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Modification of the quinolizine backbone of the alkaloid lupinine was carried out by introducing substituted 1,2,3-triazole. When NaN3 acts upon the product of the reaction of lupinine with methanesulfonyl chloride, lupinyl azide is formed which in the reaction with terminal alkynes in the presence of aqueous CuSO4 and sodium ascorbate forms the corresponding (1S,9aR)-1-[(1,2,3-triazol-1-yl)-methyl]octahydro-1H-quinolizines with various substituents at the C-4 position of the triazole ring. The structures of lupinine methanesulfonate and 1-[(1,2,3-triazol-1-yl)methyl]octahydroquinolizines were confirmed by X-ray structural analysis. 1-[(1,2,3-Triazol-1-yl)methyl]octahydroquinolizines containing a hydroxymethyl or 2-hydroxypropan-2-yl substituent at the C-4 position of the triazole ring exhibit pronounced analgesic activity.

Two crystals of quinolizidine compounds; systematic name: (rac)-(7,8,9,9a)-tetrahydro-4H-thieno[2,3-b]quinolizine-6,10-dione, (I), and (rac)-(9a,10)-10-hydroxy-8,9,9a,10-tetrahydro-4H-thieno[2,3-b]quinolizin-6(7H)-one, (II), have been compared and characterized by single-crystal X-ray diffraction and electronic analysis. N-heterocyclic rings in both structures are not planar and adopt a half-chair conformation. The molecules of (I) are linked via weak C–H···O hydrogen bonds into chains along c axis. While the crystal stacks in compound (II) are formed by strong O–H···O hydrogen bonds the molecules link into infinite zig-zag chains along the b axis. In both crystal structures, π–π stacking and C–H···π interactions are also observed. Calculation of the net atomic charges shows that O atoms in both compounds carry a relatively large negative charges, in comparison with the corresponding H atoms. Crystal, molecular and electronic structures of these compounds, which are influenced by hydrogen-bonded assemblies in the molecular crystals, are discussed in detail. Crystal, molecular and electronic structures of two related tricyclic compounds containing thienoquinolizidine ring skeleton, both structures have similar quinolizine ring moieties assuming conformations resembling half-chair.

Three-component condensation of lower aliphatic aldehydes (C1-C3) with arylamines and cyclopentadiene (the Povarov reaction) gave 3a,4,5,9b-tetrahydro-3H-cyclopenta[c]-quinolines. Ozonization of their N-trifluoroacetyl derivatives afforded the corresponding ozonides. Cyclocondensation of 4-fluoroaniline with formaldehyde and cyclopentadiene gave earlier unknown 2-fluoro-3b,6,6a,7,9,9a,10,12a-octahydrobenzo[i,j]dicyclopenta[b,g]quinolizine.

The aminobenzo[a]quinolizines were investigated as a novel class of DPP-IV inhibitors. The stereochemistry of this class plays an important role in the bioactivity. In this study, the mechanisms of how different configuration of three chiral centers of this class influences the binding affinity were investigated by molecular dynamics simulations, free energy decomposition analysis. The S configuration for chiral center 3* is decisive for isomers to maintain high bioactivity; the chirality effect of chiral center 2* on the binding affinity is largely dependent, while the S configuration for chiral center 2* is preferable to R configuration for the bioactivity gain; the effect of chiral center 11b* on the binding affinity is insignificant. The chirality specificity for three chiral centers is responsible for distinction of two van der Waals contacts with Tyr547 and Phe357, and of H-bonding interactions with Arg125 and Glu206. Particularly, the Arg125 to act as a bridge in the H-bonding network contributes to stable H-bonding interactions of isomer in DPP-IV active site.

Cyclization of 2-(4-R-piperidino)benzaldehydes with 5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one proceeding via tert-amino effect mechanism is stereoselective. Relative configuration of (3R*,4aS*,5R*)-2,3,4,4a,5,6-hexahydro-1H-benzo[c]quinolizine was established on the base of NMR spectroscopy data and X-ray analysis.

The interaction between a bioactive molecule, 3-acetyl-4-oxo-6,7-dihydro-12H indolo-[2,3-a] quinolizine (AODIQ), with human serum albumin (HSA) has been studied using steady-state absorption and fluorescence techniques. A 1:1 complex formation has been established and the binding constant (K) and free energy change for the process have been reported. The AODIQ-HSA complex results in fluorescence resonance energy transfer (FRET) from the tryptophan moiety of HSA to the probe. The critical energy-transfer distance (R 0) for FRET and the Stern-Volmer constant (K sv) for the fluorescence quenching of the donor in the presence of the acceptor have been determined. Importantly, K SV has been shown to be equal to the binding constant itself, implying that the fluorescence quenching arises only from the FRET process. The study suggests that the donor and the acceptor are bound to the same protein at different locations but within the quenching distance.

The synthesis of 2,3,4,4a,5,6-hexahydro-6H-spiro[benzo[c]quinolizine-5,4′-pyrazol]-5′-ones has been achieved by the reaction of 2-piperidinobenzaldehydes with 2-aryl-5-methyl-2,4-dihydropyrazol-3-one via the “tert-amino effect” mechanism.

A new procedure has been developed for the synthesis of fused nitrogen-containing heterocycles having a bridgehead nitrogen atom via condensation of cyclic Schiff bases with β-keto esters.

Tetrahydro-1H,7H-benzo[ij]quinolizine-1,7-diones have been obtained by the cyclization of N-alkoxyphenyl-N-(2-carboxyethyl)-β-alanines. Fission of the ester bond occurs on cyclization of N-(4-ethoxyphenyl)-N-(2-carboxyethyl)-β-alanine, but the cyclization of the 3,4-dialkoxyphenyl derivative leads to the formation of 9-alkoxy-8-hydroxy-2,3,5,7-tetrahydro-1H,7H-benzo[ij]quinolizine-1,7-diones. The corresponding dioximes and diphenylhydrazones were obtained.

Three types of dihydroberberine derivatives such as spirobenzylisoquinoline, benzindenoazepine and cyclopropanated quinolizine species were synthesized from dihydroberberine for the investigation on their anti-tumor activity. Among them, cyclopropanated quinolizine species were more effective than spirobenzylisoquinoline and benzindenoazepine against P-388 and L-1210 leukemia cell.

Four antagonists were examined for their ability to differentiate α2A from the orthologous α2Dadrenoceptors. The antagonists were (2S,12bS) 1′, 3′-di-methylspiro(1, 3, 4, 5′, 6, 6′, 7,12b-octahydro-2H-benzo[b]furo[2,3-a]quinolizine)-2,4′-pyrimidin-2′-one (MK 912), 2-[2-(methoxy-1, 4-benzodioxanyl)imidazoline (RX 821002), efaroxan and benoxathian. The α2-autoreceptors in rabbit brain cortex were chosen as α2A- and the a2-autoreceptors in guinea-pig brain cortex as α2D-adrenoceptors. Slices of the brain cortex were preincubated with 3H-noradrenaline and then superfused and stimulated electrically by brief pulse trains (4 pulses, 100 Hz) that led to little, if any, α2-autoinhibition. 5-Bromo-6-(2-imidazolin-2-ylamino)quinoxaline (UK 14,304) was used as an α2-adrenoceptor agonist.

A new approach (AB + D → ABCD) to the construction of tetracyclic 8-azagonane (cyclopenta[5,6]pyrido[2,1-a]isoquinoline or benzo[a]cyclopenta[f]quinolizine) structures was developed and exemplified by cyclocondensation of 1-alkyl-3,4-dihydroisoquinolines with ethyl 2-oxocyclopentanecarboxylate.

The purity of the investigational antibacterial Abbott-086719.1 (I) which is 8[(3S)-3-amino-1-pyrrolidinyl]-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid hydrochloride is determined using gradient elution HPLC. The chromatographic separation was optimized and the chromatographic parameters critical to separation are discussed in detail. Most acceptable separations were achieved using an Alltima C18 column (5 μm) measuring 4.6 mm I.D.×15 cm with 0.01M–0.03M citrate eluents which were modified with acetonitrile or with mixtures of acetonitrile and methanol. Related substances in I were determinable to 0.05%. Repeatability (RSD values) for determining related substances at levels of 0.50 to 0.06% ranged from ±1.9 to ±10%. Determinations of I in 5% dextrose in water and in hydroxypropyl methylcellulose were made using the same column and a simple isocratic system. The determination of I was stability indicating with precision (RSD values) of ±0.5% to ±2.0% and good agreement with theory for formulations containing I at 1.0 to 95 mg/mL concentrations. Recoveries of I from the vehicles were quantitative and linearity of the detector response of I was demonstrated to at least 0.10 mg/mL.

In the reaction of 2-(2-pyridylcarbonyl)benzoyl chloride, which exists in the form of 6,11-dioxo-6,11dihydrobenzo[b]quinolizinium chloride, with p-nitroaniline, 2-(4-nitrophenylimino)-6, 11-dihydro-2H-benzo-[b]quinolizine-6, I I -dione is unexpectedly formed. When it reacts with water or methanol there is an opening of the quinolizine ring and aromatization of the quinoid fragment with the formation of 2-[4-(4nitrophenylamino)-2-pyridylcarbonyl]benzoic acid or its methyl ester. Under the action of antimony pentachloride, 2- 2-quinolylcarbonyl)benzoylchloride-3 (2-quinolyl)-3-chloro- 1, 3-dihydrobenzo[c]furan-1 -one -is converted to 3-(2-quinolyl)-1,3-dihydrobenzo[c]furan-1-on-3-ylium hexachlorantimonate, which undergoes isomerizing recyclization upon heating to 7,12-dioxo-7,12-dihydrobenzo[b/ hexachloroantimonate. The latter enters into an analogous reaction with p-nitroaniline, thereby forming 5-(4-nitrophenylimino)-7,12-dihydro-5H-dibenzo[b,f]quinolizine-7,2-dione.

Two hydrates (tetrahydrate, I, and monohydrate, II) of a new antiallergic, sodium 5-(4-oxo-phenoxy-4H-quinolizine-3-carbox-amide)-tetrazolate (FR71021), were prepared and characterized by means of infrared spectrometry, thermal analysis, and power X-ray diffraction spectrometry. While I was confirmed to dehydrate readily resulting in an anhydrate form (noncrystalline form) below its critical relative humidity for dehydration, I was also transformed into II under humid conditions. The transformation kinetics from I to II were investigated under varying temperature and humidity conditions by a powder X-ray diffraction technique. The transformation mechanism followed a zero-order reaction, and the apparent transformation rate constant (k) could be described as a function of water vapor pressure (P), temperature (T), and the interaction orders between water vapor pressure and the samples (s) :k = A · exp(−Ea/ RT) ·Ps, where Ea is the activation energy and R is the gas constant.

The reactions of 2-(3,5-dimethylpiperidino)benzaldehyde with Meldrum's acid and cyclohexane-1,3-dione occur as a tandem of the Knoevenagel condensation and cyclization promoted by the tert-amino effect. The cyclization yields only one isomer with the axial hydrogen atoms in positions 4 and 4a of the benzoquinolizine ring.

1. The condensation of 3,4-dihydroisoquinolines with dehydroacetic acid derivatives proceeds in two principal directions: with a retention and an opening of the pyrone ring. 2. The condensation with 5,6-dihydrodehydroacetic acid leads to the formation of the vinylog lactams of the benzo[a]pyrano[f]quinolizine series, the enaminodicarbonyl grouping of which has a high reactivity.

1. The condensation of 3,4-dihydroisoquinoline N-oxide with 2-acetyl-1,3-cycloalkanediones and 5,6-dihydrodehydroacetic acid leads to the formation of tetracyclic pyridones of the benzo[a]quinolizine series via the intermediate step of tetrahydroisoquinolidenotriacyhnethanes. 2. The synthesis of 1,13-dioxo-2,3,4,4a,6,7,13,13a-octahydro-1H-dibenzo[a,f]quinolizine was accomplished.

The scope of the Sugasawa method for the synthesis of quinolizinium derivatives has been investigated. Several benzo, naphtho and naphthobenzo quinolizinium compounds have been synthesised in excellent yields, although the ring on which cyclisation was effected did not carry any activating substituents.

1. The condensation of isoquinoline with diketene leads to the formation of two isomers of the benzo-[a]pyranoquinolizine series, which differ in the g and f annulation of the pyran ring. 2. 4,5-Dioxo-2-methyl-12b,13-dihydro-4H,5H-benzo[a]pyrano[2,3-g]quinolizine under the influence of benzylamine is converted to 4-oxo-3-acetoacetyl-2-benzylamino-1,4-dihydro-11bH-benzo[a]quinolizine, whereas the isomerie benzo[a]pyrano[f]quinolizine gives 4-oxo-2-benzylamino-1,4-dihydro-11bH-benzo-[a]quinolizine and 4,5-dioxo-2-methyl-1-benzyl-1,4,12b,13-tetrahydro-5H-benzo[a]pyrido[2,3-g]quinolizine.

The oxidation of 2,4-dioxo-3-(3-hydroxybutyl)-1,2,3,4,6,7-hexahydro-11bH-benzo[a]quinolizine with either the Sarett complex or Jones reagent gives predominantly 5-oxo-2-methyl-2,3,7,8-tetrahydro-4H,5H-benzo[a]pyrano[2,3-g]quinolizine, while oxidation with CrO3 in AcOH solution gives 8,9,14-trioxo-12-methyl-5,6,8,9,10,11,15,15a-octahydro-13-oxa-12H,14H-azepino[2,1-a]isoquinoline.