WO2020015721A1 - 作为ask1抑制剂的晶型及其制备方法和应用 - Google Patents
作为ask1抑制剂的晶型及其制备方法和应用 Download PDFInfo
- Publication number
- WO2020015721A1 WO2020015721A1 PCT/CN2019/096678 CN2019096678W WO2020015721A1 WO 2020015721 A1 WO2020015721 A1 WO 2020015721A1 CN 2019096678 W CN2019096678 W CN 2019096678W WO 2020015721 A1 WO2020015721 A1 WO 2020015721A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- crystal form
- pattern
- compound
- angles
- ray powder
- Prior art date
Links
- 239000013078 crystal Substances 0.000 title claims abstract description 55
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 229940127254 ASK1 inhibitor Drugs 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 48
- 239000003814 drug Substances 0.000 claims abstract description 9
- 101001018196 Homo sapiens Mitogen-activated protein kinase kinase kinase 5 Proteins 0.000 claims abstract 2
- 102100033127 Mitogen-activated protein kinase kinase kinase 5 Human genes 0.000 claims abstract 2
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 42
- 238000001757 thermogravimetry curve Methods 0.000 claims description 19
- 230000004580 weight loss Effects 0.000 claims description 13
- 238000001938 differential scanning calorimetry curve Methods 0.000 claims description 7
- 229940079593 drug Drugs 0.000 abstract description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 4
- 201000010099 disease Diseases 0.000 abstract description 3
- 238000006243 chemical reaction Methods 0.000 description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 21
- 239000000243 solution Substances 0.000 description 20
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 238000001228 spectrum Methods 0.000 description 17
- 239000007787 solid Substances 0.000 description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- 238000000113 differential scanning calorimetry Methods 0.000 description 11
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 229940126062 Compound A Drugs 0.000 description 9
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 238000004458 analytical method Methods 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 9
- 102000011853 MAP Kinase Kinase Kinase 5 Human genes 0.000 description 8
- 108010075639 MAP Kinase Kinase Kinase 5 Proteins 0.000 description 8
- 239000000725 suspension Substances 0.000 description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 7
- 238000002474 experimental method Methods 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- 241001465754 Metazoa Species 0.000 description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 6
- 241000699670 Mus sp. Species 0.000 description 6
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 239000012065 filter cake Substances 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- 102100034256 Mucin-1 Human genes 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 230000003285 pharmacodynamic effect Effects 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 230000005855 radiation Effects 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000001291 vacuum drying Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 3
- 239000005695 Ammonium acetate Substances 0.000 description 3
- FLPJKFBHZBJFGH-UHFFFAOYSA-N Cc(cc(c(C(Nc1cccc(-c2nnc3[n]2CCCC3)n1)=O)c1)F)c1-[n]1cnc(C2CC2)c1 Chemical compound Cc(cc(c(C(Nc1cccc(-c2nnc3[n]2CCCC3)n1)=O)c1)F)c1-[n]1cnc(C2CC2)c1 FLPJKFBHZBJFGH-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 229940043376 ammonium acetate Drugs 0.000 description 3
- 235000019257 ammonium acetate Nutrition 0.000 description 3
- 208000019425 cirrhosis of liver Diseases 0.000 description 3
- 210000004185 liver Anatomy 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000004006 olive oil Substances 0.000 description 3
- 235000008390 olive oil Nutrition 0.000 description 3
- 239000012192 staining solution Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000010998 test method Methods 0.000 description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 2
- ZKHQWZAMYRWXGA-UHFFFAOYSA-N Adenosine triphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(=O)OP(O)(O)=O)C(O)C1O ZKHQWZAMYRWXGA-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 208000023275 Autoimmune disease Diseases 0.000 description 2
- 208000024172 Cardiovascular disease Diseases 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- WZUVPPKBWHMQCE-UHFFFAOYSA-N Haematoxylin Chemical compound C12=CC(O)=C(O)C=C2CC2(O)C1C1=CC=C(O)C(O)=C1OC2 WZUVPPKBWHMQCE-UHFFFAOYSA-N 0.000 description 2
- 108010055717 JNK Mitogen-Activated Protein Kinases Proteins 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 102000004232 Mitogen-Activated Protein Kinase Kinases Human genes 0.000 description 2
- 108090000744 Mitogen-Activated Protein Kinase Kinases Proteins 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 238000013231 NASH rodent model Methods 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- DEFVIWRASFVYLL-UHFFFAOYSA-N ethylene glycol bis(2-aminoethyl)tetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)CCOCCOCCN(CC(O)=O)CC(O)=O DEFVIWRASFVYLL-UHFFFAOYSA-N 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000007489 histopathology method Methods 0.000 description 2
- 208000030159 metabolic disease Diseases 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 230000004770 neurodegeneration Effects 0.000 description 2
- 208000015122 neurodegenerative disease Diseases 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 108010068338 p38 Mitogen-Activated Protein Kinases Proteins 0.000 description 2
- 102000002574 p38 Mitogen-Activated Protein Kinases Human genes 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000003642 reactive oxygen metabolite Substances 0.000 description 2
- 238000013112 stability test Methods 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- ZKHQWZAMYRWXGA-KQYNXXCUSA-J ATP(4-) Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KQYNXXCUSA-J 0.000 description 1
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 1
- SMYVLYXJTFDDMJ-UHFFFAOYSA-N Cc(cc(c(Br)c1)F)c1-[n]1cnc(C2CC2)c1 Chemical compound Cc(cc(c(Br)c1)F)c1-[n]1cnc(C2CC2)c1 SMYVLYXJTFDDMJ-UHFFFAOYSA-N 0.000 description 1
- DNCLVDGUXUSPTL-UHFFFAOYSA-N Cc(cc(c(Br)c1)F)c1N Chemical compound Cc(cc(c(Br)c1)F)c1N DNCLVDGUXUSPTL-UHFFFAOYSA-N 0.000 description 1
- GFSZRGIZTAVSNF-UHFFFAOYSA-N Cc(cc(c(Br)c1)F)c1N(CC(C1CC1)=O)C=O Chemical compound Cc(cc(c(Br)c1)F)c1N(CC(C1CC1)=O)C=O GFSZRGIZTAVSNF-UHFFFAOYSA-N 0.000 description 1
- RDYMTRLJSQFUOW-UHFFFAOYSA-N Cc(cc(c(Br)c1)F)c1NCC(C1CC1)=O Chemical compound Cc(cc(c(Br)c1)F)c1NCC(C1CC1)=O RDYMTRLJSQFUOW-UHFFFAOYSA-N 0.000 description 1
- ANMJVFKRCBKCFN-UHFFFAOYSA-N Cc(cc(c(C(O)=O)c1)F)c1-[n]1cnc(C2CC2)c1 Chemical compound Cc(cc(c(C(O)=O)c1)F)c1-[n]1cnc(C2CC2)c1 ANMJVFKRCBKCFN-UHFFFAOYSA-N 0.000 description 1
- 208000004481 Choline Deficiency Diseases 0.000 description 1
- 108010039471 Fas Ligand Protein Proteins 0.000 description 1
- 102000015212 Fas Ligand Protein Human genes 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 229910021380 Manganese Chloride Inorganic materials 0.000 description 1
- GLFNIEUTAYBVOC-UHFFFAOYSA-L Manganese chloride Chemical compound Cl[Mn]Cl GLFNIEUTAYBVOC-UHFFFAOYSA-L 0.000 description 1
- WFUXTKMZYLUQIR-UHFFFAOYSA-N Nc1cccc(C(N(CCCC2)C2=N)=N)n1 Chemical compound Nc1cccc(C(N(CCCC2)C2=N)=N)n1 WFUXTKMZYLUQIR-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 1
- 102100040247 Tumor necrosis factor Human genes 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 229910001424 calcium ion Inorganic materials 0.000 description 1
- 230000006721 cell death pathway Effects 0.000 description 1
- 208000021752 choline deficiency disease Diseases 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000004455 differential thermal analysis Methods 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 1
- 239000003651 drinking water Substances 0.000 description 1
- 235000020188 drinking water Nutrition 0.000 description 1
- 210000002472 endoplasmic reticulum Anatomy 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 230000004761 fibrosis Effects 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000013101 initial test Methods 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- 210000005228 liver tissue Anatomy 0.000 description 1
- 235000011147 magnesium chloride Nutrition 0.000 description 1
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 description 1
- 235000002867 manganese chloride Nutrition 0.000 description 1
- 239000011565 manganese chloride Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 230000002438 mitochondrial effect Effects 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000003305 oral gavage Methods 0.000 description 1
- 230000036542 oxidative stress Effects 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 230000035882 stress Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
Images
Classifications
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- 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 crystal form of the compound of formula (I), and the application of the crystal form in the preparation of a medicament for treating ASK1-related diseases.
- Apoptosis signal-regulating kinase 1 is a member of the mitogen-activated protein kinase kinase (MAP3K) family.
- ASK1 can be activated by a series of stimuli, such as oxidative stress, reactive oxygen species (ROS), LPS, TNF-a, FasL, endoplasmic reticulum stress, and increased intracellular calcium ion concentration.
- ROS reactive oxygen species
- LPS reactive oxygen species
- TNF-a TNF-a
- FasL endoplasmic reticulum stress
- ASK1 responds to this series of stimuli by activating JNK (c-Jun N-terminal kinase) and p38 MAPK (p38 mitogen-activated protein kinases), and induces a variety of apoptosis through signals involving mitochondrial cell death pathways.
- JNK c-Jun N-terminal kinase
- p38 MAPK p38 mitogen-activated protein
- ASK1 activation and signaling play an important role in many diseases, including neurodegenerative diseases, cardiovascular diseases, inflammatory diseases, autoimmune diseases and metabolic disorders. Therefore, when patients suffer from neurodegenerative diseases, cardiovascular diseases, inflammation, autoimmune diseases, and metabolic diseases, using ASK1 inhibitors as therapeutic drugs can improve patients' lives.
- the present invention provides Form A of the compound of formula (I), whose X-ray powder diffraction (XRPD) pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 8.40 ⁇ 0.2 °, 13.46 ⁇ 0.2 °, and 14.13 ⁇ 0.2 °.
- XRPD X-ray powder diffraction
- the X-ray powder diffraction pattern of the above-mentioned Form A has characteristic diffraction peaks at the following 2 ⁇ angles: 8.40 ⁇ 0.2 °, 10.56 ⁇ 0.2 °, 13.46 ⁇ 0.2 °, 14.13 ⁇ 0.2 °, 15.31 ⁇ 0.2 °, 16.79 ⁇ 0.2 °, 24.09 ⁇ 0.2 °, and 24.97 ⁇ 0.2 °.
- the XRPD pattern of the above-mentioned Form A is shown in FIG. 1.
- Table 1 XRPD pattern analysis data of Form A
- the differential scanning calorimetry (DSC) of the above-mentioned Form A has a starting point of an endothermic peak at 210.78 ° C and 237.74 ° C, and an exothermic peak at 215.70 ° C.
- the DSC spectrum of the above-mentioned Form A is shown in FIG. 2.
- thermogravimetric analysis curve (TGA) of the above-mentioned Form A has a weight loss of 1.799% at 120 ° C.
- the TGA spectrum of the above-mentioned Form A is shown in FIG. 3.
- the present invention provides Form B of the compound of formula (I), and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 8.85 ⁇ 0.2 °, 17.07 ⁇ 0.2 °, and 17.70 ⁇ 0.2 °.
- the X-ray powder diffraction pattern of the above-mentioned Form B has characteristic diffraction peaks at the following 2 ⁇ angles: 8.85 ⁇ 0.2 °, 10.20 ⁇ 0.2 °, 14.62 ⁇ 0.2 °, 17.07 ⁇ 0.2 °, 17.70 ⁇ 0.2 °, 21.57 ⁇ 0.2 °, 23.34 ⁇ 0.2 °, and 24.37 ⁇ 0.2 °.
- the XRPD pattern of the above-mentioned Form B is shown in FIG. 4.
- the differential scanning calorimetry curves of the above-mentioned Form B have a starting point of an endothermic peak at 149.17 ° C, 170.25 ° C, and 237.84 ° C, and an exothermic peak at 177.34 ° C.
- the DSC pattern of the above-mentioned Form B is shown in FIG. 5.
- thermogravimetric analysis curve of the above-mentioned Form B has a weight loss of 0.3593% at 60 ° C and a weight loss of 1.5703% at 120 ° C.
- the TGA spectrum of the above-mentioned Form B is shown in FIG. 6.
- the present invention provides the crystal form C of the compound of formula (I), whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 9.47 ⁇ 0.2 °, 16.45 ⁇ 0.2 °, and 17.32 ⁇ 0.2 °.
- the X-ray powder diffraction pattern of the above-mentioned crystal form C has characteristic diffraction peaks at the following 2 ⁇ angles: 8.72 ⁇ 0.2 °, 9.47 ⁇ 0.2 °, 10.44 ⁇ 0.2 °, 13.75 ⁇ 0.2 °, 16.45 ⁇ 0.2 °, 17.32 ⁇ 0.2 °, 19.41 ⁇ 0.2 °, and 26.82 ⁇ 0.2 °.
- the XRPD pattern of the above-mentioned crystal form C is shown in FIG. 7.
- the differential scanning calorimetry curves of the above-mentioned crystal form C each have a starting point of an endothermic peak at 105.76 ° C, 171.54 ° C, and 237.48 ° C; and an exothermic peak at 177.64 ° C.
- the DSC pattern of the above-mentioned crystal form C is shown in FIG. 8.
- thermogravimetric analysis curve of the above-mentioned crystal form C has a weight loss of 1.115% at 75.89 ° C and a weight loss of 2.958% at 164.93 ° C.
- the TGA spectrum of the above-mentioned crystal form C is shown in FIG. 9.
- the present invention provides the D crystal form of the compound of formula (I), whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 10.26 ⁇ 0.2 °, 12.73 ⁇ 0.2 °, and 20.60 ⁇ 0.2 °.
- the X-ray powder diffraction pattern of the D form has characteristic diffraction peaks at the following 2 ⁇ angles: 10.26 ⁇ 0.2 °, 11.84 ⁇ 0.2 °, 12.73 ⁇ 0.2 °, 14.70 ⁇ 0.2 °, 16.39 ⁇ 0.2 °, 20.60 ⁇ 0.2 °, 21.22 ⁇ 0.2 °, and 22.26 ⁇ 0.2 °.
- the XRPD pattern of the D crystal form is shown in FIG. 10.
- the differential scanning calorimetry curves of the D form above each have a starting point of an endothermic peak at 101.92 ° C, 171.01 ° C, and 237.29 ° C, and an exothermic peak at 179.96 ° C.
- the DSC pattern of the D crystal form is shown in FIG. 11.
- thermogravimetric analysis curve of the D crystal form described above has a weight loss of 0.4876% at 75.62 ° C and a weight loss of 2.5836% at 132.36 ° C.
- the TGA spectrum of the D crystal form is shown in FIG. 12.
- the invention also provides the application of the above A-form, B-form, C-form or D-form in the preparation of a medicament for treating ASK1 related disorders.
- the A-form, B-form, C-form and D-form of the compound of the present invention are stable, little affected by light, heat and humidity, and have very high solubility, and have broad prospects for medicine.
- the intermediate compounds of the present invention can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and those skilled in the art.
- Well-known equivalent alternatives, preferred embodiments include, but are not limited to, the embodiments of the present invention.
- the solvent used in the present invention is commercially available.
- the present invention uses the following abbreviations: DCM stands for methylene chloride; DMF stands for N, N-dimethylformamide; DMSO stands for dimethyl sulfoxide; EtOH stands for ethanol; MeOH stands for methanol; TFA stands for trifluoroacetic acid; TsOH stands for P-toluenesulfonic acid; mp for melting point; EtSO 3 H for ethanesulfonic acid; MeSO 3 H for methanesulfonic acid; ATP for adenosine triphosphate; HEPES for 4-hydroxyethylpiperazineethanesulfonic acid; EGTA for ethylene glycol bis (2 -Aminoethyl ether) tetraacetic acid; MgCl 2 stands for magnesium dichloride; MnCl 2 stands for manganese dichloride; DTT stands for dithiothreitol; DCC stands for dicyclohe
- Test method about 10-20mg sample is used for XRPD detection.
- Light tube voltage 40kV
- light tube current 40mA
- Anti-scattering slit 7.10mm
- Test method Take a sample (0.5 ⁇ 1mg) and place it in a DSC aluminum pan for testing. Heat the sample from 25 ° C (room temperature) to 300 ° C (or 350 ° C) at a heating rate of 10 ° C / min.
- Thermogravimetric (Analyzer, TGA) method of the present invention is thermogravimetric (Analyzer, TGA) method of the present invention
- Test method Take a sample (2 ⁇ 5mg) and place it in a TGA platinum pot for testing. Under the condition of 25mL / min N 2 , heat the sample from room temperature to 350 ° C or lose weight by 20% at a heating rate of 10 ° C / min.
- FIG. 1 is an XRPD spectrum of Cu-K ⁇ radiation of Form A of the compound (I);
- FIG. 2 is a DSC spectrum of the Form A of the compound (I);
- FIG. 4 is a Cu-K ⁇ radiation XRPD spectrum of the B form of the compound (I);
- FIG. 5 is a DSC spectrum of the Form B of the compound (I).
- FIG. 6 is a TGA spectrum of the Form B of the compound (I).
- FIG. 7 is a Cu-K ⁇ radiation XRPD spectrum of the C form of the compound (I);
- FIG. 8 is a DSC spectrum of the C crystal form of the (I) compound
- FIG. 9 is a TGA spectrum of the Form C of the compound (I).
- FIG. 10 is an XRPD spectrum of Cu-K ⁇ radiation of the D form of the compound (I);
- FIG. 12 is a TGA spectrum of the D crystal form of the (I) compound
- Figure 13 shows the results of in vivo pharmacodynamic experiments of the compound A of formula (I) in the MCD-induced mouse NASH model; Note: *** indicates p ⁇ 0.001 vs. normal control group; ## indicates p ⁇ 0.01 vs. model group ;
- Figure 14 shows the results of in vivo pharmacodynamic experiments of compound A of formula (I) in a CCl 4- induced liver fibrosis model in mice; Note: *** indicates p ⁇ 0.001 vs. normal control group; # indicates p ⁇ 0.05 vs. Model group; ## means p ⁇ 0.01 vs. model group.
- step 1
- the organic phase was collected, and the collected organic phase was sequentially treated with NH 4 Cl (27 wt%, 1 L), NaHCO 3 (9 wt%, 1 L), and NaCl (15 wt (%, 500 mL), then dried over anhydrous sodium sulfate (150 g), filtered, and the filtrate was spin-dried under reduced pressure (oil pump, 50 ° C) to obtain a gray solid (498 g).
- the gray solid was slurried with n-hexane (1 L) at room temperature for 2 hours, filtered, and the filter cake was spin-dried under reduced pressure (oil pump, 50 ° C) to obtain compound 3.
- Acetic anhydride 540.00mL, 5.77moL, 4eq
- formic acid 1.84L
- Compound 3 460.00 g, 1.44 moL, 1 eq, purity 89.37%) was dissolved in anhydrous dichloromethane (1.84 L) and added to the reaction system, and the reaction system was stirred at 0 ° C for 1 hour.
- Water (1 L) was added to the reaction solution, and then the pH was adjusted from 8 to 9 with NaOH (50%), and the system temperature was maintained at 0 to 15 ° C.
- the organic phase was collected.
- the organic phase was collected, washed with saturated NaCl (800 mL), dried over anhydrous sodium sulfate (200 g), filtered, and the filtrate was spin-dried under reduced pressure (water pump, 50 ° C) to obtain a tan oily liquid (420 g ).
- the tan oily liquid was dissolved in methyl tert-butyl ether (600 mL), and then n-hexane (600 mL) was slowly added to the solution until precipitation no longer occurred.
- MCD Methionine / choline deficiency feed.
- Liver propylene analysis reagents hematoxylin staining solution, one red staining solution, Sirius staining solution;
- the normal control group After the animals have been acclimated in the facility for a week, the normal control group still uses normal feed, and the rest of the animals replace the feed with MCD feed. The drinking water is replaced every 48 hours without changing the feed; starting from the fifth week, except for the normal control group and the model group, The remaining groups were treated with the test compound, and the experiment lasted a total of 8 weeks. Animal liver samples were collected for histopathological analysis after the experiment. The model group is compared with the normal control group to determine whether the modeling is successful; the drug group and the model group are compared to determine whether the drug shows efficacy. The experimental results are shown in Figure 13.
- Form A of the compound of formula (I) (6 mg / Kg BID and 60 mg / Kg BID) has a significant effect on improving liver fibrosis.
- mice Male C57BL / 6 mice, weighing 22-27 grams, were purchased from Shanghai Lingchang Biotechnology Co., Ltd.
- Form A of the compound of formula (I) (3 mg / Kg BID, 30 mg / Kg BID) has a significant effect on improving liver fibrosis.
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Cardiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Heart & Thoracic Surgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
提供式(I)化合物的晶型A、B、C和D,及所述晶型在制备治疗ASK1相关疾病的药物中的应用。
Description
本申请要求申请日为2018年7月20日的中国专利申请CN201810806190.4的优先权。本申请引用该中国专利申请的全文。
本发明涉及式(Ⅰ)化合物的晶型,以及其晶型在制备治疗ASK1相关疾病的药物中的应用。
细胞凋亡信号调节激酶1(apotosis signal-regulating kinase 1,ASK1)是细胞丝裂原活化蛋白激酶激酶激酶(mitogen-activated protein kinase kinase kinase,MAP3K)家族成员之一。ASK1可以被一系列的刺激激活,比如氧化应激、活性氧簇(ROS)、LPS、TNF-a、FasL、内质网应激及细胞内钙离子浓度的增加等。ASK1通过活化JNK(c-Jun N-terminal kinase)和p38 MAPK(p38 mitogen-activated protein kinases)以应对这一系列的刺激,并通过涉及线粒体细胞死亡途径的信号而诱导多种细胞凋亡。ASK1的活化和信号传导在很多疾病中扮演着重要的角色,这些疾病包括神经退行性疾病、心血管疾病、炎症性疾病、自身免疫性疾病及代谢障碍性疾病。因此,当患者患有神经退行性疾病,心血管疾病,炎症,自身免疫疾病和代谢疾病时,用ASK1抑制剂作为治疗药物能改善患者生活。
发明内容
本发明提供了式(Ⅰ)化合物的A晶型,其X射线粉末衍射(XRPD)图谱在下列2θ角处具有特征衍射峰:8.40±0.2°、13.46±0.2°和14.13±0.2°。
本发明的一些方案中,上述A晶型,其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:8.40±0.2°、10.56±0.2°、13.46±0.2°、14.13±0.2°、15.31±0.2°、16.79±0.2°、24.09±0.2°和24.97±0.2°。
本发明的一些方案中,上述A晶型的XRPD图谱如图1所示。
本发明的一些方案中,上述A晶型的XRPD图谱解析数据如表1所示:
表1:A晶型的XRPD图谱解析数据
在本发明的一些方案中,上述A晶型的差示扫描量热曲线(DSC)在210.78℃和237.74℃处各有一个吸热峰的起始点,在215.70℃处有一个放热峰。
在本发明的一些方案中,上述A晶型的DSC图谱如图2所示。
在本发明的一些方案中,上述A晶型的热重分析曲线(TGA)在120℃处失重达1.799%。
在本发明的一些方案中,上述A晶型的TGA图谱如图3所示。
本发明提供了式(Ⅰ)化合物的B晶型,其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:8.85±0.2°、17.07±0.2°和17.70±0.2°。
本发明的一些方案中,上述B晶型,其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:8.85±0.2°、10.20±0.2°、14.62±0.2°、17.07±0.2°、17.70±0.2°、21.57±0.2°、23.34±0.2°和24.37±0.2°。
本发明的一些方案中,上述B晶型的XRPD图谱如图4所示。
本发明的一些方案中,上述B晶型的XRPD图谱解析数据如表2所示:
表2:B晶型的XRPD图谱解析数据
在本发明的一些方案中,上述B晶型的差示扫描量热曲线在149.17℃、170.25℃和237.84℃处各有一个吸热峰的起始点,在177.34℃处有一个放热峰。
在本发明的一些方案中,上述B晶型的DSC图谱如图5所示。
在本发明的一些方案中,上述B晶型的热重分析曲线在60℃处失重达0.3593%;在120℃处失重达1.5703%。
在本发明的一些方案中,上述B晶型的TGA图谱如图6所示。
本发明提供了式(Ⅰ)化合物的C晶型,其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:9.47±0.2°、16.45±0.2°和17.32±0.2°。
本发明的一些方案中,上述C晶型,其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:8.72±0.2°、9.47±0.2°、10.44±0.2°、13.75±0.2°、16.45±0.2°、17.32±0.2°、19.41±0.2°和26.82±0.2°。
本发明的一些方案中,上述C晶型的XRPD图谱如图7所示。
本发明的一些方案中,上述C晶型的XRPD图谱解析数据如表3所示:
表3:C晶型的XRPD图谱解析数据
在本发明的一些方案中,上述C晶型的差示扫描量热曲线在105.76℃、171.54℃和237.48℃处各有一个吸热峰的起始点;在177.64℃处有一个放热峰。
在本发明的一些方案中,上述C晶型的DSC图谱如图8所示。
在本发明的一些方案中,上述C晶型的热重分析曲线在75.89℃处失重达1.115%;在164.93℃处失重达2.958%。
在本发明的一些方案中,上述C晶型的TGA图谱如图9所示。
本发明提供了式(Ⅰ)化合物的D晶型,其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:10.26±0.2°、12.73±0.2°和20.60±0.2°。
本发明的一些方案中,上述D晶型,其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:10.26±0.2°、11.84±0.2°、12.73±0.2°、14.70±0.2°、16.39±0.2°、20.60±0.2°、21.22±0.2°和22.26±0.2°。
本发明的一些方案中,上述D晶型的XRPD图谱如图10所示。
本发明的一些方案中,上述D晶型的XRPD图谱解析数据如表4所示:
表4:D晶型的XRPD图谱解析数据
在本发明的一些方案中,上述D晶型的差示扫描量热曲线在101.92℃、171.01℃和237.29℃处各有一个吸热峰的起始点,在179.96℃处有一个放热峰。
在本发明的一些方案中,上述D晶型的DSC图谱如图11所示。
在本发明的一些方案中,上述D晶型的热重分析曲线在75.62℃处失重达0.4876%;在132.36℃失重达2.5836%。
在本发明的一些方案中,上述D晶型的TGA图谱如图12所示。
本发明还提供了上述A晶型、B晶型、C晶型或D晶型在制备治疗ASK1相关病症的药物中的应用。
技术效果
本发明化合物的A晶型、B晶型、C晶型及D晶型稳定、受光热湿度影响小、溶解性非常高好,成药前景广阔。
定义和说明
除非另有说明,本文所用的下列术语和短语旨在含有下列含义。一个特定的短语或术语在没有特别定义的情况下不应该被认为是不确定的或不清楚的,而应该按照普通的含义去理解。当本文出现商品名时,旨在指代其对应的商品或其活性成分。
本发明的中间体化合物可以通过本领域技术人员所熟知的多种合成方法来制备,包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式,优选的实施方式包括但不限于本发明的实施例。
本发明具体实施方式的化学反应是在合适的溶剂中完成的,所述的溶剂须适合于本发明的化学变化及其所需的试剂和物料。为了获得本发明的化合物,有时需要本领域技术人员在已有实施方式的基础上对合成步骤或者反应流程进行修改或选择。
下面会通过实施例具体描述本发明,这些实施例并不意味着对本发明的任何限制。
本发明所使用的所有溶剂是市售的,无需进一步纯化即可使用。
本发明所使用的溶剂可经市售获得。本发明采用下述缩略词:DCM代表二氯甲烷;DMF代表N,N-二甲基甲酰胺;DMSO代表二甲亚砜;EtOH代表乙醇;MeOH代表甲醇;TFA代表三氟乙酸;TsOH代表对甲苯磺酸;mp代表熔点;EtSO
3H代表乙磺酸;MeSO
3H代表甲磺酸;ATP代表三磷酸腺苷;HEPES代表4-羟乙基哌嗪乙磺酸;EGTA代表乙二醇双(2-氨基乙基醚)四乙酸;MgCl
2代表二氯化镁;MnCl
2代表二氯化锰;DTT代表二硫苏糖醇;DCC代表二环己基碳二亚胺;DMAP代表4-二甲氨基吡啶;DIEA代表N,N-二异丙基乙胺;wt%:质量百分比。
本发明粉末X-射线衍射(X-ray powder diffractometer,XRPD)方法
仪器型号:布鲁克D8 advance X-射线衍射仪
测试方法:大约10~20mg样品用于XRPD检测。
详细的XRPD参数如下:
光管电压:40kV,光管电流:40mA
发散狭缝:0.60mm
探测器狭缝:10.50mm
防散射狭缝:7.10mm
扫描范围:3或4-40deg
步径:0.02deg
步长:0.12秒
样品盘转速:15rpm
本发明差热分析(Differential Scanning Calorimeter,DSC)方法
仪器型号:TADSCQ2000差示扫描量热仪
测试方法:取样品(0.5~1mg)置于DSC铝锅内进行测试,以10℃/min的升温速率,加热样品从25℃(室温)到300℃(或350℃)。
本发明热重分析(Thermal Gravimetric Analyzer,TGA)方法
仪器型号:TAQ5000热重分析仪
测试方法:取样品(2~5mg)置于TGA铂金锅内进行测试,在25mL/min N
2条件下,以10℃/min的升温速率,加热样品从室温到350℃或失重20%。
图1为(I)化合物的A晶型的Cu-Kα辐射的XRPD谱图;
图2为(I)化合物的A晶型的DSC谱图;
图3为(I)化合物的A晶型的TGA谱图;
图4为(I)化合物的B晶型的Cu-Kα辐射XRPD谱图;
图5为(I)化合物的B晶型的DSC谱图;
图6为(I)化合物的B晶型的TGA谱图;
图7为(I)化合物的C晶型的Cu-Kα辐射XRPD谱图;
图8为(I)化合物的C晶型的DSC谱图;
图9为(I)化合物的C晶型的TGA谱图;
图10为(I)化合物的D晶型的Cu-Kα辐射XRPD谱图;
图11为(I)化合物的D晶型的DSC谱图;
图12为(I)化合物的D晶型的TGA谱图;
图13为式(I)化合物A晶型在MCD诱导小鼠NASH模型的体内药效实验结果;注:***表示p<0.001vs.正常对照组;##表示p<0.01vs.模型组;
图14为式(I)化合物A晶型在CCl
4诱导小鼠肝纤维化模型的体内药效实验结果;注:***表示p<0.001vs.正常对照组;#表示p<0.05vs.模型组;##表示p<0.01vs.模型组。
为了更好的理解本发明的内容,下面结合具体实施例来做进一步的说明,但具体的实施方式并不是对本发明的内容所做的限制。
实施例1:式(I)化合物的制备
步骤1:
将化合物1(370g,1.81moL,1eq)和化合物2(513g,1.99moL,1.1eq,纯度98.71%)加入到干燥的5L三口烧瓶中,往反应瓶中依次加入甲苯(1.85L)和DIEA(665.00mL,3.81moL,2.1eq),将反应体系缓慢升温至100℃搅拌10小时。将反应液冷却至室温,加入水搅拌,静置,分液,收集有机相,将收集的有机相依次用NH
4Cl(27wt%,1L),NaHCO
3(9wt%,1L)和NaCl(15wt%,500mL)洗涤,然后用无水硫酸钠(150g)干燥,过滤,滤液减压旋干(油泵,50℃),得到灰色固体(498g)。将灰色固体用正已烷(1L)在室温下打浆2小时,过滤,滤饼减压旋干(油泵,50℃)得到化合物3。
1H NMR(400MHz,DMSO-d
6)δppm 0.86-0.90(m,2H)0.91-0.96(m,2H)2.09(s,3H)2.14-2.21(m,1H)4.16(d,J=5.52Hz,2H)5.27(d,J=5.52Hz,1H)6.50(d,J=6.02Hz,1H)7.05(d,J=9.29Hz,1H)。
步骤2:
将乙酸酐(540.00mL,5.77moL,4eq)和甲酸(1.84L)加入到干燥的5L三口烧瓶中,然后将体系温度降至0℃。将化合物3(460.00g,1.44moL,1eq,纯度89.37%)溶于无水二氯甲烷(1.84L)后加入到反应体系中,将反应体系在0℃下搅拌1小时。往反应液中加 入水(1L),然后用NaOH(50%)调节PH=8~9,保持体系温度为0~15℃,收集有机相,将收集的有机相依次用二氯甲烷(1.5L)和饱和氯化钠(1L)洗涤,无水硫酸钠(200g)干燥,过滤,滤液减压旋干(水泵,50℃),得到化合物4。
1H NMR(400MHz,DMSO-d
6)δppm 0.86-0.90(m,2H)0.93-0.96(m,2H)2.06-2.10(m,1H)2.25(s,3H)4.68(s,2H)7.41(d,J=9.54Hz,1H)7.61(d,J=6.78Hz,1H)8.17(s,1H)。
步骤3:
将化合物4(440g,1.33moL,1eq,纯度94.77%)加入到干燥的5L三口烧瓶中,往反应瓶中依次加入乙酸(2.2L)和乙酸铵(399.03g,5.18moL,3.9eq),将反应体系缓慢升温至115℃搅拌43h。取1滴反应液溶于1mL甲醇送LCMS,LCMS显示原料化合物4还有24.50%剩余,有70.67%的产物生成,补加乙酸铵(102.00g,1.32moL,1eq),反应体系搅拌20小时。取1滴反应液溶于1mL甲醇送LCMS,LCMS显示原料化合物4还有12.66%剩余,有76.03%的产物生成,补加乙酸铵(51.00g,661.63mmoL,0.5eq),反应体系继续搅拌15小时。取1滴反应液溶于1mL甲醇送LCMS,LCMS显示原料化合物4还有7.32%剩余,有89.36%的产物生成。往反应液中加入水(1L),然后加入乙酸异丙酯(1L)搅拌,静置,分液,收集有机相,收集的有机相用50%的NaOH调节PH=8~9,然后静置,分液,收集有机相,将上述有机相用饱和NaCl(800mL)洗涤,无水硫酸钠(200g)干燥,过滤,滤液减压旋干(水泵,50℃),得到棕褐色油状液体(420g)。将棕褐色油状液体溶于甲基叔丁基醚(600mL),然后往溶液中缓慢加入正已烷(600mL)至不再出现沉淀,溶液上层变为黄色澄清,过滤,滤液减压旋干(水泵,50℃),得到化合物5。
1H NMR(400MHz,DMSO-d
6)δppm 0.66-0.71(m,2H)0.76-0.81(m,2H)1.78-1.86(m,1H)2.13(s,3H)7.13(d,J=1.25Hz,1H)7.47(d,J=9.54Hz,1H)7.64(d,J=1.25Hz,1H)7.69(d,J=6.53Hz,1H)。
步骤4:
将化合物5(80g,238.63mmoL,1eq,纯度为88.04%)加入到干燥的3L三口烧瓶中,往反应瓶中加入无水四氢呋喃(1.20L),用氮气球置换体系内空气,重复操作两遍,将体系温度降至0℃后缓慢加人iPrMgCl(143.00mL,286.36mmoL,1.2eq,2M)搅拌2小时,往反应体系中通入CO
2(15Psi)30分钟,然后撤掉冰浴,在室温下通入CO
2(15psi)60分钟,停止反应。往反应液中加入水(1L),然后浓缩(水泵,50℃)得到黄色液体(1.2L),往反应液中加入甲基叔丁基醚(1L),搅拌,静置,分液,收集水相,收集的水相用6M的HCl调节PH=4~5,加入甲基叔丁基醚(1L)萃取,收集水相,水相用水泵(70℃)浓缩至溶液体积为400mL,冷却,静置,析出固体,混合液合并到另一批(130g投料量)混合液一起过滤,。滤饼减压旋干(水泵,50℃),得到化合物6。
1H NMR(400MHz,DMSO-d
6) δppm 0.86-0.91(m,2H)1.00-1.06(m,2H)2.00-2.07(m,1H)2.25(s,3H)7.54(d,J=11.29Hz,1H)7.75(d,J=1.00Hz,1H)8.00(d,J=6.78Hz,1H)9.31(d,J=1.51Hz,1H)。
步骤5:
将化合物6(70g,260.57mmol,1.1当量)置于DCM(700L),加入DMF(2mL,25.99mmol,0.1当量),在搅拌下向反应液中滴加(COCl)
2(35.5mL,405.55mmol,1.7当量),体系在30℃下搅拌1h,反应液完全澄清,将反应液减压旋至约200mL。加入无水DCM 500mL,再次减压旋至约200mL,此操作重复两次。向反应液中加入无水DCM 700mL,化合物7(51g,236.93mmol,1当量),DIEA(41.5mL,237.61mmol,1当量),体系在30度下搅拌1h。反应液连同另一批(同样投料量)反应液一同倒入2L水中,用DCM(1L*3)萃取,合并有机相并用水(2L),饱和NaHCO3(2L)和水(2L)洗涤,经无水硫酸镁干燥,过滤,滤液减压旋干得到粗品,粗品中加入乙腈(170mL),充分摇匀,有大量固体析出,再次加入乙腈(170mL),常温搅拌30min,过滤,用已经500mL洗涤滤饼,收集滤饼,干燥得到115.5g白色固体产品。将115.5g固体与另一批76.5g产品合并,溶于HCl溶液(120mL,0.7mol/L),随后在搅拌下加入6mol/L的NaOH水溶液,有大量固体析出,过滤,收集滤饼,滤饼置于1L水中,剧烈搅拌30min,过滤,滤饼用500mL水洗涤,70℃干燥后得到式(I)化合物。
1H NMR(400MHz,氘代氯仿)δppm 0.81-0.84(m,2H)0.87-0.92(m,2H)1.87-1.93(m,1H)1.97–1.98(m,2H)2.03-2.06(m,2H)2.29(s,3H)3.07–3.10(m,2H)4.47–4.50(m,2H)6.79(d,J=0.75Hz,1H)7.19(d,J=12.30Hz,1H)7.44(d,J=1.00Hz,1H)7.89(t,J=8.03Hz,1H)8.06(t,J=7.53Hz,2H)8.35(d,J=8.28Hz,1H)9.04(d,J=14.81Hz,1H)。
实施例2:式(I)化合物A晶型的制备
称量大约50mg式(I)化合物于样品瓶中,加入400μL丙酮(或者乙腈),使其成为混悬液。将上述混悬液在40℃条件下持续振摇3天后,离心后将残留固体放入真空干燥箱,在30℃条件下真空干燥过夜,得式(I)化合物A晶型。
实施例3:式(I)化合物B晶型的制备
称量大约50mg式(I)化合物于样品瓶中,加入210μL甲醇,使其成为混悬液。将上述混悬液在40℃条件下持续振摇3天后,离心后将残留固体放入真空干燥箱,在30℃条件下真空干燥过夜,得式(I)化合物B晶型。
实施例4:式(I)化合物C晶型的制备
称量大约50mg式(I)化合物于样品瓶中,加入200μL乙醇,使其成为混悬液。将上述混悬液在40℃条件下持续振摇3天后,离心后将残留固体放入真空干燥箱,在30℃条件下真空干燥过夜,得式(I)化合物C晶型。
实施例5:式(I)化合物D晶型的制备
称量大约50mg式(I)化合物于样品瓶中,加入200μL乙醇/水混合液(乙醇:水=3:1),使其成为混悬液。将上述混悬液在40℃条件下持续振摇3天后,离心后将残留固体放入真空干燥箱,在30℃条件下真空干燥过夜,得式(I)化合物D晶型。
实施例6:式(I)化合物A晶型的固体稳定性试验
依据《原料药与制剂稳定性试验指导原则》(中国药典2015版四部通则9001),考察式(I)化合物A晶型在高温(60℃,敞口),高湿(室温/相对湿度92.5%,敞口)及强光照(5000lx,密闭)条件下的稳定性。
称取式(I)化合物A晶型约1g,平铺于敞口的干净称量瓶中,分别放入高温、高湿及强光照储存容器内。于放样后的5天、10天取样检测,检测结果与0天的初始检测结果进行比较,试验结果见下表5所示:
表5式(I)化合物A晶型的固体稳定性试验结果
结论:式(I)化合物A晶型在高温、高湿、强光照条件下具有良好的稳定性。
效果实施例1式(I)化合物A晶型在MCD诱导小鼠NASH模型的体内药效研究实验材料:
SPF级C57BL/6雄性小鼠,体重22-25克。
MCD:蛋氨酸/胆碱缺乏饲料。
肝脏丙烯分析试剂:苏木素染色液,一红染色液,天狼星染色液;
实验方法:
动物在设施内适应一周后,正常对照组仍用正常饲料,其余动物将饲料更换为MCD饲料,饮用水不更换每48小时更换一次饲料;第5周开始,除正常对照组和模型组外,其余组给予受试化合物治疗,实验总共持续8周。实验结束后采集动物肝脏样本进行组织病理学分析。通过对比模型组和正常对照组来确定是否造模成功;通过对比给药组和模型组来确定药物是否展示药效。实验结果见图13。
实验结论:
式(I)化合物A晶型(6mg/Kg BID和60mg/Kg BID)具有显著的改善肝纤维化的作用。
效果实施例2式(I)化合物A晶型在CCl
4诱导小鼠肝纤维化模型的体内药效研究实验材料:
将雄性C57BL/6小鼠,体重22-27克,购买自上海灵畅生物科技有限公司。
实验方法:
小鼠经过一周检疫和适应期后移入实验区。动物根据体重随机分组,5只小鼠一笼分笼饲养。将CCl
4按照0.5μl/g的小鼠给药剂量溶于橄榄油中,配制成CCl
4:橄榄油=1:4的20%的CCl
4溶液,每周三次口服造模,持续4周,正常对照组仅给予相同体积的橄榄油口服。受试化合物采用经口灌胃方式口服给药,每只动物给药体积10ml/kg。开始CCl
4造模第一日同时开始给药,给药至第28日。实验结束后采集动物肝脏样本进行组织病理学分析。通过对比模型组和正常对照组来确定是否造模成功;通过对比给药组和模型组来确定药物是否展示药效。实验结果见图14。
实验结论:
式(I)化合物A晶型(3mg/Kg BID,30mg/Kg BID)具有显著的改善肝纤维化的作用。
虽然以上描述了本发明的具体实施方式,但是本领域的技术人员应当理解,这些仅 是举例说明,在不背离本发明的原理和实质的前提下,可以对这些实施方式做出多种变更或修改。因此,本发明的保护范围由所附权利要求书限定。
Claims (29)
- 根据权利要求1所述的A晶型,其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:8.40±0.2°、10.56±0.2°、13.46±0.2°、14.13±0.2°、15.31±0.2°、16.79±0.2°、24.09±0.2°和24.97±0.2°。
- 根据权利要求2所述的A晶型,其XRPD图谱如图1所示。
- 根据权利要求1~3任意一项所述的A晶型,其差示扫描量热曲线DSC在210.78℃和237.74℃处各有一个吸热峰的起始点,在215.70℃处有一个放热峰。
- 根据权利要求4所述的A晶型,其DSC图谱如图2所示。
- 根据权利要求1~3任意一项所述的A晶型,其热重分析曲线TGA在120℃处失重达1.799%。
- 根据权利要求6所述的A晶型,其TGA图谱如图3所示。
- 根据权利要求8所述的B晶型,其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:8.85±0.2°、10.20±0.2°、14.62±0.2°、17.07±0.2°、17.70±0.2°、21.57±0.2°、23.34±0.2°和24.37±0.2°。
- 根据权利要求9所述的B晶型,其XRPD图谱如图4所示。
- 根据权利要求8~10任意一项所述的B晶型,其差示扫描量热曲线在149.17℃、170.25℃和237.84℃处各有一个吸热峰的起始点,在177.34℃处有一个放热峰。
- 根据权利要求11所述的B晶型,其DSC图谱如图5所示。
- 根据权利要求8~10任意一项所述的B晶型,其热重分析曲线在60℃处失重达0.3593%;在120℃处失重达1.5703%。
- 根据权利要求13所述的B晶型,其TGA图谱如图6所示。
- 根据权利要求15所述的C晶型,其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:8.72±0.2°、9.47±0.2°、10.44±0.2°、13.75±0.2°、16.45±0.2°、17.32±0.2°、19.41±0.2°和26.82±0.2°。
- 根据权利要求16所述的C晶型,其XRPD图谱如图7所示。
- 根据权利要求15~17任意一项所述的C晶型,其差示扫描量热曲线在105.76℃、171.54℃和237.48℃处各有一个吸热峰的起始点;在177.64℃处有一个放热峰。
- 根据权利要求18所述的C晶型,其DSC图谱如图8所示。
- 根据权利要求15~17任意一项所述的C晶型,其热重分析曲线在75.89℃处失重达1.115%;在164.93℃处失重达2.958%。
- 根据权利要求20所述的C晶型,其TGA图谱如图9所示。
- 根据权利要求22所述的D晶型,其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:10.26±0.2°、11.84±0.2°、12.73±0.2°、14.70±0.2°、16.39±0.2°、20.60±0.2°、21.22±0.2°和22.26±0.2°。
- 根据权利要求23所述的D晶型,其XRPD图谱如图10所示。
- 根据权利要求22~24任意一项所述的D晶型,其差示扫描量热曲线在101.92℃、171.01℃和237.29℃处各有一个吸热峰的起始点,在179.96℃处有一个放热峰。
- 根据权利要求25所述的D晶型,其DSC图谱如图11所示。
- 根据权利要求22~24任意一项所述的D晶型,其热重分析曲线在75.62℃处失重达0.4876%;在132.36℃失重达2.5836%。
- 根据权利要求27所述的D晶型,其TGA图谱如图12所示。
- 根据权利要求1~7所述的A晶型、根据权利要求8~14所述的B晶型、根据权利要求15~21所述的C晶型或根据权利要求22~28所述的D晶型在制备治疗ASK1相关病症的药物中的应用。
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US17/260,565 US11814382B2 (en) | 2018-07-20 | 2019-07-19 | Crystal form as ASK1 inhibitor and preparation method and application thereof |
JP2021525356A JP7096460B2 (ja) | 2018-07-20 | 2019-07-19 | Ask1阻害剤としての結晶形、その製造方法及び利用 |
CN201980042258.9A CN112638912B (zh) | 2018-07-20 | 2019-07-19 | 作为ask1抑制剂的晶型及其制备方法和应用 |
EP19837948.9A EP3825315B1 (en) | 2018-07-20 | 2019-07-19 | Crystal form as ask1 inhibitor, preparation method therefor, and application thereof |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201810806190.4 | 2018-07-20 | ||
CN201810806190 | 2018-07-20 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2020015721A1 true WO2020015721A1 (zh) | 2020-01-23 |
Family
ID=69163610
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CN2019/096678 WO2020015721A1 (zh) | 2018-07-20 | 2019-07-19 | 作为ask1抑制剂的晶型及其制备方法和应用 |
Country Status (6)
Country | Link |
---|---|
US (1) | US11814382B2 (zh) |
EP (1) | EP3825315B1 (zh) |
JP (1) | JP7096460B2 (zh) |
CN (1) | CN112638912B (zh) |
TW (1) | TWI710561B (zh) |
WO (1) | WO2020015721A1 (zh) |
Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2011008709A1 (en) * | 2009-07-13 | 2011-01-20 | Gilead Sciences, Inc. | Apoptosis signal-regulating kinase inhibitors |
WO2013112741A1 (en) * | 2012-01-27 | 2013-08-01 | Gilead Sciences, Inc. | Apoptosis signal-regulating kinase inhibitor |
WO2016105453A1 (en) * | 2014-12-23 | 2016-06-30 | Gilead Sciences, Inc. | Solid forms of an ask1 inhibitor |
CN107793400A (zh) * | 2017-10-31 | 2018-03-13 | 武汉中钰钰民医药科技有限公司 | 吡啶类化合物及其在制备治疗肝脏疾病的药物中的应用 |
WO2018133866A1 (zh) * | 2017-01-22 | 2018-07-26 | 福建广生堂药业股份有限公司 | 作为ask1抑制剂的吡啶衍生物及其制备方法和应用 |
WO2018151830A1 (en) * | 2017-02-17 | 2018-08-23 | Fronthera U.S. Pharmaceuticals Llc | Pyridinyl based apoptosis signal-regulation kinase inhibitors |
WO2018157856A1 (zh) * | 2017-03-03 | 2018-09-07 | 江苏豪森药业集团有限公司 | 酰胺类衍生物抑制剂及其制备方法和应用 |
WO2019034096A1 (en) * | 2017-08-17 | 2019-02-21 | Sunshine Lake Pharma Co., Ltd. | FUSED BICYCLIC COMPOUNDS AND THEIR USES IN MEDICINE |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20150342943A1 (en) * | 2014-06-03 | 2015-12-03 | Gilead Sciences, Inc. | Methods of treating liver disease |
TW201618781A (zh) | 2014-08-13 | 2016-06-01 | 吉李德科學股份有限公司 | 治療肺高血壓之方法 |
CN110698471A (zh) * | 2018-07-10 | 2020-01-17 | 山东轩竹医药科技有限公司 | Ask1抑制剂及其应用 |
CN111107848B (zh) | 2018-08-10 | 2023-05-23 | 江苏豪森药业集团有限公司 | 一种含有酰胺类衍生物的药物组合物及其制备方法和应用 |
-
2019
- 2019-07-19 EP EP19837948.9A patent/EP3825315B1/en active Active
- 2019-07-19 US US17/260,565 patent/US11814382B2/en active Active
- 2019-07-19 TW TW108125517A patent/TWI710561B/zh active
- 2019-07-19 WO PCT/CN2019/096678 patent/WO2020015721A1/zh unknown
- 2019-07-19 JP JP2021525356A patent/JP7096460B2/ja active Active
- 2019-07-19 CN CN201980042258.9A patent/CN112638912B/zh active Active
Patent Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2011008709A1 (en) * | 2009-07-13 | 2011-01-20 | Gilead Sciences, Inc. | Apoptosis signal-regulating kinase inhibitors |
WO2013112741A1 (en) * | 2012-01-27 | 2013-08-01 | Gilead Sciences, Inc. | Apoptosis signal-regulating kinase inhibitor |
WO2016105453A1 (en) * | 2014-12-23 | 2016-06-30 | Gilead Sciences, Inc. | Solid forms of an ask1 inhibitor |
WO2018133866A1 (zh) * | 2017-01-22 | 2018-07-26 | 福建广生堂药业股份有限公司 | 作为ask1抑制剂的吡啶衍生物及其制备方法和应用 |
WO2018151830A1 (en) * | 2017-02-17 | 2018-08-23 | Fronthera U.S. Pharmaceuticals Llc | Pyridinyl based apoptosis signal-regulation kinase inhibitors |
WO2018157856A1 (zh) * | 2017-03-03 | 2018-09-07 | 江苏豪森药业集团有限公司 | 酰胺类衍生物抑制剂及其制备方法和应用 |
WO2019034096A1 (en) * | 2017-08-17 | 2019-02-21 | Sunshine Lake Pharma Co., Ltd. | FUSED BICYCLIC COMPOUNDS AND THEIR USES IN MEDICINE |
CN107793400A (zh) * | 2017-10-31 | 2018-03-13 | 武汉中钰钰民医药科技有限公司 | 吡啶类化合物及其在制备治疗肝脏疾病的药物中的应用 |
Also Published As
Publication number | Publication date |
---|---|
JP2021531343A (ja) | 2021-11-18 |
EP3825315A1 (en) | 2021-05-26 |
EP3825315B1 (en) | 2022-08-31 |
US11814382B2 (en) | 2023-11-14 |
TWI710561B (zh) | 2020-11-21 |
EP3825315A4 (en) | 2021-11-24 |
JP7096460B2 (ja) | 2022-07-06 |
US20210269441A1 (en) | 2021-09-02 |
TW202019926A (zh) | 2020-06-01 |
CN112638912A (zh) | 2021-04-09 |
CN112638912B (zh) | 2022-04-26 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
ES2883285T3 (es) | Antagonistas de tlr7/8 y sus usos | |
RU2625309C2 (ru) | Замещенные диаминокарбоксамидные и диаминокарбонитрильные производные пиримидинов, их композиции и способы лечения с их помощью | |
JP5694320B2 (ja) | Apaf−1阻害剤化合物 | |
CN102574866B (zh) | 喜树碱衍生物 | |
CN110386919A (zh) | 核转运调节剂及其用途 | |
ES2678993T3 (es) | Estra-1,3,5(10),16-tetraeno-3-carboxamidas para la inhibición de la 17beta-hidroxiesteroide deshidrogenada (AKR1C3) | |
UA125516C2 (uk) | Заміщені діазагетеробіциклічні сполуки та їх застосування | |
CN104918934A (zh) | 3-取代的吡唑及其作为dlk抑制剂的用途 | |
AU2019262016B2 (en) | Tetrazole containing apoptosis signal-regulating kinase 1 inhibitors and methods of use thereof | |
PT2651902T (pt) | Enonas tricíclicas de pirazolilo e pirimidinilo como moduladores de inflamação antioxidantes | |
TWI332835B (en) | Hemiasterlin derivatives and uses thereof | |
CN108601770A (zh) | Pad4的氮杂-苯并咪唑抑制剂 | |
JP2020536872A (ja) | 3−置換1,2,4−オキサジアゾールの結晶形態 | |
BRPI0708657A2 (pt) | utilização de pelo menos um composto | |
CN109415343A (zh) | 用于治疗增殖性疾病的取代的2,4-二氨基-喹啉衍生物 | |
CN106573907A (zh) | 新颖的喹啉衍生物及其用于神经退化性疾病的用途 | |
CA2965716C (en) | Crystalline form of jak kinase inhibitor bisulfate and a preparation method thereof | |
ES2380491T3 (es) | Formas cristalinas adicionales de la Rostafuroxina | |
WO2020015721A1 (zh) | 作为ask1抑制剂的晶型及其制备方法和应用 | |
TW200934774A (en) | Arylmethylidene heterocycles as novel analgesics | |
JP4277015B2 (ja) | ストレプトグラミン誘導体、その製造およびそれを含む製薬組成物 | |
CN108707173A (zh) | 作为fxr调节剂的阿维菌素衍生物 | |
KR20240116522A (ko) | 암 치료제로서의 5,6,7,8-테트라하이드로-2,6-나프티리딘 유도체 | |
ES2312965T3 (es) | Sulfamatos de d-homoestra-1,3,5(10)-trien-3-il-2-sustituidos con efectos antitumoral. | |
CN112189009A (zh) | 作为tcr-nck相互作用的抑制剂的色烯衍生物 |
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: 19837948 Country of ref document: EP Kind code of ref document: A1 |
|
ENP | Entry into the national phase |
Ref document number: 2021525356 Country of ref document: JP Kind code of ref document: A |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
ENP | Entry into the national phase |
Ref document number: 2019837948 Country of ref document: EP Effective date: 20210222 |