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African medicine-cyclotides as an aid during child birth

July 19, 2013 7:42 am / 3 Comments on African medicine-cyclotides as an aid during child birth

Oldenlandia affinis was used by native women in the Zaire as an aid during childbirth. A tea was made of the leaves and imbibed during labour.

Cyclotides are plant-derived peptides of approximately 30 amino acids. They have the characteristic structural features of a head-to-tail cyclized backbone and a cystine knot arrangement of their three conserved disulfide bonds. Their unique structural features lead to exceptional stability. This and their amenability to chemical synthesis have made it possible to use cyclotides as templates in protein engineering and drug design applications.

David J Craik, University of Queensland, Brisbane, Australia, whose laboratory is working over 20 years in the field, summarizes the history of cyclotides

http://www.chemistryviews.org/details/news/5012211/History_of_Cyclotides.html

more info on cyclotides

This is how it was discovered: a physician working in the Democratic Republic of Congo noticed that laboring women were drinking tea made from Oleanda affinis to induce childbirth. Theactive ingredient was the first cyclotide to be discovered. Since then, cyclotides have been shown to be antibiotic, antiviral and insecticidal.

Figure 1. Structure and sequence of the prototypic cyclotide kalata B1

Cyclotides are small disulfide-rich proteins that have the unusual feature of a cyclic backbone (hence the name cyclo – peptides). They contain six conserved cystine residues that are arranged in a cystine knot topology in which two disulfide bonds and their connecting backbone segments form an embedded ring in the structure that is penetrated by a third disulfide bond, as shown below.

Cyclotides have a range of interesting biological activities including anti-HIV and neurotensin inhibition, anti-microbial activity and insecticidal activity. They are found in a variety of tropical plants from the Rubiaceae and Violaceae families.

The structure of kalata B1 showing the distorted beta-sheet topology and the loop nomenclature enabled by the cyclic backbone.

Cyclotides are small disulfide rich peptides isolated from plants.Typically containing 28-37 amino acids, they are characterized by their head-to-tail cyclised peptide backbone and the interlocking arrangement of their three disulfide bonds. These combined features have been termed the cyclic cystine knot (CCK) motif (Figure 1). To date, over 100 cyclotides have been isolated and characterized from species of the Rubiaceae, Violaceae, and Cucurbitaceae families. Cyclotides have also been identified in agriculturally important families such as the Fabaceae and Poaceae.,

Cyclotides have been reported to have a wide range of biological activities, including anti-HIV, insecticidal, anti-tumour, antifouling, anti-microbial, hemolytic, neurotensinantagonism, trypsin inhibition, and uterotonic activities. An ability to induceuterine contractions was what prompted the initial discovery of kalata B1.

The potent insecticidal activity of cyclotides kalata B1 and kalata B2 has prompted the belief that cyclotides act as plant host-defence agents (Figure 2). The observations that dozens or more cyclotides may be present in a single plant and the cyclotide architecture comprises a conserved core onto which a series of hypervariable loops is displayed suggest that, cyclotides may be able to target many pests/pathogens simultaneously.

The cyclotides have been recognised as a family of novel circular proteins only in the last few years but the discovery of the first member of this family may be traced back to reports of native medicine applications in the early 1970s.

Kalata B1, was discovered because it is an active ingredient in a herbal medicine used by African women to assist childbirth . While on a Red Cross relief effort in the Congo region in the 1960s a Norwegian doctor, Lorents Gran, noted that during labour African women often ingested a tea made from leaves of the plant Oldenlandia affinis because of its uterotonic effects. The active ingredient was determined to be a peptide that was named kalata B1, after the local name for the native medicine. Subsequent in vivo studies in rats confirmed uterotonic activity of the purified peptide but it was not characterised as a macrocyclic peptide until some 20 year later.

The mid-1990�s was a key period in the discovery of macrocyclic peptides, with several independent groups discovering such peptides while screening for various biological activities and our group determining the three dimensional structure of kalata B1 . In the first fortuitous discovery Sch�pke et al., examined Viola arvensis and V. tricolor in a study aimed at the discovery of new saponins. While assaying for the usual hemolytic activity of saponins they discovered a macrocyclic peptide, violapeptide I, with hemolytic activity. At around the same time bio-assay driven screens for anti-HIV and anti-neurotensin activity led to the discovery of the circulins and cyclopsychotride A respectively.

Viola arvensis a cyclotide containing plant. Member of the violaceae family and found in temperate regions of Australia and Europe.

With our report of the three dimensional structure of kalata B1 in 1995 and its sequence homology with the circulins and cyclopsychotride A, we became convinced that macrocyclic peptides might be more common than had earlier been thought and we began searching for other examples. Several other macrocyclic peptides were found in the late 1990s and it became clear that the peptides formed part of a family that we subsequently named the cyclotides.

Several novel cyclotide sequences have been discovered in the last few years , with the known sequences now exceeding 45 and many more currently being characterized in our laboratories. A large proportion of the new cyclotides have been discovered based on their structural properties rather than biological activities. The cyclotides are relatively hydrophobic and can be readily identified from crude plant extracts by their characteristically late elution on RP-HPLC.

The cyclotides described above, all come from plants in the Rubiaceae or Violaceae families but the prevalence of macrocyclic peptides has recently been expanded to include the Cucurbitaceae family. This is based on the discovery of the trypsin inhibitors MCoTI-I and MCoTI-II, 34 residue macrocyclic peptides, from Momordica cochinchinensis . They have no sequence homology to the previously characterized cyclotides, with the exception of the six cysteine residues, but are of a similar size and contain a cystine knot motif (Felizmenio-Quimio, 2001). The MCoTI peptides were originally isolated based on their trypsin inhibitory activity and are homologous to linear cystine knot peptides from the squash family of trypsin inhibitors such as EETI-II and CMTI.

References

Bokesch HR, Pannell LK, Cochran PK, Sowder RC, 2nd, McKee TC and Boyd MR: A novel anti-HIV macrocyclic peptide from Palicourea condensata. J. Nat. Prod. (2001) 64:249-250.

Broussalis AM, Goransson U, Coussio JD, Ferraro G, Martino V and Claeson P: First cyclotide from Hybanthus (Violaceae). Phytochemistry (2001) 58:47-51.

Claeson P, G�ransson U, Johansson S, Luijendijk T and Bohlin L: Fractionation protocol for the isolation of polypeptides from plant biomass. J. Nat. Prod. (1998) 61:77-81.

Craik DJ, Daly NL, Bond T and Waine C: Plant cyclotides: A unique family of cyclic and knotted proteins that defines the cyclic cystine knot structural motif. J. Mol. Biol. (1999) 294:1327-1336.

G�ransson U, Luijendijk T, Johansson S, Bohlin L and Claeson P: Seven novel macrocyclic polypeptides from Viola arvensis. J. Nat. Prod. (1999) 62:283-286.

Gran L: Isolation of oxytocic peptides from Oldenlandia affinis by solvent extraction of tetraphenylborate complexes and chromatography on sephadex LH-20. Lloydia (1973a) 36:207-208.

Gran L: On the effect of a polypeptide isolated from “Kalata-Kalata” (Oldenlandia affinis DC) on the oestrogen dominated uterus. Acta Pharmacol. Toxicol. (1973b) 33:400-408.

Gustafson KR, Sowder II RC, Henderson LE, Parsons IC, Kashman Y, Cardellina II JH, McMahon JB, Buckheit Jr. RW, Pannell LK and Boyd MR: Circulins A and B: Novel HIV-inhibitory macrocyclic peptides from the tropical tree Chassalia parvifolia. J. Am. Chem. Soc. (1994) 116:9337-9338.

Hallock YF, Sowder RCI, Pannell LK, Hughes CB, Johnson DG, Gulakowski R, Cardellina JHI and Boyd MR: Cycloviolins A-D, anti-HIV macrocyclic peptides from Leonia cymosa. J. Org. Chem.(2000) 65:124-128.

Hernandez JF, Gagnon J, Chiche L, Nguyen TM, Andrieu JP, Heitz A, Trinh Hong T, Pham TT and Le Nguyen D: Squash trypsin inhibitors from Momordica cochinchinensis exhibit an atypical macrocyclic structure. Biochemistry (2000) 39:5722-5730.

Saether O, Craik DJ, Campbell ID, Sletten K, Juul J and Norman DG: Elucidation of the primary and three-dimensional structure of the uterotonic polypeptide kalata B1. Biochemistry (1995) 34:4147-4158.

Sch�pke T, Hasan Agha MI, Kraft R, Otto A and Hiller K: H�molytisch aktive komponenten aus Viola tricolor L. und Viola arvensis Murray. Sci. Pharm. (1993) 61:145-153.

Witherup KM, Bogusky MJ, Anderson PS, Ramjit H, Ransom RW, Wood T and Sardana M: Cyclopsychotride A, A biologically active, 31-residue cyclic peptide isolated from Psychotria Longipes. J. Nat. Prod. (1994) 57:1619-1625.

Extracting the Medicine from Traditional Chinese Medicine-Used as sedative and a painkiller in Oriental medicine

July 19, 2013 3:54 am / 2 Comments on Extracting the Medicine from Traditional Chinese Medicine-Used as sedative and a painkiller in Oriental medicine

Nardostachys chinensis.

Extracting the Medicine from Traditional Chinese Medicine

Nardostachys chinensis or “Gansong” – a medicinal plant in the family Valerianaceae – is used as a sedative and a painkiller in Oriental medicine. Jun Zhou, Chinese Academy of Sciences, Kunming, and colleagues have isolated a new type of sesquieterpenoid–chalcone hybrid, containing a 2,3-dihydrofuran ring fused to an aristolane-type sesquiterpenoid and a chalcone, nardokanshone A (pictured).

http://www.chemistryviews.org/details/news/5012431/Extracting_the_Medicine_from_Traditional_Chinese_Medicine.html

Zhang, X; Lan Z, Dong XP, Deng Y, Hu XM, Peng T, Guo P. (January 2007). “Study on the active components of Nardostachys chinensis”. Zhong Yao Cai: 38–41. PMID 17539300. Retrieved 12 June 2013.

Ayurveda- Obesity control

July 19, 2013 2:57 am / 2 Comments on Ayurveda- Obesity control

Currently, Indian anti-obesity drug market is bifurcated into prescription and non-prescription. Amongst the prescription anti-obesity drug market there is only one drug – Orlistat that is been used globally. While the other anti-obesity drugs, Rimonabant and Sibutramine were banned by Indian government in 2009 and 2010 as side-effects were found in those drugs.

According to the experts, the market size of anti-obesity for prescription drug (generic Orlistat) is Rs 40 crore. While market size of non-prescription drug mostly herbal and ayurvedic drugs is estimated at Rs 500 crore in India. The global anti-obesity drug market is expected to reach $11 billion by 2017.

Orlistat is originally made by multinational drug company Roche that markets the prescription drug under the brand/trade name Xenical. The drug’s patent protection ended in 2009. Currently, there is plethora of generic drug makers like Ranbaxy, Intas Pharma, Biocon Ltd, Torrent Pharma, Troikaa Pharma and Mankind Pharmaceuticals that makes generic copies of Orlistat in India.

http://ijrap.net/admin/php/uploads/870_pdf.pdf

http://www.docstoc.com/docs/19918481/Evaluation-of-certain-medicinal-plants-for-antiobesity-properties

http://nopr.niscair.res.in/bitstream/123456789/6269/1/IJTK%208(4)%20602-605.pdf

anti obesity drugs

Obesity is a medical condition in which excess body fat has accumulated to the extent that it may have an adverse effect on health, leading to reduced life expectancy and/or increased health problems. Body mass index (BMI), a measurement which compares weight and height, defines people as overweight (pre-obese) when their BMI is between 25 kg/m2 and 30 kg/m2, and obese when it is greater than 30 kg/m

Obesity increases the likelihood of various diseases, particularly heart disease, type 2 diabetes, breathing difficulties during sleep, certain types of cancer, and osteoarthritis. Obesity is most commonly caused by a combination of excessive dietary calories, lack of physical activity, and genetic susceptibility, although a few cases are caused primarily by genes, endocrine disorders, medications or psychiatric illness. Evidence to support the view that some obese people eat little yet gain weight due to a slow metabolism is limited; on average obese people have a greater energy expenditure than their thin counterparts due to the energy required to maintain an increased body mass.

The primary treatment for obesity is dieting and physical exercise. To supplement this, or in case of failure, anti-obesity drugs may be taken to reduce appetite or inhibit fat absorption. In severe cases, surgery is performed or an intragastric balloon is placed to reduce stomach volume and/or bowel length, leading to earlier satiation and reduced ability to absorb nutrients from food.

Obesity is a leading preventable cause of death worldwide, with increasing prevalence in adults and children, and authorities view it as one of the most serious public health problems of the 21st century. Obesity is stigmatized in the modern Western world, though it has been perceived as a symbol of wealth and fertility at other times in history, and still is in many parts of Africa.[

Excessive body weight is associated with various diseases, particularly cardiovascular diseases, diabetes mellitus type 2, obstructive sleep apnea, certain types of cancer, and osteoarthritis. As a result, obesity has been found to reduce life expectancy.

Obesity is one of the leading preventable causes of death worldwide. Large-scale American and European studies have found that mortality risk is lowest at a BMI of 22.5–25 kg/m in non-smokers and at 24–27 kg/m2 in current smokers, with risk increasing along with changes in either direction. A BMI above 32 has been associated with a doubled mortality rate among women over a 16-year period. In the United States obesity is estimated to cause an excess 111,909 to 365,000 death per year, while 1 million (7.7%) of deaths in the European Union are attributed to excess weight On average, obesity reduces life expectancy by six to seven years: a BMI of 30–35 reduces life expectancy by two to four years, while severe obesity (BMI > 40) reduces life expectancy by 10 year

Causes

At an individual level, a combination of excessive caloric intake and a lack of physical activity is thought to explain most cases of obesity. A limited number of cases are due primarily to genetics, medical reasons, or psychiatric illness. In contrast, increasing rates of obesity at a societal level are felt to be due to an easily accessible and palatable diet,[64] increased reliance on cars, and mechanized manufacturing. A 2006 review identified ten other possible contributors to the recent increase of obesity: (1) insufficient sleep, (2) endocrine disruptors (environmental pollutants that interfere with lipid metabolism), (3) decreased variability in ambient temperature, (4) decreased rates of smoking, because smoking suppresses appetite, (5) increased use of medications that can cause weight gain (e.g., atypical antipsychotic), (6) proportional increases in ethnic and age groups that tend to be heavier, (7) pregnancy at a later age (which may cause susceptibility to obesity in children), (8) epigenetic risk factors passed on gene rationally, (9) natural selection for higher BMI, and (10) assortative mating leading to increased concentration of obesity risk factors (this would not necessarily increase the number of obese people, but would increase the average population weight).[67] While there is substantial evidence supporting the influence of these mechanisms on the increased prevalence of obesity, the evidence is still inconclusive, and the authors state that these are probably less influential than the ones discussed in the previous paragraph.

Ways of preventing Obesity

Dieting

Main article: Dieting

Diets to promote weight loss are generally divided into four categories: low-fat, low-carbohydrate, low-calorie, and very low calorie. A meta-analysis of six randomized controlled trials found no difference between three of the main diet types (low calorie, low carbohydrate, and low fat), with a 2–4 kilogram (4.4–8.8 lb) weight loss in all studies. At two years these three methods resulted in similar weight loss irrespective of the macronutrients emphasized.[132]

Very low calorie diets provide 200–800 kcal/day, maintaining protein intake but limiting calories from both fat and carbohydrates. They subject the body to starvation and produce an average weekly weight loss of 1.5–2.5 kilograms (3.3–5.5 lb). These diets are not recommended for general use as they are associated with adverse side effects such as loss of lean muscle mass, increased risks of gout, and electrolyte imbalances. People attempting these diets must be monitored closely by a physician to prevent complications.

Exercise

With use, muscles consume energy derived from both fat and glycogen. Due to the large size of leg muscles, walking, running, and cycling are the most effective means of exercise to reduce body fat. Exercise affects macronutrient balance. During moderate exercise, equivalent to a brisk walk, there is a shift to greater use of fat as a fuel. To maintain health the American Heart Association recommends a minimum of 30 minutes of moderate exercise at least 5 days a week.

A meta-analysis of 43 randomized controlled trials by the Cochrane Collaboration found that exercising alone led to limited weight loss. In combination with diet, however, it resulted in a 1 kilogram weight loss over dieting alone. A 1.5 kilogram (3.3 lb) loss was observed with a greater degree of exercise. Even though exercise as carried out in the general population has only modest effects, a dose response curve is found, and very intense exercise can lead to substantial weight loss. During 20 weeks of basic military training with no dietary restriction, obese military recruits lost 12.5 kg (27.6 lb). High levels of physical activity seem to be necessary to maintain weight loss. A pedometer appears useful for motivation. Over an average of 18-weeks of use physical activity increased by 27% resulting in a 0.38 decreased in BMI.

Signs that encourage the use of stairs as well as community campaigns have been shown to be effective in increasing exercise in a population. The city of Bogota, Colombia for example blocks off 113 kilometers (70 miles) of roads every Sunday and on holidays to make it easier for its citizens to get exercise. These pedestrian zones are part of an effort to combat chronic diseases, including obesity.

Weight loss programs

Weight loss programs often promote lifestyle changes and diet modification. This may involve eating smaller meals, cutting down on certain types of food, and making a conscious effort to exercise more. These programs also enable people to connect with a group of others who are attempting to lose weight, in the hopes that participants will form mutually motivating and encouraging relationships.

A number of popular programs exist, including Weight Watchers, Overeaters Anonymous, and Jenny Craig. These appear to provide modest weight loss (2.9 kg, 6.4 lb) over dieting on one’s own (0.2 kg, 0.4 lb) over a two year period. Internet-based programs appear to be ineffective. The Chinese government has introduced a number of “fat farms” where obese children go for reinforced exercise, and has passed a law which requires students to exercise or play sports for an hour a day at school (see Obesity in China).

Medication

Main article: Anti-obesity medication

The two most commonly used medications to treat obesity: orlistat (Xenical) and sibutramine (Meridia)

Only two anti-obesity medications are currently approved by the FDA for long term use.[147] One is orlistat (Xenical), which reduces intestinal fat absorption by inhibiting pancreatic lipase; the other is sibutramine (Meridia), which acts in the brain to inhibit deactivation of the neurotransmitters norepinephrine, serotonin, and dopamine (very similar to some anti-depressants), therefore decreasing appetite. Rimonabant (Acomplia), a third drug, works via a specific blockade of the endocannabinoid system. It has been developed from the knowledge that cannabis smokers often experience hunger, which is often referred to as “the munchies”. It had been approved in Europe for the treatment of obesity but has not received approval in the United States or Canada due to safety concerns.[148][149] European Medicines Agency in October 2008 recommended the suspension of the sale of rimonabant as the risk seem to be greater than the benefits.

Weight loss with these drugs is modest. Over the longer term, average weight loss on orlistat is 2.9 kg (6.4 lb), sibutramine is 4.2 kg (9.3 lb) and rimonabant is 4.7 kg (10.4 lb). Orlistat and rimonabant lead to a reduced incidence of diabetes, and all three drugs have some effect on cholesterol. However, there is little information on how these drugs affect the longer-term complications or outcomes of obesity. In 2010 the FDA noted concerns that sibutramine increases the risk of heart attacks and strokes in patients with a history of cardiovascular disease.

There are a number of less commonly used medications. Some are only approved for short term use, others are used off-label, and still others are used illegally. Most are appetite suppressants that act on one or more neurotransmitters. Phendimetrazine (Bontril), diethylpropion (Tenuate), and phentermine (Adipex-P) are approved by the FDA for short term use, while bupropion (Wellbutrin), topiramate (Topamax), and zonisamide (Zonegran) are sometimes used off-label.

The usefulness of certain drugs depends upon the comorbities present. Metformin (Glucophage) is preferred in overweight diabetics, as it may lead to mild weight loss in comparison to sulfonylureas or insulin. The thiazolidinediones, on the other hand, may cause weight gain, but decrease central obesity.[155] Diabetics also achieve modest weight loss with fluoxetine (Prozac), orlistat and sibutramine over 12–57 weeks. Preliminary evidence has however found higher number of cardiovascular events in people taking sibutramine verses control (11.4% vs. 10.0%). The long-term health benefits of these treatments remain unclear.

Fenfluramine and dexfenfluramine were withdrawn from the market in 1997, while ephedrine (found in the traditional Chinese herbal medicine má huáng made from the Ephedra sinica) was removed from the market in 2004. Dexamphetamines are not approved by the FDA for the treatment of obesity due to concerns regarding addiction.[147] the use of these drugs is not recommended due to potential side effects. However, people do occasionally use these drugs illegally.

Surgery

Main article: Bariatric surgery

Bariatric surgery (“weight loss surgery”) is the use of surgical intervention in the treatment of obesity. As every operation may have complications, surgery is only recommended for severely obese people (BMI > 40) who have failed to lose weight following dietary modification and pharmacological treatment. Weight loss surgery relies on various principles: the two most common approaches are reducing the volume of the stomach (e.g. by adjustable gastric banding and vertical banded gastroplasty), which produces an earlier sense of satiation, and reducing the length of bowel that comes into contact with food (gastric bypass surgery), which directly reduces absorption. Band surgery is reversible, while bowel shortening operations are not. Some procedures can be performed laparoscopically. Complications from weight loss surgery are frequent.

Surgery for severe obesity is associated with long-term weight loss and decreased overall mortality. One study found a weight loss of between 14% and 25% (depending on the type of procedure performed) at 10 years, and a 29% reduction in all cause mortality when compared to standard weight loss measures. A marked decrease in the risk of diabetes mellitus, cardiovascular disease and cancer has also been found after bariatric surgery. Marked weight loss occurs during the first few months after surgery, and the loss is sustained in the long term. In one study there was an unexplained increase in deaths from accidents and suicide, but this did not outweigh the benefit in terms of disease prevention. When the two main techniques are compared, gastric bypass procedures are found to lead to 30% more weight loss than banding procedures one year after surgery.

The effects of liposuction on obesity are less well determined. Some small studies show benefits while others show none. A treatment involving the placement of an intragastric balloon via gastroscopy has shown promise. One type of balloon lead to a weight loss of 5.7 BMI units over 6 months or 14.7 kg (32.4 lb). Regaining lost weight is common after removal, however, and 4.2% of people were intolerant of the device.

Other Home Remedies

Honey: Mix one teaspoon of honey with two teaspoons of lime juice and some pepper. Drink this at least once a day.

Boiled Water: Drink a glass of boiled water every day after a meal.

Ginger Tea: Drink ginger tea 2-3 times a day.

Black Pepper: Seasoning foods with black pepper will decrease the need for salts and fats, and will still add flavor to foods. This will also help reduce weight.

Cinnamon: This spice can act as a low calorie sweetener to help reduce the amount of sugar needed in a recipe. It also adds a unique flavor to most cookie recipes.

Shudh Guggulu: Take Guggulu with a teaspoon of ginger and honey twice a day. This helps increase a body’s metabolism.

Trifla: This is another diet aid that contains amalaki, bibbitaki, and haritaki. This should be taken at least once a day if one chooses to use this supplement.

Raw or Cooked Cabbage: The intake of cabbage reduces the conversion of sugars to fat. Therefore, eating plenty of this well help increase the body’s ability to metabolize fatty foods.

Vitamin B-12: Take a vitamin B-12 tablet at least once daily. For further information on vitamin usage, read the directions on the vitamin bottle, and consult a doctor for more information. This vitamin comes also in leafy dark green vegetables, so eat many of these as often as possible.

Ayurvedic Medicines for Obesity

Traphala Capsules
Shuddha Guggulu Capsules
Morslim-Z slimming Capsules of Obesity

When one follow the above diet recommendations and partake in one or more of the ayurvedic remedies, that person will be cured from obesity.

When not sure about how to apply herbal remedies or diet tablets, one should consult an ayurvedic specialist who is trained to help people in determining correct dosage. This is especially true for children inflicted with any disease, but is true for everyone. All medicines should be taken within the recommended guidelines.

Shuddha Guggulu

The effective lipid regulator

In the ancient Ayurvedic text, Sushruta Samhita, Shuddha Guggulu (Indian Bdellium/Commiphora wightii) was prescribed for the treatment of medoroga, a disease that closely resembles the symptoms of hyperlipidemia including high blood cholesterol and the hardening of arteries.

Shuddha Guggulu has been used historically for centuries to support normal fat levels and metabolism. In the findings published in the American research journal Science, scholars at the Baylor College of Medicine in Houston reported that the 2,500 year old traditional Indian cholesterol support plant ‘really works’!

Another group of scholars at the University of Texas Southwestern Medical Center in Dallas found that Shuddha Guggulu supports cholesterol metabolism and exerts an antioxidant effect, which supports the normal oxidation levels of cholesterol in the body.

Shuddha Guggulu, which is actually a gum resin from the Myrrh tree or shrub, was also used historically to support normal joint function. Contemporary scholars at the South Carolina University of Health Sciences found Shuddha Guggulu to be ‘supportive of normal mobility levels.’

The antioxidant effects of Shuddha Guggulu have also undergone recent scientific scrutiny. Researchers at the Jackson Laboratory in Bar Harbor, Maine, recently reported that ‘Shuddha Guggulu and its component guggulsterone significantly support normal levels of low-density lipoproteins (LDL)’.

The herb is found across the world from Northern Africa to Central Asia. In India, it is found in the arid zones, mainly in the states Rajasthan and Gujarat.

Active constituents:

Shuddha Guggulu contains resin, volatile oils and gum. The extract has ketonic steroid compounds known as guggulsterones. E- and Z-guggulsterones are the compounds that are responsible for lowering cholesterol and triglyceride levels. As antioxidants, guggulsterones keep LDL cholesterol from oxidizing, an action which protects against atherosclerosis (artery hardening).

Herb functions:

High serum cholesterol: Guggulsterone, the active ingredient in Shuddha Guggulu, decreases LDL cholesterol and triglyceride levels, which in turn lowers the overall cholesterol levels in the blood. It modulates the lipid profile.

Atherosclerosis: Shuddha Guggulu is responsible for lowering cholesterol in the body, while at the same time boosting levels of ‘good’ cholesterol. Both of these actions help prevent atherosclerosis, the clogging and hardening of blood vessels. The herb is also an antioxidant, which helps stop the oxidization of cholesterol and the subsequent hardening of the arteries. Shuddha Guggulu also reduces the stickiness of platelets, another effect that lowers the risk of coronary artery disease.

Weight loss: Shuddha Guggulu enhances the thyroid function, which in turn regulates metabolism and can help with weight loss.

Arthritis: The herb is a potent anti-inflammatory and helps in the management of inflammatory joint disorders like arthritis.

Indications:

Hyperlipidemia (increased cholesterol level in the blood)
Arthritis
Atherosclerosis (clogging or hardening of blood vessels)
Weight management

http://www.himalayahealthcare.com/products/pharmaceuticals/shuddha-guggulu.htm

Commiphora mukul ,Guggul

as a binding agent only from modern perspective. Ayurveda mentions its use as anti-inflammatory, anti-obesity, uterine tonic, anti-hypercholesterolemic and immodulatory
dose of the gum resin is from 5 to 50 grain used in placenta previa,amenorrhoea,dysmenorrhoea sore nipples,gonorrhea and ringworm
how it is purified for gynecological disorders and what is the anupana
purification of gum guggul (loban in unani medicine) – resin is soaked in water and left for some time . the supernatant water is decanted off. this process may be repeated once again. the vessel containing the dissolved resin is placed in the open and dried, that is the water is allowed to evaporate. drying may effected mechanically also.the resin to be employed will be in the form of an extract.
Guggulu is considered to be a binding agent, though they have not used this term.
Acharya Sharangadhara mentions in Madhyama khanda 7/3….
Kuryad Avahnisiddena kwachid Gugguluna vatim!!
To prepare tablets without application of heat, Guggulu is added and tablets are advised to prepare. Here Guggulu acts as a binding agent only.
Lipid-lowering effects: Guggul (gum guggul) is a resin produced by the mukul mirth tree. Guggulipid is extracted from guggul using ethyl acetate. The preparation produced by extraction with petroleum ether is called a fraction A. Typical guggulipid preparations contain 2.5-5% of the plant sterols guggulsterones E and Z. These two components have been reported to exert effects on lipids.Several hypotheses have been advanced to explain these effects on lipids. Guggulsterones, particularly guggulsterone -pregnadiene-3,16-dione), have been reported to function as antagonists of the farsenoid X receptor (FXR) and the bile acid receptor (BAR), nuclear hormones which are involved with cholesterol metabolism and bile acid regulation. It has been reported that guggulsterone does not exert its lipid effects on mice lacking FXR. Other publications have proposed that guggul may inhibit lipogenic enzymes and HMG-Co A reductase in the liver. increase uptake of cholesterol by the liver via stimulation of LDL receptor binding. directly activate the thyroid gland and/or increase biliary and fecal excretion of cholesterol.
Antioxidant effects: Guggul extracts have been reported to possess antioxidant properties possibly mediating protection against myocardial necrosis
Platelet effects: Guggulipid has been found to inhibit platelet aggregation and increase fibrinolysis
Anti-inflammatory: the results of several studies suggest possible anti-inflammatory and antiarthritic activities of guggul. On a per-microgram basis, guggulipid appears to be significantly less potent than indomethacin or hydrocortisone. Possible effects on high-sensitivity C-reactive protein (hs-CRP) have recently been observed in a clinical trial.
Guggul has been a key component in ancient Indian Ayurvedic system of medicine. But has become so scarce because of its overuse in its two habitats in India where it is found — Gujarat and Rajasthan that the World Conservation Union (IUCN) has enlisted it in its Red Data List of endangered species.Guggul produces a resinous sap known as gum guggul. The extract of this gum, called gugulipid, guggulipid or guglipid, has been used in Ayurvedic medicine, a traditional Hindu medicine, for nearly 3,000 years in India. The active ingredient in the extract is the steroid guggulsterone, which acts as an antagonist of the farnesoid X receptor, once believed to result in decreased cholesterol synthesis in the liver. However, several studies have been published that indicate no overall reduction in total cholesterol occurs using various dosages of guggulsterone, and levels of low-density lipoprotein (“bad cholesterol”) increased in many people.
Guggul is sought for its gummy resin, which is harvested from the plant’s bark through the process of tapping. In India and Pakistan, guggul is cultivated commercially. The resin of the guggul plant, known as gum guggulu, has a fragrance similar to that of myrrh and is commonly used in incense and perfumes. It is the same product that was known in Hebrew, ancient Greek and Latin sources as bdellium.Guggul can be purchased in a loosely packed form called dhoop, an incense from India, which is burned over hot coals. This produces a fragrant, dense smoke. The burning coals which let out the smoke are then carried around to different rooms and held in all corners for a few seconds. This is said to drive away evil spirits as well as remove the evil eye from the home and its family members.

Enbrel (etanercept), Biosimilar innovator drug companies scrambling to copy

July 18, 2013 3:41 am / 5 Comments on Enbrel (etanercept), Biosimilar innovator drug companies scrambling to copy

Enbrel (etanercept)

http://www.biosimilarnews.com/enbrel-patent-in-the-us

Biosimilars are protein products that are sufficiently similar to a biopharmaceutical already approved by a regulatory agency. Several biotechnology companies and generic drug manufacturers in Asia and Europe are developing biosimilars of tumor necrosis factor inhibitors and rituximab. A biosimilar etanercept is already being marketed in Colombia and China. In the US, several natural source products and recombinant proteins have been approved as generic drugs under Section 505(b)(2) of the Food, Drug, and Cosmetic Act. However, because the complexity of large biopharmaceuticals makes it difficult to demonstrate that a biosimilar is structurally identical to an already approved biopharmaceutical, this Act does not apply to biosimilars of large biopharmaceuticals. Section 7002 of the Patient Protection and Affordable Care Act of 2010, which is referred to as the Biologics Price Competition and Innovation Act of 2009, amends Section 351 of the Public Health Service Act to create an abbreviated pathway that permits a biosimilar to be evaluated by comparing it with only a single reference biological product.

Amgen announced the issuance of U.S. Patent No. 8,063,182 related to Enbrel (etanercept).owned by Hoffmann-la roche and licensed to Amgen (exp2028) VIA immunex

A biosimilar etanercept, manufactured in China by CP Guojian Pharmaceutical Co., Ltd. (Shanghai), is already being marketed in China as Yisaipu [3] and in Colombia as Etanar [4]. Several biotechnology companies in Asia are also developing biosimilar versions of tumor necrosis factor inhibitors. Protalix Biotherapeutics, Inc. (Carmiel, Israel) is developing a biosimilar etanercept that is expressed in plant cells [5]. Mycenax Biotech (Taiwan) has completed early-phase clinical trials of a biosimilar etanercept in Southeast Asia: a phase I trial among 24 healthy subjects in South Korea and a phase I/II trial that enrolled 18 patients with rheumatoid arthritis in Taiwan [6]. Avesthagen (Bangalore, India) has received a patent from the Indian patent office for a biosimilar etanercept [7]. In South Korea, both Celltrion (Yeonsu-gu Incheon City) and Aprogen (Daejeon) are developing a biosimilar of infliximab [8] and LG Life Sciences (Seoul) is developing biosimilars of both etanercept and infliximab to treat rheumatoid arthritis and other inflammatory diseases [9].

Drug developers:

Avesthagen: Avent™ in clinical studies

read this doc

http://www.avesthagen.com/docs/020910pr.pdf

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BioXpress Therapeutics: Biosimilar in active development

http://www.bioxpress.com/pipeline/

………………………………………………………………………………………

Cipla:Etacept, Launches biosimilar in India on April 17, at a price of Rs. 6,150 ($113.43), 30% less than the innovator product.

read this

http://www.cipla.com/CiplaSite/Media/PDF/News-Archives/Press-Release-Launch-of-first-biosimilar-of-Etanercept-in-India.pdf?ext=.pdf

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Hanwha Chemical: HD203 “scheduled for launch,” company states on its website without including a date, following submission for marketing approval to South Korea’s Korea Ministry of Food and Drug Safety following completion of Phase I and Phase III trials. Hanwha has said it will seek a partner to commercialize HD203 and a biosimilar for Herceptin (trastuzumab).
http://www.thepharmaletter.com/file/105028/merck-co-links-with-koreas-hanwha-on-biosimilar-of-enbrel.html

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LG Life Sciences: LBEC0101 completed Phase I trial in South Korea

http://www.lgls.co.kr/rd/pipeline.jsp

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Mycenax Biotech: TuNEX in Phase III clinical trials in Japan and South Korea

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Protalix Biotherapeutics: PRX-106 in preclinical studies

http://www.protalix.com/product-development/prx-106.asp

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Shanghai CP Goujian Pharmaceutical: Etanar®, marketed in Colombia; Yisaipu, marketed in China

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Recently discontinued effort: Merck & Co. and Hanwha Chemical: Hanwha disclosed December 18, 2012, that Merck terminated agreement to develop and manufacture the biosimilar MK-8953, now called HD203, as well as market it in all countries except South Korea and Turkey, an up to $720 million deal signed June 2011.¹

Nature and indication: Tumor necrosis factor (TNF) blocker for rheumatoid arthritis, polyarticular Juvenile Idiopathic Arthritis (JIA) in patients aged two years or older; psoriatic arthritis; ankylosing spondylitis; and plaque psoriasis

2012 sales: $7.963 billion (includes $4.236 billion Amgen + $3.737 billion Pfizer). Amgen markets Enbrel in U.S. and Canada under an agreement with Pfizer set to expire October 31, 2013

Patent status: Patents set to expire in EU in 2015; in U.S., 2019, 2023, 2028, and 2029

Etanercept is a fusion protein produced by recombinant DNA, which fuses a soluble human TNF receptor with an IgG1 antibody. This modified protein works by blocking TNF activity, thereby reducing their ability to cause an inflammatory response as well as severe, chronic pain and discomfort to patients. The fusion protein is protected by five different molecule Key patent families (Fig 2) and are all considered to be a constraint to generic entry until expiry. Although the patent families are owned by different patentees, Amgen have entered into licensing agreements with all parties allowing them sole distributing and marketing rights of Enbrel®.

Public Health Service Act Sec. 262. Regulation of biological products.http://www.fda.gov/RegulatoryInformation/Legislation/ucm149278.htm
Woodcock J, Griffin J, Behrman R, Cherney B, Crescenzi T, Fraser B, Hixon D, Joneckis C, Kozlowski S, Rosenberg A, Schrager L, Shacter E, Temple R, Webber K, Winkle H. The FDA’s assessment of follow-on protein products: a historical perspective. Nat Rev Drug Discov. 2007;6:437–442. doi: 10.1038/nrd2307. [PubMed] [Cross Ref]
Yisaipu. http://www.cpgj-pharm.com/en/product_patient.asp?proid=22&action=intro
Rondon F, Bautista A, Salazar JC, Casas N, Santos P, Vargas F, Marquez J. Etanar therapy in real-life patients with rheumatoid arthritis [abstract]Arthritis Rheum. 2010;62(Suppl 10):1811.
Pipeline products. http://www.protalix.com/pipeline_products.html
Biosimilar TuNEX^®completes Phase I/II clinical trial in Taiwan, Phase I in Korea. http://www.mycenax.com.tw/webe/html/02news/news_show.aspx?page=1
Singh K. Avesthagen gets patent for Enbrel biosimilar. Economic Times. 2010.
Korea’s Celltrion and Aprogen in race to sell biosimilars in Japan.http://sis.windhover.com/buy/abstract.php?id=28101102003
LG Life Sciences’ Pipeline Overview. http://thinklgls.com/rnd/pipeline
Dr. Reddy’s Marketed Pharmaceutical Products.http://www.drreddys.com/products/bio_mproducts.html#
TL011 in severe, active rheumatoid arthritis patients.http://clinicaltrials.gov/ct2/show/NCT01123070
GP2013 in the treatment of RA patients refractory to or intolerant of standard therapy. http://www.clinicaltrials.gov/ct2/show/NCT01274182
View Opportunities. http://www.sourcegenerics.com/viewAllListing.asp
Rudick RA, Simonian NA, Alam JA, Campion M, Scaramucci JO, Jones W, Coats ME, Goodkin DE, Weinstock-Guttman B, Herndon RM, Mass MK, Richert JR, Salazar AM, Munschauer FE, Cookfair DL, Simon JH, Jacobs LD. Incidence and significance of neutralizing antibodies to interferon beta-1a in multiple sclerosis. Multiple Sclerosis Collaborative Research Group (MSCRG)Neurology. 1998;50:1266–1272. [PubMed]
Casadevall N, Nataf J, Viron B, Kolta A, Kiladjian JJ, Martin-Dupont P, Michaud P, Papo T, Ugo V, Teyssandier I, Varet B, Mayeux P. Pure red-cell aplasia and antierythropoietin antibodies in patients treated with recombinant erythropoietin. N Engl J Med. 2002;346:469–475. doi: 10.1056/NEJMoa011931. [PubMed] [Cross Ref]
Schellekens H, Jiskoot W. Eprex-associated pure red cell aplasia and leachates. Nat Biotechnol. 2006;24:613–614. doi: 10.1038/nbt0606-613.[PubMed] [Cross Ref]
Bennett CL, Luminari S, Nissenson AR, Tallman MS, Klinge SA, McWilliams N, McKoy JM, Kim B, Lyons EA, Trifilio SM, Raisch DW, Evens AM, Kuzel TM, Schumock GT, Belknap SM, Locatelli F, Rossert J, Casadevall N. Pure red-cell aplasia and epoetin therapy. N Engl J Med. 2004;351:1403–1408. doi: 10.1056/NEJMoa040528. [PubMed] [Cross Ref]
Federal Food, Drug, and Cosmetic Act (FD&C Act) SEC. 505. [21 USC §355] New Drugs.http://www.fda.gov/RegulatoryInformation/Legislation/FederalFoodDrugandCosmeticActFDCAct/FDCActChapterVDrugsandDevices/ucm108125.htm
Committee for Medicinal Products for Human Use. Guideline on similar biological medicinal products. London: European Medicines Agency; 2005.
Committee for Medicinal Products for Human Use. Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues. London: European Medicines Agency; 2006.
European Medicines Agency. Work plan for the biosimilar medicinal products working party (BMWP) 2011. London: European Medicines Agency; 2010.
H. R. 3590–686. Patient Protection and Affordable Care Act. Title VII– Improving Access to Innovative Medical Therapies. Subtitle A–Biologics Price Competition and Innovation. Sec. 7002. Approval Pathway for Biosimilar Biological Products.http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/UCM216146.pdf
Implementation of the Biologics Price Competition and Innovation Act of 2009.http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/ucm215089.htm

see details of etanercept

Etanercept

ATC (Anatomical Therapeutic Chemical Classification)

L04AA11,L04AB01

CAS registry number (Chemical Abstracts Service)

0185243-69-0

Chemical Formula

C2224-H3472-N618-O701-S36

Molecular Weight

51238

Therapeutic Categories

Immunosuppressant

Disease-modifying antirheumatic drug, DMARD

Biological response modifier, BRM

Anti-inflammatory agent

Tumor necrosis factor alpha (TNF-α) inhibitor

Chemical Name

Dimeric fusion protein consisting of the extracellular ligand-binding portion of the human 75 kilodalton (p75) tumor necrosis factor receptor (TNFR) linked to the Fc portion of human IgG1

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®).

Etanercept was the first biologic approved in the US for the treatment of Rheumatoid arthritis (RA), it was then later approved by the FDA for other forms of arthritis and psoriasis. Patents in families 1992-10-08 and 1999-04-19 protect the aforementioned indications, as well as the use of Etanercept as adjunctive therapy with Methotrexate for RA. Patents in the family protecting the market authorised indications are considered to constrain biosimilar entry for the indicated use, however it would be possible for generic manufacturers to ‘carve out’ market authorised indications thus circumventing these constraining patents prior to expiry.
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.

Figure 2: Molecule Key Patents landscape

International Market

Patents protecting the various technologies of the Etanercept molecule (Fig. 2) across all five families have now expired in Europe, Canada and Australia. In Europe, SPCs and paediatric extensions were granted based on the EP0418014 (1989-09-05) and EP0939121 (1989-09-12) however the last of the paediatric extensions expired in early August, 2015. Finland has been granted a national patent disclosing the Etanercept sequence in the family with priority US40324189A (1989-09-05), which would constrain generic entry until April, 2020. Cyprus has also received a five year patent extension on a national patent set to expire in mid-2016 and would be a constraint for biosimilars entering the market there.

Although the Etanercept molecule is no longer protected in the European, Canadian or Australian markets, no biosimilar has been approved in these major markets suggesting the difficulty of developing a biosimilar which complies with the stringent regulatory pathways in place. Having said that, Merck and Samsung Bioepis (a joint venture from electronics giant Samsung and biotech firm Biogen Idec) has submitted their Etanercept biosimilar candidate SB4 to the EMA, which is currently awaiting review. If approved, it is expected that they will obtain further approval in other territories where Etanercept is no longer protected. With the regulatory approval pathways differing from country to country, Etanercept biosimilars have been approved in smaller markets including India, China and South Korea.

US Market

In the US, the ‘molecule’ patents protecting active ingredient Etanercept have all expired aside from US8,063,182 (‘182) and US8,163,522 (‘522) members from priority CH331989 (1989-09-12) owned by Roche (exclusively licensed to Amgen), which are set to expire in 2028 and 2029, respectively. These patents members disclose a portion of the Etanercept sequence, so are considered to constrain biosimilar entry until expiry. The members are continuation patents filed from US5,610,279 (another member of the same family) and while they were both filed in May, 1995, were not issued until 2011 (‘182) and 2012 (‘522). Under the 35 U.S. Code § 154, these patents received 17 year patent term from the issuing date. Since these patents were applied for in 1995 during the transitional period of the TRIPS agreement, they were not published by the USPTO until they were issued. This situation often gives rise to the term ‘submarine patents’.

Currently there is no system to link relevant patents to biologic drugs in the US as with small molecule drugs (Orange Book) which makes filing biosimilars in the US a convoluted process. While the FDA are currently working on an equivalent to the Orange Book, the ‘Purple book’, companies wishing to develop biosimilars in the US need to do considerable patent landscape searching in order to avoid infringement of any patents potentially protecting the biologic drug. In the case of US member ‘182 and ‘522, upon inspection these patents are clearly relevant to Enbrel®, however without a registry there is no easy way of making this link. The patents have been flagged in the Key Patent module in Ark due to SPCs and paediatric extensions on the equivalent EP0939121 member and litigation in the US (see below).

Currently, biologic drugs approved in the US receive a 12 year data exclusivity period and in Europe, an 8 year data exclusivity period with additional 2 year market exclusivity, starting from the market authorisation date. Enbrel® was approved in 1998 and 2000, in the US and Europe, respectively and data exclusivity protection has therefore now expired.

Development of biosimilars takes considerably longer than generic medicine making it a costly venture for generic pharmaceutical manufacturers. According to Amgen, Enbrel® was protected by US5395760 (‘760) and US5605690 (‘690) members from priority 1989-09-05 which were set to lose patent protection in 2012 and 2014, respectively. In 2004, Sandoz began developing GP2015 a biosimilar equivalent of Etanercept, investing millions of dollars in the hope that they would be ready to launch by the time all the patent protection for Enbrel® expired. Currently, GP2015 is in Phase III study in the US and European Union for patients with moderate to severe chronic plaque-type psoriasis with respect to PASI 75 response rate at Week 12.

In June 2013, Sandoz filed a suit against Amgen and Roche in the US District Court for the Northern District of California seeking declaratory judgment of non-infringement, invalidity and unenforceability of the ‘182 and ‘522 patents. Sandoz claimed a ‘case of controversy’ regarding the patents, as their research and development was based on the understanding that ‘760 and ‘690 patents members were protecting Enbrel®. With the issuing of ‘182 and ‘522 patents this has essentially delayed the prospect of an Etanercept biosimilar from entering the US market until 2029.

Amgen and Roche sought a dismissal of the proceeding due to lack of subject matter jurisdiction, which was granted. Although Sandoz appealed the decision, the Court of Appeals affirmed the dismissal, since there was no real and immediate controversy as Sandoz had not yet filed an FDA application, and they had based their suit on future events and were not able to establish “real and immediate injury or threat of future injury.”

Generic Licensing News-SPIRAMYCIN Featured product

July 17, 2013 3:31 am / 8 Comments on Generic Licensing News-SPIRAMYCIN Featured product

SPIRAMYCIN

Spiramycin is a macrolide antibiotic. It is used to treat certain types of infections that are caused by bacteria. It is most commonly used to treat infections of the lung, skin, and mouth.

Spiramycin is sometimes used to treat gonorrhea for people who are allergic to penicillin. Spiramycin is also used as an alternative agent in the treatment of toxoplasmosis during pregnancy.

Click here to contact Pharma Dreams about this product.

READ Generic Licensing News-SPIRAMYCIN Featured product at

http://newsletter.lead-doctors.com/ef1/preview_campaign.php?lf1=916521877f641012625317c9856823

more info from wiki

Spiramycin is a macrolide antibiotic. It is used to treat toxoplasmosisand various other infections of soft tissues. Although used in Europe, Canada and Mexico,^[1] spiramycin is still considered an experimental drug in the United States, but can sometimes be obtained by special permission from the FDA for toxoplasmosis in the first trimester of pregnancy.^[2]

Spiramycin has been used in Europe since the year 2000 under thetrade name “Rovamycine”, produced by Rhone-Poulenc Rorer and Famar Lyon, France and Eczacibasi Ilae, Turkey. It also goes under the name Rovamycine in Canada (distributed by OdanLaboratories), where it is mostly marketed to dentists for mouth infections.

Spiramycin is a 16-membered ring macrolide (antibiotic). It was discovered in 1952 as a product of Streptomyces ambofaciens. As a preparation for oral administration it has been used since 1955, in 1987 also the parenteral form was introduced into practice. The antibacterial action involves inhibition of protein synthesis in the bacterial cell during translocation. Resistance to spiramycin can develop by several mechanisms and its prevalence is to a considerable extent proportional to the frequency of prescription in a given area. The antibacterial spectrum comprises Gram-positive cocci and rods, Gram-negative cocci and also Legionellae, mycoplasmas, chlamydiae, some types of spirochetes, Toxoplasma gondii and Cryptosporidium sp., Enterobacteria, pseudomonads and pathogenic moulds are resistant. Its action is mainly bacteriostatic, on highly sensitive strains it exerts a bactericide action. As compared with erythromycin, it is in vitro weight for weight 5 to 20 less effective, an equipotential therapeutic dose is, however, only double. This difference between the effectiveness in vitro and in vivo is explained above all by the great affinity of spiramycin to tissues where it achieves concentrations many times higher than serum levels. An important part is played also by the slow release of the antibiotic from the tissue compartment, the marked action on microbes in sub-inhibition concentrations and the relatively long persisting post-antibiotic effect. Its great advantage is the exceptionally favourable tolerance-gastrointestinal and general. It is available for parenteral and oral administration

Spiramycin advanced consumer information | Drugs.com
Toxoplasmosis at MayoClinic.com

Soliris Gets Thumbs Up From EMA’s COMP

July 17, 2013 3:06 am / 1 Comment on Soliris Gets Thumbs Up From EMA’s COMP

eculizumab

CAS number 219685-50-4

Alexion’s Soliris® (eculizumab) Receives Positive Opinion from the Committee for Orphan Medicinal Products for Treatment of Neuromyelitis Optica (NMO)

Alexion Pharmaceuticals, Inc. (Nasdaq: ALXN) today announced that Soliris® (eculizumab), the company’s first-in-class terminal complement inhibitor, has received a positive opinion for orphan medicinal product designation from the Committee for Orphan Medicinal Products (COMP) of the European Medicines Agency (EMA) for the treatment of neuromyelitis optica (NMO), a life-threatening, ultra-rare neurological disorder. The positive opinion of the COMP has now been forwarded to the European Commission for final approval and publication in the community register. Soliris is not approved in any country for the treatment of patients with NMO

http://www.pharmalive.com/soliris-gets-thumbs-up-from-emas-comp

Soliris is a formulation of eculizumab which is a recombinant humanized monoclonal IgG2/4;κ antibody produced by murine myeloma cell culture and purified by standard bioprocess technology. Eculizumab contains human constant regions from human IgG2 sequences and human IgG4 sequences and murine complementarity-determining regions grafted onto the human framework light- and heavy-chain variable regions. Eculizumab is composed of two 448 amino acid heavy chains and two 214 amino acid light chains and has a molecular weight of approximately 148 kDa.

Eculizumab (INN and USAN; trade name Soliris®) is a humanized monoclonal antibody that is a first-in-class terminal complement inhibitor and the first therapy approved for the treatment of paroxysmal nocturnal hemoglobinuria (PNH), a rare, progressive, and sometimes life-threatening disease characterized by excessive destruction of red blood cells (hemolysis).^[1] It costs £400,000 ($US 600,000) per year per patient.[1]

Eculizumab also is the first agent approved for the treatment of atypical hemolytic uremic syndrome (aHUS), an ultra-rare genetic disease that causes abnormal blood clots to form in small blood vessels throughout the body, leading to kidney failure, damage to other vital organs and premature death.^[2]^[3]

In clinical trials in patients with PNH, eculizumab was associated with reductions in chronic hemolysis, thromboembolic events, and transfusion requirements, as well as improvements in PNH symptoms, quality of life, and survival.^[1]^[4]^[5]^[6] Clinical trials in patients with aHUS demonstrated inhibition of thrombotic microangiopathy (TMA),^[7] the formation of blood clots in small blood vessels throughout the body,^[1]^[3]^[4] including normalization of platelets and lactate dehydrogenase (LDH), as well as maintenance or improvement in renal function.^[7]

Eculizumab was discovered and developed by Alexion Pharmaceuticals and is manufactured by Alexion. It was approved by the United States Food and Drug Administration (FDA) on March 16, 2007 for the treatment of PNH, and on September 23, 2011 for the treatment of aHUS. It was approved by the European Medicines Agency for the treatment of PNH on June 20, 2007, and on November 24, 2011 for the treatment of aHUS. Eculizumab is currently being investigated as a potential treatment for other severe, ultra-rare disorders

Hillmen, Young, Schubert, P, N, J, et al (2006). “The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria”.N Engl J Med 355 (12): 1233–1243. doi:10.1056/NEJMMoa061648. PMID 16990386.
Noris, Caprioli, Bresin, M, J, E, et al. (2010). “Relative role of genetic complement abnormalities in sporadic and familial aHUS and their impact on clinical phenotype”. Clin J Am Soc Nephrol 5: 1844–1859.
Caprioli, Noris, Brioschi, J, M, S, et al (2006). “Genetics of HUS: the impact of MPC, CFH, and IF mutations on clinical presentation, response to treatment, and outcome”. Blood 108: 1267–1279.
Hillman, Hall, Marsh, P, C, JC, et al (2004). “Effect of eculizumab on hemolysis and transfusion requirements in patients with paroxysmal nocturnal hemoglobinuria”. N Eng J Med 350: 552–559.
Ray, Burrows, Ginsberg, Burrows, JG, RF, JS, EA (2000). “Paroxysmal nocturnal hemoglobinuria and the risk of venous thrombosis: review and recommendations for management of the pregnant and nonpregnant patient”. Haemostasis 30: 103–107.
Kelly, Hill, Arnold, RJ, A, LM, et al (2011). “Long-term treatment with eculizumab in paroxysmal nocturnal hemoglobinuria: sustained efficacy and improved survival”. Blood 117: 6786–6792.
.Soliris® (eculizumab) prescribing information (2011). Cheshire, CT: Alexion Pharmaceuticals.http://www.soliris.net/sites/default/files/assets/soliris)pi.pdf.

Novartis investigational drug LDK378, a selective inhibitor of (ALK), shows a marked clinical response ….49th Annual Meeting of the American Society of Clinical Oncology (ASCO) on June 3, 2013

July 16, 2013 7:33 am / 2 Comments on Novartis investigational drug LDK378, a selective inhibitor of (ALK), shows a marked clinical response ….49th Annual Meeting of the American Society of Clinical Oncology (ASCO) on June 3, 2013

LDK378

J. Med. Chem. 2013, DOI:10.1021/jm400402q).

CAS Number:: 1032900-25-6

Mol. Formula:: C₂₈H₃₆ClN₅O₃S

MW:: 558.13

LDK378 is a highly selective, orally bioavailable and ATP-competitive small molecule inhibitor of ALK (Anaplastic Lymphoma Kinase), a receptor tyrosine kinase considered to be an important lung cancer drug target. LDK378 displays enhanced potency over Crizotinib and noteworthy antitumor activity for ALK-activated, non-small cell lung cancer (NSCLC).

Alessandro Riva, MD, Global Head of Oncology Development & Medical Affairs for Novartis Oncology,

The FDA recently designated LDK378 as a breakthrough therapy based on encouraging results from early clinical trials in patients with ALK-positive, non-small-cell lung cancer.

Novartis investigational drug LDK378, a selective inhibitor of the cancer target anaplastic lymphoma kinase (ALK), shows a marked clinical response in patients with ALK+ non-small cell lung cancer (NSCLC) during the 49th Annual Meeting of the American Society of Clinical Oncology (ASCO) on June 3, 2013.

Doctors and patients are clamoring for more ways to fight lung cancer, the leading cause of cancer deaths in the U.S., of which NSCLC is the most common form. In March, LDK378 received Breakthrough Therapy designation from the US Food and Drug Administration (FDA). The designation is intended to expedite the development and review of drugs that treat life-threatening conditions and show improvement over available therapies.

Currently, two Phase II clinical trials are actively recruiting patients worldwide. One study focuses on patients with ALK+ NSCLC who were previously treated with chemotherapy and crizotinib (NCT01685060). The second study examines LDK378 in patients who are crizotinib-naive (NCT01685138). In addition, Phase III clinical trials are planned to begin in the coming months, aiming to enroll more than 1,100 patients with ALK+ NSCLC at sites worldwide. Novartis plans to file for approval the drug in early 2014.

Chemical Name of LDK378

5-chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine

Chemical Synthesis of LDK378

Technical Data of LDK378
1H NMR (400 MHz, DMSO-d6 + trace D2O) δ 8.32 (s,1H), 8.27 (d, 1H), 7.88 (d, 1H), 7.67 (dd, 1H), 7.45 (dd, 1H), 7.42 (s, 1H), 6.79 (s, 1H), 4.56 – 4.48(m, 1H), 3.49 – 3.32 (m, 3H), 3.10 - 2.91 (m, 3H), 2.09 (s, 3H), 1.89 – 1.77 (m, 4H), 1.22 (d, 6H), 1.13 (d, 6H); ESMS m/z 558.1 (M + H+).

The compound LDK378, a highly selective inhibitor of ALK, has been granted “Breakthrough Therapy Designation” by the FDA for the treatment of patients with ALK-positive metastatic non-small cell lung cancer (NSCLC) who have already received treatment with crizotinib (Xalkori).

ClinicalTrials.gov. A Dose Finding Study With Oral LDK378 in Patients With Tumors Characterized by Genetic Abnormalities in Anaplastic Lymphoma Kinase (ALK) (Phase 1). http://www.http://clinicaltrials.gov/show/NCT01283516; Accessed June 7, 2013; currently recruiting participants.

ClinicalTrials.gov. LDK378 in crizotinib naïve adult patients with ALK-activated non-small cell lung cancer (Phase 2). http://www.clinicaltrials.gov/ct2/show/NCT01685138; Accessed June 7, 2013; currently recruiting participants.

ClinicalTrials.gov. LDK378 in adult patients with ALK-activated NSCLC previously treated with chemotherapy and crizotinib (phase 2) http://www.clinicaltrials.gov/ct2/show/NCT01685060; Accessed June 7,2013; currently recruiting participants.

Mehra R, Camidge DR, Sharma S, et al. First-in-human phase I study of the ALK inhibitor LDK378 in advanced solid tumors. J Clin Oncol 30, 2012 (suppl; abstr 3007).

Alice Tsang Shaw, et al., Clinical activity of the ALK inhibitor LDK378 in advanced, ALK-positive NSCLC; 2013 ASCO Annual Meeting; Abstract Number: 8010; Citation: J Clin Oncol 31, 2013 (suppl; abstr 8010)

Tom H. Marsilje, Wei Pei, Bei Chen, Wenshuo Lu, Tetsuo Uno, Yunho Jin, Tao Jiang, Sungjoon Kim, Nanxin Li, Markus Warmuth, Yelena Sarkisova, Fangxian Sun, Auzon Steffy, AnneMarie C. Pferdekamper, Sean B Joseph, Young Kim, Tove Tuntland, Xiaoming Cui, Nathanael S Gray, Ruo Steensma, Yongqin Wan, Jiqing Jiang, Jie Li, Greg Chopiuck, W. Perry Gordon, Allen G Li, Wendy Richmond, Johathan Chang, Todd Groessl, You-Qun He, Bo Liu, Andrew Phimister, Alex Aycinena, Badry Bursulaya, Christian Lee, Donald S Karanewsky, H Martin Seidel, Jennifer L Harris, and Pierre-Yves Michellys, Synthesis, Structure-Activity Relationships and In Vivo Efficacy of the Novel Potent and Selective Anaplastic Lymphoma Kinase (ALK) Inhibitor LDK378 Currently In Phase 1 and 2 Clinical Trials, Journal of Medicinal Chemistry, 2013

Carlos Garcia-Echeverria, Takanori Kanazawa, Eiji Kawahara, Keiichi Masuya, Naoko Matsuura, Takahiro Miyake, Osamu Ohmori, Ichiro Umemura; 2, 4- di (phenylamino) pyrimidines useful in the treatment of neoplastic diseases, inflammatory and immune system disorders; WO2004080980 A1

Greg Chopiuk, Qiang Ding, Carlos Garcia-Echeverria, Nathanael Schiander Gray, Jiqing Jiang, Takanori Kanazawa, Donald Karanewsky, Eiji Kawahara, Keiichi Masuya, Naoko Matsuura, Takahiro Miyake, Osamu Ohmori, Ruo Steensma, Ichiro Umemura, Yongqin Wan, Qiong Zhang; 2, 4-pyrimidinediamines useful in the treatment of neoplastic diseases, inflammatory and immune system disorders; WO2005016894 A1

Nexavar, Sorafenib, BAY 43-9006

July 16, 2013 4:14 am / 53 Comments on Nexavar, Sorafenib, BAY 43-9006

SORAFENIB

N-[4-Chloro-3-(trifluoromethyl)phenyl]({4-[2-(N-methyl-carbamoyl)(4-pyridyloxy)]phenyl}amino)carboxamide ( BAY 43–9006)

(4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)phenoxy)-N-methylpicolinamide)

Sorafenib (co-developed and co-marketed by Bayer and Onyx Pharmaceuticals as Nexavar),^[1] is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma), advanced primary liver cancer (hepatocellular carcinoma), and radioactive iodine resistant advanced thyroid carcinoma.

Sorafenib
Systematic (IUPAC) name


4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino] phenoxy]-N-methyl-pyridine-2-carboxamide
Clinical data
Trade names	Nexavar
AHFS/Drugs.com	monograph
MedlinePlus	a607051
Licence data	EMA:Link, US FDA:link
Pregnancy cat.	D (AU) D (US)
Legal status	Prescription Only (S4) (AU) ℞-only (CA) POM (UK) ℞-only (US)
Routes	Oral
Pharmacokinetic data
Bioavailability	38–49%
Protein binding	99.5%
Metabolism	Hepatic oxidation and glucuronidation (CYP3A4 & UGT1A9-mediated)
Half-life	25–48 hours
Excretion	Faeces (77%) and urine (19%)
Identifiers
CAS number	284461-73-0
ATC code	L01XE05
PubChem	CID 216239
DrugBank	DB00398
ChemSpider	187440
UNII	9ZOQ3TZI87
KEGG	D08524
ChEBI	CHEBI:50924
ChEMBL	CHEMBL1336
Synonyms	Nexavar Sorafenib tosylate
PDB ligand ID	BAX (PDBe, RCSB PDB)
Chemical data
Formula	C₂₁H₁₆Cl F₃N₄O₃
Mol. mass	464.825 g/mol

Medical uses

At the current time sorafenib is indicated as a treatment for advanced renal cell carcinoma (RCC), unresectable hepatocellular carcinomas (HCC) and thyroid cancer.^[2]^[3]^[4]^[5]

Kidney cancer

An article in The New England Journal of Medicine, published January 2007, showed compared with placebo, treatment with sorafenib prolongs progression-free survival in patients with advanced clear cell renal cell carcinoma in whom previous therapy has failed. The median progression-free survival was 5.5 months in the sorafenib group and 2.8 months in the placebo group (hazard ratio for disease progression in the sorafenib group, 0.44; 95% confidence interval [CI], 0.35 to 0.55; P<0.01).^[6] A few reports described patients with stage IV renal cell carcinomas that were successfully treated with a multimodal approach including neurosurgical, radiation, and sorafenib.^[7] This is one of two TGA-labelled indications for sorafenib, although it is not listed on the Pharmaceutical Benefits Scheme for this indication.^[5]^[8]

Liver cancer

At ASCO 2007, results from the SHARP trial^[9] were presented, which showed efficacy of sorafenib in hepatocellular carcinoma. The primary endpoint was median overall survival, which showed a 44% improvement in patients who received sorafenib compared to placebo (hazard ratio 0.69; 95% CI, 0.55 to 0.87; p=0.0001). Both median survival and time to progression showed 3-month improvements. There was no difference in quality of life measures, possibly attributable to toxicity of sorafenib or symptoms related to underlying progression of liver disease. Of note, this trial only included patients with Child-Pugh Class A (i.e. mildest) cirrhosis. The results of the study appear in the July 24, 2008, edition of The New England Journal of Medicine. Because of this trial Sorafenib obtained FDA approval for the treatment of advanced hepatocellular carcinoma in November 2007.^[10]

In a randomized, double-blind, phase II trial combining sorafenib with doxorubicin, the median time to progression was not significantly delayed compared with doxorubicin alone in patients with advanced hepatocellular carcinoma. Median durations of overall survival and progression-free survival were significantly longer in patients receiving sorafenib plus doxorubicin than in those receiving doxorubicin alone.^[10] A prospective single-centre phase II study which included the patients with unresectable hepatocellular carcinoma (HCC)concluding that the combination of sorafenib and DEB-TACE in patients with unresectable HCC is well tolerated and safe, with most toxicities related to sorafenib.^[11] This is the only indication for which sorafenib is listed on the PBS and hence the only Government-subsidised indication for sorafenib in Australia.^[8] Along with renal cell carcinoma, hepatocellular carcinoma is one of the TGA-labelled indications for sorafenib.^[5]

Thyroid cancer

A phase 3 clinical trial has started recruiting (November 2009) to use sorafenib for non-responsive thyroid cancer.^[12] The results were presented at the ASCO 13th Annual Meeting and are the base for FDA approval. The Sorafenib in locally advanced or metastatic patients with radioactive iodine-refractory differentiated thyroid cancer: The Phase 3 DECISION trial showed significant improvement in progression-free survival but not in overall survival. However, as is known, the side effects were very frequent, specially hand and foot skin reaction.^[13]

Adverse effects

Adverse effects by frequency
Note: Potentially serious side effects are in bold.
Very common (>10% frequency)

Lymphopenia
Hypophosphataemia^{[Note 1]}
Haemorrhage^{[Note 2]}
Hypertension^{[Note 3]}
Diarrhea
Rash
Alopecia (hair loss; occurs in roughly 30% of patients receiving sorafenib)
Hand-foot syndrome
Pruritus (itchiness)
Erythema
Increased amylase
Increased lipase
Fatigue
Pain^{[Note 4]}
Nausea
Vomiting^{[Note 5]}^[14]

Common (1-10% frequency)

Leucopoenia^{[Note 6]}
Neutropoenia^{[Note 7]}
Anaemia^{[Note 8]}
Thrombocytopenia^{[Note 9]}
Anorexia (weight loss)
Hypocalcaemia^{[Note 10]}
Hypokalaemia^{[Note 11]}
Depression
Peripheral sensory neuropathy
Tinnitus^{[Note 12]}
Congestive heart failure
Myocardial infarction^{[Note 13]}
Myocardial ischaemia^{[Note 14]}
Hoarseness
Constipation
Stomatitis^{[Note 15]}
Dyspepsia^{[Note 16]}
Dysphagia^{[Note 17]}
Dry skin
Exfoliative dermatitis
Acne
Skin desquamation
Arthralgia^{[Note 18]}
Myalgia^{[Note 19]}
Renal failure^{[Note 20]}
Proteinuria^{[Note 21]}
Erectile dysfunction
Asthenia (weakness)
Fever
Influenza-like illness

Transient increase in transaminase

Uncommon (0.1-1% frequency)

Folliculitis
Infection
Hypersensitivity reactions^{[Note 22]}
Hypothyroidism^{[Note 23]}
Hyperthyroidism^{[Note 24]}
Hyponatraemia^{[Note 25]}
Dehydration
Reversible posterior leukoencephalopathy
Hypertensive crisis
Rhinorrhoea^{[Note 26]}
Interstitial lung disease-like events^{[Note 27]}
Gastro-oesophageal reflux disease (GORD)
Pancreatitis^{[Note 28]}
Gastritis^{[Note 29]}
Gastrointestinal perforations^{[Note 30]}
Increase in bilirubin leading, potentially, to jaundice^{[Note 31]}
Cholecystitis^{[Note 32]}
Cholangitis^{[Note 33]}
Eczema
Erythema multiforme^{[Note 34]}
Keratoacanthoma^{[Note 35]}
Squamous cell carcinoma
Gynaecomastia (swelling of the breast tissue in men)
Transient increase in blood alkaline phosphatase
INR abnormal
Prothrombin level abnormal
bulbous skin reaction^[15]

Rare (0.01-0.1% frequency)

QT interval prolongation^{[Note 36]}
Angiooedema^{[Note 37]}
Anaphylactic reaction^{[Note 38]}
Hepatitis^{[Note 39]}
Radiation recall dermatitis
Stevens-Johnson syndrome^{[Note 40]}
Leucocytoclastic vasculitis
Toxic epidermal necrolysis^{[Note 41]}
Nephrotic syndrome
Rhabdomyolysis^{[Note 42]}

Mechanism of action

Sorafenib is a small molecular inhibitor of several tyrosine protein kinases (VEGFR and PDGFR) and Raf kinases (more avidly C-Raf than B-Raf).^[16]^[17] Sorafenib also inhibits some intracellular serine/threonine kinases (e.g. C-Raf, wild-type B-Raf and mutant B-Raf).^[10] Sorafenib treatment induces autophagy,^[18] which may suppress tumor growth. However, autophagy can also cause drug resistance.^[19]

History

Renal cancer

Sorafenib was approved by the U.S. Food and Drug Administration (FDA) in December 2005,^[20] and received European Commission marketing authorization in July 2006,^[21] both for use in the treatment of advanced renal cancer.

Liver cancer

The European Commission granted marketing authorization to the drug for the treatment of patients with hepatocellular carcinoma(HCC), the most common form of liver cancer, in October 2007,^[22] and FDA approval for this indication followed in November 2007.^[23]

In November 2009, the UK’s National Institute of Clinical Excellence declined to approve the drug for use within the NHS in England, Wales and Northern Ireland, stating that its effectiveness (increasing survival in primary liver cancer by 6 months) did not justify its high price, at up to £3000 per patient per month.^[24] In Scotland the drug had already been refused authorization by the Scottish Medicines Consortium for use within NHS Scotland, for the same reason.^[24]

In March 2012, the Indian Patent Office granted a domestic company, Natco Pharma, a license to manufacture generic Sorafenib, bringing its price down by 97%. Bayer sells a month’s supply, 120 tablets, of Nexavar for280000 (US$4,700). Natco Pharma will sell 120 tablets for 8800 (US$150), while still paying a 6% royalty to Bayer.^[25]^[26] Under Indian Patents Act, 2005 and the World Trade Organisation TRIPS Agreement, the government can issue a compulsory license when a drug is not available at an affordable price.^[27]

Thyroid Cancer

As of November 22, 2013, sorafenib has been approved by the FDA for the treatment of locally recurrent or metastatic, progressive differentiated thyroid carcinoma (DTC) refractory to radioactive iodine treatment.^[28]

Research

Lung

In some kinds of lung cancer (with squamous-cell histology) sorafenib administered in addition to paclitaxel and carboplatin may be detrimental to patients.^[29]

Brain (Recurrent Glioblastoma)

There is a phase I/II study at the Mayo Clinic^[30] of sorafenib and CCI-779 (temsirolimus) for recurrent glioblastoma.

Desmoid Tumor (Aggressive Fibromatosis)

A study performed in 2011 showed that Sorafenib is active against Aggressive fibromatosis. This study is being used as justification for using Sorafenib as an initial course of treatment in some patients with Aggressive fibromatosis.^[31]

Nexavar Controversy

In January 2014, Bayer’s CEO stated that Nexavar was developed for “western patients who [could] afford it”. At the prevailing prices, a kidney cancer patient would pay $96,000 (£58,000) for a year’s course of the Bayer-made drug. However, the cost of the Indian version of the generic drug would be around $2,800 (£1,700).^[32]

Notes

Low blood phosphate levels
Bleeding; including serious bleeds such as intracranial and intrapulmonary bleeds
High blood pressure
Including abdominal pain, headache, tumour pain, etc.
Considered a low (~10-30%) risk chemotherapeutic agent for causing emesis)
Low level of white blood cells in the blood
Low level of neutrophils in the blood
Low level of red blood cells in the blood
Low level of plasma cells in the blood
Low blood calcium
Low blood potassium
Hearing ringing in the ears
Heart attack
Lack of blood supply for the heart muscle
Mouth swelling, also dry mouth and glossodynia
Indigestion
Not being able to swallow
Sore joints
Muscle aches
Kidney failure
Excreting protein [usually plasma proteins] in the urine. Not dangerous in itself but it is indicative kidney damage
Including skin reactions and urticaria (hives)
Underactive thyroid
Overactive thyroid
Low blood sodium
Runny nose
Pneumonitis, radiation pneumonitis, acute respiratory distress, etc.
Swelling of the pancreas
Swelling of the stomach
Formation of a hole in the gastrointestinal tract, leading to potentially fatal bleeds
Yellowing of the skin and eyes due to a failure of the liver to adequately cope with the amount of bilirubin produced by the day-to-day actions of the body
Swelling of the gallbladder
Swelling of the bile duct
A potentially fatal skin reaction
A fairly benign form of skin cancer
A potentially fatal abnormality in the electrical activity of the heart
Swelling of the skin and mucous membranes
A potentially fatal allergic reaction
Swelling of the liver
A potentially fatal skin reaction
A potentially fatal skin reaction
The rapid breakdown of muscle tissue leading to the build-up of myoglobin in the blood and resulting in damage to the kidneys

4-(4-{3-[4-chloro-3-(trifluoromethyl)phenyl]ureido}phenoxy)-Λ/²-methylpyridine-2- carboxamide is commonly known as sorafenib (I). Sorafenib is prepared as its tosylate salt. Sorafenib blocks the enzyme RAF kinase, a critical component of the RAF/MEK/ERK signaling pathway that controls cell division and proliferation; in addition, sorafenib inhibits the VEGFR-2/PDGFR-beta signaling cascade, thereby blocking tumor angiogenesis.

Sorafenib, marketed as Nexavar by Bayer, is a drug approved for the treatment of advanced renal cell carcinoma (primary kidney cancer). It has also received “Fast Track” designation by the FDA for the treatment of advanced hepatocellular carcinoma (primary liver cancer). It is a small molecular inhibitor of Raf kinase, PDGF (platelet-derived growth factor), VEGF receptor 2 & 3 kinases and c Kit the receptor for Stem cell factor.

Sorafenib and pharmaceutically acceptable salts thereof is disclosed in WO0042012. Sorafenib is also disclosed in WO0041698. Both these patents disclose processes for the preparation of sorafenib.

WO0042012 and WO0041698 describe the process as given in scheme I which comprises reacting picolinic acid (II) with thionyl chloride in dimethyl formamide (DMF) to form acid chloride salt (III). This salt is then reacted with methylamine dissolved in tetrahydrofuran (THF) to give carboxamide (IV). This carboxamide when further reacted with 4- aminophenol in anhydrous DMF and potassium tert-butoxide 4-(2-(N-methylcarbamoyl)-4- pyridyloxy)aniline (V) is formed. Subsequent reaction of this aniline with 4-chloro-3- (trifluoromethyl) phenyl isocyanate (Vl) in methylene chloride yields sorafenib (I). The reaction is represented by Scheme I as given below.

Scheme I

Picolini

Sorafenib (I)

WO2006034796 also discloses a process for the preparation of sorafenib and its tosylate salt. The process comprises reacting 2-picolinic acid (II) with thionyl chloride in a solvent inert toward thionyl chloride without using dimethyl formamide to form acid chloride salt (III). This acid salt on further reaction with aqueous solution methylamine or gaseous methylamine gives compound (IV). Compound (IV) is then reacted with 4-aminophenol with addition of a carbonate salt in the presence of a base to yield compound (V).

Compound (V) can also be obtained by reacting compound (IV) with 4-aminophenol in the presence of water with addition of a phase transfer catalyst. Compound (V) when reacted with 4-chloro-3-(trifluoromethyl) phenyl isocyanate (Vl) in a non-chlorinated organic solvent, inert towards isocyanate gives sorafenib (I). Sorafenib by admixing with p- toluenesulfonic acid in a polar solvent gives sorafenib tosylate (VII). The reaction is represented by Scheme Il as given below.

Scheme Il

A key step in the synthesis of sorafenib is the formation of the urea bond. The processes disclosed in the prior art involve reactions of an isocyanate with an amine. These isocyanate compounds though commercially available are very expensive. Further synthesis of isocyanate is very difficult which requires careful and skillful handling of reagents.

Isocyanate is prepared by reaction of an amine with phosgene or a phosgene equivalent, such as bis(trichloromethyl) carbonate (triphosgene) or trichloromethyl chloroformate (diphosgene). Isocyanate can also be prepared by using a hazardous reagent such as an azide. Also, the process for preparation of an isocyanate requires harsh reaction conditions such as strong acid, higher temperature etc. Further, this isocyanate is reacted with an amine to give urea.

Reactions of isocyanates suffer from one or more disadvantages. For example phosgene or phosgene equivalents are hazardous and dangerous to use and handle on a large scale. These reagents are also not environment friendly. Isocyanates themselves are thermally unstable compounds and undergo decomposition on storage and they are incompatible with a number of organic compounds. Thus, the use of isocyanate is not well suited for industrial scale application.

Sorafenib and its pharmaceutically acceptable salts and solvates are reported for the first time in WO0041698 (corresponding US 03139605) by Bayer. In the literature only one route is disclosed for the preparation of sorafenib. According to this route (Scheme-I), picolinic acid of formula III is reacted with thionyl chloride to give the 4-chloro derivative which on treatment

VII

Scheme-I with methanol gave the methyl ester of formula V. Compound of formula V is reacted with methylamine to get the corresponding amide of formula VL Compound of formula VI is reacted with 4-aminophenol to get the ether derivative of formula VII. Compound of formula VII is reacted with 4-chloro-3-trifluoromethylphenylisocyante to get sorafenib base of formula I. Overall yield of sorafenib in this process is 10% from commercially available 2-picolinic acid of formula II. Main drawback in this process is chromatographic purification of the intermediates involved in the process and low yield at every step.

Donald Bankston’s (Org. Proc. Res. Dev., 2002, 6, 777-781) development of an improved synthesis of the above basic route afforded sorafenib in an overall yield of 63% without involving any chromatographic purification. Process improvements like reduction of time in thionyl chloride reaction; avoid the isolation of intermediates of formulae IV and V₅ reduction of base quantity in p-aminophenol reaction, etc lead to the simplification of process and improvement in yield of final compound of formula I.

Above mentioned improvements could not reduce the number of steps in making sorafenib of formula-I. In the first step all the raw materials are charged and heated to target temperature (72°C). Such a process on commercial scale will lead to sudden evolution of gas emissions such as sulfur dioxide and hydrogen chloride. Also, in the aminophenol reaction two bases (potassium carbonate and potassium t-butoxide) were used in large excess to accomplish the required transformation.

A scalable process for the preparation of sorafenib is disclosed in WO2006034796. In this process also above mentioned chemistry is used in making sorafenib of formula I. In the first step, catalytic quantity. of DMF used in the prior art process is replaced with reagents like hydrogen bromide, thionyl bromide and sodium bromide. Yield of required product remained same without any advantages from newly introduced corrosive reagents. Process improvements like change of solvents, reagents, etc were applied in subsequent steps making the process scalable. Overall yield of sorafenib is increased to 74% from the prior art 63% yield. Purity of sorafenib is only 95% and was obtained as light brown colored solid.

Main drawbacks in this process are production of low quality sorafenib and requirement of corrosive and difficult to handle reagents such as thionyl bromide and hydrogen bromide. Also, there is no major improvement in the yield of sorafenib.

Sorafenib tosylate ( Brand name: Nexavar ®, BAY 43-9006 other name, Chinese name: Nexavar, sorafenib, Leisha Wa) was Approved by U.S. FDA for the treatment of advanced kidney cancer in 2005 and liver cancer in 2007 .

Sorafenib, co-Developed and co-marketed by Germany-based Bayer AG and South San Francisco-based Onyx Pharmaceuticals , is an Oral Multi-kinase inhibitor for VEGFR1, VEGFR2, VEGFR3, PDGFRbeta, Kit, RET and Raf-1.

In March 2012 Indian drugmaker Natco Pharma received the first compulsory license ever from Indian Patent Office to make a generic Version of Bayer’s Nexavar despite the FACT that Nexavar is still on Patent. This Decision was based on the Bayer Drug being too expensive to most patients. The Nexavar price is expected to drop from $ 5,500 per person each month to $ 175, a 97 percent decline. The drug generated $ 934 million in global sales in 2010, according to India’s Patent Office.

Sorafenib tosylate

Chemical Name: 4-Methyl-3-((4 – (3-pyridinyl)-2-pyrimidinyl) amino)-N-(5 – (4-methyl-1H-imidazol-1-yl) -3 – (trifluoromethyl) phenyl) benzamide monomethanesulfonate, Sorafenib tosylate

CAS Number 475207-59-1 (Sorafenib tosylate ) , 284461-73-0 (Sorafenib)

References for the Preparation of Sorafenib References

1) Bernd Riedl, Jacques Dumas, Uday Khire, Timothy B. Lowinger, William J. Scott, Roger A. Smith, Jill E. Wood, Mary-Katherine Monahan, Reina Natero, Joel Renick, Robert N. Sibley; Omega-carboxyaryl Substituted diphenyl Ureas as RAF kinase inhibitors ; U.S. Patent numberUS7235576
2) Rossetto, Pierluigi; Macdonald, Peter, Lindsay; Canavesi, Augusto; Process for preparation of sorafenib and Intermediates thereof , PCT Int. Appl., WO2009111061
3) Lögers, Michael; gehring, Reinhold; Kuhn, Oliver; Matthäus, Mike; Mohrs, Klaus; müller-gliemann, Matthias; Stiehl, jürgen; berwe, Mathias; Lenz, Jana; Heilmann, Werner; Process for the preparation of 4 – {4 – [( {[4-chloro-3-(TRIFLUOROMETHYL) phenyl] amino} carbonyl) amino] phenoxy}-N-methylpyridine-2-carboxamide , PCT Int. Appl., WO2006034796
4) Shikai Xiang, Liu Qingwei, Xieyou Rong, sorafenib preparation methods, invention patent application Publication No. CN102311384 , Application No. CN201010212039
5) Zhao multiply there, Chenlin Jie, Xu Xu, MASS MEDIA Ji Yafei; sorafenib tosylate synthesis ,Chinese Journal of Pharmaceuticals , 2007 (9): 614 -616

Preparation of Sorafenib Tosylate (Nexavar) Nexavar, sorafenib Preparation of methyl sulfonate

Sorafenib (Sorafenib) chemical name 4 – {4 – [({[4 – chloro -3 – (trifluoromethyl) phenyl] amino} carbonyl) amino] phenoxy}-N-methyl-pyridine -2 – formamide by Bayer (Bayer) research and development, in 2005 the U.S. Food and Drug Administration (FDA) approval. Trade name Nexavar (Nexavar). This product is an oral multi-kinase inhibitor, for the treatment of liver cancer and kidney cancer.

Indian Patent Office in March this year for Bayer’s Nexavar in liver and kidney cancer drugs (Nexavar) has released a landmark “compulsory licensing” (compulsory license). Indian Patent Office that due to the high price Nexavar in India, the vast majority of patients can not afford the drug locally, thus requiring local Indian pharmaceutical company Natco cheap Nexavar sales. Nexavar in 2017 before patent expiry, Natco pay only Bayer’s pharmaceutical sales to 6% royalties. The move to make Nexavar patent drug prices, the supply price from $ 5,500 per month dropped to $ 175, the price reduction of 97%. Compulsory licensing in India for other life-saving drugs and patent medicines overpriced open a road, the Indian Patent Office through this decision made it clear that the patent monopoly does not guarantee that the price is too high. Nexavar is a fight against advanced renal cell carcinoma, liver cancer cure. In China, a box of 60 capsules of Nexavar price of more than 25,000 yuan. In accordance with the recommended dose, which barely enough to eat half of patients with advanced cancer. In September this year India a patent court rejected Bayer Group in India cheap drugmaker emergency appeal. Indian government to refuse patent medicine overpriced undo “compulsory licensing rules,” allowing the production of generic drugs Nexavar.

Sorafenat by Natco – Sorafenib – Nexavar – India natco Nexavar

Chemical Synthesis of Sorafenib Tosylate (Nexavar)

Sorafenib tosylate (brand name :Nexavar®, other name BAY 43-9006, was approved by US FDA for the treatment of kidney cancer in 2005 and advanced liver cancer in 2007.

US Patent US7235576, WO2006034796, WO2009111061 and Faming Zhuanli Shenqing(CN102311384) disclosed processes for preparation of sorafenib base and its salt sorafenib tosylate.

References

1)Bernd Riedl, Jacques Dumas, Uday Khire, Timothy B. Lowinger, William J. Scott, Roger A. Smith, Jill E. Wood, Mary-Katherine Monahan, Reina Natero, Joel Renick, Robert N. Sibley; Omega-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors; US patent numberUS7235576
2)Rossetto, pierluigi; Macdonald, peter, lindsay; Canavesi, augusto; Process for preparation of sorafenib and intermediates thereof, PCT Int. Appl., WO2009111061
3)Lögers, michael; gehring, reinhold; kuhn, oliver; matthäus, mike; mohrs, klaus; müller-gliemann, matthias; stiehl, jürgen; berwe, mathias; lenz, jana; heilmann, werner; Process for the preparation of 4-{4-[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy}-n-methylpyridine-2-carboxamide, PCT Int. Appl., WO2006034796CN102311384, CN201010212039

Full Experimental Details for the preparation of Sorafenib Tosylate (Nexavar)

Synthesis of 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline.

A solution of 4-aminophenol (9.60 g, 88.0 mmol) in anh. DMF (150 mL) was treated with potassium tert-butoxide (10.29 g, 91.7 mmol), and the reddish-brown mixture was stirred at room temp. for 2 h. The contents were treated with 4-chloro- N -methyl-2-pyridinecarboxamide (15.0 g, 87.9mmol) and K2CO3 (6.50 g, 47.0 mmol) and then heated at 80°C. for 8 h. The mixture was cooled to room temp. and separated between EtOAc (500 mL) and a saturated NaCl solution (500 mL). The aqueous phase was back-extracted with EtOAc (300 mL). The combined organic layers were washed with a saturated NaCl solution (4×1000 mL), dried (Na2SO4) and concentrated under reduced pressure. The resulting solids were dried under reduced pressure at 35°C. for 3 h to afford 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline as a light-brown solid 17.9 g, 84%):. 1H-NMR (DMSO-d6) δ 2.77 (d, J = 4.8 Hz, 3H), 5.17 (br s, 2H), 6.64, 6.86 (AA’BB’ quartet, J = 8.4 Hz, 4H), 7.06 (dd, J = 5.5, 2.5 Hz, 1H), 7.33 (d, J = 2.5 Hz, 1H), 8.44 (d, J = 5.5 Hz; 1H), 8.73 (br d, 1H); HPLC ES-MS m/z 244 ((M+H)+).

Synthesis of 4-{4-[({[4-Chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy}-N-methylpyridine-2-carboxamide (sorafenib)

4-(4-Aminophenoxy)-N-methyl-2-pyridinecarboxamide (52.3 kg, 215 mol) is suspended in ethyl acetate (146 kg) and the suspension is heated to approx. 40° C. 4-Chloro-3-trifluoromethylphenyl isocyanate (50 kg, 226 mol), dissolved in ethyl acetate (58 kg), is then added to such a degree that the temperature is kept below 60° C. After cooling to 20° C. within 1 h, the mixture is stirred for a further 30 min and the product is filtered off. After washing with ethyl acetate (30 kg), the product is dried under reduced pressure (50° C., 80 mbar). 93 kg (93% of theory) of the title compound are obtained as colorless to slightly brownish crystals. m.p. 206-208° C. 1H-NMR (DMSO-d6, 500 MHz): δ =2.79 (d, J=4.4 Hz, 3H, NCH3); 7.16 (dd, J=2.5, 5.6 Hz, 1H, 5-H); 7.18 (d, J=8.8 Hz, 2H, 3′-H, 5′-H); 7.38 (d, J=2.4 Hz, 1H, 3-H); 7.60-7.68 (m, 4H, 2′-H, 6′-H, 5″-H, 6″-H); 8.13 (d, J=1.9 Hz, 1H, 2″-H); 8.51 (d, J=5.6 Hz, 1H, 6-H); 8.81 (d, J=4.5 Hz, 1H, NHCH3); 9.05 (br. s, 1H, NHCO); 9.25 (br. s, 1H, NHCO) MS (ESI, CH3CN/H2O): m/e=465 [M+H]+.

Synthesis of Sorafenib Tosylate (Nexavar)

4-(4-{3-[4-chloro-3-(trifluoromethyl)phenyl]ureido}phenoxy)-N2-methylpyridine-2-carboxamide (sorafenib) (50g, 0.1076 mol) is suspended in ethyl acetate (500 g) and water (10g). The mixture is heated to 69°C within 0.5 h, and a filtered solution of p-toluenesulfonic acid monohydrate (3.26 g, 0.017 mol) in a mixture of water (0.65 g) and ethyl acetate (7.2 g) is added. After filtration a filtered solution of p-toluenesulfonic acid monohydrate (22g, 0.11 mol) in a mixture of ethyl acetate (48 g) and water (4.34 g) is added. The mixture is cooled to 23°C within 2 h. The product is filtered off, washed twice with ethyl acetate (92.5 g each time) and dried under reduced pressure. The sorafenib tosylate (65.5 g, 96% of theory) is obtained as colorless to slightly brownish crystals.

………………..

http://www.google.com/patents/EP2195286A2?cl=en

Example 22: Synthesis of Sorafenib

Phenyl 4-chloro-3-(trifluoromethyl)phenylcarbamate (100 g, 0.3174 mol) and 4-(4- aminophenoxy)-N-methylpicolinamide (77.14 g, 0.3174 mol) were dissolved in N₁N- dimethyl formamide (300 ml) to obtain a clear reaction mass. The reaction mass was agitated at 40-45⁰C for 2-3 hours, cooled to room temperature and diluted with ethyl acetate (1000 ml). The organic layer was washed with water (250 ml) followed by 1N HCI (250ml) and finally with brine (250 ml). The organic layer was separated, dried over sodium sulfate and degassed to obtain solid. This solid was stripped with ethyl acetate and finally slurried in ethyl acetate (1000 ml) at room temperature. It was then filtered and vacuum dried to give (118 g) of 4-(4-(3-(4-chloro-3- (trifluoromethyl)phenyl)ureido)phenoxy)-N-methylpicolinamide (sorafenib base).

Example 23: Synthesis of 1-(4-chloro-3-(trifluoromethyl)phenyl)urea (Compound 4)

Sodium cyanate (1.7 g, 0.02mol) was dissolved in water (17ml) at room temperature to obtain a clear solution. This solution was then charged drop wise to the clear solution of 3- trifluoromethyl-4-chloroaniline (5 g, 0.025 mol) in acetic acid (25 ml) at 40°C-45°C within 1- 2 hours. The reaction mass was agitated for whole day and cooled gradually to room temperature. The obtained solid was filtered washed with water and vacuum dried at 50⁰C to afford the desired product (5.8 g) i.e. 1-(4-chloro-3-(trifluoromethyl)phenyl)urea.

Example 24: Synthesis of Sorafenib

1-(4-chloro-3-(trifluoromethyl) phenyl)urea (15 g, 0.0628 mol), 1 ,8- diazabicyclo[5.4.0]undec-7-ene (11.75 ml, 0.078 mol) and 4-(4-aminophenoxy)-N- methylpicolinamide (15.27 g, 0.0628 mol) were mixed with dimethyl sulfoxide (45 ml) and the reaction mass was then heated to 110-120⁰C for 12-18 hours. The reaction mass was cooled to room temperature and quenched in water (250 ml). The quenched mass was extracted repeatedly with ethyl acetate and the combined ethyl acetate layer was then back washed with water. It was dried over sodium sulfate and evaporated under vacuum to obtain solid. The obtained solid was slurried in acetonitrile (150 ml) at ambient temperature and filtered to give 4-(4-(3-(4-chloro-3-(trifluoromethyl) phenyl) ureido) phenoxy)-N-methylpicolinamide (sorafenib base) (17.5 g).

………………………..

http://www.google.com/patents/WO2009054004A2?cl=en

http://worldwide.espacenet.com/publicationDetails/biblio?CC=WO&NR=2009054004A2&KC=A2&FT=D&date=20090430&DB=EPODOC&locale=en_gb

EXAMPLES

Example 1

Preparation of l-(4-chloro-3-(trifluoromethyl)phenyI)-3-(4-hydroxyphenyl)urea Into a 250 ml, four-necked RB flask was charged 1O g of 4-aminophenol and 100 ml of toluene. A solution of 4-chloro-3-(trifluoromethyl)phenyl isocyante (20.4 g) in toluene (50 ml) was added to the reaction mass at 25-30⁰C. The reaction mass was stirred at room temperature for 16 h. The reaction mass was filtered and washed the. solid with 50 ml of toluene. The wet material was dried in the oven at 50-60°C to get 29.8 g of title compound as white solid. M.P. is 218-222°C. IR (KBr): 3306, 1673, 1625, 1590, 1560, 1517, 1482, 1435, 1404, 1328, 1261, 1182, 1160, 1146, 1125, 1095, 1032, 884, 849, 832, 812, 766, 746, 724, 683, 539 and 434 cm^“1.

Example 2 Preparation of sorafenib tosylate

Into a 100 ml, three-necked RB flask was charged 2.0 g of l-(4-chloro-3- (trifluoromethyl)-phenyl)-3-(4-hydroxyphenyl)urea and 10 ml of DMF. Potassium tert- butoxide (2.3 g) was added to the reaction mass and stirred for 45 min at RT. 4-Chlro-N- methylpicolinamide (1.14 g) and potassium carbonate (0.42 g) were added to the reaction mass and heated to 80°C. The reaction mass was maintained at 80-85°C for 8 h and cooled to 30°C. The reaction mass was poured into water and extracted with ethyl acetate. Ethyl acetate layer was washed with water, brine and dried over sodium sulphate. Solvent was distilled of under reduced pressure.

The crude compound (4.7 g) was dissolved in 10 ml of IPA and added 1.9 g of p- toluenesulfonic acid. The reaction mass was stirred at RT for 15 h and filtered. The wet solid was washed with 10 ml of IPA and dried at 50-60°C to get 3.4 g of title compound as off-white crystalline solid.

…………………..

A Scaleable Synthesis of BAY 43-9006: A Potent Raf Kinase Inhibitor for the Treatment of Cancer

Donald Bankston,*Jacques Dumas,Reina Natero,Bernd Riedl,Mary-Katherine Monahan, andRobert Sibley

Bayer Research Center, Pharmaceutical Division, 400 Morgan Lane, West Haven, Connecticut 06516, U.S.A.

Org. Proc. Res. Dev., 2002, 6 (6), pp 777–781

DOI: 10.1021/op020205n

http://pubs.acs.org/doi/abs/10.1021/op020205n

Urea 3 (BAY 43–9006), a potent Raf kinase inhibitor, was prepared in four steps with an overall yield of 63%. Significant process research enabled isolation of each intermediate and target without chromatographic purification, and overall yield increases >50% were observed compared to those from previous methods. This report focuses on improved synthetic strategies for production of scaled quantities of 3 for preclinical, toxicological studies. These improvements may be useful to assemble other urea targets as potential therapeutic agents to combat cancer.

Synthesis of N-[4-Chloro-3-(trifluoromethyl)phenyl]({4-[2-(N-methyl-carbamoyl)(4-pyridyloxy)]phenyl}amino)carboxamide (3, BAY 43–9006).

A suspension of 9 (67.00 g, 275.43 mmol) in methylene chloride ———————-DELETE………………………………The solids were washed with methylene chloride (2 × 50 mL) and dried under vacuum for 4 h at 35 °C to afford 3 (118.19 g, 254.27 mmol, 92%) as an off-white solid.

Mp = 210−212 °C.

¹H NMR (DMSO-d₆, 300 MHz):

δ 2.77 (d, J = 4.8 Hz, 3H, −NHCH₃);

7.16 (m, 3H, aromatic);

7.37 (d, J = 2.5 Hz, 1H, aromatic);

7.62 (m, 4H, aromatic);

8.11 (d, J = 2.5 Hz, 1H, aromatic);

8.49 (d, J = 5.5 Hz, 1H, aromatic);

8.77 (br d, 1H, −NHCH₃);

8.99 (s, 1H, −NHCO−); 9.21 (s, 1H, −NHCO−).

Mass spectrum (HPLC/ES): m/e = 465 (M + 1).

Anal. Calcd for C₂₁H₁₆N₄ClF₃O₃: C, 54.26; H, 3.47; N, 12.05. Found: C, 54.11; H, 3.49; N, 12.03.

HPLC (ELS) purity >98%: t_R = 3.5 min.

Synthesis of N-[4-Chloro-3-(trifluoromethyl)phenyl]({4-[2-(N-methyl-carbamoyl)(4-pyridyloxy)]phenyl}amino)carboxamide (3, BAY 43–9006): Use of CDI.

A solution of 11 (1.25 g, 6.39 mmol) in methylene chloride———————-DELETED……………………. high vacuum at 35 °C for 2 h to afford 3 (2.55 g, 5.49 mmol, 91%) as a white solid. Proton NMR and mass-spectral data were consistent with structure.

Anal. Calcd for C₂₁H₁₆N₄ClF₃O₃: C, 54.26; H, 3.47; N, 12.05; Cl, 7.63. Found: C, 54.24; H, 3.31; N, 12.30; Cl, 7.84.

Mp (differential scanning calorimetry, 10 °C/min): 205.6 °C;

no polymorphs observed.

REFERENCES

“FDA Approves Nexavar for Patients with Inoperable Liver Cancer” (Press release). FDA. November 19, 2007. Retrieved November 10, 2012.
“Nexavar (sorafenib) dosing, indications, interactions, adverse effects, and more”. Medscape Reference. WebMD. Retrieved 26 December 2013.
“NEXAVAR (sorafenib) tablet, film coated [Bayer HealthCare Pharmaceuticals Inc.]”. DailyMed. Bayer HealthCare Pharmaceuticals Inc. November 2013. Retrieved 26 December 2013.
“Nexavar 200mg film-coated tablets – Summary of Product Characteristics (SPC) – (eMC)”. electronic Medicines Compendium. Bayer plc. 27 March 2013. Retrieved 26 December 2013.
“PRODUCT INFORMATION NEXAVAR® (sorafenib tosylate)” (PDF). TGA eBusiness Services. Bayer Australia Ltd. 12 December 2012. Retrieved 26 December 2013.
Escudier, B; Eisen, T; Stadler, WM; Szczylik, C; Oudard, S; Siebels, M; Negrier, S; Chevreau, C; Solska, E; Desai, AA; Rolland, F; Demkow, T; Hutson, TE; Gore, M; Freeman, S; Schwartz, B; Shan, M; Simantov, R; Bukowski, RM (January 2007). “Sorafenib in advanced clear-cell renal-cell carcinoma”. New England Journal of Medicine 356 (2): 125–34. doi:10.1056/NEJMoa060655. PMID 17215530.
Walid, MS; Johnston, KW (October 2009). “Successful treatment of a brain-metastasized renal cell carcinoma”. German Medical Science 7: Doc28. doi:10.3205/000087. PMC 2775194. PMID 19911072.
“Pharmaceutical Benefits Scheme (PBS) -SORAFENIB”. Pharmaceutical Benefits Scheme. Australian Government Department of Health. Retrieved 27 December 2013.
Llovet, et al. (2008). “Sorafenib in Advanced Hepatocellular Carcinoma” (PDF). New England Journal of Medicine 359 (4): 378–90.
Keating GM, Santoro A (2009). “Sorafenib: a review of its use in advanced hepatocellular carcinoma”. Drugs 69 (2): 223–40. doi:10.2165/00003495-200969020-00006. PMID 19228077.
Pawlik TM, Reyes DK, Cosgrove D, Kamel IR, Bhagat N, Geschwind JF (October 2011). “Phase II trial of sorafenib combined with concurrent transarterial chemoembolization with drug-eluting beads for hepatocellular carcinoma”. J. Clin. Oncol. 29 (30): 3960–7. doi:10.1200/JCO.2011.37.1021. PMID 21911714.
“Phase 3 Trial of Nexavar in Patients With Non-Responsive Thyroid Cancer”^{[dead link]}
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“Chemotherapy-Induced Nausea and Vomiting Treatment & Management”. Medscape Reference. WebMD. 3 July 2012. Retrieved 26 December 2013.
Hagopian, Benjamin (August 2010). “Unusually Severe Bullous Skin Reaction to Sorafenib: A Case Report”. Journal of Medical Cases 1 (1): 1–3. doi:10.4021/jmc112e. Retrieved 11 February 2014.
Smalley KS, Xiao M, Villanueva J, Nguyen TK, Flaherty KT, Letrero R, Van Belle P, Elder DE, Wang Y, Nathanson KL, Herlyn M (January 2009). “CRAF inhibition induces apoptosis in melanoma cells with non-V600E BRAF mutations”. Oncogene 28 (1): 85–94. doi:10.1038/onc.2008.362. PMC 2898184. PMID 18794803.
Wilhelm SM, Adnane L, Newell P, Villanueva A, Llovet JM, Lynch M (October 2008). “Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling”. Mol. Cancer Ther. 7 (10): 3129–40. doi:10.1158/1535-7163.MCT-08-0013. PMID 18852116.
Zhang Y (Jan 2014). “Screening of kinase inhibitors targeting BRAF for regulating autophagy based on kinase pathways.”. J Mol Med Rep 9 (1): 83–90. PMID 24213221.
Gauthier A (Feb 2013). “Role of sorafenib in the treatment of advanced hepatocellular carcinoma: An update..”. Hepatol Res 43 (2): 147–154. doi:10.1111/j.1872-034x.2012.01113.x. PMID 23145926.
FDA Approval letter for use of sorafenib in advanced renal cancer
European Commission – Enterprise and industry. Nexavar. Retrieved April 24, 2007.
“Nexavar® (Sorafenib) Approved for Hepatocellular Carcinoma in Europe” (Press release). Bayer HealthCare Pharmaceuticals and Onyx Pharmaceuticals. October 30, 2007. Retrieved November 10, 2012.
FDA Approval letter for use of sorafenib in inoperable hepatocellular carcinoma
“Liver drug ‘too expensive‘“. BBC News. November 19, 2009. Retrieved November 10, 2012.
http://www.ipindia.nic.in/ipoNew/compulsory_License_12032012.pdf
“Seven days: 9–15 March 2012”. Nature 483 (7389): 250–1. 2012. doi:10.1038/483250a.
“India Patents (Amendment) Act, 2005”. WIPO. Retrieved 16 January 2013.
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“Addition of Sorafenib May Be Detrimental in Some Lung Cancer Patients”
ClinicalTrials.gov NCT00329719 Sorafenib and Temsirolimus in Treating Patients With Recurrent Glioblastoma
“Activity of sorafenib against desmoid tumor/deep fibromatosis”
“‘We didn’t make this medicine for Indians… we made it for western patients who can afford it‘“. Daily Mail Reporter. 24 Jan 2014.

External links

Nexavar.com – Manufacturer’s website
Prescribing Information – includes data from the key studies justifying the use of sorafenib for the treatment of kidney cancer (particularly clear cell renal cell carcinoma, which is associated with the von Hippel-Lindau gene)
Patient Information from FDA
Sorafenib in Treating Patients With Soft Tissue Sarcomas
Sorafenib Sunitinib differences – diagram
ClinicalTrials.gov NCT00217399 – Sorafenib and Anastrozole in Treating Postmenopausal Women With Metastatic Breast Cancer
Cipla launches Nexavar generic at 1/10 of Bayer’s price

Reference
1	*	D. BANKSTON ET AL.: “A Scalable Synthesis of BAY 43-9006: A Potent Raf Kinase Inhibitor for the Treatment of Cancer” ORGANIC PROCESS RESEARCH & DEVELOPMENT, vol. 6, no. 6, 2002, pages 777-781, XP002523918 cited in the application
2	*	PAN W ET AL: “Pyrimido-oxazepine as a versatile template for the development of inhibitors of specific kinases” BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, PERGAMON, ELSEVIER SCIENCE, GB, vol. 15, no. 24, 15 December 2005 (2005-12-15), pages 5474-5477, XP025314229 ISSN: 0960-894X [retrieved on 2005-12-15]
Citing Patent	Filing date	Publication date	Applicant	Title
WO2011036647A1	Sep 24, 2010	Mar 31, 2011	Ranbaxy Laboratories Limited	Process for the preparation of sorafenib tosylate
WO2011036648A1	Sep 24, 2010	Mar 31, 2011	Ranbaxy Laboratories Limited	Polymorphs of sorafenib acid addition salts
WO2011058522A1	Nov 12, 2010	May 19, 2011	Ranbaxy Laboratories Limited	Sorafenib ethylsulfonate salt, process for preparation and use
WO2011092663A2	Jan 28, 2011	Aug 4, 2011	Ranbaxy Laboratories Limited	4-(4-{3-[4-chloro-3-(trifluoromethyl)phenyl]ureido}phenoxy)-n2-methylpyridine-2-carboxamide dimethyl sulphoxide solvate
WO2011113367A1 *	Mar 17, 2011	Sep 22, 2011	Suzhou Zelgen Biopharmaceutical Co., Ltd.	Method and process for preparation and production of deuterated ω-diphenylurea
US8552197	Nov 12, 2010	Oct 8, 2013	Ranbaxy Laboratories Limited	Sorafenib ethylsulfonate salt, process for preparation and use
US8604208	Sep 24, 2010	Dec 10, 2013	Ranbaxy Laboratories Limited	Polymorphs of sorafenib acid addition salts
US8609854	Sep 24, 2010	Dec 17, 2013	Ranbaxy Laboratories Limited	Process for the preparation of sorafenib tosylate
US8618305	Jan 28, 2011	Dec 31, 2013	Ranbaxy Laboratories Limited	Sorafenib dimethyl sulphoxide solvate
US8669369	Mar 17, 2011	Mar 11, 2014	Suzhou Zelgen Biopharmaceutical Co., Ltd.	Method and process for preparation and production of deuterated Ω-diphenylurea

* Cited by examiner

Dolutegravir, Biggest rival to World’s Best Selling HIV Drug Atripla, May Get FDA Approval by August 2013

July 16, 2013 3:45 am / 1 Comment on Dolutegravir, Biggest rival to World’s Best Selling HIV Drug Atripla, May Get FDA Approval by August 2013

Dolutegravir (also known as S/GSK1349572), a second-generation integrase inhibitor under development by GlaxoSmithKline and its Japanese partner Shionogi for the treatment of HIV infection, was given priority review status from the US Food and Drug Administration (FDA) in February, 2013.

GlaxoSmithKline marketed the first HIV drug Retrovir in 1987 before losing out to Gilead Sciences Inc. (GILD) as the world’s biggest maker of AIDS medicines. The virus became resistant to Retrovir when given on its own, leading to the development of therapeutic cocktails.

The new once-daily drug Dolutegravir, which belongs to a novel class known as integrase inhibitors that block the virus causing AIDS from entering cells, is owned by ViiV Healthcare, a joint venture focused on HIV in which GSK is the largest shareholder.

Raltegravir (brand name Isentress) received approval by the U.S. Food and Drug Administration (FDA) on 12 October 2007, the first of a new class of HIV drugs, the integrase inhibitors, to receive such approval. it is a potent and well tolerated antiviral agent. However, it has the limitations of twice-daily dosing and a relatively modest genetic barrier to the development of resistance, prompting the search for agents with once-daily dosing.

Elvitegravir, approved by the FDA on August 27, 2012 as part of theelvitegravir/cobicistat/tenofovir disoproxil fumarate/emtricitabine fixed-dose combination pill (Quad pill, brand name Stribild) has the benefit of being part of a one-pill, once-daily regimen, but suffers from extensive cross-resistance with raltegravir.

Gilead’s Atripla (Emtricitabine/Tenofovir/efavirenz), approved in 2006 with loss of patent protection in 20121, is the top-selling HIV treatment. The $3.2 billion medicine combines three drugs in one pill, two compounds that make up Gilead’s Truvada (Emtricitabine/Tenofovir) and Bristol- Myers Squibb Co.’s Sustiva (Efavirenz).

A three-drug combination containing dolutegravir and ViiV’s older two-in-one treatment Epzicom(Abacavir/Lamivudine, marketed outside US as Kivexa) proved better than Gilead’s market-leading Atripla in a clinical trial released in July, 2012 (See the Full Conference Report Here), suggesting it may supplant the world’s best-selling AIDS medicine as the preferred front-line therapy. In the latest Phase III study, after 48 weeks of treatment, 88% of patients taking the dolutegravir-based regimen had reduced viral levels to the goal compared with 81% of patients taking Atripla. More patients taking Atripla dropped out of the study because of adverse events compared with those taking dolutegravir — 10% versus just 2% — which was the main driver of the difference in efficacy. The result was the second positive final-stage clinical read-out for dolutegravir, following encouraging results against U.S. company Merck & Co’s rival Isentress in April, 2012 (See the Conference Abstract Here)..

Dolutegravir is viewed by analysts as a potential multibillion-dollar-a-year seller, as its once-daily dosing is likely to be attractive to patients. The FDA is scheduled to issue a decision on the drug’s approval by August 17。

Sources:

Johns, Brian Alvin; Kawasuji, Takashi; Taishi, Teruhiko; Taoda, Yoshiyuki ; Polycyclic carbamoylpyridone derivative having HIV integrase inhibitory activity and their preparation; PCT Int. Appl., WO2006116764, 02 Nov 2006

Johns, Brian Alvin; Weatherhead, Jason Gordon;Tricyclic heterocyclic compounds as antiviral agents and their preparation and use in the treatment of HIV infection; PCT Int. Appl., WO2010011812, 28 Jan 2010

Johns, Brian Alvin; Weatherhead, Jason Gordon; Tricyclic heterocyclic compounds as antiviral agents and their preparation and use in the treatment of HIV infection;PCT Int. Appl., WO2010011819, 28 Jan 2010

Yoshida, Hiroshi; Taoda, Yoshiyuki; Johns, Brian Alvin; Synthesis of fused tricyclic carbamoylpyridone HIV integrase inhibitors and intermediates;PCT Int. Appl.,WO2010068253, 17 Jun 2010

Johns, Brian Alvin; Duan, Maosheng; Hakogi, Toshikazu;Processes and intermediates for fused tricyclic carbamoylpyridone HIV integrase inhibitors;PCT Int. Appl., WO2010068262, 17 Jun 2010

Sumino, Yukihito; Okamoto, Kazuya; Masui, Moriyasu; Yamada, Daisuke; Ikarashi, Fumiya;Preparation of compounds having HIV integrase inhibitory activity; PCT Int. Appl.,WO2012018065, 09 Feb 2012

Kawasuji, Takashi; Johns, Brian A.;Discovery of dolutegravir and S/GSK1265744: Carbamoyl pyridone HIV-1 integrase inhibitors;Abstracts, 64th Southeast Regional Meeting of the American Chemical Society, Raleigh, NC, United States, November 14-17 (2012), SERM-176.

Kawasuji, Takashi; Johns, Brian A.; Yoshida, Hiroshi; Weatherhead, Jason G.; Akiyama, Toshiyuki; Taishi, Teruhiko; Taoda, Yoshiyuki; Mikamiyama-Iwata, Minako; Murai, Hitoshi; Kiyama, Ryuichi; Fuji, Masahiro; Tanimoto, Norihiko; Yoshinaga, Tomokazu; Seki, Takahiro; Kobayashi, Masanori; Sato, Akihiko; Garvey, Edward P.; Fujiwara, Tamio; Carbamoyl Pyridone HIV-1 Integrase Inhibitors. 2. Bi- and Tricyclic Derivatives Result in Superior Antiviral and Pharmacokinetic Profiles;Journal of Medicinal Chemistry (2013), 56(3), 1124-1135

Walmsley S et al. Dolutegravir (DTG; S/GSK1349572) + abacavir/lamivudine once daily statistically superior to tenofovir/emtricitabine/efavirenz: 48-week results – SINGLE (ING114467). 52nd ICAAC, 9-12 September 2012, San Francisco. Abstract H-556b.
http://www.abstractsonline.com/Plan/ViewAbstract.aspx?sKey=e1c18d5b-830f-4b4e-8671-35bcfb20eed5&cKey=af219b7d-2171-46b2-91ef-b8049552c9e5&mKey=%7b6B114A1D-85A4-4054-A83B-04D8B9B8749F%7d
http://www.natap.org/2012/ICAAC/ICAAC_06.htm
http://i-base.info/htb/20381

Raffi F et al. Once-daily dolutegravir (DTG; S/GSK1349572) is non-inferior to raltegravir (RAL) in antiretroviral-naive adults: 48 week results from SPRING-2 (ING113086). 19th International AIDS Conference. 22-27 July 2012, Washington. Late breaker oral presentation THLBB04.
http://pag.aids2012.org/abstracts.aspx?aid=20990

National Institutes of Health (U.S.). A trial comparing GSK1349572 50 mg plus abacavir/lamivudine once daily to Atripla (also called the SINGLE trial). Available from:http://clinicaltrials.gov/ct2/show/NCT01263015.

Stellbrink HJ, Reynes J, Lazzarin A, et al. Dolutegravir in combination therapy exhibits rapid and sustained antiviral response in ARV-naïve adults: 96-week results from SPRING-1 (ING112276) (Abstract 102LB). Paper presented at: 19th Conference on Retroviruses and Opportunistic Infections; 2012 March 5–8; Seattle, WA. Available from:http://www.retroconference.org/2012b/Abstracts/45432.html

Dolutegravir synthesis (EP2602260, 2013). LiHMDS as the non-nucleophilic strong base pulling compound 1 carbonyl group proton alpha position with an acid chloride after 2 and ring closure reaction to obtain 3 , 3 via primary amine 4 ring opening ring closure to obtain 5 , NBS the bromine under acidic conditions to obtain aldehyde acetal becomes 6 , 6 of the aldehyde and amino alcohols 7 and turn off the condensation reaction obtained by the ring 8 , alkaline hydrolysis 8 of bromine into a hydroxyl group and hydrolyzable ester obtained 9 after the 10 occurred acid condensation Dolutegravir.

Merck: Good Results in Alzheimer’s Trial

July 16, 2013 3:28 am / Leave a comment

Processing of the amyloid precursor protein

Merck Presents Findings from Phase 1b Study of Investigational BACE Inhibitor, MK-8931, in Patients with Alzheimer’s Disease

Merck, known as MSD outside the United States and Canada, today announced the presentation of results from a Phase Ib study showing a dose-dependent decrease in β amyloid levels in cerebral spinal fluid (CSF) following administration of MK-8931, Merck’s investigational oral β-site amyloid precursor protein cleaving enzyme (BACE1 or β secretase) inhibitor, in patients with mild to moderate Alzheimer’s disease (AD). In the study, β amyloid levels were analyzed as a measure of BACE activity. The data were presented during an oral session at the Alzheimer’s Association International Conference (AAIC) in Boston, July 13-18 (Abstract O1-06-05).

http://www.pharmalive.com/merck-good-results-in-alzheimers-trial

Beta-site APP-cleaving enzyme 1
PDB rendering based on 1fkn

Beta-secretase 1 (BACE1) also known as beta-site APP cleaving enzyme 1(beta-site amyloid precursor protein cleaving enzyme 1), memapsin-2(membrane-associated aspartic protease 2), and aspartyl protease 2 (ASP2) is an enzyme that in humans is encoded by the BACE1 gene.

β-Secretase is an aspartic-acid protease important in the formation of myelin sheaths in peripheral nerve cells. The transmembrane protein contains two active site aspartate residues in its extracellular protein domain and may function as a dimer.

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Nardostachys chinensis.

Extracting the Medicine from Traditional Chinese Medicine

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Shuddha Guggulu

The effective lipid regulator

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Enbrel (etanercept)

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SORAFENIB

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Kidney cancer

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Thyroid cancer

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Brain (Recurrent Glioblastoma)

Desmoid Tumor (Aggressive Fibromatosis)

Nexavar Controversy

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Chemical Synthesis of Sorafenib Tosylate (Nexavar)

Full Experimental Details for the preparation of Sorafenib Tosylate (Nexavar)

A Scaleable Synthesis of BAY 43-9006: A Potent Raf Kinase Inhibitor for the Treatment of Cancer

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Dolutegravir (also known as S/GSK1349572), a second-generation integrase inhibitor under development by GlaxoSmithKline and its Japanese partner Shionogi for the treatment of HIV infection, was given priority review status from the US Food and Drug Administration (FDA) in February, 2013.

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