- Lipase-catalyzed alcoholytic resolution of (R,S)-flurbiprofenyl azolides for preparation of (R)-NO-flurbiprofen ester prodrugs
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A lipase-catalyzed alcoholysis of (R,S)-flurbiprofenyl azolide in anhydrous methyl tert-butyl ether (MTBE) has been developed for the preparation of (R)-flurbiprofenyl ester, (S)-flurbiprofenyl azolide and hence (S)-flurbiprofen. On the basis of enzyme en
- Ciou, Jyun-Fen,Wang, Pei-Yun,Wu, An-Chi,Tsai, Shau-Wei
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Read Online
- Scalable 9-Step Synthesis of the Splicing Modulator NVS-SM2
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NVS-SM2, the first activator of pre-mRNA splicing, displays remarkable pharmacological in vivo activities in models of spinal muscular atrophy. Herein we describe an improved approach to the synthesis of this compound, which features a convenient introduction of sterically encumbered amine moiety onto a fluoropyridazine intermediate.
- Abou-Hamdan, Hussein,Désaubry, Laurent
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Read Online
- Synthesis method for synthesizing N-protected 3-bromopyrazole by one-pot method
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The invention provides a synthesis method for synthesizing N-protected 3-bromopyrazole by one-pot method, which comprises the steps that pyrazole reacts with a bromination reagent to obtain 3-bromo-pyrazole, and then 3-bromo-pyrazole is subjected to 'one-pot' reaction and vinyl ether reaction to obtain N-protected 3-bromo-pyrazole. According to the preparation method, the post-treatment step required by the first step of the two-step process is omitted, and the industrial production efficiency is greatly improved.
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Paragraph 0019; 0022-0037
(2021/04/10)
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- Cytotoxic Ruthenium(II) Complexes of Pyrazolylbenzimidazole Ligands That Inhibit VEGFR2 Phosphorylation
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Eight new ruthenium(II) complexes of N,N-chelating pyrazolylbenzimidazole ligands of the general formula [RuII(p-cym)(L)X]+ [where the ligand L is 2-(1H-pyrazol-1-yl)-1H-benzo[d]imidazole (L1) substituted at the 4 position of the pyrazole ring by Cl (L2), Br (L3), or I (L4) and X = Cl- and I-] were synthesized and characterized using various analytical techniques. Complexes 1 and 3 were also characterized by single-crystal X-ray crystallography, and they crystallized as a monoclinic crystal system in space groups P21/n and P21/c, respectively. The complexes display good solution stability at physiological pH 7.4. The iodido-coordinated pyrazolylbenzimidazole ruthenium(II) p-cymene complexes (2, 4, 6, and 8) are more resistant toward hydrolysis and have less tendency to form monoaquated complexes in comparison to their chlorido analogues (1, 3, 5, and 7). The halido-substituted 2-(1H-pyrazol-1-yl)-1H-benzo[d]imidazole ligands, designed as organic-directing molecules, inhibit vascular endothelial growth factor receptor 2 (VEGFR2) phosphorylation. In addition, the ruthenium(II) complexes display a potential to bind to DNA bases. The cytotoxicity profile of the complexes (IC50 ca. 9-12 μM for 4-8) against the triple-negative breast cancer cells (MDA-MB-231) show that most of the complexes are efficient. The lipophilicity and cellular accumulation data of the complexes show a good correlation with the cytotoxicity profile of 1-8. The representative complexes 3 and 7 demonstrate the capability of arresting the cell cycle in the G2/M phase and induce apoptosis. The inhibition of VEGFR2 phosphorylation with the representative ligands L2 and L4 and the corresponding metal complexes 3 and 7 in vitro shows that the organic-directing ligands and their complexes inhibit VEGFR2 phosphorylation. Besides, L2, L4, 3, and 7 inhibit the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and proto-oncogene tyrosine-protein kinase (Src), capable of acting downstream of VEGFR2 as well as independently. Compounds L2, L4, 3, and 7 have a lesser effect on ERK1/2 and more prominently affect Src phosphorylation. We extended the study for L2 and 3 in the Tg(fli1:gfp) zebrafish model and found that L2 is more effective in vivo compared to 3 in inhibiting angiogenesis.
- Acharya, Moulinath,Chakraborty, Ayan,Chakraborty, Manas Pratim,Das, Rahul,Koley, Tuhin Subhra,Mukherjee, Arindam,Purkait, Kallol,Roy, Shantanu Saha,Roy, Souryadip
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supporting information
p. 18379 - 18394
(2021/12/01)
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- Synthesis and Evaluation of Pyrazole Derivatives as Potent Antinemic Agents
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Pyrazole derivatives were synthesized by bromination of pyrazole, followed by N-alkylation of 4-bromopyrazole. The synthesized derivatives were characterized by microanalytical data and IR and 1H and 13C NMR spectra and were evaluated for their nematicidal activity against the root knot nematode Meloidogyne incognita. The compounds were screened for their egg hatch inhibition and mortality potential, and they showed significant nematicidal activity as compared to the control. 1H-Pyrazol-5(4H)-one was found to be most effective in egg hatch inhibition, and 4-bromopyrazole was found to be most effective in juvenile mortality.
- Dhillon, N. K.,Jain, N.,Kaur, G.,Utreja, D.
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p. 113 - 118
(2020/03/25)
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- PROCESSES AND INTERMEDIATES FOR MAKING A JAK INHIBITOR
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This invention relates to processes and intermediates for making {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile, useful in the treatment of diseases related to the activity of Janus kinases (JAK) including inflammatory disorders, autoimmune disorders, cancer, and other diseases.
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Paragraph 0120-0121
(2019/08/22)
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- Design and Synthesis of Novel Organic Luminescent Materials Based on Pyrazole Derivative
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Five new materials based on pyrazole derivatives have been synthesized and characterized as organic light-emitting devices. This report presents a novel approach to combine pyrazole with aromatic hydrocarbons via methylene. The formed molecules exhibited twisted structures, which resulted in high glass transition temperatures (Tg), which ranged from 83.0 to 101.1°C. They also had high optical band gaps (Eg); most of their optical band gaps are determined by the absorption edge technique as 3.43 to 3.66?eV, evaluated photophysical properties of these synthesized novel chromophores, the optical properties such as maximum absorption and emission wavelengths (λ; nm), molar extinction coefficients (ε; cm?1·M?1), Stokes' shifts (ΔλST; nm), and quantum yields (φF). These compounds exhibited intense absorption bonds between 230 and 350?nm, and the effect of solvent polarity on emission of these pyrazole derivatives was also studied. In addition, they showed blue fluorescence in different solvents and bathochromic shift with the increase in the solvent polarity.
- Duan, Yingxiang,Zhao, Qian,Yang, Yanhua,Zhang, Jinyang,Tao, Xuan,Shen, Yingzhong
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p. 1464 - 1471
(2019/03/26)
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- Photocatalytic Oxidative Bromination of Electron-Rich Arenes and Heteroarenes by Anthraquinone
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The estimated excited oxidation potential of sodium anthraquinone-2-sulfonate (SAS) increases from 1.8 V to about 2.3 V vs SCE by protonation with Br?nsted acids. This increased photooxidation power of protonated anthraquinone was used for the regio-selective oxidative bromination of electron rich (hetero)arenes and drugs in good yield. The mild reaction conditions are compatible with many functional groups, such as double and triple bonds, ketones, amides and amines, hydroxyl groups, carboxylic acids and carbamates. Mechanistic investigations indicate the photooxidation of the arene followed by nucleophilic bromide addition as the likely pathway. (Figure presented.).
- Petzold, Daniel,K?nig, Burkhard
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supporting information
p. 626 - 630
(2017/11/22)
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- ALKYL-AMIDE-SUBSTITUTED PYRIDYL COMPOUNDS USEFUL AS MODULATORS OF IL-12, IL-23 AND/OR IFNα RESPONSES
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Compounds having the following formula I: or a stereoisomer or a pharmaceutically-acceptable salt thereof, wherein R1, R2, R3, R4, and R5 are as defined herein, are useful in the modulation of IL-12, IL-23 and/or IFNα by acting on Tyk-2 to cause signal transduction inhibition.
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Page/Page column 81
(2017/09/02)
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- A mild halogenation of pyrazoles using sodium halide salts and Oxone
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A mild, inexpensive, and operationally simple pyrazole halogenation method utilizing Oxone and sodium halide salts is reported. This work documents 17 examples of alkyl, aryl, allyl, and benzyl substituted 4-chloro and 4-bromopyrazoles, obtained in up to 93% yield. Reactions are performed in water under ambient conditions and generation of organic byproducts is avoided.
- Olsen, Kathryn L.,Jensen, Matthew R.,MacKay, James A.
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supporting information
p. 4111 - 4114
(2017/09/29)
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- Synthesis of 4-substituted pyrazole-3,5-diamines: Via Suzuki-Miyaura coupling and iron-catalyzed reduction
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A general and efficient synthesis of 4-substituted-1H-pyrazole-3,5-diamines was developed to access derivatives with an aryl, heteroaryl, or styryl group, which are otherwise relatively difficult to prepare. The first step is based on the Suzuki-Miyaura cross-coupling reaction utilizing the XPhos Pd G2 precatalyst. The coupling reactions of 4-bromo-3,5-dinitro-1H-pyrazole with the electron-rich/deficient or sterically demanding boronic acids enabled the production of the corresponding dinitropyrazoles. The subsequent iron-catalyzed reduction of both nitro groups with hydrazine hydrate accomplished the synthesis. The additional demethylation of the 4-methoxystyryl derivative allowed the production of the carboanalog of CAN508 reported as a selective CDK9 inhibitor.
- Tomanová, Monika,Jedinák, Luká?,Ko?a?, Jan,Kvapil, Lubomír,Hradil, Pavel,Canka?, Petr
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p. 10200 - 10211
(2017/12/26)
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- ALKYL-AMIDE-SUBSTITUTED PYRIDYL COMPOUNDS USEFUL AS MODULATORS OF IL-12, IL-23 AND/OR IFNALPHA RESPONSES
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Compounds having the following formula (I): or a stereoisomer or a pharmaceutically-acceptable salt thereof, wherein R1, R2, R3, R4, and R5 are as defined herein, are useful in the modulation of IL-12, IL-23 and/or IFNα by acting on Tyk-2 to cause signal transduction inhibition.
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Paragraph 00173
(2015/05/26)
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- Difluoromethyl ketones: Potent inhibitors of wild type and carbamate-insensitive G119S mutant Anopheles gambiae acetylcholinesterase
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Malaria is a devastating disease in sub-Saharan Africa, and current vector control measures are threatened by emerging resistance mechanisms. With the goal of developing new, selective, resistance-breaking insecticides we explored α-fluorinated methyl ketones as reversible covalent inhibitors of Anopheles gambiae acetylcholinesterase (AgAChE). Trifluoromethyl ketones 5 demonstrated remarkable volatility in microtiter plate assays, but 5c,e-h exhibited potent (1-100 nM) inhibition of wild type (WT) AgAChE and weak inhibition of resistant mutant G119S mutant AgAChE. Fluoromethyl ketones 10c-i exhibited submicromolar to micromolar inhibition of WT AgAChE, but again only weakly inhibited G119S AgAChE. Interestingly, difluoromethyl ketone inhibitors 9c and 9g had single digit nanomolar inhibition of WT AgAChE, and 9g had excellent potency against G119S AgAChE. Approach to steady-state inhibition was quite slow, but after 23 h incubation an IC50 value of 25.1 ± 1.2 nM was measured. We attribute the slow, tight-binding G119S AgAChE inhibition of 9g to a balance of steric size and electrophilicity. However, toxicities of 5g, 9g, and 10g to adult A. gambiae in tarsal contact, fumigation, and injection assays were lower than expected based on WT AgAChE inhibition potency and volatility. Potential toxicity-limiting factors are discussed.
- Camerino, Eugene,Wong, Dawn M.,Tong, Fan,K?rber, Florian,Gross, Aaron D.,Islam, Rafique,Viayna, Elisabet,Mutunga, James M.,Li, Jianyong,Totrov, Maxim M.,Bloomquist, Jeffrey R.,Carlier, Paul R.
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p. 4405 - 4411
(2015/10/12)
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- Rapid kinetics and relative reactivity of some five membered aromatic heterocycles using hydrodynamic voltammetry
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Kinetics of the bromination of imidazole, pyrazole and thiazole by molecular bromine and N-bromosuccinimide has been studied in aqueous medium. Since the reactions are rapid special technique namely, hydrodyanamic voltammetry has been employed to follow the course of the reactions. These reactions follow second order kinetics. The comparative kinetic data determines the reactivity order for these heterocycles towards the bromination using two different brominating reagents. The study justifies the stereochemical principles ascertaining the relative reactivity of these heterocycles quantitatively using kinetics as an investigational tool.
- Walke,Bonde,Bhadane,Dangat,Jadhav
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p. 2239 - 2245
(2016/02/27)
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- PROCESS FOR MAKING BENZOXAZEPIN COMPOUNDS
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Processes are described for the preparation of PI3K inhibitor, GDC-0032, Formula (I), having the structure: Formula (I) (GDC-0032), and intermediates useful for the preparation of (I).
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Page/Page column 13; 28
(2014/09/29)
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- AMIDE-SUBSTITUTED HETEROCYCLIC COMPOUNDS USEFUL AS MODULATORS OF IL-12, IL-23 AND/OR IFN ALPHα RESPONSES
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Compounds having the following formula I: or a stereoisomer or pharmaceutically-acceptable salt thereof, where R1, R2, R3, R4, and R5 are as defined herein, are useful in the modulation of IL-12, IL-23 and/or IFNa, by acting on Tyk-2 to cause signal transduction inhibition.
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Paragraph 00249
(2014/05/24)
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- Brominations with Pr4NBr9 as a solid reagent with high reactivity and selectivity
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Tetrapropylammonium nonabromide (Pr4NBr9) is introduced as a room-temperature solid reagent for rapid bromination reactions of various substrates. The reagent exhibits reactivity similar to that of elemental bromine, but shows higher selectivity and it is easier and safer to store and to handle. Georg Thieme Verlag Stuttgart · New York.
- Beck, Thorsten M.,Haller, Heike,Streuff, Jan,Riedel, Sebastian
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p. 740 - 747
(2014/04/03)
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- PROCESSES AND INTERMEDIATES FOR MAKING A JAK INHIBITOR
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This invention relates to processes and intermediates for making {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile, useful in the treatment of diseases related to the activity of Janus kinases (JAK) including inflammatory disorders, autoimmune disorders, cancer, and other diseases.
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Paragraph 0163
(2014/09/29)
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- Synthesis of 4-aryl-1H-pyrazoles by Suzuki-Miyaura cross coupling reaction between 4-bromo-1H-1-trityl-pyrazole and arylboronic acids
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A general procedure for the synthesis of 4-aryl-1H-pyrazoles by the Suzuki-Miyaura cross coupling reaction between 4-bromo-1H-1-tritylpyrazole and commercially available arylboronic acids was developed. Using this procedure, a direct synthesis of 4-aryl-1H-pyrazoles possessing functional groups, such as hydroxyl, nitro, and amino groups, on the aryl ring was realized. Those molecules could not be prepared by our previous synthesis of 4-aryl-1H-pyrazoles via the Kumada cross coupling reaction.
- Ichikawa, Hayato,Nishioka, Miho,Arimoto, Masao,Usami, Yoshihide
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experimental part
p. 1509 - 1516
(2010/12/24)
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- PROCESSES FOR PREPARING JAK INHIBITORS AND RELATED INTERMEDIATE COMPOUNDS
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The present invention is related to processes for preparing chiral substituted pyrazolyl pyrrolo[2,3-d]pyrimidines of Formula III, and related synthetic intermediate compounds. The chiral substituted pyrazolyl pyrrolo[2,3-d]pyrimidines are useful as inhibitors of the Janus Kinase family of protein tyrosine kinases (JAKs) for treatment of inflammatory diseases, myeloproliferative disorders, and other diseases.
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Page/Page column 105
(2010/08/07)
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- Tec Kinase Inhibitors
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Disclosed are compounds of formula (I): wherein Q, R1, R2, R3, R4 and R5 are defined herein. The compounds of the invention inhibit Itk kinase and are therefore useful for treating diseases and pathological conditions involving inflammation, immunological disorders and allergic disorders. Also disclosed are processes for preparing these compounds and to pharmaceutical compositions comprising these compounds.
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Page/Page column 12
(2008/12/04)
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- 7-AZAINDOLE DERIVATIVES AND THEIR USE IN THE INHIBITION OF C-JUN N-TERMINAL KINASE
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The present invention provides a compound of formula (I); or a pharmaceutically acceptable salt thereof, the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the inhibition of c-Jun N-terminal kinase (JNK) activity and the use in medicine and particularly in the treatment of neurodegenerative disorders, inflammatory diseases and/or and autoimmune diseases. The invention also provides processes for the manufacture of said compounds of formula (I) or a pharmaceutically acceptable salt thereof and compositions containing them
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Page/Page column 225
(2008/12/08)
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- Halogenation of pyrazoles using N-halosuccinimides in CCl4 and in water
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Reaction of pyrazoles with N-halosuccinimides (NXS, X=Br, Cl) in either CCl4 or water gave 4-halopyrazoles in excellent yields. The reaction was carried out under mild conditions and did not require any catalysts or special precautions. The reaction provides an efficient method for 4-C halogenation of pyrazoles. Copyright Taylor & Francis Group, LLC.
- Zhao, Zhi-Gang,Wang, Zhong-Xia
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p. 137 - 147
(2007/10/03)
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- N-benzoylpyrazoles are novel small-molecule inhibitors of human neutrophil elastase
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Human neutrophil elastase (NE) plays an important role in the pathogenesis of pulmonary disease. Using high-throughput chemolibrary screening, we identified 10 N-benzoylpyrazole derivatives that were potent NE inhibitors. Nine additional NE inhibitors were identified through further screening of N-benzoylpyrazole analogues. Evaluation of inhibitory activity against a range of proteases showed high specificity for NE, although several derivatives were also potent inhibitors of chymotrypsin. Analysis of reaction kinetics and inhibitor stability revealed that N-benzoylpyrazoles were pseudoirreversible competitive inhibitors of NE. Structure-activity relationship (SAR) analysis demonstrated that modification of N-benzoylpyrazole ring substituents modulated enzyme selectivity and potency. Furthermore, molecular modeling of the binding of selected active and inactive compounds to the NE active site revealed that active compounds fit well into the catalytic site, whereas inactive derivatives contained substituents or conformations that hindered binding or accessibility to the catalytic residues. Thus, N-benzoylpyrazole derivatives represent novel structural templates that can be utilized for further development of efficacious NE inhibitors.
- Schepetkin, Igor A.,Khlebnikov, Andrei I.,Quinn, Mark T.
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p. 4928 - 4938
(2008/03/13)
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- Estrogen receptor modulators
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Estrogen receptor-modulating pyrazole compounds are described in addition to methods and compositions for treating or preventing estrogen receptor-mediated disorders. The compounds described have been found to have unexpected and surprising activity in modulating estrogen receptor activity. Thus, the compounds of the present invention have utility in preventing or treating estrogen receptor-mediated disorders such as osteoporosis, breast and endometrial cancers, atherosclerosis, and Alzheimer's disease.
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- Metallacarborane chelates
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Metallacarborane chelate-antibody compounds which are useful for radioimmunodetection and radiotherapy. The compounds have the formula STR1 wherein X is a metal or radioisotope of said metal, Y is a rotation resistant organic chelate bridge moiety, Z is an antibody linkage moiety and AB is an antibody. Metallacarborane chelate and carborane chelate compounds are also disclosed which are useful in preparing the final metallacarborane chelate-antibody compound which is used for radioimmunodetection and radiotherapy.
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- Metal pyrazolate polymers. Part 2. Synthesis, structure, and magnetic properties of x polymers (where X = Cl, Br, Me, H; pz = pyrazolate)
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Novel and reliable methods for the synthesis of the polymers x, (where X = H, Cl, Br, and Me; pz =pyrazolate) are presented.The X = Cl compound was obtained as green and brown forms.Single crystals of the polymers with X = Me and X = Cl (green form) suitable for X-ray analysis have been obtained. x and x are isomorphous, crystallizing with four formula units per unit-cell in the orthorhombic space group Ibam, a = 9.7436(6), 9.155(4), b = 12.6106(8), 12.968(6), and c = 7.7482(6), 7.717(5) Angstroem, respectively, for the 4-Me and 4-Cl derivatives.The structures were refined by full-matrix least-squares procedures to R = 0.027 and 0.041 for 430 and 246 reflections with I >/= 3?(I), respectively.Magnetic susceptibility studies over the temperature range 2 to 300 K have revealed that all the polymers exhibit very strong antiferromagnetic exchange between copper(II) centres in the extended linear chains.Discontinuities displayed in the susceptibility versus temperature plots suggest the presence of phase transitions at ca. 133 and ca. 108 K in the X = Cl (green form) and X = Br materials, respectively.The four compounds, X = H, Br, Me, and Cl (green form) also exhibit thermochromism over the 77 to 176 K region.The magnetic data have been analyzed employing an isotropic Heisenberg model for antiferromagnetic exchange in extended chain polymers.Values of the exchange coupling constant, J, for for the room temperature forms of these materials are determined as -81, -105, -96, -104, and -88 cm-1 for 4-X = H, Br, Me, Cl (green form), and Cl (brown form), respectively.The magnitude of the exchange coupling is discussed in relation to structural parameters for the X = H, Me, and Cl (green form) compounds.
- Ehlert, Martin K.,Rettig, Steven J.,Storr, Alan,Thompson, Robert C.,Trotter, James
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p. 432 - 439
(2007/10/02)
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- ACIDIFYING EFFECTS OF AZA GROUPS IN THE NH ACIDITY OF AMINOAZINES AND THE CH ACIDITY OF ACETYLAZINES
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The pK values for a series of aminoazines and acetylazines containing one, two, or three aza groups in the ring were determined in dimethyl sulfoxide.There is a good linear correlation between pK values of the investigated NH and CH acids.The acidifying effects (ΔpK) of the aza groups at positions 2, 3, or 4 in relation to the side chain were determined and had values of 3.1, 2.4, and 4.5 logarithmic units in the aminoazines and 3.5, 2.9 and 4.8 logarithmic units respectively in the acetylazines.Except in the case of two ortho-located aza groups the effects are additive.Compared with dimethyl sulfoxide water has a differentiating effect on the acidity of the aminoazines, and this is explained by the formation of hydrogen bonds between the molecules of the proton-donating solvent and the aza groups of the anions of the aminoazines.
- Terekhova, M. I.,Petrov, E. S.,Mikhaleva, M. A.,Shkurko, O. P.,Mamaev, V. P.,Shatenshtein, A. I.
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