EA012451B1 - Новые амидозамещённые гидрокси-6-фенилфенантридины - Google Patents

Info

Publication number

EA012451B1

EA012451B1 EA200601587A EA200601587A EA012451B1 EA 012451 B1 EA012451 B1 EA 012451B1 EA 200601587 A EA200601587 A EA 200601587A EA 200601587 A EA200601587 A EA 200601587A EA 012451 B1 EA012451 B1 EA 012451B1

Authority

EA

Eurasian Patent Office

Prior art keywords

alkyl

hydrogen

phenyl

group

compounds

Prior art date

2004-03-11

Links

• Espacenet
• Global Dossier
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• ZCOWHHNEZZCOJZ-UHFFFAOYSA-N 6-phenylphenanthridin-1-ol Chemical class C=12C=CC=CC2=C2C(O)=CC=CC2=NC=1C1=CC=CC=C1 ZCOWHHNEZZCOJZ-UHFFFAOYSA-N 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims abstract description 471
• -1 dioxothiomorpholino group Chemical group 0.000 claims description 347
• 229910052739 hydrogen Inorganic materials 0.000 claims description 196
• 239000001257 hydrogen Substances 0.000 claims description 195
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 142
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 128
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 95
• 238000000034 method Methods 0.000 claims description 90
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 72
• 150000003839 salts Chemical class 0.000 claims description 66
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 65
• 206010028980 Neoplasm Diseases 0.000 claims description 64
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 62
• 229910052757 nitrogen Inorganic materials 0.000 claims description 59
• ZYHQGITXIJDDKC-UHFFFAOYSA-N 2-[2-(2-aminophenyl)ethyl]aniline Chemical group NC1=CC=CC=C1CCC1=CC=CC=C1N ZYHQGITXIJDDKC-UHFFFAOYSA-N 0.000 claims description 56
• 201000010099 disease Diseases 0.000 claims description 56
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 51
• 125000001072 heteroaryl group Chemical group 0.000 claims description 48
• 238000002360 preparation method Methods 0.000 claims description 44
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 39
• 229910052760 oxygen Inorganic materials 0.000 claims description 38
• 239000001301 oxygen Substances 0.000 claims description 38
• 125000005842 heteroatom Chemical group 0.000 claims description 37
• 229910052717 sulfur Inorganic materials 0.000 claims description 37
• 238000011282 treatment Methods 0.000 claims description 37
• 102000003964 Histone deacetylase Human genes 0.000 claims description 35
• 108090000353 Histone deacetylase Proteins 0.000 claims description 35
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 35
• 239000011593 sulfur Substances 0.000 claims description 35
• 229910052736 halogen Inorganic materials 0.000 claims description 31
• 150000002367 halogens Chemical group 0.000 claims description 31
• 230000005764 inhibitory process Effects 0.000 claims description 29
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 29
• 201000011510 cancer Diseases 0.000 claims description 28
• 230000000694 effects Effects 0.000 claims description 28
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 28
• 239000008194 pharmaceutical composition Substances 0.000 claims description 28
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 27
• 239000003814 drug Substances 0.000 claims description 26
• 125000000623 heterocyclic group Chemical group 0.000 claims description 26
• 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 24
• 125000002947 alkylene group Chemical group 0.000 claims description 24
• 230000009826 neoplastic cell growth Effects 0.000 claims description 24
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 21
• 125000002249 indol-2-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([*])=C([H])C2=C1[H] 0.000 claims description 21
• 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 21
• 125000002950 monocyclic group Chemical group 0.000 claims description 20
• 230000002401 inhibitory effect Effects 0.000 claims description 19
• 125000000217 alkyl group Chemical group 0.000 claims description 18
• 125000003118 aryl group Chemical group 0.000 claims description 18
• 125000002619 bicyclic group Chemical group 0.000 claims description 18
• 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 16
• 229940124597 therapeutic agent Drugs 0.000 claims description 16
• 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 15
• 125000001041 indolyl group Chemical group 0.000 claims description 14
• 230000003211 malignant effect Effects 0.000 claims description 14
• ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 14
• 238000002560 therapeutic procedure Methods 0.000 claims description 14
• 125000004076 pyridyl group Chemical group 0.000 claims description 13
• 229910052799 carbon Inorganic materials 0.000 claims description 12
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 11
• 125000001624 naphthyl group Chemical group 0.000 claims description 11
• 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 10
• 239000004305 biphenyl Substances 0.000 claims description 10
• 235000010290 biphenyl Nutrition 0.000 claims description 10
• 230000004663 cell proliferation Effects 0.000 claims description 10
• 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 10
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 10
• 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 9
• 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 9
• 125000000814 indol-3-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([H])=C([*])C2=C1[H] 0.000 claims description 9
• 125000004531 indol-5-yl group Chemical group [H]N1C([H])=C([H])C2=C([H])C(*)=C([H])C([H])=C12 0.000 claims description 8
• 239000003795 chemical substances by application Substances 0.000 claims description 7
• HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 claims description 6
• 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 6
• 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 6
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
• ROFVEXUMMXZLPA-UHFFFAOYSA-N Bipyridyl Chemical group N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 claims description 5
• 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 5
• 125000004122 cyclic group Chemical group 0.000 claims description 5
• 239000003937 drug carrier Substances 0.000 claims description 5
• 206010039073 rheumatoid arthritis Diseases 0.000 claims description 5
• 125000004760 (C1-C4) alkylsulfonylamino group Chemical group 0.000 claims description 4
• 125000003830 C1- C4 alkylcarbonylamino group Chemical group 0.000 claims description 4
• 101000707770 Homo sapiens Splicing factor 3B subunit 2 Proteins 0.000 claims description 4
• 102100031436 Splicing factor 3B subunit 2 Human genes 0.000 claims description 4
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
• 125000004430 oxygen atom Chemical group O* 0.000 claims description 4
• 230000002062 proliferating effect Effects 0.000 claims description 4
• 201000000596 systemic lupus erythematosus Diseases 0.000 claims description 4
• 230000002792 vascular Effects 0.000 claims description 4
• 201000001320 Atherosclerosis Diseases 0.000 claims description 3
• 102100021943 C-C motif chemokine 2 Human genes 0.000 claims description 3
• 101000897480 Homo sapiens C-C motif chemokine 2 Proteins 0.000 claims description 3
• 208000012659 Joint disease Diseases 0.000 claims description 3
• 125000004429 atom Chemical group 0.000 claims description 3
• 230000004968 inflammatory condition Effects 0.000 claims description 3
• 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 3
• 125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 3
• 210000000329 smooth muscle myocyte Anatomy 0.000 claims description 3
• 125000005505 thiomorpholino group Chemical group 0.000 claims description 3
• GIIBCVWMOKPTPS-UDWIEESQSA-N (e)-3-[1-[4-[(benzylamino)methyl]phenyl]sulfonylpyrrol-3-yl]-2-hydroxyprop-2-enamide Chemical compound C1=C(\C=C(\O)C(=O)N)C=CN1S(=O)(=O)C(C=C1)=CC=C1CNCC1=CC=CC=C1 GIIBCVWMOKPTPS-UDWIEESQSA-N 0.000 claims description 2
• 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 2
• 229940124531 pharmaceutical excipient Drugs 0.000 claims description 2
• 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims 11
• 208000037803 restenosis Diseases 0.000 claims 2
• 230000008520 organization Effects 0.000 claims 1
• 239000003276 histone deacetylase inhibitor Substances 0.000 abstract description 9
• 210000004027 cell Anatomy 0.000 description 80
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 60
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 57
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 51
• 238000006243 chemical reaction Methods 0.000 description 46
• ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 43
• 239000000203 mixture Substances 0.000 description 40
• 230000000875 corresponding effect Effects 0.000 description 39
• 150000002431 hydrogen Chemical group 0.000 description 39
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 36
• 108090000623 proteins and genes Proteins 0.000 description 31
• 150000003254 radicals Chemical class 0.000 description 31
• 239000007787 solid Substances 0.000 description 29
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 28
• 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 26
• 235000018102 proteins Nutrition 0.000 description 24
• 102000004169 proteins and genes Human genes 0.000 description 24
• 239000004480 active ingredient Substances 0.000 description 23
• 239000003112 inhibitor Substances 0.000 description 23
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 22
• 238000003818 flash chromatography Methods 0.000 description 22
• 239000000741 silica gel Substances 0.000 description 22
• 229910002027 silica gel Inorganic materials 0.000 description 22
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 21
• 239000007858 starting material Substances 0.000 description 21
• 239000002246 antineoplastic agent Substances 0.000 description 20
• 239000002253 acid Substances 0.000 description 19
• 239000000243 solution Substances 0.000 description 19
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 19
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
• 239000000047 product Substances 0.000 description 18
• 238000005481 NMR spectroscopy Methods 0.000 description 17
• 239000012043 crude product Substances 0.000 description 17
• 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 17
• 125000006239 protecting group Chemical group 0.000 description 15
• 230000006907 apoptotic process Effects 0.000 description 14
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 14
• VHHOANRGJDNEQY-SNAWJCMRSA-N tert-butyl (e)-3-(1h-pyrrol-3-yl)prop-2-enoate Chemical compound CC(C)(C)OC(=O)\C=C\C=1C=CNC=1 VHHOANRGJDNEQY-SNAWJCMRSA-N 0.000 description 14
• SFHYNDMGZXWXBU-LIMNOBDPSA-N 6-amino-2-[[(e)-(3-formylphenyl)methylideneamino]carbamoylamino]-1,3-dioxobenzo[de]isoquinoline-5,8-disulfonic acid Chemical compound O=C1C(C2=3)=CC(S(O)(=O)=O)=CC=3C(N)=C(S(O)(=O)=O)C=C2C(=O)N1NC(=O)N\N=C\C1=CC=CC(C=O)=C1 SFHYNDMGZXWXBU-LIMNOBDPSA-N 0.000 description 13
• 102000004190 Enzymes Human genes 0.000 description 13
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• 108010033040 Histones Proteins 0.000 description 13
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
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• 229910052740 iodine Inorganic materials 0.000 description 11
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• LFKDJXLFVYVEFG-UHFFFAOYSA-N tert-butyl carbamate Chemical compound CC(C)(C)OC(N)=O LFKDJXLFVYVEFG-UHFFFAOYSA-N 0.000 description 11
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
• 241000124008 Mammalia Species 0.000 description 10
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 10
• 230000021736 acetylation Effects 0.000 description 10
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• 235000011152 sodium sulphate Nutrition 0.000 description 10
• 238000005160 1H NMR spectroscopy Methods 0.000 description 9
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• RTKIYFITIVXBLE-UHFFFAOYSA-N Trichostatin A Natural products ONC(=O)C=CC(C)=CC(C)C(=O)C1=CC=C(N(C)C)C=C1 RTKIYFITIVXBLE-UHFFFAOYSA-N 0.000 description 9
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• RTKIYFITIVXBLE-QEQCGCAPSA-N trichostatin A Chemical compound ONC(=O)/C=C/C(/C)=C/[C@@H](C)C(=O)C1=CC=C(N(C)C)C=C1 RTKIYFITIVXBLE-QEQCGCAPSA-N 0.000 description 9
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• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 8
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• 230000014509 gene expression Effects 0.000 description 7
• 125000006302 indol-3-yl methyl group Chemical group [H]N1C([H])=C(C2=C([H])C([H])=C([H])C([H])=C12)C([H])([H])* 0.000 description 7
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• SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 6
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• 125000006533 methyl amino methyl group Chemical group [H]N(C([H])([H])[H])C([H])([H])* 0.000 description 6
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• 229910000104 sodium hydride Inorganic materials 0.000 description 6
• VGGRTBIRFYVHCS-RUDMXATFSA-N tert-butyl (e)-3-[1-(4-bromophenyl)sulfonylpyrrol-3-yl]prop-2-enoate Chemical compound C1=C(/C=C/C(=O)OC(C)(C)C)C=CN1S(=O)(=O)C1=CC=C(Br)C=C1 VGGRTBIRFYVHCS-RUDMXATFSA-N 0.000 description 6
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