New Drug Approvals

Home » Posts tagged 'herbs'

Tag Archives: herbs

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

Blog Stats

  • 1,776,045 hits

Flag and hits

Flag Counter

Enter your email address to follow this blog and receive notifications of new posts by email.

Join 2,066 other followers

Follow New Drug Approvals on WordPress.com

Categories

Flag Counter

ORGANIC SPECTROSCOPY

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

Enter your email address to follow this blog and receive notifications of new posts by email.

Join 2,066 other followers

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 29 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 29 year tenure till date Aug 2016, Around 30 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 25 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 13 lakh plus views on New Drug Approvals Blog in 212 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

Personal Links

Verified Services

View Full Profile →

Categories

Flag Counter

Japanese knotweed extract (Polygonum cuspidatum) Resveratrol 98%


Shanghai Natural Bio-engineering Co., Ltd

 

http://www.hnkeyuan.com/

Shanghai Natural Bio-engineering Profile

Shanghai Natural Bio-engineering Co., Ltd, export branch of Hunan Keyuan Bio-products co., Ltd, established in 2003, is a professional large-scale high-tech manufacturer of raw materials for nutraceuticals, nutritional supplements, and pharmaceuticals. Plant extracts, Active Pharmaceutical Ingredient (API) & intermediates are our focused areas.Key products include resveratrol, curcumin,artemisinin,artemether,artesunate,dihydroartemisinin,Lumefantrine,etc

 

 

Japanese knotweed extract (Polygonum cuspidatum) Resveratrol 98%

Japanese knotweed extract (Polygonum cuspidatum) Resveratrol 98%

link is

https://www.linkedin.com/today/post/article/20140805055958-283555965-japanese-knotweed-extract-polygonum-cuspidatum-resveratrol-98?trk=hb_ntf_MEGAPHONE_ARTICLE_POST

posted by

Stanford Lee

Sales Manager at Shanghai Natural Bio-engineering Co., Ltd

 

synonyms Japanese knotweed extract, Polygonum cuspidatum, red wine extract, trans-3,5,4′-trihydroxystilbene, trans-Resveratrol, cis-resveratrol
CAS number 501-36-0
Latin Name Polygonum cuspidatum
Botanical source 1.Japanese knotweed plant Polygonum cuspidatum
2. red wine
3. red grape extracts
Molecular Formula C14H12O3
Molecular weight 228.24
Appearance white powder with slight yellow
Solubility in water 0.03 g/L
Dosage 500mg
Key benefits Anti-aging, Anti-Cancer, cardiovascular support, regulate estrogen level, weight loss
Applied industry Sports nutrition, nutraceuticals, cosmetics

What is resveratrol?

When talk about resveratrol, we have to mention red wine since resveratrol is first popularly known in red wine. In fact, resveratrol was actually first isolated in 1940 from white hellebore roots by the Japanese scientist Michio Takaoka. Red wine, in moderation, has long been thought of as heart healthy. However, the most popular source of resveratrol is from Japanese knotweed extract (Latin name:Polygonum cuspidatum)

Resveratrol (3,5,4′-trihydroxystilbene) is a polyphenolic phytoalexin. It is a stilbenoid, a derivate of stilbene, and is produced in plants with the help of the enzyme stilbene synthase.

Resveratrol exists as two geometric isomers: “cis-” (“Z”) and “trans-” (“E”). The ”trans-” form can undergo isomerisation to the “cis-” form when exposed to ultraviolet irradiation. Trans-resveratrol in the powder form was found to be stable under “accelerated stability” conditions of 75% humidity and 40 degrees C in the presence of air. Resveratrol content also stayed stable in the skins of grapes and pomace taken after fermentation and stored for a long period.

Sources of resveratrol

The resveratrol in red wine comes from the skin of grapes used to make wine. Because red wine is fermented with grape skins longer than is white wine, red wine contains more resveratrol. Simply eating grapes, or drinking grape juice, has been suggested as one way to get resveratrol without drinking alcohol. Red and purple grape juices may have some of the same heart-healthy benefits of red wine.

Other foods that contain some resveratrol include peanuts, blueberries and cranberries. It’s not yet known how beneficial eating grapes or other foods might be compared with drinking red wine when it comes to promoting heart health. The amount of resveratrol in food and red wine can vary widely.

Benefits of taking reveratrol supplements

Numerous studies have been conducted regarding various purported resveratrol benefits. Studies have primarily been conducted on laboratory animals, and while human search is very promising, is still in its earliest stages. Current research into resveratrol benefits points to resveratrol having amazing anti-aging properties, hence dubbed “The Fountain of Youth.” Many other key benefits such as cardiovascular effects, anti-cancer, estrogen regulating effects are mentioned here.

1.Resveratrol and its anti-aging benefits

The study by Harvard Medical School researchers shows that resveratrol stimulates production of SIRT1, a serum that blocks diseases by speeding up the cell’s energy production centers known as mitochondria.

Resveratrol affects the activity of enzymes called sirtuins. Sirtuins control several biological pathways and are known to be involved in the aging process. Resveratrol is only one of many natural and synthetic sirtuin-activating compounds (STACs) now known. Certain metabolic diseases, including type 2 diabetes and heart disease, tend to strike as we age. In animal studies, severely restricting calories can help prevent some of these diseases. Over a decade ago, researchers found that resveratrol can mimic calorie restriction in some ways and extend the lifespans of yeast, worms, flies and fish.

2.Resveratrol and cardiovascular benefits

Resveratrol is famous for its Cardioprotective effects.According to Wikipedia, moderate drinking of red wine has long been known to reduce the risk of heart disease. This is best known as “the French paradox”.

Studies suggest resveratrol in red wine may play an important role in this phenomenon. It achieves the effects by the following functions: (1) inhibition of vascular cell adhesion molecule expression;(2) inhibition of vascular smooth muscle cell proliferation;(3) stimulation of endolethelial nitric oxide synthase (eNOS) activity;(4) inhibition of platelet aggregation;and (5) inhibition of LDL peroxidation.

The cardioprotective effects of resveratrol also are theorized to be a form of preconditioning—the best method of cardioprotection, rather than direct therapy.Study into the cardioprotective effects of resveratrol is based on the research of Dipak K. Das, however, who has been found guilty of scientific fraud and many of his publications related to resveratrol have been retracted. A 2011 study concludes, “Our data demonstrate that both melatonin and resveratrol, as found in red wine, protect the heart in an experimental model of myocardial infarction via theSAFE pathway.”

Resveratrol, a polyphenol in red wine, induces nitric oxide (NO) synthase, the enzyme responsible for the biosynthesis of NO, in cultured pulmonary artery endothelial cells, suggesting that Resveratrol could afford cardioprotection by affecting the expression of nitric oxide synthase.

3.Reveratrol and anti-cancer benefits

Experts already claim it can help you beat cancer – from brain tumours to breast, colon, prostate cancers and many more. Resveratrol is being studied to see how it affects the initiation, promotion, and progression of cancer. With regard to tumor initiation, it has been shown to act as an antioxidant by inhibiting free radical formation and as an anti-mutagen in rat models. Studies related to progression have found that resveratrol induced human promyelocytic leukemia cell differentiation, inhibited enzymes that promote tumor growth, and exerted antitumor effects in neuroblastomas. Noting that in animal studies, resveratrol was effective against tumors of the skin, breast, gastrointestinal tract, lung, and prostate gland. Memorial Sloan-Kettering, the American pillar of cancer treatment, conducted research on theinflammatory effects on cells leading to cancer. It is widely known that an enzyme, COX-2, lies behind the stimulation of localised hormones (eicosanoids) causing inflammation, the precursor to cancer. In the research Resveratrol completely turned off the COX-2 driver. MD Anderson´s studies have shown this same anti-inflammatory benefit too. Plus, after conversion in the liver to a sulphated form the compound can attack several of the steps in the cancer process even killing cancer cells.

4. The Benefits of Resveratrol Weight Loss

Resveratrol is actually a very popular nutrient that has been shown on Dr. Oz, Oprah, Barbara Walters, and a number of other national television shows. It is quickly becoming one of the country’s best natural supplements.

How does Resveratrol help you lose weight? Resveratrol on its own will not be effective at helping you to lose weight, but you have to use it in conjunction with exercise and a proper diet if you really want to obtain the maximum benefits from the supplement.

However, the vitamin, when in concentrated form, has been proven to help speed up the metabolism. This speeding up of the metabolism causes the body to metabolize and process to food consumed faster, which causes the calories in the food to be used more effectively. When the body metabolizes food faster, there is less risk of excess calories being stored in the body in the form of fat.

However, in order to ensure that Resveratrol actually works, you need to take sufficient amounts of the vitamin. The supplement is effective because it is a concentrated form of the helpful vitamin, and taking the supplement is the best way to ensure that Resveratrol works effectively in helping you shed those excess pounds.

Another way Resveratrol helps you to lose weight is through reducing the amounts of estrogen that your body produces. Estrogen increases body fat and decreases muscle mass, so reducing the amounts of estrogen produced by your body will help you lose weight and build muscle. Taking Resveratrol can be a good way to ensure that your body doesn’t produce the amounts of estrogen that will keep it from building muscle.

Side Effects of taking resveratrol supplements

Because there have been very few studies conducted on resveratrol in humans, doctors still can’t confirm what adverse effects these supplements might have on people over the long term. So far, studies have not discovered any severe side effects, even when resveratrol is taken in large doses. However, resveratrol supplements might interact with blood thinners such as warfarin (Coumadin), and nonsteroidal anti-inflammatory medications such as aspirin and ibuprofen, increasing the risk for bleeding.

Like other supplements, resveratrol isn’t regulated by the FDA, so it’s difficult for consumers to know exactly what they’re getting when they buy a bottle, or whether the product is actually effective.

Dosage of resveratrol supplements

There also isn’t any specific dosage recommendation, and dosages can vary from supplement to supplement. The dosages in most resveratrol supplements are typically far lower than the amounts that have been shown beneficial in research studies. Most supplements contain 250 to 500 milligrams of resveratrol. To get the equivalent dose used in some animal studies, people would have to consume 2 grams of resveratrol (2,000 milligrams) or more a day.

Fallopia japonica, commonly known as Japanese knotweed, is a large, herbaceous perennial plant of the family Polygonaceae, native toEastern Asia in Japan, China and Korea. In North America and Europe the species is very successful and has been classified as aninvasive species in several countries. Japanese knotweed has hollow stems with distinct raised nodes that give it the appearance ofbamboo, though it is not closely related. While stems may reach a maximum height of 3–4 m each growing season, it is typical to see much smaller plants in places where they sprout through cracks in the pavement or are repeatedly cut down. The leaves are broad oval with a truncated base, 7–14 cm long and 5–12 cm broad,[1] with an entire margin. The flowers are small, cream or white, produced in erectracemes 6–15 cm long in late summer and early autumn.

Closely related species include giant knotweed (Fallopia sachalinensis, syn. Polygonum sachalinense) and Russian vine (Fallopia baldschuanica, syn. Polygonum aubertii, Polygonum baldschuanicum).

Other English names for Japanese knotweed include fleeceflower, Himalayan fleece vine, monkeyweed, monkey fungus, Hancock’s curse, elephant ears, pea shooters, donkey rhubarb (although it is not a rhubarb), sally rhubarb, Japanese bamboo, American bamboo, and Mexican bamboo (though it is not a bamboo). In Chinese medicine, it is known as Huzhang (Chinese: 虎杖; pinyin: Hǔzhàng), which translates to “tiger stick.” There are also regional names, and it is sometimes confused with sorrel. In Japanese, the name is itadori (虎杖, イタドリ?).[2]

Old stems remain in place as new growth appears

A hedgerow made up of roses and Japanese knotweed in Caersws, Wales in 2010

Erect inflorescence

Invasive species

It is listed by the World Conservation Union as one of the world’s worst invasive species.[3]

The invasive root system and strong growth can damage concrete foundations, buildings, flood defences, roads, paving, retaining walls and architectural sites. It can also reduce the capacity of channels in flood defences to carry water.[4]

It is a frequent colonizer of temperate riparian ecosystems, roadsides and waste places. It forms thick, dense colonies that completely crowd out any other herbaceous species and is now considered one of the worst invasive exotics in parts of the eastern United States. The success of the species has been partially attributed to its tolerance of a very wide range of soil types, pH and salinity. Its rhizomes can survive temperatures of −35 °C (−31 °F) and can extend 7 metres (23 ft) horizontally and 3 metres (9.8 ft) deep, making removal by excavation extremely difficult.

The plant is also resilient to cutting, vigorously resprouting from the roots. The most effective method of control is by herbicideapplication close to the flowering stage in late summer or autumn. In some cases it is possible to eradicate Japanese knotweed in one growing season using only herbicides. Trials in the Queen Charlotte Islands (Haida Gwaii) of British Columbia using sea water sprayed on the foliage have demonstrated promising results, which may prove to be a viable option for eradication where concerns over herbicide application are too great.[citation needed]

Two biological pest control agents that show promise in the control of the plant are the psyllid Aphalara itadori[5] and a leaf spotfungus from genus Mycosphaerella.[6]

New Zealand

It is classed as an unwanted organism in New Zealand and is established in some parts of the country.[7]

United Kingdom

In the UK, Japanese Knotweed is established in the wild in many parts of the country and creates problems due to the impact on biodiversity, flooding management and damage to property. It is an offence under section 14(2) of the Wildlife and Countryside Act 1981 to “plant or otherwise cause to grow in the wild” any plant listed in Schedule nine, Part II to the Act, which includes Japanese knotweed. It is also classed as “controlled waste” in Britain under part 2 of the Environmental Protection Act 1990. This requires disposal at licensed landfill sites. The species is expensive to remove; Defra‘s Review of Non-native Species Policy states that a national eradication programme would be prohibitively expensive at £1.56 billion.[8]

The decision was taken on 9 March 2010 in the UK to release into the wild a Japanese psyllid insect, Aphalara itadori.[9] Its diet is highly specific to Japanese knotweed and shows good potential for its control.[10][11]

In Scotland, the Wildlife and Natural Environment (Scotland) Act 2011 came into force in July 2012 that superseded the Wildlife and Countryside Act 1981. This act states that is an offence to spread intentionally or unintentionally Japanese knotweed (or other non-native invasive species).

North America

The weed can be found in 39 of the 50 United States[12] and in six provinces in Canada. It is listed as an invasive weed in Maine,Ohio, Vermont, Virginia, West Virginia, New York, Alaska, Pennsylvania, Michigan, Oregon and Washington state.[13]

Uses

A variegated variety of Japanese Knotweed, used as a landscape plant

Japanese knotweed flowers are valued by some beekeepers as an important source of nectar for honeybees, at a time of year when little else is flowering. Japanese knotweed yields a monofloral honey, usually called bamboo honey by northeastern U.S. beekeepers, like a mild-flavored version of buckwheat honey (a related plant also in the Polygonaceae).

The young stems are edible as a spring vegetable, with a flavor similar to extremely sour rhubarb. In some locations, semi-cultivating Japanese knotweed for food has been used as a means of controlling knotweed populations that invade sensitive wetland areas and drive out the native vegetation.[14] It is eaten in Japan as sansai or wild foraged vegetable.

Similarly to rhubarb, knotweed contains oxalic acid, which when eaten may aggravate conditions such as rheumatism, arthritis, gout, kidney stones or hyperacidity.[15]

Both Japanese knotweed and giant knotweed are important concentrated sources of resveratrol and its glucoside piceid,[16] replacing grape byproducts. Many large supplement sources of resveratrol now use Japanese knotweed and use its scientific name in the supplement labels. The plant is useful because of its year-round growth and robustness in different climates.[17]

This antique locomotive at Beekbergen,Netherlands is overgrown by knotweed. A few years before, it was free of knotweed

Control

Japanese knotweed has a large underground network of roots (rhizomes). To eradicate the plant the roots need to be killed. All above-ground portions of the plant need to be controlled repeatedly for several years in order to weaken and kill the entire patch. Picking the right herbicide is essential, as it must travel through the plant and into the root system below. Glyphosate is the best active ingredient in herbicide for use on Japanese knotweed as it is ’systemic’; it penetrates through the whole plant and travels to the roots.

Digging up the rhizomes is a common solution where the land is to be developed, as this is quicker than the use of herbicides, but safe disposal of the plant material without spreading it is difficult; knotweed is classed as controlled waste in the UK, and disposal is regulated by law.Digging up the roots is also very labor-intensive and not always efficient. The roots can go to up to 10 feet (3 meters) deep, and leaving only a few inches of root behind will result in the plant quickly growing back.

Covering the affected patch of ground with a non-translucent material can be an effective follow-up strategy. However, the trimmed stems of the plant can be razor sharp and are able to pierce through most materials. Covering with non-flexible materials such as concrete slabs has to be done meticulously and without leaving even the smallest splits. The slightest opening can be enough for the plant to grow back.

More ecologically-friendly means are being tested as an alternative to chemical treatments. Soil steam sterilization [18] involves injecting steam into contaminated soil in order to kill subterranean plant parts. Research has also been carried out on Mycosphaerella leafspot fungus, which devastates knotweed in its native Japan. This research has been relatively slow due to the complex life cycle of the fungus.[19]

Research has been carried out by not-for-profit inter-governmental organisation CABI in the UK. Following earlier studies imported Japanese knotweed psyllid insects (Aphalara itadori), whose only food source is Japanese knotweed, were released at a number of sites in Britain in a study running from 1 April 2010 to 31 March 2014. In 2012, results suggested that establishment and population growth were likely, after the insects overwintered successfully.[20][21]

Detail of the stalk

Controversy

In the United Kingdom, Japanese Knotweed has received a lot of attention in the press as a result of very restrictive lending policies by banks and other mortgage companies. Several lenders have refused mortgage applications on the basis of the plant being discovered in the garden or neighbouring garden.[22] The Royal Institution of Chartered Surveyors published a report in 2012 in response to lenders refusing to lend “despite [knotweed] being treatable and rarely causing severe damage to the property.” [23]

There is a real lack of information and understanding of what Japanese Knotweed is and the actual damage it can cause. Without actual advice and guidance, surveyors have been unsure of how to assess the risk of Japanese Knotweed, which can result in inconsistent reporting of the plant in mortgage valuations. RICS hopes that this advice will provide the industry with the tools it needs to measure the risk effectively, and provide banks with the information they require to identify who and how much to lend to at a time when it is essential to keep the housing market moving.

—Philip Santo, RICS Residential Professional Group[23]

In response to this guidance, several lenders have relaxed their criteria in relation to discovery of the plant. As recently as 2012, the policy at the Woolwich (part of Barclays plc) was “if Japanese Knotweed is found on or near the property then a case will be declined due to the invasive nature of the plant.”[24][25] Their criteria have since been relaxed to a category-based system depending on whether the plant is discovered on a neighbouring property (categories 1 and 2) or the property itself (categories 3 and 4) incorporating proximity to the property curtilage and the main buildings. Even in a worst-case scenario (category 4), where the plant is “within 7 metres of the main building, habitable spaces, conservatory and/or garage and any permanent outbuilding, either within the curtilage of the property or on neighbouring land; and/or is causing serious damage to permanent outbuildings, associated structures, drains, paths, boundary walls and fences” Woolwich lending criteria now specify that this property may be acceptable if “remedial treatment by a Property Care Association (PCA) registered firm has been satisfactorily completed. Treatment must be covered by a minimum 10-year insurance-backed guarantee, which is property specific and transferable to subsequent owners and any mortgagee in possession.” [26] Santander have relaxed their attitude in a similar fashion (citation needed).

Property Care Association chief executive Steve Hodgson, whose trade body has set up a task force to deal with the issue, said: “japanese knotweed is not “house cancer” and could be dealt with in the same way qualified contractors dealt with faulty wiring or damp.”[27]

Japan

The plant is known as itadori (イタドリ, 虎杖?). The kanji expression is from the Chinese meaning “tiger staff”, but as to the Japanese appellation, one straightforward interpretation is that it comes from “remove pain” (alluding to its painkilling use),[28][29] though there are other etymological explanations offered.

It grows widely throughout Japan and is foraged as a wild edible vegetable (sansai), though not in sufficient quantities to be included in statistics.[30] They are called by such regional names as: tonkiba (Yamagata),[30] itazuiko (Nagano, Mie),[30] itazura (Gifu, Toyama, Nara, Wakayama, Kagawa),[30] gonpachi (Shizuoka, Nara, Mie, Wakayama),[30]sashi (Akita, Yamagata),[30] jajappo (Shimane, Tottori, Okayama),[30] sukanpo (many areas).

Young leaves and shoots, which look like asparagus, are used. They are extremely sour; the fibrous outer skin must be peeled, soaked in water for half a day raw or after parboiling, before being cooked.

Places in Shikoku such as central parts of Kagawa Prefecture [31] pickle the peeled young shoots by weighting them down in salt mixed with 10% nigari (magnesium chloride).Kochi also rub these cleaned shoots with coarse salt-nigari blend. It is said (though no authority is cited) that the magnesium of the nigari binds with the oxalic acid thus mitigating its hazard.[32]

A novel use for a related species known as oh-itadori (Polygonum sachalinense) in Hokkaido is feeding it to larvae of sea urchins in aquaculture.[33]

See also

References

  1. Jump up^ RHS. “RHS on Japanese Knotweed”. RHS. Retrieved 6 June 2014.
  2. Jump up^ “itadori”. Denshi Jisho — Online Japanese dictionary. Retrieved 9 March 2010.
  3. Jump up^ Synergy International Limited <http://www.synergy.co.nz> (2004-01-30). “IUCN Global Invasive Species Database”. Issg.org. Retrieved 2014-06-30.
  4. Jump up^ “Article on the costs of Japanese Knotweed”. Gardenroots.co.uk. Retrieved 2014-06-30.
  5. Jump up^ Matthew Chatfield (2010-03-14). “”Tell me, sweet little lice” Naturenet article on psyllid control of knotweed”. Naturenet.net. Retrieved 2014-06-30.
  6. Jump up^ Morelle, R. Alien invaders hit the UK. BBC News October 13, 2008.
  7. Jump up^ “Asiatic knotweed”. Biosecurity New Zealand. 14 January 2010. Retrieved 29 December 2012.
  8. Jump up^ “Review of non-native species policy”. Defra. Retrieved 14 July 2013.
  9. Jump up^ Morelle, Rebecca (2010-03-09). “BBC News”. BBC News. Retrieved 2014-06-30.
  10. Jump up^ Richard H. Shaw, Sarah Bryner and Rob Tanner. “The life history and host range of the Japanese knotweed psyllid, Aphalara itadori Shinji: Potentially the first classical biological weed control agent for the European Union”. UK Biological Control. Volume 49, Issue 2, May 2009, Pages 105-113.
  11. Jump up^ “CABI Natural control of Japanese knotweed”. Cabi.org. Retrieved 2014-06-30.
  12. Jump up^ PUSDA
  13. Jump up^ National Invasive Species Information Center. “USDA weed profile for Japanese knotweed”. Invasivespeciesinfo.gov. Retrieved 2014-06-30.
  14. Jump up^ “Pilot project of Bionic Knotweed Control in Wiesbaden, Germany”. Newtritionink.de. Retrieved 2014-06-30.
  15. Jump up^ “Japanese Knotweed”. Edible Plants. Retrieved 2014-06-30.
  16. Jump up^ Wang, H.; Liu, L.; Guo, Y. -X.; Dong, Y. -S.; Zhang, D. -J.; Xiu, Z. -L. (2007). “Biotransformation of piceid in Polygonum cuspidatum to resveratrol by Aspergillus oryzae”. Applied Microbiology and Biotechnology 75 (4): 763–768. doi:10.1007/s00253-007-0874-3. PMID 17333175. edit
  17. Jump up^ Pest Diagnostic Unit, University of Guelph[dead link]
  18. Jump up^ Soil-Steaming-Report, 03. Okt. 2009
  19. Jump up^ “Notes on Biological control and Japanese knotweed”. Gardenroots.co.uk. Retrieved 2014-06-30.
  20. Jump up^ “Testing the psyllid: first field studies for biological control of knotweed United Kingdom”. CABI. Retrieved 2014-06-30.
  21. Jump up^ “On CABI Web site, Japanese Knotweed Alliance: Japanese knotweed is one of the most high profile and damaging invasive weeds in Europe and North America”. Cabi.org. Retrieved 2014-06-30.
  22. Jump up^ Leah Milner Last updated at 11:30AM, July 8, 2013 (2013-07-08). “Japanese knotweed uproots home sales”. The Times. Retrieved 2014-06-30.
  23. ^ Jump up to:a b 05 Jul 2013 (2013-07-05). “RICS targets the root of Japanese Knotweed risk to property”. Rics.org. Retrieved 2014-06-30.
  24. Jump up^ “Woolwich Lending Criteria – Property Types”.
  25. Jump up^ “Japanese knotweed, the scourge that could sink your house sale”. The Guardian. 2014-09-08.
  26. Jump up^ “Residential Lending Criteria”. Woolwich. July 2014.
  27. Jump up^ “Brokers demand action on Japanese knotweed”. Mortgagesolutions.co.uk. 2013-08-14. Retrieved 2014-06-30.
  28. Jump up^ 日本國語大辞典 (Nihon kokugo daijiten) dictionary (1976)
  29. Jump up^ Daigenkai (大言海) dictionary, citing Wakunsai(『和訓菜』)
  30. ^ Jump up to:a b c d e f g MAFF 2004 山菜関係資料(Sansai-related material) (webpage pdf). Excerpted from “山菜文化産業懇話会報告書”
  31. Jump up^ “イタドリ”. 讃岐の食(Sanuki eating). 2001. Retrieved Apr 2012.
  32. Jump up^ Given in Japanese wiki article ja:イタドリ, traced to contribution 2006.2.17 (Fri) 16:23 by ウミユスリカ
  33. Jump up^ “北海道食材ものがたり21 ウニ”. 道新TODAY. Sept-1999 1999. Retrieved Apr 2012.

External links

Advertisements

Watermelon Juice Prevents Aching Muscles


 

L-citrulline

The amino acid L-citrulline found in the fruit could help athletes avoid muscle soreness after a hard workout

Before taking a long bike ride on a hot summer day, have some watermelon: The juicy fruit may ward off muscle pains. Researchers report that people who drank watermelon juice before exercising felt less sore the next day than those who drank a pink placebo beverage (J. Agric. Food Chem. 2013, DOI: 10.1021/jf400964r). They also found that cells absorb the presumed active ingredient, L-citrulline, more readily from unpasteurized watermelon juice than from plain water spiked with the compound, suggesting the natural source is the optimal delivery medium.

http://cen.acs.org/articles/91/web/2013/07/Watermelon-Juice-Prevents-Aching-Muscles.html

Photo of watermelon juice smoothie in tall glass

The Next Sports Drink?
Watermelon drinks, like this smoothie, could help cut down on muscle soreness after intense exercise.
READ MORE AT

BioDelivery Sciences Announces FDA Acceptance of Bunavail NDA for Filing


 

buprenorphine

naloxone

RALEIGH, N.C., Oct. 9, 2013 /PRNewswire/ — BioDelivery Sciences International, Inc. announced today that its New Drug Application (NDA) for Bunavail (buprenorphine naloxone buccal film) for the maintenance treatment of opioid dependence has been accepted for filing by the U.S. Food and Drug Administration (FDA), indicating that the application is sufficiently complete to permit a substantive review. Based on timelines established by the Prescription Drug User Fee Act (PDUFA), the review of the Bunavail NDA is expected to be completed by early June 2014.

http://www.drugs.com/nda/bunavail_131014.html

VINCRISTINE……..Chemistry, Isolation


File:Vincristine2D.svg

VINCRISTINE

(3aR,3a1R,4R,5S,5aR,10bR)-methyl 4-acetoxy-3a-ethyl-9-((5S,7S,9S)-5-ethyl-5-hydroxy-9-(methoxycarbonyl)-2,4,5,6,7,8,9,10-octahydro-1H-3,7-methano[1]azacycloundecino[5,4-b]indol-9-yl)-6-formyl-5-hydroxy-8-methoxy-3a,3a1,4,5,5a,6,11,12-octahydro-1H-indolizino[8,1-cd]carbazole-5-carboxylate

…………………………………………………………..

………………………………………………………………….

Vincristine (brand name, Oncovin), formally known as leurocristine, sometimes abbreviated “VCR”, is a vinca alkaloid from the Catharanthus roseus (Madagascar periwinkle), formerly Vinca rosea and hence its name. It is amitotic inhibitor, and is used in cancer chemotherapy. Vincristine is created by the coupling of indole alkaloids vindoline and catharanthine in the vinca plant.[1]

Mechanism

Tubulin is a structural protein that polymerizes to microtubules. The cell cytoskeleton and mitotic spindle, among other things, are made of microtubules. Vincristine binds to tubulin dimers, inhibiting assembly of microtubule structures. Disruption of the microtubules arrests mitosis in metaphase. Therefore, the vinca alkaloids affect all rapidly dividing cell types including cancer cells, but also those of intestinal epithelium and bone marrow.

Uses

Vincristine is delivered via intravenous infusion for use in various types of chemotherapy regimens. Its main uses are in non-Hodgkin’s lymphoma as part of the chemotherapy regimen CHOPHodgkin’s lymphoma as part of MOPP, COPP, BEACOPP, or the less popular Stanford V chemotherapy regimen, in acute lymphoblastic leukemia, and in treatment for nephroblastoma (Wilms tumor, a kidney tumor most common in young children). It is also used to induce remission in ALL with Dexamethasone and L-Asparaginase. Vincristine is occasionally used as an immunosuppressant, for example, in treating thrombotic thrombocytopenic purpura (TTP) or chronic idiopathic thrombocytopenic purpura (ITP). It is used in combination with prednisone to treat childhood leukemia.

The main side-effects of vincristine are peripheral neuropathyhyponatremiaconstipation, and hair loss.

Peripheral neuropathy can be severe, and hence a reason to avoid, reduce, or stop the use of vincristine. One of the first symptoms of peripheral neuropathy is foot drop: A person with a family history of foot drop and/or Charcot-Marie-Tooth disease (CMT) should avoid the taking of vincristine.[2]

Accidental injection of vinca alkaloids into the spinal canal (intrathecal administration) is highly dangerous, with a mortality rate approaching 100 percent. The medical literature documents cases of ascending paralysis due to massive encephalopathy and spinal nerve demyelination, accompanied by intractable pain, almost uniformly leading to death; a handful of survivors were left with devastating neurological damage with no hope of recovery. Rescue treatments consist of washout of the cerebrospinal fluid and administration of protective medications.[3] A significant series of inadvertent intrathecal vincristine administration occurred in China in 2007 when batches of cytarabine andmethotrexate (both often used intrathecally) manufactured by the company Shanghai Hualian were found to be contaminated with vincristine.[4]

Having been used as a folk remedy for centuries, studies in the 1950s revealed that C. roseus contained 70 alkaloids, many of which are biologically active. While initial studies for its use in diabetes mellitus were disappointing, the discovery that it caused myelosuppression (decreased activity of the bone marrow) led to its study in mice withleukemia, whose lifespan was prolonged by the use of a vinca preparation. Treatment of the ground plant with Skelly-B defatting agent and an acid benzene extract led to a fraction termed “fraction A”. This fraction was further treated withaluminium oxidechromatographytrichloromethane, benz-dichloromethane, and separation by pH to yield vincristine.[5]

Vincristine was approved by the United States Food and Drug Administration (FDA) in July 1963 as Oncovin. The drug was initially discovered by a team led by Dr. J.G. Armstrong, then marketed by Eli Lilly and Company.

Like LSD, the microtubule toxin vincristine allegedly causes not-unpleasant visual hallucinations in humans. Other side-effects of vincristine include depression, agitation, and insomnia. Very small doses are needed for the effects of LSD or vincristine, for example, these drugs are active at concentrations of 4.3E-7 M-1 vincristine and 1.0E-8 M-1 LSD.

Many researchers have favored the drug-receptor theory to explain drug-induced hallucinations, usually at the 5-HT2A receptor. In the drug-receptor theory, signal amplification takes place when one molecule of drug binds to a receptor, which activates G-proteins, which affects more proteins, thus signaling cascades explain how a small amount of LSD can lead to widespread changes in the cell.

Van Woerkom suggests instead that LSD binds an element of the cytoskeleton, in a fashion similar to colchicine or vinblastine, which directly bind tubulin. The amount of LSD needed to produce hallucinations is so vanishly small, that it seems hard to believe that a submicromolar dosage of LSD could act on a substrate as vast as the cytoskeleton. However, some microtubule inhibitors such as vincristine are effective at very low dosages. The potency of vincristine may partly explain the success of this drug as a chemotherapeutic drug.

Three generic drug makers supply vincristine in the United States – APP, Mayne, and Sicor (Teva).

  1. ^ “Pharmacognosy of Vinca Alkaloids”.
  2.  Graf, W. D.; Chance, P. F.; Lensch, M. W.; Eng, L. J.; Lipe, H. P.; Bird, T. D. (1996). “Severe Vincristine Neuropathy in Charcot-Marie-Tooth Disease Type 1A”. Cancer 77 (7): 1356–1362. doi:10.1002/(SICI)1097-0142(19960401)77:7<1356::AID-CNCR20>3.0.CO;2-#PMID 8608515.
  3.  Qweider, M.; Gilsbach, J. M.; Rohde, V. (2007). “Inadvertent Intrathecal Vincristine Administration: A Neurosurgical Emergency. Case Report”. Journal of Neurosurgery: Spine 6 (3): 280–283. doi:10.3171/spi.2007.6.3.280PMID 17355029.
  4.  Jake Hooker and Walt Bogdanich (January 31, 2008). “Tainted Drugs Tied to Maker of Abortion Pill”New York Times.
  5.  Johnson, I. S.; Armstrong, J. G.; Gorman, M.; Burnett, J. P. (1963). “The Vinca Alkaloids: A New Class of Oncolytic Agents” (pdf). Cancer Research 23 (8 Part 1): 1390–1427.PMID 14070392.

External links

  • Cytostatic Vinca alkaloids rosea L. Catharanthus roseus G.Don) are now well known anticancer and particularly useful. Given the small amount of vincristine in Catharanthus present, quite a number of ways of preparation have been proposed by chemists. Thus FR-A-2296418 describes the synthesis of vincristine by coupling Catha-ranthine and vindoline. Other laboratories have achieved the transformation of vinblastine vincristine oxidation under controlled conditions, very strict.
  • FR-A-2210393 and US-A-3899493 perform the oxidation by chromic acid at -30, -90 ° C in a mixture of acetic acid-acetone or chloroform-acetic acid at -55 ° C.
  • In U.S. 4,375,432, chromic compound is also used in acid medium at -65 ° C, -50 ° C in a medium based solvent THF. In addition, EP-A-37289 boasts an oxidation mixture ferrous salt, hydrogen peroxide, perchlorate in acetonitrile. ZA-A-82 08939 discloses a method with chromic acid and an ether-chloroform.
  • HU-A-23638 offers diterbutylchromate in pelargonic acid, and finally EP-A-117861 gets vinblastinel transformation vincristine oxidant potassium permanganate in acetic acid medium. It is clear that these dimeric alkaloids are a valuable material because of their low levels in vegetable raw materials, and therefore the processes of synthesis or semi-synthesis performance are of extreme interest.
  • Vincristine is used in cancer chemotherapy, particularly for the treatment of certain acute leukemias.
  • This alkaloid is obtained mainly by extraction from leaves of Catharanthus Ro-seus (U.S. Patent No. 3,205,220) where it is accompanied by other alkaloids bis-Indo-holic, especially vinblastine.Vinblastine (I, R = CH 3), however, is present at a concentration much higher than that of vincristine and is therefore a precursor of choice for the semisynthesis of the latter.
  • Several processes of vincristine from vinblastine were disclosed. We note in particular patents or patent applications include:

    • a) Belgian Patent 739,337 (Gedeon Richter) which describes a method for the oxidation of vinblastine vincristine in a mixture chromic acid, acetic acid and acetone.
    • b) Belgian Patent 823560 (Gedeon Richter) the oxidation is performed with oxygen in the presence of formic acid and of a catalyst based on platinum at room temperature.
    • c) European Patent Application 18231 (Gedeon Richter): is carried out by oxidation with chromic acid or an alkali metal dichromate in the presence of acetic anhydride and, optionally, of ethanol and an organic solvent immis target with water.
    • d) European Patent Application 37289 (Eli Lil-ly): the oxidation is effected by the perchlorate of iron (II) in the presence of hydrogen peroxide and acetonitrile.
  • In addition, the European patent application 37. 290 discloses a process for the oxidation of vinblastine base with Na 2 Cr 2 O 7 in the presence of sulfuric acid in tetrahydrofuran. This reaction led to -50 ° C, is achieved with a yield of 80-92% calculated for each estimation.
  • Observed yields or purity of the products obtained characterizing the processes described above are, however, significant disadvantages.
  • Frequently a secondary product formed is N-demethyl vinblastine need then reformulate for vincristine.

Thus Potier and Kutney obtained products with the C18’S-C2’R absolute configuration, which is critical for anti-tumor activity, by a coupling reaction of the N.sup.b -oxide of catharanthine, or its derivatives, with vindoline, in the presence of trifluoroacetic anhydride, followed by a reduction reaction. [See Potier et. al. J. Am. Chem. Soc. 98. 7017 (1976) and Kutney et. al. Helv. Chim. Acta, 59, 2858 (1976)].

The Potier and Kutney coupling process has disadvantages. The yields are not satisfactory except for the coupling of catharanthine N-oxide with vindoline and even there the preparative yield is low. While vindoline is the most abundant alkaloid of Vinca rosea and is thus readily available, the other possible components of the Potier-Kutney coupling process (catharanthine, allocatharanthine, voacangine,) are relatively inaccessible, costly, and they do not allow a wide range of structural variation of that component of the coupling process.

  • …………………………………………………………………………………………………………………………………………………………………………………………………………..
  • EP 0117861 B1
  • clips
  • The process of the present invention produces a simple vincristine, in quantity and purity requiring little or no additional purification by recrystallization or chromatography.
  • [0009]
    The reagent used is oxidation permanganate ion dissolved in toluene or dichloromethane as solvent. An alternative consists in immobilizing the resin on a permanganate anion, for example a polymer such as polystyrene comprising ammonium groups. Solubilization can be achieved by the action of a complexing agent crown ether (“crown-ether”) of potassium permanganate.
  • [0010]
    The permanganate anion can also be solubilized by preparing an ammonium salt or quaternary phosphonium corresponding which is soluble in methylene chloride or toluene. For this purpose, it is preferable to use potassium permanganate benzyltriethylammonium.
  • [0011]
    Obtaining from vincristine vinblastine using a permanganate salt is unexpected since the potassium permanganate used in some acetone oxide derivatives of vinblastine at the portion of the molecule velbanamine (Kutney, Balsevich and Worth, Heterocycles, 11, 69, 1978). The N-methyl group of the vindoline part intact.
  • [0012]
    The formation of N-CHO indoline skeleton on a bis-indole group vinblastine using a permanganate salt has never been reported.
  • [0013]
    According to one embodiment of the method of the present invention, vinblastine, preferably in the form of sulphate, is treated in the presence of an organic acid such as acetic acid, with an excess of potassium permanganate dissolved in dichloromethane or toluene in the presence of “18-crown-6” or ether derivatives dibenzo-or di-cyclohexylcorrespondants. The reaction is conducted at a temperature between -40 ° C and -75 ° C and is preferably followed by thin layer chromatography. The reaction time generally ranges from 5 minutes to 3 hours.
  • [0014]
    Potassium permanganate is preferably dissolved in dichloromethane and the oxidation reaction is then carried out at -70 ° C.
  • [0015]
    The solubility of potassium permanganate is indeed substantially increased in the presence of a macrocyclic polyether as the “18-crown-6” ether (1, 4, 7, 10, 13, 16-hexaoxacy-clooctadécane) or derivative dibenzo – or corresponding dicyclohexyl-hexyl.
  • [0016]
    The reaction mixture is then treated simultaneously by a mild reducing and alkaline. For this purpose, use is preferably an aqueous solution of bisulfite, disulfite or sodium metabisulfite and ammonia.
  • [0017]
    The organic phase was separated and the aqueous phase is extracted several times with methylene chloride. The combined organic phases were concentrated in vacuo to give a residue containing 80-85% of base vincristine, a 90-95% yield.
  • [0018]
    Alternatively, you can proceed with the extraction of the reaction mixture after reduction without conducting a simultaneous alkalinization. The acidic aqueous solution was then extracted with dichloromethane. This route is a novel process for purification of vincristine formed in the reaction medium.
  • [0019]
    According to another embodiment of the present invention, vincristine is obtained by oxidation of vinblastine by reacting a quaternary ammonium permanganate. The ammonium cation is preferably benzyltriethylammonium group or benzyl trimethyl ammonium (see eg Angew. Chem., Intern. Ed. 13, 170, 1974). The reaction is carried out in 2 to 6 hours at -60 ° C in an inert solvent wherein the ammonium salt is soluble, and an acid, preferably an organic acid of low molecular weight. A mixture of dichloromethane and glacial acetic acid can be used. After treatment with a mild reducing agent in aqueous medium, the resulting acidic solution is extracted with dichloromethane, and the organic phase is made alkaline by washing with a basic aqueous solution and concentrated. Vincristine solvate is isolated with a yield higher than 90%.
  • [0020]
    The latest variant of the method of the invention is particularly advantageous in terms of economic and technical.
  • [0021]
    Purification or separation may be effected by crystallization and chromatography using techniques well known this from the crude product of the reaction. The product can also be lyophilized.
  • [0022]
    In most cases, vincristine thus obtained can be converted directly into an addition salt with an organic or inorganic acid, preferably pharmaceutically acceptable. This salt is preferably a sulfate that may arise in a more or less solvated or hydrated.
  • [0023]
    We can also prepare vincristine dissolved in a physiologically acceptable solvent and ready to be injected.
  • [0024]
    In particular, vincristine sulfate is obtained by addition of H 2 S0 4 to a solution of vincristine gross or recrystallized from ethanol, dissolved in a mixture of methylene chloride and anhydrous ethanol, partial removal in vacuo chloride methylene and crystallization.
  • [0025]
    Vincristine sulfate thus obtained has a purity sufficient for use as a medicament, particularly in the form of injectable solutions.

Madagascar Periwinkle: Public Domain Illustration by Sydenham Edwards

The Madagascar periwinkle, an attractive flowering plant, contains the powerful anti-cancer chemicals vinblastine and vincristine. Velvet beans, which are named from the covering of soft hairs on the young plant, contain L-dopa, a very helpful chemical in the treatment of Parkinson’s disease. The Madagascar periwinkle and the velvet bean are just two of the large number of plants that have been found to contain medicinal chemicals. There are almost certainly many more plants that have undiscovered health benefits.

The Madagascar Periwinkle

The Madagascar periwinkle is native to Madagascar and India, but is now grown in many countries as a garden plant. It has also escaped from gardens and grows as a weed. The red, purple, pink or white flowers often have a center which is a different color from the rest of the flower. Madagascar periwinkles may grow up to one meter tall and have glossy green leaves.

The sap of the Madagascar periwinkle, which has a milky appearance and is poisonous, contains vinblastine, vincristine and many other alkaloids. Researchers are discovering that many of these alkaloids are biologically active inside the human body.

Vinblastine and Vincristine

Vinblastine and vincristine have very similar chemical structures, but their effects on the body are not the same. Vinblastine is used to treat specific types of cancer, such as Hodgkin’s disease, breast cancer, testicular cancer and non-small cell lung cancer. Vincristine is used in the treatment of acute lymphoblastic leukemia (ALL) and has provided a great breakthrough in successful treatment of this disease in children. When vincristine is added to the treatment regimen for children suffering from ALL, the survival rate reaches eighty percent. Vincristine is not so impressive in the treatment of ALL in adults.

Cells contain a supporting network of protein tubules, which are known as microtubules. Microtubules also play a vital role in the process of cell division. Before a cell divides, each chromosome in the cell is replicated. The replicated chromosomes are separated from their partners and pulled to opposite ends of the cell by microtubules during a process called mitosis. The cell then divides down the middle.

Vinblastine and vincristine stop microtubule formation during mitosis and therefore prevent cells from reproducing. This effect is strongest in cells that have a high rate of division, such as cancer cells. However, vinblastine and vincristine also affect cells lining the intestine, the cells in the bone marrow that produce blood cells, and the cells in the hair follicles, since these too have a high rate of cell division.

Possible vinblastine or vincristine side effects include constipation, hair loss, a low platelet count, which can cause increased bleeding, a low white blood cell count, which can lead to increased infections, or a low red blood cell count, resulting in anemia. There may occasionally be nerve damage, possibly due to the effect of the medicines on the microctubules in the nerve cells. Vincristine is more likely to cause nerve damage than vinblastine.

,,,,,,,,,,,,,

Proceedings of the National Academy of Sciences of the United States of America

Total synthesis of (+)-vincristine (2). TFA, trifluoroacetic acid or trifluoroacetyl; DBU, 1,8-diazabicyclo[5.4.0]undec-7-ene.

Stereocontrolled total synthesis of (+)-vincristine

Proceedings of the National Academy of Sciences of the United States of America

………………….

see docstoc presentation

click below
Vincristine

var docstoc_docid=”51697405″;var docstoc_title=”Vincristine”;var docstoc_urltitle=”Vincristine”;

…………………….

isolation

Kumar A, Patil D, Rajamohanan PR, Ahmad A (2013)

Isolation, Purification and Characterization of Vinblastine and Vincristine from Endophytic Fungus Fusarium oxysporumIsolated from Catharanthus roseus. PLoS ONE 8(9): e71805. doi:10.1371/journal.pone.0071805

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0071805

Isolation, purification and characterization of vinblastine and vincristine from the endophytic fungus Fusarium oxysporum

A two stage fermentation procedure was employed for the isolation of vinblastine and vincristine by Fusarium oxysporum. In the first stage, 500 ml Erlenmeyer flasks containing 100 ml medium (MGYP, (0.3%) malt extract, (1.0%) glucose, (0.3%) yeast extract and (0.5%) peptone) were inoculated with 7 days old culture and incubated at 28°C on a rotary shaker (240 rpm) for 4–5 days, which was used as seed culture (I stage). Later, 10 ml seed culture was transferred to 500 ml Erlenmeyer flask containing 100 ml production medium called as vinca medium-1 (Glucose: 3%, Succinic acid: 1%, Sodium benzoate: 100 mg, Peptone: 1%, Magnesium sulphate: 3.6 mg, Biotin: 1 mg, Thiamine: 1 mg, Pyridoxal: 1 mg, Calcium pentothenate: 1 mg, Phosphate buffer: 1 ml (pH 6.8), L-Tryptophan: 0.1%, Geranium oil: 0.05%.) which were incubated at 28°C for 20 days as shake culture (II stage), after which it was harvested and used for further study. Culture filtrates and mycelia were separated with the help of muslin cloth and then lyophilized. Lyophilized culture filtrate was extracted using ethyl acetate as a solvent system. The organic layer was separated from the aqueous layer using separating funnel. The extraction was repeated thrice and the solvent was dried using anhydrous sodium sulphate and concentrated under vacuum using rotavapour at 40°C in order to get crude extract. A small amount of crude extract was dissolved in ethyl acetate and subjected to thin layer chromatography (TLC) on silica gel-G (0.5 mm thickness) using chloroform:methanol (8:2) as a solvent system. The TLC plates were sprayed with ceric ammonium sulphate reagent. Vinca alkaloids spots produced brilliant violet color as well as purple color with above spraying reagent. Purification of fungal vinblastine and vincristine were done by silica gel column chromatography. The crude extract was loaded on silica gel column (60–120 mesh size, 40 cm×2 cm length width) pre-equilibrated with chloroform and eluted with a gradient of chloroform:methanol (100% chloroform, 9:1, 8:2, 7:3, 1:1 and 3:7 and 100% methanol). Fractions containing compounds with Rf values similar to that of the standard vinblastine and vincristine were pooled and subjected to preparative TLC on a 0.5 mm thick (20 cm×20 cm) silica plate and developed in chloroform:methanol (8:2) solvent system. The putative bands of fungal vinblastine and vincristine were scraped and eluted out with methanol. Purity of the isolated compounds was checked on TLC in the solvent systems such as (a) chloroform:methanol (8:2) (b) chloroform:methanol (9:1) and (c) ethyl acetate: acetonitrile (8:2).

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0071805

see also

http://www.ncbi.nlm.nih.gov/pubmed/20209002

 

ALSO

large-scale isolation of native catharantine, vindoline and 3′,4′-anhydrovinblastine whereby the isolation of vincristine, vinblastine, leurosine and the corresponding desacetoxy, desacetyl and N-desmethyl derivatives in a manner known per se can also be accomplished.

For the isolation of the two monoindole alkaloids: vindoline and catharantine from the dried plant Vinca rosea L. Svoboda [J. Am. Pharm. Assoc. 48, (11), 659 (1959)] described a method, which can be accomplished only with a very modest yield. From 1 kg. of the dried plant–subjecting the whole plant to a suitable treatment–approximately 0.6 g. of vindoline and 0.05 g. of catharantine were obtained.

3′,4′-ANHYDROVINBLASTINE UNTIL NOW HAS NEITHER BEEN ISOLATED FROM THE PLANT Vinca rosea L. nor identified in it.

For the preparation of the diindole alkaloid components starting from the leaves of Vinca rosea L. there are more methods known in the art (U.S. Pat. nos. 3,097,137; 3,205,220; 3,225,030 and Hungarian Pat. Nos. 153,200; 154,715; 160,967 and 164,958 as well as Austrian Pat. Nos. 313,435, 313,485, Australian pat. No. 458,629 and Swiss Pat. No. 572,488 and British Pat Nos. 1,412,932, 1,382,460 corresponding to the preceding two patents). According to these known processes from 1 kg. of the dried leaves of Vinca rosea L. about 0.1 to 0.2 g. of leurosine can be obtained and vinblastine, vincristine and optionally the corresponding N-desmethyl, desacetyl and desacetoxy derivatives are also simultaneously isolated.

Further on it is well known that the synthetic catharantine and vindoline may be coupled by the Polonovszky reaction to give 3′,4′-anhydrovinblastine which can thereafter be epoxidized to leurosine [Potier et al. Tetrahedron Letters 3945 (1976); DT-OS 25 58,124; Helv. Chim. Acta 59, 2858 (1976); Heterocycles 4, 997 (1976), Belgian patent specification No. 842,200 equivalent to U.S. patent application Ser. No. 582,372]. Leurosine itself has a valuable tumour growth inhibiting activity and the N-desmethyl-N-formyl derivative thereof is the most promising substance against leukemia (Hungarian Pat. No. 165,986 equivalent to U.S. patent application Ser. No. 422,100, and Austrian Pat. No. 332,566 which has issued as British Pat. No. 1,412,932).

VITAMINS, COMMON INFORMATION


A vitamin (US /ˈvtəmɪn/ or UK /ˈvɪtəmɪn/) is an organic compound required by an organism as a vital nutrient in limited amounts. An organic chemical compound (or related set of compounds) is called a vitamin when it cannot be synthesized in sufficient quantities by an organism, and must be obtained from the diet. Thus, the term is conditional both on the circumstances and on the particular organism. For example, ascorbic acid (vitamin C) is a vitamin for humans, but not for most other animals, and biotin (vitamin H) and vitamin D are required in the human diet only in certain circumstances.

 

 

 

 

Thiamin

What it does:

  • helps convert the food we eat to the energy we need

Foods that have thiamin:

  • spinach, tomato juice, watermelon, sunflower seeds, ham

Deficiency problems:

  • weakness, tingling in feet and hands, poor coordination
Thiamin

Riboflavin – named for its yellow color (flavus means yellow in Latin)

What it does:

  • helps convert the food we eat to the energy we need

Foods that have riboflavin:

  • milk, cheese, liver, broccoli, asparagus, spinach

Deficiency problems:

  • eye disorders, cracks at corners of mouth, swollen tongue
riboflavin

Niacin

What it does:

  • helps our body use the fat and sugar we eat for energy
  • helps keep our skin healthy

Foods that have niacin:

  • mushrooms, tuna, green beans, broccoli, spinach, breakfast cereals

Deficiency problems:

  • diarrhea, skin problems, mental disorientation
niacin

Vitamin B6

What it does:

  • helps make red blood cells
  • helps our body use the fat and protein we eat for energy

Foods that have vitamin B6:

  • spinach, broccoli, tomato juice, banana, watermelon, chicken breast

Deficiency problems:

  • headache, convulsions, vomiting, flaky skin, sore tongue
b6

Folate

What it does:

  • helps to make new cells
  • helps prevent heart disease

Foods that have folate:

  • asparagus, broccoli, corn flakes, green beans, tomato juice, beans

Deficiency problems:

  • diarrhea, mental disorders, poor growth
folate

Vitamin B12

What it does:

  • helps to make new cells

Foods that have vitamin B12:

  • meat, fish, poultry, milk, cheese, eggs

Deficiency problems:

  • anemia, poor nerve function
b12

Vitamin C– almost all animals make vitamin C in their bodies (only humans, guinea pigs, some bats, and some fish don’t)vitamin c

What it does:

  • protects cells from damage
  • helps keep bones and skin healthy
  • may help prevent cancer and heart disease

Foods that have vitamin C:

  • oranges, strawberries, peppers, kiwi, brussel sprouts, broccoli, spinach

Deficiency problems:

  • bleeding gums, tiredness, weakness, sore muscle

 

 

 

 

 

 

 

 

Vitamin A – discovered in 1913

What it does:

  • helps with eyesight
  • keeps skin healthy
  • helps with growth of body organs (like bones)

Foods that have vitamin A:

  • liver, fish, milk, butter, eggs, carrots

Deficiency problems:

  • night blindness, poor growth, dry skin
vitamin a

Vitamin D – made in the skin by the sun

What it does:

  • helps bones grow strong

Foods that have vitamin D:

  • egg yolks, liver, butter, milk

Deficiency problems:

  • rickets (deformed bones), weak bones
vitamin d

Vitamin E – called the antiaging vitamin

What it does:

  • protects lungs against pollution damage
  • helps keep heart healthy
  • may help protect against cancer

Foods that have vitamin E:

  • sweet potatoes, peanut butter, sunflower seeds, spinach, nuts

Deficiency problems:

  • nerve destruction, red blood cell destruction
vitamin e

Vitamin K – made by bacteria in our intestines

What it does:

  • helps make blood clot
  • helps keep bones healthy

Foods that have vitamin K:

  • liver, cabbage, lettuce, spinach, milk, meat, eggs

Deficiency problems:

  • hemorrhage
vitamin k

……….

By convention, the term vitamin includes neither other essential nutrients, such as dietary mineralsessential fatty acids, or essential amino acids (which are needed in larger amounts than vitamins) nor the large number of other nutrients that promote health but are otherwise required less often. Thirteen vitamins are universally recognized at present.

Vitamins are classified by their biological and chemical activity, not their structure. Thus, each “vitamin” refers to a number of vitamer compounds that all show the biological activity associated with a particular vitamin. Such a set of chemicals is grouped under an alphabetized vitamin “generic descriptor” title, such as “vitamin A“, which includes the compounds retinalretinol, and four known carotenoids. Vitamers by definition are convertible to the active form of the vitamin in the body, and are sometimes inter-convertible to one another, as well.

itamins have diverse biochemical functions. Some, such as vitamin D, have hormone-like functions as regulators of mineral metabolism, or regulators of cell and tissue growth and differentiation (such as some forms of vitamin A). Others function as antioxidants (e.g., vitamin E and sometimesvitamin C). The largest number of vitamins, the B complex vitamins, function as precursors for enzyme cofactors, that help enzymes in their work as catalysts in metabolism. In this role, vitamins may be tightly bound to enzymes as part of prosthetic groups: For example, biotin is part of enzymes involved in making fatty acids. They may also be less tightly bound to enzyme catalysts as coenzymes, detachable molecules that function to carry chemical groups or electrons between molecules. For example, folic acid may carry methylformyl, and methylene groups in the cell. Although these roles in assisting enzyme-substrate reactions are vitamins’ best-known function, the other vitamin functions are equally important.

 

Until the mid-1930s, when the first commercial yeast-extract vitamin B complex and semi-synthetic vitamin C supplement tablets were sold, vitamins were obtained solely through food intake, and changes in diet (which, for example, could occur during a particular growing season) usually greatly altered the types and amounts of vitamins ingested. However, vitamins have been produced as commodity chemicals and made widely available as inexpensive semisynthetic and synthetic-source multivitamin dietary and food supplements and additives, since the middle of the 20th century.,,,,,,,

 

List of vitamins

Each vitamin is typically used in multiple reactions, and, therefore, most have multiple functions.

Vitamin generic

descriptor name

Vitamerchemical name(s) (list not complete) Solubility Recommended dietary allowances

(male, age 19–70)[6]

Deficiency disease Upper Intake Level

(UL/day)[6]

Overdose disease Food sources
Vitamin A Retinolretinal, and

four carotenoids

including beta carotene

Fat 900 µg Night-blindness,Hyperkeratosis, andKeratomalacia[7] 3,000 µg Hypervitaminosis A Orange, ripe yellow fruits, leafy vegetables, carrots, pumpkin, squash, spinach, liver, soy milk, milk
Vitamin B1 Thiamine Water 1.2 mg BeriberiWernicke-Korsakoff syndrome N/D[8] Drowsiness or muscle relaxation with large doses.[9] Pork, oatmeal, brown rice, vegetables, potatoes, liver, eggs
Vitamin B2 Riboflavin Water 1.3 mg Ariboflavinosis N/D Dairy products, bananas, popcorn, green beans, asparagus
Vitamin B3 Niacinniacinamide Water 16.0 mg Pellagra 35.0 mg Liver damage (doses > 2g/day)[10] and other problems Meat, fish, eggs, many vegetables, mushrooms, tree nuts
Vitamin B5 Pantothenic acid Water 5.0 mg[11] Paresthesia N/D Diarrhea; possibly nausea and heartburn.[12] Meat, broccoli, avocados
Vitamin B6 Pyridoxine,pyridoxamine,pyridoxal Water 1.3–1.7 mg Anemia[13] peripheral neuropathy. 100 mg Impairment ofproprioception, nerve damage (doses > 100 mg/day) Meat, vegetables, tree nuts, bananas
Vitamin B7 Biotin Water 30.0 µg Dermatitisenteritis N/D Raw egg yolk, liver, peanuts, certain vegetables
Vitamin B9 Folic acidfolinic acid Water 400 µg Megaloblastic anemiaand Deficiency during pregnancy is associated with birth defects, such as neural tube defects 1,000 µg May mask symptoms of vitamin B12 deficiency;other effects. Leafy vegetables, pasta, bread, cereal, liver
Vitamin B12 Cyanocobalamin,hydroxycobalamin,methylcobalamin Water 2.4 µg Megaloblastic anemia[14] N/D Acne-like rash [causality is not conclusively established]. Meat and other animal products
Vitamin C Ascorbic acid Water 90.0 mg Scurvy 2,000 mg Vitamin C megadosage Many fruits and vegetables, liver
Vitamin D Cholecalciferol Fat 10 µg[15] Rickets andOsteomalacia 50 µg Hypervitaminosis D Fish, eggs, liver, mushrooms
Vitamin E Tocopherols,tocotrienols Fat 15.0 mg Deficiency is very rare; mild hemolytic anemiain newborn infants.[16] 1,000 mg Increased congestive heart failure seen in one large randomized study.[17] Many fruits and vegetables, nuts and seeds
Vitamin K phylloquinone,menaquinones Fat 120 µg Bleeding diathesis N/D Increases coagulation in patients taking warfarin.[18] Leafy green vegetables such as spinach, egg yolks, liver

 

GLENMARK- ELOVERA , for dry skin disorders


Compositions:
Elovera extract 10% cream, Vitamin E 0.5%

Category–Locally Acting Skin Preparations

Description

* Aqueeze adequate amount of elovera moisturizing body wash onto wet hands or wet loran and work into a creamy lather. apply it all ovr the body, keep for some time and then rinse with water.

http://www.drugneed.com/glenmark-pharmaceuticals-elovera-moisturizing-body-wash-150ml-glenmak-p-2017.html#tab4

Products Name : Elovera Moisturizing Body Wash 150ml – (Glenmark)

 

Elovera Cream, manufacture by Glenmark pharmaceuticals limited , is cream enriched with vitamin E and Aloe Vera. It’s a very special cream specially for treating scars and other minor pimple spots on the face.

reviews from net

My skin is very much oily hence I get these ugly Pimples very profoundly. On top of it i have the habit of bursting out the puss from these pimples. I always play it with my hands and as a result forms some very ugly scars on my face which are visible from distant away.Though I am bit dark with my completion ,even then It’s clearly visible and my mother scolds me like hell for bursting the pimples out.Honestly I just can’t stop my hands reaching out for them no matter how busy I am so Finally has to resort to some ointments to reduce the visibility of the scars.

I did try few popular products but were of no use basically. The spots didn’t get reduced but instead effected the completion of my face.Finally my mother came to my rescue. She had hear about this Elovera Cream from some one and bought home one for me.Initially i was a bit skeptic but finally I thought of trying it. For the first few days it had no effect what-so-ever , but slowly it started clearing the skin blemishes. My skin started showing it’s effects and the scars became less visible. Not only does it clear the scars but it helped me to fight the ugly pimples as well.

My face became much more glowing and healthy and i use the cream regularly even now.It’s really a magical product and should try it for clearing the blemishes and other skin problem.

SAMIDIRECT -Healthy, Wealthy & Wise, FREE OF COST CONSULTATION on Diabetes, Cancer, Arthritis, Osteoporosis, Heart- Liver -Lung & Kidney problems, Low Immunity, Alzheimer, Weight Management, Weak Memory, Neutritional Deficiency, UTI problems


Logo

Healthy, Wealthy & Wise

For over 25 years the Sami Group has been unlocking the mystery of herbs, extracting the goodness, and gifting the world with good health.

Now the Sami Group provides YOU an opportunity to unlock the mystery of Success, Wealth & Better living.

FREE OF COST CONSULTATION on Diabetes, Cancer, Arthritis, Osteoporosis, Heart- Liver -Lung & Kidney problems, Low Immunity, Alzheimer, Weight Management, Weak Memory, Neutritional Deficiency, UTI problems etc.

(REVOLUTIONARY AYURVEDIC SOLUTIONS with ISO 22000 Certified Indian MNC after 25 years of R & D by 120 Scientists.
Numberless Testimonials.)

http://www.samidirect.com/products/

Do visit the website www.samidirect.com & have the study in detail. Have a look at the Sami Direct Corporate Video on you tube. If you get the wonderful potential of the brightest future…do call me for ‘How to get started?’

Coq Energizer Banner

Bioprotectant Banner

osteostrong Banner

Currcumin C3 Power Banner

…..

IgG Plus Banner

leangard proteindrink mix Banner

Moisturising Cream Banner

Livstrong Banner

Organic Spirulina Banner

GlycaCare Banner

Omega Bioplus Banner

Cranex Plus

DISTRIBUTOR ENQUIRY WELCOME

CONTACT MR  JAY DESAI

REGARDS
+91 9699952526
Mumbai, INDIA

email-jaydesai1502@gmail.com

Bussines Sami Direct Seminar ppt.ppt1.pdf Bussines Sami Direct Seminar ppt.ppt1.pdf
9204K   View   Download

samidirect corporate video

Samidirect

DR MAJID, FOUNDER , SAMIDIRECT

Dr. Muhammed Majeed

Dear Friend, Congratulations on your decision!

A little over three decades ago I went from a small town in South India to the United States Of America seeking fulfillment of my dreams. Today with a business conglomerate spread across the globe, I can confidently say that the future belongs to those who believe in the beauty of their dreams.

The aspiration to dream and the conviction to follow their dreams is what sets apart the extraordinary from the ordinary. Congratulations for choosing to be among the extraordinary. Now we are in it together. You have chosen the right place and the right means. The awesome combination of extensively researched products and a revolutionary business plan is a definite formula for success. We are with you at every step to help you fulfill your dreams and reach greater heights.

Dr. Muhammed Majeed

Welcome home again!

– See more at: http://www.samidirect.com/about/founder-desk/#sthash.rrOCRiJ1.dpuf

Sami Direct, as a part of the Sami Group, is the culmination of relentless Research and Development for more than two decades. We at Sami Direct are committed to offer you an unrivalled range of nutraceuticals, soon to be followed by cosmeceutical products, which have been acknowledged by the world over for its highest quality and safety standards.

Sami Direct is supported by its very own R&D facility- SAMI LABS LTD., located in Bangalore. This state-of-the-art, multi-disciplinary division pursues diverse fields of research with over 120 scientists focusing all efforts towards creating effective and safe products. With six highly advanced cutting-edge manufacturing units adhering to the strictest quality and safety standards, Sami Direct ensures that the highest quality of products are being produced.

Today the Sami Group holds a strong intellectual property portfolio with over 70 US and International Patents to its credit including awards and recognitions worldwide.

With the perfect blend of world class products and a revolutionary business plan, it is a lifetime opportunity not just to enhance your health, but also a fruitful and lasting career heightening your income.

DISTRIBUTOR ENQUIRY WELCOME

CONTACT MR  JAY DESAI

REGARDS
+91 9699952526
Mumbai, INDIA

email; jaydesai1502@gmail.com

FDA Accepts Nuvo’s New Drug Application for Review


Nuvo Research Inc. announced that its U.S. licensee for PENNSAID@ (diclofenac sodium topical solution) 1.5% w/w and PENNSAID 2% (diclofenac sodium topical solution) 2% w/w,

Mallinckrodt has advised that the U.S.  Food and Drug Administration has accepted for filing and review the New Drug Application (NDA) for PENNSAID 2% submitted by Mallinckrodt on August 7, 2013.

http://www.pharmpro.com/news/2013/08/fda-accepts-nuvos-new-drug-application-review?et_cid=3437744&et_rid=519587661&type=headline

Novartis Muscle Drug Bimagrumab Gets Breakthrough Status


immunoglobulin G1-lambda2, anti-[Homo sapiens ACVR2B (activin
A receptor type IIB, ActR-IIB)], Homo sapiens monoclonal antibody;
gamma1 heavy chain (1-445) [Homo sapiens VH (IGHV1-2*02
(91.80%) -(IGHD)-IGHJ5*01 [8.8.8] (1-115) -IGHG1*03 (CH1 (116-
213), hinge (214-228), CH2 L1.3>A (232), L1.2>A (233) (229-338),
CH3 (339-443), CHS (444-445)) (116-445)], (218-216′)-disulfide with
lambda light chain (1′-217′) [Homo sapiens V-LAMBDA (IGLV2-
23*02 (90.90%) -IGLJ2*01) [9.3.11] (1′-111′) -IGLC2*01 (112′-217′)];
dimer (224-224”:227-227”)-bisdisulfide
myostatin inhibitor
bimagrumab immunoglobuline G1-lambda2, anti-[Homo sapiens ACVR2B
(récepteur type IIB de l’activine A, ActR-IIB)], Homo sapiens
anticorps monoclonal;
chaîne lourde gamma1 (1-445) [Homo sapiens VH (IGHV1-2*02
(91.80%) -(IGHD)-IGHJ5*01 [8.8.8] (1-115) -IGHG1*03 (CH1 (116-
213), charnière (214-228), CH2 L1.3>A (232), L1.2>A (233) (229-
338), CH3 (339-443), CHS (444-445)) (116-445)], (218-216′)-
disulfure avec la chaîne légère lambda (1′-217′) [Homo sapiens
V-LAMBDA (IGLV2-23*02 (90.90%) -IGLJ2*01) [9.3.11] (1′-111′) –
IGLC2*01 (112′-217′)]; dimère (224-224”:227-227”)-bisdisulfure
inhibiteur de la myostatine

inmunoglobulina G1-lambda2, anti-[Homo sapiens ACVR2B
(receptor tipo IIB de la activina A, ActR-IIB)], anticuerpo monoclonal
de Homo sapiens;
cadena pesada gamma1 (1-445) [Homo sapiens VH (IGHV1-2*02
(91.80%) -(IGHD)-IGHJ5*01 [8.8.8] (1-115) -IGHG1*03 (CH1 (116-
213), bisagra (214-228), CH2 L1.3>A (232), L1.2>A (233) (229-338),
CH3 (339-443), CHS (444-445)) (116-445)], (218-216′)-disulfuro con
la cadena ligera lambda (1′-217′) [Homo sapiens V-LAMBDA
(IGLV2-23*02 (90.90%) -IGLJ2*01) [9.3.11] (1′-111′) -IGLC2*01
(112′-217′)]; dímero (224-224”:227-227”)-bisdisulfuro
inhibidor de la miostatina
1356922-05-8

Heavy chain / Chaîne lourde / Cadena pesada
QVQLVQSGAE VKKPGASVKV SCKASGYTFT SSYINWVRQA PGQGLEWMGT 50
INPVSGSTSY AQKFQGRVTM TRDTSISTAY MELSRLRSDD TAVYYCARGG 100
WFDYWGQGTL VTVSSASTKG PSVFPLAPSS KSTSGGTAAL GCLVKDYFPE 150
PVTVSWNSGA LTSGVHTFPA VLQSSGLYSL SSVVTVPSSS LGTQTYICNV 200
NHKPSNTKVD KRVEPKSCDK THTCPPCPAP EAAGGPSVFL FPPKPKDTLM 250
ISRTPEVTCV VVDVSHEDPE VKFNWYVDGV EVHNAKTKPR EEQYNSTYRV 300
VSVLTVLHQD WLNGKEYKCK VSNKALPAPI EKTISKAKGQ PREPQVYTLP 350
PSREEMTKNQ VSLTCLVKGF YPSDIAVEWE SNGQPENNYK TTPPVLDSDG 400
SFFLYSKLTV DKSRWQQGNV FSCSVMHEAL HNHYTQKSLS LSPGK 445
Light chain / Chaîne légère / Cadena ligera
QSALTQPASV SGSPGQSITI SCTGTSSDVG SYNYVNWYQQ HPGKAPKLMI 50
YGVSKRPSGV SNRFSGSKSG NTASLTISGL QAEDEADYYC GTFAGGSYYG 100
VFGGGTKLTV LGQPKAAPSV TLFPPSSEEL QANKATLVCL ISDFYPGAVT 150
VAWKADSSPV KAGVETTTPS KQSNNKYAAS SYLSLTPEQW KSHRSYSCQV 200
THEGSTVEKT VAPTECS 217
Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro
Intra-H 22-96 142-198 259-319 365-423
22”-96” 142”-198” 259”-319” 365”-423”
Intra-L 22′-90′ 139′-198′
22”’-90”’ 139”’-198”’
Inter-H-L 218-216′ 218”-216”’
Inter-H-H 224-224” 227-227”
N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilación
H CH2 N84.4

Bimagrumab

http://www.who.int/medicines/publications/druginformation/innlists/PL108_Final.pdf

Novartis announced that the US Food and Drug Administration (FDA) has granted breakthrough therapy designation to BYM338 for sporadic inclusion body myositis (sIBM). This designation is based on the results of a phase 2 proof-of-concept study that showed BYM338 substantially benefited patients with sIBM compared to placebo.

read all at

http://www.dddmag.com/news/2013/08/novartis-muscle-drug-gets-breakthrough-status?et_cid=3433957&et_rid=523035093&type=headline

Novartis receives FDA breakthrough therapy designation for BYM338 (bimagrumab) for sporadic inclusion body myositis (sIBM)

•    Designation highlights potential of BYM338 to address an unmet medical need in a serious disease
•    If approved, BYM338 has the potential to be the first treatment for sIBM patients
•    BYM338 is the third Novartis investigational treatment this year to receive a breakthrough therapy designation by the FDA, highlighting Novartis’ leadership in the industry in breakthrough therapy designations

Bimagrumab (BYM338) is a human monoclonal antibody developed by Novartis to treat pathological muscle loss and weakness. On August 20, 2013 it was announced that bimagrumab was granted breakthrough therapy designation for sporadic inclusion body myositis(sIBM) by US Food and Drug Administration.[1]


..

..

..

Type 2 diabetic patients treated with DPP-4, Linagliptin experience reductions in blood glucose levels


linagliptin

C25H28N8O2

CAS : 668270-12-0

Molecular Weight: 472.54

Purity: > 98%

(R)-8-(3-aminopiperidin-1-yl)-7-(but-2-ynyl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-1H-purine-2,6(3H,7H)-dione

8-(3R)-3-aminopiperidinyl)-7-butyn-2-yl-3-methyl-1-(4-methylquinazolin-2-ylmethyl)-3,7-dihydropurine-2,6-dione

Solubility: Up to 25 mM in DMSO

Synonyms: BI-1356, BI1356, Linagliptin, Tradjenta, Trajenta

BI-1356 (Linagliptin) is a highly potent and selective dipeptidyl peptidase 4 (DPP-4) inhibitor (IC50 = 1 nM) for treatment of type II diabetes. [1] BI-1356 can increase incretin levels (GLP-1 and GIP), which increases insulin secretion and inhibits glucagon release, decreases gastric emptying, and decreases blood glucose levels. BI-1356 shows 10,000-fold more selectivity for DPP-4 against other protease/peptidases, including DPP-8, DPP-9, trypsin, plasmin, and thrombin, It is a DPP-4 inhibitor developed by Boehringer Ingelheim for the treatment of type II diabetes.

Linagliptin is a highly potent, selective DPP-4 inhibitor with IC50 of 1 nM.

“This study provides much-needed data on glucose-lowering treatment of elderly people with Type 2 Diabetes, inadequately controlled with common anti-hyperglycaemic agents”

Data published in The Lancet showed that elderly people with Type 2 Diabetes (T2D) treated for 24 weeks with the dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin, marketed by Boehringer Ingelheim and Eli Lilly and Company, experienced significant reductions in blood glucose levels (HbA1c) compared with those receiving placebo. In addition, the overall safety and tolerability profile of linagliptin was similar to placebo, with no significant difference in hypoglycaemia

http://www.news-medical.net/news/20130817/Study-Type-2-diabetic-patients-treated-with-DPP-4-linagliptin-experience-reductions-in-blood-glucose-levels.aspx

 

INTRODUCTION

Linagliptin (BI-1356, trade names Tradjenta and Trajenta) is a DPP-4 inhibitor developed by Boehringer Ingelheim for treatment of type II diabetes.

Linagliptin (once-daily) was approved by the US FDA on 2 May 2011 for treatment of type II diabetes.[1] It is being marketed by Boehringer Ingelheim and Lilly.

  • Linagliptin, namely 8-(3R)-3-aminopiperidinyl)-7-butyn-2-yl-3-methyl-1-(4-methylquinazolin-2-ylmethyl)-3,7-dihydropurine-2,6-dione, of formula (A), is a long acting inhibitor of dipeptidylpeptidase-IV (DPP-IV) activity, at present under development for the treatment of type II diabetes mellitus.

    Figure imgb0001
  • The synthesis of Linagliptin is reported in US 7,407,955 , according to the scheme below, where 8-bromo xanthine of formula (B) is condensed with 3-(R)-Boc-aminopiperidine of formula (C) to obtain a compound of formula (D), which is converted to Linagliptin (A) by deprotection of the amine function

    Figure imgb0002
  • Optically active 3-aminopiperidine protected as the tert-butylcarbamate (Boc), compound (C), although commercially available, is very expensive and difficult to prepare; moreover in this process impurities are very difficult to remove, particularly on an industrial scale, in particular because of the Boc protective group. For this reason,US 2009/0192314 discloses a novel process for the preparation of Linagliptin (A) which makes use of a 3-(R)-aminopiperidine protected as a phthalimide of formula (E).

    Figure imgb0003
  • Accordingly, a compound of formula (E) can be prepared starting from 3-aminopyridine by hydrogenation, reaction with phthalic anhydride, resolution through diastereoisomeric salts using expensive D-tartaric acid, and then cleavage of the tartrate salt.
  • This intermediate is, however, still expensive and its use in the substitution reaction of the bromine derivative of formula (B) is still poorly efficient, as it takes place under drastic reaction conditions.
  • As it can be noted, these processes make use of drastic reaction conditions, or expensive, difficult to prepare starting materials, thus negatively affecting costs. There is therefore the need for an alternative synthetic route to provide Linagliptin or a salt thereof with high enantiomeric and chemical purity, from low cost starting materials.

US ‘955 is schematically represented in scheme

Figure imgf000002_0002

U.S. Patent No. 7,820,815 (“US ‘815) discloses a process for preparation of Linagliptin wherein it is prepared by deprotecting 1 -[(4-methyl-quinazolin-2-yl)methyl]-3- methyl-7-(2-butyn-1 -yl)-8-(3-(R)-phthalimidopiperidin-1 -yl)-xanthine of formula Ilia in presence of ethanolamine. The 1 -[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2- butyn-1 -yl)-8-(3-(R)phthalimidopiperidin-1 -yl)-xanthine is prepared by condensing 1 -[(4- l methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-bromo xanthine of formula III with (R)-3-phthalimidopiperidine of formula I la. The process disclosed in US ‘815 is schematically represented in scheme-ll.

Figure imgf000003_0001

Scherre

PCT Publications WO 2004/018468 and WO 2006/048427 describe synthesis of Linagliptin. Crystalline forms of Linagliptin, Forms A, B, C, D, and E are described in the PCT Publication No. WO 2007/128721. According to WO 2007/128721, Linagliptin prepared according to Publication No.

WO 2004/018468 is present in ambient temperature as a mixture of two enantiotropic polymorphs. The temperature at which the two polymorphs transform into one another is 25±15° C. The pure high temperature form (polymorph A), can be obtained by heating the mixture to temperatures>40° C. The low temperature form (polymorph B) is obtained by cooling to temperatures<10° C.”.

According to WO 2007/128721, the transition point between forms A and B is at room temperature, such that they exist as a polymorphic mixture. In addition, WO 2007/128721 teaches that form D “is obtained if polymorph C is heated to a temperature of 30-100° C. or dried at this temperature”. Since the procedure to obtain form C according to this application includes drying at 70° C., the dried form C is expected to be obtained in admixture with form D.

WO 2007/128721 teaches that Form E is obtained only at high temperatures (after melting of form D at 150±3° C.), and therefore is not relevant industrially.

 PATENT

Figure imgb0010
Figure imgb0008Figure imgb0009
Figure imgb0007
Figure imgb0006
Figure imgb0005
Figure imgb0004

Example 1: Preparation of a compound of formula (II) with X=OEt

    • The bromoxanthine of formula (B) prepared according to US 7,407, 955 (28.2 g, NMR title 90%, 56.0 mmols) and L-(+)-tartrate salt of (R)-ethylnipecotate (22.4 g, 72.8 mmols) are suspended in 50 mL of 1-methyl-2-pyrrolidone. The suspension is heated at 100° under stirring and, maintaining such temperature, diisopropylethylamine (38.3 ml, 224 mmols) is slowly dropwise added. The suspension is moderately refluxed for 2 hours. The mixture is cooled to 30°C and 400 mL of are dropwise added under vigorous stirring. The suspension is stirred for 30 minutes, then filtered off and the solid is washed with 100 mL of water. 27 g of solid product are obtained after drying with a 90% yield.
    • 1H-NMR (300 MHz, CDCl3), δ 8.02 (d, 1H), 7.87 (d, 1H), 7.76 (t, 1H), 7.51 (t, 1H), 5.55 (s, 2H), 4.90 (s, 2H), 4.25 – 4.10 (m, 2H), 3.82 (dd, 1H), 3.65 – 3.51 (m, 4H), 3.33 (dd, 1H), 3.15 (m, 1H), 2.88 – 2.72 (m, 4H), 2.08 (m, 1H), 1.92 – 1.73 (m, 6H), 1.27 (t, 3H).

Example 2: Preparation of a compound of formula (II) with X=OH

    • The compound of formula (II) having X = OEt, prepared according to Example 1 (27 g, 51 mmols), is suspended in 270 mL of MeOH and 4.1 g of NaOH scales and 13.7 mL of water are added under stirring. The reaction mixture is maintained under stirring for 2 hours at reflux temperature and then cooled to 40°C and diluted with 400 ml of water.
    • [0080]
      The mixture is then acidified by adding 6.6 mL of acetic acid and the solid is filtered off and washed with water and dried under vacuum at 50°C, obtaining 21 g of product, with a yield of 82%.
    • 1H-NMR (300 MHz, DMSO-d6), δ 8.11 (d, 1H), 7.85 (t, 1H), 7.80 (d, 1H), 7.62 (t, 1H), 5.30 (s, 2H), 4.87 (s, 2H), 3.79 (dd, 1H), 3.57 (m, 1H), 3.38 (s, 3H), 3.33 (dd, 1H), 3.10 (m, 1H), 2.85 (s, 3H), 2.62 (m, 1H), 1.95 (m, 1H), 1.78 – 1.60 (m, 6H).

Example 3: Preparation of a compound of formula (IV) with R = OCH(CH3)2

    • The compound of formula (II) with X=OH prepared according to Example 2 (0.5 g; 1 mmol), 5 ml of isopropanol and trietylamine (0.17 ml, 1.2 mmols) are mixed under stirring. 0.3 g of diphenylphosphorylazide (DPPA) are added in a sole portion. The mixture is heated at reflux temperature for 2 hours under stirring. The mixture is then cooled to room temperature and the solid is filtered off and washed with 2 ml of isopropyl alcohol. The solid is dried under vacuum at 50°C obtaining 0.4 g of product with a yield of 72%.
    • 1H-NMR (300 MHz, DMSO-d6), δ 8.12 (d, 1H), 7.85 (t, 1H), 7.80 (d, 1H), 7.63 (t, 1H), 5.28 (s, 2H), 4.85 (s, 2H), 4.75 (ep, 1H), 4.27 (d, 1H), 3.78-3.55 (m, 4H), 3.35 (s, 3H), 2.85 (s, 3H), 1.85 – 1.60 (m, 6H). 1.42 (m, 1H), 1.02 (d, 6H).

Example 4: Preparation of Linagliptin

    • The carbamate of formula (IV), prepared according to Example 3 (400 mg, 0.72 mmols), is dissolved in 5 ml of 32% HCl in water. The reaction mixture is maintained under stirring at 65-70°C for 7 hours and then cooled to room temperature. The pH of the solution is brought to about 8-9 by treatment with 30% NaOH in water and the obtained suspension is stirred for 10 minutes and then filtered off. The solid is dissolved in 10 ml of AcOEt, the solution is filtered and the filtrate is evaporated under reduced pressure. 250 mg of Linagliptin are obtained with a yield of 73%.

Example 5: Preparation of a compound of formula (IV) with R = S(CH2)11CH3

    • The compound of formula (II) with X =OH, prepared according to Example 2 (3.0 g, 6 mmols), 30 ml of acetonitrile and triethylamine (1.09 ml, 7.8 mmols) are mixed together. Subsequently, 1.55 ml (7.2 mmols) of diphenylphosphorylazide (DPPA) are added. The reaction mixture is heated at reflux temperature for 1 hour under stirring and then cooled to 60°C and treated with dodecanethiol (1.87 ml, 7.8 mmols). The mixture is maintained under stirring at the same temperature for 30 minutes and then cooled to 25°C. The formed solid is filtered off and washed with 10 ml of acetonitrile. The solid is dried under vacuum at 60°C obtaining 3.5 g of product with a yield of 85%.
    • 1H-NMR (300 MHz, DMSO-d6), δ 8.21 (d, 1H), 7.88 (t, 1H), 7.83 (d, 1H), 7.64 (t, 1H), 5.30 (s, 2H), 4.86 (s, 2H), 3.85 (m, 1H), 3.70 (d, 1H), 3.56 (d, 1H), 3.38 (s, 3H), 3.10-2.87 (m, 3H), 2.85 (s, 3H), 2.74 (t, 2H), 1.90-1.60 (m, 3H), 1.74 (s, 3H), 1.60-1.40 (m, 2H), 1.38-1.10 (m, 18H), 0.82 (t, 3H).

Example 6: Preparation of Linagliptin

    • The thiocarbamate of formula (IV) (10 g, 14,3 mmols), prepared according to Example 5, is dissolved in 100 mL of N-methylpyrrolidone (NMP) and treated with a 30% NaOH solution (7.6 g, 57.0 mmols). The reaction mixture is stirred for 3 hours and then diluted with water and acidified by adding concentrated H2SO4. The mixture is extracted with hexane and brought to pH 9.5 by adding 30% NaOH and repeatedly extracted with dichloromethane. The dichloromethane phases are collected and washed with water and then dried over Na2SO4, filtered and concentrated under reduced pressure. The so obtained oily residue is then dissolved in methyl tert-butyl ether (MTBE) and the mixture is maintained under stirring for 2 hours, then cooled to 0-5°C and the so obtained solid is filtered off, washed with MTBE and dried under vacuum at 50°C till constant weight. 4.2 g of Linagliptin with a yield of 63% are obtained.

Example 7: Preparation of a compound of formula (IV) with R=C7H5N2S (2-mercaptobenzoimidazole)

    • The compound of formula (II) with X =OH, prepared according to Example 2 (2.0 g, 4 mmols), 20 ml of acetonitrile and triethylamine (0.8 ml, 5.6 mmols) are mixed together. Subsequently, 1.43 g (5.2 mmols) of diphenylphosphorylazide (DPPA) are added. The reaction mixture is heated at reflux temperature for 1 hour under stirring and then cooled to 60°C and treated with 2-marcaptobenzimidazole (0.8 g, 5.2 mmols). The mixture is maintained under stirring at the same temperature for 30 minutes, then cooled to 25°C and evaporated under reduced pressure with Rotavapor®. The residue is treated with 50 ml of dichloromethane (CH2Cl2) and washed with 2X20 ml of 5% NaOH. The organic phase is dried over Na2SO4, filtered and concentrated under reduced pressure and the residue is triturated with 30 ml of MTBE. The so obtained solid is filtered off, dried under vacuum at 60°C till constant weight obtaining 2.5 g of light brown powder.

Example 8: Preparation of Linagliptin

  • Starting from the compound of formula (IV) as obtained in example 7 and following the procedure of example 6, product Linagliptin is obtained.

 

PAPER

Org. Biomol. Chem., 2015,13, 7624-7627
DOI: 10.1039/C5OB01111F

http://pubs.rsc.org/en/content/articlelanding/2015/ob/c5ob01111f#!divAbstract

By employing a rhodium–Duanphos complex as the catalyst, β-alkyl (Z)-N-acetyldehydroamino esters were smoothly hydrogenated in a highly efficient and enantioselective way. Excellent enantioselectivities together with excellent yields were achieved for a series of substrates. An efficient approach for the synthesis of the intermediate of the orally administered anti-diabetic drugs Alogliptin and Linagliptin in the DPP-4 inhibitor class was also developed.

 

Graphical abstract: Highly enantioselective synthesis of non-natural aliphatic α-amino acids via asymmetric hydrogenation

 

Mechanism of action

Linagliptin is an inhibitor of DPP-4, an enzyme that degrades the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Both GLP-1 and GIP increase insulin biosynthesis and secretion from pancreatic beta cells in the presence of normal and elevated blood glucose levels. GLP-1 also reduces glucagon secretion from pancreatic alpha cells, resulting in a reduction in hepatic glucose output. Thus, linagliptin stimulates the release of insulin in a glucose-dependent manner and decreases the levels of glucagon in the circulation.

 

PAPER

http://www.gosalute.it/linagliptin-nuovi-dati-presentati-allada-sugli-eventi-cardiovascolari-e-sulla-sicurezza-ed-efficacia-nei-pazienti-affetti-da-diabete-di-tipo-2-con-insufficienza-renale-da-moderata-a-grave/

PATENT

http://www.google.com/patents/WO2013098775A1?cl=en

In one aspect, the application provides a process for preparation of Linagliptin comprising reacting (R)-piperidine-3-amine of formula II or an acid addition salt thereof with 1 -[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-bromoxanthine of formula III in the presence of a suitable base in an inert organic solvent.

Figure imgf000004_0001

In another aspect, the application provides Linagliptin or a pharmaceutically acceptable salt thereof, having less than about 0.15 area % of potential process related impurities viz., regio-impurity of the formula la, bromo-impurity of the formula lb and S- isomer as measured by HPLC.

Figure imgf000004_0002

L nag pt n S- somer

Example 1 : Preparation of Linagliptin

a) Preparation of 3-methyl-7-(2-butyn-l-yl)-8-bromo-xanthine (compound of formula IV)

3-Methyl-8-bromo-xanthine (30 gm) and N,N-dimethylformamide (170 ml_) were charged into a 1000 ml_ round bottomed flask equipped with a mechanical stirrer. Diisopropylethylamine (DIPEA, 1 5.9 gm) and 1 -bromo-2-butyne (16.2 gm) were added at 30°C. The reaction mixture was heated to 85 °C and maintained the temperature for 4 hours. The reaction mixture was cooled to 30°C and pre cooled water (300 ml_) was added. The solid formed was collected by filtration and washed with pre cooled water (150 ml_) and diethyl ether (30 ml_). The solid was dried in oven under vacuum at 50°C to get 30.9 gm of the title compound.

(b) Preparation of 1 -[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8- bromoxanthine (compound of formula III) 3-Methyl-7-(2-butyn-l-yl)-8-bromo-xanthine (10 gm) and Ν,Ν-dimethylacetamide (150 mL) were charged into a 1000 mL round bottomed flask equipped with a mechanical stirrer. Potassium carbonate (9.3 gm) and 2-(chloromethyl)-4- methylquinazoline (6.8 gm) were added to the reaction mixture at room temperature. The reaction mixture was heated to 90 °C and maintained the temperature for 8 hours. The reaction mixture was cooled to 30°C and water (450 mL) was added and the mixture was stirred for 1 hour at 30°C. The solid formed was collected by filtration and washed with water (150 mL). The wet cake was charged into 500 mL round bottomed flask and toluene (220 mL) was added and the mixture was heated to reflux temperature and maintained for 1 hour. The mixture was cooled to 10°C and maintained for 2 hours. The solid was collected by filtration and washed with toluene (50 mL). The solid was dried in oven under vacuum at 80°C to get 10.8 gm of the title compound. Purity by HPLC: 99.59%

(c) Preparation of Linagliptin

1 -[(4-Methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-bromoxanthine (5 gm) and Ν,Ν-dimethylformamide (DMF, 50 mL) were charged into a 500 mL round bottomed flask equipped with a mechanical stirrer. Potassium carbonate (4.57 gm) and (R)-piperidine-3-amine dihydrochloride (2.86 gm) were added to the reaction mixture at room temperature. The reaction mixture was heated to 80 °C and maintained at that temperature for 8 hours. The reaction mixture was cooled to room temperature and DMF was evaporated under vacuum, then dichloromethane (DCM, 50 mL) was added, and stirred for 15 minutes. The reaction mixture was filtered to separate out the non- dissolved material and the non-dissolved material was washed with 15 mL of dichloromethane. The dichloromethane was evaporated under vacuum to give 4 gm of crude Linagliptin.

Example 2: One pot process for preparation of Linagliptin

3-Methyl-8-bromo-xanthine (5 gm) and Ν,Ν-dimethylformamide (DMF, 28.5 mL) were charged into a 1000 mL round bottomed flask equipped with a mechanical stirrer. Diisopropylethylamine (DIPEA, 2.6 gm) and 1 -bromo-2-butyne (2.7 gm) were added at 30 °C. The reaction mixture was heated to 85 °C and maintained at this temperature for 4 hours. The reaction mixture is cooled to 30°C and Ν,Ν-dimethylformamide (DMF, 100 ml_) was added. Potassium carbonate (4.4 gm) and 2-(chloromethyl)-4- methylquinazoline (4.2 gm) were added to the reaction mixture at room temperature. The reaction mixture was heated to 85 °C and maintained at this temperature for 4 hours. The reaction mixture was cooled to 30°C and Ν,Ν-dimethylformamide (DMF, 90 ml_) was added. Potassium carbonate (8.3 gm) and (R)-piperidine-3-amine dihydrochloride (5.2 gm) were added to the reaction mixture at room temperature. The reaction mixture was heated to 80 °C and maintained at this temperature for 8 hours. The reaction mixture was cooled to 30 °C and DMF was evaporated under vacuum. Dichloromethane (DCM, 30 ml_) was added and stirred for 15 minutes. The reaction mixture was filtered to separate out the undissolved material and the undissolved material was washed with dichloromethane (30 ml_). The dichloromethane was evaporated under vacuum and 10% acetic acid (100 ml_) was added. The resulted solution was stirred for 30 minutes and washed with dichloromethane (25 ml_x3). The pH of the aqueous layer was adjusted to 8.5 with 10% aqueous sodium bicarbonate solution. The aqueous layer was extracted with dichloromethane (25 ml_x2) and the dichloromethane was evaporated under vacuum to get 1 .2 gm of Linagliptin.

Example 3: Preparation of Linagliptin

1 -[(4-Methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-bromoxanthine (20 gm) and methyl isobutyl ketone (MIBK 200 ml_) were charged into a 1000 ml_ round bottomed flask equipped with a mechanical stirrer. Potassium carbonate (18.3 gm) and (R)-piperidine-3-amine dihydrochloride (1 1 .5 gm) were added to the reaction mixture at 30°C. The reaction mixture was heated to 95°C and maintained at that temperature for 8 hours. The reaction mixture was cooled to 30°C and filtered and washed with MIBK (40 ml_). The filtrate was charged into another flask and added 10% aqueous acetic acid solution and stirred for one hour at room temperature. The aqueous layer was separated and washed with 60 ml_ of dichloromethane. The aqueous layer was charged into another flask and 200 ml_ of dichloromethane and 100 ml_ of aqueous sodium hydroxide solution was added drop-wise at 30 °C. The mixture was stirred for one hour at 30 °C and the organic layer was separated and the aqueous layer was extracted with 100 ml of dichloromethane. Combined the organic layers and evaporated under vacuum at below 45°C. Isopropyl alcohol (100 mL) was added to the residue and stirred for 3 hours at room temperature. Filtered the compound and washed with isopropyl alcohol (20 mL) and dried the compound at below 60 °C under vacuum to give 17.6 gm of Linagliptin. PXRD pattern: Fig. 2, Purity: 99.0%

Example 4: Preparation of Linagliptin

1 -[(4-Methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-bromoxanthine (20 gm) and methyl isobutyl ketone (MIBK 200 mL) were charged into a 1000 mL round bottomed flask equipped with a mechanical stirrer. Potassium carbonate (18.3 gm) and (R)-piperidine-3-amine (1 1 .5 gm) were added to the reaction mixture at room temperature. The reaction mixture was heated to 95 °C and maintained at that temperature for 8 hours. The reaction mixture was cooled to room temperature and filtered and washed with MIBK (40 mL). The filtrate was charged into another flask and added 10% aqueous acetic acid solution and stirred for one hour at room temperature. The aqueous layer was separated and washed with 60 mL of dichloromethane. The aqueous layer was charged into another flask and 200 mL of dichloromethane and 100 mL of aqueous sodium hydroxide solution (16 gm of sodium hydroxide in 100 mL of water) was added drop-wise at room temperature. The mixture was stirred for one hour at room temperature and the organic layer was separated and the aqueous layer was extracted with 100 ml of dichloromethane. Combined the organic layers and evaporated under vacuum at below 45 °C. Hexane (100 mL) was added to the residue and stirred for 3 hours at 30 °C. Filtered the compound and washed with Hexane (40 mL) and dried the compound at below 60°C under vacuum to give 17.6 gm of Linagliptin. PXRD pattern: Fig. 2, Purity: 98.92%

Example 5: Preparation of Linagliptin

1 -[(4-Methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-bromoxanthine (20 gm) and methyl isobutyl ketone (MIBK 200 mL) were charged into a 1000 mL round bottomed flask equipped with a mechanical stirrer. Potassium carbonate (18.3 gm) and (R)-piperidine-3-amine (1 1 .5 gm) were added to the reaction mixture at 30°C. The reaction mixture was heated to 95°C and maintained at that temperature for 8 hours. The reaction mixture was cooled to 30°C and filtered and washed with MIBK (40 mL). The filtrate was charged into another flask and added 10% aqueous acetic acid solution and stirred for one hour at 30 °C. The aqueous layer was separated and washed with 60 mL of dichloromethane. The aqueous layer was charged into another flask and 200 mL of dichloromethane and 100 mL of aqueous sodium hydroxide solution (16 gm of sodium hydroxide in 100 mL of water) was added drop-wise at 30°C. The mixture was stirred for one hour at 30 °C and the organic layer was separated and the aqueous layer was extracted with 100 ml of dichloromethane. Combined the organic layers and evaporated under vacuum at below 45 °C. Toluene (100 mL) was added to the residue and stirred for 3 hours at 30 °C. Filtered the compound and washed with Toluene (40 mL) and dried the compound at below 60 °C under vacuum to give 16.8 gm of Linagliptin. Purity: 98.91 %, PXRD pattern: Fig. 2.

Example 6: Preparation of Linagliptin

1 -[(4-Methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-bromoxanthine (20 gm) and methyl isobutyl ketone (MIBK 200 mL) were charged into a 1000 mL round bottomed flask equipped with a mechanical stirrer. Potassium carbonate (18.3 gm) and (R)-piperidine-3-amine (1 1 .5 gm) were added to the reaction mixture at 30°C. The reaction mixture was heated to 95 °C and maintained at that temperature for 8 hours. The reaction mixture was cooled to 30°C and filtered and washed with MIBK (40 mL). The filtrate was charged into another flask and added 10% aqueous acetic acid solution and stirred for one hour at 30 °C. The aqueous layer was separated and washed with 60 mL of dichloromethane. The aqueous layer was charged into another flask and 200 mL of dichloromethane and 100 mL of aqueous sodium hydroxide solution (16 gm of sodium hydroxide in 100 mL of water) was added drop-wise at room temperature (pH is > 10). The mixture was stirred for one hour 30 °C and the organic layer was separated and the aqueous layer was extracted with 100 ml of dichloromethane. Combined the organic layers and evaporated under vacuum at below 45 °C. Ethyl acetate (100 mL) was added to the residue and stirred for 3 hours at 30 °C. Filtered the compound and washed with ethyl acetate (40 mL) and dried the compound at below 60 °C under vacuum to give 17.6 gm of Linagliptin. PXRD pattern: Fig. 2, Purity: 98.72%

Example 7: Preparation of Linagliptin

1 -[(4-Methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-bromoxanthine (4 gm) and methyl isobutyl ketone (MIBK 100 mL) were charged into a 1000 mL round bottomed flask equipped with a mechanical stirrer. Potassium carbonate (3.7 gm) and (R)-piperidine-3-amine dibenzoyl-D-tartrate (6.1 gm) were added to the reaction mixture at 26°C. The reaction mixture was heated to 100°C and maintained at that temperature for 6 hours. The reaction mixture was cooled to 30 °C and filtered, and the salt was washed with MIBK (8 mL). The filtrate was charged into another flask and added slowly 10% aqueous acetic acid solution (40 mL) and stirred for one hour at 26°C. The aqueous layer was separated and washed with 12 mL of dichloromethane. The aqueous layer was charged into another flask and 40 mL of dichloromethane and 20 mL of 16 % aqueous sodium hydroxide solution was added drop-wise at 26°C. The mixture was stirred for one hour at 26 °C and the organic layer was separated and the aqueous layer was extracted with 20 ml of dichloromethane. Combined the organic layers and evaporated under vacuum at below 45 °C. Isopropyl alcohol (8 mL) was added to the residue and evaporated under vacuum at below 45 °C. Isopropyl alcohol (16 mL) was added to the residue and stirred for 2 hours at 2Q°C. Filtered the compound and washed with isopropyl alcohol (4 mL) and dried the compound at 60 °C under vacuum to give 3.2 gm of Linagliptin. PXRD pattern: Fig. 2, Chemical Purity: 98.68%, Chiral Purity: 99.82%, S-isomer content: 0.12%, Regio impurity: 0.57%, Bromo impurity: 0.28%

Example 8: Preparation of Linagliptin

1 -[(4-Methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-bromoxanthine (20 gm) and methyl isobutyl ketone (MIBK 200 mL) were charged into a 1000 mL round bottomed flask equipped with a mechanical stirrer. Potassium carbonate (18.3 gm) and (R)-piperidine-3-amine dihydrochloride (8.4 gm) were added to the reaction mixture at 26°C. The reaction mixture was heated to \ 00 °C and maintained at that temperature for 4 hours. The reaction mixture was cooled to 30 °C and filtered and washed with MIBK (40 mL). The filtrate was charged into another flask and added 200 mL of 10% aqueous acetic acid solution and stirred for 30 minutes at 28 °C. The aqueous layer was separated and washed with 60 mL of dichloromethane. The aqueous layer was charged into another flask and 200 mL of dichloromethane and 100 mL of aqueous sodium hydroxide solution (16 gm of sodium hydroxide in 100 mL of water) were added drop- wise at 28°C (pH is > 10). The mixture was stirred for one hour at 28°C and the organic layer was separated and the aqueous layer was extracted with 100 ml of dichloromethane. Combined the organic layers and divided into 5 equal parts.

Part 1 : The organic layer was distilled off completely under vacuum at 45 °C. Methanol (8 mL) was added to the residue and distilled off completely under vacuum at 45°C. Methanol (16 mL) was added to the residue stirred for 30 minutes at 28 °C and 48 mL of MTBE was added over a period of 30 minutes to the resulted solution at 27°C and stirred for 1 hour. Filtered the compound and washed with 8 mL of MTBE and dried the compound at 65 °C under vacuum to give 3.0 gm of Linagliptin. PXRD pattern: Fig. 3. Chemical Purity: 99.46%, Regio impurity: 0.37%, Bromo impurity: 0.03%

Part 2: The organic layer was distilled off completely under vacuum at 45 °C. Methanol (8 mL) was added to the residue and distilled off completely under vacuum at 45°C. Methanol (24 mL) was added to the residue stirred for 30 minutes at 28 °C and the resulted solution was cooled to 5°C and stirred for 1 hour. Filtered the compound and washed with 5 mL of chilled methanol and dried the compound at 65°C under vacuum to give 3.0 gm of Linagliptin. PXRD pattern: Fig. 3. Chemical Purity: 99.41 %, Regio impurity: 0.38%, Bromo impurity: 0.03%

Part 3: The organic layer was distilled off completely under vacuum at 45 °C. Methanol (8 mL) was added to the residue and distilled off completely under vacuum at 45°C. Methanol (20 mL) was added to the residue stirred for 30 minutes at 28 °C and 20 mL of MTBE was added over a period of 30 minutes to the resulted solution at 27°C and stirred for 1 hour. Filtered the compound and washed with 8 mL of MTBE and dried the compound at 65 °C under vacuum to give 2.8 gm of Linagliptin. PXRD pattern: Fig. 3. Chemical Purity: 99.47%, Regio impurity: 0.36%, Bromo impurity: 0.03%.

Part 4: The organic layer was distilled off completely under vacuum at 45 °C. Isopropyl alcohol (8 mL) was added to the residue and distilled off completely under vacuum at 45 °C. Methanol (16 mL) was added to the residue stirred for 30 minutes at 28 °C and 16 mL of isopropyl alcohol was added over a period of 30 minutes to the resulted solution at 27°C and stirred for 1 hour. Filtered the compound and washed with 4 mL of isopropyl alcohol and dried the compound at 65 °C under vacuum to give 2.9 gm of Linagliptin. PXRD pattern: Fig. 1 .

Chemical Purity: 99.44%, Regio impurity: 0.38%, Bromo impurity: 0.02%.

Part 5: The organic layer was distilled off completely under vacuum at 45 °C. Ethyl acetate (8 mL) was added to the residue and distilled off completely under vacuum at 45 °C. Ethyl acetate (16 mL) was added to the residue stirred for 30 minutes at 28°C and 16 mL of methanol was added over a period of 30 minutes to the resulted solution at 27°C and stirred for 1 hour. Filtered the compound and washed with 4 mL of ethyl acetate and dried the compound at 65 °C under vacuum to give 0.7 gm of Linagliptin. PXRD pattern: Fig. 2.

Chemical Purity: 99.57%, Regio impurity: 0.29%, Bromo impurity: 0.02%

Example 9: Purification of Linagliptin

Linagliptin (3.5 gm) was dissolved in 10% aqueous acetic acid and stirred for 15 minutes. Dichloromethane (50 mL) was added to the solution and stirred for 30 minutes. The aqueous layer was separated and the pH of this layer was adjusted to 8.5 using 10% aqueous sodium bicarbonate solution. The aqueous layer was extracted with dichloromethane (50 mLx2). The dichloromethane was evaporated under vacuum to give 3 gm of Linagliptin.

Example 10: Purification of Linagliptin

Linagliptin (31 gm) and methanol (124 mL) were charged into 500 mL round bottomed flask and the solution was heated to 40 °C and stirred for 60 minutes. Charcoal (3 gm) was added to the clear solution and stirred for 30 minutes. The solution was filtered through Hy-flow and the Hy-flow bed was washed with methanol (30 mL). Filtrate was charged into 1000 mL round bottomed flask and methyl tertiary butyl ether was added drop-wise to the solution and stirred for 2 hours at 30 °C. The precipitate so formed was filtered and the wet cake was washed with methyl tertiary butyl ether (30 mL) to get 25.6 gm of pure Linagliptin. PXRD pattern: Fig. 3. Chemical Purity: 99.57%, Chiral purity: 99.73%, Regio impurity: 0.10%, Bromo impurity: 0.1 %

Example 1 1 : Purification of Linagliptin

Linagliptin (4 gm) and methanol (24 mL) were charged into 100 mL round bottomed flask and the solution is heated to 50 °C and stirred for 60 minutes. Methyl tertiary butyl ether (MTBE, 80mL) was charged into 500 mL round bottomed flask and the methanol solution containing linagliptin was added drop-wise at 27 °C and stirred for 2 hours at same temperature. The precipitate formed was filtered and the wet cake was washed with methyl tertiary butyl ether (8 mL) to get 2.6 gm of pure Linagliptin. PXRD pattern: Fig. 2, Bromo impurity content: 0.04%.

Example 12: Purification of Linagliptin

a) Preparation of linagliptin-(D)-tartrate

Linagliptin (10 gm) and methanol (300 mL) were charged into 1000 mL round bottomed flask and (D)-tartaric acid solution (3.3 gm of (D)-tartaric acid in 100 mL of methanol) was added at 26 °C. The solution was heated to 65 °C and stirred for 60 minutes. The solution was cooled to 28 °C and stirred for 2 hours at 27 °C. The precipitate formed was filtered and the wet cake was washed with methanol (20 mL) and the solid was dried under vacuum at 55°C to get 8.3 gm of Linagliptin-(D)-tartrate. PXRD pattern: Fig. 4. Chemical Purity: 99.72%, Chiral purity: 99.89%, Regio impurity: 0.08%, Bromo impurity: 0.05%, S-isomer: 0.1 1%.

b) Isolation of pure Linagliptin

Linagliptin-(D)-tartrate (8 gm) and water (100 mL) were charged into 1000 mL round bottomed flask and stirred for 30 minutes at 26 °C. Dichloromethane (80 mL) was added to the solution and cooled to 5°C. Aqueous sodium hydroxide solution (0.6 gm of NaOH is added to 20 mL of water) was added to the mixture at 5°C and maintained for 1 hour. Layers were separated and aqueous layer was extracted with dichloromethane (20 mL). Combined both organic layers and dried over sodium sulphate and distilled off the organic layer under vacuum at 45 °C. Hexane (20 mL) was added to the crude and stirred for 1 hour at 26°C. The precipitate was filtered and washed with 4 mL of hexane and dried the compound at 60°C under vacuum to give 6 gm of pure Linagliptin. PXRD pattern: Fig. 2, Chemical Purity: 99.67%, Chiral purity: 99.85%, (S)-isomer content: 0.1 5%, Regio impurity: 0.09%, Bromo impurity: 0.07%.

 

PATENT

http://www.google.com/patents/US20130123282

      Example 34Preparation of (R)-8-(3-amino-piperidin-1-yl)-7-(but-2-ynyl)-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydro-purine-2,6-dione (Form-XXII): A. 3-Methyl-7-(2-butyne-1-yl)-8-bromoxanthine

    • [0181]
      8-Bromo-3-methylxanthine was reacted with 1-bromo-2-butyne in the presence of base in a mixture of N-methyl pyrrolidone and toluene mixture. The reaction mixture was heated overnight. The reaction completion was determined, and the mixture was then cooled to ambient temperature. A solid precipitate formed on cooling precipitation. The product, 3-Methyl-7-(2-butyne-1-yl)-8-bromoxanthine, having greater than 95% purity was isolated by filtration and washed with toluene.

Example 35Preparation of 8-bromo-7-(but-2-ynyl)-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydro-purine-2,6-dione

    • [0182]
      3-Methyl-7-(2-butine-1-yl)-8-bromoxanthine was reacted with 2-(chloromethyl)-4-methylquinazoline in the presence of base under phase transfer catalyst using a N-methyl pyrrolidone/toluene mixture as the reaction solvent. The reaction mixture was heated overnight. When the reaction was complete, the reaction mixture was cooled to ambient temperature. A solid precipitate formed and was separated by filtration and washed with toluene and then with water to provide the product, 8-bromo-7-(but-2-ynyl)-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydro-purine-2,6-dione having more than 97% purity.

Example 36Preparation of (R)-8-(3-Amino-piperidin-1-yl)-7-(but-2-ynyl)-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydro-purine-2,6-dione (Form-XXII)

  • [0183]
    (R)-3-N-tert-Butoxycarbonylaminopiperidine was reacted with 8-bromo-7-(but-2-ynyl)-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydro-purine-2,6-dione in the presence of base. The reaction mixture was heated overnight. When the reaction was complete, the reaction mixture was cooled to ambient temperature. The cooled reaction mixture was washed several times with water and separated. The resulting 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert-butoxycarbonylamino)-piperidin-1-yl]-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine organic solution was greater than 95%. Purified by HPLC. An excess of aqueous HCl solution was added to the obtained 1-[(4-methylquinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert-butoxycarbonylamino)-piperidin-1-yl]-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine organic solution. The resulting mixture was stirred under heating until complete conversion was observed. Aqueous base was added to the reaction. The resulting mixture was stirred and separated. The organic phase was washed with aqueous base and separated. A non-polar or moderately polar solvent was added to the resulting organic phase. The mixture was partially concentrated to achieve precipitation, and the concentrated mixture was cooled and filtered to provide the wet crude product. The crude product was re-crystallized from alcohol, filtered and dried in vacuum oven with heating to afford dry solid Form-XXII of (R)-8-(3-amino-piperidin-1-yl)-7-(but-2-ynyl)-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydro-purine-2,6-dione having more than 98% purity.

Clinical trials

Results in 2010 from a Phase III clinical trial of linagliptin showed that the drug can effectively reduce blood sugar.[2]

 

 

 


Scheme:
. J. Med Chem 2009, 52, 6433..
J. Med Chem 2007, 50, 6450…

References

  • H. Spreitzer (September 1, 2008). “Neue Wirkstoffe – BI-1356”. Österreichische Apothekerzeitung (in German) (18/2008): 918.
  • Wang, Y, Serradell, N, Rosa, E, Castaner, R (2008). “BI-1356”. Drugs of the Future 33 (6): 473–477. doi:10.1358/dof.2008.033.06.1215244.
  1. ^ “FDA Approves Type 2 Diabetes Drug from Boehringer Ingelheim and Lilly”. 3 May 2011.
  2. “Four Phase III Trials Confirm Benefits of BI’s Oral, Once-Daily Type 2 Diabetes Therapy”. Genetic Engineering & Biotechnology News. 28 June 2010.
CN101735218A * Dec 17, 2009 Jun 16, 2010 廖国超 Piperidine carbamic acid ester derivative and application thereof
US7407955 Aug 12, 2003 Aug 5, 2008 Boehringer Ingelheim Pharma Gmbh & Co., Kg 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions
US20040097510 * Aug 12, 2003 May 20, 2004 Boehringer Ingelheim Pharma Gmbh & Co. Kg 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions
US20090192314 Mar 30, 2009 Jul 30, 2009 Boehringer Ingelheim International Gmbh Process for the preparation of chiral 8-(3-aminopiperidin-1yl)-xanthines
WO2005085246A1 * Feb 12, 2005 Sep 15, 2005 Boehringer Ingelheim Int 8-[3-amino-piperidin-1-yl]-xanthine, the production thereof and the use in the form of a dpp inhibitor
Reference
1 CHIRALITY vol. 7, 1995, pages 90 – 95
2 * JEAN L ET AL: “A convenient route to 1-benzyl 3-aminopyrrolidine and 3-aminopiperidine“, TETRAHEDRON LETTERS, ELSEVIER, AMSTERDAM, NL, vol. 42, no. 33, 13 August 2001 (2001-08-13), pages 5645-5649, XP004295831, ISSN: 0040-4039, DOI: DOI:10.1016/S0040-4039(01)00985-6
Citing Patent Filing date Publication date Applicant Title
WO2014033746A2 * Aug 6, 2013 Mar 6, 2014 Glenmark Pharmaceuticals Limited; Glenmark Generics Limited Process for the preparation of dipeptidylpeptidase inhibitors
WO2014059938A1 * Oct 17, 2013 Apr 24, 2014 2Y-Chem, Ltd. Method for preparing important intermediate of linagliptin
WO2014097314A1 * Dec 16, 2013 Jun 26, 2014 Mylan Laboratories Ltd An improved process for the preparation of linagliptin
WO2010072776A1 * Dec 22, 2009 Jul 1, 2010 Boehringer Ingelheim International Gmbh Salt forms of organic compound
CN101784270A * Aug 15, 2008 Jul 21, 2010 贝林格尔.英格海姆国际有限公司 Pharmaceutical composition comprising a glucopyranosyl-substituted benzene derivative
CN102127080A * Nov 2, 2005 Jul 20, 2011 贝林格尔.英格海姆国际有限公司 Method for producing chiral 8-(3-amino-piperidin-1-yl)-xanthines
Citing Patent Filing date Publication date Applicant Title
WO2015067539A1 * Oct 31, 2014 May 14, 2015 Chemelectiva S.R.L. Process and intermediates for the preparation of linagliptin
WO2015087240A1 Dec 9, 2014 Jun 18, 2015 Ranbaxy Laboratories Limited Process for the preparation of linagliptin and an intermediate thereof
WO2015107533A1 * Sep 1, 2014 Jul 23, 2015 Harman Finochem Limited A process for preparation of 1h-purine-2,6-dione, 8-[(3r)-3-amino-1-piperidinyl]-7 (2-butyn-1-yl)-3,7-dihydro-3-methyl-1-[(4-methyl-2quinazolinyl) methyl] and its pharmaceutically acceptable salts

 

Eckhardt M, et al. 8-(3-(R)-aminopiperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydropurine-2,6-dione (BI 1356), a highly potent, selective, long-acting, and orally bioavailable DPP-4 inhibitor for the treatment of type 2 diabetes. J Med Chem. 2007; 50(26):6450-3. Pubmed ID: 18052023
2. Thomas L, et al. (R)-8-(3-amino-piperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydro-purine-2,6-dione (BI 1356), a novel xanthine-based dipeptidyl peptidase 4 inhibitor, has a superior potency and longer duration of action compared with other dipeptidyl peptidase-4 inhibitors. J Pharmacol Exp Ther. 2008; 325(1):175-82. Pubmed ID: 18223196

Linagliptin.png

//////////BI-1356, BI1356, Linagliptin, Tradjenta, Trajenta, DPP-IV, DPP-4 inhibitor

 

%d bloggers like this: