283173-84-2Relevant academic research and scientific papers
Structure-based design, synthesis, and evaluation of inhibitors with high selectivity for PARP-1 over PARP-2
Yu, Jiang,Luo, Lingling,Hu, Tong,Cui, Yating,Sun, Xiao,Gou, Wenfeng,Hou, Wenbin,Li, Yiliang,Sun, Tiemin
, (2021/10/20)
The poly (ADP-ribose) polymerase (PARP) inhibitors play a crucial role in cancer therapy. However, most approved PARP inhibitors have lower selectivity to PARP-1 than to PARP-2, so they will inevitably have side effects. Based on the different catalytic domains of PARP-1 and PARP-2, we developed a strategy to design and synthesize highly selective PARP-1 inhibitors. Compounds Y17, Y29, Y31 and Y49 showed excellent PARP-1 inhibition, and their IC50 values were 0.61, 0.66, 0.41 and 0.96 nM, respectively. Then, Y49 (PARP-1 IC50 = 0.96 nM, PARP-2 IC50 = 61.90 nM, selectivity PARP-2/PARP-1 = 64.5) was proved to be the most selective inhibitor of PARP-1. Compounds Y29 and Y49 showed stronger inhibitory effect on proliferation in BRCA1 mutant MX-1 cells than in other cancer cells. In the MDA-MB-436 xenotransplantation model, Y49 was well tolerated and showed remarkable single dose activity. The design strategy proposed in this paper is of far-reaching significance for the further construction of the next generation of selective PARP-1 inhibitors.
Copper-Mediated Radiosynthesis of [18F]Rucaparib
Chen, Zijun,Destro, Gianluca,Guibbal, Florian,Chan, Chung Ying,Cornelissen, Bart,Gouverneur, Véronique
supporting information, p. 7290 - 7294 (2021/09/14)
The poly(ADP-ribose) polymerase (PARP) inhibitor rucaparib is used in the clinic to treat BRCA-mutated cancers. Herein, we report two strategies to access the 18F-isotopologue of rucaparib by applying a copper-mediated nucleophilic 18F-fluorodeboronation. The most successful approach features an aldehydic boronic ester precursor that is subjected to reductive amination post-18F-labeling and affords [18F]rucaparib with an activity yield of 11% ± 3% (n = 3) and a molar activity (Am) up to 30 GBq/μmol. Preliminary in vitro studies are presented.
Synthesis method of rucaparib camsylate
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Paragraph 0035; 0037; 0041; 0043, (2020/04/22)
The invention relates to a synthesis method of rucaparib camsylate. The method comprises the following steps: 1) carrying out a reaction on a compound M-1 and pyridinium tribromide by using tetrahydrofuran and/or dichloromethane as a solvent to obtain a compound M-2; 2) carrying out a reaction on the compound M-2 and p-formyl phenylboronic acid under the catalytic action of 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride by using N,N-dimethylacetamide as a solvent to obtain a compound M-3, wherein the reaction temperature is higher than or equal to 90 DEG C; 3) carrying out a reaction on the compound M-3 and methylamine under the catalytic action of p-toluenesulfonic acid by using methanol and/or ethanol as a solvent, adding sodium borohydride, and reducing to obtain a compound M-4; 4) carrying out a reaction on the compound M-4 and an alkali by taking water as a solvent to obtain a compound M-5; and 5) carrying out a reaction on the compound M-5 and camphorsulfonic acid by taking methanol and/or ethanol as a solvent to obtain the rucaparib camsylate. According to the invention, the compounds M-1, M-3 and M-4 react at room temperature, the conditions are mild and controllable, the reaction period is short, the synthesis efficiency can be effectively improved, the production cost is reduced, and the purity of the obtained product reaches 99.95-99.98%.
CRYSTALLINE OF CAMPHORSULFONIC ACID SALT OF RUCAPARIB AND METHOD OF PREPARING OF TRICYCLIC COMPOUNDS, RUCAPARIB AND CRYSTALLINE OF CAMPHORSULFONIC ACID SALT OF RUCAPARIB
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Paragraph 0075-0076, (2020/06/15)
A method of preparing a tricyclic compound of formula (I), comprising the step of converting a compound of formula (II) into a compound of formula (III); and hydrogenating the compound of formula (III) in the presence of hydrogenation catalyst and hydrogen to form the tricyclic compound of formula (I); wherein R1 is H or a C1-3 alkyl group; and R2 is H, a halogen element or a C1-3 alkyl group.
POLYMORPHS OF RUCAPARIB CAMSYLATE AND METHODS OF MAKING SAME
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Paragraph 0131, (2019/08/22)
Novel polymorphs of rucaparib camsylate include Form alpha having XRPD peaks at diffraction angles (2θ) of 6.14±0.2, 12.41±0.2, 15.34±0.2, 15.95±0.2, 16.36±0.2, 16.51±0.2 and 19.67±0.2, Form beta having XRPD peaks at diffraction angles (2θ) of 6.86±0.2, 9.58±0.2, 12.75±0.2, 14.56±0.2, 15.05±0.2, 20.76±0.2 and 22.45±0.2, and Form gamma having XRPD peaks at diffraction angles (2θ) of 9.5±0.2, 12.73±0.2, 14.77±0.2, 15.16±0.2, 20.62±0.2, 22.33±0.2, 22.63±0.2 and 27.29±0.2. Methods are disclosed for the preparation of such polymorphic forms and pharmaceutical compositions containing such polymorphic forms. A method is disclosed for preparing a highly pure Form B of rucaparib camsylate. Pharmaceutical compositions containing highly pure Form B prepared by the method are disclosed.
ANTI-CANCER NUCLEAR HORMONE RECEPTOR-TARGETING COMPOUNDS
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Page/Page column 207; 208, (2019/12/04)
The disclosure relates to anti-cancer compounds derived from nuclear steroid receptor binders, to products containing the same, as well as to methods of their use and preparation.
Deuterated PARP inhibitor, salt thereof, preparation method and application thereof
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Paragraph 0062; 0063; 0064; 0065, (2019/01/08)
The invention provides a deuterated compound, a pharmaceutically acceptable salt thereof, a preparation method and application thereof. The compound is a new deuterated PARP inhibitor, and the invention also provides a composition containing the deuterate
Poly(ADP-ribose) Polymerase in Neurodegeneration: Radiosynthesis and Radioligand Binding in ARC-SWE tg Mice
Alluri, Santosh R.,Riss, Patrick J.
, p. 1259 - 1263 (2018/06/26)
We report the synthesis, radiosynthesis, and characterization of a radioligand for poly(ADP-ribose) polymerase (PARP). PARP is of central importance in cell homeostasis, neuroplasticity, and neurodegeneration in the brain. A radiolabeled PARP inhibitor was developed and used for autoradiographic quantification of PARP protein concentration in wild-type and transgenic rodent brains ex vivo in high resolution. The binding of [3H]rucaparib was found to be confined to PARP-expressing domains, for example, cerebellar cortex or hippocampal regions in both models. Saturation binding experiments confirmed selective and reversible binding to a single site (Kd = 1.1 ± 0.2 nM).
Multkilogram scale-up of a reductive alkylation route to a novel PARP inhibitor
Gillmore, Adam T.,Badland, Matthew,Crook, Clare L.,Castro, Nieves M.,Critcher, Douglas J.,Fussell, Steven J.,Jones, Katherine J.,Jones, Matthew C.,Kougoulos, Eleftherios,Mathew, Jinu S.,McMillan, Lynne,Pearce, John E.,Rawlinson, Fiona L.,Sherlock, Alexandra E.,Walton, Robert
, p. 1897 - 1904 (2013/03/13)
Novel PARP inhibitor 1 is a promising new candidate for treatment of breast and ovarian cancer. A modified synthetic route to 1 has been developed and demonstrated on 7 kg scale. In order to scale up the synthesis to multikilogram scale, several synthetic challenges needed to be overcome. The key issues included significant thermal hazards present in a Leimgruber-Batcho indole synthesis, a low-yielding side-chain installation, a nonrobust Suzuki coupling and hydrogen cyanide generation during a reductive amination. In addition to these issues, changing from intravenous to oral delivery required a new salt form and therefore a new crystallization procedure. This contribution describes development work to solve these issues and scaling up of the new process in the pilot plant.
