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Merck’s New Drug Application for an Investigational Intravenous (IV) Formulation of NOXAFIL® (posaconazole) Receives FDA Priority Review

November 19, 2013 1:06 am / 1 Comment on Merck’s New Drug Application for an Investigational Intravenous (IV) Formulation of NOXAFIL® (posaconazole) Receives FDA Priority Review

Posaconazole, SCH 56592, Noxafil (Schering-Plough)

Posaconazole is a triazole antifungal drug that is used to treat invasive infections by Candida species and Aspergillus species in severely immunocompromised patients.

For prophylaxis of invasive Aspergillus and Candida infections in patients, 13 years of age and older, who are at high risk of developing these infections due to being severely immunocompromised as a result of procedures such as hematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease (GVHD), or due to hematologic malignancies with prolonged neutropenia from chemotherapy. Also for the treatment of oropharyngeal candidiasis, including oropharyngeal candidiasis refractory to itraconazole and/or fluconazole. Posaconazole is used as an alternative treatment for invasive aspergillosis, Fusarium infections, and zygomycosis in patients who are intolerant of, or whose disease is refractory to, other antifungals

Posaconazole is designated chemically as 4-[4-[4-[4-[[ (3R,5R)-5- (2,4-difluorophenyl)tetrahydro-5-(1H-1,2,4-triazol-1 -ylmethyl)-3-furanyl]methoxy]phenyl]-1 -piperazinyl]phenyl]-2-[ (1S,2S)-1 -ethyl-2- hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one with an empirical formula of C₃₇H₄₂F₂N₈O₄ and a molecular weight of 700.8.

Posaconazole is used, for example, to prevent and/or treat invasive fungal infections caused by Candida species, Mucor species, Aspergillus species,Fusarium species, or Coccidioides species in immunocompromised patients and/or in patients where the disease is refractory to other antifungal agents such as amphothericin B, fluconazole, or itraconazole, and/or in patients who do not tolerate these antifungal agents.

CAS No. 171228-49-2

Posaconazole compounds have been described inU.S. Pat. Appl. No. 2003/0055067 for “Antifungal Composition with Enhanced Bioavailability,” U.S. Pat. Appl. No. 2004/0058974 for “Treating Fungal Infections,” and European Patent Publication1372394 (A1 ) for “Liquid Suspensions of Posaconazole (SCH 56592) with Enhanced Bioavailability for Treating Fungal Infections.”

Synonyms:	Pcz;Pos;Noxafil;Sch 56592;Aids058495;Aids-058495;Posconazole;Posaconazole;Posaconazole for research;HYDROXYPROPYL]-2,4-DIHYDRO-3H-1,2,4-TRIAZOL-3-ONE

Molecular Formula:	C37H42F2N8O4
Formula Weight:	700.78

Merck’s New Drug Application for an Investigational Intravenous (IV) Formulation of NOXAFIL® (posaconazole) Receives FDA Priority Review

Marketing Authorization Application also Filed with the European Medicines Agency

WHITEHOUSE STATION, N.J., Nov. 18, 2013–(BUSINESS WIRE)–Merck (NYSE:MRK), known as MSD outside the United States and Canada, today announced that its New Drug Application for an investigational intravenous (IV) solution formulation of the company’s antifungal agent, NOXAFIL® (posaconazole), has been accepted for priority review by the U.S. Food and Drug Administration (FDA).http://www.pharmalive.com/mercks-noxafil-nda-gets-fda-priority-review

Posaconazole (CAS Registry Number 171228-49-2; CAS Name: 2,5-anhydro-1 ,3,4-trideoxy-2- C-(2,4-difluorophenyl)-4-[[4-[4-[4-[1-[(1S,2S)-1-ethyl-2-hydroxypropyl]-1 ,5-dihydro-5-oxo-4H- 1 ,2,4-triazol-4-yl]phenyl]-1-piperazinyl]phenoxy]methyl]-1-(1 H-1 ,2,4-triazol-1-yl)-D-threo-pentitol) which is represented by the following general formula (I)

(I)

is known as an antifungal agent. It is available as an oral suspension (40 mg/ml) under the trademark NOXAFIL^® from Schering Corporation, Kenilworth, NJ. WO95/17407 and WO 96/38443 disclose the compound having the general formula (I) and its use in treating fungal infections. Various pharmaceutical compositions comprising posaconazole and being adapted for oral, topical or parenteral use are described e.g. in WO 02/80678, U.S. Patent No. 5,972,381 , U.S. Patent No. 5,834,472, U.S. Patent No. 4,957,730 and WO 2005/117831. As was mentioned above, WO 95/17407 and WO 96/38443 disclose the compound having the general formula (I). However, during prosecution of the subsequently filed European patent application no. 98951994.7, now European patent EP 1 021 439 B1 , the applicant declared that the methods disclosed in these publications only lead to the compound of formula (I) as an amorphous solid.

Polymorphism is a phenomenon relating to the occurrence of different crystal forms for one molecule. There may be several different crystalline forms for the same molecule with distinct crystal structures and distinct and varying physical properties like melting point, XRPD pattern, IR-spectrum and solubility profile. These polymorphs are thus distinct solid forms which share the molecular formula of the compound from which the crystals are made up, however, they may have distinct advantageous physical properties which can have a direct effect on the ability to process and/or manufacture the drug product, like flowability, as well as physical properties such as solubility, stability and dissolution properties which can have a direct effect on drug product stability, solubility, dissolution, and bioavailability.

Three polymorphic forms of posaconazole designated as forms I, Il and III are described and characterized in WO 99/18097 (US-B-6,713,481 , US-B-6,958,337). Crystalline forms Il and III were found to be unstable under the conditions investigated, so that crystalline form I was considered to be useful in the development of a pharmaceutical product.

A. K. Saksena et al., WO 9517407; eidem, US 5661151 (1995, 1997 both to Schering);

eidem, Tetrahedron Lett. 37, 5657 (1996).

SCH-56592, a novel orally active broad spectrum antifungal agent35th Intersci Conf Antimicrob Agents Chemother (Sept 17-20, San Francisco) 1995,Abst F61

seeSaksena, A.K.; Girijavallabhan, V.M.; Lovey, R.G.; Pike, R.E.; Wang, H.; Liu, Y.-T.; Ganguly, A.K.; Bennett, F. (Schering Corp.) EP 0736030; JP 1997500658; US 5661151; US 5703079; WO 9517407

Process for the preparation of triazolonesWO 9633178

Mono N-arylation of piperazine(III): Metal-catalyzed N-arylation and its application to the novel preparations of the antifungal posaconazole and its advanced intermediateTetrahedron Lett 2002,43(18),3359

Comparative antifungal spectrum: A. Cacciapuoti et al., Antimicrob. Agents Chemother. 44, 2017 (2000).

Pharmacokinetics, safety and tolerability: R. Courtney et al., ibid. 47, 2788 (2003).

HPLC determn in serum: H. Kim et al., J. Chromatogr. B 738, 93 (2000).

Review of development: A. K. Saksena et al. inAnti-Infectives: Recent Advances in Chemistry and Structure Activity Relationships (Royal Soc. Chem., Cambridge, 1997) pp 180-199; and clinical efficacy in fungal infections: R. Herbrecht, Int. J. Clin. Pract. 58, 612-624 (2004).

synthesis 1

……………..

Synthesis of intermediate (XX): The reaction of 2-chloro-2′,4′-difluoroacetophenone (I) with sodium acetate and NaI in DMF gives 2-acetoxy-2′,4′-difluoroacetophenone (II), which by methylenation with methyltriphenylphosphonium bromide and sodium bis(trimethylsilyl)amide in THF yields 2-(2,4-difluorophenyl)-2-propen-1-ol acetate ester (III). The hydrolysis of (III) with KOH in dioxane/water affords the corresponding alcohol (IV), which is regioselectively epoxidized with titanium tetraisopropoxide and L-(+)-diethyl tartrate in dichloromethane to (S)-(-)-2-(2,4-difluorophenyl)oxirane-2-methanol (V). The reaction of (V) with 1,2,4-triazole (VI) in DMF affords (R)-2-(2,4-difluorophenyl)-3-(1,2,4-triazol-1-yl)propane-1,2-diol (VII), which is selectively mesylated with methanesulfonyl chloride and triethylamine to the monomesylate (VIII). The cyclization of (VIII) with NaH in DMF gives the oxirane (IX), which is condensed with diethyl malonate (X) by means of NaH in DMSO to yield a mixture of (5R-cis)- and (5R-trans)-5-(2,4-difluorophenyl)-2-oxo-5-(1,2,4-triazol-1-ylmethyl) tetrahydrofuran-3-carboxylic acid ethyl ester (XI). The reduction of (XI) with NaBH4 and LiCl in ethanol affords (R)-4-(2,4-difluorophenyl)-2-(hydroxymethyl)-5-(1,2,4-triazol-1-yl) pentane-1,4-diol (XII), which is selectively tosylated with tosyl chloride and triethylamine in THF to the bistosylate (XIII). The cyclization of (XIII) by means of NaH in refluxing toluene gives (5R-cis)-5-(2,4-difluorophenyl)-5-(1,2,4-triazol-1-ylmethyl) tetrahydrofuran-3-methanol tosylate ester (XIV). The reaction of (XIV) with 1-(4-hydroxyphenyl)-4-(4-nitrophenyl)piperazine (XV) to obtain compound (XVI), and the following reaction sequence (XVI) to (XVII) to (XVIII) to (XIX) to (5R-cis)-4-[4-[4-[4-[5-(2,4-difluorophenyl)-5-(1,2,4-triazol-1-ylmethyl)tetrahydrofuran-3-ylmethoxy]phenyl]piperazin-1-yl]phenyl-3,4-dihydro-2H-1,2,4-triazol-3-one (XX) has been performed according to J Med Chem 1984, 27: 894-900.

………………….pat approved expiry

United States	5661151	1999-07-19	2019-07-19
Canada	2305803	2009-12-22	2018-10-05
Canada	2179396	2001-04-17	2014-12-20
United States	5703079	1994-08-26	2014-08-26

MORE INFO

US Patent No	Patent expiry
5661151	Jul 19, 2019
5703079	Aug 26, 2014
6958337	Oct 5, 2018
8263600	Apr 1, 2022

Cornely OA, Maertens J, Winston DJ, Perfect J, Ullmann AJ, Walsh TJ, Helfgott D, Holowiecki J, Stockelberg D, Goh YT, Petrini M, Hardalo C, Suresh R, Angulo-Gonzalez D: Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia. N Engl J Med. 2007 Jan 25;356(4):348-59. Pubmed
Ullmann AJ, Lipton JH, Vesole DH, Chandrasekar P, Langston A, Tarantolo SR, Greinix H, Morais de Azevedo W, Reddy V, Boparai N, Pedicone L, Patino H, Durrant S: Posaconazole or fluconazole for prophylaxis in severe graft-versus-host disease. N Engl J Med. 2007 Jan 25;356(4):335-47. Pubmed
Bhattacharya M, Rajeshwari K, Dhingra B: Posaconazole. J Postgrad Med. 2010 Apr-Jun;56(2):163-7. Pubmed
Frampton JE, Scott LJ: Posaconazole : a review of its use in the prophylaxis of invasive fungal infections. Drugs. 2008;68(7):993-1016.Pubmed
Schiller DS, Fung HB: Posaconazole: an extended-spectrum triazole antifungal agent. Clin Ther. 2007 Sep;29(9):1862-86. Pubmed
Kwon DS, Mylonakis E: Posaconazole: a new broad-spectrum antifungal agent. Expert Opin Pharmacother. 2007 Jun;8(8):1167-78.Pubmed
Groll AH, Walsh TJ: Posaconazole: clinical pharmacology and potential for management of fungal infections. Expert Rev Anti Infect Ther. 2005 Aug;3(4):467-87. Pubmed
Rachwalski EJ, Wieczorkiewicz JT, Scheetz MH: Posaconazole: an oral triazole with an extended spectrum of activity. Ann Pharmacother. 2008 Oct;42(10):1429-38. Epub 2008 Aug 19. Pubmed
Li Y, Theuretzbacher U, Clancy CJ, Nguyen MH, Derendorf H: Pharmacokinetic/pharmacodynamic profile of posaconazole. Clin Pharmacokinet. 2010 Jun;49(6):379-96. doi: 10.2165/11319340-000000000-00000. Pubmed

FDA Approves Implanted Brain Stimulator for Epilepsy

November 15, 2013 3:27 am / 2 Comments on FDA Approves Implanted Brain Stimulator for Epilepsy

epilepsy

THURSDAY Nov. 14, 2013 — The U.S. Food and Drug Administration on Thursday gave its approval to a new implanted device that lowers the rate of seizures among people with epilepsy

http://www.drugs.com/news/fda-approves-implanted-brain-stimulator-epilepsy-48978.html

Ixabepilone for breast cancer

November 12, 2013 12:47 pm / 1 Comment on Ixabepilone for breast cancer

Ixabepilone, 219989-84-1 cas

(1R,5S,6S,7R,10S,14S,16S)-6,10-dihydroxy-1,5,7,
9,9-pentamethyl-14-[(E)-1-(2-methyl-1,3-thiazol-
4-yl)prop-1-en-2-yl]-17-oxa-13-azabicyclo[14.1.0]
heptadecane-8,12-dione

Ixabepilone (INN; also known as azaepothilone B, codenamed BMS-247550) is an epothilone B analog developed byBristol-Myers Squibb as a chemotherapeutic medication for cancer.

It is produced by Sorangium cellulosum.

It acts to stabilize microtubules. It is highly potent agent, capable of damaging cancer cells in very low concentrations, and retains activity in cases where tumor cells are insensitive to paclitaxel.

On October 16, 2007, the U.S. Food and Drug Administration approved ixabepilone for the treatment of aggressive metastaticor locally advanced breast cancer no longer responding to currently available chemotherapies. In November 2008, the EMEAhas refused a marketing authorisation for Ixabepilone.

Ixabepilone is administered through injection, and is marketed under the trade name Ixempra.

patent approval expiry

United States	7312237	2004-08-21	2024-08-21
United States	6605599	1998-05-26	2018-05-26

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	Type	RLD	US Patent No.
Bristol Myers Squibb	IXEMPRA KIT	ixabepilone	INJECTABLE;IV (INFUSION)	022065	Oct 16, 2007	RX	Yes	RE41911*PED
Bristol Myers Squibb	IXEMPRA KIT	ixabepilone	INJECTABLE;IV (INFUSION)	022065	Oct 16, 2007	RX	Yes	RE41393*PED
Bristol Myers Squibb	IXEMPRA KIT	ixabepilone	INJECTABLE;IV (INFUSION)	022065	Oct 16, 2007	RX	Yes	7,312,237*PED
Bristol Myers Squibb	IXEMPRA KIT	ixabepilone	INJECTABLE;IV (INFUSION)	022065	Oct 16, 2007	RX	Yes	7,125,899*PED

Patent No	Patent Expiry	patent use code
6670384	Jan 23, 2022	U-959
6670384	Jan 23, 2022	U-960
6670384*PED	Jul 23, 2022
7022330	Jan 23, 2022	U-958
7022330*PED	Jul 23, 2022
7125899	May 26, 2018	U-957
7125899*PED	Nov 26, 2018
7312237	Aug 21, 2024	U-965
7312237*PED	Feb 21, 2025
RE41393	Feb 8, 2022	U-961
RE41393*PED	Aug 8, 2022
RE41911	Sep 28, 2020	U-961
RE41911*PED	Mar 28, 2021

Exclusivity Code	ExclusivityDate
NCE	Oct 16, 2012
PED	Apr 18, 2015
M-61	Oct 18, 2014
PED	Apr 16, 2013

Exclusivity Code	ExclusivityDate
NCE	Oct 16, 2012

Ixabepilone, in combination with capecitabine, has demonstrated effectiveness in the treatment of metastatic or locally advanced breast cancer in patients after failure of an anthracycline and a taxane.

It has been investigated for use in treatment of non-Hodgkin’s lymphoma. In pancreatic cancer phase two trial it showed some promising results (used alone). Combination therapy trials are ongoing.

Ixabepilone is an anti cancer agent acting as a microtubule inhibitor, and which in particular are efficient in the treatment of cancer not reacting to other anti cancer agents, such as e.g. paclitaxel. Ixabepilone is marketed under the trade name Ixempra® and are approved for the treatment of aggressive metastatic or locally advanced breast cancer which not responding to the current prevailing chemotherapies.

Ixabepilone known under the CAS no. 219989-84-1 has the following structure:

Ixabepilone

Ixabepilone may be prepared from a starting material named epothilone B having the structural formula:

Epothilone B Ixabepilone as a compound is described in the USRE4191 1. USRE4191 1 furthermore disclose a process for synthesizing Ixabepilone.

The US 6,365,749 describes a process for making ixabepilone by reacting epothilone B with a palladium catalyst in the presence of a nucleophilic donor.

The USRE39356 do also describe a process for making Ixabepilone by reacting epothilone B with an azide donor agent and a reducing agent in the presence of a phase transfer catalyst and a palladium catalyst.

Ixabepilone is the treatment of metastatic and advanced breast cancer drugs.Ixabepilone as anticancer drugs alone or in combination with capecitabine (Capecitabine) in combination. October 16, 2007 approved for marketing by the FDA, trade name Ixempra, by the Bristol-Myers Squibb Company’s development.
Ixabepilone is an anti-mitotic drugs that are inhibitors of tubulin, the mechanism and paclitaxel (Taxol) the same class of drugs. Epothilone (Epothilone) by colistin (myxobacterium) Sorangium cellulosum fermentation of several macrolide metabolites in general. Anticancer activity in vitro experiments, epothilone A and epothilone B showed good activity, even in the paclitaxel-resistant cells also showed good activity. But its activity in vivo experiments in general, this is probably due to the body of the ester hydrolases that macrolide ring opening induced inactivation. In a series of epothilone derivatives activity test, it was found with the lactam bond instead of the original product of ester bonds – ixabepilone anticancer activity can be well retained.
Ixabepilone is epothilone B semi-synthetic derivatives. Epothilone B is a macrocyclic lactone, a hydroxyl moiety is allyl alcohol, the Pd catalyst can be obtained by ring-opening Pd complexes 1 , 1 received azide nucleophile attacking the anion generated with three azide product phosphorus reduction to give methyl amino acids 2 . Here we must point out that the attack was completely azide stereoselectivity, which is determined by two consecutive trans-attack lead, Pd (0)-trans lactone generate offensive allyl Pd complexes, to accept anti-azide anion type attack, to maintain the configuration of the product obtained. Amino acids 2 HoBt and EDCI generated by an amide bond to get ixabepilone.

IXEMPRA (ixabepilone) is a microtubule inhibitor belonging to a class of antineoplastic agents, the epothilones and their analogs. The epothilones are isolated from the myxobacterium Sorangium cellulosum. Ixabepilone is a semisynthetic analog of epothilone B, a 16-membered polyketide macrolide, with a chemically modified lactam substitution for the naturally existing lactone.

The chemical name for ixabepilone is (1S,3S,7S,10R,11S,12S,16R)-7,11dihydroxy-8,8,10,12,16-pentamethyl-3-[(1E)-1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]17-oxa-4-azabicyclo[14.1.0] heptadecane-5,9-dione, and it has a molecular weight of 506.7. Ixabepilone has the following structural formula:

IXEMPRA® Kit (ixabepilone) Structural Formula Illustration

IXEMPRA (ixabepilone) for injection is intended for intravenous infusion only after constitution with the supplied DILUENT and after further dilution with a specified infusion fluid . IXEMPRA (ixabepilone) for injection is supplied as a sterile, non-pyrogenic, single-use vial providing 15 mg or 45 mg ixabepilone as a lyophilized white powder. The DILUENT for IXEMPRA is a sterile, non-pyrogenic solution of 52.8% (w/v) purified polyoxyethylated castor oil and 39.8% (w/v) dehydrated alcohol, USP. The IXEMPRA (ixabepilone) for injection and the DILUENT for IXEMPRA are co-packaged and supplied as IXEMPRA Kit.

….

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DR ANTHONY MELVIN CRASTO Ph.D

amcrasto@gmail.com

MOBILE-+91 9323115463

GLENMARK SCIENTIST , NAVIMUMBAI, INDIA

Aptiom (eslicarbazepine acetate) has been approved by the U.S. Food and Drug Administration as an add-on drug to help treat adults with partial epileptic seizures.

November 12, 2013 9:20 am / 1 Comment on Aptiom (eslicarbazepine acetate) has been approved by the U.S. Food and Drug Administration as an add-on drug to help treat adults with partial epileptic seizures.

Eslicarbazepine acetate, 236395-14-5 cas no

(S)-10-Acetoxy- 10,11-dihydro- 5H-dibenz[b,f]azepine- 5-carboxamide
Sunovion Pharmaceuticals Inc. A US-based subsidiary of Japanese drugmaker Dainippon Sumitomo Pharma Announces FDA Approval of Aptiom® (eslicarbazepine acetate) as Once-Daily Adjunctive Treatment of Partial-Onset Seizures
MONDAY Nov. 11, 2013 — Aptiom (eslicarbazepine acetate) has been approved by the U.S. Food and Drug Administration as an add-on drug to help treat adults with partial epileptic seizures.

Epilepsy, caused by abnormal activity in the brain’s nerve cells, is diagnosed in some 200,000 people annually in the United States, the agency said in a news release. So-called “partial” seizures are the most common type of seizure among people with epilepsy, triggering possible symptoms including repetitive movement of limbs, unusual behavior and convulsions.http://www.drugs.com/news/aptiom-approved-seizures-48845.html

The FDA has determined that APTIOM will not be classified as a controlled substance. Sunovion expects APTIOM to be available in U.S. pharmacies in the second quarter (April – June) of 2014

APTIOM, a voltage-gated sodium channel inhibitor, is a prescription medicine approved for use as adjunctive treatment of partial-onset seizures. Treatment with APTIOM should be initiated at 400 mg once daily. After one week, dosage may be increased to the recommended maintenance dosage of 800 mg once daily. Some patients may benefit from the maximum recommended maintenance dosage of 1,200 mg once daily, although this dosage is associated with an increase in adverse reactions. The maximum dose of 1,200 mg daily should only be initiated after the patient has tolerated 800 mg daily for at least a week. For some patients, treatment may be initiated at 800 mg once daily if the need for additional seizure reduction outweighs an increased risk of adverse reactions during initiation.

The initial research and development of eslicarbazepine acetate was performed by BIAL, a privately held Portuguese research-based pharmaceutical company. Subsequently, Sunovion acquired the rights under an exclusive license to further develop and commercialize eslicarbazepine acetate in the U.S. and Canadian markets from BIAL. In February 2009, Eisai Europe Limited, a European subsidiary of Eisai Co., Ltd. (Eisai), entered into a license and co-promotion agreement with BIAL, which gave the rights to Eisai to sell eslicarbazepine acetate under the trade name Zebinix^®in Europe. Zebinix was approved by the European Commission on April 21, 2009 as adjunctive therapy in adult patients with partial-onset seizures with or without secondary generalization and is currently marketed in Europe under the agreement.

Eslicarbazepine acetate (BIA 2-093) is an antiepileptic drug. It is a prodrug which is activated to eslicarbazepine (S–licarbazepine), an active metabolite of oxcarbazepine.^[1]

It is being developed by Bial^[2] and will be marketed as Zebinix or Exalief by Eisai Co. in Europe and as Stedesa by Sepracor^[3] in America.

The European Medicines Agency (EMA) has recommended granting marketing authorization in 2009 for adjunctive therapy for partial-onset seizures, with or without secondary generalisation, in adults with epilepsy.^[1] The U.S. Food and Drug Administration (FDA) announced on 2 June 2009 that the drug has been accepted for filing.^[3]

Eslicarbazepine acetate is a prodrug for S(+)-licarbazepine, the major active metabolite of oxcarbazepine.^[4] Its mechanism of action is therefore identical to that of oxcarbazepine. ^[5] There may, however, be pharmacokinetic differences. Eslicarbazepine acetate may not produce as high peak levels of (S)-(+)-licarbazepine immediately after dosing as does oxcarbazepine which could theoretically improve tolerability.

Like oxcarbazepine, eslicarbazepine may be used to treat bipolar disorder and trigeminal neuralgia.

The first European patent to protect this drug is EP 0751129 . The priority of this European patent is the Portuguese patent application PT 101732 .

Dulsat, C., Mealy, N., Castaner, R., Bolos, J. (2009). “Eslicarbazepine acetate”. Drugs of the Future 34 (3): 189. doi:10.1358/dof.2009.034.03.1352675.
Community register of medicinal products for human use: Exalief
Medical News Today: Sepracor’s STEDESA (Eslicarbazepine Acetate) New Drug Application Formally Accepted For Review By The FDA
Rogawski, MA (Jun 2006). “Diverse Mechanisms of Antiepileptic Drugs in the Development Pipeline”. Epilepsy Res 69 (3): 273–294. doi:10.1016/j.eplepsyres.2006.02.004. PMC 1562526. PMID 16621450.
Rogawski MA, Löscher W (July 2004). “The neurobiology of antiepileptic drugs”. Nature Reviews Neuroscience 5 (7): 553–64. doi:10.1038/nrn1430. PMID 15208697.
https://newdrugapprovals.wordpress.com/2013/03/11/sunovion-announces-fda-acceptance-for-review-of-new-drug-application-resubmission-for-stedesa-eslicarbazepine-acetate/

Eslicarbazepine acetate of Formula A, chemically known as (10S)-5-carbamoyl- 10,1 l-dihydro-5H-dibenzo[Z?,/]azepin- 10-yl acetate is indicated as adjunctive therapy in adults with partial-onset seizures with or without secondary generalisation.

Formula A

lO-oxo-10,1 l-dihydro-5H-dibenzo[Z?/]azepine-5-carboxamide of Formula 1, commonly known as oxcarbazepine, is an antiepileptic drug marketed under the trade name Trileptal^®and is indicated for use as monotherapy or adjunctive therapy in the treatment of partial seizures in adults and as monotherapy in the treatment of partial seizures in children aged 4 years and above with epilepsy, and as adjunctive therapy in children aged 2 years and above with epilepsy. Oxcarbazepine is an intermediate for the preparation of eslicarbazepine.

Formula 1

Several processes are known in the literature for making and purifying eslicarbazepine acetate, for example, U.S. Patent No 5,753,646; and PCT Publications WO 2006/005951 ; WO 2007/1 17166; and WO 2010/1 13179.

U.S. Patent No. 5,753,646 provides a process for the preparation of eslicarbazepine acetate which involves adding dropwise a solution of acetyl chloride in dichloromethane to a suspension of (-)- 10-hydroxy-10,l l-dihydro-5H-dibenz/b,f/azepine-5-carboxamide in dichloromethane and pyridine at a temperature of less than 10°C under stirring. The residue obtained after workup was crystallized from a mixture of dichloromethane and ethyl acetate to give the eslicarbazepine acetate as white crystals.

U.S Publication No. 2009/0203902 provides preparation of eslicarbazepine acetate which involves the acylation of (S)-(+)-10,l l-dihydro-10-hydroxy-5H-dibenz/b,f/azepine- 5-carboxamide with acetic anhydride in presence of 4-(N,N-dimethylamino)pyridine and pyridine in dichloromethane at reflux temperature. The resulting solid obtained after work-up was slurried with isopropanol at reflux to obtain a solution. The solution was cooled to 1°C to 5°C and eslicarbazepine acetate was isolated from the reaction mass by filtration followed by washing with isopropanol.

PCT Publication No. WO 2010/1 13179 provides various purification methods of eslicarbazepine acetate which involve the use of acetonitrile/methyl tertiary butyl ether, tetrahydrofuran/n-hexane, tetrahydrofuran/methyl tertiary butyl methyl ether;

tetrahydrofuran, methyl ethyl ketone/n-hexane.

Several processes are known in the literature for making oxcarbazepine, for example, U.S. Patent Nos. 4,452,738 and 7,459,553; PCT Publication Nos. WO

2010/000196; WO 2008/012837; WO 2007/141798; WO 2006/075925; WO 2005/122671 ; WO 2005/1 18550; WO 2005/096709; WO 2005/092862; WO

2005/066133; WO 02/096881 ; WO 00/55138; and WO 96/21649.

PCT Publication No. WO 02/096881 provides a process for the preparation of oxcarbazepine which involves oxidation of 10,1 1 -dihydro- 10-hydroxy-5H- dibenz/b,f/azepine-5-carboxamide with peroxyacetic acid in presence of potassium dichromate adsorbed on silica gel at room temperature.

Japanese Patent Publication No. JP 2004- 175761 provides a process for the preparation of oxcarbazepine which involves oxidation of 10, 1 1 -dihydro- 10-hydroxy-5H- dibenzo[b,f]azepine-5-carboxamide with dimethyl sulfoxide and an activator such as sulfur trioxide-pyridine complex.

Chinese Publication No. CN 101302198 provides a process for the preparation of oxcarbazepine which involves oxidation of 10-hydroxy- 10, l 1 -dihydro-5H- dibenzo[Z?/]azepine-5-carbonitrile with TEMPO and sodium hypochlorite to provide 10- oxo- 10,1 l-dihydro-5H-dibenzo[Z?/]azepine-5-carbonitrile which was further hydrolysed with sulfuric acid to obtain oxcarbazepine.

Eslicarbazepine acetate, (S)-(-)-10-acetoxy-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide (“BIA 2-093”), is a new drug currently being developed which is useful for the treatment of various conditions, such as, for example, epilepsy and affective brain disorders, as well as pain conditions and nervous function alterations in degenerative and post-ischemic diseases. Although chemically related to carbamazepine and oxcarbazepine, eslicarbazepine acetate is believed to avoid the production of certain toxic metabolites (such as, for example, epoxides) and to avoid the unnecessary production of enantiomers or diastereoisomers of metabolites and conjugates, without losing pharmacological activity. See Benes et al., “Anticonvulsant and Sodium Channel-Blocking Properties of Novel 10,11-Dihydro-5H-dibenz[b,f]azepine-5-carboxamide Derivatives,” J. Med. Chem., 42, 2582-2587 (1999).
Like carbamazepine and oxcarbazepine, eslicarbazepine acetate is believed to be a voltage-gated sodium channel (VGSC) blocker that competitively interacts with site 2 of the inactivated state of the sodium channel. The affinity for this state of the channel is similar to that of carbamazepine, while the affinity for the resting state of the channel is about 3-fold lower than that of carbamazepine. This profile may suggest an enhanced inhibitory selectivity of eslicarbazepine acetate for rapidly firing neurons over those displaying normal activity. See Bonifacio et al., “Interaction of the Novel Anticonvulsant, BIA 2-093, with Voltage-Gated Sodium Channels: Comparison with Carbamazepine,” Epilepsia, 42, 600-608(2001).
Evaluation of the metabolic profile of eslicarbazepine acetate, following chiral analysis, in liver microsomes from rats, dogs, monkeys and humans was found to give the S(+) enantiomer of licarbazepine, (S)-(+)-10,11-dihydro-10-hydroxy-5H dibenz/b,f/azepine-5-carboxamide (also known as “eslicarbazepine”), and not the R(-) form of licarbazepine, (R)-(-)-10,11-dihydro-10-hydroxy-5H dibenz/b,f/azepine-5-carboxamide (also known as “R-licarbazepine”).
Studies in humans have shown that, after oral administration, eslicarbazepine acetate appears to be rapidly and extensively metabolized to the active metabolite eslicarbazepine and, in a minor extent, to R-licarbazepine. See Silveira et al., “BIA 2-093 Pharmacokinetics in Healthy Elderly Subjects,” Epilepsia, 45 (suppl. 3), 157 (2004). For example, the plasma concentrations of the parent drug (eslicarbazepine acetate) have been systematically found below the limit of quantification (LOQ) of the assay (10 ng/mL). See Almeida I; Almeida, L. & Soares-da-Silva, P., “Safety, Tolerability and Pharmacokinetic Profile of BIA 2-093, a Novel Putative Antiepileptic Agent, during First Administration to Humans,” Drugs R&D, 4, 269-284 (2003) (herein referred to as “Almeida II“). When a non-chiral method is used, the assay does not distinguish between eslicarbazepine and the R-enantiomer, and the mixture was reported as “BIA 2-005” or “racemic licarbazepine.”
The inventors performed entry-into-man studies in healthy subjects, the results of which they described in the Almeida I and Almeida II articles, both of which are hereby incorporated by reference. In these studies, the healthy subjects received a single oral dose of eslicarbazepine acetate wherein the dose ranged from 20 mg to 1200 mg (see Almeida II), and multiple daily-doses of eslicarbazepine acetate ranging from 200 mg twice-daily to 1200 mg once-daily (see Almeida I). Further studies (not yet published) by the inventors have investigated higher doses of eslicarbazepine acetate, including, for example, doses ranging up to 2400 mg once-daily. The studies showed that BIA 2-005 maximum observed plasma concentration (C_max) was attained at about 1 hour to about 4 hours post-dose (t_max), the extent of systemic exposure to BIA 2-005 was approximately dose-proportional, and steady-state of BIA 2-005 plasma concentrations was attained at about 4 to 5 days. The mean renal clearance of BIA 2-005 from plasma was about 20-30 mL/min, and the total amount of BIA 2-005 recovered in the urine was approximately 20% and 40% within 12 hours and 24 hours post-dose, respectively.
The studies also showed that the apparent terminal half-life of BIA 2-005 ranged from about 8 hours to about 17 hours. See, e.g., Almeida II.
U.S. Patent No. 6,296,873 discloses a sustained release delivery system for carbamazepine, which has a half-life ranging from 25 hours to 85 hours. To avoid adverse effects, U.S. Patent No. 6,296,873 teaches that the carbamazepine should be administered in tablet form up to two or more times daily to slowly release the compound to maintain concentration levels between 4-12 µg/mL. Such a delivery system requires a form that is capable of delivering the compound over an extended period of time, such as a tablet form.

http://www.sciencedirect.com/science/article/pii/S0040403913005030

ESLICARBAZEPINE ACETATE

Physiochemical Pr operties:

Molecular weight	:	296.32
Category	:	Anti-epileptic
Molecular formula	:	C17H16N2O5
Chemical Name	:	(S)-(-)-10-acetoxy-10,11-dihydro-5H-dibenz [b, f]
		azepine-5-carboxamide.
Description	:	White to off-White, odourless, non-hygroscopic,
		crystalline powder.
Solubility	:	Freely soluble in dichloromethane, sparingly soluble
		in acetone, acetonitrile, methanol, tetrahydrofuran and
		slightly soluble in ethanol and 2-propanol, insoluble in
		water
Melting Point	:	184-187°C
Storage	:	Can be easily stored at temperatures up to 30°C

HPLC, NMR

NMR NUMBERING

http://www.sciencedirect.com/science/article/pii/S0731708511006753

Lorcaserin…Eisai Expands Marketing and Supply Agreement for Anti-obesity Agent Lorcaserin to Include Most Countries Worldwide

November 11, 2013 1:57 am / 2 Comments on Lorcaserin…Eisai Expands Marketing and Supply Agreement for Anti-obesity Agent Lorcaserin to Include Most Countries Worldwide

(1R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

Eisai Expands Marketing and Supply Agreement for Anti-obesity Agent Lorcaserin to Include Most Countries Worldwide

HATFIELD, England, November 8, 2013 /PRNewswire/ —

Eisai announces today that it has expanded the marketing and supply agreement between its U.S. subsidiary Eisai Inc. and U.S-based Arena Pharmaceuticals Inc.’s Swiss subsidiary, Arena Pharmaceuticals GmbH, for the anti-obesity agent lorcaserin hydrochloride (lorcaserin) (U.S. brand name: BELVIQ®). Whilst the existing agreement granted Eisai Inc. exclusive rights to market and distribute lorcaserin in 21 countries throughout the Americas, the expanded agreement now includes most countries and territories worldwide, most notably, the member states of the European Union, Japan and China (but excludes South Korea, Taiwan, Australia, New Zealand and Israel).http://www.pharmalive.com/eisai-expands-lorcaserin-marketing-and-supply-agreement

Lorcaserin (previously APD-356), a highly selective 5HT2C receptor agonist, is used for the treatment of obesity. It has been shown to reduce body weight and food intake in animal models of obesity, and it is thought that targeting the 5HT2C receptor may alter body weight by regulating satiety. Lorcaserin is marketed as a salt form called Belviq, which is lorcaserin hydrochloride.

Lorcaserin (APD-356, trade name upon approval Belviq, expected trade name during development, Lorqess) is aweight-loss drug developed by Arena Pharmaceuticals. It has serotonergic properties and acts as an anorectic. On 22 December 2009 a New Drug Application (NDA) was submitted to the Food and Drug Administration (FDA) in the United States. On 16 September 2010, an FDA advisory panel voted to recommend against approval of the drug based on concerns over both safety and efficacy. In October 2010, the FDA stated that it could not approve the application for lorcaserin in its present form.anti-obesity drug that Arena Pharmaceuticals is creation, Eisai Co., Ltd. has the right to sell “BELVIQ ®” (generic name lorcaserin hydrochloride) was to get the FDA approval on June 27, 2012

On 10 May 2012, after a new round of studies submitted by Arena, an FDA panel voted to recommend lorcaserin with certain restrictions and patient monitoring. The restrictions include patients with a BMI of over 30, or with a BMI over 27 and a comorbidity like high blood pressure or type 2 diabetes.

On 27 June 2012, the FDA officially approved lorcaserin for use in the treatment of obesity for adults with a BMI equal to or greater than 30 or adults with a BMI of 27 or greater who “have at least one weight-related health condition, such as high blood pressure, type 2 diabetes, or high cholesterol”.

On 7 May 2013, the US Drug Enforcement Administration has classified lorcaserin as a Schedule IV drug under the Controlled Substances Act.

Obesity is a life-threatening disorder in which there is an increased risk of morbidity and mortality arising from concomitant diseases such as type II diabetes, hypertension, stroke, cancer and gallbladder disease.

Obesity is now a major healthcare issue in the Western World and increasingly in some third world countries. The increase in numbers of obese people is due largely to the increasing preference for high fat content foods but also the decrease in activity in most people’s lives. Currently about 30% of the population of the USA is now considered obese.

Whether someone is classified as overweight or obese is generally determined on the basis of their body mass index (BMI) which is calculated by dividing body weight (kg) by height squared (m2). Thus, the units of BMI are kg/m² and it is possible to calculate the BMI range associated with minimum mortality in each decade of life. Overweight is defined as a BMI in the range 25-30 kg/m², and obesity as a BMI greater than 30 kg/m² (see table below).

Classification Of Weight By Body Mass Index (BMI)

As the BMI increases there is an increased risk of death from a variety of causes that are independent of other risk factors. The most common diseases associated with obesity are cardiovascular disease (particularly hypertension), diabetes (obesity aggravates the development of diabetes), gall bladder disease (particularly cancer) and diseases of reproduction. The strength of the link between obesity and specific conditions varies. One of the strongest is the link with type 2 diabetes. Excess body fat underlies 64% of cases of diabetes in men and 77% of cases in women (Seidell, Semin Vase Med, 5:3-14 (2005)). Research has shown that even a modest reduction in body weight can correspond to a significant reduction in the risk of developing coronary heart disease.

This compound is useful in the treatment of 5-HT₂c receptor associated disorders, such as, obesity, and is disclosed in PCT patent publication, WO2003/086303.

Various synthetic routes to (R)-8-chloro-l -methyl-2,3,4,5-tetrahydro-lH-3-benzazepine, its related salts, enantiomers, crystalline forms, and intermediates, have been reported in WO 2005/019179 WO2003/086303, WO 2006/069363, WO 2007/120517, WO 2008/07011 1 , WO 2009/111004, and WO 2010/148207 each of which is incorporated herein by reference in its entirety. Combinations of (R)-8-Chloro-l -methyl-2,3,4,5-tetrahydro-lH-3-benzazepine with other agents, including without limitation, phentermine, and uses of such combinations in therapy are described in WO 2006/071740, which is incorporated herein by reference in its entirety.

Lorcaserin is a selective 5-HT_2C receptor agonist, and in vitro testing of the drug showed reasonable selectivity for 5-HT_2Cover other related targets.^[14]^[15]^[16] 5-HT_2C receptors are located almost exclusively in the brain, and can be found in the choroid plexus, cortex, hippocampus, cerebellum, amygdala, thalamus, and hypothalamus. The activation of 5-HT_2C receptors in the hypothalamus is supposed to activate proopiomelanocortin (POMC) production and consequently promote weight loss throughsatiety.^[17] This hypothesis is supported by clinical trials and other studies. While it is generally thought that 5-HT_2C receptors help to regulate appetite as well as mood, and endocrine secretion, the exact mechanism of appetite regulation is not yet known. Lorcaserin has shown 100x selectivity for 5-HT_2C versus the closely related 5-HT_2B receptor, and 17x selectivity over the 5-HT_2A receptor.

BELVIQ (lorcaserin hydrochloride) is a serotonin 2C receptor agonist for oral administration used for chronic weight management. Its chemical name is (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride hemihydrate. The empirical formula is C₁₁H₁₅Cl₂N•0.5H₂O, and the molecular weight of the hemihydrate form is 241.16 g/mol.

The structural formula is:

BELVIQ (lorcaserin hydrochloride) Structural Formula Illustration

Lorcaserin hydrochloride hemihydrate is a white to off-white powder with solubility in water greater than 400 mg/mL. Each BELVIQ tablet contains 10.4 mg of crystalline lorcaserin hydrochloride hemihydrate, equivalent to 10.0 mg anhydrous lorcaserin hydrochloride, and the following inactive ingredients: silicified microcrystalline cellulose; hydroxypropyl cellulose NF; croscarmellose sodium NF; colloidal silicon dioxide NF, polyvinyl alcohol USP, polyethylene glycol NF, titanium dioxide USP, talc USP, FD&C Blue #2 aluminum lake, and magnesium stearate NF. NDA 022529 APPR2012-06-27 TO EISAI FOR BELVIQ 10 MG ORAL TAB

METHOD FOR CHRONIC WEIGHT MANAGEMENT BY DECREASING FOOD INTAKE U1252

Patent No US	PatentExpiry Date	patent use code

7514422	Apr 10, 2023	U-1252

7977329	Apr 10, 2023	U-1252

8168624	Apr 18, 2029
8207158	Apr 10, 2023	U-1252

8273734	Apr 10, 2023	U-1254

Exclusivity Code	Exclusivity_Date
NCE	Jun 27, 2017

Compound 1 is disclosed in PCT patent publication WO2003/086303, which is incorporated herein by reference in its entirety.

Combinations of (R)-8-Chloro-l -methyl-2,3,4,5-tetrahydro-lH-3-benzazepine with other agents, including without limitation, phentermine, and uses of such combinations in therapy are described in WO 2006/071740, which is incorporated herein by reference in its entirety

The following United States provisional applications are related to (R)-8-chloro-l- methyl-2,3,4,5-tetrahydro-lH-3-benzazepine: 61/402,578; 61/403,143; 61/402,580; 61/402,628; 61/403,149; 61/402,589; 61/402,611 ; 61/402,565; 61/403, 185; each of which is incorporated herein by reference in its entirety.

Approval History
Date	Supplement No.	Action	Documents
2012-06-27	000	Approval	Review Letter Label
2013-01-04	001	Manufacturing Change or Addition
2013-11-01	002	Manufacturing Change or Addition

This compound is useful in the treatment of 5-HT₂c receptor associated disorders, such as, obesity, and is disclosed in PCT patent publication, WO2003/086303.

Various synthetic routes to (R)-8-chloro-l -methyl-2,3,4,5-tetrahydro-lH-3-benzazepine, its related salts, enantiomers, crystalline forms, and intermediates, have been reported in WO 2005/019179, WO 2006/069363, WO 2007/120517, WO 2008/07011 1 , WO 2009/111004, and WO 2010/148207 each of which is incorporated herein by reference in its entirety. Combinations of (R)-8-Chloro-l -methyl-2,3,4,5-tetrahydro-lH-3-benzazepine with other agents, including without limitation, phentermine, and uses of such combinations in therapy are described in WO 2006/071740, which is incorporated herein by reference in its entirety.

3-Benzazepines have been found to be agonists of the 5HT_2Creceptor and show effectiveness at reducing obesity in animal models (see, e.g., U.S. Ser. No. 60/479,280 and U.S. Ser. No. 10/410,991, each of which is incorporated herein by reference in its entirety). Numerous synthetic routes to 3-benzazepines have been reported and typically involve a phenyl-containing starting material upon which is built an amine- or amide-containing chain that is capable of cyclizing to form the fused 7-member ring of the benzazepine core. Syntheses of 3-benzazepines and intermediates thereof are reported in U.S. Ser. No. 60/479,280 and U.S. Ser. No. 10/410,991 as well as Nair et al., Indian J. Chem., 1967, 5, 169; Orito et al., Tetrahedron, 1980, 36, 1017; Wu et al., Organic Process Research and Development,1997, 1, 359; Draper et al., Organic Process Research and Development, 1998, 2, 175; Draper et al., Organic Process Research and Development, 1998, 2, 186; Kuenburg et al., Organic Process Research and Development, 1999, 3, 425; Baindur et al., J. Med. Chem.,1992, 35(1), 67; Neumeyer et al., J. Med. Chem., 1990, 33, 521; Clark et al., J. Med. Chem.,1990, 33, 633; Pfeiffer et al., J. Med. Chem., 1982, 25, 352; Weinstock et al., J. Med. Chem., 1980, 23(9), 973; Weinstock et al., J. Med. Chem., 1980, 23(9), 975; Chumpradit et al., J. Med. Chem., 1989, 32, 1431; Heys et al., J. Org. Chem., 1989, 54, 4702; Bremner et al., Progress in Heterocyclic Chemistry, 2001, 13, 340; Hasan et al., Indian J. Chem., 1971, 9(9), 1022; Nagle et al., Tetrahedron Letters, 2000, 41, 3011; Robert, et al., J. Org. Chem., 1987, 52, 5594); and Deady et al., J. Chem. Soc., Perkin Trans. I, 1973, 782.

Other routes to 3-benzazepines and related compounds are reported in Ladd et al., J. Med. Chem., 1986, 29, 1904; EP 204349; EP 285 919; CH 500194; Tetrahedron Letters, 1986, 27, 2023; Ger. Offen., 3418270, 21 Nov. 1985; J. Org. Chem.,1985, 50, 743; U.S. Pat. Nos. 4,957,914 and 5,015,639; Synthetic Commun., 1988, 18, 671; Tetrahedron, 1985, 41, 2557;Hokkaido Daigaku Kogakubu Kenhyu Hokoku, 1979, 96, 414; Chemical & Pharmaceutical Bulletin, 1975, 23, 2584; J. Am. Chem. Soc., 1970, 92, 5686; J. Am. Chem. Soc., 1968, 90, 6522; J Am. Chem. Soc., 1968, 90, 776; J. Am. Chem. Soc.,1967, 89, 1039; and Chang et al., Bioorg. Med. Chem. Letters, 1992, 2, 399

Its synthesis starting from compound 1 and, via SN2 coupling to form 3, thionyl chloride, to form 4, aluminum chloride catalyzed Friedel-Crafts alkylation ring closure to give the racemic product 5, through L- tartaric acid separation, obtained chiral

SYNTHESIS

Smith, J.; Smith, B. 5HT_2C receptor modulators. U.S. Patent 2003225057, 2003.

Smith, B.; Smith, J. 5HT_2C receptor modulators. U.S. Patent 6953787, 2005

PATENT

http://www.google.com/patents/US8367657

Example 6 Preparation of 2-(4-Chlorophenyl)-N-ethyl-N-2-propylchloride

To a dry 100-milliliter, round bottom flask under nitrogen with stirring was added 2-(4-chlorophenyl)ethyl-N-2-chloropropionylamide (8.8 g, 35.8 mmol) followed by borane in THF (1.8 M, 70 mL, 140 mmol) over 10 minutes (gas evolution and solid becomes solubilized). After the addition was complete, boron trifluoride in tert-butyl methyl ether (8 mL, 70.8 mmol) was added over 10 minutes with more gas evolution. After 4 hours, LC/MS showed complete reaction. The reaction mixture was quenched with 20 mL of conc. HCL (37%) with additional of gas evolution. The reaction mixture was stirred at 40° C. for 2 hours, cooled to room temperature and evaporated. Then, the white slurry was taken up in 40 mL ethyl acetate and 20 mL of 2.5 M NaOH to make a yellow solution over a white slurry. The yellow organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated to give 12.2 grams of white to yellow solid. This solid was recrystallized from ethyl acetate/hexane in two crops to give 6.7 grams of white solid product (80% yield).

¹H NMR (DMSO-d6): 9.0 (br s, 2 H, NH, HCl), 7.2 (d, 2H, J=8 Hz), 7.05 (d, 2H, J=8 Hz), 4.5 (m, 1H), 3.2 (m, 2H), 3.1 (m, 2H), 3.0 (m, 2H), 1.5 (d, 3H, J=7 Hz).

LC/MS: 1.71 minute, 232.1 M+H⁺ and 139 major fragment. Minor impurity observed at 2.46 min with 321 and 139 peaks.

Example 1 Preparation of 2-(4-chlorophenyl)ethyl-N-2-chloropropionamide

To a 1-liter, 3-necked round bottom flask under argon balloon equipped with reflux condenser and addition funnel, were added sequentially 2-(4-chlorophenyl) ethylamine (30 g, 193 mmol), 400 mL acetonitrile, triethylamine (19.5 g, 193 mmol) and 80 mL acetonitrile. The clear colorless solution was stirred and cooled to 0° C. 2-Chloropropionyl chloride (24.5 g, 193 mmol, distilled) in 5 mL acetonitrile was slowly added over 20 minutes to evolution of white gas, formation of white precipitate, and color change of reaction mixture to slight yellow. An additional 10 mL of acetonitrile was used to rinse the addition funnel. The mixture was stirred at 0° C. for 30 minutes and then warmed to room temperature and stirred vigorously for an additional one hour. The yellow reaction mixture was concentrated on the rotary evaporator to a solid containing triethylamine hydrochloride (76.36 grams). This material was taken up in 100 mL ethylacetate and 200 mL water, and stirred vigorously. The layers were separated and the aqueous layer was extracted with an additional 100 mL ethylacetate. The combined organic layers were washed twice with 25 mL of saturated brine, dried over magnesium sulfate, filtered, and concentrated to a light tan solid (41.6 grams, 88%). TLC in ethylacetate-hexane, 8:2 showed a major spot two-thirds of the way up the plate and a small spot at the baseline. Baseline spot was removed as follows: This material was taken up in 40 mL of ethylacetate and hexane was added until the solution became cloudy. Cooling to 0° C. produced a white crystalline solid (40.2 grams, 85% yield). The product is a known compound (Hasan et al., Indian J. Chem., 1971, 9(9), 1022) with CAS Registry No. 34164-14-2.

LC/MS gave product 2.45 minute; 246.1 M⁺+H⁺.

¹H NMR (CDCl₃): δ 7.2 (dd, 4H, Ar), 6.7 (br S, 1H, NM, 4.38 (q, 1H, CHCH₃), 3.5 (q, 2H, ArCH₂CH2NH), 2.8 (t, 2H, ArCH₂), 1.7 (d, 3H, CH₃).

¹³C NMR (CDCl₃): 169 (1C, C═O), 136 (1C, Ar—Cl), 132 (1C, Ar), 130 (2C, Ar), 128 (2C, Ar), 56 (1C, CHCl), 40 (1C, CHN), 34 (1C, CHAr), 22 (1C, CH₃).

Example 2 Preparation of 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-2-one

2-(4-Chlorophenyl)ethyl-N-2-chloropropionamide (10 g, 40.6 mmol) of Example 1 and aluminum chloride (16 g, 119.9 mmol) were added to a clean dry 100 mL round bottom flask equipped with an argon balloon, stirring apparatus, and heating apparatus. The white solid melted to a tan oil with bubbling at 91° C. (Note: if impure starting materials are used, a black tar can result but clean product can still be isolated). The mixture was heated and stirred at 150° C. for 12 hours. (Note: The time is dependent on the reaction scale and can easily be followed by LC/MS; higher temperatures can be used for shorter time periods. E.g., a 1 gram sample was complete in 5 hours.) The reaction can be followed by LC/MS with the starting material at 2.45 minutes (246.1 M⁺+H⁺), the product at 2.24 minutes (209.6 M⁺+H⁺) on a 5 minute reaction time from 5-95% w/0.01% TFA in water/MeCN (50:50).

After cooling to room temperature, the reaction mixture was quenched with slow addition of 10 mL of MeOH followed by 5 mL of 5% HCl in water and 5 mL of ethyl acetate. After separation of the resulting layers, the aqueous layer was extracted a second time with 10 mL of ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated to a tan solid (6.78 grams, 80% yield). LC/MS showed one peak, at 2.2 min and 209.6 MI. This material was taken up in ethyl acetate, filtered through celite and Kieselgel 60 (0.5 inch plug on a 60 mL Buchner funnel) and the filtrate was recrystallized from hexane/ethyl acetate to give final product (4.61 grams, 54% yield).

¹H NMR (CDCl₃): 7.3-7.1 (m, 3H, Ar), 5.6 (br S, 1H, NH), 4.23 (q, 1H, CHCH₃), 3.8 (m, 1H, ArCH₂CH ₂NH), 3.49 (m, 1H, ArCH₂CH ₂NH), 3.48 (m, 1H, ArCH ₂CH₂NH), 3.05 (m, 1H, ArCH ₂CH₂NH), 1.6 (d, 3H, CH₂).

¹³C NMR (CDCl₃): 178 (1C, C═O), 139 (1C, Ar), 135 (1C, Ar), 130, 129 (2C, Ar), 126 (2C, Ar), 42 (1C, C), 40 (1C, CHN), 33 (1C, CHAr), 14 (1C, CH₃).

Example 3 Preparation of 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

Procedure A

HPLC purified 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazapin-2-one (150 mg, 0.716 mmol) of Example 2 was added to a 50 mL round bottom flask with 2M borane-tetrahydrofuran solution (2 mL, 2.15 mmol). The mixture was stirred 10 hours at room temperature under an argon balloon. LC/MS showed the desired product as the major peak with approximately 5% of starting material still present. The reaction mixture was quenched with 5 mL methanol and the solvents were removed on the rotary evaporator. This procedure was repeated with methanol addition and evaporation. The mixture was evaporated on the rotary evaporator followed by 2 hours in vacuo to give the product as a white solid (117 mg, 70% yield).

NMR, LC/MS and other analytical data are provided below.

Procedure B

Recrystallized 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazapin-2-one (137 mg, 0.653 mmol) was added to a 50 mL round bottom flask with stirring under nitrogen gas. To the flask was slowly added borane-tetrahydrofuran solution (1M, 10 mL) followed by boron trifluoride TBME solution (1 mL, 8.85 mmol) with vigorous gas evolution. The mixture was stirred 6 hours at room temperature under nitrogen gas. LC/MS showed the desired product. The reaction mixture was quenched with 5 mL methanol and 3 mL conc. HCl and the solvents were removed on the rotary evaporator. This procedure was repeated with methanol and HCl addition and evaporation. The mixture was evaporated on the rotary evaporator followed by 2 hours on the pump to dryness to give 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazapine hydrochloride (106 mg, 70% yield).

¹H NMR (CDCl₃): 10.2 (br s, 1H), 9.8 (br s, 1H), 7.14 (dd, 1H, J=2, 8 Hz), 7.11 (d, 1H, J=2 Hz), 7.03 (d, 1H, J=8 Hz), 3.6 (m, 2H), 3.5 (m, 2H), 2.8-3.0 (m, 3 H), 1.5 (d, 3H, J=7 Hz).

LC/MS: 1.41 minute, 196.1 M+H⁺and 139 major fragment. No impurities were observed.

Example 4 Preparation of L-(+)-tartaric acid salt of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

To a clean, dry 50 mL round bottom flask were added 11.5 g (0.06 mol) of 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine from Example 3 to 2.23 g (0.015 mol) of L-(+)-tartaric acid. The suspension was diluted with 56 g of tert-butanol and 6.5 mL of H₂O. The mixture was heated to reflux (75-78° C.) and stirred for 10 min to obtain a colorless solution. The solution was slowly cooled down to room temperature (during 1 h) and stirred for 3 h at room temperature. The suspension was filtered and the residue was washed twice with acetone (10 mL). The product was dried under reduced pressure (50 mbar) at 60° C. to yield 6.3 g of the tartrate salt (ee=80). This tartrate salt was added to 56 g of tert-butanol and 6.5 mL of H₂O. The resulting suspension was heated to reflux and 1 to 2 g of H₂O was added to obtain a colorless solution. The solution was slowly cooled down to room temperature (over the course of 1 h) and stirred for 3 h at room temperature. The suspension was filtered and the residue was washed twice with acetone (10 mL). The product was dried under reduced pressure (50 mbar) at 60° C. to produce 4.9 g (48% yield) of product (ee>98.9).

If the ee value of the product obtained is not satisfactory, an additional recrystallization can be carried out as described. Either enantiomer can be synthesized in high ee utilizing this method.

Example 5 Conversion of Salt Form to Free Amine

The L-tartaric acid salt of 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (300 mg, 0.87 mmol) from Example 4 was added to a 25 mL round bottom flask with 50% sodium hydroxide solution (114 μL, 2.17 mmol) with an added 2 mL of water. The mixture was stirred 3 minutes at room temperature. The solution was extracted with methylene chloride (5 mL) twice. The combined organic extracts were washed with water (5 mL) and evaporated to dryness on the pump to get free amine (220 mg crude weight). LC/MS 196 (M+H).

Example 14 Preparation of Hydrochloric Acid Salt of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

To a clean, dry 25 mL round bottom flask were added (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine free amine (220 mg), 3 ML methylene chloride, and 1.74 mL of 1M HCl in ether. The mixture was stirred for 5 minutes at room temperature. The solvent was removed under reduced pressure to give a white solid, the HCl salt. The salt was re-dissolved in methylene chloride (3 mL) and an additional 1.74 mL of 1 M HCl was added and the solution was again stirred at room temperature for 5 minutes. The solvent was removed under reduced pressure to give the desired HCl salt of 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazapine (190 mg crude weight, 95% yield). NMR data was consistent with the desired product.

¹H NMR (CDCl₃): 10.2 (br s, 1H), 9.8 (br s, 1H), 7.14 (dd, 1H, J=2, 8 Hz), 7.11 (d, 1H, J=2 Hz), 7.03 (d, 1H, J=8 Hz), 3.6 (m, 2H), 3.5 (m, 2H, 2.8-3.0 (m, 3 H), 1.5 (d, 3H, J=7 Hz).

Paper

A novel synthesis of antiobesity drug lorcaserin hydrochloride was accomplished in six steps.N-protection of 2-(4-chlorophenyl)ethanamine with di-tert-butyl dicarbonate, N-alkylation with allyl bromide, deprotection, intramolecular Friedel–Crafts alkylation, chiral resolution with l-(+)-tartaric acid, and the final salification led to the target molecule lorcaserin hydrochloride in 23.1% overall yield with 99.9% purity and excellent enantioselectivity (>99.8% ee). This convenient and economical procedure is remarkably applicable for scale-up production.

Org. Process Res. Dev., 2015, 19 (9), pp 1263–1267

DOI: 10.1021/acs.oprd.5b00144

http://pubs.acs.org/doi/full/10.1021/acs.oprd.5b00144

Lorcaserin hydrochloride

(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepinehydrochloride (1)

To a solution of 16 (0.66 kg, 2.44 mol) in water (3 L) was added 20% K₂CO₃ aqueous solution. The pH was adjusted to 8–9 and extracted with cyclohexane (5 L × 2). The combined organic layer was washed with brine (5 L × 2), dried with anhydrous Na₂SO₄, filtered, and concentrated to afford lorcaserin as yellow oil. To a stirred solution of lorcaserin free base in anhydrous ethanol (500 mL) was added HCl-saturated EtOAc solution slowly until pH = 2 and stirred for another 5 h at room temperature. The reaction solution was concentrated and then stirred for 1 h in methyl tert-butyl ether (2 L) at room temperature. The precipitate was filtered, washed with methyl tert-butyl ether (200 mL), and dried under vacuum to give lorcaserin hydrochloride (1) (0.52 kg, 91.2%). HPLC purity: 99.9%, chiral purity: 99.9%. Mp: 198–199 °C.

¹H NMR (300 MHz, DMSO-d₆): δ = 9.61 (bs, 2H), 7.28–7.21 (m, 3H), 3.54–3.44 (m, 1H), 3.33–3.18 (m, 3H), 3.01 (dd, J = 15.7, 7.1 Hz, 1H), 2.91–2.83 (m, 2H), 1.34 (d, J = 7.2 Hz, 3H).

¹³C NMR (75 MHz, DMSO-d₆): δ = 145.4, 138.1, 131.5, 126.4, 126.0, 114.5, 50.1, 44.5, 34.1, 30.8, 17.5.

MS (ESI, 70 eV): m/z = 196.1 [M + H]⁺.

HPLC for 1 (t_R = 9.0 min) purity 99.9%: Intersil ODS-3 5 μm C-18 250 mm × 4.6 mm, flow rate = 1 mL/min, 35 °C, gradient elution from 20:88 A/B for 30 min to 75:25 A/B over 30 min; A = acetonitrile; B = phosphoric acid in water (pH = 6.0); UV λ = 220 nm.

Chiral HPLC for 1 (t_R = 21.6 min) purity 99.9%: Daicel AD-RH 5 μm 250 mm × 4.6 mm, flow rate = 1 mL/min, 35 °C, isocratic A/B/C = 92:8:0.1; A = n-hexane; B = isopropanol; C = diethylamine; UV λ = 220 nm.

WO2010148207A2	17 Jun 2010	23 Dec 2010	Arena Pharmaceuticals, Inc.	Processes for the preparation of 5-ht2c receptor agonists
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WO2012030938A1	31 Aug 2011	8 Mar 2012	Arena Pharmaceuticals, Inc.	Salts of lorcaserin with optically active acids
WO2012030939A1	31 Aug 2011	8 Mar 2012	Arena Pharmaceuticals, Inc.	Administration of lorcaserin to individuals with renal impairment
WO2012030951A1	31 Aug 2011	8 Mar 2012	Arena Pharmaceuticals, Inc.	Fast-dissolve dosage forms of 5-ht2c agonists
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EP2443080A2 *	17 Jun 2010	25 Apr 2012	Arena Pharmaceuticals, Inc.	Process for the preparation of 5-ht2c receptor agonists

WO2007120517A2 *

2 Apr 2007

25 Oct 2007

Arena Pharm Inc

Processes for the preparation of 8-chloro-1-methyl-2,3,4,5-tetrahydro-1h-3-benzazepine and intermediates related thereto

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DR ANTHONY MELVIN CRASTO Ph.D

amcrasto@gmail.com

MOBILE-+91 9323115463

GLENMARK SCIENTIST , NAVIMUMBAI, INDIA

FDA approves Gazyva for chronic lymphocytic leukemia

November 2, 2013 3:41 am / 2 Comments on FDA approves Gazyva for chronic lymphocytic leukemia

Drug is first with breakthrough therapy designation to receive FDA approval

The U.S. Food and Drug Administration today approved Gazyva (obinutuzumab) for use in combination with chlorambucil to treat patients with previously untreated chronic lymphocytic leukemia (CLL).

read all at

http://www.pharmalive.com/fda-approves-roche-s-gazyva

my old article cut paste

Roche’s new leukaemia drug, Obinutuzumab, superior to Rituxan in clinical trial

JULY 25, 2013 12:52 AM / 6 COMMENTS / EDIT

Reblogged from :

July 24 2013 | By Márcio Barra

Roche has announced that its experimental leukemia drug GA101, or obinutuzumab, used in combination with chemotherapy, was better than Rituxan at helping people with chronic lymphocytic leukemia live longer without their disease worsening, according to the results from the second phase of the clinical trial. Both drugs were tested and compared in combination with chlorambucil.

Roche’s Phase III leukemia drug Obinutuzumab (GA101) yields positive results

FEBRUARY 4, 2013 3:48 AM /

GA101 is the first glycoengineered, type II anti-CD20 mAb.

b-cell-ga101-1

Roche’s Phase III leukemia drug Obinutuzumab (GA101) yields positive results

Obinutuzumab (GA101)

FORMULA	C6512H10060N1712O2020S44

GA101 is the first glycoengineered, type II anti-CD20 monoclonal antibody (mAb) that has been designed for increased antibody-dependent cellular cytotoxicity (ADCC) and Direct CellDeath.1 This agent is being investigated in collaboration with Biogen Idec.

Swiss pharmaceutical company Roche has announced that its early Phase III trial of Leukemia drug obinutuzumab (GA101) demonstrated significantly improved progression-free survival in people with chronic lymphocytic leukemia (CLL).

The positive results yield from stage 1 of a three-arm study called CLL11, designed to investigate the efficacy and safety profile of obinutuzumab (GA101) plus chlorambucil, a chemotherapy, compared with chlorambucil alone in people with previously untreated chronic lymphocytic leukemia (CLL).

This phase of the study met its primary endpoint and an improvement in progression-free survival was achieved; obinutuzumab plus chlorambucil significantly reduced the risk of disease worsening or death compared to chlorambucil alone.

Roche chief medical officer and global product development head Hal Barron said; “the improvement in progression-free survival seen with GA101 is encouraging for people with CLL, a chronic illness of older people for which new treatment options are needed.”

“GA101 demonstrates our ongoing commitment to the research and development of new medicines for this disease.”

Obinutuzumab is Roche’s most advanced drug in development for the treatment of hematological malignancies.

It has been specifically designed as the first glycoengineered, type 2 anti-CD20 monoclonal antibody in development for B cell malignancies.

Afutuzumab is a monoclonal antibody being developed by Hoffmann-La Roche Inc. for the treatment of lymphoma.[1] It acts as an immunomodulator.[2][3] It was renamed obinutuzumab in 2009.[4]

References

Robak, T (2009). “GA-101, a third-generation, humanized and glyco-engineered anti-CD20 mAb for the treatment of B-cell lymphoid malignancies”. Current opinion in investigational drugs (London, England : 2000) 10 (6): 588–96. PMID 19513948.
Statement On A Nonproprietary Name Adopted By The Usan Council – Afutuzumab,American Medical Association.
International Nonproprietary Names for Pharmaceutical Substances (INN), World Health Organization.
International Nonproprietary Names for Pharmaceutical Substances (INN), World Health Organization.
OBINUTUZUMAB ISMONOCLONAL ANTIBODY

TYPE Whole antibody

SOURCE Humanized (from mouse)

TARGET CD20

OBINUTUZUMAB ISMONOCLONAL ANTIBODY
TYPE	Whole antibody
SOURCE	Humanized (from mouse)
TARGET	CD20

Cempra’s Taksta secures FDA orphan drug status for prosthetic joint infections treatment

November 1, 2013 4:10 am / 14 Comments on Cempra’s Taksta secures FDA orphan drug status for prosthetic joint infections treatment

FUSIDIC ACID, 6990-06-3

2-[(1S,2S,5R,6S,7S,10S,11S,13S,14Z,15R,17R)-13-(acetyloxy)-5,17-dihydroxy-2,6,10,11-tetramethyltetracyclo[8.7.0.0^2,7.0^11,15]heptadecan-14-ylidene]-6-methylhept-5-enoic acid

Taksta (CEM-102)
Clinical-stage pharmaceutical firm Cempra has secured orphan drug status from the US Food and Drug Administration (FDA) for its drug candidate Taksta (CEM-102) to treat patients with prosthetic joint infections (PJI).

Cempra’s Taksta secures FDA orphan drug status for prosthetic joint infections treatment

http://www.pharmaceutical-technology.com/news/newscempras-taksta-secures-fda-orphan-drug-status-prosthetic-joint-infections-treatment?WT.mc_id=DN_News

TAKSTA^TM (CEM-102)

Fusidic acid is a bacteriostatic antibiotic that is often used topically in creams and eyedrops, but may also be given systemically as tablets or injections. The global problem of advancing antimicrobial resistance has led to a renewed interest in its use recently.

Fusidic acid acts as a bacterial protein synthesis inhibitor by preventing the turnover ofelongation factor G (EF-G) from the ribosome. Fusidic acid is effective primarily ongram-positive bacteria such as Staphylococcus species, Streptococcus species, and Corynebacterium species. Fusidic acid inhibits bacterial replication and does not kill the bacteria, and is therefore termed bacteriostatic.

Fusidic acid is a true antibiotic, derived from the fungus Fusidium coccineum and was developed by Leo Laboratories in Ballerup, Denmark and released for clinical use in the 1960s. It has also been isolated from Mucor ramannianus and Isaria kogana. The drug is licensed for use as its sodium salt sodium fusidate, and it is approved for use under prescription in South Korea, Japan, UK, Canada, Europe, Australia, New Zealand, Thailand, India and Taiwan. A different oral dosing regimen, based on the compound’s Pharmacokinetic/pharmacodynamic (PK-PD) profile is in clinical development in the U.S. as Taksta.

Fusidic acid (TAKSTA^TM, CEM-102) is an antibiotic with a long history of safety and efficacy outside the United States. Cempra has exclusive rights to the supply of the compound for the U.S. market. Fusidic acid is orally active against gram-positive bacteria, including all S. aureus strains such as HA-MRSA and CA-MRSA. A novel dosing regimen has been successfully evaluated in a Phase II trial in patients with acute bacterial skin and skin structure infections (aBSSSI). Cempra is conducting a Phase II trial of TAKSTA for patients with prosthetic joint infections.

Profile of TAKSTA (CEM-102)
Prosthetic joint infections (PJI) occur in about 1% of hip replacements and 2% of knee replacements, translating to an incidence rate of about 10,000 per year in the U.S. at current hip and knee arthroplasty rates. There are few good options to treat these serious staphylococcal, often MRSA infections, which require long-term antibiotic treatment. Current therapy in the U.S. is with intravenous antibiotics such as vancomycin. An oral drug that can be safely administered for a long period of time could improve care and quality of life for these patients.

TAKSTA has shown potent activity against a large number of S. aureus strains, including CA-MRSA, HA-MRSA and linezolid-resistant strains, isolated in the U.S over a 10 year period. Its broad S. aureus coverage makes it useful for a broad range of clinical applications. Because of its safety and tolerability profile, TAKSTA could be ideal for patients suffering from staphylococcal infections that require long-term therapy such as patients with PJIs.

Cempra has developed a unique oral loading dose regimen to optimize key pathogen coverage and minimize drug resistance development. This regimen is incorporated in our Phase II trial to treat PJIs with TAKSTA in combination with rifampin, which is commonly used with injectible antibiotics such as vancomycin to treat PJIs.

Research on TAKSTA

Publications

The links for the articles go to subscription-based sites and may require a fee to view the article.

In Vitro Activity of CEM-102 (Fusidic Acid) Against Prevalent Clones and Resistant Phenotypes of Staphylococcus aureus
DF Sahm, J Deane, CM Pillar, P Fernandes
Antimicrobial Agents and Chemotherapy. June 2013 57: 4535-4346
http://aac.asm.org/content/57/9/4535

Efforts to Support the Development of Fusidic Acid in the United States
P Fernandes, D Pereira
Clinical Infectious Disease. June 2011 52:S542-6
http://www.ncbi.nlm.nih.gov/pubmed/21546632

Case report: Treatment of Chronic Osteomyelitis
CR Wolfe
Clinical Infectious Disease. June 2011 52:S538-41
http://cid.oxfordjournals.org/content/52/suppl_7/S538.long

The Safety Record of Fusidic Acid in Non-US markets: A Focus on Skin Infections
CN Kraus, BW Burnstead
Clinical Infectious Disease. June 2011 52:S527-37
http://cid.oxfordjournals.org/content/52/suppl_7/S527.long

A Randomized, Double-Blind Phase 2 Study Comparing the Efficacy and Safety of an Oral Fusidic Acid Loading-Dose Regimen to Oral Linezolid in the Treatment of Acute Bacterial Skin and Skin Structure Infections
JC Craft, SR Moriarty, K Clark, D Scott, TP Degenhardt, JG Still, GR Corey, A Das, P Fernandes
Clinical Infectious Disease. June 2011 52:S520-26
http://cid.oxfordjournals.org/content/52/suppl_7/S520.long

Application of Pharmacokinetic-Pharmacodynamic Modeling and the Justification of a Novel Fusidic Acid Dosing Regimen: Raising Lazarus from the Dead
BT Tsuji, OO Okusanya, JB Bulitta, A Forrest, SM Bhavnani, P Fernandes, PG Ambrose
Clinical Infectious Disease. June 2011 52:S513-19
http://cid.oxfordjournals.org/content/52/suppl_7/S513.long

Pharmacokinetics and Safety of Single, Multiple, and Loading Doses of Fusidic Acid in Healthy Subjects
JG Still, K Clark, TP Degenhardt, D. Scott, P. Fernandes, M. J. Gutierrez
Clinical Infectious Disease. June 2011 52:S504-12
http://cid.oxfordjournals.org/content/52/suppl_7/S504.long

Activity of Fusidic Acid Against Extracellular and Intracellular Staphylococcus aureus: Influence of pH and Comparison with Linezolid and Clindamycin
S Lemaire, F Van Bambeke, D Pierard, PC Appelbaum, PM Tulkens
Clinical Infectious Disease. June 2011 52:S493-503
http://cid.oxfordjournals.org/content/52/suppl_7/S493.long

Characterization of Global Patterns and the Genetics of Fusidic Acid Resistance
DJ Farrell, M Castanheira, I Chopra
Clinical Infectious Disease. June 2011 52:S487-92
http://cid.oxfordjournals.org/content/52/suppl_7/S493.long

In Vitro Antimicrobial Findings for Fusidic Acid Tested Against Contemporary (2008-2009) Gram-Positive Organisms Collected in the United States
RN Jones, RE Mendes, HS Sader, M Castanheira
Clinical Infectious Disease. June 2011 52:S477-86
http://cid.oxfordjournals.org/content/52/suppl_7/S477.long

New Rules for Clinical Trials in Patients with Acute Bacterial Skin and Skin Structure Iinfections: Do not Let the Perfect be the Enemy of the Good
GR Corey, ME Stryjewski
Clinical Infectious Disease. June 2011 52:S469-76
http://cid.oxfordjournals.org/content/52/suppl_7/S469.long

Introduction: Fusidic Acid Enters the United States
RC Moellering, GR Corey, ML Grayson
Clinical Infectious Disease. June 2011 52:S467-8
http://cid.oxfordjournals.org/content/52/suppl_7/S467.long

Evaluation of the Pharmacokinetics-Pharmacodynamics of Fusidic Acid Against Staphylococcus aureus and Streptococcus pyogenes Using In Vitro Infection Models: Implications for Dose Selection
OO Okusanya, BT Tsuji, JB Bulitta, A Forrest, CC Bulik, SM Bhavnani, P Fernandes, PG Ambrose
Diagnostic Microbiology & Infectious Disease. June 2011 70:101-11
http://www.ncbi.nlm.nih.gov/pubmed/21513848

In Vitro Activity of Fusidic Acid (CEM-102, Sodium Fusidate) Against Staphylococcus aureus Isolated from Cystic Fibrosis Patients and its Effect on the Activities of Tobramycin and Amikacin against Pseudomonas aeruginosa and Burkholderia cepacia
P McGhee, K Credito, L Beachel, PC Appelbaum, K Kosowaska-Shick
Antimicrobial Agents and Chemotherapy. June 2011 55:2417-19
http://www.ncbi.nlm.nih.gov/pubmed/21513848

Occurrence and Molecular Characterization of Fusidic Acid Resistance Mechanisms Among Staphylococcus spp. From European Countries (2008)
Castanheira, M., AA Watters, RE Mendes, DJ Farrell, RN Jones
Antimicrobial Agents and Chemotherapy. April 2010 65:1353-8
http://jac.oxfordjournals.org/content/65/7/1353.long

Update on Fusidic Acid (CEM-102) Tested Against Neisseria gonorrhoeae and Chlamydia trachomatis
R Jones, D Biedenbach, P Roblin, S Kohlhoff, M Hammerschlag
Antimicrobial Agents and Chemotherapy. October 2010 54: 4518-4519
http://aac.asm.org/cgi/content/citation/54/10/4518

Fusidic Acid Resistance Rates and Prevalence of Resistance Mechanisms Among Staphylococcus spp. Isolated in North America and Australia, 2007-2008
M Castanheira, AA Watters, JM Bell, JD Turnidge, RN Jones
Antimicrobial Agents and Chemotherapy. September 2010 54: 3614-3617
http://www.ncbi.nlm.nih.gov/pubmed/20566766

Spectrum of Activity, Mutation Rates, Synergistic Interactions, and the Effects of pH and Serum Proteins for Fusidic Acid (CEM-102)
D Biedenbach, P Rhomberg, R Mendes, R Jones
Diagnostic Microbiology & Infectious Disease. March 2010 66: 301-307
http://www.dmidjournal.com/article/S0732-8893(09)00424-6/abstract

Performance of Fusidic Acid (CEM-102) Susceptibility Testing Reagents: Broth Microdilution, Disk Diffusion, and Etest Methods as Applied to Staphylococcus aureus
R Jones, M Castanheira, P Rhomberg, L Woosley, M Pfaller
Journal of Clinical Microbiology. March 2010 48: 972-976
http://jcm.asm.org/cgi/content/abstract/48/3/972

Evaluation of the Activity of Fusidic Acid Tested Against Contemporary Gram-Positive Clinical Isolates From the USA and Canada
M Pfaller, M Castaneira, H Sader, R Jones
International Journal of Antimicrobial Agents. March 2010 35: 282-287
http://www.ijaaonline.com/article/S0924-8579(09)00510-X/abstract

6th ASM Conference on Biofilms 2012 (Sept 29-Oct 4) – Miami, FL 2012

Quantitative and qualitative assessment of antibiotic activity against Staphylococcus aureus biofilm.
Siala, W., M. P. Mingeot-Leclercq, P. M. Tulkens, and F. Van Bambeke.
Abstr. 6th Am. Soc. Microbiol. Conf. Biofilms, abstr A-179.
Download Poster

NACFC 2011

Activity of Fusidic Acid Against Methicillin-resistant Staphylococcus Aureus (MRSA) Isolated from CF Patients
Prabhavathi Fernandes, Donald Anderson, K. Kosowska-Shick, P. McGhee, L. Beachel and P.C. Appelbaum
Download Abstract | Download Poster

ECCMID 2011

Evaluation of L6 Ribosomal Protein Alterations in Fusidic Acid-Resistant Staphylococcus aureus: Fitness Cost and Time Kill Analysis
M Castanheira, RN Jones, LN Woosley, RE Mendes, GJ Moet, DJ Farrell
Download Abstract

Fusidic Acid Activity and Coverage of Gram-positive Pathogens Associated with Acute Bacterial Skin and Skin Structure Infections (ABSSSI) in the USA (2008-2010)
RN Jones, DJ Farrell, HS Sader, M Castanheira
Download Abstract | Download Poster

IDSA 2010

Spectrum of Activity

Activity of Fusidic Acid Tested Against Contemporary Staphylococcus aureus Collected from United States Hospitals
M. Castanheira, R.E. Mendes, P.R. Rhomberg, R.N. Jones
Download Abstract | Download Poster

ICAAC 2010

Spectrum of Activity

Pharmacokinetics-Pharmacodynamics (PK-PD) of CEM- 102 (Sodium Fusidate) Against Streptococcus pyogenes Using In Vitro Pharmacodynamic Models (IVPM)
B. T. Tsuji, A. Forrest, P. A. Kelchlin, T. Brown, P. N. Holden, O. O. Okusanya, S. M. Bhavnani, P. Fernandes, P. G. Ambrose
Download Abstract | Download Poster

Activity of CEM-102 (sodium fusidate) against 40 MRSA from Cystic Fibrosis Patients
Cynthia Todd, Pamela Mcghee, and Peter Appelbaum
Download Abstract | Download Poster

Ability of CEM-102 (Fusidic Acid), Linezolid, Daptomycin to Select Resistant S.aureus Mutants at Steady-state Serum Levels
K. Kosowska-Shick, P. Mcghee, L. Beachel, P. C. Appelbaum;
Download Abstract | Download Poster

CEM-102 (Fusidic Acid) Maintains Potency against Resistant MRSA and Prevalent Hospital Acquired, Community Acquired,and Epidemic MRSA Clones
C.M. Pillar, M.K. Torres, D.F. Sahm and P. Fernandes
Download Abstract | Download Poster

In Vitro Activity Of Fusicic Acid (CEM-102) Against Resistant Strains Of Staphylococcus aureus
J. dubois, P. Fernandes
Download Abstract | Download Poster

Trade names and preparations

Fucidin (of Leo in Canada and the US)
Fucidin H (topical cream with corticosteroid – Leo)
Fucidin (of Leo in UK/ Leo-Ranbaxy-Croslands in India)
Fucidine (of Leo in France)
Fucidin (of Leo in Norway)
Fucidin (of Adcock Ingram, licenced from Leo, in South Africa)
Fucithalmic (of Leo in the UK, the Netherlands, Denmark and Portugal)
Fucicort (topical mixture with hydrocortisone)
Fucibet (topical mixture with betamethasone)
Ezaderm (topical mixture with betamethasone)(of United Pharmaceutical “UPM” in Jordan)
Fuci (of pharopharm in Egypt)
Fucizon (topical mixture with hydrocortisone of pharopharm in Egypt)
Foban (topical cream in New Zealand)
Betafusin (cream mixture with betamethasone valerate in Greece)
Fusimax (of Schwartz in India)
Fusiderm (topical cream and ointment by indi pharma in India)
Fusid (in Nepal)
Fudic (topical cream in India)
Fucidin (후시딘, of Dong Wha Pharm in South Korea)
Stanicid (in Serbia)
Dermy (Topical cream of W.Woodwards in Pakistan)
Fugen Cream (膚即淨軟膏 in Taiwan)
Phudicin Cream (in China; 夫西地酸^[24])
Dermofucin cream ,ointment and gel (in Jordan)
Optifucin viscous eye drops (of API in Jordan)
Verutex (of Roche in Brazil)
TAKSTA (of Cempra in U.S.)
Futasole (of Julphar in Gulf and north Africa)
Stanicid (2% ointment of Hemofarm in Serbia)
Fuzidin (tablets of Biosintez in Russia)
Fuzimet (ointment with methyluracil of Biosintez in Russia)
Axcel Fusidic Acid(2% cream and ointment of Kotra Pharma, Malaysia)

MORE INFO

Figure US08450300-20130528-C00002

Fusidic acid (FA) is a tetracyclic triterpenoid or fusidane (steroidal) antibiotic derived from the fungus Fusidium coccineum that inhibits bacterial protein synthesis. FA is effective against gram-positive bacteria such as Staphylococcusspecies and Corynebacterium species (L. Verbist, J. Antimicro. Chemo. 25, Suppl. B, 1-5 (1990); A. Bryskier, Fusidic Acid, Chapter 23, in Antimicrobial Agents: Antibacterials and Antifungals (Andre Bryskier, Ed., ASM Press, Washington, USA, 2005)). FA also has moderate activity against Group A beta-hemolytic streptococci, or Streptococcus pyogenes (L. Verbist, J. Antimicro. Chemo. 25, Suppl. B, 1-5 (1990); A. Bryskier, Fusidic Acid, Chapter 23, inAntimicrobial Agents: Antibacterials and Antifungals (Andre Bryskier, Ed., ASM Press, Washington, USA, 2005); Skov et al., Diag. Micro. Infect. Dis. 40:111-116 (2001)).

Fusidic acid, chemically (3α, 4α, 8α, 9α, 11α, 13α, 14α, 16α, 17Z)-16-(Acetyloxy)-3,11-dihydroxy-29-nordammara-17(20), 24-dien-21-oic acid, is an antibacterial agent. It is a well-known antibiotic with a unique steroid-like tetracyclic ring system structure, and it is the most potent of a small family of steroidal antibiotics, the fusidanes. It is produced by fermentation under controlled conditions of the fungus Fusidium Coccineum.
The excellent distribution in various tissues, low degree of toxicity and allergic reactions and the absence cross-resistance with other clinically used antibiotics has made fusidic acid a highly valuable antibiotic,especially for skin and eye infections. The drug is used clinically both in its acid form, and as the sodium salt (Fusidin®), however Fusidin® is more favored one because of its better solubility in water, enabling a fast absorption from gastro-intestinal tract. As a result, it is more preferable to use sodium salt of fusidin in oral solid forms.
Fusidin® has the actions and uses of fusidic acid, and it has been shown that it ameliorates the course of several organ-specific immuno-inflammatory diseases such as chronic uveitis, Behcet’s disease, type I diabetes mellitus, Guillain-Barre syndrome, hepatitis, sepsis, pancreatitis, formalin-induced edema, multiple sclerosis, and scleroderma, whereby fucidin formulations have a great importance in pharmaceutical production.
Fusidin® can be presented in various formulations that differ significantly in their pharmacokinetic behaviors such as oral tablets, oral suspensions, intravenous formulations and topical preparation. Considering oral tablets, many of the early clinical studies were performed with capsule containing sodium fusidate. This was also the formulation marketed for many years in several countries. It is currently available as an oral tablet containing the sodium salt. Originally the sodium salt was available as an enteric-coated form but later it was reformulated as a film-coated tablet that appears to be better tolerated and gives higher blood levels.
Fusidic acid sodium salt was used in capsules as well as in tablets which were coated enterically. However by this enteric coating, the active fusidic acid sodium salt was not released before the tablets reached the part of the gastrointestinal tract in which the enteric coating would be dissolved. Depending on the time of passage through the stomach together with the food and the pH in the gastrointestinal tract, this led to unpredictable variations in the blood concentration of the patient undergoing treatment. Because of these adverse differences in blood concentration, the tablets without enteric coating were produced. Now, sodium fusidate is available in tablet, oral solution and injection form
PCT/WO9603128 A (LEO PHARMACEUTICALS PRODUCTS LTD. ET.AL.) describes the preparation of fusidic acid sodium salt tablets without an enteric coating by using dry granulation method in which a roller compactor was used. The compacted material so produced was size reduced to form a granulate having a bulk density in the range 0.45 to 0.9 g/m³ which was then formed into tablets.

FA was developed for clinical use in the 1960s and it is approved for human use outside of the United States, such as in the UK, Canada, Europe, Israel, Australia and New Zealand. It is typically prescribed at doses of 500 mg TID for treating skin and skin structure infections caused by Staphylococcus aureus (A. Bryskier,Fusidic Acid, Chapter 23, in Antimicrobial Agents: Antibacterials and Antifungals(Andre Bryskier, Ed., ASM Press, Washington, USA, 2005); Collignon et al., Int’l J. Antimicrobial Agents 12:S45-S58 (1999); D. Spelman, Int’l J. Antimicrobial Agents 12:S59-S66 (1999)), although some physicians have routinely prescribed the compound at 500 mg BID for treating skin and skin structure infections due to the long half-life of the compound (Fusidic Acid, in Principles and Practice of Infectious Diseases, 6^thed. (Mandell et al. eds., Elsevier, 2006)).

Treatment using FA has been well studied and it is generally regarded as safe when administered to humans, as evidenced by the fact that the drug has been in continuous use for more than 40 years. There are, however, several characteristics of FA that have prevented use of the drug against a wider spectrum of bacteria and in the treatment in additional types of infection. For example, approved dosing regimens have been shown to select for bacterial resistance, such as in S. aureus. Approved dosing regimens provide low multiples of the MIC and as a result, S. aureus resistant mutants can be selected after the first day of dosing. Once resistance has developed, FA is not effective against the resistant strains. Resistance is reported to occur if FA is used as a single drug as the resistance frequency at 4 and 8 times the MIC is in the range of 10⁻⁶or 10⁻⁸(Evans et al., J. Clin. Path. 19:555-560 (1966); Hansson et al., J. Mol. Biol.348:939-949 (2005), Jensen et al., Acta Pathol Microbiol Scand. 60:271-284 (1964); Besier et al., Antimicrob. Agents Chemo., 49(4):1426-1431 (2005); Gemmell et al., J. Antimicrobial Chemo. 57:589-608 (2006)).

The dosage of the drug cannot be simply increased as a means of avoiding development of resistance. It is difficult to achieve high concentrations of FA in the blood due to the substantial protein binding of the drug (approximately 95-97%) (K. Christiansen, International Journal of Antimicrobial Agents 12:S3-S9 (1999); Coutant et al., Diagn Microbiol Infect Dis 25:9-13 (1996); D. Reeves, J. Antimicrob. Chemo. 20:467-476 (1987); J. Turnidge, Int’l J. Antimicrobial Agents12:S23-S34 (1999); Rieutord et al., Int’l J. Pharmaceutics 119:57-64 (1995)). Moreover, high dosages of FA are not well-tolerated by patients receiving the drug. High doses of FA (e.g., 1 gram TID) are required if the drug is to be used in the treatment of bone and joint infections, less susceptible bacteria and other serious infections. However, treatment regimens using high doses of the drug induce nausea and vomiting and are rejected by patients (Fusidic Acid, inPrinciples and Practice of Infectious Diseases, 6^thed. (Mandell et al. eds., Elsevier, 2006); K. Christiansen, International Journal of Antimicrobial Agents 12:S3-S9 (1999); Nordin et al., Eur. J. Clin. Res. 5:97-106 (1994)).

In view of the tremendous costs associated with the de novo development of new anti-bacterials, expanding the indications for drugs that have already been demonstrated to be safe and effective is strongly needed. Overcoming the limitations on the uses of FA would broaden the population of bacterial infections against which it could be used and thus meet this need.

In a specific commercial pharmaceutical formulation, fusidic acid is presently marketed [see Monographs in the European Pharmacopeia 5.0] as a hemihydrate, which is the only hemihydrate form which has been described.

Patent GB 930,786 discloses salts of fusidic acid with organic and inorganic bases, solvates of fusidic acid, namely a benzene solvate and a methanol solvate. This patent further discloses an unspecified fusidic acid form with IR absorption bands (KBr) at 1265, 1385, 1695, 1730 and 3450 cm^“1 and having a specific rotation [α]_D ²² of minus 9 degrees (1% solution in CHCI₃) obtainable by crystallisation of the methanol solvate of fusidic acid from ether. However, this form is distinct from the form of the present invention evident from the depicted IR spectrum in GB 930,786 which indicates that this form actually corresponds to the presently marketed hemihydrate form.

Solvates and salts of fusidic acid have also been disclosed in British patent GB 999,794. Patent ES 2208110 discloses two solvent free crystalline forms offusidic acid called Form I and Form II, and a crystalline hemihydrate called Form III which is identical to the presently marketed hemihydrate, respectively. The crystalline forms were identified and characterised by IR spectroscopy, differential scanning calorimetry, X-ray diffraction and melting points.

Patent WO 96/03128 discloses tablets containing a sodium salt form of fusidicacid and WO 86/03966 describes an ophthalmic gel composition comprising an undefined form of suspended fusidic acid.

GADODIAMIDE, OMNISCAN Drug Patent Expiration, 1 st oct 2013

October 31, 2013 3:54 am / Leave a comment

GADODIAMIDE

GE HEALTHCARE, OMNISCAN

Drug Patent Expiration

1 st oct 2013, US5560903, CAS 122795-43-1

GADODIAMIDE

INJECTABLE; INJECTION

287MG/ML

NDA 020123

Gadodiamide is a gadolinium-based MRI contrast agent, used in MR imaging procedures to assist in the visualization of blood vessels. It is commonly marketed under the trade name Omniscan.

For intravenous use in MRI to visualize lesions with abnormal vascularity (or those thought to cause abnormalities in the blood-brain barrier) in the brain (intracranial lesions), spine, and associated tissues.

Gadodiamide is a contrast medium for cranial and spinal magnetic resonance imaging (MRI) and for general MRI of the body after intravenous administration. The product provides contrast enhancement and facilitates visualisation of abnormal structures or lesions in various parts of the body including the central nervous system (CNS). It does not cross an intactblood brain barrier but might give enhancement in pathological conditions.

Based on the behavior of protons when placed in a strong magnetic field, which is interpreted and transformed into images by magnetic resonance (MR) instruments. Paramagnetic agents have unpaired electrons that generate a magnetic field about 700 times larger than the proton’s field, thus disturbing the proton’s local magnetic field. When the local magnetic field around a proton is disturbed, its relaxation process is altered. MR images are based on proton density and proton relaxation dynamics. MR instruments can record 2 different relaxation processes, the T1 (spin-lattice or longitudinal relaxation time) and the T2 (spin-spin or transverse relaxation time). In magnetic resonance imaging (MRI), visualization of normal and pathological brain tissue depends in part on variations in the radiofrequency signal intensity that occur with changes in proton density, alteration of the T1, and variation in the T2. When placed in a magnetic field, gadodiamide shortens both the T1 and the T2 relaxation times in tissues where it accumulates. At clinical doses, gadodiamide primarily affects the T1 relaxation time, thus producing an increase in signal intensity. Gadodiamide does not cross the intact blood-brain barrier; therefore, it does not accumulate in normal brain tissue or in central nervous system (CNS) lesions that have not caused an abnormal blood-brain barrier (e.g., cysts, mature post-operative scars). Abnormal vascularity or disruption of the blood-brain barrier allows accumulation of gadodiamide in lesions such as neoplasms, abscesses, and subacute infarcts.

1.Schenker MP, Solomon JA, Roberts DA. (2001). Gadolinium Arteriography Complicated by Acute Pancreatitis and Acute Renal Failure, Journal of vascular and interventional radiology 12(3):393.[1]
2 Unal O, Arslan H. (1999). Cardiac arrest caused by IV gadopentetate dimeglumine. AJR Am J Roentgenol 172:1141.[2]
3 Cacheris WP, Quay SC, Rocklage SM. (1990). The relationship between thermodynamics and the toxicity of gadolinium complexes, Magn Reson Imaging 8(6):467-81. doi:10.1016/0730-725X(90)90055-7
4 Canavese, C; Mereu, MC; Aime, S; Lazzarich, E; Fenoglio, R; Quaglia, M; Stratta, P (2008). “Gadolinium-associated nephrogenic systemic fibrosis: the need for nephrologists’ awareness”. Journal of nephrology 21 (3): 324–36. PMID 18587720.

COUNTRY PATENT APPROVED, EXPIRY

United States	5560903	1993-10-01	2013-10-01
Canada	1335819	1995-06-06	2012-06-06
United States	5362475	1994-11-08	2011-11-08

Canada	1335819	1995-06-06	2012-06-06
United States	5560903	1993-10-01	2013-10-01

Gadolinium contrast agents are used as contrast media to enhance magnetic resonance imaging as they are paramagnetic. This compound has a low incidence of adverse side effects, although there is a rare association with nephrogenic systemic fibrosis (NSF) when given to people with severe renal impairment (ie, GFRglomerular filtration rate <30mL/min/1·73m2).It seems to be related to the liberation of free gadolinium ions, and UK CHM advice is against using the least stable of the agents – Omniscan (gadodiamide) – in patients with severe renal impairment, and carefully considering whether to use others where renal function is impaired.

OMNISCAN (gadodiamide) Injection is the formulation of the gadolinium complex of diethylenetriamine pentaacetic acid bismethylamide, and is an injectable, nonionic extracellular enhancing agent for magnetic resonance imaging. OMNISCAN is administered by intravenous injection. OMNISCAN is provided as a sterile, clear, colorless to slightly yellow, aqueous solution. Each 1 mL contains 287 mg gadodiamide and 12 mg caldiamide sodium in Water for Injection.

The pH is adjusted between 5.5 and 7.0 with hydrochloric acid and/or sodium hydroxide. OMNISCAN contains no antimicrobial preservative. OMNISCAN is a 0.5 mol/L solution of aqua[5,8-bis(carboxymethyl)11-[2-(methylamino)-2-oxoethyl]-3-oxo-2,5,8,11-tetraazatridecan-13-oato (3-)-N⁵, N⁸, N¹¹, O³, O⁵, O⁸, O¹¹, O¹³] gadolinium hydrate, with a molecular weight of 573.66 (anhydrous), an empirical formula of C₁₆H₂₈GdN₅O₉•xH₂O, and the following structural formula:

OMNISCANTM (gadodiamide) Structural Formula Illustration

Pertinent physicochemical data for OMNISCAN are noted below:

PARAMETER

Osmolality (mOsmol/kg water)	@ 37°C	789
Viscosity (cP)	@ 20°C	2
Viscosity (cP)	@ 37°C	1.4
Density (g/mL)	@ 25°C	1.14
Specific gravity	@ 25°C	1.15

OMNISCAN has an osmolality approximately 2.8 times that of plasma at 37°C and is hypertonic under conditions of use.

gadodiamide, chemical name: [5,8 _ bis (carboxymethyl) -11 – [2_ (methylamino)-2_ ethyl] -3 – O 2 ,5,8, 11 – tetraazacyclododecane-decane -13 – oxo-(3 -)] gadolinium trihydrate. Its structure is shown in formula one.

[0003] Structural Formula:

[0004]

[0005] Magnetic resonance contrast agent gadodiamide resonance than ionic contrast agents safer generation of products, it is non-ionic structure significantly reduces the number of particles in solution, osmotic balance of body fluids is very small.Meanwhile, gadodiamide relatively low viscosity to bring the convenience of nursing staff, making it easier to bolus. In addition, gadodiamide pioneered the use of amide-substituted carboxyl part, not only reduces the toxicity of carboxyl groups and ensure the non-ionic nature of the product solution.

[0006] reported in the literature and their intermediates gadodiamide synthetic route is as follows:

[0007] 1. Compound III synthetic routes for its preparation in U.S. Patent No. US5508388 described as: In the synthesis process, the inventors using acetonitrile as solvent, acetic anhydride as dehydrating agent, pyridine as acid-binding agent, at 55 ~ 60 ° C, the reaction 18h. Anti-

See the reaction should be a process. The disadvantage of this synthesis are acetonitrile toxicity, not widely used.

[0008]

[0009] Reaction a

[0010] (2) Synthesis of Compound III in many articles are reported in the patent and its implementation method similar to the patent US5508388.

[0011] In US3660388, the diethylenetriamine pentaacetic acid (Compound II), pyridine, acetic anhydride, the mixture was reacted at 65 ° C or 20h at 125 ° C the reaction 5min, to give compound III.

[0012] In US4822594, the compounds II, pyridine, acetic anhydride mixture was reacted at 65 ° C 20h, to give compound III.

[0013] In US4698263, the compounds II, pyridine, acetic anhydride heated in a nitrogen or argon atmosphere under reflux for 18h, to give compound III. [0014] In the EPO183760B1, the compounds II, pyridine, acetic anhydride mixture was reacted at 55 ° C 24h, to give compound III.

[0015] In CN1894223A, the compounds II, pyridine, acetic anhydride, the mixture above 65 ° C the reaction mixture, and the pyridine of DTPA feed ratio is: 1: (0.5 to 3).

[0016] The above patents do not provide for the compound III is post-processing method.

[0017] 3 Synthesis of Compound IV.

[0018] In U.S. Patent US4859451, the diethylenetriamine pentaacetic acid dianhydride (compound III) and ammonia, methanol and the reaction of compounds IV, see Reaction Scheme II.

[0019]

[0020] Reaction two

[0021] In the patent US5087439, the compound III with methylamine in aqueous solution for several hours, or overnight reactions, see reaction formula III.

[0022]

[0023] Reactive three

[0024] These two patents using ammonia and methylamine, which can form explosive mixtures with air, in case of fire or high pressure can cause an explosion in the production process of great insecurity. Although raw material prices are lower, but higher production conditions (such as requiring sealed, low temperature, etc.). Compared to this synthesis process,

[0025] 4, gadodiamide (Compound I) synthesis.

[0026] In the patent US4859451, the use of gadolinium chloride with the compound IV is carried out under acidic conditions, complexing. Finally, tune

Section PH neutral, see reaction IV.

[0027]

[0028] Reaction formula tetrakis [0029] in the patent US5087439, the chlorides are used as reactants, and details of the post-processing method of Compound I.

[0030] In the patent US5508388, the use of gadolinium oxide with compound IV in acetonitrile, water with stirring, the resulting compound I.

[0032] The synthetic route is as follows:

[0033]

[0034] 1) Compound II (diethylenetriamine pentaacetic acid) in pyridine, acetic anhydride in the presence of a dehydration reaction into the acid anhydride, and the product was stirred with cold DMF, leaving the solid filtered, washed with ether reagents, drying , to obtain a white powdery solid compound III (diethylenetriamine pentaacetic acid anhydride);

[0035] 2) Compound III in DMF with methylamine hydrochloride, the reaction of the compound IV (5,8 _ bis carboxymethyl methyl-11 – [2 – (dimethylamino) -2 – oxoethyl] – 3 – oxo -2,5,8,11 – tetraazacyclododecane _13_ tridecyl acid); and the control compound III: MeNH2 · HCl molar ratio = 1: (1 to 4), control the temperature between 20 ~ 80 ° C, the reaction time is 4 ~ 6h, after the treatment, the method of distillation under reduced pressure to remove DMF, the product is dissolved in a polar solvent, methanol, and then adding a solvent polarity modulation, so that the target Compound IV from system completely precipitated;

[0036] 3) Compound IV with gadolinium oxide formed in the presence of hydrochloric acid of the complex, after the reaction, filtration and drying, to obtain a white powdery compound I, i.e. gadodiamide.

[0037] Existing gadodiamide Synthesis basically from the synthesis of Compound IV as a starting material, the present invention is first introduced to the compound II as a starting material to synthesize gadodiamide. Synthesis of the conventional method of gadodiamide, the present invention has the advantage of inexpensive starting materials, convenient and easy to get. In addition, the synthetic pathway intermediates are involved in the post-processing is simple, enabling continuous reaction, saving time and cost savings, the reaction becomes controlled step by step, and try to avoid the use of toxic reagents, reducing the possibility of operator injury , while also greatly reducing damage to the environment.

Biosimilars-in-India

October 28, 2013 7:12 am / Leave a comment

http://www.ibef.org/download/Biosimilars-in-India-30312.pdf

Biosimilars – India Brand Equity Foundation

www.ibef.org/download/Biosimilars-in-India-30312.pdf‎

patented/registered biotech products, but are manufactured by new companies after the patent expiry of the originator product. The global. Biosimilars market is …

BAYER 2013 AND BEYOND

October 25, 2013 12:06 pm / 4 Comments on BAYER 2013 AND BEYOND

http://www.bayer.com/

Bayer

With 11 treatments in Phase I trials, 8 in Phase II, and 13 in Phase III, Bayer has a strong pipeline.

By far the most interest currently, given that the latest reports came out October 21st, is riociguat (BAY 63-2521),

which has had good news from its ongoing Phase III clinical trials of the treatment for pulmonary arterial hypertension, also known as PAH. PAH is a progressive condition that overburdens the heart.

Trials indicate subjects had improved heart function and could better tolerate physical exercise. Patients on riociguat improved their walking distance by 36 meters on average, while those on placebo showed no improvement.

Professor Hossein Ardeschir Ghofrani of University Hospital Giessen, the principal investigator, was quite pleased with the results and explained the value of the measurement. “The six-minute walk distance test is a well-validated clinical measure in patients with PAH, and therefore, the results of the PATENT-1 trial are encouraging. . .These data from the PATENT study suggest that riociguat may be a potential treatment option both for patients who have never been treated for PAH as well as for those who have received prior treatment.”

Hossein A. Ghofrani
Associate Professor of Internal Medicine,
MD (University of Giessen) 1995 Research interests: pulmonary hypertension, ischaemia-reperfusion, experimental therapeutics, clinical trials

http://www.uni-giessen.de/cms/fbz/fb11/forschung/graduierte/mbml/faculty

Although Bayer put forth no sales estimate for the treatment, analysts predicted 2017 sales from riociguat of $480 million

BAYER PIPELINE AS ON OCT 25 2013

phase 1

Project	Indication
CDK-Inhibitor (BAY 1000394)	Cancer
Mesothelin-ADC (BAY 94-9343)	Cancer
PSMA Bi TE Antibody (BAY 2010112)	Cancer
PI3K-Inhibitor (BAY 1082439)	Cancer
FGFR2 Antibody (BAY 1179470)	Cancer
HIF-PH (BAY 85-3934)	Anemia
Partial Adenosine A1 Agonist(BAY 1067197)	Heart Failure
Vasopressin Receptor Antagonist(BAY 86-8050)	Heart Failure
sGC Stimulator (BAY 1021189)	Heart Failure
S-PRAnt (BAY 1002670)	Symptomatic uterine fibroids
BAY 1026153	Endometriosis

phase2

Project	Indication
PI3K-Inhibitor (BAY 80-6946)	Cancer
Regorafenib	Cancer
Refametinib (MEK-Inhibitor)	Cancer
Radium-223-Dichloride	Cancer
Sorafenib	Additional Indications
MR-Antagonist (BAY 94-8862)	Congestive Heart Failure (CHF)
MR-Antagonist (BAY 94-8862)	Diabetic Nephopathy
Riociguat (sGC Stimulator)	Pulmonary Hypertension
Neutrophil Elastase Inhibitor(BAY 85-8501)	Bronchiectasis

phase 3

Project	Indication
Sorafenib	Breast Cancer
Sorafenib	Adjuvant HCC
Sorafenib	Adjuvant RCC
Regorafenib	HCC 2nd line
Rivaroxaban	Major Adverse Cardiac Events
Rivaroxaban	CHF and CAD
peg rFVIII(BAY 94-9027)	Hemophilia
Aflibercept	Myopic choroidal neovascularization (mCNV)
Aflibercept	Diabetic Macular Edema (DME)
LCS 16	Contraception
Vaginorm	Vulvovaginal atrophy (VVA)
Sodium Deoxycholate	Submental fat removal
Cipro DPI	Lung infection
Tedizolid	Skin and Lung Infections
Amikacin Inhale	Gram-negative pneumonia

Information for Download from bayer

From molecules to medicine – A journey through research and development (PDF, 3 MB)

Sorafenib tosylate

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

TEDIZOLID PHOSPHATE

https://newdrugapprovals.wordpress.com/2013/10/24/cubist-pharmaceuticals-inc-announced-that-it-has-submitted-a-nda-to-the-u-s-fda-for-approval-of-its-investigational-antibiotic-tedizolid-phosphate-tr-701/

Bayer Accelerates Clinical Development of Promising New Drug Candidates

Five new molecular entities projected to enter Phase III by 2015 / Addressing unmet medical needs in the areas of oncology, cardiology, and women’s health / Initiation of further studies with recently launched products planned to add new treatment options

Leverkusen, October 8, 2013 – Following the recent commercial introduction of five new drugs to address the medical needs of patients with various diseases, Bayer is now accelerating the development of further five promising drug candidates which are currently undergoing phase I and II clinical studies. The company today announced that it plans to progress these five new highly innovative drug candidates in the areas of oncology, cardiology, and women’s health into phase III clinical studies by 2015.

“Our Pharma research and development has done a tremendous job of bringing five new products to the market offering physicians and patients new treatment alternatives for serious diseases”, said Bayer CEO Dr. Marijn Dekkers. “Following our mission statement ‘Science For A Better Life’, the five chosen further drug candidates all have the potential to impact the way diseases are treated for the benefit of patients.”

Bayer CEO Dr. Marijn Dekkers
“Our research and development activities are strongly focused on areas where treatment options are not available today or where true breakthrough innovations are missing”, said Prof. Andreas Busch, member of the Bayer HealthCare Executive Committee and Head of Global Drug Discovery at Bayer HealthCare. “Our drug development pipeline holds a number of promising candidates which we want to bring to patients who need them urgently”, said Kemal Malik, member of the Bayer HealthCare Executive Committee, Chief Medical Officer and Head of Pharmaceutical Development at Bayer HealthCare. “Furthermore we are continuing to expand the range of indications for all our recently launched products Xarelto, Stivarga, Xofigo, Riociguat as well as Eylea and further refine the profile of these drugs in specific patient populations.”

Cl 223Ra Cl

Xofigo

https://newdrugapprovals.wordpress.com/2013/09/21/xofigo-injection-recommended-for-approval-in-eu/

The five mid-stage candidates have been selected for accelerated development based on positive “proof-of-concept” data from early clinical studies. Three of them are development compounds in the area of cardiology or the cardio-renal syndrome: Finerenone (BAY 94-8862) is a next generation oral, non-steroidal Mineralocorticoid Receptor antagonist which blocks the deleterious effects of aldosterone. Currently available steroidal MR antagonists have proven to be effective in reducing cardiovascular mortality in patients with heart failure but have significant side effects that limit their utilization. Finerenone is currently in clinical Phase IIb development for the treatment of worsening chronic heart failure, as well as diabetic nephropathy.

Finerenone (BAY 94-8862)

https://newdrugapprovals.wordpress.com/2013/10/09/finerenone-bay-94-8862-bayers-next-generation-oral-non-steroidal-mineralocorticoid-receptor-antagonist-which-blocks-the-deleterious-effects-of-aldosterone/

The second drug candidate in the area of cardiology is an oral soluble guanylate cyclase (sGC) stimulator (BAY 1021189). The start of a Phase IIb study in patients with worsening chronic heart failure is expected later this year.

For the cardio-renal syndrome, a Phase IIb program with the investigational new drug Molidustat (BAY 85-3934) is under initiation in patients with anemia associated with chronic kidney disease and/or end-stage renal disease. Molidustat is a novel inhibitor of hypoxia-inducible factor (HIF) prolyl hydroxylase (PH) which stimulates erythropoietin (EPO) production and the formation of red blood cells. Phase I data have shown that inhibition of HIF-PH by Molidustat results in an increase in endogenous production of EPO.

Molidustat (BAY 85-3934)

https://newdrugapprovals.wordpress.com/2013/10/09/molidustat-bay-85-3934-bayers-drug-under-initiation-in-patients-with-anemia-associated-with-chronic-kidney-disease-andor-end-stage-renal-disease/

In oncology, Copanlisib (BAY 80-6946), a novel, oral phosphatidylinositol-3 kinases (PI3K) inhibitor, was selected for accelerated development. Copanlisib demonstrated a broad anti-tumor spectrum in preclinical tumor models and promising early clinical signals in a Phase I study in patients with follicular lymphoma. A Phase II study in patients with Non-Hodgkin’s lymphoma is currently ongoing.

Bayer has also made good progress in the development of new treatment options for patients with gynecological diseases: sPRM (BAY 1002670) is a novel oral progesterone receptor modulator that holds the promises of long-term treatment of patients with symptomatic uterine fibroids. Based on promising early clinical data the initiation of a Phase III study is planned for mid-2014.

Initiation of further studies with recently launched products
Bayer has successfully launched five new pharmaceutical products, namely Xarelto™, Stivarga™, Xofigo™, Eylea™, and Riociguat, which has very recently been approved in Canada under the trade name Adempas™.

https://newdrugapprovals.wordpress.com/2013/05/27/xarelto-approved-for-secondary-prevention-in-acute-coronary-syndrome-patients-in-europe/

Regorafenib, stivarga

https://newdrugapprovals.wordpress.com/2013/08/31/bayers-stivarga-regorafenib-tablets-approved-in-europe/

Bayer’s Eylea (aflibercept),

https://newdrugapprovals.wordpress.com/2013/06/01/lucentis-rival-one-step-away-from-nhs-approval/

Xarelto has been approved globally for five indications across seven distinct areas of use, allowing doctors to treat patients in a greater variety of venous and arterial thromboembolic conditions than any other novel oral anticoagulant. The company continues to study the use of Xarelto for the treatment of further cardiovascular diseases. Ongoing clinical Phase III studies include COMPASS and COMMANDER-HF. The COMPASS study will assess the potential use of Xarelto in combination with aspirin, or as a single treatment to prevent major adverse cardiac events (MACE) in nearly 20,000 patients with atherosclerosis related to coronary or peripheral artery disease. The COMMANDER-HF study will evaluate the potential added benefit of Xarelto in combination with single or dual-antiplatelet therapy to help reduce the risk of death, heart attack and stroke in approximately 5,000 patients with chronic heart failure and coronary artery disease, following hospitalization for exacerbation of their heart failure.
In order to answer medically relevant questions for specific patient populations Bayer has initiated a range of additional Xarelto studies in patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention with stent placement (PIONEER-AF-PCI), cardioversion (X-VERT) or an AF ablation procedure (VENTURE-AF).
As an extension to the Xarelto clinical trial programme, a number of real-world studies are designed to observe and further evaluate Xarelto in everyday clinical practice. These include the XAMOS study of more than 17,000 orthopaedic surgery patients, which confirmed the clinical value of oral, once-daily Xarelto in routine clinical practice in adults following orthopaedic surgery of the hip or knee. XANTUS is designed to collate data on real-world protection with Xarelto in over 6,000 adult patients in Europe with non-valvular AF at risk of stroke while XANAP is designed to collate data on real-world protection with Xarelto in over 5,000 adult patients in Europe and Asia with non-valvular AF at risk of stroke. XALIA will generate information from over 4,800 patients treated for an acute DVT with either Xarelto or standard of care.

In the area of oncology, Stivarga has been approved in 42 countries for use against metastatic colorectal cancer that is refractory to standard therapies, and additionally for gastrointestinal stromal tumor (GIST) in the US and Japan. Bayer is now planning to assess Stivarga in earlier stages of colorectal cancer as well as other cancer types. A Phase III trial in patients with colorectal cancer after resection of liver metastases is currently under initiation. Based on early clinical data Bayer has also initiated a Phase III study in liver cancer in patients who have progressed on sorafenib treatment.

Furthermore, the anti-cancer drug Xofigo (radium 223 dichloride) is a first-in-class alpha-pharmaceutical which is designed for use in prostate cancer patients with ‘bone metastases’ (secondary cancers in the bone) to treat the cancer in the bone and to help extend their lives. Xofigo is approved in the US for the treatment of patients with advanced castrate-resistant prostate cancer with symptomatic bone metastases. In addition, the European CHMP recently gave a positive opinion for radium 223 dichloride for the same use. The decision of the European Commission on the approval is expected in the fourth quarter of 2013.
Based on the excellent Phase III results for Xofigo in patients with castration resistant prostate cancer and symptomatic bone metastases Bayer is looking to expand the use of Xofigo to earlier stages of the disease, and plans to initiate a Phase III study in combination with the novel anti-hormonal agent abiraterone. In addition, early stage signal-generating studies in other cancer forms where bone metastases are important causes of morbidity and mortality are planned.

In the area of pulmonary hypertension Adempas (Riociguat) is the first member of a novel class of compounds – so-called ‘soluble guanylate cyclase (sGC) stimulators’ – being investigated as a new and specific approach to treating different types of pulmonary hypertension (PH). Adempas has the potential to overcome a number of limitations of currently approved treatments for pulmonary arterial hypertension (PAH) and addresses the unmet medical need in patients with chronic thromboembolic pulmonary hypertension (CTEPH). It was approved for the treatment of CTEPH in Canada in September 2013, making it the world’s first drug approved in this deadly disease.
Riociguat has already shown promise as a potential treatment option beyond these two PH indications. An early clinical study was conducted in PH-ILD (interstitial lung disease), a disease characterized by lung tissue scarring (fibrosis) or lung inflammation which can lead to pulmonary hypertension, and, based on positive data, the decision was taken to initiate Phase IIb studies in PH-IIP (idiopathic pulmonary fibrosis), a subgroup of PH-ILD. Moreover, scientific evidence was demonstrated in preclinical models that the activity may even go beyond vascular relaxation. To prove the hypothesis Bayer is initiating clinical studies in the indication of systemic sclerosis (SSc), an orphan chronic autoimmune disease of the connective tissue affecting several organs and associated with high morbidity and mortality. If successful, Riociguat has the potential to become the first approved treatment for this devastating disease.

In the area of ophthalmology, Eylea (aflibercept solution for injection) is already approved in Europe and several additional countries for the treatment of neovascular (wet) age-related macular degeneration and for macular edema following central retinal vein occlusion. In September, Bayer HealthCare and Regeneron Pharmaceuticals presented data of the two phase III clinical trials VIVID-DME and VISTA-DME of VEGF Trap-Eye for the treatment of diabetic macular edema (DME) at the annual meeting of the Retina Society in Los Angeles and at the EURetina Congress in Hamburg, Germany. Both trials achieved the primary endpoint of significantly greater improvements in best-corrected visual acuity from baseline compared to laser photocoagulation at 52 weeks. Bayer plans to submit an application for marketing approval for the treatment of DME in Europe in 2013.

About Bayer HealthCare
The Bayer Group is a global enterprise with core competencies in the fields of health care, agriculture and high-tech materials. Bayer HealthCare, a subgroup of Bayer AG with annual sales of EUR 18.6 billion (2012), is one of the world’s leading, innovative companies in the healthcare and medical products industry and is based in Leverkusen, Germany. The company combines the global activities of the Animal Health, Consumer Care, Medical Care and Pharmaceuticals divisions. Bayer HealthCare’s aim is to discover, develop, manufacture and market products that will improve human and animal health worldwide. Bayer HealthCare has a global workforce of 54,900 employees (Dec 31, 2012) and is represented in more than 100 countries. More information at www.healthcare.bayer.com.

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On October 16, 2007, the U.S. Food and Drug Administration approved ixabepilone for the treatment of aggressive metastaticor locally advanced breast cancer no longer responding to currently available chemotherapies. In November 2008, the EMEAhas refused a marketing authorisation for Ixabepilone.

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