- AMP-ACTIVATED PROTEIN KINASE INHIBITORS AND METHODS OF MAKING AND USING THE SAME
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The present disclosure relates to compounds of Formula (I): (I); stereoisomers thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof. The present disclosure also relates to uses of the compounds, e.g., to inhibit AMP-Activated protein kinase (AMPK) and treat cancer in a subject.
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Page/Page column 82-83
(2021/01/23)
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- Generation of Highly Selective, Potent, and Covalent G Protein-Coupled Receptor Kinase 5 Inhibitors
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The ability of G protein-coupled receptor (GPCR) kinases (GRKs) to regulate the desensitization of GPCRs has made GRK2 and GRK5 attractive targets for treating diseases such as heart failure and cancer. Previously, our work showed that Cys474, a GRK5 subfamily-specific residue located on a flexible loop adjacent to the active site, can be used as a covalent handle to achieve selective inhibition of GRK5 over GRK2 subfamily members. However, the potency of the most selective inhibitors remained modest. Herein, we describe a successful campaign to adapt an indolinone scaffold with covalent warheads, resulting in a series of 2-haloacetyl-containing compounds that react quickly and exhibit three orders of magnitude selectivity for GRK5 over GRK2 and low nanomolar potency. They however retain a similar selectivity profile across the kinome as the core scaffold, which was based on Sunitinib.
- Rowlands, Rachel A.,Chen, Qiuyan,Bouley, Renee A.,Avramova, Larisa V.,Tesmer, John J. G.,White, Andrew D.
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p. 566 - 585
(2021/02/05)
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- Substituted oxindol-3-ylidenes as AMP-activated protein kinase (AMPK) inhibitors
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AMP-activated protein kinase (AMPK) is a central metabolic regulator that promotes cancer growth and survival under hypoxia and plays a role in the maintenance of cancer stem cells. A major challenge to interrogating the potential of targeting AMPK in cancer is the lack of potent and selective small molecule inhibitors. Compound C has been widely used as an AMPK inhibitor, but it lacks potency and has a poor selectivity profile. The multi-kinase inhibitor, sunitinib, has demonstrated potent nanomolar inhibition of AMPK activity and has scope for modification. Here, we have designed and synthesized several series of oxindoles to determine the structural requirements for AMPK inhibition and to improve selectivity. We identified two potent, novel oxindole-based AMPK inhibitors that were designed to interact with the DFG motif in the ATP-binding site of AMPK, this key feature evades interaction with the common recptor tyrosine kinase targets of sunitinib. Cellular engagement of AMPK by these oxindoles was confirmed by the inhibition of phosphorylation of acetyl-CoA carboxylase (ACC), a known substrate of AMPK, in myeloid leukemia cells. Interestingly, although AMPK is highly expressed and activated in K562 cells these oxindole-based AMPK inhibitors did not impact cell viability or result in significant cytotoxicity. Our studies serve as a platform for the further development of oxindole-based AMPK inhibitors with therapeutic potential.
- Backos, Donald S.,Casalvieri, Kimberly A.,Jordan, Craig T.,Matheson, Christopher J.,Minhajuddin, Mohammed,Reigan, Philip
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- Virtual Screening Identifies Irreversible FMS-like Tyrosine Kinase 3 Inhibitors with Activity toward Resistance-Conferring Mutations
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The use of covalent irreversible binding inhibitors is an established concept for drug development. Usually, the discovery of new irreversible kinase inhibitors occurs serendipitously, showing that efficient rational approaches for the rapid discovery of new drugs are needed. Herein, we report a virtual screening strategy that led to the discovery of irreversible inhibitors of FMS-like tyrosine kinase 3 (FLT3) involved in the pathogenesis of acute myeloid leukemia. A virtual screening library was designed to target the highly conserved Cys828 residue preceding the DFG motif by modification of reported reversible inhibitors with chemically reactive groups. Prospective covalent docking allowed the identification of two lead series, resulting in a massive increase in inhibition of kinase activity and cell viability by irreversible inhibitors compared to the corresponding reversible scaffolds. Lead compound 4b (BSc5371) displays superior cytotoxicity in FLT3-dependent cell lines to compounds in recent clinical trials and overcomes drug-resistant mutations.
- Bensinger, Dennis,Stubba, Daniel,Cremer, Anjali,Kohl, Vanessa,Wa?mer, Theresa,Stuckert, Johanna,Engemann, Victoria,Stegmaier, Kimberly,Schmitz, Katja,Schmidt, Boris
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p. 2428 - 2446
(2019/03/11)
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- A high-purity malic acid lin's preparation method
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The invention relates to a high-purity malic acid lin's preparation method, the method comprises the following steps: (1) the formula II compound as a starting material, the use of 1 - ethyl - (3 - dimethyl amino propyl) carbonylamino-carbodiimide hydrochloride with 1 - hydroxy benzotriazole as the condensing agent, under certain temperature and N, N diethylethylenediamine reaction to obtain compound III; (2) in the step (1) the reaction solution, between the step (1) the resulting reactant with 5 - fluoro indole - 2 - one reaction at certain temperature, to obtain compound IV; (3) in the step (2) of the reaction solution, so that the step (1) the resulting reactant with L - malic acid reaction at certain temperature, to obtain compound I; providing at least to a certain extent one of the solve the above technical problems or at least provide a useful commercial choice. The reaction route is operating time is short, simple operation, reaction system is stable, higher product yield, purity of the product is relatively high, it is suitable for industrial production.
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Paragraph 0042; 0043
(2019/04/04)
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- High-purity L-sunitinib malate preparation method
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The present invention discloses a high-purity L-sunitinib malate preparation method, which comprises the following reaction route defined in the specification, wherein the step a comprises that a B5 compound and 5-fluoroindol-2-one are subjected to an Aldol condensation reaction to obtain a sunitinib free base (B6 compound), the step b comprises that the B6 compound and L-malic acid are subjected to a salt forming reaction to obtain the L-sunitinib malate, and the step a and the step b are performed in a dark place. According to the present invention, the HPLC purity of the prepared L-sunitinib malate can achieve more than 99.8%, the single impurity content can be controlled at less than 0.1%, and the quality difficulty of the application of the L-sunitinib malate in the preparation is effectively solved.
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- Unique physicochemical and catalytic properties dictated by the B3NO2 ring system
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The expansion of molecular diversity beyond what nature can produce is a fundamental objective in chemical sciences. Despite the rich chemistry of boron-containing heterocycles, the 1,3-dioxa-5-aza-2,4,6-triborinane (DATB) ring system, which is characterized by a six-membered B3NO2 core, remains elusive. Here, we report the synthesis of m-terphenyl-templated DATB derivatives, displaying high stability and peculiar Lewis acidity arising from the three suitably arranged boron atoms. We identify a particular utility for DATB in the dehydrative amidation of carboxylic acids and amines, a reaction of high academic and industrial importance. The three boron sites are proposed to engage in substrate assembly, lowering the entropic cost of the transition state, in contrast with the operative mechanism of previously reported catalysts and amide coupling reagents. The distinct mechanistic pathway dictated by the DATB core will advance not only such amidations, but also other reactions driven by multisite activation.
- Noda, Hidetoshi,Furutachi, Makoto,Asada, Yasuko,Shibasaki, Masakatsu,Kumagai, Naoya
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p. 571 - 577
(2017/06/01)
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- 5-Hydroxy-7-azaindolin-2-one, a novel hybrid of pyridinol and sunitinib: Design, synthesis and cytotoxicity against cancer cells
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Angiogenesis plays important roles in tumor growth and metastasis. Sunitinib (Sutent) is an antitumor agent targeting receptor tyrosine kinases which are involved in angiogenesis as well as cancer cell growth and survival. Using the pyridin-3-ol scaffold, which was previously reported as an excellent antioxidant and antiangiogenic platform, we have synthesized sunitinib mimics 6 by hybridizing bicyclic pyridinol 4 as a key scaffold and pyrrole-2-carbaldehydes 7 as side chains. Cytotoxicity assays showed that compounds 6 have comparable to better anticancer activity than sunitinib against five different cancer cell lines. In addition, compounds 6 showed even lower levels of cytotoxicity against normal cells, resulting in up to 26-fold better safety windows, than sunitinib. Signaling pathway-associated transcription factor reporter assay and western blot analyses revealed that apoptosis induction in MDA-MB-231 human breast cancer cells by 6F is mainly mediated through the p53 increase and down-regulation of phospho-signal transducer and activator of transcription 3 (STAT3) and its target gene products, cyclin D, Bcl-2, and survivin. The data strongly suggest that our hybrid compounds can provide a novel anticancer scaffold with improved and safer cytotoxicity profiles than sunitinib.
- Shah, Sajita,Lee, Chaemin,Choi, Hyukjae,Gautam, Jaya,Jang, Hyeonjin,Kim, Geum Jin,Lee, Yu-Jeong,Chaudhary, Chhabi Lal,Park, Sang Won,Nam, Tae-Gyu,Kim, Jung-Ae,Jeong, Byeong-Seon
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p. 4829 - 4841
(2016/06/13)
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- A process for the preparation of nun
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The invention relates to a method for preparing sunitinib. The method comprises the steps of dissolving 5-fluoro-1,3-indoline-2-ketone and N-(2-diethylin ethyl)-2,4-dimethyl-5-formyl group-1H-pyrrole-3-formamide into methylbenzene, then carrying out backflow reaction for 2.5-3.5 hours with piperidine as a catalyst, cooling to room temperature, carrying out suction filtering, and washing and drying filter cakes obtained by suction filtration through petroleum ether, so as to obtain the sunitinib, wherein the N-(2-diethylin ethyl)-2,4-dimethyl-5-formyl group-1H-pyrrole-3-formamide is prepared through hot melting and decarboxylation of 3,5-dimethyl-1H-pyrrole-4-carbethoxy-2-carboxylic acid, Vilsmeier-Haack formylation, hydrolysis reaction and amidation. According to the method, an intermediate of the sunitinib is prepared and synthesized through a solvent-free method, so that the overall yield of the sunitinib is greatly increased; in addition, the technology for elementary reaction is optimized; furthermore, the raw materials are easy to obtain, and by optimizing all reaction steps in the synthetic process, the elementary reaction yield of each step is increased, the total yield of the sunitinib is increased, and thus the synthetic cost of the sunitinib is lowered.
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- An improved synthesis of sunitinib malate via a solvent-free decarboxylation process
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To search for an economical and convenient synthesis of sunitinib and its malate salt, optimization of a scalable synthetic route was explored by designing a standard experimental protocol on laboratory scale using commercially available materials including acetyl ethyl acetate, 4-fluoroaniline, and N 1,N 1-diethylethane-1,2-diamine. The optimal conditions were established based on investigating the main reaction steps, including cyclization, hydrolysis, decarboxylation, formylation, and condensation, giving optimized yields for each step of 94.4, 97.6, 98.5, 97.1, 91.0, 86.3, 85.5, 88.2, 99.1, 97.3, and 58.7 %, respectively. The synthesis process of 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid as the important intermediate was significantly improved by using solvent-free decarboxylation instead of the traditional process in a high-boiling-point solvent. The subsequent formylation was conducted directly using the dichloromethane solution of the crude product from decarboxylation, leading to an almost quantitative combined yield of these two steps. The overall yields of sunitinib and its salt using the optimal synthesis process were 67.3 and 40.0 % based on acetyl ethyl acetate. The obtained data could be used as reference for future industrialization, especially for avoiding expensive solvents and reducing reaction time.
- Meng, Ge,Liu, Chunyan,Qin, Shidong,Dong, Mengshu,Wei, Xiaomi,Zheng, Meilin,Qin, Liwen,Wang, Huihui,He, Xiaoshuang,Zhang, Zhiguo
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p. 8941 - 8954
(2015/10/28)
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- Synthesis and antitumor activity of 5-(5-halogenated-2-oxo-1H-pyrrolo[2,3-b]pyridin-(3Z)-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamides
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We report herein the design and synthesis of a series of novel 5-halogenated-7-azaindolin-2-one derivatives containing a 2,4-dimethylpyrrole moiety. Nine target compounds with ≥70% inhibition against MCF-7 at 30 μM were further evaluated for their in vitro antitumor activity against seven human cancer cell lines by SRB assay. Results reveal that some compounds have potent antitumor activity, and the most active 13c7 (IC50s: 4.49-15.39 μM) was found to be more active than Sunitinib (IC50s: 4.70->30 μM) against all of the tested cancer cell lines.
- Wang, Minghua,Ye, Cheng,Liu, Mingliang,Wu, Zhaoyang,Li, Linhu,Wang, Chunlan,Liu, Xiujun,Guo, Huiyuan
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p. 2782 - 2787
(2015/06/08)
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- Novel acylureidoindolin-2-one derivatives as dual Aurora B/FLT3 inhibitors for the treatment of acute myeloid leukemia
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A series of 6-acylureido derivatives containing a 3-(pyrrol-2- ylmethylidene)indolin-2-one scaffold were synthesized as potential dual Aurora B/FLT3 inhibitors by replacing the 6-arylureido moiety in 6-arylureidoindolin-2- one-based multi-kinase inhibitors. (Z)-N-(2-(pyrrolidin-1-yl)ethyl)-5-((6-(3-(2- fluoro-4-methoxybenzoyl)ureido)-2-oxoindolin-3-ylidene)methyl)-2, 4-dimethyl-1H-pyrrole-3-carboxamide (54) was identified as a dual Aurora B/FLT3 inhibitor (IC50 = 0.4 nM and 0.5 nM, respectively). Compound 54 also exhibited potent cytotoxicity with single-digit nanomolar IC50 values against the FLT3 mutant-associated human acute myeloid leukemia (AML) cell lines MV4-11 (FLT3-ITD) and MOLM-13 (FLT3-ITD). Compound 54 also specifically induced extrinsic apoptosis by inhibiting the phosphorylation of the Aurora B and FLT3 pathways in MOLM-13 cells. Compound 54 had a moderate pharmacokinetic profile. The mesylate salt of 54 efficiently inhibited tumor growth and reduced the mortality of BALB/c nude mice (subcutaneous xenograft model) that had been implanted with AML MOLM-13 cells. Compound 54 is more potent than sunitinib not only against FLT3-WT AML cells but also active against sunitinib-resistant FLT3-ITD AML cells. This study demonstrates the significance of dual Aurora B/FLT3 inhibitors for the development of potential agents to treat AML.
- Jagtap, Ajit Dhananjay,Chang, Pei-Teh,Liu, Jia-Rong,Wang, Hsiao-Chun,Kondekar, Nagendra B.,Shen, Li-Jiuan,Tseng, Hsiang-Wen,Chen, Grace Shiahuy,Chern, Ji-Wang
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p. 268 - 288
(2014/08/18)
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- PROCESS FOR PREPARATION OF SUNITINIB MALATE AND SALTS THEREOF
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A process for preparation of sunitinib malate is provided, which comprises condensing an indole intermediate with formyl amide intermediate. A process for preparation of crystalline form I of sunitinib malate is also provided, which uses methyl isobutyl ketone as solvent.
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- PROCESS FOR THE PREPARATION OF HIGH PURITY SUNITINIB AND ITS PHARMACEUTICALLY ACCEPTABLE SALT
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The present invention relates to an improved process for the preparation of N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidine)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide—Sunitinib base of formula (I) and its pharmaceutically acceptable malate salt of formula (I(a)).
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- Synthesis and antitumor activity of 5-[1-(3-(dimethylamino)propyl)-5- halogenated-2-oxoindolin-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3- carboxamides
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We report herein the design and synthesis of novel 1-[3-(dimethylamino) propyl]indolin-2-one derivatives based on the structural features of Sunitinib, a known multitargeted receptor tyrosine kinase inhibitor, and TMP-20, a previously discovered compound with good antitumor activity in our lab. These newly synthesized derivatives were evaluated for in vitro activity against five human cancer cell lines and VEGF/bFGF-stimulated HUVECs. Results revealed that all of the target compounds 1a-p show potent antitumor activity, compounds 1e-h (IC50's: 0.45-5.08 μM) are more active than Sunitinib (IC 50's: 1.35-6.61 μM), and the most active compound 1h (IC 50: 0.47-3.11 μM) is 2.1-4.6-fold more potent than Sunitinib against all five cancer cell lines. In addition, like Sunitinib, 1a-p have higher selectivity on VEGF-stimulated HUVEC other than bFGF-stimulated HUVEC.
- Lv, Kai,Wang, Li-Li,Liu, Ming-Liang,Zhou, Xin-Bo,Fan, Shi-Yong,Liu, Hong-Ying,Zheng, Zhi-Bing,Li, Song
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p. 3062 - 3065
(2011/06/24)
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- Synthesis and biological evaluation of 2-indolinone derivatives as potential antitumor agents
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Three series of 3-substituted-indolin-2-ones and azaindolin-2-ones have been synthesized and showed potential antiproliferative activity to cancer cell lines. The inhibition activities on VEGF-induced VEGFR phosphorylation were observed for selected 2-indolinones. Among the compounds synthesized, 5-fluoroindolin-2-one derivative 23 with a pyridone unit showed the most significant enzymatic and cellular activities. Flow cytometric analysis indicates that 23 plays a role in suppressing HCT-116 cell proliferation via G1 phase arrest and apoptosis in a dose dependent manner. The binding mode of compound 23 complexed with VEGFR-2 was predicted using FlexX algorithm. Described here are the chemistry and biological testing for these series which will guide the design and optimization of novel 2-indolione antitumor agents.
- Zou, Hongbin,Zhang, Liang,Ouyang, Jingfeng,Giulianotti, Marc A.,Yu, Yongping
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experimental part
p. 5970 - 5977
(2012/01/04)
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- SALTS OF SUNITINIB
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The present invention relates to salts of sunitinib and their preparation.
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Page/Page column 7
(2011/04/19)
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- A PROCESS FOR AMIDATION OF PYRROLE CARBOXYLATE COMPOUNDS
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The present invention relates to a process of amidation of pyrrole carboxylate compounds, including indolone-substituted pyrrole carboxylate compounds, characterized by using a cyclic alkyltriphosphonate anhydride coupling agent of formula (4) wherein A is C1-C6 alkyl group, preferably n-propyl group and to the use of the cyclic alkyltriphosphonate anhydride coupling agent of formula (4) in making pyrrole carboxamides.
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Page/Page column 14
(2011/10/05)
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- PROCESS FOR THE PREPARATION OF HIGH PURITY SUNITINIB AND ITS PHARMACEUTICALLY ACCEPTABLE SALT
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The present invention relates to an improved process for the preparation of N- [2- (diethylamino)ethyl]-5-[(Z)-(5-fluoro- 1,2-dihydro-2-oxo-3H-indol-3-ylidine) methyl]- 2,4-dimethyl-1H-pyrrole-3-carboxamide - Sunitinib base of formula (I) and its pharmaceutically acceptable malate salt of formula (I(a)).
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Page/Page column 29-30
(2010/01/30)
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- Treatment of excessive osteolysis with indolinone compounds
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Compounds of Formula I and Formula II, as described herein, are useful for treating excessive osteolysis, by inhibiting M-CSF mediated osteoclast development. The compounds also are useful for inhibiting phosphorylation of CSF1R, and for treating cancers that express CSF1R.
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- 5-sulfonamido-substituted indolinone compounds as protein kinase inhibitors
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The present invention relates to 5-sulfonamido substituted indolinones that modulate the activity of protein kinases (“PKs”). The compounds of this invention are therefore useful in treating disorders related to abnormal PK activity. Pharmaceutical compositions comprising these compounds, methods of treating diseases utilizing pharmaceutical compositions comprising these compounds and methods of preparing them are also disclosed.
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Page/Page column 18
(2010/02/08)
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- Amidations Using N,N′-Carbonyldiimidazole: Remarkable Rate Enhancement by Carbon Dioxide
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Carbon dioxide catalyzes the reaction of imidazolides with amines to form amides. A substantial rate enhancement is observed in the presence of CO 2 compared to the CO2-free case. The scope and limitations of this reaction are discussed.
- Vaidyanathan, Rajappa,Kalthod, Vikram G.,Ngo, Duc P.,Manley, Jerad M.,Lapekas, Sean P.
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p. 2565 - 2568
(2007/10/03)
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- 4-aryl substituted indolinones
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The present invention relates to 4-arylindolinones, as well as pharmaceutical compositions thereof, capable of modulating protein kinase signal transduction in order to regulate, modulate and/or inhibit abnormal cell proliferation. The present invention also relates to methods for treating protein kinase related disorders.
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- Combination therapy for the treatment of cancer
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The present invention relates to methods for treatment or prevention of neoplasia disorders using protein tyrosine kinase inhibitors in combination with cyclooxygenase inhibitors, in particular cyclooxygenase-2 selective inhibitors.
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- Treatment of acute myeloid leukemia with indolinone compounds
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A method of treating acute myeloid leukemia in patient positive for FLT-3-ITD is described. The treatment is accomplished by administration of a compound of Formula I or II as defined herein.
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- Prodrugs of a 3-(pyrrol-2-ylmethylidene)-2-indolinone derivatives
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The present invention relates to pyrrole substituted 2-indolinone compounds and their pharmaceutically acceptable salts which modulate the activity of protein kinases and therefore are expected to be useful in the prevention and treatment of protein kinase related cellular disorders such as cancer.
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- 5-ARALKYSUFONYL-3-(PYRROL-2-YLMETHYLIDENE)-2-INDOLINONE DERIVATIVES AS KINASE INHIBITORS
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The present invention relates to certain 5-aralkylsulfonyl-3-(pyrrol-2-yl-methylidene)-2-indolinone derivatives that inhibit kinases, in particular met kinase. Pharmaceutical compositions comprising these compounds, methods of treating diseases mediated by kinases utilizing pharmaceutical compositions comprising these compounds, and methods of preparing them are also disclosed.
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- Mannich base prodrugs of 3-(pyrrol-2-ylmethylidene)-2-indolinone derivatives
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The present invention is directed to Mannich base prodrugs of certain 3-(pyrrol-2-ylmethylidene)-2-indolinone derivatives that modulate the activity of protein kinases (“PKs”). Pharmaceutical compositions comprising these compounds, methods of treating diseases related to abnormal PK activity utilizing pharmaceutical compositions comprising these compounds and methods of preparing them are also disclosed.
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- Pyrrole substituted 2-indolinone protein kinase inhibitors
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The present invention relates to pyrrole substituted 2-indolinone compounds and their pharmaceutically acceptable salts which modulate the activity of protein kinases and therefore are expected to be useful in the prevention and treatment of protein kinase related cellular disorders such as cancer.
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- Rational design of 4,5-disubstituted-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-ones as a novel class of inhibitors of epidermal growth factor receptor (EGF-R) and Her2(p185(erbB)) tyrosine kinases.
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A novel class of 4,5-disubstituted-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-ones has been discovered as potent and selective inhibitors of the EGF-R tyrosine kinase family. These compounds selectively inhibit EGF-R kinase activity at low nanomolar concentration and tyrosine autophosphorylation in cells expressing EGF-R or Her2 (p185(erbB)). Structure-activity relationships (SARs) for this class of compounds are presented.
- Sun,Cui, Jean,Liang, Congxin,Zhou, Yong,Nematalla, Asaad,Wang, Xueyan,Chen, Hui,Tang, Cho,Wei, James
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p. 2153 - 2157
(2007/10/03)
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