CA2773661A1 - Ether derivatives of bicyclic heteroaryls - Google Patents

Ether derivatives of bicyclic heteroaryls Download PDF

Info

Publication number: CA2773661A1
Authority: CA; Canada
Prior art keywords: 7alkyl; mmol; amino; pyrrolo; pyrimidin
Prior art date: 2009-09-10
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.): Abandoned

Application number

CA2773661A

Other languages

English (en)

French (fr)

Inventor

Bei Chen

Robin Alec Fairhurst

Andreas Floersheimer

Pascal Furet

Vito Guagnano

Songchun Jiang

Wenshuo Lu

Thomas H. Marsilje

Clive Mccarthy

Pierre-Yves Michellys

Frederic Stauffer

Stefan Stutz

Andrea Vaupel

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

IRM LLC

Novartis AG

Original Assignee

IRM LLC

Novartis AG

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.)

2009-09-10

Filing date

2010-09-10

Publication date

2011-03-17

2010-09-10 Application filed by IRM LLC, Novartis AG filed Critical IRM LLC

2011-03-17 Publication of CA2773661A1 publication Critical patent/CA2773661A1/en

Status Abandoned legal-status Critical Current

Links

125000001072 heteroaryl group Chemical group 0.000 title description 3
150000002170 ethers Chemical class 0.000 title description 2
150000001875 compounds Chemical class 0.000 claims abstract description 486
238000000034 method Methods 0.000 claims abstract description 208
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 73
201000010099 disease Diseases 0.000 claims abstract description 52
239000003814 drug Substances 0.000 claims abstract description 39
238000011282 treatment Methods 0.000 claims abstract description 38
239000008194 pharmaceutical composition Substances 0.000 claims abstract description 18
-1 C1-7alkyl Chemical group 0.000 claims description 145
125000001424 substituent group Chemical group 0.000 claims description 65
125000000623 heterocyclic group Chemical group 0.000 claims description 56
150000003839 salts Chemical class 0.000 claims description 56
229910052739 hydrogen Inorganic materials 0.000 claims description 52
239000001257 hydrogen Substances 0.000 claims description 51
125000005843 halogen group Chemical group 0.000 claims description 47
206010028980 Neoplasm Diseases 0.000 claims description 39
229920006395 saturated elastomer Polymers 0.000 claims description 39
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 38
125000004429 atom Chemical group 0.000 claims description 37
125000004356 hydroxy functional group Chemical group O* 0.000 claims description 36
230000000694 effects Effects 0.000 claims description 29
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 29
125000004093 cyano group Chemical group *C#N 0.000 claims description 28
125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 27
125000000449 nitro group Chemical group [O-][N+](*)=O 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 23
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 22
230000001404 mediated effect Effects 0.000 claims description 22
208000035475 disorder Diseases 0.000 claims description 20
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 20
230000005764 inhibitory process Effects 0.000 claims description 19
229910052799 carbon Inorganic materials 0.000 claims description 16
239000003795 chemical substances by application Substances 0.000 claims description 15
125000004433 nitrogen atom Chemical group N* 0.000 claims description 13
125000004430 oxygen atom Chemical group O* 0.000 claims description 13
238000004519 manufacturing process Methods 0.000 claims description 11
125000004434 sulfur atom Chemical group 0.000 claims description 11
125000002619 bicyclic group Chemical group 0.000 claims description 10
125000002950 monocyclic group Chemical group 0.000 claims description 10
230000001028 anti-proliverative effect Effects 0.000 claims description 9
125000004432 carbon atom Chemical group C* 0.000 claims description 9
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 9
150000002431 hydrogen Chemical group 0.000 claims description 9
125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 9
102000004022 Protein-Tyrosine Kinases Human genes 0.000 claims description 8
108090000412 Protein-Tyrosine Kinases Proteins 0.000 claims description 8
125000004193 piperazinyl group Chemical group 0.000 claims description 8
125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 7
125000004568 thiomorpholinyl group Chemical group 0.000 claims description 7
125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims description 6
101100516554 Caenorhabditis elegans nhr-5 gene Proteins 0.000 claims description 6
101100134922 Gallus gallus COR5 gene Proteins 0.000 claims description 6
239000003937 drug carrier Substances 0.000 claims description 6
125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 6
125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 5
201000009030 Carcinoma Diseases 0.000 claims description 5
125000002393 azetidinyl group Chemical group 0.000 claims description 5
210000004072 lung Anatomy 0.000 claims description 5
201000008968 osteosarcoma Diseases 0.000 claims description 5
230000002611 ovarian Effects 0.000 claims description 5
210000002307 prostate Anatomy 0.000 claims description 5
125000004076 pyridyl group Chemical group 0.000 claims description 5
210000001685 thyroid gland Anatomy 0.000 claims description 5
208000026310 Breast neoplasm Diseases 0.000 claims description 4
125000003725 azepanyl group Chemical group 0.000 claims description 4
125000002618 bicyclic heterocycle group Chemical group 0.000 claims description 4
125000001153 fluoro group Chemical group F* 0.000 claims description 4
201000001441 melanoma Diseases 0.000 claims description 4
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
125000002757 morpholinyl group Chemical group 0.000 claims description 4
125000000719 pyrrolidinyl group Chemical group 0.000 claims description 4
208000001333 Colorectal Neoplasms Diseases 0.000 claims description 3
208000002699 Digestive System Neoplasms Diseases 0.000 claims description 3
208000008839 Kidney Neoplasms Diseases 0.000 claims description 3
208000034578 Multiple myelomas Diseases 0.000 claims description 3
206010029260 Neuroblastoma Diseases 0.000 claims description 3
206010061535 Ovarian neoplasm Diseases 0.000 claims description 3
206010061902 Pancreatic neoplasm Diseases 0.000 claims description 3
206010035226 Plasma cell myeloma Diseases 0.000 claims description 3
208000024770 Thyroid neoplasm Diseases 0.000 claims description 3
206010069351 acute lung injury Diseases 0.000 claims description 3
CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 claims description 3
125000002883 imidazolyl group Chemical group 0.000 claims description 3
208000020816 lung neoplasm Diseases 0.000 claims description 3
208000037841 lung tumor Diseases 0.000 claims description 3
125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 3
201000002528 pancreatic cancer Diseases 0.000 claims description 3
125000003386 piperidinyl group Chemical group 0.000 claims description 3
208000023958 prostate neoplasm Diseases 0.000 claims description 3
208000005069 pulmonary fibrosis Diseases 0.000 claims description 3
125000003831 tetrazolyl group Chemical group 0.000 claims description 3
208000013076 thyroid tumor Diseases 0.000 claims description 3
208000025421 tumor of uterus Diseases 0.000 claims description 3
206010046766 uterine cancer Diseases 0.000 claims description 3
CBQODGRJHHJAEC-UHFFFAOYSA-N 5-[3-(7-oxabicyclo[2.2.1]heptan-4-ylmethoxy)phenyl]-7-[3-[(1-oxo-1,4-thiazinan-4-yl)methyl]cyclobutyl]pyrrolo[2,3-d]pyrimidin-4-amine Chemical compound C1=C(C=2C=C(OCC34CCC(CC3)O4)C=CC=2)C=2C(N)=NC=NC=2N1C(C1)CC1CN1CCS(=O)CC1 CBQODGRJHHJAEC-UHFFFAOYSA-N 0.000 claims description 2
SWSPMOBRMONVHC-UHFFFAOYSA-N 7-[3-[(1,1-dioxo-1,4-thiazinan-4-yl)methyl]cyclobutyl]-5-[3-(7-oxabicyclo[2.2.1]heptan-4-ylmethoxy)phenyl]pyrrolo[2,3-d]pyrimidin-4-amine Chemical compound C1=C(C=2C=C(OCC34CCC(CC3)O4)C=CC=2)C=2C(N)=NC=NC=2N1C(C1)CC1CN1CCS(=O)(=O)CC1 SWSPMOBRMONVHC-UHFFFAOYSA-N 0.000 claims description 2
FMTQHAXNHBODDV-FYWDEPLMSA-N C1CN(C(=O)C)CCN1[C@@H]1C[C@H](N2C3=NC=NC(N)=C3C(C=3C=C(OCC45CCC(CC4)O5)C=CC=3)=C2)C1 Chemical compound C1CN(C(=O)C)CCN1[C@@H]1C[C@H](N2C3=NC=NC(N)=C3C(C=3C=C(OCC45CCC(CC4)O5)C=CC=3)=C2)C1 FMTQHAXNHBODDV-FYWDEPLMSA-N 0.000 claims description 2
101100294115 Caenorhabditis elegans nhr-4 gene Proteins 0.000 claims description 2
208000006168 Ewing Sarcoma Diseases 0.000 claims description 2
SICHDGGOWKHCOA-ABPGQXKISA-N N1([C@H]2C[C@H](C2)N2C=3N=CN=C(C=3C(C=3C=C(OCC45CCC(CC4)O5)C=CC=3)=C2)N)CCS(=O)(=O)CC1 Chemical compound N1([C@H]2C[C@H](C2)N2C=3N=CN=C(C=3C(C=3C=C(OCC45CCC(CC4)O5)C=CC=3)=C2)N)CCS(=O)(=O)CC1 SICHDGGOWKHCOA-ABPGQXKISA-N 0.000 claims description 2
KCANTRHVPWYUAW-ABPGQXKISA-N N1([C@H]2C[C@H](C2)N2C=3N=CN=C(C=3C(C=3C=C(OCC45CCC(CC4)O5)C=CC=3)=C2)N)CCS(=O)CC1 Chemical compound N1([C@H]2C[C@H](C2)N2C=3N=CN=C(C=3C(C=3C=C(OCC45CCC(CC4)O5)C=CC=3)=C2)N)CCS(=O)CC1 KCANTRHVPWYUAW-ABPGQXKISA-N 0.000 claims description 2
YJHXUGJSFWZTRI-UVHVAUBXSA-N NC(=O)[C@H]1CCCN1C[C@@H]1C[C@@H](N2C3=NC=NC(N)=C3C(C=3C=C(OCC45CCC(CC4)O5)C=CC=3)=C2)C1 Chemical compound NC(=O)[C@H]1CCCN1C[C@@H]1C[C@@H](N2C3=NC=NC(N)=C3C(C=3C=C(OCC45CCC(CC4)O5)C=CC=3)=C2)C1 YJHXUGJSFWZTRI-UVHVAUBXSA-N 0.000 claims description 2
YJHXUGJSFWZTRI-XZMHDNNLSA-N NC(=O)[C@H]1CCCN1C[C@@H]1C[C@H](N2C3=NC=NC(N)=C3C(C=3C=C(OCC45CCC(CC4)O5)C=CC=3)=C2)C1 Chemical compound NC(=O)[C@H]1CCCN1C[C@@H]1C[C@H](N2C3=NC=NC(N)=C3C(C=3C=C(OCC45CCC(CC4)O5)C=CC=3)=C2)C1 YJHXUGJSFWZTRI-XZMHDNNLSA-N 0.000 claims description 2
125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 2
125000006273 (C1-C3) alkyl group Chemical group 0.000 claims 6
125000006563 (C1-3) alkylaminocarbonyl group Chemical group 0.000 claims 1
IXDDSQBFYZXHOB-MUABAYHSSA-N C1CN(S(=O)(=O)C)CCN1[C@@H]1C[C@H](N2C3=NC=NC(N)=C3C(C=3C=C(OCC45CCC(CC4)O5)C=CC=3)=C2)C1 Chemical compound C1CN(S(=O)(=O)C)CCN1[C@@H]1C[C@H](N2C3=NC=NC(N)=C3C(C=3C=C(OCC45CCC(CC4)O5)C=CC=3)=C2)C1 IXDDSQBFYZXHOB-MUABAYHSSA-N 0.000 claims 1
YJHXUGJSFWZTRI-RZUKLDMISA-N NC(=O)[C@@H]1CCCN1C[C@@H]1C[C@@H](N2C3=NC=NC(N)=C3C(C=3C=C(OCC45CCC(CC4)O5)C=CC=3)=C2)C1 Chemical compound NC(=O)[C@@H]1CCCN1C[C@@H]1C[C@@H](N2C3=NC=NC(N)=C3C(C=3C=C(OCC45CCC(CC4)O5)C=CC=3)=C2)C1 YJHXUGJSFWZTRI-RZUKLDMISA-N 0.000 claims 1
XAAOIYDRJJVHEG-UHFFFAOYSA-N methyl n-[[3-[4-amino-5-[3-(7-oxabicyclo[2.2.1]heptan-4-ylmethoxy)phenyl]pyrrolo[2,3-d]pyrimidin-7-yl]cyclobutyl]methyl]carbamate Chemical compound C1C(CNC(=O)OC)CC1N1C2=NC=NC(N)=C2C(C=2C=C(OCC34CCC(CC3)O4)C=CC=2)=C1 XAAOIYDRJJVHEG-UHFFFAOYSA-N 0.000 claims 1
230000008569 process Effects 0.000 abstract description 29
238000002360 preparation method Methods 0.000 abstract description 9
230000002062 proliferating effect Effects 0.000 abstract description 9
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 383
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 360
239000000543 intermediate Substances 0.000 description 216
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 207
239000000203 mixture Substances 0.000 description 162
235000013350 formula milk Nutrition 0.000 description 149
239000011541 reaction mixture Substances 0.000 description 132
229910001868 water Inorganic materials 0.000 description 107
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 105
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 101
239000000243 solution Substances 0.000 description 95
235000019439 ethyl acetate Nutrition 0.000 description 78
229910052938 sodium sulfate Inorganic materials 0.000 description 78
235000011152 sodium sulphate Nutrition 0.000 description 78
238000006243 chemical reaction Methods 0.000 description 73
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 73
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 69
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239000007787 solid Substances 0.000 description 66
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HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 62
238000004128 high performance liquid chromatography Methods 0.000 description 61
239000012044 organic layer Substances 0.000 description 58
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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 46
QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 43
238000010898 silica gel chromatography Methods 0.000 description 43
238000005160 1H NMR spectroscopy Methods 0.000 description 41
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FLDSMVTWEZKONL-AWEZNQCLSA-N 5,5-dimethyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-1,4,7,8-tetrahydrooxepino[4,5-c]pyrazole-3-carboxamide Chemical compound CC1(CC2=C(NN=C2C(=O)N[C@@H]2C(N(C3=C(OC2)C=CC=C3)C)=O)CCO1)C FLDSMVTWEZKONL-AWEZNQCLSA-N 0.000 description 37
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 37
238000003818 flash chromatography Methods 0.000 description 37
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 36
238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 36
235000017557 sodium bicarbonate Nutrition 0.000 description 34
229910000030 sodium bicarbonate Inorganic materials 0.000 description 34
CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 33
238000003756 stirring Methods 0.000 description 33
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102000013275 Somatomedins Human genes 0.000 description 28
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QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 26
238000005481 NMR spectroscopy Methods 0.000 description 26
125000000217 alkyl group Chemical group 0.000 description 26
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 25
239000002904 solvent Substances 0.000 description 25
DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 25
238000007792 addition Methods 0.000 description 24
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239000000741 silica gel Substances 0.000 description 23
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102100039688 Insulin-like growth factor 1 receptor Human genes 0.000 description 22
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238000001816 cooling Methods 0.000 description 20
239000007858 starting material Substances 0.000 description 20
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229960004132 diethyl ether Drugs 0.000 description 19
229910052943 magnesium sulfate Inorganic materials 0.000 description 19
229910000069 nitrogen hydride Inorganic materials 0.000 description 19
229940124597 therapeutic agent Drugs 0.000 description 19
238000004809 thin layer chromatography Methods 0.000 description 19
XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 18
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 18
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
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RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 13
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125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 10
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YOGCEHQKSLCCFF-UHFFFAOYSA-N tert-butyl 3,3-dimethyl-1,1-dioxo-1,4-thiazinane-4-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCS(=O)(=O)CC1(C)C YOGCEHQKSLCCFF-UHFFFAOYSA-N 0.000 description 1
WCKXCNXEUDFDQB-UHFFFAOYSA-N tert-butyl 3,3-dimethyl-1,1-dioxo-1,4-thiazinane-4-carboxylate 5,5-dimethylthiomorpholin-3-one Chemical compound CC1(CSCC(N1)=O)C.C(C)(C)(C)OC(=O)N1C(CS(CC1)(=O)=O)(C)C WCKXCNXEUDFDQB-UHFFFAOYSA-N 0.000 description 1
WPGLRFGDZJSQGI-UHFFFAOYSA-N tert-butyl 3-aminoazetidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC(N)C1 WPGLRFGDZJSQGI-UHFFFAOYSA-N 0.000 description 1
FEYLUKDSKVSMSZ-UHFFFAOYSA-N tert-butyl n-(4-aminocyclohexyl)carbamate Chemical compound CC(C)(C)OC(=O)NC1CCC(N)CC1 FEYLUKDSKVSMSZ-UHFFFAOYSA-N 0.000 description 1
YUSRQJSDRRFCIK-UHFFFAOYSA-N tert-butyl n-[3-(4-acetylpiperazin-1-yl)cyclobutyl]carbamate Chemical compound C1CN(C(=O)C)CCN1C1CC(NC(=O)OC(C)(C)C)C1 YUSRQJSDRRFCIK-UHFFFAOYSA-N 0.000 description 1
FQFILJKFZCVHNH-UHFFFAOYSA-N tert-butyl n-[3-[(5-bromo-2-chloropyrimidin-4-yl)amino]propyl]carbamate Chemical compound CC(C)(C)OC(=O)NCCCNC1=NC(Cl)=NC=C1Br FQFILJKFZCVHNH-UHFFFAOYSA-N 0.000 description 1
229960003604 testosterone Drugs 0.000 description 1
DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 1
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
PHCBRBWANGJMHS-UHFFFAOYSA-J tetrasodium;disulfate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O PHCBRBWANGJMHS-UHFFFAOYSA-J 0.000 description 1
WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
229960003433 thalidomide Drugs 0.000 description 1
231100001274 therapeutic index Toxicity 0.000 description 1
125000001984 thiazolidinyl group Chemical group 0.000 description 1
150000003573 thiols Chemical class 0.000 description 1
BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
238000003354 tissue distribution assay Methods 0.000 description 1
239000012443 tonicity enhancing agent Substances 0.000 description 1
230000002110 toxicologic effect Effects 0.000 description 1
231100000027 toxicology Toxicity 0.000 description 1
VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
238000012546 transfer Methods 0.000 description 1
239000003558 transferase inhibitor Substances 0.000 description 1
230000009466 transformation Effects 0.000 description 1
238000002054 transplantation Methods 0.000 description 1
238000011269 treatment regimen Methods 0.000 description 1
125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical group [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
WRTMQOHKMFDUKX-UHFFFAOYSA-N triiodide Chemical compound I[I-]I WRTMQOHKMFDUKX-UHFFFAOYSA-N 0.000 description 1
LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 description 1
235000019798 tripotassium phosphate Nutrition 0.000 description 1
229940094060 tykerb Drugs 0.000 description 1
OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
238000000825 ultraviolet detection Methods 0.000 description 1
238000010518 undesired secondary reaction Methods 0.000 description 1
235000013311 vegetables Nutrition 0.000 description 1
JXLYSJRDGCGARV-CFWMRBGOSA-N vinblastine Chemical compound C([C@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-CFWMRBGOSA-N 0.000 description 1
JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
229960004528 vincristine Drugs 0.000 description 1
OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 1
229960002066 vinorelbine Drugs 0.000 description 1
229960001771 vorozole Drugs 0.000 description 1
XLMPPFTZALNBFS-INIZCTEOSA-N vorozole Chemical compound C1([C@@H](C2=CC=C3N=NN(C3=C2)C)N2N=CN=C2)=CC=C(Cl)C=C1 XLMPPFTZALNBFS-INIZCTEOSA-N 0.000 description 1
238000001262 western blot Methods 0.000 description 1
CGTADGCBEXYWNE-JUKNQOCSSA-N zotarolimus Chemical compound N1([C@H]2CC[C@@H](C[C@@H](C)[C@H]3OC(=O)[C@@H]4CCCCN4C(=O)C(=O)[C@@]4(O)[C@H](C)CC[C@H](O4)C[C@@H](/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C3)OC)C[C@H]2OC)C=NN=N1 CGTADGCBEXYWNE-JUKNQOCSSA-N 0.000 description 1
229950009819 zotarolimus Drugs 0.000 description 1

Classifications

- 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
- 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
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
- 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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2009—Inorganic compounds
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- 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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Landscapes

Health & Medical Sciences (AREA)
Chemical & Material Sciences (AREA)
Life Sciences & Earth Sciences (AREA)
General Health & Medical Sciences (AREA)
Veterinary Medicine (AREA)
Public Health (AREA)
Medicinal Chemistry (AREA)
Animal Behavior & Ethology (AREA)
Pharmacology & Pharmacy (AREA)
Organic Chemistry (AREA)
Epidemiology (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
General Chemical & Material Sciences (AREA)
Chemical Kinetics & Catalysis (AREA)
Biophysics (AREA)
Bioinformatics & Cheminformatics (AREA)
Engineering & Computer Science (AREA)
Molecular Biology (AREA)
Inorganic Chemistry (AREA)
Pulmonology (AREA)
Physical Education & Sports Medicine (AREA)
Gastroenterology & Hepatology (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Nitrogen Condensed Heterocyclic Rings (AREA)
Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

CA2773661A 2009-09-10 2010-09-10 Ether derivatives of bicyclic heteroaryls Abandoned CA2773661A1 (en)

Applications Claiming Priority (3)

Application Number	Priority Date	Filing Date	Title
US24118209P	2009-09-10	2009-09-10
US61/241,182		2009-09-10
PCT/EP2010/063334 WO2011029915A1 (en)	2009-09-10	2010-09-10	Ether derivatives of bicyclic heteroaryls

Publications (1)

Publication Number	Publication Date
CA2773661A1 true CA2773661A1 (en)	2011-03-17

Family

ID=43511862

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
CA2773661A Abandoned CA2773661A1 (en)	2009-09-10	2010-09-10	Ether derivatives of bicyclic heteroaryls

Country Status (12)

Country	Link
US (1)	US20120165310A1 (2)
EP (1)	EP2475668A1 (2)
JP (1)	JP2013504543A (2)
KR (1)	KR20120093867A (2)
CN (1)	CN102596963A (2)
AU (1)	AU2010294209A1 (2)
BR (1)	BR112012005400A2 (2)
CA (1)	CA2773661A1 (2)
EA (1)	EA201200471A1 (2)
IN (1)	IN2012DN02139A (2)
MX (1)	MX2012002997A (2)
WO (1)	WO2011029915A1 (2)

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CN107098909B (zh) *	2017-05-19	2019-02-22	四川大学华西医院	烷氧端基寡peg修饰的氨基嘧啶衍生物及抗肿瘤应用
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- 2010-09-10 CN CN2010800506564A patent/CN102596963A/zh active Pending
- 2010-09-10 BR BR112012005400A patent/BR112012005400A2/pt not_active Application Discontinuation
- 2010-09-10 MX MX2012002997A patent/MX2012002997A/es not_active Application Discontinuation
- 2010-09-10 EP EP10763143A patent/EP2475668A1/en not_active Withdrawn
- 2010-09-10 US US13/394,534 patent/US20120165310A1/en not_active Abandoned
- 2010-09-10 KR KR1020127009095A patent/KR20120093867A/ko not_active Withdrawn
- 2010-09-10 JP JP2012528376A patent/JP2013504543A/ja active Pending
- 2010-09-10 WO PCT/EP2010/063334 patent/WO2011029915A1/en not_active Ceased
- 2010-09-10 EA EA201200471A patent/EA201200471A1/ru unknown
- 2010-09-10 IN IN2139DEN2012 patent/IN2012DN02139A/en unknown
- 2010-09-10 AU AU2010294209A patent/AU2010294209A1/en not_active Abandoned

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Publication number	Publication date
AU2010294209A1 (en)	2012-03-29
US20120165310A1 (en)	2012-06-28
MX2012002997A (es)	2012-08-01
JP2013504543A (ja)	2013-02-07
EP2475668A1 (en)	2012-07-18
KR20120093867A (ko)	2012-08-23
WO2011029915A1 (en)	2011-03-17
CN102596963A (zh)	2012-07-18
EA201200471A1 (ru)	2012-10-30
BR112012005400A2 (pt)	2016-04-05
IN2012DN02139A (2)	2015-08-07

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Date	Code	Title	Description
2014-11-05	FZDE	Discontinued	Effective date: 20140910

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