93479-97-1

Basic information

• Product Name: Glimepiride
• Synonyms: AMARYL;3-ETHYL-2,5-DIHYDRO-4-METHYL-N-[2-[4-[[[[(TRANS-4-METHYLCYCLOHEXYL)AMINO]CARBONYL]AMINO]SULFONYL]PHENYL]ETHYL]-2-OXO-1H-PYRROLE-1-CARBOXAMIDE;3-ETHYL-2,5-DIHYDRO-4-METHYL-N-[2-[4-[[[[(TRANS-4-METHYLCYCLOHEXYL)AMINO]CARBONYL]AMINO]SULFONYL]PHENYL]ETHYL]-2-OXO-1H-PYRROLE-1-CARBOXYAMIDE;Gliclazide(diamicron);CLIMEPIRIDE;Glimpiride;3-Ethyl-2,5-dihydro-4-methyl-N-[2-[4-[[[[trans-4-methylcyclohexyl)amino]carbonyl]amino]sulfonyl]phenyl]ethyl]-2-oxo-1H-pyrrole-1-carboxyamide;1H-Pyrrole-1-carboxamide, 3-ethyl-2,5-dihydro-4-methyl-N-2-4-(trans-4-methylcyclohexyl)aminocarbonylaminosulfonylphenylethyl-2-oxo-
• CAS NO: 93479-97-1
• Molecular Formula: C₂₄H₃₄N₄O₅S
• Molecular Weight: 490.62
• EINECS: 642-919-5
• Product Categories: Active Pharmaceutical Ingredients;APIs;Intermediates & Fine Chemicals;Pharmaceuticals;Monovalent Ion Channels;Potassium Channel Modulators;Voltage-gated Ion Channels;API's;Chiral Reagents;Heterocycles;Sulfur & Selenium Compounds;API;NEURONTIN;Diabetes Research
• Mol File: 93479-97-1.mol

Chemical Properties

• Melting Point: 212.2-214.5 °C
• Appearance: white/solid
• Density: 1.29 g/cm³
• Refractive Index: 1.599
• Storage Temp.: Room temp
• Solubility: DMSO: >10 mg/mL
• PKA: 5.10±0.10(Predicted)
• Water Solubility: DMSO: >10 mg/mL
• Merck: 14,4440
• CAS DataBase Reference: Glimepiride(CAS DataBase Reference)
• NIST Chemistry Reference: Glimepiride(93479-97-1)
• EPA Substance Registry System: Glimepiride(93479-97-1)

Safety Data

• Hazard Codes: Xn,Xi
• Statements: 21-36/38-46-62-63
• Safety Statements: 25-26-36/37-53
• WGK Germany: 3
• RTECS: UX9363950
• Hazardous Substances Data: 93479-97-1(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
Glimepiride is used as an antidiabetic agent for the treatment of noninsulin-dependent (type 2) diabetes mellitus. It is effective in lowering blood glucose levels and can be used either as monotherapy or in combination with insulin.
Glimepiride is used as a potent KIR channel blocker and anti-diabetic agent for inhibiting pinacidil-activated cardiac Kir6 channels with an IC50 of 6.8 nM.
Used in Diabetes Management:
Glimepiride is used to increase osteoblast proliferation and differentiation, which is thought to be related to its ability to activate the PI3K and Akt pathway. It also enhances intrinsic peroxisome proliferator-activated receptor γ activity and increases protein expression of glucose transports 1 and 4.
Used in Combination Therapy:
Glimepiride is used for concomitant use with insulin for the treatment of noninsulin-dependent (type 2) diabetes mellitus, providing an additional option for managing blood glucose levels in patients who require more than one medication to control their diabetes.
Used in Prevention of Diabetes Complications:
Glimepiride can decrease the chances that someone will develop complications of type 2 diabetes, such as kidney damage, blindness, nerve problems, loss of limbs, sexual function problems, and heart attack or stroke.
Glimepiride is available only with a doctor's prescription and can be used along with a proper diet and exercise program. It may also be used in combination with other antidiabetic medicines if needed. The drug is manufactured by Sanofi-Aventis and was approved by the FDA in 1995.

References

1. https://en.wikipedia.org/wiki/Glimepiride 2. http://www.webmd.com/drugs/2/drug-12271/glimepiride-oral/details 3. https://www.drugs.com/cdi/glimepiride.html 4. http://www.medicinenet.com/glimepiride/article.htm 5. http://www.everydayhealth.com/drugs/glimepiride 6. http://www.emedicinehealth.com/drug-glimepiride/article_em.htm 7. https://www.ghc.org/kbase/topic.jhtml?docId=d03864a1 8. http://www.emedicinehealth.com/drug-glimepiride/article_em.htm 9. http://drugs.healthgrove.com/l/3454/Glimepiride

Originator

Hoechst Marion Roussel (Germany)

Manufacturing Process

By heating of a mixture of 3-ethyl-4-methyl-2-pyrrolone and 2- phenylethylisocyanate at 150°C is obtained 3-ethyl-4-methyl-2-oxo-3- pyrroline-1-(N-2-phenylethyl)-carboxamide, melting point 106°-108°C. Then the carboxamide are introduced in portions at 30°C into chlorosulfonic acid, and agitated for 1 hour at 40°C. The sulfochloride (melting point 172-175°C), introduced into concentrated ammonia, and heated for 30 min on a steam bath. The mixture of sulfonamide obtained (melting point 180°-182°C), of acetone and K2CO3 are refluxed with agitation for 6 hours. Subsequently the cyclohexyl isocyanate are added dropwise, and agitation is continued for 6 hours at boiling temperature. After standing overnight, the product is filtered, the crystals obtained are treated with dilute hydrochloric acid, and again filtered. It is prepared N-(4-[2-(3-ethyl-4-methyl-2-oxo-3-pyrroline-1- carboxamido)ethyl]benzenesulfonyl)-N'-cyclohexyl urea; melting point 185°- 187°C (from acetone) (Glimepiride).

Biological Activity

Potent K ATP channel blocker and anti-diabetic agent. Inhibits pinacidil-activated cardiac K ATP channels with an IC 50 of 6.8 nM.

Biochem/physiol Actions

Glimepiride is a potent blocker of cardiac KATP channels activated by pinacidil with an IC50 of 6.8 nM.

Veterinary Drugs and Treatments

Glimepiride may potentially be a useful adjunct in the treatment of non-insulin dependent diabetes mellitus (NIDDM) in cats. Its duration of action in humans allows it to be dosed once daily, which could be of benefit in cats. It may also have fewer side effects than glipizide in cats.

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 and miconazole and possibly voriconazole. Lipid-regulating drugs: possibly additive hypoglycaemic effect with fibrates. Sulfinpyrazone: enhanced effect of sulphonylureas.

Metabolism

The drug is extensively metabolised in the liver to two main metabolites. The cytochrome P450 isoenzyme CYP2C9 is involved in the formation of a hydroxy derivative, which is further metabolised to a carboxy derivative by cytosolic enzymes. About 60% of a dose is eliminated in the urine and 40% in the faeces.

InChI:InChI=1/C24H34N4O5S/c1-4-21-17(3)15-28(22(21)29)24(31)25-14-13-18-7-11-20(12-8-18)34(32,33)27-23(30)26-19-9-5-16(2)6-10-19/h7-8,11-12,16,19H,4-6,9-10,13-15H2,1-3H3,(H,25,31)(H2,26,27,30)/t16-,19?

Synthetic route

(1R,4R)-1-isocyanato-4-methylcyclohexane (32175-00-1) + N-{2-[4-(aminosulfonyl)phenyl]ethyl}-3-ethyl-4-methyl-2-oxo-2,5-dihydro-1H-pyrrole-1-carboxamide (119018-29-0) → glimepiride (93479-97-1)

Conditions	Yield
Stage #1: (1R,4R)-1-isocyanato-4-methylcyclohexane; N-{2-[4-(aminosulfonyl)phenyl]ethyl}-3-ethyl-4-methyl-2-oxo-2,5-dihydro-1H-pyrrole-1-carboxamide With potassium carbonate In acetonitrile at 50 - 60℃; for 6h; Stage #2: With water at 70 - 75℃; for 4h;

3-ethyl-4-methyl-3-pyrrolin-2-one (766-36-9) → glimepiride (93479-97-1)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: toluene / 2 h / 120 - 130 °C / Industrial scale 2.1: chlorosulfonic acid / dichloromethane / -5 - 30 °C 3.1: ammonium hydroxide / methanol / 2 h / 20 - 30 °C / Industrial scale 4.1: potassium carbonate / acetonitrile / 6 h / 50 - 60 °C 4.2: 4 h / 70 - 75 °C View Scheme

phenethyl isocyanate (1943-82-4) → glimepiride (93479-97-1)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: toluene / 2 h / 120 - 130 °C / Industrial scale 2.1: chlorosulfonic acid / dichloromethane / -5 - 30 °C 3.1: ammonium hydroxide / methanol / 2 h / 20 - 30 °C / Industrial scale 4.1: potassium carbonate / acetonitrile / 6 h / 50 - 60 °C 4.2: 4 h / 70 - 75 °C View Scheme

3-ethyl-4-methyl-2-oxo-N-(2-phenylethyl)-2,5-dihydro-1H-pyrrole-1-carboxamide (247098-18-6) → glimepiride (93479-97-1)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: chlorosulfonic acid / dichloromethane / -5 - 30 °C 2.1: ammonium hydroxide / methanol / 2 h / 20 - 30 °C / Industrial scale 3.1: potassium carbonate / acetonitrile / 6 h / 50 - 60 °C 3.2: 4 h / 70 - 75 °C View Scheme

Upstream product

• 32175-00-1 (1R,4R)-1-isocyanato-4-methylcyclohexane 
• 119018-29-0 N-{2-[4-(aminosulfonyl)phenyl]ethyl}-3-ethyl-4-methyl-2-oxo-2,5-dihydro-1H-pyrrole-1-carboxamide 
• 1943-82-4 phenethyl isocyanate 
• 247098-18-6 3-ethyl-4-methyl-2-oxo-N-(2-phenylethyl)-2,5-dihydro-1H-pyrrole-1-carboxamide 
• 622-24-2 2-phenylethyl chloride 
• 766-36-9 3-ethyl-4-methyl-3-pyrrolin-2-one 
• 2523-55-9 trans-4-methylcyclohexanamine 

Downstream Products

• 127554-90-9 carboxyglimepiride 
• 848488-97-1 DTPA-glimepiride 
• 620610-05-1 3-ethyl-2,5-dihydro-4-methyl-N-[2[4-[[[(trans-4-methylcyclohexyl)amino]carbonyl]aminosulfonyl]phenyl]ethyl]-2,2-difluoro-1H-pyrrole-1-N-carboxamide 
• 127554-90-9 C₂₄H₃₂N₄O₇S 

Relevant articles and documents

Preparation method of high-purity glimepiride

The invention discloses a preparation method of high-purity glimepiride. The preparation method comprises the following specific steps: 1, adding 1-[4-[2-(3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido)-ethyl]-benzenesulfonamide and potassium carbonate into a mixed solvent, and raising the temperature to dissolve the added substances; and 2, carrying out cooling crystallization on a solution obtained in step 1, and filtering the cooled solution to obtain 1-[4-[2-(3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido)-ethyl]-benzenesulfonyl]-3-(trans-4-methylcyclohexyl)-urea. The glimepiride obtained by the preparation method has a purity of above 99.9% and a high yield, impurity research is sufficient and controllable, the crystal form is correct, and the preparation product quality is good,so the use requirements of people are met.

Preparation method of hypoglycemic drug-glimepiride

The invention discloses a preparation method of a hypoglycemic drug-glimepiride. The chemical name of the hypoglycemic drug-glimepiride is 1-[4-[2-(3-ethyl-4-methyl-2-oxo-3-pyrroline-1-formamido)-ethyl]-benzenesulfonyl]-3-(trans-4- methyl cyclohexyl)-urea, the chemical formula of the hypoglycemic drug-glimepiride is C24H34N4O5S, and the structural formula of the hypoglycemic drug-glimepiride is described in the description. The preparation method is simple in process, short in synthetic route and high in yield, and especially increases the yield of 2-(3-ethyl-4-methyl-2-oxo-3-pyrroline-1-formamido)ethyl benzene sulfonic acid greatly; the application of chlorosulfonic acid has great influence on a sulfonation effect; compared with sulfonating agents such as concentrated sulfuric acid and fuming sulfuric acid which are used in the prior art, the chlorosulfonic acid has higher sulfonating capacity, so that the production of the glimepiride is further facilitated; the preparation method iseasy in obtaining of raw materials, economical and environment-friendly, high in product yield and product purity, and beneficial to industrialization.

Process for synthesizing glimepiride raw material medicine

The invention discloses a process for synthesizing a glimepiride raw material medicine. A compound A, namely 3-ethyl-4-methyl-3-pyrroline-2-ketone and a compound B, namely 2-phenethyl isocyanate are taken as start raw materials. The process is characterized in that when an intermediate 1 is synthesized, filtrate is applied mechanically, so that the loss of the intermediate 1 can be reduced, the yield can be increased, and the production efficiency can be improved; when an intermediate 2 is synthesized, hydrochloric ether is adopted as a solvent, so that isomer impurities can be greatly reduced, the content of the isomer impurities can be reduced to 0.5% or less from 8%, and later purification procedures can be simple to operate; when a glimepiride metallic salt is synthesized, acetonitrileis adopted as a solvent, sufficient reactions can be achieved, the reaction time can be greatly shortened, the residue of an intermediate 3 is reduced to 0.2% or less from 5-10%, in addition, a highsolvent recycling rate can be achieved. The process disclosed by the invention is simple and safe, low in production cost, high in yield, stable in intermediate and finished product quality and applicable to industrial large-scale production and hypoglycemic drug, namely glimepiride, synthesis processes with relatively great social, economic and environmental-friendly benefits.

An Efficient and Practical Process for the Synthesis of Glimepiride

A novel and simple approach to the synthesis of glimepiride is reported. It involves the preparation of a carbamate of 3-ethyl-4-methyl-1 H -pyrrol-2(5 H)-one, followed by its reaction with 4-(2-aminoethyl)benzenesulfonamide to produce the intermediate sulfonamide. This sulfonamide, upon reaction with phenyl (trans -4-methylcyclohexyl)carbamate, gave glimepiride. This process avoids the use of phosgene, isocyanates, or chloroformates. Furthermore, sulfonation of the aryl group was eliminated, rendering the product free of the impurities reported in earlier processes.

Method for manufacture of compounds related to the class of substituted sulfonyl urea anti-diabetics

The present invention relates to a process for preparation of sulfonyl urea compounds in high conversion rates and purity. More specifically, this invention relates to a process for manufacture of sulfonyl urea class of anti-diabetic pharmaceutical drugs in higher purity and yield. The process may effectively and economically be used to produce anti-diabetic drugs, such as glimepiride, glipizide, gliclazide, glibenclamide, glibornuride, and glisoxepide.

A NOVEL PROCESS FOR PREPARATION OF SUBSTANTIALLY PURE GLIMEPIRIDE

The present invention discloses a novel process for purification of trans-4-methyl cyclohexylamine HC1 and 4-[2-(3-Ethyl-4-methyl-2-carbonyl pyrrolidine amido) ethyl] benzene sulfonamide used in the synthesis of 3-Ethyl-2,5-dihydro-4-methyl-N-[2-[4-[[[[(trans-4-methyl cyclohexyl)amino]carbonyl]amino]sulfonyl]phenyl]ethyl]-2-oxo-1H-pyrrole-1-carboxamide(I), popularly known as Glimepiride. The present invention also discloses a novel purification of Glimepiride Form I (I), having the undesired cis isomer below 0.15%. Glimepiride (I) is useful in the treatment of diabetes mellitus.

Method for the Manufacture of Compounds Related to the Class of Substituted Sulphonyl Urea Anti-Diabetics

A process for the formation of high purity sulphonyl urea compounds in high throughput conditions. The sulphonyl urea compounds are preferably the pharmaceutically useful anti-diabetic drugs such as Glimepiride, Gliclazide, Glipizide, Glibenclamide, Glibornuride, Glisoxepide etc, where the purity and economy of the compound are of utmost importance.

A PROCESS FOR PURIFICATION

The present invention provides a process for purification of pharmaceutically active compounds selected from the group consisting of thiazolidinedione derivatives and trans-3-Ethyl-2,5-dihydro-4-methyl-N- [2-[4-[[[[(4-methylcyclohexyl)amino] carbonyl] amino]sulfonyl]phenyl]ethyl]-2-oxo-1H-pyrrole-1-carboxamide comprising extraction in a solvent comprising an alkanol (C1-C4) and ammonia.

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.