122130-63-6Relevant articles and documents
S-Nitrosocaptopril formation in aqueous acid and basic medium. A vasodilator and angiotensin converting enzyme inhibitor
Sexto, Alexia,Iglesias, Emilia
experimental part, p. 7207 - 7216 (2011/11/29)
The reaction of S-nitrosocaptopril (NOcap) formation was studied in both aqueous acid and basic medium. Captopril (cap) reacts rapidly with nitrous acid in strong acid medium to give the stable - in the timescale of the experiments - NOcap. The kinetic study of the reaction involving the use of stopped-flow, shows that at low sodium nitrite (nit) concentration, the reaction is first-order in both [nit], [H+], and is strongly catalysed by Cl - or Br- (= X-): rate = (k3 + k 4[X-])[H+][nit][cap]. In aqueous buffered solution of acetic acid-acetate the reaction rate is much slower and the decomposition of NOcap was observed; however, the rate of NOcap decay is more than 30-fold slower than its formation. In aqueous basic medium of carbonate-hydrogen carbonate buffer, as well as in alkaline medium, the kinetics of the nitroso group (NO) transfer from tert-butyl nitrite (tBN) to cap was studied using either conventional or stopped flow methods. In mild basic medium, the NOcap decomposes. The NOcap formation is first-order in both tBN and cap concentrations, and the reaction rate increases with pH until to, approximately, pH 11.5, above which value it becomes pH independent or even invariable with the [OH-]. Kinetic results show that the thiolate ion of cap is the reactive species. In fact, the presence of anionic micelles of sodium dodecyl sulfate (SDS) inhibits the reaction due to the separation of the reagents; whereas, cationic micelles of tetradecyltrimethylammonium bromide (TTABr) catalyse the reaction at low surfactant concentration due to reagents concentration in the small volume of the micelle. The rate equation is: rate = kf KSH[cap][tBN]/(KSH + [H+]). The rate of NOcap decomposition in mild basic medium is first-order in both [cap] and [NOcap], and decreases on increasing pH; but, in alkaline medium the NOcap is stable within the timescale of the experiments. Based on the results, the NOcap decomposition yields the disulfide compound that is formed in the nucleophilic attack of the -SH group of cap to the sulfur electrophilic center of NOcap, -S-NO. The resulting rate equation is: rate = kd[H +][cap][NOcap]/(KSH + [H+]).
Mechanism of the nitrosation of thiols and amines by oxygenated .NO solutions: The nature of the nitrosating intermediates
Goldstein,Czapski
, p. 3419 - 3425 (2007/10/03)
The nitrosation of various thiols and morpholine by oxygenated .NO solutions at physiological pH was investigated. The formation rates and the yields of the nitroso compounds were determined using the stopped-flow technique. The stoichiometry of this process has been determined, and is given by 4.NO + O2 + 2RSH/2RR'NH → 2RSNO/2RR'NNO + 2NO2- + 2H+. Kinetic studies show that the rate law is -d[O2]/dt = k1 [.NO]2[O2] with k1 = (2.54 + 0.26) x 106 M-2 s-1 and -d[.NO]/dt = 4k1 [.NO]2[O2] with 4k1 = (1.17 + 0.12) x 107 M-2 s-1, independent of the kind of substrate present. The kinetic results are identical to those obtained for the autoxidation of .NO, indicating that the rate of the autoxidation of .NO is unaffected by the presence of thiols and amines. The nitrosation by .NO takes place only in the presence of oxygen, and therefore the rate of the formation of S-nitrosothiols from thiols and oxygenated .NO solution is relatively slow in biological systems. Under physiological conditions where [.NO] 2] .NO in vivo. The rate-determining step of the nitrosation of thiols and amines by oxygenated .NO solution is the formation of ONOONO (or ONONO2 or O2NNO2), which is the precursor of .NO2 and N2O3. The stoichiometry of the nitrosation process suggests that .NO2 and/or N2O3 are the reactive species. We have demonstrated that .NO2 initiates the nitrosation process unless it is scavenged faster by .NO to form N2O3. The latter entity is also capable of directly nitrosating thiols and amines with rate constants exceeding 6 x 107 M-1 s-1.
S-NITROSOCAPTOPRIL COMPOUNDS AND THE USE THEREOF
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, (2008/06/13)
The invention relates to novel nitroso compounds having the formula: STR1 wherein, R is hydroxy, NH 2, NHR 4, NR 4 R. sup.5 or C 1-C 7 alkoxy, wherein R 4 and R 5 are C 1-C 4 alkyl, aryl, or C 1-C 4 alkyl substituted by aryl;R 1 is hydrogen, C 1-C 7 alkyl or C 1-C. sub.7 alkyl substituted by phenyl, amino, guanidino, NHR 6 or NR 6 R. sup.7, wherein R 6 and R 7 are methyl, or C 1-C 4 acyl; R 3 is hydrogen, C 1-C 7 alkyl or C. sub.1-C 7 alkyl substituted by phenyl;n is 0 to 2; P>A is hydrogen,lower C 1-C 7 alkyl,lower C 2-C 7 alkylene, lower C 2-C 7 alkylene substituted by hydroxy, C 1-C 4 alkyl, aryl, orP>a C 4-C 7 ring which may be fused to a benzene ring;B is hyrogen, lower C. sub.1-C 7 alkyl,phenyl, lower C 1-C 7 substituted by phenyl, hydroxy, guanidino, amino, imidazoyl, indolyl, mercapto, mercapto substituted by lower C 1-C. sub.4 alkyl, carbamoyl, or carboxyl, orlower C 2-C. sub.7 alkylene.The invention also relates to compounds having the following formula: STR2 wherein R, R 1, R 3 and n are as defined above; R 2 is hydrogen, hydroxy, C 1-C 4 alkoxy, aryloxy or C 1-C 7 alkyl; and m is 1 to 3.The invention also relates to pharmaceutical compositions comprising the nitrosothiol compounds of the invention together with a pharmaceutically acceptable carrier.The invention also relates to methods for treating acute myocardial infarction, left ventricular dysfunction without overt heat failure, hypertension, pulmonary hypertension, congestive heart failure, angina pectoris, vascular thrombosis, Raynauds syndrome, Scleroderma, toxemia of pregnancy, acute renal failure, diabetic nephropathy, and renal artery stenosis, and to methods of inhibiting ACE and effecting vasodilation comprising administering the nitrosothiol compounds of the invention to an animal.
