29094-61-9

Usage

Uses

Used in Pharmaceutical Industry:
Glipizide is used as an oral hypoglycemic agent for the treatment of type 2 diabetes mellitus (non-insulin-dependent diabetes mellitus). It helps in controlling high blood sugar and its associated symptomatology when used as an adjunct to diet and proper exercise program. Glipizide is effective in reducing the risk of heart attack, stroke, kidney damage, blindness, nerve problems, loss of limbs, and sexual function problems, which can result from hypertension.
Used in Research and Development:
Labeled Glipizide is intended for use as an internal standard for the quantification of Glipizide by gas chromatography (GC) or liquid chromatography (LC) mass spectrometry. This application aids in the accurate measurement and analysis of Glipizide in various research and development processes.
Used in Combination Therapy:
In the United States, Glipizide is available in combinations with metformin (Metaglip, generic; tablets, mg glipizide/mg metformin as hydrochloride: 2.5/250, 2.5/500, 5/500). These combinations are used to enhance the effectiveness of diabetes management in patients with type 2 diabetes mellitus.
Used in Extended-Release Formulations:
Extended-release tablets of Glipizide (Glucotrol XL, generic) are available, providing a longer-lasting hypoglycemic effect and improved convenience for patients with type 2 diabetes mellitus.
Used as a Sweetener:
Glipizide is also used as a sweetener in the food industry, offering a sugar substitute for those with diabetes or those looking to manage their sugar intake.
Used in the Treatment of Portoencephalopathy:
Glipizide is utilized in the treatment of portoencephalopathy, a neurological disorder associated with liver disease, to help manage the symptoms and improve the patient's condition.
Brand Name:
Glipizide is commercially available under the brand name Glucotrol, manufactured by Pfizer.

References

https://en.wikipedia.org/wiki/Glipizide http://www.medicinenet.com/glipizide/article.htm http://www.medicinenet.com/glipizide_tablet-oral/article.htm https://www.drugbank.ca/drugs/DB01067

Originator

Minidiab,Carlo Erba,Italy,1973

Manufacturing Process

5-Methyl pyrazine-2-carboxylic acid is refluxed with thionyl chloride in anhydrous benzene for approximately 12 hours. Benzene and thionyl chloride excess is removed by distillation. Then some anhydrous dioxane is added and this acid chloride solution is allowed to drop into p-(β-aminoethyl)- benzenesulfonamide suspension in dioxane and anhydrous pyridine. The resulting mixture is then refluxed for 3 hours. Dioxane is removed by distillation and then the residue is washed with water and acetic acid. The raw acylated sulfonamide is then filtered and crystallized from 95% ethanol, thus obtaining a product of MP 200° to 203°C. This product is then reacted with cyclohexyl isocyanate to give glipizide.

Therapeutic Function

Oral hypoglycemic

Biochem/physiol Actions

Potassium inwardly-rectifying channel, subfamily J, member 1 (KCNJ1) plays a vital role in potassium balance. It is an ATP-dependent K+?channel blocker. The encoded protein is liable for the elimination of potassium in exchange for the absorption of sodium by the epithelial sodium channel (ENaC). Mutation in KCNJ1 is linked with several diseases, such as, antenatal Bartter syndrome and diabetes. Glipizide helps to repress the development of tumors and metastasis by preventing angiogenesis.

Synthesis

Glipizide, 1-cyclohexyl-3-[[p-[2-(5-methylpyrazincarboxamido)ethyl]phenyl] sulfonyl]urea (26.2.13), differs from glyburide in the structure of the amide region of the molecule, in which the 2-methoxy-5-chlorobenzoic acid part is replaced with 6- methylpyrazincarboxylic acid. It is also synthesized by a synthesis alternative to those described above. In the given scheme, 6-methylpyrazincarboxylic acid is initially reacted with thionyl chloride, resulting in the corresponding chloride, which undergoes further action with 4-(2-aminoethyl)benzenesulfonamide, forming the corresponding amide 26.2.12. The resulting sulfonamide is reacted in a traditional scheme with cyclohexylisocyanate, forming the desired glipizide (26.2.13).

Veterinary Drugs and Treatments

Glipizide may be of benefit in treating cats with type II diabetes if they have a population of functioning beta cells. It has been suggested that there are two situations when glipizide can be recommended, 1) If an owner refuses to consider using insulin usually due to a fear of needles, and 2) the cat appears to be relatively well controlled on quite small doses of insulin and the owner would strongly prefer to no longer give insulin (Feldman 2005b). While glipizide potentially could be useful in treating canine patients with type II or III diabetes, however, by the time dogs present with hyperglycemia, they are absolutely or relatively insulinopenic and glipizide would unlikely be effective.

Drug interactions

Potentially hazardous interactions with other drugs Analgesics: effects enhanced by NSAIDs. Antibacterials: effects enhanced by chloramphenicol, sulphonamides, tetracyclines and trimethoprim; effect reduced by rifamycins. Anticoagulants: effect possibly enhanced by coumarins; also possibly changes to INR. Antifungals: concentration increased by fluconazole, posaconazole and miconazole and possibly voriconazole - avoid with miconazole. Ciclosporin: may increase ciclosporin levels. Lipid-regulating drugs: possibly additive hypoglycaemic effect with fibrates. Sulfinpyrazone: enhanced effect of sulphonylureas.

Metabolism

The metabolism of glipizide is extensive and occurs mainly in the liver. The primary metabolites are inactive hydroxylation products and polar conjugates and are excreted mainly in the urine.

InChI:InChI=1/C21H33N5O4S/c1-15-13-24-19(14-23-15)20(27)22-12-11-16-7-9-18(10-8-16)31(29,30)26-21(28)25-17-5-3-2-4-6-17/h7-10,15,17,19,23-24H,2-6,11-14H2,1H3,(H,22,27)(H2,25,26,28)

Synthetic route

carbon monoxide (201230-82-2) + C14H16N4O3S*NaCl + cyclohexylamine (108-91-8) → glipizide (29094-61-9)

Conditions	Yield
With iron(III)-acetylacetonate In methanol at 20 - 30℃; for 6h;	85%

N-(4-[2-amino-ethyl]-benzenesulfonyl)-N'-cyclohexyl urea (2015-16-9) + 5-methylpyrazine-2-carboxylic acid methyl ester (41110-33-2) → glipizide (29094-61-9)

Conditions	Yield
With water; sodium methylate In methanol at 85℃; Concentration; Temperature; Solvent;	84%

ethyl cellulose + 1-ethenyl-2-pyrrolidinone (88-12-0) → glipizide (29094-61-9)

4-(2-aminoethyl)benzenesulfonamide (35303-76-5) → glipizide (29094-61-9)

Conditions	Yield
Multi-step reaction with 4 steps 1: N,N-dimethyl-formamide / 4 h / 20 °C 2: potassium carbonate / acetone / 3 h / 50 - 55 °C 3: hydrogenchloride / methanol / 3 h / 50 - 55 °C 4: sodium methylate; water / methanol / 85 °C View Scheme

tert-butyl (4-sulfamoyl phenethyl)carbamate (258262-54-3) → glipizide (29094-61-9)

Conditions	Yield
Multi-step reaction with 3 steps 1: potassium carbonate / acetone / 3 h / 50 - 55 °C 2: hydrogenchloride / methanol / 3 h / 50 - 55 °C 3: sodium methylate; water / methanol / 85 °C View Scheme

tert-butyl (4-(N-(cyclohexylcarbamoyl)sulfamoyl)phenethyl)carbamate → glipizide (29094-61-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: hydrogenchloride / methanol / 3 h / 50 - 55 °C 2: sodium methylate; water / methanol / 85 °C View Scheme

glipizide (29094-61-9) → N-[2-[4-(amino-sulfonyl)phenyl]ethyl]-5-methylpyrazinecarboxamide (33288-71-0)

Conditions	Yield
With 3-azapentane-1,5-diamine at 120℃; for 6h; Sealed tube;	89%
With dmap; phthalic anhydride In pyridine for 5h; Reflux; Inert atmosphere;	63%
With pyridine; dmap; phthalic anhydride for 5h; Inert atmosphere; Reflux;	63%

acetic anhydride (108-24-7) + glipizide (29094-61-9) → N-<4-<2-(5-Methyl-2-pyrazincarboxamido)ethyl>benzolsulfonyl>acetamid

Conditions	Yield
With pyridine for 0.25h;	73%

diethylenetriaminepentaacetic dianhydride (23911-26-4) + glipizide (29094-61-9) → DTPA-glipizide (848488-95-9)

Conditions	Yield
Stage #1: glipizide With sodium amide In dimethyl sulfoxide at 20℃; for 0.166667h; Stage #2: diethylenetriaminepentaacetic dianhydride With sodium amide In dimethyl sulfoxide at 20℃; for 4.16667h;	61.7%

glipizide (29094-61-9) → N-Cyclohexyl-N',N''-bis-<4-<2-(5-methyl-2-pyrazincarboxamido)ethyl>benzolsulfonyl>guanidin + N-[2-[4-(amino-sulfonyl)phenyl]ethyl]-5-methylpyrazinecarboxamide (33288-71-0)

Conditions	Yield
With pyridine; p-toluenesulfonyl chloride Heating;	A 60% B 17%

water (7732-18-5) + cobalt(II) chloride (7646-79-9) + glipizide (29094-61-9) → C42H56CoN10O10S2

Conditions	Yield
Reflux;	54.16%

zirconium(II) nitrate + glipizide (29094-61-9) → C42H52N10O8S2Zr

Conditions	Yield
Reflux;	52.14%

dicyclohexyl-carbodiimide (538-75-0) + glipizide (29094-61-9) → N,N'-Dicyclohexyl-N''-<4-<2-(5-methyl-2-pyrazincarboxamido)ethyl>benzolsulfonyl>guanidin

Conditions	Yield
With pyridine Heating;	52%

succinic acid anhydride (108-30-5) + glipizide (29094-61-9) → N-Cyclohexyl-N'-4-<2-(5-methyl-2-pyrazincarboxamido)ethyl>benzolsulfonyl-bernsteinsaeurediamid

Conditions	Yield
With pyridine; dmap	35%

diisopropyl-carbodiimide (693-13-0) + glipizide (29094-61-9) → N,N'-Diisopropyl-N''-<4-<2-(5-methyl-2-pyrazincarboxamido)ethyl>benzolsulfonyl>guanidin

Conditions	Yield
With pyridine Heating;	21%

tert-butyl peroxyacetate (107-71-1) + trifluoroacetic acid (76-05-1) + glipizide (29094-61-9) → N-(4-(N-(cyclohexylcarbamoyl)sulfamoyl)phenethyl)-3,5-dimethylpyrazine-2-carboxamide trifluoroacetate + N-(4-(N-(cyclohexylcarbamoyl)sulfamoyl)phenethyl)-3,5,6-trimethylpyrazine-2-carboxamide trifluoroacetate

Conditions	Yield
With (4,4'-di-tert-butyl-2,2'-dipyridyl)-bis-(2-phenylpyridine(-1H))-iridium(III) hexafluorophosphate In acetonitrile at 30℃; Inert atmosphere; Irradiation;	A 21% B 21%

β‐cyclodextrin (7585-39-9) + glipizide (29094-61-9) → 2C21H27N5O4S*C42H70O35

Conditions	Yield
In methanol; water for 0.75h; Kneading;

β‐cyclodextrin (7585-39-9) + glipizide (29094-61-9) → C21H27N5O4S*C42H70O35 (468055-52-9)

Conditions	Yield
In methanol; water for 0.75h; Kneading;

β‐cyclodextrin (7585-39-9) + glipizide (29094-61-9) → C21H27N5O4S*2C42H70O35

Conditions	Yield
In methanol; water for 0.75h; Kneading;

β‐cyclodextrin (7585-39-9) + glipizide (29094-61-9) → C21H27N5O4S*3C42H70O35

Conditions	Yield
In methanol; water for 0.75h; Kneading;

piperazine (110-85-0) + glipizide (29094-61-9) → glipizide*piperazine

Conditions	Yield
In methanol for 0.333333h;

glipizide (29094-61-9) → N-(4-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)phenethyl)-5-methylpyrazine-2-carboxamide

Conditions	Yield
Multi-step reaction with 2 steps 1.1: dmap; phthalic anhydride / pyridine / 5 h / Reflux; Inert atmosphere 2.1: sodium hydride / tetrahydrofuran; mineral oil 2.2: 15 h / 20 °C / Inert atmosphere View Scheme

Upstream product

• 88-12-0 1-ethenyl-2-pyrrolidinone 
• 5521-55-1 2-methylpyrazin-5-carboxylic acid 
• 108-91-8 cyclohexylamine 
• 56379-88-5 cyclohexylcarbamic acid phenyl ester 
• 33288-71-0 N-[2-[4-(amino-sulfonyl)phenyl]ethyl]-5-methylpyrazinecarboxamide 
• 201230-82-2 carbon monoxide 
• 258262-54-3 tert-butyl (4-sulfamoyl phenethyl)carbamate 
• 35303-76-5 4-(2-aminoethyl)benzenesulfonamide 
• 2015-16-9 N-(4-[2-amino-ethyl]-benzenesulfonyl)-N'-cyclohexyl urea 
• 41110-33-2 5-methylpyrazine-2-carboxylic acid methyl ester 

Downstream Products

• 33288-71-0 N-[2-[4-(amino-sulfonyl)phenyl]ethyl]-5-methylpyrazinecarboxamide 
• 468055-52-9 C₂₁H₂₇N₅O₄S*C₄₂H₇₀O₃₅ 
• 848488-95-9 DTPA-glipizide 

Relevant academic research and scientific papers

Total Synthesis of Glipizide and Glibenclamide in Continuous Flow

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.

PROCESS FOR PREPARATION OF GLIPIZIDE

The present invention discloses a simple, economic, consistent, commercially viable and industrially applicable process for preparation of Glipizide in high yield and highly pure Glipizide having purity more than 95%, preferably more than 96%, more preferably more than 98% and most preferably more than 99%.

Preparation method of glipizide

The invention relates to a preparation method of glipizide. The method takes 4-[2-(5-methylpyrazine-2-formylamino)ethyl]benzenesulfonamide as a raw material, the material is subjected to a chlorination reaction, and then under existence of an iron catalyst, the material, carbon monoxide and cyclohexylamine are subjected to a reaction to obtain the product. The method is simple and practicable, and provides a novel process route for synthesis of glipizide.

OSMOTIC PUMP CONTROLLED RELEASE TABLET AND PREPARATION METHOD THEREOF

An osmotic pump controlled release tablet and the preparation method thereof are disclosed. The osmotic pump controlled release tablet is composed of tablet core, semipermeable membrane and optional film coating. The material of said semipermeable membrane is composed of ethyl cellulose and povidone in the ratio of 1:1~1:4 by weight. Said tablet core comprises drug containing layer and push layer. The osmotic pump controlled release tablet also characterizes in that; (1) the angle θ1 formed by the outer curved surface of the drug containing layer and the lateral surface is 120°-180°; and/or (2) the ratio of L1 to r is 0.27-1.0, wherein L1 is the vertical distance from the central vertex of the outer curved surface of the drug containing layer to the plane formed by the intersection line between the outer curved surface of the drug containing layer and the lateral surface, and r is the radius of the tablet core.

OSMOTIC PUMP CONTROLLED RELEASE TABLET AND PREPARATION METHOD THEREOF

An osmotic pump controlled release tablet and the preparation method thereof are disclosed. The osmotic pump controlled release tablet is composed of tablet core, semipermeable membrane and optional film coating. The material of said semipermeable membrane is composed of ethyl cellulose and povidone in the ratio of 1:1?1:4 by weight. Said tablet core comprises drug containing layer and push layer. The osmotic pump controlled release tablet also characterizes in that; (1) the angle θ1 formed by the outer curved surface of the drug containing layer and the lateral surface is 120°-180°; and/or (2) the ratio of L1 to r is 0.27-1.0, wherein L1 is the vertical distance from the central vertex of the outer curved surface of the drug containing layer to the plane formed by the intersection line between the outer curved surface of the drug containing layer and the lateral surface, and r is the radius of the tablet core.

USE OF SUBSTITUTED 2 PHENYLBENZIMIDAZOLES AS MEDICAMENTS

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

Combinations comprising dipeptidylpeptidase-iv inhibitor

The invention relates to a combination which comprises a DPP-IV inhibitor and at least one further antidiabetic compound, preferably selected from the group consisting of insulin signalling pathway modulators, like inhibitors of protein tyrosine phosphatases (PTPases), non-small molecule mimetic compounds and inhibitors of glutamine-fructose-6-phosphate amidotransferase (GFAT), compounds influencing a dysregulated hepatic glucose production, like inhibitors of glucose-6-phosphatase (G6Pase), inhibitors of fructose-1,6-bisphosphatase (F-1,6-BPase), inhibitors of glycogen phosphorylase (GP), glucagon receptor antagonists and inhibitors of phosphoenolpyruvate carboxykinase (PEPCK), pyruvate dehydrogenase kinase (PDHK) inhibitors, insulin sensitivity enhancers, insulin secretion enhancers, α-glucosidase inhibitors, inhibitors of gastric emptying, insulin, and α2-adrenergic antagonists, for simultaneous, separate or sequential use in the prevention, delay of progression or treatment of conditions mediated by dipeptidylpeptidase-IV (DPP-IV), in particular diabetes, more especially type 2 diabetes mellitus, conditions of impaired glucose tolerance (IGT), conditions of impaired fasting plasma glucose, metabolic acidosis, ketosis, arthritis, obesity and osteoporosis; and the use of such combination for the cosmetic treatment of a mammal in order to effect a cosmetically beneficial loss of body weight.

Glipizide-cyclodextrin inclusion complexes and their pharmaceutical composition

Inclusion complexes of glipizide and a nonionic surfactant with cyclodextrin and cyclodextrin derivatives. A method of preparing the inclusion complexes of glipizide and a nonionic surfactant with cyclodextrin and cyclodextrin derivatives, by wetting cyclodextrin or a derivative thereof with a nonionic surfactant, and mixing the resulting mixture with glipizide. A pharmaceutical composition containing an inclusion complex of glipizide and a nonionic surfactant with cyclodextrin and cyclodextrin derivatives, in combination with pharmaceutically acceptable excipients.