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

J Med Chem. 1987 Oct;30(10):1807-12. doi: 10.1021/jm00393a021.

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.

MeSH terms

  • Animals
  • Antipsychotic Agents / chemical synthesis*
  • Antipsychotic Agents / pharmacology
  • Avoidance Learning / drug effects
  • Behavior, Animal / drug effects
  • Corpus Striatum / drug effects
  • Corpus Striatum / metabolism
  • Membranes / drug effects
  • Membranes / metabolism
  • Mice
  • Motor Activity / drug effects
  • Rats
  • Receptors, Dopamine / metabolism
  • Saimiri
  • Self Stimulation / drug effects

Substances

  • Antipsychotic Agents
  • Receptors, Dopamine