WO2022179577A1 - 一种环丙基取代的苯并呋喃类化合物的晶型及其制备方法 - Google Patents
一种环丙基取代的苯并呋喃类化合物的晶型及其制备方法 Download PDFInfo
- Publication number
- WO2022179577A1 WO2022179577A1 PCT/CN2022/077773 CN2022077773W WO2022179577A1 WO 2022179577 A1 WO2022179577 A1 WO 2022179577A1 CN 2022077773 W CN2022077773 W CN 2022077773W WO 2022179577 A1 WO2022179577 A1 WO 2022179577A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- crystal form
- compound
- angles
- ray powder
- formula
- Prior art date
Links
- 239000013078 crystal Substances 0.000 title claims abstract description 66
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- -1 cyclopropyl-substituted benzofuran compound Chemical class 0.000 title abstract description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 84
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 40
- 238000001228 spectrum Methods 0.000 claims description 20
- 206010033645 Pancreatitis Diseases 0.000 claims description 16
- 239000003814 drug Substances 0.000 claims description 12
- 206010033647 Pancreatitis acute Diseases 0.000 claims description 11
- 201000003229 acute pancreatitis Diseases 0.000 claims description 11
- 238000001938 differential scanning calorimetry curve Methods 0.000 claims description 4
- 238000001757 thermogravimetry curve Methods 0.000 claims description 4
- 230000004580 weight loss Effects 0.000 claims description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 114
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 60
- 238000006243 chemical reaction Methods 0.000 description 41
- 239000000243 solution Substances 0.000 description 39
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 30
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 27
- 239000012043 crude product Substances 0.000 description 27
- 238000012360 testing method Methods 0.000 description 27
- 210000004027 cell Anatomy 0.000 description 21
- 239000012074 organic phase Substances 0.000 description 21
- 239000011575 calcium Substances 0.000 description 19
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 18
- 238000003756 stirring Methods 0.000 description 17
- 238000000034 method Methods 0.000 description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 239000012065 filter cake Substances 0.000 description 14
- 238000001514 detection method Methods 0.000 description 13
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 12
- 239000002994 raw material Substances 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 239000003153 chemical reaction reagent Substances 0.000 description 10
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-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
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- 239000007788 liquid Substances 0.000 description 9
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 9
- 239000000725 suspension Substances 0.000 description 9
- 102000013585 Bombesin Human genes 0.000 description 8
- 108010051479 Bombesin Proteins 0.000 description 8
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 8
- 239000008346 aqueous phase Substances 0.000 description 8
- DNDCVAGJPBKION-DOPDSADYSA-N bombesin Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(N)=O)NC(=O)CNC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CC=1NC2=CC=CC=C2C=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1NC(=O)CC1)C(C)C)C1=CN=CN1 DNDCVAGJPBKION-DOPDSADYSA-N 0.000 description 8
- 229940079593 drug Drugs 0.000 description 8
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 8
- 235000017557 sodium bicarbonate Nutrition 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- 241000699670 Mus sp. Species 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- 239000008367 deionised water Substances 0.000 description 7
- 229910021641 deionized water Inorganic materials 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 7
- 238000010438 heat treatment Methods 0.000 description 7
- 239000012071 phase Substances 0.000 description 7
- 239000013557 residual solvent Substances 0.000 description 7
- 239000004382 Amylase Substances 0.000 description 6
- 102000013142 Amylases Human genes 0.000 description 6
- 108010065511 Amylases Proteins 0.000 description 6
- 238000011740 C57BL/6 mouse Methods 0.000 description 6
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 102000004882 Lipase Human genes 0.000 description 6
- 108090001060 Lipase Proteins 0.000 description 6
- 239000004367 Lipase Substances 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 235000019418 amylase Nutrition 0.000 description 6
- 229910052791 calcium Inorganic materials 0.000 description 6
- 238000004113 cell culture Methods 0.000 description 6
- 238000011156 evaluation Methods 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 235000019421 lipase Nutrition 0.000 description 6
- 238000000926 separation method Methods 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 5
- 239000000872 buffer Substances 0.000 description 5
- 210000002472 endoplasmic reticulum Anatomy 0.000 description 5
- 239000001963 growth medium Substances 0.000 description 5
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 5
- 239000003208 petroleum Substances 0.000 description 5
- 238000005070 sampling Methods 0.000 description 5
- 210000002966 serum Anatomy 0.000 description 5
- 238000001179 sorption measurement Methods 0.000 description 5
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 102000020167 Calcium release-activated calcium channel Human genes 0.000 description 4
- 108091022898 Calcium release-activated calcium channel Proteins 0.000 description 4
- 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 4
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 239000012141 concentrate Substances 0.000 description 4
- 239000008103 glucose Substances 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 230000003834 intracellular effect Effects 0.000 description 4
- 239000007928 intraperitoneal injection Substances 0.000 description 4
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 239000011259 mixed solution Substances 0.000 description 4
- 239000001103 potassium chloride Substances 0.000 description 4
- 235000011164 potassium chloride Nutrition 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 239000006228 supernatant Substances 0.000 description 4
- OZFAFGSSMRRTDW-UHFFFAOYSA-N (2,4-dichlorophenyl) benzenesulfonate Chemical compound ClC1=CC(Cl)=CC=C1OS(=O)(=O)C1=CC=CC=C1 OZFAFGSSMRRTDW-UHFFFAOYSA-N 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 3
- 108091006146 Channels Proteins 0.000 description 3
- BQOHYSXSASDCEA-KEOHHSTQSA-N Cyclic ADP-Ribose Chemical compound C([C@@H]1[C@H]([C@H]([C@@H](O1)N1C=2N=CN3C(C=2N=C1)=N)O)O)OP(O)(=O)OP(O)(=O)OC[C@@H]1[C@@H](O)[C@@H](O)[C@H]3O1 BQOHYSXSASDCEA-KEOHHSTQSA-N 0.000 description 3
- 239000012591 Dulbecco’s Phosphate Buffered Saline Substances 0.000 description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 239000012267 brine Substances 0.000 description 3
- 201000001883 cholelithiasis Diseases 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000010253 intravenous injection Methods 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 239000012046 mixed solvent Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 230000017074 necrotic cell death Effects 0.000 description 3
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 3
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 3
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 230000005855 radiation Effects 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 238000010998 test method Methods 0.000 description 3
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 2
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 2
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 2
- 102000004859 Cholecystokinin Receptors Human genes 0.000 description 2
- 108090001085 Cholecystokinin Receptors Proteins 0.000 description 2
- 102000010911 Enzyme Precursors Human genes 0.000 description 2
- 108010062466 Enzyme Precursors Proteins 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Chemical compound IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 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
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 102000004142 Trypsin Human genes 0.000 description 2
- 108090000631 Trypsin Proteins 0.000 description 2
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- 230000010100 anticoagulation Effects 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 239000003613 bile acid Substances 0.000 description 2
- YNHIGQDRGKUECZ-UHFFFAOYSA-L bis(triphenylphosphine)palladium(ii) dichloride Chemical compound [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 description 2
- 229910001424 calcium ion Inorganic materials 0.000 description 2
- 239000006143 cell culture medium Substances 0.000 description 2
- 229940125797 compound 12 Drugs 0.000 description 2
- 102000038379 digestive enzymes Human genes 0.000 description 2
- 108091007734 digestive enzymes Proteins 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 208000001130 gallstones Diseases 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 230000004941 influx Effects 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 229910001629 magnesium chloride Inorganic materials 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- QOTXBMGJKFVZRD-HISDBWNOSA-O nicotinic acid-adenine dinucleotide phosphate Chemical compound [N+]1([C@@H]2O[C@@H]([C@H]([C@H]2O)O)COP(O)(=O)OP(O)(=O)OC[C@H]2O[C@H]([C@@H]([C@@H]2O)OP(O)(O)=O)N2C=3N=CN=C(C=3N=C2)N)=CC=CC(C(O)=O)=C1 QOTXBMGJKFVZRD-HISDBWNOSA-O 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 235000021590 normal diet Nutrition 0.000 description 2
- 238000001543 one-way ANOVA Methods 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
- 210000000496 pancreas Anatomy 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- DBABZHXKTCFAPX-UHFFFAOYSA-N probenecid Chemical compound CCCN(CCC)S(=O)(=O)C1=CC=C(C(O)=O)C=C1 DBABZHXKTCFAPX-UHFFFAOYSA-N 0.000 description 2
- 229960003081 probenecid Drugs 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- 238000010183 spectrum analysis Methods 0.000 description 2
- 238000013112 stability test Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000013517 stratification Methods 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- 239000012588 trypsin Substances 0.000 description 2
- 229910021642 ultra pure water Inorganic materials 0.000 description 2
- 239000012498 ultrapure water Substances 0.000 description 2
- 230000004584 weight gain Effects 0.000 description 2
- 235000019786 weight gain Nutrition 0.000 description 2
- BMQDAIUNAGXSKR-UHFFFAOYSA-N (3-hydroxy-2,3-dimethylbutan-2-yl)oxyboronic acid Chemical compound CC(C)(O)C(C)(C)OB(O)O BMQDAIUNAGXSKR-UHFFFAOYSA-N 0.000 description 1
- ZIIUUSVHCHPIQD-UHFFFAOYSA-N 2,4,6-trimethyl-N-[3-(trifluoromethyl)phenyl]benzenesulfonamide Chemical compound CC1=CC(C)=CC(C)=C1S(=O)(=O)NC1=CC=CC(C(F)(F)F)=C1 ZIIUUSVHCHPIQD-UHFFFAOYSA-N 0.000 description 1
- QRHUZEVERIHEPT-UHFFFAOYSA-N 2,6-difluorobenzoyl chloride Chemical compound FC1=CC=CC(F)=C1C(Cl)=O QRHUZEVERIHEPT-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 102000000074 ADP-ribosyl Cyclase Human genes 0.000 description 1
- 108010080394 ADP-ribosyl Cyclase Proteins 0.000 description 1
- 208000009663 Acute Necrotizing Pancreatitis Diseases 0.000 description 1
- 206010033646 Acute and chronic pancreatitis Diseases 0.000 description 1
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 1
- MNCFZWFXTUZLEI-UHFFFAOYSA-N CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.NC(N)COCCO Chemical compound CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.NC(N)COCCO MNCFZWFXTUZLEI-UHFFFAOYSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 102100025841 Cholecystokinin Human genes 0.000 description 1
- 101800001982 Cholecystokinin Proteins 0.000 description 1
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 1
- 101100114828 Drosophila melanogaster Orai gene Proteins 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 101001088892 Homo sapiens Lysine-specific demethylase 5A Proteins 0.000 description 1
- 108091008585 IP3 receptors Proteins 0.000 description 1
- 102100033246 Lysine-specific demethylase 5A Human genes 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 206010058096 Pancreatic necrosis Diseases 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 102000015439 Phospholipases Human genes 0.000 description 1
- 108010064785 Phospholipases Proteins 0.000 description 1
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 1
- 102000001424 Ryanodine receptors Human genes 0.000 description 1
- 102000004094 Stromal Interaction Molecule 1 Human genes 0.000 description 1
- 108090000532 Stromal Interaction Molecule 1 Proteins 0.000 description 1
- HATRDXDCPOXQJX-UHFFFAOYSA-N Thapsigargin Natural products CCCCCCCC(=O)OC1C(OC(O)C(=C/C)C)C(=C2C3OC(=O)C(C)(O)C3(O)C(CC(C)(OC(=O)C)C12)OC(=O)CCC)C HATRDXDCPOXQJX-UHFFFAOYSA-N 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- MMWCIQZXVOZEGG-HOZKJCLWSA-N [(1S,2R,3S,4S,5R,6S)-2,3,5-trihydroxy-4,6-diphosphonooxycyclohexyl] dihydrogen phosphate Chemical compound O[C@H]1[C@@H](O)[C@H](OP(O)(O)=O)[C@@H](OP(O)(O)=O)[C@H](O)[C@H]1OP(O)(O)=O MMWCIQZXVOZEGG-HOZKJCLWSA-N 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 1
- 229960004373 acetylcholine Drugs 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 229960005305 adenosine Drugs 0.000 description 1
- 238000005377 adsorption chromatography Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 210000000941 bile Anatomy 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 229940107137 cholecystokinin Drugs 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000013065 commercial product Substances 0.000 description 1
- 210000001953 common bile duct Anatomy 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000016396 cytokine production Effects 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 125000003963 dichloro group Chemical group Cl* 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 238000004455 differential thermal analysis Methods 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- KDQPSPMLNJTZAL-UHFFFAOYSA-L disodium hydrogenphosphate dihydrate Chemical compound O.O.[Na+].[Na+].OP([O-])([O-])=O KDQPSPMLNJTZAL-UHFFFAOYSA-L 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- LNJAJHJFSKUCIR-UHFFFAOYSA-N ditert-butyl chloromethyl phosphate Chemical compound CC(C)(C)OP(=O)(OCCl)OC(C)(C)C LNJAJHJFSKUCIR-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- NPTDXPDGUHAFKC-UHFFFAOYSA-N ethynylcyclopropane Chemical group C#CC1CC1 NPTDXPDGUHAFKC-UHFFFAOYSA-N 0.000 description 1
- 210000002907 exocrine cell Anatomy 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 description 1
- 239000011888 foil Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 230000037417 hyperactivation Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 210000004969 inflammatory cell Anatomy 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 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 description 1
- 238000010907 mechanical stirring Methods 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- 238000006384 oligomerization reaction Methods 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 210000000277 pancreatic duct Anatomy 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- JLFNLZLINWHATN-UHFFFAOYSA-N pentaethylene glycol Chemical compound OCCOCCOCCOCCOCCO JLFNLZLINWHATN-UHFFFAOYSA-N 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 238000007747 plating Methods 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 108091052345 ryanodine receptor (TC 1.A.3.1) family Proteins 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 1
- 238000004467 single crystal X-ray diffraction Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 239000012086 standard solution Substances 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 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
- IXFPJGBNCFXKPI-FSIHEZPISA-N thapsigargin Chemical compound CCCC(=O)O[C@H]1C[C@](C)(OC(C)=O)[C@H]2[C@H](OC(=O)CCCCCCC)[C@@H](OC(=O)C(\C)=C/C)C(C)=C2[C@@H]2OC(=O)[C@@](C)(O)[C@]21O IXFPJGBNCFXKPI-FSIHEZPISA-N 0.000 description 1
- 238000002411 thermogravimetry Methods 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
Images
Classifications
-
- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
-
- 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
- A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
Definitions
- the present invention relates to a crystal form of a cyclopropyl-substituted benzofuran compound and a preparation method thereof, in particular to the crystal form of the compound of formula (I) and a preparation method thereof.
- acetyl receptors AchR
- CCKR cholecystokinin receptors
- PLC phospholipase
- IP 3 inositol 1,4,5 triphosphate
- the receptor Under the action of cholecystokinin, the receptor combines with adenosine diphosphate ribose cyclase through an unknown pathway to generate nicotinic adenosine dinucleotide phosphate (NAADP) and cyclic adenosine diphosphate ribose (CADPR).
- NAADP nicotinic adenosine dinucleotide phosphate
- CADPR cyclic adenosine diphosphate ribose
- Depletion of the Ca 2+ pool causes the oligomerization of the Ca 2+ sensor STIM1 located on the endoplasmic reticulum and moves to the nearest endoplasmic reticulum-membrane junction, opening the channel Orail on the plasma membrane and allowing Ca 2+ influx, Causes intracellular Ca 2+ to be too high, zymogen is activated in advance, and induces the production of inflammatory factors in cells.
- Factors such as alcohol and stones can induce the release of Ca 2+ from the endoplasmic reticulum, and the reduction of the Ca 2+ stock in the endoplasmic reticulum stimulates the hyperactivation of the cellular CRAC channel (specifically, the Orai channel), resulting in a large amount of Ca 2+ Influx, the significant increase of calcium concentration in pancreatic acinar cells can cause zymogen granules to be activated to trypsin in advance, and trypsin can activate other pancreatic digestive enzymes and eventually lead to pancreatic self-digestion and necrosis.
- CRAC inhibitors can inhibit the production of Ca 2+ . internal flow to prevent necrosis of the pancreas.
- CRAC inhibitors can inhibit the release of Ca 2+ to prevent pancreatic necrosis.
- Pancreatitis due to cholelithiasis is caused by duct obstruction and the action of bile acids on pancreatic acinar cells.
- Gallstones allow bile to flow back into the pancreatic duct system, and once in pancreatic acinar cells, bile acids activate calcium into these cells via CRAC channels, causing acute episodes through unregulated activation of digestive enzymes, cytokine production, and infiltration of inflammatory cells into the pancreas.
- Pancreatitis and pancreatic exocrine cell necrosis are examples of the pancreatitis due to cholelithiasis.
- Alcohol use is the second most common cause of acute pancreatitis, but the association between alcohol and pancreatitis is not fully understood. Although alcohol use is often associated with acute and chronic pancreatitis, alcohol itself does not cause pancreatitis. Instead, it appears that metabolic byproducts of alcohol may be responsible for the disease in some patients.
- the researchers have shown that special ethanol metabolites, called fatty acid ethyl esters (FAEEs), induce a sustained release of intracellular calcium from calcium ions to activate CRAC channels, resulting in high intracellular calcium levels equivalent to gallstones and induce disease.
- FEEs fatty acid ethyl esters
- the present invention provides the A crystal form of the compound of formula (I),
- the X-ray powder diffraction pattern of the above-mentioned crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 8.892 ⁇ 0.200°, 12.617 ⁇ 0.200°, 16.793 ⁇ 0.200°, 17.583 ⁇ 0.200°, 18.959 ⁇ 0.200°, 22.113 ⁇ 0.200°, 25.029 ⁇ 0.200°, 26.512 ⁇ 0.200°.
- the X-ray powder diffraction pattern of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 8.892 ⁇ 0.200°, 11.883 ⁇ 0.200°, 12.617 ⁇ 0.200°, 13.206 ⁇ 0.200°, 16.793 ⁇ 0.200°, 17.583 ⁇ 0.200°, 18.018 ⁇ 0.200°, 18.959 ⁇ 0.200°, 22.113 ⁇ 0.200°, 25.029 ⁇ 0.200°, 25.858 ⁇ 0.200°, 26.512 ⁇ 0.200°.
- the X-ray powder diffraction pattern of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 4.474°, 8.892°, 9.571°, 10.288°, 10.533°, 11.076°, 11.883°, 12.617° degrees 23.747°, 24.107°, 25.029°, 25.414°, 25.858°, 26.512°, 28.797°, 30.039°, 31.672°, 32.596°, 35.275°.
- the X-ray powder diffraction pattern of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 3.616°, 4.474°, 8.892°, 9.571°, 10.288°, 10.533°, 11.076°, 11.883 degrees 23.031°, 23.747°, 24.107°, 25.029°, 25.414°, 25.858°, 26.512°, 28.797°, 30.039°, 31.672°, 32.596°, 35.275°.
- the XRPD pattern of the above-mentioned crystal form A is substantially as shown in FIG. 1 .
- the differential scanning calorimetry curve of the above-mentioned Form A has endothermic peaks at 138.4°C ⁇ 3°C and 163.4°C ⁇ 3°C.
- the DSC spectrum of the above-mentioned Form A is substantially as shown in FIG. 2 .
- thermogravimetric analysis curve of the above-mentioned crystal form A has a weight loss of 3.33% at 140.0°C ⁇ 3°C.
- the TGA spectrum of the above-mentioned Form A is substantially as shown in FIG. 3 .
- the present invention also provides the B crystal form of the compound of formula (I),
- the X-ray powder diffraction pattern of the above-mentioned crystal form B has characteristic diffraction peaks at the following 2 ⁇ angles: 4.389 ⁇ 0.200°, 8.797 ⁇ 0.200°, 11.786 ⁇ 0.200°, 17.578 ⁇ 0.200°, 21.997 ⁇ 0.200°.
- the X-ray powder diffraction pattern of the above-mentioned crystal form B has characteristic diffraction peaks at the following 2 ⁇ angles: 4.389 ⁇ 0.200°, 8.797 ⁇ 0.200°, 9.473 ⁇ 0.200°, 11.786 ⁇ 0.200°, 15.710 ⁇ 0.200°, 16.739 ⁇ 0.200°, 21.997 ⁇ 0.200°.
- the X-ray powder diffraction pattern of the above-mentioned crystal form B has characteristic diffraction peaks at the following 2 ⁇ angles: 4.389 ⁇ 0.200°, 8.797 ⁇ 0.200°, 13.168 ⁇ 0.200°, 16.739 ⁇ 0.200°, 17.578 ⁇ 0.200°, 18.811 ⁇ 0.200°, 21.997 ⁇ 0.200°, 26.443 ⁇ 0.200°.
- the X-ray powder diffraction pattern of the above-mentioned crystal form B has characteristic diffraction peaks at the following 2 ⁇ angles: 4.389 ⁇ 0.200°, 8.797 ⁇ 0.200°, 9.473 ⁇ 0.200°, 11.786 ⁇ 0.200°, 13.168 ⁇ 0.200°, 15.710 ⁇ 0.200°, 16.739 ⁇ 0.200°, 17.578 ⁇ 0.200°, 18.811 ⁇ 0.200°, 21.997 ⁇ 0.200°.
- the X-ray powder diffraction pattern of the above-mentioned crystal form B has characteristic diffraction peaks at the following 2 ⁇ angles: 4.389 ⁇ 0.200°, 8.797 ⁇ 0.200°, 11.786 ⁇ 0.200°, 13.168 ⁇ 0.200°, 16.739 ⁇ 0.200°, 17.578 ⁇ 0.200°, 18.811 ⁇ 0.200°, 20.617 ⁇ 0.200°, 21.997 ⁇ 0.200°, 24.970 ⁇ 0.200°, 25.804 ⁇ 0.200°, 26.443 ⁇ 0.200°.
- the X-ray powder diffraction pattern of the above-mentioned Form B has characteristic diffraction peaks at the following 2 ⁇ angles: 8.797 ⁇ 0.200°, 17.578 ⁇ 0.200°, 21.997 ⁇ 0.200°, and/or 4.389 ⁇ 0.200° , and/or 9.473 ⁇ 0.200°, and/or 10.172 ⁇ 0.200°, and/or 10.356 ⁇ 0.200°, and/or 10.953 ⁇ 0.200°, and/or 11.786 ⁇ 0.200°, and/or 12.569 ⁇ 0.200°, and /or 13.168 ⁇ 0.200°, and/or 13.454 ⁇ 0.200°, and/or 13.991 ⁇ 0.200°, and/or 14.828 ⁇ 0.200°, and/or 15.710 ⁇ 0.200°, and/or 16.231 ⁇ 0.200°, and/or 16.739 ⁇ 0.200°, and/or 17.949 ⁇ 0.200°, and/or 18.811 ⁇ 0.200°, and/or 19.577 ⁇ 0.200°
- the X-ray powder diffraction pattern of the above-mentioned crystal form B has characteristic diffraction peaks at the following 2 ⁇ angles: 4.389°, 8.797°, 9.473°, 10.172°, 10.356°, 11.786°, 12.569°, 13.168 degrees 28.731°, 30.033°, 30.962°.
- the XRPD pattern of the above-mentioned crystal form B is substantially as shown in FIG. 4 .
- the differential scanning calorimetry curve of the above-mentioned Form B has an onset of an endothermic peak at 165.7°C ⁇ 5°C.
- the DSC spectrum of the above-mentioned Form B is substantially as shown in FIG. 5 .
- thermogravimetric analysis curve of the above-mentioned crystal form B loses weight up to 1.14% at 150°C ⁇ 3°C.
- the TGA pattern of the above-mentioned Form B is substantially as shown in FIG. 6 .
- the present invention also provides the application of crystal form A or crystal form B in preparing a medicine for treating acute pancreatitis.
- the compound of the present invention has good PK properties and the effect of treating acute pancreatitis, and has stable crystal form, good hygroscopicity and little influence by light and heat.
- the intermediate compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by their combination with other chemical synthesis methods, and those skilled in the art.
- Well-known equivalents, preferred embodiments include, but are not limited to, the examples of the present invention.
- the peaks with heat flow less than 0 are endothermic peaks, and the peaks with heat flow greater than 0 are exothermic peaks.
- the structure of the compound of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention relates to the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, single crystal X-ray diffraction method (SXRD), the cultured single crystal is collected by Bruker D8 venture diffractometer, the light source is CuK ⁇ radiation, and the scanning mode is: After scanning and collecting relevant data, the crystal structure was further analyzed by the direct method (Shelxs97), and the absolute configuration could be confirmed.
- SXRD single crystal X-ray diffraction method
- the cultured single crystal is collected by Bruker D8 venture diffractometer
- the light source is CuK ⁇ radiation
- the scanning mode is: After scanning and collecting relevant data, the crystal structure was further analyzed by the direct method (Shelxs97), and the absolute configuration could be confirmed.
- the present invention will be specifically described below through examples, which do not imply any limitation to the present invention.
- Test method About 10 ⁇ 20mg samples are used for XRPD detection.
- Light tube voltage 30kV
- light tube current 40mA
- Step size 0.5 seconds
- Test method Take a sample ( ⁇ 1mg) and place it in a DSC aluminum pot for testing. Under the condition of 50mL/min N2 , at a heating rate of 10°C/min, heat the sample from 30°C (room temperature) to 300°C (or 350°C). °C).
- Thermogravimetric Analysis (Thermal Gravimetric Analyzer, TGA) method of the present invention
- Test method Take the sample (2 ⁇ 5mg) and put it in a TGA platinum pot for testing. Under the condition of 25mL/min N2 , at a heating rate of 10°C/min, heat the sample from room temperature to 350°C or lose 20% of weight.
- Test conditions Take a sample (10-15 mg) and place it in the DVS sample tray for testing.
- Hygroscopic classification ⁇ W% deliquescence Absorbs enough water to form a liquid Very hygroscopic ⁇ W% ⁇ 15% hygroscopic 15%> ⁇ W% ⁇ 2% slightly hygroscopic 2%> ⁇ W% ⁇ 0.2% No or almost no hygroscopicity ⁇ W% ⁇ 0.2%
- ⁇ W% represents the hygroscopic weight gain of the test product at 25 ⁇ 1°C and 80 ⁇ 2%RH.
- Fig. 1 is the Cu-K ⁇ radiation XRPD spectrum of compound A of formula (I);
- Fig. 2 is the DSC spectrogram of formula (I) compound A crystal form
- Fig. 3 is the TGA spectrum of formula (I) compound A crystal form
- Fig. 4 is the Cu-K ⁇ radiation XRPD spectrum of the crystal form of compound B of formula (I);
- Fig. 5 is the DSC spectrogram of formula (I) compound B crystal form
- Fig. 6 is the TGA spectrum of formula (I) compound B crystal form
- Fig. 7 is the DVS spectrum of formula (I) compound A crystal form
- Fig. 8 is the test result of the serum amylase (AMY) level of the compound of formula (I);
- Figure 9 is the test result of the serum lipase (LPS) level of the compound of formula (I).
- starting material 6-3 0.1 g, 368.27 ⁇ mol
- double pinacol borate 140.28 mg, 552.41 ⁇ mol
- anhydrous dioxane 2 mL
- potassium acetate 108.43 mg, 1.10 mmol
- [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane (30.07 mg, 36.83 ⁇ mol)
- step 1
- the raw material compound CC-6 (24.7 g, 58.01 mmol) and N,N-dimethylacetamide (250 mL) were added to the reaction solution, followed by di-tert-butyl chloromethyl phosphate (37.51 g, 145.02 mmol) in turn , cesium carbonate (47.25 g, 145.02 mmol) and potassium iodide (962.91 mg, 5.80 mmol), the reaction solution was stirred at 40° C. for 16 hours. 2000 mL of water and 300 mL of ethyl acetate were added to the reaction solution, and after stirring for 3 hours, the mixture was extracted with ethyl acetate (300 mL ⁇ 3).
- the raw material compound 22-1 (0.6 g, 1.03 mmol), acetone (10 mL) and deionized water (1 mL) were added to the reaction flask, then tris(249.58 mg, 2.06 mmol) was added, and the reaction solution was Stir at 25°C for 16 hours.
- the reaction solution is filtered, the filter cake is transferred to a flask, and the residual solvent is removed by vacuum concentration to obtain the compound of formula (I).
- step 1
- Trifluoroacetic acid (17.5 L) and dichloromethane (8.75 L) were added to the autoclave at 20°C, followed by Feed 1 (3.5 kg, 15.80 mol, 1 equiv). The temperature was lowered to 0-5°C, and N-iodosuccinimide (4.09kg, 18.17mol, 1.15 equiv.) was added to the kettle in batches. After the addition, the system was slowly heated to 20°C and reacted for 16 hours. Sampling and HPLC in-control detection after the reaction is completed, stand still, extract the supernatant, add 7L of ethanol and stir for 0.5 hour, the obtained suspension is filtered to obtain the crude product.
- the crude product was dissolved in 20L of ethyl acetate, the organic phase was washed with saturated aqueous sodium bicarbonate solution (10L*2) and saturated brine (6.5L*2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product.
- the crude product was dissolved in 60L n-heptane, passed through a silica gel adsorption column, and washed with n-heptane (20L*2). The filtrate was concentrated under reduced pressure to obtain compound 5.
- dichloromethane (8L) was added to the reactor, followed by adding raw material 7 (1.6kg, 5.60mol, 1 equiv), adding pyridine (1.11kg, 14.00mol, 2.5 equiv), cooling to 0-5°C , slowly dropwise add the solution of compound 8 (1.05kg, 5.94mol, 1.06 equiv) in dichloromethane (1.6L), slowly raise the temperature to 25°C after the dropwise addition, and react for 16 hours. 3.2L of water was added to the reaction solution, and the mixture was stirred for 2 hours. The suspension was filtered, and the filter cake was washed with water (6.4L*2) and ethanol (1.6L) to obtain the crude product.
- N,N-dimethylacetamide 13L was added to a 50L kettle (15°C), then compound 9 (1.3kg, 3.05mol, 1 equiv) was added to the N,N-dimethylacetamide solution , followed by adding compound 10 (1.97 kg, 7.63 mol, 2.5 equiv.), cesium carbonate (2.49 kg, 7.63 mol, 2.5 equiv.) and potassium iodide (50.68 g, 305.3 mmol, 0.1 equiv.), the reaction solution was a yellow suspension. After the addition was completed, the system was slowly heated to 50° C. and stirred for 40 hours. HPLC was performed to monitor raw material content ⁇ 5%.
- the mechanical stirring was turned off, and the reaction solution was pumped into a separation solution containing 50 L of water and ethyl acetate (16 L) and stirred for 3 hours. After stirring, the layers were left to stand, the aqueous phase was extracted with ethyl acetate (16 L), the organic phase was washed with 10 L of water and 10 L of brine, and the aqueous phase and brine were extracted with 5 L of ethyl acetate. After the layers were separated, the organic phase was Combined with the organic phase obtained above. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a reddish-brown viscous crude product.
- n-heptane 48 L was added slowly with stirring, followed by stirring for 3 hours, resulting in a yellow solution and a tarry reddish-brown solid sticking to the walls.
- the yellow solution was decanted, and further n-heptane (12 L) was added to the solution and stirring was continued for 16 hours to form a yellow suspension.
- the yellow suspension was suction filtered through a table filter, the solid was collected, and the residual solvent was removed in vacuo to obtain a yellow powdery crude product.
- the filtrate obtained by filtration was concentrated under reduced pressure to obtain a yellow viscous crude product.
- dichloromethane 1.2 L
- n-heptane 18 L was slowly added under stirring and stirred for 16 hours. There was a large piece of reddish-brown solid. Generated, the solvent was poured out, the reddish-brown block solid was slurried
- the heating was turned on, the temperature of the system was slowly raised to 46°C, and the mixture was stirred for 18 hours.
- 1 M citric acid (800 mL) was added dropwise to the reaction solution, and heating and stirring were continued for 24 hours after the dropwise addition. Sampling HPLC in the control detection reaction is completed.
- the weighed compound 12 (440 g, 0.858 mol, 1 equiv.) was dissolved in acetone (6.6 L) and added to a 50 L reaction kettle (15° C.). Then the weighed trimethylolaminomethane (207.99g, 1.72mol, 2 equivalents) was dissolved in 0.66L deionized water, the solution was added to the reactor at one time, the feeding was completed, the heating was turned on, and the system was slowly heated up to 25°C and stirred for 16 hours. 1 HNMR showed that the reaction was complete. The reaction solution was filtered, the filter cake was washed with acetone (1L*2), the filter cake was collected, and the residual solvent was removed in vacuo to obtain the compound of formula (I).
- the hygroscopic weight gain of the crystal form of compound A of the formula (I) at 25° C. and 80% RH is 1.308%, which is slightly hygroscopic.
- the whatman vial was placed in a shaker for 24 hours at room temperature, and the rotational speed was set at 600 r/min. Slowly press the stopper of the whatman vial to the bottom to obtain the supernatant. Check all compounds to make sure there is no precipitate in the supernatant to prevent rupture of the filter in the stopper.
- the cell culture plate was placed in an incubator at 37°C and 5% CO 2 to 80% density.
- induction buffer containing calcium ions (4mM CaCl 2 , 40 mM NaCl, 100 mM KCl, 17 mM NaHCO 3 , 12 mM glucose, 1 mM MgCl 2 , 5 mM Hepes), add 10 ⁇ L of induction buffer to the cell culture plate using FLIPR, and collect Calcium flow signal for 260 seconds.
- test compound IC50 (nM) Compound CC-6 136
- Compound CC-6 has a significant inhibitory effect on CRAC channels.
- OBJECTIVE To use male C57BL/6 mice as the test animals, the LC/MS/MS method was used to determine the plasma drug concentrations of the test compounds at different times after intravenous or intraperitoneal injection. To study the pharmacokinetic behavior of the test compound in mice, and to evaluate its pharmacokinetic characteristics.
- Drug preparation Weigh an appropriate amount of sample, and prepare a clear solution of 0.3 mg/mL or 0.5 mg/mL with 40% PEG400+20% Solutol+40% H 2 O (volume ratio).
- Dosing regimen 2 healthy male C57BL/6 mice were purchased from Beijing Weitong Lihua Laboratory Animal Co., Ltd., with normal diet.
- the intravenous injection group used 0.5 mg/mL liquid medicine, the administration volume was 2 mL/kg; the administration dose was 1 mg/kg.
- the intraperitoneal injection group used 0.3 mg/mL liquid medicine, the administration volume was 10 mL/kg; the administration dose was 3 mg/kg.
- OBJECTIVE To use male C57BL/6 mice as the test animals, the LC/MS/MS method was used to determine the plasma drug concentrations of the compounds at different times after intravenous injection. To study the pharmacokinetic behavior of compounds in mice and evaluate their pharmacokinetic characteristics.
- Drug preparation Weigh an appropriate amount of sample and prepare a 5 mg/mL clear solution with sterile normal saline.
- Dosing scheme 2 healthy male C57BL/6 mice were purchased from Beijing Weitong Lihua Laboratory Animal Co., Ltd., with normal diet, the administration volume was 10 mL/kg, and the administration dose was 50 mg/kg.
- NA means the data does not exist
- DNAUC means exposure normalized to molar dose
- OBJECTIVE To use male C57BL/6 mice as test animals, acute pancreatitis was induced by intraperitoneal injection of bombesin. The efficacy of compounds of formula (I) on acute pancreatitis was investigated.
- Drug preparation Weigh an appropriate amount of sample, and formula (I) compound is formulated into a 5 mg/mL clear solution with sterile physiological saline.
- mice Healthy male C57BL/6 mice were taken and injected with bombesin to induce pancreatitis model by intraperitoneal injection. One hour after the seventh injection of bombesin, serum was taken to measure the levels of amylase and lipase.
- the compound of formula (I) was administered by intravenous injection, and the experiment consisted of 4 groups (G1-G4).
- G1 is the healthy group
- G2 is the model group
- G3-4 is the treatment group.
- G1-3 was given the first dose of drug or vehicle 0.5h before the time point of the first injection of bombesin, and the second dose of drug or vehicle was given 0.5h after the fourth injection of bombesin.
- G4 was given the drug 0.5h before the first injection of bombesin, and the second dose was not given.
- G3 25 mg/kg, twice a day (bid);
- G3 50 mg/kg, once a day (qd).
- Plasma amylase levels by one-way ANOVA, *** represents a significant difference with G1 P ⁇ 0.001; ### represents a significant difference with G2 P ⁇ 0.001; ⁇ represents a significant difference with G3 There is a significant difference, p ⁇ 0.05.
- Plasma lipase levels by one-way analysis of variance, *** represents a significant difference with G1 P ⁇ 0.001; ### represents a significant difference with G2 P ⁇ 0.001; ⁇ represents a significant difference with G3 Significant difference, p ⁇ 0.001.
- the compound of formula (I) can significantly reduce the levels of serum amylase (AMY) and lipase (LPS), indicating that it can significantly improve the typical symptoms of acute pancreatitis. symptoms, showing excellent potential for the treatment of acute pancreatitis.
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
涉及一种环丙基取代的苯并呋喃类化合物的晶型及其制备方法,具体公开了式(I)化合物的晶型及其制备方法。
Description
本发明主张如下优先权:
CN202110214161.0,申请日:2021年02月25日。
本发明涉及一种环丙基取代的苯并呋喃类化合物的晶型及其制备方法,具体涉及式(I)化合物的晶型及其制备方法。
胰腺腺胆碱泡细胞,膜上存在乙酰受体(AchR)和胆囊收缩素受体(CCKR),2种受体都依赖Ca
2+通道。前者在乙酰胆碱作用下,激活磷脂酶(PLC)生成肌醇1,4,5三磷酸(IP
3)。后者在胆囊收缩素作用下,受体通过未知途径与二磷酸腺苷核糖环化酶结合生成烟酸腺苷二核苷磷酸(NAADP)及环二磷酸腺苷核糖(CADPR)。内质网上的IP
3及ryanodine受体,分别由IP
3和NAADP/CADPR激活,将储存的Ca
2+自内质网释放到胞质中。随着胞内Ca
2+排空。Ca
2+库耗竭引起位于内质网上Ca
2+感受器STIM1蛋白寡聚化,并向最近的内质网-细胞膜连接处移动,位于质膜上的通道Orail打开,并使Ca
2+内流,造成胞内Ca
2+过高,酶原提前活化,诱发细胞内的炎症因子产生。
酒精,结石等因素能诱导Ca
2+从内质网释放出来,而内质网Ca
2+存量的减少又刺激细胞CRAC通道(具体的应该是Orai通道)的超活化,导致大量的Ca
2+内流,胰腺腺泡细胞内钙浓度显著的升高能引起酶原颗粒提前激活为胰蛋白,胰蛋白又激活其他胰消化酶并最终导致胰腺自身消化及坏死,CRAC抑制剂能够抑制Ca
2+的内流从而防止胰腺的坏死。CRAC抑制剂能够抑制Ca
2+的释放从而防止胰腺的坏死。
在发达国家,结石和酒精使用阻塞胆总管是导致急性胰腺炎的最常见原因,占70-80%。胆石症引起的胰腺炎是由导管阻塞和胆汁酸对胰腺腺泡细胞的作用引起的。胆结石允许胆汁回流到胰管系统,并且一旦进入胰腺腺泡细胞,胆汁酸通过CRAC通道激活钙进入这些细胞,通过不受调节的消化酶活化,细胞因子产生和炎症细胞对胰腺的浸润引起急性胰腺炎和胰腺外分泌细胞坏死。酒精使用是急性胰腺炎的第二大常见原因,但酒精和胰腺炎之间的相关性尚不完全清楚。虽然酒精的使用通常与急性和慢性胰腺炎有关,但酒精本身并不会导致胰腺炎。相反,似乎酒精的代谢副产物可能是某些患者的疾病的原因。研究人员已经证明,特殊的乙醇代谢物称为脂肪酸乙酯(FAEEs),可诱导钙离子细胞内细胞内钙的持续释放,从而激活CRAC通道,由此产生的高细胞内钙水平与胆结石相同而诱发疾病。
发明内容
本发明提供了式(I)化合物的A晶型,
其特征在于其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:8.892±0.200°,17.583±0.200°,18.959±0.200°,22.113±0.200°,25.029±0.200°。
在本发明的一些方案中,上述A晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:8.892±0.200°,12.617±0.200°,16.793±0.200°,17.583±0.200°,18.959±0.200°,22.113±0.200°,25.029±0.200°,26.512±0.200°。
在本发明的一些方案中,上述A晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:8.892±0.200°,11.883±0.200°,12.617±0.200°,13.206±0.200°,16.793±0.200°,17.583±0.200°,18.018±0.200°,18.959±0.200°,22.113±0.200°,25.029±0.200°,25.858±0.200°,26.512±0.200°。
在本发明的一些方案中,上述A晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:4.474°,8.892°,9.571°,10.288°,10.533°,11.076°,11.883°,12.617°,13.206°,13.653°,14.886°,15.788°,16.301°,16.793°,17.583°,18.018°,18.959°,19.574°,19.981°,20.661°,20.964°,21.651°,22.113°,23.031°,23.747°,24.107°,25.029°,25.414°,25.858°,26.512°,28.797°,30.039°,31.672°,32.596°,35.275°。
在本发明的一些方案中,上述A晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:3.616°,4.474°,8.892°,9.571°,10.288°,10.533°,11.076°,11.883°,12.617°,13.206°,13.653°,14.886°,15.788°,16.301°,16.793°,17.583°,18.018°,18.959°,19.574°,19.981°,20.661°,20.964°,21.651°,22.113°,23.031°,23.747°,24.107°,25.029°,25.414°,25.858°,26.512°,28.797°,30.039°,31.672°,32.596°,35.275°。
在本发明的一些方案中,上述A晶型,其XRPD图谱基本上如图1所示。
在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在138.4℃±3℃和163.4℃±3℃处具有吸热峰的峰值。
在本发明的一些方案中,上述A晶型的DSC图谱基本上如图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在140.0℃±3℃时失重达3.33%。
在本发明的一些方案中,上述A晶型的TGA图谱基本上如图3所示。
本发明还提供式(I)化合物的B晶型,
其特征在于其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:8.797±0.200°,17.578±0.200°,18.811±0.200°,21.997±0.200°。
在本发明的一些方案中,上述B晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:4.389±0.200°,8.797±0.200°,11.786±0.200°,17.578±0.200°,21.997±0.200°。
在本发明的一些方案中,上述B晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:4.389±0.200°,8.797±0.200°,9.473±0.200°,11.786±0.200°,15.710±0.200°,16.739±0.200°,21.997±0.200°。
在本发明的一些方案中,上述B晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:4.389±0.200°,8.797±0.200°,13.168±0.200°,16.739±0.200°,17.578±0.200°,18.811±0.200°,21.997±0.200°,26.443±0.200°。
在本发明的一些方案中,上述B晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:4.389±0.200°,8.797±0.200°,9.473±0.200°,11.786±0.200°,13.168±0.200°,15.710±0.200°,16.739±0.200°,17.578±0.200°,18.811±0.200°,21.997±0.200°。
在本发明的一些方案中,上述B晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:4.389±0.200°,8.797±0.200°,11.786±0.200°,13.168±0.200°,16.739±0.200°,17.578±0.200°,18.811±0.200°,20.617±0.200°,21.997±0.200°,24.970±0.200°,25.804±0.200°,26.443±0.200°。
在本发明的一些方案中,上述B晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:8.797±0.200°,17.578±0.200°,21.997±0.200°,和/或4.389±0.200°,和/或9.473±0.200°,和/或10.172±0.200°,和/或10.356±0.200°,和/或10.953±0.200°,和/或11.786±0.200°,和/或12.569±0.200°,和/或13.168±0.200°,和/或13.454±0.200°,和/或13.991±0.200°,和/或14.828±0.200°,和/或15.710±0.200°,和/或16.231±0.200°,和/或16.739±0.200°,和/或17.949±0.200°,和/或18.811±0.200°,和/或19.577±0.200°,和/或19.875±0.200°,和/或20.617±0.200°,和/或20.849±0.200°,和/或22.875±0.200°,和/或23.704±0.200°,和/或24.165±0.200°,和/或24.970±0.200°,和/或25.449±0.200°,和/或25.804±0.200°,和/或26.443±0.200°,和/或26.942±0.200°,和/或27.841±0.200°,和/或28.731±0.200°,和/或29.022±0.200°,和/或29.525±0.200°,和/或30.033±0.200°, 和/或30.962±0.200°,和/或31.747±0.200°,和/或32.609±0.200°,和/或33.12±0.200°,和/或33.979±0.200°,和/或34.568±0.200°,和/或35.104±0.200°,和/或35.421±0.200°,和/或36.374±0.200°,和/或37.075±0.200°,和/或38.979±0.200°。
在本发明的一些方案中,上述B晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:4.389°,8.797°,9.473°,10.172°,10.356°,11.786°,12.569°,13.168°,13.991°,15.710°,16.739°,17.578°,17.949°,18.811°,19.577°,19.875°,20.617°,20.849°,21.997°,24.970°,25.804°,26.443°,26.942°,27.841°,28.731°,30.033°,30.962°。
在本发明的一些方案中,上述B晶型,其XRPD图谱基本上如图4所示。
在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165.7℃±5℃处具有吸热峰的起始值。
在本发明的一些方案中,上述B晶型的DSC图谱基本上如图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150℃±3℃时失重达1.14%。
在本发明的一些方案中,上述B晶型的TGA图谱基本上如图6所示。
本发明还提供A晶型或B晶型在制备治疗急性胰腺炎药物中的应用。
技术效果
本发明化合物具有较好的PK性质及治疗急性胰腺炎的作用,其晶型稳定、引湿性良好、受光热影响小。
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。
本发明的DSC图谱,热流小于0的峰为吸热峰,热流大于0的峰为放热峰。
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。
本发明的化合物可以通过本领域技术人员所熟知的常规方法来确认结构,如果本发明涉及化合物的绝对构型,则该绝对构型可以通过本领域常规技术手段予以确证。例如单晶X射线衍射法(SXRD),把培养出的单晶用Bruker D8 venture衍射仪收集衍射强度数据,光源为CuKα辐射,扫描方式:
扫描,收集相关数据后,进一步采用直接法(Shelxs97)解析晶体结构,便可以确证绝对构型。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。
本发明粉末X-射线衍射(X-ray powder diffractometer,XRPD)方法
仪器型号:布鲁克D2PHASER 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:30kV,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:3-40deg
步径:0.02deg
步长:0.5秒
样品盘转速:15rpm
本发明差热分析(Differential Scanning Calorimeter,DSC)方法
仪器型号:TA Q2000差示扫描量热仪
测试方法:取样品(~1mg)置于DSC铝锅内进行测试,在50mL/min N
2条件下,以10℃/min的升温速率,加热样品从30℃(室温)到300℃(或350℃)。
本发明热重分析(Thermal Gravimetric Analyzer,TGA)方法
仪器型号:TA Q5000IR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%。
本发明动态蒸汽吸附分析(Dynamic Vapor Sorption,DVS)方法
仪器型号:SMS DVS Advantage动态蒸汽吸附仪
测试条件:取样品(10~15mg)置于DVS样品盘内进行测试。
详细的DVS参数如下:
温度:25℃
平衡:dm/dt=0.01%/min(最短:10min,最长:180min)
干燥:0%RH下干燥120min
RH(%)测试梯级:10%
RH(%)测试梯级范围:0%-90%-0%
引湿性评价分类如表3所示:
表3.引湿性评价分类
吸湿性分类 | ΔW% |
潮解 | 吸收足量水分形成液体 |
极具吸湿性 | ΔW%≥15% |
有吸湿性 | 15%>ΔW%≥2% |
略有吸湿性 | 2%>ΔW%≥0.2% |
无或几乎无吸湿性 | ΔW%<0.2% |
注:ΔW%表示受试品在25±1℃和80±2%RH下的吸湿增重。
图1为式(I)化合物A晶型的Cu-Kα辐射XRPD谱图;
图2为式(I)化合物A晶型的DSC谱图;
图3为式(I)化合物A晶型的TGA谱图;
图4为式(I)化合物B晶型的Cu-Kα辐射XRPD谱图;
图5为式(I)化合物B晶型的DSC谱图;
图6为式(I)化合物B晶型的TGA谱图;
图7为式(I)化合物A晶型的DVS谱图;
图8为式(I)化合物的血清淀粉酶(AMY)水平的测试结果;
图9为式(I)化合物的血清脂肪酶(LPS)水平的测试结果。
下面通过实施例对本发明进行详细描述,但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明,其中也公开了其具体实施例方式,对本领域的技术人员而言,在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。
实施例1:化合物CC-6的制备
步骤1:化合物BB-3-2的合成
在预先干燥过单口瓶中加入原料BB-3-1(2g,11.49mmol)和无水二氯甲烷(50mL),随后加入三乙胺(3.49g,34.48mmol,4.80mL),N,N-二甲氨基吡啶(140.43mg,1.15mmol),2,6-二氟苯甲酰氯(4.46g,25.29mmol,3.19mL),在40℃下反应3小时,直接减压浓缩得到粗品,通过快速柱层析(石油醚:乙酸乙酯=10:1-5:1)纯化得到BB-3-2。MS(ESI)m/z:453.9[M+H]
+。
步骤2:化合物BB-3的合成
在预先干燥过的烧瓶中加入原料BB-3-2(5g,11.01mmol)和溶剂四氢呋喃(60mL),甲醇(60mL),随后加入氢氧化钠水溶液(2M,24.56mL),在25℃下,搅拌1小时,向体系中加入50mL水,乙酸乙酯萃取(150mL×3),合并有机相,20mL饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压浓缩得到粗品,通过硅胶柱层析(石油醚:乙酸乙酯=3:1-2:1)纯化得到BB-3。MS(ESI)m/z:314[M+H]
+。
1H NMR(400MHz,CDCl
3)δppm 9.50(s,1H),8.53(br s,1H),8.34(d,J=1.60Hz,1H),7.52(tt,J=8.40,6.00Hz,1H),7.07(t,J=8.00Hz,2H).
步骤3:化合物6-1的合成
在预先干燥过的烧瓶中加入原料3-2(0.1g,422.84μmol)和溶剂乙腈(2mL),随后加入试剂对甲苯磺酸(218.44mg,1.27mmol),亚硝酸钠(58.35mg,845.69μmol),碘化钾(175.48mg,1.06mmol),在25℃下,搅拌0.5小时,向体系中加入10mL饱和碳酸氢钠水溶液,乙酸乙酯萃取(30mL*3),合并有机相,5mL饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压浓缩得到粗品,通过硅胶柱层析(石油醚)纯化得到6-1。
1H NMR(400MHz,CDCl
3)δppm 7.75(s,1H),6.94(s,1H),3.66-3.85(m,3H)。
步骤4:化合物6-2的合成
在预先干燥过的烧瓶中加入原料6-1(0.07g,201.51μmol)和溶剂二异丙胺(2mL),随后加入试剂二氯(双三苯基膦)钯(7.07mg,10.08μmol),碘化亚铜(3.84mg,20.15μmol),三苯基膦(5.29mg,20.15μmol),在25℃下,搅拌0.5小时,随后加入环丙基乙炔(13.32mg,201.51μmol,16.71μL),在70℃下,搅拌12小时,向体系中加入5mL水,乙酸乙酯萃取(20mL*3),合并有机相,5mL饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压浓缩得到粗品,通过硅胶柱层析(石油醚)纯化得到6-2。
1H NMR(400MHz,CDCl
3)δppm 7.32(s,1H),6.99(s,1H),3.78(s,3H),1.35-1.51(m,1H),0.80-0.86(m,2H),0.73-0.79(m,2H)。
步骤5:化合物6-3的合成
在预先干燥过的微波管中加入原料6-2(0.05g,175.09μmol)和无水乙醇(3mL),随后加入试剂对甲苯磺酸一水合物(33.31mg,175.09μmol),在125℃下,微波反应1小时,直接减压浓缩,通过硅胶柱层析(石油醚)纯化得到6-3。
1H NMR(400MHz,CDCl
3)δppm 7.54(s,1H),7.43(s,1H),6.20(s,1H),1.84-2.01(m,1H),0.92-0.98(m,2H),0.85-0.92(m,2H)。
步骤6:化合物6-4的合成
在预先干燥过的烧瓶中加入原料6-3(0.1g,368.27μmol),双联频哪醇硼酸酯(140.28mg,552.41μmol)和无水二氧六环(2mL),随后加入乙酸钾(108.43mg,1.10mmol),[1,1-双(二苯基膦)二茂铁]二氯化钯二氯甲烷(30.07mg,36.83μmol),在100℃下,搅拌12小时,向体系中加入5mL水,乙酸乙酯萃取(20mL*3),合并有机相,5mL饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压浓缩得到6-4。MS(ESI)m/z:319[M+H]
+。
步骤7:化合物CC-6的合成
在预先干燥过的烧瓶中加入原料6-4(0.1g,313.87μmol),BB-3(65.72mg,209.25μmol)和溶剂二氧六环(2mL)/乙腈(1mL)/水(0.5mL),随后加入试剂碳酸钾(57.84mg,418.49μmol),[1,1-双(二苯基膦)二茂铁]二氯化钯二氯甲烷(17.09mg,20.92μmol),在100℃下,搅拌2小时,向体系中加入5mL水,乙酸乙酯萃取(30mL*3),合并有机相,5mL饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压浓缩得到粗品,通过制备HPLC(柱子:Phenomenex Gemini-NX C18 75*30mm*3μm;流动相:[水(10mM NH
4HCO
3)-ACN];ACN%:50%-80%,10.5min)纯化得到CC-6。
1H NMR(400MHz,CDCl
3)δppm 9.79(s,1H),8.71(d,J=1.60Hz,1H),8.44(br s,1H),7.67(s,1H),7.58(s,1H),7.44-7.56(m,1H),7.08(t,J=8.00Hz,2H),6.38(s,1H),2.01-2.14(m,1H),0.95-1.13(m,4H)。FNMR(400MHz,CDCl
3)δppm-110.929。
实施例2:式(I)化合物的制备
合成路线:
步骤1:
向反应液中加入原料化合物CC-6(24.7g,58.01mmol)和N,N-二甲基乙酰胺(250mL),然后依次加入二叔丁基氯甲基磷酸酯(37.51g,145.02mmol),碳酸铯(47.25g,145.02mmol)和碘化钾(962.91mg,5.80mmol),反应液在40℃搅拌16小时。向反应液中加入2000mL水和300mL乙酸乙酯,搅拌3小时后,乙酸乙酯(300mL×3)萃取,合并有机相并用无水硫酸钠干燥,减压浓缩得到粗产品。粗产品用二氯甲烷和正庚烷(二氯甲烷:正庚烷=1:6,600mL)重结晶,减压浓缩得到粗产品,再用乙酸乙酯和正庚烷(乙酸乙酯:正庚烷=1:5,100mL)打浆,过滤,滤饼用乙酸乙酯和正庚烷(乙酸乙酯:正庚烷=1:5)洗涤,收集滤饼真空除去残留溶剂得到化合物18-2。MS(ESI)m/z:438[M-209]
+。
步骤2:
向反应瓶中加入化合物18-2(2.0g,3.09mmol)和乙腈(10mL),然后加入磷酸氢二钠和柠檬酸的缓冲溶液(pH=3,10mL),反应液在50℃搅拌16小时。反应液降温后过滤,然后加入400mL乙酸乙酯和400mL去离子水,静置分层,有机相加去离子水洗涤(100mL×3),直到pH在7左右。向有机相中加入饱和碳酸氢钠水溶液(200mL),静置分层后,水相用乙酸乙酯萃取(100mL×3),有机相丢弃。向碳酸氢钠水相中 加入200mL乙酸乙酯,然后缓慢加入1M硫酸氢钾中和到pH=4,静置分液后,水相用乙酸乙酯萃取(200mL×3),合并有机相并用无水硫酸钠干燥,过滤后减压浓缩得到化合物22-1。MS(ESI)m/z:438[M-97]
+。
1H NMR(400MHz,CDCl
3)δ8.64-8.91(m,2H),7.51-7.61(m,1H),7.45(s,1H),7.28-7.3(m,1H),6.82(br s,3H),6.29(s,1H),5.84(br s,2H),1.96-2.04(m,1H),0.94-1.06(m,4H)。
步骤3:
向反应瓶中加入原料化合物22-1(0.6g,1.03mmol)、丙酮(10mL)和去离子水(1mL),然后加入三羟甲基胺基甲烷(249.58mg,2.06mmol),反应液在25℃搅拌16小时。反应液过滤,滤饼转移到烧瓶中,真空浓缩除去残留溶剂得到式(I)化合物。
1H NMR(400MHz,D
2O)δ8.75(br s,1H),8.44(br s,1H),7.19-7.36(m,2H),7.13(br s,1H),6.82(br s,2H),6.07(s,1H),5.65(br s,2H),3.65(s,12H),1.87(br d,J=4.4Hz,1H),0.88(br d,J=7.2Hz,2H),0.74(br d,J=3.2Hz,2H)。MS(ESI)m/z:438[M+H-340]
+,536[M M+H-242]
+。
实施例3:式(I)化合物的制备
步骤1:
20℃下,向反应釜中加入三氟乙酸(17.5L)和二氯甲烷(8.75L),随后加入原料1(3.5kg,15.80mol,1 当量)。降温至0-5℃,向釜中分批次加入N-碘琥珀酰亚胺(4.09kg,18.17mol,1.15当量),加料完毕使体系缓慢升温至20℃,反应16小时。取样HPLC中控检测反应完成后,静置,将上清液抽出,加入7L乙醇搅拌0.5小时,得到的悬浮液过滤得到粗品。粗产品用14L乙醇打浆搅拌16小时,得到的悬浮液过滤,得到化合物2。
1HNMR(400MHz,DMSO-d
6)7.98(s,1H),7.34(s,1H),3.85(s,3H)。
步骤2:
20℃下,向反应釜中加入2-甲基四氢呋喃(25L),随后加入原料2(2.5kg,7.2mol,1当量)、化合物3(618.43g,9.36mol,1.3当量)、三乙胺(2.18kg,21.59mol,3当量)和碘化亚铜(68.53g,359.84mmol,0.05当量),调节氮气流,加入二氯双(三苯基膦)钯(II)(101.03g,143.94mmol,0.02当量),反应在25℃下反应16小时。取样HPLC中控检测反应完成后,将反应液经硅藻土过滤,滤饼用6.5L乙酸乙酯洗涤,得到有机相分别用13L 1N硫酸氢钾溶液和13L饱和碳酸氢钠溶液洗涤,13L饱和食盐水洗涤,无水硫酸钠干燥,减压浓缩得到粗品。粗品用15L正庚烷:乙酸乙酯=20:1的混合溶剂打浆,搅拌1小时后过滤,滤液减压浓缩得到化合物4。
1HNMR(400MHz,DMSO-d
6)7.50(s,1H),7.38(s,1H),3.82(s,3H),1.49-1.60(m,1H),0.86-0.94(m,2H),0.69-0.76(m,2H)。该步骤,同样的试验过程,共开展了6批。
步骤3:
20℃下,向反应釜中加入乙醇(25L),随后加入原料4(2.5kg,8.75mol,1当量)。向反应釜中加入浓硫酸(858.65g,8.75mol,1当量),加料完毕使体系缓慢升温至内温80℃,反应16小时。取样HPLC中控检测反应完成后,将反应液减压浓缩得到粗品。粗品用20L乙酸乙酯溶解,有机相用饱和碳酸氢钠水溶液(10L*2)和饱和食盐水(6.5L*2)洗涤,无水硫酸钠干燥,过滤,减压浓缩得到粗品。将粗品用60L正庚烷溶解,过硅胶吸附柱,用正庚烷(20L*2)洗涤。滤液减压浓缩得到化合物5。
1HNMR(400MHz,DMSO-d
6)7.96(s,1H),7.76(s,1H),6.59(s,1H),2.08-2.18(m,1H),1.00-1.07(m,2H),0.87-0.94(m,2H)。
步骤4:
20℃下,向反应釜中加入乙醇(30L)和水(3L),随后向反应釜中加入原料5(1.5kg,5.52mol,1当量)、化合物6(2.04kg,8.29mol,1.5当量)和磷酸钾(2.93kg,13.81mol,2.5当量),调节氮气流,加入[1,1-双(二叔丁基膦)二茂铁]二氯化钯(II)(180.02g,276.21mmol,0.05当量),加料完毕使体系缓慢升温至内温80℃,反应16小时。取样HPLC中控检测反应完成后,向反应液中加入6L水,减压浓缩至干。加入45L正庚烷:乙酸乙酯=1:1的混合溶剂,体系成悬浊液,搅拌1小时后过吸附层析柱,滤饼用12L正庚烷:乙酸乙酯=1:1的混合溶剂搅拌0.5小时,再次过滤,重复两次,收集滤液。合并的滤液用水(10L*5)洗涤,再用饱和食盐水(10L*2)洗涤,有机相用无水硫酸钠干燥,减压浓缩得到粗品。粗品用7.5L正庚烷:乙酸乙酯=10:1混合溶剂打浆16小时,过滤,滤饼减压浓缩得到化合物7。
1HNMR(400MHz,DMSO- d
6)8.17(s,1H),7.96(s,1H),7.64(s,1H),7.59(s,1H),6.60(d,J=4.4Hz,3H),2.10-2.20(m,1H),1.00-1.07(m,2H),0.88-0.95(m,2H)。该步骤,同样的试验过程,共开展了5批。
步骤5:
20℃下,向反应釜中加入二氯甲烷(8L),随后加入原料7(1.6kg,5.60mol,1当量),加入吡啶(1.11kg,14.00mol,2.5当量),降温至0-5℃,缓慢滴加化合物8(1.05kg,5.94mol,1.06当量)的二氯甲烷(1.6L)溶液,滴加完毕后缓慢升至25℃,反应16小时。取样HPLC中控检测反应完成后,向反应液中加入3.2L水,搅拌2小时。悬浮液过滤,滤饼分别用水(6.4L*2)和乙醇(1.6L)洗涤得到粗品。将粗品加入6L甲基叔丁基醚和2L乙醇打浆,室温下搅拌16小时,过滤,滤饼减压浓缩得到化合物9。
1HNMR(400MHz,DMSO-d
6)11.81(s,1H),9.50(s,1H),8.74(s,1H),7.76(s,1H),7.75(s,1H),7.58-7.67(m,1H),7.27(m,2H),6.67(s,1H),2.13-2.23(m,1H),1.03-1.10(m,2H),0.93-0.98(m,2H)。
步骤6:
将N,N-二甲基乙酰胺(13L)加入到50L釜中(15℃),然后将化合物9(1.3kg,3.05mol,1当量)加入到N,N-二甲基乙酰胺溶液中,随后依次加入化合物10(1.97kg,7.63mol,2.5当量),碳酸铯(2.49kg,7.63mol,2.5当量)和碘化钾(50.68g,305.3mmol,0.1当量),反应液呈黄色悬浊液。加料完毕,体系缓慢升温至50℃,搅拌40小时。进行HPLC监测原料含量<5%。关闭机械搅拌,将反应液抽入装有50L水和乙酸乙酯(16L)的分液中搅拌3小时。搅拌后静置分层,水相用乙酸乙酯萃取(16L),有机相再依次用用10L水和10L食盐水洗涤,再用5L乙酸乙酯萃取水相和食盐水,分层后该有机相与上述所得有机相合并。将合并的有机相用无水硫酸钠干燥后,过滤后,滤液减压浓缩得到红棕色粘稠状粗产品。将粗产品用二氯甲烷(6L)完全溶解后,在搅拌下缓慢加入正庚烷(48L),然后搅拌3小时,形成黄色溶液和粘到壁上的焦油状红棕色固体。将黄色溶液倒出,向该溶液中再加入正庚烷(12L)继续搅拌16小时,形成黄色悬浊液。黄色悬浊液经桌面过滤器抽滤,收集固体,真空除去残留溶剂,得到黄色粉末状粗产品。过滤所得滤液减压浓缩得到黄色粘稠状粗产品,该粗产品再用二氯甲烷(1.2L)溶解后,在搅拌下缓慢加入正庚烷(18L)搅拌16小时,有一大块红棕色固体生成,倒出溶剂,将红棕色块状固体用乙酸乙酯和正庚烷混合溶液(乙酸乙酯:正庚烷=1:1,400mL)打浆,搅拌1小时后过滤,滤饼用乙酸乙酯和正庚烷混合溶液(1:4,200mL*3)洗涤,收集固体,真空除去残留溶剂,得到黄色粉末状粗产品。将两次得到的黄色粉末状产品合并,然后加入乙酸乙酯与正庚烷的混合溶液(乙酸乙酯:正庚烷=1:4,2L)打浆16小时,得到黄色悬浊液。黄色悬浊液经过滤器抽滤,收集固体,真空除去残留溶剂,得到化合物11。
1HNMR(400MHz,CDCl
3)δ8.33-8.90(m,2H),7.46-7.65(m,2H),7.33(br s,1H),6.87(br s,2H),6.34(s,1H),5.89(br d,J=4.8Hz,2H),1.96-2.10(m,1H),1.29-1.61(m,18H),0.97-1.07(m,4H).LCMS(ESI):m/z:438[M-209]
+。
步骤7:
将乙腈(8.5L)加入到50L釜(15℃),然后将化合物11(850g,1.314mol)加入到乙腈溶液中,随后加入由二水合磷酸氢二钠(62.3g,0.35mol,1.75L去离子水)和柠檬酸(141.85g,0.675mol,6.75L去离子水)配成pH=3的缓冲溶液。开启加热,体系缓慢升温至46℃,搅拌18小时。向反应液中滴加1M的柠檬酸(800mL),滴加完毕继续加热搅拌24小时。取样HPLC中控检测反应完成。反应液降温后,将反应液加到分液中。向分液中加入(40L)乙酸乙酯和(30L)水,静置分层后分液放出水相,有机相再加水洗涤(10L*3),合并水相并用10L乙酸乙酯洗涤,合并有机相,向有机相中加入用去离子水配成的饱和碳酸氢钠溶液(10L),搅拌1小时后静置分层,静置不分层时,加入10L去离子水后分层,有机相用30L水洗涤,水相合并到碳酸氢钠水相中,碳酸氢钠水相用乙酸乙酯萃取(10L),保留碳酸氢钠水相。向碳酸氢钠水相中加入20L乙酸乙酯,然后在搅拌下缓慢加入用去离子水配成的1M硫酸氢钾(14L)中和到pH=4,此过程无升温现象,搅拌0.5小时后静置分层,分液后水相用乙酸乙酯萃取(20L x 3),合并有机相并用无水硫酸钠干燥,过滤后滤液减压浓缩,得到粗产品化合物12。
1HNMR(400MHz,CDCl
3)δ1H NMR(400MHz,DMSO-d
6)δ8.51-9.03(m,2H),7.62-7.78(m,2H),7.51(br d,J=18.8Hz,1H),7.12(br s,2H),6.65(s,1H),5.73(br d,J=4.8Hz,2H),2.11-2.23(m,1H),1.01-1.10(m,2H),0.89-0.96(m,2H).LCMS(ESI):m/z:438[M-97]+。
步骤8:
用丙酮(6.6L)将称取的化合物12(440g,0.858mol,1当量)溶解后加入到50L反应釜中(15℃)。然后将称取的三羟甲基胺基甲烷(207.99g,1.72mol,2当量)溶解到0.66L去离子水中,将该溶液一次性加入到反应釜中,加料完毕,开启加热,体系缓慢升温至25℃,搅拌16小时。
1HNMR显示反应完成。将反应液过滤,滤饼用丙酮洗涤(1L*2),收集滤饼,真空除去残留溶剂得到式(I)化合物。
1HNMR(400MHz,DMSO-d
6)δ8.87(br s,1H),8.59(br s,1H),7.70(s,2H),7.40-7.56(m,1H),7.09(br s,2H),6.64(s,1H),5.56(br d,J=4.4Hz,2H),5.3(br s,12H),3.31(s,12H),2.12-2.22(m,1H),1.02-1.09(m,2H),0.91-0.98(m,2H).LCMS(ESI):m/z:438[M-339]
+。
实施例4:式(I)化合物A晶型的制备
在25℃向反应瓶中加入式(I)化合物(35.6g,45.01mmol,98.37%纯度,1当量)和乙酸乙酯和甲醇(乙酸乙酯:甲醇=3:1,712mL),反应液在60℃搅拌16小时。XRPD检测显示反应完成。反应液过滤,收集滤饼减压浓缩干燥。得到A晶型,其XRPD谱图如图1所示、DSC谱图如图2所示、TGA谱图如图3所示。
1H NMR(400MHz,DMSO-d
6)δ8.87(br s,1H),8.59(br s,1H),7.70(s,2H),7.47-7.50(m,1H),7.10(d,J=7.2Hz,2H),6.64(s,1H),5.51(d,J=4.8Hz,2H),3.85(br s,12H),3.32(s,12H),2.13-2.19(m,1H),1.04-1.07(m,2H),0.93-0.95(m,2H).LCMS(ESI):m/z:438[M-339]
+。
实施例5:式(I)化合物B晶型的制备
向干燥洁净的50L釜中(15℃)加入由2-甲基四氢呋喃(11.7L)和甲醇(3.9L)配成的混合溶(2-甲 基四氢呋喃:甲醇=3:1,15.6L),开启搅拌,将称取的式(I)化合物(520g,0.668mol,1当量)加入到反应釜中,加料完毕,开启加热,体系缓慢升温至60℃,搅拌16小时。XRPD检测显示反应完成。将反应液过滤,滤饼依次用2-甲基四氢呋喃(2L*2)和甲基叔丁基醚(2L*2)洗涤,收集滤饼,真空除去残留溶剂得到B晶型,其XRPD谱图如图4所示、DSC谱图如图5所示、TGA谱图如图6所示。
1H NMR(400MHz,DMSO-d
6)δ8.87(br s,1H),8.59(br s,1H),7.70(d,J=3.2Hz,2H),7.47-7.50(m,1H),7.09(s,2H),6.64(s,1H),5.57(s,2H),5.46(br s,12H)3.34(s,12H),2.13-2.18(m,1H),1.03-1.06(m,2H),0.93-0.94(m,2H).LCMS(ESI):m/z:438[M-339]
+。
实施例6:式(I)化合物A晶型的吸湿性研究
实验材料:
SMS DVS Advantage动态蒸汽吸附仪
实验方法:
取式(I)化合物A晶型10~15mg置于DVS样品盘内进行测试。
实验结果:
式(I)化合物A晶型的DVS谱图如图7所示,△W=1.308%。
实验结论:
式(I)化合物A晶型在25℃和80%RH下的吸湿增重为1.308%,略有吸湿性。
实施例7:式(I)化合物热力学溶解度测试
称取2mg左右的待测化合物至whatman小瓶中,加入缓冲液450μL磷酸缓冲液(50mM,pH=7.4)。将whatman的瓶塞压至液面附近,使瓶塞中的过滤膜与液面均匀接触。上下摇晃均匀并涡旋两分钟,记录待测化合物在whatman小瓶中的溶解现象。将whatman小瓶放在摇床中在常温下振荡24小时,转速设定600r/min。将whatman小瓶的塞子缓缓压至最下方,得到上清液。检查所有化合物,确保上清液中无沉淀,以防止瓶塞中的滤膜破裂。用稀释液配制准备线性溶液(3个标准溶液,1,20,200μM,n=1)。将上清液取出,精密量取出10μL稀释100倍。将得到的稀释液和原液与线性同时进入高效液相色谱仪中进行检测分析,根据峰面积和稀释因子通过外标法计算结果。
实验结果如表4所示:
表4:本发明化合物的溶解度
待测化合物 | 热力学溶解度(pH:7.4) |
式(I)化合物 | >200mg/mL |
结论:式(I)化合物在水中的溶解度非常好。
实施例8:式(I)化合物B晶型的固体加速稳定性研究
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B晶型在加速实验条件下的稳定性。称取式(I)化合物B晶型大约10mg,置于玻璃样品瓶的底部,摊成薄薄一层,铝箔纸封口并扎上小孔,在(40℃/75%RH)放置以及(60℃/75%RH)放置1个月,对放置后的样品进行XRPD表征,检测结果与0天的初始检测结果进行比较。结果如表5显示,式(I)化合物结晶B在所有稳定性条件下,晶型均未发生变化。
表5:式(I)化合物B晶型的固体稳定性实验结果
试验条件 | 取点条件 | 结晶变化 |
起始结晶B | / | B晶型 |
40℃/75%RH | 1月 | B晶型 |
60℃/75%RH | 1月 | B晶型 |
实验结论:式(I)化合物B晶型具有良好的稳定性。
生物测试数据:
实验例1:本发明化合物的CRAC体外细胞活性测试
1.实验材料:
1.1试剂与耗材,见表6:
表6.试剂与耗材
试剂与耗材名称 | 品牌 | 商品号 | |
1 | 384孔透底黑色微孔板 | Corning | 3712 |
2 | 384孔平底透明微孔板 | Greiner | 781201 |
3 | 384孔尖底透明微孔板 | Corning | 3656 |
4 | 细胞培养皿10cm | Corning | 430167 |
5 | 离心管15mL | Corning | 430791 |
6 | 1.5mL透明管 | Axegen | MCT-150-C |
7 | Fluo-8钙流检测试剂 | Abcam | Ab112129 |
8 | HEPES | Gibco | 15630-080 |
9 | Probenecid | Thermo | P36400 |
10 | 氯化钠 | 国药集团 | 10019318 |
11 | 氯化钾 | 国药集团 | 10016318 |
12 | 碳酸氢钠 | 国药集团 | 10018390 |
13 | 6水氯化镁 | 国药集团 | 1001218 |
14 | 氯化钙 | 国药集团 | 10005861 |
15 | 氢氧化钠 | 国药集团 | 10019718 |
16 | 葡萄糖 | Sigma | 101185414 |
17 | EGTA | Amresco | 732 |
18 | MEME细胞培养液 | Gibco | 61100 |
19 | FBS血清 | Biosera | FB-1058/500 |
20 | DPBS | Invitrogen | 14190 |
21 | 0.25%Trypsin-EDTA | Invitrogen | 25200 |
22 | DMSO | Sigma | D5879 |
23 | 青霉素/链霉素 | Biosera | 70013 |
1.2仪器,见表7:
表7.仪器
仪器 | 品牌 | |
1 | Bravo移液工作站 | Agilent |
2 | Echo 550液体工作站 | Labcyte |
3 | FLIPR检测平台 | MD |
4 | 细胞培养箱 | Thermo |
5 | 台式高速离心机 | Eppendorf |
1.3细胞株:RBL-2H3,来源于HDB细胞库。
2.实验步骤与方法:
2.1细胞铺板
1)准备生物安全操作柜,预热相关试剂。每日观察细胞,当10cm培养皿85%的面积长满细胞后,进行细胞传代。
2)取出细胞培养皿,移除培养液。使用DPBS清洗细胞表面,移除DPBS。使用1mL 0.25%Trypsin-EDTA消化细胞1-3分钟后,加入2mL培养液终止消化。使用移液枪轻柔吹打细胞直至细胞从培养皿表面脱落。
3)使用生长培养液调整细胞密度至每孔15000细胞,体积为每孔25μL培养液。
4)细胞培养板放置于37℃和5%CO
2的培养箱中培养,至80%密度。
2.2检测
1)从培养箱中取出细胞培养板,倒置离心RPM300转/30秒移除培养液,每孔加入20μL缓冲液(超纯水,40mM氯化钠,100mM氯化钾,17mM碳酸氢钠,0.1mM乙二醇双氨乙基醚四乙酸(EGTA),12mM葡萄糖,1mM氯化镁,5mM羟乙基哌嗪乙硫磺酸(Hepes),2.5mM丙磺舒,2μM Fluo8),置于培养箱中30分钟。
2)准备化合物板。化合物溶于DMSO中,根据待测浓度要求使用Echo550将化合物准备在化合物板(Greiner784201)中,并溶解于不含有钙离子的缓冲液中(超纯水,40mM NaCl,100mM KCl,17mM NaHCO
3,12mM葡萄糖,1mM MgCl
2,5mM细胞培养液结论:本发明化合物对KDM5A的抑制作用显著,4μM毒胡萝卜素(thapsigargin)),利用FLIPR添加10μL化合物至细胞培养板中,并于室温下孵育20分钟。
3)准备含有钙离子的诱导缓冲液(4mM CaCl
2,40mM NaCl,100mM KCl,17mM NaHCO
3,12mM葡萄 糖,1mM MgCl
2,5mM Hepes),利用FLIPR添加10μL诱导缓冲液至细胞培养板中,采集260秒的钙流信号。
数据处理:使用ScreenWorks,Excel,Xlfit以及GraphPad对采集的信号结果进行分析以及绘制图表。实验结果如表8所示。
表8:RBL-3H细胞实验FLIPR检测抑制Ca
2+的IC
50测试结果
受试化合物 | IC 50(nM) |
化合物CC-6 | 136 |
结论:化合物CC-6对CRAC的通道抑制作用显著。
实验例2:小鼠药代动力学评价
实验目的:以雄性C57BL/6小鼠为受试动物,应用LC/MS/MS法测定供试品化合物经静脉或腹腔注射给药后不同时刻的血浆药物浓度。研究供试品化合物在小鼠体内的药代动力学行为,评价其药动学特征。
药物配制:称取适量样品,用40%PEG400+20%Solutol+40%H
2O(体积比)配成0.3mg/mL或0.5mg/mL的澄清溶液。
给药方案:取健康雄性C57BL/6小鼠2只,购买自北京维通利华实验动物有限公司,正常饮食。静脉注射给药组使用0.5mg/mL的药液,给药体积为2mL/kg;给药剂量为1mg/kg。腹腔注射给药组使用0.3mg/mL的药液,给药体积为10mL/kg;给药剂量为3mg/kg。
操作步骤:动物给药后,在0.083、0.25、0.5、1、2、4、8、12及24小时分别采血25μL,置于预先加有EDTA-K2的商品化抗凝管中。将试管离心10分钟分离血浆,并于-60℃保存。用LC/MS/MS法测定血浆样品中的目标化合物含量。
实验结果如表9所示。
表9:化合物CC-6的小鼠药代动力学参数
结论:在小鼠药代动力学评价实验当中,经静脉和腹腔途径给予的化合物CC-6具有较高的血浆暴露量和理想的药代动力学性质。
实验例3:小鼠药代动力学评价
实验目的:以雄性C57BL/6小鼠为受试动物,应用LC/MS/MS法测定化合物经静脉注射给药后不同时刻血浆药物浓度。研究化合物在小鼠体内的药代动力学行为,评价其药动学特征。
药物配制:称取适量样品,用无菌生理盐水配成5mg/mL的澄清溶液。
给药方案:取健康雄性C57BL/6小鼠2只,购买自北京维通利华实验动物有限公司,正常饮食,给药体积为10mL/kg;给药剂量为50mg/kg。
操作步骤:动物给药后,在0.083、0.25、0.5、1、2、4、8、12及24小时分别采血25μL,置于预先加有EDTA-K2的商品化抗凝管中。将试管离心10分钟分离血浆,并于-60℃保存。用LC/MS/MS法测定血浆样品中相应化合物的含量。
实验结果:见表10。
表10:化合物的小鼠药代动力学参数
注:NA代表此数据不存在,DNAUC代表按照摩尔剂量归一化后的暴露量。
结论:在小鼠药代动力学评价实验当中,给予式(I)化合物后,其在血浆中快速消除。与此同时,自给药5min起即能够检测到大量化合物CC-6生成,且同摩尔剂量下,给予式(I)化合物后,化合物CC-6在体内的暴露量相当。
实验例4:蛙皮素诱导的小鼠急性胰腺炎药效实验
实验目的:以雄性C57BL/6小鼠为受试动物,使用蛙皮素腹腔注射诱发急性胰腺炎。研究式(I)化合物对急性胰腺炎的疗效。
药物配制:称取适量样品,式(I)化合物用无菌生理盐水配成5mg/mL的澄清溶液。
实验方案:取健康雄性C57BL/6小鼠,经腹腔注射蛙皮素诱导胰腺炎模型,注射剂量为每次50μg/kg, 一共注射7次,注射间隔为1h。第七次注射蛙皮素后1小时,取血清,测量其中的淀粉酶和脂肪酶水平。式(I)化合物经静脉注射给药,实验共4组(G1-G4)。G1为健康组,G2为模型组,G3-4为治疗组。G1-3在第一次注射蛙皮素的时间点前0.5h给予第一次给药物或溶媒,第四次注射蛙皮素后0.5h给予第二次给药物或溶媒。G4第一次注射蛙皮素前0.5h给予药物,不进行第二次给药。G3:25mg/kg,每日两次(bid);G3:50mg/kg,每日一次(qd)。
实验结果:见图8.血浆淀粉酶水平,经单因素方差分析,***代表与G1有显著性差异P<0.001;###代表与G2有显著性差异P<0.001;¥代表与G3有显著性差异,p<0.05。和图9.血浆脂肪酶水平,经单因素方差分析,***代表与G1有显著性差异P<0.001;###代表与G2有显著性差异P<0.001;¥¥¥代表与G3有显著性差异,p<0.001。
结论:在蛙皮素诱导的小鼠急性胰腺炎模型中,式(I)化合物能够非常显著地降低血清淀粉酶(AMY)和脂肪酶(LPS)水平,表明其能够显著改善急性胰腺炎的典型症状,显示了治疗急性胰腺炎的优秀潜力。
Claims (19)
- 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:8.892±0.200°,12.617±0.200°,16.793±0.200°,17.583±0.200°,18.959±0.200°,22.113±0.200°,25.029±0.200°,26.512±0.200°。
- 根据权利要求2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:8.892±0.200°,11.883±0.200°,12.617±0.200°,13.206±0.200°,16.793±0.200°,17.583±0.200°,18.018±0.200°,18.959±0.200°,22.113±0.200°,25.029±0.200°,25.858±0.200°,26.512±0.200°。
- 根据权利要求3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:3.616°,4.474°,8.892°,9.571°,10.288°,10.533°,11.076°,11.883°,12.617°,13.206°,13.653°,14.886°,15.788°,16.301°,16.793°,17.583°,18.018°,18.959°,19.574°,19.981°,20.661°,20.964°,21.651°,22.113°,23.031°,23.747°,24.107°,25.029°,25.414°,25.858°,26.512°,28.797°,30.039°,31.672°,32.596°,35.275°。
- 根据权利要求1~4任意一项所述的A晶型,其XRPD图谱基本上如图1所示。
- 根据权利要求1~4任意一项所述的A晶型,其差示扫描量热曲线在138.4℃±3℃和163.4℃±3℃处具有吸热峰的峰值。
- 根据权利要求6所述的A晶型,其DSC图谱基本上如图2所示。
- 根据权利要求1~4任意一项所述的A晶型,其热重分析曲线在140.0℃±3℃时失重达3.33%。
- 根据权利要求8所述的A晶型,其TGA图谱基本上如图3所示。
- 根据权利要求10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:4.389±0.200°,8.797±0.200°,13.168±0.200°,16.739±0.200°,17.578±0.200°,18.811±0.200°,21.997±0.200°,26.443±0.200°。
- 根据权利要求11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:4.389±0.200°,8.797±0.200°,11.786±0.200°,13.168±0.200°,16.739±0.200°,17.578±0.200°,18.811±0.200°,20.617±0.200°,21.997±0.200°,24.970±0.200°,25.804±0.200°,26.443±0.200°。
- 根据权利要求12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:4.389°,8.797°,9.473°,10.172°,10.356°,11.786°,12.569°,13.168°,13.991°,15.710°,16.739°,17.578°,17.949°,18.811°,19.577°,19.875°,20.617°,20.849°,21.997°,24.970°,25.804°,26.443°,26.942°,27.841°,28.731°,30.033°,30.962°。
- 根据权利要求10~13任意一项所述的B晶型,其XRPD图谱基本上如图4所示。
- 根据权利要求10~13任意一项所述的B晶型,其差示扫描量热曲线在165.7℃±5℃处具有吸热峰的起始值。
- 根据权利要求15所述的B晶型,其DSC图谱基本上如图5所示。
- 根据权利要求10~13任意一项所述的B晶型,其热重分析曲线在150℃±3℃时失重达1.14%。
- 根据权利要求17所述的B晶型,其TGA图谱基本上如图6所示。
- 根据权利要求1~9任意一项所述的A晶型或根据权利要求10~18任意一项所述的B晶型在制备治疗急性胰腺炎药物中的应用。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202280017074.9A CN117098756A (zh) | 2021-02-25 | 2022-02-24 | 一种环丙基取代的苯并呋喃类化合物的晶型及其制备方法 |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202110214161 | 2021-02-25 | ||
CN202110214161.0 | 2021-02-25 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2022179577A1 true WO2022179577A1 (zh) | 2022-09-01 |
Family
ID=83047935
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CN2022/077773 WO2022179577A1 (zh) | 2021-02-25 | 2022-02-24 | 一种环丙基取代的苯并呋喃类化合物的晶型及其制备方法 |
Country Status (2)
Country | Link |
---|---|
CN (1) | CN117098756A (zh) |
WO (1) | WO2022179577A1 (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN116396330A (zh) * | 2023-06-09 | 2023-07-07 | 天津辰欣药物研究有限公司 | 一种环丙基取代的2h-苯并吡喃衍生物的制备方法 |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101163478A (zh) * | 2005-01-25 | 2008-04-16 | 幸讬制药公司 | 用于炎症及免疫相关用途之化合物 |
US20100273744A1 (en) * | 2009-04-24 | 2010-10-28 | Paul Martin Gore | Compounds |
US20110263612A1 (en) * | 2010-04-27 | 2011-10-27 | Calcimedica, Inc. | Compounds that modulate intracellular calcium |
WO2012052458A1 (en) * | 2010-10-21 | 2012-04-26 | Glaxo Group Limited | Pyrazole compounds acting against allergic, immune and inflammatory conditions |
CN107530333A (zh) * | 2015-02-27 | 2018-01-02 | 钙医学公司 | 胰腺炎治疗 |
WO2021057890A1 (zh) * | 2019-09-25 | 2021-04-01 | 南京明德新药研发有限公司 | 作为crac抑制剂的2h-苯并吡喃衍生物 |
-
2022
- 2022-02-24 CN CN202280017074.9A patent/CN117098756A/zh active Pending
- 2022-02-24 WO PCT/CN2022/077773 patent/WO2022179577A1/zh active Application Filing
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101163478A (zh) * | 2005-01-25 | 2008-04-16 | 幸讬制药公司 | 用于炎症及免疫相关用途之化合物 |
US20100273744A1 (en) * | 2009-04-24 | 2010-10-28 | Paul Martin Gore | Compounds |
US20110263612A1 (en) * | 2010-04-27 | 2011-10-27 | Calcimedica, Inc. | Compounds that modulate intracellular calcium |
WO2012052458A1 (en) * | 2010-10-21 | 2012-04-26 | Glaxo Group Limited | Pyrazole compounds acting against allergic, immune and inflammatory conditions |
CN107530333A (zh) * | 2015-02-27 | 2018-01-02 | 钙医学公司 | 胰腺炎治疗 |
WO2021057890A1 (zh) * | 2019-09-25 | 2021-04-01 | 南京明德新药研发有限公司 | 作为crac抑制剂的2h-苯并吡喃衍生物 |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN116396330A (zh) * | 2023-06-09 | 2023-07-07 | 天津辰欣药物研究有限公司 | 一种环丙基取代的2h-苯并吡喃衍生物的制备方法 |
CN116396330B (zh) * | 2023-06-09 | 2023-08-25 | 天津辰欣药物研究有限公司 | 一种环丙基取代的2h-苯并吡喃衍生物的制备方法 |
Also Published As
Publication number | Publication date |
---|---|
CN117098756A (zh) | 2023-11-21 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US11866434B2 (en) | Process for making a PD-1/PD-L1 inhibitor and salts and crystalline forms thereof | |
EP3378861B1 (en) | Acrylic acid derivative, preparation method and use in medicine thereof | |
EP2968337B1 (en) | Heteroaryl compounds and uses thereof | |
EP1841760B1 (en) | Pyrimidine derivatives as kinase modulators and method of use | |
JP3348859B2 (ja) | プロテインキナーゼcインヒビター | |
EP3943087A1 (en) | Heteroaryl compounds and uses thereof | |
WO2020228513A1 (zh) | 基于苯并吡喃结构的新型cdk9抑制剂、其制备方法及应用 | |
EP3604306A1 (en) | Macrocyclic derivative of pyrazol[3,4-d]pyrimidin-3-one, pharmaceutical composition and use thereof | |
EA022087B1 (ru) | Морфолинопиримидины и их применение в терапии | |
JP2022071077A (ja) | Bcl-2タンパク質を阻害するためのN-ベンゼンスルホニルベンズアミド系化合物、その組成物および使用 | |
WO2018045993A1 (zh) | 一种取代的2-氢-吡唑衍生物的晶型、盐型及其制备方法 | |
CN103582638A (zh) | 杂芳基并嘧啶类衍生物、其制备方法和用途 | |
AU2016274961A1 (en) | Adipate forms and compositions of biaryl inhibitors of Bruton's tyrosine kinase | |
UA126847C2 (uk) | Дизаміщені піразольні сполуки як інгібітори кетогексокінази | |
WO2022179577A1 (zh) | 一种环丙基取代的苯并呋喃类化合物的晶型及其制备方法 | |
WO2018054304A1 (zh) | 呋喃并喹啉二酮类化合物及其医药用途 | |
WO2018041260A1 (zh) | 一类溴结构域识别蛋白抑制剂及其制备方法和用途 | |
CN101616912A (zh) | 大环内酯系化合物的固体及其制造方法及其药物组合物 | |
CN110526921B (zh) | 一种具有抗炎作用的化合物及其制备方法和用途 | |
JP2021522165A (ja) | 2,6−ジアミノ−3,4−ジヒドロピリミジン−4−オン誘導体および治療におけるその使用 | |
CN107973780B (zh) | 一种取代的烯烃类化合物及其制备方法和用途 | |
TWI836822B (zh) | p38 MAPK/MK2通路調節劑及其組合物、製備方法和用途 | |
CN112812145B (zh) | 一种苯并咪唑衍生物bi293及其制备方法和应用 | |
WO2021164789A1 (zh) | 一种吡唑并嘧啶类化合物的晶型及其应用 | |
WO2022242753A1 (zh) | 一种吡唑并杂芳基类衍生物的可药用盐及其结晶形式 |
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: 22758941 Country of ref document: EP Kind code of ref document: A1 |
|
WWE | Wipo information: entry into national phase |
Ref document number: 202280017074.9 Country of ref document: CN |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 22758941 Country of ref document: EP Kind code of ref document: A1 |