- NOVEL COMPOUNDS USEFUL AS POLY(ADP-RIBOSE) POLYMERASE (PARP) INHIBITORS
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The present invention provides novel poly(ADP-ribose) polymerase (PARP) inhibitors, methods of preparing them, pharmaceutical compositions containing them and methods for the treatment, prevention and/or amelioration of PARP mediated diseases or disorders using them. In particular, the compounds described herein are useful for the treatment of carcinoma of the breast, ovarian cancer, carcinoma of the liver, carcinoma of the lung, small cell lung cancer, esophageal cancer, gall bladder cancer, pancreatic cancer and stomach cancer.
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Paragraph 144
(2021/11/06)
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- Chiral Bicyclic Imidazole-Catalyzed Acylative Dynamic Kinetic Resolution for the Synthesis of Chiral Phthalidyl Esters
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Utilizing a chiral bicyclic imidazole organocatalyst and adopting a continuous injection process, an alternative route has been developed for the efficient synthesis of chiral phthalidyl ester prodrugs via dynamic kinetic resolution of 3-hydroxyphthalides through enantioselective acylation (up to 99 % ee). The computational studies suggest a general base catalytic mechanism differing from the widely accepted nucleophilic catalytic mechanism. The structure analysis of the key transition states shows that the CH-π interactions and not the previously considered cation/π-π interactions between the catalyst and substrate is the dominant factor giving rise to the observed stereocontrol.
- Zhou, Muxing,Gridneva, Tatiana,Zhang, Zhenfeng,He, Ende,Liu, Yangang,Zhang, Wanbin
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supporting information
p. 1641 - 1645
(2020/11/30)
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- Enantioselective synthesis of 3-aryl-phthalides through a nickel-catalyzed stereoconvergent cross-coupling reaction
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A nickel-catalyzed asymmetric Suzuki-Miyaura cross-coupling of racemic 3-bromo-phthalides and arylboronic acids was realized for the synthesis of diverse chiral 3-aryl-phthalides in moderate to excellent reaction yields. The reaction proceeded in a stereoconvergent manner and high enantioselectivities were observed for most examined examples. A number of functional groups like aldehyde, ester and bromide were well tolerated. Heteroaromatic boronic acids were also competent coupling partners in this reaction.
- Feng, Chen-Guo,Xu, Si-Yu,Zhang, Rui,Zhang, Shu-Sheng
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supporting information
p. 4492 - 4496
(2021/05/31)
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- Synthesis and biological profiling of novel isocoumarin derivatives and related compounds
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In the continuation of our study of substituted isocoumarins a series of novel 3-azolyl isocoumarin and their thio derivatives, including some related lactone compounds was prepared and biologically profiled against C. albicans showing moderate activity with MIC values in range of 4-60 μg mL-1, in general. The additional characterisation of selected compounds was carried out by exploring their activity on CYP3A4 and CYP2D6 enzymes, while experiments on mutagenicity were performed by AMES test. The representative isocoumarins 3b, 4a and 4b showed lower inhibitory activity on CYP enzymes, when compared to the reference inhibitors, ketoconazole and quinidine. Compound 4a showed a higher mutagenic potential than the other two compounds. Further characterization included cytotoxicity profiling against normal MRC5 cells.
- Bori?, Ivan,Eri?, Slavica,Kiec-Kononowicz, Katarzyna,Latacz, Gniewomir,Lubelska, Annamaria,Nikodinovi?-Runi?, Jasmina,Savic, Vladimir M.,Simi?, Milena R.,Vojnovi?, Sandra
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p. 639 - 649
(2021/08/21)
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- Synthesis and antifungal activities of 3-substituted phthalide derivatives
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In order to obtain novel bioactive compounds with significant antifungal activities, two series of 3-substituted phthalide derivatives were designed and synthesized via reduction, bromine substitution, and etherification. In addition, the antifungal activities of all target compounds against nine phytopathogenic fungi in vitro were tested by using the mycelial growth rate method at the concentration of 50 μg mL-1. Preliminary bioassay tests showed that some compounds exhibited more potent antifungal activities as compared with hymexazol. The preliminary structure-activity relationships (SARs) of all target compounds were also investigated.
- Fan, Lingling,Luo, Bilan,Luo, Zhongfu,Zhang, Li,Fan, Judi,Xue, Wei,Tang, Lei,Li, Yong
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p. 811 - 818
(2019/11/14)
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- Synthesis and Investigation of Phthalazinones as Antitubercular Agents
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A series of 2- and 7-substituted phthalazinones was synthesised and their potential as anti-tubercular drugs assessed via Mycobacterium tuberculosis (mc26230) growth inhibition assays. All phthalazinones tested showed growth inhibitory activity (MIC 100 μm), and those compounds containing lipophilic and electron-withdrawing groups generally exhibited better anti-tubercular activity. Several lead compounds were identified, including 7-((2-amino-6-(4-fluorophenyl)pyrimidin-4-yl)amino)-2-heptylphthalazin-1(2H)-one (MIC=1.6 μm), 4-tertbutylphthalazin-2(1H)-one (MIC=3 μm), and 7-nitro-phthalazin-1(2H)-one (MIC=3 μm). Mode of action studies indicated that selected pyrimidinyl-phthalazinones may interfere with NADH oxidation, however, the mode of action of the lead compound is independent of this enzyme. MIC=minimum inhibitory concentration.
- Santoso, Kristiana T.,Cheung, Chen-Yi,Hards, Kiel,Cook, Gregory M.,Stocker, Bridget L.,Timmer, Mattie S. M.
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supporting information
p. 1278 - 1285
(2019/02/24)
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- Industrial synthesis method of o-aldehyde phenyl fatty acid
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The invention provides an industrial synthesis method of o-aldehyde phenyl fatty acid, which comprises the following steps: by using aromatic lactone or o-methylphenyl fatty acid as a raw material, carrying out halogenation reaction and hydrolysis to obtain the o-aldehyde phenyl fatty acid. In the method, halogen is used in the production process; however, if haloid acid or haloid salt formed byhydrolysis is directly discharged to the environment, the cost of a halogen source accounts for most of the cost of the whole process, and severe environmental pollution is caused; by means of the method, an activated halogen source can be obtained in real time by adding a specific oxidant in the reaction process, so that the closed cycle of halogen elements is realized by means of the subsequenthydrolysis process; therefore, a large amount of raw material cost is saved on the whole, environmental pollution is reduced, the product yield is high, and large-scale production is facilitated.
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Paragraph 0083-0087
(2020/01/08)
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- DL-3-n-butylphthalide-Edaravone hybrids as novel dual inhibitors of amyloid-β aggregation and monoamine oxidases with high antioxidant potency for Alzheimer's therapy
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Considering the complex etiology of Alzheimer's disease (AD), multifunctional agents may be beneficial for the treatment of this disease. A series of DL-3-n-butylphthalide-Edaravone hybrids were designed, synthesized and evaluated as novel dual inhibitors of amyloid-β aggregation and monoamine oxidases. Among them, compounds 9a–d exhibited good inhibition of self-induced Aβ1-42aggregation with inhibition ratio 57.7–71.5%. For MAO, these new hybrids exhibited good balance of inhibition for MAO-A and MAO-B. In addition, all target compounds retained the antioxidant activity of edaravone, showed equal or better antioxidant activity than edaravone. The results of the parallel artificial membrane permeability assay for blood-brain barrier indicated that compounds 9a–d would be able to cross the blood-brain barrier and reach their biological targets in the central nervous system. The promising results in all assays demonstrated that the strategy behind the designing of compounds was rational and favourable. Taken together, these preliminary findings suggested that the compounds with the strongest bioactivity deserves further investigated for pharmacological development in AD therapy.
- Qiang, Xiaoming,Li, Yan,Yang, Xia,Luo, Li,Xu, Rui,Zheng, Yunxiaozhu,Cao, Zhongcheng,Tan, Zhenghuai,Deng, Yong
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supporting information
p. 718 - 722
(2017/02/10)
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- Facile construction of pyrrolo[1,2-: B] isoquinolin-10(5 H)-ones via a redox-amination-aromatization-Friedel-Crafts acylation cascade reaction and discovery of novel topoisomerase inhibitors
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An efficient redox-amination-aromatization-Friedel-Crafts acylation cascade process from trans-4-hydroxyproline and 2-formylbenzoic acids has been developed for the synthesis of pyrrolo[1,2-b]isoquinolin-10(5H)-ones. Compound 3h was identified as a new potent dual topoisomerase I/II inhibitor.
- Wu, Shanchao,Liu, Na,Dong, Guoqiang,Ma, Lin,Wang, Shengzheng,Shi, Wencai,Fang, Kun,Chen, Shuqiang,Li, Jian,Zhang, Wannian,Sheng, Chunquan,Wang, Wei
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supporting information
p. 9593 - 9596
(2016/08/01)
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- Studies on the phthalidation of heteroarenes: A facile preparation of 3-(heteroaryl)phthalides via triflic acid mediated phthalidation
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A triflic acid mediated heteroarylation of phthalaldehydic acid in 1,2-dichloroethane at reflux temperature leads to the formation of 3-heteroarylphthalides. This method for the phthalidation of heteroarenes can be utilized for the successful preparation of mono-, bis- and tris- heteroarylphthalides. Georg Thieme Verlag Stuttgart. New York.
- Nandakumar, Meganathan,Sankar, Elumalai,Mohanakrishnan, Arasambattu K.
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supporting information
p. 509 - 514
(2014/03/21)
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- Experimental and theoretical study on the photophysical properties of a pyrrolyl-isoxazole derivative
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The paper aims at characterizing the excited state of a pyrrolyl-isoxazole derivative containing, apart from these two fragments with electron donor (D) - pyrrolyl - and acceptor (A) - isoxazole - character, a third one - methylenephthalydyl - having also an A character. They are single bonded in an A-D-A arrangement. It is shown that the presence of the second A fragment in the molecule modifies the photophysical properties comparing to D-A pyrrolyl-isoxazole derivatives: lower Stokes shift, band width practically independent on the polarity of the solvent, linear dependence of the Stokes shift on the solvent polarity function. The spectral study of the inclusion complex of the studied compound in β-cyclodextrin reveals a decrease in the emission intensity in the presence of cyclodextrin. These experimental findings are consistent with the lack of a twisted intramolecular charge transfer (TICT) excited state, which in turn is present for pyrrolyl-isoxazole derivatives of the D-A type. The lack of a TICT state is further ascertained by theoretical calculations of sections through the potential energy surfaces along both possible A to D rotation dihedrals. The stable conformations are quasiplanar, while the orthogonal conformations are unstable.
- Matei, Iulia,Chiorescu, Ion,Ionescu, Sorana,Merisor, Elena,Hillebrand, Mihaela
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experimental part
p. 1039 - 1046
(2012/02/14)
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- Synthesis of chiral 3-substituted phthalides by a sequential organocatalytic enantioselective aldol-lactonization reaction. Three-step synthesis of (S)-(-)-3-butylphthalide
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(Chemical Equation Presented) The development of efficient methods for the facile construction of important molecular frameworks is an important goal in organic synthesis. Chiral 3-substituted phthalides are widely distributed in a large collection of natural products with broad, potent, and potentially path-pointing biological activities. In this investigation, we have uncovered an unprecedented organocatalytic asymmetric aldol-lactonization reaction of 2-formylbenzoic esters with ketones/aldehydes for convenient construction of the enantioenriched "privileged" scaffold. As a result of the sensitive nature of substrate structures of an organocatalytic enantioselective aldol reaction, after extensive optimization of reaction conditions, catalyst L-prolinamide alcohol IV is identified as the best promoter. Interestingly, it is found that in this reaction, addition of an acid additive PhCO2H can significantly enhance reaction efficiency with use of only as low as 2.5 mol % IV for the process. Moreover, due to the sensitivity of reaction conditions toward a sequential aldol-lactonization process without affecting enantioselectivity and racemization, it is essential to remove the catalyst for the subsequent facile lactonization reaction in the presence of K 2CO3. The aldol-lactonization processes serve as a powerful approach to the preparation of synthetically and biologically important 3-substitued phthalides with a high level of enantioselectivities. A 3-step catalytic asymmetric synthesis of the natural product of 3-butylphthalide is reported.
- Zhang, Haoyi,Zhang, Shilei,Liu, Lu,Luo, Guangshun,Duan, Wenhu,Wang, Wei
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supporting information; experimental part
p. 368 - 374
(2010/03/30)
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- Optimized palladium-based approaches to analogues of PK 11195
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(Chemical Equation Presented) The peripheral-type benzodiazepine receptor ligands such as PK 11195 and Ro 5-4864 were found more than twenty years ago in the course of research on neurobiology. These ligands were instrumental in pointing out an involvement of the peripheral-type benzodiazepine receptor (PBR) in apoptosis processes. With in mind an improvement of the solubility of PK 11195 in biological media, we report here improved reaction conditions for the palladium-based arylation reaction of alkyl 1-bromoisoquinoline-3-carboxylates and its ethyl 4-bromoquinoline-2-carboxylate isomer. The use of [1,1′-bis(diphenylphosphino) ferrocene] dichloropalladium as a precatalyst enabled a much improved preparation of an array of the 1-arylisoquinoline-3- carboxylates as well as 4-arylquinoline-3-carboxylates. This work should pave the way for the design of chemical probes aiming at the elucidation of the PBR biological role(s).
- Guillou, Sandrine,Janin, Yves L.
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experimental part
p. 1377 - 1384
(2009/04/07)
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- Furan ring opening - Isocoumarine ring closure: A recyclization reaction of 2-carboxyaryldifurylmethanes
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A general method for the synthesis of isocoumarine derivatives has been developed. Bis(5-R-2-furyl)methylbenzoic acids (R = methyl, ethyl) underwent recyclization and subsequent cyclization into tetracyclic isochromene-1-one derivatives under treatment with hydrogen chloride in methanol. It has been shown that intermediate 4-(5-R-furan-2-yl)-3-(3-oxo-3-R-propyl)-isochromene-1- ones can be obtained selectively by varying a concentration of the hydrogen chloride and reaction times. In the case of R = tert-butyl only corresponding 4-[5-(tert-butyl)-2-furyl]-3-(4,4-dimethyl-3-oxopentyl)-1-isochromenones were isolated regardless of the reaction conditions.
- Abaev, Vladimir T.,Dmitriev, Artem S.,Gutnov, Andrey V.,Podelyakin, Sergey A.,Butin, Alexander V.
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p. 1195 - 1204
(2007/10/03)
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- A Facile Synthesis of 3-Substituted Phthalides
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1(3H)-Isobenzofuranone (phthalides) and its derivatives possess a wide range of biological activities. A new method was found for the synthesis of 3-substituted phthalides featured with the convenient condensation reaction of 3-ethoxyphthalide with carbanions in high yields.
- Li, Guo,Yin, Dali,Liang, Xiao-Tian
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p. 1183 - 1189
(2007/10/03)
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- Environmentally-friendly Wohl-Ziegler bromination: Ionic-liquid reaction and solvent-free reaction
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Environmentally-friendly Wohl-Ziegler bromination of benzylic methyl groups was successfully camed out in ionic-liquid and solvent-free systems, to produce the corresponding benzylic bromides in good to moderate yields.
- Togo, Hideo,Hirai, Takeshi
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p. 702 - 704
(2007/10/03)
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- Preparation of N-[ω-(4-aryl-1-piperazinyl)ethyl/propyl]-3-hydroxyphthalimidines
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The reaction of ω-(4-aryl-1-piperizinyl)ethyl/propyl amine with 3-hydroxyphthalide furnishes the title compounds along with minor amounts of the corresponding N-[ω-(4-aryl-1-piperazinyl)ethyl/propyl]-2-formylbenzamides.
- Desai,Samant
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p. 455 - 457
(2007/10/03)
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- The investigation of nucleophilic reactions of 3 -bromo/chloro phthalide with amines
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The reaction of 3-bromo/chloro phthalide 1a/b with secondary amines in polar solvents gives the corresponding amides of 2-formylbenzoic acid, while in nonpolar solvents gives 3-aminophthalides. The reaction of 1a/b with aromatic primary amines gives 3-arylaminophthalides, while with aliphatic primary amines 3-hydroxyphthalimidines are obtained.
- Desai,Chaphekar,Samant
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p. 810 - 813
(2007/10/03)
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- 4-substituted pyrazoloquinoline derivatives
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The invention relates to compounds represented by formula 1a or 1b STR1 and pharmaceutically acceptable salts thereof wherein R1, R2, R3, R8, R9, and n are as described herein. These compounds are useful as agents in treating herpes virus infections.
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- Trifluoromethoxy substituted 1,3,4,9-tetrahydropyrano-[3,4-b]indole-1-acetic acids
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Indole derivatives characterized by having a 1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid nucleus bearing a trifluoromethoxy substituent in the 5-, 6-, 7-, or 8-position, and methods for their preparation and use, are disclosed. The derivatives are useful anti-inflammatory and analgesic agents.
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- 6-(Aminomethyl)penicillanic acid 1,1-dioxide esters and intermediates therefor
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6-alpha- and 6-beta-(Aminomethyl)penicillanic acid, 1,1-dioxide esters which are hydrolyzable under physiological conditions, particularly those wherein the ester radical is 1H-isobenzofuran-3-on-1-yl or (5-methyl-1,3-dioxol-2-on-4-yl)methyl, and an improved process and intermediates used in their synthesis.
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- 2β-Chloromethyl-2α-methylpenam-3α-carboxylic acid sulfone and salts and esters thereof
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2β-Chloromethyl-2α-methylpenam-3α-carboxylic acid sulfone and salts and esters thereof were synthesized and found to be potent inhibitors of β-lactamases.
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- Derivatives of 6-bromo penicillanic acid
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2β-Chloromethyl-2α-methylpenam-3α-carboxylic acid sulfone and salts and esters thereof were synthesized and found to be potent inhibitors of β-lactamases.
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- 1,3-Dihydro-3-(2-hydroxy-, 2-bromo- or 2-chloroethyl)-2H-isoindol-1-one derivatives
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Derivatives of 1,3-dihydro-3-(2-hydroxyethyl) -2H-isoindol-1-one are disclosed. The derivatives are useful for treating ulcers in a mammal and for preventing or decreasing the secretion or availability of excessive amounts of gastric or hydrochloric acid in a mammal suffering from hyperchlorhydria and/or associated conditions.
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- Process of preparing 3-bromophthalide
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3-Bromophthalide is produced by reaction of o-toluic acid with bromine or a bromine supplying substance according to the equation: STR1
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