WO2022100586A1 - 一种含氧杂环丁烷的螺环类化合物的晶型、制备方法及其应用 - Google Patents
一种含氧杂环丁烷的螺环类化合物的晶型、制备方法及其应用 Download PDFInfo
- Publication number
- WO2022100586A1 WO2022100586A1 PCT/CN2021/129643 CN2021129643W WO2022100586A1 WO 2022100586 A1 WO2022100586 A1 WO 2022100586A1 CN 2021129643 W CN2021129643 W CN 2021129643W WO 2022100586 A1 WO2022100586 A1 WO 2022100586A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- crystal form
- compound
- formula
- etoac
- angles
- Prior art date
Links
- 239000013078 crystal Substances 0.000 title claims abstract description 46
- 150000001875 compounds Chemical class 0.000 title claims abstract description 29
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- AHHWIHXENZJRFG-UHFFFAOYSA-N oxetane Chemical compound C1COC1 AHHWIHXENZJRFG-UHFFFAOYSA-N 0.000 title 1
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 22
- 229940126062 Compound A Drugs 0.000 claims description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- 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 claims description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 20
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 13
- 238000001914 filtration Methods 0.000 claims description 11
- 235000019439 ethyl acetate Nutrition 0.000 claims description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 8
- 238000001228 spectrum Methods 0.000 claims description 8
- 238000003756 stirring Methods 0.000 claims description 8
- 239000007787 solid Substances 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 4
- 238000001938 differential scanning calorimetry curve Methods 0.000 claims description 3
- 238000001291 vacuum drying Methods 0.000 claims description 3
- 230000004580 weight loss Effects 0.000 claims description 3
- -1 H 2 O Substances 0.000 claims description 2
- 238000001757 thermogravimetry curve Methods 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims 1
- 150000002921 oxetanes Chemical class 0.000 abstract description 2
- 238000012360 testing method Methods 0.000 description 21
- 206010028980 Neoplasm Diseases 0.000 description 19
- 239000012065 filter cake Substances 0.000 description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 13
- 241001465754 Metazoa Species 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 9
- 229910001868 water Inorganic materials 0.000 description 9
- 239000002904 solvent Substances 0.000 description 8
- 238000010171 animal model Methods 0.000 description 7
- 239000012043 crude product Substances 0.000 description 7
- 238000002411 thermogravimetry Methods 0.000 description 7
- 102100024193 Mitogen-activated protein kinase 1 Human genes 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 230000035772 mutation Effects 0.000 description 6
- 230000037361 pathway Effects 0.000 description 6
- 230000004614 tumor growth Effects 0.000 description 6
- 206010009944 Colon cancer Diseases 0.000 description 5
- 108010007457 Extracellular Signal-Regulated MAP Kinases Proteins 0.000 description 5
- 208000029742 colonic neoplasm Diseases 0.000 description 5
- 238000000113 differential scanning calorimetry Methods 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 102000004232 Mitogen-Activated Protein Kinase Kinases Human genes 0.000 description 4
- 241000699666 Mus <mouse, genus> Species 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 3
- 206010059866 Drug resistance Diseases 0.000 description 3
- 239000012824 ERK inhibitor Substances 0.000 description 3
- 101000984753 Homo sapiens Serine/threonine-protein kinase B-raf Proteins 0.000 description 3
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 3
- 102100027103 Serine/threonine-protein kinase B-raf Human genes 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 230000034994 death Effects 0.000 description 3
- 231100000517 death Toxicity 0.000 description 3
- 231100000673 dose–response relationship Toxicity 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000011521 glass Substances 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 208000031648 Body Weight Changes Diseases 0.000 description 2
- 102000043136 MAP kinase family Human genes 0.000 description 2
- 108091054455 MAP kinase family Proteins 0.000 description 2
- 230000004913 activation Effects 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
- 239000004411 aluminium Substances 0.000 description 2
- 230000004579 body weight change Effects 0.000 description 2
- 238000004364 calculation method Methods 0.000 description 2
- 239000008367 deionised water Substances 0.000 description 2
- 229910021641 deionized water Inorganic materials 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- YIXJRHPUWRPCBB-UHFFFAOYSA-N magnesium nitrate Chemical compound [Mg+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O YIXJRHPUWRPCBB-UHFFFAOYSA-N 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- 230000001681 protective effect Effects 0.000 description 2
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 2
- 230000019491 signal transduction Effects 0.000 description 2
- 230000011664 signaling Effects 0.000 description 2
- 238000001179 sorption measurement Methods 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 description 2
- 238000011144 upstream manufacturing Methods 0.000 description 2
- 230000004584 weight gain Effects 0.000 description 2
- 235000019786 weight gain Nutrition 0.000 description 2
- 238000011729 BALB/c nude mouse Methods 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 101000876610 Dictyostelium discoideum Extracellular signal-regulated kinase 2 Proteins 0.000 description 1
- 208000030453 Drug-Related Side Effects and Adverse reaction Diseases 0.000 description 1
- 102100031480 Dual specificity mitogen-activated protein kinase kinase 1 Human genes 0.000 description 1
- 101710146526 Dual specificity mitogen-activated protein kinase kinase 1 Proteins 0.000 description 1
- 101001052493 Homo sapiens Mitogen-activated protein kinase 1 Proteins 0.000 description 1
- 102000019149 MAP kinase activity proteins Human genes 0.000 description 1
- 108040008097 MAP kinase activity proteins Proteins 0.000 description 1
- 229940124647 MEK inhibitor Drugs 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 102000001253 Protein Kinase Human genes 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 206010070863 Toxicity to various agents Diseases 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- HXYXTCJDWHHCBW-UHFFFAOYSA-N acetonitrile;toluene Chemical compound CC#N.CC1=CC=CC=C1 HXYXTCJDWHHCBW-UHFFFAOYSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- 230000003542 behavioural effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000013065 commercial product Substances 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- KFGVRWGDTLZAAO-UHFFFAOYSA-N cyclopenta-1,3-diene dicyclohexyl(cyclopenta-1,3-dien-1-yl)phosphane iron(2+) Chemical compound [Fe++].c1cc[cH-]c1.C1CCC(CC1)P(C1CCCCC1)c1ccc[cH-]1 KFGVRWGDTLZAAO-UHFFFAOYSA-N 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 230000003862 health status Effects 0.000 description 1
- 108091008039 hormone receptors Proteins 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 1
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 1
- DBTNVRCCIDISMV-UHFFFAOYSA-L lithium;magnesium;propane;dichloride Chemical compound [Li+].[Mg+2].[Cl-].[Cl-].C[CH-]C DBTNVRCCIDISMV-UHFFFAOYSA-L 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 239000003226 mitogen Substances 0.000 description 1
- 239000002829 mitogen activated protein kinase inhibitor Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 238000011580 nude mouse model Methods 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000012113 quantitative test Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 230000007420 reactivation Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000004467 single crystal X-ray diffraction Methods 0.000 description 1
- 239000002356 single layer Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 150000003413 spiro compounds Chemical class 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 description 1
- 238000004441 surface measurement Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000026683 transduction Effects 0.000 description 1
- 238000010361 transduction Methods 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 230000001875 tumorinhibitory effect Effects 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 238000013298 xenograft nude mouse model Methods 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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
Definitions
- the present invention relates to a crystal form of an oxetane-containing spiro compound, a preparation method and an application thereof, in particular to a crystal form of a compound of formula (I), a preparation method and an application thereof.
- Ras/Raf/MEK/ERK pathway is a classic mitogen activated protein kinase (MAPK) signaling cascade, which is involved in the signaling of various growth factors, cytokines, mitogens and hormone receptors after activation Transduction is one of the most important signal transduction pathways controlling cell growth, differentiation and survival.
- MAPK mitogen activated protein kinase
- Extracellular regulated protein kinases are major players and downstream key nodes in the Ras/Raf/MEK/ERK pathway, and their functions can be found in many human cancers. overactive. As the terminal signaling kinase of this pathway, ERK has not yet been found to have drug resistance mutations. Therefore, drugs targeting ERK kinase are expected to overcome the drug resistance problem after upstream target inhibitor treatment and become a more potential therapeutic strategy. But so far, research on ERK inhibitors is still in the clinical stage, and no ERK inhibitors have been approved for marketing as drugs. In conclusion, there is an urgent need to develop safe and effective ERK inhibitor drugs to meet the needs of tumor treatment.
- ERKs Extracellular regulated protein kinases
- the present invention provides Form A of the compound of formula (I), whose X-ray powder diffraction (XRPD) pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 8.16 ⁇ 0.20°, 17.39 ⁇ 0.20° and 23.88 ⁇ 0.20°.
- the X-ray powder diffraction pattern of the above-mentioned crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 8.16 ⁇ 0.20°, 13.57 ⁇ 0.20°, 16.95 ⁇ 0.20°, 17.39 ⁇ 0.20°, 19.37 ⁇ 0.20 °, 22.22 ⁇ 0.20°, 23.88 ⁇ 0.20° and 25.85 ⁇ 0.20°.
- the X-ray powder diffraction pattern of the above-mentioned crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 8.16 ⁇ 0.20°, 13.57 ⁇ 0.20°, 14.51 ⁇ 0.20°, 16.95 ⁇ 0.20°, 17.39 ⁇ 0.20 °, 19.37 ⁇ 0.20°, 22.22 ⁇ 0.20°, 23.88 ⁇ 0.20° and 25.85 ⁇ 0.20°.
- the X-ray powder diffraction pattern of the above-mentioned crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 8.16 ⁇ 0.20°, 9.99 ⁇ 0.20°, 13.57 ⁇ 0.20°, 14.51 ⁇ 0.20°, 15.61 ⁇ 0.20 degrees degrees ° and 37.72 ⁇ 0.20°.
- the X-ray powder diffraction pattern of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 8.16°, 9.99°, 13.57°, 14.51°, 15.61°, 16.95°, 17.39°, 18.27° , 19.37°, 19.71°, 21.40°, 21.97°, 22.22°, 23.88°, 25.02°, 25.85°, 26.50°, 27.36°, 28.72°, 30.39°, 31.19°, 31.53°, 31.97°, 32.57°, 33.05 ° and 37.72°.
- the X-ray powder diffraction pattern of the above-mentioned Form A has characteristic diffraction peaks at the following 2 ⁇ angles: 8.16 ⁇ 0.20°, 17.39 ⁇ 0.20°, and/or 23.88 ⁇ 0.20°, and/or 13.57 ⁇ 0.20°, and/or 16.95 ⁇ 0.20°, and/or 19.37 ⁇ 0.20°, and/or 22.22 ⁇ 0.20°, and/or 25.85 ⁇ 0.20°, and/or 9.99 ⁇ 0.20°, and/or 14.51 ⁇ 0.20° , and/or 15.61 ⁇ 0.20°, and/or 18.27 ⁇ 0.20°, and/or 19.71 ⁇ 0.20°, and/or 21.40 ⁇ 0.20°, and/or 21.97 ⁇ 0.20°, and/or 25.02 ⁇ 0.20°, and /or 26.50 ⁇ 0.20°, and/or 27.36 ⁇ 0.20°, and/or 28.72 ⁇ 0.20°, and/or 30.39 ⁇ 0.20°, and/or 31
- the XRPD pattern of the above-mentioned crystal form A is shown in FIG. 1 .
- the differential scanning calorimetry curve of the differential scanning calorimetry curve has an onset of an endothermic peak at 225.5 ⁇ 3°C.
- the DSC spectrum of the above-mentioned crystal form A is shown in FIG. 2 .
- thermogravimetric analysis curve (TGA) of the above-mentioned crystal form A has a weight loss of 2.41% at 200 ⁇ 3°C.
- the TGA spectrum of the above-mentioned A crystal form is shown in FIG. 3 .
- the present invention also provides a method for preparing the crystal form A of the compound of formula (I), comprising:
- the organic solvent is ethanol, MeOH, ACN, acetone, EtOAc, dioxane, toluene, H 2 O, THF:H 2 O (v/v, 1:1), EtOH:H 2 O (v/v, 2:1), Acetone:EtOAc (v/v, 1:1), DMF:EtOAc (v/v, 5:95), DMF: H2O (v/v, 5:1) 95), acetone: H2O (v/v, 95:5), dioxane: H2O (v/v, 97:3), THF, DCM:EtOAc (v/v, 2:1) .
- the crystal form A of the compound of the present invention is stable, less affected by light, heat and humidity, and has a broad prospect for medicine; the crystal form A of the compound of formula (I) can significantly inhibit tumor growth under the administration dose, showing a dose-dependent manner; There was no significant weight loss, and the tolerance was good.
- 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 solvent used in the present invention is commercially available.
- 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.
- DCM dichloromethane
- DMF N,N-dimethylformamide
- DMSO dimethyl sulfoxide
- EtOH for ethanol
- MeOH for methanol
- 2-MeTHF 2-methyl Tetrahydrofuran
- Dioxane for dioxane
- ACN for acetonitrile
- Toluene for toluene
- Acetone for acetone
- EtOAc for ethyl acetate
- THF tetrahydrofuran
- FIG. 5 Tumor growth curve of human colon cancer HCT-116 model animal after administration of solvent and compound A crystal form of formula (I) respectively;
- Fig. 6 Body weight change rate (%) of human colon cancer HCT-116 xenograft tumor model animals during administration.
- the XRPD test was performed using an X'Pert3 X-ray diffractometer from PANalytical. The test parameters are shown in Table 2.
- the DSC spectra were collected on a TA 2500 differential scanning calorimeter, and the test parameters are shown in Table 3.
- TGA was collected on a TA 5500 thermogravimetric analyzer, and the test parameters are shown in Table 4.
- Dynamic moisture adsorption (DVS) curves were collected on a DVS Intrinsic instrument from SMS (Surface Measurement Systems), UK. The relative humidity at 25°C was corrected for the deliquescence points of lithium chloride (LiCl), magnesium nitrate [Mg( NO3 ) 2 ] and potassium chloride (KCl). The test parameters are shown in Table 5.
- 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 moisture absorption weight gain of the test product at 25°C/80%RH.
- the synthetic route is as follows:
- step 1
- the crude product was obtained by concentration under reduced pressure.
- Dioxane (500 mL) and water (2.5 L) were added to the crude product, stirred at 25° C. for 0.5 hours, and the filter cake was collected by filtration.
- the filter cake was dissolved in ethanol (2000 mL), stirred at 25° C. for 1 hour, and the filter cake was collected by filtration.
- the filter cake was dissolved in ethanol (2000 mL), stirred at 75° C. for 1 hour, cooled to 25° C., and the filter cake was collected by filtration.
- the crude product was dissolved in dioxane (500 mL) and stirred for 10 minutes, then deionized water (2.5 L) was added to continue stirring for 0.5 hour, and the filter cake was collected by filtration.
- the filter cake was dissolved in deionized water (1 L) and stirred for 1 hour, and the filter cake was collected by filtration.
- the filter cake was dissolved in absolute ethanol (2L), stirred at 25°C for 1 hour, and the filter cake was collected by filtration.
- the filter cake was dissolved in absolute ethanol (2L), stirred at 85°C for 1 hour, filtered to collect the filter cake, and the filter cake was vacuum dried at 45°C to obtain the compound of formula (I).
- test sample marked S1-condition-time is used for content and related substance detection; the test sample marked S2-condition-time is used as a preparation sample, and the test sample marked S3-condition-time is used for XRPD detection .
- Table 9 shows the results of the solid stability experiment of crystal form A.
- HCT-116 cells Human colon cancer HCT-116 cells were cultured in monolayer in vitro, and the culture conditions were McCoy's 5a medium plus 10% fetal bovine serum, and cultured in a 5% CO2 incubator at 37°C. Conventional digestion treatment with trypsin-EDTA was passaged three times a week. When the cell saturation is 80%-90% and the number reaches the requirement, the cells are collected, counted, and seeded;
- Vehicle group 5% DMSO+95% (10% HP- ⁇ -CD).
- Test compound group weigh the quantitative test compound into a dispensing bottle, add a corresponding volume of DMSO and vortex to obtain a clear solution, add a corresponding volume of 10% HP- ⁇ -CD and vortex to obtain a clear solution solution. Compounds were formulated every three days.
- Tumor diameter was measured twice a week with a vernier caliper.
- TGI (%) The tumor-inhibitory efficacy of the compounds was evaluated by TGI (%).
- the crystal form of compound A of formula (I) can significantly inhibit tumor growth under the administration dose, showing a dose-dependent manner; the body weight of the animals does not decrease significantly during the administration process, and the tolerance is good.
Abstract
提供了一种含氧杂环丁烷的螺环类化合物的晶型、制备方法及其应用,具体涉及式(I)化合物的晶型、制备方法及其应用。
Description
本申请主张如下优先权:
CN202011252031.8,申请日2020.11.11。
本发明涉及一种含氧杂环丁烷的螺环类化合物的晶型、制备方法及其应用,具体涉及式(I)化合物晶型、制备方法及其应用。
Ras/Raf/MEK/ERK通路是一条经典的有丝***原活化蛋白激酶(mitogen activated protein kinase,MAPK)信号级联通路,参与各种生长因子、细胞因子、丝裂原以及激素受体活化后的信号转导,是控制细胞生长、分化和存活最重要的信号转导途径之一。
研究表明,突变或扩增引起的Ras/Raf/MEK/ERK通路异常活化是多种癌症发生的决定因素。在人类肿瘤中,RAS突变发生率约为22%,BRAF突变发生率约为7%,MEK突变发生率约为1%,因此,该通路上的关键节点蛋白已成为癌症治疗的重要靶点(Cancer Discov.2019,9,329-341)。目前,已有多个BRAF抑制剂和MEK1/2抑制剂,以及它们的联用方案,被美国FDA批准用于黑色素瘤、BRAFV600E突变型非小细胞肺癌等癌症的治疗。然而,使用这些上游节点的BRAF和MEK抑制剂后,由于突变或通路重新激活,会快速导致耐药性问题,极大地限制了它们的临床应用。
细胞外调节蛋白激酶(extracellular regulated protein kinases,ERK),特别是ERK1和ERK2激酶,是Ras/Raf/MEK/ERK通路的主要参与者和下游关键节点,在许多人类的癌症中都可发现它们的过度激活。ERK作为该通路的末端信号激酶,目前尚未发现有耐药突变,因此,靶向ERK激酶的药物有望克服上游靶点抑制剂治疗后产生的耐药性问题,成为更具潜力的治疗策略。但迄今为止,关于ERK抑制剂的研究仍处于临床阶段,还没有ERK抑制剂作为药物批准上市。综上所述,迫切需要研发出安全、有效的ERK抑制剂药物满足肿瘤治疗的需要。
发明内容
本发明提供了式(Ⅰ)化合物的A晶型,其X射线粉末衍射(XRPD)图谱在下列2θ角处具有特征衍射峰:8.16±0.20°、17.39±0.20°和23.88±0.20°。
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:8.16±0.20°、13.57±0.20°、16.95±0.20°、17.39±0.20°、19.37±0.20°、22.22±0.20°、23.88±0.20°和25.85±0.20°。
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:8.16±0.20°、13.57±0.20°、14.51±0.20°、16.95±0.20°、17.39±0.20°、19.37±0.20°、22.22±0.20°、23.88±0.20°和25.85±0.20°。
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:8.16±0.20°、9.99±0.20°、13.57±0.20°、14.51±0.20°、15.61±0.20°、16.95±0.20°、17.39±0.20°、18.27±0.20°、19.37±0.20°、19.71±0.20°、21.40±0.20°、21.97±0.20°、22.22±0.20°、23.88±0.20°、25.02±0.20°、25.85±0.20°、26.50±0.20°、27.36±0.20°、28.72±0.20°、30.39±0.20°、31.19±0.20°、31.53±0.20°、31.97±0.20°、32.57±0.20°、33.05±0.20°和37.72±0.20°。
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:8.16°、9.99°、13.57°、14.51°、15.61°、16.95°、17.39°、18.27°、19.37°、19.71°、21.40°、21.97°、22.22°、23.88°、25.02°、25.85°、26.50°、27.36°、28.72°、30.39°、31.19°、31.53°、31.97°、32.57°、33.05°和37.72°。
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:8.16±0.20°,17.39±0.20°,和/或23.88±0.20°,和/或13.57±0.20°、和/或16.95±0.20°、和/或19.37±0.20°、和/或22.22±0.20°,和/或25.85±0.20°,和/或9.99±0.20°,和/或14.51±0.20°,和/或15.61±0.20°,和/或18.27±0.20°,和/或19.71±0.20°,和/或21.40±0.20°,和/或21.97±0.20°,和/或25.02±0.20°,和/或26.50±0.20°,和/或27.36±0.20°,和/或28.72±0.20°,和/或30.39±0.20°,和/或31.19±0.20°,和/或31.53±0.20°,和/或31.97±0.20°,和/或32.57±0.20°,和/或33.05±0.20°,和/或37.72±0.20°。
本发明的一些方案中,上述A晶型,其XRPD图谱如附图1所示。
本发明的一些方案中,上述A晶型的XRPD图谱解析数据如表1所示。
表1 式(I)化合物A晶型的XRPD解析数据
在本发明的一些方案中,上述A晶型,其差示扫描量热曲线在225.5±3℃有一个吸热峰的起始点。
在本发明的一些方案中,上述A晶型,其DSC图谱如附图2所示。
在本发明的一些方案中,上述A晶型的热重分析曲线(TGA)在200±3℃时失重达2.41%。
在本发明的一些方案中,上述A晶型的TGA图谱如图3所示。
本发明还提供了式(Ⅰ)化合物的A晶型的制备方法,包含:
1)式(I)化合物,加入有机溶剂;
2)在25~50℃温度下搅拌2天;
3)过滤收集固体,置于真空干燥箱中(45℃)干燥16小时。
本发明的一些方案中,上述有机溶剂为乙醇、MeOH、ACN、丙酮、EtOAc、二氧六环、甲苯、H
2O、THF:H
2O(v/v,1:1)、EtOH:H
2O(v/v,2:1)、丙酮:EtOAc(v/v,1:1)、DMF:EtOAc(v/v,5:95)、DMF:H
2O(v/v,5:95)、丙酮:H
2O(v/v,95:5)、二氧六环:H
2O(v/v,97:3)、THF、DCM:EtOAc(v/v,2:1)。
技术效果
本发明化合物的A晶型稳定、受光热湿度影响小、成药前景广阔;式(I)化合物A晶型在给药剂量下,能显著抑制肿瘤生长,呈现剂量依赖性;给药过程中动物的体重未见明显下降,耐受性好。
定义和说明
除非另有说明,本文所用的下列术语和短语旨在含有下列含义。一个特定的短语或术语在没有特别定义的情况下不应该被认为是不确定的或不清楚的,而应该按照普通的含义去理解。当本文出现商品名时,旨在指代其对应的商品或其活性成分。
本发明的中间体化合物可以通过本领域技术人员所熟知的多种合成方法来制备,包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式,优选的实施方式包括但不限于本发明的实施例。
本发明具体实施方式的化学反应是在合适的溶剂中完成的,所述的溶剂须适合于本发明的化学变化及其所需的试剂和物料。为了获得本发明的化合物,有时需要本领域技术人员在已有实施方式的基础上对合成步骤或者反应流程进行修改或选择。
下面会通过实施例具体描述本发明,这些实施例并不意味着对本发明的任何限制。
本发明所使用的所有溶剂是市售的,无需进一步纯化即可使用。
本发明所使用的溶剂可经市售获得。
本发明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。
本发明采用下述缩略词:DCM代表二氯甲烷;DMF代表N,N-二甲基甲酰胺;DMSO代表二甲亚砜;EtOH代表乙醇;MeOH代表甲醇;2-MeTHF代表2-甲基四氢呋喃;Dioxane代表二氧六环;ACN代表乙腈;Toluene代表甲苯;Acetone代表丙酮;EtOAc代表乙酸乙酯;THF代表四氢呋喃;H
2O代表水。
图1:式(Ⅰ)化合物A晶型的XRPD图谱;
图2:式(Ⅰ)化合物A晶型的DSC图谱;
图3:式(Ⅰ)化合物A晶型的TGA图谱;
图4:式(Ⅰ)化合物A晶型的DVS图谱;
图5:人结肠癌HCT-116模型动物在分别给予溶剂和式(Ⅰ)化合物A晶型后的肿瘤生长曲线;
图6:人结肠癌HCT-116异种移植瘤模型动物在给药过程中的体重变化率(%)。
本发明X射线粉末衍射(XRPD)仪器信息和方法
XRPD测试使用PANalytical(帕纳科)公司的X’Pert3型X射线衍射仪。测试参数如表2所示。
表2:XRPD测试参数
本发明差示扫描量热(DSC)仪器信息及方法
DSC图谱在TA 2500差示扫描量热仪上采集,测试参数如表3所示。
表3:DSC测试参数
参数 | 设定值 |
方法 | 线性升温 |
参数 | 设定值 |
样品盘 | 铝盘,压盖 |
温度范围 | 25~350℃ |
扫描速率(℃/分钟) | 10 |
保护气体 | 氮气 |
本发明热重分析(TGA)仪器信息与方法
TGA在TA 5500热重分析仪上采集,测试参数如表4所示。
表4:TGA测试参数
参数 | 设定值 |
方法 | 线性升温 |
样品盘 | 铝盘,开盖 |
温度范围 | 室温~350℃ |
扫描速率(℃/分钟) | 10 |
保护气体 | 氮气 |
本发明动态蒸汽吸附分析(DVS)仪器信息及方法
动态水分吸附(DVS)曲线在英国SMS(Surface Measurement Systems)公司的DVS Intrinsic仪器上采集。在25℃时的相对湿度用氯化锂(LiCl),硝酸镁[Mg(NO
3)
2]和氯化钾(KCl)的潮解点校正。测试参数如表5所示。
表5:DVS测试参数
引湿性评价分类如表6所示:
表6:引湿性分类
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℃/80%RH下的吸湿增重。
为了更好的理解本发明的内容,下面结合具体实施例来做进一步的说明,但具体的实施方式并不是对本发明的内容所做的限制。
实施例1:式(I)化合物的制备
合成路线如下:
步骤1:
将化合物A(200g,768.91mmol,100%纯度,1eq)和化合物B(191.40g,922.70mmol,121.91mL,99.057%纯度,1.2eq)加到反应釜中,随后加入N,N-二甲基甲酰胺(2000mL)。开启搅拌,加入碳酸铯(375.79g,1.15mol,1.5eq)。置换氮气,在25℃搅拌12小时后,将反应液缓慢倾倒至水(10L)中,搅拌0.5小时,过滤收集滤饼。然后将滤饼用乙醇(2000mL)悬浮搅拌0.5小时,过滤收集滤饼,滤饼在45℃下真空干燥得到化合物C。
1HNMR(DMSO-d
6,400MHz)δ7.51(s,1H),7.3-7.4(m,3H),7.2-7.3(m,1H),4.94(s,2H),4.87(d,J=7.4Hz,2H),4.74(d,J=7.4Hz,2H)。
步骤2:
将化合物C(100g,259.96mmol,100%纯度,1eq)和化合物D(163.79g,870.87mmol,200.23mL,3.35eq)加入反应釜中,随后加入四氢呋喃(1000mL)。置换氮气,降温至-5℃,将异丙基氯化镁氯化锂复合物溶 液(1.3M,299.95mL,1.5eq)缓慢滴加至反应釜中,滴加过程中控制温度在0℃~3℃。滴加完毕后,在0℃下搅拌60分钟后,加入MeOH(24.99g,779.88mmol,31.56mL,3eq)淬灭反应得到粗品E。粗品E直接用于下一步反应。
步骤3:
将2-甲基四氢呋喃(1000mL)和水(1000mL)加到反应釜中,随后依次加入F(78.45g,259.96mmol,98.785%纯度,1eq)、乙酸钾(76.54g,779.87mmol,3eq)和二苯基膦二茂铁二氯化钯(5.71g,7.80mmol,0.03eq)。置换氮气后,缓慢升温至75℃,然后滴加粗品E(90.88g,259.96mmol,1eq)。滴加完毕后,75℃下反应30分钟。反应完毕,减压浓缩得到粗品,将加入二氧六环(500mL)和水(2.5L)加入到粗品中,25℃拌0.5小时,过滤收集滤饼。滤饼用乙醇(2000mL)溶解,25℃搅拌1小时,过滤收集滤饼。滤饼再用乙醇(2000mL)溶解,在75℃搅拌1小时,冷却至25℃,过滤收集滤饼。滤饼再用二氯甲烷(3000mL)溶解,加入巯基硅胶(10g),45℃搅拌12小时,冷却至25℃,过滤,滤液减压浓缩得到G。
1H NMR(DMSO-d
6,400MHz):δ(ppm)9.02(s,1H),8.04(s,1H),7.33-7.43(m,3H),7.27-7.32(m,1H),5.00(s,2H),4.96(d,J=7.3Hz,2H),4.82(d,J=7.3Hz,2H),3.46(s,3H),2.70(s,3H)。
步骤4:
将G(100g,210.10mmol,100%纯度,1eq)和H(40.81g,420.20mmol,2eq)加到反应釜中,随后加入四氢呋喃(1000mL)和二氯甲烷(1000mL)。置换氮气,降温至-5℃。将六甲基二硅基胺基锂(1M,399.19mL,1.9eq)滴加到反应瓶中,控制温度在0℃搅拌2小时。向反应液中加入离子水(1L)搅拌10分钟后,45℃减压浓缩得粗品。粗品用二氧六环(500mL)溶解搅拌10分钟,然后加入去离子水(2.5L)继续搅拌0.5小时,过滤收集滤饼。滤饼用去离子水(1L)溶解搅拌1小时,过滤收集滤饼。滤饼用无水乙醇(2L)溶解,25℃搅拌1小时,过滤收集滤饼。滤饼再用无水乙醇(2L)溶解,85℃搅拌1小时,过滤收集滤饼,滤饼在45℃真空干燥得到式(I)化合物。
1H NMR(DMSO-d
6,400MHz):δ(ppm)9.47(s,1H),8.45(s,1H),7.80(s,1H),7.33-7.42(m,4H),7.29(m,J=7.0Hz,1H),6.34(d,J=1.6Hz,1H),4.98(s,2H),4.95(d,J=7.4Hz,2H),4.75(d,J=7.3Hz,2H),3.72(s,3H),2.46(s,3H)。
实施例2:式(I)化合物A晶型的制备
取5g式(I)化合物,分别用100mL表7中所示的各溶剂,在相应温度下搅拌2天,过滤收集固体。固体置于真空干燥箱中(45℃)干燥16小时,得式(I)化合物的A晶型。
表7
实施例3:式(I)化合物A晶型的吸湿性研究
1.实验方法:
1)取式(I)化合物A晶型(10~30mg)置于DVS样品盘内进行测试;
2)DVS测试前、后的样品分别测试XRPD。
2.实验结果:
式(Ⅰ)所示化合物A晶型的DVS如图4所示。
结论:DVS结果显示,样品在25℃/80%RH条件下吸湿增重0.03%,样品几乎无引湿性。
实施例4:式(I)化合物A晶型的稳定性实验
1.实验目的:
对式(I)化合物A晶型进行影响因素(高温、高湿及光照)和加速条件下(40℃/75%RH及60℃/75%RH) 稳定性的考察,评估A晶型的固体稳定性。
2.实验方法:
1)分别精密称取式(I)化合物A晶型约10mg置于干燥洁净的玻璃瓶中,称2份,分别标记为S1-条件-时间和S2-条件-时间,再称取约20mg置于干燥洁净的玻璃瓶中,标记为S3-条件-时间,摊成薄薄一层,作为供试样品,放置于影响因素试验条件下(60℃,25℃/92.5%RH,光照,光照对照)和加速条件下(40℃/75%RH和60℃/75%RH),其样品为完全暴露放样。60℃,25℃/92.5%RH,光照,光照对照在5天、10天取样分析,加速条件在1个月、2个月、3个月取样分析,分析方法如表8所示。
表8
2)在考察时间点,将相应的供试样品取出,用瓶盖盖好,0天的样品从冰箱中取出,待样品恢复至室温后进行分析。标记为S1-条件-时间的供试品用于含量和有关物质检测;标记为S2-条件-时间的供试品用作备样,标记为S3-条件-时间的供试品用于XRPD检测。
3.实验结果:
A晶型固体稳定性实验结果如表9所示。
表9
*光照(总照度可见光=1.2×10
6Lux·hr/近紫外总能量=200w·hr/m
2,敞口);**与可见光+紫外同时。
结论:式(I)化合物A晶型具有良好的稳定性。
实施例5:式(I)化合物A晶型在小鼠HCT116模型药效研究
1.实验目的:
使用人结肠癌HCT-116细胞皮下异种移植肿瘤裸小鼠模型,评价式(I)化合物A晶型的抗肿瘤作用。
2.实验动物:
种属:小鼠
品系:BALB/c裸小鼠
周龄:6-8周龄
性别:雄性
体重:18-22克
供应商:北京维通利华实验动物有限公司
动物合格证号:20170011005645
3.实验内容:
1)实验细胞及培养:人结肠癌HCT-116细胞体外单层培养,培养条件为McCoy's 5a培养基中加10%胎牛血清,37℃的5%CO2孵箱培养。一周三次用胰酶-乙二胺四乙酸进行常规消化处理传代。当细胞饱和度为80%-90%,数量到达要求时,收取细胞,计数,接种;
2)肿瘤组织接种及分组:0.2mL(5×10
6个)HCT-116细胞皮下接种于每只小鼠的右侧腋下,肿瘤平均体积达到114mm
3时,将动物随机分为四组,开始给药。实验分组和给药方案见表10:
表10 实验动物分组及给药方案
3)实验动物日常观察:本实验方案的拟定及任何修改均通过了实验动物管理与使用委员会(IACUC)的评估核准。实验动物的使用及福利遵照国际实验动物评估和认可委员会(AAALAC)的规定执行。每天监测动物的健康状况及死亡情况,例行检查包括观察肿瘤生长和药物治疗对动物日常行为表现的影响如行为活动,摄食摄水量(仅目测),体重变化(每周测量两次体重),外观体征或其它不正常情况。基于各组动物数量记录了组内动物死亡数和副作用。
4)受试物的配制
a)溶媒组:5%DMSO+95%(10%HP-β-CD)。
b)待测化合物组:称量定量的受试化合物于配药瓶内,加入相应体积的DMSO后涡旋,得到澄清溶液,在加入相应体积的10%HP-β-CD后涡旋,得到澄清溶液。化合物三天配制一次。
5)肿瘤测量和实验指标:
a)每周两次用游标卡尺测量肿瘤直径。肿瘤体积的计算公式为:TV=1/2×a×b
2,a和b分别表示肿瘤的长径和短径;
b)化合物的抑瘤疗效用TGI(%)评价。TGI(%),反映肿瘤生长抑制率。TGI(%)的计算:TGI(%)={[1-(某处理组给药结束时平均瘤体积-该处理组开始给药时平均瘤体积)]/(溶剂对照组治疗结束时平均瘤体积-溶剂对照组开始治疗时平均瘤体积)}×100%。
4.实验结果:
1)如表11和图5所示,在人结肠癌HCT-116细胞皮下异种移植肿瘤裸小鼠模型上,口服给药至第19天,式(I)化合物A晶型三个剂量组(7.5mg/kg,15mg/kg和30mg/kg)具有明显的抑制肿瘤生长作用,呈现剂量依赖性,它们的TGI分别为66%,71%和93%。
2)实验动物的体重作为间接测定药物毒性的参考指标。如图6所示,给药至第19天时,溶剂对照组和(I)化合物A晶型三个剂量组所有动物的体重均未有明显下降,无发病或死亡现象。
表11:小鼠HCT116模型体内药效实验结果
组别 | 药物 | TGI |
2 | A晶型(7.5mg/kg,PO,QD) | 66% |
3 | A晶型(15mg/kg,PO,QD) | 71% |
4 | A晶型(30mg/kg,PO,QD) | 93% |
结论:式(I)化合物A晶型在给药剂量下,能显著抑制肿瘤生长,呈现剂量依赖性;给药过程中动物的体重未见明显下降,耐受性好。
Claims (11)
- 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:8.16±0.20°、13.57±0.20°、16.95±0.20°、17.39±0.20°、19.37±0.20°、22.22±0.20°、23.88±0.20°和25.85±0.20°。
- 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:8.16±0.20°、13.57±0.20°、14.51±0.20°、16.95±0.20°、17.39±0.20°、19.37±0.20°、22.22±0.20°、23.88±0.20°和25.85±0.20°。
- 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:8.16°、9.99°、13.57°、14.51°、15.61°、16.95°、17.39°、18.27°、19.37°、19.71°、21.40°、21.97°、22.22°、23.88°、25.02°、25.85°、26.50°、27.36°、28.72°、30.39°、31.19°、31.53°、31.97°、32.57°、33.05°和37.72°。
- 根据权利要求4所述的A晶型,其XRPD图谱基本如附图1所示。
- 根据权利要求1~5任意一项所述的A晶型,其差示扫描量热曲线在225.5±3℃有一个吸热峰的起始点。
- 根据权利要求6所述的A晶型,其DSC图谱如附图2所示。
- 根据权利要求1~5任意一项所述的A晶型,其热重分析曲线在200.0±3℃时失重达2.41%。
- 根据权利要求8所述的A晶型,TGA图谱如图3所示。
- 根据权利要求10所述的式(Ⅰ)化合物A晶型的制备方法,其中,所述有机溶剂为乙醇、MeOH、ACN、丙酮、EtOAc、二氧六环、甲苯、H 2O、THF:H 2O(v/v,1:1)、EtOH:H 2O(v/v,2:1)、丙酮:EtOAc(v/v,1:1)、DMF:EtOAc(v/v,5:95)、DMF:H 2O(v/v,5:95)、丙酮:H 2O(v/v,95:5)、二氧六环:H 2O(v/v,97:3)、THF或DCM:EtOAc(v/v,2:1)。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202011252031.8 | 2020-11-11 | ||
CN202011252031 | 2020-11-11 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2022100586A1 true WO2022100586A1 (zh) | 2022-05-19 |
Family
ID=81602135
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CN2021/129643 WO2022100586A1 (zh) | 2020-11-11 | 2021-11-09 | 一种含氧杂环丁烷的螺环类化合物的晶型、制备方法及其应用 |
Country Status (1)
Country | Link |
---|---|
WO (1) | WO2022100586A1 (zh) |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008153947A2 (en) * | 2007-06-07 | 2008-12-18 | Amgen Inc. | Heterocyclic compounds as raf kinase modulators |
CN103189369A (zh) * | 2010-09-01 | 2013-07-03 | 吉利德康涅狄格有限公司 | 吡啶酮/吡嗪酮、其制备方法及使用方法 |
CN103201277A (zh) * | 2010-09-01 | 2013-07-10 | 吉利德康涅狄格有限公司 | 哒嗪酮、其制备方法及使用方法 |
WO2013130976A1 (en) * | 2012-03-01 | 2013-09-06 | Array Biopharma Inc. | Serine/threonine kinase inhibitors |
CN107074874A (zh) * | 2014-12-22 | 2017-08-18 | 伊莱利利公司 | Erk抑制剂 |
WO2020228817A1 (zh) * | 2019-05-15 | 2020-11-19 | 南京明德新药研发有限公司 | Erk抑制剂及其应用 |
-
2021
- 2021-11-09 WO PCT/CN2021/129643 patent/WO2022100586A1/zh active Application Filing
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008153947A2 (en) * | 2007-06-07 | 2008-12-18 | Amgen Inc. | Heterocyclic compounds as raf kinase modulators |
CN103189369A (zh) * | 2010-09-01 | 2013-07-03 | 吉利德康涅狄格有限公司 | 吡啶酮/吡嗪酮、其制备方法及使用方法 |
CN103201277A (zh) * | 2010-09-01 | 2013-07-10 | 吉利德康涅狄格有限公司 | 哒嗪酮、其制备方法及使用方法 |
WO2013130976A1 (en) * | 2012-03-01 | 2013-09-06 | Array Biopharma Inc. | Serine/threonine kinase inhibitors |
CN107074874A (zh) * | 2014-12-22 | 2017-08-18 | 伊莱利利公司 | Erk抑制剂 |
WO2020228817A1 (zh) * | 2019-05-15 | 2020-11-19 | 南京明德新药研发有限公司 | Erk抑制剂及其应用 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US10457666B2 (en) | Stable crystal form of tipiracil hydrochloride and crystallization method for the same | |
WO2020125747A1 (zh) | 一种mek抑制剂的晶型、无定形及其应用 | |
TWI765451B (zh) | 作為erk抑制劑的螺環類化合物及其應用 | |
TWI758999B (zh) | 作為erk抑制劑的噻唑并內醯胺類化合物及其應用 | |
JP2018537497A (ja) | ピリド[1,2−a]ピリミドン類似体、それらの結晶形、それらの中間体、及びそれらの製造方法 | |
WO2023160727A1 (zh) | 吲唑类化合物用于治疗银屑病的用途 | |
WO2022171044A1 (zh) | 一种氧氮杂螺环化合物、其盐型及其晶型 | |
WO2022100586A1 (zh) | 一种含氧杂环丁烷的螺环类化合物的晶型、制备方法及其应用 | |
CN103476742A (zh) | 阿戈美拉汀的新晶型ⅶ、其制备方法、应用和包含其的药物组合物 | |
WO2016101867A1 (zh) | 萘普替尼对甲苯磺酸盐的α晶型及制备方法和含有其的药物组合物 | |
WO2019149254A1 (zh) | 一种小分子免疫化合物的晶型、其制备方法和含有其的药物组合物 | |
WO2022063229A1 (zh) | 含芳氨基喹唑啉的化合物的盐及其制备方法和应用 | |
WO2020147838A1 (zh) | 一种egfr抑制剂的盐、晶型及其制备方法 | |
CN101083983A (zh) | 具有抗肿瘤活性的吲哚衍生物 | |
WO2019206268A1 (zh) | 一种c-MET抑制剂的晶型及其盐型和制备方法 | |
TWI825811B (zh) | 噻唑並內醯胺並螺雜環類化合物及其應用 | |
WO2022135580A1 (zh) | 吡啶并吡咯类化合物的晶型、制备方法及其应用 | |
WO2022253186A1 (zh) | 一种二甲基取代的噻唑并吡咯酮类化合物的晶型及其制备方法 | |
WO2022048545A1 (zh) | 一种吡啶并嘧啶化合物的晶型 | |
EP4365171A1 (en) | Crystal form of triazolopyridine-substituted indazole compound and preparation method therefor | |
WO2022063325A1 (zh) | 吡啶苯基类化合物的晶型及其制备方法 | |
WO2023185638A1 (zh) | 一种喹啉衍生物的晶型及其制备方法 | |
CN108658945A (zh) | 一种微管蛋白抑制剂(vda-1)的a晶型 | |
WO2023072263A1 (zh) | 5-取代的吡啶-2(1h)-酮类化合物及其应用 | |
CN113929663A (zh) | Azd9291-2-吲哚甲酸盐及其制备方法 |
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: 21891106 Country of ref document: EP Kind code of ref document: A1 |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 21891106 Country of ref document: EP Kind code of ref document: A1 |
|
32PN | Ep: public notification in the ep bulletin as address of the adressee cannot be established |
Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC (EPO FORM 1205A DATED 10/11/2023) |