- Biliary excretion of furosemide glucoronide in rabbits
-
Furosemide (F) was administered to rabbits intravenously and intraduodenaly and the biliary excretion was studied. The major metabolite excreted in bile was furosemide glucuronide (FG). P and acyl migration isomers of FG (FG-iso) were also excreted in bile. The biliary excretion rates of total F (F+ PG+FG-iso) following intraduodenal administration of F were much smaller than those following intravenous administration. The fraction of (F+PG-iso) in bile following intraduodenal administration of F were larger than those following intravenous administration. Stability of PG or FG-iso in bile and supernatant solution of the duodenum homogenate of rabbits was studied. FG was unstable in both media and its degradation followed apparent first-order kinetics in both media. In bile, PG degraded to produce several FG-iso and F, while in the supernatant solution of the duodenum homogenate, it hydrolyzed immediately to F. FG-iso were hardly detected in the supernatant solution. These results indicated that FG excreted in bile degraded easily to FG-iso and F. FG might easily hydrolyze to F enzymatically in the duodenum, and the resultant F might be reabsorbed from the intestinal tract. Unabsorbed PG-iso and P might be excreted in the feces.
- Sekikawa,Yagi,Oda,Kenmotsu,Takada,Chen,Lin,Benet
-
-
Read Online
- Toward Drug Release Using Polymer Mechanochemical Disulfide Scission
-
Traditional pharmacotherapy suffers from multiple drawbacks that hamper patient treatment, such as the buildup of antibiotic resistances or low drug selectivity and toxicity during systemic application. To overcome these challenges, drug activity can be controlled by employing delivery, targeting, or release solutions that mostly rely on the response to external physicochemical stimuli. Due to various technical limitations, mechanical force as a stimulus in the context of polymer mechanochemistry has so far not been used for this purpose, yet it has been proven to be a convenient and robust method to site-selectively rearrange or cleave bonds with submolecular precision in the realm of materials chemistry. Here, we present an unprecedented mechanochemically responsive system capable of successively releasing small furan-containing molecules, including the furylated fluorophore dansyl and the drugs furosemide as well as furylated doxorubicin, by ultrasound-induced selective scission of disulfide-centered polymers in solution. We show that mechanochemically generated thiol-terminated polymers undergo a Michael-type addition to Diels-Alder (DA) adducts of furylated drugs and acetylenedicarboxylate derivatives, initiating the downstream release of the small molecule drug by a retro DA reaction. We believe that this method can serve as a blueprint for the activation of many other small molecules.
- Shi, Zhiyuan,Wu, Jingnan,Song, Qingchuan,G?stl, Robert,Herrmann, Andreas
-
-
Read Online
- Furosemide and purification method thereof
-
The invention discloses furosemide and a purification method thereof. The furosemide purification method includes the steps of placing a furosemide crude product in an inorganic alkali solution, fully reacting to generate furosemide salt, and conducting recrystallization treatment on the filtrate after decoloration and filtration to obtain purified furosemide salt; and dissolving the purified furosemide salt in purified water, adjusting the pH value of the purified furosemide salt to an acidic condition by using an acid solution, fully hydrolyzing and crystallizing, filtering, and drying to obtain the purified furosemide. Through the mode, the furosemide crude product can be purified only through simple salification and hydrolysis steps, and recrystallization is carried out under the condition of not using an organic solvent, so that the purity and the yield of furosemide are remarkably improved. Meanwhile, the furosemide purification method provided by the invention is simple in process, easy to implement, suitable for industrial large-scale production, capable of effectively improving the production efficiency and relatively good in application prospect.
- -
-
Page/Page column 0035-0036; 0038
(2021/06/23)
-
- Design, synthesis, and biological evaluation of furosemide analogs as therapeutics for the proteopathy and immunopathy of Alzheimer's disease
-
β-Amyloid (Aβ) triggered proteopathic and immunopathic processes are a postulated cause of Alzheimer's disease (AD). Monomeric Aβ is derived from amyloid precursor protein, whereupon it aggregates into various assemblies, including oligomers and fibrils, which disrupt neuronal membrane integrity and induce cellular damage. Aβ is directly neurotoxic/synaptotoxic, but may also induce neuroinflammation through the concomitant activation of microglia. Previously, we have shown that furosemide is a known anthranilate-based drug with the capacity to downregulate the proinflammatory microglial M1 phenotype and upregulate the anti-inflammatory M2 phenotype. To further explore the pharmacologic effects of furosemide, this study reports a series of furosemide analogs that target both Aβ aggregation and neuroinflammation, thereby addressing the combined proteopathic-immunopathic pathogenesis of AD. Forty compounds were synthesized and evaluated. Compounds 3c, 3g, and 20 inhibited Aβ oligomerization; 33 and 34 inhibited Aβ fibrillization. 3g and 34 inhibited the production of TNF-α, IL-6, and nitric oxide, downregulated the expression of COX-2 and iNOS, and promoted microglial phagocytotic activity, suggesting dual activity against Aβ aggregation and neuroinflammation. Our data demonstrate the potential therapeutic utility of the furosemide-like anthranilate platform in the development of drug-like molecules targeting both the proteopathy and immunopathy of AD.
- Liu, Xiaojing,Pasangulapati, Jagadeesh Prasad,Schier, Stephanie (Wohnig),Stover, Kurt R.,Wang, Yanfei,Wang, Zhiyu,Weaver, Donald F.
-
supporting information
(2021/07/28)
-
- FUROSEMIDE ANALOGUES AND COMPOSITIONS AND USES THEREOF FOR TREATMENT OF ALZHEIMER'S DISEASE
-
The present application provides furosemide analogues of the general formula Z having activity as anti-Aβ aggregation agents and/or as inhibitors of Aβ induced neuroinflammation. Formula Z These compounds are useful in preventing, delaying and/or treating Alzheimer's Disease. Accordingly, the present application further provides pharmaceutical compositions and method for preventing, delaying and/or treating Alzheimer's Disease.
- -
-
Paragraph 0056; 0059; 0062-0063; 0066-0068
(2021/01/23)
-
- 1/20 water-containing furosemide compound and preparation method thereof
-
The invention discloses a 1/20 water-containing furosemide compound and a preparation method thereof. The compound is measured by using a powder X-ray diffraction measurement method, a diffraction angle of 2 theta +/- 0.2 degree is adopted, and characteristic diffraction peaks are shown at 6.06 degree, 12.10 degree, 18.16 degree, 18.99 degree, 22.96 degree and 24.84 degree. The prepared 1/20 water-containing furosemide compound has the advantages of good thermal stability, high purity, and no easy moisture absorption, and a simple process, high yield, high repeatability and suitability for industrial production are achieved.
- -
-
Paragraph 0038-0052
(2020/01/12)
-
- Preparation method of furosemide
-
The invention belongs to the technical field of pharmacy and discloses a preparation method of furosemide. The preparation method comprises putting 2, 4-dichloro-5-sulfamoylbenzoic acid and an acid-binding agent into an appropriate solvent, heating the solution to a certain temperature in an inert gas protective atmosphere, dropwisely adding furfuryl amine into the solution, after the reaction, adjusting pH through an acid so that crystals are precipitated, filtering the crystals to obtain a furosemide crude product, refining the crude product through an organic solvent-water mixed solvent, adjusting pH to greater than 7, carrying out heating so that the crude product is dissolved, carrying out decoloration through activated carbon, carrying out hot filtration, adjusting pH of the filtrate through an acid so that solids are precipitated and carrying out filtration and drying to obtain furosemide. The preparation method utilizes cheap and easily available raw materials, has a high conversion rate, less side products and high product purity, has simple processes and is suitable for industrial production. A HPLC analysis result shows that purity is greater than or equal to 99.0% and a total yield is 71.2%.
- -
-
Paragraph 0006; 0007; 0008
(2017/08/23)
-
- Furosemide preparation method
-
The invention belongs to the field of pharmaceutical chemicals and particularly relates to a furosemide preparation method. A chemical formula of furosemide is shown as a formula (1) in the specification. The preparation method includes: heating a tetrahydrofuran compound shown as a formula (2) and a 2-aminobenzoic acid compound shown as a formula (3) and/or salts of 2-aminobenzoic acid compound in a reaction solvent, wherein the temperature is controlled to be 80-150 DEG C, and in the formula (2), X refers to halogen, lower alkyl sulfonyloxy, arylsulfonyloxy or araklyl sulfonyloxy; performing nucleophilic reaction under the action of an acid-binding agent and/or catalyst until the reaction of the formula (3) is finished completely, wherein the reaction time is 5-36h; separating and purifying reaction liquid to obtain the furosemide shown as the formula (1). By the furosemide preparation method, high-purity high-yield furosemide preparation can be realized through simple steps without any complex purification steps, the yield is up to 97.0%, and the purity is up to 99.8%. Therefore, the furosemide preparation method has remarkable economic benefits and is pretty advantageous.
- -
-
Paragraph 0035; 0036
(2017/02/24)
-
- Preparation method of furosemide
-
The invention provides a preparation method of furosemide and relates to the technical field of pharmaceutical synthesis. The preparation method comprises the following steps: (1) 2,4-dichloro-5-sulfamoylbenzoic acid and alkali are subjected to a reaction in presence of an organic solvent, a reaction liquid is obtained and subjected to aftertreatment, and sodium 2,4-dichloro-5-sulfamoylbenzoic acid is obtained; (2) sodium 2,4-dichloro-5-sulfamoylbenzoic acid and furfurylamine are subjected to a reaction in presence of an organic solvent, furfurylamine and the solvent are recovered through reduced pressure distillation after the reaction, a reaction liquid is obtained and mixed with isopropyl alcohol, a mixture is stirred, crystallized and filtered, and sodium furosemide is obtained; (3) sodium furosemide is subjected to water dissolution, activated carbon decoloration and glacial acetic acid acidification, and a finished furosemide product is obtained. The preparation method has the advantages that raw materials are cheap and available, the cost is low, short time is consumed, reaction steps are short, operation is simple, product quality is good, yield is high, solvents can be recycled and reused, environmental pollution is small and the like, and the preparation method is suitable for industrial production.
- -
-
Paragraph 0057; 0059
(2017/01/02)
-
- Process for the preparation of furosemide
-
A new process for the preparation of furosemide ?4-chloro-N-(2-furylmethyl)-5-sulfamoyl-anthranilic acid!comprising the photochlorination of 4-chloro-2-fluoro-toluene to give 4-chloro-2-fluoro-benzotrichloride, the aminosulfonylation of the same and the subsequent condensation with furfurylamine.
- -
-
-
- Apparent intramolecular acyl migration and hydrolysis of purosemide glucuronide in aqueous solution
-
The stability of furosemide glucuronide (FG) was investigated in buffer solutions ranging from pH 1 through 10. This glucuronic acid conjugate was the major metabolite of furosemide (F) excreted in human urine, FG, obtained by extraction from human urine, was purified by ion-exchange chromatography. The concentration of FG, acyl migration isomers of FG (FG-iso), and F were determined simultaneously with an HPLC method that included fluorescence detection and gradient elution, FG was found to be unstable in highly acidic and in neutral to alkaline solutions. Hydrogen ion and hydroxy ion catalyzed the hydrolysis of FG below pH 2.8 and above pH 5.6, respectively. Above pH 3.7, FG instability led to the formation of eight FG-iso compounds. Though β-glucuronidase cleaved FG, the FG-iso compounds were resistant to the enzyme, The half-life of FG in a buffer solution at pH 7.4 and 37°C was 4.4 h. The maximum stability of FG (half-life about 62 d) occurred at approximately pH 3.2. Below pH 3.7, acyl migration products of FG were not detected. Instead, the hydrolysis of FG to F and glucuronic acid was followed by the formation of 4-chloro-5-sulfamoylanthranilic acid (CSA), a secondary product in acidic media.
- Sekikawa,Yagi,Lin,Benet
-
p. 134 - 139
(2007/10/03)
-
- Furosemide salts
-
Compounds of the formula STR1 wherein AA is a basic amino acid in optically active or racemic form having better bio-availability and a method of treating asthma.
- -
-
-
- Prodrug derivatives of carboxylic acid drugs
-
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.
- -
-
-
- High molecular weight prodrug derivatives of antiinflammatory drugs
-
Compounds of the formula 1, PS - O - A - (CH2)n- B - D (1), wherein PS-O represents an alkoxide residue of any of the free hydroxy groups of a polysaccharide (PS-OH) compound with molecular weight (Mw) of from 40,000 to 5,000,000 selected from dextran, carboxymethyl dextran, diethylaminoethyl dextran, starch, hydroxyet-hyl starch, alginates, glycogen, pullullan, agarose, cellulose, chitosan, chitin and carrageenan,A is a carbonyl group or absent,n is zero or a positive integer from 1 to 14,B is oxygen, a carbonyl group, NR wherein R is hydrogen or lower alkyl, or B is absent, and, D is (i) a group of the formula:, R1 - CO - (11), wherein R1-CO- represents the acyl residue of a carboxylic acid drug (R1-COOH) used in the treatment of inflammatory disorders; or (ii) a group of the formula:, R2 - O - (12), wherein R2-O- refers to the C-21 alkoxide residue of a known antiinflammatory steroid (R2-OH) or an alkoxide residue of any other drug or medicament containing a hydroxy functional group used in the treatment of inflammatory disorders; with the proviso that when A is absent, n is 0, and B is absent, then R1-CO- is different from the acyl residue of acetylsalicylic acid;, and non-toxic pharmaceutically acceptable acid addition salts thereof;, and non-toxic pharmaceutically acceptable cation salts thereof. Such compounds are biolabile prodrugs providing controlled release and prolonged duration of action of the parent active antiinflamma-tory agents locally at the administration site after intra-articular, intra-muscular, subcutaneous or extra-dural application while at the same time being highly stable in aqueous solution in the pH range 3--5. After oral administration of such prodrugs the parent drug is liberated selectively in the terminal ileum and the colon over an extended period of time.
- -
-
-