Stereoselective behavior of the functional diltiazem analogue 1-[(4-chlorophenyl)sulfonyl]-2-(2-thienyl)pyrrolidine, a new L-type calcium channel blocker.

We studied the stereoselective behavior of 1-[(4-chlorophenyl)sulfonyl]-2-(2-thienyl)pyrrolidine, a recently described blocker of cardiovascular L-type calcium channels that binds to the diltiazem site. Given the stereocenter at C-2 of the pyrrolidine ring, the two enantiomers were separated by chiral HPLC and, using VCD in conjunction with DFT calculations of chiroptical properties, the absolute configuration was assigned as R-(+)/S-(-). For both forms, functional, electrophysiological, and binding properties were studied and the three-dimensional superimpositions of the two enantiomers over diltiazem were obtained in silico. The significant differences observed for the two enantiomers well agreed with the experimental data, and molecular regions were hypothesized as responsible for the cardiac stereoselectivity and vascular stereospecificity.

L-Type calcium channel blockers: from diltiazem to 1,2,4-oxadiazol-5-ones via thiazinooxadiazol-3-one derivatives.

The research of compounds with L-type calcium channels (LTCCs) blocking activity continued with heterocyclic compounds containing the 1,2,4-oxadiazol-5-one ring. For a series of 22 new derivatives of 3-aryl-4[(Z)-(1-methyl-2-alkylsulphanyl-vinyl)][1,2,4]oxadiazol-5(4H)-ones, which represent the "frozen" open chain counterpart of the cyclic aryl-thiazinooxadiazolones previously examined, we report here the synthesis and the characterization as LTCC blockers, evaluated on isolated tissues of guinea pig. The most interesting compound, 8b, was tested also on L-type calcium current recorded in isolated rat tail artery myocytes. Overall, six compounds were more potent than diltiazem, and binding assays confirmed the direct interaction with the benzothiazepine binding site. As the cyclic aryl-thiazinooxadiazolones, p-bromine substituted compounds were generally more potent than the corresponding p-chlorine ones. A saturated or unsaturated alkyl chain or a bulky group at the sulfur atom were detrimental to the potency, while the compounds with S-methyl groups, i.e., thioether (8b), sulfoxide (16a,b), and sulfone (17b), gave the best results.

Discovery of novel and cardioselective diltiazem-like calcium channel blockers via virtual screening.

With the effort to discover new chemotypes blocking L-type calcium channels (LTCCs), ligand-based virtual screening was applied with a specific interest toward the diltiazem binding site. Roughly 50000 commercially available compounds served as a database for screening. The filtering through predicted pharmacokinetic properties and structural requirements reduced the initial database to a few compounds for which the similarity was calculated toward two template molecules, diltiazem and 4-chloro-Ncyclopropyl- N-(4-piperidinyl)benzene-sulfonamide, the most interesting hit of a previous screening experiment. For 18 compounds, inotropic and chronotropic activity as well as the vasorelaxant effect on guinea pig were studied "in vitro", and for the most promising, binding studies to the diltiazem site were carried out. The procedure yielded several hits, confirming in silico techniques to be useful for finding new chemotypes. In particular, N-[2-(dimethylamino)ethyl]-3-hydroxy-2-naphthamide, N,Ndimethyl- N'-(2-pyridin-3-ylquinolin-4-yl)ethane-1,2-diamine, 2-[(4-chlorophenyl)(pyridin-2-yl)methoxy]- N,N-dimethylethanamine (carbinoxamine), and 7-[2-(diethylamino)ethoxy]-2H-chromen-2-one revealed interesting activity and binding to the benzothiazepine site.

Diseño y evaluación de matrices de difusión controlada en parches transdérmicos de clorhidrato de Diltiazem / Design and evaluation of matrix diffusion controlled transdermal patches of diltiazem hydrochloride

Se desarrolló un sistema matricial de tipo dispersivo para la administración transdérmica de clorhidrato de Diltiazemusando diferentes proporciones de colofonia con Eudragit RL PM y polivinil pirrolidona. El parche preparado concolofonia y polivinil pirrolidona no era transparente y muestra una distribución irregular de polivinil pirrolidona,lo que puede ser debido al carácter hidrófi lo de ésta. Se investigó el efecto de los polímeros sobre las propiedadestecnológicas; es decir, la liberación del fármaco, la velocidad de transmisión del vapor de agua, la pérdida porcentualde humedad y el grosor. El parche con colofonia: Eudragit RL PM (6:4) dio como resultado una liberaciónde 2651 mcg en 24 horas. Con el objeto de mejorar la liberación, se incluyeron distintas proporciones de alcanforen la formulación. El parche con colofonia: Eudragit RL PM (6:4) y un 5% p/v de alcanfor dio como resultadouna liberación constante del fármaco a lo largo de un período de 24 horas. La formulación F8 resultó ser la mássatisfactoria en lo que a las propiedades tecnológicas se refi ere. Se llevaron a cabo estudios posteriores de permeacióne irritación de la piel en ratas y conejos respectivamente. Por lo tanto, se puede concluir que con el parchede colofonia: Eudragit RL PM en proporción 6:4 con un 5% p/v de alcanfor, se alcanzan los objetivos deseablesen sistemas de administración transdérmica de fármacos tales como anular el efecto de primer paso, una amplialiberación y una frecuencia de administración reducida

A matrix dispersion type transdermal drug delivery system of Diltiazem Hydrochloride was developed using differentratios of rosin with Eudragit RL PM and polyvinyl pyrrolidone. The patch prepared by the combination of rosin andpolyvinyl pyrrolidone was not transparent one, and shows an uneven distribution of polyvinyl pyrrolidone, which maybe due to the hydrophilic nature of polyvinyl pyrrolidone. The effect of the polymers on the technological properties,i.e., drug release, water vapor transmission rate, percentage moisture loss and thickness were investigated. The patchcontaining rosin: Eudragit RL PM (6:4) showed a release of 2651 mcg in 24 h. In order to improve the release variousproportions of camphor was included in the formulation. The patch containing rosin: Eudragit RL PM (6:4) with5% w/v of camphor showed a sustained release of the drug extending over a period of 24 h. Formulation F8 emergedas the most satisfactory formulation as far as the technological properties were concerned. Further skin permeationand skin irritation studies were carried out on rat skin and rabbit respectively. Therefore it can be concluded that thepatch containing rosin: Eudragit RL PM in the ratio 6:4 with 5%w/v of camphor achieved the desired objectives oftransdermal drug delivery systems, such as overcoming of fi rst pass effect, extended release and reduced frequency ofadministration

[12-acyl-6,1 2-dihydro-6-phenyl-[1 ]benzofuro[2,3-c]- and -[1,5]benzothieno[2,3-c]-[1 ,5]-benzothiazepines--tetracyclic diltiazem derivatives]. / 12-Acyl-6,12-dihydro-6-phenyl-[1]benzofuro[2,3-c]- und -[1]benzothieno-[2,3-c]-[1,5]benzothiazepine--tetracyclische Diltiazem-Derivate.

The reaction of the tetracycles 1 with chloroacetylchloride yields the amides 2. The structure of 2a was proven by X-ray analysis. The amides 2 exist as diastereomers in solution because of planar chirality. From the N-chloroacetyl compounds only 2a, b could be substituted with diethylamine to give 3a, b. Reduction experiments of 3a, b with DIBAH do not afford diltiazem analogues; instead, the starting compounds la, b are formed by hydrolysis.

Preparation and evaluation of diltiazem hydrochloride-Gelucire 43/01 floating granules prepared by melt granulation.

The basic objective of this study was to explore the application of Gelucire 43/01 for the design of multi-unit floating systems of a highly water-soluble drug diltiazem HCl. Diltiazem HCl-Gelucire 43/01 granules were prepared by melt granulation technique. The granules were evaluated for in vitro and in vivo floating ability, surface topography, and in vitro drug release. Aging effect on storage was evaluated using scanning electron microscopy, hot stage polarizing microscopy (HSPM), differential scanning calorimetry (DSC), and in vitro drug release. Granules were retained in stomach at least for 6 hours. Approximately 65% to 80% drug was released over 6 hours with initial fast release from the surface. Surface topography, HSPM, DSC study of the aged samples showed phase transformation of Gelucire. The phase transformation also caused significant increase in drug release. In conclusion, hydrophobic lipid, Gelucire 43/01, can be considered as an effective carrier for design of a multi-unit floating drug delivery system of highly water-soluble drugs such as diltiazem HCl.

[Tetracyclic derivatives of diltiazem from aurones and thioaurones]. / Tetracyclische derivate des diltiazems aus auronen und thioauronen.

Tetracyclic derivatives of diltiazem from aurones and thioaurones Heating the aurones 1a, b and the thioaurones 1c, d with 2-aminothiophenol in polyphosphoric acid (PPA) under nitrogen yields the 6,12-dihydrobenzofuro[2,3-c][1,5]benzothiazepines 3a,b and the sulfur analogues 3c, d, respectively. Reaction of the annulated benzofuranes 3a,b with 2-chloroethyl-N,N-dimethylammonium chloride and potassium carbonate leads to S-alkylation and ring opening forming the 3-imino-aurones 5. The tetracycles 3 react with sodium hydride in DMF under ring contraction to afford the benzofuro- and benzothieno[3,2-b]quinolines 6. The stability of the partially saturated tetracycles 3 is investigated by anodic oxidation using the rotating platinum electrode by means of differential pulse voltammetry. The measured half wave potentials of the 1,4-dihydropyridine partial structure in compounds 3 are compared with that of nifedipine.

A trifunctional catalyst for one-pot synthesis of chiral diols via Heck coupling-N-oxidation-asymmetric dihydroxylation: application for the synthesis of diltiazem and taxol side chain.

A heterogeneous bifunctional catalyst composed of OsO4(2-)-WO4(2-) and a trifunctional catalyst comprising PdCl4(2-)-OsO4(2-)-WO4(2-), designed and prepared by an ion-exchange technique using layered double hydroxides (LDH) as an ion-exchanger and their homogeneous bifunctional analogue, K2OsO4-Na2WO4 and trifunctional analogue, Na2PdCl4-K2OsO4-Na2WO4, devised for the first time are evaluated for the synthesis of chiral vicinal diols. These bifunctional and trifunctional catalysts perform asymmetric dihydroxylation-N-oxidation and Heck-asymmetric dihydroxylation-N-oxidation, respectively, in the presence of Sharpless chiral ligand, (DHQD)2PHAL in a single pot using H2O2 as a terminal oxidant to provide N-methylmorpholine oxide (NMO) in situ by the oxidation of N-methylmorpholine (NMM). The heterogeneous bifunctional catalyst supported on LDH (LDH-OsW) displays superior activity to afford diols with higher yields over the other heterogeneous catalysts developed by the ion exchange on quaternary ammonium salts covalently bound to resin (resin-OsW) and silica (silica-OsW) or homogeneous catalysts in the achiral dihydroxylation reactions. The LDH-OsW and its homogeneous analogue are found to be very efficient in performing a simultaneous asymmetric dihydroxylation (AD)-N-oxidation of a wide and varied range of aromatic, cyclic, and mono, di-, and trisubstituted olefins to obtain chiral vicinal diols with higher yields and ee's using H2O2. Further, the use of OsO4(2-)-WO4(2-) catalysts as such or in the supported form offers a simplified procedure for catalyst recycling, which shows consistent activity for a number of cycles. In this process, Os(VI) is recycled to Os(VIII) by a coupled electron transfer-mediator (ETM) system based on NMO-WO4(2-) using H2O2, leading to a mild and selective electron transfer. The one-pot biomimic synthesis of chiral diols is mediated by a recyclable trifunctional heterogeneous catalyst (LDH-PdOsW) consisting of active palladium, tungsten, and osmium species embedded in a single matrix. This protocol, which provides prochiral olefins and NMO in situ by Heck coupling and N-oxidation of NMM, respectively, required for the AD, unfolds a low cost process. We extended the present method to the one-pot synthesis of trisubstituted chiral vicinal diols with moderate to excellent ee's by AD of trisubstituted olefins that are obtained by in situ Heck arylation of disubstituted olefins. The heterogeneous trifunctional catalysts offers chiral diols with unprecedented ee's and excellent yields in the AD of prochiral cinnamates, which are obtained in situ from acrylates and halobenzenes for the first time. The new variants such as LDH support and Et3N*HX inherently composed in the heterogeneous multicomponent system and slow addition of H2O2 facilitates the hydrolysis of osmium monogylcolate ester to subdue the formation of bisglycolate ester to achieve higher ee's. Without resorting to recrystallization, the chiral diols of cinnamates thus synthesized with 99% ee's and devoid of osmium contamination are directly put to use in the synthesis of diltiazem and Taxol side chain with an overall improved yield to demonstrate the synthetic utility of the trifunctional heterogeneous catalyst. The high binding ability of the heterogeneous osmium catalyst enables the use of equimolar ratio of ligand to osmium to give excellent ee's in AD in contrast to the homogeneous osmium system in which the excess molar quantities of the expensive chiral ligand to osmium are invariably used. Further, the XRD, FT-IR, UV-vis DRS, and XPS studies indicate the retention of the coordination geometries of the specific divalent anions anchored to LDH matrix in their monomeric form during the ion exchange and after the reaction.

[Unexpected formation of spiro(benzofuran-2,2'-(1,4)benzothiazines) from aurones]. / Unerwartete Bildung von Spiro[benzofuran-2,2'-[1,4]benzothiazinen] aus Auronen.

The reaction between (Z)-2-benzylidene-3-coumaranones (aurones) 4B, 2-aminothiophenol and sodium ethanolate does not give the expected benzofuro[2,3-c][1,5]benzothiazepines 7, but yields the spiro compounds 8. Their structures are confirmed by an X-ray analysis.

Benzothiazepine binding domain of purified L-type calcium channels: direct labeling using a novel fluorescent diltiazem analogue.

We have synthesized a series of N-propylamino-substituted benzazepinones (NPSBs) as specific probes for the benzothiazepinone (BTZ) binding domain of muscle L-type calcium channels (LTCCs). NPSBs were identified which possess high affinity for the channel after purification. We synthesized a fluorescent NPSB, DMBODIPY-BAZ, as the first benz(othi)azepinone derivative known to reversibly label partially purified LTCCs. DMBODIPY-BAZ binds to the partially purified channel with high affinity (Kd = 25 nM, Bmax = 580 pmol/mg of protein). Fluorescence resonance energy transfer (FRET) occurred between tryptophan residues of the channel protein and the DMBODIPY fluorophore upon specific drug binding. FRET was exploited to allow highly time-resolved detection of specific drug binding kinetics. We found that the dissociation half-life (t1/2) of DMBODIPY-BAZ decreased with the concentration of an unlabeled competitor, which indicates ligand-induced accelerated dissociation. In contrast, t1/2 was concentration-dependently increased by the dihydropyridine (DHP) (+)-isradipine. These kinetic properties of DMBODIPY-BAZ indicate that a high-affinity BTZ binding domain also exists on purified LTCCs. NPSBs represent novel tools to provide further insight into the molecular pharmacology of the BTZ binding domain on LTCCs.

Synthesis of the metabolites of clentiazem.

The metabolites of clentiazem in the urine or bile of rats and dogs were investigated. Fifteen basic, 6 acidic, 2 neutral and 4 conjugated metabolites were isolated. In the present paper, fourteen reference compounds as shown in Charts 1, 2 and 3 were synthesized to identify the structures of the metabolites in procedures fundamentally similar to those employed in the synthesis of the corresponding metabolites of diltiazem.

Synthesis and antihypertensive activity of 3-acetoxy-2,3-dihydro-5-[2- (dimethylamino)ethyl]-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one (diltiazem) derivatives having substituents at the 8 position.

In order to improve the potency and duration of biological actions of diltiazem, a number of 1,5-benzothiazepine derivatives having the substituents at the 8 position were prepared and evaluated for their antihypertensive activity in spontaneously hypertensive rats. The introduction of methyl, ethyl, isopropyl, benzyl, methoxy, ethoxy, phenoxy, and methylthio groups increased the antihypertensive activity and prolonged duration of action, whereas cyclohexyl, cyclopentoxy, tolyloxy, p-methoxyphenoxy and phenylthio derivatives were less active than diltiazem. Among them, the 8-benzyl and phenoxy derivatives showed the most potent and long-lasting antihypertensive action.

Synthesis and pharmacological properties of azido derivatives of 1,5-benzothiazepine Ca antagonist.

Since azido derivatives of 1,5-benzothiazepine Ca antagonist available for photoaffinity labeling are required for further studies of voltage-sensitive Ca channels, we synthesized 3-(p-azidobenzoyloxydeacetyl)- and 3-(4-azidobutyryloxydeacetyl)-diltiazem, and studied their pharmacological properties. Both azido compounds showed similar relaxing actions to diltiazem in K(+)-depolarized dog arteries. They also showed a similar increasing action to diltiazem, but less potent, on the coronary and vertebral blood flow in the anesthetized dog. Moreover, their negative inotropic effects in the guinea pig papillary muscle were similar to or slightly more potent than that of diltiazem under physiological conditions, but were less potent when studied in K+ depolarizing solution. A radioligand binding study in rat skeletal muscle microsomes revealed that the azido derivatives had similar properties to diltiazem, but the nonspecific binding of 3-(p-azidobenzoyloxydeacetyl)-diltiazem was too high to allow estimation of its KD and Bmax values. In conclusion, we synthesized azido derivatives of diltiazem which were considered to share a common binding site on the voltage-dependent Ca channel with diltiazem in skeletal muscle microsomes and in vascular smooth muscle.