CN109481443A - A kind of taxol and adjacent benzene fluorine phthalazines ketone BTK inhibitor drug combination compositions and its application - Google Patents
A kind of taxol and adjacent benzene fluorine phthalazines ketone BTK inhibitor drug combination compositions and its application Download PDFInfo
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- CN109481443A CN109481443A CN201811282936.2A CN201811282936A CN109481443A CN 109481443 A CN109481443 A CN 109481443A CN 201811282936 A CN201811282936 A CN 201811282936A CN 109481443 A CN109481443 A CN 109481443A
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- 229940124291 BTK inhibitor Drugs 0.000 title claims abstract description 29
- -1 benzene fluorine phthalazines ketone Chemical group 0.000 title claims abstract description 28
- 229930012538 Paclitaxel Natural products 0.000 title claims abstract description 21
- 229960001592 paclitaxel Drugs 0.000 title claims abstract description 21
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 title claims abstract description 21
- 239000000203 mixture Substances 0.000 title claims abstract description 17
- 239000000890 drug combination Substances 0.000 title claims abstract description 13
- 239000000470 constituent Substances 0.000 claims abstract description 13
- 239000003814 drug Substances 0.000 claims abstract description 7
- 108010029445 Agammaglobulinaemia Tyrosine Kinase Proteins 0.000 claims abstract description 6
- 201000010099 disease Diseases 0.000 claims abstract description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 6
- 239000000463 material Substances 0.000 claims abstract description 5
- 230000002265 prevention Effects 0.000 claims abstract description 3
- 102000001714 Agammaglobulinaemia Tyrosine Kinase Human genes 0.000 claims abstract 2
- 150000001875 compounds Chemical group 0.000 claims description 62
- 238000006243 chemical reaction Methods 0.000 claims description 49
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 40
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 24
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 16
- 239000012074 organic phase Substances 0.000 claims description 16
- 238000002360 preparation method Methods 0.000 claims description 15
- 102100029823 Tyrosine-protein kinase BTK Human genes 0.000 claims description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 12
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 10
- 230000000694 effects Effects 0.000 claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 9
- 239000000243 solution Substances 0.000 claims description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 238000000605 extraction Methods 0.000 claims description 8
- 238000005406 washing Methods 0.000 claims description 8
- 239000012071 phase Substances 0.000 claims description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 6
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Substances ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 5
- 238000004090 dissolution Methods 0.000 claims description 4
- GOTYRUGSSMKFNF-UHFFFAOYSA-N lenalidomide Chemical compound C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O GOTYRUGSSMKFNF-UHFFFAOYSA-N 0.000 claims description 4
- 229960004942 lenalidomide Drugs 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- YQFOFQAQRVPMGV-UHFFFAOYSA-N 3,4-dihydroisoquinolin-5-amine Chemical compound NC1=C2CCN=CC2=CC=C1 YQFOFQAQRVPMGV-UHFFFAOYSA-N 0.000 claims description 3
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 3
- AOGYCOYQMAVAFD-UHFFFAOYSA-N chlorocarbonic acid Chemical compound OC(Cl)=O AOGYCOYQMAVAFD-UHFFFAOYSA-N 0.000 claims description 3
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 3
- 239000011541 reaction mixture Substances 0.000 claims description 3
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims description 2
- 235000011089 carbon dioxide Nutrition 0.000 claims description 2
- 238000009833 condensation Methods 0.000 claims description 2
- 230000005494 condensation Effects 0.000 claims description 2
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims description 2
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- 210000004027 cell Anatomy 0.000 description 7
- 239000007788 liquid Substances 0.000 description 6
- NKSZCPBUWGZONP-UHFFFAOYSA-N 3,4-dihydroisoquinoline Chemical compound C1=CC=C2C=NCCC2=C1 NKSZCPBUWGZONP-UHFFFAOYSA-N 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
- 102000004190 Enzymes Human genes 0.000 description 4
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- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 4
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- KXDHJXZQYSOELW-UHFFFAOYSA-N carbonic acid monoamide Natural products NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 238000010172 mouse model Methods 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 235000002639 sodium chloride Nutrition 0.000 description 3
- 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 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 2
- PJBOAJNRXBUTDJ-UHFFFAOYSA-N C1=CC=C2C(NN=CC2=C1)F Chemical class C1=CC=C2C(NN=CC2=C1)F PJBOAJNRXBUTDJ-UHFFFAOYSA-N 0.000 description 2
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 210000003719 b-lymphocyte Anatomy 0.000 description 2
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 2
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- 230000002018 overexpression Effects 0.000 description 2
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- 239000000651 prodrug Substances 0.000 description 2
- 229940002612 prodrug Drugs 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
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- 238000005303 weighing Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 101150030812 BTK gene Proteins 0.000 description 1
- 208000019838 Blood disease Diseases 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- 206010059866 Drug resistance 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
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 102100030264 Pleckstrin Human genes 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
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- 102100025387 Tyrosine-protein kinase JAK3 Human genes 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 229910021529 ammonia Inorganic materials 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
- 239000002775 capsule Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000010609 cell counting kit-8 assay Methods 0.000 description 1
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical class ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- GLUUGHFHXGJENI-UHFFFAOYSA-N diethylenediamine Natural products C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 210000000981 epithelium Anatomy 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Substances OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 1
- 230000014509 gene expression Effects 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
- 239000003112 inhibitor Substances 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 230000031700 light absorption Effects 0.000 description 1
- 239000008297 liquid dosage form Substances 0.000 description 1
- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 230000000527 lymphocytic effect Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
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- 239000012299 nitrogen atmosphere Substances 0.000 description 1
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- 239000006187 pill Substances 0.000 description 1
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- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 108020001580 protein domains Proteins 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 238000010992 reflux 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
- 239000007909 solid dosage form Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 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
- 210000003462 vein Anatomy 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
-
- 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
- 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
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
It include active constituent and pharmaceutically acceptable auxiliary material the present invention provides a kind of taxol and adjacent benzene fluorine phthalazines ketone BTK inhibitor drug combination compositions, active constituent BTK inhibitor shown in taxol and formula (I) forms, and the molar ratio of BTK inhibitor shown in taxol and formula (I) is (0.14-0.20) in the active constituent: 1.The pharmaceutical composition can be used for preparing prevention and/or treatment disease medicament relevant to bruton's tyrosine kinase, therapeutic effect are good.
Description
Technical field
The invention belongs to medicinal chemistry arts, are related to phthalazines ketone BTK inhibitor and its application, and in particular to phthalazines ketone
BTK inhibitor, preparation method, the pharmaceutical composition containing such compound and its treatment bruton's tyrosine kinase
Purposes in related disease.
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.
Summary of the invention
The present invention the following technical schemes are provided:
In a first aspect, a kind of taxol provided by the invention and adjacent benzene fluorine phthalazines ketone BTK inhibitor combination medicine group
Object is closed, includes active constituent and pharmaceutically acceptable auxiliary material, active constituent BTK as shown in taxol and formula (I)
Inhibitor composition, the molar ratio of BTK inhibitor shown in taxol and formula (I) is (0.14-0.20) in the active constituent: 1；
Wherein, the BTK inhibitor, shown in chemical formula such as formula (I),
Wherein, the preparation method of the BTK inhibitor, includes the following steps:
Step A: the compound substitution reaction of formula (7) obtains the compound of formula (8), and the compound of formula (8) is obtained with hydrazine reaction
The compound of formula (4)；
Step B: the compound of formula (1) and the compound condensation of formula (2) obtain the compound of formula (3)；
Step C: the compound of formula (3) reacts to obtain the compound of formula (5) with the compound of formula (4)；
Step D: the compound of formula (5) sloughs protecting group and obtains the compound of formula (6)；
Step E: the compound of formula (6) and substituted alkene acyl chloride reaction obtain compounds of formula I, and reaction route is as follows:
Preferably, in step A,
It takes the fluoro- 1- dimethoxy-methyl benzene of 3- in reaction flask, is added tetrahydrofuran dissolution, 60 DEG C, under nitrogen protection, add
Enter s-BuLi, reaction solution is stirred to react at -60 DEG C；It takes dry ice in reaction flask, tetrahydrofuran is added, n-BuLi is added,
Stirred under nitrogen atmosphere adds the reaction solution after being stirred to react at -60 DEG C, continues to stir, and stops reaction, and water is added, and use is dense
Salt acid for adjusting pH separates organic phase, water phase is extracted with ethyl acetate, and merges organic phase, saturated common salt water washing, anhydrous sulphur to 2
Sour sodium is dry, is recrystallized to give the compound of formula (8)；
The compound, acetic acid, hydrazine of formula (8) are weighed in reaction flask, isopropanol is added, under nitrogen protection, 100 DEG C of reflux are anti-
It answers, stops reaction, addition ethyl acetate, water, extraction merges organic phase, and anhydrous sodium sulfate is dry, hangs and does, column chromatographic purifying obtains
The compound of formula (4).
Preferably, in step B, take -2 (1H)-t-butyl formate of 5- amino -3,4- dihydro-isoquinoline and DIPEA in reaction
In bottle, methylene chloride is added, is stirred at room temperature down and chloro-carbonic acid neighbour's chlorobenzene ester is slowly added dropwise, drop finishes, and continues to stir at room temperature, stops anti-
It answers, concentrated reaction mixture, ethyl acetate, diluted hydrochloric acid aqueous solution and saturated common salt water washing is added, anhydrous sodium sulfate is dry, mistake
The compound to get formula (3) is concentrated in filter.
Preferably, in step C, the compound of modus ponens (4), formula (3) compound in reaction flask, DMF is added, at 55 DEG C
Reaction overnight, stops reaction, and water, methylene chloride is added, and extraction separates organic phase, and water phase continues to be extracted with dichloromethane, and merges
Organic phase, anhydrous sodium sulfate is dry, and column chromatographic purifying obtains the compound of formula (5).
Preferably, in step D, the compound of modus ponens (5) is added trifluoroacetic acid, stirs at room temperature in reaction flask, depressurizes
It being concentrated to dryness, ethyl acetate is added, successively use disodium hydrogen phosphate aqueous solution and saturated common salt water washing, anhydrous sodium sulfate is dry,
Filtering, be concentrated under reduced pressure formula (6) compound.
Preferably, in step E, the compound of modus ponens (6) is added methylene chloride 100ml and dissolves, at 0 DEG C in reaction flask
DIEA is added, after stirring, continues that 1- nitro acryloyl chloride is added dropwise at 0 DEG C, drop finishes, is stirred at room temperature, and stop reaction, adds water, two
Chloromethanes extraction merges organic phase, and anhydrous sodium sulfate is dry, and column chromatographic purifying obtains the compound of formula (I).
The present invention also provides a kind of adjacent benzene fluorine phthalazines ketone BTK inhibitor drug combination compositions, comprising activity at
Divide and pharmaceutically acceptable auxiliary material, active constituent BTK inhibitor group as shown in taxol, lenalidomide, formula (I)
Molar ratio at BTK inhibitor shown in, taxol in the active constituent, lenalidomide, formula (I) is (0.14-0.20):
(0.08-0.12): 1.
Pharmaceutical composition of the invention and pharmaceutically acceptable carrier, diluent or excipient can be prepared by mixing into
Pharmaceutical preparation, to be suitable for oral or parenteral.Medication includes, but are not limited in intradermal, intramuscular, peritonaeum, vein
Interior, subcutaneous, intranasal and peroral route.The preparation can be applied by any approach, such as by being transfused or inject, pass through through
The approach application that epithelium or mucocutaneous (such as oral mucosa or rectum etc.) absorb.Administration can be whole body or local.
The example of oral administration preparation includes solid or liquid dosage form, specifically, include tablet, pill, granula, pulvis, capsule,
Syrup, emulsion, suspension etc..The preparation can be prepared by methods known in the art, and include field of pharmaceutical preparations routine
Carrier, diluent or the excipient used.
The pharmaceutical composition can be in preparation prevention and/or treatment disease medicament relevant to bruton's tyrosine kinase
Application, the compound of the logical formula (I) of the present invention is applied including the tumor disease patient that over-expresses to bruton's tyrosine kinase
Or its pharmaceutically acceptable salt, isomers, solvate, crystallization or prodrug or compound comprising the logical formula (I) of the present invention or
The pharmaceutical composition of its pharmaceutically acceptable salt, isomers, solvate, crystallization or prodrug, effectively to inhibit Bu Ludun junket ammonia
Acid kinase overexpression, prevents disease progression.
Specific embodiment
The preparation of the fluoro- 2H- phthalazines -1- ketone of 1 8- of embodiment
Step 1: weighing the fluoro- 1- dimethoxy-methyl benzene (500mmol) of 3- 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.
Step 2: dry ice (50mmol) is weighed in reaction flask, is added tetrahydrofuran (200ml), is added n-BuLi (5ml),
After stirred under nitrogen atmosphere 2h, the mixture of step 1 is added, continues to stir 30min, stops reaction, water 1000ml is added, use is dense
Salt acid for adjusting pH separates organic phase, water phase is extracted with ethyl acetate, and merges organic phase, saturated common salt water washing, anhydrous sulphur to 2
Sour sodium is dry, is recrystallized to give the fluoro- 2- dimethoxy-methyl benzoic acid of 3-.
Step 3: weighing step 2 gains (400mmol), acetic acid (93mmol), hydrazine (600mmol) in reaction flask, add
Entering 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 and does, column chromatographic purifying obtains title compound.
ESI–MS:[M+H]+m/z 165。
The preparation of embodiment 2 (3,4- dihydro-isoquinoline -2 (1H)-t-butyl formate -5- base)-carbamic acid neighbour's chlorobenzene ester
Weigh -2 (1H)-t-butyl formate (50mmol) of 5- amino -3,4- dihydro-isoquinoline and DIPEA (100mmol) in
In reaction flask, methylene chloride 300ml is added, is stirred at room temperature down to be slowly added dropwise and finish with chloro-carbonic acid neighbour's chlorobenzene ester (51mmol), drop, room
Continue to stir 1h under temperature, stop reaction, ethyl acetate 70ml, diluted hydrochloric acid aqueous solution (0.2- is added in concentrated reaction mixture
It 0.3N) is dried, filtered with saturated common salt water washing, anhydrous sodium sulfate, is concentrated to give (- 2 (1H)-formic acid uncle of 3,4- dihydro-isoquinoline
Butyl ester -5- base)-carbamic acid to chlorobenzene ester, is directly used in next step, ESI-MS:[M+H]+m/z 403。
(3,4- dihydro-isoquinoline -2 (1H)-t-butyl formate -5- base)-carbamic acid -2- of embodiment 3 [8- fluoro- (2H) -
Phthalazines -1- ketone group] phenyl ester preparation
Weigh the fluoro- 2H- phthalazines -1- ketone (150mmol) of 8-, (3,4- dihydro-isoquinoline -2 (1H)-t-butyl formate -5-
Base) in reaction flask, DMF100ml is added in-carbamic acid neighbour's chlorobenzene ester (195mmol), and it reacts at 55 DEG C overnight, stops reaction,
Water 100ml, methylene chloride 200ml is added, extraction separates organic phase, and water phase continues to be extracted with dichloromethane (3*50ml), merges
Organic phase, anhydrous sodium sulfate is dry, and column chromatographic purifying obtains title compound.
ESI–MS:[M+H]+m/z 531。
[8- is fluoro- by carbamic acid -2- for embodiment 4 [1- nitro -2 (1H)-acryloyl group -3,4- dihydro-isoquinoline -5- base] -
(2H)-phthalazines -1- ketone group] phenyl ester preparation
Weigh (3,4- dihydro-isoquinoline -2 (1H)-t-butyl formate -5- base)-carbamic acid -2- [fluoro- (2H)-phthalein of 8-
Piperazine -1- ketone group] in reaction flask, addition trifluoroacetic acid 20ml stirs 1h at room temperature, is concentrated to dryness phenyl ester (50mmol),
Ethyl acetate 80ml is added, successively uses 1.5M disodium hydrogen phosphate aqueous solution and saturated common salt water washing, anhydrous sodium sulfate is dry, mistake
Filter, is concentrated under reduced pressure to obtain intermediate (1,2,3,4- tetrahydroisoquinoline -5- base) carbamic acid -2- (2H)-phthalazines -1- ketone group phenyl ester,
It directly throws in next step.
Weigh intermediate (1,2,3,4- tetrahydroisoquinoline -5- base) carbamic acid -2- (2H)-phthalazines -1- ketone group phenyl ester
(20mmol) is added methylene chloride 100ml dissolution, DIEA (40mmol) is added at 0 DEG C in reaction flask, after stirring 30min, after
Continue dropwise addition 1- nitro acryloyl chloride (20mmol) at 0 DEG C, drop finishes, and 3h is stirred at room temperature, and stops reaction, adds water 100ml, dichloromethane
Alkane extracts (3*50ml), merges organic phase, and anhydrous sodium sulfate is dry, and column chromatographic purifying obtains title compound.
1H NMR(600MHz,CDCl3) (δ, ppm): 9.50 (s, 1H), 8.78~8.75 (m, 1H), 8.13~8.11 (m,
1H), 8.09 (s, 1H), 7.92~7.89 (m, 3H), 7.78~7.76 (m, 2H), 7.54~7.53 (m, 1H), 7.24~7.20
(m, 4H), 4.25 (s, 2H), 3.61~3.59 (m, 2H), 3.13~3.11 (m, 2H)
ESI–MS:[M+H]+m/z 530。
The evaluation of 1 the compound of the present invention vitro kinase activity of experimental example
The compound of the present invention of above embodiments preparation successively dilutes after each compound is diluted to 10mM with DMSO
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.IC50 the results are shown in Table 1.
Table 1
The external Romas cell activity evaluation of 2 the compound of the present invention of experimental example
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
Claims (9)
1. a kind of taxol and adjacent benzene fluorine phthalazines ketone BTK inhibitor drug combination compositions, it is characterised in that: include activity
Ingredient and pharmaceutically acceptable auxiliary material, it is characterised in that: active constituent BTK as shown in taxol and formula (I) suppression
Preparation composition, the molar ratio of BTK inhibitor shown in taxol and formula (I) is (0.14-0.20) in the active constituent: 1；Its
In, the BTK inhibitor, shown in chemical formula such as formula (I),
2. a kind of taxol according to claim 1 and adjacent benzene fluorine phthalazines ketone BTK inhibitor drug combination compositions,
It is characterized by: the preparation method of the BTK inhibitor, includes the following steps:
Step A: the compound substitution reaction of formula (7) obtains the compound of formula (8), and the compound and hydrazine reaction of formula (8) obtain formula (4)
Compound；
Step B: the compound of formula (1) and the compound condensation of formula (2) obtain the compound of formula (3)；
Step C: the compound of formula (3) reacts to obtain the compound of formula (5) with the compound of formula (4)；
Step D: the compound of formula (5) sloughs protecting group and obtains the compound of formula (6)；
Step E: the compound of formula (6) and substituted alkene acyl chloride reaction obtain compounds of formula I, and reaction route is as follows:
3. a kind of taxol according to claim 1 and adjacent benzene fluorine phthalazines ketone BTK inhibitor drug combination compositions,
It is characterized by: in step A,
It takes the fluoro- 1- dimethoxy-methyl benzene of 3- in reaction flask, is added tetrahydrofuran dissolution, 60 DEG C, under nitrogen protection, s- is added
Reaction solution is stirred to react by BuLi at -60 DEG C；It takes dry ice in reaction flask, tetrahydrofuran is added, n-BuLi, nitrogen is added
The lower stirring of protection, adds the reaction solution after being stirred to react at -60 DEG C, continues to stir, stop reaction, water is added, uses concentrated hydrochloric acid
PH to 2 is adjusted, organic phase is separated, water phase is extracted with ethyl acetate, and merges organic phase, saturated common salt water washing, anhydrous sodium sulfate
It is dry, it is recrystallized to give the compound of formula (8)；
The compound, acetic acid, hydrazine of formula (8) are weighed in reaction flask, isopropanol is added, under nitrogen protection, 100 DEG C of back flow reactions,
Stop reaction, addition ethyl acetate, water, extraction merges organic phase, and anhydrous sodium sulfate is dry, hangs and does, column chromatographic purifying obtains formula
(4) compound.
4. a kind of taxol according to claim 1 and adjacent benzene fluorine phthalazines ketone BTK inhibitor drug combination compositions,
It is characterized by: take -2 (1H)-t-butyl formate of 5- amino -3,4- dihydro-isoquinoline and DIPEA in reaction flask in step B,
Methylene chloride is added, is stirred at room temperature down and chloro-carbonic acid neighbour's chlorobenzene ester is slowly added dropwise, drop finishes, and continues to stir at room temperature, stops reaction, dense
Ethyl acetate is added in contracting reaction mixture, and diluted hydrochloric acid aqueous solution and saturated common salt water washing, anhydrous sodium sulfate dry, filter, dense
It contracts to get the compound of formula (3).
5. a kind of taxol according to claim 1 and adjacent benzene fluorine phthalazines ketone BTK inhibitor drug combination compositions,
It is characterized by: in step C, the compound of modus ponens (4), formula (3) compound in reaction flask, DMF is added, is reacted at 55 DEG C
Overnight, stop reaction, water, methylene chloride is added, extraction separates organic phase, and water phase continues to be extracted with dichloromethane, and merges organic
Phase, anhydrous sodium sulfate is dry, and column chromatographic purifying obtains the compound of formula (5).
6. a kind of taxol according to claim 1 and adjacent benzene fluorine phthalazines ketone BTK inhibitor drug combination compositions,
It is characterized by: the compound of modus ponens (5) is added trifluoroacetic acid, stirs at room temperature in reaction flask in step D, it is concentrated under reduced pressure
To doing, ethyl acetate is added, is successively dried, filtered with disodium hydrogen phosphate aqueous solution and saturated common salt water washing, anhydrous sodium sulfate,
Be concentrated under reduced pressure formula (6) compound.
7. a kind of taxol according to claim 1 and adjacent benzene fluorine phthalazines ketone BTK inhibitor drug combination compositions,
It is characterized by: the compound of modus ponens (6) is added methylene chloride 100ml dissolution, is added at 0 DEG C in reaction flask in step E
DIEA after stirring, continues that 1- nitro acryloyl chloride is added dropwise at 0 DEG C, and drop finishes, is stirred at room temperature, and stops reaction, adds water, dichloromethane
Alkane extraction merges organic phase, and anhydrous sodium sulfate is dry, and column chromatographic purifying obtains the compound of formula (I).
8. drug combination compositions described in claim 1 are in preparation prevention and/or treat and bruton's tyrosine kinase phase
Application in the disease medicament of pass.
9. a kind of neighbour's benzene fluorine phthalazines ketone BTK inhibitor drug combination compositions, it is characterised in that: include active constituent and medicine
Acceptable auxiliary material on, it is characterised in that: active constituent BTK as shown in taxol, lenalidomide, formula (I) suppression
Preparation composition, taxol in the active constituent, lenalidomide, BTK inhibitor shown in formula (I) molar ratio be (0.14-
0.20): (0.08-0.12): 1.
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Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103153311A (en) * | 2010-06-03 | 2013-06-12 | 药品循环公司 | The use of inhibitors of bruton's tyrosine kinase (btk) |
| US20140107151A1 (en) * | 2011-05-17 | 2014-04-17 | Principia Biophama Inc. | Tyrosine kinase inhibitors |
| CN104812746A (en) * | 2012-11-16 | 2015-07-29 | 弗·哈夫曼-拉罗切有限公司 | Bruton's tyrosine kinase inhibitors |
| WO2016123504A1 (en) * | 2015-01-30 | 2016-08-04 | Pharmacyclics Llc | Btk inhibitor combinations and multidrug-resistance |
| CN107929276A (en) * | 2017-12-30 | 2018-04-20 | 南京众慧网络科技有限公司 | A kind of taxol and CDKS kinase inhibitor drug combination compositions |
| CN108125944A (en) * | 2017-12-30 | 2018-06-08 | 南京众慧网络科技有限公司 | A kind of taxol and CDKS kinase inhibitor antineoplastic combination pharmaceutical compositions |
| CN108578412A (en) * | 2017-12-30 | 2018-09-28 | 南京众慧网络科技有限公司 | A kind of taxol and diaza * and carbazole compound drug combination compositions |
| CN109180642A (en) * | 2018-10-04 | 2019-01-11 | 南京先进生物材料与过程装备研究院有限公司 | Phthalazines ketone BTK inhibitor and its application |
| CN109288830A (en) * | 2018-10-04 | 2019-02-01 | 南京先进生物材料与过程装备研究院有限公司 | A kind of taxol and novel phthalazines ketone compounds drug combination compositions |
| CN109336863A (en) * | 2018-10-04 | 2019-02-15 | 南京先进生物材料与过程装备研究院有限公司 | A kind of novel phthalazines ketone BTK inhibitor, preparation and its application |
-
2018
- 2018-10-31 CN CN201811282936.2A patent/CN109481443A/en not_active Withdrawn
Patent Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103153311A (en) * | 2010-06-03 | 2013-06-12 | 药品循环公司 | The use of inhibitors of bruton's tyrosine kinase (btk) |
| US20140107151A1 (en) * | 2011-05-17 | 2014-04-17 | Principia Biophama Inc. | Tyrosine kinase inhibitors |
| CN104812746A (en) * | 2012-11-16 | 2015-07-29 | 弗·哈夫曼-拉罗切有限公司 | Bruton's tyrosine kinase inhibitors |
| WO2016123504A1 (en) * | 2015-01-30 | 2016-08-04 | Pharmacyclics Llc | Btk inhibitor combinations and multidrug-resistance |
| CN107929276A (en) * | 2017-12-30 | 2018-04-20 | 南京众慧网络科技有限公司 | A kind of taxol and CDKS kinase inhibitor drug combination compositions |
| CN108125944A (en) * | 2017-12-30 | 2018-06-08 | 南京众慧网络科技有限公司 | A kind of taxol and CDKS kinase inhibitor antineoplastic combination pharmaceutical compositions |
| CN108578412A (en) * | 2017-12-30 | 2018-09-28 | 南京众慧网络科技有限公司 | A kind of taxol and diaza * and carbazole compound drug combination compositions |
| CN109180642A (en) * | 2018-10-04 | 2019-01-11 | 南京先进生物材料与过程装备研究院有限公司 | Phthalazines ketone BTK inhibitor and its application |
| CN109288830A (en) * | 2018-10-04 | 2019-02-01 | 南京先进生物材料与过程装备研究院有限公司 | A kind of taxol and novel phthalazines ketone compounds drug combination compositions |
| CN109336863A (en) * | 2018-10-04 | 2019-02-15 | 南京先进生物材料与过程装备研究院有限公司 | A kind of novel phthalazines ketone BTK inhibitor, preparation and its application |
Non-Patent Citations (2)
| Title |
|---|
| KAUSTAV BISWAS等: "Discovery of Potent, Orally Bioavailable Phthalazinone Bradykinin B1 Receptor Antagonists", 《JOURNAL OF MEDICINAL CHEMISTRY》 * |
| 孟繁浩等主编: "《药物化学》", 31 January 2016, 中国医药科技出版社 * |
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