cas 718-08-1, 3-OXO-4-PHENYL-BUTYRIC ACID ETHYL ESTER

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Discovery of pyrrolo[2,3-d]pyrimidine derivatives as potent Axl inhibitors: Design, synthesis and biological evaluation
Axl has emerged as an attractive target for cancer therapy due to its strong correlation with tumor growth, metastasis, poor survival, and drug resistance. Herein, we report the design, synthesis and structure-activity relationship (SAR) investigation of a series of pyrrolo[2,3-d]pyrimidine derivatives as new Axl inhibitors. Among them, the most promising compound 13b showed high enzymatic and cellular Axl potencies. Furthermore, 13b possessed preferable pharmacokinetic properties and displayed promising therapeutic effect in BaF3/TEL-Axl xenograft tumor model. Compound 13b may serve as a lead compound for new antitumor drug discovery.
Xu, Dandan,Sun, Deqiao,Wang, Wei,Peng, Xia,Zhan, Zhengsheng,Ji, Yinchun,Shen, Yanyan,Geng, Meiyu,Ai, Jing,Duan, Wenhu
(2021/05/06)

Deconstructing Noncovalent Kelch-like ECH-Associated Protein 1 (Keap1) Inhibitors into Fragments to Reconstruct New Potent Compounds
Targeting the protein-protein interaction (PPI) between nuclear factor erythroid 2-related factor 2 (Nrf2) and Kelch-like ECH-associated protein 1 (Keap1) is a potential therapeutic strategy to control diseases involving oxidative stress. Here, six classes of known small-molecule Keap1-Nrf2 PPI inhibitors were dissected into 77 fragments in a fragment-based deconstruction reconstruction (FBDR) study and tested in four orthogonal assays. This gave 17 fragment hits of which six were shown by X-ray crystallography to bind in the Keap1 Kelch binding pocket. Two hits were merged into compound 8 with a 220-380-fold stronger affinity (Ki = 16 μM) relative to the parent fragments. Systematic optimization resulted in several novel analogues with Ki values of 0.04-0.5 μM, binding modes determined by X-ray crystallography, and enhanced microsomal stability. This demonstrates how FBDR can be used to find new fragment hits, elucidate important ligand-protein interactions, and identify new potent inhibitors of the Keap1-Nrf2 PPI.
Pallesen, Jakob S.,Narayanan, Dilip,Tran, Kim T.,Solbak, Sara M. ?.,Marseglia, Giuseppe,S?rensen, Louis M. E.,H?j, Lars J.,Munafò, Federico,Carmona, Rosa M. C.,Garcia, Anthony D.,Desu, Haritha L.,Brambilla, Roberta,Johansen, Tommy N.,Popowicz, Grzegorz M.,Sattler, Michael,Gajhede, Michael,Bach, Anders
supporting information
p. 4623 - 4661
(2021/05/07)

Non-metal Lewis acid-catalyzed cross-Claisen condensation for β-keto esters
In this work, we disclose a new catalytic and highly chemoselective cross-Claisen condensation of esters. In the presence of TBSNTf2 as a non-metal Lewis acid, various esters can undergo cross-Claisen condensation to form β-keto esters which are important building blocks. Compared with the traditional Claisen condensation, this process, employing silyl ketene acetals (SKAs) as carbonic nucleophiles to achieve cross-Claisen condensation, requires mild conditions and has good tolerance of functional groups. This journal is
Han, Zhengyu,Huang, Hai,Meng, Fuliang,Yang, Zhenkun,Zhang, Tianyu,Zhou, Dapeng
supporting information
p. 9163 - 9166
(2021/11/16)

Desymmetrization of meso-dicarbonatecyclohexene with β-Hydrazino carboxylic esters via a Pd-catalyzed allylic substitution cascade
The desymmetrization of meso-dicarbonatecyclohexene with β-hydrazino carboxylic esters has been achieved via a RuPHOX/Pd-catalyzed allylic substitution cascade for the construction of chiral hexahydrocinnoline derivatives with high performance. Mechanistic studies reveal that the reaction exploits a pathway different from that of our previous work and that the first nitrogen nucleophilic process is the rate-determining step. The protocol could be conducted on a gram scale without any loss of catalytic behavior, and the corresponding chiral hexahydrocinnolines can undergo diverse transformations.
Xu, Kai,Zheng, Yan,Ye, Yong,Liu, Delong,Zhang, Wanbin
supporting information
p. 8836 - 8841
(2020/11/30)

General [4 + 1] Cyclization Approach to Access 2,2-Disubstituted Tetrahydrofurans Enabled by Electrophilic Bifunctional Peroxides
A general [4 + 1] cyclization reaction of carbonyl nucleophiles with 2-iodomethylallyl peroxides, which function as unique electrophilic oxygen synthons, for the synthesis of a broad range of 2,2-disubstituted tetrahydrofurans is achieved under operationally simple conditions. The unprecedented asymmetric version of such reaction is also realized via chiral auxiliary-assisted cyclization, thus providing a distinct approach to access chiral tetrahydrofurans with high diastereoselectivities. The new method can be applied to the synthesis of core structure of posaconazole drug.
Gao, Min,Zhao, Yukun,Zhong, Chen,Liu, Shengshu,Liu, Pengkang,Yin, Qi,Hu, Lin
supporting information
p. 5679 - 5684
(2019/08/01)

2-Arylthio-5-iodo pyrimidine derivatives as non-nucleoside HBV polymerase inhibitors
In this study, a series of 2-arylthio-5-iodo pyrimidine derivatives, as non-nucleoside hepatitis B virus inhibitors, were evaluated and firstly reported as potential anti-HBV agents. To probe the mechanism of active agents, DHBV polymerase was isolated and a non-radioisotopic assay was established for measuring HBV polymerase. The biological results demonstrated that 2-arylthio-5-iodo pyrimidine derivatives targeted HBV polymerase. In addition, pharmacophore models were constructed for future optimization of lead compounds. Further study will be performed for the development of non-nucleoside anti-HBV agents.
Wang, Jie,Zhang, Liang,Zhao, Jianxiong,Zhang, Yu,Liu, Qingchuan,Tian, Chao,Zhang, Zhili,Liu, Junyi,Wang, Xiaowei
p. 1573 - 1578
(2018/02/21)

PYRIDO-AZAHETERECYDIC COMPOUND AND PREPARATION METHOD AND USE THEREOF
The present invention discloses a pyrido-azacyclic compound represented by formula I, an isomer thereof, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, a preparation process thereof and a composition comprising the compound, and a use thereof as a multi-target protein kinase inhibitor in the preparation of a medicament for the treatment of diseases that are associated with protein kinase, especially c-Met, such as cancer and the like. The compound represented by formula I has potent inhibitory activity on tumor cells with overexpression of c-Met kinase, can effectively target c-Met-mediated signaling pathway, and can be used in the treatment of diseases such as cancer and the like that is caused by the overexpression of c-Met kinase.
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Paragraph 0087

(2018/09/21)

NRF 2 ACTIVATOR
Provided are compounds of Formula I, or pharmaceutically acceptable salts thereof, which are activators of nuclear factor erythroid 2 (NF-E2) -related factor 2 (Nrf2) and are useful to treat diseases caused by oxidative stress, such as neurodegenerative diseases or inflammation. Also provided are methods for their use and production.
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Page/Page column 80; 81

(2018/08/20)

Five Roads That Converge at the Cyclic Peroxy-Criegee Intermediates: BF3-Catalyzed Synthesis of β-Hydroperoxy-β-peroxylactones
We have discovered synthetic access to β-hydroperoxy-β-peroxylactones via BF3-catalyzed cyclizations of a variety of acyclic precursors, β-ketoesters and their silyl enol ethers, alkyl enol ethers, enol acetates, and cyclic acetals, with H2O2. Strikingly, independent of the choice of starting material, these reactions converge at the same β-hydroperoxy-β-peroxylactone products, i.e., the peroxy analogues of the previously elusive cyclic Criegee intermediate of the Baeyer-Villiger reaction. Computed thermodynamic parameters for the formation of the β-hydroperoxy-β-peroxylactones from silyl enol ethers, enol acetates, and cyclic acetals confirm that the β-peroxylactones indeed correspond to a deep energy minimum that connects a variety of the interconverting oxygen-rich species at this combined potential energy surface. The target β-hydroperoxy-β-peroxylactones were synthesized from β-ketoesters, and their silyl enol ethers, alkyl enol ethers, enol acetates, and cyclic acetals were obtained in 30-96% yields. These reactions proceed under mild conditions and open synthetic access to a broad selection of β-hydroperoxy-β-peroxylactones that are formed selectively even in those cases when alternative oxidation pathways can be expected. These β-peroxylactones are stable and can be useful for further synthetic transformations.
Vil, Vera A.,Gomes, Gabriel Dos Passos,Ekimova, Maria V.,Lyssenko, Konstantin A.,Syroeshkin, Mikhail A.,Nikishin, Gennady I.,Alabugin, Igor V.,Terent'Ev, Alexander O.
p. 13427 - 13445
(2018/11/02)

Practical and Efficient Synthesis of Polyaryl(hetaryl)-Substituted Cyclohexenones and Salicylates
A new efficient method was developed for the synthesis of triaryl-substituted cyclohexenones and salicylates. The method is based on the Robinson annulation of readily available keto esters and chalcones, followed by the aromatization of the cyclohexenone moiety. The aromatization can be accomplished either by reaction with bromine in boiling chloroform or bromination with copper(II) bromide in ethanol followed by treatment with pyridine or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). The new synthetic method was also implemented in a one-pot protocol, which in some cases resulted in higher yields of the final product compared to those obtained in the stepwise synthesis.
Shirinian, Valerii Z.,Kavun, Alexey M.,Lvov, Andrey G.,Zavarzin, Igor V.,Krayushkin, Michail M.
p. 1255 - 1263
(2017/03/11)

COMPOUNDS AND USE THEREOF IN THE EXPANSION OF HEMATOPOIETIC STEM CELLS AND/OR HEMATOPOIETIC PROGENITOR CELLS
Compounds of general formula or salts or prodrugs thereof, are provided and described herein. The compounds are useful to expand hematopoietic stem cell and/or hematopoietic progenitor cell populations. Particularly, the hematopoietic cells are human cells. The compounds are also useful in the medical treatment of hematopoietic disorder/malignancy, an autoimmune disease and/or an inherited immune-deficient disease in a subject.
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(2015/11/16)

5-Iodo-2-arylalkylthio-6-aryl pyrimidin-4(3H)-ones as non-nucleoside anti-HBV agents
A series of 5-iodo-2-arylalkylthio-6-aryl pyrimidin-4(3H)-ones, which can be considered as S-DABO derivatives, have been synthesized and their antiviral effect on extracellular HBV DNA was evaluated using the HepAD38 cell system. Compounds 6d1 and 6e3 exhibited more potent anti-HBV activity than lamivudine with EC50 values of 0.376 μM and 0.469 μM, respectively. In addition, inhibition of intracellular HBV DNA, pgRNA, HBeAg and HBsAg of compounds 6d1 and 6e3 was examined to initially infer the action mechanism. RT-PCR analysis of pgRNA demonstrated that these new S-DABO analogues could not interfere with HBV transcription. TRFIA analysis revealed that compounds 6d1 and 6e3 effectively reduced the secretion of HBeAg. These results demonstrated that 5-iodo-2-arylalkylthio-6-aryl pyrimidin-4(3H)-ones possess anti-HBV abilities and could be used as potential agents against HBV infection with an additional merit of low cytotoxicity.
Zhang, Yu,Sun, Xuefeng,Fan, Ningning,Zhao, Jianxiong,Tu, Jing,Chen, Xiangmei,Liu, Junyi,Wang, Xiaowei
p. 1438 - 1443
(2015/08/18)

Oxone-promoted hydration of electron-deficient allenic esters and ketones into 1,3-dicarbonyl compounds
Abstract A novel and mild protocol for the hydration of electron-deficient allenic esters and ketones into various 1,3-dicarbonyl compounds is described. The hydration of allenes promoted by oxone in DMF afforded the corresponding products in moderate to good yields. This work features the employment of only a catalytic amount of inexpensive and nontoxic solid reagent oxone (2KHSO5·KHSO4·K2SO4), avoiding the utility of toxic metals or traditional Br?nsted acids, in a green version of viewpoint. A possible reaction mechanism for this transformation is also primarily proposed.
Yi, Yu-Ping,Zheng, Yan,Nie, Jing,Ma, Jun-An
p. 4523 - 4526
(2015/06/30)

Hauser-Heck: Efficient Synthesis of γ-Aryl-β-ketoesters en Route to Substituted Naphthalenes
γ-Aryl-β-ketoesters can be prepared in one step from aryl bromides and bis(trimethylsilyl) enol ethers using catalytic amounts of Pd(dba)2/t-Bu3P and stoichiometric amounts of Bu3SnF. The wide range of γ-(hetero)aryl-β-ketoesters that can be obtained illustrate the scope and limitations of this novel Hauser-Heck combination. γ-Aryl-β-ketoesters with a 1,3-dioxane acetal in the ortho position can easily be transformed into the hydroxy naphthoate in very good yield. Aqueous formic acid at 65 °C provides optimal conditions for this deprotective aromatization.
Wagner, Frederic,Harms, Klaus,Koert, Ulrich
p. 5670 - 5673
(2015/12/08)

HISTONE DEMETHYLASE INHIBITORS
Provided herein are substituted pyrazolylpyridine, pyrazolylpyridazine, and pyrazolylpyrimidine derivative compounds and pharmaceutical compositions comprising said compounds. The subject compounds and compositions are useful for inhibition histone demethylase. Furthermore, the subject compounds and compositions are useful for the treatment of cancer, such as prostate cancer, breast cancer, bladder cancer, lung cancer and/or melanoma and the like.
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Paragraph 00198; 00199

(2014/06/24)

Continuous flow synthesis of toxic ethyl diazoacetate for utilization in an integrated microfluidic system
An integrated microfluidic system for multiple reactions and separations of hazardous ethyl diazoacetate is presented. The integrated techniques include: a droplet technique for liquid-liquid and/or gas-liquid separation and in situ generation of the toxic reagent, a dual channel membrane technique based on a cheap polymeric microseparator for liquid-liquid separation, and a capillary microreactor for carrying out cascade reactions in a sequential and continuous manner.
Maurya, Ram Awatar,Min, Kyoung-Ik,Kim, Dong-Pyo
supporting information
p. 116 - 120
(2014/01/06)

Synthesis and biological evaluation of novel 2-Arylalkylthio-5-iodine-6- substituted-benzyl-pyrimidine-4(3H)-ones as Potent HIV-1 Non-Nucleoside reverse transcriptase inhibitors
A novel series of 2-arylalkylthio-5-iodine-6-substitutedbenzyl-pyrimidine- 4(3H)- ones (S-DABOs) 8a-x had been synthesized via an efficient method. Their biological activity against HIV virus and RT assay were evaluated. Some compounds, especially 8h, 8l and 8n, displayed promising activity against HIV-1 RT with IC50 values in a range of 0.41 μM to 0.71 iM, which were much better than that of nevirapine. Molecular modeling studies revealed that the binding mode would be affected via forming an additional hydrogen bond by incorporating an oxygen atom on the C-2 side chain. The biological activity was in accordance with the docking results.
Zhang, Liang,Tang, Xiaowan,Cao, Yuanyuan,Wu, Shaotong,Zhang, Yu,Zhao, Jianxiong,Guo, Ying,Tian, Chao,Zhang, Zhili,Liu, Junyi,Wang, Xiaowei
p. 7104 - 7121
(2014/07/08)

Synthesis of aryl β-ketoesters by opening of aryl epoxides with ethyl diazoacetate catalyzed by BF3OEt2
A facile synthesis of 4-aryl substituted β-ketoesters from the reaction aryl epoxides with ethyl diazoacetate, in presence of BF 3OEt2 has been described with excellent yields.
Rao, D. Chandra,Reddy, D. Kumar,Shekhar,Chinababu,Rao, Ch. Bhujanga,Venkateswarlu
p. 356 - 358
(2014/05/06)

Bioisosteric replacement of an acylureido moiety attached to an indolin-2-one scaffold with a malonamido or a 2/4-pyridinoylamido moiety produces a selectively potent Aurora-B inhibitor
Bioisosteric replacement of acylureido moiety in 6-acylureido-3- pyrrolylmethylidene-2-oxoindoline derivatives resulted in a series of malonamido derivatives with indolin-2-one scaffold (11-14). Further conformational restrictions of the malonamido moiety led to 2-oxo-1,2-dihydropyridine (21-25) or a 4-oxo-1,4-dihydropyridine derivatives (31-36). 4-Oxo-1,4-dihydropyridine derivatives were more potent Aurora B inhibitors than their 2-oxo-1,2- dihydropyridine counterparts and demonstrated cytotoxicities against A549 and HepG2 cells in the submicromolar range. In A549 cells, 31h decreased phosphorylation of histone H3, triggered polyploidy, induced expression of pro-apoptotic Fas and FasL with subsequent activation of caspase 8, resulting into apoptosis. In a Huh7-xenograft mouse model, 31h demonstrated potent in vivo efficacy with a daily dose of 5 mg/kg.
Wang, Hsiao-Chun,Jagtap, Ajit Dhananjay,Chang, Pei-Teh,Liu, Jia-Rong,Liu, Chih-Peng,Tseng, Hsiang-Wen,Chen, Grace Shiahuy,Chern, Ji-Wang
p. 312 - 334
(2014/08/05)

New efficient and flexible synthetic route to Emivirine and its analogs
A revised synthetic route to Emivirine (MKC-442) via properly substituted β-keto ester converted from Meldrum's Acid was developed. This method could be applied to the synthesis of a variety of MKC-442 analogues and open the way for their systematic biological evaluation.
Li, Li,Ma, Liying,Wang, Xiaowei,Liu, Junyi
p. 164 - 168
(2013/04/24)

Novel pyridinone derivatives as non-nucleoside reverse transcriptase inhibitors (NNRTIs) with high potency against NNRTI-resistant HIV-1 strains
Novel 6-substituted-4-cycloalkyloxy-pyridin-2(1H)-ones were synthesized as non-nucleoside reverse transcriptase inhibitors (NNRTIs), and their biological activity was evaluated. Most of the compounds, especially 26 and 22, bearing a 3-isopropyl and 3-iodine group, respectively, exhibited highly potent activity against wild-type HIV-1 strains and those resistant to reverse transcriptase inhibitors (RTIs). The diastereoisomers of 26-trans and 26-cis were synthesized separately and confirmed with HPLC and NOESY spectra. The 26-trans isomers had an activity about 400-fold more potent than that of 26-cis. The pair of 26-trans enantiomers, one of the most potent inhibitors with EC50 of 4 nM and selectivity index (SI) of 75000, was highly effective against a panel of RTIs-resistant strains with single (Y181C and K103N) or double (A17) mutations in reverse transcriptase. The results suggest that these novel pyridinone derivatives have the potential to be further developed as new antiretroviral drugs with improved antiviral efficacy and drug resistance profile.
Li, Amin,Ouyang, Yabo,Wang, Ziyun,Cao, Yuanyuan,Liu, Xiangyi,Ran, Li,Li, Chao,Li, Li,Zhang, Liang,Qiao, Kang,Xu, Weisi,Huang, Yang,Zhang, Zhili,Tian, Chao,Liu, Zhenming,Jiang, Shibo,Shao, Yiming,Du, Yansheng,Ma, Liying,Wang, Xiaowei,Liu, Junyi
p. 3593 - 3608
(2013/06/27)

Access to β-keto esters by palladium-catalyzed carbonylative coupling of aryl halides with monoester potassium malonates
New tricks for an old dog: The Pd-catalyzed carbonylative α-arylation of monoethyl potassium malonates with aryl bromides and reactive aryl chlorides provides a simple and direct route to aryl β-ketoesters. Because only stoichiometric amounts of carbon monoxide are employed, the method is ideal for the introduction of carbon isotopes into more complex structures. Copyright
Korsager, Signe,Nielsen, Dennis U.,Taaning, Rolf H.,Skrydstrup, Troels
supporting information
p. 9763 - 9766
(2013/09/23)

Design, synthesis, and biological evaluation of 1-[(2-benzyloxyl/alkoxyl) methyl]-5-halo-6-aryluracils as potent HIV-1 non-nucleoside reverse transcriptase inhibitors with an improved drug resistance profile
Because the emergence of drug-resistant mutants has limited the efficacy of non-nucleoside reverse transcriptase inhibitors (NNRTIs), it is essential to develop new antivirals with better drug resistance and pharmacokinetic profiles. Here we designed and synthesized a series of 1-[(2-benzyloxyl/alkoxyl)methyl]- 5-halo-6-aryluracils, the HEPT analogues, and evaluated their biological activity using nevirapine and 18 (TNK-651) as reference compounds. Most of these compounds, especially 6b, 7b, 9b, 11b, and 7c, exhibited highly potent anti-HIV-1 activity against both wild-type and NNRTI-resistant HIV-1 strains. Compound 7b, which had the highest selectivity index (SI = 38 215), is more potent than nevirapine and 18. These results suggest that the introduction of a halogen at the C-5 position may contribute to the effectiveness of these compounds against RTI-resistant variants. In addition, meta substituents on the C-6 aromatic moiety could significantly enhance activity against NNRTI-resistant HIV-1 strains. These compounds can be further developed as next-generation NNRTIs with an improved antiviral efficacy and drug-resistance profile.
Wang, Xiaowei,Zhang, Jianfang,Huang, Yang,Wang, Ruiping,Zhang, Liang,Qiao, Kang,Li, Li,Liu, Chang,Ouyang, Yabo,Xu, Weisi,Zhang, Zhili,Zhang, Liangren,Shao, Yiming,Jiang, Shibo,Ma, Liying,Liu, Junyi
experimental part
p. 2242 - 2250
(2012/05/20)

PYRAZOLE DERIVATIVES, PREPARATION METHOD THEREOF, AND COMPOSITION FOR PREVENTION AND TREATMENT OF OSTEOPOROSIS CONTAINING SAME
The present invention provides pyrazole derivative compounds and pharmaceutically acceptable salts thereof. The compounds of the present invention have an excellent effect of preventing and treating osteoporosis.
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(2012/09/22)

Acylation of Meldrum's acid with arylacetic acid imidazolides as a convenient method for the synthesis of 4-aryl-3-oxobutanoates
C-Acylation of Meldrum's acid by (het)arylacetic acids in ethanol in the presence of 1,1′-carbonyldiimidazole leads to ethyl 4-(het)aryl-3- oxobutanoates in high yields.
Shimkin,Shirinian,Mailian,Lonshakov,Gorokhov,Krayushkin
experimental part
p. 139 - 142
(2011/09/12)

Highly diastereoselective and enantioselective synthesis of α-hydroxy β-amino acid derivatives: Lewis base catalyzed hydrosilylation of α-acetoxy β-enamino esters
By design: A series of α-acetoxy-β-enamino esters 1 were synthesized and then subjected to catalytic asymmetric hydrosilylation. In the presence of a chiral Lewis base catalyst, the reactions proceeded smoothly to provide a wide range of chiral α-acetoxy β-amino acid derivatives in high yields with good diastereoselectivities and enantioselectivities. Copyright
Jiang, Yan,Chen, Xing,Zheng, Yongsheng,Xue, Zhouyang,Shu, Chang,Yuan, Weicheng,Zhang, Xiaomei
supporting information; experimental part
p. 7304 - 7307
(2011/09/16)

Iodine catalyzed one-pot five-component reactions for direct synthesis of densely functionalized piperidines
A simple and convenient one-pot multicomponent reaction (MCR) has been developed for the synthesis of highly functionalized piperidines catalyzed by molecular iodine. This strategy demonstrated five-component reactions of 1,3-dicarbonyl compounds, amines and aromatic aldehydes in methanol using 10 mol % of iodine at room temperature. This methodology provides an alternative approach for easy access of highly and fully substituted piperidines in moderate to good yields using three readily available starting materials. Notably, this method is mild, cheap, straight forward, applicable to broad range of substrates and environmentally friendly as compared to the existing methods. Synthetic and mechanistic studies are presented here.
Khan, Abu T.,Khan, Md. Musawwer,Bannuru, Kranthi K.R.
experimental part
p. 7762 - 7772
(2010/10/20)

Synthesis of β-keto esters in-flow and rapid access to substituted pyrimidines
We have developed an in-flow process for the synthesis of β-keto esters via the BF3·OEt2-catalyzed formal C-H insertion of ethyl diazoacetate into aldehydes. The β-keto esters were then condensed with a range of amidines to give a variety of 2,6-substituted pyrimidin-4-ols.
Bartrum, Hannah E.,Blakemore, David C.,Moody, Christopher J.,Hayes, Christopher J.
supporting information; experimental part
p. 8674 - 8676
(2011/03/19)

Synthesis and biological evaluation of novel C5 halogen-functionalized S-DABO as potent HIV-1 non-nucleoside reverse transcriptase inhibitors
A series of novel S-DABO analogues (4a1-5a12) have been synthesized by an efficient method and evaluated as inhibitors of human immunodeficiency virus type-1 (HIV-1). The biological testing results clearly indicated that the substitution of halogen at the C5 position of pyrimidine ring could increase the anti-HIV-1 RT activity. The most active compounds showed activity in the low micromole range with IC50 values (IC50 0.18-3.03 μM) comparable to nevirapine (IC50 4.12 μM). The docking showed that a new halogen bond was formed between halogen and carbonyl of TYR188 in the HIV-I RT.
Qin, Hua,Liu, Chang,Guo, Ying,Wang, Ruiping,Zhang, Jianfang,Ma, Liying,Zhang, Zhili,Wang, Xiaowei,Cui, Yuxin,Liu, Junyi
scheme or table
p. 3231 - 3237
(2010/07/05)

Synthesis and biological evaluation of novel 2-arylalkylthio-4-amino-6-benzyl pyrimidines as potent HIV-1 non-nucleoside reverse transcriptase inhibitors
Novel 2-aryalkylthio-4-amino-6-benzylpyrimidines (3a-i), which can be considered as S-DABO and TMC-125 analogue hybrid molecules, have been designed and synthesized as inhibitors of HIV-1 RT. The results clearly indicated that the changes at the N3/C4 position of pyrimidine ring could affect the hydrogen bonds strength and number between N3/C4 and the Lys101 residue which are indispensable for anti-HIV-1 RT activity. The biological activity results are also in accordance with the docking study.
Qin, Hua,Liu, Chang,Zhang, Jianfang,Guo, Ying,Zhang, Siwei,Zhang, Zhili,Wang, Xiaowei,Zhang, Liangren,Liu, Junyi
scheme or table
p. 3003 - 3005
(2010/08/05)

COMPOUNDS, PHARMACEUTICAL COMPOSITION AND METHODS FOR USE IN TREATING METABOLIC DISORDERS
The present invention is directed to novel compounds of formula (I) and their use in treating metabolic diseases.
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Page/Page column 195; 222

(2010/06/22)

Novel synthesis of methyl ketones based on the blaise reaction
A facile two-step synthesis of methyl ketones from alkyl nitriles via the Blaise conversion of nitriles into -keto esters and acid-mediated hydrolysis followed by decarboxylation of the resulting -keto esters is described. Copyright Taylor & Francis Group, LLC.
Rao, H. Surya Prakash,Padmavathy,Vasantham,Rafi, Shaik
experimental part
p. 1825 - 1834
(2009/10/02)

HETEROCYCLIC COMPOUNDS AS FACTOR IXA INHIBITORS
The present invention relates to novel heterocyclic compounds of Formulae I-III: Formula I; [Chemical Formulas should be inserted here as they appears on abstract in.pdf form.] Formula II; Formula III as disclosed herein or a pharmaceutically acceptable salt, solvate, ester, prodrug or stereoisomer thereof. Also disclosed are pharmaceutical compositions comprising said compounds, and methods for using said compounds for treating or preventing a thromboembolic disorder.
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Page/Page column 99-100

(2009/12/27)

PROCESS FOR PRODUCTION OF OPTICALLY ACTIVE 3-AMINO-2 -HYDROXYPROPIONIC CYCLOPROPYLAMIDE DERIVATIVES AND SALTS THEREOF
An objective of the present application is to provide an industrially practicable method for producing an optically-active 3-amino-2-hydroxypropionic cyclopropylamide derivative or salt thereof from an inexpensive easily-available starting material. The derivative or salt thereof is useful as an intermediate for a medicine. It is also intended by the present application to provide a useful intermediate of the derivative. The objective is attained by the following method. First, an easily-available 2-halo-3-oxopropionic acid derivative is asymmetrically reduced, and then epoxidated to produce an optically-active epoxycarboxylic acid derivative. Next, the derivative is converted into an optically-active epoxyamide derivative by reaction with cyclopropylamine, and then reacted with a nitrile to obtain an optically-active oxazolinamide derivative. Subsequently, selective acid solvolysis of the oxazoline skeleton gives the optically-active 3-amino-2-hydroxypropionic cyclopropylamide derivative or salt thereof.
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(2009/04/23)

Molybdenum(VI) dichloride dioxide catalyzed synthesis of β-keto esters by C-H insertion of ethyl diazoacetate into aldehydes
Synthesis of β-keto esters by condensing various aldehydes with ethyl diazoacetate is achieved by using molybdenum(VI) dichloride dioxide. Aromatic, aliphatic, and heterocyclic aldehydes are successfully condensed with ethyl diazoacetate to obtain corresponding β-keto esters in high yields at room temperature.
Jeyakumar, Kandasamy,Chand, Dillip Kumar
p. 1685 - 1687
(2008/12/21)

PHARMACEUTICAL COMPOSITION COMPRISING PYRAZOLONE DERIVATIVE
The present invention relates to pharmaceutical compositions containing a compound represented by formula (I), or a pharmaceutically acceptable prodrug or salt thereof, or a hydrate or solvate thereof as an active ingredient, (wherein, R1, R2, R3, and R4 are the same as R1, R2, R3, and R4 in the description of the present invention).
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Page/Page column 165

(2010/11/30)

Affinity of 3-acyl substituted 4-quinolones at the benzodiazepine site of GABAA receptors
The finding that alkyl 1,4-dihydro-4-oxoquinoline-3-carboxylate and N-alkyl-1,4-dihydro-4-oxoquinoline-3-carboxamide derivatives may be high-affinity ligands at the benzodiazepine binding site of the GABAA receptor, prompted a study of 3-acyl-1,4-dihydro-4-oxoquinoline (3-acyl-4-quinolones). In general, the affinity of the 3-acyl derivatives was found to be comparable with the 3-carboxylate and the 3-carboxamide derivatives, and certain substituents (e.g., benzyl) in position 6 were again shown to be important. As it is believed that the benzodiazepine binding site is situated between an α- and a γ-subunit in the GABAA receptor, selected compounds were tested on the α1β2γ2s, α2β2γ2s and α3β2γ2s GABAA receptor subtypes. The 3-acyl-4-quinolones display various degrees of selectivity for α1- versus α2- and α3-containing receptors, and high-affinity ligands essentially selective for α1 over α3 were developed.
Lager, Erik,Nilsson, Jakob,stergaard Nielsen, Elsebet,Nielsen, Mogens,Liljefors, Tommy,Sterner, Olov
p. 6936 - 6948
(2008/12/21)

A novel synthetic method for β-keto esters
A novel synthetic method for the preparation of β-keto esters has been developed. α-Phenylseleno acetate was treated with LDA to produce a selenium-stabilised carbanion, which reacted with aldehydes, followed by selenoxide syn-elimination, to give β-keto esters.
Qian, Hao,Ge, Chunrong,Huang, Xian
p. 160 - 161
(2008/02/03)

New series of antiprion compounds: Pyrazolone derivatives have the potent activity of inhibiting protease-resistant prion protein accumulation
To find effective antiprion compounds, we synthesized and evaluated various pyrazolone derivatives. Seven of 19 compounds showed inhibition of PrP-res accumulation and the remarkably active compound 13 showed an IC50 value of 3 nM in both ScN2a and F3 cell lines. Findings from studies on physicochemical and biochemical properties suggest that the action mechanism of these compounds does not correlate with any antioxidant activities, any of hydroxyl radical scavenging activities, or any SOD-like activities.
Kimata, Ayako,Nakagawa, Hidehiko,Ohyama, Ryo,Fukuuchi, Tomoko,Ohta, Shigeru,Suzuki, Takayoshi,Miyata, Naoki
p. 5053 - 5056
(2008/03/13)

Modulation of luminescence intensity of lanthanide complexes by photoinduced electron transfer and its application to a long-lived protease probe
Luminescent lanthanide complexes (Tb3+, Eu3+, etc.) have excellent properties for biological applications, including extraordinarily long lifetimes and large Stokes shifts. However, there have been few reports of lanthanide-based functional probes, because of the difficulty in designing suitable complexes with a luminescent on/off switch. Here, we have synthesized a series of complexes which consist of three moieties: a lanthanide chelate, an antenna, and a luminescence off/on switch. The antenna is an aromatic ring which absorbs light and transmits its energy to the metal, and the switch is a benzene derivative with a different HOMO level. If the HOMO level is higher than a certain threshold, the complex emits no luminescence at all, which indicates that the lanthanide luminescence can be modulated by photoinduced electron transfer (PeT) from the switch to the sensitizer. This approach to control lanthanide luminescence makes possible the rational design of functional lanthanide complexes, in which the luminescence property is altered by a biological reaction. To exemplify the utility of our approach to the design of lanthanide complexes with a switch, we have developed a novel protease probe, which undergoes a significant change in luminescence intensity upon enzymatic cleavage of the substrate peptide. This probe, combined with time-resolved measurements, was confirmed in model experiments to be useful for the screening of inhibitors, as well as for clinical diagnosis.
Terai, Takuya,Kikuchi, Kazuya,Iwasawa, Shin-Ya,Kawabe, Takao,Hirata, Yasunobu,Urano, Yasuteru,Nagano, Tetsuo
p. 6938 - 6946
(2007/10/03)

Discovery of novel hydroxy pyrazole based factor IXa inhibitor
Synthesis and biological data of a novel selective and efficacious factor IXa inhibitor are described along with its crystal structure in factor VIIa.
Vijaykumar, Dange,Sprengeler, Paul A.,Shaghafi, Michael,Spencer, Jeffrey R.,Katz, Brad A.,Yu, Christine,Rai, Roopa,Young, Wendy B.,Schultz, Brian,Janc, James
p. 2796 - 2799
(2007/10/03)

DNA-protein cross-linking: Model systems for pyrimidine-aromatic amino acid cross-linking
We have synthesized simple model systems to explore the possibility of photo-cross-linking between the pyrimidine bases and the side chains of the aromatic amino acids. Thymine/phenylalanine and thymine/tyrosine models gave cross-links, and thymine/tryptophan models gave complex mixtures; the cytosine/phenylalanine model was unreactive. The quantum yields for the model cross-linking reactions were 18-46 times smaller than those for thymine dimer formation. Biphotonic excitation contributes little to the yield of these reactions.
Sun, Guangxing,Fecko, Christopher J.,Nicewonger, Robert B.,Webb, Watt W.,Begley, Tadhg P.
p. 681 - 683
(2007/10/03)

Preparation of polystyrene-supported α-seleno acetate and application to solid-phase synthesis of β-keto esters
A novel polystyrene-supported α-seleno acetate has been developed. This novel resin was treated with LDA to produce a selenium-stabilized carbanion, which reacted with aldehydes, followed by selenoxide syn-elimination to give β-keto esters. Georg Thieme Verlag Stuttgart.
Qian, Hao,Huang, Xian
p. 1547 - 1548
(2007/10/03)

Hydroxyl radical scavenging by edaravone derivatives: Efficient scavenging by 3-methyl-1-(pyridin-2-yl)-5-pyrazolone with an intramolecular base
We synthesized various 3-methyl-1-phenyl-5-pyrazolone (edaravone) derivatives and evaluated their oxidation potential and hydroxyl radical scavenging activity. It was found 3-methyl-1-(pyridin-2-yl)-5-pyrazolone had a much higher ability to scavenge the radical than did edaravone itself. Its efficient radical scavenging activity was assumed to be due to the increase of its anion form, an active form, by a hydrogen-bonded intramolecular base.
Nakagawa, Hidehiko,Ohyama, Ryo,Kimata, Ayako,Suzuki, Takayoshi,Miyata, Naoki
p. 5939 - 5942
(2007/10/03)

Microwave assisted rapid and efficient synthesis of aryl methyl ketones and β-keto esters using Meldrum's acid
Microwave mediated rapid and efficient synthesis of aryl methyl ketones and β-keto esters from acyl Meldrum's acid by hydrolysis and alcoholysis, respectively, has been reported.
More,Mahulikar
p. 823 - 825
(2007/10/03)

FLUORESCENT LANTHANIDE COMPLEX
A luminescent lanthanide complex using a photo induced electron transfer as the luminescence controlling principle is presented. The complex comprises a substituted 2-quinolinol containing a sensor group and a complex group and lanthanide ion (Ln3+). This complex is allowed to be co-present in a liquid phase with a material to be measured, and the luminescence of said complex is measured.
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(2008/06/13)

Chemoenzymatic formal total synthesis of (-)-bestatin
A highly stereoselective, enzymatic reduction of an α-chloro-β- keto ester provided the key intermediate for a total synthesis of the α-hydroxy-β-amino acid moiety of (-)-bestatin. The reduction product was cyclized to a glycidic ester that was opened in a Ritter reaction with benzonitrile, affording a trans-oxazoline, which was hydrolyzed under acidic conditions to the target molecule.
Feske, Brent D.,Stewart, Jon D.
p. 3124 - 3127
(2007/10/03)

Nitroalkanes and ethyl glyoxalate as common precursors for the preparation of both β-keto esters and α,β-unsaturated esters
β-Nitro acrylic esters, obtained by the reaction of nitroalkanes and ethyl glyoxalate, are the key building blocks for the immediate synthesis of both the title compounds. In fact, their treatment with titanium trichloride produce the direct conversion to the β-keto esters, while their reaction with sodium boron hydride gives the one-pot synthesis of α,β- unsaturated esters through formal substitution of the vinylic nitro group with an hydrogen.
Ballini, Roberto,Fiorini, Dennis,Palmieri, Alessandro
p. 7027 - 7029
(2007/10/03)

Thiazole and oxazole derivatives as activators of human peroxisome proliferator activated receptors
The present invention provides a compound of formula (1) wherein R1-R5, R25, R26, Y and X2 are defined as in claim 1. The compounds activate human peroxisome proliferator activated receptors (hPPARs) and arc useful for the treatment of associated disorders such as cardiovascular disease and hypercholesteremia.
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(2008/06/13)

Method for preparing chiral diphosphines
The invention concerns a method for preparing a compound of formula (1) wherein: A represents naphthyl or phenyl optionally substituted; and Ar1, Ar2independently represent a saturated or aromatic carbocyclic group, optionally substituted.
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(2008/06/13)