- Effects of immunomodulatory derivatives of thalidomide (IMiDs) and their analogs on cell-differentiation, cyclooxygenase activity and angiogenesis
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Various analogs of known immunomodulatory derivatives of thalidomide (1) (IMiDs: 3, 5) were synthesized, focusing on cell-differentiation-inducing, cyclooxygenase-inhibitory and anti-angiogenesis activities. Among the prepared compounds, NIDO-33 (14) showed cell differentiation-inducing activity on HL-60 cells and anti-angiogenic activity on human umbilical vein endothelial cells (HUVEC). AIDO-00 (7) also showed anti-angiogenic activity. NIDO-11 (8) showed an enhancing effect on all-trans retinoic acid (ATRA)-induced HL-60 cell differentiation, and AIDO-30 (13) exhibited cyclooxygenase (COX)-inhibitory activity.
- Fujimoto, Haruka,Noguchi, Tomomi,Kobayashi, Hisayoshi,Miyachi, Hiroyuki,Hashimoto, Yuichi
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Read Online
- Chemical degradation of androgen receptor (Ar) using bicalutamide analog–thalidomide protacs
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A series of PROTACs (PROteolysis-TArgeting Chimeras) consisting of bicalutamide analogs and thalidomides were designed, synthesized, and biologically evaluated as novel androgen receptor (AR) degraders. In particular, we found that PROTAC compound 13b could successfully demonstrate a targeted degradation of AR in AR-positive cancer cells and might be a useful chemical probe for the investigation of AR-dependent cancer cells, as well as a potential therapeutic candidate for prostate cancers.
- Kim, Ga Yeong,Song, Chae Won,Yang, Yo-Sep,Lee, Na-Rae,Yoo, Hyung-Seok,Son, Seung Hwan,Lee, Soo Jin,Park, Jong Seon,Lee, Jong Kil,Inn, Kyung-Soo,Kim, Nam-Jung
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Read Online
- Rational Design and Synthesis of HSF1-PROTACs for Anticancer Drug Development
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PROTACs employ the proteosome-mediated proteolysis via E3 ligase and recruit the natural protein degradation machinery to selectively degrade the cancerous proteins. Herein, we have designed and synthesized heterobifunctional small molecules that consist of different linkers tethering KRIBB11, a HSF1 inhibitor, with pomalidomide, a commonly used E3 ligase ligand for anticancer drug development.
- Choi, Myeong A.,Seo, Young Ho,Sharma, Chiranjeev,Song, Yoojin
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- The tale of proteolysis targeting chimeras (PROTACs) for Leucine-Rich Repeat Kinase 2 (LRRK2)
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Here we present the rational design and synthetic methodologies towards proteolysis-targeting chimeras (PROTACs) for the recently-emerged target leucine-rich repeat kinase 2 (LRRK2). Two highly potent, selective, brain-penetrating kinase inhibitors were selected, and their structure was appropriately modified to assemble a cereblon-targeting PROTAC. Biological data show strong kinase inhibition and the ability of the synthesized compounds to enter the cells. However, data regarding the degradation of the target protein are inconclusive. The reasons for the inefficient degradation of the target are further discussed.
- Konstantinidou, Markella,Oun, Asmaa,Pathak, Pragya,Zhang, Bidong,Wang, Zefeng,ter Brake, Frans,Dolga, Amalia M.,Kortholt, Arjan,D?mling, Alexander
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p. 959 - 965
(2020/12/30)
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- Influence of Linker Attachment Points on the Stability and Neosubstrate Degradation of Cereblon Ligands
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Proteolysis targeting chimeras (PROTACs) hijacking the cereblon (CRBN) E3 ubiquitin ligase have emerged as a novel paradigm in drug development. Herein we found that linker attachment points of CRBN ligands highly affect their aqueous stability and neosubstrate degradation features. This work provides a blueprint for the assembly of future heterodimeric CRBN-based degraders with tailored properties.
- Bricelj, Ale?a,Dora Ng, Yuen Lam,Ferber, Dominic,Gütschow, Michael,Kr?nke, Jan,Kuchta, Robert,Müller, Sina,Monschke, Marius,Sosi?, Izidor,Steinebach, Christian,Wagner, Karl G.
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p. 1733 - 1738
(2021/11/16)
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- PHOTO INDUCED CONTROL OF PROTEIN DESTRUCTION
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By hijacking endogenous E3 ligase to degrade protein targets via the ubiquitin-proteasome system, PROTACs (PRoteolysis TArgeting Chimeras) provide a new strategy to inhibit protein targets that were previously regarded as undruggable. The compounds described herein comprise a photolabile group on PROTACs, enabling the degradation of protein targets in a spatiotemporally controlled manner. By adding a photolabile caging group on ubiquitin recruiting moieties, light-inducible protein degradation was acheived. These opto-PROTACs display no activity in the dark, while restricted degradation can be induced at a specific time and rate by UVA-irradiation. Accordingly, these compounds provide light-controlled PROTACs and methods of using such compounds.
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Paragraph 0010; 0114; 0138
(2021/01/29)
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- Synthesis process for continuously preparing pomalidomide by using microchannel reactors
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The invention discloses a synthesis process for continuously preparing pomalidomide by using microchannel reactors. The synthesis process comprises the following steps tha (1) 3-nitrophthalic acid isdissolved in acetic anhydride, and a reaction is performed to obtain 3-nitrophthalic anhydride; (2) 3-nitrophthalic anhydride is dissolved in formic acid to prepare a homogeneous solution A; (3) 3-aminopiperidine-2,6-dione is dissolved in ammonium formate and formic acid to prepare a homogeneous solution B; (4) palladium on carbon and methanol are prepared into suspension C; (5) the homogeneous solution A and the homogeneous solution B are simultaneously pumped into a microstructured mixer I in a microchannel reaction device separately, and after mixing, the mixture is introduced into a microstructured reactor I; (6) the suspension C and an effluent from the microstructured reactor I are simultaneously pumped into a microstructured mixer II in the microchannel reaction device separately while the step (5) is carried out, and after mixing, the mixture is introduced into a microstructured reactor II; and (7) an effluent from the microstructured reactor II is collected to obtain pomalidomide.
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Paragraph 0055-0063
(2020/03/06)
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- Selective degradation of CDK6 by a palbociclib based PROTAC
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Development of selective kinase inhibitors that target the ATP binding site continues to be a challenge largely due to similar binding pockets. Palbociclib is a cyclin-dependent kinase inhibitor that targets the ATP binding site of CDK4 and CDK6 with similar potency. The enzymatic function associated with the kinase can be effectively probed using kinase inhibitors however the kinase-independent functions cannot. Herein, we report a palbociclib based PROTAC that selectively degrades CDK6 while sparing the homolog CDK4. We used competition studies to characterize the binding and mechanism of CDK6 degradation.
- Rana, Sandeep,Bendjennat, Mourad,Kour, Smit,King, Hannah M.,Kizhake, Smitha,Zahid, Muhammad,Natarajan, Amarnath
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p. 1375 - 1379
(2019/04/01)
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- PYRIDAZINE DERIVATIVES AS SMARCA2/4 DEGRADERS
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The present invention provides pyridazine derivatives of formula (I), which are therapeutically useful as SMARCA2/4 degraders. These compounds are useful in the treatment and/or prevention of diseases or disorders dependent upon SMARCA2/4 in a mammal. The present invention also provides preparation of the compounds and pharmaceutical compositions comprising at least one of the pyridazine derivatives of formula (I) or a pharmaceutically acceptable salt, or a stereoisomer thereof.
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- SUBSTITUTED 4-AMINOISOINDOLINE-1,3-DIONE COMPOUNDS, COMPOSITIONS THEREOF, AND METHODS OF TREATMENT THEREWITH
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Provided herein are 4-aminoisoindoline-1,3-dione compounds having the following structure: wherein R, Ring A, and n are as defined herein, compositions comprising an effective amount of a 4-aminoisoindoline-1,3-dione compound, and methods for treating or preventing disorders.
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- IMIDE-BASED MODULATORS OF PROTEOLYSIS AND METHODS OF USE
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The description relates to imide-based compounds, including bifunctional compounds comprising the same, which find utility as modulators of targeted ubiquitination, especially inhibitors of a variety of polypeptides and other proteins which are degraded and/or otherwise inhibited by bifunctional compounds according to the present invention. In particular, the description provides compounds, which contain on one end a ligand which binds to the cereblon E3 ubiquitin ligase and on the other end a moiety which binds a target protein such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of that protein. Compounds can be synthesized that exhibit a broad range of pharmacological activities consistent with the degradation/inhibition of targeted polypeptides of nearly any type.
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Page/Page column 224; 230-231; 235
(2019/08/12)
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- CEREBLON BINDERS FOR THE DEGRADATION OF IKAROS
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The present invention provides cereblon binders for the degradation of Ikaros or Aiolos by the ubiquitin proteasome pathway along with their use in therapeutic applications as described herein.
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- Preparation method of anti-tumor therapeutic medicine pomalyst
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The invention discloses a preparation method of anti-tumor therapeutic medicine pomalyst, and belongs to the field of medicine synthesis. The pomalyst is obtained by using 3-nitrophthalic acid and 3-aminopiperidine-2,6-dione hydrochloride as raw materials, performing a condensation reaction and performing nitroreduction. Compared with a method reported in the prior literature, the method providedby the invention has the advantages of fewer synthetic steps, mild reaction conditions, simple operation, avoidance of use of heavy metal reagents and toxic organic solvents because of the condensation step, low residual amount of organic solvents, environmental friendliness, a greener and more-environmentally-friendly overall process, easy-to-control quality, higher process stability and the like, and is suitable for industrialized production.
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Paragraph 0017; 0019; 0020; 0021; 0023-0025; 0027; 0028
(2019/04/26)
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- Method for preparing 3-amine-N-(2, 6-dioxo-3-piperidyl)-phthalimide compounds
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The invention discloses a method for preparing 3-amine-N-(2, 6-dioxo-3-piperidyl)-phthalimide compounds. The 3-amine-N-(2, 6-dioxo-3-piperidyl)-phthalimide compounds are compounds shown as a formula (I) or pharmacologically acceptable salt of the compounds, solvate, polymorphic substances or stereoisomer, and a molecular structural formula of the compounds shown as the formula (I) is shown. The method includes carrying out hydrolysis reaction on compounds shown as a formula (II) in solvents under the condition of the presence of acid or alkali. A molecular structural formula of the compounds shown as the formula (JJ) is shown. The method has the advantages that the compounds shown as the formula (II) are high in solubility and easy to hydrolyze, steps for carrying out reduction reaction onmetal catalysts, further purifying products and the like can be omitted, and accordingly the method includes simple preparation steps; the 3-amine-N-(2, 6-dioxo-3-piperidyl)-phthalimide compounds which are products are high in yield and purity, and the method is suitable for large-scale industrial production.
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Paragraph 0096-0113
(2019/02/13)
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- Homo-PROTACs for the Chemical Knockdown of Cereblon
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The immunomodulatory drugs (IMiDs) thalidomide, lenalidomide, and pomalidomide, all approved for the treatment of multiple myeloma, induce targeted ubiquitination and degradation of Ikaros (IKZF1) and Aiolos (IKZF3) via the cereblon (CRBN) E3 ubiquitin ligase. IMiD-based proteolysis-targeting chimeras (PROTACs) can efficiently recruit CRBN to a protein of interest, leading to its ubiquitination and proteasomal degradation. By linking two pomalidomide molecules, we designed homobifunctional, so-called homo-PROTACs and investigated their ability to induce self-directed ubiquitination and degradation. The homodimerized compound 15a was characterized as a highly potent and efficient CRBN degrader with only minimal effects on IKZF1 and IKZF3. The cellular selectivity of 15a for CRBN degradation was confirmed at the proteome level by quantitative mass spectrometry. Inactivation by compound 15a did not affect proliferation of different cell lines, prevented pomalidomide-induced degradation of IKZF1 and IKZF3, and antagonized the effects of pomalidomide on multiple myeloma cells. Homobifunctional CRBN degraders will be useful tools for future biomedical investigations of CRBN-related signaling and may help to further elucidate the molecular mechanism of thalidomide analogues.
- Steinebach, Christian,Lindner, Stefanie,Udeshi, Namrata D.,Mani, Deepak C.,Kehm, Hannes,K?pff, Simon,Carr, Steven A.,Gütschow, Michael,Kr?nke, Jan
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p. 2771 - 2782
(2018/09/25)
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- Chemically induced degradation of CK2 by proteolysis targeting chimeras based on a ubiquitin–proteasome pathway
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As a ubiquitous, highly pleiotropic and constitutively active serine/threonine protein kinase, casein kinase 2 (CK2) is closely associated with tumorigenesis by its overexpression in cancer cells. Here we report several proteolysis targeting chimeras (PROTACs) via “click reaction” to connect a CK2 inhibitor (CX-4945) and pomalidomide for degradation of CK2 protein. Among them, compound 2 degraded CK2 in a dose and time-dependent manner, and kept CK2 at a low basal level by recruiting ubiquitin-proteasome system. The degradation of CK2 resulted in the reduced phosphorylation of Akt and the up-regulation of p53. As a CK2 protein degrader, 2 showed the analogous cytotoxicity to CX-4945 but with a quite different mechanism of action from the CK2 inhibitor, hinting that degradation of CK2 proteins by PROTACs is a potential way for cancer treatments.
- Chen, Hong,Chen, Feihong,Liu, Nannan,Wang, Xinyi,Gou, Shaohua
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p. 536 - 544
(2018/09/29)
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- A preparation method of anchors the advantage amine
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The invention discloses a preparation method of pomalidomide. The preparation method of pomalidomide comprises the following step; in N,N-dimethylacetamide or a mixed solvent of N,N-dimethylacetamide and other solvents, carrying out reduction reaction shown in the formula (described in the specification) on hydrogen and a compound shown in a formula II in the presence of palladium on activated carbon, wherein other solvents can be alcohol solvents, ketone solvents or water. The preparation method of pomalidomide has the advantages of high yield, low solvent consumption and high purity and is also applicable to industrial large-scale production. The formula II is described in the specification.
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Paragraph 0032; 0033; 0036; 0038; 0040; 0042; 0044; 0046
(2018/06/23)
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- REGULATING CHIMERIC ANTIGEN RECEPTORS
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This invention is in the area of compositions and methods for regulating chimeric antigen receptor immune effector cell, for example T-cell (CAR-T), therapy to modulate associated adverse inflammatory responses, for example, cytokine release syndrome and tumor lysis syndrome, using targeted protein degradation.
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Page/Page column 297; 300; 301
(2018/09/08)
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- TUNABLE ENDOGENOUS PROTEIN DEGRADATION WITH HETEROBIFUNCTIONAL COMPOUNDS
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The present invention provides a means to modulate gene expression in vivo in a manner that avoids problems associated with CRISPR endogenous protein knock-out or knock-in strategies and strategies that provide for correction, or alteration, of single nucleotides. The invention includes inserting into the genome a nucleotide encoding a heterobifunctional compound targeting protein (dTAG) in-frame with the nucleotide sequence of a gene encoding an endogenously expressed protein of interest which, upon expression, produces an endogenous protein-dTAG hybrid protein. This allows for targeted protein degradation of the dTAG and the fused endogenous protein using a heterobifunctional compound.
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Page/Page column 281-282
(2018/09/08)
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- PROCESS FOR THE PREPARATION OF POMALIDOMIDE
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The present invention relates to a process for the preparation of pomalidomide. The present invention also provides a process for the preparation of 2-(2,6-dioxopiperidin-3-yl)-4-nitro-1H-isoindole-1,3(2H)-dione, a compound of Formula II and its use for the preparation of pomalidomide. The pomalidomide may be made having a yield greater than 97% and the 2-(2,6-dioxopiperidin-3-yl)-4-nitro-1H-isoindole-1,3(2H)-dione (Formula II) may be made having a yield greater than 88%.
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Page/Page column 8
(2018/09/19)
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- Synthesis method of pomalidomide
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The invention discloses an improved synthesis method of pomalidomide, and belongs to the field of medicinal chemistry. 3-halogenated phthalic acid 1 used as a raw material (F, Cl and Br) is condensedthrough an acetic anhydride system to obtain a phthalic anhydride compound 2; the compound 2 reacts with 3-amino-2,6-piperidone diketone salt to obtain a phthalimide derivative 4; and the compound 4 and ammonia water undergo amino displacement to obtain the pomalidomide. According to the synthesis method, the 3-halogenated phthalic acid is used as a start raw material, which replaces the current reported 3-nitrophthalic acid; amino directly replaces halogen to prepare the pomalidomide, so that high-pressure hydrogenation during nitroreduction is avoided, or use of a metal reducer such as ironpowder is avoided; a reaction process is simple, easy to operate, low in pollution and high in yield; and a solvent can be recycled and reused, thereby facilitating large-scale industrial production.
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- Efficient Synthesis of Immunomodulatory Drug Analogues Enables Exploration of Structure–Degradation Relationships
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The immunomodulatory drugs (IMiDs) thalidomide, pomalidomide, and lenalidomide have been approved for the treatment of multiple myeloma for many years. Recently, their use as E3 ligase recruiting elements for small-molecule-induced protein degradation has led to a resurgence in interest in IMiD synthesis and functionalization. Traditional IMiD synthesis follows a stepwise route with multiple purification steps. Herein we describe a novel one-pot synthesis without purification that provides rapid access to a multitude of IMiD analogues. Binding studies with the IMiD target protein cereblon (CRBN) reveals a narrow structure–activity relationship with only a few compounds showing sub-micromolar binding affinity in the range of pomalidomide and lenalidomide. However, anti-proliferative activity as well as Aiolos degradation could be identified for two IMiD analogues. This study provides useful insight into the structure–degradation relationships for molecules of this type as well as a rapid and robust method for IMiD synthesis.
- Burslem, George M.,Ottis, Philipp,Jaime-Figueroa, Saul,Morgan, Alicia,Cromm, Philipp M.,Toure, Momar,Crews, Craig M.
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supporting information
p. 1508 - 1512
(2018/07/31)
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- Improved method of pomalidomide synthesis process
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The invention relates to a preparation method of pomalidomide of high purity suitable for industrial production. 3-nitrophthalic anhydride and glutamic acid are reacted in order to obtain an intermediate, a reaction is carried out in the condition with acetic anhydride in order to obtain an intermediate, 3-nitro-N-(2,6-dioxo-3-piperidyl)phthalimide is obtained by an ammonification reaction in the DMSO condition, and palladium on carbon is used for hydrogenation in order to obtain pomalidomide. The process has the characteristics of high yield, simple operation, environmental friendliness, large scale production, and the like; a low toxicity solvent is used in order to solve the problem that products are not qualified due to solvent residues.
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- Preparation method for high-purity pomalidomide
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A preparation method for high-purity pomalidomide comprises the following steps: (1) adding 3-nitro-N-(2,6-dioxo-3-piperidyl)phthalimide, palladium carbon and N-methyl pyrrolidone to a reaction kettle, vacuumizing, then introducing hydrogen gas, carrying out suction filtration after a reaction is complete, adding medicinal charcoal to the filtrate, stirring, heating, and carrying out suction filtration; and (2) adding an alkaline aqueous solution to the filtrate finally obtained in the step (1), stirring, then adding purified water, cooling and crystallizing, carrying out suction filtration, adding purified water to the obtained filter cake, stirring, carrying out suction filtration, washing, and drying to obtain the high-purity pomalidomide product. The preparation method provided by the invention has the advantages of simple operation and mature and stable technology, and can significantly improve the quality of pomalidomide; the purity of the obtained product is greater than 99.5%, the contents of single impurities are all less than 0.1%, and the medicinal requirements are met.
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Paragraph 0053; 0054; 0055; 0056-0061
(2017/05/05)
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- PROCESS FOR PREPARATION AND PURIFICATION OF POMALIDOMIDE
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Processes are disclosed for making pomalidomide which involve reducing 2-(2,6-dioxopiperidin-3-yl)-4-nitroisoindoline-1,3-dione using a catalyst and at least one solvent. The process may include reacting 3-nitrophthalic anhydride with α-amino glutarimide hydrochloride to obtain the 2-(2,6-dioxopiperidin-3-yl)-4-nitroisoindoline-1,3-dione. The process may further include, prior to the reducing step, subjecting the 2-(2,6-dioxopiperidin-3-yl)-4-nitroisoindoline-1,3-dione to a purification process comprising heating a mixture of 2-(2,6-dioxopiperidin-3-yl)-4-nitroisoindoline-1,3-dione and 1,4-dioxane to obtain a solution, treating the obtained solution with carbon, removing the carbon from the solution to obtain a purified 2-(2,6-dioxopiperidin-3-yl)-4-nitroisoindoline-1,3-dione solution and using the purified 2-(2,6-dioxopiperidin-3-yl)-4-nitroisoindoline-1,3-dione solution for the reducing step. Processes disclosed achieve pomalidomide having a purity of greater than 99% as measured by HPLC with no individual impurity present in an amount greater than 0.1% and total impurities comprising not more than 0.5%.
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Paragraph 0057; 0058; 0059; 0060; 0061; 0062; 0063
(2017/09/25)
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- Purifying method of pomalidomide
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The invention discloses a purifying method of pomalidomide. According to the purifying method, a pomalidomide crude product with high performance liquid phase chromatography purity ranging from 80 to 99% is mixed with a mixed solvent, and then crystallization is carried out; the mixed solvent is a mixture of an organic solvent and water; the organic solvent is an amide solvent or a ketone solvent; when the organic solvent is an amide solvent, the volume ratio of the amide solvent to water is controlled to be 4:1-8:1; and when the organic solvent is the ketone solvent, the volume ratio of the ketone solvent to water is controlled to be 3:1-1:3. The purifying method is simple and convenient in operation, high in yield and purity, and is capable of satisfying requirements on industrialized production in drug Good Manufacturing Practice.
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Paragraph 0019; 0033; 0034; 0036
(2017/10/07)
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- PROCESS FOR THE PREPARATION OF POMALIDOMIDE AND ITS PURIFICATION
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The present invention is related to an improved process for the preparation of Pomalidomide with higher yields and high purity. Particularly the present invention relates to form A preparation of Pomalidomide and its purification. wherein the present process doesn't involve use of dioxane solvent and avoids higher temperatures.
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Page/Page column 5; 6
(2018/04/11)
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- CRYSTAL FORMS OF IMMUNOMODULATORY DRUG POMALIDOMIDE AND CO-CRYSTAL WITH GENTISIC ACID
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The present invention relates to novel solid crystal forms of Pomalidomide named Form B, Form M, Pomalidomide: Gentisic acid co-crystal and their preparation. Advantageously, these solid forms are used in pharmaceutical compositions for the treatment and the prevention of multiple myeloma, of inflammatory diseases, of autoimmune diseases, of immune diseases, of myelodysplastic syndrome, of myeloproliferative disorders, of anemia, of scleroderma, amyloidosis or of other diseases associated with unwanted angiogenesis.
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Page/Page column 35-36
(2017/09/16)
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- METHOD FOR THE PRODUCTION OF POMALIDOMIDE
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The object of the invention relates to a novel group of compounds of general formula 20 that may be used as an intermediate for the production of the pharmaceutical active substance pomalidomide. The object of the invention also relates to a novel, cost-effective, productive method for the production of pomalidomide that can also be implemented on industrial scales via the novel compound of formula 20 according to the invention.
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Page/Page column 16
(2017/09/02)
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- Preparation method of pomalidomide
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The invention relates to a preparation method of pomalidomide. The preparation method includes a process of using 3-aminopiperidine-2, 6-dione hydrochloride (which is a compound shown in the formula I) and disodium 3-amino phthalate (which is a compound shown in the formula II) as raw materials. The method is simple and short in route, simple to operate, available in raw materials, reduced in production cost, and suitable for massive industrial production.
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Paragraph 0029; 0030; 0031
(2018/01/03)
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- New synthesis route for the preparation of pomalidomide
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A new route for the preparation of pomalidomide is described in the study. The synthetic procedure starts from 4-nitroisobenzofuran-1,3-dione and 3-aminopiperidine-2,6-dione hydrochloride via a three-step reaction resulting in a total yield of 65% with a high-performance liquid chromatographic (HPLC) purity of 99.56% and a low palladium residue level of 2?ppm. This method can be deemed as an efficient, practical, and environmentally friendly synthetic route for the preparation of pomalidomide.
- Huang, Daowei,Shen, Chengwu,Wang, Wenya,Huang, Lei,Ni, Feng,Li, Jianqi
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p. 1343 - 1348
(2016/09/03)
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- Method for preparing anchors Ma Duan
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The invention discloses a preparation method of pomalidomide as a medicament for resisting multiple myeloma. The preparation method comprises the following steps: dissolving a compound as shown in a formula IV in a solvent, carrying out self cyclization reaction without adding any catalyst, then cooling, separating solid out, and collecting the solid, namely the target product pomalidomide. Compared with a publically reported method, the preparation method disclosed by the invention has the advantages that raw materials are easily obtained, fewer reaction steps are adopted, the conditions are mild, the posttreatment is simple and the yield is high; in addition, the target product does not contain heavy metal residues; the preparation method is suitable for large-scale industrial product. The general formula is described in the specification.
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- Pomalidomide preparation method
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The present invention discloses a preparation method of a compound 3-amino-N-(2,6-dioxo-3- piperidyl)phthalimide represented by a formula (I), wherein the compound is named pomalidomide and is an antitumor drug. According to the present invention, the synthesis method has advantages of mild reaction conditions, simple reaction process operation and high yield, and is suitable for industrial production. The formula (I) is defined in the specification.
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Paragraph 0051; 0052; 0053
(2016/10/09)
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- A method for preparing high-purity anchors Ma Duan
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The invention discloses a method for preparing high-purity pomalidomide. The method comprises the following steps: by taking 3-nitrophthalicanhydride and 3-aminopiperidine-2,6-diketone hydrochloride as raw materials, methylbenzene as a solvent, triethylamine as an acid attaching agent and N,N'-carbonyldimidazole as a condensing agent, carrying out a condensation reaction, thereby obtaining 3-nitro-N-(2,6-dioxo-3-piperidyl)-phthalimide; carrying out a hydrogenation reaction under catalysis of a palladium carbon catalyst, and recrystallizing to obtain the high-purity pomalidomide. The total yield is 62%, and the materials used in the reaction are low in price, simple and easily available; the second-step catalytic hydrogenation is performed under normal pressure, simple operations such as pulping, distilling and performing suction filtration are only used in the two-step reaction, and the operations are conventional production operations; intense heat release phenomena in the reaction process and after-treatment process are avoided, the operation is simple, and the safety is high; a mother solution obtained by after-treatment in the first-step reaction can be directly recycled, the amount of three wastes generated after after-treatment is small, and the operation is suitable for industrial production.
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Paragraph 0029; 0031
(2016/10/24)
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- Preparation anchors Ma Duan one-pot synthesis (by machine translation)
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The invention relates to a method for preparing pomalidomide (compound I) by a one-pot process. The method comprises the following steps: reacting a raw material 3-nitrophthalic acid disclosed as Formula (II) with acetic anhydride in an acidic solvent to prepare 3-nitrophthalic anhydride disclosed as Formula (III), carrying out condensation reaction with 3-aminopiperidyl-2,6-dione hydrochloride disclosed as Formula (IV) under the action of an alkali, and finally, reducing with iron powder, thereby preparing the pomalidomide (compound I) by the one-pot process. The method has the advantages of high efficiency, high yield, low cost, high safety and environmental protection.
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Paragraph 0035
(2017/03/08)
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- IMPROVED PROCESS FOR THE PREPARATION OF POMALIDOMIDE AND ITS PURIFICATION
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Methods of synthesizing pomalidomide are disclosed. Further, methods of purifying pomalidomide from a reaction mixture are also disclosed.
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Page/Page column 2; 4; 9
(2015/06/08)
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- PROCESS FOR POMALIDOMIDE
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The present invention provides a novel process for the preparation of pomalidomide crystalline Form I. The present invention also provides a process for the purification of pomalidomide.
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Page/Page column 5
(2014/11/11)
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- THIO COMPOUNDS
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A compound, or a pharmaceutically acceptable salt or ester thereof, having a structure of: wherein A, B and D are each oxygen or sulfur, provided that least one of A, B and D is sulfur; and R1-R8 are each independently hydrogen, hydroxyl, acyl, substituted acyl, acyloxy, substituted acyloxy, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, aryl, substituted aryl, amino, substituted amino, halogen, heterocycloalkyl, substituted heterocycloalkyl, heteroaryl, substituted heteroaryl, or a thio-containing group
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- Methods and Compositions Using Immunomodulatory Compounds for the Treatment and Management of Spirochete and Other Obligate Intracellular Bacterial Diseases
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Methods of treating, preventing and/or managing a spirochete and/or other obligate intracellular bacterial disease or disorder are disclosed. Specific methods encompass the administration of an immunomodulatory compound alone or in combination with a second active agent.
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- IMMUNOTHERAPY FOR HEMATOLOGICAL MALIGNANCIES
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Methods and compositions for treating, preventing and/or managing various hematological malignancies are disclosed. Specific methods and compositions relate to use of tumor cells engineered to express antigen presenting molecules which present antigens recognized by iNKT cells and eliciting antitumor immune response from iNKT cells using such tumor cells, optionally in combination with an immunomodulatory compound.
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- Method of using and comopositions comprising immunomodulatory compounds for the treatment and management of myeloproliferative diseases
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Methods of treating, preventing and/or managing a myeloproliferative disease are disclosed. Specific methods encompass the administration of an immunomodulatory compound, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, alone or in combination with a second active agent, and/or the transplantation of blood or cells. Particular second active agents are capable of suppressing the overproduction of hematopoietic stem cells or ameliorating one or more of the symptoms of a myeloproliferative disease. Pharmaceutical compositions, single unit dosage forms, and kits suitable for use in methods of the invention are also disclosed.
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- Preliminary biological evaluations of new thalidomide analogues for multiple sclerosis application
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The present work deals with the synthesis of a new series of thalidomide derivatives for therapeutic applications. These compounds were evaluated in vitro on a human endothelial cell line EA.hy926 for their antiproliferative potential and in vivo on an experimental animal multiple sclerosis model called EAE as angiogenesis inhibitors. The preliminary results obtained on EAE assays seem to validate that anti-angiogenesis compounds could be promising tools for the treatment of MS.
- Contino-Pépin, Christiane,Parat, Audrey,Périno, Sandrine,Lenoir, Christine,Vidal, Michel,Galons, Hervé,Karlik, Stephen,Pucci, Bernard
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scheme or table
p. 878 - 881
(2009/09/06)
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- Methods for treating cutaneous lupus using aminoisoindoline compounds
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Methods of treating cutaneous lupus in a human are disclosed. Specific methods encompass the administration of (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione, 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione (ACTIMID?), 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (REVLIMID?), or cyclopropyl 2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-3-oxoisoindolin-4-yl}carboxamide, alone or alternatively, in combination with a second active agent.
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Page/Page column 14-15
(2010/11/27)
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- Processes for the preparation of 4-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione compounds
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The present invention provides new processes for the preparation of unsubstituted and substituted 4-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione compounds which are usefuil, for example, for preventing or treating diseases or conditions related to an abnormally high level or activity of TNF-α. The invention can provide improved and/or efficient processes for the commercial production of unsubstituted and substituted 4-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione compounds, including, but not limited to, unsubstituted 4-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione.
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Page/Page column 11-12
(2008/06/13)
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- Methods and compositions for the prevention and treatment of atherosclerosis, restenosis and related disorders
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Methods and compositions for the prevention and treatment of all forms of atherosclerosis are described. Administration of compounds such as thalidomide, its analogs, hydrolysis products, metabolites, derivatives and precursors as well as additional compounds capable of inhibiting tumor necrosis factor α(TNF-α) are used in the invention. Also disclosed is the coating of prosthetic devices, such as stents, with the compounds of the invention for the prevention and/or treatment of restenosis.
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- Methods of using and compositions comprising immunomodulatory compounds for the treatment and management of myeloproliferative diseases
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Methods of treating, preventing and/or managing a myeloproliferative disease are disclosed. Specific methods encompass the administration of an immunomodulatory compound, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, alone or in combination with a second active agent, and/or the transplantation of blood or cells. Particular second active agents are capable of suppressing the overproduction of hematopoietic stem cells or ameliorating one or more of the symptoms of a myeloproliferative disease. Pharmaceutical compositions, single unit dosage forms, and kits suitable for use in methods of the invention are also disclosed.
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- Methods of using and compositions comprising immunomodulatory compounds for treatment and management of macular degeneration
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Methods of treating, preventing and/or managing macular degeneration are disclosed. Specific embodiments encompass the administration of an immunomodulatory compound, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, alone or in combination with a second active agent and/or surgery. Pharmaceutical compositions, single unit dosage forms, and kits suitable for use in methods of the invention are also disclosed.
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- Modulation of stem and progenitor cell differentiation, assays, and uses thereof
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The present invention relates to methods of modulating mammalian stem cell and progenitor cell differentiation. The methods of the invention can be employed to regulate and control the differentiation and maturation of mammalian, particularly human stem cells along specific cell and tissue lineages. The methods of the invention relate to the use of certain small organic molecules to modulate the differentiation of stem or progenitor cell populations along specific cell and tissue lineages, and in particular, to the differentiation of embryonic-like stem cells originating from a postpartum placenta or for the differentiation of early progenitor cells to a granulocytic lineage. Finally, the invention relates to the use of such differentiated stem or progenitor cells in transplantation and other medical treatments.
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- Substituted 2(2,6-dioxopiperidin-3-yl)isoindolines
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Substituted 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)isoindolines and 1-oxo-2-(2,6-dioxo-piperidin-3-yl)isoindolines reduce the levels of TNFα in a mammal and are useful in treating oncogenic conditions, inflammation, and autoimmune diseases. Typical embodiments are 1-oxo-2-(2,6-dioxo-3-methylpiperidin-3-yl)-4,5,6,7-tetrafluoroiso-indoline and 1,3-dioxo-2-(2,6-dioxo-3-methylpiperidin-3-yl)-4-aminoisoindoline.
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- Amino-substituted thalidomide analogs: Potent inhibitors of TNF-α production
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Thalidomide, (1), is a known inhibitor of TNF-α release in LPS stimulated human PBMC. Herein we describe the TNF-α inhibitory activity of amino substituted analogs of thalidomide (1) and its isoindolin-1-one analog, EM-12 (2). The 4-amino substituted analogs were found to be potent inhibitors of TNF-α release in LPS stimulated human PBMC.
- Muller, George W.,Chen, Roger,Huang, Shaei-Yun,Corral, Laura G.,Wong, Lu Min,Patterson, Rebecca T.,Chen, Yuxi,Kaplan, Gilla,Stirling, David I.
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p. 1625 - 1630
(2007/10/03)
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