KR20020063215A - 세포 증식 저해용 치환된 비신돌일말레이미드 - Google Patents
세포 증식 저해용 치환된 비신돌일말레이미드 Download PDFInfo
- Publication number
- KR20020063215A KR20020063215A KR1020027007517A KR20027007517A KR20020063215A KR 20020063215 A KR20020063215 A KR 20020063215A KR 1020027007517 A KR1020027007517 A KR 1020027007517A KR 20027007517 A KR20027007517 A KR 20027007517A KR 20020063215 A KR20020063215 A KR 20020063215A
- Authority
- KR
- South Korea
- Prior art keywords
- indol
- compound
- methyl
- nitro
- group
- Prior art date
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- 150000003924 bisindolylmaleimides Chemical class 0.000 title 1
- 230000035407 negative regulation of cell proliferation Effects 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 91
- 238000000034 method Methods 0.000 claims abstract description 31
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 20
- 150000003839 salts Chemical class 0.000 claims abstract description 20
- 238000011282 treatment Methods 0.000 claims abstract description 15
- 201000011510 cancer Diseases 0.000 claims abstract description 13
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 9
- 230000002062 proliferating effect Effects 0.000 claims abstract description 7
- 201000010099 disease Diseases 0.000 claims abstract description 6
- -1 -OPO 3 R 1 R 2 Chemical group 0.000 claims description 42
- 229920001223 polyethylene glycol Polymers 0.000 claims description 27
- 239000002202 Polyethylene glycol Substances 0.000 claims description 26
- 125000000217 alkyl group Chemical group 0.000 claims description 24
- 150000002148 esters Chemical class 0.000 claims description 12
- 125000003118 aryl group Chemical group 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
- 125000003545 alkoxy group Chemical group 0.000 claims description 9
- 125000005842 heteroatom Chemical group 0.000 claims description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 125000001424 substituent group Chemical group 0.000 claims description 7
- 208000026310 Breast neoplasm Diseases 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- 229910052708 sodium Inorganic materials 0.000 claims description 6
- KOLMZGIDCNVGEI-UHFFFAOYSA-N 3-[(diethylazaniumyl)methyl]benzoate Chemical compound CCN(CC)CC1=CC=CC(C(O)=O)=C1 KOLMZGIDCNVGEI-UHFFFAOYSA-N 0.000 claims description 5
- 210000000481 breast Anatomy 0.000 claims description 5
- 208000029742 colonic neoplasm Diseases 0.000 claims description 5
- 125000000623 heterocyclic group Chemical group 0.000 claims description 5
- 239000000463 material Substances 0.000 claims description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 4
- 238000007911 parenteral administration Methods 0.000 claims description 4
- 239000007858 starting material Substances 0.000 claims description 4
- 206010006187 Breast cancer Diseases 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- WYMBAXXKZCFUSW-UHFFFAOYSA-N 1-[3-[4-(1-methyl-6-nitroindol-3-yl)-2,5-dioxopyrrol-3-yl]indol-1-yl]ethyl 2,3-dimethoxybenzoate Chemical compound COC1=CC=CC(C(=O)OC(C)N2C3=CC=CC=C3C(C=3C(NC(=O)C=3C=3C4=CC=C(C=C4N(C)C=3)[N+]([O-])=O)=O)=C2)=C1OC WYMBAXXKZCFUSW-UHFFFAOYSA-N 0.000 claims description 2
- DYLSWJXYQRWEHW-UHFFFAOYSA-N 3-(1-acetylindol-3-yl)-4-(1-methyl-6-nitroindol-3-yl)pyrrole-2,5-dione Chemical compound C12=CC=CC=C2N(C(=O)C)C=C1C1=C(C=2C3=CC=C(C=C3N(C)C=2)[N+]([O-])=O)C(=O)NC1=O DYLSWJXYQRWEHW-UHFFFAOYSA-N 0.000 claims description 2
- KKEQIEIAWWPILV-UHFFFAOYSA-N 3-(1h-indol-3-yl)-4-(1-methyl-6-nitroindol-3-yl)-1-octadec-9-enoylpyrrole-2,5-dione Chemical compound C1=CC=C2C(C=3C(=O)N(C(C=3C=3C4=CC=C(C=C4N(C)C=3)[N+]([O-])=O)=O)C(=O)CCCCCCCC=CCCCCCCCC)=CNC2=C1 KKEQIEIAWWPILV-UHFFFAOYSA-N 0.000 claims description 2
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 2
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 2
- 206010009944 Colon cancer Diseases 0.000 claims description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims description 2
- 125000005018 aryl alkenyl group Chemical group 0.000 claims description 2
- 210000001072 colon Anatomy 0.000 claims description 2
- 201000005202 lung cancer Diseases 0.000 claims description 2
- 208000020816 lung neoplasm Diseases 0.000 claims description 2
- 150000004702 methyl esters Chemical class 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 abstract description 3
- 150000003233 pyrroles Chemical class 0.000 abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 38
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 38
- 239000000243 solution Substances 0.000 description 34
- 239000000203 mixture Substances 0.000 description 26
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- 235000019439 ethyl acetate Nutrition 0.000 description 17
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 17
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- 239000002904 solvent Substances 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 11
- 210000004027 cell Anatomy 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- 229940126062 Compound A Drugs 0.000 description 8
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 8
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 239000002253 acid Substances 0.000 description 7
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- 238000003818 flash chromatography Methods 0.000 description 7
- 239000010410 layer Substances 0.000 description 7
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 7
- 235000019341 magnesium sulphate Nutrition 0.000 description 7
- 230000035755 proliferation Effects 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 239000002775 capsule Substances 0.000 description 6
- 239000000969 carrier Substances 0.000 description 6
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
- 239000012267 brine Substances 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 239000008187 granular material Substances 0.000 description 5
- 238000010898 silica gel chromatography Methods 0.000 description 5
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
- FODBVCSYJKNBLO-UHFFFAOYSA-N 2,3-dimethoxybenzoic acid Chemical compound COC1=CC=CC(C(O)=O)=C1OC FODBVCSYJKNBLO-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 239000001828 Gelatine Substances 0.000 description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 4
- 150000001805 chlorine compounds Chemical class 0.000 description 4
- 229920000159 gelatin Polymers 0.000 description 4
- 235000019322 gelatine Nutrition 0.000 description 4
- JFCQEDHGNNZCLN-UHFFFAOYSA-N glutaric acid Chemical compound OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 description 4
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- 125000002768 hydroxyalkyl group Chemical group 0.000 description 4
- 239000004615 ingredient Substances 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 239000002243 precursor Substances 0.000 description 4
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- 239000011734 sodium Substances 0.000 description 4
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- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 3
- WPOXORBYXYNRFB-UHFFFAOYSA-N 3-(1h-indol-3-yl)-4-(1-methyl-6-nitroindol-3-yl)pyrrole-2,5-dione Chemical compound C12=CC=C([N+]([O-])=O)C=C2N(C)C=C1C1=C(C=2C3=CC=CC=C3NC=2)C(=O)NC1=O WPOXORBYXYNRFB-UHFFFAOYSA-N 0.000 description 3
- HFCYTEWOPOCEBG-UHFFFAOYSA-N 3-[2-(2-methoxyethoxy)ethoxy]propanoic acid Chemical compound COCCOCCOCCC(O)=O HFCYTEWOPOCEBG-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 3
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 description 3
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- 150000001412 amines Chemical class 0.000 description 3
- 125000003277 amino group Chemical group 0.000 description 3
- 125000004429 atom Chemical group 0.000 description 3
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- 230000022131 cell cycle Effects 0.000 description 3
- FZFAMSAMCHXGEF-UHFFFAOYSA-N chloro formate Chemical compound ClOC=O FZFAMSAMCHXGEF-UHFFFAOYSA-N 0.000 description 3
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- 229940125904 compound 1 Drugs 0.000 description 3
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- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
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- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- 210000004881 tumor cell Anatomy 0.000 description 3
- KZLMZUCDWYXVJZ-UHFFFAOYSA-N 1-(1-methoxyethyl)indole Chemical compound C1=CC=C2N(C(C)OC)C=CC2=C1 KZLMZUCDWYXVJZ-UHFFFAOYSA-N 0.000 description 2
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 2
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 2
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 2
- HEBMFSSLCQLEKH-UHFFFAOYSA-N 2-[1-(1-methoxyethyl)indol-3-yl]-2-oxoacetyl chloride Chemical compound C1=CC=C2N(C(C)OC)C=C(C(=O)C(Cl)=O)C2=C1 HEBMFSSLCQLEKH-UHFFFAOYSA-N 0.000 description 2
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- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 2
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- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
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- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- 229920003081 Povidone K 30 Polymers 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
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- YADJFRGSGWGMNH-UHFFFAOYSA-N [chloro(phenylmethoxy)phosphoryl]oxymethylbenzene Chemical compound C=1C=CC=CC=1COP(=O)(Cl)OCC1=CC=CC=C1 YADJFRGSGWGMNH-UHFFFAOYSA-N 0.000 description 2
- 150000008065 acid anhydrides Chemical class 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 125000003342 alkenyl group Chemical group 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 229960004977 anhydrous lactose Drugs 0.000 description 2
- 150000001450 anions Chemical class 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- ACBQROXDOHKANW-UHFFFAOYSA-N bis(4-nitrophenyl) carbonate Chemical compound C1=CC([N+](=O)[O-])=CC=C1OC(=O)OC1=CC=C([N+]([O-])=O)C=C1 ACBQROXDOHKANW-UHFFFAOYSA-N 0.000 description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- MGNZXYYWBUKAII-UHFFFAOYSA-N cyclohexa-1,3-diene Chemical compound C1CC=CC=C1 MGNZXYYWBUKAII-UHFFFAOYSA-N 0.000 description 2
- 239000008298 dragée Substances 0.000 description 2
- 239000003925 fat Substances 0.000 description 2
- 125000001072 heteroaryl group Chemical group 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 2
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 2
- 125000000814 indol-3-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([H])=C([*])C2=C1[H] 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/572—Five-membered rings
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Abstract
Description
항목 | 성분 | mg/정제 | |||||
1 | 화합물 A* | 5 | 25 | 100 | 250 | 500 | 750 |
2 | 무수 락토오스 | 103 | 83 | 35 | 19 | 38 | 57 |
3 | 크로스카르멜로스(croscarmellose) 소듐 | 6 | 6 | 8 | 16 | 32 | 48 |
4 | 포비돈(povidone) K30 | 5 | 5 | 6 | 12 | 24 | 36 |
5 | 마그네슘 스테아레이트 | 1 | 1 | 1 | 3 | 6 | 9 |
총 중량 | 120 | 120 | 150 | 300 | 600 | 900 | |
*화합물 A는 본 발명의 화합물을 나타낸다. |
항목 | 성분 | mg/캡슐 | ||||
1 | 화합물 A* | 5 | 25 | 100 | 250 | 500 |
2 | 무수 락토오스 | 159 | 123 | 148 | -- | -- |
3 | 옥수수 전분 | 25 | 35 | 40 | 35 | 70 |
4 | 활석 | 10 | 15 | 10 | 12 | 24 |
5 | 마그네슘 스테아레이트 | 1 | 2 | 2 | 3 | 6 |
총 충전 중량 | 200 | 200 | 300 | 300 | 600 | |
*화합물 A는 본 발명의 화합물을 나타낸다. |
항목 | 성분 | mg/mL |
1 | 화합물 A* | 1 mg |
2 | PEG 400 | 10-50 mg |
3 | 레시틴 | 20-50 mg |
4 | 대두유 | 1-5 mg |
5 | 글리세롤 | 8-12 mg |
6 | 물로 채움 | 1 mL |
* 화합물 A는 본 발명의 화합물을 나타낸다. |
항목 | 성분 | mg/mL |
1 | 화합물 A* | 1 mg |
2 | 글리코푸롤 | 10-50 mg |
3 | 레시틴 | 20-50 mg |
4 | 대두유 | 1-5 mg |
5 | 글리세롤 | 8-12 mg |
6 | 물 | 1 mL로 채움 |
* 화합물 A는 본 발명의 화합물을 나타낸다. |
Claims (26)
- 하기 화학식 I을 갖는 화합물:[화학식 I]및 상기 화합물의 약제학적으로 허용가능한 염.(식 중, R은 -PO3R1R2, -CHR3OCOR4, -CHR3OCO2R4, -CHR3OCONHR4및 -COR4로 구성된 군으로부터 선택되고;R1및 R2는 H, Na 및 NH4로 구성된 군으로부터 선택되고, R1또는 R2가 H가 아니라면, 동일한데, 이 경우에 다른 것은 상이할 수 있거나, 대안적으로, R1및 R2는 함께 Ca를 나타내고;R3는 H 또는 메틸로 구성된 군으로부터 선택되고;R4는 하기로 구성된 군으로부터 선택되고;-CO2R5, -NR6R7, 폴리에틸렌 글리콜, -OPO3R1R2, 히드록시, 알콕시 및 아릴로구성된 군으로부터 선택된 하나 이상의 치환체에 의해 선택적으로 치환될 수 있는 저급 알킬,-CO2R5, -NR6R7, 폴리에틸렌 글리콜, -OPO3R1R2, 히드록시, 알콕시 및 아릴로 구성된 군으로부터 선택된 하나 이상의 치환체에 의해 선택적으로 치환될 수 있는 알케닐,-CO2R5, -NR6R7, 폴리에틸렌 글리콜, -OPO3R1R2, 히드록시, 알콕시 및 아릴로 구성된 군으로부터 선택된 하나 이상의 치환체에 의해 선택적으로 치환될 수 있는 시클로알킬,헤테로 원자로서 N을 함유할 경우, N이 선택적으로 -COR8로써 치환될 수 있는 헤테로고리 및-CO2R5, 히드록시, 알콕시, 폴리에틸렌 글리콜, -OPO3R1R2및 그 자체가 히드록시, 카르복시 및 치환된 아미노로써 치환될 수 있는 알킬로 구성된 군으로부터 선택된 하나 이상의 치환체에 의해 선택적으로 치환될 수 있는 아릴;R5는 H, Na 또는 저급 알킬로 구성된 군으로부터 선택되고;R6및 R7은 H, 저급 알킬 및 -COR8로부터 독립적으로 각각 선택되거나, 대안적으로 -NR6R7기는 5 또는 6 원 헤테로시클릭 고리를 형성하고;R8은 폴리에틸렌 글리콜로써 선택적으로 치환될 수 있는 저급 알킬이다)
- 제 1 항에 있어서, R 이 -CHR3OCOR4인 화합물.
- 제 2 항에 있어서, R3가 H인 화합물.
- 제 3 항에 있어서, R4가 저급 알킬인 화합물.
- 제 4 항에 있어서, R4가 폴리에틸렌 글리콜로써 치환된 저급 알킬인 화합물.
- 제 5 항에 있어서, 폴리에틸렌 글리콜이 약 750 내지 약 5000 달톤의 분자량을 갖는 화합물.
- 제 6 항에 있어서, 폴리에틸렌 글리콜이 약 2000 달톤의 분자량을 갖는 화합물.
- 제 1 항에 있어서, R 이 -COR4인 화합물.
- 제 8 항에 있어서, R4가 헤테로고리인 화합물.
- 제 8 항에 있어서, R4가 저급 알킬인 화합물.
- 제 8 항에 있어서, R4가 -NR6R7로써 치환된 저급 알킬인 화합물.
- 제 1 항에 있어서, 폴리에틸렌 글리콜이 약 750 내지 약 5000 달톤의 분자량을 갖는 화합물.
- 제 12 항에 있어서, 폴리에틸렌 글리콜이 약 2000 달톤의 분자량을 갖는 화합물.
- 하기로 구성된 군으로부터 선택되는 화합물:3-[2-(2-메톡시-에톡시)-에톡시]-프로피온산 3-[4-(1-메틸-6-니트로-1H-인돌-3-일)-2,5-디옥소-2,5-디히드로-1H-피롤-3-일]-인돌-1-일메틸 에스테르;O-[2-[[2,5-디히드로-3-[4-(1-메틸-6-니트로-1H-인돌-3-일)-2,5-디옥소-2,5-디히드로피롤-3-일]-인돌-1-일]메톡시카르보닐]에틸]-O'-메틸폴리에틸렌 글리콜 2000;2,3-디메톡시-벤조산 3-[4-(1-메틸-6-니트로-1H-인돌-3-일)-2,5-디옥소-2,5-디히드로-1H-피롤-3-일]-인돌-1-일메틸 에스테르;3-디에틸아미노메틸-벤조산 3-[4-(1-메틸-6-니트로-1H-인돌-3-일)-2,5-디옥소-2,5-디히드로-1H-피롤-3-일]-인돌-1-일메틸 에스테르 히드로클로라이드;3-(1H-인돌-3-일)-4-(1-메틸-6-니트로-1H-인돌-3-일)-1-옥타데크-9-엔오일-피롤-2,5-디온;{3-[4-(1-메틸-6-니트로-1H-인돌-3-일)-2,5-디옥소-2,5-디히드로-1H-피롤-3-일]-인돌-1-일}-포스폰산; 및3-(1-아세틸-1H-인돌-3-일)-4-(1-메틸-6-니트로-1H-인돌-3-일)-피롤-2,5디온.
- 하기로 구성된 군으로부터 선택되는 화합물:트리플루오로-아세트산 3-(1-메틸-6-니트로-1H-인돌-3-일)-4-[1-(피페리딘-4-카르보닐)-1H-인돌-3-일]-피롤-2,5-디온;3-(1-아미노아세틸-1H-인돌-3-일)-4-(1-메틸-6-니트로-1H-인돌-3-일)-피롤-2,5-디온 히드로클로라이드;아세트산 3-[4-(l-메틸-6-니트로-1H-인돌-3-일)-2,5-디옥소-2,5-디히드로-1H-피롤-3-일]-인돌-1-일메틸 에스테르;펜탄디오산 모노-{3-[4-(1-메틸-6-니트로-1H-인돌-3-일)-2,5-디옥소-2,5-디히드로-1H-피롤-3-일]-인돌-1-일메틸} 에스테르;2,3-디메톡시-벤조산 1-{3-[4-(1-메틸-6-니트로-1H-인돌-3-일)-2,5-디옥소-2,5-디히드로-1H-피롤-3-일]-인돌-1-일}-에틸 에스테르; 및3-디에틸아미노메틸-벤조산 1-{3-[4-(1-메틸-6-니트로-1H-인돌-3-일)-2,5-디옥소-2,5-디히드로-1H-피롤-3-일]-인돌-1-일}-에틸 에스테르 히드로클로라이드.
- 활성 성분으로서 유효량의 제 1 항 내지 제 15 항 중 어느 한 항의 화합물 및 약제학적으로 허용가능한 담체 또는 부형제를 함유하는 약제학적 조성물.
- 제 16 항에 있어서, 비경구 투여에 적합한 약제학적 조성물.
- 하기 단계를 포함하는, 제 1 항 내지 제 15 항 중 어느 한 항에 정의된 화합물의 제조 방법:a) 화학식 I의 R이 -PO3R1R2또는 -COR4일 경우에, 상기 기를 수득하는 물질로의 처리에 의해, 하기 화학식의 출발 화합물내로 상기 기를 도입하는 단계,또는b) 화학식 I의 R이 -CHR3OCOR4, -CHR3OCOOR4또는 -CHR3OCONHR4일 경우에, 상기 기를 수득하는 물질로의 처리에 의해, 하기 일반식의 출발 화합물내로 상기 기를 도입하는 단계,(식 중, R3는 제 1 항과 같다)또는c) 화학식 I의 화합물을 이의 약제학적으로 허용가능한 염으로 전환하는 단계.
- 제 18 항의 방법에 의해 제조된, 1 항 내지 제 15 항 중 어느 한 항에 따른 화합물 또는 이의 명백한 화학적 동등물.
- 세포 증식 질환의 치료용 약물의 제조를 위한 제 1 항 내지 제 15 항 중 어느 한 항에 정의된 화합물의 용도.
- 암 치료용 약물의 제조를 위한 제 1 항 내지 제 15 항 중 어느 한 항에 정의된 화합물의 용도.
- 제 1 항 내지 제 15 항 중 어느 한 항에 따른 화합물의 치료적으로 유효량을 필요로 하는 환자에게 투여하는 것을 포함하는 세포 증식 질환의 치료 방법.
- 제 22 항에 있어서, 세포 증식 질환이 암인 방법.
- 제 23 항에 있어서, 암이 고형 종양인 방법.
- 제 24 항에 있어서, 암이 유방, 결장 또는 폐암인 방법.
- 이전에 기재된 신규 화합물, 과정 및 방법뿐만 아니라 실질적으로 그러한 화합물의 용도.
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US9107911B2 (en) | 2010-01-07 | 2015-08-18 | Alkermes Pharma Ireland Limited | Prodrugs of heteraromatic compounds |
EP2474541A1 (en) * | 2010-12-23 | 2012-07-11 | Johannes- Gutenberg-Universität Mainz | Conjugated 3-(indolyl)- and 3-(azaindolyl)-4-arylmaleimide compounds and their use in tumor treatment |
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GB9416467D0 (en) * | 1994-08-13 | 1994-10-05 | Wellcome Found | Compounds for use in medicine |
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