CA2442141A1 - Compounds and pharmaceutical compositions for inhibiting mrp1 - Google Patents
Compounds and pharmaceutical compositions for inhibiting mrp1 Download PDFInfo
- Publication number
- CA2442141A1 CA2442141A1 CA002442141A CA2442141A CA2442141A1 CA 2442141 A1 CA2442141 A1 CA 2442141A1 CA 002442141 A CA002442141 A CA 002442141A CA 2442141 A CA2442141 A CA 2442141A CA 2442141 A1 CA2442141 A1 CA 2442141A1
- Authority
- CA
- Canada
- Prior art keywords
- optionally substituted
- alkyl
- mmol
- heterocycle
- phenyl
- 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.)
- Abandoned
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 137
- 230000002401 inhibitory effect Effects 0.000 title claims abstract description 12
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 7
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- 102100021339 Multidrug resistance-associated protein 1 Human genes 0.000 claims abstract 2
- 108010066052 multidrug resistance-associated protein 1 Proteins 0.000 claims abstract 2
- 239000000203 mixture Substances 0.000 claims description 57
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 45
- 230000000174 oncolytic effect Effects 0.000 claims description 44
- 125000000623 heterocyclic group Chemical group 0.000 claims description 43
- 229910052757 nitrogen Inorganic materials 0.000 claims description 37
- 150000003839 salts Chemical class 0.000 claims description 36
- 238000000034 method Methods 0.000 claims description 30
- 238000009472 formulation Methods 0.000 claims description 25
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- 208000035269 cancer or benign tumor Diseases 0.000 claims description 24
- 125000000217 alkyl group Chemical group 0.000 claims description 22
- 239000001257 hydrogen Substances 0.000 claims description 19
- 229910052739 hydrogen Inorganic materials 0.000 claims description 19
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 19
- 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 claims description 15
- 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 claims description 13
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- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 claims description 7
- HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 claims description 7
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- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 claims description 7
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- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 claims description 6
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- 210000000988 bone and bone Anatomy 0.000 claims description 5
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- 239000008024 pharmaceutical diluent Substances 0.000 claims description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 23
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims 10
- 101100516568 Caenorhabditis elegans nhr-7 gene Proteins 0.000 claims 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 99
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- 239000012141 concentrate Substances 0.000 description 95
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- 239000000243 solution Substances 0.000 description 83
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 64
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 60
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 48
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 48
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 48
- 238000003756 stirring Methods 0.000 description 48
- 238000006243 chemical reaction Methods 0.000 description 47
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- 239000007787 solid Substances 0.000 description 37
- 239000012267 brine Substances 0.000 description 36
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 36
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 34
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 34
- 108050005144 Multidrug resistance proteins Proteins 0.000 description 28
- 102000014842 Multidrug resistance proteins Human genes 0.000 description 28
- 238000005160 1H NMR spectroscopy Methods 0.000 description 27
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
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- 229910052943 magnesium sulfate Inorganic materials 0.000 description 24
- 235000019341 magnesium sulphate Nutrition 0.000 description 24
- 238000002360 preparation method Methods 0.000 description 24
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- 229920006395 saturated elastomer Polymers 0.000 description 23
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 22
- 125000006239 protecting group Chemical group 0.000 description 22
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- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
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- FPIRBHDGWMWJEP-UHFFFAOYSA-N 1-hydroxy-7-azabenzotriazole Chemical compound C1=CN=C2N(O)N=NC2=C1 FPIRBHDGWMWJEP-UHFFFAOYSA-N 0.000 description 10
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 10
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- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 8
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
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- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 8
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- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 4
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- QCTVFPCCHFCDNV-UHFFFAOYSA-N 5-ethoxycarbonyl-1-[(2-methylpropan-2-yl)oxycarbonyl]piperidine-3-carboxylic acid Chemical compound CCOC(=O)C1CC(C(O)=O)CN(C(=O)OC(C)(C)C)C1 QCTVFPCCHFCDNV-UHFFFAOYSA-N 0.000 description 2
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- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 1
- RHUUGOAALKETDP-UHFFFAOYSA-N tert-butyl 3-(9-chloro-3-methyl-4-oxo-[1,2]oxazolo[4,3-c]quinolin-5-yl)-5-(hydroxymethyl)piperidine-1-carboxylate Chemical compound CC=1ON=C(C2=C(Cl)C=CC=C22)C=1C(=O)N2C1CC(CO)CN(C(=O)OC(C)(C)C)C1 RHUUGOAALKETDP-UHFFFAOYSA-N 0.000 description 1
- LBSKBLLAUPIMRP-UHFFFAOYSA-N tert-butyl 3-(9-chloro-3-methyl-4-oxo-[1,2]oxazolo[4,3-c]quinolin-5-yl)-5-(methylsulfonyloxymethyl)piperidine-1-carboxylate Chemical compound CC=1ON=C(C2=C(Cl)C=CC=C22)C=1C(=O)N2C1CC(COS(C)(=O)=O)CN(C(=O)OC(C)(C)C)C1 LBSKBLLAUPIMRP-UHFFFAOYSA-N 0.000 description 1
- OLEFBEYKJWPYLR-UHFFFAOYSA-N tert-butyl 3-(azidomethyl)-5-(9-chloro-3-methyl-4-oxo-[1,2]oxazolo[4,3-c]quinolin-5-yl)piperidine-1-carboxylate Chemical compound CC=1ON=C(C2=C(Cl)C=CC=C22)C=1C(=O)N2C1CC(CN=[N+]=[N-])CN(C(=O)OC(C)(C)C)C1 OLEFBEYKJWPYLR-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 201000003120 testicular cancer Diseases 0.000 description 1
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- 229940044693 topoisomerase inhibitor Drugs 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 230000037317 transdermal delivery Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical class OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- FKPIQXKEFGLMNA-UHFFFAOYSA-N trimethyl-[2-(2-trimethylsilylethoxy)ethyl]silane Chemical group C[Si](C)(C)CCOCC[Si](C)(C)C FKPIQXKEFGLMNA-UHFFFAOYSA-N 0.000 description 1
- JBWKIWSBJXDJDT-UHFFFAOYSA-N triphenylmethyl chloride Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 JBWKIWSBJXDJDT-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
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Classifications
-
- 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
- C07D498/02—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 two hetero rings
- C07D498/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US28264201P | 2001-04-09 | 2001-04-09 | |
| US60/282,642 | 2001-04-09 | ||
| PCT/US2002/006662 WO2002081480A1 (en) | 2001-04-09 | 2002-03-27 | Compounds and pharmaceutical compositions for inhibiting mrp1 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2442141A1 true CA2442141A1 (en) | 2002-10-17 |
Family
ID=23082449
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002442141A Abandoned CA2442141A1 (en) | 2001-04-09 | 2002-03-27 | Compounds and pharmaceutical compositions for inhibiting mrp1 |
Country Status (5)
| Country | Link |
|---|---|
| US (1) | US7101891B2 (enExample) |
| EP (1) | EP1392701A1 (enExample) |
| JP (1) | JP2004525952A (enExample) |
| CA (1) | CA2442141A1 (enExample) |
| WO (1) | WO2002081480A1 (enExample) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JO2409B1 (en) | 2000-11-21 | 2007-06-17 | شركة جانسين فارماسوتيكا ان. في | Second-phenyl carboxy amides are useful as lipid-lowering agents |
| JP2009508963A (ja) * | 2005-09-21 | 2009-03-05 | インサイト・コーポレイション | アミド化合物および医薬組成物としてのその使用 |
| WO2007101270A1 (en) * | 2006-03-02 | 2007-09-07 | Incyte Corporation | MODULATORS OF 11-β HYDROXYL STEROID DEHYDROGENASE TYPE 1, PHARMACEUTICAL COMPOSITIONS THEREOF, AND METHODS OF USING THE SAME |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6369070B1 (en) * | 1998-04-08 | 2002-04-09 | Eli Lilly And Company | Methods for inhibiting mrp1 |
| US6743794B2 (en) * | 1999-12-22 | 2004-06-01 | Eli Lilly And Company | Methods and compounds for inhibiting MRP1 |
-
2002
- 2002-03-27 WO PCT/US2002/006662 patent/WO2002081480A1/en not_active Ceased
- 2002-03-27 EP EP02723331A patent/EP1392701A1/en not_active Withdrawn
- 2002-03-27 JP JP2002579468A patent/JP2004525952A/ja active Pending
- 2002-03-27 CA CA002442141A patent/CA2442141A1/en not_active Abandoned
- 2002-03-27 US US10/473,236 patent/US7101891B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| US7101891B2 (en) | 2006-09-05 |
| WO2002081480A1 (en) | 2002-10-17 |
| EP1392701A1 (en) | 2004-03-03 |
| US20040116460A1 (en) | 2004-06-17 |
| JP2004525952A (ja) | 2004-08-26 |
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