4-Phenyl- and 4-heteroaryl-4-anilidopiperidines. A novel class of analgesic and anesthetic agents

Abstract

The incorporation of the 4-phenylpiperidine pharmacophore found in morphine into 4-anilidopiperidines related to fentanyl (1) led to a novel class of potent opioid analgesic and anesthetic agents with a favorable pharmacological profile. The synthesis, analgesic activity, and anesthetic properties of a series of 4-phenyl-4-anilidopiperidines (13-29) are discussed. Isosteric replacement of the phenyl by various heteroaryl substituents extended the series to include 4-heteroaryl-4-anilidopiperidines (30-53). Within this group, 1-[2-(1H-pyrazol-1-yl)ethyl]-4-(4-methylthiazol-2-yl)-4-(N- phenylpropionamido)piperidine (48), exhibited high analgesic potency, short duration of action, rapid recovery of motor coordination following anesthetic doses, and greater cardiovascular and respiratory safety during anesthesia as compared with opioids fentanyl (1) and alfentanil (2) currently in clinical use. Such analgesics could be of great utility to clinicians in the expanding outpatient surgical arena and for patient-controlled analgesia and computer assisted continuous infusion pain control techniques.

Long-Acting Fentanyl Analogues: Synthesis and Pharmacology of N-(1-Phenylpyrazolyl)-N-(1-phenylalkyl-4-piperidyl)propanamides

“…Next, reflux of the resulting amines in propionic anhydride afforded the desired amides 3a-d and 4a. The debenzylation could not be achieved by catalytic hydrogenation; however, treatment with 1-chloroethylchloroformate 14 followed by methanolysis removed the benzyl group in good yield. Alkylation of the N-deprotected derivatives 5a and 6 with 1-phenyl-2-bromoethane gave the respective phenethyl derivatives 3b and 4b.…”

Evolution of the 4‐anilidopiperidine class of opioid analgesics

“…Axial orientation of these aryl substituents is supported by single-crystal x-ray diffractometry of a representative compound (51). 59 Lin et al generated other heteropentacyclic systems either in a manner similar to the former one when this was feasible or, alternatively, through incorporation of the original nitrile group of appropriate a-nitrile anilines,'* and has also reported the pharmacology of the final compounds.60,61 Representative structures (56)(57)(58)(59)(60) from this second project are also shown in Table VIII. Kudzma et ~l . , '~ in general, found that the most potent analgesics had a phenethyl and a 2-or 3-thienylethyl substituent at the piperidino nitrogen and that an ortho-fluorine on the anilido phenyl enhanced analgesic activity, while a chlorine diminished analgesia (data not shown).…”

“…Additional methylation of the thiazole ring abolished activity. 59 In the 4-methyl-2-thiazole subseries substitution at the N-1 with the 2-(1H-pyrazol-l-y1) group (55) yielded the shortest-acting analgesic in the entire series as well as significantly improving the cardiovascular and respiratory safety profile relative to fentanyl and alfentanil. Compounds 51 and 55 also showed rapid recovery of motor coordination following administration of anesthetic doses in rats.…”

“…It also exhibited the highest possible ROI score (60.0) in the rat rotorod for measurement of recovery of motor coordination, a test where the clinically utilized opioids score poorly. 59 The respiratory effects of increasing analgesic doses of both of these short-acting analgesics were compared in the rat. In the conscious, freely moving rat, 55 required approximately three-fold RTF ED5,, multiples of alfentanil to elicit an increase in arterial COz levels of greater than 50% (Fig.…”

A Facile Method for Preparation of [2H3]-Sufentanil and Its Metabolites

“…15,16) Other methods of debenzylation either employ Pearlman's catalyst 12,17 at high pressure (55-60 psi) and elevated temperature (50°C) or converting the benzyl group to carbamate followed by hydrolysis. [18][19][20] Attempted catalytic transfer hydrogenation as well as hydrogenation of 7 with 10% Pd/C (10 to 25 wt% loading) at 50-60 psi hydrogen atmosphere at ambient temperature did not show any product formation in different solvents. The intermediates 5 and 6 under similar conditions were sluggish and no debenzylated product was observed.…”