Abstract:Chemoselective O‐alkylation of 1‐aryl‐3‐polyfluoroalkylpyrazol‐5‐oles under basic conditions resulted in a series of 5‐alkoxypyrazoles (26 derivatives). They showed an acceptable ADME profile (in silico) and can be considered as drug‐like. In experiments in vivo (CD‐1 mice), it was found that the obtained compounds do not have toxic properties at a dose of more than 150 mg/kg (for most compounds at a dose of >300 mg/kg, and for lead compounds – >600 mg/kg). 22 Compounds from this series demonstrated from moder… Show more
“…We considered the use of this reagent to be prospective since the recently obtained butoxyl derivative of 1phenyl-3-(trifluoromethyl)pyrazole showed promising analgesic activity in vivo in "hot plate" test acting as partial agonists of TRPV1 ion channels. [41] However, it turned out that the alkylation of pyrazoles 1 a-c with butyl bromide, regardless of various varied conditions (refluxing in acetone, DMF or MeCN in the presence of bases K 2 CO 3 , Cs 2 CO 3 , K 2 CO 3 /KI, NaOH or DBU, heating in a closed steel vessel in pentanol at 190 °C in presence of K 2 CO 3 /KI) did not proceed smoothly, and it was accompanied by the complicated mixtures formation according to GC/MS data. We were able to isolate the alkylated products only from the reaction of 4-amino-NH-pyrazole 1 a.…”
Section: Chemistrymentioning
confidence: 99%
“…The hot plate test was conducted according to established guidelines [57,58] and described in detail in our previous publication. [41]…”
Section: Analgesic Activity the "Hot Plate" Testmentioning
To develop the new analgesics, different approaches to the modification of 4‐amino‐5‐phenyl‐3‐(trifluoromethyl)pyrazoles were proposed. A series of 4‐(het)arylimino‐3‐(trifluoromethyl)‐5‐phenylpyrazoles, existing as the E‐isomer, was synthesized by condensation of the 4‐aminopyrazoles with various aldehydes. Methylation of the initial substrates occurred at the NH2 group, while alkylation with bromobutyl was successfully carried out only for NH‐pyrazole to yield 3‐ and 5‐CF3‐isomeric N‐butyl‐substituted pyrazoles. The addition of phenylisothiocyanate to 4‐aminopyrazoles allowed us to introduce a thiourea fragment into their structure. According to computer calculations, all derivatives of aminopyrazoles have an acceptable ADME profile. Using the “hot plate” test in vivo, the analgesic activity of a number of the synthesized compounds was evaluated. Introducing the phenylmethanimine fragment allows us to obtain 1‐phenyl‐N‐(5‐phenyl‐3‐(trifluoromethyl)pyrazol‐4‐yl)methan‐imine as the lead compound with the analgesic activity in 1.4–2.2 times more than effect of the initial 4‐aminopyrazole, diclofenac and metamizole. In addition, the lead compound had low acute toxicity.
“…We considered the use of this reagent to be prospective since the recently obtained butoxyl derivative of 1phenyl-3-(trifluoromethyl)pyrazole showed promising analgesic activity in vivo in "hot plate" test acting as partial agonists of TRPV1 ion channels. [41] However, it turned out that the alkylation of pyrazoles 1 a-c with butyl bromide, regardless of various varied conditions (refluxing in acetone, DMF or MeCN in the presence of bases K 2 CO 3 , Cs 2 CO 3 , K 2 CO 3 /KI, NaOH or DBU, heating in a closed steel vessel in pentanol at 190 °C in presence of K 2 CO 3 /KI) did not proceed smoothly, and it was accompanied by the complicated mixtures formation according to GC/MS data. We were able to isolate the alkylated products only from the reaction of 4-amino-NH-pyrazole 1 a.…”
Section: Chemistrymentioning
confidence: 99%
“…The hot plate test was conducted according to established guidelines [57,58] and described in detail in our previous publication. [41]…”
Section: Analgesic Activity the "Hot Plate" Testmentioning
To develop the new analgesics, different approaches to the modification of 4‐amino‐5‐phenyl‐3‐(trifluoromethyl)pyrazoles were proposed. A series of 4‐(het)arylimino‐3‐(trifluoromethyl)‐5‐phenylpyrazoles, existing as the E‐isomer, was synthesized by condensation of the 4‐aminopyrazoles with various aldehydes. Methylation of the initial substrates occurred at the NH2 group, while alkylation with bromobutyl was successfully carried out only for NH‐pyrazole to yield 3‐ and 5‐CF3‐isomeric N‐butyl‐substituted pyrazoles. The addition of phenylisothiocyanate to 4‐aminopyrazoles allowed us to introduce a thiourea fragment into their structure. According to computer calculations, all derivatives of aminopyrazoles have an acceptable ADME profile. Using the “hot plate” test in vivo, the analgesic activity of a number of the synthesized compounds was evaluated. Introducing the phenylmethanimine fragment allows us to obtain 1‐phenyl‐N‐(5‐phenyl‐3‐(trifluoromethyl)pyrazol‐4‐yl)methan‐imine as the lead compound with the analgesic activity in 1.4–2.2 times more than effect of the initial 4‐aminopyrazole, diclofenac and metamizole. In addition, the lead compound had low acute toxicity.
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