- Tumor-Cell-Specific Targeting of Ibrutinib: Introducing Electrostatic Antibody-Inhibitor Conjugates (AiCs)
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Ibrutinib is an inhibitor of Bruton's tyrosine kinase that has been approved for the treatment of patients with chronic lymphocytic leukemia, mantle cell lymphoma and Waldenstrom's macroglobulinemia and is connected with toxicities. To minimize its toxicities, we linked ibrutinib to a cell-targeted, internalizing antibody. To this end, we synthesized a poly-anionic derivate, ibrutinib-Cy3.5, that retains full functionality. This anionic inhibitor is complexed by our anti-CD20-protamine targeting conjugate and free protamine, and thereby spontaneously assembles into an electrostatically stabilized vesicular nanocarrier. The complexation led to an accumulation of the drug driven by the CD20 antigen internalization to the intended cells and an amplification of its pharmacological effectivity. In vivo, we observed a significant enrichment of the drug in xenograft lymphoma tumors in immune-compromised mice and a significantly better response to lower doses compared to the original drug.
- B?umer, Nicole,B?umer, Sebastian,Becht, Manuel,Berdel, Wolfgang E.,Dersch, Petra,Faust, Andreas,Geyer, Christiane,Greune, Lilo,Lenz, Georg,Margeta, Renato,Rüter, Christian,Schlütermann, Alina,Wittmann, Lisa
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- PROCESS FOR PREPARING IBRUTINIB
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The present application relates to a method for preparing Ibutinib as shown by the following synthetic route and the intermediate compounds involved therein.
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- Refined preparing method of ibrutinib
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The invention discloses a refined preparing method of ibrutinib. According to the method, a compound with a formula 1 is used as a raw material, and the compound with the formula 1 and a compound with a formula 2 are reacted in the presence of a mitsunobu reaction reagent to generate a compound with a formula 3, and a protecting group of the compound with the formula 3 is removed in the presence of acid to generate a compound with a formula 4; the compound with the formula 4 and a compound with a formula 5 are subjected to a Suzuki coupling reaction in the presence of alkali and a catalyst to generate a compound with a formula 6; the compound with the formula 6 and acryloyl chloride are reacted in the presence of alkali to generate ibrutinib. Finally column chromatography separation is conducted, macroporous adsorption resin is adopted as filler, the eluent is ethyl acetate or petroleum ether, and a high-purity material is obtained. According to the refined preparing method of ibrutinib, the yield is high in every step, the product is convenient to purify, the purity is high, and the industrialized production prospect is good.
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- PROCESS FOR THE SYNTHESIS OF STABLE AMORPHOUS IBRUTINIB
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Disclosed herein is a new route of synthesis and a new stable amorphous form of ibrutinib. Also disclosed are pharmaceutical compositions, oral dosage forms and the use of the amorphous ibrutinib in the treatment of mantle cell lymphoma or chronic lymphocytic leukemia.
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- PROCESS FOR THE PREPARATION OF IBRUTINIB AND NEW SYNTHESIS INTERMEDIATE
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Subject-matter of the invention is a process for the preparation of ibrutinib and intermediate compound.
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Page/Page column 7-8
(2017/02/24)
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- A PROCESS FOR THE PREPARATION OF IBRUTINIB
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The present invention provides a process for the preparation of ibrutinib of Formula I.
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- PREPARATION OF PURE AMORPHOUS IBRUTINIB
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The present invention refers to the preparation of the amorphous form of the Bruton's tyrosine kinase (Btk) inhibitor l -((R)-3-(4-armno-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1- yl)piperidin-1-yl)prop-2-en-1-one (ibrutinib). In particular, the i
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Page/Page column 19
(2017/01/31)
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- DEUTERATED IBRUTINIB
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The present invention in one embodiment provides a compound of Formula (I); or a pharmaceutically acceptable salt thereof, wherein the variables shown in Formula (I) are as defined in the specification.
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