CN114149435A - 靶向降解Btk的化合物及其应用 - Google Patents
靶向降解Btk的化合物及其应用 Download PDFInfo
- Publication number
- CN114149435A CN114149435A CN202111038421.XA CN202111038421A CN114149435A CN 114149435 A CN114149435 A CN 114149435A CN 202111038421 A CN202111038421 A CN 202111038421A CN 114149435 A CN114149435 A CN 114149435A
- Authority
- CN
- China
- Prior art keywords
- compound
- btk
- pharmaceutically acceptable
- acceptable salt
- bruton
- 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.)
- Pending
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 125
- 230000015556 catabolic process Effects 0.000 title claims abstract description 14
- 238000006731 degradation reaction Methods 0.000 title claims abstract description 14
- 230000000694 effects Effects 0.000 claims abstract description 31
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 19
- 201000010099 disease Diseases 0.000 claims abstract description 18
- 239000003814 drug Substances 0.000 claims abstract description 16
- 150000003839 salts Chemical class 0.000 claims description 29
- 230000002401 inhibitory effect Effects 0.000 claims description 23
- 239000008194 pharmaceutical composition Substances 0.000 claims description 15
- 108010029445 Agammaglobulinaemia Tyrosine Kinase Proteins 0.000 claims description 14
- 102000001714 Agammaglobulinaemia Tyrosine Kinase Human genes 0.000 claims description 14
- 230000004663 cell proliferation Effects 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 13
- 230000000593 degrading effect Effects 0.000 claims description 12
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 claims description 10
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 claims description 10
- 229940100514 Syk tyrosine kinase inhibitor Drugs 0.000 claims description 10
- 206010028980 Neoplasm Diseases 0.000 claims description 9
- 208000023275 Autoimmune disease Diseases 0.000 claims description 8
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- 238000000338 in vitro Methods 0.000 claims description 7
- 210000004881 tumor cell Anatomy 0.000 claims description 7
- 208000003950 B-cell lymphoma Diseases 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 5
- 125000001183 hydrocarbyl group Chemical group 0.000 claims description 5
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 claims description 4
- 201000004681 Psoriasis Diseases 0.000 claims description 4
- 239000000651 prodrug Substances 0.000 claims description 4
- 229940002612 prodrug Drugs 0.000 claims description 4
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 239000003112 inhibitor Substances 0.000 claims description 3
- 229940079593 drug Drugs 0.000 abstract description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 33
- 210000004027 cell Anatomy 0.000 description 30
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- 239000000243 solution Substances 0.000 description 24
- 239000000203 mixture Substances 0.000 description 14
- 238000006243 chemical reaction Methods 0.000 description 13
- -1 etc. Chemical class 0.000 description 12
- 108010087230 Sincalide Proteins 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 10
- 238000010609 cell counting kit-8 assay Methods 0.000 description 10
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 10
- 238000010828 elution Methods 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- 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 10
- 238000003786 synthesis reaction Methods 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 230000005764 inhibitory process Effects 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 9
- 238000010898 silica gel chromatography Methods 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 238000002835 absorbance Methods 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 229940125904 compound 1 Drugs 0.000 description 7
- 238000012258 culturing Methods 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 102100029823 Tyrosine-protein kinase BTK Human genes 0.000 description 6
- 238000004113 cell culture Methods 0.000 description 6
- 239000001963 growth medium Substances 0.000 description 6
- 238000011160 research Methods 0.000 description 6
- 241000282414 Homo sapiens Species 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- 235000018102 proteins Nutrition 0.000 description 5
- 102000004169 proteins and genes Human genes 0.000 description 5
- 108090000623 proteins and genes Proteins 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 239000006285 cell suspension Substances 0.000 description 4
- 239000012230 colorless oil Substances 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- 235000019441 ethanol Nutrition 0.000 description 4
- 239000012442 inert solvent Substances 0.000 description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 239000012528 membrane Substances 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 4
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 239000012980 RPMI-1640 medium Substances 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 230000003698 anagen phase Effects 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000003995 emulsifying agent Substances 0.000 description 3
- 239000012091 fetal bovine serum Substances 0.000 description 3
- 229940093915 gynecological organic acid Drugs 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 150000002367 halogens Chemical class 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- 235000005985 organic acids Nutrition 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 239000006187 pill Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 230000035755 proliferation Effects 0.000 description 3
- 239000007909 solid dosage form Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 229940124597 therapeutic agent Drugs 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 239000000080 wetting agent Substances 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- 229920001817 Agar Polymers 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 108091008875 B cell receptors Proteins 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 102100031181 Glyceraldehyde-3-phosphate dehydrogenase Human genes 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 239000002177 L01XE27 - Ibrutinib Substances 0.000 description 2
- 206010025323 Lymphomas Diseases 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
- 239000002033 PVDF binder Substances 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- 239000006180 TBST buffer Substances 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- ZEEBGORNQSEQBE-UHFFFAOYSA-N [2-(3-phenylphenoxy)-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound C1(=CC(=CC=C1)OC1=NC(=CC(=C1)CN)C(F)(F)F)C1=CC=CC=C1 ZEEBGORNQSEQBE-UHFFFAOYSA-N 0.000 description 2
- 235000011054 acetic acid Nutrition 0.000 description 2
- 235000010419 agar Nutrition 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- 208000026935 allergic disease Diseases 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 2
- 229940092714 benzenesulfonic acid Drugs 0.000 description 2
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 230000005754 cellular signaling Effects 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 239000001530 fumaric acid Substances 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 108020004445 glyceraldehyde-3-phosphate dehydrogenase Proteins 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 150000004677 hydrates Chemical class 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229960001507 ibrutinib Drugs 0.000 description 2
- 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 2
- 239000003701 inert diluent Substances 0.000 description 2
- 230000007794 irritation Effects 0.000 description 2
- 239000004310 lactic acid Substances 0.000 description 2
- 235000014655 lactic acid Nutrition 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000008297 liquid dosage form Substances 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 239000011976 maleic acid Substances 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 229910017604 nitric acid Inorganic materials 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 239000004006 olive oil Substances 0.000 description 2
- 235000006408 oxalic acid Nutrition 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 238000007747 plating Methods 0.000 description 2
- 229920005862 polyol Polymers 0.000 description 2
- 150000003077 polyols Chemical class 0.000 description 2
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 235000019260 propionic acid Nutrition 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 2
- 239000008159 sesame oil Substances 0.000 description 2
- 235000011803 sesame oil Nutrition 0.000 description 2
- 230000019491 signal transduction Effects 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 229960005322 streptomycin Drugs 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 235000012222 talc Nutrition 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 238000011200 topical administration Methods 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical class OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- 229940058015 1,3-butylene glycol Drugs 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 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
- WSNKEJIFARPOSQ-UHFFFAOYSA-N 3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-N-(1-benzothiophen-2-ylmethyl)benzamide Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(C(=O)NCC2=CC3=C(S2)C=CC=C3)C=CC=1 WSNKEJIFARPOSQ-UHFFFAOYSA-N 0.000 description 1
- GDSLUYKCPYECNN-UHFFFAOYSA-N 3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-N-[(4-fluorophenyl)methyl]benzamide Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(C(=O)NCC2=CC=C(C=C2)F)C=CC=1 GDSLUYKCPYECNN-UHFFFAOYSA-N 0.000 description 1
- FJPUKTJEFOXMJX-UHFFFAOYSA-N 3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-N-[1-(hydroxymethyl)cyclopropyl]benzamide Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(C(=O)NC2(CC2)CO)C=CC=1 FJPUKTJEFOXMJX-UHFFFAOYSA-N 0.000 description 1
- MZSAMHOCTRNOIZ-UHFFFAOYSA-N 3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-N-phenylaniline Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(NC2=CC=CC=C2)C=CC=1 MZSAMHOCTRNOIZ-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
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 235000003276 Apios tuberosa Nutrition 0.000 description 1
- 244000105624 Arachis hypogaea Species 0.000 description 1
- 235000010777 Arachis hypogaea Nutrition 0.000 description 1
- 235000010744 Arachis villosulicarpa Nutrition 0.000 description 1
- 229940124291 BTK inhibitor Drugs 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 108700039887 Essential Genes Proteins 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 241000206672 Gelidium Species 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 1
- 102000009438 IgE Receptors Human genes 0.000 description 1
- 108010073816 IgE Receptors 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
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 240000003183 Manihot esculenta Species 0.000 description 1
- 235000016735 Manihot esculenta subsp esculenta Nutrition 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 240000007817 Olea europaea Species 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 208000007452 Plasmacytoma Diseases 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 235000004443 Ricinus communis Nutrition 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 235000002595 Solanum tuberosum Nutrition 0.000 description 1
- 244000061456 Solanum tuberosum Species 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- SSZBUIDZHHWXNJ-UHFFFAOYSA-N Stearinsaeure-hexadecylester Natural products CCCCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCCCC SSZBUIDZHHWXNJ-UHFFFAOYSA-N 0.000 description 1
- 102000002689 Toll-like receptor Human genes 0.000 description 1
- 108020000411 Toll-like receptor Proteins 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- SAHIZENKTPRYSN-UHFFFAOYSA-N [2-[3-(phenoxymethyl)phenoxy]-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound O(C1=CC=CC=C1)CC=1C=C(OC2=NC(=CC(=C2)CN)C(F)(F)F)C=CC=1 SAHIZENKTPRYSN-UHFFFAOYSA-N 0.000 description 1
- ABRVLXLNVJHDRQ-UHFFFAOYSA-N [2-pyridin-3-yl-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound FC(C1=CC(=CC(=N1)C=1C=NC=CC=1)CN)(F)F ABRVLXLNVJHDRQ-UHFFFAOYSA-N 0.000 description 1
- YQYBUJYBXOVWQW-UHFFFAOYSA-N [3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxyphenyl]-(3,4-dihydro-1H-isoquinolin-2-yl)methanone Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(C=CC=1)C(=O)N1CC2=CC=CC=C2CC1 YQYBUJYBXOVWQW-UHFFFAOYSA-N 0.000 description 1
- 239000003655 absorption accelerator Substances 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 229940034982 antineoplastic agent Drugs 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 238000003149 assay kit Methods 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000012620 biological material Substances 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 238000004820 blood count Methods 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 235000019437 butane-1,3-diol Nutrition 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 230000020411 cell activation Effects 0.000 description 1
- 230000011712 cell development Effects 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 239000013592 cell lysate Substances 0.000 description 1
- 230000009087 cell motility Effects 0.000 description 1
- 238000001516 cell proliferation assay Methods 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 239000013078 crystal Chemical group 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 108010057085 cytokine receptors Proteins 0.000 description 1
- 102000003675 cytokine receptors Human genes 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 239000003599 detergent Substances 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 210000003608 fece Anatomy 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 238000001502 gel electrophoresis Methods 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- YQEMORVAKMFKLG-UHFFFAOYSA-N glycerine monostearate Natural products CCCCCCCCCCCCCCCCCC(=O)OC(CO)CO YQEMORVAKMFKLG-UHFFFAOYSA-N 0.000 description 1
- SVUQHVRAGMNPLW-UHFFFAOYSA-N glycerol monostearate Natural products CCCCCCCCCCCCCCCCC(=O)OCC(O)CO SVUQHVRAGMNPLW-UHFFFAOYSA-N 0.000 description 1
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 1
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 1
- 210000003630 histaminocyte Anatomy 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 229920003063 hydroxymethyl cellulose Polymers 0.000 description 1
- 229940031574 hydroxymethyl cellulose Drugs 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 230000002601 intratumoral effect Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 230000007721 medicinal effect Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- CQDGTJPVBWZJAZ-UHFFFAOYSA-N monoethyl carbonate Chemical compound CCOC(O)=O CQDGTJPVBWZJAZ-UHFFFAOYSA-N 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 102000037979 non-receptor tyrosine kinases Human genes 0.000 description 1
- 108091008046 non-receptor tyrosine kinases Proteins 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- NIXKBAZVOQAHGC-UHFFFAOYSA-N phenylmethanesulfonic acid Chemical compound OS(=O)(=O)CC1=CC=CC=C1 NIXKBAZVOQAHGC-UHFFFAOYSA-N 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
- PTMHPRAIXMAOOB-UHFFFAOYSA-L phosphoramidate Chemical compound NP([O-])([O-])=O PTMHPRAIXMAOOB-UHFFFAOYSA-L 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical compound OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- ILRLTAZWFOQHRT-UHFFFAOYSA-N potassium;sulfuric acid Chemical compound [K].OS(O)(=O)=O ILRLTAZWFOQHRT-UHFFFAOYSA-N 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000006884 regulation of angiogenesis Effects 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- HONNWTDYWUAZJF-UHFFFAOYSA-N tert-butyl 4-[2-[4-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxyindol-1-yl]acetyl]piperazine-1-carboxylate Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC1=C2C=CN(C2=CC=C1)CC(=O)N1CCN(CC1)C(=O)OC(C)(C)C HONNWTDYWUAZJF-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- ZIBGPFATKBEMQZ-UHFFFAOYSA-N triethylene glycol Chemical compound OCCOCCOCCO ZIBGPFATKBEMQZ-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- UAEJRRZPRZCUBE-UHFFFAOYSA-N trimethoxyalumane Chemical compound [Al+3].[O-]C.[O-]C.[O-]C UAEJRRZPRZCUBE-UHFFFAOYSA-N 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 238000001262 western blot Methods 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
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
Abstract
本发明提供了一类靶向降解Btk的化合物及其应用,具体地,本发明提供了一种如下式I所示的化合物;其中,各基团的定义如说明书中所述。本发明的化合物具有显著更强的Btk降解活性,可以用于制备治疗Btk活性相关的疾病的药物。
Description
技术领域
本发明属于医药领域,具体地涉及靶向降解Btk的化合物及其应用。
背景技术
Btk(Bruton's tyrosine kinase)即布鲁顿酪氨酸蛋白激酶,是非受体酪氨酸激酶Tec家族的成员,为细胞分化和增殖所必需基因,且在B细胞淋巴瘤、急性淋巴细胞白血病(ALL)和浆细胞瘤中均有表达。Btk为B细胞受体(BCR)信号通路的关键组成部分,是靶向治疗B细胞淋巴瘤等疾病的很好靶点。
Btk是B细胞发育、激活、信号传导和存活的关键调节物,参与对血管生成、细胞增殖和凋亡以及细胞运动的调节。除此之外,Btk还参与到许多其他造血细胞信号途径,例如,参与巨噬细胞中Toll样受体和细胞因子受体介导的信号通路,参与肥大细胞中IgE受体的信号传导等。
近年来研究显示,Btk信号通路是目前非霍奇金淋巴瘤(NHL),特别是慢性淋巴细胞白血病(CLL)、B细胞淋巴瘤及自身免疫疾病(类风湿性关节炎、银屑病等)临床治疗研究中的新热点(邓容,赵利枝。Btk抑制剂的研究进展。药学研究,2014,33(6):359-372。)。
因此,本领域技术人员致力于开发能够有效抑制、降解Btk的化合物。
发明内容
本发明的目的是提供一种能够抑制、降解Btk的化合物,及其制备和应用。
在本发明的第一方面,提供了一种如下式I所示的化合物,或其药学上可接受的盐:
其中:
X选自:C(R1)2、和C(=O);其中R1各自独立的选自:H、带有或不带有取代基的C1-4烃基;
L为连接子(linker)。
在另一优选例中,X为C(R1)2,并且R1为H。
在另一优选例中,L的结构优选如下式:
(CH2)a-O-[(CH2)b-O]n-(CH2)c
其中,a、b、c分别独立地为0-10之间的整数;n为0-5之间的整数。
在另一优选例中,b为2。
在另一优选例中,n为0-3之间的整数
本发明中0-10之间的整数包括0、1、2、3、4、5、6、7、8、9、和10。
在另一优选例中,所述L优选为以下结构:
其中,d优选0至10之间的整数。
在另一优选例中,d优选1至3之间的整数。
在另一优选例中,所述化合物选自下组:
本发明的第二方面,提供一种药物组合物及其施用方式,所述的组合物含有第一方面所述的化合物、其异构体、前药、药学上可接受的盐,以及药学上可接受的载体。
在另一优选例中,所述药物组合物,还包含另外一种或多种抗肿瘤剂。
在另一优选例中,所述的药物组合物用于抑制布鲁顿酪氨酸蛋白激酶(Btk)的活性或降低布鲁顿酪氨酸蛋白激酶(Btk)的水平。
在另一优选例中,所述的药物组合物用于治疗布鲁顿酪氨酸蛋白激酶(Btk)活性或表达量相关的疾病。
本发明的第三方面,提供了一种如本发明第一方面所述的化合物的用途,用于:
(a)制备治疗与布鲁顿酪氨酸蛋白激酶(Btk)活性或表达量相关的疾病的药物;
(b)制备布鲁顿酪氨酸蛋白激酶(Btk)靶向抑制剂或降解剂;
(c)体外非治疗性地抑制或降解布鲁顿酪氨酸蛋白激酶(Btk)的活性;
(d)体外非治疗性地抑制肿瘤细胞增殖;和/或
(e)治疗与布鲁顿酪氨酸蛋白激酶(Btk)活性或表达量相关的疾病。
在另一优选例中,所述的疾病包括肿瘤、自身免疫疾病;优选地,所述肿瘤包括非霍奇金淋巴瘤(NHL)、慢性淋巴细胞白血病(CLL)、B细胞淋巴瘤等;所述自身免疫疾病包括类风湿性关节炎、银屑病等。
本发明的第四方面,提供了一种如本发明第一方面所述的式I化合物的制备方法,包括步骤:
(a)在惰性溶剂中,用式III化合物和式II化合物反应,得到式I化合物,
M1为离去基团,M2为保护基团或氢;上述各式中,各基团的定义如上所述。
在另一优选例中,所述方法还包括步骤:
(b)在惰性溶剂中,用式IV化合物和式V化合物反应,得到式II化合物,M3为离去基团(卤素、磺酸酯等)。
具体实施方式
本发明人经过广泛而深入的研究,制备了一类具有式I所示结构的化合物,并发现其具有布鲁顿酪氨酸蛋白激酶(Btk)抑制和降解活性。且所述的化合物在极低浓度下,即对布鲁顿酪氨酸蛋白激酶(Btk)产生抑制作用,抑制活性优异,因而可以用于治疗与布鲁顿酪氨酸蛋白激酶(Btk)活性或表达量相关的疾病如肿瘤。在此基础上完成了本发明。
本发明公开一类新化合物及其能抑制并降解布鲁顿酪氨酸蛋白激酶(Btk)的用途。这些化合物能抑制并降解Btk,可用于***或自身免疫性疾病。
术语
本发明中,术语“C1-8烃基”是指只含有碳、氢两种原子的官能团,其中,碳原子的个数为1~8。烃基可以看作是相应的烃失去一个氢原子后剩下的自由基,其可为烷基、环烷基、烯基或炔基等;其结构可为直链、支链或环状;可以是脂肪族的,也可以是芳香族的。
术语“C1-6烷基”指具有1~6个碳原子的直链或支链烷基,例如甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基,或类似基团。
除非另有指示,本文所指烷基可以是直链、支链或是环状的。
本发明中,术语“含有”、“包含”或“包括”表示各种成分可一起应用于本发明的混合物或组合物中。因此,术语“主要由...组成”和“由...组成”包含在术语“含有”中。
本发明中,术语“药学上可接受的”成分是指适用于人和/或动物而无过度不良副反应(如毒性、刺激和***反应),即有合理的效益/风险比的物质。
本发明中,术语“有效量”指治疗剂治疗、缓解或预防目标疾病或状况的量,或是表现出可检测的治疗或预防效果的量。对于某一对象的精确有效量取决于该对象的体型和健康状况、病症的性质和程度、以及选择给予的治疗剂和/或治疗剂的组合。因此,预先指定准确的有效量是没用的。然而,对于某给定的状况而言,可以用常规实验来确定该有效量,临床医师是能够判断出来的。
在本文中,除特别说明之处,术语“取代”指基团上的一个或多个氢原子被选自下组的取代基取代:卤素、未取代或卤代的C1-6烷基、未取代或卤代的C2-6酰基、未取代或卤代的C1-6烷基-羟基。
除非特别说明,本发明中,所有出现的化合物均意在包括所有可能的光学异构体,如单一手性的化合物,或各种不同手性化合物的混合物(即外消旋体)。本发明的所有化合物之中,各手性碳原子可以任选地为R构型或S构型,或R构型和S构型的混合物。
如本文所用,术语“本发明化合物”指式I所示的化合物。该术语还包括及式I化合物的各种晶型形式、药学上可接受的盐、水合物或溶剂合物。
如本文所用,术语“药学上可接受的盐”指本发明化合物与酸或碱所形成的适合用作药物的盐。药学上可接受的盐包括无机盐和有机盐。一类优选的盐是本发明化合物与酸形成的盐。适合形成盐的酸包括但并不限于:盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸等无机酸,甲酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、甲磺酸、苯甲磺酸,苯磺酸等有机酸;以及天冬氨酸、谷氨酸等酸性氨基酸。
化合物及其药学上可接受的盐
本发明涉及下式I化合物或其药学上可接受的盐;
其中:
X选自:C(R1)2、和C(=O);其中R1各自独立的选自:H、带有或不带有取代基的C1-4烃基;
L为连接子(linker)。
本发明通过大量研究,对抑制并降解Btk的化合物结构进行了大量的优化和筛选,结果表明上述式I中标“*”位置为N原子时,相较于其它类型的原子,不仅表现出了更高的Btk降解活性,而且对依鲁替尼耐药的肿瘤细胞表现出了显著地抑制作用,具有更强的抗肿瘤活性,取得了预料不到的技术效果。
本发明的化合物包可以与无机酸、有机酸或碱形成药学上可接受的盐。所述的无机酸包括但不限于盐酸、氢溴酸、硝酸、高氯酸、硫酸或磷酸等;所述的有机酸包括但不限于甲磺酸、三氟甲磺酸、乙磺酸、苯磺酸、对-甲苯磺酸、富马酸、草酸、乙酸、马来酸、抗坏血酸、乳酸、酒石酸、丙二酸、乙醇酸、琥珀酸和丙酸等;所述的碱包括但不限于无机盐和胺类。
术语药学上可接受的盐指根据医学判断适用于接触人和哺乳动物的组织而无过度毒性、刺激、过敏反应等的那些盐。药学上可接受的盐为本领域公知的。
本发明还涵盖含有式I化合物的前体药物的药物组合物。前体药物包括这样的化合物,其中前体分子通过碳酸酯键、氨基甲酸酯键、酰胺键、烷基酯键、磷酸酯键、氨基磷酸酯键共价结合到式I化合物的游离羧基、羟基、氨基或胺基上。
化合物的制备
制备方法
下面更具体地描述本发明式I结构化合物的制备方法,但这些具体方法不对本发明构成任何限制。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便的制得,这样的组合可由本发明所属领域的技术人员容易的进行。
下列反应流程阐述本发明化合物的制备。除非另有指示,反应流程和随后的讨论中的各基团是如上述定义的。
一般而言,可以采用下述方案获得式I的化合物:
式I化合物的制备方法,包括步骤:
(a)在惰性溶剂中,用式III化合物和式II化合物反应,得到式I化合物,
M1为离去基团,M2为保护基团或氢;上述各式中,各基团的定义如上所述。
在另一优选例中,所述方法还包括步骤:
(b)在惰性溶剂中,用式IV化合物和式V化合物反应,得到式II化合物,M3为离去基团(卤素、磺酸酯等)。
式I化合物的应用
所述的式I化合物可用于以下的一种或多种用途:
(a)制备治疗与布鲁顿酪氨酸蛋白激酶(Btk)活性或表达量相关的疾病的药物;
(b)制备布鲁顿酪氨酸蛋白激酶(Btk)靶向抑制剂或降解剂;
(c)体外非治疗性地抑制或降解布鲁顿酪氨酸蛋白激酶(Btk)的活性;
(d)体外非治疗性地抑制肿瘤细胞增殖;和/或
(e)治疗与布鲁顿酪氨酸蛋白激酶(Btk)活性或表达量相关的疾病。
在另一优选例中,所述的疾病包括肿瘤、自身免疫疾病;优选地,所述肿瘤包括非霍奇金淋巴瘤(NHL)、慢性淋巴细胞白血病(CLL)、B细胞淋巴瘤等;所述自身免疫疾病包括类风湿性关节炎、银屑病等。
本发明的式I化合物可用于制备一种药物组合物,所述的药物组合物包括:(i)有效量的式I化合物,或其药学上可接受的盐;和(ii)药学上可接受的载体。
在另一优选例中,所述的有效量是指治疗有效量或抑制有效量。
本发明的式I化合物还可以用于抑制或降解布鲁顿酪氨酸蛋白激酶(Btk)的方法,所述的抑制是体外非治疗性的抑制也可以是治疗性的抑制。
在另一优选例中,当对抑制对象施用抑制有效量的本发明的式I化合物或其药学上可接受的盐时,所述的抑制有效量为0.001-500nmol/L,较佳地为0.01-200nmol/L。
特别地,本发明还提供了一种治疗与布鲁顿酪氨酸蛋白激酶(Btk)活性或表达量相关的疾病的方法,所述方法包括:对治疗对象施用治疗有效量的式I化合物,或所述含有式I化合物作为有效成分的药物组合物。
药物组合物和施用方法
由于本发明化合物具有优异的对布鲁顿酪氨酸蛋白激酶(Btk)的抑制活性,因此本发明化合物及其各种晶型,药学上可接受的无机或有机盐,水合物或溶剂合物,以及含有本发明化合物为主要活性成分的药物组合物可用于治疗、预防以及缓解由与Btk活性或表达量相关的疾病。根据现有技术,本发明化合物可用于治疗包括肿瘤等的疾病。
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是:化合物的量足以明显改善病情,而不至于产生严重的副作用。通常,药物组合物含有1-2000mg本发明化合物/剂,更佳地,含有5-500mg本发明化合物/剂。较佳地,所述的“一剂”为一个胶囊或药片。
“药学上可以接受的载体”指的是:一种或多种相容性固体或液体填料或凝胶物质,它们适合于人使用,而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和,而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明化合物或药物组合物的施用方式没有特别限制,代表性的施用方式包括(但并不限于):口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中,活性化合物与至少一种常规惰性赋形剂(或载体)混合,如柠檬酸钠或磷酸二钙,或与下述成分混合:(a)填料或增溶剂,例如,淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸;(b)粘合剂,例如,羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和***胶;(c)保湿剂,例如,甘油;(d)崩解剂,例如,琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠;(e)缓溶剂,例如石蜡;(f)吸收加速剂,例如,季胺化合物;(g)润湿剂,例如鲸蜡醇和单硬脂酸甘油酯;(h)吸附剂,例如,高岭土;和(i)润滑剂,例如,滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠,或其混合物。胶囊剂、片剂和丸剂中,剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备,如肠衣和其它本领域公知的材料。它们可包含不透明剂,并且,这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时,活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外,液体剂型可包含本领域中常规采用的惰性稀释剂,如水或其它溶剂,增溶剂和乳化剂,例知,乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油,特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外,组合物也可包含助剂,如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外,悬浮液可包含悬浮剂,例如,乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液,和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂,或必要时可能需要的推进剂一起混合。
本发明化合物可以单独给药,或者与其他药学上可接受的化合物联合给药。
使用药物组合物时,是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人),其中施用时剂量为药学上认为的有效给药剂量,对于60kg体重的人而言,日给药剂量通常为1~2000mg,优选5~500mg。当然,具体剂量还应考虑给药途径、病人健康状况等因素,这些都是熟练医师技能范围之内的。
本发明的主要优点包括:
1.提供了一种如式I所示的化合物。
2.提供了一种结构新颖的Btk降解剂及其制备和应用,所述的降解剂在极低浓度下即可降解Btk的活性。
3.提供了一类治疗与Btk酶活性相关疾病的药物组合物。
4.本发明通过大量研究,对化合物结构进行了优化,研究中意外发现了一类具有更高的Btk降解活性,而且对依鲁替尼耐药的肿瘤细胞表现出了显著地抑制作用的化合物,取得了预料不到的技术效果。
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件,或按照制造厂商所建议的条件。除非另外说明,否则百分比和份数是重量百分比和重量份数。本发明中涉及的生物材料(如细胞株和抗体),均可通过商业渠道购买获得。
实施例1化合物1的制备
1、化合物1-2的合成
将化合物1-1(19.5g,100mmol)、N-溴代丁二酰亚胺(18.7g,105mmol)和偶氮二异丁腈(1.65g,10mmol)溶于二氯乙烷(500mL)中,80℃反应16小时。反应液冷却,减压浓缩,残余物经硅胶柱色谱纯化(石油醚:乙酸乙酯=100:1洗脱)后得到产物18.3g,收率67%,为无色油状物。ESIMS(m/z):274.0[M+H]+.
2、化合物1-3的合成
将化合物1-2(18.3g,67mmol),化合物1-2A(11.5g,70mmol)和三乙胺(14.9g,147mmol)溶于N,N-二甲基甲酰胺(500mL)中,80℃反应40小时。反应液冷却,减压浓缩,残余物经硅胶柱色谱纯化(二氯甲烷:甲醇=50:1洗脱)后得到产物6.6g,收率34%,为白色固体。ESIMS(m/z):290.1[M+H]+.
3、化合物1-4的合成
将化合物1-3(6.6g,22.8mmol)溶于四氢呋喃(200mL)中,加入2-(三甲基硅烷基)乙氧甲基氯(4.5g,27.4mmol)和三乙胺(3.5g,34.2mmol),回流反应16h。反应液冷却,减压浓缩,残余物经硅胶柱色谱纯化(二氯甲烷:甲醇=50:1洗脱),得到产物7.0g,收率73%,为淡黄色固体。ESIMS(m/z):420.1[M+H]+.
4、化合物1-5的合成
将化合物1-4(7.0g,16.7mmol)溶于N,N-二甲基甲酰胺(100mL)和乙醇(100mL)中,加入10%钯碳(1.0g),室温氢化反应24小时。反应液过滤,滤液减压浓缩,残余物经硅胶柱色谱纯化(二氯甲烷:甲醇=30:1洗脱),得到产物5.4g,收率83%,为淡黄色固体。ESIMS(m/z):390.2[M+H]+.
5、化合物1-7的合成
氮气保护下,将化合物1-6(5.0g,16.5mmol)溶于四氢呋喃(100mL)中,加入三苯基膦(5.2g,19.8mmol)和偶氮二甲酸二异丙酯(4.3g,21.5mmol),室温下反应16小时。反应液减压浓缩,残余物经硅胶柱色谱纯化(二氯甲烷:甲醇=50:1洗脱),得到产物6.2g,收率77%,为黄色固体。ESIMS(m/z):487.2[M+H]+.
6、化合物1-8的合成
将化合物1-7(6.2g,12.7mmol)溶于二氯甲烷(50mL)中,加入三氟乙酸(10mL),室温反应4小时。反应液减压浓缩,残余物经硅胶柱色谱纯化(二氯甲烷:甲醇=20:1洗脱),得到产物4.5g,收率91%,为淡黄色油状物。ESIMS(m/z):387.2[M+H]+.
7、化合物1-9的合成
将三甘醇(15.0g,100mmol)和三乙胺(12.1g,120mmol)溶于二氯甲烷(500mL)中,加入对甲苯磺酰氯(39.8g,210mmol),室温下反应4小时。反应液用10%硫酸二氢钾水溶液(250mL×3)洗涤,无水硫酸钠干燥,减压浓缩,残余物经硅胶柱色谱纯化(二氯甲烷:甲醇=30:1洗脱),得到产物37.1g,收率81%,为无色油状物。ESIMS(m/z):459.1[M+H]+.
8、化合物1-10的合成
将化合物1-5(2.0g,5.2mmol)溶于四氢呋喃(100mL)中,分批加入化合物1-9(5.9g,12.8mmol)和碳酸铯(4.2g,12.8mmol),氮气保护下回流反应72小时。反应液用乙酸乙酯(200mL)稀释,用饱和碳酸钠水溶液(150mL×3)洗涤,无水硫酸钠干燥,减压浓缩,残余物经硅胶柱色谱纯化(二氯甲烷:甲醇=50:1洗脱),得到产物0.55g,收率15%,为无色油状物。ESIMS(m/z):676.1[M+H]+.
9、化合物1-11的合成
将化合物1-10(550mg,0.81mmol)溶于四氢呋喃(20mL)中,加入化合物1-8(346mg,0.89mmol)和二异丙基乙基胺(157mg,1.21mmol),氮气保护下60℃反应40小时。反应液冷却,减压浓缩,残余物经硅胶柱色谱纯化(二氯甲烷:甲醇=30:1洗脱),得到产物311mg,收率41%,为无色油状物。ESIMS(m/z):890.3[M+H]+.
10、化合物1的合成
将化合物1-11(311mg,0.35mmol)溶于四氢呋喃(10mL)中,加入四丁基氟化铵(274mg,1.05mmol)室温反应24小时。反应液减压浓缩,残余物经制备硅胶板纯化(二氯甲烷:甲醇=12:1洗脱),得到产物67mg,收率25%,为淡黄色固体。ESIMS(m/z):760.2[M+H]+.1H NMR(400MHz,DMSO-d6):δ10.93(s,1H),8.24(s,1H),7.71–7.62(m,2H),7.48–7.35(m,5H),7.22–7.10(m,5H),6.73–6.64(m,2H),6.39(t,J=5.7Hz,1H),5.01(dd,J=13.3,5.1Hz,1H),4.67(s,1H),4.32–4.06(m,2H),3.64–3.52(m,8H),3.31–3.25(m,2H),3.05(s,2H),2.94–2.82(m,1H),2.63–2.51(m,3H),2.39–2.12(m,5H),1.99–1.80(m,3H).
同理,参照上述实施例的方法,可以获得下表中的化合物:
实施例2 Western blot检测化合物降解BTK蛋白实验
Jeko-1细胞株用含20%胎牛血清的RPMI-1640培养基,于37℃、5%CO2、饱和湿度孵育箱内培养。待细胞生长至对数生长期,以每孔5×106个细胞接种于6孔培养板中,设定DMSO对照组、化合物测试组。
药物处理24h后,收集细胞,加入预冷的细胞裂解液,冰上裂解45min,待细胞裂解完全后,离心,取上清,冰浴保存。采用Bradford蛋白浓度测定试剂盒(去垢剂兼容型)测定蛋白浓度,制备蛋白样品。经SDS-PAGE凝胶电泳分离蛋白后,湿法转至PVDF膜上,5%BSA溶液室温封闭1h。按实验要求加入稀释后的兔抗人BTK及GAPDH,4℃孵育过夜。TBST洗膜后,加入辣根过氧化物酶标记的山羊抗兔IgG二抗稀释液,室温孵育1h。TBST洗膜后,加入ECL发光液于凝胶成像仪中进行显影成像。
使用Image J软件对各条带进行灰度分析,以GAPDH作为内参对照,计算化合物降解BTK蛋白的降解率。
结果表明,本发明化合物具有很强的降解BTK活性。
化合物 | BTK蛋白降解率(3nM) |
对照化合物1 | 31% |
1 | 70% |
对照化合物1:
实施例3化合物对TMD8细胞增殖抑制实验
细胞培养:将TMD8细胞株(人淋巴瘤细胞)培养于含有10%胎牛血清和1%青霉素-链霉素的RPMI-1640完全培养基中,于37℃、5%CO2及饱和湿度条件下的培养箱培养。
细胞铺板:取处于对数生长期的TMD8细胞,离心后,加入适量完全培养基获得单细胞混悬液,采用血球计数板进行细胞计数,配制成1.5×105个/mL细胞悬液,以每孔100μL细胞悬液接种于96孔培养板中,置于CO2细胞培养箱培养24h。
细胞给药:取待测的本发明化合物,配制成2.5μM母液,每孔加入25μL实施例化合物,摇匀,置于CO2细胞培养箱中,继续培养72h。
CCK-8检测:给药72h后,每孔加入10%CCK-8溶液,置于CO2细胞培养箱中,孵育1-4h。采用酶标仪于450nm下测定各孔吸光度。
细胞增殖抑制率计算:
细胞增殖抑制率(%)=[(Ac-As)/(Ac-Ab)]×100%
As:实验孔吸光度(含细胞、培养基、CCK-8溶液和药物溶液)
Ac:对照孔吸光度(含细胞、培养基、CCK-8溶液,不含药物)
Ab:空白孔吸光度(含培养基、CCK-8溶液,不含细胞、药物)
结果表明本发明的化合物能够显著地抑制TMD8细胞增殖,表现出了优异的抗肿瘤细胞增殖的活性。
化合物 | IC<sub>50</sub>(nM) |
对照化合物1 | 57 |
1 | 14 |
实施例4化合物对OCI-LY10细胞增殖抑制实验
细胞培养:将OCI-LY10细胞株(人淋巴瘤细胞)培养于含有10%胎牛血清和1%青霉素-链霉素的RPMI-1640完全培养基中,于37℃、5%CO2及饱和湿度条件下的培养箱培养。
细胞铺板:取处于对数生长期的OCI-LY10细胞,离心后,加入适量完全培养基获得单细胞混悬液,采用血球计数板进行细胞计数,配制成1.5×105个/mL细胞悬液,以每孔100μL细胞悬液接种于96孔培养板中,置于CO2细胞培养箱培养24h。
细胞给药:取待测的本发明化合物,配制成2.5μM母液,每孔加入25μL实施例化合物,摇匀,置于CO2细胞培养箱中,继续培养72h。
CCK-8检测:给药72h后,每孔加入10%CCK-8溶液,置于CO2细胞培养箱中,孵育1-4h。采用酶标仪于450nm下测定各孔吸光度。
细胞增殖抑制率计算:
细胞增殖抑制率(%)=[(Ac-As)/(Ac-Ab)]×100%
As:实验孔吸光度(含细胞、培养基、CCK-8溶液和药物溶液)
Ac:对照孔吸光度(含细胞、培养基、CCK-8溶液,不含药物)
Ab:空白孔吸光度(含培养基、CCK-8溶液,不含细胞、药物)
结果表明本发明的化合物能够显著地抑制OCI-LY10细胞增殖,表现出了优异的抗肿瘤细胞增殖的活性。
化合物 | IC<sub>50</sub>(nM) |
对照化合物1 | 2.5 |
1 | 1.2 |
上述测试结果表明,本发明化合物的活性要显著由于对照化合物1,在相同的极低浓度下针对BTK蛋白降解率达到了对照化合物1的两倍以上,针对TMD8细胞株细胞增殖抑制能力是对照化合物1的四倍,表现出了优异的抗肿瘤细胞增殖的活性。
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (10)
2.如权利要求1所述的化合物,或其药学上可接受的盐,其特征在于:X为C(R1)2,并且R1为H。
3.如权利要求1所述的化合物,或其药学上可接受的盐,其特征在于:L的结构优选如下式:
(CH2)a-O-[(CH2)b-O]n-(CH2)c
其中,a、b、c分别独立地为0-10之间的整数;n为0-5之间的整数。
4.如权利要求3所述的化合物,或其药学上可接受的盐,其特征在于:b为2。
7.一种药物组合物,其特征在于,所述的组合物含有权利要求1所述的化合物或其药学上可接受的盐、前药,以及药学上可接受的载体。
8.一种如权利要求1所述的化合物或其药学上可接受的盐的用途,用于:
(a)制备治疗与布鲁顿酪氨酸蛋白激酶(Btk)活性或表达量相关的疾病的药物;
(b)制备布鲁顿酪氨酸蛋白激酶(Btk)靶向抑制剂或降解剂;
(c)体外非治疗性地抑制或降解布鲁顿酪氨酸蛋白激酶(Btk)的活性;
(d)体外非治疗性地抑制肿瘤细胞增殖;和/或
(e)治疗与布鲁顿酪氨酸蛋白激酶(Btk)活性或表达量相关的疾病。
9.如权利要求8所述的用途,其特征在于,所述的疾病包括肿瘤、自身免疫疾病;优选地,所述肿瘤包括非霍奇金淋巴瘤(NHL)、慢性淋巴细胞白血病(CLL)、B细胞淋巴瘤等;所述自身免疫疾病包括类风湿性关节炎、银屑病等。
10.一种抑制或降解布鲁顿酪氨酸蛋白激酶(Btk)活性的方法,包括步骤:对抑制对象施用抑制有效量的如权利要求1所述的式I化合物或其药学上可接受的盐,或对抑制对象施用抑制有效量的如权利要求7所述的药物组合物。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN2020109315784 | 2020-09-06 | ||
CN202010931578 | 2020-09-06 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN114149435A true CN114149435A (zh) | 2022-03-08 |
Family
ID=80462544
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202111038421.XA Pending CN114149435A (zh) | 2020-09-06 | 2021-09-06 | 靶向降解Btk的化合物及其应用 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN114149435A (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN115611902A (zh) * | 2021-07-15 | 2023-01-17 | 标新生物医药科技(上海)有限公司 | 基于布鲁顿酪氨酸激酶配体设计的蛋白降解化合物及其应用 |
-
2021
- 2021-09-06 CN CN202111038421.XA patent/CN114149435A/zh active Pending
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN115611902A (zh) * | 2021-07-15 | 2023-01-17 | 标新生物医药科技(上海)有限公司 | 基于布鲁顿酪氨酸激酶配体设计的蛋白降解化合物及其应用 |
WO2023284703A1 (zh) * | 2021-07-15 | 2023-01-19 | 标新生物医药科技(上海)有限公司 | 基于布鲁顿酪氨酸激酶配体设计的蛋白降解化合物及其应用 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN109422752B (zh) | 一类具有抑制并降解布鲁顿酪氨酸蛋白激酶Btk活性的化合物 | |
CN110724174B (zh) | 吡咯并三嗪类化合物、组合物及其应用 | |
BR112020013237A2 (pt) | derivados de amino-metilpiperidina como iniciador quinase | |
EA025881B1 (ru) | Макроциклические ингибиторы flt3-киназы | |
EP2927232A1 (en) | Heteroaryl alkyne compound and application thereof | |
CN111662294A (zh) | 一类具有降解Btk活性的化合物 | |
CN112979656A (zh) | 一类靶向降解btk蛋白的化合物 | |
CN114181161B (zh) | (2-((取代氧基)苯基)氨基)嘧啶-4-基)氨基苯甲酰衍生物及其制备方法与应用 | |
CN113490669B (zh) | 一类具有降解Btk活性的化合物 | |
CN114149435A (zh) | 靶向降解Btk的化合物及其应用 | |
CN111094314A (zh) | 含有葡糖苷酸衍生物jak抑制剂的前药及其制备方法和应用 | |
CN115708410B (zh) | 靶向降解Btk的化合物及其抗肿瘤用途 | |
CN109937203B (zh) | 一类具有抑制并降解酪氨酸蛋白激酶jak1或jak2活性的化合物 | |
TWI828289B (zh) | 作為tyk2/jak1假激酶結構域抑制劑的化合物及合成和使用方法 | |
EP2405751B1 (en) | Sphingosine kinase inhibitor prodrugs | |
CN114555565B (zh) | 含氮并环化合物、其制备方法及用途 | |
RU2768451C1 (ru) | Селективный антагонист рецепторов типа A2A | |
WO2016127949A1 (zh) | 作为t790变异抑制剂的嘧啶衍生物 | |
CN114181159B (zh) | 含2,4,5-三取代嘧啶酰肼衍生物及其制备方法与应用 | |
CN114539204B (zh) | 己糖激酶抑制剂及其合成方法和应用 | |
WO2023206655A1 (zh) | 一种PI3Kδ抑制剂及其用途 | |
CN112209933B (zh) | 含有4-氮杂螺庚烷的btk抑制剂 | |
CN108822125B (zh) | 1-(噻吩并[2,3-b]噻喃甲酰基)-4-脂肪烃基哌嗪类化合物及其医药用途 | |
CN116554249A (zh) | 抗病毒化合物及其用途 | |
WO2023201044A2 (en) | Jak inhibitor analogs, formulations, and uses thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
WD01 | Invention patent application deemed withdrawn after publication | ||
WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20220308 |