- 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 64-65; 66
(2021/01/23)
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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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- 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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- Metalloporphyrin-Catalyzed Oxidation of Sunitinib and Pazopanib, Two Anticancer Tyrosine Kinase Inhibitors: Evidence for New Potentially Toxic Metabolites
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Oxidation of two tyrosine kinase inhibitors (TKIs) sunitinib and pazopanib, using a chemical catalytic system able to mimic the cytochrome P450 type oxidation, allowed us to prepare putative reactive/toxic metabolites of these anticancer drugs. Among these metabolites, aromatic aldehyde derivatives were unambiguously characterized. Such biomimetic oxidation of TKI-type drugs was essential to facilitate the identification of low amounts of aldehydes generated from these TKIs when incubated with human liver microsomes (HLM), which are classical models of human hepatic metabolism. These TKI derivative aldehydes quickly react in vitro with amines. A similar reaction is expected to occur in vivo and may be at the origin of the potentially severe hepatotoxicity of these TKIs.
- Paludetto, Marie-No?lle,Bijani, Christian,Puisset, Florent,Bernardes-Génisson, Vania,Arellano, Cécile,Robert, Anne
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p. 7849 - 7860
(2018/09/06)
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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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- 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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Paragraph 0048; 0049
(2017/08/28)
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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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- PROCESS FOR THE PERPARATION OF SUNITINIB AND ITS ACID ADDITION SALTS THEREOF
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The present invention relates to an improved process for the preparation of Sunitinb. The process involves the activation of 5-((Z)-(5-fluoro-2-oxoindolin-3-ylidene) methyl)-2,4-dimethyl-1H-pyrrole-3carboxylic acid to corresponding suitable carboxylic acid activating group. The present invention also relates to novel acid addition salts of Sunitinb and preparation thereof.
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Paragraph 0113
(2015/02/18)
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- Synthesis of sunitinib-metastin conjugate, a novel esterase-sensitive prodrug system based on lactonization reaction
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We describe a strategy for preparing sunitinib-metastin conjugate, a prodrug composed of the anticancer agent sunitinib for renal cell carcinoma and the carrier protein metastin, which are conjugated to each other by a linker. We designed a modified L-homoserine linker, which is composed of an acyl group that acts as the masking group for hydrolysis with an esterase, as well as a carbon chain of appropriate length between sunitinib and metastin. The sunitinib-metastin conjugate was converted into a hydrolyte by hydrolysis of the acyl group with an esterase, and sunitinib was released by intramolecular lactonization. Sunitinib-metastin conjugate, an esterase-sensitive amide prodrug that has a modified L-homoserine linker that participates in the intramolecular lactonization, was synthesized.
- Takahashi, Yuki,Shoji, Sunao,Morishige, Takuya,Katsumata, Aya,Tsurifune, Fumihiro,Tsutsumi, Mitsuhiro,Honda, Yoshiharu,Hasuda, Tomoyo,Hitotsuyanagi, Yukio,Terachi, Toshiro,Uchida, Toyoaki,Takeya, Koichi
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p. 1860 - 1876
(2014/08/18)
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- PROCESSES FOR THE PREPARATION OF 3-(PYRROL-2-YL)METHYLENE)-2-PYRROLONES USING 2-SILYLOXY-PYRROLES
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The present invention provides for synthetic processes for the making of substituted 3-((pyrrol-2-yl)methylene)-2-pyrrolones, including sunitinib. The present invention also provides for a process of crystallizing substantially pure sunitinib L-malate.
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Paragraph 0083
(2013/07/31)
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- PROCESS FOR PREPARATION OF HIGH PURITY N- [2- (DIETHYLAMINE) ETHYL] - 5 - FORMYL - 2, 4 - DIMETHYL - 1H - PYRROLE - 3 - CARBOXYAMIDE
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The present invention relates to preparation of high purity N-[2- (diethylamine)ethyl]-5-formyl-2,4-dimethyl- 1 H-pyrrole-3-carboxyamide, comprising purification to obtain the product including less than 0.07% of desethyl derivative, N- [2-(ethylamine)ethyl]-5-formyl-2,4-dimethyl-lH-pyrrole-3-carboxyamide. N-[2- (diethylamine)ethyl]-5-formyl-2,4-dimethyl- 1 H-pyrrole-3-carboxyamide containing less than 0.07% of desethyl derivative is the valuable intermediate in the process for preparation of active pharmaceutical ingredient sunitinib.
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Page/Page column 12-13
(2013/11/18)
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- SUNITINIB MALATE SOLID DISPERSION
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The present invention provides a novel amorphous solid dispersion of sunitinib malate in combination with a pharmaceutically acceptable carrier, process for its preparation and pharmaceutical compositions comprising it. In one aspect, the present invention provides amorphous solid dispersion of sunitinib malate in combination with a pharmaceutically acceptable carrier. In another aspect, the present invention there is provided a process for the preparation of amorphous solid dispersion of sunitinib malate in combination with a pharmaceutically acceptable carrier, which comprises: a) preparing a solution comprising a mixture of sunitinib malate and one or more pharmaceutically acceptable carriers selected form copovidone, span 20, ethyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol or soluplus in water; and b) subjecting the resulting solution to freeze drying to obtain amorphous solid dispersion of sunitinib malate in combination with a pharmaceutically acceptable carrier.
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Page/Page column 6
(2013/11/18)
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- AN IMPROVED PROCESS FOR THE PREPARATION OF SUNITINIB AND ITS ACID ADDITION SALTS THEREOF
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The present invention relates to an improved process for the preparation of Sunitinb. The process involves the activation of 5-((Z)-(5-fluoro-2- oxoindolin-3-ylidene) methyl)-2,4- dimethyl-1 H-pyrrole-3carboxylic acid to corresponding suitable carboxylic acid activating group. The present invention also relates to novel acid addition salts of Sunitinb and preparation thereof.
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Page/Page column 15; 16
(2013/10/08)
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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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Page/Page column 18
(2012/05/20)
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- PROCESSES FOR THE PREPARATION OF 3-(PYRROL-2-YL)METHYLENE)-2-PYRROLONES USING 2-SILYLOXY-PYRROLES
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The present invention provides for synthetic processes for the making of substituted 3-(Pyrrol-2-yl)methylene)-2-pyrrolones, including sunitinib. The present invention also provides for a process of crystallizing substantially pure sunitinib L-malate.
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Page/Page column 32
(2012/05/20)
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- NOVEL PROCESS
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The present invention relates to novel processes for the preparation of sunitinib and salts thereof, in particular sunitinib (2S)-2-hydroxybutanedioate. The invention further relates to novel intermediates, their use in the preparation of sunitinib or salts thereof and to processes for the preparation of said intermediates. The invention also relates to compositions comprising sunitinib or its pharmaceutically acceptable salts.
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Page/Page column 33-34
(2011/11/01)
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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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- POLYMORPHS OF SUNITINIB SALTS
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Polymorphs of Sunitinib malate and other salts have been prepared. Compositions comprising Sunitinib base, L-malic acid and another carboxylic acid are also described. Such polymorphs and compositions are useful, for example, in preparing pharmaceutical compositions.
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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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- 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 8
(2011/04/19)
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- NOVEL PROCESS
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The present invention relates to novel intermediates and further to the use of said intermediates in processes for the preparation of indolinone derivatives, in particular 3- pyrrole substituted 2-indolinones having amide moieties on the pyrrole ring. Such compounds are useful in die treatment of abnormal cell growth, such as cancer, in mammals.
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Page/Page column 48-49
(2010/04/03)
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- DIHYDROINDOLE DERIVATIVES USEFUL IN PARKINSON'S DISEASE
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The invention relates to novel heterocyclic compounds of the formula (I) in which all of the variables are as defined in the specification, in free form or in salt form, to their preparation, to their use as medicaments and to medicaments comprising them.
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Page/Page column 15
(2009/04/25)
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- POLYMORPHS OF SUNITINIB BASE AND PROCESSES FOR PREPARATION THEREOF
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The present invention provides polymorphs of Sunitinib base and processes for preparation thereof.
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Page/Page column 36
(2009/06/27)
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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 30
(2010/01/30)
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- NOVEL POLYMORPHIC FORMS OF SUNITINIB BASE
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The present invention relates to novel polymorphic forms of N-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl-2,4-dimethyl-1H-pyrrole-3-carboxamide-Sunitinib base (I). The present invention also relates to methods of preparing such polymorphic crystals.
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Page/Page column 15
(2009/12/02)
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- POLYMORPHIC FORMS OF A 3-PYRROLE SUBSTITUTED 2-INDOLINONE
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The invention relates to new crystalline polymorphic forms of N-[2- (diethylamino)ethyl]-5-[(Z)-(5-fluoro-l,2-dihydro-2-oxo-3H-indol-3-ylidine)methyl]-2,4- dimethyl-lH-pyrrole-3-carboxamide (i.e., sunitinib base), including Form I, Form II, and Form IV, processes for preparing crystalline polymorphic forms of sunitinib base, and pharmaceutically acceptable salts of new crystalline polymorphic forms of sunitinib base and pharmaceutical compositions comprising new crystalline polymorphic forms of sunitinib base, salts of new crystalline polymorphic forms of sunitinib base and mixtures thereof.
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Page/Page column 10
(2009/07/17)
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- Method of synthesizing indolinone compounds
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Disclosed are methods of preparing pyrrole compounds of formula 14 and indolinone compounds of formula 1 via a synthetic route wherein the amide sidechain on the pyrrole moiety is attached prior to pyrrole formation. The compounds 14 produced by the methods herein are useful in the synthesis of compounds of formula 1, which are useful in the treatment of abnormal cell growth, such as cancer.
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Page/Page column 16
(2010/02/15)
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- COMPOUNDS FOR IMMUNOPOTENTIATION
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Methods of stimulating an immune response and treating patients responsive thereto with 3,4-di(1H-indol-3-yl)-1H-pyrrole-2,5-diones, staurosporine analogs, derivatized pyridazines, chromen-4-ones, indolinones, quinazolines, nucleoside analogs, and other small molecules are disclosed.
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Page/Page column 109
(2010/02/15)
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- Synthesis of [18F]SU11248, a new potential PET tracer for imaging cancer tyrosine kinase
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N-[2-(Diethylamino)ethyl]-5-[(Z)-(5-[18F]fluoro-2-oxo-1, 2-dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide, a new potential positron emission tomography tracer for imaging cancer tyrosine kinase, has been prepared by the nucleophilic substitution of the nitro-precursor N-[2-(diethylamino)ethyl]-5-[(Z)-(5-nitro-2-oxo-1,2-dihydro-3H- indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide with K 18F/Kryptofix 2.2.2 followed by a simple chromatography methodology combined solid-phase extraction with high-performance liquid chromatography purification procedures in 15-25% radiochemical yields.
- Wang, Ji-Quan,Miller, Kathy D.,Sledge, George W.,Zheng, Qi-Huang
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p. 4380 - 4384
(2007/10/03)
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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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- Early amidation approach to 3-[(4-amido)pyrrol-2-yl]-2-indolinones
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A new synthesis of 3-[(4-amido)pyrrol-2-yl]-2-indolinones has been developed, where the amide side chain was installed prior to pyrrole formation. This strategy precludes the need to use any coupling reagents to install the amide side chain. This process includes a zinc-free alternative to the Knorr pyrrole synthesis.
- Manley, Jerad M.,Kalman, Monica J.,Conway, Brian G.,Ball, Cynthia C.,Havens, Jeffrey L.,Vaidyanathan, Rajappa
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p. 6447 - 6450
(2007/10/03)
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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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- 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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- Discovery of 5-[5-fluoro-2-oxo-1,2-dihydroindol-(3Z)-ylidenemethyl]-2, 4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide, a novel tyrosine kinase inhibitor targeting vascular endothelial and platelet-derived growth factor receptor tyrosine kinase
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To improve the antitumor properties and optimize the pharmaceutical properties including solubility and protein binding of indolin-2-ones, a number of different basic and weakly basic analogues were designed and synthesized. 5-[5-Fluoro-2-oxo-1,2-dihydroindol-(3Z)-ylidenemethyl]-2, 4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide (12b or SU11248) has been found to show the best overall profile in terms of potency for the VEGF-R2 and PDGF-Rβ tyrosine kinase at biochemical and cellular levels, solubility, protein binding, and bioavailability. 12b is currently in phase I clinical trials for the treatment of cancers.
- Sun, Li,Liang, Chris,Shirazian, Sheri,Zhou, Yong,Miller, Todd,Cui, Jean,Fukuda, Juri Y.,Chu, Ji-Yu,Nematalla, Asaad,Wang, Xueyan,Chen, Hui,Sistla, Anand,Luu, Tony C.,Tang, Flora,Wei, James,Tang, Cho
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p. 1116 - 1119
(2007/10/03)
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