Fluorination of 3-(3-(Piperidin-1-yl)propyl)indoles and 3-(3-(Piperazin-1-yl)propyl)indoles Gives Selective Human 5-HT_1D Receptor Ligands with Improved Pharmacokinetic Profiles

Abstract

It has previously been reported that a 3-(3-(piperazin-1-yl)propyl)indole series of 5-HT1D receptor ligands have pharmacokinetic advantages over the corresponding 3-(3-(piperidin-1-yl)propyl)indole series and that the reduced pKa of the piperazines compared to the piperidines may be one possible explanation for these differences. To investigate this proposal we have developed versatile synthetic strategies for the incorporation of fluorine into these ligands, producing novel series of 4-fluoropiperidines, 3-fluoro-4-aminopiperidines, and both piperazine and piperidine derivatives with one or two fluorines in the propyl linker. Ligands were identified which maintained high affinity and selectivity for the 5-HT1D receptor and showed agonist efficacy in vitro. The incorporation of fluorine was found to significantly reduce the pKa of the compounds, and this reduction of basicity was shown to have a dramatic, beneficial influence on oral absorption, although the effect on oral bioavailability could not always be accurately predicted.

The role of fluorine in medicinal chemistry

“…Substitution with fluorine to reduce the pK a of molecules has been investigated by van Niel et al [27] by fluorination of 3-(3-(piperidin-1-yl)propyl)indoles and 3-(3-(piperizin-1-yl)propyl)indoles to give selective human 5HT 1D receptor ligands which have improved pharmacokinetic profiles, following the discovery of the migraine drug Sumatriptan. The piperazine was found to be rapidly absorbed and orally bioavailable but the corresponding piperidine analogue lacked good absorption and bioavailability and one explanation for this was the reduced pK a of the piperazine nitrogen.…”

STEREOSELECTIVE SYNTHESIS OF PSEUDOGLYCAL C-GLYCOSIDES VIA TRICHLOROACETIMIDATE ACTIVATION OF GLYCALSa

“…Table 1) also behaved identically to give C-glycoside 8b in 89% yield. The success of C-glycosylation of 2 with silyl enol ether 9a [25] furnishing 9b (entry 7, Table 1) is notable, since this indicates that similar Boc-protected amino acid derivatives will be suitable substrates for these reaction conditions, thereby allowing access to C-glycosyl amino acids, which have become objects of synthetic interest. [26 -32] The a-configurations of compounds 8b and 9b were confirmed by the appearance of the anomeric protons as a doublet of doublet at d 4.33 with a coupling constant value of J 1,2 = 3.3, 6.1 Hz for 8b and a multiplet at d 4.39 for 9b, respectively.…”

“…[26 -32] The a-configurations of compounds 8b and 9b were confirmed by the appearance of the anomeric protons as a doublet of doublet at d 4.33 with a coupling constant value of J 1,2 = 3.3, 6.1 Hz for 8b and a multiplet at d 4.39 for 9b, respectively. 25. The a-configuration at C-1 in the reaction products was established by careful 1 H NMR analysis and comparison with the spectroscopic data recorded in literature.…”

“…Allyltrimethylsilane (3a), 2-bromoallyltrimethylsilane (4a), 2-acetoxymethylallyltrimethylsilane (5a), propargyltrimethylsilane (6a), 1-phenyl-1-trimethylsiloxyethylene (7a) and 1-trimethylsiloxycyclohexene (8a) were purchased from Aldrich Chemical and used as received. 1-tert-Butoxycarbonyl-1,2,3,6-tetrahydro-4-(trimethylsilyloxy)pyridine (9a) [25] and [1-(3-benzyloxy-4,5-dimethyltetrahydrofuran-2-yl)-vinyloxy]trimethylsilane (3a) [33] were prepared according to the literature procedures. N,N-Dimethylformamide (DMF), dichloromethane (CH 2 Cl 2 ), and pyridine were distilled from CaH 2 and stored over molecular sieves.…”

A β-Fluoroamine Inhibitor of Purine Nucleoside Phosphorylase

“…(19) There are many studies connecting the decrease in p K a associated with β-fluorination of aliphatic amines with changes in biological properties. Some examples include: reduced affinity of fluoroisoquinolines for the α 2 -adrenoceptor,(20) increased activity of lung N -methyltransferase for fluoroalkylarylamines,(21) changes in affinity and activity of propranolols for cytochrome oxidase enzymes,(22, 23) increased oral absorption of fluorinated piperidine and piperazine indoles,(24) and changes in metabolism and tissue distribution of amphetamines. (25)…”