Benzothiazepine Ring Research Articles

A Sulfur-Controlled Approach to the Synthesis of Linerixibat.

Establishing the two stereocenters in the benzothiazepine ring of linerixibat (GSK2330672) has been a long-standing problem at GSK. Our solution rests on an episulfonium-controlled Ritter reaction followed by a sulfoxide-directed reduction. A rationale for both steps is based on a mixture of literature precedent and computational experiments. Transition state modeling suggests the sulfoxide-directed reduction proceeds through electronic repulsion between the lone pair of electrons on sulfur and the incoming borohydride anion.

Modulation by CGP-37157 (CGP) Analogs of the Sarcoplasmic Reticulum Calcium ATPase SERCA)

We have reported that CGP, a 4-1 benzothiazepine (BZT) associated with cardioprotection in ischemia, is a SERCA inhibitor. CGP blocking action differs from that of thapsigargin because is Ca2+ dependent; i.e., CGP blocking potency increases when Ca2+ levels decrease. We utilized purified sarcoplasmic reticulum microsomal membranes (SRM; from rabbit skeletal muscle and pig ventricle) to test the inhibitory actions of various novel CGP analogs on ATPase function (estimated by measurements of Ca2+ loading and ATPase activity). The 4,1-benzothiazepin-2-one structural arrangement seems to be important for SERCA blocking action since function is lost within compounds where: the Sulfur is substituted by Nitrogen (as seen in benzodiazepines); the Oxygen is replaced by an alkyl group; or the arrangement between Nitrogen, Oxygen, and Sulfur in the BZT ring is reorganized (as seen in Diltiazem). Removal of Chlorine from position 7 in the BZT ring did not affect SERCA blocking potency. A combination of substitutions: 3H (benzylaminomethyl-carboxymethyl), alkylation of the Nitrogen (neopentyl) and replacement of the position 1 of benzyl group (naphtyl), significantly increased potency 10-fold (IC50 ∼ 1.5 μM, in presence of 2 μM free Ca2+). We determined (using SRM Ca2+ leak assay, [3H] ryanodine binding and channel studies in bilayers) CGP analogs can also activate ryanodine receptors (RyRs), albeit with low potency. In summary, we have identified structural features that may confer Ca2+-dependent SERCA blocking in 4,1 BZT by utilizing CGP-like molecules. We also identified ph000995, a potent blocker, which may have potential for assessing SERCA roles in cells as well as being a potential drug-template for therapeutic intervention in diseases of abnormal Ca2+ homeostasis, such as ischemia. (Supported by American Heart Association, Eskridge Foundation and APS Frontiers in Physiology Research Program).

ChemInform Abstract: Enzymatic‐ and Iridium‐Catalyzed Asymmetric Synthesis of a Benzothiazepinylphosphonate Bile Acid Transporter Inhibitor.

A synthesis of the benzothiazepine phosphonic acid 3, employing both enzymatic and transition metal catalysis, is described. The quaternary chiral center of 3 was obtained by resolution of ethyl (2-ethyl)norleucinate (4) with porcine liver esterase (PLE) immobilized on Sepabeads. The resulting (R)-amino acid (5) was converted in two steps to aminosulfate 7, which was used for construction of the benzothiazepine ring. Benzophenone 15, prepared in four steps from trimethylhydroquinone 11, enabled sequential incorporation of phosphorus (Arbuzov chemistry) and sulfur (Pd(0)-catalyzed thiol coupling) leading to mercaptan intermediate 18. S-Alkylation of 18 with aminosulfate 7 followed by cyclodehydration afforded dihydrobenzothiazepine 20. Iridium-catalyzed asymmetric hydrogenation of 20 with the complex of [Ir(COD)2BArF] (26) and Taniaphos ligand P afforded the (3R,5R)-tetrahydrobenzothiazepine 30 following flash chromatography. Oxidation of 30 to sulfone 31 and phosphonate hydrolysis completed the synthesis of 3 in 12 steps and 13% overall yield.

Enzymatic- and Iridium-Catalyzed Asymmetric Synthesis of a Benzothiazepinylphosphonate Bile Acid Transporter Inhibitor

A synthesis of the benzothiazepine phosphonic acid 3, employing both enzymatic and transition metal catalysis, is described. The quaternary chiral center of 3 was obtained by resolution of ethyl (2-ethyl)norleucinate (4) with porcine liver esterase (PLE) immobilized on Sepabeads. The resulting (R)-amino acid (5) was converted in two steps to aminosulfate 7, which was used for construction of the benzothiazepine ring. Benzophenone 15, prepared in four steps from trimethylhydroquinone 11, enabled sequential incorporation of phosphorus (Arbuzov chemistry) and sulfur (Pd(0)-catalyzed thiol coupling) leading to mercaptan intermediate 18. S-Alkylation of 18 with aminosulfate 7 followed by cyclodehydration afforded dihydrobenzothiazepine 20. Iridium-catalyzed asymmetric hydrogenation of 20 with the complex of [Ir(COD)2BArF] (26) and Taniaphos ligand P afforded the (3R,5R)-tetrahydrobenzothiazepine 30 following flash chromatography. Oxidation of 30 to sulfone 31 and phosphonate hydrolysis completed the synthesis of 3 in 12 steps and 13% overall yield.

(Z)-3-(2,4-Dichlorobenzyl)-1,5-benzothiazepin-4(5H)-one

In the title compound, C16H11Cl2NOS, the seven-membered thia­zepine ring adopts a distorted twist-boat conformation. The dihedral angle between the mean plane of the benzothia­zepine ring system and the benzene ring is 78.6 (1)°. The mol­ecular conformation is stabilized by a weak intra­molecular C—H⋯Cl hydrogen bond, which generates an S(5) ring motif. In the crystal, pairs of N—H⋯O hydrogen bonds link inversion-related mol­ecules into dimers, generating R 2 2(8) ring motifs. The crystal packing also features alternating π–π inter­actions between benzothia­zepine benzene rings [inter-centroid distance = 3.740 (3) Å] and dichloro­benzene rings [inter-centroid distance = 3.882 (3) Å] to consolidate a three-dimensional architecture.

A 1,5-benzothiazepine synthesis

The pharmaceutically active compound (±)-thiazesim was synthesized in four steps and 62% overall yield. This new approach to biologically relevant benzothiazepine ring systems features the use of water as a solvent, co-solvent or catalyst in three of the four steps.

Investigation of the Reaction of Chloroacetyl Chloride with 1,5-Benzothiazepines: Selective Synthesis of Azeto[2,1-d][1,5]benzothiazepines by Green Chemical Methods and Their Biological Activity

An efficient and exclusive synthesis of the tricyclic azeto[2,1-d][1,5]benzothiazepine ring system has been developed. By use of microwave irradiation in the presence of basic alumina, the reaction time has been brought down from hours to minutes with improved yields in comparison to conventional heating. Antimicrobial screening of the synthesized compounds has shown promising activity.

1H and 13C NMR study of tetrahydro-1,4-benzothiazepine conformationsElectronic supplementary information (ESI) available: crystal data, structure refinement and a perspective view of the X-ray crystal structure of 1. See http://www.rsc.org/suppdata/p2/b2/b205768a/

The variable temperature (298–178 K) 1H NMR spectra of tetrahydro-1,4-benzothiazepines 1–10 are described and discussed. Compounds 2–10 exist as two puckered mirror-image (enantiomorphic) conformers, with benzothiazepine ring chair-to-chair interconversion barriers of ca. 10 kcal mol−1 in CD2Cl2 solution. A similar interconversion was detected for compound 1, of lower symmetry. The ground state conformations of 1–10 were assigned on the basis of the magnitudes of 1H–1H vicinal coupling constants. The 1H and 13C NMR spectral assignments were determined by 1H–1H COSY, HETCOR, and NOESY experiments. The stereochemistry and conformation of compound 1 was further confirmed by a single crystal X-ray structure determination.

A novel octahydropyridobenzothiazepine metabolite in human urine: biomimetic formation from the melanogen 5-S-cysteinyldopa and formaldehyde via a peculiar sulfur-controlled double Pictet-Spengler condensation.

HPLC evidence is reported demonstrating the occurrence in some human urine samples of a novel catecholic metabolite, (3R,7S)-3, 7-dicarboxy-10,11-dihydroxy-2,3,4,5,6,7,8,9-octahydropyrido[ 4,3-g][1, 4]benzothiazepine (2). The compound was shown to arise by a double Pictet-Spengler condensation of the urinary melanogen 5-S-cysteinyldopa (1) with formaldehyde, in which regioselective formation of the six-membered ring ortho to the activating hydroxyl group lends assistance to the subsequent closure of the seven-membered 1,4-thiazepine moiety. Under physiologically relevant conditions, i.e., in 0.1 M phosphate buffer pH 7.4 and at 37 degrees C, the 7,8-tetrahydroisoquinoline 5 was the sole detectable intermediate in the formation of 2. N-Acetylcysteinyldopa (4) reacted likewise with formaldehyde to give the 7, 8-dihydroxytetrahydroisoquinoline 6. The anomalous regiochemistry underlying formation of 5 and 6 was rationalized with the aid of AM1/PM3 calculations on the model alkylthiocatechol 10, predicting a higher HOMO-controlled reactivity on the position ortho rather than para to the activating hydroxyl group. The potential of the reported chemistry as a convenient synthetic access to the 2,3,4, 5-tetrahydro[1,4]benzothiazepine ring system is suggested by the efficient conversion of the cysteinylcatechol 3 to 8 in the presence of formaldehyde.

Synthesis of new hetero[2,1]benzothiazepine derivatives

AbstractAs part of an investigation directed to the search of new neurotropic agents we have prepared a number of hydroxy and hydroximino derivatives of the novel thieno and pyrazolo[2,1]benzothiazepine ring systems. Assignments of the Z and E hydroximino isomers were performed by study of their 1H and 13C nmr spectra and NOE experiments.

ChemInform Abstract: Carbohydrates as Chiral Auxiliaries in Asymmetric Darzens Reactions: Enantioselective Synthesis of the Benzothiazepine Ring System of Diltiazem.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Synthesis of 1H‐ and 2H‐pyrazolo[3,4‐c][2,1]benzothiazepines

AbstractStarting from ethyl chlorosulfonylpyrazole‐4‐carboxylates we have carried out the synthesis of ketones 3 and 4 which are the first two structures of the novel 1H‐ and 2H‐pyrazolo[3,4‐c][2,1]benzothiazepine ring systems.

Synthesis of thieno[3,4‐c] and thieno[3,2‐c][2,1]benzothiazepines

AbstractStarting from [4,3‐c] and [3,2‐c] methyl chlorosulfonylthiophenecarboxylates the synthesis of ketones 7 and 8 is described. These compounds are the first two representatives of the new thieno[3,4‐c] and thieno‐[3,2‐c][2,1]benzothiazepine ring systems. The formation of methyl 3‐chlorosulfonylthiophene‐2‐carboxy‐late is also revised.

Interaction of calcium channel antagonists with calcium: spectroscopic and modeling studies on diltiazem and its Ca2+ complex.

Using spectral techniques, the solution conformation of diltiazem was studied in acetonitrile with special reference to the effect of Ca2+ on the drug structure. Complete assignment of the proton resonances in the 1H-NMR spectrum of the drug was made using one-and two-dimensional spectral analyses. A two-dimensional 1H-NOESY spectrum (in the phase-sensitive mode) was obtained to identify the interproton connectivities in the drug molecule. A molecular modeling program involving Monte Carlo simulation and energy minimization was employed to arrive at the structure of the drug. The program was run with and without the input of the interproton distances derived from the NOESY cross peaks. Both the protocols led to a structure of the drug which was generally similar to that reported from X-ray diffraction data on crystalline diltiazem hydrochloride (Kojic-Prodic, et al. Helv. Chim. Acta 1984, 67, 916-926). However, significant differences between the two structures were seen in the orientations of the substituent groups attached to the benzothiazepine ring. Substantial changes in the circular dichroic (CD) and 1H-NMR spectra of diltiazem were observed on addition of Ca2+ up to a mole ratio of 0.5 Ca2+ per drug. Relatively large changes were seen in 1H resonances of the N-methyl protons and the methylene protons attached to the heterocyclic nitrogen. Analysis of the binding isotherms from CD data at 22 +/- 1 degrees C indicated a 2:1 drug:Ca2+ "sandwich" complex with an estimated dissociation constant of 140 microM. One-dimensional difference NOE and two-dimensional NOESY spectra revealed interproton connectivities between two drug molecules that were compatible with the sandwich complex formation. The interproton distances derived from the volume integrals of the NOESY cross peaks were used as geometrical constraints in modeling the Ca(2+)-bound conformation of diltiazem. The minimum-energy conformation corresponded to the sandwich complex where Ca2+ was coordinated to three oxygens in each of the two drug molecules. Combined with our earlier data on the ability of diltiazem to translocate Ca2+ across the lipid bilayer in synthetic liposomes (Ananthanarayanan, V.S.; Taylor, L.; Pirritano, S.Biochem. Cell Biol. 1992, 70, 608-612), the structural data presented here point to a role for Ca2+ in the interaction of diltiazem with its membrane-bound receptor.