CN114787175A - 胆汁酸衍生物盐、其晶型结构及它们的制备方法和应用 - Google Patents
胆汁酸衍生物盐、其晶型结构及它们的制备方法和应用 Download PDFInfo
- Publication number
- CN114787175A CN114787175A CN202180006768.8A CN202180006768A CN114787175A CN 114787175 A CN114787175 A CN 114787175A CN 202180006768 A CN202180006768 A CN 202180006768A CN 114787175 A CN114787175 A CN 114787175A
- Authority
- CN
- China
- Prior art keywords
- degrees
- formula
- acid
- salt
- acid derivative
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000013078 crystal Substances 0.000 title claims abstract description 72
- -1 Bile acid derivative salt Chemical class 0.000 title claims description 28
- 238000002360 preparation method Methods 0.000 title claims description 25
- 150000003839 salts Chemical class 0.000 claims abstract description 48
- HSINOMROUCMIEA-FGVHQWLLSA-N (2s,4r)-4-[(3r,5s,6r,7r,8s,9s,10s,13r,14s,17r)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylpentanoic acid Chemical class C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)C[C@H](C)C(O)=O)CC[C@H]21 HSINOMROUCMIEA-FGVHQWLLSA-N 0.000 claims abstract description 40
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 19
- 201000010099 disease Diseases 0.000 claims abstract description 16
- 239000003814 drug Substances 0.000 claims abstract description 15
- 206010008635 Cholestasis Diseases 0.000 claims abstract description 12
- 230000007870 cholestasis Effects 0.000 claims abstract description 12
- 231100000359 cholestasis Toxicity 0.000 claims abstract description 12
- 208000019423 liver disease Diseases 0.000 claims abstract description 9
- 208000030159 metabolic disease Diseases 0.000 claims abstract description 9
- 208000007232 portal hypertension Diseases 0.000 claims abstract description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 91
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 78
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 66
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 59
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 56
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 55
- 239000002904 solvent Substances 0.000 claims description 50
- 150000001875 compounds Chemical class 0.000 claims description 49
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 48
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 41
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 33
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 24
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 22
- 238000000034 method Methods 0.000 claims description 20
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 19
- 239000002253 acid Substances 0.000 claims description 18
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 15
- 229910052736 halogen Inorganic materials 0.000 claims description 15
- 150000002367 halogens Chemical class 0.000 claims description 15
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 13
- 238000001938 differential scanning calorimetry curve Methods 0.000 claims description 12
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical compound COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 claims description 12
- 238000006243 chemical reaction Methods 0.000 claims description 11
- 239000001257 hydrogen Substances 0.000 claims description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims description 11
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 11
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 11
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
- 125000004400 (C1-C12) alkyl group Chemical group 0.000 claims description 9
- 229940079593 drug Drugs 0.000 claims description 9
- 238000001757 thermogravimetry curve Methods 0.000 claims description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 claims description 8
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 8
- 150000007522 mineralic acids Chemical class 0.000 claims description 8
- 150000007524 organic acids Chemical class 0.000 claims description 8
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 7
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 7
- 239000001530 fumaric acid Substances 0.000 claims description 7
- 150000002431 hydrogen Chemical class 0.000 claims description 7
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- 235000006408 oxalic acid Nutrition 0.000 claims description 7
- 125000006528 (C2-C6) alkyl group Chemical group 0.000 claims description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 6
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 6
- 229910052794 bromium Inorganic materials 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 239000000460 chlorine Substances 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 229910052731 fluorine Inorganic materials 0.000 claims description 6
- 239000011737 fluorine Substances 0.000 claims description 6
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 6
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 6
- 229940011051 isopropyl acetate Drugs 0.000 claims description 6
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 claims description 6
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 6
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 5
- 235000012000 cholesterol Nutrition 0.000 claims description 5
- 208000019425 cirrhosis of liver Diseases 0.000 claims description 5
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 5
- IQZPDFORWZTSKT-UHFFFAOYSA-N nitrosulphonic acid Chemical group OS(=O)(=O)[N+]([O-])=O IQZPDFORWZTSKT-UHFFFAOYSA-N 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- 206010019668 Hepatic fibrosis Diseases 0.000 claims description 4
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 4
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 4
- 239000012453 solvate Substances 0.000 claims description 4
- 239000004575 stone Substances 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 claims description 3
- 230000035935 pregnancy Effects 0.000 claims description 3
- 208000022309 Alcoholic Liver disease Diseases 0.000 claims description 2
- 206010008609 Cholangitis sclerosing Diseases 0.000 claims description 2
- 208000032928 Dyslipidaemia Diseases 0.000 claims description 2
- 208000035150 Hypercholesterolemia Diseases 0.000 claims description 2
- 208000017170 Lipid metabolism disease Diseases 0.000 claims description 2
- 208000012654 Primary biliary cholangitis Diseases 0.000 claims description 2
- 201000002150 Progressive familial intrahepatic cholestasis Diseases 0.000 claims description 2
- 206010041660 Splenomegaly Diseases 0.000 claims description 2
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 claims description 2
- 208000016097 disease of metabolism Diseases 0.000 claims description 2
- 208000006575 hypertriglyceridemia Diseases 0.000 claims description 2
- 150000002689 maleic acids Chemical class 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 125000005561 phenanthryl group Chemical group 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 210000003240 portal vein Anatomy 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims description 2
- 201000000742 primary sclerosing cholangitis Diseases 0.000 claims description 2
- 208000010157 sclerosing cholangitis Diseases 0.000 claims description 2
- 239000007810 chemical reaction solvent Substances 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 6
- 230000003908 liver function Effects 0.000 abstract description 3
- 239000007787 solid Substances 0.000 description 54
- 229940125904 compound 1 Drugs 0.000 description 40
- 238000002411 thermogravimetry Methods 0.000 description 34
- 235000019439 ethyl acetate Nutrition 0.000 description 30
- 238000000113 differential scanning calorimetry Methods 0.000 description 28
- 102100038495 Bile acid receptor Human genes 0.000 description 19
- 238000003756 stirring Methods 0.000 description 18
- 210000000941 bile Anatomy 0.000 description 14
- 239000003613 bile acid Substances 0.000 description 13
- 238000004458 analytical method Methods 0.000 description 11
- 238000002844 melting Methods 0.000 description 11
- 230000008018 melting Effects 0.000 description 11
- 238000005160 1H NMR spectroscopy Methods 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- 208000016261 weight loss Diseases 0.000 description 9
- 230000004580 weight loss Effects 0.000 description 9
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical group N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 8
- 230000037213 diet Effects 0.000 description 8
- 235000005911 diet Nutrition 0.000 description 8
- 238000001228 spectrum Methods 0.000 description 8
- 241000699670 Mus sp. Species 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- 238000002425 crystallisation Methods 0.000 description 7
- 230000008025 crystallization Effects 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 241000700159 Rattus Species 0.000 description 6
- 238000010521 absorption reaction Methods 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 241000699666 Mus <mouse, genus> Species 0.000 description 5
- 238000001514 detection method Methods 0.000 description 5
- 238000002050 diffraction method Methods 0.000 description 5
- 230000029142 excretion Effects 0.000 description 5
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 210000002966 serum Anatomy 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- RUDATBOHQWOJDD-UHFFFAOYSA-N (3beta,5beta,7alpha)-3,7-Dihydroxycholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)CC2 RUDATBOHQWOJDD-UHFFFAOYSA-N 0.000 description 4
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 4
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 238000001069 Raman spectroscopy Methods 0.000 description 4
- 238000001237 Raman spectrum Methods 0.000 description 4
- 238000004090 dissolution Methods 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 230000006872 improvement Effects 0.000 description 4
- RUDATBOHQWOJDD-UZVSRGJWSA-N ursodeoxycholic acid Chemical compound C([C@H]1C[C@@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)CC1 RUDATBOHQWOJDD-UZVSRGJWSA-N 0.000 description 4
- 229960001661 ursodiol Drugs 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 3
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 3
- 238000001157 Fourier transform infrared spectrum Methods 0.000 description 3
- 102000004877 Insulin Human genes 0.000 description 3
- 108090001061 Insulin Proteins 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 230000001270 agonistic effect Effects 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 230000018109 developmental process Effects 0.000 description 3
- 238000007416 differential thermogravimetric analysis Methods 0.000 description 3
- 208000035475 disorder Diseases 0.000 description 3
- 238000009826 distribution Methods 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- 229940125396 insulin Drugs 0.000 description 3
- 210000004185 liver Anatomy 0.000 description 3
- 239000011976 maleic acid Substances 0.000 description 3
- 230000010287 polarization Effects 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 238000002627 tracheal intubation Methods 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 108070000005 Bile acid receptors Proteins 0.000 description 2
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
- 206010067125 Liver injury Diseases 0.000 description 2
- 238000013231 NASH rodent model Methods 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-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
- 239000013543 active substance Substances 0.000 description 2
- 210000000013 bile duct Anatomy 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 239000012295 chemical reaction liquid Substances 0.000 description 2
- 239000002131 composite material Substances 0.000 description 2
- 238000006073 displacement reaction Methods 0.000 description 2
- 230000014509 gene expression Effects 0.000 description 2
- 238000000227 grinding Methods 0.000 description 2
- 231100000753 hepatic injury Toxicity 0.000 description 2
- 230000001976 improved effect Effects 0.000 description 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 102000006255 nuclear receptors Human genes 0.000 description 2
- 108020004017 nuclear receptors Proteins 0.000 description 2
- 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 2
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 2
- 238000003921 particle size analysis Methods 0.000 description 2
- 230000003285 pharmacodynamic effect Effects 0.000 description 2
- 230000035790 physiological processes and functions Effects 0.000 description 2
- 230000001376 precipitating effect Effects 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 230000001737 promoting effect Effects 0.000 description 2
- 230000005855 radiation Effects 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 229910002483 Cu Ka Inorganic materials 0.000 description 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 1
- BFPYWIDHMRZLRN-SLHNCBLASA-N Ethinyl estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 BFPYWIDHMRZLRN-SLHNCBLASA-N 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- 229930091371 Fructose Natural products 0.000 description 1
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 206010022489 Insulin Resistance Diseases 0.000 description 1
- 206010023126 Jaundice Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-L L-tartrate(2-) Chemical class [O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O FEWJPZIEWOKRBE-JCYAYHJZSA-L 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 101150027485 NR1H4 gene Proteins 0.000 description 1
- 108020005497 Nuclear hormone receptor Proteins 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 229930003316 Vitamin D Natural products 0.000 description 1
- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- 230000003187 abdominal effect Effects 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000011759 adipose tissue development Effects 0.000 description 1
- 125000000217 alkyl group Chemical group 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
- 230000037005 anaesthesia Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 238000007707 calorimetry Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 230000001989 choleretic effect Effects 0.000 description 1
- 230000031154 cholesterol homeostasis Effects 0.000 description 1
- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic acid Chemical class C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 description 1
- 229940121657 clinical drug Drugs 0.000 description 1
- 210000001953 common bile duct Anatomy 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- DEZRYPDIMOWBDS-UHFFFAOYSA-N dcm dichloromethane Chemical compound ClCCl.ClCCl DEZRYPDIMOWBDS-UHFFFAOYSA-N 0.000 description 1
- 238000003795 desorption Methods 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000372 effect on cholestasis Effects 0.000 description 1
- 238000002003 electron diffraction Methods 0.000 description 1
- 239000006274 endogenous ligand Substances 0.000 description 1
- OCLXJTCGWSSVOE-UHFFFAOYSA-N ethanol etoh Chemical compound CCO.CCO OCLXJTCGWSSVOE-UHFFFAOYSA-N 0.000 description 1
- LJQKCYFTNDAAPC-UHFFFAOYSA-N ethanol;ethyl acetate Chemical compound CCO.CCOC(C)=O LJQKCYFTNDAAPC-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- HJUFTIJOISQSKQ-UHFFFAOYSA-N fenoxycarb Chemical compound C1=CC(OCCNC(=O)OCC)=CC=C1OC1=CC=CC=C1 HJUFTIJOISQSKQ-UHFFFAOYSA-N 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 210000000232 gallbladder Anatomy 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 210000003494 hepatocyte Anatomy 0.000 description 1
- 230000013632 homeostatic process Effects 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 210000003405 ileum Anatomy 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000004255 ion exchange chromatography Methods 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 208000020442 loss of weight Diseases 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- COTNUBDHGSIOTA-UHFFFAOYSA-N meoh methanol Chemical compound OC.OC COTNUBDHGSIOTA-UHFFFAOYSA-N 0.000 description 1
- 238000003801 milling Methods 0.000 description 1
- 239000004570 mortar (masonry) Substances 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000000399 optical microscopy Methods 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000002633 protecting effect Effects 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000007115 recruitment Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000008844 regulatory mechanism Effects 0.000 description 1
- 230000027756 respiratory electron transport chain Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 238000004626 scanning electron microscopy Methods 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 238000004467 single crystal X-ray diffraction Methods 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 239000002689 soil Substances 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 238000000279 solid-state nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 238000012306 spectroscopic technique Methods 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 238000000859 sublimation Methods 0.000 description 1
- 230000008022 sublimation Effects 0.000 description 1
- 125000000542 sulfonic acid group Chemical group 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 238000001946 ultra-performance liquid chromatography-mass spectrometry Methods 0.000 description 1
- 210000001631 vena cava inferior Anatomy 0.000 description 1
- 238000002460 vibrational spectroscopy Methods 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 235000019166 vitamin D Nutrition 0.000 description 1
- 239000011710 vitamin D Substances 0.000 description 1
- 150000003710 vitamin D derivatives Chemical class 0.000 description 1
- 229940046008 vitamin d Drugs 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 210000002417 xiphoid bone Anatomy 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
- C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
-
- 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
- A61P3/06—Antihyperlipidemics
-
- 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
- C07J—STEROIDS
- C07J51/00—Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Diabetes (AREA)
- Gastroenterology & Hepatology (AREA)
- Epidemiology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Steroid Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明提供了一种胆汁酸衍生物的盐、其晶型形式及它们的制备方法和应用，本发明提供的胆汁酸衍生物的盐，其晶型形式以及他们的组合物可改善胆汁淤积，降低门脉压力，改善肝功能，可用于制备治疗或缓解慢性肝病、代谢性疾病或门脉高压症及其相关疾病的药物。
Description
PCT国内申请，说明书已公开。
Claims (15)
- PCT国内申请，权利要求书已公开。
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2020102725010 | 2020-04-08 | ||
| CN202010272501.0A CN113493485A (zh) | 2020-04-08 | 2020-04-08 | 胆汁酸衍生物盐、其晶型结构及它们的制备方法和应用 |
| PCT/CN2021/085785 WO2021204142A1 (zh) | 2020-04-08 | 2021-04-07 | 胆汁酸衍生物盐、其晶型结构及它们的制备方法和应用 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN114787175A true CN114787175A (zh) | 2022-07-22 |
| CN114787175B CN114787175B (zh) | 2024-08-02 |
Family
ID=77994770
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010272501.0A Withdrawn CN113493485A (zh) | 2020-04-08 | 2020-04-08 | 胆汁酸衍生物盐、其晶型结构及它们的制备方法和应用 |
| CN202180006768.8A Active CN114787175B (zh) | 2020-04-08 | 2021-04-07 | 胆汁酸衍生物盐、其晶型结构及它们的制备方法和应用 |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010272501.0A Withdrawn CN113493485A (zh) | 2020-04-08 | 2020-04-08 | 胆汁酸衍生物盐、其晶型结构及它们的制备方法和应用 |
Country Status (8)
| Country | Link |
|---|---|
| US (1) | US20230054001A1 (zh) |
| EP (1) | EP4053143A4 (zh) |
| JP (1) | JP2023504015A (zh) |
| KR (1) | KR20220088934A (zh) |
| CN (2) | CN113493485A (zh) |
| AU (1) | AU2021251935B2 (zh) |
| CA (1) | CA3162945A1 (zh) |
| WO (1) | WO2021204142A1 (zh) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019119832A1 (zh) * | 2017-12-19 | 2019-06-27 | 西安奥立泰医药科技有限公司 | 用于代谢性疾病治疗的化合物及其制备方法和应用 |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016045480A1 (zh) * | 2014-09-28 | 2016-03-31 | 上海源力生物技术有限公司 | 一种奥贝胆酸的制备方法 |
| US11578097B2 (en) * | 2014-11-26 | 2023-02-14 | Enanta Pharmaceuticals, Inc. | Tetrazole derivatives of bile acids as FXR/TGR5 agonists and methods of use thereof |
| CN104672290B (zh) * | 2015-01-05 | 2017-06-06 | 北京普禄德医药科技有限公司 | 一种用于预防或治疗fxr‑介导的疾病的药物及其制备方法和用途 |
| CN111574577A (zh) * | 2015-04-29 | 2020-08-25 | 正大天晴药业集团股份有限公司 | 鹅去氧胆酸衍生物 |
-
2020
- 2020-04-08 CN CN202010272501.0A patent/CN113493485A/zh not_active Withdrawn
-
2021
- 2021-04-07 CN CN202180006768.8A patent/CN114787175B/zh active Active
- 2021-04-07 WO PCT/CN2021/085785 patent/WO2021204142A1/zh unknown
- 2021-04-07 JP JP2022530836A patent/JP2023504015A/ja active Pending
- 2021-04-07 AU AU2021251935A patent/AU2021251935B2/en active Active
- 2021-04-07 US US17/779,979 patent/US20230054001A1/en active Pending
- 2021-04-07 KR KR1020227018193A patent/KR20220088934A/ko unknown
- 2021-04-07 EP EP21783953.9A patent/EP4053143A4/en active Pending
- 2021-04-07 CA CA3162945A patent/CA3162945A1/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019119832A1 (zh) * | 2017-12-19 | 2019-06-27 | 西安奥立泰医药科技有限公司 | 用于代谢性疾病治疗的化合物及其制备方法和应用 |
Non-Patent Citations (1)
| Title |
|---|
| 中国人民解放军第二军医大学要药学系: "《药剂学 上》", 中国人民解放军第二军医大学要药学系, pages: 273 * |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2021204142A1 (zh) | 2021-10-14 |
| JP2023504015A (ja) | 2023-02-01 |
| AU2021251935A1 (en) | 2022-06-16 |
| EP4053143A1 (en) | 2022-09-07 |
| KR20220088934A (ko) | 2022-06-28 |
| EP4053143A4 (en) | 2024-02-21 |
| CN113493485A (zh) | 2021-10-12 |
| CA3162945A1 (en) | 2021-10-14 |
| US20230054001A1 (en) | 2023-02-23 |
| AU2021251935B2 (en) | 2023-05-18 |
| CN114787175B (zh) | 2024-08-02 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP6877389B2 (ja) | オベチコール酸の調製、使用および固体形態 | |
| CA2619284A1 (en) | Novel crystalline form of a pyridazino [4,5-b] indole derivative | |
| US10550101B2 (en) | Crystalline forms of mesylate salt of pyridinyl amino pyrimidine derivative, preparation methods therefor, and applications thereof | |
| JP6849804B2 (ja) | ブロモドメインタンパク質阻害薬の結晶形及びその製造方法並びに用途 | |
| CN112876493B (zh) | 含氮三环化合物的盐及其用途 | |
| CN112876492B (zh) | 含氮三环化合物的晶型及其用途 | |
| KR101545068B1 (ko) | Ｃｄｄｏ 에틸 에스테르의 다형체 및 이의 용도 | |
| WO2022258060A1 (zh) | 一种lanifibranor的晶型及其制备方法 | |
| AU2021411658A1 (en) | 2-pyridone derivative, and preparation method therefor and pharmaceutical application thereof | |
| TWI806708B (zh) | 二胺基嘧啶類化合物或其水合物的固體形式及其製備方法和用途 | |
| WO2023193563A1 (zh) | 一种噻吩并吡啶化合物的晶型a、制备方法及其药物组合物 | |
| CN114787175B (zh) | 胆汁酸衍生物盐、其晶型结构及它们的制备方法和应用 | |
| TW202106674A (zh) | 二胺基嘧啶類化合物的鹽、其固體形式及其製備方法和用途 | |
| EP3553060B1 (en) | Polycrystalline mesylate of phosphodiesterase type 5 inhibitor, preparation method therefor, and application thereof | |
| US20230365564A1 (en) | Cocrystals of an adenosine a2b receptor antagonist | |
| WO2013170738A1 (zh) | 阿戈美拉汀酸根复合物及其制备方法和用途 | |
| WO2023147752A1 (zh) | 作为甲状腺激素受体激动剂的多晶型物及其用途 | |
| WO2022166767A1 (zh) | Ha抑制剂化合物的盐及晶型 | |
| WO2024169896A1 (zh) | 一种苯并氮杂芳环衍生物的盐、晶型及其在医药上的应用 | |
| WO2023025270A1 (zh) | 一种吲哚类化合物的固体形式及其制备方法和用途 | |
| WO2023185979A1 (zh) | 一种atx抑制剂或其盐的结晶形式及其制备方法与应用 | |
| US20230279002A1 (en) | Polymorphs of Crystalline Forms of 3,10-dimethoxy-5,8,13,13a-tetrahydro-6H-isoquinolino[3,2-a]isoquinolin-9-yl 3-fluorobenzenesulfonate and Salts Thereof | |
| WO2019086008A1 (zh) | 一种苯并三氮唑衍生物的晶型及其制备方法和用途 | |
| TW202421616A (zh) | ５－［（２，４－二硝基苯氧基）甲基］－１－甲基－２－硝基－１ｈ－咪唑之結晶形式 | |
| CN118271327A (zh) | 三环化合物的晶型及其用途 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |