Benazepril converting enzyme

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],... 

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],... 

This assay is used for the quantitative determination of benazepril and its active metabolite, benazeprilat, in human plasma by capillary gas chromatography-mass selective detection (Pommier et al. 2003). Benazepril hydrochloride, 3- [l-ethoxycarbonyl-3-phenyl-(lS)-propyl]amino -2,3,4,5-tetrahydro-2-oxo-l-(3S)-benzazepine-l-acetic acid hydrochloride, is a prodrug-type angiotensin-converting enzyme (ACE) inhibitor which, on absorption, is hydrolysed to a pharmacologically active metabolite, the dicarboxylic acid (benazeprilat). 

Sioufi A, Pommier F, Kaiser G, Dubois JP (1988) Determination of benazepril, a new angiotensin-converting enzyme inhibitor and its active metabolite, benazeprilat, in plasma and urine by capillary gas chromatography-mass-selective detection. J Chromatogr 434 239-246... 

The first technical apphcation of a cinchona-modified Pt catalyst was reported by Ciba-Geigy as early as 1986 for the synthesis of methyl ( P)-2-hydroxy-4-plieriyl butyrate (fR/-HPB ester), an intermediate for the angiotensin-converting enzyme (ACE) inhibitor benazepril (see Scheme 12.6) [22]. 

Maschio G, Alberti D, Janin G, Locatelli F, Mann JF, Motolese M, Ponticelli C, Ritz E, Zucchelli P. Effect of the angiotensin-converting-enzyme inhibitor benazepril on the progression of chronic renal insufficiency. N Engl J Med 1996 334 939-945. 

Benazepril is an angiotensin converting enzyme (ACE) inhibitor which competitively inhibits ACE, resulting in... 

Benazepril Benazeprilum CGS-14824A Briem Cibacen Cibacdne Lotensin. Angiotensin-converting enzyme inhibitor. Used to treat hypertension. Orally active peptidyidipeptide hydrolase inhibitor. Crystals mp= 148-149" [a)D = -159" (c = 1.2 EtOH). Ciba-GeigyCorp. 

A comprehensive review of asymmetric hydrogenation, mainly 2-oxo-carboxylic acids and their esters, over heterogeneous catalysts of Pt-alumina modified with alkaloids was presented in Chapter 5 of this book. Here some practical aspects of these catal5i ic systems will be considered. Thus, ethyl (i )-4-phenyl-2-hydroxybutyrate is an important intermediate for the synthesis of the angiotensin-converting enzyme inhibitor Benazepril (Scheme 7.20.) and other carboxyalkyl dipeptides like Enalapril (Scheme 7.21.)... 

De Lepeleire I, Van Hecken A, Verbesselt R, Kaiser G, Bamer A, Holmes I, De Schepper PJ. Interaction between furosemide and the converting enzyme inhibitor benazepril in healthy volunteers, EurJ Clin Pharmacol (1988) 34, 465-8. 

Examples of industrial production based largely on these modified solid catalysts are a sex hormone (Tai et al., 1978, 1979), ligands for homogeneous enantioselective hydrogenation (Bakos et al., 1981 Tai and Harada, 1986), and an intermediate in the production of the angiotensin-converting enzyme inhibitor, benazepril (Morrison and Mosher, 1971). 

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