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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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Sage Kills 51% of Melanoma Cells in Vitro and Reduces Risk in Humans


Sage Kills 51% of Melanoma Cells in Vitro and Reduces Risk in Humans: The herb sage is rich in the powerful anti-cancer compound thujone, which in this study was shown to kill 51% of human melanoma cells in vitro. But does sage reduce melanoma risk in humans? Yes, according to a study out of the Italy, where this herb is often consumed as part of the traditional diet: people eating sage at least once weekly had 32% less risk of melanoma. Apart from thujone, this super-herb contains several other compounds with proven health benefits, including cineole, carnosol, caffeic acid and chlorogenic acid. Sage has been used in traditional medicine for centuries to treat a variety of conditions, and it’s many health benefits are now being confirmed by some remarkable new clinical trials. One trial showed that 333 mg of sage extract daily significantly improved memory performance in older adults while in another clinical trial, 60 drops daily of liquid extract significantly enhanced cognitive performance in patients with Alzheimer’s. Sage is also such a powerful natural antibacterial that one clinical trial (out of Switzerland) showed that a spray of sage + echinacea performed as well as chlorhexidine + lidocaine in treating sore throats! Sage can be consumed as supplements, prepared as a tea, or used generously as a herb in a variety of dishes.<br /><br />
#Sage #Herbs #Melanoma #Antibiotic #Alzheimer’s<br /><br />
http://www.ncbi.nlm.nih.gov/pubmed/21647317

Sage Kills 51% of Melanoma Cells in Vitro and Reduces Risk in Humans: The herb sage is rich in the powerful anti-cancer compound thujone, which in this study was shown to kill 51% of human melanoma cells in vitro.

But does sage reduce melanoma risk in humans? Yes, according to a study out of the Italy, where this herb is often consumed as part of the traditional diet: people eating sage at least once weekly had 32% less risk of melanoma. Apart from thujone, this super-herb contains several other compounds with proven health benefits, including cineole, carnosol, caffeic acid and chlorogenic acid.

Sage has been used in traditional medicine for centuries to treat a variety of conditions, and it’s many health benefits are now being confirmed by some remarkable new clinical trials. One trial showed that 333 mg of sage extract daily significantly improved memory performance in older adults while in another clinical trial, 60 drops daily of liquid extract significantly enhanced cognitive performance in patients with Alzheimer’s.

Sage is also such a powerful natural antibacterial that one clinical trial (out of Switzerland) showed that a spray of sage + echinacea performed as well as chlorhexidine + lidocaine in treating sore throats! Sage can be consumed as supplements, prepared as a tea, or used generously as a herb in a variety of dishes.
http://www.ncbi.nlm.nih.gov/pubmed/21647317

 

 

 

Sage

Sage – Nature Wonder Herb

(Salvia officinalis) is cultivated as a spice and medicinal herb. This plant is known from parts of Europe, especially the Balkans, where is used for obtaining essential oils.
The Latin name of the whole genus Salvia comes from the Latin word “salvare“, which means “rescue saving curing ” because the Romans 2000 years ago appreciated and used sage for healing.

sage

The effectiveness of the leaves is due primarily to the presence of etheric oil (1.5 – 2.5 percent), which has antimicrobial and anti-inflammatory action.

It has been proven that etheric oil destroys bacteria Eshericia colli, Schigela sonei, Salmonela, and has a slightly weaker activity against bacteria of a group of staphylococci and streptococci.

It is effective in destroying certain types of fungi as: cadida albicas, cadida krusei, cadidapseudotropicalis, torulopsis glabrata and cyptococcus eoformas.

sage-oil
Etheric sage oil is colorless or yellow-green liquid with an aromatic and bitter taste.
Because of this effect, sage is a useful herb for treating inflammation and infections of the mucous membranes in the mouth, gums and throat. For these diseases gargle from sage tea is recommended.
sage-Put 2 tablespoons of crushed dried sage leaves in 2 cups of boiling water water. Cover it and let it stay like that for 20 or 30 minutes, then drain it.

For treatment to be successful, you must do gargle regularly , every 3 hours .

Sage softens the mucous secretions from the inflamed mucosa of the respiratory organs. Because of that you can drink sage tea against bronchitis.

-The tea is prepared with 1 tablespoon dried leaves and 2 cups of boiling water. Drink it three times a day.

You should avoid long term drinking tea because etheric oil from sage contains toxic substance thujone.

Dry leaves are used as a spice because it improves the taste and scent of food, and helps the digestion too.
Tea can be used for improving the functions of bile and liver, because bitter substances and etheric oil increase the secretion of digestive juices in the body.
Sage tea has a diuretic effect, which is poorly expressed and due to the presence of flavonoids . It can help with chronic disease of urinary tract .

sage

From a long time ago is known that sage tea is very effective cure for sweating. This power of sage it’s explained by its effect on the nervous center which regulates the glands that secrete sweat.

Commonly is recommended against perspiration of neuromuscular origin or the heat waves that occur during menopause.
Applied on the skin , tea tightens skin and calms inflammation. Especially good for oily skin with open pores and irritated skin.

sage

Sage is a remarkable tool for whitening teeth, strengthening gums and aid in periodontitis. A small spoon of sage leaves is mixed with 1 drop of peppermint etheric oil and abit of baking soda. With this mixture rub the teeth and gums twice a week.

BI launches COPD drug Striverdi, olodaterol in UK and Ireland


DB09080.png

Olodaterol

BI-1744
BI-1744-CL (hydrochloride) marketed as drug

Boehringer Ingelheim Pharma  innovator

synthesis…..http://wendang.baidu.com/view/d4f95541e518964bcf847c22.html

Olodaterol (trade name Striverdi) is a long acting beta-adrenoceptor agonist used as an inhalation for treating patients with chronic obstructive pulmonary disease (COPD), manufactured by Boehringer-Ingelheim.[1]

see……….https://www.thieme-connect.de/DOI/DOI?10.1055/s-0029-1219649           ……… synfacts

Olodaterol is a potent agonist of the human β2-adrenoceptor with a high β12 selectivity. Its crystalline hydrochloride salt is suitable for inhalation and is currently undergoing clinical trials in man for the treatment of asthma. Oloda­terol has a duration of action that exceeds 24 hours in two preclinical animal models of bronchoprotection and it has a better safety margin compared with formoterol.

Olodaterol hydrochloride [USAN]

Bi 1744 cl
Bi-1744-cl
Olodaterol hydrochloride
Olodaterol hydrochloride [usan]
UNII-65R445W3V9

868049-49-4 [RN] FREE FORM

CAS 869477-96-3 HCL SALT

R ENANTIOMER

2H-1,4-Benzoxazin-3(4H)-one, 6-hydroxy-8-((1R)-1-hydroxy-2-((2-(4-methoxyphenyl)- 1,1-dimethylethyl)amino)ethyl)-, hydrochloride (1:1)

2H-1,4-benzoxazin-3(4H)-one, 6-hydroxy-8-((1R)-1-hydroxy-2-((2-(4-methoxyphenyl)- 1,1-dimethylethyl)amino)ethyl)-, hydrochloride (1:1)

6-Hydroxy-8-((1R)-1-hydroxy-2-((2-(4-methoxyphenyl)-1,1-dimethylethyl)amino)ethyl)- 2H-1,4-benzoxazin-3(4H)-one hydrochloride

clinical trialshttp://clinicaltrials.gov/search/intervention=Olodaterol+OR+BI+1744

Boehringer Ingelheim has launched a new chronic obstructive pulmonary disease drug, Striverdi in the UK and Ireland.
Striverdi (olodaterol) is the second molecule to be licenced for delivery via the company’s Respimat Soft Mist inhaler, following the COPD blockbuster Spiriva (tiotropium). The drug was approved in Europe in November based on results from a Phase III programme that included more than 3,000 patients with moderate to very severe disease.http://www.pharmatimes.com/Article/14-07-01/BI_launches_COPD_drug_Striverdi_in_UK_and_Ireland.aspx

Olodaterol hydrochloride is a drug candidate originated by Boehringer Ingelheim. The product, delivered once-daily by the Respimat Soft Mist Inhaler, was first launched in Denmark and the Netherlands in March 2014 for the use as maintenance treatment of chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema. In 2013, approval was obtained in Russia and Canada for the same indication, and in the U.S, the product was recommended for approval. Phase III clinical trials for the treatment of COPD are ongoing in Japan.

ChemSpider 2D Image | Olodaterol | C21H26N2O5
Systematic (IUPAC) name
6-hydroxy-8-{(1R)-1-hydroxy-2-{[1-(4-methoxyphenyl)-2-methylpropan-2-yl]amino}ethyl}-4H-1,4-benzoxazin-3-one
Clinical data
Trade names Striverdi
AHFS/Drugs.com UK Drug Information
Pregnancy cat. No experience
Legal status POM (UK)
Routes Inhalation
Identifiers
CAS number 868049-49-4; 869477-96-3 (hydrochloride)
ATC code R03AC19
PubChem CID 11504295
ChemSpider 9679097
UNII VD2YSN1AFD
ChEMBL CHEMBL605846
Synonyms BI 1744 CL
Chemical data
Formula C21H26N2O5 free form
C21 H26 N2 O5 . Cl H; of hcl salt
Mol. mass 386.44 g/mol free form; 422.902 as hyd salt

BI launches COPD drug Striverdi in UK and Ireland

Medical uses

Olodaterol is a once-daily maintenance bronchodilator treatment of airflow obstruction in patients with COPD including chronic bronchitis and/or emphysema, and is administered in an inhaler called Respimat Soft Mist Inhaler.[2][3][4][5][6][7]

As of December 2013, olodaterol is not approved for the treatment of asthma. Olodaterol monotherapy was previously evaluated in four Phase 2 studies in asthma patients. However, currently there are no Phase 3 studies planned for olodaterol monotherapy in patients with asthma.

In late January 2013, Olodaterol CAS# 868049-49-4 was the focus of an FDA committee reviewing data for the drug’s approval as a once-daily maintenance bronchodilator to treat chronic obstructive pulmonary disease (COPD), as well as chronic bronchitis and emphysema. The FDA Pulmonary-Allergy Drugs Advisory Committee recommended that the clinical data from the Boehringer Ingelheim Phase III studies be included in their NDA.

Also known as the trade name Striverdi Respimat, Olodaterol is efficacious as a long-acting beta-agonist, which patients self-administer via an easy to use metered dose inhaler. While early statistics from clinical trials of Olodaterol were encouraging, a new set of data was released earlier this week, which only further solidified the effectual and tolerable benefits of this COPD drug.

On September 10, 2013 results from two Phase 3 studies of Olodaterol revealed additional positive results from this formidable COPD treatment. The conclusion from these two 48 week studies, which included over 3,000 patients, showed sizable and significant improvements in the lung function of patients who were dosed with Olodaterol. Patients in the aforementioned studies were administered either a once a day dosage of Olodaterol via the appropriate metered-dose inhaler or “usual care”. The “usual care” included a variety of treatment options, such as inhaled corticosteroids (not Olodaterol), short and long acting anticholinergics, xanthines and beta agonists, which were short acting. The clinical trial participants who were dosed with Olodaterol displayed a rapid onset of action from this drug, oftentimes within the first five minutes after taking this medication. Additionally, patients dispensed the Olodaterol inhaler were successfully able to maintain optimum lung function for longer than a full 24 hour period. The participants who were given Olodaterol experienced such an obvious clinical improvement in their COPD symptoms, and it quickly became apparent that the “usual care” protocol was lacking in efficacy and reliability.

A staggering 24 million patients in the United States suffer from chronic obstructive pulmonary disease, and this patient population is in need of an effectual, safe and tolerable solution. Olodaterol is shaping up to be that much needed solution. Not only have the results from studies of Olodaterol been encouraging, the studies themselves have actually been forward thinking and wellness centered. Boehringer Ingelheim is the first company to included studies to evaluate exercise tolerance in  patients with COPD, and compare the data to those patients who were dosed with Olodaterol. By including exercise tolerance as an important benchmark in pertinent data for Olodaterol, Boehringer Ingelheim has created a standard for COPD treatment expectations. The impaired lung function for patients with COPD contributes greatly to their inability to exercise and stay healthy. Patients who find treatments and management techniques to combat the lung hyperinflation that develops during exercise have a distinct advantage to attaining overall good health.

– See more at: http://www.lgmpharma.com/blog/olodaterol-offers-encouraging-results-patients-copd/#sthash.DOjcrGxc.dpuf

Data has demonstrated that Striverdi, a once-daily long-acting beta2 agonist, significantly improved lung function versus placebo and is comparable to improvements shown with the older LABA formoterol. The NHS price for the drug is £26.35 for a 30-day supply.

Boehringer cited Richard Russell at Wexham Park Hospital as saying that the licensing of Stirverdi will be welcomed by clinicians as it provides another option. He added that the trial results showing improvements in lung function “are particularly impressive considering the study design, which allowed participants to continue their usual treatment regimen. This reflects more closely the real-world patient population”.

Significantly, the company is also developing olodaterol in combination with Spiriva, a long-acting muscarinic antagonist. LAMA/LABA combinations provide the convenience of delivering the two major bronchodilator classes.

Olodaterol is a novel, long-acting beta2-adrenergic agonist (LABA) that exerts its pharmacological effect by binding and activating beta2-adrenergic receptors located primarily in the lungs. Beta2-adrenergic receptors are membrane-bound receptors that are normally activated by endogenous epinephrine whose signalling, via a downstream L-type calcium channel interaction, mediates smooth muscle relaxation and bronchodilation. Activation of the receptor stimulates an associated G protein which then activates adenylate cyclase, catalyzing the formation of cyclic adenosine monophosphate (cAMP) and protein kinase A (PKA). Elevation of these two molecules induces bronchodilation by relaxation of airway smooth muscles. It is by this mechanism that olodaterol is used for the treatment of chronic obstructive pulmonary disease (COPD) and the progressive airflow obstruction that is characteristic of it. Treatment with bronchodilators helps to mitigate associated symptoms such as shortness of breath, cough, and sputum production. Single doses of olodaterol have been shown to improve forced expiratory volume in 1 sec (FEV1) for 24 h in patients with COPD, allowing once daily dosing. A once-a-day treatment with a LABA has several advantages over short-acting bronchodilators and twice-daily LABAs including improved convenience and compliance and improved airflow over a 24-hour period. Despite similarities in symptoms, olodaterol is not indicated for the treatment of acute exacerbations of COPD or for the treatment of asthma.

Adverse effects

Adverse effects generally were rare and mild in clinical studies. Most common, but still affecting no more than 1% of patients, were nasopharyngitis (running nose), dizziness and rash. To judge from the drug’s mechanism of action and from experiences with related drugs, hypertension (high blood pressure), tachycardia (fast heartbeat), hypokalaemia (low blood levels of potassium), shaking, etc., might occur in some patients, but these effects have rarely, if at all, been observed in studies.[1]

Interactions

Based on theoretical considerations, co-application of other beta-adrenoceptor agonists, potassium lowering drugs (e. g. corticoids, many diuretics, and theophylline), tricyclic antidepressants, and monoamine oxidase inhibitors could increase the likelihood of adverse effects to occur. Beta blockers, a group of drugs for the treatment of hypertension (high blood pressure) and various conditions of the heart, could reduce the efficacy of olodaterol.[1] Clinical data on the relevance of such interactions are very limited.

Pharmacology

Mechanism of action

Like all beta-adrenoceptor agonists, olodaterol mimics the effect of epinephrine at beta-2 receptors (β₂-receptors) in the lung, which causes the bronchi to relax and reduces their resistance to airflow.[3]

Olodaterol is a nearly full β₂-agonist, having 88% intrinsic activity compared to the gold standard isoprenaline. Its half maximal effective concentration (EC50) is 0.1 nM. It has a higher in vitro selectivity for β₂-receptors than the related drugs formoterol and salmeterol: 241-fold versus β₁- and 2299-fold versus β₃-receptors.[2] The high β₂/β₁ selectivity may account for the apparent lack of tachycardia in clinical trials, which is mediated by β₁-receptors on the heart.

Pharmacokinetics

Once bound to a β₂-receptor, an olodaterol molecule stays there for hours – its dissociation half-life is 17.8 hours –, which allows for once-a-day application of the drug[3] like with indacaterol. Other related compounds generally have a shorter duration of action and have to be applied twice daily (e.g. formoterol, salmeterol). Still others (e. g. salbutamol, fenoterol) have to be applied three or four times a day for continuous action, which can also be an advantage for patients who need to apply β₂-agonists only occasionally, for example in an asthma attack.[8]

 

History

On 29 January 2013 the U.S. Food and Drug Administration (FDA) Pulmonary-Allergy Drugs Advisory Committee (PADAC) recommended that the clinical data included in the new drug application (NDA) for olodaterol provide substantial evidence of safety and efficacy to support the approval of olodaterol as a once-daily maintenance bronchodilator treatment for airflow obstruction in patients with COPD.[9]

On 18 October 2013 approval of olodaterol in the first three European countries – the United Kingdom, Denmark and Iceland – was announced by the manufacturer.[10]

 

Figure  Chemical structures of salmeterol, formoterol, inda- caterol, and emerging once-daily long-acting β2-agonists

 

CLIP

Synthetic approaches to the 2013 new drugs – ScienceDirect

Science Direct

Synthesis of olodaterol hydrochloride (XVI).

Image result for OLODATEROL DRUG FUTURE

Olodaterol hydrochloride was approved for long-term, once-daily maintenance treatment of chronic
obstructive pulmonary disease (COPD) in 2013 in the following countries: Canada, Russia, United
Kingdom, Denmark, and Iceland.142, 143 The drug has been recommended by a federal advisory panel for
approval by the FDA.142, 143 Developed and marketed by Boehringer Ingelheim, olodaterol is a longacting
β2-adrenergic receptor agonist with high selectivity over the β1- and β3-receptors (219- and 1622-fold, respectively).144 Upon binding to and activating the β2-adrenergic receptor in the airway, olodaterol
stimulates adenyl cyclase to synthesize cAMP, leading to the relaxation of smooth muscle cells in the
airway. Administered by inhalation using the Respimat®
Soft Mist inhaler, it delivers significant
bronchodilator effects within five minutes of the first dose and provides sustained improvement in
forced expiratory volume (FEV1) for over 24 hours.143 While several routes have been reported in the
patent and published literature,144-146 the manufacturing route for olodaterol hydrochloride disclosed in
2011 is summarized in Scheme 19 below.147
Commercial 2’,5’-dihydroxyacetophenone (122) was treated with one equivalent of benzyl bromide
and potassium carbonate in methylisobutylketone (MIBK) to give the 5’-monobenzylated product in
76% yield. Subsequent nitration occurred at the 4’-position to provide nitrophenol 123 in 87% yield.
Reduction of the nitro group followed by subjection to chloroacetyl chloride resulted in the construction
of benzoxazine 124 in 82% yield. Next, monobromination through the use of tetrabutylammonium
tribromide occurred at the acetophenone carbon to provide bromoketone 125, and this was followed by
asymmetric reduction of the ketone employing (−)-DIP chloride to afford an intermediate bromohydrin,
which underwent conversion to the corresponding epoxide 126 in situ upon treatment with aqueous
NaOH. This epoxide was efficiently formed in 85% yield and 98.3% enantiomeric excess. Epoxide
126 underwent ring-opening upon subjection to amine 127 to provide amino-alcohol 128 in in 84-90%
yield and 89.5-99.5% enantiomeric purity following salt formation with HCl. Tertiary amine 127 was
itself prepared in three steps by reaction of ketone 129 with methylmagnesium chloride, Ritter reaction
of the tertiary alcohol with acetonitrile, and hydrolysis of the resultant acetamide with ethanolic
potassium hydroxide. Hydrogenative removal of the benzyl ether within 128 followed by
recrystallization with methanolic isopropanol furnished olodaterol hydrochloride (XVI) in 63-70%
yield. Overall, the synthesis of olodaterol hydrochloride required 10 total steps (7 linear) from
commercially available acetophenone 122.

142. Gibb, A.; Yang, L. P. H. Drugs 2013, 73, 1841.
143. http://www.boehringeringelheim.com/news/news_releases/press_releases/2013/18_october_2013_olodaterol.html.

144. Bouyssou, T.; Hoenke, C.; Rudolf, K.; Lustenberger, P.; Pestel, S.; Sieger, P.; Lotz, R.; Heine,
C.; Buettner, F. H.; Schnapp, A.; Konetzki, I. Bioorg. Med. Chem. Lett. 2010, 20, 1410.
145. Trunk, M. J. F.; Schiewe, J. US Patent 20050255050A1, 2005.
146. Lustenberger, P.; Konetzki, I.; Sieger, P. US Patent 20090137578A1, 2009.
147. Krueger, T.; Ries, U.; Schnaubelt, J.; Rall, W.; Leuter, Z. A.; Duran, A.; Soyka, R. US Patent
20110124859A1, 2011.

 

PATENT

WO 2004045618 or

http://www.google.com/patents/EP1562603B1?cl=en

Example

 

Figure imgb0006

a)

To a solution of 3.6 g 1,1-dimethyl-2-(4-methoxyphenyl)-ethylamine in 100 mL of ethanol at 70 ° C. 7.5 g of (6-benzyloxy-4H-benzo [1,4] oxazin-3-one )-glyoxal added and allowed to stir for 15 minutes. Then within 30 minutes at 10 to 20 ° C. 1 g of sodium borohydride added. It is stirred for one hour, with 10 mL of acetone and stirred for another 30 minutes. The reaction mixture is diluted with 150 mL ethyl acetate, washed with water, dried with sodium sulfate and concentrated. The residue is dissolved in 50 mL of methanol and 100 mL ethyl acetate and acidified with conc. Hydrochloric acid. After addition of 100 mL of diethyl ether, the product precipitates. The crystals are filtered, washed and recrystallized from 50 mL of ethanol. Yield: 7 g (68%; hydrochloride), mp = 232-234 ° C.

b)

6.8 g of the above obtained benzyl compound in 125 mL of methanol with the addition of 1 g of palladium on carbon (5%) was hydrogenated at room temperature and normal pressure. The catalyst is filtered and the filtrate was freed from solvent. Recrystallization of the residue in 50 mL of acetone and a little water, a solid is obtained, which is filtered and washed.
Yield: 5.0 g (89%; hydrochloride), mp = 155-160 ° C.

The (R) – and (S)-enantiomers of Example 3 can be obtained from the racemate, for example, by chiral HPLC (for example, column: Chirobiotic T, 250 x 1.22 mm from the company Astec). As the mobile phase, methanol with 0.05% triethylamine and 0.05% acetic acid. Silica gel with a grain size of 5 microns, to which is covalently bound the glycoprotein teicoplanin can reach as column material used. Retention time (R enantiomer) = 40.1 min, retention time (S-enantiomer) = 45.9 min. The two enantiomers can be obtained by this method in the form of free bases. According to the invention of paramount importance is the R enantiomer of Example 3

 

 

PATENT

WO 2005111005

http://www.google.fm/patents/WO2005111005A1?cl=en

Scheme 1.

 

Figure imgf000013_0001

 

Figure imgf000013_0003
Figure imgf000013_0002

 

Figure imgf000013_0004

Scheme 1:

Example 1 6-Hydroxy-8-{(1-hydroxy-2-r2-(4-methoxy-phenyl) – 1, 1-dimethyl-ethylamino]-ethyl)-4H-benzor 41oxazin-3-one – Hvdrochlorid

 

Figure imgf000017_0001

a) l-(5-benzyloxy-2-hydroxy-3-nitro-phenyl)-ethanone

To a solution of 81.5 g (0.34 mol) l-(5-benzyloxy-2-hydroxy-phenyl)-ethanone in 700 ml of acetic acid are added dropwise under cooling with ice bath, 18 mL of fuming nitric acid, the temperature does not exceed 20 ° C. increases. The reaction mixture is stirred for two hours at room temperature, poured onto ice water and filtered. The product is recrystallized from isopropanol, filtered off and washed with isopropanol and diisopropyl ether. Yield: 69.6 g (72%), mass spectroscopy [M + H] + = 288

b) l-(3-Amino-5-benzyloxy-2-hydroxy-phenyl)-ethanone

69.5 g (242 mmol) of l-(5-benzyloxy-2-hydroxy-3-nitro-phenyl)-ethanone are dissolved in 1.4 L of methanol and in the presence of 14 g of rhodium on carbon (10%) as catalyst at 3 bar room temperature and hydrogenated. Then the catalyst is filtered off and the filtrate concentrated. The residue is reacted further without additional purification. Yield: 60.0 g (96%), R f value = 0.45 (silica gel, dichloromethane).

c) 8-acetyl-6-benzyloxy-4H-benzoπ .4] oxazin-3-one

To 60.0 g (233 mmol) of l-(3-Amino-5-benzyloxy-2-hydroxy-phenyl)-ethanone and 70.0 g (506 mmol) of potassium carbonate while cooling with ice bath, 21.0 ml (258 mmol) of chloroacetyl chloride added dropwise. Then stirred overnight at room temperature and then for 6 hours under reflux. The hot reaction mixture is filtered and then concentrated to about 400 mL and treated with ice water. The precipitate is filtered off, dried and purified by chromatography on a short silica gel column (dichloromethane: methanol = 99:1). The product-containing fractions are concentrated, suspended in isopropanol, diisopropyl ether, and extracted with

Diisopropyl ether. Yield: 34.6 g (50%), mass spectroscopy [M + H] + = 298

d) 6-Benzyloxy-8-(2-chloro-acetyl)-4H-benzoFl, 4] oxazin-3-one 13.8 g (46.0 mmol) of 8-benzyloxy-6-Acetyl-4H-benzo [l, 4] oxazin -3-one and 35.3 g (101.5 mmol) of benzyltrimethylammonium dichloriodat are stirred in 250 mL dichloroethane, 84 mL glacial acetic acid and 14 mL water for 5 hours at 65 ° C. After cooling to room temperature, treated with 5% aqueous sodium hydrogen sulfite solution and stirred for 30 minutes. The precipitated solid is filtered off, washed with water and diethyl ether and dried. Yield: 13.2 g (86%), mass spectroscopy [M + H] + = 330/32.

e) 6-Benzyloxy-8-((R-2-chloro-l-hydroxy-ethyl)-4H-benzori ,41-oxazin-3-one The procedure is analogous to a procedure described in the literature (Org. Lett ., 2002, 4, 4373-4376).

To 13:15 g (39.6 mmol) of 6-benzyloxy-8-(2-chloro-acetyl)-4H-benzo [l, 4] oxazin-3-one and 25.5 mg (0:04 mmol) Cρ * RhCl [(S, S) -TsDPEN] (Cp * = pentamethylcyclopentadienyl and TsDPEN = (lS, 2S)-Np-toluenesulfonyl-l ,2-diphenylethylenediamine) in 40 mL of dimethylformamide at -15 ° C and 8 mL of a mixture of formic acid and triethylamine (molar ratio = 5: 2) dropwise. It is allowed for 5 hours at this temperature, stirring, then 25 mg of catalyst and stirred overnight at -15 ° C. The reaction mixture is mixed with ice water and filtered. The filter residue is dissolved in dichloromethane, dried with sodium sulfate and the solvent evaporated. The residue is recrystallized gel (dichloromethane / methanol gradient) and the product in diethyl ether / diisopropyl ether. Yield: 10.08 g (76%), R f value = 00:28 (on silica gel, dichloromethane ethanol = 50:1).

f) 6-Benzyloxy-8-(R-oxiranyl-4H-benzo [“L4] oxazin-3-one 6.10 g (30.1 mmol) of 6-benzyloxy-8-((R)-2-chloro-l-hydroxy- ethyl)-4H-benzo [l, 4] oxazin-3-one are dissolved in 200 mL of dimethylformamide. added to the solution at 0 ° C with 40 mL of a 2 molar sodium hydroxide solution and stirred at this temperature for 4 hours. the reaction mixture is poured onto ice water, stirred for 15 minutes, and then filtered The solid is washed with water and dried to give 8.60 g (96%), mass spectroscopy [M + H] + = 298..

g) 6-Benyloxy-8-{(R-l-hydroxy-2-r2-(4-methoxy-phenyl)-dimethyl-ll-ethvIaminol-ethyl)-4H-benzo-3-Tl A1oxazin

5.25 g (17.7 mmol) of 6-benzyloxy-8-(R)-oxiranyl-4H-benzo [l, 4] oxazin-3-one and 6.30 g (35.1 mmol) of 2 – (4-methoxy-phenyl 1, 1 – dimethyl-ethyl to be with 21 mL

Of isopropanol and stirred at 135 ° C for 30 minutes under microwave irradiation in a sealed reaction vessel. The solvent is distilled off and the residue chromatographed (alumina, ethyl acetate / methanol gradient). The product thus obtained is purified by recrystallization from a mixture further Diethylether/Diisopropylether-. Yield: 5:33 g (63%), mass spectroscopy [M + H] + = 477 h) 6-Hydroxy-8-{(R)-l-hydroxy-2-[2 – (4-methoxy-phenyl)-l, l-dimethyl-ethylamino] – ethyl}-4H-benzo [1, 4, 1 oxazin-3-one hydrochloride

A suspension of 5:33 g (11.2 mmol) of 6-Benyloxy-8-{(R)-l-hydroxy-2-[2 – (4-methoxy-phenyl)-l, l-dimethyl-ethylamino]-ethyl}-4H -benzo [l, 4] oxazin-3-one in 120 mL of methanol with 0.8 g of palladium on carbon (10%), heated to 50 ° C and hydrogenated at 3 bar hydrogen pressure. Then the catalyst is filtered off and the filtrate concentrated. The residue is dissolved in 20 mL of isopropanol, and 2.5 mL of 5 molar hydrochloric acid in isopropanol. The product is precipitated with 200 mL of diethyl ether, filtered off and dried. Yield: 4.50 g (95%, hydrochloride), mass spectroscopy [M + H] + = 387

 

PATENT

WO 2007020227

http://www.google.com.ar/patents/WO2007020227A1?cl=en

 

PATENT

WO 2008090193

or

http://www.google.com/patents/EP2125759B1?cl=en

 

PAPER

Discovery of olodaterol, a novel inhaled beta(2)-adrenoceptor agonist with a 24h bronchodilatory efficacy
Bioorg Med Chem Lett 2010, 20(4): 1410

 http://www.sciencedirect.com/science/article/pii/S0960894X09018101

The discovery of the β2-adrenoceptor agonist (R)-4p designated olodaterol is described. The preclinical profile of the compound suggests a bronchoprotective effect over 24 h in humans.

Full-size image (4 K)

CLIP

 

Australia

http://www.tga.gov.au/pdf/auspar/auspar-olodaterol-140327-pi.pdf

 

CLIP

DUTCH

http://mri.medagencies.org/download/NL_H_2498_001_PAR.pdf

FDA

Click to access 203108Orig1s000ChemR.pdf

NDA 203108
Striverdi® Respimat® (olodaterol) Inhalation Spray
Boehringer Ingelheim Pharmaceuticals, Inc.

References

  1. Striverdi UK Drug Information
  2. Bouyssou, T.; Casarosa, P.; Naline, E.; Pestel, S.; Konetzki, I.; Devillier, P.; Schnapp, A. (2010). “Pharmacological Characterization of Olodaterol, a Novel Inhaled  2-Adrenoceptor Agonist Exerting a 24-Hour-Long Duration of Action in Preclinical Models”. Journal of Pharmacology and Experimental Therapeutics 334 (1): 53–62. doi:10.1124/jpet.110.167007. PMID 20371707. edit
  3. Casarosa, P.; Kollak, I.; Kiechle, T.; Ostermann, A.; Schnapp, A.; Kiesling, R.; Pieper, M.; Sieger, P.; Gantner, F. (2011). “Functional and Biochemical Rationales for the 24-Hour-Long Duration of Action of Olodaterol”. Journal of Pharmacology and Experimental Therapeutics 337 (3): 600–609. doi:10.1124/jpet.111.179259. PMID 21357659. edit
  4. Bouyssou, T.; Hoenke, C.; Rudolf, K.; Lustenberger, P.; Pestel, S.; Sieger, P.; Lotz, R.; Heine, C.; Büttner, F. H.; Schnapp, A.; Konetzki, I. (2010). “Discovery of olodaterol, a novel inhaled β2-adrenoceptor agonist with a 24h bronchodilatory efficacy”. Bioorganic & Medicinal Chemistry Letters 20 (4): 1410–1414. doi:10.1016/j.bmcl.2009.12.087. PMID 20096576. edit
  5. Joos G, Aumann JL, Coeck C, et al. ATS 2012 Abstract: Comparison of 24-Hour FEV1 Profile for Once-Daily versus Twice-Daily Treatment with Olodaterol, A Novel Long-Acting ß2-Agonist, in Patients with COPD[dead link]
  6. Van Noord, J. A.; Smeets, J. J.; Drenth, B. M.; Rascher, J.; Pivovarova, A.; Hamilton, A. L.; Cornelissen, P. J. G. (2011). “24-hour Bronchodilation following a single dose of the novel β2-agonist olodaterol in COPD”. Pulmonary Pharmacology & Therapeutics 24 (6): 666–672. doi:10.1016/j.pupt.2011.07.006. PMID 21839850. edit
  7. van Noord JA, Korducki L, Hamilton AL and Koker P. Four Weeks Once Daily Treatment with BI 1744 CL, a Novel Long-Acting ß2-Agonist, is Effective in COPD Patients. Am. J. Respir. Crit. Care Med. 2009; 179: A6183[dead link]
  8. Haberfeld, H, ed. (2009). Austria-Codex (in German) (2009/2010 ed.). Vienna: Österreichischer Apothekerverlag. ISBN 3-85200-196-X.
  9. Hollis A (31 January 2013). “Panel Overwhelmingly Supports Boehringer COPD Drug Striverdi”. FDA News/Drug Industry Daily.
  10. “New once-daily Striverdi (olodaterol) Respimat gains approval in first EU countries”. Boehringer-Ingelheim. 18 October 2013.

External links

The active moiety olodaterol is a selective beta2-adrenergic bronchodilator. The drug substance, olodaterol hydrochloride, is chemically described as 2H-1,4- Benzoxazin-3H(4H)-one, 6-hydroxy-8-[(1R)-1-hydroxy-2-[[2-(4-methoxyphenyl)-1,1-dimethylethyl]-amino]ethyl]-, monohydrochloride. Olodaterol hydrochloride is a white to off-white powder that is sparingly-slightly soluble in water and slightly soluble in ethanol. The molecular weight is 422.9 g/mole (salt): 386.5 g/mole (base), and the molecular formula is C21H26N2O5 x HCl as a hydrochloride. The conversion factor from salt to free base is 1.094.

The structural formula is:

STRIVERDI® RESPIMAT® (olodaterol) Structural Formula Illustration

The drug product, STRIVERDI RESPIMAT, is composed of a sterile, aqueous solution of olodaterol hydrochloride filled into a 4.5 mL plastic container crimped into an aluminum cylinder (STRIVERDI RESPIMAT cartridge) for use with the STRIVERDI RESPIMAT inhaler.

Excipients include water for injection, benzalkonium chloride, edetate disodium, and anhydrous citric acid. The STRIVERDI RESPIMAT cartridge is only intended for use with the STRIVERDI RESPIMAT inhaler. The STRIVERDI RESPIMAT inhaler is a hand held, pocket sized oral inhalation device that uses mechanical energy to generate a slow-moving aerosol cloud of medication from a metered volume of the drug solution. The STRIVERDI RESPIMAT inhaler has a yellow-colored cap.

When used with the STRIVERDI RESPIMAT inhaler, each cartridge containing a minimum of 4 grams of a sterile aqueous solution delivers the labeled number of metered actuations after preparation for use. Each dose (1 dose equals 2 actuations) from the STRIVERDI RESPIMAT inhaler delivers 5 mcg olodaterol in 22.1 mcL of solution from the mouthpiece. As with all inhaled drugs, the actual amount of drug delivered to the lung may depend on patient factors, such as the coordination between the actuation of the inhaler and inspiration through the delivery system. The duration of inspiration should be at least as long as the spray duration (1.5 seconds).

 

WO2002030928A1 28 Sep 2001 11 Apr 2003 Boehringer Ingelheim Pharma Crystalline monohydrate, method for producing the same and the use thereof in the production of a medicament
WO2003000265A1 8 Jun 2002 3 Jan 2003 Boehringer Ingelheim Pharma Crystalline anticholinergic, method for its production, and use thereof in the production of a drug
WO2004045618A2 * 11 Nov 2003 3 Jun 2004 Boehringer Ingelheim Pharma Novel medicaments for the treatment of chronic obstructive pulmonary diseases
EP0073505A1 * 28 Aug 1982 9 Mar 1983 Boehringer Ingelheim Kg Benzo-heterocycles
EP0321864A2 * 15 Dec 1988 28 Jun 1989 Boehringer Ingelheim Kg Ammonium compounds, their preparation and use
US4460581 12 Oct 1982 17 Jul 1984 Boehringer Ingelheim Kg Antispasmodic agents, antiallergens
US4656168 * 13 Oct 1983 7 Apr 1987 Merck & Co., Inc. Vision defects; adrenergic blocking and hypotensive agents

 

Organic spectroscopy should be brushed up and you get confidence

read my blog

 

Organic chemists from Industry and academics to interact on Spectroscopy techniques for Organic compounds ie NMR, MASS, IR, UV Etc. email me ……….. amcrasto@gmail.com

http://orgspectroscopyint.blogspot.in/  is the link

feder-0005.gif from 123gifs.euamcrasto@gmail.com

PTC Therapeutics Initiates Confirmatory Phase 3 Clinical Trial of Translarna™ (ataluren) in Patients with Nonsense Mutation Cystic Fibrosis (nmCF)


ATALUREN

PTC 124

3-[5-(2-Fluorophenyl)-1,2,4-oxadiazol-3-yl]benzoic acid

 

 MF C15H9FN2O3
Molecular Weight 284.24
CAS Registry Number 775304-57-9

PTC Therapeutics Initiates Confirmatory Phase 3 Clinical Trial of Translarna™ (ataluren) in Patients with Nonsense Mutation Cystic Fibrosis (nmCF) – MarketWatch

SOUTH PLAINFIELD, N.J., June 30, 2014 /PRNewswire/ — PTC Therapeutics, Inc. /quotes/zigman/16944148/delayed/quotes/nls/ptct PTCT -0.01% today announced the initiation of a global confirmatory Phase 3 clinical trial of Translarna™ (ataluren), an investigational new drug, in patients with nonsense mutation cystic fibrosis (nmCF). Nonsense mutations within cystic fibrosis are categorized as Class I mutations, a severe form of CF that results in little or no production of the CFTR protein. The Phase 3 confirmatory trial is referred to as ACT CF (ataluren confirmatory trial in cystic fibrosis) and the primary endpoint is lung function as measured by relative change in percent predicted forced expiratory volume in one second, or FEV1.read at

http://www.marketwatch.com/story/ptc-therapeutics-initiates-confirmatory-phase-3-clinical-trial-of-translarna-ataluren-in-patients-with-nonsense-mutation-cystic-fibrosis-nmcf-2014-06-30?reflink=MW_news_stmp

 

Ataluren, formerly known as PTC124, is a small-molecular agent designed by PTC Therapeutics and sold under the trade nameTranslarna. It makes ribosomes less sensitive to premature stop codons (referred to as “read-through”). This may be beneficial in diseases such as Duchenne muscular dystrophy where the mRNA contains a mutation causing premature stop codons or nonsense codons. There is ongoing debate over whether Ataluren is truly a functional drug (inducing codon read-through), or if it is nonfunctional, and the result was a false-positive hit from a biochemical screen based on luciferase.[1]

Ataluren has been tested on healthy humans and humans carrying genetic disorders caused by nonsense mutations,[2][3] such as some people with cystic fibrosis and Duchenne muscular dystrophy. In 2010, PTC Therapeutics released preliminary results of its phase 2b clinical trial for Duchenne muscular dystrophy, with participants not showing a significant improvement in the six minute walk distance after the 48 weeks of the trial.[4] This failure resulted in the termination of a $100 million deal with Genzyme to pursue the drug. However, other phase 2 clinical trials were successful for cystic fibrosis in Israel, France and Belgium.[5] Multicountry phase 3 clinical trials are currently in progress for cystic fibrosis in Europe and the USA.[6]

In cystic fibrosis, early studies of ataluren show that it improves nasal potential difference.[7]

Ataluren appears to be most effective for the stop codon ‘UGA’.[2]

On 23 May 2014 ataluren received a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA).[8]

It is not that ataluren is a complex molecule. To judge from one of the patents, synthesis is straightforward starting from 2-cyanobenoic acid and 2-fluorobenzoyl chloride, both commercially available. The synthetic steps are methylation of 2-cyanobenoic acid (iodomethane), nitrile hydrolysis with hydroxylamine, esterification with the fluoro acid chloride using DIPEA, high-temperature dehydration to the oxadiazole and finally ester hydrolysis (NaOH).

 

 

References

  1. Derek (2013-09-18). “The Arguing Over PTC124 and Duchenne Muscular Dystrophy. In the Pipeline:”. Pipeline.corante.com. Retrieved 2013-11-28.
  2.  Welch EM, Barton ER, Zhuo J, Tomizawa Y, Friesen WJ, Trifillis P, Paushkin S, Patel M, Trotta CR, Hwang S, Wilde RG, Karp G, Takasugi J, Chen G, Jones S, Ren H, Moon YC, Corson D, Turpoff AA, Campbell JA, Conn MM, Khan A, Almstead NG, Hedrick J, Mollin A, Risher N, Weetall M, Yeh S, Branstrom AA, Colacino JM, Babiak J, Ju WD, Hirawat S, Northcutt VJ, Miller LL, Spatrick P, He F, Kawana M, Feng H, Jacobson A, Peltz SW, Sweeney HL (May 2007). “PTC124 targets genetic disorders caused by nonsense mutations”. Nature 447 (7140): 87–91.doi:10.1038/nature05756PMID 17450125.
  3.  Hirawat S, Welch EM, Elfring GL, Northcutt VJ, Paushkin S, Hwang S, Leonard EM, Almstead NG, Ju W, Peltz SW, Miller LL (Apr 2007). “Safety, tolerability, and pharmacokinetics of PTC124, a nonaminoglycoside nonsense mutation suppressor, following single- and multiple-dose administration to healthy male and female adult volunteers”. Journal of clinical pharmacology 47 (4): 430–444. doi:10.1177/0091270006297140PMID 17389552.
  4.  “PTC THERAPEUTICS AND GENZYME CORPORATION ANNOUNCE PRELIMINARY RESULTS FROM THE PHASE 2B CLINICAL TRIAL OF ATALUREN FOR NONSENSE MUTATION DUCHENNE/BECKER MUSCULAR DYSTROPHY (NASDAQ:PTCT)”. Ptct.client.shareholder.com. Retrieved 2013-11-28.
  5.  Wilschanski, M.; Miller, L. L.; Shoseyov, D.; Blau, H.; Rivlin, J.; Aviram, M.; Cohen, M.; Armoni, S.; Yaakov, Y.; Pugatsch, T.; Cohen-Cymberknoh, M.; Miller, N. L.; Reha, A.; Northcutt, V. J.; Hirawat, S.; Donnelly, K.; Elfring, G. L.; Ajayi, T.; Kerem, E. (2011). “Chronic ataluren (PTC124) treatment of nonsense mutation cystic fibrosis”. European Respiratory Journal 38 (1): 59–69. doi:10.1183/09031936.00120910PMID 21233271. edit Sermet-Gaudelus, I.; Boeck, K. D.; Casimir, G. J.; Vermeulen, F.; Leal, T.; Mogenet, A.; Roussel, D.; Fritsch, J.; Hanssens, L.; Hirawat, S.; Miller, N. L.; Constantine, S.; Reha, A.; Ajayi, T.; Elfring, G. L.; Miller, L. L. (November 2010). “Ataluren (PTC124) induces cystic fibrosis transmembrane conductance regulator protein expression and activity in children with nonsense mutation cystic fibrosis”. American Journal of Respiratory and Critical Care Medicine 182 (10): 1262–1272.doi:10.1164/rccm.201001-0137OCPMID 20622033. edit
  6.  “PTC Therapeutics Completes Enrollment of Phase 3 Trial of Ataluren in Patients with Cystic Fibrosis (NASDAQ:PTCT)”. Ptct.client.shareholder.com. 2010-12-21. Retrieved 2013-11-28.
  7.  Wilschanski, M. (2013). “Novel therapeutic approaches for cystic fibrosis”. Discovery medicine 15 (81): 127–133. PMID 23449115. edit
  8.  http://www.marketwatch.com/story/ptc-therapeutics-receives-positive-opinion-from-chmp-for-translarna-ataluren-2014-05-23

External links

 

other sources

rINN: Ataluren
Other Names
PTC124®, 3-[5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl]benzoic acid
Pharmacological Information
Pharmacology Images

Ataluren Molecule

Ataluren.png
Web information on Ataluren
Relevant Clinical Literature
UK Guidance
Regulatory Literature
Other Literature

Orphan drug under investigation for treatment of genetic conditions where nonsense mutations result in premature termination of polypeptides. This drug, which is convenient to deliver orally, appears to allow ribosomal transcription ofRNA to continue past premature termination codon mutations with correct reading of the full normal transcript which then terminates at the proper stop codon. Problematically it has been postulated that assay artifact may have complicated evaluation of its efficacy which appears to be less than gentamicin.[1] Faults of this class in the transcription process are involved in several inherited diseases.

Some forms of cystic fibrosis and Duchenne muscular dystrophy are being targeted in the development stage of the drug.[2] Phase I and II trials are promising for cystic fibrosis.[3][4] In a mouse model of Duchenne muscular dystrophy, restoration of muscle function occurred.[5]

A potential issue is that there may be parts of the human genome whose optimal gene function through evolution has resulted from relatively recent in evolutionary terms insertion of a premature termination codon and so functional suboptimal transcripts of other proteins or functional RNAs might result.

References

  1.  Roberts RG. A read-through drug put through its paces. PLoS biology. 2013; 11(6):e1001458.(Link to article – subscription may be required.)
  2.  Hirawat S, Welch EM, Elfring GL, Northcutt VJ, Paushkin S, Hwang S, Leonard EM, Almstead NG, Ju W, Peltz SW, Miller LL. Safety, tolerability, and pharmacokinetics of PTC124, a nonaminoglycoside nonsense mutation suppressor, following single- and multiple-dose administration to healthy male and female adult volunteers. Journal of clinical pharmacology. 2007 Apr; 47(4):430-44.(Link to article– subscription may be required.)
  3.  Kerem E, Hirawat S, Armoni S, Yaakov Y, Shoseyov D, Cohen M, Nissim-Rafinia M, Blau H, Rivlin J, Aviram M, Elfring GL, Northcutt VJ, Miller LL, Kerem B, Wilschanski M. Effectiveness of PTC124 treatment of cystic fibrosis caused by nonsense mutations: a prospective phase II trial. Lancet. 2008 Aug 30; 372(9640):719-27.(Link to article – subscription may be required.)
  4.  Sermet-Gaudelus I, Boeck KD, Casimir GJ, Vermeulen F, Leal T, Mogenet A, Roussel D, Fritsch J, Hanssens L, Hirawat S, Miller NL, Constantine S, Reha A, Ajayi T, Elfring GL, Miller LL. Ataluren (PTC124) Induces Cystic Fibrosis Transmembrane Conductance Regulator Protein Expression and Activity in Children with Nonsense Mutation Cystic Fibrosis. American journal of respiratory and critical care medicine. 2010 Nov 15; 182(10):1262-72.(Link to article – subscription may be required.)
  5.  Welch EM, Barton ER, Zhuo J, Tomizawa Y, Friesen WJ, Trifillis P, Paushkin S, Patel M, Trotta CR, Hwang S, Wilde RG, Karp G, Takasugi J, Chen G, Jones S, Ren H, Moon YC, Corson D, Turpoff AA, Campbell JA, Conn MM, Khan A, Almstead NG, Hedrick J, Mollin A, Risher N, Weetall M, Yeh S, Branstrom AA, Colacino JM, Babiak J, Ju WD, Hirawat S, Northcutt VJ, Miller LL, Spatrick P, He F, Kawana M, Feng H, Jacobson A, Peltz SW, Sweeney HL. PTC124 targets genetic disorders caused by nonsense mutations. Nature. 2007 May 3; 447(7140):87-91.(Link to article – subscription may be required.)

old cut paste

A large-scale, multinational, phase 3 trial of the experimental drug ataluren has opened its first trial site, in Cincinnati, Ohio.

The trial is recruiting boys with Duchenne muscular dystrophy (DMD) or Becker muscular dystrophy (BMD) caused by anonsense mutation —  also known as a premature stop codon — in the dystrophin gene. This type of mutation causes cells to stop synthesizing a protein before the process is complete, resulting in a short, nonfunctional protein. Nonsense mutations are believed to cause DMD or BMD in approximately 10 to 15 percent of boys with these disorders.

Ataluren — sometimes referred to as a stop codon read-through drug — has the potential to overcome the effects of a nonsense mutation and allow functional dystrophin — the muscle protein that’s missing in Duchenne MD and deficient in Becker MD — to be produced.

The orally delivered drug is being developed by PTC Therapeutics, a South Plainfield, N.J., biotechnology company, to whichMDA gave a $1.5 million grant in 2005.

PTC124 has been developed by PTC Therapeutics.

India approved 26 drugs without clinical trials


New Delhi: Officials in the Indian health ministry have admitted that about 26 new drug molecules were given approval since 2010 without conducting any proper clinical trials on local population to test their safety and efficacy. Despite strict instructions by the parliamentary standing committee on health, so many new drugs have continued to make their way into the market.

19 August 2013 Officials in the Indian health ministry has accepted that about 26 new drugs were permitted for sale in the country without holding any clinical trials on Indian patients to test their safety and efficacy –

Read more at: http://www.biospectrumasia.com/biospectrum/news/193708/india-approved-26-drugs-clinical-trials#.UhHPwaI3CSo

 

 

 

DR A.M. CRASTO

Oramed Enrolls First Patient in its Phase 2a U.S. Oral Insulin Clinical Trial


Nadav Kidron

Nadav Kidron

Marks initiation of Oramed’s first FDA trial for its flagship ORMD-0801 oral insulin product

JERUSALEM, July 8, 2013

Oramed Pharmaceuticals Inc. (NASDAQCM: ORMP) (http://www.oramed.com), a developer of oral drug delivery systems, announced today that the first patient has been enrolled in a Phase 2a trial of ORMD-0801, an orally ingestible insulin capsule, on patients with type 2 diabetes. The current trial is to be a randomized, double-blind study designed to assess the safety of ORMD-0801.
Read more at

http://www.drugs.com/clinical_trials/oramed-enrolls-first-patient-phase-2a-u-s-oral-insulin-clinical-trial-15855.html

In addition to ORMD-0801, Oramed is also developing an oral GLP-1 analog, known as exenatide, and a combination therapy of ORMD-0801 and exenatide.
GLP-1, or glucagon-like peptide-1, possesses a number of physiological properties that make it and its analogs the subject of intensive investigation as a potential treatment for diabetes. Among other things, it aids in the balance of blood sugar levels by decreasing glucose levels, especially after a meal; promotes weight loss; and does not cause hypoglycemia.

Sandoz launches Phase III clinical trial for biosimilar etanercept


Etanercept

is made from the combination of two naturally occurring soluble human 75-kilodalton TNF receptors linked to an Fc portion of an IgG1. The effect is an artificially engineered dimeric fusion protein.

Sandoz launches Phase III clinical trial for biosimilar etanercept
Trial expected to support registration in the U.S. and European Union
•    Sandoz continues to advance biosimilar pipeline with seven Phase III trials across five molecules
•    Global program underscores Sandoz’s leadership in biosimilarsHolzkirchen, Germany, June 24, 2013 – Sandoz, the global leader in biosimilars, announced it has initiated a major Phase III clinical trial with its biosimilar version of etanercept (Amgen’s Enbrel®).
Read more at

http://www.drugs.com/news/novartis-begins-enbrel-phase-iii-trial-45414.html

Etanercept (trade name Enbrel) is a biopharmaceutical that treats autoimmune diseases by interfering with tumor necrosis factor (TNF; a soluble inflammatory cytokine) by acting as a TNF inhibitor. It has U.S. F.D.A. approval to treat rheumatoid, juvenile rheumatoid andpsoriatic arthritis, plaque psoriasis and ankylosing spondylitis. TNF-alpha is the “master regulator” of the inflammatory (immune) response in many organ systems. Autoimmune diseases are caused by an overactive immune response. Etanercept has the potential to treat these diseases by inhibiting TNF-alpha.
Etanercept is a fusion protein produced by recombinant DNA. It fuses the TNF receptor to the constant end of the IgG1 antibody. First, the developers isolated the DNA sequence that codes the human gene for soluble TNF receptor 2, which is a receptor that binds to tumor necrosis factor-alpha. Second, they isolated the DNA sequence that codes the human gene for the Fc end of immunoglobulin G1 (IgG1). Third, they linked the DNA for TNF receptor 2 to the DNA for IgG1 Fc. Finally, they expressed the linked DNA to produce a protein that links the protein for TNF receptor 2 to the protein for IgG1 Fc.

The prototypic fusion protein was first synthesized and shown to be highly active and unusually stable as a modality for blockade of TNF in vivo in the early 1990s by Bruce A. Beutler, an academic researcher then at the University of Texas Southwestern Medical Center at Dallas, and his colleagues.[2][3][4] These investigators also patented the protein, selling all rights to its use to Immunex, a biotechnology company that was acquired by Amgen in 2002.

It is a large molecule, with a molecular weight of 150 kDa., that binds to TNFα and decreases its role in disorders involving excess inflammation in humans and other animals, including autoimmune diseases such as ankylosing spondylitis, juvenile rheumatoid arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, and, potentially, in a variety of other disorders mediated by excess TNFα.

In North America, etanercept is co-marketed by Amgen and Pfizer under the trade name Enbrel in two separate formulations, one in powder form, the other as a pre-mixed liquid. Wyeth is the sole marketer of Enbrel outside North America excluding Japan whereTakeda Pharmaceuticals markets the drug.

Etanercept is an example of a protein-based drug created using the tools of biotechnologyand conceived through an understanding afforded by modern cell biology.

Clinical trial starts in the UK to heal hearts with genetic virus


 

A group of UK heart failure patients have been enrolled on a new clinical trial to see if a genetically engineered virus can help heal their ailing hearts.

Researchers at Imperial College London will introduce a genetic virus into the heart muscles of the 200 participants, in a bid to reverse the heart muscle’s decline.

READ ALL AT

http://www.pharmaceutical-technology.com/news/newsclinical-trial-starts-in-the-uk-to-heal-hearts-with-genetic-virus?WT.mc_id=DN_News

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