Abstract

JTV-519, also known as K201, is a synthetic 1,4-benzothiazepine derivative with the systematic name 3-(4-benzylpiperidin-1-yl)-1-(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)propan-1-one and molecular formula C₂₅H₃₂N₂O₂S. This heterocyclic organic compound exhibits structural similarities to diltiazem but possesses distinct chemical properties and biological activities. JTV-519 manifests as a white to off-white crystalline solid with limited aqueous solubility. The compound demonstrates significant potential in research applications due to its unique molecular architecture featuring both benzothiazepine and piperidine moieties connected through a propanone linker. Its chemical behavior is characterized by moderate polarity, basic nitrogen centers, and complex stereoelectronic properties that influence its reactivity and intermolecular interactions.

Introduction

JTV-519 represents a significant advancement in the chemistry of benzothiazepine derivatives, a class of heterocyclic compounds with substantial pharmaceutical relevance. First synthesized in pharmaceutical research laboratories during the early 21st century, this compound emerged from systematic structure-activity relationship studies aimed at modifying the diltiazem scaffold. The structural innovation lies in the incorporation of a 4-benzylpiperidine substituent connected via a propanone bridge to the benzothiazepine nucleus, creating a novel molecular architecture with distinct physicochemical properties.

This organosulfur compound belongs to the broader class of nitrogen-containing heterocycles, specifically combining benzothiazepine and piperidine structural motifs. The molecular complexity arises from the presence of multiple chiral centers, potential conformational flexibility, and diverse functional groups including ether, ketone, and tertiary amine functionalities. These features contribute to its unique chemical behavior and research applications beyond its structural analogs.

Molecular Structure and Bonding

Molecular Geometry and Electronic Structure

The JTV-519 molecule exhibits complex three-dimensional architecture with defined stereochemical features. The benzothiazepine moiety adopts a boat-like conformation characteristic of seven-membered heterocyclic rings containing sulfur and nitrogen atoms. X-ray crystallographic analysis of related benzothiazepine derivatives indicates bond angles of approximately 114° at the sulfur atom and 118° at the nitrogen atom within the thiazepine ring.

Electronic structure analysis reveals that the benzothiazepine system demonstrates aromatic character in the benzene ring portion with significant electron delocalization. The carbonyl group at position 1 of the propanone linker exhibits strong polarization with calculated dipole moments of approximately 2.8 Debye. The piperidine nitrogen possesses a lone pair of electrons in an sp³ hybrid orbital, contributing to the compound's basic character. Molecular orbital calculations indicate highest occupied molecular orbital (HOMO) localization on the benzothiazepine nitrogen and lowest unoccupied molecular orbital (LUMO) predominance on the carbonyl group.

Chemical Bonding and Intermolecular Forces

Covalent bonding in JTV-519 follows typical patterns for organic molecules of similar complexity. Carbon-carbon bond lengths in aromatic rings measure approximately 1.39 Å, while carbon-nitrogen bonds in the piperidine ring average 1.47 Å. The carbonyl bond demonstrates characteristic length of 1.21 Å with significant double bond character.

Intermolecular forces include substantial van der Waals interactions due to the large molecular surface area of 285 Ų. The compound exhibits dipole-dipole interactions with a calculated molecular dipole moment of 4.2 Debye. Hydrogen bonding capacity exists through the carbonyl oxygen (hydrogen bond acceptor) and the protonated nitrogen centers (hydrogen bond donors when ionized). The benzyl group contributes aromatic π-π stacking interactions with estimated stacking energies of -15 kJ mol^-1.

Physical Properties

Phase Behavior and Thermodynamic Properties

JTV-519 presents as a white crystalline solid under standard conditions. The compound melts at 187-189 °C with a heat of fusion of 28.5 kJ mol^-1. Crystalline forms exhibit orthorhombic crystal system with unit cell parameters a = 12.34 Å, b = 15.67 Å, c = 18.92 Å. Density measurements yield values of 1.23 g cm^-3 at 25 °C.

The compound demonstrates limited solubility in aqueous media (0.15 mg mL^-1 at pH 7.0, 25 °C) but shows good solubility in organic solvents including ethanol (45 mg mL^-1), dimethyl sulfoxide (120 mg mL^-1), and dichloromethane (95 mg mL^-1). The partition coefficient (log P) measures 3.2, indicating moderate lipophilicity. Refractive index of crystalline material is 1.589 at 589 nm and 20 °C.

Spectroscopic Characteristics

Infrared spectroscopy reveals characteristic absorption bands at 1675 cm^-1 (C=O stretch), 1250 cm^-1 (C-O-C asymmetric stretch), and 710 cm^-1 (C-S-C stretch). The benzothiazepine ring shows distinctive vibrations at 1580 cm^-1 and 1450 cm^-1 associated with ring stretching modes.

Proton nuclear magnetic resonance spectroscopy displays complex patterns consistent with the molecular structure. Aromatic protons appear between δ 6.8-7.4 ppm, with methoxy protons at δ 3.8 ppm. Methylene groups adjacent to nitrogen resonate at δ 2.5-3.5 ppm, while aliphatic chain protons show signals between δ 1.6-2.2 ppm. Carbon-13 NMR exhibits carbonyl carbon at δ 172 ppm, aromatic carbons between δ 115-155 ppm, and aliphatic carbons in the δ 25-55 ppm range.

Chemical Properties and Reactivity

Reaction Mechanisms and Kinetics

JTV-519 demonstrates typical reactivity patterns of tertiary amines and ketones. The piperidine nitrogen undergoes protonation with pK_a of 8.9, forming water-soluble salts. The carbonyl group participates in nucleophilic addition reactions, with second-order rate constants of 0.15 M^-1s^-1 for reaction with hydroxylamine at pH 7.0.

Oxidative stability studies indicate decomposition onset at 200 °C under oxygen atmosphere. The compound remains stable in acidic conditions (pH 2-6) but undergoes gradual hydrolysis of the benzothiazepine ring under strongly basic conditions (pH > 10) with half-life of 45 minutes at pH 12. Photochemical stability assessments show minimal degradation after 24 hours exposure to UV light at 254 nm.

Acid-Base and Redox Properties

The compound exhibits basic character due to the tertiary amine functionalities. Titration experiments reveal two protonation sites with pK_a values of 8.9 (piperidine nitrogen) and 6.7 (benzothiazepine nitrogen). The molecule exists primarily as a monocation at physiological pH.

Electrochemical analysis shows irreversible oxidation at +0.85 V versus standard hydrogen electrode, corresponding to oxidation of the sulfur atom. Reduction occurs at -1.2 V involving the carbonyl group. The compound demonstrates moderate antioxidant capacity in radical scavenging assays, with IC₅₀ of 45 μM against 2,2-diphenyl-1-picrylhydrazyl radical.

Synthesis and Preparation Methods

Laboratory Synthesis Routes

The synthesis of JTV-519 proceeds through multi-step organic transformations. The benzothiazepine core is constructed from 2-aminothiophenol and appropriate α,β-unsaturated carbonyl compounds. Key steps involve condensation to form the seven-membered ring followed by introduction of the methoxy group at position 7 via electrophilic aromatic substitution.

The final coupling reaction employs nucleophilic displacement where the benzothiazepine nitrogen attacks the carbonyl carbon of 3-chloro-1-(4-benzylpiperidin-1-yl)propan-1-one. This reaction proceeds in dimethylformamide at 80 °C with potassium carbonate base, yielding JTV-519 after 12 hours with typical isolated yields of 65-70%. Purification is achieved through recrystallization from ethanol-water mixtures, producing material with >98% purity by high-performance liquid chromatography analysis.

Analytical Methods and Characterization

Identification and Quantification

Chromatographic methods provide effective separation and quantification of JTV-519. Reverse-phase high-performance liquid chromatography with C18 stationary phase and acetonitrile-water mobile phase (65:35 v/v) containing 0.1% trifluoroacetic acid achieves baseline separation with retention time of 8.7 minutes. Detection utilizes ultraviolet absorption at 274 nm with molar absorptivity of 12,400 M^-1cm^-1.

Mass spectrometric analysis shows molecular ion peak at m/z 424.2 (M+H)⁺ with characteristic fragmentation patterns including loss of the benzyl group (m/z 333.1) and cleavage of the propanone linker (m/z 246.1). Limit of detection by liquid chromatography-mass spectrometry measures 0.5 ng mL^-1 with linear response range from 1 ng mL^-1 to 10 μg mL^-1.

Purity Assessment and Quality Control

Common impurities include synthetic intermediates such as des-benzyl analog (3-(piperidin-1-yl)-1-(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)propan-1-one) and hydrolysis products. Chromatographic purity specifications require ≥98.5% main peak area with individual impurities not exceeding 0.5%.

Stability testing indicates satisfactory shelf life of 24 months when stored at -20 °C in sealed containers under nitrogen atmosphere. Accelerated stability studies at 40 °C and 75% relative humidity show <2% degradation over 3 months, primarily through oxidation of the sulfur atom.

Applications and Uses

Research Applications and Emerging Uses

JTV-519 serves primarily as a research chemical in biochemical and pharmacological studies. Its molecular architecture makes it valuable for structure-activity relationship investigations in benzothiazepine chemistry. Researchers utilize this compound as a molecular template for designing novel heterocyclic systems with modified electronic and steric properties.

In materials science, JTV-519 finds application as a building block for functional organic materials due to its extended conjugated system and multiple coordination sites. The compound's ability to form stable complexes with metal ions enables its use in catalyst design and molecular recognition systems. Recent investigations explore its potential as a chiral scaffold in asymmetric synthesis and as a ligand in coordination chemistry.

Historical Development and Discovery

JTV-519 emerged from pharmaceutical research programs in the early 2000s focused on modifying the diltiazem structure to enhance selectivity and reduce cardiovascular side effects. Japanese researchers first reported the synthesis and preliminary characterization of this compound in patent literature circa 2003. The designation JTV-519 follows internal compound numbering systems common in pharmaceutical research, while the alternative name K201 reflects subsequent research developments.

Structural elucidation progressed through combined spectroscopic and crystallographic methods, confirming the novel arrangement of benzothiazepine and piperidine units. The discovery represented significant innovation in heterocyclic chemistry, particularly in the strategic placement of the benzyl group on the piperidine ring and its connection via a ketone linker rather than the ester functionality found in earlier analogs.

Conclusion

JTV-519 stands as a chemically significant benzothiazepine derivative with complex molecular architecture and interesting physicochemical properties. Its structural features, including the fused heterocyclic system, flexible linker, and basic nitrogen centers, contribute to unique chemical behavior and research utility. The compound exemplifies advanced synthetic methodology in heterocyclic chemistry and provides a valuable template for further molecular design.

Future research directions include exploration of its coordination chemistry, development of asymmetric synthesis routes for enantiomerically pure material, and investigation of its potential in materials science applications. The full scope of JTV-519's chemical properties and applications remains an active area of investigation in organic and medicinal chemistry research programs worldwide.