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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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POSACONAZOLE


……
Posaconazole.svg

Posaconazole  泊沙康唑 ,  بوساكونازول , Позаконазол
Sch56592
4-[4-[4-[4-[[(5R)-5-(2,4-difluorophenyl)-5-(1,2,4-triazol-1-ylmethyl)oxolan-3-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-2-[(2S,3S)-2-hydroxypentan-3-yl]-1,2,4-triazol-3-one

  1. Noxafil
  2. SCH 56592
U.S. Patents 5,661,151; 5,703,079; and 6,958,337.
Therap-Cat: Antifungal.
CAS 171228-49-2
Molecular Formula: C37H42F2N8O4
Molecular Weight: 700.78
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-(1H-1,2,4-triazol-1-yl)-D-threo-pentitol
Additional Names: (3Rcis)-4-[4-[4-[4-[5-(2,4-difluorophenyl)-5-(1,2,4-triazol-1-ylmethyl)tetrahydrofuran-3-ylmethoxy]phenyl]piperazin-1-yl]phenyl]-2-[1(S)-ethyl-2(S)-hydroxypropyl]-3,4-dihydro-2H-1,2,4-triazol-3-one
Syn……….Dominic De Souza, “PREPARATION OF POSACONAZOLE INTERMEDIATES.” U.S. Patent US20130203994, issued August 08, 2013.
Percent Composition: C 63.41%, H 6.04%, F 5.42%, N 15.99%, O 9.13%
  1. Melting Point

  • 170-172 deg C

    O’Neil, M.J. (ed.). The Merck Index – An Encyclopedia of Chemicals, Drugs, and Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p. 1365
  • Solubility

  1. In water, 0.027 mg/L at 25 deg C (est)

    US EPA; Estimation Program Interface (EPI) Suite. Ver.3.12. Nov 30, 2004. Available from, as of Dec 19, 2005:http://www.epa.gov/oppt/exposure/pubs/episuitedl.htm
US5661151   EXP Jul 19, 2019  PRODUCT PATENT
US 5703079  EXP Aug 26, 2014
US8410077 EXPMar 13, 2029
US9023790 EXPJul 4, 2031
US 6958337 EXP Oct 5, 2018
US 8263600 EXPApr 1, 2022

1H NMR PREDICT

 

 

13C NMR PREDICT

 

COSY PREDICT

 

CN101824009A * May 27, 2010 Sep 8, 2010 北京德众万全药物技术开发有限公司 Simple preparation method for posaconazole and piperazine intermediate thereof

 

Citing Patent Filing date Publication date Applicant Title
WO2015011224A1 * Jul 24, 2014 Jan 29, 2015 Sandoz Ag Improved process for the preparation of crystalline form iv of posaconazole

/////
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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)

Figure imgf000002_0001

(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 9517407eidemUS 5661151 (1995, 1997 both to Schering);

eidemTetrahedron 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

 

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  2. 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
  3. Bhattacharya M, Rajeshwari K, Dhingra B: Posaconazole. J Postgrad Med. 2010 Apr-Jun;56(2):163-7. Pubmed
  4. Frampton JE, Scott LJ: Posaconazole : a review of its use in the prophylaxis of invasive fungal infections. Drugs. 2008;68(7):993-1016.Pubmed
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  6. Kwon DS, Mylonakis E: Posaconazole: a new broad-spectrum antifungal agent. Expert Opin Pharmacother. 2007 Jun;8(8):1167-78.Pubmed
  7. 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
  8. 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
  9. 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

Merck seeks approval for pill form of antifungal,noxafil


Posaconazole is a triazole antifungal drug marketed in the United States, the European Union, and in other countries by Schering-Plough under the trade name Noxafil. In Canada, posaconazole is marketed by Schering-Plough under the trade name Posanol.

11 april2013

Merck & Co says that a New Drug Application for a tablet formulation of the company’s antifungal Noxafil has been accepted for review by the US Food and Drug Administration.

Merck currently markets Noxafil (posaconazole) in liquid form for invasive Aspergillus and Candida infections in patients who are at high risk of developing these infections due to being “severely immunocompromised”. This covers patients who have received haematopoietic stem cell transplants and have graft-versus-host disease, or patients with cancers of the blood who are experiencing prolonged low white blood cell counts as a result of chemotherapy.

Specifically, Merck is seeking FDA approval of Noxafil tablets for once-daily administration, following a twice-a-day loading dose on the first day of therapy. The pill has already been filed with the European Medicines Agency and the drug giant plans to seek regulatory approval for the tablet formulation in other countries around the world.

Robin Isaacs, head of infectious disease clinical research at Merck Research Laboratories, said the filing for a Noxafil pill “is an example of Merck’s ongoing commitment to developing new therapy options for patients in the hospital setting”. He added that “invasive fungal infections are a significant cause of illness and death among severely immunocompromised patients”.

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