Home » Posts tagged 'organic chemistry' (Page 16)
Tag Archives: organic chemistry
DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO
.....FOR BLOG HOME CLICK HEREFlag and hits
ORGANIC SPECTROSCOPY
SUBSCRIBE
Subscribe in a reader
Enter your email address:
Delivered by FeedBurner
Subscribe to New Drug Approvals by Email
Recent Comments
 | shivkr2 on SPSR Excellence Award 2025 – S… |
 | Bonkasaurus on Infigratinib phosphate |
 | PALOVAROTENE | ORGAN… on Palovarotene |
| Pfizer just purchase… on Temanogrel | |
| Pfizer To Cash In On… on Temanogrel |
Glenmark Gets USFDA Nod For Alcohol Abstinence Drug
VITAMINS, COMMON INFORMATION
A vitamin (US /ˈvaɪtəmɪn/ or UK /ˈvɪtəmɪn/) is an organic compound required by an organism as a vital nutrient in limited amounts. An organic chemical compound (or related set of compounds) is called a vitamin when it cannot be synthesized in sufficient quantities by an organism, and must be obtained from the diet. Thus, the term is conditional both on the circumstances and on the particular organism. For example, ascorbic acid (vitamin C) is a vitamin for humans, but not for most other animals, and biotin (vitamin H) and vitamin D are required in the human diet only in certain circumstances.
|
Vitamin A – discovered in 1913 What it does:
Foods that have vitamin A:
Deficiency problems:
|
 |
|
What it does:
Foods that have vitamin D:
Deficiency problems:
|
 |
|
What it does:
Foods that have vitamin E:
Deficiency problems:
|
 |
|
Vitamin K – made by bacteria in our intestines What it does:
Foods that have vitamin K:
Deficiency problems:
|
 |
……….
By convention, the term vitamin includes neither other essential nutrients, such as dietary minerals, essential fatty acids, or essential amino acids (which are needed in larger amounts than vitamins) nor the large number of other nutrients that promote health but are otherwise required less often. Thirteen vitamins are universally recognized at present.
Vitamins are classified by their biological and chemical activity, not their structure. Thus, each “vitamin” refers to a number of vitamer compounds that all show the biological activity associated with a particular vitamin. Such a set of chemicals is grouped under an alphabetized vitamin “generic descriptor” title, such as “vitamin A“, which includes the compounds retinal, retinol, and four known carotenoids. Vitamers by definition are convertible to the active form of the vitamin in the body, and are sometimes inter-convertible to one another, as well.
itamins have diverse biochemical functions. Some, such as vitamin D, have hormone-like functions as regulators of mineral metabolism, or regulators of cell and tissue growth and differentiation (such as some forms of vitamin A). Others function as antioxidants (e.g., vitamin E and sometimesvitamin C). The largest number of vitamins, the B complex vitamins, function as precursors for enzyme cofactors, that help enzymes in their work as catalysts in metabolism. In this role, vitamins may be tightly bound to enzymes as part of prosthetic groups: For example, biotin is part of enzymes involved in making fatty acids. They may also be less tightly bound to enzyme catalysts as coenzymes, detachable molecules that function to carry chemical groups or electrons between molecules. For example, folic acid may carry methyl, formyl, and methylene groups in the cell. Although these roles in assisting enzyme-substrate reactions are vitamins’ best-known function, the other vitamin functions are equally important.
Until the mid-1930s, when the first commercial yeast-extract vitamin B complex and semi-synthetic vitamin C supplement tablets were sold, vitamins were obtained solely through food intake, and changes in diet (which, for example, could occur during a particular growing season) usually greatly altered the types and amounts of vitamins ingested. However, vitamins have been produced as commodity chemicals and made widely available as inexpensive semisynthetic and synthetic-source multivitamin dietary and food supplements and additives, since the middle of the 20th century.,,,,,,,
List of vitamins
Each vitamin is typically used in multiple reactions, and, therefore, most have multiple functions.
| Vitamin generic
descriptor name |
Vitamerchemical name(s) (list not complete) | Solubility | Recommended dietary allowances
(male, age 19–70)[6] |
Deficiency disease | Upper Intake Level
(UL/day)[6] |
Overdose disease | Food sources |
|---|---|---|---|---|---|---|---|
| Vitamin A | Retinol, retinal, and
four carotenoids including beta carotene |
Fat | 900 µg | Night-blindness,Hyperkeratosis, andKeratomalacia[7] | 3,000 µg | Hypervitaminosis A | Orange, ripe yellow fruits, leafy vegetables, carrots, pumpkin, squash, spinach, liver, soy milk, milk |
| Vitamin B1 | Thiamine | Water | 1.2 mg | Beriberi, Wernicke-Korsakoff syndrome | N/D[8] | Drowsiness or muscle relaxation with large doses.[9] | Pork, oatmeal, brown rice, vegetables, potatoes, liver, eggs |
| Vitamin B2 | Riboflavin | Water | 1.3 mg | Ariboflavinosis | N/D | Dairy products, bananas, popcorn, green beans, asparagus | |
| Vitamin B3 | Niacin, niacinamide | Water | 16.0 mg | Pellagra | 35.0 mg | Liver damage (doses > 2g/day)[10] and other problems | Meat, fish, eggs, many vegetables, mushrooms, tree nuts |
| Vitamin B5 | Pantothenic acid | Water | 5.0 mg[11] | Paresthesia | N/D | Diarrhea; possibly nausea and heartburn.[12] | Meat, broccoli, avocados |
| Vitamin B6 | Pyridoxine,pyridoxamine,pyridoxal | Water | 1.3–1.7 mg | Anemia[13] peripheral neuropathy. | 100 mg | Impairment ofproprioception, nerve damage (doses > 100 mg/day) | Meat, vegetables, tree nuts, bananas |
| Vitamin B7 | Biotin | Water | 30.0 µg | Dermatitis, enteritis | N/D | Raw egg yolk, liver, peanuts, certain vegetables | |
| Vitamin B9 | Folic acid, folinic acid | Water | 400 µg | Megaloblastic anemiaand Deficiency during pregnancy is associated with birth defects, such as neural tube defects | 1,000 µg | May mask symptoms of vitamin B12 deficiency;other effects. | Leafy vegetables, pasta, bread, cereal, liver |
| Vitamin B12 | Cyanocobalamin,hydroxycobalamin,methylcobalamin | Water | 2.4 µg | Megaloblastic anemia[14] | N/D | Acne-like rash [causality is not conclusively established]. | Meat and other animal products |
| Vitamin C | Ascorbic acid | Water | 90.0 mg | Scurvy | 2,000 mg | Vitamin C megadosage | Many fruits and vegetables, liver |
| Vitamin D | Cholecalciferol | Fat | 10 µg[15] | Rickets andOsteomalacia | 50 µg | Hypervitaminosis D | Fish, eggs, liver, mushrooms |
| Vitamin E | Tocopherols,tocotrienols | Fat | 15.0 mg | Deficiency is very rare; mild hemolytic anemiain newborn infants.[16] | 1,000 mg | Increased congestive heart failure seen in one large randomized study.[17] | Many fruits and vegetables, nuts and seeds |
| Vitamin K | phylloquinone,menaquinones | Fat | 120 µg | Bleeding diathesis | N/D | Increases coagulation in patients taking warfarin.[18] | Leafy green vegetables such as spinach, egg yolks, liver |
Watson Files ANDA for Ranbaxy’s Absorica
isotretinoin
RANBAXY RECEIVES PARAGRAPH IV CERTIFICATION
Gurgaon, India, Sept. 19, 2013 – Ranbaxy Laboratories Inc. (RLI), a wholly owned subsidiary of Ranbaxy Laboratories Limited, today announced that the company has received a Paragraph IV Certification Notice of filing from Watson Laboratories Inc. of an Abbreviated New Drug Application (“ANDA”) to the U.S. Food and Drug Administration (“FDA”) for a generic version of Absorica™ (isotretinoin capsules), a product that is licensed from Cipher Pharmaceuticals Inc. (TSX: DND) (”Cipher”) of Mississauga, Ontario. read all a thttp://www.pharmalive.com/watson-files-anda-for-ranbaxys-absorica
Isotretinoin, INN, /ˌaɪsoʊtrɨˈtɪnoʊ.ɨn/, first marketed as Accutane by Hoffmann-La Roche, is a medication primarily to curecystic acne. Rarely, it is also used to prevent certain skin cancers (squamous-cell carcinoma), and can be used in the treatment of brain, pancreatic and other cancers. It is used to treat harlequin-type ichthyosis, a usually lethal skin disease, and lamellar ichthyosis. It is a retinoid, meaning it is related to vitamin A, and is found in small quantities naturally in the body.
Isotretinoin is currently the standard of care for treatment of severe, scarring cystic acne. The most common adverse effects are a transient worsening of acne (lasting 2–3 weeks), dry lips (cheilitis), dry skin, and a propensity to sunburn easily. Other side effects are rare but do include: muscle aches and pains (myalgias), headaches. Isotretinoin is known to cause birth defectsdue to in utero exposure because of the molecule’s close resemblance to retinoic acid, a natural vitamin A derivative which controls normal embryonic development.
In the United States a special procedure is required to obtain the pharmaceutical. In most other countries a consent form is required which explains these risks. Women taking isotretinoin must not get pregnant during, and for 1 month after isotretinoin therapy. Sexual abstinence, or effective contraception is mandatory during this period. Barrier methods by themselves (such as condoms) are not considered adequate due to the unacceptable failure rates of approximately 3%. Women who fall pregnant whilst on isotretinoin therapy are generally counselled to have a termination. Isotretionin has no effect on male reproduction.
There is little evidence in the medical literature linking isotretinoin use with depression and suicide. Despite this, there exists a popular misconception amongst the public that isotretinoin use commonly causes depression.
In 2009, Roche decided to remove Accutane from the US market after juries had awarded millions of dollars in damages to former Accutane users over inflammatory bowel disease claims. Other common brands are Roaccutane (Hoffman-La Roche, known as Accutane in the United States before July 2009), Amnesteem (Mylan), Claravis (Barr), Isotroin (Cipla) or Sotret(Ranbaxy).
Xofigo Injection Recommended for Approval in EU
Cl 223Ra Cl
is the structure
http://www.ama-assn.org/resources/doc/usan/radium-ra-223-dichloride.pdf check out yourself
Xofigo® (radium Ra 223 dichloride) Injection Recommended for Approval in the European Union
Oslo, Norway, 20 September 2013 – Algeta ASA (OSE: ALGETA), announced today that Bayer has received a positive opinion from the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) recommending approval of Xofigo® (radium Ra 223 dichloride) in Europe. The proposed indication is for the treatment of adults with castration-resistant prostate cancer, symptomatic bone metastases and no known visceral metastases. The decision of the European Commission (EC) on the approval is expected in the fourth quarter of 2013.
Xofigo® (radium Ra 223 dichloride) injection was approved by the US Food and Drug Administration (FDA) in May 2013 for the treatment of patients with CRPC, symptomatic bone metastases and no known visceral metastatic disease and is now available in the United States at licensed facilities. read all at
http://www.pharmalive.com/xofigo-injection-recommended-for-approval-in-eu
old article
FDA Approves Xofigo for Advanced Prostate Cancer
May 15, 2013 — The U.S. Food and Drug Administration today approved Xofigo (radium Ra 223 dichloride) to treat men with symptomatic late-stage (metastatic) castration-resistant prostate cancer that has spread to bones but not to other organs. It is intended for men whose cancer has spread after receiving medical or surgical therapy to lower testosterone.
Prostate cancer forms in a gland in the male reproductive system found below the bladder and in front of the rectum. The male sex hormone testosterone stimulates the prostate tumors to grow. According to the National Cancer Institute, an estimated 238,590 men will be diagnosed with prostate cancer and 29,720 will die from the disease in 2013.
Xofigo is being approved more than three months ahead of the product’s prescription drug user fee goal date of Aug. 14, 2013, the date the agency was scheduled to complete review of the drug application. The FDA reviewed Xofigo under the agency’s priority review program, which provides for an expedited review of drugs that appear to provide safe and effective therapy when no satisfactory alternative therapy exists, or offer significant improvement compared to marketed products.
“Xofigo binds with minerals in the bone to deliver radiation directly to bone tumors, limiting the damage to the surrounding normal tissues,” said Richard Pazdur, M.D., director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Xofigo is the second prostate cancer drug approved by the FDA in the past year that demonstrates an ability to extend the survival of men with metastatic prostate cancer.”
In August 2012, the FDA approved Xtandi to treat men with metastatic castration-resistant prostate cancer that has spread or recurred, even with medical or surgical therapy to minimize testosterone. Xtandi is approved for patients who have previously been treated the chemotherapy drug docetaxel.
Xofigo’s safety and effectiveness were evaluated in a single clinical trial of 809 men with symptomatic castration-resistant prostate cancer that spread to bones but not to other organs. Patients were randomly assigned to receive Xofigo or a placebo plus best standard of care.
The study was designed to measure overall survival. Results from a pre-planned interim analysis showed men receiving Xofigo lived a median of 14 months compared to a median of 11.2 months for men receiving placebo. An exploratory updated analysis conducted later in the trial confirmed Xofigo’s ability to extend overall survival.
The most common side effects reported during clinical trials in men receiving Xofigo were nausea, diarrhea, vomiting and swelling of the leg, ankle or foot. The most common abnormalities detected during blood testing included low levels of red blood cells (anemia), lymphocytes (lymphocytopenia), white blood cells (leukopenia), platelets (thrombocytopenia) and infection-fighting white blood cells (neutropenia).
Xofigo is marketed by Wayne, N.J.-based Bayer Pharmaceuticals. Xtandi is co-marketed by Astellas Pharma U.S., Inc. of Northbrook, Ill., and Medivation, Inc. of San Francisco, Calif.
Glaxo, Theravance Asthma Drug Elvar Ellipta OK’d in Japan
umeclidinium
vilanterol
ELVAR™ ELLIPTA™ Gains Approval in Japan for the Treatment of Asthma
LONDON, UNITED KINGDOM and SOUTH SAN FRANCISCO, CA–(Marketwired – Sep 20, 2013) – GlaxoSmithKline plc (LSE: GSK) (NYSE: GSK) and Theravance, Inc. (NASDAQ: THRX) today announced that the Japanese Ministry of Health, Labour and Welfare (MHLW) has approved RELVAR™ ELLIPTA™ for the treatment of bronchial asthma (in cases where concurrent use of inhaled corticosteroid and long-acting inhaled beta2 agonist is required). Relvar Ellipta is not indicated for the treatment of chronic obstructive pulmonary disease (COPD) in Japan.
Relvar is a combination of the inhaled corticosteroid (ICS), fluticasone furoate “FF”, and the long-acting beta2 agonist (LABA), vilanterol “VI”. The MHLW has approved two doses of FF/VI – 100/25 mcg and 200/25 mcg. Both strengths will be administered once-daily using the Ellipta, a new dry powder inhaler (DPI).
Anoro Ellipta is the proposed proprietary name for UMEC/VI, a combination of two investigational bronchodilator molecules — GSK573719 or umeclidinium bromide (UMEC), a long-acting muscarinic antagonist (LAMA) and vilanterol (VI), a long-acting beta2 agonist (LABA), administered using the Ellipta inhaler.
The FDA Advisory Committee also voted that the safety of the investigational medicine has been adequately demonstrated at the 62.5/25mcg dose for the proposed indication (10 yes, 3 no), and the efficacy data provided substantial evidence of a clinically meaningful benefit for UMEC/VI 62.5/25mcg once daily for the long-term, maintenance treatment of airflow obstruction in COPD (13 yes, 0 no).
Patrick Vallance, GSK’s President of Pharmaceuticals R&D, said: “Today’s recommendation is good news and a reflection of our commitment to giving an alternative treatment option for patients living with COPD — a disease that affects millions of Americans. If approved, Anoro Ellipta will be the first, once-daily dual bronchodilator available in the US, marking another significant milestone for GSK’s portfolio of medicines to treat respiratory disease. We will continue to work with the FDA as they complete their review.”
“We are pleased with the Advisory Committee’s support of UMEC/VI,” said Rick E Winningham, Chief Executive Officer of Theravance. “This is a transformative year for Theravance and today’s positive recommendation brings the second major respiratory medicine in our GSK collaboration closer to approval and becoming an important therapeutic option for COPD patients.”
In December 2012, a New Drug Application (NDA) was submitted to the FDA for the use of UMEC/VI administered by the Ellipta™ inhaler for the long-term once-daily maintenance bronchodilator treatment of airflow obstruction in patients with COPD, including chronic bronchitis and/or emphysema. UMEC/VI is not proposed for the relief of acute bronchospasm or for the treatment of asthma in any of the regulatory applications.
The FDA Advisory Committee provides non-binding recommendations for consideration by the FDA, with the final decision on approval made by the FDA. The Prescription Drug User Fee Act (PDUFA) goal date for UMEC/VI is 18 December 2013.
UMEC/VI is an investigational medicine and is not currently approved anywhere in the world.
Safety Information
Across the four pivotal COPD studies for UMEC/VI, the most frequently reported adverse events across all treatment arms, including placebo, were headache, nasopharyngitis, cough, upper respiratory tract infection, and back pain. COPD exacerbation was the most common serious adverse event reported. In addition, in the four pivotal COPD studies, a small imbalance was observed in cardiac ischemia which was not observed in the long term safety study.
The UMEC/VI clinical development programme involved over 6,000 COPD patients.
About COPD
Chronic obstructive pulmonary disease (COPD) is a term referring to two lung diseases, chronic bronchitis and emphysema, that are characterized by obstruction to airflow that interferes with normal breathing. COPD is the third most common cause of death in the US and The National Heart, Lung and Blood Institute (NHLBI) estimates that nearly 15 million US adults have COPD and another 12 million are undiagnosed or developing COPD(1).
According to the NHLI, long-term exposure to lung irritants that damage the lungs and the airways are usually the cause of COPD and in the United States, the most common irritant that causes COPD is cigarette smoke. Breathing in second hand smoke, air pollution, or chemical fumes or dust from the environment or workplace also can contribute to COPD. Most people who have COPD are at least 40 years old when symptoms begin.
EC Approves Second Sanofi MS Drug
Wed, 09/18/2013 – 9:50am
Source: Genzyme
http://www.dddmag.com/news/2013/09/ec-approves-second-sanofi-ms-drug
Sanofi and its subsidiary Genzyme announced that the European Commission has granted marketing authorization for Lemtrada. This follows the Aug. 30 approval of Aubagio. The company intends to begin launching both products in the EU soon.
Alemtuzumab (marketed as Campath, MabCampath or Campath-1H and currently under further development as Lemtrada) is a monoclonal antibody used in the treatment of chronic lymphocytic leukemia (CLL), cutaneous T-cell lymphoma (CTCL) and T-cell lymphoma. It is also used in some conditioning regimens for bone marrow transplantation, kidney transplantation and Islet cell transplantation.
Alemtuzumab binds to CD52, a protein present on the surface of mature lymphocytes, but not on the stem cells from which these lymphocytes are derived. After treatment with alemtuzumab, these CD52-bearing lymphocytes are targeted for destruction.
Alemtuzumab is used as second-line therapy for CLL. It was approved by the US Food and Drug Administration for CLL patients who have been treated with alkylating agents and who have failed fludarabine therapy. It has been approved by Health Canadafor the same indication, and additionally for CLL patients who have not had any previous therapies.
It is also used under clinical trial protocols for treatment of some autoimmune diseases, such as multiple sclerosis, in which it shows promise. Alemtuzumab was withdrawn from the markets in the US and Europe in 2012 to prepare for a higher-priced relaunch aimed at multiple sclerosis.
A complication of therapy with alemtuzumab is that it significantly increases the risk for opportunistic infections, in particular, reactivation of cytomegalovirus.
US FDA grants breakthrough therapy designation to Boehringer Ingelheim’s volasertib to treat patients with AML
Volasertib
755038-65-4
CHEMICAL NAMES
1. Benzamide, N-[trans-4-[4-(cyclopropylmethyl)-1-piperazinyl]cyclohexyl]-4-[[(7R)-7-
ethyl-5,6,7,8-tetrahydro-5-methyl-8-(1-methylethyl)-6-oxo-2-pteridinyl]amino]-3-
methoxy-
2. N-{trans-4-[4-(cyclopropylmethyl)piperazin-1-yl]cyclohexyl}-4-{[(7R)-7-ethyl-5-methyl-8-
(1-methylethyl)-6-oxo-5,6,7,8-tetrahydropteridin-2-yl]amino}-3-methoxybenzamide
CODE DESIGNATION BI 6727
| Ingelheim, Germany Thursday, September 19, 2013, 16:00 Hrs [IST] |
|
The US Food and Drug Administration (FDA) has granted breakthrough therapy designation to Boehringer Ingelheim’s volasertib, a selective and potent polo-like kinase (Plk) inhibitor, for the treatment of patients with acute myeloid leukaemia (AML), a type of blood cancer. |
http://www.pharmabiz.com/NewsDetails.aspx?aid=77733&sid=2
Volasertib (also known as BI 6727) is a small molecule inhibitor of the PLK1 (polo-like kinase 1) protein being developed byBoehringer Ingelheim for use as an anti-cancer agent. Volasertib is the second in a novel class of drugs called dihydropteridinone derivatives.[1]
Mechanism of action
Volasertib is a novel small-molecule targeted therapy that blocks cell division by competitively binding to the ATP-binding pocket of the PLK1 protein. PLK1 proteins are found in the nuclei of all dividing cells and control multiple stages of the cell cycle and cell division.[2] [3] [4] The levels of the PLK1 protein are tightly controlled and are raised in normal cells that are dividing. Raised levels of the PLK1 protein are also found in many cancers including; breast, non-small cell lung, colorectal, prostate, pancreatic, papillary thyroid, ovarian, head and neck and Non-Hodgkin’s Lymphoma.[5] [3] [6] [4] [7] [8] Raised levels of PLK1 increase the probability of improper segregation of chromosomes which is a critical stage in the development of many cancers. Raised levels of PLK1 have been associated with a poorer prognosis and overall survival in some cancers[4][9] [10] In addition to its role in cell division, there is evidence that PLK1 also interacts with components of other pathways involved in cancer development including the K-Ras oncogene and the retinoblastoma and p53 tumour suppressors[11] These observations have led to PLK1 being recognised as an important target in the treatment of cancer.
Volasertib can be taken either orally or via intravenous infusion, once circulating in the blood stream it is distributed throughout the body, crosses the cell membrane and enters the nucleus of cells where it binds to its target; PLK1. Volasertib inhibits PLK1 preventing its roles in the cell-cycle and cell division which leads to cell arrest and programmed cell death.[2] Volasertib binds to and inhibits PLK1 at nanomolar doses however, it has also been shown to inhibit other PLK family members; PLK2 and PLK3 at higher; micromolar doses. The roles of PLK2 and PLK3 are less well understood; however they are known to be active during the cell cycle and cell division.[12]
Volasertib inhibits PLK1 in both cancer and normal cells; however it only causes irreversible inhibition and cell death in cancer cells, because inhibition of PLK1 in cancer cells arrests the cell cycle at a different point to normal, non-cancer cells. In cancer cells PLK1 inhibition results in G2/M cell cycle arrest followed by programmed cell death, however, in normal cells inhibition of PLK1 only causes temporary, reversible G1 and G2 arrest without programmed cell death.[13] This specificity for cancer cells improves the efficacy of the drug and minimizes the drug related toxicity.
Clinical uses
Volasertib is currently undergoing investigation in phase 1 and 2 trials and has yet to be licensed by the FDA. Volasertib may be effective in several malignancies evidenced by the fact that its target PLK1 is overexpressed in up to 80% of malignancies, where it has been associated with a poorer treatment outcome and reduced overall survival.[1][4][9]Further phase 1 and 2 trials are active, investigating the effects of Volasertib both as a single agent and in combination with other agents in solid tumours and haematological malignancies including; ovarian cancer, urothelial cancer and acute myeloid leukaemia.[14]
Studies
Preclinical studies on volasertib have demonstrated that it is highly effective at binding to and blocking PLK1 function and causing programmed cell death in colon and non-small cell lung cancer cells both in vitro and in vivo. Volasertib can also cause cell death in cancer cells that have are no longer sensitive to existing anti-mitotic drugs such as vinca alkaloids and taxanes.[13] This suggests that volasertib may be effective when used as a second line treatment in patients who have developed resistance to vinca alkaloid and taxane chemotherapeutics.
A first in man trial of volasertib in 65 patients with solid cancers reported that the drug is safe to administer to patients and is stable in the bloodstream. This study also reported favourable anti-cancer activity of the drug; three patients achieved a partial response, 48% of patients achieved stable disease and 6 patients achieved progression free survival of greater than 6 months.[15] A further phase 1 trial of volasertib in combination with cytarabine in patients with relapsed / refractory acute myeloid leukaemiareported that 5 of 28 patients underwent a complete response, 2 achieved a partial response and a further 6 patients no worsening of their disease.[16]
- Schoffski, P. (2009). “Polo-like kinase (PLK) inhibitors in preclinical and early clinical development in oncology”. Oncologist 14 (6): 559–70. ISSN (Electronic) 1083-7159 (Linking) 1549-490X (Electronic) 1083-7159 (Linking).
- Barr, F. A.; H. H. Sillje, E. A. Nigg (2004). “Polo-like kinases and the orchestration of cell division”. Nat Rev Mol Cell Biol 5 (6): 429–40. ISSN (Print) 1471-0072 (Linking) 1471-0072 (Print) 1471-0072 (Linking).
- Garland, L. L.; C. Taylor, D. L. Pilkington, J. L. Cohen, D. D. Von Hoff (2006). “A phase I pharmacokinetic study of HMN-214, a novel oral stilbene derivative with polo-like kinase-1-interacting properties, in patients with advanced solid tumors”. Clin Cancer Res 12 (17): 5182–9. ISSN (Print) 1078-0432 (Linking) 1078-0432 (Print) 1078-0432 (Linking).
- Santamaria, A.; R. Neef, U. Eberspacher, K. Eis, M. Husemann, D. Mumberg, S. Prechtl, V. Schulze, G. Siemeister, L. Wortmann, F. A. Barr, E. A. Nigg (2007). “Use of the novel Plk1 inhibitor ZK-thiazolidinone to elucidate functions of Plk1 in early and late stages of mitosis”. Mol Biol Cell 18 (10): 4024–36. ISSN (Print) 1059-1524 (Linking) 1059-1524 (Print) 1059-1524 (Linking).
- Fisher, R.A.H.; D.K. Ferris (2002). “The functions of Polo-like kinases and their relevance to human disease.”. Curr Med Chem 2: 125–134.
- Holtrich, U.; G. Wolf, A. Brauninger, T. Karn, B. Bohme, H. Rubsamen-Waigmann, K. Strebhardt (1994). “Induction and down-regulation of PLK, a human serine/threonine kinase expressed in proliferating cells and tumors”. Proc Natl Acad Sci U S A 91 (5): 1736–40. doi:10.1073/pnas.91.5.1736. ISSN (Print) 0027-8424 (Linking) 0027-8424 (Print) 0027-8424 (Linking). PMC 43238. PMID 8127874.
- Steegmaier, M.; M. Hoffmann, A. Baum, P. Lenart, M. Petronczki, M. Krssak, U. Gurtler, P. Garin-Chesa, S. Lieb, J. Quant, M. Grauert, G. R. Adolf, N. Kraut, J. M. Peters, W. J. Rettig (2007). “BI 2536, a potent and selective inhibitor of polo-like kinase 1, inhibits tumor growth in vivo”. Curr Biol 17 (4): 316–22. doi:10.1016/j.cub.2006.12.037. ISSN (Print) 0960-9822 (Linking) 0960-9822 (Print) 0960-9822 (Linking). PMID 17291758.
- Winkles, J. A.; G. F. Alberts (2005). “Differential regulation of polo-like kinase 1, 2, 3, and 4 gene expression in mammalian cells and tissues”. Oncogene 24 (2): 260–6.doi:10.1038/sj.onc.1208219. ISSN (Print) 0950-9232 (Linking) 0950-9232 (Print) 0950-9232 (Linking). PMID 15640841.
- Eckerdt, F.; J. Yuan, K. Strebhardt (2005). “Polo-like kinases and oncogenesis”. Oncogene 24 (2): 267–76. doi:10.1038/sj.onc.1208273. ISSN (Print) 0950-9232 (Linking) 0950-9232 (Print) 0950-9232 (Linking). PMID 15640842.
- Weichert, W.; A. Ullrich, M. Schmidt, V. Gekeler, A. Noske, S. Niesporek, A. C. Buckendahl, M. Dietel, C. Denkert (2006). “Expression patterns of polo-like kinase 1 in human gastric cancer”. Cancer Sci 97 (4): 271–6. ISSN (Print) 1347-9032 (Linking) 1347-9032 (Print) 1347-9032 (Linking).
- Liu, X.; R. L. Erikson (2003). “Polo-like kinase (Plk)1 depletion induces apoptosis in cancer cells”. Proc Natl Acad Sci U S A 100 (10): 5789–94. doi:10.1073/pnas.1031523100.ISSN (Print) 0027-8424 (Linking) 0027-8424 (Print) 0027-8424 (Linking). PMC 156279. PMID 12732729.
- Schmit, T. L.; N. Ahmad (2007). “Regulation of mitosis via mitotic kinases: new opportunities for cancer management”. Mol Cancer Ther 6 (7): 1920–31. ISSN (Print) 1535-7163 (Linking) 1535-7163 (Print) 1535-7163 (Linking).
- Rudolph, D.; M. Steegmaier, M. Hoffmann, M. Grauert, A. Baum, J. Quant, C. Haslinger, P. Garin-Chesa, G. R. Adolf (2009). “BI 6727, a Polo-like kinase inhibitor with improved pharmacokinetic profile and broad antitumor activity”. Clin Cancer Res 15 (9): 3094–102. ISSN (Print) 1078-0432 (Linking) 1078-0432 (Print) 1078-0432 (Linking).
- ClinicalTrials.gov (2011). “Clinical Trials.gov Search of: Volasertib”. Missing or empty
|url=(help) - Gil, T.; P. Schöffski, A. Awada, H. Dumez, S. Bartholomeus, J. Selleslach, M. Taton, H. Fritsch, P. Glomb, Munzert G.M. (2010). “Final analysis of a phase I single dose-escalation study of the novel polo-like kinase 1 inhibitor BI 6727 in patients with advanced solid tumors”. J Clin Oncol 28.
- Bug, G.; R. F. Schlenk, C. Müller-Tidow, M. Lübbert, A. Krämer, F. Fleischer, T. Taube, O. G. Ottmann, H. Doehner (2010). “Phase I/II Study of BI 6727 (volasertib), An Intravenous Polo-Like Kinase-1 (Plk1) Inhibitor, In Patients with Acute Myeloid Leukemia (AML): Results of the Dose Finding for BI 6727 In Combination with Low-Dose Cytarabine”. 52nd ASH Annual Meeting and Exposition. Orange County Convention Centre, Florida: American Society of Haematology.
VOLASERTIB TRIHYDROCHLORIDE
CHEMICAL NAMES
1. Benzamide, N-[trans-4-[4-(cyclopropylmethyl)-1-piperazinyl]cyclohexyl]-4-[[(7R)-7-
ethyl-5,6,7,8-tetrahydro-5-methyl-8-(1-methylethyl)-6-oxo-2-pteridinyl]amino]-3-
methoxy-, hydrochloride (1:3)
2. N-{trans-4-[4-(cyclopropylmethyl)piperazin-1-yl]cyclohexyl}-4-{[(7R)-7-ethyl-5-methyl-8-
(1-methylethyl)-6-oxo-5,6,7,8-tetrahydropteridin-2-yl]amino}-3-methoxybenzamide
trihydrochloride
MOLECULAR FORMULA C34H50N8O3 . 3 HCl
MOLECULAR WEIGHT 728.2
SPONSOR Boehringer Ingelheim Pharmaceuticals, Inc.
CODE DESIGNATION BI 6727 CL3
CAS REGISTRY NUMBER 946161-17-7
Volasertib is a highly potent and selective inhibitor of the serine-threonine Polo like kinase 1 (Plk1), a key regulator of cell-cycle progression. Volasertib is a dihydropteridinone derivative with distinct pharmacokinetic (PK) properties. The problem underlying this invention was to develop improved dosage schedules for combination therapy of advanced and/or metastatic solid tumours.
Volasertib (I) is known as the compound N-[trans-4-[4-(cyclopropylmethyl)-1-piperazinyl]cyclohexyl]-4-[[(7R)-7-ethyl-5,6,7,8-tetrahydro-5-methyl-8-(1-methylethyl)-6-oxo-2-pteridinyl]amino]-3-methoxy-benzamide,
This compound is disclosed in WO 04/076454. Furthermore, trihydrochloride salt forms and hydrates thereof are known from WO 07/090844. They possess properties which make those forms especially suitable for pharmaceutical use. The above mentioned patent applications further disclose the use of this compound or its monoethanesulfonate salt for the preparation of pharmaceutical compositions intended especially for the treatment of diseases characterized by excessive or abnormal cell proliferation.
U.S. 8,188,086
Several dihydropteridione derivatives effectively prevent cell proliferation. G. Linz and co-inventors report a comprehensive method for preparing pharmacologically active crystalline and anhydrous forms of compound 1 (Figure 1) that are suitable for drug formulations.
The inventors list several criteria for the properties of 1 and its manufacturing procedure:
- favorable bulk characteristics such as drying times, filterability, solubility in biologically acceptable solvents, and thermal stability;
- purity of the pharmaceutical composition;
- low hygroscopicity;
- no or low tendency toward polymorphism; and
- scalability to a convenient commercial process.
They describe their finding that the tri-HCl salt of 1 satisfies these criteria as “surprising”.
Free base 1 is prepared by condensing cyclopropylmethylpiperazine derivative 2 with pteridinone 3 in the presence of p-toluenesulfonic acid (TsOH), as shown in Figure 1. After the reaction is complete, the crude free base 1 is recovered as a viscous oil. It is then treated with HCl in an organic solvent to form 1·3HCl, isolated in 91% yield. Alternatively, the free base is not isolated; instead, concd HCl is added to the reaction mixture, followed by acetone. The crude salt is recovered in 92% yield.
The salt is purified by crystallization from refluxing EtOH, adding water, and cooling to precipitate the crystals. The inventors do not report the purity of this or any other reaction product.
The inventors obtained a hydrated form of the tri-HCl salt by dissolving the free base in EtOH at room temperature, followed by adding concd HCl and cooling to 2 °C. An anhydrous form can be recovered by drying the hydrate at 130 °C. The solubility of the hydrated salt in aqueous and organic media is reported, as are X-ray diffraction data for the hydrated form. The hydrated salt has good solid-state stability.
The patent also contains the syntheses of reactants 2 and 3 (Figures 2 and 3). The preparation of 2 begins with the formation of amide 7. Acid 4 is treated with SOCl2–DMF to form acid chloride 5; the crude product is added to a suspension of chiral difunctionalized cyclohexane 6 in THF and aq K2CO3 to produce 7. The crude product is recovered in 98% yield and oxidized to 8 with RuCl3 and N-methylmorpholine N-oxide (NMMO) in 91% yield.
Amide 8 reacts with cyclopropylmethylpiperazine 9 in the presence of methanesulfonic acid (MsOH). The solvent is evaporated, and the reaction mixture is treated with NaBH4. After further workup, product 10 is isolated in 46% yield. The nitro group is then hydrogenated over Raney Ni to give 2 in 90% yield. An alternative method for preparing10 is also described.
To prepare 3, readily available amino acid 11 is esterified and alkylated to form 12. In a multistep, one-pot procedure, 11 is first treated with HC(OMe)3 and SOCl2. Further reaction with NaBH(OAc)3, acetone, and NH4OH produces 12 as its HCl salt in 90% yield. The salt is treated with aq NaOH to form the free base, which reacts with pyrimidine 13 in the presence of NaHCO3 to form 14 in 79% isolated yield.
The pteridinone system is formed by hydrogenating 14 over a Pt/C catalyst in the presence of V(acac)3. Precursor 15 is recovered in 90% yield and methylated with (MeO)2CO and K2CO3 to give 3 in 82% isolated yield.
The inventors succeeded in developing a route for making a crystalline salt that is suitable for preparing pharmaceutical formulations. The many synthetic steps, however, use a large number of solvents that are frequently evaporated to dryness. [This observation implies that the processes have a significant environmental burden. —Ed.] (Boehringer Ingelheim International [Ingelheim am Rhein, Germany]. US Patent U.S. 8,188,086,
FDA accepts new drug application for investigational compound Epanova for the treatment of severe hypertriglyceridaemia
LONDON, Sept. 18, 2013 – AstraZeneca today announced that the US Food and Drug Administration (FDA) has accepted for review a New Drug Application (NDA) for EpanovaTM, an investigational compound for the treatment for patients with severe hypertriglyceridaemia (triglyceride levels greater than or equal to 500mg/dL). The NDA submission for Epanova was filed by Omthera Pharmaceuticals, now a wholly-owned subsidiary of AstraZeneca, as a 505(b)(1) application in July 2013. The Prescription Drug User Fee Act (PDUFA) goal date for the FDA is 5 May 2014.http://www.pharmalive.com/fda-accepts-astrazeneca-nda-for-epanova
Forigerimod, (Rigerimod) also known as Lupuzor, CEP-3345 for treatment of systemic lupus erythematosus (SLE)
FORIGERIMOD
CHEMICAL NAMES
1. L-Tyrosine, L-arginyl-L-isoleucyl-L-histidyl-L-methionyl-L-valyl-L-tyrosyl-L-seryl-L-lysyl-L-arginyl-O-phosphono-L-serylglycyl-L-lysyl-L-prolyl-L-arginylglycyl-L-tyrosyl-L-alanyl-L-phenylalanyl-L-isoleucyl-L-α-glutamyl-
2. O3,140-phosphono(human U1 small nuclear ribonucleoprotein 70 kDa (snRNP70))-(131-151)-peptide
MOLECULAR FORMULA C117H181N34O32PS
MOLECULAR WEIGHT 2639
TRADEMARK Lupuzor
SPONSOR Cephalon, Inc.
CODE DESIGNATION IPP 201101
CAS REGISTRY NUMBER 497156-60-2
STRUCTURAL FORMULA
stucture, http://www.ama-assn.org/ama1/pub/upload/mm/365/forigerimod.pdf
-
Forigerimod nonproprietary drug name
http://www.ama-assn.org/resources/doc/usan/forigerimod.pdfSTATEMENT ON A NONPROPRIETARY NAME ADOPTED BY THE USAN COUNCIL. USAN. FORIGERIMOD.
…………………………………………………………………………………………………………..
FORIGERIMOD ACETATE
CAS REGISTRY NUMBER 1160237-55-7 of acetate
http://www.ama-assn.org/resources/doc/usan/forigerimod-acetate.pdf
-
Forigerimod acetate nonproprietary drug name
http://www.ama-assn.org/resources/doc/usan/forigerimod-acetate.pdfSTATEMENT ON A NONPROPRIETARY NAME ADOPTED BY THE USAN COUNCIL. USAN. FORIGERIMOD ACETATE
str is
FORIGERIMOD ACETATE
Forigerimod, also known as Lupuzor or CEP-33457, (SyB L-1001) is a CD4 T-cell modulator being investigated for the treatment of systemic lupus erythematosus (SLE). In the Phase II trials, Lupuzor was administered subcutaneously at a dose of 200 mcg once a month for 3 months. The Phase III study is anticipated to be complete in September 2012 and will measure the proportion of patients achieving a combined clinical response using the SLE responder index.
Positive final Lupuzor trial results. Marketwire. www.marketwire.com/press-release/Positive-Final-Lupuzor-Trial-Results-AIM-IMM-1176375.htm. Published November 19, 2009. Accessed June 18, 2011.
Rigerimod (IPP-201101, Lupuzor) is a polypeptide corresponding to the sequence 131-151 of the 70k snRNP protein with a serine phosphorylated in position 140.[1]
It gave encouraging results in a phase IIb trial for severe lupus.[1] Another phase IIb trial has started recruiting in the US.[2]
References
Lupuzor™ is a potential treatment for lupus, currently given the approval by the US FDA to start Phase III with a Special Protocol Assessment (SPA) and Fast Track designation. ImmuPharma holds all worldwide rights in this lead compound.
Background
Lupus (or Systemic Lupus Erythematosus) is a chronic, potentially life-threatening autoimmune disease. An estimated 1.4 million people are diagnosed in the 7 major world markets (the USA, Japan, Germany, France, Spain, the UK and Italy). Lupus is an inflammatory disease, which attacks multiple organs such as the skin, joints, kidneys, blood cells, heart and lungs. There is currently no cure.
The development of ImmuPharma’s Lupuzor™
ImmuPharma’s compound Lupuzor™ (previously known as IPP-201101 and also referred to as rigerimod or P140) has a novel mechanism of action aimed at modulating the body’s immune system so it does not attack healthy cells, without causing adverse side effects. It has the potential to halt the progression of the disease in a substantial proportion of patients.
Lupuzor™ has successfully completed Phase I, Phase IIa and Phase IIb studies and has now been given the approval by the US FDA to enter Phase III, the final testing phase.
The latest highlights of Lupuzor’s™ development as a treatment for lupus include:
- An ‘End of Phase 2’ meeting package with ImmuPharma’s Phase IIb data was submitted to the FDA and the FDA responded to all the questions
- The Investigational Medicinal Product Dossier (IMPD) submitted via the Voluntary Harmonized Procedure (VHP) in the EU was approved
- The Scientific Advice meeting with the European Medicines Evaluation Agency (EMEA) was held; the recommendations were very similar to those in the FDA’s ‘End Of Phase 2’ responses. Recommendations were incorporated into the Phase III pivotal programme
- The Japanese equivalent authorities (PMDA) have agreed to the initiation of clinical trials in Japan
- The FDA has granted Lupuzor™ the approval to start Phase III with a Special Protocol Assessment (SPA)
- The FDA has granted Lupuzor™ Fast Track designation
How Lupuzor™ works in the treatment of lupus
Lupuzor™ is a drug that specifically modulates the immune system of lupus patients by modifying the behaviour of some of the key cells involved in the pathogenesis of the disease. The clinical profile of lupus patients is generally assessed by standardised scales such as SLEDAI (SLE Disease Activity Index): the lower the score, the better the condition of the patient. During this Phase II study, the SLEDAI scores were assessed on multiple occasions even though the study was not designed or powered to demonstrate clinical benefit as the primary endpoint due to the short treatment period.
| forigerimod | IPP-201101 | oligopeptide | therapeutic | nucleolin |
| forigerimod acetate | CEP-33457, P-140, IPP-201101 | oligopeptide (salt) | therapeutic | nucleolin |
New Drug Approvals 