A New Approach to Malaria Treatment?

A New Approach to Malaria Treatment?

Halogenated natural alkaloids show herbicidal and antiplasmodial activity

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Chinese Plant Compound , Triptolide Wipes out Cancer in 40 Days, Say new Research.

Chinese Plant Compound , Triptolide Wipes out Cancer in 40 Days, Say new Research.

File:Triptolide.png

Triptolide is a diterpenoid epoxide found in the Thunder God Vine, Tripterygium wilfordii. It has in vitro and in vivo activities againstmouse models of polycystic kidney disease[1] and http://en.wikipedia.org/wiki/Pancreatic_cancer” rel=”nofollow”>pancreatic cancer, but its physical properties limit its therapeutic potential.[2] Consequently, a synthetic prodrugminnelide, is being studiedclinically instead.[2]

A little-known plant with a truly bizarre name is now making headlines as a cancer killer, with the compound of the plant vanishing tumors in mice with pancreatic cancer. Known as the ‘thunder god vine’ or lei gong teng, the Chinese plant is actually integrated into Chinese medicine and has been used for ages in remedying a number of conditions including rheumatoid arthritis.

According to the new research out of the University of Minnesota’s Masonic Cancer Center, the thunder god plant compound led to no signs of tumors after a 40 day period — even after discontinuing the treatment. Published in the journal Science Translational Medicine

http://stm.sciencemag.org/content/4/156/156ps21.full?sid=5203733d-ae1d-438e-9d36-b8bd9f16cd8d

Pancreas Cancer Meets the Thunder God

  • Sunil R. Hingorani and
  • John D. Potter

Sci Transl Med 17 October 2012 4:156ps21. DOI:10.1126/scitranslmed.3004956

…minnelide) of a natural product (triptolide) that has been shown to have potent…rheumatoid arthritis patients ( 4 ). Triptolide, a diterpenoid triepoxide, was first…show an excess of lymphomas) ( 9 ). Triptolide inhibits proliferation and/or induces…
Pancreatic Cancer A Preclinical Evaluation of Minnelide as a Therapeutic Agent Against Pancreatic Cancer 

  • Rohit Chugh,et al

Sci Transl Med 17 October 2012 4:156ra139. DOI:10.1126/scitranslmed.3004334

…characterized. One component of T. wilfordii, triptolide, has shown promising effects against…malignancies-are desperately needed, but triptolide is poorly soluble in water and thus…synthesize a water-soluble form of triptolide, Minnelide, and demonstrate efficacy…

and funded by the National Institutes of Health, even the scientists working on the project were stunned by the anti-cancer properties of the compound. Known to contain something known as triptolide, which has been identified as a cancer fighter in previous research, it is thought to be the key component that may be responsible for the anti-tumor capabilities.

http://thearrowsoftruth.com/wp-content/uploads/2012/10/thunder-god-vine-stalk_medium-300×199.jpg” width=”300″ height=”199″ />

And just like with numerous other powerful substances like turmeric and ginger, mainstream science is still slowly confirming what many traditional practitioners have known for their entire lives. This is, of course, due to the fact that there is simply no moneyfor major corporations in researching the healing powers of natural herbs and compounds such as the compound found in the thunder god vine. Turmeric and ginger, for example, have been found to be amazing anti-cancer substances that are virtually free compared to expensive and dangerous cancer drugs.

References

Triptolide
Triptolide (1) is a structurally unique diterpene triepoxide isolated from a traditional Chinese medicinal plant with anti-inflammatory, immunosuppressive, contraceptive and antitumor activities. Its molecular mechanism of action, however, has remained largely elusive to date. We report that triptolide covalently binds to human XPB (also known as ERCC3), a subunit of the transcription factor TFIIH, and inhibits its DNA-dependent ATPase activity, which leads to the inhibition of RNA polymerase II–mediated transcription and likely nucleotide excision repair. The identification of XPB as the target of triptolide accounts for the majority of the known biological activities of triptolide. These findings also suggest that triptolide can serve as a new molecular probe for studying transcription and, potentially, as a new type of anticancer agent through inhibition of the ATPase activity of XPB.
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Breast Cancer Drugs in Late-Stage Development/Recently Approved

 

The article is 2012-2013 based and reader discretion is sought to ascertian the stage of approval

Breast Cancer Drugs in Late-Stage Development/Recently Approved

 

Afinitor® (everolimus)

http://newdrugapprovals.wordpress.com/2013/04/27/drug-spotlight-afinitor-everolimus-novartis/

Sponsor: Novartis

Method of Action: Mammalian target of rapamycin (mTOR) inhibitor

Indications/Phase of Trial: Hepatocellular carcinoma; human epidermal growth factor receptor 2-positive (HER2+) breast cancer first-line and second-line; lymphoma; nonfunctional carcinoid tumor (Phase III; all new indications)

Approved in July in U.S., EU for advanced hormone-receptor-positive (HR+) and human epidermal growth factor Receptor 2-negative (HER2-) metastatic breast cancer with exemestane in postmenopausal women who have already received certain other medicines for their cancer

Approved earlier for adults with pancreatic neuroendocrine tumors (PNET) that cannot be treated with surgery; adults with advanced renal cell carcinoma (RCC) when certain other medicines have not worked; adults with angiomyolipoma, seen with tuberous sclerosis complex (TSC), when surgery is not required immediately; and adults and children with TSC who have a brain tumor called subependymal giant cell astrocytoma (SEGA) that cannot be removed completely by surgery

 

Avastin (Bevacizumab; RG435)

http://newdrugapprovals.wordpress.com/2013/02/23/fda-has-approved-a-new-use-of-avastin-bevacizumab-in-combination-with-fluoropyrimidine-based-irinotecan-or-oxaliplatin-chemotherapy-for-people-with-metastatic-colorectal-cancer-mcrc/

Sponsor: Roche/Genentech

Method of Action: Monoclonal antibody; Vascular endothelial growth factor (VEGF) inhibitor

Indications/Phase of Trial: U.S.: Relapsed ovarian cancer, platinum-sensitive (Registration); first-line metastatic breast cancer and first-line metastatic ovarian cancer (both Phase III).

EU: Relapsed platinum-resistance ovarian cancer (Phase III)

Metastatic colorectal cancer, treatment beyond progression (Registration); adjuvant breast cancer, HER2- and HER2+; adjuvant NSCLC; first-line glioblastoma (GBM) multiforme; high-risk carcinoid (all Phase III)

Approved for metastatic colorectal cancer (mCRC) when started with the first or second intravenous 5-FU–based chemotherapy for metastatic cancer; advanced nonsquamous non-small-cell lung cancer (NSCLC) with carboplatin and paclitaxel in people who have not received chemotherapy for their advanced disease; metastatic RCC (mRCC) with interferon alfa; and GBM in adult patients whose cancer has progressed after prior treatment. Effectiveness based on tumor response, as no data have shown whether Avastin improves disease-related symptoms or survival in people previously treated for GBM

Approval conditionally granted in 2008 and withdrawn November 2011 for HER2- metastatic breast cancer (mBC) with Paclitaxel

 

Buparlisib (BKM120)

Sponsor: Novartis

Method of Action: Pan-PI3K inhibitor

Indications/Phase of Trial: mBC (Phase III and confirmatory Phase I/II); with Fulvestrant, in postmenopausal women with hormone receptor-positive HER2- locally advanced or mBC which progressed on or after aromatase inhibitor (AI) treatment (Phase III; BELLE-2 study recruiting as of November 2012); with Fulvestrant, in postmenopausal women with hormone receptor-positive HER2- AI-treated, locally-advanced or mBC who progressed on or after mTOR inhibitor-based treatment (Phase III; BELLE-3 study, recruiting as of October 2012); with Paclitaxel in patients with HER2- inoperable locally advanced or mBC, with or without PI3K pathway activation (Phase III; BELLE-4 study, recruiting as of November); metastatic castration-resistant prostate cancer (CRPC; Phase II; recruiting as of October); recurrent glioblastoma (Phase II; recruiting as of November); recurrent/metastatic head and neck squamous cell carcinoma (Phase II; recruiting as of October); endometrial cancer (Phase I/II); NSCLC (Phase I/II); prostate cancer (Phase I/II); GBM multiforme (Phase I/II); with Fulvestrant in postmenopausal women with estrogen receptor-positive metastatic breast cancer (Phase I); previously treated advanced colorectal cancer (Phase I)

 File:Fulvestrant.svg

Faslodex (Fulvestrant Injection)

Sponsor: AstraZeneca

Method of Action: Estrogen receptor antagonist

Indications/Phase of Trial: First line HR+ mBC (Phase III; FALCON study commenced Oct. 29)

Approved for HR+ mBC in women who have experienced menopause and whose breast cancer has worsened after they were treated with antiestrogen medications

 

Herceptin (Trastuzumab; RG597)

http://newdrugapprovals.wordpress.com/2013/02/23/fda-approves-kadcyla-ado-trastuzumab-emtansine-a-new-therapy-for-patients-with-her2-positive-late-stage-metastatic-breast-cancer/

Sponsor: Roche, in partnership with Halozyme

Method of Action: Humanized monoclonal antibody designed to target and block the function of HER2+

Indications/Phase of Trial: EU: Early HER2+ breast cancer, subcutaneous formulation (Registration)

Approved for early-stage HER2+ breast cancer that has spread into the lymph nodes, and HER2+ breast cancer that has not spread into the lymph nodes and is estrogen receptor/progesterone receptor-negative (ER-/PR-) or have one high-risk feature. High-risk is defined as estrogen receptor/progesterone receptor-positive (ER+/PR+) with one of the following features: tumor size >2 cm, age <35 years, or tumor grade 2 or 3. Can be used with Adriamycin® (doxorubicin), Cytoxan® (cyclophosphamide), and either Taxol® (paclitaxel) or Taxotere® (docetaxel); or with Taxotere and Paraplatin® (carboplatin); or alone after treatment with multiple other therapies, including an anthracycline (Adriamycin)-based chemotherapy

Also approved alone for the treatment of HER2+ breast cancer in patients who have received one or more chemotherapy courses for metastatic disease; and with paclitaxel for first-line treatment of HER2+ mBC

 

Iniparib (Tivolza; BSI-201; SAR240550)

Sponsor: Sanofi, through acquisition of original developer BiPar Sciences

Method of Action: Poly (ADP-ribose) polymerase 1 (PARP1) inhibitor

Indications/Phase of Trial: Stage IV squamous NSCLC (Phase III; NME); solid tumors such as sarcoma and breast, uterine, lung, and ovarian cancers (Phase I/II)

Phase III trial in breast cancer failed January 2011 by failing to improve survival and progression-free survival (PFS) in breast cancer patients

 

Nexavar® (Sorafenib)

http://newdrugapprovals.wordpress.com/2013/07/16/nexavar-sorafenib/

Sponsor: Onyx Pharmaceuticals

Method of Action: Dual-action inhibitor that targets RAF/MEK/ERK pathway in tumor cells and tyrosine kinases

Indications/Phase of Trial: Liver cancer adjuvant (Phase III; STORM study); kidney cancer adjuvant (Phase III; SORCE/ASSURE study); thyroid cancer monotherapy (Phase III; DECISION study); breast cancer with capecitabine (Phase III; RESILIENCE study)

Approved for hepatocellular carcinoma (HCC) and RCC

 

Perjeta (Pertuzumab; RG1273)

http://newdrugapprovals.wordpress.com/2013/03/05/the-european-medicines-agency-ema-has-approved-roches-perjetatm-pertuzumab-for-patients-with-previously-untreated-her2-positive-metastatic-breast-cancer-mbc/

Sponsor: Roche/Genentech

Method of Action: HER2/neu receptor antagonist

Indications/Phase of Trial: EU: With Herceptin and docetaxel chemotherapy for previously-untreated HER2+ mBC or locally recurrent, inoperable breast cancer in patients who have not received previous treatment or whose disease has returned after treatment in the early-stage setting (Registration)

U.S.: Approved June 2012 for HER2+ mBC with Herceptin (trastuzumab) and docetaxel, in patients who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease

Switzerland: Approved August 2012 for HER2+ breast cancer with Herceptin (trastuzumab) and docetaxel in patients with advanced or locally recurring breast cancer that has not previously been treated with chemotherapy

 

Ridaforolimus (MK-8669; AP23573; formerly Deforolimus)

http://newdrugapprovals.wordpress.com/2013/03/05/phase-3-breast-cancer-ridaforolimus-mk-8669-ap23573-formerly-deforolimus-merck-licenseariad-pharmaceuticals/

Sponsor: Merck, under exclusive worldwide license agreement with Ariad Pharmaceuticals

Method of Action: Oral inhibitor of mammalian target of rapamycin inhibitor (mTOR)

Indications/Phase of Trial: Maintenance therapy for metastatic soft-tissue sarcoma and bone sarcomas after at least four chemotherapy cycles (under review after receiving Complete Response letter from FDA in June; NME); breast cancer with exemestane, compared to breast cancer with dalotuzumab and exemestane (Phase II; recruiting as of November); advanced head and neck cancer, NSCLC and colon cancer, with cetuximab (Phase II); pediatric patients with advanced solid tumors (Phase I; recruiting as of September); with dalotuzumab in pediatric patients with advanced solid tumors (Phase I; recruiting as of August); advanced RCC, with vorinostat (Phase I; recruiting as of October 2012); breast cancer, with dalotuzumab (Phase I: recruiting as of September); endometrial and ovarian cancers, with paclitaxel and carboplatin (Phase I; recruiting as of September 2012); advanced cancer, with MK-2206 and MK-0752 (Phase I: recruiting as of September 2012); advanced cancer, with dalotuzumab, MK-2206 and MK-0752 (Phase I: recruiting as of August 2012)

 

Tivozanib (ASP4130; AV-951)

Sponsor: Aveo Oncology and Astellas

Method of Action: Tyrosine kinase inhibitor; inhibits VEGF receptor 1, 2, and 3

Indications/Phase of Trial: U.S.: Advanced RCC (Registration; NDA filed September 2012); tivozanib biomarkers in solid tumors (Phase II; BATON study); stage IV metastatic colorectal cancer (mCRC), with mFOLFOX6, and compared with bevacizumab and mFOLFOX6 (Phase II; recruiting as of November); additional data as first-line therapy for advanced RCC, followed by sunitinib (Phase II; TAURUS study, enrollment initiated in October 2012); advanced solid tumors, with capecitabine (Xeloda®; Phase I; recruiting as of October)

EU: Advanced RCC (Phase III)

 

Trastuzumab-DM1 (T-DM1; Trastuzumab emtansine; RG3502)

http://newdrugapprovals.wordpress.com/2013/02/23/fda-approves-kadcyla-ado-trastuzumab-emtansine-a-new-therapy-for-patients-with-her2-positive-late-stage-metastatic-breast-cancer/

Sponsor: Roche, with linker technology developed by ImmunoGen

Method of Action: Antibody-drug conjugate, consisting of the antibody trastuzumab and the chemotherapy DM1 attached via a stable linker

Indications/Phase of Trial: U.S.: HER2+, unresectable locally-advanced or mBC who have received prior treatment with Herceptin (trastuzumab) and a taxane chemotherapy (Registration; Priority review approved Nov. 7; action date Feb. 26, 2013)

EU: Marketing Authorization Application for HER2+ mBC accepted for review by European Medicines Agency

 File:Lapatinib.svg

Tyverb/Tykerb (lapatinib)

http://newdrugapprovals.wordpress.com/2013/06/17/patent-of-fresenius-kabi-oncology-ltd-novel-intermediates-and-process-for-the-preparation-of-lapatinib-and/

Sponsor: GlaxoSmithKline

Method of Action: Human epidermal growth factor receptor-2 (Her2) and epidermal growth factor receptor (EGFR) dual kinase inhibitor

Indications/Phase of Trial: mBC with trastuzumab (Registration); breast cancer, adjuvant therapy (Phase III); Gastric cancer (Phase III); head & neck squamous cell carcinoma, resectable disease (Phase III)

 

Xgeva (denosumab)

http://newdrugapprovals.wordpress.com/2013/06/14/fda-approves-xgevadenosumab-to-treat-giant-cell-tumor-of-the-bone/

Sponsor: Amgen, with commercialization by GlaxoSmithKline in countries where Amgen has no presence

Method of Action: Fully human monoclonal antibody that specifically targets a ligand known as RANKL that binds to a receptor known as RANK

Indications/Phase of Trial: Delay or prevention of bone metastases in breast cancer (Phase III); delay or prevention of bone metastases in prostate cancer (Phase III)

Approved for prevention of fractures in men with advanced prostate cancer

Rejected in April for supplemental Biologics License Application to treat men with CRPC at high risk of developing bone metastases

 

Yondelis® (trabectedin)

Sponsor: Johnson & Johnson; developed in collaboration with PharmaMar

Method of Action: Binds to minor groove of DNA, interfering with the cell division and gene transcription processes, as well as DNA’s repair machinery

Indications/Phase of Trial: U.S.: Locally advanced or metastatic soft tissue sarcoma excluding leiomyosarcoma and liposarcoma who have relapsed or are refractory to standard-of-care treatment (Phase III; recruiting as of November); soft tissue sarcoma, excluding liposarcoma and leiomyosarcoma (L-type sarcoma), in previously-treated patients who cannot be expected to benefit from currently available therapeutic options (Phase III; recruiting as of November); locally advanced or metastatic L-sarcoma (liposarcoma or leiomyosarcoma) who were previously treated with at least an anthracycline and ifosfamide-containing regimen, or an anthracycline-containing regimen and one additional cytotoxic chemotherapy regimen, compared with dacarbazine group (Phase III; recruiting as of November); breast cancer and pediatric tumors (Phase II); Advanced malignancies and liver dysfunction (Phase I; recruiting as of November)

EU: Approved for advanced or metastatic soft tissue sarcoma, and for relapsed platinum-sensitive ovarian cancer, with DOXIL®/Caelyx®

 

Xtandi® Capsules (Enzalutamide; formerly MDV3100)

http://newdrugapprovals.wordpress.com/2013/05/28/astellas-pharma-and-medivation-have-announced-the-submission-of-application-for-marketing-approval-of-enzalutamide-in-japan-for-the-treatment-of-prostate-cancer/

Sponsor: Medivation in collaboration with Astellas

Method of Action: Androgen receptor inhibitor

Indications/Phase of Trial: Prechemotherapy CRPC in patients who have failed luteinizing hormone-releasing hormone (LHRH) analog treatment only, as well as patients who have failed both LHRH analog and anti-androgen treatment. (Phase III; PREVAIL study); prostate cancer neoadjuvant therapy (Phase II); prechemo metastatic prostate cancer in Europe (Phase II; TERRAIN); prechemo metastatic and nonmetastatic prostate cancer patients in U.S. (Phase II; STRIVE); prostate cancer Hormone-naïve (Phase II; ASPIRE); prostate cancer with docetaxel (Phase I); breast cancer (Phase I)

EU: Marketing Authorization Application submitted June 2012 to European Medicines Agency, for patients with metastatic CRPC who have received docetaxel-based chemotherapy

Japan: Metastatic CRPC who have received docetaxel-based chemotherapy (Phase II)

Approved Aug. 31 for patients with metastatic CRPC who have previously received docetaxel. As a post-marketing requirement, Medivation and Astellas agreed to conduct an open-label safety study of Xtandi (160 mg/day) in patients at high risk for seizure, with data to be submitted to FDA in 2019

Links

 

 

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Greek Herbs- Fennel (saunf)

 
Fennel, otherwise known as Foeniculum vulgare, is a plant belonging to the genus Foeniculum. The fennel plant is native to the Mediterranean region, and the plant produces yellow flowers. Fennel is also an edible plant considered both aromatic and flavorful. In addition to culinary uses, fennel has several purported medicinal uses. Fennel powder is the powdered form made by grinding the seeds from the plant. Health supplement manufacturers use the fennel powder to produce fennel health supplements. You should, however, speak with your doctor prior to using fennel as a health
supplement.

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[slideshare id=5669084&style=border:1px solid #CCC;border-width:1px 1px 0;margin-bottom:5px&sc=no]

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History of Fennel

Ancient Greeks and Indian cultures used fennel for cooking and as part of traditional herbal medicine. The Greeks and Indians traditionally combined fennel with other herbs to make home remedies for the relief of gastrointestinal problems such as acidity and indigestion.

Fennel Composition

The essential oil of fennel contains approximately 5 percent limonene, 50 to 80 percent anethole and 5 percent fenchone. Additionally, the oil contains trace amounts of a-pinene, estragole, b-pinene, safrole, b-myrcene, camphene and p-cymene. The seeds from the fennel plant also contain fiber and complex carbohydrates. Fennel contains nutrients including vitamin B-3, magnesium, molybdenum, copper, phosphorus, iron, calcium, manganese, vitamin C, folate and potassium.

Fennel Uses

As a health supplement, fennel can help to prevent gas, support digestion and function as an expectorant that can help to relieve minor respiratory problems such as mucus. Fennel also contains anti-inflammatory properties when used externally. The leaves from the fennel plant can facilitate the healing of wounds and burns. The root of the fennel plant is diuretic and can help treat urine infections. Fennel also contains a combination of phytonutrients including the flavonoids rutin, quercitin and kaempferol. Fennel also has antioxidant properties and as a dietary fiber, it can help lower your cholesterol levels.

Fennel Supplements

Health supplement manufacturers offer fennel supplements in powdered form. As a supplement, manufacturers recommend taking 1 to 4 g per day of the powdered fennel supplement. The Food and Drug Administration, however, has not established a recommended dose for fennel powder. There are no known side effects of consuming fennel powder supplements, although you should speak with your doctor prior to using fennel powder if you are attempting to treat a specific medical condition.

The bulb, foliage, and seeds of the fennel plant are widely used in many of the culinary traditions of the world. The small flowers of wild fennel (mistakenly known in America as fennel “pollen” ) are the most potent form of fennel, but also the most expensive.Dried fennel seed is an aromatic, anise-flavoured spice, brown or green in colour when fresh, slowly turning a dull grey as the seed ages. For cooking, green seeds are optimal. The leaves are delicately flavoured and similar in shape to those of dill. The bulb is a crisp vegetable that can be sautéed, stewed, braised, grilled, or eaten raw. They are used for garnishes and to add flavor to salads. They are also added to sauces and served with pudding. The leaves used in soups and fish sauce and sometimes eaten raw as salad.

Fennel seeds are sometimes confused with those of anise, which are similar in taste and appearance, though smaller. Fennel is also used as a flavouring in some natural toothpastes. The seeds are used in cookery and sweet desserts.

Many cultures in India, Pakistan, Afghanistan, Iran and the Middle East use fennel seed in their cookery. It is one of the most important spices in Kashmiri Pandit and Gujarati cooking. It is an essential ingredient of the Assamese/Bengali/Oriya spice mixture panch phoron and in Chinese five-spice powders. In many parts of India and Pakistan, roasted fennel seeds are consumed as mukhwas, an after-meal digestive and breath freshener. Fennel leaves are used as leafy green vegetables either by themselves or mixed with other vegetables, cooked to be served and consumed as part of a meal, in some parts of India. In Syria and Lebanon, it is used to make a special kind of egg omelette (along with onions, and flour) called ijjeh.

Many egg, fish, and other dishes employ fresh or dried fennel leaves. Florence fennel is a key ingredient in some Italian and German salads, often tossed with chicory and avocado, or it can be braised and served as a warm side dish. It may be blanched or marinated, or cooked in risotto.

In Spain the stems of the fennel plant are used in the preparation of pickled eggplants, “berenjenas de Almagro”.

Medicinal uses

Fennel (Foeniculum vulgare) essential oil in clear glass vial

Fennel contains anethole, which can explain some of its medical effects: It, or its polymers, act as phytoestrogens.

The essence of fennel can be used as a safe and effective herbal drug for primary dysmenorrhea, but could have lower potency than mefenamic acid at the current study level.

Intestinal tract

Fennel is widely employed as a carminative, both in humans and in veterinary medicine (e.g., dogs), to treat flatulence by encouraging the expulsion of intestinal gas. Anethole is responsible for the carminative action.

Mrs. Eencher Herbal states:

On account of its carminative properties, fennel is chiefly used medicinally with purgatives to allay their side effects, and for this purpose forms one of the ingredients of the well-known compound liquorice powder. Fennel water has properties similar to those of anise and dill water: mixed with sodium bicarbonate and syrup, these waters constitute the domestic ‘gripe water‘ used to correct the flatulence of infants. Volatile oil of fennel has these properties in concentration. Commercial preparations of fennel  are widely available as alternative treatment for baby colic. Fennel tea, also employed as a carminative, is made by pouring boiling water on a teaspoonful of bruised fennel seeds.

Fennel can be made into a syrup to treat babies with colic (formerly thought to be due to digestive upset), but long-term ingestion of fennel preparations by babies is a known cause of thelarche.

Eyes

In the Indian subcontinent, fennel seeds are also eaten raw, sometimes with some sweetener, as they are said to improve eyesight. Ancient Romans regarded fennel as the herb of sight.Root extracts were often used in tonics to clear cloudy eyes. Extracts of fennel seed have been shown in animal studies to have a potential use in the treatment of glaucoma.

Blood and urine

Fennel may be an effective diuretic and a potential drug for treatment of hypertension.

Breastmilk

There are historical anecdotes that fennel is a galactagogue,improving the milk supply of a breastfeeding mother. This use, although not supported by direct evidence, is sometimes justified by the fact that fennel is a source of phytoestrogens, which promote growth of breast tissue. However, normal lactation does not involve growth of breast tissue. A single case report of fennel tea ingested by a breastfeeding mother resulted in neurotoxicity for the newborn child.

Other uses

Syrup prepared from fennel juice was formerly given for chronic coughs. It is one of the plants which is said to be disliked by fleas, and powdered fennel has the effect of driving away fleas from kennels and stables.

References

  • “Herbs That Work: The Scientific Evidence of Their Healing Powers”; David Armstrong
  • “The Encyclopedia of Herbs: A Comprehensive Reference to Herbs of Flavor and Fragrance”; Arthur O. Tucker and Thomas DeBaggio; 2009
  • “Pocket Guide to Herbal Remedies”; Lane P. Johnson; 2002
  • “Encyclopedia of Natural Medicine”; Michael Murray and Joseph Pizzorno; 1997

seeds

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African medicine-cyclotides as an aid during child birth

African medicine-cyclotides as an aid during child birth

 

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

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

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

Read more

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

more info on cyclotides

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

References

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

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

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

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

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

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

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

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

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

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

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

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

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

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Tribulus terrestris-considered as an energizer and vitalizer in the indigenous system of medicine

Tribulus terrestris-considered as an energizer and vitalizer in the indigenous system of medicine

Tribulus terrestris

Tribulus terrestris is a flowering plant in the family Zygophyllaceae, native to warm temperate and tropical regions of the Old World in southern Europe, southern Asia, throughout Africa, and Australia. It can thrive even in desert climates and poor soil. Like many weedy species, this plant has many common names, including bindiibullheadburra gokharucaltropcat’s headdevil’s eyelashesdevil’s thorndevil’s weedgoatheadpuncturevine, and tackweed.

In traditional Chinese medicine Tribulus terrestris is known under the name bai ji li (白蒺藜). According to Bensky and Clavey, 2004 (Materia medica 3rd edition, pp. 975–976) Tribulus terrestris is ci ji li (刺蒺藜). “Confusion with Astragali complanati Semen (sha yuan zi) originally known as white ji li (白蒺藜 bai ji li), led some writers to attribute tonifying properties to this herb…”

T. terrestris has long been a constituent in tonics in Indian Ayurveda practice, where it is known by its Sanskrit name, “gokshura/ sarrata” It is also used in Unani, another medical system of India.

Apart from its claims for improvement of sexual functions in men, the puncturevine plant (Tribulus terrestris: TT) has long been considered as an energizer and vitalizer in the indigenous system of medicine. Sexual behavior and intracavernous pressure (ICP) measurements were taken in rats to scientifically validate the claim of TT [containing protodioscin (PTN)] as an aphrodisiac.

http://www.ncbi.nlm.nih.gov/pubmed/12804079

Tribulus has chemicals that might increase some hormones in animals. However, it doesn’t appear to increase male hormones (testosterone) in humans.

Chemical control is generally recommended for home control of T. terrestris. There are few pre-emergent herbicides that are effective. Products containing oryzalinbenefin, or trifluralin will provide partial control of germinating seeds. These must be applied prior to germination (late winter to midspring).

After plants have emerged from the soil (postemergent), products containing 2,4-dichlorophenoxyacetic acid (“2,4-D”), glyphosate, anddicamba are effective on T. terrestris. Like most postemergents, they are more effectively maintained when caught small and young. Dicamba and 2,4-D will cause harm to most broad-leaved plants, so the user should take care to avoid over-application. They can be applied to lawns without injuring the desired grass. Glyphosate will kill or injure most plants, so it should only be used as a spot treatment or on solid stands of the weed.

Simmer 500 mg of powered tribulus in organic milk or almond milk, stirring constantly for 5 minutes. You can add 500 mg of standardized maca to enhance the effect. This blend is particularly nourishing and is recommended for both men and women who have lowered libido

Tribulus is a plant that produces fruit covered with spines. Rumor has it that tribulus is also known as puncture vine because the spines are so sharp they can flatten bicycle tires. People use the fruit, leaf, and root as medicine for wide-ranging complaints.

Tribulus is used for kidney problems, including kidney stones, painful urination, a kidney disorder called Bright’s disease, and as a “water pill” (diuretic) to increase urination; for skin disorders, including eczema (atopic dermatitis), psoriasis, andscabies; for male sexual problems, including erectile dysfunction (ED), involuntary release of semen without orgasm (spermatorrhea), and to increase sexual desire; for heart and circulatory system problems, including chest pain, high blood pressure,high cholesterol, and “tired blood” (anemia); for problems with digestion, including colic, intestinal gas (flatulence), constipation, and to expel intestinal parasitic worms; for pain and swelling (inflammation) of the tissue lining the mouth (stomatitis) andsore throat; and for cancer, especially nose tumors.

Women use tribulus to tone muscles before childbirth, to cause an abortion, and to stimulate milk flow.

Some people use tribulus for gonorrhea, liver disease (hepatitis), inflammation, joint pain (rheumatism), leprosy, coughs, headache, dizziness (vertigo), chronic fatiguesyndrome (CFS), and enhancing athletic performance. It is also used for stimulating appetite and as an astringent, tonic, and mood enhancer.

recap

Tribulus terrestris, also known as puncture vine, is a herb that has been used in the traditional medicine of China and India for centuries.

In the mid-1990s, tribulus terrestris became known in North America after Eastern European Olympic athletes said that taking tribulus helped their performance.

The active compounds in tribulus are called steroidal saponins. Two types, called furostanol glycosides and spirostanol glycosides, appear to be involved with the effects of tribulus. These saponins are found primarily in the leaf.

Why Do People Use Tribulus?

Tribulus is most often used for infertility, erectile dysfunction, and low libido. In the last decade, it has become popular to improve sports performance.

Tribulus has been marketed these conditions because research performed in Bulgaria and Russia indicates that tribulus increases levels of the hormones testosterone (by increasing luteinizing hormone), DHEA, and estrogen. The design of these research studies, however, has been questioned.

A more recent study found that four weeks of tribulus supplements (at 10 to 20 milligrams per kg of body weight daily) had no effect on male sex hormones testosterone, androstenedione, or luteinizing hormone compared to people who did not take tribulus.

1) Erectile Dysfunction

Preliminary animal studies found that tribulus heightened sexual behavior and increased intracavernous pressure. This was attributed to increases in testosterone. There haven’t been any well-designed human studies to confirm these early findings.

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Rare Undersea Discovery Could Extend Your Life by 10, 20 or 30 Years

Rare Undersea Discovery Could Extend Your Life by 10, 20 or 30 Years

 

Rare Undersea Discovery Could Extend Your Life by 10, 20 or 30 Years

Scientists are claiming that they have now isolated unusual ingredients in a rare seaweed discovered by fishermen off the coast of Korea that offer incredible health benefits—including the ability to restore blood pressure to normal levels.

The first is Seanol, an extremely rare seaweed extract from Ecklonia Cava that’s proven to be 100 times more powerful than any land-based antioxidant. That’s because it stays working in your body for 12 hours, compared to land-based antioxidants that work for 30 minutes.

“Its secret is its make-up of special polyphenol antioxidants that are a whopping 40% lipid (fat) soluble,” Dr. Lee explains. “Unlike nearly all land-based antioxidants that are water soluble, Seanol’s protective compounds can get into things like the fatty tissues of your brain and penetrate all three layers of your cells, including the outside, the oil-based cell membranes, and your DNA.”

Indeed, Seanol is so powerful, it’s the only FDA-approved Ecklonia Cava marine-algae extract in existence.

The second ingredient is Calamarine, a deep-sea omega-3 discovery that delivers 85% more DHA omega-3s to your heart, brain, joints, and eyes. It’s known to combat everything from fatigue and poor memory, to vision problems, joint pain, mood swings and depression.

http://www.howlifeworks.com/Article.aspx?Cat_URL=health_beauty&AG_URL=Rare_Undersea_Discovery_

Could_Extend_Your_Life_by_10_20_or_30_Years_524&ag_id=1358&wid=DA841499-A4E6-48CA-8C7C-FDD450A22F94&did=4159&cid=1005&si_id=1718

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

Ecklonia cava is an edible marine brown alga species found in the ocean off Japan andKorea.

It is used as a herbal remedy in the form of an extract called Seanol, a polyphenolic extract. Another phlorotannin-rich natural agent, Ventol, is also extracted from E. cava.[1]

Phlorotannins, such as fucodiphlorethol G,[2] 7-phloro eckol6,6′-bieckol,[3] eckol8,8′-bieckol8,4″‘-dieckol and phlorofucofuroeckol A can be isolated from Ecklonia cava.[4]

Other components are common sterol derivatives (fucosterolergosterol and cholesterol).[3]

A brownish colored seaweed, Ecklonia Cava, is the base of Seanol trademarked food supplement

 A brownish colored seaweed, Ecklonia Cava
  1.  Kang, K.; Hwang, H. J.; Hong, D. H.; Park, Y.; Kim, S. H.; Lee, B. H.; Shin, H. C. (2004). “Antioxidant and antiinflammatory activities of ventol, a phlorotannin-rich natural agent derived from Ecklonia cava, and its effect on proteoglycan degradation in cartilage explant culture”. Research communications in molecular pathology and pharmacology. 115-116: 77–95. PMID 17564307.
  2.  Isolation of a New Phlorotannin, Fucodiphlorethol G, from a Brown Alga Ecklonia cava. Young Min Ham, Jong Seok Baik, Jin Won Hyun and Nam Ho Lee, Bull. Korean Chem. Soc. 2007, Vol. 28, No. 9 1595
  3.  Li, Y.; Qian, Z. J.; Ryu, B.; Lee, S. H.; Kim, M. M.; Kim, S. K. (2009). “Chemical components and its antioxidant properties in vitro: An edible marine brown alga, Ecklonia cava”. Bioorganic & Medicinal Chemistry 17 (5): 1963–1973.doi:10.1016/j.bmc.2009.01.031PMID 19201199.
  4. Ahn, M. J.; Yoon, K. D.; Min, S. Y.; Lee, J. S.; Kim, J. H.; Kim, T. G.; Kim, S. H.; Kim, N. G. et al. (2004). “Inhibition of HIV-1 reverse transcriptase and protease by phlorotannins from the brown alga Ecklonia cava”. Biological & pharmaceutical bulletin 27 (4): 544–547.PMID 15056863.

…………………………………………………………………………………………….

Calamarine is new super DHA

One of the myths associated with aging is that your body wears out and there is nothing we can do about it. As we get older, we just have to live with chronic disease and the only way to improve the quality of our health and life is to treat the symptoms.

Overwhelmingly, research suggests that this is simply not true. In fact, the American Journal of Clinical Nutrition and Circulation provide documented evidence that consumption of Omega-3 fatty acids from dietary sources and supplements cut the likelihood of an early death.DHA and EPA not only prevent heart disease and sudden death from a sudden heart attack, they lower the risk…

http://www.marined3.com/Omega.html

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Glenmark conferred with Best Biotech New Molecular Entity Patent award

GLENMARK PHARMA

IDMA best biotech NEW MOLECULAR ENTITY patent award to Glenmark

YEAR 2012-2013 YEAR in Mumbai India

PATENT  US 8236315

GLENMARK PHARMACEUTICALS, S.A., SWITZERLAND

INVENTORS

Elias LazaridesCatherine WoodsXiaomin FanSamuel HouHarald MottlStanislas BleinMartin BertschingerALSO PUBLISHED ASCA2712221A1CN101932606A,EP2245069A1US20090232804,WO2009093138A1

Publication number US8236315 B2
Publication type Grant
Application number US 12/358,682
Publication date 7 Aug 2012
Filing date 23 Jan 2009
Priority date 23 Jan 2008

USPTOUSPTO AssignmentEspacenetUS 8236315

The present disclosure relates generally to humanized antibodies or binding fragments thereof specific for human von Willebrand factor (vWF), methods for their preparation and use, including methods for treating vWF mediated diseases or disorders. The humanized antibodies or binding fragments thereof specific for human vWF may comprise complementarity determining regions (CDRs) from a non-human antibody (e.g., mouse CDRs) and human framework regions.

The present disclosure provides a humanized antibody or binding fragment thereof specific for vWF that comprises a heavy chain variable region sequence as set forth in SEQ ID NO: 19 and a light chain variable region sequence as set forth in SEQ ID NO: 28 ……….. CONT

MR GLEN SALDANHA

MD , CEO GLENMARK

INDIAN DRUG MANUFACTURERS’ ASSOCIATION   (IDMA)

102-B Poonam Chambers, Dr A B Road, Worli, Mumbai 400 018, INDIA
Tel : +91 – 22 – 24944625 / 24974308. Fax : ++91 – 22 – 24957023
email: ppr@idmaindia.com website : www.idma-assn.org

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Role of plants in anticancer drug discovery

Full-size image (23 K)

Role of plants in anticancer drug discovery

Volume 7, February 2014, Pages 173–181

  • a Department of Chemistry, University of Pretoria, Pretoria 0028, South Africa
  • b Centre for Microbial Ecology and Genomics, Department of Genetics, University of Pretoria, Pretoria 0028, South Africa

Highlights

Cancer is second deadly disease after cardiovascular diseases.

There is a tremendous need to discover novel safer and more effective anticancer agents.

Plants serve as a basis for promising therapeutic agents for cancer treatment.

Important plant derived anticancer agents have been discussed here.

Some potential plant derived lead molecules have also been discussed.

 


Abstract

Cancer is one of the major causes of death and the number of new cases, as well as the number of individuals living with cancer, is expanding continuously. Worldwide the alarming rise in mortality rate due to cancer has fuelled the pursuit for effective anticancer agents to combat this disease. Finding novel and efficient compounds of natural origin has been a major point of concern for research in the pharmaceutical sciences. Plants have been seen to possess the potential to be excellent lead structures and to serve as a basis of promising therapeutic agents for cancer treatment. Many successful anti-cancer drugs currently in use or their analogues are plant derived and many more are under clinical trials. This review aims to highlight the invaluable role that plants have played, and continue to play, in the discovery of anticancer agents.

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TEDIZOLID torezolid

TEDIZOLID PHOSPHATE

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

DA 7157

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

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

MOLECULAR FORMULA C17H16FN6O6P

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

……………………………..

ChemSpider 2D Image | Torezolid | C17H15FN6O3

Tedizolid, 856866-72-3

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

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

TR 700

  • Molecular Formula: C17H15FN6O3
  • Average mass: 370.337799

 

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

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

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

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

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

…………………………………………………….

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

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

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

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

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

Figure US20100305069A1-20101202-C00012

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

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

Figure US08426389-20130423-C00001

wherein R═H, PO(OH)2, and PO(ONa)2.

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

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

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

…………………………………………………………..

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

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

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

…………………………………………..

imp patents

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

…………………………………………..

TEDIZOLID disodium salt

59 nos in

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

Figure US20130102523A1-20130425-C00064

Figure US20130102523A1-20130425-C0004338 nos

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

Figure US20130102523A1-20130425-C00083

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

Figure US20130102523A1-20130425-C00084

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

Figure US20130102523A1-20130425-C00085
…………………………………………………………………………………………………………………………………………………………….

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

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

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

Figure US20100305069A1-20101202-C00016disodium salt is TR 701

……………………………………

US8580767

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

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

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

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

SYNTHESIS

US20070155798

Figure US20070155798A1-20070705-C00077

DESCRIPTION OF COMPDS

10,

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

Figure US20070155798A1-20070705-C00013

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

18

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

Figure US20070155798A1-20070705-C00013

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

33

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

Figure US20070155798A1-20070705-C00013

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

59

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

Figure US20070155798A1-20070705-C00062

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

72

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

Figure US20070155798A1-20070705-C00075

COMPLETE SYNTHESIS

Example 5

Preparation of 2-cyano-5-bromopyridine

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

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

Example 6

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

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

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

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

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

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

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

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

Example 1

Preparation of N-Carbobenzyloxy-3-fluoroaniline

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

Example 2

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

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

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

Example 3

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

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

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

Example 4

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

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

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

COMPD 10

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

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

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

COMPD 18

Figure US20070155798A1-20070705-C00013

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

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

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

COMPD 33

Figure US20070155798A1-20070705-C00013

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

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

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

COMPD 59

Figure US20070155798A1-20070705-C00062

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

1. The Primary Step

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

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

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

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

COMPD 72

Figure US20070155798A1-20070705-C00075

The Secondary Step

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

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

US20070155798

………………………………………………………

IMPURITIES

US8426389

Organic Impurities in TR-701 FA Drug Substance
Impurity
‘Name’ Structure and Chemical Name
Rx600013 ‘Des-methyl TR- 701’ Figure US08426389-20130423-C00010
dihydrogen ((5R)-3-{3-fluoro-4-[6-(2H-1,2,3,4-tetrazol-5-
yl)-3-pyridinyl]phenyl}-2-oxo-1,3-oxazolan-5-yl)methyl
phosphate
Rx600024 ‘Pyrophosphate’ Figure US08426389-20130423-C00011
trihydrogen ((5R)-3-{3-fluoro-4-[6-(1-methyl-1H-1,2,3,4-
tetraazol-5-yl)-3-pyridinyl]phenyl}-2-oxo-1,3-oxazolan-5-
yl)methyl pyrophosphate
Rx600014 ‘Ring opened’ Figure US08426389-20130423-C00012
dihydrogen 3-{3-fluoro-4-[6-(2-methyl-2H-1,2,3,4-tetraazol-5-
yl)-3-pyridinyl]aniline}-2-hydroxypropyl phosphate
Rx600023 ‘Me-isomer’ Figure US08426389-20130423-C00013
dihydrogen ((5R)-3-{3-fluoro-4-[6-(1-methyl-1H-1,2,3,4-
tetraazol-5-yl)-3-pyridinyl]phenyl}-2-oxo-1,3-oxazolan-5-
yl)methyl phosphate
Rx600025 ‘Overalkylated- phosphorylated impurity’
Figure US08426389-20130423-C00014
Figure US08426389-20130423-C00015
(R)-1-((3-(3-fluoro-4-(6-(2-methyl-2H-tetrazol-5-
yl)pyridin-3-yl)phenyl)-2-oxooxazolidin-5-yl)methoxy)-3-
hydroxypropan-2-yl dihydrogen phosphate;
(R)-3-((3-(3-fluoro-4-(6-(2-methyl-2H-tetrazol-5-
yl)pyridin-3-yl)phenyl)-2-oxooxazolidin-5-yl)methoxy)-2-
hydroxypropyl dihydrogen phosphate
Rx600020 ‘Dimer impurity’ Figure US08426389-20130423-C00016
dihydrogen bis-O-O′-[(5R)-3-{3-fluoro-4-[6-(2-methyl-
2H-1,2,3,4-tetrazol-5-yl)-3-pyridinyl]phenyl}-2-oxo-1,3-
oxazolidin-5-yl]methyl pyrophosphate
Rx600026 “Chloro” Figure US08426389-20130423-C00017
(R)-5-(chloromethyl)-3-(3-fluoro-4-(6-(2-methyl-2H-
tetrazol-5-yl)pyridin-3-yl)phenyl)oxazolidin-2-one
Rx600001 TR-700 Figure US08426389-20130423-C00018
5R)-3-{3-Fluoro-4-[6-(2-methyl-2H-1,2,3,4-tetrazol-5-yl)-
pyridin-3-yl]-phenyl}-5-hydroxymethyl-1,3-oxazolidin-2-one
Rx600022 ‘Bis phosphate’ Figure US08426389-20130423-C00019
hydrogen bis-O-O′-[(5R)-3-{3-fluoro-4-[6-(2-methyl-2H-1,2,3,4-
tetrazol-5-yl)-3-pyridinyl]phenyl}-2-oxo-1,3-oxazolidin-5-yl]methyl
phosphate
Rx600042 Figure US08426389-20130423-C00020
3-{[(5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridin-3-
yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl]methoxy}-2-hydroxypropyl
[(5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridin-3-
yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl]methyl hydrogen phosphate
Rx600043 Figure US08426389-20130423-C00021
2-{[(5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridin-3-
yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl]methoxy}-1-hydroxyethyl
[(5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridin-3-
yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl]methyl hydrogen phosphate

……………………………………………..

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………………………………………………………………………………………. art    animation

ANTHONY MELVIN CRASTO

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

GLENMARK SCIENTIST , NAVIMUMBAI, INDIA

did you feel happy, a head to toe paralysed man’s soul in action for you round the clock

need help, email or call me

MOBILE-+91 9323115463
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I was  paralysed in dec2007

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