- Induction of apoptosis in MDA-MB-231 breast cancer cells by a PARP1-targeting PROTAC small molecule
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Poly (ADP-ribose) polymerase-1 (PARP1) is a major member of the PARP superfamily that is involved in DNA damage signalling and other important cellular processes. Here we report the development of a small molecule targeting PARP1 based on the PROTAC strategy. In the MDA-MB-231 cell line, the representative compound 3 can induce significant PARP1 cleavage and programmed cell death.
- Zhao, Qiuye,Lan, Tianlong,Su, Shang,Rao, Yu
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- Indazole formamide compound as well as preparation method and application thereof
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The invention belongs to the field of chemical medicines, and particularly relates to an indazole formamide compound as well as a preparation method and application thereof. The invention provides anindazole carboxamide compound or a pharmaceutically acce
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- Synthesis method of methyl 3-formyl-2-nitrobenzoate
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The invention provides a synthesis method of methyl 3-formyl-2-nitrobenzoate. Firstly, methyl 3-methyl-2-nitrobenzoate is subjected to a substitution reaction with chlorine to obtain methyl 3-(dichloromethyl)-2-nitrobenzoate; the methyl 3-(dichloromethyl)
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Paragraph 0024; 0026; 0027; 0029
(2019/11/20)
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- PROCESSES FOR THE PREPARATION OF NIRAPARIB AND INTERMEDIATES THEREOF
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The present invention relates to novel procedures and novel intermediates useful in the synthesis of Niraparib or any salt thereof.
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Paragraph 00181; 00182
(2019/03/05)
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- Derivative based on PARP inhibitor Niraparib and a preparation method and use thereof
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The invention discloses a derivative based on a PARP inhibitor Niraparib. The derivative has a structure shown in a formula I as shown in the description, wherein R1 is selected from alkyl, alkoxy, cycloalkyl, aryl alkyl, cycloalkyl alkyl, heterocyclyl, a
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- SINGLE MOLECULE COMPOUNDS PROVIDING MULTI-TARGET INHIBITION OF PARP AND OTHER PROTEINS AND METHODS OF USE THEREOF
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The invention relates to compounds useful for inhibiting PARP and at least one other protein and to methods of treating diseases including cancer by administration of a compound(s) of Formula I-V (or pharmaceutically acceptable salts thereof) as defined herein.
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- Niraparib synthesis method
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The invention discloses a Niraparib synthesis method. The method comprises that through esterification, 3-methyl hydroformylation, 3-schiff base reaction, cyclization, amidation, BOC removal and chiral resolution, optically pure Niraparib with purity of 91% or more is prepared from 3-methyl-2-nitrobenzoic acid. The method has the advantages of simple process, high efficiency, easy operation and less equipment requirement, and is a method suitable for industrial production.
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- A prepares Nepal to pull handkerchief Nepal method (by machine translation)
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The invention discloses a compound 2 - [4 - ((3S) - 3 - piperidinyl) phenyl] - 2H - indazole - 7 - carboxamide preparation method, through the 4 - nitro phenylpyridyl with reaction produced animal pen halogenphenmethyl season ammonium salt, by sodium borohydride reduction of the pyridine quaternary ammonium salt, in the palladium reagent obtained under the action of the 3 - (4 - aminophenyl) piperidine, in the chiral reagent obtained under the action of the (S)- 3 - (4 - halophenyl) piperidine, with 3 - formyl - 2 - nitro-benzoic acid methyl ester condensation and in sodium azide formed under the action of powder medicine, after preparing the amine Niraparib (molecular entity is: 2 - [4 - ((3S) - 3 - piperidinyl) phenyl] - 2H - indazole - 7 - carboxamide). (by machine translation)
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Paragraph 0055; 0056
(2017/07/23)
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- Method for preparing Niraparib of PARP (poly-ADP-ribose polymerase) inhibitor
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The invention discloses a method for preparing 2-(4-((3S)-3-piperidyl) phenyl)-2H-indazole-7-formamide of a compound. Benzyl protected-piperidone is generated into piperidone of 3-triflic anhydride under the action of triflic anhydride, the piperidone and nitrobenzoic acid are subjected to Suzuki reaction to obtain a coupled product, 3-(4-aminophenyl) piperidine is obtained under the action of a palladium reagent, (S)-3-(4-halogenated phenyl) piperidine is prepared with a chirality resolution reagent, the (S)-3-(4-halogenated phenyl) piperidine is condensed with 3-formyl-2-methyl nitrobenzoate to form pyrazolone ring under the action of sodium azide, and the Niraparid (with the molecular entity of 2-(4-((3S)-3-piperidyl) phenyl)-2H-indazole-7-formamide) is prepared via aminolysis.
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Paragraph 0052; 0053
(2017/07/19)
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- Development of a fit-for-purpose large-scale synthesis of an oral PARP inhibitor
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Compound (1) a poly(ADP-ribose)polymerase (PARP) inhibitor has been made by a fit-for-purpose large-scale synthesis using either a classical resolution or chiral chromatographic separation. The development and relative merits of each route are discussed,
- Wallace, Debra J.,Baxter, Carl A.,Brands, Karel J. M.,Bremeyer, Nadine,Brewer, Sarah E.,Desmond, Richard,Emerson, Khateeta M.,Foley, Jennifer,Fernandez, Paul,Hu, Weifeng,Keen, Stephen P.,Mullens, Peter,Muzzio, Daniel,Sajonz, Peter,Tan, Lushi,Wilson, Robert D.,Zhou, George,Zhou, Guoyue
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experimental part
p. 831 - 840
(2012/07/03)
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- Bicyclic And Tricyclic Compounds As KAT II Inhibitors
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Compounds of Formula X: wherein A, X, Y, Z, R5, R6a, and R6b are as defined herein, and pharmaceutically acceptable salts thereof, are described as useful for the treatment of cognitive deficits associated with schizophrenia and other neurodegenerative and/or neurological disorders in mammals, including humans.
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Page/Page column 46-47
(2010/12/31)
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- PHARMACEUTICALLY ACCEPTABLE SALTS OF 2-{4-[(3S)-PIPERIDIN-3- YL]PHENYL} -2H-INDAZOLE-7-CARBOXAMIDE
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The present invention relates to pharmaceutically acceptable salts of an amide substituted indazole which are inhibitors of the enzyme poly(ADP-ribose)polymerase (PARP), previously known as poly(ADP-ribose)synthase and poly(ADP-ribosyl)transferase. The compounds of the present invention are useful as mono-therapies in tumors with specific defects in DNA-repair pathways and as enhancers of certain DNA -damaging agents such as anticancer agents and radiotherapy. Further, the compounds of the present invention are useful for reducing cell necrosis (in stroke and myocardial infarction), down regulating inflammation and tissue injury, treating retroviral infections and protecting against the toxicity of chemotherapy.
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Page/Page column 35-36
(2009/09/04)
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- Discovery of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (MK-4827): A novel oral poly(ADP-ribose)polymerase (PARP) inhibitor efficacious in BRCA-1 and -2 mutant tumors
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We disclose the development of a novel series of 2-phenyl-2H-indazole-7- carboxamides as poly(ADP-ribose) polymerase (PARP) 1 and 2 inhibitors. This series was optimized to improve enzyme and cellular activity, and the resulting PARP inhibitors display antiproliferation activities against BRCA-1 and BRCA-2 deficient cancer cells, with high selectivity over BRCA proficient cells. Extrahepatic oxidation by CYP450 1A1 and 1A2 was identified as a metabolic concern, and strategies to improve pharmacokinetic properties are reported. These efforts culminated in the identification of 2-{4-[(3S)-piperidin-3-yl] phenyl}-2H-indazole-7-carboxamide 56 (MK-4827), which displays good pharmacokinetic properties and is currently in phase I clinical trials. This compound displays excellent PARP 1 and 2 inhibition with IC50 = 3.8 and 2.1 nM, respectively, and in a whole cell assay, it inhibited PARP activity with EC50 = 4 nM and inhibited proliferation of cancer cells with mutant BRCA-1 and BRCA-2 with CC50 in the 10-100 nM range. Compound 56 was well tolerated in vivo and demonstrated efficacy as a single agent in a xenograft model of BRCA-1 deficient cancer.
- Jones, Philip,Altamura, Sergio,Boueres, Julia,Ferrigno, Federica,Fonsi, Massimiliano,Giomini, Claudia,Lamartina, Stefania,Monteagudo, Edith,Ontoria, Jesus M.,Orsale, Maria Vittoria,Palumbi, Maria Cecilia,Pesci, Silvia,Roscilli, Giuseppe,Scarpelli, Rita,Schultz-Fademrecht, Carsten,Toniatti, Carlo,Rowley, Michael
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experimental part
p. 7170 - 7185
(2010/07/04)
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- AMIDE SUBSTITUTED INDAZOLE AND BENZOTRIAZOLE DERIVATIVES AS POLY(ADP-RIBOSE)POLYMERASE (PARP) INHIBITORS
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The present invention relates to compounds of formula (I) and pharmaceutically acceptable salts or tautomers thereof which are inhibitors of poly (ADP-ribose) polymerase (PARP) and thus useful for the treatment of cancer, inflammatory diseases, reperfusio
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- BICYCLIC DERIVATIVES AS PPAR MODULATORS
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The present invention is directed to compounds represented by the following structural formula, Formula (I), and stereoisomers, pharmaceutically acceptable salts, solvates and hydrates thereof, wherein: (a) R2 is selected from the group consisting of C0-C8 alkyl and C1-4- heteroalkyl; (b) X is selected from the group consisting of a single bond, O, S, S(O)2 and N; (c) U is an aliphatic linker wherein one carbon atom of the aliphatic linker is optionally replaced with O, NH or S, and wherein such aliphatic linker is optionally substituted with from one to four substituents each independently selected from R30; (d) Y is selected from the group consisting of C, O, S, NH and a single bond; and (e) E is C(R3)(R4)A or A.
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Page/Page column 88-89
(2008/06/13)
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