- 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
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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.
- Asiri, Abdullah M.,Khan, Aftab Aslam Parwaz,Khan, Anish
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Read Online
- THE ASYMMETRIC SYNTHESIS OF (-)-CAPTOPRIL UTILISING THE IRON CHIRAL AUXILIARY 5-C5H5)Fe(CO)(PPh3)>
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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.
- Bashiardes, George,Davies, Stephen G.
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Read Online
- Preparing method of captopril isomer
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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.
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Paragraph 0032; 0040; 0041; 0042; 0043
(2019/04/26)
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- Chemoenzymatic Synthesis in Flow Reactors: A Rapid and Convenient Preparation of Captopril
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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.
- De Vitis, Valerio,Dall'Oglio, Federica,Pinto, Andrea,De Micheli, Carlo,Molinari, Francesco,Conti, Paola,Romano, Diego,Tamborini, Lucia
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p. 668 - 673
(2017/09/06)
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- A process for preparing a renin - angiotensin - aldosterone system dual inhibitor compound of intermediate
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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.
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Paragraph 0062; 0063; 0064
(2017/04/28)
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- For renin-angiotensin-aldosterone system dual inhibitor compounds
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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.
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Paragraph 0075-0077
(2016/12/01)
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- RAAS system as a dual inhibitor compounds
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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.
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Paragraph 0049-0051
(2017/02/28)
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- Overcoming Problems at Elaboration and Scale-up of Liquid-Phase Pd/C Mediated Catalytic Hydrogenations in Pharmaceutical Production
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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.
- Tungler, Antal,Szabados, Erika
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p. 1246 - 1251
(2016/07/23)
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- COMPOSITIONS AND METHODS FOR DIAGNOSING AND TREATING SALT SENSITIVITY OF BLOOD PRESSURE
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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.
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- Reaction mechanisms of allicin and allyl-mixed disulfides with proteins and small thiol molecules
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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
- Miron, Talia,Listowsky, Irving,Wilchek, Meir
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scheme or table
p. 1912 - 1918
(2010/07/04)
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- Pharmaceutically acceprable salts of aporphine compounds of carboxyl group-containing agents and methods for preparing the same
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The present invention discloses novel pharmaceutically acceptable salts of aporphine compounds and carboxyl-group containing agents. Also, the present invention discloses methods for preparing the pharmaceutically acceptable salts. These pharmaceutically acceptable salts are suitable for use in treating and/or preventing hyperglycemic disease and/or several oxidative stress related diseases.
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- USE OF SUBSTITUTED 2 PHENYLBENZIMIDAZOLES AS MEDICAMENTS
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The present invention relates to the use of a substituted 2-phenylbenzimidazole of formula I wherein R1, R2, R3, R 4, R5 and m have the meanings given in the claims, for the preparation of a medicament for the treatment or prevention of diseases involving glucagon receptors, as well as new compounds of formula I wherein R1 is a group of formula
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- A synthesis of captopril through a Baylis-Hillman reaction
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A synthesis of the antihipertensive amide 1, named captopril, is described. The strategy is based on a Baylis-Hillman reaction between N-acryloylproline and formaldehyde. Subsequential diaster eoselective hydrogenation step and functional group interconversion provided captopril in good overall yield.
- Feltrin, Melissa P.,Almeida, Wanda P.
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p. 1141 - 1146
(2007/10/03)
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- Process and device for producing liquid dosage formulations of medicinal compounds on demand from tablets and capsules
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The present invention provides a process for preparing liquid pharmaceutical formulations on demand from tablets and capsules.
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- Simple process for producing high quality captopril
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A process for producing captopril of the following formula (1) comprising subjecting a substrate compound of the following general formula (2) to a hydrolysis reaction in aqueous medium to remove the RCO group and isolating the product compound, said hydrolysis reaction in aqueous medium being conducted in the presence of a strong acid at pH not over 1 and a reaction temperature not below 40° C.
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- Leukotriene A4 hydrolase inhibitors
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The present invention relates to leukotriene A4hydrolase inhibitors containing compounds represented by the formula [I] or salts thereof as active ingredients, wherein R1represents hydrogen, alkyl, phenylalkyl, alkanoyl or benzoyl; R2and R3each represent hydrogen or alkyl; R4represents hydroxyl, alkoxy, phenylalkoxy, amino, alkylamino or phenylalkylamino; R5represents phenylalkyl or naphthylalkyl; “Z” represents sulfur or oxygen; “A” represents alkylene; and “n” represents 0, 1 or 2; providing that the phenyl ring in R1can be substituted by alkyl, alkoxy or halogen, and that the phenyl ring or the naphthyl ring in R5can be substituted by alkyl, cycloalkyl, alkoxy, alkylthio or halogen.
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- Reactivity of sulfur nucleophiles towards S-nitrosothiols
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Rate constants have been measured for the reactions of a range of S-nitrosothiols with the following sulfur-centred nucleophiles: sulfite ion, thiourea, thiocyanate ion, thiosulfate ion, thiomethoxide ion and sulfide ion. Many of the reactions were very fast and were followed in a stopped-flow spectrophotometer. For the sulfite reaction the reactive species over the pH range 4-8 was shown to be exclusively SO32-. For two RSNO species the reactivity sequence was established as: SO32- > MeS- > S2O32- ? SC(NH2)2 SCN-. The reaction with sulfide ion was also rapid and generated a fairly stable yellow species (λmax 410 nm), which was probably the nitrosodisulfide ion ONSS-, but the absorbance-time data were too complex for a simple kinetic analysis. This reaction could have some potential as an analytical procedure for the determination of RSNO species. The kinetic results are discussed in terms of the factors affecting nucleophilicity and are compared with the corresponding reactions of other nitrosating species.
- Munro, Andrew P.,Williams, D. Lyn H.
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p. 1794 - 1797
(2007/10/03)
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- Process for producing N-(D-α-methyl-β-mercaptopropionyl)-L-proline and its intermediate
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A highly convenient and efficient process for economically producing in a high yield high-quality captopril which is remarkably reduced in the content of impurities and has a high melting point and intermediates for synthesizing the same which contain only a small amount of precursors as impurities and have excellent qualities. The process comprises subjecting an acid halide and an L-proline to the Schotten-Baumann reaction and eliminating the impurities formed as the by-products in the form of the precursors represented by general formula (5) or (6) by treating, during or after the Schotten-Baumann reaction, the aqueous medium solution with active carbon or crystallization followed by deacylation. In the formula, R1 represents acyl and n represents an integer of from 2 to 4. STR1
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- A mild and efficient procedure for the preparation of acid chlorides from carboxylic acids
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Various carboxylic acids are converted into the corresponding acid chlorides by treatment with trichloroacetonitrile and triphenylphosphine in methylene chloride at room temperature. Aryl acids show higher reactivity than alkyl acids under the conditions.
- Jang, Doo Ok,Park, Doo Jin,Joonggon, Kim
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p. 5323 - 5326
(2007/10/03)
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- Thiol/disulfide exchange reactions of captopril and penicillamine with arginine vasopressin and oxytocin
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The kinetics and equilibria of the reaction of the thiol-containing drugs captopril (D-3-mercapto-2-methylpropanoyl-L-proline, CpSH) and penicillamine (β, β-dimethylcysteine, PSH) with the disulfide bonds of the neurohypophyseal peptide hormones arginine vasopressin (AVP) and oxytocin (OT) have been characterized. CpSH reacts with AVP and OT by thiol/disulfide interchange to form two peptide-CpSH mixed disulfides, which in turn react with another molecule of CpSH to form the reduced peptide and CpSSCp. Forward and reverse rate constants and the equilibrium constant are reported for both steps in the reaction of CpSH with AVP and OT at pH 7.00. The rate constant for the first step (k1) is much larger than that for the second step (k2). Also, once formed, the peptide-CpSH mixed disulfides rapidly undergo intramolecular thiol/disulfide interchange with reformation of the cyclic peptide and CpSH. PSH reacts with AVP and OT by the same two-step reaction sequence; however, the rate of the second step is very slow due to steric hindrance from the methyl groups of PSH and the PSH moiety of the peptide-PSH mixed disulfides. Using rate constants determined in this study and PSH levels in the plasma of patients on PSH therapy, it is predicted that in vivo reduction of the disulfide bonds of AVP and OT by PSH and CpSH has little effect on the plasma half-lives of AVP or OT.
- Rabenstein, Dallas L.,Yeo, Pauline L.
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p. 109 - 118
(2007/10/02)
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- Process for the preparation of 1-[3-acetylthio-2(s)-methylpropanoyl]-l-proline
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The intermediate 1-[3-acetylthio-2(s)-methylpropanoyl]-1-proline is prepared by reacting L-proline with (R)-3-acetylthio-2-methyl propanoyl chloride at 0-5° C., with pH controlled at 7.5-8.5, using 2.5M potassium hydroxide and potassium phosphate buffer, which gives >97% pure material after crystallizing from the reaction mixture.
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- Process for preparing 1-(2S)-3-mercapto-methyl-1-oxopropyl)-L-proline
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The invention relates to a novel process for preparing 1-[(2S)-3-mercapto-2-methyl-1-oxopropyl]-L-proline (captopril) of formula (I). STR1 which comprises hydrogenolysing 1-[(2S)-2-methyl-1-oxo-3-rhodanidopropyl]-L-proline of formula (II) STR2 in an inert solvent, in the presence of a catalyst, at a temperature of 50° to 120° C. under a pressure of 105 to 107 Pa. The above compound of formula (II) is new and can be prepared by acylating L-proline with a reactive acylating derivative of (2S)-2-methyl-3-rhodanido-propionic acid of formula (III). STR3
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- MOLECULAR RECOGNITION: DIRECTED HYDROGEN BONDING RECEPTORS FOR ACYLAMINO ACID CARBOXYLATES
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A new series of receptors for acylamino acid carboxylates has been synthesized and shown to have increased binding affinity for the substrate as the number of hydrogen bonding groups in the cavity increases.
- Vicent, Cristina,Fan, Erkang,Hamilton, Andrew D.
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p. 4269 - 4272
(2007/10/02)
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- Prodrug derivatives of carboxylic acid drugs
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Novel ester derivatives of carboxylic acid medicaments of formula (I), wherein R--COO--represents the acyloxy residue of a carboxylic acid drug or medicament, n is an integrer from 1 to 3, and R1 and R2 are the same or different and are selected from a group consisting of an alkyl, an alkenyl, an aryl, an aralkyl, a cycloalkyl and which group may be unsubstituted or substituted, or R1 and R2 together with the N forms a 4-, 5-, 6- or 7-membered heterocyclic ring, which in addition to the nitrogen atom may contain one or two further heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and which heterocyclic group may be substituted. These compounds are highly biolabile prodrug forms of the corresponding carboxylic acid compounds and are highly susceptible to undergoing enzymatic hydrolysis in vivo whereas they are highly stable in aqueous solution. The novel derivatives are less irritating to mucosa than the parent carboxylic acids and may provide an improved bio-availability of the drugs.
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- Controlled release formulation
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A controlled release pharmaceutical formulation which undergoes substantially or approaches zero order release of active drug is provided, preferably in the form of a coated tablet, containing a core portion from which medicament, such as procainamide hydrochloride, is slowly released over a controlled length of time. The core also includes one or more primary hydrocolloid gelling agents which is a hydropropylmethyl cellulose having a viscosity of within the range of from about 1,000 to about 6,000 centipoises in 2% solution at 20° C., and a methoxyl content of 28-30%, optionally a secondary hydrocarbon gelling agent, such as hydroxypropyl cellulose and/or methyl cellulose, one or more non-swellable binders and/or wax binders (where the medicament and/or hydrocolloid gelling agents are non-compressible), one or more inert fillers or excipients, one or more lubricants, and optionally one or more anti-adherents such as silicon dioxide and water. The above-described core is coated with a pharmaceutical coating composition containing a hydrophobic polymer and a hydrophilic polymer.
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- Process for preparing pyrrolidine derivatives
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The present invention relates to a novel process for preparing pyrrolidine derivatives of the formula(I): STR1 characterized in that the compound of formula(II): STR2 wherein, X is halogen atom such as bromo or chloro; is reacted with the aqueous solution of the compound of formula(III): STR3 wherein, M is alkali metal, Z is sulfur or oxygen; and followed by hydrolysis in the presence of an acid. The compounds according to this invention are useful as drugs for lowering blood pressure and preventing hypertension.
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- Controlled release formulation
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A controlled release pharmaceutical formulation which undergoes substantially or approaches zero order release of active drug is provided, preferably in the form of a coated tablet, containing a core portion from which medicament, such as procainamide hydrochloride, is slowly released over a controlled length of time. The core also includes one or more hydrocolloid gelling agents having a viscosity of within the range of from about 10,000 to about 200,000 centipoises in 2% solution at 20° C., such as hydroxypropylmethyl cellulose and/or methyl cellulose, one or more non-swellable binders and/or wax binders (where the medicament and/or hydrocolloid gelling agents are non-compressible), one or more inert fillers or excipients, one or more lubricants, and optionally one or more anti-adherents such as silicon dioxide and water. The above-described core is coated with a pharmaceutical coating composition containing a hydrophobic polymer and a hydrophilic polymer.
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- An improved synthesis of captopril
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An improved synthesis of captopril using methacrylic acid as the starting material is described. Treatment of methacrylic acid (I) with a hydrogen halide gave the 3-halogeno-2-methylpropanoic acids II and III, which were treated with thionyl chloride to yield the corresponding 3-halogeno-2-methylpropanoyl chlorides IV and V. Treatment of IV or V with L-proline yielded the N-(R,S-3-halogeno-2-methylpropanoyl)-L-prolines VI and VII, which were separated into optically pure R- and S-diastereoisomers using dicyclohexylamine. Treatment of halides of VI or VII with methanolic ammonium hydrosulfide gave captopril in 28% yield.
- Nam,Lee,Ryu
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p. 1843 - 1844
(2007/10/02)
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- Process for preparation of optically active N-mercaptoalkanoylamino acids
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A process is disclosed wherein an optically active N-mercaptoalkanoylamino acid is prepared by (1) reacting an optically active β-hydroxyalkanoic acid, with a halogenating reagent to prepare an optically active β-haloalkanoyl halide (2) reacting the β-haloalkanoyl halide with an amino acid to produce an optically active N-β-haloalkanoylamino acid and (3) reacting the N-β-haloalkanoylamino acid with a reagent capable of converting the halogen into the thiol group, the configuration of the formulas (II), (III), (IV), (V), and (VI) being retained in all the optically active compounds throughout the process to prepare the compound represented by formula (I). The product of the present invention, for example, N-(3-mercapto-2-D-methylpropanoyl)-L-proline inhibits the enzymatic conversion of angiotensin I into angiotensin II and therefore is useful for relieving angiotensin-related hypertension.
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- Pyridinium salts
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The invention concerns compounds of formula STR1 wherein the sulphur is bonded to the pyridinium ring at position 2 or 4, Y is --S-- or --CH2 --, R represents hydrogen, or a lower alkyl group, or other carboxylic protecting group; R1 represents hydrogen or lower alkyl; R2 represents lower alkyl, aryl of 6 to 10 carbon atoms or aralkyl of 7 to 11 carbon atoms; R3 represents hydrogen or a substituent selected from lower alkyl, halogen and lower alkoxy; q and r are each 1 or 2; and X? represents a halide ion or an organosulphonate ion, which are antihypertensive agents and are useful as intermediates to captopril and analogous compounds.
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- PROLINE DERIVATIVES AND RELATED COMPOUNDS
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New proline derivatives and related compounds which have the general formula STR1 are useful as angiotensin converting enzyme inhibitors.
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