| Identification | Back Directory | [Name]
Btk Kinase inhibitor | [CAS]
1351636-18-4 | [Synonyms]
ONO BTK
ONO-BKT
Tirabrutinib
TIRABRUTINIB;GS-4059
Btk Kinase inhibitor
ONO-4059(Tirabrutinib)
Tirabrutinib (ONO-4059)
ONO-4059;ONO 4059;ONO4059
ONO-4059(GS-4059,Tirabrutinib) free base
ONO-4059; ONO4059; ONO 4059; ONO-4059; GS 4059; GS-4059; GS4059; ONO-WG-307; TIRABRUTINIB
6-amino-9-[(3R)-1-(2-butynoyl)-3-pyrrolidinyl]-7-(4-phenoxyphenyl)-7,9-dihydro-8H-purin-8-one
6-amino-9-[(3R)-1-(but-2-ynoyl)pyrrolidin-3-yl]-7-(4-phenoxyphenyl)-7,9-dihydro-8H-purin-8-one
8H-Purin-8-one, 6-amino-7,9-dihydro-9-[(3R)-1-(1-oxo-2-butyn-1-yl)-3-pyrrolidinyl]-7-(4-phenoxyphenyl)- | [Molecular Formula]
C25H22N6O3 | [MDL Number]
MFCD28386296 | [MOL File]
1351636-18-4.mol | [Molecular Weight]
454.48 |
| Chemical Properties | Back Directory | [Boiling point ]
672.0±65.0 °C(Predicted) | [density ]
1.412±0.06 g/cm3(Predicted) | [storage temp. ]
Store at -20°C | [solubility ]
DMSO:65.0(Max Conc. mg/mL);143.02(Max Conc. mM)
DMSO:PBS (pH 7.2) (1:2):0.3(Max Conc. mg/mL);0.66(Max Conc. mM)
DMF:30.0(Max Conc. mg/mL);66.01(Max Conc. mM)
Ethanol:1.0(Max Conc. mg/mL);2.2(Max Conc. mM) | [form ]
A crystalline solid | [pka]
3.16±0.20(Predicted) | [color ]
White to yellow | [InChIKey]
SEJLPXCPMNSRAM-GOSISDBHSA-N | [SMILES]
N1(C2=CC=C(OC3=CC=CC=C3)C=C2)C2C(=NC=NC=2N)N([C@@H]2CCN(C(=O)C#CC)C2)C1=O |
| Hazard Information | Back Directory | [Description]
Btk Kinase inhibitor is highly potent and selective orally administered, small molecule, and also named tirabrutinib, Brutons tyrosine kinase (BTK) inhibitor being developed by Ono pharmaceutical and its licensee Gilead Sciences for the treatment of autoimmune disorders and haematological malignancies. | [Uses]
Tirabrutinib is a BTK inhibitor that was approved in Japan in March 2020 for the treatment of relapsed or refractory primary central nervous system lymphoma.
| [Brand name]
VelexbruTM | [Biological Functions]
In March 2020, tirabrutinib was approved in Japan to treat primary central nervous system lymphoma (PCNSL). Tirabrutinib shows excellent selectivity against all kinases with cysteines in the ATP-binding site corresponding to Cys481 in BTK with the exception of BMX, TXK, and TEC? However, it displays weaker BTK inhibition than ibrutinib (IC50 = 6.8 nM vs. 0.47 nM). | [General Description]
Class: non-receptor tyrosine kinase
Treatment: PCNSL
Elimination half-life = 6.5–8 h
Protein binding = 91%
| [Mechanism of action]
The selective inhibition of cell growth by Btk Kinase inhibitor was due to blocking of BTK-mediated signaling through AKT and cellular protein kinase D. It can inhibit autophosphorylation of the BTK at the Tyr223 position through the ERK, AKT and PKD signaling pathways. | [Side effects]
Adverse effects of the Btk Kinase inhibitor that occurred in some patients were rash, vomiting, neutropenia, arthralgia, and malaise, and drug-related Grade 3–4 Adverse effects were neutropenia, leukopenia, anemia, hypophosphatemia, PT-INR increased, pneumonitis, and acute myeloid leukemia. in prior Japanese studies, rash, hematologic adverse effects, erythema multiforme, and constipation were frequent adverse effects in a Phase I/II study of some patients with PCNSL, and rash, hematologic adverse effects, and stomatitis were the most common adverse effects in a Phase II study of some patients with WM.
| [Synthesis]
The synthesis started from 4-phenoxyaniline (384), which was reacted with diethyl chloromalonate (385) in water in the presence of a phase transfer catalyst (TBAB) to give diethyl aminomalonate (386). Condensation with ethyl foraminate gave the pyrimidine derivative 387 in 87% yield. Subsequently, the pyridine diol 387 was converted to the corresponding dichloroaryl system 388 by treatment with phosphorus oxychloride in DMF, with simultaneous N-formylation of the aniline nitrogen, probably via a Vilsmeier-Haack mechanism. Substitution reactions with compound 389 required precise control of the stoichiometry to achieve adequate conversion. Treatment with sodium hydroxide to remove the formyl group gave the diamine intermediate 390. Subsequently, the azabenzimidazolone structure was established by a CDI-mediated reaction, followed by a second SNAr reaction with benzylamine (392) to afford diamine 393 as the dihydrochloride salt after acidic deprotection. Finally, pyrroline 393 was reacted with butyric acid (394) via a T3P-mediated amidation reaction, which subsequently gave tilarabrutinib hydrochloride.
| [target]
BTK | [storage]
Store at -20°C |
|
| Company Name: |
SPIRO PHARMA
|
| Telephone: |
|
| Website: |
www.spiropharma.com.cn |
| Company Name: |
Twochem Co.Ltd
|
| Telephone: |
021-021-58111628 15800915896 |
| Website: |
www.twochem.com |
|