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RABEPRAZOLE

October 23, 2013 7:56 am / 2 Comments on RABEPRAZOLE

Pariprazole sodium;Rabeprazole sodium;LY-307640;E-3810;Aciphex;Pariet

Rabeprazole /ˌ r æ .ˈ b ɛ p .r æ .z ɔː l / is an antiulcer drug in the class of proton pump inhibitors. It was developed by Eisai Co. and is marketed by Janssen-Cilag as the sodium salt under the brand names AcipHex (/ˈ æ s ɨ f ɛ k s /, referring to pH) in the US, Pariet in Europe, Brazil, Canada, Japan, Russia and Australia, Acigard, Cyra, Rabium, Esoon,Orporo, Parit, Rabemac, Rabiloz, Razo, Rabifast, Rablet and Rabsiv in India, and Zechin in Pakistan.

Rabeprazole, 2-[[[4-(3-Methoxypropoxy)-3-methyl-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole has the following structural formula

Rabeprazole belongs to a class of antisecretory compounds (substituted benzimidazole proton-pump inhibitors) that do not exhibit anticholinergic or histamine H₂-receptor antagonist properties, but suppress gastric acid secretion by inhibiting the gastric H⁺, K⁺ATPase at the secretory surface of the gastric parietal cell. Because this enzyme is regarded as the acid (proton) pump within the parietal cell, rabeprazole has been characterized as a gastric proton-pump inhibitor. Rabeprazole blocks the final step of gastric acid secretion. So that it can effectively inhibit the secretion of an acid and is therefore effective in the therapy or prevention of human and animal peptic ulcer.

Rabeprazole Sodium is commercially available in a pharmaceutical composition under the brand name ACIPHEX® marketed by Eisai and is covered under US 5045552 (JP priority application No. JP1987002198919870202; JP1987007778419870331; JP1986027053619861113

US 5045552 discloses the preparation of Rabeprazole sodium by known traditional procedures, such as dissolution of the product in a mixture of stoichiometric quantity of aqueous sodium hydroxide and ethanol, then removal of water azeotropically, thereafter drying the residue at low pressure and then crystallization of the residue with less polar solvent such as diethyl ether, tert-butyl methyl ether.

The U.S. Pat. No. 5,045,552 discloses the Rabeprazole and many other substituted benzimidazole-type compounds having anti-ulcer activity. This patent further discloses the process for preparation of Rabeprazole by oxidation of Rabeprazole sulfide using 85% m-chloroperbenzoic acid in a mixture of dichloromethane and diethyl ether followed by work up to get product as oil. The obtained oil is crystallized from a mixture of dichloromethane/ether. Optionally the oily crude is dissolved in aqueous solution of sodium hydroxide. The obtained solution is subjected to azeotropic distillation with ethanol to remove water and adding ether to get crystalline Rabeprazole base.

According to the prior art, Rabeprazole base is crystallized using dichloromethane/ether to obtain crystalline off white product. The HPLC purity is less than or equal to 99% and the isolation procedure involves azeotropic distillation of water, during which the product is exposed to high temperature and leads to certain impurities. Repeated crystallization is needed to remove impurities to get desired quality. Using large volumes of chlorinated solvents in the plant leads to environmental hazardous.

Japanese patent application JP2001039975 teaches that the product obtained by example 33 of U.S. Pat. No. 5,045,552 with a melting range of 140-141° C. corresponds to amorphous rabeprazole sodium

The U.S. Pat. No. 6,919,459 patent also discloses the process for the preparation of Rabeprazole by oxidation of Rabeprazole sulfide using m-Chloroperbenzoic acid (m-CPBA) in a suitable solvent. The reaction mass is subjected to repeated washings at different pH levels and isolate the product from aqueous layer.

Rabeprazole is not stable at acidic conditions and decomposes to form unknown impurities. To remove these impurities repeated crystallizations are required to get desire quality of the final product.

The WO2006/117802 PCT application discloses the process for the preparation of Rabeprazole sodium by oxidation of Rabeprazole sulfide with sodium hypo halite solution in water or a mixture of water and water miscible solvent medium using alkali metal hydroxide and catalyst. The reaction mass is saturated by inorganic saturating agents and the Rabeprazole sodium salt is extracted with water immiscible organic solvent. Organic solvent is distilled and the residue is dissolved in second organic solvent to get clear solution, which is precipitated by adding antisolvent.

The WO2006/120701 PCT application discloses process for manufacture of amorphous Rabeprazole sodium by the reaction of Rabeprazole base with aqueous sodium hydroxide. Ethanol is added to the obtained solution. Solvents are distilled from the solution to get thick mass. Organic solvent is added to the obtained residue to get clear solution, to which antisolvent is added to get amorphous Rabeprazole sodium.

The prior art methods cited above have many disadvantages, these methods involve more number of organic solvents and lack successive extractions and washings of the layers during work up procedure. It leads to many impurities that ultimately affect on purity and yield loss of final product.

The U.S. Pat. No. 6,180,652 and WO 2003101452 PCT application discloses the process for the preparation of amorphous rabeprazole sodium, which is obtained by lyophilization of an aqueous solution of rabeprazole sodium acetone complex and an aqueous NaOH solution of Rabeprazole respectively.

Lyophilization technique is not suitable for production at industrial scale and it needs more time cycle and involves the cost.

We observed that rabeprazole is rapidly degraded in chlorinated solvent like dichloromethane to form unknown impurities, due to impurities while distillation gummy material is formed. It leads to yellowish color in final product, finally it leads to yield loss in final product.

According to prior art methods,

- (a) Dichloromethane/ether is used for final crystallization gives off white product with HPLC purity less than or equal to 99% and
- (b) Rabeprazole sodium is isolated by using azeotropic distillation. It needs high temperature to remove water and the reaction mass is exposed to high temperature to form unknown impurities, to remove these impurities repeated crystallizations are required to get desire quality of the final product

US 6,313,303 discloses the preparation of sulfoxides by oxidizing thio ether with a peroxoborate salt in the presence of an acid anhydride or a metal catalyst; and the preparation of sulfoxides by oxidizing thio ether with an N- halosuccinimide, l,3-dihalo-5,5-dimethyl-hydantoin or dichloroisocyanuric acid salt in the presence of a base.

IN 192030 discloses the purification process of Rabeprazole, in which sulfone enriched Rabeprazole is treated with an amino alcohol e.g. ethanolamine in the presence of an organic solvent, further the reaction mixture washed with water to remove the sulfone impurities. US 7,439,367 (IN218648, 058/MUM/2003, 193/MUM/2003) discloses the preparation of Rabeprazole by oxidizing its corresponding sulfide compound, where aqueous hypohalite solution is used as an oxidizing agent. The said oxidation is carried out at a controlled temperature and pH. During said oxidation the pH of the reaction mixture is maintained in the range of 9 to 12. This process utilizes catalyst such as pyridine, di-isopropyl ethyl amine and N,N-dimethyl amino pyridine.

US 7,060,837 discloses the purification of lansoprazole using ammonia, ammonium hydroxide, diethylamine, triethylamine and methylamine in the presence of solvent. The said patent utilizes acid for the isolation of lanzoprazole in pure form.

US 2008/0161579 (IN190/MUM/2005) discloses a process for the preparation of Rabeprazole sodium comprising oxidation of Rabeprazole sulfide with sodium hypohalite in water or a mixture of water and water miscible solvent using alkali metal hydroxide and catalyst. It also discloses a process for the preparation of Rabeprazole sulfide.

WO 2008/045777 (1856/CHE/2006) discloses the preparation of

Rabeprazole by oxidizing the corresponding sulfide compound using about 0.8 to 1.25 equivalents of an oxidizing agent in the presence of less than or about 2.25 equivalents of a base where aqueous sodium hypohalite used as an oxidizing agent.

WO 2006/024890 discloses a process for the preparation of Rabeprazole in which the Rabeprazole obtained was treated with the triethylamine in hexane. The use of n-hexane in the final stage is not suitable for manufacturing point of view as it is difficult to remove residual hexane solvent. There are several disadvantages associated with such known processes; all the methods reported in these prior arts leads to the formation of many impurities which ultimately affects the purity of the final product.

US 5,045,552 patent discloses the preparation of Rabeprazole by oxidizing the Rabeprazole sulfide using m-chloroperbenzoic acid as shown in scheme-I. The crude Rabeprazole was dissolved in sodium hydroxide and the resulting solution was azeotropically distilled together with ethanol thrice to remove the water. Finally ether was added to get the crystals of Rabeprazole sodium

WO 03/101452 discloses a method for the preparation of Rabeprazole sodium comprising dissolving Rabeprazole base in aqueous sodium hydroxide and then subjecting to lyophilization.

The condensation of 4-chloro-2,3-dimethylpyridine N-oxide (I) with 3-methoxypropanol (II) by means of NaH in DMSO gives 4-(3-methoxypropoxy)-2,3-dimethylpyridine N-oxide (III), which is treated with acetic anhydride at 90 C yielding 2-(acetoxymethyl)-4-(3-methoxypropoxy)-3-methylpyridine (IV). The hydrolysis of (IV) with NaOH in ethanol affords 2-(hydroxymethyl)-4-(3-methoxypropoxy)-3-methylpyridine (V), which by treatment with SOCl2 in dichloromethane is converted into 2-(chloromethyl)-4-(3-methoxypropoxy)-3-methylpyridine (VI). The condensation of (VI) with 2-mercaptobenzimidazole (VII) by means of NaOH in ethanol gives 2-[4-(3-methoxypropoxy)-3-methylpyridin-2-ylmethylthio]benzimidazole (VIII), which is oxidized with m-chloroperbenzoic acid in ether – dichloromethane to afford 2-[4-(3-methoxypropoxy)-3-methylpyridin-2-ylsulfinyl]benzimidazole (IX). Finally, this compound is treated wtih aqueous Na2CO3.

NEXT………………….

A synthesis for [14C]-labeled E-3810 has been described: The cyclization of o-phenylenediamine (I) with [14C]-labeled carbon disulfide (II) by means of aqueous KOH gives the potassium salt of [14C]-2-mercaptobenzimidazole (III), which is treated with acetic acid to obtain the corresponding thiol (IV). The condensation of (IV) with 2-(chloromethyl)-4-(3-methoxypropoxy)-3-methylpyridine (V) by means of NaOH in refluxing ethanol yields [14C]-labeled 2-[4-(3-methoxypropoxy)-3-methylpyridin-3-ylmethylthio]benzimidazole (VI). The oxidation of (VI) with m-chloroperbenzoic acid in dichloromethane affords the corresponding sulfoxide (VIII), which is finally treated with 0.1 N NaOH in ethanol.

References1:

Souda, S.; Ueda, N.; Miyazawa, S.; Tagami, K.; Nomoto, S.; Okita, M.; Shimomura, N.; Kaneko, T.; Fujimoto, M.; Murakami, M.; Oketani, K.; Fujisaki, H.; Shibata, H.; Wakabayashi, T. (Eisai Co., Ltd.); Pyridine derivs., pharmaceutical compsns. comprising the same, the use of the same for the manufacture of medicaments having therapeutic or preventative value, and a process for preparing the same. AU 8781138; EP 0268956; EP 0475456; EP 0654471; EP 0786461; JP 1989006270; JP 1993247035; JP 1995291967; US 5045552; US 5998445 .

References2:

Castaner, J.; Prous, J.; E-3810. Drugs Fut 1991, 16, 1, 19.

References3:

Sohda, S.; Tagami, K.; Chiku, S.; Synthesis of 14C-labelled sodium pariprazole (E3810). J Label Compd Radiopharm 1993, 33, 9, 849.

Rabeprazole as “CYRA” (Systopic Labs Pvt Ltd), “Elpizole” (Orchid Chemicals & Pharmaceuticals), Elpizole-20 (Orchid Chemicals & Pharmaceuticals), Rablet (Lupin), Acigard (3D), AcipHex, Rabeloc, Pariet, Rabider (Duta Formulations) Rabsiv 20 (Saharsh Biologicals) is supplied in:

Tablet, enteric-coated; 10 mg
Tablet, enteric-coated; 20 mg
Pali-Schöll I, Jensen-Jarolim E (April 2011). “Anti-acid medication as a risk factor for food allergy”. Allergy 66 (4): 469–77. doi:10.1111/j.1398-9995.2010.02511.x. PMID 21121928.

HPLC METHOD

Rabeprazole with more impurities, particularly at 2.12 RRT (393 mass), 3.51 RRT (491 mass), 4.47 RRT (457 mass), 4.85 RRT (684 mass) and 4.54 RRT (893 mass). The mass (molecular or formula weight) number of the impurities were identified using LCMS. Particularly, the obtained product contains unknown impurities of higher molecular weight in the range of 0.1-1.0 % at relative retention time (RRT) of 2.12, 3.51, 4.47, 4.85, and 4.54 RRT as measured by high performance liquid chromatography (HPLC) method provided below.

The purity of the product obtained is determined by high performance liquid chromatography method under the conditions mentioned below.

Column: Prontosil Kromabond 100-5-C18 (250 x 4.6 mm), 5μ,

Mobile phase A: 1.36g KH₂PO4 to 1 litre water, 0.5ml OfEt₃N, Mobile phase B: Methanol: ACN (95:5),

Diluent: Mobile phase A and ACN (70:30),

Flow Rate: 1.0 mL/min,

Detection: UV at 280 nm,

Injection Volume: 20 μL, Run Time: 60 min.

Column oven temperature: 3O⁰C. Surprisingly the applicant identified a method in which, crude Rabeprazole was treated with diethylamine and optionally addition of TBAB (tetrabutylammmonium bromide) as catalyst, where the impurity level reduced. Though the reported amines like triethyl amine, ethanolamine, and ammonia are effectively used to minimize sulfone impurity, those are failed or unsatisfactory to remove the impurities at 2.12 RRT, 3.51 RRT, 4.47 RRT, 4.85 RRT and 4.54 RRT.

SPECTRAL DATA

EP 1869015 B1 FOR RABEPRAZOLE SODIUM

IR Spectra (KBr, cm^-1): 3382, 2927, 1583, 1462, 1384, 1298, 1269, 1190, 1157, 1093, 1018, 745.

H NMR Spectra [200 M Hz, CD3OD] δ (ppm): 8.23 – 8.25 (1H, d, ArH); 7.57 – 7.62 (2H, m, ArH); 7.0 – 7.09 (2H, m, ArH); 6.87 – 6.90 (1H, d, ArH); 4.57 – 4.63 (2H, d, O=S-CH2-Ar); 4.0 – 4.1 (2H, t, -O-CH2-CH2-); 3.49 – 3.55 (2H, t, -CH2-O-CH3); 3.31 (3H, s, -OCH3); 2.1 (3H, s, Ar-CH3); 1.96 – 2.0 (2H, t, -CH2-CH2-CH2-).

As per the process described and exemplified in the U. S. Patent No.

5,045,552, rabeprazole sodium is prepared by oxidizing 2-[[4-(3- methoxyporpoxy)-3-methylpyridine-2-yl]rnethylthio]-1 H-benzimidazole with m- chloroperbenzoic acid to afford the rabeprazole base which is further converted to its sodium salt by using 0.1 N aqueous solution of sodium hydroxide, followed by addition of ethanol. The water is removed by azeotropic distillation and the product is precipitated by using ether as solvent such as diethyl ether, tert-butyl methyl ether. The melting point of the disclosed rabeprazole sodium salt is 140- 141⁰C. The isolation process described in the U. S. Patent No. 5,045,552 has numerous disadvantages such as large volume of solvents is required for azeotropic removal of water during which the product is exposed to high temperature and leads to certain impurities. Based on these drawbacks the isolation process finds to be unsuitable for preparation of amorphous rabeprazole sodium at commercial scale operations.

Japanese patent application JP 2001039975 indicates that the product obtained by example 33 of the U. S. Patent No. 5,045,552 with a melting point of

140-141⁰C corresponds to amorphous rabeprazole sodium. In this application, the X-ray powder diffraction pattern of the amorphous rabeprazole sodium is shown.

The PCT patent publication No. WO 03/101452 discloses a method for the preparation of rabeprazole sodium comprising dissolving rabeprazole base in aqueous sodium hydroxide and then subjecting to lyophilization. U.S. Patent No. 6,180,652 B1 (the ‘652 patent) describes acetone complex of rabeprazole sodium, process for its production and characterizes it by powder X-ray diffraction, infra-red spectroscopy and ¹H-NMR spectroscopy. The ‘652 patent further reports a process for preparation of amorphous rabeprazole sodium by lyophilizing (freeze-drying) an aqueous solution of rabeprazole sodium acetone complex.

However, lyophilization is a technique, which is not suitable for production at industrial scale because this process presents serious limitations on cost, time, equipment capability and environmental protection.

According to PCT patent publication No. WO 2004/085424A1 , amorphous rabeprazole sodium is obtained by heating the rabeprazole sodium acetone complex at elevated temperature, preferably between 100 and 110⁰C. It is well known that exposing rabeprazole-type compounds to high temperatures increases the risk of decomposition to form impurities and as such, heat treatment of rabeprazole sodium acetone complex into amorphous rabeprazole sodium is not adequate for the production of a rabeprazole which is suitable for pharmaceutical use.

PCT patent publication No. WO 2007/023393 A2 reports a process for preparation of amorphous rabeprazole sodium, the said process comprises: i) contacting rabeprazole sodium acetone complex with a first solvent system which includes a hydrocarbon solvent or an ether solvent or an alcohol solvent or mixtures thereof; ii) filtering the solid from the solvent system used in step i) or distilling the solvent system used in step i) under reduced or atmospheric pressure, to thereby obtain a residue; iii) contacting the wet solid or the residue of step ii) with a second solvent system which includes a hydrocarbon solvent or an ether solvent; and iv) filtering to obtain a wet solid from the solvent system used in step iii) to obtain a wet solid.

The methods for preparation of amorphous rabeprazole sodium as described in the patents U.S. Patent No. 6,180,652 B1 , PCT patent publication No. WO 2004/085424A1 and PCT patent publication No. WO 2007/023393 A2 involves lengthy process i.e., proceeds via rabeprazole sodium acetone complex intermediate and also the yields obtained in these processes are very low.

U.S. Patent Application No. US2004/0180935A1 teaches a process for production of amorphous rabeprazole sodium by dissolving rabeprazole acid in a mixture of sodium hydroxide and methanol at 25-35⁰C, removing the solvent by evaporation and precipitating the product by adding petroleum ether.

PCT patent publication No. WO 2006/120701 A1 teaches a process for manufacture of amorphous rabeprazole sodium with mean particle diameter between 10 to 55 μm, the said process comprises, addition of rabeprazole to aqueous sodium hydroxide; addition of ethyl alcohol to the solution; distillation of solvents from the solution thus obtained till thick mass is obtained; addition of an organic solvent selected from ethyl acetate, dichloromethane, chloroform, butyl acetate, ethanol, isopropyl alcohol, methanol, tetrahydrofuran, to the residue to obtain a clear solution; addition of this clear solution to an anti-solvent includes diisopropyl ether, diethyl ether, methyl tert-butyl ether, under agitation and isolation of the product.

Since a solvent may play an important role in increasing the yield rate or in determination of physical properties of drug substance such as crystal form, purity, solubility, etc., even if such a solvent is known to be toxic, there may be many cases that the use thereof in the preparation of drug substance cannot be avoided in terms of risk benefits. In such cases, this guideline (ICH guidelines Q3C(R3)) decrees that a concentration of a residual solvent in drug substance should be not more than a specified value, which is toxicologically acceptable. The methods for preparation of amorphous rabeprazole sodium as described in the patents, U.S. Patent Application No. US2004/0180935A1 and PCT patent publication No. WO 2006/120701 A1 suffers with residual solvent problem and thereby commercially not viable. These methods utilize the solvents like diisopropyl ether and petroleum ether as precipitating solvents. These solvents are difficult to remove completely by practical manufacturing techniques. According to the ICH guidelines Q3C(R3), there is no adequate toxicological data for the solvents like diisopropyl ether and petroleum ether on which to base a PDE was found. However, a need still remains for an improved and commercially viable process of preparing pure amorphous rabeprazole sodium that would solve the aforesaid problems associated with processes described in the prior art, which will be suitable for largr-scale preparation, in terms of simplicity, chemical yield and purity of the product, and which would carry out with comparatively smaller volume of solvent

Patent expiry dates

October 23, 2013 3:53 am / 1 Comment on Patent expiry dates

https://newdrugapprovals.wordpress.com/patent-expiry/

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loteprednol etabonate…Patent expiry this week……of October 20, 2013

October 23, 2013 3:49 am / 1 Comment on loteprednol etabonate…Patent expiry this week……of October 20, 2013

loteprednol etabonate

82034-46-6 cas

Drug Patent Expiry for the week of October 20, 2013

Tradename….LOTEMAX

Applicant………Pharmos

SUSPENSION/DROPS; OPHTHALMIC, o.5%

Generic Name………loteprednol etabonate

Patent No.US 5,540,930

http://www.google.co.in/patents/US5540930

The invention provides novel compositions of matter containing water-insoluble steroid drugs suitable for therapeutic use. The invention provides stable aqueous suspensions of water-insoluble steroid drugs of particle sizes of ≦15 μm which remain in such a state so as to allow for immediate suspension, when desired, even after extended periods of settling.

Approval History
Date	Supplement No.	Action	Documents
1998-03-09	000	Approval	Review Letter Label

Publication number	US5540930 A
Publication type	Grant
Application number	US 08/142,743
Publication date	30 Jul 1996
Filing date	25 Oct 1993
Priority date	25 Oct 1993
Fee status	Paid
Also published as	CA2174550A1, CA2174550C, DE69430635D1, DE69430635T2, EP0730443A1, EP0730443A4, EP0730443B1, US5747061, WO1995011669A1, Less «8 More »
Publication number	08142743, 142743, US 5540930 A, US 5540930A, US-A-5540930, US5540930 A, US5540930A
Inventors	Doron I. Friedman, Yaacov J. Guy
Original Assignee	Pharmos Corporation

	Company
LOTEMAX NDA (020583)	BAUSCH AND LOMB	LOTEPREDNOL ETABONATE
ALREX NDA (020803)	BAUSCH AND LOMB	LOTEPREDNOL ETABONATE
LOTEMAX NDA (020841)	PHARMOS	LOTEPREDNOL ETABONATE…expired
ZYLET NDA (050804)	BAUSCH AND LOMB	LOTEPREDNOL ETABONATE; TOBRAMYCIN
LOTEMAX NDA (200738)	BAUSCH AND LOMB	LOTEPREDNOL ETABONATE
LOTEMAX NDA (202872)	BAUSCH AND LOMB	LOTEPREDNOL ETABONATE

Loteprednol (as the ester loteprednol etabonate) is a corticosteroid used in optometry and ophthalmology. Marketed by Bausch and Lomb as Lotemax in the U.S., ocular applications for this drug include the treatment of inflammation of the eye due to allergies (according to the prescription information sheet), as well as chronic forms of keratitis (e.g.: adenoviral and Thygeson’s keratitis), vernal keratoconjunctivitis, pingueculitis, and episcleritis. The drug has little or no effect on intraocular pressure.

Druzgala, P.; Hochhaus, G.; Bodor, N.; J. Steroid Biochem. Mol. Biol. 1991, 38, 149.

http://dx.doi.org/10.1016/0960-0760(91)90120-T

Steward, R; et al. (November 1998). “Double-masked, placebo-controlled evaluation of loteprednol etabonate 0.5% for postoperative inflammation”. J Cataract Surg 24: 1480–1489.
Pavesio, CE; Decory, HH (2008). “Treatment of ocular inflammatory conditions with loteprednol etabonate”. Br J Ophthalmol 92 (4): 455–459. doi:10.1136/bjo.2007.132621. PMID 18245274.

COCRYSTALS IN PHARMA

October 22, 2013 4:14 am / 2 Comments on COCRYSTALS IN PHARMA

READ ALL AT

http://www.allfordrugs.com/cocrystals/

Health Canada approves Levemir® FlexTouch® prefilled insulin pen for the treatment of type 1 and type 2 diabetes

October 21, 2013 3:23 am / 2 Comments on Health Canada approves Levemir® FlexTouch® prefilled insulin pen for the treatment of type 1 and type 2 diabetes

MISSISSAUGA, ON, Oct. 18, 2013 /CNW/ – Novo Nordisk today announced that Health Canada has approved Levemir® FlexTouch®, a disposable prefilled insulin pen containing Levemir® (insulin detemir). Levemir® FlexTouch® has been designed to improve ease of use for insulin administration and to help decrease barriers to good treatment adherence for Canadians living with type 1 and type 2 diabetes mellitus (diabetes).

The approval was also announced at the 2013 Vascular Conference in Montreal, Quebec.

Health Canada approves Levemir® FlexTouch® prefilled insulin pen for the treatment of type 1 and type 2 diabetes

http://www.pharmalive.com/health-canada-approves-levemir-flextouch

World Drug Tracker: DRUG PATENT EXPIRY 2013-2016

October 18, 2013 12:53 pm / 5 Comments on World Drug Tracker: DRUG PATENT EXPIRY 2013-2016

World Drug Tracker: DRUG PATENT EXPIRY 2013-2014.

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Monoclonal antibody (mAbs) 2013

October 17, 2013 3:35 am / Leave a comment

2013——-29 monoclonal antibody (mAbs) drugs are in Phase III clinical development.

While around 350 therapeutic mAbs are currently in clinical development globally, only 28 had entered active Phase 2/3 or Phase 3 studies as of January 2013, Additionally one mAb mixture was under evaluation in Phase III.

Historically, mAbs that target antigens relevant to cancer have comprised approximately 50% of the mAb clinical pipeline,

but in 2013 the picture has changed: 66% or 19 of the antibodies to watch in 2013 are for non-cancer indications.

The non-cancer mAbs include alirocumab (Regeneron; Sanofi, hypercholesterinemia);

AMG 145 (Amgen, hypercholesterinemia),

epratuzumab (UCB, SLE),

gantenerumab (Roche; Alzheimer’s disease),

gevokizumab (Xoma/Servier, Non-infectious uveitis),

itolizumab (Biocon, Plaque psoriasis), ixekizumab (Eli Lilly and Co., psoriasis),

lebrikizumab (Roche/Genentech, rheumatoid arthritis),

mepolizumab (GSK, Asthma, COPD etc.),

ocrelizumab (Roche/Genentech, multiple sclerosis),

reslizumab (Teva, Eosinophilic asthma), romosozumab (Amgen, Postmenopausal osteoporosis),

sarilumab (Regeneron; Sanofi, rheumatoid arthritis),

secukinumab (Novartis, rheuma, psoriasis),

sirukumab (Janssen R&D LLC, rheumatoid arthritis),

solanezumab (Eli Lilly and Co., Alzheimer’s disease),

tabalumab (Eli Lilly and Co., rheuma, SLE)

and

vedolizumab (Millenium, Ulcerative colitis; Crohn disease).

The mixture of actoxumab and bezlotoxumab (MK-3415A, Merck & Co.) is being evaluated in two Phase 3 studies as a treatment for Clostridium difficile infection.

The ten cancer mAbs are:

elotuzumab (Bristol-Myers Squibb, Abbott, multiple myeloma),

farletuzumab (Morphotek, ovarian cancer),

inotuzumab ozogamicin (Pfizer; UCB, ALL, NHL),

naptumomab estafenatox (Active Biotech, renal cell carcinoma),

necitumumab (ImClone LLC, NSCL),

nivolumab (Bristol-Myers Squibb, NSCL, renal cell carcinoma),

obinutuzumab (Roche/Genetech, Diffuse large B cell lymphoma, CLL, NHL),

onartuzumab (Roche/Genetech, NSCL cancer; gastric cancer),

racotumomab (CIMAB; Laboratorio Elea S.A.C.I.F. y A, NSCL),

and ramucirumab (ImClone LLC, Gastric; liver, breast, colorectal, NSCL cancers).

Antibody

More PowerPoint presentations from Dr Alok Tripathi

monoclonal antibodies from Nasa Ahmad

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MONOCLONAL ANTIBODIES from Umair hanif

Tetraphase to Present New Data at IDWeek on Eravacycline’s Potential Activity in Treating Serious Respiratory Infections

October 4, 2013 9:52 am / 4 Comments on Tetraphase to Present New Data at IDWeek on Eravacycline’s Potential Activity in Treating Serious Respiratory Infections

eravacycline

http://www.ama-assn.org/resources/doc/usan/eravacycline.pdf

1-Pyrrolidineacetamide, N-[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-7-(dimethylamino)-
4-fluoro-5,5a,6,6a,7,10,10a,12-octahydro-1,8,10a,11-tetrahydroxy-10,12-dioxo-2-
naphthacenyl]-
(4S,4aS,5aR,12aS)-4-(dimethylamino)-7-fluoro-3,10,12,12a-tetrahydroxy-1,11-dioxo-9-
[(pyrrolidin-1-ylacetyl)amino]-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide

MOLECULAR FORMULA C27H31FN4O8
MOLECULAR WEIGHT 558.6

SPONSOR Tetraphase Pharmaceuticals, Inc.
CODE DESIGNATION TP-434
CAS REGISTRY NUMBER 1207283-85-9
WHO NUMBER 9702

Tetraphase Pharmaceuticals Inc. (NASDAQ:TTPH) today announced that it will present two posters at IDWeek 2013 that examine the potential of its lead antibiotic candidate eravacycline to treat serious multi-drug resistant (MDR) infections. The first will highlight positive results of a Phase 1 study assessing the bronchopulmonary disposition safety and tolerability of eravacycline in healthy men and women; this study represents the first clinical assessment of eravacycline for potential use in treating pneumonia. The second poster will provide the results of a study that examined the activity of eravacycline in vitro against multiple Gram-negative and Gram-positive pathogens to set quality-control limits for monitoring eravacycline activity in future testing programs.
http://www.pharmiweb.com/pressreleases/pressrel.asp?ROW_ID=79335#.Uk6MOoanonU
More: http://www.pharmiweb.com/pressreleases/pressrel.asp?ROW_ID=79335#.Uk6MOoanonU#ixzz2gkEMTtQm

Eravacycline (TP-434) is a synthetic fluorocycline antibiotic in development.

Eravacycline (TP-434 or 7-fluoro-9-pyrrolidinoacetamido-6-demethyl-6-deoxytetracycline) is a novel fluorocycline that was evaluated for antimicrobial activity against panels of recent aerobic and anaerobic Gram-negative and Gram-positive bacteria. Eravacycline showed potent broad spectrum activity against 90% of the isolates (MIC₉₀) in each panel at concentrations ranging from ≤0.008 to 2 μg/mL for all species panels except Pseudomonas aeruginosa and Burkholderia cenocepacia (MIC₉₀ values of 32 μg/mL for both organisms). The antibacterial activity of eravacycline was minimally affected by expression of tetracycline-specific efflux and ribosomal protection mechanisms in clinical isolates. Further, eravacycline was active against multidrug-resistant bacteria, including those expressing extended spectrum β-lactamases and mechanisms conferring resistance to other classes of antibiotics, including carbapenem resistance. Eravacycline has the potential to be a promising new IV/oral antibiotic for the empiric treatment of complicated hospital/healthcare infections and moderate-to-severe community-acquired infections.

Tetraphase’s lead product candidate, eravacycline, has also received an award from Biomedical Advanced Research and Development Authority (BARDA) that provides for funding to develop eravacycline as a potential counter-measure to certain biothreat pathogens. It is worth up to USD 67 million.

Process R&D of Eravacycline: The First Fully Synthetic Fluorocycline in Clinical Development

Eravacycline (TP-434)

We are developing our lead product candidate, eravacycline, as a broad-spectrum intravenous and oral antibiotic for use as a first-line empiric monotherapy for the treatment of multi-drug resistant (MDR) infections, including MDR Gram-negative bacteria. We developed eravacycline using our proprietary chemistry technology. We completed a successful Phase 2 clinical trial of eravacycline with intravenous administration for the treatment of patients with complicated intra-abdominal infections (cIAI) and have initiated the Phase 3 clinical program.

Eravacycline is a novel, fully synthetic tetracycline antibiotic. We selected eravacycline for development from tetracycline derivatives that we generated using our proprietary chemistry technology on the basis of the following characteristics of the compound that we observed in in vitro studies of the compound:

potent antibacterial activity against a broad spectrum of susceptible and multi-drug resistant bacteria, including Gram-negative, Gram-positive, atypical and anaerobic bacteria;
potential to treat the majority of patients as a first-line empiric monotherapy with convenient dosing; and
potential for intravenous-to-oral step-down therapy.

In in vitro studies, eravacycline has been highly active against emerging multi-drug resistant pathogens like Acinetobacter baumannii as well as clinically important species ofEnterobacteriaceae, including those isolates that produce ESBLs or are resistant to the carbapenem class of antibiotics, and anaerobes.

Based on in vitro studies we have completed, eravacycline shares a similar potency profile with carbapenems except that it more broadly covers Gram-positive pathogens like MRSA and enterococci, is active against carbapenem-resistant Gram-negative bacteria and unlike carbapenems like Primaxin and Merrem is not active against Pseudomanas aeruginosa. Eravacycline has demonstrated strong activity in vitro against Gram-positive pathogens, including both nosocomial and community-acquired methicillin susceptible or resistantStaphylococcus aureus strains, vancomycin susceptible or resistant Enterococcus faecium andEnterococcus faecalis, and penicillin susceptible or resistant strains of Streptococcus pneumoniae. In in vitro studies for cIAI, eravacycline consistently exhibited strong activity against enterococci and streptococci. One of the most frequently isolated anaerobic pathogens in cIAI, either as the sole pathogen or often in conjunction with another Gram-negative bacterium, is Bacteroides fragilis. In these studies eravacycline demonstrated activity against Bacteroides fragilis and a wide range of Gram-positive and Gram-negative anaerobes.

Key Differentiating Attributes of Eravacycline
The following key attributes of eravacycline, observed in clinical trials and preclinical studies of eravacycline, differentiate eravacycline from other antibiotics targeting multi-drug resistant infections, including multi-drug resistant Gram-negative infections. These attributes will make eravacycline a safe and effective treatment for cIAI, cUTI and other serious and life-threatening infections for which we may develop eravacycline, such as ABSSSI and acute bacterial pneumonias.

Broad-spectrum activity against a wide variety of multi-drug resistant Gram-negative, Gram-positive and anaerobic bacteria. In our recently completed Phase 2 clinical trial of the intravenous formulation of eravacycline, eravacycline demonstrated a high cure rate against a wide variety of multi-drug resistant Gram-negative, Gram-positive and anaerobic bacteria. In addition, in in vitro studies eravacycline demonstrated potent antibacterial activity against Gram-negative bacteria, including E. coli; ESBL-producing Klebsiella pneumoniae; Acinetobacter baumannii; Gram-positive bacteria, including MSRA and vancomycin-resistant enterococcus, or VRE; and anaerobic pathogens. As a result of this broad-spectrum coverage, eravacycline has the potential to be used as a first-line empiric monotherapy for the treatment of cIAI, cUTI, ABSSSI, acute bacterial pneumonias and other serious and life-threatening infections.
Favorable safety and tolerability profile. Eravacycline has been evaluated in more than 250 subjects in the Phase 1 and Phase 2 clinical trials that we have conducted. In these trials, eravacycline demonstrated a favorable safety and tolerability profile. In our recent Phase 2 clinical trial of eravacycline, no patients suffered any serious adverse events, and safety and tolerability were comparable to ertapenem, the control therapy in the trial. In addition, in the Phase 2 clinical trial, the rate at which gastrointestinal adverse events such as nausea and vomiting that occurred in the eravacycline arms was comparable to the rate of such events in the ertapenem arm of the trial.
Convenient dosing regimen. In our recently completed Phase 2 clinical trial we dosed eravacycline once or twice a day as a monotherapy. Eravacycline will be able to be administered as a first-line empiric monotherapy with once- or twice-daily dosing, avoiding the need for complicated dosing regimens typical of multi-drug cocktails and the increased risk of negative drug-drug interactions inherent to multi-drug cocktails.
Potential for convenient intravenous-to-oral step-down. In addition to the intravenous formulation of eravacycline, we are also developing an oral formulation of eravacycline. If successful, this oral formulation would enable patients who begin intravenous treatment with eravacycline in the hospital setting to transition to oral dosing of eravacycline either in hospital or upon patient discharge for convenient home-based care. The availability of both intravenous and oral administration and the oral step-down will reduce the length of a patient’s hospital stay and the overall cost of care.

Additionally, in February 2012, Tetraphase announced a contract award from the Biomedical Advanced Research and Development Authority (BARDA) worth up to $67 million for the development of eravacycline, from which Tetraphase may receive up to approximately $40 million in funding. The contract includes pre-clinical efficacy and toxicology studies; clinical studies; manufacturing activities; and associated regulatory activities to position the broad-spectrum antibiotic eravacycline as a potential empiric countermeasure for the treatment of inhalational disease caused by Bacillus anthracis, Francisella tularensis and Yersinia pestis.\

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Process research and development of the first fully synthetic broad spectrum 7-fluorotetracycline in clinical development is described. The process utilizes two key intermediates in a convergent approach. The key transformation is a Michael–Dieckmann reaction between a suitable substituted aromatic moiety and a key cyclohexenone derivative. Subsequent deprotection and acylation provide the desired active pharmaceutical ingredient in good overall yield.

Process R&D of Eravacycline: The First Fully Synthetic Fluorocycline in Clinical Development

Magnus Ronn *, Zhijian Zhu , Philip C. Hogan , Wu-Yan Zhang , John Niu , Christopher E. Katz ,Nicholas Dunwoody , Olga Gilicky , Yonghong Deng, Diana K. Hunt , Minsheng He , Chi-Li Chen ,Cuixiang Sun , Roger B. Clark , and Xiao-Yi Xiao

Tetraphase Pharmaceuticals Inc., 480 Arsenal Street, Suite 110, Watertown, Massachusetts, 02472, United States

Org. Process Res. Dev., 2013, 17 (5), pp 838–845

DOI: 10.1021/op4000219

Publication Date (Web): April 6, 2013

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FDA Grants QIDP Designation to Eravacycline, Tetraphase’s Lead Antibiotic Product Candidate

– Eravacycline designated as a QIDP for complicated intra-abdominal infection (cIAI) and complicated urinary tract infection (cUTI) indications –

July 15, 2013 08:30 AM Eastern Daylight Time

WATERTOWN, Mass.–(BUSINESS WIRE)–Tetraphase Pharmaceuticals, Inc. (NASDAQ: TTPH) today announced that the U.S. Food and Drug Administration (FDA) has designated the company’s lead antibiotic product candidate, eravacycline, as a Qualified Infectious Disease Product (QIDP). The QIDP designation, granted for complicated intra-abdominal infection (cIAI) and complicated urinary tract infection (cUTI) indications, will make eravacycline eligible to benefit from certain incentives for the development of new antibiotics provided under the Generating Antibiotic Incentives Now Act (GAIN Act). These incentives include priority review and eligibility for fast-track status. Further, if ultimately approved by the FDA, eravacycline is eligible for an additional five-year extension of Hatch-Waxman exclusivity.

http://www.businesswire.com/news/home/20130715005237/en/FDA-Grants-QIDP-Designation-Eravacycline-Tetraphase%E2%80%99s-Lead

Aerial Biopharma announce positive Phase II results for narcolepsy drug

October 4, 2013 3:52 am / Leave a comment

ADX-N05, ARL-N05, SKL-N05

Aerial Biopharma announce positive Phase II results for narcolepsy drug
A new drug to treat excessive daytime sleepiness associated with narcolepsy has shown positive results from a phase 2b clinical trial, US-based Aerial Biopharma has announced this week.

read all at

http://www.pharmaceutical-technology.com/news/newsaerial-biopharma-announce-positive-phase-ii-results-narcolepsy-drug?WT.mc_id=DN_News

Isavuconazole – Basilea reports positive results from study

October 2, 2013 1:35 am / 6 Comments on Isavuconazole – Basilea reports positive results from study

Isavuconazole

4-{2-[(1R,2R)-(2,5-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-1,3-thiazol-4-yl}benzonitrile

[(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl)]-1-(1H-1,2,4-triazol-1-yl)-2-(2,5-difluorophenyl)-butan-2-ol;

(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-butan-2-ol

241479-67-4 CAS

946075-13-4 cas of SULPHATE (USAN) in phase 3Aspergillosis, Infection, candidal, RO-0098557

ROCHE Originator

ChemSpider 2D Image | Isavuconazole | C22H17F2N5OS

30 September 2013

StockMarketWire.com – Basilea Pharmaceutica has revealed positive topline data from the isavuconazole phase 3 invasive aspergillosis study (SECURE). http://www.stockmarketwire.com/article/4677530/Basilea-reports-positive-results-from-study.htmlThe antifungal agent isavuconazole is being co-developed with Astellas Pharma Inc.The randomized, double-blind isavuconazole study (SECURE) achieved its primary objective in demonstrating non-inferiority versus voriconazole for the primary treatment of invasive fungal disease caused by Aspergillus species or certain other filamentous fungi.

This post is updated in sept 2015……..

BAL-4815, 241479-67-4, Bal4815, AC1OCFHQ, UNII-60UTO373KE, , BAL 4815, FT-0670421

Molecular Formula: C₂₂H₁₇F₂N₅OS Molecular Weight: 437.465086

Isavuconazole (BAL4815; trade name Cresemba) is a triazole antifungal drug. Its prodrug, isavuconazonium sulfate (BAL8557), was granted approval by the U.S. Food and Drug Administration (FDA) on March 6, 2015^[1]

During its Phase III drug trials, Astellas partnered with Basilea Pharmaceutica, the developer of the drug, for rights to co-development and marketing of isavuconazole. ^[2]

On May 28, 2013, Basilea Pharmaceutica announced it had been granted orphan drug status by the FDA for treatment of aspergillosis.^[3] Since then, it has also been granted orphan drug status for the treatment of invasive candidiasis.^[4]

Isavuconazonium sulfate (BAL8557)—a prodrug of isavuconazole.

Isavuconazium chloride hydrochloride (BAL-8557), a prodrug of Basilea Pharmaceutica’s BAL-4815 (isavuconazole), is a triazole in phase III clinical trials for the oral and intravenous treatment of severe fungal infections, including candidemia and other invasive Candida infections and invasive aspergillosis in immunocompromised patients. Additional phase III trials are ongoing for the treatment of invasive fungal infections caused by rare fungi. Phase II trials are ongoing for the treatment of candidal esophageal infection. Isavuconazole is water-soluble, highly bioavailable and can be administered in convenient once-daily or once-weekly dosing regimens.Originally developed at Roche, the drug candidate was subsequently acquired by Basilea. In May 2006, isavuconazium received fast track designation from the FDA for the treatment of infections caused by yeasts and molds, including fluconazole-resistant Candida strains, Aspergillus and zygomycetes in patients with weakened immune systems. In 2010, the product was licensed to Astellas Pharma by Basilea Pharmaceutica for codevelopment and copromotion worldwide, including an option for Japan, for the treatment of fungal infection. In 2013, FDA designated isavuconazium as a Qualified Infectious Disease Product (QIDP) designation for the treatment of invasive aspergillosis.

ISAVUCONAZOLE

CLINICAL TRIALS…LINK

PATENTS

US8207352	6-27-2012	Process for the manufacture of enantiomerically pure antifungal azoles as ravuconazole and isavuconazole
US2011281918	11-18-2011	Antifungal Composition
US7803949	9-29-2010	PROCESS FOR PREPARATION OF WATER-SOLUBLE AZOLE PRODRUGS
US7459561	12-3-2008	N-substituted carbamoyloxyalkyl-azolium derivatives
US7189858	3-14-2007	N-phenyl substituted carbamoyloxyalkyl-azolium derivatives
US6812238	11-3-2004	N-substituted carbamoyloxyalkyl-azolium derivatives
US6300353	10-10-2001	Azoles for treatment of fungal infections

Several azoles are currently used for systemic mycoses. However, none of them fulfills the needs of clinical requirement in full extent, particularly with regard 0 to broad antifungal spectrum including aspergillus fumigatus, less drug-drug interaction, and appropriate plasma half-life for once a day treatment. Other clinical requirements which are not fulfilled by the azoles currently used, are efficacy against major systemic mycoses including disseminated aspergillosis, safety, and oral or parenteral formulations. Particularly, demand of a 5 parenteral administration of the azoles is increasing for the treatment of serious systemic mycoses. Most of the azoles on the market as well as under development are highly lipophilic molecules that make the parenteral formulation difficult.

Isavuconazole [(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl)]-1-(1H-1,2,4-triazol-1-yl)-2-(2,5-difluorophenyl)-butan-2-ol; formula I, R¹and R³represent fluorine and R²represents hydrogen] as well as Ravuconazole [(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl)]-1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-butan-2-ol; formula I, R¹and R²represent fluorine and R³represents hydrogen] are useful antifungal drugs as reported in U.S. Pat. No. 5,648,372 from Feb. 1, 1995 or in U.S. Pat. No. 5,792,781 from Sep. 18, 1996 or in U.S. Pat. No. 6,300,353 from Oct. 9, 2001 (WO99/45008).

Since compounds of general formula I contain two adjacent chiral centers, synthesis of enantiomerically pure compound is complex and until now, all patented syntheses are not efficient enough and do not allow cost effective manufacturing on a technical scale:

Thus, U.S. Pat. Nos. 5,648,372 or 5,792,781 describe enantioselective synthesis of compounds of formula I (specifically Ravuconazole) from chiral 3-hydroxy-2-methyl propionic acid in 12 steps with overall yield lower than 5%. In another approach including 13 steps and low overall yield, (R)-lactic acid was used as the starting material (Chem. Pharm. Bull. 46(4), 623 (1998) and ibid. 46(7), 1125 (1998)).

Because both starting materials contain only one chiral center, in a number of inefficient steps, the second, adjacent chiral center has to be created by a diastereoselective reaction (using either Corey or Sharpless epoxidation method) which is not sufficiently selective leading mostly to a mixture of two diastereomers which have to be separated.

The second approach, based on (R)-methyl lactate, was recently very thoroughly optimized by BMS on a multi kilogram scale but it still does not fulfill requirements for cost effective manufacturing process (Organic Process Research & Development 13, 716 (2009)). The overall yield of this optimized 11 steps process is still only 16% (Scheme 1).

The manufacturing process for Isavuconazole is similar: Since Isavuconazole differentiates from Ravuconazole by only another fluorine substitution on the aromatic ring (2,5- instead of 2,4-difluorophenyl), the identical synthesis has been used (U.S. Pat. No. 6,300,353 from Oct. 9, 2001 and Bioorg. & Med. Chem. Lett. 13, 191 (2003)). Consequently, also this manufacturing process, based on (R)-lactic acid, faces the same problems: to many steps, extremely low overall yield and in addition to U.S. Pat. No. 6,300,353 claims even already known step as novel (claim 36).

Recent attempts to improve this concept as reported in WO 2007/062542 (Dec. 1, 2005), using less expensive, natural configured (S)-lactic acid, also failed: As already reported in U.S. Pat. No. 6,133,485 and in US 2003/0236419, the second chiral center was formed from an optically active allyl alcohol prepared in a few steps from (S)-lactic acid.

This allyl alcohol was subjected to Sharpless diastereoselective epoxidation providing first an opposite configured, epimeric epoxy alcohol which had to be then epimerized in an additional inversion step yielding finally the desired epoxy alcohol as the known precursor for Isavuconazole (U.S. Pat. No. 6,300,353). It is obvious that this process using less expensive (S)-lactic acid makes the entire process with an inversion step even more complex than the original approach.

Elegant and more efficient process has been claimed in US 2004/0176432 from Jun. 26, 2001) in which both chiral centers have been formed simultaneously, diastereo- and enantio-selectively pure in one single reaction step using chiral (R)-2-butynol as a chiral precursor in the presence of Pd(II)-catalyst and diethyl zinc (Scheme 2).

Since water soluble, (R)-2-butynol is expensive, recently identical process has been published, in which instead of (R)-2-butynol less water soluble and therefore, less expensive (R)-4-phenyl-3-butyn-2-ol was used (Synthetic Commun. 39, 1611 (2009)). Nevertheless, as incorrectly stated there, this process does not provide better diastereoselectivity than the original process using (R)-2-butynol: On the contrary disadvantage of this process is a very bad atom economy because huge phenyl group of (R)-4-phenyl-3-butyn-2-ol has to be “disposed” in oxidation step by the conversion of triple bond into carboxylic acid function.

All known processes for enantiomerically pure compounds of formula I have definitely too many operation steps and specifically very low overall yield. The chiral starting materials used, either 3-hydroxy-2-methyl propionic acid or (S)- or (R)-methyl lactate, contain only one chiral center and consequently, in number of steps, the second adjacent chiral center has to be ineffectively generated which makes the entire process long and expensive. The only known process, which generates both chiral centers simultaneously, requires again expensive chiral starting material (R)-2-butynol.

ISAVUCONAZOLE

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US6812238

synthetic scheme A, starting from 4-[(2R)-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)-propionyl]morpholine [which can be prepared by a same procedure as described in Chem. Pharm. Bull. 41, 1035, 1993.]. This synthesis route has been described for example in European Patent Application No. 99101360.8.

(a)

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US8207352

Example 1 (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-butan-2-ol

To a solution of racemic 3-[4-(4-cyanophenyl)thiazol-2-yl]-1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-butan-2-ol (43.7 g) in acetone (800 ml) a solution of (1R)-10-camphorsulfonic acid (23 g) in methanol (300 ml) was added and the mixture was heated under reflux until a clear solution was obtained. The solution was slowly cooled to rt, seeded with crystals of the title enantiomeric salt and let overnight. The solid was collected by filtration, washed with acetone and dried to provide (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-butan-2-ol (1R)-10-camphorsulfonate as white solid. This crude salt was then taken up in methylenechloride (100 ml) and water (ca. 100 ml) and the mixture was basified with aqueous sodium hydroxide solution. The organic layer was separated and the aqueous phase washed twice with methylenechloride (50 ml) and combined. The organic phases were then washed twice with water (2×50 ml), dried with sodium sulfate, filtrated and the solvent removed under reduced pressure. The crude product was then mixed with isopropanol (ca. 150 ml), heated for 10 min, cooled to 0° C. and stirred for ca. 2 hrs. The product was collected, washed with isopropanol and dried under reduced pressure to provide the enantiomerically pure title compound (17.5 g, 41% yield, 99.1% ee);

m.p. 164-166° C.; [α]=−30° (c=1, methanol, 25° C.);

NMR (CDCl3): 1.23 (3H, d, J=8 Hz), 4.09 (1H, q, J=8 Hz), 4.26 (1H, d, J=14 Hz), 4.92 (1H, d, J=14 Hz), 5.75 (1H, s), 6.75-6.85 (2H, m), 7.45-7.54 (2H, m), 7.62 (1H, s), 7.69 (1H, s), 7.75 (1H, d, J=8 Hz), 7.86 (1H, s), 8.03 (1H, d, J=8 Hz).

The analytical data were identical with published (U.S. Pat. No. 5,648,372 and Chem. Pharm. Bull. 1998, 46, 623-630).

Example 2 (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-butan-2-ol

Racemic 3-[4-(4-cyanophenyl)thiazol-2-yl]-1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-butan-2-ol (44 g) and (1R)-10-camphorsulfonic acid (20 g) were suspended in methanol (ca. 300 ml), the slurry was stirred intensively, warmed up to ca. 70° C. and a small addition of acetic acid was added to obtain a clear solution. After cooling of the solution to rt and then to 0° C., the mixture was seeded with enantiomerically pure salt and stirred for another 2 hrs. The crystalline solid was collected by filtration, washed with cooled methanol and dried under reduced pressure. The crystals were partitioned between methylenechloride (300 ml) and saturated aqueous sodium bicarbonate solution (200 ml). The organic layer was washed twice with water (50 ml), dried with magnesium sulphate, filtrated and evaporated under reduced pressure to give the title compound (16.9 g, 38% yield, 95% ee). The analytical data were identical with published (U.S. Pat. No. 5,648,372 or Chem. Pharm. Bull. 1998, 46, 623).

Example 3 (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-1-(1H-1,2,4-triazol-1-yl)-2-(2,5-difluorophenyl)-butan-2-ol

To a solution of racemic 3-[4-(4-cyanophenyl)thiazol-2-yl]-1-(1H-1,2,4-triazol-1-yl)-2-(2,5-difluorophenyl)-butan-2-ol (10 g) in acetone (ca. 200 ml) a solution of (1R)-10-camphorsulfonic acid (3.9 g) in methanol (50 ml) was added and the mixture was heated shortly under reflux until a clear solution was obtained. The solution was then slowly cooled to rt, seeded with crystals of the desired enantiomeric salt and let overnight. The solid precipitate was collected by filtration, washed with acetone and dried to provide (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-1-(1H-1,2,4-triazol-1-yl)-2-(2,5-difluorophenyl)-butan-2-ol (1R)-10-camphorsulfonate as white solid. This salt was then taken up in methylenechloride and water and basified with aqueous sodium bicarbonate solution. The organic layer was separated and the aqueous phase washed twice with methylenechloride. The organic phases were combined, dried with sodium sulphate, filtrated and the solvent removed under reduced pressure. The crude product was then dissolved in ethanol, the slurry heated for 20 min, small amount of water was added, the solution slowly cooled to 0° C. and stirred for ca. 2 hrs. The product was collected, washed with cold ethanol and dried under reduced pressure to provide the title enantiomerically pure compound (3.9 g, 39% yield, 96% ee). The analytical date were identical with published in U.S. Pat. No. 6,300,353 B1 and WO 99/45008.

Example 4 (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-1-(1H-1,2,4-triazol-1-yl)-2-(2,5-difluorophenyl)-butan-2-ol

To a solution of racemic 3-[4-(4-cyanophenyl)thiazol-2-yl]-1-(1H-1,2,4-triazol-1-yl)-2-(2,5-difluorophenyl)-butan-2-ol (100 g) in acetone (1000 ml) a solution of (1R)-10-camphorsulfonic acid (47 g) in methanol (500 ml) was added at rt, then slurry was heated under stirring to almost reflux for ca. 30 min, then cooled slowly to rt, seeded with the pure enantiomeric salt and stirred over night. The solid was collected by filtration, washed with methanol/acetone mixture, dried under reduced pressure. The residue was taken up with a solvent mixture of methylenechloride/water and after addition of saturated aqueous sodium bicarbonate solution the organic phase was separated and aqueous phase washed twice with methylenechloride. The combined organic phases were filtrated, the solvent removed under reduced pressure. Recrystallization of the crude product from aqueous ethanol provided enantiomerically pure title compound: 39 g (39% yield, 92% ee). The analytical data were identical with published: U.S. Pat. No. 6,300,353 and WO 99/45008.

Example 5 (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-1-(1H-1,2,4-triazol-1-yl)-2-(2,5-difluorophenyl)-butan-2-ol

A solution of the racemic 3-[4-(4-cyanophenyl)thiazol-2-yl]-1-(1H-1,2,4-triazol-1-yl)-2-(2,5-difluorophenyl)-butan-2-ol (4.4 g) and (1R)-10-camphorsulfonic acid (2 g) in toluene (40 ml) containing glacial acetic acid (0.6 ml) was warmed up to approximately 70° C., then allowed to cool slowly to 20° C., seeded with the pure enantiomeric salt whereupon the pure enantiomeric salt start to crystallize out. After ca. 2 hrs at this temperature the solid was collected, washed with cold toluene and dried. The crystals were taken with a solvent mixture of methylenechloride/water and after addition of aqueous saturated sodium bicarbonate solution the organic phase was separated and aqueous phase washed twice with methylenechloride. The combined organic phases were filtrated and the solvent removed under reduced pressure. Recrystallization of the crude product from aqueous ethanol provided enantiomerically pure title compound: 2 g (45% yield, 99% ee). The analytical data were identical with published: U.S. Pat. No. 6,300,353 and WO 99/45008.

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WO 1999045008

US6300353

The following synthetic scheme 1 illustrates the manufacture of one of the compounds of formula I′:

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Bioorganic and medicinal chemistry letters, 2003 , vol. 13, 2 p. 191 – 196

http://www.sciencedirect.com/science/article/pii/S0960894X02008922

A highly potent water soluble triazole antifungal prodrug, RO0098557 (1), has been identified from its parent, the novel antifungal agent RO0094815 (2). The prodrug includes a triazolium salt linked to an aminocarboxyl moiety, which undergoes enzymatic activation followed by spontaneous chemical degradation to release 2. Prodrug 1 showed high chemical stability and water solubility and exhibited strong antifungal activity against systemic candidiasis and aspergillosis as well as pulmonary aspergillosis in rats.





Scheme 1. Figure options Figure 1. Structure of RO0098557 and RO0094815. Chemistry Scheme 1. We synthesized a series of new triazolium derivatives of Figure 1, Figure 3 and Scheme 1. CompoundsScheme 1 and Scheme 2, 6, 9, 10 and 11 were first prepared as outlined in Scheme 2 in order to analyze their stability and ability to release Figure 1, Figure 3 and Scheme 1. Next, aromatic analogues 18, 19, 20,21 and Figure 1, Figure 3 and Scheme 3 were synthesized for optimization of 11 to increase its water solubility and conversion rate. Compounds in the second series had sarcosine esters⁶ to make them water soluble, and they were also designed to generate acetaldehyde⁷ instead of formaldehyde for a better safety profile. The synthetic procedures for the second series of the derivatives are outlined in Scheme 3. Scheme 2. (a) ClCOOCH₂Cl, diisopropylethylamine, CH₂Cl₂, rt (quant); (b) Figure 1, Figure 3 and Scheme 1, CH₃CN, 80 °C (60%); (c) (1) ClCOOCH₂Cl, Et₃N, CH₂Cl₂, rt; (2) Ac₂O, pyridine, rt (30%, two steps); (d) (1) NaI, CH₃CN, 50 °C ; (2) Figure 1, Figure 3 and Scheme 1, CH₃CN, 50 °C (88%, two steps); Synthesis of Scheme 1 and Scheme 2: (1) N-3-hydroxypropyl-N-methylamine, ClCOOCH₂Cl, Et₃N, CH₂Cl₂, rt; (2) AcCl, Et₃N, CH₂Cl₂, rt (20%, two steps); (3) Figure 1, Figure 3 and Scheme 1, NaI, CH₃CN, 50 °C (82%); Synthesis of 10: (1) l-prolinol, ClCOOCH₂Cl, Et₃N, CH₂Cl₂, rt; (2) Ac₂O, pyridine, rt (<10%, 2 steps); (3) Figure 1, Figure 3 and Scheme 1, NaI, CH₃CN, 50 °C (92%); Synthesis of 11: (1) 2-hydroxymethyl-N-methylaniline, ClCOOCH₂Cl, diisopropylethylamine, CH₂Cl₂, rt; (2) Ac₂O, diisopropylethylamine, rt (20%, two steps); (3)Figure 1, Figure 3 and Scheme 1, cat. NaI, CH₃CN, reflux (63%). Figure options Scheme 3. (a) (1) oxalyl chloride, DMF, 0 °C; (2) KO^tBu, THF, −5 °C (97%, two steps); (b) CH₃NH₂, MeOH, rt (90%); (c) LiAlH₄, THF, 0 °C (80%); (d) (1) ClCOOCH(CH₃)Cl, diisopropylethylamine, CH₂Cl₂, 0 °C; (2) Boc-Sarcosine, WSCI, DMAP, CH₂Cl₂, 0 °C (84%, two steps); (e) (1) Figure 1, Figure 3 and Scheme 1, NaI, CH₃CN, 50 °C; (2) DOWEX-1 Cl⁻ form, aqueous MeOH, rt (65%, two steps); (f) (1) HCl, EtOAc, rt; (2) lyophilization (69%, two steps); Synthesis of 18: (1) (i) (4,5-difluoro-2-methylaminophenyl)methanol, ClCOOCH(CH₃)Cl, diisopropylethylamine, CH₂Cl₂, 0 °C; (ii) Boc-Sarcosine, WSCI, DMAP, CH₂Cl₂, 0 °C (quant, two steps); (2) Figure 1, Figure 3 and Scheme 1, cat. NaI, CH₃CN, 80 °C; (50%,); (3) HCl, EtOAc, rt (90%); Synthesis of 19: (1) (i) 2-fluoro-6-methylaminophenyl)methanol, ClCOOCH(CH₃)Cl, diisopropylethylamine, CH₂Cl₂, 0 °C; (ii) Boc-Sarcosine, WSCI, DMAP, CH₂Cl₂, 0 °C (74%, two steps); (2) Figure 1, Figure 3 and Scheme 1, cat. NaI, CH₃CN, reflux; (3) HCl, EtOAc, rt (29%, two steps); Synthesis of 20: (1) (i) (5-fluoro-2-methylaminophenyl)methanol, ClCOOCH(CH₃)Cl, diisopropylethylamine, CH₂Cl₂, 0 °C; (ii) Boc-Sarcosine, WSCI, DMAP, CH₂Cl₂, 0 °C (91%, two steps); (2) Figure 1, Figure 3 and Scheme 1, cat. NaI, CH₃CN, 70 °C (72%); (3) HCl, EtOAc, rt (88%); Synthesis of 21: (1) (i) (4-chloro-2-methylaminophenyl)methanol, ClCOOCH(CH₃)Cl, diisopropylethylamine, CH₂Cl₂, 0 °C; (ii) Boc-Sarcosine, WSCI, DMAP, CH₂Cl₂, 0 °C (71%, two steps); (2) Figure 1, Figure 3 and Scheme 1, CH₃CN, 65 °C; (3) HCl, EtOAc, rt (65%, two steps).

read more at

Boyd, B.; Castaner, J. BAL-4815/BAL-8557
Drugs Fut 2006, 31(3): 187

Antimicrobial Agents and Chemotherapy, 2008 , vol. 52, 4 p. 1396 – 1400

Ohwada, J.; Tsukazaki, M.; Hayase, T.; Oikawa, N.; Isshiki, Y.; Umeda, I.; Yamazaki, T.; Ichihara, S.; Shimma, N.Development of novel water antifungal, RO0098557
21st Med Chem Symp (November 28-30, Kyoto) 2001, Abst 1P-06

Ohwada, J.; Tsukazaki, M.; Hayase, T.; et al.
RO0098557, a novel water soluble azole prodrug for parenteral and oral administration (I). Design, synthesis, physicochemical properties and bioconversion42nd Intersci Conf Antimicrob Agents Chemother (ICAAC) (September 27-30, San Diego) 2002, Abst F-820

Tasaka et al., Chem. Pharm. Bull. 41(6) pp. 1035-1042 (1993).

Clinical trials

There have been three phase III clinical trials of isavuconazole, ACTIVE, VITAL and SECURE. As of June 2015, SECURE and VITAL have been presented in abstract form and results from ACTIVE have not been released.^[9]

The SECURE trial compared voriconazole and isavuconazole in invasive fungal infections due to aspergillus. Isuvaconazole was found to be non-inferior to voriconazole, anothertriazole antifungal, with all cause mortality at 18.6%, compared to 20.2% in the voriconazole group. It additionally demonstrated a similar side effect profile.^[10]

Data from the VITAL study showed that isavuconazole could be used in treatment of invasive mucormycosis, but did not evaluate its clinical efficacy for this indication.^[11]

The ACTIVE trial is a comparison of isuvaconazole and caspofungin for invasive candida infections and results are anticipated in the second half of 2015.^[12]^[13]

References

[1]
Saboo, Alok. “Basilea Announces Global Partnership With Astellas for Its Antifungal Isavuconazole.” FierceBiotech. N.p., 24 Feb. 2010. Web.
“Basilea reports isavuconazole orphan drug designation by U.S. FDA.” Market Wired. 28 May 2013.
“FDA Grants Orphan Drug Designation to Astellas for Isavuconazole for the Treatment of Invasive Candidiasis.” News Releases. Astellas. 3 Nov 2014.
Cresemba (isovuconazole sulfate) [prescribing information]. Astella Pharma US, Inc. Revised March 2015.
Jump up^ “Aspergillosis.” Centers for Disease Control and Prevention. Centers for Disease Control and Prevention, 08 Sept. 2014.
Jump up^ “Astellas Receives FDA Approval for CRESEMBA® (isavuconazonium Sulfate) for the Treatment of Invasive Aspergillosis and Invasive Mucormycosis.” PR Newswire. N.p., 6 Mar. 2015.
Jump up^ “Isavuconazonium.” Micromedex Solutions. Truven Health Analytics, n.d. Web. <www.micromedexsolutions.com>.
Jump up^ Pettit, Natasha N.; Carver, Peggy L. (2015-07-01). “Isavuconazole A New Option for the Management of Invasive Fungal Infections”. Annals of Pharmacotherapy 49 (7): 825–842.doi:10.1177/1060028015581679. ISSN 1060-0280. PMID 25940222.
Mujais, A. “2014: M-1756. A Phase 3 Randomized, Double-Blind, Non-Inferiority Trial Evaluating Isavuconazole (ISA) vs. Voriconazole (VRC) for the Primary Treatment of Invasive Fungal Disease (IFD) Caused by Aspergillus spp. or other Filamentous Fungi (SECURE): Outcomes by Malignancy Status”. http://www.icaaconline.com. Retrieved 2015-06-19.
“Abstract: An Open-Label Phase 3 Study of Isavuconazole (VITAL): Focus on Mucormycosis (IDWeek 2014)”. idsa.confex.com. Retrieved 2015-06-19.
Ltd., Basilea. “Basilea Pharmaceutica – Portfolio – Isavuconazole”. http://www.basilea.com. Retrieved 2015-06-19.
“Isavuconazole (BAL8557) in the Treatment of Candidemia and Other Invasive Candida Infections – Full Text View – ClinicalTrials.gov”. clinicaltrials.gov. Retrieved 2015-06-19.

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Isavuconazole
Systematic (IUPAC) name


4-{2-[(1R,2R)-(2,5-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-1,3-thiazol-4-yl}benzonitrile
Clinical data
Trade names	Cresemba (prodrug form)
AHFS/Drugs.com	entry
Pregnancy category	US: C (Risk not ruled out)
Legal status	US: ℞-only ℞ (Prescription only)
Routes of administration	Oral, intravenous
Identifiers
ATC code	None
PubChem	CID: 6918485
ChemSpider	5293682
UNII	60UTO373KE
ChEBI	CHEBI:85979
ChEMBL	CHEMBL409153
NIAID ChemDB	416566
Chemical data
Formula	C₂₂H₁₇F₂N₅O S
Molecular mass	437.47 g/mol

/////

	Bosmolisib – N… on Bosmolisib
	Cenacitinib –… on Cenacitinib
	Emestedastat –… on Emestedastat
	Enrupatinib –… on Enrupatinib
	Evetifator – N… on Evetifator

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