cyclopentyl 3-{2-methoxy-4-[(o-tolylsulfonyl)carbamoyl]benzyl}-1-methyl-1H-indol-5-ylcarbamate 107753-78-6
Matassa, V.G. et al, J. Med. Chem., v. 33, 1781 (1990);
U. S. Patent No. 4,859,692;
U. S. Patent No. 5,993,859;
http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020547s031lbl.pdf
Zafirlukast is an oral leukotriene receptor antagonist (LTRA) for the maintenance treatment of asthma, often used in conjunction with an inhaled steroid and/or long-acting bronchodilator. It is available as a tablet and is usually dosed twice daily. Another leukotriene receptor antagonist is montelukast (Singulair), taken once daily. Zileuton (Zyflo), also used in the treatment of asthma via its inhibition of 5-lipoxygenase, is taken four times per day.
Zafirlukast blocks the action of the cysteinyl leukotrienes on the CysLT1 receptors, thus reducing constriction of the airways, build-up of mucus in the lungs andinflammation of the breathing passages.
Zafirlukast is marketed by Astra Zeneca with the brand names Accolate, Accoleit, and Vanticon. It was the first LTRA to be marketed in the USA and is now approved in over 60 countries, including the UK, Japan, Taiwan, Italy, Spain, Canada, Brazil, China and Turkey
Healthy young men who received a single oral 40 mg dose attained peak plasma zafirlukast concentrations that averaged 607 μg/L at 3.4 hours. The elimination half-life ranged from 12 to 20 hours. In another study involving a 20 mg single oral dose in healthy men, the elimination half-life averaged 5.6 hours.[1][2]
A letter was submitted to the FDA by Zeneca Pharmaceuticals on July 22, 1997, notifying them of a change in product labeling that includes the following potential reaction in patients undergoing a dosage reduction of oral steroids who are currently taking zafirlukast:
PRECAUTIONS-Eosinophilic Conditions: The reduction of the oral steroid dose, in some patients on ACCOLATE therapy, has been followed in rare cases by the occurrence of eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy sometimes presenting as Churg–Strauss syndrome, a systemic eosinophilic vasculitis. Although a causal relationship with ACCOLATE has not been established, caution is required when oral steroid reduction is being considered.1
NDA..020547 26/09/1996, ACCOLATE, ASTRAZENECA, 20MG TABLET
US Patent No | Expirey Date | patent use code |
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5482963 | Jan 9, 2013 | |
5612367 | Mar 18, 2014 | U-189 |
Brief background information
Salt | ATC | Formula | MM | CAS |
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– | R03DC01 | C 31 H 33 N 3 O 6 S | 575.69 g / mol | 107753-78-6 |
monohydrate | R03DC01 | C 31 H 33 N 3 O 6 S · H 2 O | 593.70 g / mol | 143052-93-1 |
calcium (2: 1) | R03DC01 | C 62 H 64 CaN 6 O 12 S 2 | 1189.43 g / mol | 107753-86-6 |
Application
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antihistamine effect
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LTD4-antagonist
Classes of substances
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Benzenesulfonamide (s -imidy), as well as their derivatives
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Esters of carbamic acid
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Cyclopentanes
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Hydroxybenzoic acid amides, and hydroxy acids alkoksibenzoynyh
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Indoles
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Zafirlukast is a synthetic, selective peptide leukotriene receptor antagonist (LTRA), with the chemical name 4(5-cyclopentyloxy-carbonylamino-1-methyl-indol-3ylmethyl)-3-methoxy-N-o-tolylsulfonylbenzamide. The molecular weight of zafirlukast is 575.7 and the structural formula is:
Zafirlukast, a fine white to pale yellow amorphous powder, is practically insoluble in water. It is slightly soluble in methanol and freely soluble in tetrahydrofuran, dimethylsulfoxide, and acetone.The empirical formula is: C31H33N3O6S
- Fischer JD, Song MH, Suttle AB, Heizer WD, Burns CB, Vargo DL, Brouwer KL. Comparison of zafirlukast (Accolate) absorption after oral and colonic administration in humans. Pharmaceut. Res. 17: 154-159, 2000.
- Bharathi DV, Naidu A, Jagadeesh B, Laxmi KN, Laxmi PR, Reddy PR, Mullangi R. Development and validation of a sensitive LC-MS/MS method with electrospray ionization for quantitation of zafirlukast, a selective leukotriene antagonist in human plasma: application to a clinical pharmacokinetic study. Biomed. Chromatogr. 22: 645-653, 2008.
- Zafirlukast (U.S. National Library of Medicine)
- Zafirlukast (patient information)
Systematic (IUPAC) name | |
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cyclopentyl 3-{2-methoxy-4-[(o-tolylsulfonyl)carbamoyl]benzyl}-1-methyl-1H-indol-5-ylcarbamate | |
Clinical data | |
Trade names | Accolate |
AHFS/Drugs.com | monograph |
MedlinePlus | a697007 |
Pregnancy cat. | B1 (Australia), B (United States) |
Legal status | POM (UK) |
Routes | Oral |
Pharmacokinetic data | |
Bioavailability | Unknown |
Protein binding | 99% |
Metabolism | Hepatic (CYP2C9-mediated) |
Half-life | 10 hours |
Excretion | Biliary |
Identifiers | |
CAS number | 107753-78-6 |
ATC code | R03DC01 |
PubChem | CID 5717 |
IUPHAR ligand | 3322 |
DrugBank | DB00549 |
ChemSpider | 5515 |
UNII | XZ629S5L50 |
KEGG | D00411 |
ChEBI | CHEBI:10100 |
ChEMBL | CHEMBL603 |
Chemical data | |
Formula | C31H33N3O6S |
Mol. mass | 575.676 g/mol |
Trade Names
Country | Trade name | Manufacturer |
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United Kingdom | Akkolat | AstraZeneca |
Italy | Akkoleit | – “- |
Zafirst | Chiesi | |
Japan | Akkolat | AstraZeneca |
USA | – “- | Zeneca |
Ukraine | No | No |
Formulations
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Tablets of 20 mg, 40 mg
is a first anti-asthmatic leukotriene antagonist (Matassa, V.G. et al, J. Med. Chem., v. 33, 1781 ‘(1990); U. S. Patent No. 4,859,692 and The Merck Index, 12th Edition, 10241). Methods for the preparation of Zafirlukast are described in J. Med. Chem., v. 33, 1781 (1990), U. S. Patent 4,859,692 and U.S. Patent 5,993,859 starting from methyl 3-methoxy-4-(l-methyl-5-nitroindol-3-ylmethyl)benzoate [la]
in the presence of an equivalent quantity of silver(I) oxide,
The above process has serious disadvantages in the isolation of the product [4] in step (b) which is due to the fact that alkylation of indole, that is unsubstituted at positions 1-, 2- and 3-, at the 3-position, is accompanied by the undesired process of poly alkylation, to form polysubstituted indoles of formula [7] and/or formula [8] :
while at the same time some quantity of the starting unreacted indole remains in the reaction mixture. Most common methods for the separation of alkyl (indol-3-ylmethyl)benzoate of formula [4] from by-products of polyalkylation and starting unreacted indole, which are all covalent compounds with similar physical properties, include column chromatography that is an unpractical method for industrial scale applications.
Formula (I) compound for the synthesis of an important intermediate of zafirlukast.Reported in the patent EP199543 synthesized compound (I) of the conventional method, the following formula:
(A) (I)
In this method, Intermediate A and 5 – nitro-indole silver oxide in the presence of a catalyst, for docking composite formula (I) compound. Reported only 45% of the reaction yield, the reaction is difficult to complete the reaction and post-treatment using chromatographic methods, resulting in product purification more difficult. And the use of more expensive silver oxide catalysts, high cost.
W00246153 reported a catalyst for the above reaction to zinc bromide, Compound (I), after treatment of the compound (I) with sodium hydroxide hydrolysis of the intermediate (B), separating the product and raw materials purification products.
The method reported in the literature a yield of 60%, but the actual operation is repeated only about 30% yield, and the operation is complicated, cumbersome and costly.
zaafirlukast is a selective and competitive receptor antagonist of leukotriene D4 and E4 (LTD4 and LTE4), components of slow-reacting substance of anaphylaxis (SRSA). Cysteinyl leukotriene production and receptor occupation have been correlated with the pathophysiology of asthma, including airway edema, smooth muscle constriction, and altered cellular activity associated with the inflammatory process, which contribute to the signs and symptoms of asthma.
The cysteinyl leukotrienes (LTC4 LTD4, LTE4) are the products of arachidonic acid metabolism and are various cells, including mast cells and eosinophills, these eicosinoids bind to cysteinyl leukotriene (CysLT) receptors. The CysLT type-1 (CysLT1) receptor is found in human airway and other pro-inflammatory cells. CysLTs have been correlated with the pathophysiology of asthma.
Zafirlukast is a synthetic, selective peptide leukotriene receptor antagonist (LTRA), useful for the treatment of asthma and is commercially available in products sold under the brand name ACCOLATE™ as 10 and 20 mg tablets for oral administration. ACCOLATE™ is indicated for the prophylaxis and treatment of asthma in adults and children 5 years of age and older.
ACCOLATE™ film coated tablets contain amorphous zafirlukast as the active ingredient and the excipients croscarmellose sodium, lactose, magnesium stearate, microcrystalline cellulose, povidone, hypromellose, and titanium dioxide.
The greatest prevalence of asthma is in preschool children; however, the clinical utility of asthma therapy for this age group is limited by a narrow therapeutic index, long-term tolerability, and frequency and/or difficulty of administration. Asthma treatment requires an immediate perceivable effect. Inhalation therapy is a very common therapy prescribed for young children; inhalation therapy has the disadvantage of high dose variability.
An Improved and Scalable Process for Zafirlukast: An Asthma Drug
Melting range: 142−145 °C; MS (m/z): 576 (M+ + H); IR (KBr, cm−1): 3326 (NH), 1679 (−C═O), 1H NMR (CDCl3) δ 7.0−8.0 (m, 11H), 3.7 (s, 3H), 4.0 (s, 2H), 3.9 (s, 3H), 2.6 (s, 3H), 1.45−1.8 (s, 9H). ……………………………………………………………….. US 20040186300 A1 http://www.google.com/patents/US20040186300 zafirlukast ethanolate as white powder with mp 132-133° C. (dec.) and 99.8% purity by HPLC. 1H NMR (CDCl3, δ, ppm): 1.22 (t, J 7.05 Hz, 3H), 1.45-1.87 (m, 8H), 2.66 (s, 3H), 3.67 (s, 3H), 3.73 (q, J 7.05 Hz, 4H), 3.79 (s, 3H), 3.98 (s, 2H), 5.08-5.23 (m, 1H), 6.58 (s, 1H), 6.73 (s, 1H), 7.01-7.51 (m, 9H), 8.23 (d, J 7.52 Hz, 1H), 9.67 (s, 1H).
Synthesis pathway
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Synthesis a)
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US 4,859,692 (ICI; 08/22/1989; GB -prior. 4/17/1985; 17.10.1985).
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EP 199 543 (ICI, Zeneca; appl. 16.4.1986; GB -prior. 4/17/1985).
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Synthesis of b)
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EP 490 649 (ICI, Zeneca; 11.12.1991; GB -prior. 12.12.1990).
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Matassa, G. et al .: J. Med. Chem. (JMCMAR) 33, 1781 (1990).
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Srinivas, K. et al .: Org. Process Res. Dev. (OPRDFK) 8 (6), 952 (2004).
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added info Asthma is a disease that causes swelling and narrowing the airways of the lungs. Airways are air carriers to and from lungs. Swollen and narrower airways affect the air flow to and from the lungs and this lead to tightness of chest, wheezing, shortness of breath and cough. These symptoms are often occurs in early morning and in night. Asthma is caused by genetic and environmental factors, it was not curable completely but this can be controlled with good medical care. Leukotriene antagonists also known as leukast are the medicaments that are used to reduce leukotrienes, which are produced by several types of cells and causes inflammation in asthma and bronchitis. Leukotriene antagonists that are available in market are Montelukast, Zafirlukast and Pranlukast. Zafirlukast is the first leukast compound approved for management of Asthma. US FDA approved zafirlukast in the form of 10 mg and 20 mg tablet with the brand name of Accolate®.1 Subsequently this was approved and launched by innovator in few other countries. There are many synthetic routes for the preparation of Zafirlukast 4 is well documented in literature. Some of the key approaches are discussed here under. Scientists from ICI Americas Inc2 have reported process for the synthesis of 4, which starts with esterification of 3-methoxy-4-methyl benzoic acid 53 using methanol in presence of acetyl chloride PRODUCT PATENT ROUTE Allylic bromination of methyl ester 54 using bromine in presence of CCl4 resulted bromo compound 55, which was reacted with 5-nitro indole 124 using silver oxide as catalyst to obtain condensed compound 125. N-methylation of 125 utilizing methyl iodide in presence of NaH afforded N-methyl indole derivative 57. Thus obtained 57 was subjected to reduction using palladium carbon (Pd/C) in methanol followed by reacted with cyclopentyl chloroformate to obtain compound 59. Hydrolysis of 59 using LiOH.H2O subsequently reaction with o-toluene sulfonamide (OTSA) in presence of 1-[3-(dimethylamino)propyl]-3-ethyl carbodiimide hydrochloride (DMAPEC) and DMAP furnished zafirlukast 4. Matassa et al3 also reported similar procedure for the synthesis of Zafirlukast 4.
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