WO2013013609A1 - Polymorphic forms of compounds as prolyl hydroxylase inhibitor, and uses thereof - Google Patents
Polymorphic forms of compounds as prolyl hydroxylase inhibitor, and uses thereof Download PDFInfo
- Publication number
- WO2013013609A1 WO2013013609A1 PCT/CN2012/079058 CN2012079058W WO2013013609A1 WO 2013013609 A1 WO2013013609 A1 WO 2013013609A1 CN 2012079058 W CN2012079058 W CN 2012079058W WO 2013013609 A1 WO2013013609 A1 WO 2013013609A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- polymorph
- compound
- ray powder
- diffraction pattern
- powder diffraction
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 126
- 229940078467 Prolyl hydroxylase inhibitor Drugs 0.000 title description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 52
- 201000010099 disease Diseases 0.000 claims abstract description 27
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 27
- 238000004519 manufacturing process Methods 0.000 claims abstract description 13
- 239000003814 drug Substances 0.000 claims abstract description 12
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 111
- 238000000034 method Methods 0.000 claims description 56
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 54
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 48
- 229910001868 water Inorganic materials 0.000 claims description 35
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 30
- 239000012046 mixed solvent Substances 0.000 claims description 29
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 27
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 24
- 235000019439 ethyl acetate Nutrition 0.000 claims description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- 238000002844 melting Methods 0.000 claims description 18
- 230000008018 melting Effects 0.000 claims description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 18
- 208000028867 ischemia Diseases 0.000 claims description 17
- 239000000203 mixture Substances 0.000 claims description 17
- 208000007502 anemia Diseases 0.000 claims description 16
- 230000000694 effects Effects 0.000 claims description 14
- 239000013078 crystal Substances 0.000 claims description 13
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 12
- 229940011051 isopropyl acetate Drugs 0.000 claims description 12
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 12
- 238000001556 precipitation Methods 0.000 claims description 12
- 230000015572 biosynthetic process Effects 0.000 claims description 11
- 238000003786 synthesis reaction Methods 0.000 claims description 11
- 230000002269 spontaneous effect Effects 0.000 claims description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 9
- 206010028980 Neoplasm Diseases 0.000 claims description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N acetic acid anhydride Natural products CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 6
- 201000011510 cancer Diseases 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- 239000002244 precipitate Substances 0.000 claims description 6
- 238000010992 reflux Methods 0.000 claims description 6
- 206010020772 Hypertension Diseases 0.000 claims description 5
- 208000002903 Thalassemia Diseases 0.000 claims description 5
- 238000011316 allogeneic transplantation Methods 0.000 claims description 5
- 239000002775 capsule Substances 0.000 claims description 5
- 229940125904 compound 1 Drugs 0.000 claims description 5
- 206010012601 diabetes mellitus Diseases 0.000 claims description 5
- 208000027866 inflammatory disease Diseases 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- 230000009885 systemic effect Effects 0.000 claims description 5
- 238000002054 transplantation Methods 0.000 claims description 5
- 230000029663 wound healing Effects 0.000 claims description 5
- 238000002689 xenotransplantation Methods 0.000 claims description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims description 4
- 239000012296 anti-solvent Substances 0.000 claims description 4
- 238000006243 chemical reaction Methods 0.000 claims description 4
- 238000004587 chromatography analysis Methods 0.000 claims description 4
- 229940125782 compound 2 Drugs 0.000 claims description 4
- 229940125898 compound 5 Drugs 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 4
- 239000012535 impurity Substances 0.000 claims description 4
- 238000000746 purification Methods 0.000 claims description 4
- 238000002390 rotary evaporation Methods 0.000 claims description 4
- 239000002671 adjuvant Substances 0.000 claims description 3
- 239000011261 inert gas Substances 0.000 claims description 3
- 239000012074 organic phase Substances 0.000 claims description 3
- UVNPEUJXKZFWSJ-LMTQTHQJSA-N (R)-N-[(4S)-8-[6-amino-5-[(3,3-difluoro-2-oxo-1H-pyrrolo[2,3-b]pyridin-4-yl)sulfanyl]pyrazin-2-yl]-2-oxa-8-azaspiro[4.5]decan-4-yl]-2-methylpropane-2-sulfinamide Chemical compound CC(C)(C)[S@@](=O)N[C@@H]1COCC11CCN(CC1)c1cnc(Sc2ccnc3NC(=O)C(F)(F)c23)c(N)n1 UVNPEUJXKZFWSJ-LMTQTHQJSA-N 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- WDBQJSCPCGTAFG-QHCPKHFHSA-N 4,4-difluoro-N-[(1S)-3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-pyridin-3-ylpropyl]cyclohexane-1-carboxamide Chemical compound FC1(CCC(CC1)C(=O)N[C@@H](CCN1CCC(CC1)N1C(=NN=C1C)C(C)C)C=1C=NC=CC=1)F WDBQJSCPCGTAFG-QHCPKHFHSA-N 0.000 claims description 2
- BWGRDBSNKQABCB-UHFFFAOYSA-N 4,4-difluoro-N-[3-[3-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octan-8-yl]-1-thiophen-2-ylpropyl]cyclohexane-1-carboxamide Chemical compound CC(C)C1=NN=C(C)N1C1CC2CCC(C1)N2CCC(NC(=O)C1CCC(F)(F)CC1)C1=CC=CS1 BWGRDBSNKQABCB-UHFFFAOYSA-N 0.000 claims description 2
- NUGPIZCTELGDOS-QHCPKHFHSA-N N-[(1S)-3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-pyridin-3-ylpropyl]cyclopentanecarboxamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CC[C@@H](C=1C=NC=CC=1)NC(=O)C1CCCC1)C NUGPIZCTELGDOS-QHCPKHFHSA-N 0.000 claims description 2
- LFZAGIJXANFPFN-UHFFFAOYSA-N N-[3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-thiophen-2-ylpropyl]acetamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CCC(C=1SC=CC=1)NC(C)=O)C LFZAGIJXANFPFN-UHFFFAOYSA-N 0.000 claims description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 2
- 229960000583 acetic acid Drugs 0.000 claims description 2
- 229940125773 compound 10 Drugs 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 239000012362 glacial acetic acid Substances 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- COQRGFWWJBEXRC-UHFFFAOYSA-N hydron;methyl 2-aminoacetate;chloride Chemical compound Cl.COC(=O)CN COQRGFWWJBEXRC-UHFFFAOYSA-N 0.000 claims description 2
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 claims description 2
- 239000000741 silica gel Substances 0.000 claims description 2
- 229910002027 silica gel Inorganic materials 0.000 claims description 2
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 claims 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims 2
- 229910019213 POCl3 Inorganic materials 0.000 claims 1
- 229910000085 borane Inorganic materials 0.000 claims 1
- 229940126214 compound 3 Drugs 0.000 claims 1
- 239000012297 crystallization seed Substances 0.000 claims 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- 239000012071 phase Substances 0.000 claims 1
- 229910000027 potassium carbonate Inorganic materials 0.000 claims 1
- 238000003756 stirring Methods 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 9
- 239000000543 intermediate Substances 0.000 abstract 1
- 208000035475 disorder Diseases 0.000 description 17
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 11
- 239000000725 suspension Substances 0.000 description 10
- 238000002441 X-ray diffraction Methods 0.000 description 8
- 239000002002 slurry Substances 0.000 description 7
- 238000009472 formulation Methods 0.000 description 5
- 208000024891 symptom Diseases 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- 206010021143 Hypoxia Diseases 0.000 description 4
- 102000003951 Erythropoietin Human genes 0.000 description 3
- 108090000394 Erythropoietin Proteins 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 229940105423 erythropoietin Drugs 0.000 description 3
- 230000007954 hypoxia Effects 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- OXCMYAYHXIHQOA-UHFFFAOYSA-N potassium;[2-butyl-5-chloro-3-[[4-[2-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol Chemical compound [K+].CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C2=N[N-]N=N2)C=C1 OXCMYAYHXIHQOA-UHFFFAOYSA-N 0.000 description 3
- 230000001737 promoting effect Effects 0.000 description 3
- KPGXRSRHYNQIFN-UHFFFAOYSA-N 2-oxoglutaric acid Chemical compound OC(=O)CCC(=O)C(O)=O KPGXRSRHYNQIFN-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 102000004079 Prolyl Hydroxylases Human genes 0.000 description 2
- 108010043005 Prolyl Hydroxylases Proteins 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 230000033444 hydroxylation Effects 0.000 description 2
- 238000005805 hydroxylation reaction Methods 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 239000012669 liquid formulation Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000012053 oil suspension Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 230000006641 stabilisation Effects 0.000 description 2
- 238000011105 stabilization Methods 0.000 description 2
- 238000013518 transcription Methods 0.000 description 2
- 230000035897 transcription Effects 0.000 description 2
- 230000002103 transcriptional effect Effects 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- 229920001817 Agar Polymers 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 238000011740 C57BL/6 mouse Methods 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 102100035882 Catalase Human genes 0.000 description 1
- 108010053835 Catalase Proteins 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 102100037249 Egl nine homolog 1 Human genes 0.000 description 1
- 101710111663 Egl nine homolog 1 Proteins 0.000 description 1
- 108010092408 Eosinophil Peroxidase Proteins 0.000 description 1
- 102100031939 Erythropoietin Human genes 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 108091005880 Hemoglobin F Proteins 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 108010044467 Isoenzymes Proteins 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 102000007999 Nuclear Proteins Human genes 0.000 description 1
- 108010089610 Nuclear Proteins Proteins 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- 102000004245 Proteasome Endopeptidase Complex Human genes 0.000 description 1
- 108090000708 Proteasome Endopeptidase Complex Proteins 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 108010090804 Streptavidin Proteins 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 102000053200 Von Hippel-Lindau Tumor Suppressor Human genes 0.000 description 1
- 108700031765 Von Hippel-Lindau Tumor Suppressor Proteins 0.000 description 1
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 125000000613 asparagine group Chemical group N[C@@H](CC(N)=O)C(=O)* 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000012131 assay buffer Substances 0.000 description 1
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 235000008504 concentrate Nutrition 0.000 description 1
- 239000013068 control sample Substances 0.000 description 1
- 239000012059 conventional drug carrier Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000037149 energy metabolism Effects 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 230000010437 erythropoiesis Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000000833 heterodimer Substances 0.000 description 1
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 1
- 230000001146 hypoxic effect Effects 0.000 description 1
- 238000003018 immunoassay Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229910000359 iron(II) sulfate Inorganic materials 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000008176 lyophilized powder Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- CRXFROMHHBMNAB-UHFFFAOYSA-N methyl 2-isocyanoacetate Chemical compound COC(=O)C[N+]#[C-] CRXFROMHHBMNAB-UHFFFAOYSA-N 0.000 description 1
- 229910021421 monocrystalline silicon Inorganic materials 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 229940097496 nasal spray Drugs 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 230000019039 oxygen homeostasis Effects 0.000 description 1
- 239000003961 penetration enhancing agent Substances 0.000 description 1
- 230000006461 physiological response Effects 0.000 description 1
- 238000007745 plasma electrolytic oxidation reaction Methods 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 230000029279 positive regulation of transcription, DNA-dependent Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000011533 pre-incubation Methods 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000010378 sodium ascorbate Nutrition 0.000 description 1
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 description 1
- 229960005055 sodium ascorbate Drugs 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 238000002877 time resolved fluorescence resonance energy transfer Methods 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- WXRGABKACDFXMG-UHFFFAOYSA-N trimethylborane Chemical compound CB(C)C WXRGABKACDFXMG-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 230000014848 ubiquitin-dependent protein catabolic process Effects 0.000 description 1
- 230000001457 vasomotor Effects 0.000 description 1
- 102100035070 von Hippel-Lindau disease tumor suppressor Human genes 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
- C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/472—Non-condensed isoquinolines, e.g. papaverine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- 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
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/06—Antianaemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Definitions
- the present invention relates to the polymorphic forms of a novel compound, and their use in inhibiting prolyl hydroxylase activity.
- the present invention also relates to a method of using at least one of the polymorphs thereof in modulating HIF level or activity, treating a disease, a disorder or a condition associated with increasing or lowing HIF level or activity, in a subject.
- HIF Hemoxia Inducible Factor
- the cellular transcription factor HIF occupies a central position in oxygen homeostasis in a wide range of organisms and is a key regulator of responses to hypoxia.
- the genes regulated by HIF transcriptional activity can play critical roles in angiogenesis, erythropoiesis, hemoglobin F production, energy metabolism, inflammation, vasomotor function, apoptosis and cellular proliferation.
- HIF can also play a role in cancer, in which it is commonly upregulated, and in the physiological responses to ischemia and hypoxia.
- HIF- ⁇ is a constitutive nuclear protein that dimerizes with oxygen-regulated HIF-a subunits. Oxygen regulation occurs through hydroxylation of the HIF-a subunits, which are then rapidly destroyed by the proteasome.
- pVHL protein von Hippel-Lindau tumor suppressor protein
- pVHL protein binds to hydroxylated HIF-subunits, thereby promoting their ubiquitin dependent proteolysis. This process is suppressed under hypoxic conditions, stabilizing HIF-a and promoting the transcription and activation of the HIFaP dimer.
- HIF-a subunits can occur on proline and asparagine residues and can be catalyzed by a family of 2-oxoglutarate dependent enzymes.
- This family includes the HIF prolyl hydroxylase isozymes (PHDs), which hydroxylate Pro 402 and Pro 564 of human HIFla, as well as Factor Inhibiting HIF (FIH), which hydroxylates Asn 803 of human HIFl . Inhibition of FIH or the PHDs leads to HIF stabilization and further transcription and activation.
- PHDs HIF prolyl hydroxylase isozymes
- FIH Factor Inhibiting HIF
- Inhibition of FIH or the PHDs leads to HIF stabilization and further transcription and activation.
- the present invention relates to approximately pure crystalline polymorphs, wherein these polymorphs are the polymorphs of the compound of Formula I, and/or a hydrate thereof, and/or a solvate thereof.
- the compound of Formula I of the present invention exists in one or more crystal forms.
- the inventors designated these crystal forms Form I, Form II, Form III, Form IV, Form V, Form VI and Form VII.
- the present invention provides a crystalline polymorph of the compound of Formula I that exhibits an X-ray powder diffraction pattern having characteristic peaks at diffraction angles 2 ⁇ of approximately 5.9°, 11.0° and 25.9°.
- the present invention further provides preferred embodiments of the crystalline polymorph.
- the X-ray powder diffraction pattern has characteristic peaks, expressed in terms of the interplanar distance, at 14.9A, 8.0A and 3.4A.
- the X-ray powder diffraction pattern has characteristic peaks at diffraction angles 2 ⁇ of approximately 5.9°, 11.0°, 17.6°, 22.6°, 25.9° and 26.9°.
- the X-ray powder diffraction pattern has characteristic peaks, expressed in terms of the interplanar distance, at 14.9A, 8.0A, 5.lA, 3.9A, 3.4A and 3.3 A.
- the X-ray powder diffraction pattern has characteristic peaks at diffraction angles 2 ⁇ of approximately 5.9°, 11.0°, 14.8°, 17.6°, 22.6°, 24.0°, 25.9° and 26.9°.
- the X-ray powder diffraction pattern has characteristic peaks, expressed in terms of the interplanar distance, at 14.9A, 8.0A, 6.0A, 5.1 A, 3.9A, 3.7A, 3.4A and 3.3A.
- the X-ray powder diffraction pattern is shown as in Figure 1.
- the polymorph has a melting point of 174-177 °C.
- the polymorph has a purity of >85%.
- the polymorph has a purity of >95%.
- the polymorph has a purity of >99%.
- the present also provides a method of preparing the crystalline polymorph, comprising the steps of dissolving the compound of Formula I as prepared in Example 1 in the mixed solvent of methanol/MTBE ( methyl tertbutyl ether ) at room temperature, followed by a spontaneous precipitation, and recovering the resulted crystalline polymorph.
- methanol/MTBE methyl tertbutyl ether
- the present invention also provides a crystalline polymorph of the compound of Formula I that exhibits an X-ray powder diffraction pattern having characteristic peaks at diffraction angles 2 ⁇ of approximately 8.2°, 14.5° and 26.6°.
- the X-ray powder diffraction pattern has characteristic peaks, expressed in terms of the interplanar distance, at 10.8 A, 6.1 A and 3.4 A.
- the X-ray powder diffraction pattern has characteristic peaks at diffraction angles 2 ⁇ of approximately 8.2°, 13.3°, 14.5°, 21.2° and 26.6°.
- the X-ray powder diffraction pattern has characteristic peaks, expressed in terms of the interplanar distance, at 10.8A, 6.7A, 6.lA, 4.2A and 3.4A.
- the X-ray powder diffraction pattern has characteristic peaks at diffraction angles 2 ⁇ of approximately 8.2°, 9.6°, 13.3°, 14.5°, 21.2°, 22.8°, 25.4° and 26.6°.
- the X-ray powder diffraction pattern has characteristic peaks, expressed in terms of the interplanar distance, at 10.8A, 9.3A, 6.7A, 6.1 A, 4.2A, 3.9A, 3.5A and 3.4A.
- the X-ray powder diffraction pattern is shown as in Figure 2.
- the polymorph has a melting point of 209-212 °C
- the polymorph has a purity of >85%.
- the polymorph has a purity of >95%.
- the polymorph has a purity of >99%.
- the present invention also provides a method of preparing the crystalline polymorph comprising the steps of slurrying excess amount of the compound of Formula I as prepared in from Example 1 in the mixed solvent of H 2 0/acetonitrile (3: 1), or H 2 0/ethanol at room temperature or 50 °C, or in methanol/H 2 0 at RT for at least 48 hrs. court and recovering the resulted crystalline polymorph.
- the present invention further provides a crystalline polymorph of the compound of Formula I that exhibits an X-ray powder diffraction pattern having characteristic peaks at diffraction angles 2 ⁇ of approximately 6.2°, 17.8° and 26.2°.
- the X-ray powder diffraction pattern has characteristic peaks, expressed in terms of the interplanar distance, at 14.3A, 5.0A and 3.4A.
- the X-ray powder diffraction pattern has characteristic peaks at diffraction angles 2 ⁇ of approximately 6.2°, 17.8°, 22.0°, 26.2° and 26.9°.
- the X-ray powder diffraction pattern has characteristic peaks at diffraction angles 2 ⁇ of approximately 6.2°, 12.1°, 15.6°, 17.8°, 22.0°, 26.2°, 26.9° and 28.9°.
- the X-ray powder diffraction pattern has characteristic peaks, expressed in terms of the interplanar distance, at 14.3A, 7.3A, 5.7A, 5.0A, 4.0A, 3.4A, 3.3A and 3.lA.
- the polymorph has a purity of >85%.
- the polymorph has a purity of >95%.
- the polymorph has a purity of >99%.
- the X-ray powder diffraction pattern is shown as in Figure 3.
- the polymorph has a melting point of 198-200 ° C .
- the present also provides a method of preparing the crystalline polymorph, comprising the steps of: dissolving the compound of Formula I as prepared in Example 1 in the mixed solvent of methanol/acetonitrile at room temperature, followed by a spontaneous precipitation, and recovering the resulted crystalline polymorpli;or,comprising the steps of slurrying excess amount of the compound of Formula I as prepared in from Example 1 in H 2 0, CH 2 C1 2 , IPAc (Isopropyl Acetate), EtOAc, or IPAc/heptane at 50 °C for at least 48 lirs. , and recovering the resulted crystalline polymorph.
- IPAc Isopropyl Acetate
- EtOAc EtOAc
- IPAc/heptane at 50 °C for at least 48 lirs.
- the present invention further provides a crystalline polymorph of the compound of Formula I that exhibits an X-ray powder diffraction pattern having characteristic peaks at diffraction angles 2 ⁇ of approximately 12.4°, 20.3° and 26.6°.
- the X-ray powder diffraction pattern has characteristic peaks, expressed in terms of the interplanar distance, at 7.1 A, 4.4A and 3.4A.
- the X-ray powder diffraction pattern has characteristic peaks at diffraction angles 2 ⁇ of approximately 11.3°, 12.4°, 20.3°, 21.4° and 26.6°.
- the X-ray powder diffraction pattern has characteristic peaks, expressed in terms of the interplanar distance, at 1.9k, 7.1 A, 4.4A, 4.1 A and 3.4A.
- the X-ray powder diffraction pattern has characteristic peaks at diffraction angles 2 ⁇ of approximately 11.3°, 12.4°, 15.0°, 17.9°, 20.3°, 21.4°, 24.8° and 26.6°.
- the X-ray powder diffraction pattern has characteristic peaks, expressed in terms of the interplanar distance, at 7.9A, 7.1 A, 5.9A, 5.0A, 4.4A, 4.1 A, 3.6A and 3.4A.
- the X-ray powder diffraction pattern is shown as in Figure 4.
- the polymorph has a melting point of 204-207 °C.
- the polymorph has a purity of >85%.
- the polymorph has a purity of >95%.
- the polymorph has a purity of >99%.
- the present invention also provides a method of preparing the crystalline polymorph comprising the steps of: slurrying excess amount of the compound of Formula I as prepared in Example 1 in MTBE, the mixed solvent of Isopropyl Acetate/heptane or ethyl acetate/heptane at room temperature for at least 48 hrs.
- the present invention further provides a crystalline polymorph of the compound of Formula I that exhibits an X-ray powder diffraction pattern having characteristic peaks at diffraction angles 2 ⁇ of approximately 6.0°, 11.1° and 24. ⁇ .
- the X-ray powder diffraction pattern has characteristic peaks, expressed in terms of the interplanar distance, at 14.8A, 8.0A and 3.7A.
- the X-ray powder diffraction pattern has characteristic peaks at diffraction angles 2 ⁇ of approximately 6.0°, 11. F, 17.7°, 24. ⁇ and 26.9°.
- the X-ray powder diffraction pattern has characteristic peaks, expressed in terms of the interplanar distance, at 14.8A, 8.0A, 5.0A, 3.7A and 3.3A.
- the X-ray powder diffraction pattern has characteristic peaks at diffraction angles 2 ⁇ of approximately 6.0°, 8.8°, 11. F, 11.9°, 14.9°, 17.7°, 24.1° and 26.9°.
- the X-ray powder diffraction pattern has characteristic peaks, expressed in terms of the interplanar distance, at 14.8A, ⁇ . ⁇ , 8.0A, 7.4A, 6.0A, 5.0A, 3.7A and 3.3A.
- the X-ray powder diffraction pattern is shown as in Figure 5.
- the polymorph has a melting point of 190-193 ° C
- the polymorph has a purity of >85%.
- the polymorph has a purity of >95%.
- the polymorph has a purity of >99%.
- the present invention also provides a method of preparing the crystalline polymorph comprising the steps of slurrying excess amount of the compound of Formula I as prepared in from Example 1 in the mixed solvent of MTBE/ ' heptaiie at 50 " C for at least 48 hrs. , and recovering the resulted crystalline polymorph;
- the present invention further provides a crystalline polymorph of the compound of Formula I that exhibits an X-ray powder diffraction pattern having characteristic peaks at diffraction angles 2 ⁇ of approximately 7. ⁇ , 22.2° and 26.9°.
- the X-ray powder diffraction pattern has characteristic peaks, expressed in terms of the interplanar distance, at 12.4A, 4.0A and 3.3A.
- the X-ray powder diffraction pattern has characteristic peaks at diffraction angles 2 ⁇ of approximately 7. ⁇ , 10.6°, 18.8°, 22.2° and 26.9°.
- the X-ray powder diffraction pattern has characteristic peaks, expressed in terms of the interplanar distance, at 12.4A, 8.4A, 4.7 A, 4.0A and 3.3A.
- the X-ray powder diffraction pattern has characteristic peaks at diffraction angles 2 ⁇ of approximately 7. ⁇ , 9.4°, 10.6°, 16.5°, 18.8°, 21.3°, 22.2° and 26.9°.
- the X-ray powder diffraction pattern has characteristic peaks, expressed in terms of the interplanar distance, at 12.4A, 9.4A, 8.4A, 5.4A, 4.7A, 4.2A, 4.0A and 3.3A.
- the X-ray powder diffraction pattern is shown as in Figure 6.
- the polymorph has a melting point of 200-203 ° C
- the polymorph has a purity of >85%.
- the polymorph has a purity of >95%.
- the polymorph has a purity of >99%.
- the present invention also provides a method of preparing the crystalline polymorph comprising the steps of: slurrying excess amount of the compound of Formula I as prepared in the method of Example 1 in the mixed solvent of acetonitrile/f ⁇ O (1 : 1) or THF/H 2 O at room temperature for at least 48 hrs, and recovering the resulted crystalline polymorph;
- the present invention further provides a crystalline polymorph of the compound of Formula I that exhibits an X-ray powder diffraction pattern having characteristic peaks at diffraction angles 2 ⁇ of approximately 6.9°, 11.7° and 21.1°.
- the X-ray powder diffraction pattern has characteristic peaks, expressed in terms of the interplanar distance, at 12.8A, 7.5A and 4.2A.
- the X-ray powder diffraction pattern has characteristic peaks at diffraction angles 2 ⁇ of approximately 6.9°, 11.7°, 15.1°, 21.1° and 25.8°.
- the X-ray powder diffraction pattern has characteristic peaks, expressed in terms of the interplanar distance, at 12.8A, 7.5A, 5.9 A, 4.2A and 3.5A.
- the X-ray powder diffraction pattern has characteristic peaks at diffraction angles 2 ⁇ of approximately 6.9°, 7.5°, 11.7°, 15.1°, 19.3°, 21. ⁇ , 22.6° and 25.8°.
- the X-ray powder diffraction pattern has characteristic peaks, expressed in terms of the interplanar distance, at 12.8A, 11.8A, 7.5A, 5.9A, 4.6A, 4.2A, 3.9A and 3.5A..
- the X-ray powder diffraction pattern is shown as in Figure 7.
- the polymorph has a purity of >85%.
- the polymorph has a purity of >95%.
- the polymorph has a purity of >99%.
- the present invention further provides a method of preparing the crystalline polymorph comprising the steps of heating the Crystalline Form VI as prepared in Example 7 to 180 °C, and recovering the resulted crystalline polymorph.
- the present invention further provides the use of these crystalline polymorphs.
- a pharmaceutical composition comprises a therapeutically effective amount of crystalline polymorphs of the present invention, and a pharmaceutically acceptable excipient adjuvant or earner.
- the present invention also provides preferable embodiments of the pharmaceutical composition.
- the pharmaceutical composition comprises a therapeutically effective amount of a crystalline polymorph of the present invention, in combination with at least one of additional active ingredient.
- the pharmaceutical composition is used in an oral administration.
- the pharmaceutical composition is used in tablets or capsules.
- the pharmaceutical composition comprises 1 wt%-99 wt% of the crystalline polymorph of the present invention.
- the pharmaceutical composition comprises 1 wt%-70 wt% of the crystalline polymorph of the present invention.
- the pharmaceutical composition comprises 10 wt%-30 wt% of the crystalline polymorph of the present invention.
- the crystalline polymorphs of the present invention can be used in manufacturing a medicament for modulating HIF level or HIF activity in a subject.
- the present invention also provides preferable embodiments of the uses of the crystalline polymorphs.
- the crystalline polymorphs of the present invention can be used in manufacturing a medicament for the treatment of a disease, a disorder, or a condition associated with HIF level or HIF activity.
- the crystalline polymorphs of the present invention can be used in manufacturing a medicament for the treatment of ischemia, anemia, or a disease, disorder, or condition associated with ischemia or anemia.
- the crystalline polymorphs of the present invention can be used in manufacturing a medicament for the treatment of a disease, a disorder, or a condition selected from ischemia, anemia, wound healing, auto-transplantation, allo-transplantation, xeno-transplantation, systemic high blood pressure, thalassemia, diabetes, cancer or an inflammatory disorder, or a combination of two or more thereof, in a subject.
- a method for treating a disease, a disorder, or a condition associated with HIF level or HIF activity in a subject by administering to the subject one crystalline polymorph of the present invention.
- ischemia anemia, or a disease, a disorder or a condition associated with ischemia or anemia in a subject by administering to the subject one crystalline polymorph of the present invention.
- substantially pure refers to at least 85 wt%, preferably at least 95 wt%, more preferably at least 99 wt% of the compound of Formula I exists in a crystal form of the present invention, particularly in the crystal forms of Form I, Form II, Form III, Form IV, Form V, Form VI or Form VII.
- the X-ray powder diffraction pattern shown as in Figure 1 refers to the X-ray powder diffraction pattern that show major peaks as in Figure 1, wherein major peaks refer to those with the relative intensity greater than 10%, preferably greater than 30%, relative to the highest peak (with its relative intensity designated to be 100%) in Figure 1.
- the X-ray powder diffraction pattern shown as in Figure 2, 3, 4, 5, 6 or 7 refers to the X-ray powder diffraction pattern that show major peaks as in Figure 2, 3, 4, 5, 6 or 7, wherein major peaks refer to those with the relative intensity greater than 10%, preferably greater than 30%, relative to the highest peak (with its relative intensity designated to be 100%) in Figure 2, 3, 4, 5, 6 or 7, respectively.
- the present invention also provides a method of preparing the compound of Formula I, as follows,
- the present invention also provides a method of preparing Crystalline Form I, Crystalline Form II, Crystalline Form III, Crystalline Form IV, Crystalline Form V, Crystalline Form VI or Crystalline Form VII of the compound of Formula I..Crystallizing the compound of the present invention from a suitable solvent system comprising at least one solvent, can be achieved by methods of spontaneous precipitation (evaporation), cooling, and/or adding anti-solvent (in which the compound of the present invention has relatively lower solubility), in order to achieve oversaturation in solvent system.
- Crystallization also cars be achieved by using or not using crystal seeds that is suitable for crystallizing the compound of the present invention.
- the present invention further provides a pharmaceutical composition, comprising a therapeutically effective amount of one or more crystalline polymorphs of Crystalline Form I, Crystalline Form II, Crystalline Form III, Crystalline Form IV, Crystalline Form V, Crystalline Form VI or Crystalline Form VII of the compound of Formula I, and a pharmaceutically acceptable excipient, adjuvant or carrier.
- the pharmaceutical composition contains 1 wt%-99 wt%, preferably 1 wi.%-70 wt%, more preferably 10 wt%-30 wt% of any one crystalline polymorph of Crystalline Form I, Crystalline Form II, Crystalline Form III, Crystalline Form IV, Crystalline Form V Crystalline Form VI or Crystalline Form VII of the compound of Formula I.
- the present invention also provides the use of the compound of Formula I, or a crystalline polymorph selected from Crystalline Form I, Crystalline Form II, Crystalline Form III, Crystalline Form IV, Crystalline Form V, Crystalline Form VI and Crystalline Form VII thereof, in manufacturing a medicament for modulating HIF level or HIF activity.
- the present invention also provides a use of the compound of Formula I, or a crystalline polymorph selected from Crystalline Form I, Crystalline Form II, Crystalline Form III, Crystalline Form IV, Crystalline Form V, Crystalline Form VI and Crystalline Form VII thereof, in manufacturing a medicament for the treatment of ischemia, anemia, or a disease, disorder or condition associated with ischemia or anemia.
- the present invention also provides a use of the compound of Formula I, or a crystalline polymorph selected from Crystalline Form I, Crystalline Form II, Crystalline Form III, Crystalline Form IV, Crystalline Form V, Crystalline Form VI and Crystalline Form VII thereof, in manufacturing a medicament for the treatment of a disease, disorder, or condition selected from ischemia, anemia, wound healing, auto-transplantation, allo-transplantation, xeno-transplantation, systemic high blood pressure, thalassemia, diabetes, cancer or an inflammatory disorder, or a combination of two or more thereof.
- a disease, disorder, or condition selected from ischemia, anemia, wound healing, auto-transplantation, allo-transplantation, xeno-transplantation, systemic high blood pressure, thalassemia, diabetes, cancer or an inflammatory disorder, or a combination of two or more thereof.
- terapéuticaally effective amount refers to the amount of a compound that, when administered to a subject for treating a disease, or at least one of the clinical symptoms of a disease or disorder, is sufficient to affect such treatment for the disease, disorder, or symptom.
- the "therapeutically effective amount” can vary with the compound, the disease, disorder, and/or symptoms of the disease or disorder, severity of the disease, disorder, and/or symptoms of the disease or disorder, the age of the subject to be treated, and/or the weight of the subject to be treated. An appropriate amount in any given instance can be apparent to those skilled in the art or can be determined by routine experiments.
- the "therapeutically effective amount refers to the total amount of the combination objects for the effective treatment of a disease, a disorder or a condition.
- the pharmaceutical composition comprising the compound of the present invention can be administrated via oral, inhalation, rectal, parenteral or topical administration to a subject who needs treatment.
- the pharmaceutical composition may be a regular solid formulation such as tablets, powder, granule, capsules and the like, a liquid formulation such as water or oil suspension or other liquid formulation such as syrup, solution, suspension or the like; for parenteral administration, the pharmaceutical composition may be solution, water solution, oil suspension concentrate, lyophilized powder or the like.
- the formulation of the pharmaceutical composition is selected from tablet, coated tablet, capsule, suppository, nasal spray or injection, more preferably tablet or capsule.
- the pharmaceutical composition can be a single unit administration with an accurate dosage.
- the pharmaceutical composition may further comprise additional active ingredients.
- compositions of the present invention can be produced by the conventional methods in the pharmaceutical field.
- the active ingredient can be mixed with one or more excipients, then to make the desired formulation.
- the "pharmaceutically acceptable carrier” refers to conventional pharmaceutical carriers suitable for the desired pharmaceutical formulation, for example: a diluent, a vehicle such as water, various organic solvents, etc, a filler such as starch, sucrose, etc; a binder such as cellulose derivatives, alginates, gelatin and polyvinylpyrrolidone (PVP ) ; a wetting agent such as glycerol; a disintegrating agent such as agar, calcium carbonate and sodium bicarbonate; an absorption enhancer such as quaternary ammonium compound; a surfactant such as hexadecanol; an absorption carrier such as Kaolin and soap clay; a lubricant such, as talc, calcium, stearate, magnesium stearate, polyethylene glycol, etc.
- the pharmaceutical composition further comprises other pharmaceutically acceptable excipients such as a decentralized agent, a stabi lizer, a thickener, a compiexing agent, a buffering agent, a permeation enhancer, a polymer, aromatics, a sweetener, and a dye.
- excipient is suitable for desired formulation and administration type.
- the term "disease” or “disorder” or “condition” refers to any disease, discomfort, illness, symptoms or indications.
- Figure 1 shows the X-ray powder diffraction pattern of Crystalline Form I of the compound of Formula I
- Figure 2 shows the X-ray powder diffraction pattern of Crystalline Form II of the compound of Formula I
- Figure 3 shows the X-ray powder diffraction pattern of Crystalline Form III of the compound of Formula I
- Figure 4 shows the X-ray powder diffraction pattern of Crystalline Form IV of the compound of Formula I
- Figure 5 shows the X-ray powder diffraction pattern of Crystalline Form V of the compound of Formula I
- Figure 6 shows the X-ray powder diffraction pattern of Crystalline Form VI of the compound of Formula I
- Figure 7 shows the X-ray powder diffraction pattern of Crystalline Form VII of the compound of Formula I
- the X-ray powder diffraction (XRPD) patterns shown as in Figure 1, 2, 3, 4, 5, 6 and 7 were generated on a PANalytical X-ray Diffraction System with Empyrean console.
- the diffraction peak positions were calibrated by single crystal silicon which has a 2 ⁇ value of 28.443 degree.
- the K- Alpha radiation of an Empyrean Cu LEF X-ray tube was used as the light source of the X-ray.
- Example 4 a slurry suspension of excess amount of the Crystalline Form III as prepared in Example 4 was stirred in the mixed solvent of FFiO/acetone at 50 ° C for 12-14 days, to obtain the desired Crystalline Form IV, with the melting point of 204-207 ° C .
- Ciystalline Form V prepared from the method of Example 6 was heated to 180 °C, to obtain the desired Crystalline Form VH.
- HIF-PHD2 activity was measured using homogeneous TR-FRET technology (see also, US2008/004817; Dao JH et al., Anal Biochem. 2009, 384:213-23).
- DMSO solution of test compound To each well of a l/2Area 96-well plate was added 2 ⁇ . DMSO solution of test compound and 40 ⁇ . of assay buffer (50 mM Tris PH7.4/0.01% Tween-20/0.1 mg/ml BSA/1 mM Sodium ascorbate/20 ug/ml Catalase/10 ⁇ FeS04) containing 600 nM full length PHD2.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Diabetes (AREA)
- Immunology (AREA)
- Epidemiology (AREA)
- Cardiology (AREA)
- Hematology (AREA)
- Endocrinology (AREA)
- Heart & Thoracic Surgery (AREA)
- Obesity (AREA)
- Transplantation (AREA)
- Emergency Medicine (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Dermatology (AREA)
- Vascular Medicine (AREA)
- Urology & Nephrology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Description
Claims
Priority Applications (10)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA2842730A CA2842730C (en) | 2011-07-22 | 2012-07-23 | Polymorphic forms of compounds as prolyl hydroxylase inhibitor, and uses thereof |
ES12817360.6T ES2606631T3 (en) | 2011-07-22 | 2012-07-23 | Polymeric forms of compounds as a prolyl hydroxylase inhibitor, and uses thereof |
EP12817360.6A EP2734504B1 (en) | 2011-07-22 | 2012-07-23 | Polymorphic forms of compounds as prolyl hydroxylase inhibitor, and uses thereof |
US14/233,902 US9206134B2 (en) | 2011-07-22 | 2012-07-23 | Polymorphic forms of compounds as prolyl hydroxylase inhibitor, and uses thereof |
AU2012289429A AU2012289429B2 (en) | 2011-07-22 | 2012-07-23 | Polymorphic forms of compounds as prolyl hydroxylase inhibitor, and uses thereof |
CN201280036322.0A CN104024227B (en) | 2011-07-22 | 2012-07-23 | Suppress crystal formation and the application thereof of the compound of Protocollagen prolyl hydroxylase activity |
JP2014520521A JP6099644B2 (en) | 2011-07-22 | 2012-07-23 | Polymorphs of compounds as prolyl hydroxylase inhibitors and uses thereof |
KR1020147004452A KR102029951B1 (en) | 2011-07-22 | 2012-07-23 | Polymorphic forms of compounds as prolyl hydroxylase inhibitor, and uses thereof |
IL230580A IL230580B (en) | 2011-07-22 | 2014-01-22 | Polymorphic forms of compounds as prolyl hydroxylase inhibitor, and uses thereof |
ZA2014/01310A ZA201401310B (en) | 2011-07-22 | 2014-02-20 | Polymorphic forms of compounds as prolyl hydroxylase inhibitor,and uses thereof |
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201110207175 | 2011-07-22 | ||
CN201110207175.6 | 2011-07-22 | ||
CN201110209657.5 | 2011-07-25 | ||
CN201110209657 | 2011-07-25 | ||
CN201110211297.2 | 2011-07-26 | ||
CN201110211297 | 2011-07-26 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2013013609A1 true WO2013013609A1 (en) | 2013-01-31 |
Family
ID=47600518
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CN2012/079058 WO2013013609A1 (en) | 2011-07-22 | 2012-07-23 | Polymorphic forms of compounds as prolyl hydroxylase inhibitor, and uses thereof |
Country Status (11)
Country | Link |
---|---|
US (1) | US9206134B2 (en) |
EP (1) | EP2734504B1 (en) |
JP (1) | JP6099644B2 (en) |
KR (1) | KR102029951B1 (en) |
CN (1) | CN104024227B (en) |
AU (1) | AU2012289429B2 (en) |
CA (1) | CA2842730C (en) |
ES (1) | ES2606631T3 (en) |
IL (1) | IL230580B (en) |
WO (1) | WO2013013609A1 (en) |
ZA (1) | ZA201401310B (en) |
Cited By (21)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2014014834A1 (en) * | 2012-07-16 | 2014-01-23 | Fibrogen, Inc. | Process for making isoquinoline compounds |
CN103539735A (en) * | 2012-07-16 | 2014-01-29 | 菲布罗根有限公司 | Crystalline forms of a prolyl hydroxylase inhibitor |
CN103694172A (en) * | 2013-12-26 | 2014-04-02 | 辽宁亿灵科创生物医药科技有限公司 | Derivative of aza-aryl compound |
US8883823B2 (en) | 2012-07-16 | 2014-11-11 | Fibrogen, Inc. | Crystalline forms of a prolyl hydroxylase inhibitor |
WO2015073779A1 (en) * | 2013-11-15 | 2015-05-21 | Akebia Therapeutics, Inc. | Solid forms of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, compositions, and uses thereof |
WO2016118858A1 (en) * | 2015-01-23 | 2016-07-28 | Akebia Therapeutics, Inc. | Solid forms of 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid, compositions, and uses thereof |
EP3305769A1 (en) | 2016-10-07 | 2018-04-11 | Zentiva K.S. | Method for preparation of (7-phenoxy-4-hydroxy-1-methyl-isoquinoline-3-carbonyl)-glycine (roxedustat) and its intermediates based on simultaneous opening of oxazolic ring, fission of ether and creation of imine |
CN108424388A (en) * | 2018-04-19 | 2018-08-21 | 杭州科巢生物科技有限公司 | A kind of preparation method of chronic anaemia drug |
EP3275881A4 (en) * | 2015-03-27 | 2018-09-12 | Shenyang Sunshine Pharmaceutical Co., Ltd. | Compound of 5-hydroxyl-1,7-naphthyridine substituted by aryloxy or heterooxy, preparation method thereof and pharmaceutical use thereof |
US10092558B2 (en) | 2003-06-06 | 2018-10-09 | Fibrogen, Inc. | Nitrogen-containing heteroaryl compounds and methods of use thereof |
US10246416B2 (en) | 2011-06-06 | 2019-04-02 | Akebia Therapeutics, Inc. | Process for preparing [(3-hydroxypyridine-2-carbonyl)amino] alkanoic acids, esters and amides |
WO2019106621A1 (en) * | 2017-12-01 | 2019-06-06 | Dr. Reddy's Laboratories Limited | Process for the preparation of roxadustat and its intermediates |
US10765672B2 (en) | 2013-06-06 | 2020-09-08 | Fibrogen, Inc. | Pharmaceutical formulations of a HIF hydroxylase inhibitor |
US10889546B2 (en) | 2015-10-09 | 2021-01-12 | Jiangsu Hengrui Medicine Co., Ltd. | Alkynyl pyridine prolyl hydroxylase inhibitor, and preparation method and medical use thereof |
WO2021077994A1 (en) | 2019-10-22 | 2021-04-29 | 苏州科睿思制药有限公司 | Crystal form of hypoxia-inducible factor-prolyl hydroxylase inhibitor |
WO2021252295A1 (en) | 2020-06-13 | 2021-12-16 | Suzhou Pengxu Pharmatech Co., Ltd. | Process of making roxadustat |
US11324734B2 (en) | 2015-04-01 | 2022-05-10 | Akebia Therapeutics, Inc. | Compositions and methods for treating anemia |
CN115144480A (en) * | 2021-03-31 | 2022-10-04 | 成都倍特药业股份有限公司 | Method for detecting morpholine and/or tetramethylmethanediamine from intermediate of roxasistat |
US11524939B2 (en) | 2019-11-13 | 2022-12-13 | Akebia Therapeutics, Inc. | Solid forms of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino} acetic acid |
US11713298B2 (en) | 2018-05-09 | 2023-08-01 | Akebia Therapeutics, Inc. | Process for preparing 2-[[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino]acetic acid |
US11857543B2 (en) | 2013-06-13 | 2024-01-02 | Akebia Therapeutics, Inc. | Compositions and methods for treating anemia |
Families Citing this family (29)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104910113B (en) * | 2015-05-21 | 2017-05-10 | 中国科学院宁波材料技术与工程研究所 | Preparation method of hydroxy benzene anhydride |
CN104892509B (en) * | 2015-06-04 | 2018-03-09 | 苏州明锐医药科技有限公司 | Nuo get Si Ta preparation method |
CN108367017A (en) * | 2015-08-13 | 2018-08-03 | 索马根尼科斯公司 | For the short and small hairpin RNA of wound healing and the composition and method of microRNA |
CN106916105A (en) * | 2015-12-28 | 2017-07-04 | 徐州万邦金桥制药有限公司 | A kind of method that purifying can win U.S. |
CN106187888A (en) * | 2016-07-18 | 2016-12-07 | 江苏德源药业股份有限公司 | FG 4592 monocrystalline and preparation method thereof |
CN107954931B (en) * | 2016-10-17 | 2021-06-22 | 上海医药集团青岛国风药业股份有限公司 | Preparation method of nodispat |
CN108017583B (en) * | 2016-11-01 | 2021-04-06 | 徐州万邦金桥制药有限公司 | Preparation method of kebomei |
CN111511371A (en) * | 2017-08-11 | 2020-08-07 | 雷迪博士实验室有限公司 | Polymorphs and co-crystals of rosuvastatin |
PL3679017T3 (en) * | 2017-09-04 | 2022-01-17 | Sandoz Ag | Co-crystal of an orally available hif prolyl hydroxylase inhibitor |
CN109956870A (en) * | 2017-12-14 | 2019-07-02 | 南京卡文迪许生物工程技术有限公司 | A kind of Luo Shasi his synthetic method and its midbody compound |
CN108059679B (en) * | 2017-12-27 | 2020-03-24 | 吉林大学 | Humanized single-chain antibody and application thereof |
CN110218184B (en) * | 2018-03-01 | 2022-09-27 | 广东东阳光药业有限公司 | Nodesserts eutectic and preparation method thereof |
WO2019174631A1 (en) * | 2018-03-16 | 2019-09-19 | 上海医药集团股份有限公司 | Method for preparing norstat |
CN110903242B (en) * | 2018-09-14 | 2023-05-12 | 四川科伦药物研究院有限公司 | Preparation method of Luo Shasi his intermediate |
CN109369525A (en) * | 2018-12-29 | 2019-02-22 | 安礼特(上海)医药科技有限公司 | Its novel crystal forms and preparation method thereof of Luo Shasi |
WO2020178847A1 (en) | 2019-03-01 | 2020-09-10 | Mylan Laboratories Limited | Cocrystal of roxadustat and d-proline |
CN109776415B (en) * | 2019-03-07 | 2020-11-17 | 福建南方制药股份有限公司 | Preparation method of Roxadustat intermediate |
CN109956901B (en) * | 2019-04-25 | 2022-09-06 | 南京正大天晴制药有限公司 | Preparation method of isoquinolone compound |
US20220340532A1 (en) | 2019-08-07 | 2022-10-27 | Teva Pharmaceuticals International Gmbh | Processes for the preparation of roxadustat and intermediates thereof |
CN112679428A (en) * | 2019-10-17 | 2021-04-20 | 罗欣药业(上海)有限公司 | New crystal form of roxasistat and preparation method thereof |
CN112679430B (en) * | 2019-10-18 | 2023-05-05 | 上海迪赛诺化学制药有限公司 | Method for preparing isoquinolinones compound |
WO2021073623A1 (en) * | 2019-10-18 | 2021-04-22 | 上海迪赛诺化学制药有限公司 | Method for preparing isoquinolinone compounds |
CN112679431B (en) * | 2019-10-18 | 2023-05-05 | 上海迪赛诺化学制药有限公司 | Method for preparing isoquinolinones compound |
CN112679429B (en) * | 2019-10-18 | 2023-05-05 | 上海迪赛诺化学制药有限公司 | Method for preparing isoquinolinones compound |
CN111205224B (en) * | 2020-04-22 | 2020-08-25 | 南京佰麦生物技术有限公司 | Crystal form of roxasistat hydrate, and preparation method and application thereof |
CN112500344B (en) * | 2020-11-18 | 2022-07-01 | 江苏豪森药业集团有限公司 | Crystalline form of roxasistat and preparation method thereof |
CN112194624A (en) * | 2020-11-18 | 2021-01-08 | 江苏豪森药业集团有限公司 | Crystal form of isoquinoline compound and preparation method thereof |
CN115724796A (en) * | 2021-08-26 | 2023-03-03 | 成都苑东生物制药股份有限公司 | New crystal form of roxasistat and preparation method thereof |
WO2023095162A1 (en) | 2021-11-26 | 2023-06-01 | Mylan Laboratories Limited | Cocrystal of roxadustat and nicotinamide |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004108681A1 (en) | 2003-06-06 | 2004-12-16 | Fibrogen, Inc. | Nitrogen-containing heteroaryl compounds and their use in increasing endogenous erythropoietin |
WO2006133391A2 (en) | 2005-06-06 | 2006-12-14 | Fibrogen, Inc. | Improved treatment for anemia using a hif-alpha stabilising agent |
WO2007070359A2 (en) | 2005-12-09 | 2007-06-21 | Amgen Inc. | Quinolone based compounds exhibiting prolyl hydroxylase inhibitory activity, and compositions, and uses thereof |
WO2007146438A1 (en) | 2006-06-15 | 2007-12-21 | Fibrogen, Inc. | Hif hydroxylase inhibitors for treatment of anemia of cancer |
US20080004817A1 (en) | 2006-06-30 | 2008-01-03 | Akira Nishimizu | Method and apparatus for evaluating length of defect in eddy current testing |
WO2011006355A1 (en) | 2009-07-15 | 2011-01-20 | Beijing Beta Pharma Inc. | Compounds as hypoxia mimetics, and compositions, and uses thereof |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5470285A (en) * | 1977-11-14 | 1979-06-05 | Tanabe Seiyaku Co Ltd | Production of 4-hydroxyisocarbostyryl-3-carboxylic analog |
DE19746287A1 (en) * | 1997-10-20 | 1999-04-22 | Hoechst Marion Roussel De Gmbh | Substituted isoquinoline-2-carboxylic acid amides, their preparation and their use as medicaments |
US7893071B2 (en) * | 2001-04-23 | 2011-02-22 | University Of Virginia Patent Foundation | Synthesis and evaluation of novel phthalimide mimics as anti-angiogenic |
US7189697B2 (en) | 2004-04-13 | 2007-03-13 | Trustees Of Tufts College | Compositions and uses of a galectin for treatment of dry eye syndrome |
JP5161793B2 (en) * | 2006-01-27 | 2013-03-13 | フィブロジェン, インコーポレイテッド | Cyanoisoquinoline compounds that stabilize hypoxia-inducing factor (HIF) |
-
2012
- 2012-07-23 KR KR1020147004452A patent/KR102029951B1/en active IP Right Grant
- 2012-07-23 WO PCT/CN2012/079058 patent/WO2013013609A1/en active Application Filing
- 2012-07-23 US US14/233,902 patent/US9206134B2/en active Active
- 2012-07-23 AU AU2012289429A patent/AU2012289429B2/en active Active
- 2012-07-23 CN CN201280036322.0A patent/CN104024227B/en active Active
- 2012-07-23 CA CA2842730A patent/CA2842730C/en active Active
- 2012-07-23 ES ES12817360.6T patent/ES2606631T3/en active Active
- 2012-07-23 JP JP2014520521A patent/JP6099644B2/en not_active Expired - Fee Related
- 2012-07-23 EP EP12817360.6A patent/EP2734504B1/en not_active Not-in-force
-
2014
- 2014-01-22 IL IL230580A patent/IL230580B/en active IP Right Grant
- 2014-02-20 ZA ZA2014/01310A patent/ZA201401310B/en unknown
Patent Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004108681A1 (en) | 2003-06-06 | 2004-12-16 | Fibrogen, Inc. | Nitrogen-containing heteroaryl compounds and their use in increasing endogenous erythropoietin |
WO2006133391A2 (en) | 2005-06-06 | 2006-12-14 | Fibrogen, Inc. | Improved treatment for anemia using a hif-alpha stabilising agent |
CN101394843A (en) * | 2005-06-06 | 2009-03-25 | 菲布罗根公司 | Improved treatment for anemia using a HIF-alpha stabilising agent |
WO2007070359A2 (en) | 2005-12-09 | 2007-06-21 | Amgen Inc. | Quinolone based compounds exhibiting prolyl hydroxylase inhibitory activity, and compositions, and uses thereof |
WO2007146438A1 (en) | 2006-06-15 | 2007-12-21 | Fibrogen, Inc. | Hif hydroxylase inhibitors for treatment of anemia of cancer |
CN101500569A (en) * | 2006-06-15 | 2009-08-05 | 菲布罗根公司 | HIF hydroxylase inhibitors for treatment of anemia of cancer |
US20080004817A1 (en) | 2006-06-30 | 2008-01-03 | Akira Nishimizu | Method and apparatus for evaluating length of defect in eddy current testing |
WO2011006355A1 (en) | 2009-07-15 | 2011-01-20 | Beijing Beta Pharma Inc. | Compounds as hypoxia mimetics, and compositions, and uses thereof |
Non-Patent Citations (4)
Title |
---|
DAO JH ET AL., ANAL BIOCHEM., vol. 384, 2009, pages 213 - 23 |
HSIEH MM ET AL., BLOOD, vol. 110, 2007, pages 2140 - 7 |
ROBINSON A ET AL., GASTROENTEROLOGY, vol. 134, 2008, pages 145 - 55 |
See also references of EP2734504A4 |
Cited By (62)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10092558B2 (en) | 2003-06-06 | 2018-10-09 | Fibrogen, Inc. | Nitrogen-containing heteroaryl compounds and methods of use thereof |
US10646482B2 (en) | 2003-06-06 | 2020-05-12 | Fibrogen, Inc. | Nitrogen-containing heteroaryl compounds and methods of use thereof |
US11229637B2 (en) | 2003-06-06 | 2022-01-25 | Fibrogen, Inc. | Nitrogen-containing heteroaryl compounds and methods of use thereof |
US11267785B2 (en) | 2011-06-06 | 2022-03-08 | Akebia Therapeutics, Inc. | Process for preparing [(3-hydroxypyridine-2-carbonyl)amino]alkanoic acids, esters and amides |
US10246416B2 (en) | 2011-06-06 | 2019-04-02 | Akebia Therapeutics, Inc. | Process for preparing [(3-hydroxypyridine-2-carbonyl)amino] alkanoic acids, esters and amides |
US10738010B2 (en) | 2011-06-06 | 2020-08-11 | Akebia Therapeutics, Inc. | Process for preparing [(3-hydroxypyridine-2-carbonyl)amino] alkanoic acids, esters and amides |
AU2013290437B2 (en) * | 2012-07-16 | 2017-11-02 | Fibrogen, Inc. | Process for making isoquinoline compounds |
US9918977B2 (en) | 2012-07-16 | 2018-03-20 | Fibrogen, Inc. | Crystalline forms of a prolyl hydroxylase inhibitor |
US9340511B2 (en) | 2012-07-16 | 2016-05-17 | Fibrogen, Inc. | Process for making isoquinoline compounds |
US9371288B2 (en) | 2012-07-16 | 2016-06-21 | Fibrogen, Inc. | Crystalline forms of a prolyl hydroxylase inhibitor |
KR20150058154A (en) * | 2012-07-16 | 2015-05-28 | 피브로겐, 인크. | Crystalline forms of the prolyl hydroxylase inhibitor [(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid |
EP4029854A1 (en) * | 2012-07-16 | 2022-07-20 | Fibrogen, Inc. | Crystalline forms of a prolyl hydroxylase inhibitor |
US9617218B2 (en) | 2012-07-16 | 2017-04-11 | Fibrogen, Inc. | Crystalline forms of a prolyl hydroxylase inhibitor |
EP3470397B1 (en) | 2012-07-16 | 2021-12-29 | Fibrogen, Inc. | Crystalline forms of a prolyl hydroxylase inhibitor |
US9708269B2 (en) | 2012-07-16 | 2017-07-18 | Fibrogen, Inc. | Process for making isoquinoline compounds |
CN103539735B (en) * | 2012-07-16 | 2017-08-04 | 菲布罗根有限公司 | The crystal habit of prolyl hydroxylase inhibitors |
US8883823B2 (en) | 2012-07-16 | 2014-11-11 | Fibrogen, Inc. | Crystalline forms of a prolyl hydroxylase inhibitor |
CN107382860A (en) * | 2012-07-16 | 2017-11-24 | 菲布罗根有限公司 | The crystal habit of prolyl hydroxylase inhibitors |
CN107382859A (en) * | 2012-07-16 | 2017-11-24 | 菲布罗根有限公司 | The crystal habit of prolyl hydroxylase inhibitors |
CN107501177A (en) * | 2012-07-16 | 2017-12-22 | 菲布罗根有限公司 | The crystal habit of prolyl hydroxylase inhibitors |
CN107540607A (en) * | 2012-07-16 | 2018-01-05 | 菲布罗根有限公司 | The crystal habit of prolyl hydroxylase inhibitors |
US9115085B2 (en) | 2012-07-16 | 2015-08-25 | Fibrogen, Inc. | Crystalline forms of a prolyl hydroxylase inhibitor |
KR102318720B1 (en) | 2012-07-16 | 2021-10-28 | 피브로겐, 인크. | Crystalline forms of the prolyl hydroxylase inhibitor [(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid |
US10272078B2 (en) | 2012-07-16 | 2019-04-30 | Fibrogen, Inc. | Crystalline forms of a prolyl hydroxylase inhibitor |
KR20200102556A (en) * | 2012-07-16 | 2020-08-31 | 피브로겐, 인크. | Crystalline forms of the prolyl hydroxylase inhibitor [(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid |
EP2872488B1 (en) | 2012-07-16 | 2018-08-22 | Fibrogen, Inc. | Crystalline forms of a prolyl hydroxylase inhibitor |
KR102149380B1 (en) | 2012-07-16 | 2020-08-28 | 피브로겐, 인크. | Crystalline forms of the prolyl hydroxylase inhibitor [(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid |
WO2014014835A3 (en) * | 2012-07-16 | 2014-08-21 | Fibrogen, Inc. | Criystalline forms of the prolyl hydroxylase inhibitor [(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid |
US10118897B2 (en) | 2012-07-16 | 2018-11-06 | Fibrogen, Inc. | Crystalline forms of a prolyl hydroxylase inhibitor |
WO2014014834A1 (en) * | 2012-07-16 | 2014-01-23 | Fibrogen, Inc. | Process for making isoquinoline compounds |
EP3470397A1 (en) * | 2012-07-16 | 2019-04-17 | Fibrogen, Inc. | Crystalline forms of a prolyl hydroxylase inhibitor |
CN109369524A (en) * | 2012-07-16 | 2019-02-22 | 菲布罗根有限公司 | The crystal habit of prolyl hydroxylase inhibitors |
CN103539735A (en) * | 2012-07-16 | 2014-01-29 | 菲布罗根有限公司 | Crystalline forms of a prolyl hydroxylase inhibitor |
US10765672B2 (en) | 2013-06-06 | 2020-09-08 | Fibrogen, Inc. | Pharmaceutical formulations of a HIF hydroxylase inhibitor |
US11857543B2 (en) | 2013-06-13 | 2024-01-02 | Akebia Therapeutics, Inc. | Compositions and methods for treating anemia |
US10149842B2 (en) | 2013-11-15 | 2018-12-11 | Akebia Therapeutics, Inc. | Solid forms of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, compositions, and uses thereof |
KR102495018B1 (en) | 2013-11-15 | 2023-02-06 | 아케비아 테라퓨틱스 인코포레이티드 | Solid forms of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, compositions, and uses thereof |
KR20220042498A (en) * | 2013-11-15 | 2022-04-05 | 아케비아 테라퓨틱스 인코포레이티드 | Solid forms of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, compositions, and uses thereof |
CN105916502A (en) * | 2013-11-15 | 2016-08-31 | 阿克比治疗有限公司 | Solid forms of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, compositions, and uses thereof |
US9701636B2 (en) | 2013-11-15 | 2017-07-11 | Akebia Therapeutics, Inc. | Solid forms of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, compositions, and uses thereof |
WO2015073779A1 (en) * | 2013-11-15 | 2015-05-21 | Akebia Therapeutics, Inc. | Solid forms of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, compositions, and uses thereof |
US9987262B2 (en) | 2013-11-15 | 2018-06-05 | Akebia Therapeutics, Inc. | Solid forms of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, compositions, and uses thereof |
US10596158B2 (en) | 2013-11-15 | 2020-03-24 | Akebia Therapeutics, Inc. | Solid forms of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, compositions, and uses thereof |
US11690836B2 (en) | 2013-11-15 | 2023-07-04 | Akebia Therapeutics, Inc. | Solid forms of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, compositions, and uses thereof |
US11065237B2 (en) | 2013-11-15 | 2021-07-20 | Akebia Therapeutics, Inc. | Solid forms of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, compositions, and uses thereof |
CN103694172A (en) * | 2013-12-26 | 2014-04-02 | 辽宁亿灵科创生物医药科技有限公司 | Derivative of aza-aryl compound |
US10150734B2 (en) | 2015-01-23 | 2018-12-11 | Akebia Therapeutics, Inc. | Solid forms of 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid, compositions, and uses thereof |
WO2016118858A1 (en) * | 2015-01-23 | 2016-07-28 | Akebia Therapeutics, Inc. | Solid forms of 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid, compositions, and uses thereof |
EP3275881A4 (en) * | 2015-03-27 | 2018-09-12 | Shenyang Sunshine Pharmaceutical Co., Ltd. | Compound of 5-hydroxyl-1,7-naphthyridine substituted by aryloxy or heterooxy, preparation method thereof and pharmaceutical use thereof |
US11324734B2 (en) | 2015-04-01 | 2022-05-10 | Akebia Therapeutics, Inc. | Compositions and methods for treating anemia |
US11844756B2 (en) | 2015-04-01 | 2023-12-19 | Akebia Therapeutics, Inc. | Compositions and methods for treating anemia |
US10889546B2 (en) | 2015-10-09 | 2021-01-12 | Jiangsu Hengrui Medicine Co., Ltd. | Alkynyl pyridine prolyl hydroxylase inhibitor, and preparation method and medical use thereof |
EP3305769A1 (en) | 2016-10-07 | 2018-04-11 | Zentiva K.S. | Method for preparation of (7-phenoxy-4-hydroxy-1-methyl-isoquinoline-3-carbonyl)-glycine (roxedustat) and its intermediates based on simultaneous opening of oxazolic ring, fission of ether and creation of imine |
WO2019106621A1 (en) * | 2017-12-01 | 2019-06-06 | Dr. Reddy's Laboratories Limited | Process for the preparation of roxadustat and its intermediates |
CN108424388A (en) * | 2018-04-19 | 2018-08-21 | 杭州科巢生物科技有限公司 | A kind of preparation method of chronic anaemia drug |
US11713298B2 (en) | 2018-05-09 | 2023-08-01 | Akebia Therapeutics, Inc. | Process for preparing 2-[[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino]acetic acid |
EP4049999A4 (en) * | 2019-10-22 | 2023-04-19 | Crystal Pharmaceutical (Suzhou) Co., Ltd. | Crystal form of hypoxia-inducible factor-prolyl hydroxylase inhibitor |
WO2021077994A1 (en) | 2019-10-22 | 2021-04-29 | 苏州科睿思制药有限公司 | Crystal form of hypoxia-inducible factor-prolyl hydroxylase inhibitor |
US11524939B2 (en) | 2019-11-13 | 2022-12-13 | Akebia Therapeutics, Inc. | Solid forms of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino} acetic acid |
WO2021252295A1 (en) | 2020-06-13 | 2021-12-16 | Suzhou Pengxu Pharmatech Co., Ltd. | Process of making roxadustat |
CN115144480A (en) * | 2021-03-31 | 2022-10-04 | 成都倍特药业股份有限公司 | Method for detecting morpholine and/or tetramethylmethanediamine from intermediate of roxasistat |
CN115144480B (en) * | 2021-03-31 | 2023-11-28 | 成都倍特药业股份有限公司 | Method for detecting morpholine and/or tetramethyl methane diamine from roflumilast intermediate |
Also Published As
Publication number | Publication date |
---|---|
US20150031721A1 (en) | 2015-01-29 |
CN104024227B (en) | 2015-12-02 |
JP6099644B2 (en) | 2017-03-22 |
EP2734504A1 (en) | 2014-05-28 |
CA2842730A1 (en) | 2013-01-31 |
EP2734504B1 (en) | 2016-09-14 |
CA2842730C (en) | 2018-08-21 |
JP2014524920A (en) | 2014-09-25 |
EP2734504A4 (en) | 2014-12-31 |
AU2012289429B2 (en) | 2016-07-28 |
IL230580A0 (en) | 2014-03-31 |
US9206134B2 (en) | 2015-12-08 |
ZA201401310B (en) | 2015-04-29 |
CN104024227A (en) | 2014-09-03 |
AU2012289429A1 (en) | 2014-03-20 |
IL230580B (en) | 2019-07-31 |
KR20140049004A (en) | 2014-04-24 |
ES2606631T3 (en) | 2017-03-24 |
KR102029951B1 (en) | 2019-11-08 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US9206134B2 (en) | Polymorphic forms of compounds as prolyl hydroxylase inhibitor, and uses thereof | |
WO2022138988A1 (en) | Triazine derivative having virus propagation inhibitory effect, and pharmaceutical composition containing same | |
Yaseen et al. | Pyridazinone substituted benzenesulfonamides as potent carbonic anhydrase inhibitors | |
JP2016145212A (en) | Polymorphs of cddo ethyl ester and uses thereof | |
CA2767911C (en) | Compounds as hypoxia mimetics, and compositions, and uses thereof | |
JP2014534208A5 (en) | ||
US20220401419A1 (en) | Hydrogen peroxide-responsive keap1-nrf2 ppi inhibitor prodrug, and preparation method therefor | |
US9238637B2 (en) | Stable polymorphic forms of compound as hypoxia mimetics, and uses thereof | |
CN111349077B (en) | Pyridazine derivative and preparation method and medical application thereof | |
TWI582078B (en) | Crystal types of compounds inhibiting activity of prolyl hydroxylase and use thereof | |
TW201736373A (en) | Tricyclic compound acting as immunomodulator | |
TWI424842B (en) | Heterocyclic compound with substituent, pharmaceutical composition, and the use thereof | |
TW201321361A (en) | Stable crystal form of compound for inhibiting proline hydroxylase activity and application thereof | |
WO2023192864A2 (en) | Covalent parp16 inhibitors | |
CN118530297A (en) | Ketone amide compound, preparation method and application thereof | |
JP2015163602A (en) | Crystalline forms of [(4-hydroxy-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl)carbonyl]glycine compound and method for producing the same | |
CA2940942A1 (en) | Polymorphs of cddo ethyl ester and uses thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 12817360 Country of ref document: EP Kind code of ref document: A1 |
|
ENP | Entry into the national phase |
Ref document number: 2014520521 Country of ref document: JP Kind code of ref document: A |
|
ENP | Entry into the national phase |
Ref document number: 2842730 Country of ref document: CA |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
ENP | Entry into the national phase |
Ref document number: 20147004452 Country of ref document: KR Kind code of ref document: A |
|
REEP | Request for entry into the european phase |
Ref document number: 2012817360 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2012817360 Country of ref document: EP |
|
ENP | Entry into the national phase |
Ref document number: 2012289429 Country of ref document: AU Date of ref document: 20120723 Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 14233902 Country of ref document: US |