WHITE PAPER: QA/QC: Catching Up With The Competiton

By Robert G. McGregor, General Manager, Brookfield Engineering Laboratories, Inc.
In the world of pharmaceutical products, there is almost always a leader in every category of major application. Take skin creams, for example. The reputation is earned because the product solves the customer’s problem, such as relieving facial acne or soothing aching joints. Working with the formulation chemists who create the product are the physical scientists, who specify how to process the material. They also have responsibility for characterizing the flow behavior of the cream when used by the customer and for specifying the QC test that verifies compliance.

http://click.news.pharmaceuticalonline.com/?qs=8128bef0c9388fd63799fffb1bd80c814cf83d6b5070e6bc328e9f7986a3c309a7585649f4f98369

KRN5500

Antitumor agent

151276-95-8  cas

IUPAC/Chemical name: 

(2E,4E)-N-(2-(((2R,3R,4R,5R,6S)-6-((7H-purin-6-yl)amino)-2-((S)-1,2-dihydroxyethyl)-4,5-dihydroxytetrahydro-2H-pyran-3-yl)amino)-2-oxoethyl)tetradeca-2,4-dienamide

C28H43N7O7

Exact Mass: 589.32240

L-glycero-beta-L-manno-Heptopyranosylamine, 4-deoxy-4-((((1-oxo-2,4-tetradecadienyl)amino)acetyl)amino)-N-1H-purin-6-yl-, (E,E)-

L-glycero-beta-L-manno-Heptopyranosylamine, 4-deoxy-4-(((((2E,4E)-1-oxo-2,4-tetradecadienyl)amino)acetyl)amino)-N-1H-purin-6-yl-

Kirin Brewery (Originator), National Cancer Institute (Codevelopment)

DARA BioSciences receives FDA orphan drug designation for KRN5500
DARA BioSciences has received orphan drug designation from the US Food and Drug Administration’s (FDA) Office of Orphan Products Development for KRN5500, for treating multiple myeloma

http://www.pharmaceutical-technology.com/news/newsdara-biosciences-receives-fda-orphan-drug-designation-for-krn5500-4295251?WT.mc_id=DN_News

Multiple myeloma is a hematologic cancer or cancer of the blood.

KRN5500 is a non-opioid, non-narcotic compound that is currently being tested in Phase I clinical trial.

Earlier this year, KRN5500 received orphan status to be developed for the parenteral treatment of painful, chronic, chemotherapy-induced peripheral neuropathy (CCIPN) that is refractory to conventional analgesics in patients with cancer.

“We believe this myeloma-specific orphan designation enhances both the viability and the future market opportunity for this valuable pipeline product.”

DARA BioSciences MD, CEO and chief medical officer David J Drutz said: “It is noteworthy in this regard that up to 20% of myeloma patients have intrinsic peripheral neuropathy, an incidence that increases to the range of 75% in patients treated with neurotoxic drugs such as thalidomide or bortezomib.

KRN5500 is a semisynthetic derivative of the nucleoside-like antineoplastic antibiotic spicamycin, originally isolated from the bacterium Streptomyces alanosinicus. KRN 5500 inhibits protein synthesis by interfering with endoplasmic reticulum and Golgi apparatus functions. This agent also induces cell differentiation and caspase-dependent apoptosis.

KRN5500 is available as a solution for intravenous (IV) administration.  KRN5500 was discovered in an effort to identify new agents that induced differentiation of myeloid leukemia cells.

Safety and efficacy data from Phase I trials have been leveraged to support DARA Therapeutics’ active IND and ongoing Phase 2a clinical trial.  The objective of this Phase 2a feasibility study is to determine the potential of KRN5500 (a spicamycin analogue) to be a breakthrough medicine for the treatment of neuropathic pain in cancer patients.

Four clinical trials have been conducted in cancer patients, including one in Japan and 3 in the United States.  Three of these studies are complete; the fourth was closed to patient accrual and treatment in December 2004.

A total of 91 patients with solid tumors have been treated with single IV KRN5500 doses of up to 21 mg/m2 and weekly doses of up to 42 mg/m2.  While KRN5500 has not shown anti-cancer efficacy in any trial, its use in pain elimination is encouraging. (source: http://www.darabiosciences.com/krn5500.htm).

Chemical structures of KRN5500 and its known metabolites.

………………..

http://www.google.com/patents/EP0525479A1?cl=en

spk 241

• 6-[4'-N-(N'-trans,trans-2,4-tridecadienylglycyl)spicamynyl-amino]purine,
• (20) SPK241:

Example 52: Preparation of SPK241

• [0214]
  To trans-2-dodecenal (4.5 g) dissolved in methylene chloride (80 ml) was added (carbomethoxymethylene)triphenylphosphorane (8.3 g), and the mixture was stirred for 2 hours. The reaction mixture was subjected to chromatography on a silica gel column with eluent systems of n-hexane- ethyl acetate (from 100:1 to 20:1) to give the methyl ester of trans,trans-2,4-tetradecadienoic acid (5.4 g). Potassium hydroxide (6.5 g) was dissolved in a mixed solvent of ethanol-water (1:1) (100 ml). The methyl ester of trans,trans-2,4-tetradecadienoic acid (5.4 g) was added to the mixture, and the resulting mixture was stirred at 60 °C for 40 minutes. After the reaction mixture was cooled, it was adjusted to the weak acidic range of pH with citric acid and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated to give trans,trans-2,4-tetradecadienoic acid (4.4 g). Hereafter, the title compound can be synthesized by the two methods described below.
• [0215]
  In the first method, trans,trans-2,4-tetradecadienoic acid (4.3 g) is first dissolved in N,N-dimethylformamide (DMF, 50 ml). Para-nitrophenol (2.67 g) and N,N’-dicyclohexylcarbodiimide (3.9 g) were added to trans,trans-2,4-tetradecadienoic acid solution, and the mixture was stirred for 12 hours. After precipitates produced were removed by filtration and the solvent (DMF) was removed by distillation, the residue was subjected to chromatography on a silica gel column with eluent systems of n-hexane-ethyl acetate (from 200:1 to 50:1) to give the active ester of trans,trans-2,4-tetradecadienoic acid (5.1 g). To the active ester (500 mg) dissolved in DMF (30 ml) were added 6-(4′-N-glycyl-spicamynyl-amino)purine hydrochloride (556 mg) and triethylamine (1.2 ml). The mixture was stirred for 12 hours. After the solvent was removed by distillation, the residue was subjected to chromatography on a silica gel column with eluent systems of chloroform-methanol (from 7:1 to 5:1) to give SPK241 in the yield of 398 mg.
• [0216]
  In the second method, trans,trans-2,4-tetradecadienoic acid (99.6 g) was dissolved in thionyl chloride (87 ml), and the mixture was stirred at room temperature. The excessive thionyl chloride was removed by distillation to give trans,trans-2,4-tetradecadienoic acid chloride (102.0 g). To glycine (66.8 g) dissolved in an aqueous 2N sodium hydroxide solution (540 ml) were added at the same time trans,trans-2,4-tetradecadienoic acid chloride (102.0 g) and 2N sodium hydroxide (270 ml) with 1/10 portions at a 3 minute interval. After the addition was completed, the mixture was warmed to room temperature, stirred for 15 minutes and acidified with concentrated hydrochloric acid (140 ml) under ice-cooling. Precipitates thus produced were collected by filtration and desiccated to give trans,trans-2,4-tetradecadienoyl glycine (75.0 g). To the solution of trans,trans-2,4-tetradecadienoyl glycine (4.7 g) and 6-(4′-N-glycyl-spicamynyl-amino)-purine (5.1 g) in N,N-dimethylformamide (DMF, 60 ml) was added N-hydroxysuccinimide (2.1 g), and the mixture was ice-cooled. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (3.4 g) dissolved in DMF (100 ml) was added dropwise to the mixture. After the addition was completed, the mixture was heated to room temperature and stirred for 12 hours. Water (500 ml) was added to the reaction mixture, and precipitates produced were collected by filtration and desiccated. Sodium methoxide (3.1 g) was added to a suspension of the precipitates in methanol (100 ml), and the mixture was stirred at room temperature, then ice-cooled and acidified by adding dropwise thereto a 10% methanolic hydrochloric acid solution. Precipitates produced were filtered, dried and subjected to chromatography on a silica gel column with eluent systems of chloroform-methanol (from 7:1 to 5:1) to give SPK241 in the yield of 5.00 g.

Physicochemical properties of SPK241

• [0217]
  • (1) Melting point: 182-183 °C,
  • (2) Specific rotation [a]₀ ^2S = 0 (c = 0.1, in methanol),
  • (3) Elementary analysis:
  • (4) FD mass spectrum (m/z): 590 (M + H) , C₂₈ H_{4 3} N₇0₇
  • (5) Infrared spectrum (KBr disc): 3250 cm-¹, 1650 cm-¹, 1620 cm-¹,
  • (6) Proton nuclear magnetic resonance spectrum (500 MHz, in CD₃0D) δ_H: 0.89 (3H, t, J = 7.3 Hz), 1.20-1.50 (14H, m), 2.18 (2H, dt, J = 7.3, 7.3 Hz), 3.6-3.8 (5H, m), 3.95 (1 H, d, J = 16.3 Hz), 3.98 (1H, d, J = 16.3 Hz), 4.00 (1H, dd, J = <1, 2.9 Hz), 4.15 (1H, dd, J = 10.8, 10.8 Hz), 5.66 (1 H, brs), 5.98 (1 H, d, J = 15.7 Hz), 6.12 (1 H, dt, J = 7.3, 15.7 Hz), 6.22 (1 H, dd, J = 10.0, 15.7 Hz), 7.17 (1 H, dd, J = 10.0, 15.7 Hz), 8.15 (1 H, s), 8.30 (1 H, s).

The hydrolysis of the spicamycin mixture (I) with R = alkyl by means of HCl in alcohol or water gives 6-(spicaminylamino)purine (II). (The hydrolysis can also be performed with other inorganic acids such as H2SO4 or organic ones such as acetic acid or formic acid.) The condensation of (II) with N-(tert-butoxycarbonyl)glycine (III) by the active ester method yields the protected glycyl derivative (IV), which is deprotected with TFA (or methanolic HCl) to afford the glycyl derivative (V). Finally, this compound is condensed with tetradeca-2(E),4(E)-dienoic acid (VI) by the active ester method to provide the target carboxamide derivative.

Worldwide Intellectual Property Service
The five largest Intellectual Property (IP) offices in the world discussed how to further increase co-operation
Read more

http://www.chemistryviews.org/details/news/6285151/Worldwide_Intellectual_Property_Service.html

BRAZIL WORLD CUP WEEK 2014

BRAZIL WORLDCUP WEEK 2014

BRAZIL WORLDCUP WEEK 2014

BRAZIL WORLDCUP WEEK 2014

BRAZIL WORLDCUP WEEK 2014

The Hetero Group, one of the largest manufacturers and suppliers of activepharmaceutical ingredients to the Indian pharmaceutical industry, yesterdayannounced the launch of its first biosimilar product in India, darbepoetin alfa.

This launch marks a significant advancement for Hetero in a biosimilars market expected to grow to US$ 24B in the next five years. In partnership with several prominent pharmaceutical companies, Hetero is launching the drug across India.

http://www.biosimilarnews.com/hetero-launches-darbepoetin-alfa-biosimilar-in-india  june 19 2014

Darbepoetin alfa (rINN) /dɑrbəˈpɔɪtɨn/ is a synthetic form of erythropoietin. It stimulates erythropoiesis (increases red blood celllevels) and is used to treat anemia, commonly associated with chronic renal failure and cancer chemotherapy. Darbepoetin is marketed by Amgen under the trade name Aranesp.

The drug was approved in September 2001 by the Food and Drug Administration for treatment of anemia in patients with chronic renal failure by intravenous or subcutaneous injection.^[1] In June 2001, it had been approved by the European Medicines Agency for this indication as well as the treatment of anemia in cancer patients undergoing chemotherapy.^[2]

Dr. Reddy’s Laboratories launched darbepoetin alfa in India under the brand name ‘Cresp’ in August 2010. This is the world’s first generic darbepoetin alfa. Cresp has been approved in India.

Human erythropoietin with 2 aa substitutions to enhance glycosylation (5 N-linked chains), 165 residues (MW=37 kD). Produced in Chinese hamster ovary (CHO) cells by recombinant DNA technology.

APPRLICDSRVLERYLLEAKEAENITTGCAEHCSLNENITVPDTKVNFYAWKRMEVGQQA
VEVWQGLALLSEAVLRGQALLVNSSQPWEPLQLHVDKAVSGLRSLTTLLRALGAQKEAIS
PPDAASAAPLRTITADTFRKLFRVYSNFLRGKLKLYTGEACRTGDR

Darbepoetin is produced by recombinant DNA technology in modified Chinese hamster ovary cells.^{[citation needed]} It differs from endogenous erythropoietin (EPO) by containing two more N-linked oligosaccharide chains. It is an erythropoiesis-stimulating 165-amino acid protein.

Like EPO, its use increases the risk of cardiovascular problems, including cardiac arrest, arrhythmia, hypertension and hypertensive encephalopathy, congestive heart failure, vascular thrombosis or ischemia, myocardial infarction, edema, and stroke. It can also increase risk of seizures. A recent study has extended these findings to treatment of patients exhibiting cancer-related anemia (distinct from anemia resulting from chemotherapy).^[3] Pre-existing untreated hypertension is a contra-indication for darbepoetin, as well as some hematologic diseases. Other reported adverse reactions include hypotension, fever, chest pains, nausea and myalgia.

Like EPO, it has the potential to be abused by athletes seeking a competitive advantage. Its use during the 2002 Winter Olympic Games to improve performance led to the disqualification of cross-country skiers Larisa Lazutina and Olga Danilova of Russia and Johann Mühlegg of Spain from their final races.

Safety advisories in anemic cancer patients

Amgen sent a “dear doctor” letter in January, 2007, that highlighted results from a recent anemia of cancer trial, and warned doctors to consider use in that off-label indication with caution.

Amgen advised the U.S. Food and Drug Administration (FDA) as to the results of the DAHANCA 10 clinical trial. The DAHANCA 10 data monitoring committee found that 3-year loco-regional control in subjects treated with Aranesp was significantly worse than for those not receiving Aranesp (p=0.01).

In response to these advisories, the FDA released a Public Health Advisory^[4] on March 9, 2007, and a clinical alert^[5] for doctors on February 16, 2007, about the use of erythropoeisis-stimulating agents such as epogen and darbepoetin. The advisory recommended caution in using these agents in cancer patients receiving chemotherapy or off chemotherapy, and indicated a lack of clinical evidence to support improvements in quality of life or transfusion requirements in these settings.

In addition, on March 9, 2007, drug manufacturers agreed to new “black box” warnings about the safety of these drugs. On November 8, 2007, additional “black box” warnings were included on the aranesp label, at the request of the FDA.

On March 22, 2007, a congressional inquiry into the safety of erythropoeitic growth factors was reported in the news media. Manufacturers were asked to suspend drug rebate programs for physicians and to also suspend marketing the drugs to patients.

Business considerations for drug manufacturers

Epogen and Darbepoetin alfa had more than $6 billion in combined sales in 2006. Procrit sales were about $3.2 billion in 2006.

Darbepoetin alfa

Clinical data
AHFS/Drugs.com	monograph
MedlinePlus	a604022
Licence data	EMA:Link, US FDA:link
Pregnancy cat.	B3 (AU)
Legal status	Prescription Only (S4) (AU)
Identifiers
CAS number	11096-26-7
ATC code	B03XA02
DrugBank	DB00012
Chemical data
Formula	C815H1317N233O241S5
Mol. mass	18396.1 g/mol

Aranesp (darbepoetin alfa) is an erythropoiesis-stimulating protein that is produced in Chinese hamster ovary (CHO) cells by recombinant DNA technology. Aranesp is a 165-amino acid protein that differs fromrecombinant human erythropoietin in containing 5 N-linked oligosaccharide chains, whereas recombinant human erythropoietin contains 3 chains. The 2 additional N-glycosylation sites result from amino acid substitutions in the erythropoietin peptide backbone. The approximate molecular weight of darbepoetin alfa is 37,000 daltons.

Aranesp is formulated as a sterile, colorless, preservative-free solution containing polysorbate for intravenous or subcutaneous administration. Each 1 mL contains polysorbate 80 (0.05 mg), sodium chloride (8.18 mg), sodium phosphate dibasic anhydrous (0.66 mg), and sodium phosphate monobasic monohydrate (2.12 mg) in Water for Injection, USP (pH 6.2 ± 0.2).

References

1.  Jay P. Siegel (2001-09-17). “Product Approval Information – Licensing Action”. United States Food and Drug Administration. Archived from the original on 2006-10-22. Retrieved 2007-01-27.
2.  “European Public Assessment Report (Abstract)” (PDF). European Medicines Agency. 2001-06-08. Retrieved 2007-01-27.
3.  Pollack, Andrew (2007-01-26). “Amgen Finds Anemia Drug Holds Risks in Cancer Use”. The New York Times. Retrieved 2007-01-27.
4. “FDA Public Health Advisory: Erythropoiesis-Stimulating Agents (ESAs): Epoetin alfa (marketed as Procrit, Epogen), Darbepoetin alfa (marketed as Aranesp)”. Archived from the original on 2007-05-28. Retrieved 2007-06-05.
5.  “Information for Healthcare Professionals: Erythropoiesis Stimulating Agents (ESA)”. Archived from the original on 2007-05-15. Retrieved 2007-06-05.

June 21, 2014

 

Regulators in the USA have given the green light to Cubist Pharmaceuticals’ antibiotic Sivextro for serious skin infections, including those caused by MRSA.

The US Food and Drug Administration has approved Sivextro (tedizolid) for acute bacterial skin and skin structure infections (ABSSSI) caused by certain susceptible bacteria, including Staphylococcus aureus (MRSA) and enterococcus faecalis. The thumbs-up is based in two trials of 1,315 adults with ABSSSI which showed that Sivextro was as effective as linezolid, another antibacterial.

Read more at: http://www.pharmatimes.com/Article/14-06-21/FDA_approves_Cubist_s_Sivextro_to_treat_skin_infections.aspx#ixzz35QhW3gVU

OLD POST

TEDIZOLID (torezolid)

January 4, 2014

http://newdrugapprovals.org/2014/01/04/tedizolid-torezolid/

TEDIZOLID PHOSPHATE

[(5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl]phenyl}-2-oxo-5-oxazolidinyl]methyl]phosphate,

DA 7157

THERAPEUTIC CLAIM Treatment of complicated skin and skin structure infections
CHEMICAL NAMES
1. 2-Oxazolidinone, 3-[3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)-3-pyridinyl]phenyl]-5- [(phosphonooxy)methyl]-, (5R)-
2. [(5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl]phenyl}-2-oxooxazolidin-5- yl]methyl hydrogen phosphate

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

MOLECULAR FORMULA C17H16FN6O6P

MOLECULAR WEIGHT 450.3
TRADEMARK None as yet
SPONSOR Trius Therapeutics
CODE DESIGNATION TR-701 FA
CAS REGISTRY NUMBER 856867-55-5
Note: This adoption statement supersedes the USAN torezolid phosphate (N09/81), which is hereby rescinded and replaced by the USAN tedizolid phosphate (N10/118).\

……………………………..

Tedizolid, 856866-72-3

(5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl]phenyl}-5-(hydroxymethyl)-1,3-oxazolidin-2-one

(5R)-3-[3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)-3-pyridinyl]phenyl]-5-(hydroxymethyl)-2-oxazolidinone,

TR 700

• Molecular Formula: C17H15FN6O3
• Average mass: 370.337799

 

Torezolid (also known as TR-701 and now tedizolid[1]) is an oxazolidinone drug being developed by Trius Therapeutics (originator Dong-A Pharmaceuticals) for complicated skin and skin-structure infections (cSSSI), including those caused by Methicillin-resistantStaphylococcus aureus (MRSA).[2]

As of July 2012, tedizolid had completed one phase III trial, with another one under way. [3]Both trials compare a six-day regimen of tedizolid 200mg once-daily against a ten-day regimen of Zyvox (linezolid) 600mg twice-daily.

The prodrug of tedizolid is called “TR-701″, while the active ingredient is called “TR-700″.[4][5]

Trius Therapeutics will soon be reporting data from its second phase III trial (ESTABLILSH-2) and the recently announced publication of the data from its first phase III trial (ESTABLISH-1) in the Journal of the American Medical Association (JAMA)

1. “Trius grows as lead antibiotic moves forward”. 31 Oct 2011.
2. “Trius Completes Enrollment In Phase 2 Clinical Trial Evaluating Torezolid (TR-701) In Patients With Complicated Skin And Skin Structure Infections”. Jan 2009.
3. http://clinicaltrials.gov/ct2/results?flds=Xf&flds=a&flds=b&term=tedizolid&phase=2&fund=2&show_flds=Y
4. PMID 19528279 In vitro activity of TR-700, the active ingredient of the antibacterial prodrug TR-701, a novel oxazolidinone antibacterial agent.
5. PMID 19218276 TR-700 in vitro activity against and resistance mutation frequencies among Gram-positive pathogens.

…………………………………………………….

Emergence of bacterial resistance to known antibacterial agents is becoming a major challenge in treating bacterial infections. One way forward to treat bacterial infections, and especially those caused by resistant bacteria, is to develop newer antibacterial agents that can overcome the bacterial resistance. Coates et al. (Br. J. Pharmacol. 2007; 152(8), 1147-1154.) have reviewed novel approaches to developing new antibiotics. However, the development of new antibacterial agents is a challenging task. For example, Gwynn et al. (Annals of the New York Academy of Sciences, 2010, 1213: 5-19) have reviewed the challenges in the discovery of antibacterial agents.

Several antibacterial agents have been described in the prior art (for example, see PCT International Application Nos. PCT/US2010/060923, PCT/EP2010/067647, PCT/US2010/052109, PCT/US2010/048109, PCT/GB2009/050609, PCT/EP2009/056178 and PCT/US2009/041200). However, there remains a need for potent antibacterial agents for preventing and/or treating bacterial infections, including those caused by bacteria that are resistant to known antibacterial agents.

Various oxazolidinone-containing compounds have been disclosed for use asantibiotics. For example, oxazolidinone-containing compounds have been described in U.S. patent application Ser. No. 10/596,412 (filed Dec. 17, 2004), and WO 04/048350, WO 03/022824 and WO 01/94342, which are incorporated herein by reference.

U.S. patent application Ser. No. 12/577,089 (filed Oct. 9, 2009) and U.S. patent application Ser. No. 12/699,864 (filed Feb. 3, 2010), which are assigned to the same assignee as in the present application, disclose phosphate dimer impurities made during the process of making of the compounds disclosed therein. Surprisingly, it has been found that compounds containing at least two phosphates binding two oxazolidinone-containing moieties, such as dimers of oxazolidinone-containing compounds have antibacterial activity similar to their dihydrogen monophosphate analog

active drug of Formula I is (5R)-3-[3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)-3-pyridinyl]phenyl]-5-(hydroxymethyl)-2-oxazolidinone, i.e.,

These active compounds have been disclosed in WO 05/058886 and US Patent Publication No. 20070155798, while processes for making these and related compounds have been disclosed in U.S. patent application Ser. No. 12/577,089 (filed Oct. 9, 2009), and a crystalline form of the phosphate ester and related salts of the above compound has been disclosed in U.S. patent application Ser. No. 12/699,864 (filed Feb. 3, 2010).

US Patent Publication No. 20070155798,  recently disclosed a series of potently anti-bacterial oxazolidinones including

wherein R═H, PO(OH)₂, and PO(ONa)₂.

Cubist Announces Submission of New Drug Application for Investigational Antibiotic Tedizolid for Treatment of Serious Skin Infections

LEXINGTON, Mass.–(BUSINESS WIRE)– Cubist Pharmaceuticals, Inc. today announced that it has submitted a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for approval of its investigational antibiotic tedizolid phosphate (TR-701). Cubist is seeking approval of tedizolid phosphate for the treatment of acute bacterial skin and skin structure infections (ABSSSI). Tedizolid phosphate is a once daily oxazolidinone being developed for both intravenous (I.V.) and oral administration for the treatment of serious Gram-positive infections, including those caused by methicillin-resistant Staphylococcus aureus (MRSA).

http://www.drugs.com/nda/tedizolid_131023.html

…………………………………………………………..

Efficacy of DA-7218, a new oxazolidinone prodrug, in the treatment of experimental actinomycetoma produced by Nocardia brasiliensis.

Espinoza-González NA, Welsh O, de Torres NW, Cavazos-Rocha N, Ocampo-Candiani J, Said-Fernandez S, Lozano-Garza G, Choi SH, Vera-Cabrera L.

Molecules. 2008 Jan 11;13(1):31-40.

…………………………………………..

imp patents

US2010305069	12-3-2010	OXAZOLIDINONE CONTAINING DIMER COMPOUNDS, COMPOSITIONS AND METHODS TO MAKE AND USE
US7816379	10-20-2010	Oxazolidinone derivatives
US2009192197	7-31-2009	NOVEL OXAZOLIDINONE DERIVATIVES

…………………………………………..

TEDIZOLID disodium salt

59 nos in

http://www.google.com/patents/US20130102523

38 nos

Tedizolid (formerly known as torezolid or TR-700) is the active hydroxymethyl oxazolidinone having the following formula:

Pharmaceutical prodrugs such as tedizolid phosphate (also referred to as TR-701, torezolid phosphate, and TR-701 “free acid” or FA) have the following formula:

The disodium salt of tedizolid phosphate, has the following structure:

…………………………………………………………………………………………………………………………………………………………….

US20100305069

Example 1 Preparation of the Phosphate Monohydrogen Diester, Formula III
In this and the following Examples, “Formula III” refers to a compound wherein Z is
Figure US20100305069A1-20101202-C00024
and M=OH.
A 1-L, three-neck round-bottom flask equipped with a magnetic stirrer, nitrogen inlet/outlet and thermocouple was charged with the compound of Formula Ia below (16.0 g, 0.0499 mol], THF (320 mL, 20 vol) and Et3N (21.9 g, 0.216 mol, 5.0 equiv.).
Figure US20100305069A1-20101202-C00025
POCl3 (3.31 g, 0.0216 mol, 0.5 equiv.) was added dropwise via syringe over 5 minutes. The reaction temperature was maintained below 25° C. The batch was aged for 16 hours at room temperature at which point HPLC analysis (XBridge, C18) indicated that the reaction was complete. The reaction vessel was then immersed in an ice-water bath and a 500-mL addition funnel charged with 320 mL of H2O was attached to the reaction vessel. When the temperature of the reaction reached 2.7° C., H2O was added drop wise over 30 minutes. The temperature of the reaction was maintained below 10° C. Upon completion of the H2O addition, the ice-water bath was removed and the batch was aged for 3 hours. The solution was transferred to a 2-L round-bottom flask and concentrated under reduced pressure on a rotary evaporator. After removal of most of the THF from the solution, the aqueous mixture was extracted with 5 1-L portions of CH2Cl2:MeOH (9:1). The CH2Cl2 layers were combined and concentrated to a dark oil. This crude material was purified on 200 g of silica gel, eluting with 10% MeOH/CH2Cl2 to 20% 2 N NH3 in MeOH/CH2Cl2. Fractions containing mostly the bis-ester (as judged by TLC Rf=0.3 eluting with 20% 2 N NH3 in MeOH/CH2Cl2) were combined and concentrated under reduced pressure on a rotary evaporator, during which time a white precipitate was observed. The flask containing the slurry was removed from the rotary evaporator and equipped with a magnetic stir bar and allowed to stir while cooling to room temperature over 3 hours, during which time the slurry thickened. The solid was filtered and dried in a vacuum oven at 45° C. for 16 hours to give 3.55 g of bis-ester as an off-white solid (20% yield). HPLC analysis (Method A): 99.0% (AUC), tR=16.3 min. This reaction was repeated and the combined lots of the compound of Formula III (6.7 g) were slurried in 100 mL of MeOH (15 vol). The slurry was heated to 40° C. for 30 minutes and then allowed to cool to room temperature over 1 hour. The off-white solid was filtered and dried in a vacuum oven at 40° C. for 16 hours to give 6.15 g of the compound of Formula III (92% yield). The 1H NMR analysis of the product was consistent with the assigned structure. HPLC analysis (Method A): 99.0% (AUC), tR=16.3 min.

Example 2 Preparation of the Diphosphate Dihydrogen Diester, Formula IV
In Examples 2-5, “Formula IV” refers to a compound wherein Z is
Figure US20100305069A1-20101202-C00026
n=0 and M=O-imidazolium salt.

A 250-mL 3-neck round-bottom flask equipped with a magnetic stirrer, nitrogen inlet/outlet and thermocouple was charged with the compound of Formula IIa below (5.0 g, 11.1 mmol), carbonyldiimidazole (890 mg, 5.55 mmol, 0.5 equiv.) and DMF (100 mL, 20 vol).
Figure US20100305069A1-20101202-C00027
The suspension was heated to 50° C. and held at that temperature for 4 hours at which point HPLC analysis (XBridge, C18) indicated that the reaction was complete. The reaction was filtered at 50° C. and dried in a vacuum oven at 50° C. for 24 hours to give 5.15 g of the imidazolium salt (i.e., the compound of Formula IV) as an off-white solid (98% yield). The 1H NMR analysis of the product was consistent with the assigned structure. HPLC analysis (Method A): 94.5% (AUC), tR=14.6 min.
TABLE 1
Method A (Waters XBridge C18 Column)
Time (min) Flow (mL/min) % A % B
0.0 1.0 98.0 2.0
15.0 1.0 5.0 95.0
25.0 1.0 5.0 95.0
27.0 1.0 98.0 2.0
30.0 1.0 98.0 2.0
A = 87% 25 mM ammonium bicarbonate solution in water/13% Acetonitrile
B = Acetonitrile
Wavelength = 300 nm

disodium salt is TR 701

……………………………………

US8580767

Various oxazolidinone-containing compounds have been disclosed for use as antibiotics. For example, oxazolidinone-containing compounds have been described in U.S. patent application Ser. No. 10/596,412 (filed Dec. 17, 2004), and WO 04/048350, WO 03/022824 and WO 01/94342, which are incorporated herein by reference.

U.S. patent application Ser. No. 12/577,089 (filed Oct. 9, 2009) and U.S. patent application Ser. No. 12/699,864 (filed Feb. 3, 2010), which are assigned to the same assignee as in the present application, disclose phosphate dimer impurities made during the process of making of the compounds disclosed therein. Surprisingly, it has been found that compounds containing at least two phosphates binding two oxazolidinone-containing moieties, such as dimers of oxazolidinone-containing compounds have antibacterial activity similar to their dihydrogen monophosphate analog,

These active compounds have been disclosed in WO 05/058886 and US Patent Publication No. 20070155798, while processes for making these and related compounds have been disclosed in U.S. patent application Ser. No. 12/577,089 (filed Oct. 9, 2009), and a crystalline form of the phosphate ester and related salts of the above compound has been disclosed in U.S. patent application Ser. No. 12/699,864 (filed Feb. 3, 2010). The latter two applications are assigned to the same assignee as in the present application

………………………………………………………………………………………………………………………..

SYNTHESIS

US20070155798

DESCRIPTION OF COMPDS

10,

(R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-hydroxymethyl oxazolidin-2-on (compound 10)

………………………………………………………………………………………………………………………….

18

Preparation of (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-fluoromethyl oxazolidin-2-on (compound 18)

………………………………………………………………………………………………………………………………………………………….

33

(R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-methoxymethyl oxazolidin-2-on (compound 33)

…………………………………………………………………………………………………………………………………………..

59

(R)-[3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl disodiumphosphate (compound 59)

………………………………………………………………………………………………………………………………………………………

72

mono-[(R)-[3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl]phosphate (compound 72)

COMPLETE SYNTHESIS

Example 5

Preparation of 2-cyano-5-bromopyridine

In 1 L of dimethylformamide was dissolved 100 g of 2,5-dibromopyridine, 32 g of cupper cyanide and 17.8 g of sodium cyanide were added to the solution at room temperature and the solution was stirred at the temperature of 150° C. for 7 hours for reaction. After being cooled to room temperature, the reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with brine, dehydrated, filtered and concentrated in vacuo. The title compound 54 g was obtained. Yield 70%.

¹HNMR(CDCl₃) δ 8.76(s,1H), 7.98(dd,1H), 7.58(dd,1H)

Example 6

Preparation of 2-(tetrazol-5-yl)-5-bromopyridine

10 g of 2-cyano-5-bromopyridine prepared in the Preparation example 5 was dissolved in 100 ml of dimethylformamide, 5.33 g of sodiumazide, and 4.4 g of ammonium chloride were added to the solution at room temperature, and the solution was stirred at the temperature of 110° C. for 3 hours for reaction. The reaction mixture was added with water and then was extracted with ethyl acetate. The organic layer, thus separated, was washed with brine, dehydrated, filtrated and concentrated in vacuo thereby to obtain 10.5 g of the title compound. Yield 85%.

Preparation Example 7 Preparation of 2-(1-methyltetrazol-5-yl)-5-bromopyridine and 2-(2-methyltetrazol-5-yl)-5-bromopyridine

10.5 g of 2-(tetrazol-5-yl)-5-bromopyridine prepared in the Preparation example 6 was dissolved in 100 ml of dimethylformamide. And then 6.5 g of sodium hydroxide was added to the solution and 9.3 g of iodomethane was slowly added to the solution at the temperature of 0° C. The solution was stirred for 6 hours at room temperature, added with water, extracted with ethyl acetate. And then the organic layer was washed with brine, dehydrated, filtrated, concentrated in vacuo and purified by column chromatography to obtain 4 g of 2-(1-methyltetrazol-5-yl)-5-bromopyridine and 5 g of 2-(2-methyltetrazol-5-yl)-5-bromopyridine.

1) 2-(1-methyltetrazol-5-yl)-5-bromopyridine

¹HNMR(CDCl₃) δ 8.77(t,1H), 8.23(dd,1H), 8.04(dd,1H), 4.46(s,3H)

2) 2-(2-methyltetrazol-5-yl)-5-bromopyridine

¹HNMR(CDCl₃) δ 8.80(t,1H), 8.13(dd,1H), 7.98(dd,1H), 4.42(s,3H)

Example 1

Preparation of N-Carbobenzyloxy-3-fluoroaniline

3-fluoroaniline 100 g was dissolved in 1 L of tetrahydrofuran (THF) and the solution was added with 150 g (1.8 mol) of sodium bicarbonate (NaHCO₃). After being cooled to 0° C., the solution was slowly added with 154 ml of N-carbobenzyloxy chloride (CbzCl) for reaction. While the temperature was maintained at 0° C., the reaction mixture was let to react for 2 hours with stirring. Afterwards, the reaction was extracted with 0.5 L of ethyl acetate. The organic layer, after being separated, was washed with brine, dried over anhydrous magnesium sulfate (MgSO₄) and concentrated in vacuo. The residue was washed twice with n-hexane to afford the title compound as white crystal. 132 g. Yield 85%.

Example 2

Preparation of (R)-3-(3-fluorophenyl)-2-oxo-5-oxazolidinylmethanol

132 g of N-carbobenzyloxy-3-fluoroaniline 132 g prepared in the Preparation example 1 was dissolved in 1.3 L of tetrahydrofuran and the solution was cooled to −78° C. 370 ml of n-buthyllitium (n-BuLi, 1.6M/n-hexane) was slowly added to the solution in a nitrogen atmosphere, followed by stirring for 10 min. And 84 ml of (R)-(−)-glycidylbuthylate was slowly added to the reaction mixture, stirred at the same temperature for 2 hours and allowed to react for 24 hours at room temperature. After completion of the reaction, the solution was added with ammonium chloride (HH₄Cl) solution and extracted with 0.5 L of ethyl acetate at room temperature. The organic layer, thus separated, was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was dissolved in 100 ml of ethyl acetate and washed with n-hexane to give white crystals, which were purified to the title compound. 80 g. Yield 70%.

¹H NMR (DMSO-d₆) δ 7.85(t,1H), 7.58(dd,1H), 7.23(dd,1H), 4.69(m,1H), 4.02 (t,1H), 3.80(dd,1H), 3.60(br dd,2H).

Example 3

Preparation of (R)-3-(4-iodo-3-fluorophenyl)-2-oxo-5-oxazolidinylmethanol

In 300 ml of acetonitryl was dissolved 30 g of (R)-3-(3-fluorophenyl)-2-oxo-5-oxazolidinylmethanol prepared in the Preparation example 2, and 46 g of trifluoroacetic acid silver salt (CF₃COOAg) and 43 g of iodide were added to the solution. After being stirred for one day at room temperature, the solution was added with water and was extracted with ethyl acetate. The organic layer, thus separated, was washed with brine and dehydrated. And then the residue was filtered, concentrated in vacuo and dried thereby to form the title compound 44 g. Yield 94%.

¹H NMR (DMSO-d₆) δ 7.77(t,1H), 7.56(dd,1H), 7.20(dd,1H), 5.20(m,1H), 4.70 (m,1H), 4.07(t,1H), 3.80(m,1H), 3.67(m,2H), 3.56(m,3H)

Example 4

Preparation of (R)-3-(4-tributhylstannyl-3-fluorophenyl)-2-oxo-5-oxazolidinylmethanol

In 660 ml of 1,4-dioxan was dissolved 50 g of (R)-3-(4-iodo-3-fluorophenyl)-2-oxo-5-oxazolidinylmethanol prepared in the Preparation example 3, 52 g of hexabutylditin ((Bu₃Sn)₂) and 9.3 g of dichlorobistriphenylphosphinpalladium were added into the solution, and stirred for 2 hours. The solution was filtered using celite and concentrated in vacuo. The residue was purified by column chromatography and 45 g of the title compound was formed.

¹H NMR (DMSO-d₆) δ 7.74(m,3H), 5.20(t,1H), 4.71(m,1H), 4.08(t,1H), 3.82(dd,1H), 3.68(m,1H), 3.52(m,1H), 1.48(m, 6H), 1.24(m, 6H), 1.06(m,6H), 0.83(t,9H)

COMPD 10

Example 1 Preparation of (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-hydroxymethyl oxazolidin-2-on (compound 10)

In 150 ml of 1-methyl-2-pyrrolidone was dissolved 37 g of (R)-3-(4-tributhylstannyl-3-fluorophenyl)-2-oxo-5-oxazolidinylmethanol. The solution was added with 19.7 g of 2-(2-methyltetrazol-5-yl)-5-bromopyridine, 10.44 g of lithium chloride and 2.9 g of dichlorobistriphenylphospine palladium(II) at room temperature and then stirred at the temperature of 120° C. for 4 hours. The reaction mixture was added with water and then extracted with ethyl acetate. The organic layer, thus separated, was washed with brine, dehydrated, filtrated, concentrated in vacuo and purified by column chromatography to provide 8 g of the title compound. Yield 26%.

¹H NMR (DMSO-d₆) δ 8.90(s,1H), 8.18(m,2H), 7.70(m,2H), 7.49(dd,1H), 5.25(t,1H), 4.74(m,1H), 4.46(s,3H), 4.14(t,1H), 3.88(dd,1H), 3.68(m,1H), 3.58 (m,1H)

COMPD 18

Example 28 Preparation of (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-fluoromethyl oxazolidin-2-on (compound 18)

In 5 ml of methylenchloride was dissolved 100 mg of the compound 10. The solution was added with 43 mg of diethylaminosulfurtrifloride (DAST) and 0.078 ml of triethylamine and then stirred for 24 hours. After being concentrating, the reaction mixture was purified by column chromatography to obtain the title compound 75 mg. Yield 75%.

¹H NMR (DMSO-d₆) δ 8.91(s,1H), 8.19(m,2H), 7.74(t,1H), 7.66(dd,1H) 7.49 (dd,1H), 5.06(m,1H), 4.89(m,2H), 4.46(s,3H), 4.23(t,1H), 3.95(dd,1H)

COMPD 33

Example 37 Preparation of (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-methoxymethyl oxazolidin-2-on (compound 33)

In 10 ml of methanol was dissolved 400 mg of (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-methansulfonyloxymethyl oxazolidin-2-on prepared in the secondary step of the Example 24. The solution was added with 90 mg of sodium methoxide at room temperature and then stirred for one day at room temperature. The solution was extracted with ethyl acetate and the organic layer, thus separated, was washed with water and brine. The organic layer was dehydrated, filtered, concentrated in vacuo and purified by column chromatography to provide the title compound 200 mg. Yield 58%.

¹H NMR(CDCl₃) δ 8.90(s,1H), 8.29(d,1H), 8.04(d,1H), 7.61(dd,1H), 7.58 (t,1H), 7.38(dd,1H), 4.80(m,1H), 4.45(s,3H), 4.08(t,1H), 3.96(dd,1H), 3.67 (m,2H), 3.43(s,3H)

COMPD 59

Example 58 Preparation of mono-[(R)-[3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl]phosphate (compound 72) and (R)-[3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl disodiumphosphate (compound 59)

1. The Primary Step

In 10 ml of mixture solvent (tetrahydrofuran:methylenchloride=1:1) was dissolved 1 g of compound 10. The solution was added with 0.6 g of tetrazole and 2.3 g of di-tetrabutyl diisoprophylphosphoamidite and stirred for 15 hours at room temperature. The reaction mixture was refrigerated to −78° C., added with 0.7 g of metachloroperbenzoic acid and stirred for 2 hours. After being cooling to −78° C., the reaction mixture was added with metachloroperbenzoic acid (0.7 g). When the reaction mixture was stirred for 2 hours, the temperature of the reaction mixture was raised to room temperature. The reaction mixture was then added with ethyl acetate. The organic layer, thus separated, was washed with sodium bisulfate, sodium bicarbonate and brine, dehydrated, filtered and concentrated in vacuo, followed by purification with column chromatography thereby to provide (R)-[3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl phosphoric acid ditetrabuthylester (0.71 g, 71%).

¹H NMR (DMSO-d₆) δ 8.90(s,1H), 8.18(m,2H), 7.74(t,1H), 7.68 (dd,1H), 7.49(dd,1H), 4.98(m,1H), 4.46(s,3H), 4.23(t,1H), 4.18(m,1H), 4.09(m,1H), 3.89 (dd,1H), 1.39(s,9H), 1.38(s,9H)

The crystal prepared the above method was dissolved in a mixture of methanol and chloroform. And then the solution added with 3.4 ml of sodium methoxide (0.3M methanol solution) at the room temperature and stirred for 10 hours. The reaction mixture was concentrated to prepare the residue. The residue was crystallized and filtered thereby to obtain the title compound (compound 59) 300 mg.

¹H NMR (D₂O) δ 8.27(s,1H), 7.56(dd,2H), 7.06(m,2H), 6.90(m,1H), 4.79 (m,1H), 4.63(s,3H), 3.90(m,4H)

COMPD 72

The Secondary Step

In 30 ml of methylenchloride was dissolved the compound (0.7 g) in the Primary Step. The solution was added with 15 ml of trifluoroacetic acid and then stirred for 1 hour at room temperature. The reaction mixture was concentrated in vacuo to prepare the residue. The residue was crystallized with ethanol and ethyl ether to obtain mono-[(R)-[3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl]phosphate (compound 72) 400 mg.

¹H NMR (DMSO-d₆) δ 8.92(s,1H), 8.20(m,2H), 7.74(t,1H), 7.66(dd,1H), 7.500(dd,1H), 4.95 (m,1H), 4.46(s,3H), 4.21(t,1H), 4.05(m,2H), 3.91(dd,1H)

US20070155798

………………………………………………………

IMPURITIES

US8426389

Organic Impurities in TR-701 FA Drug Substance
Impurity
‘Name’	Structure and Chemical Name
Rx600013 ‘Des-methyl TR- 701’
	dihydrogen ((5R)-3-{3-fluoro-4-[6-(2H-1,2,3,4-tetrazol-5-
	yl)-3-pyridinyl]phenyl}-2-oxo-1,3-oxazolan-5-yl)methyl
	phosphate
Rx600024 ‘Pyrophosphate’
	trihydrogen ((5R)-3-{3-fluoro-4-[6-(1-methyl-1H-1,2,3,4-
	tetraazol-5-yl)-3-pyridinyl]phenyl}-2-oxo-1,3-oxazolan-5-
	yl)methyl pyrophosphate
Rx600014 ‘Ring opened’
	dihydrogen 3-{3-fluoro-4-[6-(2-methyl-2H-1,2,3,4-tetraazol-5-
	yl)-3-pyridinyl]aniline}-2-hydroxypropyl phosphate
Rx600023 ‘Me-isomer’
	dihydrogen ((5R)-3-{3-fluoro-4-[6-(1-methyl-1H-1,2,3,4-
	tetraazol-5-yl)-3-pyridinyl]phenyl}-2-oxo-1,3-oxazolan-5-
	yl)methyl phosphate
Rx600025 ‘Overalkylated- phosphorylated impurity’
	(R)-1-((3-(3-fluoro-4-(6-(2-methyl-2H-tetrazol-5-
	yl)pyridin-3-yl)phenyl)-2-oxooxazolidin-5-yl)methoxy)-3-
	hydroxypropan-2-yl dihydrogen phosphate;
	(R)-3-((3-(3-fluoro-4-(6-(2-methyl-2H-tetrazol-5-
	yl)pyridin-3-yl)phenyl)-2-oxooxazolidin-5-yl)methoxy)-2-
	hydroxypropyl dihydrogen phosphate
Rx600020 ‘Dimer impurity’
	dihydrogen bis-O-O′-[(5R)-3-{3-fluoro-4-[6-(2-methyl-
	2H-1,2,3,4-tetrazol-5-yl)-3-pyridinyl]phenyl}-2-oxo-1,3-
	oxazolidin-5-yl]methyl pyrophosphate
Rx600026 “Chloro”
	(R)-5-(chloromethyl)-3-(3-fluoro-4-(6-(2-methyl-2H-
	tetrazol-5-yl)pyridin-3-yl)phenyl)oxazolidin-2-one
Rx600001 TR-700
	5R)-3-{3-Fluoro-4-[6-(2-methyl-2H-1,2,3,4-tetrazol-5-yl)-
	pyridin-3-yl]-phenyl}-5-hydroxymethyl-1,3-oxazolidin-2-one
Rx600022 ‘Bis phosphate’
	hydrogen bis-O-O′-[(5R)-3-{3-fluoro-4-[6-(2-methyl-2H-1,2,3,4-
	tetrazol-5-yl)-3-pyridinyl]phenyl}-2-oxo-1,3-oxazolidin-5-yl]methyl
	phosphate
Rx600042
	3-{[(5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridin-3-
	yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl]methoxy}-2-hydroxypropyl
	[(5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridin-3-
	yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl]methyl hydrogen phosphate
Rx600043
	2-{[(5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridin-3-
	yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl]methoxy}-1-hydroxyethyl
	[(5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridin-3-
	yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl]methyl hydrogen phosphate

……………………………………………..

US4128654	10 Feb 1978	5 Dec 1978	E. I. Du Pont De Nemours And Company	5-Halomethyl-3-phenyl-2-oxazolidinones
US4250318	9 Aug 1978	10 Feb 1981	Delalande S.A.	Novel 5-hydroxymethyl oxazolidinones, the method of preparing them and their application in therapeutics
US4340606	23 Oct 1980	20 Jul 1982	E. I. Du Pont De Nemours And Company	3-(p-Alkylsulfonylphenyl)oxazolidinone derivatives as antibacterial agents
US4461773	5 Jan 1984	24 Jul 1984	E. I. Dupont De Nemours And Company	P-Oxooxazolidinylbenzene compounds as antibacterial agents
US4476136	24 Feb 1982	9 Oct 1984	Delalande S.A.	Aminomethyl-5 oxazolidinic derivatives and therapeutic use thereof
US4948801	29 Jul 1988	14 Aug 1990	E. I. Du Pont De Nemours And Company	Aminomethyloxooxazolidinyl arylbenzene derivatives useful as antibacterial agents
US5523403	22 May 1995	4 Jun 1996	The Upjohn Company	Tropone-substituted phenyloxazolidinone antibacterial agents
US5565571	28 Apr 1994	15 Oct 1996	The Upjohn Company	Substituted aryl- and heteroaryl-phenyloxazolidinones
US5652238	27 Sep 1994	29 Jul 1997	Pharmacia & Upjohn Company	Esters of substituted-hydroxyacetyl piperazine phenyl oxazolidinones
US5688792	16 Aug 1994	18 Nov 1997	Pharmacia & Upjohn Company	Substituted oxazine and thiazine oxazolidinone antimicrobials
US6365751	17 Apr 2001	2 Apr 2002	Zeneca Ltd.	Antibiotic oxazolidinone derivatives
US6627646 *	17 Jul 2001	30 Sep 2003	Sepracor Inc.	Norastemizole polymorphs
US6689779	18 May 2001	10 Feb 2004	Dong A Pharm. Co., Ltd.	Oxazolidinone derivatives and a process for the preparation thereof
US7129259	1 Dec 2004	31 Oct 2006	Rib-X Pharmaceuticals, Inc.	Halogenated biaryl heterocyclic compounds and methods of making and using the same
US7141583	23 Apr 2001	28 Nov 2006	Astrazeneca Ab	Oxazolidinone derivatives with antibiotic activity
US7144911	24 Dec 2003	5 Dec 2006	Deciphera Pharmaceuticals Llc	Anti-inflammatory medicaments
US7202257	6 Jul 2004	10 Apr 2007	Deciphera Pharmaceuticals, Llc	Anti-inflammatory medicaments
US7396847	9 Sep 2002	8 Jul 2008	Astrazeneca Ab	Oxazolidinone and/or isoxazoline as antibacterial agents
US7462633	29 Jun 2004	9 Dec 2008	Merck & Co., Inc.	Cyclopropyl group substituted oxazolidinone antibiotics and derivatives thereof
US7473699	25 Feb 2003	6 Jan 2009	Astrazeneca Ab	3-cyclyl-5-(nitrogen-containing 5-membered ring)methyl-oxazolidinone derivatives and their use as antibacterial agents
US7498350	24 Nov 2003	3 Mar 2009	Astrazeneca Ab	Oxazolidinones as antibacterial agents
US7816379	17 Dec 2004	19 Oct 2010	Dong-A Pharm. Co., Ltd.	Oxazolidinone derivatives
US20020115669	29 Aug 2001	22 Aug 2002	Wiedeman Paul E.	Oxazolidinone chemotherapeutic agents
US20030166620	18 May 2001	4 Sep 2003	Jae-Gul Lee	Novel oxazolidinone derivatives and a process for the preparation thereof
US20040180906	24 Dec 2003	16 Sep 2004	Flynn Daniel L	Anti-inflammatory medicaments
US20050038092	29 Jun 2004	17 Feb 2005	Yasumichi Fukuda	Cyclopropyl group substituted oxazolidinone antibiotics and derivatives thereof
US20050107435	9 Sep 2002	19 May 2005	Gravestock Michael B.	Oxazolidinone and/or isoxazoline as antibacterial agents
US20050288286	6 Jul 2004	29 Dec 2005	Flynn Daniel L	Anti-inflammatory medicaments
US20060116386	24 Nov 2003	1 Jun 2006	Astrazeneca Ab	Oxazolidinones as antibacterial agents
US20060116400	24 Nov 2003	1 Jun 2006	Astrazeneca Ab	Oxazolidinone and/or isoxazoline derivatives as antibacterial agents
US20060270637	24 Feb 2004	30 Nov 2006	Astrazeneca Ab	Hydroxymethyl substituted dihydroisoxazole derivatives useful as antibiotic agents
US20070155798	17 Dec 2004	5 Jul 2007	Dong-A Pharm. Co., Ltd.	Novel oxazolidinone derivatives
US20070185132	29 Jun 2004	9 Aug 2007	Yasumichi Fukuda	Cyclopropyl group substituted oxazolidinone antibiotics and derivatives thereo
US20070191336	23 Dec 2004	16 Aug 2007	Flynn Daniel L	Anti-inflammatory medicaments
US20070203187	22 Jan 2007	30 Aug 2007	Merck & Co., Inc.	Cyclopropyl group substituted oxazolidinone antibiotics and derivatives thereof
US20070208062	24 May 2005	6 Sep 2007	Astrazeneca Ab	3-(4-(2-dihydroisoxazol-3-ylpyridin-5-yl)phenyl)-5-triazol-1-ylmethyloxazolidin-2-one derivatives as mao inhibitors for the treatment of bacterial infections
US20080021012	24 May 2005	24 Jan 2008	Astrazeneca Ab	3-[4-{6-Substituted Alkanoyl Pyridin-3-Yl}-3-Phenyl]-5-(1H-1,2,3-Triazol-1-Ylmethyl)-1,3-Oxazolidin-2-Ones As Antibacterial Agents
US20080021071	24 May 2005	24 Jan 2008	Astrazeneca Ab	3-{4-(Pyridin-3-Yl) Phenyl}-5-(1H-1,2,3-Triazol-1-Ylmethyl)-1,3-Oxazolidin-2-Ones as Antibacterial Agents
US20080064689	24 May 2004	13 Mar 2008	Astrazeneca Ab	3-[4-(6-Pyridin-3-Yl)-3-Phenyl] -5-(1H-1,2,3-Triazol-1-Ylmethyl)-1,3-Oxazolidin-2-Ones as Antibacterial Agents
US20090018123	19 Jun 2006	15 Jan 2009	Milind D Sindkhedkar	Oxazolidinones Bearing Antimicrobial Activity Composition and Methods of Preparation
US20090192197	16 Sep 2008	30 Jul 2009	Dong-A Pharm. Co., Ltd.	Novel oxazolidinone derivatives
US20100093669	9 Oct 2009	15 Apr 2010	Trius Therapeutics	Methods for preparing oxazolidinones and compositions containing them
US20100227839	3 Feb 2010	9 Sep 2010	Trius Therapeutics	Crystalline form of r)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin- 5-yl)-3-fluorophenyl)-5-hydroxymethyl oxazolidin-2-one dihydrogen phosphate
AU2004299413A1				Title not available
AU2009200606A1				Title not available
CA2549062A1	17 Dec 2004	30 Jun 2005	Chong Hwan Cho	Novel oxazolidinone derivatives
CN101982468A	17 Dec 2004	2 Mar 2011	东亚制药株式会社	Novel oxazolidinone derivatives and pharmaceutical compositions comprising the derivatives
EP0312000A1	12 Oct 1988	19 Apr 1989	The Du Pont Merck Pharmaceutical Company	Aminomethyl oxooxazolidinyl aroylbenzene derivatives useful as antibacterial agents
EP0352781A2	27 Jul 1989	31 Jan 1990	The Du Pont Merck Pharmaceutical Company	Aminomethyloxooxazolidinyl arylbenzene derivatives useful as antibacterial agents
EP1699784A1	17 Dec 2004	13 Sep 2006	Dong-A Pharmaceutical Co., Ltd.	Novel oxazolidinone derivatives
EP2305657A2	17 Dec 2004	6 Apr 2011	Dong-A Pharmaceutical Co., Ltd.	Oxazolidinone derivatives
EP2435051A1	27 May 2010	4 Apr 2012	Trius Therapeutics	Oxazolidinone containing dimer compounds, compositions and methods to make and use
IN236862A1				Title not available
JPS5799576A				Title not available
KR20110071107A				Title not available
NZ547928A				Title not available
NZ575842A				Title not available
WO1993009103A1	5 Oct 1992	13 May 1993	Upjohn Co	Substituted aryl- and heteroarylphenyloxazolidinones useful as antibacterial agents
WO1993023384A1	21 Apr 1993	25 Nov 1993	Michael Robert Barbachyn	Oxazolidinones containing a substituted diazine moiety and their use as antimicrobials
WO1995007271A1	16 Aug 1994	16 Mar 1995	Michael R Barbachyn	Substituted oxazine and thiazine oxazolidinone antimicrobials
WO1995014684A1	27 Sep 1994	1 Jun 1995	Michel R Barbachyn	Esters of substituted-hydroxyacetyl piperazine phenyl oxazolidinones
WO2001094342A1	18 May 2001	13 Dec 2001	Cho Jong Hwan	Novel oxazolidinone derivatives and a process for the preparation thereof
WO2002081470A1	3 Apr 2002	17 Oct 2002	Astrazeneca Ab	Oxazolidinones containing a sulfonimid group as antibiotics
WO2003022824A1	9 Sep 2002	20 Mar 2003	Astrazeneca Ab	Oxazolidinone and/or isoxazoline as antibacterial agents
WO2003035648A1	23 Oct 2002	1 May 2003	Astrazeneca Ab	Aryl substituted oxazolidinones with antibacterial activity
WO2003047358A1	2 Dec 2002	12 Jun 2003	Vaughan Leslie Crow	Cheese flavour ingredient and method of its production
WO2003072575A1	25 Feb 2003	4 Sep 2003	Astrazeneca Ab	3-cyclyl-5-(nitrogen-containing 5-membered ring) methyl-oxazolidinone derivatives and their use as antibacterial agents
WO2003072576A2	25 Feb 2003	4 Sep 2003	Astrazeneca Ab	Oxazolidinone derivatives, processes for their preparation, and pharmaceutical compositions containing them
WO2004048350A2	24 Nov 2003	10 Jun 2004	Astrazeneca Ab	Oxazolidinones as antibacterial agents
WO2004083205A1	16 Mar 2004	30 Sep 2004	Astrazeneca Ab	Antibacterial 1, 3- oxazolidin -2- one derivatives
WO2005005398A2	29 Jun 2004	20 Jan 2005	Yasumichi Fukuda	Cyclopropyl group substituted oxazolidinone antibiotics and derivatives thereof
WO2005051933A1	23 Nov 2004	9 Jun 2005	Vijay Kumar Kaul	An improved process for the synthesis of 4-(4-benzyloxy-carbonylamino-2-fluorophenyl)-piperazine-1-carboxylic acid tert-butyl ester, a key intermediate for oxazolidinone antimicrobials and compounds prepared thereby
WO2005058886A1	17 Dec 2004	30 Jun 2005	Dong A Pharm Co Ltd	Novel oxazolidinone derivatives
WO2005116017A1	24 May 2005	8 Dec 2005	Astrazeneca Ab	Process for the preparation of aryl substituted oxazolidinones as intermediates for antibacterial agents
WO2006038100A1	6 Oct 2005	13 Apr 2006	Ranbaxy Lab Ltd	Oxazolidinone derivatives as antimicrobials
WO2007023507A2	19 Jun 2006	1 Mar 2007	Milind D Sindkhedkar	Oxazolidinones bearing antimicrobial activity composition and methods of preparation
WO2007138381A2	13 Oct 2006	6 Dec 2007	Delorme Daniel	Phosphonated oxazolidinones and uses thereof for the prevention and treatment of bone and joint infections
WO2010042887A2	9 Oct 2009	15 Apr 2010	Trius Therapeutics	Methods for preparing oxazolidinones and compositions containing them
WO2010091131A1	3 Feb 2010	12 Aug 2010	Trius Therapeutics	Crystalline form of r)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-hydroxymethyl oxazolidin-2-one dihydrogen phosphate
WO2010138649A1	27 May 2010	2 Dec 2010	Trius Therapeutics, Inc.	Oxazolidinone containing dimer compounds, compositions and methods to make and use

 

 

……………………………………………………………………………………….

THANKS AND REGARD’S
DR ANTHONY MELVIN CRASTO Ph.D

GLENMARK SCIENTIST , NAVIMUMBAI, INDIA

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After a series of late-stage failures, Sanofi has returned the rights to the cancer compound MM-121 to Merrimack Pharmaceuticals.

MM-121, a monoclonal antibody designed to block ErbB3 activation in patients with heregulin-positive tumours, has been tested in Phase II trials in partnership with the French giant in ovarian, breast and lung cancer. However, none of them have met their primary endpoints and Sanofi has decided  to pull the plug, although it will continue to fund the existing MM-121 Phase II programme for the next six months.

SAR256212 (MM-121)

---

SAR256212 (MM-121) HER3 ErbB3 antibody

Targeting ErbB3

ErbB3 is a kinase-dead critical mediator of pro-survival signaling through PI3K/AKT activation and potentially through activation of other pathways involved in proliferation, differentiation, and survival of cancer cells.²⁰ Signaling is mediated by ErbB3 ligands such as heregulin (HRG) and epidermal growth factor receptor (EGFR) ligands like betacellulin (BTC).²¹ Signaling through ErbB3 is a major mechanism by which cancer cells acquire resistance to targeted therapies (including EGFR and HER2 inhibitors); chemotherapies; and, potentially, radiotherapy.<sup>20,21References:
20. Schoeberl et al. Cancer Res. 2010;70:2485-2494; 21. Schoeberlet al. Sci Signal. 2009;2:ra31;</sup>  

Investigational anti-ErbB3 mAB

SAR256212 is an investigational fully human monoclonal antibody that targets the HER3 (ErbB3) receptor.²¹ SAR256212 potently inhibits ligand-induced signaling through HER3.²¹ By targeting ErbB3, SAR256212 blocks heregulin (HRG1-β1) binding to HER3, induces HER3 internaliztion and degradation, and blocks BTC-induced phosphorylation of HER3, leading to inhibition of HRG1-β1- and BTC-induced survival signaling.²⁰ SAR256212 activity has been evaluated in a broad range of preclinical tumor xenograft models.²¹

The clinical significance of these findings is currently under investigation.

SAR256212 | Sanofi Oncology Pipeline

http://www.sanofioncology.com › Our Pipeline

SAR256212 (MM-121). SAR256212 (MM-121) HER3 ErbB3 antibody. Targeting ErbB3. ErbB3 is a kinase-dead critical mediator of pro-survival signaling …

VIDEO...http://www.sanofioncology.com/pipeline/SAR256212.aspx

 

Clinical development

SAR256212 is being codeveloped with Merrimack Pharmaceuticals Inc. SAR256212 is currently being investigated in a phase I trial in patients with refractory advanced solid tumors; in a phase I/II trial, in combination with erlotinib, in patients with NSCLC; in a phase I trial in combination with the investigational agent SAR245408 in solid tumors; in a phase I trial in combination with cetuximab and irinotecan in solid tumors; and in a phase I trial in combination with multiple chemotherapeutic agents in solid tumors. SAR256212 is also being investigated in a phase II trial in ER/PR+ HER2- breast cancer patients in combination with exemestane. In combination with paclitaxel, SAR256212 is being studied in a phase II trial in ER/PR+ HER2- breast cancer and TNBC, and a phase II trial in platinum-resistant/refractory ovarian cancer.

ER=estrogen receptor; HER2=human epidermal growth factor receptor 2; PR=progesterone receptor; TNBC=triple negative breast cancer.

SAR256212 is an investigational agent and has not been approved by the FDA or any other regulatory agency worldwide for the uses under investigation

ErbB3 is a critical activator of phosphoinositide 3-kinase (PI3K) signaling in epidermal growth factor receptor (EGFR; ErbB1), ErbB2 [human epidermal growth factor receptor 2 (HER2)], and [hepatocyte growth factor receptor (MET)] addicted cancers, and reactivation of ErbB3 is a prominent method for cancers to become resistant to ErbB inhibitors. In this study, we evaluated the in vivo efficacy of a therapeutic anti-ErbB3 antibody, MM-121. We found that MM-121 effectively blocked ligand-dependent activation of ErbB3 induced by either EGFR, HER2, or MET. Assessment of several cancer cell lines revealed that MM-121 reduced basal ErbB3 phosphorylation most effectively in cancers possessing ligand-dependent activation of ErbB3. In those cancers, MM-121 treatment led to decreased ErbB3 phosphorylation and, in some instances, decreased ErbB3 expression. The efficacy of single-agent MM-121 was also examined in xenograft models. A machine learning algorithm found that MM-121 was most effective against xenografts with evidence of ligand-dependent activation of ErbB3. We subsequently investigated whether MM-121 treatment could abrogate resistance to anti-EGFR therapies by preventing reactivation of ErbB3. We observed that an EGFR mutant lung cancer cell line (HCC827), made resistant to gefitinib by exogenous heregulin, was resensitized by MM-121. In addition, we found that a de novo lung cancer mouse model induced by EGFR T790M-L858R rapidly became resistant to cetuximab. Resistance was associated with an increase in heregulin expression and ErbB3 activation. However, concomitant cetuximab treatment with MM-121 blocked reactivation of ErbB3 and resulted in a sustained and durable response. Thus, these results suggest that targeting ErbB3 with MM-121 can be an effective therapeutic strategy for cancers with ligand-dependent activation of ErbB3.

Cancer Res. 2010 Mar 15;70(6):2485-94. doi: 10.1158/0008-5472.CAN-09-3145. Epub 2010 Mar 9.

An ErbB3 antibody, MM-121, is active in cancers with ligand-dependent activation.

Schoeberl B¹, Faber AC, Li D, Liang MC, Crosby K, Onsum M, Burenkova O, Pace E, Walton Z, Nie L, Fulgham A, Song Y, Nielsen UB, Engelman JA, Wong KK.

Author information

• ¹Merrimack Pharmaceuticals, Inc, Cambridge, Massachusetts, USA.

Angiogenesis is a valid target in the treatment of epithelial ovarian cancer. Trebananib inhibits the binding of angiopoietins 1 and 2 to the Tie2 receptor, and thereby inhibits angiogenesis. We aimed to assess whether the addition of trebananib to single-agent weekly paclitaxel in patients with recurrent epithelial ovarian cancer improved progression-free survival.

Lancet Oncol. 2014 Jun 17. pii: S1470-2045(14)70244-X. doi: 10.1016/S1470-2045(14)70244-X.

http://www.ncbi.nlm.nih.gov/pubmed/24950985

old cut paste

Amgen’s Experimental Ovarian Cancer Drug, Trebananib, Shows Positive Results In Late Stage Clinical Trials

June 13, 2013 8:13 am

Takeda Pharmaceutical

by

Dr. Rainer Steinbach

Rainer studied chemistry and economics in Germany (Bonn, Marburg) and did postdoctoral work at Stanford University (CA, USA). He held various positions (R&D, Market Research, Marketing, Strategic Planning, Sourcing, etc) while working at Rütgers, Novartis, Syngenta, SK, Clariant, Archimica. His international background (he worked out of Belgium, Germany, Italy, Switzerland and the USA) combined with broad experience gained in China and India (he audited more than 200 companies) is the foundation of CAP INTELLIGENCE.

Dr Rainer Steinbach of CAP Intelligence profiles Japan’s most global drugs firm

Takeda is the largest Asian pharmaceuticals company. The company started as early as 1977 to establish major co-operations with Western firms. As a result, it has the most global orientation amongst Japanese pharmaceutical companies. The latest major acquisition, Nycomed, is part of this globalisation strategy.

History

Takeda dates back to 1781, when Chobei Takeda started selling Japanese and Chinese traditional medicines. In 1895, the firm started the first production of pharmaceuticals in Osaka. Research activities started in 1914 and in 1944 fermentation activities were added.

In 1981, the antibiotics Takesulin and Pansporin were launched in Japan. In 1985, Takeda formed TAP Pharmaceuticals, a 50:50 joint venture (JV) in the US with Abbott Laboratories. TAP began marketing the prostate cancer treatment leuprorelin (Lupron) in the same year. 1997 saw the launch in Europe of candesartan celexetil (Blopress/Kensen), an anti-hypertensive agent which is also marketed by AstraZeneca.

In 2008, Takeda acquired Millennium Pharmaceutical of Cambridge, Massachusetts, an oncology research specialist, for $8.8 billion. Larger still was the acquisition of Swiss company Nycomed for €9.6 billion ($13.3 billion) in 2011, not including Nycomed’s US-based dermatological business. Nycomed had itself grown substantially by acquiring the pharmaceuticals interests of Altana in Germany and Bradley Pharmaceuticals in 2007.

The acquired parts of Nycomed had revenues of about €2.84 billion in 2011 and a workforce of about 11,800 employees, plus production locations in 11 countries worldwide. Its revenues were mainly in Europe (48%), Russia (17%) and Latin America (13%), plus other emerging markets. The acquisition also gained Takeda access to romiflumast (Daliresp), a new drug against chronic obstructive pulmonary disease.

In 2012, Takeda acquired URL Pharma, a privately owned company headquartered in Philadelphia and employing about 500, for an upfront payment of $800 million and future performance-based contingent earn out payments. URL’s 2011 revenues amounted of nearly $600 million, over two thirds coming from colchicine (Colcrys), which is used to treat and prevent gout flares. URL Pharma was sold to Sun Pharma in January 2013.

Table 1 – Locations of Takeda sites

Structure

Takeda is a public share company that is listed at the Tokyo and Osaka stock exchange, with the ticker symbol 4502. The main shareholders are financial institutions (33%), foreign investors (30%), some 280,000 individuals (27%) security companies and others (10%). The three biggest single shareholders are Nippon Life Insurance, with 7.1%, Japan Trustee Services Bank (4.4%) and the Master Trust Bank of Japan (4.3%).

The company is headquartered in Osaka, with its European headquarters in London and the American one headquarters Deerfield, Illinois. It has 17 manufacturing sites and three JV manufacturing sites, the most important of which are listed in Table 1. It employs a global workforce of about 30,500. Regional data about this are not published, apart from in Japan itself. CAP Intelligence estimates the workforce split as 31% in Japan, 30% in Europe, 25% in the USA and 14% in the rest of the world.

As of today, the Takeda Group has 61 consolidated companies and 14 affiliates. Major subsidiaries include: Takeda Nycomed Pharmaceuticals, Takeda Europe Holdings (Amsterdam), Takeda USA Holdings (New York), Millennium Chemicals (Cambridge, Massachusetts), Nihon Pharmaceutical, Wako Pure Chemicals and Mizuzawa Industrial Chemicals (all Japan) and Tianjin Takeda Pharmaceuticals (China).

Takeda’s financial year starts on April 1 and ends on March 31. The company’s financial results are reported in Yen, but are given here in US dollars for ease of comparison with other profiled firms. Figure 1 shows revenues, EBITDA, operating income and net earnings for the years since 2002.

In the year to March 2013, earnings fell by 13.3% to $16.57 billion, but EBITDA was up by 6.1% to $5.52 million and operating income was 27.4% up to $4.28 billion while earnings more than doubled to $3.48 million. Consequently, the net profit margin shot up from the 8% mark in the previous two years to 21.2%.

Figure 1 - Takeda’s revenues & profits ($ billion), 2011-2013 fiscal years

Main activities

Takeda is overwhelmingly focused on ethical products, which account for 90% of its revenues. Within this, cardiovascular and metabolic therapies account for 74%, followed by oncology with 13.5% and inflammatory with the other 2.5%. The remainder of its revenues is split between consumer healthcare products, including cold remedies and vitamin-containing products (4%), and others (6%). The company’s five best selling products account for close to $10 billion in sales, more than half of the total (Figure 2).

Sales are 47% in Japan, 23% in North America, 16% in Europe, 4% each in the rest of Asia, Russia and the CIS and Latin America and 2% in the rest of the world. As the Japanese market will not deliver major growth opportunities, the company’s objective is to be strongly present in emerging markets, especially China and Russia. Sales and marketing efforts have been intensified to this end. In fiscal 2012, Takeda all started an e-commerce website for direct selling in Japan called the Takeda Online Shop as part of the consumer healthcare business.

Takeda’s stated vision is “to embody global pharmaceutical leadership through innovation, culture, and growth, guided by an unwavering commitment to significantly improve the lives of patients”. Its strategy includes:

• A strong focus on emerging markets
• An improved presence in China and Korea
• The integration of Nycomed and reducing over-reliance on the Japanese and American markets
• Leveraging Nycomed’s strength in emerging markets to drive growth and combine the strength of both companies
• Securing a top market share by establishing new products and maximising the sales of the existing portfolio
• Concentration of management resources into new core therapeutic areas of metabolic and cardiovascular disease, oncology and diseases of the central nervous system (CNS), plus exploring further immunology and inflammatory medications
• Increasing promotional efficiency
• Making strategic investments actively and flexibly, while pursuing all opportunities, including M&A, product acquisition and the introduction of pipeline drugs

Takeda is one of the few Japanese pharmaceuticals companies that have a truly global presence. Because of this, in addition to its Japanese competitors, such as Astellas, Eisai, Mitsubishi, Otsuka, Shionogi, Taiho and Teijin, it also competes with all the major international companies, including generics companies. The strongest competitors in its main area of cardiovascular and metabolic drugs are AstraZeneca, Bayer, Bristol-Myers Squibb (BMS), Boehringer Ingelheim (BI), Daiichi Sankyo, Dainippon Sumitomo, Merck & Co., Novartis, Pfizer and Sanofi.

Table 2 – Takeda’s leading brands by sales, 2010-2013 fiscal years

R&D structure

About 6,000 Takeda employees work in R&D. In 2012-2013, the company invested more than $3.9 billion in R&D, almost 21% of total revenues. It has R&D sites in: Osaka and Fujisawa in Japan; Palo Alto, San Diego, Deerfield, Cambridge, Bozeman and Fort Collins in the US; Cambridge and London, UK; Roskilde, Denmark; Konstanz, Germany; Singapore; Guangzhou, China; and, Sao Jerônimo in Brazil.

Following the opening of the new drug discovery research centre, the Shonan Research Centre in Osaka, a new R&D structure was implemented in early 2011, creating ‘Drug Discovery Units (DDUs)’, with research functions around each of the four core research activities of metabolic diseases, oncology, CNS-related diseases and inflammatory diseases.

In addition, R&D alliances continue to form a key part of Takeda’s strategy. This has included alliances with Advinus Therapeutics in India, Seattle Genetics, Sage Bionetworks, Xoma and Zinfandel Pharma in the US and BC Cancer Agency in Canada. The company has stated that R&D expenditure over the next three years will be divided as follows between different therapeutic areas: oncology 31%, cardiovascular and metabolic 27%, CNS 14%, immunology and respiratory 12%, general medicine and vaccines 16%.

Clinical development

As of July 2013, Takeda had more than 40 products in clinical development, with the main emphasis on cardiovascular and metabolic indications and oncology. These comprised 14 compounds in Phase I, six (all NMEs) in Phase II and 12 (including seven NMEs) in Phase III.

Eight products, including three NMEs, had been submitted for approval and submissions had been filed for: vedolizumab, a monoclonal antibody developed to treat Crown’s disease and ulcerative colitis (Figure 2a); vortioxetine an anti-depressant co-developed with Lundbeck to treat generalised anxiety disorder; and, BLB-750, a vaccine developed to prevent pandemic influenza. Amongst the developmental drugs in Phase III are:

• Alisertib (MLN8237, Figure 2b), a developmental kinase inhibitor to treat non-small lung cancer, breast cancer, ovarian cancer and T-cell lymphoma
• Fasiglifam (TAK-875, Figure 2c), an experimental drug against diabetes mellitus, belonging to the group of fatty acid receptor agonists
• Ixazomib (MLN7908, Figure 2d), a protease inhibitor developed to treat multiple myeloma and relapsed primary amyloidosis
• Orteronel (TAK 700, Figure 2e), an experimental non-steroidal proteasome inhibitor developed to treat prostate cancer
• Trebananib (AMG 386), a developmental antineoplastic immunoglobulin that is being co-developed with Amgen
• Trelagliptin (SYR-472, Figure 2f), a long-acting dipeptidyl peptidase-4 inhibitor developed to treat Type 2 diabetes
• Vonoprazan (TAK-438, Figure 2g) an acid blocker developed to treat peptic ulcer and other acid-related diseases

Figure 3 – Pipeline drugs at Takeda

Key products

The main market products from Takeda have already been listed above in Table 2. The five most important by sales in the most recent fiscal year are as follows in alphabetical order, with the generic name first and the brand name in brackets after. Further information about the rest of the portfolio is available from CAP Intelligence.

Bortezomib (Velcade, Figure 3a) belongs to the class of targeted intra-cellular tumour therapeutics. It was the first therapeutic protease inhibitor ever approved and was originally developed by Myogenics, a company that was sold to Leukosite. This firm was in turn acquired by Millennium, which ultimately became part of Takeda.

Amongst others, bortezomib is approved against multiple myeloma and mantle cell lymphoma. Chemically, it is an N-protected dipeptide. The protection group contains a boron atom which binds the catalytic site of the 26S proteasome that regulates protein expression. Bortezomib is co-marketed with Johnson & Johnson (J&J) under the same trade name Velcade. Pharmstandard markets it in Russia.

Depending on the specific indication multiple myeloma, competing drugs include: other targeted tumour therapeutics, such as lenalidomide (Revlimid), pomalidomide (Pomast) and thalidomide (Thalidomide), all by Celgene; enzyme inhibitors, such as carfilzomib (Kyprolix by Onyx); and, topomerase inhibitors, such as doxorubicin (Doxil/Caelyx) by J&J.

Candesartan (Blopress/Kensen, Figure 3b) belongs to the class of angiotensin II receptor antagonists (ARBs) or ‘sartans’, which are chemically 2-tetrazoylbiphenyl derivatives. The drug is used for treatment of hypertension (high blood pressure). Depending on the specific indication, competing drugs include:

• Other sartans, such as irbesartan (Avarpro/Avalide by BMS, Approvel by Sanofi or Irbetan by Shionogi), olmesartan (Olmetec by Daiichi Sankyo), telmisartan (Micardis by BI) and valsartan (Diovan by Novartis)
• Angiotensin-converting enzyme inhibitors  or ‘prils’, such as benazepril (Lotensin by Novartis), captopril (Capoten by BMS), enalapril (Vasotec by Merck & Co.), fosinopril (Monopril by BMS), lisinopril (Prinivil by Merck & Co., Zestril by AstraZeneca), perindopril (Coversyl by Servier), quinapril (Accupril by Pfizer), ramipril (Tritace by Sanofi, Altace by King), zofenopril (Zofenopril, Zopranol or Zantipres by Menarini)
• Renin inhibitors or ‘kirens’, such as aliskiren (Tekturna/Rasilez by Novartis)
• Drugs from other classes, such as calcium channel blockers

Figure 3 – Key market products by Takeda

Lansoprazole (Takepron/Ogast/Lansox, Figure 4c) belongs to the sub-group or proton pump inhibitors (PPIs) or ‘prazoles’ in the class of drugs for acid-related disorders. PPIs reduce acid secretion by inhibiting the enzyme ATPase in gastric parientel cells.

Lansoprazole is used to treat stomach ulcers, peptic ulcers and gastroesophagal reflux. The originator drug is marketed by Takeda but is now generic, being marketed as Lansul and Lansoptol by Krka, Lansopran by Sawai and Opiren by Almirall and as an over-the-counter drug by Novartis under the name Prevacid 24H. Depending on the specific indication, lansoprazole competes with:

• Other PPIs, such as dexlansoprazole (Dexilant Takeda), Nexium by AstraZeneca, omeprazole (Losec and Prilosec, also by Astra Zeneca, plus generic versions), pantoprazole (by Nycomed) and rabeprazole (Aciphex and Pariet by J&J)
• H2-antagonists (‘tidines’), such as cimetidine (Tagamet by Glaxo Smithkline (GSK)), famotidine (Pepicidine and Pepcid by J&J and Merck & Co., Gaster by Astellas, loratidine (Claritin by Schering Plough and Shionogi), nizatidine (Tazac by Eli Lilly), ranitidine (Zantac by GSK)
• Prostaglandins or ‘prosts’, such as misoprostol (Cytotex by Pfizer)
• Non-classified drugs, such as repabimide (e.g. Mucosta by Otsuka), teprenone (Seftac by Sawai, Selbex by Eisai), etc.

Leuprorelin (Leuplin/Enatoe, Figure 3d) is an analogue to the gonadotropin-releasing hormone (GnRH) and acts as agonist at pituitary GnRH receptors. It regulates down the secretion of gonadotropins-luteinizing hormones (LHs) and follicle-stimulating hormones (FSHs), reducing estradiol and testosterone levels in both sexes.

Leuprolin is marketed by various companies, such as Eligard by Sanofi and Astellas and Vidadur by Bayer. Competing GnRH medications include goserelin (Zalodex by AstraZeneca), buserelin (Suprefact by Sanofi), histrelin (Vantas and Supprelin by Elan), triptorelin (Decapentyl by Ipsen, Gonapeptyl by Ferring, Trelstar by Watson), deslorelin (Ovuplant by Peptech) and nafarelin (Synarel by Pfizer).

Pioglitazone (Actos/Glustin/Zanctos, Figure 3e) belongs to the sub group of insulin sensitisers in the class of anti-diabetic drugs. These work against the core problem of Type II diabetes, insulin resistance. In India, the drug is marketed by Zydus Cadila. Depending on the specific indication, competing drugs include:

• Insulin sensitisers, such as metformin (e.g. Glucophage by Merck & Co. or Daiichi Sankyo; Glycoran by Nippon Shinyaku; Metgluco/Melbin by Dainippon Sumitomo, etc.) and ‘glitazones’, such as rosiglitazone (Avandia by GSK)
• Insulin secretagogues, which trigger the release of insulin by inhibiting the K-ATPase channel of the pancreatic beta cells, including sulfonyl ureas, such as glimeripide (Amaryl by Sanofi), glipizide (Gluctrol by Pfizer), gliclazide (Diamicron Servier), glibenclamide (e.g. Glimel by Dong-A), etc; meglitinides or ‘glinides’, such as nateglinide (e.g. Starlix by Par), repaglinide (e.g. Prandin by Novo Nordisk), glucagon-like peptide 1 analogues, such as exenatide (Byetta/Bydurone by Amylin and Eli Lilly), liraglutide (Victoza by Novo Nordisk) and lixenatide (Lyxumia by Sanofi); and, dipeptidyl dipetidase-4 inhibitors, such as linagliptin (Trajenta by Eli Lilly and BI), sitagliptin (Januvia by Merck), saxagliptin (Onglyza by AstraZeneca and BMS), vidagliptin (Galvus by Novartis), etc.
• Insulin analogues, including long-acting insulins, such as insulin glargine (Lantus by Sanofi) and insulin detemir (Levemir by Novo Nordisk), and short-acting insulins, such as insulin lispro (Humalog by Eli Lilly) or insulin glulisine (Apidra by Sanofi), etc.
• Alpha-glucosidase inhibitors, such as acarbose (Glucobay by Bayer), miglitol (Diastabol by Sanofi), voglibose (Basen by Takeda) and other non-classified drugs
• Sodium-glucose transport protein inhibitors, such as canaglifozin (Invokanna by Jansssen) and empaglifozin, which is under investigation by Eli Lilly and BI
• Amylin analogues, such as pramlintide (Symlin by Amylin)

 http://www.specchemonline.com/articles/view/takeda-pharmaceutical#.U6fUjUCs_yV

Contact:

Dr Rainer Steinbach
CEO
CAP Intelligence
Tel: +49 231 73 56 84
E-mail: rainer.steinbach@cap-intelligence.de
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AZD 6564

SYNTHESIS SUPP INFO…..http://pubs.acs.org/doi/suppl/10.1021/ml400526d/suppl_file/ml400526d_si_001.pdf

NMR PG 16/32 AS ABOVE

R1 = NEOPENTYL R2=H

5-[(2R,4S)-2-(2,2-Dimethylpropyl)piperidin-4-yl]-1,2-oxazol-3(2H)-one

5-((2R,4S)-2-Neopentylpiperidin-4-yl)isoxazol-3(2H)-one

238.326

C13 H22 N2 O2

Antifibrinolytics

AstraZeneca (Innovator)

SYNTHESIS SUPP INFO…..http://pubs.acs.org/doi/suppl/10.1021/ml400526d/suppl_file/ml400526d_si_001.pdf

NMR PG 16 0F 32

……………………..

Discovery of the fibrinolysis inhibitor AZD6564, acting via interference of a protein – Protein interaction
ACS Med Chem Lett 2014, 5(5): 538

http://pubs.acs.org/doi/abs/10.1021/ml400526d

A class of novel oral fibrinolysis inhibitors has been discovered, which are lysine mimetics containing an isoxazolone as a carboxylic acid isostere. As evidenced by X-ray crystallography the inhibitors bind to the lysine binding site in plasmin thus preventing plasmin from binding to fibrin, hence blocking the protein–protein interaction. Optimization of the series, focusing on potency in human buffer and plasma clotlysis assays, permeability, and GABAa selectivity, led to the discovery of AZD6564 (19) displaying an in vitro human plasma clot lysis IC₅₀ of 0.44 μM, no detectable activity against GABAa, and with DMPK properties leading to a predicted dose of 340 mg twice a day oral dosing in humans.

SUPP INFO…..http://pubs.acs.org/doi/suppl/10.1021/ml400526d/suppl_file/ml400526d_si_001.pdf

 

Step 9: 5,((2R,4S),2,Neopentylpiperidin,4,yl)isoxazol,3(2H),one

Starting from (2R,4S),methyl 2,neopentyl,4,(3,oxo,2,3,dihydroisoxazol,5,

yl)piperidine,1,

carboxylate (0.8 g, 2.7 mmol) and following the procedure described in 15, Step8

the title

compound was obtained (0.44 g, 69 %):

1H NMR (600 MHz, DMSO,d6) δ 0.92 (s, 9H), 1.11 –1.34 (m, 3H), 1.35 – 1.46 (m, 1H), 1.79 – 1.98 (m, 2H), 2.65 – 2.93 (m, 3H),

3.03 – 3.14 (m,1H), 5.74 (s, 1H);13C NMR (101 MHz, CH4,d4) δ 177.39, 174.72, 95.42, 54.83, 49.32, 45.50,

37.13, 34.75, 31.19, 30.07, 28.06;

[α]20D+43.8 (MeOH/H2O 1:1, c = 1); HRMS calculated for[C13H23N2O2]+: 239.1759; found: 239.1753

………………………
http://www.google.com/patents/EP2417131A1?cl=en

Compounds of formula I- V may be prepared by the following route:Scheme A. Preparation of intermediatesMETHOD A

O

L C^O”

 

METHOD B

O

 

METHOD C

 

METHOD D

RIB(OR)₂

 

X = Cl, Br

 

METHOD E

METHOD F

METHOD G

 

R1 = 1-methyl-1 H-tetrazol-5-yl and 2-methyl-2H-tetrazol-5-yl

Scheme B. Formation of 5-isoxazol-3-ones

°Y I ‘relative

°Y J ‘relative

………………….

http://www.google.com/patents/EP2417131A1?cl=en

Example 14

5-((2R,4S)-2-Neopentylpiperidin-4-yl)isoxazol-3(2H)-one

Step 1 : Cis-methyl 2-neopentyl-4-(3-oxo-23-dihvdroisoxazol-5-yl)piperidine-l-carboxylate The compound was prepared as described in Example 1, Step 2 starting from cis-methyl 4-(3- ethoxy-3-oxopropanoyl)-2-neopentylpiperidine-l -carboxylate (2.68 g, 8.19 mmol) which resulted in cis-methyl 2-neopentyl-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-l- carboxylate (1.60 g, 66 %) : IH NMR (400 MHz, cdcl3) δ 0.89 (s, 9H), 1.18 (dd, IH), 1.45 (dd, IH), 1.80 – 1.92 (m, 2H), 1.97 – 2.17 (m, 2H), 2.94 – 3.02 (m, IH), 3.11 – 3.23 (m, IH), 3.71 (s, 3H), 3.88 – 3.99 (m, IH), 4.22 – 4.32 (m, IH), 5.72 (s, IH); m/z (MH⁺) 297.

Step 2: (2R,4S)-Methyl 2-neopentyl-4-(3-oxo-2,3-dihvdroisoxazol-5-yl)piperidine-l- carboxylate

Following the procedure described in Example 1, Step 3, racemic cis-methyl 2-neopentyl-4- (3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-l -carboxylate (1.60 g, 5.4 mmol) was subjected to chiral separation using Chiralcel IC mobile phase heptane/IP A/FA 60/40/0.1 which resulted in (2R,4S)-methyl 2-neopentyl-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-l-carboxylate (0.8 g, 2.7 mmol).

Step 3: 5-((2R,4S)-2-Neopentylpiperidin-4-yl)isoxazol-3(2H)-one

5 Starting from (2R,4S)-methyl 2-neopentyl-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-l- carboxylate (0.8 g, 2.7 mmol) and following the procedure described in Example 1, Step 4 the title compound was obtained (0.44 g, 69 %): ¹H NMR (600 MHz, DMSO-d6) δ 0.89 (s, 9H), 1.18 (m, 2H), 1.50 (m, 2H), 1.82-1.90 (m, 2H), 2.70-2.85 (m, 3H), 3.08 (m, IH), 5.71 (s, IH). [α]²⁰ _D +43.8 (MeOH/H₂O 1:1, c = 1); HRMS calculated for [C₁₃H₂₃N₂O₂]+: 239.1759; found: 10 239.1753.

–

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The award, established in 2005 by the Kiel Institute, is bestowed upon individuals who have been pioneers in finding solutions to global economic problems.
BANGALORE: Biotech major Biocon today said its Chairperson and Managing Director Kiran Mazumdar-Shaw has been awarded the Kiel Institute’s most coveted ’2014 Global Economy Prize’ for Business.

She was honoured at the institute’s 100th anniversary celebrations at Kiel in Germany.

The award, established in 2005 by the Kiel Institute, is bestowed upon individuals who have been pioneers in finding solutions to global economic problems by strongly influencing and implementing eco ..

With Prof. Thaler and President Sirleaf — in Kiel, Germany.

http://economictimes.indiatimes.com/news/news-by-company/corporate-trends/biocon-chief-kiran-mazumdar-shaw-receives-kiel-institutes-2014-global-economy-prize/articleshow/37076858.cms

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Signed register at the Kiel Institute. — in Kiel, Germany.