49637-20-9Relevant articles and documents
Conformational analysis of 5-piperidinevaleric acid, 5-(N- methylpiperidine)valerate and their hydrogen halides by MO calculations, X- ray, diffraction and FTIR spectroscopy
Szafran, Miroslaw,Dega-Szafran, Zofia,Dulewicz, Ewa,Kosturkiewicz, Zofia,Nowakowska, Magdalena,Orwat, Wioletta,Ratajczak-Sitarz, Malgorzata
, p. 125 - 138 (1999)
The most stable conformers of 5-(piperidine)valeric acid (1), 5-(N- methylpiperidine)valerate (2) and their hydrogen halides (3 and 4) were analyzed by the semiempirical PM3 method and selected compounds by the B3LYP/6-31G(d,p) method. As some of the investigated compounds are charged and the others can be neutral, some have acidic proton, others do not. They are capable of forming ionic bonds (via Coulombic attraction between the oppositely charged groups) or of forming the various types of hydrogen bonded conformers. As a result these compounds are ideally suited to study the importance of electrostatic interactions and hydrogen bonding on the relative stabilities of conformers. In the case of compounds containing N- methylpiperidine unit, for a particular conformer, the intramolecular attractive electrostatic interactions between the charged group play key roles in their relative stability in the gas phase. The electrostatic interaction of the X- ion with the positively charged nitrogen atom decreases their proton-acceptor properties and COOH···X- hydrogen bonds are present in all hydrogen halides (3). 5-Piperidine valeric acid with HF forms a molecular complex, while with HCl, HBr and HI an ion pair, according to the B3LYP calculations. The PM3 calculations predict a molecular complex also with HCl. The crystal structure of 5-(piperidine)valeric acid hydrogen bromide (4HBr), space group of crystals P21/n with a = 6.204(1), b = 32.777(7), c = 6.416(1) A, β = 106.21(3)°, Z = 4 and R = 0.0685 was characterized by X-ray crystallography methods. Br- ion forms two types of hydrogen bonds: Br···N(1), 3.247(14) A, and O(1) ···Br, 3.118(11) A. Moreover, C-H···Br short contacts, which can be recognized as weak hydrogen bonds, exist in the crystal. The FTIR spectrum of 1 in the solid state shows an intense broad absorption in the 1600-400 cm-1 region typical for a very short NHO hydrogen bonds. In solution the hydrogen bond seems to be longer. The bands of vC=O at 1708 cm-1 and v(as)COO- at 1615 cm-1 in CD3CN solution show that OH···N ? O-···HN+ equilibrium exists. Ab initio calculations predict molecular structures of three most stable conformers of 1 in the gas phase.
Discovery of a novel alpha-7 nicotinic acetylcholine receptor agonist series and characterization of the potent, selective, and orally efficacious agonist 5-(4-acetyl[1,4]diazepan-1-yl)pentanoic acid [5-(4-methoxyphenyl)-1H- pyrazol-3-yl] amide (SEN15924, WAY-361789)
Zanaletti, Riccardo,Bettinetti, Laura,Castaldo, Cristiana,Cocconcelli, Giuseppe,Comery, Thomas,Dunlop, John,Gaviraghi, Giovanni,Ghiron, Chiara,Haydar, Simon N.,Jow, Flora,MacCari, Laura,Micco, Iolanda,Nencini, Arianna,Scali, Carla,Turlizzi, Elisa,Valacchi, Michela
, p. 4806 - 4823 (2012/07/28)
Alpha-7 nicotinic acetylcholine receptors (α7 nAChR) are implicated in the modulation of many cognitive functions such as attention, working memory, and episodic memory. For this reason, α7 nAChR agonists represent promising therapeutic candidates for the treatment of cognitive impairment associated with Alzheimer's disease (AD) and schizophrenia. A medicinal chemistry effort, around our previously reported chemical series, permitted the discovery of a novel class of α7 nAChR agonists with improved selectivity, in particular against the α3 receptor subtype and better ADME profile. The exploration of this series led to the identification of 5-(4-acetyl[1,4] diazepan-1-yl)pentanoic acid [5-(4-methoxyphenyl)-1H-pyrazol-3-yl] amide (25, SEN15924, WAY-361789), a novel, full agonist of the α7 nAChR that was evaluated in vitro and in vivo. Compound 25 proved to be potent and selective, and it demonstrated a fair pharmacokinetic profile accompanied by efficacy in rodent behavioral cognition models (novel object recognition and auditory sensory gating).
Aqueous basicity and proton affinity of zwitterionic ω-(N-methylpiperidine)-alkanocarboxylates and ω-(N-piperidine)-alkanocarboxylic acids
Barczynski,Dega-Szafran,Dulewicz,Petryna,Szafran
, p. 1149 - 1161 (2007/10/03)
The pK a values of 5 ω-(N-methylpiperidine)-alkanocarboxylates (N-methylpiperidine betaines) and 5 ω-(N-piperidine)-alkanocarboxylic acid were determined by potentiometric titration of their hydrohalides with KOH. Semiempirical geometry optimizations were performed for gaseous betaines. Four conformers were characterized and their PA values estimated. The PA values fulfilled the linear correlation with the aqueous pKa values estimated in ref. 1. A linear correlation between the calculated heat of formation (ΔHt) and the sum of the N...O1 and N...O2 distances, for the conformers containing the same number of CH2 groups, indicates that they are stabilized by the intramolecular electrostatic interactions between the positively charged nitrogen atom and oxygen atoms of the carboxylate group.
