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Defibrotide
Defibrotide sodium is an oligonucleotide mixture with profibrinolytic properties. The chemical name of defibrotide sodium is polydeoxyribonucleotide, sodium salt. Defibrotide sodium is a polydisperse mixture of predominantly single-stranded (ss) polydeoxyribonucleotide sodium salts derived from porcine intestinal tissue having a mean weighted molecular weight of 13-20 kDa, and a potency of 27-39 and 28-38 biological units per mg as determined by two separate assays measuring the release of a product formed by contact between defibrotide sodium, plasmin and a plasmin substrate. The primary structure of defibrotide sodium is shown below.
DEFITELIO (defibrotide sodium) injection is a clear, light yellow to brown, sterile, preservative-free solution in a single-patient-use vial for intravenous use. Each milliliter of the injection contains 80 mg of defibrotide sodium and 10 mg of Sodium Citrate, USP, in Water for Injection, USP. Hydrochloric Acid, NF, and/or Sodium Hydroxide, NF, may have been used to adjust pH to 6.8-7.8.
Defibrotide is the sodium salt of a mixture of single-stranded oligodeoxyribonucleotides derived from porcine mucosal DNA. It has been shown to have antithrombotic, anti-inflammatory and anti-ischemic properties (but without associated significant systemic anticoagulant effects). It is marketed under the brand names Dasovas (FM), Noravid, and Prociclide in a variety of countries, but is currently not approved in the USA. The manufacturer is Gentium.
Defibrotide is used to treat or prevent a failure of normal blood flow (occlusive venous disease, OVD) in the liver of patients who have had bone marrow transplants or received certain drugs such as oral estrogens, mercaptopurine, and many others.
In 2012, an IND was filed in Japan seeking approval of the compound for the treatment of veno-occlusive disease.
Approved 3/30/3016 US FDA, defibrotide sodium, (NDA) 208114
To treat adults and children who develop hepatic veno-occlusive disease with additional kidney or lung abnormalities after they receive a stem cell transplant from blood or bone marrow called hematopoietic stem cell transplantation
Polydeoxyribonucleotides from bovine lung or other mamalian organs with molecular weight between 15,000 and 30,000 Da
CAS 83712-60-1
Defibrotide is a polydisperse mixture of oligonucleotides produced by random, chemical cleavage (depolymerisation) of porcine DNA. It is predominantly single stranded, of varying base sequence, lengths and conformations; unfolded, folded or combined. The mean oligonucleotide length is 50 bases with a mean molecular weight of 17 ± 4 kDa. No individually defined component is at more than femtomolar concentration. The only meaningful scientific information that can be obtained about the biochemical nature of defibrotide (aside from determination of percentage of each nucleobase) is a measurement of its average length and its average percentage double stranded character. Therefore, it can be established that this active substance is of highly heterogenic nature.
Defibrotide (Defitelio, Gentium)[1] is a deoxyribonucleic acid derivative (single-stranded) derived from cow lung or porcine mucosa. It is an anticoagulant with a multiple mode of action (see below).
It has been used with antithrombin III.[2]
Jazz Pharmaceuticals plc announced that the FDA has accepted for filing with Priority Review its recently submitted New Drug Application (NDA) for defibrotide. AS ON OCT 2015
Defibrotide is an investigational agent proposed for the treatment of patients with hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), with evidence of multi-organ dysfunction (MOD) following hematopoietic stem-cell transplantation (HSCT).
Priority Review status is designated for drugs that may offer major advances in treatment or provide a treatment where no adequate therapy exists. Based on timelines established by the Prescription Drug User Fee Act (PDUFA), FDA review of the NDA is expected to be completed by March 31, 2016.
“The FDA’s acceptance for filing and Priority Review status of the NDA for defibrotide is an important milestone for Jazz and reflects our commitment to bringing meaningful medicines to patients who have significant unmet needs,” said Karen Smith, M.D., Ph.D., Global Head of Research and Development and Chief Medical Officer of Jazz Pharmaceuticals. “We look forward to continuing to work closely with the FDA to obtain approval for defibrotide for patients with hepatic VOD with evidence of MOD in the U.S. as quickly as possible, as there are no other approved therapies for treating this rare, often fatal complication of HSCT.”
The NDA includes safety and efficacy data from three clinical studies of defibrotide for the treatment of hepatic VOD with MOD following HSCT, as well as a retrospective review of registry data from the Center for International Blood and Marrow Transplant Research. The safety database includes over 900 patients exposed to defibrotide in the clinical development program for the treatment of hepatic VOD.
The compound was originally developed under a collaboration between Sanofi and Gentium. In December 2001, Gentium entered into a license and supply agreement with Sigma-Tau Pharmaceuticals, pursuant to which the latter gained exclusive rights to distribute, market and sell the product for the treatment of VOD in the U.S. This agreement was expanded in 2005 to include all of North America, Central America and South America.
Defibrotide was granted orphan drug designations from the FDA in July 1985, May 2003 and January 2007 for the treatment of thrombotic thrombocytopenic purpura (TTP), for the treatment of VOD and for the prevention of VOD, respectively. Orphan drug was also received in the E.U. for the prevention and treatment of hepatic veno-occlusive disease (VOD) in 2004 and for the prevention of graft versus host disease (GvHD) in 2013.
Pharmacokinetics
Defibrotide is available as an oral, intravenous, and intramuscular formulation. Its oral bioavailability is in the range of 58-70% of theparenteral forms. T1/2 alpha is in the range of minutes while T1/2 beta is in the range of hours in studies with oral radiolabelleddefibrotide. These data suggest that defibrotide, in spite of its macromolecular nature, is absorbed well after oral administration. Due to the drug’s short half-life, it is necessary to give the daily dose divided in 2 to 4 doses (see below).
In 2014, Jazz Pharmaceuticals (parent of Gentium) acquired the rights of the product in U.S. and in the Americas
Mode of action
The drug appears to prevent the formation of blood clots and to help dissolve blood clots by increasing levels of prostaglandin I2, E2, and prostacyclin, altering platelet activity, increasing tissue plasminogen activator (tPA-)function, and decreasing activity of tissue plasminogen activator inhibitor. Prostaglandin I2 relaxes the smooth muscle of blood vessels and prevents platelets from adhering to each other. Prostaglandin E2 at certain concentrations also inhibits platelet aggregation. Moreover, the drug provides additional beneficial anti-inflammatory and antiischemic activities as recent studies have shown. It is yet unclear, if the latter effects can be utilized clinically (e.g., treatment of ischemic stroke).
Unlike heparin and warfarin, defibrotide appears to have a relatively mild anticoagulant activity, which may be beneficial in the treatment of patients at high risk of bleeding complications. Nevertheless, patients with known bleeding disorders (e.g., hemophilia A) or recent abnormal bleedings should be treated cautiously and under close medical supervision.
The drug was marketed under the brand names Dasovas (FM), Noravid, and Prociclide in a variety of countries. It is currently not approved in the USA. The manufacturer is Gentium.
Defibrotide also received fast track designation from the FDA for the treatment of severe VOD in recipients of stem cell transplants. In 2011, the compound was licensed to Medison Pharma by Gentium in Israel and Palestine. The license covers the management of named-patient sales program and local registration, authorization, marketing, reimbursement and medical affairs for the treatment of peripheral vascular disease.
Usual indications
Defibrotide is used to treat or prevent a failure of normal blood flow (Veno-occlusive disease, VOD) in the liver of patients having had bone marrow transplants or received certain drugs such as oral estrogens, mercaptopurine, and many others. Without intensive treatment, VOD is often a fatal condition, leading to multiorgan failure. It has repeatedly been reported that defibrotide was able to resolve the condition completely and was well tolerated.
Other indications are: peripheral obliterative arterial disease, thrombophlebitis, and Raynaud’s phenomenon. In very high doses, defibrotide is useful as treatment of acute myocardial infarction. The drug may also be used for the pre- and postoperative prophylaxis of deep venous thrombosis and can replace the heparin use during hemodialytic treatments.
It has been investigated for use in treatment of chronic venous insufficiency.[3]
Potential indications in the future
Other recent preclinical studies have demonstrated that defibrotide used in conjunction with Granulocyte Colony-Stimulating Factor (rhG-CSF) significantly increases the number of Peripheral Blood Progenitor Cells (Stem cells). The benefit of this increase in stem cells may be crucial for a variety of clinical indications, including graft engineering procedures and gene therapy programs. This would expand the clinical usefulness of defibrotide to a complete distinct area.
Very recently (since early 2006) combination therapy trials (phase I/II) with defibrotide plus melphalan, prednisone, and thalidomide in patients with multiple myeloma have been conducted. The addition of defibrotide is expected to decrease the myelosuppressive toxicity of melphalan. However, is too early for any definitive results at that stage.
Cautions and contraindications
- The efficacy of the drug has been reported to be poorer in patients with diabetes mellitus.
- Pregnancy: The drug should not be used during pregnancy, because adequate and well controlled human studies do not exist.
- Lactation: No human data is available. In order to avoid damage to the newborn, the nursing mother should discontinue either the drug or breastfeeding, taking into account the importance of treatment to the mother.
- Known Bleeding Disorders or Bleeding Tendencies having occurred recently: Defibrotide should be used cautiously. Before initiation of treatment, the usual coagulation values should be obtained as baseline and regularly controlled under treatment. The patient should be observed regularly regarding local or systemic bleeding events.
Side-effects
Increased bleeding and bruising tendency, irritation at the injection site, nausea, vomiting, heartburn, low blood pressure. Serious allergic reactions have not been observed so far.
Drug interactions
Use of heparin with defibrotide may increase the aPTT, reflecting reduced ability of the body to form a clot. Nothing is known about the concomitant application of other anticoagulants than heparin and dextran containing plasma-expanders, but it can be anticipated that the risk of serious bleeding will be increased considerably.
PATENT
WO 2001078761
G-CSF (CAS registry number 143011-2-7/Merck Index, 1996, page 4558) is a haematopoietic growth factor which is indispensable in the proliferation and differentiation of the progenitor cells of granulocytes; it is a 18-22 kDa glycoprotein normally produced in response to specific stimulation by a variety of cells, including monocytes, fibroblasts and endothelial cells. The term defibrotide (CAS registry number 83712-60-1) normally identifies a polydeoxyribonucleotide obtained by extraction (US 3,770,720 and US 3,899,481) from animal and/or vegetable tissue; this polydeoxyribonucleotide is normally used in the form of a salt of an alkali metal, generally sodium. Defibrotide is used principally for its anti- thrombotic activity (US 3,829,567) although it may be used in different applications, such as, for example, the treatment of acute renal insufficiency (US 4,694,134) and the treatment of acute myocardial ischaemia (US 4,693,995). United States patents US 4,985,552 and US 5,223,609, finally, describe a process for the production of defibrotide which enables a product to be obtained which has constant and well defined physico-chemical characteristics and is also free from any undesired side-effects
References
- “Jazz Pharma Acquiring Gentium for $1B”. Gen. Eng. Biotechnol. News (paper) 34 (2). January 15, 2014. p. 10.
- Haussmann U, Fischer J, Eber S, Scherer F, Seger R, Gungor T (June 2006). “Hepatic veno-occlusive disease in pediatric stem cell transplantation: impact of pre-emptive antithrombin III replacement and combined antithrombin III/defibrotide therapy”. Haematologica 91 (6): 795–800. PMID 16769582.
- Coccheri S, Andreozzi GM, D’Addato M, Gensini GF (June 2004). “Effects of defibrotide in patients with chronic deep insufficiency. The PROVEDIS study”. Int Angiol 23 (2): 100–7.PMID 15507885.
External links
- Palmer KJ, Goa KL. Defibrotide: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in vascular disorders. Drugs 1993;45:259-94.
- http://www.globalrx.com/medinfo/Defibrotide.htm
- Fisher J, Holland TK, Pescador R, Porta R, Ferro L (January 1996). “Study on pharmacokinetics of radioactive labelled defibrotide after oral or intravenous administration in rats”. Thromb. Res. 81 (1): 55–63. doi:10.1016/0049-3848(95)00213-8. PMID 8747520.
- http://www.gentium.it/Defibrotide.aspx (information provided by manufacturer)
- “Melphalan: profile and news”. Archived from the original on 2007-09-28. (on cytostatic combination therapy)
- Beşişik SK, Oztürk GB, Calişkan Y, Sargin D (March 2005). “Complete resolution of transplantation-associated thrombotic microangiopathy and hepatic veno-occlusive disease by defibrotide and plasma exchange”. Turk J Gastroenterol 16 (1): 34–7. PMID 16252186.
| WO2003101468A1 * | Jun 2, 2003 | Dec 11, 2003 | Guenther Eissner | Method for the protection of endothelial and epithelial cells during chemotherapy |
| US4985552 | Jul 5, 1989 | Jan 15, 1991 | Crinos Industria Farmacobiologica S.P.A. | Process for obtaining chemically defined and reproducible polydeoxyribonucleotides |
| US5223609 | May 26, 1992 | Jun 29, 1993 | Crinos Industria Farmacobiologica S.P.A. | Process for obtaining chemically defined and reproducible polydeoxyribonucleotides |
| Cited Patent | Filing date | Publication date | Applicant | Title |
|---|---|---|---|---|
| WO1999026639A1 * | 24 Nov 1998 | 3 Jun 1999 | Allegheny University Of The He | Methods for mobilizing hematopoietic facilitating cells and hematopoietic stem cells into the peripheral blood |
| EP0317766A1 * | 20 Oct 1988 | 31 May 1989 | Crinos Industria Farmacobiologica S.p.A. | A method for preventing blood coaguli from being formed in the extra-body circuit of dialysis apparatus and composition useful thereof |
| EP0416678A1 * | 10 Aug 1990 | 13 Mar 1991 | Crinos Industria Farmacobiologica S.p.A. | Topical compositions containing Defibrotide |
| US5199942 * | 26 Sep 1991 | 6 Apr 1993 | Immunex Corporation | Method for improving autologous transplantation |
| US5977083 * | 5 Jun 1995 | 2 Nov 1999 | Burcoglu; Arsinur | Method for using polynucleotides, oligonucleotides and derivatives thereof to treat various disease states |
| Reference | ||
|---|---|---|
| 1 | * | CARLO-STELLA, C. (1) ET AL: “Defibrotide significantly enhances peripheral blood progenitor cell mobilization induced by recombinant human granulocyte colony – stimulating factor ( rhG – CSF.” BLOOD, ( NOVEMBER 16, 2000 ) VOL. 96, NO. 11 PART 1, PP. 553A. PRINT. MEETING INFO.: 42ND ANNUAL MEETING OF THE AMERICAN SOCIETY OF HEMATOLOGY SAN FRANCISCO, CALIFORNIA, USA DECEMBER 01-05, 2000 AMERICAN SOCIETY OF HEMATOLOGY. , XP002176349 |
| 2 | * | GURSOY A: “PREPARATION, CHARACTERIZATION AND ANTI-INFLAMMATORY EFFECT OF DEFIBROTIDE LIPOSOMES” PHARMAZIE,DD,VEB VERLAG VOLK UND GESUNDHEIT. BERLIN, vol. 48, no. 7, 1 July 1993 (1993-07-01), pages 549-550, XP000372658 ISSN: 0031-7144 |
| Citing Patent | Filing date | Publication date | Applicant | Title |
|---|---|---|---|---|
| WO2005017160A2 * | 12 Aug 2004 | 24 Feb 2005 | Childrens Hosp Medical Center | Mobilization of hematopoietic cells |
| WO2009115465A1 * | 13 Mar 2009 | 24 Sep 2009 | Gentium Spa | Synthetic phosphodiester oligonucleotides and therapeutical uses thereof |
| EP2103689A1 * | 19 Mar 2008 | 23 Sep 2009 | Gentium S.p.A. | Synthetic phosphodiester oligonucleotides and therapeutical uses thereof |
| US7417026 | 12 Aug 2004 | 26 Aug 2008 | Children’s Hospital Medical Center | Mobilization of hematopoietic cells |
| US7915384 | 5 Jan 2009 | 29 Mar 2011 | Children’s Hospital Medical Center | Chimeric peptides for the regulation of GTPases |
| US8242246 | 28 Feb 2011 | 14 Aug 2012 | Children’s Hospital Medical Center | Chimeric peptides for the regulation of GTPases |
| US8674075 | 13 Aug 2012 | 18 Mar 2014 | Children’s Medical Center Corporation | Chimeric peptides for the regulation of GTPases |
| US8980862 | 12 Nov 2010 | 17 Mar 2015 | Gentium S.P.A. | Defibrotide for use in prophylaxis and/or treatment of Graft versus Host Disease (GVHD) |
| Clinical data | |
|---|---|
| AHFS/Drugs.com | International Drug Names |
| Pregnancy category |
|
| Legal status |
|
| Routes of administration |
oral, i.m., i.v. |
| Pharmacokinetic data | |
| Bioavailability | 58 – 70% orally (i.v. and i.m. = 100%) |
| Biological half-life | t1/2-alpha = minutes; t1/2-beta = a few hours |
| Identifiers | |
| CAS Registry Number | 83712-60-1  |
| ATC code | B01AX01 |
| DrugBank | DB04932 |
| UNII | 438HCF2X0M |
| KEGG | D07423 |
///////////Approved, 3/30/3016, US FDA, defibrotide sodium, NDA 208114, FDA 2016
Updates……….
FDA approves first treatment for rare disease in patients who receive stem cell transplant from blood or bone marrow
For Immediate Release
March 30, 2016
Release
The U.S. Food and Drug Administration today approved Defitelio (defibrotide sodium) to treat adults and children who develop hepatic veno-occlusive disease (VOD) with additional kidney or lung abnormalities after they receive a stem cell transplant from blood or bone marrow called hematopoietic stem cell transplantation (HSCT). This is the first FDA-approved therapy for treatment of severe hepatic VOD, a rare and life-threatening liver condition.
HSCT is a procedure performed in some patients to treat certain blood or bone marrow cancers. Immediately before an HSCT procedure, a patient receives chemotherapy. Hepatic VOD can occur in patients who receive chemotherapy and HSCT. Hepatic VOD is a condition in which some of the veins in the liver become blocked, causing swelling and a decrease in blood flow inside the liver, which may lead to liver damage. In the most severe form of hepatic VOD, the patient may also develop failure of the kidneys and lungs. Fewer than 2 percent of patients develop severe hepatic VOD after HSCT, but as many as 80 percent of patients who develop severe hepatic VOD do not survive.
“The approval of Defitelio fills a significant need in the transplantation community to treat this rare but frequently fatal complication in patients who receive chemotherapy and HSCT,” said Richard Pazdur, M.D., director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research.
The efficacy of Defitelio was investigated in 528 patients treated in three studies: two prospective clinical trials and an expanded access study. The patients enrolled in all three studies had a diagnosis of hepatic VOD with liver or kidney abnormalities after HSCT. The studies measured the percentage of patients who were still alive 100 days after HSCT (overall survival). In the three studies, 38 to 45 percent of patients treated with Defitelio were alive 100 days after HSCT. Based on published reports and analyses of patient-level data, the expected survival rates 100 days after HSCT would be 21 to 31 percent for patients with severe hepatic VOD who received only supportive care or interventions other than Defitelio.
The most common side effects of Defitelio include abnormally low blood pressure (hypotension), diarrhea, vomiting, nausea and nosebleeds (epistaxis). Serious potential side effects of Defitelio that were identified include bleeding (hemorrhage) and allergic reactions. Defitelio should not be used in patients who are having bleeding complications or who are taking blood thinners or other medicines that reduce the body’s ability to form clots.
The FDA granted the Defitelio application priority review status, which facilitates and expedites the development and review of certain drugs in light of their potential to benefit patients with serious or life-threatening conditions. Defitelio also received orphan drug designation, which provides incentives such as tax credits, user fee waivers and eligibility for exclusivity to assist and encourage the development of drugs for rare diseases.
Defitelio is marketed by Jazz Pharmaceuticals based in Palo Alto, California
Efficacy and Safety of Olive in the Management of Hyperglycemia
Postprandial hyperglycemia indicates the abnormality in glucose turnover leading to the onset of type 2 diabetes. Therefore, correction of postprandial hyperglycemia is crucial in the early stage of diabetes therapy. One of the most effective strategies to control postprandial hyperglycemia is medication combined with intake restriction and an exercise program. However, along with the prevalence of chronic diseases with multi-pathogenic factor, drugs with single chemical composition are usually not effective. In this view, phytotherapy has a promising future in the management of diabetes, considered to have less side effects as compared to synthetic drugs.
The World Health Organization estimates that in developing countries about 80% of the population now still depend on herbal treatment. Olive (Olea europea) (OE) has been used in traditional remedies in Europe and Mediterranean countries as a food and medicine for over 5,000 years especially for the prevention and treatment of chronic diseases such as hypertension, atherosclerosis , cancer and diabetes. In addition, olive is considered as the most important component of the Mediterranean diet with many health benefits.
Several experimental studies have demonstrated the beneficial effect of OE on diabetes. This effect has been demonstrated in the animal models such as streptozotocin-induced diabetic rats, alloxaninduced diabetic rats and obese diabetic sand rats fed a hypercaloric diet. In these models olive extracts have been shown to exhibit a significant reduction on both blood glucose and insulin levels. Few randomized clinical trials have demonstrated the beneficial effect of olive and one study has shown that the subjects treated with olive leaf extract exhibited significantly lower Glycated hemoglobin (HbA1c) and fasting plasma insulin levels.
Another study performed in recent onset type 2 diabetic patients has revealed that OE leaves exhibited antidiabetic activity when it added as a mixture of extract of leaves of Juglans regia, Urtica dioica and Atriplex halimus. The underlying mechanism seems to be the improvement of glucose uptake and no side effect was reported while extracts from OE have been found to exhibit cytotoxic effects only at concentrations higher than 500 μg/ mL in cells from the liver hepatocellular carcinoma cell line (HepG2) and cells from the rat L6 muscle cell line. As far as the phytochemical analysis is concerned, it is now well-established that major fatty acid constituents and minor phenolic components in olives and olive oil exert important health benefits particularly for cardiovascular diseases, metabolic syndrome and inflammatory conditions.
Hydroxytyrosol and oleuropein are considered as major polyphenolic compounds in olive leaf. Oleuropeoside, a phenylethanoid isolated from OE demonstrated a significant hypoglycemic activity in alloxan-induced diabetes and the hypoglycemic activity of this compound may result from both the increased peripheral uptake of glucose and potentiation of glucose-induced insulin secretion. In addition, Maslinic acid (MA), a natural triterpene from OE with hypoglycemic activity is a wellknown inhibitor of glycogen phosphorylase in diabetic rats without affecting hematological, histopathologic and biochemical variables, thus suggesting a sufficient margin of safety for its putative use as a nutraceutical. More recently a study has showed that MA exerts antidiabetic effects by increasing glycogen content and inhibiting glycogen phosphorylase activity in HepG2 cells.
Furthermore, MA was shown to induce the phosphorylation level of insulin-receptor β-subunit, protein kinase B (Akt) and glycogen synthase kinase-3β. MA treatment of mice fed with a high-fat diet reduced the model-associated adiposity, mRNA expression of proinflammatory cytokines and then insulin resistance, and increased the accumulated hepatic glycogen.
Finally, a recent clinical study has revealed that supplementation with olive leaf polyphenols significantly improved insulin sensitivity and pancreatic β-cell secretory capacity in overweight middle-aged men at risk of developing the metabolic syndrome. In conclusion, OE has been and continue to represent a natural source of phytocompounds eliciting a beneficial effect in human health especially in the management of hyperglycemia [1–15].
- Bennani-Kabchi N Fdhil H,Cherrah Y,El Bouayadi F,Kehel L,et al.(2000) Therapeutic effect ofOleaeuropeavar. oleaster leaves on carbohydrate and lipid metabolism in obese and prediabetic sand rats (Psammomysobesus).Ann Pharm Fr 58: 271-7.
- Said O,Fulder S, Khalil K,Azaizeh H, Kassis E, et al. (2008) Maintaining a physiological blood glucose level with ‘glucolevel’, a combination of four anti-diabetesplants used in the traditional arab herbal medicine. Evid Based Complement Alternat Med 5:421-8.
- Bouallagui Z,Han J,Isoda H,Sayadi S. Hydroxytyrosol rich extract from olive leaves modulates cell cycle progression in MCF-7 human breast cancer cells (2011) Food ChemToxicol 49:179-84.
- Nan JN,Ververis K ,Bollu S,Rodd AL,Swarup O,et al. (2014) Biological effects of the olive polyphenol, hydroxytyrosol: An extra view from genome-wide transcriptome analysis.Hell J Nucl Med 17: 62-9.
- Guan T, Qian Y, Tang X, Huang M, Huang L, et al. (2011) Maslinic acid, a natural inhibitor of glycogen phosphorylase, reduces cerebral ischemic injury in hyperglycemic rats by GLT-1 up-regulation. Neurosci Res 89: 1829-39.
- Sánchez-González M, Lozano-Mena G, Juan ME, García-Granados A, Planas JM (2013)Assessment of thesafetyof maslinic acid, a bioactive compound from Oleaeuropaea L.Mol Nutr Food Res 57:339-46.
- Liu J, Wang X, Chen YP, Mao LF, Shang J, et al. (2014) Maslinic acidmodulates glycogen metabolism by enhancing the insulin signaling pathway and inhibiting glycogen phosphorylase.Chin J Nat Med 12: 259-65.
- de Bock M, Derraik JG, Brennan CM, Biggs JB, Morgan PE,(2013) Olive(Oleaeuropaea L.) leaf polyphenols improve insulin sensitivity in middle-aged overweight men: a randomized, placebo-controlled, crossover trial.
Prof. Mohamed Eddouks
Dean, Polydisciplinary Faculty of Errachidia
Moulay Ismail University, Morocco
RESEARCH EXPERIENCE
- Eddouks M, Chattopadhyay D, Zeggwagh NA.Animal models as tools to investigate antidiabetic and anti-inflammatory plants.Evid Based Complement Alternat Med. 2012;2012:142087.
- Zeggwagh NA, Michel JB, Eddouks M.Vascular Effects of Aqueous Extract of Chamaemelum nobile: In Vitro Pharmacological Studies in Rats.Clin Exp Hypertens. 2012.
- Oufni L, Taj S, Manaut B, Eddouks M. 2011.Transfer of uranium and thorium from soil to different parts of medicinal plants using SSNTD. Journal of Radioanalytical and Nuclear Chemistry, 287; 403-411.
- Zeggwagh NA, Moufid A, Michel JB, Eddouks M. Hypotensive effect of Chamaemelum nobile aqueous extract in spontaneously hypertensive rats.Clin Exp Hypertens. 2009.31(5):440-50.
- Zeggwagh NA, Farid O, Michel JB, Eddouks M. Cardiovascular effect of Artemisia herba alba aqueous extract in spontaneously hypertensive rats.Methods Find Exp Clin Pharmacol. 2008. 30(5):375-81.
- Eddouks M, Maghrani M, Louedec L, Haloui M, Michel JB.Antihypertensive activity of the aqueous extract of Retama raetam Forssk. leaves in spontaneously hypertensive rats.J Herb Pharmacother. 2007;7(2):65-77.
- Zeggwagh, N-A., Eddouks, M . Anti-hyperglycaemic and hypolipidemic effects of Ocimum basilicum aqueous extract in diabetic rats. American Journal of Pharmacology and Toxicology. 2(3): 123-129, 2007.
- Lemhadri, A., Burcelin, R., Eddouks, M. Chamaemelum nobile L. aqueous extract represses endogenous glucose production and improves insulin sensitivity in streptozotocin-induced diabetic mice. American Journal of Pharmacology and Toxicology. 2(3): 116-122, 2007.
- Lemhadri, A., Eddouks, M., Burcelin, R. Anti-hyperglycaemic and anti-obesity effects of Capparis spinosa and Chamaemelum nobile aqueous extracts in HFD mice. American Journal of Pharmacology and Toxicology. 2(3): 106-110, 2007.
- Zeggwagh, N.A., Michel, J.B, and Eddouks, M. Acute Hypotensive and Diuretic Activities of Chamaemelum nobile Aqueous Extract in Normal Rats. American Journal of Pharmacology and Toxicology. 2(3): 140-145, 2007.
- Zeggwagh, N-A., Michel, JB., Eddouks, M . Cardiovascular effect of Capapris spinosa aqueous extract in rats Part II: Furosemide-like effect of Capparis spinosa aqueous extract in normal rats. 2(3): 130-134, 2007.
- Zeggwagh, N-A., Michel, JB., Eddouks, M . Cardiovascular effect of Capparis spinosa aqueous extract. Part III: Antihypertensive effect in spontaneously hypertensive rats. American Journal of Pharmacology and Toxicology. 2(3): 111-115, 2007.
- Zeggwagh, N-A., Eddouks, M .Michel, JB. Cardiovascular effect of Capparis spinosa aqueous extract. Part VI: in vitro vasorelaxant effect.American Journal of Pharmacology and Toxicology. 2(3): 135-139, 2007.
- Eddouks, M., Ouahidi, M.L., Farid, O., Moufid, A., Lemhadri, A. The use of medicinal plants in the treatment of diabetes in Morocco. Phytothérapie. 2007, 5, no4, pp.194-203.
- Eddouks M; Khalidi A; Zeggwagh N.-A; Pharmacological approach of plants traditionally used in treating hypertension in Morocco. Phytothérapie. 2009, 7, no2, pp. 122-127.
- Zeggwagh NA, Ouahidi ML, Lemhadri A, Eddouks M. 2006. Study of hypoglycaemic and hypolipidemic effects of Inula viscosa L. aqueous extract in normal and diabetic rats. Journal ofEthnopharmacology. 24; 108(2): 223-7.
- Lemhadri A, Hajji L, Michel JB, Eddouks M. Cholesterol and triglycerides lowering activities of caraway fruits in normal and streptozotocin diabetic rats. Journal ofEthnopharmacology 2006 19; 106(3):321-6.
- Eddouks, M., Maghrani, M, Michel, J-B.Antihypertensive action of Lepidium sativum in SHR rats. In Press. Journal of Herbal Pharmacotherapy.Eddouks, M., Michel, J-B., Mghrani, M. Effect of Lepidium sativum L. On renal glucose reabsorption and urinary TGF B levels in diabetic rats. Phytotherapy Research. 2008 ;22(1):1-5.
- Eddouks M, Maghrani M, Michel JB.2005.Hypoglycaemic effect of Triticum repens P. Beauv. in normal and diabetic rats. Journal of Ethnopharmacology. 2005 ; 102(2):228-32.
- Eddouks, M. 2005. Les plantes anti-diabétiques. Phytothérapie Européenne. 28, 8-12.
- Zhang J, Onakpoya IJ, Posadzki P, Eddouks M. The safety of herbal medicine: from prejudice to evidence. Evid Based Complement Alternat Med. 2015;2015:316706.
- Yakubu MT, Sunmonu TO, Lewu FB, Ashafa AO, Olorunniji FJ, Eddouks M. Efficacy and safety of medicinal plants used in the management of diabetes mellitus. Evid Based Complement Alternat Med. 2014; 2014: 793035.
- Eddouks M, Chattopadhyay D, De Feo V, Cho WC. Medicinal plants in the prevention and treatment of chronic diseases 2013. Evid Based Complement Alternat Med. 2014;2014:180981.
- Eddouks M, Bidi A, El Bouhali B, Hajji L, Zeggwagh NA. Antidiabetic plants improving insulin sensitivity. J Pharm Pharmacol. 2014 Sep;66(9):1197-214.
Efficacy and Safety of Olive in the Management of Hyperglycemia
Eddouks M*
Faculty of Sciences and Techniques Errachidia, Moulay Ismail university, BP 21, Errachidia, 52000, Morocco
MOHAMED EDDOUKS
Professor
Faculty of Sciences and Techniques Errachidia
Moulay Ismail University
Morocco
Dr. Mohamed Eddouks is currently working as a professor at Moulay ismail university, morocco. He worked as assistant professor at faculty of sciences and techniques errachidia (1995) and as head of the department of biology at faculty of sciences and techniques errachidia (2003). He completed his PhD degree in Physiology and Pharmacology from University of Liege, Belgium and Sidi Mohammed Ben Abdellah University. He published many articles in international journals.
Eddouks M
Faculty of Sciences and Techniques Errachidia
Moulay Ismail university, BP 21
Errachidia, 52000, Morocco
Tel: +212535574497
Fax: +212535574485
E-mail: mohamed.eddouks@laposte.net
Citation: Eddouks M (2015) Efficacy and Safety of Olive in the Management of Hyperglycemia. Pharmaceut Reg Affairs 4:e145. doi:10.4172/2167-7689.1000e145
Er Rachidi; Errachidia
………..
Morocco
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New FDA Requirements for the Development of Herbal Medicinal Products
The previous FDA guideline for herbal medicinal products from 2004 is supposed to be replaced by a new version. In August 2015, the FDA has presented the draft of the revised guideline. Find out more about the FDA Guideline Botanical Drug Development.
In August 2015, the FDA has published a draft of the guideline “Botanical Drug Development”. This guideline addresses issues arising from the particular nature of herbal medicinal products. After its finalization it is supposed to replace the previous guideline from June 2004.
The general approach in the development of herbal medicinal products remained unchanged since 2004. But due to the better understanding of herbal medicinal products and the experience gained during the review of the approval documents for herbals (NDAs/New Drug Applications and INDs/Investigational New Drug Applications), specific recommendations could be adjusted. Still, new sections will be supplemented to better address the late development phase.
The…
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Genotoxic impurities: the new ICH M7 addendum to calculation of compound-specific acceptable intakes
Genotoxic impurities: the new ICH M7 addendum to calculation of compound-specific acceptable intakes
The draft for a guideline ICH M7(R1) published recently supplements the ICH-M7 guideline published last year. Read more about the calculation of compound-specific acceptable intakes of genotoxic impurities.
The final document of the ICH-Guideline M7 was published in June 2014. It describes the procedure for evaluating the genotoxic potential of impurities in medicinal products (see also our news Final ICH M7 Guideline on Genotoxic Impurities published dated 23 July 2014).
An important approach to the risk characterisation of impurities is the TTC concept (TTC = threshold of toxicological concern). According to this approach the exposure to a mutagenic impurity having the concentration of 1.5 µg per adult person per day is considered to be associated with a negligible risk. It can be used as default evaluation approach to most pharmaceuticals for long-term treatment (> 10 years)…
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TR 700, TR 701FA, Tedizolid phosphate
“TR-700”
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
US Patent Publication No. 20070155798, which is hereby incorporated by reference in its entirety, recently disclosed a series of potently anti-bacterial oxazolidinones including
wherein R═H, PO(OH)2, and PO(ONa)2.
(R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-hydroxymethyl oxazolidin-2-one dihydrogen phosphate, CAS 856867-55-5
DISODIUM SALT
CAS 856867-39-5
- C17 H16 F N6 O6 P . 2 Na
- 2-Oxazolidinone, 3-[3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)-3-pyridinyl]phenyl]-5-[(phosphonooxy)methyl]-, sodium salt (1:2), (5R)-
-
- DA 7218, Tedizolid phosphate disodium salt
In addition, improved methods of making the free acid are disclosed in U.S. patent application Ser. No. 12/577,089, which is assigned to Trius Therapeutics, Inc., and which is incorporated herein by reference
crystalline (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-hydroxymethyl oxazolidin-2-one dihydrogen phosphate 1 (R═PO(OH)2), was more stable and non-hygroscopic than the salt forms that were tested. In addition, unlike typical crystallizations, where the crystallization conditions, such as the solvent and temperature conditions, determine the particular crystalline form, the same crystalline form of 1 (R═PO(OH)2) was produced using many solvent and crystallization conditions. Therefore, this crystalline form was very stable, was made reproducibly, and ideal for commercial production because it reduced the chances that other polymorphs would form contaminating impurities during production. However, in all preliminary testing, the free acid crystallized as fine particles, making filtering and processing difficult.
To overcome difficulties in filtering and processing crystalline (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-hydroxymethyl oxazolidin-2-one dihydrogen phosphate 1 (R═PO(OH)2), processes described herein result in significantly reduced filtering time, avoid more toxic solvents, and significantly increased ease of preparing dosage forms such as tablets. It has been found that implementing various processes can control the particle size distribution of the resulting material, which is useful for making the crystalline form, and for commercial production and pharmaceutical use. Surprisingly, the process for increasing the particle size reduces the amount of the dimer impurity, in comparison to the process for making the free acid disclosed in U.S. patent application Ser. No. 12/577,089. Thus, various methods of making and using the crystalline form are also provided.
In addition, by using methods of making the free acid disclosed in U.S. patent application Ser. No. 12/577,089, which is assigned to the same assignee as in the present application, and by using the crystallization methods described herein, a crystalline free acid having at least 96% purity by weight may be formed that comprises a compound having the following formula:
(hereinafter “the chloro impurity”), i.e., (R)-5-(chloromethyl)-3-(3-fluoro-4-(6-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)phenyl)oxazolidin-2-one in an amount less than 1%.
Similarly, by using methods of making the free acid disclosed in U.S. patent application Ser. No. 12/577,089, which is assigned to the same assignee as in the present application, and by using the crystallization methods described herein, a crystalline free acid having at least 96% purity by weight may be formed that comprises a compound having the following formula:
(hereinafter “TR-700”), i.e., 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, in an amount less than 1%.
The crystalline free acid may have one or more of the attributes described herein.
In some aspects, a purified crystalline (R)-3-(4-(2-(2-methyltetrazol-5-yl)-pyridin-5-yl)-3-fluorophenyl)-5-hydroxymethyl oxazolidin-2-one dihydrogen phosphate, i.e., the free acid, has a purity of at least about 96% by weight. In some embodiments, the crystalline free acid has a median volume diameter of at least about 1.0 μm.
BRIEF DESCRIPTION OF THE DRAWINGS……http://www.google.com/patents/US8426389
FIG. 1 the FT-Raman spectrum of crystalline 1 (R═PO(OH)2).
FIG. 2 shows the X-ray powder pattern of crystalline 1 (R═PO(OH)2).
http://www.google.com/patents/US8426389
FIG. 3 shows the differential scanning calorimetry (DSC) thermogram of crystalline 1 (R═PO(OH)2).
http://www.google.com/patents/US8426389
FIG. 4 shows the 1H NMR spectrum of 1 (R═PO(OH)2).
FIG. 5 depicts the TG-FTIR diagram of crystalline 1 (R═PO(OH)2).
http://www.google.com/patents/US8426389
FIG. 6 is a diagram showing the dynamic vapor sorption (DVS) behavior of crystalline 1 (R═PO(OH)2).
FIG. 7 is a manufacturing process schematic for 1 (R═PO(OH)2) (TR-701 FA) in a tablet dosage form.
FIG. 8 is a manufacturing process schematic for 1 (R═PO(OH)2) (TR-701 FA) Compounding Solution for Lyophilization.
FIG. 9 is a manufacturing process schematic for 1 (R═PO(OH)2) (TR-701 FA) for Injection, 200 mg/vial: sterile filtering, filling, and lyophilization.
FIG. 10 is a representative particle size distribution of crystalline free acid without regard to controlling particle size distribution as also described herein.
FIG. 11 is a representative particle size distribution of crystalline free acid made using laboratory processes to control particle size described herein.
FIG. 12 is a representative particle size distribution of crystalline free acid made using scaled up manufacturing processes to control particle size described herein.
These impurities include
i.e., 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 (“TR-700”) and/or
i.e., (R)-5-(chloromethyl)-3-(3-fluoro-4-(6-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)phenyl)oxazolidin-2-one (“chloro impurity”).
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Wockhardt, WO 2007023507, N-[[3-[3,5-difluoro-4-[4-(tetrazol-2-yl)piperidin-1-yl]phenyl]-2-oxo-1,3-oxazolidin-5-yl]methyl]acetamide
Cas 928156-95-0,
Acetamide, N-[[(5S)-3-[3,5-difluoro-4-[4-(2H-tetrazol-2-yl)-1-piperidinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-
| C18H21F2N7O3 | |
| Molecular Weight: | 421.401246 g/mol |
|---|
N-[[3-[3,5-difluoro-4-[4-(tetrazol-2-yl)piperidin-1-yl]phenyl]-2-oxo-1,3-oxazolidin-5-yl]methyl]acetamide
Example- 14 and 15
(S)-N- { 3- [4-(4-(2H-tetrazol-2-yl)-piperidin- 1 -yl)-3 , 5-difluorophenyl] -2-oxo-oxazolidin-
5-ylmethyl }-acetamide and
(S)-N- { 3- [4-(4-(l H-tetrazol- 1 -yl)-piperidin- 1 -yl)-3 , 5-difluorophenyl] -2-oxo-oxazolidin-
5-ylmethyl }-acetamide
and
A mixture of (S)-N-{3-[4-methanesulphonyloxy piperidin-l-yl)-3,5-difluorophenyl]-2- oxo-oxazolidin-5-ylmethyl}-acetamide (1.12 mM), tetrazole (1.68 mM), and K2CO3 (1.68 mM) in DMF (6 ml) was heated for 22 hrs at 850C. The resulting mixture was poured into ice-water mixture, stirred for 30 min. And the separated solid was purified by column chromatography to obtain two isomeric products in 18% and 12% yields respectively. Isomer A: M.P. 234-2370C; MS(M+1)- 422 ; M.F. C18H21F2N7O3 Isomer B: M.P. 214-2170C; MS(M+1)- 422 ; M.F. C18H2JF2N7O3
WOCKHARDT LIMITED [IN/IN]; D-4, MIDC Area, Chikalthana, Aurangabad 431006 (IN)
Our New Drug Discovery team has developed a number of lead molecules, mainly in the area of anti-infectives; these are currently at various stages of development.
Of these molecules, the most advanced of the New Chemical Entities (NCE) is WCK 771, which has commenced Phase II human clinical trials.
WCK 771 is a broad-spectrum antibiotic, which has proven effective in treating diverse staphylococcal infections like MRSA and VISA.
Other lead molecules at various stages of pre-clinical trials are: WCK 2349, WCK 4873 and WCK 4086.
http://www.wockhardt.com/how-we-touch-lives/new-drug-discover.aspx
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Wockhardt, WO 2015136473, sodium (2S, 5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylate
WO-2015136473
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015136473&redirectedID=true
WOCKHARDT LIMITED [IN/IN]; D-4, MIDC Area, Chikalthana, Aurangabad 431006 (IN)
Our New Drug Discovery team has developed a number of lead molecules, mainly in the area of anti-infectives; these are currently at various stages of development.
Of these molecules, the most advanced of the New Chemical Entities (NCE) is WCK 771, which has commenced Phase II human clinical trials.
WCK 771 is a broad-spectrum antibiotic, which has proven effective in treating diverse staphylococcal infections like MRSA and VISA.
Other lead molecules at various stages of pre-clinical trials are: WCK 2349, WCK 4873 and WCK 4086.
http://www.wockhardt.com/how-we-touch-lives/new-drug-discover.aspx
WO-2015136473
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015136473&redirectedID=true
Process for the synthesis of sodium (2S, 5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylate (disclosed in WO2014135929) is claimed. Used as an intermediate in the synthesis of several antibacterial compounds. For a concurrent filing see WO2015136387, claiming the combination of an antibacterial agent with sulbactam.
In September 2015, Wockhardt’s pipeline lists several antibacterial programs, including WCK-771 and WCK-2349 (both in phase II), WCK-5107 (phase I), and also investigating iv and oral second generation oxazolidinones, WCK-4873, and iv and oral formulation of WCK-4086 (in preclinical stage) for treating the bacterial infection.
For a prior filing see WO2015125031, claiming the combination of an antibacterial agent (eg cefepime or cefpirome) and nitrogen containing bicyclic compound, useful for treating bacterial infection.
A compound of Formula (I), chemically known as sodium (25, 5i?)-6-(benzyloxy)-7-oxo-l,6-diazabicyclo[3.2.1]octane-2-carboxylate, can be used as an intermediate in the synthesis of several antibacterial compounds and is disclosed in PCT International Patent Application No. PCT/IB2013/059264. The present invention discloses a process for preparation of a compound of Formula (I).
Scheme 1
Example 1
Synthesis of sodium (25, 5R)-6-(benzyloxy)-7-oxo-l,6-diazabicvclor3.2.11octane-2- carboxylate
Step 1; Preparation of -Γl-Γ(feΓt-butyldimethylsilyl -oxymethyll-5-Γdimethyl(oxido -λ-4-sulfanylidenel-4-oxo-pentyll-carbamic acid tert-butyl ester (III):
To a suspension of trimethylsulfoxonium iodide (180.36 gm, 0.819 mol) in tetrahydrofuran (900 ml), sodium hydride (32.89 g, 0.819 mol, 60% in mineral oil) was charged in one portion at 30°C temperature. The reaction mixture was stirred for 15 minutes and then dropwise addition of dimethylsulphoxide (1.125 ml) was done over a period of 3 hours at room temperature to provide a white suspension. The white suspension was added to a pre-cooled a solution of 2-(feri-butyldimethylsilyl-oxymethyl)-5-oxo-pyrrolidine-l-carboxylic acid tert-buty\ ester (II) (225 g, 0.683 mol, prepared as per J. Org Chem.; 2011, 76, 5574 and WO2009067600) in tetrahydrofuran (675 ml) and triethylamine (123.48 ml, 0.887 mol) mixture at -13°C by maintaining the reaction mixture temperature below -10°C. The resulting suspension was stirred for additional 1 hour at -10°C. The reaction mixture was carefully quenched by addition of saturated aqueous ammonium chloride (1.0 L) at -10°C to 10°C. The reaction was extracted by adding ethyl acetate (1.5 L). The layers were separated and aqueous layer was re-extracted with ethyl acetate (500 ml x 3). The combined organic layer was washed successively with saturated aqueous sodium bicarbonate (1.0 L), water (2.0 L) followed by saturated aqueous sodium chloride solution (1.0 L). Organic layer was dried over sodium sulfate and evaporated under vacuum to provide 265 g of 5-[l-[(ieri-butyldimethylsilyl)-oxymethyl]-5-[dimethyl(oxido)- -4-sulfanylidene]-4-oxo-pentyl]-carbamic acid tert-buty\ ester (III) as an yellow oily mass.
Analysis:
Mass: 422.3 (M+l); for Molecular weight: 421.68 and Molecular Formula: 
1H NMR (CDC13): δ 4.77 (br d, 1H), 4.38 (br s, 1H), 3.58 (br s, 3H), 3.39 (s, 3H), 3.38 (s, 3H), 2.17-2.27 (m, 2H), 1.73-1.82 (m, 2H), 1.43 (s, 9H), 0.88 (s, 9H), 0.01 (s, 3H), 0.04 (s, 3H).
Step 2: Preparation of 5-r4-benzyloxyimino-l-(fert-butyldimethylsilyl-oxymethyl)-5-chloro-pentyll-carbamic acid tert- butyl ester (IV):
To a suspension of 5-[l-[(ieri-butyldimethylsilyl)-oxymethyl]-5-[dimethyl(oxido)- -4-sulfanylidene]-4-oxo-pentyl]-carbamic acid tert-butyl ester (III) (440.0 g, 1.045 mol) in tetrahydrofuran (6.6 L), O-benzhydroxylamine hydrochloride (200.0 g, 1.254 mol) was charged. The reaction mixture was heated to 50°C for 2.5 hours. The reaction mixture was filtered through pad of celite and filtrate was concentrated to provide a residue. The residue was dissolved in ethyl acetate (5.0 L) and washed successively with saturated aqueous sodium bicarbonate (1.5 L), water (1.5 L) and saturated aqueous sodium chloride (1.5 L). Organic layer was dried over sodium sulfate. Solvent was evaporated under vacuum to yield 463.0 g of 5-[4-benzyloxyimino-l-(tert-butyldimethylsilyl-oxymethyl)-5-chloro-pentyl]-carbamic acid tert-butyl ester (IV) as an oily mass.
Analysis:
Mass: 486.1 (M+l); for Molecular weight: 485.4 and Molecular Formula: 
1H NMR (CDCI3): δ 7.26-1 6 (m, 5H), 5.10 (s, 2H), 4.66 (br d, 1H), 3.58-4.27 (m, 2H), 3.56-3.58 (m, 3H), 2.40-2.57 (m, 2H), 1.68-1.89 (m, 2H), 1.44 (s, 9H), 0.89 (s, 9H), 0.02 (s, 3H), 0.04 (s, 3H).
Step 3: Preparation of 5-5-benzyloxyimino-2-(fert-butyldimethylsilyl-oxymethyl)-piperidine-l-carboxylic acid tert-butyl ester (V):
To a solution of 5-[4-benzyloxyimino-l-(tert-butyldimethylsilyl-oxymethyl)-5-chloro-pentyl]-carbamic acid tert-butyl ester (IV) (463.0 g 0.954 mol) in tetrahydrofuran (6.9 L), was charged potassium feri-butoxide (139.2 g, 1.241 mol) in portions over a period of 30 minutes by maintaining temperature -10°C. The resulting suspension was stirred for additional 1.5 hours at -10°C to -5°C. The reaction mixture was quenched by addition of saturated aqueous ammonium chloride (2.0 L) at -5°C to 10°C. The organic layer was separated and aqueous layer was extracted with ethyl acetate (1.0 L x 2). The combined organic layer was washed with saturated aqueous sodium chloride solution (2.0 L). Organic layer was dried over sodium sulfate, and then evaporated under vacuum to yield 394.0 g of 5-5-benzyloxyimino-2-(ieri-butyldimethylsilyl-oxymethyl)-piperidine- 1 -carboxylic acid tert-butyl ester (V) as an yellow oily mass.
Analysis:
Mass: 449.4 (M+l) for Molecular weight: 448.68 and Molecular Formula: C24H4oN204Si;
1H NMR (CDC13): δ 7.25-1 3 (m, 5H), 5.04-5.14 (m, 2H), 4.35 (br s, 1H), 3.95 (br s, 1H), 3.63-3.74 (br d, 2H), 3.60-3.63 (m, 1H), 2.70-2.77 (m, 1H), 2.33-2.41 (m, 1H), 1.79-1.95 (m, 2H), 1.44 (s, 9H), 0.88 (s, 9H), 0.03 (s, 3H), 0.04 (s, 3H).
Step 4: Preparation of (25,5R5)-5-benzyloxyamino-2-(tert-butyldimethylsilyl-oxymethyl)-piperidine-l-carboxylic acid tert-butyl ester (VI):
To a solution of 5-5-benzyloxyimino-2-(feri-butyldimethylsilyl-oxymethyl)-piperidine-l-carboxylic acid tert-butyl ester (V) (394.0 g, 0.879 mol) in dichloromethane (5.0 L) and glacial acetic acid (788 ml), was charged sodium cyanoborohydride (70.88 g, 1.14 mol) one portion. The resulting reaction mixture was stirred at temperature of about 25 °C to 30°C for 2 hours. The mixture was quenched with adding aqueous solution of sodium bicarbonate (1.3 kg) in water (5.0 L). The organic layer was separated and aqueous layer was extracted with dichloromethane (2.0 L). The combined organic layer washed successively with water (2.0 L), saturated aqueous
sodium chloride (2.0 L) and dried over sodium sulfate. Solvent was evaporated under vacuum to provide a residue. The residue was purified by silica gel column chromatography to yield 208 g of (25,5i?5)-5-benzyloxyamino-2-(ieri-butyldimethylsilyl-oxymethyl)-piperidine- 1 -carboxylic acid tert-buty\ ester (VI) as pale yellow liquid.
Analysis:
Mass: 451.4 (M+l); for Molecular weight: 450.70 and Molecular Formula: C24H42N204Si;
1H NMR (CDC13): δ 7..26-7.36 (m, 5H), 4.90-5.50 (br s, 1H), 4.70 (dd, 2H), 4.09-4.25 (m, 2H), 3.56-3.72 (m, 2H), 2.55-3.14 (m, 2H), 1.21-1.94 (m, 4H), 1.45 (s, 9H), 0.89 (s, 9H), 0.05 (s, 6H).
Step 5: Preparation of (25,5R5)-5-benzyloxyamino-2-(tert-butyldimethylsilyl-oxymethyl)-piperidine (VII):
To a solution of 5-5-benzyloxyamino-2-(feri-butyldimethylsilyl-oxymethyl)-piperidine-l-carboxylic acid tert-butyl ester (VI) (208 g, 0.462 mol) in dichloromethane (3.0 L), boron trifluoride diethyletherate complex (114.15 ml, 0.924 mol) was charged in one portion. The resulting reaction mixture was stirred at temperature of about 25°C to 35°C temperature for 2 hours. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (2.0 L). The organic layer was separated and aqueous layer was extracted with dichloromethane (1.5 L x 2). The combined organic layer was washed with saturated aqueous sodium chloride (1.0 L) and dried over sodium sulfate. Solvent was evaporated under vacuum to yield 159 g of (25,5i?5)-5-benzyloxyamino-2-(feri-butyldimethylsilyl-oxymethyl)-piperidine (VII) as a yellowish syrup.
Analysis:
Mass: 351.3 (M+l); for Molecular weight: 350.58 and Molecular Formula: C19H34N202Si.
Step-6: Preparation of (25,5R)-6-benzyloxy-2-(fert-butyl-dimethylsilyl-oxymethyl)-7-oxo-l,6-diaza-bicyclo-r3.2.11octane (VIII):
Part 1; Preparation of (2S,5RS)-6-benzyloxy-2-(fert-butyl-dimethylsilyl-oxymethyl)-7-oxo-l,6-diaza-bicvclo-r3.2.11octane:
To a solution of (25,5i?5)-5-benzyloxyamino-2-(feri-butyldimethylsilyl-oxymethyl)-piperidine (VII) (159.0 g, 0.454 mol) in a mixture of acetonitrile (2.38 L) and diisopropylethylamine (316.5 ml, 1.81 mol) was added triphosgene (59.27 gm, 0.199 mol) dissolved in acetonitrile (760 ml) at -15°C over 30 minutes under stirring. The resulting reaction mixture was stirred for additional 1 hour at -10°C. The reaction mixture was quenched by addition of saturated aqueous sodium bicarbonate (2.0 L) at -5°C to 10°C. Acetonitrile was evaporated from the reaction mixture under vacuum and to the left over aqueous phase, dichloromethane (2.5 L) was added. The organic layer was separated and aqueous layer extracted with dichloromethane (1.5 L x 2). The combined organic layer was washed successively with water (2.0 L), saturated aqueous sodium chloride (2.0 L) and dried over sodium sulfate. Solvent was evaporated under vacuum and the residue was passed through a silica gel bed to yield 83.0 g of diastereomeric mixture (25, 5i?5)-6-benzyloxy-2-(feri-butyl-dimethylsilyl-oxymethyl)-7-oxo-l,6-diaza-bicyclo-[3.2.1]octane in 50:50 ratio as a yellow liquid.
Part-2: Separation of diastereomers to prepare (25,5R)-6-benzyloxy-2-(fert-butyl-dimethylsilyl-oxymethyl)-7-oxo-l,6-diaza-bicvclo-r3.2.11octane:
A mixture of diastereomers (2S,5Z?S)-6-benzyloxy-2-(teri-butyl-dimethylsilyl-oxymethyl)-7-oxo-l,6-diaza-bicyclo-[3.2.1]octane in 50:50 ratio (47.0 gm, 0.125 mol), was dissolved in n-hexane (141 ml) and stirred at temperature of about 10°C to 15°C for 1 hour. Precipitated solid was filtered and washed with n-hexane (47 ml) to provide 12.0 g of diastereomerically pure (25,5i?)-6-benzyloxy-2-(tert-butyl-dimethylsilyl-oxymethyl)-7-oxo- 1,6-diaza-bicyclo-[3.2.1] octane (VIII) as a white crystalline material.
Analysis:
Mass: 377.3 (M+l); for Molecular weight: 376.58 and Molecular Formula: 
1H NMR (CDCI3): δ Ί -Ί.ΑΑ (m, 5H), 4.95 (dd, 2H), 3.76-3.85 (ddd, 2H), 3.37-3.40 (m, 1H), 3.28-3.31 (m, 2H), 2.89 (brd, 1H), 1.90-2.02 (m, 2H), 1.62- 1.74 (m, 2H), 1.56 (s, 9H), 0.06 (s, 3H), 0.05 (s, 3H).
Diastereomeric purity as determined by HPLC: 99.85%
Step-7: Preparation of (25,5R)-6-benzyloxy-2-hvdroxymethyl)-7-oxo-l,6-diaza-bicvclo-r3.2.11octane (IX):
To a solution of (25,5i?)-6-benzyloxy-2-(ieri-butyl-dimethylsilyl-oxymethyl)-7-oxo- l,6-diaza-bicyclo-[3.2.1]octane (VIII) ( 12.0 g, 31.9 rnmol) in tetrahydrofuran (180 ml) was charged tetra 7? -butyl ammonium fluoride (38.0 ml, 38 mmol, 1 M in tetrahydrofuran) at room temperature. The reaction mixture was stirred for 2 hours. It was quenched with saturated aqueous ammonium chloride ( 100 ml). The organic layer was separated and aqueous layer extracted with dichloromethane (150 ml x 3). The combined organic layer was washed with saturated aqueous sodium chloride (150 ml), dried over sodium sulfate and evaporated under vacuum to yield 24.0 g of (25,5i?)-6-benzyloxy-2-hydroxymethyl)-7-oxo-l ,6-diaza-bicyclo-[3.2.1]octane (IX) as a yellow liquid. The compound of Formula (IX) was purified by silica gel (60-120 mesh) column chromatography using a mixture of ethyl acetate and hexane as an eluent.
Analysis:
Mass: 263.1 (M+l); for Molecular weight: 262.31 and Molecular Formula: C14H18N203
1H NMR (CDCb): δ 7.34-7.42 (m, 5H), 4.95 (dd, 2H), 3.67-3.73 (m, 1H), 3.53-3.60 (m, 2H), 3.32-3.34 (m, 1H), 2.88-3.01 (m, 2H), 2.09 (brs, 1H), 1.57-2.03 (m, 2H), 1.53- 1.57 (m, 1H), 1.37- 1.40 (m, 1H).
Step 8: Preparation of sodium salt of (25, 5R)-6-benzyloxy-7-oxo-l,6-diaza-bicvclor3.2.11-octane-2-carboxylic acid (I):
Step I:
Compound of Formula (IX) obtained in step 8 above was used without any further purification. To the clear solution of (25,5i?)-6-benzyloxy-2-hydroxymethyl)-7-oxo-l,6-diaza-bicyclo-[3.2.1]octane (IX) (24.0 g, 31.8 mmol) (quantities added based upon theoretical basis i.e 8.3 g ) in dichloromethane (160 ml), was added Dess-Martin reagent (24.1 g, 57.24 mmol) in portions over 15 minutes. The resulting suspension was stirred for 2 hours at 25°C. The reaction was quenched by adding a solution, prepared from saturated aqueous sodium hydrogen carbonate solution (160 ml) and 72.0 g of sodium thiosulfate. Diethyl ether (160 ml) was added to the reaction mixture and it was stirred for 5-10 minutes and filtered through celite. Biphasic layer from filtrate was separated. Organic layer was washed with saturated aqueous sodium hydrogen carbonate solution (160 ml) followed by saturated aqueous sodium chloride solution (160 ml). Organic layer was dried over sodium sulfate and evaporated to dryness at 30°C to obtain 20.0 g of intermediate aldehyde, which was used immediately for the next reaction.
Step II:
To the crude intermediate aldehyde (20.0 g, 31.6 mmol) (quantities added based upon theoretical yield i.e. 8.2 g) obtained as above, was charged i-butyl alcohol (160 ml) and cyclohexene (10.8 ml, 110.6 mmol). The reaction mixture was cooled to temperature of about 10°C to 15°C. To this mixture was added clear solution prepared from sodium hypophosphate (14.8 g, 94.8 mmol) and sodium chlorite (5.7 g, 63.2 mmol) in water (82.0 ml) over a period of 30 minutes by maintaining temperature between 10°C to 15°C. The reaction mixture was further stirred for 1 hour and was quenched with saturated aqueous ammonium chloride solution. The reaction mixture was subjected to evaporation under vacuum at 40°C to remove i-butyl alcohol. Resulting mixture was extracted with dichloromethane (3 x 150 ml). Layers were separated. Combined organic layer was washed with aqueous brine solution, dried over sodium sulfate and evaporated to dryness under vacuum to obtain 16.0 g of crude residue. To this residue was added acetone (83 ml) to provide a clear solution and to it was added dropwise a solution of sodium 2-ethyl hexanoate (4.5 g) in acetone (24 ml). The reaction mixture was stirred for 15 hours at 25°C to 30°C to provide a suspension. To the suspension was added diethyl ether (215 ml) and stirred for 30 minutes. Resulting solid was filtered over suction, and wet cake was washed with cold acetone (83 ml) followed by diethyl ether (83 ml). The solid was dried under vacuum at 40°C to provide 3.6 g of off-white colored, non-hygroscopic sodium salt of (25, 5i?)-6-benzyloxy-7-oxo-l,6-diaza-bicyclo[3.2.1]-octane-2-carboxylic acid (I).
Analysis:
Mass: 275.2 as M-1 (for free acid) for Molecular Weight: 298 and Molecular Formula: 
NMR (DMSO-d6): δ 7.43-7.32 (m, 5H), 4.88 (q, 2H), 3.48 (s, IH), 3.21 (d, IH), 2.73 (d, IH), 2.04-2.09 (m, IH), 1.77-1.74 (m, IH), 1.65-1.72 (m, IH), 1.55-1.59 (m, IH);
Purity as determined by HPLC: 97.47%;
[a]D25: -42.34° (c 0.5, water).
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GSK2334470
GSK2334470
GSK2334470; 1227911-45-6; GSK-2334470; GSK 2334470;
(3S,6R)-1-[6-(3-Amino-1H-indazol-6-yl)-2-(methylamino)-4-pyrimidinyl]-N-cyclohexyl-6-methyl-3-piperidinecarboxamide
(3S.6/?V1-r6-(3-Amino-1 H-indazol-6-ylV2-(methylaminoV4-pyrimidinyll-Λ/-cvclohexyl-6- methyl-3-piperidinecarboxamide
| Molecular Weight | 462.59 |
| Formula | C25H34N8O |
| CAS Number | 1227911-45-6 |
Phosphoinositide Dependent Kinase (PDK) 1 Inhibitors
[α]20D = – 32.6 o (c 1.17, MeOH)
[α] D = -27.6 (Concentration = 1.16, Solvent = Methanol)
SOL………DMSO to 100 mM
ethanol to 100 mM
nmr……http://www.chemietek.com/Files/Line2/Chemietek,%20GSK2334470%20(1),%20NMR-DMSO.pdf
http://file.selleckchem.com/downloads/nmr/S708702-GSK2334470-HNMR-Selleck.pdf
GSK2334470 is a potent and selective PDK1 (3-Phosphoinositide dependent protein kinase-1) inhibitor. GSK2334470 blocks the phosphorylation of known PDK1 substrates, but surprisingly find that the potency and kinetics of inhibition vary for different PDK1 targets. GSK2334470 subsequent activation of PDK1 substrates S6K1, SGK and RSK in HEK293, U87 and mouse embryonic fibroblast cell lines.
GSK2334470 inhibited activation of an Akt1 mutant lacking the PH domain (pleckstrin homology domain) more potently than full-length Akt1, suggesting that GSK2334470 is more effective at inhibiting PDK1 substrates that are activated in the cytosol rather than at the plasma membrane. GSK2334470 also suppressed T-loop phosphorylation and activation of RSK2 (p90 ribosomal S6 kinase 2), another PDK1 target activated by the ERK (extracellular-signal-regulated kinase) pathway.
GSK2334470 is a highly specific and potent inhibitor of PDK1 (3-Phosphoinositide dependent protein kinase-1) with IC50 of 10 nM. It does not suppress activity on other 96 kinases, including Aurora, ROCK, p38 MAPK and PI3K. GSK2334470 has been used in cells to ablate T-loop phosphorylation and activate SGK, S6K1 and RSK as well as suppress the activation of Akt.
PATENT
WO 2010059658
http://www.google.com/patents/WO2010059658A1?cl=en
Example 78
(3S.6/?V1-r6-(3-Amino-1 H-indazol-6-ylV2-(methylaminoV4-pyrimidinyll-Λ/-cvclohexyl-6- methyl-3-piperidinecarboxamide
To (3S,6R)-1-[6-(4-cyano-3-fluorophenyl)-2-(methylamino)-4-pyrimidinyl]-Λ/-cyclohexyl-6- methyl-3-piperidinecarboxamide (260 mg, 0.58 mmol) in EtOH (10 ml.) as a suspension at room temperature in a microwave vial was added hydrazine monohydrate (807 uL, 16.7 mmol, 30 equiv) in one portion. The mixture was capped and heated at 100 0C for 48 hours. A duplicate run was performed. The crude reactions from both runs were combined, and concentrated in vacuo. The residue was taken up in 10 ml. of water. The resulting suspension was sonicated briefly, and filtered. The solids collected were dried under vacuum at room temperature over P2O5 for 18 hours, and then at 65 0C under vacuum for another 18 hours to afford the title compound (410 mg) as a cream-colored solid. LC-MS (ES) m/z = 463 [M+H]+. 1H NMR (400 MHz, CD3OD): δ 1.16 – 1.32 (m, 3H),1.29 (d, J = 6.8 Hz, 3H), 1.34 – 1.45 (m, 2H), 1.65 – 1.68 (m, 1 H), 1.76 – 1.81 (m, 5H), 1.85 – 1.92 (m, 2H), 1.97 – 2.05 (m, 1 H), 2.35 – 2.42 (m, 1 H), 2.97 (s, 3H), 3.1 1 – 3.15 (m, 1 H),3.64 – 3.70 (m, 1 H), 4.45 – 4.65 (bs, 1 H), 4.72 – 4.92 (bs, 1 H), 6.45 (s, 1 H), 7.52 (dd, J =8.5, 1.14 Hz, 1 H), 7.75 (d, J = 8.3 Hz, 1 H), 7.85 (s, 1 H).
ntermediate 112
Cis- methyl-6-methyl-3-piperidinecarboxylate
A solution of cis-3-methyl 1-(phenylmethyl)-6-methyl-1 ,3-piperidinedicarboxylate (69 g, 237 mol) in EtOH (50 mL) and EtOAc (300 mL) was added to a slurry of 10% Pd/C (3.7 g) in EtOAc (30 mL) and EtOH (10 mL) EtOH under nitrogen in a Parr Shaker bottle. The mixture was hydrogenated under 65 psi at room temperature for 4 hours. The mixture was filtered through celite, and washed with EtOAc. The filtrate was concentrated in vacuo to give 37 g of the title compound as a liquid. LC-MS (ES) m/z = 158 [M+H]+.
Intermediate 113
Methyl (3S,6f?)-6-methyl-3-piperidinecarboxylate L-(+)-tartaric acid salt 
L-(+)-Tartaric acid salt A suspension of L-(+)-tartaric acid (39 g, 260 mmol, 1.05 equiv) in IPA (200 ml.) and water (13 mL) water was heated in a water bath at 600C until all dissolved. To this hot stirred solution was added neat racemic methyl (3S,6R)-6-methyl-3-piperidinecarboxylate (39 g, 248 mmol), followed by addition of 25 mL of IPA rinse. The resulting mixture was heated to 60 0C, resulting in a clear solution, and then cooled to room temperature, while the hot water bath was removed. This hot solution was seeded with a sample of methyl (3S,6R)-6-methyl-3-piperidinecarboxylate L-(+)-tartaric acid salt that had a chiral purity of 98% ee, and aged at ambient temperature (with the water bath removed) for 20 minutes. The mixture turned into an oily texture with seeds still present. To the mixture was added 5 mL of water, and heated in the warm water bath at 43 0C. The mixture became clear with the seeds still present. The heating was stopped, and the mixture was stirred in the warm water bath. After 20 minutes, the mixture gradually turned into a paste. After another 10 min, the water bath was removed, and the mixture was stirred at ambient temperature for another 1 hour. The resulting paste was filtered. The cake was washed with 50 mL of IPA, giving 62 g of wet solids. This cake was taken up in 150 mL of IPA and 8 mL of water, and stirred as a slurry while being heated in a water bath to 60 0C (internal temp 55 0C) for 5 minutes. The heating was turned off while the mixture was still stirred in the warm water bath. After 30 min, the mixture was filtered. The cake was washed with 100 mL of IPA. Drying under house vacuum at room temperature for 48 hours gave 46.7 g of solids. An analytical sample was derivatised to the corresponding N-Cbz derivative (as in the preparation of intermediate 1 11 ), which was determined by chiral HPLC (methods used to analyze the resolution of intermediate 11 1 above) to have 85% ee. This material was taken up in IPA (420 mL) and water (38 mL) as a suspension. The mixture was heated in a water bath to 65 0C, at which time the mixture became a clear solution. The heating bath was removed. The mixture was seeded and aged at ambient temp for 20 hours. The solids formed were filtered, and washed with 100 mL of IPA. The solids collected were dried under house vacuum at room temperature for 24 h, and then under vacuum at room temperature for another 24 hours to give 28.5 g of the title compound. An analytical sample was converted to the N-Cbz derivative. The ee was determined to be 97.7%. LC-MS (ES) m/z = 158 [M+H]+.
Intermediate 114 4,6-Dichloro-Λ/-methyl-2-pyrimidinamine
Methylamine (2M solution, 113 ml_, 217 mmol, 2.05 equiv) was charged to a 1 L 3-neck flask fitted with a magnetic stirrer and a thermometer. The mixture was chilled in an ice bath. To this stirred solution was added via addition funnel a solution of 4,6-dichloro-2-(methylsulfonyl)pyrimidine (25 g, 1 10 mmol) in EtOAc (250 ml.) portionwise over a 25 minutes period. The temp was between 5-10 0C. After completion of addition, the ice bath was removed, and the mixture was stirred for 1 hour at ambient temperature. LCMS showed conversion complete. The suspension was filtered, and washed with EtOAc. The filtrate was concentrated in vacuo. The residue was partitioned between water (100 ml.) and EtOAc (450 ml_). The organic was washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give white solids, which were triturated in 150 ml. of CH2CI2. These solids were collected by filtration and washing with cold CH2CI2 (50 ml_). Drying under house vacuum at room temperature for 20 hours, and then high vacuum at room temperature for 3 hours gave 9.31 g of the title compound as a solid. LC-MS (ES) m/z = 179 [M+H]+.
Intermediate 121 (3S,6/?)-1-r6-Chloro-2-(methylamino)-4-pyrimidinyll-Λ/-cvclohexyl-6-methyl-3-piperidinecarboxamide
To a suspension of (3S,6/?)-1-[6-chloro-2-(methylamino)-4-pyrimidinyl]-6-methyl-3-piperidinecarboxylic acid (3.05 g, 10.71 mmol) in CH2CI2 (50 ml.) at room temperature was added Hunig’s base (2.70 ml_, 15.43 mmol, 1.3 equiv) and cyclohexylamine (1.60 ml_, 14.2 mmol, 1.2 equiv), and the resulting mixture was chilled in an ice bath. To this stirred solution was added HATU (4.96 g, 13.1 mmol, 1.1 equiv) in one portion, and the resulting suspension was stirred in the ice bath for 30 minutes. LCMS showed conversion complete. The mixture was diluted with CH2CI2 (50 ml.) and filtered through celite. The filtrate was washed water (2 X 25 ml.) and then brine. The organic was dried over Na2SO4, filtered, and concentrated in vacuo. Silica gel column chromatography using gradient elution of 1 % EtOAc in CHCI3 to 50% EtOAc in CHCI3 afforded the title compound (4.26 g) as a foam. LC-MS (ES) m/z = 366 [M+H]+.
PAPER
Journal of Medicinal Chemistry (2011), 54(6), 1871-1895.
http://pubs.acs.org/doi/full/10.1021/jm101527u
Phosphoinositide-dependent protein kinase-1(PDK1) is a master regulator of the AGC family of kinases and an integral component of the PI3K/AKT/mTOR pathway. As this pathway is among the most commonly deregulated across all cancers, a selective inhibitor of PDK1 might have utility as an anticancer agent. Herein we describe our lead optimization of compound 1toward highly potent and selective PDK1 inhibitors via a structure-based design strategy. The most potent and selective inhibitors demonstrated submicromolar activity as measured by inhibition of phosphorylation of PDK1 substrates as well as antiproliferative activity against a subset of AML cell lines. In addition, reduction of phosphorylation of PDK1 substrates was demonstrated in vivo in mice bearing OCl-AML2 xenografts. These observations demonstrate the utility of these molecules as tools to further delineate the biology of PDK1 and the potential pharmacological uses of a PDK1 inhibitor.
REFERENCES
Najafov, et al., Characterization of GSK2334470, a novel and highly specific inhibitor of PDK1. Biochem.J. (2011), 433 (2) 357.
For a PDK1 inhibitor, the substrate matters.
Knight ZA. Biochem J. 2011 Jan 15;433(2):e1-2. PMID: 21175429.
Characterization of GSK2334470, a novel and highly specific inhibitor of PDK1.
Najafov A, et al. Biochem J. 2011 Jan 15;433(2):357-69. PMID: 21087210.
Jeffrey Axten
Director, Medicinal Chemistry, Virtual Proof of Concept DPU at GlaxoSmithKline
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Improved one-pot synthesis of N, N-diisopropyl-3-(2-Hydroxy-5-methylphenyl)-3-phenyl propanamide; a key intermediate for the preparation of racemic Tolterodine
Tolterodine is chemically known as (R)-N,N-disiopropyl-3-(2-hydroxy-5-methyl phenyl)-3-phenyl propyl amine. Tolterodine acts as a muscarinic receptor antagonist. It is useful in the treatment of urinary incontinence [1]. Tolterodine tartrate acts by relaxing the smooth muscle tissues in the walls of the bladder by blocking cholinergic receptors[2]. Tolterodine tartrate [3] is marketed by Pharmacia & Upjohn in the brand name of Destrol®.
The present invention relates to a novel process for the preparation of N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropanamide (4); a key intermediate for the preparation of Tolterodine (1). Some different approaches have been published [4–8] for the preparation of N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropanamide (4). These methods involve multistep synthesis using hazardous, expensive reagents and some of the methods [6] involve activators like Grignard reagents, LDA, n-butyl lithium, Lewis acids. Hence there is a need to develop an alternative, plant friendly procedure for the preparation of N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropanamide (4) from 3,4-dihydro-6-methyl-4-phenylcoumarin (2) (Fig1).
Ring opening reactions of dihydrocoumarins are well known in literature[9–11]. But in the present invention, we have described a new methodology (Scheme 1 & Scheme2) for the preparation ofN,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropanamide (4) by using inexpensive and commercially vailable starting materials like 3, 4-dihydro-6-methyl 4-phenylcoumarin (2), which was synthesized from p-cresol and trans-cinnamic acid [12].
Scheme 1
N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropanamide 4.
Scheme 2
N-Isopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropanamide 5.
3,4-Dihyhydro-6-methyl 4-phenylcoumarin (2) reacts with diisopropylamine (6) in presence of acetic acid gives N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropanamide (4) at room temperature. This process of compound 4 is very useful for commercialization of Tolterodine 1 in plant.
General procedure for the synthesis of compounds 4-4c & 5-5c
To a solution of 3,4-dihyhydro-6-methyl 4-phenylcoumarin 2 (10 g, 42 mmol) in diisopropylether (200 mL), N,N-diisopropylamine (33.95 g, 336 mmol) and acetic acid (10 g, 168 mmol) were added at room temperature. The suspension was stirred for 16 h at room temperature. The reaction mass was concentrated, the resulting residue was crystallized with D.M.Water (50 mL) and diisopropyl ether (50 mL) mixture to gave N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropanamide 4 (10.6 g, 75% yield).
N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropanamide 4
IR (KBr) cm-1: 3024 (Aromatic C-H, str.), 2949, 2904, 2869 (Aliphatic C-H, str.), 1630 (C═O, str.), 1609, 1555, 1510 (C═C, str.), 1469, 1459 (CH2 bending), 1270 (C-N, str.), 1072 (C-O, str.), 788, 769 (Aromatic CH Out-of-plane bend). 1H NMR (300 MHz, DMSO-d6) δ 1.04 (d, 12H), 2.089 (s, 3H), 2.79 (m, 2H), 3.037 (m, 2H), 4.702 (t, 1H), 6.6 (d, 1H), 6.75 (d, 2H), 7.127-7.246 (m, 5H). 13C NMR (125 MHz, DMSO-d6) δ 19.39, 20.36, 45.69, 115.33, 125.70, 127.20, 128.15, 130.60, 144.43, 152.23, 173.37. MS m/z: 340 [(M + H)+].
Improved one-pot synthesis of N, N-diisopropyl-3-(2-Hydroxy-5-methylphenyl)-3-phenyl propanamide; a key intermediate for the preparation of racemic Tolterodine
2Engineering Chemistry Department, AU college of Engineering, Andhra University, Visakhapatnam 530003, Andhra Pradesh, India
The electronic version of this article is the complete one and can be found online at:http://www.sustainablechemicalprocesses.com/content/2/1/2
http://www.sustainablechemicalprocesses.com/content/2/1/2/additional
Srinivas garaga
scientist at Aurobindo Pharma
Chemical Research and Development Department, Aurobindo Pharma Ltd
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Chlorzoxazone
Chlorzoxazone
| Chlorzoxazone; Paraflex; Chlorzoxazon; Myoflexin; Solaxin; 95-25-0; |
5-chloro-3H-1,3-benzoxazol-2-one
A centrally acting central muscle relaxant with sedative properties. It is claimed to inhibit muscle spasm by exerting an effect primarily at the level of the spinal cord and subcortical areas of the brain. (From Martindale, The Extra Pharmacopoea, 30th ed, p1202)
| Property | Value | Source |
|---|---|---|
| melting point | 191-191.5 | Marsh, D.F.; US. Patent 2,895,877; July 21, 1959; assigned to McNeil Laboratories, Inc. |
Marsh, D.F.; US. Patent 2,895,877; July 21, 1959; assigned to McNeil Laboratories, Inc.
Chlorzoxazone (Paraflex) is a centrally acting muscle relaxant used to treat muscle spasm and the resulting pain or discomfort. It acts on the spinal cord by depressing reflexes. It is sold as Muscol or Parafon Forte, a combination of chlorzoxazone and acetaminophen (Paracetamol). Possible side effects include dizziness, lightheadedness, malaise, nausea, vomiting, and liver dysfunction. Used with acetaminophen it has added risk of hepatoxicity, which is why the combination is not recommended. It can also be administered for acute pain in general and for tension headache (muscle contraction headache).
Synthesis
Chlorzoxazone, 5-chloro-2-benzoxazolione, is synthesized by a hetercyclization reaction of 2-amino-4-chlorophenol with phosgene.
2
The Chlorzoxazone with CAS registry number of 95-25-0 is also known as 2-Benzoxazolol, 5-chloro-. The IUPAC name is 5-Chloro-3H-1,3-benzoxazol-2-one. It belongs to product categories of Oxazole&Isoxazole; Intermediates & Fine Chemicals; Pharmaceuticals. Its EINECS registry number is 202-403-9. In addition, the formula is C7H4ClNO2 and the molecular weight is 169.57. This chemical should be stored in sealed containers in cool, dry place and away from oxidizing agents.
Physical properties about Chlorzoxazone are: (1)ACD/LogP: 2.19; (2)# of Rule of 5 Violations: 0; (3)ACD/LogD (pH 5.5): 2.19; (4)ACD/LogD (pH 7.4): 2.15; (5)ACD/BCF (pH 5.5): 27.16; (6)AACD/KOC (pH 7.4): 340.79; (7)#H bond acceptors: 3; (8)#H bond donors: 1; (9)#Freely Rotating Bonds: 0; (10)Index of Refraction: 1.603; (11)Molar Refractivity: 39.18 cm3; (12)Molar Volume: 114 cm3; (13)Surface Tension: 50 dyne/cm; (14)Density: 1.486 g/cm3; (15)Flash Point: 157.5 °C; (16)Enthalpy of Vaporization: 60.3 kJ/mol; (17)Boiling Point: 336.9 °C at 760 mmHg; (18)Vapour Pressure: 5.58E-05 mmHg at 25 °C.
Preparation of Chlorzoxazone: it is prepared by reaction of 5-chloro-2-hydroxy-benzamide. The reaction needs reagents iodobenzene diacetate, KOH and solvent methanol at the temperature of 0 °C. The yield is about 68%.
References
- D.F. Marsh, U.S. Patent 2,895,877 (1959).
- Dong DL, Luan Y, Feng TM, Fan CL, Yue P, Sun ZJ, Gu RM, Yang BF. (2006). “Chlorzoxazone inhibit contraction of rat thoracic aorta”. Eur J Pharmacol 545 (2–3): 161–6. doi:10.1016/j.ejphar.2006.06.063. PMID 16859676.
- Park J, Kim K, Park P, Ha J (2006). “Effect of high-dose aspirin on CYP2E1 activity in healthy subjects measured using chlorzoxazone as a probe”. J Clin Pharmacol 46 (1): 109–14. doi:10.1177/0091270005282635. PMID 16397290.
- Wan J, Ernstgård L, Song B, Shoaf S (2006). “Chlorzoxazone metabolism is increased in fasted Sprague-Dawley rats”. J Pharm Pharmacol 58 (1): 51–61. doi:10.1211/jpp.58.1.0007. PMC 1388188. PMID 16393464.
- PARAFON DSC (chlorzoxazone) tablet, Daily Med, U.S. National Library of Medicine
 |
|
| Systematic (IUPAC) name | |
|---|---|
|
5-chloro-3H-benzooxazol-2-one
|
|
| Clinical data | |
| Trade names | Parafonforte |
| AHFS/Drugs.com | monograph |
| MedlinePlus | a682577 |
| Routes of administration |
oral |
| Pharmacokinetic data | |
| Bioavailability | well absorbed |
| Protein binding | 13–18% |
| Metabolism | hepatic |
| Biological half-life | 1.1 hr |
| Excretion | urine (<1%) |
| Identifiers | |
| CAS Registry Number | 95-25-0 |
| ATC code | M03BB03 |
| PubChem | CID: 2733 |
| IUPHAR/BPS | 2322 |
| DrugBank | DB00356 |
| ChemSpider | 2632 |
| UNII | H0DE420U8G |
| KEGG | D00771 |
| ChEBI | CHEBI:3655 |
| ChEMBL | CHEMBL1371 |
| Chemical data | |
| Formula | C7H4ClNO2 |
| Molecular mass | 169.565 g/mol |
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DR ANTHONY MELVIN CRASTO
ORGANIC SPECTROSCOPY
New Drug Approvals 