- Design, synthesis and biological evaluation of novel pteridinone derivatives possessing a sulfonyl moiety as potent dual inhibitors of PLK1 and BRD4
-
The simultaneous inhibition of PLK1 and BRD4 by a single molecule could lead to the development of an effective therapeutic strategy for a variety of diseases in which PLK1 and BRD4 are implicated. Herein, two series of novel pteridinone derivatives possessing a sulfonyl moiety were designed, synthesized and evaluated for their biological activity. Most compounds exhibited moderate to excellent cytotoxic activity against HCT116, PC3 and BT474 cell lines. Among them, the most promising compound B2 showed high antiproliferative effects on the three cell lines with IC50 values of 0.30 μM, 1.82 μM and 1.69 μM, respectively. In the enzymatic assay, B2 was identified as a potent PLK1 and BRD4 dual inhibitor (PLK1 IC50 = 6.3 nM, BRD4 IC50 = 179 nM). Further explorations in bioactivity were conducted to clarify the anticancer mechanism of compound B2. The results showed that compound B2 obviously inhibited the proliferation of HCT116 cell lines, induced a great decrease in the mitochondrial membrane potential leading to apoptosis of HCT116 cells and arrested the G2 phase of HCT116 cells.
- Chen, Fei,Cui, Xinhua,Gao, Zhanfeng,Gong, Ping,Hou, Yunlei,Li, Zhiwei,Liu, Jiuyu,Liu, Yajing,Qin, Mingze,Wang, Shihui,Wang, Yu,Wang, Yuehan,Zhao, Yanfang
-
p. 1246 - 1259
(2022/02/07)
-
- Expanding the Protecting Group Scope for the Carbonyl Olefin Metathesis Approach to 2,5-Dihydropyrroles
-
Chiral pyrrolidine derivatives are important building blocks for natural product synthesis. Carbonyl olefin metathesis has recently emerged as a powerful tool for the construction of such building blocks from chiral amino acid derivatives. Here, we demons
- Catti, Lorenzo,Huck, Fabian,Reber, Gian Lino,Tiefenbacher, Konrad
-
supporting information
p. 419 - 428
(2022/01/03)
-
- Preparation method of (S)-(+)-2-aminobutanamide hydrochloride
-
The invention discloses a preparation method of (S)-(+)-2-aminobutanamide hydrochloride, and relates to a preparation method of a levetiracetam key intermediate, and the method comprises the followingspecific steps: carrying out esterification reaction on L-2-aminobutyric acid serving as a starting material and thionyl chloride, and concentrating part of solvent after the reaction is finished; introducing ammonia gas to neutralize generated hydrogen chloride and residual thionyl chloride; and filtering, introducing ammonia gas, and carrying out an ammonolysis reaction to obtain the (S)-2-aminobutanamide hydrochloride after the treating is finished. According to the preparation method, the starting material is simple and easy to obtain, the one-pot method is adopted, the atom utilization rate is high, operation is easy and convenient, and the obtained product quality is high.
- -
-
Paragraph 0043-0048; 0054-0059; 0065-0070; 0076-0081
(2020/08/02)
-
- Method for preparing levetiracetam
-
The invention relates to a method for preparing levetiracetam. The method comprises the following steps: reacting aminobutyric acid in lower alcohol and thionyl chloride to obtain an intermediate I; adding ammonia water to continue the reaction, and adding hydrochloric acid to adjust the pH value to about 3 to salify to obtain a salified intermediate II refined product; reacting the intermediate II in the presence of KOH in the presence of a catalyst and dichloromethane, and then adding 4-chlorobutyryl chloride to continuously react; adding water to hydrolyze, adjusting the pH to be weakly alkaline by using diluted hydrochloric acid, and crystallizing to obtain a levetiracetam crude product; decolorizing and crystallizing in ethyl acetate to obtain a refined product of levetiracetam. The invention also relates to the levetiracetam prepared by the method and pharmaceutical application thereof, for example, the levetiracetam can be used for treating or preventing epilepsy, Parkinson's disease, dyskinesia, migraine, tremor, idiopathic tremor, bipolar disorder, chronic pain, neuropathic pain, or bronchial, asthma or allergic diseases.
- -
-
Paragraph 0075; 0080-0082; 0087; 0088; 0093-0094; 0099; 0100
(2020/02/14)
-
- Method for preparing levetiracetam
-
The invention relates to the technical field of drug synthesis, and provides a method for preparing levetiracetam. The method includes the following steps: taking L-2-aminobutyric acid as a starting material, and preforming esterification with thionyl chloride to obtain (S)-2-methyl aminobutyrate hydrochloride; performing aminolysis reaction between the (S)-2-methyl aminobutyrate hydrochloride andammonia water to generate (S)-2-aminobutylamine hydrochloride; preforming acylation reaction between the(S)-2-aminobutylamine hydrochloride and the mixed solution of 4-chlorobutyryl chloride and dichloromethane; directly performing cyclization reaction between the intermediate product with the dichloromethane and tetrabutyl ammonium bromide to obtain a crude product of levetiracetam; and recrystallizing the crude product to generate the levetiracetam. The preparation method uses the easily-obtained starting material to ensure good reproducibility of the synthesis route, simple unit operationand economic accounting. The reaction in each step is easy to purify, the quality is controllable, and the reaction yield is greatly improved.
- -
-
Paragraph 0112-0116; 0129-0132
(2019/01/23)
-
- Rhodium-Catalyzed Enantioselective Synthesis of Oxazinones via an Asymmetric Ring Opening-Lactonization Cascade of Oxabicyclic Alkenes
-
The rhodium-catalyzed asymmetric ring opening reaction of oxabicyclic alkenes is shown to be an efficient method for synthesizing chiral heterocycles. We demonstrate that the pairwise combination of chiral catalyst with chiral amino-acid-derived pronucleophiles results in a stereodivergent synthesis of diastereomeric hydroxyesters. A favorable conformational preference induces the subsequent lactonization of one diastereomer leading to the highly enantioselective synthesis of oxazinones.
- Yen, Andy,Pham, Anh Hoang,Larin, Egor M.,Lautens, Mark
-
supporting information
p. 7549 - 7553
(2019/10/02)
-
- N-1 BRANCHED CYCLOALKYL SUBSTITUTED IMIDAZO[4,5-C]QUINOLINE COMPOUNDS, COMPOSITIONS, AND METHODS
-
lmidazo[4,5-c]quinoline compounds of formula (II) having a substituent that is attached at the N-l position by a branched group, single enantiomers of the compounds, pharmaceutical compositions containing the compounds, and methods of making the compounds
- -
-
Page/Page column 44
(2019/12/15)
-
- Benzoxaborole Antimalarial Agents. Part 5. Lead Optimization of Novel Amide Pyrazinyloxy Benzoxaboroles and Identification of a Preclinical Candidate
-
Carboxamide pyrazinyloxy benzoxaboroles were investigated with the goal to identify a molecule with satisfactory antimalarial activity, physicochemical properties, pharmacokinetic profile, in vivo efficacy, and safety profile. This optimization effort discovered 46, which met our target candidate profile. Compound 46 had excellent activity against cultured Plasmodium falciparum, and in vivo against P. falciparum and P. berghei in infected mice. It exhibited good PK properties in mice, rats, and dogs. It was highly active against the other 11 P. falciparum strains, which are mostly resistant to chloroquine and pyrimethamine. The rapid parasite in vitro reduction and in vivo parasite clearance profile of 46 were similar to those of artemisinin and chloroquine, two rapid-acting antimalarials. It was nongenotoxic in an Ames assay, an in vitro micronucleus assay, and an in vivo rat micronucleus assay when dosed orally up to 2000 mg/kg. The combined properties of this novel benzoxaborole support its progression to preclinical development.
- Zhang, Yong-Kang,Plattner, Jacob J.,Easom, Eric E.,Jacobs, Robert T.,Guo, Denghui,Freund, Yvonne R.,Berry, Pamela,Ciaravino, Vic,Erve, John C. L.,Rosenthal, Philip J.,Campo, Brice,Gamo, Francisco-Javier,Sanz, Laura M.,Cao, Jianxin
-
p. 5889 - 5908
(2017/07/22)
-
- THERAPEUTIC COMPOUNDS AS INHIBITORS OF THE OREXIN-1 RECEPTOR
-
The present invention relates to compounds that are inhibitors of the orexin-1 receptor. The compounds have the structural formula I defined herein. The present invention also relates to processes for the preparation of these compounds, to pharmaceutical compositions comprising them, and to their use in the treatment of diseases or disorders associated with orexin-1 receptor activity.
- -
-
Page/Page column 105
(2016/03/19)
-
- BRD4 Structure-Activity Relationships of Dual PLK1 Kinase/BRD4 Bromodomain Inhibitor BI-2536
-
A focused library of analogues of the dual PLK1 kinase/BRD4 bromodomain inhibitor BI-2536 was prepared and then analyzed for BRD4 and PLK1 inhibitory activities. Particularly, replacement of the cyclopentyl group with a 3-bromobenzyl moiety afforded the most potent BRD4 inhibitor of the series (39j) with a Ki = 8.7 nM, which was equipotent against PLK1. The superior affinity of 39j over the parental compound to BRD4 possibly derives from improved interactions with the WPF shelf. Meanwhile, substitution of the pyrimidine NH with an oxygen atom reversed the PLK1/BRD4 selectivity to convert BI-2536 into a BRD4-selective inhibitor, likely owing to the loss of a critical hydrogen bond in PLK1. We believe further fine-tuning will furnish a BRD4 "magic bullet" or an even more potent PLK1/BRD4 dual inhibitor toward the expansion and improved efficacy of the chemotherapy arsenal.
- Chen, Lijia,Yap, Jeremy L.,Yoshioka, Makoto,Lanning, Maryanna E.,Fountain, Rachel N.,Raje, Mithun,Scheenstra, Jacob A.,Strovel, Jeffrey W.,Fletcher, Steven
-
supporting information
p. 764 - 769
(2015/08/06)
-
- Synthesis of tritium-labeled levetiracetam ((2S)-2-(2-oxopyrrolidin-1-yl) butanamide) with high specific activity
-
A method for the preparation of [A3H]levetiracetam with a high specific activity of 98Ci/mmol (3.6TBq/mmol) is described. The radioligand proved to be highly useful for the labeling of specific levetiracetam binding sites in rat brain membrane preparations.
- Hildenbrand, Simone,Baqi, Younis,Mueller, Christa E.
-
experimental part
p. 48 - 51
(2012/06/29)
-
- METHOD FOR PRODUCING OPTICALLY ACTIVE CYCLOPROPANE CARBOXYLIC ACID ESTER COMPOUND, ASYMMETRIC COPPER COMPLEX, AND OPTICALLY ACTIVE SALICYLIDENEAMINOALCOHOL COMPOUND
-
A process for producing an optically active cyclopropanecarboxylic acid ester compound represented by the formula (4): (wherein R5, R6 and * each represents the same meaning as defined below), comprising reacting a diazoacetic acid e
- -
-
Page/Page column 21
(2011/07/29)
-
- COMPOUNDS FOR THE TREATMENT OF ALZHEIMER'S DISEASE
-
The invention relates to substituted 1,2-ethylenediamines of general formula (I), wherein the radicals R1-R13, A, B, L and i are as defined in the description and the claims. The invention also relates to the use thereof for treating Alzheimer's disease (AD) and similar diseases.
- -
-
Page/Page column 67
(2010/06/19)
-
- PREPARATION OF (S)-2-AMINOBUTYRIC ACID
-
Processes for the preparation of (S)-2-aminobutyric acid, embodiments including selective hydrolysis of racemic N-protected-2-aminobutyric acid using an acylase enzyme, such as one derived from Thermococcus litorolis or Aspergillus melleus.
- -
-
Page/Page column 9
(2010/04/03)
-
- Facile synthesis of β-amino disulfides, cystines, and their direct incorporation into peptides
-
Herein, we report a simple and efficient methodology for the synthesis of β-amino disulfides by regioselective ring opening of sulfamidates with benzyltriethylammonium tetrathiomolybdate [BnNEt3] 2MoS4. Stability and reactivity of different protecting groups under the reaction conditions have been discussed. This methodology has also been extended to serine and threonine derived sulfamidates to furnish cystine and 3,3′-dimethyl cystine derivatives. Georg Thieme Verlag.
- Nasir Baig,Kanimozhi, Catherine K.,Sudhir, V. Sai,Chandrasekaran, Srinivasan
-
scheme or table
p. 1227 - 1232
(2009/09/06)
-
- CRF RECEPTOR ANTAGONISTS AND METHODS RELATING THERETO
-
CRF receptor antagonists are disclosed which may have utility in the treatment of a variety of disorders, including the treatment of disorders manifesting hypersecretion of CRF in mammals, such as stroke. The CRF receptor antagonists of this invention have the following structure (a) including pharmaceutically acceptable salts, esters, solvates, stereoisomers, and prodrugs thereof, wherein R1, R2, R3, Y, Ar, and Het are as defined herein. Compositions containing a CRF receptor antagonist and a pharmaceutically acceptable carrier are also disclosed, as well as methods for use of the same.
- -
-
Page/Page column 58
(2010/02/12)
-
- Preparation of amino acid amides
-
A process for making amino acid amides, comprising reacting an amino acid, or acid salt of an amino acid, with a halogenating agent, or with a substance that reacts with carboxylic acids to form a leaving group, to form an intermediate, then reacting the intermediate with ammonia. When the amino acid or acid salt is enantiomerically pure, the amide will be a stereoisomer. An amide made by the process can be used to form levetiracetam.
- -
-
Page/Page column 2
(2008/06/13)
-
- Enantioselective synthesis of β-amino alcohols and α-amino acids via a copper catalyzed addition of diorganozinc reagents to N-phosphinoylimines
-
Enantioenriched β-amino alcohols were prepared via an asymmetric addition of diethylzinc, catalyzed by the BozPHOS·Cu(I) complex, on in situ formed N-phosphinoylimines. The nature of the hydroxyl protecting groups was found to affect the enantioselectivities. Subsequent deprotection and oxidation of N-phosphinoyl β-amino alcohols afforded optically active α-amino acids (97% ee).
- Desrosiers, Jean-Nicolas,C?té, Alexandre,Charette, André B.
-
p. 6186 - 6192
(2007/10/03)
-
- Stereospecific Amination by Dynamic Kinetic Resolution Utilizing 2-Oxoimidazolidine-4-carboxylate as a Novel Chiral Auxiliary
-
A novel type of stereospecific amination by dynamic kinetic resolution using (4S)-2-oxoimidazolidine-4-carboxylate (1) as a chiral auxiliary was developed. A reaction of a diastereomeric mixture of (4S)-3--2-oxoimidazolidine-4-carboxylates 4 with an amine in the presence of a base in HMPA predominantly afforded (4S)-3--2-oxoimidazolidine-4-carboxylates (S,R)-7 in good yields.The reaction proceeded by stereospecific SN2 type amination incorporated with rapid interconversion between the substrates (S,S)-4 and (S,R)-4.Mechanistic study suggested that the unique stereoselectivity was induced through the interaction between an amine and the ester group of (S,S)-4 in the transition state.The chiral auxiliary was easily removed with alkoxide anion to afford the α-amino acid synthon in good yields.
- Kubota, Hitoshi,Kubo, Akira,Takahashi, Masami,Shimizu, Ryo,Da-te, Tadamasa,et al.
-
p. 6776 - 6784
(2007/10/03)
-
- RELATIONSHIPS BETWEEN THE STRUCTURE AND THE PHYTOTOXICITY OF THE FUNGAL TOXIN TENUAZONIC ACID
-
Tenuazonic acid (3-acetyl 5-sec-butyl pyrrolidine-2,4-dione) is a metabolite produced by the fungal pathogen of rice Pyricularia oryzae.It inhibits growth of plants by interferring with protein synthesis at the ribosome level.We have synthesized analogues of tenuazonic acid with various substituents at C-3 and C-5.Substituents at C-5 other than sec-butyl or n-propyl, decrease the phytotoxicity of the analogues.But substitutions at C-3 abolish the toxicity.Thus, tenuazonic acid seems to have the optimal structure for phytotoxicity.Tenuazonic acid induces rice leaf defence reactions (browning) of reactive varieties which are resistant to P. oryzae.Some of the analogues synthesized have a low level of phytotoxicity and are able to induce this leaf browning of the reactive rice varieties.Thus different structural features are required for phytotoxicity and for leaf browning.Key Word Index - Tenuazonic acid; pyrrolidine-2,4-diones; rice; phytotoxicity; Pyricularia oryzae; structure-activity.
- Lebrun, M. H.,Nicolas, L.,Boutar, M.,Gaudemer, F.,Ranomenjanahary, S.,Gaudemer, A.
-
-
- Chirospecific Synthesis of (+)-Pilocarpine
-
An efficient chirospecific synthesis for (+)-pilocarpine (1a) using D-methionine or D-2-aminobutanol as chiral educt is described.Formation of the C3-C4 carbon bond at an early stage gave the key intermediate diethyl phosphonate.Wittig coupling of this phosphonate with 1-methyl-5-imidazolecarboxaldehyde introduced the imidazole moiety of the pilocarpine skeleton.Selective reduction of an α,β-unsaturated nitrile to the corresponding allylic alcohol, stereocontrolled hydrogenation of the olefin, and epimerization of (+)-isopilocarpine to (+)-pilocarpine via kinetic protonation led to formation of the natural alkaloid.This methodology allows chirospecific syntheses of the four possible stereoisomers of pilocarpine.A short and convenient route to (+/-)-pilocarpine based on the key intermediate phosphonate is also described.
- Compagnone, Reinaldo S.,Rapoport, Henry
-
p. 1713 - 1719
(2007/10/02)
-
- Von der basenkatalysierten Ringoeffnung von 2H-Azirinen zu einer α-Alkylierungsmethode von primaeren Aminen
-
It is shown than fluorene-9'-spiro-2-(3-phenyl-2H-azirine) (1) on treatment with various alcohols in the presence of the corresponding alkoxide ions yields N-(9'-fluorenyl)benzimidates 2a-d (Scheme 1). 2,2,3-Triphenyl-2H-aziridine (3) reacts with methanol in a similar manner (Scheme 2).Benzimidates 2a (Scheme 3), 8 (Scheme 4) and 10 (Scheme 5) can easily be deprotonated by butyllithium (BuLi) or lithium diisopropylamide (LDA) in tetrahydrofuran (THF) to 1-methoxy-2-aza-allylanions, that can be alkylated, at C(3), exclusively, by various electrophiles (e.g.R-X (X = I, Br), RCHO or methyl acrylate (see also Scheme 6)).As the acidic hydrolyses (1 N HCl) of benzimidates 9 and 11 leads to the corresponding α-alkylated free amines 15 and 18 (Scheme 7 and 8), benzoyl derivatives 16 and 19 are obtained from the hydrolysis under basic conditions.On the other hand it is observed that a catalyzed Chapman rearrangement of 9 and 11 results in the formation of N-benzoyl-N-methyl derivatives 17 and 20 (Scheme 7 and 8).The described reactions offer a simple method for the α-alkylation of actived primary amines.
- Schulthess, Adrian Heinz,Hansen, Hans-Juergen
-
p. 1322 - 1336
(2007/10/02)
-
- L-Vinylglycine
-
Optically pure L-vinylglycine (1) has been synthesized from L-methionine in 54percent overall yield.The process consists in first preparing N-methionine methyl ester (9) which is then oxidized to methyl 2-amino>-
- Afzali-Ardakani, Ali,Rapoport, Henry
-
p. 4817 - 4820
(2007/10/02)
-