10238-21-8 Usage
Uses
Used in Pharmaceutical Industry:
Glibenclamide is used as a hypoglycemic agent for the treatment of mild, non-insulin-dependent diabetes. It acts by modulating insulin production through the inhibition of ATP-dependent K+ channels (KIR6, KATP) in beta cells of the pancreas, leading to depolarization and the release of Ca2+, which in turn stimulates insulin production.
Used in Antihyperglycemic Applications:
Glibenclamide is used as an antihyperglycemic agent, particularly for patients with type 2 diabetes. It helps in controlling blood sugar levels by increasing insulin secretion from the pancreas.
Used in Drug Delivery Systems:
Glibenclamide is used as an ATP-dependent KIR6 and CFTR Clchannel blocker, which can be employed in the development of novel drug delivery systems to enhance its applications and efficacy in treating diabetes.
Hypoglycemic agents
Glibenclamide belongs to the second generation oral sulfonylurea drugs with the mechanism of action being similar as tolbutamide and the hypoglycemic effect being strongest among sulfonylurea drugs. Its intensity of action is about 200 to 250 times of that of Tolbutamide. It can selectively act on the pancreatic β-cells, promote insulin secretion; can enhance the hypoglycemic effect of exogenous insulin and strengthen the post-receptor effect of insulin. It has fast oral absorption with high protein binding rate. It begins to take effect after 30 minutes with the effect being strongest at 1.5 hours and the duration of 16 to 24 hours. It has a distribution volume of 0.1L/kg, plasma protein binding rate of 90% to 95% and half-life of 4 to 8 hours. It is mainly consumed by the liver metabolism with six metabolites. Two of them are known as hydroxylated compounds with no hypoglycemic effect and is mainly excreted from the urine and a small amount is excreted by the stool. It is clinically mainly used for the treatment of mild to moderate non-insulin dependent diabetes mellitus.
Recently, an international study found that the commonly used diabetes drug glibenclamide can help the body's immune system to fight against certain bacterial infections, e.g. in the treatment of melioidosis, the mortality rate can be reduced by about half.
Melioidosis is a disease prevalent in tropical areas such as Southeast Asia and northern Australia. It is caused by Burkholderia pseudomallei with the symptoms including sepsis and pneumonia. The mortality rate is high. Diabetic patients tend to be more susceptible to melioidosis, but the mortality rate is lower compared with other patients.
Hypoglycemic effect
Glibenclamide is currently one of the most commonly used drugs for the treatment of type 2 diabetes. Because this product has fast and strong effect, so the effect after the application remarkable, being able to have good control of blood sugar; being applicable for patients of high blood sugar who get bad efficacy when treated with other sulfonyl Urea hypoglycemic agents.
Two commonly sulfonylurea oral hypoglycemic agents are glibenclamide and glimepiride, the comparison of hypoglycemic effect of them two are as follow:
(1) The effect on glucose transport and metabolism: Glibenclamide and glimepiride can stimulate the key enzymes in the glucose metabolism and improve the glucose transporter (GLUT4) translocation/dephosphorylation to promote the glucose uptake of the surrounding tissue, specifically exhibited in glycogen synthesis and increased fat formation. Glycogen synthase and 3-phosphoglycerol fatty acyltransferase are the key enzymes in glycogen and fat synthesis, and glimepiride is more active than glibenclamide in activating these key enzymes, such as for activating glycogen synthase activity, glimepiride is 2.5 times that of glibenclamide; for the capability to activate lipase, glimepiride is 1.9 times that of glibenclamide. Glimepiride increased the expression of GLUT4 on the cell membrane by inducing dephosphorylation of GLUT4.
?(2) Effect on glycosylated-phosphatidylinositol-specific phospholipase (GPI-PLC): GPI is located in the outer layer of the cell membrane and participates in insulin signal transduction, which can interfere with glucose metabolism of muscle and adipocytes. GPI-PLC can shed the GPI, thereby improving the cell phosphorylation status. Insulin and sulfonylureas can activate GPI-PLC, helping muscle, adipose tissue for the uptake and transport of glucose. However, in the presence of insulin resistance, insulin itself is very difficult to activate GPI-PLC, but glimepiride can still activate the enzyme. In vitro and in vivo studies have shown that, glimepiride has the strongest pancreatic effect in sulfonylurea drugs, which can increase glucose synthesis by 2.5 times and fat synthesis by 4 times. The ratio of glimepiride to glibenclamide was 2: 1. Therefore, glimepiride has a lower secondary failure incidence than other sulfonylurea drugs.
Precautions
Glibenclamide should be started at low doses. During treatment, it should be regularly checked of the urine sugar, urine ketone body, urine protein and blood sugar, blood routine examination, liver and kidney function, vision, retinal blood vessels.
(1) Patients of liver and kidney dysfunction, leukopenia, sulfa allergy, pregnant women and diabetes complicated by acidosis and acute infection should be disabled.
(2) It can cause abdominal distension, abdominal pain, anorexia, nausea and other gastrointestinal reactions. It can also appear as allergy (skin erythema or urticaria), leukopenia, granulocyte deficiency, thrombocytopenia, hypoglycemia, etc., should be immediately discontinued and treated. Among them, hypoglycemia reaction is more common.
(3) Glibenclamide and other sulfonylurea hypoglycemic agents can’t be combined with thiazide diuretics or glucocorticoids.
(4) It should be avoided to taken together with anticoagulant drugs such as dicoumaroline.
(5) When combined with phenylbutazone, the hypoglycemic effect can be enhanced, causing acute hypoglycemia.
(6) Combination with sulfonamides can enhance both the effect and toxicity of glibenclamide, not suitable for use.
(7) Combination with chloramphenicol can also enhance the effect and toxicity of this product; combination of two drugs demands dose adjustment according to the patient's blood sugar levels, otherwise can cause hypoglycemic shock.
(8) Sulfonylurea drugs can enhance the toxicity of alcohol; alcohol should be avoided during treatment.
Hazards & Safety Information
Category : Toxic substances
Toxic classification:? poisoning
Acute toxicity:? Intraperitoneal-rat LD50: 3750 mg/kg; Oral-mouse LD50: 3250 mg/kg
Flammability Hazardous characteristics : Thermal decomposition releases toxic nitrogen oxides, sulfur oxides, chloride fumes
Storage and transport characteristics:? Treasury: low temperature, ventilated and dry
Extinguishing agent : water, carbon dioxide, foam, dry powder
Originator
Daonil,Hoechst,Germany
Manufacturing Process
To a solution of 10.2 g of 4-(β-(2-ethoxy-5-chlorobenzamido)ethyl)-
benzenesulfonamide in 12.5 ml of 2 N sodium hydroxide solution and 30 ml
acetone are added dropwise, at 0-5°C, 3.3 g of cyclohexyl isocyanate. The
whole is stirred for 3 hours, diluted with water and methanol, undissolved
matter is separeted by filtration. The filtrate is acidified with dilute
hydrochloric acid. The 4-(β-(2-ethoxy-5-chlorobenzamido)ethyl)-
benzenesulfonyl)-N'-cyclohexylurea which precipitates in the form of crystals
melts after recrystallization from methanol at 168-170°C.
Therapeutic Function
Oral hypoglycemic
Biological Activity
ATP-dependent K + channel (K ATP ) and CFTR Cl - channel blocker. Inhibits K ATP currents in the pancreas, causing an increase in intracellular Ca 2+ and insulin secretion. Inhibits recombinant CFTR Cl- channels with an IC 50 of 20 μ M.
Biochem/physiol Actions
Selectively blocks ATP-sensitive K+ channels; high affinity binding sites found in brain, pancreatic β cells, and cardiovascular system.
Mechanism of action
This drug belongs to the second-generation sulfonylurea derivatives. Like all of the other
oral hypoglycemic drugs examined, it is a β-cell stimulant in pancreas; but on the other
hand, it increases the sensitivity to insulin, the degree to which it binds with target cells.
At the same time, it differs in that it is easier to tolerate. The hypoglycemic effect sets in at significantly lower doses than with first-generation drugs.
Clinical Use
Non-insulin dependent diabetes mellitus
Synthesis
Glyburide, 1-[4-[2-(5-chloro-2-methoxybenzamido)ethyl]-phenylsulfonyl]-3-
cyclohexylurea (26.2.11), is a second-generation drug that differs from those described above
in that it has a more complex structure in the sulfonylamide region of the molecule into which
an additional pharmacophore group is added. It is synthesized from 2-methoxy-5-chlorobenzoic
acid chloride, which is transformed into an amide 26.2.9 by reacting it with 2-phenylethylamine.
This undergoes subsequent sulfonylchlorination by chlorosulfonic acid, and then
amination by ammonia, which gives sulfonamide 26.2.10. The resulting sulfonamide is
reacted with cylclohexylisocyanate to give the desired glyburide (26.2.11).
Drug interactions
Potentially hazardous interactions with other drugs
Analgesics: effects enhanced by NSAIDs.
Antibacterials: effects enhanced by chloramphenicol,
sulphonamides, tetracyclines and trimethoprim;
effects possibly enhanced by ciprofloxacin and
norfloxacin; effect reduced by rifamycins.
Anticoagulants: effect possibly enhanced by
coumarins; also possibly changes to INR.
Antifungals: concentration increased by fluconazole
and miconazole and possibly voriconazole.
Bosentan: increased risk of hepatoxicity - avoid.
Ciclosporin: may increase ciclosporin levels.
Lipid-regulating drugs: absorption reduced by
colesevelam; concentration possibly increased by
fluvastatin; possibly additive hypoglycaemic effect
with fibrates.
Sulfinpyrazone: enhanced effect of sulphonylureas.
Metabolism
Glibenclamide is metabolised, almost completely, in the
liver, the principal metabolite being only very weakly
active.
About 50% of a dose is excreted in the urine and 50% via
the bile into the faeces.
References
1) Brogden et al. (1979), Glipizide: a review of its pharmacological properties and therapeutic use; Drugs, 18 329
2) Sheppard and Welsh (1992), Effect of ATP-sensitive K+ channel regulators on cystic fibrosis transmembrane conductance regulator chloride currents; J. Gen. Physiol., 100 573
Check Digit Verification of cas no
The CAS Registry Mumber 10238-21-8 includes 8 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 5 digits, 1,0,2,3 and 8 respectively; the second part has 2 digits, 2 and 1 respectively.
Calculate Digit Verification of CAS Registry Number 10238-21:
(7*1)+(6*0)+(5*2)+(4*3)+(3*8)+(2*2)+(1*1)=58
58 % 10 = 8
So 10238-21-8 is a valid CAS Registry Number.
InChI:InChI=1/C23H22ClN3O5S/c1-32-21-12-9-17(24)15-20(21)22(28)25-14-13-16-7-10-19(11-8-16)33(30,31)27-23(29)26-18-5-3-2-4-6-18/h2-12,15H,13-14H2,1H3,(H,25,28)(H2,26,27,29)
10238-21-8Relevant articles and documents
Total Synthesis of Glipizide and Glibenclamide in Continuous Flow
Sagandira, Cloudius R.,Khasipo, Agnes Z.,Watts, Paul
, p. 16028 - 16035 (2021/10/14)
Glipizide and glibenclamide remain some of the widely prescribed antidiabetic sulfonylurea drugs for the treatment of type 2 diabetes mellitus. Herein the authors report on an isocyanate-free synthetic procedure towards the preparation of these on demand drugs at multigram scale using continuous flow technology. The safety concern over the use of isocyanates in most of the existing synthetic routes was dealt with in this present work by using N-carbamates synthesised in situ from activation of amines with chloroformates as safer alternatives. An overall yield of 80–85 % was obtained for the semi-telescoped steps within 10 min total residence time.
Synthesis method of glibenclamide
-
, (2018/04/26)
The invention discloses a synthesis method of glibenclamide, which includes the steps of: 1) protection of amino groups with trichloroacetic anhydride; 2) sulfonation; 3) sulfo-amidation; 4) amidation: performing a reaction to 5-chloro-2-methoxybenzoic acid with N,N-carbonyl diimidazole and performing a reaction to the product with a compound (III) under effect of a second acid-binding agent; 5) addition: adding the second acid-binding agent and crown ether, in catalytic amount, to perform an addition reaction to a compound (IV) with cyclohexyl isocyanate to prepare the glibenclamide. The method is high in yields in all steps, wherein residue of impurities is effectively reduced during processes of protection, deprotection, acid treatment, alkali treatment and water-adding separation of the substrate. According to the method, a phase-transfer catalyst is matched with the second acid-binding agent, so that compatibility between the isocyanate and the compound (IV) is effectively increased, and the nucleophilic reaction is carried out more completely. The produced product is higher in purity.
Synthesis technology of glibenclamide
-
Paragraph 0048; 0049; 0050; 0051, (2017/08/25)
The invention provides a novel synthesis technology of a glibenclamide bulk pharmaceuticals. The glibenclamide product is finally prepared by taking sulfamide as a starting raw material through the four steps of a secondary condensation reaction, a compounding reaction, a dealcoholization reaction and refining. The technology has the advantages of being high in yield, low in purity, easy and convenient to operate, suitable for industrialized production and the like.
A sulfonyl urea, sulfonamide ethyl ester preparation method of compound (by machine translation)
-
Paragraph 0094; 0100-0104; 0110-0115, (2017/08/02)
The description relates to a compound of formula (I) compound of the preparation method, wherein formula (II) with a compound represented by formula (III) as shown in the catalysis of palladium catalyst, under a carbon monoxide atmosphere, reacts in a solvent to obtain the compound. The invention related to the method of the reaction do not require strict-free conditions, does not need a high pressure carbon monoxide atmosphere, convenient and simple to operate, to a functional group and has very high power density and universality, the catalyst consumption is very small, the cost of reaction is very low, and can be widely used for preparing sulfonyl urea compound. R1 - SO2 - NH - CO - X (R3 )n - R2 (I) R1 - SO2 - R4 (II) HX (R3 )n - R2 (III) wherein X is O or N; n is 0 or 1; when X is when O, n=0; when X is when N, n=1; R1 Selected from aryl, heteroaryl, alkyl, alkenyl or alkynyl; R2 Selected from aryl, heteroaryl, alkyl, alkenyl or alkynyl; R3 Is selected from H, R2 , Or R3 And R2 A ring of connection; R4 For N3 Or a halogen atom; when R4 For nails halogen original, system also comprises a sodium azide. (by machine translation)
Design and Performance Validation of a Conductively Heated Sealed-Vessel Reactor for Organic Synthesis
Obermayer, David,Znidar, Desiree,Glotz, Gabriel,Stadler, Alexander,Dallinger, Doris,Oliver Kappe
, p. 11788 - 11801 (2016/12/09)
A newly designed robust and safe laboratory scale reactor for syntheses under sealed-vessel conditions at 250 °C maximum temperature and 20 bar maximum pressure is presented. The reactor employs conductive heating of a sealed glass vessel via a stainless steel heating jacket and implements both online temperature and pressure monitoring in addition to magnetic stirring. Reactions are performed in 10 mL borosilicate vials that are sealed with a silicone cap and Teflon septum and allow syntheses to be performed on a 2-6 mL scale. This conductively heated reactor is compared to a standard single-mode sealed-vessel microwave instrument with respect to heating and cooling performance, stirring efficiency, and temperature and pressure control. Importantly, comparison of the reaction outcome for a number of different synthetic transformations performed side by side in the new device and a standard microwave reactor suggest that results obtained using microwave conditions can be readily mimicked in the operationally much simpler and smaller conventionally heated device.
Product-Derived Bimetallic Palladium Complex Catalyzes Direct Carbonylation of Sulfonylazides
Zhao, Jin,Li, Zongyang,Song, Shaole,Wang, Ming-An,Fu, Bin,Zhang, Zhenhua
, p. 5545 - 5549 (2016/05/09)
A novel product-derived bimetallic palladium complex catalyzes a sulfonylazide-transfer reaction with the σ-donor/π-acceptor ligand CO, and is advantageous given its broad substrate scope, high efficiency, and mild reaction conditions (atmospheric pressure of CO at room temperature). This methodology provides a new approach to sulfonylureas, which are present in both pharmaceuticals and agrochemicals. The synthesis of Glibenclamide on a gram scale further revealed the practical utility of this procedure. Mechanistically, the generation of a bridged bimetallic palladium species derived from the product sulfonylurea is disclosed as the crucial step for this catalytic cycle.
Mechanosynthesis of pharmaceutically relevant sulfonyl-(thio)ureas
Tan, Davin,?trukil, Vjekoslav,Mottillo, Cristina,Fri??i?, Tomislav
supporting information, p. 5248 - 5250 (2014/05/06)
We demonstrate the first application of mechanochemistry to conduct the synthesis of sulfonyl-(thio)ureas, including known anti-diabetic drugs tolbutamide, chlorpropamide and glibenclamide, in good to excellent isolated yields by either stoichiometric base-assisted or copper-catalysed coupling of sulfonamides and iso(thio)cyanates. the Partner Organisations 2014.
Voltammetric and spectrophotometric study on the complexation of glibenclamide with β-cyclodextrin
Radi, Abd-Elgawad,Eissa, Shimaa
experimental part, p. 417 - 421 (2012/01/02)
The formation of an inclusion complex of glibenclamide (GL) with β-cyclodextrin (β-CD) in an aqueous ethanolic buffer solution of pH 7.0 has been investigated by UV spectrophotometry and differential pulse voltammetry and its stability constant is determined to be 855 and 354.15 M-1, respectively. The phase solubility profile, based on the spectrophotometric absorbance's variations, was classified as AL-type, indicating the formation of 1:1 stoichiometric inclusion complex of glibenclamide with β-CD with a stability constant value, KS, of 846 M-1.
USE OF SUBSTITUTED 2 PHENYLBENZIMIDAZOLES AS MEDICAMENTS
-
, (2008/06/13)
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
Novel diabetes imaging probes
-
, (2008/06/13)
The present invention relates to novel imaging probes and methods for using the probes in diagnostic imaging processes and other imaging processes to determine physiological functions.
