ZA200306648B - Cyano-substituted dihydropyrimidine compounds and their use to treat diseases. - Google Patents

Cyano-substituted dihydropyrimidine compounds and their use to treat diseases. Download PDF

Info

Publication number: ZA200306648B
Authority: ZA; South Africa
Prior art keywords: methyl; cyano; dihydro; phenyl; pyrimidinecarboxylic acid
Prior art date: 2001-03-29

Application number

ZA200306648A

Other languages

English (en)

Inventor

Louis J Lombardo

Laurence I Wu

Original Assignee

Bristol Myers Squibb Co

Priority date (The priority date 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 date listed.)

2001-03-29

Filing date

2003-08-26

Publication date

2004-11-26

2003-08-26 Application filed by Bristol Myers Squibb Co filed Critical Bristol Myers Squibb Co

2004-11-26 Publication of ZA200306648B publication Critical patent/ZA200306648B/en

Links

-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
229930012538 Paclitaxel Natural products 0.000 claims description 3
239000000365 Topoisomerase I Inhibitor Substances 0.000 claims description 3
230000000340 anti-metabolite Effects 0.000 claims description 3
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
229960003668 docetaxel Drugs 0.000 claims description 3
229960004679 doxorubicin Drugs 0.000 claims description 3
229930013356 epothilone Natural products 0.000 claims description 3
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
229960000303 topotecan Drugs 0.000 claims description 3
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
238000000524 positive electrospray ionisation mass spectrometry Methods 0.000 description 38
239000000243 solution Substances 0.000 description 36
239000000047 product Substances 0.000 description 31
239000011541 reaction mixture Substances 0.000 description 29
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
238000012544 monitoring process Methods 0.000 description 23
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
229910052799 carbon Inorganic materials 0.000 description 14
238000004128 high performance liquid chromatography Methods 0.000 description 14
239000004202 carbamide Substances 0.000 description 13
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
108091022875 Microtubule Proteins 0.000 description 11
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
210000004688 microtubule Anatomy 0.000 description 11
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-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
IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 10
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
238000003556 assay Methods 0.000 description 10
230000022131 cell cycle Effects 0.000 description 10
230000000394 mitotic effect Effects 0.000 description 10
239000012044 organic layer Substances 0.000 description 10
238000002953 preparative HPLC Methods 0.000 description 10
229910002027 silica gel Inorganic materials 0.000 description 10
239000000741 silica gel Substances 0.000 description 10
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
229910052740 iodine Inorganic materials 0.000 description 9
229910052757 nitrogen Inorganic materials 0.000 description 9
239000003921 oil Substances 0.000 description 9
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 9
WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 8
HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
125000005196 alkyl carbonyloxy group Chemical group 0.000 description 8
238000003782 apoptosis assay Methods 0.000 description 8
230000006907 apoptotic process Effects 0.000 description 8
239000000460 chlorine Substances 0.000 description 8
125000004093 cyano group Chemical group *C#N 0.000 description 8
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 8
125000002950 monocyclic group Chemical group 0.000 description 8
230000005522 programmed cell death Effects 0.000 description 8
229910000104 sodium hydride Inorganic materials 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
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 7
GCPWJFKTWGFEHH-UHFFFAOYSA-N acetoacetamide Chemical compound CC(=O)CC(N)=O GCPWJFKTWGFEHH-UHFFFAOYSA-N 0.000 description 7
125000003342 alkenyl group Chemical group 0.000 description 7
229910000147 aluminium phosphate Inorganic materials 0.000 description 7
229910052786 argon Inorganic materials 0.000 description 7
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 7
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239000012267 brine Substances 0.000 description 7
230000000694 effects Effects 0.000 description 7
239000012948 isocyanate Substances 0.000 description 7
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125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 7
239000001301 oxygen Substances 0.000 description 7
KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 7
229920005989 resin Polymers 0.000 description 7
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150000003384 small molecules Chemical class 0.000 description 7
HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 6
WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 6
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241000894007 species Species 0.000 description 6
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NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
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150000001721 carbon Chemical group 0.000 description 4
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FQGZYCCIGLIJFM-UHFFFAOYSA-N 5-cyano-6-methyl-4-(3-nitrophenyl)-2-oxo-1,4-dihydropyrimidine-3-carboxylic acid Chemical compound OC(=O)N1C(=O)NC(C)=C(C#N)C1C1=CC=CC([N+]([O-])=O)=C1 FQGZYCCIGLIJFM-UHFFFAOYSA-N 0.000 description 3
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KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 3
239000004215 Carbon black (E152) Substances 0.000 description 3
229910021591 Copper(I) chloride Inorganic materials 0.000 description 3
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
102000010638 Kinesin Human genes 0.000 description 3
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229910052754 neon Inorganic materials 0.000 description 1
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ANRQGKOBLBYXFM-UHFFFAOYSA-M phenylmagnesium bromide Chemical compound Br[Mg]C1=CC=CC=C1 ANRQGKOBLBYXFM-UHFFFAOYSA-M 0.000 description 1
NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
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HBCQSNAFLVXVAY-UHFFFAOYSA-N pyrimidine-2-thiol Chemical class SC1=NC=CC=N1 HBCQSNAFLVXVAY-UHFFFAOYSA-N 0.000 description 1
125000000714 pyrimidinyl group Chemical group 0.000 description 1
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150000003254 radicals Chemical class 0.000 description 1
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108700038288 rhodamine-phalloidin Proteins 0.000 description 1
238000007363 ring formation reaction Methods 0.000 description 1
229930195734 saturated hydrocarbon Natural products 0.000 description 1
230000036573 scar formation Effects 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
125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
238000007086 side reaction Methods 0.000 description 1
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201000009890 sinusitis Diseases 0.000 description 1
210000003491 skin Anatomy 0.000 description 1
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239000001632 sodium acetate Substances 0.000 description 1
235000017281 sodium acetate Nutrition 0.000 description 1
235000017557 sodium bicarbonate Nutrition 0.000 description 1
229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
238000010532 solid phase synthesis reaction Methods 0.000 description 1
238000007614 solvation Methods 0.000 description 1
239000002904 solvent Substances 0.000 description 1
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238000010186 staining Methods 0.000 description 1
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230000004083 survival effect Effects 0.000 description 1
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125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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238000002560 therapeutic procedure Methods 0.000 description 1
125000001113 thiadiazolyl group Chemical group 0.000 description 1
125000005309 thioalkoxy group Chemical group 0.000 description 1
AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 description 1
210000001519 tissue Anatomy 0.000 description 1
231100000440 toxicity profile Toxicity 0.000 description 1
239000003053 toxin Substances 0.000 description 1
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125000004306 triazinyl group Chemical group 0.000 description 1
ZBZJXHCVGLJWFG-UHFFFAOYSA-N trichloromethyl(.) Chemical compound Cl[C](Cl)Cl ZBZJXHCVGLJWFG-UHFFFAOYSA-N 0.000 description 1
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230000005747 tumor angiogenesis Effects 0.000 description 1
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125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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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
- 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)

ZA200306648A 2001-03-29 2003-08-26 Cyano-substituted dihydropyrimidine compounds and their use to treat diseases. ZA200306648B (en)

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US27995601P	2001-03-29	2001-03-29

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ZA200307320A ZA200307320B (en)	2001-03-29	2003-09-18	Novel cyano-substituted dihydropyrimidine compounds and their use to treat diseases.

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ZA200307320A ZA200307320B (en)	2001-03-29	2003-09-18	Novel cyano-substituted dihydropyrimidine compounds and their use to treat diseases.

Country Status (26)

Country	Link
US (1)	US6809102B2 (cs)
EP (1)	EP1373221A4 (cs)
JP (1)	JP2005504725A (cs)
KR (1)	KR20030086327A (cs)
CN (1)	CN1507435A (cs)
AR (1)	AR034585A1 (cs)
BG (1)	BG108180A (cs)
BR (1)	BR0208405A (cs)
CA (1)	CA2442482A1 (cs)
CZ (1)	CZ20032645A3 (cs)
EE (1)	EE200300474A (cs)
HR (1)	HRP20030875A2 (cs)
HU (1)	HUP0400350A3 (cs)
IL (1)	IL157441A0 (cs)
IS (1)	IS6967A (cs)
MX (1)	MXPA03008634A (cs)
NO (1)	NO20034300L (cs)
PE (1)	PE20021013A1 (cs)
PL (1)	PL373759A1 (cs)
RU (1)	RU2003130961A (cs)
SK (1)	SK11062003A3 (cs)
TW (1)	TWI228416B (cs)
UY (1)	UY27232A1 (cs)
WO (1)	WO2002079149A2 (cs)
YU (1)	YU75803A (cs)
ZA (2)	ZA200306648B (cs)

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US20050282838A1 (en) *	2003-10-16	2005-12-22	Shyamlal Ramchandani	Compounds, compositions, and methods
BRPI0513513A (pt) *	2004-07-22	2008-05-06	Astrazeneca Ab	composto ou um sal farmaceuticamente aceitável do mesmo, processo para preparar o mesmo, composição farmacêutica, uso de um composto ou um sal farmaceuticamente aceitável do mesmo, e, métodos para produzir um efeito inibitório de eg5 e um efeito anticáncer em um animal de sangue quente, e para tratar carcinomas em um animal de sangue quente
US20060041128A1 (en) *	2004-08-18	2006-02-23	Astrazeneca Ab	Selected fused heterocyclics and uses thereof
MX2007001953A (es) *	2004-08-18	2007-05-09	Astrazeneca Ab	Enantiomeros de pirimidonas fusionadas seleccionadas y usos en el tratamiento y prevencion del cancer.
US20100093767A1 (en) *	2004-12-03	2010-04-15	Takeda San Diego, Inc.	Mitotic Kinase Inhibitors
JPWO2006101103A1 (ja) *	2005-03-22	2008-09-04	協和醗酵工業株式会社	造血器腫瘍治療剤
KR20070113300A (ko) *	2005-03-22	2007-11-28	교와 핫꼬 고교 가부시끼가이샤	고형종양 치료제
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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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 BR BR0208405-8A patent/BR0208405A/pt not_active IP Right Cessation
- 2002-03-26 HU HU0400350A patent/HUP0400350A3/hu unknown
- 2002-03-26 MX MXPA03008634A patent/MXPA03008634A/es unknown
- 2002-03-26 JP JP2002577776A patent/JP2005504725A/ja not_active Withdrawn
- 2002-03-26 CA CA002442482A patent/CA2442482A1/en not_active Abandoned
- 2002-03-26 IL IL15744102A patent/IL157441A0/xx unknown
- 2002-03-26 YU YU75803A patent/YU75803A/sh unknown
- 2002-03-26 CZ CZ20032645A patent/CZ20032645A3/cs unknown
- 2002-03-26 CN CNA028074556A patent/CN1507435A/zh active Pending
- 2002-03-26 WO PCT/US2002/009497 patent/WO2002079149A2/en active Search and Examination
- 2002-03-26 EE EEP200300474A patent/EE200300474A/xx unknown
- 2002-03-26 SK SK1106-2003A patent/SK11062003A3/sk unknown
- 2002-03-26 EP EP02728592A patent/EP1373221A4/en not_active Withdrawn
- 2002-03-26 KR KR10-2003-7012604A patent/KR20030086327A/ko not_active Application Discontinuation
- 2002-03-26 PL PL02373759A patent/PL373759A1/xx not_active Application Discontinuation
- 2002-03-26 RU RU2003130961/04A patent/RU2003130961A/ru not_active Application Discontinuation
- 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
KR20030086327A (ko)	2003-11-07
HUP0400350A2 (hu)	2005-01-28
CZ20032645A3 (cs)	2004-06-16
JP2005504725A (ja)	2005-02-17
BR0208405A (pt)	2004-03-30
HRP20030875A2 (en)	2004-08-31
MXPA03008634A (es)	2003-12-08
IS6967A (is)	2003-09-24
YU75803A (sh)	2006-05-25
US20030008888A1 (en)	2003-01-09
WO2002079149A2 (en)	2002-10-10
CA2442482A1 (en)	2002-10-10
RU2003130961A (ru)	2005-04-10
PE20021013A1 (es)	2002-11-10
AR034585A1 (es)	2004-03-03
HUP0400350A3 (en)	2005-06-28
NO20034300D0 (no)	2003-09-26
BG108180A (en)	2004-09-30
EP1373221A4 (en)	2004-09-29
WO2002079149A3 (en)	2003-02-27
UY27232A1 (es)	2002-11-29
PL373759A1 (en)	2005-09-05
NO20034300L (no)	2003-11-07
SK11062003A3 (sk)	2004-08-03
EP1373221A2 (en)	2004-01-02
ZA200307320B (en)	2004-12-20
CN1507435A (zh)	2004-06-23
EE200300474A (et)	2003-12-15
IL157441A0 (en)	2004-03-28
TWI228416B (en)	2005-03-01
US6809102B2 (en)	2004-10-26

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