CN109485636A - A kind of hydrochloride of novel B TK kinase inhibitor and preparation method thereof and purposes - Google Patents
A kind of hydrochloride of novel B TK kinase inhibitor and preparation method thereof and purposes Download PDFInfo
- Publication number
- CN109485636A CN109485636A CN201811164079.6A CN201811164079A CN109485636A CN 109485636 A CN109485636 A CN 109485636A CN 201811164079 A CN201811164079 A CN 201811164079A CN 109485636 A CN109485636 A CN 109485636A
- Authority
- CN
- China
- Prior art keywords
- formula
- compound
- preparation
- hydrochloride
- group
- 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.)
- Withdrawn
Links
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 title claims abstract description 28
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 229940043355 kinase inhibitor Drugs 0.000 title abstract description 4
- 239000003757 phosphotransferase inhibitor Substances 0.000 title abstract description 4
- -1 phenyl ester Chemical class 0.000 claims abstract description 15
- 150000002148 esters Chemical class 0.000 claims abstract description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims description 38
- 238000006243 chemical reaction Methods 0.000 claims description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 20
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- 206010028980 Neoplasm Diseases 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 5
- 229940079593 drug Drugs 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 3
- QXKHYNVANLEOEG-UHFFFAOYSA-N Methoxsalen Chemical group C1=CC(=O)OC2=C1C=C1C=COC1=C2OC QXKHYNVANLEOEG-UHFFFAOYSA-N 0.000 claims description 2
- HFBMWMNUJJDEQZ-UHFFFAOYSA-N acryloyl chloride Chemical compound ClC(=O)C=C HFBMWMNUJJDEQZ-UHFFFAOYSA-N 0.000 claims description 2
- 238000009833 condensation Methods 0.000 claims description 2
- 230000005494 condensation Effects 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 2
- 125000006239 protecting group Chemical group 0.000 claims description 2
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims description 2
- 108091000080 Phosphotransferase Proteins 0.000 description 15
- 102000020233 phosphotransferase Human genes 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- 230000000694 effects Effects 0.000 description 10
- 239000000243 solution Substances 0.000 description 9
- 102100029823 Tyrosine-protein kinase BTK Human genes 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 8
- 239000007788 liquid Substances 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- UWYZHKAOTLEWKK-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline Chemical compound C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 229940088598 enzyme Drugs 0.000 description 4
- 238000011156 evaluation Methods 0.000 description 4
- 239000012530 fluid Substances 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 238000005303 weighing Methods 0.000 description 4
- 229940124291 BTK inhibitor Drugs 0.000 description 3
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 3
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Substances ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 3
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 3
- 238000010172 mouse model Methods 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 235000002639 sodium chloride Nutrition 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- PWWYQZOIPIJRJV-UHFFFAOYSA-N 1,2-dihydrophthalazine Chemical class C1=CC=C2CNN=CC2=C1 PWWYQZOIPIJRJV-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- NKSZCPBUWGZONP-UHFFFAOYSA-N 3,4-dihydroisoquinoline Chemical compound C1=CC=C2C=NCCC2=C1 NKSZCPBUWGZONP-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 2
- XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical group [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 210000003719 b-lymphocyte Anatomy 0.000 description 2
- KXDHJXZQYSOELW-UHFFFAOYSA-N carbonic acid monoamide Natural products NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 2
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 2
- 238000012217 deletion Methods 0.000 description 2
- 230000037430 deletion Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 230000000968 intestinal effect Effects 0.000 description 2
- 208000032839 leukemia Diseases 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 230000001376 precipitating effect Effects 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- KJAMZCVTJDTESW-UHFFFAOYSA-N tiracizine Chemical compound C1CC2=CC=CC=C2N(C(=O)CN(C)C)C2=CC(NC(=O)OCC)=CC=C21 KJAMZCVTJDTESW-UHFFFAOYSA-N 0.000 description 2
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- YQFOFQAQRVPMGV-UHFFFAOYSA-N 3,4-dihydroisoquinolin-5-amine Chemical compound NC1=C2CCN=CC2=CC=C1 YQFOFQAQRVPMGV-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 108010029445 Agammaglobulinaemia Tyrosine Kinase Proteins 0.000 description 1
- 201000010000 Agranulocytosis Diseases 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 101150030812 BTK gene Proteins 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 208000019838 Blood disease Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 206010018687 Granulocytopenia Diseases 0.000 description 1
- 108010072039 Histidine kinase Proteins 0.000 description 1
- 101000934996 Homo sapiens Tyrosine-protein kinase JAK3 Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- 239000002177 L01XE27 - Ibrutinib Substances 0.000 description 1
- 206010061523 Lip and/or oral cavity cancer Diseases 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 102000057297 Pepsin A Human genes 0.000 description 1
- 108090000284 Pepsin A Proteins 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 102100030264 Pleckstrin Human genes 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
- 108010087230 Sincalide Proteins 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- 102100025387 Tyrosine-protein kinase JAK3 Human genes 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000011260 aqueous acid Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000010609 cell counting kit-8 assay Methods 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- AOGYCOYQMAVAFD-UHFFFAOYSA-N chlorocarbonic acid Chemical compound OC(Cl)=O AOGYCOYQMAVAFD-UHFFFAOYSA-N 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 239000013078 crystal 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
- MVEAAGBEUOMFRX-UHFFFAOYSA-N ethyl acetate;hydrochloride Chemical compound Cl.CCOC(C)=O MVEAAGBEUOMFRX-UHFFFAOYSA-N 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 230000003694 hair properties Effects 0.000 description 1
- 208000014951 hematologic disease Diseases 0.000 description 1
- 208000018706 hematopoietic system disease Diseases 0.000 description 1
- 229960001507 ibrutinib Drugs 0.000 description 1
- XYFPWWZEPKGCCK-GOSISDBHSA-N ibrutinib Chemical compound C1=2C(N)=NC=NC=2N([C@H]2CN(CCC2)C(=O)C=C)N=C1C(C=C1)=CC=C1OC1=CC=CC=C1 XYFPWWZEPKGCCK-GOSISDBHSA-N 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 1
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 1
- 150000002537 isoquinolines Chemical class 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 230000031700 light absorption Effects 0.000 description 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 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
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 230000000527 lymphocytic effect Effects 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 1
- 230000003448 neutrophilic effect Effects 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 208000020717 oral cavity carcinoma Diseases 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 229940111202 pepsin Drugs 0.000 description 1
- 108010026735 platelet protein P47 Proteins 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 108020001580 protein domains Proteins 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 230000011664 signaling Effects 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
- 150000003384 small molecules Chemical class 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000026683 transduction Effects 0.000 description 1
- 238000010361 transduction Methods 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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
The invention belongs to field of medicinal chemistry, it is related to a kind of hydrochloride and preparation method thereof of novel B TK kinase inhibitor, specifically, the present invention relates to [2 (1H)-acryloyl groups -3, 4- dihydro-isoquinoline -5- base]-carbamic acid -4- [8- methoxyl group-(2H)-phthalazines -1- ketone group] phenyl ester hydrochloride and preparation method thereof and purposes, [2 (the 1H)-acryloyl groups -3, 4- dihydro-isoquinoline -5- base]-carbamic acid -4- [8- methoxyl group-(2H)-phthalazines -1- ketone group] phenyl ester structural formula such as formula (a) shown in, its hydrochloric acid salt-stable is high, low in hygroscopicity, solubility is good, bioavilability is high.
Description
Technical field
The invention belongs to field of medicinal chemistry, are related to a kind of hydrochloride and preparation method thereof of novel B TK kinase inhibitor,
In particular it relates to [2 (1H)-acryloyl group -3,4- dihydro-isoquinoline -5- base]-carbamic acid -4- [8- methoxyl group -
(2H)-phthalazines -1- ketone group] phenyl ester hydrochloride and preparation method thereof and purposes.
Background technique
Bu Ludun histidine kinase (Bruton's tyrosine kinase, BTK) belongs to the member of Tec family.It is by only
N- terminal domains, that is, PH (pleckstrin homology) structural domain, TH (Tec homology) homologous region, SH3 (Src of spy
Homology3) structural domain, SH2 (Src homology2) structural domain and catalyst structure domain, also referred to as SH1/TK (Src
Homologyl/Tyrosine kinase) structural domain or kinase domain form (Akinleye et al:Ibrutinib
and novel BTK inhibitors in clinical development.Journal of Hematology&
Oncology2013,6:59).In bone-marrow-derived lymphocyte development process, the correct expression of BTK gene difference protein domain is in B
There is key effect in the function of cell and a variety of transduction pathway.
It is B cell class tumour such as leukaemia, hair property myeloma based on BTK signal transduction pathway exploitation small molecule targeted drug
And the treatment of B cell para-immunity disease provides a completely new approach.The evidence of effect of the BTK in autoimmune disease is
(Kil LP, et al:Bruton's tyrosine is provided by BTK- deletion form mouse and BTK- abundance type mouse model experiment
kinase mediated signaling enhances leukemogenesis in a mouse model for
Chronic lymphocytic leukemia.Am J Blood Res2013,3 (1): 71-83.).It is white in chronic lymphocytic
In blood disease (CLL) mouse model, BTK- deletion form mouse abrogates chronic lymphocytic leukemia completely, and BTK overexpression can add
Fast leukaemia morbidity, increases the death rate.
The selectivity for being currently known BTK inhibitor is undesirable, in addition to inhibiting BTK, also inhibit other a variety of kinases (such as ETK,
EGF, BLK, FGR, HCK, YES, BRK and JAK3 etc.), to generate more side effect；Meanwhile BTK binding site occurs to dash forward
It frequently can lead to the generation of drug resistance after change.Therefore more BTK inhibitor are clinically needed, for treating the diseases such as tumour,
Such adverse events can be overcome simultaneously.
[2 (1H)-acryloyl group -3,4- dihydro-isoquinoline -5- base]-carbamic acid -4- [8- methoxyl group-of compound (a)
(2H)-phthalazines -1- ketone group] phenyl ester, vitro kinase activity detects discovery, and it has good inhibitory activity, IC to BTK kinases50Value
For 5.5nM, the Small side effects such as anaemia, decrease of platelet and Neutrophilic granulocytopenia have a good application prospect.But in chemical combination
In the druggability research process of object (a), the inventors found that different compound (a) pharmaceutical salts are in water-soluble, biology
Availability etc. has biggish difference.Therefore, further investigation, which is found, is suitble to medicinal [2 (1H)-acryloyl group -3,4- dihydros
Isoquinolin -5- base]-carbamic acid -4- [8- methoxyl group-(2H)-phthalazines -1- ketone group] phenyl ester salt form, it is very necessary.
Summary of the invention
On the one hand, the present invention provides [2 (1H)-acryloyl group -3,4- dihydro-isoquinoline -5- base]-carbamic acid -4- [8-
Methoxyl group-(2H)-phthalazines -1- ketone group] phenyl ester hydrochloride, [2 (1H)-acryloyl group -3,4- dihydro-isoquinoline -5- base]-ammonia
Shown in the structural formula such as formula (a) of base formic acid -4- [8- methoxyl group-(2H)-phthalazines -1- ketone group] phenyl ester, hydrochloric acid salt-stable is high,
Low in hygroscopicity, solubility is good, and bioavilability is high,
On the other hand, the present invention provides [2 (1H)-acryloyl group -3,4- dihydro-isoquinoline -5- base]-carbamic acid -4-
The preparation method of [8- methoxyl group-(2H)-phthalazines -1- ketone group] phenyl ester hydrochloride, comprising the following steps:
Step A: the compound of formula (1) and the compound condensation of formula (2) obtain the compound of formula (3)；
Step B: the compound of formula (3) reacts to obtain the compound of formula (5) with the compound of formula (4)；
Step C: the compound of formula (5) sloughs protecting group and obtains the compound of formula (6)；
Step D: the compound of formula (6) reacts to obtain formula a compound with acryloyl chloride；
Step E: formula (a) compound is reacted with HCl is made formula (a) compound hydrochloride, and reaction route is as follows:
In some preferred embodiments, the solvent that step E Chinese style (a) compound is reacted with HCl is selected from ethyl acetate
And methylene chloride.
In some preferred embodiments, the usage amount of solvent is 3-10 times of formula (a) compound quality in step E；It is excellent
Selection of land, the usage amount of solvent is 3-5 times of formula (a) compound quality in step E.
In some specific embodiments, at room temperature, formula (a) compound is dissolved in 5 times of formula (a) compound qualities
In ethyl acetate solvent, saturation hydrogen chloride ethyl acetate is added and is generated to supernatant without precipitating, continues to stir 10- at room temperature
30min to obtain the final product.
The third aspect contains that [2 (1H)-acryloyl group -3,4- dihydros are different the present invention provides a kind of pharmaceutical composition
Quinoline -5- base] hydrochloride of-carbamic acid -4- [8- methoxyl group-(2H)-phthalazines -1- ketone group] phenyl ester and pharmaceutically acceptable
Carrier.
Fourth aspect, the present invention provides [2 (1H)-acryloyl group -3,4- dihydro-isoquinoline -5- base]-carbamic acid -4-
[8- methoxyl group-(2H)-phthalazines -1- ketone group] phenyl ester hydrochloride includes [2 (1H)-acryloyl group -3,4- dihydro isoquinolines
Quinoline -5- base]-carbamic acid -4- [8- methoxyl group-(2H)-phthalazines -1- ketone group] phenyl ester hydrochloride pharmaceutical composition preparation use
Application in the drug for the treatment of and/or pre- preventing tumor, the tumour includes but is not limited to solid tumor, preferably lung cancer, neck
Portion's tumour, colorectal cancer, bladder cancer, cancer of pancreas, breast cancer, prostate cancer, gastric cancer, carcinoma of mouth, liver cancer, oophoroma.More preferably
Ground, the tumour are non-small cell lung cancer.
Specific embodiment
The present invention is explained in more detail with reference to embodiments, the embodiment of the present invention is merely to illustrate technology of the invention
Scheme not limits the scope of the invention.
Embodiment 1 [2 (1H)-acryloyl group -3,4- dihydro-isoquinoline -5- base]-carbamic acid -4- [8- methoxyl group -
(2H)-phthalazines -1- ketone group] phenyl ester preparation
Step 1: weighing -2 (1H)-t-butyl formate (50mmol) of 5- amino -3,4- dihydro-isoquinoline and DIPEA
(100mmol) is added methylene chloride 300ml, is stirred at room temperature down and is slowly added dropwise with chloro-carbonic acid to chlorobenzene ester in reaction flask
(51mmol), drop finish, and continue to stir 1h at room temperature, stop reaction, and ethyl acetate 70ml, dilute salt is added in concentrated reaction mixture
Aqueous acid (0.2-0.3N) and saturated common salt water washing, anhydrous sodium sulfate dry, filter, and are concentrated to give (3,4- dihydro-isoquinolines-
2 (1H)-t-butyl formate -5- bases)-carbamic acid to chlorobenzene ester, is directly used in next step, ESI-MS:[M+H]+m/z 403。
Step 2: weighing 3- methoxyl group -1- dimethoxy-methyl benzene (500mmol) in reaction flask, tetrahydrofuran is added
(800ml) dissolution, 60 DEG C, under nitrogen protection, be added s-BuLi (565mmol), reaction solution is stirred into 1h at -60 DEG C；It weighs
Dry ice (50mmol) is added tetrahydrofuran (200ml) in another reaction flask, is added n-BuLi (5ml), stirred under nitrogen atmosphere
After 2h, said mixture is added, continues to stir 30min, stops reaction, water 1000ml is added, adjusts pH to 2 with concentrated hydrochloric acid, point
From organic phase, water phase is extracted with ethyl acetate, and merges organic phase, and saturated common salt water washing, anhydrous sodium sulfate is dry, recrystallizes
To 6- methoxyl group -2- dimethoxy-methyl benzoic acid；Weigh 6- methoxyl group -2- dimethoxy-methyl benzoic acid (400mmol), second
Sour (93mmol), hydrazine (600mmol) are in reaction flask, addition isopropanol 300ml, under nitrogen protection, 100 DEG C of back flow reaction 2h,
Stop reaction, ethyl acetate 300ml, water 500ml is added, extraction merges organic phase, and anhydrous sodium sulfate is dry, hangs dry, column chromatography
Purify to obtain 8- methoxyl group -2H- phthalazines -1- ketone, ESI-MS:[M+H]+m/z 177。
Step 3: weighing 8- methoxyl group -2H- phthalazines -1- ketone (150mmol), (3,4- dihydro-isoquinoline -2 (1H)-formic acid uncle
Butyl ester -5- base) in reaction flask, DMF100ml is added to chlorobenzene ester (195mmol) in-carbamic acid, and it reacts overnight at 55 DEG C, stops
It only reacts, water 100ml, methylene chloride 200ml is added, extraction separates organic phase, and water phase continues that (3* is extracted with dichloromethane
50ml), merge organic phase, anhydrous sodium sulfate is dry, and column chromatographic purifying obtains (- 2 (1H)-t-butyl formate-of 3,4- dihydro-isoquinoline
5- yl)-carbamic acid -4- [8- methoxyl group-(2H)-phthalazines -1- ketone group] phenyl ester.
Step 4: weighing (3,4- dihydro-isoquinoline -2 (1H)-t-butyl formate -5- base)-carbamic acid -4- [8- methoxy
Base-(2H)-phthalazines -1- ketone group] in reaction flask, addition trifluoroacetic acid 20ml stirs 1h at room temperature, depressurizes phenyl ester (50mmol)
It is concentrated to dryness, ethyl acetate 80ml is added, successively use 1.5M disodium hydrogen phosphate aqueous solution and saturated common salt water washing, anhydrous slufuric acid
Sodium dries, filters, and intermediate (1,2,3,4- tetrahydroisoquinoline -5- base) carbamic acid -8- methoxyl group -2- is concentrated under reduced pressure to obtain
(2H)-phthalazines -1- ketone group phenyl ester；Weigh gained intermediate (1,2,3,4- tetrahydroisoquinoline -5- base) carbamic acid -8- methoxy
Base -2- (2H)-phthalazines -1- ketone group phenyl ester (20mmol) is added methylene chloride 100ml dissolution, is added at 0 DEG C in reaction flask
DIEA (40mmol) after stirring 30min, continues that acryloyl chloride (20mmol) is added dropwise at 0 DEG C, and drop finishes, and 3h is stirred at room temperature, and stops
Reaction adds water 100ml, and methylene chloride extracts (3*50ml), merges organic phase, and anhydrous sodium sulfate is dry, and column chromatographic purifying obtains [2
(1H)-acryloyl group -3,4- dihydro-isoquinoline -5- base]-carbamic acid -4- [8- methoxyl group-(2H)-phthalazines -1- ketone group] benzene
Ester.
1H NMR(600MHz,CDCl3) (δ, ppm): 9.50 (s, 1H), 8.10 (s, 1H), 7.80~7.78 (m, 2H),
7.58~7.55 (m, 2H), 7.44~7.43 (m, 1H), 7.28~7.26 (m, 3H), 7.18~7.15 (m, 2H), 6.62~
6.60 (m, 1H), 5.96~5.94 (m, 1H), 5.36~5.3 (m, 1H), 4.22 (s, 2H), 3.84 (s, 2H), 3.61~3.59
(m, 2H), 3.13~3.11 (m, 2H).
ESI–MS:[M+H]+m/z 497。
Embodiment 2:[2 (1H)-acryloyl group -3,4- dihydro-isoquinoline -5- base]-carbamic acid -4- [8- methoxyl group -
(2H)-phthalazines -1- ketone group] phenyl ester hydrochloride preparation
1 compound of embodiment (0.5mmol) is weighed in reaction flask, adds ethyl acetate 2mL, saturation chlorination is added at room temperature
Hydroacetic acid ethyl ester solution continues to stir 10min at room temperature, evaporating solvent under reduced pressure, vacuum is dry at room temperature to there is no precipitatings to generate
Dry acquisition title compound.
1H NMR(600MHz,CDCl3) (δ, ppm): 9.50 (s, 1H disappear after heavy water exchange), 8.10 (s, 1H), 7.80
~7.78 (m, 2H), 7.58~7.55 (m, 2H), 7.44~7.43 (m, 1H), 7.28~7.26 (m, 3H), 7.18~7.15 (m,
2H), 6.62~6.60 (m, 1H), 5.96~5.94 (m, 1H), 5.36~5.3 (m, 1H), 4.22 (s, 2H), 3.84 (s, 2H),
3.61~3.59 (m, 2H), 3.13~3.11 (m, 2H).
Experimental example 1: vitro kinase activity evaluation
By Examples 1 and 2 prepare compound, after being diluted to 10mM with DMSO, be successively diluted to 1uM, 100nM, 10nM,
1nM、0.1nM、0.01nM。
Take the 10 μ l of compound solution of each concentration into 96 orifice plates, addition 90 μ l1 × kinase buffer liquid (50mMHEPES,
PH7.5,0.0015%Brij-35,10mMMgCl2,2mM DTT, prepared before use)；Set up DMSO control group and without enzyme simultaneously
Control group living, contains only 10 μ lDMSO and 90 μ l1 × kinase buffer liquid.Each group mixes 10min at room temperature, then shifts respectively
5 μ l are into 384 orifice plates；Kinase b TK is dissolved in 1 × kinase buffer liquid, is configured to 2.5 × kinase solution, then shifts 10 μ l2.5
× kinase solution is into above-mentioned 384 orifice plates containing each concentration compound；10 μ l2.5 × kinase solution is added in DMSO control group；Nothing
1 × kinase buffer liquid that 10 μ l are free of kinases is added in enzyme activity control group.It is incubated for 10min at room temperature；By FAM label polypeptide and
ATP is dissolved in 1 × kinase buffer liquid, is configured to 2.5 × substrate solution, then shifts 10 μ l2.5 × substrate solution to above-mentioned 384 hole
In plate, 28 DEG C of incubation 1hr；25 μ l (100mMHEPES, pH7.5,0.015%Brij-35,0.2% are added in each hole
CoatingReagent#3,50mMEDTA prepared before use), terminate liquid terminates reaction；It is placed on LabChipEZReader and reads
Conversion data, and inhibiting rate I% is calculated, calculation formula is I%=(Max-Conversion)/(Max-Min) × 100,
Middle Max is the conversion ratio of DMSO control group, and Min is the conversion ratio of no enzyme activity control group, and Conversion is compound processing group
Conversion ratio, data handle through XLfit, are fitted to obtain IC50。IC50Value indicates that compound presses down with not plus compared with compound processing group
Make corresponding compound concentration when 50% enzyme activity.IC50It the results are shown in Table 1.
Table 1
| Test-compound | IC 50(nM) | Test-compound | IC 50(nM) |
| Embodiment 1 | 5.5 | Embodiment 2 | 5.2 |
The evaluation of the external Romas cell activity of experimental example 2
It takes in exponential phase of growth in good condition one bottle of Raji cell, collects cell, low speed desk centrifuge, 1500
Turn/min, is centrifuged 3min.Supernatant is abandoned, 5mL complete medium is added with pipettor and carries out cell resuspension.Use cell count instrument meter
Number, complete medium are diluted, adjustment cell density to 5 × 104A/mL.It is inoculated on 96 orifice plates using the volley of rifle fire, 100 μ L/
Constant temperature CO is set in hole2It is cultivated 24 hours in incubator.Compound sample-adding, which is carried out, using nanoliter sample adding instrument adds CCK-8 after 72 hours,
Its light absorption value is detected in 10 holes μ L/ at Envision microplate reader 450nm after 2 hours, calculate inhibiting rate, and calculate IC50, as a result see
Table 2.
Table 2
| Test-compound | IC 50(μM) | Test-compound | IC 50(μM) |
| Embodiment 1 | 7 | Embodiment 2 | 5 |
It is above-mentioned the experimental results showed that 2 compound of embodiment have good external Romas cell inhibitory activity.
The evaluation of 3 dissolubility of experimental example
By the four solubility experiment method experiments of pharmacopeia in 2015, experimental result is shown in Table 3.
Table 3
| Compound | 2 compound of embodiment |
| It is water-soluble | It is readily soluble |
| The simulated gastric fluid of pH1.8 | It is readily soluble |
| The simulated intestinal fluid of pH5.0 | It is readily soluble |
Note: readily soluble to refer to that solute 1g (ml) be in water 1~less than dissolving in 10ml；
The preparation method of the simulated gastric fluid of pH1.8 are as follows: take concentrated hydrochloric acid 0.765mL, add water about 80mL, pepsin 1.0g,
Sodium chloride 0.2g after shaking up, is diluted with water into 100mL, with aqueous hydrochloric acid solution tune pH to 1.8；
The preparation method of the simulated intestinal fluid of pH5.0 are as follows: take 0.865g glacial acetic acid, 0.831g natrii tauroglycocholas, 0.288g lecithin
Rouge, 1.520g potassium chloride are placed in 100mL volumetric flask, and 100mL is dissolved and be settled to water, extremely with sodium hydrate aqueous solution tune pH
5.0。
Embodiment 4 draws moist evaluation
2 compound 10mg of embodiment is weighed, using dynamic water absorption (DVS) instrument in 0%RH~80%RH at 25 DEG C
Drawing for the interior test crystal form of RH range is moist, the experimental results showed that, 2 compound of embodiment is in 0%RH to 80%RH model
Weight change in enclosing is 0.5%, almost non-hygroscopic.
Claims (8)
- [1. 2 (1H)-acryloyl group -3,4- dihydro-isoquinoline -5- base]-carbamic acid -4- [8- methoxyl group-(2H)-phthalazines -1- Ketone group] phenyl ester hydrochloride, [2 (1H)-acryloyl group -3,4- dihydro-isoquinoline -5- base]-carbamic acid -4- [the 8- methoxy Base-(2H)-phthalazines -1- ketone group] phenyl ester structural formula such as formula (a) shown in,
- 2. the preparation method of hydrochloride described in claim 1, comprising the following steps:Step A: the compound of formula (1) and the compound condensation of formula (2) obtain the compound of formula (3)；Step B: the compound of formula (3) reacts to obtain the compound of formula (5) with the compound of formula (4)；Step C: the compound of formula (5) sloughs protecting group and obtains the compound of formula (6)；Step D: the compound of formula (6) reacts to obtain formula a compound with acryloyl chloride；Step E: formula (a) compound is reacted with HCl is made formula (a) compound hydrochloride, and reaction route is as follows:
- 3. preparation method as claimed in claim 2, it is characterised in that: the solvent that formula (a) compound is reacted with HCl is selected from acetic acid Ethyl ester and methylene chloride.
- 4. preparation method as claimed in claim 2, it is characterised in that: the usage amount of solvent is that 3-10 times of formula (a) is changed in step E Close amount of substance.
- 5. preparation method as claimed in claim 2, it is characterised in that: the usage amount of solvent is that 3-5 times of formula (a) is changed in step E Close amount of substance.
- 6. the pharmaceutical composition comprising hydrochloride and pharmaceutically acceptable carrier described in claim 1.
- 7. hydrochloride described in claim 1 and pharmaceutical composition as claimed in claim 6 are in preparation for treating and/or preventing Application in the drug of tumour.
- 8. as claimed in claim 7 preparation for treat and/or the drug of pre- preventing tumor in application, it is characterised in that: The tumour is non-small cell lung cancer.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811164079.6A CN109485636A (en) | 2018-10-04 | 2018-10-04 | A kind of hydrochloride of novel B TK kinase inhibitor and preparation method thereof and purposes |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811164079.6A CN109485636A (en) | 2018-10-04 | 2018-10-04 | A kind of hydrochloride of novel B TK kinase inhibitor and preparation method thereof and purposes |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN109485636A true CN109485636A (en) | 2019-03-19 |
Family
ID=65689426
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201811164079.6A Withdrawn CN109485636A (en) | 2018-10-04 | 2018-10-04 | A kind of hydrochloride of novel B TK kinase inhibitor and preparation method thereof and purposes |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109485636A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US12083114B2 (en) | 2018-12-19 | 2024-09-10 | Disarm Therapeutics, Inc. | Inhibitors of SARM1 in combination with neuro-protective agents |
| US12338238B2 (en) | 2018-06-07 | 2025-06-24 | Disarm Therapeutics, Inc. | Inhibitors of SARM1 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20140107151A1 (en) * | 2011-05-17 | 2014-04-17 | Principia Biophama Inc. | Tyrosine kinase inhibitors |
| US20150064196A1 (en) * | 2012-04-20 | 2015-03-05 | Advinus Therapeutics Limited | Substituted Hetero-Bicyclic Compounds, Compositions and Medicinal Applications Thereof |
| CN104812746A (en) * | 2012-11-16 | 2015-07-29 | 弗·哈夫曼-拉罗切有限公司 | Bruton's tyrosine kinase inhibitors |
-
2018
- 2018-10-04 CN CN201811164079.6A patent/CN109485636A/en not_active Withdrawn
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20140107151A1 (en) * | 2011-05-17 | 2014-04-17 | Principia Biophama Inc. | Tyrosine kinase inhibitors |
| US20150064196A1 (en) * | 2012-04-20 | 2015-03-05 | Advinus Therapeutics Limited | Substituted Hetero-Bicyclic Compounds, Compositions and Medicinal Applications Thereof |
| CN104812746A (en) * | 2012-11-16 | 2015-07-29 | 弗·哈夫曼-拉罗切有限公司 | Bruton's tyrosine kinase inhibitors |
Non-Patent Citations (2)
| Title |
|---|
| DONALD J. P. PINTO: "Discovery of a Parenteral Small Molecule Coagulation Factor XIa Inhibitor Clinical Candidate (BMS-962212)" * |
| 孟繁浩等, 中国医药科技出版社 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US12338238B2 (en) | 2018-06-07 | 2025-06-24 | Disarm Therapeutics, Inc. | Inhibitors of SARM1 |
| US12083114B2 (en) | 2018-12-19 | 2024-09-10 | Disarm Therapeutics, Inc. | Inhibitors of SARM1 in combination with neuro-protective agents |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN109180642A (en) | Phthalazines ketone BTK inhibitor and its application | |
| CN109288830A (en) | A kind of taxol and novel phthalazines ketone compounds drug combination compositions | |
| CN109336863A (en) | A kind of novel phthalazines ketone BTK inhibitor, preparation and its application | |
| CN101932582B (en) | Salts of the janus kinase inhibitor (r)-3-(4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)-1h-pyrazol-1-yl)-3-cyclopentylpropanenitrile | |
| CN105001168A (en) | Tri-alkoxy-substituted benzo quinazoline type tyrosine kinase inhibitor and application thereof | |
| CN109485636A (en) | A kind of hydrochloride of novel B TK kinase inhibitor and preparation method thereof and purposes | |
| CN113784971A (en) | A kind of crystal form of EGFR inhibitor and preparation method thereof | |
| CN109331018A (en) | A kind of taxol and nitro phthalazone BTK inhibitor drug combination compositions and its application | |
| Li et al. | Design, synthesis, and antiproliferative evaluation of novel longifolene-derived tetraline pyrimidine derivatives with fluorescence properties | |
| CN109223787A (en) | A kind of camptothecine and novel phthalazines ketone compounds drug combination compositions | |
| CN109276571A (en) | A kind of taxol and novel nitro phthalazone BTK inhibitor drug combination compositions and its application | |
| CN109394766A (en) | A kind of taxol and to benzene nitrophthalide zionoes BTK inhibitor drug combination compositions and its application | |
| CN109481441A (en) | A kind of taxol and novel methoxyl group phthalazines ketone BTK inhibitor drug combination compositions and its application | |
| CN109293635A (en) | A kind of P crystal form of novel B TK kinase inhibitor and preparation method thereof | |
| CN111886228B (en) | Crystal form of c-MET/AXL inhibitor | |
| CN111433213A (en) | Salt forms and crystalline forms thereof as Akt inhibitors | |
| CN109172562A (en) | A kind of taxol and methoxyl group phthalazines ketone BTK inhibitor drug combination compositions and its application | |
| Gangjee et al. | Design, synthesis and evaluation of 2-amino-4-m-bromoanilino-6-arylmethyl-7H-pyrrolo [2, 3-d] pyrimidines as tyrosine kinase inhibitors and antiangiogenic agents | |
| CN109180644A (en) | A kind of mesylate of novel B TK kinase inhibitor and preparation method thereof and purposes | |
| CN109485695A (en) | A kind of protein degradation targeting chimera and preparation method and application based on VEGFR-2 inhibitor S7 | |
| CN109336864A (en) | Phthalazines ketone compound crystal form N and preparation method thereof | |
| CN115814095A (en) | Combination of RAD51 inhibitors and anti-cancer therapeutics | |
| US7045617B2 (en) | Bisbubstrate inhibitors of kinases | |
| CN109223759A (en) | A kind of taxol and novel phthalazines ketone BTK inhibitor drug combination compositions and its application | |
| CN109172592A (en) | A kind of antineoplastic pharmaceutical compositions |
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 | ||
| WW01 | Invention patent application withdrawn after publication |
Application publication date: 20190319 |
|
| WW01 | Invention patent application withdrawn after publication |