.000 claims description 9
• 229910052739 hydrogen Inorganic materials 0.000 claims description 9
• 230000002401 inhibitory effect Effects 0.000 claims description 9
• 229960001592 paclitaxel Drugs 0.000 claims description 9
• 229960000762 perphenazine Drugs 0.000 claims description 9
• 125000006678 phenoxycarbonyl group Chemical group 0.000 claims description 9
• 150000005353 phenylfurans Chemical class 0.000 claims description 9
• RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 claims description 9
• 201000009030 Carcinoma Diseases 0.000 claims description 8
• PWWVAXIEGOYWEE-UHFFFAOYSA-N Isophenergan Chemical compound C1=CC=C2N(CC(C)N(C)C)C3=CC=CC=C3SC2=C1 PWWVAXIEGOYWEE-UHFFFAOYSA-N 0.000 claims description 8
• YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 8
• 208000009956 adenocarcinoma Diseases 0.000 claims description 8
• 238000002512 chemotherapy Methods 0.000 claims description 8
• 229950005911 hydroxystilbamidine Drugs 0.000 claims description 8
• VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 claims description 8
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 8
• 229960003910 promethazine Drugs 0.000 claims description 8
• 229910052717 sulfur Inorganic materials 0.000 claims description 8
• SWMNGXODFOCPKQ-BTJKTKAUSA-N (z)-but-2-enedioic acid;n'-methoxy-4-[5-[4-[(z)-n'-methoxycarbamimidoyl]phenyl]furan-2-yl]benzenecarboximidamide Chemical compound OC(=O)\C=C/C(O)=O.C1=CC(C(=N)NOC)=CC=C1C1=CC=C(C=2C=CC(=CC=2)C(=N)NOC)O1 SWMNGXODFOCPKQ-BTJKTKAUSA-N 0.000 claims description 7
• KXHZWUUTWSKONE-UHFFFAOYSA-N 4-[4-(4-carbamimidoylphenoxy)butoxy]benzenecarboximidamide Chemical compound C1=CC(C(=N)N)=CC=C1OCCCCOC1=CC=C(C(N)=N)C=C1 KXHZWUUTWSKONE-UHFFFAOYSA-N 0.000 claims description 7
• UYPLKQKDGJVOME-UHFFFAOYSA-N 4-[4-(4-carbamimidoylphenyl)thiophen-2-yl]benzenecarboximidamide Chemical compound C1=CC(C(=N)N)=CC=C1C1=CSC(C=2C=CC(=CC=2)C(N)=N)=C1 UYPLKQKDGJVOME-UHFFFAOYSA-N 0.000 claims description 7
• IUJKKCRARYRWFG-UHFFFAOYSA-N 4-[7-(4-carbamimidoylphenoxy)heptoxy]benzenecarboximidamide Chemical compound C1=CC(C(=N)N)=CC=C1OCCCCCCCOC1=CC=C(C(N)=N)C=C1 IUJKKCRARYRWFG-UHFFFAOYSA-N 0.000 claims description 7
• CFQYOTZLYKJVKS-UHFFFAOYSA-N 4-[9-(4-carbamimidoylphenoxy)nonoxy]benzenecarboximidamide Chemical compound C1=CC(C(=N)N)=CC=C1OCCCCCCCCCOC1=CC=C(C(N)=N)C=C1 CFQYOTZLYKJVKS-UHFFFAOYSA-N 0.000 claims description 7
• 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 7
• KLBQZWRITKRQQV-UHFFFAOYSA-N Thioridazine Chemical compound C12=CC(SC)=CC=C2SC2=CC=CC=C2N1CCC1CCCCN1C KLBQZWRITKRQQV-UHFFFAOYSA-N 0.000 claims description 7
• GMJFVGRUYJHMCO-UHFFFAOYSA-N dibrompropamidine Chemical compound BrC1=CC(C(=N)N)=CC=C1OCCCOC1=CC=C(C(N)=N)C=C1Br GMJFVGRUYJHMCO-UHFFFAOYSA-N 0.000 claims description 7
• 229960000493 dibrompropamidine Drugs 0.000 claims description 7
• XNYZHCFCZNMTFY-UHFFFAOYSA-N diminazene Chemical compound C1=CC(C(=N)N)=CC=C1N\N=N\C1=CC=C(C(N)=N)C=C1 XNYZHCFCZNMTFY-UHFFFAOYSA-N 0.000 claims description 7
• 229950007095 diminazene Drugs 0.000 claims description 7
• DMABBVCVVXMJDH-UHFFFAOYSA-N phenamidine Chemical compound C1=CC(C(=N)N)=CC=C1OC1=CC=C(C(N)=N)C=C1 DMABBVCVVXMJDH-UHFFFAOYSA-N 0.000 claims description 7
• WIKYUJGCLQQFNW-UHFFFAOYSA-N prochlorperazine Chemical compound C1CN(C)CCN1CCCN1C2=CC(Cl)=CC=C2SC2=CC=CC=C21 WIKYUJGCLQQFNW-UHFFFAOYSA-N 0.000 claims description 7
• 229960003111 prochlorperazine Drugs 0.000 claims description 7
• WTFXJFJYEJZMFO-UHFFFAOYSA-N propamidine Chemical compound C1=CC(C(=N)N)=CC=C1OCCCOC1=CC=C(C(N)=N)C=C1 WTFXJFJYEJZMFO-UHFFFAOYSA-N 0.000 claims description 7
• 229960003761 propamidine Drugs 0.000 claims description 7
• 229960002784 thioridazine Drugs 0.000 claims description 7
• 229960002324 trifluoperazine Drugs 0.000 claims description 7
• ZEWQUBUPAILYHI-UHFFFAOYSA-N trifluoperazine Chemical compound C1CN(C)CCN1CCCN1C2=CC(C(F)(F)F)=CC=C2SC2=CC=CC=C21 ZEWQUBUPAILYHI-UHFFFAOYSA-N 0.000 claims description 7
• IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical compound C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 claims description 6
• YHFXGBOUSIKGMZ-UHFFFAOYSA-N 3-(2-chloro-10-phenothiazinyl)-N-methyl-1-propanamine Chemical compound C1=C(Cl)C=C2N(CCCNC)C3=CC=CC=C3SC2=C1 YHFXGBOUSIKGMZ-UHFFFAOYSA-N 0.000 claims description 6
• 208000031261 Acute myeloid leukaemia Diseases 0.000 claims description 6
• PLDUPXSUYLZYBN-UHFFFAOYSA-N Fluphenazine Chemical compound C1CN(CCO)CCN1CCCN1C2=CC(C(F)(F)F)=CC=C2SC2=CC=CC=C21 PLDUPXSUYLZYBN-UHFFFAOYSA-N 0.000 claims description 6
• 208000017604 Hodgkin disease Diseases 0.000 claims description 6
• 208000010747 Hodgkins lymphoma Diseases 0.000 claims description 6
• 208000033776 Myeloid Acute Leukemia Diseases 0.000 claims description 6
• 206010033128 Ovarian cancer Diseases 0.000 claims description 6
• 206010061535 Ovarian neoplasm Diseases 0.000 claims description 6
• 229960005054 acepromazine Drugs 0.000 claims description 6
• NOSIYYJFMPDDSA-UHFFFAOYSA-N acepromazine Chemical compound C1=C(C(C)=O)C=C2N(CCCN(C)C)C3=CC=CC=C3SC2=C1 NOSIYYJFMPDDSA-UHFFFAOYSA-N 0.000 claims description 6
• SLFGIOIONGJGRT-UHFFFAOYSA-N cyamemazine Chemical compound C1=C(C#N)C=C2N(CC(CN(C)C)C)C3=CC=CC=C3SC2=C1 SLFGIOIONGJGRT-UHFFFAOYSA-N 0.000 claims description 6
• 229960004278 cyamemazine Drugs 0.000 claims description 6
• 108010051357 endoexonuclease Proteins 0.000 claims description 6
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• 201000005202 lung cancer Diseases 0.000 claims description 6
• 229950008620 methopromazine Drugs 0.000 claims description 6
• VRQVVMDWGGWHTJ-CQSZACIVSA-N methotrimeprazine Chemical compound C1=CC=C2N(C[C@H](C)CN(C)C)C3=CC(OC)=CC=C3SC2=C1 VRQVVMDWGGWHTJ-CQSZACIVSA-N 0.000 claims description 6
• 229940042053 methotrimeprazine Drugs 0.000 claims description 6
• NELCSOKBRZAQRH-UHFFFAOYSA-N n'-hydroxy-4-[3-[4-(n'-hydroxycarbamimidoyl)-2-methoxyphenoxy]propoxy]-3-methoxybenzenecarboximidamide Chemical compound COC1=CC(C(\N)=N/O)=CC=C1OCCCOC1=CC=C(C(\N)=N/O)C=C1OC NELCSOKBRZAQRH-UHFFFAOYSA-N 0.000 claims description 6
• IJDNQMDRQITEOD-UHFFFAOYSA-N n-butane Chemical compound CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 claims description 6
• CBHCDHNUZWWAPP-UHFFFAOYSA-N pecazine Chemical compound C1N(C)CCCC1CN1C2=CC=CC=C2SC2=CC=CC=C21 CBHCDHNUZWWAPP-UHFFFAOYSA-N 0.000 claims description 6
• 229950007538 pecazine Drugs 0.000 claims description 6
• WEYVCQFUGFRXOM-UHFFFAOYSA-N perazine Chemical compound C1CN(C)CCN1CCCN1C2=CC=CC=C2SC2=CC=CC=C21 WEYVCQFUGFRXOM-UHFFFAOYSA-N 0.000 claims description 6
• 229960002195 perazine Drugs 0.000 claims description 6
• 239000003801 protein tyrosine phosphatase 1B inhibitor Substances 0.000 claims description 6
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 6
• XCTYLCDETUVOIP-UHFFFAOYSA-N thiethylperazine Chemical compound C12=CC(SCC)=CC=C2SC2=CC=CC=C2N1CCCN1CCN(C)CC1 XCTYLCDETUVOIP-UHFFFAOYSA-N 0.000 claims description 6
• 229960004869 thiethylperazine Drugs 0.000 claims description 6
• 229960004728 thiopropazate Drugs 0.000 claims description 6
• AIUHRQHVWSUTGJ-UHFFFAOYSA-N thiopropazate Chemical compound C1CN(CCOC(=O)C)CCN1CCCN1C2=CC(Cl)=CC=C2SC2=CC=CC=C21 AIUHRQHVWSUTGJ-UHFFFAOYSA-N 0.000 claims description 6
• 125000004174 2-benzimidazolyl group Chemical group [H]N1C(*)=NC2=C([H])C([H])=C([H])C([H])=C12 0.000 claims description 5
• UHNLSPPEMSHVID-UHFFFAOYSA-N 4-[5-(4-carbamimidoylphenyl)thiophen-2-yl]benzenecarboximidamide Chemical compound C1=CC(C(=N)N)=CC=C1C1=CC=C(C=2C=CC(=CC=2)C(N)=N)S1 UHNLSPPEMSHVID-UHFFFAOYSA-N 0.000 claims description 5
• GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 claims description 5
• 125000002252 acyl group Chemical group 0.000 claims description 5
• 229960002949 fluorouracil Drugs 0.000 claims description 5
• MNWFXJYAOYHMED-UHFFFAOYSA-M heptanoate Chemical compound CCCCCCC([O-])=O MNWFXJYAOYHMED-UHFFFAOYSA-M 0.000 claims description 5
• BRABPYPSZVCCLR-UHFFFAOYSA-N methopromazine Chemical compound C1=CC=C2N(CCCN(C)C)C3=CC(OC)=CC=C3SC2=C1 BRABPYPSZVCCLR-UHFFFAOYSA-N 0.000 claims description 5
• 238000002360 preparation method Methods 0.000 claims description 5
• 229960003904 triflupromazine Drugs 0.000 claims description 5
• XSCGXQMFQXDFCW-UHFFFAOYSA-N triflupromazine Chemical compound C1=C(C(F)(F)F)C=C2N(CCCN(C)C)C3=CC=CC=C3SC2=C1 XSCGXQMFQXDFCW-UHFFFAOYSA-N 0.000 claims description 5
• KRUVSRGJKCHYMY-UHFFFAOYSA-N 1,3-bis(3-carbamimidoylphenyl)urea Chemical compound NC(=N)C1=CC=CC(NC(=O)NC=2C=C(C=CC=2)C(N)=N)=C1 KRUVSRGJKCHYMY-UHFFFAOYSA-N 0.000 claims description 4
• UVOIBTBFPOZKGP-CQSZACIVSA-N 1-[10-[(2r)-2-(dimethylamino)propyl]phenothiazin-2-yl]propan-1-one Chemical compound C1=CC=C2N(C[C@@H](C)N(C)C)C3=CC(C(=O)CC)=CC=C3SC2=C1 UVOIBTBFPOZKGP-CQSZACIVSA-N 0.000 claims description 4
• 101710175516 14 kDa zinc-binding protein Proteins 0.000 claims description 4
• YBEQGLWWCCCCRA-UHFFFAOYSA-N 4-[3-(4-carbamimidoyl-2-methoxyphenoxy)propoxy]-3-methoxybenzenecarboximidamide Chemical compound COC1=CC(C(N)=N)=CC=C1OCCCOC1=CC=C(C(N)=N)C=C1OC YBEQGLWWCCCCRA-UHFFFAOYSA-N 0.000 claims description 4
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• OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 claims description 4
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