CN116444529B - 一种氘代氮杂环丁烷类jak抑制剂及其用途 - Google Patents
一种氘代氮杂环丁烷类jak抑制剂及其用途 Download PDFInfo
- Publication number
- CN116444529B CN116444529B CN202310716911.3A CN202310716911A CN116444529B CN 116444529 B CN116444529 B CN 116444529B CN 202310716911 A CN202310716911 A CN 202310716911A CN 116444529 B CN116444529 B CN 116444529B
- Authority
- CN
- China
- Prior art keywords
- deuterated
- compound
- pharmaceutically acceptable
- azetidine
- acceptable salts
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 229940122245 Janus kinase inhibitor Drugs 0.000 title claims abstract description 17
- 150000001539 azetidines Chemical class 0.000 title claims abstract description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 22
- 238000002360 preparation method Methods 0.000 claims description 14
- 150000003839 salts Chemical class 0.000 claims description 13
- -1 deuterated azetidine compound Chemical class 0.000 claims description 10
- 229910052805 deuterium Inorganic materials 0.000 claims description 4
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 3
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims description 2
- 239000002775 capsule Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000008187 granular material Substances 0.000 claims description 2
- 239000007924 injection Substances 0.000 claims description 2
- 238000002347 injection Methods 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- 239000002674 ointment Substances 0.000 claims description 2
- 239000006187 pill Substances 0.000 claims description 2
- 239000000843 powder Substances 0.000 claims description 2
- 239000000829 suppository Substances 0.000 claims description 2
- 239000006188 syrup Substances 0.000 claims description 2
- 235000020357 syrup Nutrition 0.000 claims description 2
- 239000003826 tablet Substances 0.000 claims description 2
- 239000002552 dosage form Substances 0.000 claims 1
- 150000003840 hydrochlorides Chemical class 0.000 claims 1
- 150000002688 maleic acid derivatives Chemical class 0.000 claims 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 claims 1
- 235000021317 phosphate Nutrition 0.000 claims 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 claims 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 12
- 239000003814 drug Substances 0.000 description 9
- 102000042838 JAK family Human genes 0.000 description 7
- 108091082332 JAK family Proteins 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 238000004440 column chromatography Methods 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 101000997835 Homo sapiens Tyrosine-protein kinase JAK1 Proteins 0.000 description 5
- 101000997832 Homo sapiens Tyrosine-protein kinase JAK2 Proteins 0.000 description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- 102100033438 Tyrosine-protein kinase JAK1 Human genes 0.000 description 5
- 102100033444 Tyrosine-protein kinase JAK2 Human genes 0.000 description 5
- 238000003556 assay Methods 0.000 description 5
- 229940125904 compound 1 Drugs 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 238000001308 synthesis method Methods 0.000 description 5
- 238000010189 synthetic method Methods 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 229940079593 drug Drugs 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 230000019491 signal transduction Effects 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 231100000331 toxic Toxicity 0.000 description 4
- 230000002588 toxic effect Effects 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 101000934996 Homo sapiens Tyrosine-protein kinase JAK3 Proteins 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 102100025387 Tyrosine-protein kinase JAK3 Human genes 0.000 description 3
- 229940125782 compound 2 Drugs 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000013642 negative control Substances 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 239000007995 HEPES buffer Substances 0.000 description 2
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- 102000008986 Janus Human genes 0.000 description 2
- 108050000950 Janus Proteins 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 2
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 239000012190 activator Substances 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 229940098773 bovine serum albumin Drugs 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 229960002897 heparin Drugs 0.000 description 2
- 229920000669 heparin Polymers 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].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.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 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000013518 transcription Methods 0.000 description 2
- 230000035897 transcription Effects 0.000 description 2
- 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 1
- 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 1
- BPXKZEMBEZGUAH-UHFFFAOYSA-N 2-(chloromethoxy)ethyl-trimethylsilane Chemical compound C[Si](C)(C)CCOCCl BPXKZEMBEZGUAH-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 101000844245 Homo sapiens Non-receptor tyrosine-protein kinase TYK2 Proteins 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- 230000004163 JAK-STAT signaling pathway Effects 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 102100032028 Non-receptor tyrosine-protein kinase TYK2 Human genes 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical class CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- QTBSBXVTEAMEQO-GUEYOVJQSA-N acetic acid-d4 Chemical compound [2H]OC(=O)C([2H])([2H])[2H] QTBSBXVTEAMEQO-GUEYOVJQSA-N 0.000 description 1
- 208000009956 adenocarcinoma Diseases 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000013584 assay control Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000003445 biliary tract Anatomy 0.000 description 1
- 201000009036 biliary tract cancer Diseases 0.000 description 1
- 208000020790 biliary tract neoplasm Diseases 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 229940125797 compound 12 Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000010250 cytokine signaling pathway Effects 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000012636 effector Substances 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 238000001952 enzyme assay Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 210000001508 eye Anatomy 0.000 description 1
- 208000024519 eye neoplasm Diseases 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229940047124 interferons Drugs 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
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 description 1
- 201000011682 nervous system cancer Diseases 0.000 description 1
- 201000008106 ocular cancer Diseases 0.000 description 1
- 230000002611 ovarian Effects 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical class [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 108091006106 transcriptional activators Proteins 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- 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
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/05—Isotopically modified compounds, e.g. labelled
-
- 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)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种氘代氮杂环丁烷JAK抑制剂，如下式Ⅰ所示，本发明涉及氘代氮杂环丁烷JAK抑制剂、其药物组合物及用途。
Description
技术领域
本发明属于生物医药领域，具体涉及一种氘代氮杂环丁烷类JAK抑制剂及其用途。
背景技术
AK/STAT(Janus protein tyrosine kinase/signal transducer and activatorof transcription，Janus蛋白酪氨酸激酶/信号转导子和转录激活子)信号通路是20世纪90年代人们研究干扰素时所发现的一种重要的细胞因子信号转导通路，可完成从胞质到核内的信号转导。哺乳动物JAK家族有四个成员，分别为JAK1、JAK2、JAK3和TYK2。该信号通路与免疫、炎症以及细胞增殖、分化、存活和凋亡等有关。JAK激酶包含JAK1、JAK2、JAK3和Tyk2四个亚型，与下游效应分子STAT（signal transducers and activators oftranscription）组成的JAK-STAT信号通路调控体内50多种细胞因子的炎症、免疫信号，JAK-STAT信号通路在多种炎症疾病，如类风湿关节炎的发辫机制中发挥重要的作用，JAK抑制剂可选择性抑制JAK激酶，阻断JAK-STAT通路，从而从源头上阻断类风湿关节炎的进展。巴瑞替尼是一类JAK 抑制剂，可选择性阻断JAK1和JAK2，抑制被激活的炎症通路。
氘代药物，既将药物分子的一个或多个碳氢键用碳氘键替代的新药物分子，可以通过改善原有药物的药代动力学性质，进而克服药物原有的易于代谢、副作用较大等缺陷。
本发明为多位点氘代氮杂环丁烷类JAK抑制剂药物，相对于单位点氘代化合物，可以进一步改善目前JAK抑制剂药物巴瑞替尼的药代动力学性质，降低给药剂量和可能的毒副作用。
发明内容
本发明提供的多位点氘代氮杂环丁烷类JAK抑制剂巴瑞替尼化合物及其药学上可接受的盐，可以进一步改善JAK抑制剂巴瑞替尼的氘代氮杂环丁烷类化合物及其药学上可接受的盐的药代动力学性质，降低给药剂量和可能的毒副作用。
为了实现上述目的，如本发明所述一种如下式Ⅰ所示的JAK抑制剂的氘代氮杂环丁烷类化合物及其药学上可接受的盐：
其中，R1, R2, R3, R4, R5, R6独立地选自H或氘，且R1, R2, R3, R4, R5, R6不同时为H.
进一步本发明所述JAK抑制剂的氘代氮杂环丁烷类化合物，其结构为：
。
本发明所述JAK抑制剂的氘代氮杂环丁烷类化合物及其药学上可接受的盐，进一步，其药学上可接受的盐选自甲磺酸盐、马来酸盐、盐酸盐或磷酸盐。
本发明所述的氘代氮杂环丁烷类化合物及其药学上可接受的盐，包括其在制备抗肿瘤药物中的应用。
进一步，所述的肿瘤选自肺癌、胰腺癌、膀胱癌、结肠癌、髓系障碍、前列腺癌、甲状腺癌、黑色素瘤、腺癌和卵巢、眼、肝脏、胆道和神经系统癌。
本发明所述的氘代氮杂环丁烷类化合物及其药学上可接受的盐，包括氘代氮杂环丁烷类化合物及其药学上可接受的盐作为活性成分和药学上可接受的载体组成。
本发明所述的氘代氮杂环丁烷类化合物及其药学上可接受盐的药物组合物，所述药物组合物选自胶囊剂、散剂、片剂、颗粒剂、丸剂、注射剂、糖浆剂、口服液、吸入剂、软膏剂、栓剂或贴剂。有益效果：与现有技术相比，本发明具有如下优点：
本发明提供一类氘代氮杂环丁烷类JAK抑制剂药物，进一步改善JAK抑制剂的药代动力学性质，降低给药剂量和可能的毒副作用。
具体实施方式
以下结合实施例对本发明作进一步说明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。
实施例1：化合物1的制备
化合物1的合成方法如下所示
向中间体1（0.5 mmol）的N,N-二甲基甲酰胺（10 mL）溶液中加入氢氧化钾（2mmol，4eq）和碘单质（1 mmol，2eq）,室温反应3小时，TLC监测反应完全，加入亚硫酸钠饱和溶液淬灭反应，水相用乙酸乙酯（10 mL*2）萃取，水（20 mL*2）洗，饱和食盐（20 mL）水洗无水硫酸钠干燥，浓缩柱层析，得中间体2。
向中间体2（0.5 mmol）的氘代醋酸溶液（8 mL）中加入醋酸钠（1 mmol，2eq），2小时滴完，室温反应24小时，TLC检测反应完全，减压浓缩，柱层析得中间体3。
将中间体4（3mmol）用DMF（3mL）溶解，0℃条件下加入钠氢（6mmol），并继续搅拌反应半小时，将SEM氯化物（6mmol）滴加入反应液中，移至室温继续反应过夜。TLC检测反应完全，加入水，用乙酸乙酯萃取，有机相收集浓缩得中间体5。
将中间体5（3mmol）和中间体3（3mmol）用1, 4-二氧六环（50mL）溶解，再加入四三苯基膦钯（10%mol）和碳酸钾（6mmol）并用氮气保护，升温至100℃搅拌16小时。浓缩后，经柱层析得中间体6。
中间体6（1mmol）用2mL的1N盐酸溶解，10℃搅拌1小时后，有机相浓缩，浓缩溶剂后，经柱层析得中间体7。
向中间体7（0.5 mmol）和中间体8（0.5mmol）用1, 4-二氧六环（10mL）溶解，再加入四三苯基膦钯（10%mol）和碳酸钾（1 mmol）并用氮气保护，升温至100℃搅拌16小时。浓缩后，经柱层析得中间体9。
中间体9（0.5 mmol）用2mL的三氟乙酸溶解，室温搅拌4小时后，有机相浓缩，加入2mL的甲醇，进一步加入1mL的乙二胺，置于室温搅拌过夜，浓缩溶剂后，经柱层析得化合物1。1H NMR (500 MHz, Chloroform-d) δ 9.86 (t, J = 2.1 Hz, 1H), 8.84 (s, 1H),8.10 (s, 1H), 7.49 – 7.31 (m, 2H), 3.68 (s, 1H), 3.67 (s, 1H), 2.79 (s, 2H),2.51 (q, J = 7.0 Hz, 2H), 1.37 (t, J = 6.9 Hz, 3H)。
实施例2：化合物2的制备
化合物2的合成方法如下所示
将实施例1中的中间体5(0.5 mmol)溶于二氯甲烷溶于氘代叔丁醇（2.5mmol），加入Ru3(CO)12(5%mol)，氮气保护的条件下，置于115℃反应三小时，旋干溶剂，经柱层析得中间体10。
参照实施例1的合成方法，把中间体5替换成中间体10，可制得化合物2. 1H NMR(500 MHz, Chloroform-d) δ 8.90 (s, 1H), 8.17 (s, 1H), 7.60 (d, J = 2.6 Hz,1H), 3.73 – 3.55 (m, 4H), 2.79 (s, 2H), 2.51 (q, J = 7.0 Hz, 2H), 1.37 (t, J= 6.9 Hz, 3H)。
实施例3：化合物3的制备
参照中间体2的合成方法，可制得化合物3。1H NMR (500 MHz, Chloroform-d) δ8.84 (s, 1H), 8.46 (s, 1H), 8.17 (s, 1H), 7.48 (d, J = 2.6 Hz, 1H), 3.76 –3.46 (m, 4H), 2.78 (s, 2H), 2.51 (q, J = 7.0 Hz, 2H), 1.37 (t, J = 6.9 Hz,3H)。
实施例4：化合物4的制备
参照实施例1的合成方法，把中间体4替换成7H-吡咯[2,3-d]吡啶-7-氘-4-氯，可制得化合物4。1H NMR (500 MHz, Chloroform-d) δ 8.87 (s, 1H), 8.11 (d, J = 4.2Hz, 1H), 8.03 (s, 1H), 7.45 (d, J = 4.4 Hz, 1H), 3.78 – 3.46 (m, 4H), 2.79(s, 2H), 2.51 (q, J = 7.0 Hz, 2H), 1.37 (t, J = 6.9 Hz, 3H)。
实施例5：化合物5的制备
参照实施例4的合成方法，可制得化合物5。1H NMR (500 MHz, Chloroform-d) δ8.80 (s, 1H), 8.32 (s, 1H), 8.02 (s, 1H), 7.98 (d, J = 4.4 Hz, 1H), 7.38 (d,J = 4.4 Hz, 1H), 3.72 – 3.49 (m, 4H), 2.78 (s, 2H), 2.51 (q, J = 7.0 Hz, 2H),1.37 (t, J = 6.9 Hz,
3H)。
实施例6：化合物6的制备
参考实施例1的合成方法，将中间体5替换成中间体12，可制得化合物6. 1H NMR(500 MHz, Chloroform-d) δ 9.55 (s, 1H), 8.36 (s, 1H), 3.76 – 3.48 (m, 4H),2.79 (s, 2H), 2.51 (q, J = 7.0 Hz, 2H), 1.37 (t, J = 6.9 Hz, 3H)。
实施例7：化合物7的制备
参考实施例4的合成方法，可制得化合物7. 1H NMR (500 MHz, Chloroform-d) δ9.15 (s, 1H), 8.66 (s, 1H), 8.37 (s, 1H), 3.74 – 3.45 (m, 4H), 2.78 (s, 2H),2.51 (q, J = 7.0 Hz, 2H), 1.37 (t, J = 6.9 Hz, 3H)。
实施例8：化合物8的制备
参考实施例1的合成方法，可制得化合物8. 1H NMR (500 MHz, Chloroform-d) δ8.46 (s, 1H), 7.56 (s, 1H), 7.25 (d, J = 23.8 Hz, 2H), 3.95 – 3.65 (m, 2H),3.30 – 2.97 (m, 2H), 1.23 (s, 3H)。
实施例9：化合物9的制备
参考实施例2的合成方法，可制得化合物9。1H NMR (500 MHz, Chloroform-d) δ9.82 (s, 1H), 8.46 (s, 1H), 7.51 (s, 1H), 7.35 (s, 1H), 3.95 – 3.68 (m, 2H),3.28 – 3.00 (m, 2H), 1.23 (s, 3H)。
实施例10：化合物10的制备
参考实施例4的合成方法，可制得实施例10. 1H NMR (500 MHz, Chloroform-d)δ 8.35 (s, 1H), 7.56 (s, 1H), 7.46 (s, 1H), 7.12 (s, 1H), 3.98 – 3.69 (m,2H), 3.36 – 3.01 (m, 2H), 1.23 (s, 3H)。
实施例11：化合物11的制备
参考实施例5的合成方法，可制得实施例11. 1H NMR (500 MHz, Chloroform-d)δ 8.33 (d, J = 43.2 Hz, 2H), 8.04 (s, 1H), 7.47 (s, 1H), 6.96 (s, 1H), 3.79 –3.52 (m, 2H), 3.34 – 2.86 (m, 2H), 1.23 (s, 3H)。
实施例12：化合物12的制备
参考实施例7的合成方法，可制得实施例12. 1H NMR (500 MHz, Chloroform-d)δ 9.53 (s, 1H), 7.31 (s, 1H), 3.98 – 3.56 (m, 2H), 3.35 – 3.08 (m, 2H), 1.23(s, 3H)。
试验例1：JAK酶活性测试
将测试品溶于二甲亚砜(DMSO)中至30mM的储备浓度。在DMSO中产生11点半对数连续稀释液，最高浓度为600μΜ测试化合物板还包含阳性对照组孔，其含有已知的抑制剂以定义100%抑制作用，以及含有DMSO以定义无抑制作用的阴性对照组孔。将化合物板经1比60稀释以使最终测定化合物的最高浓度为10μΜ并且DMSO浓度为2%。将测试品和测定对照物加至384孔板中。反应混合物含有20mM HEPES(pH=7.4), 10mM氯化镁,0.01%牛血清白蛋白(BSA)、0.0005%吐温20,4μΜ或1mM ATP。
JAK测定液含有lμM JAKtide通过加入1nM JAK1或JAK2酶，并对于JAK在室温下孵育75分钟来开始测定。对各个新的酶制剂的酶浓度和孵育时间均进行优化，并且随时间略作修改以确保有20%-30%的磷酸化作用。用最终浓度为10mM EDTA, 0.1%涂覆剂和100 mMHEPES (pH=7.4)以使测定停止。将测定板置于Caliper Life Science Lab Chip 3000(LC3000)仪器上，并使用适当的分离条件对各孔进行取样以测量未磷酸化和磷酸化的肽。
IC50分析：抑制率＝1-(实验孔读值-阴性对照孔读值)/(阳性对照孔读值-阴性对照孔读值)，将药物浓度和相应抑制率输入GraphPad Prism 5处理可计算出相应的IC50。表1代表本发明化合物对JAK3激酶的抑制活性数据。
表1：本发明实施例化合物抑制JAK的酶学数据
由表1的结果表明本发明实施例化合物对JAK1或JAK2均具有优良的抑制作用，且与巴瑞替尼相比抑制作用更优。
试验例2：化合物的药代动力学实验
（一）实验仪器和材料
高速冷冻离心机,涡旋振荡器(Vortex Genius3),高速离心机(Eppendorf5415D)，一次性使用注射器,移液枪(Eppendorf)，实验所用SD雄性大鼠均购自扬州大学，EDTA-K2真空采血管，生理盐水。所有口服组大鼠在给药前禁食12h，自由饮水,给药期间自由进水和进食。
（二）实验步骤
将实施例1的中间体1和化合物1使用DMSO/solutol/water（10/10/80）溶解制成澄清溶液，鼻内给药化合物剂量25mg/kg，尾静脉给药化合物的剂量为5mg/kg。于尾静脉给药后的2 min, 10 min, 30 min, 1 h, 2 h, 3 h, 5 h, 8 h, 12 h, 16 h, 24 h，从眼底静脉丛连续取血0.5 mL至肝素管中，鼻内给药后的5 min, 15 min, 30 min, 1 h, 2 h, 3h, 5 h, 8 h, 12 h, 16 h, 24 h，从眼底静脉丛连续取血0.5 mL肝素管中。将样品在8000r，4 0C条件下离心10 min后，取上层血浆0.15 mL，-200C条件下保存，之后进行LC-MS/MS分析。数据通过WinNolin非房室模型分析，得到关键药代动力学参数。
（三）实验结果
表2药代动力学参数
由表2数据可以看出，相对于巴瑞替尼，化合物1口服给药的半衰期提高明显，可以有效改进给药剂量，从而降低高剂量给药的毒副作用。
最后有必要说明的是，以上对本发明的具体实施例进行了详细描述，但其只作为范例，本发明并不限制于以上描述的具体实施例。对于本领域技术人员而言，任何对本发明进行的等同修改和替代也都在本发明的范畴之中。因此，在不脱离本发明的精神和范围下所作的均等变换和修改，都应涵盖在本发明的范围内。
Claims (5)
1.一种式Ⅰ所示氘代氮杂环丁烷类化合物及其药学上可接受的盐，
；
其中，R1, R2, R3, R4, R5, R6独立地选自H或氘，且R1, R2, R3, R4, R5, R6不同时为H，X1, X2, X3, X4, X5, X6独立地选自H或氘；其特征在于选自以下化合物：
。
2.根据权利要求1所述的氘代氮杂环丁烷类化合物及其药学上可接受的盐，其特征在于所述药学上可接受的盐选自甲磺酸盐、马来酸盐、盐酸盐或磷酸盐。
3.根据权利要求1所述的氘代氮杂环丁烷类化合物及其药学上可接受的盐在制备JAK抑制剂中的应用。
4.一种药物组合物，其特征在于，所述药物组合物由权利要求1所述的氘代氮杂环丁烷类化合物及其药学上可接受的盐作为活性成分和药学上可接受的载体组成。
5.根据权利要求4所述的药物组合物，其特征在于，所述药物组合物的剂型选自胶囊剂、散剂、片剂、颗粒剂、丸剂、注射剂、糖浆剂、口服液、吸入剂、软膏剂、栓剂或贴剂。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310716911.3A CN116444529B (zh) | 2023-06-16 | 2023-06-16 | 一种氘代氮杂环丁烷类jak抑制剂及其用途 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310716911.3A CN116444529B (zh) | 2023-06-16 | 2023-06-16 | 一种氘代氮杂环丁烷类jak抑制剂及其用途 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN116444529A CN116444529A (zh) | 2023-07-18 |
| CN116444529B true CN116444529B (zh) | 2023-12-05 |
Family
ID=87124167
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202310716911.3A Active CN116444529B (zh) | 2023-06-16 | 2023-06-16 | 一种氘代氮杂环丁烷类jak抑制剂及其用途 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN116444529B (zh) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN117186078A (zh) * | 2023-11-06 | 2023-12-08 | 药康众拓(北京)医药科技有限公司 | 氘代氮杂环丁烷类jak抑制剂药物及用途 |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102026999A (zh) * | 2008-03-11 | 2011-04-20 | 因塞特公司 | 作为jak抑制剂的氮杂环丁烷和环丁烷衍生物 |
| CN106551912A (zh) * | 2015-09-29 | 2017-04-05 | 南京优科制药有限公司 | 一种提高难溶性药物溶出度的方法 |
| WO2017097224A1 (zh) * | 2015-12-11 | 2017-06-15 | 四川科伦博泰生物医药股份有限公司 | 氮杂环丁烷衍生物、其制备方法及用途 |
| WO2020173364A1 (zh) * | 2019-02-27 | 2020-09-03 | 四川科伦博泰生物医药股份有限公司 | 以氮杂环丁烷衍生物为活性成分的口服药物组合物、其制备方法及用途 |
| WO2022012693A1 (zh) * | 2020-07-17 | 2022-01-20 | 轶诺(浙江)药业有限公司 | 一类肠道裂解型共药及其制备和用途 |
| CN115850179A (zh) * | 2022-12-13 | 2023-03-28 | 北京科翔中升医药科技有限公司 | 一种氘代吲唑类mapk抑制剂药物及用途 |
-
2023
- 2023-06-16 CN CN202310716911.3A patent/CN116444529B/zh active Active
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102026999A (zh) * | 2008-03-11 | 2011-04-20 | 因塞特公司 | 作为jak抑制剂的氮杂环丁烷和环丁烷衍生物 |
| CN106551912A (zh) * | 2015-09-29 | 2017-04-05 | 南京优科制药有限公司 | 一种提高难溶性药物溶出度的方法 |
| WO2017097224A1 (zh) * | 2015-12-11 | 2017-06-15 | 四川科伦博泰生物医药股份有限公司 | 氮杂环丁烷衍生物、其制备方法及用途 |
| WO2020173364A1 (zh) * | 2019-02-27 | 2020-09-03 | 四川科伦博泰生物医药股份有限公司 | 以氮杂环丁烷衍生物为活性成分的口服药物组合物、其制备方法及用途 |
| CN113508114A (zh) * | 2019-02-27 | 2021-10-15 | 四川科伦博泰生物医药股份有限公司 | 以氮杂环丁烷衍生物为活性成分的口服药物组合物、其制备方法及用途 |
| WO2022012693A1 (zh) * | 2020-07-17 | 2022-01-20 | 轶诺(浙江)药业有限公司 | 一类肠道裂解型共药及其制备和用途 |
| CN116249533A (zh) * | 2020-07-17 | 2023-06-09 | 轶诺(浙江)药业有限公司 | 一类肠道裂解型共药及其制备和用途 |
| CN115850179A (zh) * | 2022-12-13 | 2023-03-28 | 北京科翔中升医药科技有限公司 | 一种氘代吲唑类mapk抑制剂药物及用途 |
Non-Patent Citations (1)
| Title |
|---|
| 王世真主编.《分子核医学》.中国协和医科大学出版社,2001,第388-390页. * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN116444529A (zh) | 2023-07-18 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN112442030B (zh) | 作为krasg12c突变蛋白抑制剂的吡啶酮并嘧啶类衍生物 | |
| CN116444529B (zh) | 一种氘代氮杂环丁烷类jak抑制剂及其用途 | |
| EP4043450A1 (en) | 2h-benzopyran derivatives as crac inhibitors | |
| JP2021073256A (ja) | セミカルバジド感受性アミンオキシダーゼ（ｓｓａｏ）の阻害剤の医薬的塩形態 | |
| JP2022526926A (ja) | イミダゾロニルキノリン化合物およびそれらの治療への使用 | |
| JP2021073259A (ja) | セミカルバジド感受性アミンオキシダーゼ酵素阻害剤としての結晶性化合物 | |
| CN113717245B (zh) | 含有2,8,9-三取代-9h-嘌呤结构片段的egfr降解剂及其盐和应用 | |
| CN110028509B (zh) | 作为选择性jak2抑制剂的吡咯并嘧啶类化合物、其合成方法及用途 | |
| CN115353508A (zh) | 5-吡啶-1h-吲唑类化合物、药物组合物和应用 | |
| AU2022379782A1 (en) | Synthesis, preparation method and use of shp2 and cdk4/6 dual-target inhibitory compound | |
| CN116283997A (zh) | 氘代hgfr抑制剂药物及用途 | |
| CN116041324A (zh) | 一种氘代吡唑二氯苯甲酰胺类化合物、药物组合物和用途 | |
| CN116496280B (zh) | 氘代丙烯酰胺类jak3抑制剂药物及用途 | |
| CN110283174B (zh) | 一类PI3Kδ抑制剂及其用途 | |
| CN117186078A (zh) | 氘代氮杂环丁烷类jak抑制剂药物及用途 | |
| CN112645955A (zh) | 一种[1,2,4]三唑并[4,3-b]哒嗪类化合物及其制备方法和用途 | |
| CN111484495A (zh) | 含二氢蝶啶二酮骨架衍生物的制备方法和用途 | |
| CN111349057A (zh) | 一类新型姜黄素衍生物的合成制备方法以及在肿瘤治疗的应用 | |
| CN115572294B (zh) | 一种氘代氮杂吲哚联吡唑类化合物、药物组合物和用途 | |
| CN115746002B (zh) | 一种氘代氮杂吲哚氨基-吡唑甲酰胺类化合物及其用途 | |
| CN116478141B (zh) | 氘代kras抑制剂药物及用途 | |
| CN115716829B (zh) | 一种喹啉并咪唑酮联氘代吡唑类化合物及其应用 | |
| CN109796415B (zh) | Egfr抑制剂及其应用 | |
| CN116444496B (zh) | 一种嘧啶联氘代吡唑类化合物及其应用 | |
| CN115397827B (zh) | Fgfr4抑制剂的盐型、晶型及其用途 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20231108 Address after: 224500 4th floor, North building, building 2, enterprise accelerator, Xin'an Avenue, Binhai Pharmaceutical Industrial Park, Binhai County, Yancheng City, Jiangsu Province Applicant after: Yaokang Zhongtuo (Jiangsu) Pharmaceutical Technology Co.,Ltd. Address before: 100036 Beijing city Haidian District Cuiwei Road No. 2, building A, room 1209, static source in Applicant before: Beijing Kexiang Zhongsheng Pharmaceutical Technology Co.,Ltd. |
|
| TA01 | Transfer of patent application right | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |