62571-86-2 Usage
Chemical Properties
White or almost white, crystalline powder.
Originator
Lopirin,Von Heyden,W. Germany,1980
Uses
Different sources of media describe the Uses of 62571-86-2 differently. You can refer to the following data:
1. Orally active angiotensin-converting enzyme (ACE) inhibitor
2. anesthetic
3. angiotensin-converting enzyme (ACE) inhibitor,anti-hypertensive
4. Captopril has also been shown to inhibit the formation of angiotensin II, a bioactive peptide that stimulates angiogenesis and increases microvessel density. Captopril demonstrates noncompetitive inhibition of tyrosinase monophenolase activity and competitive inhibition of diphenolase activity
Definition
ChEBI: A L-proline derivative in which L-proline is substituted on nitrogen with a (2S)-2-methyl-3-sulfanylpropanoyl group. It is used as an anti-hypertensive ACE inhibitor drug.
Manufacturing Process
The first step is the manufacture of L-proline tert-butyl ester. L-proline (230 g)
is dissolved in a mixture of water (1 l) and 5 N sodium hydroxide (400 ml).
The solution is chilled in an ice bath, and under vigorous stirring, 5 N sodium
hydroxide (460 ml) and benzyloxycarbonyl chloride (340 ml) are added in five
equal aliquots during a half-hour period. After one hour stirring at room
temperature, the mixture is extracted twice with ether and acidified with
concentrated hydrochloric acid. The precipitate is filtered and dried. Yield is
442 g; MP 78°C to 80°C.The benzyloxycarbonyl-L-proline thus obtained (180 g) is dissolved in a
mixture of dichloromethane (300 ml), liquid isobutylene (800 ml) and
concentrated sulfuric acid (7.2 ml). The solution is shaken in a pressure bottle
for 72 hours. The pressure is released, the isobutylene is allowed to evaporate
and the solution is washed with 5% sodium carbonate, water, dried over
magnesium sulfate and concentrated to dryness in vacuo, to obtain
benzyloxycarbonyl-L-proline tert-butyl ester, yield 205 g.Benzyloxycarbonyl-L-proline tert-butyl ester (205 g) is dissolved in absolute
ethanol (1.2 l) and hydrogenated at normal pressure with 10% Pd on carbon
(10 g) until only a trace of carbon dioxide is observed in the hydrogen exit
gas (24 hours). The catalyst is filtered off and the filtrate is concentrated in
vacuo at 30 mm Hg. The residue is distilled in vacuo, to obtain L-proline tert-butyl ester, BP1mm 50°C to 51°C.The next step yields 1-(3-acetylthio-2-methylpropanoyl)-L-proline tert-butyl
ester. L-proline tert-butyl ester (5.1 g) is dissolved in dichloromethane (40 ml)
and the solution stirred and chilled in an ice bath. Dicyclohexylcarbodiimide
(15 ml) is added followed immediately by a solution of 3-acetylthio-2-
methylpropanoic acid (4.9 g) in dichloromethane (5 ml). After 15 minutes
stirring in the ice bath and 16 hours at room temperature, the precipitate is
filtered off and the filtrate is concentrated to dryness in vacuo. The residue is
dissolved in ethyl acetate and washed neutral. The organic phase is dried over magnesium sulfate and concentrated to dryness in vacuo. The residue 1-(3-
acetylthio-2-methylpropanoyl)-L-proline tert-butyl ester is purified by column
chromatography (silica gel-chloroform), yield 7.9 g.Then, 1-(3-acetylthio-2-methylpropanoyl)-L-proline is produced. The 1-(3-
acetylthio-3-methylpropanoyl)-L-proline tert-butyl ester (7.8 g) is dissolved in
a mixture of anisole (55 ml) and trifluoroacetic acid (110 ml). After one hour
storage at room temperature the solvent is removed in vacuo and the residue
is precipitated several times from ether-hexane. The residue (6.8 g) is
dissolved in acetonitrile (40 ml) and dicyclohexylamine (4.5 ml) is added. The
crystalline salt is boiled with fresh acetonitrile (100 ml), chilled to room
temperature and filtered, yield 3.8 g, MP 187°C to 188°C. This material is
recrystallized from isopropanol [α]D-67° (C 1.4, EtOH). The crystalline
dicyclohexylamine salt is suspended in a mixture of 5% aqueous potassium
bisulfate and ethyl acetate. The organic phase is washed with water and
concentrated to dryness. The residue is crystallized from ethyl acetate-hexane
to yield the 1-(3-acetylthio-2-D-methylpropanoyl)-L-proline, MP 83°C to 85°C.Finally, Captopril is produced. The thioester (0.85 g) is dissolved in 5.5 N
methanolic ammonia and the solution is kept at room temperature for 2
hours. The solvent is removed in vacuo and the residue is dissolved in water,
applied to an ion exchange column on the H+ Cycle (Dowex 50, analytical
grade) and eluted with water. The fractions that give positive thiol reaction are
pooled and freeze dried. The residue is crystallized from ethyl acetate-hexane,
yield 0.3 g. The 1-(3-mercapto-2-D-methylpropanoyl)-L-proline has a melting
point of 103°C to 104°C.
Brand name
Capoten (Par).
Therapeutic Function
Antihypertensive
Biological Functions
Captopril (Capoten) is an orally effective ACE inhibitor
with a sulfhydryl moiety that is used in binding to the
active site of the enzyme. Captopril blocks the blood
pressure responses caused by the administration of angiotensin
I and decreases plasma and tissue levels of angiotensin
II.
General Description
Captopril, 1-[(2S)-3-mercapto-2-methyl-1-oxopropionyl]proline (Capoten), blocks the conversion of angiotensinI to angiotensin II by inhibiting the convertingenzyme. The rational development of captopril as an inhibitorof ACE was based on the hypothesis that ACE and carboxypeptidaseA functioned by similar mechanisms. It wasnoted that d-2-benzylsuccinic acid was a potent inhibitor ofcarboxypeptidase A, but not ACE. By use of this small molecule as a prototype, captopril was designed with a carboxylgroup on a proline and a thiol group was introduced toenhance the binding to the zinc ion of ACE. The importantbinding points at the active site of ACE are thought to be anarginine residue, which provides a cationic site that attracts acarboxylate ion, and a zinc ion, which can polarize a carbonylgroup of an amide function to make it more susceptible to hydrolysis.Hydrophobic pockets lie between these groups in theactive site, as does a functional group that forms a hydrogenbond with an amide carbonyl.
Biochem/physiol Actions
Angiotensin converting enzyme inhibitor. Inhibits the formation of angiotensin II, a bioactive peptide that stimulates angiogenesis and increases microvessel density.
Pharmacology
Treatment with captopril reduces blood pressure in
patients with renovascular disease and in patients with
essential hypertension.The decrease in arterial pressure
is related to a reduction in total peripheral resistance.
Most studies demonstrate a good correlation between
the hypotensive effect of inhibitors and the degree of
blockade of the renin–angiotensin system.Many of the
pharmacological effects of captopril are attributable to
the inhibition of angiotensin II synthesis. However,
ACE is a relatively nonselective enzyme that also catabolizes
a family of kinins to inactive products. Bradykinin, one of the major kinins, acts as a vasodilator
through mechanisms related to the production
of nitric oxide and prostacyclin by the vascular endothelium.
Thus, administration of the ACE inhibitor
captopril not only inhibits angiotensin II production but
also prevents the breakdown of bradykinin. Increases in
bradykinin concentrations after administration of ACE
inhibitors contribute to the therapeutic efficacy of these
compounds in the treatment of hypertension and congestive
heart failure. However, alterations in bradykinin concentrations are also thought to contribute to cough
and angioedema sometimes seen after ACE inhibition.
The hypotensive response to captopril is accompanied
by a fall in plasma aldosterone and angiotensin II
levels and an increase in plasma renin activity. Serum
potassium levels are not affected unless potassium supplements
or potassium-sparing diuretics are used concomitantly;
this can result in severe hyperkalemia.
There is no baroreflex-associated increase in heart rate,
cardiac output, or myocardial contractility in response
to the decrease in pressure, presumably because captopril
decreases the sensitivity of the baroreceptor reflex.
Captopril enhances cardiac output in patients with
congestive heart failure by inducing a reduction in ventricular
afterload and preload. Converting enzyme inhibitors
have been shown to decrease the mass and wall thickness of the left ventricle in both normal and hypertrophied
myocardium. ACE inhibitors lack metabolic
side effects and do not alter serum lipids.
Clinical Use
Captopril, as well as other ACE inhibitors, is indicated
in the treatment of hypertension, congestive heart
failure, left ventricular dysfunction after a myocardial
infarction, and diabetic nephropathy. In the treatment
of essential hypertension, captopril is considered firstchoice
therapy, either alone or in combination with a
thiazide diuretic. Decreases in blood pressure are primarily
attributed to decreased total peripheral resistance
or afterload. An advantage of combining captopril
therapy with a conventional thiazide diuretic is that the
thiazide-induced hypokalemia is minimized in the presence
of ACE inhibition, since there is a marked decrease
in angiotensin II–induced aldosterone release.
If the patient is asymptomatic, captopril can be used
as monotherapy in the treatment of congestive heart
failure. The use of ACE inhibitors in the treatment of
congestive heart failure is supported by results from
large-scale clinical trials demonstrating a general reduction
in the relative risk of death. In symptomatic patients
captopril should be used in conjunction with a diuretic
because of the weak natriuretic properties of
ACE inhibitors. In combination, captopril will reduce
afterload and preload and prevent diuretic-induced activation
of the renin–angiotensin system. Finally, ACE
inhibitors may slow the progression of congestive heart
failure by limiting left ventricular hypertrophy.
In the treatment of diabetic nephropathy associated
with type I insulin-dependent diabetes mellitus, captopril
decreases the rate of progression of renal insufficiency
and retards the worsening of renal function.
Side effects
Approximately 10% of the patients treated with
captopril report a dose-related maculopapular rash
that often disappears when the dosage of captopril is
reduced. Other common adverse effects are fever, a
persistent dry cough (incidence as high as 39%), initial
dose hypotension, and a loss of taste that may result in
anorexia. These effects are reversed when drug therapy
is discontinued. More serious toxicities include a
1% incidence of proteinuria and glomerulonephritis;
less common are leukopenia and agranulocytosis.
Since food reduces the bioavailability of captopril by
30 to 40%, administration of the drug an hour before
meals is recommended. All converting enzyme inhibitors
are contraindicated in patients with bilateral
renal artery disease or with unilateral renal artery disease
and one kidney. Use under these circumstances
may result in renal failure or paradoxical malignant
hypertension.
Synthesis
Captopril, 1-[(2S)-3-mercapto-2-methylpropionyl]-L-proline (22.7.4), is synthesized
by direct acylation of L-proline with 3-acetylthio-2-methylpropionic acid chloride
(22.7.2), which is synthesized from 3-acetylthio-2-methylpropionic acid (22.7.1), which is
in turn synthesized by reacting methacrylic and thioacetic acid. 1-(3-Acetylthio-2-Dmethylpropanoyl)-
L-proline (22.7.3) is formed by reacting L-proline with 3-acetylthio-2-
methylpropionic acid chloride, and it undergoes further ammonolysis with ammonia, to
give the desired captopril (22.7.4).
Veterinary Drugs and Treatments
The principle uses of captopril in veterinary medicine, at present,
are as a vasodilator
in the treatment of CHF and in the treatment
of hypertension. Because of fewer adverse effects,
enalapril and
benazepril have largely supplanted the use of this drug in veterinary
medicine.
Drug interactions
Potentially hazardous interactions with other drugs
Anaesthetics: enhanced hypotensive effect.
Analgesics: antagonism of hypotensive effect and
increased risk of renal impairment with NSAIDs;
hyperkalaemia with ketorolac and other NSAIDs.
Antihypertensives: increased risk of hyperkalaemia,
hypotension and renal failure with ARBs and
aliskiren.
Bee venom extract: possible severe anaphylactoid
reactions when used together.
Ciclosporin: increased risk of hyperkalaemia and
nephrotoxicity.
Cytotoxics: increased risk of angioedema with
everolimus.
Diuretics: enhanced hypotensive effect;
hyperkalaemia with potassium-sparing diuretics.
ESAs: increased risk of hyperkalaemia; antagonism
of hypotensive effect.
Gold: flushing and hypotension with sodium
aurothiomalate.
Lithium: reduced excretion, possibility of enhanced
lithium toxicity.
Potassium salts: increased risk of hyperkalaemia.
Tacrolimus: increased risk of hyperkalaemia and
nephrotoxicity
Metabolism
The onset of action following oral administration of
captopril is about 15 minutes, with peak blood levels
achieved in 30 to 60 minutes. Its apparent biological
half-life is approximately 2 hours, with its antihypertensive
effects observed for 6 to 10 hours. The kidneys appear
to play a major role in the inactivation of captopril.
Purification Methods
Purify it by recrystallisation from EtOAc/hexane. It is also purified by dissolving in EtOAc and chromatographed on a column of Wakogel C200 using a linear gradient of MeOH in EtOAc (0-100o) and fractions which give a positive nitroprusside test (for SH), are combined, evaporated and recrystallised from EtOAc/hexane (1:1), to give white crystals with [] D -128.2o (c 2.0, EtOH). [Nam J Pharm Sci 73 1843 1984]. Alternatively, dissolve it in H2O, apply to a column of AG-50Wx2 (BioRad) and elute with H2O. The free acid is converted to the dicyclohexylamine salt in MeCN by addition of the amine until the pH is 8-9. The salt is converted to the free acid by shaking with EtOAc and 10% aqueous KHSO4 or passage through an AG50Wx2 column. The EtOAc solution is dried (MgSO4), evaporated to dryness and the residue is recrystallised as above from EtOAc/hexane [Cushman et al. Biochemistry 16 5484 1977, NMR and IR: Horii & Watanabe Yakugaku Zasshi (J Pharm Soc Japan) 81 1786 1961]. It is an antihypertensive because it is a potent competitive inhibitor of the angiotensive convertive enzyme (ACE-inhibitor) with a Ki value of 0.0017\M [Shimazaki et al. Chem Pharm Bull Jpn 30 3139 1982].
References
1) Cushman?et al. (1999),?Design of angiotensin converting enzyme inhibitors; Nat.Med.,?5?1110
2) Orning?et al. (1991),?Inhibition of leukotriene A4 hydrolase/aminopeptidase by captopril; J.Biol.Chem.,?266?16507
Check Digit Verification of cas no
The CAS Registry Mumber 62571-86-2 includes 8 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 5 digits, 6,2,5,7 and 1 respectively; the second part has 2 digits, 8 and 6 respectively.
Calculate Digit Verification of CAS Registry Number 62571-86:
(7*6)+(6*2)+(5*5)+(4*7)+(3*1)+(2*8)+(1*6)=132
132 % 10 = 2
So 62571-86-2 is a valid CAS Registry Number.
InChI:InChI=1/C9H15NO3S/c1-6(5-14)8(11)10-4-2-3-7(10)9(12)13/h6-7,14H,2-5H2,1H3,(H,12,13)/p-1/t6-,7+/m1/s1
62571-86-2Relevant articles and documents
Spectroscopic investigation on kinetics and mechanistic aspects to electron-transfer process into quinolinium dichromate oxidation of a high blood pressure drug captopril in acidic medium
Asiri, Abdullah M.,Khan, Aftab Aslam Parwaz,Khan, Anish
, p. 1 - 6 (2015)
This study investigated on kinetics of oxidation of captopril by QDC was studied spectrophotometrically in acidic medium along with its mechanistic pathway. Such studies are greatly helpful in gaining an insight into the interaction of metal ions through the study of the mechanistic pathway of CPL in redox reactions. The oxidative product of captopril was found to be captopril disulfide was separated, and identified by FT-IR. A suitable free radical mechanism was proposed. The reaction exhibited first-order kinetics with respect to [oxidant] and fractional order in CPL. Consequently, the interaction between the complex species and CPL is supported kinetic orders of reaction by spectrophotometric verification, positive entropy of activation and the first-order rate constant increased with the increase in the dielectric constant and increase ionic strength of the medium. The reaction constants involved in the mechanism were computed and the overall activation parameters were evaluated which lend support to the proposed mechanism.
THE ASYMMETRIC SYNTHESIS OF (-)-CAPTOPRIL UTILISING THE IRON CHIRAL AUXILIARY 5-C5H5)Fe(CO)(PPh3)>
Bashiardes, George,Davies, Stephen G.
, p. 5563 - 5564 (1987)
Stereoselective alkylation of (R)-5-C5H5)Fe(CO)(PPh3)COCH2CH3> with bromomethyl-t-butyl sulphide, followed by oxidative decomplexation in the presence of L-proline t-butyl ester gave, after deprotection, (-)-Captopril enantiomerically and diastereomerically pure in an overall yield of 59percent.
Preparing method of captopril isomer
-
Paragraph 0032; 0040; 0041; 0042; 0043, (2019/04/26)
The invention provides a preparing method of a captopril isomer. The method includes the steps of resolving mixed 3-sulfanyl-2-methyl propionic acid into L-3-sulfanyl-2-methyl propionic acid, making L-3-sulfanyl-2-methyl propionic acid react with thionyl chloride to prepare L-3-sulfanyl-2-methylpropionyl chloride (L-acyl chloride for short), making L-acyl chloride react with L-proline or D-prolineto generate 1-(3-sulfanyl-2-methylpropionyl)-proline (free acid for short), and conducting hydrolysis deprotection on the free acid to prepare the isomer. The preparing method is good in resolving effect, the obtained isomer is high in optical purity, the resolving reaction time and temperature range is large, and control is easy.
Chemoenzymatic Synthesis in Flow Reactors: A Rapid and Convenient Preparation of Captopril
De Vitis, Valerio,Dall'Oglio, Federica,Pinto, Andrea,De Micheli, Carlo,Molinari, Francesco,Conti, Paola,Romano, Diego,Tamborini, Lucia
, p. 668 - 673 (2017/09/06)
The chemoenzymatic flow synthesis of enantiomerically pure captopril, a widely used antihypertensive drug, is accomplished starting from simple, inexpensive, and readily available reagents. The first step is a heterogeneous biocatalyzed regio- and stereoselective oxidation of cheap prochiral 2-methyl-1,3-propandiol, performed in flow using immobilized whole cells of Acetobacter aceti MIM 2000/28, thus avoiding the use of aggressive and environmentally harmful chemical oxidants. The isolation of the highly hydrophilic intermediate (R)-3-hydroxy-2-methylpropanoic acid is achieved in-line by using a catch-and-release strategy. Then, three sequential high-throughput chemical steps lead to the isolation of captopril in only 75 min. In-line quenching and liquid–liquid separation enable breaks in the workflow and other manipulations to be avoided.
A process for preparing a renin - angiotensin - aldosterone system dual inhibitor compound of intermediate
-
Paragraph 0062; 0063; 0064, (2017/04/28)
The invention relates to an intermediate compound for preparing RAAS (renin-angiotensin-aldosterone system) dual inhibitor compounds. RAAS dual inhibitors can be used for treating diseases related to an RAAS such as high blood pressure and heart diseases.
Overcoming Problems at Elaboration and Scale-up of Liquid-Phase Pd/C Mediated Catalytic Hydrogenations in Pharmaceutical Production
Tungler, Antal,Szabados, Erika
, p. 1246 - 1251 (2016/07/23)
The practical solutions for scale-up and production of intermediates or precursors of pharmaceuticals by liquid-phase Pd/C mediated hydrogenation can be of considerable interest and deserve broader attention even if they have not been the focus of previously published research due to regulations of patent law. The practical obstacles are persistent and have been known for a long time, but for the most part remained unpublished. The most important discoveries and solutions that contributed to the successful scale-up of hydrogenations for pharmaceutical production were the following: (i) the poisoning of Pd/C catalyst with Fe2+ ions for the selective hydrogenation of 2,6-dimethyl-1-nitrosopiperidine to the corresponding hydrazo compound; (ii) alloying of the deposited Pd metal with Cu for converting the aromatic acid chlorides into the corresponding aldehydes; (iii) alteration of the pH of the reaction mixture to basic values which enhanced the stereoselectivity of paracetamol hydrogenation; (iv) a useful modification of the catalyst preparation process, i.e., the acidification of the catalyst resulted in the hydrogenolysis of benzylic OH in a molecule containing a basic N atom; (v) use of two liquid phases, altogether a four-phase system, which permitted the hydrogenolysis of the S-S bond in a potential catalyst poisoning molecule; (vi) the preservation of the metallic Pd surface of the catalyst by saturation of the reaction mixture with hydrogen, resulting in a high H2/substrate ratio, increased the aldehyde yield in the hydrogenation of 4-chloro-butyric-acid-chloride by avoiding the unwanted poisoning effect of the hydrochloric acid. In the present article, these problems and their solutions, as they emerged during the scale-up of the processes, will be discussed in detail.
For renin-angiotensin-aldosterone system dual inhibitor compounds
-
Paragraph 0075-0077, (2016/12/01)
The invention relates to a compound for a renin-angiotensin-aldosterone system dual inhibitor, which can be used for treating and blocking diseases related to an RAS system such as hypertension, congestive heart failure, pulmonary hypertension, renal insufficiency, renal ischemia, kidney failure, renal fibrosis, cardiac insufficiency, cardiomegaly, cardiac fibrosis, myocardial ischemia, cardiomyopathy, glomerulonephritis, renal colic, complication caused by diabetes such as nephropathy, vasculopathy, neuropathy, glaucoma, intraocular pressure elevation, atherosclerosis, restenosis after the arteries transluminal angioplasty, complication of blood vessels or cardiac surgical procedures, erectile dysfunction, hyperaldosteronism, lung fibrosis, scleroderma, anxiety, cognitive disorder, complication caused by the treatment of immunosuppressor and other diseases associated to the renin-angiotensin system.
RAAS system as a dual inhibitor compounds
-
Paragraph 0049-0051, (2017/02/28)
The invention discloses a compound used as a dual inhibitor for RAAS (rennin angiotensin aldosterone system) and particularly relates to a compound shown in formula (I), a stereisomer thereof or a pharmaceutically acceptable salt thereof. The compound can be used for treating and blocking RAS-associated diseases such as hypertension and heart disease, can be used for preventing or treating hypertension, congestive heart failure, pulmonary hypertension, renal insufficiency, renal ischemia, kidney failure, renal fibrosis, cardiac insufficiency, cardiac hypertrophy, cardiac fibrosis, myocardial ischemia, cardiomyopathy, glomerulonephritis, renal colic, complications such as nephropathy caused by diabetes, vasculopathy, vasculopathy, glaucoma, intraocular pressure elevation, atherosis, restenosis after revascularization, complications after blood vessel or cardiac operation, erectile dysfunction, hyperaldosteronism, lung fibrosis, scleroderma, anxiety, cognitive disorder, complications caused by immunosuppressor treatment as well as other known diseases associated with the rennin angiotensin aldosterone system.
COMPOSITIONS AND METHODS FOR DIAGNOSING AND TREATING SALT SENSITIVITY OF BLOOD PRESSURE
-
, (2015/02/05)
To characterize the urinary exosome miRNome, microarrays were used to identify the miRNA spectrum present within urinary exosomes from ten individuals that were previously classified for their salt sensitivity status. The present application discloses distinct patterns of selected exosomal miRNA expression that were different between salt-sensitive (SS), salt-resistant (SR), and inverse salt-sensitive (ISS) individuals. These miRNAs can be useful as biomarkers either individually or as panels comprising multiple miRNAs. The present invention provides compositions and methods for identifying, diagnosing, monitoring, and treating subjects with salt sensitivity of blood pressure. The applications discloses panels of miRNAs useful for comparing profiles, and in some cases one or more of the miRNAs in a panel can be used. The miRNAs useful for distinguishing SS and SR or ISS and SR subjects. One or more of the 45 miRNAs can be used. Some of the miRNAs have not been previously reported to be circulating. See those miRNAs with asterisks in FIG. 1 and below. The present invention encompasses the use of one or more of these markers for identifying and diagnosing SR, SS, and ISS subjects.
Reaction mechanisms of allicin and allyl-mixed disulfides with proteins and small thiol molecules
Miron, Talia,Listowsky, Irving,Wilchek, Meir
scheme or table, p. 1912 - 1918 (2010/07/04)
Allylsulfides from garlic are chemopreventive agents. Entering cells they are expected to initially interact with glutathione. Accordingly, reaction mechanisms of the product, S-allylthio-glutathione, with model proteins and thiols were analyzed in cell f
