- Novel preparation method of olaparib
-
The invention relates to a novel preparation method of olaparib. The novel preparation method comprises the following preparation steps: 1, reacting 4-methylphthalazin-1(2H)-one with NBS and AIBN in a reaction solvent; 2, carrying out a coupling reaction on 4-(bromomethyl)phthalazin-1(2H)-one and (4-fluoro-3-(methoxycarbonyl)phenyl)boric acid in a reaction solvent under the action of a catalyst and an alkali; 3, hydrolyzing methyl 2-fluoro-5-((4-oxo-3, 4-phthalazin-1-yl)methyl)benzoate in a reaction solvent under the action of alkali; and 4, reacting the 2-fluoro-5-((4-oxo-3, 4-dihydrophthalazin-1-yl)methyl)benzoic acid with cyclopropyl (piperazine-1-yl)methyl ketone hydrochloride in a reaction solvent under the action of a condensing agent and alkali to obtain a crude olaparib product, and recrystallizing to obtain the high-purity olaparib. According to the process of the novel preparation method, the total yield can be effectively improved, impurities caused by cyano hydrolysis can be obviously reduced, and the purity and quality of the prepared olaparib are improved.
- -
-
Paragraph 0020; 0024
(2021/08/11)
-
- Design, synthesis and activity evaluation of new phthalazinone parp inhibitors
-
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.
- Cai, Jin,Chen, Xixi,Huang, Mingqi,Ji, Min,Li, Xiaojing,Ren, Jinghui,Tang, Tu,Wang, Yuhong,Yang, Jia,Yang, Zhenyong
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p. 620 - 629
(2021/07/09)
-
- Preparation method of olaparib key intermediate
-
The invention provides a preparation method of an olaparib key intermediates 4-(3-bromo-4-fluorobenzyl)phthalazin-1(2H)-one (a compound shown as a formula IV) and 2-fluoro-5-[(4-oxo-3,4-dihydro-1-phthalazinyl)methyl]benzoic acid (a compound shown as a formula V). Specifically, (3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonic acid dimethyl ester is used as a raw material to be subjected to a Wittig-Horner reaction with 3-bromo-4-fluorobenzaldehyde to obtain a formula III, the formula III and hydrazine hydrate are subjected to cyclization to obtain a formula IV, and the formula IV is subjected toa reaction with n-butyllithium and carbon dioxide to obtain an olaparib intermediate V. The method is economical and environment-friendly, and the yield is greatly improved.
- -
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Paragraph 0071-0075; 0084-0089
(2021/03/31)
-
- Olaparib intermediate and preparation method of olaparib
-
The invention discloses an olaparib intermediate and a preparation method of olaparib, and the method comprises the following steps: suspending a compound II in a solvent, adding alkali, heating to areaction temperature, and reacting to obtain a compound III; mixing the compound III with a solvent, adding hydrazine hydrate and alkali, heating to a reaction temperature, and keeping the temperatureto react to a reaction end point to obtain a compound IV; and mixing and stirring the compound IV, a catalyst and a solvent, heating to a reaction temperature, adding thionyl chloride, carrying out aheat preservation reaction to the reaction end point, cooling, sequentially adding an alkali and cyclopropanoyl piperazine, carrying out a heat preservation reaction until the reaction is complete, and reacting to obtain olaparib according to a reaction formula shown in the specification. The method provided by the invention has the advantages of cheap and easily available raw materials, simple operation, mild reaction conditions, high purity and high yield of the obtained target product, no highly toxic substances, simple post-treatment and less three wastes, and meets the green and environment-friendly production requirements.
- -
-
Paragraph 0015; 0028; 0031-0032; 0035; 0038-0039; 0042; 0045
(2021/03/18)
-
- Preparation method of 2-fluoro-5-[(4-oxo-3H-2,3-diazanaphthalene)methyl]benzoic acid
-
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.
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-
-
- Novel synthesis method of olaparib bulk drug
-
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.
- -
-
-
- Identification of probe-quality degraders for Poly(ADP-ribose) polymerase-1 (PARP-1)
-
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.
- Chang, Xinyue,Huang, Wenhai,Liang, Meihao,Ma, Zhen,Shen, Zhengrong,Wang, Zunyuan,Zeng, Shenxin,Zhang, Chixiao,Zhang, Zhimin
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p. 1606 - 1615
(2020/08/19)
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- ANTI-CANCER NUCLEAR HORMONE RECEPTOR-TARGETING COMPOUNDS
-
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.
- -
-
-
- Synthetic method of olaparib
-
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%.
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-
-
- Simple preparation method of 4-substituted methyl-1-(2H)-phthalazinone
-
The invention provides a simple preparation method of 4-substituted methyl-1-(2H)-phthalazinone (I). According to the method, condensation is carried out on a two G substituted benzene (II) and a compound represented by a formula III in the presence of a solvent A and an alkali, a compound represented by a formula IV is obtained through hydrolysis, and then, condensation is carried out on the compound represented by the formula IV or an esterification product of the compound represented by the formula IV and hydrazine hydrate to prepare 4-(pyridin-4-yl)-methyl-1-(2H)-phthalazinone (IA) or 4-(4-fluoro-3-carboxyphenyl)methyl-1-(2H)-phthalazinone (IB) which can be used for preparing vatalanib and olaparib. The preparation method is simple and convenient in technological process, is high in reaction reproducibility, is easy to operate, and is good in product stability and high in purity.
- -
-
-
- Synthesis, preliminarily biological evaluation and molecular docking study of new Olaparib analogues as multifunctional PARP-1 and cholinesterase inhibitors
-
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.
- 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)
-
- ANTI-CANCER NUCLEAR HORMONE RECEPTOR-TARGETING COMPOUNDS
-
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.
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-
-
- Pyridazinone derivative, and preparation method and medical application thereof
-
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.
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-
-
- Synthesis, Cytotoxicity, and Mechanistic Investigation of Platinum(IV) Anticancer Complexes Conjugated with Poly(ADP-ribose) Polymerase Inhibitors
-
Many clinical trials using combinations of platinum drugs and PARP-1 inhibitors (PARPi) have been carried out, with the hope that such combinations will lead to enhanced therapeutic outcomes against tumors. Herein, we obtained seven potential PARPi with structural diversity and then conjugated them with cisplatin-based platinum(IV) complexes. Both the synthesized PARPi ligands and PARPi-Pt conjugates [PARPi-Pt(IV)] show inhibitory effects against PARP-1's catalytic activity. The PARPi-Pt(IV) conjugates are cytotoxic in a panel of human cancer cell lines, and the leading ones display the ability to overcome cisplatin resistance. A mechanistic investigation reveals that the representative PARPi-Pt(IV) conjugates efficiently enter cells, bind to genomic DNA, disturb cell cycle distribution, and induce apoptotic cell death in both cisplatin-sensitive and-resistant cells. Our study provides a strategy to improve the cytotoxicity of platinum(IV)-based anticancer complexes and overcome cisplatin resistance by using a small-molecule anticancer complex that simultaneously damages DNA and inhibits PARP.
- Xu, Zoufeng,Li, Cai,Zhou, Qiyuan,Deng, Zhiqin,Tong, Zixuan,Tse, Man-Kit,Zhu, Guangyu
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p. 16279 - 16291
(2019/11/28)
-
- Preparation method of olaparib
-
The invention relates to a preparation method of olaparib. 2-(2-(4-fluoro-3-carboxylphenyl)acetyl)benzoate and a hydrazine reagent are subjected to a chemical reaction to obtain a 2-fluoro-5-((4-oxo-3,4-dihydrophthalazine-1-yl)methyl)benzoic acid compound, then, 2-fluoro-5-((4-oxo-3,4-dihydrophthalazine-1-yl)methyl)benzoic acid and 1-cyclopropyl formylpiperazine are subjected to a condensation reaction, and olaparib is prepared. Besides, 2-(2-(4-fluoro-3-carboxylphenyl)acetyl)benzoate is firstly subjected to the condensation reaction with 1-cyclopropyl formylpiperazine and then subjected to the chemical reaction with the hydrazine reagent, and olaparib is prepared.
- -
-
Paragraph 0028-0029
(2019/09/17)
-
- RADIOLABELLED COMPOUND
-
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.
- -
-
Page/Page column 62-64
(2019/10/19)
-
- Synthetic method of olaparib
-
The invention discloses a synthetic method of olaparib. The synthetic method comprises the following steps: with phthalhydrazide as a starting material, reacting with phosphorus oxychloride to generate 1-chloro-4-carbonylpyridazine, and further reacting with ethyl 2-fluoro-5-bromomethylbenzoate, so as to generate ethyl 2-fluoro-5-[(4-carbonyl-3,4-dihydropyridazin-1-yl)methyl]benzoate; and carryingout hydrolysis and acylation, and carrying out condensation reaction by virtue of ethyl 2-fluoro-5-[(4-carbonyl-3,4-dihydropyridazin-1-yl)methyl]benzoate and 1-(cyclopropylcarbonyl)-piperazine, so asto generate olaparib. The synthetic method has the beneficial effects that phthalhydrazide is taken as the starting material for the first time, is easily available and is environmentally friendly; by utilizing Neigishi coupling, organic metal is utilized for reaction, catecholborane with a relatively high cost is not used, and zinc powder is used, so that the production cost is lowered, and thetotal yield of the route reaches 70.2%; and the reaction route is relatively short, reaction conditions are mild, and the synthetic method is suitable for industrial production.
- -
-
Paragraph 0044; 0048; 0071; 00730075
(2018/07/06)
-
- HETEROCYCLIC-IMIDAZOLE COMPOUNDS, PHARMACEUTICAL COMPOSITIONS THEREOF, PREPARATION METHOD THEREFOR AND USE THEREOF
-
The present invention relates to a heterocyclic-imidazole derivative, a preparation method therefor, and a medical use thereof, and particularly to a new heterocyclic-imidazole derivative of general Formula (I), a preparation method therefor, a pharmaceutical composition comprising the same, and use thereof as a therapeutic agent, particularly as a poly(ADP-ribose)polymerase (PARP) inhibitor.
- -
-
Paragraph 0104
(2018/03/09)
-
- Preparation method of olaparib drug intermediate
-
The invention provides a preparation method of an olaparib drug intermediate, and particularly relates to the technical field of preparation of drug intermediates. The method comprises the steps thatS1, 2-carboxybenzaldehyde, triethylamine and dichloromethane are mixed and stirred, then dimethyl phosphite is added for a reaction at the room temperature, methane sulfonic acid is added, a reactionsolution is concentrated to dryness, water is added for beating, filtering and drying are conducted, and beating with petroleum ether is conducted to obtain a white solid; S2, the solid obtained in the first step, 3-cyano-4-fluorobenzaldehyde and dichloromethane are mixed and then cooled, triethylamine is added dropwise for a reaction, a reaction solution is concentrated to dryness, water is addedfor beating, filtering and drying are conducted, and beating with methyl tert-butyl ether is conducted to obtain a white solid; S3, the solid obtained in the second step is mixed with water, coolingis conducted, hydrazine hydrate is added for a reaction, then acetone is added, a NaOH aqueous solution is added for a reaction, cooling is conducted to the room temperature, extraction is conducted,the pH value is adjusted, the white solid is precipitated, and filtering, rinsing with cold water and recrystallization are conducted to obtain the white solid. The preparation method has the advantages that the yield is increased, the production cost is reduced, and the operation is simple and convenient.
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-
-
- A micro-channel modular reaction device for continuously preparing aurar handkerchief nepal intermediates (by machine translation)
-
The present invention discloses a micro-channel aurar handkerchief nepal modular reaction device for the continuous production of the intermediates, including 3 - hydroxy isobenzofuran - 1 (3 H) - ketone and dimethyl methylene chloride solution of dichloromethane solution in the micro-reactor in the 1st reaction, liquid obtained by (3 - oxo - 1, 3 - ISO-benzofuran - 1 - yl) dimethyl phosphate effluent; then with 2 - fluoro - 5 - formyl phenyl nitrile dichloromethane solution of triethylamine in methylene chloride solution and 2nd micro-reactor to react to generate 2 - fluoro - 5 - (3 - oxo - 3 H - isobenzofuran - 1 - yl methylene) reaction of the nitrile; finally the reaction liquid with the ethanol solution of sodium hydroxide is obtained by stirring with hydrazine hydrate of homogeneous mixed solution in the micro-reactor in the 3rd reaction, processing effluent to obtain the aurar handkerchief nepal intermediate 2 - fluoro - 5 - [(4 - oxo - 3, 4 - dihydrodi diazonaphthalene - 1 - yl) methyl] benzoic acid. (by machine translation)
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-
- A method for preparing aurar handkerchief Nepal (by machine translation)
-
The invention discloses a method for preparing aurar handkerchief Nepal, comprises the following steps: step one: synthesis of (3 - oxo - 1, 3 - dihydro - isobenzofuran - 1 - yl) phosphonic acid dimethyl ester; step two: synthesis of 2 - fluoro - 5 - (3 - oxo - 1, 3H - ISO-benzofuran asian base methyl) benzonitrile; step three: synthesis of 2 - fluoro - 5 - ((4 - oxo - 3, 4 - dihydro taitai qin - 1 - yl) methyl) benzoic acid; step four: synthetic aurar handkerchief Nepal. Compared with the prior art, the invention of the preparation method of the aurar handkerchief Nepal, cheap raw materials, has little influence to environment, the equipment requirement is low, the reaction time is short, the purity of the product after the purification and the like, can improve the production efficiency. (by machine translation)
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-
- PROCESS FOR THE PREPARATION OF OLAPARIB AND POLYMORPHS THEREOF
-
The present invention is directed to process for preparation of Olaparib of formula (I). The present invention further relates to novel polymorphic forms of Olaparib, pharmaceutical compositions containing them, and method of treatment using the same.
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- Preparing method for Olaparib
-
The invention discloses a preparing method for Olaparib. 5-bromomethyl-2-fluorobenzaote serves as a raw material and is subjected to a boric acid reaction with catecholborane, and a compound 3 is obtained; the compound 3 is subjected to a Suzuki coupling reaction, and a compound 5 is obtained; the compound 5 is subjected to a hydrolysis reaction, and a compound 6 is obtained; the compound 6 reacts with a compound 7 under the action of a CDI catalyst, and Olaparib is obtained. According to the preparing method, the raw material is easy to obtain, the course is short, operation and posttreatment are simple, the reaction conditions in all the steps are mild, the reaction yields of all the steps reach 90% or above, the total yield is increased to 82.3% from 49% achieved in the prior art, and the preparing method is environmentally friendly and suitable for industrial production.
- -
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Paragraph 0051; 0052
(2017/03/23)
-
- Heterocycle and imidazole compounds, pharmaceutical composition comprising heterocycle and imidazole derivatives as well as preparation method and application of heterocycle and imidazole compounds
-
The invention relates to heterocycle and imidazole derivatives as well as a preparation method and a pharmaceutical application of heterocycle and imidazole derivatives, in particular to novel heterocycle and imidazole derivatives as shown in the general formula (I), a preparation method of the heterocycle and imidazole derivatives, pharmaceutical composition comprising the heterocycle and imidazole derivatives as well as an application of the heterocycle and imidazole derivatives as a therapeutic agent and particularly as a PARP (poly (ADP-ribose) polymerase) inhibitor.
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-
- Synthesis and evaluation of a radioiodinated tracer with specificity for poly(ADP-ribose) polymerase-1 (PARP-1) in vivo
-
Interest in nuclear imaging of poly(ADP-ribose) polymerase-1 (PARP-1) has grown in recent years due to the ability of PARP-1 to act as a biomarker for glioblastoma and increased clinical use of PARP-1 inhibitors. This study reports the identification of a lead iodinated analog 5 of the clinical PARP-1 inhibitor olaparib as a potential single-photon emission computed tomography (SPECT) imaging agent. Compound 5 was shown to be a potent PARP-1 inhibitor in cell-free and cellular assays, and it exhibited mouse plasma stability but approximately 3-fold greater intrinsic clearance when compared to olaparib. An 123I-labeled version of 5 was generated using solid state halogen exchange methodology. Ex vivo biodistribution studies of [123I]5 in mice bearing subcutaneous glioblastoma xenografts revealed that the tracer had the ability to be retained in tumor tissue and bind to PARP-1 with specificity. These findings support further investigations of [123I]5 as a noninvasive PARP-1 SPECT imaging agent.
- Zmuda, Filip,Malviya, Gaurav,Blair, Adele,Boyd, Marie,Chalmers, Anthony J.,Sutherland, Andrew,Pimlott, Sally L.
-
supporting information
p. 8683 - 8693
(2015/11/25)
-
- HETEROCYCLIC DERIVATES, PREPARATION PROCESSES AND MEDICAL USES THEREOF
-
Disclosed are heterocyclic derivatives, methods for making them, compositions containing the same and uses thereof. Particularly, their pharmaceutical use as inhibitors of PARP is disclosed.
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-
- HETEROCYCLIC DERIVATES,PREPARATION PROCESSES AND MEDICAL USES THEREOF
-
Disclosed are heterocyclic derivatives, methods for making them, compositions containing the same and uses thereof. Particularly, their pharmaceutical use as inhibitors of PARP is disclosed.
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-
- TRICYCLIC INHIBITORS OF POLY(ADP-RIBOSE)POLYMERASE
-
The invention provides for compositions comprising phosphorous containing tricyclic compounds, including phthalazin-l(2H)-one derivatives. The compounds are potent inhibitors of the enzyme poly(ADP-ribose)polymerase (PARP), particularly PARP-1 and potentially PARP-2. The also show good cellular activity in inhibiting poly(ADP- ribose) oligomer formation. The compounds may be useful as mono-therapy or in combination with other therapeutic agents in the treatment conditions where PARP is implicated, such as cancer, inflammatory diseases and ischemic conditions. Thus, also provided are methods for the treatment of a condition where PARP is implicated comprising administering to an effective amount of a compound of the invention to an individual in need thereof.
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-
- 4-[3-(4-Cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorobenzyl] -2H-phthalazin-1-one: A novel bioavailable inhibitor of poly(ADP-ribose) polymerase-1
-
Poly(ADP-ribose) polymerase activation is an immediate cellular response to metabolic-, chemical-, or ionizing radiation-induced DNA damage and represents a new target for cancer therapy. In this article, we disclose a novel series of substituted 4-benzyl-2H-phthalazin-1-ones that possess high inhibitory enzyme and cellular potency for both PARP-1 and PARP-2. Optimized compounds from the series also demonstrate good pharmacokinetic profiles, oral bioavailability, and activity in vivo in an SW620 colorectal cancer xenograft model. 4-[3-(4-Cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorobenzyl] -2H-phthalazin-1-one (KU-0059436, AZD2281) 47 is a single digit nanomolar inhibitor of both PARP-1 and PARP-2 that shows standalone activity against BRCA1-deficient breast cancer cell lines. Compound 47 is currently undergoing clinical development for the treatment of BRCA1- and BRCA2-defective cancers.
- Menear, Keith A.,Adcock, Claire,Boulter, Robert,Cockcroft, Xiao-Ling,Copsey, Louise,Cranston, Aaron,Dillon, Krystyna J.,Drzewiecki, Jan,Garman, Sheila,Gomez, Sylvie,Javaid, Hashim,Kerrigan, Frank,Knights, Charlotte,Lau, Alan,Loh Jr., Vincent M.,Matthews, Ian T. W.,Moore, Stephen,O'Connor, Mark J.,Smith, Graeme C. M.,Martin, Niall M. B.
-
experimental part
p. 6581 - 6591
(2009/10/17)
-
- PHTHALAZINONE DERIVATIVE
-
4-[3-(4-cyclopropanecarbonyl-piperazine-1-carbonyl)-4-fluoro-benzyl]-2H-phthalazin-1-one as crystalline Form A.
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Page/Page column 28
(2008/12/05)
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- Phthalazinones 2: Optimisation and synthesis of novel potent inhibitors of poly(ADP-ribose)polymerase
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We have previously described the discovery of poly(ADP-ribose)polymerase-1 (PARP-1) inhibitors based on a phthalazinone scaffold. Subsequent optimisation of inhibitory activity, metabolic stability and pharmacokinetic parameters has led to a novel series of meta-substituted 4-benzyl-2H-phthalazin-1-one PARP-1 inhibitors which retain low nM cellular activity and show good stability in vivo and efficacy in cell based models.
- Cockcroft, Xiao-Ling,Dillon, Krystyna J.,Dixon, Lesley,Drzewiecki, Jan,Kerrigan, Frank,Loh Jr., Vincent M.,Martin, Niall M.B.,Menear, Keith A.,Smith, Graeme C.M.
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p. 1040 - 1044
(2007/10/03)
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- Phthalazinone derivatives
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Compounds of the formula (I): wherein A and B together represent an optionally substituted, fused aromatic ring; X can be NRX or CRXRY; if X═NRX then n is 1 or 2 and if X═CRXRY then n is 1; RX is selected from the group consisting of H, optionally substituted C1-20 alkyl, C5-20 aryl, C3-20 heterocyclyl, amido, thioamido, ester, acyl, and sulfonyl groups; RY is selected from H, hydroxy, amino; or RX and RY may together form a spiro-C3-7 cycloalkyl or heterocyclyl group; RC1 and RC2 are both hydrogen, or when X is CRXRY, RC1, RC2, RX and RY, together with the carbon atoms to which they are attached, may form an optionally substituted fused aromatic ring; and R1 is selected from H and halo.
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- PHTHALAZINONE DERIVATIVES
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Compounds of the formula (I): wherein A and B together represent an optionally substituted, fused aromatic ring; X can be NRX or CRXRY; if X NRX then n is 1 or 2 and if X = CRXRY then n is 1; RX is selected from the group consisting of H, optionally substituted C1-20 alkyl, C5-20 aryl, C3-20 heterocyclyl, amido, thioamido, ester, acyl, and sulfonyl groups; RY is selected from H, hydroxy, amino; or RX and RY may together form a spiro-C3-7 cycloalkyl or heterocyclyl group; RC1 and RC2 are both hydrogen, or when X is CRX RY, RC1, RC2, RX and RY, together with the carbon atoms to which they are attached, may form an optionally substituted fused aromatic ring; and R1 is selected from H and halo.
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