Gemfibrozil

Gemfibrozil

CAS: 25812-30-0

 5-(2,5-Dimethylphenoxy)-2,2-dimethylpentanoic acid

2,2-dimethyl-5-(2,5-xylyloxy)valeric acid

Manufacturers' Codes: CI-719

Trademarks: Decrelip (Ferrer); Genlip (Teofarma); Gevilon (Pfizer); Lipozid (Pfizer); Lipur (Pfizer); Lopid (Pfizer)

MF: C15H22O3

MW: 250.33

Percent Composition: C 71.97%, H 8.86%, O 19.17%

Properties: Crystals from hexane, mp 61-63°. bp0.02 158-159°. LD50 in mice, rats (mg/kg): 3162, 4786 orally (Kurtz).

Melting point: mp 61-63°

Boiling point: bp0.02 158-159°

Toxicity data: LD50 in mice, rats (mg/kg): 3162, 4786 orally (Kurtz)

Therap-Cat: Antilipemic.

Gemfibrozil

5-(2,5-Dimethylphenoxy)-2,2-dimethylpentanoic Acid

Gemfibrozil is classified as a fibric acid derivative and is used in the treatment of hyperlipidaemias. It has effects on plasma-lipid concentrations similar to those described under bezafibrate. The major effects of gemfibrozil have been a reduction in plasma-triglyceride concentrations and an increase in high-density lipoprotein (HDL) cholesterol concentrations. A reduction in very-low-density lipoprotein (VLDL)-triglyceride appears to be largely responsible for the fall in plasma triglyceride although reductions in HDL and low-density lipoprotein (LDL)-triglycerides have also been reported.

The effects of gemfibrozil on total cholesterol have been more variable: in general, LDL-cholesterol may be decreased in patients with pre-existing high concentrations and raised in those with low concentrations. The increase in HDL-cholesterol concentrations has resulted in complementary changes to the ratios of HDL-cholesterol to LDL-cholesterol and to total cholesterol. Gemfibrozil has successfully raised HDL-cholesterol concentrations in patients with isolated low levels of HDL-cholesterol but otherwise normal cholesterol concentrations.The Helsinki heart study assessed gemfibrozil for the primary prevention of ischaemic heart disease in middle-aged men with hyperlipidaemia. The usual dose, by mouth, is 1.2 g daily in two divided doses given 30 min before the morning and evening meals. Gemfibrozil is available as tablets for oral administration (Lopid: USP).

IR (KBr, cm^–1): 2959.03, 2919.78, 2877.65, 1709.42, 1613.44, 1586.60, 1511.07, 1473.81, 1414.01, 1387.89, 1317.61, 1286.34, 1271.91, 1214.39, 1159.26, 1048.83, 996.57, 803.75;

¹H NMR (DMSO, 500 MHz, δ ppm): 1.12 (s, 6H), 1.60 and 1.67 (m, 4H), 2.08 (s, 3H), 2.24 (s, 3H), 3.90 (t, 2H), 6.62 (d, 1H), 6.70 (s, 1H), 6.97 (d, 1H);

¹³C NMR and DEPT (DMSO, 500 MHz, δ ppm): 15.39 (CH₃), 20.94 (CH₃), 24.67 (CH₂), 24.87 (CH_3, CH₃), 36.43 (CH₂), 40.91 (C), 67.57 (CH₂), 112.07 (CH), 120.45 (CH), 122.44 (C), 129.96 (CH), 135.93 (C), 156.43 (C), 178.56 (C);

MS M/_Z (ESI): 251.16 [(MH)⁺].

Solvent:CDCl3Instrument Type:JEOLNucleus:1HFrequency:400 MHzChemical Shift Reference:TMS

¹H NMR spectrum of C₁₅H₂₂O₃ in CDCL3 at 400 MHz

Gemfibrozil is the generic name for an oral drug used to lower lipid levels. It belongs to a group of drugs known as fibrates. It is most commonly sold as the brand name, Lopid. Other brand names include Jezil and Gen-Fibro.

history

Gemfibrozil was selected from a series of related compounds synthesized in the laboratories of the American company Parke Davisin the late 1970s. It came from research for compounds that lower plasma lipid levels in humans and in animals.^[1]

Actions

• Is an activator of peroxisome proliferator-activated receptor-alpha (PPARα), a nuclear receptor that is involved in metabolism ofcarbohydrates and fats, as well as adipose tissue differentiation. This increase in the synthesis of lipoprotein lipase thereby increases the clearance of triglycerides.^{[citation needed]}

Therapeutic effects

• Reduce triglyceride levels ^[2]
• Reduce very low density lipoprotein (VLDL) levels
• Modest reduction of low density lipoprotein (LDL) levels
• Moderate increase in high density lipoprotein (HDL) levels

Nontherapeutic effects and toxicities

• GI distress
• Musculoskeletal pain
• Increased incidence of gallstone
• Hypokalemia (low blood potassium)
• Increased risk of cancer

Indications

• Hyperlipidemia (Type III): Gemfibrozil is the drug of choice for therapy.
• Hypertriglyceridemia (Type IV): Gemfibrozil, though not as effective as niacin, is better tolerated.^{[citation needed]}

Contraindications and precautions

• Gemfibrozil should not be given to these patients:
  • Hepatic dysfunction
• Gemfibrozil should be used with caution in these higher risk categories:
  • Biliary tract disease
  • Renal dysfunction
  • Pregnant women
  • Obese patients

Drug interactions

• Anticoagulants: Gemfibrozil potentiates the action of warfarin and indanedione anticoagulants.^{[citation needed]}
• Statin drugs: Concomitant administration of fibrates (including gemfibrozil) with statin drugs increases the risk of muscle cramping, myopathy, andrhabdomyolysis.
• Gemfibrozil inhibits the activation of the liver's Cytochrome P450 system, reducing hepatic metabolism of many drugs, and prolonging their half lives and duration of action.
  • Drugs metabolized by the Cytochrome P450 system include:
    • Many antidepressants
    • Many antipsychotics
    • Many antiepileptics
    • Theophylline and other methylxanthine drugs
    • Several anesthetic agents
    • Oral contraceptive pills
    • Statins
    • Warfarin

Environmental data

Gemfibrozil has been detected in biosolids (the solids remaining after wastewater treatment) at concentrations up to 2650 ng/g wet weight.^[3] This indicates that it survives the wastewater treatment process.

SYNTHESIS

The sodium isobutyrate (I) is metallated with lithium diisopropylamide, and the resulting compound is alkylated with 3- (2,5-dimethylphenoxy) propyl bromide.

PATENT

Paul, L. C. 2,2-Dimethyl-ω-aryloxy alkanoic acids and salts and ester thereof. U.S. 3,674,836, 1972.

http://www.google.co.in/patents/US3674836

CLIP

Production of Gemfibrozil(1)2,5-Dimethylphenol and 1-Bromo-3-chloropropane reaction of 1-(2,5-dimethylphenoxy)-3-chloropropane. The reaction is carried out in toluene, adding new clean off reflux 5h. Just as follows:

(2)N/A can be used to manufacture Gemfibrozil.

PAPER

Improved Process for Preparation of Gemfibrozil, an Antihypolipidemic

Suri Babu Madasu†‡, N. A. Vekariya*†, Hero Velladurai†, Aminul Islam†, Paul Douglas Sanasi‡, and Raghu Babu Korupolu‡

^† Chemical Research and Development, Aurobindo Pharma Ltd., Survey No. 71 and 72, Indrakaran (V), Sangareddy (M), Medak District-502329, Andhra Pradesh, India

^‡ Engineering Chemistry Department, AU College of Engineering, Andhra University, Visakhapatnam-530003, Andhra Pradesh, India

Org. Process Res. Dev., 2013, 17 (7), pp 963–966

DOI: 10.1021/op400034f, http://pubs.acs.org/doi/full/10.1021/op400034f

*E-mail: navekariya1@rediffmail.com.

An improved process for the preparation of gemfibrozil, an antihypolipodimic drug substance, with an overall yield of 80% and ∼99.9% purity (including three chemical reactions) is reported. Formation and control of possible impurities are also described. Finally, gemfibrozil is isolated from water without any additional solvent purification.

Literature References:

Serum lipid regulating agent. Prepn: P. L. Creger, DE 1925423; eidem, US 3674836 (1969, 1972, both to Parke, Davis).

Production: O. P. Goel, US 4126637 (1978 to Warner-Lambert).

Pharmacology: A. H. Kissebach et al.,Atherosclerosis 24, 199 (1976); M. T. Kahonen et al., ibid. 32, 47 (1979).

Series of articles on metabolism, clinical pharmacology, kinetics and toxicology: Proc. R. Soc. Med. 69, Suppl 2, 1-120 (1976).

Toxicity data: S. M. Kurtz et al., ibid. 15.

Clinical trial in hyperlipidemia: J. E. Lewis et al., Pract. Cardiol. 9, 99 (1983).

Clinical reduction of cardiovascular risk in patients with low HDL levels: H. B. Rubins et al., N. Engl. J. Med. 341, 410 (1999).

References

1.  Rodney, G; et al. (1976). "The Hypolipidemic Effect of Gemfibrozil (CI-719) in Laboratory Animals". Proc. roy. Soc. Med. 69 (Supplement 2): 6–9. PMC 1864017. PMID 828263.
2.  "Gemfibrozil." WebMD.com Accessed 14 June 2014. http://www.webmd.com/drugs/drug-11423-gemfibrozil+oral.aspx
3.  http://water.epa.gov/scitech/wastetech/biosolids/tnsss-overview.cfm

External links

• DrugBank Gemfibrozil
• NIH Gemfibrozil Drug Info
• Lopid International Study
• Author (2004). "Safety of Statins". Circulation. 109: III–50–III–57. doi:10.1161/01.cir.0000131519.15067.1f.
• http://www.ihs.gov/nptc/documents/NPTC%20Lipid%20Review.pdf

Gemfibrozil

Systematic (IUPAC) name
5-(2,5-dimethylphenoxy)-2,2-dimethyl-pentanoic acid
Clinical data
Trade names	Lopid
AHFS/Drugs.com	Monograph
MedlinePlus	a686002
Pregnancy category	Category C
Routes of administration	Oral
Legal status
Legal status	By Prescription
Pharmacokinetic data
Bioavailability	Close to 100%
Protein binding	95%
Metabolism	Hepatic (CYP3A4)
Biological half-life	1.5 hours
Excretion	Renal 94% Feces 6%
Identifiers
CAS Number	25812-30-0
ATC code	C10AB04 (WHO)
PubChem	CID 3463
IUPHAR/BPS	3439
DrugBank	DB01241
ChemSpider	3345
UNII	Q8X02027X3
KEGG	D00334
ChEBI	CHEBI:5296
ChEMBL	CHEMBL457
Chemical data
Formula	C15H22O3
Molar mass	250.333 g/mol

LOPID® (gemfibrozil tablets, USP) is a lipid regulating agent. It is available as tablets for oral administration. Each tablet contains 600 mg gemfibrozil. Each tablet also contains calcium stearate, NF; candelilla wax, FCC; microcrystalline cellulose, NF; hydroxypropyl cellulose, NF; hypromellose, USP; methylparaben, NF; Opaspray white; polyethylene glycol, NF; polysorbate 80, NF; propylparaben, NF; colloidal silicon dioxide, NF; pregelatinized starch, NF. The chemical name is 5-(2,5-dimethylphenoxy)2,2-dimethylpentanoic acid, with the following structural formula:

The empirical formula is C₁₅H₂₂O₃ and the molecular weight is 250.35; the solubility in water and acid is 0.0019% and in dilute base it is greater than 1%. The melting point is 58° –61°C. Gemfibrozil is a white solid which is stable under ordinary conditions.

/////////Gemfibrozil,  Antilipemic,  Fibrates, 25812-30-0,

CC1=CC(OCCCC(C)(C)C(O)=O)=C(C)C=C1

Grünersee, Grüner See, 

Austria

Grüner See

Lake in Austria

Grüner See is a lake in Styria, Austria in a village named Tragöß. The lake is surrounded by the Hochschwab Mountains and forests. The name "Green Lake" originated because of its emerald-green water. Wikipedia

Parent range: Alps

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