HRP20030875A2 - Novel cyano-substituted dihydropyrimidine compounds and their use to treat diseases - Google Patents
Novel cyano-substituted dihydropyrimidine compounds and their use to treat diseases Download PDFInfo
- Publication number
- HRP20030875A2 HRP20030875A2 HR20030875A HRP20030875A HRP20030875A2 HR P20030875 A2 HRP20030875 A2 HR P20030875A2 HR 20030875 A HR20030875 A HR 20030875A HR P20030875 A HRP20030875 A HR P20030875A HR P20030875 A2 HRP20030875 A2 HR P20030875A2
- Authority
- HR
- Croatia
- Prior art keywords
- methyl
- cyano
- oxo
- dihydro
- pyrimidine
- Prior art date
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- -1 cyano-substituted dihydropyrimidine compounds Chemical class 0.000 title claims description 117
- 201000010099 disease Diseases 0.000 title claims description 20
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims description 20
- 150000001875 compounds Chemical class 0.000 claims description 323
- 238000000034 method Methods 0.000 claims description 163
- 125000000217 alkyl group Chemical group 0.000 claims description 84
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 78
- ZFCHNZDUMIOWFV-UHFFFAOYSA-N pyrimidine-2-carboxylic acid Chemical compound OC(=O)C1=NC=CC=N1 ZFCHNZDUMIOWFV-UHFFFAOYSA-N 0.000 claims description 45
- 125000003118 aryl group Chemical group 0.000 claims description 41
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 30
- 125000001072 heteroaryl group Chemical group 0.000 claims description 29
- 238000011282 treatment Methods 0.000 claims description 26
- 206010028980 Neoplasm Diseases 0.000 claims description 25
- 125000003545 alkoxy group Chemical group 0.000 claims description 23
- 229910052739 hydrogen Inorganic materials 0.000 claims description 23
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 21
- 125000000623 heterocyclic group Chemical group 0.000 claims description 21
- 201000011510 cancer Diseases 0.000 claims description 18
- 102000004169 proteins and genes Human genes 0.000 claims description 18
- 108090000623 proteins and genes Proteins 0.000 claims description 18
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 17
- 229910052760 oxygen Inorganic materials 0.000 claims description 17
- 230000002062 proliferating effect Effects 0.000 claims description 15
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 14
- 229910052717 sulfur Inorganic materials 0.000 claims description 14
- 229910052799 carbon Inorganic materials 0.000 claims description 13
- 125000005885 heterocycloalkylalkyl group Chemical group 0.000 claims description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- 125000001188 haloalkyl group Chemical group 0.000 claims description 11
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 10
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 10
- 239000002246 antineoplastic agent Substances 0.000 claims description 9
- 230000006907 apoptotic process Effects 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 9
- 241000124008 Mammalia Species 0.000 claims description 8
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 8
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 8
- 229940002612 prodrug Drugs 0.000 claims description 8
- 239000000651 prodrug Substances 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical class C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 7
- 125000002837 carbocyclic group Chemical group 0.000 claims description 7
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 7
- 230000008569 process Effects 0.000 claims description 7
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Divinylene sulfide Natural products C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 6
- 125000003342 alkenyl group Chemical group 0.000 claims description 6
- 239000004202 carbamide Substances 0.000 claims description 6
- 150000002148 esters Chemical class 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 6
- 125000002252 acyl group Chemical group 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 5
- 239000012948 isocyanate Substances 0.000 claims description 5
- 150000002513 isocyanates Chemical group 0.000 claims description 5
- 229920000388 Polyphosphate Polymers 0.000 claims description 4
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 239000001205 polyphosphate Substances 0.000 claims description 4
- 235000011176 polyphosphates Nutrition 0.000 claims description 4
- 239000012453 solvate Substances 0.000 claims description 4
- 229930192474 thiophene Natural products 0.000 claims description 4
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 3
- 125000003302 alkenyloxy group Chemical group 0.000 claims description 3
- 125000001475 halogen functional group Chemical group 0.000 claims description 3
- 229940127084 other anti-cancer agent Drugs 0.000 claims description 3
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 claims description 3
- LDHHDUBMXCTXAK-UHFFFAOYSA-N 3-(4,5-dihydro-1,3-oxazol-2-yl)-6-methyl-4-(3-nitrophenyl)-2-oxo-1,4-dihydropyrimidine-5-carbonitrile Chemical compound O=C1NC(C)=C(C#N)C(C=2C=C(C=CC=2)[N+]([O-])=O)N1C1=NCCO1 LDHHDUBMXCTXAK-UHFFFAOYSA-N 0.000 claims description 2
- PZNXVVIBILFGNE-UHFFFAOYSA-N 3-butanoyl-4-(3,5-dichlorophenyl)-6-methyl-2-oxo-1,4-dihydropyrimidine-5-carbonitrile Chemical compound N#CC1=C(C)NC(=O)N(C(=O)CCC)C1C1=CC(Cl)=CC(Cl)=C1 PZNXVVIBILFGNE-UHFFFAOYSA-N 0.000 claims description 2
- AFTFIIOLGIFECX-UHFFFAOYSA-N 3-butanoyl-6-methyl-4-(3-nitrophenyl)-2-oxo-1,4-dihydropyrimidine-5-carbonitrile Chemical compound N#CC1=C(C)NC(=O)N(C(=O)CCC)C1C1=CC=CC([N+]([O-])=O)=C1 AFTFIIOLGIFECX-UHFFFAOYSA-N 0.000 claims description 2
- JYFQCIZXTGAUNK-UHFFFAOYSA-N 4-(3,5-dichlorophenyl)-6-methyl-2-oxo-3-(thiophene-2-carbonyl)-1,4-dihydropyrimidine-5-carbonitrile Chemical compound O=C1NC(C)=C(C#N)C(C=2C=C(Cl)C=C(Cl)C=2)N1C(=O)C1=CC=CS1 JYFQCIZXTGAUNK-UHFFFAOYSA-N 0.000 claims description 2
- MCLSNWBAQVPPKJ-UHFFFAOYSA-N 4-(3,5-difluorophenyl)-6-methyl-2-oxo-3-(piperidine-1-carbonyl)-1,4-dihydropyrimidine-5-carbonitrile Chemical compound O=C1NC(C)=C(C#N)C(C=2C=C(F)C=C(F)C=2)N1C(=O)N1CCCCC1 MCLSNWBAQVPPKJ-UHFFFAOYSA-N 0.000 claims description 2
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 claims description 2
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical class C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims description 2
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000004104 aryloxy group Chemical group 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 claims description 2
- 230000001939 inductive effect Effects 0.000 claims description 2
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical class C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000005309 thioalkoxy group Chemical group 0.000 claims description 2
- 150000003577 thiophenes Chemical class 0.000 claims description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 112
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 96
- 238000005160 1H NMR spectroscopy Methods 0.000 description 91
- 239000000543 intermediate Substances 0.000 description 80
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 57
- 238000000524 positive electrospray ionisation mass spectrometry Methods 0.000 description 48
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 46
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 43
- 210000004027 cell Anatomy 0.000 description 40
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 37
- 239000000243 solution Substances 0.000 description 33
- 239000000203 mixture Substances 0.000 description 30
- 239000000047 product Substances 0.000 description 30
- 239000011541 reaction mixture Substances 0.000 description 28
- 235000019439 ethyl acetate Nutrition 0.000 description 26
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 24
- 239000011734 sodium Substances 0.000 description 24
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 23
- 238000012544 monitoring process Methods 0.000 description 23
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 22
- 239000007787 solid Substances 0.000 description 22
- 102100027629 Kinesin-like protein KIF11 Human genes 0.000 description 20
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 19
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 16
- 125000004432 carbon atom Chemical group C* 0.000 description 16
- 238000006243 chemical reaction Methods 0.000 description 16
- 230000011278 mitosis Effects 0.000 description 16
- 125000001424 substituent group Chemical group 0.000 description 15
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 14
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 14
- 238000004128 high performance liquid chromatography Methods 0.000 description 14
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 13
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 12
- 125000005842 heteroatom Chemical group 0.000 description 12
- 229910052740 iodine Inorganic materials 0.000 description 12
- ZETIVVHRRQLWFW-UHFFFAOYSA-N 3-nitrobenzaldehyde Chemical compound [O-][N+](=O)C1=CC=CC(C=O)=C1 ZETIVVHRRQLWFW-UHFFFAOYSA-N 0.000 description 11
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 11
- 230000022131 cell cycle Effects 0.000 description 11
- 125000005843 halogen group Chemical group 0.000 description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- 102000029749 Microtubule Human genes 0.000 description 10
- 108091022875 Microtubule Proteins 0.000 description 10
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 10
- 210000004688 microtubule Anatomy 0.000 description 10
- 239000012044 organic layer Substances 0.000 description 10
- 238000002953 preparative HPLC Methods 0.000 description 10
- 239000000741 silica gel Substances 0.000 description 10
- 229910002027 silica gel Inorganic materials 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 9
- 229910052757 nitrogen Inorganic materials 0.000 description 9
- 229920006395 saturated elastomer Polymers 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
- 239000007832 Na2SO4 Substances 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- 238000003782 apoptosis assay Methods 0.000 description 8
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 8
- 125000002950 monocyclic group Chemical group 0.000 description 8
- 239000003921 oil Substances 0.000 description 8
- 230000005522 programmed cell death Effects 0.000 description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 8
- 150000003384 small molecules Chemical class 0.000 description 8
- 229910052938 sodium sulfate Inorganic materials 0.000 description 8
- 235000011152 sodium sulphate Nutrition 0.000 description 8
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 8
- LOBCDGHHHHGHFA-LBPRGKRZSA-N (S)-monastrol Chemical compound CCOC(=O)C1=C(C)NC(=S)N[C@H]1C1=CC=CC(O)=C1 LOBCDGHHHHGHFA-LBPRGKRZSA-N 0.000 description 7
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 description 7
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 7
- 229910052786 argon Inorganic materials 0.000 description 7
- 125000002619 bicyclic group Chemical group 0.000 description 7
- 239000012267 brine Substances 0.000 description 7
- YSHOWEKUVWPFNR-UHFFFAOYSA-N burgess reagent Chemical compound CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC YSHOWEKUVWPFNR-UHFFFAOYSA-N 0.000 description 7
- 239000000460 chlorine Substances 0.000 description 7
- 239000003112 inhibitor Substances 0.000 description 7
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 7
- 239000001301 oxygen Substances 0.000 description 7
- 229920005989 resin Polymers 0.000 description 7
- 239000011347 resin Substances 0.000 description 7
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 6
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- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 125000003282 alkyl amino group Chemical group 0.000 description 6
- 150000001721 carbon Chemical group 0.000 description 6
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 6
- 235000019341 magnesium sulphate Nutrition 0.000 description 6
- 230000036456 mitotic arrest Effects 0.000 description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 5
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 5
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- 238000006467 substitution reaction Methods 0.000 description 5
- 239000011593 sulfur Substances 0.000 description 5
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- ASOFZHSTJHGQDT-UHFFFAOYSA-N 3,5-difluorobenzaldehyde Chemical compound FC1=CC(F)=CC(C=O)=C1 ASOFZHSTJHGQDT-UHFFFAOYSA-N 0.000 description 4
- NMTUHPSKJJYGML-UHFFFAOYSA-N 3-(trifluoromethyl)benzaldehyde Chemical compound FC(F)(F)C1=CC=CC(C=O)=C1 NMTUHPSKJJYGML-UHFFFAOYSA-N 0.000 description 4
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 4
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- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
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- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
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- 125000004414 alkyl thio group Chemical group 0.000 description 3
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000003776 cleavage reaction Methods 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
- JMYVMOUINOAAPA-UHFFFAOYSA-N cyclopropanecarbaldehyde Chemical compound O=CC1CC1 JMYVMOUINOAAPA-UHFFFAOYSA-N 0.000 description 3
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- 231100000599 cytotoxic agent Toxicity 0.000 description 3
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- 238000004821 distillation Methods 0.000 description 3
- 231100000673 dose–response relationship Toxicity 0.000 description 3
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/20—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D239/22—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to ring carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
- C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
-
- 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
- C07D403/02—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 two hetero rings
- C07D403/10—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 two hetero rings linked by a carbon chain containing aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Vascular Medicine (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US27995601P | 2001-03-29 | 2001-03-29 | |
| PCT/US2002/009497 WO2002079149A2 (en) | 2001-03-29 | 2002-03-26 | Novel cyano-substituted dihydropyrimidine compounds and their use to treat diseases |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| HRP20030875A2 true HRP20030875A2 (en) | 2004-08-31 |
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| HR20030875A HRP20030875A2 (en) | 2001-03-29 | 2003-10-28 | Novel cyano-substituted dihydropyrimidine compounds and their use to treat diseases |
Country Status (26)
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| US (1) | US6809102B2 (sh) |
| EP (1) | EP1373221A4 (sh) |
| JP (1) | JP2005504725A (sh) |
| KR (1) | KR20030086327A (sh) |
| CN (1) | CN1507435A (sh) |
| AR (1) | AR034585A1 (sh) |
| BG (1) | BG108180A (sh) |
| BR (1) | BR0208405A (sh) |
| CA (1) | CA2442482A1 (sh) |
| CZ (1) | CZ20032645A3 (sh) |
| EE (1) | EE200300474A (sh) |
| HR (1) | HRP20030875A2 (sh) |
| HU (1) | HUP0400350A3 (sh) |
| IL (1) | IL157441A0 (sh) |
| IS (1) | IS6967A (sh) |
| MX (1) | MXPA03008634A (sh) |
| NO (1) | NO20034300L (sh) |
| PE (1) | PE20021013A1 (sh) |
| PL (1) | PL373759A1 (sh) |
| RU (1) | RU2003130961A (sh) |
| SK (1) | SK11062003A3 (sh) |
| TW (1) | TWI228416B (sh) |
| UY (1) | UY27232A1 (sh) |
| WO (1) | WO2002079149A2 (sh) |
| YU (1) | YU75803A (sh) |
| ZA (2) | ZA200306648B (sh) |
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| US6900214B2 (en) * | 2001-03-29 | 2005-05-31 | Bristol-Myers Squibb Company | Cyano-substituted dihydropyrimidine compounds and their use to treat diseases |
| EP1454903B9 (en) * | 2001-12-11 | 2011-10-05 | Kyowa Hakko Kirin Co., Ltd. | Thiadiazoline derivatives for treating cancer |
| MY141583A (en) * | 2003-03-07 | 2010-05-14 | Astrazeneca Ab | Novel fused heterocycles and uses thereof |
| WO2006018628A1 (en) * | 2003-03-07 | 2006-02-23 | Astrazeneca Ab | Enantiomers of selected fused pyrimidones and uses in the treatment and preventi on of cancer |
| ATE537158T1 (de) | 2003-04-18 | 2011-12-15 | Kyowa Hakko Kirin Co Ltd | M-stage-kinesin-inhibitor |
| WO2004111024A1 (ja) * | 2003-06-10 | 2004-12-23 | Kyowa Hakko Kogyo Co., Ltd. | チアジアゾリン誘導体 |
| US7157461B2 (en) | 2003-07-23 | 2007-01-02 | Bristol-Myers Squibb Co. | Substituted dihydropyrimidine inhibitors of calcium channel function |
| US7166603B2 (en) | 2003-07-23 | 2007-01-23 | Bristol-Myers Squibb Co. | Dihydropyrimidone inhibitors of calcium channel function |
| JP2007509074A (ja) * | 2003-10-16 | 2007-04-12 | サイトキネティクス・インコーポレーテッド | 化合物、組成物、および方法 |
| CN101023082A (zh) * | 2004-07-22 | 2007-08-22 | 阿斯利康(瑞典)有限公司 | 用于治疗和预防癌症的稠合嘧啶酮类 |
| JP2008509977A (ja) * | 2004-08-18 | 2008-04-03 | アストラゼネカ アクチボラグ | 癌の処置及び予防における選択された縮合複素環の鏡像異性体及びその使用 |
| US20060041128A1 (en) * | 2004-08-18 | 2006-02-23 | Astrazeneca Ab | Selected fused heterocyclics and uses thereof |
| WO2006060737A2 (en) * | 2004-12-03 | 2006-06-08 | Takeda San Diego, Inc. | Mitotic kinesin inhibitors |
| CN101193878A (zh) * | 2005-03-22 | 2008-06-04 | 协和发酵工业株式会社 | 实体肿瘤治疗剂 |
| WO2006101103A1 (ja) * | 2005-03-22 | 2006-09-28 | Kyowa Hakko Kogyo Co., Ltd. | 造血器腫瘍治療剤 |
| WO2006137490A1 (ja) * | 2005-06-24 | 2006-12-28 | Kyowa Hakko Kogyo Co., Ltd. | 再狭窄治療剤 |
| DE102006002065B4 (de) * | 2006-01-16 | 2007-11-29 | Infineon Technologies Austria Ag | Kompensationsbauelement mit reduziertem und einstellbarem Einschaltwiderstand |
| CN110464722B (zh) * | 2019-06-06 | 2023-05-23 | 暨南大学 | 一类小分子化合物或其药学上可接受的盐在制备抗肿瘤转移药物中的应用 |
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| US6211198B1 (en) | 1993-04-05 | 2001-04-03 | Synaptic Pharmaceutical Corporation | Dihydropyridines and new uses thereof |
| EE9700209A (et) | 1994-11-16 | 1998-04-15 | Synaptic Pharmaceutical Corporation | Dihüdropürimidiinid ja nende kasutamine |
| WO1997017969A1 (en) | 1995-11-16 | 1997-05-22 | Synaptic Pharmaceutical Corporation | Dihydropyrimidines and uses thereof |
| JP2000506904A (ja) | 1996-05-16 | 2000-06-06 | シナプティック・ファーマスーティカル・コーポレーション | ジヒドロピリミジン類およびその使用 |
| US6172066B1 (en) | 1996-05-16 | 2001-01-09 | Synaptic Pharmaceutical Corporation | Dihydropyrimidines and uses thereof |
| US6080760A (en) | 1997-06-18 | 2000-06-27 | Merck & Co., Inc. | Alpha 1A adrenergic receptor antagonists |
| WO1998057639A1 (en) | 1997-06-18 | 1998-12-23 | Merck & Co., Inc. | ALPHA 1aADRENERGIC RECEPTOR ANTAGONISTS |
| AU1403099A (en) | 1997-11-14 | 1999-06-07 | Merck & Co., Inc. | Alpha-1a adrenergic receptor antagonists |
| WO1999050440A2 (en) | 1998-04-01 | 1999-10-07 | Yale University | Method to identify modulators of survivin - tubulin interaction |
| US6300084B1 (en) | 1998-10-08 | 2001-10-09 | The Regents Of The University Of California | Anti-mitotic agent screening process |
| AUPQ171999A0 (en) | 1999-07-20 | 1999-08-12 | University Of Sydney, The | Neurotropic virus transport |
| DE19935303A1 (de) | 1999-07-28 | 2001-02-08 | Aventis Pharma Gmbh | Oligonukleotide zur Inhibierung der Expression von humanem eg5 |
| US6617115B1 (en) | 1999-10-27 | 2003-09-09 | Cytokinetics, Inc. | Methods of screening for modulators of cell proliferation |
| BR0015110A (pt) | 1999-10-27 | 2002-07-02 | Cytokinetics Inc | Métodos de tratamento de doenças de proliferação celular, de tratamento de um distúrbio associado com a atividade da cinesina ksp, de inibição da cinesina ksp, de triagem de moduladores da cinesina kps e de triagem de compostos que se ligam na cinesina ksp, e, compostos |
| US6284480B1 (en) | 2000-04-03 | 2001-09-04 | Cytokinetics, Inc. | Antifungal assay |
| US6900214B2 (en) | 2001-03-29 | 2005-05-31 | Bristol-Myers Squibb Company | Cyano-substituted dihydropyrimidine compounds and their use to treat diseases |
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| JP2005504725A (ja) | 2005-02-17 |
| WO2002079149A2 (en) | 2002-10-10 |
| UY27232A1 (es) | 2002-11-29 |
| NO20034300D0 (no) | 2003-09-26 |
| AR034585A1 (es) | 2004-03-03 |
| CN1507435A (zh) | 2004-06-23 |
| US6809102B2 (en) | 2004-10-26 |
| MXPA03008634A (es) | 2003-12-08 |
| HUP0400350A2 (hu) | 2005-01-28 |
| NO20034300L (no) | 2003-11-07 |
| ZA200306648B (en) | 2004-11-26 |
| PE20021013A1 (es) | 2002-11-10 |
| HUP0400350A3 (en) | 2005-06-28 |
| RU2003130961A (ru) | 2005-04-10 |
| BR0208405A (pt) | 2004-03-30 |
| TWI228416B (en) | 2005-03-01 |
| CA2442482A1 (en) | 2002-10-10 |
| PL373759A1 (en) | 2005-09-05 |
| KR20030086327A (ko) | 2003-11-07 |
| EP1373221A2 (en) | 2004-01-02 |
| IL157441A0 (en) | 2004-03-28 |
| CZ20032645A3 (cs) | 2004-06-16 |
| YU75803A (sh) | 2006-05-25 |
| WO2002079149A3 (en) | 2003-02-27 |
| EE200300474A (et) | 2003-12-15 |
| SK11062003A3 (sk) | 2004-08-03 |
| BG108180A (en) | 2004-09-30 |
| IS6967A (is) | 2003-09-24 |
| US20030008888A1 (en) | 2003-01-09 |
| EP1373221A4 (en) | 2004-09-29 |
| ZA200307320B (en) | 2004-12-20 |
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