JP2008513398A - 2位が置換されたチアゾリノン置換キノリン - Google Patents
2位が置換されたチアゾリノン置換キノリン Download PDFInfo
- Publication number
- JP2008513398A JP2008513398A JP2007531677A JP2007531677A JP2008513398A JP 2008513398 A JP2008513398 A JP 2008513398A JP 2007531677 A JP2007531677 A JP 2007531677A JP 2007531677 A JP2007531677 A JP 2007531677A JP 2008513398 A JP2008513398 A JP 2008513398A
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- JP
- Japan
- Prior art keywords
- compound
- general formula
- lower alkylene
- lower alkyl
- quinolin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Ceased
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- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 title abstract description 4
- SMWDFEZZVXVKRB-UHFFFAOYSA-N anhydrous quinoline Natural products N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 title 1
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 11
- 238000004519 manufacturing process Methods 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 145
- 125000002947 alkylene group Chemical group 0.000 claims description 65
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 46
- 125000000217 alkyl group Chemical group 0.000 claims description 39
- 239000000203 mixture Substances 0.000 claims description 36
- 229910052757 nitrogen Inorganic materials 0.000 claims description 25
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 23
- 229910052739 hydrogen Inorganic materials 0.000 claims description 23
- 239000001257 hydrogen Substances 0.000 claims description 23
- 229910052717 sulfur Chemical group 0.000 claims description 23
- 239000011593 sulfur Chemical group 0.000 claims description 23
- 125000004432 carbon atom Chemical group C* 0.000 claims description 22
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 19
- 125000005842 heteroatom Chemical group 0.000 claims description 19
- 229910052760 oxygen Inorganic materials 0.000 claims description 19
- 239000001301 oxygen Substances 0.000 claims description 19
- 150000003839 salts Chemical class 0.000 claims description 19
- 125000001072 heteroaryl group Chemical group 0.000 claims description 18
- 239000003814 drug Substances 0.000 claims description 17
- 125000003118 aryl group Chemical group 0.000 claims description 16
- 229940079593 drug Drugs 0.000 claims description 16
- 201000010099 disease Diseases 0.000 claims description 15
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 14
- 239000011541 reaction mixture Substances 0.000 claims description 13
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 12
- 206010028980 Neoplasm Diseases 0.000 claims description 12
- 150000001412 amines Chemical class 0.000 claims description 12
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 12
- 150000002431 hydrogen Chemical class 0.000 claims description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
- 125000003282 alkyl amino group Chemical group 0.000 claims description 10
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 10
- 229910052736 halogen Inorganic materials 0.000 claims description 9
- 125000001424 substituent group Chemical group 0.000 claims description 9
- 150000002367 halogens Chemical class 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- 201000011510 cancer Diseases 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 5
- RSOZQZMENWFFPQ-UHFFFAOYSA-N 5-[(2-amino-4-ethoxyquinolin-6-yl)methylidene]-2-[2-(3-fluorophenyl)ethylamino]-1,3-thiazol-4-one Chemical compound C1=C2C(OCC)=CC(N)=NC2=CC=C1C=C(C(N=1)=O)SC=1NCCC1=CC=CC(F)=C1 RSOZQZMENWFFPQ-UHFFFAOYSA-N 0.000 claims description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 4
- 239000012022 methylating agents Substances 0.000 claims description 4
- YEGQTKTWDVTXSQ-CHISUXBFSA-N (5z)-5-[(2-aminoquinolin-6-yl)methylidene]-2-[[(1r,2s)-2-phenylcyclopropyl]amino]-1,3-thiazol-4-one Chemical compound C1([C@@H]2C[C@H]2NC=2S\C(C(N=2)=O)=C/C2=CC3=CC=C(N=C3C=C2)N)=CC=CC=C1 YEGQTKTWDVTXSQ-CHISUXBFSA-N 0.000 claims description 3
- MKDVOYBVMQFXLH-UHFFFAOYSA-N n-[4-ethoxy-6-[[2-[2-(oxan-4-yl)ethylamino]-4-oxo-1,3-thiazol-5-ylidene]methyl]quinolin-2-yl]acetamide Chemical compound C1=C2C(OCC)=CC(NC(C)=O)=NC2=CC=C1C=C(C(N=1)=O)SC=1NCCC1CCOCC1 MKDVOYBVMQFXLH-UHFFFAOYSA-N 0.000 claims description 3
- WZFPWQGBBRXPSS-UHFFFAOYSA-N n-[6-[[2-(1,4-dioxin-2-ylmethylamino)-4-oxo-1,3-thiazol-5-ylidene]methyl]-4-ethoxyquinolin-2-yl]acetamide Chemical compound C1=C2C(OCC)=CC(NC(C)=O)=NC2=CC=C1C=C(C(N=1)=O)SC=1NCC1=COC=CO1 WZFPWQGBBRXPSS-UHFFFAOYSA-N 0.000 claims description 3
- DDUAFBYFPQDAMW-UHFFFAOYSA-N n-[6-[[2-(cyclopropylamino)-4-oxo-1,3-thiazol-5-ylidene]methyl]-4-ethoxyquinolin-2-yl]acetamide Chemical compound C1=C2C(OCC)=CC(NC(C)=O)=NC2=CC=C1C=C(C(N=1)=O)SC=1NC1CC1 DDUAFBYFPQDAMW-UHFFFAOYSA-N 0.000 claims description 3
- NWYNGUWOWMEVOJ-UHFFFAOYSA-N n-[6-[[2-(cyclopropylmethylamino)-4-oxo-1,3-thiazol-5-ylidene]methyl]-4-ethoxyquinolin-2-yl]acetamide Chemical compound C1=C2C(OCC)=CC(NC(C)=O)=NC2=CC=C1C=C(C(N=1)=O)SC=1NCC1CC1 NWYNGUWOWMEVOJ-UHFFFAOYSA-N 0.000 claims description 3
- IUXVOZATFYNDFC-UHFFFAOYSA-N 2-amino-5-[(2-amino-4-ethoxyquinolin-6-yl)methylidene]-1,3-thiazol-4-one Chemical compound C1=C2C(OCC)=CC(N)=NC2=CC=C1C=C1SC(N)=NC1=O IUXVOZATFYNDFC-UHFFFAOYSA-N 0.000 claims description 2
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 claims description 2
- RJRFVERVXDKPEA-UHFFFAOYSA-N n-[6-[(2-amino-4-oxo-1,3-thiazol-5-ylidene)methyl]-4-ethoxyquinolin-2-yl]acetamide Chemical compound C1=C2C(OCC)=CC(NC(C)=O)=NC2=CC=C1C=C1SC(N)=NC1=O RJRFVERVXDKPEA-UHFFFAOYSA-N 0.000 claims description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 2
- 150000003457 sulfones Chemical class 0.000 claims description 2
- 239000002671 adjuvant Substances 0.000 claims 1
- 230000006369 cell cycle progression Effects 0.000 claims 1
- 125000005843 halogen group Chemical group 0.000 claims 1
- 125000000623 heterocyclic group Chemical group 0.000 claims 1
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- 230000001028 anti-proliverative effect Effects 0.000 abstract description 6
- 239000002246 antineoplastic agent Substances 0.000 abstract description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 48
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 45
- 238000006243 chemical reaction Methods 0.000 description 45
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 33
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 29
- 238000002360 preparation method Methods 0.000 description 29
- 239000007787 solid Substances 0.000 description 29
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 26
- 239000000243 solution Substances 0.000 description 23
- 239000002585 base Substances 0.000 description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 230000000694 effects Effects 0.000 description 16
- -1 methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy Chemical group 0.000 description 15
- 239000002244 precipitate Substances 0.000 description 15
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 239000000725 suspension Substances 0.000 description 12
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 10
- 229960000583 acetic acid Drugs 0.000 description 10
- 238000001914 filtration Methods 0.000 description 10
- 239000000463 material Substances 0.000 description 10
- 108091007914 CDKs Proteins 0.000 description 9
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 9
- 108010068150 Cyclin B Proteins 0.000 description 9
- 102000002427 Cyclin B Human genes 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 238000003556 assay Methods 0.000 description 9
- 229910002091 carbon monoxide Inorganic materials 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 8
- 238000007796 conventional method Methods 0.000 description 8
- 239000010410 layer Substances 0.000 description 8
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- 102000004169 proteins and genes Human genes 0.000 description 8
- 108090000623 proteins and genes Proteins 0.000 description 8
- 239000000758 substrate Substances 0.000 description 8
- 238000000967 suction filtration Methods 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- PDZVAJOHDGQTBM-UHFFFAOYSA-N n-(4-ethoxy-6-formylquinolin-2-yl)acetamide Chemical compound C1=C(C=O)C=C2C(OCC)=CC(NC(C)=O)=NC2=C1 PDZVAJOHDGQTBM-UHFFFAOYSA-N 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 108091000080 Phosphotransferase Proteins 0.000 description 6
- 102000001253 Protein Kinase Human genes 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000000908 ammonium hydroxide Substances 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 150000004820 halides Chemical group 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- FEVKOVQXBYKWIU-UHFFFAOYSA-N n-[4-ethoxy-6-[(4-oxo-2-sulfanylidene-1,3-thiazolidin-5-ylidene)methyl]quinolin-2-yl]acetamide Chemical compound C1=C2C(OCC)=CC(NC(C)=O)=NC2=CC=C1C=C1SC(=S)NC1=O FEVKOVQXBYKWIU-UHFFFAOYSA-N 0.000 description 6
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 6
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- 239000000741 silica gel Substances 0.000 description 6
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- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 5
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- 102000056838 human CDK1 Human genes 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 125000005462 imide group Chemical group 0.000 description 1
- 150000003949 imides Chemical class 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- 238000005462 in vivo assay Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 229940102213 injectable suspension Drugs 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 1
- INQOMBQAUSQDDS-BJUDXGSMSA-N iodomethane Chemical group I[11CH3] INQOMBQAUSQDDS-BJUDXGSMSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- BPHPUYQFMNQIOC-NXRLNHOXSA-N isopropyl beta-D-thiogalactopyranoside Chemical compound CC(C)S[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O BPHPUYQFMNQIOC-NXRLNHOXSA-N 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000006166 lysate Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 230000001035 methylating effect Effects 0.000 description 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 description 1
- PSOFAXPWEITBPG-UHFFFAOYSA-N n-(cyclopropylmethyl)-1,3-thiazol-2-amine Chemical compound C1CC1CNC1=NC=CS1 PSOFAXPWEITBPG-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 239000006225 natural substrate Substances 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- JMJRYTGVHCAYCT-UHFFFAOYSA-N oxan-4-one Chemical compound O=C1CCOCC1 JMJRYTGVHCAYCT-UHFFFAOYSA-N 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 239000006174 pH buffer Substances 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- LXNAVEXFUKBNMK-UHFFFAOYSA-N palladium(II) acetate Substances [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 239000008024 pharmaceutical diluent Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- ZNNZYHKDIALBAK-UHFFFAOYSA-M potassium thiocyanate Chemical compound [K+].[S-]C#N ZNNZYHKDIALBAK-UHFFFAOYSA-M 0.000 description 1
- 229940116357 potassium thiocyanate Drugs 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 150000003248 quinolines Chemical group 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 229910052701 rubidium Inorganic materials 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000000526 short-path distillation Methods 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical compound [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 description 1
- 235000019254 sodium formate Nutrition 0.000 description 1
- 239000012439 solid excipient Substances 0.000 description 1
- 238000000527 sonication Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 150000003548 thiazolidines Chemical class 0.000 description 1
- CFOAUYCPAUGDFF-UHFFFAOYSA-N tosmic Chemical compound CC1=CC=C(S(=O)(=O)C[N+]#[C-])C=C1 CFOAUYCPAUGDFF-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- ISPSHPOFLYFIRR-UHFFFAOYSA-N trihexylsilicon Chemical compound CCCCCC[Si](CCCCCC)CCCCCC ISPSHPOFLYFIRR-UHFFFAOYSA-N 0.000 description 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
- 241000701447 unidentified baculovirus Species 0.000 description 1
- 239000013598 vector Substances 0.000 description 1
- 230000007998 vessel formation Effects 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D521/00—Heterocyclic compounds containing unspecified 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
Abstract
Description
R1は、水素、低級アルキル、アリールオキシ-低級アルキル、-C(O)2[CH2CH2O]p-R9、[CH2CH2O]v-R8、R2-(X)n-のいずれかであり;
Xは、低級アルキレン、ヒドロキシ-低級アルキレン、シクロ-低級アルキレン、アリール-低級アルキレン、カルボキシ-低級アルキレン、アミド-低級アルキレン、モノハロ-低級アルキレン、ジハロ-低級アルキレン、アミノ-低級アルキレン、モノ低級アルキルアミノ-低級アルキレン、ジ低級アルキルアミノ-低級アルキレン、イミド-低級アルキレンのいずれかであり;
R2は、
R5、R6、R7は、独立に、ヒドロキシ、低級アルキル-スルホン、ヒドロキシ-低級アルキル、水素、低級アルキル、ハロゲン、ペルフルオロ-低級アルキル、低級アルコキシ、アミノ、モノ低級アルキルアミノ、ジ低級アルキルアミノからなるグループの中から選択されるか、置換基R5、R6、R7のうちの2つが環:
R4は、水素、-(O)k(CH2CH2O)y-R10、
-O-(CH2)m-R14のいずれかであり;
R19は水素であり;
R20は、水素、低級アルキル、
R8とR9は、独立に、水素または低級アルキルであり;
R10とR11は低級アルキルであり;
R14はペルフルオロ-低級アルキルであり;
R17とR18は、独立に、水素、低級アルキル、
nとkは0または1の整数であり;
w、y、zは0〜3の整数であり;
pは0〜6の整数であり;
vとmは1〜6の整数である)
または、R2が複素芳香族環に窒素を含む化合物のN-オキシド、またはR2がヘテロシクロアルキル環または複素芳香族環にイオウを含むスルホン;
またはCDKの活性、中でもCDK1の活性を抑制するその医薬的に許容可能な塩が発見された。
R1'は、水素、低級アルキル、低級アルコキシアルキルのいずれかであり;R4、R19、R20は上記の通りである);またはその医薬的に許容可能な塩と、一般式(I-B)の化合物:
R1"はR2'-(X')n-であり;
n、R4、R19、R20は上記の通りであり;
X'は、低級アルキレン、ヒドロキシ-低級アルキレン、シクロ-低級アルキレン、モノハロ-低級アルキレン、ジハロ-低級アルキレンのいずれかであり;
R2'は
R5'とR6'は、独立に、ヒドロキシ、低級アルキル-スルホン、ヒドロキシ-低級アルキル、水素、低級アルキル、ハロゲン、ペルフルオロ-低級アルキル、低級アルコキシ、アミノ、モノ低級アルキルアミノ、ジ低級アルキルアミノからなるグループの中から選択される);
またはR2'が複素芳香族環に窒素を含む化合物のN-オキシド、またはR2'がヘテロシクロアルキル環または複素芳香族環にイオウを含むスルホン;
またはその医薬的に許容可能な塩がある。
R1-NH2 (VI)
の化合物(ただしR1は上記のものである)を一般式(III-A)の化合物と反応させることを通じた直接的な置換によって直接形成することができる。この置換反応は、一般に、一般式(IX)のチエニル化合物に含まれるチエニル基のアクチベータの存在下とアミン塩基の存在下で行なわせる。好ましいアクチベータとして塩化第二水銀などがある。この反応は、不活性な有機溶媒の中で行なわせる。一般的な任意の不活性な有機溶媒(例えばアセトニトリル、塩化メチレンなど)を使用できる。この反応を行なわせる際には、アミン塩基(例えばジイソプロピルエチルアミン)を用いる。この反応では温度と圧力は重要でないため、室温にて大気圧下で実施することができる。この反応を行なわせる際には、チエニル基をアミンで置換する任意の従来法を利用することができる。
5-[1-(2-アミノ-キノリン-6-イル)-メト-(Z)-イリデン]-2-((1R,2S)-2-フェニル-シクロプロピルアミノ)-チアゾル-4-オン;トリフルオロ酢酸との化合物
実施例2
実施例3
実施例4
実施例5
実施例6
実施例7
実施例8
実施例9
実施例10
100×{1 - (テスト化合物 - 非特異的)/(合計 - 非特異的)}
ただし“テスト化合物”は、複数のテスト用複製に関する1分間当たりの平均カウント数であり、“非特異的”は、CDK1/サイクリンBなどを添加しないときの1分間当たりの平均カウント数であり、“合計”は、化合物を添加しないときの1分間当たりの平均カウント数である。IC50値は、記載したテスト条件下でプロテイン・-キナーゼによって誘導される放射性標識の取り込みを50%低下させるテスト化合物の濃度である。阻害定数Kiの値は、Ki = IC50/(1+ [S]/Km)によって計算される。ただし[S]はATPの濃度であり、Kmはミカエリス定数である。
Claims (19)
- 一般式(I)の化合物:
R1は、水素、低級アルキル、アリールオキシ-低級アルキル、-C(O)2[CH2CH2O]p-R9、[CH2CH2O]v-R8、R2-(X)n-のいずれかであり;
Xは、低級アルキレン、ヒドロキシ-低級アルキレン、シクロ-低級アルキレン、アリール-低級アルキレン、カルボキシ-低級アルキレン、アミド-低級アルキレン、モノハロ-低級アルキレン、ジハロ-低級アルキレン、アミノ-低級アルキレン、モノ低級アルキルアミノ-低級アルキレン、ジ低級アルキルアミノ-低級アルキレン、イミド-低級アルキレンのいずれかであり;
R2は、
R5、R6、R7は、独立に、ヒドロキシ、低級アルキル-スルホン、ヒドロキシ-低級アルキル、水素、低級アルキル、ハロゲン、ペルフルオロ-低級アルキル、低級アルコキシ、アミノ、モノ低級アルキルアミノ、ジ低級アルキルアミノからなるグループの中から選択されるか、置換基R5、R6、R7のうちの2つが環:
R4は、水素、-(O)k(CH2CH2O)y-R10、
-O-(CH2)m-R14のいずれかであり;
R19は水素であり;
R20は、水素、低級アルキル、
R8とR9は、独立に、水素または低級アルキルであり;
R10とR11は低級アルキルであり;
R14はペルフルオロ-低級アルキルであり;
R17とR18は、独立に、水素、低級アルキル、
nとkは0または1の整数であり;
w、y、zは0〜3の整数であり;
pは0〜6の整数であり;
vとmは1〜6の整数である)
または、R2が複素芳香族環に窒素を含む化合物のN-オキシド、またはR2がヘテロシクロアルキル環または複素芳香族環にイオウを含むスルホン;
またはその医薬的に許容可能な塩。 - R1'が水素であり;
R4が-(O)k(CH2CH2O)y-R10であり;
R10、k、yが請求項1に定義した通りである、請求項2に記載の化合物。 - N-(6-{2-アミノ-4-オキソ-4H-チアゾル-5-イリデンメチル}-4-エトキシ-キノリン-2-イル)-アセトアミドと
2-アミノ-5-(2-アミノ-4-エトキシ-キノリン-6-イルメチレン)-チアゾル-4-オンである、請求項3に記載の化合物。 - 一般式(I-B)の化合物:
R1"はR2'-(X')n-であり;
n、R4、R19、R20は請求項1に定義した通りであり;
X'は、低級アルキレン、ヒドロキシ-低級アルキレン、シクロ-低級アルキレン、モノハロ-低級アルキレン、ジハロ-低級アルキレンのいずれかであり;
R2'は
R5'とR6'は、独立に、ヒドロキシ、低級アルキル-スルホン、ヒドロキシ-低級アルキル、水素、低級アルキル、ハロゲン、ペルフルオロ-低級アルキル、低級アルコキシ、アミノ、モノ低級アルキルアミノ、ジ低級アルキルアミノからなるグループの中から選択される)である、請求項1に記載の化合物;
またはR2'が複素芳香族環に窒素を含む化合物のN-オキシド、またはR2'がヘテロシクロアルキル環または複素芳香族環にイオウを含むスルホン;
またはその医薬的に許容可能な塩。 - X'が低級アルキレンであり;
R2'が、場合によってはハロゲンで置換されているフェニルであり;
R4が-O-CH2-CH3であり;
nが1である、請求項5に記載の化合物。 - 5-(2-アミノ-4-エトキシ-キノリン-6-イルメチレン)-2-[2-(3-フルオロ-フェニル)-エチルアミノ]-チアゾル-4-オンである、請求項6に記載の化合物。
- X'が低級アルキレンであり;
R2'が、3〜5個の炭素原子と、酸素、窒素、イオウからなるグループの中から選択した1〜2個のヘテロ原子とを含む複素環であり;
R4が-O-CH2-CH3であり;
nが1である、請求項5に記載の化合物。 - N-(4-エトキシ-6-{4-オキソ-2-[2-(テトラヒドロ-ピラン-4-イル)-エチルアミノ]-4H-チアゾル-5-イリデンメチル}-キノリン-2-イル)-アセトアミド、
N-(4-エトキシ-6-{4-オキソ-2-[(テトラヒドロ-ピラン-4-イルメチル-アミノ)-4H-チアゾル-5-イリデンメチル]-キノリン-2-イル}-アセトアミド、
N-(6-{2-[([1,4]ジオキシン-2-イルメチル)-アミノ]-4-オキソ-4H-チアゾル-5-イリデンメチル}-4-エトキシ-キノリン-2-イル)-アセトアミドである、請求項8に記載の化合物。 - X'が低級アルキレンであり;
R2'が、置換されていないシクロプロピル、またはフェニルで置換されているシクロプロピルであり;
R4が-O-CH2-CH3であり;
nが0または1である、請求項5に記載の化合物。 - N-[6-(2-シクロプロピルメチルアミノ-4-オキソ-4H-チアゾル-5-イリデンメチル)-4-エトキシ-キノリン-2-イル]-アセトアミド、
N-[6-(2-シクロプロピルアミノ-4-オキソ-4H-チアゾル-5-イリデンメチル)-4-エトキシ-キノリン-2-イル]-アセトアミド、
5-[1-(2-アミノ-キノリン-6-イル)-メト-(Z)-イリデン]-2-((1R,2S)-2-フェニル-シクロプロピルアミノ)-チアゾル-4-オンである、請求項10に記載の化合物。 - ステップb)における上記メチル化剤がヨードメタンである、請求項12に記載の方法。
- がん、その中でも固形腫瘍の治療用である、請求項1に記載の一般式(I)の化合物。
- 一般式(I)で表わされる1種類以上の化合物と、医薬的に許容可能なアジュバントとを含む、がん治療用、その中でも固形腫瘍治療用の医薬組成物。
- 細胞周期の進行の乱れが主な原因である疾患を治療する薬を製造するための、請求項1に記載の一般式(I)の化合物。
- がん、その中でも固形腫瘍を治療する薬を製造するための、請求項1に記載の一般式(I)の化合物。
- 請求項12に記載の方法によって調製される請求項1に記載の一般式(I)の化合物。
- 実質的に上に記載した内容の新規な化合物、方法、組成物及び使用。
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US61076704P | 2004-09-17 | 2004-09-17 | |
PCT/EP2005/009927 WO2006029863A1 (en) | 2004-09-17 | 2005-09-15 | Thiazolinone 2-substituted quinolines |
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WO2014080345A2 (en) * | 2012-11-20 | 2014-05-30 | Shasun Pharmaceuticals Limited | Improved process for the preparation of pregabalin |
RU2521390C1 (ru) * | 2013-03-14 | 2014-06-27 | Общество с ограниченной ответственностью "Тиацен" | Производное роданина и средство для профилактики опухолевых заболеваний |
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WO1999021845A2 (en) * | 1997-10-27 | 1999-05-06 | Agouron Pharmaceuticals, Inc. | 4-aminothiazole derivatives, their preparation and their use as inhibitors of cyclin-dependent kinases |
WO2004006916A1 (en) * | 2002-07-10 | 2004-01-22 | Applied Research Systems Ars Holding Nv | Use of compounds for increasing spermatozoa motility |
WO2004007491A1 (en) * | 2002-07-10 | 2004-01-22 | Applied Research Systems Ars Holding N.V. | Azolidinone-vinyl fused-benzene derivatives |
WO2004047760A2 (en) * | 2002-11-22 | 2004-06-10 | Smithkline Beecham Corporation | Novel chemical compounds |
WO2005011686A1 (en) * | 2003-07-28 | 2005-02-10 | Applied Research Systems Ars Holding N.V. | 2-imino-4-(thio) oxo-5-poly cyclovinylazolines for use as p13 kinase ihibitors |
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EP1215208B1 (en) | 1997-10-27 | 2006-07-12 | Agouron Pharmaceuticals, Inc. | 4-Aminothiazole derivatives, their preparation and their use as inhibitors of cyclin-dependent kinases |
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- 2005-09-15 KR KR1020097004678A patent/KR20090031797A/ko not_active Application Discontinuation
- 2005-09-15 CN CNA2005800309029A patent/CN101018785A/zh active Pending
- 2005-09-15 KR KR1020077005967A patent/KR100901091B1/ko not_active IP Right Cessation
- 2005-09-15 EP EP05788472A patent/EP1791836A1/en not_active Withdrawn
- 2005-09-15 RU RU2007114126/04A patent/RU2395509C2/ru not_active IP Right Cessation
- 2005-09-15 MX MX2007002721A patent/MX2007002721A/es active IP Right Grant
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- 2005-09-15 WO PCT/EP2005/009927 patent/WO2006029863A1/en active Application Filing
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WO1999021845A2 (en) * | 1997-10-27 | 1999-05-06 | Agouron Pharmaceuticals, Inc. | 4-aminothiazole derivatives, their preparation and their use as inhibitors of cyclin-dependent kinases |
WO2004006916A1 (en) * | 2002-07-10 | 2004-01-22 | Applied Research Systems Ars Holding Nv | Use of compounds for increasing spermatozoa motility |
WO2004007491A1 (en) * | 2002-07-10 | 2004-01-22 | Applied Research Systems Ars Holding N.V. | Azolidinone-vinyl fused-benzene derivatives |
WO2004047760A2 (en) * | 2002-11-22 | 2004-06-10 | Smithkline Beecham Corporation | Novel chemical compounds |
WO2005011686A1 (en) * | 2003-07-28 | 2005-02-10 | Applied Research Systems Ars Holding N.V. | 2-imino-4-(thio) oxo-5-poly cyclovinylazolines for use as p13 kinase ihibitors |
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AU2005284294A1 (en) | 2006-03-23 |
KR20070043886A (ko) | 2007-04-25 |
EP1791836A1 (en) | 2007-06-06 |
KR100901091B1 (ko) | 2009-06-08 |
WO2006029863A1 (en) | 2006-03-23 |
US20060063804A1 (en) | 2006-03-23 |
MX2007002721A (es) | 2007-04-23 |
BRPI0515451A (pt) | 2008-07-29 |
CN101018785A (zh) | 2007-08-15 |
RU2395509C2 (ru) | 2010-07-27 |
US7241893B2 (en) | 2007-07-10 |
RU2007114126A (ru) | 2008-10-27 |
KR20090031797A (ko) | 2009-03-27 |
CA2579348A1 (en) | 2006-03-23 |
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