ES2702524T3 - Compuestos como miméticos de hipoxia, y composiciones, y usos de estos - Google Patents
Compuestos como miméticos de hipoxia, y composiciones, y usos de estos Download PDFInfo
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- ES2702524T3 ES2702524T3 ES10799353T ES10799353T ES2702524T3 ES 2702524 T3 ES2702524 T3 ES 2702524T3 ES 10799353 T ES10799353 T ES 10799353T ES 10799353 T ES10799353 T ES 10799353T ES 2702524 T3 ES2702524 T3 ES 2702524T3
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- substituted
- alkyl
- compound
- alkoxy
- halogen
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 232
- -1 hypoxia mimetics Chemical class 0.000 title claims description 80
- 239000000203 mixture Substances 0.000 title description 17
- 206010021143 Hypoxia Diseases 0.000 title description 8
- 230000007954 hypoxia Effects 0.000 title description 6
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 94
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 93
- 150000002367 halogens Chemical class 0.000 claims abstract description 89
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 63
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims abstract description 63
- 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 claims abstract description 45
- 125000003118 aryl group Chemical group 0.000 claims abstract description 40
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 38
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims abstract description 35
- 125000001188 haloalkyl group Chemical group 0.000 claims abstract description 32
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims abstract description 32
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 30
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 29
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 28
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 27
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 24
- 125000004438 haloalkoxy group Chemical group 0.000 claims abstract description 23
- 125000003107 substituted aryl group Chemical group 0.000 claims abstract description 23
- 150000003839 salts Chemical class 0.000 claims abstract description 22
- 125000000547 substituted alkyl group Chemical group 0.000 claims abstract description 20
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 16
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 14
- 125000005843 halogen group Chemical group 0.000 claims abstract description 14
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 14
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 13
- 125000000304 alkynyl group Chemical group 0.000 claims abstract description 13
- 125000001424 substituent group Chemical group 0.000 claims abstract description 12
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims abstract description 12
- 239000001257 hydrogen Substances 0.000 claims abstract description 11
- 239000012453 solvate Substances 0.000 claims abstract description 10
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims abstract description 9
- 125000004429 atom Chemical group 0.000 claims abstract description 9
- 125000004450 alkenylene group Chemical group 0.000 claims abstract description 8
- 125000005103 alkyl silyl group Chemical group 0.000 claims abstract description 8
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 8
- 125000004419 alkynylene group Chemical group 0.000 claims abstract description 8
- 125000005017 substituted alkenyl group Chemical group 0.000 claims abstract description 8
- 125000004426 substituted alkynyl group Chemical group 0.000 claims abstract description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 7
- 239000013522 chelant Substances 0.000 claims abstract description 6
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 5
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims abstract description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 56
- 201000010099 disease Diseases 0.000 claims description 30
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 29
- 208000035475 disorder Diseases 0.000 claims description 26
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 21
- 230000000694 effects Effects 0.000 claims description 14
- 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 claims description 13
- 229910052801 chlorine Inorganic materials 0.000 claims description 12
- 229910052731 fluorine Inorganic materials 0.000 claims description 12
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 12
- 208000007502 anemia Diseases 0.000 claims description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims description 11
- 208000028867 ischemia Diseases 0.000 claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- 206010028980 Neoplasm Diseases 0.000 claims description 9
- 201000011510 cancer Diseases 0.000 claims description 9
- 238000004519 manufacturing process Methods 0.000 claims description 9
- 208000002903 Thalassemia Diseases 0.000 claims description 8
- 206010012601 diabetes mellitus Diseases 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 8
- 230000029663 wound healing Effects 0.000 claims description 8
- 238000002689 xenotransplantation Methods 0.000 claims description 8
- 239000002671 adjuvant Substances 0.000 claims description 7
- 238000011316 allogeneic transplantation Methods 0.000 claims description 7
- 208000027866 inflammatory disease Diseases 0.000 claims description 7
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
- 208000037905 systemic hypertension Diseases 0.000 claims description 7
- 125000004076 pyridyl group Chemical group 0.000 claims description 6
- 125000005415 substituted alkoxy group Chemical group 0.000 claims description 6
- 239000003981 vehicle Substances 0.000 claims description 6
- XQUJXDCYCANMCH-UHFFFAOYSA-N 2-[[4-hydroxy-2-oxo-8-[3-(trifluoromethyl)phenyl]chromene-3-carbonyl]amino]acetic acid Chemical compound C=12OC(=O)C(C(=O)NCC(=O)O)=C(O)C2=CC=CC=1C1=CC=CC(C(F)(F)F)=C1 XQUJXDCYCANMCH-UHFFFAOYSA-N 0.000 claims description 4
- 125000004414 alkyl thio group Chemical group 0.000 claims description 3
- GQWSJBDFFCLFQM-UHFFFAOYSA-N 2-[(4-hydroxy-2-oxo-7-phenylchromene-3-carbonyl)amino]acetic acid Chemical compound C1=C2OC(=O)C(C(=O)NCC(=O)O)=C(O)C2=CC=C1C1=CC=CC=C1 GQWSJBDFFCLFQM-UHFFFAOYSA-N 0.000 claims description 2
- XWBVTPDNZPTHIF-UHFFFAOYSA-N 2-[(4-hydroxy-2-oxo-7-pyridin-3-ylchromene-3-carbonyl)amino]acetic acid Chemical compound C1=C2OC(=O)C(C(=O)NCC(=O)O)=C(O)C2=CC=C1C1=CC=CN=C1 XWBVTPDNZPTHIF-UHFFFAOYSA-N 0.000 claims description 2
- PNGRZARBGBCVQC-UHFFFAOYSA-N 2-[(4-hydroxy-2-oxo-7-pyridin-4-ylchromene-3-carbonyl)amino]acetic acid Chemical compound C1=C2OC(=O)C(C(=O)NCC(=O)O)=C(O)C2=CC=C1C1=CC=NC=C1 PNGRZARBGBCVQC-UHFFFAOYSA-N 0.000 claims description 2
- QJRMHRZSVIXIAM-UHFFFAOYSA-N 2-[[4-hydroxy-2-oxo-7-(3,4,5-trifluorophenyl)chromene-3-carbonyl]amino]acetic acid Chemical compound C1=C2OC(=O)C(C(=O)NCC(=O)O)=C(O)C2=CC=C1C1=CC(F)=C(F)C(F)=C1 QJRMHRZSVIXIAM-UHFFFAOYSA-N 0.000 claims description 2
- IAWWTKGFCRMRCI-UHFFFAOYSA-N 2-[[4-hydroxy-2-oxo-7-[3-(trifluoromethoxy)phenyl]chromene-3-carbonyl]amino]acetic acid Chemical compound C1=C2OC(=O)C(C(=O)NCC(=O)O)=C(O)C2=CC=C1C1=CC=CC(OC(F)(F)F)=C1 IAWWTKGFCRMRCI-UHFFFAOYSA-N 0.000 claims description 2
- XZTYLGWJFOBYTJ-UHFFFAOYSA-N 2-[[4-hydroxy-2-oxo-7-[3-(trifluoromethyl)phenyl]chromene-3-carbonyl]amino]acetic acid Chemical compound C1=C2OC(=O)C(C(=O)NCC(=O)O)=C(O)C2=CC=C1C1=CC=CC(C(F)(F)F)=C1 XZTYLGWJFOBYTJ-UHFFFAOYSA-N 0.000 claims description 2
- PRVDWMUCVHSLOZ-UHFFFAOYSA-N 2-[[4-hydroxy-2-oxo-7-[4-(trifluoromethoxy)phenyl]chromene-3-carbonyl]amino]acetic acid Chemical compound C1=C2OC(=O)C(C(=O)NCC(=O)O)=C(O)C2=CC=C1C1=CC=C(OC(F)(F)F)C=C1 PRVDWMUCVHSLOZ-UHFFFAOYSA-N 0.000 claims description 2
- WAALSRXNKALSSD-UHFFFAOYSA-N 2-[[4-hydroxy-2-oxo-7-[4-(trifluoromethyl)phenyl]chromene-3-carbonyl]amino]acetic acid Chemical compound C1=C2OC(=O)C(C(=O)NCC(=O)O)=C(O)C2=CC=C1C1=CC=C(C(F)(F)F)C=C1 WAALSRXNKALSSD-UHFFFAOYSA-N 0.000 claims description 2
- UPRZQSOGEWNLBE-UHFFFAOYSA-N 2-[[4-hydroxy-2-oxo-8-(3,4,5-trifluorophenyl)chromene-3-carbonyl]amino]acetic acid Chemical compound C=12OC(=O)C(C(=O)NCC(=O)O)=C(O)C2=CC=CC=1C1=CC(F)=C(F)C(F)=C1 UPRZQSOGEWNLBE-UHFFFAOYSA-N 0.000 claims description 2
- UAUBZCPCBQNYJZ-UHFFFAOYSA-N 2-[[4-hydroxy-2-oxo-8-[3-(trifluoromethoxy)phenyl]chromene-3-carbonyl]amino]acetic acid Chemical compound C=12OC(=O)C(C(=O)NCC(=O)O)=C(O)C2=CC=CC=1C1=CC=CC(OC(F)(F)F)=C1 UAUBZCPCBQNYJZ-UHFFFAOYSA-N 0.000 claims description 2
- BLXWBOGYYXGCHA-UHFFFAOYSA-N 2-[[4-hydroxy-2-oxo-8-[4-(trifluoromethoxy)phenyl]chromene-3-carbonyl]amino]acetic acid Chemical compound C=12OC(=O)C(C(=O)NCC(=O)O)=C(O)C2=CC=CC=1C1=CC=C(OC(F)(F)F)C=C1 BLXWBOGYYXGCHA-UHFFFAOYSA-N 0.000 claims description 2
- VKCWXFGQPZTWPB-UHFFFAOYSA-N 2-[[4-hydroxy-2-oxo-8-[4-(trifluoromethyl)phenyl]chromene-3-carbonyl]amino]acetic acid Chemical compound C=12OC(=O)C(C(=O)NCC(=O)O)=C(O)C2=CC=CC=1C1=CC=C(C(F)(F)F)C=C1 VKCWXFGQPZTWPB-UHFFFAOYSA-N 0.000 claims description 2
- BKLJTUMUSAJMQK-UHFFFAOYSA-N 2-[[4-hydroxy-7-(3-methoxyphenyl)-2-oxochromene-3-carbonyl]amino]acetic acid Chemical compound COC1=CC=CC(C=2C=C3OC(=O)C(C(=O)NCC(O)=O)=C(O)C3=CC=2)=C1 BKLJTUMUSAJMQK-UHFFFAOYSA-N 0.000 claims description 2
- SAKKIQANFNOMQE-UHFFFAOYSA-N 2-[[4-hydroxy-7-(3-methylphenyl)-2-oxochromene-3-carbonyl]amino]acetic acid Chemical compound CC1=CC=CC(C=2C=C3OC(=O)C(C(=O)NCC(O)=O)=C(O)C3=CC=2)=C1 SAKKIQANFNOMQE-UHFFFAOYSA-N 0.000 claims description 2
- IVGRAINASGPBHC-UHFFFAOYSA-N 2-[[4-hydroxy-7-(4-methoxyphenyl)-2-oxochromene-3-carbonyl]amino]acetic acid Chemical compound C1=CC(OC)=CC=C1C1=CC=C(C(O)=C(C(=O)NCC(O)=O)C(=O)O2)C2=C1 IVGRAINASGPBHC-UHFFFAOYSA-N 0.000 claims description 2
- KWWRZRSSDDWGLG-UHFFFAOYSA-N 2-[[4-hydroxy-7-(4-methylphenyl)-2-oxochromene-3-carbonyl]amino]acetic acid Chemical compound C1=CC(C)=CC=C1C1=CC=C(C(O)=C(C(=O)NCC(O)=O)C(=O)O2)C2=C1 KWWRZRSSDDWGLG-UHFFFAOYSA-N 0.000 claims description 2
- IWYFVVWNUKLMKY-UHFFFAOYSA-N 2-[[4-hydroxy-7-(6-methoxypyridin-3-yl)-2-oxochromene-3-carbonyl]amino]acetic acid Chemical compound C1=NC(OC)=CC=C1C1=CC=C(C(O)=C(C(=O)NCC(O)=O)C(=O)O2)C2=C1 IWYFVVWNUKLMKY-UHFFFAOYSA-N 0.000 claims description 2
- LXTBGJQEBUNWIZ-UHFFFAOYSA-N 2-[[4-hydroxy-8-(3-methoxyphenyl)-2-oxochromene-3-carbonyl]amino]acetic acid Chemical compound COC1=CC=CC(C=2C=3OC(=O)C(C(=O)NCC(O)=O)=C(O)C=3C=CC=2)=C1 LXTBGJQEBUNWIZ-UHFFFAOYSA-N 0.000 claims description 2
- YVKNNNVAKTWJPO-UHFFFAOYSA-N 2-[[4-hydroxy-8-(3-methylphenyl)-2-oxochromene-3-carbonyl]amino]acetic acid Chemical compound CC1=CC=CC(C=2C=3OC(=O)C(C(=O)NCC(O)=O)=C(O)C=3C=CC=2)=C1 YVKNNNVAKTWJPO-UHFFFAOYSA-N 0.000 claims description 2
- KAEYBTXGARFSES-UHFFFAOYSA-N 2-[[4-hydroxy-8-(4-methoxyphenyl)-2-oxochromene-3-carbonyl]amino]acetic acid Chemical compound C1=CC(OC)=CC=C1C1=CC=CC2=C1OC(=O)C(C(=O)NCC(O)=O)=C2O KAEYBTXGARFSES-UHFFFAOYSA-N 0.000 claims description 2
- HATJKDJVUKAARX-UHFFFAOYSA-N 2-[[4-hydroxy-8-(4-methylphenyl)-2-oxochromene-3-carbonyl]amino]acetic acid Chemical compound C1=CC(C)=CC=C1C1=CC=CC2=C1OC(=O)C(C(=O)NCC(O)=O)=C2O HATJKDJVUKAARX-UHFFFAOYSA-N 0.000 claims description 2
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Classifications
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- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
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- A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
- A61K31/37—Coumarins, e.g. psoralen
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/42—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms in positions 2 and 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/42—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms in positions 2 and 4
- C07D311/56—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms in positions 2 and 4 without hydrogen atoms in position 3
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- 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
- C07D405/02—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 two hetero rings
- C07D405/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond
Landscapes
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pyrane Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910089274 | 2009-07-15 | ||
| PCT/CN2010/001057 WO2011006355A1 (en) | 2009-07-15 | 2010-07-14 | Compounds as hypoxia mimetics, and compositions, and uses thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ES2702524T3 true ES2702524T3 (es) | 2019-03-01 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES10799353T Active ES2702524T3 (es) | 2009-07-15 | 2010-07-14 | Compuestos como miméticos de hipoxia, y composiciones, y usos de estos |
Country Status (13)
| Country | Link |
|---|---|
| US (1) | US8742138B2 (enExample) |
| EP (1) | EP2454249B1 (enExample) |
| JP (1) | JP5847710B2 (enExample) |
| KR (1) | KR20120065311A (enExample) |
| CN (1) | CN102164905B (enExample) |
| AU (1) | AU2010273101B2 (enExample) |
| CA (1) | CA2767911C (enExample) |
| ES (1) | ES2702524T3 (enExample) |
| IL (1) | IL217531A0 (enExample) |
| IN (1) | IN2012DN00549A (enExample) |
| SG (1) | SG177598A1 (enExample) |
| WO (1) | WO2011006355A1 (enExample) |
| ZA (1) | ZA201200293B (enExample) |
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| JP2014523917A (ja) * | 2011-07-29 | 2014-09-18 | ベイジン ベータ ファーマシューティカルズ カンパニー， リミテッド | 低酸素模倣剤としての化合物の安定な多形体、およびその使用 |
| CN105384687B (zh) | 2014-09-02 | 2018-05-01 | 广东东阳光药业有限公司 | 喹啉酮类化合物及其在药物中应用 |
| US20160193238A1 (en) * | 2015-01-05 | 2016-07-07 | National Cancer Center | HNF4-alpha ANTAGONIST AND USE THEREOF |
| CN113694077A (zh) * | 2015-08-13 | 2021-11-26 | 索马根尼科斯公司 | 用于伤口愈合的短小发夹rna与微rna的组合物以及方法 |
| AU2018264313B2 (en) | 2017-05-09 | 2020-06-04 | Kind Pharmaceutical | Indolizine derivatives and application thereof in medicine |
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| WO2007038571A2 (en) * | 2005-09-26 | 2007-04-05 | Smithkline Beecham Corporation | Prolyl hydroxylase antagonists |
| CA2634168C (en) | 2005-12-09 | 2013-04-23 | Amgen Inc. | Quinolone based compounds exhibiting prolyl hydroxylase inhibitory activity, and compositions, and uses thereof |
| TW200808793A (en) * | 2006-03-07 | 2008-02-16 | Smithkline Beecham Corp | Prolyl hydroxylase inhibitors |
| PL2134720T3 (pl) * | 2007-03-29 | 2011-04-29 | Novartis Ag | Heterocykliczne spiro-związki |
| US8324405B2 (en) * | 2008-02-05 | 2012-12-04 | Fibrogen, Inc. | Chromene derivatives and use thereof as HIF hydroxylase activity inhibitors |
| EP2341904A1 (en) * | 2008-08-26 | 2011-07-13 | Fibrogen, Inc. | Methods for treatment of multiple sclerosis |
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| HK1161234A1 (en) | 2012-08-24 |
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| WO2011006355A1 (en) | 2011-01-20 |
| KR20120065311A (ko) | 2012-06-20 |
| AU2010273101A2 (en) | 2012-03-15 |
| EP2454249B1 (en) | 2018-09-19 |
| AU2010273101A1 (en) | 2012-02-02 |
| JP2012532897A (ja) | 2012-12-20 |
| SG177598A1 (en) | 2012-02-28 |
| US20120172399A1 (en) | 2012-07-05 |
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