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Drug spotlight- Zafirlukast

December 3, 2013 4:09 am / 3 Comments on Drug spotlight- Zafirlukast

ZAFIRLIKAST

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
5482963	Jan 9, 2013
5612367	Mar 18, 2014	U-189

Brief background information

Salt	ATC	Formula	MM	CAS
–	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

antihistamine effect
LTD4-antagonist

Classes of substances

Benzenesulfonamide (s -imidy), as well as their derivatives
- Esters of carbamic acid
  - Cyclopentanes
    - Hydroxybenzoic acid amides, and hydroxy acids alkoksibenzoynyh
      - Indoles

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)

Zafirlukast
Systematic (IUPAC) name


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
United Kingdom	Akkolat	AstraZeneca
Italy	Akkoleit	– “-
Italy	Zafirst	Chiesi
Japan	Akkolat	AstraZeneca
USA	– “-	Zeneca
Ukraine	No	No

Formulations

Tablets of 20 mg, 40 mg

Zafirlukast, cyclopentyl 3 – [2-methoxy-4- [(o-tolylsulfonyl)carbamoyl]- benzyl]-l-methyIindole-5-carbamate, having the formula:

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]

Alkyl (l-alkylindol-3-ylmethyl)benzoates of formula [lb] are useful as chemical intermediates in the pharmaceutical industry.

These compounds may be obtained by a process described in J. Med. Chem., v. 33, 1781 (1990) and U. S. Patent 4,859,692. This process comprises the steps of:

(a) reacting an alkyl (halomethyl)benzoate of formula [2] with an equivalent amount of an indole of formula [3]

in the presence of an equivalent quantity of silver(I) oxide,

(b) isolating the alkyl (indol-3-ylmethyl)benzoates of formula [4] from the reaction mixture obtained in step (a) above,

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 (LTC₄LTD₄, 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.

……………………

Process for the preparation of zafirlukast
US 20040186300 A1

In comparison, the known process for the preparation of zafirlukast described in J. Med. Chem., v. 33, 1781 (1990) and U.S. Pat. No. 4,859,692 involves separation steps, e.g. column chromatography, that are not practical for industrial scale applications. The known process is summarized in Scheme 3:

,……………………………………………………..

An Improved and Scalable Process for Zafirlukast: An Asthma Drug

Gilla Goverdhan ,^{ET AL}

Research and Development, Integrated Product Development, Dr. Reddy’s Laboratories Ltd., Survey No.’s 42, 45, 46, and 54, Bachupally, Qutubullapur, Ranga Reddy District – 500 072, Andhra Pradesh, India, Institute of Science and Technology, Center for Environmental Science, J.N.T. University, Kukatpally, Hyderabad – 500 072, Andhra Pradesh, India, and Research and Development, Inogent Laboratories Private Limited (A GVK BIO Company), 28A, IDA, Nacharam, Hyderabad – 500 076, India

Org. Process Res. Dev., 2009, 13 (1), pp 67–72

DOI: 10.1021/op800137b

http://pubs.acs.org/doi/abs/10.1021/op800137b

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

Synthesis a)

Synthesis of b)

Synthesis a)
- US 4,859,692 (ICI; 08/22/1989; GB -prior. 4/17/1985; 17.10.1985).
- EP 199 543 (ICI, Zeneca; appl. 16.4.1986; GB -prior. 4/17/1985).
Synthesis of b)
- EP 490 649 (ICI, Zeneca; 11.12.1991; GB -prior. 12.12.1990).
- Matassa, G. et al .: J. Med. Chem. (JMCMAR) 33, 1781 (1990).
- Srinivas, K. et al .: Org. Process Res. Dev. (OPRDFK) 8 (6), 952 (2004).

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.

zafirlukast…….{3-[2-Methoxy-4-(toluene-2-sulfonylaminocarbonyl) benzyl]-1-methyl-1H-indol-5-yl} acetic acid cyclopentyl ester……………………………….Arie, G.; Genndy, N.; Igor, Z.; Victor, P.; Maxim, S. WO 02/46153 A2, 2002.

FDA okays Vifor Fresenius phosphate binder Velphoro

November 29, 2013 3:31 am / 3 Comments on FDA okays Vifor Fresenius phosphate binder Velphoro

THERAPEUTIC CLAIM Oral phosphate binder, treatement of elevated
phosphate levels in patients undergoing dialysis
CHEMICAL DESCRIPTIONS
1. Ferric hydroxide oxide
2. Mixture of iron(III) oxyhydroxide, sucrose, starches
3. Polynuclear iron(III) oxyhydroxide stabilized with sucrose and starches
structure
O =Fe -OH
MOLECULAR FORMULA FeHO2•xC12H22O11•y(C6H10O5)n

SPONSOR Vifor (International) Inc.
CODE DESIGNATIONS PA21
CAS REGISTRY NUMBER 12134-57-5

sucroferric oxyhydroxide

Sucroferric oxyhydroxide nonproprietary drug name

https://www.ama-assn.org/resources/doc/…/sucroferric–oxyhydroxide.pdf‎

1. February 27, 2013. N13/36. STATEMENT ON A NONPROPRIETARY NAME ADOPTED BY THE USAN COUNCIL. USAN (ZZ-19). SUCROFERRIC …

The US Food and Drug Administration has given the green light to Vifor Fresenius Medical Care Renal Pharma’s hyperphosphatemia drug Velphoro.

The approval for Velphoro (sucroferric oxyhydroxide), formerly known as PA21, is based on Phase III data demonstrated that the drug successfully controls the accumulation of phosphorus in the blood with the advantage of a much lower pill burden than the current standard of care in patients with chronic kidney disease on dialysis, namely Sanofi’s Renvela (sevelamer carbonate). read this at

http://www.pharmatimes.com/Article/13-11-28/FDA_okays_Vifor_Fresenius_phosphate_binder_Velphoro.aspx

Velphoro (PA21) receives US FDA approval for the treatment of hyperphosphatemia in Chronic Kidney Disease Patients on dialysis
Velphoro(sucroferric oxyhydroxide) has received US Food and Drug Administration (FDA) approval for the control of serum phosphorus levels in patients with Chronic Kidney Disease (CKD) on dialysis. Velphoro will be launched in the US by Fresenius Medical Care North America in 2014.

Velphoro (previously known as PA21) is an iron-based, calcium-free, chewable phosphate binder. US approval was based on a pivotal Phase III study, which met its primary and secondary endpoints. The study demonstrated that Velphoro^® successfully controls hyperphosphatemia with fewer pills than sevelamer carbonate, the current standard of care in patients with CKD on dialysis. The average daily dose to control hyperphosphatemia was 3.3 pills per day after 52 weeks.

Velphoro was developed by Vifor Pharma. In 2011, all rights were transferred to Vifor Fresenius Medical Care Renal Pharma, a common company of Galenica and Fresenius Medical Care. In the US, Velphorowill be marketed by Fresenius Medical Care North America, a company with a strong marketing and sales organization, and expertise in dialysis care. The active ingredient of Velphoro is produced by Vifor Pharma in Switzerland.

Hyperphosphatemia, an abnormal elevation of phosphorus levels in the blood, is a common and serious condition in CKD patients on dialysis. Most dialysis patients are treated with phosphate binders. However, despite the availability of a number of different phosphate binders, up to 50% of patients depending on the region are still unable to achieve and maintain their target serum phosphorus levels. In some patients, noncompliance due to the high pill burden and poor tolerability appear to be key factors in the lack of control of serum phosphorus levels. On average, dialysis patients take approximately 19 pills per day with phosphate binders comprising approximately 50% of the total daily pill burden. The recommended starting dose of Velphoro is 3 tablets per day (1 tablet per meal).

Full results from the pivotal Phase III study involving more than 1,000 patients were presented at both the 50^th ERA-EDTA (European Renal Association European Dialysis and Transplant Association) Congress in Istanbul, Turkey, in May 2013, and the American Society of Nephrology (ASN) Kidney Week in Atlanta, Georgia, in November 2013. Velphorowas shown to be a potent phosphate binder, with lower pill burden and a good safety profile.

Based on these data, Vifor Fresenius Medical Care Renal Pharma believes that Velphoro offers a new and effective therapeutic option for the control of serum phosphorus levels in patients with chronic kidney disease on dialysis.
The regulatory processes in Europe, Switzerland and Singapore are ongoing and decisions are expected in the first half 2014. Further submissions for approval are being prepared.

VBL Therapeutics announced FDA has granted Fast Track designation to its lead oncology drug VB-111

November 28, 2013 3:37 am / 1 Comment on VBL Therapeutics announced FDA has granted Fast Track designation to its lead oncology drug VB-111

GT-111
VB-111

GT-111 is a gene therapy product candidate in early clinical development for the treatment of advanced differentiated thyroid cancer, for the treatment of relapsed glioblastoma multiform and for the treatment of ovarian cancer.

patents, VBL Therapeutics

WO 2011083466, WO-2011083464, WO-2012052878

VBL Therapeutics announced today that the U.S. Food and Drug Administration (FDA) has granted Fast Track designation to its lead oncology drug VB-111, for prolongation of survival in patients with recurrent glioblastoma multiforme (rGBM).

VB-111 – highly targeted anti-angiogenic agent for the specific inhibition of tumor vascular growth

VB-111 is the first highly targeted anti-angiogenic agent for the specific inhibition of tumor vascular growth to use VTS™™, our proprietary platform technology, for cancer therapy. VB-111 is an IV-administered anti angiogenic agent that works in a manner akin to a “biological knife” to destroy tumor vasculature, thus cutting off blood vessels feeding the tumor.

Preclinical Insights

VB-111 has shown significant promise as a targeted cancer treatment with the potential to work synergistically in combination with conventional chemotherapy treatments to provide an effective treatment regimen for cancer patients. Pharmacological and toxicology studies of VB-111 have showed tissue specificity for the tumor tissue, no significant damage to normal non-cancerous tissues or to the normal vasculatures in the body and more than 90 percent tumor burden reduction in a metastatic lung cancer model with only one injection. Similar efficacy was shown in other tumor models.

Completed Clinical Trials

Phase 1 Clinical Trial – in a Phase 1 “all comers” dose escalation study in 33 patients with advanced metastatic cancer, therapeutic doses of VB-111 demonstrated antitumor activity and was found to be safe and well tolerated with no effect on liver function or major changes in complete blood count. Findings have been presented at the American Association of Cancer Research (AACR) and the American Society of Clinical Oncology (ASCO) annual meetings.

GSK obtains FDA approval for bird flu vaccine

November 27, 2013 4:33 am / 1 Comment on GSK obtains FDA approval for bird flu vaccine

GlaxoSmithKline (GSK) has received approval from the US Food and Drug Administration (FDA) for the first adjuvanted vaccine to prevent H5N1 influenza, also known as bird flu.

GSK obtains FDA approval for bird flu vaccine http://www.pharmaceutical-technology.com/news/newsgsk-obtains-fda-approval-bird-flu-vaccine?WT.mc_id=DN_News

26 November 2013

GlaxoSmithKline (GSK) has received approval from the US Food and Drug Administration (FDA) for the first adjuvanted vaccine to prevent H5N1 influenza, also known as bird flu.

The FDA cleared the pandemic Influenza A (H5N1) virus monovalent vaccine, adjuvanted (also referred to as Q-Pan H5N1 influenza vaccine), for use in people aged 18 and older who are at increased risk of exposure to the virus.

The vaccine is composed of monovalent, inactivated, split A/H5N1 influenza virus antigen and GSK’s AS03 adjuvant.

The company said that in clinical studies, the adjuvanted formulation stimulated the required immune response while using a smaller amount of antigen as compared with a formulation without adjuvant.

FDA Approves Olysio (simeprevir) for Hepatitis C Virus

November 26, 2013 4:02 am / 2 Comments on FDA Approves Olysio (simeprevir) for Hepatitis C Virus

Simeprevir

Inhibits HCV NS3/4A protease.

MEDIVIR … originator

launched 2013

923604-59-5 CAS

C38H47N5O7S MF

749.93908 MW

IUPAC standard name
(1R, 4R, 6S, 15R, 17R)-N-(cyclopropanesulfonyl) -17 – ({7-methoxy-8-methyl-2-[4 – (propan-2-yl) -1,3-thiazol-2 -yl] quinolin-4-yl} oxy)-13-methyl-2 ,14-dioxo-3 ,13-diazatricyclo [13.3.0.0 4 , 6 ] octadec-7-ene-4-carboxamide
IUPAC traditional name
(1R, 4R, 6S, 15R, 17R)-N-(cyclopropanesulfonyl) -17 – {[2 – (4-isopropyl-1 ,3-thiazol-2-yl)-7-methoxy-8-methylquinolin-4- yl] oxy}-13-methyl-2 ,14-dioxo-3 ,13-diazatricyclo [13.3.0.0 4 , 6 ] octadec-7-ene-4-carboxamide

Olysio
Simeprevir
TMC 435
TMC 435350
TMC-435
TMC435
TMC435350
UNII-9WS5RD66HZ

November 22, 2013 — The U.S. Food and Drug Administration approved Olysio (simeprevir), a new therapy to treat chronic hepatitis C virus infection.

OLYSIO™ is the first once-daily protease inhibitor approved for the treatment of chronic hepatitis C in a combination antiviral regimen for adults with compensated liver disease

Hepatitis C is a viral disease that causes inflammation of the liver that can lead to diminished liver function or liver failure. Most people infected with the hepatitis C virus have no symptoms of the disease until liver damage becomes apparent, which may take several years. Most of these people then go on to develop chronic hepatitis C. Some will also develop scarring and poor liver function (cirrhosis) over many years, which can lead to complications such as bleeding, jaundice (yellowish eyes or skin), fluid accumulation in the abdomen, infections or liver cancer. According to the Centers for Disease Control and Prevention, about 3.2 million Americans are infected with the hepatitis C virus

Hepatitis C virus (HCV) infections affect approximately 3 percent of the worldwide population and often lead to cirrhosis and hepatocellular carcinoma. The standard therapy of pegylated- interferon and ribavirin induces serious side effects and provides viral eradication in less than 50% of patients. Combination therapy of HCV including ribavirin and interferonare currently is the approved therapy for HCV. Unfortunately, such combination therapy also produces side effects and is often poorly tolerated, resulting in major clinical challenges in a significant proportion of patients. Numerous direct acting agents (DAAs) have been or are being developed for treatment of HCV, such as telaprevir and boceprevir (both received MA approved in 2011 for use with interferon and ribavirin based therapy), however direct acting agents are linked to increased toxicity of treatment, the emergence of resistance, and to date do not provide a standard of care which is interferon free. The combination of direct acting agents can also result in drug-drug interactions. To date, no HCV therapy has been approved which is interferon free. There is therefore a need for new combination therapies which have reduced side effects, and interferon free, have a reduced emergence of resistance, reduced treatment periods and/or and enhanced cure rates.

Simeprevir (formerly TMC435) is an experimental drug candidate for the treatment of hepatitis C. It is being developed byMedivir and Johnson & Johnson‘s pharmaceutical division Janssen Pharmaceutica and is currently in Phase III clinical trials.^[1]

Simeprevir is a hepatitis C virus protease inhibitor.^[2]

Simeprevir is being tested in combination regimens with pegylated interferon alfa-2a and ribavirin,^[3] and in interferon-free regimens with other direct-acting antiviral agents including daclatasvir^[4] and sofosbuvir ^[5]

Simeprevir has been launched in 2013 in Japan by Janssen Pharmaceutical (JP) for use in combination with pegylated interferon (Peg-IFN) and ribavirin for the treatment of genotype 1 chronic hepatitis C virus (HCV) patients who are treatment naïve, prior non responders or relapsed following treatment with Peg-IFN with or without ribavirin. In 2013, the product has also been approved in the U.S. by Medivir and Janssen R&D Ireland for the oral treatment of chronic hepatitis C genotype 1 infection, in combination with peginterferon alfa and ribavirin in adults with compensated liver disease, including cirrhosis, who are treatment-naïve or who have failed previous interferon therapy (pegylated or non-pegylated) with ribavirin.

The drug candidate was originally developed at Medivir, which was acquired by Janssen R&D Ireland in 2012. In November 2004, Medivir entered into a license and research collaboration agreement with Tibotec, a Johnson & Johnson subsidiary, for the discovery and development of orally active protease inhibitors of the NS3/4A protease of HCV. In 2011, a codevelopment agreement between Pharmasset (now Gilead Sciences) and Tibotec was signed for the treatment of chronic hepatitis C (HCV) in combination with PSI-7977. Also in 2011, fast track designation was received in the U.S. for the treatment of chronic hepatitis C (CHC) genotype-1 infection.

In 2011, Tibotec Therapeutics, Division of Centocor Ortho Biotech Products, L.P. announced that it had changed its name to Janssen Therapeutics, Division of Janssen Products, LP.

“Hepatitis C is a complex disease and Janssen is committed to working with the HCV community, caregivers, and health care systems to address this global epidemic,” said Gaston Picchio, Hepatitis Disease Area Leader, Janssen Research & Development. “We are pleased that the FDA has granted simeprevir Priority Review, as it is a significant step forward in making this therapy available to physicians and their hepatitis C patients.”

Hepatitis C virus (HCV) is the leading cause of chronic liver disease worldwide.

Following initial acute infection, a majority of infected individuals develop chronic hepatitis because HCV replicates preferentially in hepatocytes but is not directly cytopathic. Chronic hepatitis can progress to liver fibrosis leading to cirrhosis, end- stage liver disease, and HCC (hepatocellular carcinoma), making it the leading cause of liver transplantations. This and the number of patients involved, has made HCV the focus of considerable medical research. Replication of the genome of HCV is mediated by a number of enzymes, amongst which is HCV NS3 serine protease and its associated cofactor, NS4A. NS3 serine protease is considered to be essential for viral replication and has become an attractive target for drug discovery.

Current anti-HCV therapy is based on (pegylated) interferon-alpha (IFN-α) in combination with ribavirin. Not only does this therapy result in a limited efficacy in that only part of the patients are treated successfully, but it also faces significant side effects and is poorly tolerated in many patients. Hence there is a need for further HCV inhibitors that overcome the disadvantages of current HCV therapy such as side effects, limited efficacy, poor tolerance, the emergence of resistance, as well as compliance failures.

Various agents have been described that inhibit HCV NS3 serine protease. WO05/073195 discloses linear and macrocyclic NS3 serine protease inhibitors with a central substituted proline moiety and WO 05/073216 with a central cyclopentyl moiety. Amongst these, the macrocyclic derivatives are attractive by overcoming one or more of the disadvantages of current anti-HCV therapy

(I) simeprevir

The compound of formula (I) is an inhibitor of the Hepatitis C virus (HCV) serine protease and is described in WO 2007/014926, published on 8 February 2007. This compound overcomes several of the disadvantages of current anti-HCV therapy and in particular shows pronounced activity against HCV, has an attractive pharmacokinetic profile, and is well-tolerated. Following the synthesis procedure described in Example 5 of WO 2007/014926, an amorphous solid form is obtained.

It now has been found that the compound of formula (I) can be converted into crystalline forms, which can advantageously be used as active ingredients in anti-HCV therapy. To that purpose, these crystalline forms are converted into pharmaceutical formulations.

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SIMEPREVIR

…………………………

simeprevir

OLYSIO (simeprevir) is an inhibitor of the HCV NS3/4A protease.

The chemical name for simeprevir is (2R,3aR,10Z,11aS,12aR,14aR)-N-(cyclopropylsulfonyl)-2[[2-(4-isopropyl-1,3-thiazol-2-yl)-7-methoxy-8-methyl-4-quinolinyl]oxy]-5-methyl-4,14-dioxo2,3,3a,4,5,6,7,8,9,11a,12,13,14,14atetradecahydrocyclopenta[c]cyclopropa[g][1,6]diazacyclotetradecine-12a(1H)-carboxamide. Its molecular formula is C₃₈H₄₇N₅O₇S₂ and its molecular weight is 749.94. Simeprevir has the following structural formula:

OLYSIO (simeprevir) Structural Formula Illustration

Simeprevir drug substance is a white to almost white powder. Simeprevir is practically insoluble in water over a wide pH range. It is practically insoluble in propylene glycol, very slightly soluble in ethanol, and slightly soluble inacetone. It is soluble in dichloromethane and freely soluble in some organic solvents (e.g., tetrahydrofuran and N,N-dimethylformamide).

OLYSIO (simeprevir) for oral administration is available as 150 mg strength hard gelatin capsules. Each capsule contains 154.4 mg of simeprevir sodium salt, which is equivalent to 150 mg of simeprevir. OLYSIO (simeprevir) capsules contain the following inactive ingredients: colloidal anhydrous silica, croscarmellose sodium, lactose monohydrate, magnesium stearate and sodium lauryl sulphate. The white capsule contains gelatin and titanium dioxide (E171) and is printed with ink containing iron oxide black (E172) and shellac (E904).

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Synthesis

WO2008092954A2

Example 1 : preparation of 17-[2-(4-isopropylthiazole-2-yl)-7-methoxy-8-methyl- quinolin-4-yloxy]- 13-methyl-2, 14-dioxo-3, 13-diazatricyclo[ 13.3.0.0⁴‘⁶]octadec-7-ene- 4-carboxylic acid (16)

Synthesis of 4-hydroxy-2-(4-isopropylthiazole-2-yl)-7-methoxy-8-methylquinoline (6) Step 1 : synthesis of Λ/-(tert-butyloxycarbonyl)-3-methoxy-2-methylaniline (2)

¹ 2

Triethylamine (42.4 mL, 302 mmol) was added to a suspension of 3-methoxy-2- methylbenzoic acid (45.6 g, 274 mmol) in dry toluene (800 mL). A clear solution was obtained. Then, dppa (65.4 mL, 302 mmol) in toluene (100 mL) was slowly added. After 1 h at room temperature, the reaction mixture was successively heated at 50⁰C for 0.5 h, at 70⁰C for 0.5 h then at 100⁰C for 1 h. To this solution, t-BuOH (30.5 g, 411 mmol) in toluene (40 mL) was added at 100⁰C and the resulting mixture was refluxed for 7h. The solution was cooled to room temperature then successively washed with water, 0.5 N HCl, 0.5 N NaOH and brine, dried (Na₂SO₄), and evaporated to give 67 g of the target product: m/z = 237 (M)⁺.

_2: synthesis of 3-methoxy-2-methylaniline (3)

TFA (40.7 mL, 548 mmol) was added to a solution of jV-(teτt-butyloxycarbonyl)- 3-methoxy-2-methylaniline, in dichloro methane (500 mL). After 2 h at room temperature, TFA (40.7 mL, 548 mmol) was added and the resulting mixture was stirred at room temperature overnight. Then, volatiles were evaporated. The residue was triturated with toluene (100 mL) and diisopropylether (250 mL), filtered off and washed with diisopropyl ether (100 mL) to give 56.3 g of the title product as a TFA salt: m/z = 138 (M+H)⁺. The TFA salt was transformed to the free aniline by treatment with NaHCO₃.

Step 3: synthesis of (2-amino-4-methoxy-3-methylphenyl)(methyl)ketone (4)

A solution Of BCl₃ (1.0 M, 200 mL, 200 mmol) in CH₂Cl₂ was slowly added under nitrogen to a solution of 3-methoxy-2-methylaniline (26.0 g, 190 mmol) in xylene (400 mL). The temperature was monitored during the addition and was kept below 10⁰C. The reaction mixture was stirred at 5°C for 0.5 h. Then, dry acetonitrile (13 mL, 246 mmol) was added at 5°C. After 0.5 h at 5°C, the solution was transferred into a dropping funnel and slowly added at 5°C to a suspension OfAlCl₃ (26.7 g, 200 mmol) in CH₂Cl₂ (150 mL). After 45 min at 5°C, the reaction mixture was heated at 70⁰C under a nitrogen stream. After evaporation Of CH₂Cl₂, the temperature of the reaction mixture reached 65°C. After 12 h at 65°C, the reaction mixture was cooled at 0⁰C, poured onto ice (300 g), and slowly heated to reflux for 7h. After 2 days at room temperature, 6 N NaOH (50 mL) was added. The pH of the resulting solution was 2-3. The xylene layer was decanted. The organic layer was extracted with CH₂Cl₂. The xylene and CH₂Cl₂ layers were combined, successively washed with water, IN NaOH, and brine, dried (Na₂SO₄) and evaporated. The residue was triturated in diisopropyl ether at O⁰C, filtered off and washed with diisopropylether to give 13.6 g (40 %) of the title product as a yellowish solid: m/z = 180 (M+H)⁺.

Step 4: synthesis of 2′-[[(4-isopropylthiazole-2-yl)(oxo)methyl]amino]-4′-methoxy-3 ‘- methylacetophenone (5)

A solution of the compound 4 (18.6 g, 104 mmol) in dioxane (50 rnL) was added under nitrogen to a suspension of 4-isopropylthiazole-2-carbonyl chloride in dioxane (250 rnL). After 2 h at room temperature, the reaction mixture was concentrated to dryness. Then, the residue was partitioned between an aqueous solution of NaHCOs and AcOEt, organic layer was washed with brine, dried (Na₂SO₄), and evaporated. The residue was triturated in diisopropyl ether, filtered off and washed with diisopropyl ether to give 30.8 g (90 %) of the title product 5.

Step 5: synthesis of 4-hydroxy-2-(4-isopropylthiazole-2-yl)-7-methoxy-8- methylquinoline (6)

Potassium tert-butoxide (21.8 g, 195 mmol) was added to a suspension of the compound 5 (30.8 g, 92.7 mmol) in tert-butanol. The resulting reaction mixtures was heated at 100⁰C overnight. Then, the reaction mixture was cooled at room temperature and diluted with ether (100 mL). The precipitate was filtered off and washed with Et₂O to give a powder (fraction A). The mother liquor was concentrated in vacuo, triturated in ether, filtered off, and washed with ether to give a powder (fraction 2). Fractions 1 and 2 were mixed and poured into water (250 mL). The pH of the resulting solution was adjusted to 6-7 (control with pH paper) with HCl IN. The precipitate was filtered off, washed with water and dried. Then, the solid was triturated in diisopropyl ether, fϊltered off and dried to give 26 g (88%) of the compound 6 as a brownish solid: m/z = 315 (M+H)⁺.

Synthesis of (hex-5-enyl)(methyl)amine (8)

O CF,

FX N Br’ N O NH

H 7

(a) Sodium hydride (1.05 eq) was slowly added at 0⁰C to a solution of JV-methyl- trifluoro-acetamide (25 g) in DMF (140 mL). The mixture was stirred for Ih at room temperature under nitrogen. Then, a solution of bromohexene (32,1 g) in DMF

(25 mL) was added dropwise and the mixture was heated to 70⁰C for 12 hours. The reaction mixture was poured on water (200 mL) and extracted with ether (4 x 50 mL), dried (MgSO₄), filtered and evaporated to give 35 g of the target product 7 as a yellowish oil which was used without further purification in the next step.

(b) A solution of KOH (187.7 g) in water (130 mL) was added dropwise to a solution of 7 (35 g) in methanol (200 mL). The mixture was stirred at room temperature for

12 hours. Then, the reaction mixture was poured on water (100 mL) and extracted with ether (4 x 50 mL), dried (MgSO₄), filtered and the ether was distilled under atmospheric pressure. The resulting oil was purified by distillation under vacuum (13 mm Hg pressure, 50⁰C) to give 7,4 g (34 %) of the title product 8 as a colourless oil: ¹H-NMR (CDCl₃): δ 5.8 (m, IH), 5 (ddd, J = Yl 2 Hz, 3.5 Hz, 1.8 Hz, IH), 4.95 (m, IH), 2.5 (t, J = 7.0 Hz, 2H), 2.43 (s, 3H), 2.08 (q, J= 7.0 Hz, 2H), 1.4 (m, 4H), 1.3 (br s, IH).

Preparation of 17-[2-(4-isopropylthiazole-2-yl)-7-methoxy-8-methylquinolin-4-yloxyl- 13-methyl-2, 14-dioxo-3, 13-diazatricyclo[ 13.3.0.0⁴‘⁶loctadec-7-ene-4-carboxylic acid (16)

3-Oxo-2-oxa-bicyclo[2.2.1]heptane-5-carboxylic acid 9 (500 mg, 3.2 mmol) in 4 mL DMF was added at 0⁰C to HATU (1.34 g, 3.52 mmol) and JV-methylhex-5-enylamine (435 mg, 3.84 mmol) in DMF (3 mL), followed by DIPEA. After stirring for 40 min at 0⁰C, the mixture was stirred at room temperature for 5 h. Then, the solvent was evaporated, the residue dissolved in EtOAc (70 rnL) and washed with saturated NaHCOs (IO mL). The aqueous layer was extracted with EtOAc (2 x 25 mL). The organic phases were combined, washed with saturated NaCl (20 mL), dried (Na₂SO₄), and evaporated. Purification by flash chromatography (EtO Ac/petroleum ether, 2:1) afforded 550 mg (68%) of the target product 10 as a colorless oil: m/z = 252 (M+H)⁺.

A solution of LiOH (105 mg in 4 mlof water) was added at 0⁰C to the lactone amide 10. After Ih, the conversion was completed (HPLC). The mixture was acidified to pH 2 – 3 with IN HCl, extracted with AcOEt, dried (MgSO₄), evaporated, co-evaporated with toluene several times, and dried under high vacuum overnight to give 520 mg (88%) of the target product 11: m/z = 270 (M+H)⁺.

The l-(amino)-2-(vinyl)cyclopropanecarboxylic acid ethyl ester hydrochloride 12

(4.92 g, 31.7 mmol) and HATU (12.6 g, 33.2 mmol) were added to 11 (8.14 g,

30.2 mmol). The mixture was cooled in an ice bath under argon, and then DMF (100 mL) and DIPEA (12.5 mL, 11.5 mmol) were successively added. After 30 min at 0⁰C, the solution was stirred at room temperature for an additional 3 h. Then, the reaction mixture was partitioned between EtOAc and water, washed successively with 0.5 N HCl (20 mL) and saturated NaCl (2 x 20 mL), and dried (Na₂SO₄). Purification by flash chromatography (AcOEt/CH₂Cl₂/Petroleum ether, 1 :1 :1) afforded 7.41 g (60%) of the target product 13 as a colorless oil: m/z = 407 (M+H)⁺.

DIAD (1.02 niL, 5.17 mmol) was added at -15°C under nitrogen atmosphere to a solution of 13 (1.5 g, 3.69 mmol), quinoline 6 (1.39 g, 4.43 mmol) and triphenyl- phosphine (1.26 g, 4.80 mmol) in dry THF (40 mL). After 4.5 h, at -15°C, the reaction mixture was partitioned between ice-cold water and AcOEt, dried (Na₂SO₄) and evaporated. The crude material was purified by flash column chromatography (gradient of petroleum AcOEt/CH₂Cl₂, 1 :9 to 2:8) to give 1.45 g (56 %) of the target product 14: m/z = 703 (M+H)⁺.

A solution of 14 (1.07 g, 1.524 mmol) and Hoveyda-Grubbs 1^st generation catalyst (33 mg, 0.03 eq) in dried and degassed 1 ,2-dichloroethane (900 mL) was heated at 75°C under nitrogen for 12 h. Then, the solvent was evaporated and the residue purified by silica gel chromatography (25% EtOAc in CH₂Cl₂). 620 mg (60%) of pure macrocycle 15 were obtained, m/z = 674 (M+H)⁺. ¹H NMR (CDCl₃): 1.18-1.39 (m, 12H), 1.59 (m, IH), 1.70-2.08 (m, 5H), 2.28 (m, IH), 2.38 (m, IH), 2.62 (m, 2H), 2.68 (s, 3H), 2.83 (m, IH), 3.06 (s, 3H), 3.19 (sept, J= 6.7 Hz, IH), 3.36 (m, IH), 3.83 (m, IH), 3.97 (s, 3H), 4.09 (m, 2H), 4.65 (td, J= 4 Hz, 14 Hz, IH), 5.19 (dd, J= 4 Hz,

10 Hz, IH), 5.31 (m, IH), 5.65 (td, J= 4 Hz, 8 Hz, IH), 7.00 (s, IH), 7.18 (s, IH), 7.46

(d, J= 9 Hz, IH), 7.48 (s, IH), 8.03 (d, J= 9 Hz, IH).

A solution of lithium hydroxide (1.65 g, 38.53 mmol) in water (15 rnL) was added to a stirred solution of ester 15 (620 mg, 0.920 mmol) in THF (30 mL) and MeOH (20 mL). After 16 h at room temperature, the reaction mixture was quenched with NH₄Cl sat., concentrated under reduced pressure, acidified to pH 3 with HCl IN and extracted with CH₂Cl₂, dried (MgSO₄) and evaporated to give 560 mg (88%) of carboxylic acid 16. m/z = 647 (M+H)⁺. ¹H NMR (CDCl₃): 1.11-1.40 (m, 8H), 1.42-1.57 (m, 2H), 1.74 (m, 2H), 1.88-2.00 (m, 2H), 2.13 (m, IH), 2.28 (m, IH), 2.40 (m, IH), 2.59 (m, 2H), 2.67 (s, 3H), 2.81 (m, IH), 2.97 (s, 3H), 3.19 (m, IH), 3.31 (m, IH), 3.71 (m, IH), 3.96 (s, 3H), 4.56 (dt, J= 4 Hz, 12 Hz, IH), 5.23 (m, 2H), 5.66 (m, IH), 7.01 (s, IH), 7.10 (s, IH), 7.22 (d, J= IO Hz, IH), 7.45 (s, IH), 8.00 (d, J= 10 Hz, IH).

Example 2: Preparation of Λ/-[17-[2-(4-isopropylthiazole-2-yl)-7-methoxy-8-methyl- quinolin-4-yloxy]- 13-methyl-2, 14-dioxo-3, 13-diazatricyclo[ 13.3.0.0⁴‘⁶]octadec-7-ene- 4-carbonyll(cvclopropyl)sulfonamide (17) SIMEPREVIR

A solution of the compound 16 (560mg, 0.867 mmol) prepared according to Example 4, and carbonyldiimidazole (308 mg, 1.90 mmol) in dry THF (10 mL) was stirred at reflux under nitrogen for 2h. The reaction mixture was cooled to room temperature and cyclopropylsulfonamide (400 mg, 3.301 mmol) and DBU (286 mg, 1.881 mmol) were added. This solution was heated at 50⁰C for 15 h. Then, the reaction mixture was cooled down at room temperature and concentrated under reduced pressure. The residue was partitioned between CH₂Cl₂ and HCl 1 N, the organic layer was washed with brine, dried (MgSO₄) and evaporated. Purification by flash chromatography (gradient of EtOAc (0 to 25%) in CH₂Cl₂) afforded 314 mg of an off-white solid which was further washed with water, then isopropylether, and dried in the vacuum oven to deliver 282 mg (40%) of the pure title product 17, which is the compound of formula (I) SIMEPREVIR , as a white powder: m/z = 750 (M+H)⁺.

¹H NMR (CDCl₃): 0.99-1.52 (m, 14H), 1.64-2.05 (m, 4H), 2.77 (m, IH), 2.41 (m, 2H), 2.59 (m, 2H), 2.69 (s, 3H), 2.92 (m, 2H), 3.04 (s, 3H), 3.19 (m, IH), 3.40 (m, 2H), 3.98 (s, 3H), 4.60 (t, J= 13 Hz, IH), 5.04 (t, J= 11 Hz, IH), 5.37 (m, IH), 5.66 (m, IH), 6.21 (s, IH), 7.02 (s, IH), 7.22 (d, J= IO Hz, IH), 7.45 (s, IH), 7.99 (d, J= 10 Hz, IH), 10.82 (broad s, IH).

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SYNTHESIS

WO2007014926A1

Example 4: preparation of 17-[2-(4-isopropylthiazole-2-yl)-7-methoxy-8-methyl- quinolin-4-yloxy] – 13 -methyl-2, 14-dioxo-3 , 13 -diazatricyclo[ 13.3.0.0⁴‘⁶]octadec-7-ene- 4-carboxylic acid (46) FREE ACID

Synthesis of 4-hvdroxy-2-(4-isopropylthiazole-2-yl)-7-methoxy-8-methylquinoline (36) Step 1: synthesis of iV-(tert-butyloxycarbonyl)-3-methoxy-2-methylaniline (32)

31 32

Triethylamine (42.4 mL, 302 mmol) was added to a suspension of 3-methoxy-2- methylbenzoic acid (45.6 g, 274 mmol) in dry toluene (800 mL). A clear solution was obtained. Then, dppa (65.4 mL, 302 mmol) in toluene (100 mL) was slowly added. After 1 h at room temperature, the reaction mixture was successively heated at 50°C for 0.5 h, at 70°C for 0.5 h then at 100°C for 1 h. To this solution, t-BuOH (30.5 g, 411 mmol) in toluene (40 mL) was added at 100°C and the resulting mixture was refluxed for 7h. The solution was cooled to room temperature then successively washed with water, 0.5 N HCl, 0.5 N NaOH and brine, dried (Na₂SO₄), and evaporated to give 67 g of the target product: m/z = 237 (M)⁺.

Step 2: synthesis of 3-methoxy-2-methylaniline (33)

TFA (40.7 mL, 548 mmol) was added to a solution of iV-(tert-butyloxycarbonyl)-3- methoxy-2-methylaniline, in dichloromethane (500 mL). After 2 h at room temperature, TFA (40.7 mL, 548 mmol) was added and the resulting mixture was stirred at room temperature overnight. Then, volatiles were evaporated. The residue was triturated with toluene (100 mL) and diisopropylether (250 mL), filtered off and washed with diisopropyl ether (100 mL) to give 56.3 g of the title product as a TFA salt: m/z = 138 (M+H)⁺. The TFA salt was transformed to the free aniline by treatment with NaHCO₃.

Step 3: synthesis of (2-amino-4-methoxy-3-methylphenyl)(methyl)ketone (34)

A solution OfBCl₃ (1.0 M, 200 mL, 200 mmol) in CH₂Cl₂ was slowly added under nitrogen to a solution of 3-methoxy-2-methylaniline (26.0 g, 190 mmol) in xylene (400 mL). The temperature was monitored during the addition and was kept below 10°C. The reaction mixture was stirred at 5°C for 0.5 h. Then, dry acetonitrile (13 mL, 246 mmol) was added at 5°C. After 0.5 h at 5°C, the solution was transferred into a dropping funnel and slowly added at 5°C to a suspension OfAlCl₃ (26.7 g, 200 mmol) in CH₂Cl₂ (150 mL). After 45 min at 5°C, the reaction mixture was heated at 70°C under a nitrogen stream. After evaporation Of CH₂Cl₂, the temperature of the reaction mixture reached 65°C. After 12 h at 65°C, the reaction mixture was cooled at 0°C, poured onto ice (300 g), and slowly heated to reflux for 7h. After 2 days at room temperature, 6 N NaOH (50 mL) was added. The pH of the resulting solution was 2-3. The xylene layer was decanted. The organic layer was extracted with CH₂Cl₂. The xylene and CH₂Cl₂ layers were combined, successively washed with water, IN NaOH, and brine, dried (Na₂SO₄) and evaporated. The residue was triturated in diisopropyl ether at O⁰C, filtered off and washed with diisopropylether to give 13.6 g (40 %) of the title product as a yellowish solid: m/z = 180 (M+H)⁺.

Step 4: synthesis of 2′-[[(4-isopropylthiazole-2-yl)(oxo)methyl]amino]-4′-methoxy-3 ‘- methylacetophenone (35)

A solution of (2-amino-4-methoxy-3-methylphenyl)(methyl)ketone (18.6 g, 104 mmol) in dioxane (50 mL) was added under nitrogen to a suspension of 4-isopropylthiazole-2- carbonyl chloride in dioxane (250 mL). After 2 h at room temperature, the reaction mixture was concentrated to dryness. Then, the residue was partitioned between an aqueous solution OfNaHCO₃and AcOEt, organic layer was washed with brine, dried (Na₂SO₄), and evaporated. The residue was triturated in diisopropyl ether, filtered off and washed with diisopropyl ether to give 30.8 g (90 %) of the title product 35.

Step 5: synthesis of 4-hydroxy-2-(4-isopropylthiazole-2-yl)-7-methoxy-8- methylquinoline (36)

Potassium tert-butoxide (21.8 g, 195 mmol) was added to a suspension of 2′-[[(4-iso- propylthiazole-2-yl)(oxo)methyl]amino]-4′-methoxy-3′-methylacetophenone (35, 30.8 g, 92.7 mmol) in tert-butanol. The resulting reaction mixtures was heated at 100°C overnight. Then, the reaction mixture was cooled at room temperature and diluted with ether (100 mL). The precipitate was filtered off and washed with Et₂O to give a powder (fraction A). The mother liquor was concentrated in vacuo, triturated in ether, filtered off, and washed with ether to give a powder (fraction 2). Fractions 1 and 2 were mixed and poured into water (250 mL). The pH of the resulting solution was adjusted to 6-7 (control with pH paper) with HCl IN. The precipitate was filtered off, washed with water and dried. Then, the solid was triturated in diisopropyl ether, filtered off and dried to give 26 g (88%) of the title product 36 as a brownish solid: m/z = 315 (M+H)⁺.

Synthesis of (hex-5-enyl)(methyl)amine (38)

Sodium hydride (1.05 eq) was slowly added at 0°C to a solution of iV-methyltrifluoro- acetamide (25 g) in DMF (140 mL). The mixture was stirred for Ih at room temperature under nitrogen. Then, a solution of bromohexene (32,1 g) in DMF (25 mL) was added dropwise and the mixture was heated to 70°C for 12 hours. The reaction mixture was poured on water (200 mL) and extracted with ether (4 x 50 mL), dried (MgSO₄), filtered and evaporated to give 35 g of the target product 37 as a yellowish oil which was used without further purification in the next step.

Step B:

A solution of potassium hydroxide (187.7 g) in water (130 mL) was added dropwise to a solution of 37 (35 g) in methanol (200 mL). The mixture was stirred at room temperature for 12 hours. Then, the reaction mixture was poured on water (100 mL) and extracted with ether (4 x 50 mL), dried (MgSO₄), filtered and the ether was distilled under atmospheric pressure. The resulting oil was purified by distillation under vacuum (13 mm Hg pressure, 50°C) to give 7,4 g (34 %) of the title product 38 as a colourless oil: ¹H-NMR (CDCl₃): δ 5.8 (m, IH), 5 (ddd, J= 17.2 Hz, 3.5 Hz, 1.8 Hz, IH), 4.95 (m, IH), 2.5 (t, J= 7.0 Hz, 2H), 2.43 (s, 3H), 2.08 (q, J= 7.0 Hz, 2H), 1.4 (m, 4H), 1.3 (br s, IH).

Preparation of 17-r2-(4-isopropylthiazole-2-yl)-7-methoxy-8-methylquinolin-4-yloxyl-

13-methyl-2,14-dioxo-3,13-diazatricvclori3.3.0.0⁴‘⁶loctadec-7-ene-4-carboxylic acid

£46}

3-Oxo-2-oxa-bicyclo[2.2.1]heptane-5-carboxylic acid 39 (500 mg, 3.2 mmol) in 4 mlDMF was added at 0°C to HATU (1.34 g, 3.52 mmol) and iV-methylhex-5- enylamine (435 mg, 3.84 mmol) in DMF (3 mL), followed by DIPEA. After stirring for 40 min at 0°C, the mixture was stirred at room temperature for 5 h. Then, the solvent was evaporated, the residue dissolved in EtOAc (70 mL) and washed with saturated NaHCO₃ (10 mL). The aqueous layer was extracted with EtOAc (2 x 25 mL). The organic phases were combined, washed with saturated NaCl (20 mL), dried (Na₂SO₄), and evaporated. Purification by flash chromatography (EtOAc/petroleum ether, 2:1) afforded 550 mg (68%) of the target product 40 as a colorless oil: m/z = 252 (M+H)⁺.

A solution of LiOH (105 mg in 4 mlof water) was added at 0°C to the lactone amide 40. After Ih, the conversion was completed (HPLC). The mixture was acidified to pH 2 – 3 with IN HCl, extracted with AcOEt, dried (MgSO₄), evaporated, co-evaporated with toluene several times, and dried under high vacuum overnight to give 520 mg (88%) of the target product 41: m/z = 270 (M+H)⁺.

The l-(amino)-2-(vinyl)cyclopropanecarboxylic acid ethyl ester hydrochloride 42 (4.92 g, 31.7 mmol) and HATU (12.6 g, 33.2 mmol) were added to 41 (8.14 g, 30.2 mmol). The mixture was cooled in an ice bath under argon, and then DMF (100 mL) and DIPEA (12.5 mL, 11.5 mmol) were successively added. After 30 min at 0°C, the solution was stirred at room temperature for an additional 3 h. Then, the reaction mixture was partitioned between EtOAc and water, washed successively with 0.5 N HCl (20 mL) and saturated NaCl (2 x 20 mL), and dried (Na₂SO₄). Purification by flash chromatography (AcOEt/CH₂Cl₂/Petroleum ether, 1:1:1) afforded 7.41 g (60%) of the target product 43 as a colorless oil: m/z = 407 (M+H)⁺.

DIAD (1.02 mL, 5.17 mmol) was added at -15°C under nitrogen atmosphere to a solution of 43 (1.5 g, 3.69 mmol), quinoline 36 (1.39 g, 4.43 mmol) and triphenyl- phosphine (1.26 g, 4.80 mmol) in dry THF (40 mL). After 4.5 h, at -15°C, the reaction mixture was partitioned between ice-cold water and AcOEt, dried (Na₂SO₄) and evaporated. The crude material was purified by flash column chromatography (gradient of petroleum AcOEt/CH₂Cl₂, 1 :9 to 2:8) to give 1.45 g (56 %) of the target product 44: m/z = 703 (M+H)⁺.

A solution of 44 (1.07 g, 1.524 mmol) and Hoveyda-Grubbs 1^st generation catalyst (33 mg, 0.03 eq) in dried and degassed 1,2-dichloroethane (900 mL) was heated at 75°C under nitrogen for 12 h. Then, the solvent was evaporated and the residue purified by silica gel chromatography (25% EtOAc in CH₂Cl₂). 620 mg (60%) of pure macrocycle 45 were obtained, m/z = 674 (M+H)⁺. ¹H NMR (CDCl₃): 1.18-1.39 (m, 12H), 1.59 (m, IH), 1.70-2.08 (m, 5H), 2.28 (m, IH), 2.38 (m, IH), 2.62 (m, 2H), 2.68 (s, 3H), 2.83 (m, IH), 3.06 (s, 3H), 3.19 (sept, J= 6.7 Hz, IH), 3.36 (m, IH), 3.83 (m, IH), 3.97 (s, 3H), 4.09 (m, 2H), 4.65 (td, J= 4 Hz, 14 Hz, IH), 5.19 (dd, J= 4 Hz, 10 Hz, IH), 5.31 (m, IH), 5.65 (td, J= 4 Hz, 8 Hz, IH), 7.00 (s, IH), 7.18 (s, IH), 7.46 (d, J= 9 Hz, IH), 7.48 (s, IH), 8.03 (d, J= 9 Hz, IH).

Step F

A solution of lithium hydroxide (1.65 g, 38.53 mmol) in water (15 mL) was added to a stirred solution of ester 45 (620 mg, 0.920 mmol) in THF (30 mL) and MeOH (20 mL). After 16 h at room temperature, the reaction mixture was quenched with NH₄Cl sat., concentrated under reduced pressure, acidified to pH 3 with HCl IN and extracted with CH₂Cl₂, dried (MgSO₄) and evaporated to give 560 mg (88%) of carboxylic acid 46. m/z = 647 (M+H)⁺. ¹H NMR (CDCl₃): 1.11-1.40 (m, 8H), 1.42-1.57 (m, 2H), 1.74 (m, 2H), 1.88-2.00 (m, 2H), 2.13 (m, IH), 2.28 (m, IH), 2.40 (m, IH), 2.59 (m, 2H), 2.67 (s, 3H), 2.81 (m, IH), 2.97 (s, 3H), 3.19 (m, IH), 3.31 (m, IH), 3.71 (m, IH), 3.96 (s, 3H), 4.56 (dt, J= 4 Hz, 12 Hz, IH), 5.23 (m, 2H), 5.66 (m, IH), 7.01 (s, IH), 7.10 (s, IH), 7.22 (d, J= 10 Hz, IH), 7.45 (s, IH), 8.00 (d, J= 10 Hz, IH).

Example 5: Preparation of JV-ri7-r2-(4-isopropylthiazole-2-yl)-7-methoxy-8- methylquinolin-4- yloxyl – 13 -methyl-2, 14-dioxo-3 , 13 -diazatricyclol^“ 13.3.0.0⁴‘⁶loctadec- 7-ene-4-carbonyll (cvclopropyPsulfonamide (47) SIMEPREVIR

A solution of 17-[2-(4-isopropylthiazole-2-yl)-7-methoxy-8-methylquinolin-4-yloxy]- 13-methyl-2, 14-dioxo-3, 13-diazatricyclo[l 3.3.0.04,6]octadec-7-ene-4-carboxylic acid 46 (560mg, 0.867 mmol) prepared according to Example 4, and carbonyldiimidazole (308 mg, 1.90 mmol) in dry THF (10 mL) was stirred at reflux under nitrogen for 2h. The reaction mixture was cooled to room temperature and cyclopropylsulfonamide (400 mg, 3.301 mmol) and DBU (286 mg, 1.881 mmol) were added. This solution was heated at 50°C for 15 h. Then, the reaction mixture was cooled down at room temperature and concentrated under reduced pressure. The residue was partitioned between CH2CI2 and HCl 1 N, the organic layer was washed with brine, dried (MgSO₄) and evaporated. Purification by flash chromatography (gradient of EtOAc (0 to 25%) in CH2CI2) afforded 314 mg of an off-white solid which was further washed with water, then isopropylether, and dried in the vacuum oven to deliver 282 mg (40%) of the pure title product 47 SIMEPREVIR as a white powder: m/z = 750 (M+H)⁺.

¹H NMR (CDCl₃): 0.99-1.52 (m, 14H), 1.64-2.05 (m, 4H), 2.77 (m, IH), 2.41 (m, 2H), 2.59 (m, 2H), 2.69 (s, 3H), 2.92 (m, 2H), 3.04 (s, 3H), 3.19 (m, IH), 3.40 (m, 2H), 3.98 (s, 3H), 4.60 (t, J= 13 Hz, IH), 5.04 (t, J= 11 Hz, IH), 5.37 (m, IH), 5.66 (m, IH), 6.21 (s, IH), 7.02 (s, IH), 7.22 (d, J= 10 Hz, IH), 7.45 (s, IH), 7.99 (d, J= 10 Hz, IH), 10.82 (broad s, IH).

…………………..

REFERENCES

“Medivir Announces That Simeprevir (TMC435) Data Will Be Presented at the Upcoming AASLD Meeting”. Yahoo News. October 1, 2012. Retrieved November 6, 2012.
Lin, TI; Lenz, O; Fanning, G; Verbinnen, T; Delouvroy, F; Scholliers, A; Vermeiren, K; Rosenquist, A et al. (2009). “In vitro activity and preclinical profile of TMC435350, a potent hepatitis C virus protease inhibitor”. Antimicrobial agents and chemotherapy 53 (4): 1377–85. doi:10.1128/AAC.01058-08. PMC 2663092. PMID 19171797. |displayauthors= suggested (help)
“Phase 3 Studies Show Simeprevir plus Interferon/Ribavirin Cures Most Patients in 24 Weeks”. hivandhepatitis.com. December 27, 2012.
Medivir announces TMC435 in an expanded clinical collaboration. Medivir. 18 April 2012.
Results from a phase IIa study evaluating Simeprevir and Sofosbuvir in prior null responder Hepatitis C patients have been presented at CROI. 6 March 2013.
TMC-435350
Drugs Fut 2009, 34(7): 545
Structure-activity relationship study on a novel series of cyclopentane-containing macrocyclic inhibitors of the hepatitis C virus NS3/4A protease leading to the discovery of TMC435350
Bioorg Med Chem Lett 2008, 18(17): 4853
Synthesis of enantiomerically pure trans-3,4-substituted cyclopentanols by enzymatic resolution
Acta Chem Scand (1989) 1992, 46: 1127

PATENTS

WO 2008092954
WO 2007014926
WO 2008092955
WO 2000009543
CN 102531932
WO 2013061285
WO 2011113859
WO 2013041655

WO2010097229A2 *	26 Feb 2010	2 Sep 2010	Ortho-Mcneil-Janssen Pharmaceuticals Inc	Amorphous salt of a macrocyclic inhibitor of hcv
WO2013037705A2 *	7 Sep 2012	21 Mar 2013	Fovea Pharmaceuticals	Aniline derivatives,their preparation and their therapeutic application

WO2005073195A2 *	28 Jan 2005	11 Aug 2005	Per-Ola Johansson	Hcv ns-3 serine protease inhibitors
WO2007014926A1 *	28 Jul 2006	8 Feb 2007	Tibotec Pharm Ltd	Macrocyclic inhibitors of hepatitis c virus

The compound ritonavir, and pharmaceutically acceptable salts thereof, and methods for its preparation are described in WO94/14436. For preferred dosage forms of ritonavir, see US6,037, 157, and the documents cited therein: US5,484, 801, US08/402,690, and WO95/07696 and WO95/09614. Ritonavir has the following formula:

Bayer, Onyx win early FDA OK for Nexavar (sorafenib) in thyroid cancer

November 25, 2013 3:57 am / 4 Comments on Bayer, Onyx win early FDA OK for Nexavar (sorafenib) in thyroid cancer

The U.S. Food and Drug Administration said on Friday it has expanded the approved use of the cancer drug Nexavar to include late-stage differentiated thyroid cancer.

Differentiated thyroid cancer is the most common type of thyroid cancer, the FDA said. The National Cancer Institute estimates that 60,220 people in the United States will be diagnosed with it and 1,850 will die from the disease in 2013.

The drug, made by Germany’s Bayer AG and Onyx Pharmaceuticals, is already approved to treat advanced kidney cancer and liver cancer that cannot be surgically removed. Onyx was acquired by Amgen Inc earlier this year.

READ ABOUT SORAFENIB IN MY EARLIER BLOGPOST

https://newdrugapprovals.wordpress.com/2013/07/16/nexavar-sorafenib/

European Commission Approves Gilead’s VitektaTM, an Integrase Inhibitor for the Treatment of HIV-1 Infection

November 24, 2013 3:27 am / 2 Comments on European Commission Approves Gilead’s VitektaTM, an Integrase Inhibitor for the Treatment of HIV-1 Infection

Elvitegravir

697761-98-1 CAS

FOSTER CITY, Calif.–(BUSINESS WIRE)–Nov. 18, 2013– Gilead Sciences, Inc. (Nasdaq: GILD) today announced that the European Commission has granted marketing authorization for VitektaTM (elvitegravir 85 mg and 150 mg) tablets, an integrase inhibitor for the treatment of HIV-1 infection in adults without known mutations associated with resistance to elvitegravir. Vitekta is indicated for use as part of HIV treatment regimens that include a ritonavir-boosted protease inhibitor.http://www.pharmalive.com/eu-oks-gileads-vitekta Vitekta interferes with HIV replication by blocking the virus from integrating into the genetic material of human cells. In clinical trials, Vitekta was effective in suppressing HIV among patients with drug-resistant strains of HIV.http://www.pharmalive.com/eu-oks-gileads-vitekta

Elvitegravir (EVG, formerly GS-9137) is a drug used for the treatment of HIV infection. It acts as an integrase inhibitor. It was developed^[1] by the pharmaceutical company Gilead Sciences, which licensed EVG from Japan Tobacco in March 2008.^[2]^[3]^[4] The drug gained approval by U.S. Food and Drug Administration on August 27, 2012 for use in adult patients starting HIV treatment for the first time as part of the fixed dose combination known as Stribild.^[5]

According to the results of the phase II clinical trial, patients taking once-daily elvitegravir boosted by ritonavir had greater reductions in viral load after 24 weeks compared to individuals randomized to receive a ritonavir-boosted protease inhibitor.^[6]

Human immunodeficiency virus type 1 (HIV-1) is the causative agent of acquired immunodeficiency disease syndrome (AIDS). After over 26 years of efforts, there is still not a therapeutic cure or an effective vaccine against HIV/AIDS. The clinical management of HIV-1 infected people largely relies on antiretroviral therapy (ART). Although highly active antiretroviral therapy (HAART) has provided an effective way to treat AIDS patients, the huge burden of ART in developing countries, together with the increasing incidence of drug resistant viruses among treated people, calls for continuous efforts for the development of anti-HIV-1 drugs. Currently, four classes of over 30 licensed antiretrovirals (ARVs) and combination regimens of these ARVs are in use clinically including: reverse transcriptase inhibitors (RTIs) (e.g. nucleoside reverse transcriptase inhibitors, NRTIs; and non-nucleoside reverse transcriptase inhibitors, NNRTIs), protease inhibitors (PIs), integrase inhibitors and entry inhibitors (e.g. fusion inhibitors and CCR5 antagonists).

Gilead Press Release Phase III Clinical Trial of Elvitegravir July 22, 2008
Gilead Press Release Gilead and Japan Tobacco Sign Licensing Agreement for Novel HIV Integrase Inhibitor March 22, 2008
Shimura K, Kodama E, Sakagami Y, et al. (2007). “Broad Anti-Retroviral Activity and Resistance Profile of a Novel Human Immunodeficiency Virus Integrase Inhibitor, Elvitegravir (JTK-303/GS-9137)”. J Virol 82 (2): 764. doi:10.1128/JVI.01534-07. PMC 2224569. PMID 17977962.
Stellbrink HJ (2007). “Antiviral drugs in the treatment of AIDS: what is in the pipeline ?”. Eur. J. Med. Res. 12 (9): 483–95. PMID 17933730.
Sax, P. E.; Dejesus, E.; Mills, A.; Zolopa, A.; Cohen, C.; Wohl, D.; Gallant, J. E.; Liu, H. C.; Zhong, L.; Yale, K.; White, K.; Kearney, B. P.; Szwarcberg, J.; Quirk, E.; Cheng, A. K.; Gs-Us-236-0102 Study, T. (2012). “Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir versus co-formulated efavirenz, emtricitabine, and tenofovir for initial treatment of HIV-1 infection: A randomised, double-blind, phase 3 trial, analysis of results after 48 weeks”.The Lancet 379 (9835): 2439–2448. doi:10.1016/S0140-6736(12)60917-9. PMID 22748591. edit
Thaczuk, Derek and Carter, Michael. ICAAC: Best response to elvitegravir seen when used with T-20 and other active agents Aidsmap.com. 19 Sept. 2007.

The life cycle of HIV-1. 1. HIV-1 gp120 binds to CD4 and co-receptor CCR5/CXCR4 on target cell; 2. HIV-1 gp41 mediates fusion with target cell; 3. Nucleocapsid containing viral genome and enzymes enters cells; 4. Viral genome and enzymes are released; 5. Viral reverse transcriptase catalyzes reverse transcription of ssRNA, forming RNA-DNA hybrids; 6. RNA template is degraded by ribonuclease H followed by the synthesis of HIV dsDNA; 7. Viral dsDNA is transported into the nucleus and integrated into the host chromosomal DNA by the viral integrase enzyme; 8. Transcription of proviral DNA into genomic ssRNA and mRNAs formation after processing; 9. Viral RNA is exported to cytoplasm; 10. Synthesis of viral precursor proteins under the catalysis of host-cell ribosomes; 11. Viral protease cleaves the precursors into viral proteins; 12. HIV ssRNA and proteins assemble under host cell membrane, into which gp120 and gp41 are inserted; 13. Membrane of host-cell buds out, forming the viral envelope; 14. Matured viral particle is released

Elvitegravir, also known as GS 9137 or JTK 303, is an investigational new drug and a novel oral integrase inhibitor that is being evaluated for the treatment of HIV-1 infection. After HIVs genetic material is deposited inside a cell, its RNA must be converted (reverse transcribed) into DNA. A viral enzyme called integrase then helps to hide HIVs DNA inside the cell’s DNA. Once this happens, the cell can begin producing genetic material for new viruses. Integrase inhibitors, such as elvitegravir, are designed to block the activity of the integrase enzyme and to prevent HIV DNA from entering healthy cell DNA. Elvitegravir has the chemical name: 6-(3-chloro-2-fluorobenzyl)-1-[(S)-1 -hydroxy -methyl-2- methylpropyl]-7-methoxy-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid and has the following structural formula:

WO 2000040561 , WO 2000040563 and WO 2001098275 disclose 4-oxo-1 , 4-dihydro-3- quinoline which is useful as antiviral agents. WO2004046115 provides certain 4- oxoquinoline compounds that are useful as HIV Integrase inhibitors.

US 7176220 patent discloses elvitegravir, solvate, stereoisomer, tautomer, pharmaceutically acceptable salt thereof or pharmaceutical composition containing them and their method of treatment. The chemistry involved in the above said patent is depicted below in the Scheme A. Scheme-A

Toluene, DIPEA

SOCl₂ ,COCl (S)-(+)-Valinol

Toluene

,4-Difluoro-₅-iodo- benzoic acid

THF

dichlorobis(triphenylphosphine)

palladium argon stream,

Elvitegravir Form ] Elvitegravir (residue) US 7635704 patent discloses certain specific crystalline forms of elvitegravir. The specific crystalline forms are reported to have superior physical and chemical stability compared to other physical forms of the compound. Further, process for the preparation of elvitegravir also disclosed and is depicted below in the Scheme B. The given processes involve the isolation of the intermediates at almost all the stages.

Scheme B

–

Zn THF,

CK Br THF CU “ZnBr dιchlorobis(trιphenylphos

phine)palladium

Elvitegravir WO 2007102499 discloses a compound which is useful as an intermediate for the synthesis of an anti-HIV agent having an integrase-inhibiting activity; a process for production of the compound; and a process for production of an anti-HIV agent using the intermediate.

WO 2009036161 also discloses synthetic processes and synthetic intermediates that can be used to prepare 4-oxoquinolone compounds having useful integrase inhibiting properties.

The said processes are tedious in making and the purity of the final compound is affected because of the number of steps, their isolation, purification etc., thus, there is a need for new synthetic methods for producing elvitegravir which process is cost effective, easy to practice, increase the yield and purity of the final compound, or that eliminate the use of toxic or costly reagents.

US Patent No 7176220 discloses Elvitegravir, solvate, stereoisomer, tautomer, pharmaceutically acceptable salt thereof or pharmaceutical composition containing them and ■ their method of treatment. US Patent No 7635704 discloses Elvitegravir Form II, Form III and processes for their preparation. The process for the preparation of Form Il disclosed in the said patent is mainly by three methods – a) dissolution of Elvitegravir followed by seeding with Form II, b) recrystallisation of Elvitegravir, and c) anti-solvent method.

The process for the preparation of Form III in the said patent is mainly by three methods – a) dissolution of Form Il in isobutyl acetate by heating followed by cooling the reaction mass, b) dissolution of Form Il in isobutyl acetate by heating followed by seeding with Form III, and c) dissolving Form Il in 2-propanol followed by seeding with Form III.

Amorphous materials are becoming more prevalent in the pharmaceutical industry. In order to overcome the solubility and potential bioavailability issues, amorphous solid forms are becoming front-runners. Of special importance is the distinction between amorphous and crystalline forms, as they have differing implications on drug substance stability, as well as drug product stability and efficacy.

An estimated 50% of all drug molecules used in medicinal therapy are administered as salts. A drug substance often has certain suboptimal physicochemical or biopharmaceutical properties that can be overcome by pairing a basic or acidic drug molecule with a counter- ion to create a salt version of the drug. The process is a simple way to modify the properties of a drug with ionizable functional groups to overcome undesirable features of the parent drug. Salt forms of drugs have a large effect on the drugs’ quality, safety, and performance. The properties of salt-forming species significantly affect the pharmaceutical properties of a drug and can greatly benefit chemists and formulators in various facets of drug discovery and development.

chemical synthesis from a carboxylic acid 1 starts after conversion to the acid chloride iodide NIS 2 , and with three condensation 4 . 4 and the amino alcohol 5 addition-elimination reaction occurs 6 , 6 off under alkaline conditions with TBS protected hydroxy get the ring 7 , 7 and zinc reagent 8 Negishi coupling occurs to get 9 , the last 9 hydrolysis and methoxylated

Elvitegravir dimer impurity, WO2011004389A2

Isolation of 1-[(2S)-1-({3-carboxy-6-(3-chloro-2-fluorobenzyl)-1 -[(2S)-I- hydroxy-3-methylbutan-2-yl]-4-oxo-1 , 4-dihydroquinolin-7-yl}oxy)-3- methylbutan-2-yl 6-(3-chloro-2-fluorobenzyl)-7-methoxy-4-oxo-1 , 4-dihydroquinoline-3-carboxylic acid (elvitegravir dimer impurity, 13)

After isolation of the elvitegravir from the mixture of ethyl acetate-hexane, solvent from the filtrate was removed under reduced pressure. The resultant residue purified by column chromatography using a mixture of ethyl acetate-hexane (gradient, 20-80% EtOAc in hexane) as an eluent. Upon concentration of the required fractions, a thick solid was obtained which was further purified on slurry washing with ethyl acetate to get pure elvitegravir dimer impurity (13). The ¹H-NMR, ¹³C-NMR and mass spectral data complies with proposed structure.

¹H-NMR (DMSO-Cf₆, 300 MHz, ppm) – δ 0.79 (m, d=6.3 Hz, 6H, 20 & 2O’)\ 1.18 & 1.20 (d, J=6.3 Hz & J=6.2 Hz, 6H, 21 & 21′)¹, 2.42-2.49 (m, 2H, 19 & 19′), 3.81-3.89 (m, 3H, T & 17’Ha), 3.94-4.01 (m, 1 H, 17’Hb), 4.01 (s, 3H, 23), 4.11 (s, 2H, 7), 4.83-4.85 (m, 3H, 17 & 18′), 5.22 (t, J=4.7 Hz, 1H, OH), 5.41-5.44 (m, 1 H, 18), 6.73-6.78 (t, J=7.1 Hz, 1 H, 1¹)¹‘ ², 6.92-6.98 (t, J=8.0 Hz, 1H, 3′) ¹‘², 7.12-7.22 (m, 2H, 1 & 3), 7.34-7.39 (m, 1H, 2′),

7.45-7.48 (m, 1 H, 2), 7.49, 7.56 (s, 2H, 15 & 15′), 7.99, 8.02 (s, 2H, 9 & 9′), 8.89, 9.01 (s, 2H, 13 & 13′), 15.30, 15.33 (s, 2H, COOH’ & COOH”).

¹³C-NMR (DMSO-Cf₆, 75 MHz, ppm)- δ 18.87, 19.03 (2OC, 20’C), 19.11 , 19.24 (21 C, 21 ‘C), 27.94 (7’C), 28.40 (7C), 28.91 , 30.08 (19C, 19’C), 56.80(23C), 60.11 (17¹C), 63.59 (18C), 66.52 (18’C), 68.53 (17C), 97.86, 98.97 (15, 15′), 107.43, 108.16 (12C, 12’C),

118.77, 119.38 (1OC, 10’C), 119.57 (d, J=17.6 Hz, 4¹C), 119.61 (d, J=17.9 Hz, 4C),

124.88 (d, J=4.3 Hz, 3¹C), 125.18 (d, J=4.2 Hz, 3C), 126.59, 126.96 (9C₁ 9’C), 127.14 (8’C), 127.62 (d, J=15.9 Hz, 6¹C), 127.73 (8C), 127.99 (d, J=15.2 Hz, 6C), 128.66 (2’C),

128.84 (1¹C), 128.84 (2C), 130.03 (d, J=3.4 Hz, 1C), 142.14, 142.44 (14C, 14’C), 144.37, 145.56 (13C, 13¹C), 155.24 (d, J=245.1 Hz, 5’C)₁ 155.61 (d, J=245.1 Hz, 5C),

160.17 (16’C), 162.04 (16C), 166.00, 166.14 (22C, 22’C), 176.17, 176.22 (11C, 11¹C).

DIP MS: m/z (%)- 863 [M+H]⁺, 885 [M+Na]⁺.

Europace Publishes Data Supporting Use Of BRINAVESS™ (Vernakalant) As A First Line Agent For Pharmacological Cardioversion Of Atrial Fibrillation

November 22, 2013 4:07 am / 6 Comments on Europace Publishes Data Supporting Use Of BRINAVESS™ (Vernakalant) As A First Line Agent For Pharmacological Cardioversion Of Atrial Fibrillation

Vernakalant, MK-6621, RSD 1235

(3R)-1-{(1R,2R)-2-[2-(3,4-dimethoxyphenyl)
ethoxy]cyclohexyl}pyrrolidin-3-ol

C₂₀H₃₁NO₄ , 349.47, Brinavess , Kynapid

cas no 794466-70-9
748810-28-8 (HCl)

EMA:Link click here

PATENT WO 2004099137

VANCOUVER, Nov. 21, 2013 /PRNewswire/ – Cardiome Pharma Corp. (NASDAQ: CRME / TSX: COM) today announced that a publication titled, Pharmacological Cardioversion of Atrial Fibrillation with Vernakalant: Evidence in Support of the ESC Guidelines, was published in Europace, the official Journal of the European Heart Rhythm Association, and was made available in the advanced online article access section. The authors conclude that BRINAVESS is an efficacious and rapid acting pharmacological cardioversion agent, for recent-onset atrial fibrillation (AF,) that can be used first line in patients with little or no underlying cardiovascular disease and in patients with moderate disease, such as stable coronary and hypertensive heart disease.

http://www.prnewswire.com/news-releases/europace-publishes-data-supporting-use-of-brinavess-vernakalant-as-a-first-line-agent-for-pharmacological-cardioversion-of-atrial-fibrillation-232816731.html

Vernakalant (INN; codenamed RSD1235, proposed tradenames Kynapid and Brinavess) is an investigational drug under regulatory review for the acute conversion of atrial fibrillation. It was initially developed by Cardiome Pharma, and the intravenous formulation has been bought for further development by Merck in April 2009.^[1] In September 2012, Merck terminated its agreements with Cardiom and has consequently returned all rights of the drug back to Cardiom.

On 11 December 2007, the Cardiovascular and Renal Drugs Advisory Committee of the USFood and Drug Administration (FDA) voted to recommend the approval of vernakalant,^[2]but in August 2008 the FDA judged that additional information was necessary for approval.^[1] The drug was approved in Europe on 1 September 2010.^[3]

An oral formulation underwent Phase II clinical trials between 2005 and 2008.^[4]^[5]

Like other class III antiarrhythmics, vernakalant blocks atrial potassium channels, thereby prolonging repolarization. It differs from typical class III agents by blocking a certain type of potassium channel, the cardiac transient outward potassium current, with increased potency as the heart rate increases. This means that it is more effective at high heart rates, while other class III agents tend to lose effectiveness under these circumstances. It also slightly blocks the hERG potassium channel, leading to a prolonged QT interval. This may theoretically increase the risk of ventricular tachycardia, though this does not seem to be clinically relevant.^[6]

The drug also blocks atrial sodium channels.^[6]

“Merck and Cardiome Pharma Sign License Agreement for Vernakalant, an Investigational Drug for Treatment of Atrial Fibrillation”. FierceBiotech. 9 April 2009. Retrieved 12 October 2010.
“FDA Advisory Committee Recommends Approval of Kynapid for Acute Atrial Fibrillation”. Drugs.com. Retrieved 2008-03-15.
“BRINAVESS (vernakalant) for Infusion Approved in the European Union for Rapid Conversion of Recent Onset Atrial Fibrillation” (Press release). Merck & Co., Inc. 1 September 2010. Retrieved 28 September 2010.
ClinicalTrials.gov NCT00267930 Study of RSD1235-SR for the Prevention of Atrial Fibrillation/Atrial Flutter Recurrence
ClinicalTrials.gov NCT00526136 Vernakalant (Oral) Prevention of Atrial Fibrillation Recurrence Post-Conversion Study
Miki Finnin, Vernakalant: A Novel Agent for the Termination of Atrial Fibrillation: Pharmacology, Medscape Today, retrieved 12 October 2010

Arzneimittel-Fachinformation (EMA)
Cheng J.W. Vernakalant in the management of atrial fibrillation. Ann Pharmacother, 2008, 42(4), 533-42Pubmed
Dobrev D., Nattel S. New antiarrhythmic drugs for treatment of atrial fibrillation. Lancet, 2010, 375(9721), 1212-23 Pubmed
Finnin M. Vernakalant: A novel agent for the termination of atrial fibrillation. Am J Health Syst Pharm, 2010, 67(14), 1157-64 Pubmed
Mason P.K., DiMarco J.P. New pharmacological agents for arrhythmias. Circ Arrhythm Electrophysiol, 2009, 2(5), 588-97 Pubmed
Naccarelli G.V., Wolbrette D.L., Samii S., Banchs J.E., Penny-Peterson E., Stevenson R., Gonzalez M.D. Vernakalant – a promising therapy for conversion of recent-onset atrial fibrillation. Expert Opin Investig Drugs, 2008, 17(5), 805-10 Pubmed
European Patent No. 1,560,812
WO 2006138673, WO 200653037
WO 200597203, WO 200688525
Vernakalant HydrochlorideDrugs Fut 2007, 32(3): 234

//////////////////////////////////////////////////////

Nitrogen: dark blue, oxygen: red, hydrogen: light blue

NMR

1H NMR (300 MHz, CDCI3) 5 6.75 (m, 3H), 4.22 (m, 1H), 3.87 (s, 3H), 3.85 (m, 3H), 3.74 (m, 1H), 3.57 (m, 1H), 3.32 (td, J =
7.7, 3.5, 1H), 2.96-2.75 (m, 5H), 2.64 (dd, J= 10.0, 5.0, 1H), 2.49-2.37 (m, 2H), 2.05-1.98 (m, 2H), 1.84 (m, 1H), 1.69-1.62 (m, 3H), 1.35-1.19 (m, 4H).

WO 201240846

Arrhythmias are abnormal rhythms of the heart. The term “arrhythmia” refers to a deviation from the normal sequence of initiation and conduction of electrical impulses that cause the heart to beat. Arrhythmias may occur in the atria or the ventricles. Atrial arrhythmias are widespread and relatively benign, although they place the subject at a higher risk of stroke and heart failure. Ventricular arrhythmias are typically less common, but very often fatal.

Arrhythmia is a variation from the normal rhythm of the heart beat and generally represents the end product of abnormal ion-channel structure, number or function. Both atrial arrhythmias and ventricular arrhythmias are known. The major cause of fatalities due to cardiac arrhythmias is the subtype of ventricular arrhythmias known as ventricular fibrillation (VF). Conservative estimates indicate that, in the U.S. alone, each year over one million Americans will have a new or recurrent coronary attack (defined as myocardial infarction or fatal coronary heart disease). About 650,000 of these will be first heart attacks and 450,000 will be recurrent attacks. About one-third of the people experiencing these attacks will die of them. At least 250,000 people a year die of coronary heart disease within 1 hour of the onset of symptoms and before they reach a hospital. These are sudden deaths caused by cardiac arrest, usually resulting from ventricular fibrillation.

Atrial fibrillation (AF) is the most common arrhythmia seen in clinical practice and is a cause of morbidity in many individuals (Pritchett E.L., N. Engl. J. Med. 327(14):1031 Oct. 1, 1992, discussion 1031-2; Kannel and Wolf, Am. Heart J. 123(l):264-7 Jan. 1992). Its prevalence is likely to increase as the population ages and it is estimated that 3-5% of patients over the age of 60 years have AF (Kannel W.B., Abbot R.D., Savage D.D., McNamara P.M., N. Engl. J. Med. 306(17): 1018-22, 1982; Wolf P.A., Abbot R.D., Kannel W.B. Stroke. 22(8):983-8, 1991). While AF is rarely fatal, it can impair cardiac function and is a major cause of stroke (Hinton R.C., Kistler J.P., Fallon J.T., Friedlich A.L., Fisher CM., American Journal of Cardiology 40(4):509-13, 1977; Wolf P.A., Abbot R.D., Kannel W.B., Archives of Internal Medicine 147(9): 1561 -4, 1987; Wolf P. A., Abbot R.D., Kannel W.B. Stroke. 22(8):983-8, 1991; Cabin H.S., Clubb K.S., Hall C, Perlmutter R.A., Feinstein A.R., American Journal of Cardiology 65(16): 1112-6, 1990).

WO95/08544 discloses a class of aminocyclohexylester compounds as useful in the treatment of arrhythmias.

WO93/ 19056 discloses a class of aminocyclohexylamides as useful in the treatment of arrhythmia and in the inducement of local anaesthesia.

WO99/50225 discloses a class of aminocyclohexylether compounds as useful in the treatment of arrhythmias.

Antiarrhythmic agents have been developed to prevent or alleviate cardiac arrhythmia. For example, Class I antiarrhythmic compounds have been used to treat supraventricular arrhythmias and ventricular arrhythmias. Treatment of ventricular arrhythmia is very important since such an arrhythmia can be fatal. Serious ventricular arrhythmias (ventricular tachycardia and ventricular fibrillation) occur most often in the presence of myocardial ischemia and/or infarction. Ventricular fibrillation often occurs in the setting of acute myocardial ischemia, before infarction fully develops. At present, there is no satisfactory pharmacotherapy for the treatment and/or prevention of ventricular fibrillation during acute ischemia. In fact, many Class I antiarrhythmic compounds may actually increase mortality in patients who have had a myocardial infarction.

Class la, Ic and HI antiarrhythmic drugs have been used to convert recent onset AF to sinus rhythm and prevent recurrence of the arrhythmia (Fuch and Podrid, 1992; Nattel S., Hadjis T., Talajic M., Drugs 48(3):345-7l, 1994). However, drug therapy is often limited by adverse effects, including the possibility of increased mortality, and inadequate efficacy (Feld G.K., Circulation. <°3(<5):2248-50, 1990; Coplen S.E., Antman E.M., Berlin J.A., Hewitt P., Chalmers T.C., Circulation 1991; S3(2):714 and Circulation 82(4):1106-16, 1990; Flaker G.C., Blackshear J.L., McBride R., Kronmal R.A., Halperin J.L., Hart R.G., Journal of the American College of Cardiology 20(3):527-32, 1992; CAST, N. Engl. J. Med. 321:406, 1989; Nattel S., Cardiovascular Research. 37(3):567 -77, 1998). Conversion rates for Class I antiarrhythmics range between 50-90% (Nattel S., Hadjis T., Talajic M., Drugs 48(3)345-71, 1994; Steinbeck G., Remp T., Hoffmann E., Journal of Cardiovascular Electrophysiology. 9(8 Suppl):S 104-8, 1998). Class ILT antiarrhythmics appear to be more effective for terminating atrial flutter than for AF and are generally regarded as less effective than Class I drugs for terminating of AF (Nattel S., Hadjis T., Talajic M., Drugs. 48(3):345-71, 1994; Capucci A., Aschieri D., Villani G.Q., Drugs & Aging 13(l):5l- 70, 1998). Examples of such drugs include ibutilide, dofetilide and sotalol. Conversion rates for these drugs range between 30-50% for recent onset AF (Capucci A., Aschieri D., Nillani G.Q., Drugs & Aging J3(l):5l-70, 1998), and they are also associated with a risk of the induction of Torsades de Pointes ventricular tachyarrhythmias. For ibutilide, the risk of ventricular proarrhythmia is estimated at ~4.4%, with ~1.7% of patients requiring cardioversion for refractory ventricular arrhythmias (Kowey P.R., NanderLugt J.T., Luderer J.R., American Journal of Cardiology 78(8A):46-52, 1996). Such events are particularly tragic in the case of AF as this arrhythmia is rarely a fatal in and of itself.

Atrial fibrillation is the most common arrhythmia encountered in clinical practice. It has been estimated that 2.2 million individuals in the United States have paroxysmal or persistent atrial fibrillation. The prevalence of atrial fibrillation is estimated at 0.4% of the general population, and increases with age. Atrial fibrillation is usually associated with age and general physical condition, rather than with a specific cardiac event, as is often the case with ventricular arrhythmia. While not directly life threatening, atrial arrhythmias can cause discomfort and can lead to stroke or congestive heart failure, and increase overall morbidity.

There are two general therapeutic strategies used in treating subjects with atrial fibrillation. One strategy is to allow the atrial fibrillation to continue and to control the ventricular response rate by slowing the conduction through the atrioventricular (AV) node with digoxin, calcium channel blockers or beta-blockers; this is referred to as rate control. The other strategy, known as rhythm control, seeks to convert the atrial fibrillation and then maintain normal sinus rhythm, thus attempting to avoid the morbidity associated with chronic atrial fibrillation. The main disadvantage of the rhythm control strategy is related to the toxicities and proarrhythmic potential of the anti-arrhythmic drugs used in this strategy. Most drugs currently used to prevent atrial or ventricular arrhythmias have effects on the entire heart muscle, including both healthy and damaged tissue. These drugs, which globally block ion channels in the heart, have long been associated with life-threatening ventricular arrhythmia, leading to increased, rather than decreased, mortality in broad subject populations. There is therefore a long recognized need for antiarrhythmic drugs that are more selective for the tissue responsible for the arrhythmia, leaving the rest of the heart to function normally, less likely to cause ventricular arrhythmias.

One specific class of ion channel modulating compounds selective for the tissue responsible for arrhythmia has been described in U.S. Pat. No. 7,057,053, including the ion channel modulating compound known as vernakalant hydrochloride. Vernakalant hydrochloride is the non-proprietary name adopted by the United States Adopted Name (USAN) council for the ion channel modulating compound (1R,2R)-2-[(3R)-hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexane monohydrochloride, which compound has the following formula:

Vernakalant hydrochloride may also be referred to as “vernakalant” herein.

Vernakalant hydrochloride modifies atrial electrical activity through a combination of concentration-, voltage- and frequency-dependent blockade of sodium channels and blockade of potassium channels, including, e.g., the ultra-rapidly activating (l_Kur) and transient outward (l_to) channels. These combined effects prolong atrial refractoriness and rate-dependently slow atrial conduction. This unique profile provides an effective anti-fibrillatory approach suitable for conversion of atrial fibrillation and the prevention of atrial fibrillation.

C₂₀H₃₂ClNO₄, M_r = 385.9 g/mol

Pfizer’s Xalkori Granted Regular FDA Approval

November 22, 2013 3:18 am / 2 Comments on Pfizer’s Xalkori Granted Regular FDA Approval

Pfizer’s XALKORI® Granted Regular FDA Approval
Standard of Care for Patients With Metastatic ALK-Positive Non-Small Cell Lung Cancer

NEW YORK, November 21, 2013–(BUSINESS WIRE)–Pfizer Inc. announced today that the U.S. Food and Drug Administration (FDA) has granted Pfizer’s XALKORI® (crizotinib) regular approval for the treatment of patients with metastatic ALK-positive non-small cell lung cancer (NSCLC) as detected by an FDA-approved test. XALKORI was previously granted accelerated approval in August 2011 due to the critical need for new agents for people living with ALK-positive NSCLC

read all at

http://www.pharmalive.com/pfizer%E2%80%99s-xalkori-granted-regular-fda-approval

https://newdrugapprovals.wordpress.com/2013/03/01/pfizer-gains-china-approval-of-kinase-specific-lung-cancer-drug-xalkori-crizotinib/

Daiichi Sankyo anticoagulant edoxaban succeeds in Phase III

November 21, 2013 3:59 am / 1 Comment on Daiichi Sankyo anticoagulant edoxaban succeeds in Phase III

Edoxaban, DU-176b

Daiichi Sankyo, APPROVED IN JAPAN as tosylate monohydrate salt in 2011 for the prevention of venous embolism in patients undergoing total hip replacement surgery

for synthesis see….http://www.sciencedirect.com/science/article/pii/S0968089613002642 Bioorganic & Medicinal Chemistry 21 (2013) 2795–2825, see s[pecific page 2808 for description ie 14/31 of pdf

WO 2010071121, http://www.google.com/patents/WO2010071121A1

WO 2007032498

N’-(5-chloropyridin-2-yl)-N-[(1S,2R,4S)-4-(dimethylcarbamoyl)-2-[(5-methyl-6,7-dihydro-4H-[1,3]thiazolo[5,4-c]pyridine-2-carbonyl)amino]cyclohexyl]oxamide

NOV20, 2013

Daiichi Sankyo will file edoxaban on both sides of the Atlantic shortly after the bloodthinner proved as effective and safer than warfarin in a Phase III trial of patients with atrial fibrillation.

The company has presented data on edoxaban, a once-daily oral factor Xa inhibitor, at the American Heart Association meeting in Dallas, from a study involving 21,105 patients across 46 countries. The drug, evaluated in 60mg and 30mg doses, met its primary endpoint of non-inferiority compared to warfarin for the prevention of stroke or systemic embolic events in patients with non-valvular AF.http://www.pharmatimes.com/Article/13-11-20/Daiichi_Sankyo_anticoagulant_edoxaban_succeeds_in_Phase_III.aspx

Edoxaban (INN, codenamed DU-176b, trade name Lixiana) is an anticoagulant drug which acts as a direct factor Xa inhibitor. It is being developed by Daiichi Sankyo. It was approved in July 2011 in Japan for prevention of venous thromboembolisms (VTE) following lower-limb orthopedic surgery.^[1]

In animal studies, edoxaban is potent, selective for factor Xa and has good oral bioavailability.^[2]

Daichi Sankyo’s edoxaban tosilate is an orally administered
coagulation factor Xa inhibitor that was approved and launched
in Japan for the preventive treatment of venous thromboembolic
events (VTE) in patients undergoing total knee arthroplasty, total
hip arthroplasty, or hip fracture surgery. Edoxaban has been
shown to have a rapid onset of anticoagulant effect due to short
Tmax (1–2 h) after dosing and sustained for up to 24 h post-dose.
Marketed under the brand name Lixiana, it is currently in phase
III studies in the US for the prevention of stroke and systemic embolic
events in patients with atrial fibrillation (AF) and venous
thromboembolism (VTE).

Several Phase II clinical trials have been conducted, for example for thromboprophylaxis after total hip replacement^[3] (phase III early results compare well to enoxaparin^[4]), and for stroke prevention in patients with atrial fibrillation^[5]^[6].Those papers follow similar recent major trials showing similar results for the other new factor Xa inhibitors, rivaroxaban and apixaban.

A large phase III trial showed that edoxaban was non inferior to warfarin in preventing recurrent venous thromboembolic events with fewer episodes of major bleeding.^[7]

“First market approval in Japan for LIXIANA (Edoxaban)”. Press Release. Daiichi Sankyo Europe GmbH. 2011-04-22.
Furugohri T, Isobe K, Honda Y, Kamisato-Matsumoto C, Sugiyama N, Nagahara T, Morishima Y, Shibano T (September 2008). “DU-176b, a potent and orally active factor Xa inhibitor: in vitro and in vivo pharmacological profiles”. J. Thromb. Haemost. 6 (9): 1542–9. doi:10.1111/j.1538-7836.2008.03064.x. PMID 18624979.
Raskob, G.; Cohen, A. T.; Eriksson, B. I.; Puskas, D.; Shi, M.; Bocanegra, T.; Weitz, J. I. (2010). “Oral direct factor Xa inhibition with edoxaban for thromboprophylaxis after elective total hip replacement”. Thrombosis and Haemostasis 104 (3): 642–649. doi:10.1160/TH10-02-0142.PMID 20589317. edit
“Phase III Trial Finds Edoxaban Outclasses Enoxaparin in Preventing Venous Thromboembolic Events”. 8 Dec 2010.
Weitz JI, Connolly SJ, Patel I, Salazar D, Rohatagi S, Mendell J, Kastrissios H, Jin J, Kunitada S (September 2010). “Randomised, parallel-group, multicentre, multinational phase 2 study comparing edoxaban, an oral factor Xa inhibitor, with warfarin for stroke prevention in patients with atrial fibrillation”. Thromb. Haemost. 104 (3): 633–41. doi:10.1160/TH10-01-0066.
Edoxaban versus Warfarin in Patients with Atrial Fibrillation Robert P. Giugliano, M.D., Christian T. Ruff, M.D., M.P.H., Eugene Braunwald, M.D., Sabina A. Murphy, M.P.H., Stephen D. Wiviott, M.D., Jonathan L. Halperin, M.D., Albert L. Waldo, M.D., Michael D. Ezekowitz, M.D., D.Phil., Jeffrey I. Weitz, M.D., Jindřich Špinar, M.D., Witold Ruzyllo, M.D., Mikhail Ruda, M.D., Yukihiro Koretsune, M.D., Joshua Betcher, Ph.D., Minggao Shi, Ph.D., Laura T. Grip, A.B., Shirali P. Patel, B.S., Indravadan Patel, M.D., James J. Hanyok, Pharm.D., Michele Mercuri, M.D., and Elliott M. Antman, M.D. for the ENGAGE AF-TIMI 48 InvestigatorsDOI: 10.1056/NEJMoa1310907
“Edoxaban versus Warfarin for the Treatment of Symptomatic Venous Thromboembolism”. N. Engl. J. Med. August 2013. doi:10.1056/NEJMoa1306638. PMID 23991658.
WO 03/000657 pamphlet WO 03/000680 pamphlet WO 03/016302 pamphlet WO 04/058715 pamphlet WO 05/047296 pamphlet WO 07/032498 pamphlet WO 08/129846 pamphlet WO 08/156159 pamphlet
J Am Chem Soc 1978, 100(16): 5199

Drug formulation , lixiana, edoxaban tosylate monohydrate, CAS 912273-65-5, C24 H30 Cl N7 O4 S . C7 H8 O3 S . H2 O, 738.274

N¹-(5-chloropyridin-2-yl)-N²-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamide p-toluenesulfonic acid monohydrate represented by the following formula (A) (hereinafter, also referred to as compound A) :
is known as a compound that exhibits an inhibitory effect on activated blood coagulation factor X (FXa), and is useful as a preventive and/or therapeutic drug for thrombotic diseases (Patent Literature 1 to 8).
For example, a method comprising mixing the free form of compound A represented by the following formula (B) (hereinafter, also referred to as compound B):
with p-toluenesulfonic acid or p-toluenesulfonic acid monohydrate, followed by crystallization from aqueous ethanol, is known as a method for obtaining compound A (Patent Literature 1 to 8). These literature documents do not make any mention about adding p-toluenesulfonic acid or p-toluenesulfonic acid monohydrate in a stepwise manner in the step of obtaining compound A from compound B.

Citation ListPatent Literature

- Patent Literature 1: International Publication No. WO 03/000657
- Patent Literature 2: International Publication No. WO 03/000680
- Patent Literature 3: International Publication No. WO 03/016302
- Patent Literature 4: International Publication No. WO 04/058715
- Patent Literature 5: International Publication No. WO 05/047296
- Patent Literature 6: International Publication No. WO 07/032498
- Patent Literature 7: International Publication No. WO 08/129846
- Patent Literature 8: International Publication No. WO 08/156159

SIMILAR

OTHER SALTS

Edoxaban hydrochloride
CAS Number: 480448-29-1
Molecular Formula: C₂₄H₃₀ClN₇O₄S · HCl
Molecular Weight: 584.52 g.mol^-1

Edoxaban is reported to be a member of the so-called “Xaban-group” and as such to be a low molecular inhibitor of the enzyme factor Xa, participating in the blood coagulation system. Therefore, edoxaban is classified as an antithrombotic drug and its possible medical indications are reported to be treatment of thrombosis and thrombosis prophylaxis after orthopaedic operations, such as total hip replacement, as well as for stroke prevention in patients with atrial fibrillation, the prophylaxis of the acute coronary syndrome and the prophylaxis after thrombosis and pulmonary embolism.

The IUPAC name for edoxaban is N’-(5-chloropyridin-2-yl)-N-[(15,2^,4S)-4- (dimethylcarbamoyl)-2-[(5-methyl-6,7-dihydro-4H-[l ,3]thiazolo[5,4-c]pyridine-2- carbonyl)amino]cyclohexyl]oxamide. The chemical structure of edoxaban is shown in the formula (1) below:

formula ( 1 ) While Edoxaban is reported to be soluble in strongly acidic aqueous solutions, its solubility is considered to be very low in neutral or alkaline aqueous media. EP 2 140 867 A 1 claims an edoxaban-containing pharmaceutical composition comprising a water-swelling additive and/or a sugar alcohol. Further, it is alleged that compositions comprising lactose or cornstarch do not have good dissolution properties. The claimed pharmaceutical compositions in EP 2 140 867 Al are considered to show good dissolution properties in a neutral aqueous medium as well. Tablets comprising said composition were produced by wet granulation. However, it turned out that prior art pharmaceutical formulations comprising edoxaban being suitable for oral administration are still improvable with regards to dissolution rate and bioavailability. Further, stability and content uniformity of the known formulations could be improved. Further, due to the intolerance of many people to sugar alcohol(s), such as sorbitol, the use of sugar alcohol(s) should be avoided.

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NDA..020547 26/09/1996, ACCOLATE, ASTRAZENECA, 20MG TABLET

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An Improved and Scalable Process for Zafirlukast: An Asthma Drug

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1. February 27, 2013. N13/36. STATEMENT ON A NONPROPRIETARY NAME ADOPTED BY THE USAN COUNCIL. USAN (ZZ-19). SUCROFERRIC …

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VB-111 – highly targeted anti-angiogenic agent for the specific inhibition of tumor vascular growth

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Simeprevir

923604-59-5 CAS

C38H47N5O7S MF

749.93908 MW

November 22, 2013 — The U.S. Food and Drug Administration approved Olysio (simeprevir), a new therapy to treat chronic hepatitis C virus infection.

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