- Novel phenylpyrazole derivative and application thereof in medicine for reducing blood sugar
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The invention belongs to the field of drug synthesis, and particularly relates to a phenyl pyrazole derivative and a preparation method thereof, and an application thereof in a hypoglycemic drug. The invention provides a novel phenylpyrazole derivative and a general formula thereof. In addition, the invention also provides a preparation method of the derivative and an application of the derivative in hypoglycemic drugs.
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Paragraph 0011-0012; 0015-0018
(2021/10/11)
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- Benzopyrazolo ring derivative and application thereof in antitumor drugs
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The invention belongs to the technical field of medicines, and provides a benzopyrazolo ring derivative as shown in a general formula and a preparation method thereof. The invention further disclosesthe benzene bipyrazolo ring derivative which can inhibit
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Paragraph 0022; 0024-0026
(2020/07/12)
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- Phenyl-1H-pyrazole derivative and application thereof in antitumor drugs
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The invention belongs to the technical field of medicines, and provides a phenyl-1H-pyrazole derivative shown as a general formula and a preparation method thereof. The invention also discloses that the phenyl-1H-pyrazole derivative can inhibit the mutual combination of a programmed cell death receptor 1/a programmed cell death ligand 1 (PD-1/PD-L1) and can be used for preparing a PD-1/PD-L1 inhibitor.
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Paragraph 0023; 0025-0026
(2020/07/12)
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- Pyrazole-4-Carboxamide (YW2065): A Therapeutic Candidate for Colorectal Cancer via Dual Activities of Wnt/β-Catenin Signaling Inhibition and AMP-Activated Protein Kinase (AMPK) Activation
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Dysregulation of the Wnt/β-catenin signaling pathway has been widely recognized as a pathogenic mechanism for colorectal cancer (CRC). Although numerous Wnt inhibitors have been developed, they commonly suffer from toxicity and unintended effects. Moreover, concerns have been raised in targeting this pathway because of its critical roles in maintaining stem cells and regenerating tissues and organs. On the basis of the anthelmintic drug pyrvinium and previous lead FX1128, we have developed a compound YW2065 (1c) which demonstrated excellent anti-CRC effects in vitro and in vivo. YW2065 achieves its inhibitory activity for Wnt signaling by stabilizing Axin-1, a scaffolding protein that regulates proteasome degradation of β-catenin. Simultaneously, YW2065 also led to the activation of the tumor suppressor AMPK, providing an additional anticancer mechanism. In addition, YW2065 showed favorable pharmacokinetic properties without obvious toxicity. The anti-CRC effect of YW2065 was highlighted by its promising efficacy in a mice xenograft model.
- Yang, Wei,Li, Yingjun,Ai, Yong,Obianom, Obinna N.,Guo, Dong,Yang, Hong,Sakamuru, Srilatha,Xia, Menghang,Shu, Yan,Xue, Fengtian
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p. 11151 - 11164
(2019/12/27)
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- Discovery of 2-phenylthiazole-4-carboxylic acid, a novel and potent scaffold as xanthine oxidase inhibitors
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The xanthine oxidase (XO) plays an important role in producing uric acid, and therefore XO inhibitors are considered as one of the promising therapies for hyperuricemia and gout. We have previously reported a series of XO inhibitors with pyrazole scaffold to extend the chemical space of current XO inhibitors. Herein, we describe further structural optimization to explore the optimal heterocycle by replacing the thiazole ring of Febuxostat with 5 heterocycle scaffolds unexplored in this field. All of these efforts resulted in the identification of compound 8, a potent XO inhibitor (IC50 = 48.6 nM) with novel 2-phenylthiazole-4-carboxylic acid scaffold. Moreover, lead compound 8 exhibited hypouricemic effect in potassium oxonate-hypoxanthine-induced hyperuricemic mice. These results promote the understanding of ligand-receptor interaction and might help to design more promising XO inhibitors.
- Xu, Xue,Deng, Liming,Nie, Lu,Chen, Yueming,Liu, Yanzhi,Xie, Rongrong,Li, Zheng
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supporting information
p. 525 - 528
(2019/01/09)
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- Hydroxamic Acid-Based Histone Deacetylase (HDAC) inhibitors bearing a pyrazole scaffold and a cinnamoyl linker
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Genetic abnormalities have been conventionally considered as hallmarks of cancer. However, recent studies have demonstrated that epigenetic mechanisms are also implicated in the insurgence and development of cancer. Patterns of the epigenetic component in
- Zagni, Chiara,Rescifina, Antonio,Citarella, Andrea,Maugeri, Alessandro,Navarra, Michele,Scala, Angela,Piperno, Anna,Micale, Nicola,Oussama, Mahjoub
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- Biphenyl heterocyclic derivatives, their preparation and their use as medicaments (by machine translation)
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The present invention relates to a novel biphenyl heterocyclic derivative represented by a general formula (I) and a preparation method thereof and use of a pharmaceutical composition containing the derivative for preparation of a drug for treating diabetes. The biphenyl heterocyclic derivative has extremely excellent hypoglycemic activity in vivo, and excellent in vivo safety and low liver toxicity risk of the compound having such a structure are unexpectedly found, and the novel biphenyl heterocyclic derivative may be used for preventing or treating diabetes.
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Paragraph 0363-0366
(2018/06/21)
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- CALPAIN MODULATORS AND THERAPEUTIC USES THEREOF
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Disclosed herein are small molecule calpain modulator compositions, pharmaceutical compositions, the use and preparation thereof.
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Paragraph 0891
(2018/04/17)
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- Synthesis, nematicidal activity and docking study of novel chromone derivatives containing substituted pyrazole
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A series of chromone derivatives containing substituted pyrazole were designed and synthesized. Preliminary bioassays showed that most of the synthesized compounds exhibited good nematicidal activity in vivo against Meloidogyne incognita at 10 mg/L. Among the tested compounds, A10 and A11 exhibited 100% inhibition rates. In addition, the molecular docking results indicated that both compound A10 and A11 interacts with amino acid residue Tyr121, Trp279, Tyr70, Trp84 and Phe330 of AChE via hydrogen bond and π–π stacking. This investigation suggested that the chromone containing substituted pyrazole scaffold could be further optimized to explore novel, high-bioactivity nematicidal leads.
- Li, Wei,Li, Jiuhui,Shen, Hongfeng,Cheng, Jiagao,Li, Zhong,Xu, Xiaoyong
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supporting information
p. 911 - 914
(2017/11/01)
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- WNT SIGNALING PATHWAY INHIBITORS FOR TREATMENTS OF DISEASE
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Compounds and compositions are provided as inhibitors of the Wnt/β-catenin pathway for the treatment of diseases that implicate the same.
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- Design, synthesis and evaluation of aromatic heterocyclic derivatives as potent antifungal agents
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To further enhance the anti-Aspergillus efficacy of our previously discovered antifungal lead compounds (1), a series of aromatic heterocyclic derivatives were designed, synthesized and evaluated for in vitro antifungal activity. Many of the target compounds showed good inhibitory activity against Candida albicans and Cryptococcus neoformans. In particular, the isoxazole nuclei were more suited for improving the activity against Aspergillus spp. Among these compounds, 2-F substituted analogues 23g and 23h displayed the most remarkable in vitro activity against Candida spp., C. neoformans, A. fumigatus and fluconazole-resistant C.alb. strains, which is superior or comparable to the activity of the reference drugs fluconazole and voriconazole. Notably, the compounds 23g and 23h exhibited low inhibition profiles for various isoforms of human cytochrome P450 and excellent blood plasma stability.
- Zhao, Shizhen,Zhang, Xiangqian,Wei, Peng,Su, Xin,Zhao, Liyu,Wu, Mengya,Hao, Chenzhou,Liu, Chunchi,Zhao, Dongmei,Cheng, Maosheng
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- Design, synthesis, and biological evaluation of N,N-disubstituted-4-arylthiazole-2-methylamine derivatives as cholesteryl ester transfer inhibitors
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Cholesteryl ester transfer protein (CETP) has been identified as a potential target for cardiovascular disease (CVD) for its important role in the reverse cholesteryl transfer (RCT) process. In our previous work, compound 5 was discovered as a moderate CETP inhibitor. The replacement of the amide linker by heterocyclic aromatics and then a series of N,N-substituted-4-arylthiazole-2-methylamine derivatives were designed by utilizing a conformational restriction strategy. Thirty-six compounds were synthesized and evaluated for their CETP inhibitory activities. Structure-activity relationship studies indicate that electron donor groups substituted ring A, and electron-withdrawing groups at the 4-position of ring B were critical for potency. Among these compounds, compound 30 exhibited excellent CETP inhibitory activity (IC50 = 0.79 ± 0.02 μM) in vitro and showed an acceptable metabolic stability.
- Wang, Xinran,Lin, Xuehua,Xu, Xuanqi,Li, Wei,Hao, Lijuan,Liu, Chunchi,Zhao, Dongmei,Cheng, Maosheng
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- Design, synthesis and Structure-activity relationship studies of new thiazole-based free fatty acid receptor 1 agonists for the treatment of type 2 diabetes
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The free fatty acid receptor 1 (FFA1/GPR40) has attracted interest as a novel target for the treatment of type 2 diabetes. Several series of FFA1 agonists including TAK-875, the most advanced compound terminated in phase III studies due to concerns about liver toxicity, have been hampered by relatively high molecular weight and lipophilicity. Aiming to develop potent FFA1 agonists with low risk of liver toxicity by decreasing the lipophilicity, the middle phenyl of TAK-875 was replaced by 11 polar five-membered heteroaromatics. Subsequently, systematic exploration of SAR and application of molecular modeling, leads to the identification of compound 44, which was an excellent FFA1 agonist with robustly hypoglycemic effect both in normal and type 2 diabetic mice, low risks of hypoglycemia and liver toxicity even at the twice molar dose of TAK-875. Meanwhile, two important findings were noted. First, the methyl group in our thiazole series occupied a small hydrophobic subpocket which had no interactions with TAK-875. Furthermore, the agonistic activity revealed a good correlation with the dihedral angle between thiazole core and the terminal benzene ring. These results promote the understanding of ligand-binding pocket and might help to design more promising FFA1 agonists.
- Li, Zheng,Qiu, Qianqian,Xu, Xue,Wang, Xuekun,Jiao, Lei,Su, Xin,Pan, Miaobo,Huang, Wenlong,Qian, Hai
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supporting information
p. 246 - 257
(2016/03/08)
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- Synthesis and biofilm formation reduction of pyrazole-4-carboxamide derivatives in some Staphylococcus aureus strains
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The ability of several N-phenyl-1H-pyrazole-4-carboxamide derivatives and other pyrazoles opportunely modified at the positions 3, 4 and 5, to reduce the formation of the biofilm in some Staphylococcus aureus strains (ATCC 29213, ATCC 25923 and ATCC 6538) were investigated. All the tested compounds were able, although to a different extent, to reduce the biofilm formation of the three bacterial strains considered. Among these, the 1-(2,5-dichlorophenyl)-5-methyl-N-phenyl-1H-pyrazole-4-carboxamide 14 resulted as the best inhibitor of biofilm formation showing an IC50ranging from 2.3 to 32 μM, against all the three strains of S. aureus. Compound 14 also shows a good protective effect in vivo by improving the survival of wax moth larva (Galleria mellonella) infected with S. aureus ATCC 29213. These findings indicate that 14d is a potential lead compound for the development of new anti-virulence agents against S. aureus infections.
- Cascioferro, Stella,Maggio, Benedetta,Raffa, Demetrio,Raimondi, Maria Valeria,Cusimano, Maria Grazia,Schillaci, Domenico,Manachini, Barbara,Plescia, Fabiana,Daidone, Giuseppe
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- A new efficient synthesis of pyrazoles from hydrazonoyl halides and β-oxophosphonates
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A new practical and efficient synthesis of 1,3,5-trisubstituted pyrazoles has been developed by reacting of hydrazonoyl halides with β-oxophosphonates under mild conditions in good yields with excellent regioselectivity. This process employs an addition-elimination sequence. Wide scope, functional group compatibility has been established.
- Sun, Aixue,Ye, Jia-Hai,Yu, Haitao,Zhang, Wenchao,Wang, Xiaolong
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supporting information
p. 889 - 892
(2015/03/03)
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- A new efficient synthesis of pyrazoles from hydrazonoyl halides and β-oxophosphonates
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A new practical and efficient synthesis of 1,3,5-trisubstituted pyrazoles has been developed by reacting of hydrazonoyl halides with β- oxophosphonates under mild conditions in good yields with excellent regioselectivity. This process employs an addition-elimination sequence. Wide scope, functional group compatibility has been established.
- Sun, Aixue,Ye, Jia-Hai,Yu, Haitao,Zhang, Wenchao,Wang, Xiaolong
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supporting information
p. 889 - 892
(2014/02/14)
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- Optimization of non-ATP competitive CDK/cyclin groove inhibitors through REPLACE-mediated fragment assembly
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A major challenge in drug discovery is to develop and improve methods for targeting protein-protein interactions. Further exemplification of the REPLACE (REplacement with Partial Ligand Alternatives through Computational Enrichment) strategy for generatin
- Liu, Shu,Premnath, Padmavathy Nandha,Bolger, Joshua K.,Perkins, Tracy L.,Kirkland, Lindsay O.,Kontopidis, George,McInnes, Campbell
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p. 1573 - 1582
(2013/04/10)
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- New one-pot, efficient, and regioselective method for the synthesis of 3-Trifluoromethyl-1H-1-phenylpyrazoles and alkyl 3-carboxylate analogs
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An efficient and regioselective procedure for the synthesis of a series of alkyl(aryl/heteroaryl) substituted 3-trifluoromethyl-1H-1-phenylpyrazoles and alkyl 3-carboxylate analogs, from the cyclocondensation reactions of 4-alkoxy-1,1,1-trihaloalk-3-en-2-ones [CX3C(O)CR2=CR 1(OMe/OEt), where R1 = H, Me, Ph, 2-Furyl; R2 = H; R1-R2 = -C4H8- and X = F, Cl] and 1-phenylsemicarbazide in an acidified alcoholic medium (R 3OH/H2SO4), where R3 = Me, Et, Pri was successfully applied and is described here in detail. 2012 Elsevier Ltd. All rights reserved.
- Bonacorso, Helio G.,Correa, Michele S.,Porte, Liliane M.F.,Pittaluga, Everton P.,Zanatta, Nilo,Martins, Marcos A.P.
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p. 5488 - 5491
(2012/11/07)
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- Functionalized 4-aminoquinolines by rearrangement of pyrazole N-heterocyclic carbenes
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(Figure Presented) Thermal decarboxylation of 1-phenyl pyrazolium-3- carboxylates from the mesomeric betaine class of substances leads to pyrazole-N-heterocyclic carbenes, which immediately rearrange to multiply substituted 4-aminoquinolines (see scheme). These species are of interest for the synthesis of heterocycles and pharmacologically active compounds.
- Schmidt, Andreas,Muenster, Niels,Dreger, Andrij
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supporting information; experimental part
p. 2790 - 2793
(2010/07/04)
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- Synthesis of N-methoxy-N-methyl-β-enaminoketoesters: New synthetic precursors for the regioselective synthesis of heterocyclic compounds
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Weinreb amides react with the lithium or sodium acetylide of ethyl propynoate in a hitherto unexplored acyl substitution-conjugate addition sequence to furnish (E)-N-methoxy-N-methyl-β-enaminoketoesters. This approach provides a diverse entry to densely functionalized heterocyclic compounds, including pyrazoles through regioselective cyclocondensations with hydrazines in a microwave-assisted reaction.
- Persson, Tobias,Nielsen, John
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p. 3219 - 3222
(2007/10/03)
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- Preparation of 2,6-Bis(l-menthopyrzol-3-yl)pyridines and their Catalytic Activity for Asymmetric Diels Alder Reaction
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3-Aryl-l-menthopyrazoles 1 and 2 and related compounds were prepared from l-menthone, and their enantioselective activities were discussed as chiral ligands. In this series of compounds, 2,6-bis(2-methyl-l-menthopyrazol-3-yl)pyridine (8a), which had both
- Kashima, Choji,Shibata, Saori,Yokoyama, Hiroyo,Nishio, Takehiko
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p. 773 - 782
(2007/10/03)
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- New pyrazolium-carboxylates as structural analogues of the pseudo-cross-conjugated betainic alkaloid nigellicine
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Pyrazolium-3-carboxylates were examined as relatives of the betainic alkaloid Nigellicine and as new examples of the sparsely populated class 16 of heterocyclic pseudo-cross-conjugated mesomeric betaines (PCCMB). The title compounds were prepared in a 4-step procedure starting from β-diketo compounds 8 which were cyclized with substituted hydrazines. The resulting isomeric pyrazole esters 9 and 10 were separated and subsequently quaternized with dimethyl sulfate in the presence of nitrobenzene to pyrazolium esters 11 and 12. Saponification was best accomplished in diluted sulfuric acid, which resulted in the formation of the pseudo-cross-conjugated mesomeric betaines 13 and 14 in one step. Protonation to the corresponding carboxylic acids required the treatment of the betaines with tetrafluoroboric acid in dichloromethane. The effect of negative solvatochromism proves the charge separation in the ground state of the molecules. X-ray crystallographic analyses, semiempirical calculations, and ESI mass spectrometric measurements were performed to gain knowledge about the phenomenon of pseudo-cross-conjugation.
- Schmidt, Andreas,Habeck, Tobias,Kindermann, Markus Karl,Nieger, Martin
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p. 5977 - 5982
(2007/10/03)
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- Pyrazolecarboxamide human neuropeptide Y5 receptor ligands with in vivo antifeedant activity
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1-Aryl-3-carboxamido-5-alkylpyrazoles were prepared based on a hit found in high-throughput screening of our corporate compound library in an assay measuring affinity for the human neuropeptide Y5 receptor. 1-(3-Trifluoromethylphenyl)-3-[N-(5-quinolinyl)carboxamido]-5-methylpyrazole (31) bound to the human neuropeptide Y5 receptor with a 80 nM IC50and was shown to inhibit cumulative food consumption 43.2% 2-6 h after ip dosing in a fasting-induced feeding model in rats.
- Kordik, Cheryl P.,Luo, Chi,Zanoni, Brian C.,Lovenberg, Timothy W.,Wilson, Sandy J.,Vaidya, Anil H.,Crooke, Jeffrey J.,Rosenthal, Daniel I.,Reitz, Allen B.
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p. 2287 - 2290
(2007/10/03)
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- Haloacetylated enol ethers. 11 [16]. Synthesis of 1-methyl- and 1- phenyl pyrazole-3(5)-ethyl esters. A one-pot procedure
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A one-pot synthesis of 1-methyl- and 1-phenylpyrazole-3(5)-ethyl esters 2,3a-e by the cyclocondensation of β-alkoxyvinyl trichloromethyl ketones 1a- e with methyl and phenyl hydrazine hydrochloride under mild conditions, is reported. A study using compounds la-e with different substituents proved that these are versatile building blocks for the synthesis of pyrazole derivatives, having a 3(5)-ethoxycarbonyl substituent in good yields (60- 89%). The hydrazine and β-alkoxyvinyl trichloromethyl ketone substituent effects on the reaction regiochemistry on the formation of the 1,3- and 1,5- isomer were observed.
- Martins, Marcos A. P.,Freitag, Rogerio A.,Da Rosa, Adriano,Flores, Alex F. C.,Zanatta, Nilo,Bonacorso, Helio G.
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p. 217 - 220
(2007/10/03)
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- Reaction of Carbonyl Compounds with Ethyl Lithiodiazoacetate. Studies Dealing with the Rhodium(II)-Catalyzed Behavior of the Resulting Adducts
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The carbenoid intermediate derived by treating ethyl 2-diazo-4-phthalimidobutyrate with rhodium(II) octanoate undergoes transannular cyclization onto the adjacent imido carbonyl group.The resulting cyclic carbonyl ylide diploe was trapped with several dipolarophiles.In an attempt to prepare related substrates for cyclization studies, the reaction of ethyl lithiodiazoacetate with various aldehydes and ketones was studied.Treatment of the α-diazo-β-hydroxy ester derived from acetone or cyclopentanone with rhodium(II) octanoate gave rise to a β-keto ester.The exclusive phenyl shift encountered with acetophenone is in keeping with migration to an electron-deficient center.The reaction works well with acrolein, leading to high yields of 3-oxo-4-pentenoate.The 1,2-hydrogen shift pathway was found to proceed much faster than intramolecular cyclopropanation.Dehydration of the α-diazo-β-hydroxy esters generates vinyl diazo esters, which readily cyclize to 1H-pyrazoles on thermolysis.
- Padwa, Albert,Kulkarni, Yashwant S.,Zhang, Zhijia
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p. 4144 - 4153
(2007/10/02)
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