Towards the Discovery of New Hypnotic Agents: Synthesis and Preliminary Pharmacological Evaluation of a Novel Class of Dibenzo[a,d]cycloheptene Derivatives

Abstract

Sleep deprivation is well documented to result in physiologic stress and mood disorders (depression, irritability and anxiety), and sleep disturbances are among the most prevalent clinical problems and physical signs of depression.[1] Nonspecific pharmacotherapy available for sleep disorders currently falls into four categories: GABA receptor agonists, over-the-counter antihistamines, melatonin receptor agonists and sedating antidepressants. However, benzodiazepine and non-benzodiazepine GABA A receptor agonists all share a common adverse effect profile related to the drug class, including daytime somnolence, dizziness, headache and memory impairment.[2] Hence, there is still a medical need for the development of new drugs with improved efficacy for the treatment of sleep disorders.It has been suggested that brain histamine is involved in the regulation of the sleep/awake cycle, arousal, cognition and memory, mainly through the histamine H 1 receptor, producing a reduction of sleep latency both in preclinical [3] and clinical studies.[4] In parallel, selective blockade of the serotonin 5-HT 2A receptor has been proved in both preclinical [5] and clinical studies [6] to be efficacious in reducing wake after sleep onset, increasing slow-wave sleep and total sleep time, therefore, providing consolidation of sleep. On the other hand, pharmacological studies have shown that mirtazapine (1) and mianserin (2), two noradrenergic and specific serotonergic antidepressants (NaSSAs), act by blocking 5-HT 2A receptors, [7] and their broad pharmacological profile is characterized by a potent H 1 antagonistic activity. [8] As part of a program aimed at discovering novel chemical entities useful for the treatment of various sleep disorders, the model compounds mirtazapine (1) and mianserin (2) were used to design novel tetracyclic derivatives (see general template 3-4; Figure 1). This template is characterized by the presence of a spiro junction connecting the classical tricyclic core, suitably substituted, to a fourth exocycle ring with the nitrogen atom that can either be endo (3, X= N, W = H) or exo (4, X = CH, W = NH(CH 3 ) and N(CH 3 ) 2 ) with respect to that ring.To the best of our knowledge, the synthesis of compounds 3 has never been described, while the synthetic route to prepare compounds 4 has recently been reported by us in a patent application. [9] In particular, the preparation of compounds 3 a (X = N, W = H, Y = CH 2 , Z= CH 2 , R and R 1 = H) and2 is respectively CH 3 and H, R 3 = CH 3 , Z = CH 2 , R and R 1 = H) is described in detail. The tetracyclic derivative 3 a was synthesized as shown in Scheme 1. Starting from the known [10] 5-oxo-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-10-carbonitrile (5), the alkylation reaction was performed with lithium bis(trimethylsilyl)amide in the presence of 1,3-dimethyl-2-imidazolidinone and ethylbromoacetate to afford racemic a-alkylated nitrile 6 in moderate yield. The reduction of both the nitrile and ketone functionalities via catalytic hydrogenation, followed by spo...

Novel Spirotetracyclic Zwitterionic Dual H1/5-HT2A Receptor Antagonists for the Treatment of Sleep Disorders

“…The spirocyclic skeleton of our lead is an unexplored scaffold in organic chemistry; therefore, it was necessary to identify a novel synthetic route to successfully prepare compounds 43 − 73 and 74 − 77 (Scheme ). The synthesis of compound 9′a has already been reported in a previous communication, while herein we illustrate an optimized synthesis, which has been adapted for the purpose of introducing substituents on the scaffold (such as R = Cl or F) and different heteroatoms (such as X = O and S) in place of the carbon in the benzhydrylic position in the lower part of the compound. Thus, starting from the appropriately substituted ketone 1 , the first step of the synthesis was a potassium tert -butoxide promoted bis-alkylation with allyl bromide .…”

“…For example, intermediates 8a , 8b , and 8c have been resolved and the two enantiomers have been named 8a (ent 1), 8a (ent 2), 8b (ent 1), 8b (ent 2), and 8c (ent 1), 8c (ent 2) depending on their respective retention times in the corresponding HPLC separation. For compounds 8a (ent 1) and 8a (ent 2) the absolute stereochemistry was determined by means of ab initio vibrational circular dichroism (VCD) analysis; hence, 8a (ent 1) was assigned as the (1 R )-enantiomer and 8a ( ent 2 ) as the (1 S )-enantiomer. Henceforth, compound 8a (ent 1) is named 8a ( R ) and 8a (ent 2) is named 8a ( S ).…”

“…endowed with promising dual H 1 /5-HT 2A in vitro activity. 10 Compound 9 0 a represents a low molecular weight lead, although it is characterized by poor selectivity toward human adrenergic R 1 receptors and the human ether-a-go-go-related gene (hERG) potassium channel as well as by suboptimal physiochemical parameters. When preliminary pharmacokinetic data were gathered, a very high rat in vitro intrinsic clearance (Cli), a low free fraction measured in vitro in homogenized brain tissue (Br-fu), and a strong inhibition of the 2D6 isoform of the human CYP450 were also observed.…”

“…As part of a broad drug discovery strategy aimed at the identification of novel hypnotic agents, we reasoned on the possibility of optimizing (1 S ,3 R )-5′,11′-dihydrospiro[cyclopentane-1,10′-dibenzo[ a , d ]cyclohepten]-3-yl(dimethyl)amine ( 9′a , Figure ), a novel spirotetracyclic compound endowed with promising dual H 1 /5-HT 2A in vitro activity . Compound 9′a represents a low molecular weight lead, although it is characterized by poor selectivity toward human adrenergic α 1 receptors and the human ether-a-go-go-related gene (hERG) potassium channel as well as by suboptimal physiochemical parameters.…”

Systematic Approach to Conformational Sampling for Assigning Absolute Configuration Using Vibrational Circular Dichroism

“…Chirality is a structural feature of many marketed drugs and an important focus of drug discovery teams in the pharmaceutical industry. Owing to the difficulty in assigning absolute configuration (AC), several methods are commonly employed, including single crystal X-ray diffraction, NMR combined with chiral derivatization, electronic circular dichroism (ECD), optical rotation, and structural proofs based on synthetic transformations. − A relatively new technique for assigning absolute configuration, − vibrational circular dichroism (VCD), has gained favor in recent years. Recent perspectives on the method emphasize that VCD can play a critical role for SAR development and provide insight into the dominant conformations of a molecule in solution. , It has been emphasized that uptake of VCD into the pharmaceutical industry is still surprisingly slow…”