cas 19171-18-7, 2-(2,6-dioxopiperidin-3-yl)-4-nitroisoindoline-1,3-dione

Articles about 19171-18-7Total 33 be found

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Chemically induced degradation of CK2 by proteolysis targeting chimeras based on a ubiquitin–proteasome pathway
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
p. 536 - 544
(2018)
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Homo-PROTACs for the Chemical Knockdown of Cereblon
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
p. 2771 - 2782
(2018)
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New synthesis route for the preparation of pomalidomide
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
p. 1343 - 1348
(2016)
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Preliminary biological evaluations of new thalidomide analogues for multiple sclerosis application
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
p. 878 - 881
(2009)
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Rational Design and Synthesis of HSF1-PROTACs for Anticancer Drug Development
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
(2022/03/15)

The tale of proteolysis targeting chimeras (PROTACs) for Leucine-Rich Repeat Kinase 2 (LRRK2)
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
supporting information
p. 959 - 965
(2020/12/30)

Influence of Linker Attachment Points on the Stability and Neosubstrate Degradation of Cereblon Ligands
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.
supporting information
p. 1733 - 1738
(2021/11/16)

Synthesis process for continuously preparing pomalidomide by using microchannel reactors
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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(2020/03/06)

DIMERIC IMMUNO-MODULATORY COMPOUNDS AGAINST CEREBLON-BASED MECHANISMS
Disclosed are small molecules against cereblon to enhance effector T cell function. Methods of making these molecules and methods of using them to treat various disease states are also disclosed.
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Page/Page column 123

(2020/02/06)

PYRIDAZINE DERIVATIVES AS SMARCA2/4 DEGRADERS
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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Page/Page column 111

(2019/11/12)

Selective degradation of CDK6 by a palbociclib based PROTAC
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
supporting information
p. 1375 - 1379
(2019/04/01)

PIPERIDINE-2,6-DIONE DERIVATIVE AND TREATMENT FOR ULCERATIVE COLITIS
Disclosed are piperidine-2,6-dione derivatives and treatment of ulcerative colitis.
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Paragraph 0170

(2019/10/16)

De-novo design of cereblon (CRBN) effectors guided by natural hydrolysis products of thalidomide derivatives
Targeted protein degradation via cereblon (CRBN), a substrate receptor of an E3 ubiquitin ligase complex, is an increasingly important strategy in various clinical settings, in which the substrate specificity of CRBN is altered via the binding of small-molecule effectors. To date, such effectors are derived from thalidomide and confer a broad substrate spectrum that is far from being fully characterized. Here, we employed a rational and modular approach to design novel and minimalistic CRBN effectors. In this approach, we took advantage of the binding modes of hydrolyzed metabolites of several thalidomide-derived effectors, which we elucidated via crystallography. These yielded key insights for the optimization of the minimal core binding moiety and its linkage to a chemical moiety that imparts substrate specificity. Based on this scaffold, we present a first active de-novo CRBN effector that is able to degrade the neo-substrate IKZF3 in the cell culture.
Heim, Christopher,Pliatsika, Dimanthi,Mousavizadeh, Farnoush,B?r, Kerstin,Hernandez Alvarez, Birte,Giannis, Athanassios,Hartmann, Marcus D.
p. 6615 - 6629
(2019/08/20)

Preparation method of substituted dioxopiperidine derivative
The invention discloses a preparation method of a substituted dioxopiperidine derivative. The preparation method comprises the following steps that a compound shown in the formula (II) and formamide react in the presence of C1-C4 alkanol alkali metal salt or alkaline earth metal salt, and a compound shown in the formula (I) is obtained; substituent groups in the compound shown in the formula (I) and the compound shown in the formula (II) are defined in the description. The product obtained through method is high in yield and purity, and the method is easy and convenient to operate. The formulas are shown in the description.
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Paragraph 0129-0131

(2019/04/30)

Preparation method of anti-tumor therapeutic medicine pomalyst
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; 0018; 0021; 0022; 0025; 0026

(2019/04/26)

IMIDE-BASED MODULATORS OF PROTEOLYSIS AND METHODS OF USE
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

(2019/08/12)

SUBSTITUTED 4-AMINOISOINDOLINE-1,3-DIONE COMPOUNDS, COMPOSITIONS THEREOF, AND METHODS OF TREATMENT THEREWITH
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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Paragraph 0188; 0189

(2019/11/05)

PROCESS FOR THE PREPARATION OF POMALIDOMIDE
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)

Efficient Synthesis of Immunomodulatory Drug Analogues Enables Exploration of Structure–Degradation Relationships
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.
supporting information
p. 1508 - 1512
(2018/07/31)

REGULATING CHIMERIC ANTIGEN RECEPTORS
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; 298

(2018/09/08)

TUNABLE ENDOGENOUS PROTEIN DEGRADATION WITH HETEROBIFUNCTIONAL COMPOUNDS
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 278-279

(2018/09/08)

PROCESS FOR THE PREPARATION OF POMALIDOMIDE AND ITS PURIFICATION
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

(2018/04/11)

THALIDOMIDE ANALOGS AND METHODS OF USE
Thalidomide analogs and methods of using the thalidomide analogs are disclosed. Some embodiments of the disclosed compounds exhibit anti- angiogenic and/or anti-inflammatory activity. Certain embodiments of the disclosed compounds are non-teratogenic.
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Sheet 1

(2017/08/01)

Antitumor drug lenalidomide intermediate preparation method
The invention discloses an antitumor drug lenalidomide intermediate preparation method. The preparation method comprises the following steps: 1) under existence of cuprous iodide and organic alkali, performing contact reaction between 4-nitro indoline and 3-bromine-2,6-piperidine to obtain 3-(4-nitro-1,3-xylylenimine-2-yl)piperidine-2,6-diketone; 2) performing oxidizing reaction on the 3-(4-nitro-1,3-xylylenimine-2-yl)piperidine-2,6-diketone obtained in the step 1) to obtain lenalidomide intermediate of 3-(4-nitro-1-oxo-1,3-xylylenimine-2-yl)piperidine-2,6-diketone. The method disclosed by the invention has obviously smaller steps, the raw materials are easy to obtain, a yield is also improved, and the method is more suitable for industrial production.
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(2018/09/21)

Improved method of pomalidomide synthesis process
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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Paragraph 0014; 0015

(2018/03/13)

A 3 - nitro - N - (2, 6 - dioxo - 3 - piperidinyl) phthalic acid imide preparation method
The present invention discloses a method for preparing 3-nitro-N-(2,6-dioxo-3-piperidinyl) phthalimide. The method is as follows: 3-nitro-phthalic acid or 3-nitro-phthalic anhydride is added into an acetic acid solution which contains water, 3-amino-piperidine-2,6-dione hydrochloride and sodium acetate for refluxing, cooling, filtering and drying to obtain a desired product. The method is practical in process, overcomes the defects and deficiencies of existing pomalidomide intermediate 3-nitro-N-(2,6-dioxo-3-piperidinyl) phthalimide preparation method, the yield is high, product is pure, and the method is more suitable for industrial production.
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Paragraph 0039; 0040

(2017/08/31)

PROCESS FOR PREPARATION AND PURIFICATION OF POMALIDOMIDE
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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Page/Page column 5

(2017/09/25)

A method for preparing high-purity anchors Ma Duan
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 0030

(2016/10/24)

Methods for the treatment of cancer and inflammatory diseases using cereblon as a predictor
Uses of the protein cereblon as a predictor of clinical sensitivity to cancer, inflammatory diseases, and patient response to drug treatment.
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Page/Page column 66

(2016/09/26)

Preparation anchors Ma Duan one-pot synthesis (by machine translation)
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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(2017/03/08)

IMPROVED PROCESS FOR THE PREPARATION OF POMALIDOMIDE AND ITS PURIFICATION
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; 8

(2015/06/08)

THIO COMPOUNDS
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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Paragraph 0089

(2013/06/26)

Amino-substituted thalidomide analogs: Potent inhibitors of TNF-α production
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.
p. 1625 - 1630
(2007/10/03)