61260-15-9Relevant articles and documents
Scalable 18F processing conditions for copper-mediated radiofluorination chemistry facilitate DoE optimization studies and afford an improved synthesis of [18F]olaparib
Bowden, Gregory D.,Chailanggar, Nantanat,Maurer, Andreas,Pichler, Bernd J.
supporting information, p. 6995 - 7000 (2021/08/25)
A convenient and scalable base-free method for processing [18F]fluoride as [18F]TBAF is reported and applied to copper-mediated radiofluorination radiosyntheses. A central feature of this method is that a single production of [18F]TBAF can be divided into small aliquots that can be used to perform multiple small-scale reactions in DoE optimization studies. The results of these studies can then be reliably translated to full batch tracer productions using automated synthesizers. The processing method was applied to the DoE optimization of [18F]olaparib, affording the tracer in high radiochemical yields via both manual (%RCY = 78 ± 6%, n = 4 (CMRF step only)) and automated (up to 80% (%RCY); 41% activity yield (%AY)) radiosynthesis procedures.
Preparation method of 2-fluoro-5-[(4-oxo-3H-2,3-diazanaphthalene)methyl]benzoic acid
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Paragraph 0005; 0012, (2021/04/10)
The invention discloses a preparation method of 2-fluoro-5-[(4-oxo-3H-2,3-diazanaphthalene)methyl]benzoic acid, wherein the method comprises the steps: S1, preparation of (3-oxo-1,3-dihydroisobenzofuran-1-yl)dimethyl phosphate; S2, preparation of 2-fluoro-5-(3-oxo-3H-isobenzofuran-1-yl methylene)bromobenzene; S3, preparation of 2-fluoro-5-(3-oxo-3H-isobenzofuran-1-yl methylene)methyl benzoate; and S4, preparation of 2-fluoro-5-[(4-oxo-3H-2,3-diazanaphthalene)methyl]benzoic acid. The preparation method has the advantages of simple operation, mild reaction conditions, easy purification of the intermediates, increase of the total yield compared with the prior art, and reduction of the industrial cost.
Novel synthesis method of olaparib bulk drug
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Paragraph 0016, (2021/06/22)
The invention introduces a novel synthesis method of an antitumor drug, namely olaparib. According to the invention, a dimer impurity is effectively removed by an acid-base pouring method in virtue of the different chemical properties that the dimer impurity cannot form salt and a previous intermediate of olaparib can form salt, and the HPLC purity of the obtained finished product can reach 99.9%. According to a route in the invention, the yield of the olaparib finished product is effectively improved, the total yield of six steps reaches 42.4%, and the route has important significance on industrial production of olaparib.
Design, synthesis and activity evaluation of new phthalazinone parp inhibitors
Cai, Jin,Chen, Xixi,Huang, Mingqi,Ji, Min,Li, Xiaojing,Ren, Jinghui,Tang, Tu,Wang, Yuhong,Yang, Jia,Yang, Zhenyong
, p. 620 - 629 (2021/07/09)
Poly(ADP-ribose)polymerase (PARP) is a significant therapeutic target for the treatment of numerous human diseases. Olaparib has been approved as a PARP inhibitor. In this paper, a series of new compounds were designed and synthesized with Olaparib as the lead compound. In order to evaluate the inhibitory activities against PARP1 of the synthesized compounds, in vitro PARP1 inhibition assay and intracellular PARylation assay were conducted. The results showed that the inhibitory activities of the derivatives were related to the type of substituent and the length of alkyl chain connecting the aromatic ring. 3-(4,5-Dimethyl- 2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT)-based assay also proved that these compounds demonstrating strong inhibition to PARP1 also have high anti-proliferative activities against BRCA2-deficient cell line (Capan-1). Analysis of the entire results suggest that compound 23 with desirable inhibitory efficiency may hold promise for further in vivo exploration of PARP inhibition.
Synthetic method of olaparib
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Paragraph 0051-0057, (2020/03/06)
The invention discloses a synthesis method of olaparib, which comprises the following steps: carrying out reaction on dimethyl phosphite and o-carboxybenzaldehyde to generate (3-oxo-1, 3-dihydroisobenzofuran-1-yl) dimethyl phosphate; enabling (3-oxo-1, 3-dihydroisobenzofuran-1-yl) dimethyl phosphate to react with 2-fluoro-5-formylbenzoic acid to generate 2-fluoro-5-[(4-oxo-3, 4-dihydro naphthyridine-1-yl) methyl] benzoic acid; reacting 2-fluoro-5-[(4-oxo-3, 4-dihydro naphthyridine-1-yl) methyl] benzoic acid with oxalyl chloride to generate 2-fluoro-5-[(4-oxo-3, 4-dihydro naphthyridine-1-yl) methyl] benzoyl chloride; reacting 2-fluoro-5-[(4-oxo-3, 4-dihydro naphthyridine-1-yl) methyl] benzoyl chloride to react with piperazine cyclopropyl ketone, so as to generate olaparib. The invention provides a new olaparib synthesis route, the raw materials are easy to obtain, the operation post-treatment is simple, the reaction conditions of each step are mild, and the total yield reaches 93%.
Identification of probe-quality degraders for Poly(ADP-ribose) polymerase-1 (PARP-1)
Chang, Xinyue,Huang, Wenhai,Liang, Meihao,Ma, Zhen,Shen, Zhengrong,Wang, Zunyuan,Zeng, Shenxin,Zhang, Chixiao,Zhang, Zhimin
, p. 1606 - 1615 (2020/08/19)
Poly(ADP-ribose) polymerase-1 (PARP-1), a critical DNA repair enzyme in the base excision repair pathway, has been pursued as an attractive cancer therapeutic target. Intervention with PARP-1 has been proved to be more sensitive to cancer cells carrying BRCA1/2 mutations. Several PARP-1 inhibitors have been available on market for the treatment of breast, ovarian and prostatic cancer. Promisingly, the newly developed proteolysis targeting chimaeras (PROTACs) may provide a more potential strategy based on the degradation of PARP-1. Here we report the design, synthesis, and evaluation of a proteolysis targeting chimaera (PROTAC) based on the combination of PARP-1 inhibitor olaparib and the CRBN (cereblon) ligand lenalidomide. In SW620 cells, our probe-quality degrader compound 2 effectively induced PARP-1 degradation which results in anti-proliferation, cells apoptosis, cell cycle arresting, and cancer cells migratory inhibition. Thus, our findings qualify a new chemical probe for PARP-1 knockdown.
RADIOLABELLED COMPOUND
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Page/Page column 62-63, (2019/10/19)
The present invention relates to radiolabelled olaparib and in particular [ 18 F]olaparib, a process for producing radiolabelled olaparib, and uses of radiolabelled olaparib in medical imaging.
Synthesis, preliminarily biological evaluation and molecular docking study of new Olaparib analogues as multifunctional PARP-1 and cholinesterase inhibitors
Gao, Cheng-Zhi,Dong, Wei,Cui, Zhi-Wen,Yuan, Qiong,Hu, Xia-Min,Wu, Qing-Ming,Han, Xianlin,Xu, Yao,Min, Zhen-Li
, p. 150 - 162 (2018/11/30)
A series of new Olaparib derivatives was designed and synthesized, and their inhibitory activities against poly (ADP-ribose) polymerases-1 (PARP-1) enzyme and cancer cell line MDA-MB-436 in vitro were evaluated. The results showed that compound 5l exhibited the most potent inhibitory effects on PARP-1 enzyme (16.10 ± 1.25 nM) and MDA-MB-436 cancer cell (11.62 ± 2.15 μM), which was close to that of Olaparib. As a PARP-1 inhibitor had been reported to be viable to neuroprotection, in order to search for new multitarget-directed ligands (MTDLs) for the treatment of Alzheimer’s disease (AD), the inhibitory activities of the synthesized compounds against the enzymes AChE (from electric eel) and BChE (from equine serum) were also tested. Compound 5l displayed moderate BChE inhibitory activity (9.16 ± 0.91 μM) which was stronger than neostigmine (12.01 ± 0.45 μM) and exhibited selectivity for BChE over AChE to some degree. Molecular docking studies indicated that 5l could bind simultaneously to the catalytic active of PARP-1, but it could not interact well with huBChE. For pursuit of PARP-1 and BChE dual-targeted inhibitors against AD, small and flexible non-polar groups introduced to the compound seemed to be conducive to improving its inhibitory potency on huBChE, while keeping phthalazine-1-one moiety unchanged which was mainly responsible for PARP-1 inhibitory activity. Our research gave a clue to search for new agents based on AChE and PARP-1 dual-inhibited activities to treat Alzheimer’s disease.
Pyridazinone derivative, and preparation method and medical application thereof
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Paragraph 0026-0029, (2019/10/07)
The invention provides a pyridazinone derivative, and a preparation method and a medical application thereof. O-formylbenzoic acid used as a raw material reacts with dimethyl phosphite to obtain dimethyl (3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate, the dimethyl (3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate reacts with 3-cyano-4-fluorobenzaldehyde in the presence of triethylamine to prepare (Z,E)-2-fluoro-5-[(3-oxoisobenzofuran-1(3H)-ylidene)methyl]benzonitrile, and the (Z,E)-2-fluoro-5-[(3-oxoisobenzofuran-1(3H)-ylidene)methyl]benzonitrile is reduced by hydrazine hydrate to prepare 2-fluoro-5-[(4-oxo-3,4-dihydropyridazin-1-yl)methyl]benzoic acid; and benzaldehyde or substituted aromatic formaldehyde or furfural used as a raw material and malonic acid undergo a Knoevenagel reaction to obtain cinnamic acid or substituted cinnamic acid or furan-2-acrylic acid, the cinnamic acid or substituted cinnamic acid or furan-2-acrylic acid and 1-tert-butoxycarbonylpiperazine undergo an amidation reaction, a tert-butoxycarbonyl group is removed from the obtained amidation product in the presence of trifluoroacetic acid, and the obtained product and the 2-fluoro-5-[(4-oxo-3,4-dihydropyridazin-1-yl)methyl]benzoic acid undergo the amidation reaction to obtain a series of (E)-4-{3-[4-[(3-substituted aryl)acryloyl]piperazin-1-carbonyl]-4-fluorobenzyl}-2H-pyridazin-1-one derivatives. Results of preliminary pharmacological activity screening show that the compound represented by a general formula shown in the present invention has a certain in-vitro PARP-1 inhibition ability and a certain in-vitro tumor cell proliferation resisting activity. The structural general formula of compound is shown in the description; and in the general formula, Ar is selected from two formulas also shown in the description, and R1, R2, R3, R3, R4 and R5 can be the hydrogen atom, the fluorine atom, the chlorine atom, the bromine atom, a methyl group, a methoxy group, a tetrafluoromethyl group and a nitro group.
Phthalazone or phthalazinylphenol derivatives and application thereof
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Paragraph 0048; 0050-0052, (2018/07/15)
The invention relates to the technical field of chemical synthesis, in particular to phthalazone or phthalazinylphenol derivatives serving as PARP and HDACs double-target inhibitors and application thereof, and aims at providing phthalazone derivatives or phthalazinylphenol derivatives serving as a kind of novel PARP and HDACs double-target inhibitors. The structures of phthalazone or phthalazinylphenol derivatives are shown in formula I or formula II. Phthalazone or phthalazinylphenol derivatives have significant activity of inhibiting poly(ADP-ribose)polymerase and histone deacetylase and have effective anti-tumor effects; new choices are provided for developing and applying anti-tumor drugs related to inhibiting activity of poly(ADP-ribose)polymerase and histone deacetylase. (The formulae are shown in the description.).
