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.”

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

MORE INFO

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