CN113574058A - 吲哚类大环衍生物、其制备方法及其在医药上的应用 - Google Patents
吲哚类大环衍生物、其制备方法及其在医药上的应用 Download PDFInfo
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- CN113574058A CN113574058A CN202080021819.XA CN202080021819A CN113574058A CN 113574058 A CN113574058 A CN 113574058A CN 202080021819 A CN202080021819 A CN 202080021819A CN 113574058 A CN113574058 A CN 113574058A
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- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 150000001975 deuterium Chemical group 0.000 description 1
- 125000004431 deuterium atom Chemical group 0.000 description 1
- 238000002059 diagnostic imaging Methods 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- GWQVMPWSEVRGPY-UHFFFAOYSA-N europium cryptate Chemical compound [Eu+3].N=1C2=CC=CC=1CN(CC=1N=C(C=CC=1)C=1N=C(C3)C=CC=1)CC(N=1)=CC(C(=O)NCCN)=CC=1C(N=1)=CC(C(=O)NCCN)=CC=1CN3CC1=CC=CC2=N1 GWQVMPWSEVRGPY-UHFFFAOYSA-N 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000012737 fresh medium Substances 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
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- 125000000592 heterocycloalkyl group Chemical group 0.000 description 1
- 238000002868 homogeneous time resolved fluorescence Methods 0.000 description 1
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
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- 238000007918 intramuscular administration Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical class CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical class IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- VUZBZSALKUQCHO-HWKANZROSA-N methyl (E)-4-(4-bromo-2-methoxyphenyl)but-2-enoate Chemical compound BrC1=CC(=C(C=C1)C/C=C/C(=O)OC)OC VUZBZSALKUQCHO-HWKANZROSA-N 0.000 description 1
- OXOKLYPPZNYFBN-UHFFFAOYSA-N methyl 4-(4-bromo-2-methoxyphenyl)butanoate Chemical compound BrC1=CC(=C(C=C1)CCCC(=O)OC)OC OXOKLYPPZNYFBN-UHFFFAOYSA-N 0.000 description 1
- LWBZGCSTRHHUEJ-UHFFFAOYSA-N methyl 6-chloro-7-[3-(iodomethyl)-1,5-dimethylpyrazol-4-yl]-3-(3-methoxy-3-oxopropyl)-1-methylindole-2-carboxylate Chemical compound ClC1=CC=C2C(=C(N(C2=C1C=1C(=NN(C=1C)C)CI)C)C(=O)OC)CCC(=O)OC LWBZGCSTRHHUEJ-UHFFFAOYSA-N 0.000 description 1
- RDMVSUNLQQNCJG-UHFFFAOYSA-N methyl 6-chloro-7-[3-[[5-(chloromethyl)-1-methylpyrazol-3-yl]methylsulfanylmethyl]-1,5-dimethylpyrazol-4-yl]-3-(3-methoxy-3-oxopropyl)-1-methylindole-2-carboxylate Chemical compound ClC1=CC=C2C(=C(N(C2=C1C=1C(=NN(C=1C)C)CSCC1=NN(C(=C1)CCl)C)C)C(=O)OC)CCC(=O)OC RDMVSUNLQQNCJG-UHFFFAOYSA-N 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- XZMHJYWMCRQSSI-UHFFFAOYSA-N n-[5-[2-(3-acetylanilino)-1,3-thiazol-4-yl]-4-methyl-1,3-thiazol-2-yl]benzamide Chemical compound CC(=O)C1=CC=CC(NC=2SC=C(N=2)C2=C(N=C(NC(=O)C=3C=CC=CC=3)S2)C)=C1 XZMHJYWMCRQSSI-UHFFFAOYSA-N 0.000 description 1
- RIVIDPPYRINTTH-UHFFFAOYSA-N n-ethylpropan-2-amine Chemical compound CCNC(C)C RIVIDPPYRINTTH-UHFFFAOYSA-N 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 231100000344 non-irritating Toxicity 0.000 description 1
- 239000000346 nonvolatile oil Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 238000011369 optimal treatment Methods 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000009666 routine test Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical class [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- WGRQANOPCQRCME-PMACEKPBSA-N teneligliptin Chemical compound O=C([C@H]1NC[C@H](C1)N1CCN(CC1)C1=CC(=NN1C=1C=CC=CC=1)C)N1CCSC1 WGRQANOPCQRCME-PMACEKPBSA-N 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- VLPFTAMPNXLGLX-UHFFFAOYSA-N trioctanoin Chemical compound CCCCCCCC(=O)OCC(OC(=O)CCCCCCC)COC(=O)CCCCCCC VLPFTAMPNXLGLX-UHFFFAOYSA-N 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D515/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D515/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains four or more hetero rings
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本公开涉及吲哚类大环衍生物、其制备方法及其在医药上的应用。具体而言,本公开涉及一种通式(I)所示的吲哚类大环衍生物、其制备方法及含有该衍生物的药物组合物以及其作为治疗剂,特别是作为MCL‑1抑制剂的用途,和其治疗肿瘤、自身免疫性疾病或免疫系统疾病的用途,其中通式(I)的各取代基与说明书中的定义相同。
Description
PCT国内申请,说明书已公开。
Claims (18)
- PCT国内申请,权利要求书已公开。
Applications Claiming Priority (3)
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CN201910363884 | 2019-04-30 | ||
CN201910363884X | 2019-04-30 | ||
PCT/CN2020/087671 WO2020221272A1 (zh) | 2019-04-30 | 2020-04-29 | 吲哚类大环衍生物、其制备方法及其在医药上的应用 |
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CN113574058A true CN113574058A (zh) | 2021-10-29 |
CN113574058B CN113574058B (zh) | 2024-04-16 |
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US20220396587A1 (en) * | 2019-01-23 | 2022-12-15 | Ascentage Pharma (Suzhou) Co., Ltd. | Macrocyclic fused pyrrazoles as mcl-1 inhibitors |
EP4263556A1 (en) | 2020-12-17 | 2023-10-25 | JANSSEN Pharmaceutica NV | Branched macrocyclic 4-(pyrazol-5-yl)-indole derivatives as inhibitors of mcl-1 |
WO2022251247A1 (en) * | 2021-05-28 | 2022-12-01 | Zeno Management, Inc. | Macrocyclic compounds |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101743224A (zh) * | 2007-04-16 | 2010-06-16 | 雅培制药有限公司 | 7-取代的吲哚mcl-1抑制剂 |
CN109071566A (zh) * | 2016-04-22 | 2018-12-21 | 阿斯利康(瑞典)有限公司 | 用于治疗癌症的大环mcl-1抑制剂 |
TW201904976A (zh) * | 2017-03-31 | 2019-02-01 | 瑞典商阿斯特捷利康公司 | Mcl-1抑制劑及其使用方法 |
Family Cites Families (1)
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WO2020103864A1 (en) * | 2018-11-22 | 2020-05-28 | Ascentage Pharma (Suzhou) Co., Ltd. | Macrocyclic indoles as mcl-1 inhibitors |
-
2020
- 2020-04-29 CN CN202080021819.XA patent/CN113574058B/zh active Active
- 2020-04-29 WO PCT/CN2020/087671 patent/WO2020221272A1/zh active Application Filing
- 2020-04-29 TW TW109114342A patent/TW202106693A/zh unknown
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101743224A (zh) * | 2007-04-16 | 2010-06-16 | 雅培制药有限公司 | 7-取代的吲哚mcl-1抑制剂 |
CN109071566A (zh) * | 2016-04-22 | 2018-12-21 | 阿斯利康(瑞典)有限公司 | 用于治疗癌症的大环mcl-1抑制剂 |
TW201904976A (zh) * | 2017-03-31 | 2019-02-01 | 瑞典商阿斯特捷利康公司 | Mcl-1抑制劑及其使用方法 |
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