5744-51-4Relevant academic research and scientific papers
Discovery of TDI-10229: A Potent and Orally Bioavailable Inhibitor of Soluble Adenylyl Cyclase (sAC, ADCY10)
Fushimi, Makoto,Buck, Hannes,Balbach, Melanie,Gorovyy, Anna,Ferreira, Jacob,Rossetti, Thomas,Kaur, Navpreet,Levin, Lonny R.,Buck, Jochen,Quast, Jonathan,Van Den Heuvel, Joop,Steegborn, Clemens,Finkin-Groner, Efrat,Kargman, Stacia,Michino, Mayako,Foley, Michael A.,Miller, Michael,Liverton, Nigel J.,Huggins, David J.,Meinke, Peter T.
, p. 1283 - 1287 (2021)
Soluble adenylyl cyclase (sAC) has gained attention as a potential therapeutic target given the role of this enzyme in intracellular signaling. We describe successful efforts to design improved sAC inhibitors amenable for in vivo interrogation of sAC inhibition to assess its potential therapeutic applications. This work culminated in the identification of TDI-10229 (12), which displays nanomolar inhibition of sAC in both biochemical and cellular assays and exhibits mouse pharmacokinetic properties sufficient to warrant its use as an in vivo tool compound.
Synthesis process of lapatinib intermediate ethyl 1, 5-dimethyl-1H-pyrazole-3-formate
-
Paragraph 0010-0013, (2021/02/24)
The invention relates to a synthesis process of a lapatinib intermediate ethyl 1, 5-dimethyl-1H-pyrazole-3-formate, which comprises the following steps: 1, making diethyl oxalate react with acetone togenerate an intermediate product, and 2, making the intermediate product prepared in the step 1 react with methylhydrazine to generate the ethyl 1, 5-dimethyl-1H-pyrazole-3-formate. Diethyl oxalate and acetone are used as main raw materials, and a target product is synthesized through condensation and cyclization reactions. Particularly, during the second-step cyclization reaction, the conversionrate of the product is effectively increased, the content of impurities is inhibited, and the purity and yield of the product are improved by controlling the temperature, the feeding sequence and thepH value of the reaction solution.
PYRAZOLE DERIVATIVES AS H4 ANTAGONIST COMPOUNDS
-
Paragraph 37; 45, (2020/05/21)
The disclosures herein relate to novel compounds of formula (1): and salts thereof, wherein A; X;n; R1 and R2 are defined herein, and their use in treating, preventing, ameliorating, controlling or reducing the risk of disorders associated with H4 receptors.
1-methyl-3-((methylamino)methyl)-1H-pyrazole-5-nitrile synthesis method
-
, (2019/01/14)
The invention belongs to the technical field of medicine and relates to a 1-methyl-3-((methylamino)methyl)-1H-pyrazole-5-nitrile synthesis method. Diethyl oxalate and acetone are easily acquirable andused as starting materials to obtain 1-methyl-3-((methylamino)methyl)-1H-pyrazole-5-nitrile through 7-step reaction including condensation, cyclization, methylation, amidation, oxidation, brominationand amination. By adoption of the method, preparation of 1-methyl-3-((methylamino)methyl)-1H-pyrazole-5-nitrile which is a key intermediate of antitumor drug lorlatinib (PF-06463922) is realized, thetotal yield reaches 5.7% or above, and simplicity in operation, convenience in aftertreatment, short time consumption and low cost are realized while industrialization can be realized beneficially. The intermediate and 5-fluoro-3-methyl isobenzofuran-1(3H)-ketone are subjected to reaction steps including ammonolysis, substitution, coupling, chiral resolution and the like to finally synthesize lorlatinib, and a novel method is provided for synthesis of the antitumor drug lorlatinib.
Pyrazole functionalized n-heterocyclic carbene ruthenium compound with anticancer activity and preparation method and application thereof
-
Paragraph 0027; 0028; 0029, (2017/08/28)
The invention discloses a pyrazole functionalized n-heterocyclic carbene ruthenium compound with anticancer activity and a preparation method and application thereof. The pyrazole functionalized n-heterocyclic carbene ruthenium compound is prepared by using 5-methyl-1-hydrogen-pyrazole ethyl formate through alkylation, reduction, chlorination, salt formation and metal exchange reaction, and the general formula of the pyrazole functionalized n-heterocyclic carbene ruthenium compound is [LRu(p-cymene)Cl](X) (L=pyrazole functionalized n-heterocyclic carbene ligand, and X is anions). In the cytotoxicity test of breast cancer cells (Bcap-37), intestinal cancer cells (LoVo), gastric cancer cells (SCG7901) and cisplatin-resistant gastric cancer cells (SCG7901-R), the n-heterocyclic carbene ruthenium compound can effectively inhibit cancer cell division and reproduction. The n-heterocyclic carbene ruthenium compound is variable in structure, convenient to synthesize, stable in performance, environmentally friendly, capable of stably existing in air for a long time, and promising in application prospect of pharmaceutical industry and fine chemical engineering industry.
Structure-guided design of a series of MCL-1 inhibitors with high affinity and selectivity
Bruncko, Milan,Wang, Le,Sheppard, George S.,Phillips, Darren C.,Tahir, Stephen K.,Xue, John,Erickson, Scott,Fidanze, Steve,Fry, Elizabeth,Hasvold, Lisa,Jenkins, Gary J.,Jin, Sha,Judge, Russell A.,Kovar, Peter J.,Madar, David,Nimmer, Paul,Park, Chang,Petros, Andrew M.,Rosenberg, Saul H.,Smith, Morey L.,Song, Xiaohong,Sun, Chaohong,Tao, Zhi-Fu,Wang, Xilu,Xiao, Yu,Zhang, Haichao,Tse, Chris,Leverson, Joel D.,Elmore, Steven W.,Souers, Andrew J.
, p. 2180 - 2194 (2015/03/30)
Myeloid cell leukemia 1 (MCL-1) is a BCL-2 family protein that has been implicated in the progression and survival of multiple tumor types. Herein we report a series of MCL-1 inhibitors that emanated from a high throughput screening (HTS) hit and progressed via iterative cycles of structure-guided design. Advanced compounds from this series exhibited subnanomolar affinity for MCL-1 and excellent selectivity over other BCL-2 family proteins as well as multiple kinases and GPCRs. In a MCL-1 dependent human tumor cell line, administration of compound 30b rapidly induced caspase activation with associated loss in cell viability. The small molecules described herein thus comprise effective tools for studying MCL-1 biology.
Synthesis and enzyme inhibitory activities of some new pyrazole-based heterocyclic compounds
Harit, Tariq,Malek, Fouad,Bali, Brahim El,Khan, Ajmal,Dalvandi, Kourosh,Marasini, Bishnu P.,Noreen, Shagufta,Malik, Rizwana,Choudhary, M. Iqbal,Khan, Sadia
, p. 2772 - 2778,7 (2020/08/24)
Three tridentate N,N-bis(3,5-dimethylpyrazol- 1-ylmethyl)-1-hydroxy-2- aminoethane (2), N,N-bis(3,5-dimethylpyrazol- 1-ylmethyl)-cyclohexylamine (3) and 2-[bis (1,5-dimethyl-1H-pyrazol-3-ylmethyl)amino]ethan-1-ol (4) are synthesized and spectroscopically characterized togetherwith 1-hydroxymethyl-3,5-dimethylpyrazole (1). These have been tested in inhibitory activities against various hyperactive enzymes like urease, β- glucuronidase, phosphodiesterase, α-chymotrypsin, acetylcholinesterase and butyrylcholinesterase. Compounds 1, 2 and 3 were found to be selective inhibitors of urease. Compound 4 was found to be selective inhibitor of butyrylcholinesterase. The nature of the junction between pyrazoles cycles determined the activities of these tripods. While the tripods are inactive towards urease or glucuronidase, they turn to be selective towards butyrylcholinesterase.
From a simple pyrazole-derived 1,2-amino alcohol to mono- and multinuclear complexes by tailoring hydrogen bond patterns
Seubert, Christoph K.,Sun, Yu,Lan, Yanhua,Powell, Annie K.,Thiel, Werner R.
experimental part, p. 1768 - 1775 (2011/06/25)
Starting from easily accessible ethyl-5(3)-methylpyrazole-3(5)-carboxylate, 2-[(1,5-dimethyl)pyrazol-3-yl]propan-2-ol (3) can be obtained in good yields in just two steps. The latter compound undergoes coordination to a series of transition metal ions; the resulting complexes were characterized by means of spectroscopy and magnetic measurements.
Stereoselective synthesis of 12,13-cyclopropyl-epothilone B and side-chain-modified variants
Schiess, Raphael,Gertsch, Juerg,Schweizer, W. Bernd,Altmann, Karl-Heinz
supporting information; experimental part, p. 1436 - 1439 (2011/05/13)
A general strategy has been devised for the stereoselective synthesis of 12,13-cyclopropyl-epothilone B and side-chain-modified variants thereof, which relies on late stage introduction of the heterocycle through Wittig olefination of ketone 14. Formation of the macrocycle was achieved through RCM-based ring closure and introduction of the cyclopropane moiety involved a highly selective Charette cyclopropanation of allylic alcohol 7.
Synthesis of N-methoxy-N-methyl-β-enaminoketoesters: New synthetic precursors for the regioselective synthesis of heterocyclic compounds
Persson, Tobias,Nielsen, John
, p. 3219 - 3222 (2007/10/03)
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.
