NO333006B1 - Triheterosykliske forbindelser, farmasoytiske sammensetninger og fremgangsmate for fremstilling derav - Google Patents

Info

Publication number

NO333006B1

NO333006B1 NO20056057A NO20056057A NO333006B1 NO 333006 B1 NO333006 B1 NO 333006B1 NO 20056057 A NO20056057 A NO 20056057A NO 20056057 A NO20056057 A NO 20056057A NO 333006 B1 NO333006 B1 NO 333006B1

Authority

NO

Norway

Prior art keywords

pyrrol

dimethyl

ylmethylene

methoxy

compound

Prior art date

2003-05-30

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• 150000001875 compounds Chemical class 0.000 title claims abstract description 336
• 238000000034 method Methods 0.000 title claims abstract description 62
• 238000002360 preparation method Methods 0.000 title claims description 36
• 239000008194 pharmaceutical composition Substances 0.000 title claims description 4
• 206010028980 Neoplasm Diseases 0.000 claims abstract description 100
• 201000011510 cancer Diseases 0.000 claims abstract description 69
• -1 R n Chemical compound 0.000 claims description 46
• 239000003960 organic solvent Substances 0.000 claims description 39
• 241000282414 Homo sapiens Species 0.000 claims description 37
• 150000003839 salts Chemical class 0.000 claims description 30
• 238000011282 treatment Methods 0.000 claims description 30
• 125000000217 alkyl group Chemical group 0.000 claims description 26
• 239000002253 acid Substances 0.000 claims description 23
• OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 22
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 20
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 19
• 241001465754 Metazoa Species 0.000 claims description 17
• AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical class CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 14
• 239000002246 antineoplastic agent Substances 0.000 claims description 14
• 125000000623 heterocyclic group Chemical group 0.000 claims description 14
• 239000011734 sodium Substances 0.000 claims description 14
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 13
• 125000003118 aryl group Chemical group 0.000 claims description 13
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
• 125000004432 carbon atom Chemical group C* 0.000 claims description 12
• 229940127089 cytotoxic agent Drugs 0.000 claims description 10
• 239000003937 drug carrier Substances 0.000 claims description 10
• 229910052736 halogen Inorganic materials 0.000 claims description 9
• 125000002950 monocyclic group Chemical group 0.000 claims description 9
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
• 150000002367 halogens Chemical class 0.000 claims description 8
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 7
• 239000001301 oxygen Substances 0.000 claims description 7
• 229910052760 oxygen Inorganic materials 0.000 claims description 7
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 6
• 125000002619 bicyclic group Chemical group 0.000 claims description 6
• 125000005842 heteroatom Chemical group 0.000 claims description 6
• 229910052757 nitrogen Inorganic materials 0.000 claims description 6
• 229910052717 sulfur Chemical group 0.000 claims description 6
• 239000011593 sulfur Chemical group 0.000 claims description 6
• 150000003892 tartrate salts Chemical class 0.000 claims description 6
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
• 229910052708 sodium Inorganic materials 0.000 claims description 5
• VQMGACKMYHTCKF-UHFFFAOYSA-N N1C(C)=CC(C)=C1C=C1C(O)=CC(C=2NC3=CC=CC=C3C=2)=N1 Chemical compound N1C(C)=CC(C)=C1C=C1C(O)=CC(C=2NC3=CC=CC=C3C=2)=N1 VQMGACKMYHTCKF-UHFFFAOYSA-N 0.000 claims description 4
• QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
• 239000000010 aprotic solvent Substances 0.000 claims description 4
• 229910052744 lithium Inorganic materials 0.000 claims description 4
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
• 229910052700 potassium Inorganic materials 0.000 claims description 4
• 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 3
• 125000002947 alkylene group Chemical group 0.000 claims description 3
• 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 3
• 229910052792 caesium Inorganic materials 0.000 claims description 3
• 229910052799 carbon Inorganic materials 0.000 claims description 3
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
• 229910052701 rubidium Inorganic materials 0.000 claims description 3
• CVCLJVVBHYOXDC-OBPOFPIRSA-N (2z)-2-[5-[(3,5-dimethyl-1h-pyrrol-2-yl)methylidene]-4-methoxypyrrol-2-ylidene]indole Chemical compound COC1=C\C(=C/2N=C3C=CC=CC3=C\2)NC1=CC=1NC(C)=CC=1C CVCLJVVBHYOXDC-OBPOFPIRSA-N 0.000 claims description 2
• WFCZCBKVIVXNBH-UHFFFAOYSA-N 2,3-dihydroxypropyl 2-[5-[(3,5-dimethyl-1h-pyrrol-2-yl)methylidene]-4-methoxypyrrol-2-yl]indole-1-carboxylate Chemical compound COC1=CC(C=2N(C3=CC=CC=C3C=2)C(=O)OCC(O)CO)=NC1=CC=1NC(C)=CC=1C WFCZCBKVIVXNBH-UHFFFAOYSA-N 0.000 claims description 2
• CLNXHDSFEOZONO-UHFFFAOYSA-N 2-[2-[5-[(3,5-dimethyl-1h-pyrrol-2-yl)methylidene]-4-methoxypyrrol-2-yl]indol-1-yl]acetic acid Chemical compound COC1=CC(C=2N(C3=CC=CC=C3C=2)CC(O)=O)=NC1=CC=1NC(C)=CC=1C CLNXHDSFEOZONO-UHFFFAOYSA-N 0.000 claims description 2
• GAASVHJTPNDQKY-UHFFFAOYSA-N 2-[2-[5-[(3,5-dimethyl-1h-pyrrol-2-yl)methylidene]-4-methoxypyrrol-2-yl]indol-1-yl]ethanol Chemical compound COC1=CC(C=2N(C3=CC=CC=C3C=2)CCO)=NC1=CC=1NC(C)=CC=1C GAASVHJTPNDQKY-UHFFFAOYSA-N 0.000 claims description 2
• GXEKUWLFMWGRKX-UHFFFAOYSA-N 2-[5-[(3,5-dimethyl-1h-pyrrol-2-yl)methylidene]-4-methoxypyrrol-2-yl]-n,n-dimethylindole-1-carboxamide Chemical compound COC1=CC(C=2N(C3=CC=CC=C3C=2)C(=O)N(C)C)=NC1=CC=1NC(C)=CC=1C GXEKUWLFMWGRKX-UHFFFAOYSA-N 0.000 claims description 2
• NKTWKORNMRHVRY-UHFFFAOYSA-N 2-[5-[(3,5-dimethyl-1h-pyrrol-2-yl)methylidene]-4-methoxypyrrol-2-yl]-n-(4-phenylmethoxyphenyl)indole-1-carboxamide Chemical compound COC1=CC(C=2N(C3=CC=CC=C3C=2)C(=O)NC=2C=CC(OCC=3C=CC=CC=3)=CC=2)=NC1=CC=1NC(C)=CC=1C NKTWKORNMRHVRY-UHFFFAOYSA-N 0.000 claims description 2
• CORQRBLIPJANAT-UHFFFAOYSA-N 2-[5-[1-(3,5-dimethyl-1h-pyrrol-2-yl)ethylidene]-4-methoxypyrrol-2-yl]-1h-indole Chemical compound COC1=CC(C=2NC3=CC=CC=C3C=2)=NC1=C(C)C=1NC(C)=CC=1C CORQRBLIPJANAT-UHFFFAOYSA-N 0.000 claims description 2
• XKTYXVDYIKIYJP-UHFFFAOYSA-N 3h-dioxole Chemical compound C1OOC=C1 XKTYXVDYIKIYJP-UHFFFAOYSA-N 0.000 claims description 2
• SIXZEEGPJZXYLZ-UHFFFAOYSA-N 4-[[2-[5-[(3,5-dimethyl-1h-pyrrol-2-yl)methylidene]-4-methoxypyrrol-2-yl]indol-1-yl]methyl]phenol Chemical compound COC1=CC(C=2N(C3=CC=CC=C3C=2)CC=2C=CC(O)=CC=2)=NC1=CC=1NC(C)=CC=1C SIXZEEGPJZXYLZ-UHFFFAOYSA-N 0.000 claims description 2
• ZWPXCNKYMHUFEQ-UHFFFAOYSA-N CC(C)OC1=CC(=NC1=Cc1[nH]c(C)cc1C)c1[nH]c2ccccc2c1CCN1CCOCC1 Chemical compound CC(C)OC1=CC(=NC1=Cc1[nH]c(C)cc1C)c1[nH]c2ccccc2c1CCN1CCOCC1 ZWPXCNKYMHUFEQ-UHFFFAOYSA-N 0.000 claims description 2
• XQYGVAPFGUOCNT-UHFFFAOYSA-N CC(C)OC1=CC(C=2NC3=CC(Cl)=CC=C3C=2)=NC1=CC=1NC(C)=CC=1C Chemical compound CC(C)OC1=CC(C=2NC3=CC(Cl)=CC=C3C=2)=NC1=CC=1NC(C)=CC=1C XQYGVAPFGUOCNT-UHFFFAOYSA-N 0.000 claims description 2
• DCELYGDWNFTXKN-UHFFFAOYSA-N CC(C)OC1=CC(C=2NC3=CC(F)=CC=C3C=2)=NC1=CC=1NC(C)=CC=1C Chemical compound CC(C)OC1=CC(C=2NC3=CC(F)=CC=C3C=2)=NC1=CC=1NC(C)=CC=1C DCELYGDWNFTXKN-UHFFFAOYSA-N 0.000 claims description 2
• QTXPXUUNKMPPDR-UHFFFAOYSA-N CC(C)OC1=CC(C=2NC3=CC(O)=CC=C3C=2)=NC1=CC=1NC(C)=CC=1C Chemical compound CC(C)OC1=CC(C=2NC3=CC(O)=CC=C3C=2)=NC1=CC=1NC(C)=CC=1C QTXPXUUNKMPPDR-UHFFFAOYSA-N 0.000 claims description 2
• QCIGRJQCNQBLPU-UHFFFAOYSA-N CC(C)OC1=CC(C=2NC3=CC=C(F)C=C3C=2)=NC1=CC=1NC(C)=CC=1C Chemical compound CC(C)OC1=CC(C=2NC3=CC=C(F)C=C3C=2)=NC1=CC=1NC(C)=CC=1C QCIGRJQCNQBLPU-UHFFFAOYSA-N 0.000 claims description 2
• GOVQOMVHEFGMCB-UHFFFAOYSA-N CC(C)OC1=CC(C=2NC3=CC=CC(OC(=O)OC(C)(C)C)=C3C=2)=NC1=CC=1NC(C)=CC=1C Chemical compound CC(C)OC1=CC(C=2NC3=CC=CC(OC(=O)OC(C)(C)C)=C3C=2)=NC1=CC=1NC(C)=CC=1C GOVQOMVHEFGMCB-UHFFFAOYSA-N 0.000 claims description 2
• AOEDATGCLMVFJJ-UHFFFAOYSA-N CC(C)OC1=CC(C=2NC3=CC=CC=C3C=2)=NC1=CC=1NC(C)=CC=1C Chemical compound CC(C)OC1=CC(C=2NC3=CC=CC=C3C=2)=NC1=CC=1NC(C)=CC=1C AOEDATGCLMVFJJ-UHFFFAOYSA-N 0.000 claims description 2
• GBNPKRNTHHQKQR-UHFFFAOYSA-N CCOC1=CC(C2=C(C3=CC=CC=C3N2)CCC2NCCC2)=NC1=CC=1NC(C)=CC=1C Chemical compound CCOC1=CC(C2=C(C3=CC=CC=C3N2)CCC2NCCC2)=NC1=CC=1NC(C)=CC=1C GBNPKRNTHHQKQR-UHFFFAOYSA-N 0.000 claims description 2
• GRBKPOYYMOJPFH-UHFFFAOYSA-N CCOC1=CC(C2=C(C3=CC=CC=C3N2)CCN2CCOCC2)=NC1=CC=1NC(C)=CC=1C Chemical compound CCOC1=CC(C2=C(C3=CC=CC=C3N2)CCN2CCOCC2)=NC1=CC=1NC(C)=CC=1C GRBKPOYYMOJPFH-UHFFFAOYSA-N 0.000 claims description 2
• DOUWJWNVCULODD-UHFFFAOYSA-N CCOC1=CC(C=2NC3=CC=CC=C3C=2)=NC1=CC=1NC(C)=CC=1C Chemical compound CCOC1=CC(C=2NC3=CC=CC=C3C=2)=NC1=CC=1NC(C)=CC=1C DOUWJWNVCULODD-UHFFFAOYSA-N 0.000 claims description 2
• BWNVTBFOYWTWCY-UHFFFAOYSA-N COC(=O)CCC1=C(C)NC(C=C2C(=CC(=N2)C=2NC3=CC=CC=C3C=2)OC)=C1C Chemical compound COC(=O)CCC1=C(C)NC(C=C2C(=CC(=N2)C=2NC3=CC=CC=C3C=2)OC)=C1C BWNVTBFOYWTWCY-UHFFFAOYSA-N 0.000 claims description 2
• RKICCXUXLKBFOT-UHFFFAOYSA-N COC1=C(CO)C(=NC1=Cc1[nH]c(C)cc1C)c1[nH]c2ccccc2c1CNC(C)C Chemical compound COC1=C(CO)C(=NC1=Cc1[nH]c(C)cc1C)c1[nH]c2ccccc2c1CNC(C)C RKICCXUXLKBFOT-UHFFFAOYSA-N 0.000 claims description 2
• YFZKBFKNXAIVEE-UHFFFAOYSA-N COC1=CC(=NC1=Cc1[nH]c(C)c(I)c1C)c1cc2ccccc2[nH]1 Chemical compound COC1=CC(=NC1=Cc1[nH]c(C)c(I)c1C)c1cc2ccccc2[nH]1 YFZKBFKNXAIVEE-UHFFFAOYSA-N 0.000 claims description 2
• HEDSPHDQPNIXOS-UHFFFAOYSA-N COC1=CC(=NC1=Cc1[nH]c(C)cc1C)c1[nH]c2ccccc2c1CN1CCOCC1 Chemical compound COC1=CC(=NC1=Cc1[nH]c(C)cc1C)c1[nH]c2ccccc2c1CN1CCOCC1 HEDSPHDQPNIXOS-UHFFFAOYSA-N 0.000 claims description 2
• PWYRJZLIQWDOSY-UHFFFAOYSA-N COC1=CC(C2=C(C3=CC=CC=C3N2)C(=O)C2=COC=C2)=NC1=CC=1NC(C)=CC=1C Chemical compound COC1=CC(C2=C(C3=CC=CC=C3N2)C(=O)C2=COC=C2)=NC1=CC=1NC(C)=CC=1C PWYRJZLIQWDOSY-UHFFFAOYSA-N 0.000 claims description 2
• JAMRLDANBKIUKG-UHFFFAOYSA-N COC1=CC(C2=C(C3=CC=CC=C3N2)C(=O)C2=CSC=C2)=NC1=CC=1NC(C)=CC=1C Chemical compound COC1=CC(C2=C(C3=CC=CC=C3N2)C(=O)C2=CSC=C2)=NC1=CC=1NC(C)=CC=1C JAMRLDANBKIUKG-UHFFFAOYSA-N 0.000 claims description 2
• CDBPOHXJYGLRMQ-UHFFFAOYSA-N COC1=CC(C2=C(C3=CC=CC=C3N2)C(=O)C2=NOC=C2)=NC1=CC=1NC(C)=CC=1C Chemical compound COC1=CC(C2=C(C3=CC=CC=C3N2)C(=O)C2=NOC=C2)=NC1=CC=1NC(C)=CC=1C CDBPOHXJYGLRMQ-UHFFFAOYSA-N 0.000 claims description 2
• UDHUFFVBTLQHNU-UHFFFAOYSA-N COC1=CC(C2=C(C3=CC=CC=C3N2)C(=O)C=2SC(=CC=2)C=2N=CC=CC=2)=NC1=CC=1NC(C)=CC=1C Chemical compound COC1=CC(C2=C(C3=CC=CC=C3N2)C(=O)C=2SC(=CC=2)C=2N=CC=CC=2)=NC1=CC=1NC(C)=CC=1C UDHUFFVBTLQHNU-UHFFFAOYSA-N 0.000 claims description 2
• OOMJTSZVTRBRRD-UHFFFAOYSA-N COC1=CC(C2=C(C3=CC=CC=C3N2)C(=O)NCCCO)=NC1=CC=1NC(C)=CC=1C Chemical compound COC1=CC(C2=C(C3=CC=CC=C3N2)C(=O)NCCCO)=NC1=CC=1NC(C)=CC=1C OOMJTSZVTRBRRD-UHFFFAOYSA-N 0.000 claims description 2
• HTPSOSVHVJPAMO-UHFFFAOYSA-N COC1=CC(C2=C(C3=CC=CC=C3N2)C(O)=O)=NC1=CC=1NC(C)=CC=1C Chemical compound COC1=CC(C2=C(C3=CC=CC=C3N2)C(O)=O)=NC1=CC=1NC(C)=CC=1C HTPSOSVHVJPAMO-UHFFFAOYSA-N 0.000 claims description 2
• IPJHTKUCWVYJPD-UHFFFAOYSA-N COC1=CC(C2=C(C3=CC=CC=C3N2)C=O)=NC1=CC=1NC(C)=CC=1C Chemical compound COC1=CC(C2=C(C3=CC=CC=C3N2)C=O)=NC1=CC=1NC(C)=CC=1C IPJHTKUCWVYJPD-UHFFFAOYSA-N 0.000 claims description 2
• IDRUAJILWUUCOM-UHFFFAOYSA-N COC1=CC(C2=C(C3=CC=CC=C3N2)CN2CCN(CC2)C=2C=CC=CC=2)=NC1=CC=1NC(C)=CC=1C Chemical compound COC1=CC(C2=C(C3=CC=CC=C3N2)CN2CCN(CC2)C=2C=CC=CC=2)=NC1=CC=1NC(C)=CC=1C IDRUAJILWUUCOM-UHFFFAOYSA-N 0.000 claims description 2
• OLTJDOXTENYCGR-UHFFFAOYSA-N COC1=CC(C2=C(C3=CC=CC=C3N2)CO)=NC1=CC=1NC(C)=CC=1C Chemical compound COC1=CC(C2=C(C3=CC=CC=C3N2)CO)=NC1=CC=1NC(C)=CC=1C OLTJDOXTENYCGR-UHFFFAOYSA-N 0.000 claims description 2
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• YFOCIORIFDVNES-UHFFFAOYSA-N COC1=CC(C=2NC3=CC=CC=C3C=2)=NC1=CC=1NC(C)=C(CCCO)C=1C Chemical compound COC1=CC(C=2NC3=CC=CC=C3C=2)=NC1=CC=1NC(C)=C(CCCO)C=1C YFOCIORIFDVNES-UHFFFAOYSA-N 0.000 claims description 2
• YSMNYKQZMDHYMA-UHFFFAOYSA-N COC1=CC(C=2NC3=CC=CC=C3C=2)=NC1=CC=1NC=CC=1OC Chemical compound COC1=CC(C=2NC3=CC=CC=C3C=2)=NC1=CC=1NC=CC=1OC YSMNYKQZMDHYMA-UHFFFAOYSA-N 0.000 claims description 2
• OEKRNHNRVNAZGT-UHFFFAOYSA-N COC1=CC=CC(COC=2C(N=C(C=2)C=2NC3=CC=CC=C3C=2)=CC2=C(C=C(C)N2)C)=C1 Chemical compound COC1=CC=CC(COC=2C(N=C(C=2)C=2NC3=CC=CC=C3C=2)=CC2=C(C=C(C)N2)C)=C1 OEKRNHNRVNAZGT-UHFFFAOYSA-N 0.000 claims description 2
• CGGAFBHTZTVFPT-UHFFFAOYSA-N N1C2=CC=CC=C2C(C(=O)CCCC(=O)OC)=C1C(C=C1OC)=NC1=CC=1NC(C)=CC=1C Chemical compound N1C2=CC=CC=C2C(C(=O)CCCC(=O)OC)=C1C(C=C1OC)=NC1=CC=1NC(C)=CC=1C CGGAFBHTZTVFPT-UHFFFAOYSA-N 0.000 claims description 2
• HXPAKEYMZGMSMG-UHFFFAOYSA-N N1C2=CC=CC=C2C(CNC)=C1C(C(=C1OC)CO)=NC1=CC=1NC(C)=CC=1C Chemical compound N1C2=CC=CC=C2C(CNC)=C1C(C(=C1OC)CO)=NC1=CC=1NC(C)=CC=1C HXPAKEYMZGMSMG-UHFFFAOYSA-N 0.000 claims description 2
• HWDJOGLEPVATBT-UHFFFAOYSA-N [2-[5-[(3,5-dimethyl-1h-pyrrol-2-yl)methylidene]-4-methoxypyrrol-2-yl]indol-1-yl]-phenylmethanone Chemical compound COC1=CC(C=2N(C3=CC=CC=C3C=2)C(=O)C=2C=CC=CC=2)=NC1=CC=1NC(C)=CC=1C HWDJOGLEPVATBT-UHFFFAOYSA-N 0.000 claims description 2
• ITSLQTNJPPKRJO-UHFFFAOYSA-N [2-[5-[(3,5-dimethyl-1h-pyrrol-2-yl)methylidene]-4-methoxypyrrol-2-yl]indol-1-yl]methyl 2,2-dimethylpropanoate Chemical compound COC1=CC(C=2N(C3=CC=CC=C3C=2)COC(=O)C(C)(C)C)=NC1=CC=1NC(C)=CC=1C ITSLQTNJPPKRJO-UHFFFAOYSA-N 0.000 claims description 2
• SIKJAQJRHWYJAI-UHFFFAOYSA-N benzopyrrole Natural products C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 2
• 125000004494 ethyl ester group Chemical group 0.000 claims description 2
• PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 2
• RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 2
• ROSDSFDQCJNGOL-UHFFFAOYSA-N protonated dimethyl amine Natural products CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims description 2
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