ZA200306648B - Cyano-substituted dihydropyrimidine compounds and their use to treat diseases. - Google Patents
Cyano-substituted dihydropyrimidine compounds and their use to treat diseases. Download PDFInfo
- Publication number
- ZA200306648B ZA200306648B ZA200306648A ZA200306648A ZA200306648B ZA 200306648 B ZA200306648 B ZA 200306648B ZA 200306648 A ZA200306648 A ZA 200306648A ZA 200306648 A ZA200306648 A ZA 200306648A ZA 200306648 B ZA200306648 B ZA 200306648B
- Authority
- ZA
- South Africa
- Prior art keywords
- methyl
- cyano
- dihydro
- phenyl
- pyrimidinecarboxylic acid
- Prior art date
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- -1 Cyano-substituted dihydropyrimidine compounds Chemical class 0.000 title claims description 51
- 201000010099 disease Diseases 0.000 title claims description 24
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims description 24
- 150000001875 compounds Chemical class 0.000 claims description 225
- 238000000034 method Methods 0.000 claims description 147
- 125000000217 alkyl group Chemical group 0.000 claims description 85
- 125000003118 aryl group Chemical group 0.000 claims description 43
- 239000000203 mixture Substances 0.000 claims description 37
- 238000011282 treatment Methods 0.000 claims description 33
- 229910052739 hydrogen Inorganic materials 0.000 claims description 30
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 claims description 28
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 28
- 125000001072 heteroaryl group Chemical group 0.000 claims description 27
- 206010028980 Neoplasm Diseases 0.000 claims description 24
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 23
- 229910052760 oxygen Inorganic materials 0.000 claims description 23
- 125000000623 heterocyclic group Chemical group 0.000 claims description 20
- JLLYLQLDYORLBB-UHFFFAOYSA-N 5-bromo-n-methylthiophene-2-sulfonamide Chemical compound CNS(=O)(=O)C1=CC=C(Br)S1 JLLYLQLDYORLBB-UHFFFAOYSA-N 0.000 claims description 19
- 201000011510 cancer Diseases 0.000 claims description 17
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 17
- 102000004169 proteins and genes Human genes 0.000 claims description 17
- 108090000623 proteins and genes Proteins 0.000 claims description 17
- 230000002062 proliferating effect Effects 0.000 claims description 16
- 125000001424 substituent group Chemical group 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
- 125000001188 haloalkyl group Chemical group 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
- 230000036456 mitotic arrest Effects 0.000 claims description 12
- 239000003112 inhibitor Substances 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 11
- 229940002612 prodrug Drugs 0.000 claims description 10
- 239000000651 prodrug Substances 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 8
- 239000002246 antineoplastic agent Substances 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 7
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 claims description 6
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 230000001939 inductive effect Effects 0.000 claims description 6
- 239000012453 solvate Substances 0.000 claims description 6
- 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 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 229910052731 fluorine Inorganic materials 0.000 claims description 5
- 229940127084 other anti-cancer agent Drugs 0.000 claims description 5
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 5
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 claims description 4
- 229940123780 DNA topoisomerase I inhibitor Drugs 0.000 claims description 3
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 claims description 3
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- 239000000365 Topoisomerase I Inhibitor Substances 0.000 claims description 3
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- 229940100197 antimetabolite Drugs 0.000 claims description 3
- 239000002256 antimetabolite Substances 0.000 claims description 3
- 229960004316 cisplatin Drugs 0.000 claims description 3
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 claims description 3
- 125000002720 diazolyl group Chemical group 0.000 claims description 3
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- 229960004679 doxorubicin Drugs 0.000 claims description 3
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- 229960005420 etoposide Drugs 0.000 claims description 3
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 claims description 3
- 229960001592 paclitaxel Drugs 0.000 claims description 3
- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- 229960001603 tamoxifen Drugs 0.000 claims description 3
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 claims description 3
- 125000000335 thiazolyl group Chemical group 0.000 claims description 3
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 claims description 3
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- 125000002877 alkyl aryl group Chemical group 0.000 claims description 2
- 125000005418 aryl aryl group Chemical group 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims 12
- HTJDQJBWANPRPF-UHFFFAOYSA-N Cyclopropylamine Chemical compound NC1CC1 HTJDQJBWANPRPF-UHFFFAOYSA-N 0.000 claims 6
- GYFAVTPTDNOSQJ-UHFFFAOYSA-N 5-cyano-4-(4-fluoro-3-pyridin-3-ylphenyl)-6-methyl-2-oxo-1,4-dihydropyrimidine-3-carboxylic acid Chemical compound OC(=O)N1C(=O)NC(C)=C(C#N)C1C1=CC=C(F)C(C=2C=NC=CC=2)=C1 GYFAVTPTDNOSQJ-UHFFFAOYSA-N 0.000 claims 5
- SKKMKZQWHMGZAL-UHFFFAOYSA-N 5-cyano-4-(2-fluoro-5-pyridin-3-ylphenyl)-6-methyl-2-oxo-1,4-dihydropyrimidine-3-carboxylic acid Chemical compound OC(=O)N1C(=O)NC(C)=C(C#N)C1C1=CC(C=2C=NC=CC=2)=CC=C1F SKKMKZQWHMGZAL-UHFFFAOYSA-N 0.000 claims 3
- WLNRXSLTHNJVFW-UHFFFAOYSA-N 5-cyano-6-methyl-4-[3-(4-methylpyridin-3-yl)phenyl]-2-oxo-1,4-dihydropyrimidine-3-carboxylic acid Chemical compound OC(=O)N1C(=O)NC(C)=C(C#N)C1C1=CC=CC(C=2C(=CC=NC=2)C)=C1 WLNRXSLTHNJVFW-UHFFFAOYSA-N 0.000 claims 3
- 150000001408 amides Chemical class 0.000 claims 3
- 238000004519 manufacturing process Methods 0.000 claims 3
- 229940124087 DNA topoisomerase II inhibitor Drugs 0.000 claims 2
- 239000000317 Topoisomerase II Inhibitor Substances 0.000 claims 2
- 150000003883 epothilone derivatives Chemical class 0.000 claims 2
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 claims 2
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 claims 2
- RCUBVHYVCYOEAP-UHFFFAOYSA-N 4-[2-(4-chlorophenyl)phenyl]-5-cyano-6-methyl-2-oxo-1,4-dihydropyrimidine-3-carboxylic acid Chemical compound OC(=O)N1C(=O)NC(C)=C(C#N)C1C1=CC=CC=C1C1=CC=C(Cl)C=C1 RCUBVHYVCYOEAP-UHFFFAOYSA-N 0.000 claims 1
- JTVOVVQOZNYGOY-UHFFFAOYSA-N 4-[3-(4-chlorophenyl)phenyl]-5-cyano-6-methyl-2-oxo-1,4-dihydropyrimidine-3-carboxylic acid Chemical compound OC(=O)N1C(=O)NC(C)=C(C#N)C1C1=CC=CC(C=2C=CC(Cl)=CC=2)=C1 JTVOVVQOZNYGOY-UHFFFAOYSA-N 0.000 claims 1
- KZZKOVLJUKWSKX-UHFFFAOYSA-N cyclobutanamine Chemical compound NC1CCC1 KZZKOVLJUKWSKX-UHFFFAOYSA-N 0.000 claims 1
- NISGSNTVMOOSJQ-UHFFFAOYSA-N cyclopentanamine Chemical compound NC1CCCC1 NISGSNTVMOOSJQ-UHFFFAOYSA-N 0.000 claims 1
- 125000001475 halogen functional group Chemical group 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 99
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 57
- 238000005160 1H NMR spectroscopy Methods 0.000 description 53
- 239000000543 intermediate Substances 0.000 description 43
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 41
- 210000004027 cell Anatomy 0.000 description 39
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 38
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- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 27
- 235000019439 ethyl acetate Nutrition 0.000 description 26
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 26
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 24
- 238000006243 chemical reaction Methods 0.000 description 23
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- 239000007787 solid Substances 0.000 description 23
- 239000011734 sodium Substances 0.000 description 22
- 125000003545 alkoxy group Chemical group 0.000 description 21
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 21
- 102100027629 Kinesin-like protein KIF11 Human genes 0.000 description 18
- 125000004432 carbon atom Chemical group C* 0.000 description 18
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 17
- 229920006395 saturated elastomer Polymers 0.000 description 15
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 14
- 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
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- 238000004128 high performance liquid chromatography Methods 0.000 description 14
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- 125000005843 halogen group Chemical group 0.000 description 12
- 125000005842 heteroatom Chemical group 0.000 description 12
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 12
- 230000011278 mitosis Effects 0.000 description 12
- 102000029749 Microtubule Human genes 0.000 description 11
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- YSHOWEKUVWPFNR-UHFFFAOYSA-N burgess reagent Chemical compound CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC YSHOWEKUVWPFNR-UHFFFAOYSA-N 0.000 description 11
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
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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 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
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 9
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- 229910052757 nitrogen Inorganic materials 0.000 description 9
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- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 9
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 8
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Classifications
-
- 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 (1)
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| CN (1) | CN1507435A (hu) |
| AR (1) | AR034585A1 (hu) |
| BG (1) | BG108180A (hu) |
| BR (1) | BR0208405A (hu) |
| CA (1) | CA2442482A1 (hu) |
| CZ (1) | CZ20032645A3 (hu) |
| EE (1) | EE200300474A (hu) |
| HR (1) | HRP20030875A2 (hu) |
| HU (1) | HUP0400350A3 (hu) |
| IL (1) | IL157441A0 (hu) |
| IS (1) | IS6967A (hu) |
| MX (1) | MXPA03008634A (hu) |
| NO (1) | NO20034300L (hu) |
| PE (1) | PE20021013A1 (hu) |
| PL (1) | PL373759A1 (hu) |
| RU (1) | RU2003130961A (hu) |
| SK (1) | SK11062003A3 (hu) |
| TW (1) | TWI228416B (hu) |
| UY (1) | UY27232A1 (hu) |
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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 |
| PT1847534E (pt) * | 2001-12-11 | 2011-08-01 | Kyowa Hakko Kirin Co Ltd | Derivado de tiadiozolina para o tratamento do cancro |
| CA2518224C (en) * | 2003-03-07 | 2010-06-15 | Astrazeneca Ab | Novel isothiazolopyrimidinones and isoxazolopyrimidinones 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 |
| CN101787000B (zh) | 2003-04-18 | 2011-08-03 | 协和发酵麒麟株式会社 | M期驱动蛋白抑制剂 |
| KR20060014071A (ko) * | 2003-06-10 | 2006-02-14 | 교와 핫꼬 고교 가부시끼가이샤 | 티아디아졸린 유도체 |
| 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 |
| WO2005037799A1 (en) * | 2003-10-16 | 2005-04-28 | Cytokinetics, Inc. | Compounds, compositions, and methods |
| EP1773830A1 (en) * | 2004-07-22 | 2007-04-18 | AstraZeneca AB | Fused pyrimidones useful in the treatment and the prevention of cancer |
| US20060041128A1 (en) * | 2004-08-18 | 2006-02-23 | Astrazeneca Ab | Selected fused heterocyclics and uses thereof |
| KR20070046176A (ko) * | 2004-08-18 | 2007-05-02 | 아스트라제네카 아베 | 특정 융합 피리미돈의 거울상이성질체 및 이의 암 치료 및예방에 있어서의 용도 |
| WO2006060737A2 (en) * | 2004-12-03 | 2006-06-08 | Takeda San Diego, Inc. | Mitotic kinesin inhibitors |
| WO2006101103A1 (ja) * | 2005-03-22 | 2006-09-28 | Kyowa Hakko Kogyo Co., Ltd. | 造血器腫瘍治療剤 |
| CA2602397A1 (en) * | 2005-03-22 | 2006-09-28 | Kyowa Hakko Kogyo Co., Ltd. | Therapeutic agent for solid tumor |
| US7910611B2 (en) * | 2005-06-24 | 2011-03-22 | Kyowa Hakko Kirin Co., Ltd. | Therapeutic agent for restenosis |
| 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 |
| PL320263A1 (en) | 1994-11-16 | 1997-09-15 | Synaptic Pharma Corp | Dihydropyrimidines and their application |
| WO1997017969A1 (en) | 1995-11-16 | 1997-05-22 | Synaptic Pharmaceutical Corporation | Dihydropyrimidines and uses thereof |
| US6172066B1 (en) | 1996-05-16 | 2001-01-09 | 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 |
| CA2294349A1 (en) | 1997-06-18 | 1998-12-23 | Michael A. Patane | Alpha 1aadrenergic receptor antagonists |
| US6080760A (en) | 1997-06-18 | 2000-06-27 | Merck & Co., Inc. | Alpha 1A adrenergic 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 |
| MXPA02004162A (es) | 1999-10-27 | 2003-08-20 | Cytokinetics Inc | Metodo y composiciones que utilizan quinazolinonas. |
| 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 |
-
2002
- 2002-03-22 US US10/104,257 patent/US6809102B2/en not_active Expired - Lifetime
- 2002-03-25 TW TW091105771A patent/TWI228416B/zh not_active IP Right Cessation
- 2002-03-25 PE PE2002000232A patent/PE20021013A1/es not_active Application Discontinuation
- 2002-03-26 YU YU75803A patent/YU75803A/sh unknown
- 2002-03-26 CA CA002442482A patent/CA2442482A1/en not_active Abandoned
- 2002-03-26 JP JP2002577776A patent/JP2005504725A/ja not_active Withdrawn
- 2002-03-26 SK SK1106-2003A patent/SK11062003A3/sk unknown
- 2002-03-26 BR BR0208405-8A patent/BR0208405A/pt not_active IP Right Cessation
- 2002-03-26 MX MXPA03008634A patent/MXPA03008634A/es unknown
- 2002-03-26 EE EEP200300474A patent/EE200300474A/xx unknown
- 2002-03-26 WO PCT/US2002/009497 patent/WO2002079149A2/en active Search and Examination
- 2002-03-26 PL PL02373759A patent/PL373759A1/xx not_active Application Discontinuation
- 2002-03-26 EP EP02728592A patent/EP1373221A4/en not_active Withdrawn
- 2002-03-26 IL IL15744102A patent/IL157441A0/xx unknown
- 2002-03-26 KR KR10-2003-7012604A patent/KR20030086327A/ko not_active Application Discontinuation
- 2002-03-26 HU HU0400350A patent/HUP0400350A3/hu unknown
- 2002-03-26 RU RU2003130961/04A patent/RU2003130961A/ru not_active Application Discontinuation
- 2002-03-26 CN CNA028074556A patent/CN1507435A/zh active Pending
- 2002-03-26 CZ CZ20032645A patent/CZ20032645A3/cs unknown
- 2002-03-27 UY UY27232A patent/UY27232A1/es not_active Application Discontinuation
- 2002-03-27 AR ARP020101168A patent/AR034585A1/es unknown
-
2003
- 2003-08-26 ZA ZA200306648A patent/ZA200306648B/en unknown
- 2003-09-17 BG BG108180A patent/BG108180A/xx unknown
- 2003-09-18 ZA ZA200307320A patent/ZA200307320B/en unknown
- 2003-09-24 IS IS6967A patent/IS6967A/is unknown
- 2003-09-26 NO NO20034300A patent/NO20034300L/no not_active Application Discontinuation
- 2003-10-28 HR HR20030875A patent/HRP20030875A2/hr not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| UY27232A1 (es) | 2002-11-29 |
| WO2002079149A2 (en) | 2002-10-10 |
| WO2002079149A3 (en) | 2003-02-27 |
| CZ20032645A3 (cs) | 2004-06-16 |
| BR0208405A (pt) | 2004-03-30 |
| CA2442482A1 (en) | 2002-10-10 |
| KR20030086327A (ko) | 2003-11-07 |
| BG108180A (en) | 2004-09-30 |
| IL157441A0 (en) | 2004-03-28 |
| PE20021013A1 (es) | 2002-11-10 |
| US20030008888A1 (en) | 2003-01-09 |
| HRP20030875A2 (en) | 2004-08-31 |
| EP1373221A2 (en) | 2004-01-02 |
| HUP0400350A2 (hu) | 2005-01-28 |
| IS6967A (is) | 2003-09-24 |
| JP2005504725A (ja) | 2005-02-17 |
| SK11062003A3 (sk) | 2004-08-03 |
| RU2003130961A (ru) | 2005-04-10 |
| NO20034300L (no) | 2003-11-07 |
| NO20034300D0 (no) | 2003-09-26 |
| ZA200307320B (en) | 2004-12-20 |
| CN1507435A (zh) | 2004-06-23 |
| EP1373221A4 (en) | 2004-09-29 |
| HUP0400350A3 (en) | 2005-06-28 |
| US6809102B2 (en) | 2004-10-26 |
| TWI228416B (en) | 2005-03-01 |
| EE200300474A (et) | 2003-12-15 |
| YU75803A (sh) | 2006-05-25 |
| AR034585A1 (es) | 2004-03-03 |
| PL373759A1 (en) | 2005-09-05 |
| MXPA03008634A (es) | 2003-12-08 |
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