- 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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supporting information
(2021/12/09)
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- BTK Inhibitors and uses thereof
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The invention discloses a bruton's tyrosine kinase (BTK) inhibitor and use thereof. Specifically, the invention provides heteroaromatic compounds or stereoisomers, geometrical isomers, tautomers, racemates, nitrogen oxides, hydrates, solvates, metabolites and pharmaceutically acceptable salts or prodrugs thereof, and pharmaceutical compositions containing the heteroaromatic compounds; the invention also discloses use of the heteroaromatic compounds or the pharmaceutical compositions containing the heteroaromatic compounds in preparation of medicines; the medicines can be used for treating autoimmune diseases, inflammatory diseases or proliferative diseases.
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Paragraph 0448; 0453-0455; 1480; 1494-1496; 1726; 1731-1733
(2020/05/02)
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- ANTITUMOR-EFFECT ENHANCER USING PYRAZOLO[3,4-D]PYRIMIDINE COMPOUND
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To provide a method for treating cancer using a pyrazolo[3,4-d]pyrimidine compound or a salt thereof. The present invention provides an antitumor agent comprising a pyrazolo[3,4-d]pyrimidine compound of formula (I) wherein X, Y, Z1, Z2/su
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Paragraph 0286
(2020/01/22)
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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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- AN IMPROVED PROCESS FOR THE PREPARATION OF IBRUTINIB
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The present invention relates to an improved process for the preparation of Ibrutinib with high purity and high yields. The present process is cost effective and feasible in large scale production also. The present process avoids the mitsunobu reagent conditions also. The present Invention also relates to a process for the preparation of Crystalline form A and Crystalline form C of Ibrutinib.
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Page/Page column 12
(2018/02/28)
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- COMPOUNDS
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Disclosed are novel compounds that inhibit LRRK2 kinase activity, processes for their preparation, compositions containing them and their use in the treatment of or prevention of diseases characterized by LRRK2 kinase activity, for example Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis(ALS).
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Page/Page column 183
(2017/02/09)
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- NOVEL SALT OF FUSED PYRIMIDINE COMPOUND AND CRYSTAL THEREOF
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Provided is a salt having a high selectivity to BTK and is useful as a drug ingredient for a pharmaceutical product. It has been found that fumarate of Compound A is free of a characteristic of channel hydrate and is stable and excellent in absorptive property, compared to Compound A or other salts thereof.
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Paragraph 0187
(2017/04/11)
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- NOVEL PYRAZOLO[3,4-d]PYRIMIDINE COMPOUND OR SALT THEREOF
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To provide a novel compound having a HER2 inhibitory effect and having a cytostatic effect. It is also intended to provide a medicament useful in the prevention and/or treatment of a disease involving HER2, particularly, cancer, on the basis of the HER2 i
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Paragraph 0335
(2017/08/26)
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- Preventive and/or therapeutic agent of immune disease
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Provided is a preventive and/or therapeutic agent for immune diseases containing a compound having a BTK inhibitory activity or a salt thereof, as an active ingredient. A preventive and/or therapeutic agent of immune diseases, comprising a compound repres
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Page/Page column 40
(2017/10/28)
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- TYROSINE KINASE INHIBITORS
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The present disclosure provides compounds of formula (I) that are tyrosine kinase inhibitors, in particular Bruton tyrosine kinase ("BTK") inhibitors, and are therefore useful for the treatment of diseases treatable by inhibition of BTK such as cancer, au
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Page/Page column 76
(2017/04/19)
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- PROCESS FOR THE PREPARATION OF IBRUTINIB
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A processes for the preparation of 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4- d]pyrimidin-1-yl]-1-piperidinyl]-2-propen-1-one (ibrutinib). The disclosed process may be useful for preparing ibrutinib that may be included in pharmaceutical dosage forms.
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Page/Page column 21
(2017/01/02)
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- Chiral-1-tert-butoxy-carbonyl-3-hydroxy-piperidine, and the preparation of chiral turning method
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The invention relates to preparation of chirality-1-t-butyloxycarboryl-3-hydroxy piperidine and a method for chirality turning. The preparation mainly comprises the following steps: resolving N-benzyl-3-hydroxy piperidine as a raw material to obtain a (S) or (R)-1-benzyl-3-hydroxy piperidine camphorsulfonic acid salt, performing alkali freedom to obtain (S) or (R)-1-benzyl-3-hydroxy piperidine, performing palladium carbon hydrogenation debenzylation/t-butyloxycarboryl protection to obtain (S) or (R)-1-t-butyloxycarboryl-3-hydroxy piperidine, acylating substituting sulfonyl chloride of (R) or (S)-1-substituting-3-hydroxy piperidine as a raw material to obtain (R) or (S)-1-substituting-3-hydroxy piperidine sulfonate, substituting by using substituting carboxylate to obtain (S) or (R)-1-substituting-3-hydroxy piperidine carboxylic ester, and performing alkaline hydrolysis to obtain (S) or (R)-1-substituting-3-hydroxy piperidine. The synthesis route is gentle in reaction condition, and is applicable to industrial large-scale production.
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- BTK inhibitor and uses thereof
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The present invention provides a BTK inhibitor compound (having s structure represented by a formula (I)) and uses of the BTK inhibitor compound in medicines. According to the present invention, the compound and the pharmaceutical composition can be used for treatment of diffuse large B-cell lymphoma, follicular lymphoma or chronic lymphocytic leukemia. The formula (I) is defined in the specification.
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Paragraph 0152; 0167-0168
(2017/01/09)
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- A PROCESS FOR THE PREPARATION OF IBRUTINIB
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The present invention provides processes for the preparation of ibrutinib, intermediate compounds of Formula VI and Formula VIII, and salts thereof. The processes of the present invention are commercially viable, cost-effective, environmentally friendly, and make use of inexpensive, non-hazardous, safe chemicals that are easy to handle.
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Page/Page column 25
(2016/06/15)
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- Bruton tyrosine kinases inhibitor
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The invention relates to pyrazolo[3,4-d]pyrimidine derivatives, and a preparation method and application thereof to medicines. Concretely, the invention relates to new pyrazolo[3,4-d]pyrimidine derivatives shown as general formulas I and IA, a preparation method of the derivatives, a pharmaceutical composition containing the derivatives, and application of the derivatives as therapy equipment especially as a Bruton tyrosine kinases inhibitor.
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Paragraph 0105; 0112; 0113; 0114
(2016/10/08)
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- PROCESS FOR THE PREPARATION OF 1-[(3R)-3-[4-AMINO-3-(4-PHENOXYPHENVL)-1H- PVRAZOLO[3,4-D]PYRINIIDIN-1-Y1]-1-PIPERIDINVL]-2-PROPEN-1-ONE AND ITS POLYMORPHS THEREOF
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The present invention relates to an improved process for the preparation of 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)- 1 H-pyrazolo[3,4-d]pyrimidin- 1 -yl]- 1 -piperidin yl]-2-propen-1-one compound of formula- 1 and its polymorphs thereof, which is represented by the following structural formula:
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Page/Page column 32; 33
(2016/11/14)
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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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Page/Page column 11
(2016/10/11)
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- NOVEL FUSED PYRIMIDINE COMPOUND OR SALT THEREOF
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Provided is a novel compound having BTK inhibitory action and a cell proliferation suppressing effect. Also provided is a medicine useful for the prevention and/or treatment of a disease associated with BTK, particularly cancer, based on BTK inhibitory ac
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Paragraph 0228
(2015/12/08)
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- PYRAZOLOPYRIMIDINE DERIVATIVES USEFUL AS INHIBITORS OF BRUTON'S TYROSINE KINASE
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This invention relates to novel compounds. The compounds of the invention are tyrosine kinase inhibitors. Specifically, the compounds of the invention are useful as inhibitors of Bruton's tyrosine kinase (BTK). The invention also contemplates the use of the compounds for treating conditions treatable by the inhibition of Bruton's tyrosine kinase, for example cancer, lymphoma, leukemia and immunological diseases.
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Paragraph 00224
(2014/12/12)
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- Optimisation of a triazolopyridine based histone demethylase inhibitor yields a potent and selective KDM2A (FBXL11) inhibitor
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A potent inhibitor of the JmjC histone lysine demethylase KDM2A (compound 35, pIC50 7.2) with excellent selectivity over representatives from other KDM subfamilies has been developed; the discovery that a triazolopyridine compound binds to the active site of JmjC KDMs was followed by optimisation of the triazole substituent for KDM2A inhibition and selectivity. This journal is
- England, Katherine S.,Tumber, Anthony,Krojer, Tobias,Scozzafava, Giuseppe,Ng, Stanley S.,Daniel, Michelle,Szykowska, Aleksandra,Che, Kahing,Von Delft, Frank,Burgess-Brown, Nicola A.,Kawamura, Akane,Schofield, Christopher J.,Brennan, Paul E.
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supporting information
p. 1879 - 1886
(2015/01/09)
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- NEW INDANYLOXYDIHYDROBENZOFURANYLACETIC ACIDS
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The present invention relates to compounds of general formula I, wherein the groups R1, R2 and m are defined as in claim 1, which have valuable pharmacological properties, in particular bind to the GPR40 receptor and modulate its activity. The compounds are suitable for treatment and prevention of diseases which can be influenced by this receptor, such as metabolic diseases, in particular diabetes type 2.
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Paragraph 0521-0522; 0523
(2013/10/07)
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- GAMMA SECRETASE INHIBITORS
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Disclosed herein are compounds of Formula (I) and pharmaceutically acceptable salts thereof, wherein each of the substituents is given the definition as set forth in the specification and claims. Also disclosed are pharmaceutical compositions containing t
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Page/Page column 81
(2012/10/18)
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- AMINOPYRIMIDINES USEFUL AS KINASE INHIBITORS
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The present invention relates to compounds useful as inhibitors of Aurora protein kinases. The invention also provides pharmaceutically acceptable compositions comprising those compounds and methods of using the compounds and compositions in the treatment
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Page/Page column 33
(2010/06/16)
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- BENZO[C][2,7]NAPHTHYRIDINE DERIVATIVES, AND THEIR USE AS KINASE INHIBITORS
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The present invention relates to Benzo[c] [2,7] naph thy ri dine Derivatives of formula (I), compositions comprising an effective amount of a Benzo[c] [2,7]naphthyridine Derivative, methods for treating or preventing a proliferative disorder or an autoimmune disease, comprising administering to a subject in need thereof an effective amount of a Benzo[c] [2,7]naphthyridine Derivative, methods for modulating PDK-I activity, PKA activity, Akt activity, S6K activity, or PKC activity, comprising administering to a subject in need thereof an effective amount of a Benzo[c] [2,7] naphthyridine Derivative. The invention also relates to processes for preparing a Benzo[c] [2,7] naphthyridine Derivative.
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Page/Page column 217-218
(2008/12/08)
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- Convenient preparation of optically pure 3-aryloxy-pyrrolidines
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Chiral 3-methanesulfonyl-1-Boc-pyrrolidine and piperidine were reacted with sodium phenolates, resulting in a mixture of displacement and elimination products. Following carbamate deprotection and pH adjustment, the 3-pyrroline and tetrahydropyridine by-products resulting from elimination were easily removed through aqueous partitioning and/or concentration. Although the pyrrolidines were formed with a high degree of optical purity, slight racemization was observed for the piperidine case because elevated temperatures were required to effect displacement. Copyright Taylor & Francis Group, LLC.
- Benard, Christophe,Mohammad, Rahim,Saraswat, Neerja,Shan, Rudong,Maiti, Samarendra N.,Wuts, Peter G. M.,Stier, Michael,Lints, Teresa,Bradow, James,Schwarz, Jacob B.
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p. 517 - 524
(2008/04/12)
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- Identification of novel series of human CCR1 antagonists
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A hit-to-lead optimization process was carried out on the high throughput screening hit compound 1 resulting in the identification of several potent and selective CCR1 receptor antagonists. Compound 37 shows the best overall profile with IC50 values of 100 nM in binding and functional assays.
- Xie, Yun Feng,Sircar, Ila,Lake, Kirk,Komandla, Mallareddy,Ligsay, Kathleen,Li, Jian,Xu, Kui,Parise, Jason,Schneider, Lisa,Huang, Dingqiu,Liu, Juping,Sakurai, Naoki,Barbosa, Miguel,Jack, Rick
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p. 2215 - 2221
(2008/12/21)
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