- Design, synthesis, and evaluation of novel hydrazide hydrochlorides of 6-aminopyrazolo[1,5-a]pyrimidine-3-carboxamides as potent Aurora kinase inhibitors
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Abstract: The Aurora kinases play a key role in mitosis and are overexpressed in multiple human tumor types; there has been considerable interest in developing Aurora kinase inhibitors as antitumor agents, particularly Aurora A and Aurora B kinases. A series of novel hydrazide hydrochlorides of pyrazolo[1,5-a]pyrimidine carboxamides were designed and synthesized and their inhibitory activities against Aurora kinases were evaluated. Some of the tested compounds exhibited low micromolar to nanomolar activity with respect to the inhibition of Aurora A kinase. The most potent compound in this series was found to be a potent inhibitor of Aurora A in an HTRF enzymatic assay with an IC50 as low as 23?nM. A structure–activity relationship study indicated that halogen substitution in the benzene ring of amide plays an important role in kinase inhibitory potency. Graphical abstract: [Figure not available: see fulltext.].
- Kumar, A. K. Ajeesh,Bodke, Yadav D.,Sambasivam, Ganesh,Lakra, Peter Serjious
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- Synthesis and biological evaluation of 7-(aminoalkyl)pyrazolo[1,5-a]pyrimidine derivatives as cathepsin K inhibitors
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A series of novel 7-aminoalkyl substituted pyrazolo[1,5-a]pyrimidine derivatives were synthesized and tested for inhibition of cathepsin K. The synthetic methodology comprises cyclization of 5-aminopyrazoles with N-Boc-α-amino acid-derived ynones followed by transformation of the ester and the Boc-amino functions. It allows for easy diversification of the pyrazolo[1,5-a]pyrimidine scaffold at various positions. Molecular docking studies with pyrazolo[1,5-a]pyrimidine derivatives were also performed to elucidate the binding mode in the active site of cathepsin K. The synthesized compounds exhibited moderate inhibition activity (Ki ≥ 77 μM).
- Petek, Nejc,?tefane, Bogdan,Novinec, Marko,Svete, Jurij
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p. 226 - 238
(2018/12/04)
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- Synthetic method of allopurinol
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The invention relates to a synthetic method of allopurinol. The synthetic method comprises the following steps: (1) adding methyl cyanoacetate, triethyl orthoformate and ethyl acetic anhydride into areaction kettle, and stirring and heating for reflux, so as to obtain red brown alpha-ethoxylated methyl cyanoacetate; (2) adding absolute ethyl alcohol and hydrazine hydrate into the reaction kettle,heating for reflux, cooling for crystallization, and filtering, so as to obtain a crystal 3-amino-4-methoxycarbonyl pyrazole; (3) adding 3-amino-4-methoxycarbonyl pyrazole and formamide into the reaction kettle, stirring for reaction, and cooling for crystallization, so as to obtain crude allopurinol; and (4) adding an acid liquid into the reaction kettle, adding crude allopurinol and activated carbon, carrying out suction filtration while the liquid is hot, and carrying out low-temperature crystallization, so as to obtain allopurinol. The method is simple in process, the yield and purity ofthe product are effectively increased, the energy consumption is low in the reaction process, the environmental pollution is low, the raw materials are easily available, the price of allopurinol is low, the quality of the allopurinol is controllable, and an allopurinol finished product meets the standards of 2015 edition of the Pharmacopoeia and is suitable for industrial production.
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Paragraph 0005; 0027; 0031; 0035; 0039; 0043; 0047; 0051
(2018/03/01)
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- Pyridines IRAK4 inhibitors, preparation method and application thereof (by machine translation)
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The invention belongs to the field of medicine, in particular to a formula (I) of the structural features of pyridine of compound or its pharmaceutically acceptable salt, preparation method thereof, and their use as IRAK4 inhibitors. Experimental results show that, the compound of the invention IRAK4 has prominent inhibit function, can be used for the treatment of autoimmune disease, inflammatory disease, cancer, autoimmune disease and thromboembolism as heterogeneous. (by machine translation)
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Paragraph 0086; 0087; 0088
(2017/09/01)
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- ALPHA-UNSUBSTITUTED ARYLMETHYL PIPERAZINE PYRAZOLO[1,5-A] PYRIMIDINE AMIDE DERIVATIVES
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Methods of preventing, treating or delaying the onset of HIV in a subject by administering to the subject novel pharmaceutically active arylmethyl pyrazolo[1,5-α ]pyrimidine amide derivatives, or pharmaceutical compositions containing the same are described. Additionally, compounds of novel pharmaceutically active arylmethyl piperazine pyrazolo[l,5-α]pyrimidine amide derivatives and their use for the manufacture of specific medicaments are described.
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Page/Page column 168
(2008/12/08)
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- Pyrazolopyrimidines
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Pyrazolopyrimidines of the formula in which R1, R2, R3, R4, R5 and X are as defined in the description, processes for preparing these compounds and their use for controlling unwanted microorganisms.
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Page/Page column 46
(2008/12/09)
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- Synthesis and pharmacological activity of triazole derivatives inhibiting eosinophilia
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In order to develop novel antiasthmatic agents based on a new mechanism of action, a series of 3-substituted 5-amino-1- [(methylamino)(thiocarbonyl)]-1H-1,2,4-triazole derivatives were synthesized and evaluated in a model in which eosinophilia was induced in the airway through intravenous (iv) injection of Sephadex particles on days 0, 2, and 5. After screening of several hundred derivatives, we finally identified the highly potent eosinophilia inhibitor 5-amino-3-(4-chlorophenyl)-1- [(methylamino)(thiocarbonyl)]-1H-triazole (23c, GCC-AP0341), which had ID50 values of 0.3 and 0.07 mg/kg when administered orally (os) and intraperitoneally (ip), respectively. This compound showed complete inhibition of the hypersensitivity induced by ascaris inhalation at an ip dose of 1 mg/kg as well as low toxicity, with an LD50 value of >2.0 g/kg in mice. Extensive study of its mechanism of action revealed that 23c inhibited eosinophil survival induced by interleukin-5 (IL-5), but had little or no effect on leukotriene D4 (LTD4) or platelet-activating factor (PAF)- induced responses. Taken together, these results suggest 23c as a novel candidate for the treatment of chronic asthma. Further studies are now underway.
- Naito, Youichiro,Akahoshi, Fumihiko,Takeda, Shinji,Okada, Takehiro,Kajii, Masahiko,Nishimura, Hiroko,Sugiura, Masanori,Fukaya, Chikara,Kagitani, Yoshio
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p. 3019 - 3029
(2007/10/03)
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