ES2305887T3 - Derivados de pirido y pirimidopirimidinas como agentes antiproliferativos. - Google Patents
Derivados de pirido y pirimidopirimidinas como agentes antiproliferativos. Download PDFInfo
- Publication number
- ES2305887T3 ES2305887T3 ES04804852T ES04804852T ES2305887T3 ES 2305887 T3 ES2305887 T3 ES 2305887T3 ES 04804852 T ES04804852 T ES 04804852T ES 04804852 T ES04804852 T ES 04804852T ES 2305887 T3 ES2305887 T3 ES 2305887T3
- Authority
- ES
- Spain
- Prior art keywords
- alkyl
- het
- alkyloxy
- hydroxy
- optionally substituted
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
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- 230000001028 anti-proliverative effect Effects 0.000 title description 4
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 312
- 150000001875 compounds Chemical class 0.000 claims abstract description 177
- -1 hydroxy, formyl Chemical group 0.000 claims abstract description 152
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 138
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 115
- 239000001257 hydrogen Substances 0.000 claims abstract description 115
- 125000001424 substituent group Chemical group 0.000 claims abstract description 83
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract description 62
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 41
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 40
- 125000001475 halogen functional group Chemical group 0.000 claims abstract description 27
- 150000003839 salts Chemical class 0.000 claims abstract description 27
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims abstract description 25
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims abstract description 6
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims abstract description 5
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 claims abstract description 4
- 125000000000 cycloalkoxy group Chemical group 0.000 claims abstract description 4
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 4
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 3
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims abstract 14
- 125000000623 heterocyclic group Chemical group 0.000 claims description 88
- 239000000543 intermediate Substances 0.000 claims description 70
- 125000002757 morpholinyl group Chemical group 0.000 claims description 65
- 125000003386 piperidinyl group Chemical group 0.000 claims description 63
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 61
- 239000013067 intermediate product Substances 0.000 claims description 42
- 125000004193 piperazinyl group Chemical group 0.000 claims description 40
- 238000002360 preparation method Methods 0.000 claims description 39
- 238000000034 method Methods 0.000 claims description 33
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 28
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 27
- 125000003342 alkenyl group Chemical group 0.000 claims description 18
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 18
- 239000003814 drug Substances 0.000 claims description 16
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 15
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 14
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 13
- 125000000335 thiazolyl group Chemical group 0.000 claims description 13
- 206010028980 Neoplasm Diseases 0.000 claims description 12
- 150000001448 anilines Chemical class 0.000 claims description 12
- 238000006798 ring closing metathesis reaction Methods 0.000 claims description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims description 9
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 8
- 201000011510 cancer Diseases 0.000 claims description 8
- 230000008878 coupling Effects 0.000 claims description 8
- 238000010168 coupling process Methods 0.000 claims description 8
- 238000005859 coupling reaction Methods 0.000 claims description 8
- 125000002883 imidazolyl group Chemical group 0.000 claims description 8
- 125000006542 morpholinylalkyl group Chemical group 0.000 claims description 8
- 125000001715 oxadiazolyl group Chemical group 0.000 claims description 8
- 201000001320 Atherosclerosis Diseases 0.000 claims description 7
- 125000005879 dioxolanyl group Chemical group 0.000 claims description 7
- 125000002541 furyl group Chemical group 0.000 claims description 7
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 7
- 125000002971 oxazolyl group Chemical group 0.000 claims description 7
- 230000002062 proliferating effect Effects 0.000 claims description 7
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 7
- 125000004076 pyridyl group Chemical group 0.000 claims description 7
- 208000037803 restenosis Diseases 0.000 claims description 7
- 101100070530 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) het-6 gene Proteins 0.000 claims description 6
- 150000001298 alcohols Chemical class 0.000 claims description 6
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 6
- CDAWCLOXVUBKRW-UHFFFAOYSA-N 2-aminophenol Chemical class NC1=CC=CC=C1O CDAWCLOXVUBKRW-UHFFFAOYSA-N 0.000 claims description 5
- YBAUXEUJXJTKCH-UHFFFAOYSA-N 4-chloro-6-methylsulfanylpyrimido[5,4-d]pyrimidine Chemical compound N1=CN=C(Cl)C2=NC(SC)=NC=C21 YBAUXEUJXJTKCH-UHFFFAOYSA-N 0.000 claims description 5
- 239000004480 active ingredient Substances 0.000 claims description 5
- BWESROVQGZSBRX-UHFFFAOYSA-N pyrido[3,2-d]pyrimidine Chemical compound C1=NC=NC2=CC=CN=C21 BWESROVQGZSBRX-UHFFFAOYSA-N 0.000 claims description 5
- 125000004485 2-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])C1([H])* 0.000 claims description 4
- 125000000304 alkynyl group Chemical group 0.000 claims description 4
- 125000005883 dithianyl group Chemical group 0.000 claims description 4
- 229940043355 kinase inhibitor Drugs 0.000 claims description 4
- 125000003884 phenylalkyl group Chemical group 0.000 claims description 4
- 239000003757 phosphotransferase inhibitor Substances 0.000 claims description 4
- 125000004568 thiomorpholinyl group Chemical group 0.000 claims description 4
- NCWDBNBNYVVARF-UHFFFAOYSA-N 1,3,2-dioxaborolane Chemical compound B1OCCO1 NCWDBNBNYVVARF-UHFFFAOYSA-N 0.000 claims description 3
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 3
- 125000003302 alkenyloxy group Chemical group 0.000 claims description 2
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 2
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 2
- 125000001041 indolyl group Chemical group 0.000 claims description 2
- 125000003072 pyrazolidinyl group Chemical group 0.000 claims description 2
- 150000002431 hydrogen Chemical group 0.000 claims 25
- ZTZZRTNLSNFTGA-UHFFFAOYSA-N (4-chloropyrimido[5,4-d]pyrimidin-6-yl) acetate Chemical compound N1=CN=C(Cl)C2=NC(OC(=O)C)=NC=C21 ZTZZRTNLSNFTGA-UHFFFAOYSA-N 0.000 claims 2
- 125000004448 alkyl carbonyl group Chemical group 0.000 abstract description 4
- 125000006526 (C1-C2) alkyl group Chemical group 0.000 abstract 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 1
- 125000000815 N-oxide group Chemical group 0.000 abstract 1
- 239000000203 mixture Substances 0.000 description 47
- 125000005843 halogen group Chemical group 0.000 description 45
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 39
- 239000000243 solution Substances 0.000 description 34
- 238000006243 chemical reaction Methods 0.000 description 33
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 27
- 239000002904 solvent Substances 0.000 description 27
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 26
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 23
- 239000000047 product Substances 0.000 description 22
- 239000011541 reaction mixture Substances 0.000 description 22
- 239000002253 acid Substances 0.000 description 20
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 19
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 17
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 17
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 14
- 210000004027 cell Anatomy 0.000 description 14
- 239000000460 chlorine Substances 0.000 description 14
- 125000004432 carbon atom Chemical group C* 0.000 description 13
- 239000007787 solid Substances 0.000 description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 12
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 12
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 description 12
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 11
- 150000001412 amines Chemical class 0.000 description 11
- 208000035475 disorder Diseases 0.000 description 11
- 125000006239 protecting group Chemical group 0.000 description 11
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 10
- 238000004128 high performance liquid chromatography Methods 0.000 description 10
- 239000000741 silica gel Substances 0.000 description 10
- 229910002027 silica gel Inorganic materials 0.000 description 10
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 9
- 229910052801 chlorine Inorganic materials 0.000 description 9
- 229940079593 drug Drugs 0.000 description 9
- 239000003480 eluent Substances 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
- 241001465754 Metazoa Species 0.000 description 8
- 229910052794 bromium Inorganic materials 0.000 description 8
- 238000004587 chromatography analysis Methods 0.000 description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 8
- 229930195733 hydrocarbon Natural products 0.000 description 8
- 230000002285 radioactive effect Effects 0.000 description 8
- 239000003826 tablet Substances 0.000 description 8
- 239000004215 Carbon black (E152) Substances 0.000 description 7
- 239000002585 base Substances 0.000 description 7
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 7
- 239000003795 chemical substances by application Substances 0.000 description 7
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 description 7
- 125000004674 methylcarbonyl group Chemical group CC(=O)* 0.000 description 7
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- 239000012071 phase Substances 0.000 description 7
- 150000003254 radicals Chemical class 0.000 description 7
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 6
- CMWKITSNTDAEDT-UHFFFAOYSA-N 2-nitrobenzaldehyde Chemical class [O-][N+](=O)C1=CC=CC=C1C=O CMWKITSNTDAEDT-UHFFFAOYSA-N 0.000 description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 239000005551 L01XE03 - Erlotinib Substances 0.000 description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 238000003818 flash chromatography Methods 0.000 description 6
- 239000011737 fluorine Substances 0.000 description 6
- 229910052731 fluorine Inorganic materials 0.000 description 6
- YLMAHDNUQAMNNX-UHFFFAOYSA-N imatinib methanesulfonate Chemical compound CS(O)(=O)=O.C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 YLMAHDNUQAMNNX-UHFFFAOYSA-N 0.000 description 6
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 description 6
- 239000002244 precipitate Substances 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- JOZPEVMCAKXSEY-UHFFFAOYSA-N pyrimido[5,4-d]pyrimidine Chemical class N1=CN=CC2=NC=NC=C21 JOZPEVMCAKXSEY-UHFFFAOYSA-N 0.000 description 6
- 102000027426 receptor tyrosine kinases Human genes 0.000 description 6
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- 238000003786 synthesis reaction Methods 0.000 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 description 5
- ZKHQWZAMYRWXGA-UHFFFAOYSA-N Adenosine triphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(=O)OP(O)(O)=O)C(O)C1O ZKHQWZAMYRWXGA-UHFFFAOYSA-N 0.000 description 5
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- 230000015572 biosynthetic process Effects 0.000 description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 5
- 229910052799 carbon Inorganic materials 0.000 description 5
- 238000011161 development Methods 0.000 description 5
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- 238000001914 filtration Methods 0.000 description 5
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- 125000004433 nitrogen atom Chemical group N* 0.000 description 5
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical group CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 5
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 5
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- 125000004665 trialkylsilyl group Chemical group 0.000 description 5
- FVNFFJZCBGWGDZ-UHFFFAOYSA-N 4,6-dichloropyrimido[5,4-d]pyrimidine Chemical compound N1=CN=C(Cl)C2=NC(Cl)=NC=C21 FVNFFJZCBGWGDZ-UHFFFAOYSA-N 0.000 description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 4
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- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
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- 229910052736 halogen Inorganic materials 0.000 description 4
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- 229940040692 lithium hydroxide monohydrate Drugs 0.000 description 4
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 4
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- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
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- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
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- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 3
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/18—Bridged systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/16—Peri-condensed systems
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- A—HUMAN NECESSITIES
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- 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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- 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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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/18—Bridged systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
- C07D487/16—Peri-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains four or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP0351058 | 2003-12-18 | ||
| WOPCT/EP03/51062 | 2003-12-18 | ||
| WOPCT/EP03/51058 | 2003-12-18 | ||
| EP0351062 | 2003-12-18 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ES2305887T3 true ES2305887T3 (es) | 2008-11-01 |
Family
ID=34702160
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES04804852T Expired - Lifetime ES2305887T3 (es) | 2003-12-18 | 2004-12-15 | Derivados de pirido y pirimidopirimidinas como agentes antiproliferativos. |
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| Country | Link |
|---|---|
| US (3) | US7799772B2 (https=) |
| EP (1) | EP1697384B1 (https=) |
| JP (1) | JP4936897B2 (https=) |
| KR (1) | KR101174672B1 (https=) |
| AR (1) | AR046957A1 (https=) |
| AU (1) | AU2004298448B2 (https=) |
| CA (1) | CA2549869C (https=) |
| DE (1) | DE602004012891T2 (https=) |
| EA (1) | EA013904B1 (https=) |
| ES (1) | ES2305887T3 (https=) |
| IL (1) | IL176357A (https=) |
| MX (1) | MXPA06007017A (https=) |
| MY (1) | MY146415A (https=) |
| NO (1) | NO337701B1 (https=) |
| NZ (1) | NZ547794A (https=) |
| TW (1) | TWI347187B (https=) |
| UA (1) | UA83881C2 (https=) |
| WO (1) | WO2005058913A1 (https=) |
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| UA83881C2 (en) | 2003-12-18 | 2008-08-26 | Янссен Фармацевтика Н.В. | Pyrido- and pyrimidopyrimidine derivatives as anti-proliferative agents |
| MY169441A (en) | 2004-12-08 | 2019-04-11 | Janssen Pharmaceutica Nv | 2,4, (4,6) pyrimidine derivatives |
| NI200700147A (es) | 2004-12-08 | 2019-05-10 | Janssen Pharmaceutica Nv | Derivados de quinazolina inhibidores de cinasas dirigidos a multip |
| JO3088B1 (ar) * | 2004-12-08 | 2017-03-15 | Janssen Pharmaceutica Nv | مشتقات كوينازولين كبيرة الحلقات و استعمالها بصفتها موانع كينيز متعددة الاهداف |
| NZ568325A (en) | 2005-11-16 | 2011-05-27 | S Bio Pte Ltd | Macrocyclic oxygen linked pyrimidine derivatives |
| CA2654583C (en) * | 2006-07-13 | 2015-11-24 | Janssen Pharmaceutica N.V. | Mtki quinazoline derivatives |
| CA2664148A1 (en) * | 2006-10-27 | 2008-05-02 | Janssen Pharmaceutica Nv | Vegfr3 inhibitors |
| WO2008060248A1 (en) * | 2006-11-15 | 2008-05-22 | S*Bio Pte Ltd. | Indole sustituted pyrimidines and use thereof in the treatment of cancer |
| CA2687909C (en) * | 2007-06-21 | 2015-09-15 | Janssen Pharmaceutica Nv | Indolin-2-ones and aza-indolin-2-ones |
| ES2562218T3 (es) | 2007-07-27 | 2016-03-03 | Janssen Pharmaceutica, N.V. | Pirrolopirimidinas útiles para el tratamiento de enfermedades proliferativas |
| PT2350075E (pt) | 2008-09-22 | 2014-06-09 | Array Biopharma Inc | Compostos imidazo[1,2b]piridazina substituídos como inibidores da trk cinase |
| AR074052A1 (es) | 2008-10-22 | 2010-12-22 | Array Biopharma Inc | Compuestos pirazolo{1,5-a}pirimidina sustituida como inhibidores de trk cinasa |
| US8765727B2 (en) | 2009-01-23 | 2014-07-01 | Incyte Corporation | Macrocyclic compounds and their use as kinase inhibitors |
| AR077468A1 (es) | 2009-07-09 | 2011-08-31 | Array Biopharma Inc | Compuestos de pirazolo (1,5 -a) pirimidina sustituidos como inhibidores de trk- quinasa |
| GB0921203D0 (en) | 2009-12-03 | 2010-01-20 | Al Lamee Kadem G | Drugs formulations for cardiovascular stents |
| NZ604708A (en) | 2010-05-20 | 2015-05-29 | Array Biopharma Inc | Macrocyclic compounds as trk kinase inhibitors |
| WO2012125668A1 (en) * | 2011-03-17 | 2012-09-20 | Merck Sharp & Dohme Corp. | TrkA KINASE INHIBITORS, COMPOSITIONS AND METHODS THEREOF |
| BR112014007654A8 (pt) * | 2011-09-30 | 2018-06-12 | Ipsen Pharma | Inibidores de lrrk2 quinase macrocíclicos. |
| KR20150072412A (ko) | 2012-10-05 | 2015-06-29 | 리겔 파마슈티칼스, 인크. | Gdf-8 억제제 |
| CN105164136B (zh) * | 2013-05-06 | 2017-12-22 | 默克专利股份公司 | 作为激酶抑制剂的大环化合物 |
| RU2733405C2 (ru) * | 2014-02-07 | 2020-10-01 | Экзитера Фармасьютикалз Инк. | Терапевтические соединения и композиции |
| MA39823A (fr) | 2014-04-03 | 2018-01-09 | Janssen Pharmaceutica Nv | Dérivés de pyridine macrocyclique |
| MA39822A (fr) | 2014-04-03 | 2018-02-06 | Janssen Pharmaceutica Nv | Dérivés de pyrimidine bicycle |
| HUE061448T2 (hu) | 2014-11-16 | 2023-07-28 | Array Biopharma Inc | (S)-N-(5-((R)-2-(2,5-difluorofenil)-pirrolidin-1-il)-pirazolo[1,5-A]pirimidin-3-il) -3-hidroxipirrolidin-1-karboxamid-hidrogénszulfát kristályos formája |
| CN107531666A (zh) | 2015-02-20 | 2018-01-02 | 里格尔药品股份有限公司 | Gdf‑8抑制剂 |
| KR20180086187A (ko) | 2015-10-05 | 2018-07-30 | 더 트러스티이스 오브 콜롬비아 유니버시티 인 더 시티 오브 뉴욕 | 자가포식 유동의 활성체 및 포스포리파제 d 및 타우를 포함하는 단백질 응집물의 클리어런스 및 단백질질환의 치료 |
| CN108697708A (zh) | 2015-10-26 | 2018-10-23 | 洛克索肿瘤学股份有限公司 | Trk抑制剂抗性癌症中的点突变以及与此相关的方法 |
| US10045991B2 (en) | 2016-04-04 | 2018-08-14 | Loxo Oncology, Inc. | Methods of treating pediatric cancers |
| ES2987474T3 (es) | 2016-04-04 | 2024-11-15 | Loxo Oncology Inc | Formulaciones líquidas de (S)-N-(5-((R)-2-(2,5-difluorofenil)-pirrolidin-1-IL)-pirazolo[1,5-A]pirimidin-3-IL)-3-hidroxipirrolidina-1-carboxamida |
| ES2836222T3 (es) | 2016-05-18 | 2021-06-24 | Loxo Oncology Inc | Preparación de (S)-N-(5-((R)-2-(2,5-difluorofenil)pirrolidin-1-il)pirazolo[1,5-a]pirimidin-3-il)-3-hidroxipirrolidina-1-carboxamida |
| JOP20190092A1 (ar) | 2016-10-26 | 2019-04-25 | Array Biopharma Inc | عملية لتحضير مركبات بيرازولو[1، 5-a]بيريميدين وأملاح منها |
| JOP20190213A1 (ar) | 2017-03-16 | 2019-09-16 | Array Biopharma Inc | مركبات حلقية ضخمة كمثبطات لكيناز ros1 |
| WO2019201282A1 (zh) * | 2018-04-18 | 2019-10-24 | 成都先导药物开发股份有限公司 | 一种大环类激酶抑制剂 |
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| MY169441A (en) * | 2004-12-08 | 2019-04-11 | Janssen Pharmaceutica Nv | 2,4, (4,6) pyrimidine derivatives |
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| CA2687909C (en) | 2007-06-21 | 2015-09-15 | Janssen Pharmaceutica Nv | Indolin-2-ones and aza-indolin-2-ones |
| ES2562218T3 (es) | 2007-07-27 | 2016-03-03 | Janssen Pharmaceutica, N.V. | Pirrolopirimidinas útiles para el tratamiento de enfermedades proliferativas |
| EP2283024B1 (en) * | 2008-03-10 | 2013-05-15 | Janssen Pharmaceutica, N.V. | 4-aryl-2-anilino-pyrimidines as plk kinase inhibitors |
-
2004
- 2004-12-15 UA UAA200607007A patent/UA83881C2/ru unknown
- 2004-12-15 EP EP04804852A patent/EP1697384B1/en not_active Expired - Lifetime
- 2004-12-15 CA CA2549869A patent/CA2549869C/en not_active Expired - Lifetime
- 2004-12-15 DE DE602004012891T patent/DE602004012891T2/de not_active Expired - Lifetime
- 2004-12-15 US US10/596,512 patent/US7799772B2/en not_active Expired - Lifetime
- 2004-12-15 NZ NZ547794A patent/NZ547794A/en not_active IP Right Cessation
- 2004-12-15 MX MXPA06007017A patent/MXPA06007017A/es active IP Right Grant
- 2004-12-15 ES ES04804852T patent/ES2305887T3/es not_active Expired - Lifetime
- 2004-12-15 AU AU2004298448A patent/AU2004298448B2/en not_active Expired
- 2004-12-15 WO PCT/EP2004/053501 patent/WO2005058913A1/en not_active Ceased
- 2004-12-15 JP JP2006544440A patent/JP4936897B2/ja not_active Expired - Lifetime
- 2004-12-15 EA EA200601177A patent/EA013904B1/ru not_active IP Right Cessation
- 2004-12-16 MY MYPI20045196A patent/MY146415A/en unknown
- 2004-12-17 TW TW093139376A patent/TWI347187B/zh not_active IP Right Cessation
- 2004-12-17 AR ARP040104750A patent/AR046957A1/es unknown
-
2006
- 2006-06-15 IL IL176357A patent/IL176357A/en active IP Right Grant
- 2006-07-14 KR KR1020067014283A patent/KR101174672B1/ko not_active Expired - Lifetime
- 2006-07-18 NO NO20063323A patent/NO337701B1/no unknown
-
2010
- 2010-03-15 US US12/724,203 patent/US8772272B2/en active Active
-
2013
- 2013-03-13 US US13/799,689 patent/US8933067B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| EP1697384A1 (en) | 2006-09-06 |
| CA2549869C (en) | 2015-05-05 |
| IL176357A (en) | 2011-08-31 |
| MXPA06007017A (es) | 2006-08-31 |
| US20130231353A1 (en) | 2013-09-05 |
| HK1099293A1 (zh) | 2007-08-10 |
| TW200528111A (en) | 2005-09-01 |
| KR20060126716A (ko) | 2006-12-08 |
| IL176357A0 (en) | 2006-10-05 |
| US20100173913A1 (en) | 2010-07-08 |
| KR101174672B1 (ko) | 2012-08-20 |
| US8933067B2 (en) | 2015-01-13 |
| JP4936897B2 (ja) | 2012-05-23 |
| EP1697384B1 (en) | 2008-04-02 |
| US8772272B2 (en) | 2014-07-08 |
| AR046957A1 (es) | 2006-01-04 |
| NO20063323L (no) | 2006-07-18 |
| EA200601177A1 (ru) | 2006-10-27 |
| NZ547794A (en) | 2009-11-27 |
| TWI347187B (en) | 2011-08-21 |
| AU2004298448B2 (en) | 2010-09-09 |
| DE602004012891T2 (de) | 2009-04-09 |
| JP2007514712A (ja) | 2007-06-07 |
| CA2549869A1 (en) | 2005-06-30 |
| WO2005058913A1 (en) | 2005-06-30 |
| US7799772B2 (en) | 2010-09-21 |
| UA83881C2 (en) | 2008-08-26 |
| DE602004012891D1 (de) | 2008-05-15 |
| AU2004298448A1 (en) | 2005-06-30 |
| US20070078132A1 (en) | 2007-04-05 |
| NO337701B1 (no) | 2016-06-06 |
| EA013904B1 (ru) | 2010-08-30 |
| MY146415A (en) | 2012-08-15 |
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