- Method for synthesizing metronidazole under catalysis of solid acid
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The invention discloses a method for synthesizing metronidazole under catalysis of solid acid. The method comprises the following steps that 2-methyl-5-nitroimidazole as a raw material and the solid acid as a catalyst react with ethylene oxide to obtain the metronidazole, wherein a reaction system is filtered to recycle the solid acid; a filtrate is concentrated and evenly mixed by adding water, and the pH value is adjusted to be 2-3 by adding alkali; the 2-methyl-5-nitroimidazole is recycled by filtration, the pH value of the filtrate is adjusted to be 10 again by adding alkali, and then themetronidazole can be obtained. The synthesizing process route is simple, the production cost is low, and the solid acid catalyst is environmentally friendly and can be recycled.
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Paragraph 0029-0058
(2019/09/05)
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- Synthetic method for producing metronidazole raw medicinal material
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The invention discloses a synthetic method for producing a metronidazole raw medicinal material. The synthetic method comprises the following steps: (1) a synthetic reaction: putting reaction raw materials including 2.4 to 2.6 g of 2-methyl-5-nitroimidazole, 73 ml of absolute ethyl alcohol, 1.5 to 2 g of ethylene chlorohydrin and 4.5 to 5 g of K2CO3 into a reaction tank, raising the temperature to75 DEG C, preserving the temperature, controlling the temperature at 75 to 80 DEG C, reacting for 8 to 10 h, and stopping the reaction; and (2) carrying out immediate filtration in which a filter cake is byproduct potassium chloride, continuously evaporating a filter liquor to dryness, using methylene dichloride to dissolve at the temperature of 40 DEG C, cooling, separating out crystals, filtering, drying, and thus obtaining metronidazole. The method disclosed by the invention is mild in preparation condition and low in cost, and is applicable for industrial production.
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Paragraph 0013-0014
(2018/07/30)
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- Tritiated metronidazole and preparation method thereof
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The invention belongs to the field of radioactive isotope labeling preparation, and particularly relates to tritiated metronidazole and a preparation method thereof. The preparation method includes: using 2-methyl-5-nitroimidazole as a raw material to react with N-iodosuccinimide to obtain 4-iodine-2-methyl-5nitroimidazole; under catalysis of palladium carbon, enabling 4-iodine-2-methyl-5nitroimidazole and tritium gas to be in tritium-halogen exchange to generate 4-3H-2-methyl-5-nitroimidazole; enabling 4-3H-2-methyl-5-nitroimidazole to react with ethylene oxide to obtain 4-3H-metronidazole. A synthetic product is purified through a prepared liquid phase to obtain4-3H-metronidazole with high specific activity (22.08Ci/g), high radiochemical purity (greater than or equal to 98%) and high chemical purity (greater than or equal to 98%). The tritiated metronidazole can be used as a radioactive tracer in studying absorption, distribution, metabolism and residue elimination of metronidazole in animal bodies.
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Paragraph 0044; 0045
(2017/08/28)
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- Environment-friendly method for metronidazole synthesis
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The invention discloses an environment-friendly method for metronidazole synthesis. Formic acid is replaced with acetic acid, alcohol is added for esterification, neutralization is performed for three times, sodium sulfate and ethylene glycol are recovered, a nitration product is effectively recovered from a metronidazole mother solution, derivatives such as acetic ester, anhydrous sodium sulfate and the like are obtained, by-products such as ethylene glycol and the like are chemical raw materials with wide applications, resources are recycled, the raw materials are greatly saved, the production cost is reduced, and the whole novel process adopts simple steps and is convenient to operate.
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Paragraph 0040; 0041; 0047; 0048
(2016/10/07)
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- Metronidazule raw materials method for producing synthetic cleaning
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The invention relates to a clean production method for synthesizing metronidazole, and belongs to the field of the organic synthesis of drugs. The method comprises the following steps: 1, utilizing a neutralizing second mother liquor (with the pH value of 10.5-11.0) in a metronidazole synthesis process to substitute a 30% sodium hydroxide solution to be used in a neutralization reaction of a metronidazole hydroxylation liquid; and 2, carrying out concentrated recovery on the above finally obtained metronidazole production mother liquor before emission, neutralizing the mother liquor by sulfuric acid until the pH value is 5.0-6.0, allowing the neutralized solution to stand for above 6h, centrifuging to obtain a nitro substance, and sending the recovered mother liquor to a sewage treatment station. About 200kg of the 30% sodium hydroxide solution is saved each batch, the emission of the neutralizing second mother liquor (with the pH value of 10.5-11.0) is reduced, cycle production is formed, the environmental protection throughput is reduced, and the production cost is reduced. The wet product of the recovered nitro substance in each batch is about 18kg, so the production cost is reduced, and the environmental protection throughout is reduced.
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Paragraph 0030-0070
(2018/01/19)
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- Metronidazole esters: A new class of antiglycation agents
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A series of metronidazole ester derivatives 1-34 has been synthesized with the aim of developing new leads with antiglycation activity. The in vitro evaluation of antiglycation potential of 1-34 showed that the ester derivatives 28, 16, and 3 have IC50 values 218.97 ± 2.5, 245.3 ± 5.1, and 278.6 ± 0.8 μM, respectively, comparable to the standard agent, rutin (IC50 = 294.5 ± 1.50 μM). The study identifies a new class of potent antiglycation agents. A structure-activity relationship has also been evaluated. All the compounds were characterized by using spectroscopic techniques, including 1H NMR, IR, and EI-MS.
- Zeb, Aurang,Malik, Imran,Rasheed, Saima,Choudhary, Muhammad Iqbal,Basha, Fatima Z.
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p. 846 - 852
(2012/10/29)
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- External preparation for skin diseases containing nitroimidazole
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An external preparation for skin disease which comprises a nitroimidazole derivative represented by the following formula (I): wherein R1, R3 and R4 may be the same or different and represent a hydrogen atom, a nitro group, a lower alkyl group, a substituted lower alkyl group, a lower alkenyl group, or a substituted lower alkenyl group; and R2 represents a hydrogen atom, a lower alkyl group, a substituted lower alkyl group and a lower alkenyl group or a substituted lower alkenyl group, provided that any one of R1, R3 and R4 is a nitro group.
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- Gel compositions containing metronidazole
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An aqueous solution of metronidazole in which the concentration of metronidazole is higher than 0.75%. The solution contains the solubility enhancer hydroxypropyl-betacyclodextrin and may additionally contain niacinamide. Methods of manufacture and therapeutic use of the solution are disclosed.
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- Chemical compounds having ion channel blocking activity for the treatment of immune dysfunction
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The present invention relates to chemical compounds having inhibitory activity on an intermediate conductance Ca 2+ activated potassium channel (IK Ca), and the use of such compounds for the treatment or alleviation of diseases or conditions relating to immune dysfunction. Moreover, the invention relates to a method of screening a chemical compound for inhibitory activity on an intermediate conductance Ca 2+ activated potassium channel (IK Ca).
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- Synthesis, chemical and enzymatic hydrolysis, and bioavailability evaluation in rabbits of metronidazole amino acid ester prodrugs with enhanced water solubility
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A series of amino acid esters (3a-e) have been synthesized and evaluated as potential prodrugs of metronidazole with the aim of improving aqueous solubility and therapeutic efficacy. The aqueous solubility and the lipophilicity (expressed as the log P value) of metronidazole and its esters were investigated. In general the prodrugs revealed enhanced water solubility compared with metronidazole. N,N-diethylglycinate hydrochloride (3a) and 4-ethylpiperazinoacetate (3e) derivatives displayed higher aqueous solubility, which exceeded that of the parent drug by factors of approximately 140 and 100, respectively. All the esters revealed lower log P values than metronidazole except for the 4-phenylpiperazinoacetate derivative (3f), which was 6.5-times more lipophilic than metronidazole. The hydrolysis kinetics of the esters were studied in aqueous phosphate buffer (pH 7.4) and 80% human plasma at 37°C. In all cases the hydrolysis followed pseudo-first-order kinetics and resulted in a quantitative reversion to metronidazole as evidenced by HPLC analysis. The prodrugs exhibited adequate chemical stability (half-life, t1/2, 4-16 h) in aqueous phosphate solution of pH 7.4. In 80% human plasma they were hydrolysed within a few minutes to metronidazole. The esters 3d (methylpiperazinoacetate derivative) and 3f were exempted since their t1/2 values were approximately 2.5 and 8.5 h, respectively. A comparative pH-rate profile study of N,N-diethylglycinate hydrochloride (3a) and 4-ethylpiperazinoacetate (3e) derivatives in aqueous buffer solution over the pH range 2.2-10 was investigated. The results indicated that 3a showed marked stability at pH 2-6 followed by accelerated hydrolysis at pH 7.4. The basic ester 3e was found to be less stable at lower pH values but exhibited comparative stability at physiological pH. Moreover, in-vivo experiments in rabbits revealed a higher metronidazole plasma level with sustained release characteristics within the prodrug-treated animals (10- and 2.5-fold) as compared with the parent drug-treated group. In conclusion, the designed amino acid esters 3a and 3c-e might be considered as good candidates for water-soluble prodrug forms of metronidazole.
- Mahfouz,Hassan
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p. 841 - 848
(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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- Lipophilic metronidazole derivatives and their absorption through hairless mouse skin
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Previously we have shown that the diacyl glyceryl ester of naproxen is absorbed into excised mouse skin and slowly degraded to release naproxen. In the present work we have synthesised some organic acid and fatty acid derivatives of metronidazole, and studied the in-vitro degradation in aqueous buffer solutions and serum as well as their permeation through hairless mouse skin. The derivatives were enzymatically degraded in serum to form metronidazole. Only the acetic acid and butyric acid derivatives were able to permeate hairless mouse skin intact. The fatty acid derivatives released metronidazole within the skin. The metronidazole delivery through the skin was significant when the metronidazole oleate was used. This compound could therefore be considered as a suitable pro drug for dermal applications.
- Masson,Thorsteinsson,Sigurdsson,Loftsson
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p. 369 - 371
(2007/10/03)
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- Marine lipids for prodrugs, soft compounds and other pharmaceutical applications
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In the present review we discuss different approaches to pharmaceutical applications of marine lipids. Investigation of the use of marine lipids as dermal permeation enhancers, the synthesis of triacylglycerols highly enriched in polyunsaturated fatty acids, dermal pro-drugs derivatives of unsaturated fatty acids and diacyl glyceryl derivatives, and the possible synthesis of soft disinfectants from marine fatty acids.
- Masson,Loftsson,Haraldsson
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p. 172 - 177
(2007/10/03)
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- Metronidazole twin ester prodrugs II: Non identical twin esters of metronidazole and some antiprotozoal halogenated hydroxyquinoline derivatives
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New non identical twin ester prodrugs 3a-d were synthesized by linking metronidazole and some antiprotozoal halogented 8-hydroxyquinoline derivatives via dicarboxylic acid spacers with the aim of improving the therapeutic efficacy of both drugs. The synthesis necessitates the preparation of the precursor metronidazole hemisuccinate or hemiphthalate followed by estrification with the respective hydroxyquinoline derivative. To assess their suitability as prodrugs, the lipophilic properties, chemical stability as well as in vitro and in vivo enzymatic hydrolysis were investigated. The lipophilic properties, expressed as Rm values were determined using RP-TLC and showing enhanced lipophilicity as compared with the parent drugs. Hydrolysis kinetics of the prepared twin esters at 37°C using HPLC, indicated a quantitative release of the parent drugs in two step reaction (K1 and K2) via formation of metronidazole hemiesters followed by spontaneous hydrolysis of the later to metronidazole. The twin esters were adequately stable in aqueous buffer solutions than in biological media and the second rate (K2) of hydrolysis is more accelerated than the first (K1). Bioavailability study of 1-(5-chloro-7-iodoquinolin-8-yl)-4-[2-(2-methyl-5- nitro-1-H-imidazolyl)ethyl]butandioate, 3a, as well as equivalent amount of the corresponding physical mixture of metronidazole and 5-chloro 7-iodo-8- hydroxyquinoline in rabbits has shown that, the plasma level of the released metronidazole from the prodrug is higher than that resulting from the physical combination. A considerable amount of 5-chloro-7-iodo- hydroxyquinoline was detected in plasma, however, no measurable concentration of the quinoline derivative was observed in rabbit plasma from the physical mixture.
- Aboul-Fadl, Tarek,Mahfouz, Nadia M.
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p. 309 - 324
(2007/10/03)
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- Metronidazole twin ester prodrugs: Synthesis, physicochemical properties, hydrolysis kinetics and antigiardial activity
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A series of identical twin esters 3a-e of metronidazole was synthesized and evaluated as potential prodrugs with improved physicochemical and pharmacokinetic properties. The synthesis of the twin esters 3a-e was achieved by interaction of metronidazole with the respective dicarboxylic acid anhydride or their dichloride. Their structures were verified by elemental and spectroscopic analyses. The lipophilicity of metronidazole and the prodrugs 3a-e, expressed as R(m), values, were determined using reversed- phase TLC and revealed enhanced lipophilic properties compared with metronidazole. Reversion kinetics of the parent drug from its twin esters was investigated in aqueous buffer solutions (pH 1.2 and 7.4) as well as in biological media (80% human plasma and 20% rat liver homogenate) at 37 °C using HPLC. In all cases, the hydrolysis followed pseudo-first-order kinetics in a two-step reaction (k1 and k2) via the intermediate formation of the respective metronidazole hemiester. All the synthesized twin ester prodrugs 3a-e were proved to be chemically stable at acidic pH (t(1/2) ~ 25-72 h) and also at the physiological pH (t(1/2) ~ 13-40 h). Meanwhile, the release of the first molecule of metronidazole from its twin esters 3a-d ensued rapidly in 80% human plasma (t(1/2) ~ 10-150 min) and in rat liver homogenate (t(1/2) ~ 4-55 min). The resulting hemiesters 2a-d showed a sustained release of the second molecule in the same biological fluids (t(1/2) ~ 3-9 h and 1-11 h respectively). In vivo evaluation studies of metronidazole and its twin esters 3a-d in mice and 3b in rabbits revealed that the prodrugs have been absorbed almost unhydrolyzed with considerable higher plasma level. Antiparasitic activity of the synthesized compounds was evaluated in mice against Giardia muris, the prodrug 3b showed improved antigiardial activity compared to the parent drug. These results suggest that the synthesized identical twin esters 3a-d may be useful as a promising new prodrug form of metronidazote for oral drug delivery.
- Mahfouz, Nadia M.,Aboul-Fadl, Tarek,Diab, Ahmed K.
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p. 675 - 683
(2007/10/03)
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- Prodrugs - Part 2. Acylbenzoate esters of metronidazole
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The design and synthesis of a series of chain and cyclic acylbenzoate esters of metronidazole are described. The esters are designed to be both lipophilic and reactive in their hydrolysis reactions. The alkaline hydrolyses of the chain 2-acylbenzoates are relatively rapid, employing an intramolecular catalytic route, while the reactions of the 4-formylbenzoate and cyclic 2-formylbenzoate are also relatively rapid using the normal pathway. The anti-bacterial activity of the esters are comparable to that of metronidazole.
- Bowden,Izadi
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p. 995 - 1000
(2007/10/03)
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- Composes nitroaromatiques cytotoxiques et radiosensibilisateurs: etudes cinetiques de la dismutation des radicaux par radiolyse pulsee
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Nitroheterocyclic compounds have radiosensitizing properties in vitro.These compounds are also antibiotics against hypoxic or anoxic bacteria and protozoans.These pharmacological properties are related to the reduction of ArNO2, catalyzed or not by a nitroreductase yielding the ArNO2*(1-) or ArNO2*H radical.A study, by pulse radiolysis, of the interaction of the nitroradical with various cellular extracts or purified enzymes having nitroreductase, oxygen reductase, superoxide dismutase or nitrite reductase activity, lead to conclude to the absence of anitro-radical dismutase activity.In hypoxic cells, the nitro radical decays probably via the disproportionation reaction.This reaction which is not catalyzed could well be a rate-limiting step in the cellular reduction process of ArNO2.
- Lougmani, N.,Guissani, A.,Henry, Y.,Hickel, B.
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p. 931 - 942
(2007/10/02)
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- Radicaux libres de composes nitroaromatiques cytotoxiques et radiosensibilisateurs: parametres cinetiques et interactions avec des oxydases a cuivre
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Interactions of the nitro radical of nitroaromatic compounds ArNO2 with two copper oxidases, laccase and ceruloplasmin, have been studied by pulse radiolysis, by following the absorbance variations around 410 nm for the radical and 610 nm for the type 1 Cu(2+) site.We observed a fast electron transfer reaction (1 x 106 to 4 x 107 M-1s-1) between the radical and the type 1 Cu(2+).The site is not reoxidized by ArNO2 but by interaction with O2.This electron transfer reaction does not correspond to an enzymatic reaction.These two oxidases have neither nitroreductase nor nitro-radical dismutase activity.Ceruloplasmin plasmatic normal concentration, close to 2 μM, can reach 10 μM in the interstitial fluid of some tumours or in inflammation cases.The observed reaction between the nitro radical and ceruloplasmin may correspond to a "futile" cycle similar to that observed with O2, and therefore be of some importance in aromatic compounds pharmacokinetics.
- Lougmani, N.,Guissani, A.,Henry, Y.,Hickel, B.
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p. 943 - 956
(2007/10/02)
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- SYNTHESIS OF DIPEPTIDE ESTERS OF METRONIDAZOLE AND EVALUATION OF THEIR HYDROLYTIC STABILITY
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Amino acid and dipeptide esters of metronidazole were synthesized and evaluated on their hydrolytic stability in various buffers and culture media.The hydrolytic susceptibility of the different esters was minimal in the pH range 3-5.In the alkaline region, pH 6.5-8, the half-lifes were of the order of 1-6.6 hrs.At alkaline pH the dipeptide esters were more susceptible towards hydrolysis.At pH 8.8 the observed half-life for the gly-gly and the gly-phe esters was 0.2 h, whereas for the gly and the phe ester it was 1.1 h, respectively 2.7 h.It was demonstrated that the increased rate of hydrolysis for the dipeptide esters was due to an intramolecular aminolysis with the formation of a diketopiperazine accompanied by the release of free metronidazole.
- Permentier, Dirk,Vansteenkiste, Stefan,Schacht, Etienne,Vermeersch, Hans,Remon, Jean Paul
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p. 701 - 708
(2007/10/02)
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- Platinum complexes with one radiosensitizing ligand
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Methods to inhibit tumor growth and to radiosensitize hypoxic cells and pharmaceutical compositions therefor are disclosed. These methods and compositions use compounds of the formula wherein n is 1 or 2, and wherein when n is 2, X is a monovalent biologically acceptable anion, and when n is 1, X is a divalent biologically acceptable anion; each R is independently H or alkyl, or both Rs together are a piperidino or morpholino residue; and L is a radiosensitizing ligand selected from a mononitro-substituted imidazole, a mononitro-substituted pyrazole, a mononitro-substituted thiazole and a mononitro-substituted isothiazole.
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- Platinum complexes with one radiosensitizing ligand
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Complexes of platinum II containing a single radiosensitizer ligand and an amino or ammine substituent shows superior binding to DNA and are useful in chemotherapy and sensitization of hypoxic tumors to radiation. The chemotherapeutic value of these compounds is enhanced by administration of vasoactive agents.
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- Serum-catalyzed hydrolysis of metronidazole amino acid esters
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Glycine (Gly), alanine (Ala), valine (Val), leucine (Leu), isoleucine (Ile), phenylalanine (Phe), and lysine (Lys) esters of metronidazole were synthesized using dicyclohexylcarbodiimide (DCC) coupling or a mixed-anhydride route, using tert-butyloxycarbonyl (tert-Boc) amino acids. Human serum-catalyzed hydrolysis of these esters at 37°C give half-lives varying from 4.5 min for the Phe ester to 96 h for the Ile ester. Also determined was the pH-rate profile for hydrolysis in aqueous buffers at 25°C. A linear relationship was observed between the logarithmic value of the hydrolysis rate constant in serum and that of the OH--catalyzed hydrolysis of cationic esters. This finding may indicate that the esters studied are 'equally' poor substrates for binding to the enzymes in serum and, thus, the difference observed in the serum-catalyzed hydrolysis rate is solely derived from the chemical lability of an ester bond. Interestingly, the extent of chemical activation observed in the buffer system appears to be amplified in the serum-catalyzed hydrolysis.
- Cho,Haynes
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p. 883 - 885
(2007/10/02)
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- Process for isolating organic compounds and lithium salt complexes useful in said process
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An improved process for isolating organic compounds from crude product or reaction mixtures by dissolving said crude product or reaction mixture in a suitable solvent, contacting the resulting solution with a lithium salt to form a solid metal salt complex, separating, and thereafter recovering a pure product by decomposing the lithium salt complex.
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- Metronidazole phosphate - A water-soluble prodrug for parenteral solutions of metronidazole
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To develop a parenteral solution of relatively water-insoluble metronidazole (2-methyl-5-nitro-1H-imidazole-1-ethanol), its phosphate ester was synthesized via two routes. One route utilized 2-cyanoethyl phosphate and the other utilized pyrophosphoryl tetrachloride. The first method used dicyclohexylcarbodiimide as a coupling agent and the cyamoethyl group was removed under mild alkaline conditions. The second method was a one-step procedure in which free acid of metronidazole phosphate was isolated as a crystalline solid. The solubility of metronidazole in various solvents was determined at 25°. From the pH-dependence of its aqueous solubility, the pKa of the conjugate acid of metronidazole was estimated to be 2.62, which agreed well with the pKa values of other nitroimidazoles. Metronidazole phosphate behaved as a zwitterionic compound in an acidic medium with a minimum solubility at pH 2.0. At pH 7, its solubility was ~50 times that of metronidazole. The phosphate ester was so soluble at pH higher than 7 that it was difficult to measure the solubility accurately. In human serum, the hydrolysis of metronidazole phosphate followed zero-order kinetics at an initial concentration of 0.25 mg/ml or higher, presumably due to enzyme saturation (0.035 mg/ml/hr at 37°). A reversed-phase HPLC procedure was adopted to monitor the appearance of metronidazole and the disappearance of metronidazole phosphate. Subcutaneous administration of metronidazole phosphate to rats produced a blood level of bioactivity comparable to that observed after administration of metronidazole.
- Cho,Kurtz,Lewis,Machkovech,Houser
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p. 410 - 414
(2007/10/02)
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