- Synthesis and antibacterial activity of thienopyrimidine amide derivatives
-
Thienopyrimidine amide derivatives are important class of organic compounds and show wide range of biological activity. Hence the researchers are paying more attention towards the synthesis of these compounds. A series of thienopyrimidine amide derivatives (13a-m) were synthesized. The newly synthesized amide derivatives (13a-m) were characterized by 1H NMR, 13C NMR, Mass and IR spectral data. Further these compounds were also evaluated for their antibacterial activity.
- Tharikoppula, Giri,Eppakayala, Laxminarayana,Maringanti, Thirumala Chary,Kamalapuram, Chiranjeevi,Kudle, Karunakar Rao
-
-
Read Online
- Synthesis of 5-alkoxythieno[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine derivatives and evaluation of their anticonvulsant activities
-
This work concerns the design and synthesis of novel, substituted 5-alkoxythieno[2,3-e][1,2,4]triazolo[4,3-c ]pyrimidine derivatives 5a-p prepared from 3-amino-2-thiophenecarboxylic acid methyl ester. The final compounds were screened for their in vivo anticonvulsant activity using maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) tests. Neurotoxicity (NT) was tested using a rotarod test. The structure-anticonvulsant activity relationship analysis revealed that the most effective structural motif involves a substituted phenol, especially when substituted with a single chlorine, fluorine or trifluoromethyl group (at the meta-position), or two chlorine atoms. These molecules possessed high activity according to the MES and scPTZ models. Quantitative assessment of the compounds after intraperitoneal administration in mice showed that the most active compound was 5-[3-(trifluoromethyl)phenoxy]thieno[2,3-e] [1,2,4]triazolo[4,3-c]pyrimidine (5o) with ED50 values of 11.5 mg/kg (MES) and 58.9 mg/kg (scPTZ). Furthermore, compound 5o was more effective in the MES and scPTZ tests than the well-known anticonvulsant drugs carbamazepine and ethosuximide.
- Wang, Shi-Ben,Piao, Guang-Chun,Zhang, Hong-Jian,Quan, Zhe-Shan
-
-
Read Online
- Synthesis, crystal and antiproliferative activity of 2-[2-(2-fluorobenzylidene) hydrazinyl]-4-(1-methyl-1H-indol-3-yl)thieno[3,2-d]pyrimidine
-
The title compound 2-[2-(2-fluorobenzylidene)hydrazinyl]-4-(1-methyl-1H-indol-3-yl) thieno[3,2-d]pyrimidine (C22H16FN5S) was prepared and its structure was confirmed by IR, 1H NMR, MS, elemental analyses and X-ray diffraction. The crystal of the title compound belongs to the monoclinic system, space group P21/c with a = 14.4546(17) ?, b = 17.0895(19) ?, c = 17.9621(15) ?, α = 90°, β = 122.717(6), γ = 90°, V = 3733.1(7) ?3, Z = 4, and R = 0.0412 for 4816 observed reflections with I > 2σ(I). In addition, the compound possesses distinct effective inhibition on the proliferation of HT-29, A549 and MKN45 cell lines.
- Chen, Ye,Ding, Shi,Gong, Yi-Lin,Liu, Ju,Shi, Jian–Tao
-
-
Read Online
- Antiproliferative activities of halogenated thieno[3,2-d]pyrimidines
-
The in vitro evaluation of thieno[3,2-d]pyrimidines identified halogenated compounds 1 and 2 with antiproliferative activity against three different cancer cell lines. A structure activity relationship study indicated the necessity of the chlorine at the C4-position for biological activity. The two most active compounds 1 and 2 were found to induce apoptosis in the leukemia L1210 cell line. Additionally, the compounds were screened against a variety of other microbial targets and as a result, selective activity against several fungi was also observed. The synthesis and preliminary biological results are reported herein.
- Temburnikar, Kartik W.,Zimmermann, Sarah C.,Kim, Nathaniel T.,Ross, Christina R.,Gelbmann, Christopher,Salomon, Christine E.,Wilson, Gerald M.,Balzarini, Jan,Seley-Radtke, Katherine L.
-
-
Read Online
- Synthesis and antibacterial activity of novel 4-{4-(methylamino)thieno[3,2-d]pyrimidin-2-yl}-benzohydrazide derivatives
-
A series of novel 4-{4-(methylamino)thieno[3,2-d]pyrimidin-2-yl}benzohydrazide derivatives were synthesized and evaluated for their antibacterial activity. Most of the compounds demonstrated high activity towards Escherichia coli, Pseudomonas, Staphylococcus aureus, and Bacillus. Structures of all synthesized compounds were confirmed by spectral analysis.
- Giri,Sailaja,Laxminarayana,Thirumala Chary,Ramesh
-
-
Read Online
- N-{2-[(2-chlorothieno[3,2-d]pyrimidin-4-yl)amino]ethyl}-3-methoxybenzamide: design, synthesis, crystal structure, antiproliferative activity, DFT, Hirshfeld surface analysis and molecular docking study
-
The compound N-{2-[(2-chlorothieno[3,2-d]pyrimidin-4-yl)amino]ethyl}-3-methoxybenzamide (8) was synthesized by the condensation of 3-methoxybenzoic acid (7) with N 1-(2-chlorothieno[3,2-d]pyrimidin-4-yl)ethane-1,2-diamine (6). This intermediate was prepared from methyl 3-aminothiophene-2-carboxylate (1) by the condensation with urea, chlorination with phosphorus oxychloride and then condensation with ethane-1,2-diamine. The crystal structure of the title compound was determined and the crystal of the title compound belongs to the tetragonal system, space group P4(3) with a = 9.4694(10) ?, b = 9.4694(10) ?, c = 18.886(3) ?, α = 90°, β = 90°, γ = 90°. The optimized geometric bond lengths and bond angles obtained by using density functional theory (DFT) have been compared with X-ray diffraction values. The calculated HOMO and LUMO energies showed the character of the title compound. The molecular electrostatic potential (MEP) surface map of the related molecule was investigated with theoretical calculations at the B3LYP/6-311 + G(d,p) levels. A quantitative analysis of the intermolecular interactions in the crystal structures has been performed using Hirshfeld surface analysis. In addition, the title compound possesses marked inhibition against the proliferation of human colon cancer cell line HT-29 (IC50 = 1.76 μM), human lung adenocarcinoma cell line A549 (IC50 = 1.98 μM) and human gastric cancer cell line MKN45 (IC50 = 2.32 μM), displaying promising anticancer activitiy. The molecular docking studies revealed that the title compound may exhibit activity inhibiting PDB:3D15. Communicated by Ramaswamy H. Sarma.
- Huang, Pei,Zhao, Juan,Gao, Yan-Hong,Jin, Ling-Xia,Wang, Qin,Yu, Xiao-Hu,Ji, Xiao-Hui,Lu, Jiu-Fu
-
-
Read Online
- Antagonists of the human adenosine A2A receptor. Part 2: Design and synthesis of 4-arylthieno[3,2-d]pyrimidine derivatives
-
We describe herein the discovery and development of a series of 4-arylthieno[3,2-d]pyrimidines which are potent adenosine A2A receptor antagonists. These novel compounds show high degrees of selectivity against the human A1, A2B and A3 receptor sub-types. Moreover, a number of these compounds show promising activity in vivo, suggesting potential utility in the treatment of Parkinson's disease.
- Gillespie, Roger J.,Cliffe, Ian A.,Dawson, Claire E.,Dourish, Colin T.,Gaur, Suneel,Giles, Paul R.,Jordan, Allan M.,Knight, Antony R.,Lawrence, Anthony,Lerpiniere, Joanne,Misra, Anil,Pratt, Robert M.,Todd, Richard S.,Upton, Rebecca,Weiss, Scott M.,Williamson, Douglas S.
-
-
Read Online
- Synthesis and anticancer activities of thieno[3,2-d]pyrimidines as novel HDAC inhibitors
-
A series of thieno[3,2-d]pyrimidines bearing a hydroxamic acid moiety as novel HDAC inhibitors were designed and synthesized. The structures of the new synthesized compounds were confirmed using IR, 1H, 13C NMR spectrum. Compounds 11-13 showed potent inhibitory activities against HDACs with IC50 values at 0.38, 0.49 and 0.61 μM. Most of target compounds displayed strong anti-proliferative activity by a MTT assay on three human cancer cell lines including HCT-116, MCF-7 and HeLa. Compound 11, having potent inhibitory activities against HDACs, induced apoptosis and G2/M cell cycle arrest in HCT-116 cell line.
- Tan, Qiu,Zhang, Zhitao,Hui, Jie,Zhao, Yu,Zhu, Li
-
-
Read Online
- PARP-1/PI3K double-target inhibitor or pharmaceutically acceptable salt thereof, preparation method and application thereof
-
The invention discloses a PARP-1/PI3K double-target inhibitor or a pharmaceutically acceptable salt thereof, a preparation method and application thereof. According to the invention, the single active component can play a dual inhibition role on PARP-1 and PI3K, so that the dosage is reduced, the treatment effect is improved, and the toxic and side effects are reduced; and the dual inhibition effect on PARP-1 and PI3K is significant, the IC50 value of each target does not exceed 1.0 [mu]M, and the drug using the PARP-1/PI3K double-target inhibitor as the active component can be used for treating a variety of cancers or tumors related to PARP-1 and/or PI3K.
- -
-
Paragraph 0157-0161; 0191-0194
(2021/07/01)
-
- Identification of Thieno[3,2- d]pyrimidine Derivatives as Dual Inhibitors of Focal Adhesion Kinase and FMS-like Tyrosine Kinase 3
-
Focal adhesion kinase (FAK) is overexpressed in highly invasive and metastatic cancers. To identify novel FAK inhibitors, we designed and synthesized various thieno[3,2-d]pyrimidine derivatives. An intensive structure-activity relationship (SAR) study led
- Cho, Hanna,Choi, Hwan Geun,Jeon, Eunhye,Kim, Nam Doo,Kim, Sunghoon,Kim, Younghoon,Kwon, Nam Hoon,Lee, Jiwon,Moon, Youngji,Ryu, Seongshick,Shin, Injae,Sim, Taebo,Song, Chiman,Yoon, Hojong
-
p. 11934 - 11957
(2021/08/20)
-
- Discovery of novel and potent PARP/PI3K dual inhibitors for the treatment of cancer
-
PARP inhibitors have achieved great success in cancers with BRCA mutations, but only a small portion of patients carry BRCA mutations, which results in their narrow indication spectrum. Recently, emerging evidence has demonstrated that combinations of PARP and PI3K inhibitors could evoke unanticipated synergistic effects in various cancers, even including BRCA-proficient ones. In this work, a series of PARP/PI3K dual inhibitors were designed, synthesized, and evaluated for their biological activities. It was found that compounds 9a and 23a exhibited excellent inhibitory activities against PARP-1 (9a: IC50 = 1.57 nM, 23a: IC50 = 0.91 nM) and PI3Kα (9a: IC50 = 2.0 nM, 23a: IC50 = 1.5 nM), and showed promising antiproliferative activities against both BRCA-deficient (HCT-116, HCC-1937) and BRCA-proficient (SW620, MDA-MB-231/468) tumor cells. 9a and 23a also exhibited considerable in vivo antitumor efficacy in an MDA-MB-468 xenograft mouse model, with TGI values of 56.39% and 48.77%, respectively. Additionally, 23a possessed promising profiles including high kinase selectivity and low cardiotoxicity. Overall, this work indicates 9a and 23a might be potential PARP/PI3K dual inhibitors for cancer therapy and deserve further research.
- Wu, Zhengyang,Bai, Ying,Jin, Jiaming,Jiang, Teng,Shen, Hui,Ju, Qiurong,Zhu, Qihua,Xu, Yungen
-
-
- Design, synthesis and biological evaluation of thieno[3,2-d]pyrimidine derivatives containing aroyl hydrazone or aryl hydrazide moieties for PI3K and mTOR dual inhibition
-
Recently, PI3K and mTOR have been regarded as promising targets for cancer treatment. Herein, we designed and synthesized four series of novel thieno[3,2-d]pyrimidine derivatives that containing aroyl hydrazone or aryl hydrazide moieties. These derivatives act as PI3K/mTOR dual inhibitors, suggesting that they can be used as cancer therapeutic agents. All compounds were tested for anti-proliferative activity against four cancer cell lines. The structure-activity relationship (SAR) studies were conducted by varying the moieties at the C-6 and C-2 positions of the thieno[3,2-d]pyrimidine core. It indicated that aryl hydrazide at C-6 position and 2-aminopyrimidine at C-2 position are optimal fragments. Compound 18b showed the most potent in vitro activity (PI3Kα IC50 = 0.46 nM, mTOR IC50 = 12 nM), as well as good inhibition against PC-3 (human prostate cancer), HCT-116 (human colorectal cancer), A549 (human lung adenocarcinoma) and MDA-MB-231 (human breast cancer) cell lines. Furthermore, Annexin-V and propidium iodide (PI) double staining confirmed that 18b induces apoptosis in cytotoxic HCT-116 cells. Moreover, the influence of 18b on cell cycle distribution was assessed on the HCT-116 cell line, and a cell cycle arrest was observed at the G1/S phases.
- Dong, Jiawen,Fu, Siyu,Han, Yufei,Hou, Yunlei,Jiang, Jia,Qin, Mingze,Tian, Ye,Wang, Ruxin,Zhao, Yanfang
-
-
- Design, synthesis and antitumor activity of novel thiophene-pyrimidine derivatives as EGFR inhibitors overcoming T790M and L858R/T790M mutations
-
Five series of novel thiophene-pyrimidine derivatives (9a-h, 10a-f, 11a-f, 12a-f, 13a-f) have been synthesized and tested for their anti-proliferative activity against several cancer cell lines in which EGF is highly expressed. Most of the target compounds showed excellent activity against one or more cancer cell lines. The most promising compound 13a, of which IC50 values on of cell lines A549 and A431 (4.34 ± 0.60 μM and 3.79 ± 0.57 μM) were similar to the lead compound Olmutinib, showed strong activity and selectivity to EGFRT790M and EGFRT790M/L858R. Inhibition data of human normal hepatoma cell line LO2 indicated that most target compounds were less toxic to normal cells and had selective inhibitory effects on cancer cells. In addition, the structure-activity relationship was analyzed and the mechanism of apoptosis induced by the 13a was studied. The results showed that compound 13a induced late apoptosis of A431 cancer cells in a dose-dependent manner.
- Xiao, Zhen,Zhou, Zhihui,Chu, Cilong,Zhang, Qian,Zhou, Lingjia,Yang, Zunhua,Li, Xin,Yu, Liying,Zheng, Pengwu,Xu, Shan,Zhu, Wufu
-
-
- COMBINATION THERAPY WITH A PHOSPHOINOSITIDE 3-KINASE INHIBITOR WITH A ZINC BINDING MOIETY
-
The invention provides a method of treating cancer in a subject in need thereof, comprising administering to the subject: (a) a compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein R is hydrogen or an acyl group; and (b) a PD-1 signaling inhibitor; wherein the compound of Formula I or pharmaceutically acceptable salt thereof and the PD-1 signaling inhibitor are administered in amounts which in combination are therapeutically effective. The invention further provides a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, a PD-1 signaling inhibitor and a pharmaceutically acceptable carrier or excipient.
- -
-
Paragraph 0087; 0099-0100
(2020/04/09)
-
- Preparation method of thienopyrimidine compounds and application thereof
-
The invention relates to thienopyrimidine derivatives as shown in a general formula I, pharmaceutically acceptable salts or prodrugs and a preparation method thereof, which belong to the technical field of medicinal chemistry. In the general formula I, substituent groups L and R2 have meanings given in the specification. The invention also relates to a compound shown in the general formula I, which has a strong effect of inhibiting PI3K. The invention also relates to an application of the compounds and pharmaceutically acceptable salts, solvates or prodrugs thereof in preparation of drugs fortreating and/or preventing diseases caused by abnormal high expression of PI3K, especially the application in preparation of drugs for treating and/or preventing cancers.
- -
-
Paragraph 0057-0059
(2020/05/05)
-
- Design, synthesis and biological evaluation of novel 2,4-bismorpholinothieno[3,2-d]pyrimidine and 2-morpholinothieno[3,2-d]pyrimidinone derivatives as potent antitumor agents
-
To develop novel therapeutic agents with anticancer activities, two series of novel 2,4-bismorpholinyl-thieno[3,2-d]pyrimidine and 2-morpholinothieno[3,2-d]pyrimidinone derivatives were designed, synthesized and evaluated for their biological activities. Among them, compound A12 showed the most potent antitumor activities against HCT116, PC-3, MCF-7, A549 and MDA-MB-231 cell lines with IC50 values of 3.24 μM, 14.37 μM, 7.39 μM, 7.10 μM, and 16.85 μM, respectively. Further explorations in bioactivity were conducted to clarify the anticancer mechanism of compound A12. The results showed that compound A12 obviously inhibited the proliferation of A549 cell lines and decreased mitochondrial membrane potential, which led to the apoptosis of cancer cells and suppressed the migration of tumor cells.
- Ye, Tianyu,Han, Yufei,Wang, Ruxin,Yan, Pingzhen,Chen, Shaowei,Hou, Yunlei,Zhao, Yanfang
-
-
- Discovery of an Orally Active and Long-Acting DPP-IV Inhibitor through Property-Based Optimization with an in Silico Biotransformation Prediction Tool
-
Long-acting dipeptidyl peptidase IV inhibitors have emerged as promising molecules for interventions for type 2 diabetes. Once weekly dosing brings greater patient compliance and more stable glycemic control. Starting from our previous highly potent compound with a thienoprimidine scaffold, which is unfortunately severely hit by hepatic biotransformation, a lead compound was rapidly generated by drawing on the experience of our previously discovered long-acting compounds with pyrrolopyrimidine scaffold. With the aid of an in silico biotransformation prediction tool, (R)-2-((2-(3-aminopiperidin-1-yl)-4-oxo-6-(pyridin-3-yl)thieno[3,2-d]pyrimidin-3(4H)-yl)methyl)-4-fluorobenzonitrile was eventually generated and determined to have high potency, a fine pharmacokinetic profile, and a long-acting in vivo efficacy.
- Zeng, Shaogao,Dou, Wenyuan,Li, Manna,Zhou, Yang,Guo, Jiehuang,Zhao, Nan,Huang, Hong,Zhou, Qiaoli,Hu, Wenhui,Ma, Yanfang,Zhao, Xin,Xie, Hui
-
supporting information
p. 1608 - 1617
(2020/07/06)
-
- NOVEL TRYPTOPHAN HYDROXYLASE INHIBITOR AND PHARMACEUTICAL COMPOSITION INCLUDING SAME
-
The present invention relates to a novel tryptophan hydroxylase inhibitor and a pharmaceutical composition including same, wherein the novel tryptophan hydroxylase inhibitor has an excellent inhibitory effect on TPH1, and thus can be usefully used for the prevention or treatment of disorders, such as metabolic disorders, cancer, digestive or cardiovascular system disorders, related to TPH1 activity. In particular, the novel tryptophan hydroxylase inhibitor has an excellent treatment effect on inflammatory bowel disorders, and thus can be usefully used for the treatment of inflammatory bowel disorder.
- -
-
Paragraph 0174-0175
(2020/07/15)
-
- Thieno [3,2-d] pyrimidine derivative containing indole structure and application thereof
-
The invention belongs to the technical field of medication and relates to a novel thieno [3,2-d] pyrimidine derivative containing indole structure shown as structural formula (I), a medicinal acidulation salt and an application thereof. A pharmacological activity screening result shows that the thieno [3,2-d] pyrimidine derivative containing indole structure has an obvious inhibiting effect on human lung adenocarcinoma cells A549, human gastric carcinoma cells MKN-45 and human colon cancer cells HT-29 and has an excellent development and application prospect in researching antitumor drugs.
- -
-
Paragraph 0054; 0055
(2019/06/30)
-
- Novel thienopyrimidine derivative and application thereof [3,2-d] (by machine translation)
-
The invention belongs to, the field (I) of medicines, and particularly relates to a novel thienopyrimidine derivative [3,2 - d] with the structure shown. in the general (I) formula (, I) (I) and a pharmacological activity screening result of the compound. represented n by Ar the general formula shown. in the specification MKN45, A549 HT29. (by machine translation)
- -
-
Paragraph 0044-0045
(2020/01/03)
-
- Follow on-based optimization of the biphenyl-DAPYs as HIV-1 nonnucleoside reverse transcriptase inhibitors against the wild-type and mutant strains
-
The present work follows our preliminary discovery of biphenyl diarylpyrimidines (DAPYs) as HIV-1 nonnucleoside reverse transcriptase inhibitors. Further structural optimization of biphenyl-DAPYs led to the identification of a new series of biphenyl-substituted thiophene[3,2-d]pyrimidine analogues by a scaffold-hopping strategy. Biological evaluation of this series showed that these compounds possessed up to single-digit nanomolar potency (EC50 = 7.8–526.2 nM) and prominently low toxicity (CC50 = 18.5–280.8 μM) against wild-type (WT) HIV-1-infected cells. Furthermore, the results also demonstrated that compounds 29–32 exhibited high, broad-spectrum antiviral effects against clinically observed HIV-1 mutants. Specifically, compound 30, which had the highest selectivity index (SI = 16094) and the best anti-reverse transcriptase ability (IC50 = 39 nM), displayed marked inhibitory activity (EC50 = 13.5, 9.4, 17.0, 52.0, and 58.2 nM) against WT, K103N, E138K, L100I, Y181C mutants and moderate activity against double mutants. This study provides important avenues for the further design of HIV-1 inhibitors.
- Sang, Yali,Han, Sheng,Han, Shuwen,Pannecouque, Christophe,De Clercq, Erik,Zhuang, Chunlin,Chen, Fener
-
-
- Thienopyrimidinone compound or pharmaceutically-acceptable salt thereof and preparation method and application thereof
-
The invention provides a thienopyrimidinone compound or pharmaceutically-acceptable salt thereof and a preparation method and application thereof. The thienopyrimidinone compound or the pharmaceutically-acceptable salt thereof has a novel chemical structure, it is verified through in-vitro and in-vivo experiments that a very good selective inhibiting effect on DPP-IV is achieved, the activity of DPP-VIII and DPP-IX is barely affected while the activity of DPP-IV is effectively inhibited, meanwhile, the inhibition ratio of a potassium ion channel is low, and it can be predicted that the toxicity is low after the compound is developed into medicine. Compared with medicine trelagliptin orally taken once every week on the market, the thienopyrimidinone compound has fairly high or higher bioavailable efficiency, it can be predicted that after the compound is developed, the treatment effect that the compound is orally taken once for a long time, and the convenience and compliance of a patient are greatly improved. The preparation method is simple, the raw materials are easy to obtain, and the preparation method is suitable for industrial large-scale production.
- -
-
Paragraph 0127-0132
(2019/01/23)
-
- Design, synthesis, and biological evaluation of novel thienopyrimidine derivatives as PI3Kα inhibitors
-
Three series of novel thienopyrimidine derivatives 9a-l, 15a-l, and 18a-h were designed and synthesized, and their IC50 values against four cancer cell lines HepG-2, A549, PC-3, and MCF-7 were evaluated. Most compounds show moderate cytotoxicity against the tested cancer cell lines. The most promising compound 9a showed moderate activity with IC50 values of 12.32 ± 0.96, 11.30 ± 1.19, 14.69 ± 1.32, and 9.80 ± 0.93 μM, respectively. The inhibitory activities of compounds 9a and 15a against PI3Kα and mTOR kinase were further evaluated. Compound 9a exhibited PI3Kα kinase inhibitory activity with IC50 of 9.47 ± 0.63 μM. In addition, docking studies of compounds 9a and 15a were also investigated.
- Yu, Lide,Wang, Qinqin,Wang, Caolin,Zhang, Binliang,Yang, Zunhua,Fang, Yuanying,Zhu, Wufu,Zheng, Pengwu
-
-
- Pyrimidine derivatives, preparation method therefor and application of pyrimidine derivatives
-
The invention belongs to the field of drug synthesis and relates to novel pyrimidine derivatives, pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof, preparation methods of thenovel pyrimidine derivatives and the pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof and use of the novel pyrimidine derivatives and the pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof in preparation of therapeutic agents, particularly PAK inhibitors. The derivatives disclosed by the invention are represented by a general formula (I) or (II), wherein each substituent is as defined in claims.
- -
-
Paragraph 0150; 0151; 0152; 0153
(2018/03/26)
-
- Preparation method of 2,4-dichlorothiopheno[3,2-D]pyrimidine
-
The invention relates to a preparation method of 2,4-dichlorothiopheno[3,2-D]pyrimidine. Particularly, 3-aminothiophene-2-formamide, triphosgene and phosphorus oxychloride are taken as raw materials to be subjected to two steps, i.e., ring closure reaction and chlorination to synthesize the 2,4-dichlorothiopheno[3,2-D]pyrimidine with high yield. The preparation method of the 2,4-dichlorothiopheno[3,2-D]pyrimidine, provided by a synthesis route disclosed by the invention has the advantages of high yield, low cost, easiness in operation and suitability for industrialization.
- -
-
Paragraph 0020; 0021
(2018/11/22)
-
- COMBINATION THERAPY WITH A PHOSPHOINOSITIDE 3-KINASE INHIBITOR WITH A ZINC BINDING MOIETY
-
The invention provides a method of treating cancer in a subject in need thereof, comprising administering to the subject: (a) a compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein R is hydrogen or an acyl group; and (b) a BCL-2 inhibitor; wherein the compound of Formula I or pharmaceutically acceptable salt thereof and a BCL-2 inhibitor are administered in amounts which in combination are therapeutically effective. The invention further provides a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, a BCL-2 inhibitor and a pharmaceutically acceptable carrier or excipient.
- -
-
Page/Page column 25; 30
(2018/05/24)
-
- FUSED PYRIMIDINES AS ISOFORM SELECTIVE PHOSPHOINOSITIDE-3-KINASE-ALPHA INHIBITORS AND PROCESS FOR PREPARATION THEREOF
-
The present invention relates to fused pyrimidines of formulae I and II wherein, R1, R2 are as herein described. The present invention particularly relates to isoform selective PI3Kα inhibition and their medicinal use as anticancer agents.
- -
-
Page/Page column 16-17
(2017/06/23)
-
- HETEROCYCLE COMPOUNDS AND USES THEREOF
-
Compounds having the general formula (I) and pharmaceutical compositions that can be used as Bruton's Tyrosine Kinase (BTK), ITK, JAK3, and selective mutant epidermal growth factor receptor tyrosine kinase (EGFR-TK) inhibitor and their uses in the treatment of related diseases and disorders such as cancer.
- -
-
Paragraph 00142; 00145; 00146
(2017/07/28)
-
- THIENO-PYRIMIDINE DERIVATIVES AND USES THEREOF
-
Compounds having the general formula I or III,and pharmaceutical compositions comprising the same. The compounds of the present invention are useful as selective mutant epidermal growth factor receptor tyrosine kinase (EGFR-TK) inhibitor, and for the treatment of EGFR related diseases and disorders such as cancer.
- -
-
Paragraph 00111; 00114
(2017/12/28)
-
- HETEROARYL DERIVATIVES AS SEPIAPTERIN REDUCTASE INHIBITORS
-
Inhibitors of sepiapterin reductase of formula (I) or (I'), wherein the substituents are defined as in the claims, and uses of sepiapterin reductase inhibitors in analgesia, treatment of acute and chronic pain, anti-inflammation, and immune cell regulation are disclosed.
- -
-
Paragraph 00347-00350
(2017/05/31)
-
- Thiophene pyrimidines and preparation and its preparation method and application
-
The invention discloses a pyrantel compound and preparation, as well as a preparation method and application of the pyrantel compound and preparation, belonging to the technical field of chemical medicines and preparations thereof. According to the pyrantel compound or pharmaceutically acceptable salt thereof, HDAC (histone deacetylase)/PI3K (phosphatidylinositide 3-kinase) double-target inhibitor is used for selectively inhibiting tumor cell messenger core protein kinase target PI3K and epigenetic target HDAC which are synergized, and is capable of destroying the network of tumor cell messengers, thus exerting a great killing effect on various tumor cells. In multiple blood and entity heterogenic transplanted tumor animal models, the inhibitor can be used for intensively effectively inhibiting tumor growth and especially has a remarkable effect on various blood B-cell malignant tumors, and safety evaluation tests indicate that the inhibitor has high safety and security. The pyrantel compound and preparation can be used for effectively treating patients with later reoccurrence of lymphoma, myeloma and lymphatic leukemia or drug resistance.
- -
-
Page/Page column 0103; 0117; 0118; 0119
(2017/08/22)
-
- Phosphoinositide 3-kinase inhibitor with a zinc binding moiety
-
The invention provides a compound of Formula I, Pharmaceutical compositions comprising such compounds and the use of such compounds in the treatment of phosphoinositide 3-kinase related diseases and disorders such as cancer. The instant application further relates to the treatment of histone deacetylase related disorders and diseases related to both histone deacetylase and phosphoinositide 3-kinase.
- -
-
Page/Page column 36
(2016/02/26)
-
- Combinations of phosphoinositide 3-kinase inhibitor compounds and chemotherapeutic agents for the treatment of hematopoietic malignancies
-
Combinations of PI3K inhibitor compounds having Formula I and chemotherapeutic agents, including stereoisomers, geometric isomers, tautomers, metabolites and pharmaceutically acceptable salts thereof, are useful for treating hematopoietic malignancies. Methods of using such combinations for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed
- -
-
Page/Page column 70
(2016/08/03)
-
- The structure containing [...] of thienopyrimidines preparation and application
-
The invention discloses a thienopyrimidine compound containing a chromone hydrazone structure, a geometrical isomer of the compound, pharmaceutically acceptable salts, hydrates, solvates or prodrugs of the compound, as well as application of the compound to preparation of medicines for treating and/or preventing hyperplastic diseases, application of the compound to preparation of medicines for treating and/or preventing cancers and application of the compound to preparation of medicines for treating and/or preventing lung cancers, liver cancers, gastric cancers, colon cancers and breast cancers.
- -
-
Paragraph 0117; 0118; 0119
(2016/11/21)
-
- NOVEL PROCESS FOR PREPARING NOVEL THIOXO THIENOPYRIMIDINONE DERIVATIVES AND INTERMEDIATES USED THEREIN
-
The present invention relates to a preparation method of 2-thioxo thienopyrimidin-4-one represented by chemical formula 1, and an intermediate product used thereto. The preparation method of the present invention comprises the steps of: having a reaction
- -
-
-
- THIENO- AND PYRROLOPYRIMIDINE ANALOGUES AS ANTICANCER AGENTS AND METHODS OF USE THEREOF
-
The present invention provides for the design and synthesis of halogenated thieno- and pyrrolopyrimidine compounds that exhibit cancer proliferation inhibitory activity and the use thereof for cancer treatment.
- -
-
Paragraph 0062
(2016/09/26)
-
- Design, synthesis and docking studies of novel thienopyrimidine derivatives bearing chromone moiety as mTOR/PI3Kα inhibitors
-
Two series of thienopyrimidine derivatives (10a-k, 16a-j) bearing chromone moiety were designed and synthesized. All the compounds were evaluated for inhibitory activity against mTOR kinase at a concentration of 10uM. Four selected compounds were further evaluated for the IC50 values against mTOR kinase, PI3Kα kinase and two cancer cell lines. Some of the target compounds exhibited moderate to excellent mTOR/PI3Kα kinase inhibitory activity and cytotoxicity. The most promising compound 16i showed good inhibitory activity against mTOR/PI3Kα kinase and good antitumor potency for H460 and PC-3 cell lines with IC50 values of 0.16 ± 0.03 μM, 2.35 ± 0.19 μM, 1.20 ± 0.23 μM and 0.85 ± 0.04 μM, which were 8.6, >5, 7.9 and 19.1 times more active than compound I (1.37 ± 0.07 μM, >10 μM, 9.52 ± 0.29 μM, 16.27 ± 0.54 μM), respectively. Structure-activity relationships (SARs) and docking studies indicated that the chromone moiety is necessary for the potent antitumor activity and cytotoxicity of these compounds. Substitution of the chromone moiety at the 6-position has a significant impact to the inhibitory activity, in particular a carboxylic acid group, produced the best potency.
- Zhu, Wufu,Chen, Chen,Sun, Chengyu,Xu, Shan,Wu, Chunjiang,Lei, Fei,Xia, Hui,Tu, Qidong,Zheng, Pengwu
-
-
- PHOSPHOINOSITIDE 3-KINASE INHIBITORS WITH ZINC BINDING MOIETY
-
PROBLEM TO BE SOLVED: To provide phosphoinositide 3-kinase inhibitors with a zinc binding moiety. SOLUTION: There is provided a compound represented by formula (I) in the figure. (X is S, O or the like; Y is CH, N or the like; G1 is optionally substituted N or the like; R1 and R2 are each independently H or the like; C is a substituted heterocycle or the like; B is a linear alkyl or the like; Ra and Rb together with the nitrogen atom coupled to them are morpholino or the like; G2 is an indazole ring or the like; q, r and s are independently from 0 to 1, provided that at least one of them is 1; t is from 0 to 1; n is from 0 to 4; and p is from 0 to 2.) COPYRIGHT: (C)2016,JPOandINPIT
- -
-
Paragraph 0172
(2016/10/07)
-
- Phosphoinositides 3-serinekinase inhibitor compd. antialopecic agent and combinations, and method of use
-
Combinations of PI3K inhibitor compounds having Formulas I and II and chemotherapeutic agents, including stereoisomers, geometric isomers, tautomers, metabolites and pharmaceutically acceptable salts thereof, are useful for treating hyperproliferative disorders such as cancer. Methods of using such combinations for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed.
- -
-
Paragraph 0331-0332
(2016/10/09)
-
- Identification of 2,4-diamino-6,7-dimethoxyquinoline derivatives as G9a inhibitors
-
G9a is a histone lysine methyltransferase (HKMT) involved in epigenetic regulation via the installation of histone methylation marks. 6,7-Dimethoxyquinazoline analogues, such as BIX-01294, are established as potent, substrate competitive inhibitors of G9a. With an objective to identify novel chemotypes for substrate competitive inhibitors of G9a, we have designed and synthesised a range of heterocyclic scaffolds, and investigated their ability to inhibit G9a. These studies have led to improved understanding of the key pharmacophoric features of BIX-01294 and the identification of a new core quinoline inhibitory scaffold, which retains excellent potency and high selectivity. Molecular docking was carried out to explain the observed in vitro data. This journal is
- Srimongkolpithak, Nitipol,Sundriyal, Sandeep,Li, Fengling,Vedadi, Masoud,Fuchter, Matthew J.
-
p. 1821 - 1828
(2015/01/08)
-
- THIENYL [3, 2-D]PYRIMIDIN-4-ONE COMPOUNDS, PREPARATION METHOD, PHARMACEUTICAL COMPOSITIONS AND USE THEREOF
-
Disclosed are new thienyl [3, 2-d] pyrimidin-4-one compounds shown as the general formula (I), preparation method, pharmaceutical compositions and pharmacological use thereof. The compounds are strong DPPIV (dipeptide peptidase IV) inhibitors and can trea
- -
-
Paragraph 0055
(2014/10/16)
-
- THIENYL [3,2-D] PYRIMIDIN-4-ONE COMPOUNDS, PREPARATION METHOD, PHARMACEUTICAL COMPOSITIONS AND USE THEREOF
-
Disclosed are new thienyl[3,2-d]pyrimidin-4-one compounds shown as the general formula (I), preparation method, pharmaceutical compositions and pharmacological use thereof. The compounds are strong DPPIV (dipeptide peptidase IV) inhibitors and can treat t
- -
-
Paragraph 0133-0134
(2014/11/11)
-
- 2,4,7-SUBSTITUTED THIENO[3,2-D]PYRIMIDINE COMPOUNDS AS PROTEIN KINASE INHIBITORS
-
Disclosed are a 2,4,7-substituted thieno[3,2-d]pyrimidine compound having a protein kinase inhibition activity, a pharmaceutically acceptable salt, and a pharmaceutical composition for prevention and treatment of diseases caused by abnormal cell growth comprising the compound as an effective ingredient. Since the novel 2,4,7-substituted thieno[3,2-d]pyrimidine compound exhibits superior inhibition activity against various protein kinases involved in growth factor signal transduction, it is useful as an agent for preventing or treating diseases caused by abnormal cell growth.
- -
-
Paragraph 0129-0131
(2013/03/26)
-
- A practical synthesis of a PI3K inhibitor under noncryogenic conditions via functionalization of a lithium triarylmagnesiate intermediate
-
We report a practical synthesis of PI3K inhibitor GDC-0941. The synthesis was achieved using a convergent approach starting from a thienopyrimidine intermediate through a sequence of formylation and reductive amination followed by Suzuki-Miyaura cross-coupling. Metalation of the thienopyrimidine intermediate involving the intermediacy of triarylmagnesiates allowed formylation under noncryogenic conditions to produce the corresponding aldehyde. We also investigated aminoalkylation via a benzotriazolyl-piperazine substrate as an alternative to the reductive amination route. We evaluated both palladium and nickel catalyzed processes for the borylation and Suzuki-Miyaura cross-coupling. Final deprotection and salt formation afforded the API.
- Tian, Qingping,Cheng, Zhigang,Yajima, Herbert M.,Savage, Scott J.,Green, Keena L.,Humphries, Theresa,Reynolds, Mark E.,Babu, Srinivasan,Gosselin, Francis,Askin, David,Kurimoto, Isao,Hirata, Norihiko,Iwasaki, Mitsuhiro,Shimasaki, Yasuharu,Miki, Takashi
-
-
- TREATMENT OF CANCERS HAVING K-RAS MUTATIONS
-
The present invention provides a method of treating a cancer associated with a K-ras mutation in a subject in need thereof. The method comprises the steps of: (1) identifying a subject with a cancer associated with a K-ras mutation; and (2) administering to the subject (i) an inhibitor of PI3 kinase and (ii) an HDAC inhibitor, wherein the PI3 kinase inhibitor and the HDAC inhibitor are administered in amounts which together are therapeutically effective.
- -
-
Paragraph 0174
(2013/05/08)
-
- PROTEIN KINASE D INHIBITORS
-
Compounds according to Formula (I), are potent inhibitors of protein kinase D (pan-PKD) activity. PKD controls key signaling cascades in cells, affecting cell proliferation, gene transcription, and protein trafficking. Accordingly, pharmaceutically acceptable compositions of the inventive compounds are candidate therapeutics for pathological conditions conditioned by changes in PKD activity.
- -
-
Page/Page column 58
(2012/06/30)
-
- Design, synthesis and anticancer activity of 4-morpholinothieno[3,2-d]- pyrimidine derivatives bearing arylmethylene hydrazine moiety
-
Three series of 4-morpholinothieno[3,2-d]pyrimidine derivatives containing arylmethylene hydrazine moiety (11a-f, 13a-k and 15a-h) were synthesized and their chemical structures as well as the relative stereochemistry were confirmed. The synthesized compounds were evaluated for their cytotoxicity against three cancer cell lines (H460, HT-29, MDA-MB-231). Most of them exhibited moderate to significant cytotoxicity and high-selectivity against one or more cell lines, especially compounds 11c, 13b, 15f and 15g possessing dramatically increased cytotoxicity as compared with the positive controls, which were further evaluated for six other cancer cell lines and one normal cell line. The most promising compound 11c, bearing 3,4-methylenedioxy phenyl group, showed remarkable cytotoxicity against H460, HT-29 and MDA-MB-231 cell lines with IC50 values of 0.003 μM, 0.42 μM and 0.74 μM, which was 1.6- to 290-fold more potent than GDC-0941.
- Zhu, Wufu,Zhai, Xin,Fu, Qiangqiang,Guo, Fei,Bai, Mei,Wang, Jianqiang,Wang, Haiyan,Gong, Ping
-
experimental part
p. 1037 - 1045
(2012/10/08)
-
- Design, synthesis and 3D-QSAR analysis of novel 2-hydrazinyl-4- morpholinothieno[3,2-d]pyrimidine derivatives as potential antitumor agents
-
A series of 2-hydrazinyl-4-morpholinothieno[3,2-d]pyrimidine derivatives were synthesized and evaluated for their cytotoxic activities against five cancer cell lines. Most of them exhibited moderate to significant cytotoxic activities and high-selectivity against one or more cell lines, and nearly all of them had higher potency than positive controls against MDA-MB-231 cell line. The most promising compound 15f showed strong cytotoxic activities against H460, HT-29 and MDA-MB-231 cell lines, which were 1.7- to 66.5-folds more active than 2-(1H-Indazol-4-yl)-6-((4-(methylsulfonyl)-1-piperazinyl)methyl)-4-(4- morpholinyl)thieno[3,2-d]pyrimidine(GDC-0941). To investigate the SARs of thieno[3,2-d]pyrimidine derivatives in more details, CoMFA (q2 = 0.436, r2 = 0.937) and CoMSIA (q2 = 0.706, r2 = 0.947) models on H460 cell line were established. The generated 3D-QSAR models can be used for further rational design of novel thienopyrimidines as highly potent and selective cytotoxic agents.
- Zhu, Wufu,Liu, Yajing,Zhai, Xin,Wang, Xiao,Zhu, Yan,Wu, Di,Zhou, Hongyu,Gong, Ping,Zhao, Yanfang
-
p. 162 - 175
(2013/01/15)
-
- Synthesis and evaluation of anticonvulsant and antidepressant activities of 5-alkoxytetrazolo[1,5-c]thieno[2,3-e]pyrimidine derivatives
-
A series of 5-alkoxytetrazolo[1,5-c]thieno[2,3-e]pyrimidine derivatives were synthesized and their anticonvulsant and antidepressant activities were evaluated. Pharmacological tests showed that four of the synthesized compounds had weak anticonvulsant activity, while most of the compounds had excellent antidepressant activity. The most active compound was 5-(2,4-dichlorobenzyloxy) tetrazolo[1,5-c] thieno[2,3-e]pyrimidine, which decreased the immobility time by 51.62% at a dose of 100 mg/kg. The results of open-field tests of this compound indicated that it had no significant effects on the locomotor activity compared with the control group at the doses assayed in the forced swimming tests test. This means that the antidepressant activity detected in the FST for the compound is not the result of central nervous system stimulant properties, and further confirms its antidepressant-like effect.
- Wang, Shi-Ben,Deng, Xian-Qing,Zheng, Yan,Yuan, Yan-Ping,Quan, Zhe-Shan,Guan, Li-Ping
-
p. 139 - 144
(2013/01/15)
-
- Synthesis and cytotoxic activity of novel 2,6-disubstituted-4-mor- pholinothieno[3,2-d]pyrimidines as potent anti-tumor agents
-
A series of 2,6-disubstituted-4-morpholinothieno[3,2-d]pyrimidine derivatives were synthesized and their cytotoxic activity against H460, HT-29, MDA-MB-231, U87MG and H1975 cancer cell lines were evaluated in vitro. Most of the target compounds exhibited moderate to excellent activity to the tested cell lines. The most promising compound 23 (0.84 μmol/L, 0.23 μmol/L, 2.52 μmol/L, 1.80 μmol/L) was 1.0, 2.9, 29.3 and 4.3 times more active than GDC-0941 (0.87 μmol/L, 0.66 μmol/L, 73.8 μmol/L, 7.77 μmol/L) against H460, HT-29, MDA-MB-231 and U87MG cell lines, respectively.
- Zhu, Wu Fu,Zhai, Xin,Li, Sai,Cao, Yun Yun,Gong, Ping,Liu, Ya Jing
-
scheme or table
p. 703 - 706
(2012/07/16)
-
- 2,7-SUBSTITUTED THIENO[3,2-D] PYRIMIDINE COMPOUNDS AS PROTEIN KINASE INHIBITORS
-
Disclosed are a 2,7-substituted thieno[3,2-d]pyrimidine compound having a protein kinase inhibition activity, a pharmaceutically acceptable salt, and a pharmaceutical composition for prevention and treatment of diseases caused by abnormal cell growth comp
- -
-
Page/Page column 7
(2012/11/08)
-
