cas 55314-16-4, 1-(3-Pyridyl)-3-(dimethylamino)-2-propen-1-one

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Microscale Parallel Synthesis of Acylated Aminotriazoles Enabling the Development of Factor XIIa and Thrombin Inhibitors
Herein we report a microscale parallel synthetic approach allowing for rapid access to libraries of N-acylated aminotriazoles and screening of their inhibitory activity against factor XIIa (FXIIa) and thrombin, which are targets for antithrombotic drugs. This approach, in combination with post-screening structure optimization, yielded a potent 7 nM inhibitor of FXIIa and a 25 nM thrombin inhibitor; both compounds showed no inhibition of the other tested serine proteases. Selected N-acylated aminotriazoles exhibited anticoagulant properties in vitro influencing the intrinsic blood coagulation pathway, but not extrinsic coagulation. Mechanistic studies of FXIIa inhibition suggested that synthesized N-acylated aminotriazoles are covalent inhibitors of FXIIa. These synthesized compounds may serve as a promising starting point for the development of novel antithrombotic drugs.
Platte, Simon,Korff, Marvin,Imberg, Lukas,Balicioglu, Ilker,Erbacher, Catharina,Will, Jonas M.,Daniliuc, Constantin G.,Karst, Uwe,Kalinin, Dmitrii V.
supporting information
p. 3672 - 3690
(2021/08/07)

Discovery of highly potent tubulin polymerization inhibitors: Design, synthesis, and structure-activity relationships of novel 2,7-diaryl-[1,2,4]triazolo[1,5-a]pyrimidines
By removing 5-methyl and 6-acetyl groups in our previously reported compound 3, we designed a series of novel 2,7-diaryl-[1,2,4]triazolo[1,5-a]pyrimidine derivatives as potential tubulin polymerization inhibitors. Among them, compound 5e displayed low nanomolar antiproliferative efficacy on HeLa cells which was 166-fold higher than the lead analogue 3. Interestingly, 5e displayed significant selectivity in inhibiting cancer cells over HEK-293 (normal human embryonic kidney cells). In addition, 5e dose-dependently arrested HeLa in G2/M phase through the alterations of the expression levels of p-cdc2 and cyclin B1, and caused HeLa cells apoptosis by regulation of expressions of cleaved PARP. Further evidence demonstrated that 5e effectively inhibited tubulin polymerization and was 3-fold more powerful than positive control CA-4. Moreover, molecular docking analysis indicated that 5e overlapped well with CA-4 in the colchicine-binding site. These studies demonstrated that 2,7-diaryl-[1,2,4]triazolo[1,5-a]pyrimidine skeleton might be used as the leading unit to develop novel tubulin polymerization inhibitors as potential anticancer agents.
Huo, Xian-Sen,Jian, Xie-Er,Ou-Yang, Jie,Chen, Lin,Yang, Fang,Lv, Dong-Xin,You, Wen-Wei,Rao, Jin-Jun,Zhao, Pei-Liang
(2021/05/10)

Method for preparing N-(5-carboxyl-2-methylphenyl)-4-(3-pyridine)-2-pyrilamine
The invention discloses a method for preparing N-(5-carboxyl-2-methylphenyl)-4-(3-pyridine)-2-pyrilamine. The method specifically comprises the following steps: step 1, carrying out ethyl esterification reaction on 3-nitro-4-methyl benzoic acid serving as an initial raw material to generate a compound 2; step 2, reducing nitro of the compound 2 through hydrogenation reduction reaction in the presence of palladium on carbon to generate a compound 3; step 3, reacting the compound 3 with a nitrile amine aqueous solution, and then carrying out base exchange to obtain a compound 4; step 4, carrying out cyclization between the compound 4 and a compound 6 to obtain a compound 7; and step 5, hydrolyzing the compound 7 under the action of an alkaline to generate a compound 8, namely N-(5-carboxyl-2-methylphenyl)-4-(3-pyridine)-2-pyrilamine. The method overcomes the defects that in the prior art such as long reaction time, low yield, high cost, difficulty for industrial production, and the like. A preparation method, which is high in yield, is environmentally-friendly, and is suitable for industrial production, is provided.
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Paragraph 0035; 0036

(2021/05/05)

Structure-Based Discovery of Pyrimidine Aminobenzene Derivatives as Potent Oral Reversal Agents against P-gp- And BCRP-Mediated Multidrug Resistance
Overexpression of ATP binding cassette (ABC) transporters, including P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), is an important factor leading to multidrug resistance (MDR) in cancer treatments. Three subclasses of dual inhibitors of P-gp and BCRP were designed based on the active moieties of BCRP inhibitors, tyrosine kinase inhibitors, and P-gp inhibitors, of which compound 21 possessed low cytotoxicity, high reversal potency, and good lipid distribution coefficient. 21 also increased the accumulation of Adriamycin (ADM) and Mitoxantrone (MX), blocked Rh123 efflux, and made no change in the protein expression of P-gp and BCRP. Importantly, coadministration of 21 can significantly improve the oral bioavailability of paclitaxel (PTX). It was also demonstrated that 21 significantly inhibited the growth of K562/A02 xenograft tumors by increasing the sensitivity of ADM in vivo. In summary, 21 has the potential to overcome MDR caused by P-gp and BCRP and to improve the oral bioavailability of PTX.
Qiu, Qianqian,Zou, Feng,Li, Huilan,Shi, Wei,Zhou, Daoguang,Zhang, Ping,Li, Teng,Yin, Ziyu,Cai, Zilong,Jiang, Yuxuan,Huang, Wenlong,Qian, Hai
p. 6179 - 6197
(2021/06/01)

Synthesis of imatinib, a tyrosine kinase inhibitor, labeled with carbon-14
Imatinib (Gleevec) is a multiple tyrosine kinase inhibitor that decreases the activity of the fusion oncogene called BCR-ABL (breakpoint cluster region protein-Abelson murine leukemia viral oncogene homolog) and is clinically used for the treatment of chronic myelogenous leukemia and acute lymphocytic leukemia. Small molecule drugs, such as imatinib, can bind to several cellular proteins including the target proteins in the cells, inducing undesirable effects along with the effects against the disease. In this study, we report the synthetic optimization for 14C-labeling and radiosynthesis of [14C]imatinib to analyze binding with cellular proteins using accelerator mass spectroscopy. 14C-labeling of imatinib was performed by the synthesis of 14C-labeld 2-aminopyrimidine intermediate using [14C]guanidine·HCl, which includes an in situ reduction of an inseparable byproduct for easy purification by HPLC, followed by a cross-coupling reaction with aryl bromide precursor. The radiosynthesis of [14C]imatinib (specific activity, 631 MBq/mmol; radiochemical purity, 99.6%) was achieved in six steps with a total chemical yield of 29.2%.
Kang, Julie,Lee, Jun Young,Park, Jeong-Hoon,Chang, Dong-Jo
p. 174 - 182
(2020/02/13)

Synthesis and biological evaluation of (3/4-(pyrimidin-2-ylamino)benzoyl)-based hydrazine-1-carboxamide/carbothioamide derivatives as novel RXRα antagonists
Abnormal alterations in the expression and biological function of retinoid X receptor alpha (RXRα) have a key role in the development of cancer. Potential modulators of RXRα as anticancer agents are explored in growing numbers of studies. A series of (4/3-(pyrimidin-2-ylamino)benzoyl)hydrazine-1-carboxamide/carbothioamide derivatives are synthesised and evaluated for anticancer activity as RXRα antagonists in this study. Among all synthesised compounds, 6A shows strong antagonist activity (half maximal effective concentration (EC50) = 1.68 ± 0.22 μM), potent anti-proliferative activity against human cancer cell lines HepG2 and A549 cells (50% inhibition of cell viability (IC50) values 50 values > 100 μM). Further bioassays indicate that 6A inhibits 9-cis-RA-induced activity in a dose-dependent manner, and selectively binds to RXRα-=LΒD with submicromolar affinity (Kd = 1.20 × 10?7 M). 6A induces time-and dose-dependent cleavage of poly ADP-ribose polymerase, and significantly stimulates caspase-3 activity, leading to RXRα-dependent apoptosis. Finally, molecular docking studies predict the binding modes for RXRα-LBD and 6A.
Chen, Xiaohui,Fang, Meijuan,Guo, Kaiqiang,Liu, Jie,Liu, Weihao,Qin, Jingbo,Tang, Bowen,Wu, Chunxiao,Wu, Tong,Wu, Zhen,Xu, Jianwen,Zhou, Hu
p. 880 - 896
(2020/04/07)

Computer Modeling and Synthesis of Potential Inhibitors of Tyrosine Kinase BCR-ABL with the T315I Mutation
Abstract—: A comparative analysis of the interaction of the chimeric protein BCR-ABL, of the normal type and with the T315I mutation, with known inhibitors as well as compounds potentially capable of inhibiting the mutant protein has been carried out by computer modeling. It has been shown that the compounds proposed are incorported into the structure of the protein with the retention of the basic hydrogen bonds and intermolecular interactions. Two structures containing the pyrrole cycle have been synthesized, which, according to the results of computer modeling, appear to be most promising.
Fedarkevich, A. N.,Sharko, O. L.,Shmanai, V. V.
p. 187 - 198
(2020/05/04)

Synthesis method of imatinib and imatinib mesylate
The invention relates to a synthesis method of imatinib and imatinib mesylate. The method comprises the following steps: condensing 3-acetylpyridine and N,N-dimethylformamide dimethyl acetal which aretaken as initial raw materials to obtain 3-dimethylamino-1-(3-pyridyl)-2-propen-1-one, then reacting with 2-methyl-5-nitrophenylguanidine nitrate to form a pyrimidine ring, performing nitro reductionto obtain N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidinamine, amidating the N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidinamine and 4-(chloromethyl)benzoyl chloride, performing affinitysubstitution with 1-methylpiperazine to obtain imatinib, and salifying the imatinib and methanesulfonic acid. The products obtained by the method have the advantages of few impurities, simplicity in post-treatment, high total yield, greenness, environmental protection and safety, and is suitable for a production process for large-scale industrial production of imatinib mesylate.
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(2020/05/02)

COMPOUNDS AND METHODS FOR HEMATOPOIETIC REGENERATION
The invention relates to compounds that promote hematopoietic regeneration. The invention further relates to methods of promoting hematopoietic regeneration using the novel compounds of the invention.
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(2019/06/17)

Molecular requirements for the expression of antiplatelet effects by synthetic structural optimized analogues of the anticancer drugs imatinib and nilotinib
Background: Platelets play important roles in cancer progression and metastasis, as well as in cancer-associated thrombosis (CAT). Tyrosine kinases are implicated in several intracellular signaling pathways involved in tumor biology, thus tyrosine kinase inhibitors (TKIs) represent an important class of anticancer drugs, based on the concept of targeted therapy. Purpose: The objective of this study is the design and synthesis of analogues of the TKIs imatinib and nilotinib in order to develop tyrosine kinase inhibitors, by investigating their molecular requirements, which would express antiplatelet properties. Methods: Based on a recently described by us improved approach in the preparation of imatinib and/or nilotinib analogues, we designed and synthesized in five-step reaction sequences, 8 analogues of imatinib (I–IV), nilotinib (V, VI) and imatinib/nilotinib (VII, VIII). Their inhibitory effects on platelet aggregation and P-selectin membrane expression induced by arachidonic acid (AA), adenosine diphosphate (ADP) and thrombin receptor activating peptide-6 (TRAP-6), in vitro, were studied. Molecular docking studies and calculations were also performed. Results: The novel analogues V–VIII were well established with the aid of spectroscopic methods. Imatinib and nilotinib inhibited AA-induced platelet aggregation, exhibiting IC50 values of 13.30 μΜ and 3.91 μΜ, respectively. Analogues I and II exhibited an improved inhibitory activity compared with imatinib. Among the nilotinib analogues, V exhibited a 9-fold higher activity than nilotinib. All compounds were less efficient in inhibiting platelet aggregation towards ADP and TRAP-6. Similar results were obtained for the membrane expression of P-selectin. Molecular docking studies showed that the improved antiplatelet activity of nilotinib analogue V is primarily attributed to the number and the strength of hydrogen bonds. Conclusion: Our results show that there is considerable potential to develop synthetic analogues of imatinib and nilotinib, as TKIs with antiplatelet properties and therefore being suitable to target cancer progression and metastasis, as well as CAT by inhibiting platelet activation.
Alivertis, Dimitrios,Brentas, Alexios,Ntemou, Nikoleta,Pantazi, Despoina,Skobridis, Konstantinos,Tselepis, Alexandros D.
p. 4225 - 4238
(2019/12/25)

Synthesis of Imatinib by C-N Coupling Reaction of Primary Amide and Bromo-Substituted Pyrimidine Amine
A new method for imatinib synthesis is described by using the C-N coupling reaction of 4-(4-methylpiperazine-1-methyl)benzamide with N-(5-bromo-2-tolyl)-4-(3-pyridyl)pyrimidin-2-amine to form imatinib. In this synthetic route, the high efficiency and high selectivity of nano-ZnO as a catalyst is key to the mild hydrolysis of 4-(4-methylpiperazine-1-methyl)benzonitrile into the corresponding amide. The total imatinib yield was 51.3%, and the purity was 99.9%. This simple and effective synthetic pathway avoids gene-impurity production (as classified by the FDA Center for Drug Evaluation and Research), and the synthesis is environmentally friendly with a short reaction time.
Wang, Cuiling,Bai, Xiao,Wang, Rui,Zheng, Xudong,Ma, Xiumei,Chen, Huan,Ai, Yun,Bai, Yajun,Liu, Yifeng
p. 1918 - 1925
(2019/09/07)

Investigations into the potential role of metabolites on the anti-leukemic activity of imatinib, nilotinib and midostaurin
The efficacy and side-effects of drugs do not just reflect the biochemical and pharmacodynamic properties of the parent compound, but often comprise of cooperative effects between the properties of the parent and active metabolites. Metabolites of imatinib, nilotinib and midostaurin have been synthesised and evaluated in assays to compare their properties as protein kinase inhibitors with the parent drugs. The N-desmethylmetabolite of imatinib is substantially less active than imatinib as a BCR-ABL1 kinase inhibitor, thus providing an explanation as to why patients producing high levels of this metabolite show a relatively low response rate in chronic myeloid leukaemia (CML) treatment. The hydroxymethylphenyl and N-oxide metabolites of imatinib and nilotinib are only weakly active as BCR-ABL1 inhibitors and are unlikely to play a role in the efficacy of either drug in CML. The 3-(R)-HO-metabolite of midostaurin shows appreciable accumulation following chronic drug administration and, in addition to mutant forms of FLT3, potently inhibits the PDPK1 and VEGFR2 kinases (IC50 values 100 nM), suggesting that it might contribute to drug efficacy in acute myeloid leukaemia patients. The case studies discussed here provide further examples of how the synthesis and characterisation of metabolites can make important contributions to understanding the clinical efficacy of drugs.
Manley, Paul W.
p. 561 - 570
(2019/09/03)

Highly Site-Selective Metal-Free C-H Acyloxylation of Stable Enamines
A highly site-selective acyloxylation of stable enamines with PhI(OAc)2 under metal-free conditions to afford (E)-vinyl acetate derivatives in good to excellent yields is described. Depending on the judicious choice of the solvent system, either the α- or β-site-selective product could be obtained with high selectivity. For the α-site-selective product, the rearranged amide compound is obtained as the major product. This reaction proceeds under mild reaction conditions (room temperature, metal-free, and open-flask) and features a broad substrate scope.
Wang, Fei,Sun, Wangbing,Wang, Yixin,Jiang, Yaojia,Loh, Teck-Peng
supporting information
p. 1256 - 1260
(2018/02/23)

Copper-catalyzed C-S direct cross-coupling of thiols with 5-arylpenta-2,4-dienoic acid ethyl ester
A selective copper (Cu)-catalyzed C-S bond direct cross-coupling of thiols with 5-arylpenta-2,4-dienoic acid ethyl ester was developed. Notably, various biologically active 5-phenyl-3-phenylsulfanylpenta-2,4-dienoic acid ethyl ester derivatives were efficiently synthesized under moderate conditions. Finally, a plausible Cu(i)/Cu(iii) reaction mechanism was proposed.
Cai, Rongrong,Zhou, Zhuoda,Chai, Qianqian,Zhu, Yueer,Xu, Runsheng
p. 26828 - 26836
(2018/08/07)

COMPOUND OF 5-HYDROXYL-1,7-NAPHTHYRIDINE SUBSTITUTED BY ARYL OR HETEROARYL, PREPARATION METHOD THEREOF AND PHARMACEUTICAL USE THEREOF
Disclosed are a compound of the following formula (I) or a pharmaceutically acceptable salt thereof, a preparation method thereof, pharmaceutical compositions and uses thereof in the preparation of a medicine for inhibiting HIF prolyl hydroxylase or a medicine for promoting the generation of endogenous EPO, wherein in the formula (I), R1 and R2 are each independently hydrogen; R3 is hydrogen or C1-3 alkyl; and Ar is an aromatic ring or an heteroaromatic ring selected from a naphthalene ring, a pyridine ring, a thiophene ring, a furan ring and a substituted benzene ring.
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(2018/03/25)

Design, synthesis and anti-inflammatory activity of pyrimidine scaffold benzamide derivatives as epidermal growth factor receptor tyrosine kinase inhibitors
Novel serious of pyrimidine scaffold benzamide derivatives (9 a-k) were synthesized and characterized by IR, HRMS, and NMR. Docking study of compounds 9 g, 9 h exhibited H-bonding interacts with Met769 into ATP binding site of EGFR-TK which showed similar binding mode to Lapitinib (PDB code: 1M17). Results indicated the ability to potent and selective inhibitors of the Epidermal Growth Factor Receptor tyrosine kinase (EGFR-TK). The molecular electrostatic potential (MEP), frontier molecular orbitals (FMOs) and HOMO-LUMO energy gap of the title compounds were investigated by using the B3LYP/6-31G method. The synthesized compounds were screened for in vitro anti-inflammatory activity.
Thirumurugan,Lakshmanan, Sivalingam,Govindaraj, Dharman,Daniel Prabu, D. Sam,Ramalakshmi,Arul Antony
p. 541 - 550
(2018/06/20)

Synthesis of C5-tethered indolyl-3-glyoxylamide derivatives as tubulin polymerization inhibitors
A series of C5-tethered Indolyl-3-glyoxylamide derivatives were synthesized and evaluated for their in?vitro cytotoxic activity against DU145 (prostate), PC-3 (prostate), A549 (lung) and HCT-15 (colon) cancer cell lines by employing the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Among all the synthesized compounds, compound 7f displayed cytotoxicity of IC50?=?140?nM towards DU145 cancer cell line. The treatment of DU145?cells with 7f led to inhibition of cell migration ability. Futher, the detailed studies such as acridine orange/ethidium Bromide (AO/EB), DAPI, annexin V-FITC/propidium iodide staining assay suggested that the compound 7f induced apoptosis in DU145?cells. The influence of the cytotoxic compound 7f on the cell cycle distribution was assessed on the DU145?cell line, exhibiting a cell cycle arrest at the G2/M phase (hallmark of tubulin polymerization) and next inhibited tubulin polymerization with IC500.40?μM. Furthermore, the treatment with compound 7f caused collapse of mitochondrial membrane potential and elevated intracellular superoxide ROS levels in DU145?cells. Western blotting was performed to examine the levels of apoptotic proteins (Bcl-2 and Bax); the study confirmed that compound 7f induced apoptosis through apoptosis-related protein expression. Thus, these studies provided a new molecular scaffold for the further development of anticancer agents that target tubulin.
Guggilapu, Sravanthi Devi,Lalita, Guntuku,Reddy, T. Srinivasa,Prajapti, Santosh Kumar,Nagarsenkar, Atulya,Ramu, Shymala,Brahma, Uma Rani,Lakshmi, Uppa Jaya,Vegi, Ganga Modi Naidu,Bhargava, Suresh K.,Babu, Bathini Nagendra
p. 1 - 12
(2017/02/05)

Design, Synthesis, and Evaluation of the Kinase Inhibition Potential of Pyridylpyrimidinylaminophenyl Derivatives
In view of potent kinase inhibitors for the treatment of myriad human disorders, we synthesized some structurally variant amide/cyclic amide derivatives based on pyridylpyrimidinylaminophenyl amine, the key pharmacophore of the kinase inhibitor drug molecule, imatinib, and evaluated their kinase inhibition potency. Among the various synthesized amides, compound 20, a cyclic amide/pyridin-2(1H)-one derivative, exhibited an IC50 value comparable to that of the drug imatinib against c-Src kinase, and another compound (14) containing a 2-((4-methyl-2-oxo-2H-chromen-6-yl)oxy)acetamide demonstrated an IC50 value of 8.39 μM. Furthermore, the constitution of the cyclic amide derivative was confirmed by the single-crystal X-ray diffraction technique. These results may serve as a gateway for developing novel next-generation kinase inhibitors.
Manchanda, Priyanka,Parshad, Badri,Kumar, Amit,Tiwari, Rakesh K.,Shirazi, Amir N.,Parang, Keykavous,Sharma, Sunil K.
(2017/04/11)

Synthesis and biological evaluation of oxindole linked indolyl-pyrimidine derivatives as potential cytotoxic agents
In our endeavor towards the development of effective cytotoxic agents, a series of oxindole linked indolyl-pyrimidine derivatives were synthesized and characterized by IR, 1H NMR, 13C NMR and Mass spectral analysis. All the newly synthesized target compounds were assessed against PA-1 (ovarian), U-87MG (glioblastoma), LnCaP (prostate), and MCF-7 (Breast) cancer cell lines for their cytotoxic potential, with majority of them showing inhibitory activity at low micro-molar concentrations. Significantly, compound 8e was found to be most potent amongst all the tested compounds with an IC50 value of (2.43 ± 0.29 μM) on PA-1 cells. The influence of the most active cytotoxic compound 8e on the cell cycle distribution was assessed on the PA-1 cell line, exhibiting a cell cycle arrest at the G2/M phase. Moreover, acridine orange/ethidium bromide staining and annexin V binding assay confirmed that compound 8e can induce cell apoptosis in PA-1 cells. These preliminary results persuade further investigation on the synthesized compounds aiming to the development of potential cytotoxic agents.
Prajapti, Santosh Kumar,Nagarsenkar, Atulya,Guggilapu, Sravanthi Devi,Gupta, Keshav Kumar,Allakonda, Lingesh,Jeengar, Manish Kumar,Naidu,Babu, Bathini Nagendra
supporting information
p. 3024 - 3028
(2016/06/13)

An optimized approach in the synthesis of imatinib intermediates and analogues
We revisited the classical synthetic procedure for imatinib synthesis providing an improved and optimized approach in the preparation of a series of new imatinib analogues. The proposed methodology effectively overcomes certain problematic steps, saves time and labor, provides a very high yield and purity and has the potential to be used for the synthesis of many analogues. The formation of the desired guanidine salt 4, one of the key steps to the imatinib synthesis, was proceeded almost quantitatively by the reaction of the hydrochloride of the suitable aniline 3 with excess of molten cyanamide, without any solvent. Pure arylamine intermediates 6a-d were obtained quantitatively in a short reaction time after reduction of the nitro group of the intermediate pyrimidines 5a-d with hydrogen over the Adam's catalyst. In addition, the application of this optimized approach can be extended in the synthesis of nilotinib and its analogues intermediates.
Kinigopoulou,Filippidou,Gogou,Giannousi,Fouka,Ntemou,Alivertis,Georgis,Brentas,Polychronidou,Voulgari,Theodorou,Skobridis
p. 61458 - 61467
(2016/07/12)

A Practical Preparation of Imatinib Base
A practical preparation of imatinib base was reported in this article. Compared with reported works, the features of this work were the concise procedures, the industrially available starting materials, the avoidance of expensive or highly toxic transition-metal catalysts or reagents, and the genotoxic impurities 6-methyl-N 1-[4-(pyridin-3-yl)pyrimidin-2-yl]benzene-1,3-diamine and 4-(chloromethyl)-N-(4-methyl-3-{[4-(pyridin-3-yl)pyrimidin-2-yl]amino}phenyl)benzamide. The method was scalable to at least 100 mmol, and the products were separated by simple recrystallizations.
Zhang, Xu,Sun, Jingjing,Chen, Tian,Yang, Chenggen,Yu, Lei
p. 2233 - 2236
(2016/10/24)

Design and Performance Validation of a Conductively Heated Sealed-Vessel Reactor for Organic Synthesis
A newly designed robust and safe laboratory scale reactor for syntheses under sealed-vessel conditions at 250 °C maximum temperature and 20 bar maximum pressure is presented. The reactor employs conductive heating of a sealed glass vessel via a stainless steel heating jacket and implements both online temperature and pressure monitoring in addition to magnetic stirring. Reactions are performed in 10 mL borosilicate vials that are sealed with a silicone cap and Teflon septum and allow syntheses to be performed on a 2-6 mL scale. This conductively heated reactor is compared to a standard single-mode sealed-vessel microwave instrument with respect to heating and cooling performance, stirring efficiency, and temperature and pressure control. Importantly, comparison of the reaction outcome for a number of different synthetic transformations performed side by side in the new device and a standard microwave reactor suggest that results obtained using microwave conditions can be readily mimicked in the operationally much simpler and smaller conventionally heated device.
Obermayer, David,Znidar, Desiree,Glotz, Gabriel,Stadler, Alexander,Dallinger, Doris,Oliver Kappe
p. 11788 - 11801
(2016/12/09)

Aniline pyrimidine compound and its preparation and use
The invention belongs to the field of synthesis of medicaments, and relates to an aniline pyrimidine compound of a general formula (I), in particular to an N-[4-methyl-3-[[4-(3-pyridine)-2-pyrimidine] amino] phenyl]-benzamide of which the 4th site is substituted by a quaternary heterocyclic ring, a preparation method for the compound and application in medicine. In vitro anti-tumor activity test results show that the in vitro anti-tumor activity IC50 value of the compound on MKN-45 gastric cancer strains is nM level and the compound can obviously inhibit activity of tumor cells and can be used for preparing new anti-tumor medicaments.
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(2019/06/09)

PROCESS FOR THE PREPARATION OF SUBSTITUTED PYRIMIDINES
This invention relates to an improved process of making compounds of Formula (I) and synthetic intermediates thereof. (I) In particular, the invention relates to an improved process to prepare N-(2-aminophenyl)-4- ((pyrimidin-2-ylamino)methyl)benzamides which requires fewer steps, is efficient, can be used on an industrial scale, and results in a final product which is suitable for pharmaceutical use.
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(2015/02/02)

Enantioselective synthesis of α-secondary and α-tertiary piperazin-2- Ones and piperazines by catalytic asymmetric allylic alkylation
The asymmetric palladium-catalyzed decarboxylative allylic alkylation of differentially N-protected piperazin-2- ones allows the synthesis of a variety of highly enantioenriched tertiary piperazine-2-ones. Deprotection and reduction affords the corresponding tertiary piperazines, which can be employed for the synthesis of medicinally important analogues. The introduction of these chiral tertiary piperazines resulted in imatinib analogues which exhibited comparable antiproliferative activity to that of their corresponding imatinib counterparts.
Korch, Katerina M.,Eidamshaus, Christian,Behenna, Douglas C.,Stoltz, Brian M.,Nam, Sangkil,Horne, David
supporting information
p. 179 - 183
(2015/02/05)

DMF Dimethyl Acetal as Carbon Source for α-Methylation of Ketones: A Hydrogenation-Hydrogenolysis Strategy of Enaminones
A novel heterogeneous catalytic hydrogenation-hydrogenolysis strategy has been developed for the α-methylation of ketones via enaminones using DMF dimethyl acetal as carbon source. This strategy provides a very convenient route to α-methylated ketones using a variety of ketones without any base or oxidant. (Chemical Equation Presented).
Borah, Ashwini,Goswami, Limi,Neog, Kashmiri,Gogoi, Pranjal
p. 4722 - 4728
(2015/05/13)

Oligomer-protein tyrosine kinase inhibitor conjugates
The invention relates to (among other things) oligomer-PTK inhibitor conjugates and related compounds. A compound of the invention, when administered by any of a number of administration routes, exhibits advantages over PTK inhibitor compounds lacking a water-soluble, non-peptidic oligomer.
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(2015/09/22)

AN IMPROVED PROCESS FOR THE PREPARATION OF NILOTINIB AND PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF
The present invention relates to an improved process for the preparation of nilotinib and pharmaceutically acceptable salts thereof, with high purity and yields.
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(2015/06/25)

Synthesis and Biological Activity of Some Novel Aryl-Substituted 1,3,4-Oxadiazole Mannich Bases Containing Pyrimidine Rings
A series of novel Mannich base derivatives (E1-E15) of 5-aryl-1,3,4-oxadiazole-2-thione with substituted pyrimidine were synthesized and characterized by elemental analysis, IR, 1H-NMR. The antifungal activities of these compounds were also originally studied. The results showed that most of the title compounds exhibited relatively good fungicidal activities. Especially compounds E8 and E13 showed better antifungal activity than comparison compound hymexazol. The relationship of structure and activity revealed that the presence of the methyl group at four and six positions of pyrimidine ring remarkably enhanced the antifungal activity of title compounds.
Shen, Shengqiang,Sun, Xiaohong,Liu, Yuanfa,Chen, Bang,Jin, Ruyi,Ma, Haixia
p. 1296 - 1301
(2015/10/06)

Oxazolidinone Compounds and Their Uses in Preparation of Antibiotics
The invention belongs to the field of medicaments, and particularly relates to oxazolidinone compounds and their uses in the preparation of antibiotics. A technical problem to be solved by the invention is to provide new oxazolidinone compounds having the structure represented by Formula I. The oxazolidinone compounds of the invention, which are new compounds obtained through numerous screening, have significant antibacterial activity against bacteria such as drug-resistant staphylococcus aureus, fecal coliform bacteria, and streptococcus pneumoniae, while exhibiting low toxicity. The invention provides new options for the development and application of antibiotics.
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(2014/05/25)

OXAZOLIDINONE COMPOUNDS AND THEIR USES IN PREPARATION OF ANTIBIOTICS
The invention belongs to the field of medicaments, and particularly relates to oxazolidinone compounds and their uses in the preparation of antibiotics. A technical problem to be solved by the invention is to provide new oxazolidinone compounds having the structure represented by Formula I. The oxazolidinone compounds of the invention, which are new compounds obtained through numerous screening, have significant antibacterial activity against bacteria such as drug-resistant staphylococcus aureus, fecal coliform bacteria, and streptococcus pneumoniae, while exhibiting low toxicity. The invention provides new options for the development and application of antibiotics.
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(2014/06/24)

Imatinib intermediate as a two in one dual channel sensor for the recognition of Cu2+ and I- ions in aqueous media and its practical applications
An imatinib intermediate, 6-methyl-N-[4-(pyridin-3-yl)pyrimidin-2-yl] benzene-1,3-diaminepyridopyrimidotoluidine (PPT-1), was developed for the colorimetric sensing of Cu2+ ions in aqueous solution. With Cu 2+, the receptor PPT-1 showed a highly selective naked-eye detectable color change from colorless to red over the seventy other tested cations. The colorimetric sensing ability of PPT-1 was successfully utilized in the preparation of test strips and supported silica for the real samples analysis to detect Cu2+ ions from 100% aqueous environment. Moreover, the iodide-sensing ability of receptor PPT-1 was explored among the ten examined anions.
Patil, Samadhan R.,Nandre, Jitendra P.,Jadhav, Devising,Bothra, Shilpa,Sahoo,Devi, Manisha,Pradeep, Chullikkattil P.,Mahulikar, Pramod P.,Patil, Umesh D.
supporting information
p. 13299 - 13306
(2014/10/16)

Imatinib analogs as potential agents for PET imaging of Bcr-Abl and c-KIT expression at a kinase level
We synthesized two series of imatinib mesylate (STI-571) analogs to develop a Bcr-Abl and c-KIT receptor-specific labeling agent for positron emission tomography (PET) imaging to measure Bcr-Abl and c-KIT expression levels in a mouse model. The methods of molecular modeling, synthesis of STI-571 and its analogs, in vitro kinase assays, and radiolabeling are described. Molecular modeling revealed that these analogs bind the same Bcr-Abl and c-KIT binding sites as those bound by STI-571. The analogs potently inhibit the tyrosine kinase activity of Bcr-Abl and c-KIT, similarly to STI-571. [ 18F]-labeled STI-571 was prepared with high specific activity (75 GBq/μmol) by nucleophilic displacement and an average radiochemical yield of 12%. [131I]-labeled STI-571 was prepared with high purity (>95%) and an average radiochemical yield of 23%. The uptake rates of [ 18F]-STI-571 in K562 cells expressing Abl and in U87WT cells overexpressing c-KIT were significantly higher than those in the U87 cell and could be inhibited by STI-71 (confirming the specificity of uptake). PET scans of K562 and U87WT tumor-bearing mice with [18F]-STI-571 as a contrast agent showed visible tumor uptake and tumor-to-non-target contrast.
Peng, Zhenghong,Maxwell, David S.,Sun, Duoli,Bhanu Prasad, Basvoju A.,Pal, Ashutosh,Wang, Shimei,Balatoni, Julius,Ghosh, Pradip,Lim, Seok T.,Volgin, Andrei,Shavrin, Aleksander,Alauddin, Mian M.,Gelovani, Juri G.,Bornmann, William G.
p. 623 - 632
(2014/01/17)

Facile synthesis of 2-phenylquinoline-4-carboxamide derivatives with variant structural features
The quinoline scaffold is an important class of heterocyclic compounds that possesses diverse chemotherapeutic activities. Thus, the 2-phenylquinoline-4- carboxamide derivatives containing a variety of moieties, such as 2-(2-furanyl)-1,3,4-oxadiazole, N-(2-methylphenyl)-4-(3-pyridinyl)-2- pyrimidinamine, 4,4′-bithiazole, purine, adamantine and resorcinol, have been designed and synthesized via Suzuki coupling, acid-base coupling and other typical reactions.
Islam, Rafiqul,Hossain, Md. Imran,Okamoto, Yoshinari,Nagamatsu, Tomohisa,Anraku, Kensaku,Okawara, Tadashi
p. 693 - 708
(2014/04/03)

An expeditious synthesis of imatinib and analogues utilising flow chemistry methods
A flow-based route to imatinib, the API of Gleevec, was developed and the general procedure then used to generate a number of analogues which were screened for biological activity against Abl1. The flow synthesis required minimal manual intervention and was achieved despite the poor solubility of many of the reaction components.
Hopkin, Mark D.,Baxendale, Ian R.,Ley, Steven V.
supporting information
p. 1822 - 1839
(2013/04/23)

Synthesis and antibacterial activity of a series of heterocyclic sulfonate ligands and their metal complexes
A series of heterocyclic sulfonate ligands and their barium(II), silver(I), manganese(II), zinc(II) and cobalt(II) coordination compounds have been synthesized. Through antibacterial activities experiments of these complex compounds, metal salts as well as ligands, the rational conclusion is arrived that antibacterial activities of these compounds come from metal ions.
Dong, Hua-Ze,Feng, Xiao-Jun,Dai, Bi-Sheng,Su, Cheng-Bai,Zheng-Zheng,Wang, Lin
p. 2035 - 2037
(2013/05/09)

Design and synthesis of minimalist terminal alkyne-containing diazirine photo-crosslinkers and their incorporation into kinase inhibitors for cell- and tissue-based proteome profiling
Less is more: A minimalist "clickable" photo-crosslinker (see scheme) was incorporated with numerous small-molecule kinase inhibitors. The resulting probes were used for both in vitro (cell lysates) and in situ (live cells) proteome profiling, for large-scale identification of their potential cellular kinase targets and shows improved outcomes over previous probes. Copyright
Li, Zhengqiu,Hao, Piliang,Li, Lin,Tan, Chelsea Y. J.,Cheng, Xiamin,Chen, Grace Y. J.,Sze, Siu Kwan,Shen, Han-Ming,Yao, Shao Q.
supporting information
p. 8551 - 8556
(2013/09/12)

L-proline-catalyzed activation of methyl ketones or active methylene compounds and DMF-DMA for syntheses of (2E)-3-dimethylamino-2- propen-1-ones
A cascade organocatalysis is reported for the nucleophilic and electrophilic dual activation taking place in the reaction of methyl ketones or active methylene compounds with DMF-DMA (N,N-dimethylformamide dimethyl acetal). L-Proline serves as an efficient organocatalyst in the covalent and noncovalent synchronous mode for the ambiphilic activation of various aryl, heteroaryl, and styryl methyl ketones, cyclic ketones, and 1,3-diketones with DMF-DMA to achieve the convenient syntheses of the versatile synthons (2E)-1-aryl/ heteroaryl/styryl-3-(dimethylamino)-2-propen-1-ones, (E)-α- [(dimethylamino)formylidene]cycloalkanones, and (E)-2-(dimethylamino) formylidene-1,3-diketones in high yields under solvent-free conditions.
Kumar, Dinesh,Kommi, Damodara N.,Chopra, Pradeep,Ansari, Md Imam,Chakraborti, Asit K.
p. 6407 - 6413,7
(2020/09/16)

Synthesis and antimicrobial activity of novel 7-(Heteroaryl)-1,2,4- triazolo[1,5-a]-pyrimidine derivatives
The synthesis, characterization and antimicrobial activity of novel 1,2,4-triazolo[1,5-a]pyrimidines have been reported. The compounds were prepared by acid catalyzed condensation of 3-amino-1,2,4-triazole with 3-(dialkylamino)acryloalkanone.
Rama Rao, R. Janaki,Rao, A.K.S. Bhujanga,Swapna,Rani, B. Baby,Murthy
experimental part
p. 1837 - 1843
(2012/08/07)

Completely N1-selective palladium-catalyzed arylation of unsymmetric imidazoles: Application to the synthesis of nilotinib
The completely N1-selective Pd-catalyzed arylation of unsymmetric imidazoles with aryl halides and triflates is described. This study showed that imidazoles have a strong inhibitory effect on the in situ formation of the catalytically active Pd(0)-ligand complex. The efficacy of the N-arylation reaction was improved drastically by the use of a preactivated solution of Pd2(dba)3 and L1. From these findings, it is clear that while imidazoles can prevent binding of L1 to Pd, once the ligand is bound to the metal, these heterocycles do not displace it. The utility of the present catalytic system was demonstrated by the regioselective synthesis of the clinically important tyrosine kinase inhibitor nilotinib.
Ueda, Satoshi,Su, Mingjuan,Buchwald, Stephen L.
supporting information; experimental part
p. 700 - 706
(2012/03/07)

Facile synthesis of 6-aryl-3-cyanopyridine-2-(1H)-thiones from aryl ketones
An improved synthesis of 6-aryl-3-cyanopyridine-2-(1H)-thiones utilizing enaminones as starting materials catalyzed by 1,4-diazabicyclo[2.2.2]octane (DABCO) was described. Moreover, a convenient one-pot conversion of aryl ketones to 6-aryl-3-cyanopyridine-2-(1H)-thiones was also developed in moderate to good yields (up to 80%). Copyright Taylor & Francis Group, LLC.
Zheng, Ren-Lin,Zeng, Xiu-Xiu,He, Hai-Yun,He, Jun,Yang, Sheng-Yong,Yu, Luo-Ting,Yang, Li
experimental part
p. 1521 - 1531
(2012/04/17)

A "catch-react-release" method for the flow synthesis of 2-aminopyrimidines and preparation of the imatinib base
The development of a monolith-supported synthetic procedure is reported, taking advantage of flow processing and the superior flow characteristics of monolithic reagents over gel-phase beads, to allow facile access to an important family of 2-aminopyrimidine derivatives. The process has been successfully applied to a key precursor on route to Imatinib (Ar = 3-pyridyl, R1 = 2-methyl-5-nitrobenzyl, R2 = H).
Ingham, Richard J.,Riva, Elena,Nikbin, Nikzad,Baxendale, Ian R.,Ley, Steven V.
supporting information; experimental part
p. 3920 - 3923
(2012/09/22)

Efficient organocatalytic dual activation strategy for preparing the versatile synthons (2 E)-1-(Het)aryl/styryl-3-(dimethylamino)prop-2-en-1-ones and -(E)-[(dimethylamino)methylene]cycloalkanones
A novel organocatalytic dual activation strategy is reported for an efficient synthesis of the versatile synthons (2E)-1-aryl/heteroaryl/styryl-3- (dimethylamino)prop-2-en-1-ones and -(E)-[(dimethylamino)methylene] cycloalkanones. 2-Guanidinoacetic acid (10 mol%) serves as an ambifunctional organocatalyst for the reaction of various aryl/heteroaryl/styryl methyl ketones and cyclic ketones having an -methylene moiety with N,N-dimethylformamide dimethyl acetal at 100 C for 1-3 hours under solvent-free conditions to afford the corresponding (2E)-3-(dimethylamino)prop-2-en-1-ones in 72-95% yields. Georg Thieme Verlag Stuttgart - New York.
Bindal, Sachin,Kumar, Dinesh,Kommi, Damodara N.,Bhatiya, Sonam,Chakraborti, Asit K.
experimental part
p. 1930 - 1935
(2011/07/31)

N-[2-methyl-5-(triazol-1-yl)phenyl]pyrimidin-2-amine as a Scaffold for the synthesis of inhibitors of Bcr-Abl
N-[2-Methyl-5-(triazol-1-yl)phenyl]pyrimidin-2-amine derivatives were synthesized and evaluated invitro for their potential use as inhibitors of Bcr-Abl. The design is based on the bioisosterism between the 1,2,3-triazole ring and the amide group. The synthesis involves a copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) as the key step, with the exclusive production of anti-(1,4)-triazole derivatives. One of the compounds obtained shows general activity similar to that of imatinib; in particular, it was observed to be more effective in decreasing the fundamental function of cdc25A phosphatases in the K-562 cell line. Willing and Abl inhibitors! N-[2-Methyl-5-(triazol-1-yl)phenyl]pyrimidin-2-amine derivatives were synthesized by a copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) as a key step, with anti-(1,4)-triazole derivatives as the exclusive products. One of these compounds shows general activity similar to that of imatinib, and in particular, it is more effective in decreasing the fundamental function of cdc25A phosphatases in the K-562 cell line.
Arioli, Federica,Borrelli, Stella,Colombo, Francesco,Falchi, Federico,Filippi, Irene,Crespan, Emmanuele,Naldini, Antonella,Scalia, Giusy,Silvani, Alessandra,Maga, Giovanni,Carraro, Fabio,Botta, Maurizio,Passarella, Daniele
experimental part
p. 2009 - 2018
(2012/06/30)

PROCESSES FOR PREPARING IMATINIB AND PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF
The processes for preparing imatinib and its pharmaceutically acceptable salts, specifically imatinib mesylate, are disclosed.
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Page/Page column 14

(2011/04/25)

Synthesis and apoptosis inducing ability of new anilino substituted pyrimidine sulfonamides as potential anticancer agents
A series of anilino substituted pyrimidine sulfonamides were prepared and evaluated for their anticancer activity. These sulfonamides showed promising activity with IC50 values ranging from 5.6 to 12.3 μM. The detailed biological aspects of some of the promising compounds (3d, 3e and 3g) on the K562 cell line were studied. Interestingly, compounds induced G1 cell cycle arrest and down regulation of G1 phase cell cycle regulatory proteins such as cyclin D1, CDK4. These compounds also exhibited inhibition of NF-κB as well as its downstream target gene Akt1 and the phosphorylated form of AKt ser 474 proteins. One of the representative compound 3e could be considered as the potential lead for its development as a new anticancer agent.
Kamal, Ahmed,Dastagiri,Janaki Ramaiah,Surendranadha Reddy,Vijaya Bharathi,Kashi Reddy,Victor Prem Sagar,Lakshminarayan Reddy,Pushpavalli,Pal-Bhadra, Manika
experimental part
p. 5817 - 5824
(2011/12/22)

Synthesis and antibacterial activity of novel 5-(heteroaryl)isoxazole derivatives
The synthesis, characterization and antibacterial activity of novel isoxazole derivatives were reported. 3-Di (alkylamino)acryloalkanones were prepared and used as synthons to get the target isoxazole derivatives via reaction with hydroxylamine hydrochloride or hydroxylamine-O-sulphonic acid.
RamaRao, R. Janaki,Rao, A.K.S. Bhujanga,Sreenivas,Kumar, B. Suneel,Murthy
experimental part
p. 243 - 250
(2011/06/26)

PYRONE COMPOUND AND ITS USE FOR PEST CONTROL
A pyrone compound represented by formula (1) has an excellent controlling effect on pests. Since the compound of formula (1) has a controlling activity on pests, the compound is useful as an active ingredient of a pest control agent.
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Page/Page column 287-288

(2011/05/06)

ALGORITHM FOR DESIGNING IRREVERSIBLE INHIBITORS
The invention is an algorithm and method for designing an inhibitor that covalently binds a target polypeptide. The algorithm and method can be used to rapidly and efficiently convert reversible inhibitors into irreversible inhibitors.
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(2010/08/07)

Novel imatinib derivatives with altered specificity between Bcr-Abl and FMS, KIT, and PDGF receptors
Imatinib is a clinically important ATP analogue inhibitor that targets the tyrosine kinase domain of the intracellular Abl kinase and the PDGF receptor family. Imatinib has revolutionised the treatment of chronic myeloid leukaemia, which is caused by the oncogene Bcr-Abl and certain solid tumours that harbor oncogenic mutations of the PDGF receptor family. As a leading kinase inhibitor, imatinib also provides an excellent model system to investigate how changes in drug design impact biological activity, which is an important consideration for rational drug design. Herein we report a new series of imatinib derivatives that in general have greater activity against the family of PDGF receptors and poorer activity against Abl, as a result of modifications of the phenyl and N-methylpiperazine rings. These new compounds provide a platform for further drug development against the therapeutically important PDGF receptor family and they also provide insight into the engineering of drugs with altered biological activity.
Skobridis, Konstantinos,Kinigopoulou, Maria,Theodorou, Vassiliki,Giannousi, Emilia,Russell, Alison,Chauhan, Rakhee,Sala, Roberta,Brownlow, Nicola,Kiriakidis, Serafim,Domin, Jan,Tzakos, Andreas G.,Dibb, Nick J.
scheme or table
p. 130 - 139
(2010/11/02)