1,3-Dialkyl-4-(iminoarylmethyl)-1H-pyrazol-5-ols. A series of novel potential antipsychotic agents

Abstract

2-(Diethylamino)-N-[4-(2-fluorobenzoyl)-1,3-dimethyl-1H-pyrazol-5-yl] acetamide (1) was recently found to have an antipsychotic-like profile in behavioral animal tests but, unlike clinically available antipsychotic agents, did not interact with dopamine receptors. Compound 1 was apparently metabolized to (5-amino-1,3-dimethyl-1H-pyrazol-4-yl)(2-fluorophenyl)methanone (2), which was both active in the behavioral animal tests and toxic. The synthesis and pharmacological evaluation of a series of 1,3-dialkyl-4-(iminoarylmethyl)-1H-pyrazol-5-ols are described in which the hydroxy and imine functionalities were selected as possible isosteric replacements for the amino and ketone groups of the earlier series. The initial target, 1,3-dimethyl-4-(iminophenylmethyl)-1H-pyrazol-5-ol (28), like known antipsychotics, reduced spontaneous locomotion in mice at doses that did not cause ataxia, and unlike known agents, it did not bind to D2 dopamine receptors in vitro. An examination of the SAR of related compounds indicated that maximal activity was obtained with analogues containing methyl groups at the 1- and 3-positions on the pyrazole ring and with a 3-chloro substituent on the phenyl ring. Replacement of the hydrogen atom of the imine moiety with various substituents led to loss of activity. Attempts to synthesize the 2-fluorophenyl compound analogous to 2 resulted in ring-closure to 1,3-dimethyl[1]benzopyrano[2,3-c]pyrazol-4-(1H)-one (65). 4-[(3-Chlorophenyl)iminomethyl]-1,3-dimethyl-1H-pyrazol-5-ol (41) was evaluated in additional tests. It inhibited conditioned avoidance responding in both rats and monkeys but, unlike available antipsychotic drugs, did not elicit dystonic movements in a primate model of antipsychotic-induced extrapyramidal side effects.

Synthesis and antimicrobial activity of substituted [(pyrazol‐4‐yl)methylene]hydrazono‐2,3‐dihydrothiazoles and their sugar derivatives

“…Deprotection of the acetylated sugar of unnatural nucleoside derivative 9 using a methanolic ammonia solution afforded the free hydroxyl nucleoside 10 in 91% yield (Scheme 2). The structures of these alkylated products were proved by IR, 1 H NMR, and mass spectra which agreed with the assigned structure.…”

“…The chemistry of 1H-pyrazole containing compounds is particularly interesting because of their potential application in medicinal chemistry as analgesic [1,2], anti-inflammatory [3], antitumor [4,5], antimicrobial [6][7][8][9] and therapeutic agents [10], as well as based on their wide applications in agriculture as potent insecticides [11] and herbicides [12], although scarcely found in nature [13]. Due to many promising pharmacological, agrochemical, and analytical applications, a number of substituted pyrazoles are being used as inhibitors of heat-shock protein 90 (HSP90) and as therapeutics of cancer and therefore they have been the focus of many synthetic targets over the past decades [14].…”

A convenient synthesis and molecular modeling study of novel pyrazolo[3,4-d]pyrimidine and pyrazole derivatives as anti-tumor agents

“…The chemistry of 1H-pyrazole-containing compounds is particularly interesting because of their potential application in medicinal chemistry as analgesic 1,2 , anti-inflammatory 3,4 , antitumor 5,6 , antimicrobial [7][8][9][10][11] and therapeutic agents 12 , as well as based on their wide applications in agriculture as potent insecticides 13,14 and herbicides 15,16 , although scarcely found in nature 17 . Due to many promising pharmacological, agrochemical, and analytical applications, a number of substituted pyrazoles are being used as inhibitors of heat-shock protein 90 (HSP90) and as therapeutics of cancer and therefore they have been the focus of many synthetic targets over the past decades 18 .…”

“…On the other hand, refluxing the acid hydrazide 10 with carbon disulfide in alcoholic KOH afforded 1,3,4-oxadiazole-2(3H) 1 H NMR that revealed the presence of signals of NH 2 , NH groups in 12 as well as one additional singlet signal for NH 2 group at 2.0 ppm for compound 13. Their 13 C NMR spectra correspond very well with their assigned structures.…”

A Concise One‐Pot Synthesis of 3,4‐Diaryl‐1H‐pyrazoles from Natural Isoflavones and Hydrazine Hydrate

“…-The chemistry of 1H-pyrazoles is particularly interesting because of their potential application in medicinal chemistry as analgesic [1] [2], anti-inflammatory [3] [4], antitumor [5] [6], antimicrobial [7] [8], or therapeutic agents [9], as well as based on their wide applications in agriculture as potent insecticides [10] [11] and herbicides [12] [13], although scarcely found in nature [14]. Due to many promising pharmacological, agrochemical, and analytical applications, 3,4-diarylpyrazoles are being used as inhibitors of heat-shock protein 90 (HSP90) and as therapeutics of cancer.…”