Rosiglitazone

Rosiglitazone Property

Melting point:

153-155 C

Boiling point:

585.0±35.0 °C(Predicted)

Density 

1.315±0.06 g/cm3(Predicted)

storage temp. 

2-8°C

solubility 

DMSO: ≥10mg/mL

pka

6.34±0.50(Predicted)

form 

powder

color 

White to Off-White

Merck 

14,8265

InChI

InChI=1S/C18H19N3O3S/c1-21(16-4-2-3-9-19-16)10-11-24-14-7-5-13(6-8-14)12-15-17(22)20-18(23)25-15/h2-9,15H,10-12H2,1H3,(H,20,22,23)

InChIKey

YASAKCUCGLMORW-UHFFFAOYSA-N

SMILES

S1C(CC2=CC=C(OCCN(C)C3=NC=CC=C3)C=C2)C(=O)NC1=O

CAS DataBase Reference

122320-73-4(CAS DataBase Reference)

IARC

3 (Vol. 108) 2016

Safety

Hazard Codes 

Xi

Risk Statements 

36/38

Safety Statements 

26-37/39

WGK Germany 

3

RTECS 

XJ5813850

HS Code 

2934100000

Hazardous Substances Data

122320-73-4(Hazardous Substances Data)

Hazard and Precautionary Statements (GHS)

Symbol(GHS)

Signal word

Warning

Hazard statements

H319Causes serious eye irritation

H361Suspected of damaging fertility or the unborn child

H410Very toxic to aquatic life with long lasting effects

Precautionary statements

P201Obtain special instructions before use.

P202Do not handle until all safety precautions have been read and understood.

P264Wash hands thoroughly after handling.

P264Wash skin thouroughly after handling.

P273Avoid release to the environment.

P280Wear protective gloves/protective clothing/eye protection/face protection.

P281Use personal protective equipment as required.

P305+P351+P338IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continuerinsing.

P308+P313IF exposed or concerned: Get medical advice/attention.

P391Collect spillage. Hazardous to the aquatic environment

P405Store locked up.

P501Dispose of contents/container to..…

Rosiglitazone Chemical Properties,Usage,Production

Description

Rosiglitazone is a type of thiazolidinedione antidiabetics. Thiazolidinedione are agonists for peroxisome-proliferator–activated receptor γ (PPAR-γ). PPAR-γ receptors are ligand-activated nuclear transcription factors that modulate gene expression, lowering blood glucose primarily by increasing insulin sensitivity in peripheral tissues.
Rosiglitazone is widely used to lower blood glucose levels in patients with type 2 diabetes mellitus. Rosiglitazone functionalizes by makes the cells of the body more sensitive to the naturally produced insulin in body. It shouldn’t be used if the patient is injecting or inhaling insulin. Using rosiglitazone with insulin could increase the risk of heart failure. Patients having heart failure with symptoms or moderate to severe heart failure should not use Rosiglitazone.

References

[1] http://www.nejm.org/doi/full/10.1056/NEJMoa072761#t=article
[2] http://circ.ahajournals.org/content/128/8/785
[3] https://www.drugs.com/cdi/rosiglitazone.html

Chemical Properties

Crystallized from methanol, melting point 153-155°C.

Uses

antidiabetic

Uses

A potent and selective PPARγ agonist.

Uses

Rosiglitazone is an insulin sensitizer; binds to peroxisome proliferator activated receptor gamma (PPAR- γ).

Indications

Rosiglitazone is approved for use as monotherapy and in conjunction with metformin, though it is sometimes combined with a sulfonylurea or insulin. It is usually taken once or twice a day with or without food. Rosiglitazone may cause a modest increase in lowdensity lipoprotein and triglyceride concentrations, but it is unclear whether this effect has any clinical significance or persists in the long term.

Definition

ChEBI: Rosiglitazone is an aminopyridine and a member of thiazolidinediones. It has a role as an insulin-sensitizing drug, a ferroptosis inhibitor and an EC 6.2.1.3 (long-chain-fatty-acid--CoA ligase) inhibitor. It is a conjugate acid of a rosiglitazone(1-).

brand name

Avandia (GlaxoSmithKline).

General Description

Rosiglitazone is 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione, and is availableas the maleate salt in tablets containing the drug alone(Avandia) or in combination products with metformin(Avandamet) or with glimepiride (Avandaryl). The2-aminopyridine moiety allows for salt formation; the marketedformulations contain the 1:1 salt with maleic acid, inwhich the pyridine nitrogen accepts a proton, forming the2-aminopyridinium species.

General Description

Rosiglitazone, (±)-5-[[4-[2-(methyl-2-pyridinylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione(Avandia), is a white to off-white solid with pKavalues of 6.8 and 6.1. Rosiglitazone is readily soluble inethanol and a buffered aqueous solution with pH of 2.3; solubilitydecreases with increasing pH in the physiologicalrange. The molecule has a single chiral center and is presentas a racemate. Even so, the enantiomers are functionally indistinguishablebecause of rapid interconversion.

Biological Activity

rosiglitazone is a potent agonist of peroxisome proliferator-activated receptor γ (pparγ), a subfamily of the nuclear-receptor superfamily which is predominately expressed in adipose tissue and regulates gene expression responding to ligand binding. belonging to the thiazolidinedione (tzd) class, rosiglitazone, like other tzd members, binds to pparγ dna as heterodimers and activate transcription of various metabolic regulators involved in the differentiation of stem cells into adipocytes and increased expression of genes regulating the metabolism of glucose and lipid. rosiglitazone is used to treat patients with type ii diabetes mellitus for its strong ability to improve insulin sensitization through its effects either on fatty acid uptake and storage in adipose tissue or on adiokines.peter j. cox, david a. ryan, frank j. hollis, ann-marie harris, ann k. miller, marika vousden and hugh cowley. absorption, disposition, and metabolism of rosiglitazone, a potent thiazolidinedione insulin sensitizer, in humans. drug metabolism and disposition 2000; 28 (7): 772-780adie vilioen and alan sinclair. safety and efficacy of rosiglitazone in the elderly diabetic patient. vascular health and risk management 2009: 5 389-395

Biochem/physiol Actions

Rosiglitazone is a potent agonist for PPARγ with an EC50 of 43 nM for the human receptor. It is antidiabetic, working as an insulin sensitizer by binding to the PPARγ receptors in fat cells and making the cells more responsive to insulin.

Clinical Use

Although rosiglitazone is extensively biotransformed—playing the major role in both transformations, and some involvementof CYP2C9.21,47 The sulfate conjugate M10 is thepredominant circulating metabolite by 4-hour postdose. Theextraordinarily high plasma protein binding of this metabolite(and the N-demethylated sulfate conjugate M4) in humans accountsfor the lengthy residence time of the radioactivity in thebody, despite the relatively short pharmacokinetic half-life(4–4.5 hours) of rosiglitazone itself.

Synthesis

[1] Preparation of catalyst: 1.2 g of cobalt(II) chloride hexahydrate was dissolved in 120 ml of N,N-dimethylformamide (DMF), followed by the addition of 8.0 g of dimethylethylene dioxime. Stirring was done until a clarified blue-green solution was formed. [2] Preparation of reducing agent solution: 27.2 g of sodium borohydride was slowly dissolved in 300 ml of 0.1 M sodium hydroxide solution at room temperature with continuous stirring. [3] Reduction reaction: 16.8 g of sodium hydroxide was dissolved in 1200 ml of distilled water, followed by the addition of 120 g of rosiglitazone EPO benzylidene derivative. The mixture was stirred until complete dissolution and heated to 55±5°C. Once the temperature was reached, the catalyst solution (1/5 volume of the solution prepared in step [1] for about 1 min) was added dropwise, followed by the reductant solution (1/5 volume of the solution prepared in step [2] for about 2 min). The reaction was maintained at 55 ± 5 °C with stirring for 50 min. The addition of catalyst and reducing agent (1/5 of the previous volume each time) was repeated four times, maintaining 55±5°C stirring for 50 min after each addition. [4] Crude product isolation: the reaction mixture was kept at 55±5°C and 300 ml of ethyl acetate was added with vigorous stirring, followed by the slow addition of 260 ml of 1:1 hydrochloric acid. No external heating was required and 55±5°C was maintained. Slowly add 600 ml of 10% sodium bicarbonate solution. The suspension was stirred and slowly cooled to 30-40°C for about 20 minutes and filtered. The filter cake was washed sequentially with 6 x 200 ml of water and 3 x 200 ml of ethanol. Vacuum dried to constant weight to obtain crude rosiglitazone base I, melting point 153-155°C, yield 93% (HPLC purity 99.0%, cobalt residue 11 μg/g). [5] Crystallization and purification: 110 g of crude rosiglitazone base I was dissolved in 200 ml of acetic acid and heated at 70-80°C for 15 min. Add ethanol according to the following procedure: add 250 ml of ethanol within 5 min and filter at 65°C; slowly cool the filtrate to 57°C and stir for 15 min; continue to cool to 50°C and stir for 20 min; quickly add 250 ml of ethanol and stir at 45°C for 10 min; repeat the rapid addition of 250 ml of ethanol and stir at 38°C for 10 min; and finally add 250 ml of ethanol quickly and stir at 30°C for 10 minutes. In total, 1000 ml of ethanol was added over 70 minutes and the suspension was cooled to 30 °C. Filtration, the filter cake was washed with 2 x 150 ml ethanol and vacuum dried to give 90-95 g of white crystalline product with melting point 155-156°C (HPLC purity 99.90%, cobalt residue 1 μg/g). [6] Alternative crystallization method: 10110g of crude rosiglitazone base I was dissolved in 200ml acetic acid, and ethanol was added under stirring at 70-80°C according to the following procedure: 250ml ethanol was added within 5 minutes, and stirred at 75-70°C for 10 minutes; 250ml ethanol was added within 5 minutes, and stirred at 65-60°C for 20 minutes; 250ml ethanol was added quickly, and stirred at 55-50°C for 10 minutes; rapid addition of 250 ml ethanol, 45-40 ℃ stirring 10 minutes. In total, 1000 ml of ethanol was added over 1 hour and the suspension was cooled to 40°C. Filtration, the filter cake was washed with 2×150 ml ethanol and vacuum dried to give 92.2 g of white crystalline product in 83.8% yield (HPLC purity >99.95%, cobalt residue 1.5 μg/g). [7] Small scale crystallization: 12 g of crude rosiglitazone base I was dissolved in 200 ml of acetic acid and 250 ml of ethanol (75-78°C) was added within 5 min at 80°C with stirring.

storage

+4°C

References

[1] Chemistry - An Asian Journal, 2017, vol. 12, # 18, p. 2364 - 2368
[2] Tetrahedron, 2010, vol. 66, # 18, p. 3314 - 3317
[3] Patent: WO2006/125402, 2006, A1. Location in patent: Page/Page column 10-16
[4] Patent: WO2006/26934, 2006, A1. Location in patent: Page/Page column title page; 3; 7; 9
[5] Patent: WO2006/26934, 2006, A1. Location in patent: Page/Page column title page; 3; 7; 9