4-Amino-4-arylcyclohexanones and their derivatives: a novel class of analgesics. 2. Modification of the carbonyl function

Abstract

The effect on potency of modification of the carbonyl function of analgesics derived from 4-(dimethylamino)-4-arylcyclohexan-1-one was studied by reduction and by addition of nucleophiles. The resulting amino alcohols were separated and assigned structures on the basis of X-ray crystallography, NMR, and TLC mobility. The trans (OH and N) isomers were invariably more potent than the cis. Inclusion of flat lipophilic moieties (phenyl, cyclohexenyl) at a distance of at least two carbon atoms from the carbon bearing hydroxyl led to increases in potency by orders of magnitude. The possible significance of this on receptor interaction is discussed.

A Small‐Molecule Inhibitor of Prion Replication and Mutant Prion Protein Toxicity

“…We identified six compounds ( 55 , 58 , 59 , 60 , 68 and 95 ) capable of rescuing cell viability in the DBCA in a dose‐dependent fashion (Figure ). Interestingly, five of these molecules ( 55 , 58 – 60 and 68 ) share a high degree of chemical similarity, with a common alkynylcyclohexenylamine‐based scaffold . These compounds showed relatively low intrinsic cytotoxicity, as assayed in HEK293 expressing ΔCR or wild‐type (WT) PrP (Figures S3 and S4).…”

“…Interestingly,f ive www.chemmedchem.org of these molecules (55, 58-60 and 68)s hare ah igh degree of chemicals imilarity,w ithac ommon alkynylcyclohexenylaminebased scaffold. [12] These compounds showed relativelyl ow intrinsic cytotoxicity,a sa ssayed in HEK293 expressing DCR or wild-type (WT) PrP ( Figures S3 and S4).…”

Synthesis of tritium and deuterium labeled 8‐N‐n‐butyl‐N‐methylamino‐8‐(3‐hydroxyphenyl)‐1,4‐dioxaspiro[4,5]decane hydrochloride

“…The title compound l c (1) isa member of a group of 4-amino-4arylcyclohexanone derivatives which exhibit interesting analgesic activities (1)(2)(3)(4). Compound Ic was selected as a candidate with potential clinical utility, and we undertook the synthesis of a radioactive form of the compound for conducting drug metabolism and disposition studies in test animals.…”

“…Compound Ic was selected as a candidate with potential clinical utility, and we undertook the synthesis of a radioactive form of the compound for conducting drug metabolism and disposition studies in test animals. subsequently for specifically preparing I c from 1,4-dioxaspir0 [4,5]decan-8-one (2) and this route has been modified to permit synthesis of labeled 1 as shown in Scheme 1. We took advantage of the enolizable protons a t the C-7 and C-9 positions of 2, which could be readily exchanged with tritium from tritiated water.…”

“…was obtained in 18.2% chemical yield from tritium labeled 1.4-dioxaspiro [4,5]decan-8-one (36). The specific activities of 3b and lb were 304.1 hour.…”