Synthesis and Characterization of new Azecine-Derivatives as Potential Neuroleptics

Zergiebel, Stephanie; Fleck, Christian; Arndt, Hans‐Dieter; Enzensperger, Christoph; Seeling, Andreas

doi:10.1055/s-0043-108651

Cited by 6 publications

(11 citation statements)

References 21 publications

(45 reference statements)

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“…Separation of the prodrugs, metabolites and the internal standard requires only for some substances ( basic conditions, at pH 10, the azecine derivatives are very easy to determine [4]. However, the acidic buffer was preferred and validated in this study, because the test substances have a higher longterm stability in this medium.…”

Section: Hplc Methods Developmentmentioning

confidence: 99%

“…For the most part, the test substances are only moderately soluble in water and thus inaccessible to enzymatic tests. In other studies, DMSO was used as a solubilizer [4]. In this case, however, a sufficient solubility could not be achieved with all substances.…”

Section: In Vitro Esterase Stabilitymentioning

confidence: 98%

“…A further 10 min, the system was rinsed on the starting conditions of 10 % A. Separations were achieved using a C18 reversed-phase column (Nucleodur C18 Isis 3 µm, 125 × 4 mm, Macherey-Nagel, Germany) and a precolumn (EC 4/3 Universal RP, SN E15101206 LOT 4014, Machery-Nagel, Germany). As standard substances 1, 2, 3, 4 [5] and 7-methyl-5,6,7,8,9,15-hexahydro-benzo[f] [1,3]dioxolo [4,5]k]benzazecine (rMD3) [8] were used. The substances were injected 3 times and the average value of the obtained retention times went into the calculation.…”

Section: Chromatographic Determination Of Octanol/water Partition Coementioning

confidence: 99%

“…The substances were injected 3 times and the average value of the obtained retention times went into the calculation. The octanol/water partition coefficients of the reference substances were taken from literature [4].…”

Section: Chromatographic Determination Of Octanol/water Partition Coementioning

confidence: 99%

“…To solve this problem, derivatives of the hexahydrodibenzo[d;g]acezine have been synthesized in further work. Some of the substances have already been tested for effectiveness and duration of action in vivo [4]. A significant inhibition of the conditioned avoidance response (CAR) could be demonstrated up to 90 min after substance application by the use of an ester prodrug.…”

Section: Introductionmentioning

confidence: 99%

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In Vitro Studies on Physiological and Chemical Stability of New LE404-Derivatives with Extended Half-Life

Zergiebel

Seeling

2018

Drug Res (Stuttg)

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Dibenzoazecines are a class of potential neuroleptics with high affinity to dopamine and serotonin receptors. The efficacy and high therapeutic range has already been demonstrated in vivo with the lead structure 7-methyl-5,6,7,8,9,14-hexahydrodibenzo[d,g]azecin-3-ol (LE404: ) and selected derivatives. There is a variety of new synthesized structurally different dibenzoazecine derivatives with the aim to improve pharmacokinetic parameters, all of which contain the lead structure LE404: . For a multitude of these substances is still a lack of information, inclusive of stability, physicochemical parameters, pharmacokinetics and metabolism. Therefore, the present study investigated the stability properties of 17 new azecine derivatives, including esterase cleavage, stability in simulated gastrointestinal fluid, stability at different pH-values and determination of octanol/water-partition coefficients. These findings, in correlation to the properties and efficacy of the already in vivo tested substances, will be useful for safety and efficacy in further in vivo tests.

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Section: Hplc Methods Developmentmentioning

confidence: 99%

Section: In Vitro Esterase Stabilitymentioning

confidence: 98%

Section: Chromatographic Determination Of Octanol/water Partition Coementioning

confidence: 99%

Section: Chromatographic Determination Of Octanol/water Partition Coementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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In Vitro Studies on Physiological and Chemical Stability of New LE404-Derivatives with Extended Half-Life

Zergiebel

Seeling

2018

Drug Res (Stuttg)

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Robust and Fast UV–HPLC Method for Biotransformation Analysis of Azecines

Zergiebel

Seeling

2021

Chromatographia

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Dibenzoazecines are a new class of drug candidates for the treatment of schizophrenia. Compared to the drugs currently used in therapy, the azecines have a novel mechanism of action. Thus, they have the potential to cause fewer side effects compared to the standard therapy with a constant high neuroleptic potency. This theory was substantiated by comparative in vivo tests with haloperidol and risperidone. Seventeen new azecine derivatives have already been tested furthermore of stability, physicochemical parameters, pharmacokinetics including esterase cleavage, stability in simulated gastrointestinal fluid, stability at different pH values and determination of octanol/water-partition coefficients. For these substances, class is still a lack of information concerning the metabolism. Therefore, the present study investigated and developed a reliable and reproducible gradient reversed-phase HPLC–UV method to determinate the lead structure LE404 alongside emerging metabolites in compliance with international requirements like ICH guidelines and the European Pharmacopoeia. Up to now, there is no innovative method suitable for such a determination. Chromatographic separations were achieved with a phenomenex™ Gemini column (5 µm C18 110 Å, 250 × 4.60 mm) using a mixture of acetonitrile/potassium dihydrogen phosphate buffer (4 mmol L−1, pH 2.5) as mobile phase. The gradient method flow rate was 1.0 mL min−1, and UV detection was made at 220 nm. The optimized HPLC method was found to be specific, accurate, reproducible and robust for determination of LE404.

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HPLC–UV Monitored Photostability-Test of LE404 and Identification of the Degradation Products via NMR and LC–HRMS

Zergiebel,

Ueberschaar,

Plentz

et al. 2024

Chromatographia

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Dibenzoazecines are a new class of potential neuroleptics with a high potential for the treatment of schizophrenia. Initial stress tests indicated that the lead compound, LE404, decomposed when exposed to oxygen and sunlight. In this follow up study, the in uence of oxidative stress and photosensitivity was examined in compliance with ICH guidelines. The results of this study are important for identifying and predicting potential impurities of LE404 and for adjusting storage condition to prevent compound degradation. The exposure of LE404 to a light source, similar to the natural sunlight spectrum and intensity, was investigated in compliance with ICH-Q1B. The in uence of oxidizing agents was investigated under exclusion of light. Two degradation products were observed. The extent and rate of degradation in both experiments were continuously monitored using RP-HPLC-UV. Chromatographic separations were achieved with a phenomenex™ Gemini 5 µm C18 110 Å (250×4.60 mm) column at 220 nm, using acetonitrile/KH 2 PO 4 buffer (4 mmol⋅L -1 , pH 2.5) as mobile phase.The photodegradation product was isolated by using semi-preparative RP-HPLC. The oxidation product was obtained by quantitative conversion of LE404 in hydrogen peroxide followed through puri cation using preparative TLC. The structures of both degradation products were elucidated using HR-MS/MS, 1D-and 2D-NMR as well as FTIR spectroscopy.The structural characterization of the degradation products serves as the basis for subsequent investigations into their toxicity. This is of high importance because phototoxic and photoallergic reactions pose a signi cant risk, especially with long-term medications, as it is not possible to completely avoid exposure to sunlight.

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Synthesis and Characterization of new Azecine-Derivatives as Potential Neuroleptics

Cited by 6 publications

References 21 publications

In Vitro Studies on Physiological and Chemical Stability of New LE404-Derivatives with Extended Half-Life

In Vitro Studies on Physiological and Chemical Stability of New LE404-Derivatives with Extended Half-Life

Robust and Fast UV–HPLC Method for Biotransformation Analysis of Azecines

HPLC–UV Monitored Photostability-Test of LE404 and Identification of the Degradation Products via NMR and LC–HRMS

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