Benazepril inhibitors

Some developments have been carried out for the enantioselective synthesis of biologically active compounds. One such example is the synthesis of ethyl (R)-2-hydroxy-4-phenylbutyrate, an important intermediate for the angiotensinconverting enzyme (ACE) inhibitor benazepril, or for coenzyme A, using the NORPHOS ligand (Scheme 33.9) [21]. 

Scheme 33.9 Enantioselective hydrogenation with Rh-NOR-PHOS complex as a key step in the synthesis of the ACE inhibitor benazepril (see Table 33.2).

In vitro studies were also conducted to discover the enzymes responsible for bioactivation of benazepril. With different preparations and eserine as an inhibitor, the involvement of arylesterases (EC 3.1.1.2) and cholinesterases (EC 3.1.1.8) was ruled out, while that of carboxylesterases (EC 3.1.1.1) was... 

Undesired effects. The magnitude of the antihypertensive effect of ACE inhibitors depends on the functional state of the RAA system. When the latter has been activated by loss of electrolytes and water (resulting from treatment with diuretic drugs), cardiac failure, or renal arterial stenosis, administration of ACE inhibitors may initially cause an excessive fall in blood pressure. In renal arterial stenosis, the RAA system may be needed for maintaining renal function and ACE inhibitors may precipitate renal failure. Dry cough is a fairly frequent side effect, possibly caused by reduced inactivation of kinins in the bronchial mucosa. Rarely, disturbances of taste sensation, exanthema, neutropenia, proteinuria, and angioneurotic edema may occur. In most cases, ACE inhibitors are well tolerated and effective. Newer analogues include lisinopril, perindo-pril, ramipril, quinapril, fosinopril, benazepril, cilazapril, and trandolapril. 

Benazepril (Lotensin) [Antihypertensive/ACEI] Uses HTN DN, CHF Action ACE inhibitor Dose 10 0 mg/d PO Caution [C (1st tri), D (2nd 3rd tri), +] Contra Angioedema, Hx edema, bilateral RAS Disp Tabs 5, 10, 20, 40 mg SE Symptomatic i BP w/ diuretics dizziness, HA, nonproductive cough Interactions T Effects W/ a-blockers, diuretics, capsaicin effects W/ NSAIDs, ASA T effects OF insulin, Li T risk of hyperkalemia W/ trimethoprim K-sparing diuretics EMS Monitor EGG for signs of hyperkalemia angioedema is rare but can occur persistent cough /or taste changes may develop OD Profound hypotension treat w/ IV fluid... 

Many of the orally active ACE inhibitors are prodrugs. These include perindopril, quinapril, benazepril, ramipril, enalapril, trandolapril, and fosinopril. 

Angiotensin converting enzyme (ACE) inhibitors benazepril captopril cilazapril enalaprilat enalapril maleate fosinopril sodium lisinopril... 

Enalapril is an oral prodrug that is converted by hydrolysis to a converting enzyme inhibitor, enalaprilat, with effects similar to those of captopril. Enalaprilat itself is available only for intravenous use, primarily for hypertensive emergencies. Lisinopril is a lysine derivative of enalaprilat. Benazepril, fosinopril, moexipril, perindopril, quinapril, ramipril, and trandolapril are other long-acting members of the class. All are prodrugs, like enalapril, and are converted to the active agents by hydrolysis, primarily in the liver. 

The next example originates from our own laboratory Two potential intermediates for the angiotensin-converting enzyme inhibitor benazepril can be synthesized using cinchona modified noble metal catalysts (3). While the hydrogenation of the a-ketoester has been developed and scaled-up into a production process (10-200 kg scale, chemical yield >98%, ee 79-82%), the novel enantioselective hydrodechlorination reaction (see Section in) could be a potential alternative to the established synthesis where the racemic a-bromobenzazepinon is used [75]. At the moment both selectivity and productivity of the catalyst are too low and substitution reactions occur less readily with the chloro analog. 

An important step in the asymmetric synthesis of the angiotensin-converting enzyme inhibitor, benazepril HC1 132, was the reduction of the ketoester 128 (obtained from 127 by condensation with diethyl oxalate) with baker s yeast to give the chiral cr-hydroxy ester 129 in high yield and ee (Scheme 17). Direct formation of the 1//-1-benzazepin-2-one 131 from 129 proceeded in 42% yield (without racemization at C-3) or in 74% yield in two steps via 130, again with no racemization <2003TA2239>. 

Angiotensin-converting enzyme (ACE) inhibitors, such as benazepril (Lotensin), enalapril (Vasotec), fosinopril (Monopril), lisinopril (Prinivil, Zestril), quinapril (Accupril), and ramipril (Altace). 

Novartis (Ciba Geigy) has reported the synthesis of Benazepril (163) (Scheme 12.63), an angiotensin-converting enzyme inhibitor, via an intermediate prepared by cinchona-modified Pt asymmetric hydrogenation (10-200-kg scale, >98%, 79-82% ee).5 The low optical purities can be tolerated because enantio-enrichment is relatively easy in the latter stages of the synthesis.22... 

Wade et al. reported the use of a novel statistical approach for the comparison of analytical methods to measure angiotensin converting enzyme [peptidyl-dipeptidase A] activity, and to measure enalaprilat and benazeprilat [8]. Two methods were used to measure peptidyl-dipeptidase A, namely hippuryl histidyl leucine (HHL-method) [9], and inhibitor binding assay (IBA method) [10]. Three methods were used to measure enalaprilat, namely a radioimmunoassay (RIA) method [11], the HHL method, and the IBA method. Three methods were used to measure benazeprilat (then active metabolite of benazepril) in human plasma, namely gas chromatography-mass spectrometry (GC-MS method) [12], the HHL method, and the IBA method, and were statistically compared. First, the methods were compared by the paired t test or analysis of variance, depending on whether two or three different methods were under comparison. Secondly, the squared coefficients of variation of the... 

A derivative UV spectrophotometric method was used by Bonazzi et al. for the determination of benazepril hydrochloride and other angiotensin converting enzyme inhibitors in their pharmaceutical dosage forms [17],... 

Sereda et al. developed an electron-capture gas chromatographic detection method for the detection of benazepril and other angiotensinconverting enzyme (peptidyl-dipeptidase) inhibitors [26]. Sample solutions (0.001-0.1 mL) containing the inhibitor or metabolite were... 

Bonazzi et al. used an HPLC method and a second derivative ultraviolet spectroscopy method for the analysis of benazepril and other angio-tensen-converting enzyme inhibitors [17]. For HPLC, 20 pL sample solutions containing the drug and an internal standard dissolved in 1 1 acetonitrile/20 mM sodium heptanesulfonate (pH 2.5) were used. HPLC was performed on a 5 pm Hypersil ODS column (25 cm x 4.5 mm) with a mobile phase mixture consisting of (A) 20 mM sodium heptanesulfonate (pH 2.5) and (B) 19 1 acetonitrile-tetrahydrofuran, eluted at a flow rate of 1 mL/min, and with detection at 215 nm. The A/B mixture used was 52 48 for benazepril. A low pH of 2.5 was essential to avoid peak splitting and band broadening. 

The same authors also applied capillary electrophoresis to the study of benazepril hydrochloride and several angiotensin-converting enzyme inhibitors [43]. Separation of the compounds was performed by means of two phosphate buffers (each 0.1 M) at pH 7 and 6.25, respectively [42], Due to the highest selectivity of the first mentioned running buffer, the same system has been applied for the quantification of benazepril and other compounds in their corresponding pharmaceutical formulations. It was found that the possibility of simultaneous identification and quantification of the active ingredient in the finished products was especially attractive, and that excipients do not adversely affect the results. This article deals with the validation of some parameters of the quantitative analysis, namely linearity, precision, accuracy, and robustness [43],... 

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