CA2281721C - Phthalazines with angiogenesis inhibiting activity - Google Patents
Phthalazines with angiogenesis inhibiting activity Download PDFInfo
- Publication number
- CA2281721C CA2281721C CA002281721A CA2281721A CA2281721C CA 2281721 C CA2281721 C CA 2281721C CA 002281721 A CA002281721 A CA 002281721A CA 2281721 A CA2281721 A CA 2281721A CA 2281721 C CA2281721 C CA 2281721C
- Authority
- CA
- Canada
- Prior art keywords
- phenyl
- halogen
- compound
- hydroxy
- alkyl
- 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 - Fee Related
Links
- 230000033115 angiogenesis Effects 0.000 title claims abstract description 19
- LFSXCDWNBUNEEM-UHFFFAOYSA-N phthalazine Chemical class C1=NN=CC2=CC=CC=C21 LFSXCDWNBUNEEM-UHFFFAOYSA-N 0.000 title description 54
- 230000002401 inhibitory effect Effects 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 392
- -1 cyano, carboxy Chemical group 0.000 claims abstract description 221
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 123
- 150000003839 salts Chemical class 0.000 claims abstract description 94
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 78
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 68
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 67
- 150000001204 N-oxides Chemical class 0.000 claims abstract description 58
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 58
- 150000002367 halogens Chemical class 0.000 claims abstract description 57
- 125000001841 imino group Chemical group [H]N=* 0.000 claims abstract description 57
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 52
- 241000534944 Thia Species 0.000 claims abstract description 51
- 125000001589 carboacyl group Chemical group 0.000 claims abstract description 40
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 36
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims abstract description 34
- 125000004414 alkyl thio group Chemical group 0.000 claims abstract description 33
- 125000004076 pyridyl group Chemical group 0.000 claims abstract description 33
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 28
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims abstract description 25
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims abstract description 21
- 125000003118 aryl group Chemical group 0.000 claims abstract description 18
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 15
- 125000000547 substituted alkyl group Chemical group 0.000 claims abstract description 13
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims abstract description 12
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 12
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims abstract description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract 47
- 125000003282 alkyl amino group Chemical group 0.000 claims description 84
- 150000003254 radicals Chemical class 0.000 claims description 66
- 238000011282 treatment Methods 0.000 claims description 60
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 56
- 201000010099 disease Diseases 0.000 claims description 53
- 238000002360 preparation method Methods 0.000 claims description 52
- 125000001424 substituent group Chemical group 0.000 claims description 51
- 206010028980 Neoplasm Diseases 0.000 claims description 47
- 125000004432 carbon atom Chemical group C* 0.000 claims description 40
- 125000003545 alkoxy group Chemical group 0.000 claims description 39
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 38
- 125000005236 alkanoylamino group Chemical group 0.000 claims description 27
- 239000008194 pharmaceutical composition Substances 0.000 claims description 25
- 102000009484 Vascular Endothelial Growth Factor Receptors Human genes 0.000 claims description 23
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 21
- 125000004423 acyloxy group Chemical group 0.000 claims description 17
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical compound [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 claims description 14
- 230000005764 inhibitory process Effects 0.000 claims description 14
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 13
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 13
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 claims description 12
- 125000005530 alkylenedioxy group Chemical group 0.000 claims description 12
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 12
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 12
- 125000000043 benzamido group Chemical group [H]N([*])C(=O)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 11
- 125000004304 oxazol-5-yl group Chemical group O1C=NC=C1* 0.000 claims description 11
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 11
- UIOAQJNADLELPQ-UHFFFAOYSA-N C[C]1OCCO1 Chemical group C[C]1OCCO1 UIOAQJNADLELPQ-UHFFFAOYSA-N 0.000 claims description 10
- 125000003342 alkenyl group Chemical group 0.000 claims description 10
- 125000005115 alkyl carbamoyl group Chemical group 0.000 claims description 10
- 230000014399 negative regulation of angiogenesis Effects 0.000 claims description 10
- 230000002074 deregulated effect Effects 0.000 claims description 9
- 239000003937 drug carrier Substances 0.000 claims description 8
- YCOYDOIWSSHVCK-UHFFFAOYSA-N vatalanib Chemical compound C1=CC(Cl)=CC=C1NC(C1=CC=CC=C11)=NN=C1CC1=CC=NC=C1 YCOYDOIWSSHVCK-UHFFFAOYSA-N 0.000 claims description 7
- 108091008605 VEGF receptors Proteins 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 claims description 4
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 claims description 4
- ZYHQGITXIJDDKC-UHFFFAOYSA-N 2-[2-(2-aminophenyl)ethyl]aniline Chemical group NC1=CC=CC=C1CCC1=CC=CC=C1N ZYHQGITXIJDDKC-UHFFFAOYSA-N 0.000 claims description 3
- 125000006276 2-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C(*)C([H])=C1[H] 0.000 claims description 3
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims description 3
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 3
- 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 claims description 3
- LJGHYPLBDBRCRZ-UHFFFAOYSA-N 3-(3-aminophenyl)sulfonylaniline Chemical group NC1=CC=CC(S(=O)(=O)C=2C=C(N)C=CC=2)=C1 LJGHYPLBDBRCRZ-UHFFFAOYSA-N 0.000 claims description 3
- 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 claims description 3
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 3
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims description 3
- 125000004208 3-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C([H])C(*)=C1[H] 0.000 claims description 3
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 3
- 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 claims description 3
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 3
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 125000004199 4-trifluoromethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C(F)(F)F 0.000 claims description 3
- UKJLNMAFNRKWGR-UHFFFAOYSA-N cyclohexatrienamine Chemical group NC1=CC=C=C[CH]1 UKJLNMAFNRKWGR-UHFFFAOYSA-N 0.000 claims description 3
- YSCVOKMJKSNAMT-UHFFFAOYSA-N n-(4-bromophenyl)-4-(pyridin-4-ylmethyl)phthalazin-1-amine Chemical compound C1=CC(Br)=CC=C1NC(C1=CC=CC=C11)=NN=C1CC1=CC=NC=C1 YSCVOKMJKSNAMT-UHFFFAOYSA-N 0.000 claims description 3
- FAYDFKSMRTYYNR-UHFFFAOYSA-N n-(4-fluorophenyl)-4-(pyridin-4-ylmethyl)phthalazin-1-amine Chemical compound C1=CC(F)=CC=C1NC(C1=CC=CC=C11)=NN=C1CC1=CC=NC=C1 FAYDFKSMRTYYNR-UHFFFAOYSA-N 0.000 claims description 3
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 3
- ZSNZPFYMIVNIMW-UHFFFAOYSA-N 3-[[4-(pyridin-4-ylmethyl)phthalazin-1-yl]amino]phenol Chemical compound OC1=CC=CC(NC=2C3=CC=CC=C3C(CC=3C=CN=CC=3)=NN=2)=C1 ZSNZPFYMIVNIMW-UHFFFAOYSA-N 0.000 claims description 2
- RJTXGOMLCHEWDN-UHFFFAOYSA-N 3-n-[4-(pyridin-4-ylmethyl)phthalazin-1-yl]benzene-1,3-diamine Chemical compound NC1=CC=CC(NC=2C3=CC=CC=C3C(CC=3C=CN=CC=3)=NN=2)=C1 RJTXGOMLCHEWDN-UHFFFAOYSA-N 0.000 claims description 2
- UECARSVRLSHXNH-UHFFFAOYSA-N 4-(pyridin-4-ylmethyl)-n-[4-(trifluoromethyl)phenyl]phthalazin-1-amine Chemical compound C1=CC(C(F)(F)F)=CC=C1NC(C1=CC=CC=C11)=NN=C1CC1=CC=NC=C1 UECARSVRLSHXNH-UHFFFAOYSA-N 0.000 claims description 2
- ZYBSZFIPVRRAOR-UHFFFAOYSA-N 4-[[4-(pyridin-4-ylmethyl)phthalazin-1-yl]amino]benzonitrile Chemical compound C1=CC(C#N)=CC=C1NC(C1=CC=CC=C11)=NN=C1CC1=CC=NC=C1 ZYBSZFIPVRRAOR-UHFFFAOYSA-N 0.000 claims description 2
- WQADYQNSWQTHBP-UHFFFAOYSA-N 4-[[4-(pyridin-4-ylmethyl)phthalazin-1-yl]amino]phenol Chemical compound C1=CC(O)=CC=C1NC(C1=CC=CC=C11)=NN=C1CC1=CC=NC=C1 WQADYQNSWQTHBP-UHFFFAOYSA-N 0.000 claims description 2
- SVAROSTUIFRLMR-UHFFFAOYSA-N n-(2-methoxyphenyl)-4-(pyridin-4-ylmethyl)phthalazin-1-amine Chemical compound COC1=CC=CC=C1NC(C1=CC=CC=C11)=NN=C1CC1=CC=NC=C1 SVAROSTUIFRLMR-UHFFFAOYSA-N 0.000 claims description 2
- UIFQBRNVJVUAKO-UHFFFAOYSA-N n-(3,4-dichlorophenyl)-4-(pyridin-4-ylmethyl)phthalazin-1-amine Chemical compound C1=C(Cl)C(Cl)=CC=C1NC(C1=CC=CC=C11)=NN=C1CC1=CC=NC=C1 UIFQBRNVJVUAKO-UHFFFAOYSA-N 0.000 claims description 2
- KXGQVPDIEXTECH-UHFFFAOYSA-N n-(3-chloro-4-fluorophenyl)-4-(pyridin-4-ylmethyl)phthalazin-1-amine Chemical compound C1=C(Cl)C(F)=CC=C1NC(C1=CC=CC=C11)=NN=C1CC1=CC=NC=C1 KXGQVPDIEXTECH-UHFFFAOYSA-N 0.000 claims description 2
- AZIKUFVQGGFYBF-UHFFFAOYSA-N n-(3-chloro-4-methoxyphenyl)-4-(pyridin-4-ylmethyl)phthalazin-1-amine Chemical compound C1=C(Cl)C(OC)=CC=C1NC(C1=CC=CC=C11)=NN=C1CC1=CC=NC=C1 AZIKUFVQGGFYBF-UHFFFAOYSA-N 0.000 claims description 2
- QSBVFBSIEWYFOV-UHFFFAOYSA-N n-(3-chlorophenyl)-4-(pyridin-4-ylmethyl)phthalazin-1-amine Chemical compound ClC1=CC=CC(NC=2C3=CC=CC=C3C(CC=3C=CN=CC=3)=NN=2)=C1 QSBVFBSIEWYFOV-UHFFFAOYSA-N 0.000 claims description 2
- UHSUYVQDJJMDAA-UHFFFAOYSA-N n-(3-methoxyphenyl)-4-(pyridin-4-ylmethyl)phthalazin-1-amine Chemical compound COC1=CC=CC(NC=2C3=CC=CC=C3C(CC=3C=CN=CC=3)=NN=2)=C1 UHSUYVQDJJMDAA-UHFFFAOYSA-N 0.000 claims description 2
- UTBZTQCKLUFYTQ-UHFFFAOYSA-N n-(3-methylphenyl)-4-(pyridin-4-ylmethyl)phthalazin-1-amine Chemical compound CC1=CC=CC(NC=2C3=CC=CC=C3C(CC=3C=CN=CC=3)=NN=2)=C1 UTBZTQCKLUFYTQ-UHFFFAOYSA-N 0.000 claims description 2
- OHJRTXSBHFKDQN-UHFFFAOYSA-N n-(3-phenylmethoxyphenyl)-4-(pyridin-4-ylmethyl)phthalazin-1-amine Chemical compound C=1C=CC=CC=1COC(C=1)=CC=CC=1NC(C1=CC=CC=C11)=NN=C1CC1=CC=NC=C1 OHJRTXSBHFKDQN-UHFFFAOYSA-N 0.000 claims description 2
- SJDGLBJMCUMNTP-UHFFFAOYSA-N n-(4-methoxyphenyl)-4-(pyridin-4-ylmethyl)phthalazin-1-amine Chemical compound C1=CC(OC)=CC=C1NC(C1=CC=CC=C11)=NN=C1CC1=CC=NC=C1 SJDGLBJMCUMNTP-UHFFFAOYSA-N 0.000 claims description 2
- XPCHMPWXUOYJGJ-UHFFFAOYSA-N n-(4-methylphenyl)-4-(pyridin-4-ylmethyl)phthalazin-1-amine Chemical compound C1=CC(C)=CC=C1NC(C1=CC=CC=C11)=NN=C1CC1=CC=NC=C1 XPCHMPWXUOYJGJ-UHFFFAOYSA-N 0.000 claims description 2
- FOZIFOSSSDWNSN-UHFFFAOYSA-N n-benzyl-4-(pyridin-4-ylmethyl)phthalazin-1-amine Chemical compound C=1C=CC=CC=1CNC(C1=CC=CC=C11)=NN=C1CC1=CC=NC=C1 FOZIFOSSSDWNSN-UHFFFAOYSA-N 0.000 claims description 2
- WFPYLUYNQSOURF-UHFFFAOYSA-N n-phenyl-4-(pyridin-4-ylmethyl)phthalazin-1-amine Chemical compound N=1N=C(NC=2C=CC=CC=2)C2=CC=CC=C2C=1CC1=CC=NC=C1 WFPYLUYNQSOURF-UHFFFAOYSA-N 0.000 claims description 2
- 239000012453 solvate Substances 0.000 claims description 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims 2
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims 1
- 229940127557 pharmaceutical product Drugs 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 284
- 235000013350 formula milk Nutrition 0.000 description 205
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- 238000000034 method Methods 0.000 description 97
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- 239000000243 solution Substances 0.000 description 78
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 69
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 67
- 235000002639 sodium chloride Nutrition 0.000 description 58
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- XSCHRSMBECNVNS-UHFFFAOYSA-N benzopyrazine Natural products N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 description 44
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- 238000001035 drying Methods 0.000 description 38
- 238000010265 fast atom bombardment Methods 0.000 description 38
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 35
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- 229910052739 hydrogen Inorganic materials 0.000 description 32
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 30
- 238000003818 flash chromatography Methods 0.000 description 30
- 239000012074 organic phase Substances 0.000 description 30
- DLYUQMMRRRQYAE-UHFFFAOYSA-N tetraphosphorus decaoxide Chemical compound O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 30
- 239000000047 product Substances 0.000 description 29
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- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 26
- 239000004480 active ingredient Substances 0.000 description 26
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- LVSFOJFCLFTXTO-UHFFFAOYSA-N 1-chloro-4-(pyridin-4-ylmethyl)phthalazine Chemical compound C12=CC=CC=C2C(Cl)=NN=C1CC1=CC=NC=C1 LVSFOJFCLFTXTO-UHFFFAOYSA-N 0.000 description 21
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- 238000003756 stirring Methods 0.000 description 21
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- 125000004356 hydroxy functional group Chemical group O* 0.000 description 18
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- VVZNYMSMDNYBQQ-UHFFFAOYSA-N phthalazin-3-ium;chloride Chemical compound Cl.C1=NN=CC2=CC=CC=C21 VVZNYMSMDNYBQQ-UHFFFAOYSA-N 0.000 description 14
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- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
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Classifications
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- 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
- C07D401/06—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 only aliphatic carbon atoms
-
- 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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- 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
- C07D401/12—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 chain containing hetero atoms as chain links
-
- 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
- C07D401/14—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 three or more hetero 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
- C07D403/06—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 only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero 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
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- 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
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pyridine Compounds (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH315/97 | 1997-02-13 | ||
| CH31597 | 1997-02-13 | ||
| PCT/EP1998/000764 WO1998035958A1 (en) | 1997-02-13 | 1998-02-11 | Phthalazines with angiogenesis inhibiting activity |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2281721A1 CA2281721A1 (en) | 1998-08-20 |
| CA2281721C true CA2281721C (en) | 2008-01-22 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002281721A Expired - Fee Related CA2281721C (en) | 1997-02-13 | 1998-02-11 | Phthalazines with angiogenesis inhibiting activity |
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| ES (1) | ES2234097T3 (enExample) |
| HU (1) | HU227972B1 (enExample) |
| ID (1) | ID23698A (enExample) |
| IL (1) | IL131273A0 (enExample) |
| MY (1) | MY128645A (enExample) |
| NO (1) | NO317367B1 (enExample) |
| NZ (1) | NZ337064A (enExample) |
| PE (1) | PE52499A1 (enExample) |
| PL (1) | PL197371B1 (enExample) |
| PT (1) | PT970070E (enExample) |
| RU (1) | RU2207132C2 (enExample) |
| SI (1) | SI0970070T1 (enExample) |
| SK (1) | SK285757B6 (enExample) |
| TR (1) | TR199901953T2 (enExample) |
| TW (1) | TWI250151B (enExample) |
| WO (1) | WO1998035958A1 (enExample) |
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| CN1252054C (zh) | 1996-09-25 | 2006-04-19 | 曾尼卡有限公司 | 抑制生长因子的作用的喹啉衍生物 |
| CO4950519A1 (es) * | 1997-02-13 | 2000-09-01 | Novartis Ag | Ftalazinas, preparaciones farmaceuticas que las comprenden y proceso para su preparacion |
| DE69838172T2 (de) | 1997-08-22 | 2008-04-10 | Astrazeneca Ab | Oxindolylchinazolinderivate als angiogenesehemmer |
| ES2342240T3 (es) | 1998-08-11 | 2010-07-02 | Novartis Ag | Derivados de isoquinolina con actividad que inhibe la angiogenia. |
| AU5733099A (en) * | 1998-08-13 | 2000-03-06 | Novartis Ag | Method for treating ocular neovascular diseases |
| ATE329596T1 (de) | 1999-03-30 | 2006-07-15 | Novartis Pharma Gmbh | Phthalazinderivate zur behandlung von entzündlicher erkrankungen |
| US6271233B1 (en) | 1999-08-10 | 2001-08-07 | Ciba Vision Corporation | Method for treating ocular neovascular diseases |
| AR025068A1 (es) * | 1999-08-10 | 2002-11-06 | Bayer Corp | Pirazinas sustituidas y piridazinas fusionadas, composicion farmaceutica que las comprenden, uso de dichos compuestos para la manufactura de un medicamentocon actividad inhibidora de angiogenesis |
| AR025752A1 (es) * | 1999-09-28 | 2002-12-11 | Bayer Corp | Piridinas y piridacinas sustituidas con actividad de inhibicion de angiogenesis |
| US6689883B1 (en) | 1999-09-28 | 2004-02-10 | Bayer Pharmaceuticals Corporation | Substituted pyridines and pyridazines with angiogenesis inhibiting activity |
| PT1244647E (pt) | 1999-11-05 | 2006-10-31 | Astrazeneca Ab | Derivados de quinazolina como inibidores de vegf |
| DE19963607B4 (de) * | 1999-12-23 | 2005-12-15 | Schering Ag | Verfahren zur Herstellung von 4-(Heteroaryl-methyl) halogen-1(2H)-phthalazinonen |
| WO2001058899A1 (en) * | 2000-02-09 | 2001-08-16 | Novartis Ag | Pyridine derivatives inhibiting angiogenesis and/or vegf receptor tyrosine kinase |
| US7087608B2 (en) | 2000-03-03 | 2006-08-08 | Robert Charles Atkins | Use of PDGF receptor tyrosine kinase inhibitors for the treatment of diabetic nephropathy |
| IL151626A0 (en) | 2000-04-07 | 2003-04-10 | Astrazeneca Ab | Quinazoline compounds |
| US7977333B2 (en) | 2000-04-20 | 2011-07-12 | Bayer Healthcare Llc | Substituted pyridines and pyridazines with angiogenesis inhibiting activity |
| EP1166799A1 (en) * | 2000-06-28 | 2002-01-02 | Schering Aktiengesellschaft | Combinations and compositions which interfere with VEGF/VEGF and angiopoietin/Tie receptor function and their use (II) |
| PT1292335E (pt) * | 2000-06-23 | 2007-08-13 | Bayer Schering Pharma Ag | Combinações e composições que interferem na função de receptores vegf/vegf e angiopoietina/ tie e a sua utilização (ii) |
| EP1166798A1 (en) * | 2000-06-23 | 2002-01-02 | Schering Aktiengesellschaft | Combinations and compositions which interfere with VEGF/VEGF and angiopoietin/ Tie receptor function and their use |
| US20030207878A1 (en) * | 2000-08-09 | 2003-11-06 | Hennequin Lawrent Francois Andre | Chemical compounds |
| US6903101B1 (en) | 2000-08-10 | 2005-06-07 | Bayer Pharmaceuticals Corporation | Substituted pyridazines and fused pyridazines with angiogenesis inhibiting activity |
| KR100600550B1 (ko) | 2000-10-20 | 2006-07-13 | 에자이 가부시키가이샤 | 질소 함유 방향환 유도체 |
| HU228960B1 (hu) * | 2000-10-30 | 2013-07-29 | Kudos Pharm Ltd | Ftalazinon-származékok |
| AU2002223684A1 (en) * | 2000-11-22 | 2002-06-03 | Novartis Pharma Gmbh | Combination comprising an agent decreasing vegf activity and an agent decreasing egf activity |
| US7814641B2 (en) * | 2001-01-09 | 2010-10-19 | Black & Decker Inc. | Method of forming a power tool |
| US7096566B2 (en) * | 2001-01-09 | 2006-08-29 | Black & Decker Inc. | Method for making an encapsulated coil structure |
| CN1551767A (zh) | 2001-02-19 | 2004-12-01 | ��˹��ŵ�� | 癌症的治疗 |
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| TWI315982B (en) | 2001-07-19 | 2009-10-21 | Novartis Ag | Combinations comprising epothilones and pharmaceutical uses thereof |
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| RU2320344C2 (ru) * | 2001-09-12 | 2008-03-27 | Новартис Аг | Применение 4-пиридилметилфталазинов для лечения рака |
| AU2002342678B2 (en) * | 2001-09-12 | 2006-08-24 | Novartis Ag | Use of 4-pyridylmethylphthalazines for cancer treatment |
| EP1712234B1 (en) * | 2001-09-12 | 2009-01-28 | Novartis AG | Use of 4-Pyridylmethylphthalazines for Renal Cancer Treatment |
| US20040266779A1 (en) * | 2001-09-27 | 2004-12-30 | Anderson Kenneth C. | Use of c-kit inhibitors for the treatment of myeloma |
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| CA2471314A1 (en) * | 2001-12-21 | 2003-07-24 | Bayer Pharmaceuticals Corporation | Anti-angiogenesis combination therapies comprising pyridazine or pyridine derivatives |
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| AU717744B2 (en) * | 1996-01-15 | 2000-03-30 | Janssen Pharmaceutica N.V. | Angiogenesis inhibiting pyridazinamines |
| DE19617863A1 (de) | 1996-04-23 | 1997-10-30 | Schering Ag | Phthalazinderivate, deren Herstellung und Verwendung als Arzneimittel |
| CO4950519A1 (es) * | 1997-02-13 | 2000-09-01 | Novartis Ag | Ftalazinas, preparaciones farmaceuticas que las comprenden y proceso para su preparacion |
| ITMI981670A1 (it) * | 1998-07-21 | 2000-01-21 | Zambon Spa | Derivati ftalazinici inibitori della fosfodiesterasi 4 |
| AU5733099A (en) * | 1998-08-13 | 2000-03-06 | Novartis Ag | Method for treating ocular neovascular diseases |
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1998
- 1998-02-05 CO CO98005806A patent/CO4950519A1/es unknown
- 1998-02-11 JP JP53533698A patent/JP3544675B2/ja not_active Expired - Fee Related
- 1998-02-11 DE DE69826841T patent/DE69826841T2/de not_active Expired - Lifetime
- 1998-02-11 AR ARP980100616A patent/AR011135A1/es active IP Right Grant
- 1998-02-11 CA CA002281721A patent/CA2281721C/en not_active Expired - Fee Related
- 1998-02-11 RU RU99119224/14A patent/RU2207132C2/ru active
- 1998-02-11 KR KR10-1999-7007317A patent/KR100441362B1/ko not_active Expired - Fee Related
- 1998-02-11 AU AU66218/98A patent/AU731852B2/en not_active Ceased
- 1998-02-11 PL PL335113A patent/PL197371B1/pl unknown
- 1998-02-11 MY MYPI98000541A patent/MY128645A/en unknown
- 1998-02-11 AT AT98908086T patent/ATE278686T1/de active
- 1998-02-11 WO PCT/EP1998/000764 patent/WO1998035958A1/en not_active Ceased
- 1998-02-11 TR TR1999/01953T patent/TR199901953T2/xx unknown
- 1998-02-11 DK DK98908086T patent/DK0970070T3/da active
- 1998-02-11 CZ CZ0285399A patent/CZ297534B6/cs not_active IP Right Cessation
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- 1998-02-11 CN CN988036045A patent/CN1251097B/zh not_active Expired - Fee Related
- 1998-02-11 ES ES98908086T patent/ES2234097T3/es not_active Expired - Lifetime
- 1998-02-11 HU HU0001046A patent/HU227972B1/hu not_active IP Right Cessation
- 1998-02-11 PT PT98908086T patent/PT970070E/pt unknown
- 1998-02-11 SI SI9830726T patent/SI0970070T1/xx unknown
- 1998-02-11 SK SK1096-99A patent/SK285757B6/sk not_active IP Right Cessation
- 1998-02-11 ID IDW990869D patent/ID23698A/id unknown
- 1998-02-11 PE PE1998000098A patent/PE52499A1/es not_active Application Discontinuation
- 1998-02-11 US US09/367,273 patent/US6258812B1/en not_active Expired - Lifetime
- 1998-02-11 EP EP98908086A patent/EP0970070B1/en not_active Expired - Lifetime
- 1998-02-11 BR BRPI9807685-0A patent/BR9807685B1/pt not_active IP Right Cessation
- 1998-02-12 ZA ZA981155A patent/ZA981155B/xx unknown
- 1998-03-17 TW TW087102062A patent/TWI250151B/zh not_active IP Right Cessation
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1999
- 1999-08-12 NO NO19993888A patent/NO317367B1/no not_active IP Right Cessation
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2001
- 2001-05-17 US US09/859,858 patent/US6514974B2/en not_active Expired - Fee Related
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2003
- 2003-01-07 US US10/338,062 patent/US6710047B2/en not_active Expired - Fee Related
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2006
- 2006-02-13 CY CY0600004A patent/CY2550B1/xx unknown
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