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DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO .....FOR BLOG HOME CLICK HERE

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ORGANIC SPECTROSCOPY

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

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

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Daiichi Sankyo Receives Approval in Japan for Manufacture and Marketing of PRALIA ®


Daiichi Sankyo Receives Approval 25 mar 2013, in Japan for Manufacture and Marketing of PRALIA ® for the osteoporosis treatment PRALIA ®subcutaneous injection 60mg syringe (INN: Denosumab; genetic recombination) for the treatment of osteoporosis.

Denosumab[1] is a fully human monoclonal antibody for the treatment of osteoporosis, treatment-induced bone loss, bone metastases, rheumatoid arthritis, multiple myeloma, and giant cell tumor of bone.[2][3] It was developed by the biotechnology company Amgen.[4]
Denosumab is designed to inhibit RANKL (RANK ligand), a protein that acts as the primary signal for bone removal. In many bone loss conditions, RANKL overwhelms the body’s natural defenses against bone destruction.
In June 2010, denosumab was approved by the U.S. Food and Drug Administration (FDA) for use in postmenopausal women with risk of osteoporosis under the trade name Prolia,[5] and in November 2010, as Xgeva, for the prevention of skeleton-related events in patients with bone metastases from solid tumors.[6] Denosumab is the first RANKL inhibitor to be approved by the FDA.[7] In the summer of 2011 clinical trials were investigating denosumab in giant cell tumors, multiple myeloma with bone metastases, and hypercalcemia of malignancy, and further investigating its dosing and safety.[8]

  1. Pageau, Steven C. (2009). “Denosumab”MAbs 1 (3): 210–215. doi:10.4161/mabs.1.3.8592PMC 2726593.PMID 20065634.
  2. McClung, Michael R.; Lewiecki, E. Michael; Cohen, Stanley B.; Bolognese, Michael A.; Woodson, Grattan C.; Moffett, Alfred H.; Peacock, Munro; Miller, Paul D. et al. (2006). “Denosumab in Postmenopausal Women with Low Bone Mineral Density”. New England Journal of Medicine 354 (8): 821–31. doi:10.1056/NEJMoa044459PMID 16495394.
  3.  Ellis, G. K.; Bone, H. G.; Chlebowski, R.; Paul, D.; Spadafora, S.; Smith, J.; Fan, M.; Jun, S. (2008). “Randomized Trial of Denosumab in Patients Receiving Adjuvant Aromatase Inhibitors for Nonmetastatic Breast Cancer”. Journal of Clinical Oncology 26 (30): 4875–82. doi:10.1200/JCO.2008.16.3832.PMID 18725648.
  4. “Prolia (denosumab)”Products. Amgen. Retrieved 6 May 2012.
  5. Matthew Perrone (June 2, 2010). “FDA clears Amgen’s bone-strengthening drug Prolia”. BioScience Technology.
  6.  “Amgen’s Denosumab Cleared by FDA for Second Indication”. 19 Nov 2010.
  7.  “FDA Approves Denosumab for Osteoporosis”. 2 June 2010.
  8.  Russell S. Crawford, BPharm; Morgane C. Diven, PharmD; Laura Yarbro, PharmD (2011). “Denosumab: A Review of Its Pharmacology and Clinical Implications”Contemporary Oncology 3 (1).
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MHLW, sNDA, JAPAN, Daiichi Sankyo has received approval for Anticancer Agent irinotecan hydrochloride hydrate


Irinotecan (Camptosar, Pfizer; Campto, Yakult Honsha) is a drug used for the treatment of cancer.

Irinotecan prevents DNA from unwinding by inhibition of topoisomerase 1. In chemical terms, it is a semisynthetic analogue of the natural alkaloid camptothecin.

Its main use is in colon cancer, in particular, in combination with other chemotherapy agents. This includes the regimen FOLFIRI, which consists of infusional 5-fluorouracil,leucovorin, and irinotecan.

Irinotecan received accelerated approval by the U.S. Food and Drug Administration (FDA) in 1996[1] and full approval in 1998.[2] During development, it was known as CPT-11.

Daiichi Sankyo has received  new approvals from MHLW today 25 MAR 2013
for a supplemental new drug application (sNDA) for an additional indication for Topotecin® intravenous drip infusion 40 mg and 100 mg (irinotecan hydrochloride hydrate) for pediatric malignant solid tumor to Japan’s Ministry of Health, Labor and Welfare.

Japan, Shionogi Receives Marketing and Manufacturing Approval of a Drug for Lipodystrophy,METRELEPTIN for Subcutaneous Injection


Leptin

Metreleptin, an analog of the human hormone leptin, is a unique potential therapy for certain metabolic disorders in patients with rare forms of inherited or acquired lipodystrophy. Lipodystrophy is a very rare condition characterized by loss of subcutaneous fat.

Shionogi & Co., Ltd. today announced that it received marketing and manufacturing approval of recombinant human leptin, “METRELEPTIN for subcutaneous injection 11.25 mg ‘SHIONOGI'”
(generic name: metreleptin) for lipodystrophy on March 25,2013 in Japan.
Metreleptin was in-licensed by Shionogi from US-based AmylinPharmaceuticals, LLC., a subsidiary of Bristol-Myers Squibb Company currently.

Metreleptin is being studied as a potential therapy for certain metabolic disorders in patients with inherited or acquired lipodystrophy. Metreleptin is believed to work by reducing fat accumulation in organs, caused by the disease, thereby improving insulin sensitivity. Clinical studies have been conducted by investigators at the National Institutes of Health (NIH) and other academic institutions in the US, Europe, and Japan to determine whether metreleptin can improve glycemic control and hypertriglyceridemia in patients with lipodystrophy.

In April 2012, Amylin completed its Biologics License Application (BLA) for metreleptin to treat diabetes and/or hypertriglyceridemia (high levels of triglycerides in the bloodstream) in patients with rare forms of lipodystrophy and requested Priority Review by the FDA.

If approved, metreleptin would be the first therapy indicated specifically for the treatment of diabetes and/or hypertriglyceridemia in patients with inherited or acquired lipodystrophy, and the first approved therapeutic use of a leptin analog.

About Lipodystrophy

Lipodystrophy is a life-threatening, “ultra orphan” rare disease that is estimated to impact a few thousand people worldwide, often with an early age of onset, for which there is a significant unmet medical need. There are currently no approved drugs that treat the underlying cause of the disease.

Fat tissue is a major endocrine organ producing important metabolic hormones such as leptin. People with lipodystrophy lack the required fat tissue for normal metabolic function. This can be partial, affecting select areas of the body, or generalized, affecting nearly the entire body. A lack of fat tissue can lead to relative deficiency of leptin.

Without adequate leptin function, the metabolic system, which regulates food intake and the storage and break-down of dietary fat and carbohydrates, falls out of balance. As a result, fat accumulates in the blood and organs such as liver and muscle, which can lead to life-threatening complications including insulin-resistant diabetes, hypertriglyceridemia (high levels of triglycerides in the bloodstream), acute pancreatitis, and hepatic steatosis or steatohepatitis, also known as fatty liver disease. There are no approved drugs that address the underlying relative leptin deficiency that is believed to contribute in large part to the metabolic abnormalities that occur in lipodystrophy. Currently available therapies for diabetes and hypertriglyceridemia are often rendered marginally effective due to the severity of the condition.

NOVARTIS TOBI Podhaler receives FDA approval for cystic fibrosis patients with Pseudomonas aeruginosa


Tobramycin

MAR 22.2013, FDA approves TOBI Podhaler to treat a type of bacterial lung infection in cystic fibrosispatients

The U.S. Food and Drug Administration today approved TOBI Podhaler (tobramycininhalation powder) for the management of cystic fibrosis patients with Pseudomonas aeruginosa, a bacterium that causes lung infections.

Cystic fibrosis is a genetic disease that affects about 30,000 pediatric and adult patients in the United States. Cystic fibrosis causes the body to produce thick, sticky mucus that builds up in the lungs and blocks airways. The buildup of mucus makes it easy for bacteria like P. aeruginosa to grow and cause a chronic lung infection that, over time, can severely damage the lungs. Many patients with cystic fibrosis are treated with antibiotics using a nebulizer machine.

Tobramycin is an aminoglycoside antibiotic derived from Streptomyces tenebrarius and used to treat various types of bacteria infections, particularly Gram-negative infections. It is especially effective against species of Pseudomonas.

TOBI Podhaler, a plastic, handheld inhaler device, contains a dry powder formulation of tobramycin, an antibiotic used to treat P. aeruginosa infection. The powder is inhaled twice daily using the Podhaler device for 28 days. Patients should then stop TOBI Podhaler therapy for 28 days before resuming again.

“Today’s approval broadens the available delivery mechanism options for patients withcystic fibrosis who require treatment for P. aeruginosa,” said Edward Cox, M.D., M.P.H, director of the Office of Antimicrobial Products in the FDA’s Center for Drug Evaluation and Research. “This product is the first dry powder antibacterial drug delivered with a handheld dry powder inhaler.”

Florbetaben (18F), FDA and EMA accept NDA and MAA for Piramal‘s Alzheimer’s imaging agent


Florbetaben (18F)

PHOTO CREDIT-KEGG

902143-01-5 cas no

(18F-AV-1/ZK; BAY-94-9172; 18F-BAY-94-9172; ZK-6013443)

Mr Ajay Piramal, Chairman, Piramal Healthcare

Imaging with amyloid-β PET can potentially aid the early and accurate diagnosis of Alzheimer’s disease. Florbetaben (¹⁸F) is a promising ¹⁸F-labelled amyloid-β-targeted PET tracer in clinical development. We aimed to assess the sensitivity and specificity of florbetaben (¹⁸F) PET in discriminating between patients with probable Alzheimer’s disease and elderly healthy controls.

METHODS:

We did a multicentre, open-label, non-randomised phase 2 study in 18 centres in Australia, Germany, Switzerland, and the USA. Imaging with florbetaben (¹⁸F) PET was done on patients with probable Alzheimer’s disease (age 55 years or older, mini-mental state examination [MMSE] score=18-26, clinical dementia rating [CDR]=0·5-2·0) and age-matched healthy controls (MMSE ≥ 28, CDR=0). Our primary objective was to establish the diagnostic efficacy of the scans in differentiating between patients with probable disease and age-matched healthy controls on the basis of neocortical tracer uptake pattern 90-110 min post-injection. PET images were assessed visually by three readers masked to the clinical diagnosis and all other clinical findings, and quantitatively by use of pre-established brain volumes of interest to obtain standard uptake value ratios (SUVRs), taking the cerebellar cortex as the reference region. This study is registered with ClinicalTrials.gov, number NCT00750282.

FINDINGS:

81 participants with probable Alzheimer’s disease and 69 healthy controls were assessed. Independent visual assessment of the PET scans showed a sensitivity of 80% (95% CI 71-89) and a specificity of 91% (84-98) for discriminating participants with Alzheimer’s disease from healthy controls. The SUVRs in all neocortical grey-matter regions in participants with Alzheimer’s disease were significantly higher (p < 0·0001) compared with the healthy controls, with the posterior cingulate being the best discriminator. Linear discriminant analysis of regional SUVRs yielded a sensitivity of 85% and a specificity of 91%. Regional SUVRs also correlated well with scores of cognitive impairment such as the MMSE and the word-list memory and word-list recall scores (r -0·27 to -0·33, p ≤ 0·021). APOE ɛ4 was more common in participants with positive PET images compared with those with negative scans (65%vs 22% [p=0·027

MAR 21 2013

Piramal Imaging SA, a division of Piramal Enterprises, today announced that the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have accepted its applications for review of the investigational PET amyloid imaging agent [18F] florbetaben. A New Drug Application (NDA) was submitted to the U.S. Food and Drug Administration (FDA) and a Marketing Authorization Application to the EMA for [18F] florbetabenuse in the visual detection of beta-amyloid in the brains of adultswith cognitive impairment who are being evaluated for Alzheimer’s disease and other causes of cognitive decline.[18F] florbetaben binds to beta-amyloid plaques in the human brain, a hallmark characteristic in Alzheimer’s disease.

Today, Alzheimer’s disease is usually diagnosed after a person with a cognitive impairment undergoes an extensive clinical examination which typically includes family and medical history, physical and neurological examinations, laboratory tests, and imaging procedures such as computed tomography (CT) and magnetic resonance imaging (MRI) scans. Still, a definitive diagnosis of Alzheimer’s disease can only be made after death where an autopsy can reveal the presence of beta-amyloid plaques and neurofibrillary tangles in the brain. However, post-mortem studies looking for accumulations of beta-amyloid in the brain have shown that 10 to 30 percent of diagnoses based on clinical examinations are incorrect. [18F] florbetaben is being studied to determine its potential ability to detect beta-amyloid plaquesin living subjects with cognitive impairment.

 


FLORBETABEN F18

Diagnostic radiopharmaceutical

1. Benzenamine, 4-[(1E)-2-[4-[2-[2-[2-(fluoro-18F)ethoxy]ethoxy]ethoxy]phenyl]
ethenyl]-N-methyl-

2. 4-{(1E)-2-(4-{2-[2-(2-[18F]fluoroethoxy)ethoxy]ethoxy}phenyl)eth- 1-en-1-yl}-N-methylaniline

C21H26[18F]NO3
358.5
Bayer Healthcare

UNII-TLA7312TOI
CAS REGISTRY NUMBER  902143-01-5
https://www.ama-assn.org/resources/doc/usan/florbetaben-f18.pdf

4-[(E)-2-(4-{2-[2-(2-fluoroethoxy)ethoxy]ethoxy}phenyl)vinyl]-N-methylaniline has been labeled with [F-18]fluoride and is claimed by patent application WO2006066104 and members of the corresponding patent family.

Figure imgf000002_0001

4-[(E)-2-(4-{2-[2-(2-[F-18]fluoroethoxy)ethoxy]- ethoxy}phenyl)vinyl]-N-methylaniline

The usefulness of this radiotracer for the detection of Αβ plaques have been reported in the literature (W. Zhang et al., Nuclear Medicine and Biology 32 (2005) 799-809; C. Rowe et al., Lancet Neurology 7 (2008) 1 -7).

The synthesis of 4-[(E)-2-(4-{2-[2-(2-[F-18]fluoroethoxy)ethoxy]ethoxy}phenyl)- vinyl]-N-methylaniline has been described before:

a) W. Zhang et al., Nuclear Medicine and Biology 32 (2005) 799-809.

Figure imgf000003_0001

4-[(E)-2-(4-{2-[2-(2-[F-18]fluoroethoxy)ethoxy]- ethoxy}phenyl)vinyl]-N-methylaniline

4 mg precursor 2a (2-[2-(2-{4-[(E)-2-{4-[(tert-butoxycarbonyl)(methyl)amino]- phenyl}vinyl]phenoxy}ethoxy)ethoxy]ethyl methanesulfonate) in 0.2 mL

DMSO were reacted with [F-18]fluoride/kryptofix/potassium carbonate complex. The intermediate was deprotected with HCI and neutralized with

NaOH. The mixture was extracted with ethyl acetate. The solvent was dried and evaporated, the residue was dissolved in acetonitrile and purified by semi-preparative HPLC. 20% (decay corrected), 1 1 % (not corrected for decay) 4-[(E)-2-(4-{2-[2-(2-[F-18]fluoroethoxy)ethoxy]ethoxy}phenyl)vinyl]-N- methylaniline were obtained in 90 min.

WO2006066104

4 mg precursor 2-[2-(2-{4-[(E)-2-{4-[(tert-butoxycarbonyl)(methyl)amino]- phenyl}vinyl]phenoxy}ethoxy)ethoxy]ethyl methanesulfonate in 0.2 mL DMSO were reacted with [F-18]fluoride/kryptofix/potassium carbonate complex. The intermediates was deprotected with HCI and neutralized with NaOH. The mixture was extracted with ethyl acetate. The solvent was dried and evaporated, the residue was dissolved in acetonitrile and purified by semi- preparative HPLC. 30% (decay corrected), 17% (not corrected for decay) 4- [(E)-2-(4-{2-[2-(2-[F-18]fluoroethoxy)ethoxy]ethoxy}phenyl)vinyl]-N- methylaniline were obtained in 90 min. to yield N-Boc protected 4-[(E)-2-(4-{2-[2-(2-[F- 18]fluoroethoxy)ethoxy]ethoxy}phenyl)vinyl]-N-methylaniline. The unreacted perfluorinated precursor was removed using a fluorous phase cartridge.

Deprotection, final purification and formulation to obtain a product, suitable for injection into human is not disclosed. Furthermore, the usefulness (e.g. regarding unwanted F-19/F-18 exchange) of this approach at a higher radioactivity level is not demonstrated. Finally, this method would demand a two-pot setup (first reaction vessel: fluorination, followed by solid-phase- extraction, and deprotection in the second reaction vessel).

However, the focus of the present invention are compounds and methods for an improved “one-pot process” for the manufacturing of 4-[(E)-2-(4-{2-[2-(2- [F-18]fluoroethoxy)ethoxy]ethoxy}phenyl)vinyl]-N-methylaniline.

Very recently, further methods have been described:

d) US201001 13763

The mesylate precursor 2a was reacted with [F-18]fluoride species in a solvent mixture consisting of 100 μΙ_ acetonitrile and 500 μΙ_ tertiary alcohol. After fluorination for 10 min at 100-150 °C, the solvent was evaporated. After deprotection (1 N HCI, 5 min, 100-120 °C), the crude product was purified by HPLC (C18 silica, acetonitrile / 0.1 M ammonium formate).

e) H. Wang et al., Nuclear Medicine and Biology 38 (201 1 ) 121 -127

5 mg precursor 2a (2-[2-(2-{4-[(E)-2-{4-[(tert-butoxycarbonyl)(methyl)amino]- phenyl}vinyl]phenoxy}ethoxy)ethoxy]ethyl methanesulfonate) in 0.5 ml_

DMSO were reacted with [F-18]fluoride/kryptofix/potassium carbonate complex. The intermediate was deprotected with HCI and neutralized with NaOH. The crude product was diluted with acetonitrile / 0.1 M ammonium dformate (6/4) and purified by semi-preparative HPLC. The product fraction was collected, diluted with water, passed through a C18 cartridge and eluted with ethanol, yielding 17% (not corrected for decay) 4-[(E)-2-(4-{2-[2-(2-[F- 18]fluoroethoxy)ethoxy]ethoxy}phenyl)vinyl]-N-methylaniline within 50 min. In the paper, the conversion of an unprotected mesylate precursor (is described:

5 mg unprotected mesylate precursor (2-{2-[2-(4-{(E)-2-[4- (methylamino)phenyl]vinyl}phenoxy)ethoxy]-ethoxy}ethyl 4- methanesulfonate) in 0.5 ml_ DMSO were reacted with [F- 18]fluoride/kryptofix/potassium carbonate complex. The crude product was diluted with acetonitrile / 0.1 M ammonium formate (6/4) and purified by semi- preparative HPLC. The product fraction was collected, diluted with water, passed through a C18 cartridge and eluted with ethanol, yielding 23% (not corrected for decay) 4-[(E)-2-(4-{2-[2-(2-[F-

18]fluoroethoxy)ethoxy]ethoxy}phenyl)vinyl]-N-methylaniline within 30 min. Beside the purification by HPLC, a process based on solid-phase-extraction was investigated, but the purity was inferior to that with HPLC purification. So far, one-pot radiolabelings have been performed using a mesylate precursor. It is know, that for F-18 labeling of stilbenes, mesylates have advantages over corresponding tosylates by providing more clean reactions with less amount of by-products (W. Zhang et al. Journal of Medicinal Chemistry 48 (2005) 5980- 5988), whereas the purification starting from the tosylate precursor was tedious and time consuming resulting in a low yield.

In contrast to this teaching of the prior art, we found advantages of tosylate and further arylsulfonate precursors for 4-[(E)-2-(4-{2-[2-(2-[F- 18]fluoroethoxy)ethoxy]ethoxy}phenyl)vinyl]-N-methylaniline compared to the corresponding mesylate. Less non-radioactive by-products that eluted close to the retention time of 4-[(E)-2-(4-{2-[2-(2-[F-

18]fluoroethoxy)ethoxy]ethoxy}phenyl)vinyl]-N-methylaniline were found in the crude products if arylsulfonate precursors were used (Example 2 – Example 6) compared to the crude mixture that was obtained after conversion of the mesylate precursor (Example 1 ).

The favorable by-product profile after radiolabeling of tosylate precursor 2b (Figure 10) compared to the radiolabeling of mesylate precursor 2a (Figure 7) supported an improved cartridge based purification (Example 8, Example 9).

…………………

WO2011151281A1

The term “F-18” means fluorine isotope 18F. The term”F-19″ means fluorine isotope 19F. EXAMPLES

Example 1 Radiolabeling of mesylate precursor 2a

Figure imgf000016_0001

4-[(E)-2-(4-{2-[2-(2-[F-18]fluoroethoxy)ethoxy]- ethoxy}phenyl)vinyl]-N-methylaniline

Radiolabeling was performed on a remote controlled synthesis module (Tracerlab FXN). Precursor 2a (2 mg) in 0.5 mL DMSO + 0.5 mL acetonitrile was treated with dried potassium carbonate/kryptofix/[F-18]fluoride complex for 6 min at 100 °C. 1 M HCI (1 mL) + 10 mg ascorbic acid was added and the mixture was heated for 4 min at 100 °C. 2M NaOH (0.5 mL), water (6 mL) and ethanol (1 mL) were added and the crude mixture was trapped on a C18 cartridge. The crude product mixture was eluted with acetonitrile and diluted with 0.1 M ammonium formiat buffer (1 mL) + 5 mg ascorbic acid. A sample of the crude product was taken and analyzed by analytical HPLC (Figure 1 ). After purification by semi- preparative HPLC, the product was diluted with water + 5 mg ascorbic acid, trapped on a C18 cartridge and eluted with 1 mL ethanol.

Yield of 4-[(E)-2-(4-{2-[2-(2-[F-18]fluoroethoxy)ethoxy]ethoxy}phenyl)-vinyl]-N- methylaniline: 21 % (corrected for decay).

Example 2 Synthesis and radiolabeling of tosylate precursor 2b

Figure imgf000017_0001
Figure imgf000017_0002

4-[(E)-2-(4-{2-[2-(2-[F-18]fluoroethoxy)ethoxy]- ethoxy}phenyl)vinyl]-N-methylaniline

4-Dimethylaminopyridine (26.7 mg) and triethylamine (225 μΙ_) were added to a solution of 1 .0 g terf-butyl {4-[(E)-2-(4-{2-[2-(2- hydroxyethoxy)ethoxy]ethoxy}phenyl)vinyl]phenyl}methylcarbamate (4) in dichloromethane (12 mL) at 0 °C. A solution of p- toluenesulfonyl chloride (417 mg) in dichloromethane (13.5 mL) was added at 0 °C. The resulting mixture was stirred at room temperature over night. The solvent was removed under reduced pressure and the crude product was purified by flash chromatography (silica, 0- 80% ethyl acetate in hexane). 850 mg 2b were obtained as colorless solid.

1 H NMR (300 MHz, CDCI3) δ ppm 1 .46 (s, 9 H), 2.43 (s, 3 H), 3.27 (s, 3 H), 3.59-3.73 (m, 6 H), 3.80- 3.86 (m, 2 H), 4.05-4.19 (m, 2 H), 6.88-7.05 (m, 4 H), 7.21 (d, J = 8.3 Hz, 2 H), 7.32 (d, J = 8.3 Hz, 2 H), 7.39-7-47 (m, 4 H), 7.80 (d, J = 8.3 Hz, 2 H). MS (ESIpos): m/z = 612 (M+H)+

Radiolabeling was performed on a remote controlled synthesis module (Tracerlab FXN). Precursor 2b (2 mg) in 0.5 mL DMSO + 0.5 mL acetonitrile was treated with dried potassium carbonate/kryptofix/[F-18]fluoride complex for 6 min at 100 °C. 1 M HCI (1 mL) + 10 mg ascorbic acid was added and the mixture was heated for 4 min at 100 °C. 2M NaOH (0.5 mL), water (6 mL) and ethanol (1 mL) were added and the crude mixture was trapped on a C18 cartridge. The crude product mixture was eluted with acetonitrile and diluted with 0.1 M ammonium formiat buffer (1 mL) + 5 mg ascorbic acid. A sample of the crude product was taken and analyzed by analytical HPLC (Figure 2). After purification by semi- preparative HPLC, the product was diluted with water + 5 mg ascorbic acid, trapped on a C18 cartridge and eluted with 1 mL ethanol.

Yield of 4-[(E)-2-(4-{2-[2-(2-[F-18]fluoroethoxy)ethoxy]ethoxy}phenyl)-vinyl]-N- methylaniline: 25% (corrected for decay).

Example 3 Synthesis and radiolabeling of 2c (2-[2-(2-{4-[(E)-2-{4-[(tert- butoxycarbonyl)(methyl)amino]phenyl}vinyl]phenoxy}ethoxy)ethoxy]ethyl

4-bromobenzenesulfonate)

Figure imgf000018_0001

4-[(E)-2-(4-{2-[2-(2-[F-18]fluoroethoxy)ethoxy]- ethoxy}phenyl)vinyl]-N-methylaniline To a stirred solution of 100 mg (0,219 mmol) tert-butyl-{4-[(E)-2-(4-{2-[2-(2- hydroxyethoxy)ethoxy]ethoxy}phenyl)vinyl]phenyl}methylcarbamate

(WO2006/066104) in 2 mL THF was added a solution of 140 mg (0.548 mmol) 4-brombenzene sulfonylchlorid in 3 mL THF drop by drop. The reaction mixture was cooled to 0°C. 156.8 mg (1 .1 mmol) potassium trimethylsilanolat was added. The milky suspension was stirred at 0°C for 2 hours and at 80°C for another 2 hours. The reaction mixture was poured onto ice-cooled water. The aqueous solution was extracted with dichloromethane several times. The combined organic phases were dried with sodium sulphate and concentrated in vacuum. The crude product was purified using silica gel with ethyl acetate/hexane-gradient as mobile phase. The desired product 2c was obtained with 77 mg (0.1 14 mmol, 52.0 % yield).

1 H NMR (300 MHz, CDCI3) δ ppm 1 .39 (s, 10 H) 3.20 (s, 3 H) 3.50 – 3.57 (m, 2 H) 3.57 – 3.61 (m, 2 H) 3.61 – 3.66 (m, 2 H) 3.72 – 3.80 (m, 2 H) 4.02 – 4.10 (m, 2 H) 4.10 – 4.17 (m, 2 H) 6.79 – 6.85 (m, 2 H) 6.91 (d, J=8.10 Hz, 2 H) 7.10 – 7.17 (m, 2 H) 7.32 – 7.41 (m, 5 H) 7.57 – 7.65 (m, 2 H) 7.67 – 7.74 (m, 2 H)

MS (ESIpos): m/z = 676/678 (M+H)+

Radiolabeling was performed on a remote controlled synthesis module (Tracerlab FXN). Precursor 2c (2 mg) in 0.5 mL DMSO + 0.5 mL acetonitrile was treated with dried potassium carbonate/kryptofix/[F-18]fluoride complex for 6 min at 100 °C. 1 M HCI (1 mL) + 10 mg ascorbic acid was added and the mixture was heated for 4 min at 100 °C. 2M NaOH (0.5 mL), water (6 mL) and ethanol (1 mL) were added and the crude mixture was trapped on a C18 cartridge. The crude product mixture was eluted with acetonitrile and diluted with 0.1 M ammonium formiat buffer (1 mL) + 5 mg ascorbic acid. A sample of the crude product was taken and analyzed by analytical HPLC (Figure 3). After purification by semi- preparative HPLC, the product was diluted with water + 5 mg ascorbic acid, trapped on a C18 cartridge and eluted with 1 mL ethanol.

Yield of 4-[(E)-2-(4-{2-[2-(2-[F-18]fluoroethoxy)ethoxy]ethoxy}phenyl)-vinyl]-N- methylaniline: 43% (corrected for decay). Example 4 Synthesis and radiolabeling of 2d (2-[2-(2-{4-[(E)-2-{4-[(tert- butoxycarbonyl)(methyl)amino]phenyl}vinyl]phenoxy}ethoxy)ethoxy]ethyl

4-(adamantan-1 -yl)benzenesulfonate)

Figure imgf000020_0001

4-[(E)-2-(4-{2-[2-(2-[F-18]fluoroethoxy)ethoxy]- ethoxy}phenyl)vinyl]-N-methylaniline

To a stirred solution of 151 mg (0,330 mmol) tert-butyl-{4-[(E)-2-(4-{2-[2-(2- hydroxyethoxy)ethoxy]ethoxy}phenyl)vinyl]phenyl}methylcarbamate

(WO2006/066104), 4.03 mg (0,033 mmol) DMAP und 36.7 mg (363 mmol) triethylamine in 4 mL dichlormethane was added a solution of 97,4 mg (0,313 mmol) 4-(adamantan-1 -yl)benzene sulfonylchloride in 1 mL dichlormethane at 0°C. The reaction mixture was stirred at 0°C for 1 hour and over night at room temperature. 7.3 mg (0,072 mmol) triethylamin und 19.5 mg (0.062 mmol) 4- (adamantan-l -yl)benzenesulfonyl chloride were added to the reaction mixture. The reaction mixture was stirred at room temperature for 3 days. It was concentrated in vacuum. The crude product was purified using silica gel with ethyl acetate/hexane-gradient as mobile phase. The desired product 2d was obtained with 104 mg (0.142 mmol, 43.4% yield).

1 H NMR (300 MHz, CDCI3) δ ppm 1 .51 (s, 9 H), 1 .62 (s, 1 H), 1 .74 – 1 .91 (m, 6 H), 1 .94 (d, J=3.20 Hz, 6 H), 2.16 (br. s., 3 H), 3.31 (s, 3 H), 3.63 – 3.69 (m, 2 H), 3.69 – 3.73 (m, 2 H), 3.76 (dd, J=5.27, 4.52 Hz, 2 H), 3.89 (d, J=4.90 Hz, 2 H), 4.13 – 4.26 (m, 4 H), 6.95 (d, J=8.85 Hz, 2 H), 7.02 (d, J=8.29 Hz, 2 H), 7.25 (d, J=8.48 Hz, 2 H), 7.40 – 7.52 (m, 4 H), 7.55 (m, J=8.67 Hz, 2 H), 7.89 (m, J=8.67 Hz, 2 H)

MS (ESIpos): m/z = 732 (M+H)+

Radiolabeling was performed on a remote controlled synthesis module (Tracerlab FXN). Precursor 2d (2 mg) in 0.5 mL DMSO + 0.5 mL acetonitrile was treated with dried potassium carbonate/kryptofix/[F-18]fluoride complex for 6 min at 100 °C. 1 M HCI (1 mL) + 10 mg ascorbic acid was added and the mixture was heated for 4 min at 100 °C. 2M NaOH (0.5 mL), water (6 mL) and ethanol (1 mL) were added and the crude mixture was trapped on a C18 cartridge. The crude product mixture was eluted with acetonitrile and diluted with 0.1 M ammonium formiat buffer (1 mL) + 5 mg ascorbic acid. A sample of the crude product was taken and analyzed by analytical HPLC (Figure 4). After purification by semi- preparative HPLC, the product was diluted with water + 5 mg ascorbic acid, trapped on a C18 cartridge and eluted with 1 mL ethanol.

Yield of 4-[(E)-2-(4-{2-[2-(2-[F-18]fluoroethoxy)ethoxy]ethoxy}phenyl)-vinyl]-N- methylaniline: 27% (corrected for decay).

Example 5 Synthesis and radiolabeling of 2e (2-[2-(2-{4-[(E)-2-{4-[(tert- butoxycarbonyl)(methyl)amino]phenyl}vinyl]phenoxy}ethoxy)ethoxy]ethyl

4-cyanobenzenesulfonate)

Figure imgf000022_0001
Figure imgf000022_0002

4-[(E)-2-(4-{2-[2-(2-[F-18]fluoroethoxy)ethoxy]- ethoxy}phenyl)vinyl]-N-methylaniline

To a stirred solution of 151 mg (0.330 mmol) tert-butyl-{4-[(E)-2-(4-{2-[2-(2- hydroxyethoxy)ethoxy]ethoxy}phenyl)vinyl]phenyl}methylcarbamate

(WO2006/066104), 4.03 mg (0.033 mmol) DMAP und 36.7 mg (0.363 mmol) triethylamine in 4 mL dichlormethane was added a solution of 63.2 mg (0.313 mmol) 4-cyanobenzenesulfonyl chloride in 1 mL dichlormethane at 0°C. The reaction mixture was stirred over night and concentrated in vacuum. The crude product was purified using silica gel with ethyl acetate/hexane-gradient as mobile phase. The desired product 2e was obtained with 118 mg (0.190 mmol, 57.6 % yield).

1 H NMR (400 MHz, CDCI3) δ ppm 1 .47 (s, 9 H) 3.28 (s, 3 H) 3.58 – 3.63 (m, 2 H) 3.63 – 3.68 (m, 2 H) 3.70 – 3.75 (m, 2 H) 3.81 – 3.87 (m, 2 H) 4.1 1 – 4.18 (m, 2 H) 4.24 – 4.30 (m, 2 H) 6.91 (d, J=8.59 Hz, 2 H) 6.99 (dt, 2 H) 7.22 (d, J=8.34 Hz, 2 H) 7.39 – 7.50 (m, 4 H) 7.83 (m, J=8.59 Hz, 2 H) 7.98 – 8.1 1 (m, 2 H)

MS (ESIpos): m/z = 623 (M+H)+

Radiolabeling was performed on a remote controlled synthesis module (Tracerlab FXN). Precursor 2e (2 mg) in 0.5 mL DMSO + 0.5 mL acetonitrile was treated with dried potassium carbonate/kryptofix/[F-18]fluoride complex for 6 min at 100 °C. 1 M HCI (1 mL) + 10 mg ascorbic acid was added and the mixture was heated for 4 min at 100 °C. 2M NaOH (0.5 mL), water (6 mL) and ethanol (1 mL) were added and the crude mixture was trapped on a C18 cartridge. The crude product mixture was eluted with acetonitrile and diluted with 0.1 M ammonium formiat buffer (1 mL) + 5 mg ascorbic acid. A sample of the crude product was taken and analyzed by analytical HPLC (Figure 5). After purification by semi- preparative HPLC, the product was diluted with water + 5 mg ascorbic acid, trapped on a C18 cartridge and eluted with 1 mL ethanol.

Yield of 4-[(E)-2-(4-{2-[2-(2-[F-18]fluoroethoxy)ethoxy]ethoxy}phenyl)-vinyl]-N- methylaniline: 31 % (corrected for decay).

Example 6 Synthesis and radiolabeling of 2f (2-[2-(2-{4-[(E)-2-{4-[(tert- butoxycarbonyl)(methyl)amino]phenyl}vinyl]phenoxy}ethoxy)ethoxy]ethyl

2-nitrobenzenesulfonate)

Figure imgf000023_0001
Figure imgf000023_0002

4-[(E)-2-(4-{2-[2-(2-[F-18]fluoroethoxy)ethoxy]- eth oxy} phe nyl )vi ny I] -N -methyla n i I i ne

To a stirred solution of 200 mg (0.437 mmol) tert-butyl-{4-[(E)-2-(4-{2-[2-(2- hydroxyethoxy)ethoxy]ethoxy}phenyl)vinyl]phenyl}methylcarbamate

(WO2006/066104), 5.34 mg (0.044 mmol) DMAP und 47.5 mg (0.470 mmol) triethylamine in 4 mL dichlormethane was added a solution of 92 mg (0,415 mmol) 2-nitrobenzenesulfonyl chloride in 1 mL dichlormethane at 0°C. The reaction mixture was stirred over night and concentrated in vacuum. The crude product was purified with ethyl acetate/hexane-gradient as mobile phase using silica gel. The desired product 2f was obtained with 77 mg (0.1 19 mmol, 59.5 % yield). 1 H NMR (400 MHz, CDCI3) δ ppm 1 .39 (s, 9 H) 3.20 (s, 3 H) 3.55 – 3.63 (m, 4 H) 3.59 (m, 4 H) 3.69 – 3.74 (m, 2 H) 3.75 – 3.80 (m, 2 H) 4.06 (dd, J=5.68, 3.92 Hz,

2 H) 4.32 – 4.37 (m, 2 H) 6.80 – 6.84 (m, 2 H) 6.84 – 6.98 (dt, 2 H) 7.14 (d, J=8.59 Hz, 2 H) 7.35 (d, J=3.03 Hz, 2 H) 7.37 (d, J=2.78 Hz, 2 H) 7.62 – 7.74 (m,

3 H) 8.06 – 8.1 1 (m, 1 H)


Med.Chem.Cool

Lomitapide (Juxtapid)

FDA approved  on 21 December 2012

Lomitapide is a cholesterol-lowering medication. It reduces blood levels of “bad” cholesterol, such as low-density lipoprotein (LDL) or non-high-density liproprotein (non-HDL), as well as a protein that carries bad cholesterol in the blood. Lomitapide is used together with a low-fat diet and other treatments to lower total cholesterol in people with homozygous familial hypercholesterolemia (an inherited type of high cholesterol).

It is not known whether lomitapide will lower your risk of heart disease.

What is the most important information I should know about lomitapide?

Do not use lomitapide if you are pregnant. Some medicines can interact with lomitapide and should not be used at the same time. Tell your doctor about all medicines you use, and those you start or stop using during your treatment with lomitapide.

Grapefruit and grapefruit juice may interact with lomitapide and lead to unwanted side effects. Do…

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Transverse myletis, one in a million ailment, will give self support to any one


Today when this blog has taken 10,000 views across 100 countries in 2 months, I take this opportunity to update any one needing information on transverse myletis, one in a million ailment, which I am going through myself , will give self support to any one approaching on mail, person or phone

IT CAN BE CONQUERED

amcrasto@gmail.com

call me in India, +91 9323115463

DETAILS

Paralysis head to toe, from DEC 2007 TILL TODAY MAR 2013. poor recovery, hands ok , head ok and miraculously all organs ok, diabetic and medical attention needed for that

on a wheel chair

bowel zero, all sensation zero below neck

plus points

motivation unmatched, sleep 5 hrs, office work 7 hrs, computer or ipad 6 hrs

 

special care

control blood thickness, avoid vein thrombosis, stretch limbs physically using help,try more exercises on bed, avoid fever, try antibiotics quickly in iv format, keep tight control on diabetes if any

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sixth sense extraordinary, knowledge grasp 1000 times more, motivation high to live and focussed on living only, no much desires except childrens happiness. television, news , sports are hobbies

 

Biogen’s Tecfidera MS Drug Wins EU Agency’s Backing


Tecfidera

Biogen Idec Inc. won European Union backing for Tecfidera, one of the first therapies for multiple sclerosis available in an easy-to-take pill that analysts say may generate $3.25 billion in annual sales.

Current MS drugs, including Biogen’s Avonex and Tysabri, are given by injection or intravenous infusion, and patient anticipation for Tecfidera may drive it to capture as much as 20 percent of the market within a year, according to Eric Schmidt of Cowen & Co. Sanofi (SAN)’s oral MS drug, Aubagio, was also recommended for marketing authorization today in Europe.

Biogen’s drug, formerly known as BG-12, will follow Novartis AG’s Gilenya to the market in the EU as an oral option for the treatment of MS. Because of its safety profile and efficacy, Weston, Massachusetts-based Biogen’s Tecfidera may generate $3.25 billion by 2017

 

Sanofi/Genzyme’s Lemtrada shows durable effect in MS trial


 

 

About Alemtuzumab/LEMTRADA™

Alemtuzumab is a monoclonal antibody that selectively targets CD52, a protein abundant on T and B cells. Treatment with alemtuzumab results in the depletion of circulating T and B cells thought to be responsible for the damaging inflammatory process in MS. Alemtuzumab has minimal impact on other immune cells. The acute anti-inflammatory effect of alemtuzumab is immediately followed by the onset of a distinctive pattern of T and B cell repopulation that continues over time, rebalancing the immune system in a way that potentially reduces MS disease activity.

mar22, 2013

There was good news for French drug giant Sanofi this week as data from an extension study backed the long-term efficacy of its multiple sclerosis drug Lemtrada.

Interim data from the first 12 months of the extension trial showed that relapse rates and sustained accumulation of disability were low among patients previously treated with Lemtrada (alemtuzumab) in either of the two-year Phase III CARE-MS I or CARE-MS II studies.

In both these Phase III trials, Lemtrada was was given as an IV administration on five consecutive days, and the second course was administered on three days 12 months later.

After the first year of the extension arm, more than 80% of patients did not need further treatment with the drug, and more than half remained relapse-free through the first year of the extension study, the drugmaker said.

Alemtuzumab (marketed as Campath, MabCampath or Campath-1H and currently under further development as Lemtrada) is a monoclonal antibody used in the treatment of chronic lymphocytic leukemia (CLL), cutaneous T-cell lymphoma (CTCL) and T-cell lymphoma. It is also used in some conditioning regimens for bone marrow transplantation, kidney transplantation and Islet cell transplantation.

Alemtuzumab binds to CD52, a protein present on the surface of mature lymphocytes, but not on the stem cells from which these lymphocytes are derived. After treatment with alemtuzumab, these CD52-bearing lymphocytes are targeted for destruction.

Alemtuzumab is used as second-line therapy for CLL. It was approved by the US Food and Drug Administration for CLL patients who have been treated with alkylating agents and who have failed fludarabine therapy. It has been approved by Health Canada for the same indication, and additionally for CLL patients who have not had any previous therapies.

It is also used under clinical trial protocols for treatment of some autoimmune diseases, such as multiple sclerosis, in which it shows promise.[1][2] Alemtuzumab was withdrawn from the markets in the US and Europe in 2012 to prepare for a higher-priced relaunch aimed at multiple sclerosis.[3]

A complication of therapy with alemtuzumab is that it significantly increases the risk for opportunistic infections, in particular, reactivation of cytomegalovirus.

  1. Drug may reverse MS brain damage”. 22 Oct 2008.
  2. “Sanofi and Genzyme Report New Positive Data from First Phase III Study with MS Drug”. 24 Oct 2011.
  3. “Sanofi withdraws Campath in US and EU”. Pharma Times Online. August 21, 2012.

NN1954, Long acting oral insulin may be a reality with NovoNordisk Using Merrion Pharmaceuticals GIPET Technology


20 MAR 2013

OI362GT (NN1954)

:Type 1 and 2 diabetes
:Phase 1

A long-acting oral basal insulin analogue intended as a tablet treatment.

Merrion Pharmaceuticals plc  today announces that its partner, Novo Nordisk, successfully completed a single dose Phase I trial with a novel oral insulin (NN1954). Merrion Pharmaceuticals GIPET Technology was used in the formulation of NN1954.

The aim of this randomised, double-blind placebo and active controlled single ascending dose trial was to investigate the safety, tolerability, pharmacokinetics (exposure of drug) and pharmacodynamics (effect on blood glucose levels) of NN1954.

Under the terms of the license agreement entered into with Novo Nordisk in 2008 Merrion, receives payments on achievement of certain development, regulatory and sales milestones as well as royalties on sales.

Merrion’s Chairman, Michael Donnelly, said “This is another step towards improving the management options for diabetes. This type of ascending dose trial is a critical stage in the development of a new therapeutic. We continue to be encouraged with the commitment of Novo Nordisk to the incorporation of Merrion’s GIPET technology in the plan to bring an oral insulin tablet to the market.”

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